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.

Key words

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

References

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10

As expected, the minor diastereomer observed in all cases is the alternative 4,5-syn isomer. No significant amounts of anti adducts were indeed detected throughout the overall study.

12

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

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.