A synthetic route to fully substituted chiral cyclopentylamine derivatives: Precursors of carbanucleosides

Article abstract of DOI:10.1055/s-0029-1218677

Removal of silyl protection from d-glucose derived substrate 6 afforded 7, which upon acetonide deprotection followed by reaction with N- benzylhydroxylamine furnished two isomeric isoxazolidinocyclopentane derivatives via spontaneous cyclization of an in situ generated nitrone. The methyl xanthate derivative of the tertiary hydroxyl group of one isomer was isolated and subjected to radical deoxygenation reaction to form epimeric products, while with the other isomer it underwent spontaneous 1,2-elimination to form a mixture of the two possible endocyclic olefins. Hydrogenolytic cleavage of the isoxazolidine rings of the purified products followed by insertion of 5-amino-4-chloropyrimidine moiety and purine ring construction smoothly afforded structurally unique carbanucleoside analogues. Various spectroscopic methods on the synthesized compounds and X-ray analysis on one important intermediate were used to assign the structures and stereochemistry of the products. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218677

PAPER
1303
A Synthetic Route to Fully Substituted Chiral Cyclopentylamine Derivatives:
Precursors of Carbanucleosides
Fully
S
ubstituted
a
C
hiral Cyc
m
lopentylamine
D
eri
p
vatives rasad Ghosh,a Joy Krishna Maity,a Michael G. B. Drew,b Basudeb Achari,a Sukhendu B. Mandal*a
a
Chemistry Division, Indian Institute of Chemical Biology (a unit of CSIR), Jadavpur, Kolkata 700 032, India
Fax +91(33)24735197; E-mail: sbmandal@iicb.res.in
b
Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
Received 21 December 2009; revised 15 January 2010
provements are realized in regard to the desired pharma-
cological activity. Among such nucleosides, carbovir
(3),12 abacavir (4),13 (–) BCA (5),14 carba-5-bromovinyl-
2¢-deoxyuridine,15 and carba-2¢-ara-fluoroguanosine16 are
Abstract: Removal of silyl protection from D-glucose derived sub-
strate 6 afforded 7, which upon acetonide deprotection followed by
reaction with N-benzylhydroxylamine furnished two isomeric isox-
azolidinocyclopentane derivatives via spontaneous cyclization of
an in situ generated nitrone. The methyl xanthate derivative of the important due to their potent anti-HIV activity in vitro. In
tertiary hydroxyl group of one isomer was isolated and subjected to
addition, many of the intermediate aminocarbocycles
have glycosidase inhibitory activity17 or are used as anti-
radical deoxygenation reaction to form epimeric products, while
with the other isomer it underwent spontaneous 1,2-elimination to
biotics.18
form a mixture of the two possible endocyclic olefins. Hydro-
genolytic cleavage of the isoxazolidine rings of the purified prod-
NH2
O
N
NH2
ucts followed by insertion of 5-amino-4-chloropyrimidine moiety
and purine ring construction smoothly afforded structurally unique
carbanucleoside analogues. Various spectroscopic methods on the
synthesized compounds and X-ray analysis on one important inter-
mediate were used to assign the structures and stereochemistry of
the products.
N
N
N
N
N
N
N
NH
N
OH
OH
OH
HO
N
NH2
N
OH
HO
OH
3
1
2
Key words: cyclopentylamine, INC reaction, carbanucleosides, D-
glucose
NH2
NH
N
N
N
N
N
OH
N
HO
N
N
NH2
Natural nucleosides, susceptible to various enzymes for
glycosidic bond cleavage,1 exist in a dynamic equilibrium
between North-type and South-type geometry2 in solution
due to rapid change of the furanose ring in the pseudoro-
tational cycle in which a conformationally unrestricted
furanose ring can adopt a number of envelope or twist
forms. However, only one conformer is found in the solid
state and only one conformer is responsible for forming a
nucleoside-enzyme complex, which shows activity. Thus,
much attention has been given to structural modifications
of nucleosides3 to confer metabolic stability as well as
conformational restriction in the furanose ring. Various
analogues of substituted cyclopentane containing
carbanucleosides4–7 have been synthesized for potential
antiviral activity.8 They are inert towards free radical-
induced degradation by C-4¢-H abstraction9 as is observed
with the ribose ring. The importance of the carbanucleo-
sides has been realized after the isolation of (–)-
aristeromycin10 (1) and (–)-neplanocin A (2),11 both dis-
playing antibiotic and antitumor activity, from natural
sources (Figure 1). By modifying these biologically ac-
tive compounds, structurally similar but non-natural syn-
thetic carbanucleoside analogues are generated where the
molecular complexity is kept to a minimum whilst im-
HO
4
5
Figure 1 Structure of some carbanucleosides 1–5
Based on these observations, we describe herein an ap-
proach to the synthesis of fully substituted and more
crowded cyclopentylamine derivatives, precursors of car-
banucleosides, through an application of intramolecular
nitrone cycloaddition (INC) reactions19,20 on an appropri-
ate sugar derived substrate having requisite functionalities
at the proper positions.
We started our investigation by synthesizing cyclopentyl-
amine derivatives via INC reaction on D-glucose derived
precursors. Toward this end, removal of silyl protection
from 621by tetrabutylammonium fluoride furnished 7
(93%), which upon acetonide deprotection followed by
reaction with benzylhydroxylamine (Scheme 1) in reflux-
ing ethanol generated two isomeric isoxazolidinocyclo-
pentane derivatives 9 (36%) and 10 (32%) through the in
situ generated 1,3-dipolar enose nitrone 8. The success of
this reaction was evident from the absence of olefinic pro-
ton signals and the occurrence of ten aromatic proton sig-
1
nals in the H NMR spectra of these two products. An
alternative bridged [3.2.1] structure, which could have
formed through the other mode of cyclization, was ruled
out from the absence of upfield proton and carbon signals
SYNTHESIS 2010, No. 8, pp 1303–1310
Advanced online publication: 11.02.2010
DOI: 10.1055/s-0029-1218677; Art ID: P17209SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

1304
R. Ghosh et al.
PAPER
for a methylene group in the H and 13C NMR spectra.
Since these isoxazolidino-cyclopentanes belong to the bi-
cyclo[3.3.0]octane system, the ring juncture stereochem-
istry of cis should be energetically favored. Structural
confirmation was finally obtained from a single crystal X-
ray crystallographic study (the ORTEP diagram is given
in Figure 2) of 9. The structure of 10 was thus settled as
indicated in the structure.
1
OBn
OBn
(i) NaH, THF
0 °C, 5 min, N2
OBn
OH
OBn
BnO
Bn
BnO
Bn
OBn
9
+
(ii) BnBr, Bu4NI
0 °C to r.t., 3 h, N2
N
N
O
11 (80%)
O
12 (9%)
OBn
(i) NaH, THF, CS2
reflux, 2 h, N2
(ii) cool to r.t., MeI,
OBn
BnO
Bn
Bu3SnH, AIBN
SMe
11
toluene, reflux
6 h, N2
O
reflux, 2 h, N2
79%
S
N
(i) H2SO4 (4%)
MeCN−H2O (3:1)
r.t., 12 h
O
O
O
Bu4NF
THF
O
O
13
TBDMSO
HO
OBn
(ii) BnNHOH
reflux, 5 h
OBn
r.t., 2 h
93 %
O
O
BnO
BnO
OBn
OBn
6
BnO
Bn
7
BnO
+
OBn
OBn
N
N
Bn
OH
OH
O
O
OH
HO
HO
O
HO
HO
14 (59%)
15 (10%)
+
OH
N
N
+
Bn
Scheme 2 Removal of tertiary hydroxy group of 9
Bn
N
O
Bn
O
OH
BnO
10 (32%)
8
9 (36%)
(Scheme 3). The disposition of the double bond was de-
duced by the appearance of carbon signals in 18 at d =
117.5 (C-4) and 151.6 (C-5) and in 19 at d = 128.8 (C-4)
and 141.7 (C-3a) in their 13C NMR spectra. The facile 1,2-
elimination in case of 17 as contrasted with 11 appears to
be due to the absence of steric hindrance by the isoxazoli-
dine ring (in the b-face) to cyclic transition state formation
in the former case.
Scheme 1 Cyclopentane derivatives 9 and 10 through INC reaction
OBn
OBn
OBn
OBn
(i) NaH, THF
0 °C, 5 min
BnO
Bn
BnO
Bn
OBn
OH
10
(ii) BnBr, Bu4NI
0 °C to r.t., 3 h
+
N
N
O
O
16 (7%)
17 (68%)
Figure 2 ORTEP diagram of 9 with ellipsoids at 50% probability
OBn
4
OBn
OBn
OBn
5
BnO
Bn
BnO
4
(i) NaH, THF
CS2, reflux, 2 h
We next turned our attention to deoxygenating the tertiary
hydroxyl group generating a number of cyclopentane de-
rivatives with different substitution patterns. Thus, selec-
tive benzylation (NaH, BnBr, Bu4NI) to protect the
primary and secondary hydroxyl groups of 9 furnished the
derivative 11 (Scheme 2) in 80% yield together with the
fully substituted minor product 12. Protection of the hy-
droxy group in 11 as methyl xanthate (using NaH, CS2,
MeI) afforded 13 (79%). Radical-induced reduction of the
methyl xanthate group with Bu3SnH and AIBN furnished
a mixture of 14 (59%) and 15 (10%). Formation of 14 as
the major product could be anticipated as the approach of
the hydrogen radical to the tertiary carbon radical from the
exo-face of the 5,5-bicycle takes place preferentially due
to the hindrance offered by the isoxazolidine ring in the
endo-face.
+
3a
N
N
1
Bn
(ii) cool to r.t., MeI,
reflux, 2 h
O
O
19 (33%)
18 (39%)
Scheme 3 Formation of olefins 18 and 19 during the preparation of
methyl xanthate on 17
Cleavage of the isoxazolidine rings and removal of the
benzyl protections from 9 and 10 by hydrogenation reac-
tion over Pd/C (Scheme 4) afforded their respective cy-
clopentylamine derivatives 20 (63%) and 21 (70%).
Similar hydrogenolysis reaction on 19 furnished 22 (60%)
and 23 (8%) as the double bond reduced products;22 how-
ever, the other olefin 18 failed to afford any desired prod-
uct and furnished instead a mixture of polymeric products.
The product 22 on transfer hydrogenolysis reaction with
Pd/C–cyclohexene23generated the desired amine deriva-
tive 24. The formation of the cis-fused isomer as the major
product from the hydrogenation reaction of 19 was ex-
pected, as the trans stereochemistry is energetically unfa-
vorable.
Similar benzylation of 10 produced the major product 17
(68%) together with the minor compound 16 (7%). Dur-
ing the preparation of the methyl xanthate of 17 for deoxy-
genation reaction, the olefinic compounds 18 and 19 were,
however, obtained instead in almost equivalent yields
Synthesis 2010, No. 8, 1303–1310 © Thieme Stuttgart · New York

PAPER
Fully Substituted Chiral Cyclopentylamine Derivatives
1305
OH
NH2
tion of 21 with 5-amino-4,6-dichloropyrimidine to 27
(60%) and its reaction with triethyl orthoformate in acidic
condition.
HO
HO
HO
Pd/C (10%), H2 (1 atm)
9
EtOH, r.t., 12 h
63%
OH
20
In conclusion, this work describes the application of an
INC reaction on a D-glucose derived precursor featuring
vinyl and hydroxymethyl functionalities at C-4 and a la-
tent aldehyde moiety at C-1 to produce polyhydroxylated
aminocarbocycles. These constitute potential intermedi-
ates to synthesize bioactive carbanucleosides and unnatu-
ral oligonucleotides. An added advantage of this approach
is that the aminocarbocycles may have glycosidase inhib-
itory activity as well.
OH
NH2
OH
HO
HO
Pd/C (10%), H2 (1 atm)
EtOH, r.t., 18 h
10
70%
HO
21
OBn
OBn
BnO
Pd/C (10%)
BnO
OBn
OBn
19
H
2 (1 atm)
+
EtOH, r.t., 12 h
N
N
Bn
Bn
O
O
23 (8%)
22 (60%)
Melting points were taken in open capillaries and are uncorrected.
1H and 13C NMR spectra were recorded in CDCl3, C5D5N, DMSO-
d6, CD3OD, or D2O as solvent using TMS as internal standard. Mass
spectra were recorded in ESI and FAB mode. Specific rotations
were measured at 589 nm. Pre-coated plates (0.25 mm, silica gel 60
F254) were used for TLC analyses. All the solvents were distilled and
purified as necessary. Petroleum ether (PE) used refers to the frac-
tion boiling at 60–80 °C.
OH
HO
OH
Pd/C (10%), cyclohexene
22
EtOH, reflux, 6 h
58%
H2N
OH
24
Scheme 4 Conversion of 9, 10, and 19 to cyclopentylamine deriva-
tives
3-O-Benzyl-1,2-O-isopropylidene-4-vinyl-b-L-arabinofuranose
(7)
Finally, to demonstrate the feasibility of converting the
aminocyclopentane derivatives to the corresponding nu-
cleoside analogues, we chose the products 20 and 21
(Scheme 5). Coupling reaction of 20 with 5-amino-4,6-
dichloropyrimidine in refluxing n-butanol in presence of
triethylamine produced the pyrimidinyl pentahydroxylat-
ed carbocycle derivative 25 (57%). Construction of a pu-
rine ring from the pyrimidine ring was accomplished by
treatment with triethyl orthoformate in acidic medium to
furnish the chloropurine carbanucleoside 26 (64%). The
To a solution of 6 (664 mg, 1.58 mmol) in THF (50 mL) was added
Bu4NF (494 mg, 1.89 mmol) portionwise and the mixture was
stirred at r.t. for 2 h. The solvent was evaporated in vacuo and the
residue was extracted with CHCl3 (3 × 30 mL). The CHCl3 solution
was washed with brine (2 × 30 mL), dried (Na2SO4), and concen-
trated to afford a gummy mass. The crude product was purified by
column chromatography on silica gel (100–200 mesh) using
EtOAc–PE (17:83) as eluent to afford 7 as a colorless liquid; yield:
452 mg (93%); [a]D25 +20.9 (c 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 1.57 (s, 3 H,
diastereomeric carbanucleoside 28 was obtained (68%) CH3), 3.52 (d, J = 11.8 Hz, 1 H, H-5), 3.62 (d, J = 11.8 Hz, 1 H, H-
5), 4.16 (d, J = 2.5 Hz, 1 H, H-3), 4.57 (d, J = 11.8 Hz, 1 H, CH2Ph),
via a similar sequence of reactions, namely, by the reac-
4.66 (dd, J = 2.8, 4.1 Hz, H-2), 4.74 (d, J = 11.8 Hz, 1 H, CH2Ph),
5.28 (d, J = 11.0 Hz, 1 H, CH2=CH), 5.47 (d, J = 17.3 Hz, 1 H,
Cl
CH2=CH), 5.90–6.00 (m, 2 H, H-1 and CH=CH2), 7.34 (m, 5 H,
ArH).
HO
H2N
5-amino-4,6-dichloro-
pyrimidine, anhyd Et3N
N
HO
HO
HO
HO
13C NMR (75 MHz, CDCl3): d = 27.6 (CH3), 28.1 (CH3), 65.6 (C-
5), 72.8 (CH2Ph), 84.6 (C-3), 86.7 (C-2), 89.5 (C -4), 104.1 (C-1),
114.0 (CCH3), 116.6 (CH2=CH), 128.0 (2 × CH, Ar), 128.2 (CH,
Ar), 128.8 (2 × CH, Ar), 134.9 (CH=CH2), 137.9 (C, Ar).
20
N
N
BuOH, reflux, 30 h
N2
H
HO
HO
OH
OH
57%
25
Cl
N
FABMS: m/z = 329 (M + Na)+.
N
HC(OEt)3, PTSA, 10 °C
N
N
16 h, N2
64%
Anal. Calcd for C17H22O5: C, 66.65; H, 7.24. Found: C, 66.38; H,
7.00.
26 OH
Cl
(2S,3S,4S,5R,6S)-1-Benzyl-5-benzyloxy-4-hydroxymethyl-
hexahydrocyclopenta[c]isoxazole-4,6-diol (9) and
HO
H2N
N
5-amino-4,6-dichloro-
pyrimidine, anhyd Et3N
HO
(2R,3R,4S,5R,6S)-1-Benzyl-5-benzyloxy-4-hydroxymethyl-
hexahydrocyclopenta[c]isoxazole-4,6-diol (10)
21
N
H
N
BuOH, reflux, 30 h, N2
60%
HO
Compound 7 (3.50 g, 11.44 mmol) dissolved in 4% H2SO4 in
MeCN–H2O (3:1, 75 mL) was stirred at r.t. for 12 h. The solution
was neutralized with solid CaCO3, filtered, and the filtrate was
evaporated to furnish a mixture of anomers as a thick oil. To a solu-
tion of this oil (dried over P2O5) in anhyd EtOH (40 mL) was added
N-benzylhydroxylamine (4.16 g, 33.84 mmol) and the mixture was
heated at reflux for 5 h. The solvent was evaporated to furnish a
brown residue, which was purified by silica gel column chromatog-
raphy (100–200 mesh). Careful elution with EtOAc–PE (2:3) af-
forded 9 and 10 as crystalline solids.
OH
HO
27
Cl
OH
N
N
HC(OEt)3, PTSA, 10 °C
HO
HO
16 h, N2
68%
N
N
HO
OH
28
Scheme 5 Preparation of carbanucleosides 26 and 28 from 20 and
21
Synthesis 2010, No. 8, 1303–1310 © Thieme Stuttgart · New York

1306
9
R. Ghosh et al.
PAPER
with CHCl3 (3 × 25 mL). The CHCl3 solution was washed with
H2O, dried (Na2SO4), and concentrated to afford a liquid, which was
purified by column chromatography on silica gel (60–120 mesh).
Elution with EtOAc–PE (1:19) furnished 12 and with EtOAc–PE
(9:91) afforded 11 as colorless solids.
25
Yield: 1.53 g (36%); mp 123–124 °C (EtOAc–PE, 2:3); [a]D
–154.5 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 2.76 (br s, 1 H, H-3a), 3.02 (t,
J = 7.5 Hz, 1 H, H-6a), 3.46–3.49 (m, 2 H), 3.75–3.87 (m, 4 H), 3.98
(t, J = 6.0 Hz, 1 H), 4.05 (t-like, J = 7.5, 8.6 Hz, 1 H), 4.19 (d,
J = 12.8 Hz, 1 H, NCH2Ph), 4.38 (d, J = 9.2 Hz, 1 H), 4.61 (d,
J = 11.3 Hz, 1 H, OCH2Ph), 4.81 (d, J = 11.3 Hz, 1 H, OCH2Ph),
7.32–7.35 (m, 10 H, ArH), signal for 1 H was not discernible.
11
25
Yield: 656 mg (80%); mp 165–166 °C (EtOAc–PE, 1:3); [a]D
+39.3 (c 0.32, CHCl3).
1H NMR (300 MHz, CDCl3): d = 2.83 (s, 1 H, OH), 3.24 (ddd,
J = 2.7, 2.7, 7.8 Hz, 1 H, H-3a), 3.37 (d, J = 9.3 Hz, 1 H), 3.55 (t-
like, J = 7.2, 7.7 Hz, 1 H), 3.68 (d, J = 9.0 Hz, 1 H), 3.71 (partially
merged t, J = 7.2 Hz, 1 H), 3.85 (d, J = 12.5 Hz, 1 H, NCH2Ph),
3.99–4.12 (m, 3 H), 4.29–4.34 (m, 2 H, CH2Ph), 4.49–4.63 (m, 3 H,
CH2Ph), 4.71 (s, 2 H, OCH2Ph), 7.20–7.42 (m, 20 H, ArH).
13C NMR (75 MHz, CDCl3): d = 51.3 (C-3a), 61.1 (C-3), 66.5 (C-
6a), 66.8 (NCH2Ph), 72.5 (OCH2), 73.3 (OCH2Ph), 73.6 (OCH2Ph),
74.1 (OCH2Ph), 78.5 (C-4), 80.0 (C-6 or C-5), 87.0 (C-5 or C-6),
127.9–128.9 (19 × CH, Ar), 130.3 (CH, Ar), 138.2 (2 × C, Ar),
138.6 (C, Ar), 139.0 (C, Ar).
13C NMR (75 MHz, C5D5N): d = 57.3 (C-3a), 62.3 (C-3), 65.2
(CH2OH), 68.1 (NCH2Ph), 74.1 (OCH2Ph), 77.7 (C-6a), 81.1 (C-5
or C-6), 83.2 (C-4), 93.6 (C-6 or C-5), 128.9 (CH, Ar), 129.2 (CH,
Ar), 129.5 (2 × CH, Ar), 130.1 (2 × CH, Ar), 130.2 (2 × CH, Ar),
131.2 (2 × CH, Ar), 140.5 (C, Ar), 141.4 (C, Ar).
ESIMS: m/z = 394 (M + Na)+.
Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77. Found: C,
67.75; H, 6.58; N, 3.51.
Crystal Data of 924
C21H25NO5, M = 371.42, orthorhombic, space group P212121, Z = 4,
a = 5.3774(4), b = 12.0047(14), c = 28.822(4), U = 1860.6(4)°,
dcalc = 1.326 g/cm3. A set of 5298 independent data were collected
with MoKa radiation at 100 K using the Oxford Diffraction X-Cal-
ibur CCD System. The crystal was positioned at 50 mm from the
CCD. 321 frames were measured with a counting time of 10 s. Data
analysis was carried out with the CrysAlis program.25a The structure
was solved using direct methods with the Shelxs97 program.25b The
non-hydrogen atoms were refined with anisotropic thermal param-
eters. The hydrogen atoms bonded to carbon were included in geo-
metric positions and given thermal parameters equivalent to 1.2
times those of the atom to which they were attached. The structure
was refined on F2 using Shelxl97 to R1 0.0522; wR2 0.1193 for 2797
reflections with I > 2s(I).
ESIMS: m/z = 552 (M + H)+, 574 (M + Na)+.
Anal. Calcd for C35H37NO5: C, 76.20; H, 6.76; N, 2.54. Found: C,
75.95; H, 6.53; N, 2.30.
12
Yield: 23 mg (9%); mp 141–142 °C (CHCl3–PE, 1:3); [a]D25 +23.7
(c 0.6, CHCl3).
1H NMR (300 MHz, CDCl3): d = 3.56 (m, 2 × CH), 3.64 (d,
J = 10.2 Hz, 1 H), 3.79–3.86 (m, 3 H), 4.03 (d, J = 12.6 Hz, 1 H)
4.09 (m, 1 H), 4.19 (d, J = 12.4 Hz, 1 H, NCH2Ph), 4.23 (d, J = 9.0
Hz, 1 H), 4.33 (br d, J = 8.0 Hz, 1 H), 4.44–4.59 (m, 4 H), 4.71 (t,
J = 11.7 Hz, 2 H, OCH2Ph), 4.83 (d, J = 11.7 Hz, 1 H, OCH2Ph),
7.25–7.43 (m, 25 H, ArH).
13C NMR (75 MHz, CDCl3): d = 49.7 (C-3a), 60.8 (C-3), 64.9 (C-
6a), 67.2 (OCH2), 67.4 (NCH2Ph), 70.9 (OCH2Ph), 72.3 (OCH2Ph),
73.3 (OCH2Ph), 73.9 (OCH2Ph), 81.0 (C-5 or C-6), 81.9 (C-4), 87.4
(C-6 or C-5), 127.4–128.8 (24 × CH, Ar), 130.4 (CH, Ar), 136.3 (C,
Ar), 138.4 (C, Ar), 138.7 (C, Ar), 139.3 (2 × C, Ar).
10
25
Yield: 1.36 g (32%); mp 82–84 °C (EtOAc–PE, 2:3); [a]D +27.2
(c 0.41, CHCl3).
1H NMR (300 MHz, C5D5N): d = 3.63 (dt, J = 4.4, 4.8 8.7 Hz, 1 H,
H-3a), 3.95 (d, J = 13.5 Hz, 1 H), 4.07–4.13 (m, 2 H), 4.22 (d,
J = 9.0 Hz, 1 H), 4.28 (d, J = 11.0 Hz, 1 H, NCH2Ph), 4.40 (d,
J = 6.4 Hz, 1 H), 4.46 (d, J = 11.0 Hz, 1 H, NCH2Ph), 4.65–4.69 (m,
2 H), 4.96 (d, J = 12.0 Hz, 1 H, OCH2Ph), 5.03 (d, J = 12.0 Hz, 1 H,
OCH2Ph), 6.43 (br s, 1 H, OH), 6.57 (br s, 1 H, OH), 7.11 (br s, 1
H, OH), 7.18–7.31 (m, 6 H, ArH), 7.45–7.54 (m, 4 H, ArH).
ESIMS: m/z = 642 (M + H)+, 664 (M + Na)+.
Anal. Calcd for C42H43NO5: C, 78.60; H, 6.75; N, 2.18. Found: C,
78.44; H, 6.56; N, 2.05.
(2S,3S,4S,5R,6S)-Dithiocarbonic Acid O-[1-Benzyl-5,6-bis(ben-
zyloxy)-4-benzyloxymethylhexahydrocyclopenta[c]isoxazol-4-
yl] Ester S-Methyl Ester (13)
13C NMR (75 MHz, C5D5N): d = 55.3 (C-3a), 60.4 (C-3), 63.4
(CH2OH), 66.2 (NCH2Ph), 72.3 (OCH2Ph), 75.8 (C-6a), 79.4 (C-5
or C-6), 81.4 (C-4), 91.6 (C-6 or C-5), 127.2 (CH, Ar), 127.4 (CH,
Ar), 127.7 (2 × CH, Ar), 128.0 (2 × CH, Ar), 128.3 (2 × CH, Ar),
129.4 (2 × CH, Ar), 138.7 (C, Ar), 139.5 (C, Ar).
To a solution of 11 (500 mg, 0.91 mmol) in anhyd THF (50 mL) at
0 °C was added NaH (132 mg, 5.5 mmol, 60% suspension in oil)
portionwise under N2. After 10 min of vigorous stirring, CS2 (1.1
mL, 18.2 mmol) was added and the mixture was heated at reflux for
2 h. The mixture was cooled to r.t., MeI (0.28 mL, 4.55 mmol) was
added and heated at reflux for 2 h. Excess NaH was destroyed by
slow addition of cold H2O (5 mL) and the solvent was evaporated.
The residue thus obtained was dissolved in CH2Cl2 (40 mL) and the
solution was repeatedly washed with H2O (3 × 20 mL), brine (40
mL), and dried (Na2SO4). The solvent was evaporated to furnish a
crude solid, which was purified by silica gel column chromatogra-
phy (60–120 mesh) using CHCl3–PE (19:1) as eluent to obtain 13
as a yellowish solid; yield: 461 mg (79%); mp 68–71 °C (CHCl3–
PE, 1:3); [a]D25 –2.1 (c 0.8, CHCl3).
ESIMS: m/z = 372 (M + H) +, 394 (M + Na)+.
Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77. Found: C,
68.19; H, 6.95; N, 3.55.
(2S,3S,4S,5R,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazol-4-ol (11) and
(2S,3S,4S,5R,6S)-1-Benzyl-4,5,6-tris(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazole (12)
Oil-free NaH (247 mg, 10.29 mmol) was added portionwise to a so-
lution of 9 (476 mg, 1.29 mmol) in anhyd THF (30 mL) at 0 °C un-
der N2 and the mixture was stirred for 5 min. To the reaction
mixture, benzyl bromide (0.31 mL, 2.57 mmol) and Bu4NI (48 mg,
0.13 mmol) were added and the mixture was stirred at r.t. for 3 h un-
der N2. Excess NaH was destroyed by adding aq NH4Cl (5 mL) .
The solvent was evaporated in vacuo and the residue was extracted
1H NMR (300 MHz, CDCl3): d = 2.47 (s, 3 H, CH3), 3.56 (t, J = 7.5
Hz, 1 H), 3.79–4.04 (m, 5 H), 4.17 (m, 2 H), 4.32 (d, J = 12.6 Hz, 1
H, OCH2Ph), 4.37 (t, J = 8.0 Hz, 1 H and m, 1 H), 4.44 (s, 2 H,
OCH2Ph), 4.62 (d, J = 12.2 Hz, 1 H, OCH2Ph), 4.81 (s, 2 H,
OCH2Ph), 7.13–7.37 (m, 20 H, ArH).
Synthesis 2010, No. 8, 1303–1310 © Thieme Stuttgart · New York

PAPER
Fully Substituted Chiral Cyclopentylamine Derivatives
1307
13C NMR (75 MHz, CDCl3): d = 20.0 (CH3), 50.3 (C-3a), 60.9 (C-
3), 65.9 (C-6a), 66.5 (NCH2Ph), 68.2 (OCH2), 72.3 (OCH2Ph), 73.8
(OCH2Ph), 74.0 (OCH2Ph), 77.7 (C-5 or C-6), 87.6 (C-6 or C-5),
94.1 (C-4), 127.8–130.1 (20 × CH, Ar), 137.4 (C, Ar), 138.2 (C,
Ar), 138.9 (C, Ar), 139.1 (C, Ar), 214.6 (CS2CH3).
(2R,3R,4S,5R,6S)-1-Benzyl-4,5,6-tris(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazole (16) and
(2R,3R,4S,5R,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazol-4-ol (17)
Compounds 16 and 17 were prepared from 10 according to the pre-
vious procedure (described for 11 and 12 from 9) using the protocol:
10 (750 mg, 2.02 mmol), oil-free NaH (389 mg, 16.9 mmol), anhyd
THF (60 mL), benzyl bromide (0.47 mL, 4.04 mmol), and Bu4NI
(72 mg, 0.20 mmol). Purification of the crude mixture by column
chromatography on silica gel (60–120 mesh) using EtOAc–PE
(7:93) furnished 16 and EtOAc–PE (1:9) mixture gave 17 as color-
less solids.
ESIMS: m/z = 642 (M + H)+.
Anal. Calcd for C37H39NO5S2: C, 69.24; H, 6.12; N, 2.18. Found: C,
69.03; H, 6.09; N, 2.07.
(2S,3S,4S,5S,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazole (14) and
(2S,3S,4R,5S,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazole (15)
16
25
To a solution of 13 (60 mg, 0.09 mmol) in toluene (10 mL) were
added Bu3SnH (0.25 mL, 0.94 mmol) and AIBN (2 mg, 0.01 mmol)
and the mixture was heated at reflux for 6 h under N2. The solvent
was evaporated and the crude mixture was partitioned between
MeCN and PE (20 mL, 2:3). The MeCN solution was taken and
evaporated to a residue, which was purified by column chromatog-
raphy (100–200 mesh) using EtOAc–PE (1:24) to yield 15 and 14
as colorless solids.
Yield: 90 mg (7%); mp 120–121 °C (EtOAc–benzene, 1:3); [a]D
–6.4 (c 0.49, CHCl3).
1H NMR (300 MHz, CDCl3): d = 3.38–3.45 (m, H-3a), 3.67 (d,
J = 12.6 Hz, 1 H), 3.74 (d, J = 11.3 Hz, 1 H), 3.78–3.82 (m, 1 H),
3.96–3.99 (m, 4 H), 4.08–4.14 (m, 2 H), 4.47–4.56 (m, 6 H), 4.69
(d, J = 11.8 Hz, 2 H, OCH2Ph), 7.18–7.39 (m, 25 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.1 (C-3a), 61.1 (C-3), 66.3
(NCH2Ph), 67.3 (OCH2), 69.1 (OCH2Ph), 72.3 (OCH2Ph), 72.5
(OCH2Ph), 73.6 (C-6a), 74.1 (OCH2Ph), 86.3 (C-4), 87.8 (C-5 or C-
6), 88.2 (C-6 or C-5), 127.7–130.0 (25 × CH, Ar), 137.1 (C, Ar),
138.4 (C, Ar), 138.6 (C, Ar), 138.9 (C, Ar) 139.5 (C, Ar).
14
25
Yield: 28 mg (59%); mp 135–136 °C (EtOAc–benzene, 1:3); [a]D
–57.8 (c 0.7, CHCl3).
1H NMR (300 MHz, CDCl3): d = 2.20–2.26 (m, 1 H, H-3a or H-4),
3.19–3.23 (m, 1 H, H-4 or H-3a), 3.46 (t, J = 9.8 Hz, 1 H), 3.55 (t,
J = 7.2 Hz, 1 H), 3.66–3.74 (m, 2 H), 3.88–4.04 (m, 5 H), 4.22 (d,
J = 12.0 Hz, 1 H, CH2Ph), 4.39 (d, J = 12.0 Hz, 1 H, OCH2Ph), 4.48
(d, J = 12.0 Hz, 1 H, OCH2Ph), 4.52 (t, J = 12.0 Hz, 2 H, OCH2Ph),
4.83 (d, J = 11.4 Hz, 1 H, OCH2Ph), 7.20–7.42 (m, 20 H, ArH).
13C NMR (75 MHz, CDCl3): d = 41.8 (C-3a or C-4), 44.8 (C-4 or C-
3a), 61.3 (OCH2), 65.3 (C-6a), 66.9 (NCH2Ph), 69.3 (OCH2), 72.2
(OCH2Ph), 73.6 (OCH2Ph), 73.7 (OCH2Ph), 82.6 (C-5 or C-6), 84.6
(C-6 or C-5), 127.9–130.5 (20 × CH, Ar), 137.5 (C, Ar), 138.5 (C,
Ar), 138.6 (C, Ar), 139.1 (C, Ar).
ESIMS: m/z = 642 (M + H)+, 664 (M + Na)+.
Anal. Calcd for C42H43NO5: C, 78.60; H, 6.75; N, 2.18. Found: C,
78.43; H, 6.51; N, 2.01.
17
Yield: 757 mg (68%); mp 139–140 °C (EtOAc–benzene, 1:3);
[a]D25 +24.1 (c 0.46, CHCl3).
1H NMR (300 MHz, CDCl3): d = 3.14 (s, 1 H, OH), 3.18–3.25 (m,
1 H, H-3a), 3.66 (d, J = 9.5 Hz, 1 H), 3.71 (d, J = 12.8 Hz, 1 H),
3.77–3.83 (m, 3 H), 3.88 (br s, 1 H), 4.01 (t-like, J = 8.3, 9.5 Hz, 1
H), 4.03 (partially merged d, 1 H), 4.11 (dd, J = 4.5, 9.0 Hz, 1 H),
4.36 (d, J = 12.0 Hz, 1 H, OCH2Ph), 4.42 (d, J = 12.0 Hz, 1 H,
OCH2Ph), 4.51 (d, J = 12.0 Hz, 1 H, OCH2Ph), 4.55 (s, 2 H,
OCH2Ph), 4.61 (d, J = 12.0 Hz, 1 H, OCH2Ph), 7.18–7.42 (m, 20 H,
ArH).
ESIMS: m/z = 558 (M + Na)+.
Anal. Calcd for C35H37NO4: C, 78.48; H, 6.96; N, 2.61. Found: C,
78.31; H, 6.73; N, 2.40.
15
13C NMR (75 MHz, CDCl3): d = 55.0 (C-3a), 60.7 (C-3), 66.0
(NCH2Ph), 70.3 (OCH2), 71.8 (OCH2Ph), 72.1 (OCH2Ph), 73.2 (C-
6a), 73.6 (OCH2Ph), 80.7 (C-4), 86.6 (C-5 or C-6), 87.7 (C-6 or C-
5), 127.4–129.4 (20 × CH, Ar), 136.7 (C, Ar), 137.5 (C, Ar), 138.1
(2 × C, Ar).
25
Yield: 5 mg (10%); mp 125–127 °C (EtOAc–benzene, 1:3); [a]D
+98.8 (c 0.58, CHCl3).
1H NMR (600 MHz, CDCl3): d = 2.28 (m, 1 H, H-3a or H-4), 3.50
(br s, 1 H, H-4 or H-3a), 3.79 (br s, 2 H), 3.82 (d, J = 8.4 Hz, 1 H),
3.84 (d, J = 8.4 Hz, 1 H), 3.94 (q, J = 10.2 Hz, 2 H), 4.03 (br t-like,
1 H), 4.12 (t, J = 7.2 Hz, 1 H), 4.26 (d, J = 8.4 Hz, 1 H), 4.35 (d,
J = 12.0 Hz, 1 H, OCH2Ph), 4.43 (d, J = 12.0 Hz, 1 H, OCH2Ph),
4.47 (d, J = 12.0 Hz, 1 H, OCH2Ph), 4.62 (d, J = 12.6 Hz, 1 H,
OCH2Ph), 4.75 (s, 2 H, OCH2Ph), 7.15–7.38 (m, 20 H, ArH).
13C NMR (150 MHz, CDCl3): d = 50.3 (C-3a or C-4), 60.6 (OCH2),
65.3 (C-4 or C-3a), 67.2 (NCH2Ph), 67.9 (OCH2), 71.9 (OCH2Ph),
73.3 (OCH2Ph), 73.6 (OCH2Ph), 77.3 (C-6a), 77.8 (C-5 or C-6),
86.5 (C-5 or C-6), 127.3–129.6 (20 × CH, Ar), 137.1 (C, Ar), 137.7
(C, Ar), 138.5 (C, Ar), 138.6 (C, Ar).
ESIMS: m/z = 552 (M + H)+, 574 (M + Na)+.
Anal. Calcd for C35H37NO5: C, 76.20; H, 6.76; N, 2.54. Found: C,
75.91; H, 6.57; N, 2.25.
(2R,3R,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxymethyl-
3,3a,6,6a-tetrahydro-1H-cyclopenta[c]isoxazole (18) and
(2R,5S,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxymethyl-
3,5,6,6a-tetrahydro-1H-cyclopenta[c]isoxazole (19)
Compound 17 (700 mg, 1.27 mmol) was subjected to a procedure
similar to that described earlier (for the conversion of 11 to 13) us-
ing the protocol: (i) NaH (183 mg, 7.6 mmol, 60% suspension in
oil), (ii) CS2 (1.53 mL, 25.4 mmol), (iii) MeI (0.40 mL, 6.35 mmol),
and (iv) anhyd THF (50 mL) to yield 18 as a brownish liquid and 19
as a white semi-solid mass after purification by silica gel column
chromatography (100–200 mesh) using EtOAc–PE as eluents in the
ratios of 1:9 and 13:87, respectively.
ESIMS: m/z = 536 (M + H)+, 558 (M + Na)+.
Anal. Calcd for C35H37NO4: C, 78.48; H, 6.96; N, 2.61. Found: C,
78.54; H, 6.67; N, 2.37.
18
Yield: 264 mg (39%); [a]D25 +73.4 (c 0.59, CHCl3).
Synthesis 2010, No. 8, 1303–1310 © Thieme Stuttgart · New York

1308
R. Ghosh et al.
PAPER
(2R,3R,4R,5S,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazole (22) and
(2R,3S,4S,5S,6S)-1-Benzyl-5,6-bis(benzyloxy)-4-benzyloxy-
methylhexahydrocyclopenta[c]isoxazole (23)
Pd/C (10%, 100 mg) was added to a solution of 19 (200 mg, 0.38
mmol) in EtOH (15 mL) and hydrogenated with H2 under atmo-
spheric pressure at r.t. for 12 h. The catalyst was filtered off, the sol-
vent evaporated, and the residue was purified by silica gel column
chromatography (100–200 mesh). Elution with EtOAc–PE in the
ratios of 1:19 and 7:93 afforded 22 and 23, respectively, as colorless
thick liquids.
1H NMR (300 MHz, CDCl3): d = 3.71 (br d, J = 6.3 Hz, 1 H), 3.73
(d, J = 12.0 Hz, 1 H), 3.79–3.85 (m, 2 H), 4.05–4.18 (m, 6 H), 4.38
(d, J = 12.0 Hz, 1 H, OCH2Ph), 4.43 (d, J = 12.0 Hz, 1 H, OCH2Ph),
4.69 (br s, 1 H), 4.73 (d, J = 12.0 Hz, 1 H, OCH2Ph), 4.97 (d,
J = 12.0 Hz, 1 H, OCH2Ph), 7.12–7.48 (m, 20 H, ArH).
13C NMR (75 MHz, CDCl3): d = 49.7 (C-3a), 60.1 (C-3), 63.8
(OCH2), 68.7 (NCH2Ph), 70.2 (OCH2Ph), 70.7 (OCH2Ph), 71.7
(OCH2Ph), 71.8 (C-6a), 85.2 (C-6), 117.5 (C-4), 127.4–129.7
(20 × CH, Ar), 136.5 (C, Ar), 137.2 (C, Ar), 137.5 (C, Ar), 138.3
(C, Ar), 151.6 (C-5).
ESIMS: m/z = 556 (M + Na)+.
22
Anal. Calcd for C35H35NO4: C, 78.77; H, 6.61; N, 2.62. Found: C,
78.49; H, 6.37; N, 2.42.
Yield: 122 mg (60%); [a]D25 +130.2 (c 0.52, CHCl3).
1H NMR (300 MHz, CDCl3): d = 2.65 (t-like, J = 6.0, 6.8 Hz, 1 H,
H-3a or H-4), 3.32 (t-like, J = 6.7, 7.3 Hz, 1 H, H-4 or H-3a), 3.59
(m, 1 H), 3.63 (d, J = 8.6 Hz, 1 H), 3.73–3.79 (m, 2 H), 3.85 (d,
J = 3.7 Hz, 2 H), 3.97 (t, J = 8.5 Hz, 1 H), 4.12–4.16 (m, 2 H), 4.20
(d, J = 11.8 Hz, 1 H, CH2Ph), 4.28 (d, J = 11.8 Hz, 1 H, OCH2Ph),
4.34 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.49 (s, 2 H, OCH2Ph), 4.59 (d,
J = 11.9 Hz, 1 H, OCH2Ph), 7.14–7.44 (m, 20 H, ArH).
13C NMR (75 MHz, CD3OD): d = 43.7 (C-3a or C-4), 47.8 (C-4 or
C-3a), 61.2 (OCH2), 66.8 (NCH2Ph), 67.2 (OCH2), 71.3 (OCH2Ph),
71.4 (OCH2Ph), 73.2 (OCH2Ph), 75.8 (C-6a), 83.8 (C-5 or C-6),
87.2 (C-6 or C-5), 127.5–129.9 (20 × CH, Ar), 137.2 (C, Ar), 138.5
(C, Ar), 138.7 (C, Ar), 138.8 (C, Ar).
19
Yield: 223 mg (33%); [a]D25 +25.3 (c 0.7, CHCl3).
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 3.80 (br s, 1 H, H-6a),
3.92 (d, J = 14.0 Hz, 1 H), 4.00 (d, J = 14.0 Hz, 1 H), 4.07–4.20 (m,
3 H), 4.28 (d, J = 13.0 Hz, 1 H), 4.34 (d, J = 13.0 Hz, 1 H), 4.47–
4.56 (m, 4 H), 4.64–4.66 (m, 2 H), 4.91 (br s, 1 H), 7.26–7.53 (m,
20 H, ArH).
13C NMR (75 MHz, CDCl3): d = 60.4 (C-3 or CH2OBn), 62.0
(CH2OBn or C-3), 64.5 (NCH2Ph), 71.1 (OCH2Ph), 71.5
(OCH2Ph), 71.6 (OCH2Ph), 75.4 (C-6a), 89.6 (C-5 or C-6), 91.6 (C-
6 or C-5), 126.3–128.3 (20 × CH, Ar), 128.8 (C-4), 137.2 (C, Ar),
137.7 (C, Ar), 137.8 (C, Ar), 137.9 (C, Ar), 141.7 (C-3a).
ESIMS: m/z = 536 (M + H)+, 558 (M + Na)+.
ESIMS: m/z = 534 (M + Na)+, 556 (M + Na)+.
Anal. Calcd for C35H37NO4: C, 78.48; H, 6.96; N, 2.61. Found: C,
78.25; H, 6.73; N, 2.22.
Anal. Calcd for C35H35NO4: C, 78.77; H, 6.61; N, 2.62. Found: C,
78.56; H, 6.48; N, 2.36.
23
Yield: 16 mg (8%); [a]D25 –50.2 (c 0.45, CHCl3).
(1S,2R,3S,4S,5S)-4-Amino-1,5-bis(hydroxymethyl)cyclopen-
tane-1,2,3-triol (20)
1H NMR (300 MHz, CDCl3): d = 2.13 (br s, 1 H, H-3a or H-4), 3.07
(br s, 1 H, H-4 or H-3a), 3.46 (br t, 1 H), 3.55–3.57 (m, 2 H), 3.76–
3.87 (m, 3 H), 4.06–4.16 (m, 3 H), 4.37–4.56 (m, 5 H), 4.72–4.76
(m, 1 H), 7.17–7.42 (m, 20 H, ArH).
13C NMR (150 MHz, CDCl3): d = 45.0 (C-3a or C-4), 47.2 (C-4 or
C-3a), 69.7 (OCH2), 70.7 (NCH2Ph), 71.9 (C-6a), 71.9 (OCH2),
72.5 (OCH2Ph), 73.1 (2 × OCH2Ph), 77.0 (C-5 or C-6), 81.9 (C6 or
C-5), 127.4–129.7 (20 × CH, Ar), 136.8 (C, Ar), 138.4 (C, Ar),
138.5 (C, Ar), 138.7 (C, Ar).
Pd/C (10%, 60 mg) was added to a solution of 9 (275 mg, 0.74
mmol) in EtOH (20 mL) and the mixture was hydrogenolyzed under
atmospheric pressure at r.t. for 12 h. The catalyst was filtered off
and the solvent was evaporated to afford 20 as hygroscopic solid;
yield: 91 mg (63%); [a]D25 –2.1 (c 0.48, MeOH).
1H NMR (300 MHz, CD3OD + D2O): d = 2.20 (td, J = 6.8, 5.7 Hz,
1 H, H-5), 3.45 (t, J = 5.5 Hz, 1 H), 3.59 (s, 2 H), 3.79–3.92 (m, 3
H), 4.00 (d, J = 6.0 Hz, 1 H).
13C NMR (75 MHz, CD3OD): d = 47.1 (C-5), 54.3 (C-4), 57.7
(CHCH2OH), 65.3 (CCH2OH), 78.8 (C-3 or C-2), 81.1 (C-1), 86.1
(C-2 or C-3).
ESIMS: m/z = 536 (M + H)+ and 558 (M + Na)+.
Anal. Calcd for C35H37NO4: C, 78.48; H, 6.96; N, 2.61. Found: C,
78.29; H, 6.79; N, 2.40.
ESIMS: m/z = 194 (M + H)+.
(1S,2S,3R,4R,5R)-3-Amino-4,5-bis(hydroxymethyl)cyclopen-
tane-1,2-diol (24)
(1R,2S,3R,4R,5S)-4-Amino-1,5-bis(hydroxymethyl)cyclopen-
tane-1,2,3-triol (21)
To a solution of 22 (70 mg, 0.13 mmol) in EtOH (8 mL) were added
cyclohexene (1.0 mL) and Pd/C (10%, 36 mg), and the mixture was
heated at reflux for 6 h. The catalyst was filtered off and the solvent
was evaporated in vacuo to yield a crude residue, which was puri-
fied by reverse phase (LiChroprep RP-18, particle size 25–40 mm)
column chromatography using H2O as eluent to furnish 24 as thick
gum; yield: 13 mg (58%).
1H NMR (300 MHz, D2O): d = 2.34–2.38 (m, 1 H, H-3a or H-4),
2.63–2.71 (m, 1 H, H-4 or H-3a), 3.18–3.27 (m, 2 H), 3.40–3.48 (m,
2 H), 3.95–4.08 (m, 2 H), 4.21 (dd, J = 4.0, 6.0 Hz, 1 H).
A solution of 10 (200 mg, 0.54 mmol) in EtOH (10 mL) was hydro-
genolyzed over Pd/C (10%, 85 mg) under atmospheric pressure at
r.t. for 18 h. The catalyst was filtered off and the solvent was evap-
orated to afford 21 as hygroscopic material; yield: 73 mg (70%);
[a]D25 +39.6 (c 0.28, MeOH).
1H NMR (300 MHz, CD3OD): d = 2.32 (td, J = 6.8, 7.5 Hz, 1 H, H-
5), 3.47 (d, J = 6.3 Hz, 1 H), 3.53 (d, J = 8.1 Hz, 1 H), 3.69–3.85
(m, 5 H).
13C NMR (75 MHz, CD3OD): d = 51.1 (C-5), 57.7 (C-4), 58.2
(CHCH2OH), 62.5 (CCH2OH), 81.4 (C-1), 85.3 (C-2 or C-3), 85.6
(C-3 or C-2).
ESIMS: m/z = 200 (M + Na)+.
ESIMS: m/z = 216 (M + Na)+.
(1S,2R,3S,4S,5S)-4-(5¢-Amino-6¢-chloropyrimidin-4¢-ylamino)-
1,5-bis(hydroxymethyl)cyclopentane-1,2,3-triol (25)
To a solution of 20 (90 mg, 0.47 mmol) in n-BuOH (15 mL) were
added 5-amino-4,6-dichloropyrimidine (116 mg, 0.71 mmol) and
Synthesis 2010, No. 8, 1303–1310 © Thieme Stuttgart · New York

PAPER
Fully Substituted Chiral Cyclopentylamine Derivatives
1309
Et3N (1.5 mL), and the solution was heated at reflux for 30 h under
N2. The solvent was evaporated and the residue was dissolved in
H2O (10 mL). The aqueous solution was washed with CHCl3
(2 × 15 mL) to remove free pyrimidine base and evaporated to thick
oil. Purification by reverse phase (LiChroprep RP-18, particle size
25–40 mm) flash column chromatography with H2O yielded 25 as a
Anal. Calcd for C11H17ClN4O5: C, 41.19; H, 5.34; N, 17.47. Found:
C, 41.10; H, 5.09; N, 17.23.
(1S,2R,3S,4R,5R)-4-(6¢-Chloropurin-9¢-yl)-1,5-bis(hydroxy-
methyl)cyclopentane-1,2,3-triol (28)
Conversion of 27 to 28 was done (according to the earlier method
described in the preparation of 26 from 25) using 27 (100 mg, 0.31
mmol), HC(OEt)3 (4 mL), PTSA (75 mg, 0.39 mmol) to furnish 28
25
foamy solid; yield: 85 mg (57%); mp 190–195 °C (dec.); [a]D
–21.4 (c 0.53, MeOH).
25
as a foamy solid; yield: 70 mg (68%); mp 187–180 °C (dec.); [a]D
–83.5 (c 0.30, MeOH).
1H NMR (300 MHz, CD3OD + D2O): d = 2.00 (ddd, J = 5.6,
5.9,12.0 Hz, 1 H, H-5), 3.63 (d, J = 6.0 Hz, 1 H), 3.66 (d, J = 6.0 Hz,
1 H), 3.96–4.13 (m, 3 H), 4.44 (d, J = 10.3 Hz, 1 H), 4.85 (d,
J = 10.5 Hz, 1 H), 7.95 (s, 1 H, H-2¢).
13C NMR (150 MHz, D2O): d = 50.2 (C-5), 55.4 (C-4), 56.8
(CHCH2OH), 63.3 (CCH2OH), 80.1 (C-1), 83.1 (C-2 or C-3), 85.0
(C-3 or C-2), 123.5 (C-5¢), 140.2 (C-6¢), 149.8 (C-2¢), 154.1 (C-4¢).
1H NMR (600 MHz, D2O): d = 2.58 (dd, J = 4.2, 7.2 Hz, 1 H, H-5),
3.61 (d, J = 11.4 Hz, 2 H), 4.02 (d, J = 12.6 Hz, 1 H), 4.21 (t, J = 9.0
Hz, 2 H), 4.61 (d, J = 7.8 Hz, 1 H, H-3), 5.06 (t, J = 7.2 Hz, 1 H, H-
4), 8.45 (s, 1 H, H-8¢), 8.53 (s, 1 H, H-2¢).
13C NMR (150 MHz, D2O): d = 49.4 (C-5), 56.9 (C-4), 58.0
(CHCH2OH), 63.1 (CCH2OH), 78.6 (C-1), 80.2 (CH), 80.9 (CH),
130.1 (C-5¢), 148.2 (C-8¢), 148.9 (C-6¢), 150.5 (C-2¢), 154.0 (C-4¢).
ESIMS: m/z = 343 (M + Na)+ for 35Cl and 345 (M + Na)+ for 37Cl.
Anal. Calcd for C11H17ClN4O5: C, 41.19; H, 5.34; N, 17.47. Found:
C, 41.00; H, 5.14; N, 17.19.
ESIMS: m/z = 353 (M + Na)+ for 35Cl and 355 (M + Na)+ for 37Cl.
Anal. Calcd for C12H15ClN4O5: C, 43.58; H, 4.57; N, 16.94. Found:
C, 43.31; H, 4.40; N, 16.71.
(1S,2R,3S,4S,5S)-4-(6¢-Chloropurin-9¢-yl)-1,5-bis(hydroxy-
methyl)cyclopentane-1,2,3-triol (26)
A solution of 25 (60 mg, 0.19 mmol) in anhyd DMF (5 mL) was
treated with HC(OEt)3 (2.5 mL) and PTSA (44 mg, 0.23 mmol). The
mixture was stirred at 10 °C for 16 h under N2. The solvent was
evaporated in vacuo and the gummy residue was dissolved in
MeOH (10 mL) and neutralized by stirring with Dowex-1 OH– resin
for 5 min at r.t. The neutralized methanolic solution was filtered and
the solvent was evaporated to give a crude residue, which was puri-
fied by reverse phase (LiChroprep RP-18, particle size 25–40 mm)
flash column chromatography using H2O as eluent to furnish 26 as
a white foamy solid; yield: 40 mg (64%), mp 160–162 °C (dec.);
[a]D25 –65.8 (c 0.5, MeOH).
1H NMR (300 MHz, CD3OD + D2O): d = 1.94 (ddd, J = 5.6, 5.9,
12.6 Hz, 1 H, H-5), 3.48–3.65 (m, 1 H), 3.82–4.17 (m, 4 H), 4.39 (d,
J = 10.2 Hz, 1 H, H-3), 5.34 (d, J = 10.5 Hz, 1 H, H-4), 8.49 (s, 1 H,
H-8¢), 8.56 (s, 1H, H-2¢).
13C NMR (150 MHz, D2O): d = 50.5 (C-5), 55.4 (C-4), 56.8
(CHCH2OH), 62.9 (CCH2OH), 80.0 (C-1), 81.0 (C-2 or C-3), 82.3
(C-3 or C-2), 130.9 (C-5¢), 148.1 (C-8¢), 150.1 (C-6¢), 151.9 (C-2¢),
153.0 (C-4¢).
Acknowledgment
The Council of Scientific and Industrial Research (CSIR) Network
Project No. NWP00036 supported the work. The authors gratefully
acknowledge CSIR for providing Senior Research Fellowships
(R.G. and J.K.M.) and an Emeritus Scientist scheme (to B.A). We
also thank the EPSRC and the University of Reading for funds for
the CCD diffractometer.
References
(1) (a) Jenkins, G. N.; Turner, N. J. Chem. Soc. Rev. 1995, 169.
(b) Wachtmeister, J.; Classon, B.; Samuelsson, B.;
Kvarnstrõm, I. Tetrahedron 1995, 51, 2029.
(2) Altona, C.; Sunderalingam, M. J. Am. Chem. Soc. 1972, 94,
8205.
(3) (a) Mandal, S. B.; Sahabuddin, Sk.; Singha, K.; Roy, A.;
Roy, B. G.; Maity, J. K.; Achari, B. Proc. Indian Natl. Sci.
Acad. 2005, 71A, 283; and references cited therein.
(b) Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A.
L. J. Org. Chem. 2000, 65, 8499; and references cited
therein. (c) Gurjar, M. K.; Maheswar, K. J. Org. Chem.
2001, 66, 7552. (d) Ono, M.; Nishimura, K.; Tsubouchi, H.;
Nagaoka, Y.; Tomoika, K. J. Org. Chem. 2001, 66, 8199.
(4) (a) Jin, Y. H.; Liu, P.; Wang, J.; Baker, R.; Huggins, J.; Chu,
C. K. J. Org. Chem. 2003, 68, 9012. (b) Seley, K. L.;
Mosley, S. L.; Zeng, F. Org. Lett. 2003, 5, 4401. (c) Li, F.;
Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J. J. Org.
Chem. 2004, 69, 4538.
ESIMS: m/z = 353 (M + Na)+ for 35Cl and 355 (M + Na)+ for 37Cl.
Anal. Calcd for C12H15ClN4O5: C, 43.58; H, 4.57; N, 16.94. Found:
C, 43.38; H, 4.39; N, 16.70.
(1S,2R,3S,4R,5R)-4-(5¢-Amino-6¢-chloropyrimidin-4¢-ylamino)-
1,5-bis(hydroxymethyl)cyclopentane-1,2,3-triol (27)
The preparation of 27 was carried out following the earlier proce-
dure (described in the preparation of 25 from 20) using 21 (70 mg,
0.36 mmol), 5-amino-4,6-dichloropyrimidine (89 mg, 0.54 mmol),
n-BuOH (15 mL), and Et3N (1.0 mL). Workup and purification
yielded 27 as amorphous solid; yield: 69 mg (60%); mp 198–201 °C
(dec.); [a]D25 –102.0 (c 0.25, MeOH).
1H NMR (600 MHz, D2O): d = 2.58 (dd, J = 3.6, 6.0 Hz, 1 H, H-5),
3.67 (d, J = 11.4 Hz, 1 H), 3.70 (d, J = 6.0 Hz, 2 H), 3.80 (d,
J = 12.0 Hz, 1 H), 3.91 (d, J = 6.6 Hz, 1 H), 4.18 (t, J = 7.2 Hz, 1
H), 4.66 (dd, J = 6.6, 9.0 Hz, 1 H), 7.91 (s, 1 H, H-2¢).
(5) (a) Khan, F. A.; Rout, B. J. Org. Chem. 2007, 72, 7011.
(b) Arjona, O.; Gómez, A. M.; López, C.; Plumet, J. Chem.
Rev. 2007, 107, 1919.
(6) (a) Marcé, P.; Djaz, Y.; Matheu, M. I.; Castillón, S. Org.
Lett. 2008, 10, 4735. (b) Yoshimura, Y.; Ohta, M.; Imahori,
T.; Imamichi, T. Org. Lett. 2008, 10, 3449. (c) Leung, L.
M. H.; Gibson, V.; Linclau, B. J. Org. Chem. 2008, 73,
9197. (d) Besada, P.; Gonzalezmoa, M. J.; Teran, C.
Synthesis 2008, 2363. (e) Quadrelli, P.; Piccanello, A.;
Mella, M.; Corsaro, A.; Pistara, V. Tetrahedron 2008, 64,
3541.
13C NMR (150 MHz, D2O): d = 49.3 (C-5), 56.8 (C-4), 57.8
(CHCH2OH), 61.8 (CCH2OH), 81.1 (C-1), 82.6 (C-2 or C-3), 83.3
(C-3 or C-2), 123.5 (C-5¢), 141.2 (C-2¢), 149.0 (C-6¢), 155.0 (C-4¢).
ESIMS: m/z = 343 (M + Na)+ for 35Cl and 345 (M + Na)+ for 37Cl.
(7) (a) Cesario, C.; Miller, M. J. J. Org. Chem. 2009, 74, 5730.
(b) Jessel, S.; Meier, C. Nucleic Acids Symp. Ser. 2008, 52,
615.
Synthesis 2010, No. 8, 1303–1310 © Thieme Stuttgart · New York

1310
R. Ghosh et al.
PAPER
(8) (a) Wang, J.; Jin, Y.; Rapp, K. L.; Schinazi, R. F.; Chu, C. K.
J. Med. Chem. 2007, 50, 1828. (b) Migliore, M. D.; Zontra,
N.; McGuigan, C.; Henson, G.; Andrei, G.; Resnoeck, R.;
Balzarini, J. J. Med. Chem. 2007, 50, 6485. (c) Ahn, H.;
Choi, T. H.; De Castro, K.; Lee, K. C.; Kim, B.; Moon, B. S.;
Hong, S. H.; Lee, J. C.; Chun, K. S.; Cheon, G. J.; Lim, S.
M.; An, G. I.; Rhee, H. J. Med. Chem. 2007, 50, 6032.
(d) Kim, H.-J.; Sharon, A.; Bal, C.; Wang, J.; Allu, M.;
Huang, Z.; Murray, M. G.; Bassit, L.; Schinazi, R. F.; Korba,
B.; Chu, C. K. J. Med. Chem. 2009, 52, 206. (e) Boyer, P.
L.; Vu, B. C.; Ambrose, Z.; Julias, J. G.; Warnecke, S.; Liao,
C.; Meier, C.; Marquez, V. E.; Hughes, S. H. J. Med. Chem.
2009, 52, 5356.
(9) (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1387. (b) Pratbiel, G.; Bernadou, J.;
Meunier, B. Angew. Chem., Int. Ed. Engl. 1995, 34, 746.
(10) Kusuka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi,
T.; Mizuno, K. J. Antibiot. 1968, 21, 255.
(11) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. J. Antibiot. 1981, 34, 359.
(18) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497.
(19) (a) Singha, K.; Roy, A.; Dutta, P. K.; Tripathi, S.;
Sahabuddin, S. k.; Achari, B.; Mandal, S. B. J. Org. Chem.
2004, 69, 6507. (b) Sahabuddin, S. k.; Drew, M. G. B.; Roy,
A.; Achari, B.; Mandal, S. B. J. Org. Chem. 2006, 71, 5980.
(c) Roy, B. G.; Maiti, J. K.; Drew, M. G. B.; Achari, B.;
Mandal, S. B. Tetrahedron Lett. 2006, 47, 8821.
(d) Tripathi, S.; Roy, B. G.; Drew, M. G. B.; Achari, B.;
Mandal, S. B. J. Org. Chem. 2007, 72, 7427.
(20) (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863. (b) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J. G.
J. Chem. Soc., Chem. Commun. 1989, 1280. (c) Gallos, J.
K.; Stathakis, C. I.; Kotoulas, S. S.; Koumbis, A. E. J. Org.
Chem. 2005, 70, 6884.
(21) Maity, J. K.; Ghosh, R.; Drew, M. G. B.; Achari, B.; Mandal,
S. B. J. Org. Chem. 2008, 73, 4305.
(22) We tried several times to cleave the isoxazolidine ring in
addition to reducing the double bond of 19 by hydrogenation
reaction, but every time only the double bond was reduced.
In contrast, successful isoxazolidine ring cleavage occurred
in the cases of 9 and 10. We do not have an explanation for
this.
(23) (a) Anantharamaiah, G. M.; Sivanandaiah, K. M. J. Chem.
Soc., Perkin Trans. 1 1977, 490. (b) Hanessian, S.; Liak, T.
J.; Vanasse, B. Synthesis 1981, 396. (c) Collins, P. M.;
Ashwood, M. S.; Eder, H.; Wright, S. H. B.; Kennedy, D. J.
Tetrahedron Lett. 1990, 31, 2055.
(12) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
(13) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.;
St. Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.;
Reardon, J. E.; Dornsife, R. E.; Averette, D. R.; Krenitsky,
T. A. Antimicrob. Agents Chemother. 1997, 41, 1082.
(14) Katagiri, N.; Nomura, N.; Sato, H.; Kaneko, C.; Tusa, K.;
Tsuruo, T. J. Med. Chem. 1992, 35, 1882.
(15) Balzarini, J.; Baumgartner, H.; Bodenteich, M.; De Clercq,
(24) Crystal data for 9 have been deposited at the Cambridge
Crystallographic Data Centre with reference number CCDC
750271. Data can be obtained via www.ccdc.cam.ac.uk/
data_request/cif.
(25) (a) CrysAlis; Oxford Diffraction Ltd.: Abingdon UK, 2006.
(b) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
E.; Griengl, H. J. Med. Chem. 1989, 32, 1861.
(16) Borthwick, A. D.; Butt, S.; Biggadike, K.; Exall, A. M.;
Roberts, S. M.; Youds, P. M.; Kirk, B. E.; Booth, B. R.;
Cameron, J. M.; Cox, S. W.; Marr, C. L. P.; Shill, M. D.
J. Chem. Soc., Chem. Commun. 1988, 656.
(17) (a) Ando, O.; Nakajima, M.; Hamano, K.; Itoi, K.; Takahasi,
S.; Takamatsu, Y.; Sato, A.; Enokita, R.; Okazaki, T.;
Haruyama, H.; Kinoshita, T. J. Antibiot. 1993, 46, 1116.
(b) Wen, X.; Norling, H.; Hegedus, L. S. J. Org. Chem.
2000, 65, 2096.
Synthesis 2010, No. 8, 1303–1310 © Thieme Stuttgart · New York