Structure-based organic synthesis of a tricyclic N-malayamycin analogue

Article abstract of DOI:10.1021/jo061904r

The solid-state structure of crystalline malayamycin A reveals a urea substituent that bisects the plane of the chairlike tetrahydropyran subunit. On the basis of this topological feature, we synthesized a tricyclic N-nucleoside analogue in which an ethan

Full text of DOI:10.1021/jo061904r

Structure-Based Organic Synthesis of a Tricyclic N-Malayamycin
Analogue
Stephen Hanessian* and Dougal J. Ritson
Department of Chemistry, UniVersite´ de Montre´al, C. P. 6128, Succursale Centre-Ville, Montre´al, Que´bec
H3C 3J7, Canada
stephen.hanessian@umontreal.ca
ReceiVed September 14, 2006
The solid-state structure of crystalline malayamycin A reveals a urea substituent that bisects the plane of
the chairlike tetrahydropyran subunit. On the basis of this topological feature, we synthesized a tricyclic
N-nucleoside analogue in which an ethano bridge linked the urea NH group with the ring junction of the
bicyclic tetrahydrofuropyran unit.
Introduction
more commonly encountered monocyclic pentofuranosyl or
hexopyranosyl residues. For example, ezomycin A2 1 and
4
octosyl acid A5 2 are representatives of such bicyclic N-
nucleosides, while ezomycin B26 3 is a C-nucleoside equivalent
(Figure 1). The ezomycins have been reported to exhibit
antifungal and antibiotic activities.6 Quantamycin 4, an unnatural
synthetic analogue of lincomycin, was designed as a potential
antibacterial agent.7 Some years ago, scientists at the Syngenta
Crop Protection Laboratories in Jealott’s Hill, U.K., isolated a
new C-nucleoside from the soil organism Streptomyces malay-
siensis, which they named malayamycin A (5).8 The gross
structure of 5 was based on detailed NMR studies and
degradation work. The proposed structure and stereochemical
identity of 5 were recently confirmed by a total synthesis.9
Except for the commonly shared perhydrofuropyran core, the
presence of a urea group, and the 5-substituted pyrimidinone
units, the nature of functional groups and appendages in 5 were
different from those in ezomycin B2. Furthermore, 5 exhibited
Naturally occurring purine and pyrimidine nucleosides have
been the cornerstones of the chemistry and biology of nature’s
genetic code since the beginning of creation.1 N- and C-
nucleosides with nontraditional heterocyclic as well as sugar
components have also been found outside the DNA/RNA
world.2 Some of these have been endowed with impressive
chemotherapeutic properties as anticancer, antiviral, and anti-
infective agents in medical practice for decades.3
A select group of N- and C-pyrimidine nucleosides contains
a bicyclic perhydrofuropyran “sugar” moiety rather than the
(1) (a) Gesteland, T. R.; Cech, T. R.; Atkins, J. F. In The RNA World,
2nd ed.; Cold Springs Harbor Laboratory Press: New York, 1999. (b)
Sarma, R. H.; Sarma, M. H. In DNA Double Helix and the Chemistry of
Cancer; Adenine Press: New York, 1988. (c) Watson, J. D.; Crick, F. H.
C. Nature 1953, 171, 737.
(2) For examples, see: (a) Ichikawa, S.; Kato, K. Curr. Med. Chem.
2001, 8, 3895. (b) Gao, H.; Mitra, A. K. Synthesis 2000, 329. (c) Knapp,
S. Chem. ReV. 1995, 95, 1859. (d) Postema, M. H. D. In C-Glycoside
Synthesis; CRC Press: Boca Raton, FL, 1995. (e) Townsend, L. B. In
Chemistry of Nucleosides and Nucleotides; Plenum Press: New York, 1994;
pp 421-535.
(3) For examples, see: (a) Simons, C.; Wu, Q.; Htar, T. T. Curr. Top.
Med. Chem. 2005, 5, 1191. (b) Rachakonda, S.; Cartee, L. Curr. Med. Chem.
2004, 11, 775. (c) Pathak, T. Chem. ReV. 2002, 102, 1623. (d) Hosmane,
R. S. Curr. Top. Med. Chem. 2002, 2, 1093. (e) Antisense Drug Technology;
Crooke, S. T., Ed.; Dekker: New York, 2001. (f) Mansur, T. S.; Storer, R.
Curr. Pharm. Des. 1997, 3, 227.
(5) For the total synthesis of octosyl acid, see: (a) Knapp, S.; Thakur,
V. V.; Madurru, M. R.; Malolanarasimhan, K.; Morriello, G. J.; Doss, G.
A. Org. Lett. 2006, 8, 1335. (b) Danishefsky, S; Hungate, R. J. Am. Chem.
Soc. 1986, 108, 2486. (c) Hanessian, S.; Kloss, J.; Sugawara, T. J. Am.
Chem. Soc. 1986, 108, 2758. For isolation, see: (d) Isono, K.; Crain, P.
K.; McCloskey, J. A. J. Am. Chem. Soc. 1975, 97, 943.
(6) Sakata, K.; Sakurai, A.; Tamura, S. Tetrahedron Lett. 1975, 3191.
(7) Hanessian, S.; Sato, K.; Liak, T. J.; Danh, N.; Dixit, D.; Cheney, B.
V. J. Am. Chem. Soc. 1984, 106, 6114.
(4) (a) Sakata, K.; Sakurai, A.; Tamura, S. Agric. Biol. Chem. 1975, 39,
885. (b) Sakata, K.; Sakurai, A.; Tamura, S. Tetrahedron Lett. 1974, 49,
4327. (c) Sakata, K.; Bakurai, A.; Tamura, S. Agric. Biol. Chem. 1973, 39,
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(8) (a) Benner, J. P.; Boehlendorf, B. G. H.; Kipps, M. R.; Lamber, N.
E. P.; Luck, R.; Molleyres, L-P.; Neff, S.; Schuez, T. C.; Stanley, P. D.
WO, 03/062242, CAN 139:132519. (b) Hanessian, S.; Machaalani, R.;
Marcotte, S. WO, 04/069842.
10.1021/jo061904r CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/29/2006
J. Org. Chem. 2006, 71, 9807-9817
9807

Hanessian and Ritson
of X-ray crystal structures of complexes involving synthetic
compounds with relevant enzymes has popularized so-called
structure-based design in the quest for new therapeutic lead
compounds.12 Application of these notions to three-dimensional
structural information in conjunction with bioactive conforma-
tions of natural products, alone or complexed with biological
macromolecules such as enzymes15 and RNA,16 provides a
powerful tool to explore synthetic chemistry in new directions.11
Synthesis Plan
Clearly, a major challenge in the synthesis of 7 was the
elaboration of the N-C ethano bridge in a stereocontrolled
manner. In the disconnection illustrated in Scheme 1, we chose
to first create the more demanding C-bridgehead tether and
subsequently to engage it in aza-ring formation (Scheme 1).
The allylic ether, readily available from diacetone-D-glucose,
would be an appropriate substrate for a ring-closure metathesis
reaction17 to generate the bicyclic core system. Following a
stereo- and regiocontrolled functionalization of the double bond
to give the cis-amino alcohol, the tether would be engaged in
an intramolecular nucleophilic attack by the nitrogen to give
the tricyclic core structure. Alternatively, the amino group in
the tether could be the nucleophile. Elaboration of the acetal
via anomeric activation, introduction of the cytosine, and func-
tional group adjustments would afford the intended target 7.
FIGURE 1. Natural (1, 2, 3, and 5) and unnatural (4 and 6)
perhydrofuropyranyl N- and C-nucleosides.
potent fungicidal activity,8 which instigated efforts toward the
synthesis of N-purinyl and N-pyrimidinyl analogues.10 Indeed,
a total synthesis of N-cytosinyl malayamycin A (6) revealed
fungicidal activity at least equivalent to 5 (Figure 1).10
(12) For related approaches, see: (a) Structure-Based Drug DiscoVery:
An OVerView; Hubbard, R. F., Ed.; Royal Society of Chemistry: Cambridge,
2006. (b) Analogue-Based Drug DiscoVery; Fischer, J., Ganellin, C. R.,
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Biotechnol. 2004, 22, 513. (d) Anderson, A. C. Chem. Biol. 2003, 10, 787.
(e) Klebe, G. J. Mol. Med. 2000, 78, 269. (f) Kubinyi, H. Curr. Opin. Drug
DiscoVery DeV. 1998, 1, 4. (g) Bohacek, R. S.; McMartin, C.; Guida, W.
C. Med. Res. ReV. 1996, 16, 3. See also: (h) Rees, D. C.; Congreve, M.;
Murray, C. W.; Carr, R. Nat. ReV. Drug DiscoVery 2004, 3, 660. (i) Erlanson,
D. A.; McDowell, R. S.; O’Brien, T. J. Med. Chem. 2004, 47, 3463. (j)
Pellechia, M.; Sem, D. S.; Wuthrich, K. Nat. ReV. Drug DiscoVery 2002,
1, 211. (k) Fejzo, J.; Lepre, C. A.; Peng, J. W.; Bemis, G. W.; Murcko, M.
A.; Moore, J. M. Chem. Biol. 1999, 6, 755. (l) Shuker, S. B.; Hajduk, P. J.;
Meadows, R. P.; Fesik, S. W. Science 1996, 274, 1531. For an academic
perspective, see: Hof, F.; Diederich, F. J. Chem. Soc., Chem. Commun.
2004, 477.
In the course of our synthetic efforts, we obtained X-ray
quality crystals of 5 from water after slow evaporation. The
three-dimensional solid-state structure as seen in the ORTEP
diagram of one of the hydrated crystals revealed several
interesting topological features (Figure 2). Most prominent was
the orthogonal orientation of the axial C5 urea group which
bisects the plane of the chairlike tetrahydropyran ring of the
bicyclic system, with the N-H group pointing “inward”.
Previous functional group modifications10 have delineated the
importance of stereochemistry as well as substitution to maintain
fungicidal activity in this series. We therefore utilized the three-
dimensional functional characteristics shown in the crystal
structure of 5 to derive a tricyclic analogue 7 in which the axially
oriented urea group was connected to C3 (malayamycin A
numbering) by an ethano bridge. Preliminary superposition of
a modeled and minimized structure over the X-ray structure of
5 showed excellent congruence. Thus, we embarked on the
synthesis of the proposed tricyclic analogue as part of a program
dealing with structure-based organic synthesis.11 In this ap-
proach, structural data available from bioactive natural products
are used in the design and synthesis of unnatural congeners.12
Interestingly, such an approach was used many years ago in
our de novo conception and synthesis of quantamycin 4, a hybrid
structure intended to simulate recognition of the peptidyl amino
acid transfer step by a modified lincomycin.7,13,14 The advent
(13) Cheney, B. V. J. Med. Chem. 1974, 17, 590.
(14) (a) Verdier, A. L.; Berthe, G.; Gharbi-Benarous, J.; Girauef, J-P.
Bioorg. Med. Chem. 2000, 8, 1225. (b) Fitzhugh, A. L. Bioorg. Med. Chem.
Lett. 1998, 8, 87.
(15) (a) Tyndall, J. D. A.; Nall, T.; Fairlie, D. P. Chem. ReV. 2005, 105,
973. (b) Loughlin, W. A.; Tyndall, J. D. A.; Glenn, M. P.; Fairlie, D. P.
2004, 104, 6085. (c) Greco, M. N.; Maryanoff, B. F. AdVances in Amino
Acid Mimetics and Peptidomimetics; JAI Press: Greenwich, CT, 2002; Vol.
1, p 41. (d) Babine, R. E.; Bender, S. L. Chem. ReV. 1997, 97, 1359. See
also: (e) Sharff, A.; Jhoti, H. Curr. Opin. Chem. Biol. 2003, 7, 340T. (f)
Blundell, L.; Jhoti, C.; Abell, C. Nat. ReV. Drug DiscoVery 2002, 1, 45. (g)
Nienaber, V. L.; Richardson, P. L.; Klighofer, V.; Bouska, J. J.; Giranda,
V. L.; Greer, J. Nat. Biotechnol. 2000, 18, 1105.
(16) (a) Ogle, J. M.; Ramakrishnan, V. Annu. ReV. Biochem. 2005, 74,
129. (b) Francois, B.; Russell, R. J. M.; Murray, J. B.; Aboulela, F.;
Masquida, B.; Vicens, Q.; Westhof, E. Nucleic Acids Res. 2005, 33, 5677.
(c) Vicens, Q.; Westhof, E. J. Mol. Biol. 2003, 326, 1175. (d) Hansen, J.
L.; Moore, P. B.; Steitz, T. A. J. Mol. Biol. 2003, 330, 10611. (e) Vicens,
Q.; Westhof, E. Chem. Biol. 2002, 9, 747. (f) Schlunzen, F.; Harms, J.;
Tocilj, A.; Albrecht, R.; Yonath, A.; Franceschi, F. Nature 2001, 413, 814.
(g) Vicens, Q.; Westhof, E. Structure 2001, 9, 647. (h) Wimberley, B. T.;
Brodersen, D. E.; Clemons, W. M., Jr.; Morgan-Warren, R. J.; Caster, A.
P.; Vonrhein, C.; Hartsch, T.; Ramakrishnan, V. Nature 2000, 407, 327.
(i) Carter, A. P.; Clemons, W. M.; Brodersen, D. E.; Morgan-Warren, R.
J.; Wimberley, B. T.; Ramakrishnan, V. Nature 2000, 407, 340. (j) Kirillov,
S.; Porse, B. T.; Vester, B.; Woolley, P.; Garrett, R. A. FEBS Lett. 1997,
406, 223.
(9) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G. Org. Lett.
2003, 5, 4277.
(10) (a) Loiseleur, O.; Schneider, H.; Huang, G. H.; Machaalani, R.;
Selles, P.; Crowley, P.; Hanessian, S. Org. Process Res. DeV. 2006, 10,
518. (b) Hanessian, S.; Huang, G. H.; Chenel, C.; Machaalani, R.; Loiseleur,
O. J. Org. Chem. 2005, 70, 6721. (c) Hanessian, S.; Marcotte, S.;
Machaalani, R.; Huang, G. H.; Crowley, P. J.; Loiseleur, O. WO,
2005005432, 2005.
(17) For pertinent reviews, see: (a) Grubbs, R.; Chang, S. Tetrahedron
1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1998,
371. (c) Furstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, H. H. J. Chem.
Soc., Chem. Commun. 1998, 1315. (d) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. 1997, 36, 2036.
(11) Hanessian, S. Chem. Med. Chem., published online Nov 8, 2006,
http://dx.doi.org/10.1002/cmdc.200600203.
9808 J. Org. Chem., Vol. 71, No. 26, 2006

Synthesis of a Tricyclic N-Malayamycin Analogue
FIGURE 2. ORTEP diagram of malayamycin A hydrate and a tricyclic N-cytosinyl malayamycin A.
SCHEME 1. Disconnective Analysis
Although the essentials of this proposed route were previously
accomplished in the synthesis of N-malayamycin A analogues,10
we were not in a position to ensure safe passage to 7, being
cognizant of the influence of steric effects and the uncertainty
of ring strain in the elaboration of the acetal functionality in a
bridged tricyclic ring system.
with azide ion, no doubt due to a sterically impeded path caused
by the benzyloxyethyl tether (Scheme 3). An alternative
approach involved the cis-dihydroxylation of 16 in the presence
of OsO4 and NMO in aqueous acetone. The diol 19 (dr > 100:
1) was easily separable from traces of the minor diastereoiso-
meric diol by column chromatography on silica gel. The
configuration of 19 was established by nOe experiments.
Mesylation of the diol 19 with 1.1 equiv of mesyl chloride at
-78 °C afforded the monomesylate 20 selectively, most likely
due to the pseudoequatorial disposition of the C5 alcohol. The
mesylate 20 was recovered unchanged when treated with NaN3,
even after prolonged periods of reflux in 2-methoxyethanol.
Alternatively, treatment of 19 under Mitsunobu conditions with
diphenylphosphoryl azide was also unsuccessful.
Results
Oxidation of diacetone-D-glucose 8 and treatment of the
resulting ketone with allylmagnesium bromide gave the known18
C-allyl product 9 in 77% overall yield (Scheme 2). Ozonolysis
followed by treatment of the ozonide with NaBH4 in MeOH
gave a cyclic alkoxyborane 10, which necessitated treatment
with ammonia in MeOH at 75 °C before the desired diol 11
could be liberated. Although O-benzylation of the primary
hydroxyl group of 11 took place at room temperature in the
presence of NaH in DMF, O-allylation of the tertiary hydroxyl
group in 12 required heating at 100 °C in THF containing
HMPA to give 13 in 97% yield. The distal acetonide of 13 was
selectively cleaved, and the diol 14, after bis-mesylation, was
subjected to a Finklestein-type elimination19 to give olefin 15.
Ring-closure metathesis employing Grubbs first-generation
catalyst20 led to the tethered bicyclic core 16 in 93% yield.
We then attempted to introduce the vicinal azido alcohol
groups by first epoxidizing 16 to the R-epoxide 17 with
m-CPBA, followed by opening with azide ion to the intended
18. However, this sequence was abandoned because of the poor
yield of epoxidation and the reluctance of the epoxide to open
At this juncture, we reversed the order of bond-forming events
leading to the desired aza-tricyclic system. Thus, diol 19 was
debenzylated by catalytic hydrogenation, and the product was
converted to the bis-tosylate 21 in 71% yield (Scheme 4). As
expected, the pseudoaxial hydroxyl group at C6 in 21 remained
free after bis-tosylation. The position of the tosylate in 21 was
confirmed via oxidation of the alcohol by the Dess-Martin
periodinane reagent21 in CH2Cl2 to the corresponding ketone,
and the latter compound was analyzed by 1H NMR. Treatment
of 21 with NaN3 in DMF at 90 °C led to smooth and selective
displacement of the primary tosylate to give 22 in 96% yield.
We were now poised to effect an intramolecular ring closure
(20) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
(18) Banerjee, S.; Ghosh, S. J. Org. Chem. 2003, 68, 3981.
(19) (a) Jones, J. K. N.; Thompson, J. L. Can. J. Chem. 1957, 35, 955.
(b) Finklestein, F. Ber. 1910, 43, 1528.
(21) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. For a review,
see: (c) Moriarty, R. M. Org. React. 1999, 54, 273.
J. Org. Chem, Vol. 71, No. 26, 2006 9809

Hanessian and Ritson
SCHEME 2. Synthesis of the Bicyclic Corea
a Reagents and conditions: (a) CrO3, pyridine, Ac2O, CH2Cl2, 0 °C to rt; (b) allylmagnesium bromide, THF, -10 °C to rt, 77% (two steps); (c) O3,
CH2Cl2, -78 °C then NaBH4, MeOH, -78 °C to 75 °C, NH3, rt to 75 °C then AcOH, rt, 59 to 84%; (d) NaH, BnBr, THF, 0 °C to rt, 88%; (e) NaH, allyl
bromide, HMPA, THF, 100 °C, 97%; (f) 85% AcOH/H2O, rt, 88%; (g) MsCl, Et3N, CH2Cl2, 0 °C; (h) NaI, DMA, 100 °C, 83% (two steps); (i) 5 mol %
Grubbs first-generation catalyst, CH2Cl2, rt, 93%.
SCHEME 3a
and pyridine to a solution of 23 in acetonitrile provided 24 in
good overall yield. We were now in a position to “invert” the
C6 hydroxyl group and to O-methylate. To do so, we first
oxidized the alcohol in 24 to the ketone 25 using the Dess-
Martin periodinane reagent. Reduction with NaBH4 in MeOH/
CH2Cl2 was highly stereoselective giving the “inverted” alcohol
26 in good yield (the epimer was not observed). Being wary of
forming a cyclic carbamate during O-methylation of 26 under
basic conditions, we examined a number of acidic conditions
for the O-methylation of 26, such as CH2N2/silica gel,22 Me2-
SO4/NaHCO3,23 and Me3O+BF4-/proton sponge.24 Unfortu-
nately, all of these attempts were unsuccessful, and the use of
MeI and Ag2O in MeCN25 resulted in the deprotection of the
Fmoc group to give 27. The trichloroethoxycarbonyl (Troc)
group was then utilized due to its higher tolerance of basic
conditions. However, exposure of 29, which was synthesized
in a manner analogous to that of 26, to MeI and Ag2O in
acetonitrile led to the cyclic carbamate 30.
a Reagents and conditions: (a) m-CPBA, Na2HPO4, CH2Cl2, rt, 19%;
(b) NaN3, CH2OHCH2OMe, 130 °C; (c) NaN3, NH4Cl, MeCN/H2O, 130
°C; (d) NaN3, NH4Cl, CH2OHCH2OMe, 130 °C; (e) 5 mol % OsO4, NMO,
acetone/H2O, rt, 92%, dr > 100:1; (f) MsCl, Et3N, CH2Cl2, -78 °C, 45%;
(g) NaN3, CH2OHCH2OMe, 155 °C.
It was clear that a far more robust protecting group would
be required for the successful O-methylation of the C6 alcohol.
Accordingly, we opted for the t-butylsulfonyl (Bus) group,
originally reported by Sun and Weinreb26 and subsequently used
in isolated instances only.27 Treatment of 23 with t-butylsulfinyl
chloride, followed by oxidation with m-CPBA, gave the desired
N-Bus derivative 31 (Scheme 5). The oxidation-reduction
sequence was repeated as before, and the alcohol 32 was
from the azide extremity of the tether, after reduction to the
primary amine, onto the C5 tosylate group. In the event,
reduction of the azide group in 22 in the presence of Pd black
containing pyridine in EtOH, followed by heating in MeCN
containing Et3N, effected ring closure to the aza-tricyclic system
23.
(22) Ohno, K.; Nishiyama, H.; Nagase, H. Tetrahedron Lett. 1979, 4405.
(23) Merz, A. Angew. Chem., Int. Ed. 1973, 12, 846.
(24) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. J. Prakt.
Chem. 1937, 147, 257.
(25) Greene, A. E.; Drian, C. L.; Crabbe, P. J. Am. Chem. Soc. 1980,
102, 7583.
(26) Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604.
(27) (a) Hanessian, S.; Del Valle, J. R.; Xue, Y.; Blomberg, N. J. Am.
Chem. Soc. 2006, 128, 10491. (b) Koep, S.; Gais, H.-J.; Raabe, G. J. Am.
Chem. Soc. 2003, 125, 13243. (c) Gontcharov, A. V.; Liu, H.; Sharpless,
K. B. Org. Lett. 1999, 1, 783.
Before proceeding with the elaboration of the acetal into an
anomerically activatable group, we had to select an appropriate
N-protecting group that would be resistant to the acidic
conditions required to cleave the 1,2-acetonide group and for
the nucleobase coupling step, yet removable once the nucleosidic
linkage was established. Initially, the 9-fluorenylmethyloxycar-
bonyl (Fmoc) protecting group was chosen. Addition of FmocCl
9810 J. Org. Chem., Vol. 71, No. 26, 2006

Synthesis of a Tricyclic N-Malayamycin Analogue
SCHEME 4a
a Reagents and conditions: (a) Pd(OH)2, H2 (1 atms), EtOAc, rt; (b) TsCl, pyridine, -20 °C, 71% (two steps); (c) NaN3, DMF, 90 °C, 96%; (d) Pd black,
H2 (1 atm), pyridine, EtOH, rt; (e) Et3N, MeCN, 95 °C; (f) FmocCl, pyridine, MeCN, rt, 50% (three steps); (g) Dess-Martin periodinane, CH2Cl2, rt; (h)
NaBH4, MeOH/CH2Cl2, rt, 66% for 26, 89% for 29 (two steps); (i) Ag2O, MeI, MeCN, rt; (j) TrocCl, pyridine, MeCN, rt, 45% (three steps).
methylated under standard Williamson conditions to give the
methyl ether 33.
and nucleophilic attack by the bis-TMS derivative of N-
acetylcytosine to give 37 as a crystalline compound. Single-
crystal X-ray analysis32 confirmed the 1,2-trans-disposition of
the N-cytosinyl moiety. Finally, cleavage of the N-Bus group
could be effected with TfOH in CH2Cl2 containing anisole.
Subsequent installation of the urea group as previously re-
ported9,10 and deprotection gave the intended tricyclic N-
cytosinyl malayamycin A, 7, as an amorphous, colorless solid.
The synthesis of 7 was achieved starting with diacetone-D-
glucose over 27 steps in an overall yield of 1.5%.
Previous reports from our laboratory7,9,10b,28 and the Knapp
group29 had shown the utility of γ-hydroxy dialkyl dithioacetals
as intermediates for the synthesis of the alkyl thioglycosides,
en route to nucleosidic bond formation in monocyclic as well
as bicyclic systems. The feasibility of the same chemistry in
the case of the bridged tricycle 33 as a precursor required some
exploration. The mildest condition to effect acetal cleavage and
formation of a diphenyldithioacetal was treatment of 33 with
benzenethiol and Amberlyst-15 (H+) as a suspension in CH2-
Cl2.10 The diphenyldithioacetal 34 was then treated with NBS
in CH2Cl2 at 0 °C to effect cycloetherification,28 affording 35
in 71% yield. A trace amount of a byproduct which may have
been the â-anomer (not shown) was not isolated or characterized.
Protection of the alcohol in 35 as the pivalate ester 36 gave
X-ray quality crystalline material. As seen in the ORTEP
diagram,30 all the anticipated bond-forming sequences had taken
place with the correct stereo- and regiochemistries. We con-
tinued the synthesis with the crystalline pivalate 36, relying on
its ability to direct anomeric substitution through neighboring
group participation. The penultimate steps in the synthesis
involved activation of the thioglycoside 36 with NIS/TfOH29,31
Discussion
The failure of nucleophilic attack by the azide ion, even under
forcing conditions, of the epoxide 17 (or the mesylate 20) is
not surprising. It can be argued that the azide ion would have
to approach the mesylate 20, for example, from a trajectory that
is sterically challenged. Furthermore, the required overlap with
the σ* C-O bond would be inaccessible in a chair conformation
as in A (Figure 3). A boat conformer, B, would better expose
the σ* C-O orbital to the incoming charged nucleophile,
although the benzyloxyethyl tether would still be an impediment.
The intramolecular cyclization of the amine derived from 22 in
MeCN at 90 °C diminishes the energetic penalty of a sterically
impeded bimolecular attack by azide ion. A suprafacial trajectory
of attack by the tethered aminoethyl group finds the requisite
angle to effectively overlap with the σ* orbital of the now axially
disposed tosylate in 22, presumably in a boat conformer, as
shown in C (Figure 3).
(28) Hanessian, S.; Dixit, D. M.; Liak, T. J. Pure Appl. Chem. 1981, 53,
129.
(29) (a) Knapp, S.; Shieh, W.-C.; Jaramillo, C.; Triller, R.; Nandau, S.
R. J. Org. Chem. 1994, 59, 946. (b) Knapp, S.; Shieh, W.-C. Tetrahedron
Lett. 1991, 32, 3627.
(30) For an ORTEP diagram of compound 36, see Supporting Information
S64.
(31) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron
Lett. 1990, 31, 1331.
(32) For an ORTEP diagram of compound 37, see Supporting Information
S73.
J. Org. Chem, Vol. 71, No. 26, 2006 9811

Hanessian and Ritson
SCHEME 5a
a Reagents and conditions: (a) t-Butylsulfinyl chloride, Et3N, rt; (b) m-CPBA, CH2Cl2, rt, 51% (four steps); (c) Dess-Martin periodinane, CH2Cl2, rt; (d)
NaBH4, CH2Cl2/MeOH, rt; (e) NaH, MeI, THF, rt, 98% (three steps); (f) PhSH, Amberlyst-15, CH2Cl2, rt, 80%; (g) NBS, CH2Cl2, 0 °C, 71%; (h) PivCl,
DMAP, CH2Cl2/pyridine, rt, 81%; (i) 4-(N-trimethylsilyl)-acetamido-2-(trimethylsilyloxy)-pyrimidine, NIS, TfOH, CH2Cl2, rt, 52% (based on recovered
starting material); (j) TfOH, anisole, CH2Cl2, rt; (k) Cl3C(O)NCO, pyridine, rt; (l) MeNH2, MeOH/H2O, rt, 52% (three steps).
that transient R-phenylthio epoxides may also be present (not
shown). The successful cyclization to 35 in good yield is
therefore remarkable.
Thioglycosides are well-known precursors to O-glycosides
proceeding by activation with thiophilic reagents.31 In spite of
precedents in the synthesis of bicyclic N-malayamycin A and
related analogues,10 it is noteworthy that the formation of the
nucleosidic bond in the tricycle 37 takes place in spite of the
strained nature of the intermediates. Generation of the oxocar-
benium ion A (Figure 4) must be followed by participation of
the neighboring pivalate to the planar 1,2-dioxolenium ion B
which imposes a fourth ring in the system. Attack of the
pyrimidine base takes place in an anti-fashion to give the
observed 1,2-trans-stereochemistry in 37. Direct â-attack of the
pyrimidine base on the oxocarbenium ion A is also possible.
The apparent spatial tolerance of the axially disposed syn-aza-
bridge with a bulkyl N-Bus group to the incoming O-silylated
pyrimidine is certainly a felicitous result, in spite of the modest
yield of this step.
FIGURE 3. Inaccessible (A and B) approaches of an intermolecular
nucleophile and the proposed boat conformation (C) allowing intramo-
lecular cyclization.
Anomeric activation through oxocarbenium ion intermediates
is at the core of glycoside and nucleoside chemistry.2,33 The
ease of cycloetherification in going from the diphenyldithioacetal
34 to thioglycoside 35 deserves comment (Figure 4). This type
of reactivity was at the basis of our early construction of
nucleosides of perhydrofuropyrans.28 It was thought, however,
that extension to a bridged, trans-fused dioxabicyclic precursor
such as 35 would present additional torsional strain in the
transition state involving intramolecular attack of the hydroxyl
group onto the phenylthionium ion. This reaction is best done
in the absence of an ester-protecting group next to the dithio-
acetal group because of its participating ability.10b It is possible
Clearly, much remains to be learned from the chemistry of
thionium and oxonium ions in these polycyclic systems in
particular.33,34
(34) For insightful work on the reactivity and stereochemistry of
oxocarbenium ions, see: (a) Shenoy, S. R.; Smith, D. M.; Woerpel, K. A.
J. Am. Chem. Soc. 2006, 128, 8671. (b) Larsen, C. H.; Ridgway, B. H.;
Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127,
10879. (c) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521. (d) Schmitt, A.;
Reissig, H.-U. Eur. J. Org. Chem. 2001, 1169. (e) Schmitt, A.; Reissig,
H.-U. Eur. J. Org. Chem. 2000, 3893.
(33) See pertinent chapters in: (a) The Organic Chemistry of Sugars;
Levy, D. E., Fugedi, P., Eds.; CRC Press: Boca Raton, FL, 2006. (b)
Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sanay¨,
P., Eds.; Wiley-VCH: Weinheim, Germany, 2000. (c) PreparatiVe Car-
bohydrate Chemistry; Hanessian, S., Ed.; Dekker: New York, 1997. (d)
Modern Methods in Carbohydrate Synthesis; Khan, S. H., O’Neill, R. A.,
Eds.; Harwood Academic: Amsterdam, 1996.
9812 J. Org. Chem., Vol. 71, No. 26, 2006

Synthesis of a Tricyclic N-Malayamycin Analogue
FIGURE 4. Activation at the anomeric center-thioglycoside and N-nucleoside formation.
1
ν 3474, 1374, 1073; H NMR (400 MHz, CDCl3) δ (ppm) 6.01
(m, 1H), 5.69 (d, J ) 3.7, 1H), 5.18 (m, 2H), 4.38 (d, J ) 3.8,
1H), 4.16 (m, 2H), 3.93 (ddd, J ) 9.3, 5.7, 4.2, 1H), 3.83 (d, J )
8.2, 1H), 2.67 (ddt, J ) 14.4, 5.8, 1.5, 2H), 2.20 (dd, J ) 14.5,
Conclusion
We have conceived and synthesized a tricyclic analogue of
N-malayamycin A in a stereocontrolled manner, based on the
solid-state X-ray crystal structure of the parent malayamycin
A. Topological information gleaned from the structure led to
the choice of an ethano bridge tethering the proximal urea
nitrogen atom with C3 at the junction of the perhydrofuropyran
ring system. Intramolecular cyclization from an amino terminal
group on the tether was successfully performed onto a tosylate
as a leaving group, possibly passing through a boatlike
conformation to allow for better access to a σ* orbital.
The utility of thionium and oxocarbenium ion intermediates
in the construction of the tricyclic nucleoside highlights the
successful completion of the synthesis. Unfortunately, prelimi-
nary testing of 7 as a fungicide did not show any activity, which
may reflect a truly delicate balance between structure, function,
and donor-acceptor interactions of the urea group in malaya-
mycin A and its analogues in the presence of biological receptors
and requisite enzymes. The possible role of the urea group in a
preformed bioactive conformation of malayamycin A is pres-
ently under study.
8.7, 1H), 1.61 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H); 13
NMR (75 MHz, CDCl3) δ (ppm) 132.5, 118.7, 112.3, 109.5, 103.4,
81.9, 81.1, 78.5, 73.0, 67.8, 36.6, 26.53, 26.52, 26.2, 25.1; LRMS
(ESI) 301 (10%) [M + H]+.
C
3-C-(2-Hydroxyethyl)-1,2:5,6-di-O-isopropylidene-D-allofura-
nose (11). The alkene 9 (1.50 g, 5.00 mol) was dissolved in CH2-
Cl2 (25 mL) and cooled to -78 °C. Ozone was bubbled through
the solution until an excess was present. The excess ozone was
removed by sparging O2 through the solution, after which NaBH4
(454 mg, 12.0 mmol) and MeOH (25 mL) were added. The reaction
was brought to room temperature and then refluxed for 1.5 h. After
being cooled to room temperature, NH3(g) was bubbled through the
solution for 30 min, followed by refluxing for a period of 8 h. The
reaction was finally cooled and taken to pH 8 using MeOH/AcOH
solution. The solvents were evaporated, and the material was
purified by flash chromatography (7:3 to 1:9, hexanes/ethyl acetate)
to provide 11 (1.27 g, 4.2 mmol, 84%) as a colorless solid. Rf )
0.13 (1:1, hexanes/ethyl acetate); mp 85 °C; [R]25D +22.7 (c 0.67,
CHCl3); IR (neat) ν 3539, 3452, 1388; 1H NMR (400 MHz, CDCl3)
δ (ppm) 5.72 (d, J ) 3.8, 1H), 4.56 (d, J ) 3.9, 1H), 4.13 (m, 2H),
3.95 (m, 3H), 3.77 (d, J ) 7.9, 1H), 2.75 (br s, 2H), 2.16 (ddd, J
) 14.8, 8.1, 4.6, 1H), 1.61 (s, 3H), 1.58 (m, 1H), 1.46 (s, 3H),
1.38 (s, 6H); 13C NMR (75 MHz, CDCl3) δ (ppm) 112.2, 109.3,
103.1, 81.9, 80.8, 79.4, 72.8, 67.4, 58.0, 32.6, 26.26, 26.27, 26.0,
24.9; HRMS (ESI) calcd for C14H24O7Na [M + Na] 327.1414,
found 327.1408
3-C-(2-Benzyloxyethyl)-1,2:5,6-di-O-isopropylidene-D-allo-
furanose (12). A solution of 11 (5.34 g, 17.6 mmol) in anhydrous
THF (65 mL) was cooled to 0 °C under an Ar atmosphere. NaH
(60% dispersion in mineral oil, 850 mg, 21.3 mmol) was added
portionwise and stirred for 1 h at 0 °C. BnBr (2.93 mL, 4.21 g,
24.6 mmol) was added dropwise, stirred for 30 min at 0 °C, then
warmed to room temperature, and stirred for 3 days. A saturated
solution of NH4Cl (50 mL) was added slowly, and the layers were
separated. The aqueous layer was extracted with Et2O (3 × 60 mL),
and the organic layers were combined, dried (Na2SO4), filtered,
and concentrated. The residual material was purified by flash
chromatography (85:15, hexanes/EtOAc), which yielded 12 (6.12
g, 15.5 mmol, 88%) as a colorless solid. Rf ) 0.16 (4:1, hexanes/
ethyl acetate); [R]25D +19.7 (c 0.58, CHCl3); IR (neat) ν 3480, 1386,
1373; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.34 (m, 5H), 5.70 (d,
J ) 3.7, 1H), 4.69 (d, J ) 3.7, 1H), 4.56 (d, J ) 12.7, 1H), 4.52
(d, J ) 12.6, 1H), 4.13 (m, 2H), 3.92 (dd, J ) 11.4, 8.4, 1H), 3.85
(m, 2H), 3.76 (dt, J ) 9.4, 5.7, 1H), 2.89 (br s, 1H), 2.14 (ddd, J
) 14.6, 5.6, 5.6, 1H), 1.78 (ddd, J ) 14.6, 7.4, 5.6, 1H), 1.61 (s,
3H), 1.47 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H); 13C NMR (75 MHz,
Experimental Section
1,2:5,6-Di-O-isopropylidene-3-C-allyl-D-allofuranose (9). To
a dry flask was charged CrO3 (6.46 g, 64.6 mmol), under Ar
atmosphere, containing anhydrous CH2Cl2 (110 mL), which was
cooled to 0 °C. Anhydrous pyridine (11.8 mL, 11.5 g, 146 mmol)
and Ac2O (7.0 mL, 7.56 g, 74.0 mmol) were added followed by
diacetone-D-glucose (10.0 g, 38.4 mmol), which was added por-
tionwise over 30 min. After being stirred for 30 min, the reaction
was brought to room temperature, and after a further 2 h the black
solution was poured into EtOAc (ca. 400 mL). The mixture was
filtered through silica washed with EtOAc. All the solvents were
removed, and the residue was pumped overnight.
The crude oil was dissolved in anhydrous THF (120 mL) and
added slowly to allylmagnesium bromide (1 M in Et2O, 80 mL) at
-10 °C. After the addition, the reaction was allowed to warm to
room temperature and was stirred for 3 h. The reaction was then
poured into ice/water (ca. 250 mL), and the majority of the solvent
was evaporated in vacuo. The pH of the solution was taken to pH
7, with a solution of AcOH in Et2O, and the products were extracted
with Et2O (3 × 200 mL), dried (Na2SO4), filtered, and concentrated.
The residue was purified by flash chromatography (hexanes/ethyl
acetate, 85:15), which gave the product 9 (8.45 g, 28.2 mmol, 77%)
as a colorless solid, and recrystallized from EtOAc/hexanes. Rf )
0.77 (hexanes/ethyl acetate, 1:1); mp 108-110; lit.18 124 °C; [R]25
D
+42.4 (c 1.40, CHCl3); lit.18 [R]25D +42.8 (c 3.0, CHCl3); IR (neat)
J. Org. Chem, Vol. 71, No. 26, 2006 9813

Hanessian and Ritson
CDCl3) δ (ppm) 137.7, 128.1, 127.4, 127.7, 112.1, 109.3, 103.2,
81.8, 81.0, 78.6, 72.93, 72.90, 67.6, 65.4, 31.1, 26.35, 26.33, 26.0,
24.9; HRMS (ESI) calcd for C21H30O7Na [M + Na] 417.1884,
found 417.1882.
15 (5.97 g, 16.6 mmol, 83%) as a very pale yellow oil. Rf ) 0.91
(1:1, hexanes/ethyl acetate); [R]25D +41.2 (c 0.49, CHCl3); 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.34 (m, 5H), 5.91 (ddt, J ) 17.2,
10.4, 5.3, 1H), 5.82 (ddd, J ) 16.7, 10.7, 5.8, 1H), 5.72 (d, J )
3.7, 1H), 5.46 (dt, J ) 17.3, 1.7, 1H), 5.28 (m, 2H), 5.15 (ddd, J
) 10.4, 3.2, 1.7, 1H), 4.64 (m, 1H), 4.58 (d, J ) 3.7, 1H), 4.50 (s,
2H), 4.14 (dt, J ) 5.4, 1.5, 2H), 3.64 (dt, J ) 6.8, 1.2, 2H), 2.07
(dt, J ) 14.8, 6.8, 1H), 1.80 (dt, J ) 14.9, 6.7, 1H), 1.60 (s, 3H),
1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 137.8, 134.7,
132.1, 128.1, 127.32, 127.26, 118.2, 115.8, 112.2, 103.1, 83.7, 82.3,
81.1, 72.7, 65.5, 65.1, 30.2, 26.5, 26.1; HRMS (ESI) calcd for
C21H28O5Na [M + Na] 383.1829, found 383.1819.
(3aR,3bS,7aS,8aR)-3b-(2-Benzyloxyethyl)-2,2-dimethyl-3a,5,-
7a,8a-tetrahydro-3bH-1,3,4,8-tetraoxacyclopenta[a]indene (16).
A solution of 15 (5.97 g, 16.6 mmol) in anhydrous CH2Cl2 (2.1 L)
was degassed, and an Ar atmosphere was applied. Grubbs first-
generation catalyst (4 mol %, 0.66 mmol, 542 mg) was added, and
the reaction was stirred overnight at room temperature. EtOAc (100
mL) was then added, and the reaction was filtered through silica
washing with CH2Cl2/EtOAc (9:1). The solvents were removed,
and the oily residue was purified by flash chromatography (4:1,
hexanes/ethyl acetate) to yield 16 (5.18 g, 15.6 mmol, 93%) as a
viscous, pale brown oil. Rf ) 0.74 (1:1, hexanes/ethyl acetate);
[R]25D -5.6 (c 0.87, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm)
7.33 (m, 5H), 6.18 (m, 1H), 5.83 (d, J ) 3.4, 1H), 5.66 (ddd, J )
10.5, 5.5, 2.5, 1H), 4.82 (dd, J ) 3.5, 0.8, 1H), 4.68 (m, 1H), 4.57
(d, J ) 11.8, 1H), 4.52 (d, J ) 11.8, 1H), 4.42 (ddd, J ) 17.9, 5.4,
2.6, 1H), 4.22 (ddt, J ) 17.9, 3.7, 2.5, 1H), 3.78 (ddd, J ) 9.6,
6.9, 5.8, 1H), 3.68 (m, 1H), 2.18 (dt, J ) 15.6, 5.5, 1H), 1.62 (s,
3H), 1.44 (ddd, J ) 15.6, 7.9, 6.2, 1H), 1.36 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 137.9, 128.0, 127.2, 125.7, 123.9,
112.6, 105.6, 79.0, 78.4, 77.4, 72.8, 72.5, 65.5, 64.5, 27.4, 25.8,
25.5; HRMS (ESI) calcd for C19H24O5Na [M + Na] 355.1516,
found 355.1507.
3-O-Allyl-3-C-(2-benzyloxyethyl)-1,2:5,6-di-O-isopropylidene-
D-allofuranose (13). To a solution of 12 (7.75 g 19.7 mmol) in
anhydrous THF (110 mL), under Ar atmosphere, was added NaH
(60% dispersion, 1.25 g, 31.3 mmol) portionwise. The reaction was
heated to gentle reflux for 2 h and then cooled to room temperature
when HMPA (12 mL) was added, followed by allyl bromide (3.60
mL, 4.98 g, 41.2 mmol). The reaction was refluxed at 95 °C for
1.5 h and cooled to room temperature, and H2O (100 mL) was
added. The products were extracted with Et2O (3 × 100 mL), dried
(Na2SO4), filtered, and concentrated. The crude material was
purified by flash chromatography (4:1, hexanes/ethyl acetate) to
provide 13 (8.33 g, 19.1 mmol, 97%) as pale yellow oil. Rf ) 0.25
(4:1, hexanes/ethyl acetate); [R]25D +41.0 (c 0.33, CHCl3); 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.36 (m, 5H), 5.93 (ddt, J ) 17.2,
10.4, 5.2, 1H), 5.62 (d, J ) 3.5, 1H), 5.30 (dtd, J ) 17.2, 3.6, 1.7,
1H), 5.13 (dtd, J ) 10.4, 3.4, 1.5, 1H), 4.62 (d, J ) 3.5, 1H), 4.52
(s, 2H), 4.32 (dt, J ) 5.2, 1.6, 1H), 4.19 (dt, J ) 5.1, 1.6, 1H),
4.04-4.17 (m, 3H), 3.92 (dd, J ) 8.0, 5.6, 1H), 3.74 (m, 2H),
2.18 (dt, J ) 14.8, 6.6, 1H), 1.89 (dt, J ) 14.8, 6.9, 1H), 1.59 (s,
3H), 1.44 (s, 3H), 1.35 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 137.8, 135.0, 128.1, 127.34, 127.29, 115.2, 112.3,
109.2, 102.8, 83.2, 83.1, 80.9, 72.8, 72.6, 68.1, 65.8, 65.2, 30.4,
26.6, 26.13, 26.12, 25.0; HRMS (ESI) calcd for C24H34O7Na [M
+ Na] 457.2197, found 457.2194.
3-O-Allyl-3-C-(2-benzyloxyethyl)-1,2-O-isopropylidene-D-al-
lofuranose (14). Compound 13 (9.91 g, 22.8 mmol) was stirred in
AcOH/H2O (85:15 v/v, 100 mL) for 48 h at room temperature. A
saturated solution of NaHCO3 (200 mL) was added slowly, and
the reaction was neutralized carefully with solid NaHCO3. The
products were extracted with Et2O (3 × 250 mL), dried (Na2SO4),
filtered, and concentrated, and the crude material was purified by
flash chromatography (7:3 to 1:1, hexanes/ethyl acetate), which gave
14 (7.90 g, 20.1 mmol, 88%) as a pale yellow oil. Rf ) 0.36 (1:1,
(3aR,3bR,6S,7S,7aS,8aR)-3b-(2-Benzyloxyethyl)-2,2-dimeth-
ylhexahydro-1,3,4,8-tetraoxacyclopenta[a]indene-6,7-diol (19).
To a solution of 16 (5.18 g, 15.6 mmol) in acetone/H2O (8:1, 130
mL) were added 4-methylmorpholine N-oxide (3.67 g, 31.3 mmol)
hexanes/ethyl acetate); [R]25 +47.6 (c 0.53, CHCl3); IR (neat) ν
D
1
t
3436; H NMR (400 MHz, CDCl3) δ (ppm) 7.37 (m, 5H), 5.90
and then 2.5 wt % solution of OsO4 in BuOH (9.78 mL, ca. 3.5
(m, 1H), 5.66 (d, J ) 3.6, 1H), 5.24 (ddt, J ) 17.2, 3.3, 1.6, 1H),
5.14 (ddt, J ) 10.5, 3.0, 1.4, 1H), 4.59 (d, J ) 3.6, 1H), 4.53 (d,
J ) 11.8, 1H), 4.50 (d, J ) 11.8, 1H), 4.25 (ddt, J ) 12.1, 5.0,
1.6, 1H), 4.15 (ddt, J ) 12.1, 5.5, 1.4, 1H), 4.07 (d, J ) 9.0, 1H),
3.85 (m, 2H), 3.69 (m, 3H), 2.90 (br s, 1H), 2.20 (dt, J ) 15.0,
6.9, 1H), 1.89 (dt, J ) 14.8, 6.9, 1H), 1.80 (br s, 1H), 1.59 (s, 3H),
1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 137.4, 134.2,
128.1, 127.5, 127.4, 116.1, 112.5, 103.6, 84.0, 82.1, 78.3, 72.9,
69.3, 66.5, 65.1, 64.3, 30.9, 26.4, 26.1; LRMS (ESI) 395 (25%)
[M + H]+.
(3aR,5S,6R,6aR)-6-Allyloxy-6-(2-benzyloxyethyl)-2,2-dimethyl-
5-vinyltetrahydrofuro[2,3-d][1,3]dioxole (15). A solution of 14
(7.90 g, 20.1 mmol) in anhydrous CH2Cl2 (110 mL), under an Ar
atmosphere, was cooled to 0 °C. Et3N (7.10 mL, 5.13 g, 50.3 mmol)
was added, and the temperature of the solution was allowed to
equilibrate before MsCl (3.40 mL, 5.03 g, 43.9 mmol) was added
dropwise. The reaction was stirred at 0 °C for 1 h, then H2O (55
mL) was added, and the reaction was stirred for a further 10 min
at this temperature. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The organics were
combined, dried (Na2SO4), filtered, and concentrated.
The oily residue was dissolved in anhydrous dimethylacetamide
(110 mL), and NaI (19.6 g, 131 mmol) was added. The reaction
was heated to 100 °C for 6 h and then cooled to room temperature,
and a saturated solution of Na2S2O3 (100 mL) was poured into the
reaction mixture. Stirring was continued until the color had
disappeared, then H2O (100 mL) was added, and the products were
extracted with Et2O (3 × 200 mL), dried (Na2SO4), and filtered.
After evaporation of the solvents in vacuo, the residue was purified
by flash chromatography (9:1, hexanes/ethyl acetate), which gave
mol %) at room temperature. After 2.5 h, a saturated solution of
Na2S2O3 (100 mL) was added, and the solution was stirred
overnight. The majority of the acetone was removed in vacuo, and
the black solution was extracted with EtOAc (3 × 100 mL), dried
(MgSO4), filtered, and concentrated. The residue was purified by
flash chromatography (9:1, ethyl acetate/hexanes) to yield 19 (5.28
g, 14.4 mmol, 92%) as an off-white foam and >100:1 mixture of
diastereoisomers, the minor, of which, was not characterized. Rf )
0.33 (ethyl acetate); [R]25D +59.7 (c 1.7, CHCl3); IR (neat) ν 3446,
2250; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.36 (m, 5H), 5.79 (d,
J ) 3.4, 1H), 4.69 (d, J ) 3.5, 1H), 4.56 (d, J ) 11.7, 1H), 4.51
(d, J ) 11.7, 1H), 4.23 (d, J ) 10.5, 1H), 4.11 (m, 2H), 4.01 (m,
1H), 3.85 (dd, J ) 13.5, 2.0, 1H), 3.72 (dt, J ) 9.5, 6.9, 1H), 3.64
(ddd, J ) 9.6, 7.1, 5.4, 1H), 2.50 (br s, 1H), 2.20 (dt, J ) 15.5,
5.4, 1H), 1.85 (br s, 1H), 1.63 (s, 3H), 1.47 (dt, J ) 15.5, 7.1, 1H),
1.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 137.6, 128.1,
127.4, 127.3, 113.3, 104.4, 80.7, 79.7, 75.1, 73.0, 68.6, 67.7, 66.8,
64.6, 25.8, 25.7, 25.4; HRMS (ESI) calcd for C19H27O7 [M + H]
367.1751, found 367.1768.
Bis-p-toluenesulfonate Ester 21. Compound 19 (364 mg, 0.99
mmol) was dissolved in EtOAc (10 mL), and Pd(OH)2/C 20 wt %
(40 mg) was added. The suspension was degassed, and an H2
atmosphere was applied (1 atm). The reaction was stirred at room
temperature for 2 h, and then the suspension was filtered and washed
with hot EtOAc and then warm MeOH. The solution was
concentrated in vacuo to provide a colorless solid.
The crude material was dissolved in anhydrous pyridine (9 mL)
and cooled to -20 °C. TsCl (850 mg, 4.46 mmol) was added in
three portions with 3-h intervals, and the reaction was stirred at
-20 °C overnight. MeOH was then added, the reaction was stirred
9814 J. Org. Chem., Vol. 71, No. 26, 2006

Synthesis of a Tricyclic N-Malayamycin Analogue
for 10 min, and the solvents were removed in vacuo. The residue
was dissolved in H2O (20 mL) and extracted with Et2O (3 × 20
mL), dried (Na2SO4), filtered, and concentrated. The crude material
was purified by flash chromatography (3:2 to 1:1, hexanes/ethyl
acetate) to yield 21 (414 mg, 0.71 mmol, 71%) as a colorless foam.
Rf ) 0.22 (1:1, hexanes/ethyl acetate); [R]25D +32.1 (c 0.43, CHCl3);
CH2Cl2 (1 mL) was added Dess-Martin peridodinane (34 mg, 0.081
mmol) at room temperature. After 2.5 h, a saturated solution of
Na2S2O3 (2 mL) was added, and the reaction was stirred for 30
min. The products were extracted with CH2Cl2 (3 × 3 mL), and
the combined organics were washed with a saturated solution of
NaHCO3 (2 × 4 mL), dried (Na2SO4), filtered, and concentrated.
The residue was dissolved in CH2Cl2/MeOH (1:1, 1 mL) at room
temperature, and to the stirred solution was added NaBH4 (4 mg,
0.11 mmol). After 30 min, a saturated solution of NH4Cl (2 mL)
was added, and the reaction was stirred for 10 min. The layers
were separated. The aqueous layer was extracted with EtOAc (3
× 4 mL), after which the organics were combined, dried (MgSO4),
and filtered, and the solvent was removed. The solid residue was
purified by flash chromatography (3:2, ethyl acetate/hexanes) to
yield 26 (17 mg, 0.035 mmol, 66%) as a colorless solid. Rf ) 0.19
1
IR (neat) ν 3525, 1598, 1358, 1176; H NMR (400 MHz, CDCl3)
δ (ppm) 7.84 (d, J ) 8.4, 2H), 7.80 (d, J ) 8.4, 2H), 7.39 (d, J )
7.9, 2H), 7.37 (d, J ) 7.9, 2H), 5.64 (d, J ) 3.5, 1H), 4.79 (dd, J
) 11.5, 3.5, 1H), 4.39 (d, J ) 11.5, 1H), 4.37 (d, J ) 3.5, 1H),
4.28 (m, 1H), 4.15 (m, 2H), 4.08 (dd, J ) 13.6, 1.3, 1H), 3.70 (dd,
J ) 13.5, 1.9, 1H), 2.54 (br s, 1H), 2.49 (s, 6H), 2.23 (m, 1H),
1.58 (s, 3H), 1.54 (m, 1H), 1.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 145.1, 145.0, 132.5, 132.2, 129.7, 129.6, 127.6,
127.5, 113.7, 104.1, 81.3, 79.1, 77.5, 71.4, 67.6, 66.7, 64.6, 25.7,
25.6, 25.1, 21.4, 21.3; LRMS (ESI) 585 (100%) [M + H]+.
Azide 22. Compound 21 (414 mg, 0.71 mmol) was dissolved in
anhydrous DMF (10 mL), and NaN3 (46 mg, 0.71 mmol) was added
before the reaction was heated to 90 °C. After 50 min, LC-MS
indicated consumption of starting material, and therefore the solution
was cooled to room temperature and diluted with brine (15 mL).
The product was extracted with EtOAc (3 × 15 mL), and the
combined organics were washed with H2O (2 × 10 mL), then dried
(MgSO4), filtered, and concentrated. The crude material was purified
by flash chromatography (1:1, hexanes/ethyl acetate) to yield 22
(311 mg, 0.68 mmol, 96%) as a colorless foam. Rf ) 0.34 (1:1,
(1:1, ethyl acetate/hexanes); mp 90-93 °C; [R]25 -3.4 (c 0.85,
D
1
CHCl3); IR (neat) ν 3432, 1694; H NMR (400 MHz, CDCl3) δ
(ppm) 7.79 (d, J ) 7.6, 2H), 7.59 (d, J ) 7.4, 2H), 7.44 (t, J )
7.3, 2H), 7.34 (t, J ) 7.3, 2H), 5.81 (d, J ) 3.0, 0.7H), 5.77 (br s,
0.3H), 4.91 (s, 0.7H), 4.55 (m, 1.3H), 4.43 (dd, J ) 10.4, 6.7, 0.7H),
4.34 (d, J ) 2.9, 0.7H), 4.27 (t, J ) 6.5, 1H), 4.15 (br s, 0.3H),
3.85-4.25 (m, 3.7H), 3.80 (br s, 0.3H), 3.53-3.74 (m, 2.0H), 3.44
(m, 0.3H), 2.20 (m, 0.7H), 1.95 (m, 0.3H), 1.63 (m, 4H), 1.39 (s,
2.1H), 1.35 (s, 0.9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 158.8,
143.3, 143.2, 141.0, 127.5, 127.0, 126.8, 124.7, 124.5, 124.2, 124.1,
119.7, 114.2, 105.2, 82.1, 81.3, 70.8, 76.9, 73.1, 72.2, 68.5, 67.8,
67.3, 66.8, 64.4, 52.8, 46.8, 38.8, 37.5, 28.4, 26.8, 26.2, 26.0, 25.7;
HRMS (ESI) calcd for C16H28NO7S [M + H] 378.1581, found
378.1576.
N-Trichloroethylcarbamate 28. To a solution of 22 (100 mg,
0.22 mmol) in EtOH/pyridine (99:1, 5.5 mL) was added Pd black
(17 mg), the suspension was degassed, and an H2 atmosphere (1
atm) was applied. After being stirred at room temperature for 2 h,
the suspension was filtered and washed with warm MeOH/pyridine
(99:1), and the solution was concentrated and dried on the pump
overnight. The crude material was dissolved in MeCN (6 mL) with
Et3N (90 µL, 66 mg, 0.66 mmol), and the reaction was refluxed
(95 °C) for 24 h. The solution was then cooled to 0 °C, and pyridine
(23 µL, 23 mg, 0.29 mmol) and TrocCl (56 mg, 36 µL, 0.24 mmol)
were added. After 3 h, LC-MS indicated the consumption of the
amine, and the solvents were removed in vacuo. The brown residue
was dissolved in 0.2 M HCl (5 mL), and the products were extracted
with EtOAc (3 × 15 mL), dried (MgSO4), filtered, and concentrated.
The crude material was purified by flash chromatography (1:1, ethyl
acetate/hexanes) to yield 28 (43 mg, 0.10 mmol, 45%) as a colorless
solid. Rf ) 0.49 (7:3, ethyl acetate/hexanes); mp >175 °C dec;
[R]25D +5.5 (c 1.0, CHCl3); IR (neat) ν 3461, 1713; 1H NMR (400
MHz, CDCl3) δ (ppm) 5.80 (d, J ) 3.2, 0.5H), 4.78 (d, J ) 3.4,
0.5H), 4.93 (d, J ) 11.9, 0.5H), 4.83 (d, J ) 11.9, 0.5H), 4.53-
4.68 (m, 3H), 4.37 (d, J ) 3.3, 0.5H), 4.35 (d, J ) 3.6, 0.5H),
4.05-4.25 (m, 2H), 3.95 (d, J ) 2.2, 0.5H), 3.92 (d, J ) 2.8, 0.5H),
3.60-3.80 (m, 2H), 2.80 (br s, 0.4H), 2.40 (br s, 0.5H), 2.20 (m,
1H), 1.65 (s, 3H), 1.63 (m, 1H), 1.39 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 147.5, 146.9, 110.84, 110.79, 101.7, 93.2, 81.9,
81.8, 76.5, 74.7, 74.6, 73.6, 70.0, 69.9, 68.5, 66.8, 66.6, 54.1, 53.9,
41.0, 39.9, 31.1, 30.9, 29.9, 29.5; HRMS (ESI) calcd for C15H21-
Cl3NO7 [M + H] 432.0378, found 432.0384.
hexanes/ethyl acetate); [R]25 +43.5 (c 0.95, CHCl3); IR (neat) ν
D
1
3503, 2102; H NMR (400 MHz, CDCl3) δ (ppm) 7.86 (d, J )
8.3, 2H), 7.38 (d, J ) 8.0, 2H), 5.70 (d, J ) 3.5, 1H), 4.89 (dd, J
) 11.5, 3.5, 1H), 4.53 (d, J ) 3.5, 1H), 4.43 (d, J ) 11.6, 1H),
4.33 (m, 1H), 4.14 (dd, J ) 13.5, 1.3, 1H), 3.81 (dd, J ) 13.5, 2.0,
1H), 3.47 (m, 2H), 2.48 (s, 3H), 2.10 (m, 2H), 1.60 (s, 3H), 1.33
(s, 3H), 1.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 145.0,
132.6, 129.5, 127.6, 113.7, 104.2, 81.5, 79.2, 77.6, 71.5, 67.8, 66.6,
45.2, 25.8, 25.7, 24.9, 21.4; HRMS (ESI) calcd for C19H25N3O8-
SNa [M + Na] 478.1255, found 478.1247.
N-9-Fluorenylmethylcarbamate 24. To a solution of 22 (100
mg, 0.22 mmol) in EtOH/pyridine (99:1, 5.5 mL) was added Pd
black (16 mg), and the suspension was degassed, and an H2
atmosphere (1 atm) was applied. After being stirred at room
temperature for 1.5 h, the suspension was filtered and washed with
warm MeOH/pyridine (99:1), and the solution was concentrated
and dried on the pump overnight.
The crude material was dissolved in MeCN (6 mL) with Et3N
(90 µL, 66 mg, 0.66 mmol), and the reaction was refluxed (95 °C)
for 24 h. The solution was then cooled to 0 °C, and pyridine (18
µL, 17 mg, 0.22 mmol) and FmocCl (63 mg, 0.24 mmol) were
added. After 3 h, LC-MS indicated the consumption of the amine,
and the solvents were removed in vacuo. The brown residue was
dissolved in 0.2 M HCl (5 mL), and the products were extracted
with EtOAc (3 × 15 mL), dried (MgSO4), filtered, and concentrated.
The crude material was purified by flash chromatography (1:1 to
7:3, ethyl acetate/hexanes) to yield 24 (54 mg, 0.11 mmol, 50%)
as a colorless foam. Rf ) 0.16 (1:1, ethyl acetate/hexanes); [R]25
D
10.6 (c 1.8, CHCl3); IR (neat) ν 3449, 1697; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.78 (m, 2H), 7.58 (m, 2H), 7.30-7.46 (m, 4H),
5.76 (d, J ) 3.3, 0.4H), 5.72 (d, J ) 3.3, 0.6H), 4.67 (dd, J )
10.7, 5.2, 0.4H), 4.63 (dd, J ) 10.7, 4.7, 0.6H), 4.55 (m, 1.4H),
4.45 (dd, J ) 10.8, 6.2, 0.4H), 4.33 (d, J ) 3.1, 0.6H), 4.31 (d, J
) 0.4H), 4.25 (m, 1.6H), 4.23 (m, 1H), 3.90 (m, 1.4H), 3.70 (d, J
) 13.6, 0.6H), 3.43 (m, 2H), 3.28 (br s, 0.6H), 2.75 (m, 1H), 1.64
(s, 1.2H), 1.61 (s, 1.8H), 1.38 (s, 1.2H), 1.35 (s, 1.8H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 149.1, 148.6, 137.1, 138.0, 137.9, 137.7,
135.8, 135.58, 135.54, 135.4, 123.2, 123.0, 122.8, 122.6, 122.45,
122.40, 120.6, 120.4, 120.3, 115.88, 115.85, 115.80, 115.7, 110.7,
110.6, 101.6, 81.9, 76.6, 73.5, 73.4, 70.0, 68.4, 68.9, 67.5, 66.8,
56.4, 54.4, 54.1, 49.1, 49.0, 40.0, 39.8, 31.2, 31.0, 29.8, 29.5; HRMS
(ESI) calcd for C27H30NO7 [M + H] 480.2017, found 480.2020.
Alcohol 26. To a solution of 24 (26 mg, 0.054 mmol) in dry
Alcohol 29. To a solution of 28 (26 mg, 0.060 mmol) in dry
CH2Cl2 (1 mL) was added Dess-Martin peridodinane (39 mg, 0.092
mmol) at room temperature. After 2.5 h, a saturated solution of
Na2S2O3 (2 mL) was added, and the reaction was stirred for 20
min. The products were extracted with CH2Cl2 (3 × 3 mL), and
the combined organics were washed with a saturated solution of
NaHCO3 (2 × 5 mL), dried (Na2SO4), filtered, and concentrated.
The residue was dissolved in CH2Cl2/MeOH (1:1, 1 mL) at room
temperature, and to the stirred solution was added NaBH4 (4 mg,
0.11 mmol). After 30 min, a saturated solution of NH4Cl (2 mL)
was added, and the reaction was stirred for 10 min. The layers
were separated. The aqueous layer was extracted with EtOAc (3
J. Org. Chem, Vol. 71, No. 26, 2006 9815

Hanessian and Ritson
× 4 mL), after which the organics were combined, dried (MgSO4),
and filtered, and the solvent was removed. The solid residue was
purified by flash chromatography (1:1, ethyl acetate/hexanes) to
yield 29 (23 mg, 0.053 mmol, 89%) as a colorless, glassy solid. Rf
solution of NH4Cl (6 mL), and the products were extracted with
Et2O (3 × 10 mL), which was dried (Na2SO4), filtered, and
concentrated. The crude product was purified by flash chromatog-
raphy (1:1, ethyl acetate/hexanes) to yield 33 (122 mg, 0.31 mmol,
95%, average of three runs) as a colorless foam. Rf ) 0.29 (1:1,
hexanes/ethyl acetate); [R]25D +6.5 (c 1.19, CHCl3); 1H NMR (400
MHz, CDCl3) δ (ppm) 5.85 (d, J ) 3.3, 1H), 4.71 (br s, 1H), 4.20
(m, 2H), 3.89 (br s, 2H), 3.66 (br s, 3H), 3.53 (s, 3H), 1.88 (br s,
1H), 1.73 (m, 1H), 1.62 (s, 3H), 1.42 (s, 9H), 1.37 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 113.4, 105.4, 81.1, 75.1, 72.8,
71.2, 67.8, 61.6, 58.3, 51.5, 42.3, 27.7, 26.0, 25.6, 23.9; HRMS
(ESI) calcd for C17H30NO7S [M + H] 392.1738, found 392.1735.
) 0.50 (7:3, ethyl acetate/hexanes); [R]25 -8.0 (c 1.2, CHCl3);
D
IR (neat) ν 3460, 1613; 1H NMR (400 MHz, CDCl3) δ (ppm) 5.82
(s, 0.4H), 5.81 (s, 0.6H), 4.9- 5.05 (m, 1.4H), 4.85 (d, J ) 11.9,
0.6H), 4.71 (d, J ) 11.9, 0.6H), 4.63 (d, J ) 12.0, 0.4H), 4.33 (d,
J ) 3.0, 0.6H), 4.28 (d, J ) 2.7, 0.4H), 3.98-4.23 (m, 3.4H), 3.95
(d, J ) 2.4, 0.4H), 3.78 (m, 2.4H), 3.59 (m, 0.4H), 3.43 (br s, 0.6H),
2.21 (m, 1H), 1.69 (m, 1H), 1.64 (s, 3H), 1.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 156.8, 114.1, 113.8, 105.5, 105.3, 94.8,
82.9, 81.4, 76.8, 75.2, 74.9, 73.0, 72.7, 67.9, 67.1, 66.4, 65.0, 52.9,
52.3, 38.3, 38.0, 27.9, 26.8, 26.1, 26.0, 25.7, 25.6; HRMS (ESI)
calcd for C16H28NO7S [M + H] 378.1581, found 378.1576.
N-tert-Butylsulfamate 31. To a solution of 22 (200 mg, 0.44
mmol) in EtOH/pyridine (99:1, 10 mL) was added Pd black (25
mg), the suspension was degassed, and an H2 atmosphere (1 atm)
was applied. After being stirred at room temperature for 1.5 h, the
suspension was filtered and washed with warm MeOH/pyridine (99:
1), and the solution was concentrated and dried on the pump
overnight.
Diphenyldithioacetal 34. Compound 33 (112 mg, 0.29 mmol)
was dissolved into anhydrous CH2Cl2 (6 mL) under an Ar
atmosphere, then PhSH (300 µL, 318 mg, 2.90 mmol) was added,
followed by Amberlyst-15 (280 mg), which was added in two
portions in a 24-h interval. The reaction was stirred at room
temperature for 60 h. After this time, a saturated solution of
NaHCO3 (8 mL) was poured into the reaction vessel and stirred
for 30 min. The layers were separated, and the aqueous phase was
extracted with CH2Cl2 (3 × 5 mL), dried (Na2SO4), filtered, and
concentrated. The crude material was purified by flash chroma-
tography (65:35, hexanes/ethyl acetate) to yield 34 (129 mg, 0.23
mmol, 80%) as a colorless foam. Rf ) 0.41 (1:1, hexanes/ethyl
The crude material was dissolved in MeCN (10 mL) with Et3N
(180 µL, 133 mg, 1.31 mmol), and the reaction was refluxed
overnight (95 °C). When LC-MS showed the disappearance of
starting material, the reaction was cooled to room temperature, and
Et3N (310 µL, 223 mg, 2.20 mmol) and then a 1.0 M solution of
tert-butylsulfinyl chloride in CH2Cl2 (480 µL, 0.48 mmol) were
added. After 4 h, H2O (10 mL) was added to the reaction, and the
majority of the MeCN was removed in vacuo. The product was
extracted with EtOAc (3 × 7 mL), dried (MgSO4), filtered, and
concentrated. The residue was filtered through silica to remove Et3N
and washed with EtOAc/MeOH (95:5). The solvent was removed
in vacuo, and the residue was dissolved in CH2Cl2 (5 mL), to which
m-CPBA (75 mg, 0.43 mmol) was added. After being stirred for
1.5 h at room temperature, a saturated solution of Na2SO3 (5 mL)
was decanted into the reaction, and stirring was continued for a
further 30 min. The layers were separated, and the organic layer
was washed with a saturated solution of NaHCO3 (2 × 5 mL) and
dried (Na2SO4). After filtration and concentration, the crude material
was purified by flash chromatography (7:3, ethyl acetate/hexanes)
to yield 31 (85 mg, 0.23 mmol, 51%) as a colorless solid. Rf )
0.54 (ethyl acetate); mp >175 °C dec; [R]25D -16.2 (c 1.18, CHCl3);
IR (neat) ν 3482, 2254, 1314; 1H NMR (400 MHz, CDCl3) δ (ppm)
5.80 (d, J ) 3.4, 1H), 4.49 (d, J ) 3.3, 1H), 4.30 (m, 4H), 3.95
(dd, J ) 13.1, 3.0, 1H), 3.58 (m, 2H), 2.07 (br s, 1H), 1.86 (m,
1H), 1.65 (s, 3H), 1.63 (m, 1H), 1.43 (s, 9H), 1.38 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 113.6, 104.6, 81.6, 73.2, 70.8,
69.3, 68.6, 61.9, 56.3, 40.9, 27.6, 26.0, 25.7, 23.9; HRMS (ESI)
calcd for C16H28NO7S [M + H] 378.1581, found 378.1576.
O-Methyl Ether 33. To a solution of 31 (121 mg, 0.32 mmol)
in dry CH2Cl2 (6 mL) was added Dess-Martin peridodinane (191
mg, 0.45 mmol) at room temperature. After 1 h, a saturated solution
of Na2S2O3 (6 mL) was added, and the reaction was stirred for 20
min. The products were extracted with CH2Cl2 (3 × 5 mL), and
the combined organics were washed with a saturated solution of
NaHCO3 (2 × 6 mL), dried (Na2SO4), filtered, and concentrated.
The residue was dissolved in CH2Cl2/MeOH (1:1, 6 mL) at room
temperature, and to the stirred solution was added NaBH4 (19 mg,
0.33 mmol). After 30 min, a saturated solution of NH4Cl (7 mL)
was added, and the reaction was stirred for 10 min. The layers
were separated. The aqueous layer was extracted with EtOAc (3
× 10 mL), after which the organics were combined, dried (MgSO4),
and filtered, and the solvent was removed.
acetate); [R]25 +29.5 (c 1.29, CHCl3); IR (neat) ν 3451, 2250,
D
1307; 1H NMR 400 MHz, CDCl3) δ (ppm) 7.44 (m, 4H), 7.28 (m,
6H), 5.00 (d, J ) 1.8, 1H), 4.33 (m, 1H), 4.05 (d, J ) 1.7, 1H),
3.95 (m, 3H), 3.67 (d, J ) 2.4, 1H), 3.58 (m, 3H), 3.42 (s, 3H),
2.41 (ddd, J ) 14.5, 13.1, 8.0, 1H), 2.10 (dd, J ) 14.6, 4.3, 1H),
1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 134.7, 134.1,
131.2, 130.8, 128.7, 128.6, 127.1, 127.0, 78.5, 75.2, 72.5, 67.3,
64.3, 61.8, 58.7, 57.6, 54.8, 42.7, 26.4, 24.0; HRMS (ESI) calcd
for C26H35NO6S3Na [M + Na] 576.1519, found 576.1512.
Thioglycoside 35. A solution of 34 (125 mg, 0.23 mmol) in
CH2Cl2 (10 mL) was cooled to 0 °C, and NBS (62 mg, 0.35 mmol)
was added. After being stirred at 0 °C for 30 min, a saturated
solution of Na2S2O3 (15 mL) was added, and the biphasic mixture
was stirred until colorless. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organics
were combined, dried (Na2SO4), and filtered, and the solvents were
evaporated in vacuo. The crude product was purified by flash
chromatography (1:1, hexanes/ethyl acetate) to yield 35 (72 mg,
0.16 mmol, 71%) as a colorless foam. Rf ) 0.20 (1:1, hexanes/
ethyl acetate); [R]25 +170.8 (c 0.72, CHCl3); IR (neat) ν 3467,
D
1
2433, 1315; H NMR 400 MHz, CDCl3) δ (ppm) 7.53 (dd, J )
8.2, 1.3, 2H), 7.28 (m, 3H), 5.75 (d, J ) 4.3, 1H), 4.78 (m, 1H),
4.20 (dd, J ) 12.2, 8.1, 1H), 4.08 (d, J ) 4.4, 1H), 3.98 (m, 2H),
3.68 (br s, 3H), 3.53 (s, 3H), 2.92 (s, 1H), 1.83 (m, 2H), 1.42 (s,
9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 135.2, 130.5, 128.7,
128.5, 126.7, 93.3, 76.9, 75.1, 74.4, 72.2, 70.5, 68.1, 58.3, 51.5,
42.1, 27.6, 23.9; HRMS (ESI) calcd for C20H30NO6S2 [M + H]
444.1509, found 444.1500.
O-Pivaloyl Ester 36. To a solution of 35 (72 mg, 0.16 mmol)
and DMAP (90 mg, 0.74 mmol) in anhydrous CH2Cl2/pyridine (2:
1, 2 mL) was added PivCl (300 µL, 294 mg, 2.44 mmol) under an
Ar atmosphere at room temperature. After 5 h, the solvents were
removed in vacuo (without heating), and the residue was dissolved
in CH2Cl2 (6 mL), which was washed sequentially with 0.1 M HCl
(2 × 3 mL) and H2O (3 mL), dried (Na2SO4), filtered, and
concentrated. The crude product was purified by flash chromatog-
raphy (4:1, hexanes/ethyl acetate) to yield 36 (70 mg, 0.13 mmol,
81%) as a colorless foam and recrystallized by slow evaporation
of CHCl3. Rf ) 0.68 (1:1, hexanes/ethyl acetate); [R]25D +118.2 (c
1
0.45, CHCl3); IR (neat) ν 2255, 1742, 1481, 1317; H NMR 400
The solid residue, 32, was dissolved in anhydrous THF (6 mL),
to which NaH (60% dispersion in mineral oil, 28 mg, 0.70 mmol)
was added at room temperature. After being stirred for 20 min,
MeI (56 µL, 127 mg, 0.90 mmol) was added, and the reaction was
stirred overnight. The reaction was then poured into a saturated
MHz, CDCl3) δ (ppm) 7.54 (m, 2H), 7.30 (m, 3H), 5.84 (d, J )
4.9, 1H), 5.24 (d, J ) 4.3, 1H), 4.76 (br s, 1H), 4.09 (m, 1H), 3.95
(m, 2H), 3.65 (m, 3H), 3.54 (s, 3H), 1.83 (m, 2H), 1.43 (s, 9H),
1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.3, 134.6,
9816 J. Org. Chem., Vol. 71, No. 26, 2006

Synthesis of a Tricyclic N-Malayamycin Analogue
130.8, 128.5, 127.0, 91.1, 75.2, 74.0, 72.0, 67.8, 65.5, 61.6, 58.2,
51.3, 42.1, 38.9, 26.8, 23.9, 14.9; LRMS (ESI) 528 (85%) [M +
H]+.
20 mg, 1.04 mmol) and then anhydrous pyridine (7.5 µL, 7 mg,
0.093 mmol) were added, and the reaction was stirred at room
temperature until LC-MS showed full conversion of the amine to
the protected urea. At this point, the solvents were removed in vacuo
(without heating), and the solid residue was stirred in 40 wt %
MeNH2 in H2O/MeOH (3:1, 0.9 mL). After 24 h, 40 wt % MeNH2
in H2O solution (0.10 mL) was added, and the reaction was stirred
for a further 48 h. The reaction was lypophilized, and the crude
material was purified by preparative TLC (3:2, CHCl3/MeOH) to
N-Nucleoside 37. A solution of 36 (24 mg, 0.046 mmol) in dry
CH2Cl2 (0.7 mL) was added to a solution of bis-silylated
N-acetylcytosine10b (0.32 mmol of crude material) in dry CH2Cl2
(0.5 mL) under an Ar atmosphere at room temperature. NIS (41
mg, dried by lypophilization overnight) was added, followed
immediately by triflic acid (5 µL, 8 mg, 0.055 mmol). Triflic acid
(3 µL, 5 mg, 0.034 mmol) was added in two portions at 24-h
intervals, and after 4 days the reaction was quenched with a
saturated solution of Na2S2O3 (3 mL) and a saturated solution of
NaHCO3 (2 mL) and stirred for 30 min. The products were extracted
with EtOAc (4 × 6 mL), dried (MgSO4), filtered, and concentrated.
Flash chromatography of the crude material (4:1 to 1:4, hexanes/
ethyl acetate) gave recovered starting material (10 mg, 0.019 mmol)
and 37 (8 mg, 0.014 mmol, 52% based on recovered starting
material) as a colorless solid. The crude product was recrystallized
from EtOAc/hexanes. Rf ) 0.32 (ethyl acetate); mp >210 °C dec;
[R]25D +91.4 (c 0.35, EtOAc); 1H NMR 400 MHz, CDCl3) δ (ppm)
9.16 (br s, 1H), 8.53 (br s, 1H), 7.52 (d, J ) 7.4, 1H), 5.86 (s, 1H),
4.90 (br s, 1H), 4.87 (s, 1H), 4.16 (dd, J ) 12.1, 7.6, 1H), 4.05 (m,
1H), 3.82 (m, 3H), 3.60 (m, 1H), 3.48 (s, 3H), 2.25 (s, 3H), 1.83
(m, 1H), 1.52 (m, 1H),1.46 (s, 9H), 1.27 (s, 9H); 13C NMR (100
MHz, CD3OD) δ (ppm) 177.4, 172.5, 164.0, 156.9, 144.9, 97.2,
93.4, 78.5, 75.0, 74.2, 71.6, 68.3, 67.8, 62.5, 58.4, 53.3, 39.2, 28.9,
27.0, 25.9, 24.1; LRMS (ESI) 571 (100%) [M + H]+.
yield 7 (5 mg, 0.014 mmol, 52%) as a colorless solid. Rf ) 0.22
1
(75:25, CHCl3/MeOH); [R]25 +25.8 (c 0.06, MeOH); H NMR
D
(400 MHz, D2O) δ (ppm) 7.53 (d, J ) 7.5, 1H), 5.88 (d, J ) 7.6,
1H), 5.48 (s, 1H), 5.28 (br s, 1H), 4.07 (dd, J ) 10.2, 5.6, 1H),
3.92 (d, J ) 2.7, 1H), 3.79 (m, 3H), 3.55 (br s, 1H), 3.39 (br s,
1H), 3.32 (s, 3H), 1.79 (dd, J ) 16.2, 6.1, 1H), 1.34 (m, 1H); 13C
NMR (100 MHz, CD3OD) δ (ppm) 166.3, 161.0, 156.7, 139.4, 95.3,
94.4, 78.0, 75.3, 73.5, 71.1, 66.9, 56.6, 39.8, 36.3, 27.3; HRMS
(ESI) calcd for C15H22N5O6 [M + H] 368.1565, found 368.1573.
Acknowledgment. We thank NSERC and Syngenta for
generous financial support. We also thank Drs. Olivier Loiseleur
(Syngenta, Basel, Switzerland) and Patrick Crowley (Syngenta,
Jealott’s Hill, U.K.) for stimulating discussions, Dr. Minh Tan
Phan Viet for assistance with NMR experiments, and Dr. Michel
Simard for X-ray crystal structure determination.
Supporting Information Available: 1H NMR and 13C NMR
spectra of compounds 9, 11-19, 21, 22, 24, 26, 28, 29, 31, 33-
37, and 7 and X-ray crystallographic data for compounds 5, 36,
and 37. This material is available free of charge via the Internet at
http://pubs.acs.org.
Tricyclic N-Malayamycin A (7). The sulfonamide 37 (15 mg,
0.026 mmol) was dissolved in anhydrous CH2Cl2 (1.0 mL) under
an Ar atmosphere. Anisole (43 µL, 43 mg, 0.39 mmol) and then
triflic acid (8 µL, 14 mg, 0.10 mmol) were added, and the reaction
was stirred at room temperature until LC-MS showed the disap-
pearance of starting material. Trichloroacetyl isocyanate (13 µL,
JO061904R
J. Org. Chem, Vol. 71, No. 26, 2006 9817