Stereodivergence in the Ireland-Claisen Rearrangement of α-Alkoxy Esters

Article abstract of DOI:10.1021/acs.orglett.8b02011

A systematic investigation into the Ireland-Claisen rearrangement of α-alkoxy esters is reported. In all cases, the use of KN(SiMe₃)₂ in toluene gave rearrangement products corresponding to a Z-enolate intermediate with excellent diastereoselectivity, presumably because of chelation control. On the other hand, chelation-controlled enolate formation could be overcome for most substrates through the use of lithium diisopropylamide (LDA) in tetrahydrofuran (THF).

Full text of DOI:10.1021/acs.orglett.8b02011

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereodivergence in the Ireland−Claisen Rearrangement of
α‑Alkoxy Esters
̌
Masa Podunavac, Jacob J. Lacharity, Kerry E. Jones, and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: A systematic investigation into the Ireland−Claisen
rearrangement of α-alkoxy esters is reported. In all cases, the use of
KN(SiMe3)2 in toluene gave rearrangement products correspond-
ing to a Z-enolate intermediate with excellent diastereoselectivity,
presumably because of chelation control. On the other hand,
chelation-controlled enolate formation could be overcome for most
substrates through the use of lithium diisopropylamide (LDA) in
tetrahydrofuran (THF).
he Ireland−Claisen rearrangement has represented a
Scheme 1. Proposed Stereodivergent Access to Both
Diastereomeric Ireland−Claisen Rearrangement Products
of α-Alkoxy Esters
T
powerful tool in chemical synthesis for over 40 years.1
The utility of this method is underscored by the ease of
preparation of the requisite allylic esters and the predictable
stereochemical outcome of the reaction.2 The stereochemistry
of the alcohol fragment is reliably transferred to the α and β
positions of the carboxylic acid product with high enantiose-
lectivity and diastereoselectivity, usually via a chairlike
transition state, providing a powerful approach to the
construction of sterically congested vicinal stereocenters.3
Furthermore, the carboxy group formed in the reaction can
serve as an effective proxy to a wide variety of other functional
groups.4
Efficient transmission of chirality during the Ireland−Claisen
rearrangement is critically dependent on the stereoselective
formation of an E- or Z-enolate. In the case of α-alkoxy esters,
it is widely expected that formation of the Z-enolate is
kinetically favored, because of chelation of the alkoxy and
carbonyl oxygen atoms with the metal cation of the base.
Indeed, selective Z-enolate formation in the Ireland−Claisen
rearrangement of esters derived from glycolic and lactic acid
has been observed in numerous cases.5−9 Therefore, we were
surprised to find a report from Langlois and co-workers that
described selective E-enolate formation in the Ireland−Claisen
rearrangement of an α-OPMB ester when LDA was used as the
base in tetrahydrofuran (THF).10 In this single reported
example, a 3:1 ratio of products arising from the E- and Z-
enolates, respectively, was observed. This selectivity was
reversed when Et2O or toluene were used as the solvent,
when HMPA was employed as an additive, or when
KN(SiMe3)2 was used as the base.
no systematic studies on the divergence in the diastereose-
lectivity in the Ireland−Claisen rearrangement, based on the
choice of the enolization reagent, has been reported for this
class of substrates. If it is indeed possible to achieve selective E-
or Z-enolate formation from the same substrate, facile access to
both diasteromeric Ireland−Claisen products could be
realized.
We became interested in exploring whether the effect of the
base used for the enolization of α-alkoxy esters on the
diastereochemical outcome of the Ireland−Claisen rearrange-
ment is general. If so, practical levels of diastereomer ratios
(dr) can be achieved for both isomers from the same substrate
simply by the choice of base (see Scheme 2). To this end, we
prepared a library of these compounds to examine the effects
of the reaction conditions and the structure of the ester on the
diastereoselectivity of the rearrangement.
Using α-benzyloxy hydrocinnamate 1 as a representative α-
alkoxy ester, initial studies focused on identifying suitable
reaction conditions capable of selectively delivering both
diastereomeric products based on the choice of base. The
To the best of our knowledge, this work represents the only
case of nonchelation-controlled, E-selective enolization of an
α-alkoxy ester. It is an important observation because it is
generally presumed that only one diastereomer is accessible by
the Ireland−Claisen rearrangement of α-alkoxy esters
attributed to the overwhelming preference for the Z-enolate
via chelation-controlled enolization (see Scheme 1).11 Thus,
Received: June 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
presence of bases KN(SiMe3)2 or LDA (see Table 1). We
began by screening a variety of α-alkoxy hydrocinnamic acid
esters bearing distinct R2/R3 substituents, in addition to
different R1 alkoxy substituents. KN(SiMe3)2 as a base afforded
acids via a Z enolate in moderate to excellent yields (79%−
90%) with diastereoselectivities as high as 25:1. In all examples,
a slight decrease in dr was observed when the alkoxy
substituent R1 was changed from Bn to a methyl group. It
was found that the nature of the R1 substituent had little effect
on the reaction in terms of yield. In contrast, using LDA as the
base led to the rearrangement via an E enolate in comparable
yields (72%−92%), but with noticeably smaller dr (17:1 being
the highest). A substantial decrease in yield was observed for
esters derived from primary alcohols compared with secondary
(R2 = H instead of Me). This result is due to competitive
lithiation of the allylic methylene, leading to the formation of
C-silylated byproducts (see the SI). Although yields were
similar for acids with R2 = CH3, in most cases, α-benzyloxy
esters gave products with higher dr.
Scheme 2
screening of several different bases in different solvents
revealed that KN(SiMe3)2 in PhMe is optimal for the
formation of the chelation-controlled diastereomer. Remark-
ably, LDA in THF proved most effective for the formation of
the opposite diastereomeric product (see Scheme 1).
Furthermore, the temperature and time of enolization also
proved to be critical parameters influencing diastereocontrol
(see the Supporting Information (SI) for full details of
optimization experiments).
A series of α-alkoxy esters were prepared and subjected to
the optimal [3,3] sigmatropic rearrangement protocols in the
a
Table 1. Substrate Scope in the α-Alkoxy Hydrocinnamic Ester Series
a
The substrate was treated with the indicated base at −78 °C (KN(SiMe3)2) or −100 °C (LDA). Internal quench with Me3SiCl was used for LDA.
1
Isomer ratio determined by H NMR spectroscopy. See the SI for details.
B
DOI: 10.1021/acs.orglett.8b02011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope in the Lactic Ester Series
a
The substrate was treated with the indicated base at −78 °C (KN(SiMe3)2) or −100 °C (LDA). Internal quench with Me3SiCl was used for LDA.
1
Isomer ratio determined by H NMR spectroscopy. See the SI for details.
We then examined the Ireland−Claisen rearrangement of α-
alkoxy propionic acid esters (see Table 2). Unlike α-alkoxy
hydrocinnamic acid esters, the use of LDA as a base generally
did not favor formation of an E enolate in this class of
substrates. Both bases typically gave the same major rearrange-
ment products, corresponding to the Z-enolate intermediates,
in comparable yields, with KN(SiMe3)2 giving significantly
higher dr. Notable exceptions to this pattern occurred when
the alcohol fragment of the allylic ester contained a Z-
configured olefin (4e and 4f). These substrates were able to
overcome chelation-controlled enolization and gave rise to E-
enolization products (albeit with modest selectivity). Surpris-
ingly, higher dr is achieved when R1 = Me, compared to R1=
Bn, which is the opposite of what was observed for the esters in
Table 1.
one-carbon homologation of the carboxylic acid alkyl side
chain, relative to the esters in Table 1, once again led to E-
selective enolization when LDA was used as the base, although
a much higher diastereomeric ratio was obtained for α-OBn
substrate 7a (1:6), relative to the corresponding α-OMe ester
7b (1:1.1), as is consistent with our previous observations. α-
Cyclopropyl substrate 7c proved to be more resistant to E-
enolization, with a modest diastereoselectivity of 1:1.1 favoring
the E-enolate-derived product obtained when the rearrange-
ment was performed using LDA as the base. These results
seem to suggest that while Z-selective enolization and
rearrangement is highly predictable and selective with
KN(SiMe3)2, E-selective enolization for α-alkoxy esters is
very sensitive to the structure of the alkyl side chains. In
addition, greater selectivity is generally observed for larger
alkoxy substituents (for example, for OBn versus OMe).
In conclusion, we have conducted a detailed investigation
into the Ireland−Claisen rearrangement of α-alkoxy esters.
Excellent chelation-controlled selectivity (dr >10:1 in all cases)
was observed when the reaction was performed using
To gain insight into the structural constraints required to
achieve selective E-enolization with LDA, we performed
additional experiments, as summarized in Table 3. The
optimized conditions for the rearrangement were applied to
α-alkoxy butyric acid esters 7a and 7b. Remarkably, this simple
C
DOI: 10.1021/acs.orglett.8b02011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Table 3. Additional Substrate Scope
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zakarian@chem.ucsb.edu
ORCID
Armen Zakarian: 0000-0002-9120-1232
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSF (No. CHE 1463819). Dr.
Hongjun Zhou (UCSB) is acknowledged for assistance with
NMR spectroscopy. Dr. Dmitriy Uchenik and the UCSB mass
spectroscopy facility are thanked for assistance with mass-
spectroscopic analysis. We also thank Dr. Guang Wu (UCSB)
for assistance with X-ray crystallography.
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ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02011.
1
Detailed experimental procedures, H and 13C NMR
spectra of all new compounds and HPLC trace analysis
of enantioenriched compounds (PDF)
Accession Codes
CCDC 1853280 and 1853281 contain the supplementary
crystallographic data for this paper. These data can be obtained
D
DOI: 10.1021/acs.orglett.8b02011
Org. Lett. XXXX, XXX, XXX−XXX