Synthesis of (+)-9a-epi-Stemoamide via DBU-Catalyzed Michael Addition of Nitroalkane

Abstract

We describe a practical synthesis of (+)-9a-epi-stemo­amide, which has been achieved in six steps from α,β-unsaturated γ-butyrolactone. The main features of the current approach include a DBU-catalyzed Michael addition of nitroalkane and a reductive lactamization of nitro esters.

Key words

Michael addition - nitroalkane - stemoamide - synthesis - unsaturated butyrolactone

References and Notes

• 3a Goetz M. Edwards OE. In The Alkaloids   Vol. 9:  Manske RHF. Academic Press; New York: 1976.  p.545 ; and references cited therein
• 3b Nakanishi K. Goto T. Ito S. Natori S. Nozoe S. In Natural Products Chemistry   Vol. 2:  Academic Press; New York: 1975.  p.292 
• 4a Jiang R.-W. Hon P.-M. Zhou Y. Chan Y.-M. Xu Y.-T. Xu H.-X. Greger H. Shaw P.-C. But PP.-H. J. Nat. Prod.  2006,  69:  749 
• 4b Lin L.-G. Zhong Q.-X. Cheng T.-Y. Tang C.-P. Ke C.-Q. Lin G. Ye Y. J. Nat. Prod.  2006,  69:  1051 
• 5 Lin W.-H. Ye Y. Xu R.-S. J. Nat. Prod.  1992,  55:  571 
• 6 Kohno Y. Narasaka K. Bull. Chem. Soc. Jpn.  1996,  69:  2063 
• 7a Jacobi PA. Lee K. J. Am. Chem. Soc.  1997,  119:  3409 
• 7b Jacobi PA. Lee K. J. Am. Chem. Soc.  2000,  122:  4295 
• 8 Williams DR. Reddy JP. Amato GS. Tetrahedron Lett.  1994,  35:  6417 
• 9a Kinoshita A. Mori M. J. Org. Chem.  1996,  61:  8356 
• 9b Kinoshita A. Mori M. Heterocycles  1997,  46:  287 
• 10 Gurjar MK. Reddy DS. Tetrahedron Lett.  2002,  43:  295 
• 11 Sibi MP. Subramanian T. Synlett  2004,  1211 
• 12 Olivo HF. Tovar-Miranda R. Barragán E. J. Org. Chem.  2006,  71:  3287 
• 13a Bogliotti N. Dalko PI. Cossy J. Synlett  2005,  349 
• 13b Bogliotti N. Dalko PI. Cossy J. Synlett  2006,  2664 
• 13c Bogliotti N. Dalko PI. Cossy J. J. Org. Chem.  2006,  71:  9528 
• 14 Torssell S. Wanngren E. Somfai P. J. Org. Chem.  2007,  72:  4246 
• 15 Khim S.-K. Schultz AG. J. Org. Chem.  2004,  69:  7734 
• 16 Yu P. Wang T. Li J. Cook JM. J. Org. Chem.  2000,  65:  3173 
• 17 Rosso GB. Pilli RA. Tetrahedron Lett.  2006,  47:  185 
• For the preparation of ent-(+)-5 {Lit.^¹8a [α]_D ^²5 +31.5 (c 2.00)}, see:
• 18a Hanessian S. Hodges PJ. Murray PJ. Sahoo SP. J. Chem. Soc., Chem. Commun.  1986,  754 
• The enantiomer, 5 {[α]_D ^²5 -32.7 (c 2.4, CHCl₃)}, was synthesized in a similar manner^¹8a from (R)-tert-butyl[3-(oxiran-2-yl)propoxy]diphenylsilane, an epoxide prepared^¹8b-d from l-ascorbic acid:
• 18b Hubschwerlen C. Synthesis  1986,  962 
• 18c Sharma GVM. Punna S. Krishna PR. Chorghade MS. Ley SV. Tetrahedron: Asymmetry  2005,  16:  1125 
• 18d Brimble MA. Park JH. Taylor CM. Tetrahedron  2003,  59:  5861 

1

Current address: GlaxoSmithKline R&D China, Building No. 3, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, P. R. of China.

2

Current address: Department of Chemistry, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA.

19

This was performed by following Narasaka’s protocol.⁶

20

Preparation of New Compounds
Compounds 4: Compound 5 (1.00 g, 2.63 mmol) was mixed with methyl 4-nitrobutanoate (580 mg, 3.94 mmol), and DBU (40 mg, 0.26 mmol) was introduced into the system. The mixture was stirred with no solvent at r.t. for 24 h and concentrated. The residue was chromatographed (PE-EtOAc,­ 5:1) to afford 4 (1.23 g, 89%) as a colorless oil (2:1 epimers). ^¹H NMR (300 MHz, CDCl₃): δ = 1.05 (s, 9 H), 1.05-1.92 (m, 4 H), 2.01-2.58 (m, 5 H), 2.62-2.84 (m, 2 H), 3.69 (s, 3 H), 3.60-3.79 (m, 2 H), 4.32-4.42 (m, 1 H), 4.58-4.72 (m, 1 H), 7.38-7.42 (m, 6 H), 7.63-7.68 (m, 4 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.1, 26.3, 26.8, 28.1, 29.3, 29.4, 30.9, 31.0, 31.6, 31.9, 43.4, 43.5, 52.0, 62.7, 62.8, 80.6, 82.0, 87.7, 88.3, 127.6, 127.6, 129.6, 129.6, 133.5, 133.6, 135.5, 171.9, 172.0, 173.7, 173.8. ESI-MS: m/z (%) = 550 (100) [M + 1], 450 (7). Anal. Calcd for C₂₈H₃₇NO₇Si: C, 63.73; H, 7.07; N, 2.65. Found: C, 64.02; H, 7.10; N, 2.62.
Compounds 3: Freshly prepared Raney Ni (ca. 1.20 g) was added to a solution of compound 4 (1.91 g, 3.62 mmol) in MeOH (72 mL). The mixture was hydrogenated under one atmosphere of hydrogen at r.t. for 24 h. After Raney Ni was filtered off, the filtrate was concentrated to give a residue, which was chromatographed (CH₂Cl₂-MeOH, 30:1) to afford compound 3 (1.455 g, 86%) as a colorless oil (2:1 epimers). ^¹H NMR (400 MHz, CDCl₃): δ = 1.04 (s, 9 H), 1.60-1.74 (m, 5 H), 2.26-2.40 (m, 5 H), 2.62-2.72 (m, 1 H), 3.64-3.75 (m, 3 H), 4.25-4.38 (m, 1 H), 7.34-7.43 (m, 6 H), 7.60-7.66 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 19.2, 24.5, 25.2, 26.8, 28.2, 29.8, 30.0, 30.6, 30.7, 31.6, 32.3, 45.3, 45.6, 55.5, 56.2, 63.0, 63.2, 81.9, 82.5, 127.7, 129.7, 133.6, 135.5, 175.3, 178.8, 179.0. ESI-MS: m/z (%) = 520 (13) [M + Na + MeOH], 504 (8) [M + K], 488 (97) [M + Na]. ESI-HRMS: m/z calcd for C₂₇H₃₅NO₄SiNa [M + Na]: 488.2233; found: 488.2228. Anal. Calcd for C₂₇H₃₅NO₄Si: C, 69.64; H, 7.58; N, 3.01. Found: C, 69.20; H, 7.43; N, 2.89.
Compound 6a: To a stirred solution of compounds 3 (1.30 g, 2.79 mmol) in THF (20 mL), Et₃N˙2HF (2.00 mL, 13.9 mmol) was added, and the mixture was stirred at r.t. for 3 d. NaHCO₃ (1.20 g, 14.3 mmol) was added, and the mixture was stirred for 10 min. The solvent was concentrated to give a residue, which was chromatographed (EtOAc-MeOH, 10:1) to afford the epimeric primary alcohols (842 mg) as a pale yellow solid. The alcohols were dissolved in CH₂Cl₂ (10 mL), and then DMAP (34 mg, 0.28 mmol), Et₃N (1.20 mL, 8.61 mmol), and MsCl (0.32 mL, 4.18 mmol) were added sequentially. The mixture was stirred at r.t. overnight, neutralized with sat. aq NaHCO₃ solution, extracted with CHCl₃-i-PrOH (4:1; 3 × 40 mL), dried (Na₂SO₄), and filtered. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc-MeOH, 4:1) to give the mesylation products. The mesylates were dissolved in THF (50 mL) and added to a stirred suspension of NaH (60%, 1.12 g, 28.0 mmol) in THF (150 mL) at 0 ˚C. After warming to r.t. and stirring for 20 h, the reaction was quenched at 0 ˚C by the addition of sat. aq NH₄Cl solution. The mixture was extracted with CHCl₃-i-PrOH (4:1), and the combined organic layers were dried (Na₂SO₄). The solvents were removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc-MeOH, 100:1) to afford a mixture of 6a and 6b (252 mg, 43% over the three steps from 3) as a white solid. The ratio of 6a/6b was found to be ca. 5:1 according to the line integrals of the ^¹H NMR spectrum. A pure sample of 6a was obtained by careful recrystallization of the 5:1 mixture of 6a/6b from EtOAc-MeOH (100:1).
Analytical Data of Compound 6a: Mp 106-108 ˚C; [α]_D ^²8 +23.3 (c 0.52, MeOH). ^¹H NMR (300 MHz, CDCl₃): δ = 1.58-1.90 (m, 4 H), 2.14-2.53 (m, 6 H), 2.60-2.68 (m, 1 H), 3.13-3.22 (m, 1 H), 3.54 (dd. J = 16.5, 7.5 Hz, 1 H), 3.78-3.87 (m, 1 H), 4.31-4.41 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 22.1, 24.1, 30.1, 30.4, 32.9, 40.3, 48.5, 60.8, 83.2, 174.0, 174.5. MS (EI): m/z (%) = 209 (31) [M⁺], 191 (7), 124 (19), 110 (33), 98 (100). HRMS (EI): m/z calcd for C₁₁H₁₅NO₃ [M⁺]: 209.1052; found: 209.1047.
Compound 2: To a solution of 6a (22 mg, 0.11 mmol) in anhyd THF (1 mL) at -78 ˚C was added LiHMDS solution in THF (1.0 M, 0.19 mL, 0.19 mmol). After 1 h, MeI (13 µL, 0.21 mmol) was added at -78 ˚C, and the stirring was continued for an additional 1 h. The reaction mixture was quenched with sat. NH₄Cl, warmed to r.t., and extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give a residue, which was purified by silica gel chromatography (EtOAc-MeOH, 15:1) to furnish 2 (14 mg, 60%) as a white solid: mp 86-88 ˚C; [α]_D ^²8 +74.9 (c 0.30, MeOH). ^¹H NMR (300 MHz CDCl₃):
δ = 1.29 (d, J = 7.5 Hz, 3 H), 1.62-1.90 (m, 4 H), 2.18-2.56 (m, 5 H), 2.75-2.88 (m, 1 H), 2.98-3.09 (m, 1 H), 3.60-3.69 (m, 1 H), 3.83-3.93 (m, 1 H), 4.52 (dt, J = 10.5, 4.8 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 10.8, 21.6, 23.2, 30.0, 30.2, 38.4, 40.8, 52.3, 57.8, 80.5, 174.0, 178.0. MS (EI): m/z (%) = 223 (37) [M⁺], 208 (21), 180 (20), 98 (100). HRMS (EI): m/z calcd for C₁₂H₁₇NO₃ [M⁺]: 223.1208; found: 223.1207.