A novel strategy towards the asymmetric synthesis of orthogonally funtionalised 2-N-benzyl-N-α-methylbenzyl-amino-5-carboxymethyl- cyclopentane-1-carboxylic acid

Article abstract of DOI:10.3390/90500373

The asymmetric synthesis of the orthogonally funtionalised compounds tert-butyl 2-N-benzyl-N-α-methylbenzylamino-5- methoxycarbonylmethylcyclopentane-1-carboxylate and methyl 2-N-benzyl-N-α- methylbenzylamino-5-carboxymethylcyclo-pentane-1-carboxylate by a domino reaction of tert-butyl methyl (E,E)-octa-2,6-diendioate with lithium N-α-methylbenzyl-N-benzylamide initiated by a Michael addition, subsequent 5-exo-trig intramolecular cyclisation and posterior selective hydrolysis with trifluoroacetic acid is reported.

Full text of DOI:10.3390/90500373

Molecules 2004, 9, 373–382
molecules
ISSN 1420-3049
http://www.mdpi.org
A Novel Strategy Towards the Asymmetric Synthesis of
Orthogonally Funtionalised 2-N-Benzyl-N-α-methylbenzyl-
amino-5-carboxymethyl-cyclopentane-1-carboxylic acid.
Narciso M. Garrido *, Mohamed M. El Hammoumi, David Díez, Mercedes García and Julio G.
Urones
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008,
Salamanca, Spain. Tel. (+34)-923-294474, Fax (+34) 923-294574.
* Author to whom correspondence should be addressed; e-mail: nmg@usal.es
Received: 15 March 2004; in revised form: 24 March 2004 / Accepted: 24 March 2004 / Published: 30
April 2004
Abstract: The asymmetric synthesis of the orthogonally funtionalised compounds
tert-butyl 2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethylcyclopentane-
1-carboxylate and methyl 2-N-benzyl-N-α-methylbenzylamino-5–carboxymethylcyclo-
pentane-1-carboxylate by a domino reaction of tert-butyl methyl (E,E)-octa-2,6-
diendioate with lithium N-α-methylbenzyl-N-benzylamide initiated by a Michael
addition, subsequent 5-exo-trig intramolecular cyclisation and posterior selective
hydrolysis with trifluoroacetic acid is reported.
Keywords: Asymmetric synthesis, chiral lithium amide, β-amino acids, domino reaction,
β-aminocyclopentane carboxilate, aminodiester orthogonal protection.
Introduction
The asymmetric synthesis of polyfunctionalised cyclopentane derivatives has been widely pursued
in organic synthesis, with much recent interest focusing around strategies for the asymmetric synthesis
of cis-pentacin (1) and trans-pentacin (2), respectively. The cis-diastereoisomer shows potent

Molecules 2004, 9
374
antifungal activity while Fülop et al. have recently demonstrated that oligomers of cis-pentacin adopt a
sheet type structure in DMSO [1]. Furthermore, Gellman et al. have demonstrated that short chain β-
peptides derived from trans-pentacin adopt 12-membered helical structures [2-5] and when a
pyrrolidine–base β-amino acid is incorporated into the hexa-β-peptide 3, it confers water solubility
when the ring nitrogen is protonated [6-7]. In addition, oligomers composed of the 3-substituted trans-
pentacin residues 4, 5 and 6 fold in water, which should facilitate the design of β-peptides for
biological applications (Figure 1)[8].
Figure 1
NH2
NH2
O
O
O
O
H
N
COOH
COOH
H2N
CO NH2
N
H
N
H
Ph
O
N
H
O
n
O
trans-Pentacin
n
cis-Pentacin
2
1
H
N
H
N
H
N
H
N
NH2
N
N
O
O
H2
O
O
O
H2
n=2
CF3CO2
3
CF3CO2
NH2
NH2
NH2
MeO
PhO
COOH
COOH
COOH
BocHN
4
5
6
We have recently demonstrated the asymmetric synthesis of the eight stereoisomers of 2-amino-5-
carboxymethyl-cyclopentane-1-carboxylate (I) using (E,E)-octa-2,6-diendioate as the only prochiral
precursor [9], as shown in the retrosynthesis in Scheme 1. The set of trans-C(1)-C(2)-stereoisomeric β-
amino diacids (II) are readily prepared via a diastereoselective tandem conjugate addition-cyclisation
protocol with either (R)- or (S)-N-benzyl-N-α-methylbenzylamine [(R)- or (S)-7], hydrogenolysis and
ester hydrolysis. The synthsis of the array of cis-C(1)-C(2)-stereoisomeric β-amino diacids utilises a
protocol involving N-oxidation and Cope elimination of the major diastereoisomeric product arising
from conjugate addition and cyclisation (II), giving homochiral (R)- or (S)-5-carboxymethylcyclo-
pentene-1-carboxylate derivatives (III). Conjugate addition of either lithium (R)- or (S)-7 and
diastereoselective protonation with 2,6-di-tert-butyl phenol, hydrogenolysis and ester hydrolysis, gives
the cis-C(1)-C(2)-stereoisomeric β-amino diacids (IV). With the β-aminodiacids in hand the synthesis
of the orthogonally protected aminodiester was envisaged in order to give further options when trying
to link the monomer to build the β-peptide.

Molecules 2004, 9
375
Scheme 1
NH
2
NR
2
Ph
Ph
¶
#
COOH
#
D
COOR
#
Ph
N
N
Ph
A
Li
Li
*
COOH
COOR
(R)-7
*
(S)-7
I
IV
COOR
COOR
C
D
NR
2
COOR
COOR
B
*
COOR
*
*
*
COOR
III
II
A:domino reaction: Michael addition/intramolecular 5-exo-cyclisation. B: Cope stereoespecific sin elimination.
C: Stereoselective Michael conjugate addition . D: Deprotection.
Results and Discussion
We have obtained dimethyl and di-(1-ethylpropyl)(E,E)-octa-2,6-diendioate on a multigram scale
using the method published by Scheffer et al. [10]. Treatment of sebacic acid with thionyl chloride
followed by bromine, while irradiating the entire apparatus with a 300-W sunlamp and then the
addition of alcohol (methanol or 1-ethylpropanol) produces the appropriate dibromodiester, which
yields the required diendioate upon refluxing with DMF. It was not possible to obtain the convenient
di-tert-butyl diester using this procedure and we used the methodology developed by Mestres et al.
[11-14] (Scheme 2) to obtain diunsaturated dicarboxylic acids by oxidative coupling of the dianions of
unsaturated carboxylic acids.
The oxidative coupling of the dianion derived from crotonic acid (8), as shown in Scheme 3,
afforded a 70% yield of a 2:1 mixture of (E,E)-octa-2,6-diendioic and (E)-5-vinyl-hex-2-endioic acids
(9 and 10) that could be easily separated by crystallization of 9 [13]. Methylation of these diacids using
diazomethane or methanol in acid media is quantitative. The di-tert-butyldiester 13 is obtained (67%
after CC) by reaction of diacid 10 with trifluoroacetic anhydride and tert-butanol, but under the same
conditions diacid 9 afforded an easily separable mixture of di-tert-butyl ester 14 (42%) and monoester
15 (57%) which upon further treatment with diazomethane produced the orthogonally protected tert-
butyl methyl (E,E)-octa-2,6-diendioate 16. Compound 14 has been used to synthesize the
aforementioned β-aminocyclopentanoic acid [9] and 16 provided two differentiated Michael acceptors
to be tested with the homochiral lithium amide.

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376
Scheme 2
COOR
COOR
COOR
OLi
OLi
b
+
2:1
COOR
1
a
9, R=R = H
10, R= H
1
c
c
11, R=R = Me
1
d
12, R= Me
O
d
t
t
14, R=R = Bu +
OH
1
13, R= Bu
t
15, R= Bu, R =H
1
8
c
t
16, R= Bu, R =Me
1
t
a: LiNEt . b: I . c: MeOH,HCl ó CH N . d: TFAA, BuOH
2
2
2 2
Addition of tert-butyl methyl (E,E)-octa-2,6-diendioate 16 to homochiral lithium (S)- N-benzyl-N-
α-methylbenzylamine [(S)-7] gave a 90% yield of a 3:1 mixture of 17 and 18 (Scheme 3). The ratio
was determined by integration of the respective methyl group signals of each compound observed at
1
3.44 and 3.62 ppm in the H-NMR spectra (vide infra). The absolute configuration of this compound
26
was established by obtaining 19 ([α]D +50.5; lit. [9] –51.3 for the enantiomer) by reaction of the
17/18 mixture with trifluoroacetic acid and then diazomethane. Therefore both compounds have the
same configuration, consistent with the asymmetric addition of the lithium amine and anti alkylation of
the enolate produced. The only difference being the chemoselectivity observed due to the different
alkyl group in each Michael acceptor, giving a favorable addition to the less bulky methyl.
Scheme 3
Ph
Ph
Ph
Ph
Ph
N
N
COOMe
t
COO Bu
Ph
N
COOMe
Li
+
t
t
(S)-7
COO Bu
COOMe
COO Bu
90%
16
18
17
3:1
a,b
a
Ph
Ph
Ph
Ph
N
Ph
Ph
N
N
t
COO Bu
COOMe
COOMe
COOMe
b
COOMe
COOH
+
18
19
20
a: TFA. b: CH N .
2
2

Molecules 2004, 9
377
The X-ray structure of 19 [9] shows the carbonyl on C-1 almost perpendicular to the ring plane,
consequently very shielded by the adjacent groups at C-2 and C-5. So the 18/19 mixture could be easily
resolved upon treatment with trifluoroacetic acid in a short period of time, as only the lateral tert-butyl
ester at C-5 is hydrolyzed, giving rise to the straightforwardly separable unreacted diester 18 (21%) and
the acid compound 20 (61%) from which 19 is obtained as well by methylation with diazomethane.
All the spectroscopic assignments of 20 and 19 have been unambiguously established by 1H-NMR
techniques, including 2-dimensional homonuclear COSY, heteronuclear HMQC and HMBC
(noteworthy signals are shown in Figure 2, each methyl group is clearly differentiated), nOe and
ROESY experiments.
Figure 2
Ph
Ph
Ph
Ph
N
N
O
O
.
.
.
.
Me
Me
2
2
.
O
3.43
174.7 O 3.42
COOH
1
174.O2
1
5
5
3.60
.
.
Me
.
O
19
13C
20
172.0
1H long range correlations
.
Conclusions
Crotonic acid is an excellent starting material to obtain the orthogonally substituted tert-butyl,
methyl (E,E)-octa-2,6-diendioate, which upon treatment with lithium N-α-methylbenzyl-N-
benzylamine stereoselectively yields both methyl 2-N-benzyl-N-α-methylbenzylamino-5-tert-butoxy-
carbonylmethylcyclopentane-1-carboxylate and tert-butyl 2-N-benzyl-N-α-methylbenzylamino-5-
methoxycarbonylmethylcyclopentane-1-carboxylate in a 3:1 ratio, resulting from a domino reaction
started by a chemoselective asymmetric Michael addition and subsequent 5-exo-trig intramolecular
cyclization. A chemo- and stereoselective tert-butyl hydrolysis of the mixture of reaction with
trifluoroacetic acid provides the easily separable unreacted diester 20 (21%) and the acid compound
methyl 2-N-benzyl-N-α-methylbenzylamino-5-carboxymethylcyclopentane-1-carboxylate (21) (61%).
Here we demonstrate an efficient strategy towards the synthesis of a cyclopentane β-aminodiester
with three different orthogonal protecting groups on each functionality, which can then submitted to
appropriate modifications for use in β-peptide synthesis. The extension of this strategy to the
preparation of a range of different orthogonally substituted cyclopentane and cyclohexane derived β-
amino acids is currently under investigation in our laboratory.

Molecules 2004, 9
378
Acknowledgements
The authors wish to thank the CICYT, Junta de Castilla y Leon and F. S. E. for financial support
(SA 036/01).
Experimental
General
13
1H-NMR and C-NMR spectra were recorded in CDCl3 at 200 and 400 MHz (1H) or 50 and 100
MHz (13C) on Varian 200 VX and BRUKER DRX 400 instruments, respectively. Multiplicities were
determined by DEPT experiments. IR spectra were registered using a BOMEM 100 FTIR
spectrophotometer. Optical rotations were determined using a Perkin-Elmer 241 polarimeter in a 1 dm
cell and are given in units of 10-1 deg cm2 g-1. Concentrations are quoted in g per 100mL. The electron
impact (EI) mass spectra were run on a VG-TS 250 spectrometer using a 70 eV ionising voltage.
HRMS were recorded using a VG Platform (Fisons) spectrometer using Chemical Ionisation (ammonia
as gas) or Fast Atom Bombardment (FAB) techniques. Thin layer chromatography (tlc) was performed
on aluminium sheets coated with 60 F254 silica. Sheets were visualised using iodine, UV light or 1%
aqueous KMnO4 solution. Column chromatography (CC) was performed with Merck silica gel 60 (70-
230 mesh). Solvents and reagents were generally distilled prior to use: THF from sodium
benzophenone ketyl and dichloromethane (DCM) from KOH. Compounds 9-12 were prepared
according to the published procedures [13-14].
Preparation of (E)-di-tert-butyl-5-vinylhex-2-enedioate (13).
The diacid 10 (208 mg, 1.22 mmol) was dissolved in trifluoroacetic acid (TFAA, 1 mL) at 0 ºC and
the solution was stirred for 30 min. and then tert-BuOH (1 mL) was added. The mixture was stirred for
5 h, then water (10 mL) was added and the crude product extracted with Et2O. The combined organic
extracts were washed with NaHCO3 5%, water and brine. After drying and concentration the residue
was purified by chromatography (95:5 n-hexanol-EtOAc) to give 13 (231 mg, 67%); IR (film) ν (cm-1)
2980, 2934, 1728, 1657, 1460, 1360, 1258, 982, 849; 1H-NMR (200 MHz) 1.42-1.45 (18H, C(CH3)3),
2.39 (1H, ddd, J = 13.0, 6.5 y 6.5Hz, H-4A), 2.58 (1H, ddd, J = 13.0, 6.5 y 6.5Hz, H-4B), 3.10 (1H, c,
J = 6.5Hz, H-5), 5.15 (2H, dd, J =15.5 y 2.0Hz, H-2'A), 5.19 (2H, dd, J =7.5 y 2.0Hz, H-2'B), 5.75
(1H, d, J= 16.0Hz, H-2), 5.80 (1H, ddd, J = 15.5, 7.5 y 6.5Hz, H-1'), 6.75(1H, dt, J = 16.0 y 6.5Hz, H-
3); 13C-NMR (50 MHz) 27.9 and 28.1(3CH3, C(CH3)3), 34.4 (CH2, C-4), 49.7 (CH, C-5), 80.0 (C,
C(CH3)3), 81.0 (C, C(CH3)3), 117.3 (CH2, C-2'), 125.0 (CH, C-2), 135.3 (CH, C-1'), 143.7 (CH, C-3),
165.5 (C, C-1), 171.9 (C, C-6).

Molecules 2004, 9
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Preparation of di-tert-butyl (E,E)-octa-2,6-diendioate and tert-butyl and hydrogen (E,E)-octa-2,6-
diendioates 14 and 15.
To the diacid 9 (593 mg, 3.5 mmol) at 0˚C was added TFAA (1.5 mL) and, after stirring for 30
min., tert-BuOH (1.5 mL) and the mixture was kept at room temperature for 5 h. The reaction product
was partitioned between 10% NaHCO3 (70 mL) and EtOAc (3 x 40 mL). The organic extracts were
washed with water and brine. After drying and concentration compound 14 (407 mg, 42%) was
obtained. The NaHCO3 solution was treated with 6M HCl to pH = 2 and extracted with Et2O. The
organic extracts were washed with water and brine to give, after drying and concentration, compound
15 (450 mg, 57%).
Compound 14: IR (film) ν (cm-1) 2980, 1723, 1655, 1559, 1368, 1329, 1142, 1028, 982; 1H-NMR (200
MHz) 1.45 (18H, s, C(CH3)3), 2.45 (4H, m, H-4 y H-5), 5.75 (2H, d, J = 15.0Hz, H-2 y H-7), 6.8 (2H,
dt, J = 15.6 y 6.6Hz, H-3 y H-6); 13C-NMR (50 MHz) 28.1 (6CH3, C(CH3)3), 30.3 (2CH2, C-4 and C-
5), 80.0 (2C, C(CH3)3), 124.0 (2CH, C-2 y C-7), 149.9 (2CH, C-3 and C-6), 165.6 (2C, COOR).
Compound 15: IR (film) ν (cm-1) 3650, 1717, 1653, 1559, 1458, 1154; 1H-NMR (200 MHz) 1.49 (9H,
s, C(CH3)3), 2.45(4H, m, H-4 y H-5), 5.80(2H, d, J = 15.0Hz, H-2 and H-7), 6.85(1H, dt, J = 15.6 and
13
6.6Hz H-6), 7.15(1H, dt, J = 15.6 y 6.6Hz, H-3); C-NMR (50 MHz) 28.1 (3CH3, C(CH3)3), 30.1
(CH2, C-5), 30.5 (CH2, C-4), 80.0 (C, C(CH3)3), 121.4 (CH, C-7), 124.2 (CH, C-2), 146.3 (CH, C-3),
149.6(CH, C-6), 165.6(C, C-8), 170.4(C, C-1).
Preparation of tert-butyl methyl (E,E)-octa-2,6-diendioate (16).
.
Compound 15 (12 mg, 0.053 mmol) was treated with a solution of gaseous CH2N2 in ether. The
reaction product was concentrated in vacuo to give 16 (12 mg, 95%); IR (film) ν (cm-1) 2978, 1705,
1653, 1559, 1458, 1150 ; 1H-NMR (200 MHz) 1.47 (9H, s, C(CH3)3), 2.45 (4H, m, H-4 and H-5), 3.73
(3H, s, CH3), 5.61 (2H, d, J =16.0Hz, H-2 and H-7), 6.88 (2H, dd, J =16.0 y 6.5Hz, H-3 and H-6);
13C-NMR (50 MHz) 28.0 (3CH3, C(CH3)3), 30.2 and 30.4 (CH2, C-4 and C-5), 51.2 (CH3, COOCH3),
80.1 (C, C(CH3)3), 121.8 and 124.1 (2CH, C-2 and C-7), 145.6 and 147.1 (2CH, C-3 and C-6), 165.6
and 166.6 (C, C-1 and C-8).
Preparation of methyl (1S,2S,5S,αS)-2-N-benzyl-N-α-methylbenzylamino-5-tert-butoxycarbonyl-
methylcyclopentane-1-carboxylate (17) and tert-butyl (1S,2S,5S,αS)-2-N-benzyl-N-α-methylbenzyl-
amino-5-methoxycarbonylmethyl-cyclopentane-1-carboxylate (18).
n-BuLi (1.6 M, 0.50 mL, 0.80 mmol) was added to a stirred solution of (R)-N-benzyl-N-α-methyl-
benzylamine (182 mg, 0.86 mmol) in THF (3 mL) at –78˚C and stirred for 30 minutes prior to the
addition of a solution of 16 (122 mg, 0.50 mmol) in THF (0.5 mL) at –78˚C. After two hours, saturated

Molecules 2004, 9
380
aqueous NH4Cl solution was added and the resulting solution warmed to r.t., partitioned between DCM
(3 x 50 mL) and brine, dried and concentrated in vacuo gave a 3:1 mixture of 17/18 (203 mg, 90%), as
deduced by integration of the methyl ester signals in the 1H-NMR at 3.44 and 3.62 ppm respectively.
Preparation of methyl (1S,2S,5S,αS)-2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethyl-
cyclopentane-1-carboxylate (19).
The 17/18 mixture (58 mg, 0.13 mmol) was dissolved in TFA (0.5 mL) and stirred for 2 hours at rt
before concentration in vacuo to give 40 mg of product, which upon treatment with a solution of
gaseous CH2N2 in ether gave 19 (49 mg, 95%) after concentration in vacuo (yield 72% after
26
crystallization from 7:3 hexane-Et2O); [α]D +50.5 (c 1.21, CHCl3); m.p. 82-84 ºC; C25H31NO4
requires C, 73,32; H. 7,63; N. 3,42; found: C, 73,45; H. 7,46; N. 3,59; IR (film) ν (cm-1) 2950, 1920,
1840, 1740, 1490, 1450; 1H-NMR (400 MHz) 1.31 (1H, m, H-4A), 1.29 (3H, d, J = 6.8, C(α)Me),
1.70-1.85 (2H, m, H-3), 1.95 (1H, m, H-4B), 2.21 (1H, dd, J = 12.0, 8.4, CHAHCO2Me), 2.29-2.39 (2H,
m, H-5 and CHBHCO2Me), 2. 48 (1H, app t, J = 9.8, H-1), 3.43 (3H, s, CO2Me), 3.52 (1H, dt, J = 9.8,
5.0, H-2), 3.60 (3H, s, CO2Me), 3.68 (1H, AB, JAB = 12.4, NCHAHPh), 3.80 (1H, q, J = 6.8, C(α)H),
3.83 (1H, AB, JAB = 12.4, NCHAHBPh), 7.10-7.38 (8H, m, Ar-H), 7.48-7.52 (2H, m, Ar-H); 13C-NMR
(100 MHz) 14.1 (CH3, C(α)Me), 26.5 (CH2, C-3), 30.9 (CH2, C-4), 38.1 (CH, C-5), 38.8 (CH2,
CH2COOMe), 50.0 (CH2, NCH2), 50.0 (CH3, CO2Me), 51.4 ( CH3, CH2CO2Me), 55.3 (CH, C-1), 56.7
(CH, Cα), 63.5 (CH, C-2), 126.5, 126.8, 127.0, 127.8, 127.9, 128.2, 128.6, 128.8 (CH, Ar), 141.1 (C,
CipsoCH2N), 144.2 (C, CipsoCα), 172.4 (C,CH2CO2Me), 174.6 (C, CO2Me); EIMS m/z (%) 409 (M+,
5), 394 (8), 250 (30), 146 (50), 105 (78), 91 (100), 77 (22); HRMS (EI) C25H32NO4 requires 410.2331;
found 410.2329.
Preparation of methyl (1S,2S,5S,αS)-2-N-benzyl-N-α-methylbenzylamino-5-carboxymethylcyclo-
pentane-1-carboxylate (20).
The 18/19 mixture (40 mg, 0.09 mmol) was dissolved in TFA (0.2 mL) and stirred for 15 min. at
0ºC. Then water (1 mL) was added and the mixture was extracted with DCM (3 x 20 mL). The
combined organic layers were washed with water and brine and dried over Na2SO4. Concentration
followed by flash chromatography on silica gel (7:3 n-hexane-EtOAc: gave 18 (8.4 mg, 21%) and 20
(22 mg, 61%).
Compound 18: [α]D26 +37.0 (c 0.26, CHCl3); IR (film) ν (cm-1) 2967, 1734, 1653, 1373, 1148, 667.;
1H-NMR (400 MHz) 1.31 (1H, m, H-4A), 1.35 (3H, d, J = 6.9, C(α)Me), 1.39 (9H, s, C(CH3)3), 1.58
(1H, m, H-3A), 1.76 (1H, m, H-3B), 1.95 (1H, m, H-4B), 2.16 (1H, dd, J = 12.2, 6.8, CHAHCO2Me),
2.29 (1H, m, H-5), 2.38 (1H, app t, J = 10.0, H-1), 2.43 (1H, dd, J = 12.2, 3.0, CHBHCO2Me), 3.62
(3H, s, CO2Me), 3.63 (1H, m, H-2), 3.65 (1H, AB, JAB = 15.7, NCHAHPh), 3.75 (1H, AB, JAB = 15.7,
13
NCHAHBPh),3.85 (1H, q, J = 6.9, C(α)H), 7.10-7.40 (8H, m, Ar-H), 7.45-7.50 (2H, m, Ar-H); C-

Molecules 2004, 9
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NMR (100 MHz) 15.2 (CH3, C(α)Me), 26.3 (CH2, C-3), 28.1 (3CH3, C(CH3)3), 29.6 (CH2, C-4), 38.4
(CH, C-5), 38.6 (CH2, CH2COOMe), 49.9 (CH2, NCH2), 51.3 (CH3, CO2Me), 55.7 (CH, C-1), 57.6
(CH, Cα), 63.2 (CH, C-2), 80.0 (C, C(CH3)3), 126.5, 126.6, 127.5, 127.7, 127.8, 128.0, 128.1, 128.5
t
(CH, Ar), 141.6 (C, CipsoCH2N), 144.1 (C, CipsoCα), 172.6 (C,CH2CO2Me), 173.8 (C, CO2 Bu);
EIMS m/z (%) (M+, 2), 346 (8), 290 (12), 256 (13), 199 (100), 149 (13), 105 (42), 69 (48); HRMS (EI)
C28H37O4N requires 451.2723; found 451.2720.
Compound 20: C24H29O4N requires C, 72,89; H. 7,39; N. 3,54; found: C, 72,97; H. 7,15; N. 3,65;
IR (film) ν (cm-1) 3600-2600 (broad), 1738, 1710, 1495, 1454, 1373, 1283, 1157, 1028, 912; 1H-NMR
(400 MHz,) 1.30 (3H, d, J = 6.9, C(α)Me), 1.35 (1H, m, H-4A), 1.68-1.78 (2H, m, H-3), 1.99 (1H, m,
H-4B), 2.25 (1H, dd, J = 12.2, 7.2, CHAHCO2H), 2.30 (1H, m, H-5), 2.43 (1H, dd, J = 12.2, 3.0,
CHBHCO2H), 2.50 (1H, app t, J = 10.0, H-1), 3.42 (3H, s, CO2Me), 3.55 (1H, q, J = 7.5, H-2), 3.70
(1H, AB, JAB = 15.7, NCHAHPh), 3.85 (1H, AB, JAB = 15.7, NCHAHBPh), 3.87 (1H, q, J = 6.9,
C(α)H), 7.10-7.40 (8H, m, Ar-H), 7.45-7.50 (2H, m, Ar-H); 13C-NMR (100 MHz) 13.7 (CH3,
C(α)Me), 26.2 (CH2, C-3), 30.9 (CH2, C-4), 37.7 (CH, C-5), 38.5 (CH2, CH2COOH), 49.8 (CH2,
NCH2), 51.5 (CH3, CO2Me), 55.3 (CH, C-1), 56.4 (CH, Cα), 62.9 (CH, C-2), 80.0 (C, C(CH3)3), 126.4,
126.8, 127.7, 127.8, 128.2, 128.7 (CH, Ar), 140.9 (C, CipsoCH2N), 144.0 (C, CipsoCα), 174.7 (C,
CO2Me), 177.0 (C, CO2H); EIMS m/z (%) 395(M+,2), 290(5), 251(5), 196(100), 149(9), 91(80),
69(15); HRMS (EI) C24H29O4N requires 395.2097; found 395.2125. In a separate experiment
compound 19 (36 mg, 0.091 mmol) was treated with a solution of gaseous CH2N2 in ether. The
reaction product was concentrated in vacuo to give 20 (36 mg, 96%).
Preparation of (1S,2S,5S,αS)-2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethylcyclo-
pentane- 1-carboxylic acid (21).
The 18/19 mixture (100 mg, 0.22 mmol) was dissolved in TFA (1 mL) and stirred for 30 min. at rt.
Water (2 mL) was then added and the mixture was extracted with DCM (3 x 40 mL). The combined
organic layers were washed with water and brine and dried over Na2SO4. Concentration followed by
flash chromatography on silica gel (7:3 n-hexane-EtOAc) gave 18 (12 mg, 12%), 20 (29 mg, 45%) and
an inseparable 1:1 mixture of 20/21 (13 mg, 22%), from which compound 21 could not be isolated, but
its structure is proposed to be that of the title compound.
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Sample Availability: Available from the authors.
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