Total synthesis of N-malayamycin A and related bicyclic purine and pyrimidine nucleosides

Article abstract of DOI:10.1021/jo050727b

Methods are described for the total synthesis of bicyclic perhydrofuropyran nucleosides as N-analogues of the naturally occurring malayamycin A. Formation of the N-nucleosides relied on the activation of thioglycosides, proceeding via sulfonium intermedia

Full text of DOI:10.1021/jo050727b

Total Synthesis of N-Malayamycin A and Related Bicyclic Purine
and Pyrimidine Nucleosides
Stephen Hanessian,* Guobin Huang, Caroline Chenel, Roger Machaalani, and
Olivier Loiseleur†
Department of Chemistry, Universite´ de Montre´al, C. P. 6128, Succ. Centre-Ville, Montre´al,
P. Q., Canada H3C 3J7, and Syngenta Crop Protection AG, WRO 1060.5.04, Schwarzwaldaller,
CH-4002 Basel, Switzerland
stephen.hanessian@umontreal.ca
Received April 12, 2005
Methods are described for the total synthesis of bicyclic perhydrofuropyran nucleosides as
N-analogues of the naturally occurring malayamycin A. Formation of the N-nucleosides relied on
the activation of thioglycosides, proceeding via sulfonium intermediates. Ring closure metathesis
was used in two approaches to build the bicyclic dioxa heterocycle. Another approach relied on the
use of a sugar precursor and cyclization to the bicyclic thioglycoside.
Introduction
and octosyl acid A, 2,6 are examples of bicyclic uracilyl
nucleosides with reported antifungal activity (Figure 1).
Quantamycin 37 is an example of a “man-made” hybrid
analogue of lincomycin, which was designed to mimic the
natural f-Met t-RNA starter unit during ribosomal pro-
tein synthesis. Ezomycin B2, 4,8 is the C-nucleoside
counterpart of ezomycin A2. The most recent entry in the
small arsenal of bicyclic C-nucleosides is malayamycin
A, 5, a potent fungicide which was isolated from the soil
organism Streptomyces malaysiensis by a group at the
Syngenta Crop Protection Laboratories in Jealott’s Hill
U.K.9 The structure and absolute configuration of ma-
layamycin A was recently confirmed by total synthesis.10
The phenomenal advances in the chemistry and biology
of purine and pyrimidine ribonucleosides over the past
few decades have unraveled many of life’s mysteries,
culminating with the deciphering of the genetic code.
Nature has also been a generous provider of a rich source
of non-DNA/RNA related nucleosides, possessing fasci-
nating structures and impressive chemotherapeutic ef-
fects.1 Indeed, some of the most potent anticancer and
antiviral agents of clinical importance are nucleosides.2
Extensive efforts have been made over the years toward
the development of synthetic or semisynthetic analogues
to broaden the biological profile and potential toxic effects
of certain naturally occurring nucleosides.3
(4) Hanessian, S.; Dixit, D.-M.; Liak, T.-J. Pure Appl. Chem. 1981,
53, 129.
(5) (a) Sakata, K.; Bakurai, A.; Tamura, S. Agric. Biol. Chem. 1973,
37, 697. (b) Sakata, K.; Sakurai, A.; Tamura, S. Agric. Biol. Chem.
1975, 39, 885; 3141.
(6) For the total synthesis of octosyl acid, see: (a) Danishefsky, S.;
Hungate, R. J. Am. Chem. Soc. 1986, 108, 2486. (b) Hanessian, S.;
Kloss, J.; Sugawara, T. J. Am. Chem. Soc. 1986, 108, 2758. For
isolation, see: (c) Isono, K.; Crain, P. F.; McCloskey, J. A. J. Am. Chem.
Soc. 1975, 97, 043.
(7) Hanessian, S.; Sato, K.; Liak, T. J.; Danh, N.; Dixit, D. M.;
Cheney, B. V. J. Am. Chem. Soc. 1984, 106, 6114.
(8) Sakata, K.; Sakurai, A. Tamura, S. Tetrahedron Lett. 1975, 3191.
(9) Benner, J. P.; Boehlendorf, B. G. H.; Kips, M. R.; Lambert, N.
E. P.; Luck, R.; Molleyres, L.-P.; Neff, S.; Schuez, T. C.; Stanley, P. D.
WO 03/062242, CAN 139:132519.
There are a handful of N- and C-nucleosides in which
the “sugar” part consists of a bicyclic perhydrofuropyran
rather than the commonly encountered monocyclic pento-
furanosyl and hexofuranosyl subunits.4 Ezomycin A2, 1,5
† Syngenta Crop Protection AG.
(1) For pertinent reviews, see (a) Ichikawa, S.; Kato, K. Curr. Med.
Chem. 2001, 8, 3895. (b) Knapp, S. Chem. Rev. 1995, 95, 1859. (c) Isono,
K. Pharm. Ther. 1991, 52, 264.
(2) (a) Walker, M. P.; Appleby, T. C.; Zhong, W.; Lau, j. Y. N.; Hong,
Z. Antiviral Chem. Chemother. 2003, 14, 1. (b) Mansour, T.; Storer, R.
Curr. Pharm. Design 1997, 3, 227.
(3) Gao, H.; Mitra, A. K. Synthesis 2000, 329.
10.1021/jo050727b CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/21/2005
J. Org. Chem. 2005, 70, 6721-6734
6721

Hanessian et al.
FIGURE 2. Disconnective analyses.
FIGURE 1. Structures of N- and C-bicyclic nucleosides.
we intended to synthesize the N-malayamycins with
1-uracilyl, 1-cytosinyl, 1-thyminyl, 9-adeninyl, and 9-hy-
poxanthinyl heterocyclic aglycones.
Although ezomycin B2 and malayamycin A share the
common “nucleoside” portion, there are notable differ-
ences in the nature and stereochemistries of the func-
tional groups present in the six-membered tetrahydro-
pyran subunit (Figure 1).
By analogy to the naturally occurring N- and C-
ezomycins, it was of interest to consider a total synthesis
of N-malayamycin A, 6, and related purine and pyrimi-
dine congeners. The availability of such analogues with
modified heterocyclic aglycones would also provide an
opportunity to test their biological activities, since the
corresponding C-malayamycins are presently not avail-
able. We therefore set out to develop methods for the
stereocontrolled construction of the bicyclic core,11 allow-
ing for flexibility of anomeric diversity. Toward that goal,
We chose two approaches that would converge to a
common precursor. In the first, ring closure metathesis12
of an appropriate diene prepared from D-ribose would
generate the unsaturated perhydrofuropyran, which
would undergo site-selective functionalization to install
the syn-disposed azido and alcohol groups (Figure 2A).
In an alternative disconnection we would build the azido
intermediate from D-xylose and elaborate the bicyclic
system via a glycosyl nitrile (Figure 2B). An anomeric
phenylthio group would then be used to introduce the
heterocyclic aglycones en route to the intended targets.
We have previously exploited the activation of thiogly-
cosides with thiophilic agents as a means to prepare
quantamycin and other bicyclic nucleosides.4,7,13 A major
challenge however, was to maintain the integrity of the
trans-fused and relatively strained bicyclic core during
the exchange of a thiophenyl group to a purine or
pyrimidine moiety.
(10) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G. Org.
Lett. 2003, 5, 4277.
(11) For the synthesis of related bicyclic fused compounds, see: (a)
Ravn, J.; Nielsen, P. J. Chem. Soc., Perkin Trans. 1 2001, 985. (b) Oh,
J.; Lee, C. R.; Chun, K. H. Tetrahedron Lett. 2001, 42, 4879. (c)
Leeuwenburgh, M. A.; Kulker, C.; Dugnster, H. I.; Overkleeft, H. S.;
van der Marel, G. A.; van Boom, J. Tetrahedron 1999, 55, 8253. (d)
Meur, R.; Gru¨schow, S.; Leumann, C. Helv. Chim. Acta 1999, 82, 1813.
(e) Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van
Boom, J. Synlett 1997, 1263. (f) Nicolaou, K. C.; Postema, H. D.;
Claiborne, C. I. J. Am. Chem. Soc. 1996, 118, 1565. (g) Clark, J. S.
Kettle, J. G.; Tetrahedron Lett. 1997, 38, 127. (h) Oishi, T.; Nagumo,
Y.; Hirama, M. Chem. Commun. 1998, 1041. (i) Delgado, M.; Martin,
J. D. Tetrahedron Lett. 1997, 38, 6299. (j) Peris, E.; Cave´, A.; Estornell,
E.; Zafra,-Polo, M. C.; Frigade`re, B.; Cortes, D.; Bermejo´, A. Tetrahe-
dron 2002, 58, 1335.
(12) For pertinent reviews, see: (a) Grubbs, R.; Chang, S. Tetrahe-
dron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans.
1998, 371. (c) Fu¨rstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, H. H.
Chem. Commun. 1998, 1315. (d) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. 1997, 36, 2036.
(13) For related methods, see: (a) Knapp, S.; Shieh, W.-C. Tetra-
hedron Lett. 1991, 32, 3627. (b) Knapp, S.; Shih, W.-C.; Jaramillo, C.;
Triller, R. V.; Nandau, S. R. J. Org. Chem. 1994, 59, 946.
6722 J. Org. Chem., Vol. 70, No. 17, 2005

Total Synthesis of N-Malayamycin A
SCHEME 1a
a Reagents and conditions: (a) IBX, MeCN, reflux, 2 h, 92%, or CrO3, pyridine, CH2Cl2, rt, 30min, 70%; (b) Ph3P+CH3Br-, n-BuLi,
THF, -78 °C, 3 h, 85%; (c) catalytic TsOH, MeOH, reflux, 24 h, 83%; (d) allyl bromide, Bu2SnO, Bu4N+I, 4Å MS, MeCN, reflux, 5 h 58%;
(e) BnBr, NaH, DMF, rt, overnight, 91%; (f) Cl2RuCHPh(PCy3)2 (5% mol), CH2Cl2 (c ) 0.01 M), reflux, 8 h, 68%; (g) NBS, THF/H2O (1:1),
rt, 2 h; (h) 1 N NaOH, THF, reflux, 1 h; (i) NaN3, 2-methoxyethanol, 126 °C, 53% in 3 steps; (j) Dess-Martin periodinane, CH2Cl2, rt, 2.5
h; (k) NaBH4, MeOH, 0 °C, 1 h; (l) MeI, NaH, DMF, rt, overnight, 81% in 3 steps.
Results
The readily available acetonide 714 was converted to
azide ion to give the regioisomeric 14a.10 Evidently,
epoxidation had occurred from the least hindered face of
the endocyclic double bond, possibly due to the proximal
O-benzyl ether. This preference has precedence21,22 and
can also be rationalized by considering the favorable
electron-donating ability of the C-H σ bond with the
developing antibonding orbital in the transition state
model C leading to the observed epoxide (Scheme 2).23
Approach of the peracid from the opposite side as
depicted in D would not benefit from the same stereo-
electronic effect. The transition state model in the ep-
oxidation of the tricyclic acetonide analogue E, in which
an impeding benzyl ether is absent, also takes place from
the same side as in 11 (Scheme 2, see below). Likewise,
treatment with NBS in aqueous THF gave the R-orien-
tated epibromonium ion, which underwent trans-diaxial
attack by hydroxide ion leading to the diaxial bromohy-
drin 12. Subsequent treatment with base generated the
correct regioisomeric epoxide 13 (Scheme 2B).
The stereocontrolled introduction of various purine and
pyrimidine heterocycles at the anomeric position en route
to N-malayamycin and analogues presented certain chal-
lenges. We had previously shown that related bicyclic
phenylthio glycosides could be converted to adenine
nucleosides simply by activation with bromine and ad-
dition of adenine in DMF.4,7 Activation of the phenylthio
group via a sulfonium intermediate followed by direct
attack of adenine or by participation of a 2′-benzoate had
the 5-vinyl derivative, 8, via oxidation to the aldehyde
and Wittig olefination (Scheme 1).15 Selective acetal
cleavage to 9 and treatment with dibutyltin oxide and
allyl bromide16 gave the desired regioisomer 9 (58%) and
the 2-O-allyl analogue 9a, which could be easily sepa-
rated by chromatography. Treatment of 9 with benzyl
bromide under usual alkylation conditions gave 10 in
quantitative yield. Reversing the order of alkylation by
first treatment with dibutyltin oxide and benzyl bromide
gave a 1:1 mixture of both regioisomers.
With the two olefin appendages in place, we proceeded
with the ring closure metathesis reaction using the
Grubbs first generation catalyst12,17 to give the bicyclic
intermediate 11 in 68% yield. Treatment of 11 with NBS
in aqueous THF followed by NaOH18 gave the epoxide
13. Subsequent opening with sodium azide in 2-meth-
oxyethanol afforded the desired regioisomeric azide 14
in good overall yield. Inversion of configuration was
achieved by oxidation with the Dess-Martin periodinane
reagent19 to 15. Reduction with NaBH4, and methylation
gave the fully functionalized perhydrofuropyran subunit
17.
Initially, we had explored a direct epoxidation route
to 13 (Scheme 2A). Thus, treatment of 11 with mCPBA20
gave 13a, which underwent a trans-diaxial opening with
(14) Leonard, N. J.; Carraway, K. L. J. Heterocycl. Chem. 1966, 3,
485.
(15) Butterworth: R. F.; Hanessian, S. Can. J. Chem. 1971, 49, 2755.
(16) For a review, see: David, S.; Hanessian, S. Tetrahedron 1985,
41, 643.
(17) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
(18) (a) Bannard, R. A. B.; Casselman, A. A.; Hawkins, L. R. Can.
J. Chem. 1965, 43, 2398. (b) Bannard, R. A. B.; Casselman, A. A.;
Langstaff, E. J.; Moir, R. Y. Can. J. Chem. 1968, 46, 35.
(19) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. for a
review, see: Moriarty, R. M. Org. React. 1999, 54, 273.
(20) For a review, see: Krow, G. R. Org. React. 1993, 43, 251.
(21) Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J. Org. Chem.
2003, 68, 7219.
(22) (a) Hussain, N.; Leonard, J. Tetrahedron Lett. 1987, 28, 4871.
(b) McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 26, 4895. (c)
Leeper, F. J.; Howard, S. Tetrahedron Lett. 1995, 36, 2335.
(23) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540.
J. Org. Chem, Vol. 70, No. 17, 2005 6723

Hanessian et al.
SCHEME 2
the presence of NBS gave directly the bicyclic R-phen-
ylthioglycoside 23 in 76% yield. Formation of the O-
benzyl analogue 25 from 17 was also achieved under the
same conditions. It is of interest that the trans-fused
bicyclic perhydrofuropyran thioglycosides 23 and 25 are
obtained in good yields and in anomerically pure form
from their respective acyclic S-phenylthionium precursor
20. Most likely, this must take place by a π-face selective
approach of the tetrahydropyranyl C-3 hydroxyl group.4,7,13
Although initial epoxide formation from 20 and opening
with inversion cannot be excluded in the case of 23, the
high yield cyclization of O-benzyl 17 to 25 favors the
direct attack on the thionium intermediate. To ensure a
stereocontrolled introduction of the uracil unit, we chose
to protect C2′ as the pivalate 24 rather than to reben-
zoylate. Activation of the phenylthio group with NIS and
triflic acid in the presence of 2, 4-trimethysiloxypyrimi-
dine13 led to 26 in 62% yield as the only detectable
anomer, as a result of pivalate participation.27 This
reaction was accompanied by the formation of the 5-iodo
uracil nucleoside 27, which could be separated by chro-
matography.28 Reduction of the azido group in 26 and
27 under Staudinger conditions,29 followed by treatment
with trichloroacetyl isocyanate13b gave the corresponding
ureas 28 and 29. Cleavage of the trichloroacetyl and
pivaloyl groups from 28 with methylamine30 gave N-
malayamycin A 6, as an amorphous colorless solid.
Catalytic hydrogenation to remove the iodo group in 29
and subsequent urea formation also gave 6. Using the
same protocol, the thioglycoside 24 was transformed
individually into the thymine 30, cytosine 31, adenine
32, and inosine 33 nucleosides (Scheme 4). Elaboration
of functional groups as described above, gave N-malaya-
mycin nucleoside analogues 34-37.
An alternative synthesis of the dithioacetal precursor
19 is shown in Scheme 5. The readily available 3-azido
analogue 38, prepared from D-xylose in four steps,31 was
treated with aqueous acetic acid followed by esterification
with benzoyl chloride to give the corresponding benzo-
ylated analogue 39 in excellent yield. Activation of the
anomeric benzoate in the presence of BF3‚Et2O in MeNO2
and treatment with TMSCN32 afforded 3-azido-2,4-di-O-
benzyl-â-D-ribofuranosyl nitrile 40 and its R-anomer in
a ratio of >4:1 and a 73% combined yield. Treatment with
trimethylaluminum and N,O-dimethylhydroxylamine33
gave the Weinreb amide 41 in 68% yield after separation
of the R-anomer. Dibal-H reduction led to the primary
alcohol which was oxidized with the Dess-Martin perio-
dinane19 reagent to the aldehyde 42.
led to an anomeric mixture of bicyclic nucleosides.
Knapp13 has also shown that similar activation was
possible using NIS and triflic acid24 in the synthesis of
the bicyclic unit of ezomycin A1.
We first explored the reactivity of a diphenyldithio-
acetal intermediate in a synthesis of the intermediate
phenylthio glycoside (Scheme 3). To secure a 1′,2′-trans
relationship of the intended nucleosides, we relied on a
neighboring group participation by the C2′-benzoate.
25
Thus, treatment of 17 with RuCl3/NaIO4 gave the
desired benzoate 18 in 80% yield. The diphenyldithio-
acetal 19 was easily obtained from 18 by treatment with
benzene thiol and BF3‚Et2O.26 Treatment of 19 with NBS
did not lead to the desired bicyclic thioglycoside 21
presumably because of concomitant participation of the
neighboring benzoate, at the intermediate S-phenyl-
thionium ion 20 stage, and subsequent degradation.
However, cyclization of the free C2′ OH analogue 22 in
Treatment of 42 with the lithium anion derived from
bis(phenylthio)methane led to a 2:1 mixture of epimeric
alcohols, which was enriched in the desired R-isomer 43
(27) Sato, S.; Nonomura, S.; Nakano, T.; Ito, Y.; Ogano, T. Tetra-
hedron Lett. 1988, 29, 4097.
(28) See, for example: Robins, M. J.; Barr, P. J.; Giziewicz, J. Can.
J. Chem. 1982, 60, 554.
(29) (a) Vaultier, M.; Knouz, N.; Carrie, R. Tetrahedron Lett. 1983,
24, 763. (b) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(30) Griffin, B. E.; Jarman, M.; Reese, C. B. Tetrahedron 1968, 24,
639.
(24) Veeneman, G. h.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331.
(25) (a) Tamura, J.; Koike, S.; Shimadate, T. J. Carbohydr. Chem.
1991, 11, 531. (b) Schuda, P. F.; Cichowicz, M. B.; Heimann, M. R.
Tetrahedron Lett. 1983, 24, 3829. (c) Kim, B. M.; Sharpless, C. B.
Tetrahedron Lett. 1989, 30, 655.
(31) McDevitt, J. P.; Lansbury, P. T. J. Am. Chem. Soc. 1996, 118,
3818.
(32) Brunel, F. M.; Leduc, A.-M.; Mashuta, M. S.; Taylor, K. G.;
Spatola, A. F. Lett. Pept. Sci. 2002, 9, 111.
(26) Furneaux, R. H.; Martin, B.; Rendle, P. M.; Taylor, C. M.
Carbohydr. Res. 2002, 337, 1999.
(33) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Barha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4271.
6724 J. Org. Chem., Vol. 70, No. 17, 2005

Total Synthesis of N-Malayamycin A
SCHEME 3a
a Reagents and conditions: (a) RuCl3‚3H2O, NaIO4, MeCN/CCl4/H2O (1:1:1.5), 16 °C, 24 h, 80%; (b) PhSH, BF3‚Et2O, CH2Cl2, -78°C,
3 h, 97% for 19, or 91% for 25; (c) NBS, CH2Cl2, 0 °C, 20 min, 76% for 23, or 80% for 25 ; (d) K2CO3, MeOH, rt, 30 min, 93%; (e) PivCl,
DMAP, pyridine, rt, overnight, 100%; (f) O,O′-bis(trimethylsilyl)uracil, NIS, trifluoromethanesulfonic acid, CH2Cl2, rt, 4 h, 62% for 26,
24% for 27; (g) Me3P, THF/H2O, reflux, 60 min; (h) trichloroacetyl isocyanate, CH2Cl2, rt, 2 h; (i) 40% w/v MeNH2, MeOH, rt, 3 days, 50%
in 3 steps from 26; (j) 10% palladium-on-carbon, H2, Et3N, 60 psi, rt, 24 h, then 40% w/v MeNH2, MeOH, rt, 3 days, 45% in 3 steps from
27.
SCHEME 4a
ylation and mild acid hydrolysis led to 22, identical with
a sample prepared via the RCM route.
In an effort to study the functional importance of the
methyl ether, we sought another route to bicyclic inter-
mediates that would be amenable to diversification.
Starting with the readily available D-glucose, a six-step
sequence has been reported to give intermediate 45 in
70% overall yield11c (Scheme 6). Ring closure metathesis
of 45 using the Grubbs first generation catalyst gave the
tricyclic olefin 46 in 92% yield. In their studies of the
application of the Grubbs RCM reaction to carbohydrates,
van Boom and co-workers11c reported a 63% yield for the
formation of 46 at a substrate concentration of 0.02 M
in order to avoid dimerization. Quite independently, we
had performed the same cyclization at a concentration
of 0.01 M and a catalyst loading of 5 mol %. On a 2 g
scale the yield was consistently over 90%. Clearly, a
higher dilution appears to be beneficial in the RCM
cyclizations of relatively strained tricyclics such as 46.
Application of the bromohydrin-epoxidation and azide
opening protocol as described for 11 led to 47 in 57% yield
for three steps.
a Reagents and conditions: (a) O,O′-bis(trimethylsilyl)thymine,
N4-acetyl-O,N4-bis(trimethylsilyl)cytosine, O,N9-bis(trimethylsilyl)
hypoxanthine, or N6-benzoyl-N,6N9-bis(trimethylsilyl) adenine,
NIS, TfOH, CH2Cl2; (b) Me3P, THF/H2O, reflux; (c) trichloroacetyl
isocyanate, CH2Cl2; (d) 40% w/v MeNH2, MeOH.
Oxidation with the Dess-Martin periodinane re-
agent,19 followed by treatment of the ketone with MeMg-
Br in THF at -78 °C, led to the corresponding tertiary
alcohol, as the only detectable isomer, albeit in modest
overall yield. Methylation gave 48, whose stereochemistry
was ascertained by 1H NMR (COSY, NOESY).34 The
ketone intermediate resulting from the oxidation of 47
after chromatographic separation. To differentiate the
three hydroxyl groups in 43, it was treated in sequence
with n-Bu4NF and then with 2-methoxypropene in the
presence of pTSA to afford the cyclic acetal 44. Meth-
J. Org. Chem, Vol. 70, No. 17, 2005 6725

Hanessian et al.
SCHEME 5a
SCHEME 6a
a Reagents and conditions: (a) AcOH/H2O (1/1), 100 °C, 85%;
(b) BzCl, Et3N, DMAP, DCM, 97%; (c) TMSCN, TMSOTf, MeNO2,
73%, â/R 4:1; (d) (i) NaOMe 0.1 equiv, MeOH, 1 h, (ii) NaOH 5
M/MeOH (1/1), 50 °C, 2 h, (iii) TMSCl, MeOH, 75% over three
steps; (e) TBDMSCl, imid., DCM, 95%; (f) AlMe3, HCl.HN(Me)OMe,
68%; (g) (i) DIBALH, toluene, -78 °C, 2 h, (ii) Dess-Martin
periodinane, NaHCO3(s), DCM, 2 h; (h) (PhS)2CH2, BuLi, -78 °C,
30 min, 75% over three steps, (R)/(S) 2:1; (i) TBAF, 4Å MS, THF,
92%; (j) PTSA, Na2SO4, 2-methoxypropene, DCM, 91%; (k) NaH
1.5 equiv, MeI 1.2 equiv, 0 °C, 93%; (l) PTSA, MeOH, 100%.
a Reagents and conditions: (a) Cl2RuCHPh(PCy3)2 (5% mol),
CH2Cl2 (c ) 0.01 M), reflux, 3 h, 92%; (b) NBS, THF/H2O (1:1), rt,
2 h; (c) 1 N NaOH, THF, reflux, 1 h; (d) NaN3, 2-methoxyethanol,
126 °C, 1 h, 57% in 3 steps; (e) (i) Dess-Martin periodinane,
CH2Cl2, rt, 2.5 h, (ii) MeMgBr, THF, -78 °C, 1 h, 18% in 2 steps,
(iii) MeI, NaH, DMF, rt, 2 h, 75% for 48; (f) DAST, CH2Cl2, -78
°C to rt, 30% for 49; (g) PhSH, Amberlyst-15, CH2Cl2, 80% for 50,
85% for 51; (h) NBS, CH2 Cl2; (i) PivCl, DMAP, pyridine, 72% for
52, 69% for 53 in 2 steps; (j) N4-acetyl-O-trimethylsilylcytosine,
NIS, trifluoromethanesulfonic acid, CH2Cl2, rt, 4 h, 66% for 54,
70% for 55; (k) (i) Me3P, THF/H2O, reflux, 60 min, (ii) trichloro-
acetyl isocyanate, CH2Cl2, rt, 2 h, (iii) 40% w/v MeNH2, MeOH,
rt, 3 days, 9% for 56, 30% for 57 in 3 steps.
was prone to epimerization of the axially disposed azide
group. It was used without purification, hence the low
overall yield of 48. Treatment of 47 with DAST35 gave
the inverted fluoride 49 in modest yield. The reaction was
accompanied by the formation of baseline material, and
attempts to increase the yields were not successful.
Cleavage of the acetal with concomitant dithioacetal
formation in 48 and 49 was most efficiently done with
benzenethiol in the presence of Amberlyst-15 suspended
36
in CH2Cl2 to give the corresponding products 50 and
51 in 80% and 85% yields, respectively. Thioglycoside
formation in the presence of NBS followed by pivaloyla-
tion proceeded in good overall yield to give 52 and 53
(72% and 69%, respectively). In this series we chose to
prepare the corresponding N-cytosinyl analogues. Ap-
plication of the same protocol for the synthesis of 31
(Scheme 4) proceeded smoothly to give 54 and 55 which
were individually transformed into the C6 modified
analogues 56 and 57 (Scheme 6).
In conclusion, we have described the total synthesis
of N-malayamycin A and related pyrimidine and purine
nucleosides using three approaches. The key carbocy-
clization step to bicyclic perhydrofuropyran intermediates
in two of the approaches involved a Grubbs ring closure
metathesis reaction that proceeded in excellent yield.
Regioselective functionalization of the bicyclic olefins was
achieved through stereocontrolled epoxidation and diaxial
opening with azide ion. The formation of bicyclic N-
nucleosides was achieved with a variety of purine and
pyrimidine bases, and new analogues substituted in the
dihydropyran unit were synthesized from a common
intermediate. Further aspects of the chemistry and
biological properties of these unique class of bicyclic C-
and N-nucleosides related to malayamycin A will be
reported in due course.
Experimental Section
Methyl 5,6-Dideoxy-2,3-O-isopropylidene-â-D-ribo-hex-
5-enofuranoside (8). To a suspension of methyltriphenylphos-
phonium bromide (12.9 g, 36 mmol) in 350 mL of anhydrous
THF was added dropwise 14.4 mL of BuLi (2.5 M solution in
hexanes, 36 mmol) at -78 °C under argon atmosphere. After
addition was completed, the resulting mixture was stirred at
0 °C for 30 min and then cooled to -78 °C again. A solution of
(34) See Supporting Information.
(35) For a review, see: Hudlicky, M. Org. React. 1988, 35, 513.
(36) Loiseleur, O.; Vifian, T. Syngenta Crop Protection, Basel,
Switzerland; unpublished results.
6726 J. Org. Chem., Vol. 70, No. 17, 2005

Total Synthesis of N-Malayamycin A
aldehyde (6.06 g, 30 mmol) obtained from the oxidation of 715
in 60 mL of anhydrous THF was added to this solution over
30 min. The mixture was warmed to room temperature, stirred
for 3 h at this temperature, then quenched by adding saturated
NH4Cl (400 mL). The mixture was extracted with Et2O (200
mL × 3), and the combined organic layer was washed with
saturated NaHCO3, dried over anhydrous Na2SO4, filtered, and
concentrated. Purification by flash silica gel chromatography
(hexanes/ethyl acetate, 10:1) afforded product 8 (5.1 g, 85%)
as a colorless oil: [R]D -57.6° (c 1.15, CHCl3); IR (thin film) ν
2989, 2939, 1461, 1425, 1373, 1211, 1105, 868 cm-1; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.31 (s, 3H, -CH3), 1.48 (s, 3H,
-CH3), 3.33 (s, 3H, -OMe), 4.64 (m, 3H), 4.97 (s, 1H), 5.14 (d,
82.5, 106.6, 117.9, 128.2, 128.4, 128.8, 134.8, 138.1, 138.2;
HRMS (FAB) calcd for C17
H22O4 [M+] 290.1518, found 290.1518.
(2R,3R,3aR,7aR)-3-Benzyloxy-2-methoxy-3,3a,5,7a-tet-
rahydro-2H-furo[3,2-b]pyran (11). To a solution of 10 (1.0
g, 3.66 mmol) in 366 mL of dry degassed CH2Cl2 was added 5
mol % Grubbs catalyst [Cl2RuCHPh(PCy3)2] (150 mg, 0.18
mmol) under argon atmosphere at room temperature, and the
mixture was heated to reflux for 8 h until the starting material
disappeared. The mixture was concentrated and the residue
was purified by flash silica gel chromatography (hexane/ethyl
acetate, 5:1) to afford 11 (650 mg, 68%) as a colorless oil: [R]D
-49.7° (c 0.3, CHCl3); IR (thin film) ν 2933, 1730, 1454, 1367,
1100, 1027, 926, 689 cm-1; 1H NMR (400 MHz, CDCl3) δ (ppm)
3.38 (s, 3H, -OMe), 3.57 (dd, 1H, J ) 8.9, 4.3 Hz), 3.94 (d,
1H, J ) 4.3 Hz), 4.43 (m, 2H), 4.54 (d, 1H, J ) 8.9 Hz), 4.64
(d, 1H, J ) 12.0 Hz, PhCH2-), 4.84 (d, 1H, J ) 12.0 Hz,
PhCH2-), 4.95 (s, 1H), 5.66 (m, 1H), 6.24 (d, 1H, J ) 10.3 Hz),
7.29-7.39 (m, 5H, -Ph); 13C NMR (100 MHz, CDCl3) δ (ppm)
55.8, 68.6, 71.3, 72.0, 78.3, 79.6, 109.3, 126.6, 127.5, 127.6,
127.7, 128.3, 137.7; HRMS (FAB) calcd for C15H18O4 [M+]
262.1205, found 262.1202.
(2R,3R,3aR,6R,7R,7aR)-7-Azido-3-benzyloxy-2-methoxy-
hexahydro-furo[3,2-b]pyran-6-ol (14). To a solution of 11
(464 mg, 1.77 mmol) in 20 mL of THF/H2O (1:1) was added
N-bromosuccinimide (550 mg, 3.1 mmol) at room temperature.
The mixture was stirred vigorously for 1.5 h, poured into 20
mL H2O containing 1.0 g Na2S2O3 and extracted with EtOAc
(50 mL ×3). The combined organic layer was dried over
anhydrous Na2SO4, filtered and concentrated to afford crude
product 12, which was engaged in the next reaction.
1H, J ) 10.3 Hz), 5.25 (d, 1H, J ) 16.7 Hz), 5.85 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ (ppm) 25.4, 26.9, 54.5, 84.39, 85.4,
88.3, 109.1, 112.2, 117.2, 137.5; HRMS (FAB) calcd for
+
C10H17O4 [M + H] 201.1127, found 201.1126.
Methyl 3-O-Allyl-5,6-dideoxy-â-D-ribo-hex-5-enofura-
noside (9). A mixture of 8 (4.5 g, 22.5 mmol) and TsOH (0.5
g) in dry MeOH (500 mL) was refluxed for 24 h, pyridine (0.5
mL) was added, and the mixture was concentrated. Purifica-
tion by flash silica gel chromatography (hexanes/ethyl acetate,
2:1) afforded a mixture of R and â diols (3.0 g, 83%) as a
colorless oil with a 1:7 ratio: [R]D -24.2° (c 2.18, CHCl3); IR
(thin film) ν 3402, 2936, 1646, 1426, 1196, 1124, 1030, 933
1
cm-1; H NMR (400 MHz, CDCl3) δ (ppm) 2.38 (br, 2H, -OH
× 2), 3.40 (s, 3H, -OMe), 4.14 (m, 1H, H-2), 4.17 (m 1H, H-4),
4.33 (t, 1H, J ) 6.8 Hz, H-3), 4.87 (s, 1H, H-1), 5.21 (d, 1H, J
) 12.8 Hz), 5.36 (d, 1H, J ) 17.1 Hz), 5.90 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 55.2, 75.2, 75.3, 85.2, 107.9, 117.4,
136.9; HRMS (FAB) calcd for C7H12O4 [M+] 160.0736, found
160.0734.
To a solution of 12 in 25 mL of THF was added 1 N NaOH
(13 mL). The solution was refluxed for 1 h, poured into 50 mL
of H2O, and extracted with EtOAc (60 mL × 3). The combined
organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated to afford 13 as a crude oil.
This product was dissolved in 100 mL of 2-methoxyethanol,
2.56 g (39.3 mmol) of sodium azide was added, and the mixture
was heated to 126 °C for 2 h. The mixture was poured into
200 mL of saturated brine and extracted with EtOAc (60 mL
× 4), and the combined organic layer was dried over anhydrous
Na2SO4, filtered and concentrated. The residue was purified
by flash silica gel chromatography (hexanes/ethyl acetate, 4:1)
to afford azide 14 (300 mg) as a white powder: yield 53%; mp
120-122 °C; [R]D -3.05° (c 1.8, CHCl3); IR (thin film) ν 3067,
To a solution of the above diol (2.62 g, 16.4 mmol) in 200
mL of dry MeCN were added Bu2SnO (4.9 g, 19.7 mmol), n-Bu4-
NI (4.84 g, 13.1 mmol), allyl bromide (1.42 g, 16.4 mmol), and
4Å molecular sieves (17.0 g) at room temperature under argon
atmosphere. The mixture was refluxed for 5 h, and solvent
was removed by evaporation. To the residue were added Et2O
(200 mL) and H2O (200 mL), and the organic layer was
separated. The aqueous layer was extracted with Et2O (100
mL × 2), and the combined organic layer was washed with
saturated NaHCO3, brine, then dried over anhydrous Na2SO4,
filtered, and concentrated. Purification by flash silica gel
chromatography (hexanes/ethyl acetate, 10:1) afforded the
product 9 (1.9 g, 58%) as a colorless oil: [R]D +82.5° (c 0.2,
CHCl3); IR (thin film) ν 3557, 3083, 2987, 2918, 2850, 1733,
1646 cm-1; 1H NMR (400 MHz, CDCl3) δ (ppm) 2.74 (d, 1H, J
) 8.9 Hz, -OH), 3.41 (s, 3H, -OMe), 3.61 (dd, 1H, J ) 7.0,
3.7 Hz), 4.17 (m, 3H, H-2 and -CH2O-), 4.44 (t, 1H, J ) 5.1
Hz, H-4), 4.91 (d, 1H, J ) 4.6 Hz, H-1), 5.2-5.4 (m, 4H, CH2d
CH-), 5.80-5.95 (m, 2H, H-5 and CH2dCH-); 13C NMR (100
MHz, CDCl3) δ (ppm) 55.5, 71.1, 72.2, 79.4, 82.9, 102.4, 116.8,
117.7, 134.1, 135.7.
1
2911, 2101, 1454, 1124, 1061, 1022, 903 cm-1; H NMR (400
MHz, CDCl3) δ (ppm) 2.3 (d, 1H, J ) 6.9 Hz, -OH), 3.39 (s,
3H, -OMe), 3.70 (m, 1H, H-6), 3.77-3.90 (m, 3H, H-5 and
H-3a), 3.96 (d, 1H, J ) 4.3 Hz, H-3), 4.29 (m, 1H, H-7), 4.46
(dd, 1H, J ) 10.3, 3.2 Hz, H-7a), 4.65 (d, 1H, J ) 12.0 Hz,
PhCH2-), 4.79 (d, 1H, J ) 12.0 Hz, PhCH2-), 4.90 (s, 1H, H-2),
7.3-7.39 (m, 5H, -Ph); 13C NMR (100 MHz, CDCl3) δ (ppm)
56.2, 61.4, 69.0, 70.3, 72.7, 74.7, 74.8, 91.1, 107.6, 128.2, 128.4,
128.9, 137.9; HRMS (FAB) calcd for C15H19N3O4 [M+] 321.1325,
found 321.1323.
Methyl 3-O-allyl-2-O-benzyl-5,6-dideoxy-â-D-ribo-hex-
5-enofuranoside (10). To a solution of alcohol 9 (1.9 g, 9.5
mmol) in 40 mL of dry DMF were added NaH (60% dispersion
in mineral oil) (750 mg, 18.8 mmol) and BnBr (1.93 g, 11.3
mmol) at 0 °C under argon atmosphere. After stirring over-
night, the reaction was quenched by adding saturated NaHCO3
(100 mL), and the mixture was extracted with CH2Cl2 (50 mL
× 3). The combined organic layer was washed with saturated
NaHCO3, brine, then dried over anhydrous Na2SO4, filtered,
concentrated. Purification by flash silica gel chromatography
(hexanes/ethyl acetate, 10:1) afforded 10 (2.5 g, 91%) as a
colorless oil: [R]D +8.8° (c 0.5, CHCl3); IR (thin film) ν 3402,
(2R,3R,3aR,6S,7R,7aR)-7-Azido-3-benzyloxy-2,6-di-
methoxy-hexahydrofuro[3,2-b]pyran (17). To a solution of
14 (300 mg, 0.93 mmol) in 200 mL of dry CH2Cl2 was added
Dess-Martin periodinane reagent (1.5 g, 3.54 mmol) at room
temperature under argon atmosphere, and the mixture was
stirred for 2.5 h. After starting material disappeared, 20 mL
of saturated NaHCO3 solution and 20 mL of saturated Na2S2O3
solution were added. The mixture was stirred for 10 min,
extracted with CH2Cl2, dried over anhydrous Na2SO4, filtered
and concentrated to give crude ketone 15.
To a solution of ketone 15 in 20 mL of MeOH was added
230 mg of NaBH4 at 0 °C. The resulting mixture was stirred
for 1 h and concentrated, and the residue was extracted with
EtOAc (40 mL × 3). The combined organic layer was dried
over anhydrous Na2SO4, filtered and concentrated to afford
16 as a crude oil.
1
2936, 1646, 1426, 1196, 1124, 1030, 933 cm-1; H NMR (400
MHz, CDCl3) δ (ppm) 3.37 (s, 3H, -OMe), 3.87 (m, 2H, H-2
and H-3), 4.00 (m, 2H), 4.52 (t, 1H, J ) 3 Hz), 4.65 (d, 1H, J
) 11.0 Hz, PhCH2-), 4.72 (d, 1H, J ) 11.0 Hz, PhCH2-), 4.91
(s, 1H), 5.1-5.2 (m, 4H), 5.87 (m, 2H), 7.2-7.4 (m, 5H, -Ph);
13C NMR (100 MHz, CDCl3) δ (ppm) 55.5, 72.0, 72.8, 80.2, 82.3,
To a solution of the above oil 16 in 20 mL of dry DMF was
added NaH (60% suspension in oil) (60 mg, 1.50 mmol). After
J. Org. Chem, Vol. 70, No. 17, 2005 6727

Hanessian et al.
stirring for 30 min at 0 °C under argon atmosphere, 100 mg
of MeI was added, and the mixture was stirred for 3 h. The
reaction was quenched by adding 10 mL of H2O, and the
mixture was extracted with EtOAc (40 mL × 3). The combined
organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated. The residue was purified
by flash silica gel chromatography (hexanes/ethyl acetate, 10:
1) to afford 17 (253 mg. 81%) as a colorless oil: [R]D -11.6° (c
mg, 93%) as a colorless oil: [R]D +28.3° (c 0.79, CHCl3); 1H
NMR (400 MHz, CDCl3) δ (ppm) 3.22 (t, 1H, J ) 10.6 Hz, H-6),
3.35 (ddd, 1H, J ) 10.6, 4.8, 3.0 Hz, H-5), 3.40 (s, 3H, -OMe),
3.63 (ddd, 1H, J ) 10.6, 4.8, 1.1 Hz, H-6), 3.69 (dd, 1H, J )
9.1, 3.2 Hz, H-3), 3.76 (t, 1H, J ) 9.1 Hz, H-2), 3.90 (dd, 1H,
J ) 8.2, 2.2 Hz, H-1′), 4.26 (t, 1H, J ) 3.2 Hz, H-4), 4.87 (d,
1H, J ) 2.2 Hz, H-2′), 7.26-7.50 (m, 10H, -Ph);13C NMR (100
MHz, CDCl3) δ (ppm) 56.9, 62.4, 63.2, 71.9, 72.7, 75.6, 76.0,
127.9, 128.0, 128.9, 129.1, 132.3; FAB-MS m/z (relative
intensity) 433 (M+, 25), 324 (M+ - PhS, 80); HRMS (FAB) calcd
for C20H23N3O4S2 [M+] 433.1130, found 433.1132.
(2R,3R,3aR,6S,7R,7aR)-7-Azido-6-methoxy-2-phenyl-
sulfanyl-hexahydrofuro[3,2-b]pyran-3-ol (23). To a solu-
tion of diol 22 (185 mg, 0.43 mmol) in 20 mL of dry CH2Cl2
was added NBS (80 mg, 0.45 mmol) in an ice bath under argon
atmosphere. After stirring for 20 min, the mixture was
quenched by adding saturated Na2S2O3 and then stirred for
10 min. The mixture was extracted with CH2Cl2 (30 mL × 4),
and the combined organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated. Purification
by flash silica gel chromatography (hexanes/ethyl acetate, 3:1)
afforded 23 (105 mg, 76%) as a colorless oil: [R]D +87.5° (c
0.76, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm) 2.50 (d, 1H,
J ) 2.2 Hz, -OH), 3.48 (s, 3H, -OMe), 3.58 (ddd, 1H, J )
10.4, 5.1, 3.0 Hz, H-6), 3.69 (dd, 1H, J ) 11.0, 10.6 Hz, H-5),
3.80 (dd, 1H, J ) 9.8, 4.8 Hz, H-3a), 4.0 (dd, 1H, J ) 11.0, 5.1
Hz, H-5), 4.06 (dd, 1H, J ) 9.8, 2.8 Hz, H-7a), 4.55 (dd, 1H, J
) 5.1, 4.1 Hz, H-3), 4.64 (dd, 1H, J ) 3.0, 2.8 Hz, H-7), 5.80
(d, 1H, J ) 4.1 Hz, H-2), 7.26-7.53 (m, 5H, -Ph); 13C NMR
(100 MHz, CDCl3) δ (ppm) 57.4, 58.8, 65.6, 69.5, 73.9, 74.1,
76.2, 93.8, 127.1, 128.9, 130.9, 134.4; FAB-MS m/z (relative
intensity) 323 (M+, 20); HRMS (FAB) calcd for C14H18N3O4S
[M + H]+ 324.1018, found 324.1008.
1
2.4, CHCl3); IR (thin film) ν 2989, 2101, 1125, 1062 cm-1; H
NMR (400 MHz, CDCl3) δ (ppm) 3.39 (s, 3H, -OMe), 3.45 (s,
3H, -OMe), 3.51 (ddd, 1H, J ) 10.4, 2.7, 1.1 Hz), 3.73 (t, 1H,
J ) 10.4 Hz, H-5), 3.9-4.0 (m, 3H, H-3, H-5 and H-3a), 4.08
(dd, 1H, J ) 9.8, 2.6 Hz, H-7a), 4.58 (t, 1H, J ) 2.8 Hz, H-7),
4.62 (d, 1H, J ) 12.0, PhCH2-), 4.76 (d, 1H, J ) 12.0 Hz,
PhCH2-), 4.92 (s, 1H, H-2), 7.2-7.4 (m, 5H, -Ph); 13C NMR (100
MHz, CDCl3) δ (ppm) 55.6, 57.3, 59.2, 66.0, 72.1, 74.2, 75.9,
78.9, 108.6, 127.6, 127.7, 128.3, 137.5; HRMS (FAB) calcd for
C16H21N3O5 [M+] 335.1481, found 335.1481.
(2R,3R,3aR,6S,7R,7aR)-7-Azido-3-benzoyloxy-2,6-di-
methoxy-hexahydrofuro[3,2-b]pyran (18). To a solution of
17 (200 mg, 0.6 mmol) in 8 mL of CH3CN/CCl4/H2O (1:1:1.5)
were added RuCl3‚3H2O (28.4 mg, 0.12 mmol) and NaIO4 (153
mg, 0.71 mmol) at 16 °C under argon atmosphere. The mixture
was stirred for 24 h at this temperature, and 392 mg of NaIO4
was added in portions during 24 h. After starting material
disappeared, excess isopropyl alcohol (5 mL) and H2O (20 mL)
were added, and the mixture was extracted with CH2Cl2 (30
mL × 3), dried over anhydrous Na2SO4, filtered and concen-
trated. Purification by flash silica chromatography (hexanes/
ethyl acetate, 10:1) afforded 18 (165 mg, 79%) as white solid:
mp 85-87 °C; [R]D +2.36° (c 0.57, CHCl3); IR (thin film) ν 2929,
2108, 1726, 1583, 1439, 1268, 1108 cm-1; 1H NMR (400 MHz,
CDCl3) δ (ppm) 3.44 (s, 3H, -OMe), 3.48 (s, 3H, -OMe), 3.50
(m, 1H, H-6), 3.60 (dd, 1H, J ) 11.1, 10.5 Hz, H-5), 3.94 (dd,
1H, J ) 11.1, 5.0 Hz, H-5), 4.05 (dd, 1H, J ) 10.0, 2.7 Hz,
H-7a), 4.17 (dd, 1H, J ) 10.0, 4.3 Hz, H-3a), 4.61 (t, 1H, J )
2.7 Hz, H-7), 5.08 (s, 1H, H-2), 5.37 (d, 1H, J ) 4.3 Hz, H-3),
7.42-8.05 (m, 5H, -Ph). 13C NMR (100 MHz, CDCl3) δ (ppm)
55.9, 57.4, 59.1, 66.1, 72.4, 73.9, 75.5, 76.2, 108.3, 128.3, 129.1,
129.7, 133.3, 165.1; FAB-MS m/z (relative intensity) 350 (M+
+ H, 32), 318 (M+ - OMe, 30); HRMS (FAB) calcd for
C16H20N3O6 [M + H+] 350.1352, found 350.1358.
(1′R,2R,3R,4S,5S)-4-Azido-2-(1′-benzoyloxy-2′,2′-bisphen-
ylsulfanylethyl)-5-methoxy-tetrahydropyran-3-ol (19). To
a solution of 18 (165 mg, 0.47 mmol) in 10 mL of dry CH2Cl2
were added PhSH (0.15 mL, 1.42 mmol) and BF3‚Et2O (0.1
mL, 0.79 mmol) at -78 °C under argon atmosphere. After
stirring for 3.5 h at this temperature, the mixture was
quenched by adding saturated NaHCO3 (10 mL), warmed to
room temperature and extracted with CH2Cl2 (20 mL × 3).
The combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The residue was
purified by flash silica gel chromatography (hexanes/ethyl
acetate, 5:1) to afford dithiane 19 (245 mg, 97%) as a colorless
oil: [R]D +20.6° (c 0.33, CHCl3); IR (thin film) ν 2926, 2104,
1728, 1602, 1452, 1272, 1112 cm-1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 2.56 (d, 1H, J ) 8.6 Hz, -OH), 3.47 (s, 3H, -OMe),
3.50 (m, 1H, H-5), 3.53 (dd, 1H, J ) 11.2, 9.5 Hz, H-6), 3.60
(m, 1H, H-2), 3.75 (m, 1H, H-6), 4.08 (m, 2H, H-3 and H-4),
4.96 (d, 1H, J ) 3.4 Hz, H-2′), 5.63 (dd, 1H, J ) 3.4, 2.5 Hz,
H-1′), 7.30-8.10 (m, 15H, -Ph); 13C NMR (100 MHz, CDCl3)
δ (ppm) 57.1, 60.3, 61.1, 62.2, 63.1, 68.8, 74.5, 76.6, 127.7,
128.1, 128.3, 128.9, 129.0, 129.4, 129.9, 132.3, 133.2, 133.4,
133.5, 134.4, 165.9; FAB-MS m/z (relative intensity) 537 (M+,
2), 428 (M+ - PhS, 15).
(2R,3R,3aR,6S,7R,7aR)-7-Azido-6-methoxy-2-phenyl-
sulfanyl-3-pivaloyloxy- hexahydrofuro[3,2-b]pyran (24).
To a solution of 23 (105 mg, 0.32 mmol) in 5 mL of dry pyridine
were added DMAP (200 mg) and then PivCl (0.15 mL) at room
temperature under argon atmosphere. The mixture was stirred
overnight, pyridine was removed under reduced pressure, and
the residue was dissolved with 50 mL of dichloromethane,
washed with saturated NaHCO3, brine, dried over anhydrous
Na2SO4, filtered and concentrated. Purification by flash silica
gel chromatography (hexanes/ethyl acetate, 5:1) afforded 24
(130 mg, 100%) as a colorless oil: [R]D +187.3° (c 0.41, CHCl3);
IR (thin film) ν 2977, 2107, 1741, 1480, 1279, 1146, 1059 cm-1
;
1H NMR (400 MHz, CDCl3) δ (ppm)1.30 (s, 9H, PivO-); 3.47
(s, 3H, -OMe), 3.51 (m, 1H, H-6), 3.61 (dd, 1H, J ) 11.6, 10.0,
H-5), 3.84 (dd, 1H, J ) 10.0, 3.4 Hz, H-3a), 3.92 (dd, 1H, J )
11.6, 4.4 Hz, H-5), 3.97 (dd, 1H, J ) 10.0, 3.4 Hz, H-7a), 4.62
(t, 1H, J ) 3.2 Hz, H-7), 5.68 (t, 1H, J ) 3.4 Hz, H-3), 5.90 (d,
1H, J ) 3.4 Hz, H-2), 7.27-7.51 (m, 5H, -Ph); 13C NMR (100
MHz, CDCl3) δ (ppm) 27.6, 39.8, 57.9, 59.2, 66.0, 70.4, 73.9,
75.3, 76.8, 92.3, 127.8, 129.5, 131.6, 134.8, 177.1; FAB-MS m/z
(relative intensity) 408 (M + H+, 60), 407 (M+, 15), 298 (M+
-
PhS, 100); HRMS (FAB) calcd for C19H26N3O5S [M + H]+
408.1601, found 408.1586.
General Procedure for N-Glycosidation. To a solution
of phenylthio glycoside 24 (0.1 mmol) in 2 mL of dry CH2Cl2
were added silylated base (0.2 mmol), NIS (0.2 mmol), and then
triflic acid (0.1 mmol) at room temperature under argon
atmosphere. After stirring for 2-5 h, the reaction was quenched
by adding saturated Na2S2O3 (10 mL). The mixture was
extracted with CH2Cl2 (30 mL × 3), and the combined organic
layer was washed with saturated NaHCO3 and brine, dried
over anhydrous Na2SO4, filtered and concentrated. Purification
by flash silica chromatography (CH2Cl2/MeOH, 40:1) afforded
the N-nucleoside.
(2R,3R,3aR,6S,7R,7aR)-7-Azido-3-benzyloxy-6-methoxy-
2-phenylsulfanyl-hexahydrofuro[3,2-b]pyran (25). To a
solution of 17 (112 mg, 0.33 mmol) in 10 mL of dry CH2Cl2
were added PhSH (0.1 mL, 0.95 mmol) and BF3‚Et2O (0.1 mL,
0.79 mmol) at -78 °C under argon atmosphere. After stirring
(1′R,2R,3R,4S,5S)-4-Azido-2-(1′-hydroxy-2′,2′-phenyl-
sulfanylethyl)-5-methoxy-tetrahydropyran-3-ol (22). To
a solution of 19 (245 mg, 0.46 mmol) in 20 mL of methanol
was added K2CO3 (10 mg) at room temperature. After stirring
for 30 min, the mixture was evaporated under reduced
pressure, and the residue was purified by flash silica gel
chromatography (hexanes/ethyl acetate, 2:1) to afford 22 (184
6728 J. Org. Chem., Vol. 70, No. 17, 2005

Total Synthesis of N-Malayamycin A
for 3.5 h at this temperature, the mixture was quenched by
adding saturated NaHCO3 (10 mL), warmed to room temper-
ature and extracted with CH2Cl2 (20 mL × 3). The combined
organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated. The residue was purified
by flash silica gel chromatography (hexane/ethyl acetate, 5:1)
to afford the dithioacetal (160 mg, 91%) as a colorless oil.
2110, 1712, 1666, 1562, 1493, 1385, 1277, 1151 cm-1; 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.21 (s, 9H, PivO-), 2.25 (s, 3H, CH3-
CO-), 3.46 (s, 3H, -OMe), 3.56 (m, 1H, H-6), 3.58 (t, 1H, J )
10.6 Hz, H-5), 3.77 (dd, 1H, J ) 10.0, 4.5 Hz, H-3a), 3.87 (dd,
1H, J ) 10.0, 2.8 Hz, H-7a), 3.95 (dd, 1H, J ) 10.6, 4.3 Hz,
H-5), 4.70 (s, 1H, H-7), 5.32 (d, 1H, J ) 4.5 Hz, H-3), 5.99 (s,
1H, H-2), 7.48 (d, 1H, J ) 7.5 Hz, H-5′), 8.15 (d, 1H, J ) 7.5
Hz, H-6′), 10.1 (brs, 1H, -NH); 13C NMR (100 MHz, CDCl3) δ
(ppm) 26.9, 29.4, 38.7, 57.6, 58.8, 65.8, 71.6, 72.3, 75.9, 76.6,
91.1, 96.8, 143.8, 154.3, 162.9, 170.9, 178.2; LC-MS m/z
(relative intensity) 350 (M+, 100).
(2R,3R,3aR,6S,7R,7aR)-7-Azido-2-(6′-oxo-1′,6′-dihydro-
purin-9′-yl)-6-methoxy-3-pivaloyloxy-hexahydrofuro[3,2-
b]pyran (32). Colorless oil: yield 75% based on recovered
starting material; [R]D +80.0° (c 0.6, CHCl3); IR (thin film) ν
2932, 2111, 1709, 1590, 1480, 1348, 1180, 1149, 1093, 1057
cm-1; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.29 (s, 9H, PivO-),
3.50 (s, 3H, -OMe), 3.63 (m, 2H, H-5 and H-6), 4.0 (m, 3H,
H-5, H-3a and H-7a), 4.76 (m, 1H, H-7), 5.58 (d, 1H, J ) 3.9
Hz, H-3), 6.47 (s, 1H, H-2), 8.22 (s, 1H, H-2′), 8.51 (s, 1H, H-8′),
11.8 (brs, 1H, -NH); 13C NMR (100 MHz, CDCl3) δ (ppm) 27.5,
39.4, 58.2, 59.5, 66.5, 71.8, 73.9, 76.9, 77.1, 92.2, 114.6, 141.6,
145.2, 156.3, 159.3, 176.9; FAB-MS m/z (relative intensity) 434
(M + H+, 6), 298 (M+ - hypoxanthine, 30); HRMS (FAB) calcd
for C18H24N7O6 [M + H]+ 434.1788, found 434.1774.
To a solution of the above compound (160 mg, 0.3 mmol) in
10 mL of dry CH2Cl2 was added NBS (70 mg, 0.38 mmol) at 0
°C under argon atmosphere. After stirring for 20 min, the
mixture was quenched by adding a saturated solution of Na2-
SO4 and stirred for 10 min. The mixture was extracted with
CH2Cl2 (20 mL × 3), and the combined organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated. Purification by flash silica gel chromatography
(hexanes/ethyl acetate, 5:1) afforded 25 (100 mg, 80%) as a
1
colorless oil: [R]D +25.0° (c 0.4, CHCl3); H NMR (400 MHz,
CDCl3, ppm) δ 3.46 (s, 3H, - OCH3), 3.59 (m, 2H), 3.78 (dd,
1H, J ) 10.0, 4.5 Hz), 3.98 (dd, 1H, J ) 9.6, 3.2 Hz), 4.15 (dd,
1H, J ) 10.0, 3.0 Hz), 4.27 (t, 1H, J ) 4.3 Hz), 4.62 (m, 1H),
4.75 (d, 1H, J ) 12.1 Hz), 4.91 (d, 1H, J ) 12.1 Hz), 5.83 (d,
1H, J ) 4.4 Hz), 7.22-7.52 (m, 10H); 13C NMR (100 MHz,
CDCl3, ppm) δ 56.8, 61.1, 61.9, 63.4, 71.0, 73.4, 75.1, 75.5, 83.9,
127.3, 127.5. 128.2. 128.4, 128.5, 128.9, 134.2, 135.0; MS (FAB)
414.2 (M + H+).
(2R,3R,3aR,6S,7R,7aR)-7-Azido-2-(6′-benzoylamino-pu-
rin-9′-yl)-6-methoxy-3-pivaloyloxy-hexahydrofuro[3,2-b]-
pyran (33). Colorless oil: yield 22%; [R]D +55.3° (c 0.7, CHCl3);
IR (thin film) ν 2933, 2108, 1741, 1704, 1610, 1582, 1480, 1455,
(2R,3R,3aR,6S,7R,7aR)-7-Azido-2-(2′,4′-dioxo-3′,4′-dihy-
dro-2H-pyrimidin-1′-yl)-6-methoxy-3-pivaloyloxy-hexahy-
drofuro[3,2-b]pyran (26) and (2R,3R,3aR,6S,7R,7aR)-7-
Azido-2-(5′-iodo-2′,4′-dioxo-3′,4′-dihydro-2H-pyrimidin-1′-
yl)-6-methoxy-3-pivaloyloxy-hexahydrofuro[3,2-b]-
pyran (27). The combined yield was 85%. For 26: [R]D +85.5°
(c 0.6, CHCl3); IR (thin film) ν 2932, 2109, 1693, 1459, 1277,
1
1280, 1146 cm-1; H NMR (400 MHz, CDCl3) δ (ppm) 1.29 (s,
(H, PivO-); 3.50 (s, 3H, -OMe), 3.61 (m, 1H, H-6), 3.73 (t, 1H,
J ) 11.0 Hz, H-5), 3.93 (dd, 1H, J ) 10.2, 3.2 Hz, H-7a), 4.02
(dd, 1H, J ) 11.0, 5.4 Hz, H-5), 4.52 (dd, 1H, J ) 10.2, 4.5 Hz,
H-3a), 4.69 (m, 1H, H-7), 5.58 (d, 1H, J ) 4.5 Hz, H-3), 6.21
(s, 1H, H-2), 7.52 (t, 2H, J ) 7.8 Hz, -Ph), 8.37 (s, 1H, H-2′),
8.83 (s, 1H, H-8′), 8.96 (brs, 1H, -NH); 13C NMR (100 MHz,
CDCl3) δ (ppm) 26.9, 38.8, 57.5, 58.7, 65.9, 71.9, 72.7, 76.2,
76.3, 89.3, 123.1, 127.7, 128.7, 130.9, 132.7, 133.4, 140.9, 149.5,
151.0, 152.9, 164.3, 176.6; FAB-MS m/z (relative intensity) 537
(M + H+, 5), 298 (M+ - N6-benzoyladenine, 10); HRMS (FAB)
calcd for C25H29N8O6 [M + H]+ 537.2210, found 537.2200.
General Procedure for the Formation of Urea. To a
solution of azide (0.02 mmol) in 2 mL of anhydrous THF was
added 1 M Me3P in toluene (50 µL, 0.05 mmol) at room
temperature under argon atmosphere. After stirring for 30
min, 3 µL of H2O was added, and the resulting mixture was
refluxed for 40 min and then evaporated. The residue was
dried under reduced pressure (1 mmHg) for 1.5 h and dissolved
in 2 mL of dry CH2Cl2. To this solution was added trichloro-
acetyl isocyanate (10 µL) at room temperature under argon
atmosphere. After stirring for 60 min, CH2Cl2 was removed
and the residue was dissolved with MeOH (2 mL) and 40%
MeNH2 in H2O (2 mL), and stirred over 3 days. The mixture
was evaporated and purified by flash silica gel chromatography
(CH2Cl2/MeOH, 9:1) to afford product.
1
1149, 1059 cm-1; H NMR (400 MHz, CDCl3) δ (ppm) 1.23 (s,
9H, -OPiv), 3.49 (s, 3H, -OMe), 3.58 (m, 1H, H-6), 3.66 (dd,
1H, J ) 11.0, 10.7 Hz, H-5), 3.79 (dd, 1H, J ) 10.1, 2.7 Hz,
H-7a), 3.84 (dd, 1H, J ) 10.1, 5.0 Hz, H-3a), 3.99 (dd, 1H, J )
11.0, 5.1 Hz, H-5), 4.68 (brs, 1H, H-7), 5.28 (d, 1H, J ) 5.0 Hz,
H-3), 5.81 (d, 1H, J ) 8.1 Hz, H-5′), 5.91 (s, 1H, H-2), 7.58 (d,
1H, J ) 8.1 Hz, H-6′), 8.42 (brs, 1H, -NH); 13C NMR (100
MHz, CDCl3) δ (ppm) 27.5, 39.3, 58.1, 59.3, 66.4, 72.4, 73.0,
76.2, 77.1, 91.2, 103.4, 139.7, 149.9, 163.0, 177.0; FAB-MS m/z
(relative intensity) 410 (M + H+, 20), 298 (M+ - PhS, 35). For
27: [R]D +76.6° (c 0.95, CHCl3); IR (thin film) ν 2977, 2110,
1693, 1609, 1439, 1275, 1138 cm-1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.24 (s, 9H, -OPiv), 3.50 (s, 3H, -OMe), 3.59 (ddd,
1H, J ) 10.7, 5.0, 3.0 Hz, H-6), 3.68 (dd, 1H, J ) 11.1, 10.7,
H-5), 3.86 (m, 2H, H-3a and H-7a), 3.99 (dd, 1H, J ) 11.1, 5.0
Hz, H-5), 4.72 (brs, 1H, H-7), 5.32 (d, 1H, J ) 4.1 Hz, H-3),
5.86 (s, 1H, H-2), 8.24 (s, 1H, H-6′), 8.76 (brs, 1H, -NH); 13C
NMR (100 MHz, CDCl3) δ (ppm) 27.5, 39.3, 58.1, 59.4, 60.8,
66.5, 68.7, 72.2, 72.9, 76.6, 91.2, 144.7, 149.6, 159.9, 176.8;
FAB-MS m/z (relative intensity) 536 (M + H+, 5), 298 (M+
-
PhS - I, 15); HRMS (FAB) calcd for C17H23N5O7I [M+]
536.0642, found 536.0664.
(2R,3R,3aR,6S,7R,7aR)-7-Azido-2-(5′-methyl-2′,4′-dioxo-
3′,4′-dihydro-2H-pyrimidin-1′-yl)-6-methoxy-3-pivaloyloxy-
hexahydrofuro[3,2-b]pyran (30). Colorless oil: yield 86%;
[R]D +80.8° (c 0.7, CHCl3); IR (thin film) ν 2930, 2109, 1711,
(2R,3R,3aS,6S,7R,7aR)-3-Hydroxyl-2-(2′,4′-dioxo-3′,4′-
dihyro-2H-pyrimidin-1′-yl)-6-methoxy-hexahydrofuro-
[3,2-b]pyran-7-yl]-urea (N-Malayamycin) (6). White
1
1463, 1278, 1151 cm-1; H NMR (400 MHz, CDCl3,) δ (ppm)
1
solid: yield 50%; [R]D +27.5° (c 0.08, MeOH); H NMR (400
1.23 (s, (H, PivO-), 1.95 (s, 3H, -Me), 3.49 (s, 3H, -OMe), 3.56
(m, 1H, H-6), 3.66 (dd, 1H, J ) 10.1, 2.4 Hz, H-7a), 3.77 (dd,
1H, J ) 10.1, 2.6 Hz, H-3a), 3.92 (m, 1H, H-5), 3.96 (m, 1H,
H-5), 4.68 (d, 1H, J ) 2.4 Hz, H-7), 5.28 (d, 1H, J ) 2.6 Hz,
H-3), 5.92 (s, 1H, H-2), 7.37 (s, 1H, H-6′), 8.8 (s, 1H, -NH);
13C NMR (100 MHz, CDCl3) δ (ppm) 13.1, 27.5, 39.3, 58.1, 59.4,
66.2, 72.5, 73.0, 76.2, 76.9, 93.0, 111.9, 135.5, 150.0, 163.8,
177.9; FAB-MS m/z (relative intensity) 424 (M + H+, 18), 408
(M+ - Me, 10), 298 (M+ - thymine, 35).
MHz, CD3OD) δ (ppm) 3.37 (s, 3H, -OMe), 3.46 (dd, 1H, J )
11.9, 11.0 Hz, H-5), 3.54 (m, 1H, H-6), 3.67 (dd, 1H, J ) 11.0,
5.4 Hz, H-5), 3.97 (dd, 1H, J ) 11.4, 5.4 Hz, H-3a), 4.01 (dd,
1H, J ) 11.4, 5.4 Hz, H-7a), 4.25 (d, 1H, J ) 5.4 Hz, H-3),
4.95 (m, 1H, H-7), 5.66 (d, 1H, J ) 8.3 Hz, H-5′), 5.68 (s, 1H,
H-2), 7.67 (d, 1H, J ) 8.3 Hz, H-6′); 13C NMR (100 MHz, CD3-
OD) δ (ppm) 48.3, 55.2, 66.0, 72.3, 73.8, 74.2, 77.6, 94.1, 101.2,
10.8, 150.9, 161.3, 164.8; HRMS (FAB) calcd for C13H18N4O7-
Na [M + Na]+ 365.1073, found 365.1064.
(2R,3R,3aR,6S,7R,7aR)-7-Azido-2-(4′-acetylamino-2′-
oxo-3′,4′-dihydro-2H-pyrimidin-1′-yl)-6-methoxy-3-pi-
valoyloxy-hexahydrofuro[3,2-b]pyran (31). Colorless oil:
yield 71%; [R]D +98.8° (c 0.8, CHCl3); IR (thin film) ν 2934,
(2R,3R,3aS,6S,7R,7aR)-3-Hydroxy-6-methoxy-[2-(5′-
methyl-2′,4′-dioxo-3′,4′-dihyro-2H-pyrimidin-1-yl)-hexahy-
drofuro[3,2-b]pyran-7-yl]-urea (34). White solid: yield 76%;
1
[R]D +72.0° (c 0.125, MeOH); H NMR (400 MHz, CD3OD) δ
J. Org. Chem, Vol. 70, No. 17, 2005 6729

Hanessian et al.
(ppm) 1.90 (s, 3H, -Me), 3.37 (s, 3H, -OMe), 3.50 (m, 2H, H-5
and H-6), 3.69 (m, 1H, H-5), 3.95 (dd, 1H, J ) 10.5, 5.4 Hz,
H-3a), 4.02 (dd, 1H, J ) 10.5, 3.4 Hz, H-7a), 4.21 (d, 1H, J )
5.4 Hz, H-3), 4.96 (m, 1H, H-7), 5.68 (s, 1H, H-2), 7.52 (s, 1H,
H-6′); 13C NMR (100 MHz, CD3OD) δ (ppm) 11.7, 48.6, 55.8,
66.6, 72.6, 73.7, 74.0, 76.9, 93.9, 106.0, 139.0, 151.2, 161.0,
163.0; FAB-MS m/z (relative intensity) 379 (M + Na+, 40), 357
(M + H+, 100); HRMS (FAB) calcd for C14H21N4O7 [M + H]+
357.1410, found 357.1418.
(2R,3R,3aS,6S,7R,7aR)-[2-(4′-Amino-2′-oxo-2H-pyrimi-
din-1′-yl)-3-hydroxy-6-methoxy-hexahydrofuro[3,2-b]py-
ran-7-yl]-urea (35). White solid: yield 50%; [R]D +91.7 (c 0.06,
MeOH); 1H NMR (400 MHz, CD3OD) δ (ppm) 3.35 (m, 1H,
H-6), 3.37 (s, 3H, -OMe), 3.50 (m, 2H, H-5 and H-6), 3.66 (dd,
1H, J ) 10.6, 5.3 Hz, H-3a), 3.96 (dd, 1H, J ) 11.6, 5.4 Hz,
H-5), 4.05 (dd, 1H, J ) 10.6, 2.3 Hz, H-7a), 4.19 (d, 1H, J )
4.3 Hz, H-3), 4.97 (m, 1H, H-7), 5.67 (s, 1H, H-2), 5.87 (d, 1H,
J ) 7.5 Hz, H-5′), 7.73 (d, 1H, J ) 7.5 Hz, H-6′); 13C NMR
(100 MHz, CD3OD) δ (ppm) 48.8, 55.8, 66.6, 72.6, 73.5, 74.1,
76.9, 94.7, 94.8, 140.7, 156.9, 161.3, 166.7; FAB-MS m/z
(relative intensity) 364 (M + Na+, 35), 342 (M + H+, 18), 325
(M+ - NH2, 8).
(2R,3R,3aS,6S,7R,7aR)-3-Hydroxy-[2-(6′-oxo-1′,6′-dihy-
dro-purin-9′-yl)-6-methoxy-hexahydrofuro[3,2-b]pyran-
7-yl]-urea (36). White solid: yield 42%; [R]D +95.0° (c 0.2,
MeOH); 1H NMR (400 MHz, CD3OD) δ (ppm) 3.37 (s, 3H,
-OMe), 3.51 (dd, 1H, J ) 11.6, 10.8 Hz, H-5), 3.70 (m, 2H,
H-6 and H-7a), 3.98 (dd, 1H, J ) 11.6, 5.6 Hz, H-5), 4.16 (dd,
1H, J ) 10.7, 4.2 Hz, H-3a), 4.42 (d, 1H, J ) 4.2 Hz, H-3),
5.02 (brs, 1H, H-7), 6.30 (s, 1H, H-2), 8.03 (s, 1H, H-2′), 8.26
(s, 1H, H-8′); 13C NMR (100 MHz, CD3OD) δ (ppm) 48.0, 55.3,
66.1, 72.7, 73.2, 73.6, 76.8, 94.2, 115.2, 140.4, 144.9, 154.3,
156.5, 162.2; FAB-MS m/z (relative intensity) 366 (M+, 8).
(2R,3R,3aS,6S,7R,7aR)-[2-(6′-Amino-purin-9′-yl)-3-hy-
droxy-6-methoxy-hexahydrofuro[3,2-b]pyran-7-yl]-
urea (37). White solid: yield 30%; [R]D +44.0° (c 0.15, MeOH);
1H NMR (400 MHz, CD3OD) δ (ppm) 3.29 (m, 1H, H-6), 3.39
(s, 3H, -OMe), 3.56 (t, 1H, J ) 11.0 Hz, H-5), 3.69 (dd, 1H, J
) 10.0, 4.7 Hz, H-7a), 4.00 (dd, 1H, J ) 11.0, 5.1 Hz, H-5),
4.11 (dd, 1H, J ) 10.0, 3.2 Hz, H-3a), 4.51 (d, 1H, J ) 4.5 Hz,
H-3), 4.96 (brs, 1H, H-7), 6.03 (s, 1H, H-2), 8.12 (s, 1H, H-2′),
8.23 (s, 1H, H-8′); 13C NMR (100 MHz, CD3OD) δ (ppm) 48.8,
55.9, 66.6, 72.6, 73.8, 74.3, 76.8, 93.1, 112.3, 139.5, 148.6, 152.8,
156.8, 161.8; LC-MS m/z (relative intensity) 366 (M + H+, 100).
3-Azido-1,2,4-Tri-O-benzoyl-3-deoxy-D-xylopyranose
(39). Compound 3832 (1.075 g, 5.0 mmol) was dissolved in
water (125 mL) and acetic acid (125 mL). After refluxing for 3
h, the mixture was concentrated, and the residue was purified
by flash chromatography (hexanes/ethyl acetate, 1:4) to give
the desired triol (757 mg, 86%) as an oil, which was very
difficult to dry. An 85:15 mixture of pyranose and furanose
was obtained, both being a mixture of R and â isomers.
To a mixture of the above triol (757 mg, 4.3 mmol),
anhydrous Et3N (3.62 mL, 26.0 mmol) and DMAP (32 mg, 2.6
mmol), dissolved in dry CH2Cl2 (15 mL) and cooled to 0 °C,
was added dropwise a solution of BzCl (3.0 mL, 26.0 mmol) in
anhydrous CH2Cl2 (15 mL) under argon atmosphere. After
stirring for 1 h at room temperature, the mixture was diluted
with EtOAc (210 mL), and the organic phase was washed
successively with saturated NaHCO3 (210 mL × 2) and brine
(210 mL × 2), then dried over anhydrous Na2SO4, filtered, and
concentrated. Purification by flash silica gel chromatography
(hexanes/ethyl acetate, 2:1) gave the expected triester (2.0 g,
97%), as a pyranose (major) and furanose (minor) mixture. IR
(thin film) ν 3073, 3011, 2887, 2678, 2564, 2112, 1727, 1690,
1602, 1585 cm-1; 1H NMR (400 MHz, CDCl3) δ (ppm) 4.22 (m,
2H), 4.49 (t, 1H, J ) 3.49 Hz), 5.68-5.55 (m, 2H), 6.48 (d, 1H,
J ) 5.10 Hz), 7.29-7.24 (m, 1H), 7.57-7.39 (m, 9H), 7.69-
7.59 (m, 4H), 8.00-7.97 (m, 1H), 8.09-8.01 (m, 1H), 8.23-
8.15 (m, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 58.4, 58.5,
59.9, 63.2, 66.6, 68.3, 68.6, 69.3, 89.1, 91.6, 95.1, 99.3, 128.8,
128.9, 129.0, 129.0, 129.0, 129.1, 129.1, 129.2, 130.4, 130.5,
130.6, 130.6, 134.1, 134.2, 134.2, 134.4, 164.8, 4 × 3CO2 esters,
165.0, 165.4, 165.5, 165.7, 165.9, 166.2, 166.6; FAB-MS m/z
(relative intensity) 488.1 (M + H+, 7), 366.2 (M+ - PhCO2,
100).
(3R,4S,5S)-4-Azido-3,5-bis-O-benzoyl-tetrahydropyran-
2-carbonitrile (40). Method A. To a mixture of 39 (487 mg,
1.0 mmol) and TMSCN (400 µL, 3.0 mmol) in 10 mL of dry
MeNO2 at 0 °C was added 181 µL (1.0 mmol) of TMSOTf. After
stirring for 18 h, the solution was diluted with EtOAc (40 mL
× 2), and quenched with saturated NaHCO3 (40 mL). The
aqueous phase was extracted with EtOAc (40 mL), and the
combined organic phases were dried over anhydrous Na2SO4,
filtered, and concentrated. Purification by flash chromatogra-
phy (hexanes/ethyl acetate, 3:1) gave 40 (287 mg, 73%) as a
4:1 â and R mixture, in favor of the â anomer (determined by
NMR): IR (thin film) ν 3065, 2960, 2885, 2114, 1728, 1602,
1585, 1452 cm-1; 1H NMR (400 MHz, CDCl3) â-anomer δ (ppm)
3.95 (t, 1H, J ) 10.11 Hz,), 4.13 (dd, 1H, J ) 11.46, 3.97 Hz),
4.62 (m, 1H), 8.16-8.07 (m, 4H), 4.83 (d, 1H, J ) 8.22 Hz),
5.459-5.42 (m, 2H), 7.51-7.46 (m, 4H), 7.64-7.59 (m, 2H) ;
13C NMR (100 MHz, CDCl3) δ (ppm) 59.6, 60.8, 63.1. 64.5, 64.7,
67.7, 69.3, 70.2, 76.5, 80.8, 115.5, 116.2, 128.4, 128.6, 129.0,
129.1, 129.1, 129.2, 129.6, 130.3, 130.4, 130.5, 130.6, 134.0,
134.3, 134.6, 134.7, 165.3, 165.6; HRMS (EI): calcd for
C20H16N4O5 [M+] 392.1120, found 392.1123.
Method B. To a mixture of 39 (974 mg, 2.0 mmol) and
TMSCN (800 µL, 6.0 mmol) in 10 mL of dry MeNO2 was added
253 µL (2.0 mmol) of BF3‚OEt2. After stirring for 17 h at room
temperature, the solution was diluted with EtOAc (48 mL),
and quenched by a NaHCO3 saturated solution (48 mL). The
aqueous phase was extracted with EtOAc (48 mL × 2), and
the combined organic phases were dried over anhydrous Na2-
SO4, filtered, and concentrated. Purification by flash chroma-
tography (hexanes/ethyl acetate 3/1) afforded 40 (426 mg, 54%)
as a 14:1 â and R mixture, in favor of the â anomer (determined
1
by NMR). H NMR (400 MHz, CDCl3) â-anomer δ (ppm) 3.95
(t, 1H, J ) 10.11 Hz,), 4.13 (dd, 1H, J ) 11.46, 3.97 Hz), 4.62
(m, 1H), 4.83 (d, 1H, J ) 8.22 Hz), 5.459-5.42 (m, 2H), 7.51-
7.46 (m, 4H), 7.64-7.59 (m, 2H), 8.16-8.07 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 59.6, 60.8, 64.5, 64.7, 67.7, 69.3,
70.2, 76.5, 80.9, 115.4, 128.6, 129.0, 129.1, 129.2, 130.3, 130.4,
130.5, 130.6, 133.9, 134.3, 134.5, 134.6, 165.3, 165.6.
(2R,3R,4S,5S)-4-Azido-3,5-bis(tert-butyldimethylsila-
nyloxy)-tetrahydropyran-2-carboxylic Acid Methoxy-
methylamide (41). To a solution of cyanide 40 (6.66 g, 17
mmol) in 100 mL of distilled MeOH was added 3.4 mL (1.7
mmol) of a NaOMe solution (0.5 M in MeOH). After stirring
for 1 h at room temperature the solvent was evaporated under
vacuum. The crude product was hydrolyzed upon heating in a
mixture of 50 mL of a 5 M aqueous NaOH solution and 50 mL
of MeOH at 45 °C for 3 h. The pH was then brought to 1 by
addition of a 1 M HCl solution, and the solvent was removed
under reduced pressure. The mixture was resolved in MeOH,
and the NaCl formed was filtered under vacuum. The solvent
was evaporated again, and the crude acid dissolved in 100 mL
of distilled MeOH was treated with TMSCl (6.5 mL, 51 mmol)
for 13 h at room temperature. After evaporation the residue
was purified by flash chromatography (ethyl acetate/hexanes,
4:1), affording the expected methyl ester (2.72 g, 75%) as an
R,â-mixture.
A mixture of the above diol (2.72 g, 12.5 mmol), TBDMSCl
(7.55 g, 50 mmol), and imidazole (3.41 g, 50 mmol), in
anhydrous CH2Cl2 (60 mL) under argon atmosphere, was
stirred for 15 h at room temperature. The reaction was
quenched by addition of water (120 mL), and the aqueous
phase was extracted with EtOAc (120 mL × 2). The combined
organic phases were dried over anhydrous Na2SO4, filtered,
and concentrated. Purification by flash silica gel chromatog-
raphy (hexanes/ethyl acetate, 9:1) gave the expected product
(5.3 g, 95%), isolated as a sticky oil of R,â-anomers.
To a solution of N,O-dimethylhydroxylamine hydrochloride
(2.51 g, 25.7 mmol, 2.2 equiv) in CH2Cl2 (140 mL) under argon
6730 J. Org. Chem., Vol. 70, No. 17, 2005

Total Synthesis of N-Malayamycin A
atmosphere at 0 °C was slowly added 12.85 mL of a 2 M in
toluene AlMe3 solution (25.7 mmol, 2.2 equiv). After stirring
for 40 min at 0 °C, a solution of protected methyl ester (5.20
g, 11.68 mmol) in 25 mL of CH2Cl2 under argon atmosphere
was added dropwise. The mixture was stirred for 22 h letting
the temperature slowly rise with the ice bath to room tem-
perature, then it was cooled to 0 °C again, and the reaction
was quenched by careful addition of a 0.5M HCl solution (65
mL) (Caution: can be quite violent). The aqueous phase was
extracted with CH2Cl2 (140 mL × 2), the combined organic
phases were dried over anhydrous Na2SO4, filtered and
concentrated. Flash silica gel chromatography (hexanes/ethyl
acetate, 4:1) afforded 41 (3.70 g, 68%) as a sticky oil, along
with 1 g of R-anomer (19%): [R]D -25.0° (c 1.0, CH2Cl2); IR
(thin film) ν 2957, 2931, 2898, 2859, 2106, 1672 cm-1; 1H NMR
(400 MHz, CDCl3) δ (ppm) 0.06 (s, 3H, -CH3), 0.10 (s, 3H,
-CH3), 0.14 (s, 6H, 2 × -CH3), 0.90 (s, 9H, 3 × -CH3), 0.94
(s, 9H, 3 × -CH3), 3.23 (s, 3H, -NMe), 3.58 (t, 1H, J ) 10.59
Hz, H-5), 3.68 (dd, 1H, J ) 10.91, 5.05 Hz, H-5), 3.77 (s, 3H),
3.93 (m, 1H, -OMe), 4.00 (ddd, 1H, J ) 10.14, 5.18, 3.20 Hz,
H-4), 4.06 (dd, 1H, J ) 9.14, 3.14 Hz, H-2), 4.49 (d, 1H, J )
9.16 Hz, H-1); 13C NMR (100 MHz, CDCl3) δ (ppm) -4.6, -4.4,
-4.2, -4.1, 18.4, 18.4, 26.0, 26.1, 32.5, 62.5, 66.8, 68.5, 68.6,
69.8, 70.7, 169.9.
(2R,3R,4S,5S)-4-Azido-3,5-bis(tert-butyldimethylsila-
nyloxy)-tetrahydropyran-2-carbaldehyde (42). A solution
of 41 (237 mg, 0.5 mmol) in anhydrous toluene (5 mL) under
argon atmosphere was cooled to -78 °C and treated with 750
µL (0.75 mmol) of a 1 M in DIBAL-H in hexanes. After stirring
for 2 h at -78 °C, the mixture was quenched by addition of a
1 M HCl solution (1 mL), warmed to room temperature, then
diluted with EtOAc (50 mL). Rochelle’s salt (50 mL) was added,
and the mixture was stirred at room temperature until the
two phases became clear. The aqueous phase was extracted
with EtOAc (50 mL × 2), and the combined organic phases
were dried over anhydrous Na2SO4, filtered, and concentrated.
The crude product was dissolved in 50 mL of CH2Cl2, and
Dess-Martin periodinane reagent (318 mg, 0.75 mmol) and
solid NaHCO3 (109 mg, 1.3 mmol) were added to the solution.
After stirring for 2 h at room temperature, the reaction was
quenched by addition of a NaHCO3 saturated solution (50 mL)
and saturated Na2S2O3 (50 mL). The mixture was stirred for
30 min, and the aqueous phase was extracted with CH2Cl2 (100
mL × 2). The combined organic phases were dried over
anhydrous Na2SO4, filtered, and concentrated. The aldehyde,
isolated as a white crystalline solid, was used directly in the
next step without further purification: 1H NMR (400 MHz,
CDCl3) δ (ppm) 0.16 (s, 12H, 4 × -CH3), 0.94 (s, 18H, 6 ×
-CH3), 3.54 (t, 1H, J ) 10.39 Hz, H-6), 3.74-3.69 (m, 1H, H-6),
3.81 (dd, 1H, J ) 9.62, 2.90 Hz, H-2), 3.90-3.86 (m, 2H, H-4
+ H-5), 4.08 (d, 1H, J ) 9.63 Hz, H-2), 9.73 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) -4.6, -4.5, -4.3, -3.7, 18.4, 18.4,
26.0, 26.0, 66.3, 68.2, 68.4, 69.6, 79.1, 199.2.
mg, 25%). For 43: [R]D +69.6° (c 0.5, CH2Cl2); IR (thin film):
ν 2856, 2931, 2859, 2107, 1473 cm-1 1H NMR (300 MHz,
;
CDCl3) δ (ppm) 0.17 (s, 12H, 4 × -CH3), 0.96 (s, 18H), 3.39 (t,
1H, J ) 10.59 Hz, H-6′), 3.49 (dd, 1H, J ) 10.64, 5.10 Hz, H-6′),
3.62 (s, 1H, H-2), 3.90-3.73 (m, 5H, H-2′, H-3′, H-4′, H-5′ and
-OH), 4.79 (s, 1H, H-1), 7.28 (m, 6H), 7.46 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ (ppm) -4.4, -4.3, -4.3, 3.5, 18.4, 18.5, 26.1,
26.2, 63.2, 66.8, 68.1, 69.2, 73.2, 73.8, 75.6, 128.0, 128.2, 129.3,
129.3, 133.1, 133.7, 134.9, 135.0. For epi-43: 1H NMR (300
MHz, CDCl3) δ (ppm) 0.13 (s, 12H, 4 × -CH3), 0.93 (s, 18H),
2.97 (d, 1H, J ) 5.21 Hz, -OH), 3.32 (t, 1H, J ) 10.39 Hz,
H-6′), 3.55 (dd, 1H, J ) 10.52 Hz, 4.67, H-6′), 3.76 (dd, 1H, J
) 8.52, 5.32 Hz, H-1), 3.92-3.84 (m, 3H, H-3′, H-4′ and H-5′),
4.01 (d, 1H, J ) 9.62 Hz, H-2′), 4.62 (d, 1H, J ) 9.21 Hz, H-1),
7.37-7.24 (m, 6H), 7.52-7.44 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ (ppm) -4.6, -4.4, -4.2, -3.8, 18.4, 18.5, 26.1, 26.1,
63.8, 66.7, 68.3, 68.7, 69.0, 69.7, 73.7, 128.3, 128.9, 129.3, 129.4,
129.5, 132.4, 133.2, 134.4, 134.5.
(4R,5R,7S,8S,9R)-(8-Azido-4-(bis-phenylsulfanylmethyl)-
2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxin-7-ol (44).
To a mixture of 43 (450 mg, 0.70 mmol) and 4 Å MS suspended
in anhydrous THF (7 mL) under argon atmosphere was added
dropwise TBAF solution (1 M in THF) (1.53 mL, 1.53 mmol).
After stirring for 16 h at room temperature, the reaction was
quenched by addition of silica gel, filtered under vacuum and
concentrated. The crude product was directly purified by flash
silica gel chromatography (ethyl acetate/hexanes 3:1) to afford
triol (264 mg, 91%): [R]D +175.4° (c 0.5, CH2Cl2); IR (thin
film): ν 3401, 3059, 2926, 2110, 1582, 1480, 1439 cm-1 1H
;
NMR (400 MHz, CDCl3) δ (ppm) 3.06 (t, 1H, J ) 10.70 Hz),
3.44 (d, 1H, J ) 2.74 Hz), 3.58 (dd, 1H, J ) 10.75, 5.14 Hz),
3.68 (m, 1H), 3.81 (m, 2H), 3.92 (m, 1H), 4.17 (m, 2H), 4.90 (s,
1H), 7.42-7.28 (m, 8H), 7.53 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 63.0, 65.6, 66.2, 72.9, 73.6, 76.4, 128.4, 128.7,
129.6, 129.8, 132.8, 132.8, 133.6.
Method A. To a mixture of above the triol (25 mg, 0.06
mmol), PTSA (6 mg, 0.03 mmol), and solid Na2SO4 (85 mg,
0.6 mmol, dried in the oven for 24 h prior to use) in anhydrous
CH2Cl2 (1.8 mL) under argon atmosphere was added slowly
2-methoxypropene (29 µl, 0.3 mmol). After stirring for 4 h at
room temperature, the reaction mixture was poured into 10
mL of saturated NaHCO3, and the aqueous phase was ex-
tracted with CH2Cl2 (10 mL × 2). The combined organic phases
were dried over anhydrous Na2SO4, filtered, and concentrated.
Purification by flash silica gel chromatography (hexanes/ethyl
acetate, 1:1) afforded 44 (22 mg, 81%) as a white crystalline
solid, along with 3 mg (12%) of recovered starting material.
Method B. To a mixture of the above triol (25 mg, 0.06
mmol), PTSA (6 mg, 0.03 mmol), and solid Na2SO4 (85 mg,
0.6 mmol, dried in the oven for 24 h prior to use) in anhydrous
CH2Cl2 (1.8 mL) under argon atmosphere was added slowly
2,2-dimethoxypropane (37 µl, 0.3 mmol). After stirring for 4 h
at room temperature, the reaction mixture was poured into
10 mL of a NaHCO3 saturated solution, and the aqueous phase
was extracted with CH2Cl2 (10 mL × 2). The combined organic
phases were dried over anhydrous Na2SO4, filtered, and
concentrated. Purification by flash silica gel chromatography
(hexanes/ethyl acetate, 1:1) afforded 44 (23 mg, 84%) as a
white crystalline solid: [R]D +145.2° (c 1.95, CH2Cl2); IR (thin
film) ν 3437, 2995, 2939, 2869, 2110, 1642, 1471, 1440, 1383
(1R,2′R,3′R,4′S,5′S)-1-[4′-Azido-3′,5′-bis(tert-butyldi-
methylsilanyloxy)-tetrahydropyran-2′-yl]-2,2-bis-phenyl-
sulfanyl-ethanol (43). To a solution of (PhS)2CH2 (279 mg,
1.2 mmol) in anhydrous THF (12 mL) under argon atmosphere,
cooled to -10 °C, was added dropwise 0.85 mL (1.15 mmol) of
a 1.35 M BuLi solution in hexanes (titrated). After stirring
for 25 min at -10 °C, the mixture was cooled to -78 °C, and
a solution of the crude aldehyde (0.5 mmol) dissolved in
anhydrous THF (5 mL) under argon atmosphere and cooled
to -78 °C, was slowly added to the flask. The reaction was
stirred for 30 min at -78 °C and quenched by adding 2 mL of
a 1 M HCl solution. After warming to room temperature, the
mixture was diluted with EtOAc (50 mL) and water (50 mL),
and the aqueous phase was extracted with EtOAc (100 mL ×
2). The combined organic phases were washed with brine (150
mL), dried over anhydrous Na2SO4, filtered, and concentrated.
Purification by flash silica gel chromatography (hexanes/ethyl
acetate, 95:5) gave the desired product 43 (161 mg, 50%) as a
white crystalline solid, along with the S diastereoisomer (82
1
cm-1; H NMR (400 MHz, CDCl3) δ (ppm) 1.47 (s, 3H, CH3),
1.52 (s, 3H, -CH3), 2.09 (d, 1H, J ) 10.53 Hz, OH-7), 3.16 (t,
1H, J ) 10.71 Hz, H-6), 3.80-3.67 (m, 3H, H-6, H-7 and H-9),
4.12 (d, 1H, J ) 9.43 Hz, H-4), 4.17 (s, 1H, H-8), 4.76 (s, 1H),
7.30-7.28 (m, 6H), 7.47-7.44 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 19.8, 29.2, 60.3, 63.2, 66.5, 67.5, 69.2, 71.8,
75.3, 101.2, 127.8, 128.3, 129.3, 129.4, 132.5, 133.4, 133.7,
134.7.
(1′R,2R,3R,4S,5S)-4-Azido-2-(1′-hydroxy-2′,2′-bis-phen-
ylsulfanylethyl)-5-methoxy-tetrahydropyran-3-ol (22). To
a solution of 44 (39 mg, 0.08 mmol) dissolved in anhydrous
DMF (2 mL) under argon atmosphere and cooled to 0 °C, was
J. Org. Chem, Vol. 70, No. 17, 2005 6731

Hanessian et al.
added 2.5 mg (0.1 mmol) of a 95% NaH suspension. After 5
min, 11.5 µL (0.1 mmol) of MeI was added dropwise, and the
mixture was stirred for 1 h at 0 °C. A spatula tip of additional
NaH was added to consume the remaining starting material,
and the reaction was quenched by addition of MeOH (2 mL).
The mixture was diluted with water (10 mL), and the aqueous
phase was extracted with CH2Cl2 (20 mL × 3). The combined
organic phases were dried over anhydrous Na2SO4, filtered,
and concentrated. Purification by flash silica gel chromatog-
raphy (hexanes/ethyl acetate, 3:1) gave the desired methylated
product (37 mg, 93%).
°C; [R]D +42.5° (c 2, CHCl3); IR (thin film) ν 3310, 2107, 1261,
1
1132, 1000 cm-1; H NMR (400 MHz, CDCl3) δ (ppm) 1.35 (s,
3H, -CH3), 1.58 (s, 3H, -CH3), 2.58 (s, 1H), 3.54 (dd, 1H, J )
9.79, 4.21 Hz), 3.72-3.90 (m, 3 H), 4.31 (dd, 1H, J ) 9.78,
3.28 Hz), 4.34 (s, 1H), 4.66 (t, 1H, J ) 3.56 Hz), 5.84 (d, 1H, J
) 3.38 Hz, H-2); 13C NMR (100 MHz, CDCl3) δ (ppm) 25.9,
26.1, 68.5, 68.6, 69.7, 72.0, 75.0, 76.3, 104.3, 113.8; LRMS
(ESI): 258.1 [M + H]+.
(3aR,3bR,6S,7S,7aR,8aR)-7-Azido-6-methoxy-2,2,6-tri-
methyl-hexahydro-1,3,4,8-tetraoxa-cyclopenta[a]in-
dene (48). To a solution of 47 (600 mg, 2.33 mmol) in CH2Cl2
(70 mL) was added Dess-Martin periodinane reagent (2.36
g, 7.74 mmol) and the mixture was stirred at room tempera-
ture for 2.5 h. Saturated solutions of NaHCO3 (30 mL) and
Na2S2O3 (30 mL) were added to the mixture and stirred at
room temperature for 10 min. The two phases were separated,
the aqueous phase was extracted with CH2Cl2 (3 × 50 mL),
and the combined organic phases were washed with a satu-
rated solution of NaHCO3 (50 mL) and dried with Na2SO4.
After concentration, the crude product was dried in vacuo for
30 min, then dissolved in THF (30 mL) and cooled to -78 °C.
MeMgBr (1 mL, 3.0 mmol, 3 M solution in ether) was added,
and the mixture was stirred at -78 °C for 1 h and then at
room temperature for 30 min. The mixture was quenched with
a saturated solution of NH4Cl (30 mL) and extracted with ether
(50 mL × 3), and the combined organic phases were washed
with brine (50 mL) and dried with Na2SO4. The crude oil was
then purified by flash silica gel chromatography (ethyl acetate/
hexanes, 1:1) to afford the product as a colorless gum (115 mg,
0.42 mmol, 18%, 2 steps): Rf ) 0.41 (ethyl acetate/hexanes,
1:1); [R]D +72.9° (c 3.8, CHCl3); IR (thin film) ν 3469, 2988,
To a solution of product (33 mg, 0.07 mmol) in distilled
MeOH (6 mL) under argon atmosphere was added 13 mg (0.07
mmol) of PTSA. After stirring for 24 h at room temperature,
the reaction was quenched by addition of saturated NaHCO3
(3 mL), and the product was extracted with CH2Cl2 (20 mL ×
3). The combined organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated. Purification by flash silica
gel chromatography (hexanes/ethyl acetate, 1:1) gave 22 (30
1
mg, quant): [R]D +28.0° (c 0.6, CHCl3); H NMR (400 MHz,
CDCl3) δ (ppm) 3.22 (t, 1H, J ) 10.6 Hz, H-6), 3.35 (ddd, 1H,
J ) 10.6, 4.8, 3.0 Hz, H-5), 3.40 (s, 3H, -OMe), 3.63 (ddd, 1H,
J ) 10.6, 4.8, 1.1 Hz, H-6), 3.69 (dd, 1H, J ) 9.1, 3.2 Hz, H-3),
3.76 (t, 1H, J ) 9.1 Hz, H-2), 3.90 (dd, 1H, J ) 8.2, 2.2 Hz,
H-1′), 4.26 (t, 1H, J ) 2.2 Hz, H-4), 4.87 (d, 1H, J ) 2.2 Hz,
H-2′), 7.26-7.50 (m, 10H, -Ph); 13C NMR (100 MHz, CDCl3)
δ (ppm) 56.9, 62.4, 63.2, 71.9, 72.7, 75.6, 76.0, 127.9, 128.0,
128.9, 129.1, 132.3
(3aR,3bR,7aR,8aR)-2,2-Dimethyl-3a,5,7a,8a-tetrahydro-
3bH-1,3,4,8-tetraoxa-cyclopenta[a]indene (46). To a solu-
tion of 4511c (2 g, 7.8 mmol) in CH2Cl2 (860 mL) was added
Grubbs catalyst (375 mg, 0.45 mmol) and the mixture was
stirred at reflux (45 °C) for 3 h. The solvent was removed by
evaporation and the crude product was purified by flash silica
gel chromatography (hexanes/ethyl acetate, 4:1) to afford the
product 46 as a white solid (1.42 g, 7.17 mmol, 92%): Rf )
0.16 (hexanes/ethyl acetate, 4:1); mp 64-65 °C; [R]D +17.7° (c
2936, 2872, 2111, 1376 cm-1 1H NMR (400 MHz, CDCl3) δ
;
(ppm) 1.34 (s, 3H, -CH3), 1.40 (s, 3H, -CH3), 1.57 (s, 3H,
-CH3), 2.41 (s, 1H), 3.48 (q, 2H, J ) 11.3 Hz), 3.60 (m, 1H),
4.09 (s, 1H), 4.11 (d, 1H, J ) 3.04 Hz), 4.86 (t, 1H, J ) 3.59
Hz), 5.86 (d, 1H, J ) 3.37 Hz, H-2); 13C NMR (100 MHz, CDCl3)
δ (ppm) 24.2, 25.8, 26.1, 66.9, 69.3, 73.2, 73.5, 75.4, 75.7, 105.6,
113.8.
3.3, CHCl3); IR (thin film) ν 3142, 1620, 1384, 1215, 1023 cm-1
;
1H NMR (400 MHz, CDCl3) δ (ppm) 1.32 (s, 3H, -CH3), 1.53
(s, 3H, -CH3), 3.26 (dd, 1H, J ) 8.14, 3.92 Hz), 4,38 (s, 1H),
4.40 (s, 2 H), 4.63 (t, 1H, J ) 3.57 Hz), 5.64 (d, 1H, J ) 2.06
Hz, H-7), 5.83 (d, 1H, J ) 3.50 Hz, H-6), 6.18 (d, 1H, J ) 8.14
Hz, H-2); 13C NMR (100 MHz, CDCl3) δ (ppm) 25.8, 26.0, 68.6,
69.4, 76.1, 78.9, 105.6, 113.2, 126.3, 127.3; LRMS (ESI) 199.1
[M + H]+.
To a solution of the above alcohol (115 mg, 0.42 mmol) in
DMF (14 mL) at 0 °C was added NaH (22 mg, 0.55 mmol, 60%
dispersion in mineral oil) and the mixture was stirred at 0 °C
for 10 min. Iodomethane (0.035 mL, 0.55 mmol) was then
added, and the mixture was stirred at room temperature for
2 h. The mixture was quenched with a saturated solution of
NH4Cl (14 mL) and extracted with ethyl acetate (40 mL × 3)
and the combined organic phases were washed with water (20
mL) and with brine (20 mL). The organic phase was dried with
Na2SO4, concentrated and the residue was purified by flash
silica gel chromatography (ethyl acetate/hexanes, 1:1) to afford
the product 48 as a white solid (90 mg, 0.32 mmol, 75%): Rf
) 0.54 (ethyl acetate/hexanes, 1:1); mp 117-120 °C; [R]D
+58.26° (c 2.25, CHCl3); IR (thin film) ν 2987, 2937, 2108, 1460,
(3aR,3bR,6R,7R,7aR,8aR)-7-Azido-2,2-dimethyl-hexahy-
dro-1,3,4,8-tetraoxa-cyclopenta[a]inden-6-ol (47). To a
mixture of 46 (1.41 g, 7.73 mmol), THF (133 mL) and water
(133 mL) was added NBS (1.6 g, 9.2 mmol). The solution was
stirred at room temperature (in the absence of light) for 2 h,
and water (133 mL) was added followed by Na2S2O3‚5H2O (0.1
g, 0.40 mmol). After stirring for 5 min, the solution was
extracted with ether (250 mL × 3), and the combined organic
phases were dried with Na2SO4 and concentrated.
The crude product was then dissolved in THF (255 mL), a
solution of 1 M NaOH (67 mL) was added, and the mixture
was stirred at reflux (110 °C) for 1 h. Once the mixture was
cooled to room temperature, water (133 mL) was added and
the organic phase was extracted with ether (300 mL × 3). The
combined organic phases were then dried over Na2SO4 and
concentrated to afford a white crude solid.
This was then dissolved in 2-methoxyethanol (400 mL),
NaN3 (7 g, 108.7 mmol) was added, and the mixture was
stirred at reflux (126 °C) for 1 h. The solution was then cooled
to room temperature, concentrated (45 °C, 1 mmHg), and
diluted with ether (400 mL) and with brine (200 mL). The two
phases were separated, the aqueous phase was extracted with
ether (100 mL × 3), and the combined organic phase was dried
with Na2SO4. After evaporation, the crude oil was purified by
flash silica gel chromatography (ethyl acetate/hexanes, 1:1) to
afford the product 47 as a white solid (1.14 g, 4.43 mmol, 57%
3 steps): Rf ) 0.23 (ethyl acetate/hexanes, 1:1); mp 117-118
1
1376, 1057 cm-1; H NMR (300 MHz, CDCl3) δ (ppm) 1.34 (s,
3H), 1.41 (s, 3H), 1.57 (s, 3H), 3.29 (s, 3H), 3.71 (m, 3H), 3.97
(dd, 1 H, J ) 3.07, 3.05 Hz), 4.25 (d, 1H, J ) 2.3 Hz), 4.62 (t,
1H, J ) 3.62 Hz), 5.84 (d, 1H, J ) 3.41 Hz); 13C NMR (100
MHz, CDCl3) δ (ppm) 20.6, 25.8, 26.1, 49.2, 62.5, 71.8, 72.2,
74.6, 75.6, 75.7, 105.6, 113.6; LRMS (ESI) 286.3 [M + H]+.
(3aR,3bR,6S,7S,7aR,8aR)-7-Azido-6-fluoro-2,2-dimeth-
yl-hexahydro-1,3,4,8-tetraoxa-cyclopenta[a]indene (49).
Compound 47 (400 mg, 1.56 mmol) in CH2Cl2 (5 mL) was
added to a solution of diethylamino sulfurtrifluoride (DAST)
(0.8 mL, 6.23 mmol) in CH2Cl2 (2 mL) at -78 °C. The mixture
was stirred at room temperature for 18 h followed by the slow
addition of water (4 mL). The two phases were separated, the
aqueous phase was extracted with CH2Cl2 (4 mL × 3), the
combined organic phases were washed with brine (10 mL) and
dried with Na2SO4. After concentration, the crude product was
purified by flash silica gel chromatography (hexanes/ethyl
acetate, 3:1) to afford 49 as a colorless oil (120 mg, 0.46 mmol,
30%): Rf ) 0.27 (hexanes/ethyl acetate, 3:1); [R]D +52.3° (c 6,
CHCl3); IR (thin film) ν 2989, 2939, 2360, 2112, 1113, 1003;
6732 J. Org. Chem., Vol. 70, No. 17, 2005

Total Synthesis of N-Malayamycin A
1H NMR (300 MHz, CDCl3) δ (ppm) 1.33 (s, 3H, -CH3), 1.57
(s, 3H, -CH3), 3.57 (dd, 1H, J ) 9.52, 4.15 Hz), 3.75 (dd, 1H,
J ) 42.6, 13.7 Hz), 4.22 (t, 1H, J ) 3.37 Hz), 4.30 (m, 1H),
4.57 (m, 2H), 4.67 (t, 1H, J ) 3.6 Hz), 5.82 (d, 1H, J ) 3.31
Hz, H-2); 13C NMR (75 MHz, CDCl3) δ (ppm) 25.8, 26.1, 58.2,
58.5, 67.1, 72.0, 74.4, 88.4, 104.5, 113.9; LRMS (ESI) 260.0
[M + H]+.
General Procedure for Dithioacetals 50 and 51. To a
solution of 48 (90 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added
PhSH (0.33 mL, 3.2 mmol) followed by Amberlyst-15 (107 mg).
The mixture was stirred at room temperature for 18 h,
quenched with a saturated solution of NaHCO3 (10 mL) and
stirred for 5 min. After the separation of the two phases, the
aqueous phase was extracted with CH2Cl2 (10 mL × 3). The
combined organic phases were washed with brine (10 mL),
dried with MgSO4, filtered and concentrated. The crude
product was purified by flash silica gel chromatography
(hexanes/ethyl acetate, 2:1) to afford the product as a white
solid.
(1′R,2R,3R,4S,5S)-4-Azido-2-(1′-hydroxy-2′,2′-bis-phen-
ylsulfanyl-ethyl)-5-methoxy-5-methyl-tetrahydro-pyran-
3-ol (50). Yield: 80% from 48; Rf ) 0.54 (hexanes/ethyl acetate,
1:1); mp 137-140 °C; [R]D +147.3 ° (c 2.8, CHCl3); IR (thin
film) ν 3436, 2109, 1582, 1086, 690 cm-1; 1H NMR (300 MHz,
CDCl3) δ (ppm) 1.25 (s, 3H, -CH3), 3.21 (d, 2H, J ) 10 Hz),
3.25 (s, 3H, -OCH3), 3.50 (s, 2H), 3.80 (m, 2H), 3.96 (m, 2H),
4.89 (d, 1H, J ) 2.0 Hz), 7.29 (m, 6H), 7.45 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 19.3, 49.1, 62.5, 65.7, 68.3, 70.5, 73.9,
74.1, 75.9, 127.8, 127.9, 128.9, 129.1, 132.4, 133.5, 133.9.
(1′R,2R,3R,4S,5S)-4-Azido-5-fluoro-2-(1′-hydroxy-2′,2′-
bis-phenylsulfanyl-ethyl)-tetrahydro-pyran-3-ol (51).
Yield: 85% from 49; Rf ) 0.21 (hexanes/ethyl acetate, 4:1);
mp 127-129 °C; [R]D +184.2° (c 4, CHCl3); IR (thin film) ν
3369, 2114, 1439, 1272, 1139 cm-1; 1H NMR (300 MHz, CDCl3)
δ (ppm) 3.33 (dd, 1H, J ) 40.3, 13.7 Hz), 3.72 (t, 1H, J ) 14
Hz), 3.87 (t, 1H, J ) 8.89 Hz), 4.12 (m, 3H), 4.48 (d, 1H, J )
42.0 Hz), 4.92 (s, 1H), 7.31 (m, 6H), 7.44 (m, 2H), 7.52 (m, 2H);
13C NMR (75 MHz, CDCl3) δ (ppm) 59.6, 59.9, 62.3, 64.2, 64.4,
70.2, 72.8, 75.9, 86.3, 88.7, 127.9, 128.2, 129.0, 132.2, 132.5,
132.9, 133.9; LRMS (ESI) 422.2 [M + H]+.
Thioglycoside Formation 52 and 53. To a solution of 50
(96 mg, 0.22 mmol) in CH2Cl2 (11 mL) at 0 °C, NBS (61 mg,
0.34 mmol) was added and the mixture was stirred at 0 °C for
45 min. A saturated solution of Na2S2O3 (18 mL) was added
and the solution was stirred at room temperature until it
became colorless. The two phases were separated and the
aqueous phase was extracted with CH2Cl2 (10 mL × 3). The
combined organic phases were washed with brine (20 mL),
dried with Na2SO4, filtered and concentrated. Flash silica gel
chromatography (hexanes/ethyl acetate, 1:1) afforded the
product as a white solid.
less oil: yield 69% (2 steps) from 51; Rf ) 0.43 (hexanes/ethyl
acetate, 4:1); [R]D +141.0° (c 2, CHCl3); IR (thin film) ν 2976,
2908, 2107, 1742, 1480, 1279 cm-1; 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.30 (s, 9H), 3.71 (m, 2H), 4.05 (t, 1H, J ) 15.1 Hz),
4.55 (m, 3H), 5.73 (t, 1H, J ) 4.35 Hz), 5.85 (d, 1H, J ) 4.35
Hz), 7.29 (m, 3H), 7.51 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 27.0, 39.3, 58.1, 58.4, 66.5, 66.8, 70.2, 73.2, 73.4, 85.9,
88.3, 90.2, 127.2, 128.9; LRMS (ESI) 396.1 [M + H]+.
(2R,3R,3aR,6S,7S,7aR)-2-(4′-Acetylamino-2′′-oxo-2H-py-
rimidin-1′-yl)-7-azido-6-methoxy-6-methyl-3-pivaloyloxy-
hexahydrofuro[3,2-b]pyran (54). To a mixture of 52 (55 mg,
0.13 mmol), N4-acetyl bis-O-TMS cytosine (100 mg, 0.44 mmol)
and NIS (100 mg, 0.44 mmol) in CH2Cl2 (1.7 mL) at room
temperature was added TfOH (20 µL, 0.23 mmol) portionwise
over a period of 20 min. Mixture was stirred at room temper-
ature for 4 h, followed by the addition of a saturated solution
of Na2S2O3 (2 mL), and the two phases were separated. The
aqueous phase was extracted with CH2Cl2 (5 mL × 3), and
the combined organic phases were washed with a saturated
solution of NaHCO3 (5 mL) and dried with Na2SO4. After
concentration, the crude product was purified by flash silica
gel chromatography (CH2Cl2/MeOH, 20:1) to afford the product
as a colorless oil: yield 66%; Rf ) 0.3 (CH2Cl2/MeOH, 20:1);
[R]D +188.5° (c 0.87, MeOH); IR (thin film) ν 2972, 2106, 1710,
1
1664, 1138, 1065 cm-1; H NMR (300 MHz, CD3OD) δ (ppm)
1.26 (s, 9H), 1.41 (s, 3H), 2.17 (s, 3H), 3.32 (s, 3H), 3.47 (d,
1H, J ) 11.2 Hz), 3.68 (d, 1H, J ) 11.2 Hz), 3.88 (m, 1H), 4.08
(m, 1H), 4.64 (s, 1H), 5.37 (d, 1H, J ) 4.77 Hz), 5.87 (s, 1H),
7.48 (d, 1H, J ) 7.51 Hz), 8.25 (d, 1H, J ) 7.56 Hz); 13C NMR
(75 MHz, CD3OD) δ (ppm) 20.9, 24.6, 27.6, 30.6, 39.9, 64.1,
72.8, 73.8, 74.1, 76.5, 93.2, 98.2, 145.5, 157.3, 164.7, 173.0,
177.7; LRMS (ESI) 465.2 [M + H]+.
(2R,3R,3aR,6S,7S,7aR)-2-(4′-Acetylamino-2′′-oxo-2H-py-
rimidin-1′-yl)-7-azido-6-fluoro-3-pivaloyloxy-hexahydro-
furo[3,2-b]pyran (55). Same procedure as for compound 54.
Yield: 70% from 53; Rf ) 0.3 (CH2Cl2/MeOH, 20:1); [R]D
+165.1° (c 1, CHCl3); 1H NMR (400 MHz, CD3OD) δ (ppm) 1.25
(s, 9H), 2.19 (s, 3H), 3.85 (dd, 1H, J ) 42.8, 14.0 Hz), 4.09 (m,
2H), 4.21 (s, 1H), 4.80 (m, 2H), 5.50 (s, 1H), 5.89 (s, 1H), 7.49
(d, 1H, J ) 6.98 Hz), 8.10 (d, 1H, J ) 7.10 Hz); 13C NMR (75
MHz, CD3OD) δ (ppm) 24.6, 27.5, 30.6, 39.9, 59.9, 60.4, 72.7,
74.2, 76.3, 87.5, 89.9, 93.2, 98.3, 146.1, 157.3, 164.8, 173.0,
178.2; LRMS (ESI) 439.1 [M + H]+.
(2R,3R,3aS,6S,7S,7aR)-[2-(4′-Amino-2′-oxo-2H-pyrimi-
din-1′-yl)-3-hydroxy-6-methoxy-6-methyl-hexahydrofuro-
[3,2-b]pyran-7-yl]urea (56). To a solution of 54 (35 mg, 0.075
mmol) in THF (8 mL) was added Me3P (0.19 mL, 1 M in THF)
and the mixture was stirred at room temperature for 30 min.
Water (11 µL) was then added and the mixture was stirred at
reflux (65 °C) for 60 min, cooled to room temperature,
concentrated and dried under vacuo for 2 h.
To a mixture of the above product (50 mg, 0.15 mmol),
pyridine (3 mL) and DMAP (92 mg, 0.75 mmol) was added
PivCl (0.055 mL, 0.45 mmol) and the mixture was stirred at
room temperature for 18 h. The mixture was then concentrated
and the crude product was purified by flash silica gel chro-
matography (hexanes/ethyl acetate, 4:1) to afford the product.
(2R,3R,3aR,6S,7S,7aR,8R,9R)-7-Azido-6-methoxy-6-meth-
yl-2-phenylsulfanyl-3-pivaloyloxy-hexahydrofuro[3,2-b]-
pyran (52). Colorless oil: yield 72% (2 steps) from 50; Rf )
0.44 (hexanes/ethyl acetate, 4:1); [R]D +183.9° (c 1.5, CHCl3);
The crude product was dissolved in CH2Cl2 (8 mL), trichlo-
roacetyl isocyanate (35 µL) was added, and the mixture was
stirred at room temperature for 2 h and concentrated. The
product was then dissolved in MeOH (2 mL), MeNH2 (2 mL,
40% in water) was added, the solution was stirred at room
temperature for 3 days and concentrated, and the crude
product was purified by flash silica gel chromatography (15%
MeOH in CH2Cl2) to afford the final compound as a white
solid: yield 9% (3 steps); Rf ) 0.14 (30% MeOH in CH2Cl2);
[R]D +33.55° (c 0.1, MeOH); 1H NMR (300 MHz, CD3OD) δ
(ppm) 1.48 (s, 3H), 3.30 (s, 3H), 3.43 (dd, 1H, J ) 10.08, 4.71
Hz), 3.52 (s, 2H), 4.15 (m, 2H), 4.62 (d, 1H, J ) 3.05 Hz), 5.65
(s, 1H), 5.83 (d, 1H, J ) 7.52 Hz), 7.71 (d, 1H, J ) 7.53 Hz);
13C NMR (75 MHz, CD3OD) δ (ppm) 22.2, 48.1, 49.9, 73.5, 74.4,
75.7, 76.8, 95.6, 141.8, 167.7; LRMS (ESI) 356.1 [M + H]+.
1
IR (thin film) ν 2977, 2108, 1809, 1743, 1480, 1279 cm-1; H
NMR (300 MHz, CDCl3) δ (ppm) 1.33 (s, 9H), 1.39 (s, 3H), 3.31
(s, 3H), 3.47 (d, 1H, J ) 1.1 Hz), 3.51 (d, 1H, J ) 1.1 Hz), 3.80
(dd, 1H, J ) 5.35, 4.61 Hz), 4.13 (dd, 1H, J ) 10.1, 3.10 Hz),
4.33 (d, 1H, J ) 3.01 Hz), 5.69 (t, 1H, J ) 3.93 Hz), 5.86 (d,
1H, J ) 4.45 Hz), 7.33 (m, 3H), 7.51 (m, 2H); 13C NMR (75
MHz, CDCl3) δ (ppm) 20.5, 26.4, 27.1, 39.3, 49.2, 62.5, 69.8,
71.3, 73.6, 74.5, 74.6, 91.5, 127.3, 128.9, 130.9, 134.3, 176.5;
LRMS (ESI) 422.1 [M + H]+.
(2R,3R,3aS,6S,7S,7aR)-[2-(4′-Amino-2′-oxo-2H-pyrimi-
din-1′-yl)-6-fluoro-3-hydroxy-hexahydrofuro[3,2-b]pyran-
7-yl]urea (57). Same procedure as for compound 56. Yield:
30% (3 steps) from 55; Rf ) 0.16 (30% MeOH in CH2Cl2); [R]D
1
(2R,3R,3aR,6S,7R,7aR)-7-Azido-6-fluoro-2-phenylsulfa-
nyl-3-pivaloyloxy-hexahydrofuro[3,2-b]pyran (53). Color-
+20.1° (c 0.33, MeOH); H NMR (400 MHz, CD3OD) δ (ppm)
2.55 (s, 1H), 3.91 (m, 2H), 4.16 (d, 1H, J ) 14 Hz), 4.24 (m,
J. Org. Chem, Vol. 70, No. 17, 2005 6733

Hanessian et al.
1H), 4.35 (d, 1H, J ) 5.25 Hz), 4.74 (m, 2H), 5.51 (s, 1H), 5.91
(d, 1H, J ) 7.52 Hz), 7.67 (d, 1H, J ) 7.50 Hz); 13C NMR (75
MHz, CD3OD) δ (ppm) 25.4, 51.1, 68.8, 73.5, 74.3, 88.7, 91.1,
96.2, 144.2, 158.0, 161.5, 167.9; HRMS (FAB) calcd for
C12H16N5O5F [M + H+] 330.12082, found 330.12108.
cal assistance and Dr. Patrick Crowley (Syngenta, U.K)
for stimulating discussions.
Supporting Information Available: Spectral data (1H
NMR and 13C NMR) for compounds 6, 11, 14, 17, 18, 22-24,
26, 34-37, 41-44, and 46-57. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank NSERC and Syngenta
for generous financial support. We also thank Thomas
Vifian (Syngenta, Basel, Switzerland) for skillful techni-
JO050727B
6734 J. Org. Chem., Vol. 70, No. 17, 2005