Synthesis of D- And L-carbocyclic nucleosides via rhodium-catalyzed asymmetric hydroacylation as the key step

Article abstract of DOI:10.1021/ol801791g

(Chemical Equation Presented) D- and L-carbocyclic nucleosides were obtained by a new procedure involving an enantioselective rhodium/duphos- catalyzed hydroacylation reaction as the key step. The 3-hydroxymethyl- cyclopentanol intermediate was obtained by stereoselective reduction of ketone and by dynamic kinetic resolution (DKR).

Full text of DOI:10.1021/ol801791g

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4735-4738
Synthesis of D- and L-Carbocyclic
Nucleosides via Rhodium-Catalyzed
Asymmetric Hydroacylation as the Key
Step
Patricia Marce´, Yolanda D´ıaz, M. Isabel Matheu, and Sergio Castillo´n*
Departament de Qu´ımica Anal´ıtica i Qu´ımica Orga`nica, UniVersitat RoVira i Virgili,
C/Marcel.l´ı Domingo s/n, 43007 Tarragona, Spain
sergio.castillon@urV.cat
Received August 1, 2008
ABSTRACT
D- and L-carbocyclic nucleosides were obtained by a new procedure involving an enantioselective rhodium/duphos-catalyzed hydroacylation
reaction as the key step. The 3-hydroxymethyl-cyclopentanol intermediate was obtained by stereoselective reduction of ketone and by dynamic
kinetic resolution (DKR).
Carbocyclic nucleosides are structural analogues of natural
and synthetic nucleosides, where the endocyclic oxygen atom
is replaced by a methylene group. These analogues which
lack the labile glycosidic bond are stable to cleavage by
phosphorylases and hydrolases. Relevant members of this
family of compounds are the naturally occurring carbocyclic
nucleosides aristeromycin1 and neplanocine A2 (Figure 1)
that exhibit powerful antitumor and antiviral activities.
(1) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.;
Mizuno, K. J. Antibiot. 1968, 21, 255.
(2) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani,
M. J. Antibiot. 1981, 34, 359.
Figure 1. Relevant carbocyclic nucleosides.
(3) (a) Wang, P.; Schinazi, R. Y.; Chu, C. K. Bioorg. Med. Chem. Lett.
1998, 8, 1585. (b) Vince, R.; Hua, M.; Brownel, J.; Dalugue, S.; Lee, F.;
Shannon, W. M.; Lavelle, G. C.; Qualls, J.; Weislow, O. S.; Kiser, R.;
Canonico, P. G.; Schultz, R. H.; Narayanan, V. L.; Mayo, J. G.; Shoemaker,
R. H.; Boyd, M. R. Biochem. Biophys. Res. Commun. 1988, 156, 1046.
(4) For reviews about the synthesis of carbocyclic nucleosides, see: (a)
Jeong, L. S.; Lee, J. A. AntiVir. Chem. Chemother. 2004, 15, 235. (b)
Rodr´ıguez, J. B.; Com´ın, M. J. Mini ReV. Med. Chem. 2003, 3, 95. (c)
Crimmins, M. T. Tetrahedron 1998, 54, 9229. (d) Agrofolio, L.; Suhas,
E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R.
Tetrahedron 1994, 50, 10611.
Carbovir and carbocyclic-ddA are synthetic derivatives that
showed high activity against HIV and hepatitis B virus,
respectively.3
Carbocyclic nucleosides have been prepared starting from
the chiral pool and by using asymmetric synthesis proce-
dures.4 Relevant examples of this last approach are the
10.1021/ol801791g CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

synthesis of carbocyclic nucleosides precursors 15 and 26
which were obtained enantiomerically pure by enzymatic
kinetic resolution, compound 37 that was prepared by
asymmetric aldol condensation followed by ring-closing
metathesis, and compound 48 prepared by palladium-
catalyzed asymmetric allylic substitution from the cyclopen-
tadiene monoepoxide (Figure 2). Carbocyclic-ddA has been
Scheme 2. Synthesis of Intermediate 8
in 98% yield12 (Scheme 2). Compound 10 was then reacted
with ethyl vinyl ether using Hg(TFA)2 as catalyst13 affording
11, which was then heated in benzonitrile to give the pentenal
8 in 70% yield through a [3 + 3] sigmatropic rearrangement.
The intramolecular hydroacylation of 8 was initially
explored using Wilkinson’s catalyst affording the expected
cyclopentanone 7 in modest yield (entry 1, Table 1). The
Figure 2. Carbocyclic intermediates in the synthesis of carbocyclic
nucleosides.
Table 1. Intramolecular Hydroacylation of 8a
prepared from D-ribose3a and from 1.9 In both cases, long
reaction sequences are required for synthesizing the car-
bocycle or for introducing the purinic base. Herein, we report
a short and efficient approach to L- and D-carbocyclic-ddA
(5) that avoids those synthetic problems, via the use of an
enantioselective hydroacylation reaction.
Intramolecular hydroacylation is a rhodium-catalyzed
process that yields cyclopentanones from γ,δ-pentenals.10
This reaction has been scarcely used in organic and asym-
metric synthesis.11 Scheme 1 shows the retrosynthesis of 5.
ee %
entry
[Rh] (%)
RhCl(PPh3)3
[Rh(NBD)dppe]BF4
[Rh(NBD)dppe]BF4
[Rh(NBD)DPPF]BF4
[Rh(NBD)(R,R)-Me-Duphos]
BF4
mol % [Rh] yield (config)d
1b
2
5
42% --
-- --
70% --
-- --
5
3c
4c
10
30
5
6
5
5
85% >95 (R)e
85% >95 (S)e,f
[Rh(NBD)(S,S)-Me-Duphos]
BF4
a Acetone was used as the solvent at reflux, and the reaction was
completed in 12 h. b CH2Cl2 was used as a solvent. c The reaction was
completed in 5 h. d ee determined by 13C NMR. e The enantiomer was not
observed. f ent-7 was obtained.
Scheme 1. Retrosynthesis of Carbocyclic-ddA (5)
use of a cationic catalyst bearing dppe as ligand gave no
conversion at low catalyst loading even at high temperature
(entry 2). Increasing the catalyst concentration to 10 mol %
at room temperature did not afford the expected cyclopen-
tanone either. When the reaction was performed at 65 °C,
the cyclopentanone 7 was obtained in 70% yield (entry 3).
(5) Taylor, S. J. C.; Sutherland, A. G.; Lee, C.; Wisdom, R.; Thomas,
S.; Evans, C. J. Chem. Soc., Chem. Commun. 1990, 1121.
(6) Evans, C. T.; Roberts, S. M.; Shoberu, K. A.; Sutherland, A. G.
J. Chem. Soc., Perkin Trans. I 1992, 589.
We have considered that cyclopentanol 6, a precursor of 5,
can be obtained from ketone 7 by a stereoselective reduction
or by a nonstereoselective reduction followed by dynamic
kinetic resolution (DKR). The key cyclopentanone 7 would
be obtained by an enantioselective hydroacylation reaction
from pentenal 8.
Thus, the required pentenal 8 was prepared from diol 9
by selectively protecting one of the hydroxyl groups by
reaction with NaH and TBDPSCl affording the alcohol 10
(7) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192.
(8) (a) Trost, B. M.; Kuo, G.-H.; Benneche, T. J. Am. Chem. Soc. 1988,
110, 621. (b) Peel, M. R.; Sternbach, D. D.; Johnson, M. R. J. Org. Chem.
1991, 56, 4990.
(9) (a) Taylor, S. J. C.; Sutherland, A. G.; Lee, C.; Wisdom, R.; Thomas,
S.; Roberts, S. M.; Evans, C. J. Chem. Soc., Chem. Commun. 1990, 1120.
(b) McGuigan, C.; Hassan-Abdallah, A.; Srinivisan, S.; Wang, Y.; Siddiqui,
A.; Daluge, S. M.; Gudmudsson, K. S.; Zhou, H.; Peckham, J. P.; Burnette,
T. C.; Marr, H.; Hazen, R.; Condreay, L. D.; Johnson, L.; Balzarini, J.
J. Med. Chem. 2006, 49, 7215.
(10) Larock, R. C.; Oertle, K.; Potter, G. F. J. Am. Chem. Soc. 1980,
102, 190.
4736
Org. Lett., Vol. 10, No. 21, 2008

The cationic Rh/DPPF14 system was also tested, but the
expected cyclopentanone was not obtained (entry 4). Since
the highest activity was achieved with dppe as ligand, which
forms a five-membered ring upon coordination at the metal,
the reaction was next carried out using (R,R)-Me-Duphos.15
Satisfactorily, the intramolecular hydroacylation using (R,R)-
Me-Duphos, 5 mol % of catalyst, in acetone at reflux afforded
cyclopentanone 7 in good yield and excellent enantioselec-
tivity (entry 5). When (S,S)-Me-Duphos was employed, the
reaction proceeded yielding the opposite enantiomer ent-7
(entry 6). In both cases, the yield and the enantioselectivity
were identical, and the results were reproducible.
At this point, the stereoselective reduction of 7 was
essential to obtain the nucleoside 5 with the appropriate
configuration. Initially, the reduction of the cyclopentanones
7 and ent-7 was carried out with DIBAL-H in CH2Cl2 at
-78 °C affording the epimeric mixture of cyclopentanols
6a (trans) and 12 (cis), and ent-6a (trans) and ent-12 (cis),
respectively, in quantitative yield but low stereoselectivity
(cis/trans ) 2:1). We therefore considered two methodolo-
gies to obtain the alcohol derivative with the required
configuration: (a) a dynamic kinetic resolution (DKR) of the
diastereomeric mixture of alcohols16,17 and (b) a directed
reduction of the cyclopentanone using sodium triacetoxyboro-
hydride.
Table 2. Dynamic Kinetic Resolution of 6a (trans) + 12 (cis)a
entry time (h) convn (%)b 7 (%)b 13 (%)b 13 de (%)b,c dEd
1e
24
48
48
72
72
51
77
53
73
93
51
54
25
11
--
--
23
28
62
93
--
80
--
11
>50
>50
>150
2f
3g
4g
5g,h
>95i
>95i
>95i
a Reactions were performed on a 0.03 mmol scale with 15 mg of enzyme,
0.09 mmol of p-ClPhOAc, and 4 mol % of [Ru] in 0.5 mL of toluene at 70
b
°C. Determined by H NMR. c Diastereomeric excess. d Diastereomeric
ratio. e 1.5 mg of enzyme was added. f 0.015 mmol of 2,4-dimethyl-3-
pentanol was added. g H2 gas (1 atm) was used. h 6 mol % of Ru was added.
i The other diastereomer was not observed.
1
with excellent diastereoselectivities (>99%, entries 4 and
5). However, after 48 h, 25% of ketone 7 was still detected
(entry 3), and after 72 h, the ketone concentration was only
reduced to 11% (entry 4). To quench ketone formation, the
catalyst loading was increased to 6 mol %. Under these
conditions, the analysis of the reaction residue revealed the
absence of ketone, and the obtained conversion rate and
diastereomeric ratio were excellent (dE >150, entry 5).
Similar results were obtained starting from ent-6a, but in
this case the major isomer was acylated affording compound
14 (Scheme 3). These results are in agreement with Ka-
zlauskas’ rule.17
Initially, we optimized the conditions for the kinetic
resolution process. Candida antarctica (Novozyme 435,
N-435) and Pseudomonas cepacia (PSC) lipases were
screened with different acyl donors. The best conditions
found were employing PSC and p-chlorophenyl acetate18
in toluene at 70 °C which provided high conversions and
diastereoselectivities (dE ) 100).
On the basis of our preliminary KR results, the KR of
cyclopentanol 6a + 12 was carried out in the presence of
the Shvo’s catalyst20 to perform a DKR process. The results
are summarized in Table 2. The first run was performed using
6a + 12, enzyme PSC, Shvo’s catalysts, and p-ClPhOAc,
but no acetylated product was obtained (entry 1). However,
large amounts of the corresponding ketone 7 formed during
the hydrogen transfer process were observed (entry 1).
Hence, two hydrogen sources were tested to direct the
reaction equilibrium back toward cyclopentanols 6a + 12.
The addition of 0.015 mmol of 2,4-dimethyl-3-pentanol
improved the reaction providing a 23% conversion of the
acetylated product.
Scheme 3. Dynamic Kinetic Resolution of ent-6a + ent-12
The second approach involved the reduction of alde-
hydes and ketones using NaBH(OAc)3.21,22 For this
purpose, the tert-butyldiphenylsilyl group in 7 was depro-
tected by adding 1.5 equiv of TBAF in THF to afford 15 in
80% yield (Scheme 4). Compound 15 was diastereoselec-
tively reduced using this reagent in different solvents such
After 48 h, 77% of the reagents were converted into
products, and the diastereomeric ratio was dE ) 11 (entry
2); however, the ketone concentration was still high (54%).
To improve these results, H2 gas (1 bar) was added. H2
effectively inhibited ketone formation, and 13 was obtained
Scheme 4. Diastereoselective Synthesis of 16
(11) (a) Kundu, K.; McCullagh, J. V.; Morehead, A. T., Jr. J. Am. Chem.
Soc. 2005, 127, 16042. (b) Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.;
Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai, K.;
Suemune, H. J. Org. Chem. 2000, 65, 5806.
(12) Craig, D.; Henry, G. D. Eur. J. Org. Chem. 2006, 3558.
(13) Aloise, A. D.; Layton, M. E.; Shair, M. D. J. Am. Chem. Soc. 2000,
122, 12610.
(14) (a) Stemmler, R. T.; Bolm, C. AdV. Synth. Catal. 2007, 349, 1185.
(b) Kokubo, K.; Matsumasa, K.; Nishinaka, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1999, 72, 303.
Org. Lett., Vol. 10, No. 21, 2008
4737

Scheme 5. Synthesis of D- and L-Carbocyclic-ddA 5 and ent-5 from 13 and Alcohols 16 and ent-16
as acetonitrile,23,19 acetic acid,21b,22,24 and ethyl acetate.21a,25
The best results, however, were obtained when a mixture of
ethyl acetate/acetonitrile 1:1 was used. In this case, com-
pound 16 was obtained in 70% yield as the only diastere-
omer. Following a similar procedure, ent-16 was obtained
from ent-7.
Subsequently, 16 was reacted with TBDPSCl in CH2Cl2
using Et3N and DMAP affording 6a, in 65% yield. 6a
was also obtained in quantitative yield by hydrolysis of
13. Additionally, the reaction of 6a with adenine under
Mitsunobu conditions furnished 17a in good yields (70%,
Scheme 5), and the further treatment with TBAF afforded
the deprotected carbocyclic nucleoside 5.
ytrityl group to give ent-6b. The reaction of ent-6b with
adenine under Mitsunobu conditions afforded ent-17b in
good yields. The deprotection of the DMT group using TFA
in THF furnished ent-5 in 75% yield.
In conclusion, we have demonstrated that both enantiomers
of 3-hydroxymethyl-cyclopentanone 7 and ent-7 can be
obtained with high yields and enantioselectivities via a Rh/
duphos-catalyzed asymmetric intramolecular hydroacylation.
Ketones 7 and ent-7 were stereoselectively reduced to
cyclopentanols 6a and ent-6a, which were efficiently trans-
formed into D- and L-carbocyclic-ddA. This synthesis
involves a new and enantioselective approach to carbocyclic
nucleosides.
Since the removal of the tetrabutylammonium fluoride was
tedious, compound ent-16 was protected with the dimethox-
The key intermediate 6a can also be obtained with
excellent stereoselectivity from the diastereomeric mixture
6a + 12 by DKR using PSC/ruthenium catalysts affording
13, followed by methanolysis.
(15) Barnhart, R. W.; McMorran, D. A.; Bosnich, B. Chem. Commun.
1997, 589.
(16) Pa`mies, O.; Ba¨ckvall, J. E. Chem. ReV. 2003, 103, 3247.
(17) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656.
Acknowledgment. The authors acknowledge the financial
support of Ministerio de Educacio´n y Ciencia (MEC), Spain
(CTQ2005-03124 and CSD2006-0003). We thank Servei de
Recursos Cient´ıfics (URV) for technical assistance. P.M.
acknowledges MEC for a grant. We also thank Dr. Oscar
Pa`mies (URV) for interesting suggestions.
(18) Ghanem, A.; Aboul-Enein, H. J. Chirality 2005, 17, 1.
(19) Persson, B. A.; Larsson, A. L. E.; LeRay, M.; Ba¨ckvall, J. E. J. Am.
Chem. Soc. 1999, 121, 1645.
(20) Menasche, N.; Shvo, Y. Organometallics 1991, 10, 3885.
(21) (a) Gribble, G. W.; Nutaitis, C. F. Tetrahedron Lett. 1983, 24, 4287.
(b) Turnbull, M. D.; Hatter, G.; Ledgerwood, D. E. Tetrahedron Lett. 1984,
25, 5449.
(22) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
Supporting Information Available: General experimental
experimental procedures, compounds characterization data,
and NMR spectra for compounds 5-8, 10, 11, and 13-17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(24) (a) Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24,
273. (b) Robins, M. J.; Sarker, S.; Samano, V.; Wnuk, S. F. Tetrahedron
1997, 53, 441. (c) Liu, Y.-T.; Wong, J. K.; Tao, M.; Osterman, R.;
Sannigrahi, M.; Girijavallabhan, V. M.; Saksena, A. Tetrahedron Lett. 2004,
45, 6097
.
(25) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939
.
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