Acyclic stereocontrol in the Ireland-Claisen rearrangement of α-branched esters

Article abstract of DOI:10.1002/anie.200702142

(Chemical Equation Presented) To overcome the limitation of the poor diastereoselectivity of the title reaction with α-branched esters, chiral amides were used to generate the enolate intermediates diastereoselectively. The desired rearrangement then took

Full text of DOI:10.1002/anie.200702142

Communications
DOI: 10.1002/anie.200702142
Synthetic Methods
Acyclic Stereocontrol in the Ireland–Claisen Rearrangement of
a-Branched Esters**
Ying-chuan Qin, Craig. E. Stivala, and Armen Zakarian*
The Ireland–Claisen rearrangement is a powerful synthetic
method that has found extensive application in chemical
synthesis.[1,2] The substrates for this reaction can be prepared
readily and convergently by the coupling of an allylic alcohol
with a carboxylic acid, and the chirality of the allylic alcohol is
relayed efficiently to the carbon–carbon bond formed in the
rearrangement. The absolute configuration of the two ste-
reocenters created in the Ireland–Claisen reaction can be
predicted reliably on the basis of a chairlike-transition-state
model. The reaction can even be used to assemble two
contiguous quaternary stereogenic centers under mild con-
ditions. One of the current deficiencies of the method,
however, is the low diastereoselectivity observed in the
rearrangement of a-branched esters (Scheme 1). This short-
coming became apparent to us when we chose the Ireland–
Claisen rearrangement as an underlying strategy for the
synthesis of the spiroimine core of gymnodimine and related
natural products:[3,4] We envisaged the efficient formation of
the sterically congested C7 and C22 stereocenters through the
rearrangement of ester 3 (Scheme 1).
For efficient chirality transfer to each of the two
stereocenters that form upon the rearrangement of a-
branched esters such as 3, E/Z-selective enolization is
required. Herein, we describe the only method developed to
date that enables this type of stereoselective enolization,[5] as
well as the application of this method to the Ireland–Claisen
rearrangement and the enantioselective synthesis of the
cyclohexene ring of gymnodimine.
Our initial experiments focused on the selective produc-
tion of E or Z enolates from esters in which the difference in
the steric and electronic properties of the a substituents R1
and R2 is minimal. The chirality of lithium amides 4–6 was
used to control the stereoselectivity of deprotonation
(Scheme 2).[6] The starting amines were selected for their
Scheme 2. Practical synthesis of chiral amines 5 and 6 bythe method
developed byO’Brien and co-workers. [7] Ms=methanesulfonyl.
Scheme 1. The Ireland–Claisen rearrangement of a-branched esters as
a strategy for the synthesis of the spiroimine core of gymnodimine and
related natural products. PMB=p-methoxybenzyl, Pv=pivaloyl,
TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
ready availability. OꢀBrien and co-workers had described a
particularly efficient synthesis of amines such as 7, which can
be prepared from inexpensive styrene oxide on a large scale
with no chromatographic separation.[7] Importantly, the chiral
amines are not consumed in the deprotonation reaction and
can be recovered in high yield by simple extraction with
aqueous acid.
Although the stereogenic center at the a position of the
ester is destroyed upon deprotonation, it is reintroduced as a
quaternary stereogenic center through the [3,3] sigmatropic
shift. Ester 8a derived from commercially available (S)-2-
methylbutyric acid served as the model substrate for a
preliminary study of the deprotonation step (Table 1). In a
control experiment, the treatment of 8a with LDA followed
[*] Dr. Y.-c. Qin, C. E. Stivala, Prof. A. Zakarian
Department of Chemistryand Biochemistry
Florida State University
Tallahassee, FL 32306 (USA)
Fax: (+1)850-644-8281
E-mail: zakarian@chem.fsu.edu
[**] This research was supported bythe Department of Chemistryand
Biochemistry, Florida State University, and in part by the ACS
Petroleum Research Fund (43838-G1). We thank Dr. Umesh Goli of
the Department of Chemistryfor assistance with the HRMS
experiments, and Thomas Gedris for assistance with NMR
spectroscopy.
b y MeSiCl gave the E and Z isomers of the corresponding
enolate with low selectivity (Z/E 2:1), as expected (Table 1,
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3
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Table 1: Preliminarystudyof the stereoselectivityof enolization.
1
EntryEster
R
R2
Base[a]
Z/E[b]
67:33
95:5
21:79
24:76
92:8
8:92
92:8
91:9
8:92
50:50
82:18
98:2
75:25
50:50
>95:5
29:71
>98:2
65:35
>98:2
1
2
8a
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2Ph
LDA
8a
8a
8a
8a
8a
8a
8b
8b
8c
8c
8c
8c
8c
8c
8c
8c
8d
8d
(S,S)-4
(R,R)-4
(S)-5
(R)-5
(S)-6
(R)-6
(S)-6
(R)-6
LDE
3
4
5
6
7
8
9
Scheme 3. Enolization of compound 11 as a model for ester 3.
CH3
10
11
12
13
14
15
16
17
18
19
(CH2)4OPMB
(CH2)4OPMB
(CH2)4OPMB
(CH2)4OPMB
(CH2)4OPMB
(CH2)4OPMB
(CH2)4OPMB
(CH2)4OPMB
CH2CH3
controlled by an appropriate chiral base. The chiral amines
were recovered by extraction with acid in high yield. Thus, the
rearrangement of ester 3 to 2 occurred in 95% yield, and (S)-6
was recovered in 90% yield (Table 2, entry 9). Notably, a-
branched esters in which the double bond involved in the
sigmatropic rearrangement has the substitution pattern found
in 14 and 15 give products with two contiguous all-carbon
quaternary stereocenters with high diastereoselectivity
(Table 2, entries 5–7). Overall, this transformation allows an
efficient relay of chirality from readily accessible chiral allylic
alcohols and a-branched carboxylic acids to new congested
LDA
(R,R)-4
(S,S)-4
(R)-5
(S)-5
(R)-6
(S)-6
LDA
CH2CH3
CH2Ph
(R,R)-4
[a] LDA=lithium diisopropylamide, LDE=lithium diethylamide. [b] The
ratio of isomers was determined by 1H NMR spectroscopyat 500 MHz of
the crude mixture of products. The configuration was established by
NOE experiments.
entry 1). However, with (S,S)-4 as the base, the Z silyl ketene
acetal 9a was produced selectively (95:5; Table 1, entry 2).
The selectivity was reversed with (R,R)-4 to afford predom-
inantly the E isomer (79:21; Table 1, entry 3). Next, we
explored the reactivity of amides
5 and 6 (Table 1,
entries 4–7). Amide 6 exerted a higher degree of diastereo-
selectivity: Thus, the use of (S)-6 led to the E isomer 10a
(91:9) as the major diastereomer, whereas (R)-6 gave
predominantly the Z silyl ketene acetal (92:8). Other
substrates included in the preliminary investigation were
esters 8c and 8d. Intriguingly, whereas the deprotonation of
8c with lithium diethylamide (LDE) afforded a 1:1 mixture of
9c and 10c, enolization with LDA was relatively selective
(82:12; Table 1, entry 11). The matched enantiomers of all
three chiral bases showed excellent Z selectivity with 8c, b ut
only (R)-6 was able to overcome the intrinsic selectivity for
the Z silyl ether to give 9c as the major isomer (71:29; Table 1,
entry 16). The enolization of 8d with (R,R)-4 also proceeded
with excellent selectivity to afford the Z silyl ether 10d.
The enolization of ester 11 with (S)-6 and (R)-6 was
investigated to evaluate the suitability of the chiral amine 6 as
Scheme 4. Construction of the cyclohexene ring of gymnodimine.
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DIBAL=diisobutyl-
aluminum hydride, Ts=toluenesulfonyl, TMS=trimethylsilyl.
the base for the Ireland–Claisen rearrangement of
3
(Scheme 3). Although there is virtually no difference in the
size of the a substituents of this ester, the E and Z enolates
were generated with high stereoselectivity with the appro-
priate enantiomer of 6.[8]
We then investigated the utility of the stereoselective
enolization in the Ireland–Claisen rearrangement. A series of
allylic esters were prepared and subjected to the standard
rearrangement protocol in the presence of bases 4–6
(Table 2). The stereoselectivity of each reaction could be
Scheme 5. An empirical predictive model for the stereoselective enoli-
zation. Sv.=solvent molecule.
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Table 2: Diastereoselective Ireland–Claisen rearrangement of a-branched esters.
ciently into ester 27 by treatment
with diazomethane generated in
situ. The reduction of 27 followed
by protection of the primary alco-
hol and removal of the PMB group
gave 28.[9] Ozonolysis,[10] the addi-
tion of MeMgBr, and oxidation[11]
then yielded 1, which was subjected
to an intramolecular aldol conden-
sation: Ketoaldehyde 1 underwent
cyclization to give 29 upon treat-
ment with piperidine in the pres-
ence of p-toluenesulfonic acid in
toluene.[12]
[a]
EntryBase
Substrate
Product[b]
Yield [%], d.r.[c]
85, 16:1
1
2
(S,S)-4
(S)-6
80, 5:1
On the basis of our observa-
tions during this study, we propose
an empirical model to predict the
stereoselectivity of the enolization
step and consequently of the Ire-
3
(S,S)-4
82, >20:1
land–Claisen
rearrangement
(Scheme 5). If the a substituents
R1 and R2 in the ester are similar
alkyl groups and the substrate is
drawn as structure A, the amide
base (R)-6 will produce enolate B
preferentially, whereas (S)-6 will
give enolate C. This model is in
agreement with all our current
results, and further studies are
under way to test its validity.
4
5
(S)-6
71, 3.5:1
95, 13:1
(S,S)-4
The reasons for the observed
6
7
(S,S)-4
(S)-6
100, >20:1
selectivity are unclear at present,
although the transition structures
for enolization proposed by Ire-
land et al. served as inspiration for
the development of this method-
ology.[1b] We speculated that if the
enolate configuration is deter-
mined by a highly organized tran-
sition structure during the proton
transfer, groups R1 and R2 would
have little influence on whether a
structure of type 30 or type 31 is
preferred. On the other hand,
chiral substituents on the amide
nitrogen atom may have a more
profound effect on the relative
energies of 30 and 31, and the
presence of such substituents may
lead to a selective enolization step.
The precise interactions responsi-
ble for the observed selectivity will
be the subject of further studies.
In summary, we have devel-
85, 5:1
8
9
(R,R)-4
(S)-6
88, 7:1
95, 10:1
10
(R)-6
95, 5:1
[a] The preparation of the substrates is described in the Supporting Information. [b] The configuration
was confirmed byderivatization and NOE experiments for selected compounds. [c] The ratio of isomers
was determined by 1H NMR spectroscopyat 500 MHz of the crude mixture of products.
stereocenters through the formation of a carbon–carbon
bond.
Next, we applied the methodology to the synthesis of the
cyclohexene ring of gymnodimine (Scheme 4). After the key
rearrangement of 3, the resulting acid was converted effi-
oped a diastereoselective Ireland–Claisen rearrangement of
a-branched allylic esters through an unprecedented stereo-
selective enolization. A high level of selectivity was observed
when the chirality of the ester substrates and lithium amide
bases were matched. The stereodefined enolates could
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[5] For previous studies on the chelation-controlled stereoselective
potentially serve as intermediates in other asymmetric trans-
formations in which enolate geometry dictates stereoselec-
tivity.
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Tetrahedron 1988, 44, 7587; b) J. C. Gilbert, T. A. Kelly, Tetrahe-
dron Lett. 1989, 30, 4193; c) J. C. Gilbert, R. D. Selliah,
Tetrahedron 1994, 50, 1651; for selected examples of the
stereoselective generation of tetrasubstituted enolates by other
methods by taking advantage of chelation or ring constraint, see:
d) P. N. Devine, A. I. Meyers, J. Am. Chem. Soc. 1994, 116, 2633;
e) D. Enders, M. Knopp, Tetrahedron 1996, 52, 5805; f) S. A.
Calad, K. A. Woerpel, J. Am. Chem. Soc. 2005, 127, 2046;
g) ref. [1b].
Received: May 15, 2007
Revised: July 10, 2007
Published online: August 10, 2007
Keywords: chiral amines · diastereoselectivity· enolization ·
.
Ireland–Claisen rearrangement · synthetic methods
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