Lithiated Dimethoxymethyl Diphenyl Phosphine Oxide, A Versatile Formiate Carbanion Equivalent

Abstract

Aldehydes are homologated to the corresponding α-hydroxy methyl esters using lithiated dimethoxymethyl diphenyl phosphine oxide. The primary addition product of this Horner-Wittig process collapses to the corresponding α-hydroxy ester under proton-catalyzed conditions.

Key words

aldehydes - amino aldehydes - carbanions - hydrolyses - Wittig reactions

References

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9

Typical Procedure for the Formylation of Aldehydes: (1S,2RS)- [1-Benzyl-3-(diphenyl-phosphinoyl)-2-hydroxy-3,3-dimethoxy-propyl] carbamic acid benzyl ester(18): To a solution of lithiumdiisopropyl amide (5 mmol) in dry THF (60 mL) was added dimethoxymethyl phosphine oxide (332 mg, 6 mmol) in 20 mL dry THF at -110 °C under nitrogen atmosphere. Two minutes after addition the respective aldehyde 11 (425 mg, 1.5 mmol) in dry THF (20 mL) was added dropwise, followed directly by aq hydrolysis. Once the mixture is warmed up to r.t. it was concentrated in vacuo. After the resulting aq suspension was extracted with dichloromethane (5 ×), the combined organic layers were dried over MgSO₄ and evaporated. The residue was purified by column chromatography (silica gel; petroleum ether/ethyl acetate 1:4) to yield the adduct 18 (353 mg, 0.63 mmol, 42%).
Selected spectroscopic data for adduct 18: ¹H NMR (200 MHz, CDCl₃): δ = 8.12-7.75 (m, 4 H, H-aromat.), 7.55-7.08 (m, 14 H, H-aromat.), 7.05-6.94 (m, 2 H, H-aromat.), 6.08 (d, J = 6.8 Hz, 1 H, OH), 5.08 (d, J = 1.8 Hz, 1 H, NH), 4.96 and 4.82 (2 d, J = 12.5 Hz, 2 H, PhCH₂O), 3.90 (m, 2 H, 1-H, 2-H), 3.29 and 3.19 (2 s, 6 H, 2 × OMe), 2.94 (m, 2 H, PhCH₂); ¹³C NMR (100 MHz, CDCl₃): δ = 157.2 (s, NCO₂), 138.3, 136.7, 133.0, 132.8 (s, C-aromat.), 2 × 132.1, 131.9, 2 × 131.7, 2 × 131.6, 131.5, 131.4, 129.2, 128.6, 128.4, 128.3, 128.2, 2 × 128.1, 2 × 127.8, 126.0 (d, C-aromat.), 103.9 (s, C-3), 74.8 (d, C-2), 66.3 (t, PhCH₂O), 60.4 (d, C-1), 52.6 (q, OMe), 51.7 (q, OMe′), 38.2 (t, CH₂Ph).

10

Typical Experimental Procedure for the Generation of α-Hydroxy Esters by Proton-induced Fragmentation: Dichloromethane (200 mL) and hydrochloric acid (2 N, 10 mL) were stirred for 10 min. The aq phase was seperated and the acidity (1.5 mmol/L) of the organic phase was determined by titration with 0.1 N NaOH. (2RS,3S)-3-Benzyloxycarbonylamino-2-hydroxy-4-phenyl butyric acid methyl ester(25): Acidic dichloromethane (1.5 mL) was added to a solution of the phosphine oxide 18 (112 mg, 0.2 mmol) in dichloromethane (3 mL). The pure ester 25 was obtained after gel filtration (67 mg, 0.195 mmol, 97.5%).
Selected spectroscopic data for the hydroxy ester: (syn-25); Mp 92 °C (CH₂Cl₂); [a]²³ _D +7.9 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 7.38-7.20 (m, 10 H, H-aromat.), 5.09 (d, J = 8.0 Hz, 1 H, NH), 5.04 (s, 2 H, PhCH₂O), 4.33 (dddd, J = 8.9, 8.0, 7.1 and 1.8 Hz, 1 H, 3-H), 4.08 (d, J = 1.8 Hz, 1 H, 2-H), 3.70 (s, 3 H, OMe), 2.94 (s, 1 H, OH), 2.97 and 2.89 (2 × dd, J = 13.2 and 8.9 Hz, J = 13.2 and 7.1 Hz, 2 × 1 H, 4-H, 4-H′); ¹³C NMR (100 MHz, CDCl₃): δ = 174.1 (s, C-1), 155.7 (s, NCO₂), 137.2, 136.3 (s, C-aromat.), 129.4, 128.6, 128.5, 128.1, 127.9, 126.7 (d, C-aromat.), 70.1 (d, C-2), 66.8 (t, PhCH₂O), 54.7 (d, C-3), 52.9 (q, OMe), 38.3 (t, C-4).
(anti-25); Mp 120 °C (CH₂Cl₂); [a]^22.5 _D +73.6, (c 1.0, CHCl₃); ¹H NMR (200 MHz, CDCl₃): δ = 7.40-7.14 (m, 10 H, H-aromat.), 5.12 (d, J = 8.8 Hz, 1 H, NH), 5.05 (s, 2 H, PhCH₂O), 4.41 (m, 1 H, 3-H), 4.34 (m, 1 H, 2-H), 3.57 (s, 3 H, OMe), 3.22 (s, 1 H, OH), 2.8 (m, 2 H, 4-H); ¹³C NMR (50 MHz, CDCl₃): δ = 173.0 (s, C-1), 155.9 (s, NCO₂), 136.8, 136.3 (d, C-aromat.), 129.4, 128.5, 128.4, 128.1, 128.0, 126.7 (s, C-aromat.), 72.2 (d, C-2), 66.8 (t, PhCH₂O), 54.6 (d, C-3), 52.7 (q, OMe), 35.6 (t, C-4).
The absolute and relative configuration of both diastereomers 25 was independently confirmed after t-BuOK-promoted elimination followed by asymmetric dihydroxylation using ADmix-α (affording anti-25) or ADmix-β (affording syn-25). The configuration was determined as described in ref. [14] (Scheme [4] ).

Scheme 4