Remote stereoinduction in the acylation of fully substituted enolates: Tandem reformatsky/quaternary claisen condensations of silyl glyoxylates and β-lactones

Article abstract of DOI:10.1021/ja108848d

Reformatsky reagents react sequentially with silyl glyoxylates and β-lactones to give highly functionalized Claisen condensation products. A heretofore undocumented instance of stereochemical 1,4-induction results in efficient transmission of β-lactone st

Full text of DOI:10.1021/ja108848d

Published on Web 11/18/2010
Remote Stereoinduction in the Acylation of Fully Substituted Enolates:
Tandem Reformatsky/Quaternary Claisen Condensations of Silyl Glyoxylates
and ꢀ-Lactones
Stephen N. Greszler, Justin T. Malinowski, and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
Received September 30, 2010; E-mail: jsj@unc.edu
Abstract: Reformatsky reagents react sequentially with silyl
glyoxylates and ꢀ-lactones to give highly functionalized Claisen
condensation products. A heretofore undocumented instance of
stereochemical 1,4-induction results in efficient transmission of
ꢀ-lactone stereochemistry to the emerging fully substituted ste-
reocenter. Second-stage transformations reveal that the five
heteroatom-containing functionalities embedded within the prod-
ucts are entirely chemo-differentiated, a circumstance that permits
rapid assembly of the leustroducsin B core substructure.
Figure 1. Reformatsky reactions of silyl glyoxylates.
The Claisen condensation is a classic transformation in organic
synthesis and remains the prototypical ꢀ-ketoester synthesis. In spite
by nucleophilic attack on substituted ꢀ-lactones (eq 2). This
of its ubiquity, use of the Claisen condensation as an asymmetric
transformation could in principle address two challenges associated
C-acylation method is largely undeveloped because the thermody-
with the quaternary Claisen condensation: first, the release of ring
namically driven product deprotonation in most cases precludes
strain in the nucleophilic acyl substitution should disfavor the
maintenance of an intact R-stereocenter. The purpose of this
normally dominant retro-Claisen pathway; and second, equilibration
of (Z)-2 and (E)-2 provides a mechanism for control of the enolate
communication is to report a three-component coupling reaction
for the assembly of complex acyclic functional arrays; the key step
of the sequence is a new strain release-driven stereoselective
quaternary Claisen condensation.
Table 1. Substrate Scopea,b,d
Extant strategies directed toward stereoselective C-acylation
include Evans’s ꢀ-ketoimide synthesis,1 which forms products that
are insulated from enolization by A1,3 strain and several examples
of silyl ketene acetal acylations that generate nonenolizable
quaternary stereocenters.2a-d The formation of quaternary centers
via the Claisen condensation under basic conditions is challenging
due to an equilibrium that commonly favors the disubstituted ester
enolate when deprotonation of the ꢀ-ketoester product cannot
occur.2d-f In an effort to address this problematic transforma-
tion, we investigated reactions of Reformatsky reagents, silyl
glyoxylates,3a and ꢀ-lactones, guided by the mechanistic consid-
erations that follow.
Silyl glyoxylates (1)3 have emerged as useful conjunctive
reagents for the geminal difunctionalization of glycolate units. We
previously reported a double Reformatsky reaction cascade of silyl
glyoxylates and ketones that afforded highly substituted γ-butyro-
lactone products bearing vicinal quaternary centers with surprisingly
high diastereoselection (Figure 1, eq 1).3a The observed stereocon-
trol in that system was dependent on substitution on the Refor-
matsky reagent (R1 in eq 1). Equilibration of the kinetically formed
(Z)-enolate3a,f to the more stable (E)-isomer, presumably driven
by formation of a stronger chelate with the pendant ethyl ester,
allowed the ꢀ-stereocenter to influence the electrophile approach
to the unhindered diastereotopic face of (E)-2.
We envisioned a modification of this chemistry wherein acylation
of the intermediate glycolate enolate, exposed after [1,2]-Brook
rearrangement4 of the initial zinc aldolate, would be accomplished
a All reactions: [1]0 ) 0.05 M. b Yields of isolated products; d.r.
determined by 1H NMR spectroscopy. c Yield over two steps. d See
Supporting Information for more details.6
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C O M M U N I C A T I O N S
geometry through coordination with the ester carbonyl. ꢀ-Lactones
are building blocks that are readily available in enantioenriched
form,5 but the degree to which preexisting substrate chirality would
impinge upon the incipient quaternary center lacked precedent.
Preliminary studies focused on defining the reaction parameters
necessary for achieving the desired Reformatsky/Claisen cascade
leading to 3a (terminating electrophile: 4-((trimethylsilyl)ethyny-
l)oxetan-2-one). In our prior work with Reformatsky reagents, a
stepwise addition of the silyl glyoxylate and ketone was necessary
to avoid competitive Reformatsky reactions with the secondary
electrophile. Those chemoselectivity issues are significantly attenu-
ated here: the synchronous addition of 1 and the ꢀ-lactone led to
efficient formation of 3a without appreciable reaction between the
excess Reformatsky reagent and ꢀ-lactone. These results are
particularly gratifying given the known capacity of the latter to
undergo Claisen condensation with magnesium and lithium acetate
enolates.7 Moreover, the excellent diastereomeric ratio observed
for the formation of 3a (>20:1) was a fortunate and unexpected
divergence from what had been previously observed in reactions
of an unsubstituted (acetate-derived) Reformatsky reagent and 1.3a
A variety of strained electrophiles exhibited similar reactivity.
Asymmetric syntheses of ꢀ-lactones are prevalent in the literature,
giving direct access to diverse functionality in the coupling
products.5 ꢀ-Lactones derived from R,ꢀ-unsaturated, alkyl, and aryl
aldehydes were all viable substrates (3a, 3d, 3e, Table 1), as were
lactones bearing potentially chelating functionalities (3f). The
reaction was amenable to the use of R,ꢀ-disubstituted lactones,
although lower diastereoselection was observed for certain substrates
(dr3k > dr3i,j). γ-Butyrolactone provided analogous reactivity, but
protection of the crude product as the corresponding silyl ether was
necessary to avoid a potential retro-Claisen pathway during
purification (3h).8 Finally, ꢀ-lactams afforded the corresponding
ꢀ-amino ketone products9 (3l,m), albeit as a 1:1 mixture of
separable diastereomers.
The title reaction provides products immediately amenable to
reliable diastereoselective reductions for the synthesis of function-
alized diols. Reduction of 3b via the Evans10a and Prasad10b
protocols afforded diols 5 and 7, respectively (Scheme 1). Cycliza-
tion of 5 (TsOH, PhMe, 80 °C) gave the mono(lactone) 6, while 7
afforded bis(lactone) 8 under the same conditions. This divergence
in reactivity may be rationalized by the presumably higher energy
barrier for lactonization of anti-diol 5 to a trans-fused bis(lactone).11
NOESY experiments on 6 and 8 were internally consistent and
confirmed the configuration at the quaternary carbon.
Scheme 1. Secondary Transformations of Ketone Products
The two ester groups occupy distinct chemical environments that
permit differentiation based on steric effects: the syn-acetonide 9
undergoes selective reduction to the mono(alcohol) with DIBAL-H
(Scheme 2, eq 3) or to the corresponding diol with LiBHEt3 (eq
4).
Scheme 2. Diester Functionalization
The relevant stereochemical issues associated with these dias-
tereoselective C-acylations are summarized in Figure 2. A closed
transition state involving the approach of the enolate on the
diastereotopic face opposite the ꢀ-substituent of the lactone appears
most plausible, but subtle stereocontrol elements must be at play
to account for the dominance of 4 over 4′. The cyclic transition
state depicted in Figure 2 provides a plausible means for dif-
ferentiating the facial approach of the glycolate enolate, and dipole
minimization of the coordinated lactone electrophile or lone pair
repulsion with the benzyloxy substituent potentially suppresses
formation of the minor diastereomer and favors reaction through
4. Circumstantial evidence for the proposed model was provided
by the observation of reversed diastereoselection for ꢀ-keto ester
3i (derived from an anti-ꢀ-lactone); steric effects would be predicted
to destabilize structure 4 with such an electrophile. Additional
experimentation will be necessary to discount alternative models,
but the poor diastereoselection observed with ꢀ-lactams suggests
that they react through topographically distinct transition states.
The potential application of this chemistry toward the assembly
of stereochemically and functionally complex linear natural products
is illustrated in Scheme 3. Mitsunobu reaction of diol 7 was highly
selective for reaction at the more activated and less hindered
propargylic site and proceeded with complete inversion of stere-
ochemistry and concomitant protection of the hydroxyl group as
the chloroacetate.12 Phosphorylation of the remaining hydroxyl
functionality afforded 11, which constitutes the bulk of the carbon
skeleton of leustroducsin B, a potent colony-stimulating factor
inducer isolated from Streptomyces platensis.13 Notably, the
preparation of 3a was achieved on multigram scale with no
deterioration in yield.
Scheme 3. Synthesis of the Leustroducsin B Core
Figure 2. Potential competing transition states.
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C O M M U N I C A T I O N S
Linghu, X.; Satterfield, A. D.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128,
9302. (d) Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.; Johnson,
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In conclusion, a new reactivity pattern has been observed for
Reformatsky reagents and silyl glyoxylates with lactone and lactam
electrophiles. The resulting Reformatsky/Claisen cascade affords
highly substituted ketone products bearing an R-quaternary center
through an unprecedented acylation of fully substituted glycolate
enolate intermediates. Remarkable diastereoselection is observed
for these transformations through the transfer of stereochemical
information from the ꢀ-lactone terminating electrophiles to the
emerging quaternary center. The products contain useful orthogonal
functionality that can be selectively manipulated in downstream
transformations.
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Acknowledgment. The project described was supported by
Award R01 GM084927 from the National Institute of General
Medical Sciences. Additional support from Novartis and Amgen
is gratefully acknowledged.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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