Diastereoselective synthesis of methylenecyclopropanes from chiral cyclopropene derivatives

Article abstract of DOI:10.1002/anie.200600531

(Chemical Equation Presented) Directed delivery: Chiral methylenecyclopropanes were prepared from cyclopropene derivatives upon reaction with Grignard reagents. A higher-order dependence of the reaction on the concentration of the Grignard reagent was revealed, and based on this finding, it was possible to reverse the regioselectivity of the process (see scheme; MEM = methoxyethoxymethyl).

Full text of DOI:10.1002/anie.200600531

Communications
Synthetic Methods
DOI: 10.1002/anie.200600531
Diastereoselective Synthesis of
Methylenecyclopropanes from Chiral
Cyclopropene Derivatives**
Zhe Yang, Xiaocong Xie, and Joseph M. Fox*
Described herein is a new method for the preparation of
chiral methylenecyclopropanes from cyclopropene deriva-
tives and Grignard reagents. Methylenecyclopropanes[1] have
broad utility for the rapid generation of molecular complexity
through a number of reactions that are enabled by their
considerable strain energy (ca. 40 kcalmolÀ1).[2] Of particular
utility is the growing body of stereospecific transformations of
methylenecyclopropanes.[1,3] A limitation for the chemistry of
methylenecyclopropanes is that there are few preparations of
enantiomerically enriched derivatives.[4] The utility of meth-
ylenecyclopropanes would be greatly enhanced by a common
intermediate approach that provides access to a range of
enantiomerically enriched derivatives. Herein, conditions for
the selective synthesis of methylenepropanes from chiral
cyclopropene precursors[5] are reported, thus providing access
to diverse types of highly functionalized methylenecyclopro-
panes that possess chiral quaternary centers. The cyclo-
propene precursors are readily available in enantiomerically
enriched form.[5b–d]
The discovery that Grignard reagents can convert cyclo-
propenes into methylenecyclopropanes was serendipitous and
resulted from an attempt to use the directed cyclopropene
carbometallation reaction to prepare 2 (Scheme 1).[6] Organ-
Scheme 1. Precedent for synthesis of methylenecyclopropanes.
ometallic and metal-hydride reagents normally add to 1-
alkylcyclopropenes by introducing the nucleophile to the
more substituted side of the multiple bond.[6] The unusual
reversal of regioselectivity to produce 3a suggested a pathway
[*]Dr. Z. Yang, X. Xie, Prof. Dr. J. M. Fox
Department of Chemistry and Biochemistry
University of Delaware
Brown Laboratories
Newark, DE 19716 (USA)
Fax: (+1)302-831-6335
E-mail: jmfox@udel.edu
[**]This work was supported by NIH grant GM068640-01A1.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
Table 2: Higher-order dependence on MeMgBr for product formation.[a]
for the diastereoselective synthesis of functionalized methyl-
enecyclopropanes.[7,8]
By following the result in Scheme 1, it was found that
changing the Grignard counterion from chloride to bromide
can alter the regioselectivity to favor exclusive formation of
the methylenecyclopropane. Under the optimized conditions
(Table 1), the directed reaction proceeded with excellent
MeMgBr
Conversion [%]Yield of
3c [%]Yield of
27
4 [%]
1 equiv
2 equiv
4 equiv
40
40
60
ca. 0
20
43
9
4
Table 1: Synthesis of methylenecyclopropanes from chiral cyclopro-
[a]Yields and conversions were measured by 1H NMR spectroscopy;
reactions were conducted at 238C and quenched after one hour (prior to
completion).
penes.[a]
Allowing this reaction to continue overnight did not result in
the formation of methylenecyclopropane 3c. Although the
mechanism of the isomerization is unclear at this point, the
formation of the diene was suppressed and the yield of 3c
increased when the amount of MeMgBr was increased to
two equivalents. The ratio of 3c:4 was further increased to
10:1 when the amount of MeMgBr was increased to four
equivalents.
The results in Table 2 suggest that the magnesium center
may serve a second role as a Lewis acid in the reactions of
cyclopropenes with Grignard reagents. The addition of MgBr2
did not have an effect on the rate of the reaction,[10] thus
suggesting that an alkyl magnesium species serves as the
Lewis acid. We hypothesized that coordination of the
magnesium center by the MEM ether group influences the
regioselectivity. For substrates that lack a coordinating
oxygen atom (that is, 1-(n-alkyl)cyclopropenes), it is estab-
lished that delivery of the nucleophile occurs at the more
substituted carbon atom.[6b] Accordingly, it was speculated
that a sterically demanding trityl ether group would disfavor
metal coordination and restore the “normal” regioselectivity.
A working hypothesis of the interactions leading to this
difference is shown in Scheme 2. Although only two metal
[a]All reactions gave a single isomer (d.r. >95%) as determined by
1H NMR spectroscopic analysis. Percentages represent yields of isolated
product as the average of two runs.
regio- and diastereoselectivity. Methyl-, alkyl- (18 or 28), allyl-,
and benzylmagnesium halides were suitable nucleophiles, and
the MEM and SEM ethers (MEM = methoxyethoxymethyl;
SEM = 2-(trimethylsilyl)ethoxymethyl) proved to be superior
to methyl ethers in terms of both regio- and diastereoselec-
tivity.[9] In contrast to our previous system for cyclopropene
carbometallation,[6a] CuI was not needed for the reactions to
form methylenecyclopropanes. The precursors for this
chemistry are readily available in enantiomerically enriched
form. Thus, 3-hydroxymethylcyclopropenes 1a and 1b were
prepared by a straightforward sequence of [Rh2(dosp)4]-
catalyzed enantioselective cyclopropenation[5b] (70 and
82% ee, respectively) and reduction with DIBAL (dosp =
(N-dodecylbenzenesulfonyl)prolinate; DIBAL = diisobutyl-
aluminum hydride). Furthermore, it was demonstrated that
1b could easily be resolved to enantiomeric purity by a
method that we have described previously.[5d]
Scheme 2. a) Plausible model for chelation-controlled nucleophilic
delivery. b) Replacement of the MEM group by a trityl group is
expected to prevent coordination and reverse regioselectivity.
The dependence of selectivity on the counterion sug-
gested that the reaction rates might have a higher-order
dependence on the concentration of the Grignard reagent.
Therefore, reactions of metalated 1b with varying amounts of
MeMgBr were studied (Table 2). Reactions were quenched
after one hour (prior to completion). While detailed kinetic
analysis was complicated by the heterogeneous nature of the
reaction, it was clear that the reaction had a higher-order
dependence on the concentration of the Grignard reagent.
Only an isomeric diene side product 4 was observed in the
reaction of metalated 1b with a single equivalent of MeMgBr.
centers are shown in Scheme 2, a mechanism that is higher-
order with respect to concentration of magnesium cannot be
ruled out. Regardless, the major roles for magnesium
(nucleophilic delivery and Lewis acid activation) are con-
veyed by Scheme 2, which proves to be a useful and predictive
model for chelation control of regioselectivity. Thus, efficient
reversal of regioselectivity was observed when trityl ether 5
(Scheme 3) was used instead of the corresponding MEM
ether 1b. The best results were obtained when catalytic CuI
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Communications
Horikawa, R. A. Kloster, N. A. Hawryluk, E. J. Corey, J. Am.
Chem. Soc. 2004, 126, 8916.
[6] a) L.-a. Liao, J. M. Fox, J. Am. Chem. Soc. 2002, 124, 14322;
recent reviews on addition of organometallic reagents to cyclo-
propenes: b) J. M. Fox, N. Yan, Curr. Org. Chem. 2005, 9, 719;
c) M. Nakamura, H. Isobe, E. Nakamura, Chem. Rev. 2003, 103,
1295; recent examples of regio- and stereoselective hydro-
metallation reactions of cyclopropenes: d) E. Zohar, I. Marek,
Org. Lett. 2004, 6, 341; e) M. Rubina, M. Rubin, V. Gevorgyan, J.
Am. Chem. Soc. 2004, 126, 3688, and references therein.
[7] Methylenecyclopropanes had previously been prepared by base-
promoted isomerization of cyclopropenes. Variants of that
reaction involve capture by electrophiles.[4a,7c] The method
presented here is distinct because it involves nucleophilic
addition to the alkene. For isomerization approaches to cyclo-
propenes, see references [4a], [6c], and: a) R. Kꢀster, S. Arora, P.
Binger, Angew. Chem. 1969, 81, 64 2;Angew. Chem. Int. Ed.
Engl. 1969, 8, 205; b) M. Vincens, C. Dumont, M. Vidal,
Tetrahedron 1981, 37, 2683; c) A. Padwa, M. W. Wannamaker,
Tetrahedron 1991, 47, 6139; d) M. Vidal, M. Vincens, P. Arnaud,
Bull. Soc. Chim. Fr. 1972, 665; e) A. A. Formanovskii, L. I.
Leonova, N. I. Yakushkina, M. Bakhbukh, Y. K. Grishin, I. G.
Bolesov, Zh. Org. Khim. 1977, 13, 1883; A. A. Formanovskii,
L. I. Leonova, N. I. Yakushkina, M. Bakhbukh, Y. K. Grishin,
I. G. Bolesov, J. Org. Chem. USSR (Engl. Transl.) 1977, 13, 1745.
[8] There was a single example of palladium-catalyzed nucleophilic
substitution on a cyclopropenyl methyl ester to give a methyl-
enecyclopropane in 27% yield (as the minor regioisomer of the
reaction); see: a) H. Nüske, S. Brꢁse, A. de Meijere, Synlett 2000,
1467. Recently, a report appeared that describes the addition of
soft nucleophiles to a chiral cyclopropene with a bromine atom
at the allylic position. Complementary to the work reported
here, the facial control in that work is determined by steric
considerations; see: b) R. A. Weatherhead-Kloster, E. J. Corey,
Org. Lett. 2006, 8, 171.
Scheme 3. Reversal of regioselectivity starting from trityl ether 5.
was included, but the formation of 6 still predominated (4.5:1
ratio of 6:3c) under conditions that were identical to those
used to form 3c from 1b as described in Table 1.
In summary, general conditions were described for the
regio- and diastereoselective synthesis of methylenecyclopro-
panes from common intermediate precursors. The reaction is
counterion-dependent and requires more than one equivalent
of Grignard reagent. These observations suggested a Lewis
acidic role for the magnesium reagent. This hypothesis was
subsequently used to design experiments that reverse the
regioselectivity of the nucleophilic delivery. Efforts are
currently being made to apply these reactions in target-
directed synthesis.
Received: February 9, 2006
Published online: May 9, 2006
Keywords: chirality · diastereoselectivity · regioselectivity ·
.
small ring systems · strained molecules
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[9] The reaction of 1 (where R = Me, R’’ = Ph; see Table 1) with
MeMgBr still gave 3c as the major product (ca. 55%), but with
significant contamination by the diasteromeric product
(ca. 15%) and two regioisomeric products (ca. 30%).
[10] A reaction was conducted that was similar to the second entry in
Table 2, with the modification that four equivalents of MgBr2
were added. After one hour, the reaction was quenched, and the
yield of the corresponding methylenecyclopropane was mea-
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1
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