Abstract
Addition of vinyl aluminum-NMO reagents to N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman products (d.r. 7:1 to 12:1) that result from addition of the reagent from the least hindered direction. Hydrogenation of the aza-MBH adducts with a Rh(I) catalyst affords anti-α-substituted N-sulfinyl-β-amino esters in good yield and high dr (10:1 to 21:1).
Introduction
The development of new and improved methodologies for the asymmetric synthesis of β-amino acids continues to be an important objective because of their valuable biological properties, their utility as chiral building blocks, and as precursors of β-lactams.1,2 Substitution of β-amino acids for α-amino acids results in β-peptides with novel activity and increased enzyme stability.3 For these reasons many methods have been devised for the synthesis of β-amino acids,1,2 including the diastereoselective addition of enolates to enantiopure sulfinimines (N-sulfinyl imines).4 However, only a few methods have been reported for the enantioselective synthesis of acyclic α-substituted β-amino acids.1,5
As part of a program aimed at the asymmetric synthesis of N-sulfinyl α-substituted β-amino esters and ketones, we have been exploring the addition of prochiral Weinreb amide enolates to sulfinimines.5a Another way to access these compounds is the stereoselective reduction of sulfinimine-derived α-(aminoalkyl)acrylates (aza-Morita-Baylis-Hillman) adducts (Figure 1).6 However, sulfinimines have rarely been employed in the aza-Morita-Baylis-Hillman (aza-MBH) reaction.7 Aggarwal et al. reported the seven-day reaction of methyl acrylate with sulfinimines to give aza-MBH adducts with modest diastereoselectivity and yield.8 In the presence of PhPMe2, cyclopent-2-ene-one reacts with aromatic aldehyde-derived sulfinimines to give aza-MBH adducts with poor to good diastereoselectivity.9 More recently Scheidt and co-workers described the addition of lithium allenolates, in the presence of HMPA, to sulfinimines affording β-substituted aza-MBH products in good yield and high selectivity.10
Figure 1.
Retrosynthetic approach to α-substituted N-sulfinyl β-amino esters.
In a series of papers, Li and co-workers explored the addition of vinylcuprates, prepared by Michael addition of R2CuLi to α-acetylenic esters, to sulfinimines at -23 °C to give novel branched aza-MBH adducts.11 For the addition to occur, stoichiometric amounts of Et2AlCl or 40 mol% of Yb(OTf)3 were required. Careful control of the reaction conditions was also necessary for good yields.11 These workers also reported that vinylaluminum reagents were unreactive.11c Ramachandran and co-workers described a new procedure for the synthesis of vinylaluminum reagents from DIBAL-H, α-acetylenic esters and 4-methylmorpholine N-oxide (NMO).12 These workers demonstrated that their vinylaluminum reagents gave good yields of MBH adducts on reaction with aldehydes and ketones. Inspired by these studies we describe the application of this protocol to the asymmetric syntheses of N-sulfinyl α-(aminoalkyl)acrylates (aza-Morita Baylis-Hillman products) and their stereoselective reduction to N-sulfinyl-α-substituted β-amino esters.
Results and Discussion
Following the Ramachandran procedure, an NMO (2.0 equiv) THF solution was added to a THF solution of DIBAL-H (1.5 equiv) at 0 °C to give a clear solution. After 1 h, to this solution was added 1.0 equiv of ethyl propiolate (1) and l.0 equiv of (S)-(+)-N-(benzylidene)-p-toluenesufinamide (3) (Scheme 1). (SS,R)-(-)-Ethyl-2-[phenyl-(p-toluenesulfinylamino)methyl]acrylate (4) was formed as a 9:1 mixture of diastereoisomers, but the isolated yield of the major diastereoisomer was low (Table 1, entry 1). When the amount of the vinylaluminum reagent 2 was increased three-fold the yield of (+)-4 improved to 65%. Use of Zn(OTf)2 in these reactions had little or no effect on the yield or diastereoselectivity. These results are summarized in Table 1.
Scheme 1.
Table 1.
Reaction of (S)-(+)-3 with [α-(ethoxycarbonyl)vinyl]diisobutylaluminum (2) at 0 °C in THF for 6 h.
| Entry | Conditions (equiv)a 1:DIBAL-H:NMO | d.r.b | (+)-4 % isolated yieldc |
|---|---|---|---|
| 1 | 1:1.5:2.0 | 9:1 | 17 |
| 2 | 3.0:4.5:6.0 | 7:1 | 65 |
| 3 | 3.0:4.5:6.0 [3 Zn(OTf)2] | 8:1 | 63 |
Equivalents based on sulfinamide (+)-3.
Determined by 1H NMR on the crude reaction mixture.
Isolated yield of major diastereoisomer.
In the sulfinimine-mediated aza-MBH reaction,8,9 Re-face addition of the vinyl anion species to (S)-(+)-3 gave the aza-MBH product having the S-configuration at the new C-N stereogenic center.8,9,11 However, the 1H NMR of these products and (+)-4 were significantly different suggesting that they were different compounds. For example, the vinyl protons in (+)-4 appear at δ 6.02 and 6.48 ppm whereas in the (SS,S) aza-MBH adduct reported by Aggrawal theses protons appear at 5.8 and 6.4 ppm, respectively.8
Because (+)-4 is an oil it was not possible to determine its absolute configuration by X-ray analysis and therefore it was necessary to convert it into products of known absolute stereochemistry. This requires the stereoselective reduction of the α-methylene group in (+)-4 to a methyl group. The homogenous hydrogenation of Baylis-Hillman adducts has been reported and generally gives anti-products.6,13 Hydrogenation of N-acyl β-amino-α-methylene esters using Rh(II) and Rh(I) catalysts at high pressure (30 atm) gives the corresponding anti-α-substituted β-amino esters.14 However, there are no reports of the reduction of N-sulfinyl β-amino-α-methylene esters.
Hydrogenation of (+)-4 at rt using 7.5 mol% of cationic rhodium complex A for 48 h gave a 22:1 mixture of diastereoisomers with isolation of the major diastereoisomer (SS,2R,3S)-(+)-5 in 88% yield (Scheme 2). Oxidation with m-CPBA gave (2R,3S)-(-)-7 and hydrolysis afforded the known acid (2R,3S)-(-)-8 in 87% yield.15 To further confirm the trans stereochemistry, the acid was treated with DCC/4-pyrrolidino-pyridine to give β-lactam (3R,4S)-(-)-9, also a known compound (Scheme 2).15a In (-)-9 the J3,4 coupling constant was 3.2 Hz and similar to the reported value of 3.0 Hz (cis = J3,4 = 6 Hz).15a These results indicate that the vinylaluminum reagent adds to the Si-face in sulfinimine (S)-(+)-3. Formation of the anti-product (+)-5 is consistent with coordination of the Rh-catalyst A with the sulfinyl nitrogen atom and addition of hydrogen from the more hindered face of the C-C double bond.13.14
Scheme 2.
Structures resulting from the addition of organometallic reagents to the C-N double bond of sulfinimines can generally be predicted by assuming chelated, chair-like transition states resulting from coordination of the metal ion with the sulfinyl oxygen. The sulfinimine-mediated aza-MBH reaction9 and the addition of vinylcuprates11 to sulfinimines are in agreement with this transition state hypothesis. However, there are exceptions where the organometallic reagent adds to the C-N double bond from the least hindered direction, away from the bulky sulfinyl group.16 As previously suggested by us, a Yamamoto-type model TS-A (Figure 2), where the vinyl aluminum reagent adds to the Si-face of the CN double bond explains our results.16b We suggest that the added NMO, which acts as a ligand to aluminum to suppress the tendency of DIBAL-H to reduce C=O and C=N groups,17 also prevents complexation of aluminum with the sulfinyl group. In the presence of HMPA lithium allenolates also add to the Si-face of sulfinimines.10
Figure 2.
Model for the addition of vinylaluminum to the si-face of (S)-(+)-3.
The addition of β-substituted vinyl aluminum reagents to sulfinimines was next examined. Addition of [α-(ethoxycarbonyl)-β-methylvinyl]diisobutylaluminum, prepared from propargylic ester 10, afforded 13 as a 5:1 mixture of inseparable diastereoisomers (Table 2, entry 1). In the past we have solved this separation problem by changing the N-sulfinyl auxiliary.18 However, reaction of 2 with (RS)-(-)-N-(benzylidene)-2-methylpropanesulfinamide (12a) at rt resulted in no reaction (Table 2, entry 2). When the temperature was increased to 70 °C for 15 h, compound (RS,S)-(-)-14a was obtained as a 12:1 mixture of diastereoisomers with isolation of the major diastereoisomer in 65% yield (Table 2, entry 5).19 Under these conditions addition of [α-(ethoxycarbonyl)-β-methylvinyl]diisobutylaluminum and [α-(ethoxycarbonyl)-β-phenylvinyl]diisobutylaluminum to (-)-12a gave (RS,S)-(-)-14b and (RS,S)-(-)-14c, respectively, as 7:1 mixtures of diastereoisomers. The major diastereoisomers were isolated in 71% and 73% yields (Table 2, entries 6 and 7). Similar results were observed for addition of the β-substituted vinylaluminum reagents to (RS)-(-)-N-(ethylidene)-2-methylpropanesulfinamide (12b), to give 14d (R = H), 14e (R = Me), and 14f (R = Ph). However, the diastereoisomers of 14d (13:1) and 14e (11:1) could not be separated (Scheme Table 2, entries 8-10). Based on earlier studies, the stereochemistry 14, is expected to be Z.12,20 Upon irradiation of the C-3 vinyl proton at δ 6.28 ppm in (-)-14b, a positive NOE was observed on the C-2 amine proton at δ 5.28 (8.3%) consistent with Z olefin geometry.
Table 2.
Reaction of propargylic esters 1, 10, and 11 with sulfinimines (+)-(S)-3 and (-)-(R)-12.
| entry | sulfinamide | 1, 10, or 11:DIBAL-H:NMO (equiv) | °C (h) | Products % yielda (dr)b |
|---|---|---|---|---|
| 1 | (+)-3 | (10: R = Me) 3.0:4.5:6.0 | 25 (16) | 13, 61 (5:1)c |
| 2 | (-)-12a (R' = Ph) | (1: R = H) 3.0:4.5:6.0 | 25 (6) | No reaction |
| 3 | (1: R = H) 3.0:4.5:6.0 | 25 (23) | 14a, 41 (3:1) | |
| 4 | (1: R = H) 3.0:4.5:6.0 | 45 (15) | 14a, 38 (12:1) | |
| 5 | (1: R = H) 3.0:4.5:6.0 | 70 (15) | 14a, 65 (12:1) | |
| 6 | (10: R = Me) 3.0:4.5:6.0 | 70 (15) | 14b 71 (7:1) | |
| 7 | (11: R = Ph) 3.0:4.5:6.0 | 70 (15) | 14c, 73 (7:1) | |
| 8 | (-)-12b (R' = Et) | (1: R = H) 3.0:4.5:6.0 | 70 (15) | 14d, 58 (13:1)c,d |
| 9 | (10: R = Me) 3.0:4.5:6.0 | 70 (15) | 14e, 50 (11:1)c,d | |
| 10 | (11: R = Ph) 3.0:4.5:6.0 | 70 (15) | 14f, 35 (6.2:1) |
Isolated yield of major diastereoisomer.
Determined by 1H NMR on the crude reaction mixture.
Inseparable isomers.
Determined by 1H NMR on the mixture after purification.
Hydrogenation of 14 as before gave 15 in good yield (Table 3). When R was hydrogen, reduction was complete within 48 h at rt and 1 atm of H2 (Table 3, entries 1 and 4). When R in 14 was Me or Ph, longer times (72 h) and higher pressures of H2 (25 atm) were necessary. β-Amino ester 15e was formed as a mixture of inseparable diastereoisomers contaminated with starting material (Scheme 4). Prolonged hydrogenation (> 90 h) resulted in decomposition.
Table 3.
Hydrogenation of aza-Morita-Baylis-Hillman adducts with catalysts A.
| entry | 14 (R', R =) | Conditions Time (h), atm of H2 | solvent | 15 dr (% yield)a |
|---|---|---|---|---|
| 1 | 14a (Ph, H) | 48, 1 | CH2Cl2 | 15a, 21:1 (83%) |
| 2 | 14b (Ph, Me) | 72, 25 | ClCH2CH2Cl | 15b, 20:1(81%) |
| 3 | 14c (Ph, Ph) | 72, 25 | ClCH2CH2Cl | 15c, 20:1 (79%) |
| 4 | 14d (Et, H) | 48, 1 | CH2Cl2 | 15d, 10:1 (55%) |
| 5 | 14e (Et, Me) | 72, 25 | ClCH2CH2Cl | 15e, decomposition |
| 6 | 14f (Et,Ph) | 72, 25 | ClCH2CH2Cl | 15d, 17:1 (79%) |
Isolated yield of major diastereoisomer.
Scheme 4.
In summary, reaction of vinylaluminum-NMO reagents with sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman products that result from addition of the reagent from the least hindered direction via a non-chelation control mechanism. Hydrogenation of the aza-MBH adducts affords anti-α-substituted N-sulfinyl-β-amino esters and is a useful new method for their preparation.21,22
Experimental Section
Sulfinimines (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (3),23 (R)-(-)-N-(benzylidene)-2-methylpropanesulfinamide (12a),24 and (R)-(-)-N-(propylidene)-2-methylpropanesulfinamide (12b)24 were prepared as previously described. Catalyst (bicyclo[2.2.1]hepta-2,5-diene)[1,4-bisdiphenylphosphino)butanerhodium(I) tetrafluoroborate A was purchased from Aldrich.
(SS,2R)-(+)-Ethyl 2-[phenyl(p-toluenesulfinylamino)methyl]acrylate (4)
In a 50 mL, dry, single-necked round bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NMO (0.696 g, 5.92 mmol) in THF (8 mL) and the solution was cooled to 0 °C. To the solution was added DIBAL-H (4.48 mL, 1.0 M in THF) at 0 °C and the mixture was stirred at this temperature for 0.5 h before ethyl propiolate (1) (0.304 mL, 2.96 mmol) was added. The mixture was stirred for 1 h at 0 °C, and a solution of (S)-(+)-3 (0.240g, 0.984 mmol) in THF (8 mL) was added. The mixture was warmed to rt, stirred for 4 h, quenched with Rochelle salt (NaKC4H4O6·H2O) (10 mL), diluted with EtOAc (15 mL), and vigorously stirred for 30 min. At this time the solution was extracted with EtOAc (3 X 15 mL), the combined organic phases were washed with brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (50% EtOAc/hexanes) provided 0.220 g (65%) of a colorless oil; [α]20D +30.0 (c 0.28, CHCl3); IR (neat) 3204, 1711, 1053 cm-1; 1H NMR (CDCl3) δ 7.61(d, J = 6.4 Hz, 2H), 7.24 (m, 7H), 6.47 (s, 1H), 6.03 (d, J = 0.8 Hz, 1H), 5.35 (d, J = 7.2 Hz, 2H), 4.93 (d, J = 7.2 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1.20 (t, J = 6.8 Hz, 3H); 13C NMR δ 166.0, 141.8, 141.6, 140.5, 129.9, 128.9, 128.0, 127.4, 127.2, 126.0, 61.3, 58.4, 21.7, 14.5 (one carbon could not be identified due to overlap). HRMS calcd for C19H22NO3S(M+H) 344.1320. Found 344.1327.
Ethyl (Rs,2S)-(-)-2-[phenyl-(2-methylpropanesulfinylamino)methyl]acrylate (14a)
In a 50 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum, a reflux condenser, and argon balloon was placed NMO (0.606 g, 5.16 mmol) in THF (6 mL). To the solution was added DIBAL-H (3.9 mL, 1.0 M solution in THF) at 0 °C and the mixture was stirred for 30 min. Ethyl propiolate (1) (0.264 mL, 2.59 mmol) was added via syringe, and the mixture was stirred for 1 h at 0 °C, and (R)-(-)-12a (0.180 g, 0.864 mmol) in anhydrous THF (6 mL) was added. The mixture was heated to 70 °C and stirred for 15 h, cooled to rt, quenched by addition of sat. aqueous Rochelle salt (10 mL), diluted with EtOAc (15 mL), and stirred vigorously for 0.5 h. The organic phase was washed with brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (25% EtOAc/hexanes) provided 0.174 g (65%) of a colorless oil; [α]20D - 1.40 (c 0.93, CHCl3); IR (KBr) 3233, 2980, 1717, 1061 cm-1; 1H NMR (CDCl3) δ 7.26 (m, 5H), 6.45 (s, 1H), 5.99 (s, 1H), 5.49 (d, J = 4.8 Hz, 1H), 4.12 (m, 2H), 3.76 (d, J = 4.8 Hz, 1H), 1.25 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3) δ 166.0, 141.6, 140.7, 129.1, 128.3, 127.9, 126.8, 61.3, 59.8, 56.5, 23.0, 14.4. HRMS calcd. for C16H24NO3S (M+H) 310.1477. Found 310.1472.
(Z)-Ethyl (Rs,2S)-(-)-2-[phenyl-(2-methylpropanesulfinylamino)methyl] but-2-enoate (14b). General procedure
In a 50 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum, a reflux condenser, and argon balloon was placed NMO (0.606 g, 5.16 mmol) in THF (6 mL). The solution was cooled to 0 °C, DIBAL-H (3.9 mL, 1.0 M solution in THF) was added, and the reaction mixture was stirred for 30 min at which time ethyl but-2-ynoate (10) (0.300 mL, 2.59 mmol) was added via syringe. After stirring for 4 h at rt (R)-(-)-12a (0.180 g, 0.864 mmol) in THF (6 mL) was added. The reaction mixture was heated to 70 °C, stirred for 15 h, cooled to rt and quenched by addition of sat. aqueous Rochelle salt (10 mL). The solution was diluted with EtOAc (15 mL), vigorously stirred, and the organic phase was washed with brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (33% EtOAc/hexanes) provided 0.329 g (71%) of a colorless oil; [α]20D -24.8 (c 0.29, CHCl3); IR (KBr) 3214, 3030, 2959, 2869, 1717 cm-1; 1H NMR (CDCl3) major isomer δ 7.25 (m, 5H), 6.35 (q, J = 7.2 Hz, 1H), 5.34 (d, J = 6.4 Hz, 1H), 4.09 (m, 2H), 3.85 (d, J = 6.4 Hz, 1H), 2.05 (dd, J = 0.8, 7.2 Hz, 3H), 1.23 (s, 9H), 1.15 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ 166.7, 141.0, 138.8, 133.8, 128.7, 127.8, 127.4, 61.9, 60.5, 56.2, 22.8, 15.7, 14.2. HRMS calcd for C17H26NO3S (M+H) 324.1633. Found 324.1649.
(Z)-Ethyl (Rs,2R)-(-)-2-[phenyl(2-methylpropanesulfinylamino)methyl]-3-phenylacrylate (14c)
Flash chromatography (25% EtOAc/hexanes) provided 73% of a colorless oil; [α]20D -41.0 (c 1.05, CHCl3); IR (KBr) 3211, 1734, 1225 cm-1; 1H NMR (CDCl3) δ 7.46 (m, 2H), 7.36 (m, 3H), 7.28 (m, 5H), 6.94 (s, 1H), 5.45 (d, J = 6.0 Hz, 1H), 4.00 (m, 2H), 3.91 (d, J = 6.0 Hz, 1H), 1.27 (s, 9H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ 168.1, 139.9, 135.7, 135.4, 134.9, 128.8, 128.6, 128.5, 128.3, 128.2, 127.7, 62.7, 60.9, 56.4, 22.8 (3C), 13.7. HRMS calcd for C22H28NO3S (M+H) 386.1790. Found 386.1805.
(RS,3S)-(-)-Ethyl 3-(1,1-dimethylethylsulfinamido)-2-methylenepentanoate (14d)
Flash chromatography (40% EtOAc/hexanes) provided 55% of a colorless oil; IR (neat) 3212, 1718 cm-1; [α]20D -39.6 (c 1.26, CHCl3); 1H NMR (CDCl3) δ 6.26 (s, 1H), 5.27 (s, 1H), 4.22 (m, 2H), 4.04 (dt, J = 6.8 Hz, 1H), 3.68 (d, J = 6.8 Hz, 1H), 1.86 (m, 2H), 1.31 (t, J = 6.8 Hz, 3H), 1.19 (s, 9H), 0.93 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3) δ 166.4, 141.3, 126.3, 61.2, 60.1, 56.1, 29.1, 22.9, 14.5, 11.3. HRMS calcd for C12H24NO3S (M+H) 262.1477. Found 262.1455.
(Z)-(RS,3S)-(-)-Ethyl 3-(1,1-dimethylethylsulfinamido)-2-ethylidenepentanoate (14e)
Flash chromatography (40% EtOAc/hexanes) provided 50% of a colorless oil; [α]20D -51.5 (c 1.20, CHCl3); IR (neat,) 3224, 1714, 1454, cm-1; 1H NMR (CDCl3) δ 6.11 (m, 1H), 4.21 (m, 2H), 3.87 (q, J = 6.8 Hz, 1H), 3.58 (d, J = 6.0 Hz, 1H), 1.97 (d, J = 6.8 Hz, 3H), 1.79 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3) δ 167.5, 137.7, 133.8, 62.6, 60.7, 55.9, 29.4, 22.9, 15.8, 14.6, 11.3. HRMS calcd for C13H26NO3S (M+H) 276.1633. Found 276.1635.
Ethyl (Z)-(Rs,2S)-(-)-2-[ethyl(2-methylpropanesulfinylamino)methyl]-3-phenylacrylate (14f)
Flash chromatography (50% EtOAc/hexanes) provided 35% of a colorless oil; [α]20D -36.3 (c 0.84, CHCl3); IR (KBr) 3211, 1722, 1225, 1061 cm-1; 1H NMR (CDCl3) δ 7.22 (m, 5H), 6.77 (s, 1H), 4.07 (m, 3H), 3.47 (d, J = 5.2 Hz, 1H), 1.98 (m, 1H), 1.83 (m, 1H), 1.20 (s, 9H), 1.06 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3) δ 168.7, 135.7, 135.3, 134.8, 128.7, 128.6 128.5, 62.7, 61.1, 56.1, 29.3, 22.9, 14.0, 11.4. HRMS calcd for C18H28NO3S (M+H) 338.1790. Found 338.1781.
(SS,2R,3S)-(+)-Ethyl 2-methyl-3-(4-methylphenylsulfinamido)-3-phenyl-propanoate (5)
In an oven-dried, 25 mL one neck round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and an H2 balloon was placed (+)-4 (0.200 g, 0.585 mmol) and rhodium complex A (0.031 g, 0.044 mmol) in anhydrous DCM (5.0 mL). The solution was evacuated and filled with H2, and this sequence was repeated 5 times. The reaction mixture was stirred for 48 h at rt, and concentrated. Flash chromaatography (50% EtOAc/hexanes) afforded 0.180 g (88%) of a colorless oil; [α]20D +33.6 (c 0.65, CHCl3); IR (neat) 3206, 1730, 1090, 1053 cm-1; 1H NMR (CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.21 (m, 3H), 7.11 (m, 4H), 5.06 (d, J = 7.2 Hz, 1H), 4.50 (dd, J = 7.2, 8.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.88 (dq, J = 6.8, 8.0 Hz, 1H), 2.32 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.46 (d, J = 6.8 Hz, 3H);13C NMR δ 175.0, 142.0, 141.4, 141.1, 129.5, 129.0, 127.9, 127.3, 126.1, 61.1, 60.4, 46.9, 21.6, 15.8, 14.5. HRMS calcd for C19H23NO3SNa (M+Na) 368.1296. Found 368.1304.
(RS,2S,3R)-(-)-Ethyl 2-methyl-3-(4-methylphenylsulfinamido)-3-phenyl propanoate (15a)
Flash chromatograpy (50% EtOAc/hexanes) afforded 83% of a colorless oil; [α]20D -20.6 (c 0.18, CHCl3); IR (neat) 3584, 3256, 1734 cm-1; 1H NMR (CDCl3) δ 7.32 (m, 5H), 4.46 (dd, J = 8.4, 8.4 Hz, 1H), 4.12 (q, J = 7.3 Hz, 2H), 3.96 (d, J = 8.4 Hz, 1H), 2.92 (dq, J = 7.2, 8.4 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.11 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3) δ 174.9, 140.4, 128.9, 128.2, 127.4, 63.1, 60.8, 56.4, 46.8, 22.7, 15.2, 14.3. HRMS calcd for C16H26NO3S (M+H) 312.1633. Found 312.1625.
(RS,S)-(-)-Ethyl 2-[(R)-(1,1-dimethylethylsulfinamido)(phenyl)methyl]butanoate (15b)
In an oven-dried, 25 mL one necked, round-bottomed flask equipped with a magnetic stirring bar was placed (-)-14b (0.0302 g, 0.093 mmol) and rhodium complex A (0.005 g, 0.007 mmol) in 1,2-dichloroethane (4.5 mL). The solution was placed in a high-pressure vessel (Series 4650 2.50 Inch Inside Diameter HP/HT from Parr Instrument Company). The vessel was tightly closed and was filled with H2 until the inner pressure reached 25 atm at which time it was evacuated and refilled with H2 to 25 atm. This sequence was repeated 3 times. The reaction mixture was stirred at 25 atm of H2 for 72 h at rt, at which time the solution was concentrated. Preparative TLC (50% EtOAc/hexanes) afforded 0.0241 g (81%) of a colorless oil; [α]20D -44.4 (c 0.41, CHCl3); IR (neat): 3216, 1732, 1052 cm-1; 1H NMR (CDCl3) δ 7.30 (m, 5H), 4.60 (dd, J = 7.6, 7.6 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.66 (d, J = 7.6 Hz, 1H), 2.80 (m, 1H), 1.63 (m, 2H), 1.20 (s, 9H), 1.04 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3) δ 173.0, 140.6, 128.6, 128.0, 127.3, 61.7, 60.4, 56.5, 54.2, 22.7, 22.1, 14.0, 11.9. HRMS calcd for C17H28NO3S (M+H) 326.1790. Found 326.1782.
(RS,2S,3R)-(-)-Ethyl 2-benzyl-3-(1,1-dimethylethylsulfinamido)-3-phenyl-propanoate (15c)
Preparative TLC (50% EtOAc/hexanes) afforded 79% of a colorless oil; [α]20D -19.5 (c 0.57, CHCl3); IR (neat) 3221, 1730, 1052 cm-1; 1H NMR (CDCl3) δ 7.30 (m, 10H), 4.66 (dd, J = 7.2, 7.2 Hz, 1H), 3.81 (m, 3H), 3.20 (m, 1H), 3.06 (m, 1H), 2.92 (m, 1H), 1.23(s, 9H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3) δ 172.3, 140.0, 138.8, 128.8, 128.6, 128.4, 128.1, 127.3, 126.4, 61.9, 60.3, 56.5, 54.6, 35.0, 22.6, 13.7. HRMS calcd for C22H29NO3SNa (M+Na) 410.1765. Found 410.1766.
(Rs,2S,3S)-(-)-Ethyl-2-methyl-3-(tert-butylsulfinylamino)pentanoate (15d)
In a 50 mL, dry, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and an H2 balloon was placed (-)-14d (0.05 g, 0.17 mmol) and rhodium complex A (0.009 g, 0.013 mmol) in anhydrous DCM (5 mL). The solution was evacuated and filled with H2, and this sequence was repeated 5 times. The reaction mixture was stirred at rt for 48 h. Preparative TLC (50% EtOAc/hexane) afforded 0.0255 g (55%) of a colorless oil; [⟨]20D -31.46 (c 0.06, CHCl3); IR (neat) 3280, 1732, 1462, cm-1; 1H NMR (CDCl3) TM 4.06 (m, 2H), 3.62 (d, J = 12 Hz, 1H), 3.29 (m, 1H), 2.69 (m, 1H), 1.72 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H) 1.23 (s, 9H), 1.19 (d, J = 7.2 Hz, 3H) 0.99 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3) TM 174.9, 61.3, 60.4, 56.2, 43.4, 27.37, 22.7, 14.7, 14.2, 10.0. HRMS calcd for C12H26NO3S (M+H) 264.1633. Found 264.1613.
(Rs,2S,3S)-(-)-Ethyl 2-benzyl-3-(1,1-dimethylethylsulfinamido)pentanoate (15f)
Preparative TLC (50% EtOAc/hexanes) afforded 77% of a colorless oil; [α]20D -27.7 (c 0.51, CHCl3); IR (neat) 3228, 1731, 1053 cm-1; 1H NMR (CDCl3) major isomer δ 7.19 (m, 5H), 4.00 (q, J = 7.6 Hz, 2H), 3.66 (m, 1H), 3.23 (d, J = 7.6 Hz, 1H), 2.96 (m, 2H), 2.85 (m, 1H), 1.77 (m, 1H), 1.62 (m, 1H), 1.20 (s, 9H), 1.10 (t, J = 8.1 Hz, 3H), 0.97 (t, J = 7.6 Hz, 3H) ; 13C NMR (CDCl3) δ 173.2, 139.2, 128.8, 128.5, 126.4, 60.4, 59.8, 56.2, 52.0, 34.1, 26.8, 22.9, 14.1, 10.4. HRMS calcd for C18H29NO3SNa (M+Na) 362.1766. Found 362.1761.
(2R,3S)-(-)-Ethyl 2-methyl-3-(4-methylphenylsulfonamido)-3-phenylpropanoate (7) from (+)-5
In an oven-dried, 10 mL one neck, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (+)-5 (0.168 g, 0.486 mmol) in DCM (18.0 mL). The solution was cooled to 0 °C, m-CPBA (0.336 g, 1.458 mmol, 75% wt) was added in one portion, the reaction mixture was warmed to rt, stirred for 1.5 h, and quenched by addition of sat. Na2S2O3 solution (10 mL). The solution was extracted with DCM (2 × 5 mL), the combined organic phases were washed with sat. NaHCO3 solution (2 × 5 mL), brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (50% EtOAc/hexanes) afforded 0.145 g (88%) of a colorless oil; [α]20D -43.0 (c 1.09, CHCl3); IR (neat) 3279, 1733, 1161 cm-1; 1H NMR (CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H), 7.12 (m, 3H), 7.05 (d, J = 8.4 Hz, 2H), 7.00 (m, 2H), 5.96 (d, J = 8.8 Hz, 1H), 4.50 (dd, J = 6.0, 8.4 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 2.79 (quint, J = 6.4 Hz, 1H), 2.31 (s, 3H), 1.13 (m, 6H); 13C NMR δ 174.9, 143.1, 139.4, 138.4, 129.5, 128.6, 127.7, 127.3, 126.9, 61.2, 60.5, 46.3, 21.7, 15.8, 14.3. Spectral properties were consistent with literature values.25
(2S,3R)-(+)-Ethyl 2-methyl-3-(4-methylphenylsulfonamido)-3-phenyl-propanoate the enantiomer of (-)-(7) from (RS,2S)-(-)-15a
In an oven-dried, 50 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum and argon balloon was placed (-)-15a (0.110 g, 0.354 mmol) in anhydrous MeOH (13 mL). The solution was cooled to 0 °C, HCl (0.7 mL, 2.0 M in Et2O) was added dropwise, warmed up to rt, stirred for 3 h, and quenched by addition of 1 N NaOH solution adjusting the pH to 9. The solution was extracted with EtOAc (3 × 5 mL), washed with brine (5 mL), dried (MgSO4), and concentrated. The residue was placed in a 15 mL single necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon in DCM (5.2 mL). TsCl (0.067 g, 0.531 mmol) was added, the solution was cooled to 0 °C, and Et3N (0.1 mL, 0.708 mmol) and DMAP (2.1 mg, 0.0177 mmol) were added. The reaction mixture was warmed to rt, stirred for 12 h, and quenched with H2O (3 mL). The solution was extracted with DCM (3 × 5 mL), the combined organic phases were washed with brine (5 mL), dried (MgSO4), and concentrated. Chromatography (25% EtOAc/hexanes) afforded 0.101 g (79%) of colorless oil; [α]20D +45.0 (c 0.21, CHCl3), [α]20D -43.0 (c 1.09, CHCl3) for the enantiomer of (-)-7; IR (neat) 3279, 1733, 1161 cm-1; 1H NMR (CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H), 7.12 (m, 3H), 7.05 (d, J = 8.4 Hz, 2H), 7.0 (m, 2H), 5.96 (d, J = 8.8 Hz, 1H), 4.50 (dd, J = 6.0, 8.4 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 2.79 (quint, J = 6.4 Hz, 1H), 2.31(s, 3H), 1.13 (m, 6H); 13C NMR δ 174.9, 143.1, 139.4, 138.4, 129.5, 128.6, 127.7, 127.3, 126.9, 61.2, 60.5, 46.3, 21.7, 15.8, 14.3. HRMS calcd for C19H22NO4S(M+H) 362.1426. Found 362.1419.
(2R,3S)-(-)-2-Methyl-3-(4-methylphenylsulfonamido)-3-phenylpropanoic acid (8)
In an oven-dried, 10 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, and rubber septum was placed (-)-7 (0.0435 g, 0.120 mmol) and LiOH monohydrate (0.0435 g, 0.120 mmol) in THF (9 mL) and H2O (0.33 mL). The reaction mixture was refluxed for 16 h at 67 °C, cooled to rt, and concentrated. The residue was diluted with DCM (10 mL), and 1 N HCl was added until the solution reached pH >2. The solution was stirred for 10 min, extracted with DCM (3 × 5 mL), the combined organic phases were washed with brine (4 mL), dried (MgSO4), and concentrated. Preparative TLC (50% EtOAc/hexanes) afforded 0.0363 g (91%) of white solid, mp 131-133 °C; [lit15b mp 135-136 °C]; [α]20D -23.6 (c 0.49, EtOAc), [lit15b [α]20D -25.6 (c 0.06, EtOAc), lit15a [α]20D -28.1 (c 1.0, EtOAc)]; IR (neat) 3263, 1712, 1160 cm-1; 1H NMR (CDCl3) δ 7.47 (m, 2H), 7.11 (m, 3H), 7.02 (m, 4H), 6.20 (d, J = 9.2 Hz, 1H), 4.50 (dd, J = 7.2, 8.8 Hz, 1H), 2.87 (quint, J = 6.8 Hz, 1H), 2.29(s, 3H), 1.17(d, J = 6.8 Hz, 3H);13C NMR δ 178.6, 143.3, 138.9, 138.0, 129.5, 128.7, 127.9, 127.3, 127.1, 60.5, 46.1, 21.7, 15.7. HRMS calcd for C17H20NO4S(M+H) 334.1113. Found 334.1126. Spectral properties were consistent with literature values.15
(3R,4S)-(-)-3-Methyl-4-phenyl-1-tosylazetidin-2-one (9)
In an oven-dried, 10 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (-)-8 (0.0224 g, 0.067 mmol), DCC (0.017 mg, 0.0804 mmol), and 4-pyrrolidinopyridine (3.7 mg) in DCM (2.5 mL). The reaction mixture was stirred for 16 h at rt, filtered through celite and the filtrate was washed with water (3.0 mL), 5% aqueous HOAc (3 mL), and water (3 mL). The combined organic phases were washed with brine (3.5 mL), dried (MgSO4), and concentrated. Preparative TLC (25% EtOAc/hexanes) afforded 0.0165 g (80%) of a white solid, mp 133-135 °C [lit15a mp 134-135 °C; [α]20D -103 (c 0.58, EtOAc), lit15a [α]20D -114 (c 1.05, EtOAc)]; IR (neat) 1794, 1361, 1168 cm-1; 1H NMR (CDCl3) δ 7.62 (dd, J = 3.2, 6.4 Hz, 2H), 7.26 (m, 7H), 4.60 (d, J = 3.2 Hz, 1H), 3.16 (m, 1H), 2.42 (s, 3H), 1.34 (d, J = 7.6 Hz, 3H); 13C NMR δ 167.9, 145.4, 136.5, 136.1, 130.1, 129.3, 129.2, 127.8, 126.9, 65.4, 55.0, 22.0, 12.8. HRMS calcd for C17H18NO3S [M+H] 316.1007. Found 316.1013. Spectra properties were consistent with literature values.15
Supplementary Material
Scheme 3.
Acknowledgements
We thank Professor Rodrigo Andrade of Temple University for helpful suggestions. This work was supported by a grant from the National Institutes of General Medical Sciences (GM 57870) and Boehringer Ingelheim Pharmaceuticals.
Footnotes
Supporting Information Available. Spectroscopic data for all new compounds are provided. This material is available free of charge via the World Wide Web at http://pubs.acs.org.
References
- (1).For a review see: Liu M, Sibi MP. Tetrahedron. 2002;58:7991..
- (2).Juaristi E, Lopez-Ruiz H. Curr. Med. Chem. 1999;3:2037. [PubMed] [Google Scholar]
- (3).(a) For recent reviews on β-peptides see: Seebach D, Gardiner J. Acc. of Chem. Res. 2008;41:1366. doi: 10.1021/ar700263g.. Aguilar M-I, Purcell AW, Devi R, Lew R, Rossjohn J, Smith AI, Perlmutter P. Org. & Biomolecular Chem. 2007;5:2884. doi: 10.1039/b708507a.. Fulop F, Martinek TA, Toth GK. Chem. Soc. Rev. 2006;35:323. doi: 10.1039/b501173f..
- (4).For reviews of sulfinimine chemistry which also include discussions of β-amino acid syntheses see: Morton D, Stockman RA. Tetrahedron. 2006;62:8869.. Davis FA. J. Org. Chem. 2006;71:8993. doi: 10.1021/jo061027p.. Senanayake CH, Krishnamurthy D, Lu Z-H, Han Z, Gallou I. Aldrichimica Acta. 2005;38:93.. Zhou P, Chen B-C, Davis FA. Tetrahedron. 2004;60:8003.. Ellman JA, Owens TD, Tang TP. Acc. Chem. Res. 2002;35:984. doi: 10.1021/ar020066u..
- (5).For the application of sulfinimines in the asymmetric synthesis of α-alkyl-β-amino acids see: Davis FA, Song M. Org. Lett. 2007;9:2413. doi: 10.1021/ol0708166.. Tang TP, Ellman JA. J. Org. Chem. 2002;67:7819. doi: 10.1021/jo025957u.. Garcia Ruano JL, Fernandez I, del Prado Catalina M, Hermoso JA, Sanz-Aparicio J, Martinez-Ripoll M. J. Org. Chem. 1998;63:7157. doi: 10.1021/jo972303q..
- (6).For a review on the Morita-Baylis-Hillman reaction see: Basavaiah D, Rao AJ, Satyanarayana T. Chem. Rev. 2003;103:811. doi: 10.1021/cr010043d..
- (7).Thermal elimination of benzenesulfenic acid from α-phenylsulfinylmethyl-β-(N-sulfinylamino) esters is reported to give α-methylene-β-(N-sulfinyamino) esters see: Kamimura A, Okawa H, Morisaki Y, Ishikawa S, Undo H. J. Org. Chem. 2007;72:3569. doi: 10.1021/jo062251h..
- (8).Aggarwal VK, Castro AMM, Mereu A, Adams H. Tetrahedron Lett. 2002;43:1577. [Google Scholar]
- (9).Shi M, Xu Y-M. Tetrahedron: Asymmetry. 2002;13:1195. [Google Scholar]
- (10).Reynolds TE, Binkley MS, Scheidt KA. Org. Lett. 2008;10:5227. doi: 10.1021/ol802227t. [DOI] [PubMed] [Google Scholar]
- (11).(a) Wei H-X, Hook JD, Fitzgerald KA, Li G. Tetrahedron: Asymmetry. 1999;10:661. [Google Scholar]; (b) Li G, Wei H-X, Hook JD. Tetrahedron Lett. 1999;40:4611. [Google Scholar]; (c) Li G, Wei H-X, Whittlesey BR, Batrice NN. J. Org. Chem. 1999;64:1061. doi: 10.1021/jo981976l. [DOI] [PubMed] [Google Scholar]
- (12).Ramachandran PV, Rudd MT, Burghardt TE, Reddy MVR. J. Org. Chem. 2003;68:9310. doi: 10.1021/jo034954u. [DOI] [PubMed] [Google Scholar]
- (13).Brown JM. Angew. Chem. Int. Ed. Engl. 1987;26:190. [Google Scholar]
- (14).Yamamoto K, Takagi M, Tsuji J. Bull. Chem. Soc. Jpn. 1988;61:319. [Google Scholar]
- (15).(a) Abrahams I, Motevalli M, Robinson AJ, Wyatt PB. Tetrahedron. 1994;50:12755. [Google Scholar]; (b) Roos GHP, Balasubramaniam S. Syn. Com. 1999;29:755. [Google Scholar]
- (16).(a) Mikolajczyk M, Lyzwa P, Drabowicz J, Wieczorek MW, Blaszcsyk J. Chem. Commun. 1996:1503. [Google Scholar]; (b) Davis FA, McCoull W. J. Org. Chem. 1999;64:3396. doi: 10.1021/jo990303f. [DOI] [PubMed] [Google Scholar]; (b) Davis FA, Wu Y, Yan H, McCoull W, Prasad KR. J. Org. Chem. 2003;68:2410. doi: 10.1021/jo020707z. [DOI] [PubMed] [Google Scholar]
- (17).Tsuda T, Yoshida T, Kawamoto T, Saegusa T. J. Org. Chem. 1987;52:1624. [Google Scholar]
- (18).Davis FA, Song M. Org. Lett. 2007;9:2413. doi: 10.1021/ol0708166. [DOI] [PubMed] [Google Scholar]
- (19).The absolute stereochemistry of (RS,S)-14a was established by transforming it into the enantiomer of (2R,3S)-(-)-7 isomer (2S,3R)-(+)-7 by hydrogenation with catalyst A (90%), removal of the sulfinyl group with HCl-H2O and conversion into the Ts sulfonamide with Ts-Cl, Et3N and DMAP (79%). See experimental section.
- (20).Ramachandran PV, Reddy MVR, Rudd MT, de Alaniz JR. Tetrahedron Lett. 1998;39:8791. [Google Scholar]
- (21).For leading references to the asymmetric synthesis of anti-α-substituted β-amino esters via the α-alkylation of β-amino esters dianions see: Wang J, Hou Y, Wu P, Qu Z, Chan ASC. Tetrahedron: Asymmetric. 1999;10:4553.. McNeil AJ, Toombes GES, Gruner SM, Lobkovsky E, Collum DB, Chandramouli SV, Vanasse BJ, Ayers TA. J. Am. Chem. Soc. 2004;126:16559. doi: 10.1021/ja045144i..
- (22).For other methods for the asymmetric synthesis of anti-α-substituted β-amino esters see: Davies SG, Walters IAS. J. Chem. Soc, Perking Trans 1. 1994:1129.. Sibi MP, Prabagaran N, Ghorpade SG, Jasperse CP. J. Am. Chem. Soc. 2003;125:11796. doi: 10.1021/ja0372309.. Ainara I, Vicario JL, Carrillo L, Badia D. Synthesis. 2006:4065.. (d) Ref. 5c.
- (23).(a) Davis FA, Reddy RE, Szewczyk JM, Reddy GV, Portonovo PS, Zhang H, Fanelli D, Reddy RT, Zhou P, Carroll P. J. Org. Chem. 1997;62:2555. doi: 10.1021/jo970077e. [DOI] [PubMed] [Google Scholar]; (b) Davis FA, Zhang Y, Andemichael Y, Fang T, Fanelli D, Zhang H. J. Org. Chem. 1999;64:1403. [Google Scholar]; (c) Finelli DL, Szewczyk JM, Zhang Y, Reddy GV, Burns DM, Davis FA. Organic Syntheses. 2004;Coll. Vol. 10:47. [Google Scholar]
- (24).Liu G, Cogan DA, Ellman JA. J. Am. Chem. Soc. 1997;119:9913. [Google Scholar]
- (25).Campi EM, Holmes A, Permutter P, Teo CC. Aust. J. Chem. 1995;48:1535. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.