Catalytic dynamic kinetic resolutions with N-heterocyclic carbenes: Asymmetric synthesis of highly substituted β-lactones

Article abstract of DOI:10.1002/anie.201203382

New DKR type: An N-heterocyclic carbene (NHC)-catalyzed dynamic kinetic resolution of racemic α-substituted β-keto esters has been developed. This method relies on the epimerization of an NHC-enol intermediate before subsequent aldol/acylation events. Hig

Full text of DOI:10.1002/anie.201203382

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Chemie
DOI: 10.1002/anie.201203382
Asymmetric Catalysis
Catalytic Dynamic Kinetic Resolutions with N-Heterocyclic Carbenes:
Asymmetric Synthesis of Highly Substituted b-Lactones**
Daniel T. Cohen, Chad C. Eichman, Eric M. Phillips, Emily R. Zarefsky, and Karl A. Scheidt*
The conversion of a racemic substrate to enantioenriched
products, commonly referred to as a kinetic resolution, is an
established method with broad applications.[1,2] Due to the
intrinsic lack of efficiency with this strategy where the
theoretical yield is only 50%, many creative dynamic kinetic
resolutions (DKRs) have been developed in which > 99%
yields are possible.[3] For these processes, the rapid intercon-
version between each enantiomer of a starting material
provides an opportunity for a selective catalyst system[4] to
promote a desired reaction favoring only one enantiomer,
assuming the interconversion is faster than the irreversible
step. Both transition metal and enzyme-based DKR reactions
have seen significant development over the past two de-
cades.[5] Dynamic kinetic resolutions based on organocatalysis
are emerging as powerful and complementary approaches for
the conversion of racemic substrates to products with high
enantioselectivity. Organocatalytic DKRs have employed
a wide variety of activation strategies, including Lewis
bases,[6] hydrogen bond donors,[7] chiral Brønsted acids,[8]
enamine/iminium ions,[9] and peptide-based biaryl oxida-
tions.[10] While N-heterocyclic carbene (NHC) catalysis has
Scheme 1. NHC-catalyzed dynamic kinetic resolution.
been used in very few cases of traditional kinetic resolu-
tions[11,12] or parallel kinetic resolutions, NHC-DKRs should
provide significant new opportunities.[13] Here, we report
a new NHC-DKR with b-keto esters to generate highly
substituted b-lactones[14] with excellent levels of stereoselec-
tivity (Scheme 1). This unique process leverages the basic
conditions necessary to generate the NHC catalyst from the
azolium salt to promote racemization of the substrates.
For a successful NHC-catalyzed DKR process, the race-
mic starting material must undergo facile epimerization under
basic conditions typical with carbene generation. Given our
experience with NHC-catalyzed homoenolate[15] and enolate
reactions[16] we predicted that a similar approach could be
applied to racemic a-substituted b-keto esters (1). The
potential epimerization of the a-position under the basic
reaction conditions could favor only one NHC-enol inter-
mediate that would undergo the aldol/acylation (see below).
A significant challenge for this process is controlling the
selectivity to favor one of four potential diastereomeric
products (Scheme 1). This approach provides access to cyclo-
pentane-fused b-lactones (2) or substituted cyclopentanes (3)
with three contiguous stereogenic centers [Scheme 1,
Eq. (1)].
Our investigation began by treating racemic enals with an
azolium salt (10 mol%) and a stoichiometric amount of
Hꢀnigꢁs base (Table 1). Azolium precursors A–D furnished
the product b-lactone with moderate diastereoselectivity but
with little to no conversion (entries 1–4). Triazolium E gave
complete conversion of starting material with a 7:1 d.r. and
90% ee, but there was a significant amount of decarboxyla-
tion to the corresponding cyclopentene, with a 31% yield of
the isolated product lactone (entry 5).[17,18] In this NHC-DKR
process, the mitigation of the decarboxylation pathway is
essential because complete decarboxylation of a 5:1 diaste-
reomeric mixture of (+)-2a and (+)-2b would provide
a cyclopentene product with only a ca. 65% ee.
[*] D. T. Cohen, Dr. C. C. Eichman, E. M. Phillips, E. R. Zarefsky,
Prof. K. A. Scheidt
Department of Chemistry, Center for Molecular Innovation and
Drug Discovery, Chemistry of Life Processes Institute
Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
E-mail: scheidt@northwestern.edu
[**] Financial support has been generously provided by the NIH
(NIGMS RO1-GM073072). D.T.C. thanks the ACS Division of
Organic Chemistry for a 2011-12 Graduate Fellowship (sponsored
by Organic Syntheses/Organic Reactions. E.M.P. also thanks the
ACS Division of Organic Chemistry Graduate fellowship sponsored
by Organic Reactions (2008–2009). We thank John M. Roberts (NU)
and Dr. Amy A. Sarjeant for assistance with X-ray crystallography.
We explored azolium F which we have observed in
previous carbene-catalyzed processes to provide high yields
and selectivity.[17e] Gratifyingly, this NHC catalyst afforded
a reproducible increase in enantioselectivity (99% ee) with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203382.
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Table 1: Reaction optimization.[a]
We also examined the effect of base and solvent on the
ethyl ester substrate. Our goal was to increase the a-proton
acidity through the use of a more polar solvent or stronger
base. Coordinating polar aprotic solvents (i.e., THF, DMSO)
provided sluggish reactions with poor selectivity while
stronger bases resulted in starting material decomposition
or poor reactivity. After screening a large array of solvent
combinations and bases (not shown), it was determined that
the most favorable conditions were observed when running
the reaction in 1,2-dichloroethane (DCE) with cesium
carbonate (30 mol%) as the base. Under these optimized
conditions, the desired lactones were isolated in high yield
(86%) with good diastereoselectivity (6:1 d.r.) and excellent
enantioselectivity (Table 1, entry 11).
Entry
Variation of the
P:SM[b]
d.r.[c]
ee
standard conditions
[%][d]
1
A, X=OEt
2:3
1.2:1
1:20
1:3
4:1
5:1
34
35
52
70
77
90
35
–
2
B, X=OEt
[e]
3
C, X=OEt
–
4
D, X=OEt
4:1
7:1
5:1
1:1
–
8:1
–
6:1
5
E, X=OEt
>20:1 (31)[f]
>20:1 (72)
>20:1
6
F, X=OEt
7
8
F, X=NBn2
F, X=SPh
[g]
–
With the optimized reaction conditions established, we
explored the scope of this NHC-catalyzed DKR (Table 2).
Electron-deficient aromatic ketones led to desired lactones 6–
12 in good yield (64–88%), with good diastereoselectivity,
and excellent enantioselectivity (97–99%). Notably, the 2-
9
F, X=OCH2CF3
F, X=OCH(CF3)2
F, X=OEt
>20:1 (64)
99
–
98
10
1:1[h]
11[i]
>20:1 (86)
DCE, Cs2CO3 (30mol%)
Table 2: Lactone substrate scope.[a–d]
[a] See the Supporting Information for details. [b] Ratio of product (P) to
starting material (SM) determined by 1H NMR spectroscopy (500 MHz).
Number in parentheses is the isolated yield of both diastereomers (on
1
a 0.4 mmol scale). [c] Ratio determined by H NMR spectroscopy
(500 MHz) prior to purification. [d] Enantiomeric excess of the major
diastereomer determined by HPLC. [e] Starting material recovered.
[f] Yield of major diastereomer only. [g] Full consumption of starting
material but with no productive products observed. [h] Incomplete
conversion. [i] 7 mol% catalyst loading.
a slight decrease in diastereoselectivity. More importantly, the
use of azolium F provided a much-improved yield with trace
amounts of decarboxylation (72% isolated yield, Table 1,
entry 6). In an attempt to improve the diastereoselectively of
this process we examined other 1,3-dicarbonyl compounds
(entries 6–10) with varying acidities at the a-position with the
idea that different electron-withdrawing groups would per-
turb the acidity of the a-position and thus increase the rate of
enantiomer interconversion. With a b-ketoamide, the resul-
tant lactone was formed in a 1:1 mixture of diastereomers,
presumably due to the A1,3 strain created when tautomerizing
to the enol form (entry 7).[19] The b-keto thioester enal was
not productive and only decomposed rapidly under the
reaction conditions to unidentified products (entry 8). Fluo-
rinated ester substrates were also investigated as a means to
modulate the acidity of the a-proton. The trifluoroethyl ester
gave an increase in diastereoslectivity (8:1 d.r.) with excellent
enantioselectivity (99% ee) but with a decreased yield (64%)
(entry 9). Increasing the acidity further by switching to the
hexafluoroisopropyl ester gave incomplete conversion and
unproductive products (entry 10). Other alkyl esters such as
tert-butyl or benzyl gave similar or lower selectivities (not
shown).
[a] 0.4 mmol scale. [b] Yields of isolated products are an average of two
reactions. Diastereomers separable by column chromatography. Com-
bined yield of both diastereomers is given. [c] Diastereomeric ratio
1
determined by H NMR spectroscopy (500 MHz) prior to purification.
[d] Enantiomeric excess of the major diastereomer determined by HPLC.
[e] 10 mol% F. [f] Yield of major diastereomer only. Minor not stable to
column chromatography. [g] 30 mol% of F.
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fluorophenyl substrate exhibited high diastereoselectivity
(20:1) and enantioselectivity, but with a decreased yield.
Para-phenyl substitution provided the lactone product (13)
with excellent diastereoselectivity. Electron-donating substi-
tution was tolerated in the meta-position furnishing lactone
products 15 and 16 in high yield (73–77%) with good
selectivities. Finally, the cyclopropyl ketone proceeded to
furnish lactone 17 in moderate yield and enantioselectivity,
but with excellent diastereoselectivity.[20]
In this organocatalytic DKR process, electron-rich aryl
ketones proceeded directly to the cyclopentene product
(Table 3). Presumably, more available electron density pro-
Scheme 3. Synthetic transformations (see the Supporting Information
for details): a) PhCH2NH2, CH2Cl2, 238C; b) SiO2, C6H6, 608C;
c) LiAlH4, Et2O, 0 to 238C; d) [Ir(py)(cod)PCy3], H2, CH2Cl2, 238C;
e) ClSO2NH2, pyridine, CH2Cl2, 0 to 238C; f) [Rh2(OAc)4], MgO, PhI-
(OAc)2, CH2Cl2, 408C.
Table 3: Enantioselective synthesis of cyclopentenes.[a–c]
natural product synthesis.[23] To demonstrate the potential
utility of this DKR, we processed these b-lactones into diverse
compounds (Scheme 3). The treatment of 5a with benzyl-
amine gave amide 24 in 94% yield while heating 5a with SiO2
at 608C[24] followed by lithium aluminum hydride provided
homoallylic alcohol 25 in 84% yield over two steps. A
selective hydrogenation with Crabtreeꢁs catalyst[25] afforded
trans-cyclopentane 26 (79%, 8:1 d.r.), while 10% Pd/C
hydrogenation favored the cis-cyclopentane (91%, 2.2:1
d.r., see the Supporting Information). Following a similar
reaction sequence, sulfonylamine 27 was prepared in three
steps with a 60% overall yield. The exposure of 27 to
Du Boisꢁs conditions generated bicyclic aziridine 28 (91%
yield).[26]
Our current understanding of this DKR process is
depicted in Scheme 4. Addition of the NHC to enal (Æ)-
1 induces the formation of the extended Breslow intermedi-
ate. The homoenolate undergoes b-protonation to form enols
I and III. The mildly basic reaction conditions allow for these
two intermediates to be in rapid equilibrium. Addition to the
re-face of the enol is favored for both intermediates (I and III)
due to a favorable hydrogen-bonding interaction between the
NHC-enol and ketone forming a 6-membered transition state
(II and IV). The importance of the hydrogen bonding is
reinforced by the poor conversion observed with solvents that
disturb this hydrogen-bonding interaction (coordinating polar
aprotic). The major diastereomer ((+)-2a) arises from enol II,
in which the ester is in a pseudo axial orientation. This
conformation is more favorable than IV, which yields minor
diastereomer ((+)-2b), due to destabilization created by
a gauche interaction of the ethyl ester and the aryl group. This
destabilization is increased with ortho substituted substrates
(favoring intermediate II) and as a result virtually none of the
minor diastereomer ((+)-2b) is observed (lactone 10 and
cyclopentene 18). The combination of a fast aldol addition
with II compared to IV and the rapid equilibrium of I and III
drives the reaction primarily in the direction of (+)-2a (97–
99% ee). The rationale behind the absence of the corre-
sponding enantiomer (À)-2a (which would arise from si-face
attack of III) is twofold. First, there is an unfavorable
arylester syn destabilization, and second, there is no hydrogen
bonding to promote the aldol/acylation. The minor diaste-
[a] 0.4 mmol scale. [b] Yields of isolated products (average of two
reactions). [c] ee determined by HPLC. [d] Lactone decarboxylated on
SiO2.
motes a facile decarboxylation. Unfortunately, along with this
process comes an inherent decrease in enantioselectivity and
investigations are underway to increase the selectivity. The 2-
ethoxyphenyl ketone proceeded in high yield and enantiose-
lectivity (90% ee). Other substrates, however, provided
decreased yields and enantioselectivities of cyclopentene
products 19–21.[21]
Given the highly selective nature of the method, we
envisioned a stereodivergent parallel kinetic resolution
(PKR) would be possible.[22] In contrast to a standard kinetic
resolution, a PKR converts both enantiomers of a starting
material into two distinct products. For this process we
employed a racemic substrate that is not epimerizable under
the reaction conditions (Scheme 2). The reaction proceeded
as planned with a-methylated b-keto ester 22 and complete
Scheme 2. Parallel kinetic resolution.
cyclization to diastereomeric b-lactone products 23 was
achieved in excellent yield (50% theoretical yield for each)
and enantioselectivity.
b-Lactones are highly useful building blocks for the
synthesis of target compounds, especially in the area of
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Scheme 4. Proposed reaction pathway.
reomer (+)-2b (arising from intermediate IV) was likewise
formed with high enantioselectivity (92–95% ee) (Table 2,
lactones 5 and 6, see the Supporting Information).
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In conclusion, a new NHC-catalyzed dynamic kinetic
resolution has been developed. This process takes advantage
of the conditions necessary to generate the active NHC
catalyst to simultaneously promote the epimerization of a b-
ketoester substrate. The present study provides efficient
access to highly enantioenriched b-lactones and cyclopen-
tenes in good yield with good to excellent diastereoselectivity.
With this blueprint for a new type of organocatalytic DKR
process, further studies to probe the general reactivity, expand
the substrate scope and application of this new NHC-DKR
process in total synthesis are underway.
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Experimental Section
In a nitrogen-filled dry box a screw-capped vial equipped with
a magnetic stirbar was charged with the corresponding enal b-
ketoester 4 (0.400 mmol), azolium precatalyst F (0.07 equiv), and
cesium carbonate (0.30 equiv). The vial was capped with a septum
cap, removed from the drybox and put under positive N2 pressure.
The heterogeneous mixture was then diluted with degassed 1,2-
dichloroethane (12 mL, 0.033m) and stirred for 12 h under static
nitrogen pressure. Upon consumption of the aldehyde (all reactions
were completed within 12 h) the reaction mixture was diluted with
dichloromethane (5 mL) washed with brine (10 mL) and separated.
The aqueous phase was back extracted with dichloromethane (5 mL).
The combined organic layers were filtered through a Biotage Isolute
phase separator, and the organic filtrate was concentrated. The
material was purified by flash chromatography with EtOAc/hexanes
to afford the corresponding b-lactone.
Received: May 2, 2012
Published online: && &&, &&&&
Keywords: aldols · asymmetric synthesis ·
.
dynamic kinetic resolution · homoenolates ·
N-heterocyclic carbenes
4
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Schroeder, D. T. Cohen, K. A. Scheidt, Angew. Chem. 2012, 124,
5047; Angew. Chem. Int. Ed. 2012, 51, 4963.
[21] The observed enantioselectivity for these cyclopentenes is a due
to the diastereoselectivity for the NHC-catalyzed process. These
cyclopentenes are not epimerizable under reaction conditions.
See the Supporting Information for details.
[22] a) E. Vedejs, X. Chen, J. Am. Chem. Soc. 1997, 119, 2584; for
a good review, see: b) L. C. Miller, R. Sarpong, Chem. Soc. Rev.
2011, 40, 4550.
[23] For selected examples of b-lactones in synthesis, see: a) R. L.
Danheiser, J. S. Nowick, J. Org. Chem. 1991, 56, 1176; b) J.
Taunton, J. L. Collins, S. L. Schreiber, J. Am. Chem. Soc. 1996,
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Org. Chem. 1998, 63, 2058; d) X. Shen, A. S. Wasmuth, J. Zhao,
C. Zhu, S. G. Nelson, J. Am. Chem. Soc. 2006, 128, 7438; e) V. C.
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122, 2645; Angew. Chem. Int. Ed. 2010, 49, 2591; g) T. R. Vargo,
J. S. Hale, S. G. Nelson, Angew. Chem. 2010, 122, 8860; Angew.
Chem. Int. Ed. 2010, 49, 8678; h) G. Liu, D. Romo, Angew.
Chem. 2011, 123, 7679; Angew. Chem. Int. Ed. 2011, 50, 7537.
[24] The enantioselectivity was maintained following decarboxyla-
tion. See the Supporting Information for details.
[25] R. Crabtree, Acc. Chem. Res. 1979, 12, 331.
[26] a) K. Guthikonda, P. M. Wehn, B. J. Caliando, J. Du Bois,
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
D. T. Cohen, C. C. Eichman, E. M. Phillips,
E. R. Zarefsky,
K. A. Scheidt*
&&&& — &&&&
Catalytic Dynamic Kinetic Resolutions
with N-Heterocyclic Carbenes:
Asymmetric Synthesis of Highly
Substituted b-Lactones
New DKR type: An N-heterocyclic car-
bene (NHC)-catalyzed dynamic kinetic
resolution of racemic a-substituted b-
keto esters has been developed. This
method relies on the epimerization of an
NHC-enol intermediate before subse-
quent aldol/acylation events. Highly sub-
stituted b-lactones are produced in good
yield with good to excellent selectivities
(see scheme).
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!