An improved approach to chiral cyclopentenone building blocks. Total synthesis of pentenomycin I and neplanocin A

Article abstract of DOI:10.1021/jo050987t

An improved approach to enantiomerically pure hydroxylated cyclopentenones is reported here, which involves intramolecular nitrone cycloaddition of sugar-derived chiral pent-4-enals and hex-5-en-ones-2 followed by N-O bond cleavage, quaternization of the amine thus produced, and finally oxidative elimination of the amino group. Synthesis of pentenomycin I and neplanocin A is described following this methodology.

Full text of DOI:10.1021/jo050987t

An Improved Approach to Chiral Cyclopentenone Building Blocks.
Total Synthesis of Pentenomycin I and Neplanocin A†
John K. Gallos,* Christos I. Stathakis, Stefanos S. Kotoulas, and Alexandros E. Koumbis
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
igallos@chem.auth.gr
Received May 18, 2005
An improved approach to enantiomerically pure hydroxylated cyclopentenones is reported here,
which involves intramolecular nitrone cycloaddition of sugar-derived chiral pent-4-enals and hex-
5-en-ones-2 followed by N-O bond cleavage, quaternization of the amine thus produced, and finally
oxidative elimination of the amino group. Synthesis of pentenomycin I and neplanocin A is described
following this methodology.
Introduction
metric5 and chiral pool6 approaches. Additionally, pen-
tenomycin I (2), a hydroxymethylated cyclopentenone
isolated from culture broths of Streptomyces eurythermus,
is a member of the well-studied family of pentenomycin
antibiotics which show combined activity against Gram-
positive and Gram-negative bacteria.7 This branched
analogue of deprotected (+)-1 has been targeted by
several groups, and several of its syntheses8 have been
released during the past decades. On the other hand, (-)-
neplanocin A (3), isolated from Ampullariella regularis,9
and (-)-carbovir (4) are two of the most popular carbocy-
clic nucleosides. They heavily caught the attention of
synthetic chemists10-12 because of their remarkable
antiviral and anticancer activity.13
Cyclopentenones (+)-1 and (-)-1 are very important
chiral building blocks, widely used in organic synthesis.1
Indeed, a plethora of natural and nonnatural products,
such as carbocyclic nucleosides,2 azasugars,3 and pros-
taglandins,4 have been prepared from these key inter-
mediates. Therefore, work toward their enantioselective
syntheses has been published, including both asym-
† Respectfully dedicated to Prof. G. Karabatsos.
(1) Johnson, C. R. Acc. Chem. Res. 1998, 31, 333-341.
(2) Selected recent publications: (a) Shato, S.; Obara, T.; Saito, Y.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Matsuda, A. J. Med. Chem. 1996,
39, 2392-2399. (b) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu,
C. K. Tetrahedron Lett. 1997, 38, 4207-4210. (c) Jeong, L. S.; Buenger,
G.; McCormack, J. J.; Cooney, D. A.; Hao, Z.; Marquez, V. E. J. Med.
Chem. 1998, 41, 2572-2578. (d) Wang, P.; Agrofoglio, L. A.; Newton,
M. G.; Chu, C. K. J. Org. Chem. 1999, 64, 4173-4178. (e) Song, G. Y.;
Paul, V.; Choo, H.; Morrey, J.; Sidweii, R. W.; Schinazi, R. F.; Chu, C.
K. J. Med. Chem. 2001, 44, 3985-3993. (f) Chu, C. K.; Jin, Y. H.; Baker,
R. O.; Huggins, J. Bioorg. Med. Chem. Lett. 2003, 13, 9-12. (g) Jin, Y.
H.; Liu, P.; Wang, J.; Baker, R.; Huggins, J.; Chu, C. K. J. Org. Chem.
2003, 68, 9012-9018.
(5) Selected recent publications: (a) Deardorff, D. R.; Shambayati,
S.; Myles, D. C.; Heerding, D. J. Org. Chem. 1988, 53, 3614-3615. (b)
Sundermann, B.; Scharf, H.-D. Tetrahedron: Asymmetry 1996, 7, 1995-
1998. (c) Biadatti, T.; Esker, J. L.; Johnson, C. R. Tetrahedron:
Asymmetry 1996, 7, 2313-2320. (d) Armstrong, A.; Hayter, B. R.
Tetrahedron: Asymmetry 1997, 8, 1677-1684. (e) Lin, C.-C.; Wang,
Y.-C.; Hsu, J.-L.; Chiang, C.-C.; Su, D.-W.; Yan, T.-H. J. Org. Chem.
1997, 62, 3806-3807. (f) Nakashima, H.; Sato, M.; Taniguchi, T.;
Ogasawara, K. Synthesis 2000, 817-823.
(6) Selected recent publications: (a) Be´langer, P.; Prasit, P. Tetra-
hedron Lett. 1988, 29, 5521-5524. (b) Ali, S. M.; Ramesh, K.;
Borchardt, R. T. Tetrahedron Lett. 1990, 31, 1509-1512. (c) 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. (d) Moon, H.
R.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron: Asymmetry 2002,
13, 1189-1193. (e) Reference 2g.
(7) (a) Umino, K.; Furama, T.; Matzuzawa, N.; Awataguchi, Y.; Ito,
Y.; Okuda, T. J. Antibiot. 1973, 26, 506-512. (b) Umino, K.; Takeda,
N.; Ito, Y.; Okuda, T. Chem. Pharm. Bull. 1974, 22, 1233-1238.
(3) Selected recent publications: (a) Johnson, C. R.; Golebiowski,
A.; Braun, M. P.; Sundram, H. Tetrahedron Lett. 1994, 35, 1833-1834.
(b) Johnson, C. R.; Nerurkar, B. M.; Golebiowski, A.; Sundram, H.;
Esker, J. L. J. Chem. Soc., Chem. Commun. 1995, 1139-1140. (c)
Johnson, C. R.; Golebiowski, A.; Schoffers, E.; Sundram, H.; Braun,
M. P. Synlett 1995, 313-314. (d) Tanaka, K.; Taniguchi, T.; Ogasawara,
K. Tetrahedron Lett. 2001, 42, 1049-1052.
(4) (a) Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1988, 110,
4726-4735. (b) Johnson, C. R.; Chen, Y.-F. J. Org. Chem. 1991, 56,
3344-3351. (c) Johnson, C. R.; Chen, Y.-F. J. Org. Chem. 1991, 56,
3352-3357. (d) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993,
115, 11014-11015.
10.1021/jo050987t CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/16/2005
6884
J. Org. Chem. 2005, 70, 6884-6890

Chiral Cyclopentenone Building Blocks
SCHEME 1. Retrosynthetic Plan
as well as elaborate description for the synthesis of the
required nitrone adducts15 are also given. Moreover, the
same approach was evaluated in the direct construction
of the carbocyclic core of 3 and 4.
Recently, we have reported a short and efficient total
synthesis of 2 from L-arabinose.14 On the basis of the
methodology described in that earlier communication, we
now wish to report a new simple method for the prepara-
tion of both parent (+)-1 and (-)-1 through key nitrone
cycloaddition intermediates using again naturally abun-
dant carbohydrates as starting materials. Full details for
the preparation of 2 according to optimized procedures
Results and Discussion
We envisioned that a common and versatile retrosyn-
thetic plan (Scheme 1) could easily lead to our proposed
targets. This plan involves three key steps: (i) cyclopen-
tenone derivative 5 could be accessible from quaternized
ammonium salt 6 upon oxidative elimination, (ii) hy-
droxyamine needed for the preparation of 6 could be
obtained from bicyclic isoxazolidine 7 upon reductive
rupture of N-O bond, and (iii) carbocycle 7 could be the
intramolecular cycloaddition adduct derived from the
suitable functionalized sugar derivative 8. Cyclopenten-
ones 5 are considered to be either simple protected
derivatives of 1-2 or advanced precursors of nucleosides
mimics 3 and 4.
This concept was originally tested by our group in the
synthesis of pentenomycin I14 and proved to be very
successful. Thus, the acetonide of L-erythrose (9)16 was
used as the starting point for the preparation of the
required pent-4-enal 13 (Scheme 2). The quaternary
chiral center was constructed according to a well-
established approach,17,18 namely, the aldol condensation
of our sugar substrate with formaldehyde. The resulting
alcohol 10 after tritylation18 was subjected to a Wittig
olefination to yield 12, almost quantitatively. Oxidation
of the latter under normal Swern reaction conditions
afforded the rather unstable aldehyde 13 which was
directly used in a two-step procedure involving formation
of the intermediate nitrone and intramolecular cycload-
dition upon heating. This sequence produced in a good
overall yield the two possible diastereoisomeric adducts
(8) Selected publications: (a) Verheyden, J. P. H.; Richardson, A.
C.; Bhatt, R. S.; Grant, B. D.; Fitch, W. L.; Moffatt, J. G. Pure Appl.
Chem. 1978, 50, 1363-1383. (b) Hetmanski, M.; Purcell, N.; Stoodley,
R. J.; Palfreyman, M. N. J. Chem. Soc., Perkin Trans. 1 1984, 2089-
2096. (c) Pohmakotr, M.; Popuang, S. Tetrahedron Lett. 1991, 32, 275-
278. (d) Sugahara, T.; Ogasawara, K. Synlett 1999, 419-420. (e)
Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2000, 41, 4291-4293.
(f) Ramana G. V.; Rao G. V. Tetrahedron Lett. 2003, 44, 5103-5105.
(g) Rivero, M. R.; de la Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc.
2003, 125, 14992-14993. (h) Rivero, M. R.; Alonso, I.; Carretero, J. C.
Chem. Eur. J. 2004, 10, 5443-5459.
(9) (a) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. J. Antibiot. 1981, 34, 359-366. (b) Hayashi, M.;
Yaginuma, S.; Yoshioka, H.; Nakatsu, K. J. Antibiot. 1981, 34, 675-
680.
(10) For general reviews of carbocyclic nucleoside syntheses, see:
(a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-623.
(b) Crimmins, M. T. Tetrahedron 1998, 54, 9229-9272.
(11) Selected syntheses for (-)-neplanocin A: (a) Medich, J. R.;
Kunnen, K. B.; Johnson, C. R. Tetrahedron Lett. 1987, 28, 4131-4134.
(b) Marquez, V. E.; Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.; Priest,
M. A.; Khan, M. S.; Kaskar, B. J. Org. Chem. 1988, 53, 5709-5714.
(c) Reference 5a. (d) Bestmann, H. J.; Roth, D. Angew. Chem., Int. Ed.
Engl. 1990, 29, 99-100. (e) Wolfe, M. S.; Anderson, B. L.; Borcherding,
D. R.; Borchardt, R. T. J. Org. Chem. 1990, 55, 4712-4717. (f)
Vanhessche, K.; Bello, C. G.; Vandewalle, M. Synlett 1991, 921-922.
(g) Hill, J. M.; Hutchinson, E. J.; Le Grand, D. M.; Roberts, S. M.;
Thorpe, A. J.; Turner, N. J. J. Chem. Soc., Perkin Trans. 1 1994, 1483-
1487. (h) Ohira, S.; Sawamoto, T.; Yamato, M. Tetrahedron Lett. 1995,
36, 1537-1538. (i) Niizuma, S.; Shuto, S.; Matsuda, A. Tetrahedron
1997, 53, 13621-13632. (j) Yoshida, N.; Kamikubo, T.; Ogasawara,
K. Tetrahedron Lett. 1998, 39, 4677-4678. (k) Trost, B. M.; Madsen,
R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc. 2000, 122, 5947-5956.
(l) Hegedus, L. S.; Geisler, L. J. Org. Chem. 2000, 65, 4200-4203. (m)
Reference 2e. (n) Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka,
Y.; Tomioka, K. J. Org. Chem. 2001, 66, 8199-8203.
(12) Selected syntheses for (-)-carbovir: (a) Jones, M. F.; Myers,
P. L.; Robertson, C. A.; Storer, R.; Williamson, C. J. Chem. Soc., Perkin
Trans. 1 1991, 2479-2484. (b) Peel, M. R.; Sternbach, D. D.; Johnson,
M. R. J. Org. Chem. 1991, 56, 4990-4993. (c) Evans, C. T.; Roberts,
S. M.; Shoberu, K. A.; Sutherland, A. G. J. Chem. Soc., Perkin Trans.
1 1992, 589-592. (d) Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem.
Soc. 1992, 114, 8745-8747. (e) Asami, M.; Takahashi, J.; Inoue, S.
Tetrahedron: Asymmetry 1994, 5, 1649-1652. (f) Nokami, J.; Mats-
uura, H.; Nakasima, K.; Shibata, S. Chem. Lett. 1994, 1071-1074. (g)
Hodgson, D. M.; Witherington, J.; Moloney, B. A. J. Chem. Soc., Perkin
Trans. 1 1994, 3373-3378. (h) Hildbrand, S.; Troxler, T.; Scheffold,
R. Helv. Chim. Acta 1994, 77, 1236-1240. (g) Crimmins, M. T.; King,
B. W. J. Org. Chem. 1996, 61, 4192-4193. (h) Mart´ınez, L. E.; Nugent,
W. A.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 7963-7966. (i) Olivo,
H. F.; Yu, J. J. Chem. Soc., Perkin Trans. 1 1998, 391-392. (j) Kapeller,
H.; Marschner, C.; WeiBenbacher, M.; Griengl, H. Tetrahedron 1998,
54, 1439-1456. (k) Reference 11k. (l) Brown, B.; Hegedus, L. S. J. Org.
Chem. 2000, 65, 1865-1872. (m) Crimmins, M. T.; King, B. W.;
Zuercher, W. J.; Choy, A. L. J. Org. Chem. 2000, 65, 8499-8509.
(13) (-)-Neplanocin A: (a) Wolfe, M. S.; Borchardt, R. T. J. Med.
Chem. 1991, 34, 1521-1530. (b) De Clercq, E. Biochem. Pharmacol.
1987, 36, 2567-2575. (c) Niitsu, N.; Yamamoto-Yamaguchi, Y.; Ka-
natani, Y.; Shuto, S.; Matsuda, A.; Umeda, M.; Honma, Y. Exp.
Hematol. 1997, 25, 1296-1303. (-)-Carbovir: (a) Vince, R.; Hua, M.
J. Med. Chem. 1990, 33, 17-21. (b) Orr, D. C.; Figueiredo, H. T.; Mo,
C.-L.; Penn, C. R.; Cameron, J. M. J. Biol. Chem. 1992, 267, 4177-
4182.
(14) Gallos, J. K.; Damianou, K. C.; Dellios, C. C. Tetrahedron Lett.
2001, 42, 5769-5771.
(15) Gallos, J. K.; Goga, E. G.; Koumbis, A. E. J. Chem. Soc., Perkin
Trans. 1 1994, 613-614.
(16) Thompson, D. K.; Hubert, C. N.; Wightman, R. H. Tetrahedron
1993, 49, 3827-3840.
(17) (a) Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623-1626. (b) Bols,
M. Carbohydrate Building Blocks; John Wiley & Sons: New York,
1996. (c) Zhao, S.; Petrus, L.; Serianni, A. S. Org. Lett. 2001, 3, 3819-
3822.
(18) Koumbis, A. E.; Dieti, K. M.; Vikentiou, M. G.; Gallos, J. K.
Tetrahedron Lett. 2003, 44, 2513-2516.
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Gallos et al.
SCHEME 3. Synthesis of Pentenomycin Ia
SCHEME 2. Synthesis of Pentenomycin I
Precursorsa
a Reagents and conditions: (i) ref 16; (ii) HCHO, K2CO3, MeOH,
65 °C, 82%; (iii) TrCl, pyridine, 60 °C, 87%; (iv) Ph3P+CH3Br-,
n-BuLi, 12-crown-4-ether, -60 to 20 °C, 98%; (v) (COCl)2, DMSO,
CH2Cl2 then Et3N, -60 to 20 °C; (vi) MeNHOH‚HCl, Na2CO3,
EtOH, 20 °C; (vii) PhCl, 135 °C, 6% of 14 and 50% of 15 overall
from 12; (viii) Zn, AcOH, Et2O, 20 °C, 90%.
a Reagents and conditions: (i) MeI, K2CO3, THF, 20 °C; (ii) PDC,
CH2Cl2, 20 °C; 98% overall from 16; (iii) MeOTs, K2CO3, THF, 65
°C; (iv) as in ii, 66% overall from 16; (v) Ag2O, H2O, 20 °C; (vi) as
in ii, 70% overall from 16; (vii) HCl, Et2O, 20 °C, 90%.
14 and 15 in a ratio of ca. 1:8, showing that steric
hindrance induced by the acetonide is significantly
greater than the one trityloxymethyl substituent imposes.
The minor diastereoisomer 14 could not be obtained pure;
anion exchange upon treatment with aqueous silver
oxide,21 led after oxidation to the desired intermediate
21. It was found, however, that whereas the tosylate path
works better in small-scale runs, reproducibility of the
reactions is more consistent via the corresponding hy-
droxides even in larger quantities. Moreover, tosylate
reaction mixtures demand tedious purifications since
methyl tosylate has a similar Rf with the desired product.
The same sequence (e.g., reductive cleavage, quaterniza-
tion with MeI, exchange with hydroxide and oxidation)
was also applied to the mixture of diastereoisomers 14
and 15 furnishing 21 in a similar overall yield (68%).
Cyclopentenone 21, produced either from 14 or 15, was
then deprotected in a straightforward way upon acidic
hydrolysis to yield pentenomycin I (2).22
It was apparent that the synthetic scheme described
above is also applicable to the synthesis of the parent
cyclopentenones (+)-1 and (-)-1, using the appropriate
aminocyclopentitols. These intermediates (26a and 31)
could be shortly approached starting from carbohydrates
as well. We have reported some time ago15 a facile entry
to chiral aminocyclopentitols in high yield and with
excellent stereoselectivity starting from D-ribose (Scheme
4). Application of Vasella’s reaction conditions23 to iodo-
derivative 22 led to the required volatile aldehyde 23.
This enal, which could also be derived from L-arabinose,24
1
however, its structure was easily deduced from the H
NMR spectra of its mixture with 15. The structural
assignment of both diastereoisomers was based on NOE
studies which revealed the indicated crucial effects (see
Scheme 2). The major one was smoothly taken forward
in the synthetic scheme giving initially the corresponding
amino alcohol 16 upon reductive cleavage of the N-O
bond with Zn in the presence of acetic acid. These
reaction conditions highly improved the yields of the
isolated product in comparison with heterogeneous Pd-
(OH)2/C hydrogenolysis performed initially by us.14 This
is possibly explained by accepting a nonreversible ab-
sorption of the substrates on the surface of catalyst.
Having in place the right carbocyclic core, the next
manipulation to deal with was the formation of the enone
system. However, this was proved quite tricky since
simple quaternization of 16 with methyl iodide (prepara-
tion of iodide 17) and subsequent oxidative cleavage19
with PDC yielded exclusively the iodinated analogue of
pentenomycin I 18 (Scheme 3). It was obvious that iodide
is also oxidized to iodine and that the latter simply
iodinates the protected pentenomycin derivative 21 formed
initially.20 To overcome this unpleasant result, we sought
to examine the oxidative elimination of quaternary
ammonium salts with different counteranions. p-Tolu-
enesulfonate 19, formed directly from the corresponding
amine, and hydroxide 20, derived from iodide 17 with
(21) Cope, A. C.; Bach, R. D. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, pp 315-320.
(22) Target compounds (+)-1, (-)-1, 2, and 3 have physical and
spectroscopic properties identical to those reported in the literature.
All new compounds gave spectroscopic and analytical data consistent
with the proposed structures. These data and detailed experimental
procedures are given either in the Experimental Section or in the
Supporting Information.
(19) (a) Jiang, S.; Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron
Lett. 1994, 35, 5505-5508. (b) van Boggelen, M. P.; van Dommelen,
B. F. G. A.; Jiang, S.; Singh, G. Tetrahedron Lett. 1995, 36, 1899-
1902. (c) Jiang, S.; Mekki, B.; McCoullouth, K. J.; Singh, G.; Wightman,
R. H. J. Chem. Soc., Perkin Trans. 1 1997, 1805-1814.
(20) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B.
W.; Uskovic¸, M. R.; Wonkulich, P. M. Tetrahedron Lett. 1992, 33, 917-
918.
(23) (a) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990-
2016. (b) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 2400-
2410. (c) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 2411-
2431.
(24) (a) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1990, 55,
3853-3857. (b) Reference 11g.
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Chiral Cyclopentenone Building Blocks
SCHEME 4. Synthesis of Aminocyclopentitols
SCHEME 6. Synthesis of Cyclopentenones (+)-1
and (-)-1a
26-27a
a Reagents and conditions: (i) MeI, K2CO3, THF, 20 °C; (ii)
Ag2O, H2O, 20 °C; (iii) PDC, CH2Cl2, 20 °C, (+)-1: 45% overall
from 26a, (-)-1: 42% overall from 31.
SCHEME 7. Synthesis of Neplanocin Aa
a Reagents and conditions: (i) ref 24; (ii) Zn, EtOH, 80 °C; (iii)
RNHOH‚HCl, Na2CO3, EtOH, 20 °C; (iv) PhCl, 135 °C, 70% of 25a,
62% of 25b, 53% of 25c overall from 22; (v) Zn, AcOH, Et2O, 0-20
°C, 99% for 26a, 91% for 26b, 78% for 26c; (vi) H2, Pd/C,
HCO2NH4, MeOH, 20 °C, 98% from 25b.
SCHEME 5. Synthesis of Aminocyclopentitol 31a
a Reagents and conditions: (i) ref 26; (ii) NaH, Ph3P+CH3Br-,
THF, DMSO, -10 °C to 60 °C, 93%; (iii) DMSO, DCC, TFA, py,
benzene, 0-20 °C, 84%; (iv) MeNHOH‚HCl, Na2CO3, EtOH, 20
°C; (v) PhCl, 135 °C 84% overall from 38; (vi) MeNHOH‚HCl,
pyridine, 20 °C; (vii) as in v, 75% overall from 38; (viii) Zn, AcOH,
Et2O, 20 °C, 98%; (ix) MeI, K2CO3, THF, 20 °C; (x) Ag2O, H2O, 20
°C; (xi) PDC, CH2Cl2, 20 °C, 60% overall from 41; (xii) LAH, THF,
0 °C, 100%; (xiii) Ph3P, DIAD, adenine, THF, 0-20 °C, 63%; (xiv)
TFA, 20 °C, 89%.
a Reagents and conditions: (i) ref 25; (ii) MeNHOH‚HCl,
Na2CO3, EtOH, 20 °C; (iii) PhCl, 135 °C, 72% overall from 28; (iii)
Zn, AcOH, Et2O, 0-20 °C, 95%.
gave with a range of N-substituted hydroxylamines the
corresponding nitrones 24. These dipoles underwent
thermal cycloadditions producing 25 as the single prod-
ucts. The N-O bond in bicyclic isoxazolidines 25 was
then cleaved to prepare either parent aminocyclopentitol
27 (precursor of noraristeromycin) or N-substituted
derivatives 26, depending on the conditions and sub-
strates involved. Following the same general pathway,
N-methyl-aminocyclopentitol 31 was synthesized using
the enantiomeric pentenal 28 (derives from D-arabinose25)
as the key intermediate (Scheme 5). Both enantiomeric
carbocyclic amines 26a and 31 were then quaternized
with MeI (Scheme 6). To avoid iodination in the next step,
where the enone functionality is formed, the iodide anion
was replaced by hydroxide on treatment with Ag2O to
obtain 33 and 35 from 32 and 34, respectively. Further-
more, oxidation of the secondary hydroxyl groups with
PDC gave directly the protected enantiomerically pure
cyclopentenones (+)-1 and (-)-1 in very good overall
yields.22
Being acquainted with this methodology, we speculated
that enone 38 (Scheme 7) could result in the branched
cyclopentenone 42, which is the direct precursor of
neplanocin A and related carbocyclic nucleosides.11h This
goal was realized using D-ribose as starting material
through its suitably protected26 derivative 36. Thus,
Wittig olefination of lactol 36 gave alkene 37, which upon
(25) (a) Reference 16. (b) Hall, A.; Meldrum, K. P.; Therond, P. R.;
Wightman, R. H. Synlett 1997, 123-125. (c) Gallos, J. K.; Dellios, C.
C.; Spata, E. E. Eur. J. Org. Chem. 2001, 79-82.
J. Org. Chem, Vol. 70, No. 17, 2005 6887

Gallos et al.
SCHEME 8. A Model Approach toward Carbovira
Moffatt oxidation afforded 38. Marginal C-2 epimerisa-
tion (sugar numbering) was observed during the Wittig
reaction. It seemed that template 38 would smoothly
enter the next steps, for example, nitrone formation and
cycloaddition to produce 40. Surprisingly, previously
applied conditions, where nitrone was formed in the
presence of sodium carbonate, led almost exclusively to
the reverse Cope rearrangement27 product 39 whereas
the desired adduct 40 was formed only in traces.28 The
structure of the unexpected oxazine 39 was undoubtly
confirmed from its spectral data.29 To increase the yield
of the desired adduct 40, we thoroughly investigated
different bases and reaction temperatures. We were
delighted to discover that treatment of 38 with MeNHOH
in pyridine at 25 °C affords the desired intermediate
nitrone, which without isolation is converted to isoxazo-
lidine 40 by refluxing in chlorobenzene for 1 h in 75%
overall yield. This event is not fully rationalized and
further exploration of the specific role of the base is
currently underway. The structural assignment of 40 was
based again on NOE studies (see Scheme 7). Unevent-
fully, 40 was easily converted to 42 in high overall yield,
according to the general procedure, namely, N-O bond
cleavage by Zn in AcOH to produce 41, quaternization
of the amine produced with excess of MeI, and replace-
ment of iodide by hydroxide on treatment with Ag2O,
followed by standard PDC oxidation of the secondary
hydroxyl group. Cyclopentenone 42 is known to give
neplanocin A in three steps.11h Indeed, highly stereose-
lective LiAlH4 reduction of keto group led to the forma-
tion of 43, as the single diastereoisomer isolated. Then,
introduction of the adenine moiety under Mitsunobu
conditions (preparation of nucleoside 44) and full depro-
tection by neat trifluoroacetic acid afforded 3.22
Next, we were keen to explore the possibility of
synthesizing carbovir (4) according to the general scheme.
The initial plan involved the preparation of enals 48 and
subsequently the investigation of cycloaddition reactions
(Scheme 8). The results of this model scheme could be
transferred to a chiral approach leading finally to the
required enantiopure cyclopentenone30 ready for the
introduction of the purine base and the completion of the
synthesis. Therefore, two different monoprotected deriva-
tives31,32 of cis-butene-1,4-diol (45) were selected as the
readily available substrates of choice to check the role of
the bulkiness of the protecting groups in the following
reactions. Condensation of alcohols 45 with betaine 4633
yielded the acrylic acid derivatives 47 which in turn
served as substrates for Claisen rearrangements.34,35
Pentenals 48 were isolated in good overall yields36
a Reagents and conditions: (i) for 47a: NaH, 46, THF, 60 °C,
91%, for 47b see ref 34; (ii) for 48a: 155 °C, 15 mmHg, 80%, for
48b see ref 34; (iii) MeNHOH‚HCl, Na2CO3, EtOH, 20 °C, 76%
for 49a, 78% for 49b.
through this two-step sequence, whereas a direct acid-
catalyzed Johnson-Claisen rearrangement37 of cis-butene-
1,4-diol in the presence of ortho esters produced the
corresponding enoates in disappointing yields. Formation
of the nitrones 49 was followed by a direct attempt to
reach adducts 50 upon heating, but only slow decomposi-
tion of the dipoles was observed. Considering that using
crude nitrones in the cycloaddition reactions was the
issue, we purified them and reexamined their reactivity.
Unexpectedly, we were unable to detect the formation of
the desired isoxazolidines although several reaction
conditions were examined for both entries. It seems quite
intriguing that these 3-substituted pentenals failed to
undergo cycloaddition taking into account that more
hindered systems, like enone 38 derived nitrone, react
smoothly under similar conditions. The most plausible
explanation we can adopt is that these systems prefer to
keep apart the two reacting sites (e.g., nitrone and double
bond) and only in cases where the dipole and dipolarphile
are locked into close proximity does the intramolecular
addition take place.38 We are currently engaged in further
investigation of this unexpected observation.
In conclusion, the work described in this article pre-
sents a short, efficient, and general synthetic approach
for the preparation of enantiomeric cyclopentenones.
(26) Choi, W. J.; Moon, H. R.; Kim, H. O.; Yoo, B. N.; Lee, J. A.;
Shin, D. H.; Jeong, L. S. J. Org. Chem. 2004, 69, 2634-2636.
(27) Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243-269.
(28) Very slow formation of oxazine 39 was detected during the
preparation of the corresponding nitrone whereas heating in chlo-
robenzene substantially accelerated this event.
(29) Crucial for the determination of stereochemistry of C-4 was the
observation of a Jax-ax coupling constant between H-3a and H-4 (9.2
Hz) whereas H-3a and H-7a have a smaller coupling constant of 5.5
Hz (Jax-eq).
(30) The same cyclopentenone moiety could also serve as the direct
precursor for the synthesis of other carbocyclic nucleosides, e.g.,
Abacavir.
(31) Monosilylated derivative 45a was prepared according to Ko-
zlowski, M. C.; Bartlett, P. A. J. Org. Chem. 1996, 61, 7681-7696.
(32) Monobenzylated derivative 45b is commercially available.
(33) (a) Bu¨chi, G.; Vogel, D. E. J. Org. Chem. 1983, 48, 5406-5408.
(b) Vogel, D. E.; Bu¨chi, G. Org. Synth. 1988, 66, 29-36.
(34) Benzylated derivative 47b was lately prepared according to this
method, see: Marotta, E.; Righi, P.; Rosini, G. Org. Lett. 2000, 2, 4145-
4148.
(35) For recent reviews on Claisen rearrangements, see: (a) Wipf,
P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, U.K., 1991; Vol. 5, Chapter 7.2, pp 827-
873. (b) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry
1996, 7, 1847-1882, (c) Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28,
43-50.
(36) Pentenal 48a was found to easily decompose upon column
chromatography purification. Therefore, it was used crude in the
nitrone formation.
(37) Rico, R.; Zapico, J.; Bermejo, F.; Bamidele Sanni, S.; Garcia-
Granda, S. Tetrahedron: Asymmetry 1998, 9, 293-303.
(38) Saito, S.; Ishikawa, T.; Moriwake, T. J. Org. Chem. 1994, 59,
4375-4377.
6888 J. Org. Chem., Vol. 70, No. 17, 2005

Chiral Cyclopentenone Building Blocks
continued for 90 min while the temperature was kept between
-5 to 0 °C. Then, the mixture was recooled to -10 °C and a
solution of 36 (3.25 g, 7.5 mmol) in dry THF (25 mL) was added
dropwise. After stirring at this temperature for 1 h, the
reaction mixture was allowed to warm to RT, was left for 1 h,
and warmed to reflux for 2 h. The reaction after cooling was
quenched by the addition of saturated aqueous NH4Cl (5 mL).
CH2Cl2 (50 mL) was added, and the mixture was washed with
water (100 mL). The aqueous phase was extracted with
dichloromethane (3 × 100 mL), the combined organic phases
were dried, and the solvent was evaporated. The residue was
purified by column chromatography (EtOAc/hexanes ) 1/12)
to give alcohol 37 (2.98 g, 93%) as a white solid: mp 78-80
Thus, synthesis of the parent ones, (+)-1 and (-)-1, two
widely used key intermediates in organic synthesis, was
accomplished in a straightforward manner. Moreover,
branched analogues such as pentenomycin I (2) and the
pseudo-sugar moiety of neplanocin A (3) are easily
approached according to the same methodology.
Experimental Section
General Procedure (A): Preparation of Nitrones in the
Presence of Na2CO3. The crude aldehyde obtained as de-
scribed in each case was dissolved in EtOH 95% (10 mL/mmol),
and RNHOH‚HCl (1.2-2.4 equiv) along with Na2CO3 (2-3
equiv) was added. The mixture was stirred at RT for 1-4 h,
while the reaction progress was monitored with TLC. Then,
the solids were removed by filtration, and the filtrate was
concentrated. The resulting nitrone was used in the cycload-
dition reaction as it was unless otherwise mentioned.
General Procedure (B): Cycloaddition Reactions. The
residue, which contained the intermediate nitrone, was dis-
solved in chlorobenzene (10 mL/mmol), and the solution was
heated at reflux for 1-2 h, while the reaction progress was
monitored with TLC. Then, the solvent was evaporated and
the residue was purified by column chromatography.
General Procedure (C): Reductive Cleavage of Isox-
azolidines with Zn. To a solution of isoxazolidine in Et2O
(20 mL/mmol) kept in an icebath were added glacial acetic acid
(2.2 mL/mmol) and activated39 Zn dust (15 equiv). The suspen-
sion was allowed to reach RT and was stirred vigorously for
24 h. Then, the solids were filtered off and the filtrate was
neutralized with 2 M NaOH under cooling. The organic layer
was washed with H2O (150 mL), and the aqueous one was
extracted with CH2Cl2 (3 × 150 mL). The combined organic
phases were dried and concentrated in a vacuum and the
residue was purified by column chromatography.40
General Procedure (D): Preparation of Ammonium
Iodides. Amino alcohol was dissolved in dry THF (20 mL/
mmol), and K2CO3 (2.5 equiv) was added. Subsequently, MeI
(20 equiv) was added portionly under an inert atmosphere.
The mixture was stirred at RT for 20 h and after evaporating
off the volatiles the resulting solid (ammonium iodide deriva-
tive) was used in the next reaction without any further
purification.
General Procedure (E): Preparation of Ammonium
Hydroxides. Crude iodide was dissolved in water (20 mL/
mmol). Ag2O (1.5 equiv) was added under vigorous stirring
and the mixture was allowed to react for 48 h at RT. After
filtration, the solvent was evaporated giving a crude solid,
which was used in the next reaction without any further
purification.
°C (lit.26 78.2-79.5 °C); [R]D25 -5.2° (c 2.3, CHCl3) [lit.26 [R]D
25
-5.0° (c 2.2, CHCl3)]; FTIR (neat film) 3468, 3058, 2986, 2933,
2878, 1595, 1491, 1449, 1381, 1217, 1059, 1032, 874 cm-1; 1H
NMR and 13C NMR spectra are identical with those reported
in the literature;26 HRMS m/e calcd for C28H30O4Na: [(M +
Na)+]: 453.2036; found: 453.2036.
1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-tri-
tyloxy1-ethanone (38). To a solution of pyridine (1.2 mL, 7.0
mmol) in dry benzene (25 mL), TFA (0.6 mL, 7.0 mmol) and
DMSO (2 mL, 28 mmol) were added. This was added to a
solution of 37 (2.96 g, 6.9 mmol) in dry benzene (30 mL), and
the mixture was cooled to 0 °C. Then, DCC (3.6 g, 17.5 mmol)
was added under an inert atmosphere and the resulting
solution was allowed to warm to RT. After 20 h of stirring,
ether (30 mL) was added, and dicyclohexylurea precipitated
as a white solid. The clear solution obtained by filtration was
washed with water (50 mL) and the aqueous phase was
extracted with dicloromethane (2 × 100 mL). The combined
organic phases were dried and the solvent was evaporated off.
The residue was purified by column chromatography (EtOAc/
hexanes ) 1/15) to give ketone 38 (2.47 g, 84%) as a white
solid: mp 105-107 °C (lit.26 mp 106.8-107.6 °C); [R]D25 -18.9°
(c 1.6, CHCl3) [lit.26 [R]D25 -19.1° (c 1.73, CHCl3)]; FTIR (neat
film) 3059, 3031, 2988, 2927, 2915, 2861, 1733, 1597, 1490,
1
1450, 1378, 1260, 1213, 1158, 1108, 1001, 938, 871 cm-1; H
NMR and 13C NMR spectra are identical with those reported
in the literature;26 HRMS m/e calcd for C28H28O4Na: [(M +
Na)+]: 451.1880, found: 451.1881.
(3aS,4S,7R,7aS)-2,2,4,5-Tetramethyl-7-trityloxymethyl-
hexahydro[1,3]dioxolo[4,5-c]pyridin-7-ol (39). Prepared
from 38 (925 mg, 2.2 mmol) following successively general
procedures A and B. Elution with EtOAc/hexanes ) 1:7 to
25
obtain 39 (880 mg, 84%, overall from 38) as a foam: [R]D
+29.7° (c 1.1, CHCl3); FTIR (neat film) 3445, 3088, 3061, 3023,
2979, 2934, 2878, 1598, 1489, 1463, 1447, 1417, 1372, 1219,
1073, 941, 780, 747, 702, 633 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.49 (d, J ) 7.9 Hz, 6H), 7-32-7.20 (m, 9H), 4.27 (bs, 1H),
4.16 (d, J ) 5.5 Hz, 1H), 3.94 (dd, J ) 9.2, 5.5 Hz, 1H), 3.26
(s, 2H), 2.60 (s, 3H), 2.56-2.48 (m, 1H), 1.41 (s, 3H), 1.33 (s,
3H), 1.10 (d, J ) 6.1 Hz, 3H);13C NMR (75 MHz, CDCl3) δ
143.6, 128.8, 127.7, 127.0, 109.4, 97.4, 86.7, 77.1, 74.3, 65.2,
62.6, 42.4, 28.0, 26.2, 14.9; HRMS m/e calcd for C29H33NO5-
Na: [(M + Na)+]: 498.2251, found: 498.2251.
General Procedure (F): Oxidative Elimination with
PDC. Crude iodide or tosylate or hydroxide prepared as
described in each case was suspended in dry CH2Cl2 (20 mL/
mmol) in the presence of PDC (1.3 equiv) at RT. After 4 h, the
solution was washed with water (20 mL) and dried, and the
organic solvent was removed in a vacuum at RT. The residue
was purified by column chromatography.
(1R)-1-[(4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-
2-trityloxy-1-ethanol (37). NaH (95%) (593 mg, 23.5 mmol)
was suspended in dry THF (15 mL), and DMSO (3.35 mL, 47.0
mmol) was added at 0 °C. The mixture was stirred under an
argon atmosphere for 30 min, and then it was transferred to
a suspension of methyl triphenylphosphonium bromide (8.45
g, 23.7 mmol) in dry THF (25 mL) at -5 °C. Stirring was
(1R,2R,6R,7S)-4,4,9-Trimethyl-1-trityloxymethyl-3,5,8-
trioxa-9-aza-tricyclo [5.2.1.02,6]decane (40). Ketone 38 (2.4
g, 5.6 mmol) was dissolved in dry pyridine (60 mL) and
MeNHOH‚HCl (1.64 g, 19.6 mmol) was added at RT. The
resulting solution was stirred under an inert atmosphere for
24 h until complete consumption of the starting material.
Then, the solvent was evaporated and the crude nitrone was
dissolved in chlorobenzene (50 mL). The resulting solution was
heated to reflux for 1 h. Evaporation of the solvent afforded a
residue which was purified by (EtOAc/hexanes ) 1/10) to give
adduct 40 (1.92 g, 75%) as an amorphous solid: [R]D25 -33.7°
(c 0.8, CHCl3); FTIR (neat film) 3058, 2986, 2929, 2885, 1634,
(39) Casey, M.; Leonard, J.; Lygo, B.; Procter, G. Advanced Practical
Organic Chemistry; Blackie and Son: Glasgow, U.K., 1991; p 49.
(40) Optical rotation value for 27 was mistakenly assigned in our
original comunication paper. The correct value is given here and it is
in accordance with the one given in the literature, see: Marco-
Contelles, J.; Rodr´ıguez-Ferna´ndez, M. M. Tetrahedron: Asymmetry
1997, 8, 2249-2256.
1491, 1449, 1375, 1208, 1072, 864, 768, 701 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.50-7.47 (m, 6H), 7.33-7.21 (m, 9H),
4.39-4.29 (m, 3H), 3.60 (d, J ) 10.4 Hz, 1H), 3.34 (d, J ) 10.4
Hz, 1H), 2.41 (s, 3H), 1.91-1.81 (m, 2H), 1.42 (s, 3H), 1.33 (s,
J. Org. Chem, Vol. 70, No. 17, 2005 6889

Gallos et al.
3H); 13C NMR (75 MHz, CDCl3) δ 143.6, 128.8, 127.8, 127.1,
111.1, 86.8, 80.1, 79.6, 71.9, 58.4, 41.6, 29.7, 29.5, 25.8, 24.6;
HRMS m/e calcd for C29H31NO4Na: [(M + Na)+]: 480.2145,
found: 480.2144.
(243 mg, 0.93 mmol), and adenine (75 mg, 0.56 mmol) in dry
THF (6 mL) was kept at 0 °C. DIAD (0.11 mL, 0.56 mmol)
was added dropwise under an argon atmosphere, and the
resulting mixture was allowed to reach room temperature
under stirring for 3 h. The mixture was filtered to remove the
resulting solids and then was concentrated in vacuo. The
residue was purified by column chromatography (EtOAc/
hexanes ) 1/1) to give protected neplanocin A 44 (157 mg, 63%)
(3aS,4R,6R,6aR)-2,2-Dimethyl-6-methylamino-6-tri-
tyloxymethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-
ol (41). Prepared from 40 (915 mg, 2 mmol) following general
procedure C. Elution with EtOAc/hexanes ) 2:1 to obtain
amino alcohol 41 (900 mg, 98%) as an oil: [R]D25 -8.2° (c 2.6,
CHCl3); FTIR (neat film) 3325, 3022, 3058, 2933, 1597, 1491,
25
as a thick oil: [R]D -25.2° (c 1.7, CHCl3); FTIR (neat film)
3439, 3055, 2974, 2923, 2856, 1580, 1554, 1448, 1356, 1111,
1078, 717 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.65
(s, 1H), 7.47-7.44 (m, 9H), 7.29 (t, J ) 7.0 Hz, 6H), 6.04 (bs,
1H), 5.61 (bs, 1H), 5.24 (d, J ) 6.0 Hz, 1H), 4.66 (d, J ) 6.0
Hz, 1H), 4.00 (d, J ) 15.0 Hz, 1H), 3.85 (d, J ) 15.0 Hz, 1H),
1.42 (s, 3H), 1.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 149.9,
149.8, 149.4, 143.7, 132.1, 132.0, 129.3, 128.5, 127.9, 127.1,
122.3, 112.4, 87.2, 84.7, 84.2, 64.3, 61.4, 27.5, 26.1; HRMS m/e
calcd for C33H31N5O3Na: [(M + Na)+]: 568.2319, found:
568.2322.
1
1449, 1381, 1210, 1122, 1059, 889 cm-1; H NMR (300 MHz,
CDCl3) δ 7.52-7.49 (m, 6H), 7.32-7.20 (m, 9H), 4.68 (d, J )
5.5 Hz, 1H), 4.46 (d, J ) 5.5 Hz, 1H), 3.97 (d, J ) 4.3 Hz, 1H),
3.38 (d, J ) 9.5 Hz, 1H), 3.37 (bs, 2H), 3.02 (d, J ) 9.5 Hz,
1H), 1.88 (s, 3H), 1.71 (bd, J ) 14.0 Hz, 1H), 1.56 (dd, J )
14.0, 4.3 Hz, 1H), 1.38 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 143.8, 128.6, 127.6, 126.9, 110.0, 87.0, 86.4, 83.9, 75.9,
68.8, 58.8, 34.7, 25.4, 26.2, 24.0; HRMS m/e calcd for C29H33-
NO4Na: [(M + Na)+]: 460.2482, found: 460.2481.
(3aR,6aR)-2,2-Dimethyl-6-trityloxymethyl-3a,6a-dihy-
dro-4H-cyclopenta[d][ 1,3]dioxol-4-one (42). Prepared from
41 (355 mg, 0.77 mmol) following successively general proce-
dures D-F). Elution with EtOAc/hexanes ) 1:8 to obtain
cyclopentenone 42 (198 mg, 60%, overall from 41) as a white
solid: mp 160-162 °C (lit.26 161.2-163.2 °C); [R]D25 +10.8° (c
(-)-Neplanocin A (3). Protected neplanocin A (44, 130 mg,
0.24 mmol) was dissolved in TFA (6 mL) under an inert
atmosphere at room temperature and was left stirring for 4
h. Then, volatiles were evaporated off at 20 °C, and the residue
was refluxed with ether. The supernatant ethereal face was
discarded and the same procedure was repeated twice giving
a semicrystalline material which was then dissolved in boiling
methanol. This cloudy solution was filtered through a short
pad of Celite, and the filtrate was alkalized with the addition
of 15% aqueous NH4OH to pH 11-12. The resulting solution
was evaporated to dryness at 35 °C to give a gummy residue.
The latter was crystallized upon trituration with 70% aqueous
25
2.0, CHCl3) [lit.26 [R]D +10.56° (c 1.8, CHCl3)]; FTIR (neat
film) 3058, 3034, 2990, 2935, 1724, 1626, 1491, 1448, 1373,
1209, 1152, 1080, 871, 766, 703 cm-1; 1H NMR, and 13C NMR
spectra are identical with those reported in the literature;26
HRMS m/e calcd for C28H26O4Na: [(M + Na)+]: 449.1723,
found: 449.1721.
EtOH (56 mg, 89%): mp 211-213 °C (lit.11b 212-213 °C); [R]D
25
(3aS,4S,6aR)-2,2-Dimethyl-6-trityloxymethyl-4,6a-di-
hydro-3aH-cyclopenta [d][1,3]dioxol-4-ol (43). To a solu-
tion of enone 42 (292 mg, 0.69 mmol) in dry THF (10 mL) was
added LiAlH4 (40 mg, 1 mmol) at -5 °C. The mixture was
stirred at this temperature for 2 h under an inert atmosphere.
At this point, the reaction was quenched by the addition of
EtOAc (5 mL). Then, the solids were filtered off and the solvent
was removed by evaporation. The residue was purified by
column chromatography (EtOAc/hexanes ) 1/6) to give alcohol
43 (293 mg, 100%) as a white solid: mp 137-139 °C (lit.11h
138-138.5 °C); [R]D25 +29.9° (c 1.5, CHCl3) [lit.26 [R]D25 +29.4°
(c 1.52, CHCl3)]; IR, 1H NMR and 13C NMR spectra are
identical with those reported in the literature;11h HRMS m/e
calcd for C28H28O4Na: [(M + Na)+]: 451.1880, found: 451.1877.
9-((3aS,4R,6aR)-4,6a-Dihydro-6-(trityloxymethyl)-2,2-
dimethyl-3aH-cyclopenta[d][1,3]dioxol-4-yl)-9H-purin-6-
amine (44). A solution of alcohol 43 (198 mg, 0.46 mmol), Ph3P
-153.5° (c 0.3, H2O) [lit.11b [R]D -153.8° (c 0.3, H2O)]; 1H
25
NMR, and 13C NMR spectra are identical with those reported
in the literature;11b HRMS m/e calcd for C11H13N5O3Na [(M +
Na)+]: 286.2424, found: 286.2425.
Acknowledgment. A fellowship to C. I. S. from the
Hellenic Ministry of Education is gratefully acknowl-
edged.
Supporting Information Available: Experimental and
spectral data of the compounds in Schemes 2-6 and 8. 1H and
13C NMR spectra of isolated intermediates and final products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050987T
6890 J. Org. Chem., Vol. 70, No. 17, 2005