A One-Pot Multicomponent Coupling Reaction for the Stereocontrolled Synthesis of (Z)-Trisubstituted Allylic Alcohols

Article abstract of DOI:10.1021/ja0396145

In this Communication, we outline a new one-pot, multicomponent coupling reaction that allows easy access to (Z)-trisubstituted allylic alcohols. Our strategy is based on E to Z isomerization of the 1-bromo-1-dialkylvinylborane upon reaction with dialkylzinc reagents, and subsequent transmetalation to give (Z)-trisubstituted vinylzinc species. In situ trapping of the reactive vinylzinc intermediates with aldehydes furnished a series of (Z)-trisubstituted allylic alcohols. This method represents a viable alternative to the Still?Gennari modification of the HWE olefination reaction, and it has the advantage that it allows coupling of larger fragments. Copyright

Full text of DOI:10.1021/ja0396145

Published on Web 03/05/2004
A One-Pot Multicomponent Coupling Reaction for the Stereocontrolled
Synthesis of (Z)-Trisubstituted Allylic Alcohols
Young K. Chen and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania, 231 South 34th
Street, Philadelphia, PennsylVania 19104-6323
Received November 15, 2003; E-mail: pwalsh@sas.upenn.edu
Scheme 1. Proposed Coupling Mechanism
Allylic alcohols are among the most versatile intermediates in
organic synthesis and are pervasive in natural products. Thus,
development of new multicomponent coupling reactions that allow
assembly of allylic alcohols in a stereocontrolled manner is in high
demand. Although substantial progress has been made in the
synthesis of (E)-di- and (E)-trisubstituted allylic alcohols,1-5 the
direct synthesis of (Z)-trisubstituted allylic alcohols remains a
formidable challenge.6
Among the most frequently employed methods to access (Z)-
trisubstituted olefins are the Still-Gennari7 modification of the
Horner-Wadsworth-Emmons (HWE) olefination, and other vari-
ants of the Wittig reaction. The Still-Gennari method, however,
is generally a linear two-carbon homologation and not a viable
method for the direct coupling of larger fragments.
The addition of (Z)-vinylorganometallic reagents to aldehydes,
such as the Nozaki-Hiyama-Kishi (NHK) reaction,8 is also an
attractive route to (Z)-allylic alcohols. The NHK reaction is rarely
used in this construction, however, because the synthesis of the
requisite stereochemically pure (Z)-trisubstituted vinyliodides is
difficult.9
Table 1. Multicomponent Synthesis of Allylic Alcohols
entry
R1
R2
R3CHO
yield %
1
2
3
4
5
6
7
8
9
n-Bu
n-Bu
CH2OTBDPS
CH2OTBDPS
CH2OBn
Et
Et
Et
Et
Et
Et
Et
Et
Cy
Cy
CH2O
70a
61
71
84
65
61a
82
84
60
63
Me2CHCH2CHO
Me2CHCH2CHO
p-ClC6H4CHO
p-ClC6H4CHO
CH2O
p-MeC6H4CHO
p-MeC6H4CHO
p-MeC6H4CHO
o-MeOC6H4CHO
CH2OBn
CH2CH2OTBS
CH2CH2OTBS
n-Bu
10
n-Bu
As part of our continuing program in the application of vinylzinc
reagents in organic synthesis,5,10,11 we report a one-pot, multicom-
ponent coupling method for the direct synthesis of (Z)-trisubstituted
allylic alcohols. The underpinning strategy is based on the addition
of organometallic reagents to 1-bromo-1-alkenyboranes with con-
current migration of an alkyl group from boron to the alkene
terminus. This crucial migration occurs with inversion at the vinylic
center (Scheme 1).12 Subsequent in situ transmetalation of the newly
formed (Z)-vinylborane with the dialkylzinc reagent generates a
stereodefined (Z)-vinylzinc species that undergoes addition to
aldehydes to provide isomerically pure (Z)-allylic alcohols.
Hydroboration of 1-bromoalkynes is known to proceed with high
regioselectivity to generate 1-bromo-1-vinylboranes (Scheme 1).12-15
We initially examined use of diethylborane (generated in situ from
Et3B and BH3‚SMe2) and dicyclohexylborane. We propose that
treatment of the resulting 1-bromo-1-vinylboranes with excess
diethylzinc (2.2 equiv) at -78 °C followed by warming to 0 °C
generates (Z)-trisubstituted vinylzinc reagents. On following the
reaction by 11B NMR, the only boron-containing product was
observed at 86 ppm, indicating formation of Et3B. Trapping the
vinylzinc intermediates with 2 equiv of formaldehyde gave good
yields of the allylic alcohol. Use of other aldehydes, however,
resulted in 30-40% yields of the isolated allylic alcohols. A
byproduct of these reactions was formed by ethyl addition to the
aldehydes. This side reaction may be promoted by a zinc bromide
species formed during the migration step (Scheme 1). Fortunately,
the yield of the coupling was greatly improved when the volatile
contents of the reaction mixture, including excess Et2Zn, were
evacuated prior to introduction of the aldehyde. Thus, use of
1-bromo-1-hexyne to generate the (Z)-vinylzinc reagent, followed
a Two equivalents of paraformaldehyde was added without removal of
the volatile materials.
by addition of isovaleraldehyde, afforded the (Z)-trisubstituted
allylic alcohol in 61% yield, (eq 1, Table 1, entry 2).
We next employed a series of 1-bromo-1-alkynes bearing
protected alcohols to demonstrate the compatibility of these
protecting groups with the reaction conditions. The reaction of
TBDPS-protected 1-bromo-propargyl alcohol, Et2BH, and Et2Zn
with either isovaleraldehyde or p-chlorobenzaldehyde provided (Z)-
allylic alcohols in 71% and 84% yield (entries 3 and 4). The reaction
was equally effective for benzyl protected 1-bromopropargyl
alcohol, which furnished (Z)-trisubstituted allylic alcohols with
p-chlorobenzaldehyde and paraformaldehyde in 65% and 61% yield
(entry 5 and 6). 1-Bromo-1-butyn-4-ol, protected as TBS-ether, was
also effective as an alkyne source. Trisubstituted allylic alcohols
were isolated in good yield with p-methylbenzaldehyde and
p-chlorobenzaldehyde (entries 7 and 8).
Dicyclohexylborane was employed to examine the transfer of
secondary alkyl groups. As highlighted in entries 9 and 10,
hydroboration of 1-bromo-1-hexyne with dicyclohexylborane was
followed by treatment with Et2Zn under the standard conditions.
(Z)-Trisubstituted allylic alcohols derived from o-methoxybenzal-
dehyde and p-tolualdehyde were produced in good yields (entries
9 and 10). It should be noted that up to 20% ethyl migration was
9
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J. AM. CHEM. SOC. 2004, 126, 3702-3703
10.1021/ja0396145 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Potential Building Block for Migrastatin and
Scheme 2
Discodermolide
Table 2. Multicomponent Synthesis of Allylic Alcohols
common to both (+)-migrastatin and (+)-discodermolide (Scheme
3). Aldehyde 1 was converted to the corresponding bromoacetylene
2 in two steps (91% yield) using a modified Corey-Fuchs17
protocol. Subjecting 2 to the conditions outlined above gave 318 in
73% yield as a single enantiomer (as determined by 1H NMR
spectroscopy of the Mosher ester). Compound 3 was an intermediate
in the total synthesis of (-)-hennoxazole A.18
entry
R1
R3CHO
yield %
1
2
3
4
5
n-Bu
CH2CH2OTBDPS
n-Bu
n-Bu
n-Bu
CH2O
CH2O
Me2CHCH2CHO
p-MeC6H4CHO
p-ClC6H4CHO
75a
77a
92
71
70
a Two equivalents of paraformaldehyde was added without removal of
the volatile materials.
In summary, a new one-pot, multicomponent coupling reaction
that allows facile access into (Z)-trisubstituted allylic alcohols in a
stereocontrolled manner is reported. The advantage of this meth-
odology over the Still-Gennari7 modification of the HWE olefi-
nation is that it allows coupling of larger fragments. We are
currently examining the application of these novel vinylzinc reagents
to other reactions.
observed when addition of Et2Zn was performed at higher tem-
perature (0 °C). At -78 °C, however, ethyl migration is negligible.
The most common class of (Z)-allylic alcohols found in natural
products is the R-methyl substituted (Z)-allylic alcohols. The ability
to synthesize such groups would greatly broaden the synthetic utility
of our method. Therefore, we examined the use of dimethylborane
as described in Scheme 1; however, low yields of the coupling
products were obtained. This reaction is experimentally difficult,
because the preparation of Me2BH is tedious. Our recourse was to
substitute Br2BH for Me2BH in the hydroboration (Scheme 2).
Reaction of the resulting 1-bromo-1-vinyldibromoborane with
excess Me2Zn was envisioned to begin with boron-halogen
exchange. Further reaction of the resultant vinyldimethylborane with
Me2Zn induces migration, which is followed by transmetalation
and addition to the aldehyde.
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0315913).
Supporting Information Available: Procedures and full charac-
terization of new compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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To illustrate the synthetic potential of our methodology, we
synthesized (Z)-trisubstituted allylic alcohol 3, a segment that is
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