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Synlett 2010(1): 131-133  
DOI: 10.1055/s-0029-1218529
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Asymmetric Synthesis of α- and β-Benzylhydroxy-γ-butyrolactones

Pedro Pinho*, Mikael Pelcman, Tatiana Agback, Bertil Samuelsson
Medivir AB, Box 1086, 141 22 Huddinge, Sweden
Fax: +46(8)54683199; e-Mail: pedro.pinho@medivir.se;
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Publication History

Received 14 September 2009
Publication Date:
30 November 2009 (online)

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Abstract

Herein we describe a new asymmetric synthesis of α-benzyl-α-hydroxy-γ-butyrolactone, a core building block of new HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimic. Immediate access to β-benzyl-β-hydroxy-γ-butyro-lactone is also possible from a common intermediate. Both lactones are useful building blocks in their own right.

Key words

lactones - asymmetric catalysis - epoxidations - oxidations - HIV

    References and Notes

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  • 8d

    Typical experimental procedure for the oxidation of 7 to 8: A two-neck flask fitted with a reflux condenser was loaded with 7 (93 mg, 0.30 mmol) and EtOAc (4 mL). To the stirring solution was added NaHCO3 (30 mg), H2O (4 mL) and 2-PrOH (0.80 mL). Pt/C (5 wt%, 40 mg) was added and the mixture heated at 70 ˚C for 24 to 48 h while bubbling air through a gas dispersion tube. NOTES: 1) the reaction is considerably faster using oxygen, but the combination of O2 and Pt(0) can easily cause fire and should be carefully controlled. 2) The transformation should be carefully monitored by LC-MS since, due to the four phase system, reaction times can vary. When complete, or nearly complete, the mixture was cooled to r.t. and the catalyst was filtered off. Organic solvents were removed by evaporation and MeOH (equal volume to that of H2O) was added. The solution was acidified with 2 M H2SO4 and stirred for 30 min. The solution was diluted with EtOAc (20 mL) and poured into an extraction funnel. The organic phase was washed with H2O (4 × 5 mL), dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (EtOAc-hexane, 40%) yielded 8 (38 mg, 66%). [α]D ²0 -49.9 (c 1.4, MeOH); ¹H NMR (400 MHz, CDCl3): δ = 7.19-7.40 (m, 5 H), 4.11-4.32 (m, 2 H, γ-CH2), 2.97-3.02 (m, 2 H, β-Bn-CH2), 2.44-2.73 (m, 2 H, α-CH2), 2.27 (br s, 1 H, OH); ¹³C NMR (100 MHz, CDCl3): δ = 175.3, 134.9, 129.8, 129.0, 127.6, 77.9, 76.8, 43.9, 41.9. The structure was confirmed through conventional gHMBC experiments. The 1D ¹H NMR spectrum shows three different sets of CH2 protons. The first observed quartet at δ = 4.11-4.32 ppm was assigned to the γ-CH2 due to the largest downfield chemical shift when compared to the others. Furthermore it also shows a weak three-bond interaction with the carbonyl carbon in the gHMBC spectrum. The second set, a collapsed quartet at δ = 2.97-3.02 ppm, shows interaction with the aromatic carbons in the gHMBC spectrum, and was therefore assigned to the β-Bn-CH2. Finally, the observed quartet at higher field, δ = 2.44-2.73 ppm was assigned to the α-CH2, showing a strong two-bond interaction with the carbonyl carbon in the gHMBC spectrum. LC-MS (ESI+): m/z = 193 [M + 1], 210 [M+NH4 +].

9

Typical experimental procedure for the oxidation of 7 to 2: To a cold (0 ˚C) solution of 7 (2.12 g, 6.83 mmol) in CH2Cl2-DMSO (3:1, 20 mL) was added Et3N (3 equiv) followed by SO3˙pyridine complex (1.1 equiv). The ice bath was removed and the reaction was allowed to stir at r.t. for 1 h. The solution was then poured into an extraction funnel, diluted with EtOAc (50 mL) and washed with brine (3 × 10 mL). The solvent was removed by evaporation and the crude aldehyde was dissolved in t-BuOH (25 mL). To the solution were added H2O (5 mL), NaHCO3 (2.5 equiv), 2-methyl-2-butene (1.1 equiv) and NaClO2 (2.1 equiv). After stirring for 2 h the solvent was removed, the residue was taken into EtOAc (75 mL) and the pH was adjusted to 2 with 0.5 M NaHSO4. Upon phase separation the solvent was removed and the crude acid was taken into MeOH (20 mL). H2O (5 mL) was added and the stirring mixture was treated with concd HCl (6 mL). After 15 min the reaction was evaporated to dryness and the residue was purified by flash chromatog-raphy on silica gel (EtOAc-hexane, 40%) to yield 2 (800 mg, 61%). [α]D ²0 -72.6 (c 1.5, CH2Cl2); ¹H NMR (400 MHz, CDCl3): δ = 7.22-7.36 (m, 5 H), 4.24-4.31 (m, 1 H), 3.73-3.81 (m, 1 H), 3.06 (s, 1 H), 2.89 (s, 1 H), 2.25-2.41 (m, 2 H); ¹³C NMR (100 MHz, CDCl3): δ = 178.8, 134.2, 130.0, 128.7, 127.5, 73.3, 65.2, 43.5, 34.0; LC-MS (ESI+): m/z =
193 [M + 1], 210 [M + NH4 +].