Stereoselective synthesis of homo-apioneplanocin A as potential inhibitor of S-adenosylhomocysteine hydrolase

Article abstract of DOI:10.1080/15257770701493559

Homo-apioneplanocin A (1) as a potential inhibitor of S- adenosylhomocysteine hydrolase was synthesized from D-ribose, employing stereoselective hydroxymethylation, regioselective oxidation, and regio- and chemoselective hydroboration as key steps. Copyri

Full text of DOI:10.1080/15257770701493559

Nucleosides, Nucleotides, and Nucleic Acids, 26:729–732, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701493559
STEREOSELECTIVE SYNTHESIS OF HOMO-APIONEPLANOCIN A
AS POTENTIAL INHIBITOR OF S-ADENOSYLHOMOCYSTEINE
HYDROLASE
Moon Woo Chun, Hyuk Woo Lee, and Jin-Hee Kim
College of Pharmacy,
2
Seoul National University, Seoul, Korea
Hea Ok Kim, Kang Man Lee, and Shantanu Pal
College of Pharmacy, Ewha
2
Womans University, Seoul, Korea
Hyung Ryong Moon
College of Pharmacy and Research Institute for Drug
2
Development, Pusan National University, Busan, Korea
Lak Shin Jeong College of Pharmacy, Ewha Womans University, Seoul, Korea
2
Homo-apioneplanocin A (1) as a potential inhibitor of S-adenosylhomocysteine hydrolase was
2
synthesized from D-ribose, employing stereoselective hydroxymethylation, regioselective oxidation, and
regio- and chemoselective hydroboration as key steps.
Keywords Ring-closing metathesis; S-adenosylhomocysteine hydrolase; homo-apione-
planocin A
INTRODUCTION
Neplanocin A[1] and aristeromycin[2] (Figure 1) are representative of
carbocyclic nucleosides and showed potent antitumor and antiviral activ-
ities by inhibiting S-adenosylhomocysteine (AdoHcy) hydrolase.[3] Inhibi-
tion of AdoHcy hydrolase induced inhibitory activity against methyltrans-
ferases, which are essential enzymes to formation of cap structure of viral
mRNA. Therefore, inhibition of AdoHcy hydrolase results in antiviral activ-
ity by inhibiting the formation of viral mRNA cap structure. Neplanocin A
has been known to be a potent inhibitor of AdoHcy hydrolase, but it was
too cytotoxic to be developed as a clinically useful antiviral agent and was
This research was supported by a grant from the Korea Research Foundation (KRF-2005-005-
J01502).
Address correspondence to Moon Woo Chun, College of Pharmacy, Seoul National University,
Seoul 151–742, Korea. E-mail: mwchun@snu.ac.kr
729

730
M. W. Chun et al.
FIGURE 1 Rationale for the design of the desired nucleoside 1.
also metabolized by adenosine deaminase (ADA) to the biologically inactive
compound, the inosine analogue.[4]
Apio-ddA,[5] in which 4ꢁ-hydroxymethyl group of ddA is moved to C3ꢁ
position, was found to exhibit anti-HIV activity comparable to that of the
parent nucleoside ddA and improved stability of glycosidic bond. From
these findings, apio-neplanocin A[6] was designed and synthesized by our
laboratory for the purpose of searching for more potent antiviral agent
with benefits such as resistance to ADA and increasing stability of glycosidic
bond, but it showed neither antiviral activity nor inhibitory activity against
AdoHcy hydrolase. However, the fact that homo-neplanocin A,[7] another
neplanocin A-modified nucleoside was reported to exhibit a significant in-
hibitory activity against AdoHcy hydrolase stimulated us to synthesize homo-
apioneplanocin A (1). Here, we wish to report enantioselective synthesis of
homo-apioneplanocin A (1) from D-ribose via regio- and chemoselective hy-
droboration and chemoselective oxidation as key steps.
RESULTS AND DISCUSSION
Synthesis of the key intermediate 7 for the synthesis of homo-
apioneplanocin A (1) is shown in Scheme 1. Treatment of D-ribose with
anhydrous acetone in the presence of c-H2SO4 gave 2,3-O-isopropylidene-
D-ribose, which was reacted with vinylmagnesium bromide to give (S)-allylic
alcohol 2 as a single stereoisomer. Oxidative diol cleavage of 2 gave lactol 3,
which was converted to diene 4 by stereoselective hydroxymethylation fol-
lowed by Wittig reaction. Stereoselective hydroxymethylation was explained
by an aldol-retroaldol reaction mechanism.[6] Chemoselective oxidation
of 4 with TEMPO followed by ring-closing metathesis (RCM) with second
SCHEME 1 Reagents and conditions: a) i. acetone, c-H2SO4; ii. CH2 =CHMgBr, THF; b) NaIO4,
CH2Cl2, H2O; c) i. CH2O, K2CO3, MeOH; ii. CH3PPh3Br, KOt-Bu, THF; d) i. TEMPO, TBACl, NCS,
aqueous NaHCO3 and K2CO3 (pH = 8.6). CH2Cl2; ii. Second generation Grubbs catalyst, CH2Cl2;
e) CH3Ph3PBr, KOt-Bu, THF; f) i. Sia2BH, THF; ii. NaBO3, H2O.

Homo-Apioneplanocin A
731
generation Grubbs catalyst afforded cyclopentenol 5. However, reverse
reaction sequence (RCM followed by chemoselective oxidation) failed to
give the desired product 5. Wittig reaction of 5 with methyltriphenylphos-
phonium bromide in the presence of potassium tert-butoxide smoothly
generated olefin 6, which was subjected to hydroboration and oxidation.
Several hydroboration reagents (9-BBN in THF or catecholborane and
Wilkinson catalyst, etc.) were attempted to achieve chemo- and regioselec-
tive hydroboration, but only Sia2BH afforded the desired product 7 after
oxidation with sodium perborate.
Protection of the primary hydroxyl group of 7 as trityl ether followed
by conversion of the remaining secondary hydroxyl group into the tosylate
gave 8, which could be an appropriate glycosyl donor for the synthesis of 1,
as shown in Scheme 2. Condensation of 8 with adenine base in the presence
of potassium carbonate and 18-Crown-6 in DMF at 80◦C gave two separable
regioisomers, N -7 isomer 9 (3%) and N -9 isomer 10 (78%). Anomeric as-
signments of regioisomers 9 and 10 were easily determined by comparison
of their UV data with UV literature data.[8] Removal of trityl and isopropy-
lidene groups of 10 with 1% aqueous HCl in methanol affrded the final
homo-apioneplanocin A (1).
SCHEME 2 Reagents and conditions: a) i. TrCl, pyridine, DMAP; ii. TsCl, DMAP, CH2Cl2; b) adenine,
K2CO3, 18-Crown-6, DMF, 80◦C; c) 1% HCl, MeOH.
Unfortunately, compound 1 did not show significant inhibition of Ado-
Hcy hydrolase, maybe due to the inability of hydroxyethyl group to induce
the favorable binding to AdoHcy hydrolase and/or the presence of tertiary
hydroxyl group, which cannot be oxidized by cofactor-bound NAD+.
In conclusion, enantioselective synthesis of homo-apioneplanocin A (1)
as potential AdoHcy hydrolase inhibitor was accomplished from D-ribose, us-
ing stereoselective hydroxymethylation, regioselective oxidation, and regio-
and chemoselective hydroboration as key steps. Although the final com-
pound 1 did not exhibit significant inhibitory activity against AdoHcy hy-
drolase, all chemistries employed here will contribute to the discovery of
new carbocyclic nucleosides.
REFERENCES
1. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani, M. Studies on neplanocin A,
new antitumor antibiotic. I. Producing organism, isolation and characterization. J. Antibiot. 1981, 34,
359–366.

732
M. W. Chun et al.
2. Kishi, T.; Muroi, M.; Kusaka, T.; Nishikawa, M.; Kamiya, K.; Mizuno, K. Chem. Pharm. Bull. 1972, 20,
940.
3. Borchardt, R.T.; Keller, B.T.; Patel-Thombre, U. Neplanocin A.
A potent Inhibitor of S-
adenosylhomocysteine hydrolase and of vaccinia virus multiplication in mouse L929 cells. J. Biol.
Chem. 1984, 259, 4353–4358.
4. Shuto, S.; Obara, T.; Toriya, M.; Hosoya, M.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E. New
Neplanocin Analogs. 1. Synthesis of 6ꢁ-modified neplanocin A derivatives as broad-spectrum antiviral
agents. J. Med. Chem. 1992, 35, 324–331.
5. Terao, Y.; Akamatsu, M.; Achiwa, K. Synthesis of chiral 3-substituted gamma-lactones and 9-
furanosyladenine from (R)-2-(2,2-diethoxyethyl)-1,3-propanediol monoacetate prepared by lipase-
catalyzed reaction. Chem. Pharm. Bull. 1991, 39, 823–825.
6. Moon, H.R.; Kim, H.O.; Lee, K.M.; Chun, M.W.; Kim, J.H.; Jeong, L.S. Stereoselective synthesis of a
novel apio analogue of neplanocin A as potential S-adenosylhomocysteine hydrolase iinhibitor. Org.
Lett. 2002, 4, 3501–3503.
7. Shuto, S.; Obara, T.; Saito, Y.; Andrei, G.; Snoeck, R.; De Clercq, E.; Matsuda, A. New neplanocin
analogues. 6. Synthesis and potent antiviral acitivity of 6ꢁ-homoneplanocin A. J. Med. Chem. 1996, 39,
2392–2399.
8. Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. The stereoselective synthesis of 4ꢁ-β-
thioribonucleosides via the Pummerer reaction. J. Am. Chem. Soc. 2000, 122, 7233–7243.