Synthesis of novel sila-substituted β-amino acids

Article abstract of DOI:10.1016/S0040-4039(02)01085-7

A highly efficient and stereoselective synthesis of unnatural cyclic sila-substituted β-amino acids has been developed from simple starting materials. The key step is nucleophilic ring opening of an intermediate aziridine with an umpolung synthon for the

Full text of DOI:10.1016/S0040-4039(02)01085-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5401–5404
Synthesis of novel sila-substituted b-amino acids
Jennifer L. Matthews,a,b,* Duncan R. McArthura and Kenneth W. Muira
aDepartment of Chemistry, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
bDivision of Biochemistry and Molecular Biology, Institute of Biomedical & Life Sciences, Joseph Black Building,
University of Glasgow, Glasgow G12 8QQ, UK
Received 29 April 2002; accepted 7 June 2002
Abstract—A highly efficient and stereoselective synthesis of unnatural cyclic sila-substituted b-amino acids has been developed
from simple starting materials. The key step is nucleophilic ring opening of an intermediate aziridine with an umpolung synthon
for the carboxylate anion. Functional group manipulation and deprotection reactions allow access to the desired trans b-amino
acids. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
We wish to extend this range by synthesising a series of
novel cyclic sila-substituted b-amino acids. Sila-substi-
tution, the replacement of a carbon atom by a silicon
atom in a compound with biological activity, has been
shown to generate compounds with differing physico-
chemical properties, chemical reactivity and biological
activity. This phenomenon has been used in the search
for improvements in a number of areas of medicinal
chemistry.4 In particular, the use of trimethylsilylala-
nine as a bioisosteric replacement for phenylalanine has
been shown to improve biological stability of certain
b-Amino acids have received a great deal of attention
from synthetic chemists over the last decade and this is
in part due to their important applications in medicinal
chemistry.1 For example, cyclic and linear oligomers of
b-amino acids have been shown to exhibit high bio-
logical activity as mimics2 for the peptide hormone
somatostatin and cyclo-b-tripeptides have been
shown to be antiproliferatives against human cancer
cell lines.3
-
CO2
CN
i
ii
iii
R2SiCl2
X
NTs
X
X
X
+
NH3
NHTs
1
2
3
4
a: X = SiMe2; b: X = SiPh2; c: X = Si(CH2)3CH2; d: X = CH2
Scheme 1. Reagents and conditions: (i) Cp2TiCl2 (5 mol%), H2CꢀCHMgBr (2.1 equiv.), THF, −40°C, 4 h; (ii) Chloramine-T (1.1
equiv.), PTAB (10 mol%), MeCN, rt, 5 h; (iii) Et2AlCN (4 equiv.), PhMe, 100°C, 17 h.
Table 1.
Step (i) yield (%) of 1
Step (ii) yield (%) of 2
Step (iii) yield (%) of 3
a
b
c
79
77
45
n/a
67
81
65
89
75
73
72
70
d
Keywords: aziridine ring opening; b-amino acids; silicon.
* Corresponding author. Tel.: +44 (0)141 3305936; fax: +44 (0)141 3304888; e-mail: j.matthews@chem.gla.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01085-7

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J. L. Matthews et al. / Tetrahedron Letters 43 (2002) 5401–5404
CN
NHTs
i
Ph2
Si
NTs
Ph2Si
Ph2Si
+
O
NHTs
3b (40%)
2b
7 (15%)
Scheme 2. Reagents and conditions: (i) Me2C(OH)CN, Yb(OiPr)3, THF, 50°C.
peptidomimetics whilst retaining biological activity.
Herein we describe the synthesis of several novel b-
amino acids containing silicon in a five-membered ring.
is thought to be in equilibrium with the less stable
isonitrile which may be rapidly hydrolysed in the pres-
ence of water to the observed by-product 5.9 Silanol 5
slowly dimerises upon standing at room temperature,
eliminating water to form the disiloxane 6.
2. Discussion
We then turned our attention to the use of lanthanide
based reagents. Inoue’s procedure10 involving the use of
acetone cyanohydrin as a source of CN− with a triva-
Synthesis of the unnatural amino acids was achieved by
following the route outlined in Scheme 1. This involves
aziridination of the silacyclopent-3-ene 1, affording
aziridines 2. Ring opening methodology gave the cyano
compounds 3, followed by amine deprotection and
nitrile hydrolysis yielding the target b-amino acids 4.
We have also used the described methodology to syn-
thesise a carbon-based amino acid 4d, where the R2Si
moiety is replaced by H2C. This amino acid will be used
as a comparison with our silicon based compounds in
biological testing studies.
The silacyclopent-3-ene starting materials 1a–c were
obtained using the titanocene dichloride catalysed reac-
tion system of Watabe (Scheme 1).5 The cyclopentene
products were obtained in 45–79% yields (Table 1).
This methodology proved to be far superior to alterna-
tive strategies6 with improved yields and a wider range
of silacyclopent-3-enes being made available. The use of
cyclopentene 1d as the starting material leads to the
formation of the carbon analogue 4d.
The key intermediates in our syntheses, aziridines 2,
were prepared directly from 1 using the Chloramine-T/
PTAB system of Sharpless (Scheme 1, Table 1).7 X-Ray
crystal structure analysis of bicyclohexane 2b revealed
unexpected potential transannular H-bond interactions
across the ring system between the nitrogen lone pair
and an aromatic C–H group. We have already
described8 some of our work in this area and further
crystallographic studies are currently underway to
determine the exact nature of this interaction.
Figure 1. X-Ray crystal structure analysis of 7. Isopropyl
hydrogens are omitted.
The key ring opening step required extensive experi-
mentation, with several Lewis acids and sources of
cyanide being screened. Treatment of aziridine 2b with
KCN/t-Bu4NCN in THF/water resulted in undesirable
ring opening at silicon, by either water or CN−. Inter-
esting by-products 5 and 6 were identified, and their
formation rationalised by comparison with literature
precedent: the initial adduct could be formed by nucle-
ophilic attack of cyanide at silicon. The resulting nitrile
Ph2
Si
Ph2
Si
Ph2
Si
HO
NHTs
TsHN
NHTs
O
5
6
Figure 2. X-Ray crystal structure analysis of 3b.

J. L. Matthews et al. / Tetrahedron Letters 43 (2002) 5401–5404
5403
lent ytterbium alkoxide (10 mol%) resulted in the for-
mation of 3b in 40% yield (Scheme 2). A side reaction
was also observed during this reaction: ring opening at
silicon by isopropoxide is observed resulting in the
formation of the unusual alkoxysilyl species 7. The
structure of this surprisingly stable by-product has been
confirmed by X-ray crystal structure analysis (Fig. 1).
This compound opens up further potential for the
development of novel amino acid analogues and we are
now investigating its potential.
saponified with NaOH to give amino acid 4 (Scheme 3,
Table 2). The nitrile 9d was converted directly into the
amino acid 4d simply by heating in concentrated HCl
(aq.). We are currently investigating the resolution of
esters 10 under enzymatic hydrolysis conditions, using
Candida antartica lipase immobilised on a solid sup-
port. Enantiomeric excesses of up to 47% have been
obtained thus far, and work is ongoing in this area.
3. Conclusion
Eventually, we established that the method of choice
for the stereoselective aziridine ring cleavage involves
the use of Et2AlCN (Nagata’s reagent)11 and gives
exclusively anti attack at the aziridine ring to yield
racemic nitrile products 3 in high yield (Scheme 1,
Table 1). The stereochemistry of 3b was proven by
X-ray crystal structure analysis (Fig. 2).
A highly efficient and stereoselective route to unnatural
sila-substituted b-amino acids has been developed,
incorporating the key ring opening reaction of aziridi-
nes 2 with a commercially available source of CN−.† We
are currently investigating incorporation of our amino
acids into b-peptides and analogues of known drugs to
compare their biological activities with those of the
corresponding carbon analogues.
Removal of the tosyl group from 3 was achieved in
excellent yield by initially protecting the amine with a
Boc group under DMAP catalysis, giving adducts 8
(Scheme 3, Table 2). Reduction with magnesium chips
in methanol under the conditions developed by Rag-
narsson resulted in mild detosylation affording the Boc
protected amines 9.12,13 Direct hydrolysis of the amino-
nitriles 9 to the amino acid 4 was problematic. Cleavage
of the five-membered silacycle was observed under basic
conditions and the nitrile proved unreactive towards
aqueous acid.
Acknowledgements
We thank The Royal Society for a Dorothy Hodgkin
Research Fellowship (to J.L.M.) and a Research Equip-
ment Grant. We are grateful for support from the
University of Glasgow (Loudon Bequest Studentship
for D.R.M.) and from the EPSRC for X-ray
crystallography‡ (GR/M91433). The assistance of Dr.
M.-C. Parker, Dr. M. Quiros and Professor D. J.
Robins is gratefully acknowledged.
Nitrile 9 was therefore converted into the ethyl ester 10
using anhydrous ethanol saturated with HCl, then
-
CO2
CO2Et
CN
CN
iv
i
iii
X
ii
X
X
(±)3
X
+
NH3
NH2
NTs
Boc
NHBoc
8
9
10
4
Scheme 3. Reagents and conditions: (i) Boc2O (1.3 equiv.), DMAP (10 mol%), MeCN, rt, 5 h; (ii) Mg (10 equiv.), MeOH,
sonication, 40 min; (iii) saturated HCl in EtOH, rt, 22 h; (iv) 2 M NaOH (aq.) rt, 22 h.
Table 2.
Step (i) yield (%) of 8
Step (ii) yield (%) of 9
Step (iii) yield (%) of 10
Step (iv) yield (%) of 4
a
b
c
95
98
99
98
98
81
97
92
95
97
90
n/a
78
88
86
85
d
† Typical experimental procedure for ring opening: diethylaluminium cyanide (24.8 mL, 0.0248 mol, 1 M in toluene) was added dropwise to a
stirred solution of 4-aza-4-tosyl-1,1-diphenyl-1-silabicyclo[3.1.0]hexane (2.512 g, 6.196 mmol) in toluene (12 mL). The reaction mixture was then
heated at 100°C for 17 h, after which time the reaction was quenched by pouring it portionwise onto a mixture of fresh ice and NaOH (150
mL, 2 M aq. solution). The aqueous layer was extracted with DCM (3×100 mL). The organic extracts were combined and dried over MgSO4,
filtered and concentrated in vacuo to yield the crude product. Flash chromatography eluting with petroleum ether–EtOAc (3:1) yielded the
desired product as a white solid. Recrystallisation from petroleum ether–EtOAc yielded white needles (1.957 g, 73% yield).
‡ Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 184658 and 184659. 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 email: deposit@ccdc.cam.ac.uk].

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J. L. Matthews et al. / Tetrahedron Letters 43 (2002) 5401–5404
Dejean, V.; Manuel, G. Synth. Commun. 1998, 28, 1163.
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