Highly diastereoselective synthesis of homoallylic alcohols bearing adjacent quaternary centers using substituted allylic zinc reagents

Article abstract of DOI:10.1021/ja071380s

Staring from readily available polysubstituted allylic chlorides, a range of polysubstituted allylic zinc chlorides were obtained using a LiCl-mediated zinc dust insertion in 55-84% yield. A highly diastereoselective synthesis of homoallylic alcohols bear

Full text of DOI:10.1021/ja071380s

Published on Web 04/05/2007
Highly Diastereoselective Synthesis of Homoallylic Alcohols Bearing
Adjacent Quaternary Centers Using Substituted Allylic Zinc Reagents
Hongjun Ren, Guillaume Dunet, Peter Mayer, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Butenandtstrasse 5-13,
Haus F, 81377 Mu¨nchen, Germany
Received March 2, 2007; E-mail: paul.knochel@cup.uni-muenchen.de
Scheme 2. Reaction of the Allylic Zinc Reagent 1e with Various
Methyl Ketones
The stereoselective generation of quaternary centers is one of
the major challenges in asymmetric synthesis.1 The addition of
highly substituted allylic organometallics to carbonyl derivatives2
offers a straightforward synthesis of homoallylic alcohols bearing
quaternary centers. This approach requires a convenient preparation
of the allylic organometallics.3 Although allylic lithium and
magnesium reagents are highly reactive, they are difficult to prepare
and are unstable.3e Allylic zinc reagents are much more readily
available. Thus, allylzinc bromide is produced in high yield by the
direct zinc insertion to allyl bromide.4 The zinc insertion to
substituted allylic bromides is less satisfactory, and increased
amounts of homocoupling products are formed. Thus, cyclohex-
enylzinc bromide can only be prepared by the direct zinc insertion
in 65% yield5 and is best obtained by an indirect route via an
allyltributylstannane.6,7 Recently, we have reported a LiCl-mediated
insertion of zinc dust into alkyl, aryl, and heteroaryl iodides leading
to organozincs in good yields.8 Herein, we wish to report that this
method allows also the preparation of di- and trisubstituted allylic
zinc reagents starting from the corresponding allylic chlorides, with
a moderate formation of homocoupling products. Thus, the dropwise
addition of cyclohexenyl chloride (1.0 equiv) to a suspension of
zinc dust (5.0 equiv) and dry LiCl (1.2 equiv) in THF provides,
after 36 h at 0 °C, cyclohexenylzinc chloride (1a) in 84% yield
(Scheme 1).
Scheme 3. Chair-like Transition State 7 and Substituted
Tetrahydrofurans 5 and 6
regioselectively under exceedingly mild conditions (-78 °C, 1 h).
Aromatic ketones 2a,b afford, regardless of the substitution pattern
of the aromatic ring, the homoallylic alcohols 3a,b bearing a
quaternary center (dr >99:1, entries 1 and 2). Related ketones, such
as 6-methoxy-1-tetralone (2d) or the ferrocenyl ketone (2e), are
leading to the homoallylic alcohols (3d,e) with dr >96:4 (entries 4
and 5). Interestingly, this organometallic reaction is compatible with
the presence of a free NH2 group. Thus, the addition of 1a to the
benzaldehyde 2c furnishes the amino alcohol 3c (dr >99:1; 94%
yield, entry 3). This allylic addition is also highly chemoselective.9
Thus, a chloromethyl ketone such as 2f or a ketone bearing an azido
function in an R-position such as 2g reacts with cyclohexenylzinc
chloride (1a), providing the tertiary homoallylic alcohols 3f and
3g (dr >98:2, 93-97% yield, entries 6 and 7). The structure of 3g
was confirmed by X-ray analysis of its 1,2,3-triazole derivative.10
Cyclopentenylzinc chloride (1b) reacts similarly with the aro-
matic ketone 2h, affording the homoallylic alcohol 3h (dr >99:1;
95% yield, entry 8). In the case of 3-methyl-2-cyclohexenylzinc
chloride (1c), a regiospecific addition is observed. The new carbon-
carbon bond is formed exclusively from the most substituted end
of the allylic system, leading to the homoallylic alcohols 3i,j in
98-99% yield (dr >97:3, entries 9-10). Noticeably, the alcohol
3j bearing two adjacent quaternary centers was obtained with a dr
>98:2 (entry 13). Similarly, the 2,3-disubstituted allylic zinc species
(1d) adds to pivaldehyde (2k), affording the homoallylic alcohol
3k10 (dr >98:2, 96% yield, entry 11). Interestingly, the cinnamylzinc
chloride (1e) displays high diastereoselectivities11 (Scheme 2). Thus,
the addition of various methyl ketones, such as 3-methylbutan-2-
one, 1-cyclopropylethanone, 1-cyclohexylethanone, or even 1,1,1-
trifluoropropan-2-one, led to the corresponding alcohols with dr
>99:1 (4a-e, 77-99% yield). The structures of the homoallylic
alcohols resulting from the addition to aromatic ketones could be
Scheme 1. LiCl-Mediated Preparation of Substituted Allylic Zinc
Chlorides by the Direct Insertion of Zinc Dust (Yields Determined
by Iodinolysis)
This procedure can be successfully extended to previously
unknown allylic zinc reagents, such as cyclopentenylzinc chloride
(1b, 58% yield) and the trisubstituted 3-methylcyclohexenylzinc
chloride (1c, 55% yield). Starting from 2-(1-chloromethyl)apo-
pinene, the allylic zinc reagent 1d is obtained in 70% (25 °C, 24
h). Importantly, the preparation of aryl-substituted allylic zinc
reagents (such as 1e or 1f) can be achieved starting either from the
corresponding allylic chloride (X ) Cl; 20 °C, 1 h, 78%) or from
the corresponding allylic phosphate (X ) OP(O)(OEt)2; 20 °C, 18
h, 72%). The addition of these highly reactive allylic organome-
tallics to various aldehydes and ketones was then studied (Table 1
and Scheme 2). This reaction proceeds diastereoselectively and
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10.1021/ja071380s CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Diastereoselective Preparation of Homoallylic Alcohols of
Type 3 Using Allylic Zinc Reagents of Type 1
In conclusion, we have described a convenient method for
preparing new allylic zinc chlorides using a LiCl-mediated zinc
dust insertion to allylic chlorides. These add with remarkable
diastereoselectivity and regioselectivity to various aldehydes or
ketones, affording homoallylic alcohols bearing quaternary centers.
Extensions of this work are currently underway in our laboratories.
Acknowledgment. We thank the Fonds der Chemischen In-
dustrie, the DFG, Merck Research Laboratories (MSD), Chemetall
GmbH (Frankfurt), and BASF AG (Ludwigshafen) for financial
support.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
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