Carbocyclic sinefungin

Article abstract of DOI:10.1016/j.tetlet.2007.05.079

(3aS,4S,6R,6aR)-Tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta[d][1,3]-dioxol-4-ol, itself available from ribose, provided a convenient entry point for an 18-step preparation of carbocyclic sinefungin. This procedure is adaptable to a number of carbocycli

Full text of DOI:10.1016/j.tetlet.2007.05.079

Tetrahedron Letters 48 (2007) 4809–4811
Carbocyclic sinefungin
Xueqiang Yin, Guoxia Zhao and Stewart W. Schneller*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, United States
Received 11 April 2007; revised 14 May 2007; accepted 14 May 2007
Available online 18 May 2007
Abstract—(3aS,4S,6R,6aR)-Tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta[d][1,3]-dioxol-4-ol, itself available from ribose, pro-
vided a convenient entry point for an 18-step preparation of carbocyclic sinefungin. This procedure is adaptable to a number of
carbocyclic sinefungin analogs with diversity of heterocyclic base and in the amino acid bearing side chain.
Ó 2007 Elsevier Ltd. All rights reserved.
Sinefungin (1)1 is an amino acid-containing nucleoside
NH2
NH2
isolated from the cultures of Streptomyces griseolus2a
N
N
N
N
N
N
and Streptomyces incarnatus.2b The C-60 primary
amino center renders sinefungin structurally similar to
S-adenosylmethionine (2, AdoMet). This resemblance
has served as the mechanistic focal point for rationaliz-
ing sinefungin’s in vivo and in vitro biological activi-
ties, including antiviral,3–5 antifungal,2,6 amoebicidal,7
and antiparasitical,8 through inhibition of, primar-
ily,3 AdoMet-dependent methyltransfrases.4 However,
the clinical promise of 1 is restricted by its in vivo
toxicity.9
N
N
X
O
H2N
H3C
S
+
HO OH
COOH
HO OH
COOH
H2N
H2N
2
1, X = O
3, X = CH2
Figure 1.
Brown allylboration13 7 produced 8 in consistent yields
(de 90% by NMR).
In our antiviral drug discovery program sinefungin rep-
resents an important target for structural modification
in order to improve its therapeutic index. Among the
many compounds, which have been synthesized and
evaluated in the sinefungin series,10 carbocyclic sinefun-
gin (3) has been proven to be elusive.11 This Letter dis-
closes a practical synthesis of 3, that is, adaptable to
analog development (Fig. 1).
The side-chain stereochemistry of 8 was clarified by a
modified Horeau method14 using 2-phenylbutryl chlo-
ride, pyridine and DMAP as reagents. The recovered
optically active 2-phenylbutanoic acid was levorotatory.
Thus,14b the homoallylic configuration of 8 is S. This re-
sult is consistent with the si face selectivity for the
Brown allylboration conditions used.13
A retrosynthetic analysis of carbocyclic sinefungin led us
to a convergent approach involving a purine base and an
appropriately crafted (stereochemically and function-
ally) cyclopentane. Thus, protection of the secondary
alcohol of 412 to 5 was followed by hydroboration to
provide the primary alcohol 6. Oxidation of 6 by a mod-
ified Swern procedure gave aldehyde 7. Calling on the
Mesylation of 8 followed by sodium azide nucleophilic
substitution produced 9. Transformation of 9 into
azide–alcohol 10 was accomplished by sodium periodate
glycolization/cleavage with, subsequent, Luche reduc-
tion (NaBH4/CeCl3Æ7H2O).15 (It is to be noted that use
of NaBH4 alone in the last step of 9 to 10 conversion
led to an intractable mixture of two products.16)
Derivative 10 was readily converted into iodide 11 using
the reagent obtained from iodine–imidazole. The lith-
ium salt of (2R)-3,6-dihydro-2,5-dimethoxy-3-isopropyl-
pyrazine reacted with 11 in the presence of Cu(I)17 to
Keywords: Stereospecific allylboration; Pyrazine protected aminoacid;
Horeau method.
*
Corresponding author. Tel.: +1 334 844 5737; fax: +1 334 844
5748; e-mail: schnest@auburn.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.079

4810
X. Yin et al. / Tetrahedron Letters 48 (2007) 4809–4811
HO
ref. 12
c
OR
b
on 5
OPMB
D-ribose
O
O
O
O
4, R=H
5, R=PMB
6
a
X
Y
OHC
d
f
OPMB
OPMB
on 9
O
O
O
O
7
8, X=OH;Y=H
9, X=H;Y=N3
e
N3
N3
h
j
OPMB
OR
on 11
on 13
O
O
O
O
X
g
N
MeO
OMe
N
10, X=OH
11, X=I
12, R=PMB
13, R=H
i
NH2
N
N
N
N
N3
k
3
O
O
N
MeO
OMe
N
14
Scheme 1. Reagents and conditions: (a) PMBCl, NaH, DMF, 95%; (b) (i) 9-BBN, THF; (ii) MeOH, H2O2, NaOH, 98% for two steps; (c) SO3Æpy,
DMSO, DIPEA, CH2Cl2, 94%; (d) (i) (+)-B-methoxydiisopinocampheylborane, CH2@CHCH2MgBr, Et2O/THF; (ii) MeOH, H2O2, NaOH, 96% for
two steps; (e) (i) MsCl, Et3N, DMAP, CH2Cl2; (ii) NaN3, DMF, 85% for two steps; (f) (i) NalO4, OsO4, MeOH/H2O; (ii) NaBH4, CeCl3Æ7 H2O,
MeOH, 77% for two steps; (g) TPP, imidazole, I2, toluene/MeCN, 90%; (h) (2R)-3,6-dihydro-2,5-dimethoxy-3-isopropylpyrazine, BuLi, CuCN,
THF, 87%; (i) DDQ, CH2Cl2/H2O, 88%; (j) (i) Tf2O, pyridine, CH2Cl2; (ii) adenine, NaH, DMF, 45% for two steps; (k) (i) 0.5 N HCl MeOH; (ii)
Pd(OH)2/C, cyclohexene; (iii) LiOH, MeOH/H2O, 55% for three steps.
provide requisite 12 as one diastereomer (by NMR).
Oxidative deprotection of the PMB ether group of 12
yielded 13 (Scheme 1).
yak and Minmin Yang of the Auburn group assisted in
the design of the successful synthesis described here.
Use of the Mitsunobu reaction18 to construct the purine
conjugate (that is, with 13 and 6-chloropurine) was
successful but the subsequent ammonolysis at the purine
C-6 center yielded mostly decomposed materials. Thus,
a more traditional nucleophilic coupling process was
undertaken by derivatizing 13 as its triflate that was,
in turn, treated with the sodium salt of adenine to yield
14. Hydrolytic (acidic) removal of the pyrazine and
isopropylidene units followed by azide reduction and
saponification (of the methyl ester made available by
breakdown of the pyrazine ring) led to achievement of
carbocyclic sinefungin (3).19
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Acknowledgments
This research was supported by funds from the NIH (AI
56540). The preliminary investigations of Tetyana Shul-

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19. Selected data for 3: white foam; 1H NMR (D2O,
250 MHz)
d 8.23 (s, 1H), 8.18 (s, 1H), 4.80 (d,
J = 2.8 Hz, 1H), 4.58 (m, 1H), 4.03 (m, 2H), 3.70 (m,
1H), 2.56 (m, 1H), 2.26–1.73 (m, 8H); 13C NMR (D2O,
100 MHz) d 188.5, 158.1, 154.9, 151.8, 143.4, 121.4, 77.42,
77.38, 62.54, 62.47, 52.9, 42.4, 42.3, 34.9, 27.06, 27.00;
HRMS Calcd for C16H24N6O5 [MꢀH2O + H+] 362.1945.
Found: 362.1941.