Highly stereoselective C-C bond formation by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and chiral allylic alcohols

Article abstract of DOI:10.1021/ja303023n

The tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor rhodium carbenoids and chiral allyl alcohols is a convergent C-C bond forming process, which generates two vicinal stereogenic centers. Any of the four possible stereoisomers can be selectively synthesized by appropriate combination of the chiral catalyst Rh₂(DOSP)₄ and the chiral alcohol.

Full text of DOI:10.1021/ja303023n

Article
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Highly Stereoselective C−C Bond Formation by Rhodium-Catalyzed
Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement between
Donor/Acceptor Carbenoids and Chiral Allylic Alcohols
Zhanjie Li,† Brendan T. Parr, and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: The tandem ylide formation/[2,3]-sigmatropic rearrangement
between donor/acceptor rhodium carbenoids and chiral allyl alcohols is a
convergent C−C bond forming process, which generates two vicinal stereogenic
centers. Any of the four possible stereoisomers can be selectively synthesized by
appropriate combination of the chiral catalyst Rh2(DOSP)4 and the chiral alcohol.
catalyzed by either Rh2(R-DOSP)4 or Rh2(S-DOSP)4 (Table
1). The reactions of the four possible combinations of (E)-1
and Rh2(DOSP)4 revealed that all the stereoisomers of the
products 3 could be obtained in a stereoselective manner (>9:1
dr and >99% ee7) (entries 1−4). A comparison of entries 1 and
2 (and 3 and 4) demonstrated that the stereocenter at C3 of the
product was governed by the configuration of the allyl alcohol.
In contrast, a comparison of entries 1 and 3 (and 2 and 4)
demonstrated that the chiral catalyst controlled the config-
uration at C2. The reactions of (S,Z)-1 with Rh2(R-DOSP)4 and
Rh2(S-DOSP)4 were also examined (entries 5 and 6).
Significant matched and mismatched interactions between the
chiral entities were displayed in these reactions.8 The Rh2(R-
DOSP)4-catalyzed reaction of (S,Z)-1 with 2 was very efficient,
generating (2S,3S)-3 in 69% yield and with 94:6 dr and >99%
ee (entry 5). The stereochemical configuration of the product
was the same as that of the product derived from the Rh2(R-
DOSP)4-catalyzed reaction of (R,E)-1 (entry 4). However, the
Rh2(S-DOSP)4-catalyzed reaction of (S,Z)-1 with 2 was a
mismatched reaction. In this case a 3:1 mixture of
diastereomers was produced in low overall yield (35% for the
major diastereomer) (entry 6).
1. INTRODUCTION
Chiral allylic alcohols are readily available and have been widely
used as versatile building blocks in organic synthesis.1 Recently
we discovered an unexpected reaction between rhodium
carbenoids and allylic alcohols.2 Normally alcohols react with
carbenoids to form O−H insertion products.3−5 However, we
found that the reaction between donor/acceptor-substituted
carbenoids and racemic allylic alcohols bearing a 3,3-dimethyl
functionality resulted in an enantioselective [2,3]-sigmatropic
rearrangement.2a,6 Homoallylic alcohols containing a single
stereogenic center were formed in which the enantioselectivity
was governed by the chirality of the catalyst rather than the
chirality of the starting alcohol. As the resulting products can be
used in extended domino sequences,2b we became interested in
broadening the substrate scope and generality of the reaction.
In particular, we wished to explore the possibility of generating
products containing vicinal stereocenters in a stereoselective
manner (Scheme 1). In this paper, we demonstrate that all four
Scheme 1. Rhodium(II)-Catalyzed [2,3]-Sigmatropic
Rearrangement of Allyl Alcohols
The tandem ylide formation/[2,3]-sigmatropic rearrange-
ment was examined with a series of donor/acceptor-substituted
diazoacetates with a variety of aryl and alkenyl substituents. In
all cases, the major diastereomer was produced with very high
asymmetric induction (>99% ee), but the diastereoselectivity
was variable. In the case of the aryldiazoacetates, 4a and 4b, the
diastereoselectivity was ≥9:1 (Table 2, entries 1−2). The p-
bromostyryl derivative 4c (entry 3) was comparable to the
unsubstituted phenyl system (Table 1, entry 1). The butenyl-
and propenyl-substituted diazo compounds (4d and 4e,
respectively) underwent the rhodium-catalyzed transformation
with high levels of asymmetric induction (entries 4 and 5).
These results are consistent with previous examples of the high
enantioselectivity exhibited in the Rh2(S-DOSP)4 catalyzed
of the possible stereoisomers of the products can be selectively
and predictably generated by using the appropriate combina-
tion of chiral allylic alcohol and chiral catalyst. The allylic
stereocenter of the products is controlled by the chirality of the
allylic alcohol and the alkene geometry, whereas the
homoallylic stereocenter is dictated by the chirality of the
catalyst.
2. RESULTS AND DISCUSSION
We began our investigations by studying the reaction of the
Received: March 28, 2012
stereoisomers of 3-penten-2-ol (1) with styryldiazoacetate 2,
© XXXX American Chemical Society
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a
Table 1. Stereocontrolling Elements of the Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement
a
Reaction conditions: To a pentane solution of the allyl alcohol (1 equiv) and Rh2(S-DOSP)4 (0.01 equiv) at 0 °C under an atmosphere of Ar was
added a solution of the diazo compound (2.0 equiv) in pentane solution over 1.5 h. The reaction was stirred for 1 h further at 0 °C and then
b
c
1
concentrated under reduced pressure. Isolated yield of the major diastereomer. Determined by H NMR analysis of the crude reaction mixture.
Determined by chiral HPLC.
d
reactions of diazoacetates 4a−e.2 In entry 6, the unsubstituted
a
Table 2. Reaction of (S,E)-1 with 4a−f
vinyldiazoacetate 4f was obtained in modest yield (43%) and
with poor diastereoselectivity (79:21 dr). It is well established
that Rh2(S-DOSP)4-catalyzed cyclopropanations with 4f
proceed with moderate enantiocontrol8,9 and the moderate
diastereoselectivity observed in entry 6 is consistent with a low
level of stereocontrol by Rh2(S-DOSP)4 in this case.
The tolerance of the reaction to various substituents on the
alcohols was then studied, and these results are summarized in
Table 3. In general, extended aliphatic and aryl substituents at
the C3 position of the alcohol 6 were well tolerated (entries 1−
2) including the 3,3-disubstituted substrate (entry 3). This
substrate exemplified the utility of the metal-carbenoid
transformation, facilitating the high yielding preparation of a
product bearing two contiguous quaternary stereogenic centers
with high levels of enantio- and diastereoselectivity. Allyl
alcohols with relatively bulky substituents, such as isopropyl
and trimethylsilyl (6d and 6e), also afforded the corresponding
rearrangement products, but the yields were modest (60% and
42%, respectively). An array of alcohols bearing C2-substitution
(6f−h) were evaluated, and they were also amenable to this
transformation (entries 6−8). It was expected that, in the
a
b
metal-bound oxonium-ylide intermediate formed, any function-
ality at C2 would be oriented away from the catalyst and, thus,
would have little consequence on the reactivity. Finally, the
effect of various functional groups at the carbinol position was
explored in entries 9−11, and in all cases the desired products
Same reaction conditions as described in Table 1. Isolated yield of
c
the major diastereomer. Determined by 1H NMR analysis of the
crude reaction mixture. Determined by chiral HPLC.
d
B
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a
Table 3. Scope of the Allyl Alcohol 6
a
b
c
Same reaction conditions as described in Table 1. Isolated yield of the major diastereomer. Determined by 1H NMR analysis of the crude reaction
d
mixture. Determined by chiral HPLC.
were formed. Of particular significance is the reaction of the
monobenzyl-protected 1,2-diol 6k, which was capable of
selective reaction at the allylic alcohol over the benzyl ether
functionality.
The synthetic utility of the rhodium-catalyzed sigmatropic
rearrangement with the chiral alcohols lies in the ability to
generate two adjacent stereogenic centers in a controlled and
predictable manner. A distinctive feature of the transformation
is the generation of a quaternary hydroxyl carbonyl moiety
bearing a vicinal stereocenter, which is a structural feature
embedded in a number of natural products.10 We also decided
to demonstrate the broader synthetic potential of the reaction
by illustrating a two-step conversion of the products to enones,
containing a chiral center α to the carbonyl (eqs 1 and 2).
Enones containing quaternary (8a) and tertiary (8b) stereo-
centers α to the carbonyl were readily prepared in excellent
yields. A particularly appealing feature of this approach to chiral
enones is the likelihood that a chiral catalyst would not be
required because the stereogenic center α to the carbonyl is
controlled by the chirality of the starting alcohol.
C
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Present Address
Due to the uniformly high levels of asymmetric induction for
the tandem ylide formation/[2,3]-sigmatropic rearrangement,
we sought a general transition-state model which would
rationalize the observed stereochemical results.6 It has been
well established that the Rh2(S-DOSP)4-catalyzed reactions of
vinyldiazoacetates result in attack at the Re face of the
vinylcarbenoid.11 The [2,3]-sigmatropic rearrangement would
be expected to proceed through an envelope-like transition
state, in which A1,3-strain is minimized.12 A reasonable model,
which takes into account the established stereochemical
understanding of these reactions, is shown in Figure 1. Re
†Department of Chemistry & Chemical Biology, Harvard
University, 12 Oxford Street, Cambridge, MA 02138.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institutes of
Health (GM099142). We thank Dr. Ken Hardcastle (Emory
University) for the X-ray crystallographic structural determi-
nation.
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3. CONCLUSION
In summary, the tandem ylide formation/[2,3]-sigmatropic
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ASSOCIATED CONTENT
* Supporting Information
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of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
hmdavie@emory.edu
■
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