Enhanced diastereoselectivity in asymmetric crotylation reactions using propargylic dicobalt hexacarbonyl complexes.

Article abstract of DOI:10.1021/ol016016r

[reaction: see text] Hexacarbonyl dicobalt complexes of propargylic acetals undergo Lewis acid catalyzed crotylation reactions with enhanced levels of diastereoselectivity (dr 6 to >20:1, syn/anti) while efficiently producing stereochemically well-defined

Full text of DOI:10.1021/ol016016r

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2439-2442
Enhanced Diastereoselectivity in
Asymmetric Crotylation Reactions Using
Propargylic Dicobalt Hexacarbonyl
Complexes
Meng Sui and James S. Panek*
Department of Chemistry and Center for Streamlined Synthesis,
Metcalf Center for Science and Engineering, 590 Commonwealth AVenue,
Boston UniVersity, Boston, Massachusetts 02215
panek@chem.bu.edu
Received April 21, 2001
ABSTRACT
Hexacarbonyl dicobalt complexes of propargylic acetals undergo Lewis acid catalyzed crotylation reactions with enhanced levels of
diastereoselectivity (dr 6 to >20:1, syn/anti) while efficiently producing stereochemically well-defined homoallylic ethers. These results are in
contrast to uncomplexed propargylic acetals, which undergo the crotylation reactions with low selectivity (dr < 2:1, syn/anti). After removal
of the cobalt complex, the reactions afford propargylic ethers in high yields.
The chemistry of functionalized acetylenes and their ap-
plications in synthesis have certainly been enhanced by the
use of transition-metal complexes.1 These complexes have
been employed as temporary intermediates that have lead to
the increased utility of functionalized propargylic systems.2
For instance, it has been well documented that formation of
mononuclear3 and dinuclear4 complexes results in significant
changes in alkyne structure and reactivity.2e In that regard,
dicobalt complexes of acetylenes are among the most useful
members of the dinuclear class and have proven to be useful
in synthesis. The purpose of this Letter is to report our
findings concerning the increased levels of diastereoselec-
tivity obtained in Lewis acid catalyzed crotylations of
hexacarbonyl dicobalt complexes of propargylic acetals. In
regards to our plans for the synthesis of cystothiazole A, we
required a syn-crotylation reaction that would give access
to a stereochemically well-defined propargylic ether. This
R,â-branched alkyne 1 would serve as a precessor to a
(1) (a) Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1
2000, 11, 1657-1668. (b) Sugihara, T.; Yamaguchi. M.; Nishizawa, M. J.
Synth. Org. Chem. Jpn. 1999, 3, 158-169. (c) Collman, J. P.; Hegedus, L.
S.; Norton, J. R.; Finke, R. G. Principles and Applications of Organotransi-
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(d) Pearson, A. J. In The Chemistry of the Carbon-Metal Bond; Hartley, F.
R., Patai, S., Eds.; Wiley: New, York, 1987; Vol. 4, p 890. (e) Pearson, A.
J. Metallo-organic Chemistry; Wiley: New York, 1985.
(2) For recent examples and leading references, see: (a) Lu, Y. F.; Green,
J. R. Synlett 2001, 2, 243-247. (b) Balsells, J.; Vazquez, J.; Moyano, A.;
Pericas, M. A.; Riera. A. J. Org. Chem. 2000, 65, 7291-7302. (c)
Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 21, 3262-3283. (d)
Roush, W. R.; Park, J. C. J. Org. Chem. 1990, 55, 1143-1144. (e) Schreiber,
S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem. Soc. 1987, 109, 5749-
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T. J. Am. Chem. Soc. 1978, 100, 1750.
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104, 3858-3875.
10.1021/ol016016r CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/10/2001

vinylmetal species, which would effectively participate in a
cross-coupling reaction with bisthiazole 2. The bisthiazole-
containing antibiotics were recently isolated from a culture
broth of the myxobacterium Cystobacter fuscus. Cystothia-
zole A exhibit enhanced antifungal and antitumor activities,
and its cytotoxicity is lower than the related antibiotic
myxothiazol.5
Scheme 2
The retrosynthetic analysis of cystothiazole A leads to two
fragments through the cleavage of the C7-C8 bonds (Scheme
1). Fragment 2 bearing the bisthiazole ring system can be
Scheme 1. Retrosynthesis of Cystothiazole A
5. Two Lewis acids, TMSOTf and BF3‚OEt2, were compared
as the catalysts for this reaction. For the cases that we
examined, only a trace of product was observed using
TMSOTf. BF3‚OEt2 produced considerably higher yields and
therefore was chosen as the promoter for subsequent experi-
ments.
Although the reaction produced the crotylation product in
high yield (82%), it did so without useful levels of selectivity
(∼2:1 syn/anti). The selectivity was not improved at lower
temperature (-78 and -50 °C).
The stereochemical outcome of this reaction may be
interpreted by two related anti-periplanar transition state
models, where the participating π-bonds are oriented at 180°
to each other (Scheme 3).8 On the basis of steric destabilizing
derived from commercially available 2,4-thiazolidinedione.
Fragment 1 could be obtained from the cleavage of the
double bond of â,γ-unsaturated ester 3, followed by aldol
reaction to install the â-methoxy enoate. The C4-C5 syn
relationship of methoxy and methyl groups can be established
by addition of chiral crotylsilane 4 to propargylic dimethyl
acetal 5.
Scheme 3. Transition State Analysis
Our approach required an efficient crotylation reaction
between a chiral silane and a functionalized propargylic
acetal. This crucial bond construction would introduce the
necessary carbons for the C1-C7 acyclic fragment 1. This
functionalized subunit also possesses a syn-homoallylic ether
bearing the C4-C5 stereocenters. However, the direct
crotylation between silane 4 and uncomplexed propargylic
acetals was unselective, which prompted us to seek other
options (Scheme 2).6 A reasonable and practical solution to
this problem is the use of a dicobalt acetylene complex,
which have been employed to enhance selectivity in Lewis
acid promoted aldol reactions.7
interactions, TSsyn is only marginally favored over TSanti,
suggesting that decreasing steric interactions between the
TMS-acetylene and the vinyl methyl group of the silane is
manifested in a loss of selectivity.
Our initial experiments in this area were aimed at the direct
crotylation between silane (S)-4 and the propargylic acetal
In the present case, the propargylic aldehyde lacks
sufficient steric bulk, required to favor TSsyn versus TSanti.
Therefore, the difference of ∆Gq of the competing transition
states is not great enough to achieve useful levels of facial
bias.
(5) Makoro, O.; Yoshihiro, S.; Akane, T.; Youji, S.; Ryosuke, F.;
Toshihiko, Y.; Shigeru, Y. Jpn. J. Antibiot. 1998, 51, 275-281.
(6) (a) Panek, J. S.; Beresis, R. T. J. Org. Chem. 1993, 58, 809-811.
(b) Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S. Tetrahedron Lett.
1995, 36, 8727-8730.
(7) For several papers in which Co2(CO)8 complexes of propargylic
aldehydes have been shown to give enhanced diastereoselectivity in aldol
reactions, see: (a) Ju, J.; Reddy, B. R.; Khan, M.; Nicholas, K. M. J. Org.
Chem. 1989, 54, 5426-5428. (b) Mukai, C.; Nagami, K.; Hanaoka, M.
Tetrahedron Lett. 1989, 30, 5623-5426. (c) Mukai, C.; Nagami, K.;
Hanaoka, M. Tetrahedron Lett. 1989, 30, 5627-5630.
(8) (a) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (b)
Fleming, I. Org. React. 1989, 37, 57. (c) Birkover, L.; Stuhl, O. In The
Chemistry of Organic Silicon Compounds; Patai, S., Rappoport, Z., Eds.;
Wiley: New York, 1989; Chapter 10.
2440
Org. Lett., Vol. 3, No. 16, 2001

To get around this problem, a propargylic dicobalt complex
was used to add steric bulk to the alkyne. As shown in
Scheme 4, propargylic acetal 5 was converted to its dicobalt
complex by treatment with dicobalt octacarbonyl. Crotylation
reaction between 6a and (S)-4 provided the dicobalt complex
of syn-homoallylic ether 7a,9 which was converted to
propargylic ether 3a by treatment with Me3NO in MeOH.
We were pleased to learn that the diastereoselectivity was
significantly improved to 10:1 with good yield.
Scheme 4
Encouraged by these results, we examined an array of
propargylic acetals. The important results are summarized
in Table 1.
Table 1 illustrates the effectiveness of dicobalt complexes
6 in crotylations. The reaction exhibits a useful level of
selectivity for both branched alkyl and aromatic propargylic
acetals. For example, the dibenzyl acetal cobalt complexes
derived from 4-phenyl-1-butyne gave a single isomer when
reacted with (S)-crotylsilane (entry 6). The selectivity is
indepentent of the type of acetals, as good diastereoselectivity
was observed for ethyl, benzyl, and methyl acetal. The
powerful effect of the cobalt carbonyl unit is underscored
by comparison of the above results with the reactions of the
free propargylic acetals 5 with chiral crotylsilane 4 in which
case little or no stereoselctivity was observed.
Table 1. Crotylation of Dicobalt Complexes of Propargylic
Acetals
The relative stereochemical assignment for the reaction
products was assigned on the basis of anology with pro-
pargylic ether 3g.10 Specifically, measurement of the three-
bond coupling constants (3JH1,H2 ) 3.6 Hz) of the derived
acetonide 11 permitted the stereochemical assignment as a
Scheme 5. Assignment of Relative Stereochemistry
syn bond construction. Accordingly the ester 3g was con-
verted to actonide 11 in four steps as shown in Scheme 5:
(9) Typical Procedure. A solution of propargyl acetal cobalt complex
(52.6 mg, 0.11 mmol) and S-crotylsilane (37.6 mg, 0.14 mmol) in 1 mL of
CH2Cl2 was cooled to -30 °C, and freshly distilled (CaH2) BF3‚OEt2 (25
µL, 0.197 mmol, 1.8 equiv) was added. The solution was stirred for 12 h
at -30 °C, diluted with saturated NaHCO3, and warmed to room temperature
with stirring. The reaction mixture was extracted with CH2Cl2 (2 × 5 mL),
dried (MgSO4), and concentrated in vaccum. Purification by chromatography
on silica gel (2% EtOAc/hexane eluent) afforded 80% of product.
1
a Ratio of products was determined by H NMR (400 MHz). b Isolated
yields for free alkyne averaged 83%. c Isolated yields for the crotylation
reactions ranged between 82% and 93%. d Only one isomer is observed by
1H NMR.
Org. Lett., Vol. 3, No. 16, 2001
2441

(i) oxidation of the trans double bond of 3g resulting in the
formation of the intermediate aldehyde 8, (ii) reduction of
the aldehyde to alcohol 9 by LiBH4 in THF,11 (iii) depro-
tection of the benzyloxy group,12 and (iv) conversion of the
diol 10 into acetonide 11 in a solution of 2,2-methoxy
propane containing a catalytic amount of pyridinium p-
toluenesulfonate (PPTS).
In summary, the diastereoselective crotylations of dicobalt
complexes of propargylic acetals provides a convenient route
to stereochemically well-defined homoallylic ethers. Ap-
plications in natural product synthesis will be reported in
due course.
Acknowledgment. This work has been financially sup-
ported by the National Institutes of Health (RO1GM55740).
Supporting Information Available: General experimen-
tal procedures and full characterization of compounds 3a-h
and procedures for ee analysis. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Analysis to determine ee was carried out using chiral HPLC (with
chiral OD column); see Supporting Information for details.
(11) (a) Schwab, J. M.; Lin, D. C. T. J. Am. Chem. Soc. 1985, 107,
6046-6052. (b) Williams, D. R.; White, F. H. J. Org. Chem. 1987, 52,
5067-5079.
(12) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc.
1989, 111, 1923-1925.
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