Synthesis of Nonracemic β-Hydroxy Ketones and Carbonate Derivatives from Homopropargylic Alcohols through Iodolactonization

Full text of DOI:10.1021/jo990439d

3798
J . Org. Chem. 1999, 64, 3798-3799
alkyne 2a resulted in complex mixtures of inseparable
products. In an effort to trap the intermediate mercurium
species, we attempted an oxymercuration of the tert-butyl
carbonate 3a . Once again a complex mixture of products was
formed. We then considered subjecting carbonate 3a to
iodolactonization conditions, a transformation well prece-
dented for homoallylic carbonates6 but not the homopro-
pargylic analogues. Thus, we were pleased to find that upon
treatment with IBr in methylene chloride,6 carbonate 3a was
cleanly converted to the cyclic iodo carbonate 4a (eq 3). This
Syn th esis of Non r a cem ic â-Hyd r oxy Keton es
a n d Ca r bon a te Der iva tives fr om
Hom op r op a r gylic Alcoh ols th r ou gh
Iod ola cton iza tion
J ames A. Marshall* and Mathew M. Yanik
Department of Chemistry, McCormick Road, University of
Virginia, Charlottesville, Virginia 22901
Received March 11, 1999
Additions of nonracemic allenylmetal reagents I to alde-
hydes yield syn or anti adducts II with high diastereoselec-
tivity, particularly when R-branched aldehydes are em-
ployed.1 These homopropargylic alcohol adducts can be
efficiently elaborated to stereotriad, tetrad, and pentad
subunits (e.g. IV) of polyketide natural products by a
sequence involving partial reduction of the alkyne, epoxi-
dation, and addition of methylcuprate or hydride reagents
to the intermediate epoxide III (eq 1).2 Such subunits have
intermediate was readily isolable but proved rather labile
and was therefore reduced without purification. Reduction
was achieved with Bu3SnH to afford the novel cyclic carbon-
ate 5a in 80% overall yield. Initiation of the hydrogenolysis
reaction was best achieved with Et3B.7 Use of AIBN as the
initiator required higher temperatures which caused partial
destruction of the iodo lactone.
Cleavage of enol carbonate 5a to the â-hydroxy ketone 6a
was not successful under typical saponification conditions.
For example, treatment with methanolic K2CO3 led to
products of elimination and epimerization. However, the
desired conversion was readily effected with LiOOH at room
temperature.8 Methanolic i-Pr2NEt effected methanolysis of
cyclic carbonate 5a leading to the methyl carbonate 7a at
room temperature. Methanolysis could also be achieved with
DMAP as the base catalyst, but only at reflux. The use of
Et3N gave the carbonate 7a along with 5-10% of elimination
product. Amine-catalyzed alcoholysis with BnOH or p-
MeOC6H4CH2OH (PMBOH) could not be achieved. However,
prolonged heating with these alcohols at 115-130 °C yielded
the carbonates 8a and 9a in high yield. Presumably other
alcohols could be used as well to afford a variety of carbonate
derivatives.
traditionally been accessed by means of aldol reactions
employing chiral auxiliaries.3 In the aldol approach, high
levels of substrate-induced stereocontrol can be realized in
cases where the enolate partner possesses stereogenic
centers at the R′ position (V f VI).4 With the aim of merging
the allenylmetal and aldol approaches to polyketide sub-
units, we initiated an investigation directed toward the
regioselective hydration of the alkyne moiety of the ho-
mopropargylic alcohols adducts II to afford enantioenriched
R′-methylated ketones V (eq 2).
For our initial studies we employed the racemic homopro-
pargylic alcohol 2a , readily prepared through addition of an
allenylzinc reagent formed in situ from propargylic mesylate
1, to cyclohexanecarboxaldehyde. Attempts to prepare the
â-hydroxy ketone 6a directly through oxymercuration5 of
Additional studies were conducted with the racemic
homopropargylic alcohols 2b-f to probe the scope of the new
reaction sequence (Table 1). The methyl-substituted adducts
3b, 3d , and 3f were prepared by alkylation of the terminal
alkynes 3a , 3c, and 3e with iodomethane. The intermediate
iodo lactones 5a -f were quite sensitive to heat and light.
(1) (a) Marshall, J . A.; Perkins, J . F.; Wolf, M. A. J . Org. Chem. 1995,
60, 5556. (b) Marshall, J . A.; Palovich, M. R. J . Org. Chem. 1997, 62, 6001.
(c) Marshall, J . A.; Adams, N. D. J . Org. Chem. 1998, 63, 3812. (d) Marshall,
J . A.; Grant, C. M. J . Org. Chem. 1999, 64, 696.
(2) Marshall, J . A.; Palovich, M. R. J . Org. Chem. 1998, 63, 4381.
Marshall, J . A.; Lu, Z.-H.; J ohns, B. A. J . Org. Chem. 1998, 63, 817.
Marshall, J . A.; J ohns, B. A. J . Org. Chem. 1998, 63, 7885.
(3) Heathcock, C. H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.6. Evans,
D. A. Aldrichimica Acta 1982, 15, 23.
(4) Paterson, I.; Scott, J . P. Tetrahedron Lett. 1997, 38, 7441. Review:
Cowden, C. J .; Paterson, I. Org. React. 1997, 51, 1.
(5) (a) Brown, H. C.; Kurek, J . T.; Rei, M. H.; Thompson, K. L. J . Org.
Chem. 1984, 49, 2551. (b) Overman, L. E.; Campbell, C. B. J . Org. Chem.
1974, 39, 1474
(6) Duan, J . J .-W.; Smith, A. B. J . Org. Chem. 1993, 58, 3703. Bongeni,
A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J . Org. Chem. 1982, 47,
4626.
(7) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto,
K. Bull. Chem. Soc. J pn. 1989, 62, 143.
(8) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett. 1987,
28, 6141.
10.1021/jo990439d CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/06/1999

Communications
J . Org. Chem., Vol. 64, No. 11, 1999 3799
Ta ble 1. Con ver sion of th e Ra cem ic Hom op r op a r gylic
Alcoh ols 2a -f to Keto Der iva tives
Consequently, these intermediates were subjected to the
hydrogenolysis reaction without purification. The methyl-
substituted hydrogenolysis products 5b, 5d , and 5f were
obtained as nearly 1:1 mixtures of (E) and (Z) isomers.
Additional studies were conducted on the nonracemic anti,
anti and syn, anti stereotriads 10, 11 and 18, 19.2 For these
studies the methyl-substituted triads 11 and 19 were
prepared by methylation of the alkynyl carbonates 10 and
18. The ability to alkylate the terminal alkyne of these
homopropargylic carbonates adds considerable flexibility to
the reaction sequence as both enantiomers of the 3-butyn-
2-ol precursor of mesylate 1 are commercially available.9
Thus, intermediates 10 and 18, and diastereomers thereof,
could serve as precursors to ketones such as 17 and 25 with
various R substituents.
The methyl carbonate products 16, 17, 24, and 25 of the
foregoing sequence were obtained as single isomers. Hence,
as expected, methanolysis proceeds without detectable epimer-
ization. These findings extend the utility of enantioenriched
homopropargylic alcohols as intermediates for the synthesis
of polyketide natural products.
Ack n ow led gm en t. This research was supported by
Grant AI31422 from the National Institute of Allergy and
Infectious Disease.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures for all compounds and 1H NMR spectra for all new
compounds lacking C and H analysis. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) The (S), (R), and racemic forms are available from the Aldrich
Chemical Co., Inc., Milwaukee, WI.
J O990439D