Asymmetric synthesis of a homochiral differentially protected pseudo-meso bis-β-amino acid scaffold

Article abstract of DOI:10.1016/S0957-4166(01)00544-4

A strategy for the asymmetric synthesis of a homochiral differentially protected pseudo-meso bis-β-amino acid scaffold utilising the conjugate addition of homochiral lithium amides and subsequent selective deprotection is demonstrated.

Full text of DOI:10.1016/S0957-4166(01)00544-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2941–2945
Asymmetric synthesis of a homochiral differentially protected
pseudo-meso bis-b-amino acid scaffold
Steven D. Bull, Stephen G. Davies* and Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 15 November 2001; accepted 27 November 2001
Abstract—A strategy for the asymmetric synthesis of a homochiral differentially protected pseudo-meso bis-b-amino acid scaffold
utilising the conjugate addition of homochiral lithium amides and subsequent selective deprotection is demonstrated. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
and >99% e.e. using the double conjugate addition of
homochiral lithium (S)-N-benzyl-N-a-methylbenzyl-
amide 2 to bis-functionalised a,b-unsaturated acceptor
1 to furnish (3R,aS,3%R,a%S)-3, followed by hydrogeno-
lytic debenzylation as described in Fig. 1.5
There has been much recent interest in the b-amino
acid structural motif, not only due to its potent phar-
macological activity,1 but also due to the propensity of
pseudopeptide sequences containing this functionality
to generate novel secondary and tertiary structures.2
Similarly, advances in the understanding of the factors
which promote peptide folding have led to the use of
topological templates3 that constrain the conforma-
tional freedom of attached peptides and help to nucle-
ate structural interactions, enabling progress in the area
of synthetic protein design.4 The potential combination
of these two concepts led us to prepare a range of C2
symmetric (R,R)-bis-b-amino scaffolds as templates for
probing the secondary structure of attached a- and
b-pseudopeptidic fragments. For example, (R,R)-bis-b-
amino ester 4 can be efficiently prepared in 95% d.e.
The potential utility of these bis-b-amino acid deriva-
tives could be extended if a flexible approach could be
developed that would allow for the unambiguous
preparation of not only the (R,R)- or (S,S)-
diastereoisomers, but also a suitably protected variant
of the (R,S)-meso diastereoisomer.6 A synthetic strategy
for the construction of a protected meso diastereoiso-
mer 5 is described in Fig. 2 and requires the prepara-
tion of a,b-unsaturated ester 6, which in turn may be
constructed via Horner–Wadsworth–Emmons method-
ology from aldehyde 7, or via palladium-mediated
Heck methodology from the halide 8.
Figure 1.
* Corresponding author. E-mail: steve.davies@chemistry.oxford.ac.uk
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00544-4

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S. D. Bull et al. / Tetrahedron: Asymmetry 12 (2001) 2941–2945
Figure 2.
While the generation of meso (R,S)-5 itself is of inter-
est, it is not of paramount importance since it would
not be possible to elaborate selectively peptide chains
onto either the (R)- or (S)-b-amino acid fragments.
Rather it was envisaged that a pseudo-meso equivalent
of 5, which by virtue of differential protection would
allow selective elaboration, would be the most appro-
priate target. We now report herein our preliminary
results directed toward these aims.
rated acceptor 6 proceeded in 96% crude d.e., furnish-
ing the known C2 symmetric bis-b-amino ester
(3R,aS,3%R,a%S)-3 in 82% yield and in 96% d.e. after
purification, with identical spectroscopic properties to
that previously reported.5 Conjugate addition of
2. Results and discussion
Synthetic investigations into the preparation of meso-
diamine 5 were initially directed towards the prepara-
tion of chiral aldehyde 7. Our strategy was to use the
known propensity of lithium amides to form a-amino
alkoxides upon addition to aldehydes,7 thus acting as
an in situ protecting group for the aldehyde, and
enabling the a,b-unsaturated ester functionality to
undergo an asymmetric conjugate addition reaction.
Indeed, addition of an excess of lithium amide (S)-2 to
tert-butyl 3-(4-formylphenyl)prop-2-enoate8
9
pro-
ceeded to furnish the required b-amino aldehyde 7 in
97% d.e. and in 81% isolated yield, presumably through
intermediate a-amino alkoxides 10 and 11. Subsequent
Horner–Emmons reaction of aldehyde 7 with the
lithium anion of tert-butyl diethylphosphonoacetate
gave a,b-unsaturated acceptor 6 in 97% crude d.e.,9 and
in 89% yield and 97% d.e. after chromatographic purifi-
cation (Scheme 1).
With the synthesis of a,b-unsaturated acceptor 6 in
hand, the propensity of either enantiomer of lithium
amide 2 toward conjugate addition was evaluated.
Thus, addition of lithium amide (S)-2 to a,b-unsatu-
Scheme 1. Reagents and conditions: (i) (S)-2 (3 equiv.), THF,
−78°C then NH4Cl (aq.); (ii) tert-butyl diethylphosphono-
acetate (1.15 equiv.), n-BuLi (1.1 equiv.), THF, −78°C to rt.

S. D. Bull et al. / Tetrahedron: Asymmetry 12 (2001) 2941–2945
2943
lithium amide (R)-2 to acceptor 6 proceeded in 97%
crude d.e., furnishing meso-bis-b-amino ester
(aS,3R,a%R,3%S)-5 in 89% yield and in 97% d.e. The
(aS,3R,a%R,3%S) stereochemistry of 5 was assigned by
analogy with previous models developed to explain the
stereoselectivity observed during addition of lithium
amide (R)-2 to a,b-unsaturated acceptors,10 combined
group using Wilkinson’s catalyst in the presence of
N-benzyl nitrogen protecting groups12 seemed ideally
suited for differentiation of the nitrogen protecting
groups. The relative acid and base lability of tert-butyl
and iso-propyl esters was selected for differentiation of
the acid functionality,13 and so the synthesis of a model
pseudo-meso diamine 13, in which the nitrogen or ester
functionalities could be selectively deprotected was
investigated (Fig. 3).
1
with the number of resonances observed in the H and
13C NMR spectra which were consistent with high
symmetry, and lack of an observable specific rotation.
Subsequent N-benzyl deprotection via hydrogenation, a
process known to proceed without loss of stereochemi-
cal integrity,5 furnished meso-diamine (3R,3%S)-12 in
81% yield (Scheme 2).
Having demonstrated that aldehyde 7 is a viable pre-
cursor to meso (R,S)-5, the ability of bromide 15 to act
as a precursor for the synthesis of pseudo-meso 13 via a
Heck coupling approach was evaluated. Thus, conju-
gate addition of lithium (R)-N-benzyl-N-a-methylben-
zylamide 2 to (E)-iso-propyl 3-(4-bromophenyl)prop-
2-enoate 14 gave b-amino ester (3S,aR)-15 in 95%
crude d.e., and in 89% yield and in 95% d.e. after
purification. Palladium mediated Heck reaction of bro-
mide (3S,aR)-15 with tert-butyl acrylate gave a,b-
unsaturated ester (3S,aR)-16 in 89% yield and in 95%
d.e after purification. Conjugate addition of lithium
(S)-N-allyl-N-a-methylbenzylamide 17 furnished the
required pseudo-meso scaffold 13 in 95% crude d.e.,
and in 79% yield and in 95% d.e. after purification
(Scheme 3).
With synthetic routes in hand for the preparation of
either C2 symmetric (R,R) or (S,S) diastereoisomers
and (R,S)-meso diastereoisomers of bis-b-amino acid
scaffolds, the second generation of b-amino acid tem-
plates were designed to allow for the selective function-
alisation of either of the nitrogen or acid functionality
through protecting group manipulation. This concept
has previously been elegantly applied by Mutter et al.
for protein de novo design, with Regioselectively
Addressable Functionalised Templates (RAFTs) pro-
posed for the preparation of complex protein architec-
tures.11 For this purpose, the ready availability of
lithium N-allyl-N-a-methylbenzylamide and lithium N-
benzyl-N-a-methylbenzylamide in either enantiomeric
form, and the ability to deprotect the N-allyl protecting
As a model system for selective peptide scaffold forma-
tion, deallylation of template 13 by treatment with
Wilkinson’s catalyst gave diamine 18 in 79% yield,
leaving the benzylic N-protecting groups intact and
thereby enabling differentiation between the N-sub-
stituents. To simulate the formation of a peptide bond,
the secondary amine functionality of 18 was protected
as its Z-carbamate to afford amide 19 in 70% yield.
Treatment of amide 19 with formic acid under reflux14
gave acid 20 in 75% yield, in which differential depro-
tection of both the ester and N-protecting fragments of
the pseudo-meso diamino template 13 has been
achieved (Scheme 4).15
In conclusion, the synthesis and selective deprotection
of a pseudo-meso bis-b-amino acid template using a
matrix of protecting groups for the potential attach-
ment of a- and b-pseudopeptidic fragments for sec-
ondary structural investigations has been achieved.
Further investigations within this area are currently
underway.
Scheme 2. Reagents and conditions: (i) (S)-2 (3 equiv.), THF,
−78°C; (ii) (R)-2 (3 equiv.), THF, −78°C; (iii) Pd(OH)2,
MeOH, AcOH, H2 (5 atm).
Figure 3.

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S. D. Bull et al. / Tetrahedron: Asymmetry 12 (2001) 2941–2945
Acknowledgements
The authors wish to acknowledge the support of the
EPSRC and Rhoˆne Poulenc Rorer for a CASE Award
(A.D.S.) and New College, Oxford for a Junior
Research Fellowship (A.D.S.).
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Scheme 4. Reagents and conditions: (i) Rh(PPh3)3Cl,
MeCN:H2O (8.5:1.5), D; (ii) Cbz2O, vacuum, rt; (iii) HCO2H,
60°C.

S. D. Bull et al. / Tetrahedron: Asymmetry 12 (2001) 2941–2945
2945
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