Synthesis of the 6′-iso analogues of neplanocin A and 5′-homoneplanocin A

Article abstract of DOI:10.1016/j.tetlet.2009.10.016

An efficient synthesis of 6′-isoneplanocin A and 6′ -isohomoneplanocin A is reported. The key steps in the synthesis include an enyne metathesis and a regioselective oxidation.

Full text of DOI:10.1016/j.tetlet.2009.10.016

Tetrahedron Letters 50 (2009) 7156–7158
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the 60-iso analogues of neplanocin A and 50-homoneplanocin A
*
Wei Ye, Mingzhu He, Stewart W. Schneller
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, United States
a r t i c l e i n f o
a b s t r a c t
An efficient synthesis of 60-isoneplanocin A and 60-isohomoneplanocin A is reported. The key steps in the
synthesis include an enyne metathesis and a regioselective oxidation.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 11 September 2009
Revised 1 October 2009
Accepted 2 October 2009
Available online 8 October 2009
Keywords:
Carbocyclic nucleosides
Grubbs reaction
Mitsunobu reaction
1. Introduction
C-40 hydroxymethyl substituents.6 Apio-neplanocin A 37 and apio-
homoneplanocin A 4,8 which are the C-30 isomers of 1 and 2, have
Inhibition of S-adenosyl-
L
-homocysteine hydrolase (AdoHcy
been reported. While failing to inhibit AdoHcy hydrolase, 3 was
found to have biological activity as a potent, selective A3 adenosine
receptor agonist.7b The failure of 3 and 4 to inhibit the hydrolase
could be the consequence of their C-30-tertiary center9 (Fig. 1).
In our pursuit of neplanocin A analogues with non-toxic, antivi-
ral potential, the 60-iso analogues 5 and 6 emerged as worthy tar-
gets. An enantiomerically efficient preparation of the 60-
hydrolase) has been recognizedas animportantapproach to develop
new antiviral agents 1. As one of the most potent inhibitors of Ado-
Hcy hydrolase, the naturally occurring carbocyclicnucleoside nepla-
nocin A (1) has shown significant broad antiviral activities.2
However, this antiviral potential is limited by its toxicity as a result
of phosphorylation of the C-50 primary hydroxyl group.3 In seeking
ways to circumvent this undesirable transformation, 50-homonepla-
nocin A (2) with a C-50-extended side-chain was synthesized and
found tohavesignificantactivityagainstHBVand HCVwithoutasso-
ciated toxicity.4 Other C-50 neplanocin A modifications have consid-
ered adding a methyl group to enhance the steric interference to
phosphorylation at this site5 and removal of the C-50 hydroxyl or
isoneplanocin A analogues 5 and 6 from D-ribose is reported here.
2. Results
The synthesis began with the protected glycol enal 7,10 which can
be prepared in large scale from inexpensive -ribose in two steps
D
NH2
NH2
N
NH2
N
N
N
N
N
N
N
HO
HO
6'
N
n
HO
N
N
N
4'
HO
n
HO
HO
OH
OH
OH
1, n=1
2, n=2
5, n=1
6, n=2
3, n=1
4, n=2
Figure 1. Neplanocin A and related analogues.
* Corresponding author. Tel.: +1 334 844 5737; fax: +1 334 844 5748.
E-mail address: schnest@auburn.edu (S.W. Schneller).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.016

W. Ye et al. / Tetrahedron Letters 50 (2009) 7156–7158
7157
HO
OH
O
R
OR
OTBS
c on 9
d
a
R'
O
O
O
O
O
O
O
O
10
8, R=H
7
b
11, R=H; R'=OTBS
12, R=OTBS; R'=H
9, R=TBS
ref. 10
(D)-Ribose
Scheme 1. Reagents and conditions: (a) HC„CMgBr, THF, 86%; (b) TBSCl, imidazole, CH2Cl2, 83%; (c) first generation Grubbs catalyst, ethylene, CH2Cl2, 86%; (d) AD-mix-a, t-
BuOH/H2O, 83%.
NH2
N
NH2
N
N
N
N
N
R'
HO
HO
R'
N
g on 18
e on 16
N
OR
O
O
O
O
OH
5
11, R=TBS; R'=CH(OH)CH2OH
13, R=TBS; R'=CHO
a
b
c
17, R'=CH2OTBS
18, R'=CH2OH
f
14, R=TBS; R'=CH2OH
15, R=H; R'=CH2OH
d
16, R=H; R'=CH2OTBS
Scheme 2. Reagents and conditions: (a) NaIO4, MeOH/H2O, 92%; (b) NaBH4, CeCl3ꢀ7H2O, MeOH, 92%; (c) TBAF, THF; (d) TBSCl, imidazole, CH2Cl2, 82% in two steps from 14; (e)
DIAD, PPh3, 1 equiv adenine, THF; (f) TBAF, THF, 46% in two steps from 16; (g) HCl, MeOH, 94%.
TBSO
TBSO
R'
OR
f
e on 22
O
OH
O
O
O
O
O
O
12, R=TBS; R'=CH(OH)CH2OH
19, R=TBS; R'=CH(OH)CH2OBz
20, R=TBS, R'=CH(OMs)CH2OBz
21, R=H; R'=CH2CH2OH
a
b
c
24
23
d
22, R=H; R'=CH2CH2OTBS
g
NH2
N
NH2
N
OH
N
R'
N
N
N
i on 26
N
N
O
O
HO
OH
6
25, R'=CH2CH2OTBS
26, R'=CH2CH2OH
h
Scheme 3. Reagents and conditions: (a) BzCl, Et3N, CH2Cl2, 97%; (b) MsCl, Et3N, CH2Cl2; (c) LiAlH4, THF, 72% in two steps; (d) TBSCl, imidazole, CH2Cl2, 97%; (e) IBX, EtOAc; (f)
NaBH4, CeCl3ꢀ7H2O, MeOH, 86% in two steps from 22; (g) DIAD, PPh3, 1 equiv adenine, THF; (h) TBAF, THF, 43% in two steps from 24; (i) HCl, MeOH, 91%.
(Scheme 1). Ethynylmagnesium bromide addition to 7 gave enyne 8,
which was protected as its tert-butyldimethylsilyl derivative 9. An
enyne metathesis11 of substrate 9 gave product 10 in excellent yield.
The a- and b-isomers of 10 could not be separated at this stage and
were used directly in the next step. Taking advantage of the different
reaction rates between a terminal alkene and an internal one in the

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W. Ye et al. / Tetrahedron Letters 50 (2009) 7156–7158
2. Borchardt, R. T.; Keller, B. T.; Patel-Thombre, U. J. Biol. Chem. 1984, 259, 4353.
3. Wolfe, M. S.; Borchardt, R. T. J. Med. Chem. 1991, 34, 1521.
4. Yang, M.; Schneller, S. W.; Korba, B. J. Med. Chem. 2005, 48, 5043.
5. Shuto, S.; Minakawa, N.; Niizuma, S.; Kim, H.-S.; Wataya, Y.; Matsuda, A. J. Med.
Chem. 2002, 45, 748.
6. Wolfe, M. S.; Lee, Y.; Bartlett, W. J.; Borcherding, D. R.; Borchardt, R. T. J. Med.
Chem. 1992, 35, 1782.
7. (a) Moon, H. R.; Kim, H. O.; Lee, K. M.; Chun, M. W.; Kim, J. H.; Jeong, L. S. Org.
Lett. 2002, 4, 3501; (b) Lee, J. A.; Moon, H. R.; Kim, H. O.; Kim, K. R.; Lee, K. M.;
Kim, B. T.; Hwang, K. J.; Chun, M. W.; Jacobson, K. A.; Jeong, L. S. J. Org. Chem.
2005, 70, 5006.
8. (a) Kim, J.-H.; Kim, H. O.; Lee, K. M.; Chun, M. W.; Moon, H. R.; Jeong, L. S.
Tetrahedron 2006, 62, 6339; (b) Chun, M. W.; Lee, H. W.; Kim, J.-H.; Kim, H. O.;
Lee, K. M.; Pal, S.; Moon, H. R.; Jeong, L. S. Nucleosides Nucleotides Nucleic Acids
2007, 26, 729.
9. Paisley, S. D.; Wolfe, M. S.; Borchardt, R. T. J. Med. Chem. 1989, 32, 1415.
10. Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69, 3993.
11. Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082.
12. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong,
K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang, X. J. Org. Chem. 1992, 57,
2768.
Figure 2. X-ray structure of 21.
Sharpless asymmetric dihydroxylation,12 the highly regioselective
products 11 and 12 were achieved by treating 10 with AD-mix-
in the absence of methanesulfonamide. The two isomers ( and b)
were easily isolated by flash column chromatography and the ratio
of isomer 11 was then cho-
isomer to b isomer was ca. 4:5.13 The
a
a
13. The configuration of the protected allylic hydroxyl group was assigned by
comparing the NMR spectrum of 11 with the Sharpless oxidation product of
10
chromatography and their structures assigned by 1H NMR spectroscopy (i.e.,
Ha of 8b is a singlet while Ha of 8 is multiplet; Hb of 8b is a doublet while Hb
a (see below). For this purpose, 8a and 8b were readily separated by column
a
a
sen to synthesize neplanocin A analogue 5 while the b isomer 12 was
selected for homoneplanocin A analogue 6.
a
of 8
a
is a triplet).
Oxidative cleavage of 11 (to 13) (Scheme 2) followed by reduc-
tion using Luche reagent produced 14. Removal of the TBS group of
14 with TBAF (to 15) and selective protection of the primary hydro-
xyl group with TBS yielded 16. The Mitsunobu coupling4 of 16 with
1 equiv of adenine14 (to 17) followed by desilylation afforded 18.
The target compound 60-isoneplanocin A (5)15 was achieved by re-
moval of the isopropylidene of 18 under acidic conditions.
To achieve 6 (Scheme 3), the primary alcohol of 12 was first ben-
zoylated (to 19) that was followed by mesylation to 20. Reduction of
20 using lithium aluminum hydride removed the mesyl, benzoyl,
and TBS groups to afford diol 21, whose crystal structure (Fig. 2)
was obtained (which further supported the previous stereochemical
assignment of 11 and 12).16 The primary hydroxyl of 21 was selec-
tively protected with a TBS group. Because of difficulties using Mits-
unobu conditions to invert the allylic hydroxyl group of 22, an
oxidation–reduction approach was selected. Thus, 22 was first oxi-
dized using IBX (2-iodoxybenzoic acid) in refluxing EtOAc17 to afford
enone 23. This was followed by a Luche reduction to avail the desired
Grubbs 1st generation
catalyst, ethylene,
3 days
R
a
OH
O
b
R'
O
low conversion
O
O
8
8β, R=OH; R'=H
8α, R=H; R'=OH
TBSOTf
10α, R=H; R'=OTBS
14. A was observed when more than 1 equiv of adenine was used. However, A
could be converted to 5 and 6 under the acidic deprotection.
NH2
N=PPh3
N
N
N
N
HO
N
TBSO
O
n
N
n
N
HCl/MeOH
N
a
isomer 24. Pursuing steps similar to the synthesis of 5, Mitsunobu
HO
OH
coupling4 of 24 with 1 equiv of adenine14 and followed by removal of
hydroxyl protection completed the synthesis of 6.18
O
5, n=1
6, n=2
A
In summary, an efficient pathway to the 60-isoneplanocin A tar-
gets 5 and 6 has been developed. The antiviral data associated with
this new class of carbocyclic nucleosides is forthcoming.
15. Selected data for 5: 1H NMR (400 MHz, DMSO-d6): d 8.09 (s, 1H), 8.06 (s, 1H),
7.21 (s, 2H), 5.92 (s, 1H), 5.33 (d, 1H, J = 5.6 Hz), 5.04 (m, 1H), 4.84 (m, 2H), 4.47
(m, 2H), 3.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6): d 156.5, 152.8, 150.1,
145.2, 141.0, 129.1, 120.0, 76.4, 71.8, 65.4, 58.3. HRMS calcd for C11H13N5O3
263.1018, found 263.1017.
Acknowledgments
16. Crystallographic data (excluding structure factors) for the structure in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 744708. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
17. Ocejo, M.; Vicario, J. L.; Badia, D.; Carrillo, L.; Reyes, E. Synlett 2005, 2110.
18. Selected data for 6: 1H NMR (400 MHz, MeOD-d4): d 8.14 (s, 1H), 8.10 (s, 1H),
5.96 (s, 1H), 5.45 (m, 1H), 4.59 (m, 1H), 4.55 (m, 1H), 3.55 (m, 2H), 2.08 (m, 1H),
1.90 (m, 1H); 13C NMR (100 MHz, MeOD-d4): d 154.4, 150.8, 148.1, 141.3,
139.2, 128.6, 75.1, 70.5, 65.2, 57.6, 41.8, 30.0. HRMS calcd for C12H15N5O3
277.1175, found 277.1182.
This research was supported by funds from Department of
Health and Human Services (AI 56540). We thank Drs. Thomas
Albrecht-Schmitt and John Gorden, Auburn University, for securing
the X-ray data for 21.
References and notes
1. De Clercq, E. Nucleosides Nucleotides Nucleic Acids 2005, 24, 1395.