Convenient route to both enantiomers of a highly functionalized trans-disubstituted cyclopentene. Synthesis of the carbocyclic core of the nucleoside BCA

Article abstract of DOI:10.1021/jo0502504

Synthesis of both enantiomers of a highly functionalized cyclopentenol derivative, versatile building block for a vast array of biologically active compounds, is described. The key steps involve stereocontrolled synthesis of a diene with two syn-disposed

Full text of DOI:10.1021/jo0502504

program on the synthesis of carbocyclic nucleosides
accomplishing a synthesis of (()-cyclobut A5 and (-)-
carbovir.6
Convenient Route to Both Enantiomers of
a Highly Functionalized
Trans-Disubstituted Cyclopentene.
Synthesis of the Carbocyclic Core of the
Nucleoside BCA
Shyamapada Banerjee, Sarita Ghosh, Saikat Sinha, and
Subrata Ghosh*
Department of Organic Chemistry, Indian Association for
the Cultivation of Science, Jadavpur,
Kolkata 700 032, India
We next focused our attention on the synthesis of the
carbocyclic moiety of BCA. While considering this syn-
thesis, we were guided by our desire to design a synthesis
of an enantiopure cyclopentene derivative that allows
access not only to BCA but also to a vast array of vicinally
substituted bioactive cyclopentanoids such as prostag-
landins,7 jasmones,8 brefeldin,9 etc. We visualized that
the cyclopentenol 4 would be a versatile building block
for entry into these classes of compounds. We herein
report a stereocontrolled approach to the synthesis of
both enantiomers of the highly functionalized cyclopen-
tene derivative 4 and conversion of one of them to the
amino cyclopentene 5, an intermediate to (-)-BCA 3.
ocsg@mahendra.iacs.res.in
Received February 7, 2005
Synthesis of both enantiomers of a highly functionalized
cyclopentenol derivative, versatile building block for a vast
array of biologically active compounds, is described. The key
steps involve stereocontrolled synthesis of a diene with two
syn-disposed substituents from a (R)-(+)-glyceraldehyde
derivative, ring-closing metathesis of this diene, and func-
tional group manipulation of the resulting trans-disubsti-
tuted cyclopentene. One of the enantiomers of the cyclopen-
tenol thus obtained has been converted to an amino
cyclopentene, the carbocyclic core of the nucleoside (-)-BCA,
a potent inhibitor of HIV reverse transcriptase.
(2) For reviews on synthesis of carbocyclic nucleosides, see: (a)
Crimmins, M. T. Tetrahedron 1998, 54, 9229-9272. (b) Ferrero, M.;
Gotor, V. Chem. Rev. 2000, 100, 4319-4347. For selected recent
synthesis, see: (c) Kuang, R.; Ganguly, A. K.; Chan, T.-M.; Pramanik,
B. N.; Blythin, D. J.; McPhail, A. T.; Saksena, A. K. Tetrahedron Lett.
2000, 41, 9575-9579. (d) Brown, B.; Hegedus, L. S. J. Org. Chem. 2000,
65, 1865-1872. (e) Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka,
Y.; Tomioka, K. J. Org. Chem. 2001, 66, 8199-8203. (f) Choi, W. J.;
Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon, H. R.; Chun, M. W.; Jung, Y.
H.; Jeong, L. S. J. Org. Chem. 2001, 66, 6490-6494. (g) Gurjar, M. K.;
Maheshwar, K. J. Org. Chem. 2001, 66, 7552-7554. (h) Ewing, D. F.;
Glacon, V.; Mackenzie, G.; Leu, C. Tetrahedron Lett. 2002, 43, 989-
991. (i) Kim, K. H.; Miller, M. J. Tetrahedron Lett. 2003, 44, 4571-
4573. (j) Hong, J. H.; Oh, C.-H.; Cho, J.-H. Tetrahedron 2003, 59, 6103-
6108. (k) Fang, Z.; Hong, J. H. Org. Lett. 2004, 6, 993-995. (l) Davis,
F. A.; Wu, Y. Org. Lett. 2004, 6, 1269-1272. (m) Joshi, B. V.; Moon,
H. R.; Fettinger, J. C.; Marquez, V. E.; Jacobson, K. A. J. Org. Chem.
2005, 70, 439-447.
(3) For selected approaches to (-)-carbovir, see: (a) Trost, B. M.;
Leping, L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114, 8745-8747. (b)
Evans, C. T.; Roberts, S. M.; Shoberu, K. A.; Sutherland, A. G. J. Chem.
Soc., Perkin Trans. 1 1992, 589-592. (c) Asami, M.; Takahashi, J.;
Inoue, S. Tetrahedron: Asymmetry 1994, 5, 1649-1652. (d) Hodgson,
D. M.; Witherington, I.; Moloney, B. A. J. Chem. Soc., Perkin Trans. 1
1994, 3373-3378. (e) Nokami, J.; Matsuura, H.; Nakasima, K.;
Shibata, S. Chem. Lett. 1994, 1071-1074, and references therein. (f)
Roulland, E.; Monneret, C.; Florent, J. C. Tetrahedron Lett. 2003, 44,
4125-4128. For synthesis of abacavir, see: (g) Crimmins, M. T.; King,
B. W. J. Org. Chem. 1996, 61, 4192-4193. (h) Crimmins, M. T.;
Zuercher, W. J. Org. Lett. 2000, 2, 1065.
Nucleosides1 exhibit a wide range of biological activity.
The metabolic instability of nucleosides caused by cleav-
age of glycosidic bonds by the enzymes phosphorylases
has restricted their therapeutic application. The search
for metabolically stable nucleosides with potent antitu-
mor and antiviral activities led to several structural
modifications. One such modification is replacement of
the oxygen atom of the sugar ring by a methylene unit
resulting in carbocyclic nucleosides. The carbocyclic
nucleosides are highly resistant to phosphorylases with
comparable biological activity to the parent nucloesides.
With the outbreak of the AIDS epidemic, the search for
new carbocyclic nucleoside analogues2 intensified to a
great extent. Several carbocyclic nucleosides2a,b such as
carbovir 1, abacavir 2, and bis(hydroxymethyl)cyclopen-
tenyl adenine (BCA) 3 have been found to be inhibitors
of HIV, the causative agent of AIDS. Several approaches3
to the synthesis of the carbocyclic core of the nucleosides
1 and 2 have been reported. However, there are only few
reports4 on the synthesis of BCA. We have initiated a
(4) (a) Katagiri, N.; Nomura, M.; Sato, H.; Kaneko, C.; Yusa, K.;
Tsuruo, T. J. Med. Chem. 1992, 35, 1882-1886. (b) Katagiri, N.;
Toyota, A.; Shiraishi, T.; Sato, H.; Kaneko, C. Tetrahedron Lett. 1992,
33, 3507-3510. (c) Tanaka, M.; Norimine, Y.; Fujita, T.; Suemune, H.;
Sakai, K. J. Org. Chem. 1996, 61, 6952-6957.
(5) Panda, J.; Ghosh, S.; Ghosh, S. J. Chem. Soc., Perkin Trans. 1
2001, 3013-3016.
(6) Nayek, A.; Banerjee, S.; Sinha, S.; Ghosh, S. Tetrahedron Lett.
2004, 45, 6457-6460.
(7) Stork, G. In Classics in Total Synthesis; Nicolaou, K. C.,
Sorensen, E. J., Eds.; VCH Publishers, Inc.: New York, 1996; Chapter
9.
(1) (a) Nucleosides and Nucleotides as Antitumor and Antiviral
Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993.
(b) Chemistry of Nucleosides and Nucleotides; Townsend, L. B., Ed.;
Plenum Press: New York, 1988.
(8) Suzuki, K.; Inomata, K.; Endo, Y. Org. Lett. 2004, 409-411 and
references therein.
(9) Wu, Y.; Shen, X.; Yang, Y. Q.; Hu, Q.; Huang, J. H. Tetrahedron
Lett. 2004, 45, 199-202.
10.1021/jo0502504 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/05/2005
J. Org. Chem. 2005, 70, 4199-4202
4199

SCHEME 1
SCHEME 2a
A retrosynthetic analysis (Scheme 1) dictated that the
cyclopentenol 4 in principle could be obtained from the
cyclopentene derivative 6 through functionalization. This
should be available from ring-closing metathesis (RCM)10
of the diene 7. The diene 7 can be constructed from the
glyceraldehyde derivative 8. Sacrificing the chirality
present in the ketal moiety at a suitable step in the
synthetic sequence will ensure complete transfer of
chirality from the C-2 center of the glyceraldehyde
derivative 8 to the cyclopentenol 4.
a Reagents and conditions: (i) NaIO4, MeCN/H2O (3:2), K2CO3,
P(O)(OEt)2CH2CO2Et, 67%; (ii) LiAlH4, Et2O, -60 °C, 62%; (iii)
CH3C(OEt)3, propionic acid, 140 °C, 6 h, 68%; (iv) KOH, EtOH-
H2O, 85 °C, 2 h, then 80% AcOH, 85 °C, 4 h, 61%.
The synthesis begins with the unsaturated esters 12
and 13. These were prepared from the protected D-
mannitol derivative 9 (Scheme 2).11 Wittig-Horner reac-
tion of the in situ-generated aldehyde 8 from periodate
cleavage of the diol 9 with triethyl phosphonoacetate
afforded a mixture of the unsaturated ester 10 and its
(Z)-isomer in a 4:1 ratio, which without separation was
reduced with LiAIH4 to give the alcohol 11 and its (Z)-
isomer in a 4:1 ratio. Ortho ester Claisen rearrangement
of this unsaturated alcohol mixture 11 gave a mixture
of the unsaturated esters 12 and 13 in a ca. 1:1 ratio.
Compounds 12 and 13 were separated by flash chroma-
tography. For stereochemical assignment, the esters 12
and 13 were converted to the lactones 15 and 14,
respectively, through alkaline hydrolysis of the ester
followed by acid-induced deketalization. Stereochemical
assignment is based on comparison of the chemical shifts
of HA and HC between the lactones 14 and 15. The global
energy minimum structure of the lactones as obtained
by AM1 calculations12 shows that in the lactone 14 in
which the hydroxymethyl and the vinyl groups are cis to
each other, HA lies in the shielding cone of the vinyl
group13 and is shielded to δ 3.81 compared to HA (δ 3.92)
in the lactone 15. Similarly, HC, which is cis to the vinyl
group in 15, is shielded to δ 4.25 in 15 in comparison to
that (δ 4.54) in the lactone 14. A positive NOE (1%)
between HA and the vinylic proton HD in the lactone 14
and that between HC and the vinylic proton HD in the
lactone 15 also indicated the assigned structures. The
inversion of configuration at C-2 of the esters 12 and 13
from S to R at C-5 during formation of the lactones 14
and 15 arises through intramolecular displacement of the
protonated ketal oxygen in the intermediate 12i by the
carboxyl group. Thus, the unsaturated ester that pro-
duced the lactone 14 has the stereochemistry depicted
in the structure 13. The unsaturated ester giving the
lactone 15 posseses the structure 12. The absolute
configuration at C-3 of the esters 12 and 13 was con-
firmed earlier as S and R, respectively, through trans-
formation of the ester 13 to a cyclopentenol derivative of
known absolute configuration.6
With the unsaturated esters 12 and 13 ready in hand,
we proceeded toward the synthesis of the diene 7 from
alkylation of the enolate generated from the ester 13. On
the basis of Houk’s model14 for addition of electrophiles
to CdC double bonds having an R-chiral center, we
anticipated that allylation would take place from the side
of the C-3 H to produce the diene 7 as the major product,
which bears the required anti relationship between the
ketal and the CO2Et groups. Allylation of the lithium
enolate of the ester 13 gave an inseparable mixture of
the desired diene (2S,3S,2′S)-7 and its (2R,3S,2′S)-
diastereoisomer in a ca. 3:1 ratio. Allylation of the enolate
of the ester 12 also produced an inseparable mixture of
the (2R,3R,2′S)- and (2S,3R,2′S)-allylated products in
an almost similar ratio (3:1). The relative orientation
between the ketal and the CO2Et moieties in the major
(10) (a) For reviews on the RCM reaction, see: Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036-2056. (b) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (c) Pariya, C.;
Jayaprakash, K. N.; Sarkar, A. Coord. Chem. Rev. 1998, 168, 1-48.
(d) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (e)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (f) Kotha,
S.; Sreenivasachary, N. Indian J. Chem. 2001, 40B, 763-780. (g)
Dieters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199-2238.
(11) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60,
585-587.
(12) AM1 calculations were done using MOPAC, version 1.10.
Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am.
Chem. Soc. 1985, 107, 3901-3909.
(13) cf.: Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980,
102, 5253-5261.
(14) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1223.
4200 J. Org. Chem., Vol. 70, No. 10, 2005

SCHEME 3a
pentene derivative 21 with mCPBA gave mainly the
epoxide 22 with a trace amount of the other diastereoi-
someric epoxide. Although the stereochemistry of the
epoxide could not be ascertained at this stage, it may be
speculated that the benzyloxy methyl group at the allylic
position probably directed epoxidation from its opposite
face due to steric reasons. An attempt to convert the
15
epoxide 22 to the cyclopentenol 23 by using LiNEt2
produced a complex mixture of products. Finally, we
employed the procedure developed by Sharpless16 for
converting epoxide to allylic alcohol. Sequential treat-
ment of the epoxide 22 with PhSeSePh-NaBH4 and H2O2
(30%) afforded a mixture of the regioisomeric cyclopen-
tenols 23 and 24. Chromatographic purification of the
mixture gave the desired cyclopentenol 23 in 40% yield
and the isomeric cyclopentenol 24 in 20% yield. The
cyclopentenol 23 was characterized by the appearance
of two olefinic CH at δ 5.89 (1H, m) and 5.94 (1H, dd, J
) 1.7 and 5.8 Hz). In contrast, the isomeric cyclopentenol
24 displayed only one olefinic CH as a singlet at δ 5.77.
The cis stereochemical assignment of the C-1 OH group
with C-4 benzyloxymethyl group was ascertained from
NOE (0.5%) between C-1 and C-4 hydrogens. This also
confirms the stereochemical assignment of the epoxide
as depicted in the structure 22. The cyclopentenol 23
obtained as above from the unsaturated ester 13 exhibits
an optical rotation [R]D ) -41 (c 0.2, CHCl3). Application
of the same protocol to unsaturated ester 12 afforded the
enantiomer of the cyclopentenol derivative 23 with an
optical rotation [R]D ) +40.25 (c 0.4, CHCl3).
Transformation of the cyclopentenol 23 to the amino
cyclopentene 27 was achieved through standard protocol.
Inversion of the stereochemistry of the C-1 OH group in
23 was accomplished by Mitsunobu reaction17 to afford
the cyclopentenol 25. The cyclopentenol 25 was then
converted to the azide 26 through the corresponding
mesylate. Lithium aluminum hydride reduction of the
azide 26 finally afforded the amino cyclopentene 27. It
is noteworthy that the MOM ether analogue 28 of
the amino cyclopentene 27, prepared by Tanaka et al.,4c
has been converted to (-)-BCA. An analogue of
the cyclopentenol 24 has also been converted to nucleo-
sides.18
a Reagents and conditions: (i) LDA, THF, CH2dCHCH2Br,
HMPA, -78 °C-rt, 84%. (ii) 16, C6H6, 60 °C, 20 h, 96%. (iii)
NaOEt-EtOH, reflux, 10 h, then CH2N2, Et2O, 84%. (iv) 75%
AcOH, 18 h, then NaIO4, MeOH-H2O, rt, 1 h, 71%. (v) NaBH4,
MeOH, 55%. (vi) LiAlH4, Et2O, 0 °C-rt, 1 h, 68%. (vii) NaH,
PhCH2Br, THF, HMPA, reflux, 6 h, 75%. (viii) m-CPBA, CH2Cl-
CH2Cl, 0 °C-rt, 5 h, 85%. (ix) PhSeSePh/NaBH4, then 30% H2O2,
40%. (x) p-NO2C6H4COOH, DEAD, PPh3, C6H6, 78%, then KOH,
EtOH-H2O, reflux, 30 min, 91%. (xi) (a) MsCl, pyridine, 0 °C; (b)
NaN3, DMF, 100 °C.
isomer 7 could be established only after transformation
of the mixture to the disubstituted cyclopentene 18 as
shown in Scheme 3. RCM of the mixture of the diene 7
and its diastereoisomer with Grubbs’ catalyst, Ph-
CHdRu(PCy3)2Cl2 (16), in benzene at 60 °C proceeded
smoothly to provide a mixture of the cyclopentene deriva-
tive (1S,2S,2′S)-6 and its (1R,2S,2′S)-diastereoisomer in
about the same ratio (3:1) in excellent yield. This mixture
was equilibrated with 2% NaOEt in EtOH to produce a
single cyclopentene derivative 17 after diazomethane
treatment of the resulting carboxylic acid. The compound
17 was then converted to the hydroxy ester 19 through
a three-step sequence involving acid-induced cleavage of
the ketal, periodate cleavage of the resulting diol to the
aldehyde 18, and sodium borohydride reduction of the
aldehyde 18 to the hydroxy ester 19. After alkaline
hydrolysis, 19 failed to provide any lactone. This con-
firmed the trans orientation of the vicinal substituents
in the cyclopentenes 6, 18, and 19 and hence the syn
relationship of the corresponding substituents in their
precursor, diene 7. After the trans orientation of the
vicinal substituents was established, the cyclopentene 18
was reduced with LiAIH4 to produce the diol 20. The diol
20 was protected to give the dibenzyl ether 21. For
introduction of the hydroxyl group at the allylic position
of the cyclopentene 21, we decided to proceed through
an epoxide elimination route. Epoxidation of the cyclo-
In conclusion, we have developed a route to the
synthesis of trans vicinally disubstituted hydroxy- and
amino cyclopentenes in enantiomerically pure form using
an (R)-(+)-glyceraldehyde derivative as the chiral adju-
vant.19 The present approach provides access to both
enantiomers of the cyclopentenyl derivatives from (R)-
(+)-glyceraldehyde derivative. The key step involves ring-
closing metathesis of a prebuilt diene carrying two anti-
disposed substituents. Functional group manipulation in
the cyclopentene obtained in this way finally led to the
(15) Kissel, C. L.; Rickborn, B. J. Org. Chem. 1972, 37, 2060-2063.
(16) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95,
2697-2699.
(17) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
React. 1992, 42, 335-656.
(18) Wachtmeister, J.; Classon, B.; Samuelsson, B.; Kvarnstrom, D.
Tetrahedron 1995, 51, 2029-2038.
(19) (a) For a review on application of optically pure glyceraldehyde
derivatives in asymmetric synthesis, see: Jurczak, J.; Pikul, S.; Bauer,
T. Tetrahedron 1986, 42, 447-488. (b) For our recent work on synthesis
using (R)-(+)-glyceraldehyde derivative, see: Sarkar, N.; Nayek, A.;
Ghosh, S. Org. Lett. 2004, 6, 1903-1905 and ref 6.
J. Org. Chem, Vol. 70, No. 10, 2005 4201

Supporting Information Available: Experimental pro-
cedures for all new compounds with microanalytical data, as
well as copies of NMR (1H, 13C, and DEPT) for compounds 6,
7, 9-15, and 17-27. This material is available free of charge
via the Internet at http://pubs.acs.org.
trans-disubstituted functionalized cyclopentene, the car-
bocyclic core of the nucleoside BCA.
Acknowledgment. Financial support from Depart-
ment of Science and Technology, Government of India,
is gratefully acknowledged. S.B., S.G., and S.S. wish to
thank CSIR, New Delhi, for research fellowships.
JO0502504
4202 J. Org. Chem., Vol. 70, No. 10, 2005