Total synthesis of (+)-sinefungin

Article abstract of DOI:10.1021/jo960670g

Sinefungin (1) a nucleoside antibiotic isolated from Streptomyces has been synthesized from D-ribose. Both the C-6 and C-9 stereogenic centers were constructed by efficient asymmetric syntheses. The C-6 amine stereochemistry was set by a highly diastereoselective allylation (> 99% de) of a (1S,2R)-1-amino-2-indanol-derived oxazolidinone 9 followed by a Curtius rearrangement of 11 to 12. The C-9 amino acid stereochemistry of sinefungin (1) was established by a rhodium chiral bisphosphine-catalyzed asymmetric hydrogenation of an α-(acylamino)acrylate derivative. The anomeric adenosylation of the mixture of anomeric acetates 20 in the presence of C-6 urethane NH was found to be extremely difficult. Conversion of the C-6 urethane NH as its N-benzyl derivative 21 was necessary prior to the adenosylation reaction. Successful adenosylation was effectively carried out by Vorbruggen's protocol utilizing persilylated N⁶-benzoyladenine and trimethylsilyl triflate.

Full text of DOI:10.1021/jo960670g

J . Org. Chem. 1996, 61, 6175-6182
6175
Tota l Syn th esis of (+)-Sin efu n gin
Arun K. Ghosh* and Wenming Liu
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
Received April 10, 1996X
Sinefungin (1) a nucleoside antibiotic isolated from Streptomyces has been synthesized from D-ribose.
Both the C-6 and C-9 stereogenic centers were constructed by efficient asymmetric syntheses. The
C-6 amine stereochemistry was set by a highly diastereoselective allylation (>99% de) of a (1S,2R)-
1-amino-2-indanol-derived oxazolidinone 9 followed by a Curtius rearrangement of 11 to 12. The
C-9 amino acid stereochemistry of sinefungin (1) was established by a rhodium chiral bisphosphine-
catalyzed asymmetric hydrogenation of an R-(acylamino)acrylate derivative. The anomeric
adenosylation of the mixture of anomeric acetates 20 in the presence of C-6 urethane NH was
found to be extremely difficult. Conversion of the C-6 urethane NH as its N-benzyl derivative 21
was necessary prior to the adenosylation reaction. Successful adenosylation was effectively carried
out by Vorbru¨ggen’s protocol utilizing persilylated N6-benzoyladenine and trimethylsilyl triflate.
Sch em e 1
In tr od u ction
The “small molecule” biological methylations are in-
volved in numerous crucial biochemical processes with
well-defined physiological function. S-Adenosylmethion-
ine (SAM) serves as a methyl donor, and various methyl
transferase enzymes catalyze these transmethylation
reactions.1 For example, catechol-O-methyltransferase
catalyzes the transfer of a methyl group from SAM to a
catechol substrate which represents the major extraneu-
ronal inactivation pathway of endogenous catechola-
mines.2 Since the discovery of SAM by Cantoni3 in 1952,
many SAM-dependendent methyl transferases have been
recognized. As a consequence, various methyltransferase
enzymes have become potential targets for the design of
chemotherapeutic agents.4 Sinefungin, a novel antifun-
gal nucleoside isolated5 from the cultures of Streptomyces
griseolus, has been shown to inhibit many methyltrans-
ferase enzymes.6 Sinefungin, which is structurally re-
lated to SAM, has also exhibited many other significant
biological properties including antifungal, antitumor,
antiparasitic, and antiviral activities.7 However, clinical
use of sinefungin is severely limited because of its known
in vivo toxicity.8 Many of the biological activities of
sinefungin are believed to be related to inhibition of the
SAM-dependent methyl transferase enzymes. The sig-
nificant biological properties of sinefungin continue to
foster immense interest in its chemistry and total syn-
thesis.9,10 In connection with our interest in sinefungin-
based design of antiviral agents, we required an efficient,
flexible, and enantioselective synthesis of sinefungin. We
describe here a stereocontrolled synthesis of sinefungin
in which both the C-6 and C-9 remote chiral centers were
constructed through efficient asymmetric synthesis in a
stereopredictable fashion.
Resu lts a n d Discu ssion
Our retrosynthetic analysis of sinefungin is outlined
in Scheme 1. The key elements of our synthesis involved
a Curtius rearrangement to incorporate the C-6 amino
functionality and an asymmetric hydrogenation of the
R-(acylamino)acrylate derivative to establish the C-9
asymmetric center. To set the stereochemistry at C-6,
our desired intermediate was the allyl derivative 3, which
would be obtained by a diastereoselective alkylation of
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) Salvatore, F.; Borek, E.; Zappia, V.; Williams-Ashman, H. G.;
Schlenk, F.; Eds. The Biochemistry of Adenosylmethionine, Columbia
University Press: New York, 1977.
(2) (a) Wolfenden, R. Annu. Rev. Biophys. Bioeng. 1976, 5, 271. (b)
Gulberg, H. C.; Marsden, C. A. Pharmacol. Rev. 1975, 27, 135.
(3) Cantoni, G. L. J . Am. Chem. Soc. 1952, 74, 2942.
(4) Borchardt, R. T. J . Med. Chem. 1980, 23, 347.
(5) (a) Hamil, R. L.; Hoehn, M. M. Intersci. Conf. Antimicrob. Agents
Chemother., 11th 1971, Abstr. 21. (b) Hamil, R. L.; Hoehn, M. M. J .
Antibiot. 1973, 26, 463.
(6) (a) Fuller, R. W.; Nagarajan, R. Biochem. Pharmacol. 1978, 27,
1981. (b) McCamnon, M. T.; Parks, L. W. J . Bacteriol. 1981, 145, 106
and references cited therein.
(9) For total synthesis, see; (a) Maguire, M. P.; Feldman, P. L.;
Rapoport, H. J . Org. Chem. 1990, 55, 948. (b) Buchanan, J . G.; Flinn,
A.; Mundill, P. H.; Wightman, R. H. Nucleosides Nucleotides 1986, 5,
313. (c) Geze, M.; Blanchard, P.; Fourrey, J . L.; Robert-Gero, M. J .
Am. Chem. Soc. 1983, 103, 7638. (d) Mock, G. A.; Moffat, J . G. Nucleic
Acids Res. 1982, 10, 6223. For synthesis of 6-deaminosinefungin
derivatives, see; Peterli-Roth, P.; Maguire, M. P.; Leon, E.; Rapoport,
H. J . Org. Chem. 1994, 59, 4186.
(10) For synthetic studies, see; (a) Mizuno, Y.; Tsuchida, K.; Tampo,
H. Chem. Pharm. Bull. 1984, 32, 2915. (b) Moorman, A. R.; Martin,
T.; Borchardt, R. T. Carbohydr. Res. 1983, 113, 233. (c) Lyga, J . W.;
Secrist, J . A., III. J . Org. Chem. 1983, 48, 1982.
(7) (a) Suhadolnik, R. J . Nucleotides as Biological Probes; Wiley:
New York, 1979; pp 19-23. (b) Pugh, C. S. G.; Borchardt, R. T.; Stone,
H. O. J . Biol. Chem. 1978, 253, 4075.
(8) Zweygerth, E.; Schillinger, D.; Kaufmann, W.; Roettcher, D. Trop.
Med. Parasitol. 1986, 37, 255.
S0022-3263(96)00670-6 CCC: $12.00 © 1996 American Chemical Society

6176 J . Org. Chem., Vol. 61, No. 18, 1996
Ghosh and Liu
Sch em e 2a
Sch em e 3a
a
Key: (a) DMSO, (COCl)2, CH2Cl2, -60 °C to -50 °C, 2 h and
then Et3N; (b) NaH, (EtO)2P(O)CH2CO2Et, THF, 0 °C to 23 °C;
(c) H2, 10% Pd-C, EtOAc; (d) LiOH, THF-H2O, 23 °C; (e)
Me3CCOCl, Et3N, THF, -15 °C to 0 °C then -78 °C and then
N-lithiooxazolidinone 8; (f) (TMS)2NLi, THF, -78 °C, 1 h and then
CH2dCHCH2I, -78 °C to -40 °C, 6 h; (g) LiOOH, THF-H2O, 0
-23 °C.
a
Key: (a) (PhO)2P(O)N3, Et3N, PhMe, 114 °C, 2 h and then
PhCH2OH, 114 °C, 12 h; (b) NaH, PhCH2Br, nBu4N+I- (cat),
THF-DMF (10:1); (c) O3, CH2Cl2-MeOH (1:1), -78 °C then Me2S,
-78 °C to 23 °C; (d) KOtBu, (PhO)2P(O)CH(NHAc)CO2Et, CH2Cl2,
-78 °C, 1 h and then above aldehyde, -78 °C to 23 °C, 4 h; (e) H2,
[Rh(COD)(R,R-DIPAMP)2]+BF4-, 50 psi, MeOH, 23 °C, 10 h; (f)
H2, 20% Pd(OH)2-C, MeOH; (g) PhCH2OCOCl, Et3N, DMAP,
the corresponding chiral imide. The required chiral
imide would be derived from D-ribose, and the adenine
was planned to be introduced toward the end of the
synthesis. Thus, the protected methyl glycoside 511 was
readily converted to R,â-unsaturated ester 6 by Swern
oxidation of 5 followed by immediate exposure of the
resulting aldehyde to a Horner-Emmons olefination
reaction with triethyl phosphonoacetate and sodium
hydride in THF at 23 °C for 30 min. Only the trans R,â-
unsaturated ester 6 was isolated in 72% yield after silica
gel chromatography. Hydrogenation of 6 with 10% Pd-C
in ethyl acetate and saponification of the resulting
saturated ester with 1 M aqueous LiOH at 23 °C for 12
h afforded the glycosidic acid 7. To establish the stere-
ochemistry of the C-6 amine, the acid 7 was subjected to
a diastereoselective asymmetric alkylation process. The
acid 7 was first converted to carboximide 9 utilizing
Evans’s protocol12 as follows: the chiral oxazolidinone 813
was deprotonated with n-BuLi at -60 °C in THF; the
resulting lithio derivative was reacted with the mixed
anhydride derived from acid 7, pivaloyl chloride, and
triethylamine at -78 °C to furnish the carboximide 9 in
70% yield after silica gel chromatography. Treatment
CH2Cl2; (h) aqueous HCl, dioxane, 23 °C; (i) Ac2O, pyridine, 0 °C
to 23 °C, 10 h; (j) H2, [Rh(norbornadiene)(S,S-Chiraphos)]+ClO4
,
-
MeOH, 50 psi, 23 °C, 10 h.
of this carboximide with lithum hexamethyldisilazide in
THF at -78 °C for 1 h provided the lithium enolate which
was reacted with allyl iodide at -78 °C to -40 °C for 6 h
to afford the allylation product 10 in 78% yield after
chromatography over silica gel. The 1H-NMR (400 MHz)
and HPLC analysis before and after chromatography
reveal the presence of a single diastereomer. The re-
moval of the chiral auxiliary was effected by exposure to
lithium hydroperoxide in aqueous THF under standard
reaction conditions to provide the acid 11.14 The stere-
ochemistry of the asymmetric alkylation process was
assigned based upon the comparison of an authentic
sample 11, prepared utilizing (S)-(-)benzyl-2-oxazolidi-
none as the chiral auxiliary (single isomer, 81% yield in
the alkylation step). The stereochemical course of such
an alkylation process has been well established previ-
ously.15 The observed diastereoselectivity and isolated
yields of the asymmetric alkylation process in both cases
(11) (a) Ghosh, A. K.; McKee, S. P.; Sanders, W. M.; Darke, P. L.;
Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Quintero, J . C.; Huff, J . R.;
Anderson, P. S. Drug Des. Discovery 1993, 10, 77. (b) Levene, P. A.;
Stiller, E. T. J . Biol. Chem. 1934, 299.
(12) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011.
(13) Ghosh, A. K.; Duong, T. T.; McKee, S. P. J . Chem. Soc., Chem.
Commun. 1992, 1673.
(14) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141.
(15) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737. (b) Evans, D. A. Aldrichim. Acta 1982, 15, 23.

Total Synthesis of (+)-Sinefungin
J . Org. Chem., Vol. 61, No. 18, 1996 6177
Sch em e 4a
the resulting mixture was heated at a reflux for 12 h to
furnish the urethane 12 (Cbz-derivative) in 79% yield
(from 10) after silica gel chromatography. The stereo-
chemistry of the urethane bearing chiral center in 12 was
assigned based upon the fact that the Curtius rearrange-
ment proceeds with retention of configuration of the
migrating carbon atom.17 For the anomeric adenosyla-
tion reaction, it was necessary to convert the urethane
NH as its N-benzyl urethane 13. This was accomplished
by N-benzylation of 12 with sodium hydride and benzyl
bromide in a mixture of THF/DMF (10:1) at 23 °C for 12
h to provide 13. To elaborate the C-9 amino acid
stereochemistry, the N-benzyl urethane 13 was then
transformed into the corresponding R-(acylamino)acrylate
derivatives 16 and 17. Thus, ozonolysis of the terminal
olefin of 13 in a mixture (1:1) of methanol and CH2Cl2 at
-78 °C followed by reductive workup with dimethyl
sulfide afforded the corresponding aldehyde which was
exposed to a Horner-Emmons type olefination with the
enolate derived from ethyl N-acetyl-R-(diethylphosphon-
yl)glycinate18 and KOtBu in CH2Cl2 at -78 °C to 23 °C
for 5 h. This provided a 1:5 mixture of E and Z-enamides
16 and 17 in 64% yield (from 12) after silica gel chro-
1
matography. Determination of the isomer ratio by H-
NMR (CDCl3 or DMSO-d6) was complicated due to the
presence of the Cbz-protecting group which resulted in
a number of rotational isomers at 23 °C. When the
temperature was raised, the rotation about the N-C
bond became appreciable and at coalescence temperature
(Tc, ca. 74 °C in DMSO-d6), the mixture of broad peaks
merged into sharp peaks corresponding to major and
a
Key: (a) aqueous HCl, dioxane, 23 °C; (b) Ac2O, pyridine, 0
°C to 23 °C, 10 h; (c) TMSOTf, silyl N6-benzoyladenine 25,
ClCH2CH2Cl, 23 °C, 3 h; (d) SnCl4, adenine, CH3CN, 23 °C.
Sch em e 5a
1
minor isomers (1:5 mixture by H-NMR integration) 16
and 17. The eneamides 14 and 15 derived from 12,
however, revealed the presence of a 1:6 mixture of the
1
corresponding E- and Z-enamide by H-NMR (400 MHz)
in CDCl3. Identification of the E- and Z-isomers derived
1
from 12 or 13 was made by H-NMR (400 MHz, CDCl3)
spectroscopy. The vinylic chemical shift value (6.6 ppm)
for the Z-isomer 17 is about 0.3 ppm upfield relative to
the E-isomer 16 (6.9 ppm) which is characteristic of the
double bond configuration of the E- and Z-enamido
ester.19 The E,Z-isomers 14 and 15 or 16 and 17 were
inseparable by chromatography. Since “Rh-(R,R)-DI-
PAMP” based asymmetric hydrogenation of both E- and
Z-isomers is well known20 to provide the S-enantiomer
with excellent enantiomeric excess, the mixture was
utilized in the subsequent reaction. Thus, asymmetric
hydrogenation of the mixture of enamides (16 and 17;
1:5 mixture) was carried out in methanol in the presence
of [Rh(COD)(R,R-DIPAMP)2]+BF4 (6 mol %) catalyst21
-
a
Key: (a) TMSOTf, silyl N6-benzoyladenine 22, ClCH2CH2Cl,
at 23 °C under 50 psi hydrogen pressure for 10 h to
provide the 9-S-isomer 18. The 1H-NMR of 18 was again
complicated by the presence of a 4:1 mixture of rotational
isomers. At coalescence temperature (Tc, ca. 70 °C in
DMSO-d6), the mixture of peaks merged into one sharp
45 °C, 2 h; (b) K2CO3, MeOH, 23 °C, 8 h; (c) NH2NH2, H2O, 23 °C,
2 h and then H3O+ (pH 7.0); (d) H2, 20% Pd(OH)2-C, MeOH, 48
h.
are quite comparable. Thus, the constrained chiral
oxazolidinone 8 complements the chiral oxazolidinone
derived from the L-phenylalaninol.
For conversion of the carboxylic acid to the correpond-
ing protected amine derivative, a Curtius rearrangement
was sought.16 Thus, the above acid 11 without further
purification was exposed to 1.2 equiv of diphenyl phos-
phorazidate and 1.2 equiv of triethylamine in refluxing
toluene for 2 h. Benzyl alcohol (2 equiv) was added, and
(17) (a) Banthorpe, D. V. In The Chemistry of Azide Group; Patai,
S., Ed.; Interscience: New York, 1971; pp 397-405. (b) Smith, P. A.
S. Derivatives of Hydrazine and other Hydronitrogens Having N-N
Bonds; Benjamin: Reading, 1983; pp 272-273. (c) Glass, R. S.;
McConnell, W. W.; Andruski, S. P. J . Org. Chem. 1986, 51, 5123.
(18) Schmidt, U.; Lieberknecht, A.; Wild, J . Synthesis 1984, 53.
(19) Pham. T.; Lubell, W. D. J . Org. Chem. 1994, 59, 3676.
(20) Scott, J . W.; Keith, D. D.; Nix, G., J r.; Parrish, D. R.; Remington,
S.; Roth, G. P.; Townsend, J . M.; Valentine, D., J r.; Yang, R. J . Org.
Chem. 1981, 46, 5086.
(16) (a) Ninomiya, K.; Shiori, T.; Yamada, S.; Tetrahedron 1974, 30,
2151. (b) Grunewald, G. L.; Ye, Q.; J . Org. Chem. 1988, 53, 4021. (c)
Ghosh, A. K.; McKee, S. P.; Thompson, W. J .; Darke, P. L.; Zugay, J .
C. J . Org. Chem. 1993, 58, 1025.
(21) (a) Knowles, W. S.; Sabacky, M. J .; Vineyard, B. D.; Weinkauff,
D. J . J . Am. Chem. Soc. 1975, 97, 2567. (b) Vineyard, B. D.; Knowles,
W. S.; Sabacky, M. J .; Bachman, G. L.; Weinkauff, D. J . J . Am. Chem.
Soc. 1977, 99, 5946.

6178 J . Org. Chem., Vol. 61, No. 18, 1996
Ghosh and Liu
spectrum. The removal of both N-benzyl and Cbz-group
by a catalytic hydrogenation over Pd(OH)2-C in metha-
nol afforded the corresponding amine whose 1H-NMR
(400 MHz) revealed the presence of a single isomer.
Further reaction of the amine with benzyl chloroformate
in the presence of triethylamine and a catalytic amount
of DMAP furnished the Cbz-derivative 19.22 The 13C-
NMR analysis of 19 has also established the presence of
a single isomer. In order to have access to the C-9(R)-
diastereomer, asymmetric hydrogenation of the mixture
of eneamides (14 and 15) was accomplished in methanol
in the presence of [Rh(norbornadiene)(S,S)-Chiraphos)]+Cl-
effectively carried out as follows: N6-benzoyladenine was
treated with TMSCl in hexamethyldisilazane at reflux
for 5 h and the resulting bis-silyl-N-benzoyladenine 25
(1.2 equiv)27 was reacted with triacetate 24 in the
presence of 1.2 equiv of TMSOTf in dichloroethane at 23
°C for 3 h to afford the protected â-nucleoside 26 in 98%
yield after silica gel chromatography. Slight modification
of the above reaction conditions proved to be optimum
for the adenosylation of anomers 21. Thus, reaction of
the mixture (1:1) of anomers 21 with 4 equiv of bis-silyl-
N-benzoyladenine 25 and 4 equiv of TMSOTf in dichlo-
roethane at 45 °C for 2 h furnished the protected
sinefungin derivative 29 in 93% yield after silica gel
chromatography. In contrast, adenosylation of 21 with
adenine and SnCl4 in acetonitrile at 23 °C to 60 °C under
a variety of conditions afforded only a trace amount of
N6-debenzoyl derivative of 29. Similarly, reactions of
anomeric acetates 24 with SnCl4 provided only a small
amount of desired adenosylation product (5-8% yield).
On the other hand, adenosylation of the mixture of
anomeric acetates 27 provided the corresponding â-nu-
cleoside 28 in 58% yield after chromatography.28 Thus,
it is apparent that the substitutent at C-6 has a pro-
nounced effect on the adenosylation reaction; however,
the exact role is not clear.
O4 (6 mol %) as the catalyst23 to provide 22 in 95%
-
isolated yield. The diastereomeric excess of various
asymmetric hydrogenation processes was determined by
HPLC analysis using a Daicel OD column24 with 10%
2-propanol in hexane as the eluent. The optical purity
of 18 was determined to be >98% by HPLC. Further
HPLC analysis of 19 derived from 18 has established the
diastereomeric excess to be 98%.25 The asymmetric
hydrogenation of eneamides 14 and 15 with [Rh(COD)-
(R,R-DIPAMP)2]+BF4- has also provided 19 with 98% de
(by HPLC). The 1H-NMR and 13C-NMR, however, re-
vealed one isomer. In contrast, the diastereomeric excess
of C-9(R)-diastereomer 22 was found to be 81% by HPLC.
To complete the synthesis of sinefungin, we needed to
remove various protecting groups in 29. This was
accomplished in one pot by a three-step sequence. Thus,
exposure of 29 with K2CO3 in methanol at 23 °C for 8 h
followed by removal of methanol and treatment with 5
equiv of aqueous hydrazine at 23 °C for 2 h effected the
hydrolysis of esters, benzoyl amide as well as acetamide
functionalities affording the sinefungin derivative 30.29
Subsequent removal of the carbobenzyloxy and N-benzyl
protecting groups of 30 was carried out after evaporation
of solvent from the above reaction mixture under reduced
pressure followed by hydrogenation of the residue in
methanol in the presence of Pd(OH)2/C (20% wt) under
atmospheric hydrogen for 48 h. The resulting crude
sinefungin was purified by silica gel chromatography
(eluent, MeOH:CHCl3:NH4OH ) 3:5:1) to furnish the
synthetic (+)-sinefungin 1 (RD23 +13.4; c, 0.12, H2O; lit.9a
After introduction of appropriate chirality at the C-6
and C-9 positions corresponding to (+)-sinefungin struc-
ture, the next synthetic plan was to incorporate adenine
at the anomeric position. The removal of the isopropyl-
idene group as well as the methyl acetal was effected by
treatment of 18 with aqueous HCl and dioxane at 23 °C
for 12 h, providing the corresponding triol. Without
further purification, the resulting triol was exposed to
acetic anhydride in pyridine at 0 °C to 23 °C for 10 h to
1
furnish the triacetate 21 (3:2 mixture of anomers by H-
NMR) in 70% yield after chromatography. The mixture
of anomers was difficult to separate by silica gel chro-
matography and was utilized for the subsequent adeno-
sylation reaction. For initial anomeric adenosylation,
urethane 20 (1:1 mixture of anomers) was employed;
however, no desired product was obtained under a variety
of reagents and reaction conditions. Treatment of 20
with excess of adenine and SnCl4 in acetonitrile26 at 23
°C to 60 °C did not yield any adenosylation product, and
the starting triacetates 20 were found to be destroyed
under these reaction conditions. Similarly, attempts to
effect the adenosylation reaction of 23 derived from 12
under a variety of reagents and reaction conditions were
unsuccessful. The mixture (1:1) of anomeric acetates 24
derived from the N-benzyl urethane derivative 13, how-
ever, underwent adenylation smoothly under Vorbru¨ggen27
reaction conditions. Anomeric adenosylation of 24 was
1
RD23 +12.4 ( 0.2°; c, 0.227, H2O) with H-NMR (400 MHz)
1
spectroscopic data in full agreement with the H-NMR
spectra of both natural and synthetic (+)-sinefungin
kindly provided by Professor Henry Rapoport.
Con clu sion
A concise synthesis of (+)-sinefungin has been ac-
complished in a stereocontrolled fashion from D-ribose.
The key steps in the synthesis are a diastereoselective
alkylation and Curtius rearrangement to set the C-6
amine functionality. A chiral bisphosphine-rhodium-
catalyzed asymmetric hydrogenation of an R-(acylamino)-
acrylate derivative is used to set the C-9 amino acid
stereochemistry. Diastereoselective alkylation of a
(1S,2R)-1-amino-2-indanol-derived oxazolidinone is note-
worthy. Since both enantiomers of cis-1-amino-2-in-
danols are commercially available,30 the present asym-
(22) For HPLC analysis, a mixture of C-9 diastereomers were
prepared by hydrogenation of the mixture of enamides 14 and 15 over
5% Pd-C in methanol under a hydrogen filled balloon at 23 °C for 8
h. This has afforded a mixture (60:40) of 19 and 22 in 78% isolated
yield.
(23) Fryzuk, M. D.; Bosnich, B. J . Am. Chem. Soc. 1977, 99, 6262.
(24) Daicel OD column was purchased from Chiral Technologies,
730 Springdale Dr., Exton, PA.
(25) Isocratic normal phase HPLC analysis on
a Chiralcel OD
column (25 cm) using 10% 2-propanol in hexane as eluant (flow rate:
1.1 mL/min) and UV detection at 254 nm indicated that both diaster-
eomers could be cleanly separated. Retention times for diastereomer
19: 17.10 min and diastereomer 22: 20.67 min.
(26) Saneyoshi, M.; Satoh, E.; Chem. Pharm. Bull. 1979, 27, 2518.
Also see ref 9a.
(27) Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234. For recent application of this reaction, see J ohnson, C. R.;
Esker, J . L.; Van Zandt, M. C. J . Org. Chem. 1994, 59, 5854.
(28) The presence of azide functionality at C-6 also does not interfere
with the adenosylation reaction under this conditions. Rapoport has
reported9a 59% yield of the corresponding â-nucleoside by a SnCl4-
catalyzed adenosylation reaction of the anomeric acetates containing
C-6 azide and C-9 amino acid protected as p-toluenesulfonamide and
tert-butyl ester.
(29) The 1H-NMR (D2O) of a crude sample of 30 indicated the
absence of benzoyl, acetyl, and ethyl ester groups.

Total Synthesis of (+)-Sinefungin
J . Org. Chem., Vol. 61, No. 18, 1996 6179
then allowed to warm up to 23 °C for 30 min. The reaction
was quenched with saturated aqueous NH4Cl solution, and
the layers were separated. The aqueous layer was extracted
with EtOAc (2 × 50 mL), and the combined organic layers were
washed with brine and dried over anhydrous Na2SO4. Evapo-
ration of the solvent provided a residue which was chromato-
graphed over silica gel (10% EtOAc/hexanes) to provide the
metric alkylation would provide access to either ste-
reochemistry at C-6. Similarly, with choice of chiral
catalyst, asymmetric hydrogenation of the R-(acylamino)-
acrylate derivative would enable one to obtain either
stereoisomer at C-9. The current synthesis is flexible and
therefore provides a convenient access to the synthesis
of various sinefungin analogues for biological evaluation.
Further study of the chemistry and biology of sinefungin
is an active area of research in our laboratory.
23
title ester 6 as a clear oil (3.53 g, 72%). [R]D -38.3 (c 1.3,
1
CHCl3); H-NMR(CDCl3) δ ; 1.29 (t, 3 H, J ) 7.2 Hz), 1.30 (s,
3 H), 1.50 (s, 3 H), 3.37 (s, 3 H), 4.20 (q, 2 H, J ) 7.1 Hz), 4.60
(d, 1 H, J ) 5.9 Hz), 4.66 (d, 1 H, J ) 5.9 Hz), 4.75 (d, 1 H, J
) 7.1 Hz), 5.01 (s, 1 H), 5.99 (d, 1 H, J ) 15.5 Hz), 6.88 (dd, 1
H, J ) 15.7,7.1 Hz); IR (neat) 2984, 2938, 1722, 1372, 1177,
Exp er im en ta l Section
1092, 981, 868 cm-1; MS (CI) m/ z 273 (M+ + H), 257 (M+
Me), 241 (M+ - OMe), 214.
-
All melting points were recorded and uncorrected. Analyti-
cal HPLC analyses were performed on a Daicel OD column
(4.6 mm × 25 cm) with 10% iPrOH/hexane as the solvent, flow
rate 1.1 mL/min, λ 254 nm). Anhydrous solvents were
obtained as follows: 1,2-dichloroethane was first refluxed for
2 h over P2O5 and then followed by distillation; tetrahydrofu-
ran distillation from sodium and benzophenone; methylene
chloride, distillation from P2O5; trimethylchlorosilane, pyri-
dine, and dimethoxyethane distillation from CaH2. All other
solvents were HPLC grade. N6-Benzoyladenine was recrystal-
lized from MeOH. Column chromatography was performed
with Whatman 240-400 mesh silica gel under low pressure
of 5-10 psi. Thin-layer chromatography (TLC) was carried
out with E. Merck silica gel 60 F-254 plates.
Meth yl 2,3-O-Isopr opyliden e-â-D-r ibofu r an oside 5. Pow-
dered D-ribose (5.85 g, 39 mmol) and anhydrous cuprous
sulfate (12.4 g) were suspended in a mixture of acetone (110
mL) and methanol (32 mL) containing a catalytic amount of
concentrated sulfuric acid (0.2 mL). The resulting mixture was
stirred at 40 °C for 48 h. After this period, the mixture was
filtered and the filter cake was washed with a mixture of
acetone and methanol (1:1 mixture, 100 mL). The resulting
solution was neutralized with saturated NaHCO3 aqueous
solution, and the methanol and acetone were removed under
reduced pressure. The residue was extracted with EtOAc (3
× 50 mL). The combined EtOAc layers were washed with
brine and dried (Na2SO4). Concentration and chromatography
Met h yl 5,6-Did eoxy-2,3-O-(1-m et h ylet h ylid en e)-â-D-
r ibo-h ep tofu r a n osid u r on ic a cid 7. To a solution of 6 (3.27
g, 12 mmol) in ethyl acetate (200 mL) was suspended 10% Pd/C
(490 mg). The resulting mixture was hydrogenated under a
hydrogen-filled balloon for 9 h. After this period, the mixture
was filtered through a Celite pad, and the Celite pad was
washed with additional ethyl acetate (50 mL). Evaporation
of the solvent under reduced pressure gave a residue which
was chromatographed over silica gel to furnish the correspond-
ing saturated ester as an oil (3.29 g, 99%). [R]D23 -34.3 (c 1.0,
CHCl3); 1H-NMR (CDCl3, 400 MHz) δ; 1.22 (t, 3 H, J ) 7.1
Hz), 1.27 (s, 3 H), 1.43 (s, 3 H), 1.85 (m, 2 H), 2.42 (m, 2 H),
3.31 (s, 3 H), 4.10 (m, 3 H), 4.51 (d, 1 H, J ) 5.9 Hz), 4.59 (d,
1 H, J ) 5.9 Hz), 4.91 (s, 1 H); 13C-NMR (CDCl3, 100 MHz) δ;
14.08, 24.84, 26.35, 30.10, 30.90, 54.97, 60.32, 83.91, 85.35,
86.06, 109.56, 112.17, 172.83; IR (neat) 2983, 2937, 1720, 1372,
1209, 1162, 1093, 869 cm-1; MS (CI) m/ z 275 (M+ + H), 259
(M+ - Me), 243 (M+ - OMe), 216.
To a mixture of the above ester (2.2 g, 8.03 mmol) in water
(50 mL) and THF (10 mL) at 23 °C was added solid LiOH‚H2O
(1 g, 24 mmol), and the resulting reaction mixture was stirred
for 12 h. After this period, the solvents were removed under
reduced pressure, and the residue was cooled down to 0 °C
and carefully acidified with 10% citric acid to pH 4. The
mixture was thoroughly extracted with ethyl acetate (3 × 70
mL). The combined organic layers were dried over anhydrous
Na2SO4 and evaporated under reduced pressure to give the
title acid as an oil (1.98 g, 100%) which was used for the next
23
(25%EtOAc/hexanes) provided 5 as an oil (5.69 g, 72%). [R]D
-73.8 (c 1.1, CHCl3); lit.31 [R]D23 -78.5 (c 2.0, CHCl3); 1H-NMR
(CDCl3, 400 MHz) δ; 1.31 (s, 3 H), 1.47 (s, 3 H), 3.25 (br s, 1
H), 3.43 (s, 3 H), 3.60 (dd, 1 H, J ) 12.5, 3.1 Hz), 3.69 (dd, 1
H, J ) 12.5, 2.2Hz), 4.43 (t, 1 H, J ) 2.6 Hz), 4.57 (d, 1 H, J
) 5.9 Hz), 4.83 (d, 1 H, J ) 5.9 Hz), 4.97 (s, 1 H); IR (neat)
23
reaction without further purification. [R]D -37.9° (c 1.0,
CHCl3); 1H-NMR (CDCl3, 400 MHz) δ; 1.30 (s, 3 H), 1.46 (s, 3
H), 1.87 (dd, 2 H, J ) 15.0, 7.6 Hz), 2.50 (m, 2 H), 3.34 (s, 3
H), 4.20 (t, 1 H, J ) 7.7 Hz), 4.53 (d, 1 H, J ) 5.9 Hz), 4.61 (d,
1 H, J ) 5.9 Hz), 4.95 (s, 1 H); 13C-NMR (CDCl3, 100 MHz) δ;
24.84, 26.35, 29.81, 30.61, 55.09, 83.90, 85.33, 85.85, 109.65,
112.31, 178.99. IR (neat) 3200-3600, 2989, 2937, 1714, 1383,
1210, 1092, 962, 866 cm-1; MS (CI) m/ z 247 (M+ + H), 231
(M+ - Me), 229 (M+ - OH), 215 (M+ - OMe), 157.
3458, 2988, 2940, 1383, 1210, 1093, 1044, 870 cm-1
.
tr a n s-Eth yl [Meth yl 5,6-d id eoxy-2,3-O-(1-m eth yleth -
ylid en e)-â-D-r ibo-h ep t-5-en ofu r a n osid ]u r on a te (6). To a
stirred solution of DMSO (3.9 mL) in dry CH2Cl2 (45 mL) at
-60 °C was added oxalyl chloride (2.4 mL) over a period of 5
min. The resulting mixture was stirred for additional 3 min
and then the alcohol 5 (3.74 g, 18.3 mmol) in CH2Cl2 (30 mL)
was added over 2 min. The mixture was stirred at -60 °C for
2 h. After this period, the reaction was quenched with
triethylamine (10 mL), and the resulting mixture was stirred
for an additional 5 min at -60 °C and then allowed to warm
to 23 °C. The reaction mixture was diluted with water (20
mL), the resulting mixture was concentrated under reduced
pressure, and the residue was extracted with EtOAc (3 × 50
mL). The combined EtOAc layers were washed with brine and
dried over anhydrous Na2SO4. Evaporation of the solvent gave
the crude aldehyde which was used directly without further
purification.
To suspension of NaH (60%, 1.47 g, 36.8 mmol) in THF (100
mL) at 0 °C was added triethyl phosphonoacetate (7.3 mL, 36.8
mmol) dropwise over a period of 5 min. The resulting reaction
mixture was allowed to warm up to 23 °C and was stirred for
another 40 min. After this period, the reaction mixture was
cooled to 0 °C and the above crude aldehyde in THF (20 mL)
was added. The reaction mixture was stirred for 5 min and
N-[Meth yl 5,6-d id eoxy-2,3-O-(1-m eth yleth ylid en e)-â-D-
r ibo-h ep tofu r a n osid u r on yl]-(4S,5R)-in d a n o[1,2-d ]oxa zo-
lid in -2-on e 9. To a stirred solution of 7 (1.82 g, 7.5 mmol) in
dry THF (50 mL) at -15 °C was added triethylamine (2 mL)
followed by trimethylacetyl chloride (1 mL). After 15 min, the
reaction slurry was allowed to warm up to 0 °C over 20 min
and then recooled to -78 °C. In a separate flask, the (4S,5R)-
indano[1,2-d]oxazolidin-2-one 8 (1.43 g, 8 mmol) was dissolved
in dry THF (75 mL), and the resulting solution was cooled to
-60 °C. To this cold solution, was added n-butyllithium (1.6
M in hexane, 5.1 mL) over a period of 15 min. After stirring
for 10 min, the solution was taken up in a syringe and added
to the white slurry prepared as described above. After the
mixture was stirred for 1 h at -78 °C, 1 N sodium bisulfate
(30 mL) was added and the reaction was allowed to warm to
23 °C. The resulting reaction mixture was concentrated under
reduced pressure, and the residue was extracted with ethyl
acetate (3 × 50 mL). The combined extracts were washed with
brine and dried over anhydrous Na2SO4. Evaporation of the
solvent under reduced pressure and purification by silica gel
chromatography (25% EtOAc/hexanes) provided the oxazolid-
(30) Available from Aldrich Chemical Co., Milwaukee, WI and
Sepracor Inc., Marlborough, MA 01752.
(31) Boullais, C.; Zylber, N.; Zylber, J .; Guilhem, J .; Gaudemfr, A.
Tetrahedron 1983, 39, 759.
23
none 9 as an oil (2.1 g, 70%). [R]D +158.2 (c 1.7, CHCl3);
1H-NMR (CDCl3, 400 MHz) δ; 1.31 (s, 3 H), 1.47 (s, 3 H), 1.95
(m, 2 H), 3.09 (m, 2 H), 3.33 (s, 3 H), 3.48 (d, 2 H, J ) 3.4 Hz),

6180 J . Org. Chem., Vol. 61, No. 18, 1996
Ghosh and Liu
4.25 (dd, 1 H, J ) 9.0, 6.3 Hz), 4.60 (dd, 2 H, J ) 8.1, 6.0 Hz),
4.94 (s, 1 H), 5.28 (m, 1 H), 5.91 (d, 1 H, J ) 7.0 Hz), 7.27 (m,
3 H), 7.60 (d, 1 H, J ) 7.6 Hz); 13C-NMR (CDCl3, 100 MHz) δ;
24.95, 26.42, 29.29, 31.95, 37.92, 55.14, 62.99, 78.05, 84.00,
85.42, 85.89, 109.66, 112.21, 125.12, 127.14, 128.06, 129.78,
139.00, 139.41, 152.88, 172.74; IR (neat) 2985, 2935, 1784,
1689, 1364, 1192, 1107, 869, 757 cm-1; MS (CI) m/ z 404
(MH+), 388 (M+ - Me), 372 (M+ - OMe), 314, 285, 204. Anal.
Calcd for C21H25NO7: C, 62.52; H, 6.25; N, 3.47. Found: C,
62.35; H, 5.99; N, 3.67.
for 2 h, and then benzyl alcohol (0.3 mL, 3.1 mmol) was added.
Stirring and refluxing were continued for an additional 12 h.
After this period, the reaction was cooled to 23 °C, and the
solvents were evaporated under reduced pressure. The result-
ing residue was partitioned between ethyl acetate and satu-
rated aqueous NaHCO3. The layers were separated, and the
organic phase was washed with brine and dried over anhy-
drous Na2SO4. Evaporation of the solvent under reduced
pressure gave a residue which was chromatographed over
silica gel (5% EtOAc/benzene) to furnish 12 (475 mg, 79%) as
a white foam. [R]D23 +3.9 (c 1.0, CHCl3); 1H-NMR (CDCl3, 400
MHz) δ; 1.30 (s, 3 H), 1.47 (s, 3 H), 1.59 (m, 1 H), 1.80 (m, 1
H), 2.30 (m, 2 H), 3.34 (s, 3 H), 3.95 (m, 1 H), 4.33 (dd, 1 H, J
) 11.0, 3.8 Hz), 4.53 (d, 1 H, J ) 5.9 Hz), 4.59 (d, 1 H, J ) 5.9
Hz), 4.89 (d, 1 H, J ) 9.0 Hz), 4.96 (s, 1 H), 5.08 (m, 4 H), 5.75
(m, 1 H), 7.33 (m, 5 H); 13C-NMR (CDCl3, 100 MHz) δ; 24.87,
26.38, 39.08, 39.47, 48.18, 55.23, 66.49, 83.72, 84.44, 85.36,
109.15, 112.27, 118.11, 127.96, 128.38, 128.40, 133.89, 136.52,
155.73; IR (neat) 3360, 2919, 1698, 1520, 1265, 1212, 1108,
1057, 964, 870, 695 cm-1; MS (CI) m/ z 392 (M+ + H), 360 (M+
- OMe), 350, 316. Anal. Calcd for C21H29NO6: C, 64.43; H,
7.47; N, 3.58. Found: C, 64.35; H, 7.54; N, 3.51.
N-[Meth yl 5,6-dideoxy-2,3-O-(1-m eth yleth yliden e)-6(S)-
a llyl-â-D-r ibo-h ep tofu r a n osid u r on yl]-(4S,5R)-in d a n o[1,2-
d ]oxa zolid in -2-on e 10. To a stirred solution of 9 (1 g, 2.5
mmol) in dry THF (100 mL) at -78 °C was added lithium
hexamethyldisilazide (1 M in hexane, 3.75 mL). The resulting
solution was stirred at -78 °C for 1 h, and then allyl iodide
(0.45 mL, 5 mmol) was added. The reaction mixture was
stirred for 3 h, and then it was allowed to warm to -40 °C
over 3 h. After this period, the reaction was quenched with
saturated aqueous NH4Cl (20 mL), and the resulting mixture
was warmed up to 23 °C. The reaction mixture was concen-
trated under reduced pressure, and the residue was extracted
with ethyl acetate (3 × 50 mL). The combined organic layers
were dried over anhydrous Na2SO4 and evaporation of the
solvent provided a residue which was purified by silica gel
chromatography (25% EtOAc/hexanes) to afford the allylation
6(S)-Allyl-N-(p h en ylm et h yl)-N-[(p h en ylm et h oxy)ca r -
bon yl][m eth yl 5,6-d id eoxy-2,3-O-(1-m eth yleth ylid en e)-â-
D-r ibo-h ep tofu r a n osid ]u r a m in e 13. To a stirred suspen-
sion of NaH (60%, 290 mg) in a mixture (10:1) of THF-DMF
(50 mL) at 23 °C was added the urethane 12 (475 mg, 1.2
mmol) in THF (2 mL). The mixture was stirred at 23 °C for
1 h. After this period, benzyl bromide (1.25 g, 7.3 mmol)
followed by tetrabutylammonium iodide (25 mg) were added,
and the resulting reaction mixture was stirred for an ad-
ditional 10 h at 23 °C. The reaction was quenched with
saturated aqueous NH4Cl, and the mixture was concentrated
under reduced pressure to a small volume. The residue was
extracted with ethyl acetate (3 × 50 mL), and the combined
extracts were washed with brine and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by purification
of the residue by silica gel chromatography (10% EtOAc/
hexanes) provided the N-benzyl derivative 13 (510 mg, 87%)
23
product 10 (855 mg, 78% yield) as an oil. [R]D +118 (c 0.6,
CHCl3); 1H-NMR (CDCl3, 400 MHz) δ; 1.30 (s, 3 H), 1.47 (s, 3
H), 1.75 (m, 1 H), 2.05 (m, 1 H), 2.25 (m, 1 H), 2.41 (m, 1 H),
3.38 (s, 5 H), 4.12 (m, 1 H), 4.23 (dd, 1 H, J ) 10.9, 4.5 Hz),
4.58 (dd, 2 H, J ) 12.1, 6.0 Hz), 4.95 (m, 3 H), 5.27 (m, 1 H),
5.68 (m, 1 H), 5.95 (d, 1 H, J ) 6.9 Hz), 7.20-7.38 (m, 3 H),
7.54 (d, 1 H, J ) 7.6 Hz); 13C-NMR (CDCl3, 100 MHz) δ; 24.82,
26.39, 35.63, 37.10, 37.79, 38.92, 55.53, 63.04, 77.96, 84.32,
84.44, 85.37, 109.94, 112.09, 117.67, 125.06, 127.01, 127.98,
129.68, 134.22, 139.16, 139.37, 152.50, 175.29. IR (neat) 2979,
2935, 1779, 1695, 1360, 1189, 1088, 758 cm-1; MS (CI) m/ z
444 (M+ + H), 412 (M+ - OMe), 354, 325, 269. Anal. Calcd
for C24H29NO7: C, 65.00; H, 6.59; N, 3.16. Found: C, 64.81;
H, 6.63; N, 3.30.
23
as an oil. [R]D +27.0 (c 1.0, CHCl3); 1H-NMR (major, CDCl3,
400 MHz) δ; 1.29 (s, 3 H), 1.47 (s, 3 H), 1.70 (m, 1 H), 2.01 (m,
1 H), 2.36 (m, 2 H), 3.32 (s, 3 H), 3.86 (br s, 1 H), 4.27 (m, 2
H), 4.50 (m, 2 H), 4.69 (d, 1 H, J ) 15.8 Hz), 4.90 (m, 3 H),
5.15 (d, 1 H, J ) 5.0 Hz), 5.21 (s, 1 H), 5.49 (m, 1 H), 7.18-7.45
(m, 10 H); 13C-NMR (CDCl3, 100 MHz) δ; 24.81, 26.36, 36.75,
37.88, 38.67, 55.26, 56.02, 66.89, 67.40, 83.90, 84.25, 85.44,
109.92, 112.06, 117.08, 127.17, 127.79, 128.02, 128.14, 128.32,
135.15, 136.56, 138.48, 155.50; IR (neat) 2985, 2933, 1697,
1454, 1371, 1230, 1089, 1010, 869, 750, 699 cm-1; MS (CI) m/ z
482 (M+ + H), 450 (M+ - OMe), 440, 408. Anal. Calcd for
C28H35NO6: C, 69.83; H, 7.33; N, 2.91. Found: C, 70.06; H,
7.29; N, 2.94.
Eth yl [Meth yl 9-(N-acetylam in o-6(S)-[N-(ph en ylm eth yl)-
N-[(ph en ylm eth oxy)car bon yl]am in o]-5,6,7,8,9-pen tadeoxy-
2,3-O-(1-m eth yleth ylid en e)-â-D-r ibo-d ec-8-en ofu r a n osid ]-
u r on a te 16 a n d 17. To a stirred solution of 13 (445 mg, 0.9
mmol) in a mixture of methanol (100 mL) and CH2Cl2 (100
mL) at -78 °C was bubbled through a stream of ozonized
oxygen until the blue color persisted (10 min). After the
solution was flushed with nitrogen for 5 min, dimethyl sulfide
(1.5 mL) was added to the reaction mixture at -78 °C. The
dry ice bath was removed and the reaction mixture was
allowed to warm to 23 °C. Evaporation of the solvent under
reduced pressure gave the crude aldehyde which was used
directly without further purification. In a separate flask,
potassium tert-butoxide (330 mg, 2.8 mmol) was suspended
in dry CH2Cl2 (5 mL) at -78 °C, and to it was added a solution
of N-acyl-R-(diethylphosphonyl)glycine ethyl ester (780 mg, 2.8
mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred
for 1 h at -78 °C, and then the crude aldehyde in CH2Cl2 (15
mL) was added dropwise for 5 min. The reaction mixture was
continued to stir at -78 °C for an additional 20 min, the cooling
bath was removed and the reaction was allowed to warm to
23 °C and stirred for another 4 h. After this period, the
reaction was quenched with saturated aqueous NH4Cl solution,
and the two layers were separated. The aqueous layer was
Meth yl 5,6-Did eoxy-2,3-O-(1-m eth yleth ylid en e)-6(S)-
a llyl-â-D-r ibo-h ep tofu r a n osid u r on ic Acid 11. To a stirred
solution of 10 (775 mg, 1.75 mmol) in a mixture of THF (30
mL) and water (10 mL) at 0 °C was added solid LiOH‚H2O
(145 mg, 3.5 mmol) followed by hydrogen peroxide (30%, 0.7
mL). The resulting mixture was stirred for 1 h at 0 °C and
then 3 h at 23 °C. After this period, the reaction was quenched
with 1.5 M aqueous Na2SO3 solution (1.5 mL) followed by
saturated aqueous NaHCO3 solution (10 mL). The mixture
was concentrated under reduced pressure. The remaining
residue was diluted with water (25 mL) and then extracted
with dichloromethane (2 × 25 mL) to remove the chiral
auxiliary. The aqueous phase was carefully acidified with 1
N HCl to pH 1 and extracted with ethyl acetate (3 × 50 mL).
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and evaporated. The resulting
residue was purified by silica gel chromatography (25% EtOAc/
hexanes) to afford the title acid 11 (498 mg, 98%) as an oil.
[R]D23 -19.5° (c 1.0, CHCl3); 1H-NMR (CDCl3, 400 MHz) δ; 1.30
(s, 3 H), 1.47 (s, 3 H), 1.73 (m, 1 H), 1.85 (m, 1 H), 2.30 (m, 1
H), 2.43 (m, 1 H), 2.75 (m, 1 H), 3.35 (s, 3 H), 4.28 (dd, 1 H, J
) 11.2, 4.1 Hz), 4.53 (d, 1 H, J ) 5.9 Hz), 4.61 (d, 1 H, J ) 5.9
Hz), 4.95 (s, 1 H), 5.60 (m, 2 H), 5.75 (m, 1 H); 13C-NMR
(CDCl3, 100 MHz) δ; 24.83, 26.33, 36.23, 36.68, 41.63, 55.28,
84.30, 84.73, 85.37, 109.97, 112.25, 117.55, 134.42, 180.42; IR
(neat) 3150, 3077, 2982, 2937, 1737, 1708, 1441, 1374, 1193,
1093, 1060, 963, 869 cm-1; MS (CI) m/ z 287 (M+ + H), 271
(M+ - Me), 269 (M+ - OH), 255 (M+ - OMe), 229, 214, 197,
157 Anal. Calcd for C14H22O6: C, 58.73; H, 7.74. Found: C,
58.56; H, 7.82.
6(S)-Allyl-N-[(p h en ylm et h oxy)ca r b on yl][m et h yl 5,6-
d id eoxy-2,3-O-(1-m eth yleth ylid en e)-â-D-r ibo-h ep tofu r a -
n osid ]u r a m in e 12. To a stirred solution of acid 11 (440 mg,
1.55 mmol) in dry toluene (50 mL) were added diphenyl
phosphorazidate (0.4 mL, 1.85 mmol) and triethylamine (0.25
mL, 1.85 mmol). The resulting mixture was heated at reflux

Total Synthesis of (+)-Sinefungin
J . Org. Chem., Vol. 61, No. 18, 1996 6181
extracted with CH2Cl2 (2 × 25 mL). The combined organic
layers were washed with brine and dried over anhydrous Na2-
SO4. Evaporation of the solvent under reduced pressure gave
a residue which was chromatographed over silical gel (50%
ethy acetate/hexane) to furnish the mixture (1:5) of olefins 16
and 17 (418 mg, 74% from compound 13) as an oil. 1H-NMR
(major isomer CDCl3, 400 MHz) δ; 1.25 (t, 3 H, J ) 7.0 Hz),
1.30 (s, 3 H), 1.46 (s, 3 H), 1.67 (t, 1 H, J ) 11.2 Hz), 1.90 (m,
1 H), 2.01 (s, 3 H), 2.27 (m, 1 H), 2.62 (m, 1 H), 3.33 (s, 3 H),
3.85 (br s, 1 H), 4.11 (q, 2 H, J ) 7.0 Hz), 4.20 (m, 2 H), 4.45
(d, 2 H, J ) 5.8 Hz), 4.97 (s, 1 H), 5.19 (m, 2 H), 5.85 (br s, 1
H), 6.33 (br s, 1 H), 7.10-7.40 (m, 10 H); IR (neat) 3310, 2983,
2937, 1694, 1498, 1454, 1372, 1232, 1092, 1027, 869, 753, 702
cm-1; MS (CI) m/ z 611 (M+ + H), 579 (M+ - OMe), 537, 533,
440. Anal. Calcd for C33H42N2O9: C, 64.90; H, 6.93; N, 4.59.
Found: C, 64.71; H, 6.78; N, 4.62.
E t h yl [Met h yl 9-(N-a cet yla m in o)-6(S)-[N-[(p h en yl-
m eth oxy)ca r bon yl]a m in o]-5,6,7,8,9-p en ta d eoxy-2,3-O-(1-
m et h ylet h ylid en e)-â-D-r ibo-d ec-8-en ofu r a n osid ]u r on -
a te 14 a n d 15. Following the procedure described above for
16 and 17, urethane 12 (228 mg, 0.58 mmol) was converted to
a mixture (1:6) of eneamides 14 and 15 (230 mg, 76% yield).
1H-NMR (major isomer, CDCl3, 400 MHz) δ; 1.25 (t, 3 H, J )
7.1 Hz), 1.30 (s, 3 H), 1.45 (s, 3 H), 1.75 (m, 2 H), 2.05 (s, 3 H),
2.40 (m, 2 H), 3.31 (s, 3 H), 3.90 (m, 1 H), 4.20 (q, 2 H, J ) 7.1
Hz), 4.30 (m, 1 H), 4.57 (dd, 2 H, J ) 6.0, 13.9 Hz), 4.94 (s, 1
H), 5.08 (s, 2 H), 5.77 (d, 1 H, J ) 8.4 Hz), 6.55 (t, 1 H, J ) 4.8
Hz), 7.2-7.4 (m, 5 H); IR (neat) 3384, 2983, 2298, 1244, 851,
755 cm-1; MS (CI) m/ z 521 (M+ + H), 489 (M+ - OMe), 447,
443, 350.
1 H, J ) 7.8 Hz), 7.23-7.35 (m, 5 H); 13C-NMR (CDCl3, 100
MHz) δ; 14.05, 22.98, 24.83, 26.36, 28.89, 31.12, 39.80, 48.48,
51.90, 55.27, 61.42, 66.56, 83.66, 84.40, 85.27, 110.00, 112.28,
127.95, 127.99, 128.40, 136.42, 155.92, 169.90, 172.26; IR
(neat) 3300-3400, 2940, 2241, 1733, 1708, 1651, 1537, 1454,
1372, 1256, 1092, 1026, 877 cm-1; MS (CI) c/ z 523 (M+ + H),
492, 447, 355.
Eth yl 9(S)-(N-Acetyla m in o)-6(S)-[N-(p h en ylm eth yl)-N-
[(p h en ylm eth oxy)ca r bon yl]a m in o]-5,6,7,8,9-p en ta d eoxy-
1,2,3-tr i-O-a cetyl-â-D-r ibo-d ecofu r a n osid ]u r on a te a n d Its
C-1 Ep im er 21. To a stirred solution of 18 (208 mg, 0.34
mmol) in dioxane (24 mL) at 23 °C, aqueous 4 N HCl (8 mL)
was added. The resulting mixture was stirred at 23 °C for 12
h. After this period, the reaction mixture was cooled to 0 °C,
and the reaction was quenched with saturated aqueous
NaHCO3. The mixture was concentrated under reduced
pressure, and the remaining residue was extracted with ethyl
acetate (3 × 100 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and evaporated under reduced
pressure to provide the corresponding triol. The above triol,
without further purification was dissolved in dry pyridine (8
mL) and cooled to 0 °C, and acetic anhydride (692 mg, 6.8
mmol) was added. The resulting reaction mixture was stirred
at 0 °C to 23 °C for 10 h. After this period, the reaction
mixture was concentrated under reduced pressure, and satu-
rated aqueous NaHCO3 solution was added. The mixture was
extracted with ethyl acetate (2 × 50 mL). The combined
extracts were dried over anhydrous Na2SO4 and evaporated.
The resulting residue was purified by silica gel chromatogra-
phy (75% EtOAc/hexanes) to provide the mixture (3:2) of
anomeric acetates 21 (164 mg, 70% from compound 18) as an
Eth yl [Meth yl 9(S)-(N-a cetyla m in o)-6(S)-[N-(p h en yl-
m et h yl)-N-[(p h en ylm et h oxy)ca r b on yl]a m in o]-5,6,7,8,9-
p en t a d eoxy-2,3-O-(1-m et h ylet h ylid en e)-â-D-r ibo-d eco-
fu r an osid]u r on ate 18. In a hydrogenation bottle, the mixture
(1:5) of enamide 16 and 17 (305 mg, 0.5 mmol) was dissolved
in methanol (10 mL) and the catalyst [Rh(COD)(R,R-DI-
23
oil. [R]D +29.0 (c 1.1, CHCl3); 1H-NMR (DMSO-d6, 70 °C,
400 MHz) δ; 1.15 (t, 3 H, J ) 7.1 Hz), 1.40-1.70 (m, 6 H),
1.84 (s, 3 H), 1.95 (s, 1.5 H), 1.99 (s, 3 H), 2.00 (s, 3 H), 2.05 (s,
1.5 H), 3.95 (m, 2 H), 4.06 (q, 2 H, J ) 7.1 Hz), 4.13 (m, 1 H),
4.25 (dd, 1 H, J ) 15.6, 10.0 Hz), 4.47 (d, 1 H, J ) 15.7 Hz),
4.83 (t, 1 H, J ) 5.8 Hz, major), 4.90 (t, 1 H, J ) 5.4 Hz, minor),
5.11 (s, 2 H), 5.20 (m, 1 H), 5.95 (s, 1 H, â-anomer), 6.23 (d, 1
H, J ) 4.7 Hz, R-anomer), 7.18-7.38 (m, 10 H), 7.82 (br s, 1
H); IR (neat) 3323, 2957, 2203, 1739, 1689, 1372, 1223, 1011,
-
PAMP)]+BF4 (15 mg) was added to it. The bottle was then
thoroughly flushed with nitrogen and charged with hydrogen
to a pressure of 50 psig. The mixture was shaken on a Parr
apparatus for 10 h under 50 psig at 23 °C. After this period,
the solvent was removed by rotary evaporation and the residue
was passed through a short silica gel column (50% ethyl
acetate/hexane) to give the title hydrogenation product 18 (290
763, 701 cm-1
.
MS (CI) m/ z 685 (M+ + H), 653, 626, 625,
565. Anal. Calcd for C35H44N2O12: C, 61.39; H, 6.48; N, 4.09.
Found: C, 60.95; H, 6.51; N, 4.34.
23
mg, 95%) as an oil. [R]D +24.3 (c 0.7, CHCl3); 1H-NMR
E t h yl [Met h yl 9(R)-(N-a cet yla m in o)-6(S)-[(p h en yl-
m eth oxy)ca r bon yl]a m in o]-5,6,7,8,9-p en ta d eoxy-2,3-O-(1-
m eth yleth ylid en e)-â-D-r ibo-d ecofu r a n osid ]u r on a te 22. In
a hydrogenation bottle, the mixture (1:6) of enamide 14 and
15 (30 mg, 0.058 mmol) was dissolved in methanol (5 mL),
and the catalyst (S,S)-CHIRAPHOS (10 mg) was added to it.
The bottle was then thoroughly flushed with nitrogen and then
charged with hydrogen to a pressure of 50 psig. The mixture
was shaken on a Parr apparatus for 10 h under 50 psig at 23
°C. After this period, the solvent was removed by rotary
evaporation, and the residue was passed through a short silica
gel column (75% ethyl acetate/hexane) to give the title
hydrogenation product 22 (29 mg, 96%) as an oil. [R]D23 -16.0
(c 0.3, CHCl3); 1H-NMR (CDCl3, 400 MHz) δ; 1.26 (t, 3 H, J )
7.2 Hz), 1.30 (s, 3 H), 1.47 (s, 3 H), 1.5-2.0 (m, 6 H), 2.04 (s,
3 H), 3.32 (s, 3 H), 3.90 (m, 1 H), 4.18 (q, 2 H, J ) 7.1 Hz),
4.29 (dd, 1 H, J ) 3.3, 11.2 Hz), 4.51 (d, 1 H, J ) 5.9 Hz), 4.95
(d, 1 H, J ) 7.6 Hz), 7.36 (m, 5 H); 13C-NMR (CDCl3, 100 MHz)
δ; 14.06, 23.05, 24.84, 26.37, 28.59, 31.46, 40.04, 48.60, 52.40,
55.27, 61.44, 66.69, 83.64, 84.40, 85.28, 110.34, 112.35, 127.96,
128.01, 128.42, 136.37, 156.17, 170.06, 172.17; MS (CI) c/ z 523
(M+ + H), 491, 449, 352.
6(S)-Allyl-N-(p h en ylm et h yl)-N-[(p h en ylm et h oxy)ca r -
bon yl][m eth yl 5,6-d id eoxy-1,2,3-tr i-O-a cetyl-â-D-r ibo-h ep -
tofu r a n osid ]u r a m in e 24 a n d Its C-1 Ep im er . Following
the procedure described above for 21, N-benzyl urethane 13
(214 mg, 0.44 mmol) was converted to a mixture (1:1) of
anomeric acetates 24 (288.5 mg, 93% yield). 1H-NMR (CDCl3,
400 MHz) δ; 1.64 (m, 1 H), 2.03 (s, 3 H), 2.09 (s, 3 H), 2.10 (s,
3 H), 2.20 (m, 2 H), 2.36 (m, 1 H), 3.80-4.20 (series of m, 3
H), 4.65 (m, 1 H), 4.77-5.07 (m, 3 H), 5.17 (s, 2 H), 5.26 (m, 1
H), 5.50 (m, 1 H), 6.08 (d, 1 H, J ) 5.9 Hz, â-anomer), 6.32 (d,
1 H, J ) 4.5 Hz, R-anomer), 7.15-7.40 (m, 10 H).
(DMSO-d6, 70 °C, 400 MHz) δ; 1.15 (t, 3 H, J ) 7.1 Hz), 1.21
(s, 3 H), 1.33 (s, 3 H), 1.35-1.66 (m, 6 H), 1.82 (s, 3 H), 3.20
(s, 3 H), 3.90 (m, 2 H), 4.03 (q, 2 H, J ) 7.1 Hz), 4.15 (m, 1 H),
4.35 (s, 1 H), 4.41 (AB q, 2 H, ∆νAB ) 81 Hz, J AB ) 15.7 Hz),
4.45 (d, 1 H J ) 5.9 Hz), 4.81 (s, 1 H), 5.13 (s, 2 H), 7.20-7.39
(m,10 H), 7.85 (d, 1 H, J ) 7.3 Hz); IR (neat) 3300-3600, 2937,
2242, 1738, 1686, 1540, 1454, 1209, 1093, 1026, 870, 752, 700
cm-1; MS (CI) m/ z 613 (M+ + H), 582 (M+ + H - OMe), 581
(M+ - OMe), 537, 445 Anal. Calcd for C33H44N2O9: C, 64.71;
H, 7.19; N, 4.58. Found: C, 64.22; H, 7.34; N, 4.42.
Eth yl [Meth yl 9(S)-(N-acetylam in o)-6(S)-[(ph en ylm eth -
oxy)ca r bon yl]a m in o]-5,6,7,8,9-p en ta d eoxy-2,3-O-(1-m eth -
ylet h ylid en e)-â-D-r ibo-d ecofu r a n osid ]u r on a t e 19. To a
stirred solution of 18 (20 mg, 0.033 mmol) in methanol (2 mL)
was suspended 20 wt % Pd(OH)2/C (5 mg) at 23 °C. The
resulting mixture was hydrogenated under hydrogen-filled
balloon for 12 h. The reaction mixture was then filtered
through a pad of Celite, and the Celite pad was washed with
methanol (10 mL). Evaporation of the solvent provided the
crude amine. Without further purification, the amine was
dissolved in CHCl3 (3 mL) and benzyl chloroformate (17 mg,
1 mmol) followed by the addition of triethylamine (10 mg, 1
mmol) and DMAP (4 mg, 0.033 mmol). The resulting mixture
was stirred at 23 °C for 12 h. After this period, the solution
was concentrated, and the residue was chromatographed over
silica gel (75%ethyl acetate/hexane) to give 19 (5 mg, 29% from
23
1
18) as an oil. [R]D +16.3 (c 0.84, CHCl3); H-NMR (CDCl3,
400 MHz) δ; 1.25 (t, J ) 7.1 Hz, 3 H), 1.28 (s, 3 H), 1.45 (s, 3
H), 1.53 (m, 3 H), 1.70 (m, 2 H), 1.83 (m, 1 H), 1.97 (s, 3 H),
3.31 (s, 3 H), 3.79 (m, 1 H), 4.15 (q, 2 H, J ) 7.0 Hz), 4.28 (dd,
1 H, J ) 11.0, 3.4 Hz), 4.50 (d, J ) 5.9 Hz, 1 H), 4.55 (m, 2 H),
4.94 (s, 1 H), 5.03 (d, 1 H, J ) 9.2 Hz), 5.08 (s, 2 H), 6.30 (d,

6182 J . Org. Chem., Vol. 61, No. 18, 1996
Ghosh and Liu
6(S)-Allyl-1-[6-N-ben zoyl-9H-pu r in -9-yl]-2,3-di-O-acetyl-
N-(ph en ylm eth yl)-N-[(ph en ylm eth oxy)car bon yl]-â-D-r ibo-
h ep tofu r a n osid ]u r a m in e 26. To a stirred suspension of N6-
benzoyladenine (17.9 mg, 0.075 mmol) in 1,1,1,3,3,3-hexa-
methyldisilazane (1.5 mL) at 23 °C was added trimethylchloro-
silane (0.3 mL), and the resulting mixture was heated at reflux
for 5 h. The reaction mixture was cooled to 23 °C, and the
solvent was removed under reduced pressure to provide the
crude silylated N6-benzoyladenine 25. Dry 1,2-dichloroethane
(2 mL) followed by the mixture of anomeric acetates 24 (32
mg, 0.057 mmol) dissolved in 1,2-dichloroethane (2 mL) was
added to the silylated N6-benzoyladenine 25 at 23 °C. The
resulting mixture was then treated with TMSOTf (16.7 mg,
0.075 mmol) in 1,2-dichloroethane (0.2 mL). The reaction
mixture was stirred at 23 °C for 3 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 (1 mL), and
the resulting mixture was extracted with ethyl acetate (3 ×
10 mL). The combined extracts were dried over anhydrous
Na2SO4 and evaporated. The resulting residue was chromato-
graphed over silica gel (2% MeOH/CHCl3) to furnish the
nucleoside derivative 26 (42 mg, 98%) as an oil. 1H-NMR
(CDCl3, 300 MHz) δ; 1.80 (m, 1 H), 2.04 (s, 6 H), 2.16-2.45
(m, 3 H), 4.00 (m, 2 H), 4.35 (m, 1 H), 4.55 (m, 1 H), 4.95 (m,
3 H), 5.19 (s, 2 H), 5.30 (s, 1 H), 5.55 (br m, 1 H), 5.91 (s, 1 H),
7.12-7.40 (m, 10 H), 7.52 (t, J ) 7.7 Hz, 2 H), 7.60 (t, J ) 7.7
Hz, 1 H), 8.00 (d, J ) 7.7 Hz, 2 H), 8.77 (s, 1 H), 9.09 (s, 1 H).
N-[5,6-Did eoxy-1,2,3-tr i-O-a cetyl-â-D-r ibo-h ep tofu r a n -
u r on yl]-(4S,5R)-in d a n o[1,2-d ]oxa zolid in -2-on e 27 a n d Its
C-1 Ep im er . Following the procedure described above for 21,
oxazolidinone 9 (181 mg, 0.45 mmol) was converted to a
mixture (3:1) of anomeric acetates 27 (148 mg, 69% yield). 1H-
NMR (major anomer, CDCl3, 400 MHz) δ; 1.90-2.20 (m, 2 H),
2.05 (s, 3 H), 2.10 (s, 3 H), 2.13 (s, 3 H), 3.05 (m, 2 H), 3.39 (m,
2 H), 4.31 (m, 1 H), 5.20 (dd, 1 H, J ) 4.8, 7.4 Hz), 5.30 (m, 1
H), 5.92 (d, 1 H, J ) 6.9 Hz), 6.11 (s, 1 H), 7.20-7.35 (m, 3 H),
7.60 (d, 1 H, J ) 7.4 Hz); IR (neat) 3422, 1769, 1747, 1693,
1649, 1366, 1220, 1010, 757 cm-1; MS (CI) m/ z 476 (M+ + H),
416, 356.
the solvent was removed under reduced pressure to provide
the crude silylated N6-benzoyladenine 25. Dry 1,2-dichloro-
ethane (4 mL) followed by a mixture of anomeric acetates 21
(40 mg, 0.058 mmol) dissolved in 1,2-dichloroethane (8 mL)
was added to the silylated N6-benzoyladenine 25 at 23 °C. The
resulting mixture was then treated with TMSOTf (0.044 mL,
0.24 mmol) in 1,2-dichloroethane (0.4 mL). The reaction
mixture was heated at 45 °C for 2 h. After this period, the
mixture was cooled to 23 °C and the reaction was quenched
with saturated aqueous NaHCO3 (4 mL), and the resulting
mixture was extracted with ethyl acetate (3 × 50 mL). The
combined extracts were dried over anhydrous Na2SO4 and
evaporated. The resulting residue was chromatographed over
silica gel (2% MeOH/CHCl3) to furnish the nucleoside deriva-
tive 29 (46 mg, 93%) as an oil. [R]D +4.9 (c 0.6, CHCl3); H
NMR (DMSO-d6, 70 °C, 400 MHz) δ; 1.12 (t, 3 H, J ) 7.1 Hz),
1.20-1.70 (series of m, 6 H), 1.82 (s, 3 H), 2.00 (s, 3 H), 2.05
(s, 3 H), 3.90 (m, 2 H), 4.01 (q, 2 H, J ) 7.1 Hz), 4.12 (m, 1 H),
4.40 (AB q, 2 H, ∆ν ) 60 Hz, J ) 15.6 Hz), 5.10 (d, 2 H, J )
7.0 Hz), 5.20 (t, 1 H, J ) 5.0 Hz), 6.00 (t, 1 H, J ) 5.5 Hz),
6.12 (d, 1 H, J ) 5.5 Hz), 7.18-7.38 (m, 10 H), 7.55 (t, 2 H, J
) 7.5 Hz), 7.65 (d, 1 H, J ) 7.4 Hz), 7.80 (m, 1 H), 8.04 (d, 2
H, J ) 7.4 Hz), 8.60 (s, 1 H), 8.71 (s, 1 H); 13C-NMR (CDCl3,
100 MHz) δ; 14.04, 20.33, 20.51, 23.09, 29.59, 51.57, 61.41,
67.49, 72.92, 73.26, 79.07, 86.79, 124.92, 127.32, 127.82,
127.89, 128.39, 128.80, 132.82, 136.33, 142.14, 149.60, 151.45,
152.49, 169.28, 169.42, 169.80, 172.06; IR (neat) 3301, 2928,
1745, 1693, 1454, 1245, 1096, 752, 701 cm-1; MS (CI) m/ z 864
(M+ + H), 625 (M+ - N6-benzoyladenine), 565, 523. Anal.
Calcd for C45H49N7O11: C, 62.56; H, 5.72; N, 11.35. Found:
C, 62.25; H, 5.78; N, 11.23.
23
1
(+)-Sin efu n gin (1). To a stirred solution of the nucleoside
29 (23.2 mg, 0.027 mmol) in methanol (10 mL) was added solid
potassium carbonate (18.6 mg, 0.135 mmol). The resulting
mixture was stirred at 23 °C for 8 h. After this period, the
reaction mixture was concentrated under reduced pressure.
The resulting residue was dissolved in water (10 mL), and
hydrazine (4.3 mg, 0.13 mmol) was added. The reaction
mixture was then stirred at 23 °C for 2 h, and the water was
removed under reduced pressure. The residue was diluted
with water (1 mL) and neutralized with 1 N aqueous HCl to
pH 7 to provide 30.29 The resulting mixture was concentrated
under reduced pressure, the residue was dissolved in MeOH
(10 mL), and 20% Pd(OH)2/C (30 mg) was added to the
solution. The resulting mixture was hydrogenated under a
balloon filled with hydrogen for 48 h. The reaction mixture
was then filtered through a pad of Celite, and the Celite pad
was washed with MeOH (30 mL). The filtrate was concen-
trated under reduced pressure to leave a residue which was
chromatographed over silica gel using a mixture of methanol,
chloroform, and ammonium hydroxide (MeOH:CHCl3:NH4OH
) 3:5:1) as the eluent to provide the synthetic sinefungin (7.4
N-[1-[9-Ad en yl]-2,3-d i-O-a cet yl-5,6-d id eoxy-â-D-r ibo-
h ep t ofu r a n u r on yl]-(4S,5R)-in d a n o[1,2-d ]oxa zolid in -2-
on e 28. To a stirred solution of 27 (74.2 mg, 0.156 mmol) in
dry acetonitrile (3 mL) at 23 °C under nitrogen were added
adenine (21.1 mg, 0.156 mmol) and SnCl4 (0.16 mL, 1.0 M
solution in CH2Cl2, Aldrich). The resulting mixture was
stirred at 25 °C for 3 h. After this period, CHCl3 (20 mL)
followed by aqueous NaHCO3 solution (5 mL) were added. The
layers were separated, and the aqueous layer was extracted
with CHCl3 (2 × 10 mL). The combined extracts were dried
over anhydrous Na2SO4 and evaporated. The resulting residue
was chromatographed over silica gel (5% MeOH/CHCl3) to
furnish the nucleoside derivative 28 (49.8 mg, 58%) as an oil.
23
1
[R]D +107.9 (c 1.05, CHCl3); H-NMR (CDCl3, 300 MHz) δ;
2.05 (s, 3 H), 2.11 (s, 3 H), 2.25 (dd, 2 H, J ) 7, 14 Hz), 3.08
(m, 2 H), 3.37 (s, 2 H), 4.32 (dd, 1 H, J ) 6.1, 12.3 Hz), 5.70
(m, 1 H), 5.52 (t, 1 H, J ) 5.4 Hz), 5.90 (t, 2 H, J ) 5.4 Hz),
5.95 (s, 2 H), 6.06 (d, 1 H, J ) 5.0 Hz), 7.18-7.34 (m, 3 H),
7.56 (d, 1 H, J ) 7.7 Hz), 7.95 (s, 1 H), 8.30 (s, 1 H); 13C-NMR
(CDCl3, 100 MHz) δ; 20.36, 20.49, 27.30, 31.27, 37.89, 62.93,
73.05, 73.29, 77.15, 78.14, 81.03, 86.31, 120.05, 125.11, 127.11,-
128.07, 129.82, 138.81, 139.21, 139.34, 149.56, 152.87, 155.26,
169.39, 169.62, 172.47; IR (neat) 3404, 1757, 1632, 1364, 1240,
753 cm-1; MS (CI) m/ z: 551 (M+ + H), 416, 357.
23
23
mg, 72% from 29); [R]D +13.4 (c, 0.12 H2O); lit.9a RD +12.4
( 0.2°; c, 0.227, H2O).
Ack n ow led gm en t. Financial support for this work
was provided by the University of Illinois at Chicago
and Merck Research Laboratories. The authors thank
Professor Henry Rapoport for providing 1H NMR spectra
of natural and synthetic sinefungin and Dr. Scott
Laneman of NSC Technologies for a generous gift of
R,R-DIPAMP-Rh catalyst. We also thank Dr. Kurt
Ritter of BASF, Germany, for a gift of optically active
cis-1-amino-2-indanol used as chiral auxiliary in the
synthesis. W.L. thanks the University of Illinois at
Chicago for a University Fellowship.
Eth yl 2,3-Di-O-a cetyl-1,5,6,7,8,9-h exa d eoxy-1-[6-N-ben -
zoyl-9H-p u r in -9-yl]-9(S)-(N-a cetyla m in o)-6(S)-[N-(p h en -
ylm eth yl)-N-[(p h en ylm eth oxy)ca r bon yl]a m in o]-â-D-r ibo-
d ecofu r a n u r on a t e 29. To a stirred suspension of N6-
benzoyladenine (56 mg, 0.24 mmol) in 1,1,1,3,3,3-hexa-
methyldisilazane (4 mL) at 23 °C, was added trimethylchlo-
rosilane (0.4 mL) and the resulting mixture was heated at
reflux for 5 h. The reaction mixture was cooled to 23 °C, and
J O960670G