Enantioselective Michael Reaction of Acetals with Nitroalkenes: An

Research Article pubs.acs.org/journal/ascecg

Enantioselective Michael Reaction of Acetals with Nitroalkenes: An Improvement of the Oseltamivir Synthesis Pavol Tisovský, Tibor Peňaška, Mária Mečiarová, and Radovan Šebesta* Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynska dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia S Supporting Information *

ABSTRACT: Synthesis of key chiral intermediates for oseltamivir and its derivatives from corresponding alkyloxyacetaldehyde acetals is described. Acetals are deprotected in the presence of acidic ionic liquid and water. These deprotection conditions are compatible with subsequent stereoselective Michael addition. The key chiral intermediate in the organocatalytic synthesis of oseltamivir can be obtained in yields of up to 90%, syn:anti ratios of up to 83:17, and enantiomeric purities of the required syn isomer of up to 98:2 e.r. Even further cyclization can be realized in a one-pot fashion. Therefore, a three-step sequence comprising acetal deprotection, Michael addition, and cyclization can be performed in a convenient one-pot operation. KEYWORDS: Asymmetric organocatalysis, One-pot synthesis, Michael addition, Acetal hydrolysis, Nitroalkene, Antiviral drug, Oseltamivir

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INTRODUCTION Synthesis of biologically active chiral compounds with the help of asymmetric organocatalysis has become a viable alternative to other methods of asymmetric synthesis.1,2 Asymmetric organocatalysis can provide safer and more economical routes to compounds of medicinal and biological relevance.3,4 Furthermore, exclusion of heavy metals, especially from later stages of syntheses, can be advantageous in the industrial production of pharmaceuticals. Oseltamivir phosphate is an active component of Tamiflu, one of the most potent antiviral drugs currently on the market. It features on the World Health Organization’s list of the essential medicines.5 Oseltamivir is currently produced by Roche from shikimic acid via a 13-step synthesis.6 This synthesis suffers from the potentially unreliable source of the starting material and involvement of hazardous procedures, like the conversion of azides, in the synthesis.7 Therefore, great effort has been devoted to developing alternative syntheses of oseltamivir.8−10 Organocatalytic approaches to oseltamivir appear to be particularly useful as they also address the issue of heavy metal exclusion. Use of asymmetric organocatalysis in the synthesis of oseltamivir has been pioneered by Hayashi and co-workers.11−14 They showed that 2-nitroacrylate and 3pentyloxyacetaldehyde undergo highly enantioselective Michael addition under catalysis of diphenylprolinol silyl ether catalyst.15,16 An ester group needs to be transformed to an acetamido group via Curtius rearrangement. The cyclohexene core of the oseltamivir was then assembled via a cyclization reaction comprised of Michael addition and Horner−Wadsworth−Emmons reaction with a vinyl phosphonate. An alternative strategy was proposed by Ma and others.17−19 This approach utilizes suitably protected 2-aminonitroethene as a Michael acceptor, thus eliminating the need for potentially © XXXX American Chemical Society

hazardous Curtius rearrangement. Both these approaches rely on the use of 3-pentyloxyacetaldehyde. However, this compound is not easily accessible and is rather unstable. Without any treatment, it decomposes within 1 day, and even when stabilized with hydroquinone, it can be stored for only approximately 7 days. Furthermore, this compound is synthesized using toxic osmium tetroxide,11 or low-yield ozonolysis.18 Therefore, investigating alternative starting materials for the Michael addition, which would install a required 3-pentyl group in the oseltamivir molecule, is worthwhile. Many organocatalytic Michael additions require the presence of the acidic cocatalyst. Also, Michael additions leading to oseltamivir were shown to proceed better in the presence of organic acids such as benzoic acid, chloroacetic acid, and formic acid. Even other sufficiently acidic organic compounds such as phenols are often suitable acidic cocatalysts.20 Apart from the influence of acid on the reaction speed, the nature of the acidic cocatalyst also influences the diastereoselectivity of the addition. It participates in the stereodetermining step of the reaction that is addition of enamine to the nitroalkene.21,22 Given the instability and inconvenient synthesis of 3-pentyloxyacelaldehyde, we posed the question of whether the corresponding acetal might be a suitable donor in the Michael addition. We argued that acidic conditions of the reaction might also bring about continuous acetal cleavage and thus release the necessary aldehyde, which would immediately react with nitroalkene. Furthermore, the reaction of 3-pentyloxyacelaldehyde with N-(2-nitrovinyl)acetamide proceeds well in the chloroform/water mixture, Received: September 28, 2015 Revised: October 23, 2015

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DOI: 10.1021/acssuschemeng.5b01172 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering

Interestingly, molecular iodine was found to be a very good catalyst for the deprotection of acetals 3. The reaction of acetals 3a and 3b in acetone at room temperature for 18 h proceeded with an aldehyde:acetal ratio of 88:12. After reaction at room temperature for 3 h, the conversion of acetal 3a was 77%, and after 1 h at reflux, 82% of aldehyde 4a was detected in the reaction mixture (Table S2, entries 8−10). No aldehyde was observed after reaction under microwave irradiation (100 °C for 30 min) or in methanol at room temperature for 3 h. However, iodine is not compatible with subsequent Michael addition and had to be removed after the deprotection. Therefore, we did not consider its use as a viable method for further development. A range of other deprotection strategies were evaluated on acetal 3a, too. These included use of Lewis acids such as CaCl2, In(OTf)3, InCl3, or [3,5-(CF3)2C6H3]4BNa,26 various temperatures, and microwave irradiation setups. For details, see the Supporting Information. Recently, Gupta et al. have described the deprotection of acetals and thioacetals using an acidic ionic liquid, 1-butyl-3methylimidazolium hydrogen sulfate ([bmim]HSO4).27 This ionic liquid (pH 1.00, 10% aqueous solution of ionic liquid) was an efficient reagent for acetal deprotection under microwave irradiation. Therefore, we applied this method to the deprotection of alkyloxyacetaldehyde acetals 3a and 3b. The reaction of acetal 3a at 110 °C for 2 h proceeded with only 27% conversion. Deprotection under MWI at 130 °C for 15 min resulted in a 4a:3a ratio of 16:84. A longer reaction time (30 min) improved conversion to 34% (Table 1, entries 1−3).

and water would be also required for acetal hydrolysis. In this context, we report herein utilization of acetals of alkyloxyacetaldehydes as starting materials for this critical Michael addition in the oseltamivir synthesis.

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RESULTS AND DISCUSSION Synthesis and Deprotection of Acetals. First, we prepared alkyloxyacetaldehyde acetals 3a−f from 2-bromo1,1-dialkyloxyethanes 1a and 1b and corresponding alcohols 2a−e (Scheme 1). Two operationally simple protocols, using either metallic sodium or NaH as a base, appeared to be suitable for obtaining these acetals.23−25 Scheme 1. Synthesis of Acetals 3

Reactions of 2-bromo-1,1-dialkyloxyethane (1a and 1b) with pentan-3-ol (2a) gave the corresponding acetals 3a and 3b in 42% yields after 7.5 h, when Na was used. Sodium hydride is the more competent base for this reaction, as it affords acetal 3a in 60% yield. The reaction of starting material 1b with alcohol 2a using NaH and Bu4NI gave compound 3b in 42% yield [see the Supporting Information for details (Table S1, entries 1− 4)]. Several other acetals, 3c−f, were synthesized by this procedure (Table S1, entries 5−8). Some other derivatives, such as (4-nitrophenyl)methanol, were inactive under these reaction conditions. With acetals 3 in hand, we started to investigate their possible direct utilization as donors in Michael additions. Preliminary experiments showed that the direct Michael addition of acetals 3 with various nitroalkenes did not proceed. Therefore, we decided to search for an effective method for deprotection of acetals 3 (Scheme 2). Ideally, these

Table 1. Deprotection of Acetals 3 Using Acidic Ionic Liquids under MWI

Scheme 2. Deprotection of Acetals 3a and 3c Using Acidic Ionic Liquid [bmim]HSO4

entry

acetal

temp (°C)

ionic liquid

time (h)

4:3 ratioa

1 2 3 4 5 6 7 8 9 10

3a 3a 3a 3a 3a 3a 3b 3a 3a 3c

110 130 130 130 130 150 150 150 130 130

[bmim]HSO4 [bmim]HSO4 [bmim]HSO4 [bmim]HSO4 [Hmim]HSO4 [bmim]HSO4 [bmim]HSO4 [Hmim]HSO4 [bmim]HSO4 [bmim]HSO4

2 0.25 0.5 1 1 1 1 1 1b 1

27:73 16:84 34:66 75:25 7:93 79:21 85:15 54:46 78:22 95:5

a The 4a:3a ratio was determined from 1H nuclear magnetic resonance spectra. bReaction in an oil bath.

The reaction of acetal 3a with an equimolar amount of [bmim]HSO4 under MWI at 130 °C proceeded with 75% conversion. On the other hand, an even more acidic ionic liquid, methylimidazolium hydrogen sulfate, afforded only 7% of acetal 4a (Table 1, entries 4 and 5). An increase in the reaction temperature to 150 °C resulted in a slightly higher conversion (79%). The deprotection of acetal 3b had a somewhat better course (4b:3b, 85:15) under the same condition. Deprotection using [Hmim]HSO4 at 150 °C for 1 h provided a 4a:3a ratio of 54:46 (Table 1, entries 6−8). These reaction conditions are not limited only to microwave irradiation. When we performed this reaction at 130 °C for 1 h in a sealed glass reactor immersed in an oil bath, the aldehyde:acetal ratio was similar to those obtained in a microwave reactor (Table 1, entry 9). Interestingly, the deprotection of acetal 3c did not proceed with the same results as deprotection of acetal 3a. The

deprotection conditions should be compatible with subsequent Michael addition with minimal additional manipulations. We have also quickly found out that standard methods for acetal hydrolysis, such as the use of Brønsted acid and water, did not work well for alkyloxyacetaldehyde acetals 3a−f. Under these reactions, usually complex mixtures of products were obtained. Possibly, ether cleavage also occurred under these conditions. Using this methodology, the best result was obtained with HCl in refluxing THF [see the Supporting Information for details (Table S2, entry 1)]. However, HCl is too acidic for subsequent Michael addition. B


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ACS Sustainable Chemistry & Engineering deprotection worked with CaCl2, chloroacetic acid, a THF/ HCl mixture, and neat water at high temperatures, giving the aldehyde in 85−90% yields. The deprotection of acetal 3c under more forcing conditions, such as pure water, a water/ THF mixture, or a water/ethanol mixture under MWI at higher temperatures and pressures (150−180 °C, 1−1.4 MPa), gave, with the exception of aldehyde 4c, benzyl alcohol in high yields. Interestingly, no aldehyde 4c was observed in the reaction mixture, when the deprotection of acetal 3c was supposed to take place in a water/THF mixture (4:1 to 1:4) under classical heating at reflux. Interestingly, application of iodine in boiling acetone, which gave promising results with acetal 3a, did not work with acetal 3c. For more details about deprotections of acetal 3c, see the Supporting Information. The best conditions for deprotection of acetal 3c (4c:3c, 95:5) comprise again a mixture of water and the acidic ionic liquid [bmim][HSO4] under MWI at 130 °C for 1 h (Table 1, entry 10, and Table S4, entry 6). Gratifyingly, these deprotection conditions were compatible with the next reaction step, stereoselective organocatalyzed Michael addition. Michael Addition of Acetals. Acetal 3a was deprotected in water with 1 equiv of [bmim]HSO4 under MWI as described earlier. The resulting reaction mixture was then used, without isolation of the aldehyde, in the stereoselective Michael addition to (Z)-N-(2-nitrovinyl)acetamide (5) (Scheme 3).

Table 2. Michael Addition of Acetal 3a to Nitroalkene 5 entry

reaction conditions

catalyst

yield of 6a (%)

syn:anti

e.r. (syn:anti)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

rt, 24 h rt, 24 ha rt, 24 hb 0 °C, 5 h 0 °C, 5 hb 0 °C, 8 h 0 °C, 16 hc 0 °C, 8 hd 0 °C, 8 he 0 °C, 8 he 0 °C, 8 hf 0 °C, 8 h 0 °C, 8 hg 0 °C, 8 he,h 5 °C, 24 hi 0 °C − r.t., 3 h

C1 C1 C1 C1 C1 C1 C1 C1 C1 C3 C1 C4 C1 C1 C2 C2

76 57 74 74 80 90 80 85 86 80 80 63 53 85 77 65

74:26 80:20 68:32 75:25 72:28 75:25 78:22 74:26 80:20 83:17 72:28 68:32 66:34 80:20 67:33 75:25

96:4/78:22 88:12/58:42 92:8/56:44 98:2/78:22 96:4/57:43 98:2/78:22 97:3/79:21 97:3/76:24 98:2/75:25 97:3/76:24 97:3/79:21 90:10/72:28 96:4/77:23 98:2/75:25 90:10/76:24 66:34/52:48

a

Deprotection: I2, Me2CO, rt, 18 h. bWithout an acidic additive. Reaction with a 4-fold amount of starting acetal. dWith BrCH2CO2H. e With HCO2H. fWith [bmim]HSO4. gMichael addition was performed in a PhCl/H2O (1:1) mixture. hDeprotection in an oil bath. i ClCH2CO2H (30 mol %). c

selectivity. The syn:anti ratio was from 72:28 to 83:17. Product syn-6a formed with high enantiomeric purity (97:3 to 98:2 e.r.), while product anti-6a was less enantiopure (75:25 to 79:21 e.r.) (Table 2, entries 6 and 8−11). When catalyst C4 was used instead of catalyst C1 with ClCH2CO2H, the chemical yield of 6a decreased to 63%, and the syn:anti ratio was 68:32. The enantiomeric purity of both diastereoisomers remained unchanged (Table 2, entry 12). When we performed this reaction at a larger scale, starting from 4.88 mmol of acetal 3a instead of 1.22 mmol, the reaction time had to be prolonged from 8 to 16 h. The isolated yield of adduct 6a slightly decreased from 90 to 80%, but diastereoselectivity, as well as enantioselectivity, remained unchanged (Table 2, entries 6 and 7). Michael addition of in situ-obtained aldehyde 4a with the nitroalkene 5 in a chlorobenzene/water mixture (1:1) at room temperature for 8 h proceeded with a 53% yield, a syn:anti ratio of 66:34, and e.r. (syn) 96:4 and e.r. (anti) 77:23 (Table 2, entry 13). When we performed deprotection of acetal 3a in an oil bath and formic acid was used as an acidic additive in Michael addition, adduct 6a was obtained in 85% yield with a syn:anti ratio of 80:20. Again, isomer syn-6a had a high enantiomeric purity (98:2 e.r.), and the corresponding antiisomer (anti-6a) had a lower enantiomeric purity (75:25 e.r.) (Table 2, entry 14). The Michael addition using catalysts C2 at 5 °C for 24 h gave 77% of 6a with a syn:anti ratio of 67:33, e.r. (syn) 90:10, and e.r. (anti) 76:24. We also tested the effect of ultrasound, in an attempt to improve mixing of the heterogeneous reaction mixture. Ultrasonic irradiation slightly improved the diastereoselectivity (75:25 d.r.) of the addition, but the enantioselectivity was lower (Table 2, entries 15 and 16). Michael additions from acetal 3c (Scheme 4) with catalysts C1−C3 in a DMSO/water mixture (1:1) at 5 °C for 72 h afforded adduct 6c in 12−28% yields with syn:anti ratios of 55:45 to 60:40 (Table 3, entries 1−3). Considerably better yields were achieved in a CHCl3/water (1:1) mixture. Using catalysts C1 and C3, adduct 6c was isolated in 42 and 40%

Scheme 3. One-Pot Acetal Deprotection and Michael Addition

The reaction with catalyst C1 at room temperature for 24 h proceeded with a 76% yield of Michael adduct 6a with a syn:anti ratio of 74:26. The enantiomeric ratio for syn-6a was 96:4 and for anti-6a was 78:22. Similar results were obtained when deprotection was conducted with I2 in acetone as well as when Michael addition was conducted without an additional acidic additive (Table 2, entries 1−3). Reactions at 0 °C proceeded with yields, diastereoselectivities, and enantioselectivities comparable to those observed for the reaction at room temperature (Table 2, entries 4 and 5). The product 6a was isolated in 90% yield when chloroacetic acid was used as an acidic additive, and the reaction proceeded at 0 °C for 8 h. Compound 6a was isolated in 85% yield using bromoacetic acid as an acidic additive, and the reaction with formic acid gave product 6a in 86% (C1) and 80% (C3) yields. The reaction with the acidic ionic liquid [bmim]HSO4 gave product 6a in 80% yield. Acid additives had an only negligible effect on the C


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ACS Sustainable Chemistry & Engineering Scheme 4. Michael Additions Using Acetals 3c, 3e, and 3f

Table 3. Michael Additions Using Acetals 3c, 3e, and 3fa

a

entry

acetal

deprotection conditions

1 2 3 4 5 6 7 8 9

3c 3c 3c 3c 3c 3c 3e 3e 3f

B B B B B B A A B

conditions for Michael addition C1, C2, C3, C1, C2, C3, C1, C1, C2,

DMSO, H2O, 72 h, 5 °C DMSO, H2O, 72 h, 5 °C DMSO, H2O, 72 h, 5 °C CHCl3, H2O, 72 h, 5 °C CHCl3, H2O, 72 h, 5 °C CHCl3, H2O, 72 h, 5 °C DMSO, rt, 24 h CHCl3/H2O, 0 °C, 8 h CHCl3/H2O, 5 °C, 72 h

yield (%)

syn:anti

e.r. (syn:anti)

12 28 12 42 66 40 60 34 52

60:40 55:45 60:40 65:35 68:32 71:29 50:50 50:50 67:33

not determined not determined not determined 91:9/84:16 94:6/89:11 95:5/83:17 77:23/68:32 75:25/64:36 94:6/89:11

Condition A: HCl, THF, reflux, 1 h. Condition B: [bmim]HSO4, H2O, 130 °C MWI, 1 h.

Scheme 5. Michael Addition of Aldehyde 4a with βNitrostyrene (7)

yields, respectively. The highest yield of adduct 6c (66%) was reached with catalyst C2. Syn:anti ratios were from 65:35 to 71:29. Product syn-6c was obtained with 91:9 e.r. (C1), 94:6 e.r. (C2), and 95:5 e.r. (C3). anti-6c was prepared with 84:16 e.r. (C1), 89:11 e.r. (C2), and 83:17 e.r. (C3) (Table 3, entries 4−6, respectively). The Michael addition in a PhCl/water (1:1) mixture at room temperature for 24 h did not proceed. Deprotection of acetal 3e did not proceed in acetone under iodine or under In(OTf)3 catalysis. When we tried to deprotect acetal 3e in water under MWI with CaCl2 or [bmim]HSO4, only starting acetal and traces of the corresponding aldehyde 4e were detected in the reaction mixture. After reaction in THF with HCl at reflux for 1 h, the 4e:3e ratio was 78:22 according to 1H nuclear magnetic resonance. This reaction mixture was used without isolation of aldehyde 4e in the Michael addition with nitroalkene 5 and catalyst C1 (Scheme 4). Michael addition performed in DMSO at room temperature for 24 h gave adduct 6e in 60% yield without any diastereoselectivity. Diastereomer syn-6e was obtained with an enantiomeric purity of 77:23 e.r. and isomer anti-6e with that of 68:32 e.r. The yield decreased to 34% when the reaction was performed in the CHCl3/water (1:1) mixture at 0 °C for 8 h (Table 3, entries 7 and 8). Acetal 3f was also resistant to deprotection in acetone with iodine. Only traces of aldehyde 4f were observed. Deprotection of 3f in THF with HCl proceeded with results similar to those obtained in deprotection of 3e. The 4f:3f ratio in the crude reaction mixture was 70:30. Aldehyde 4f was prepared from acetal 3f in water with an equimolar amount of [bmim]HSO4 under MWI, and the raw reaction mixture was used in Michael addition at 5 °C for 72 h. Product 6f was isolated in 52% yield with an syn:anti ratio of 67:33. Adduct syn-6f was prepared with 94:6 e.r. and adduct anti-6f with 89:11 e.r. (Table 3, entry 9). To show the usefulness of the described method, we have also performed the Michael addition of deprotected aldehyde 4a to β-nitrostyrene (7) (Scheme 5). This reaction proceeded in a CHCl3/water (1:1) mixture using catalyst C1 with a 60− 85% yield of adduct 8. The best yield, as well as diastereoselectivity (syn:anti ratio of 68:32), was achieved

with chloroacetic acid as an acidic additive. Using formic acid, the product yield decreased to 68%, but the syn:anti ratio was practically the same. When ionic liquid [bmim]HSO4 was used as an acidic additive, the yield decreased to 60%, and the d.r. was 50:50. Both diastereomers formed in excellent optical purities (Table 4, entries 1−3). Lowering the temperature to 5 Table 4. Michael Addition from Acetal 3a to β-Nitrostyrene (7) entry

catalyst

acid

yield of 8 (%)

syn:anti

e.r. (syn:anti)

1 2 3 4 5 6

C1 C1 C1 C1a C2 C3

ClCH2CO2H HCO2H [bmim]HSO4 ClCH2CO2H ClCH2CO2H ClCH2CO2H

85 68 60 74 62 66

68:32 64:36 50:50 71:29 50:50 50:50

98:2/97:3 97:3/96:4 96:4/95:5 98:2/96:4 95:5/93:7 96:4/95:5

a

Reaction at 5 °C for 72 h.

°C and prolonging the time to 72 h had no significant effect on the reaction course (Table 4, entry 4). Use of a bulky silyl substitution in the diphenylprolinol silyl ether organocatalysts (C2 and C3) had no expected effect on diastereoselectivity. Compound 8 was isolated in 62 and 66% yield with d.r. 50:50. The enantioselectivity remained unchanged (Table 4, entries 5 and 6). D


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ACS Sustainable Chemistry & Engineering Assembly of the Oseltamivir Skeleton. We started the study of cyclization with isolated adduct 6a using conditions described by Hayashi.13 The reaction of compound 6a with phosphonate 9 in chlorobenzene with cesium carbonate as a base at 0 °C for 3 h afforded compound 10 in 30% yield for both diastereomers (Scheme 6). The (R,R,S)-10:(R,R,R)-10

media in the presence of an equimolar amount of acidic ionic liquid gave corresponding aldehydes, which without isolation participated as donors in Michael addition with nitroalkenes. Michael addition from acetal 3a to β-nitrostyrene proceeded with good yields, mediocre diastereoselectivity, and excellent enantioselectivity for both diastereoisomers. A one-pot, threestep sequence consisting of acetal deprotection, Michael addition, and cyclization via HWE reaction afforded cyclic product 10 in 56% yield with d.r. 33:67. We believe that the described method constitutes a considerable improvement in the organocatalytic oseltamivir synthesis. Furthermore, it can also be useful in other organocatalytic syntheses, which use Michael additions of an unstable or unavailable aldehyde as donors.

Scheme 6. One-Pot Acetal Deprotection, Michael Addition, and Cyclization

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EXPERIMENTAL SECTION

For preparation and characterization data of acetals, see the Supporting Information. Typical Procedure for Acetal Deprotection Followed by Michael Addition to Alkene 5. Acetal 3a (1.22 mmol, 0.25 g), [bmim]HSO4 (1.22 mmol, 0.29 g), and distilled water (4 mL) were added to a glass vessel. The reaction vessel was then placed in a microwave reactor. After being stirred at 130 °C for 1 h, the reaction mixture was cooled to rt, and this solution was added to a mixture of alkene 5 (0.538 mmol, 70 mg) and ClCH2CO2H (0.107 mmol, 10.3 mg) in CHCl3 (3 mL). The mixture was then cooled to 0 °C, and catalyst C1 (0.054 mmol, 17.5 mg) dissolved in CHCl3 (1 mL) was added. The resulting reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 8 h. The reaction mixture was extracted with CHCl3 (3 × 10 mL). The combined organic extracts were dried over Na2SO4, and the solvent was evaporated under reduced pressure to leave a brown oil, which was purified by column chromatography on SiO2 (hexanes/EtOAc, 3:1 → 1:1). Typical Procedure for Acetal Deprotection Followed by Michael Addition to β-Nitrostyrene. Acetal 3a (1.22 mmol, 0.25 g), [bmim]HSO4 (1.2 mmol, 0.29 g), and distilled water (4 mL) were added to a glass vessel. The reaction vessel was then placed in a microwave reactor. After its contents had been stirred at 130 °C for 1 h, the vessel was cooled to rt, and this solution was added to a mixture of β-nitrostyrene (0.538 mmol, 80 mg) and ClCH2CO2H (0.107 mmol, 10.3 mg) in CHCl3 (3 mL). Catalyst C1 (0.054 mmol, 17.5 mg) dissolved in CHCl3 (1 mL) was then added to this solution. The resulting reaction mixture was stirred at rt under a nitrogen atmosphere for 24 h. The reaction mixture was diluted with H2O (10 mL) and extracted with CHCl3 (3 × 10 mL). The combined organic extracts were dried over Na2SO4, and the solvent was evaporated under reduced pressure. Purification by column chromatography on SiO2 (hexanes/EtOAc, 7:1) afforded (3S)-4nitro-2-(pentan-3-yloxy)-3-phenylbutanal (8) (125 mg, 85%) as a colorless oil. Typical Procedure for Cyclization of Adducts 6. Michael adduct 6a (crude product, after deprotection of the acetal and subsequent Michael addition) (110 mg) and solvent (CHCl3 or CH2Cl2) (3 mL) were placed in the glass vessel, and then under an Ar atmosphere, K2CO3 (133 mg, 0.96 mmol), 18-crown-6 (12 mg, 0.045 mmol), and phosphonate 9 (95 mg, 0.403 mmol) were added. The resulting reaction mixture was exposed to microwave radiation for 2 h

diastereomeric ratio was 46:54 (Table 5, entry 1). Next, we applied this method in the cyclization of adduct 6a without its isolation. Phosphonate 9 and base (Cs2CO3) were added to crude product 6a, which was formed after the one-pot deprotection of acetal 3a and subsequent Michael addition with alkene 5. After 48 h at 5 °C, the corresponding product 10 was isolated in 23% yield. It formed as a mixture of diastereomers with an (R,R,S)-10:(R,R,R)-10 ratio of 43:57 (Table 5, entry 2). Somewhat better yields were obtained under reaction conditions that we have recently described.18 Cyclization of adduct 6a (without purification) with phosphonate 9 under microwave irradiation in the presence of 18-crown-6 and K2CO3 at 70 °C for 2 h in CH2Cl2 provided product 10 in 56% yield with d.r. 33:67. The cyclization in CHCl3 afforded compound 10 in a somewhat lower yield (43%). The diastereoselectivity remained unchanged (Table 5, entries 3 and 4).

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CONCLUSIONS We have shown that the key step in the organocatalytic synthesis of oseltamivir, Michael addition, can be successfully performed also with the corresponding acetal instead of unstable 3-pentyloxyacetaldehyde. The resulting Michael adducts were obtained in high yields and with high enantiomeric purities. Deprotection of acetals in aqueous Table 5. Cyclization from Acetal 3a

a

entry

solvent

base

reaction conditions

yield of 10 (%)b

d.r. (R,R,S)-10:(R,R,R)-10

1 2 3 4

PhCl CHCl3 CH2Cl2 CHCl3

Cs2CO3 Cs2CO3 K2CO3a K2CO3a

0 °C, 3 h 5 °C, 48 h MWI, 70 °C, 2 h MWI, 70 °C, 2 h

30 23 56 43

46:54 43:57 33:67 35:65

18-crown-6. bYield calculated to alkene 5. E


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ACS Sustainable Chemistry & Engineering at 70 °C. After the mixture had cooled, a saturated solution of NH4Cl (10 mL) was added, and the aqueous layer was extracted with CHCl3 or CH2Cl2 (3 × 15 mL). The combined organic layers were dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on SiO2 (hexanes/EtOAc, 2:1).

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(12) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. High-Yielding Synthesis of the Anti-Influenza Neuraminidase Inhibitor (−)-Oseltamivir by Two “One-Pot” Sequences. Chem. - Eur. J. 2010, 16, 12616−12626. (13) Mukaiyama, T.; Ishikawa, H.; Koshino, H.; Hayashi, Y. One-Pot Synthesis of (−)-Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction. Chem. - Eur. J. 2013, 19, 17789−17800. (14) Ishikawa, H.; Bondzic, B. P.; Hayashi, Y. Synthesis of (−)-Oseltamivir by Using a Microreactor in the Curtius Rearrangement. Eur. J. Org. Chem. 2011, 2011, 6020−6031. (15) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol Silyl Ethers as Efficient Organocatalysts for the Asymmetric Michael Reaction of Aldehydes and Nitroalkenes. Angew. Chem., Int. Ed. 2005, 44, 4212−4215. (16) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Enantioselective Organocatalyzed alpha Sulfenylation of Aldehydes. Angew. Chem., Int. Ed. 2005, 44, 794−797. (17) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Organocatalytic Michael Addition of Aldehydes to Protected 2-Amino-1-Nitroethenes: The Practical Syntheses of Oseltamivir (Tamiflu) and Substituted 3Aminopyrrolidines. Angew. Chem., Int. Ed. 2010, 49, 4656−4660. (18) Rehák, J.; Hut’ka, M.; Latika, A.; Brath, H.; Almássy, A.; Hajzer, V.; Durmis, J.; Toma, S.; Šebesta, R. Thiol-free synthesis of oseltamivir and its analogues via organocatalytic michael additions of oxyacetaldehydes to 2-acylaminonitroalkenes. Synthesis 2012, 44, 2424− 2430. (19) Weng, J.; Li, Y.-B.; Wang, R.-B.; Lu, G. Organocatalytic Michael Reaction of Nitroenamine Derivatives with Aldehydes: Short and Efficient Asymmetric Synthesis of (−)-Oseltamivir. ChemCatChem 2012, 4, 1007−1012. (20) Hajzer, V.; Latika, A.; Durmis, J.; Šebesta, R. Enantioselective Michael Addition of the 2-(1-Ethylpropoxy)acetaldehyde to N-[(1Z)2-Nitroethenyl]acetamide − Optimization of the Key Step in the Organocatalytic Oseltamivir Synthesis. Helv. Chim. Acta 2012, 95, 2421−2428. (21) Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Organocatalyzed Michael Addition of Aldehydes to Nitro Alkenes − Generally Accepted Mechanism Revisited and Revised. Helv. Chim. Acta 2011, 94, 719−745. (22) Duschmale, J.; Wiest, J.; Wiesner, M.; Wennemers, H. Effects of internal and external carboxylic acids on the reaction pathway of organocatalytic 1,4-addition reactions between aldehydes and nitroolefins. Chem. Sci. 2013, 4, 1312−1318. (23) Otley, K. D.; Saccomano, B. W.; McKee, S. A.; Nizialek, G. A.; Hamilton, D. S.; Sherrow, L. K.; Jones, C. Y.; Rosenstein, I. J. Synthesis of three selectively deuterated propylene oxides. J. Labelled Compd. Radiopharm. 2011, 54, 308−311. (24) Solladie-Cavallo, A.; Suffert, J.; Gordon, M. TiCl4 Induced opening of chiral acetals: a route to β-adrenergic blocking agents. Tetrahedron Lett. 1988, 29, 2955−2958. (25) Palfray, L.; Sabetay, S.; Rotbart, M. Compt. Rend. 1933, 196, 1508−1510. (26) Chang, C.-C.; Liao, B.-S.; Liu, S.-T. Deprotection of Acetals and Ketals in a Colloidal Suspension Generated by Sodium Tetrakis(3,5trifluoromethylphenyl)borate in Water. Synlett 2007, 2007, 0283− 0287. (27) Gupta, N.; Sonu; Kad, G. L.; Singh, J. Acidic ionic liquid [bmim]HSO4: An efficient catalyst for acetalization and thioacetalization of carbonyl compounds and their subsequent deprotection. Catal. Commun. 2007, 8, 1323−1328.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.5b01172. Experimental procedures and characterization data for all compounds and copies of 1H and 13C nuclear magnetic resonance spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Fax: +421 2 60296 337. Telephone: +421 2 60296208. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Slovak Research and Development Agency (Grants APVV-0067-11 and APVV0593-11). This publication is the result of the project implementation 26240120025 supported by the Research & Development Operational Programme funded by the European Regional Development Fund.

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DEDICATION Dedicated to Dr. Rajender Varma on the occasion of his 65th birthday. REFERENCES

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