Regioselective synthesis of fluoroaldols. Studies toward fluoroepothilones syntheses via antibody catalysis

Article abstract of DOI:10.1016/S0040-4039(00)01469-6

A general method for the synthesis of fluoromethyl aldols has been developed. Tributylboron enolates of fluoroacetone react with thiazole aldehydes (6) to provide fluoromethylaldols (4) regioselectively in high yields. Regioisomeric fluoroaldols (5) are produced as a 1:1 isomeric mixture of the erythro and threo products via a two-step procedure: first, aldol reaction with Weinreb amide and then Grignard reaction. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01469-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8243–8246
Regioselective synthesis of fluoroaldols. Studies toward
fluoroepothilones syntheses via antibody catalysis
Subhash C. Sinha,* Shantanu Dutta and Jian Sun
Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
Received 13 June 2000; revised 22 August 2000; accepted 23 August 2000
Abstract
A general method for the synthesis of fluoromethyl aldols has been developed. Tributylboron enolates
of fluoroacetone react with thiazole aldehydes (6) to provide fluoromethylaldols (4) regioselectively in high
yields. Regioisomeric fluoroaldols (5) are produced as a 1:1 isomeric mixture of the erythro and threo
products via a two-step procedure: first, aldol reaction with Weinreb amide and then Grignard reaction.
© 2000 Published by Elsevier Science Ltd.
Fluoro analogs of natural products are routinely synthesized to increase the potency of drugs
and are also used as probes for conformational analysis studies in solution. In continuation of
our program on the synthesis of epothilones by antibody catalysis, we became interested in
synthesizing fluoro analogs of epothilones. Several fluoro analogs of epothilones (1)1,2 have
already been reported and some possess higher potency than the natural compounds. We
anticipated that recently produced aldolase antibodies could be used to resolve enantiomerically
pure thiazole aldols 4 and 5, and the latter compounds would be converted to 13-fluoromethyl
epothilones (2) and 13-methyl-14-fluoro epothilones (3).3
Regioselective aldol reaction of fluoroacetone with an aldehyde, in principle, could afford
both fluoroaldol products 4 and 5 (Fig. 1). However, synthesis of fluoroaldols by aldol reaction
using fluoroketones as donors poses a major challenge and to the best of our knowledge there
are no chemical methods to achieve this goal in respectable yields. Based on our previous studies
with aldolase antibodies, it was expected that compounds 5 could be obtained as a major
product by aldol reaction of fluoroacetone with aldehydes 6. In our initial studies, we found that
the antibody 38C24 catalyzes the aldol reaction of fluoroacetone with aldehyde 6a5 providing 5
as a major product. Unfortunately, the stereo- and enantioselectivities of the reaction were low.
To overcome this problem, we decided to produce 4 and 5 by resolution of their racemic
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01469-6

8244
Figure 1.
mixtures using aldolase antibody 84G3.6 Since there is no straightforward method for the
synthesis of racemic fluoroaldols, such as 4 and 5, we decided to find suitable methods, which
could be used to synthesize them in reasonable yields. Here, we report a general method for the
aldol reaction of fluoroacetone with thiazole aldehydes (6a–c) to produce fluoromethyl thiazole
aldols (4a–c), regioselectively. We also report a two-step process for the synthesis of the
regioisomeric fluoroaldols 5a–c and efficient methods for the large-scale production of thiazole
aldehydes 6b and 6c.
Synthesis of thiazole aldehydes (6a–c): Syntheses of thiazole aldehydes 6b and 6c were similar
to that of 6a,7 starting from 7a, and required a slight modification in the condensation of 7b and
7c with ethyl bromopyruvate to produce the corresponding ester. Compound 7b8 was reacted
with ethyl bromopyruvate in ethanol with a catalytic amount of concentrated HCl at reflux
temperature for 2 h to produce the thiazole ester 8b. The thiazole ester 8c, on the other hand,
was obtained by heating 7c9 with ethyl bromopyruvate in benzene at 80°C for 1 h. The produced
thiazole esters 8b and 8c were first reduced with DIBAL-H affording 9b and 9c, respectively, and
the latter compounds were then reacted with 2-(triphenylphosphoranylidene)-propionaldehyde
to produce aldehydes 6b and 6c (Scheme 1).
Scheme 1. Synthesis of thiazole aldehydes 6a–c. (TBDPS=tert-butyldiphenylsilyl). Key: (a) for 8a: see reference 7; for
8b: ethanol, HCl (cat.), reflux, 2 h; for 8c: benzene, 80°C, 1 h; (b) DIBAL-H, CH2Cl2, −78°C, 2 h; (c) 2-(triphenyl-
phosphoranylidene)-propionaldehyde, benzene, 100°C, 1 h

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Synthesis of fluoromethylaldols (4):10 Aldol reaction of fluoroacetone with an aldehyde using
bases of alkali metals, including LDA, NaN(SiMe3)2, and KN(SiMe3)2, is not trivial and usually
no desired products are obtained from this reaction. Now, we found that aldolization of
aldehydes 6a–c with fluoroacetone could be achieved regioselectively using the boron enolate of
the latter to provide 4a–c. In a typical reaction, fluoroacetone (0.14 mL, 2 mmol) was added
dropwise to a solution of dibutylboron triflate (1 M in CH2Cl2, 2 mL, 2 mmol) and i-Pr2NEt
(0.42 mL, 2.4 mmol) in dry CH2Cl2 (10 mL) at 0°C. After 2 h, a solution of aldehyde 6a (167
mg, 1 mmol) in dry CH2Cl2 (2 mL) was added dropwise and the reaction mixture was stirred at
0°C to room temperature overnight. Diethyl ether (10 mL) and ethanolamine (2 mL) were
subsequently added, the mixture was stirred at room temperature for 6 h and then worked up
with ether and water. The organic layer was washed with brine, concentrated and chro-
matographed over silica gel to afford 4a (143 mg, 62%). Similarly, compounds 4b and 4c were
obtained in 60–70% yield (Scheme 2). The regioisomers of compounds 4a–c, if any formed,
could not be isolated.
Scheme 2. Aldol reactions of aldehydes 6a–c with fluoroacetone to ( )-4
Synthesis of fluoroaldols 5a–c: Reversal of regioselectivity of the addition of fluoroacetone to
aldehyde 6 could afford the desired compound 5. We briefly checked the effect of other amines,
such as 2,6-lutidine and collidine, on the enolization of fluoroacetone with tributylborontriflate.
With no favorable results, we decided to check a two-step process, in which Weinreb amide 10
was condensed with a thiazole aldehyde and then the resulting hydroxy amide 11 was reacted
with an alkyl Grignard reagent (Scheme 3).11 This method proved successful and provided an
easy access to 5a–c in 80–90% overall yield.
Scheme 3. Synthesis of fluoroaldols ( )-5. Key: (a) LDA, THF, −78°C, 2 h; (b) MeMgBr, THF, 0°C, 1 h
In a typical process, the Weinreb amide 10 (557 mg, 4.6 mmol) in dry THF (5 mL) was added
dropwise to a solution of LDA (prepared from n-BuLi, 1.6 M in hexanes, 3.2 mL, 5.02 mmol
and i-Pr2NH, 0.89 mL, 6.34 mmol in 15 mL dry THF at 0°C) at −78°C. After stirring for 1 h
at −78–0°C, a solution of 6a (470 mg, 2.81 mmol) in dry THF (5 mL) was added dropwise at
−78°C and then the mixture was stirred at −78°C for 2 h. Usual work-up and purification
afforded the hydroxyamide 11a (704 mg) in 93% yield. Compound 11a was then reacted with
methyl magnesium bromide as follows. To a solution of 11a (200 mg, 0.72 mmol) in dry THF
(3 mL), MeMgBr (1.4 M in THF, 1.4 mL, 1.96 mmol) was added at 0°C and the mixture was

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stirred at the same temperature for 1 h. Usual work-up and purification afforded the hydroxyke-
tone 5a (141 mg) in 85% yield. Similarly compounds 5b and 5c were obtained in 88 and 81%
overall yields, respectively.
After having compounds 4a–c and 5a–c in hand, we are now checking their resolutions using
aldolase antibody 84G3. In our preliminary investigation, we have found that compound 4a
could be resolved in enantiomerically pure form using aldolase antibody 84G3 or its congeners,
85H6 and 93F3.3c
In conclusion, general methods for the synthesis of both regioisomers of fluoroaldols have
been found and applied to prepare the starting materials for fluoroepothilones. Studies toward
stereoselective addition of 10 with 6 to produce 11 (threo or erythro), antibody catalyzed
resolutions of 4 and 5, and total synthesis of fluoroepothilones using enantiomerically pure
fluoroaldols are in progress and will be reported in due course.
Acknowledgements
We thank the Skaggs Institute of Chemical Biology for financial support.
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