Synthesis of stereotriads by oxymercuration of substituted cyclopropylcarbinols.

Article abstract of DOI:10.1021/ol0162365

[structure: see text] Cyclopropylcarbinol derivatives bearing an adjacent methyl-substituted stereocenter and a remote beta-hydroxy group protected as a pivalate underwent anchimerically assisted regio- and diastereoselective oxymercurations, affording af

Full text of DOI:10.1021/ol0162365

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2567-2569
Synthesis of Stereotriads by
Oxymercuration of Substituted
Cyclopropylcarbinols
Janine Cossy,* Nicolas Blanchard, and Christophe Meyer
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI,
10 rue Vauquelin 75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received June 6, 2001
ABSTRACT
Cyclopropylcarbinol derivatives bearing an adjacent methyl-substituted stereocenter and a remote â-hydroxy group protected as a pivalate
underwent anchimerically assisted regio- and diastereoselective oxymercurations, affording after reductive demercuration, an access to
stereotriads.
Polypropionate fragments are found in a large variety of
natural products of biological interest, such as polyene
macrolide antibiotics (rapamycin, milbemycin), “unusual
macrolides” (rutamycin), polyether ionophores (ionomycin),
marine natural products (discodermolide, denticulatin), and
macrocyclic lactams (rifamycin, streptovaricin).1,2 In con-
nection with our studies concerning the development of
methods for polyketide synthesis,3 the oxymercuration-
demercuration of cyclopropylcarbinol derivatives of type A
having a stereogenic center at C2 (R ) CH3) and a protected
hydroxy group at C1 has been investigated, with the aim of
obtaining functionalized stereotriads4 of type B (Scheme 1).
However, when compounds of type A (R1 ) H or TBDPS
and R ) R2 ) H, trans diastereomers) were treated with
mercuric trifluoroacetate, a complex mixture of products was
obtained, but the reaction proceeded in modest yield when
R1 ) COCH3.5b Although internal participation of the ester
moiety was suggested, no further evidence was provided.
In light of these results, substrates 1a-c8 were protected
as pivaloic esters 2a-c and subjected to oxymercuration
(Figure 1).
When compounds 2a-c were treated with mercuric
trifluoroacetate (2 equiv, CH2Cl2, rt),5b a rapid reaction
occurred, and after treatment with an aqueous solution of
Scheme 1. Oxymercuration-Demercuration of Cyclopropanes A
High levels of regio- and stereocontrol are usually
observed in the oxymercuration of cyclopropylcarbinols.5-7
(1) Paterson, I.; Norcross, R. Chem. ReV. 1995, 95, 2041-2114 and
references therein.
(2) Marchionni, C.; Vogel, P. HelV. Chim. Acta 2001, 84, 431-472 and
references therein.
Figure 1. Cyclopropanes 1a-c and 2a-c.
10.1021/ol0162365 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/17/2001

KBr, the organomercuric bromides 3 were formed, isolated,
and characterized in the case of 2a and 2c. A reductive
demercuration using n-Bu3SnH and AIBN in THF9 afforded
stereotriads 4. The results are reported in Table 1.
demercuration of 3a and 3′a led respectively to 4a (96%)
and 4′a (92%). These two compounds, which only differ by
the positioning of the ester group, were reduced with LiAlH4
and converted to the same known anti,anti-triol 5 (Scheme
2).11 Similarly, the oxymercuration of 2b and subsequent
Table 1. Oxymercuration of Cyclopropanes 2a-c
Scheme 2. Correlation of Configuration for Compounds 4
reductive demercuration afforded a regioisomeric mixture
of diols 4b and 4′b (80% yield, 95/5 ratio).10 The relative
configuration of 4b was unambiguously deduced after
reduction with LiAlH4 to the known anti,syn-triol 6 (Scheme
2).11
In the case of compound 2c, the oxymercuration led to
three organomercuric bromides 3c, 3′c, and 3′′c in a ratio of
80/15/5.10 After purification by flash chromatography, 3c was
isolated in 60% yield and an inseparable mixture of 3′c and
3”c (75/25 ratio) was obtained in 17% yield. Reductive
demercuration of 3c afforded the corresponding stereotriad
4b (88%), and the mixture of 3′c and 3′′c was transformed
to stereotriads 4′c/4′b (70% yield, 75/25 ratio). From this
study, it appears that the presence of an ester group, such as
a pivalate, is essential to the success of these diasteroselective
oxymercurations.12 Furthermore, they proceed with inversion
of configuration () 95% diastereoselection) at the stereo-
center bearing the newly introduced secondary oxygenated
moiety (C3). However, mixtures of products are obtained,
due to partial migration of the ester group from the primary
to the secondary hydroxyl group. A reasonable scenario
involved an anchimerically assisted oxymercuration by the
ester carbonyl moiety that would predominantly proceed with
inversion of configuration, leading to an intermediate diox-
acarbenium species, which upon hydrolysis would afford a
regioisomeric mixture of the secondary and primary pivalate
esters of the corresponding stereotriad (Scheme 3).
To obtain stereotriads having the two primary alcohol
functions differentiated, we investigated the oxymercura-
(5) (a) Collum, D. B.; Mohamadi, F.; Hallock, J. S. J. Am. Chem. Soc.
1983, 105, 6882-6889. (b) Collum, D. B.; Still, W. C.; Mohamadi, F. J.
Am. Chem. Soc. 1986, 108, 2094-2096.
(6) Barrett, A. G. M.; Tam, W. J. Org. Chem. 1997, 62, 4653-4664.
(7) Kocovsky, P.; Grech, J. M.; Mitchell, W. L. J. Org. Chem. 1995,
60, 1482-1483.
The oxymercuration of 2a led to two separable organo-
mercuric bromides, 3a and 3′a, in 60% and 15% yield,
respectively. A third minor component, whose structure could
not be fully elucidated, was assigned as 3′′a and was also
detected in the crude reaction mixture (<5%).10 The reductive
(8) (a) Cossy, J.; Blanchard, N.; Hamel, C.; Meyer, C. J. Org. Chem.
1999, 64, 2608-2609. (b) Cossy, J.; Blanchard, N.; Meyer, C. Synthesis
1999, 1063-1075.
(9) Whitesides, G. M.; San Fillipo, J., Jr. J. Am. Chem. Soc. 1970, 92,
6611-6624
(10) The ratios of regio- and diastereomers have been determined by
NMR.
(11) Domon, L.; Vogeleisen, F.; Uguen, D. Tetrahedron Lett. 1996, 37,
2773-2776.
(12) No reaction was observed for substrates of type A (R ) CH3, R1 )
PMB, R2 ) H) bearing a p-methoxybenzyl protecting group.
(3) BouzBouz, S.; Popkin, M. E.; Cossy, J. Org. Lett. 2000, 2, 3449-
3451.
(4) (a) Hoffman, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489-
503. (b) Hoffman, R. W.; Dakmann, G.; Andersen, M. W. Synthesis 1994,
629-638.
2568
Org. Lett., Vol. 3, No. 16, 2001

Scheme 3. Anchimeric Assistance of the Ester Group in the
Oxymercuration of 2a
Scheme 4. Synthesis of Stereotriadsa
a (a) Hg(OCOCF3)2, CH2Cl2, rt, then aqueous saturated KBr; (b)
n-Bu3SnH, catalytic AIBN, THF, rt; (c) LiAlH4, THF, 0 °C.
The oxymercuration of cyclopropylcarbinol derivatives
bearing a methyl-substituted adjacent stereocenter and a
remote oxygenated moiety protected as an ester affords a
possible route to all diastereomeric sterotriads by simply
varying the relative configuration of the cyclopropane ring
(cis or trans) and the syn or anti relative configuration of
the adjacent stereocenter. Application of this method to
natural product synthesis is currently underway.
tion of the benzyl ethers 7a-d. These compounds were
subjected to a three-step sequence involving oxymercuration
with mercuric trifluoroacetate (2 equiv, CH2Cl2, rt) and
subsequent aqueous workup with KBr, reductive demercu-
ration with n-Bu3SnH, and deprotection of the pivalate with
LiAlH4. Better results were observed using this two-step
reduction protocol, although LiAlH4 could also initiate the
reductive demercuration.5b The diastereomeric stereotriads
8a-d were obtained in 38-65% overall yields and in a
diastereoselective fashion (dr ) 95/5). Their relative con-
figurations were confirmed by comparison with the literature
data,13-15 confirming that these anchimerically assisted
oxymercurations proceed with inversion of configuration
(Scheme 4).
Acknowledgment. N.B. thanks the M.R.E.S. for a grant.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0162365
(13) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 23, 3873-3888.
(14) Gennari, C.; Colombo, L.; Bertolini, G.; Schimperna, G. J. Org.
Chem. 1987, 52, 2754-2760.
(15) Yokoyama, Y.; Terada, Y.; Kawashima, H. Bull. Chem. Soc. Jpn.
1991, 64, 2563-2565.
Org. Lett., Vol. 3, No. 16, 2001
2569