Parallel kinetic resolution of acyclic γ-amino-α,β- unsaturated esters: Application to the asymmetric synthesis of 4-aminopyrrolidin-2-ones

Article abstract of DOI:10.1021/ol203011u

Conjugate addition of a 50:50 pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and lithium (S)-N-3,4- dimethoxybenzyl-N-(α-methylbenzyl)amide to a range of racemic acyclic γ-amino-α,β-unsaturated esters (derived from the corresponding α-amino acids) effects their efficient parallel kinetic resolution, allowing the preparation of enantiopure β,γ-diamino esters. The β,γ-diamino ester products of these reactions are readily converted into the corresponding substituted 4-aminopyrrolidin-2-ones via N-debenzylation and cyclization.

Full text of DOI:10.1021/ol203011u

ORGANIC
LETTERS
2012
Vol. 14, No. 1
218–221
Parallel Kinetic Resolution of Acyclic
γ-Amino-r,β-unsaturated Esters:
Application to the Asymmetric Synthesis
of 4-Aminopyrrolidin-2-ones
Stephen G. Davies,* James A. Lee, Paul M. Roberts, James E. Thomson, and
Jingda Yin
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steve.davies@chem.ox.ac.uk
Received November 8, 2011
ABSTRACT
Conjugate addition of a 50:50 pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(R-methylbenzyl)amide and lithium (S)-N-3,4-dimeth-
oxybenzyl-N-(R-methylbenzyl)amide to a range of racemic acyclic γ-amino-R,β-unsaturated esters (derived from the corresponding
R-amino acids) effects their efficient parallel kinetic resolution, allowing the preparation of enantiopure β,γ-diamino esters. The β,γ-diamino
ester products of these reactions are readily converted into the corresponding substituted 4-aminopyrrolidin-2-ones via N-debenzylation and
cyclization.
Kinetic resolution is a venerable concept within organic
chemistry. It was first observed by Marckwald and
McKenzie in 1899, during the esterification of racemic
mandelic acid with (ꢀ)-menthol.1 Such is the importance
of kinetic resolution that over 100 years later it, together
with dynamic kinetic resolution (DKR)2 and parallel
kinetic resolution (PKR),3 is employed widely in the pre-
paration of enantiomerically pure materials on both lab-
oratory and industrial scales. We have previously devel-
oped the PKR of a range of chiral 3- and 5-substituted
cyclopent-1-enecarboxylates, and 6-substituted cyclohex-
1-enecarboxylates using a 50:50 pseudoenantiomeric mix-
tureof enantiopurelithium amides.4 This protocol has thus
far been limited to these cyclic R,β-unsaturated esters due to
the requirement for high levels of substrate control. In this
manuscript we report the efficient PKR of racemic acyclic
N-protected γ-amino-R,β-unsaturatedesters(whichexhibit
very high levels of substrate control) using a 50:50 pseu-
doenantiomeric mixture of lithium (R)-N-benzyl-N-(R-me-
thylbenzyl)amide and lithium (S)-N-3,4-dimethoxy-
benzyl-N-(R-methylbenzyl)amide. The enantiopure
(1) Marckwald, W.; McKenzie, A. Ber. Dtsch. Chem. Ges. 1899, 32,
2130.
(2) Pellissier, H. Tetrahedron 2003, 59, 8291. Pellissier, H. Tetrahe-
dron 2008, 64, 1563.
(3) Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885. Dehli, J. R.;
Gotor, V. Chem. Soc. Rev. 2002, 31, 365.
(4) Davies, S. G.; Dıez, D.; El Hammouni, M. M.; Garner, A. C.;
Garrido, N. M.; Long, M. J. C.; Morrison, R. M.; Smith, A. D.; Sweet,
M. J.; Withey, J. M. Chem. Commun. 2003, 2410. Davies, S. G.; Garner,
A. C.; Long, M. J. C.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org.
Biomol. Chem. 2004, 2, 3355. Davies, S. G.; Garner, A. C.; Long,
M. J. C.; Morrison, R. M.; Roberts, P. M.; Savory, E. D.; Smith,
A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2005, 3, 2762.
Aye, Y.; Davies, S. G.; Garner, A. C.; Roberts, P. M.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195. Abraham, E.; Davies,
S. G.; Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 1356.
Davies, S. G.; Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts,
P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Toms, S. M.
Tetrahedron: Asymmetry 2008, 19, 2870.
r
10.1021/ol203011u
Published on Web 12/07/2011
2011 American Chemical Society

β,γ-diamino ester products of these reactions are valuable
building blocks for further elaboration, as demonstrated by
their facile conversion to the corresponding substituted 4-
aminopyrrolidin-2-ones.
potential of racemic γ-amino-R,β-unsaturated esters (()-
22ꢀ28 as substrates for our PKR protocol.
Addition of 1.6 equiv of lithium amide 29 to (()-22ꢀ26
resulted in >95% conversion to the corresponding
β,γ-diamino esters (()-32ꢀ36 (g88:12 dr in all cases), indicat-
inghigh levels of substrate control. Chromatographic puri-
fication allowed isolation of β,γ-diamino esters (()-32ꢀ36
in 60ꢀ86% yield and in g97:3 dr (Scheme 2). The relative 3,4-
syn-configuration within (()-34 (R = Bn) was unambigu-
ously established by single crystal X-ray diffraction anal-
ysis of the corresponding hydrochloride salt (()-34•HCl.
The relative 3,4-syn-configurations within (()-32, (()-33,
(()-35, and (()-36 were assigned by analogy.7 Mean-
while, (()-28 proved recalcitrant to addition of lithium
amide 29, even over extended reaction times and when the
amount of lithium amide was increased from 1.6 to 10
equiv. Addition to (()-27 proceeded with low levels of
substrate control to give a 27:73 mixture of 3,4-syn-
37:3,4-anti-43, which were isolated in 15 and 48% yield
as single diastereoisomers (>99:1 dr). The relative 3,4-
anti-configuration within 43 was unambiguously estab-
lished by single crystal X-ray diffraction analysis, which
therefore allowed the relative 3,4-syn-configuration with-
in 37 to be assigned unambiguously (Scheme 2).
A range of racemic acyclic N-protected γ-amino-
R,β-unsaturated esters was prepared from the correspond-
ing racemic R-amino acids (()-1ꢀ7 using a modification of
the procedure reported by Reetz and co-workers.5 Ex-
haustive benzylation of (()-1ꢀ7 was achieved upon treat-
ment with BnBr in boiling aq K2CO3 to give (()-8ꢀ14 and
was followed by reduction with LiAlH4 to give the corre-
sponding N,N-dibenzyl protected R-amino alcohols (()-
15ꢀ21. Swern oxidation of R-amino alcohols (()-15ꢀ21
and olefination of the resultant aldehydes then gave the
desired R,β-unsaturated esters (()-22ꢀ28 in 18ꢀ57%
overall yield (Scheme 1).
Scheme 1
Scheme 2
a Yield over 4 steps.
When investigating PKR,4 we have promulgated that
it is prudent to follow a strategy of first investigating
the levels of substrate control offered by the chiral R,β-
unsaturated ester upon conjugate addition of an achiral
lithium amide, viz. lithium N-benzyl-N-isopropylamide 29.
The levels of enantiorecognition between the chiral R,β-
unsaturated ester (substrate) and lithium N-benzyl-N-(R-
methylbenzyl)amide 30 (chiral reagent) are then eva-
luated by investigation of their mutual kinetic resolution
(MKR), i.e., addition of racemic lithium amide (()-30 to
racemic R,β-unsaturated ester. This approach eliminates
any complicating effects of mass action and allows the
maximum levelsofenantiodiscrimination (asquantifiedby
the factor, E)6 to be very simply determined by analysis of
the product distribution by 1H NMR spectroscopy. Final-
ly, having identified those substrates that undergo efficient
MKR upon addition of racemic lithium amide (()-30,
their PKR employing a 50:50 pseudoenantiomeric mix-
ture of enantiopure lithium N-benzyl-N-(R-methylbenzyl)
amide 30 and enantiopure lithium N-3,4-dimethoxy-
benzyl-N-(R-methylbenzyl)amide 31 may be performed.
We therefore adopted this approach to investigate the
a 17% of a 68:32 mixture of 36:42 was also isolated.
Previous investigations concerning conjugate addition
of a range of nucleophiles to R,β-unsaturated carbonyl
compounds with a stereocenter at the γ-position often
invoke a modified FelkinꢀAnh model to rationalize the
(7) Comparison with the substrate control elicited in the MKR of
(()-22ꢀ26 with lithium amide (()-30, as well as in the PKR of (()-22ꢀ26
with lithium amides (R)-30 and (S)-31, allows these configurational
assignments to be made confidently. In addition, the relative configura-
tions within β,γ-diamino esters (()-36 and (()-42 [and (3S,4R,RR)-48]
were subsequently unambiguously established by single crystal X-ray
diffraction analysis of a cyclic derivative; see the Supporting Informa-
tion for full experimental details.
€
(5) Reetz, M. T.; Rohrig, D. Angew. Chem., Int. Ed. Engl. 1989, 28,
1706.
(8) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H.
J. Am. Chem. Soc. 1992, 114, 7652. Kireev, A. S.; Manpadi, M.;
Kornienko, A. J. Org. Chem. 2006, 71, 2630.
(6) Horeau, A. Tetrahedron 1975, 31, 1307.
Org. Lett., Vol. 14, No. 1, 2012
219

observed diastereoselectivity.8 However, one other sim-
plistic model (not dissimilar to a FelkinꢀAnh model)
which is able to rationalize successfully the experimental
data in this case uses insight obtained from single crystal
X-ray diffraction analysis of R,β-unsaturated ester (()-22.
This revealed a solid state conformation in which the C(4)-
hydrogen atom lies almost perpendicular to the plane
of the R,β-unsaturated system, with the bulky C(4)-
N,N-dibenzylamino substituent occupying the less hindered
“outside” position and the C(4)-methyl group in the more
hindered “inside” position (Figure 1). Conjugate addition
of lithium amide 29 to (()-22 in this conformation would
be predicted to occur on the least hindered face past the
“small” hydrogen substituent to give (()-3,4-syn-32, as
observed experimentally. A similar analysis applied to
R,β-unsaturated esters (()-23ꢀ26 (R=Et,Bn,iBu, CH2OBn)
would also successfully rationalize the observed substrate
diastereofacial control, leading to (()-3,4-syn-33ꢀ36.
However, increased steric bulk of the C(4)-substituents in
R,β-unsaturated esters (()-27 and (()-28 would serve to
disfavor analogous conformations, thereby providing a
rationale for their differing behavior. Presumably, the very
large steric congestion around C(4) in the case of (()-28
(R = iPr) precludes addition of the sterically demanding
lithium amide to C(3) completely.
Scheme 3
a 70% of a sample of 46 in 95:5 dr was also isolated.
(()-47 [and, hence, (()-44, (()-46, and (()-48] are in
accordance with that predicted by the transition state
mnemonic developed by us to rationalize the exceptional
facial bias of this class of lithium amide.9 This reagent
control, when combined with that of the R,β-unsaturated
ester (substrate control: production of the 3,4-syn-diaster-
eoisomer favored), results in very highly selective reac-
tions. These results suggest that R,β-unsaturated esters
(()-22ꢀ26 are viable substrates for our PKR protocol4
(Scheme 3).
The PKR of R,β-unsaturated esters (()-22ꢀ26 using a
50:50 pseudoenantiomeric mixture of lithium amides (R)-
30 (2 equiv) and (S)-31 (2 equiv) was next investigated.
These reactions produced, in each case, a 50:50 mixture of
thecorresponding (RR)-adducts44ꢀ48in g95:5drand the
(RS)-adducts 49ꢀ53 in g95:5 dr. Facile separation and
purification via flash column chromatography allowed
isolation of (RR)-44ꢀ48 in >99:1 dr and 31ꢀ42% yield
and (RS)-49ꢀ53 in >99:1 dr and 40ꢀ43% yield. In each
case, the product of addition of lithium amide (R)-30 was
spectroscopically identical to the major diastereoisomer
formed in the corresponding MKR reaction. Additionally,
the relative configuration within β,γ-diamino ester 49 was
unambiguously established via single crystal X-ray diffrac-
tion analysis, with the absolute (3R,4R,RS)-configuration
being assigned from the known (S)-configuration of the
R-methylbenzyl stereocenter. Given the pseudoenantiomeric
nature of lithium amides (R)-30 and (S)-31, this analysis
Figure 1. Chem 3D representation of the single crystal X-ray
diffraction structure of (()-22 [(S)-enantiomer depicted; se-
lected H atoms are omitted for clarity], and Newman projection
along the C(3)ꢀC(4) bond.
The extent of enantiorecognition between R,β-unsatu-
rated esters (()-22ꢀ26 (which offered high levels of sub-
strate control) and lithium amide (()-30 was next in-
vestigated, with high levels of enantiorecognition being
expected. Indeed, addition of 1.6 equiv of lithium amide
(()-30 to (()-22ꢀ26 gave, in each case, essentially a single
diastereoisomeric product 44ꢀ48 in g95:5 dr, indicating
very high levels of enantiorecognition between substrate
and reagent, and consistent with E g196 in each case.
Purification facilitated isolation of diastereoisomeric-
ally pure (>99:1 dr) samples of (()-44ꢀ48. The relative
(3RS,4RS,RSR)-configurations within (()-45 and (()-47
were unambiguously established by single crystal X-ray
diffraction analyses, and therefore the relative configura-
tions within (()-44, (()-46, and (()-48 were assigned by
analogy. It is notable that the relative configurations of the
C(3)- and C(R)-stereogenic centers within both (()-45 and
(9) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asym-
metry 1994, 5, 1999. For a review, see: Davies, S. G.; Smith, A. D.; Price,
P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
ꢀ
(10) Hoang, C. T.; Bouillere, F.; Johannesen, S.; Zulauf, A.; Panel,
ꢀ
C.; Pouilhes, A.; Gori, D.; Alezra, V.; Kouklovsky, C. J. Org. Chem.
2009, 74, 4177.
(11) In the case of β,γ-diamino ester 48, the yield of the corresponding
4-aminopyrrolidin-2-one 68 (60% isolated yield) was somewhat com-
promised by the formation of methyl (3S,4R)-3,4-diacetamido-5-hydro-
xypentanoate 69 (25% isolated yield). This presumably arises from
competing lactone formation (rather than lactam formation) from 58
under the reaction conditions, followed by methanolysis upon workup
of the acetylation procedure.
220
Org. Lett., Vol. 14, No. 1, 2012

Scheme 4
Scheme 5
a Yield over 3 steps. bFor 48, R0 = Bn; for 58 and 63, R0 = H; for 68,
R0 =Ac.
configurations of the precursor β,γ-diamino esters 44ꢀ48;
1H NMR NOE analyses of 64ꢀ68 were also supportive of
a relative 4,5-syn-configuration (Scheme 5).
In conclusion, conjugate addition of a 50:50 pseudoe-
nantiomeric mixture of lithium (R)-N-benzyl-N-(R-meth-
ylbenzyl)amide and lithium (S)-N-3,4-dimethoxybenzyl-
N-(R-methylbenzyl)amide to a range of racemic acyclic
γ-amino-R,β-unsaturated esters (derived from the corre-
sponding R-amino acids) effects their efficient parallel
kinetic resolution, allowing the preparation of enantiopure
β,γ-diamino esters. The β,γ-diamino ester products of
these reactions are readily converted into the correspond-
ing substituted 4-aminopyrrolidin-2-ones via N-deben-
zylation and cyclization. Further applications of this
methodology are currently under investigation within
our laboratory.
also allows the assigned relative (3RS,4RS,RSR)-config-
uration within racemic 44 to be unambiguously confirmed,
with the absolute (3S,4S,RR)-configuration within enan-
tiopure 44 following from the known (R)-configuration of
the R-methylbenzyl stereocenter. By similar reasoning,
given the known relative configurations within racemic
45 and 47, the absolute (3S,4S,RR)-configurations with-
in enantiopure 45 and 47 may be assigned from the known
(R)-configuration of the R-methylbenzyl stereocenter.
Hence, the absolute (3R,4R,RS)-configurations within
50 and 52 can be unambiguously assigned. The absolute
(3R,4R,RS)-configurations within 51 and 53 were assigned
by analogy (Scheme 4).
Acknowledgment. The authors would like to thank the
EPSRC and SCI-Ink for a Dorothy Hodgkin Postgradu-
ate Award (J.Y.).
With a range of enantiopure β,γ-diamino esters in hand,
their synthetic utility was demonstrated by elaboration of
44ꢀ48 to the corresponding 5-substituted 4-aminopyrro-
lidin-2-ones. Hydrogenolytic N-debenzylation of 44ꢀ48
was followed by acid-promoted cyclization10 to the corre-
sponding 4-aminopyrrolidin-2-ones 59ꢀ63, which were
isolated as their acetate derivatives 64ꢀ68 in 60ꢀ78%
yield over three steps.11 The absolute configurations
within 64ꢀ68 were assigned from the known absolute
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C NMR
spectra, and crystallographic information files (for struc-
tures CCDC 852571ꢀ852577). This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
221