Double asymmetric induction as a mechanistic probe: Conjugate addition for the asymmetric synthesis of a pseudotripeptide

Article abstract of DOI:10.1039/b401293c

Double asymmetric induction as a mechanistic probe indicates that, for the conjugate addition of (R)- and (S)-lithium N-benzyl-N-α-methylbenzylamide to (S)-3′-phenylprop-2′-enoyl-4-benzyloxazolidinone, the reactive conformation of the N-acyl oxazolidinone is the anti-s-cis form, facilitating the asymmetric synthesis of a pseudotripeptide.

Full text of DOI:10.1039/b401293c

Double asymmetric induction as a mechanistic probe: conjugate addition
for the asymmetric synthesis of a pseudotripeptide
Stephen G. Davies,* Gesine J. Hermann, Miles J. Sweet and Andrew D. Smith
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford,
UK OX1 3TA. E-mail: steve.davies@chemistry.ox.ac.uk
Received (in Cambridge, UK) 27th January 2004, Accepted 10th March 2004
First published as an Advance Article on the web 8th April 2004
Double asymmetric induction as a mechanistic probe indicates
that, for the conjugate addition of (R)- and (S)-lithium N-
benzyl-N-a-methylbenzylamide to (S)-3A-phenylprop-2A-enoyl-
4-benzyloxazolidinone, the reactive conformation of the N-acyl
oxazolidinone is the anti-s-cis form, facilitating the asymmetric
synthesis of a pseudotripeptide.
Scheme 1 Reagents and conditions: (i) Lithium dibenzylamide (1.6 eq),
The conjugate addition of nucleophiles to a,b-unsaturated carbonyl
THF, 278 °C; (ii) LiOH, H2O2, THF : H2O (3 : 1), 0 °C to rt; (iii) MeOH
: H2O : AcOH (40 : 4 : 1), Pd(OH)2 on C, H2 (1 atm); (iv) 1 M HCl then
compounds plays a fundamental role in the stereoselective
formation of b-functionalised carbonyl components. Stereochem-
ical control in these reactions is typically achieved by the use of
chiral auxiliaries,1 or chiral catalysts,2 with the diastereoselective
conjugate addition of nucleophiles to N-enoyl derivatives of
oxazolidinones being used extensively.3 In these reactions, it is
possible for an (E)-a,b-unsaturated oxazolidinone component to
undergo diastereoselective 1,4-addition via any of the four possible
syn- or anti-, and s-cis or s-trans conformations 1–4 (Fig. 1).4 An
intriguing mechanistic dichotomy exists, since the same face
selectivity on either the syn-s-cis or the anti-s-trans conformations
leads to the same stereochemical result, as with the syn-s-trans or
the anti-s-cis pair. In these systems, it has been proposed that the
diastereoselective conjugate addition of organocuprates occurs via
the Lewis acid chelated syn-s-cis conformation,5 with the diaster-
eoselectivity postulated to reflect the populations of the reactive
conformers of these substrates.6,7 As lithium amides are widely
recognised to add in a conjugate fashion to (E)-a,b-unsaturated
acceptors in the s-cis conformation,8 the reaction of lithium amides
and N-enoyl oxazolidinones may be used as a mechanistic probe;
we communicate herein a novel strategy employing double
asymmetric induction to determine the reactive conformation of the
oxazolidinone in this manifold.
Dowex 50W-8 ion exchange chromatography.
oxazolidinone,5 the low diastereoselectivity observed in this
protocol is compatible with a number of mechanistic scenarios.
Addition of lithium dibenzylamide may occur (i) with high facial
selectivity to an unequilibrating 79 : 21 mixture of anti-s-cis to syn-
s-cis conformers of (S)-5; (ii) with moderate (79 : 21) facial
selectivity via exclusive addition to the anti-s-cis conformation of
(S)-5; (iii) to a 58 : 42 mixure of anti- to syn-s-cis conformers, with
complete facial selectivity for addition to the anti-s-cis conformer
but with zero selectivity to the syn-s-cis conformer; (iv) to a rapidly
equilibrating mixture of anti-s-cis to syn-s-cis conformers with
unknown facial control. To distinguish between these alternate
reaction manifolds, the conjugate additions of lithium (R)- and (S)-
N-benzyl-N-a-methylbenzylamide 8 to (S)-5 were deployed, as the
observation of double asymmetric induction, combined with the
sense of the matched and mismatched pairings, should determine
the reactive conformation of the acceptor. Conjugate addition of
lithium amide (R)-8 to acceptor (S)-5 gave an inseparable mixture
of diastereoisomers with low diastereoselectivity (66% d.e.),11
furnishing (4S,3AS,aR)-9 in 83% isolated yield and 66% d.e. after
chromatographic purification. However, conjugate addition of
lithium amide (S)-8 to (S)-5 gave (4S,3AR,aS)-10 in > 98% d.e.11
and in 84% isolated yield after crystallisation from the crude
reaction mixture (Fig. 2). The (4S,3AS,aR)- and (4S,3AR,aS)-
configurations within 9 and 10 from the mismatched and matched
reactions respectively were confirmed unambiguously by a sepa-
rate chemical synthesis in each case, with the sense of asymmetric
induction consistent with the stereocontrol of the chiral lithium
amide, not the oxazolidinone, dominating the reaction selectivity.12
Conjugate additions of lithium amides (R)-8 and (S)-8 in the
presence of chelating components such as LiBr, MeMgBr, Ti(Oi-
Given the known preference for lithium amides to react with (E)-
a,b-unsaturated acceptors exclusively in the s-cis conformation,8
conjugate addition to an (E)-N-enoyl oxazolidinone may occur only
via either the syn- or anti-s-cis conformations 1 and 2 respectively.9
Addition of lithium dibenzylamide to (S)-N-3A-phenylprop-2A-
enoyl-4-benzyloxazolidinone 5 furnished a 79 : 21 mixture of
diastereoisomers (58% d.e.) in 91% combined yield, with purifica-
tion of the major diastereoisomer (4S,3AR)-6 by fractional crystal-
lisation facilitating its isolation in 53% yield and > 98% d.e. The
configuration at C(3A) within b-amino ester (4S,3AR)-6 was
confirmed by deprotection via hydrolysis and hydrogenolysis,
22
giving (R)-b-phenylalanine 7 {[a]D +6.2 (c 0.6, H2O), lit.10
19
[a]D +6.5 (c 1.0, H2O)} after purification by ion exchange
chromatography (Scheme 1).
On the reasonable assumption that addition of lithium dibenzyla-
mide occurs anti to the benzyl stereodirecting group of the
Fig. 1 Possible conformations of (E)-N-enoyl oxazolidinones for conjugate
Fig. 2 Model to rationalise the observed matched and mismatched double
addition.
asymmetric induction.
1128
C h e m . C o m m u n . , 2 0 0 4 , 1 1 2 8 – 1 1 2 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Pr)3Cl and Zn(OTf)2, in which the carbonyl groups of the N-enoyl
oxazolidinone may be expected to be held in the syn conformation,5
were next investigated. Upon addition of lithium amides (R)-8 and
(S)-8 to (S)-5 in the presence of these additives, the observed level
of diastereoselectivity remained unchanged (66% d.e. and > 98%
d.e. respectively), although 70–90% of the starting material was
recovered, even upon extended reaction times.
potential of this methodology for the efficient asymmetric synthesis
of a novel a- and b-amino acid containing pseudotripeptide has
been demonstrated. By systematic variation of the a-amino acid
components and b-substitution of the a,b-unsaturated acceptor, this
methodology should allow access to a vast number of unnatural
oligomers with bespoke substitution patterns on the peptide
backbone. Further application of double asymmetric induction as a
mechanistic tool, and the application of this methodology for the
synthesis of a range of pseudopeptides is currently underway in our
laboratory.
The observation of matched and mismatched double asymmetric
induction in these reactions rules out the reaction proceeding under
Curtin–Hammett control {scenario (iv)}, as in this mechanistic
scheme conjugate addition of both (R)-8 and (S)-8 to syn-s-cis and
anti-s-cis (S)-5 respectively would be matched, and proceed with
equal and high diastereocontrol. If the reaction proceeds under
hypothesis (i), a mixture of matched {(R), syn and (S), anti} and
mismatched {(S), syn and (R), anti} reactions would be observed,
so in neither case would a high d.e. be expected. For case (iii),
assuming the addition of a Lewis acid alters the ratio of syn : anti
conformers, a change in the level of diastereoselectivity upon
addition of both lithium amides (R)-8 and (S)-8 would be observed.
In this way, the observed results can only be consistent with
scenario (ii). In the matched case, addition of lithium amide (S)-8 to
acceptor 5 in the anti-s-cis conformation results in the preferential
formation of (4S,3AR,aS)-10 with high diastereoselectivity. In the
mismatched case, addition of lithium amide (R)-8 to acceptor 5 in
the anti-s-cis conformation results in the preferential formation of
(4S,3AS,aR)-9 with reduced levels of diastereoselectivity (Fig. 2).
Furthermore, the lower conversions but unchanged stereoselectiv-
ities upon addition of (R)-8 and (S)-8 to (S)-5 in the presence of
Lewis acids is consistent with the syn-s-cis conformation being
unreactive.
The authors wish to thank the EPSRC, the Rhodes Trust (M. J.
S.) and New College, Oxford for a Junior Research Fellowship (A.
D. S.) for funding.
Notes and references
1 For a review see B. E. Rossiter and N. M. Swingle, Chem. Rev., 1992,
92, 771; for other examples see T. Mukaiyama and N. Iwasawa, Chem.
Lett., 1981, 913; M. Bergdahl, M. Nilsson and T. Olsson, J. Organomet.
Chem., 1990, 391, c19; M. Bergdahl, T. Iliefski, M. Nilsson and T.
Olsson, Tetrahedron Lett., 1995, 36, 3227; S. Kanemasa, H. Suenaga
and K. Onimura, J. Org. Chem., 1994, 59, 6949.
2 M. P. Sibi and J. Ji, J. Am. Chem. Soc., 1996, 118, 9200; J. Kang, J. H.
Lee and D. S. Lim, Tetrahedron: Asymmetry, 2003, 14, 305; D. A.
Evans, M. C. Willis and J. N. Johnston, Org. Lett., 1999, 1, 865; M.
Kanai, Y. Nakagawa and K. Tomioka, Tetrahedron, 1999, 55, 3843.
3 For example see P. Wipf and H. Takahashi, Chem. Commun., 1996,
2675; M. P. Sibi, C. P. Jasperse and J. Ji, J. Am. Chem. Soc., 1995, 117,
10779; C. Schneider and O. Reese, Synthesis, 2000, 1689; D. R.
Williams, W. S. Kissel, J. J. Li and R. J. Mullins, Tetrahedron Lett.,
2002, 43, 3723.
The synthetic utility of this double asymmetric induction
protocol was then demonstrated. Although homo-oligomers of both
a- and b-amino acid derivatives are known to show secondary
structural characteristics, we are interested in the preparation and
structural characterisation of ‘mixed’ oligomers containing both a-
and b-amino acids.13 b-Amino ester (4S,3AS,aR)-10 was envisaged
as part of a novel asymmetric approach towards the preparation of
a pseudotripeptide derived from a- and b-amino acids. In this
strategy, the protected functionality within the oxazolidinone chiral
auxiliary was to be unmasked as a latent a-amino acid via
endocyclic cleavage of the auxiliary, a process that typically
predominates under standard hydrolysis conditions with either
bulky a-substituted or b-heteroatom derivatives of oxazolidi-
nones.14,15 Hydrogenolysis of tertiary b-amino ester 10 to the
primary amine and subsequent coupling with N-Boc-Phe gave
pseudopeptide 11, which gave alcohol 12 upon treatment with
LiOH. Oxidation of 12 to the acid with Jones reagent followed by
N-Boc deprotection furnished the pseudopeptide a,b,a-tri(phenyl-
alanine) 13 (Scheme 2).
4 C. Börner, W. A. König and S. Woodward, Tetrahedron Lett., 2001, 42,
327.
5 E. Nicholas, K. C. Russell and V. J. Hruby, J. Org. Chem., 1993, 58,
766; B-S. Lou, G. Li, F-D. Lung and V. J. Hruby, J. Org. Chem., 1995,
60, 5509. For NMR investigations of the conformations adopted by
oxazolidinones in asymmetric reactions see S. Castellino and W. J.
Dwight, J. Am. Chem. Soc., 1993, 115, 2986; G. Cardillo, L. Gentilucci,
M. Gianotti and A. Tolomelli, Org. Lett., 2001, 3, 1165.
6 D. R. Williams, W. S. Kissel and J. J. Li, Tetrahedron Lett., 1998, 39,
8593.
7 The anti-s-cis conformation has been proposed to account for the
reversal of selectivity noted in the TMSI promoted additions of
monoorganocuprates: P. Pollock, J. Dambacher, R. Anness and M.
Bergdahl, Tetrahedron Lett., 2002, 43, 3693. A similar reversal in
selectivity has been reported in the conjugate addition reactions
promoted by Et2AlCl and TiCl4: R. Amoroso, G. Cardillo, P. Sabatino,
C. Tomasini and A. Trerè, J. Org. Chem., 1993, 58, 5615.
8 N. Asao, T. Uyehara and Y. Yamamoto, Tetrahedron, 1990, 46, 4563;
S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994,
1129.
9 We have previously demonstrated that conjugate addition of homochiral
lithium amide (R)-8 to achiral N-cinnamoyl oxazolidinone proceeds
with high diastereoselectivity ( > 95%); see S. G. Davies, A. J. Edwards
and I. A. S. Walters, Recl. Trav. Chim. Pays-Bas, 1995, 114, 175.
10 V. A. Soloshonok, N. A. Forina, A. V. Rybakova, I. P. Shishinka, S. V.
Galushko, A. E. Sorochinsky and V. P. Kukhar, Tetrahedron:
Asymmetry, 1995, 6, 1601.
In conclusion, double asymmetric induction in the reaction
between homochiral lithium N-benzyl-N-a-methylbenzylamide
and N-enoyl oxazolidinone 5 demonstrates that the conjugate
addition reaction occurs via the anti-s-cis conformation. The
11 All diastereoselectivities were determined by 1H NMR spectroscopic
analysis of the crude reaction mixture.
12 Conjugate addition of (R)-8 and (S)-8 to tert-butyl cinnamate gave the
known b-amino esters tert-butyl (3S,aR)- and (3R,aS)-3-N-benzyl-N-a-
methylbenzylamino-3-phenylpropanoate, which were transformed to
(4S,3AS ,aR)-9 and (4S,3AR,aS)-10 respectively by ester hydrolysis and
subsequent coupling with (S)-4-benzyl-oxazolidin-2-one.
13 For recent examples of mixed a,b-peptides showing secondary structure
see A. Hayen, M. A. Schmitt, F. N. Ngassa, K. A. Thomasson and S. H.
Gellman, Angew. Chem., Int. Ed., 2004, 43, 505; S. De Pol, C. Zorn, C.
D. Klein, O. Zerbe and O. Reiser, Angew. Chem., Int. Ed., 2004, 43,
511.
14 D. A. Evans, T. C. Britton and J. A. Ellman, Tetrahedron Lett., 1987, 28,
6141.
15 For alternative procedures to promote endocyclic oxazolidinone
cleavage see M. P. Sibi, B. J. Harris, J. J. Shay and S. Haja, Tetrahedron,
1998, 54, 7221; A. Bouzide and G. Sauve, Tetrahedron Lett., 2002, 43,
1961; S. J. Katz and S. C. Bergmeier, Tetrahedron Lett., 2002, 43,
557.
Scheme 2 Reagents and conditions: (i) Pd(OH)2 on C, AcOH, H2 (5 atm),
rt; (ii) Boc-Phe, DCC, THF, 0 °C; (iii) LiOH (4.8 eq), THF : H2O (2 : 1), rt;
(iv) CrO3, H2SO4, acetone, 0 °C; (v) TFA : DCM (1 : 1), rt then purification
on reverse phase RP-18 gel.
C h e m . C o m m u n . , 2 0 0 4 , 1 1 2 8 – 1 1 2 9
1129