Preparative Synthesis of the Key Intermediate, (4R,5R)-3-Benzyloxymethyl-4,5-isopropylidenedioxycyclopent-2-enone for Carbocyclic Nucleosides

Article abstract of DOI:10.1246/cl.2004.506

(4R,5R)-3-Benzyloxymethyl-4,5-isopropylidenedioxycyclopent-2-enone (1), a versatile intermediate for the synthesis of carbocyclic nucleosides was synthesized from D-ribose in 10 steps and 26 percent overall yield.

Full text of DOI:10.1246/cl.2004.506

506
Chemistry Letters Vol.33, No.5 (2004)
Preparative Synthesis of the Key Intermediate,
(4R,5R)-3-Benzyloxymethyl-4,5-isopropylidenedioxycyclopent-2-enone
for Carbocyclic Nucleosides
Hyung Ryong Moon,y;yy Won Jun Choi,y Hea Ok Kim,y and Lak Shin Jeongꢀy
yLaboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea
yyCollege of Pharmacy, Pusan National University, Pusan 609-735, Korea
(Received January 27, 2004; CL-040102)
(4R,5R)-3-Benzyloxymethyl-4,5-isopropylidenedioxycy-
have already reported the practical and efficient syntheses of 2
from D-ribose, we have been interested in synthesizing the key
intermediate 1 in a preparative scale. This is highly desirable
for structure-activity relationship study of the carbocyclic nu-
cleosides, based on the lead, (ꢁ)-neplanocin A. In this commu-
nication, we wish to report the improved and large-scale (>10 g)
synthesis of 1, which serves as a versatile intermediate for the
synthesis of carbocyclic nucleosides including (ꢁ)-neplanocin
A, from D-ribose.
clopent-2-enone (1), a versatile intermediate for the synthesis
of carbocyclic nucleosides was synthesized from D-ribose in
10 steps and 26% overall yield.
(ꢁ)-Neplanocin A is a naturally occurring nucleoside of po-
tential use in cancer and viral chemotherapy.1 It belongs to the
carbocyclic nucleoside family which possesses the metabolic
and chemical stability to glycosidic bond hydrolysis. (ꢁ)-Nepla-
nocin A has a strong antiviral activity against various RNA and
DNA viruses.2 The antiviral activity of (ꢁ)-neplanocin A has
been correlated with its ability to inhibit S-adenosylhomocys-
teine hydrolase (SAH) and its ability to increase cellular levels
of S-adenosylhomocysteine.3 The mechanism of inhibition by
(ꢁ)-neplanocin A has been known as a cofactor depletion mech-
anism, involving reduction of the enzyme-bound cofactor,
NADþ to NADH with simultaneous oxidation of (ꢁ)-neplanocin
A to its 30-keto derivative.4
BnO
HO
OH
O
HO
OH
O
a
b,c
OH
93%
80%
O
O
O
O
OH OH
4
3
d
92%
BnO
HO
OH
BnO
HO
BnO
OH
O
O
Based on this promising biological activity of (ꢁ)-neplano-
cin A, several asymmetric syntheses of (ꢁ)-neplanocin A, start-
ing from cyclopentadiene,5 D-ribose,6 D-ribonic gamma-lac-
tone,7 or L-tartaric acid8 have been reported. These syntheses
have been completed via the key intermediates such as (4R,5R)-
3-benzyloxymethyl-4,5-isopropylidenedioxycyclopent-2-enone
(1) and (4R,5R)-4,5-isopropylidenedioxycyclopent-2-enone (2)
(Figure 1).
Recently, ring-closing metathesis (RCM) reaction was uti-
lized for the synthesis of the key intermediates, 19 and 2,10,11 im-
proving the number of steps and overall yields greatly. Jacobson
and his co-workers9 have reported the elegant synthesis of the in-
termediate 1 from D-ribonic gamma-lactone in 11 steps, but in a
small scale (<1 g). Since our laboratory10 and Chu’s laboratory11
f
e
81%
O
O
O
O
O
O
7
6
5
75%
from 6
g
BnO
BnO
BnO
i
h
OH
O
OH
84%
87%
O
O
O
O
O
O
10
9
8
j 84%
NH2
N
N
BnO
O
N
RO
N
ref. 7
HO
NH2
O
O
O
N
N
N
1
OH OH
O
O
(−)-Neplanocin A
N
HO
Reagentsa: a) c-H2SO4, acetone, rt, 2.5 h; b) Ph3PCH3Br, KO-tBu, THF, rt,
12 h; c) i.Bu2Sn=O, toluene, reflux. ii. TBAI, BnBr, 75 °C, 16 h; d) (COCl)2,
DMSO, CH2Cl2, -78 °C, 1 h and then Et3N, rt, 1 h; e) OsO4, NMO,
acetone/H2O (8:1), rt, 30 h; f) Ph3PCH3Br, KO-tBu, THF, rt, 2 d; g) NaIO4,
H2O, CH2Cl2, rt, 2 h; h) CH2=CHMgBr, THF, −78 °C, 1 h; i) 2nd generation
Grubbs catalyst, CH2Cl2, rt, 2 d; j) TPAP, NMO, CH2Cl2, MS, rt, 24 h.
1
O
OH OH
(−)-Neplanocin A
O
O
2
Synthesis of the key intermediate, 1 is illustrated in
Scheme 1. D-Ribose was converted to the isopropylidene 312 un-
der acidic conditions (93%). The Wittig reaction of 3 with meth-
Figure 1. The key intermediates, 1 and 2 for the synthesis of
(ꢁ)-neplanocin A.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.5 (2004)
507
yl triphenylphosphonium ylide in THF afforded vinyl diol deriv-
ative which was subjected to selective benzylation of the pri-
mary hydroxy group using organotin chemistry to give vinyl
benzylether 4 (80% from 3). The Swern oxidation of 4 followed
by dihydroxylation of the resulting ketone 5 with osmium tetrox-
ide and NMO gave the diol 6 as a diastereomeric mixture in very
good yield. The Wittig reaction of the mixture 6 with methyl tri-
phenylphosphonium ylide in THF afforded vinyl diol 7, which
was treated with sodium metaperiodate to give aldehyde 8
(75% from 7). Treatment of 8 with vinylmagnesium bromide
gave divinyl derivative 9 (87%) as a diastereomeric mixture
(2:1). It is interesting to note that no stereoselectivity during
Grignard reaction was observed, despite of two available sites
(ꢀ- and ꢁ-oxygen) for chelation,13 indicating two oxygens of
the isopropylidene group do not form ꢀ- and ꢁ-chelates. Diene
9 was subjected to RCM reaction using the second generation
Grubbs catalyst14 in methylene chloride to give cyclopentenol
1015 (84%), which was oxidized to the key intermediate 17,9 us-
ing tetrapropylammonium perruthenate (TPAP) and NMO in
methylene chloride (84%). This key intermediate 1 was convert-
ed to (ꢁ)-neplanocin A according to the known procedure.7 This
intermediate also serves as a versatile synthon for the synthesis
of other carbocyclic nucleosides.
5
a) M. Arita, K. Adachi, Y. Ito, H. Sawai, and M. Ohno, J.
Am. Chem. Soc., 105, 4049 (1983). b) J. R. Medich, K. B.
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(1987).
S. M. Ali, K. Ramesh, and R. T. Borchardt, Tetrahedron
Lett., 31, 1509 (1990).
a) V. E. Marquez, M.-I. Lim, C. K. H. Tseng, A. Markovac,
M. A. Priest, M. S. Khan, and B. Kaskar, J. Org. Chem., 53,
5709 (1988). b) M. S. Wolfe, B. L. Anderson, D. R.
Borcherding, and R. T. Borchardt, J. Org. Chem., 55, 4712
(1990).
6
7
8
9
H. J. Bestman, and D. Roth, Angew. Chem., Int. Ed. Engl.,
29, 99 (1990).
K. Lee, C. Cass, and K. A. Jacobson, Org. Lett., 3, 597
(2001).
10 H. R. Moon, W. J. Choi, H. O. Kim, and L. S. Jeong,
Tetrahedron: Asymmetry, 13, 1189 (2002).
11 Y. H. Jin, and C. K. Chu, Tetrahedron Lett., 43, 4141 (2002).
12 a) M. Kiso, and A. Hasegawa, Carbohydr. Res., 52, 95
(1976). b) A. P. Rauter, F. Ramoa-Ribeiro, A. C. Fernandes,
and J. A. Figueiredo, Tetrahedron, 51, 6529 (1995).
13 J. A. Marco, M. Carda, F. Gonzalez, S. Rodriguez, E.
Castillo, and J. Murga, J. Org. Chem., 63, 698 (1998).
14 a) M. Scholl, S. Ding, C. W. Lee, and R. H. Grubbs, Org.
Lett., 1, 953 (1999). b) T. M. Tmka and R. H. Grubbs,
Acc. Chem. Res., 34, 18 (2001).
15 Experimental procedure for the synthesis of compound 10:
To a stirred solution of 9 (13.46 g, 43.83 mmol) in methylene
chloride (200 mL) was added 2nd generation Grubbs catalyst
(115 mg, 0.14 mmol) and the reaction mixture was stirred at
room temperature for 20 h. After an additional addition of
2nd generation Grubbs catalyst (86 mg, 0.10 mmol), the mix-
ture was stirred for an addtional 28 h at room temperature.
After evaporation of the reaction mixture in vacuo, the re-
sulting residue was purified by silica gel column chromatog-
raphy using hexane and ethyl acetate (2.5:1) as the eluent to
give 10 (10.11 g, 84%) as a pale brownish syrup and the re-
covered starting material (1.083 g).
In summary, we have accomplished the improved and prep-
arative synthesis of 1 from D-ribose using ring-closing metathe-
sis as a key reaction in 10 steps and 26% overall yield. Our meth-
od has synthetic advantages such as large scale synthesis
(>10 g), use of cheap starting material, D-ribose and no use of
expensive reagent like TBDPSCl. This synthetic method will
be extensively utilized for the structure-activity relationship
study of various carbocyclic nucleosides including (ꢁ)-neplano-
cin A.
This work was supported by the grant from the Korea Health
R & D Project, Ministry of Health & Welfare, Korea (02-PJ2-
PG10-21503-0004).
References and Notes
1
1
a) S. Yaginuma, N. Muto, M. Tsujino, Y. Sudate, M.
Hayashi, and M. Otani, J. Antibiot., 34, 359 (1980). b) M.
Hayashi, S. Yaginuma, H. Yoshioka, and K. Nakatsu, J.
Antibiot., 34, 675 (1981).
ꢀ-cyclopentenol: H NMR (400 MHz, CDCl3) ꢂ 7.33–7.27
(m, 5H, Ph), 5.78 (m, 1H, 5-H), 5.16 (d, 1H, J ¼ 5:6 Hz,
3a-H), 4.71 (m, 1H, 4-H), 4.56 (s, 2H, CH2Ph), 4.51 (d, 1
H, J ¼ 6:0 Hz, 6a-H), 4.18–4.10 (m, 2H, 6-H), 1.71 (br s,
1H, OH), 1.36 (s, 3H, CH3), 1.32 (s, 3H, CH3).
2
3
E. De Clercq, Biochem. Pharmacol., 36, 2567 (1987).
a) M. Hasobe, J. G. McKee, and R. T. Borchardt, Antimicrob.
Agents Chemother., 33, 828 (1989). b) M. Cools and E. De
Clercq, Biochem. Pharmacol., 40, 2259 (1990).
M. S. Wolfe, and R. T. Borchardt, J. Med. Chem., 34, 1521
(1991) and references cited therein.
1
ꢁ-cyclopentenol: H NMR (400 MHz, CDCl3) ꢂ 7.33–7.26
(m, 5H, Ph), 5.78 (s, 1H, 5-H), 4.95 (d, 1H, J ¼ 6:0 Hz, 4-
H), 4.74 (t, 1H, J ¼ 5:6 Hz, 3a-H), 4.55–4.54 (m, 3H, 6a-
H, CH2Ph), 4.14 (s, 1H, BnOCHH), 4.13 (s, 1H, BnOCHH),
2.54 (br s, 1H, OH), 1.40 (s, 3H, CH3), 1.38 (s, 3H, CH3).
4
Published on the web (Advance View) March 30, 2004; DOI 10.1246/cl.2004.506