Studies Related to the Carbohydrate Sectors of Esperamicin and

May 1, 1995 - Calicheamicin: Definition of the Stability Limits of the. Esperamicin Domain and Fashioning of a Glycosyl Donor from the Calicheamicin D...
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J. Am. Chem. SOC. 1995,117, 5720-5749

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Studies Related to the Carbohydrate Sectors of Esperamicin and Calicheamicin: Definition of the Stability Limits of the Esperamicin Domain and Fashioning of a Glycosyl Donor from the Calicheamicin Domain Randall L. Halcomb? Serge H.BoyerJ Mark D. Wittman? Steven H. Olson,? Derek J. Denhart,+Kevin K. C. LiuJvS and Samuel J. Danishefsky*”*$# Contribution jkom the Department of Chemistry, Yale University, New Haven, Connecticutt 0651I , Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, Box 106, New York, New York 10021, and Department of Chemistry, Columbia University, New York, New York 10027 Received January 6, 1995@

Abstract: The core trisaccharide regions of esperamicin and the aryltetrasaccharide region of calicheamicin have been synthesized. The minimum protection modalities necessary to stabilize structures against rearrangement to an isomeric azafuranose series were ascertained (see compounds 12 and 65). Deprotection of the 2-(trimethylsily1)ethoxycarbonyl carbamate from 65 led to azafuranose 14 characterized as methyl glycoside 15. Using this insight, it was possible to fashion, for the first time, a pre-glycosyl donor (see compound 128) corresponding to the complete arylsaccharide sector of calicheamicin yll at the oxidation level of the domain. Among the key assembly strategies were the conversion of a-thiophenylpseudoglycalsto allal derivatives (see 44 45); the interfacing of epoxidemediated glycosylation with iodoglycosylation (see 30 47 48); the synthesis of hydroxylamine glycosides via triflate displacement (see 61 91 101); and a new route to p-hydroxybenzonitriles (see formation of 86).

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Background, Synthetic Goals, and Overview The structures of calicheamicin y1’ (1)’ and esperamicin AI, (2)* were disclosed in 1987 by workers at Lederle Laboratories

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the sorts of transformations which might be feasible for assembling the carbohydrate domain and then to assemble this domain in such a fashion that it might be presented as a glycosyl (4)For synthetic efforts conceming the aglycons of 1 and 2, see: (a)

and at Bristol-Myers. Rarely has the discovery of a class of Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. SOC. 1988,110, 4866.(b) Danishefsky, S. J.; Yamashita, compounds initiated such intense research activity in issues of D. S.; Mantlo, N. B. Tetrahedron Lett. 1988.29.4861.(c) Danishefsky, S. mechanism of action, and drug design.* J.; Mantlo, N. B.; Yamashita, D.S.; Shulte, G. J. Am. Chem. SOC.1988, An important step in realizing a total synthesis of calicheami110,6890.(d) Kende, A. S.; Smith, C. A. Tetrahedron Lett. 1988,29,4217. (e) Magnus, P.; Carter, P. A. J. Am. Chem. SOC.1988,110,1626.(f) Magnus, cin yl* involved the total synthesis of the aglycon, which we P.;Lewis, R. T.; Huffman, J. C. J. Am. Chem. SOC.1988,110, 6921.(g) termed calicheamicinone.6 With this goal accomplished, and Schreiber, S. L.; Kiessling, L. L. Tetrahedron Lett. 1989,30, 433. (h) with major advances in the carbohydrate sector being registered Schoenen, F. J.; Porco, J. A.; Schreiber, S. L.; VanDuyne, G. D.; Clardy, J. Tetrahedron Lett. 1989,30,3765.(i) Haseltine, J. N.; Danishefsky, S. on a continuing basis? the next threshold would be the total J.; Shulte, G. J. Am. Chem. SOC. 1989,111, 7638.(i) Magnus, P.; Lewis, synthesis of calicheamicin. Indeed, the completion of this total R. T.; Bennett, F. J. Chem. SOC., Chem. Commun. 1989,916.(k) Magnus, synthesis by Nicolaou and co-workers’ is a milestone in P.; Bennett, F. Tetrahedron Lett. 1989,30,3637.(1) Magnus, P.; Lewis, R. T. Tetrahedron Lett. 1989,30, 1905.Magnus, P.;Annoura, H.; Harling, J. synthetic organic chemistry. J. Org. Chem. 1990, 55, 1711. (m) Yamashita, D. S.; Rocco, V. P.; Here and in the following paper, we document our approach Danishefsky, S. J. Tetrahedron Lett. 1991,32,6667.(n) Rocco, V. P.; Danishefsky, S. J.; Shulte, G. Tetrahedron Lett. 1991,32,6671. which, building from our calicheamicinone total synthesis, (0)Kadow, allowed us to achieve the total synthesis of calicheamicin y ~ ’ . ~ J. F.;Tun, M. M.; Vyas, D. M.; Wittman, M. D.; Doyle, T. W. Tetrahedron Lett. 1992, 33, 1423. (p) Magnus, P.; Carter, P.; Elliott, J.; Lewis, R.; To accomplish our goal, it was necessary to gain insight as to Harling, J.; Pittema, T.; Bauta, W. W.; Fortt, S . J. Am. Chem. SOC.1992,

* Address correspondence to this author at the Sloan-Kettering Institute for Cancer Research or Columbia University. + Yale University. Sloan-Kettering Institute for Cancer Reseach. Columbia University. Abstract published in Advance ACS Abstracts, May 1, 1995. (1)(a) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton, G. 0.;Borders, D. B. J. Am. Chem. SOC. 1987,109,3464.(b) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. 0.; McGahren, W. J.; Borders, D.B. J. Am. Chem. SOC.1987,209,3466.(c) Lee, M. D.; Ellestad, G. A.; Borders, D. B. Acc. Chem. Res. 1991,24,235. (d) Lee, M. D.; Dunne, T. S . ; Chang, C. C.; Siegel, M. M.; Morton, G. 0.; Ellestad, G. A.; McGahren, W. J.; Borders, D. B. J. Am. Chem. SOC. 1992,

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114,985. (2) (a) Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.4.; Doyle, T. W. J. Am. Chem. SOC. 1987,109, 3461.(b) Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.4.; Doyle, T. W. J. Am. Chem. SOC. 1987,109,3462. (3)For a recent review of the enediyne antibiotics, see: Nicolaou, K. C.; Dai, W.-M. Angew. Chem., In?. Ed. Engl. 1991,30, 1387.

114,2544.(4)Magnus, P.; Lewis, R.; Bennett, F. J. Am. Chem. SOC. 1992, 114,2560. (r) Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am. Chem. SOC.1992,114,3134. (s) Smith, A. L.; Pitsinos, E. N.; Hwang, C.-K.; Mizuno, Y.; Saimoto, H.; Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. J. Am. Chem. SOC. 1993, 115, 7612. (t) Semmelhack, M. F.; Gallagher, J. Tetrahedron Lett. 1993,34, 4121. ( 5 ) For other synthetic studies of the oligosaccharide domains of 1 and

2,see: (a) Kahne, D.; Yang, D.; Lee, M. D. Tetrahedron Lett. 1990,31, 21. (b) Yang, D.; Kim, S.-H.; Kahne, D. J. Am. Chem. SOC. 1991,113, 4715.(c) Nicolaou, K. C.; Groneberg, R. D.; Stylianides, N. A.; Miyazaki, T. J. Chem. SOC.,Chem. Commun. 1990, 1275. (d) Nicolaou, K. C.; Groneberg, R. D. J. Am. Chem. SOC. 1990,112,4085.(e) Nicolaou, K. C.; Groneberg, R. D.;Miyazaki, T.; Stylianides, N. A,; Schulze, T. J.; Stahl, W. J. Am. Chem. SOC.1990, 112,8193.(f) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. J. Am. Chem. SOC. 1993, 115, 7593.(g) Nicolaou, K. C.; Schreiner, E. P.; Stahl, W. Angew. Chem., Int. Ed. Engl. 1991,30,585.(h) Nicolaou, K. C.; Clark, D. Angew. Chem., In?. Ed. Engl. 1992,31, 855. (i) Van Laak, K.; Scharf, H.-D. Tetrahedron Lett. 1989,30, 4505.(i) Toufik, B.; Lancelin, J.-M.; Beau, J.-M. J. Chem. Soc., Chem. Commun. 1992,1494.(k) Kim, S.-H.; Augeri, D.; Kahne, D. J. Am. Chem. SOC. 1994,116, 1766.

0002-7863/95/1517-5720$09.00/00 1995 American Chemical Society

Carbohydrate Sectors of Esperamicin and Calicheamicin

J. Am. Chem. SOC., Vol. 117, No. 21, 1995 5721

2

0

h0

CH,

Figure 1.

donor to a late stage version of the aglycon. As will be described, these studies were amply rewarded when it was shown to be possible to deliver this carbohydrate domain to calicheamicinone protected only as its ketal.6c Before describing these investigations, it is instructive to briefly place the problem in a somewhat broader context. (6) For the first total synthesis of calicheamicinone, see: (a) Cabal, M. P.; Coleman, R. S.; Danishefsky, S. J. J. Am. Chem. SOC.1990, 112, 3523. (b) Haseltine, J. N.; Cabal, M. P.; Mantlo, N. P.; Iwasawa, N.; Yamashita, D. S.; Coleman, R. S.; Schulte, G. M.; Danishefsky, S. J. J. Am. Chem. SOC.1991, 113, 3856. (c) Hitchcock, S. A.; Boyer, S. H.; Chu-Moyer, M. Y . ; Olson, S. H.; Danishefsky, S. J. Angew. Chem., lnt. Ed. Engl. 1994, 33, 858. (7) (a) Nicolaou, K. C.; Hummel, C. W.; Pitsinos, E. N.; Nakada, M.; Smith, A. L.; Shibayama, K.; Saimoto, H. J. Am. Chem. SOC.1992, 114, 10082. (b) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.; Pitsinos, E. N.; Saimoto, H.; Mizuno, Y.; Baldenius, K.-U.; Smith, A. L. J. Am. Chem. SOC. 1993, 115, 7625. (8) Mechanism of action: (a) Long, B. H.; Golik, J.; Forenza, S.; Ward, B.; Rehfuss, R.; Dabrowiak, J. C.; Catino, J. J.; Musial, S. T.; Brookshire, K. W.; Doyle, T. W. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 2. (b) Mantlo, N. B.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 2781. (c) Haseltine, J. N.; Danishefsky, S. J. J. Org. Chem. 1990,55,2576. (d) Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P. J. Am. Chem. SOC.1990, 112,4986. (e) Myers, A. G.; Cohen, S. B.; Kwon, B. M. J. Am. Chem. SOC.1994, 116, 1255. (0 Snyder, J. P. J. Am. Chem. SOC.1989,111,7630. De Voss, J. J.; Hangeland, J. J.; Townsend C. A. J. Am. Chem. SOC.1990,112,4554. (g) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992,25,497. (h) Nicolaou, K. C.; Smith, A. L., Yue, E. W. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5881. (i) Nicolaou, K. C.; Maligres, P.; Suzuki, T.; Wendebom, S. V.; Dai, W.-M.; Chadha, R. K. J. Am. Chem. SOC. 1992, 114,8890. (i) Nicolaou, K. C.; Dai, W.-M. J. Am. Chem. SOC.1992,114, 8908. (k) Nicolaou, K. C.; Dai, W.-M.; Tsay, S. C.; Estevez, V. A.; Wrasidlo, W. Science 1992,256, 1172. (1) Nicolaou, K. C.; Dai, W.-M.; Hong, Y. P.; Tsay, S.-C.; Baldridge, K. K.; Siegel, J. S. J. Am. Chem. SOC. 1993, 115, 7944. (m) Boger, D. L.; Zhou, J. J. Org. Chem. 1993, 58, 3018. (n) Tokuda, M.; Fujiwara, K.; Gomibuchi, T.; Hirama, M.; Uesugi, M.; Sugiura, Y. Tetrahedrrn Lett. 1993, 34, 669. (0) Nicolaou, K. C.; Li, T.; Nakada, M.; Hummc'!, . . ' Hiatt, A.; Wrasidlo, W. Angew. Chem., lnt. Ed. Engl. 1994, 33, 183.

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Calicheamicin and esperamicin are the first two characterized members of a growing class of enediyne-containing antibiotics (Figure 1) which now includes dynemicin A (3)? kedarcidin chromophore (4),1°and C-1027 chromophore (5)" The previously isolated neocarzinostatin chromophore (6)12possesses an epoxidized variant of the enediyne unit and is included in this class of compounds because of its related structure and mechanism of action.I2 Both calicheamicin and esperamicin are extraordinarily active against a number of tumor cell lines. They exhibit a potency 3-4 orders of magnitude greater than that of adriamycin in some assays.'$* Presumptive evidence indicates that the cytotoxicity of these drugs is derived from their known ability to cleave DNA in a double-stranded f a ~ h i 0 n . lThis ~ process is initiated by an in vivo reduction of the trisulfide functionality of the (9) (a) Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; VanDuyne, G. D.; Clardy, J. J. Antibiot. 1989,42, 1449. (b) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.; Clardy, J. J. Am. Chem. SOC. 1990, 112, 3715. (10) (a) Leet, J. E.; Schroeder, D. R.; Hofstead, S. J.; Golik, J.; Colson, K. L.; Huang, S.; Klohr, S. E.; Doyle, T. W.; Matson, J. A. J. Am. Chem. SOC. 1992, 114, 7946. (b) Leet, J. E.; Schroeder, D. R.; Langley, D. R.; Colson, K. L.; Huang, S.; Klohr, S. E.; Lee, M. S.; Golik, J.; Hofstead, S.; Doyle, T. W.; Matson, J. A. J. Am. Chem. SOC.1993, 115, 8432. (11) Yoshida, K.; Minami, Y . ; Azuma, R.; Saeki, M.; Otani, T. Tetrahedron Lett. 1993, 34, 2637. (12) (a) Napier, M. A.; Holmquist, B.; Strydom, D. J.; Goldberg, I. H. Biochem. Biophys. Res. Commun. 1979, 89, 635. (b) Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake, N.; Ishida, N. Tetrahedron Lett. 1985, 26, 331. (c) Myers, A. G. Tetrahedron Lett. 1987, 28, 4493. (13) (a) Zein, N.; Sinha, A. M.; McGahren, W. J.; Ellestad, G. A. Science 1988, 240, 1198. (b) Zein, N.; Poncin, M.; Nilakantan, R.; Ellestad, G. A. Science 1989, 244, 697. (c) Sugiura, Y.; Uewawa, Y.; Takahashi, Y.; Kuwahara, J.; Golik, J.; Doyle, T. W. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 7672. (d) Dedon, P. C.; Salzberg, A. A,; Xu, J. BiochemistT 1993, 32, 3617.

5722 J. Am. Chem. Soc., Vol. 117,No. 21, 1995

Scheme 1

Halcomb et al.

Scheme 2a

SSSCH3

CH CH3S*0

2-

a 0 I

7

1 or2

a

I

O2 DNA scission

aglycon to an allylic thiolate 7 (Scheme 1).8e This thiolate species cyclizes to the bridgehead enone to generate the intermediate 8. Bergman-type cycloar~matization’~ of the enediyne unit in 1 or 2 is itself prevented by the enone double bond because the resulting 1,Cdiradical would contain a highly strained anti-Bredt olefin. The rehybridization of the bridgehead center from sp2 to sp3 lowers the strain of the resulting diyl 9 and provides an attainable kinetic pathway for cyclization under mild condition^.'^ The 1,Qdiradical 9 produced by the cycloaromatization abstracts hydrogen atoms from the sugar backbone of DNA. Further reaction of these DNA radicals with 0 2 results in DNA strand scission.’6a Calicheamicin and esperamicin each bind to DNA in the minor Calicheamicin was shown to be quite sequence selective in cleaving DNA;’3a esperamicin is less selective.I6 Calicheamicin cleaves DNA predominantly by abstracting the p r o 4 hydrogen atom from C-5’ of the 5’-cytosine of TCCT sequences and another from C-4’ of the residue on the opposing strand, which is three base pairs in the 3’ direction from this site.I8 Other sequences were identified as also being susceptible to ~1eavage.I~ Although the origins of sequenceselective cleavage by 1 are the subject of some debate, it is clear that the aryltetrasaccharide domain plays a very important role in the DNA recognition event prior to cleavage. It was proposed that the major contributions to binding made by the carbohydrate subunit are hydrophobic in nature.20 Walker et (14) (a) Bergman, R. G. Arc. Chem. Res. 1973, 6, 25. (b) Darby, N.; Kim, C. U.; Salaiin, J. A.; Shelton, K. W.; Takada, S . ; Masamune, S . J. Chem. Soc., Chem. Commun. 1971, 1516. (15) For discussions on the nature of this triggering process, see refs 4a and 8d. (16) (a) Christner, D. F.; Frank, B. L.; Kozarich, J. W.; Stubbe; J. A,; Golik, J.; Doyle, T. W.; Rosenberg, I. E.; Krishnan, B. J. J. Am. Chem. SOC. 1990,112,4554. (b) Uesugi, M.; Sugiura, Y .J. Am. Chem. SOC. 1993, 115, 4622. (17) Zein, N.; McGahren, W. J.; Morton, G. 0.;Ashcroft, J.; Ellestad, G. A. J. Am. Chem. SOC. 1989, 1 1 1 , 6888. (18) (a) De Voss, J. J.; Townsend, C. A.; Ding, W.-d.; Morton, G.0.; Ellestad, G. A.; Zein, N.; Tabor, A. B.; Schreiber, S . L. J. Am. Chem. SOC. 1990, 112, 9669. (b) Hangeland, J. J.; De Voss, J. J.; Heath, J. A,; Townsend, C. A.; Ding, W.-d.; Ashcroft, J. S . ; Ellestad, G.A. J. Am. Chem. SOC. 1992, 114, 9200. (19) Walker, S.; Landovitz, R.; Ding, W.-d.; Ellestad, G.A.; Kahne, D. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 4608.

y-Lqd OCH3

16

X-H

17

X I protectinggroup

Reagents: (a) NaBfi, CHsOH; (b) CH30H, AcOH.

aLZ1and Paloma et ale2*have shown, through NMR studies, that calicheamicin adopts an extended, highly preorganized conformation in solution, making it well suited to function as a minor groove binder. They have further demonstrated that the hydroxylamine glycosidic linkage plays a key role in maintaining this extended structure.23 An early line of evidence which identified the role of the carbohydrate domain in DNA recognition was the finding that our synthetic aglycon, calicheamicinone, lacked any discemible sequence selectivity though it retained modest double-strand cleavage t e n d e n c i e ~ . ~ ~ The studies described herein were initiated with several goals in mind. It was felt that synthetic routes to the carbohydrate domains of 1 and 2 provided more promising avenues for obtaining material than degradation of the natural products. The likelihood of obtaining the two drugs in amounts which were ample for proper chemical investigation was not promising. Such information suggested that the prospect of retrieving the entire carbohydrate by hydrolysis, even if the drug were available, was unlikely. The indications were that, at least in the case of calicheamicin, this domain would not survive detachment of the carbohydrate A ring from the aglycon, calicheamicinone (11).6a-CFurthermore, in the esperamicin series, there was a report which suggested that the carbohydrate domain, containing a free “reducing end” in ring A (see 16, Scheme 2), was inherently unstable and underwent rapid rearrangement.25 The finding was that treatment of compound 2 with sodium borohydride led not to 16 (or its derived alditol reduction (20) Ding, W.-d.; Ellestad, G.A. J. Am. Chem. SOC. 1991, 113, 6617. (21) (a) Walker, S.; Valentine, K. G.;Kahne, D. J. Am. Chem. Soc. 1990, 112, 6428. (b) Walker, S.; Andreotti, A. H.; Kahne, D. E. Tetrahedron 1994, 50, 1351. (c) Walker, S.; Mumick, J.; Kahne, D. J. Am. Chem. SOC. 1993, 115, 7954. (22) Paloma. L. G.:Smith. J. A,: Chazin. W. J.: Nicolaou. K. C. J. Am. Chem. SOC. 1994, 116, 3697. (23) (a) Walker, S . ; Yang, D.; Kahne, D.; Gange, D. J. Am. Chem. SOC. 1991, 113, 4716. (b) Walk&, S . ; Gange, D.; Gusa, V.; Kahne, D. J. Am. Chem. SOC. 1994, 116, 3197. (24) (a) Drak, J.; Iwasawa, N.; Crothers, D. M.; Danishefsky, S . J. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7464 (an account of calicheamicin containing truncated carbohydrate domains is provided in this paper). (b) Aiyar, J.; Hitchcock, S . A,; Denhart, D.; Liu, K. K.-C.; Danishefsky, S . J.; Crothers, D. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 855.

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Carbohydrate Sectors of Esperamicin and Calicheamicin

product) but to a compound whose structure was assigned as 14" (Scheme 2). Thus, synthesis was seen to provide several advantages relative to retrieval of the carbohydrates from the natural products. The length and nature of the carbohydrate domain could be strictly defined. Also, synthesis seemed to provide the most promising prospect for exploring the rearrangement of a properly defined system of the type 16 to the pyrrolidine sugar 14. Only in this way could one evaluate whether the formation of 14 from 16 was so fast as to effectively preclude the use of the latter in a total synthesis venture. As mentioned above, the aglycon, calicheamicinone, retains a double-stranded cleaving capacity which, while only 10-20% that of the drug itself, is still formidable in the broader world of organic DNA cleaving agents. However, the aglycon exhibited no sequence specificity. These studies by implication identified the saccharide section as the source of specific DNA recognition. This surmise was validated by studies of methyl glycoside 13 conducted concurrently by Nicolaou and ourse1ves.21b,26-28 It was to establish the role of the aryltetrasaccharide segment in DNA recognition and to document its chemical character that these studies were undertaken. Furthermore, synthesis carried with it, in principle, the possibility of protecting the hydroxylamino nitrogen during the synthetic buildup. In that way, rearrangement to systems of the type 14 would be avoided until it could be examined in a clear setting. Afinal goal of our synthesis was that the entire carbohydrate domain, particularly that of calicheamicin, be rendered presentable as a viable glycosyl donor to an appropriate aglycon construct. This concept was, from the beginning, our guiding paradigm for a total synthesis of 1. If the rearrangement of presumed 16 to 14 as described by the Bristol-Myers workers25 was spontaneous, it would be necessary to protect the connecting hydroxylamino NH linkage in addition to the N-ethyl function in the E ring (as well as some or all of the hydroxyl functions in the domain). Through chemical synthesis of this domain, the tolerance of the aryltetrasaccharide sector for the steps required in a total synthesis could be delineated. In this paper, we describe the attainment of these objectives. The evolving logic employed in the syntheses of the carbohydrate domains 12 and 13 of esperamicin and calicheamicin, respectively, is presented and documented (Figure 2). As a result of our studies, the rearrangement of 16 to 14 was rigorously demonstrated rather than surmised. The feasibility for precluding this rearrangement (see compounds 12, 13, and 17) was also established. Armed with this insight, we established that the goal of generating a construct of the calicheamicin domain which is suitably protected and activated to function as a glycosyl donor was achieved.6c Finally, the actual glycosylation of a calicheamicin construct with a glycosyl donor embracing the full calicheamicin carbohydrate domain was demonstrated for the first time.29,30It was through a detailed command of the nuances of the aryltetrasaccaharide domain that a maximally advanced glycosyl donor could, in time, be (25) Golik, J.; Wong, H.; Krishnan, B.; Vyas, D.; Doyle, T. W. Tetrahedron Lett. 1991, 32, 1851. (26) Aiyar, J.; Danishefsky, S. J.; Crothers, D. M . J. Am. Chem. SOC. 1992, 114, 7552. (27) (a) Nicolaou, K. C.; Tsay, S.-C.; Suzuki, T.; Joyce, G. F. J. Am. Chem. SOC. 1992, 114,7555. (b) Li, T.; Estevez, V. A,; Baldenius, K. U.; Nicolaou, K. C.; Joyce, G. F. J. Am. Chem. SOC. 1994, 116, 3709. (28) Previously, the Schrieber group used molecular modeling to propose that the sequence selectivity was due to the oligosaccharide fragment. Hawley, R. C.; Kiessling, L. L.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 1105. (29) For a preliminary account of the synthetic work in the esperamicin series, see: Halcomb, R. L.; Wittman, M. D.; Olson, S . H.; Danishefsky, S. J.; Golik, J.; Wong, H.; Vyas, D. J. Am. Chem. Soc. 1991, 113, 5080.

11

'V

I

12

Figure 2.

Scheme 3 PUN A

O'CH~

CH.

dCH3 20 22

'H'

fashioned and presented to a maximally advanced acceptor in our total synthesis of the drug itself.6c

Synthetic Planning Not distant from our plans was the notion of employing glyc,als as building blocks. It was anticipated that significant relief from lengthy functional group manipulations would follow from their use. The targets of the synthesis seemed appropriate for expanding the glycal-based methodologies developed in our group.3' The fashioning and assembly of each building block would be used to further probe the limitations in the emerging chemistry of glycals. Two general approaches to the core trisaccharide (cf. 18) were conceived. In Scheme 3, we leave unspecified the nature of (30) For a preliminary account in the calicheamicin series and the first account of glycosylation by the entire carbohydrate domain see: Halcomb, R. L.; Boyer, S . H.; Danishefsky, S. J. Angew. Chem., In?. Ed. Engl. 1992, 31, 338. (31)(a) Halcomb, R. L.; Danishefsky, S . J. J. Am. Chem. SOC. 1989, 1 1 1 , 6661. (b) Friesen, R. W.; Danishefsky, S. J . J. Am. Chem. SOC. 1989, 111, 6656. (c) Griffith, D. A.; Danishefsky, S . J. J. Am. Chem. Soc. 1990, 112,5811. (d) Suzuki, K.; Sulikowsky, G. A,; Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. SOC. 1990, 112, 8895. (e) Griffith, D. A,; Danishefsky, S . J. J. Am. Chem. SOC.1991, 113, 5863. (f)Danishefsky, S. J.; Gervay, J.; Peterson, J. M.; McDonald, F. E.; Koseki, K.; Oriyama, T.; Griffith, D. A.; Wong, C.-H.; Dumas, D. P. J. Am. Chem. Soc. 1992, 114, 8329. (g) Danishefsky, S. J.; Koseki, K.; Griffith, D. A.; Gervay, J.; Peterson, J. M.; McDonald, F. E.; Oriyama, T. J. Am. Chem. Soc. 1992, 114, 8331. (h) Randoluh, J. T.: Danishefskv. S. J. J. Am. Chem. Soc. 1993, 125. 8473. (i) Danishkfsky, S. J.; McClure; K. F.; Randolph, J. T.; Ruggeri, R. B. Science 1993, 260, 1307.

5724 J. Am. Chem. SOC.,Vol. 117, No. 21, 1995

Halcomb et al.

Scheme 4 PLAN B

X

I

HQ-NX'

22

X, Y, and Z. Thus, in principle, the plan could be considered either for the core trisaccharide of esperamicin or the aryltetrasaccharide domain of calicheamicin (compounds 12 and 13, respectively). In the first approach, plan A (Scheme 3), we envisioned the addition of the oxygen atom of a hydroxylamine, present in disaccharide 20, to the double bond of glycal 19 or its derivatives. It was postulated that a sterically demanding protecting group on 0 - 3 of 19 would coax addition of the nucleophile to the ,L? face of the double bond. The disaccharide subunit, in turn, was to be synthesized from glycals 21 and 22. The second approach, plan B (Scheme 4), differed fundamentally from the first in the manner in which the hydroxylamine linkage would be installed. This scheme involved using a nucleophilic version of a suitable 0-glycosylhydroxylamine (23) to displace an axial leaving group at C-4 of the disaccharide 24.5b Compound 23 was to be synthesized by addition of an N-protected hydroxylamine of the 8 , face of the glycal 19. Disaccharide 24 was to be synthesized from 25 and 22 in a fashion analogous to that in plan A. After initial explorations, it was found that plan A could not be implemented. At no point could we realize any version of the transformation generalized as 19 20 18.32 While the bicyclic domain corresponding to 20 was synthesized, the hydroxyl linkage of the hydroxylamine moiety never functioned as a glycosyl acceptor in the context needed. Hence we contine this report to a description of plan B, which was implemented in both the esperamicin and the calicheamicin series.

+

-

Results and Discussion The first task undertaken was the synthesis of the three glycal building blocks. The synthesis of the glycal precursor to the amino sugar began with the known methyl glycoside 2633 (Scheme 5). Treatment of 26 with thiophenol and BFyEt2034 provided a mixture of thioglycosides 27. Oxidation of these (32) In our initial explorations, (M. D. Wittman and R. L. Halcomb), the possibility of directly 0-glycosylating hydroxylamines such as 20 with glycal donors such as 19 was examined and met with limited success, though not in the desired sense. Most successful attempts to join the two fragments produced nitrones, apparrently via an N-glycosylated intermediate. For the synthesis of hydroxylamines such as 20, see: Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J. J. Org. Chem. 1991, 55, 1981. (33) Golik, J.; Wong, H.; Vyas, D.; Doyle, T. W. Terrahedron Lett. 1989, 30, 2497. (34) (a) Hanessian, S.; Guindon, Y. J. Carbohydr. Res. 1980, 86, C3. (b) Nicolaou, K. C.; Selitz, S. P.; Paphatjis, D. P. J. Am. Chem. SOC.1983, 105, 2430.

'H'

Scheme Sa Phll~N&~"' OCHi

P h t h N q s m OCH3 27

26

29 a Conditions: PhSH, BFyEt20, CHzC12; (b) MCPBA, CHzC12,O "C; (c) benzene, reflux; (d) (i) NaOMe, MeOH; (ii) BuzSnO; (iii) PMBBr, CsF, DMF, 80 "C.

thioglycosides with MCPBA followed by thermally induced elimination of the resulting sulfoxide^^^ gave glycal28 in 83% overall yield. Di-U-acetyl-D-fucal (29)36 was chosen as the starting point for the synthesis of the glycal precursor to the hydroxylamino sugar (Scheme 5). Deacetylation of 29 with sodium methoxide, stannylene formation with di-n-butyltin oxide, and selective benzylation of the equatorial in sequence, provided glycal 30 in 73% yield. Initial proposals to synthesize a glycal bearing the thio functionality of the B ring (cf. 19) contemplated S ~ Z l i k e inversion of configuration at C-3 of substrates such as 31 to establish the axial oxygen functionality at C-3.38 However, in practice, several such attempts to achieve direct displacements on substrates such as 31 led, instead, to products (cf. 33) derived from the well-known Femer rearrangement39(Scheme 6 ) . Additionally, sequences involving oxidation to the corresponding ketone followed by selective reduction were not (35) Danishefsky, S. J.; Armistead, D. M.; Wincott, F. E.; Selnick, H. G.; Hungate, R. J. Am. Chem. SOC.1989, I l l , 2967. (36) Whistler, R. C.; Wolfrom, M. L. Methods Carbohydr. Chem. 1963, 2, 451. (37) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643. (38) Lopez, J. C.; Fraser-Reid, B. J. Chem. SOC.,Chem. Commun. 1992, 94. (39) (a) Valverde, S.; Garcia-Ochoa, S.; Martin-Lomas, M. J. Chem. SOC., Chem. Commun. 1987, 383. (b) Femer, J. J. Adv. Carbohydr. Chem. Biochem. 1969, 24, 199.

J. Am. Chem. SOC., Vol. 117, No. 21, 1995 5725

Carbohydrate Sectors of Esperamicin and Calicheamicin

Scheme 8=

Scheme 6

,OAc

SPh

38

-

NU

q

HO

b

32

33

39

e, f ___)

SPh

Scheme 7 7

r

OH

38

37

satisfactory. These reverses prompted the development of a new and general methodology for the synthesis of glycals bearing axial C-3 oxygenation.@ The crux of the method, as illustrated in Scheme 7, is a [2,3]-sigmatropic rearrangement of an anomeric sulfoxide 3641to afford glycal 37, exploiting the suprafacial nature of the process to transfer chirality from C-1 to C-3. In this way, advantage could be taken of the tendency of the Femer rearrangement to direct nucleophiles to the a face of glycals at C-1.42 Our starting material was tri-0-acetyl-D-galactal(38, Scheme 8).43 Reaction of 38 with thiophenoPgprovided the pseudoglycal 39, which upon deacylation and subsequent selective tosylation provided 41 via the intermediate diol 40. Reductive cleavage of the tosylate afforded 42, and subsequent introduction of sulfur functionality at C-4 by displacement of the corresponding axial mesylate with KSAc led to thiolacetate 43. The thiol group, obtained by reductive deacylation, was protected as a dinitrophenyl thioether (see compound 44).& This protective arrangement was intended to serve two important ends. It would differentiate the two sulfur atoms and thus allow chemoselective oxidation of the anomeric sulfide. Furthermore, it would help to circumvent the otherwise likely migration of the acetyl group from the thiol at C-4 to the hydroxyl group at c-3.45 In practice, treatment of compound 44 with MCPBA selectively oxidized the anomeric sulfide to the corresponding sulfoxide. Upon exposure to diethylamine, the presumed sulfoxide gave rise to glycal45 ostensibly by [2,3]-sigmatropic (40) Wittman, M. D.; Halcomb, R. L.;Danishefsky, S. J.; Golik, J.; Vyas, D. J. 0 r g . Chem. 1990, 55, 1979. (41) (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7 , 147. (b) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow, K. J. Am. Chem. SOC. 1968, 90, 4869. (42) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon: New York, 1983. (b) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen; Springer-Verlag: Berlin, 1983. (43) All attempts to accomplish a Femer rearrangement with di-0-acetylo-fucal and thiophenol failed to provide useful yields of the desired pseusoglycal. Therefore, this process was formally carried out by performing the rearrangement with tri-0-acetyl-D-galactal and later deoxygenating C-6. (44) Shaltiel, S. Eiochem. Biophys. Res. Commun. 1967, 29, 178. (45) Such migrations had been observed from C-4 acetates?O prompting consideration of the possibility of participation of the C-4 acetate as an altemative to the [2,3]-sigmatropic shift in producing the axial alcohol at C-3 of glycals from C- l a phenylsulfinyl pseud~glycals.~~ This mechanistic issue has not been investigated further.

g, h

PrAc

L P=DNP

43

44

X=OH

40

r R=H

'L

45

R=TBS 46

Conditions: (a) PhSH, SnC14, CH2C12, -20 "C; (b) NaOMe, MeOH; (c) (i) BuzSnO, MeOH, reflux; (ii) TsC1, CHCl3, BuDBr, room temperature; (d) LiAlK, THF, reflux; (e) MsCl, CHzC12, Et3N, 0 "C; (0 KSAc, DMF, room temperature; (g) LiAlK, THF, 0 "C; (h) DNPF, room temperature; (i) (i) MCPBA, CHzC12, -40 "C; (ii) Et2NH, THF, room temperature; (i)TBSOTf, pyr, CH2C12, 0 "C.

rearrangement. The axial alcohol function of compound 45 was protected as the silyl ether 46 in anticipation of further transformations. The core trisaccharide was rapidly assembled from the three glycal building blocks as shown in Scheme 9. Treatment of glycal 30 with dimethyldi~xirane~'~ followed by methanol afforded the methyl glycoside 47, along with a minor amount (