Synthesis of γ, δ-unsaturated glycolic acids via sequenced brook and Ireland - Claisen rearrangements

Article abstract of DOI:10.1021/ol9029353

(Figure Presented) Organozinc, -magnesium, and -lithium nucleophiles Initiate a Brook/lreland-Clalsen rearrangement sequence of allylic silyl glyoxylates resulting in the formation of γ, δ-unsaturated a-silyloxy acids.

Full text of DOI:10.1021/ol9029353

ORGANIC
LETTERS
2010
Vol. 12, No. 5
944-947
Synthesis of γ,δ-Unsaturated Glycolic
Acids via Sequenced Brook and
Ireland-Claisen Rearrangements
Daniel C. Schmitt and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
jsj@unc.edu
Received December 21, 2009
ABSTRACT
Organozinc, -magnesium, and -lithium nucleophiles initiate a Brook/Ireland-Claisen rearrangement sequence of allylic silyl glyoxylates resulting
in the formation of γ,δ-unsaturated r-silyloxy acids.
New methods to produce the glycolic acid moiety continue
to be important in the creation of small-molecule building
blocks.1 γ,δ-Unsaturated glycolic acid derivatives repre-
sent a functional-group-rich subset of substituted R-
hydroxy acids with significant potential for further
elaboration. The preparation of such compounds may be
achieved via Ireland-Claisen rearrangement of allyl
glycolate esters.2 While the standard Ireland-Claisen
rearrangement is performed by sequential enolization and
silylation of allylic esters, alternative approaches to the
requisite silyl ketene acetal have been reported. Methods
include 1,4-addition to enoates,3 and silylene transfer
followed by 6π-electrocyclization,4 or by Rh-catalyzed
reduction of enoates.5 These methods allow for the
generation of chiral products from achiral starting materi-
als; however, a method that introduces multiple R sub-
stituents in a single-pot process could potentially allow a
more rapid buildup of molecular complexity.
Silyl glyoxylates are reagents for the geminal linking
of nucleophile/electrophile pairs at a glycolic acid junc-
tion.6 Because multicomponent couplings involving silyl
glyoxylates are believed to proceed through a glycolate
enolate intermediate, the use of an allylic ester might allow
[3,3]-sigmatropic rearrangement to proceed in preference
to intermolecular addition to an electrophile (Scheme 1).
(1) Ley, S. V.; Sheppard, T. D.; Myers, R. M.; Chorghade, M. S. Bull.
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1987, 1979–1980. (e) Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki,
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M. C. Tetrahedron 2002, 58, 2905–2928.
10.1021/ol9029353  2010 American Chemical Society
Published on Web 02/09/2010

glyoxylate. This result underscores the chemoselectivity
displayed in previously reported three-component coupling
reactions, where the nucleophile reacts selectively with
silyl glyoxylate, rather than the terminal electrophile, and
the intermediate glycolate enolate reacts selectively with
a terminal electrophile, rather than a second equivalent
of silyl glyoxylate. The proposed Ireland-Claisen rear-
rangement requires a nucleophile capable of completely
consuming silyl glyoxylate prior to oligomerization.
Scheme 1. Silyl Glyoxylate Reactivity
An assessment of other Grignard reagents revealed that
MeMgBr had potential as an effective nucleophile because
it cleanly added to cinnamyl silyl glyoxylate 1a at 0 °C.
In this case, Brook rearrangement did not occur below
room temperature. When the reaction was allowed to
warm, only decomposition was observed. Silyl ketene
acetal formation was then attempted by the addition of
MeMgBr at 0 °C, followed by warming to room temper-
ature and the addition of TMSCl; however, this also
resulted in decomposition. Given that no TMS incorpora-
tion had occurred, we turned to TMSOTf, which induced
the desired Ireland-Claisen rearrangement and provided
the γ,δ-unsaturated glycolic acid 7 in 55% yield (Table
1, entry 1). Silyl glyoxylates 1b and 1c reacted with
similar efficiency (entries 2 and 3). The lithium enolate
of tBuOAc also initiates the Brook/Ireland-Claisen
sequence with excellent diastereoselectivity (Table 1,
entry 4).
In the proposed reaction, the addition of a nucleophile
to acylsilane would give a tetrahedral intermediate (Scheme
2). The proper alignment of the C-Si σ orbital with the
Scheme 2. Proposed Reaction
Organozinc nucleophiles were also found to be effective.
ZnEt2 serves as an efficient hydride donor, triggering the
sequential Brook and Ireland-Claisen rearrangements, to
afford glycolic acid 11 in 69% yield with good diaste-
reoselectivity (Table 1, entry 5). The reduction of R-ke-
toesters with ZnEt2 or EtMgBr has been previously
reported; however, it is typically a minor byproduct to
ethyl addition.9 Allylzinc bromide and allenylzinc bromide
were useful triggers as well (Table 1, entries 6-10).
Substituted allylic zinc nucleophiles were also competent
initiators. Methallylzinc bromide provided the desired prod-
ucts with slightly diminished diastereoselectivity relative to
allylzinc bromide (Table 1, entries 11 and 12). The reaction
was also tolerant of crotyl- and cinnamylzinc reagents;
however, products were obtained as a complex mixture of
diastereomers (not shown). Notably, none of the organozinc
nucleophiles required silyl ketene acetal formation because
the zinc enolate underwent [3,3]-rearrangement spontane-
ously.
Extension to other organozinc bromides proved chal-
lenging. Benzylzinc bromide, propynylzinc bromide, and
Reformatsky nucleophiles resulted in alkene dimer 19
(Scheme 3). This dimer was cleanly formed by the addition
of the glycolate enolate to a second equivalent of silyl
glyoxylate. The derived alkoxide suffered Brook rear-
rangement and elimination. It appears that allyl- and
allenylzinc bromide nucleophiles consumed silyl glyoxy-
adjacent CdO π* orbital in tetrahedral intermediate 2
would allow [1,2]-Brook rearrangement7 to proceed,
forming glycolate enolate 3. At this point, the allylic ester
enolate could undergo Ireland-Claisen rearrangement to
afford a γ,δ-unsaturated acid.
Ireland-Claisen rearrangement proceeds via a well-
understood transition state wherein the enolate geometry
dictates the stereochemistry of the product.8 The E/Z
geometry of the intermediate glycolate enolate has not
been established in reactions of silyl glyoxylates; therefore,
determination of the enolate geometry would augment our
understanding of the silyl glyoxylate reactivity and provide
mechanistic insight for future endeavors. Furthermore, this
process would create two new C-C bonds, allowing
access to densely functionalized glycolic acids. Herein,
we describe experiments directed toward these ends.
Preliminary work focused on defining a compatible
nucleophilic component. Previously employed nucleo-
philes such as vinylmagnesium bromide and zinc acetyl-
ides were found to trigger oligomerization of silyl
(9) (a) Hameury, T.; Guillemont, J.; Van Hijfte, L.; Bellosta, V.; Cossy,
J. Org. Lett. 2009, 11, 2397. (b) Fennie, M. W.; DiMauro, E. F.; O’Brien,
E. M.; Annamalai, V.; Kozlowski, M. C. Tetrahedron 2005, 61, 6249–
6265.
Org. Lett., Vol. 12, No. 5, 2010
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Table 1. Sequential Brook/Ireland-Claisen Rearrangements of
Silyl Glyoxylates
Scheme 3. Dimerization Limits Nucleophile Scope
bromides, providing glycolic acid derivatives in moderate
diastereoselectivity (Table 2). These results demonstrate
that the Brook/Ireland-Claisen sequence may show
promise for the construction of adjacent chiral quaternary
centers.
Table 2. Generation of Contiguous Quaternary Centers
The enolate geometry was inferred by examination of the
relative stereochemistry of the γ,δ-unsaturated glycolic acid
products. The products could be converted to cyclic products
by iodolactonization or ring-closing metathesis, allowing for
NOESY analysis.10 In each case, the major diastereomer was
found to be consistent with a (Z)-glycolate enolate.
late more rapidly, and therefore dimerization was not
competitive.
Geranyl silyl glyoxylate 20 underwent the title trans-
formation when treated with allenylic or allylic zinc
The degree of diastereocontrol depended on the identity
of both the nucleophile and the ester. While cinnamyl silyl
(10) See the Supporting Information for experimental details and NOESY
data.
946
Org. Lett., Vol. 12, No. 5, 2010

glyoxylate 1a reacted with allylzinc bromide (Table 1, entry
6) and allenylzinc bromide (entry 9) with modest diastereo-
control, analogous reactions with crotyl silyl glyoxylate 1b
resulted in substantially higher diastereomeric ratios (entries
7 and 10). The formation of the chelated alkoxide 2 appears
likely in light of the established tendencies for bidentate
coordination in R-dicarbonyl electrophiles and the derived
addition products.11 Stereoelectronic considerations would
suggest the subsequent formation of (Z)-enolate 3 arising
from Brook rearrangement. The resulting silyl ether will
dramatically weaken chelation,12 potentially permitting eno-
late equilibration (via the C-Zn tautomer 5) to compete with
[3,3]-rearrangement from the Z isomer. The rate of sigma-
tropic rearrangement should be linked to steric demand at
C1 and C6, where a less hindered substrate undergoes more
rapid [3,3]-rearrangement;13 therefore, it is hypothesized that
the more encumbered 1a undergoes enolate equilibration to
a greater extent prior to sigmatropic rearrangement. The result
is an erosion of the initial enolate geometric ratio and a
corresponding decrease in the product diastereoselectivity.
This proposal is consistent with the experimental observa-
tions within the organozinc nucleophile series: the product
diastereomer ratio increases as the nucleophile bulk at C1
decreases (hydride > propargyl ≈ allyl > methallyl).
selectivity reflects the Z/E magnesium enolate ratio at the
time of silylation.
The high diastereoselectivity observed for the lithium
enolate (Table 1, entry 4) can be explained if generation
of the C-Li tautomer 5 is slow and sigmatropic rear-
rangement outcompetes enolate equilibration. This may
be directly contrasted with a recent reaction between zinc
enolates and silyl glyoxylates that do undergo facile
enolate equilibration.6b
In summary, we have developed a one-pot Brook/
Ireland-Claisen rearrangement sequence that generates γ,δ-
unsaturated glycolic acids containing two new C-C bonds
and two contiguous stereocenters. To our knowledge, this is
the first report of a Brook rearrangement initiating a [3,3]-
sigmatropic process. The reaction is tolerant of various
reaction partners, but diastereoselectivity is linked to the
identity of the metal cation and the ester. In diastereoselective
cases, the stereochemical outcome of the reaction is consis-
tent with a (Z)-enolate intermediate proceeding through a
chairlike transition state. The work suggests that diastereo-
control and the enolate geometry in reactions of silyl
glyoxylates can be tuned with the judicious selection of the
metal cation and that the rate of the “second stage” reaction
can have an impact.
It is notable that MeMgBr initiates Ireland-Claisen
rearrangement with diastereoselectivity independent of the
ester. This may be a result of silyl ketene acetal formation
prior to sigmatropic rearrangement. Provided there is no
enolate equilibration after TMSOTf trapping, the diastereo-
Acknowledgment. This research was supported by the
National Institutes of Health (National Institute of General
Medical Sciences Grant GM084927) and Novartis. We thank
a reviewer for a detailed analysis of the mechanism and some
suggestions that were incorporated herein.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W.
J. Am. Chem. Soc. 1999, 121, 686–699. (b) Masuyama, Y.; Tsunoda, T.;
Kurusu, Y. Chem. Lett. 1989, 1647–1650.
(12) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265–268.
(13) (a) Hiersemann, M.; Abraham, L. Org. Lett. 2001, 3, 49–52. (b)
Wilcox, C. S.; Babston, R. E. J. Am. Chem. Soc. 1986, 108, 6636–6642.
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