Enantioconvergent synthesis of functionalized γ-butyrolactones via (3 + 2)-annulation

Article abstract of DOI:10.1021/ja511701j

A dynamic kinetic resolution of α-halo β-keto esters in an asymmetric homoenolate reaction is described. A chiral N-hetereocyclic carbene catalyzes the a³ → d³-umpolung addition of β,α-enals to racemic β-keto esters, forming γ-butyrolactones with three contiguous stereocenters. The addition occurs with high regio-, diastereo-, and enantiocontrol. This methodology constitutes an intermolecular DKR process to set three stereocenters during the key bond forming event.

Full text of DOI:10.1021/ja511701j

Communication
pubs.acs.org/JACS
Enantioconvergent Synthesis of Functionalized γ‑Butyrolactones via
(3 + 2)-Annulation
C. Guy Goodman, Morgan M. Walker, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
Stereodynamic methods that generate three stereocenters are
limited.4,5 The preponderance of these methods use catalyst or
ABSTRACT: A dynamic kinetic resolution of β-halo α-
keto esters in an asymmetric homoenolate reaction is
described. A chiral N-hetereocyclic carbene catalyzes the a3
→ d3-umpolung addition of α,β-enals to racemic α-keto
esters, forming γ-butyrolactones with three contiguous
stereocenters. The addition occurs with high regio-,
diastereo-, and enantiocontrol. This methodology con-
stitutes an intermolecular DKR process to set three
stereocenters during the key bond forming event.
substrate control to independently establish one stereocenter
and dynamic bond formation to furnish the other two. The
intramolecular DKR transformation of β-keto esters to β-
lactones reported by Scheidt and co-workers serves as a
counter-example, whereby simultaneous generation of all three
stereocenters can occur during the same step.6 To the best of
our knowledge, an intermolecular DKR or dynamic kinetic
asymmetric transformation (DyKAT) that establishes three
stereocenters during the key bond-forming event is heretofore
unknown. In this communication we describe a DKR utilizing
carbene-generated homoenolate equivalents for the chemo-
selective formation of γ-butyrolactones from α,β-unsaturated
aldehydes and racemic α-keto esters with excellent levels of
diastereo- and enantiocontrol.
ynamic kinetic asymmetric transformations are potent
Dmethods to generate functionalized and stereochemically
defined products from racemic starting materials, and a number
of enzymatic and chemocatalytic reactions have been put
forward utilizing this paradigm.1 Concomitant with the
burgeoning number of dynamic methodologies has been an
increase in the stereochemical complexity generated in these
systems. At the bottom of this gradient resides methods that
generate a single stereocenter; a prototypical example is the
conversion of racemic alcohols into optically pure acetates
enabled by redox processing (Scheme 1).2 The second echelon
in complexity-generation includes dynamic pathways that
generate two stereocenters. The asymmetric hydrogenation of
configurationally labile α-substituted β-keto esters is the
archetypical example.3
The exploitation of homoenolate (d3) nucleophiles generated
by the union of N-heterocyclic carbenes (NHC) and α,β-
unsaturated aldehydes has seen widespread use.7 This method
of catalytic umpolung (polarity inversion) has grown to include
the use of imines,8 carbonyls,9 and Michael acceptors10 as
electrophilic components; however, to this point the reaction of
enals with linear α-keto esters been reported in only low
diasterocontrol (1.5:1) and moderate enantioselectivity (78%
ee).11 In connection with our interest in enantioconvergent
carbon−carbon bond constructions involving racemic electro-
philes,12 we sought to develop NHC-catalyzed homoenolate
addition of α,β-unsaturated aldehydes to configurationally labile
α-keto esters. This endeavor presents a significant challenge in
rate constant management: eight stereoisomers are possible and
byproducts arising from mechanistically validated cross-
benzoin12c,13 and enal dimerization pathways were a legitimate
concerns (Scheme 2).14
Scheme 1. Degrees of Stereocomplexity in Dynamic Kinetic
Transformations
Our studies began by examining the reaction of cinnamalde-
hyde and α-keto ester 1a-Me. A preliminary screen showed that
NHC catalyst A12c delivers γ-butyrolactone 2 in low regio- and
diastereoselectivity (Table 1, entry 1).15 Using 1a, which has a
more sterically demanding tert-butyl ester, in combination with
A yielded 2a as a single product in a 6:1 diastereomeric ratio
(dr) (Table 1, entry 2). Taking this result as an indication that a
sterically hindered ester was likely necessary for the efficacy of
this transformation, we began a systematic screening of carbene
catalysts with 1a. Catalyst B and C revealed no marked increase
in stereoselectivity (Table 1, entry 3−4). In tandem, these
results indicated that increasing the steric bias of phenylalanine
Received: November 13, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja511701j
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Journal of the American Chemical Society
Communication
Catalyst F,17 which is a derivative of pyroglutamic acid,
delivered exclusively 2a, in 9:1 dr and 93:7 er (Table 1, entry
7). Deploying catalyst G furnished 2a in 33:1 dr and 99:1 er
(Table 1, entry 8). Using the β-bromo α-keto ester of 1a under
identical conditions maintained high levels of isomer selectivity
but suffered from poor reactivity (Table 1, entry 9). Lowering
the catalyst loading to 5 mol % had no deleterious effects on
reaction efficiency or selectivity (Table 1, entry 10).
Scheme 2. Chemoselectivity Challenges for the Carbene
Catalyzed Coupling of α,β-Enals (Blue) and Enolizable α-
Keto Esters (Red)
With suitable conditions in hand we began to probe the
allowable steric and electronic parameters of this annulation,
initially by varying the identity of the α,β-unsaturated aldehyde
(Table 2). Changing the electronic features of the aldehyde
delivered 2b and 2c without loss of reaction fidelity. While both
Table 2. Variation of α−β Unsaturated Aldehydes in the
a
Homoenolate Addition to β-Chloro-α-Keto Esters
Table 1. Catalyst and Substrate Optimization
a
b
bc
,
d
entry
R
cat
conv (%)
2a/3a
dr
er
1
2
3
4
5
6
7
8
Me
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
A
A
B
C
D
E
100
100
88
5:1
3:1
90:10
84:16
73:27
85:15
−
78:22
93:7
99:1
−
>20:1
>20:1
3.5:1
6:1
3:1
64
2:1
100
100
100
100
40
2:1
6:1
>20:1
>20:1
>20:1
>20:1
>20:1
3:1
F
9:1
G
G
G
33:1
>20:1
33:1
e
9
f
10
100
99:1
a
b
1
All reactions were run on a 0.10 mmol scale. Determined by H
c
NMR analysis of the crude reaction mixture. dr is only reported for
d
homoenolate product 2a. Determined by chiral SFC analysis.
e
f
Conducted on the corresponding β-bromo analogue of 1a. Five
mol % of catalyst G.
derived NHC catalysts was ineffectual to increasing reaction
selectivity. Aminoindanol-derived catalyst D16 showed poor
differentiation between the acyl anion and homoenolate
pathway yielding a 2:1 ratio of products 2a/3a (Table 1,
entry 5). Catalyst E provided 2a as the sole product with a 3:1
dr and an enatiomeric ratio (er) of 78:22 (Table 1, entry 6).
a
All reactions were run on a 0.20 mmol scale at room temperature for
14 h. No acyl anion addition was observed for any example.
Diastereomeric ratios were determined by 1H NMR; enantiomeric
b
ratios by chiral SFC. Yields are of isolated products. Using (Z)-
c
cinnamaldehyde. Yield shown is a 1H NMR yield of the major
diastereomer utilizing mesitylene as an internal standard.
B
DOI: 10.1021/ja511701j
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
meta- and para-toluyl-derived cinnamaldehydes cleanly deliv-
ered 2d and 2e, the heightened steric encumbrance of ortho-
methylcinnamaldehyde resulted in no reaction. Similarly, 2g
and 2h, products that would arise from the addition of a
trisubstituted alkene12d and (Z)-cinnamaldehyde, respectively,
were inaccessible. Heteroaromatic 2i was isolated in 45:1 dr
and 98.5:1.5 er, while 2j was obtained with 6:1 dr and 95:5 er.
Products 2k and 2l demonstrated the viability of nonaromatic
substitution, albeit with low dr for the addition of (E)-4-
oxobut-2-enoic acid ethyl ester.
Scheme 3. Gram Scale Reaction of 1i and Cinnamaldehyde
Variation of the α-keto ester also provided information
regarding reaction scope (Table 3). Reducing the chain length
chloro substitutent is manifested by the conserved anti-
relationship between the nascent tertiary alcohol and the
resident halogen.12b,c This outcome is consistent with stereo-
control based on Felkin-Anh or Cornforth models.19
Table 3. Variation of β-Halo α-Keto Esters in the
a
Homoenolate Addition of Cinnamaldehyde
In conclusion, we have developed the first stereoconvergent
homoenolate reaction that utilizes racemic electrophiles. This
NHC-catalyzed process between β-halo-α-keto esters and α,β-
unsaturated aldehydes also constitutes the first intermolecular
dynamic kinetic resolution in which three stereocenters are
established during the enantiodetermining step. The resultant
γ-butyrolactones bear a fully substituted glycolic acid moiety
and are often obtained as single products in high diastereo- and
enantioselectivity. Further manipulations of this product class
and continued expansions of complexity-generating dynamic
processes are of ongoing interest in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral and HPLC data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*jsj@unc.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Award R01
GM103855 from the National Institute of General Medical
Sciences. C.G.G. acknowledges a Burroughs Welcome Fellow-
ship in Organic Chemistry from the University of North
Carolina. X-ray crystallography performed by Dr. Peter S.
White.
a
All reactions were run on a 0.20 mmol scale at room temperature for
14 h. Diastereomeric and product ratios were determined by 1H NMR;
enantiomeric ratios by chiral SFC. Yields are of isolated products.
b
c
1
Using THF as the solvent. Yield shown is a H NMR yield of the
major diastereomer utilizing mesitylene as an internal standard.
d
Unambiguous differentiation between regioisomers and diaster-
eomers was not feasible; an isomer ratio (ir) is reported.
Unambiguous identification of isomer ratios was not possible.
Isolation of 2s was achieved via chromatography.
e
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D
DOI: 10.1021/ja511701j
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