Stereoselective synthesis of 3-hydroxymethyl-D-cyclopentenone, the versatile intermediate for the synthesis of carbocyclic nucleosides

Article abstract of DOI:10.1081/NCN-200061832

The preparative and stereoselective synthesis (45-50% overall yields, >50 g scale) of the key carbasugars 7a-d was achieved from D-ribose via stereoselective Grignard reaction and oxidative rearrangement as key reactions. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200061832

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STEREOSELECTIVE SYNTHESIS OF 3-HYDROXYMETHYL-
D-CYCLOPENTENONE, THE VERSATILE INTERMEDIATE
FOR THE SYNTHESIS OF CARBOCYCLIC NUCLEOSIDES
Won Jun Choi a , Hyung Ryong Moon b , Hea Ok Kim a , Young Mi Ko a , Hye Jin Kim a , Jeong
A. Lee a , Kang Man Lee a , Mi Kyung Yun a , Dae Hong Shin a , Moon Woo Chun b , Yhun Y.
Sheen a , Kilhyoun Kim a & Lak Shin Jeong a
a Laboratory of Medicinal Chemistry , College of Pharmacy, Ewha Womans University , Seoul,
Korea
b College of Pharmacy, Pusan National University , Pusan, Korea
Published online: 28 Jul 2006.
To cite this article: Won Jun Choi , Hyung Ryong Moon , Hea Ok Kim , Young Mi Ko , Hye Jin Kim , Jeong A. Lee , Kang
Man Lee , Mi Kyung Yun , Dae Hong Shin , Moon Woo Chun , Yhun Y. Sheen , Kilhyoun Kim & Lak Shin Jeong (2005)
STEREOSELECTIVE SYNTHESIS OF 3-HYDROXYMETHYL-D-CYCLOPENTENONE, THE VERSATILE INTERMEDIATE FOR THE SYNTHESIS
OF CARBOCYCLIC NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 611-613, DOI: 10.1081/NCN-200061832
To link to this article: http://dx.doi.org/10.1081/NCN-200061832
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5--7):611–613, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200061832
STEREOSELECTIVE SYNTHESIS OF 3-HYDROXYMETHYL-D-CYCLO-
PENTENONE, THE VERSATILE INTERMEDIATE FOR THE SYNTHESIS
OF CARBOCYCLIC NUCLEOSIDES
5
Won Jun Choi
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans
University, Seoul, Korea
5
Hyung Ryong Moon
College of Pharmacy, Pusan National University, Pusan, Korea
Hea Ok Kim, Young Mi Ko, Hye Jin Kim, Jeong A. Lee, Kang Man Lee,
5
Mi Kyung Yun, and Dae Hong Shin
Laboratory of Medicinal Chemistry, College of
Pharmacy, Ewha Womans University, Seoul, Korea
5
Moon Woo Chun
College of Pharmacy, Seoul National University, Seoul, Korea
5
Yhun Y. Sheen, Kilhyoun Kim, and Lak Shin Jeong
Laboratory of Medicinal
Chemistry, College of Pharmacy, Ewha Womans University, Seoul, Korea
5
The preparative and stereoselective synthesis (45---- 5 0 % overall yields, >50 g scale) of the key
carbasugars 7a--d was achieved from D-ribose via stereoselective Grignard reaction and oxidative
rearrangement as key reactions.
Keywords 3-Hydroxymethyl-D-cyclopentenone, Carbocyclic Nucleosides
INTRODUCTION
Although carbocyclic nucleosides such as neplanocin A[1] and aristeromycin[2]
exhibited potent biological activity, limited structure-activity relationship (SAR)
study of these carbocyclic nucleosides was carried out due to the synthetic
difficulties in preparing the D-carbasugars. Thus, modifications have mainly been
done on the base moiety,[3] not on the carbasugars. Many synthetic methods to the
carbasugars have so far been reported, but they have drawbacks such as
inconsistent and low overall yields, lengthy synthetic routes, racemization, lack of
large-scale preparations, and sensitivity to reaction conditions such as temperature
This work was supported by Korea Research Foundation Grant (KRF-2003-005-F00022).
Address correspondence to Lak Shin Jeong, Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans University, Seoul 120-750, Korea.
611
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612
W. J. Choi et al.
and moisture. Therefore, a short and efficient procedure to the D-carbasugars has
been highly desirable for the development of carbocyclic nucleosides with new
carbasugar templates. In this article, we wish to report the highly efficient synthesis
(7 steps and 45--50% overall yields) of the key carbasugar, 3-hydroxymethyl-D-
cylcopentenone was accomplished from D-ribose via stereoselective Grignard
reaction for the formation of the tertiary b-allylic alcohol and the oxidative
rearrangement of the tertiary b-allylic alcohol.
RESULTS AND DISCUSSION
Synthesis of the key carbasugars 7a--d started from 2,3-O-isopropylidene-D-
ribose (1a--d) with various protecting groups, which were easily prepared from
D-ribose, as shown in Scheme 1. Wittig reactions of 1a--d with methyltriphe-
nylphosphonium bromide in the presence of potassium t-butoxide in THF gave
monovinyl derivatives 2a--d in good yields. Oxidation of 2a--d using oxalyl
chloride and DMSO afforded ketone derivatives 3a--d. The introduction of the
second vinyl group was achieved using a Grignard reaction. Treatment of 3a--d
with vinylmagnesium bromide produced the inseparable diasteromeric mixture
of diene derivatives 4a--d, in which their diastereomeric ratio were found to be
greatly affected by the size of the protecting groups, resulting in formation of a
single stereoisomer in case of TBDPS and trityl groups.
Exposure of dienes 4a--d to a Grubbs catalyst[4] in methylene chloride
afforded the separable b-cyclopentenols 5a--d and a-cyclopentenols 6a--d. The
bulkier protecting groups, the more formation of the tertiary b-cyclopentenol was
obtained. Oxidative rearrangements of the b-tertiary cyclopentenols 5a--d to the
desired carbasugars 7a--d were achieved using PDC in DMF, while minor
isomers, a-cyclopentenols 6a--d failed to give the same carbasugars 7a--d under
the various oxidation conditions (PCC, PDC, and CrO3 in various solvents
(CH2Cl2, DMSO, ClCH2CH2Cl, and DMF). This result clearly indicates that steric
SCHEME 1

W. J. Choi et al.
613
hindrance by the 2,3-isopropylidene group prevented the conversion of the tertiary
chromate ester to the desired product. In summary, we have accomplished the
preparative synthesis of the key synthons 7a--d with various protective groups,
starting from D-ribose in 7 steps and 45--50% overall yields (>50 g scale). To the
best of our knowledge, this synthetic method is regarded as the best procedures
from the viewpoint of number of steps, overall yields, large-scale preparation, and
mild reaction conditions and has a great potential to be utilized extensively in the
SAR study of the carbocyclic nucleosides.
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