Polarity inversion of donor-acceptor cyclopropanes: Disubstituted δ-lactones via enantioselective iridium catalysis

Article abstract of DOI:10.1021/ja2090993

The coupling of carbonyl electrophiles at the donor position of donor-acceptor cyclopropanes is described, representing an inversion of polarity with respect to conventional reactivity modes displayed by these reagents. Specifically, upon exposure of donor-acceptor cyclopropanes to alcohols in the presence of a cyclometalated iridium catalyst modified by (S)-BINAP, catalytic C-C coupling occurs, providing enantiomerically enriched products of carbonyl allylation. Identical products are obtained upon isopropanol-mediated transfer hydrogenation of donor-acceptor cyclopropanes in the presence of aldehydes. The reaction products are directly transformed to cis-4, 5-disubstituted δ-lactones.

Full text of DOI:10.1021/ja2090993

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Polarity Inversion of DonorÀAcceptor Cyclopropanes: Disubstituted
δ-Lactones via Enantioselective Iridium Catalysis
Joseph Moran,† Austin G. Smith,‡ Ryan M. Carris,‡ Jeffrey S. Johnson,*,‡ and Michael J. Krische*,†
†Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
‡Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S Supporting Information
b
ABSTRACT: The coupling of carbonyl electrophiles at the
donor position of donorÀacceptor cyclopropanes is de-
scribed, representing an inversion of polarity with respect to
conventional reactivity modes displayed by these reagents.
Specifically, upon exposure of donorÀacceptor cyclopro-
panes to alcohols in the presence of a cyclometalated iridium
catalyst modified by (S)-BINAP, catalytic CÀC coupling
occurs, providing enantiomerically enriched products of
carbonyl allylation. Identical products are obtained upon
isopropanol-mediated transfer hydrogenation of donorÀ
acceptor cyclopropanes in the presence of aldehydes.
The reaction products are directly transformed to cis-4,
5-disubstituted δ-lactones.
yclopropanes are useful synthetic building blocks for organic
synthesis because of their multifaceted reactivity and relative
C
ease of preparation.1 DonorÀacceptor (DÀA) cyclopropanes
are a particularly useful subset capable of reacting with diverse
partners upon exposure to the proper kinetic trigger.2 All polar
reactions of DÀA cyclopropanes involve nucleophilic trapping at
the donor site and electrophilic trapping at the acceptor site, as
illustrated in the stereoselective syntheses of five- and six-
membered ring products (Figure 1a,b).3 Although inversion
(or umpolung) of these polarity patterns would increase the
diversity of products accessible from DÀA cyclopropanes, such
reactivity remains elusive (Figure 1a,d).4 Here we report that
exposure of DÀA cyclopropanes to cyclometalated iridium
catalysts results in umpolung of the DÀA cyclopropanes, leading
to electrophilic trapping at the donor site, as illustrated by the
enantioselective CÀC coupling of DÀA cyclopropanes and
carbonyl electrophiles to furnish δ-lactones.
Figure 1. Lewis acid and transition metal activation of DÀA cyclo-
propanes.
products (Figure 1c).5 While the generation of nucleophilic
π-allyls from DÀA cyclopropanes is unknown (Figure 1d),4 the
feasibility of umpoled carbonyl additions involving DÀA
cyclopropanes is suggested by recently developed reductive
couplings of allylic carboxylates to carbonyl partners catalyzed
by ortho-cyclometalated iridium C,O-benzoates.6,7 A unique
feature of such iridium-catalyzed carbonyl allylations resides in
the use of alcohols as terminal reductants, allowing highly
enantioselective carbonyl addition from the alcohol or aldehyde
oxidation level in the absence of stoichiometric metallic re-
agents. Although similar capabilities may be envisioned
for corresponding DÀA cyclopropane-mediated processes,
π-allyl generation requires a malonic ester moiety to function
as an efficient nucleofuge for oxidative addition,7 which at the
onset of these studies had not been demonstrated for iridium.
The reaction of DÀA cyclopropanes with transition metals
to form electrophilic π-allyl intermediates is an established
mode of reactivity used to prepare carbo- and heterocyclic
Received: September 27, 2011
Published: October 25, 2011
r
2011 American Chemical Society
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Table 1. Optimization of DÀA Cyclopropane-Mediated
Table 2. DÀA Cyclopropane-Mediated Carbonyl Allylation
Carbonyl Allylation of Benzyl Alcohol (2a)a
from the Alcohol Oxidation Levela
K3PO4
mol %
H2O
temp
1a
%
% ee
(dr)
entry
mol %
(°C)
mol %
yield
1
2
3
4
5
6
50
0
500
500
500
0
50
50
50
50
60
60
200
200
200
200
200
150
37
0
99 (>20:1)
N/A
5
81
0
98 (8:1)
N/A
5
5
500
500
84
84
98 (7:1)
98 (6:1)
5
a Yields are of material isolated by silica gel chromatography. Enantio-
meric excess was determined by chiral-stationary-phase HPLC analysis.
See the Supporting Information for further details.
Further, as reported by one of the present authors,5d under the
conditions of palladium catalysis, DÀA cyclopropanes and
aldehydes combine by way of π-allyl intermediates to form
tetrahydrofurans (conceptualized in Figure 1c). Thus, the
proposed umpoled process must compete with an efficient
π-allyl-mediated transformation involving identical reactants,
rendering the outcome of this endeavor uncertain.
a As described for Table 1.
Table 3. DÀA Cyclopropane-Mediated Carbonyl Allylation
from the Aldehyde Oxidation Levela
Vinylcyclopropane 1a was prepared directly from the
commercial reagents dimethyl malonate and (E)-1,4-dibro-
mobut-2-ene.5d In preliminary experiments, 1a (200 mol %)
and benzyl alcohol (2a; 100 mol %) were exposed to the
chromatographically isolated π-allyliridium complex (R)-I
(5 mol %) at 50 °C under conditions effective for related
crotylations employing α-methylallyl acetate.7d Gratifyingly,
the desired adduct 4a formed as a single regioisomer with
nearly complete levels of diastereo- and enantioselectivity,
although the isolated yield was modest (Table 1, entry 1). The
diastereoselectivity observed in the formation of 4a was
amplified by competing base-catalyzed lactonization arising
predominantly from the minor diastereomer. As all atoms in
vinylcyclopropane 1a and alcohol 2a appear in the product, it
was postulated that exogenous base may be unnecessary and in
fact may impede the reaction. While upon omission of K3PO4
adduct 4a was not formed (entry 2), a decreased loading of
K3PO4 (5 mol %) dramatically improved the isolated yield of
4a (entry 3). Upon a slight increase in temperature (entries 5
and 6) and decrease in the loading of vinylcyclopropane
1 (entry 6), adduct 4a was produced in 84% isolated yield
with good levels of diastereoselectivity and excellent levels of
enantioselectivity.
a As described for Table 1.
upon use of i-PrOH (200 mol %) as the terminal reductant
under otherwise identical reaction conditions. Again, good
isolated yields and diastereo- and enantioselectivities were
observed (Table 3). Thus, umpoled DÀA cyclopropane-
mediated carbonyl allylation occurs with equal facility from
the alcohol or aldehyde oxidation level (Tables 2 and 3). The
absolute stereochemical assignment of adducts 4aÀe was
These latter conditions were applied to benzylic alcohols 2a
and 3a, allylic alcohols 2c and 2d, and aliphatic alcohol 2e.
Good isolated yields of the corresponding adducts 4aÀe were
observed, and in each case, good levels of diastereoselectivity
were accompanied by exceptional levels of enantiocontrol
(Table 2). As observed in prior studies,6,7 an identical set of
adducts 4aÀe are accessible from the aldehyde oxidation level
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Scheme 1. Formation of cis-4,5-Disubstituted δ-Lactones 5a,
’ ASSOCIATED CONTENT
5b, and 5e via Krapcho Decarboxylationa
S
Supporting Information. Experimental procedures; spec-
b
tral and HPLC data; and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu; jsj@unc.edu
a Conditions A: LiCl (500 mol %), 3 Å molecular sieves, DMSO (1 M),
150 °C. Conditions B: NaCl (500 mol %), DMSO (0.2 M), 160 °C.
’ ACKNOWLEDGMENT
The Robert A. Welch Foundation (F-0038), NIH NIGMS
(R01-GM069445), and NSF (CHE-0749691) are acknowledged
for financial support. The Natural Sciences and Engineering
Research Council of Canada (NSERC) is acknowledged for
generous postdoctoral support (J.M.). This paper is dedicated to
Professors D. A. Evans and B. M. Trost on the occasion of their
70th birthdays.
Scheme 2. Reactions of DÀA Cyclopropane 1b Incorporat-
ing a Phosphonoacetate Moietya
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a Reagents: (a) Standard conditions as described in Table 1 using
catalyst (R)-I. (b) K2CO3, CH2O, H2O, 60 °C. (c) DCC, DMAP,
CH2Cl2, 23 °C.
made on the basis of single-crystal X-ray diffraction analysis, as
described in the Supporting Information.
To explore the utility of the coupling products, adducts 4a, 4b,
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phoslactomycin9 (Scheme 1). The range of compounds availed
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glutarolactone 7. The enantiomeric excess was determined at this
stage (Scheme 2).
In summary, we report umpoled reactions of donorÀ
acceptor cyclopropanes, as illustrated by diastereo- and
enantioselective iridium-catalyzed DÀA cyclopropane-mediated car-
bonyl allylations from the alcohol or aldehyde oxidation levels. These
studies open new routes to optically enriched cis-4,5-disubstituted
δ-lactones. Of broader significance, identification of the structural and
interactional features of the catalytic system required for polarity
inversion provide a foundation for the development of related CÀC
coupling processes.
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’ NOTE ADDED AFTER ASAP PUBLICATION
The version published ASAP October 31, 2011, did not contain
the final corrections in the text and the first graphic. The
corrected version was reposted November 16, 2011.
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