Enantioselective synthesis of cyclobutanes via sequential Rh-catalyzed bicyclobutanation/Cu-catalyzed homoconjugate addition

Article abstract of DOI:10.1021/ja403811t

Enantiomerically enriched cyclobutanes are constructed by a three-component process in which t-butyl (E)-2-diazo-5-arylpent-4-enoates are treated with Rh₂(S-NTTL)₄ to provide enantiomerically enriched bicyclobutanes, which can subsequently engage in homoconjugate addition/enolate trapping sequence to give densely functionalized cyclobutanes with high diastereoselectivity. This three-component, two-catalyst procedure can be carried out in a single flask. Rh₂(S-NTTL)₄-catalyzed reaction of t-butyl (Z)-2-diazo-5-phenylpent-4-enoate gives the Buechner cyclization product in excellent enantioselectivity.

Full text of DOI:10.1021/ja403811t

Communication
pubs.acs.org/JACS
Enantioselective Synthesis of Cyclobutanes via Sequential Rh-
catalyzed Bicyclobutanation/Cu-catalyzed Homoconjugate Addition
Robert Panish, Srinivasa R. Chintala, David T. Boruta, Yinzhi Fang, Michael T. Taylor,
and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
Scheme 1. Multicomponent Cyclobutane Synthesis
ABSTRACT: Enantiomerically enriched cyclobutanes are
constructed by a three-component process in which t-butyl
(E)-2-diazo-5-arylpent-4-enoates are treated with Rh2(S-
NTTL)4 to provide enantiomerically enriched bicyclobu-
tanes, which can subsequently engage in homoconjugate
addition/enolate trapping sequence to give densely
functionalized cyclobutanes with high diastereoselectivity.
This three-component, two-catalyst procedure can be
carried out in a single flask. Rh2(S-NTTL)4-catalyzed
reaction of t-butyl (Z)-2-diazo-5-phenylpent-4-enoate
gives the Buchner cyclization product in excellent
̈
enantioselectivity.
bicyclobutane derivatives were unknown. While bicyclobutane-
carboxylates have been known since 1959,13 homoconjugate
additions to unsubstituted bicyclobutanecarboxylates had been
limited to additions of thiolate and alkoxide nucleophiles.14
Also critical for the enantioselective bicyclobutanation in
Scheme 1 is the ability to engage carbenes from A in
intramolecular cyclopropanation in preference to intramolecu-
lar β-hydride migration to give E.15 Bicyclobutane carboxylates
were first prepared from ethyl α-allyl-α-diazoacetate in seminal
work by Ganem.16 However, β-hydride migration was a
significant side reaction. In recent years, our group15 and that
of Hashimoto17 have developed intermolecular Rh-catalyzed
transformations of α-alkyl-α-diazoesters that tolerate β-hydro-
gens, including reactions that produce cyclopropenes, cyclo-
propanes, dioxolanes, tetrahydrofurans, and functionalized
indoles. Low temperatures (−78 °C) and bulky carboxylate
ligands are key to the success and the dramatic suppression of
β-hydride migration.15
Our success with intermolecular cyclopropanation led us to
question if enantiomerically enriched bicyclobutanes could be
prepared via intramolecular cyclopropanation. To develop a
system that would function in subsequent homoconjugate
addition reactions with Grignard reagents, we focused on the
preparation of tert-butyl bicyclobutanecarboxylates which were
expected to be resistant toward nucleophilic attack at the ester
carbonyl. In the course of our studies, Davies18 very recently
reported the first enantioselective intramolecular cyclopropa-
nation to yield bicyclobutanecarboxylates. In this elegant study,
the catalyst Rh2(R-BTPCP)4 was used to achieve bicyclobuta-
nation in 61−74% yield and up to 94% ee. Davies’ system is
most effective for methyl or ethyl (E)-2-diazo-5-arylpent-4-
enoates. The method described herein is complementary, as it
tereochemically rich cyclobutanes are prevalent subunits in
1
Snatural products with diverse biological activity. A number
of methods have been developed for cyclobutane synthesis,2
including photochemical [2 + 2] cycloadditions,1c,d,3,4 catalyzed
[2 + 2] cycloadditions,4,5 cyclobutanone syntheses via ketenes,6
ring expansion of cyclopropylcarbinyl precursors,7 and cyclo-
butanes CH activation.8 Despite advances, there remains a need
for new approaches to functionalized cyclobutanes.
Bicyclobutanes are intriguing precursors to functionalized
cyclobutanes9 that display unusual reactivity as a consequence
of their unusual bonding and high strain energy (63.9 kcal/
mol).10 However, the synthetic applications of bicyclobutanes
have been relatively limited. In a striking series of papers, Wipf
has shown that bicyclobutane derivatives are capable of catalyst-
promoted ring expansion reactions,11a formal [2 + 2]
cycloadditions,11b and Alder-ene reactions.11c−e These exam-
ples illustrate how complexity can be rapidly generated in
strain-releasing reactions of bicyclobutanes.
We envisioned that cyclobutanes could be constructed via
bicyclobutane intermediates with the multi-component process
shown in Scheme 1, in which an α-allyl-α-diazocarbonyl
compound (A) is treated with a chiral catalyst to provide an
enantiomerically enriched bicyclobutane (B). We envisioned
that intermediate B could subsequently engage in homoconju-
gate addition to give enolate (C) and subsequent enolate
trapping to give densely functionalized cyclobutanes (D).
To realize Scheme 1, a challenge was to develop a protocol
for homoconjugate addition of organometallic nucleophiles to
bicyclobutanecarboxylates. In seminal studies, Gaoni showed
that cuprate reagents can add across the central C−C bond of
1-sulfonyl bicyclobutanes.12 The diastereoselectivity for such
processes was variable. Moreover, analogous reactions of other
Received: April 16, 2013
Published: June 11, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
functions most efficiently with the corresponding tert-butyl
esters as required for subsequent homoconjugate addition.
The development of an enantioselective bicyclobutanation
procedure began with (E)-2-diazo-5-arylpent-4-enoates, which
are readily prepared by alkylation of t-butyl acetoacetate with
the cinnamyl halides and subsequent diazo transfer. Building on
earlier experience with enantioselective intermolecular reactions
of α-alkyl-α-diazoesters,15 we screened the bicyclobutanation of
1a using dirhodium carboxylates with N-imido-tert-leucinate
ligands.19 An optimization study (see Supporting Information)
revealed that Rh2(S-NTTL)4 in toluene at −78 °C is effective
for bicyclobutane formation, providing (S,S)-2a in 83% yield,
and 95% ee. As shown in Table 1, tert-butyl (E)-2-diazo-5-
and 67% yield. tert-Butyl (E)-2-diazo-6-phenylhex-4-enoate
gave the benzyl substituted 2j in 80% yield but 71% ee.
Comparison of the Rh-catalyzed reactions of alkene stereo-
isomers 1k and 1l provided mechanistic insight. The (E)-
isomer 1k gave bicyclobutane 2k in 80% yield and 73% ee. In
1
low yield (8% by H NMR), the (Z)-isomer 1l also gave 2k,
along with inseparable dienes from β-hydride migration. The
stereoconvergent formation of 2k rules out a concerted
cyclopropanation mechanism for 1l. It is likely that zwitterionic
F is an intermediate from the reaction of 1l, and possibly a
common intermediate from the reaction of 1k. Similarly, (Z)-
alkene 1m provided 15% of the bicyclobutane 2athe same
diastereomer obtained from (E)-alkene 1a. Again, the stereo-
convergence supports a zwitterionic intermediate from (Z)-
alkene 1m. Interestingly, the major product from 1m was the
Table 1. Enantioselective Bicyclobutanation
Buchner product20 (+)-3, obtained in 69% yield and 99% ee.
̈
We next studied the addition reactions of 2a with Grignard
reagents (Table 2). The uncatalyzed addition of PhMgBr in
Table 2. Optimization of Homoconjugate Addition
Et2O gave only traces of diastereomers 4 upon acidic quench
(entry 1). Conditions of Gaoni12 (CuI in Et2O) gave 4 in only
8% yield (entry 2). Neither CuCN nor CuBr•SMe2 promoted
the reaction under similar conditions (entries 3,4). After a
number of Cu-sources, ligands and solvents were screened, it
was found that CuBr•SMe2 (30 mol %), PBu3 (1.2 equiv) and
THF provide a catalyst system that is highly effective. When 2a
was combined for 30 min with two equivalents of PhMgBr or
MeMgCl, cyclobutanes 4 and 5 were obtained in 88% and 90%
yield, respectively. The same conditions with less MeMgCl (1.5
equiv) gave 5 in a somewhat lower 75% yield (entry 7).
Likewise, 5 was obtained in 83% yield with less catalyst (10 mol
% CuBr•SMe2/40 mol % PBu3), (entry 8). Given the low cost
of the catalyst and nucleophiles, we continued with 30 mol %
copper and 2 equiv of Grignard reagents.
a
ee determined for the alcohol from DIBAL reduction of 16, Table 3.
b
Diene products from β-hydride migration predominated and were
1
inseparable from 2k. The yield of 2k from 1l was estimated by H
As shown in Table 3, a one-flask, two-catalyst procedure was
developed for the three-component preparation of enantiomeri-
cally enriched cyclobutanes from (E)-2-diazo-5-arylpent-4-
enoates, Grignard reagents and electrophiles. While toluene
was the best solvent for the bicyclobutanation, it was
detrimental to the conjugate addition. Thus, a solvent swap
was conducted by simply removing toluene in vacuo prior to the
conjugate addition. In this manner, cyclobutane product 4 was
obtained in 80% yield from 1a and as a 1.1:1 epimer at the C1
position. With a subsequent step (15 h), 4 could be readily
improved to 21:1 dr using catalytic tBuOK in THF. Other
NMR.
arylpent-4-enoates 1a−g with aromatic halogen, CF3, nitrile,
ester and ether substituents were productive substrates under
Rh2(S-NTTL)4-catalyzed conditions to give bicyclobutane
products in 76−88% yield and 91−95% ee. Bicyclobutane 2h,
with an ortho-methoxy substitutent, was formed with high
enantioselectivity (94% ee) but a more modest 65% yield.
Likewise, the α-naphthyl substituted 2i was formed in 90% ee
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Communication
was speculated that the sense of diastereoselectivity could be
reversed by using BHT as a sterically demanding proton source
(Scheme 2). Indeed, BHT quench gave 5 and 16 in 1:6 dr and
1:17 dr, respectively.
Table 3. One-flask, Multicomponent Bicyclobutane
Synthesis
Scheme 2. Reversal of Diastereoselectivity
Upon conjugate addition, the resulting enolate products
could also be directly quenched with electrophiles to provide
cyclobutanes that contain quaternary stereocenters (Table 3).
Electrophiles included allyliodide, EtI, BnBr, PhSSPh, and 4-
bromobenzoyl chloride to give products 6−10 with 7:1−14:1
dr. X-ray crystallography established the absolute stereo-
chemistry of 10 as well as the bicyclobutane precursor 2a.
In conclusion, enantiomerically enriched cyclobutanes can be
constructed by a 3-component, 2-catalyst, single-flask process in
which (E)-2-diazo-5-arylpent-4-enoates are treated with Rh2(S-
NTTL)4 to provide enantiomerically enriched bicyclobutanes.
A subsequent sequence of Cu-catalyzed homoconjugate
addition/enolate trapping provides highly substituted cyclo-
butanes with high diastereoselectivity.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details, 1H and 13C NMR spectra, and
crystallographic (CIF) data are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jmfox@udel.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIH (R01 GM068650, 5T32GM008550) and NSF
CHE 1300329 for support. For instrumentation we thank NSF
CHE 0840401; CHE 1048367; NIH S10 RR026962; COBRE
2P20RR017716. We thank Gabe Andrade for x-ray, Don
Watson for insightful discussions.
a
b
Determined by 1H NMR analysis. Epimerization in separate
experiment using tBuOK (20 mol %), THF (0.1 M) for 15 h at r.t.
c
proceeded in 88−98% yield. The enantiomeric excess of the major
diastereomer of 5 was confirmed to be 95% ee by chiral HPLC.
d
Determined ee with alcohol obtained by reducing 16 with DIBAL.
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