# Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated N, O-Acets Derived from L-Tartaric Acid

Abdelkhalek Ben Jamaa, Fabienne Grellepois

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Abdelkhalek Ben Jamaa, Fabienne Grellepois. Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated N, O -Acets Derived from L -Tartaric Acid. Journal of Organic Chemistry, 2017, 82 (19), pp.10360 - 10375. 10.1021/acs.joc.7b01814 . hal-01886709

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# Diastereoselective Ritter-like reaction on cyclic trifluoromethylated *N*,*O*-acetals derived from (L)-tartaric acid

Abdelkhalek Ben Jamaa, Fabienne Grellepois*

Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS
UMR 7312, UFR des Sciences Exactes et Naturelles, BP 1039, 51687 Reims Cedex 2, France

fabienne.grellepois@univ-reims.fr

<figure><img src="image_2.png" /></figure>

*R¹ = H, Bn Oxazoline only (dr = 100:0, yield up to 89%)*

*R¹ = Me Mixture of oxazoline and amide (ratio = 87:13, dr = 100:0)*

*R¹ = Ac Amide only (dr = 85:15)*

Despite the presence of the highly electron-withdrawing fluorinated substituent, cyclic α-trifluoromethylated *N*-acyliminium ions were successfully generated from fluorinated *O*-acetyl-*N*,*O*-acetals (L)-tartaric acid derivatives. Addition of nitriles on these intermediates occurred with high to excellent *syn* diastereoselectivity and led, in most cases, to oxazolines and/or amides as single diastereomer. The diastereoselectivity of the addition and the nature of the reaction product depend on the substituents on the hydroxyl groups of the tartaric acid scaffold. This methodology gave access to enantiopure, highly functionalized 5-(trifluoromethyl)pyrrolidin-2-one derivatives bearing the fluorinated substituent on a tetrasubstituted carbon.
Introduction

5-Membered azaheterocycles are one of the privileged fragments of synthetic and natural biologically active substances.¹ Of these, 2-pyrrolidone structural motifs exhibit a high potential as a precursor of other N-heterocycles, such as pyrrolidines² and cyclic amidines,³ and as core of small molecules with multiple biological interests.⁴ By way of an example, *inter alia*, 2-pyrrolidone derivatives have been described as γ-lactam analogs of prostaglandins being potent and selective EP4 receptor agonist and exhibiting a good pharmacological profile.⁵

Many pharmaceuticals or agrochemicals include a fluorine atom and/or a fluorine-
containing group⁶ as the introduction of this family of substituents may have a range of
beneficial effects on the biological and physicochemical properties of bioactive molecules.⁷ For
example, the substitution of one or more hydrogen atoms by fluorine close to an amine function
not only decreases its basicity but also enhances its metabolic stability.⁸ Amongst all the
fluorinated substituents, the trifluoromethyl group is one of the most important.⁹

5-(Trifluoromethyl)-pyrrolidin-2-ones, for which the fluorinated substituent is borne by a tetrasubstituted carbon, have been reported as conformationally restricted amino acids,¹⁰ thrombin inhibitor¹¹ and natural product analogues.¹² This family of synthons has been mainly prepared by construction of the γ-lactam ring.¹⁰,¹²c,¹³ A more challenging pathway, scarcely explored, is the elaboration of the tetrasubstituted carbon bearing the trifluoromethyl group by addition of a nucleophile on a cyclic α-trifluoromethylated N-acyliminium ion.¹¹,¹²a,b

*N*-Acyliminium ions have been widely used in organic synthesis.¹⁴ Due to their highly reactive nature as electrophiles, they have to be generated *in situ* from a more stable precursor, usually a *N*,*O*-acetal.¹⁴ However, as the trifluoromethyl group not only strongly stabilizes *N*,*O*-acetal functions, and thus renders the formation of the *α*-trifluoromethyl *N*-acyliminium ions difficult, but also greatly destabilizes and hinders these latter, few studies dealing with the addition of nucleophiles on these peculiar species have been reported.¹¹,¹²a,b,¹⁵ To date, only two
leading to the functionalization of 5-(trifluoromethyl)-pyrrolidin-2-one derivatives have been described and none is asymmetric.¹¹,¹²a,b Fused nitrogen heterocycles carrying the fluorinated group on the bridgehead position were obtained by an intramolecular Friedel-Craft reaction on 5-silyloxy or 5-hydroxy-5-(trifluoromethyl)-pyrrolidin-2-ones using an excess of relatively strong Brønsted acid.¹²a,b Creation of a C-O bound was performed by addition of methanol in the presence of hydrochloric acid on a α-trifluoromethylated *N*,*F*-acetal lactam derivative, the corresponding *N*,*O*-acetal resisting most deoxygenation procedures except for deoxyfluorination.¹¹ The creation of a tetrasubstituted stereogenic carbon bearing a sterically demanding trifluoromethyl substituent by addition of a nucleophile on a α-trifluoromethylated *N*-acyliminium ion is still challenging.

A few years ago we have reported the diastereoselective synthesis of aziridines, morpholines and oxazepanes bearing a trifluoromethyl group on a tetrasubstituted carbon starting from (L)-tartaric acid following a strategy based on the ring construction of these aza-heterocycles.¹⁶ We now report a practical way to prepare some original, highly functionalized derivatives of 2-trifluoromethylpyrrolidinones using a strategy based on the creation of the tetrasubstituted carbon bearing the fluorinated substituent. For this purpose, we have studied the addition of various nitriles¹⁷ on cyclic α-trifluoromethyl *N*-acyliminium ions derived from (L)-tartaric acid which were generated *in situ* under acidic treatment of the corresponding α-trifluoromethyl *N*,*O*-acetals. During this work, we have highlighted the influence of the protecting groups of the tartaric acid scaffold alcohols both on the nature of the reaction product and on the diastereoselectivity of the reaction.
## Results and Discussion

The requisite tartrimides **1a-e** were prepared by a one-pot activation-condensation-ring closure sequence applied to the suitable *O*,*O'*-diprotected (L)-tartaric acid derivatives or directly to the (L)-tartaric acid.<sup>18,19</sup>

The nucleophilic trifluoromethylation of various cyclic imides have been reported using trifluoromethyltrimethylsilane in the presence of an activating agent as trifluoromethide equivalent. Although most studies were performed under conventional conditions, with a fluoride anion as initiator in THF,<sup>11,12b,20</sup> the use of tri-*tert*-butylphosphine in DMF also enabled this reaction.<sup>21</sup> Our results concerning the nucleophilic trifluoromethylation of tartrimides **1a-e** are summarized in table 1. After screening of a wide variety of fluoride anions, we found that the best yield for the nucleophilic trifluoromethylation of tartrimide **1a**, *O*- and *N*-protected with a benzyl group, was obtained using 2.04 equivalents of CF<sub>3</sub>SiMe<sub>3</sub> and 0.048 equivalent of tetramethylammonium fluoride (TMAF.4H<sub>2</sub>O) in THF (table 1, entry 1). The *in situ* hydrolysis of the formed silylether led to the *N*,*O*-acetal **2a** as a 86:14 mixture of two diastereomers which were isolated in 80% yield. Both diastereomers of **2a** can be easily separated by chromatography on silica gel. The *N*-para-methoxybenzyl-*O*,*O'*-dibenzyltartrimide **1b** being not soluble in THF, these conditions were not suitable for the preparation of the corresponding *N*,*O*-acetal **2b**. However, smooth trifluoromethylation of tartrimide **1b** took place upon treatment with 4 equivalents of CF<sub>3</sub>SiMe<sub>3</sub> and 0.2 equivalents of K<sub>2</sub>CO<sub>3</sub> in DMF (table 1, entry 2).<sup>16a,22</sup> After treatment of the reaction mixture, desilylation was best achieved using fluoride instead of water and the *N*,*O*-acetal **2b** was isolated in 63% yield as a 71:29 mixture of two diastereomers. Both experimental conditions were applied to the *N*-benzyl-*O*,*O'*-dimethyl tartrimide **1c**. Nucleophilic trifluoromethylation in the presence of TMAF.4H<sub>2</sub>O followed by the hydrolysis step led to the *N*,*O*-acetal **2c** as a 84:16 mixture of two diastereomers albeit in moderate yield (39%) due to the formation of a considerable amount of a trifluoromethylated
by-product whose structure could not be elucidated (table 1, entry 3). Using $CF_3SiMe_3$ and $K_2CO_3$ in DMF substantially improved the yield of *N,O*-acetal **2c** which was directly isolated in 77% yield after the trifluoromethylation step but with a slightly lower diastereoselectivity (75:25) (table 1, entry 4). These latter conditions were successfully applied to the *N*-benzyl-tartrimide **1d** containing free alcohol functions (table 1, entry 5). The desired *N,O*-acetal **2d** was obtained with a very good yield (90%) and a good diastereoselectivity (89:11). Disappointingly, none of the experimental conditions permitted the nucleophilic trifluoromethylation of tartrimide **1e** whose hydroxyl groups were protected as acetyl groups (table 1, entry 6).
<figure><img src="image_3.png" /><figcaption>Table 1. Synthesis of α-trifluoromethylated N,O-acetal 2a-d.</figcaption></figure>

<table><thead><tr><th>entry</th><th>tartri-<br>mide</th><th>conditions<sup>a</sup></th><th>N,O-<br>acetal (trans:cis)</th><th>dr<sup>b</sup></th><th>yield<sup>c</sup></th></tr></thead><tbody><tr><td>1</td><td><b>1a</b></td><td>A</td><td><b>2a</b></td><td>86:14</td><td>80<sup>d</sup></td></tr><tr><td>2</td><td><b>1b</b></td><td>B</td><td><b>2b</b></td><td>71:29</td><td>63</td></tr><tr><td>3</td><td><b>1c</b></td><td>A</td><td><b>2c</b></td><td>84:16</td><td>39</td></tr><tr><td>4</td><td><b>1c</b></td><td>B</td><td><b>2c</b></td><td>75:25</td><td>77</td></tr><tr><td>5</td><td><b>1d</b></td><td>B</td><td><b>2d</b></td><td>89:11</td><td>90</td></tr><tr><td>6</td><td><b>1e</b></td><td>A or B<sup>e</sup></td><td>-</td><td>-</td><td>-</td></tr></tbody></table>

<footnote><sup>a</sup>reaction conditions A: CF₃TMS (2.04 equiv), TMAF.4H₂O (0.048 equiv), THF, -20°C then H₂O, rt; reaction conditions B: CF₃TMS (3.9-4 equiv), K₂CO₃ (0.2 equiv), DMF, rt then TBAF (0.5-1 equiv), THF:H₂O (3:1), rt. <sup>b</sup>diastereomeric ratio determined by <sup>19</sup>F NMR of the crude mixture. <sup>c</sup>unless noticed, the diastereomers were not separated. <sup>d</sup>both diastereomers were separated by chromatography on silica gel (yield major diastereomer *trans*-2a: 68%, yield minor diastereomer *cis*-2a: 12%). <sup>e</sup>no reaction observed whatever the experimental conditions.</footnote>
Since the configuration of the leaving group can have a strong impact on the generation of the iminium ion,²³ the absolute configuration of the created trifluoromethylated stereocenter has been determined for the two diastereomers. The X-ray crystallography of the major diastereomer of **2a**²⁴ revealed a *cis*-relationship between the CF₃ group and the neighboring benzyloxy group and that the absolute configuration of the new quaternary stereocenter is *R* (table 1). To rationalize the stereochemical outcome of the reaction, we propose that the attack of the rather bulky CF₃-nucleophile on the carbonyl group of the imide occurred on the face where steric repulsion with the benzyloxy group is minimized according to the Bürgi-Dunitz trajectory,²⁵ affording the *trans*-isomer as major diastereomer (scheme 1).

<figure><img src="image_4.png" /><figcaption>**Scheme 1.** Proposed transition state for the nucleophilic trifluoromethylation of tartrimides.</figcaption></figure>

We first attempted to generate the α-trifluoromethylated *N*-acyliminium ions directly from the trifluoromethylated *N*,*O*-acetals **2a** and **2d**. *N*,*O*-Acetals **2a** and **2d** were treated with 3 equivalents of BF₃.Et₂O in acetonitrile, the standard conditions reported for the reaction of nitrile with *N*-acyliminium ions derived from (4S)-4,5-dihydroxypyrrolidin-2-one¹⁷ª (table 2).
No reaction occurred at room temperature (table 2, entries 1 and 2). The reaction was then conducted at reflux of nitrile. Starting from the *O*,*O'*-benzyl *N*,*O*-acetal **2a**, only the fully *O*-debenzylated oxazoline derivative **3** was formed and was isolated in 77% yield (table 2, entry 3). This oxazoline **3** can be obtained in a similar yield (77%) directly from the *N*,*O*-acetal **2d** bearing two non-protected hydroxyl groups (table 2, entry 4).

<figure><img src="image_5.png" /><figcaption>**Table 2.** Reaction of *N*,*O*-acetal **2a,d** with acetonitrile in the presence of *BF*₃.*Et*₂*O*.ᵃ</figcaption></figure>

<table><thead><tr><th>entry</th><th>N,O-acetal</th><th>T (°C)</th><th>time (h)</th><th>yield (%)</th></tr></thead><tbody><tr><td>1</td><td><b>2a</b></td><td>rt</td><td>7.5</td><td>-<sup>b</sup></td></tr><tr><td>2</td><td><b>2d</b></td><td>rt</td><td>18</td><td>-<sup>b</sup></td></tr><tr><td>3</td><td><b>2a</b></td><td>reflux</td><td>5</td><td>75</td></tr><tr><td>4</td><td><b>2d</b></td><td>reflux</td><td>2</td><td>77</td></tr></tbody><tfoot><tr><td colspan="5"><sup>a</sup>reaction conditions: <i>BF</i>3·<i>Et</i>2<i>O</i> (3 equiv) in <i>MeCN</i>. <sup>b</sup>no reaction.</td></tr></tfoot></table>

In order to use milder reaction temperature to generate the *N*-acyliminium ions, the *O*-acetyl *N*,*O*-acetals **4**, analogues of *N*,*O*-acetals **2** containing a better leaving group, were thus prepared and evaluated as precursors.

Treatment of each diastereomers of the *N*,*O*-acetal **2a** as well as the mixture of diastereomers of **2a-c** with 1.7 equivalents of acetic anhydride, 1.5 equivalents of pyridine and
0.1 equivalent of DMAP in dichloromethane led to the corresponding *O*-acetyl-*N*,*O*-acetal *trans*-4a, *cis*-4a and 4a-c with a very good yield ranging from 83 to 99% (table 3, entries 1-5).

Reaction of **2d** in which alcohols functions are not protected was performed using a bigger excess of acetic anhydride (5 equivalents) and pyridine (4.51 equivalents) in the presence of DMAP (0.3 equivalent) in order to esterify the three hydroxyl groups (table 3, entry 6). Thus, the corresponding peracetyl-*N*,*O*-acetal **4d** was isolated in 95% yield. Using this procedure circumvented the absence of reaction of *O*,*O'*-acyltartrimide **1e** under the nucleophilic trifluoromethylation conditions (table 1, entry 6)
<figure><img src="image_6.png" /><figcaption>**Table 3. Synthesis of α-trifluoromethylated *O*-acetyl-*N*,*O*-acetal 4a-d.</figcaption></figure>

<table><thead><tr><th>entry</th><th>N,O-acetal</th><th>dr<sup>a</sup><br>trans:cis</th><th>O-acetyl-N,O-acetal</th><th>yield<br>(%)</th></tr></thead><tbody><tr><td>1</td><td>trans-2a</td><td>100:0</td><td>trans-4a</td><td>99</td></tr><tr><td>2</td><td>cis-2a</td><td>0:100</td><td>cis-4a</td><td>93</td></tr><tr><td>3</td><td>2a</td><td>86:14</td><td>4a</td><td>92</td></tr><tr><td>4</td><td>2b</td><td>71:29</td><td>4b</td><td>83</td></tr><tr><td>5</td><td>2c</td><td>75:25</td><td>4c</td><td>91</td></tr><tr><td>6</td><td>2d</td><td>89:11</td><td>4d</td><td>95</td></tr></tbody></table>

The experimental conditions for the addition of acetonitrile were optimized on the major diastereomer *trans*-4a and 3 equivalents of BF₃.Et₂O were utilized in all cases (table 4, entries 1-4). Using acetonitrile as solvent at rt, the *O*-benzyl oxazoline **5a** was smoothly formed (24h of reaction) and was then isolated with an excellent yield of 97% (table 4, entry 1). Noteworthy, this Ritter-like's reaction product **5a** can be also obtained in only 90 min at reflux of acetonitrile but in a slightly lower yield (80%) due to the formation of a small amount of amide **6a** (table 4, entry 2). Amide **6a** results from the ring opening of oxazoline **5a** with water (see table 8 for structure). The reaction could be also performed with only 10 equivalents of acetonitrile in dichloromethane as solvent (table 4, entries 3 and 4). At rt, the reaction was not complete (90%)

<footnote><sup>a</sup>diastereomeric ratio of starting materials **2a-d** and of products **4a-d**, determined by <sup>19</sup>F NMR.</footnote>
conversion after 30h of stirring) and oxazoline 5a was isolated in only 65% yield due to the
concomitant formation of a non negligible amount of N,O-acetals *cis*-4a and 2a (6 and 18%
conversion detected respectively in the ¹⁹F NMR of the crude reaction mixture) (table 4, entry
3). At reflux of dichloromethane, the reaction was faster (97% conversion after 8h of stirring),
the yield of oxazoline 5a was slightly improved to 71% but similar amounts of N,O-acetals *cis*-
4a and 2a were also formed (5% and 17% detected respectively in the ¹⁹F NMR of the crude
reaction mixture) (table 4, entry 4). The formation of *cis*-2a, *trans*-2a and *cis*-4a during the
course of the reaction can be rationalized by the competitive nucleophilic attack of H₂O and
AcOBF₃ on the intermediate *N*-acyliminium ion. Noteworthy, using *O*-acetyl *N*,*O*-acetal 4a as
starting material no traces of debenzylated oxazoline 3 was detected in the ¹⁹F NMR spectra of
the crude reaction mixture whatever the reaction conditions. Better conversions in oxazoline 5a
have been obtained using acetonitrile as solvent (table 4, entries 1 and 2) instead of only 10
equivalents in dichloromethane (table 4, entries 3 and 4) but these latter conditions will be
particularly advantageous for nitriles that cannot be used as solvent. The best experimental
conditions (acetonitrile as solvent, at rt) were then applied to the *N*,*O*-acetal *cis*-4a, the minor
diastereomer (table 4, entry 5). Only 42% conversion of *cis*-4a in oxazoline 5a after 18h of
stirring being detected by ¹⁹F NMR, the oxazoline 5a was thus isolated in 39% yield. The
slowness of this reaction on *cis*-4a might be attributed to the more difficult generation of the
intermediate *N*-acyliminium ion from the minor *cis*-4a diastereomer in comparison with the
major *trans*-4a for conformational reasons.²³ The structure of 5a was confirmed by 2D NOESY
and ¹⁹F-¹H-HOESY (Heteronuclear NOESY) experiments (figure 1).
<figure><img src="image_7.png" /><figcaption>Table 4. Optimisation of the Ritter-like reaction conditions on *N*,*O*-acetal *trans*- and *cis*-4a.ª</figcaption></figure>

<table><thead><tr><th>entry</th><th>N,O-acetal<sup>b</sup></th><th>MeCN</th><th>T (°C)</th><th>time (h)</th><th>yield (%)</th></tr></thead><tbody><tr><td>1</td><td>trans-4a</td><td>solvent</td><td>rt</td><td>24</td><td>97</td></tr><tr><td>2</td><td>trans-4a</td><td>solvent</td><td>reflux</td><td>1.5</td><td>80<sup>c</sup></td></tr><tr><td>3</td><td>trans-4a</td><td>10 equiv</td><td>rt</td><td>30</td><td>65<sup>d</sup></td></tr><tr><td>4</td><td>trans-4a</td><td>10 equiv</td><td>reflux</td><td>8</td><td>71<sup>e</sup></td></tr><tr><td>5</td><td>cis-4a</td><td>solvent</td><td>rt</td><td>26</td><td>39<sup>f</sup></td></tr></tbody></table>

<footnote>ªreaction conditions: BF₃.Et₂O (3 equiv) in MeCN or BF₃.Et₂O (3 equiv), MeCN (10 equiv) in CH₂Cl₂. ᵇtrans-4a: from major diastereomer of 2a, the absolute configuration of the stereocenter bearing the CF₃ group is *R*. cis-4a: from minor diastereomer of 2a, the absolute configuration of the stereocenter bearing the CF₃ group is *S*. ᶜratio oxazoline 5a:amide 6a 85:15 determined in the ¹⁹F NMR spectra of the crude reaction mixture. 12% of amide 6a were also isolated. ᵈ90% conversion. 6% of cis-4a and 18% of 2a (rd trans:cis = 96:4) were also detected by ¹⁹F NMR of the crude reaction mixture. ᶠ97% conversion. 5% of cis-4a and 17% of 2a (rd trans:cis = 99:1) were also detected by ¹⁹F NMR of the crude reaction mixture. ᶤ42% conversion determined by ¹⁹F NMR.</footnote>
<figure><img src="image_8.png" /><figcaption>Figure 1. nOe connectivities on oxazoline 5a.</figcaption></figure>

Even if the Ritter-type reaction was sluggish with the minor diastereomer of *N*,*O*-acetal **4a**, the addition of various nitriles in the presence of 3 equivalents of *BF*₃·*Et*₂*O was carried out on a mixture of diastereomers of *O*,*O'*-benzyl *N*,*O*-acetal **4a** and **4b** at room temperature (table 5). Optimized conditions, nitrile as solvent, were used except for nitrile having a high boiling point for which only 10 equivalents were used in dichloromethane to facilitate the purification of the oxazoline. Addition of various aliphatic nitriles led to the corresponding oxazolines **5a-d**, which were isolated in good to very good yields (ranging from 70 to 83%). However, due to the steric hindrance around the electrophilic carbon of the iminium ion function caused by the trifluoromethyl substituent, addition of sterically hindered *iso*-propyl cyanide or *tert*-butyl cyanide was slower than the addition of acetonitrile (41-48h instead of 28-31h). A similar long reaction time (40h) was necessary to complete the addition of phenyl cyanide on *N*,*O*-acetal **4a**. After purification, oxazoline **5e** was isolated in 83% yield. Reaction with benzyl cyanide was performed in dichloromethane and gave, after 48h at room temperature, the corresponding oxazoline **5f** in a slightly lower yield (63%). Addition of allyl cyanide resulted in oxazoline **5g** in which the double bond *C*=*C* migrated to be conjugated with the double *C*=*N* bond. Oxazoline **5g** was isolated in 89% yield after 21h of reaction.
<figure><img src="image_9.png" /><figcaption>**Table 5.** Ritter-type reaction on benzyl protected *N*,*O*-acetals 4a and 4b.ª</figcaption></figure>

ªreaction conditions for **5a-e** and **5g**: BF₃.Et₂O (3 equiv) in R²CN, rt, 21-48h; reaction conditions for **5f**: BnCN (10 equiv), BF₃.Et₂O (3.05 equiv) in CH₂Cl₂, rt, 48h.

The influence of α-trifluoromethylated *N*,*O*-acetals bearing other hydroxyl protecting groups on the course of the reaction was then evaluated.

The reaction of *O*,*O'*-methyl-*N*,*O*-acetal **4c** with acetonitrile in the presence of 3 equivalents of BF₃.Et₂O was first examined (table 6). The reaction was not complete after 23h at room temperature (73% conversion) (table 6, entry 1). The oxazoline **5h**, which formation implied a challenging demethylation step during the reaction, was the slightly major compound.
As this demethylation step is not favored, the *O,O'*-methyl amide *cis*-7a was also isolated. It is interesting to note that although the diastereoselectivity of the addition of nucleophiles to *N*-acyliminium ions generated *in situ* from cyclic imides derived from tartaric acid or malic acid is typically modest,¹⁴c amide 7a was formed as a single diastereomer. The *cis* relationship between the amide group and the adjacent oxygenated substituent of 7a²⁴ was determined from its X-ray structural analysis. Conducting the reaction at higher temperatures allowed a full conversion of the starting *N,O*-acetal 4c, increased the intramolecular cyclisation rate leading to the oxazoline 5h and thus decreased the formation of amide *cis*-7a (until a 87:13 ratio at reflux of acetonitrile) (table 6, entries 2 and 3). At reflux of acetonitrile, oxazoline 5h and amide *cis*-7a were isolated in respectively 68% and 13% yield (table 6, entry 3).
<figure><img src="image_10.png" /><figcaption>Table 6. Addition of acetonitrile on *O*,*O'*-methyl protected *N*,*O*-acetal 4c.ª</figcaption></figure>

<table><thead><tr><th rowspan="2">entry</th><th rowspan="2">T (°C)</th><th rowspan="2">time<br>(h)</th><th colspan="2">Ratio<sup>b</sup></th><th colspan="2">yield (%)</th></tr><tr><th>5h:cis-7a</th><th>5h</th><th>cis-7a</th></tr></thead><tbody><tr><td>1</td><td>rt</td><td>23<sup>c</sup></td><td>55:45</td><td>29</td><td>19</td></tr><tr><td>2</td><td>50°C</td><td>6</td><td>63:37</td><td>46</td><td>21</td></tr><tr><td>3</td><td>reflux</td><td>1.5</td><td>87:13</td><td>68</td><td>13</td></tr></tbody></table>

ªreaction conditions: BF₃.Et₂O (3 equiv) in MeCN. ᵇratio determined by ¹⁹F NMR of the crude reaction mixture, a single diastereomer detected for each compound **5h** and *cis-7a*. ᶜ73% conversion determined by ¹⁹F NMR of the crude reaction mixture.

The excellent *cis* diastereoselectivity for the formation of oxazolines **5a-h** and of amide **7a** can be rationalized based on the mechanism suggested by Pyne¹⁷ª for the addition of nitriles on *N*-acyliminium ions derived from (4S)-4,5-dihydroxypyrrolidone and (4S)-4-(benzyloxy)-5-hydroxypyrrolidone (scheme 2). The attack of nitriles on *N*-acyliminium ion **A** giving the *cis*- and *trans*-nitrilium ion **B** might be reversible and, due to its *cis* stereochemistry, *cis*-nitrilium ion **B** more readily cyclizes to the oxazoline cationic intermediate **C**.²⁶ Debenzylation or demethylation gives the oxazolines **5a-h**. Demethylation being less favorable than
debenzylation, and amide **7a** being only obtained as its *cis* isomer, we propose that *cis-7a* stem from the concomitant hydrolysis of the methoxy cyclic intermediate **C**, not from the hydrolysis of nitrilium ion **B**.

<figure><img src="image_11.png" /><figcaption>**Scheme 2.** Proposed mechanism for the formation of oxazolines 5a-h and amide cis-7a from N,O-acetal 4a-c.</figcaption></figure>
*O,O'-Acetyl-*N,*O*-acetal **4d** was then treated under the same experimental conditions (table 7). At room temperature, only a low conversion of the starting *N,O*-acetal **4d** was observed (45%, table 7, entry 1). Amide **7b** (89:11 mixture of *cis:trans* diastereomers) was the only product formed. The *cis* relationship between the amide group and the adjacent oxygenated substituent of the major diastereomer of **7b**²⁴ was determined from its X-ray structural analysis.

At 50°C, acetal **4d** was fully converted in *O,O'-acetyl* amides **7b** which were formed in a 86:14 mixture of diastereomers and isolated in respectively 73% and 10% yields (table 7, entry 2).

Similar results were obtained at reflux of acetonitrile (table 7, entry 3). The oxygen atom of the neighboring acetoxy group being less nucleophile than the one of benzyloxy- or methoxy-groups, no traces of oxazoline was formed, even at reflux.
<figure><img src="image_12.png" /><figcaption>Table 7. Addition of acetonitrile on *O,O'*-acetyl protected *N,O*-acetal 4d.ª</figcaption></figure>

<table><thead><tr><th rowspan="2">entry</th><th rowspan="2">T (°C)</th><th rowspan="2">Time (h)</th><th>dr 7b</th><th colspan="2">yield (%)</th></tr><tr><th>cis:trans<sup>b</sup></th><th>cis-7b</th><th>trans-7b</th></tr></thead><tbody><tr><td>1</td><td>rt</td><td>46<sup>c</sup></td><td>89:11</td><td></td><td>31<sup>d</sup></td></tr><tr><td>2</td><td>50°C</td><td>30</td><td>86:14</td><td>73</td><td>10</td></tr><tr><td>3</td><td>reflux</td><td>6</td><td>85:15</td><td>63</td><td>13</td></tr></tbody></table>

ªreaction conditions: BF₃.Et₂O (3 equiv) in MeCN. ᵇdiastereomeric ratio of amides **7b** determined by ¹⁹F NMR of the crude reaction mixture. ᶜ45% conversion determined by NMR ¹⁹F of the crude reaction mixture. ᵈdiastereomers not separated.

The formation of a 85:15 to 89:11 mixture of *cis* and *trans* amide **7b** should reflect the prevalent *syn* addition of nitrile on *N*-acyliminium ion generated from *O,O'*-acetyl-*N*,*O*-acetal **4d**. Since the neighbouring group participation of the 4-*O*-acetyl group in the stereocontrol of the reaction should favor the *anti* addition of the nucleophile,¹⁴d,²⁷ it would appear that the 3-*O*-acetyl group provided the anchimeric assistance leading to the preferential formation of the *cis*-isomer²⁸ (scheme 3).
<figure><img src="image_13.png" /><figcaption>Scheme 3. Proposed mechanism for the *syn* selectivity of the addition of acetonitrile on *O,O'*-acetyl *N*-acyliminium ion derived from *N,O*-acetal 4d.</figcaption></figure>

Acid hydrolysis of oxazolines 5a-f,h with HCl in methanol at room temperature led to the corresponding *cis*-hydroxyamides 6a-g in which one alcohol function has been selectively deprotected (table 8). With most of the substituents on the oxazoline ring (methyl, *iso*-propyl or benzyl), this reaction was complete in a short reaction time (4h or less) and amides 6a-c,f,g were isolated with a yield ranging from 80% to 94%. However, the efficiency of the reaction seems to depend of the bulkiness of this substituent. With *tert*-butyl and phenyl groups the reactions were not complete even after long reaction times (55% and 75% conversion after 46-48h at room temperature) and the corresponding amides 6d and 6e were thus isolated in only 43 and 69% yield respectively.
<figure><img src="image_14.png" /><figcaption>Table 8. Hydrolysis of oxazolines 5a-f,h in corresponding hydroxylamides 6a-g.</figcaption></figure>

The retention of the *cis* relationship between the hydroxyl group and the *exo* amide function was confirmed by 2D NOESY and ¹⁹F-¹H-HOESY (Heteronuclear NOESY) experiments on compound **6a** (figure 2).
<figure><img src="image_15.png" /><figcaption>**Figure 2.** *n*-Oe connectivities on hydroxyamide 6a.</figcaption></figure>

Full deprotection of oxazoline 5a with HCl in methanol at 60°C gave, after 29h of reaction, the conformationally stable *cis*-hydroxyamine 8 in 68% yield (scheme 4).

<figure><img src="image_16.png" /><figcaption>**Scheme 4.** Hydrolysis of oxazoline 5a in corresponding hydroxylamine 8.</figcaption></figure>

Finally, we have shown that the Ritter-like reaction and the hydrolysis step can also be carried out without purification of the intermediate oxazoline (table 9). Treatment of *N*,*O*-acetal 4a with acetonitrile in the presence of 3 equivalents of *BF*₃·*Et*₂*O at room temperature followed, after work-up, by the hydrolysis under acidic conditions (HCl 6N aq. in methanol) led to the hydroxyamide 6a or the hydroxylamine 8 depending on the temperature of the deprotection reaction. These two-step sequences get similar yields to the ones obtained when the oxazoline 5a was purified (respectively 64% and 54% instead of 70% and 52%). This process was particularly convenient for performing the reaction with nitriles having a high boiling point for which purification of the intermediate oxazoline can be difficult. In this case, the Ritter-like
reaction step is performed with 10 equivalents of suitable nitrile in dichloromethane as solvent and, after hydrolysis, the hydroxyamides **6f,h,i**, variously substituted on the amide alkyl chain, were obtained in moderate to quite good yields (from 31% to 58%). These yields reflect the partial conversion observed for one or both steps of the reaction sequence. Yield of **6f** was identical to the global one obtained when oxazoline **5f** was isolated. This approach was also applied directly to the *N*,*O*-acetal **2d**. In this latter case, the Ritter-like reaction step was performed at reflux of acetonitrile and the hydroxyamide **6j** was isolated, after the acid hydrolysis reaction, in 70% yield.
<figure><img src="image_17.png" /><figcaption>Table 9. Reaction sequence “addition of nitrile – acid hydrolysis” on N,O-acetals 4a and</figcaption></figure>

areaction conditions for **6a** and **6f**: RCN (solvent), BF₃.Et₂O (3 equiv), rt then HCl (6N aq.), MeOH, rt. reaction conditions for **8**: MeCN (solvent), BF₃.Et₂O (3 equiv), rt then HCl (6N aq.), MeOH, 60°C. reaction conditions for **6h-i**: RCN (10 equiv), BF₃.Et₂O (3 equiv), CH₂Cl₂, rt then HCl (6N aq.), MeOH, rt. reaction conditions for **6j**: MeCN (solvent), BF₃.Et₂O (3 equiv), reflux then HCl (6N aq.), MeOH, rt. byield for the whole sequence with purification of the intermediate oxazoline is indicated between brackets.

Conclusion

Although electron-withdrawing trifluoromethyl group has not only rendered the
formation of adjacent N-acyliminium ion difficult by strongly stabilizing the N,O-acetal
precursor but has also destabilized and hindered this latter rendering the reactions with nucleophiles arduous, α-trifluoromethylated iminium ions have been successfully generated by treatment of *O*-acetyl-*N*,*O*-acetals derived from (L)-tartaric acid with $BF_3.Et_2O$. Using nitriles as nucleophiles afforded the corresponding 3a-(trifluoromethyl)-pyrrolo[2,3-*d*]-oxazolone and/or 2-acyl-2-trifluoromethylpyrrolidone derivatives. Hydroxyl groups and ether substituents directed the Ritter-like reaction mostly or exclusively towards the formation of oxazoline derivatives, while esters led to an amide function which was obtained with high *syn* diastereoselectivity. A small library of original, highly functionalized 5-(trifluoromethyl)-pyrrolidin-2-ones bearing the fluorinated substituent on a tetrasubstituted carbon was thereby obtained.

## Experimental section

THF, $CH_2Cl_2$ and MeCN were dried using a Pure Solv solvent drying system over aluminium oxide under an Argon atmosphere. DMF (extra-dry, water < 0,005%) was purchased from Acros Organics. $CF_3SiMe_3$ was distilled under Ar prior to use. Thin-layer chromatography using precoated aluminium backed plates (Merck Kieselgel 60F254) were visualized by UV light and/or by phosphomolybdic acid. Silicagel 40-63 µm (Macherey-Nagel GmbH & Co KG) was used for flash chromatography. NMR spectra were recorded in $CDCl_3$ with 250 MHz, 500 MHz, or 600 MHz spectrometers. Chemicals shifts (δ) are reported in ppm relative to TMS for ¹H and ¹³C NMR spectra and to $CFCl_3$ for ¹⁹F NMR spectra. In the ¹³C NMR data (J-MOD), reported signal multiplicities are related to C-F coupling. The following abbreviations are used to indicate the multiplicities: s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), quint (quintet), hept (heptuplet), m (multiplet). COSY, HSQC and HMBC 2D NMR experiments were used to confirm the NMR peak assignments for compounds 2-8. Diastereomeric ratios (dr) were determined by ¹⁹F NMR. HRMS were recorded on an ESI-Q-
TOF mass spectrometer using an electrospray source in positive mode. Melting points (mp) were determined on a Tottoli apparatus and were uncorrected. Optical rotations were measured at room temperature (c.a. 20 °C).

**General procedure for preparation of tartrimide 1a-c by one-pot "activation-condensation-ring closure sequence".**¹⁸ A solution of *O,O'*-protected (L)-tartaric acid in acetyl chloride (8.4-16.5 equiv) was heated at reflux under Ar for 4h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the solid anhydride was dissolved in dichloromethane. Amine (1.08-1.21 equiv) was added dropwise at 0°C. After 15 min of stirring at 0°C and 5h at reflux, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. A solution of amido acid in acetylchloride (8.4-16.5 equiv) was heated at reflux for 6h, then cooled to room temperature and concentrated under reduced pressure. Purification of the residue afforded the tartrimide **1**.

(3R,4R)-1-benzyl-3,4-bis(benzyloxy)pyrrolidine-2,5-dione **1a**. According to the general procedure, a solution of *O,O'*-benzyl (L)-tartaric acid²⁵ (13.7 g, 41.5 mmol) reacted with acetyl chloride (25 mL, 350.3 mmol, 8.4 equiv), then the formed anhydride reacted with benzylamine (5.5 mL, 50.3 mmol, 1.2 equiv) in CH₂Cl₂ (23 mL) and finally the obtained amido acid reacted with acetylchloride (25 mL, 350.3 mmol, 8.4 equiv). Purification by chromatography on silica gel (PE:EtOAC 8:1) afforded the known tartrimide **1a**²⁹ (12.9 g, 78%) as a white solid; mp 90°C; [α]D²⁰ = +152 (c 1.00, CHCl₃); IR (KBr) νmax 698, 1022, 1080, 1102, 1337, 1709, 1786, 2863, 3030 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.41 (s, 2H), 4.66 (d, *J* = 14.0 Hz, 1H), 4.69 (d, *J* = 14.0 Hz, 1H), 4.78 (d, *J* = 11.5 Hz, 2H), 5.02 (d, *J* = 11.5 Hz, 2H), 7.31-7.41 (m, 15H); ¹³C NMR (125.8 MHz, CDCl₃) δ 42.4, 73.6, 78.9, 128.30, 128.36, 128.37, 128.8, 129.0, 135.1, 136.6, 172.5; HRMS (ESI⁺) *m/z* calcd for C₂₅H₂₃NNaO₄ [M+Na]⁺ 424.1525, found 424.1522.

(3R,4R)-3,4-bis(benzyloxy)-1-(4-methoxybenzyl)pyrrolidine-2,5-dione **1b**. According to the general procedure, *O,O'*-benzyl (L)-tartaric acid²⁵ (7.1 g, 21.5 mmol) reacted with acetyl
chloride (15 mL, 210.2 mmol, 9.8 equiv), then the formed anhydride reacted with *p*-methoxybenzylamine (3.4 mL, 26.0 mmol, 1.21 equiv) in CH₂Cl₂ (23 mL) and finally the obtained amido acid reacted with acetylchloride (20 mL, 280.2 mmol, 13 equiv). Purification by recrystallisation in EtOAc afforded the known tartrimide **1b**¹⁸,²⁵ (7.04 g, 76%) as a beige solid; mp 132°C; [α]D²⁰ = +203 (c 0.80, CH₂Cl₂); IR (KBr) νmax 699, 746, 1105, 1251, 1342, 1606, 1722, 2062, 2610, 2886, 3427 cm⁻¹; ¹H NMR (250 MHz, CDCl₃) δ 3.78 (s, 3H), 4.38 (s, 2H), 4.60 (s, 2H), 4.75 (d, *J* = 11.5 Hz, 2H), 5.00 (d, *J* = 11.5 Hz, 2H), 6.84 (d, *J* = 8.5 Hz, 2H), 7.32 (m, 12H); ¹³C NMR (62.9 MHz, CDCl₃) δ 41.9, 55.4, 73.6, 79.0, 114.2, 127.4, 128.4, 128.6, 130.9, 136.6, 159.6, 172.5; HRMS (ESI⁺) *m/z* calcd for C₂₆H₂₅NNaO₅ [M+Na]⁺ 454.1630, found 454.1614.

(3R,4R)-1-benzyl-3,4-dimethoxypyrrolidine-2,5-dione **1c**. According to the general procedure, *O,O'-methyl (L)-tartaric acid*³⁰ (3.32 g, 18.6 mmol) reacted with acetyl chloride (22 mL, 308.3 mmol, 16.5 equiv), then the formed anhydride reacted with benzylamine (2.2 mL, 20.1 mmol, 1.08 equiv) in CH₂Cl₂ (25 mL) and finally the obtained amino acid reacted with acetylchloride (22 mL, 308.3 mmol, 16.5 equiv). Purification by chromatography on silica gel (PE:EtOAc 4:1) afforded the tartrimide **1c** (2.19 g, 47%) as a white solid; mp 126°C; [α]D²⁰ = +190 (c 1.01, CHCl₃); IR (KBr) νmax 703, 961, 1074, 1118, 1152, 1340, 1431, 1716, 2834, 2951, 2987, 3486 cm⁻¹; ¹H NMR (250 MHz, CDCl₃) δ 3.68 (s, 6H), 4.12 (s, 2H), 4.63 (s, 2H), 7.30 (m, 5H); ¹³C NMR (62.9 MHz, CDCl₃) δ 42.3, 59.8, 81.4, 128.3, 128.8, 129.0, 135.1, 172.2. HRMS (ESI⁺): *m/z* calcd for C₁₃H₁₅NNaO₄ [M+Na]⁺ 272.0899, found 272.0893.

(3R,4R)-1-benzyl-2,5-dioxopyrrolidine-3,4-diyl diacetate **1e**. A solution of (L)-tartaric acid (15 g, 100 mmol) in acetyl chloride (73 mL, 1023 mmol, 10.2 equiv) was heated at reflux under Ar for 24h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the solid residue was dissolved in anhydrous THF (120 mL). Benzylamine (12 mL, 109.9 mmol, 1.1 equiv) was added dropwise at 0°C. After 15 min of stirring at 0°C and
3h at reflux, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. A solution of the residue in acetylchloride (70 mL, 981 mmol, 9.8 equiv) was heated at reflux for 5h, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a sat. aq. sol. of NaHCO₃. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and an aq. sol. of HCl 10% (v/v), dried (MgSO₄), filtered and concentrated under reduced pressure to give the known tartrimide **1e**³¹ (25.2 g, 82%) as a white solid; mp 121°C; [α]D²⁰ = +113 (c 1.01, CH₂Cl₂); IR (KBr) vmax 705, 1023, 1072, 1174, 1224, 1354, 1439, 1720, 3007, 3492 cm⁻¹; ¹H NMR (250 MHz, CDCl₃) δ 2.17 (s, 6H), 4.67 (d, *J* = 14.0 Hz, 1H), 4.76 (d, *J* = 14.0 Hz, 1H), 5.53 (s, 2H), 7.30-7.38 (m, 5H); ¹³C NMR (62.9 MHz, CDCl₃) δ 20.4, 43.2, 72.8, 128.4, 128.9, 134.6, 169.2, 169.9; HRMS (ESI⁺): *m/z* calcd for C₁₅H₁₅NNaO₆ [M+Na]⁺ 328.0797, found 328.0798.

(3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione **1d**. A solution of tartrimide **1e** (20 g, 65.5 mmol) and acetyl chloride (14 mL, 196 mmol, 3 equiv) was stirred 15 min at 0°C and 24h at rt and was then concentrated under reduced pressure to give the known tartrimide **1d**³² (14.4 g, 99%) as a yellowish solid; mp 201°C; [α]D²⁰ = +135 (c 2.00, MeOH); IR (KBr) vmax 693, 1007, 1162, 1348, 1711, 2922, 3287 cm⁻¹; ¹H NMR (250 MHz, CD₃OD) δ 4.27 (s, 2H), 4.39 (d, *J* = 15.0 Hz, 1H), 4.46 (d, *J* = 15.0 Hz, 1H), 6.18 (br s, 2H), 7.14 (m, 5H); ¹³C NMR (62.9 MHz, CD₃OD) δ 50.7, 84.0, 137.0, 138.1, 145.5, 184.1; HRMS (ESI⁺): *m/z* calcd for C₁₁H₁₁NNaO₄ [M+Na]⁺ 244.0586, found 244.0583.

**General procedure for the preparation of N,O-acetals 2a-d by nucleophilic trifluoromethylation of tartrimides 1a-d.**

**General procedure A:** To a solution of tartrimide **1** in THF were slowly added, at -20 °C under Ar, TMAF.4H₂O (0.048 equiv) and CF₃TMS (2.04 equiv). The reaction was stirred at this temperature until the full conversion of starting tartrimide (reaction monitored by TLC and ¹⁹F
NMR), water was added and the reaction was stirred at room temperature. After the complete conversion of the silyl ether intermediate (reaction monitored by TLC and ¹⁹F NMR), the reaction was extracted three times with Et₂O. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel afforded the N,O-acetal 2.

**General procedure B:** To a solution of tartrimide 1 and K₂CO₃ (0.1 equiv) in DMF was slowly added, at 0 °C under Ar, CF₃TMS (2 equiv). After 20 min of stirring at 0 °C and 2 h at room temperature, supplementary amounts of K₂CO₃ (0.1 equiv) and CF₃TMS (2 equiv) were added. After the complete conversion of the starting tartrimide (reaction monitored by TLC and ¹⁹F NMR), the reaction was quenched with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated under reduced pressure. The residue was then dissolved in a mixture of THF:H₂O (3:1) and a solution of tetra-n-butylammonium fluoride (1M in THF, 0.1 equiv) was added at room temperature. After the complete conversion of the silyl ether intermediate (reaction monitored by TLC and ¹⁹F NMR), the reaction was quenched with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel afforded the N,O-acetal 2.

(3R,4R)-1-benzyl-3,4-bis(benzyloxy)-5-hydroxy-5-(trifluoromethyl)pyrrolidin-2-one 2a.

According to the general procedure A, a solution of tartrimide 1a (4.8 g, 12.0 mmol), TMAF·4H₂O (95 mg, 0.58 mmol, 0.048 equiv) and CF₃TMS (3.6 mL, 24.5 mmol, 2.04 equiv) in THF (115 mL) was stirred 1h30 and was then hydrolyzed with H₂O (100 mL) for 21h. Purification of the residue (dr = 86:14) on silica gel (CH₂Cl₂:Et₂O 10:0 to 19:1) afforded the minor diastereomer *cis*-2a (650 mg, 12%) followed by the major diastereomer *trans*-2a (3.86 g, 68%). *cis*-2a: pale yellow solid; mp 73°C; [α]D²⁰ +79 (c 1.01, CHCl₃); IR (KBr) νmax 701,
948, 1031, 1112, 1180, 1321, 1454, 1735, 2951, 3033, 3357 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -80.6 (s, 3F, CF₃); ¹⁹F NMR (CD₃OD, 235.5 MHz) δ -80.6 (s, 3F, CF₃); ¹H NMR (CD₃OD, 500 MHz) δ 4.19 (d, ³J = 5.0 Hz, 1H, CH-C-CF₃), 4.29 (d, ³J = 5.0 Hz, 1H, CH-C=O), 4.48 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.60 (d, ²J = 12.0 Hz, 1H, CHₐHb-O-CH-C-CF₃), 4.63 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.74 (d, ²J = 12.0 Hz, 1H, CHₐHb-O-CH-C=O), 4.76 (d, ²J = 12.0 Hz, 1H, CHₐHb-O-CH-C-CF₃), 4.86 (br s, 1H, OH), 4.92 (d, ²J = 12.0 Hz, 1H, CHₐHb-O-CH-C=O), 7.20-7.37 (m, 15H, 15 CHar.); ¹³C NMR (CD₃OD, 125.7 MHz) δ 44.9 (N-CH₂), 73.8 (CH₂-O-CH-C=O), 74.3 (CH₂-O-CH-C-CF₃), 79.0 (CH-C-CF₃), 80.2 (CH-C=O), 88.3 (q, ¹JCF = 32.5 Hz, C-CF₃), 124.4 (q, ²JCF = 286.0 Hz, CF₃), 128.1 (CHar.), 128.7 (CHar.), 129.07 (CHar.), 129.15 (CHar.), 129.18 (CHar.), 129.4 (CHar.), 137.9 (CIVar. N-Bn), 138.3 (CIVar. CF₃-C-CH-O-Bn), 138.6 (CIVar. O=C-CH-O-Bn), 173.8 (C=O); HRMS (ESI⁺) *m/z* calcd for C₂₆H₂₄F₃NNaO₄ [M+Na]⁺ 494.1555, found 494.1556. *trans*-2a. White solid; mp 104 °C; [α]D²⁰ +80 (c 1.00, CHCl₃); IR (KBr) νmax 694, 738, 1025, 1062, 1163, 1197, 1256, 1358, 1451, 1498, 1690, 3031, 3184 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -78.6 (s, 3F, CF₃); ¹⁹F NMR (CD₃OD, 235.5 MHz) δ -74.6 (s, 3F, CF₃); ¹H NMR (CD₃OD, 500 MHz) δ 4.29 (d, ³J = 8.0 Hz, 1H, CH-C-CF₃), 4.40 (d, ³J = 8.0 Hz, 1H, CH-C=O), 4.52 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.61 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.70 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃), 4.75 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C=O), 4.93 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃), 4.97 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C=O), 7.20-7.36 (m, 15H, 15 CHar.); ¹³C NMR (CD₃OD, 125.7 MHz) δ 44.0 (N-CH₂), 74.2 (CH₂-O-CH-C=O), 75.0 (CH₂-O-CH-C-CF₃), 79.5 (CH-C=O), 88.5 (CH-C-CF₃), 88.6 (q, ²JCF = 30.5 Hz, C-CF₃), 124.9 (q, ²JCF = 288.0 Hz, CF₃), 128.1 (CHar.), 128.6 (CHar.), 128.9 (CHar.), 129.1 (CHar.), 129.2 (CHar.), 129.3 (CHar.), 129.4 (CHar.), 138.4 (CIVar. N-Bn), 138.6 (CIVar. CF₃-C-CH-O-Bn), 138.8 (CIVar. O=C-CH-O-Bn), 172.3 (C=O); HRMS (ESI⁺) *m/z* calcd for C₂₆H₂₄F₃NNaO₄ [M+Na]⁺ 494.1555, found 494.1548. An analytical sample of *trans*-2a was crystallized from Et₂O/PE.
(3R,4R)-3,4-bis(benzyloxy)-5-hydroxy-1-(4-methoxybenzyl)-5-(trifluoromethyl)pyrrolidin-2-one 2b. According to the general procedure B, a mixture of tartrimide 1b (1.5 g, 3.47 mmol), K₂CO₃ (98 mg, 0.71 mmol, 0.2 equiv) and CF₃TMS (2 mL, 13.53 mmol, 3.9 equiv) in DMF (28 mL) was stirred 21h. After treatment, a solution of the residue and TBAF (1.75 mL, 1.75 mmol, 0.5 equiv) in a mixture of THF:H₂O (40 mL) was stirred 1h. Purification of the residue (dr = 71:29) on silica gel (PE:EtOAc 4:1) afforded the N,O-acetal 2b (1.1 g, 63%, dr = 71:29) as a yellow oil; IR (film) vₘₐₓ 699, 754, 1029, 1111, 1193, 1250, 1353, 1454, 1514, 1613, 1699, 2935, 3032, 3273 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ-76.9 (s, 3F, CF₃, major), -79.4 (s, 3F, CF₃, minor); ¹H NMR (CDCl₃, 500 MHz) δ 3.73 (s, 3H, OCH₃, major), 3.76 (s, 3H, OCH₃, minor), 3.89 (br s, 1H, OH, major), 4.06 (d, ³J = 5.0 Hz, 1H, CH-C=O, minor), 4.16 (m, 1H, CH-C-CF₃, major), 4.17 (m, 1H, CH-C-CF₃, minor), 4.22 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, major), 4.31 (d, ³J = 8.0 Hz, 1H, CH-C=O, major), 4.38 (br s, 1H, OH, minor), 4.46 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, minor), 4.56 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, minor), 4.63 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, major), 4.65 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, minor), 4.73 (d, ²J= 11.5 Hz, 1H, CHₐHb-O-CH-C=O, major), 4.74 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C=O, minor), 4.76 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, major), 4.79 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, minor), 4.81 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, major), 5.01 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C=O, minor), 5.04 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C=O, major), 6.78 (m, 2H, 2 CHar., major), 6.81 (m, 2H, 2 CHar., minor), 7.22-7.38 (m, 12H, 12 CHar., major and minor); ¹³C NMR (CDCl₃, 125.7 MHz) δ 43.1 (N-CH₂, major), 44.1 (N-CH₂, minor), 55.3 (OCH₃, minor), 55.4 (OCH₃, major), 73.0 (CH₂-O-CH-C=O, minor), 73.6 (CH₂-O-CH-C=O, major), 73.9 (CH₂-O-CH-C-CF₃, major), 74.0 (CH₂-O-CH-C-CF₃, minor), 77.2 (CH-C-CF₃, minor), 78.1 (CH-C-C=O, minor), 78.4 (CH-C-C=O, major), 85.9 (q, ²JCF = 33.0 Hz, C-CF₃, minor), 87.1 (CH-C-CF₃, major), 88.0 (q, ²JCF = 31.0 Hz, C-CF₃, major), 113.8 (CHar., minor), 114.2 (CHar., major), 122.9 (q, ¹JCF = 288.5 Hz, CF₃, minor), 123.3 (q, ¹JCF =
286.0 Hz, CF₃, major), 128.0 (CHar., major), 128.1 (CHar., minor), 128.2 (CHar., major), 128.4 (CHar., minor), 128.48 (CHar., minor), 128.53 (CHar., major), 128.6 (CHar., major), 128.7 (CHar., minor), 128.83 (CHar., major), 128.86 (CHar., minor), 129.4 (CIVar., N-CH₂-Ph, major), 129.7 (CHar., major), 129.9 (CHar., minor), 135.7 (CIVar., CF₃-C-CH-O-Bn, minor), 137.00 (CIVar., O=C-CH-O-Bn, minor), 137.04 (CIVar., CF₃-C-CH-O-Bn, major), 137.4 (CIVar., O=C-CH-O-Bn, major), 159.00 (CIVar., CH₃-O-Ph, major), 159.03 (CIVar., CH₃-O-Ph, minor), 170.6 (C=O, major), 171.8 (C=O, minor); HRMS (ESI⁺) *m/z* calcd for C₂₇H₂₆F₃NNaO₅ [M+Na]⁺ 524.1661, found 524.1656.

(3R,4R)-1-benzyl-5-hydroxy-3,4-dimethoxy-5-(trifluoromethyl)pyrrolidin-2-one **2c**.

According to the general procedure B, a mixture of tartrimide **1c** (1.2 g, 4.81 mmol), K₂CO₃ (135 mg, 0.98 mmol, 0.2 equiv) and CF₃TMS (2.86 mL, 19.34 mmol, 4 equiv) in DMF (25 mL) was stirred 7h30. After treatment, *N*,*O*-acetal **2c** (dr = 75:25) was directly purified on silica gel (PE:EtOAc 3:1) to afford the *N*,*O*-acetal **2c** (1.18 g, 77%, dr = 75:25) as a yellow oil; IR (film) *ν*max 699, 757, 1075, 1199, 1265, 1350, 1449, 1709, 2841, 2941, 3004, 3280 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) *δ* -77.4 (s, 3F, CF₃, major), -79.7 (s, 3F, CF₃, minor); ¹H NMR (CDCl₃, 600 MHz) *δ* 3.53 (s, 3H, CH₃-O-CH-C-CF₃, major), 3.60 (s, 3H, CH₃-O-CH-C=O, major), 3.61 (s, 3H, CH₃-O-CH-C-CF₃, minor), 3.64 (s, 3H, CH₃-O-CH-C=O, minor), 3.84 (d, ³J = 5.0 Hz, 1H, CH-C=O, minor), 3.88 (d, ³J = 5.0 Hz, 1H, CH-C-CF₃, minor), 3.93 (d, ³J = 8.0 Hz, 1H, CH-C-CF₃, major), 4.01 (d, ³J = 8.0 Hz, 1H, CH-C=O, major), 4.32 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, major), 4.36 (br s, 1H, OH, minor), 4.52 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, minor), 4.59 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, minor), 4.70 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, major), 4.80 (br s, 1H, OH, major), 7.20-7.29 (m, 5H, 5 CHar., major and minor); ¹³C NMR (CDCl₃, 151 MHz) *δ* 43.4 (N-CH₂, major), 44.6 (N-CH₂, minor), 59.3 (CH₃-O-CH-C=O, minor), 59.64 (CH₃-O-CH-C-CF₃, minor), 59.7 (CH₃-O-CH-C=O, major), 60.2 (CH₃-O-CH-C-CF₃, major), 79.1 (CH-C-CF₃, minor), 80.3 (CH-C=O, major), 80.8 (CH-C=O, minor), 85.7 (q, ²JCF = 33.5 Hz, C-CF₃,
minor), 87.8 (q, $^2J_{CF}$= 31.0 Hz, C-CF$_3$, major), 89.7 (CH-C-CF$_3$, major), 122.7 (q, $^1J_{CF}$= 286.0 Hz, CF$_3$, minor), 123.2 (q, $^1J_{CF}$= 288.5 Hz, CF$_3$, major), 127.6 (CHar., major), 127.8 (CHar., major), 128.2 (CHar., minor), 128.4 (CHar., minor), 128.7 (CHar., major), 136.2 (CIVar., minor), 137.0 (CIVar., major), 170.6 (C=O, major), 171.7 (C=O, minor); HRMS (ESI$^+$) *m/z* calcd for C$_{14}$H$_{16}$F$_3$NNaO$_4$ [M+Na]$^+$ 342.0929, found 342.0921.

(3R,4R)-1-benzyl-3,4,5-trihydroxy-5-(trifluoromethyl)pyrrolidin-2-one 2d. According to the general procedure B, a mixture of tartrimide 1d (2 g, 9.04 mmol), K$_2$CO$_3$ (252 mg, 1.82 mmol, 0.2 equiv) and CF$_3$TMS (5.40 mL, 36.53 mmol, 4 equiv) in DMF (50 mL) was stirred 5h. After treatment, a solution of the residue and TBAF (9 mL, 9 mmol, 1 equiv) in a mixture of THF:H$_2$O (40 mL) was stirred 2h. Purification of the residue (dr = 89:11) on silica gel (PE:EtOAc 3:1) afforded N,O-acetal 2d (2.37 g, 90%, dr = 89:11) as a beige solid; IR (KBr) ν$_{max}$ 698, 959, 1114, 1191, 1354, 1415, 1704, 2925, 3339 cm$^{-1}$; $^{19}$F NMR (CD$_3$OD, 235.5 MHz) δ-78.0 (s, 3F, CF$_3$, major), -80.6 (s, 3F, CF$_3$, minor); $^1$H NMR (CD$_3$OD, 500 MHz) δ major isomer 4.18 (m, 1H, CH-C-CF$_3$), 4.29 (d, $^3J$= 8.5 Hz, 1H, CH-C=O), 4.49 (d, $^2J$= 15.5 Hz, 1H, N-CH$_a$H$_b$), 4.55 (d, $^2J$= 15.5 Hz, 1H, N-CH$_a$H$_b$), 7.19-7.22 (m, 1H, CHar.), 7.25-7.30 (m, 4H, 4 CHar.); $^{13}$C NMR (CD$_3$OD, 125.7 MHz) δ major isomer 44.2 (N-CH$_2$), 74.1 (CH-C=O), 83.4 (CH-C-CF$_3$), 88.5 (q, $^2J_{CF}$= 30.0 Hz, C-CF$_3$), 125.0 (q, $^1J_{CF}$= 288.0 Hz, CF$_3$), 128.0 (CHar.), 128.6 (CHar.), 129.2 (CHar.), 138.6 (CIVar.), 174.1 (C=O); HRMS (ESI$^+$) *m/z* calcd for C$_{12}$H$_{12}$F$_3$NNaO$_4$ [M+Na]$^+$ 314.0616, found 314.0612.

**General procedure for the preparation of oxazoline 3 from N,O-acetal 2a and 2d.** A solution of α-trifluoromethylated N,O-acetal **2a,d** and BF$_3$.Et$_2$O (3 equiv) in acetonitrile was heated at reflux under Ar. The reaction mixture was cooled to rt, quenched with a sat. aq. Sol. of NaHCO$_3$ and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (MgSO$_4$) and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel.
(3aR,6R,6aS)-4-benzyl-6-hydroxy-2-methyl-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 3. From 2a: According to the general procedure, a solution of N,O-acetal 2a (80 mg, 0.17 mmol) and BF3.OEt2 (65 µL, 0.53 mmol, 3 equiv) in acetonitrile (5 mL) was stirred 5h at reflux. Purification on silica gel (PE:EtOAc 7:1) afforded the oxazoline 3 (40 mg, 75%) as a white solid. From 2d: According to the general procedure, a solution of N,O-acetal 2d (80 mg, 0.27 mmol) and BF3.OEt2 (101 µL, 0.82 mmol, 3 equiv) in acetonitrile (5 mL) was stirred 2h at reflux. Purification on silica gel (PE:EtOAc 7:1) afforded the oxazoline 3 (66 mg, 77%) as a white solid. mp 114 °C; [α]D20 +6 (c 0.50, CHCl3); IR (KBr) νmax 735, 969, 1014, 1127, 1174, 1202, 1337, 1658, 1710, 3390 cm-1; 19F NMR (CD3OD, 235.5 MHz) δ-78.9 (s, 3F, CF3); 1H NMR (CD3OD, 500 MHz) δ 2.09 (s, 3H, CH3), 4.39 (d, 3J = 1.5 Hz, 1H, CH-C=O), 4.49 (d, 2J = 16.0 Hz, 1H, N-CHaHb), 4.72 (d, 2J = 16.0 Hz, 1H, N-CHaHb), 4.95 (d, 3J = 1.5 Hz, 1H, CH-C-CF3), 7.23-7.31 (m, 5H, 5 CHar.); 13C NMR (CD3OD, 125.7 MHz) δ 14.0 (CH3), 46.6 (N-CH2), 74.0 (CH-C=O), 85.9 (CH-C-CF3), 93.3 (q, 2JCF = 33.0 Hz, C-CF3), 124.3 (q, 1JCF = 283.0 Hz, CF3), 128.3 (CHar.), 128.6 (CHar.), 129.2 (CHar.), 137.6 (CIVar., N-Bn), 174.4 (C=N), 174.9 (C=O); HRMS (ESI+) m/z calcd for C14H13F3N2NaO3 [M+Na]⁺ 337.0776, found 337.0768.

**General procedure for the preparation of O-acetyl-N,O-acetals 4a-d from 2a-d.** A solution of α-trifluoromethylated N,O-acetal **2a-d**, pyridine, acetic anhydride and DMAP in dichloromethane was stirred at rt under Ar. After the complete conversion of the starting N,O-acetal (reaction monitored by TLC and 19F NMR), the reaction was quenched with an aqueous solution of hydrochloric acid (10%) and extracted twice with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel (PE:EtOAc).
(2R,3R,4R)-1-benzyl-3,4-bis(benzyloxy)-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl acetate *trans*-4*a. According to the general procedure, a solution of *N*,*O*-acetal *trans*-2*a (1.50 g, 3.18 mmol), pyridine (387 µL, 4.80 mmol, 1.5 equiv), acetic anhydride (510 µL, 5.40 mmol, 1.7 equiv) and DMAP (40 mg, 0.33 mmol, 0.1 equiv) in CH<sub>2</sub>Cl<sub>2</sub> (23 mL) was stirred 1h30. Purification on silica gel (PE:EtOAc 4:1) afforded the *O*-acetyl-*N*,*O*-acetal *trans*-4*a (1.63 g, 99%) as a colourless oil; [α]<sub>D<sup>20</sup></sub> +33 (c 1.00, CHCl<sub>3</sub>); IR (film) ν<sub>max</sub> 699, 1038, 1118, 1206, 1363, 1425, 1741, 2874, 2929, 3032, 3065 cm<sup>-1</sup>; <sup>19</sup>F NMR (CDCl<sub>3</sub>, 235.5 MHz) δ-75.5 (s, 3F, CF<sub>3</sub>); <sup>1</sup>H NMR (CDCl<sub>3</sub>, 600 MHz) δ 1.74 (s, 3H, CH<sub>3</sub>), 4.39 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.40 (d, <sup>3</sup>J = 7.0 Hz, 1H, CH<sub>-C=O</sub>), 4.60 (d, <sup>2</sup>J = 11.5 Hz, 1H, CH<sub>a</sub>H<sub>b</sub>-O-CH-C-CF<sub>3</sub>), 4.63 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.69 (d, <sup>2</sup>J = 11.5 Hz, 1H, CH<sub>a</sub>H<sub>b</sub>-O-CH-C-CF<sub>3</sub>), 4.81 (d, <sup>2</sup>J = 11.5 Hz, 1H, CH<sub>a</sub>H<sub>b</sub>-O-CH-C=O), 5.05 (d, <sup>2</sup>J = 11.5 Hz, 1H, CH<sub>a</sub>H<sub>b</sub>-O-CH-C=O), 5.22 (d, <sup>3</sup>J = 7.0 Hz, 1H, CH<sub>-C-CF3</sub>), 7.25-7.39 (m, 15H, 15 CHar.) ; <sup>13</sup>C NMR (CDCl<sub>3</sub>, 151 MHz) δ 21.4 (CH<sub>3</sub>), 44.5 (N-CH<sub>2</sub>), 72.8 (CH<sub>2</sub>-O-CH-C=O), 74.2 (CH<sub>2</sub>-O-CH-C-CF<sub>3</sub>), 78.9 (CH<sub>-C=O</sub>), 80.6 (CH<sub>-C-CF3</sub>), 92.1 (q, <sup>2</sup>J<sub>CF</sub> = 32.0 Hz, <sub>C</sub>-CF<sub>3</sub>), 122.1 (q, <sup>2</sup>J<sub>CF</sub> = 288.0 Hz, CF<sub>3</sub>), 127.7 (CHar.), 128.0 (CHar.), 128.2 (CHar.), 128.3 (CHar.), 128.50 (CHar.), 128.54 (CHar.), 128.55 (CHar.), 128.6 (CHar.), 135.5 (C<sub>IVar</sub>. N-Bn), 136.8 (C<sub>IVar</sub>. CF<sub>3</sub>-C-CH-O-Bn), 137.8 (C<sub>IVar</sub>. O=C-CH-O-Bn), 168.2 (CH<sub>3</sub>-C<sub>-O</sub>=O), 171.6 (C=O); HRMS (ESI<sup>+</sup>) *m/z* calcd for C<sub>28</sub>H<sub>26</sub>F<sub>3</sub>NNaO<sub>5</sub> [M+Na]<sup>+</sup> 536.1661, found 536.1669.

(2S,3R,4R)-1-benzyl-3,4-bis(benzyloxy)-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl acetate *cis*-4*a. According to the general procedure, a solution of *N*,*O*-acetal *cis*-2*a (725 mg, 1.54 mmol), pyridine (188 µL, 2.32 mmol, 1.52 equiv), acetic anhydride (249 µL, 2.63 mmol, 1.7 equiv) and DMAP (19 mg, 0.16 mmol, 0.1 equiv) in CH<sub>2</sub>Cl<sub>2</sub> (15 mL) was stirred 3h. Purification by chromatography (PE:EtOAc 4:1) afforded the *O*-acetyl *N*,*O*-acetal *cis*-4*a (732 mg, 93%) as a colourless oil; [α]<sub>D<sup>20</sup></sub> +43 (c 0.41, CHCl<sub>3</sub>); IR (film) ν<sub>max</sub> 700, 744, 1026, 1137, 1194, 1312, 1353, 1455, 1737, 1770, 2944, 3033, 3064 cm<sup>-1</sup>; <sup>19</sup>F NMR (CD<sub>3</sub>OD, 235.5 MHz)
$\delta$-75.6 (s, 3F, CF$_3$); ¹H NMR (CD$_3$OD, 500 MHz) $\delta$ 1.61 (s, 3H, CH$_3$), 4.27 (d, $^2J$ = 15.5 Hz, 1H, N-CH$_a$H$_b$), 4.34 (d, $^3J$ = 5.0 Hz, 1H, CH$_-C-CF_3$), 4.48 (d, $^3J$ = 5.0 Hz, 1H, CH$_-C=O$), 4.53 (d, $^2J$ = 11.5 Hz, 1H, CH$_a$H$_b$-O-CH$_-C-CF_3$), 4.60 (d, $^2J$ = 11.5 Hz, 1H, CH$_a$H$_b$-O-CH$_-C-CF_3$), 4.79 (d, $^2J$ = 11.5 Hz, 1H, CH$_a$H$_b$-O-CH$_-C=O$), 4.89 (d, $^2J$ = 15.5 Hz, 1H, N-CH$_a$H$_b$), 5.04 (d, $^2J$ = 11.5 Hz, 1H, CH$_a$H$_b$-O-CH$_-C=O$), 7.19-7.21 (m, 2H, 2 CHar.), 7.26-7.39 (m, 13H, 13 CHar.); ¹³C NMR (CD$_3$OD, 125.7 MHz) $\delta$ 20.9 (CH$_3$), 45.1 (N-CH$_2$), 73.9 (CH$_2$-O-C=O), 74.2 (CH$_2$-O-CH$_-C-CF_3$), 79.4 (CH$_-C-CF_3$), 80.7 (CH$_-C=O$), 91.6 (q, $^2J_{CF}$ = 32.5 Hz, C-CF$_3$), 123.5 (q, $^1J_{CF}$ = 285.5 Hz, CF$_3$), 128.8 (CHar.), 128.9 (CHar.), 129.08 (CHar.), 129.12 (CHar.), 129.4 (CHar.), 129.5 (CHar.), 129.6 (CHar.), 129.9 (CHar.), 136.8 (C$_{IVar.}$ N-Bn), 138.2 (C$_{IVar.}$ CF$_3$-C-CH$_-O-Bn), 138.6 (C$_{IVar.}$ O=C-CH$_-O-Bn), 170.6 (CH$_3$-C=O), 174.9 (C=O); HRMS (ESI$^+$) *m/z* calcd for C$_{28}$H$_{26}$F$_3$NNaO$_5$ [M+Na]$^+$ 536.1661, found 536.1658.

(3R,4R)-1-benzyl-3,4-bis(benzyloxy)-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl acetate **4a**.
According to the general procedure, a mixture of *N*,*O*-acetal **2a** (1.51 g, 3.20 mmol, dr = 86:14), pyridine (390 µL, 4.83 mmol, 1.5 equiv), acetic anhydride (515 µL, 5.45 mmol, 1.7 equiv) and DMAP (39 mg, 0.32 mmol, 0.1 equiv) in CH$_2$Cl$_2$ (25 mL) was stirred 5h30. Purification on silica gel (PE:EtOAc 7:1) afforded the *O*-acetyl *N*,*O*-acetal **4a** (1.52 g, 92%, dr = 86:14) as a colourless oil; HRMS (ESI$^+$): *m/z* calcd for C$_{28}$H$_{26}$F$_3$NNaO$_5$ [M+Na]$^+$ 536.1661, found 536.1670.

(3R,4R)-3,4-bis(benzyloxy)-1-(4-methoxybenzyl)-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl acetate **4b**. According to the general procedure, a solution of *N*,*O*-acetal **2b** (1.08 g, 2.15 mmol, dr = 71:29), pyridine (260 µL, 3.22 mmol, 1.5 equiv), acetic anhydride (345 µL, 3.65 mmol, 1.7 equiv) and DMAP (27 mg, 0.22 mmol, 0.1 equiv) in CH$_2$Cl$_2$ (18 mL) was stirred 19h. Purification on silica gel (PE:EtOAc 6:1) afforded the *O*-acetyl *N*,*O*-acetal **4b** (972 mg, 83%, dr = 71:29) as a yellow oil; IR (film) $v_{max}$ 699, 741, 1032, 1112, 1205, 1317, 1514, 1612, 1736, 1767, 2939, 3032, 3415 cm$^{-1}$; $^{19}$F NMR (CDCl$_3$, 235.5 MHz) $\delta$-75.4 (s, 3F, CF$_3$, major), -78.0
(s, 3F, CF₃, minor); ¹H NMR (CDCl₃, 500 MHz) δ 1.59 (s, 3H, CH₃, minor), 1.78 (s, 3H, CH₃, major), 3.783 (s, 3H, OCH₃, major), 3.786 (s, 3H, OCH₃, minor), 4.12 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, minor), 4.29 (d, ³J = 5.5 Hz, 1H, CH-С-CF₃, minor), 4.34 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, major), 4.39 (d, ³J = 7.0 Hz, 1H, CH-C=O, major), 4.55 (d, ³J = 5.5 Hz, 1H, CH-C=O, minor), 4.56 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, minor), 4.59 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, major), 4.61 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, major), 4.62 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, minor), 4.70 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C-CF₃, major), 4.78 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C=O, minor), 4.82 (d, ²J = 12.0 Hz, 1H, CHₐHb-O-CH-C=O, major), 4.99 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, minor), 5.06 (d, ²J = 12.0 Hz, 1H, CHₐHb-O-CH-C=O, major), 5.18 (d, ²J = 11.5 Hz, 1H, CHₐHb-O-CH-C=O, minor), 5.22 (d, ³J = 7.0 Hz, 1H, CH-C-CF₃, major), 6.83 (m, 2H, 2 CHar., major and minor), 7.20-7.40 (m, 12H, 12 CHar., major and minor); ¹³C NMR (CDCl₃, 125.7 MHz) δ 21.0 (CH₃, minor), 21.5 (CH₃, major), 43.6 (N-CH₂, minor), 44.0 (N-CH₂, major), 55.3 (O-CH₃, major), 55.4 (O-CH₃, minor), 72.7 (CH₂-O-CH-C=O, major), 73.2 (CH₂-O-CH-C=O, minor), 73.3 (CH₂-O-CH-C-CF₃, minor), 74.2 (CH₂-O-CH-C-CF₃, major), 78.3 (CH-C-CF₃, minor), 78.9 (CH-C-C=O, major), 79.8 (CH-C-C=O, minor), 80.6 (CH-C-CF₃, major), 90.4 (q, ²JCF= 32.5 Hz, C-CF₃, minor), 92.1 (q, ²JCF = 32.0 Hz, C-CF₃, major), 112.1 (q, ¹JCF = 288.1 Hz, CF₃, major), 112.3 (q, ¹JCF = 286.0 Hz, CF₃, minor), 113.8 (CHar., minor), 113.9 (CHar., major), 127.60 (CIVar. N-CH₂-Ph, major), 127.66 (CIVar. N-CH₂-Ph, minor), 127.7 (CHar., minor), 128.0 (CHar., major), 128.06 (CHar., minor), 128.13 (CHar., major), 128.15 (CHar., major), 128.3 (CHar., minor), 128.46 (CHar., minor), 128.48 (CHar., minor), 128.5 (CHar., major), 128.6 (CHar., major), 130.0 (CHar., major), 130.6 (CHar., minor), 136.8 (CIVar., CF₃-C-CH-O-Bn, major), 137.0 (CIVar., CF₃-C-CH-O-Bn, minor), 137.4 (CIVar., O=C-CH-O-Bn, minor), 137.5 (CIVar., O=C-CH-O-Bn, major), 159.1 (CIVar., CH₃-O-Ar, major), 159.3 (CIVar., CH₃-O-Ar, minor), 168.2 (CH₃-C=O,
major), 168.5 (CH<sub>3</sub>-C=O, minor), 171.6 (C=O, major), 173.0 (C=O, minor); HRMS (ESI<sup>+</sup>) *m/z* calcd for C<sub>29</sub>H<sub>28</sub>F<sub>3</sub>NNaO<sub>6</sub> [M+Na]<sup>+</sup> 566.1766, found 566.1765.

(3R,4R)-1-benzyl-3,4-dimethoxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl acetate **4c**.

According to the general procedure, a solution of *N*,*O*-acetal **2c** (1.17 g, 3.67 mmol, dr = 74 :26), pyridine (445 µL, 5.51 mmol, 1.5 equiv), acetic anhydride (590 µL, 6.24 mmol, 1.7 equiv) and DMAP (45 mg, 0.37 mmol, 0.1 equiv) in CH<sub>2</sub>Cl<sub>2</sub> (18 mL) was stirred 4h.
Purification on silica gel (PE:EtOAc 5:1) afforded the *O*-acetyl *N*,*O*-acetal **4c** (1.20 g, 91%, dr = 75 :25) as a colourless oil; IR (neat) ν<sub>max</sub> 700, 1014, 1037, 1125, 1180, 1315, 1736, 1767, 2840, 2940 cm<sup>-1</sup>; <sup>19</sup>F NMR (CDCl<sub>3</sub>, 235.5 MHz) δ -75.8 (s, 3F, CF<sub>3</sub>, major), -78.1 (s, 3F, CF<sub>3</sub>, minor); <sup>1</sup>H NMR (CDCl<sub>3</sub>, 500 MHz) δ 1.56 (s, 3H, CH<sub>3</sub>-C=O, minor), 1.82 (s, 3H, CH<sub>3</sub>-C=O, major), 3.49 (s, 3H, CH<sub>3</sub>-O-CH-C-CF<sub>3</sub>, minor), 3.53 (s, 3H, CH<sub>3</sub>-O-CH-C-CF<sub>3</sub>, major), 3.70 (s, 3H, CH<sub>3</sub>-O-CH-C=O, major), 3.73 (s, 3H, CH<sub>3</sub>-O-CH-C=O, minor), 3.97 (d, <sup>3</sup>J = 5.0 Hz, 1H, CH-C-CF<sub>3</sub>, minor), 4.10 (d, <sup>3</sup>J = 7.0 Hz, 1H, CH-C=O, major), 4.12 (d, <sup>2</sup>J = 15.0 Hz, 1H, N-CH<sub>2</sub>H<sub>6</sub>, minor), 4.26 (d, <sup>3</sup>J = 5.0 Hz, 1H, CH-C=O, minor), 4.38 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>2</sub>H<sub>6</sub>, major), 4.64 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>2</sub>H<sub>6</sub>, major), 4.95 (d, <sup>3</sup>J = 7.0 Hz, 1H, CH-C-CF<sub>3</sub>, major), 5.02 (d, <sup>2</sup>J = 15.0 Hz, 1H, N-CH<sub>2</sub>H<sub>6</sub>, minor), 7.23-7.30 (m, 5H, 5 CHar., major and minor); <sup>13</sup>C NMR (CDCl<sub>3</sub>, 125.7 MHz) δ 20.7 (CH<sub>3</sub>-C=O, minor), 21.5 (CH<sub>3</sub>-C=O, major), 44.1 (N-CH<sub>2</sub>, minor), 44.4 (N-CH<sub>2</sub>, major), 59.2 (CH<sub>3</sub>-O-CH-C=O, major), 59.3 (CH<sub>3</sub>-O-CH-C=O, minor), 59.6 (CH<sub>3</sub>-O-CH-C-CF<sub>3</sub>, minor), 60.3 (CH<sub>3</sub>-O-CH-C-CF<sub>3</sub>, major), 80.6 (CH-C-CF<sub>3</sub>, minor), 80.8 (CH-C=O, major), 82.0 (CH-C=O, minor), 83.7 (CH-C-CF<sub>3</sub>, major), 90.1 (q, <sup>2</sup>J<sub>CF</sub> = 32.5 Hz, C-CF<sub>3</sub>, minor), 92.2 (q, <sup>2</sup>J<sub>CF</sub> = 32.0 Hz, C-CF<sub>3</sub>, major), 122.1 (q, <sup>1</sup>J<sub>CF</sub> = 288.0 Hz, CF<sub>3</sub>, major), 122.2 (q, <sup>1</sup>J<sub>CF</sub> = 286.0 Hz, CF<sub>3</sub>, minor), 127.7 (CHar., major), 127.9 (CHar., minor), 128.47 (CHar., minor), 128.52 (CHar., major), 128.54 (CHar., major), 129.3 (CHar., minor), 135.3 (C<sub>14</sub>var., minor), 135.5 (C<sub>14</sub>var., major), 168.37 (CH<sub>3</sub>-C=O, major), 168.38 (CH<sub>3</sub>-
C=O, minor), 171.2 (C=O, major), 172.7 (C=O, minor); HRMS (ESI+) *m/z* calcd for C₁₆H₁₈F₃NNaO₅[M+Na]⁺ 384.1035, found 384.1024.

(3R,4R)-1-benzyl-5-oxo-2-(trifluoromethyl)pyrrolidine-2,3,4-triyl triacetate 4d. According to the general procedure, a solution of N,O-acetal 2d (500 mg, 1.72 mmol, dr = 89 :11), pyridine (625 µL, 7.75 mmol, 4.51 equiv), acetic anhydride (810 µL, 8.57 mmol, 5 equiv) and DMAP (62 mg, 0.51 mmol, 0.3 equiv) in CH₂Cl₂ (10 mL) was stirred 4h. Purification on silica gel (PE:EtOAc 4:1) afforded the O-acetyl N,O-acetal 4d (680 mg, 95%, dr = 89 :11) as a pale yellow oil; IR (film) νmax 702, 754, 975, 1039, 1227, 1369, 1434, 1760, 2945, 3029, 3497 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ-75.9 (s, 3F, CF₃, major), -78.7 (s, 3F, CF₃, minor); ¹H NMR (CDCl₃, 500 MHz) δ 1.54 (s, 3H, CH₃, minor), 1.81 (s, 3H, CH₃, major), 2.07 (s, 3H, CH₃, minor), 2.13 (s, 3H, CH₃, major), 2.16 (s, 3H, CH₃, minor), 2.19 (s, 3H, CH₃, major), 4.15 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, minor), 4.41 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, major), 4.75 (d, ²J = 15.5 Hz, 1H, N-CHₐHb, major), 5.15 (d, ²J = 15.0 Hz, 1H, N-CHₐHb, minor), 5.71 (d, ³J = 6.0 Hz, 1H, CH-C=O, minor), 5.77 (d, ³J = 6.0 Hz, 1H, CH-C-CF₃, minor), 5.78 (d, ³J = 7.0 Hz, 1H, CH-C=O, major), 6.41 (d, ³J = 6.0 Hz, 1H, CH-C-CF₃, major), 7.25-7.32 (m, 5H, 5 CHar., major and minor); ¹³C NMR (CDCl₃, 125.7 MHz) δ 20.5 (CH₃, major), 20.6 (CH₃, minor), 20.7 (CH₃, major), 21.1 (CH₃, major), 44.6 (N-CH₂, minor), 45.9 (N-CH₂, major), 69.5 (CH-C-CF₃, minor), 71.2 (CH-C=O, major), 72.6 (CH-C-CF₃, major), 73.7 (CH-C=O, minor), 91.0 (q, ²JCF = 32.0 Hz, C-CF₃, major), 121.9 (q, ¹JCF = 286.5 Hz, CF₃, minor), 123.9 (q, ¹JCF = 288.0 Hz, CF₃, major), 128.0 (CHar., major), 128.2 (CHar., minor), 128.63 (CHar., major), 128.66 (CHar., minor), 128.9 (CHar., major), 129.4 (CHar., minor), 134.8 (CIVar., minor), 135.0 (CIVar., major), 168.1 (C=O, major), 168.2 (O-C=O, minor), 168.5 (O-C=O, major), 168.6 (O-C=O, minor), 169.3 (C=O, minor), 169.8 (O-C=O, major), 169.9 (O-C=O, major), 170.0 (O-C=O, minor); HRMS (ESI+) *m/z* calcd for C₁₈H₁₈F₃NNaO₇[M+Na]⁺ 440.0933, found 440.0925.

**General procedures for the addition of nitriles on O-acetyl-N,O-acetal 4a-d.**
**General procedure C (with nitrile as solvent):** To a solution of *O*-acetyl-*N*,*O*-acetal **4a-d** in nitrile was slowly added, at rt under Ar, BF<sub>3</sub>.OEt<sub>2</sub> (3 equiv). After stirring of the reaction mixture at room temperature (with acetals **4a,b**) or at reflux (with acetals **4c,d**) (reaction monitored by TLC and <sup>19</sup>F NMR), the reaction was quenched with a sat. aq. sol. of NaHCO<sub>3</sub> and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (MgSO<sub>4</sub>) and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel (PE:EtOAc).

**General procedure D (using 10 equivalents of nitrile in dichloromethane):** To a solution of *O*-acetyl-*N*,*O*-acetal **4a** and nitrile (10 equiv) in dichloromethane was slowly added, at rt under Ar, BF<sub>3</sub>.OEt<sub>2</sub> (3 equiv). After stirring at room temperature (reaction monitored by TLC and <sup>19</sup>F NMR), the reaction was quenched with a sat. aq. sol. of NaHCO<sub>3</sub> and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (MgSO<sub>4</sub>) and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel (PE:EtOAc).

(3aR,6R,6aS)-4-benzyl-6-(benzyloxy)-2-methyl-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 5a. According to the general procedure C, a solution of *N*,*O*-acetal **4a** (100 mg, 0.19 mmol) and BF<sub>3</sub>.OEt<sub>2</sub> (72 µL, 0.59 mmol, 3 equiv) in acetonitrile (4 mL) was stirred 31h at rt. Purification on silica gel (PE:EtOAc 3:1) afforded the oxazoline **5a** (60 mg, 76%) as a colourless oil; [α]<sub>D<sup>20</sup></sub> +50 (c 0.40, CHCl<sub>3</sub>); IR (film) ν<sub>max</sub> 704, 738, 978, 1027, 1113, 1195, 1268, 1338, 1402, 1659, 1721, 2927, 3060, 3329 cm<sup>-1</sup>; <sup>19</sup>F NMR (CDCl<sub>3</sub>, 235.5 MHz) δ -77.2 (s, 3F, CF<sub>3</sub>); <sup>1</sup>H NMR (CDCl<sub>3</sub>, 600 MHz) δ 2.07 (s, 3H, CH<sub>3</sub>), 4.19 (d, <sup>3</sup>J = 1.5 Hz, 1H, CH-C=O), 4.56 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.78 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.91 (d, <sup>2</sup>J = 12.0 Hz, 1H, O-CH<sub>a</sub>H<sub>b</sub>), 4.92 (d, <sup>3</sup>J = 1.5 Hz, 1H, CH-C-CF<sub>3</sub>), 5.03 (d, <sup>2</sup>J = 12.0 Hz, 1H, O-CH<sub>a</sub>H<sub>b</sub>), 7.26-7.45 (m, 10H, 10 CHar.); <sup>13</sup>C NMR (CDCl<sub>3</sub>, 151 MHz) δ 14.3 (CH<sub>3</sub>), 45.7 (N-CH<sub>2</sub>), 72.9 (O-CH<sub>2</sub>), 77.6 (CH-C=O), 82.4 (CH-C-CF<sub>3</sub>), 92.4 (q, <sup>2</sup>J<sub>CF</sub> = 33.0 Hz, C-
CF₃), 122.8 (q, ¹JCF = 283.5 Hz, CF₃), 127.5 (CHar.), 127.9 (CHar.), 128.30 (CHar.), 128.36 (CHar.), 128.39 (CHar.), 128.7 (CHar.), 136.1 (CIVar., N-Bn), 136.6 (CIVar., O-Bn), 171.1 (C=N), 171.8 (C=O); HRMS (ESI⁺): m/z calcd for C₂₁H₁₉F₃N₂NaO₃ [M+Na]⁺ 427.1245, found 427.1241.

(3aR,6R,6aS)-6-(benzyloxy)-4-(4-methoxybenzyl)-2-methyl-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 5b. According to the general procedure C, a solution of N,O-acetal 4b (250 mg, 0.46 mmol) and BF₃.OEt₂ (170 µL, 1.38 mmol, 3 equiv) in acetonitrile (6 mL) was stirred 28h at rt. Purification on silica gel (PE:EtOAc 2:1) afforded the oxazoline 5b (140 mg, 70%) as a yellow oil; [α]D²⁰ +35 (c 0.50, CHCl₃); IR (film) vmax 702, 978, 1029, 1111, 1176, 1247, 1303, 1338, 1400, 1513, 1695, 1722, 2935, 3418 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -77.2 (s, 3F, CF₃); ¹H NMR (CDCl₃, 500 MHz) δ 2.04 (s, 3H, CH₃), 3.78 (s, 3H, O-CH₃), 4.13 (d, ³J = 1.0 Hz, 1H, CH-C=O), 4.47 (d, ²J = 15.0 Hz, 1H, N-CHₐHb), 4.67 (d, ²J = 15.0 Hz, 1H, N-CHₐHb), 4.86 (s, 1H, CH-C-CF₃), 4.87 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 4.99 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 6.83 (m, 2H, 2 CHar.), 7.27 (m, 2H, 2 CHar.), 7.31-7.42 (m, 5H, 5 CHar.); ¹³C NMR (CDCl₃, 125.7 MHz) δ 14.3 (CH₃), 45.3 (N-CH₂), 55.3 (O-CH₃), 72.9 (O-CH₂), 77.6 (CH-C=O), 82.5 (CH-C-CF₃), 92.4 (q, ²JCF = 33.0 Hz, C-CF₃), 113.7 (CHar.), 122.9 (q, ¹JCF = 283.5 Hz, CF₃), 128.3 (CHar.), 128.32 (CIVar. N-CH₂-Ph), 128.4 (CHar.), 128.7 (CHar.), 129.6 (CHar.), 136.6 (CIVar. O-Bn), 159.0 (CIVar. CH₃-O-Ph), 170.9 (C=O), 171.7 (C=N); HRMS (ESI⁺) m/z calcd for C₂₂H₂₁F₃N₂NaO₄ [M+Na]⁺ 457.1351, found 457.1342.

(3aR,6R,6aS)-4-benzyl-6-(benzyloxy)-2-isopropyl-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 5c. According to the general procedure C, a solution of N,O-acetal 4a (250 mg, 0.49 mmol) and BF₃.OEt₂ (180 µL, 1.46 mmol, 3 equiv) in isobutyronitrile (4 mL) was stirred 48h at rt. Purification on silica gel (PE:EtOAc 9:1) afforded the oxazoline 5c (175 mg, 83%) as a colourless oil; [α]D²⁰ +18 (c 0.50, CHCl₃); IR (film) vmax 700, 979, 1028,
1189, 1330, 1400, 1650, 1723, 2879, 2979, 3033, 3426 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -77.2 (s, 3F, CF₃); ¹H NMR (CDCl₃, 500 MHz) δ 1.11 (d, ³J = 7.0 Hz, 3H, CH₃), 1.13 (d, ³J = 7.0 Hz, 3H, CH₃), 2.56 (hept, ³J = 7.0 Hz, 1H, CH(CH₃)₂), 4.13 (d, ³J = 1.5 Hz, 1H, CH-C=O), 4.46 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.67 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.87 (d, ³J = 1.5 Hz, 1H, CH-C-CF₃), 4.88 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 5.00 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 7.23-7.35 (m, 6H, 6 CHar.), 7.37-7.43 (m, 4H, 4 CHar.); ¹³C NMR (CDCl₃, 125.7 MHz) δ 19.2 (CH₃), 19.3 (CH₃), 28.5 (CH(CH₃)₂), 45.7 (N-CH₂), 72.9 (O-CH₂), 77.8 (CH-C=O), 82.1 (CH-C-CF₃), 92.4 (q, ²J₄F = 33.0 Hz, C-CF₃), 123.0 (q, ¹J₄F = 283.5 Hz, CF₃), 127.5 (CHar.), 128.2 (CHar.), 128.3 (CHar.), 128.33 (CHar.), 128.7 (CHar.), 136.4 (CIVar. N-Bn), 136.7 (CIVarom. O-Bn), 170.9 (C=O), 178.5 (C=N); HRMS (ESI+) *m/z* calcd for C₂₃H₂₃F₃N₂NaO₃ [M+Na]⁺ 455.1558, found 455.1552.

(3aR,6R,6aS)-4-benzyl-6-(benzyloxy)-2-(tert-butyl)-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 5d. According to the general procedure C, a solution of N,O-acetal 4a (300 mg, 0.58 mmol) and BF₃.OEt₂ (216 µL, 1.75 mmol, 3 equiv) in trimethylacetonitrile (4 mL) was stirred 41h at rt. Purification on silica gel (PE:EtOAc 10:1) afforded the oxazoline 5d (199 mg, 76%) as a yellow oil; [α]D²⁰ +2 (c 0.50, CHCl₃); IR (film) νmax 699, 980, 1028, 1106, 1197, 1338, 1400, 1643, 1723, 2875, 2976, 3034, 3423 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -77.2 (s, 3F, CF₃); ¹H NMR (CDCl₃, 500 MHz) δ 1.11 (s, 9H, 3 CH₃), 4.10 (d, ³J = 1.5 Hz, 1H, CH-C=O), 4.61 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.71 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.85 (d, ³J = 1.5 Hz, 1H, CH-C-CF₃), 4.87 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 5.00 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 7.21-7.42 (m, 10H, 10 CHar.); ¹³C NMR (CDCl₃, 125.7 MHz) δ 27.4 (CH₃), 33.8 (CIV), 45.7 (N-CH₂), 72.9 (O-CH₂), 78.0 (CH-C=O), 82.2 (CH-C-CF₃), 92.6 (q, ²J₄F = 33.0 Hz, C-CF₃), 123.1 (q, ¹J₄F = 283.5 Hz, CF₃), 127.5 (CHar.), 128.31 (CHar.), 128.32 (CHar.), 128.7 (CHar.), 136.5 (CIVar., N-Bn), 136.7 (CIVar., O-Bn), 170.9
(C=O), 180.5 (C=N); HRMS (ESI+) *m/z* calcd for C₂₄H₂₅F₃N₂NaO₃ [M+Na]⁺ 469.1715, found
469.1714.

(3aR,6R,6aS)-4-benzyl-6-(benzyloxy)-2-phenyl-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 5e. According to the general procedure C, a solution of N,O-acetal 4a (200 mg, 0.39 mmol) and BF₃.OEt₂ (150 µL, 1.22 mmol, 3.1 equiv) in benzonitrile (5 mL) was stirred 40h at rt. Purification on silica gel (PE:EtOAc 10:1) afforded the oxazoline 5e (150 mg, 83%) as a colourless oil; [α]D²⁰ +72 (c 0.51, CHCl₃); IR (film) vmax 701, 735, 1027, 1121, 1197, 1349, 1452, 1496, 1581, 1640, 1724, 2926, 3033, 3065 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ-76.8 (s, 3F, CF₃); ¹H NMR (CDCl₃, 600 MHz) δ 4.27 (d, ³J = 1.5 Hz, 1H, CH-C=O), 4.71 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.73 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.92 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 5.05 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 5.07 (d, ³J = 1.5 Hz, 1H, CH-C-CF₃), 7.21-7.45 (m, 12H, 12 CHar.), 7.56 (t, ³J = 7.5 Hz, 1H, 1 CHar.), 7.87 (m, 2H, 2 CHar.); ¹³C NMR (CDCl₃, 151 MHz) δ 45.8 (N-CH₂), 73.0 (O-CH₂), 77.8 (CH-C=O), 82.5 (CH-C-CF₃), 92.7 (q, ²JCF = 33.0 Hz, C-CF₃), 123.1 (q, ¹JCF= 283.5 Hz, CF₃), 125.4 (CIVar. N=C-Ph), 127.5 (CHar.), 128.2 (CHar.), 128.36 (CHar.), 128.38 (CHar.), 128.4 (CHar.), 128.72 (CHar.), 128.73 (CHar.), 129.3 (CHar.), 133.4 (CHar.), 136.3 (CIVar. N-Bn), 136.7 (CIVar. O-Bn), 169.2 (C=N), 170.9 (C=O); HRMS (ESI+) *m/z* calcd for C₂₆H₂₁F₃N₂NaO₃ [M+Na]⁺ 489.1402, found 489.1408.

(3aR,6R,6aS)-2,4-dibenzyl-6-(benzyloxy)-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 5f. According to the general procedure D, a solution of N,O-acetal 4a (150 mg, 0.29 mmol), benzyl cyanide (340 µL, 2.95 mmol, 10 equiv) and BF₃.OEt₂ (108 µL, 0.88 mmol, 3.05 equiv) in CH₂Cl₂ (3 mL) was stirred 48h at rt. Purification on silica gel (PE:EtOAc 7:1) afforded the oxazoline 5f (88 mg, 63%) as a pale yellow oil; [α]D²⁰ +14 (c 0.50, CHCl₃); IR (film) vmax 700, 980, 1026, 1110, 1175, 1337, 1398, 1455, 1497, 1653, 1724, 2928, 3033, 3064 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ-77.1 (s, 3F, CF₃); ¹H NMR (CDCl₃,
600 MHz) δ 3.62 (d, $^2J$= 15.0 Hz, 1H, N=C-CH$_a$H$_b$), 3.66 (d, $^2J$= 15.0 Hz, 1H, N=C-CH$_a$H$_b$), 4.07 (d, $^3J$= 1.5 Hz, 1H, CH-C=O), 4.62 (d, $^2J$= 15.5 Hz, 1H, N-CH$_a$H$_b$), 4.70 (d, $^2J$= 15.5 Hz, 1H, N-CH$_a$H$_b$), 4.83 (d, $^2J$= 12.0 Hz, 1H, O-CH$_a$H$_b$), 4.90 (d, $^3J$= 1.5 Hz, 1H, CH-C-CF$_3$), 4.96 (d, $^2J$= 12.0 Hz, 1H, O-CH$_a$H$_b$), 7.15 (m, 2H, 2 CHar.), 7.27-7.37 (m, 13H, 13 CHar.); $^{13}$C NMR (CDCl$_3$, 151 MHz) δ 34.8 (CH$_2$-C=N), 45.8 (N-CH$_2$), 72.9 (O-CH$_2$), 77.6 (CH-C=O), 82.6 (CH-C-CF$_3$), 92.4 (q, $^2J_{CF}$= 33.0 Hz, C-CF$_3$), 122.9 (q, $^1J_{CF}$= 283.5 Hz, CF$_3$), 127.6 (CHar.), 127.7 (CHar.), 128.1 (CHar.), 128.3 (CHar.), 128.35 (CHar.), 128.4 (CHar.), 128.7 (CHar.), 128.9 (CHar.), 129.0 (CHar.), 133.1 (C$_{IVar.}$ N=C-Bn), 136.1 (C$_{IVar.}$ N-Bn), 136.5 (C$_{IVar.}$ O-Bn), 170.9 (C=O), 172.8 (C=N); HRMS (ESI$^+$) m/z calcd for C$_{27}$H$_{23}$F$_3$N$_2$NaO$_3$ [M+Na]$^+$ 503.1558, found 503.1550.

(3aR,6R,6aS)-4-benzyl-6-(benzyloxy)-2-((E)-prop-1-en-1-yl)-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one 5g. According to the general procedure C, a solution of N,O-acetal 4a (205 mg, 0.40 mmol) and BF$_3$·OEt$_2$ (149 µL, 1.20 mmol, 3 equiv) in allyl cyanide (3 mL) was stirred 21h at rt. Purification of the residue by chromatography (PE:EtOAc 6:1) afforded the oxazoline 5g (152 mg, 89%) as a colourless oil; [α]$_D^{20}$ +22 (c 0.50; CHCl$_3$); IR (film) ν$_{max}$ 701, 736, 973, 1031, 1113, 1191, 1351, 1398, 1605, 1670, 1722, 2923, 3034, 3422 cm$^{-1}$; $^{19}$F NMR (CDCl$_3$, 235.5 MHz) δ -77.1 (s, 3F, CF$_3$); $^{1}$H NMR (CDCl$_3$, 500 MHz) δ 1.92 (dd, $^3J$= 7.0 Hz, $^4J$= 1.5 Hz, 3H, CH$_3$), 4.18 (s, 1H, CH-C=O), 4.55 (d, $^2J$= 15.5 Hz, 1H, N-CH$_a$H$_b$), 4.75 (d, $^2J$= 15.5 Hz, 1H, N-CH$_a$H$_b$), 4.89 (d, $^2J$= 12.0 Hz, 1H, O-CH$_a$H$_b$), 4.91 (s, 1H, CH-C-CF$_3$), 5.02 (d, $^2J$= 12.0 Hz, 1H, O-CH$_a$H$_b$), 5.95 (dq, $^3J$= 16.0 Hz, $^4J$= 1.5 Hz, 1H, CH=CH-CH$_3$), 6.81 (dq, $^3J$= 16.0 Hz, $^3J$= 7.0 Hz, 1H, CH=CH-CH$_3$), 7.24-7.35 (m, 6H, 6 CHar.), 7.40 (m, 4H, 4 CHar.); $^{13}$C NMR (CDCl$_3$, 125.7 MHz) δ 18.8 (CH$_3$), 45.8 (N-CH$_2$), 72.9 (O-CH$_2$), 77.8 (CH-C=O), 81.9 (CH-C-CF$_3$), 92.3 (q, $^2J_{CF}$= 33.0 Hz, C-CF$_3$), 117.4 (CH=CH-CH$_3$), 123.0 (q, $^1J_{CF}$= 283.5 Hz, CF$_3$), 127.4 (CHar.), 128.0 (CHar.), 128.31 (CHar.), 128.34 (CHar.), 128.4 (CHar.), 128.7 (CHar.), 136.2 (C$_{IVar.}$ N-Bn), 136.7
(C<sub>IVar</sub>. O-Bn), 145.3 (CH<sub>3</sub>-CH<sub>3</sub>), 168.3 (C=N), 171.1 (C=O); HRMS (ESI<sup>+</sup>) *m/z* calcd for C<sub>23</sub>H<sub>21</sub>F<sub>3</sub>N<sub>2</sub>NaO<sub>3</sub> [M+Na]<sup>+</sup> 453.1402, found 453.1408.

(3aR,6R,6aR)-4-benzyl-6-methoxy-2-methyl-3a-(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one **5h** and (2R,3S,4R)-N-1-benzyl-3,4-dimethoxy-5-oxo-2-(trifluoromethyl) pyrrolidin-2-yl)acetamide cis-7a. According to the general procedure C, a solution of N,O-acetal **4c** (160 mg, 0.44 mmol) and BF<sub>3</sub>.OEt<sub>2</sub> (165 µL, 1.34 mmol, 3 equiv) in acetonitrile (4 mL) was stirred 1h30 at reflux. Purification of the residue (mixture of **5h**:cis-7a = 87:13) on silica gel (PE:EtOAc from 4:1 to 3:2) afforded the oxazoline **5h** (98 mg, 68%) followed by the amide cis-7a (21 mg, 13%). oxazoline **5h**: white solid; mp 66°C; [α]<sub>D<sup>20</sup></sub> +5 (c 0.41, CHCl<sub>3</sub>); IR (neat) ν<sub>max</sub> 696, 709, 727, 963, 1016, 1171, 1192, 1314, 1651, 1724, 2925 cm<sup>-1</sup>; <sup>19</sup>F NMR (CDCl<sub>3</sub>, 235.5 MHz) δ -77.3 (s, 3F, CF<sub>3</sub>); <sup>1</sup>H NMR (CDCl<sub>3</sub>, 500 MHz) δ 2.06 (s, 3H, N=C-CH<sub>3</sub>), 3.66 (s, 3H, O-CH<sub>3</sub>), 3.98 (d, <sup>3</sup>J = 1.0 Hz, 1H, CH-C=O), 4.50 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.75 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.84 (d, <sup>3</sup>J = 1.0 Hz, 1H, CH-C-CF<sub>3</sub>), 7.22-7.31 (m, 5H, 5 CHar.); <sup>13</sup>C NMR (CDCl<sub>3</sub>, 125.7 MHz) δ 14.3 (N=C-CH<sub>3</sub>), 45.7 (N-CH<sub>2</sub>), 59.2 (CH<sub>3</sub>), 80.6 (CH-C=O), 81.9 (CH-C-CF<sub>3</sub>), 92.4 (q, <sup>2</sup>J<sub>CF</sub> = 33.0 Hz, C-CF<sub>3</sub>), 122.8 (q, <sup>1</sup>J<sub>CF</sub> = 283.5 Hz, CF<sub>3</sub>), 127.5 (CHar.), 127.9 (CHar.), 128.4 (CHar.), 136.0 (C<sub>IVar</sub>. N-Bn), 170.8 (C=O), 171.8 (C=N); HRMS (ESI<sup>+</sup>) *m/z* calcd for C<sub>15</sub>H<sub>15</sub>F<sub>3</sub>N<sub>2</sub>NaO<sub>3</sub> [M+Na]<sup>+</sup> 351.0932, found 351.0925. amide cis-7a: Pale yellow solid; mp 148°C; [α]<sub>D<sup>20</sup></sub> +44 (c 0.41, CHCl<sub>3</sub>); IR (neat) ν<sub>max</sub> 696, 720, 1085, 1115, 1155, 1179, 1263, 1307, 1696, 2923, 3051, 3210 cm<sup>-1</sup>; <sup>19</sup>F NMR (CDCl<sub>3</sub>, 235.5 MHz) δ -77.5 (s, 3F, CF<sub>3</sub>); <sup>1</sup>H NMR (CDCl<sub>3</sub>, 600 MHz) δ 1.66 (s, 3H, H<sub>3</sub>C-C=O), 3.47 (s, 3H, H<sub>3</sub>C-O-CH-C-CF<sub>3</sub>), 3.74 (s, H<sub>3</sub>C-O-CH-C=O), 3.93 (d, <sup>3</sup>J = 6.0 Hz, 1H, CH-C-CF<sub>3</sub>), 4.23 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.40 (d, <sup>3</sup>J = 6.0 Hz, 1H, CH-C=O), 4.76 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 5.77 (s, 1H, NH), 7.21-7.27 (m, 5H, 5 CHar.); <sup>13</sup>C NMR (CDCl<sub>3</sub>, 151 MHz) δ 23.5 (H<sub>3</sub>C-C=O), 44.3 (N-CH<sub>2</sub>), 59.22 (H<sub>3</sub>C-O-CH-C-CF<sub>3</sub>), 59.23 (H<sub>3</sub>C-O-CH-C=O), 76.1 (q, <sup>2</sup>J<sub>CF</sub> = 30.0 Hz, C-CF<sub>3</sub>), 80.9 (CH-C-CF<sub>3</sub>), 82.2 (CH-C=O), 123.5 (q, <sup>1</sup>J<sub>CF</sub> =
287.0 Hz, CF₃), 127.5 (CHar.), 128.4 (CHar.), 128.5 (CHar.), 136.1 (C<sub>IVar.</sub> N-Bn), 170.7 (H₃C-<sup>C</sup>=O), 172.9 (C=O); HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₉F₃N₂NaO₄ [M+Na]⁺ 383.1195, found 383.1189. An analytical sample of *cis*-7a was crystallized from CHCl₃/pentane.

(3S,4R)-2-acetamido-1-benzyl-5-oxo-2-(trifluoromethyl)pyrrolidine-3,4-diyl diacetate 7b.
According to the general procedure C, a solution of N,O-acetal 4d (130 mg, 0.31 mmol) and BF₃.OEt₂ (115 µL, 0.93 mmol, 3 equiv) in acetonitrile (5 mL) was stirred 6h at reflux.
Purification of the residue (dr = 13 :87) on silica gel (PE:EtOAc 1 :1) afforded the amide trans-7b (8 mg, 6%) followed by the amide cis-7b (82 mg, 63%). *amide trans-7b:* White solid ; mp 196°C; [α]<sub>D</sub>²⁰⁻⁴ (c 0.50 ; CH₂Cl₂); IR (KBr) νmax 702, 1070, 1184, 1231, 1370, 1554, 1716, 1761, 2939, 3045, 3214, 3283 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -75.0 (s, 3F, CF₃); ¹H NMR (CDCl₃, 500 MHz) δ 1.87 (s, 3H, CH₃-(C=O)-NH), 2.11 (s, 3H, CH₃-(C=O)-O-CH-C=O), 2.18 (s, 3H, CH₃-(C=O)-O-CH-C-CF₃), 4.48 (d, ²J = 15.5 Hz, 1H, N-CHₐH₇), 4.51 (d, ²J = 15.5 Hz, 1H, N-CHₐH₇), 5.82 (d, ³J = 7.5 Hz, 1H, CH-C=O), 6.08 (s, 1H, NH), 6.55 (d, ³J = 7.5 Hz, 1H, CH-C-CF₃), 7.23-7.30 (m, 5H, 5 CHar.); ¹³C NMR (CDCl₃, 125.7 MHz) δ 20.6 (CH₃-(C=O)-O-CH-C-CF₃), 20.8 (CH₃-(C=O)-O-CH-C=O), 23.7 (CH₃-(C=O)-NH), 44.7 (N-CH₂), 70.8 (CH-C=O), 73.0 (CH-C-CF₃), 76.5 (q, ²J<sub>CF</sub> = 29.5 Hz, C-CF₃), 122.9 (q, ¹J<sub>CF</sub> = 289.0 Hz, CF₃), 127.7 (CHar.), 128.1 (CHar.), 128.6 (CHar.), 135.6 (C<sub>IVar.</sub> N-Bn), 168.1 (C=O), 170.10 (O=C-O-CH-C=O), 170.12 (O=C-CH-C-CF₃), 170.8 (O=C-NH); HRMS (ESI⁺) *m/z* calcd for C₁₈H₁₉F₃N₂NaO₆ [M+Na]⁺ 439.1093, found 439.1099. *amide cis-7b:* White solid; mp 199°C; [α]<sub>D</sub>²⁰⁺³³ (c 0.51, CH₂Cl₂); IR (KBr) νmax 707, 1020, 1089, 1183, 1234, 1303, 1370, 1414, 1548, 1709, 1759, 3056, 3309 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -77.8 (s, 3F, CF₃); ¹H NMR (CDCl₃, 500 MHz) δ 1.64 (s, 3H, CH₃-(C=O)-NH), 2.06 (s, 3H, CH₃-(C=O)-O-CH-C-CF₃), 2.15 (s, 3H, CH₃-(C=O)-O-CH-C=O), 4.23 (d, ²J = 15.5 Hz, 1H, N-CHₐH₇), 4.90 (d, ²J = 15.5 Hz, 1H, N-CHₐH₇), 5.75 (d, ³J = 6.0 Hz, 1H, CH-C-CF₃), 5.82 (s, 1H, NH), 5.85 (d, ³J = 6.0 Hz, 1H, CH-C=O), 7.26-7.31 (m, 5H, 5 CHarom.); ¹³C NMR (CDCl₃, 125.7 MHz) δ
20.6 (CH₃-(C=O)-O-CH-C-CF₃), 20.7 (CH₃-(C=O)-O-CH-C=O), 23.1 (CH₃-(C=O)-NH), 44.6 (N-CH₂), 70.0 (CH-C-CF₃), 74.2 (CH-C=O), 75.6 (q, ²J₄F = 30.5 Hz, C-CF₃), 123.2 (q, ¹J₄F = 289.0 Hz, CF₃), 127.9 (CHar.), 128.5 (CHar.), 128.6 (CHar.), 135.5 (C₇Var. N-Bn), 169.1 (O=C-CH-C-CF₃), 169.4 (C=O), 170.1 (O=C-O-CH-C=O), 170.5 (O=C-NH); HRMS (ESI⁺) m/z calcd for C₁₈H₁₉F₃N₂NaO₆ [M+Na]⁺ 439.1093, found 439.1097. An analytical sample of cis-7b was crystallized from hexane/CH₂Cl₂.

**General procedures for the synthesis of amides 6a-j and amine 8.**

**General procedure E (acid hydrolysis of oxazolines 5a-f, h):** A solution of oxazoline 5a-f, h in MeOH and 6N aq. HCl (1:1 mixture) was stirred at room temperature (synthesis of amides 6) or at 60°C (synthesis of amine 8). After completion of the reaction (reaction monitored by TLC and ¹⁹F NMR), the mixture was neutralized with solid NaHCO₃ and extracted five times with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel (PE:EtOAc).

**General procedure F (reaction sequence “addition of nitrile – acid hydrolysis” on N,O-acetal 4a or 2d):** To a solution of α-trifluoromethylated *N*,*O*-acetal **4a** or **2d** in nitrile or a solution of α-trifluoromethylated *O*-acetyl-*N*,*O*-acetal **4a** and nitrile (10 equiv) in dichloromethane was slowly added, at rt under Ar, BF₃.OEt₂ (3 equiv). After stirring at room temperature (with **4a**) or at reflux (with **2d**) (reaction monitored by TLC and ¹⁹F NMR), the reaction was quenched with a sat. aq. sol. of NaHCO₃ and extracted thrice with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated under reduced pressure. The resulting residue was then dissolved in MeOH and 6N aq. HCl (1:1 mixture) at room temperature (reaction monitored by TLC and ¹⁹F NMR). The reaction mixture was neutralized with solid NaHCO₃ and extracted five times with EtOAc. The combined
organic layers were washed with brine, dried ($MgSO_4$) and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel (PE:EtOAc).

N-((2R,3S,4R)-1-benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)acetamide 6a. From 5a: According to the general procedure E, a solution of oxazoline 5a (70 mg, 0.38 mmol) in MeOH and 6N aq. HCl (8 mL) was stirred 40min at rt. Purification on silica gel (PE:EtOAc 1:1) afforded the hydroxylamide 6a (68 mg, 93%) as a white solid. From 4a: According to the general procedure F, a solution of *N*,*O*-acetal 4a (2.5 g, 4.87 mmol) and $BF_3.OEt_2$ (1.80 µL, 14.58 mmol, 3 equiv) in acetonitrile (40 mL) was stirred 28h at rt. A solution of the resulting residue in MeOH and 6N aq. HCl (12 mL) was stirred 1h at rt. Purification on silica gel (PE:EtOAc 1:1) afforded the hydroxylamide 6a (1.40 g, 68%) as a white solid; mp 141°C; [α]$_D^{20}$ +17 (c 0.50, $CH_2Cl_2$); IR (KBr) ν$_{max}$ 702, 751, 1016, 1118, 1168, 1297, 1573, 1681, 1714, 2930, 3094, 3290 cm$^{-1}$; $^{19}$F NMR ($CDCl_3$ neutralized on basic $Al_2O_3$, 235.5 MHz) δ -77.4 (s, 3F, $CF_3$); $^{1}$H NMR ($CDCl_3$ neutralized on basic $Al_2O_3$, 600 MHz) δ 1.40 (s, 3H, $CH_3$), 2.99 (d, $^{3}J$= 11.0 Hz, 1H, OH), 3.97 (d, $^{2}J$= 15.5 Hz, 1H, N-$CH_aH_b$), 4.46 (dd, $^{3}J$= 11.0 Hz, $^{3}J$=6.0 Hz, 1H, CH-C-$CF_3$), 4.64 (d, $^{3}J$= 6.0 Hz, 1H, CH-C=O), 4.92 (d, $^{2}J$= 12.0 Hz, 1H, O-$CH_aH_b$), 5.11 (d, $^{2}J$= 12.0 Hz, 1H, O-$CH_aH_b$), 5.22 (d, $^{2}J$= 15.5 Hz, 1H, N-$CH_aH_b$), 5.80 (s, 1H, NH), 7.25-7.32 (m, 6H, 6 CHar.), 7.36 (t, $^{3}J$= 7.5 Hz, 2H, 2 CHar.), 7.45 (d, $^{3}J$= 7.5 Hz, 2H, 2 CHar.); $^{13}$C NMR ($CDCl_3$ neutralized on basic $Al_2O_3$, 151 MHz) δ 23.1 ($CH_3$), 44.1 (N-$CH_2$), 73.2 (O-$CH_2$), 74.6 ($CH$-C-$CF_3$), 76.7 (q, $^{2}J_{CF}$ = 29.5 Hz, $C$-$CF_3$), 80.7 ($CH$-C=O), 123.8 (q, $^{1}J_{CF}$ = 283.5 Hz, C-$C_{F_3}$), 128.0 (CHar.), 128.1 (CHar.), 128.2 (CHar.), 128.4 (CHar.), 128.6 (CHar.), 129.0 (CHar.), 136.3 ($C_{IVar.}$ N-Bn), 137.5 ($C_{IVar.}$ O-Bn), 171.8 (C=O), 172.9 (NH-C=O); HRMS (ESI$^+$) *m/z* calcd for $C_{21}H_{21}F_3N_2NaO_4$ [M+Na]$^+$ 445,1351, found 445.1351.

N-((2R,3S,4R)-4-(benzyloxy)-3-hydroxy-1-(4-methoxybenzyl)-5-oxo-2
(trifluoromethyl)pyrrolidin-2-yl)acetamide 6b. According to the general procedure E, a solution
of oxazoline 5b (110 mg, 0.25 mmol) in MeOH and 6N aq. HCl (10 mL) was stirred 3h30 at rt.
Purification on silica gel (PE:EtOAc 1:2) afforded the hydroxylamide **6b** (92 mg, 80%) as a white solid; mp 168°C; [α]D²⁰ +8 (c 0.50, CH₂Cl₂); IR (KBr) νmax 1025, 1109, 1177, 1253, 1301, 1514, 1675, 1711, 3102, 3234, 3297 cm⁻¹; ¹⁹F NMR (CDCl₃ neutralized on basic Al₂O₃, 235.5 MHz) δ-77.5 (s, 3F, CF₃); ¹H NMR (CDCl₃ neutralized on basic Al₂O₃, 500 MHz) δ 1.47 (s, 3H, CH₃), 2.94 (d, ³J = 11.0 Hz, 1H, OH), 3.76 (s, 3H, O-CH₃), 3.92 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.44 (dd, ³J = 11.0 Hz, ³J=6.0 Hz, 1H, CH-C-CF₃), 4.62 (d, ³J = 6.0 Hz, 1H, CH-C=O), 4.91 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.10 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.16 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 5.79 (s, 1H, NH), 6.83 (m, 2H, 2 CHar.), 7.18 (m, 2H, 2 CHar.), 7.30 (m, 1H, CHar.), 7.37 (m, 2H, 2 CHar.), 7.44 (m, 2H, 2 CHar.); ¹³C NMR (CDCl₃ neutralized on basic Al₂O₃, 125.7 MHz) δ 23.3 (CH₃), 43.5 (N-CH₂), 55.5 (O-CH₃), 73.2 (O-CH₂), 74.6 (CH-C-CF₃), 76.7 (q, ²JCF = 29.5 Hz, C-CF₃), 80.7 (CH-C=O), 114.3 (CHar.), 123.8 (q, ¹JCF = 287.5 Hz, CF₃), 128.1 (CHar.), 128.2 (CHar.), 128.4 (CIVar. N-CH₂-Ph), 128.6 (CHar.), 129.7 (CHar.), 137.5 (CIVar. O-Bn), 159.3 (CIVar. CH₃-O-Ph), 171.7 (C=O), 172.7 (NH-C=O); HRMS (ESI⁺) m/z calculated for C₂₂H₂₃F₃N₂NaO₅ [M+Na]⁺ 475.1457, found 475.1465.

N-((2R,3S,4R)-1-benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)isobutyramide **6c**. According to the general procedure E, a solution of oxazoline **5c** (125 mg, 0.29 mmol) in MeOH and 6N aq. HCl (10 mL) was stirred 4h at rt. Purification on silica gel (PE:EtOAc 3:1) afforded the hydroxylamide **6c** (111 mg, 85%) as a white solid; mp 127°C; [α]D²⁰ +25 (c 0.50, CH₂Cl₂); IR (KBr) νmax 700, 1109, 1182, 1230, 1295, 1551, 1667, 1707, 2975, 3067, 3282 cm⁻¹; ¹⁹F NMR (CDCl₃ neutralized on basic Al₂O₃, 235.5 MHz) δ -77.6 (s, 3F, CF₃); ¹H NMR (CDCl₃ neutralized on basic Al₂O₃, 500 MHz) δ 0.80 (d, ³J = 7.0 Hz, 3H, CH₃), 0.93 (d, ³J = 7.0 Hz, 3H, CH₃), 1.86 (hept, ³J = 7.0 Hz, 1H, CH(CH₃)₂), 2.97 (d, ³J = 10.5 Hz, 1H, OH), 4.08 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.49 (dd, ³J = 10.5 Hz, ³J = 6.0 Hz, 1H, CH-C-CF₃), 4.68 (d, ³J = 6.0 Hz, 1H, CH-C=O), 4.90 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.03 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 5.14 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.84 (s, 1H, NH), 7.24-7.31
(m, 6H, 6 CHar.), 7.36 (t, $^3J$ = 7.5 Hz, 2H, 2 CHar.), 7.45 (m, 2H, 2 CHar.); $^{13}$C (CDCl$_3$ neutralized on basic Al$_2$O$_3$, 125.7 MHz) $\delta$ 18.5 (CH$_3$), 19.5 (CH$_3$), 35.5 (CH(CH$_3$)$_2$), 44.2 (N-CH$_2$), 73.4 (O-CH$_2$), 74.6 (CH-C-CF$_3$), 76.6 (q, $^2J_{CF}$ = 29.5 Hz, C-CF$_3$), 81.0 (CH-C=O), 123.8 (q, $^1J_{CF}$ = 287.5 Hz, CF$_3$), 127.9 (CHar.), 128.0 (CHar.), 128.15 (CHar.), 128.2 (CHar.), 128.6 (CHar.), 128.8 (CHar.), 136.3 (CIVar. N-Bn), 136.7 (CIVar. O-Bn), 172.0 (C=O), 179.2 (NH-C=O); HRMS (ESI$^+$) m/z calcd for C$_{23}$H$_{25}$F$_3$N$_2$NaO$_4$ [M+Na]$^+$ 473.1664, found 473.1655.

N-((2R,3S,4R)-1-benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)pivalamide **6d**. According to the general procedure E, a solution of oxazoline **5d** (160 mg, 0.36 mmol) in MeOH and 6N aq. HCl (12 mL) was stirred 48h at rt. Purification on silica gel (PE:EtOAc 4:1) afforded the hydroxylamide **6d** (71 mg, 43%) as a colourless oil; [α]$_D^{20}$ +2 (c 0.50, CH$_2$Cl$_2$); IR (film) ν$_{max}$ 701, 739, 1113, 1168, 1301, 1404, 1453, 1521, 1710, 2967, 3034, 3451 cm$^{-1}$; $^{19}$F NMR (CDCl$_3$ neutralized on basic Al$_2$O$_3$, 235.5 MHz) $\delta$ -77.6 (s, 3F, CF$_3$); $^1$H NMR (CDCl$_3$ neutralized on basic Al$_2$O$_3$, 600 MHz) $\delta$ 0.92 (s, 9H, C(CH$_3$)$_3$), 2.89 (t, $^3J$ = 11.0 Hz, 1H, OH), 4.11 (d, $^2J$ = 15.5 Hz, 1H, N-CH$_a$H$_b$), 4.52 (dd, $^3J$ = 10.0 Hz, $^3J$=6.0 Hz, 1H, CH-C-CF$_3$), 4.72 (d, $^3J$ = 6.0 Hz, 1H, CH-C=O), 4.93 (d, $^2J$ = 11.5 Hz, 1H, O-CH$_a$H$_b$), 5.05 (d, $^2J$ = 15.5 Hz, 1H, N-CH$_a$H$_b$), 5.20 (d, $^2J$ = 11.5 Hz, 1H, O-CH$_a$H$_b$), 6.01 (s, 1H, NH), 7.26-7.46 (m, 10H, 10 CHar.); $^{13}$C NMR (CDCl$_3$ neutralized on basic Al$_2$O$_3$, 151 MHz) $\delta$ 27.0 (CH$_3$), 39.6 (C(CH$_3$)$_3$), 44.1 (N-CH$_2$), 73.4 (O-CH$_2$), 74.7 (CH-C-CF$_3$), 76.5 (q, $^2J_{CF}$ = 29.0 Hz, C-CF$_3$), 81.1 (CH-C=O), 123.9 (q, $^1J_{CF}$ = 283.5 Hz, CF$_3$), 127.9 (CHar.), 128.0 (CHar.), 128.2 (CHar.), 128.6 (CHar.), 128.8 (CHar.), 136.4 (CIVar. N-Bn), 137.7 (CIVar. O-Bn), 172.0 (C=O), 180.7 (NH-C=O); HRMS (ESI$^+$) m/z calcd for C$_{24}$H$_{27}$F$_3$N$_2$NaO$_4$ [M+Na]$^+$ 487.1821, found 487.1817.

N-((2R,3S,4R)-1-benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)benzamide **6e**. According to the general procedure E, a solution of oxazoline **5e** (168 mg, 0.36 mmol) in MeOH and 6N aq. HCl (12 mL) was stirred 46h at rt. Purification on silica gel (PE:EtOAc 3:1) afforded the hydroxylamide **6e** (120 mg, 69%) as a white solid; mp 74°C;
[α]D²⁰ +72 (c 0.40, CH₂Cl₂); IR (KBr) νmax 701, 1000, 1113, 1178, 1279, 1532, 1713, 2930, 3064, 3387 cm⁻¹; ¹⁹F NMR (CDCl₃ neutralized on basic Al₂O₃, 235.5 MHz) δ-77.4 (s, 3F, CF₃); ¹H NMR (CDCl₃ neutralized on basic Al₂O₃, 600 MHz) δ 3.10 (d, ³J = 10.5 Hz, 1H, OH), 4.07 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.58 (dd, ³J = 10.5 Hz, ³J = 6.0 Hz, 1H, CH-C-CF₃), 4.81 (d, ³J = 6.0 Hz, 1H, CH-C=O), 4.96 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.17 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.19 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 6.35 (s, 1H, NH), 6.91 (t, ³J = 7.5 Hz, 1H, CHar.), 7.05 (t, ³J = 7.5 Hz, 2H, 2 CHar.), 7.21 (t, ³J = 7.5 Hz, 3H, 3 CHar.), 7.29 (m, 5H, 5 CHar.), 7.38 (t, ³J = 7.5 Hz, 2H, 2 CHar.), 7.48 (m, 3H, 3 CHar.); ¹³C NMR (CDCl₃ neutralisé sur Al₂O₃ basique, 151 MHz) δ 44.3 (N-CH₂), 73.4 (O-CH₂), 74.8 (CH-C-CF₃), 77.2 (q, ²JCF = 29.0 Hz, C-CF₃), 80.9 (CH-C=O), 123.9 (q, ¹JCF = 287.5 Hz, CF₃), 127.0 (CHar.), 127.7 (CHar.), 128.0 (CHar.), 128.1 (CHar.), 128.2 (CHar.), 128.58 (CHar.), 128.61 (CHar.), 128.8 (CHar.), 131.8 (CIVar. NH-CO-Ph), 132.9 (CHar.), 135.9 (CIVar. N-Bn), 137.6 (CIVar. O-Bn), 168.8 (NH-C=O), 172.0 (C=O); HRMS (ESI⁺) m/z calcd for C₂₆H₂₃F₃N₂NaO₄ [M+Na]⁺ 507.1508, found 507.1516.

*N-((2R,3S,4R)-1-benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)-2-phenylacetamide 6f.* From **5f**: According to the general procedure E, a solution of oxazoline **5f** (90 mg, 0.19 mmol) in MeOH and 6N aq. HCl (8 mL) was stirred 4h at rt. Purification on silica gel (PE:EtOAc 2:1) afforded the hydroxylamide **6f** (88 mg, 94%) as a white solid. *From 4a:* According to the general procedure F, a solution of *N,O*-acetal **4a** (250 mg, 0.486 mmol), benzyl cyanide (560 µL, 4.85 mmol, 10 equiv) and BF₃.OEt₂ (180 µL, 1.46 mmol, 3 equiv) in dichloromethane (40 mL) was stirred 48h at rt. A solution of the resulting residue in MeOH and 6N aq. HCl (12 mL) was stirred 2h at rt. Purification on silica gel (PE:EtOAc 3:1) afforded the hydroxylamide **6f** (140 mg, 58%) as a white solid; mp 98°C; [α]D²⁰ +8 (c 0.50 ; CH₂Cl₂); IR (KBr) νmax 699, 1079, 1112, 1177, 1299, 1549, 1707, 2928, 3034, 3064, 3300, 3403 cm⁻¹; ¹⁹F NMR (CDCl₃ neutralized on basic Al₂O₃, 235.5 MHz) δ-77.9 (s, 3F, CF₃);
¹H NMR (CDCl₃ neutralized on basic Al₂O₃, 600 MHz) δ 2.87 (d, ³J = 10.5 Hz, 1H, OH), 2.96 (d, ²J = 16.5 Hz, 1H, CHₐHb-C=O), 3.06 (d, ²J = 16.5 Hz, 1H, CHₐHb-C=O), 4.00 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.47 (dd, ³J = 10.5 Hz, ³J = 6.0 Hz, 1H, CH-C-CF₃), 4.71 (d, ³J = 6.0 Hz, 1H, CH-C=O), 4.92 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.09 (d, ²J = 15.5 Hz, 1H, NCHaHb), 5.15 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.82 (s, 1H, NH), 6.93 (dd, ³J = 7.5 Hz, ⁴J = 2.0 Hz, 2H, 2 CHar.), 7.26-7.42 (m, 11H, 11 CHar.), 7.47 (d, ³J = 7.0 Hz, 2H, 2 CHar.); ¹³C NMR (CDCl₃ neutralized on basic Al₂O₃, 151 MHz) δ 43.1 (CH₂-CO-NH), 44.1 (N-CH₂), 73.3 (O-CH₂), 74.5 (CH-C-CF₃), 76.6 (q, ²JCF = 29.5 Hz, C-CF₃), 80.8 (CH-C=O), 123.6 (q, ¹JCF = 287.5 Hz, CF₃), 128.0 (CHar.), 128.05 (CHar.), 128.07 (CHar.), 128.2 (CHar.), 128.3 (CHar.), 128.6 (CHar.), 128.9 (CHar.), 129.3 (CHar.), 129.4 (CHar.), 132.8 (CIVar. O=C-Bn), 136.3 (CIVar. N-Bn), 137.5 (CIVar. O-Bn), 171.9 (NH-C=O), 173.3 (C=O); HRMS (ESI⁺) m/z calcd for C₂₇H₂₅F₃N₂NaO₄ [M+Na]⁺ 521.1664, found 521.1671.

N-((2R,3S,4R)-1-benzyl-3-hydroxy-4-methoxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)acetamide 6g. According to the general procedure E, a solution of oxazoline 5h (83 mg, 0.25 mmol) in MeOH and 6N aq. HCl (8 mL) was stirred 1h at rt. Purification on silica gel (PE:EtOAc 1:2) afforded the hydroxylamide 6g (80 mg, 92%) as a white solid; mp 181°C; [α]D²⁰ +91 (c 0.50, EtOAc); IR (neat) νmax 604, 663, 721, 971, 1117, 1129, 1169, 1274, 1403, 1678, 1697, 3326 cm⁻¹; ¹⁹F NMR (CD₃COCD₃, 235.5 MHz) δ -74.2 (s, 3F, CF₃); ¹H NMR (CD₃COCD₃, 600 MHz) δ 1.82 (s, 3H, O=C-CH₃), 3.65 (s, 3H, O-CH₃), 4.27 (d, ³J = 6.0 Hz, 1H, CH-C=O), 4.36 (dd, ³J = 7.5 Hz, ³J = 6.0 Hz, 1H, CH-C-CF₃), 4.41 (d, ²J = 16.0 Hz, 1H, N-CHₐHb), 4.47 (d, ²J = 16.0 Hz, 1H, N-CHₐHb), 5.09 (d, ³J = 7.5 Hz, 1H, OH), 7.23 (m, 1H, CHar.), 7.28 (d, ³J = 7.5 Hz, 4H, 4 CHar.), 7.86 (s, 1H, NH); ¹³C NMR (CD₃COCD₃, 151 MHz) δ 23.3 (O=C-CH₃), 44.8 (N-CH₂), 59.0 (O-CH₃), 74.1 (CH-C-CF₃), 77.6 (q, ²JCF = 29.0 Hz, C-CF₃), 84.3 (CH-C=O), 124.8 (q, ¹JCF = 283.5 Hz, CF₃), 127.9 (CHar.), 128.89 (CHar.), 128.91
(CHar.), 138.0 (C<sub>IV</sub>ar. N-Bn), 172.1 (O=C-CH<sub>3</sub>), 173.9 (C=O); HRMS (ESI<sup>+</sup>) *m/z* calcd for C<sub>15</sub>H<sub>17</sub>F<sub>3</sub>N<sub>2</sub>NaO<sub>4</sub> [M+Na]<sup>+</sup> 369.1038, found 369.1041.

*Methyl* 3-(((2R,3S,4R)-1-benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2(trifluoromethyl)pyrrolidin-2-yl)amino)-3-oxopropanoate **6h**. According to the general procedure F, a solution of N,O-acetal **4a** (250 mg, 0.49 mmol), methyl cyanoacetate (430 µL, 4.87 mmol, 10 equiv) and BF<sub>3</sub>.OEt<sub>2</sub> (180 µL, 1.46 mmol, 3 equiv) in CH<sub>2</sub>Cl<sub>2</sub> (4 mL) was stirred 28h at rt. A solution of the resulting residue in MeOH and 6N aq. HCl (12 mL) was stirred 1h at rt. Purification on silica gel (PE:EtOAc 2:1) afforded the hydroxylamide **6h** (125 mg, 54%) as a colourless oil; [α]<sub>D<sup>20</sup></sub> +24 (c 0.50, CH<sub>2</sub>Cl<sub>2</sub>); IR (film) ν<sub>max</sub> 701, 1019, 1081, 1113, 1171, 1271, 1353, 1407, 1442, 1556, 1720, 2953, 3066, 3310 cm<sup>-1</sup>; <sup>19</sup>F NMR (CDCl<sub>3</sub> neutralized on basic Al<sub>2</sub>O<sub>3</sub>, 235.5 MHz) δ-77.7 (s, 3F, CF<sub>3</sub>); <sup>1</sup>H NMR (CDCl<sub>3</sub> neutralized on basic Al<sub>2</sub>O<sub>3</sub>, 500 MHz) δ 2.37 (d, <sup>2</sup>J = 19.5 Hz, 1H, O=C-CH<sub>a</sub>H<sub>b</sub>), 2.85 (d, <sup>3</sup>J = 10.5 Hz, 1H, OH), 2.89 (d, <sup>2</sup>J = 19.5 Hz, 1H, O=C-CH<sub>a</sub>H<sub>b</sub>), 3.68 (s, 3H, CH<sub>3</sub>), 3.96 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 4.48 (dd, <sup>3</sup>J = 10.5 Hz, <sup>3</sup>J = 6.0 Hz, 1H, CH-C-CF<sub>3</sub>), 4.64 (d, <sup>3</sup>J = 6.0 Hz, 1H, CH-C=O), 4.92 (d, <sup>2</sup>J = 11.5 Hz, 1H, O-CH<sub>a</sub>H<sub>b</sub>), 5.12 (d, <sup>2</sup>J = 11.5 Hz, 1H, O-CH<sub>a</sub>H<sub>b</sub>), 5.26 (d, <sup>2</sup>J = 15.5 Hz, 1H, N-CH<sub>a</sub>H<sub>b</sub>), 7.23-7.31 (m, 6H, 6 CHar.), 7.36 (m, 2H, 2 CHar.), 7.45 (m, 2H, 2 CHar.), 8.64 (s, 1H, NH); <sup>13</sup>C NMR (CDCl<sub>3</sub> neutralized on basic Al<sub>2</sub>O<sub>3</sub>, 125.7 MHz) δ 38.9 (O=C-CH<sub>2</sub>), 44.1 (N-CH<sub>2</sub>), 52.9 (O-CH<sub>3</sub>), 73.3 (O-CH<sub>2</sub>), 74.4 (CH-C-CF<sub>3</sub>), 76.4 (q, <sup>2</sup>J<sub>CF</sub> = 29.5 Hz, C-CF<sub>3</sub>), 80.8 (CH-C=O), 123.8 (q, <sup>1</sup>J<sub>CF</sub> = 287.5 Hz, CF<sub>3</sub>), 127.7 (CHar.), 128.1 (CHar.), 128.2 (CHar.), 128.57 (CHar.), 128.59 (CHar.), 128.8 (CHar.), 136.1 (C<sub>IV</sub>ar. N-Bn), 137.5 (C<sub>IV</sub>ar. O-Bn), 167.2 (HN-C=O), 170.1 (O-C=O), 171.7 (C=O); HRMS (ESI<sup>+</sup>) *m/z* calcd for C<sub>23</sub>H<sub>23</sub>F<sub>3</sub>N<sub>2</sub>NaO<sub>6</sub> [M+Na]<sup>+</sup> 503.1406, found 503.1408.

*N-((2R,3S,4R)-1-benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)cinnamamide 6i*. According to the general procedure F, a solution of N,O-acetal **4a** (250 mg, 0.49 mmol), cinnamonitrile (610 µL, 4.86 mmol, 10 equiv) and BF<sub>3</sub>.OEt<sub>2</sub> (180 µL, 1.46 mmol,
3 equiv) in CH₂Cl₂ (4 mL) was stirred 48h at rt. A solution of the resulting residue in MeOH and 6N aq. HCl (12 mL) was stirred 30h at rt. Purification on silica gel (PE:EtOAc 3:1) afforded the hydroxylamide **6i** (78 mg, 31%) as a colourless oil; [α]D²⁰ +70 (c 0.50; CH₂Cl₂); IR (film) vmax 699, 976, 1110, 1169, 1216, 1349, 1549, 1627, 1710, 2929, 3063, 3302 cm⁻¹; ¹⁹F NMR (CDCl₃ neutralized on basic Al₂O₃, 235.5 MHz) δ -77.4 (s, 3F, CF₃); ¹H NMR (CDCl₃ neutralized on basic Al₂O₃, 600 MHz) δ 3.22 (d, ³J = 11.0 Hz, 1H, OH), 4.05 (d, ²J = 15.5 Hz, 1H, NCHₐHb), 4.54 (dd, ³J = 11.0 Hz, ³J = 6.0 Hz, 1H, CH-C-CF₃), 4.76 (d, ³J = 6.0 Hz, 1H, CH-C=O), 4.96 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.15 (d, ²J = 11.5 Hz, 1H, O-CHₐHb), 5.19 (d, ²J = 15.5 Hz, 1H,NCHₐHb), 5.77 (d, ³J = 15.5 Hz, 1H, O=C-CH=CH), 5.83 (s, 1H, NH), 7.05 (t, ³J = 7.5 Hz, 1H, CHar.), 7.19 (t, ³J = 7.5 Hz, 2H, 2 CHar.), 7.26 (d, ³J = 7.5 Hz, 1H, CHar.), 7.29-7.40 (m, 9H, 9 CHar.), 7.33 (d, ³J = 15.5 Hz, 1H, O=C-CH=CH), 7.46 (d, ³J = 7.5 Hz, 2H, 2 CHar.); ¹³C NMR (CDCl₃ neutralized on basic Al₂O₃, 151 MHz) δ 44.3 (N-CH₂), 73.3 (O-CH₂), 74.9 (CH-C-CF₃), 77.2 (q, ²JCF = 29.5 Hz, C-CF₃), 80.9 (CH-C=O), 117.9 (CH=CH-Ph), 123.8 (q, ¹JCF = 287.5 Hz, CF₃), 127.7 (CHar.), 128.1 (CHar.), 128.2 (CHar.), 128.25 (CHar.), 128.28 (CHar.), 128.6 (CHar.), 128.9 (CHar.), 129.1 (CHar.), 130.7 (CHar.), 133.8 (CIVar. HC=CH-Ph), 136.1 (CIVar. N-Bn), 137.5 (CIVar. O-Bn), 144.2 (CH=CH-Ph), 167.8 (NH-C=O), 172.0 (C=O); HRMS (ESI+) m/z calcd for C₂₈H₂₅F₃N₂NaO₄ [M+Na]⁺ 533.1664, found 533.1670.

*N-((2R,3S,4R)-1-benzyl-3,4-dihydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl)acetamide* **6j.** According to the general procedure F, a solution of *N,O*-acetal **2d** (250 mg, 0.86 mmol) and BF₃.OEt₂ (317 µL, 2.57 mmol, 3 equiv) in acetonitrile (6 mL) was stirred 2h30 at reflux. A solution of the resulting residue in MeOH and 6N aq. HCl (12 mL) was stirred 4h at rt. Purification on silica gel (EtOAc 100%) afforded the hydroxylamide **6j** (200 mg, 70%) as a white solid; mp 165°C; [α]D²⁰ +58 (c 0.50, MeOH); IR (KBr) vmax 1105, 1184, 1296, 1413, 1575, 1674, 1710, 2398, 3089, 3225, 3279, 3399 cm⁻¹; ¹⁹F NMR (CD₃OD, 235.5 MHz) δ -78.6
(s, 3F, CF₃); ¹H NMR (CD₃OD, 600 MHz) δ 1.74 (s, 3H, CH₃), 4.28 (d, ³J = 6.5 Hz, 1H, CH-C-CF₃), 4.32 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.55 (d, ³J = 6.5 Hz, 1H, CH-C=O), 4.62 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 7.21-7.27 (m, 5H, 5 CHar.); ¹³C NMR (CD₃OD, 151 MHz) δ 22.9 (CH₃), 45.5 (N-CH₂), 75.6 (CH-C-CF₃), 76.4 (CH-C=O), 78.1 (q, ²JCF = 29.0 Hz, C-CF₃), 125.0 (q, ¹JCF = 286.0 Hz, CF₃), 128.3 (CHar.), 129.1 (CHar.), 129.4 (CHar.), 137.5 (CIVar. N-Bn), 174.3 (NH-C=O), 176.8 (C=O); HRMS (ESI⁺) *m/z* calcd for C₁₄H₁₅F₃N₂NaO₄ [M+Na]⁺ 355.0882, found 355.0878.

(3R,4S,5R)-5-amino-1-benzyl-3-(benzyloxy)-4-hydroxy-5-(trifluoromethyl)pyrrolidin-2-one
**8. From 5a:** According to the general procedure E, a solution of oxazoline **5a** (100 mg, 0.25 mmol) in MeOH and 6N aq. HCl (10 mL) was stirred 29h at 60°C. Purification on silica gel (PE:EtOAc 2:1) afforded the hydroxylamine **8** (64 mg, 68%) as a colourless oil. *From 4a:* According to the general procedure F, a solution of N,O-acetal **4a** (200 mg, 0.39 mmol), BF₃.OEt₂ (145 µL, 1.17 mmol, 3 equiv) in MeCN (4 mL) was stirred 48h at rt. A solution of the resulting residue in MeOH and 6N aq. HCl (12 mL) was stirred 48h at 60°C. Purification on silica gel (PE:EtOAc 2:1) afforded the hydroxylamine **8** (80 mg, 54%) as a colourless oil; [α]D²⁰ +12 (c 0.41, CH₂Cl₂); IR (KBr) νmax 701, 746, 1110, 1165, 1264, 1415, 1609, 1700, 2931, 3033, 3402 cm⁻¹; ¹⁹F NMR (CDCl₃, 235.5 MHz) δ -78.4 (s, 3F, CF₃); ¹H NMR (CDCl₃, 500 MHz) δ 1.85 (br s, 2H, NH₂), 3.62 (br s, 1H, OH), 4.13 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 4.18 (d, ³J = 7.0 Hz, 1H, CH-C=O), 4.33 (d, ³J = 7.0 Hz, 1H, CH-C-CF₃), 4.84 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 5.01 (d, ²J = 15.5 Hz, 1H, N-CHₐHb), 5.07 (d, ²J = 12.0 Hz, 1H, O-CHₐHb), 7.26-7.34 (m, 8H, 8 CHar.), 7.41 (m, 2H, 2 CHar.); ¹³C NMR (CDCl₃, 125.7 MHz) δ 44.2 (N-CH₂), 72.4 (CH-C-CF₃), 73.1 (O-CH₂), 75.2 (q, ²JCF = 30.0 Hz, C-CF₃), 79.1 (CH-C=O), 124.2 (q, ¹JCF = 287.0 Hz, CF₃), 128.0 (CHar.), 128.1 (CHar.), 128.22 (CHar.), 128.23 (CHar.), 128.6 (CHar.), 128.8 (CHar.), 136.6 (CIVar. N-Bn), 137.3 (CIVar. O-Bn), 171.4 (C=O); HRMS (ESI⁺) *m/z* calcd for C₁₉H₁₉F₃N₂NaO₃ [M+Na]⁺ 403.1245, found 403.1247.
Acknowledgments

We gratefully acknowledged the “région Champagne-Ardenne” for financial support, CNRS, the Conseil Régional de Champagne-Ardenne and the EU-program FEDER for the facilities of the analytical platform (PlAneT CPER project). We thank A. Martinez (NMR analyses including nOe measurements), S. Lanthony (chiral HPLC analyses and HRMS), Dr S. Chevreux (X-ray crystallographic structure determination), Dr D. Harakat (HRMS), A. Robert (NMR analyses) as well as A. Vallée and L. Lepolard (synthesis of some of the tartrimides 1). We also thank the French Fluorine Network (GIS CNRS).

Supporting Information

Copies of all 1D NMR spectra for compounds **1-8** and X-ray structural data (CIF) for *trans*-**2a**, *cis*-**7a** and *cis*-**7b**. This material is available free of charge *via* the Internet at http://pubs.acs.org.

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24 CCDC-1553380 (*trans*-2*a*), CCDC-1553381 (*cis*-7*a*) and CCDC-1553382 (*cis*-7*b*) contain the supplementary crystallographic data this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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