Scheme 2
Scheme 4a
carboxaldehyde could be generated by a chiral hydrobora-
tion-oxidation sequence to provide 3.
The synthesis of fragment 3 (Scheme 3) was commenced
by protection of (2S,3R)-1,2-epoxy-3-butanol 8 as its p-
methoxybenzyl (PMB) ether. This was achieved by treating
compound 8 with sodium hydride and PMB bromide to give
5 in 85% yield.7
The Normant coupling reaction with epoxide 5 was
performed conveniently as follows.8 After forming the
Grignard reagent from the reported bromide 9, addition of
CuBr-DMS complex and stirring for several hours at low
temperature led to a black solution of cuprate reagent.
Condensation of propyne (g) into the cuprate solution at low
temperature was followed by addition of lithiohexyne.
Alkylation of the resultant vinyl cuprate 10 was accomplished
over the course of 1 day at -25 °C following addition of
epoxide 5. Chromatography of the crude product provided
the diastereomerically pure (Z)-alkene 11 in 76% yield. The
a (a) (i) Bu2BOTf, DIPEA, CH2Cl2, 0 °C then add 17 at -78
°C, (ii) Raney Ni, acetone, 60 °C, 45 min, 70% combined; (b) (i)
TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 95%; (ii) LiOH, H2O2,
THF/H2O, rt, 82%.
alcohol moiety of alkenol 11 was derivatized with SEMCl
and DIPEA to provide a SEM ether, 12. Removal of the
PMB ether of 12 with DDQ left the SEM ether intact to
give the alcohol 13. Oxidation of 13 was then effected under
Swern conditions to afford the methyl ketone 14 in 85%
yield. Wadsworth-Emmons olefination of ketone 14 with
the known phosphonate 7 led to the production of diaste-
reomerically clean triene 15 in 72% yield.9 Finally, diaste-
reoselective hydroboration of the triene 15 using (i-PC)2BH10
followed by oxidative workup and subsequent Swern oxida-
tion of the resulting alcohol 16 furnished the enantiomerically
pure aldehyde 3 in 92% yield.
For the aldol condensation shown in Scheme 1, the silyl-
protected keto acid 4 was required. This acid could be
prepared as reported in our earlier work via an Evans
enantioselective aldol condensation.6 The dibutylboron eno-
late of the reported oxazolidinone 17 reacted with keto
aldehyde 18 to give an R-thiomethyl amide aldol intermedi-
ate. Desulfuration was readily accomplished using Raney Ni,
providing the corresponding R:S aldol adducts 19 in a 23:
77 ratio, respectively (70% yield). After silylation with
TBDMSOTf and removal of the auxiliary, we obtained 4 in
good overall yield.
Scheme 3a
The optimum conditions for the aldol condensation of keto
acid 4 with aldehyde 3 required generation of the dilithio
(5) (a) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.;
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a (a) PMB-Br, NaH, Bu4N-I, THF, 0 °C, 85%; (b) (i) Mg, ether,
rt, (ii) CuBr-DMS, ether, DMS, -45 °C, 3 h, (iii) propyne, -45
to -23 °C, 4 h, then lithiohexyne, -78 °C, 1 h, (iv) epoxide 5,
-78 °C, 1 h, -25 °C, 24 h, 76%; (c) SEMCl, DIPEA, DCM, 0
°C, 92%; (d) DDQ/water (8:2), 88%; (e) DMSO, (COCl)2, DCM,
TEA, -78 °C, 85%; (f) 7, n-BuLi, THF, then 14, 72%; (g)
(i-PC)2BH, THF, 0.5 h, aqueous NaBO3; and (h) DMSO, (COCl)2,
DCM, TEA, -78 °C, 92%.
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Org. Lett., Vol. 3, No. 23, 2001