Enantioselective conversion of primary alcohols to α- Exo -methylene γ-butyrolactones via iridium-catalyzed C-C bond-forming transfer hydrogenation: 2-(Alkoxycarbonyl)allylation

Article abstract of DOI:10.1021/ja303839h

Upon exposure of acrylic ester 1 to alcohols 2a-i in the presence of a cyclometalated iridium catalyst modified by (-)-TMBTP, catalytic C-C coupling occurs, providing enantiomerically enriched 5-substituted α-exo-methylene γ-butyrolactones 3a-i. Bromination of the methylene butyrolactone products followed by zinc-mediated reductive aldehyde addition provides the disubstituted α-exo-methylene γ-butyrolactones 6a and 6b with good to excellent levels of diastereoselectivity.

Full text of DOI:10.1021/ja303839h

Communication
pubs.acs.org/JACS
Enantioselective Conversion of Primary Alcohols to α-exo-Methylene
γ-Butyrolactones via Iridium-Catalyzed C−C Bond-Forming Transfer
Hydrogenation: 2-(Alkoxycarbonyl)allylation
T. Patrick Montgomery, Abbas Hassan, Boyoung Y. Park, and Michael J. Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: Upon exposure of acrylic ester 1 to alcohols
2a−i in the presence of a cyclometalated iridium catalyst
modified by (−)-TMBTP, catalytic C−C coupling occurs,
providing enantiomerically enriched 5-substituted α-exo-
methylene γ-butyrolactones 3a−i. Bromination of the
methylene butyrolactone products followed by zinc-
mediated reductive aldehyde addition provides the
disubstituted α-exo-methylene γ-butyrolactones 6a and
6b with good to excellent levels of diastereoselectivity.
α-exo-Methylene γ-butyrolactones display an enormous array of
biological activities and constitute approximately 10% of the
>30 000 known natural products.1 Among methods for their
preparation, carbonyl-addition-triggered lactonization reactions
involving 2-(alkoxycarbonyl)allylmetal reagents are especially
convergent protocols. To date, discrete 2-(alkoxycarbonyl)-
allylmetal reagents based on boron,2 silicon,3 tin,4 zinc,5 and
nickel6 have been utilized in this capacity. Additionally,
umpoled reactions of 2-(alkoxycarbonyl)allyl halides promote
the formation of α-exo-methylene γ-butyrolactones, including
Reformatsky and Nozaki−Hiyama type reactions.7 Methods for
asymmetric carbonyl addition−lactonization to form α-exo-
methylene γ-butyrolactones largely rely upon stoichiometric
chirality transfer from auxiliaries.2a,b,d,e,l,7j Furthermore, high
enantioselectivities are obtained only when two chiral auxiliaries
are used in concert.2b,d Remarkably, related catalytic enantiose-
lective processes for the formation of α-exo-methylene γ-
butyrolactones remain an unmet challenge.8 Here we report the
first highly enantioselective catalytic 2-(alkoxycarbonyl)-
allylations to form α-exo-methylene γ-butyrolactones, which
are achieved directly from the alcohol oxidation level under the
conditions of iridium-catalyzed C−C bond-forming transfer
hydrogenation (Figure 1).9
Our earlier work on iridium-catalyzed enantioselective
carbonyl allylation10 revealed that allylic carboxylates incorpo-
rating monosubstituted olefins are required. This constraint
arises because olefin coordination precedes ionization of the
allylic leaving group to form the π-allyl, and the stability of late
transition metal−olefin π complex decreases with increasing
degree of olefin substitution.11 However, we recently found that
enhanced π back-bonding12,13 associated with carboxy sub-
stitution compensates for such destabilization, enabling vinyl-
ogous aldol addition from the alcohol or aldehyde oxidation
level.14 This result supported the feasibility of using acrylic ester
1 as a 2-(alkoxycarbonyl)allylmetal equivalent.
Figure 1. Formation of α-exo-methylene γ-butyrolactones via
enantioselective carbonyl 2-(alkoxycarbonyl)allylation.
In preliminary experiments, the catalytic C−C coupling of
acrylic ester 1 and alcohol 2b was explored using the achiral π-
allyliridium C,O-benzoate complex derived from [Ir(cod)Cl]2,
4-chloro-3-nitrobenzoic acid, allyl acetate, and 2,2′-bis-
(diphenylphosphino)biphenyl (BIPHEP). This complex, des-
ignated as Ir(BIPHEP), was isolated by conventional silica gel
chromatography. However, upon exposure of acrylic ester 1 to
alcohol 2b under conditions effective in related vinylogous aldol
additions, only trace quantities of the desired butyrolactone 3b
were generated (Table 1, entry 1). The catalyst used in the
vinylogous aldol addition was isolated by precipitation and
hence may have contained residual cesium carbonate. This
hypothesis prompted us to conduct the reaction under the
aforementioned conditions in the presence of added cesium
carbonate (20 mol %), which promoted generation of
butyrolactone 3b in 31% isolated yield (Table 1, entry 2).
Decreased loadings of cesium carbonate (10 and 5 mol %)
increased the isolated yield of butyrolactone 3b (Table 1,
entries 3 and 4). Finally, upon adjustment of the reaction
temperature, acrylic ester 1 and alcohol 2b were converted to
butyrolactone 3b in 77% isolated yield (Table 1, entries 5 and
6). The concentration of trace metals in the cesium carbonate
had a significant impact on the isolated yield. For the best
results, high-grade cesium carbonate (>99.7% purity) with trace
metal concentrations of <10 ppm had to be employed.
Received: April 21, 2012
Published: June 26, 2012
© 2012 American Chemical Society
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Communication
Table 1. Selected Optimization Experiments in the C−C
Table 3. Enantioselective 2-(Alkoxycarbonyl)allylation via
a
Coupling of Ester 1 to Alcohol 2b [R = (CH2)2Ph]
Iridium-Catalyzed C−C Bond-Forming Transfer
a
Hydrogenation
a
Yields are of materials isolated by silica gel chromatography. See the
Supporting Information for further details.
Under the optimal conditions identified for the conversion of
acrylic ester 1 and alcohol 2b to racemic butyrolactone 3b,
catalysts modified by diverse axially chiral chelating phosphine
ligands were assayed. The chiral ligands assayed included
BINAP, Xylyl-BINAP, SEGPHOS, DM-SEGPHOS, C3-TU-
NEPHOS, MeO-BIPHEP, Cl,MeO-BIPHEP, and CTH-P-
PHOS, among others. However, the degree of asymmetric
induction was disappointing, with 80% ee or lower in each case.
In contrast, the chiral complex modified by (−)-2,2′,5,5′-
tetramethyl-3,3′-bis(diphenylphosphine)-4,4′-bithiophene
[(−)-TMBTP],15 designated as Ir(TMBTP), provided butyr-
olactone 3b in 79% yield with 88% ee (Table 2, entry 1). The
a
b
c
As described for Table 2. THF (0.5 M). The cyclometalated
Table 2. Selected Optimization Experiments in the
d
catalyst derived from 4-CN-3-NO2-BzOH was used. (R)-DM-
SEGPHOS was used as the ligand. See the Supporting Information
for further details.
Enantioselective C−C Coupling of Ester 1 to Alcohol 2b [R
a
= (CH2)2Ph]
conversion of aldehyde 4g to butyrolactone 3g, 2-
(alkoxycarbonyl)allylation can be conducted from the aldehyde
oxidation level using isopropanol as a terminal reductant
(Scheme 1). Butyrolactones 3a and 3b were previously
prepared in optically enriched form and served to corroborate
the assignment of absolute stereochemistry for butyrolactones
3a−i.
Scheme 1. Enantioselective 2-(Alkoxycarbonyl)allylation via
Iridium-Catalyzed Aldehyde Reductive Coupling via
Transfer Hydrogenation
a
a
Yields are of materials isolated by silica gel chromatography.
Enantiomeric excesses were determined by chiral stationary phase
HPLC analysis. See the Supporting Information for further details.
isolated yields and degree of asymmetric induction were both
highly solvent-dependent. Whereas reactions performed in 2-
Me-THF and dioxane provided butyrolactone 3b in 68% yield
with 77% ee and 33% yield with 72% ee, respectively, a 31%
yield with 92% ee was obtained in MeCN (Table 2, entries 2−
4). To balance the yield and enantioselectivity, reactions were
conducted in THF/MeCN mixtures over 3 days (Table 2,
entries 5 and 6).
The optimal conditions identified for the enantioselective
process were applied to primary aliphatic alcohols 2a−i. The
corresponding α-exo-methylene γ-butyrolactones 3a−i were
produced in good to excellent isolated yields with enantiose-
lectivities ranging from 82 to 95% ee (Table 3). Benzylic
alcohols also participated in the 2-(alkoxycarbonyl)allylation,
but the enantioselectivities were modest.16 As illustrated by the
a
As described for Table 2. See the Supporting Information for further
details.
To illustrate the potential utility of adducts 3a−i,
butyrolactone 3f was converted into allylic bromide 5, which
was subjected to zinc-mediated reductive coupling to p-
bromobenzaldehyde and 3-phenylpropanal (Scheme 2).17 The
corresponding adducts 6a and 6b were generated diaster-
eoselectively, thereby establishing entry to disubstituted α-exo-
methylene γ-butyrolactones with control of the relative and
absolute stereochemistries.
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Communication
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Scheme 2. Conversion of rac-3f to Disubstituted α-exo-
Methylene γ-Butyrolactones 6a and 6b
a
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Reagents: (a) Br2 (110 mol %), NaOAc (150 mol %), DCM (0.08
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In summary, although α-exo-methylene γ-butyrolactones
represent a vast family of naturally occurring compounds, the
catalytic enantioselective formation of such butyrolactones via
carbonyl 2-(alkoxycarbonyl)allylation was hitherto unknown.
Here we have reported the first examples of catalytic
enantioselective carbonyl 2-(alkoxycarbonyl)allylation through
iridium-catalyzed transfer hydrogenative C−C coupling of
acrylic ester 1 to alcohols 2a−i. As illustrated by the formation
of adducts 6a and 6b, this methodology provides entry to fully
substituted α-exo-methylene γ-butyrolactones with control of
the relative and absolute stereochemistries. Future studies will
focus on the application of this methodology to the synthesis of
α-exo-methylene γ-butyrolactone natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral, HPLC, and GC data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Reformatsky and Nozaki−Hiyama type reactions, see: (a) Loffler,
̈
AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The Robert A. Welch Foundation (F-0038) and the NIH
NIGMS (R01-GM069445) are acknowledged for partial
support of this research. Merck is acknowledged for the
generous donation of (−)-TMBTP. The Higher Education
Commission of Pakistan is acknowledged for graduate student
fellowship support (A.H.).
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