Asymmetric synthesis of (1R,2S,3R)-γ-methyl-cis-pentacin by a kinetic resolution protocol

Article abstract of DOI:10.1039/b209728c

The asymmetric synthesis of (1R,2S,3R)-3-methyl-2-aminocyclopentane carboxylic acid has been achieved via kinetic resolution of racemic tert-butyl 3-methyl-cyclopentene-1-carboxylate with homochiral lithium (S)-N-benzyl-N-α-methylbenzylamide.

Full text of DOI:10.1039/b209728c

Asymmetric synthesis of (1R,2S,3R)-g-methyl-cis-pentacin by a kinetic
resolution protocol
Simon Bailey,b Stephen G. Davies,*a Andrew D. Smitha and Jonathan M. Witheya
a The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, UK OX1 3QY.
E-mail: steve.davies@chemistry.oxford.ac.uk
b Discovery Chemistry, IPC 818, Pfizer Global Research and Development, Sandwich, Kent, UK CT13 9NJ
Received (in Cambridge, UK) 3rd October 2002, Accepted 22nd October 2002
First published as an Advance Article on the web 5th November 2002
The asymmetric synthesis of (1R,2S,3R)-3-methyl-2-amino-
cyclopentane carboxylic acid has been achieved via kinetic
resolution of racemic tert-butyl 3-methyl-cyclopentene-
1-carboxylate with homochiral lithium (S)-N-benzyl-N-a-
methylbenzylamide.
allows a rapid evaluation of the stereoselectivity factor (E) for
the reaction, which in this case is identical to the diaster-
eoselectivity (since the effects of mass action are eliminated) on
the assumption that there are no non-linear effects operating.8
Thus, (±)-1 was added to a solution of (±)-2 at 278 °C and
quenched by addition of 2,6-di-tert-butylphenol. 1H NMR
spectroscopic analysis of the crude reaction mixture indicated
the presence of the two C(1) epimeric diastereoisomers (±)-6
and (±)-7 (95+5) together with < 1.5% of a third diastereoi-
somer, consistent with > 98.5% control at the b-centre during
the conjugate addition. Purification of the major diaster-
The cyclic a-alkyl-b-amino acid (1R,2S)-2-aminocyclopentane
carboxylic acid (cis-pentacin) has aroused much commercial
and synthetic interest as a result of its potent antifungal
activity.1 The synthesis and screening of a number of deriva-
tives and analogues of cis-pentacin has demonstrated that the
saturated 5-membered ring backbone is essential for biological
activity, as is the (1R,2S)-absolute configuration.2 We have
previously shown that the conjugate addition of homochiral
lithium amides derived from a-methylbenzylamine to a,b-
unsaturated esters represents a versatile methodology for the
asymmetric synthesis of b-amino acid derivatives,3 as demon-
strated for the preparation of homochiral cis-pentacin.4 In order
to extend this methodology to the asymmetric synthesis of the
homochiral 3-methyl analogue, the simplest route would be to
employ the unprecedented kinetic resolution of racemic tert-
butyl 3-methyl cyclopentene-1-carboxylate 1 with homochiral
lithium amide 2 (Fig. 1).
eoisomeric
product,
g-methyl-cis-pentacin
(1RS,2SR,3RS,aSR)-6,9 to homogeneity by column chromatog-
raphy and subsequent complete conversion to the thermody-
namic epimer, g-methyl-trans-pentacin (1SR,2SR,3RS,aSR)-7,
by treatment with KOtBu/tBuOH (3 h at reflux) confirmed that
the two diastereoisomers (±)-6 and (±)-7 were epimeric at C(1)
(Scheme 2).
Fig. 1
The required conjugate acceptor for this approach was readily
prepared on a multigram scale from adipoyl chloride. Esterifica-
tion5 and subsequent Dieckmann cyclisation6 afforded b-keto
ester 3, which underwent regioselective g-methylation to
furnish 4 as a 5+2 mixture of diastereoisomers. Sequential
reduction, tosylation and elimination furnished (±)-tert-butyl
3-methyl cyclopentene-1-carboxylate 1 (Scheme 1).
Scheme
2 Reagents and conditions: (i). (±)-lithium N-benzyl-N-a-
methylbenzylamide (2 eq.), THF, 278 °C; (ii). 2,6-di-tert-butylphenol,
THF, 278 °C to rt; (iii). KOtBu, tBuOH, D, 3 h.
The configuration at C(2) within (±)-6 and (±)-7 relative to
the N-a-methylbenzyl stereocentre was assigned by analogy
with previous models developed to explain the stereoselectivity
observed during addition of lithium amide 2 to a,b-unsaturated
acceptors.10 1H NOE difference analysis subsequently gave
enhancements consistent with the (1RS,2SR,3RS,aSR) config-
uration of diastereoisomer (±)-6 and the (1SR,2SR,3RS,aSR)
configuration of diastereoisomer (±)-7, consistent with the
expected thermodynamics of the system, as described in Fig.
2.
t
Scheme 1 Reagents and conditions: (i). PhNMe2 (3.15 eq.), BuOH (3.25
eq.), Et2O, rt; (ii). NaH (1.05 eq.), tBuOH (cat), PhMe, D; (iii). NaH (1.05
eq.) then n-BuLi (1.0 eq.), then MeI (1.1 eq.), 278 °C to 0 °C; (iv). NaBH4,
EtOH, 0 °C; (v). TsCl (1.1 eq.), pyridine, 0 °C to rt; (vi). DBU, DCM, 0
°C.
Fig. 2 Selected NOE difference enhancements for diastereoisomers (±)-6
and (±)-7; other NOE enhancements omitted for clarity.
Initially the mutual kinetic resolution7 of the racemic
acceptor (±)-1 and (±)-lithium N-benzyl-N-a-methylbenzyla-
mide 2 was performed to assay the level of enantiorecognition
between the two reactants. This racemic/racemic strategy
Notably, while both diastereoisomers exhibited a 7.1% NOE
enhancement between their C(2)H and C(3)Me protons, the
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8.1% enhancement between C(1)H and C(2)H of the major
diastereoisomer (±)-6 was only 3.1% for the minor diastereoi-
somer (±)-7. This indicates that both diastereoisomers (±)-6 and
(±)-7 have the same anti-configuration between C(2)H and
C(3)Me, but while the major diastereoisomer has a syn-
relationship between C(1)H and C(2)H, the minor diastereoi-
somer (±)-7 has the anti-relationship between C(1)H and
C(2)H. Thus, the nucleophilic lithium amide adds to the a,b-
unsaturated acceptor anti to the C(3) methyl group, while
protonation of the resultant enolate occurs anti to the amine,
resulting in the preferential formation of g-methyl-cis-pentacin
(1RS,2SR,3RS,aSR)-6. As measurement of the diastereoiso-
meric product ratios in a mutual kinetic resolution reaction
allows the magnitude of the stereoselectivity factor to be
assessed, the magnitude of the stereoselectivity factor, E could
be quantified as > 70. Having established the high level of
recognition between the g-methyl conjugate acceptor 1 and
racemic lithium amide 2, the kinetic resolution of (±)-1 with
homochiral lithium (S)-N-benzyl-N-a-methylbenzylamide 2
was undertaken. Thus, treatment of (±)-1 with 0.7 eq. of (S)-2 at
278 °C for three hours before the addition of 2,6-di-tert-butyl
phenol gave, at approximately 51% conversion, a 95.5+1.7+2.8
mixture of diastereoisomers 6:7+8, consistent with E > 130,
and (S)-1 {[a]2D4 284.7, (c. 1.1, CHCl3)} in 99 ± 0.5% ee.11
(Scheme 3).
In conclusion, this protocol allows for the diastereoselective
synthesis of g-methyl cis- and trans-pentacin analogues, which
are of interest for pharmacological evaluation and for b-peptide
structural studies respectively.13 Furthermore, the asymmetric
synthesis of (1R,2S,3R)-3-methyl-2-aminocyclopentane car-
boxylic acid has been achieved by kinetic resolution of (±)-tert-
butyl 3-methylcyclopentene-1-carboxylate with a homochiral
lithium amide and subsequent deprotection. The extension of
this methodology to the preparation of other homochiral cis-
and trans-pentacin analogues from (±)-tert-butyl g-alkyl cyclo-
pentene-1-carboxylates is currently under investigation.
The authors wish to thank Pfizer for an industrial CASE
award (J. M. W.) and New College, Oxford for a Junior
Research Fellowship (A. D. S.).
Notes and references
1 For instance see M. Konishi, M. Nishio, K. Saitoh, T. Miyaki, T. Oki
and H. Kawaguchi, J. Antibiot., 1989, 42, 1749; T. Oki, M. Hirano, K.
Tomatsu, K. Numata and H. Kamei, J. Antibiot., 1989, 42, 1756.
2 H. Ohki, Y. Inamoto, K. Kawabata, T. Kamimura and K. Sakane, J.
Antibiot., 1991, 44, 546 and references contained therein.
3 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2, 183; S.
G. Davies, N. M. Garrido, O. Ichihara and I. A. S. Walters, J. Chem.
Soc., Chem. Commun., 1993, 1153.
4 S. G. Davies, O. Ichihara and I. A. S. Walters, Synlett, 1993, 461; S. G.
Davies, O. Ichihara, I. Lenoir and I. A. S. Walters, J. Chem. Soc., Perkin
Trans. 1, 1994, 1411.
5 J. H. Babler and S. J. Sarussi, J. Org. Chem., 1987, 52, 3462.
6 D. Henderson, K. A. Richardson, R. J. K Taylor and J. Saunders,
Synthesis, 1983, 12, 996.
7 For related examples of mutual kinetic resolution see C. H. Heathcock,
M. C. Pirrung, J. Lampe, C. T. Buse and S. D. Young, J. Org. Chem.,
1981, 46, 2290; C. R. Johnson and N. A. Meanwell, J. Am. Chem. Soc.,
1981, 103, 7667; D. Alickmann, R. Fröhlich and E.-U. Würthwein, Org.
Lett., 2001, 3, 1527.
8 A. C. R. Horeau, Tetrahedron, 1975, 31, 1307.
9 Experimental procedure for the preparation of (±)-6: a solution of tert-
butyl (±)-3-methylcyclopentene-1-carboxylate 1 (200 mg, 1.10 mmol)
in anhydrous THF (0.5 ml) was added dropwise to a stirred solution of
(±)-lithium N-benzyl-N-a-methylbenzylamide 2 (2.20 mmol) in THF
(2ml) at 278 °C. After 3 h a precooled solution of 2,6-di-tert-
butylphenol (453 mg, 2.20 mmol) in anhydrous THF (0.5 ml) was added
slowly via cannula and allowed to warm to rt. The reaction mixture was
partitioned between sat. NH4Cl(aq) (5 ml) and Et2O (3 3 50 ml), dried,
filtered and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (2% Et2O, n-pentane) gave (±)-6 (324 mg, 75%);
Found: C, 79.0; H, 9.3; N, 3.6%; C26H35NO2 requires C, 79.3; H, 9.0;
N, 3.6%; nmax (film) 1712 (CNO), 1149 (C–O); dH (400 MHz, CDCl3)
0.99–1.04 (1H, m, C(4)HA), 1.02 (3H, d, J6.5, C(3)Me), 1.19 (3H, d,
J6.9, C(a)Me), 1.51 (9H, s, OCMe3), 1.52 (1H, m, C(5)HA), 1.72 (1H,
m, C(5)HB), 1.97 (1H, m, C(4)HB), 2.28 (1H, m, C(3)H), 2.53 (1H, ddd,
J4.0, 7.7 and 7.7, C(1)H), 2.82 (1H, dd, J7.7 and 10.5, C(2)H), 3.96 and
4.16 (2 3 1H, d, J15.9, NCH2Ph), 4.15 (1H, q, J6.9, C(a)H), 7.21–7.52
(10H, m, Ph); dC (50MHz, CDCl3) 19.5, 20.5, 26.9, 28.1, 30.7, 34.6,
46.7, 50.9, 60.1, 70.4, 80.0, 126.4, 127.0, 127.8, 127.9, 128.1 and 128.3,
143.6, 145.6, 176.5; m/z (CI+) 394 (MH+, 100%).
Scheme
3 Reagents and conditions: (i). (S)-lithium N-benzyl-N-a-
methylbenzylamide (0.7 eq.), THF, 278 °C; (ii). 2,6-di-tert-butylphenol,
THF, 278 °C to rt.
With the relative configurations within 6 and 7 known in the
racemic series from the mutual recognition studies, the absolute
configurations of (1R,2S,3R,aS)-6 and (1S,2S,3R,aS)-7 derive
from the known configuration of the N-a-methylbenzyl ster-
eocentre. The C(1) configuration of the third minor diaster-
eoisomeric product 8 arising from the kinetic resolution
protocol is presently unknown. Purification by column chroma-
tography and recrystallisation gave 6 in 39% yield (78% of
theoretical maximum) and 99 ± 0.5% de. As 6 has the (1R,2S)
configuration of cis-pentacin required for biological activity,
deprotection to the b-amino acid was undertaken to prepare the
g-methyl analogue of the natural product. Thus, Pd mediated N-
debenzylation and treatment with TFA gave (1R,2S,3R)-
3-methyl-2-aminocyclopentane carboxylic acid 9 in 69% yield
and 98 ± 1% ee12 after purification by ion exchange chromatog-
raphy (Scheme 4).
10 J. F. Costello, S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry,
1994, 5, 3919.
11 As shown by 1H NMR chiral shift experiments with homochiral
Eu(hfc)3 and reference to an authentic racemic sample.
12 As shown by 19F and 1H NMR spectroscopic analysis of the derived
methyl esters and subsequent derivatisation with both racemic and 99%
ee MosherAs acid chloride.
13 The secondary structural characteristics of oligomers of trans-pentacin
have been investigated thoroughly; see D. H. Appella, L. A. Christian-
son, D. A. Klein, D. R. Powell, X. Huang, J. J. Barchi and S. H. Gellman,
Nature, 1997, 387, 381; D. H. Appella, L. A. Christianson, D. A. Klein,
M. R. Richards, D. R. Powell and S. H. Gellman, J. Am. Chem. Soc.,
1999, 121, 7574; J. J. Barchi Jr, X. Huang, D. H. Appella, L. A.
Christianson, S . R. Durell and S. H. Gellman, J. Am. Chem. Soc., 2000,
122, 2711.
Scheme 4 Reagents and conditions: (i). Pd(OH)2 on C, MeOH, H2 (5 atm);
(ii). TFA+DCM (1+1) then Dowex 50W-X8.
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