Gold(I)-catalyzed enantioselective ring expansion of allenylcyclopropanols

Article abstract of DOI:10.1021/ja904055z

(Chemical Equation Presented) The asymmetric gold(I)-catalyzed ring expansion of 1-allenylcyclopropanols is described. The method provides synthetically valuable cyclobutanones with a vinyl-substituted quaternary stereogenic center in high enantioselectivities and yields. The method shows a broad substrate scope, tolerating protected alcohols and amines, alkenes, unsaturated esters, and acetals. The reaction is easily adjustable to large-scale synthesis, leading to product formation without significant loss of selectivity or yield with only 0.5 mol% catalyst loading.

Full text of DOI:10.1021/ja904055z

Published on Web 06/16/2009
Gold(I)-Catalyzed Enantioselective Ring Expansion of Allenylcyclopropanols
Florian Kleinbeck and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received May 19, 2009; E-mail: fdtoste@berkeley.edu
Substituted cyclobutanes constitute valuable building blocks for
organic synthesis because of their rich chemistry and are addition-
ally found as motifs in numerous natural products.1 Among the
various approaches to cyclobutanes, ring expansion of cyclopro-
panols by a Wagner-Meerwein shift to the corresponding cyclobu-
tanones is considered one of the most powerful and versatile
methods.2 While ring expansion of small ring systems can generally
be induced by coordination of π-acidic transition-metal catalysts
to alkenyl-, alkynyl-, and allenylcycloalkanols,3 only a few reports
have described asymmetric catalytic Wagner-Meerwein shifts
based on this strategy for the synthesis of cycloalkanones.4
In the past decade, cationic gold(I) complexes have evolved as
mild Lewis acid catalysts for transformations requiring the activation
of π bonds.5 In 2005, we reported the ring expansion of 1-alky-
nylcyclopropanols catalyzed by [(p-CF3C6H4)3P]AuSbF6, which
provides efficient access to a range of alkylidenecyclobutanols.6,7
We hypothesized that an analogous rearrangement of 1-allenylcy-
clopropanols using chiral gold-phosphine complexes might allow
for the catalytic construction of cyclobutanones possessing a vinyl-
substituted quaternary stereogenic center.8
further increased the enantioselectivity, providing 2 in 89 and 91%
ee with xylyl-BINAP and MeO-DM-BIPHEP, respectively (entries
8 and 9).10 Control experiments indicated that the improved
selectivity in the case of NaBARF presumably results from
suppression of an inherent background reaction by trace amounts
of HNTf2 formed under the reaction conditions.11
Scheme 1. Substrate Scopea
Table 1. Optimization of Reaction Conditions
entry
ligand (L)
MX
T (°C)
ee (%)
1
2
3
4
5
6
7
8
9
(R)-xylyl-BINAP
(R)-xylyl-BINAP
(R)-xylyl-BINAP
(R)-xylyl-BINAP
(R)-tolyl-BINAP
(R)-BINAP
(R)-MeO-DM-BIPHEP
(R)-xylyl-BINAP
(R)-MeO-DM-BIPHEP
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
NaBARFa
NaBARFa
0
-10
-20
-30
-30
-30
-30
-30
-30
75
81
83
84
48
32
86
89
91
a NaBARF ) sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
During initial experiments to establish standard reaction condi-
tions, (R)-xylyl-BINAP was identified as promising ligand. When
allenylcyclopropanol 1 was treated with the (R)-xylyl-BINAP-
derived cationic gold(I) complex at 0 °C, cyclobutanone 2 was
isolated in 75% ee (Table 1, entry 1). When the temperature of the
reaction was decreased, the enantioselectivity increased, reaching
84% at -30 °C (entry 4). Notably, the enantioselectivity showed a
pronounced leveling behavior, with only a small increase in
selectivity between -10 and -30 °C (entries 2-4). Decreasing
the steric encumbrance around the phosphine led to a drop in the
enantioselectivity (entries 5 and 6).9 A slight improvement in
selectivity was obtained with MeO-DM-BIPHEP, giving 2 in 86%
ee at -30 °C (Table 1, entry 7). Replacement of AgNTf2 with
sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF)
a Conditions: 2.5 mol% (R)-MeO-DM-BIPHEP(AuCl)2,
5 mol%
NaBARF, 0.100 mmol of substrate, 0.12 M in 1,2-DCE, -30 °C, 24 h.
Yields refer to isolated material; ee’s were determined by chiral HPLC.
See the Supporting Information for details. b Reaction run at 0.25 M for
48 h. c Reaction run with 5 mol% catalyst and 10 mol% NaBARF at 0.08
M for 48 h. d Reaction run with (S)-xylyl-BINAP(AuCl)2.
With these results in hand, we examined the scope of the gold(I)-
catalyzed enantioselective ring expansion of 1-allenylcyclopropanols
(Scheme 1). Straightforward access to all of the substrates was
achieved using three different strategies: (1) direct allenylation of
cyclopropanone generated in situ from 1-ethoxycyclopropanol; (2)
Johnson-Claisen rearrangement of propargyl alcohols; and (3) SN2′
9
9178 J. AM. CHEM. SOC. 2009, 131, 9178–9179
10.1021/ja904055z CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
displacement of propargyl mesylates with cuprate reagents (see the
Supporting Information for details). A wide range of cyclobutanones
were accessible in synthetically useful yields12 and good to excellent
enantioselectivities.13 Substrates possessing aromatic substituents
(2-6) were generally well tolerated, with the more electron-deficient
1-allenylcyclopropanols 5 and 6 requiring longer reaction times.
Alkyl-substituted compounds were excellent substrates for this
method, giving cyclobutanones 7 to 9 in high enantioselectivities.
The mildness of the method allowed the incorporation of various
functional groups in the side chain, e.g., protected alcohols (10)
and amines (11), acetals (12), alkenes (13), and R,ꢀ-unsaturated
esters (14).
Acknowledgment. We thank Dr. David J. Buchanan and Daniel
L. Gray for initial studies. We gratefully acknowledge NIGMS
(RO1 GM073932), Bristol-Myers Squibb, and Novartis for financial
support. F.K. thanks the German Academic Exchange Service
(DAAD) for a postdoctoral fellowship. We acknowledge Solvias
and Takasago for the generous donation of phosphine ligands and
Johnson Matthey for a gift of AuCl3.
Supporting Information Available: Experimental procedures,
compound characterization data, and crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
The amount of catalyst could be reduced without significant loss
of enantioselectivity or yield. Cyclobutanone 9 was obtained in 88%
yield and 89% ee on a 1.5 mmol scale with only 0.5 mol% of the
chiral gold(I) catalyst (eq 1). The low catalyst loading combined
with the air and moisture of the reaction should make this method
suitable for the synthesis of chiral cyclobutanones on a large scale.
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A proposed mechanism for the gold(I)-catalyzed enantioselective
ring expansion of 1-allenylcyclopropanols is outlined in Scheme
2. Coordination of the cationic gold(I) catalyst to the internal double
bond of the allene moiety in 1 triggers a ring expansion by a
Wagner-Meerwein shift, generating vinylgold intermediate A. A
subsequent protodemetalation liberates the catalyst and releases the
product 2. This mechanistic proposal is in agreement with results
from computational studies carried out for the related rearrangement
of 1-alkynylcyclopropanols.14
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(9) For all three major bisphosphine ligand families (BINAP, BIPHEP, and
Segphos), the same trend was observed, with the xylyl-substituted
representatives providing the highest selectivity within each family.
(10) While AgNTf2, AgPF6, and AgSbF6 all provided cyclobutanone 2 in 83%
ee at 20 °C with (R)-xylyl-BINAP as the ligand, AgBF4, AgOTf, and AgOTs
led to formation of 2 in only 67, 34, and 15% ee, respectively.
(11) AgNTf2 was found to slowly catalyze the ring expansion of 1. While AgOAc
was not a competent catalyst, almost instantaneous reaction was observed
with HNTf2. These observations suggest that the achiral catalyst causing
the background reaction was not the silver cation.
Scheme 2. Proposed Reaction Mechanism
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structure analysis of the corresponding tosylhydrazone. The absolute
configurations of compounds 2 and 9 were assigned by comparison of the
optical rotation with reported values (see ref 4a). The absolute configurations
of all the other compounds were assigned by analogy.
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129, 12402. (b) Tarselli, M. A.; Chianese, A. R.; Lee, S. J.; Gagne´, M. R.
Angew. Chem., Int. Ed. 2007, 46, 6670. (c) Hamilton, G. L.; Kang, E. J.;
Mba, M.; Toste, F. D. Science 2007, 317, 496. (d) Liu, C.; Widenhoefer,
R. A. Org. Lett. 2007, 9, 1935. (e) LaLonde, R. L.; Sherry, B. D.; Kang,
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In summary, we have developed an asymmetric ring expansion
reaction of 1-allenylcyclopropanols catalyzed by chiral phosphine
gold(I)-phosphine complexes. The method provides access to a
wide range of cyclobutanones with a vinyl-substituted quaternary
stereogenic center. Moreover, this method constitutes the first report
of an enantioselective gold-catalyzed 1,2-alkyl migration7 and
thereby expands the class of reactions amenable to asymmetric
catalysis by gold.15 Further studies of the application of this
methodology to the synthesis of natural products are ongoing in
our laboratories.
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