cis -Dihydroxylated α-Trifluoromethylated N, O-Acetal from l -Tartaric Acid: Synthesis of Tetrasubstituted Stereocenter via Diastereoselective Pictet-Spengler Cyclization of N-Acyliminium Ions

Abdelkhalek Ben Jamaa, Mohammed Latrache, Emmanuel Riguet, Fabienne Grellepois

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Abdelkhalek Ben Jamaa, Mohammed Latrache, Emmanuel Riguet, Fabienne Grellepois. cis -Dihydroxylated α-Trifluoromethylated N, O -Acetal from l -Tartaric Acid: Synthesis of Tetrasubstituted Stereocenter via Diastereoselective Pictet-Spengler Cyclization of N -Acyliminium Ions. Journal of Organic Chemistry, 2020, 85 (15), pp.9585-9598. 10.1021/acs.joc.0c00801 . hal-02926094

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*cis*-Dihydroxylated α-Trifluoromethylated *N*,*O*-Acetal from L-Tartaric Acid: Synthesis of Tetrasubstituted Stereocenter *via* Diastereoselective Pictet-Spengler cyclization of *N*-Acyliminium Ions.

Abdelkhalek Ben Jamaa, Mohammed Latrache, Emmanuel Riguet, Fabienne Grellepois*

Université de Reims Champagne-Ardenne, CNRS, Institut de Chimie Moléculaire de Reims

UMR 7312, 51097 Reims, France

*E-mail : fabienne.grellepois@univ-reims.fr

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

The synthesis of cyclic, chiral α-trifluoromethylated *N*,*O*-acetals having a protected *cis*-diol moiety has been readily achieved in two steps from a known bis-Weinreb amide derived from L-tartaric acid. Reaction of *O*-acetyl analogues of these *N*,*O*-acetals with triflic acid in HFIP at 0°C generated *in situ* the corresping electrophilic α-trifluoromethyl *N*-acyliminium ions which undergo Pictet-Spengler-type cyclizations. After only 10 min of reaction, original enantiopure aza-tricyclic scaffolds bearing a trifluoromethyl substituent at the bridgehead position were obtained with diastereoselectivities ranging from 75:25 to 97:3.
Introduction

*N*-acyliminium ions are well recognized as highly reactive electrophilic intermediates for C-C and C-heteroatom bond-forming reactions.¹ Cyclization reactions with arenes and hetero-arenes π-nucleophiles in particular have been extensively studied for the construction of fused heterocyclic nitrogen-containing scaffolds as cores of polycyclic alkaloids or as non-natural related systems.¹b,g Diastereoselective intramolecular Pictet-Spengler cyclization of five-membered ring *N*-acyliminium ions leading to trisubstituted stereogenic center has been detailed in numerous reports as being under steric control and forming in most cases virtually a single diastereomer.¹g In contrast much fewer describe this reaction with fully substituted *N*-acyliminium ions for constructing tetrasubstituted stereocenter. Reading the literature, the sense of diastereocontrol and the diastereoselectivity of the addition depend significantly on the reaction conditions² and the substituents already contained within the pyrrolidin-2-one core.³,⁴,⁵

Because of the intrinsic properties of the fluorine atom⁶ the use of α-trifluoromethylated *N*-acyliminium ions for the elaboration of tetrasubstituted carbons on saturated nitrogen heterocycles is challenging and still largely underdeveloped,⁷ even in intramolecular cyclization processes.⁷a,c Reaction involving these particular intermediates was disclosed for the first time by Eguchi and co-workers to prepare indolizidine derivatives, trifluoromethylated at the bridgehead position (Scheme 1).⁷a The intramolecular addition of arene and hetero-arene nucleophiles required the treatment of the *N*-acyliminium ion precursor, an *N*,*O*-acetal, with 2 equiv of triflic acid in dichloromethane at room temperature for at least one day. Years later Anbarasan and his colleague reported a sequential process for the generation of α-trifluoromethylated *N*,*O*-acetals and the cyclization steps, with the latter being performed in the presence of 5 equiv of methanesulfonic acid under heating in 1,2-dichloroethane for a couple
of hours (Scheme 1).⁷c It is noteworthy that imide derived from cyclohexyl-1,2-dicarboxylic acid afforded the nitrogen-containing tetracyclic product as a 60:40 mixture of stereoisomers whose relative configurations were not determined.⁷c

As part of our project concerning the study of α-amidoalkylations of chiral α-trifluoromethyl N-acylimium ions we have previously examined the diastereoselective intermolecular addition of nitriles.⁷d These electrophilic intermediates were generated *in situ* by reaction of the precursors *O*-acetyl *N*,*O*-acetals derived from L-tartaric acid with 3 equiv of Lewis acid (BF₃.Et₂O) at room temperature. Enantiopure 3a-(trifluoromethyl)-pyrrolo[2,3-d]oxazolones having *trans*-diol moiety were thus obtained in good yields. The use of enantiopure N-acyliminium ions generated from the chiral pool is a popular strategy to study diastereoselective α-amidoalkylation reactions.¹,⁴⁻⁵,⁷d However, the limited number of readily available chiral starting molecules convenient for the synthesis of 5-membered ring α-substituted N-acyliminium ions impact the diversity of substituents on aza-heterocycle skeletons. In this article we wish to disclose the straightforward synthesis of chiral α-trifluoromethylated *N*,*O*-acetals having a protected *cis*-diol moiety. Studies of diastereoselective Pictet-Spengler cyclizations on this new family of N-acyliminium ions precursors will lead to original, enantiopure trifluoromethylated fused aza-tricyclic scaffolds (Scheme 1).
# Scheme 1: Pictet-Spengler cyclization with α-CF₃-N-Acyliminium Ions: Previous Reports and Present Work.

## Previous reports:

- Eguchi and co-workers<sup>7a</sup>

<figure><img src="image_3.png" /></figure>

- Anbarasan and co-worker<sup>7c</sup>

<figure><img src="image_4.png" /></figure>

## Present work:

<figure><img src="image_5.png" /></figure>

## Results and Discussion

A few years ago, in the course of our studies, a control experiment highlighted that trifluoromethyltrimethylsilane in the presence of fluoride ion can undergo nucleophilic trifluoromethylation of bis-Weinreb amide derived from L-tartaric acid to give the corresponding mono trifluoromethylated silylated hemiaminal.⁸,⁹ As this functional group can be easily transformed into trifluoromethyl ketones,¹⁰ we studied this reaction on bis-Weinreb tartramide 1, protected with an acetonide group, in order to gain access to the corresponding mono trifluoromethylketone. Our investigations are summarized in Table 1. Attempts to perform the nucleophilic trifluoromethylation of 1 were first realized with 1 equiv of
trifluoromethyltrimethylsilane in the presence of cesium fluoride in THF or toluene.¹⁰ Regardless the solvent, the reaction was not complete and the mono-trifluoromethylated hemiaminal **2** was isolated in moderate yields (51% and 40%, respectively, Table 1, entries 1-2). No traces of the bis-trifluoromethylated derivative were detected in the ¹⁹F NMR spectrum of the crude reaction mixture. All usual ammonium fluorides in THF gave a complex mixture of fluorinated compounds (Table 1, entry 3). The use of tetrabutylammonium difluorotriphenylsilicate (TBAT) led to the silylated hemiaminal **2** and a small amount of hydrated ketone¹¹ **3**, isolated in 62% and 10% yields, respectively (Table 1, entry 4). The use of 2 equiv of $CF_3SiMe_3$ in the presence of this fluoride source made it possible to increase the overall yield of the desired trifluoromethylated products **2** and **3** to 88% (84% of silylated hemiaminal **2** and 4% of hydrated ketone **3**, respectively, Table 1, entry 5). It is noteworthy that none of these reaction conditions enabled us to perform the nucleophilic trifluoromethylation of *O*,*O'*-dibenzyl-protected bis-Weinreb amide derived from L-tartaric acid.

<caption>**Table 1. Attempts for the Nucleophilic Trifluoromethylation of Bis-Weinreb Amide 1.**</caption>
<figure><img src="image_6.png" /></figure>

<table><thead><tr><th rowspan="2">entry</th><th rowspan="2">source of fluoride</th><th rowspan="2">solvent</th><th colspan="2">yield (%)</th></tr><tr><th>2</th><th>3</th></tr></thead><tbody><tr><td>1</td><td>CsF</td><td>THF</td><td>51<sup>b</sup></td><td>5</td></tr><tr><td>2</td><td>CsF<sup>c</sup></td><td>toluene</td><td>40<sup>b</sup></td><td>traces</td></tr><tr><td>3</td><td>TBAF or TMAF<sup>d</sup></td><td>THF</td><td>-<sup>c</sup></td><td>-<sup>c</sup></td></tr><tr><td>4</td><td>TBAT</td><td>THF</td><td>62<sup>b</sup></td><td>10</td></tr><tr><td>5<sup>f</sup></td><td>TBAT</td><td>THF</td><td>84<sup>b</sup></td><td>4</td></tr></tbody></table>

<sup>a</sup>Reaction conditions: CF<sub>3</sub>TMS (1 equiv), fluoride (0.05 equiv), 0°C to rt <sup>b</sup>Diastereomeric ratio (dr) of 2 determined by <sup>19</sup>F NMR of the crude reaction mixture: 70:30 (entry 1), 84:16 (entry 2), 99:1 (entries 4 and 5). <sup>c</sup>0.2 equiv. <sup>d</sup>0.05 equiv or 0.2 equiv of anhydrous TBAF in THF solution or TBAF·3H<sub>2</sub>O or TMAF. <sup>e</sup>A complex mixture was obtained according to the <sup>19</sup>F NMR spectrum of the crude reaction mixture. <sup>f</sup>2 equiv of CF<sub>3</sub>TMS were used.

Having found the optimized reaction conditions for the mono trifluoromethylation of bis-Weinreb amide 1, this reaction step was followed by an *in situ* acidic treatment to cleave the silylated hemiaminal 2 and to give the corresponding ketone by elimination of the amino substituent. The hydrated ketone 3 was thus isolated in 80% yield and its structure was confirmed by single crystal X-ray analysis (Scheme 2). All our attempts to isolate the non-hydrated form of the ketone 3 were unsuccessful.<sup>11,12</sup>
<figure><img src="image_7.png" /><figcaption>Scheme 2: Synthesis of Hydrated Ketone 3 from Bis-Weinreb Amide 1.</figcaption></figure>

We were then pleasantly surprised to observe that the treatment of the hydrated ketone 3 with 2 equiv of benzylamine at reflux of toluene for 4h led only to the chiral cyclic hemiaminal 4a. X-ray analysis of a single crystal of 4a highlighted an unexpected cis protected diol motif.13 Cyclic hemiaminal 4a was formed with an excellent diastereocontrol ($dr = 97:3$ for the formation of the new stereocenter bearing the trifluoromethyl group according to the ¹⁹F NMR spectrum of the crude reaction mixture), and was isolated as a single diastereomer in 82% yield (Table 2). Reaction of hydrated ketone 3 with chiral amines occurred also with an excellent diastereoselectivity ($dr = 99:1$ according to the ¹⁹F NMR spectra of the crude reaction mixtures). The enantiopure cyclic hemiaminals 4b-c were thus isolated in similar good yields (75% and 77% respectively) (Table 2). The epimerisation of the carbon in β-position of the trifluoromethyl substituent was unequivocally supported by X-ray diffraction analysis of cyclic hemiaminal 4b, N-substituted by a chiral auxiliary. Thus we have found an original and straightforward route towards enantiopure α-trifluoromethylated N,O-acetals having a protected cis-diol moiety which allows to circumvent the “meso-imide problem”.14 Such N,O-acetals could not have been conventionally obtained by nucleophilic trifluoromethylation of imides7b-d,15 from meso-tartaric acid as it is optically inactive.
<figure><img src="image_8.png" /><figcaption>Table 2. Reaction of Chiral Hydrated Ketone 3 with Benzylamine and its Derivatives.</figcaption></figure>

The formation of cyclic hemiaminals **4a-c** from hydrated ketone **3** involves at least four successive reactions and an excellent diastereofacial control for two of them. A possible reaction mechanism first requires the dehydration of **3** into the corresponding ketone at reflux of toluene.¹³ The deprotonation of the acidic proton in α-position to the trifluoromethyl ketone¹¹ by amine followed by the reprotonation of the formed enolate from the least hindered upper *re*-face leads to the epimerization of the carbon in β-position from the trifluoromethyl group. Formation of the new stereocenter bearing the trifluoromethyl group would imply the highly diastereoselective addition of aza-nucleophile on the epimerized trifluoromethyl ketone. The aza nucleophile could be the benzyl amine (intermolecular reaction) or the benzyl amide resulting from the transamidation of Weinreb amide¹⁶ (intramolecular reaction).¹⁷ According to the stereochemical outcome of the reaction, regardless the nucleophile, addition to the trifluoromethyl ketone would happen *via* the Felkin-Anh transition state **TS-2**,¹⁸,¹⁹ as shown in Figure 1. Cyclization towards hemiaminals **4a-c** is made possible thanks to the *syn* stereochemical relationship of the acetonide-protected diol.
<figure><img src="image_9.png" /><figcaption>**Figure 1.** Felkin-Anh Model for the Diastereoselective Nucleophilic Addition of Aza-Nucleophile on the α-Trifluoromethyl Ketone Function.</figcaption></figure>

Having developed a short and highly efficient synthesis of enantiopure α-trifluoromethylated *N*,*O*-acetals having a *cis*-diol motif, we envisaged to use this reaction sequence to prepare original *N*-acyliminium ions precursors allowing to study diastereoselective Pictet-Spengler cyclization. The required starting *N*,*O*-acetals **5a-g** were easily prepared by reacting the hydrated ketone **3** with 2 equiv of variously substituted phenethylamines or the 1-methyltryptamine at reflux of toluene (Table 3). As α-trifluoromethyl *N*-acyliminium ions are known to be difficult to generate,⁷ especially under mild reaction conditions suitable with the acetonide protecting group, *O*-acetyl-*N*,*O*-acetals **6a-g** containing a better leaving group⁷d were then prepared from the enantiopure **5a-g** using standard reaction conditions (Table 3).
<figure><img src="image_10.png" /><figcaption>**Table 3.** Preparation of Enantiopure Cyclic α-Trifluoromethyl *N*,*O*-Acetals 5a-g and *O*-Acetyl-*N*,*O*-Acetals 6a-g.</figcaption></figure>

The experimental conditions for the cyclization were optimized on 0.20-0.25 mmol of the *O*-acetyl *N*,*O*-acetal **6a**, substituted with the electron-rich 3,4-dimethoxyphenyl group. Our results are summarized in Table 4. *BF*₃·*Et*₂*O was first evaluated to promote this reaction as it has already been used for the *in situ* generation of α-*CF*₃ *N*-acyliminium ion derived from L-tartaric acid at room temperature.⁷d Such reaction conditions have been reported several times to be compatible with the acid-labile acetonide protecting group.¹ The reaction of *O*-acetyl *N*,*O*-acetal **6a** with 3 equiv of *BF*₃·*Et*₂*O in dichloromethane at room temperature was very sluggish, full conversion of **6a** was obtained after 28h (Table 4, entry 1). Examination of the ¹⁹F NMR spectrum of the crude reaction mixture showed the presence of the two diastereomers of the Pictet-Spengler product **7a** and *epi*-**7a** in only 21% amount. The structure of **7a** was determined by single crystal X-ray crystallography. Deprotection of the acetonide occurred during the prolonged reaction time leading to the Pictet-Spengler products **8**²⁰ and *epi*-**8**²⁰ (23%) and the
O-acetyl N,O-acetal 9 (28%). While both diastereomers of the protected Pictet-Spengler product 7a and *epi*-7a can be easily separated by chromatography on silica gel, deprotected diastereomers 8 and *epi*-8 are unfortunately unseparable forcing us to find some reaction conditions avoiding the cleavage of the protecting group. In order to reduce the reaction time and thus the amount of deprotected products, the reaction was then performed with 10 equiv of Lewis acid (Table 4, entry 2). Under these conditions, full conversion of 6a was obtained after only 4h of reaction. Cyclized products 7a and *epi*-7a were the main products (80%), but the diastereoselectivity of the reaction was still very low (51:49 instead of 45:55, Table 4, entries 1-2). Performing the reaction at 0°C led, after 22h, to a complex mixture of compounds according to the ¹⁹F NMR spectrum (Table 4, entry 3). Pictet-Spengler products 7a, *epi*-7a, 8 and *epi*-8 were formed in only small amounts (20%) and with a similar poor diastereoselectivity. The obtention of the (*R*,*S*,*R*) diastereomer of the deprotected O-acetyl N,O-acetal 9²¹ as main product suggests that the *N*-acylimium ion is difficult to form from 6a with BF₃.Et₂O at this temperature. The π-nucleophile cyclization was then performed with strong Brönsted acids (Table 4, entries 4-10). With 10 equiv of methanesulfonic acid in dichloromethane at room temperature, the cyclization products 7a, *epi*-7a, 8 and *epi*-8 were formed in good amounts, albeit in favour of the deprotected ones (23% of 7a and *epi*-7a, 49% of 8 and *epi*-8), and with a better diastereoselectivity (78:22) after 6h of stirring (Table 4, entry 4). A non-negligeable amount of 10 (18%), for which the acetonide protecting group has migrated, was also formed.²² Performing the reaction at 0°C improved the amount of desired products 7a and *epi*-7a (42%) but also of deprotected O-acetyl N,O-acetal 9 (34%) (Table 4, entry 5). Despite the good diastereoselectivities observed for the cyclization reaction with methanesulfonic acid (Table 4, entries 4-5), the significant amounts of deprotected products 8 and/or 9 and of alcohol 10 formed during the reaction course led us to evaluate a stronger Brönsted acid, the trifluoromethanesulfonic acid (Table 4, entries 6-10). The reaction of O-
acetyl *N*,*O*-acetal **6a** with 3 equiv of triflic acid in dichloromethane at 0°C was very sluggish (Table 4, entry 6). The long reaction time (29h30) led to the formation of a complex mixture of compounds according to the ¹⁹F NMR spectrum. The Pictet-Spengler cyclized products **7a** and *epi*-**7a** were formed in only 38% amount albeit in good diastereoselectivity (74:26 in favor of **7a**) with only traces of deprotected derivatives **8** and *epi*-**8** (5%). Other products having been identified were the deprotected *O*-acetyl *N*,*O*-acetal **9** (32%) and the alcohol **10** (23%). Changing dichloromethane for 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP),²³ a very suitable solvent to carry out reactions involving short-lived carbocations, considerably shortened the reaction time (Table 4, entry 7). Full conversion of **6a** was achieved in only 1h20 instead of more than 29h (Table 4, entries 6-7). The crude reaction mixture contained almost only the protected products **7a** and *epi*-**7a** (83%) and the deprotected ones **8** and *epi*-**8** (13%) with a global 73:27 facial diastereoselectivity for the cyclization reaction. Using more equivalents of triflic acid (10 equiv) reduced dramatically the reaction time to only 10 min while maintaining the high amount of protected cyclized products **7a** and *epi*-**7a** (86%) and the diastereoselectivity (75:25) (Table 4, entry 8). Finally, performing the reaction at lower temperature (-10°C) in a 1:1 mixture of dichloromethane and HFIP neither increased the amount of **7a** and *epi*-**7a** nor the diastereoselectivity (Table 4, entry 9). The best conditions found for this Pictet-Spengler cyclization, 10 equiv of trifluoromethanesulfonic acid in HFIP at 0°C, were then applied to 1.5 mmol of *O*-acetyl *N*,*O*-acetal **6a** (Table 4, entry 10). After 10 min of reaction, the diastereomers of the protected cyclized products **7a** and *epi*-**7a** were formed in an amount of 97% as a 77:23 mixture. After purification by chromatography on silica gel, the major **7a** was isolated in 60% yield and the minor *epi*-**7a** in 21% yield (Table 4, entry 10 and Table 5).
<figure><img src="image_11.png" /><figcaption>Table 4. Screening of Reaction Conditions for the Pictet-Spengler cyclization reaction of the O-Acetyl N,O-Acetal 6a Substituted with an Electron Rich Phenyl Group.ª</figcaption></figure>

<table><thead><tr><th>ent.</th><th>acid (equiv)</th><th>solvent</th><th>T(°C)</th><th>time</th><th>7a+epi-7a (%)<br>(dr)<sup>b</sup></th><th>8+epi-8 (%)<br>(dr)<sup>b</sup></th><th>dr<sup>b</sup><br>(7a+8):epi-(7a+8)</th><th>9 (%)<sup>b</sup></th><th>10 (%)<sup>b</sup></th></tr></thead><tbody><tr><td>1</td><td>BF<sub>3</sub>.Et<sub>2</sub>O (3)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>rt</td><td>28h</td><td>21 (71:29)</td><td>23 (22:78)</td><td>45:55</td><td>28<sup>c</sup></td><td>-</td></tr><tr><td>2</td><td>BF<sub>3</sub>.Et<sub>2</sub>O (10)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>rt</td><td>4h</td><td>80 (52:48)</td><td>2 (0:100)</td><td>51:49</td><td>4</td><td>-</td></tr><tr><td>3</td><td>BF<sub>3</sub>.Et<sub>2</sub>O (10)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>0°C</td><td>22h</td><td>6 (100:0)</td><td>14 (37:63)</td><td>57:43</td><td>34<sup>c</sup></td><td>1</td></tr><tr><td>4</td><td>MeSO<sub>3</sub>H (10)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>rt</td><td>6h</td><td>23 (100:0)</td><td>49 (68:32)</td><td>78:22</td><td>6</td><td>18</td></tr><tr><td>5</td><td>MeSO<sub>3</sub>H (10)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>0°C</td><td>6h30</td><td>42 (89:11)</td><td>4 (27:73)</td><td>83:17</td><td>34<sup>c</sup></td><td>11</td></tr><tr><td>6</td><td>CF<sub>3</sub>SO<sub>3</sub>H (3)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>0°C</td><td>29h30</td><td>38 (74:26)</td><td>5 (18:82)</td><td>67:33</td><td>32<sup>c</sup></td><td>23</td></tr><tr><td>7</td><td>CF<sub>3</sub>SO<sub>3</sub>H (3)</td><td>HFIP</td><td>0°C</td><td>1h20</td><td>83 (79:21)</td><td>13 (32:68)</td><td>73:27</td><td>3</td><td>-</td></tr><tr><td>8</td><td>CF<sub>3</sub>SO<sub>3</sub>H (10)</td><td>HFIP</td><td>0°C</td><td>10 min</td><td>86 (75:25)</td><td>8 (26:74)</td><td>71:29</td><td>1</td><td>2</td></tr><tr><td>9</td><td>CF<sub>3</sub>SO<sub>3</sub>H (10)</td><td>HFIP:CH<sub>2</sub>Cl<sub>2</sub><br>(1:1)</td><td>-10°C</td><td>18 min</td><td>82 (74:26)</td><td>2 (18:82)</td><td>73:27</td><td>3</td><td>4</td></tr><tr><td>10<sup>d</sup></td><td>CF<sub>3</sub>SO<sub>3</sub>H (10)</td><td>HFIP</td><td>0°C</td><td>10 min</td><td>97 (77:23)</td><td>1 (0:100)</td><td>76:24</td><td>&lt;1</td><td>1</td></tr></tbody></table>

<footnote>ªReaction performed on 0.20-0.25 mmol scale, except for entry 10. ᵇPercentage of products and diastereomeric ratios (dr) determined by ¹⁹F NMR (470MHz, CDCl₃) of the crude reaction mixture: δ (ppm) -67.0 (br s) epi-7a, -68.7 (s) epi-8, -71.9 (s) 8, -74.1 (s) 7a, -77.8 (s) 10, -78.4 (s) 6a, -80.2 (s) 9 major, -80.6 (s) 9 minor.</footnote>

<footnote>ᶜDiastereomeric ratios (dr R:S) for 9: 95:5 (entry 1), 93:7 (entry 3), 89:11 (entry 5), 91:9 (entry 6). ᵈReaction performed on 1.5 mmol scale (100% conversion), both diastereomers were separated by chromatography on silica gel (major 7a: 60% yield, minor epi-7a: 21% yield, see Table 5).</footnote>
Having identified the optimized reaction conditions for the intramolecular Pictet-Spengler cyclization (10 equiv of triflic acid in HFIP, 0°C for 10 min), an overview of the scope and limitations of the substituted aryl group was investigated. As shown in Table 5, electron-enriched as well as electron-poor phenyl group are tolerated. In all cases, both diastereomers were separated by chromatography on silica gel. Electron-enriched phenyl ring substituted with *para*-methoxy group led cleanly to the diastereomeric cyclized products **7b** and *epi*-**7b** as a 73:27 mixture. Pictet-Spengler products **7c** and *epi*-**7c**, from the cyclization of the phenyl group, were obtained with a similar diastereoselection.²⁴ Electron-poor *para*-chloro and *para*-fluorophenethylamine were also effective to cyclize leading to the Pictet-Spengler products **7d**/*epi*-**7c** and **7e**/*epi*-**7e** with a better diastereoselectivity (85:15 and 90:10 respectively). 2,4-Dichlorophenyl unfortunately led to a complex mixture containing only 52% of Pictet-Spengler products **7f**/*epi*-**7f** (according to the ¹⁹F NMR spectrum of the crude reaction mixture) albeit in an excellent diastereoselectivity of 97:3. The major diastereomer **7f** was thus isolated in 35% yield. Hemiaminal **11** resulting from the nucleophilic addition of HFIP²³ on the highly reactive α-CF₃ *N*-acylimium ion was also formed in 17% amount during the reaction course and was isolated in 12% yield (the structure of **11** was confirmed by 2D NOESY and ¹⁹F-¹H-HOESY experiments) (Figure 2). Unfortunately, treatment of the *O*-acetyl *N*,*O*-acetal **6g** containing an *N*-methylindole ring under this strong acidic conditions led only to a very complex mixture from which Pictet-Spengler products could not be identified.

The major diastereomers **7a** and **7f** obtained for the Pictet-Spengler cyclization of **6a** and **6f** were unambiguously established by X-ray crystallography to have the *S* configuration for the newly formed stereogenic center. Similar trends in the ¹⁹F chemical shifts observed for the major diastereomer **7a-f** (s, -73.6-74.1 ppm) and for the minor diastereomer *epi*-**7a-f** (br s,²⁵ -66.1-67.0 ppm) of all Pictet-Spengler products allowed the assignment of the same stereochemistry.
<figure><img src="image_12.png" /><figcaption>**Table 5.** Pictet-Spengler cyclization of *O*-Acetyl *N*,*O*-Acetals 6a-f with Triflic Acid in *HFIP*.<sup>a,b</sup></figcaption></figure>

<sup>a</sup>Reaction performed on 1.54 mmol of **6a** and 0.45-0.53 mmol scale for **6b-f**. <sup>b</sup>Diastereomeric ratios (*dr*) determined by <sup>19</sup>F NMR of the crude reaction mixture.

<figure><img src="image_13.png" /><figcaption>**Figure 2.** NOE Connectivities on *N*,*O*-Acetal 11.</figcaption></figure>

The preferential formation of the *S* stereocenter during the Pictet-Spengler cyclization implies that the favoured approach of the aromatic ring towards the electrophilic carbon of the
α-trifluoromethyl *N*-acyliminium ion is from the same side of the acetonide protecting group, the most hindered face (*syn* selective addition). Surprising at first sight, these results can be rationalized on the basis of the computational studies reported recently by Pyne and co-workers on the intermolecular *syn* addition of indoles on β-methoxy α-cyclopropyl *N*-acyliminium ion derived from L-lactic acid.²⁶ By analogy with their observations, we postulate that transition-state where the bulky²⁷ and highly electronwithdrawing trifluoromethyl group is forced towards the *O*-protected substituent leading to the *anti* intramolecular addition of the aromatic ring is less stable than transition-state where the fluorinated substituent is furthest from the acetonide group leading to the *syn*-addition product.

Deprotection of the acetonide protecting group of Pictet-Spengler products **7a** and *epi-7a* was performed under treatment with a 1:1 mixture of aq. HCl in THF at 50°C (Scheme 3).

Deprotected derivatives **8** and *epi-8* were isolated in 96% and 99% yields, respectively.

**Scheme 3.** Deprotection of Acetonide Protecting Groups of Pictet-Spengler Products **7a** and *epi-7a*.

<figure><img src="image_14.png" /></figure>

Reduction of the amide function of both diastereomers **7a** and *epi-7a* of the protected polycyclic derivative under standard conditions⁷ª gave the amines **12** and *epi-12* in 82% and 71% yields, respectively (Scheme 4). The acetonide protecting group of amines **12** and *epi-12* is then removed under acidic treatment to give the original, enantiopure alkaloid-like trifluoromethyl derivatives **13** and *epi-13* having a *cis*-diol moiety.
<figure><img src="image_15.png" /><figcaption>Scheme 4. Towards Alkaloid-Like Trifluoromethyl Aza-Derivatives 13 and epi-13.</figcaption></figure>

Conclusion

We have shown that the nucleophilic trifluoromethylation of a well-known bis-Weinreb amide derived from L-tartaric acid, having the natural *trans*-diol motif protected by an acetonide group, followed by an acidic treatment gave the corresponding mono-amide mono-trifluoromethylketone analogue. Treatment of this compound with a primary amine at reflux of toluene led surprisingly to the clean formation of a chiral cyclic α-trifluoromethylated *N*,*O*-acetal having a *cis*-diol moiety. This reaction sequence enabled to circumvent the “*meso*-imide problem”.

Despite that highly electrophilic α-trifluoromethylated *N*-acyliminium ions are difficult to generate from the corresponding fluorinated *N*,*O*-acetals,⁷ an excess of triflic acid in HFIP allowed to perfor intramolecular Pictet-Spengler cyclizations with α-trifluoromethylated *O*-acetyl *N*,*O*-acetals *N*-substituted with phenethyl amine derivatives at 0°C in less than 10 min. Formation of the tetrasubstituted stereocenter bearing the trifluoromethyl group occurred in good to very good diastereoselectivities in favor to the *syn*-addition product. As electron-rich
as well as electron-deficient phenyl rings were tolerated, various original, enantiopure trifluoromethylated fused aza-polycyclic scaffolds were thereby obtained.

## Experimental section

THF, toluene and $CH_2Cl_2$ were dried using a Pure Solv solvent drying system over aluminum oxide under an Argon atmosphere. HFIP was dried over molecular sieves 3Å. $CF_3SiMe_3$ was distilled under Ar and TBAT was recrystallized from EtOAc prior to use. Molecular Sieves were activated by heating at 200°C under vacuum for at least 6 hours and were stored in a vacuum oven at 70°C. Thin-layer chromatography using precoated aluminum backed plates (Merck Kieselgel 60F254) were visualized by UV light and/or by phosphomolybdic acid, potassium permanganate or ninhydrine solutions. Silicagel 40-63 µm (Macherey-Nagel GmbH & Co KG) was used for flash chromatography. NMR spectra were recorded in $CDCl_3$ with 250, 500, or 600 MHz spectrometers. Chemicals shifts ($δ$) were reported in ppm relative to TMS for $^1H$ and $^{13}C^{1}H$ NMR spectra and to $CFCl_3$ for $^{19}F$ NMR spectra. In the $^{13}C^{1}H$ NMR data (J-MOD or DEPT-Q), reported signal multiplicities are related to C-F coupling. The following abbreviations were used to indicate the multiplicities: s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), quint (quintuplet), hept (heptuplet), m (multiplet). Diastereomeric ratios ($dr$) were determined by $^{19}F$ NMR. HRMS were recorded on an ESI-Q-TOF mass spectrometer using an electrospray source in positive mode. Optical rotations were measured at room temperature (c.a. 20 °C).

*(4R,5R)-N-methoxy-N,2,2-trimethyl-5-(2,2,2-trifluoro-1,1-dihydroxyethyl)-1,3-dioxolane-4-carboxamide 3.* $CF_3SiMe_3$ (3.25 mL, 21.2 mmol, 2 equiv) was added dropwise, at 0°C and under Ar, to a solution of bis-Weinreb amide 1$^{28}$ (3.03 g, 10 mmol) and TBAT (270 mg, 0.5 mmol, 0.05 equiv) in THF (50 mL). After 20 min of stirring at 0°C and 18h at rt, the reaction mixture was hydrolyzed with HCl 12M aq. sol. (450 µL, 5.40 mmol, 2 equiv) for 2h. The
reaction mixture was diluted with EtOAc. The organic layer was washed with a sat. aq. sol. of
NaHCO₃, brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification
of the residue by chromatography on silica gel (PE/EtOAC 3:2) afforded hydrated α-
trifluoromethyl ketone **3** (2.69 g, 80%) as a white amorphous solid : [α]D²⁰ = -31 (c 1.01,
MeOH); IR (KBr) νmax 725, 845, 1073, 1259, 1377, 1504, 1641, 2954, 2998, 3218, 3429 cm⁻¹;
¹⁹F NMR (470 MHz, CD₃OCD₃) δ -83.7 (s, 3F) ; ¹H NMR (500 MHz, CD₃OCD₃) δ 6.42 (br s,
1H), 6.03 (s, 1H), 5.12 (br s, 1H), 4.84 (d, *J* = 6.5 Hz, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 1.45 (s,
3H), 1.37 (s, 3H); ¹³C {¹H} NMR (125.7 MHz, CD₃OCD₃) δ 170.4, 124.3 (q, *J* = 288.5 Hz),
112.9, 92.9 (q, *J* = 31.0 Hz), 78.4, 73.1, 62.3, 32.4, 26.9, 26.6; HRMS (ESI⁺) m/z calcd for
C₁₀H₁₆F₃NNaO₆ [M+Na]⁺ 326.0827, found 326.0816. An analytical sample of **3** was
crystallized from Et₂O/hexane.

**General procedure for the synthesis of cyclic N,O-acetal 4a-c and 5a-g from hydrated ketone 3. General Procedure A.** A solution of hydrated ketone **3** and amine (2 equiv) was heated at reflux of toluene with a heating mantle. After completion of the reaction (monitored by ¹⁹F NMR), the solution was cooled to rt and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel afforded N,O-acetals **4a-c** and **5a-g**.

(3aR,6R,6aS)-5-benzyl-6-hydroxy-2,2-dimethyl-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 4a. According to General Procedure A, hydrated ketone 3 (207 mg, 0.68 mmol) reacted with benzylamine (150 µL, 1.37 mmol, 2 equiv) at reflux of toluene (5 mL) for 5h. Purification on silica gel (PE/EtOAc 5 :1) afforded N,O-acetal 4a (182 mg, 82%) as a pale yellow amorphous solid : [α]D²⁰ = -58 (c 1.00, MeOH); IR (KBr) νmax 608, 707, 937, 1109, 1179, 1409, 1499, 1706, 2939, 2996, 3314 cm⁻¹; ¹⁹F NMR (235.5 MHz, CDCl₃) δ -81.0 (s, 3F) ; ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, *J* = 7.5 Hz, 2H), 7.30-7.21 (m, 3H), 4.81 (d, *J* = 6.0 Hz, 1H), 4.72 (d, *J* = 6.0 Hz, 1H), 4.71 (d, *J* = 15.0 Hz, 1H), 4.44 (d, *J* = 15.0 Hz,
1H), 4.14 (br s, 1H), 1.42 (s, 3H), 1.30 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.5, 136.6, 128.41, 128.39, 127.6, 122.9 (q, *J* = 286.0 Hz), 114.9, 86.8 (q, *J* = 32.5 Hz), 76.8, 73.9, 44.1, 26.9, 26.3; HRMS (ESI⁺) *m/z* calcd for C₁₅H₁₆F₃NNaO₄ [M+Na]⁺ 354.0929, found 354.0922. An analytical sample of **4a** was crystallized from Et₂O/PE.

(3aR,6R,6aS)-6-hydroxy-2,2-dimethyl-5-((R)-1-phenylethyl)-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one **4b**. According to General Procedure A, hydrated ketone **3** (252 mg, 0.83 mmol) reacted with (R)-(+)-α-methylbenzylamine (211 µL, 1.66 mmol, 2 equiv) at reflux of toluene (8 mL) for 4h. Purification on silica gel (PE/EtOAc 4 :1) afforded N,O-acetal **4b** (217 mg, 75%) as a white amorphous solid : [α]D²⁰ = -105 (c 1.01, MeOH); IR (KBr) νmax 510, 704, 931, 1109, 1179, 1418, 1700, 3001, 3377 cm⁻¹; ¹⁹F NMR (235.5 MHz, CDCl₃) δ -81.0 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.42 (d, *J* = 7.0 Hz, 2H), 7.30 (t, *J* = 7.0 Hz, 2H), 7.22 (m, 1H), 4.84 (q, *J* = 6.5 Hz, 1H), 4.73 (d, *J* = 5.5 Hz, 1H), 4.71 (d, *J* = 5.5 Hz, 1H), 4.38 (br s, 1H), 1.80 (d, *J* = 7.0 Hz, 3H), 1.53 (s, 3H), 1.48 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.7, 140.1, 128.3, 127.3, 122.8 (q, *J* = 285.5 Hz), 114.8, 86.8 (q, *J* = 32.5 Hz), 76.8, 73.8, 53.1, 27.5, 26.6, 19.8; HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₈F₃NNaO₄ [M+Na]⁺ 368.1086, found 368.1070. An analytical sample of **4b** was crystallized from CH₂Cl₂:PE.

(3aR,6R,6aS)-6-hydroxy-2,2-dimethyl-5-((S)-1-phenylethyl)-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one **4c**. According to General Procedure A, hydrated ketone **3** (206 mg, 0.68 mmol) reacted with (S)-(-)-α-methylbenzylamine (171 µL, 1.36 mmol, 2 equiv) at reflux of toluene (5 mL) for 5h. Purification on silica gel (PE/EtOAc 4 :1) afforded N,O-acetal **4c** (179 mg, 77%) as a white amorphous solid : [α]D²⁰ = -60 (c 1.01, MeOH); IR (KBr) νmax 700, 989, 1108, 1170, 1420, 1709, 2996, 3398 cm⁻¹; ¹⁹F NMR (235.5 MHz, CDCl₃) δ -81.6 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, *J* = 7.5 Hz, 2H), 7.29 (t, *J* = 7.5 Hz, 2H), 7.23 (m, 1H), 4.75 (q, *J* = 7.5 Hz, 1H), 4.67 (d, *J* = 6.0 Hz, 1H), 4.65 (d, *J* = 6.0 Hz, 1H), 4.21 (br s, 1H), 1.85 (d, *J* = 7.5 Hz), 1.37 (s, 3H), 1.01 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃)
δ 169.8, 139.9, 128.20, 128.19, 127.7, 123.1 (q, J = 285.5 Hz), 114.6, 86.6 (q, J = 32.5 Hz), 77.0, 73.8 (q, J = 1.0 Hz), 53.0, 26.8, 26.7, 16.3; HRMS (ESI+) m/z calcd for C₁₆H₁₈F₃NNaO₄ [M+Na]⁺ 368.1086, found 368.1086.

(3aR,6R,6aS)-5-(3,4-dimethoxyphenethyl)-6-hydroxy-2,2-dimethyl-6-(trifluoromethyl)

dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 5a. According to General Procedure A, hydrated ketone 3 (5.88 g, 19.4 mmol) reacted with (3,4-dimethoxyphenyl)ethylamine (6.55 mL, 38.8 mmol, 2 equiv) at reflux of toluene (140 mL) for 22h. Purification on silica gel (PE/EtOAc 2 :1) afforded N,O-acetal 5a (6.49 g, 82%) as a white amorphous solid : [α]D²⁰ = +5 (c 1.00, CHCl₃); IR (film) vmax 614, 755, 939, 1107, 1179, 1444, 1698, 2946, 2994, 3414 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.9 (s, 3F); ¹H NMR (600 MHz, CDCl₃) δ 6.80-6.75 (m, 3H), 4.77 (d, J = 6.0 Hz, 1H), 4.70 (d, J = 6.0 Hz), 4.00 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.65 (ddd, J = 14.0 Hz, J = 11.0 Hz, J = 5.0 Hz, 1H), 3.46 (ddd, J = 14.0 Hz, J = 10.5 Hz, J = 6.0 Hz, 1H), 2.96 (ddd, J = 13.0 Hz, J = 11.0 Hz, J = 6.0 Hz, 1H), 2.83 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 5.0 Hz, 1H), 1.46 (s, 3H), 1.44 (s, 3H); ¹³C{¹H} NMR (150.9 MHz, CDCl₃) δ 170.4, 149.0, 147.8, 130.9, 123.0 (q, J = 285.5 Hz), 120.9, 115.1, 112.0, 111.2, 86.4 (q, J = 32.5 Hz), 76.8, 73.7, 56.00, 55.98, 42.6, 33.7, 27.1, 26.3; HRMS (ESI+) m/z calcd for C₁₈H₂₂F₃NNaO₆ [M+Na]⁺ 428.1297, found 428.1284. An analytical sample of 5a was crystallized from Et₂O/hexane.

(3aR,6R,6aS)-6-hydroxy-5-(4-methoxyphenethyl)-2,2-dimethyl-6-(trifluoromethyl)

dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 5b. According to General Procedure A, hydrated ketone 3 (1.51 g, 5.0 mmol) reacted with (4-methoxyphenyl)ethylamine (1.45 mL, 9.9 mmol, 2 equiv) at reflux of toluene (30 mL) for 23h. Purification on silica gel (PE/Et₂O 2 :1) afforded N,O-acetal 5b (1.53 g, 82%) as a pale yellow amorphous solid : [α]D²⁰ = +12 (c 1.00, CHCl₃); IR (film) vmax 629, 770, 979, 1105, 1179, 1405, 1701, 2840, 2961, 2994, 3385 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.9 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.16 (d, J = 8.5
Hz, 2H), 6.84 (d, *J* = 8.5 Hz, 2H), 4.76 (d, *J* = 6.0 Hz, 1H), 4.69 (d, *J* = 6.0 Hz, 1H), 3.90 (s, 1H), 3.78 (s, 3H), 3.64 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 5.0 Hz, 1H), 3.43 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 6.5 Hz, 1H), 2.97 (ddd, *J* = 13.0 Hz, *J* = 10.5 Hz, *J* = 6.5 Hz, 1H), 2.83 (ddd, *J* = 13.0 Hz, *J* = 10.5 Hz, *J* = 5.0 Hz, 1H), 1.47 (s, 3H), 1.46 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.4, 158.5, 130.5, 130.0, 123.0 (q, *J* = 285.5 Hz), 115.0, 114.1, 86.4 (q, *J* = 32.5 Hz), 76.8, 73.7, 55.4, 42.7, 33.1, 27.1, 26.3; HRMS (ESI⁺) *m/z* calcd for C₁₇H₂₀F₃NNaO₅ [M+Na]⁺ 398.1191, found 398.1191.

(3aR,6R,6aS)-6-hydroxy-2,2-dimethyl-5-phenethyl-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 5c. According to General Procedure A, hydrated ketone 3 (1.01 g, 3.32 mmol) reacted with phenylethylamine (850 µL, 6.65 mmol, 2 equiv) at reflux of toluene (25 mL) for 16h. Purification on silica gel (PE/EtOAc 6:1) afforded N,O-acetal 5c (969 mg, 84%) as a colorless oil: [α]D²⁰ = +9 (c 1.00, CHCl₃); IR (film) νmax 636, 744, 978, 1101, 1187, 1407, 1703, 2994, 3383 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.9 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.33-7.19 (m, 5H), 4.77 (d, *J* = 6.0 Hz, 1H), 4.71 (d, *J* = 6.0 Hz), 4.08 (br s, 1H), 3.69 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 5.0 Hz, 1H), 3.48 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 6.5 Hz, 1H), 3.05 (ddd, *J* = 13.0 Hz, *J* = 10.5 Hz, *J* = 6.5 Hz, 1H), 2.90 (ddd, *J* = 13.0 Hz, *J* = 10.5 Hz, *J* = 5.0 Hz, 1H), 1.47 (s, 3H), 1.46 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.4, 138.4, 129.0, 128.6, 126.7, 122.9 (q, *J* = 285.5 Hz), 115.0, 86.4 (q, *J* = 32.5 Hz), 76.7, 73.7, 42.5, 33.9, 27.0, 26.2; HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₉F₃NO₄ [M+H]⁺ 346.1266, found 346.1265.

(3aR,6R,6aS)-5-(4-chlorophenethyl)-6-hydroxy-2,2-dimethyl-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 5d. According to General Procedure A, hydrated ketone 3 (1.02 g, 3.36 mmol) reacted with 2-(4-chlorophenyl)ethylamine (934 µL, 6.72 mmol, 2 equiv) at reflux of toluene (30 mL) for 20h. Purification on silica gel (PE/EtOAc 6:1) afforded N,O-acetal 5d (910 mg, 71%) as a white amorphous solid; [α]D²⁰ = +8 (c 1.02,
CHCl₃); IR (film) vmax 870, 977, 1105, 1186, 1407, 1721, 2989, 3342 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.9 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.25 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 4.76 (d, J = 6.0 Hz, 1H), 4.70 (d, J = 6.0 Hz, 1H), 4.04 (br s, 1H), 3.63 (ddd, J = 14.0 Hz, J = 10.5 Hz, J = 6.0 Hz, 1H), 3.44 (ddd, J = 14.0 Hz, J = 10.5 Hz, J = 6.0 Hz, 1H), 3.00 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 6.0 Hz, 1H), 2.85 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 5.0 Hz, 1H), 1.45 (s, 3H), 1.44 (s, 3H); ¹³C {¹H} NMR (125.7 MHz, CDCl₃) δ 170.4, 136.9, 132.6, 130.4, 128.8, 123.0 (q, J = 285.5 Hz), 115.1, 86.4 (q, J = 32.5 Hz), 76.7, 73.7 (q, J = 1.0 Hz), 42.3, 33.3, 27.0, 26.2; HRMS (ESI⁺) m/z calcd for C₁₆H₁₈ClF₃NO₄ [M+H]⁺ 380.0876, found 380.0876.

(3aR,6R,6aS)-5-(4-fluorophenethyl)-6-hydroxy-2,2-dimethyl-6-(trifluoromethyl) dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 5e. According to General Procedure A, hydrated ketone 3 (963 mg, 3.18 mmol) reacted with 2-(4-fluorophenyl)ethylamine (833 µL, 6.35 mmol, 2 equiv) at reflux of toluene (30 mL) for 20h. Purification on silica gel (PE/EtOAc 6:1) afforded N,O-acetal 5e (878 mg, 76%) as a yellow oil: [α]D²⁰ = +4 (c 0.99, CHCl₃); IR (film) vmax 730, 824, 978, 1109, 1159, 1190, 1511, 1710, 1719, 2940, 2992, 3342 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.9 (s, 3F), -116.4 (ddd, J = 14.0 Hz, J = 9.0 Hz, J = 5.5 Hz, 1F); ¹H NMR (500 MHz, CDCl₃) δ 7.19 (dd, J = 8.5 Hz, J = 5.5 Hz, 2H), 6.97 (t, J = 8.5 Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 4.70 (d, J = 6.0 Hz, 1H), 4.07 (br s, 1H), 3.63 (ddd, J = 14.0 Hz, J = 10.5 Hz, J = 5.0 Hz, 1H), 3.44 (m, 1H), 3.00 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 6.5 Hz, 1H), 2.86 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 5.0 Hz, 1H), 1.45 (s, 6H); ¹³C NMR {¹H} (125.7 MHz, CDCl₃) δ 170.4, 161.8 (d, J = 244.5 Hz), 134.1 (d, J = 3.0 Hz), 130.5 (d, J = 8.0 Hz), 123.0 (q, J = 285.5 Hz), 115.5 (d, J = 21.0 Hz), 115.1, 86.4 (q, J = 32.5 Hz), 76.7, 73.7 (q, J = 1.0 Hz), 42.5, 33.2, 27.0, 26.2; HRMS (ESI⁺) m/z calcd for C₁₆H₁₈F₄NO₄ [M+H]⁺ 364.1172, found 364.1172.

(3aR,6R,6aS)-5-(2,4-dichlorophenethyl)-6-hydroxy-2,2-dimethyl-6-(trifluoromethyl)
dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 5f. According to General Procedure A, hydrated ketone 3 (1.05 g, 3.46 mmol) reacted with 2-(2,4-dichlorophenyl)ethylamine (842 µL, 6.93 mmol, 2 equiv) at reflux of toluene (30 mL) for 20h. Purification on silica gel (PE/EtOAc 5:1) afforded N,O-acetal 5f (1.00 g, 70%) as a white amorphous solid: [α]~D~²⁰ = +8 (c 1.00, CHCl₃); IR (film) νmax 730, 823, 976, 1106, 1167, 1718, 2987, 3355, 3664 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.9 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, *J* = 2.0 Hz, 1H), 7.22 (d, *J* = 8.0 Hz, 1H), 7.17 (dd, *J* = 8.0 Hz, *J* = 2.0 Hz, 1H), 4.77 (d, *J* = 6.0 Hz, 1H), 4.71 (d, *J* = 6.0 Hz, 1H), 4.06 (s, 1H), 3.64 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 5.5 Hz, 1H), 3.49 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 6.0 Hz, 1H), 3.10 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 6.0 Hz, 1H), 3.03 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 5.5 Hz, 1H), 1.48 (s, 3H), 1.46 (s, 3H); ¹³C NMR {¹H} (125.7 MHz, CDCl₃) δ 170.5, 135.1, 134.8, 133.3, 132.0, 129.5, 127.3, 122.9 (q, *J* = 285.5 Hz), 115.2, 86.4 (q, *J* = 32.5 Hz), 76.7, 73.7 (q, *J* = 1.5 Hz), 40.3, 31.4, 27.1, 26.2; HRMS (ESI⁺) *m/z* calculated for C₁₆H₁₇Cl₂F₃NO₄ [M+H]⁺ 414.0487, found 414.0484.

(3aR,6R,6aS)-6-hydroxy-2,2-dimethyl-5-(2-(1-methyl-1H-indol-3-yl)ethyl)-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4(5H)-one 5g. According to General Procedure A, hydrated ketone 3 (1.00 g, 3.30 mmol) reacted with 1-methyltryptamine (1.12 g, 6.43 mmol, 1.95 equiv) at reflux of toluene (25 mL) for 19h. Purification on silica gel (PE/Et₂O 1:1) afforded N,O-acetal 5g (1.06 g, 81%) as a beige amorphous solid: [α]~D~²⁰ = -1 (c 0.98, CHCl₃); IR (film) νmax 742, 1097, 1155, 1703, 2940, 3444 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.9 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.72 (d, *J* = 8.0 Hz, 1H), 7.29 (d, *J* = 8.0 Hz, 1H), 7.23 (ddd, *J* = 8.0 Hz, *J* = 7.0 Hz, *J* = 1.0 Hz, 1H), 7.13 (ddd, *J* = 8.0 Hz, *J* = 7.0 Hz, *J* = 1.0 Hz, 1H), 6.93 (s, 1H), 4.81 (d, *J* = 6.0 Hz, 1H), 4.73 (d, *J* = 6.0 Hz, 1H), 4.09 (s, 1H), 3.74 (s, 3H), 3.73 (m, 1H), 3.56 (ddd, *J* = 14.0 Hz, *J* = 11.0 Hz, *J* = 6.0 Hz, 1H), 3.17-3.05 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.5, 137.1, 127.8, 127.1, 123.0 (q, *J* = 285.5 Hz), 121.8, 119.21, 119.15, 115.1, 111.1, 109.3, 86.5 (q, *J* = 32.5 Hz), 76.9,
73.9, 41.8, 32.7, 27.2, 26.4, 23.9; HRMS (ESI+) *m/z* calcd for C₁₉H₂₂F₃N₂O₄ [M+H]⁺ 399.1532, found 399.1532.

**General procedure for the preparation of O-acetyl-N,O-acetals 6a-g from 5a-g.** *General Procedure B.* A solution of α-trifluoromethylated N,O-acetal **5a-g**, pyridine, acetic anhydride and DMAP in dichloromethane was stirred at rt under Ar. After the complete conversion of starting N,O-acetal **5a-g**, the reaction was quenched with an aq. sol. of hydrochloric acid (10% vol.) and extracted twice with CH₂Cl₂. 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 N,O-acetals **6a-g**.

(3aS,4R,6aR)-5-(3,4-dimethoxyphenethyl)-2,2-dimethyl-6-oxo-4-(trifluoromethyl) tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4-yl acetate **6a**. According to General Procedure B, a solution of N,O-acetal **5a** (285 mg, 0.70 mmol), pyridine (90 µL, 1.11 mmol, 1.58 equiv), acetic anhydride (115 µL, 1.21 mmol, 1.73 equiv) and DMAP (9 mg, 0.07 mmol, 0.1 equiv) in CH₂Cl₂ (5 mL) was stirred 16h. Purification on silica gel (PE/EtOAc 4:1) afforded O-acetyl-N,O-acetal **6a** (304 mg, 96%) as a colorless oil : [α]D²⁰ = +16 (c 1.00, CHCl₃); IR (film) νmax 1154, 1191, 1236, 1515, 1733, 1778, 2941 cm⁻¹; ¹⁹F NMR (CDCl₃, 470 MHz) δ -78.4 (s, 3F); ¹H NMR (CDCl₃, 500 MHz) δ 6.80-6.73 (m, 3H), 5.07 (d, J = 6.0 Hz, 1H), 4.75 (d, J = 6.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.49 (td, J = 13.0 Hz, J = 5.0 Hz, 1H), 3.42 (ddd, J = 14.0 Hz, J = 11.5 Hz, J = 5.0 Hz, 1H), 2.96 (td, J = 12.0 Hz, J = 5.5 Hz, 1H), 2.77 (td, J = 12.0 Hz, J = 5.0 Hz, 1H), 2.14 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.8, 166.6, 149.1, 147.9, 130.9, 122.3 (q, J = 288.5 Hz), 120.8, 114.9, 112.2, 111.4, 91.0 (q, J = 32.5 Hz), 76.3, 73.9, 56.02, 56.00, 44.0, 33.5, 26.2, 25.9, 21.4; HRMS (ESI+) *m/z* calcd for C₂₀H₂₄F₃NNaO₇ [M+Na]⁺ 470.1403, found 470.1414.

(3aS,4R,6aR)-5-(4-methoxyphenethyl)-2,2-dimethyl-6-oxo-4-(trifluoromethyl)
tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4-yl acetate **6b**. According to General Procedure B, a solution of N,O-acetal **5b** (1.13 g, 3.01 mmol), pyridine (380 µL, 4.67 mmol, 1.55 equiv), acetic anhydride (500 µL, 5.28 mmol, 1.75 equiv) and DMAP (37 mg, 0.30 mmol, 0.1 equiv) in CH₂Cl₂ (20 mL) was stirred 23h. Purification on silica gel (PE/EtOAc 5:1) afforded O-acetyl-N,O-acetal **6b** (1.05 g, 83%) as a yellow oil : [α]D²⁰ = +46 (c 1.00, CHCl₃); IR (film) νmax 1193, 1513, 1733, 1778, 2942, 2993 cm⁻¹; ¹⁹F NMR (CDCl₃, 470 MHz) δ-78.2 (s, 3F); ¹H NMR (CDCl₃, 500 MHz) δ 7.15 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.08 (d, J = 6.0 Hz, 1H), 4.75 (d, J = 6.0 Hz, 1H), 3.78 (s, 3H), 3.50-3.38 (m, 2H), 2.96 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 6.5 Hz, 1H), 2.79 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 6.0 Hz, 1H), 2.14 (s, 3H), 1.44 (s, 3H), 1.41 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.8, 166.5, 158.5, 130.4, 129.9, 122.4 (q, J= 288.0 Hz), 114.8, 114.1, 91.0 (q, J= 32.5 Hz), 76.4, 73.9, 55.4, 44.0, 33.0, 26.3, 26.0, 21.4; HRMS (ESI⁺) m/z calcd for C₁₉H₂₂F₃NNaO₆ [M+Na]⁺ 440.1297, found 440.1294.

(3aS,4R,6aR)-2,2-dimethyl-6-oxo-5-phenethyl-4-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4-yl acetate **6c**. According to General Procedure B, a solution of N,O-acetal **5c** (670 mg, 1.94 mmol), pyridine (250 µL, 3.01 mmol, 1.6 equiv), acetic anhydride (320 µL, 3.38 mmol, 1.75 equiv) and DMAP (24 mg, 0.19 mmol, 0.1 equiv) in CH₂Cl₂ (20 mL) was stirred 16h. Purification on silica gel (PE/EtOAc 9:1) afforded O-acetyl-N,O-acetal **6c** (547 mg, 73%) as a colorless oil : [α]D²⁰ = +48 (c 1.00, CHCl₃); IR (film) νmax 1090, 1192, 1734, 1778, 2943, 2992 cm⁻¹; ¹⁹F NMR (CDCl₃, 470 MHz) δ-78.2 (s, 3F); ¹H NMR (CDCl₃, 500 MHz) δ 7.33-7.28 (m, 2H), 7.25-7.20 (m, 3H), 5.09 (d, J = 6.0 Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 3.55-3.43 (m, 2H), 3.04 (ddd, J = 13.0 Hz, J = 9.5 Hz, J = 7.5 Hz, 1H), 2.86 (ddd, J = 13.0 Hz, J = 9.5 Hz, J = 6.5 Hz, 1H), 2.13 (s, 3H), 1.45 (s, 3H), 1.41 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.8, 166.6, 138.4, 129.0, 128.7, 126.8, 122.5 (q, J = 290.0 Hz), 114.8, 91.0
(q, J = 32.5 Hz), 76.4, 74.0, 43.9, 33.9, 26.3, 26.0, 21.4; HRMS (ESI+) m/z calcd for C₁₈H₂₀F₃NNaO₅ [M+Na]⁺ 410.1191, found 410.1194.

(3aS,4R,6aR)-5-(4-chlorophenethyl)-2,2-dimethyl-6-oxo-4-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4-yl acetate 6d. According to General Procedure B, a solution of N,O-acetal 5d (476 mg, 1.25 mmol), pyridine (156 µL, 1.94 mmol, 1.55 equiv), acetic anhydride (220 µL, 2.19 mmol, 1.75 equiv) and DMAP (15 mg, 0.13 mmol, 0.1 equiv) in CH₂Cl₂ (10 mL) was stirred 18h. Purification on silica gel (PE/EtOAc 7:1) afforded O-acetyl-N,O-acetal 6d (517 mg, 98%) as a colorless oil; [α]D²⁰ = +49 (c 0.99, CHCl₃); IR (film) vₘₐₓ 1089, 1193, 1736, 1779, 2942, 2991 cm⁻¹; ¹⁹F NMR (CDCl₃, 470 MHz) δ -78.3 (s, 3F); ¹H NMR (CDCl₃, 500 MHz) δ 7.25 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 5.07 (d, J = 6.0 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 3.50-3.38 (m, 2H), 3.00 (ddd, J = 13.0 Hz, J = 10.0 Hz, J = 6.5 Hz, 1H), 2.80 (ddd, J = 13.0 Hz, J = 10.0 Hz, J = 6.0 Hz, 1H), 2.11 (s, 3H), 1.42 (s, 3H), 1.39 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.8, 166.5, 136.8, 132.6, 130.3, 128.8, 122.4 (q, J = 288.0 Hz), 114.8, 90.9 (q, J = 32.5 Hz), 76.3, 73.9, 43.6, 33.2, 26.2, 25.9, 21.3; HRMS (ESI+) m/z calcd for C₁₈H₁₉ClF₃NNaO₅ [M+Na]⁺ 444.0802, found 444.0803.

(3aS,4R,6aR)-5-(4-fluorophenethyl)-2,2-dimethyl-6-oxo-4-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4-yl acetate 6e. According to General Procedure B, a solution of N,O-acetal 5e (741 mg, 2.00 mmol), pyridine (250 µL, 3.10 mmol, 1.55 equiv), acetic anhydride (357 µL, 3.57 mmol, 1.75 equiv) and DMAP (24 mg, 0.20 mmol, 0.1 equiv) in CH₂Cl₂ (15 mL) was stirred 18h. Purification on silica gel (PE/EtOAc 7:1) afforded O-acetyl-N,O-acetal 6e (717 mg, 89%) as a colorless oil : [α]D²⁰ +42 (c 1.02, CHCl₃); IR (film) vₘₐₓ 1089, 1193, 1736, 1779, 2942, 2991 cm⁻¹; ¹⁹F NMR (CDCl₃, 470 MHz) δ -78.3 (s, 3F), -116.4 (ddd, J = 14.0 Hz, J = 8.5 Hz, J = 5.5 Hz, 1F); ¹H NMR (CDCl₃, 500 MHz) δ 7.18 (dd, J = 8.5 Hz, J = 5.5 Hz, 2H), 6.96 (t, J = 8.5 Hz, 2H), 5.07 (d, J = 6.0 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 3.50-3.38 (m, 2H), 2.99 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 6.5 Hz, 1H), 2.80 (ddd, J = 13.0 Hz, J = 8.5 Hz, 2H), 6.96 (t, J = 8.5 Hz, 2H), 5.07 (d, J = 6.0 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H),
Hz, J = 10.5 Hz, J = 5.5 Hz, 1H), 2.12 (s, 3H), 1.42 (s, 3H), 1.39 (s, 3H); ¹³C {¹H} NMR (125.7 MHz, CDCl₃) δ 170.8, 166.5, 161.8 (d, J = 244.5 Hz), 134.0 (d, J = 3.0 Hz), 130.4 (d, J = 8.0 Hz), 122.4 (q, J = 288.0 Hz), 115.4 (d, J = 21.5 Hz), 114.8, 90.9 (q, J = 32.5 Hz), 76.3, 73.9, 43.8, 33.0, 26.2, 25.9, 21.3; HRMS (ESI⁺) m/z calcd for C₁₈H₁₉F₄NNaO₅ [M+Na]⁺ 428.1097, found 428.1098.

(3aS,4R,6aR)-5-(2,4-dichlorophenethyl)-2,2-dimethyl-6-oxo-4-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4-yl acetate 6f. According to General Procedure B, a solution of N,O-acetal 5f (393 mg, 0.95 mmol), pyridine (119 µL, 1.47 mmol, 1.55 equiv), acetic anhydride (166 µL, 1.66 mmol, 1.75 equiv) and DMAP (12 mg, 0.09 mmol, 0.1 equiv) in CH₂Cl₂ (7 mL) was stirred 18h. Purification on silica gel (PE/EtOAc 7:1) afforded O-acetyl-N,O-acetal 6f (371 mg, 86%) as a colorless oil : [α]D²⁰ = +54 (c 0.71, CHCl₃); IR (film) vₘₐₓ 1090, 1194, 1736, 1779, 2941 cm⁻¹; ¹⁹F NMR (CDCl₃, 470 MHz) δ -78.0 (s, 3F); ¹H NMR (CDCl₃, 500 MHz) δ 7.36 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.17 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 5.10 (d, J = 6.0 Hz, 1H), 4.74 (d, J = 6.0 Hz, 1H), 3.53-3.43 (m, 2H), 3.12 (m, 1H), 3.00 (m, 1H), 2.13 (d, J = 1.0 Hz, 3H), 1.43 (s, 3H), 1.39 (s, 3H); ¹³C {¹H} NMR (125.7 MHz, CDCl₃) δ 170.9, 166.5, 134.8, 134.5, 133.4, 132.2, 129.4, 127.5, 122.4 (q, J = 288.5 Hz), 114.6, 90.9 (q, J = 32.5 Hz), 76.4, 74.0, 41.6, 31.2, 26.4, 26.0, 21.3; HRMS (ESI⁺) m/z calcd for C₁₈H₁₈Cl₂F₃NNaO₅ [M+Na]⁺ 478.0412, found 478.0413.

(3aS,4R,6aR)-2,2-dimethyl-5-(2-(1-methyl-1H-indol-3-yl)ethyl)-6-oxo-4-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolidin-4-yl acetate 6g. According to General Procedure B, a solution of N,O-acetal 5g (833 mg, 2.09 mmol), pyridine (260 µL, 3.24 mmol, 1.55 equiv), acetic anhydride (345 µL, 3.65 mmol, 1.75 equiv) and DMAP (25 mg, 0.20 mmol, 0.1 equiv) in CH₂Cl₂ (15 mL) was stirred 23h. Purification on silica gel (PE/EtOAc 4:1) afforded O-acetyl-N,O-acetal 6g (766 mg, 83%) as a yellow oil : [α]D²⁰ = +56 (c 1.00, CHCl₃); IR (film) vₘₐₓ 731, 1188, 1207, 1731, 1775, 2934 cm⁻¹; ¹⁹F NMR (CDCl₃, 470 MHz) δ -78.2 (s,
3F); ¹H NMR (CDCl₃, 500 MHz) δ 7.69 (d, *J* = 8.0 Hz, 1H), 7.30 (d, *J* = 8.0 Hz, 1H), 7.24 (ddd, *J* = 8.0 Hz, *J* = 7.0 Hz, *J* = 1.0 Hz, 1H), 7.14 (ddd, *J* = 8.0 Hz, *J* = 7.0 Hz, *J* = 1.0 Hz, 1H), 6.94 (s, 1H), 5.12 (d, *J* = 6.0 Hz, 1H), 4.79 (d, *J* = 6.0 Hz, 1H), 3.75 (s, 3H), 3.63-3.49 (m, 2H), 3.18 (ddd, *J* = 13.5 Hz, *J* = 11.5 Hz, *J* = 6.0 Hz, 1H), 3.04 (ddd, *J* = 13.5 Hz, *J* = 11.5 Hz, *J* = 5.5 Hz, 1H), 2.13 (s, 3H), 1.46 (s, 3H), 1.43 (s, 3H); ¹³C {¹H} NMR (125.7 MHz, CDCl₃) δ 171.0, 166.6, 137.2, 127.8, 127.2, 122.6 (q, *J* = 288.0 Hz), 121.8, 119.1, 119.0, 114.8, 111.0, 109.4, 91.1 (q, *J* = 32.5 Hz), 76.5, 74.1, 43.2, 32.7, 26.4, 26.1, 23.5, 21.4; HRMS (ESI⁺) *m/z* calcd for C₂₁H₂₃F₃N₂NaO₅ [M+Na]⁺ 463.1457, found 463.1457.

**General procedure for the Pictet-Spengler cyclization of *O*-acetyl *N*,*O*-acetal **6a-f**.** *General Procedure C.* A solution of *O*-acetyl *N*,*O*-acetal **6a-f** and trifluoromethanesulfonic acid (10 equiv) in hexafluoroisopropanol (HFIP) containing 3Å molecular sieves was stirred 10 min at 0°C and under Ar. The reaction mixture was then diluted with CH₂Cl₂ and hydrolyzed with a sat. sol. of NaHCO₃. The organic layer was separated, washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure. Purification of the residue (mixture of 2 diastereomers) on silica gel afforded the major diastereomer of Pictet-Spengler product **7a-f** and then the minor diastereomer *epi-7a-e*.

(8aR,11aR,11bS)-2,3-dimethoxy-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one **7a** and (8aR,11aR,11bR)-2,3-dimethoxy-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one *epi-7a*. According to General Procedure C, *O*-acetyl *N*,*O*-acetal **6a** (690 mg, 1.54 mmol) and triflic acid (1.35 mL, 15.4 mmol, 10 equiv) reacted in HFIP (18 mL). Purification of the residue (*dr* **7a**:epi-**7a** = 77 :23) on silica gel (PE/Et₂O 1:1) afforded cyclized derivative **7a** (360 mg, 60%) as a pale yellow amorphous solid and cyclized derivative *epi-7a* (119 mg, 21%) as a pale yellow moss. **7a**: [*α*]D²⁰ = +216 (c 1.00, CHCl₃); IR (film) *v*max 783, 1107, 1256, 1524, 1723 cm⁻¹; ¹⁹F NMR
(470 MHz, CDCl₃) δ -74.1 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 6.85 (s, 1H), 6.62 (s, 1H), 4.99 (d, *J* = 5.5 Hz, 1H), 4.92 (d, *J* = 5.5 Hz, 1H), 4.41 (dd, *J* = 13.0 Hz, *J* = 6.5 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.26 (td, *J* = 13.5 Hz, *J* = 5.0 Hz, 1H), 2.85 (ddd, *J* = 16.0 Hz, *J* = 12.0 Hz, *J* = 6.5 Hz, 1H), 2.74 (dd, *J* = 16.0 Hz, *J* = 4.0 Hz, 1H), 1.34 (s, 3H), 1.16 (s, 3H); ¹³C>{¹H} NMR (125.7 MHz, CDCl₃) δ 171.3, 149.6, 147.7, 128.2, 125.5 (q, *J* = 288.5 Hz), 117.8, 113.2, 111.5, 110.8 (q, *J* = 2.5 Hz), 78.1 (q, *J* = 2.0 Hz), 76.0, 67.6 (q, *J* = 26.5 Hz), 56.3, 55.9, 36.0, 27.5, 27.2, 26.6; HRMS (ESI⁺) *m/z* calcd for C₁₈H₂₁F₃NO₅ [M+H]⁺ 388.1372, found 388.1374.

An analytical sample of **7a** was crystallized from Et₂O:hexane. epi-7a : [α]D²⁰ = -150 (c 1.20, CHCl₃); IR (film) νmax 781, 1121, 1177, 1519, 1714 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -67.0 (br s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 6.92 (s, 1H), 6.59 (s, 1H), 5.00 (d, *J* = 7.0 Hz, 1H), 4.66 (d, *J* = 7.0 Hz, 1H), 4.42 (dd, *J* = 13.5 Hz, *J* = 7.5 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.36 (td, *J* = 13.0 Hz, *J* = 5.5 Hz, 1H), 2.96 (ddd, *J* = 16.5 Hz, *J* = 12.0 Hz, *J* = 7.5 Hz, 1H), 2.67 (dd, *J* = 16.5 Hz, *J* = 5.5 Hz, 1H), 1.56 (s, 3H), 1.43 (s, 3H); ¹³C>{¹H} NMR (125.7 MHz, CDCl₃) δ 170.3, 150.0, 148.2, 127.9, 124.4 (q, *J* = 287.5 Hz), 121.8, 115.5, 112.0, 109.2 (q, *J* = 1.5 Hz), 80.4, 77.5, 67.4 (q, *J* = 27.5 Hz), 56.4, 56.0, 36.3 (d, *J* = 1.0 Hz), 26.5, 25.9, 25.5; HRMS (ESI⁺) *m/z* calcd for C₁₈H₂₁F₃NO₅ [M+H]⁺ 388.1372, found 388.1375.

(8aR,11aR,11bS)-3-methoxy-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one **7b** and (8aR,11aR,11bR)-3-methoxy-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one epi-7b. According to General Procedure C, O-acetyl N,O-acetal **6b** (214 mg, 0.51 mmol) and triflic acid (450 µL, 5.08 mmol, 10 equiv) reacted in HFIP (7 mL). Purification of the residue (dr **7b**:epi-7b = 73:27) on silica gel (PE/Et₂O 1:1) afforded cyclized derivative **7b** (82 mg, 45%) as a white amorphous solid and cyclized derivative epi-7b (42 mg, 23%) as a colorless oil. **7b**: [α]D²⁰ = +240 (c 1.00, CHCl₃); IR (film) νmax 1151, 1170, 1194, 1408, 1715 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -73.9 (s, 3F);
¹H NMR (500 MHz, CDCl₃) δ 7.10 (d, *J* = 8.5 Hz, 1H), 6.96 (m, 1H), 6.90 (dd, *J* = 8.5 Hz, *J* = 2.5 Hz, 1H), 5.00 (d, *J* = 5.0 Hz, 1H), 4.92 (d, *J* = 5.0 Hz, 1H), 4.40 (ddd, *J* = 12.5 Hz, *J* = 6.5 Hz, *J* = 2.0 Hz, 1H), 3.83 (s, 3H), 3.26 (td, *J* = 12.5 Hz, *J* = 5.5 Hz, 1H), 2.84 (m, 1H), 2.77 (ddd, *J* = 16.0 Hz, *J* = 5.5 Hz, *J* = 2.5 Hz, 1H), 1.34 (s, 3H), 1.17 (s, 3H); ¹³C {¹H} NMR (150.9 MHz, CDCl₃) δ 171.3, 157.9, 130.4, 127.4, 127.0, 125.4 (q, *J* = 288.5 Hz), 114.8, 113.7 (q, *J* = 2.5 Hz), 113.2, 78.0, 76.1, 67.8 (q, *J* = 26.5 Hz), 55.5, 36.2, 27.5, 26.8, 26.5; HRMS (ESI⁺) *m/z* calcd for C₁₇H₁₉F₃NO₄ [M+H]⁺ 358.1266, found 358.1269.
epi-7b : [α]D²⁰ = -185 (c 0.84, CHCl₃); IR (film) νmax 1149, 1180, 1209, 1246, 1715 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -66.9 (br s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.08 (d, *J* = 8.5 Hz), 7.03 (s, 1H), 6.90 (dd, *J* = 8.5 Hz, *J* = 2.5 Hz, 1H), 5.03 (d, *J* = 5.0 Hz, 1H), 4.65 (d, *J* = 5.0 Hz, 1H), 4.43 (dd, *J* = 13.5 Hz, *J* = 7.5 Hz, 1H), 3.83 (s, 3H), 3.36 (dddd, *J* = 13.5 Hz, *J* = 12.0 Hz, *J* = 5.5 Hz, *J* = 1.5 Hz, 1H), 2.94 (ddd, *J* = 16.5 Hz, *J* = 12.0 Hz, *J* = 7.5 Hz, 1H), 2.71 (dd, *J* = 16.5 Hz, *J* = 5.5 Hz, 1H), 1.56 (s, 3H), 1.43 (s, 3H); ¹³C {¹H} NMR (150.9 MHz, CDCl₃) δ 170.3, 158.4, 131.1, 131.0, 127.0, 124.4 (q, *J* = 287.5 Hz), 115.6, 115.5, 112.1, 80.5, 77.4, 67.7 (q, *J* = 27.5 Hz), 55.6, 36.4, 26.0, 25.9, 25.5; HRMS (ESI⁺) *m/z* calcd for C₁₇H₁₉F₃NO₄ [M+H]⁺ 358.1266, found 358.1268.

(8aR,11aR,11bS)-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one **7c** and (8aR,11aR,11bR)-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one **epi-7c**. According to General Procedure C, *O*-acetyl *N*,*O*-acetal **6c** (175 mg, 0.45 mmol) and triflic acid (400 µL, 4.52 mmol, 10 equiv) reacted in HFIP (7 mL). Purification of the residue (**dr 7c:epi-7c = 76:24**) on silica gel (PE/EtOAc 4:1) afforded cyclized derivative **7c** (74 mg, 50%) as a white amorphous solid and cyclized derivative **epi-7c** (35 mg, 24%) as a colorless oil. **7c** : [α]D²⁰ = +173 (c 1.00, CHCl₃); IR (film) νmax 1113, 1152, 1183, 1714 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -74.1 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.44
(dt, *J* = 7.5 Hz, *J* = 2.0 Hz, 1H), 7.31 (m, 2H), 7.18 (dd, *J* = 7.5 Hz, *J* = 2.5 Hz, 1H), 5.04 (d, *J* = 5.0 Hz, 1H), 4.93 (d, *J* = 5.0 Hz, 1H), 4.42 (ddd, *J* = 13.5 Hz, *J* = 6.5 Hz, *J* = 2.0 Hz, 1H), 3.30 (td, *J* = 12.5 Hz, *J* = 5.0 Hz, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 1.33 (s, 3H), 1.15 (s, 3H); ¹³C>{¹H} NMR (125.7 MHz, CDCl₃) δ 171.3, 135.4, 129.6, 129.0, 128.9 (q, *J* = 2.5 Hz), 126.7, 126.2, 125.5 (q, *J* = 288.5 Hz), 113.2, 78.0 (q, *J* = 2.5 Hz), 76.1, 67.8 (q, *J* = 26.5 Hz), 35.9, 27.5, 27.4, 26.5; HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₇F₃NO₃ [M+H]⁺ 328.1161, found 328.1164.

**epi-7c** : [α]D²⁰ = -119 (c 0.58, CHCl₃); IR (film) νmax 1148, 1179, 1257, 1715 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -67.0 (br s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.54 (m, 1H), 7.33 (m, 2H), 7.16 (m, 1H), 5.04 (d, *J* = 7.0 Hz, 1H), 4.65 (d, *J* = 7.0 Hz, 1H), 4.45 (dd, *J* = 13.5 Hz, *J* = 7.5 Hz, 1H), 3.40 (td, *J* = 13.5 Hz, *J* = 5.5 Hz, 1H), 3.03 (m, 1H), 2.79 (dd, *J* = 17.0 Hz, *J* = 5.5 Hz, 1H), 1.57 (s, 3H), 1.42 (s, 3H); ¹³C>{¹H} NMR (150.9 MHz, CDCl₃) δ 170.2, 135.3, 130.3, 130.1, 129.5, 127.2, 126.9 (q, *J* = 1.5 Hz), 124.4 (q, *J* = 288.5 Hz), 115.5, 80.5, 77.4, 67.4 (q, *J* = 27.5 Hz), 36.2, 26.7, 25.9, 25.4; HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₇F₃NO₃ [M+H]⁺ 328.1161, found 328.1165.

(8aR,11aR,11bS)-2-chloro-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one **7d** and (8aR,11aR,11bR)-2-chloro-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one **epi-7d**. According to General Procedure C, O-acetyl N,O-acetal **6d** (225 mg, 0.53 mmol) and triflic acid (473 µL, 5.34 mmol, 10 equiv) reacted in HFIP (8 mL). Purification of the residue (**dr 7d:epi-7d = 85:15**) on silica gel (PE/Et₂O 3:2) afforded cyclized derivative **7d** (116 mg, 61%) as a white amorphous solid and cyclized derivative **epi-7d** (25 mg, 13%) as a colorless oil. **7d** : [α]D²⁰ = +214 (c 0.50, CHCl₃); IR (film) νmax 1109, 1157, 1193, 1257, 1403, 1713, 1732 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -74.0 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.43 (t, *J* = 2.0 Hz, 1H), 7.30 (dd, *J* = 8.5 Hz, *J* = 2.0 Hz, 1H), 7.13 (d, *J* = 8.5 Hz, 1H), 5.00 (d, *J* = 5.0 Hz, 1H), 4.93 (d, *J* = 5.0 Hz,
1H), 4.42 (ddd, J = 13.5 Hz, J = 5.5 Hz, J = 3.0 Hz, 1H), 3.26 (m, 1H), 2.90-2.80 (m, 2H), 1.34 (s, 3H), 1.16 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 171.1, 133.9, 132.4, 130.8, 129.4, 128.2 (q, J = 3.0 Hz), 127.9, 125.2 (q, J = 288.5 Hz), 113.4, 77.9 (q, J = 2.0 Hz), 75.9 (q, J = 1.5 Hz), 67.5 (q, J = 26.5 Hz), 35.7, 27.4, 27.1, 26.5; HRMS (ESI⁺) m/z calcd for C₁₆H₁₆ClF₃NO₃ [M+H]⁺ 362.0771, found 362.0772. *epi-7d* : [α]D²⁰ = -174 (c 0.23, CHCl₃); IR (film) vmax 1109, 1158, 1173, 1257, 1403, 1713, 1732 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -67.0 (br s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.53 (s, 1H), 7.32 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.00 (d, J = 7.0 Hz, 1H), 4.67 (d, J = 7.0 Hz, 1H), 4.45 (dd, J = 13.5 Hz, J = 7.5 Hz, 1H), 3.37 (dddd, J = 13.5 Hz, J = 2.0 Hz, J = 5.5 Hz, J = 1.5 Hz, 1H), 2.96 (m, 1H), 2.77 (dd, J = 17.0 Hz, J = 5.5 Hz, 1H), 1.57 (s, 3H), 1.43 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 170.0, 133.8, 132.9, 132.1, 131.4, 129.9, 127.0 (q, J = 2.0 Hz), 124.2 (q, J = 287.5 Hz), 115.8, 80.5, 77.4, 67.4 (q, J = 28.0 Hz), 35.9 (q, J = 1.5 Hz), 26.3, 25.9, 25.4; HRMS (ESI⁺) m/z calcd for C₁₆H₁₆ClF₃NO₃ [M+H]⁺ 362.0771, found 362.0771.

(8aR,11aR,11bS)-2-fluoro-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one **7e** and (8aR,11aR,11bR)-2-fluoro-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one *epi-7e*. According to General Procedure C, *O*-acetyl *N*,*O*-acetal **6e** (220 mg, 0.54 mmol) and triflic acid (480 µL, 5.42 mmol, 10 equiv) reacted in HFIP (8 mL). Purification of the residue (*dr* **7e**: *epi-7e* = 90:10) on silica gel (PE/EtOAc 5:1) afforded cyclized derivative **7e** (146 mg, 78%) as a white amorphous solid and cyclized derivative *epi-7e* (18 mg, 10%) as a colorless oil. **7e**: [α]D²⁰ = +143 (c 1.01, CHCl₃); IR (film) vmax 1107, 1149, 1188, 1246, 1406, 1713, 1732 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -74.1 (s, 3F), -114.8 (td, J = 9.0 Hz, J = 6.5 Hz, 1F); ¹H NMR (500 MHz, CDCl₃) δ 7.15 (m, 2H), 7.04 (td, J = 8.5 Hz, J = 2.5 Hz, 1H), 5.00 (d, J = 5.0 Hz, 1H), 4.92 (dt, J = 5.0 Hz, J = 1.5 Hz, 1H), 4.44 (m, 1H), 3.26 (m, 1H), 2.86-2.81 (m, 2H), 1.33 (s, 3H), 1.15 (s, 3H); ¹³C{¹H}
NMR (125.7 MHz, CDCl₃) δ 171.1, 161.1 (d, *J* = 245.5 Hz), 131.1 (d, *J* = 3.0 Hz), 131.0 (d, *J* = 8.0 Hz), 127.8 (d, *J* = 7.5 Hz), 125.2 (q, *J* = 288.5 Hz), 116.6 (d, *J* = 21.5 Hz), 115.1 (dq, *J* = 23.5 Hz, *J* = 2.5 Hz), 113.5, 77.9 (q, *J* = 2.0 Hz), 76.0 (q, *J* = 1.5 Hz), 67.7 (qd, *J* = 26.5 Hz, *J* = 2.0 Hz), 35.9, 27.4, 26.9, 26.4; HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₆F₄NO₃ [M+H]⁺ 346.1066, found 346.1066.

epi-7e : [α]D²⁰ = -108 (c 0.24, CHCl₃); IR (film) νmax 1144, 1187, 1416, 1704, 1724 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -66.9 (br s, 3F), -113.8 (m, 1F); ¹H NMR (600 MHz, CDCl₃) δ 7.26 (m, 2H), 7.15 (dd, *J* = 8.5 Hz, *J* = 5.5 Hz, 1H), 7.06 (td, *J* = 8.5 Hz, *J* = 2.0 Hz, 1H), 4.99 (d, *J* = 7.0 Hz, 1H), 4.68 (d, *J* = 7.0 Hz, 1H), 4.45 (dd, *J* = 14.0 Hz, *J* = 7.5 Hz, 1H), 3.37 (m, 1H), 2.96 (m, 1H), 2.77 (dd, *J* = 17.0 Hz, *J* = 5.5 Hz, 1H), 1.57 (s, 3H), 1.43 (s, 3H); ¹³C{¹H} NMR (150.9 MHz, CDCl₃) δ 170.1, 161.3 (d, *J* = 247.0 Hz), 131.9 (d, *J* = 6.5 Hz), 131.7 (d, *J* = 7.5 Hz), 130.9 (d, *J* = 3.5 Hz), 124.2 (q, *J* = 287.5 Hz), 117.0 (d, *J* = 21.0 Hz), 115.8, 113.9 (dq, *J* = 23.0 Hz, *J* = 1.5 Hz), 80.5, 77.4, 67.5 (qd, *J* = 28.0 Hz, *J* = 1.5 Hz), 36.1 (q, *J* = 1.0 Hz), 26.2, 25.9, 25.4; HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₆F₄NO₃ [M+H]⁺ 346.1066, found 346.1068.

(8aR,11aR,11bS)-2,4-dichloro-10,10-dimethyl-11b-(trifluoromethyl)-5,6,11a,11b-tetrahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinolin-8(8aH)-one 7f and (3aR,6S,6aS)-5-(2,4-dichlorophenethyl)-6-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-2,2-dimethyl-6-(trifluoromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-4(5H)-one 11. According to General Procedure C, O-acetyl N,O-acetal 6f (223 mg, 0.49 mmol) and triflic acid (433 µL, 4.89 mmol, 10 equiv) reacted in HFIP (8 mL). Purification of the residue [containing 52% of Fridel-Crafts product (dr 7f:epi-7f = 97:3) and 17% of 11] on silica gel (PE/EtOAc 6:1) afforded N,O-acetal 11 (33 mg, 12%) as a colorless oil and cyclized derivative 7f (68 mg, 35%) as a white amorphous solid. 7f: [α]D²⁰ = +184 (c 0.18, CHCl₃); IR (film) νmax 1114, 1159, 1181, 1403, 1722 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -73.6 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.47 (s, 1H), 7.37 (s, 1H), 5.00 (d, *J* = 5.0 Hz, 1H), 4.93 (d, *J* = 5.0 Hz, 1H), 4.50 (dd, *J* = 13.5 Hz, *J* =
7.5 Hz, 1H), 3.24 (td, *J* = 13.5 Hz, *J* = 5.0 Hz, 1H), 3.09 (dd, *J* = 17.5 Hz, *J* = 5.0 Hz, 1H), 2.66 (1H), 1.35 (s, 3H), 1.17 (s, 3H); ¹³C>{¹H} NMR (125.7 MHz, CDCl₃) δ 170.8, 135.5, 132.7, 132.2, 130.1, 129.6, 127.0 (q, *J* = 3.0 Hz), 125.1 (q, *J* = 288.5 Hz), 113.6, 78.0 (q, *J* = 2.0 Hz), 75.9 (q, *J* = 1.5 Hz), 67.3 (d, *J* = 27.0 Hz), 34.9, 27.4, 26.5, 24.8; HRMS (ESI⁺) *m/z* calcd for C₁₆H₁₅Cl₂F₃NO₃ [M+H]⁺ 396.0381, found 396.0384. An analytical sample of **7f** was crystallized from Et₂O:hexane. **11** : [α]D²⁰ = -56 (c 0.67, CHCl₃); IR (film) νmax 1103, 1165, 1196, 1284, 1456, 1746 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -71.4 (br s, 3F), -72.6 (m, 3F), -72.8 (m, 3F); ¹H NMR (500 MHz, CDCl₃) δ 7.38 (d, *J* = 2.0 Hz, 1H), 7.25 (d, *J* = 8.0 Hz, 1H), 7.20 (dd, *J* = 8.0 Hz, *J* = 2.0 Hz, 1H), 4.83 (d, *J* = 5.5 Hz, 1H), 4.78 (d, *J* = 5.5 Hz, 1H), 4.29 (hept, *J* = 5.0 Hz, 1H), 3.65 (td, *J* = 13.5 Hz, *J* = 5.0 Hz, 1H), 3.48 (ddd, *J* = 13.5 Hz, *J* = 11.5 Hz, *J* = 5.5 Hz, 1H), 3.14 (ddd, *J* = 12.5 Hz, *J* = 11.5 Hz, *J* = 5.0 Hz, 1H), 3.02 (td, *J* = 12.5 Hz, *J* = 5.5 Hz, 1H), 1.45 (s, 3H), 1.44 (s, 3H); ¹³C>{¹H} NMR (125.7 MHz, CDCl₃) δ 173.2, 135.0, 133.85, 133.82, 132.1, 129.7, 127.7, 121.5 (q, *J* = 286.5 Hz), 120.6 (qq, *J* = 283.5 Hz, *J* = 3.0 Hz), 115.7, 94.7 (q, *J* = 32.5 Hz), 78.4, 75.5 (d, *J* = 1.0 Hz), 70.8 (hept, *J* = 34.0 Hz), 42.1, 30.7, 27.1, 26.4; HRMS (ESI⁺) *m/z* calcd for C₁₉H₁₇Cl₂F₉NO₄ [M+H]⁺ 564.0391, found 564.0386.

(3S,4R)-1-(3,4-dimethoxyphenethyl)-3,4-dihydroxy-5-oxo-2-(trifluoromethyl)pyrrolidin-2-yl acetate 9 [dr (R,S,R):(S,S,R) = 89:11]. Colorless oil : IR (film) νmax 727, 754, 1025, 1137, 1227, 1515, 1704, 1755, 2941, 3388 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.2 (s, 3F major), -80.6 (s, 3F minor); ¹H NMR (500 MHz, CDCl₃) δ 6.80-6.69 (m, 1H, major and minor), 5.54 (d, *J* = 6.0 Hz, 1H, minor), 5.25 (d, *J* = 5.5 Hz, 1H, major), 4.94 (br s, 1H, major), 4.62 (d, *J* = 5.5 Hz, 1H, major), 4.50 (br s, 1H, minor), 4.49 (d, *J* = 6.0 Hz, 1H, minor), 3.85 (s, 3H, major), 3.83 (s, 3H, minor), 3.82 (s, 3H, major), 3.62 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 4.5 Hz, 1H, major and minor), 3.42 (ddd, *J* = 14.0 Hz, *J* = 10.5 Hz, *J* = 6.5 Hz, major and minor), 2.98 (m, 1H, minor), 2.96 (ddd, *J* = 13.0 Hz, *J* = 10.5 Hz, *J* = 6.5 Hz, 1H major), 2.79 (ddd, *J* = 13.0 Hz, *J* = 10.5 Hz, *J* = 4.5 Hz, 1H major and minor), 2.36 (br s, 1H, major and minor), 2.17 (s, 3H,
major), 2.11 (s, 3H, minor); ¹³C {¹H} NMR (125.7 MHz, CDCl₃) δ 173.2 (minor), 170.5 (major), 169.4 (minor), 169.3 (major), 149.0 (major), 148.9 (major), 147.9 (minor), 147.7 (major), 131.1 (major), 130.9 (minor), 123.2 (q, J = 285.5 Hz, major), 122.8 (q, J = 285.5 Hz, minor), 121.0 (major and minor), 112.8 (minor), 112.5 (major), 111.6 (major), 111.4 (minor), 87.0 (q, J = 33.0 Hz, major), 69.9 (major), 69.2 (minor), 68.0 (minor), 67.1 (major), 56.04 (major), 56.01 (minor), 55.96 (minor), 55.92 (major), 42.5 (major and minor), 33.7 (major), 33.1 (minor), 20.4 (major), 20.2 (minor); HRMS (ESI⁺) *m/z* calcd for C₁₇H₂₁F₃NO₇ [M+H]⁺ 408.1270, found 408.1268.

(3aR,6R,6aS)-4-(3,4-dimethoxyphenethyl)-6-hydroxy-2,2-dimethyl-3a-(trifluoromethyl) dihydro-3aH-[1,3]dioxolo[4,5-b]pyrrol-5(4H)-one 10. Colorless oil : [α]D²⁰ = +47 (c 0.96, CHCl₃); IR (film) νmax 727, 884, 1027, 1064, 1141, 1156, 1177, 1515, 1727, 2938, 2992, 3445, 3667 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -77.8 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 6.81-6.74 (m, 3H), 4.92 (d, J = 5.0 Hz, 1H), 4.41 (t, J = 5.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.56-3.47 (m, 2H), 3.42 (ddd, J = 14.0 Hz, J = 12.5 Hz, J = 5.0 Hz, 1H), 2.99 (td, J = 12.5 Hz, J = 5.0 Hz, 1H), 2.73 (td, J = 12.5 Hz, J = 5.0 Hz, 1H), 1.51 (s, 3H), 1.47 (s, 3H); ¹³C {¹H} NMR (125.7 MHz, CDCl₃) δ 173.2, 149.1, 147.9, 130.9, 122.1 (q, J = 283.0 Hz), 120.8, 117.3, 112.1, 111.5, 93.6 (q, J = 35.0 Hz), 77.0, 69.4, 56.01, 55.98, 42.7, 33.9, 27.6, 26.1; HRMS (ESI⁺) *m/z* calcd for C₁₈H₂₃F₃NO₆ [M+H]⁺ 406.1477, found 406.1479.

**General procedure for the deprotection of the acetonide protecting group.** *General Procedure D.* A solution of acetonide-protected compound in a 1 : 1 (v/v) mixture of THF and 10% aq. sol. of HCl was heated at 50°C with a heating mantle. After completion, the reaction mixture was cooled to rt, concentrated under reduced pressure and purified.

(1R,2R,10bS)-1,2-dihydroxy-8,9-dimethoxy-10b-(trifluoromethyl)-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one 8. According to General Procedure D, a solution of Pictet-Spengler product 7a (110 mg, 0.28 mmol) in THF (1 mL) and 10% aq. sol.
of HCl (1 mL) was heated 8h. Purification of the residue on silica gel (EtOAc/Et₂O 1:1) afforded diol **8** (95 mg, 96%) as a colorless amorphous solid: $[\alpha]_{D}^{20} = +234 (c 1.00, CHCl₃); IR (film) $v_{max}$ 777, 924, 1119, 1162, 1261, 1520, 1695, 2940, 3345 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) $\delta$ -71.9 (s, 3F); ¹H NMR (500 MHz, CDCl₃) $\delta$ 6.85 (s, 1H), 6.62 (s, 1H), 4.79-4.76 (m, 2H), 4.70 (s, 1H), 4.34 (dd, $J$ = 13.0 Hz, $J$ = 6.0 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.36 (s, 1H), 3.24 (td, $J$ = 13.0 Hz, $J$ = 4.5 Hz, 1H), 2.88 (ddd, $J$ = 16.0 Hz, $J$ = 12.0 Hz, $J$ = 6.5 Hz, 1H), 2.73 (dd, $J$ = 16.0 Hz, $J$ = 3.5 Hz, 1H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) $\delta$ 173.5, 149.6, 147.9, 128.4, 125.7 (q, $J$ = 288.0 Hz), 117.8, 111.8, 110.5 (q, $J$ = 2.5 Hz), 70.4 (q, $J$ = 3.0 Hz), 69.3, 68.9 (q, $J$ = 26.5 Hz), 56.2, 55.9, 36.1, 27.2; HRMS (ESI⁺) *m/z* calcd for C₁₅H₁₇F₃NO₅ [M+H]⁺ 348.1059, found 348.1061.

(1R,2R,10bR)-1,2-dihydroxy-8,9-dimethoxy-10b-(trifluoromethyl)-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one epi-8. According to General Procedure D, a solution of Pictet-Spengler product epi-7a (110 mg, 0.28 mmol) in THF (1 mL) and 10% aq. sol. of HCl (1 mL) was heated 2h45. Purification of the residue on silica gel (EtOAc/Et₂O 1:1) afforded diol epi-8 (98 mg, 99%) as a pale yellow amorphous solid: $[\alpha]_{D}^{20} = -124 (c 1.00, CHCl₃); IR (film) $v_{max}$ 774, 1117, 1160, 1229, 1260, 1519, 1689, 2851, 2933, 3417 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) $\delta$ -68.7 (s, 3F); ¹H NMR (500 MHz, CDCl₃) $\delta$ 7.16 (s, 1H), 6.59 (s, 1H), 5.52 (d, $J$ = 4.0 Hz, 1H), 4.47 (t, $J$ = 8.5, 1H), 4.39 (dd, $J$ = 13.5 Hz, $J$ = 7.0 Hz, 1H), 4.31 (dd, $J$ = 8.5 Hz, $J$ = 4.0 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.80 (d, $J$ = 8.5 Hz, 1H), 3.40 (td, $J$ = 13.0 Hz, $J$ = 5.5 Hz, 1H), 2.87 (m, 1H), 2.77 (dd, $J$ = 16.5 Hz, $J$ = 4.5 Hz, 1H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) $\delta$ 172.8, 149.8, 148.4, 126.3, 125.5 (q, $J$ = 288.5 Hz), 122.8, 111.4, 109.7, 74.3, 67.8, 67.6 (q, $J$ = 26.5 Hz), 56.3, 56.0, 35.8, 26.7; HRMS (ESI⁺) *m/z* calcd for C₁₅H₁₇F₃NO₅ [M+H]⁺ 348.1059, found 348.1060.

**General procedure for the reduction of lactam.** *General Procedure E.* To a solution of lactam **7a** or epi-7a in THF was added dropwise, at rt and under Ar, BH₃.Me₂S (2M sol. in THF). After
full conversion of amide, ethanol (14 mL) was carefully added to the reaction mixture. After
30 min of stirring, the reaction was concentrated under reduced pressure and the residue was
purified by chromatographie on silica gel to afford amine **12** or *epi-12*.

(8aS,11aR,11bS)-2,3-dimethoxy-10,10-dimethyl-11b-(trifluoromethyl)-5,6,8,8a,11a,11b-hexahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinoline **12**. According to General Procedure E, lactam **7a** (96 mg, 0.25 mmol) reacted with BH₃.Me₂S (2M in THF, 1.25 mL, 2.50 mmol, 10 equiv) in THF (3 mL) for 5h. Purification of the residue on silica gel (PE/EtOAc 9:1) afforded amine **12** (76 mg, 82%) as a colorless oil : [α]D²⁰ = +44 (c 1.00, CHCl₃); IR (film) vmax 859, 1132, 1209, 1519, 2835, 2937 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -74.7 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 6.85 (q, J = 1.5 Hz, 1H), 6.59 (s, 1H), 5.07 (d, J = 5.5 Hz, 1H), 4.84 (td, J = 5.5 Hz, J = 2.0 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.58 (ddd, J = 12.5 Hz, J = 5.0 Hz, J = 1.0 Hz, 1H), 3.24-3.11 (m, 3H), 2.79 (ddd, J = 15.0 Hz, J = 9.0 Hz, J = 5.0 Hz, 1H), 2.67 (dt, J = 15.0 Hz, J = 4.5 Hz, 1H), 1.27 (s, 3H), 1.10 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 148.5, 146.5, 130.6, 127.0 (q, J = 288.0 Hz), 120.9, 114.1 (q, J = 2.0 Hz), 112.7, 110.5, 84.2, 80.9, 72.7 (q, J = 24.0 Hz), 59.0, 56.3, 55.7, 48.7, 28.8, 26.6, 24.9; HRMS (ESI⁺) *m/z* calcd for C₁₈H₂₃F₃NO₄ [M+H]⁺ 374.1579, found 374.1578.

(8aS,11aR,11bR)-2,3-dimethoxy-10,10-dimethyl-11b-(trifluoromethyl)-5,6,8,8a,11a,11b-hexahydro-[1,3]dioxolo[4',5':3,4]pyrrolo[2,1-a]isoquinoline epi-12.

According to General Procedure E, lactam *epi-7a* (260 mg, 0.67 mmol) reacted with BH3.Me2S (2M in THF, 6.7 mL, 13.4 mmol, 20 equiv) in THF (8 mL) for 5h. Purification of the residue on silica gel (PE/EtOAc 3:1) afforded amine *epi-12* (178 mg, 71%) as a colorless oil : [α]D²⁰ = -19 (c 0.52, CHCl₃); IR (film) vmax 855, 1104, 1125, 1518, 2849, 2940 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -66.2 (br s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 6.92 (s, 1H), 6.56 (s, 1H), 4.97 (d, J = 6.0 Hz, 1H), 4.63 (dd, J = 6.0 Hz, J = 5.0 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.41 (td, J = 14.0 Hz, J = 5.5 Hz, 1H), 3.21 (d, J = 11.0 Hz, 1H), 3.14 (dd, J = 14.5 Hz, 6.5 Hz, 1H), 3.00
(m, 1H), 2.97 (dd, *J* = 11.0 Hz, *J* = 4.5 Hz, 1H), 2.42 (dd, *J* = 17.5 Hz, *J* = 5.5 Hz, 1H), 1.61 (s, 3H), 1.36 (s, 3H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 149.1, 147.9, 128.4, 125.6 (q, *J* = 285.0 Hz), 121.3, 112.6, 111.7, 111.1 (q, *J* = 1.5 Hz), 87.5, 78.1, 70.5 (q, *J* = 26.0 Hz), 56.2, 55.9, 53.9, 41.5, 25.7, 24.9, 20.4; HRMS (ESI⁺) *m/z* calcd for C₁₈H₂₃F₃NO₄ [M+H]⁺ 374.1579, found 374.1579.

(1R,2S,10bS)-1,2-dihydroxy-8,9-dimethoxy-10b-(trifluoromethyl)-2,3,4,5,6,10b-hexahydro-1H-pyrrolo[2,1-a]isoquinolin-4-ium chloride **13**. According to General Procedure D, a solution of acetonide-protected amine **12** (76 mg, 0.20 mmol) in THF (1 mL) and 10% aq. sol. of HCl (1 mL) was heated 2h. Purification of the residue on reverse-phase chromatography (C-18 silica) (H₂O/MeOH 2:1) afforded amino diol hydrochloride **13** (50 mg, 67%) as a white amorphous solid : [α]D²⁰ = +57 (c 0.99, MeOH); IR (film) vmax 1096, 1135, 1256, 1517, 2939, 3436 cm⁻¹; ¹⁹F NMR (470 MHz, MeOD) δ -75.3 (s, 3F); ¹H NMR (500 MHz, MeOD) δ 7.01 (s, 1H), 6.76 (s, 1H), 4.44 (s, 2H), 3.84 (s, 6H), 3.35 (m, 1H), 3.23 (m, 1H), 3.00-2.79 (m, 3H), 2.59 (m, 1H); ¹³C{¹H} NMR (125.7 MHz, MeOD) δ 150.0, 148.1, 132.9, 128.1 (q, *J* = 285.0 Hz), 122.8, 115.2 (q, *J* = 2.5 Hz), 112.5, 75.2, 72.2 (q, *J* = 25.0 Hz), 71.0 (q, *J* = 2.5 Hz), 57.9, 56.7, 56.3, 47.9, 26.4; HRMS (ESI⁺) *m/z* calcd for C₁₅H₁₉F₃NO₄ [M+H]⁺ 334.1266, found 334.1269.

(1R,2S,10bR)-1,2-dihydroxy-8,9-dimethoxy-10b-(trifluoromethyl)-2,3,4,5,6,10b-hexahydro-1H-pyrrolo[2,1-a]isoquinolin-4-ium chloride epi-13. According to General Procedure D, a solution of acetonide-protected amine epi-12 (84 mg, 0.23 mmol) in THF (1 mL) and 10% aq. sol. of HCl (1 mL) was heated 2h. Purification of the residue on reverse-phase chromatography (C-18 silica) (H₂O/MeOH 2:1) afforded amino diol hydrochloride epi-13 (58 mg, 70%) as a white amorphous solid : [α]D²⁰ = -52 (c 1.21, MeOH); IR (film) vmax 708, 1093, 1113, 1150, 1518, 2868, 2945, 3357, 3476 cm⁻¹; ¹⁹F NMR (470 MHz, MeOD) δ -69.2 (s, 3F); ¹H NMR (500 MHz, MeOD) δ 7.10 (d, *J* = 1.0 Hz, 1H), 6.71 (s, 1H), 4.37 (d, *J* = 5.0 Hz, 1H),
3.97 (q, J = 5.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.32 (m, 1H), 3.27 (m, 1H), 3.10 (m, 2H), 3.00-2.91 (m, 2H), 2.44 (m, 1H); ¹³C{¹H} NMR (125.7 MHz, MeOD) δ 150.3, 149.1, 130.2, 127.7 (q, J = 285.5 Hz), 124.3, 112.9, 112.3 (q, J = 2.5 Hz), 82.7, 70.2, 69.7 (q, J = 25.0 Hz), 56.7, 56.5, 56.3, 45.2 (q, J = 1.0 Hz), 23.0; HRMS (ESI+) m/z calcd for C₁₅H₁₉F₃NO₄ [M+H]⁺ 334.1266, found 334.1266.

(3R,4S,5R)-1-(3,4-dimethoxyphenethyl)-3,4,5-trihydroxy-5-(trifluoromethyl)

pyrrolidin-2-one 14. From 5a: According to General Procedure D, a solution of protected N,O-acetal 5a (269 mg, 0.66 mmol) in THF (2 mL) and 10% aq. sol. of HCl (2 mL) was heated 22h. Purification of the residue on silica gel (PE/EtOAc 1:4) afforded triol 14 (240 mg, 99%) as a colorless oil. From 6a: According to General Procedure D, a solution of protected O-acetyl N,O-acetal 6a (151 mg, 0.34 mmol) in THF (1 mL) and 10% aq. sol. of HCl (1 mL) was heated 20h. Purification of the residue on silica gel (hexane/EtOAc 1:4) afforded triol 14 (82 mg, 66%) as a colorless oil. From 9: According to General Procedure D, a solution of deprotected O-acetyl N,O-acetal 9 [dr(R,S,R):(S,S,R) = 89:11] (79 mg, 0.19 mmol) in THF (700 µL) and 10% aq. sol. of HCl (700 µL) was heated 20h. Purification of the residue on silica gel (PE/EtOAc 1:4) afforded triol 14 (55 mg, 78%) as a colorless oil: [α]D²⁰ = +70 (c 0.94, CHCl₃); IR (film) νmax 728, 1025, 1139, 1171, 1261, 1515, 1692, 3376 cm⁻¹; ¹⁹F NMR (470 MHz, CDCl₃) δ -80.1 (s, 3F); ¹H NMR (500 MHz, CDCl₃) δ 6.75 (d, J = 8.0 Hz, 1H), 6.72-6.70 (m, 2H), 5.64 (br s, 1H), 5.24 (br s, 1H), 4.82 (br s, 1H), 4.53-4.48 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.58 (ddd, J = 13.5 Hz, J = 11.0 Hz, J = 5.0 Hz, 1H), 3.43 (ddd, J = 13.5 Hz, J = 10.5 Hz, J = 6.0 Hz, 1H), 2.91 (ddd, J = 13.0 Hz, J = 11.0 Hz, J = 6.0 Hz, 1H), 2.75 (ddd, J = 13.0 Hz, J = 10.5 Hz, J = 5.0 Hz, 1H); ¹³C{¹H} NMR (125.7 MHz, CDCl₃) δ 174.5, 149.0, 147.9, 130.8, 123.2 (q, J = 285.0 Hz), 121.0, 112.3, 111.5, 87.4 (q, J = 33.0 Hz), 68.9, 68.0, 56.00, 55.97, 42.3, 33.7; HRMS (ESI+) m/z calcd for C₁₅H₁₉F₃NO₆ [M+H]⁺ 366.1164, found 366.1165.
**Supporting Information**

Copies of all NMR spectra of all new compounds and of X-ray crystallographic data (CIF) for 3, 4a, 4b, 5a, 7a and 7f. This material is available free of charge *via* the Internet at http://pubs.acs.org.

**Acknowledgments**

We gratefully acknowledged the “région Champagne-Ardenne” (“région Grand Est” at present), the “Université de Reims-Champagne Ardenne” and the “Institut de Chimie Moléculaire de Reims” for financial support (ABJ and ML). The CNRS, the Conseil Régional de Champagne-Ardenne and the EU-program FEDER are acknowledged for the facilities of the analytical platform (PIAneT CPER project). We warmly thank C. Machado and S. Lanthony (HRMS), Dr S. Chevreux and Dr C. Kowandy (X-ray crystallographic structure determinations) as well as A. Truchon (technical assistance for the synthesis of few compounds). We also thank the French Fluorine Network (GIS CNRS).

**References and Footnotes**

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⁵ For diastereoselective Pictet-Spengler cyclization with α-substituted *N*-acyliminium ions *N*-substituted by a chiral chain, see for example: (a) Allin, S. M. ; James, S. L. ; Martin, W. P. ; Smith, T. A. D. ; Elsegood, M. R. J. Stereoselective Synthesis of the Pyrroloisoquinoline Ring System. *J. Chem. Soc., Perkin Trans. 1*, **2001**, 3029-3036. (b) Allin, S. M. ; James, S. L. ; Elsegood, M. R. J. ; Martin, W. P. Facile and Highly Stereoselective Synthesis of the Tetracyclic Erythrinane Core. *J. Org. Chem.* **2002**, *67*, 9464-9467. (c) Garcia, E. ; Arrasate, S. ; Lete, E. ; Sotomayor, N. Diastereoselective Intramolecular [2]-Amidoalkylation Reactions of L-DOPA Derivatives. Asymmetric Synthesis of Pyrrolo[2,1-*a*]isoquinolines. *J. Org. Chem.* **2005**, *70*, 10368-10374.

⁶ O'Hagan, D. Understanding Organofluorine Chemistry. An Introduction to the C–F Bond. *Chem. Soc. Rev.* **2008**, *37*, 308-319.

⁷ (a) Okano, T. ; Sakaida, T. ; Eguchi, S. Synthesis of Indoleine Derivatives Trifluoromethylated at the Bridgehead Position *via* Acyl Iminium Ion Intermediates Derived from Ring-Chain Tautomerism of 5,5,5-Trifluoro-4-oxopentanoylarylethylamides. *Heterocycles* **1997**, *44*, 227-236. (b) Hoffmann-Röder, A. ; Schweizer, E. ; Egger, J. ; Seiler, P. ; Obst-Sander, U. ; Wagner, B. ; Kansy, M. ; Banner, D. W. ; Diederich, F. Mapping the Fluorophilicity of a Hydrophobic Pocket: Synthesis and Biological Evaluation of Tricyclic Thrombin Inhibitors Directing Fluorinated Alkyl Groups into the P Pocket. *ChemMedChem* **2006**, *1*, 1205-1215. (c) Pandey, V. K. ; Anbarasan, P. One-Pot Cascade Trifluoromethylation/Cyclization of Imides: Synthesis of α-Trifluoromethylated Amine Derivatives. *J. Org. Chem.* **2014**, *79*, 4154-4160. (d) Ben Jamaa, A. ; Grellepois, F.
Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated *N*,*O*-Acetals Derived from L-Tartaric Acid. *J. Org. Chem.* **2017**, *82*, 10360-10375.

<sup>8</sup> Nonnenmacher, J. ; Massicot, F. ; Grellepois, F. ; Portella, C. Enantiopure Quaternary α-Trifluoromethyl-α-alkoxyaldehydes from L-Tartaric Acid Derived Ketoamides. *J. Org. Chem.* **2008**, *73*, 7990-7995.

<sup>9</sup> For the monotrifluoromethylation of bis-ketone derived from L-tartaric acid, see : (a) Massicot, F. ; Monnier-Benoit, N. ; Deka, N. ; Plantier-Royon, R. ; Portella, C. Synthesis of Enantiopure Trifluoromethyl Building Blocks *via* a Highly Chemo- and Diastereoselective Nucleophilic Trifluoromethylation of Tartaric Acid-Derived Diketones. *J. Org. Chem.* **2007**, *72*, 1174-1180. (b) Harakat, D. ; Massicot, F. ; Nonnenmacher, J. ; Grellepois, F. ; Portella C. The Role of the Counterion and of Silicon Chelation in the Selective Mono(trifluoromethylation) of Tartaric Acid Derived 1,4-Diketones. *Chem. Eur. J.* **2011**, *17*, 10636-10642.

<sup>10</sup> Rudzinski, DA. M. ; Kelly, C. B. ; Leadbeater N. E. A Weinreb Amide Approach to the Synthesis of Trifluoromethylketones. *Chem. Comm.* **2012**, *48*, 9610-9612.

<sup>11</sup> (a) Bégué, J.-P. ; Bonnet-Delpon, D. Preparation of Trifluoromethyl Ketones and related Fluorinated Ketones. *Tetrahedron* **1991**, *47*, 3207-3258. (b) Kelly, C.B. ; Mercadante, M.A. ; Leadbeater, N.E. Trifluoromethyl Ketones: Properties, Preparation, and Application. *Chem. Comm.* **2013**, *49*, 11133-11148.

<sup>12</sup> Heating the hydrated ketone **3** at reflux of toluene with a heating mantle led to the formation of a new product [<sup>19</sup>F NMR (470MHz, CD<sub>3</sub>OCD<sub>3</sub>) = -76.4 ppm ; <sup>19</sup>F NMR (470MHz, CDCl<sub>3</sub>) = -76.1 ppm] which give back partially to the hydrated ketone **3** [<sup>19</sup>F NMR (470MHz, CD<sub>3</sub>OCD<sub>3</sub>) = -83.7 ppm ; <sup>19</sup>F NMR (470MHz, CDCl<sub>3</sub>) = -83.9 ppm] after concentration of the reaction mixture. A small quadruplet at 188.3 ppm (*J* = 35.5 Hz) is detected in the <sup>13</sup>C{*<sup>1</sup>H}*
NMR spectrum (125.7 Mz, CDCl₃) of the crude reaction mixture containing an average 40% of
3 and 60% of the new product.

¹³ For isomerization and partial racemization of L-tartaric acid derivatives with amines under harsh heating conditions, see : (a) Gonzalez, S. V., Carlsen P. Tartradiamide Formation by Thermolysis of Tartaric Acid with Alkylamines. *Tetrahedron Lett.* **2008**, *49*, 3925-3926. (b) Heng, J.-L. ; Zhang, Y.-F. ; Zhao, W. ; Tong, J.-S. ; Ruan, Y.-P. ; Huang, P.-Q. A Study on the Racemization Step in the Synthesis of Pyrrolidinols *via* Cyclic α-Hydroxyimides. *Tetrahedron* : *Asymmetry* **2011**, *22*, 257-263.

¹⁴ (a) Miller, S. A. ; Chamberlin, R. Enantiomerically Pure Polyhydroxylated Acyliminium Ions. Synthesis of the Glycosidase Inhibitors (-)-Swainsonine and (+)-Castanospermine. *J. Am. Chem. Soc.* **1990**, *112*, 8100-8112. (b) Hoffmann, R. W. *meso* Compounds : Stepchildren or Favored Children of Stereoselective Synthesis ? *Angew. Chem. Int. Ed.* **2003**, *42*, 1096-1109.

15 (a) Hoffmann-Röder, A. ; Seiler, P. ; Diederich, F. Nucleophilic Trifluoromethylation of Cyclic Imides using (trifluoromethyl)trimethylsilane CF3SiMe3. *Org. Biomol. Chem.* **2004**, *2*, 2267-2269.
(b) Mizuta, S. ; Shibata, N. ; Sato, T. ; Fujimoto, H. ; Nakamura, S. ; Toru, T. *tri-tert*-Butylphosphine is an Efficient Promoter for the Trifluoromethylation Reactions of Aldehydes, Ketones, Imides and Imines. *Synlett* **2006**, *2*, 267-270.
(c) Mizuta, S. ; Shibata, N. ; Hibino, M. ; Nagano, S. ; Nakamura, S. ; Toru, T. Ammonium Bromides/KF Catalyzed Trifluoromethylation of Carbonyl Compounds with (trifluoromethyl)trimethylsilane and its Application in the Enantioselective Trifluoromethylation Reaction. *Tetrahedron* **2007**, *63*, 8521-8528.

¹⁶ Ornelas, M. A. ; Gonzalez, J. ; Sach, N. W. ; Richardson, P. F. ; Bunker, K. D. ; Linton, A. ; Kephart, S. E. ; Pairish, M. ; Guo, C. An Efficient Synthesis of Highly Functionalized Chiral Lactams. *Tetrahedron Lett.* **2011**, *52*, 4760-4763.
17 Mitobe, K. ; Kawasaki-Takasuka, T. ; Agou, T. ; Kubota, T. ; Yamazaki, T. Divergent Pathways for Reactions of CF3-Containing Isobenzofuran-1-ones and Amines. *J. Fluorine Chem.* **2019**, *218*, 36-41.

18 Mengel, A. ; Reiser, O. Around and Beyond Cram's Rule. *Chem. Rev.* **1999**, *99*, 1191-1223.

19 Funabiki, K., Shibata, A. ; Iwata, H. ; Hatano, K. ; Kubota, Y. ; Komura, K. ; Ebihara, M. ; Matsui, M. Asymmetric Synthesis of (*α*R)-Polyfluoroalkylated Prolinols Based on the Perfluoroalkyl-Induced Highly Stereoselective Reduction of Perfluoroalkyl *N*-Boc-pyrrolidyl Ketones. *J. Org. Chem.* **2008**, *73*, 4694-4697.

20 Cleavage of the acetonide protecting group of fused polycyclic derivative **7a** and *epi-7a* under acidic conditions (aq HCl:THF, 50°C) allowed the identification of **8** and *epi-8* and the assignment of their stereochemistry, see scheme 3.

21 Treatment of a 89:11 mixture of diastereomers of deprotected *O*-acetyl *N*,*O*-acetal **9** under acidic conditions led mostly to the triol **14** (isolated in 78% yield). Triol **14** was also obtained by acid hydrolysis of the protected *N*,*O*-acetal **5a** and *O*-acetyl *N*,*O*-acetal **6a** in 99% and 66% yields, respectively. All these results confirmed unambiguously the configurations of the stereocenters of the major stereoisomer of **9** as *R*,*S*,*R* (see experimental section for details). It is noteworthy that HCl is not effective to generate *α*-CF₃ *N*-acylimium ions, see for examples ref 7a,b.

<figure><img src="image_16.png" /></figure>

22 It is noteworthy that reaction of *N*,*O*-acetal **5a** with BF₃.Et₂O (10 equiv) in CH₂Cl₂ at rt for 24h or CF₃SO₃H (10 equiv) in HFIP at 0°C for 1h led to the formation of compound **10** as sole
product, no traces of Pictet-Spengler derivatives were detected in the ¹⁹F NMR spectra of the
crude reaction mixture.

²³ Colomer, I., Chamberlain, A.E.R. ; Haughey, M.B. ; Donohoe, T.J. Hexafluoroisopropanol as a Highly Versatile Solvent. *Nat. Rev. Chem.* **2017**, *1*, 0088.

²⁴ Attempt to cyclize *O*-acetyl *N*,*O*-acetal **6c** using 10 equiv of *BF*₃·*Et*₂*O in *CH*₂*Cl*₂ at rt led to a very complex mixture containing only 19% of the desired Pictet-Spengler products **7c** and *epi*-**7c** as a 38:62 mixture of diastereomers according to the ¹⁹F NMR analysis of the crude reaction mixture.

²⁵ Exceptionally broad signal in ¹⁹F NMR spectrum at 298K (CDCl₃) reveal hindered CF₃ rotations for the minor isomer of all Pictet-Spengler products *epi*-7a-f, see : Prakash, G. K. S. ; Wang, F. ; Rahm, M. ; Shen, J. ; Ni, C. ; Haiges, R. ; Olah, G. A. On the Nature of C-H···F-C Interactions in Hindered CF₃-C(sp³) Bond Rotations. *Angew. Chem. Int. Ed.* **2011**, *50*, 11761-11764.

²⁶ Ryder, G. M. ; Wille, U. ; Willis, A. C. ; Pyne, S. G. 1,2-Addition *versus* Homoconjugate Addition Reactions of Indoles and Electron-Rich Arenes to α-Cyclopropyl N-Acyliminium Ions: Synthetic and Computational Studies. *Org. Biomol. Chem.* **2019**, *7*, 7025-7035.

²⁷ The van der Waals volume of CF₃ is greater than that of a methyl and similar to that of an isopropyl group, see : Ruzziconi, R. ; Spizzichino, S. ; Mazzanti, A. ; Lunazzi, L. ; Schlosser, M. The Biphenyl-Monitored Effective Size of Unsaturated Functional or Fluorinated *ortho*-Substituents. *Org. Biomol. Chem.* **2010**, *8*, 4463-4471.

²⁸ Nugiel, D.A. ; Jacobs, K. ; Worley, T. ; Patel, M. ; Kaltenbach III, R.F. ; Meyer, D.T. ; Jadhav, P.K. ; De Lucca, G.V. ; Smyser, T.E. ; Klabe, R.M. ; Bacheler, L.T. ; Rayner, M.M. ; Seitz, S.P. Preparation and Structure-Activity Relationship of Novel P1/P1'-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors. *J. Med. Chem.* **1996**, *39*, 2156-2169.