# A New Approach for the Synthesis of Sotolon in Racemic and Enantioenriched Forms

Bui Thuy Trang, Cao Hai Thuong, Pham Xuan Thao, Dinh Hung Mac, Rene Gree

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Bui Thuy Trang, Cao Hai Thuong, Pham Xuan Thao, Dinh Hung Mac, Rene Gree. A New Approach for the Synthesis of Sotolon in Racemic and Enantioenriched Forms. Vietnam Journal of Chemistry, 2021, 59 (1), pp.42-46. 10.1002/vjch.202000095. hal-03217110

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# A New Approach for the Synthesis of Sotolon in Racemic and Enantioenriched Forms

Thuy Trang Buiª, Hai Thuong Cao*ª, Thao Xuan Phamª, Dinh Hung Macᵇ, Rene Gréeᶜ

ªLe Quy Don Technical University, 236 - Hoang Quoc Viet - Hanoi - Vietnam

ᵇVietNam National University, 144 - Xuân Thuy Street - Cau Giay - Hanoi - Vietnam

ᶜUniversité de Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc 35042 - Rennes Cedex, France

Received ....; Accepted for Publication....

## Abstract

Sotolon (3-hydroxy-4,5-dimethyl-2(5H)-furanone) has been synthezised both in racemic and enantioenriched forms by a short sequence involving intramolecular tandem isomerization-aldolisation and tandem izomerization/Mannich reactions as key steps. Optically active Sotolon has been obtained by using (S)-*N-tert*-butane sulfinimine as chiral starting material.

**Keywords** Sotolon, Isomerization-Mannich, Catalysis, Nickel, α-aminoester

## 1. INTRODUCTION

3-Hydroxy-4,5-dimethyl-2(5H)-furanone (Sotolon) is a powerful flavor compound found in various foods and spices, as well as in beverages including aged beers, wines and sake. It has an extremely powerful aroma with a typical smell of fenugreek, maple syrup, caramel and burnt sugar at low concentration.[1,2] Both the olfactory properties and the odour intensity are very different for the two enantiomers: in dry white wines for instance, the perception threshold of (R)-sotolon was determined to be 89 µg/l, whereas the threshold of (S)-sotolon was significantly 100 times lower with 0.8µg/l.[3] It has been proposed that, in wine, Sotolon was produced by the oxidative degradation of ascorbic acid,[4] whereas in aged sake, this molecule was formed by condensation of α-ketobutyrate and acetaldehyde, both being acid decomposition products of threonine.[5] Blank et al. have formulated a pathway for the formation of Sotolon via thermally induced oxidation of 4-hydroxy isoleucine and its lactones with α-dicarbonyl.[6] The results showed that methylglyoxal was the best dicarbonyl compound at a 1:10 molar ratio and aminolactone was a better precursor than its aminoacid 4-hydroxyl isoleucine. Very recently, Lanfermann et al. gave support for this pathway in cultures of *Laetiporus sulphureus* by using labelled derivatives as precursors.[7]

## 2. MATERIALS AND METHODS

All reagents were obtained commercially and used without further purification. All reactions have been carried out under a nitrogen atmosphere and dry conditions. The solvents used were freshly distilled under anhydrous conditions, unless otherwise specified. The reaction mixtures have been magnetically stirred with teflon stirring bars, and the temperatures were measured externally. Reactions that require anhydrous conditions have been carried out by using oven dried (120°C, 24 h) glassware. Yields refer to chromatographically and spectroscopically (¹H- and ¹³C-NMR) homogeneous materials, and the reactions have been monitored by thin layer chromatography (TLC), carried out on 0.25 mm Merck silica gel plates (60 F254). The eluents used were mixtures of *n*-pentane (Pent) and ethyl acetate (EtOAc), with detection by UV light, or a *p*-anisaldehyde staining solution. Acros silica gel (60, particle size 0.040–0.063 mm) was used for column chromatography. Nuclear magnetic resonance (NMR) spectra have been recorded with Bruker Avance 300 spectrometers. ¹H NMR spectra: δ (H) are given in ppm relative to tetramethylsilane (TMS), using [δ(CHCl₃) = 7.26 ppm] as internal reference. ¹³C NMR spectra: δ (C) are given in ppm relative to TMS, using [δ(CDCl₃) = 77.0 ppm] as internal reference. Multiplicities were designated as singlet (s), doublet (d), triplet (t), quadruplet (q), quintuplet (qt), multiplet (m) or br (broad). Mass spectral analyses have been performed at the Centre Régional de Mesures Physiques de l'Ouest (CRMPO) in Rennes (France). The optical
rotation values have been measured with a Perkin-
Elmer 141 Polarimeter, at 589 nm. The concentration
was reported in gram per milliliter (c, g. ml⁻¹).

**Tandem isomerization-aldolization reaction from allylic alcohol with ethylglyoxalate using Fe(CO)₅ as the catalyst.**

**Synthesis of 3 and 4.** A solution of alcohol 1 (200 mg, 2.78 mmol); ethyl glyoxalate (238 mg, 2.78 mMol) and Fe(CO)₅ (37 µL, 0.278 mMol) in THF (15 mL) was irradiated with a Philip HPK125 lamp during 1h. Solvent was removed under reduced pressure and residue was filtered on silica gel with Et₂O as eluent to afford a diastereoisomeric mixture of aldols (2 diastereoisomers: 75/25 by ¹H NMR). These products were separated by column chromatography on silica gel with Pent/EtOAc (70/30) as eluent. The organic extracts were combined, dried (Na₂SO₄) and concentrated under vacuum. The crude product was purified by chromatography on SiO₂ by using as eluent a 4:6 mixture of *n*-pentane and EtOAc. The two diastereoisomers **3** and **4** were isolated as colorless solids in 98% overall yield (46.8 mg).

**Isomer syn-3:** Rf (syn-3)=0.35; Mp=116-118°C. IR $v_{max}$ cm⁻¹: 3400 (br, m), 1700 (s), 1620 (m), 1420 (m), 1380 (m), 1220 (s), 1160 (s), 930 (m), 860 (m), 780 (m). ¹H NMR (500 MHz, CDCl₃) δ (ppm) 4.59 (dd, *J* = 4.0 Hz, *J* = 7.4 Hz, 1H (*CHOH*)); 4.27 (q, *J* = 7.1 Hz, 2H (*CH₂CH₃*)); 2.96 (dq, *J* = 4.0 Hz, *J* = 7.4 Hz, 1H (*CHCH₃*)); 2.24 (s, 3H (*COCH₃*)); 1.31 (t, *J* = 7.1 Hz, 3H (*CH₂CH₃*)); 1.23 (d, *J* = 7.1 Hz, 3H (*CHCH₃*)); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 9.9, 13.7, 27.6, 49.6, 61.5, 70.6, 172.9, 208.9.

**Isomer anti-4:** Rf (anti-4)=0.30; Mp=122-124°C. IR $v_{max}$ cm⁻¹: 3400 (br, m), 1760 (s), 1620 (m), 1430 (m), 1380 (m), 1210 (s), 1150 (s), 930 (m), 860 (m), 780 (m). ¹H NMR (500 MHz, CDCl₃) δ (ppm) 4.29 (dd, *J* = 5.1 Hz, *J* = 7.2 Hz, 1H (*CHOH*), 4.23 (q, *J* = 7.1 Hz, 2H (*CH₂CH₃*)); 3.03 (dq, *J* = 5.1 Hz, *J* = 7.2 Hz, 1H (*CHCH₃*)); 2.20 (s, 3H (*COCH₃*)), 1.28 (d, *J* = 7.2 Hz, 3H (*CH₂CH₃*)); 1.13 (d, *J* = 7.2 Hz, 3H (*CHCH₃*)); ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 12.2, 13.7, 28.4, 49.8, 61.2, 72.1, 172.9, 209.7.

**Tandem cyclisation and reduction of the mixture syn-3 and anti-4 using NaBH₄ and BnBr.**

NaBH₄ (456 mg, 12 mMol) was added in 3 portions, under nitrogen at 0°C, to a solution of the mixture of α-hydroxy ester *syn-3* and *anti-4* (1.03 g, 6.0 mMol) and BnBr (2.85 mL, 24 mMol), in MeOH (30 mL). The reaction mixture was kept under magnetic stirring at 0°C until the starting material disappeared (TLC monitoring, about 1 h). After addition of water (15 mL) and extraction with EtOAc (3x15 mL), the organic phases were combined, washed with a saturated solution aqueous of NaCl, dried (Na₂SO₄), and concentrated under vacuum. The crude product was purified by chromatography on SiO₂ by using a

4:6 mixture of *n*-pentane and EtOAc as the eluent.
The **5**, mixture of more than 3 diastereoisomers, was
collected in 90% overall yield (702 mg).

**Synthesis of Sotolon in racemic form:** A solution of oxalyl chloride (152 mg, 1.2 mMol) in 10 ml of freshly distilled CH₂Cl₂ was cooled to -78°C, and DMSO (187 mg, 2.4 mMol) was carefully added under nitrogen atmosphere. After stirring for 15 min, a solution of hydroxylactone **5** (78 mg, 0.6 mMol) in CH₂Cl₂ (5 ml) and Et₃N (7.0 ml) was added successively. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 2.5 h. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous Na₂CO₃ solution, brine and dried over anhydrous Na₂SO₄. After removal of the solvent under reduced pressure, the crude product was purified by silica gel chromatography by using as eluent a 4:6 mixture of *n*-pentane and EtOAc, sotolon was isolated in 90% yield (69.1 mg). IR $v_{max}$ cm⁻¹: 3350 (br, m), 1750 (s), 1710 (s), 1680 (m), 1335 (m), 1220 (s), 1160 (s), 1065 (m), 1025 (m), 920 (m), 780 (m). ¹H NMR (500 MHz, CDCl₃) δ (ppm) 5.43 (s, br, 1H (*CHOH*)); 4.45 (dq, *J* = 7.1 Hz, *J* = 1.5 Hz, 1H (*CHCO*)); 1.95 (d, *J* = 1.5 Hz, 3H (*CCH₃*)); 1.40 (d, *J* = 7.1 Hz, 3H (*CHCH₃*)). ¹³C NMR (125 MHz, CDCl₃) δ (ppm) 14.2, 29.7, 60.5, 123.8, 140.8, 178.6.

**(S)-Sotolon:** Aminolactone **7** [11] (45 mg, 0.27 mMol) was dissolved in a phosphate buffer (20 mL, 0.1 mol/L, pH 5.0) at room temperature, then methylglyoxal (20 mg, 2.7 mMol) was added. The solution was boiled for 1 h. After cooling down, water (20 mL) were added. The mixture was saturated with NaCl, then the pH was adjusted to 4 with HCl (1 mol/L) and extracted with Et₂O. The extract was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel chromatography by using as eluent a 4:6 mixture of *n*-pentane and EtOAc, (S)-sotolon was isolated in 32% yield (11 mg). ¹H NMR (300 MHz, CDCl₃) δ (ppm) 6.0 (s, br, 1H (*CHOH*)); 4.83 (dq, *J*=6.8 Hz, *J*=1.5 Hz, 1H(*CHCO*)); 1.95 (d, *J*=1.5 Hz, 3H (*CHCH₃*)); 1.40 (d, *J*=6.8 Hz, 3H (*CHCH₃*)). ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 12.2, 17.8, 76.4, 118.5, 139.5, 173.1. HRMS: Calcd for C₆H₁₂NO₂ [M+H]⁺ 129.0868; found [M+H]⁺ 129.0867. [α]ᵢD²₀ = +7.2 (c 0.02, Et₂O). By using the most recent data on (S)-Sotolon (+15.2),[12] this translates into 47% ee.

**(R)-Sotolon:** The same procedure that used for synthesis of (S)-Sotolon: lactone **8** [11] (56 mg, 0.34 mMol), methylglyoxal (244 mg, 3.4 mMol), 30 ml phosphate buffer, (R)-Sotolon was obtained in 33% yield (14.4 mg). ¹H and ¹³C NMR was the same of (S)-Sotolon. HRMS: Calcd for C₆H₁₂NO₂ [M+H]⁺
129.0868; found [M+H]$^+$ 129.0870. [$\alpha_D^{20}$] = -6.6 (c = 0.18, Et$_2$O). By using the most recent data on (R)-Sotolon (-23.1),[12] this translates into 29% ee.

### 3. RESULTS AND DISCUSSION

To date, several syntheses of Sotolon and its derivatives have been reported but there are only few procedures to obtain the final product in optically active form.[8] In this paper, we describe a novel strategy toward the synthesis of Sotolon either in racemic form or as optically active derivatives. The racemic synthesis involves a tandem isomerization-aldolisation reaction from an allylic alcohol with ethyl glyoxylate to produce α-hydroxyesters (A), followed by a reduction/cyclization step to afford α-hydroxylactones (B). Finally, Swern oxidation of these lactones should afford the desired racemic Sotolon (Figure 1).

The second pathway involves a tandem isomerization-Mannich reaction with a chiral sulfinylimine as the electrophilic component, to produce a N-protected α-aminoester (C), followed by a reduction/cyclization to afford an aminolactone. Then, cleavage of N-protecting group can give aminolactone (D). Finally, reaction of the primary amine with an α-dicarbonyl compound should result in a Schiff base which, after double bond shift and subsequent hydrolysis, will give rise to Sotolon (Figure 1).[6,7]

<figure><img src="image_1.png" /><figcaption>**Figure 1** Retrosynthetic analysis for the preparation of racemic (1) and optically active Sotolon (2)</figcaption></figure>

Thus, for the synthesis of racemic Sotolon, the tandem isomerization-aldolisation reaction of allylic alcohol 2 with ethylglyoxylate, and using Fe(CO)$_5$ at 10 mol % as catalyst, afforded in excellent yield the α-hydroxy esters 3 and 4 in a 75/25 diastereoisomeric ratio (Scheme 1). The separation of these aldol products was performed easily by chromatography on silica gel. In agreement with previous results,[9] the stereochemistry of these α-hydroxyesters was established by ¹H NMR: the *anti*-diastereoisomer $J_{12}$

(Scheme 1) coupling constants were larger (5.1 Hz) than the syn one (4.0 Hz). However, the separation of these derivatives was not absolutely required since the two diastereoisomers could be used together directly for the next transformation.

<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Tandem isomerization- aldolisation starting from allylic alcohol 2 and preparation of intermediates 3 and 4.</figcaption></figure>

The next step was the reduction of ketone to the corresponding hydroxyl group. Several agents were tried for the reaction, such as LiAlH$_4$, NaBH$_4$, L-selectride, Super-hydride... In every case, the reaction was not selective and afforded the desired product 5 as a complex mixture with several byproducts, such as the opened form derivatives and over reduction products of lactone 5. This result has been also observed recently by Wagner *et al.*[10]

<figure><img src="image_3.png" /><figcaption>**Scheme 2.** Synthesis of racemic Sotolon</figcaption></figure>

The combination of NaBH$_4$ and BnBr was found to be the most effective agent for this reduction. The tandem reduction-cyclization of the mixture of 3 and 4 with NaBH$_4$ in presence of BnBr in MeOH at 0°C afforded in 90% overall yield the mixture of lactones 5 (Scheme 2). Finally, the transformation of lactones 5 to Sotolon was carried out by Swern oxidation in CH$_2$Cl$_2$ at -78°C. This reaction afforded first an unstable intermediate 6, which isomerized immediately to racemic Sotolon (Scheme 2). The ¹H, ¹³C NMR data of this product were in complete agreement with those reported in the literature.[6]

For the synthesis of optically active Sotolon, (S)-*N*-tert-butane sulfinimine was used as an excellent chiral auxiliary. We have already reported the tandem isomerization-Mannich reaction from glyoxylate sulfinimine and allylic alcohol 2 by using the NiHCl(dppe)/MgBr$_2$ catalytic system, affording in excellent yield the protected β-aminoketones 7 (74%, 75/25 diastereoisomeric ratio). Separation of major syn product, followed by the reduction of this
amino ketone by the NaBH₄/BnBr combination, and cleavage of the sulfinyl group gave the two optically pure (ee>99%) aminolactones **8** and **9** in 37% and 29.6% yield respectively (Scheme 3).[11]

<figure><img src="image_4.png" /><figcaption>**Scheme 3.** Preparation of aminolactones **8** and **9**.[11]</figcaption></figure>

The transformation of these lactones amino hydrochlorides **8** and **9** to optically active (*S*)- and (*R*)-Sotolon was carried out with methylglyoxal in a phosphate buffer solution, following a procedure reported in the literature.[7] Reaction between each aminolactone and the dicarbonyl compound produced first the corresponding Schiff base. This was followed by migration of the double bond, and a final hydrolysis of this regioisomeric imine generated (*S*)- and (*R*)-Sotolon in 32% and 33% yields respectively. Spectral data of these derivatives were identical to previous racemic compound. Comparison of the [α]<sup>D</sup> values with the most recent datas,[12] indicated that these derivatives were obtained in 47% et 29% ee's only. Since this process has been performed earlier only with racemic compounds,[7] we demonstrate here that some racemization is occurring during this step. It is interesting to remark that a slow racemization of Sotolon has been already demonstrated also in wine model solutions.[3]

<figure><img src="image_5.png" /><figcaption>**Scheme 4.** Synthesis of (*S*)- and (*R*)- Sotolon.</figcaption></figure>

In conclusion, we reported herein the synthesis of Sotolon in both racemic and enantiomerically enriched forms by using tandem isomerization-aldolisation and isomerization-Mannich reactions starting from cheap and commercially available raw materials. This method can be extented to analogues of Sotolon, even in larger scale. Moreover, this strategy offers an efficient strategy towards new [■]-hydroxyesters and [■]-aminoesters, as well as amino-

lactones, which can be considered as interesting building blocks for organic and medicinal chemistry.

### 4. CONCLUSIONS

In conclusion, we reported herein the synthesis of Sotolon in both racemic and enantiomerically enriched forms by using tandem isomerization-aldolisation and isomerization-Mannich reactions starting from cheap and commercially available raw materials. This method can be extented to analogues of Sotolon, even in larger scale. Moreover, this strategy offers an efficient strategy towards new α-hydroxyesters and α-aminoesters, as well as amino lactones, which can be considered as interesting building blocks for organic and medicinal chemistry.

### REFERENCES

1. For representatives publications on this topic see: (a) Scholtes, C.; Nizet, S.; Collin, S. *J. Agric. Food Chem.* **2015**, *63*, 2886-2892; (b) Rapior, S.; Fons, F.; Bessière J-M. *Mycologia* **2000**, *92*, 305-308. (c) Pham, T. T.; Guichard, E.; Schlich, P.; Charpentier, C. *J. Agric. Food. Chem.* **1995**, *43*, 2616-2629; (d) Blank, I.; Schierberle P. *Flavour Fragr. J.* **1993**, *8*, 191-195; (e) Martin, B. ; Etiévant, P. X. ; Le Quéré, J. L. ; Schlich P. *J. Agric. Food. Chem.* **1992**, *40*, 475-478; (f) Guichard, E.; Etiévant, P.; Henry, R.; Mosandl A. Z. *Lebensm. Unters. Forsch.* **1992**, *195*, 540-544 and references cited therein.

2. Sotolon has been also found to be responsible for the characteristic odor of maple syrup urine disease: Podebrad, F.; Heil, M.; Reichert, S.; Mosandl, A.; Sewell, A. C.; Böhles H. *J. Inher. Metabolic Disease* **1999**, *22*, 107-114.

3. Pons, A.; Lavigne, V.; Landais, Y.; Darriet, P.; Dubourdieu, D. *J. Agric. Food. Chem.* **2008**, *56*, 1606-1610.

4. Pons, A.; Lavigne, V.; Landais, Y.; Darriet, P.; Dubourdieu D. *J. Agric. Food. Chem.* **2010**, *58*, 7273-7279.

5. Takahashi, N.; Tandenuma, M.; Sato, S. *Agr. Biol. Chem.* **1976**, *40*, 325-330.

6. Blank, I.; Lin, J.; Fumeaux, R.; Welti, D. H.; Fay, L. B. *J. Agric. Food Chem.*, **1996**, *44*, 1851-1856.

7. Lanfermann, I.; Krings, U.; Schopp, S.; Bergera. R. G. *Flavour Fragr. J.* **2014**, *29*, 233-239.

8. a) Xie, J.; Han, H.; Sun, L.; Zheng, H.; Sun B. *Flavour Fragr. J.* **2012**, *27*, 244-249; b) Fräter, G. ; Müller U. *Tetrahedron Lett.* **1993**, *34*, 2753-2756; c) Fronza, G. ; Fuganti, C.; Pedrocchi-Fantoni, G. ; Servi S. *Tetrahedron Lett.* **1992**, *33*, 5625-5628; d) Zaak A. *J. Org. Chem.* **1992**, *57*, 4558-4560; e) Okada, K.; Kobayashi, A.; Mori K. *Agric. Biol. Chem.* **1983**, *47*, 325-330; f) Sulser, H.; Habegger, M.; Büchi W. Z. *Lebensm. Unters. Forsch.* **1972**, *148*, 215-221.
9. Cuperly, D. ; Petrignet, J. ; Crévisy, C. ; Grée, R. *Chem. Eur. J.* **2006**, *12*, 3261-3274.

10. Marin, S. D. L.; Catala, C.; Kumar, S. R.; Valleix, A.; Wagner, A.; Mioskowski, C. *Eur. J. Org. Chem.* **2010**, 3985–3989.

11. Cao, H. T.; Roisnel, T.; Valleix, A.; Grée, R. *Eur. J. Org. Chem.* **2011**, 3430–3436.

12. A. Nakanishi, T. Yaguichi, N. Miura, M. Emura, K. *Monde J. Nat. Prod.* **2011**, *74*, 707-711.

*Corresponding author:* Hai Thuong Cao
Le Quy Don Technical University
236 Hoang Quoc Viet, Bac Tu Liem, Hanoi, Vietnam
Email: [haithuongcaok11@gmail.com](mailto:haithuongcaok11@gmail.com); Tel: 0978945469

A New
Approach for
the Synthesis of
Sotolon in
Racemic and
Enantioenriched Forms

Thuy Trang Bui,
Hai Thuong
Cao*, Thao Xuan
Pham, Dinh
Hung Mac, Rene
Grée

<figure><img src="image_6.png" /></figure>

tandem isomerization
-aldolisation reaction

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

Sotolon

tandem isomerization
-Mannich reaction

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>