Diastereoselective conjugate addition/cyclization/bromination: Access to four stereocenters in a single step

Article abstract of DOI:10.1016/j.tetlet.2018.03.080

A stereoselective tandem conjugate addition reaction with a chiral amine-derived nucleophile is reported in which the enolate intermediate is quenched with 1,2-dibromotetrachloroethane as a mild brominating reagent. X-ray analysis of a subsequent derivative was used to prove the configuration at each of the four newly formed stereocenters. The resulting α-bromoester underwent selective transesterification catalyzed by mild base to allow selective manipulation of the two ester groups of the product.

Full text of DOI:10.1016/j.tetlet.2018.03.080

Accepted Manuscript
Diastereoselective Conjugate Addition/Cyclization/Bromination: Access to
Four Stereocenters in a Single Step
Junzhuo Liao, Dale G. Drueckhammer
PII:
S0040-4039(18)30407-6
https://doi.org/10.1016/j.tetlet.2018.03.080
TETL 49849
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 January 2018
23 March 2018
26 March 2018
Please cite this article as: Liao, J., Drueckhammer, D.G., Diastereoselective Conjugate Addition/Cyclization/
Bromination: Access to Four Stereocenters in a Single Step, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.03.080
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Diastereoselective Conjugate Addition/Cyclization/Bromination: Access to Four
Stereocenters in a Single Step
Junzhuo Liao and Dale G. Drueckhammer*
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
Abstract
A stereoselective tandem conjugate addition reaction with a chiral amine-derived nucleophile is
reported in which the enolate intermediate is quenched with 1,2-dibromotetrachloroethane as a
mild brominating reagent. X-ray analysis of a subsequent derivative was used to prove the
configuration at each of the four newly formed stereocenters. The resulting -bromoester
underwent selective transesterification catalyzed by mild base to allow selective manipulation of
the two ester groups of the product.
*Corresponding author.
email address: dale.drueckhammer@stonybrook.edu.
Keywords: Asymmetric synthesis; Conjugate addition; Electrophilic bromination
Introduction
The asymmetric conjugate addition of the –methylbenzylamine-derived lithium amide 1 to a
range of -unsaturated esters has been widely used in the synthesis of -aminoacid
derivatives.1 Tandem asymmetric conjugate addition/cyclization of a bis--unsaturated ester 2
initiated by 1 has been demonstrated for the synthesis of trisubstituted cyclopentane,
cyclohexane, and piperidine derivatives 3 (Scheme 1).2-6 The ready availability of both
enantiomers of the chiral amine nucleophile allows access to either enantiomer of the product. In
related work but using a chiral bornylamine-derived nucleophile 4, the enolate from the
cyclization step was trapped with an aldehyde electrophile to generate products 6 having two
additional stereocenters (Scheme 2).7 The enolate has been similarly trapped with a second
Michael acceptor, with reaction occurring from the same face of the enolate as in the aldol
trapping.8 In simple conjugate additions to reactants having only one -unsaturated ester
group, the enolate has also been trapped with alkylating agents or with an oxaziridine to
introduce a hydroxyl group.9-10 This chemistry has been applied to the construction of cyclic -
amino acid motifs and other synthetic targets.3, 6, 11 In the course of a molecular design project in
this lab, we desired products related to 3 but with a heteroatom substituent (Y ≠ H) at the

Scheme 1. Asymmetric Conjugate Addition/Cyclization Method of Davies et al.
Scheme 2. Conjugate Addition/Cyclization/Aldol Method of Ozeki et al.
position of the cyclization-derived enolate. We report here the diastereoselective trapping of the
enolate from conjugate addition/cyclization with a brominating agent and subsequent
transformations and structural analysis of the resulting product.
Results and Discussion
The reactant 7 was prepared by bis-alkylation of 2-methoxyethylamine with the known benzyl-4-
bromocrotonate12-13 following procedures for the synthesis of related structures.3 Reaction with
the –methylbenzylamine-derived lithium amide 1 followed by mild acid quench gave a product
3 (Scheme 1). Efforts were then made to replace the acid quench with a source of electrophilic
bromine. Initial attempts using N-bromosuccinimide were unsuccessful, giving a mixture of
products. 1,2-dibromotetrachloroethane has been reported as a reagent for the bromination of an
organocuprate14 and for -bromination of ketones via an enolate intermediate.15-16 Trapping of
the enolate 8 with this reagent gave the desired brominated product 9, with the major isomer
isolated in 79% yield (scheme 3). If bromination occurs from the same relative face as in the
trapping with an aldehyde (scheme 2)7 or Michael acceptor,8 the major product should have the
stereochemistry shown in 9. The product 9 showed substantial decomposition within 24 h at
room temp but was stable for weeks at -20 °C. Reaction of 9 with sodium azide gave the azide
product 10, which was sufficiently stable for further manipulation and analysis.

Scheme 3. Conjugate Addition/Cyclization/Bromination and Conversion to a Crystalline
Derivative.
Applying HCl gas to a solution of 10 in ether formed the hydrochloride salt 11 as a solid. 11 was
recrystallized from acetonitrile, and a single crystal was selected for analysis. The structure of 11
was obtained via single crystal diffraction. The structure confirmed the expected stereochemistry
(Figure 1), with stereocenters formed in the conjugate addition and cyclization having the
Fig. 1. X-ray crystal structure of 11.

configuration observed in previous studies and the azide bearing carbon having the R
configuration, consistent with the assigned S configuration in the initial brominated product 9.
Synthetic targets in this lab require selective manipulation of the two benzyl ester groups.
Treatment of the brominated product 9 with sodium carbonate in methanol at 0 °C resulted in
selective transesterification of one of the two benzyl esters to form a single benzyl/methyl ester
product (scheme 4).17 The selectivity is attributed to greater reactivity of the -bromoester due to
the inductive effect of bromine to give the product 12 shown, though this is also consistent with
selectivity observed in hydrolysis of a pent-3-yl diester of the acid quench product 3 with
LiOH.18 Under the given conditions, no epimerization was detected in the formation of 12 as
1
indicated by a single isomer in the H-NMR spectrum. Reaction of 12 with sodium azide gave
the azide product 13, which was subsequently reduced to the amine 14. Any of a number of
methods for cleavage of benzyl esters may permit subsequent selective deprotection of the
benzyl ester.19
Scheme 4. Selective Transesterification and Subsequent Transformation to an Amine.
Further experiments were conducted to support the assigned regioselectivity in the
transesterification step. The nonbrominated product 3 (scheme 1, Y=H) resulting from mild acid
quench of the enolate intermediate 8 was subjected to the precise conditions of the
transesterification step in forming 12. No reaction was observed, indicating that the inductive
effect of the bromine is necessary for transesterification under these mildly basic conditions and
supporting the assigned regioselectivity. When the mixed methyl/benzyl ester 15 was subjected
to the cyclization-bromination conditions, it resulted in an approximately 1:1 mixture of 12 and
the apparent isomer resulting from initial addition to the -carbon of the methyl ester rather than
the benzyl ester (scheme 5). This was as expected, though 3:1 selectivity for conjugate addition

Scheme 5. Conjugate Addition/Cyclization/Bromination of a Mixed Methyl Benzyl Diester.
to the methyl ester of a mixed methyl, t-butyl ester as well as selective conjugate addition to the
ester of a mixed ester/acid have been observed, where 2D NMR experiments were used for
structural assignment of the resulting isomers.20-21 The two products could not be separated but
1
gave two distinct sets of peaks in the H-NMR spectrum of the mixture. One set of peaks was
identical to those of the product 12 of the transesterification reaction in scheme 4, while the
peaks assigned to the isomer were not detected in the transesterification product of 9. This
further supports the formation of the single product 12 in the transesterification reaction.
Efforts are currently underway to use the product 12 from the cyclization/bromination and
transesterification sequence in the synthesis of more advanced molecular design targets.
Conclusion
Using a cascade reaction of a tandem conjugate addition/cyclization reaction followed by an in
situ bromination, four stereogenic centers were successfully generated in one step. The resulting
–bromoester had a much higher reactivity than the non-brominated ester, enabling selective
ester manipulation in the cyclized product.
Acknowledgements
This work was supported by National Science Foundation grant 0848334. We thank Dr. Jue Liu
and Prof. Joseph Lauher (Stony Brook University) for assistance in solving the structure of 11.
Supplementary data
Supplementary data (synthetic procedures, compound characterization data, and NMR spectra)
associated with this article can be found, in the online version. Crystallographic data (excluding
structure factors) for compound 11 has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 1580971. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
(0)1223-336033 or e-mail:deposit@ccdc.cam.ac.Uk).
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An enolate was quenched stereoselectively with a bromine source.
A highly functionalized piperidine was prepared with four stereocenters.
The structure and stereochemistry was proven by x-ray analysis.
One of two ester groups of the product was modified selectively.