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
`
`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.
`(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,
`697.
`
`10.1021/jo061904r CCC: $33.50 © 2006 American Chemical Society
`Published on Web 11/29/2006
`
`more commonly encountered monocyclic pentofuranosyl or
`4 1 and
`hexopyranosyl residues. For example, ezomycin A2
`octosyl acid A5 2 are representatives of such bicyclic N-
`6 3 is a C-nucleoside equivalent
`nucleosides, while ezomycin B2
`(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
`
`(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.
`(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.
`
`J. Org. Chem. 2006, 71, 9807-9817
`
`9807
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`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.
`(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.,
`Eds.; Wiley-VCH: Weinheim, Germany, 2005. (c) Thiel, K. A. Nat.
`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.
`(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.
`(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.
`
`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
`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
`
`(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.
`(11) Hanessian, S. Chem. Med. Chem., published online Nov 8, 2006,
`http://dx.doi.org/10.1002/cmdc.200600203.
`
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`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.
`
`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 (cid:176)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 (cid:176)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
`
`(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.
`
`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 (cid:176)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.
`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 (cid:176)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.
`(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
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`SCHEME 2.
`
`Synthesis of the Bicyclic Corea
`
`Hanessian and Ritson
`
`a Reagents and conditions: (a) CrO3, pyridine, Ac2O, CH2Cl2, 0(cid:176)C to rt; (b) allylmagnesium bromide, THF, -10 (cid:176)C to rt, 77% (two steps); (c) O 3,
`CH2Cl2, -78 (cid:176)C then NaBH 4, MeOH, -78 (cid:176)C to 75 (cid:176)C, NH 3, rt to 75 (cid:176)C then AcOH, rt, 59 to 84%; (d) NaH, BnBr, THF, 0 (cid:176)C to rt, 88%; (e) NaH, allyl
`bromide, HMPA, THF, 100 (cid:176)C, 97%; (f) 85% AcOH/H 2O, rt, 88%; (g) MsCl, Et3N, CH2Cl2, 0 (cid:176)C; (h) NaI, DMA, 100 (cid:176)C, 83% (two steps); (i) 5 mol %
`Grubbs first-generation catalyst, CH2Cl2, rt, 93%.
`
`SCHEME 3 a
`
`a Reagents and conditions: (a) m-CPBA, Na2HPO4, CH2Cl2, rt, 19%;
`(b) NaN3, CH2OHCH2OMe, 130 (cid:176)C; (c) NaN 3, NH4Cl, MeCN/H2O, 130
`(cid:176)C; (d) NaN 3, NH4Cl, CH2OHCH2OMe, 130 (cid:176)C; (e) 5 mol % OsO 4, NMO,
`acetone/H2O, rt, 92%, dr > 100:1; (f) MsCl, Et3N, CH2Cl2, -78 (cid:176)C, 45%;
`(g) NaN3, CH2OHCH2OMe, 155 (cid:176)C.
`
`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.
`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
`
`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-
`-/proton sponge.24 Unfortu-
`SO4/NaHCO3,23 and Me3O+BF4
`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.
`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
`
`(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.
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`Synthesis of a Tricyclic N-Malayamycin Analogue
`
`SCHEME 4 a
`
`a Reagents and conditions: (a) Pd(OH)2, H2 (1 atms), EtOAc, rt; (b) TsCl, pyridine, -20 (cid:176)C, 71% (two steps); (c) NaN 3, DMF, 90 (cid:176)C, 96%; (d) Pd black,
`H2 (1 atm), pyridine, EtOH, rt; (e) Et3N, MeCN, 95 (cid:176)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.
`Previous reports from our laboratory7,9,10b,28 and the Knapp
`group29 had shown the utility of (cid:231)-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 (cid:176)C to effect cycloetherification, 28 affording 35
`in 71% yield. A trace amount of a byproduct which may have
`been the (cid:226)-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
`
`(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.
`
`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%.
`
`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 (cid:243)* C-O bond would be inaccessible in a chair conformation
`as in A (Figure 3). A boat conformer, B, would better expose
`the (cid:243)* 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 (cid:176)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 (cid:243)* orbital of the now axially
`disposed tosylate in 22, presumably in a boat conformer, as
`shown in C (Figure 3).
`
`(32) For an ORTEP diagram of compound 37, see Supporting Information
`S73.
`
`J. Org. Chem, Vol. 71, No. 26, 2006 9811
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`SCHEME 5 a
`
`Hanessian and Ritson
`
`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 (cid:176)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 (cid:226)-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.
`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.
`
`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
`
`(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
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`Synthesis of a Tricyclic N-Malayamycin Analogue
`
`FIGURE 4. Activation at the anomeric center-thioglycoside and N-nucleoside formation.
`
`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 (cid:243)* 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.
`
`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 (cid:176)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 (cid:176)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(cid:2) 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 (cid:176) C; [R]25
`+42.4 (c 1.40, CHCl3); lit.18 [R]25
`D +42.8 (c 3.0, CHCl3); IR (neat)
`
`D
`
`(cid:238) 3474, 1374, 1073; 1H NMR (400 MHz, CDCl3) (cid:228) (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,
`8.7, 1H), 1.61 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H); 13C
`NMR (75 MHz, CDCl3) (cid:228) (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]+.
`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 (cid:176)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 (cid:176)C; [R] 25
`D +22.7 (c 0.67,
`CHCl3); IR (neat) (cid:238) 3539, 3452, 1388; 1H NMR (400 MHz, CDCl3)
`(cid:228) (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) (cid:228) (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