Asymmetric syntheses of enantiopure C(5)-substituted transpentacins via diastereoselective Ireland-Claisen rearrangements

Article abstract of DOI:10.1039/c3cc43250e

Asymmetric syntheses of (S,S,S)-2-amino-5-methylcyclopentanecarboxylic acid and (S,S,S)-2-amino-5-phenylcyclopentanecarboxylic acid were achieved in 9 steps from commercially available starting materials via the Ireland-Claisen rearrangement of two enanti

Full text of DOI:10.1039/c3cc43250e

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Asymmetric syntheses of enantiopure C(5)-substituted
transpentacins via diastereoselective Ireland–Claisen
rearrangements†
Cite this: Chem. Commun., 2013,
49, 7037
Received 2nd May 2013,
Accepted 26th June 2013
Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, James E. Thomson and
Charlotte M. Zammit
DOI: 10.1039/c3cc43250e
www.rsc.org/chemcomm
Asymmetric syntheses of (S,S,S)-2-amino-5-methylcyclopentanecarboxylic
acid and (S,S,S)-2-amino-5-phenylcyclopentanecarboxylic acid were
achieved in 9 steps from commercially available starting materials via
the Ireland–Claisen rearrangement of two enantiopure b-amino allyl
esters, followed by ring-closing metathesis, reduction and deprotection.
There has been considerable interest in the secondary structural
characteristics of oligomers of the cyclic b-amino acids cispentacin
and transpentacin (the enantiopure diastereoisomers of 2-amino-
cyclopentanecarboxylic acid).1,2 In order to enhance the structural
diversity of enantiopure monomeric cispentacin and transpentacin
derivatives available we have developed efficient parallel kinetic
resolution (PKR) procedures for the asymmetric syntheses of
C(3)- and C(5)-substituted analogues 1–3,3 and subsequently investi-
gated the secondary structural characteristics of some of their oligo-
mers.4 Herein we report an alternative procedure for the syntheses of
1,2-anti-1,5-syn-diastereoisomers 6, which are not accessible using the
PKR protocol. It was predicted that the Ireland–Claisen rearrange-
ment5 of silyl ketene acetals derived from b-amino allyl esters 4 would
proceed via a chair-like transition state 7 in which 1,3-allylic strain
between the C(3)-substituents and the C(1)–O bond is minimised, and
rearrangement occurs on the face opposite the bulky N-benzyl-N-(a-
methylbenzyl) group. The resultant a-substituted b-amino acid
Fig. 1 Substituted cispentacin and transpentacin analogues 1–3 and the Ireland–
Claisen rearrangement strategy to access transpentacins 6.
products 5 could then be elaborated to the corresponding yield and >99 : 1 dr after chromatographic purification. Hydrolysis of
C(5)-substituted transpentacins 6 via ring-closing metathesis the tert-butyl ester moiety within 10 upon treatment with TFA,
and hydrogenolytic reduction/deprotection (Fig. 1).
conversion of the resultant carboxylic acid to the corresponding
Rearrangement precursors 11 and 12 were prepared from acid chloride, and treatment with either alcohol 23 or alcohol 24
commercially available sorbic acid 8 in four steps. Esterification of 8 (which were both prepared in >99 : 1 dr upon reduction of the
upon treatment with isobutylene/H+ gave a,b-unsaturated ester 9 in corresponding alkynes 21 and 22) gave b-amino allyl esters 11 and 12
80% isolated yield. Conjugate addition of lithium (S)-N-benzyl-N-(a- in 57 and 63% yield, respectively, over the two step procedure.
methylbenzyl)amide6 to 9 produced the known b-amino ester 107,8 Ireland–Claisen rearrangement of 12 was achieved via deprotonation
as a single diastereoisomer (>99 : 1 dr), which was isolated in 89% with LiHMDS and treatment of the resultant lithium (E)-b-amino
enolate9 with TMSCl, followed by heating the corresponding silyl
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: steve.davies@chem.ox.ac.uk;
Fax: +44 (0)1865 275633; Tel: +44 (0)1865 275695
ketene acetal at reflux in PhMe, which gave a 76 : 24 mixture of
b-amino acids 15 and 16, respectively. Conversion of this mixture to
the corresponding methyl esters 19 and 20 (for ease of handling and
isolation) was then achieved upon treatment with MeI and DBU,10
and 19 and 20 were then isolated as single diastereoisomers (>99 : 1 dr)
in 69 and 16% yield, respectively (Scheme 1). The relative configurations
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterisation data, copies of 1H and 13C NMR spectra, and crystal-
lographic data. CCDC 936128–936131. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc43250e
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Fig. 2 X-ray crystal structures of (S,S,S,S,E)-19ꢀHBF4 [left] and (2R,3S,10R,aS,E)-20
[right] (selected H atoms are omitted for clarity).
of the crude reaction mixture by flash column chromatography
(Scheme 2). The 1H and 13C NMR data for this sample of 26
were in excellent agreement with those reported previously;3d
this analysis therefore enabled the configurations within 18, 25
and 26 to be assigned.
For both 17 and 19 (the major diastereoisomers arising from
Ireland–Claisen rearrangement of 11 and 12, respectively), ring-
closing metathesis in the presence of Grubbs I catalyst gave 27 and
28 as single diastereoisomers (>99 : 1 dr) in 85 and 80% yield,12
respectively, and subsequent tandem hydrogenation/hydrogenolysis
gave primary amines 29 and 30 as single diastereoisomers
(>99 : 1 dr) in 83 and 87% yield (Scheme 3). The relative configura-
tions within 27–30 were initially assigned by 1H NMR nOe analyses
and these assignments were subsequently confirmed unambigu-
ously by single crystal X-ray diffraction analyses (Fig. 3):11 in the case
of 29, single crystal X-ray diffraction analysis of the corresponding
2,6-difluorobenzoic acid salt and the determination of a Flack x
parameter13 of 0.005(11) for this crystal structure allowed the
assigned absolute (S,S,S)-configuration within 29 to be confirmed,
whilst for 30, single crystal X-ray diffraction analysis of the corre-
sponding HBF4 salt and the determination of a Flack x parameter13
of ꢁ0.03(16) for the crystal structure of 30ꢀHBF4 allowed the assigned
absolute (S,S,S)-configuration within 30 to also be confirmed.
Scheme 1
within both 19ꢀHBF4 and 20 were unambiguously assigned by single
crystal X-ray diffraction analyses (Fig. 2),11 with the absolute configura-
tions within (S,S,S,S,E)-19 and (2R,3S,10R,aS,E)-20 being assigned from
the known configuration of the (S)-a-methylbenzyl fragment. Analogous
Ireland–Claisen rearrangement of 11 produced a (separable) 80 : 20
mixture of b-amino acids 13 and 14, which after esterification gave 17
and 18 in >99 : 1 dr and 45 and 14% isolated yield, respectively
(Scheme 1). The configurations within both 17 and 18 were initially
assigned by analogy to those within 19 and 20, and these assignments
were subsequently confirmed by chemical correlation and single crystal
X-ray diffraction analysis of a derivative (vide infra). In both
cases, the configurations within the major diastereoisomers 17
and 19 were consistent with the predicted stereochemical out-
come of transition state model 7 (Fig. 1).
The configuration within 18 (the minor diastereoisomer derived
from rearrangement of 11) was unambiguously established by
chemical correlation: ring-closing metathesis of 18 (>99 : 1 dr) upon
treatment with Grubbs I catalyst gave 25 in 77% yield and >99 : 1 dr.
Subsequent hydrogenolytic reduction of 25 in the presence of Pd/C
gave a complex mixture of products including the known b-amino
ester 26, which was isolated in 9% yield after exhaustive purification
Scheme 2
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2 For a review, see: F. Fu¨lop, Chem. Rev., 2001, 101, 2181.
´
3 (a) S. G. Davies, D. Dıez, M. M. El Hammouni, A. C. Garner,
N. M. Garrido, M. J. C. Long, R. M. Morrison, A. D. Smith,
M. J. Sweet and J. M. Withey, Chem. Commun., 2003, 2410;
(b) M. E. Bunnage, A. M. Chippindale, S. G. Davies, R. M. Parkin,
A. D. Smith and J. M. Withey, Org. Biomol. Chem., 2003, 1, 3698;
(c) S. G. Davies, A. C. Garner, M. J. C. Long, A. D. Smith, M. J. Sweet
and J. M. Withey, Org. Biomol. Chem., 2004, 2, 3355; (d) S. G. Davies,
A. C. Garner, M. J. C. Long, R. M. Morrison, P. M. Roberts,
E. D. Savory, A. D. Smith, M. J. Sweet and J. M. Withey, Org. Biomol.
Chem., 2005, 3, 2762; (e) Y. Aye, S. G. Davies, A. C. Garner,
P. M. Roberts, A. D. Smith and J. E. Thomson, Org. Biomol. Chem.,
2008, 6, 2195; ( f ) E. Abraham, S. G. Davies, A. J. Docherty, K. B. Ling,
P. M. Roberts, A. J. Russell, J. E. Thomson and S. M. Toms, Tetra-
hedron: Asymmetry, 2008, 19, 1356.
4 E. Abraham, T. D. W. Claridge, S. G. Davies, B. Odell, P. M. Roberts,
A. J. Russell, A. D. Smith, L. J. Smith, H. R. Storr, M. J. Sweet,
A. L. Thompson, J. E. Thomson, G. E. Tranter and D. J. Watkin,
Tetrahedron: Asymmetry, 2011, 22, 69.
5 For related Ireland–Claisen rearrangements of substrates derived from
b-amino esters, see: (a) C. P. Dell, K. M. Khan and D. W. Knight, J. Chem.
Soc., Chem. Commun., 1989, 1812; (b) P. Barbie, L. Huo, R. Mu¨ller and
U. Kazmaier, Org. Lett., 2012, 14, 6064; (c) D. Becker and U. Kazmaier,
J. Org. Chem., 2013, 78, 59.
Scheme 3
6 For reviews, see: (a) S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:
Asymmetry, 2005, 16, 2833; (b) S. G. Davies, A. M. Fletcher, P. M. Roberts
and J. E. Thomson, Tetrahedron: Asymmetry, 2012, 23, 1111.
7 (a) S. G. Davies and G. D. Smyth, J. Chem. Soc., Perkin Trans. 1, 1996, 2467;
(b) S. G. Davies and G. D. Smyth, Tetrahedron: Asymmetry, 1996, 7, 1001.
8 The stereochemical outcome of this reaction is in accordance with
our transition state mnemonic; see: J. F. Costello, S. G. Davies and
O. Ichihara, Tetrahedron: Asymmetry, 1994, 5, 1999.
9 (a) S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1,
1994, 1129; (b) S. G. Davies, E. M. Foster, C. R. McIntosh,
P. M. Roberts, T. E. Rosser, A. D. Smith and J. E. Thomson, Tetra-
hedron: Asymmetry, 2011, 22, 1035.
10 D. Mal, Synth. Commun., 1986, 16, 331.
11 X-ray crystal structure data were collected using an Oxford Diffraction
SuperNova diffractometer with graphite monochromated Cu-Ka radia-
tion, using standard procedures at 150 K. The structures were solved by
direct methods (SIR92); all non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were added at idealised
positions. X-ray crystal structure data for 19ꢀHBF4 [C31H36BF4NO2]:
M = 541.43, orthorhombic, P212121, a = 9.3325(1) Å, b = 15.3112(2) Å,
c = 20.0967(2) Å, V = 2871.65(5) Å3, Z = 4, m = 0.784 mmꢁ1, colourless
block, crystal dimensions = 0.23 ꢂ 0.26 ꢂ 0.30 mm3. A total of 6010
unique reflections were measured for 4 o y o 77 and 5068 reflections
were used in the refinement. The final parameters were wR2 = 0.102
and R1 = 0.038 [I > ꢁ3.0s(I)]. CCDC 936128.† X-ray crystal structure data
for 20 [C31H35NO2]: M = 453.62, monoclinic, P21, a = 7.9925(2) Å, b =
16.7779(4) Å, c = 10.6442(3) Å, b = 111.582(3)1, V = 1327.29(7) Å3, Z = 2, m =
0.541 mmꢁ1, colourless plate, crystal dimensions = 0.05 ꢂ 0.20 ꢂ
0.24 mm3. A total of 4653 unique reflections were measured for 4 o
y o 77 and 4635 reflections were used in the refinement. The final
parameters were wR2 = 0.083 and R1 = 0.034 [I > ꢁ3.0s(I)]. CCDC 936129.†
X-ray crystal structure data for 29ꢀC7H4F2O2ꢀCHCl3 [C16H20Cl3F2NO4]: M =
434.69, monoclinic, C2, a = 25.0016(5) Å, b = 6.6915(1) Å, c = 12.9605(2) Å,
b = 110.830(2)1, V = 2026.55(7) Å3, Z = 4, m = 4.452 mmꢁ1, colourless
prism, crystal dimensions = 0.11 ꢂ 0.12 ꢂ 0.29 mm3. A total of 4226
unique reflections were measured for 4 o y o 76 and 4207 reflections
were used in the refinement. The final parameters were wR2 = 0.082 and
R1 = 0.033 [I > ꢁ3.0s(I)]. CCDC 936130.† X-ray crystal structure data for
30ꢀHBF4 [C13H18BF4NO2]: M = 307.09, monoclinic, P21, a = 5.5150(2) Å, b =
7.6423(3) Å, c = 17.2563(6) Å, b = 90.531(3)1, V = 727.27(5) Å3, Z = 2, m =
1.099 mmꢁ1, colourless block, crystal dimensions = 0.22 ꢂ 0.23 ꢂ
0.27 mm3. A total of 2045 unique reflections were measured for 5 o
y o 76 and 2038 reflections were used in the refinement. The final
parameters were wR2 = 0.092 and R1 = 0.036 [I > ꢁ3.0s(I)]. CCDC 936131†.
12 Compounds 27 and 28 were also isolated in 63 and 51% overall yield
from 11 and 12, respectively, for the 3 step procedure, without
purification of any intermediates.
Fig. 3 X-ray crystal structures of (S,S,S)-29ꢀ2,6-difluorobenzoic acidꢀCHCl3 [left]
and (S,S,S)-30ꢀHBF4 [right] (selected H atoms and CHCl3 are omitted for clarity).
These crystallographic studies therefore also secured the assigned
configurations within 17, 27 and 28. Finally hydrolysis of the methyl
ester functionalities within both 29 and 30, upon treatment with
6.0 M aq HCl at reflux for 16 h, gave b-amino acids 31 and 32 which
were isolated as single diastereoisomers (>99 : 1 dr) in 84 and 89%
yield, respectively, after purification on Dowex 50WX8 ion exchange
resin (Scheme 3).
In conclusion, the Ireland–Claisen rearrangement of two enantio-
pure b-amino allyl esters, followed by ring-closing metathesis,
reduction and deprotection, enabled the asymmetric syntheses of
(S,S,S)-2-amino-5-methylcyclopentanecarboxylic acid and (S,S,S)-2-
amino-5-phenylcyclopentanecarboxylic acid in 9 steps and >99 : 1 dr
in both cases, and 18 and 19% overall yield, respectively, from
commercially available starting materials.
Notes and references
1 For instance, see: (a) D. H. Appella, L. A. Christianson, D. A. Klein,
D. R. Powell, X. Huang, J. J. Barchi and S. H. Gellman, Nature, 1997,
´
´
387, 381; (b) T. A. Martinek, G. K. Tath, E. Vass, M. Hollosi and
F. Fu¨lop, Angew. Chem., Int. Ed., 2002, 41, 1718; (c) E. Abraham,
C. W. Bailey, T. D. W. Claridge, S. G. Davies, K. B. Ling, B. Odell,
T. L. Rees, P. M. Roberts, A. J. Russell, A. D. Smith, L. J. Smith,
H. R. Storr, M. J. Sweet, A. L. Thompson, J. E. Thomson, G. E. Tranter
and D. J. Watkin, Tetrahedron: Asymmetry, 2010, 21, 1797.
13 (a) H. D. Flack, Acta Crystallogr., Sect. A: Found. Crystallogr., 1983,
39, 876; (b) H. D. Flack and G. Bernardinelli, J. Appl. Crystallogr.,
2000, 33, 1143.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7037--7039 7039