Dimethyl 3-hydroxy-4-hydroxymethylcyclopentane-1,1-dicarboxylate: An optically pure precursor of spiro carbocylic deoxyribonucleosides

Article abstract of DOI:10.1246/bcsj.75.1771

A concise, two-step preparation of dimethyl 3-hydroxy-4-hydroxymethylcyclopentane-1,1-dicarboxylate, an optically pure precursor of spiro carbocyclic nucleosides is described.

Full text of DOI:10.1246/bcsj.75.1771

c. Jpn.
© 2002 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 75, 1771–1775 (2002) 1771
e Chemical
ciety of Ja-
n
e Chemical
ciety of Ja-
n
Dimethyl 3-Hydroxy-4-hydroxymethylcyclopentane-1,1-dicarboxylate:
an Optically Pure Precursor of Spiro Carbocylic Deoxyribonucleosides
Precursor of Spiro Carbocylic Nucleosides
A. Renard et al.
Annabelle Renard, Jean Lhomme, and Mitsuharu Kotera*
02
71
75
Chimie Bioorganique, L.E.D.S.S., Associé au CNRS, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9,
France
SJA8
09-2673
010
(Received January 15, 2002)
A concise, two-step preparation of dimethyl 3-hydroxy-4-hydroxymethylcyclopentane-1,1-dicarboxylate, an opti-
cally pure precursor of spiro carbocyclic nucleosides is described.
02
02
1
Nucleoside analogues are useful compounds as bases for
important therapies including antiviral and anticancer treat-
ments.1 The interest in spiro nucleosides, a class of structural-
ly constrained compounds, has primarily arisen from the dis-
covery of hydantocidin 1 (Fig. 1), a natural product isolated
from Streptomyces hygroscopicus.2 This spiro hydantoin ribo-
furanose derivative 1 has demonstrated high herbicidal activity
without animal toxicity. The origin of this activity has been
shown to be inhibition of adenylosuccinate synthase, an en-
zyme involved in the de novo purine synthesis.3 Also a newly
synthesized spiro pyranoside 2 has been shown to possess
some inhibitory activity against glycogen phosphorylase, thus
providing a new approach to the treatment of diabetes.4
Scheme 1.
represents a new access to the amino diol 8, that is used as a
precursor in the synthesis of important carbocyclic nucleo-
sides.7
Results and Discussion
Racemic diol ( )-7 was synthesized from the cyclopentene
diester 9 which is easily accessible by condensation of dimeth-
yl malonate and cis-1,4-dichloro-2-butene.8 Upon treatment of
Fig. 1. The Hydantocidin and the corresponding spiro pyra-
9 under Prins reaction conditions9 (paraformaldehyde, AcOH,
noside.
H2SO4, 60 °C, 24 h), a complex mixture was obtained from
which the diacetate 10 was isolated in 9% yield (Scheme 2).
We recently reported that the deoxy derivative 3 of hydanto-
cidin and its spiro epimer 4 were shown to interchange in ba-
sic medium.5 We also designed new spiro barbiturates 5 and 6
in which the hydantoin ring is replaced by the barbiturate ring
that also possesses thymine-like hydrogen bonding capacity
against adenine derivatives.6 The spiro barbituric deoxyribo-
furanose 5 exhibited rapid nucleophilic ring opening in aque-
ous medium, while its carbocyclic analogue 6 showed much
greater stability (Scheme 1).
To prepare compound 6, it was necessary to develop a syn-
thetic approach to the optically active synthon (−)-7. In this
article, we describe the synthesis of the optically pure chiral
dihydroxy diester (−)-7. We report the determination of the
absolute configuration of (−)-7 by its transformation into the
known chiral amino diol (+)-8. This series of reactions also
We postulated that in the drastic reaction conditions used, for-
mation of a mixture of compounds 11 resulting from hydroly-
sis of the methyl esters and/or acetylation of the alcohol func-
tions could occur. Indeed when the crude reaction mixture was
treated directly in transesterification conditions, i.e., refluxing
in methanol in the presence of TMSCl, the dihydroxy diester
( )-7 was obtained from 9 in 60% yield.
We next focused on the optical resolution of this diol ( )-7.
Among the number of enzyme catalyzed transformations stud-
ied in organic synthesis, lipase catalyzed transesterifications
have been widely used for the kinetic resolution of varieties of
chiral racemic alcohols.10 This method seemed quite attractive
in the present case, in particular because the structurally relat-
ed cyclopentane diol derivatives 12 have been resolved by this
technique.11 Using vinyl acetate as the acetyl donor, we stud-

1772 Bull. Chem. Soc. Jpn., 75, No. 8 (2002)
Table 1. Enzyme Catalyzed Optical Resolution of Diol ( )-7.
Precursor of Spiro Carbocylic Nucleosides
Enzyme
Time/h
% Conva)
% ee of 14b)
E valuec)
Lipase from Pseudomonas cepacia
Lipase from hog pancreas
Pancreatin from porcine pancreas
10
1
4
39
53
41
78
73
76
13.2
16.1
12.3
a) Conversion ratios were determined by 13C NMR. b) The enantiomeric excess values (% ee) of 14 were
determined by 1H NMR spectroscopy using a chiral shift reagent [Eu(hfc)]. c) Index of enantioselectiv-
ity, see Ref. 19
Scheme 4. Conversion of (−)-7 to (+)-8.
(a) TBSCl, imidazole, 90%. (b) NaCl, DMSO, 170 °C,
89%. (c) KOH; (PhO)2P(O)N3; BnOH; separation, 27%.
(d) TBAF; H2, Pd–C; 71%.
Scheme 2. Synthesis of ( )-7.
g) was treated under the pancreatin catalyzed transesterifica-
tion conditions until about 70% conversion was achieved (3.5
h, 25 °C). After chromatographic separation of monoacetate
14, the optically pure12 diol (−)-7 was recovered with 25%
yield (2.70 g, ee > 98%).
The absolute configuration of (−)-7 was determined by its
conversion to the known amino diol (+)-8.13 Diol (−)-7 was
first converted to the disilylated derivative 15 and treated sub-
sequently under the Krapcho dealkoxycarbonylation
conditions14 to give a 1:1 mixture of the two epimeric mo-
noesters 16.15 Without separation of the two diastereoisomers,
the ester function was saponified and transformed to the benzyl
carbamate 17 by a Curtius-type reaction using diphenoxyphos-
phoryl azide.16 The two isomers were separated ((1R)-17:
Scheme 3. Enzymatic resolution of ( )-7.
27%, (1S)-17: 31%).17 Deprotection of the (1R)-isomer 17
was performed by successive treatments with TBAF in THF
ied resolution of diol ( )-7 with three enzymes of different
sources (Scheme 3).
and H2/Pd-C to give the amino diol (+)-8, that was unambigu-
ously identified as the (1R, 3S, 4R)-isomer by all analytical
data ([α]2D5 = +30.8 (c = 0.86, DMF), lit.7b [α]2D5 = +31.0 (c
= 1.0, DMF)). This series of transformations established
without ambiguity the absolute (3S, 4R) configuration of diol
(−)-7.
The optically pure diol 7 obtained in three steps from di-
methyl malonate and cis-1,4-dichloro-2-butene represents a
useful precursor for building up spiro carbocyclic nucleosides,
as exemplified by synthesis of the spiro barbiturate 6.18 In ad-
dition, further transformation of (−)-7 by the reaction se-
quence outlined in Scheme 4 constitutes a new route to amino
diol (+)-8 which is a key intermediate in the preparation of
important carbocyclic nucleosides.7
Table 1 summarizes the results obtained. Good enantiose-
lectivities for monoacetylation were observed for all three en-
zymes examined (as judged by the% ee of monoacetate formed
14). It is to be noticed that even when operating with a large
excess of enzyme and a prolonged reaction time, acetylation of
the secondary alcohol was never observed (data not shown).
Also, our initial attempts to perform resolution via the monosi-
lylated derivative 13 were unsuccessful, leading to full recov-
ery of the starting material.
We estimated that the observed enantioselectivities of the
enzyme catalyzed acetylation of 7 were satisfactory to operate
gram-scale resolution of diol ( )-7. Racemic diol ( )-7 (10.7

A. Renard et al.
Bull. Chem. Soc. Jpn., 75, No. 8 (2002) 1773
1 H, OH), 3.51 (dd, J = 8.1, 10.0 Hz, 1 H, H-5), 3.54–3.70 (m, 1
H, H-5), 3.69, 3.71 (2s, 6 H, OCH3), 4.04 (m, 1 H, H-3). 13C
NMR (75 MHz, CDCl3) δ 18.1 (SiC(CH3)3), 25.8 (SiC(CH3)3),
34.0 (C-6), 41.7 (C-2), 48.8 (C-4), 52.6, 52.8 (2 OCH3), 57.3 (C-
1), 64.8 (C-5), 74.2 (C-3), 172.4, 172.9 (2 CwO). MS (DCI, NH3
+ isobutane) m/z 347 [M + H]+. Anal. Calcd for C16H30O6Si: C
55.66, H 8.73%; Found: C 55.57, H 8.66%.
Experimental
General. All chemicals and solvents were purchased from
Fluka, Aldrich, Merck, SDS, or Carlo-Elba. They were of analyti-
cal or HPLC grade, and otherwise distilled before use. Lipases
from Pseudomonas cepacia (Ref. 62309) and lipase from hog
pancreas (Ref. 62300) were purchased from Fluka, pancreatin
from porcine pancreas (Ref. P7545) was purchased from Sigma.
TLC: Merck Kieselgel 60 F254, layer thickness 0.25 mm. Visual-
ization by UV light (254 nm), H2SO4 solution, and/or phosphomo-
lybdic acid solution. Preparative column chromatographies: Mer-
ck Kieselgel, 230–400 mesh. Mp: Reichert Thermovar (uncor-
rected). Optical rotations: Perkin-Elmer polarimeter 341. IR:
Nicolet Impact 400. UV/Vis: Perkin-Elmer lambda 5. NMR:
Bruker WP80, AM200, WP250, AM300, and Varian U+500 spec-
trometers. NMR spectra were referenced to the residual solvent
peak; chemical shifts δ in ppm; apparent scalar coupling constants
J in Hz. MS: Delsi-Nermag R10-10. Elemental analyses were
performed by “Service central de microanalyse du CNRS”.
Enzymatic Resolution of Diol ( )-7. A mixture of ( )-7
(10.7 g, 46.0 mmol), vinyl acetate (43 mL), and pancreatine (8.6
g) in tBuOMe (176 mL) was vigorously stirred at 25 °C for 3.5 h.
This suspension was then filtered on celite and the solid was thor-
oughly washed with tBuOMe (300 mL). The filtrate was concen-
trated under vacuum and the resulting residue was chromato-
graphed on silica gel (MeOH/CH2Cl2 2:98 to 10:90) to give the
diol (−)-7 (2.7 g, 11.6 mmol, 25%, ee > 98%) and the
monoacetylated alcohol (+)-14 (8.1 g, 29.5 mmol, 64%, ee 49%).
Data for diol (−)-7: TLC (MeOH/ CH2Cl2 8:92): Rf 0.24. [α]2D5
1
−12.5 (c 2.23, CHCl3). H NMR (200 MHz, CDCl3) δ 1.79 (dd, J
= 9.6, 13.7 Hz, 1 H, H-2 or H-6), 1.95–2.25 (m, 2H, H-4, H-2 or
H-6), 2.40–2.65 (m, 2 H, H-2 or H-6), 3.53 (dd, J = 7.2, 10.6 Hz,
1 H, H-5), 3.6–3.75 (m, 1 H, H-5), 3.68 (s, 3 H, CH3), 3.70 (s, 3 H,
CH3), 4.06 (m, 1 H, H-3). 13C NMR (50 MHz, CDCl3) δ 34.1 (C-
6), 41.7 (C-2), 48.8 (C-4), 52.8, 52.9 (2 CH3), 57.2 (C-1), 64.2 (C-
5), 75.2 (C-3), 172.5, 172,9 (2 CwO). MS (DCI, NH3 + isobu-
tane) m/z 233 [M+H]+. Anal. Calcd for C10H16O6•0.20 H2O: C
50.93, H 7.01%; Found: C 51.13, H 6.92%.
Dimethyl
(3S*,4R*)-3-Hydroxy-4-(hydroxymethyl)cyclo-
pentane-1,1-dicarboxylate (( )-7). A stirred mixture of 9
(20.2 g, 110 mmol), paraformaldehyde (6.60 g, 220 mmol), Ac2O
(16.5 mL), and H2SO4 (5.5 mL) in AcOH (110 mL) was heated at
60 °C for 16 h. The solution was cooled at r.t., then H2O (300 mL)
and AcOEt (500 mL) were added. The aqueous phase was extract-
ed four times with AcOEt and the combined organic phase was
dried over MgSO4. The solvents were then removed under vacu-
um and the resulting residue was co-evaporated three times with
toluene and dissolved in MeOH (700 mL). After TMSCl (60 mL)
was added, the mixture was stirred under reflux for 3 h. The vola-
tile materials were removed under vacuum and to the resulting
residue was added a saturated solution of NaCl (300 mL) and
AcOEt (500 mL). The aqueous phase was extracted three times
with AcOEt and the combined organic phase was dried over
MgSO4. After concentration under vacuum, the crude material
was chromatographed on silica gel (MeOH/CH2Cl2 8:92) to af-
ford ( )-7 as a colorless oil (16.0 g, 69.0 mmol, 60%). TLC
(MeOH/CH2Cl2 8:92): Rf 0.24. 1H NMR (200 MHz, CDCl3) δ
1.79 (dd, J = 9.6, 13.7 Hz, 1 H, H-2ꢀ or H-6ꢀ), 1.95–2.25 (m, 2H,
H-4, H-2 or H-6), 2.40–2.65 (m, 2 H, H-2 or H-6), 3.53 (dd, J =
7.2, 10.6 Hz, 1 H, H-5), 3.6–3.75 (m, 1 H, H-5), 3.68 (s, 3 H,
CH3), 3.70 (s, 3 H, CH3), 4.06 (m, 1 H, H-3). 13C NMR (50 MHz,
CDCl3) δ = 34.1 (C-6ꢀ), 41.7 (C-2), 48.8 (C-4), 52.8, 52.9 (2
CH3), 57.2 (C-1), 64.2 (C-5), 75.2 (C-3), 172.5, 172.9 (2 CwO).
MS (FAB+, glycerol) m/z 233 [M + H]+. Anal. Calcd for
C10H16O6•0.25 H2O: C 50.74 , H 7.03%; Found: C 50.80, H
6.88%.
Data for monoacetylated alcohol (−)-14: TLC (MeOH/ CH2Cl2
8:92): Rf 0.51. [α]2D5 +3.9 (c 2.53, CHCl3). 1H NMR (200
MHz,CDCl3) δ 1.89 (dd, J = 9.6, 13.6 Hz, 1 H, H-2 or H-6), 2.03
(s, 3 H, CH3CO), 2.15–2.25 (m, 2H, H-4, H-2 or H-6), 2.36 (d, 1
H, OH), 2.45–2.65 (m, 2 H, H-2 or H-6), 3.70 (s, 3 H, OCH3),
3.73 (s, 3 H, OCH3), 4.07 (m, 2 H, H-5). 13C NMR (50 MHz,
CDCl3) δ 20.81 (CH3CO), 34.7 (C-6), 41.7 (C-2), 46.5 (C-4),
52.9, 53.0 (2 OCH3), 57.2 (C-1), 64.9 (C-5), 74.3 (C-3), 171.2,
172.1, 172.9 (3 CwO). MS (DCI, NH3 + isobutane) m/z 274
[M]+.
Dimethyl
(3S,4R)-3-(t-Butyldimethylsiloxy)-4-(t-butyldi-
methylsiloxymethyl)cyclopentane-1,1-dicarboxylate ((−)-15).
To a solution of diol (−)-7 (2.0 g, 8.6 mmol) in DMF (17 mL)
were added imidazole (3.50 g, 52.0 mmol) and TBSCl (3.90 g,
26.0 mmol). The reaction mixture was stirred at r.t. under argon
for 10 h. This solution was directly filtered on silica gel and the
disilylated compound was eluted with AcOEt/pentane (1:5). The
first 100 mL fraction was recovered and concentrated under re-
duced pressure. The resulting residue was chromatographed on
silica gel (AcOEt/pentane (5:95)) to afford (−)-15 as a colorless
oil (3.60 g, 90%). TLC (AcOEt/hexane (1:6)): Rf 0.40. [α]2D5 −8.3
(c 2.37, CHCl3). 1H NMR (200 MHz, CDCl3) δ 0.01 ( s, 12 H,
MeSi), 0.8 (2s, 18 H, tBuSi), 1.76 (dd, J = 8.9, 13.7 Hz, 1 H, H-
6), 1.95-2.25 (m, 2 H, H-4, H-2), 2.45–2.70 (m, 2 H, H-2, H- 6),
3.51 (d, J = 4.8 Hz, 2 H, H-5), 3.68 (s, 3 H, CH3), 3.69 (s, 3 H,
CH3), 4.06 (q, J = 5.8 Hz, 1 H, H-3). 13C NMR (50 MHz, CDCl3)
δ = −4.7 (4 C, MeSi), 17.9, 18.2 (s, 2 C, Me3C), 25.7, 25.8 (2s, 6
C, MeSi), 33.5 (C-6), 42.3 (C-2), 49.7 (C-4), 52.5 (2 CH3), 57.3
(C-1), 62.3 (C-5), 73.5 (C-3), 172.4, 172.9 (2 CwO). MS (DCI,
Monosilylation of the Diol ( )-7 to ( )-13.
To a stirred
mixture of diol ( )-7 (2.32 g, 10.0 mmol) and imidazole (1.69 g,
24.8 mmol) in DMF (20 mL) was added TBSCl (1.68 g, 11.2
mmol) at 4 °C. The solution was stirred at 4 °C for 1.5 h. The sol-
vent was removed under vacuum and H2O (40 mL) and AcOEt (50
mL) were added to the residue. The aqueous phase was extracted
three times with 40 mL of AcOEt. The combined organic phase
was dried over MgSO4 and the solvent was removed under vacu-
um. The resulting foam was chromatographed on silica gel (AcO-
Et/cyclohexane 2:3) to afford the monosilylated diol ( )-13 as a
NH3 + isobutane) m/z 461 [M+H]+.
Anal. Calcd for
C22H44O6Si2: C 57.35 , H 9.63%; found: C 57.44, H 9.78%.
Demethoxycarbonylation of (−)-15. To a solution of com-
pound (−)-15 (940 mg, 2.00 mmol) in DMSO (3 mL) were added
H2O (0.2 mL) and NaCl (400 mg) at r.t. The mixture was stirred at
170 °C for 8 h. The suspension was cooled at r.t. and H2O (20
mL) was added. This solution was extracted three times with Et2O
1
foam (2.7 g, 78%). TLC (AcOEt/hexane 2:3): Rf 0.30. H NMR
(300 MHz, CDCl3) δ 0.02, 0.03 (2s, 6 H, Si(CH3)2), 0.85 (s, 9 H,
SiC(CH3)3), 1.80 (dd, J = 10.0, 14.0 Hz, 1 H, H-6), 2.09 (m, 1 H,
H-4), 2.16 (dd, J = 7.0, 14.0 Hz, 1 H, H-2), 2.46 (dd, J = 7.8,
14.0 Hz, 1 H, H-2), 2.57 (dd, J = 7.0, 13.5 Hz, 1 H, H-6), 2.66 (d,

1774 Bull. Chem. Soc. Jpn., 75, No. 8 (2002)
Precursor of Spiro Carbocylic Nucleosides
(50 mL) and the combined organic phase was washed with brine,
then dried over MgSO4. The solvent was removed under vacuum
and the residue was chromatographed on silica gel (AcOEt/pen-
tane 5:95) to afford the diastereoisomeric mixture 16 (1R:1S =
1:1) as an oil (720 mg, 89%). TLC (AcOEt/pentane 3:97): Rf
0.33. 1H NMR: vide infra. 13C NMR (62 MHz, CDCl3) δ −5.4,
−4.7, −4.6 (4 C, Si(CH3)2), 18.0, 18.3 (2 C, SiC(CH3)3), 25.8,
25.9 (6 C, SiC(CH3)3), 28.4, 30.4 (C-5), 38.2, 38.6 (C-2), 39.9,
40.9 (C-1), 49.1, 50.8 (CH3O), 51.6, 51.7 (C-4), 62.7, 64.0 (C-6),
74.0, 74.6 (C-3), 176.4, 176.7 (CwO). MS (DCI, NH3 + isobu-
tane) m/z 403 [M]+. Anal. Calcd for C20H42O4Si2: C 59.65, H
10.51%; Found: C 59.13, H 10.42%.
SiC(CH3)3), 25.9, 26.0 (6 C, SiC(CH3)3), 33.8 (C-5), 43.0 (C-2),
48.9 (C-1), 50,2 (C-4), 63.4 (C-5), 66.4 (CH2Ar), 73.3 (C-3),
127.9, 128.3, 136.6 (arom. C), 155.5 (CwO). MS (FAB+, glycer-
ol) m/z 494 [M+H]+. Calcd for C26H47N1O4Si2: C 63.24, H 9.59 ,
N 2.84% ; Found: C 63.20 H 9.54 , N 2.89%.
Data for the (1S)-isomer: TLC (CH2Cl2): Rf 0.40. [α]2D5 = +
1
25.3 (c 1.02, CHCl3). H NMR (200 MHz, CDCl3) δ 0.01, 0.03,
0.04, 0.05 (4s, 12 H, SiCH3), 0.84, 0.86 (2s, 18 H, SiC(CH3)3),
1.45–2.70 (m, 2 H, H-5, H-2), 1.72–1.98 (m, 2 H, H-2, H-4), 2.17
(m, 1 H, H-5), 3.31 (dd, J = 6.9, 9.9 Hz, 1 H, H-6), 3.50 (dd, J =
5.1, 9.9 Hz, 1 H, H-6), 4.05–4.25 (m, 2 H, H-1 and H-3), 5.06 (s, 2
H, CH2), 5.65 (m, 1 H, NH), 7.25–7.35 (m, 5 H, arom. H). MS
(FAB+, glycerol) m/z 494 [M+H]+.
In order to determine the relative configuration at C-1 for each
diastereoisomer, a pure sample of each isomer (1R)-16 and (1S)-
16 was obtained by two successive chromatographies (using AcO-
Et/pentane 3:97 for the first column, CH2Cl2 for the second col-
umn). The compounds (1R)-16 and (1S)-16 were separately char-
acterized by 1H NMR 1D, NOE, and 2D COSY experiments.
(+)-(1R,3S,4R)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl-
amine ((+)-8). To a solution of (1R)-17 (140 mg, 0.284 mmol)
in THF (2 mL) was added a solution of 1 M TBAF in THF (0.70
mL). This solution was stirred at r.t. for 3.5 h. The solvent was
then removed under reduced pressure and the resulting residue
was chromatographed three times on silica gel (MeOH/CH2Cl2
10:90) in order to remove residual TBAF. The intermediate ben-
zyl carbamate was thus obtained as a white powder (55 mg, 72%):
mp 86–88 °C. TLC (MeOH/CH2Cl2 10:90): Rf 0.28. [α]2D5 +10.5
(c 0.82, CHCl3). IR (KBr) 3390, 3339, 3281, 2960, 1680, 1537,
1
Data for the isomer (1R)-16: TLC (CH2Cl2): Rf 0.59. H NMR
(300 MHz, CDCl3) δ 0.01 (s, 12 H, Si(CH3)2), 0.84, 0.86 (2s, 18
H, SiC(CH3)3), 1.48 (m, 1 H, H-5), 1.79 (m, 1 H, H-2), 1.85–2.05
(m, 2 H, H-2, H-4), 2.13 (m, 1 H, H-5), 2.99 (m, 1 H, H-1), 3.48
(d, J = 5.8 Hz, 2 H, H-6), 3.64 (s, 3 H, CH3O), 4.12 (m, 1 H, H-3).
1
Data for the isomer (1S)-16: TLC (CH2Cl2): Rf 0.53. H NMR
1352, 1284, 1267, 1218, 1155, 1036 cm−1 1H NMR (250 MHz,
.
(300 MHz, CDCl3) δ 0.01 (s, 12 H, Si(CH3)2), 0.84, 0.86 (2s, 18
H, SiC(CH3)3), 1.68 (m, 1 H, H-5), 1.83 (m, 1 H, H-2), 1.95 (m, 1
H, H-4), 2.05–2.15 (m, 2 H, H-2, H-5), 2.13 (m, 1 H, H-5), 2.62
(m, 1 H, H-1), 3.53 (d, J = 4.3 Hz, 2 H, H-6), 3.64 (s, 3 H, CH3O),
3.97 (m, 1 H, H-3).
CDCl3) δ 1.16 (m, 1 H, H-5), 1.62 (m, 1 H, H-2), 1.72–2.10 (m, 3
H, H-2, H-4 and OH), 2.10–2.30 (m, 2 H, H-5 and OH), 3.58 (dd,
J = 7.9, 10.3 Hz, 1 H, H-6), 3.79 (dd, J = 4.7, 10.3 Hz, 1 H, H-6),
4.11, 4.28 (m, 2 H, H-1 and H-3), 4.92 (m, 1 H, NH), 5.05 (s, 2 H,
CH2), 7.22–7.35 (2s, 5 H, arom. H). 13C NMR (62.5 MHz,
CDCl3) δ 34.3 (C-5), 41.5 (C-2), 48.7 (C-4), 49.6 (C-1), 63.8 (C-
6), 66.4 (CH2Ar), 73.6 (C-3), 127.9, 128.4, 136.5 (arom. C), 155.9
(CwO). MS (FAB−, glycerol) m/z 264 [M−H]. Anal. Calcd for
C14H19NO4: C 63.38, H 7.22, N 5.28%; Found: C 63.22 H 7.52, N
5.08%.
A solution of the above benzyl carbamate (48 mg, 0.19 mmol)
in MeOH (2 mL) was vigorously stirred for 2 h at r.t. under H2 at-
mosphere with Pd/C-10% (20 mg). This suspension was then fil-
tered on celite and the solid was thoroughly washed with MeOH.
The filtrate was concentrated under reduced pressure and the oily
residue was dried under high vacuum to afford (+)-8 as an oil (24
mg, 99%). [α]2D5 +30.8 (c 0.86, DMF). (lit.7b [α]2D5 +31.0 (c 1.0,
DMF)). 1H NMR (300 MHz, MeOD-d4) δ 1.14 (m, 1 H, H-5),
1.69 (m, 1 H, H-2), 1.82–2.05 (m, 2 H, H-2 and H-4), 2.21 (m, 1
H, H-5), 3.43–3.60 (m, 3 H, H-6 and H-1), 4.04 (m, 1 H, H-3).
13C NMR (75 MHz, MeOD-d4) δ 37.3 (C-5), 43.9 (C-2), 51.0 (C-
4), 51.3 (C-1), 64.7 (C-6), 74.6 (C-3). MS (IE) m/z 131 [M]+, 114
[M − OH], 100 [M − CH2OH], 96 [M − 2OH], 72, 69, 56, 44.
Benzyl (+)-(1R, 3S, 4R)-N-[3-(t-Butyldimethylsiloxy)-4-(t-
butyldimethylsiloxymethyl)cyclopentyl]carbamate (17).
A
solution of the diastereoisomeric mixture 16 (680 mg, 1.7 mmol)
in ethanolic KOH (310 mg in 17 mL) was stirred at 30 °C for 20 h.
The solvent was then removed under vacuum and the resulting
residue was dissolved in Et2O (100 mL). This solution was cooled
at 4 °C, then washed with a solution of 0.05 M HCl (100 mL).
The aqueous phase was extracted three times with Et2O, and the
combined organic phase was dried over MgSO4. The solvent was
then removed under reduced pressure to give the intermediate
crude acid (660 mg, 99%).
To a solution of the above acid in toluene (17 mL) were added
at 0 °C, diphenoxyphosphoryl azide (0.42 mL) and Et3N (0.28
mL). The mixture was stirred at 0 °C for 30 min, then at r.t. for 1
h, and finally at 80 °C for 2 h. The solution was cooled at 10 °C
and benzyl alcohol (0.40 mL) and dibutyltin dilaurate (40 µL)
were added. This solution was stirred at 80 °C for 3 h, then at 100
°C for 30 min. After being cooled to r.t., the mixture was diluted
with Et2O. The organic phase was washed with a solution of 1 M
NaHCO3. The aqueous phase was extracted three times with
Et2O, the combined organic phase was washed with brine, and
then dried over MgSO4. The solvent was removed under reduced
pressure and the resulting residue was chromatographed on silica
gel (CH2Cl2, three successive columns) to afford the (1R)-isomer
17 (201 mg, 27%) and the (1S)-isomer (220 mg, 31%), both as
oils.
References
1
a) C. Périgaud, G. Gosselin, and J.-L. Imbach, Nucleosides
Nucleotides, 11, 903 (1992). b) E. De Clercq, Nucleosides Nucle-
otides, 13, 1271 (1994).
2
M. Nakajima, K. Itoi, Y. Takamatsu, T. Kinoshita, T.
Okazaki, K. Kawakubo, M. Shindo, T. Honma, M. Tohjigamori,
and T. Haneishi, J. Antibiot., 44, 293 (1991).
Data for the (1R)-isomer 17: TLC (CH2Cl2): Rf 0.33. [α]2D5
1
+26.4 (c 0.97, CHCl3). H NMR (200 MHz, CDCl3) δ 0.01, 0.03,
3
a) D. R. Heim, C. Cseke, B. C. Gerwick, M. G. Murdoch,
0.04, 0.05 (4s, 12 H, SiCH3), 0.84, 0.86 (2s, 18 H, SiC(CH3)3),
1.23 (m, 1 H, H-5), 1.65–2.10 (m, 3 H, H-2, H-4), 2.16 (m, 1 H,
H-5), 3.55 (m, 2 H, H-6), 4.05–4.22 (m, 2 H, H-1 and H-3), 5.06
(s, 2 H, CH2), 7.25–7.35 (m, 5 H, arom. H). 13C NMR (62 MHz,
CDCl3) δ −5.3, −4.7, −4.4 (4 C, SiCH3), 18.0, 18.5 (2 C,
and S. B. Green, Pestic. Biochem. Physiol., 53, 138 (1995). b) D.
L. Siehl, M. V. Subramanian, E. W. Walters, S.-F. Lee, R. J.
Anderson, and A. G. Toschi, Plant Physiol., 110, 753 (1996). c)
R. Fonné-Pfister, P. Chemla, E. Ward, M. Girardet, K. E. Kreuz, R.
B. Honzatko, H. J. Fromm, H.-P. Schär, M. G. Grütter, and S. W.

A. Renard et al.
Bull. Chem. Soc. Jpn., 75, No. 8 (2002) 1775
Cowan-Jacob, Proc. Natl. Acad. Sci. U. S. A., 93, 9431 (1996). d)
H. Sano, S. Mio, J. Kitagawa, and S. Sugai, Tetrahedron: Asym-
metry, 5, 2233 (1994). e) H. Sano, S. Mio, M. Hamura, J.
Kitagawa, M. Shindou, T. Honma, and S. Sugai, Biosci. Biotech-
nol. Biochem., 59, 2247 (1995). f) H. Sano, S. Mio, N.
Tsukaguchi, and S. Sugai, Tetrahedron, 51, 1387 (1995). g) H.
Sano, and S. Sugai, Tetrahedron, 51, 4635 (1995). h) H. Sano, S.
Mio, J. Kitagawa, M. Shindou, T. Honma, and S. Sugai, Tetrahe-
dron, 51, 12563 (1995). i) H. Sano, and S. Sugai, Tetrahedron:
Asymmetry, 6, 1143 (1995). j) H. Sano, S. Mio, Y. Kumagawa, J.
Kitagawa, M. Shindou, T. Honma, and S. Sugai, Biosci. Biotech-
nol. Biochem., 60, 1198 (1996).
10 a) S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1999, 1.
b) G. Carrea, and S. Riva, Angew. Chem., Int. Ed., 39, 2226
(2000).
11 a) F. Theil and S. Ballschuh, Tetrahedron: Asymmetry, 7,
3565 (1996). b) J. Weidner, F. Theil, and H. Schick, Tetrahedron:
Asymmetry, 5, 751 (1994).
12 The enantiomeric excess (ee %) of the diol (−)-7 was de-
termined after disilylation (to 15) by NMR spectroscopy using
1
chiral shift reagent [Eu(hfc)3]. In the H NMR spectrum of ( )-
15 (23 mM in CDCl3), the resonance signals of two O-methyl
groups are observed at δ = 3.70 and 3.73 ppm. Upon addition of
0.4 eguivmol of Eu(hfc)3, two splitted signals are observed at δ =
4.06/4.09 and 4.37/4.43 ppm. The optical purity (>98%) of (−)-
15 was estimated by comparison with NMR spectra registered in
the same conditions for 95–98% ee material prepared by adding
1–5% of racemic product.
4
C. De la Fuente, T. M. Krülle, K. A. Watson, M. Gregoriou,
L. N. Johnson, K. E. Tsitsanou, S. E. Zographos, N. G.
Oikonomakos, and G. W. J. Fleet, Synlett, 1997, 485.
5
a) A. Renard, M. Kotera, and J. Lhomme, Tetrahedron
Lett., 39, 3129 (1998). b) A. Renard, M. Kotera, and J. Lhomme,
Nucleosides Nucleotides, 18, 1437 (1999). c) A. Renard, M.
Kotera, M.-C. Brochier, and J. Lhomme, Eur. J. Org. Chem.,
2000, 1831.
13 See Ref. 7. A similar scheme was used by: K-H. Altmann,
R. Kesselring, and U. Pieles, Tetrahedron, 52, 12699 (1996).
14 P. Krapcho, Synthesis, 1982, 805.
15 The mixture of the two diastereoisomers of 16 is hardly
separable. However, a sample was separated and the C-1 configu-
ration of each isomer was assigned by NOE NMR experiments.
16 K. Ninomiya, T. Shioiri, and S. Yamada, Tetrahedron, 30,
2151 (1974).
17 The configuration of C-1 in 17 was firmly assigned (1) by
direct NOE NMR experiments, (2) by chemical correlation exper-
iment from separated (1R)-16 to (1R)-17, and (3) by the obtention
of the final amino diol (+)-8.
18 Renard, J. Lhomme, and M. Kotera, J. Org. Chem., 67,
1302 (2002).
6
(1968).
7
Y. Kyogoku, R. C. Lord, and A. Rich, Nature, 218, 69
a) B. L. Bray, S. C. Dolan, B. Halter, J. W. Lackey, M. B.
Schilling, and D. J. Tapolczay, Tetrahedron Lett., 36, 4483 (1995).
b) J. Béres, G. Sagi, E. Baitz-Gács, I. Tömösközi, and L. Ötvös,
Tetrahedron, 44, 6207 (1988). c) L. Ötvös, J. Béres, G. Sági, I.
Tömösközi, and L. Gruber, Tetrahedron Lett., 28, 6381 (1987).
8
9
J.-P. Deprés and A. E. Greene, Org. Synth., 75, 195 (1997).
a) D. R. Adams, and S. P. Bhatnagar, Synthesis, 1977, 661.
b) I. Tömöskozi, L. Gruber, G. Kovacs, I. Székely, and V.
Simodidesz, Tetrahedron Lett., 50, 4639 (1976). c) I. Tömöskozi,
L. Gruber, and E. Baitz-Gács, Tetrahedron, 48, 10345 (1992).
19 C.-S. Chen, Y. Fujimoto, G.Girdaukas and C. J. Sih, J. Am.
Chem. Soc., 104, 7294 (1982).