Double Stereodifferentiating Aldol Reactions Based on Chiral Ketones Derived from Lactic Acid: Synthesis of C1-C6 Fragment of Erythronolides

Abstract

Highly stereoselective titanium-mediated aldol additions of ethyl ketones derived from lactic acid to α-methyl-β-OTBDPS chiral aldehydes are documented. One of these double stereodifferentiating processes represents the key step of a straightforward and efficient synthetic approach to the C1-C6 fragment of erythronolides.

aldol reactions - chiral ketones - erythronolides - stereoselective synthesis - titanium

References

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Overall yields of purified materials are indicated. Diastereomeric ratios have been established through HPLC and NMR analysis.

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20

The relative 3,4-syn-4,5-syn configuration was secured by NMR studies of the dioxane moiety.

21

Unexpectedly, this step turned out to be troublesome. Debenzylation with Pd(OH)₂/C was sluggish in EtOAc and afforded a complex mixture in MeOH. Better results (60% yield) were obtained with 10% Pd/C in EtOH, although it was not possible to prevent partial removal of acetonide protecting group and the corresponding triol was produced in 25% yield. Finally, alcohol 16 was isolated in excellent yield (91%) after 3 h in EtOAc.

22

Physical and spectroscopic data of ketone 13 are in agreement with those previously reported. See ref. 16a, 16f. Compound 13: colorless oil. R_f (hexanes-EtOAc 85:15) = 0.45. [α]_D +23.1 (c 1.8, CHCl₃). IR (film): ν = 2933, 1717, 1111, 1017 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.66-7.54 (4 H, m, ArH), 7.43-7.36 (6 H, m, ArH), 4.22 (1 H, d, J = 2.5 Hz, CH₃COCHO), 3.73 (1 H, dd, J = 9.6 Hz, J = 1.9 Hz, CHOCHCH₂OSi), 3.57 (1 H, dd, J = 10.3 Hz, J = 4.3 Hz, CH_xH_yOSi), 3.49 (1 H, dd, J = 10.3 Hz, J = 5.7 Hz, CH_xH_yOSi), 2.12 (3 H, s, CH₃CO), 2.03-1.95 [1 H, m, OHCCH(CH₃)CHO], 1.83-1.78 (1 H, m, CHCH₂OSi), 1.48 (3 H, s, CH₃CCH₃), 1.41 (3 H, s, CH₃CCH₃), 1.06 [9 H, s, SiC(CH₃)₃], 1.05 (3 H, d, J = 6.8 Hz, CH₃CHCH₂OSi), 0.70 [3 H, d, J = 6.6 Hz, OHCCH(CH₃)CHO]. ¹³C NMR (100.6 MHz, CDCl₃): δ = 209.3 (C), 135.6 (CH), 135.5 (CH), 133.5 (C), 133.4 (C), 129.7 (CH), 127.7 (CH), 127.6 (CH), 99.4 (C), 79.4 (CH), 75.2 (CH), 64.9 (CH₂), 36.7 (CH), 32.4 (CH), 29.8 (CH₃), 27.0 (CH₃), 26.8 (CH₃), 19.3 (C), 19.1 (CH₃), 14.2 (CH₃), 6.5 (CH₃). HRMS (+FAB): m/z calcd for C₂₈H₄₁O₄Si [M + H]⁺: 469.2774. Found: 469.2762.