Synthesis of a protected (±)-calicheamicinone derivative by sequential introduction of functionality into the bicyclo[7.3.1]enediyne core structure

Article abstract of DOI:10.1021/ja970743t

The core bicyclo[7.3.0]enediyne 3 has been synthesized from the protected cyclohexane-1,2-dione 6 and enediyne component 9. Conversion of 20 into more highly functionalized enediynes was accomplished by oxidation and amination to give 27. ProteCtion of 27

Full text of DOI:10.1021/ja970743t

J. Am. Chem. Soc. 1997, 119, 6739-6748
6739
Synthesis of a Protected (()-Calicheamicinone Derivative by
Sequential Introduction of Functionality into the
Bicyclo[7.3.1]enediyne Core Structure
Philip Magnus,* Gregory F. Miknis, Neil J. Press, Didier Grandjean,
G. Mark Taylor, and John Harling
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712
ReceiVed March 7, 1997X
Abstract: The core bicyclo[7.3.0]enediyne 3 has been synthesized from the protected cyclohexane-1,2-dione 6 and
enediyne component 9. Conversion of 20 into more highly functionalized enediynes was accomplished by oxidation
and amination to give 27. Protection of 27, and conversion into 31, gave on treatment with (MeO)2P(O)CH2CO2Me
the lactone 32, which was transformed into the trisulfide 39. All attempts to deprotect 39, using conditions that
other workers successfully applied to similar substrates, only resulted in the cyclic sulfides 42 and 43.
Introduction
Here is reported the culmination of this strategy, resulting in
the synthesis of a protected version of (()-calicheamicinone 2,
the aglycon of calicheamicin γ1 1. The essence of our overall
strategy has been to devise a sequence of reactions to convert
the bicyclo[7.3.1]enediyne core compound 3 into 2, Scheme 1.
The enediyne antitumor antibiotics have attracted a great deal
of attention because of their unusual structures and potent
biological activity.1 Notable contributions to their synthesis and
in Vitro mechanism of action have been made by Danishefsky,2
Nicolaou,3 Clive,4 and others.5 We have adopted an approach
to their synthesis that uses η2Co2(CO)6-propargylic cation
complexes to form the bicyclo[7.3.1]enediyne core structure.6
Retrosynthetic Analysis
Our initial research indicated that the bicyclo[7.3.1] enediyne
core structure 3 could be assembled Via the retrosynthetic
pathway shown in Scheme 2. Addition of the lithioenediyne 5
to the mono-tert-butyldimethylsilyl enol ether of cyclohexane-
1,2-dione 6 followed by oxidation should allow access to 4.
An aldol reaction, initiated by conjugate addition to 4, leads to
3. We anticipated that a Lewis acid mediated aldol reaction
would result in a synclinal intermediate through chelation and
give the correct 12â-hydroxyl stereochemistry shown in 3.7 The
remaining steps involve the introduction of the carbamate at
C-2, a carbonyl at C-3, and the allylic trisulfide at C-13.
X Abstract published in AdVance ACS Abstracts, July 1, 1997.
(1) Enediyne Antibiotics as Antitumor Agents; Borders, D. B., Doyle, T.
W., Eds.; Dekker, Inc.: New York, 1995. Lee, M. D.; Durr, F. E.; Hinman,
L. M.; Hamann, P. R.; Ellestad, G. A. AdVances in Medicinal Chemistry;
Maryanoff, B. E., Maryanoff, C. A., Eds.; JAI Press: Greenwich, CT, 1993;
Vol. 2. Lee, M. D.; Ellestad, G. A.; Borders, D. B. Acc. Chem. Res. 1991,
24, 235. Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497.
Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387.
Lee, M. D.; Dunne, T. S.; Seigel, M. M.; Chang, C. C.; Morton, G. O.;
Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464. Lee, M. D.; Dunne, T.
S.; Chang, C. C.; Ellestad, G. A.; Seigel, M. M.; Morton, G. O.; McGahren,
W. J.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3466. For esperamicin,
see: Golik, J.; Dubay, G.; Groenwold, G.; Kawaguchi, M.; Konishi, M.;
Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. Soc.
1987, 109, 3462. Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.;
Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, M.; Saitoh, K.; Doyle,
T. W. J. Am. Chem. Soc. 1987, 109, 3461. Konishi, M.; Ohkuma, H.; Saitoh,
K.; Kawaguchi, H.; Golik, J.; Dubay, G.; Groenewold, G.; Krishnan, B.;
Doyle, T. W. J. Antibiot. 1985, 38, 1605.
(2) Shair, M. D.; Danishefsky, S. J. J. Org. Chem. 1996, 61, 16 and
references therein. Cabal, M. P.; Coleman, R. S.; Danishefsky, S. J. J. Am.
Chem. Soc. 1990, 112, 3253. Haseltine, J. N.; Cabal, M. P.; Mantlo, N. B.;
Iwasawa, N.; Yamashita, D. S.; Coleman, R. S.; Danishefsky, S. J.; Schulte,
G. K. J. Am. Chem. Soc. 1991, 113, 3850.
(3) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1993, 32, 1377, and
references therein. Nicolaou, K. C.; Hummel, W.; Pitsinos, E. N.; Nakada,
M.; Smith, A. L.; Shibayama, K.; Saimoto, H. J. Am. Chem. Soc. 1992,
114, 10082.
We considered that allylic oxidation of 3 to give 7 would
allow an amination process to take place Via an addition-
elimination mechanism to give 8. The trisulfide functionality
can be introduced using Wadsworth-Emmons chemistry,
reduction and conversion into 2 using the sequence we published
in 1989.8 This sequence of transformations has been used
successfully by Danishefsky, Nicolaou, and Clive in their
respective syntheses of calicheamicinone. In all cases they had
to make modifications to prevent participation by the 12â-
hydroxyl group.9
The key step in Scheme 2 is the introduction of the nitrogen
functionality at C-2. In a more general sense there are relatively
few methods for the direct introduction of nitrogen functionality
into the R-position of a carbonyl group. We decided that the
examination of methodology for the amination of ketone enol
derivatives that operate under mild conditions would be a
(4) Clive, D. L. J.; Bo, Y.; Tao, Y.; Daigneault, S.; Wu, Y-J.; Meignan
G. J. Am. Chem. Soc. 1996, 118, 4904.
(5) For a recent extensive review, see: Lhermitte, H.; Grierson, D. S.
Contemporary Organic Synthesis 1996, 3, 41 and 1996, 3, 93. Kende, A.
S.; Smith, C. A. Tetrahedron Lett. 1988, 29, 4217. Schreiber, S. L.;
Kiessling, L. L. J. Am. Chem. Soc. 1988, 110, 631. Schreiber, S. L.;
Kiessling, L. L. Tetrahedron Lett. 1989, 30, 433. Maier, M. E.; Brandstetter,
T. Tetrahedron Lett. 1992, 33, 7511. Maier, M. E.; Brandstetter, T. Liebigs
Ann. Chem. 1993, 1009. Tomioka, K.; Fujita, H.; Koga, K. Tetrahedron
Lett. 1989, 30, 851.
(6) For a review of our previous work in this area, see: Magnus, P.
Tetrahedron 1994, 50, 1397. Magnus, P. The Use of η2Co2(CO)6-Acetylene
Complexes for the Synthesis of Enediyne Antitumor Antibiotics. SmithKline
Beecham Research Symposium, Organometallic Reagents in Organic
Synthesis; Academic Press Ltd.: 1994; Chapter 1, p 1.
(7) Kadow, J. F.; Tun, M. M.; Vyas, D. M.; Wittman, M. D.; Doyle, T.
W. Tetrahedron Lett. 1992, 33, 1423. Kadow, J. F.; Cook, D. J.; Doyle, T.
W.; Langley, D. R.; Pham, K. M.; Vyas, D. M.; Wittman, M. D. Tetrahedron
1994, 50, 1519. Dr. John Kadow is thanked for exchanges of information
concerning the conversion of 16 into 20.
(8) Magnus, P.; Lewis, R. T.; Bennett, F. J. Chem. Soc., Chem. Commun.
1989, 916. Magnus, P.; Lewis, R.; Bennett, F. J. Am. Chem. Soc. 1992,
114, 2560.
S0002-7863(97)00743-9 CCC: $14.00 © 1997 American Chemical Society

6740 J. Am. Chem. Soc., Vol. 119, No. 29, 1997
Magnus et al.
Scheme 1
tion to the enone 6 followed by quenching the mixture with
allyl chloroformate gave 11. In this sequence of transformations
the initially formed adduct 10 must undergo silyl migration to
give 10a, which is trapped by the chloroformate. Palladium
diacetate catalyzed oxidation of 11 gave the enone 12.13 This
very convenient procedure could be operated on a large scale
(>40 g) in good yields. Removal of the THP group in 12 was
achieved using Amberlyst H-15 acid resin in methanol to give
the alcohol 13 (97%). Complexation of 13 with Co2(CO)8 was
not entirely regiospecific and resulted in a mixture of the
required adduct 15 and 14 (6:1). The adducts were separated,
and 14 was recycled to 13 by oxidative removal of the cobalt
complex with ceric(IV) ion. Oxidation of 15 using the Saigo
procedure gave the aldehyde cobalt complex 16.14 This
sequence of reactions can be carried out on >100 gram scale.
Treatment of 16 with PhSAlMe2 at -78 °C followed by Ti-
(OPri)4 and warming to -10 °C gave the cyclized adduct 17.15
We have spent a great deal of time trying to optimize this
reaction and make it reproducible on a convenient scale (ca.
5-10 g). The reagent PhSAlMe2 rapidly adds to 16 to give
two diastereomeric â-sulfides (Via 16a). Only one of these
adducts proceeds to form the product 17, presumably Via the
chelate 16b. The reaction is worked-up by quenching with cold
(-78 °C) silica gel to prevent retro-aldol reaction to 18. It was
found that it was best to oxidize the sulfide 17 with MCPBA
to give directly 19, which is far more stable since it cannot
undergo a retro-aldol reaction. Cobalt decomplexation of 19
provides the crystalline enone 20 (12 steps from propargyl
alcohol). Protection of the 12â-ol 20 as the derived TBS ether
21 was necessary for the next step to be successful.
Scheme 2
Introduction of C-3 Oxygen and C-2 Nitrogen
Functionality (Scheme 4)
While there are a number of allylic oxidation procedures that,
in principle, are capable of converting 21 directly into 22, only
the Nicoloau reagent proved successful.16 Surprisingly,17 when
21 was treated with N-(phenylselenenyl)phthalimide the bis-
selenide 22 was formed. This turned out to be ideal, since
22 was readily oxidized to the desired enedione 23. It is essential
that the N-(phenylselenenyl)phthalimide be freshly recrystallized
for this reaction to be successful.18
Conjugate addition of azide anion to the enedione 23 at C-2
should be a possible method for the introduction of an amine
worthwhile endeavor in itself, regardless of its eventual ap-
plicability to the synthesis of calicheamicinone.10
(10) The efforts to introduce the C2-amino group into 7 has lead to a
number of new reactions involving PhIO/trimethylsilyl azide chemistry and
other electrophilic aminating species. Magnus, P.; Lacour, J.; Evans, P. A.;
Roe, M. B.; Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406. Magnus, P.;
Lacour, J. J. Am. Chem. Soc. 1992, 114, 3993. Magnus, P.; Lacour, J.;
Coldham, I.; Mugrage, B.; Bauta, W. B. Tetrahedron, 1995, 51, 11087.
Magnus, P.; Barth, L. Tetrahedron 1995, 51, 11075. Magnus, P.; Lacour,
J.; Weber, W. J. Am. Chem. Soc. 1993, 115, 9347. Magnus, P.; Hulme, C.;
Weber, W. J. Am. Chem. Soc. 1994, 116, 4501.
(11) Magnus, P.; Eisenbeis, S. A.; Fairhurst, R. A.; Iliadis, T.; Magnus,
N. A.; Parry, D. J. Am. Chem. Soc. 1997, 119, 5591-5605.
(12) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313.
Ratovelomanana, V.; Linstrumelle, G. Tetrahedron Lett. 1984, 25, 6001.
Guillerm, D.; Linstrumelle, G. Tetrahedron Lett. 1986, 27, 5857. Guillerm.
D.; Linstumelle, G. Tetrahedron Lett. 1985, 26, 3811.
(13) Tsuji, J.; Minami, I.; Shimizu, I.; Kataoka, H. Chem. Lett. 1984,
1133. Shimizu, I.; Tsuji, J. J. Am. Chem. Soc. 1982, 104, 5844.
(14) For an example of the Saigo oxidation on a η2Co2(CO)6-proparglic
alcohol see: Marshall, J. A.; Gung, W. Y. Tetrahedron Lett. 1989, 30, 309.
Narasaka, K.; Morikawa, A.; Saigo, K.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 1977, 50, 2773. Meyers, A. I.; Comins, D. L.; Roland, D. M.; Henning,
R.; Shimizu, K. J. Am. Chem. Soc. 1978, 101, 7104.
Synthesis of Bicyclo[7.3.1]enediyne Core (Scheme 3)
Coupling of propargyl alcohol-THP ether to cis-1,2-dichlo-
roethylene under the usual conditions [Pd(Ph3P)4/CuI/BuNH2/
PhH] followed coupling to trimethylsilylacetylene under the
same conditions, and desilylation gave the enediyne 9.11,12
Treatment of 9 with lithium bis(trimethylsilyl)amide and addi-
(9) Treatment of the diol 33 with thiolacetic acid under Mitsunobu
conditions gave the cyclic ether 33a (70%). Using the modified reaction
conditions reported by Danishefsky (ref 2) also gave 33a. Consequently,
we were forced to proceed by the protection deprotection sequence depicted
in Scheme 4, as were both Nicolaou and Clive (refs 3 and 4), but using
different protecting groups.
(15) Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1981, 54, 274.
(16) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J.
Am. Chem. Soc. 1979, 101, 3704. Nicolaou, K. C.; Petasis, N. A.; Claremon,
D. A. Tetrahedron 1985, 41, 4835.

Synthesis of a Protected (()-Calicheamicinone DeriVatiVe
J. Am. Chem. Soc., Vol. 119, No. 29, 1997 6741
Scheme 3a
a Conditions: (a) LiN(TMS)2/THF/-78 to -30 °C/recool to -78 °C add 6, warm to 25 °C, recool to -78 °C, add allylchloroformate, 11 (90%).
(b) Pd(OAc)2 (cat)/MeCN reflux, 12 (76%). (c) Amberlyst H-15, MeOH, 13 (97%). (d) Co2(CO)8/CH2Cl2/0 °C 15 (85%), 14 (14%). (e) t-BuOMgBr/
THF/1,1′-azodicarbonyldipiperidine/THF/0 °C, 16 (81%). (f) PhSAlMe2/THF/CH2Cl2 at -78 °C, followed by Ti(OPri)4 -78 to 10 °C, recool to
-78 °C, workup with SiO2 quench, 17 (45-71%). (g) MCPBA/CH2Cl2, 19 (64%). (h) Ce(NH4)2(NO2)6/acetone/-10 °C, 20 (76%). (i) TBSOTf/
i
CH2Cl2/NEtPr2 /0 °C, 21 (93%).
group at this position.19 It was found that treatment of 23
with NaN3 in CF3CH2OH/DMF gave the amine 24, albeit in
low yield (<10%), which became even lower on a larger
scale (>10 mg).20
OH only gave the 1,2-aziridine 25 (isolated as the -NCO2Me
derivative). Eventually, it was discovered that the 12â-alcohol
26 reacted with Ph2SdNH in tetrahydrofuran to give the
2-amino adduct 27 (65-85%).22 Presumably, the success of
this procedure is due to intramolecular protonation of the C1-
Diphenylsulfilimine (Ph2SdNH) is known to add to enediones
to produce aziridines in a protic solvent (MeOH) and enamines
in benzene.21 Exposure of 23 to Ph2SdNH‚H2O in CF3CH2-
(18) The best results were obtained with N-(phenylselenenyl)phthalimide
that was crystallized to constant melting point. While we could not detect
impurities by TLC and NMR, the yields with unpurified reagent were <30%,
and sometimes the substrate 21 was completely destroyed.
(19) Magnus, P.; Barth, L. Tetrahedron 1995, 51, 11075. Patonay, T.;
Hoffman, R. V. J. Org. Chem. 1995, 60, 2368. Effenberger, F.; Beisswenger,
T.; Az, R. Chem. Ber. 1985, 118, 4869. Effenberger, F.; Beisswenger, T.
Chem. Ber. 1984, 117, 1497. R-Azidoketones (iv) undergo elimination of
nitrogen to give an imine (v), which usually tautomerizes to the enamine
(vi).
(17) Our earlier work on the 12-desoxy series had shown that treatment
of (i) with N-(phenylselenenyl)phthalimide/DBU gave the monoselenide
(ii), which on oxidation provided access to the 3â-ol (iii). Magnus, P.; Lewis,
R.; Bennett, F. J. Am. Chem. Soc. 1992, 114, 2560.

6742 J. Am. Chem. Soc., Vol. 119, No. 29, 1997
Magnus et al.
Scheme 4a
a Conditions: (a) N-(phenylselenenyl)phthalimide/DBU/CH2Cl2/25 °C, 22 (79%). (b) H2O2/CH2Cl2/0-25 °C, 23 (89%). (c) NaN3/CF3CH2OH/
i
DMF, 24 (<10%). (d) Ph2SdNH‚H2O/CF3CH2OH, followed by triphosgene/NEtPr2 /MeOH, 25 (95%). (e) CF3SO3H/H2O/THF, 26 (87%). (f)
Ph2SdNH/THF/25 °C, 27 (65%). (g) Camphor sulfonic acid/dioxane/ethylene glycol, 28 (65%). (h) 27/TESOTf/NEt3/CH2Cl2, 29 (90%). (i) (Boc)2O/
DMAP/NEt3/CH2Cl2, 30 (95%). (j) CF3SO3H/H2O/THF, 31 (95%).
C13 enolate by the 12â-hydroxyl, competing with the 1,3-
elimination of Ph2S.
Attempted ketalization of 27 was unsuccessful due to an
unexpected reaction resulting in 28, presumably Via the iminium
ion 27a. The structure of 28 was established by X-ray
crystallography, Figure 1. Since we could not use the C-3
ethylene ketal protecting group (that could have successfully
completed the synthesis),2-4 we explored various enol deriva-
tives that could be made under neutral to basic conditions. It
was found that treatment of 27 with TESOTf/Et3N gave 29,
Figure 1. Chem 3D of 28 from X-ray coordinates (-TBS).
and both the 2-amino group and the C-3 carbonyl could be
Introduction of the Trisulfide and Final Complications
protected as the tris-Boc derivative 30. Selective deprotection
(Scheme 5)
of 30 (TfOH/THF/H2O) gave the 12â-alcohol 31.
The introduction of the C14 and C15 carbon atoms of the
(20) The solvent system CF3CH2OH/DMF was the only medium that
allylic trisulfide can be achieved by Wadsworth-Emmons
phosphonate chemistry.23 Since Danishefsky has conducted this
transformation intramolecularly,2 we converted 31 into the
derived the â-phosphono-ester, but using the Rathke conditions24
(or NaH and LiHMDS), we did not observe any lactone 32.25
Only slow conversion into 31 took place. Fortunately, the
classical intermolecular Wadsworth-Emmons conditions cleanly
converted 31 into 32 (88%). We could not detect the other
stereoisomer (1H NMR).
gave 24. If we treated 23 with NaN3/MeOH a low yield of the triazole 23a
resulted.
Both Nicolaou and Danishefsky have reduced lactones similar
to 32 (3-ethylene ketal and 2-NPhth) in their respective syntheses
of 2, using DIBAL-H (lactol) followed by NaBH4 to give the
(21) Furukawa, N.; Yoshimura, T.; Ohtsu, M.; Akasaka, T.; Oae, S.
Tetrahedron 1980, 36, 73. Yoshimura, T.; Omata, T.; Furukawa, N.; Oae,
S. J. Org. Chem. 1976, 41, 1728.
(22) During the course of this work it was reported that Ph2SdNH reacts
with similar enones to give an aziridine. Clark, D. A.; De Riccardis, F.;
Nicolaou, K. C. Tetrahedron 1994, 50, 11391. Ulibarri, G.; Nadler, W.;
Skrydstrup, T.; Audrain, H.; Chiaroni, A.; Riche, C.; Grierson, D. S. J.
Org. Chem. 1995, 60, 2753.
(23) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733.
(24) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.

Synthesis of a Protected (()-Calicheamicinone DeriVatiVe
J. Am. Chem. Soc., Vol. 119, No. 29, 1997 6743
Scheme 5a
a Conditions: (a) (MeO)2P(O)CH2CO2Me/LiN(TMS)2/THF/0 °C, 32 (88%). (b) NaBH4/MeOH/H2O, 33 (81%). (c) 2,4-(NO2)2C6H3SCl/py/CH2Cl2,
34 (73%). (d) MeOCOCl/py/CH2Cl2, 35 (74%). (e) PhSH/py/THF, 36 (87%). (f) Ms2O/NEt3/CH2Cl2, 37 (83%). (g) KSAc/acetone, 38 (81%). (h)
DIBAL-H/THF/-78 °C, workup with Rochelle’s salt, followed by PhthSSMe, 39 (90%). (i) TESOTf/CH2Cl2/NEt3, 41 (39%) and 42 (49%). (j)
39/MeSO3H/CH2Cl2, 42 (86%). (k) TESOTf/2,6-lutidine/CH2Cl2, 43 (76%). (l) NaBH4/MeOH, 44 (42%).
respective diol. We found this two-step procedure to be
unreliable and low yielding.
The lactone 32 was readily reduced to the diol 33 (81%) by
treatment with NaBH4/MeOH. Selective protection of the
primary alcohol was achieved by sulfenylation with 2,4-
(NO2)2C6H3SCl to give 34,26 and the propargylic hydroxyl group
(25) The ketophosphonate (vii) did not undergo intramolecular cyclization
to give (viii) under a variety of conditions [NaH, LiN(TMS)2, DBU/LiCl,
Et3N/LiBr] and was slowly converted into the alcohol (ix). In contrast,
treatment of (ix) with the standard Wadsworth-Emmons reagent under
intermolecular reaction conditions proceeded cleanly to give the lactone
(viii) in >80% yield.
Figure 2. Chem 3D of 38 from X-ray coordinates (-TBS, -3 Boc’s).
was converted into the carbonate derivative 35. Treatment of
35 with thiophenol gave 36. The derived mesylate 37 was
converted into the thiol acetate 38, and its structure and relative
stereochemistry were confirmed by single crystal X-ray analysis,
Figure 2.
Reductive cleavage of the thiolacetate 38 with DIBAL-H and
in situ treatment of the thiolate anion with the Harpp reagent
PhthSSMe27 gave a mixture of the trisulfide 39 and disulfide
Ketalization of 26 gave (x) which underwent intermolecular Wadsworth-
40.28 Whereas, workup of the above reaction with MeOH/
Emmons reaction to give (xi) (83%). Hydrolysis of (xi) gave (xii), which
would not undergo C-2 amination with Ph2SdNH under the conditions that
worked well for the enedione 26. More vigorous reaction conditions gave
(26) Letsinger, R. L.; Fontaine, J.; Mahadevan, V.; Schexnayder, D. A.;
extensive decomposition.
Leone, R. E. J. Org. Chem. 1964, 29, 2615.

6744 J. Am. Chem. Soc., Vol. 119, No. 29, 1997
Magnus et al.
Scheme 6
Rochelle’s salt and addition of Harpp’s reagent (now to the thiol)
only gave the trisulfide 39.29 If the thiolacetate 38 is reductively
cleaved with NaBH4, the cyclic sulfide 44 was formed. We
have observed this type of cyclic sulfide in earlier model
work.8
Treatment of 39 with camphor sulfonic acid/THF/H20 at 25
°C (conditions used by Danishefsky, Nicoloau, and Clive) gave
no reaction, and warming the mixture resulted in extensive
decomposition. Exposure of 39 to TESOTf/Et3N cleanly gave
41 (39%) and 42 (49%). Excess TESOTf/2,6-lutidine resulted
in the completely deprotected cyclic sulfide 43 (76%). More
vigorous deprotection conditions (MeSO3H) gave 42 (86%),
Scheme 5. Apparently, the enol-Boc group is removed first to
give 41, which upon removal of one of the N-Boc groups results
in 45, which allows the iminium ion 45a to form (see 27a,
Scheme 4), and sulfide participation to give 42 and 43, Scheme
6. It is instructive to recall that the Lederle group had observed
that 1 on treatment with NaBH4, followed acid catalyzed
methanolysis, isolated the cyclic sulfide 46.30 These results
vividly illustrate that calicheamicinone precursors are delicately
poised to be either converted into 2 or proceed down the
pathway of iminium ion chemistry in the same manner as
observed in the original structure/degradation studies.
Summary
(27) Harpp, D. N. Studies in Organic Chemistry 28. PerspectiVes in The
Organic Chemistry of Sulfur; Zwanenburg, B., Klunder, A. H., Eds.;
Elsevier: Amsterdam, 1987. Harpp, D. N.; Steliou, K.; Chen, T. H. J. Am.
Chem. Soc. 1978, 100, 1222. Harpp, D. N.; Ash, D. K. Int. J. Sulfur. Chem.
A 1971, 1, 211. Harpp, D. N.; Ash, D. K. Int. J. Sulfur. Chem. A 1971, 1,
57. Sullivan, A. B.; Boustany, K. Int. J. Sulfur. Chem. A 1971, 1, 207.
Mott, A. W.; Barany, G. Synthesis 1984, 657.
(28) McGahren, W. J.; Ding, W-D.; Ellestad, G. A. Disulfide Calicheam-
icins and the Chemistry of the Allylic Trisulfide group. Enediyne Antibiotics
as Antitumor Agents; Borders, D. B., Doyle, T. W., Eds.; Dekker, Inc.:
New York, 1995; Chapter 5, p 75.
The conversion of a simple bicyclo[7.3.1]enediyne core
structure such as 20 into a fully functionalized system 39 has
been accomplished and demonstrates that a variety of unusual
reactions can be conducted on the core in an efficient manner.
One of the most difficult problems in the above approach has
been the conjugate addition-aldol reaction to convert 16 into
20. This reaction does not scale-up well and drastically reduces
the amount of material needed for the more detailed investigation
of protecting group options, and exploring, for example, the
potential uses of the aziridine 25 as an isomeric analogue of
calicheamicinone. Consequently, as a realization of the limita-
tions imposed by the above we have devised a much more
efficient synthesis of theenedione 23.31
(29) Exposure of 37 to the standard Mitsunobu reaction conditions (PPh3/
i
DEAD) in the presence of the Soderquist thiol (HSSiPr3 ), (Miranda, E. I.;
Diaz, M. J.; Rosado, I.; Soderquist, J. A. Tetrahedron Lett. 1994, 35, 3221)
resulted in clean conversion into the protected sulfide xiii (45%). Exposure
of xiii to HF/pyridine in the presence of the Harpp reagent (PhthNSSMe)
gave the trisulfide 39 in low yield. Whereas, treatment of xiii with CsF/
DMF resulted in clean formation of the disulfide 40 (70%). Presumably, in
the latter process the thiolate xiv attacks the terminal sulfur atom with
PhthNS- as the leaving group, and in the former reaction (HF/pyridine) the
thiol displaces PhthN-.
Experimental Section32
6-[(Z)-7-[(Tetrahydropyranyl)oxy]hept-1,5-diyn-3-ene]-6-[(tert-
butyldimethylsilyl)oxy]-1-[carboallyloxy]cyclohex-1-ene (11).
A
solution of 9 (17.5 g, 92 mmol) in anhydrous tetrahydrofuran (275 mL)
was cooled to -78 °C under argon. Lithium bis(trimethylsilyl)amide
(1 M in tetrahydrofuran, 110 mL, 110 mol, 1.2 equiv) was added over
5 min, and the mixture stirred for 5 min at -78 °C and for 15 min at
-30 °C. The solution was cooled to -78 °C, and a solution of 6 (24.9
g, 110 mmol, 1.2 equiv) in anhydrous tetrahydrofuran (25 mL) was
added Via cannula over 10 min. The mixture was stirred for 15 min at
-78 °C, allowed to warm to room temperature, and stirred at ambient
temperature for 3 h. The mixture was recooled to -78 °C, and allyl
chloroformate (15.6 mL, 147 mmol, 1.6 equiv) was added over 5 min.
The mixture was stirred at -78 °C for 5 min, allowed to warm to room
temperature and stirred for a further 2 h. The mixture was quenched
by the addition of saturated aqueous NaHCO3 (300 mL), the layers
(30) Lee, M. D. Identification, Isolation, and Structure Determination.
Enediyne Antibiotics as Antitumor Agents; Borders, D. B., Doyle, T. W.,
Eds.; Dekker, Inc.: New York, 1995; Chapter 4, p 49.
(31) Hallett, D. Unpublished results from this laboratory.

Synthesis of a Protected (()-Calicheamicinone DeriVatiVe
J. Am. Chem. Soc., Vol. 119, No. 29, 1997 6745
were separated, and the aqueous phase was extracted with Et2O (300
mL). The combined extracts were dried (MgSO4) and concentrated in
Vacuo. Purification of the crude product by chromatography over silica
gel eluting with 95:5 hexanes/Et2O gave 11 as a pale yellow oil (41.45
over 5 min to a stirred solution of 13 (15.9 g, 48.1 mmol) in
dichloromethane (240 mL) at 0 °C under argon. The mixture was
stirred until the evolution of gas ceased, and TLC (hexanes/EtOAc,
80:20) showed complete consumption of starting material. The solvent
was evaporated in Vacuo, and the mixture purified by chromatography
over silica gel eluting with 80:20 hexanes/Et2O to give 15 (25.2 g,
85%) and 14 (5.0 g, 14%). 1H NMR spectroscopy on these compounds
produced very broad-peaked spectra.
g, 90%). IR (thin film) 2930, 2855, 1768, 1652 cm-1 1H NMR (300
.
MHz, CDCl3) δ 5.82-5.96 (2H, m), 5.80 (1H, s), 5.53 (1H, t, J ) 4
Hz), 5.34 (1H, dd, J ) 17, 1 Hz), 5.22 (1H, dd, J ) 11, 1 Hz), 4.79
(1H, br s), 4.57-4.65 (2H, m), 4.30-4.47 (2H, m), 3.77-3.85 (1H,
m), 3.47-3.53 (1H, m), 2.01-2.22 (4H, m), 1.45-1.84 (8H, m), 0.82
(9H, s), 0.18 (6H, s). 13C NMR (75 MHz, CDCl3) δ 153.5, 147.4,
131.5, 119.5, 119.2, 118.9, 117.4, 98.2, 96.9, 92.9, 83.0, 82.4, 68.6,
68.2, 61.9, 54.8, 40.6, 30.2, 25.6, 25.3, 24.0, 19.0, 18.9, 18.0, -3.0,
-3.5. HRMS calcd for C28H41O6Si (M+ + 1) 501.2672. Found
501.2663.
Recycling 14. A stirred solution of 14 (14 g, 22.7 mmol) in acetone
(220 mL) and triethylamine (0.575 mL) was treated with cerium(IV)
ammonium nitrate in small portions until the solution became light
orange (total added: 40 g, 72.9 mmol, 3.2 equiv). Celite 545 (10 g)
was added, and the mixture stirred vigorously for a further 15 min.
The solids were filtered, the filtrate was concentrated to a volume of
ca. 20 mL and diluted with EtOAc (200 mL), and the solution was
washed with saturated aqueous NaHCO3 (250 mL). The aqueous layer
was extracted with EtOAc (4 × 250 mL), and the combined organic
phases were dried (MgSO4) and concentrated in Vacuo. Purification
of the residue by chromatography over silica gel eluting with 60:40
hexanes/Et2O gave 13 (6.57 g, 87%).
6-[(Z)-7-[(Tetrahydropyranyl)oxy]hept-1,5-diyn-3-ene]-6-[(tert-
butyldimethylsilyl)oxy]cyclohex-2-en-1-one 12. To a solution of 11
(41.7 g, 83.3 mmol) in anhydrous acetonitrile (420 mL) heated at reflux
under argon was added palladium(II) acetate (375 mg, 1.67 mmol, 2
mol %), and the mixture heated at 80 °C for 4 h until TLC (hexanes/
Et2O, 80:20) showed complete reaction. Celite 545 (15 g) was added,
and the mixture was allowed to cool with vigorous stirring over 30
min. The solution was filtered through a pad of Celite, and the solvent
evaporated in Vacuo to give the crude product, which was immediately
purified by chromatography over silica gel eluting with 80:20 hexanes/
Et2O to give 12 as a colorless oil (26.2 g, 76%). IR (thin film) 2928,
6-((Z)-6-Formylhex-1,5-diyn-5,6-η2-hexacarbonyldicobaltio-3-
ene)-6-[(tert-butyldimethylsilyl)oxy]cyclohex-2-en-1-one 16. To a
solution of 15 (16.8 g, 27.25 mmol) in anhydrous tetrahydrofuran (136
mL) at 0 °C under argon was added dropwise over 5 min tert-
butoxymagnesium bromide (0.5 M in tetrahydrofuran, 65.4 mL, 32.7
mmol, 1.2 equiv), and the mixture stirred for a further 5 min. 1,1′-
(Azodicarbonyl)dipiperidine (8.25 g, 32.7 mmol, 1.2 equiv) in anhy-
drous tetrahydrofuran (50 mL) was added over 5 min, and the mixture
stirred at 0 °C until TLC (hexanes/EtOAc, 80:20) showed complete
consumption of the starting material (ca. 30 min). The mixture was
quenched with saturated aqueous NH4Cl (250 mL), and the organic
layer separated. The aqueous phase was extracted with Et2O (2 × 250
mL), and the combined extracts were dried (MgSO4). Concentration
in Vacuo left a dark red solid which was triturated with Et2O and filtered
through a 5 cm pad of florisil eluting with Et2O. The filtrate was
concentrated, and the residue purified by chromatography over silica
gel eluting with 90:10 hexanes/Et2O to afford 16 (13.6 g, 81%). IR
2854, 1706, 1620 cm-1 1H NMR (300 MHz, CDCl3) δ 6.84-6.89
.
(1H, m), 5.95 (1H, bd), 5.77-5.88 (2H, m), 4.78 (1H, bt), 4.32-4.46
(2H, m), 3.78-3.84 (1H, m), 3.46-3.55 (1H, m), 2.50-2.66 (1H, m),
2.35-2.47 (1H, m), 2.17-2.41 (2H, m), 1.50-1.83 (6H, m), 0.86 (9H,
s), 0.20 (3H, s), 0.18 (3H, s). 13C NMR δ (75 MHz, CDCl3) δ 193.6,
149.8, 126.9, 120.2, 118.9, 96.9, 94.4, 93.2, 84.4, 82.9, 73.2, 62.0, 54.7,
38.8, 30.2, 25.8, 25.3, 25.1, 19.0, 18.3, -3.2, -3.1. HRMS calcd for
C24H35O4Si (M+ + 1) 415.2315. Found 415.2305.
6-((Z)-7-Hydroxyhepta-1,5-diyn-3-ene)-6-[(tert-butyldimethylsi-
lyl)oxy]cyclohex-2-en-1-one 13. Amberlyst H-15 (5.2 g) was added
to a stirred solution of 12 (11.4 g, 27.5 mol) in methanol (125 mL) at
room temperature. After 3 h the reaction was complete by TLC
(hexanes/EtOAc, 80:20). The mixture was filtered through a pad of
silica gel (5 cm × 10 cm dia) and washed thoroughly with methanol
(250 mL) and Et2O (500 mL). The filtrate was concentrated in Vacuo,
and the residues were purified by chromatography over silica gel eluting
with hexanes/Et2O 80:20) to give 13 as a colorless oil (8.83 g, 97%).
(thin film) 2955, 2930, 2094, 2059, 2031, 1705, 1675 cm-1 1H NMR
.
(300 MHz, C6D6) δ 10.49 (1H, s), 6.17 (1H, m), 6.12 (1H, d, J ) 10.7
Hz), 5.87 (1H, m), 5.44 (1H, d, J ) 10.7 Hz), 2.21 (1H, m), 2.02 (3H,
m), 1.01 (9H, s), 0.38 (3H, s), 0.32 (3H, s). 13C NMR (75 MHz, C6D6)
δ 192, 189, 150, 136, 127, 111, 101, 88, 85, 83, 74, 38, 26, 24, 19,
-2.9, -3.0. HRMS calcd for C25H25O9SiCo2 (M+ + 1) 614.9956.
Found 614.9961.
IR (thin film) 3428, 2928, 2885, 2855, 2708, 2206, 1697, 1620 cm-1
.
1H NMR (300 MHz, CDCl3) δ 6.90 (1H, ddd, J ) 10, 4.1, 4.0 Hz),
5.96 (1H, ddd, J ) 10, 1.7, 1.6 Hz), 5.86 (1H, dt, J ) 10.8, 1.7 Hz),
5.78 (1H, d, J ) 10.8 Hz), 4.39 (2H, s), 2.41-2.65 (3H, m), 2.18-
2.27 (2H, m), 0.84 (9H, s), 0.19 (3H, s), 0.17 (3H, s). 13C NMR (75
MHz, CDCl3) δ 193.9, 150.5, 126.8, 120.9, 118.9, 95.8, 94.2, 84.8,
82.6, 73.0, 51.4, 38.4, 25.7, 24.7, 18.3, -3.2, -3.3. HRMS calcd for
C19H27O3Si (M+ + 1) 331.1730. Found 331.1728.
13-Oxo-2â-thiophenyl-12â-hydroxy-5-[(tert-butyldimethylsilyl)-
oxy]bicyclo[7.3.1]trideca-6,10-diyn-(10,11-η2-hexacarbonyldicobal-
tio)-8-ene 17. Redistilled thiophenol (1.06 mL, 10.4 mmol) was added
slowly to a solution of trimethyl aluminum (2 M in hexanes, 5.2 mL,
10.4 mmol) in anhydrous dichloromethane (21 mL) stirred at 0 °C under
argon. The mixture was stirred at 0 °C for 20 min, after which time
anhydrous tetrahydrofuran (845 µL, 10.4 mmol) was added. The
mixture was cooled to -78 °C and stirred for 10 min. The aldehyde
16 (3.19 g, 5.2 mmol) in anhydrous dichloromethane (10 mL; stirred
over 4Å molecular sieves for 24 h) was added dropwise over 5 min,
and the mixture stirred for a further 10 min at -78 °C. Titanium
tetraisopropoxide (12.36 mL, 41.5 mmol, 8 equiv) was added dropwise
over 15 min. The mixture was stirred at -78 °C for 10 min, after
which time the cold bath was replaced by an ice-water bath. The
mixture was allowed to reach 10 °C over 2 h and was stirred for a
further 45 min at 10 °C, after which time TLC showed almost all the
starting material converted to product. The mixture was recooled to
-78 °C, and precooled (-78 °C) silica gel (40 g) added slowly over
10 min Via a solid addition funnel. The argon line was removed, and
the mixture stirred for a further 45 min in air. The mixture was filtered
through a plug of silica, and the plug washed with Et2O. The filtrate
was concentrated in Vacuo, and the residue purified by chromatography
over silica gel eluting with 95:5-80:20 hexanes/Et2O to give a mixture
of â-thiophenol adducts 18 (510 mg, 16%), starting material 16 (160
mg, 5%), and the cyclized material 17 (2.66 g, 71%). IR (CHCl3) 3500,
6-((Z)-7-Hydroxyhepta-1,5-diyn-5,6-η2-hexacarbonyldicobaltio-
3-ene)-6-[(tert-butyldimethylsilyl)oxy]cyclohex-2-en-1-one 15. Di-
cobalt octacarbonyl (16.45 g, 48.1 mmol, 1 equiv) was added in portions
(32) Melting points were taken on a Thomas-Hoover capillary tube
apparatus and are uncorrected. Boiling points are uncorrected. Infrared
spectra were recorded on a Perkin-Elmer 881 grating spectrophotometer or
a Perkin-Elmer 1600 FT-IR spectrometer either neat or in CHCl3 as
indicated. 1H NMR spectra were recorded on a General Electric QE-300
(300 MHz) spectrometer as solutions in deuterochloroform (CDCl3) unless
otherwise indicated and are reported in ppm downfield from TMS. 13C NMR
spectra were recorded on General Electric QE-300 (75 MHz) instrument
as solutions in CDCl3 unless otherwise indicated. Low resolution chemical
ionization (CI) mass spectra were obtained on a TSQ 70 instrument, and
the exact mass determinations were obtained on a VG analytical ZAB2-E
instrument. Routine monitoring of reactions was performed using Merck
60 F254 silica gel, aluminum-backed TLC plates. Preparative layer
chromatography (plc) was performed using Merck 60H F254 silica gel,
glass supported plates. Flash column chromatography was performed with
the indicated solvents on Merck 60H F254 silica gel. Air and moisture
sensitive reactions were performed under usual inert atmosphere conditions.
Reactions requiring anhydrous conditions were performed in glassware dried
by a Bunsen flame or in an oven at 140 °C, then cooled under argon, and
performed under a blanket of argon. Solvents and commercial reagents were
dried and purified before use: Et2O and tetrahydrofuran were distilled from
sodium benzophenone ketyl; dichloromethane and benzene were distilled
from calcium hydride under argon.
2929, 2094, 2059, 2030, 1731 cm-1 1H NMR (300 MHz, C6D6) δ
.
7.42 (2H, d, J ) 7.3 Hz), 6.98 (3H, m), 6.34 (1H, d, J ) 10 Hz), 5.22
(1H, d, J ) 10 Hz), 5.17 (1H, m), 4.20 (1H, br. s), 3.11 (1H, d, J )
9.2 Hz), 2.47 (1H, m), 2.02 (2H, m), 1.62 (1H, m), 1.25 (1H, d, J )

6746 J. Am. Chem. Soc., Vol. 119, No. 29, 1997
Magnus et al.
7.4 Hz), 1.06 (9H, s), 0.39 (3H, s), 0.34 (3H, s). Anal. Calcd for
C31H30O9SSiCo2: C, 51.38; H, 4.18. Found: C, 51.19; H, 4.26%.
J ) 1.5 Hz), 2.46 (1H, d, J ) 16.4 Hz), 1.72 (1H, dd, J ) 16.4, 2.9
Hz), 1.15 (9H, s), 0.97 (9H, s), 0.45 (3H, s), 0.31 (3H, s), 0.27 (3H, s),
0.25 (3H, s). Compound 22 was used immediately in the next step.
13-Oxo-12â-hydroxy-5-[(tert-butyldimethylsilyl)oxy]bicyclo[7.3.1]-
trideca-6,10-diyn-(10,11-η2-hexacarbonyldicobaltio)-1,8-diene 19. To
a solution of 17 (849 mg, 1.2 mmol) in dichloromethane (50 mL) at
-78 °C under argon was added m-chloroperoxybenzoic acid (242 mg,
1.4 mmol) in one portion, and the cooling bath removed. Stirring was
continued at room temperature for 3 h. The mixture was poured into
saturated aqueous NaHCO3 (50 mL), and the aqueous layer extracted
with dichloromethane (3 × 50 mL). The combined extracts were dried
(MgSO4) and concentrated in Vacuo, and the residue was purified by
chromatography over Florisil eluting with 80:20 hexanes/Et2O to afford
19 (466 mg, 64%). IR (CHCl3) 3500, 2929, 2094, 2059, 2030, 1731
3,13-Dioxo-5,12â-bis[(tert-butyldimethylsilyl)oxy]bicyclo[7.3.1]-
trideca-6,10-diyn-1,8-diene 23. Pyridine (171 µL, 2.12 mmol, 2 equiv)
was added to a solution of 22 (800 mg, 1.06 mmol) in dichloromethane
(10 mL), and the mixture cooled to 0 °C. 30% Aqueous hydrogen
peroxide solution (280 µL, 2.12 mmol, 2 equiv) was added, and the
mixture stirred at 0 °C for 5 min and then at room temperature for 1
h. The mixture was quenched with water (10 mL), and the aqueous
layer extracted with dichloromethane (3 × 10 mL). The combined
extracts were dried (MgSO4) and concentrated in Vacuo, and the crude
product was purified by chromatography over silica gel eluting with
Et2O/hexanes (95:5-90:10) to give 23 (430 mg, 89%). IR (thin film)
cm-1 1H NMR (300 MHz, CD3OD) δ 6.27 (1H, d, J ) 10.7 Hz),
.
2955, 2930, 2896, 2858, 1737, 1694 cm-1 1H NMR (300 MHz, CDCl3)
.
5.50 (1H, br s), 5.23 (1H, d, J ) 10.7 Hz), 4.91 (1H, d, J ) 1.7 Hz),
4.87 (1H, d, J ) 1.7 Hz), 1.78 (2H, m), 1.55 (2H, m), 0.94 (9H, s),
0.15 (3H, s), 0.13 (3H, s). 13C NMR (75 MHz, CD3OD) δ 200.0, 143.8,
133.4, 128.6, 110.5, 97.5, 93.4, 79.5, 70.1, 64, 38.4, 26.3, 23.7, -2.3,
-2.6. LRMS (FAB) 613, 586, 530, 502, 473, 445, 305. See 20 for
complete characterization.
δ 6.32 (1H, d, J ) 1.75 Hz), 5.90 (1H, d, J ) 9.5 Hz), 5.90 (1H, d, J
) 9.5 Hz), 5.50 (1H, s), 3.23 (1H, dd, J ) 17.4, 1.7 Hz), 2.93 (1H, d,
J ) 17.4 Hz), 0.95 (9H, s), 0.93 (9H, s), 0.23 (3H, s), 0.19 (3H, s),
0.16 (6H, s). 13C NMR (CDCl3, 75 MHz) δ 194.5, 188.8, 151.8, 131.9,
123.8, 123.2, 99.1, 96.1, 90.9, 89.6, 75.9, 68, 51.2, 25.8, 25.7, 18.3,
-3.0, -3.3, -4.7. HRMS calcd for C25H36O4Si2 (M+) 456.2152.
Found 456.2159.
13-Oxo-12â-hydroxy-5-[(tert-butyldimethylsilyl)oxy]bicyclo[7.3.1]-
trideca-6,10-diyn-1,8-diene 20. To a solution of 19 (468 mg, 0.76
mmol) in acetone (50 mL) at -10 °C was added cerium(IV) ammonium
nitrate in small portions until the solution turned a light orange color.
The mixture was diluted with Et2O (150 mL), washed with saturated
aqueous NaHCO3 (200 mL), and dried (MgSO4). Evaporation of the
solvent in Vacuo and purification of the residue by chromatography
over Florisil eluting with 75:25 hexanes/Et2O gave 20 (190 mg, 76%).
Mp 123-124 °C (Et2O). IR (CHCl3) 3457, 3024, 2959, 2856, 1698
3,13-Dioxo-5,12â-bis[(tert-butyldimethylsilyl)oxy]-1,2-iminobicy-
clo [7.3.1]trideca-6,10-diyn-8-ene 25. A solution of 23 (150 mg, 328
µmol) and diphenylsulfilimine monohydrate (216 mg, 984 µmol, 3
equiv) in 2,2,2-trifluoroethanol (33 mL) was heated to reflux under
argon. After 1 h, TLC (hexanes/EtOAc, 80:20) showed the complete
consumption of starting material and the formation of one new product
plus diphenyl sulfide. The solvent was evaporated in Vacuo, and the
residue purified by flash column chromatography over silica gel eluting
with Et2O/hexanes (20:80) to give 25 (147 mg, 95%). Due to slow
inversion of the imine and hydration of the C-13 carbonyl group it
was difficult to obtain good spectral data. Consequently, 25 was
cm-1 1H NMR (300 MHz, CDCl3) δ 6.39 (1H, m), 5.87 (1H, d, J )
.
9.5 Hz), 5.84 (1H, d, J ) 9.5 Hz), 5.24 (1H, d, J ) 10.5 Hz), 2.53
(2H, m), 2.26 (1H, m), 2.14 (1H, m), 0.92 (9H, s), 0.22 (3H, s), 0.19
(3H, s). 13C NMR (75 MHz, CDCl3) δ 197, 140, 137, 125, 123, 101,
96, 93, 88, 75, 69, 35, 26, 25, 18, -2.8, -3.1. Anal. Calcd for
C19H24O3Si: C, 69.48; H, 7.37. Found: C, 69.56; H, 7.40%.
converted into its -NCO2Me derivative by treatment with triphosgene/
i
NEtPr2 followed by methanol. IR (CHCl3) 1735, 1715 cm-1
.
1H NMR
(300 MHz, CDCl3) δ 5.95 (1H, d, J ) 10.1 Hz), 5.91 (1H, dd, J )
10.1, 1.2 Hz), 4.31 (1H, d, J ) 1.2 Hz), 3.78 (3H, s), 3.20 (1H, d, J )
1.4 Hz), 3.02 (1H, d, J ) 14.2 Hz), 2.77 (1H, dd, J ) 14.2, 1.4 Hz),
0.95 (9H, s), 0.88 (9H, s), 0.15 (3H, s), 0.14 (3H, s), 0.12 (3H, s), 0.10
(3H, s). HRMS calcd for C27H39NO6Si2 (M+) 529.2316. Found
529.2309.
13-Oxo-5,12â-bis[(tert-butyldimethylsilyl)oxy]bicyclo[7.3.1]trideca-
6,10-diyn-1,8-diene 21. To a solution of 20 (266 mg, 0.81 mmol)
and diisopropylethylamine (700 µL, 4.02 mmol, 5 equiv) in anhydrous
dichloromethane (8 mL) at 0 °C under argon was added tert-
butyldimethylsilyl trifluoromethanesulfonate (372 µL, 1.62 mmol, 2
equiv) by syringe over 5 min. The mixture was stirred for 10 min at
0 °C and at room temperature for a further 10 min to completion by
TLC (hexanes/EtOAc, 80:20). The mixture was quenched with water
(10 mL), and the aqueous phase extracted with dichloromethane (3 ×
10 mL). The extracts were dried (MgSO4) and evaporated in Vacuo,
and the crude product was purified by chromatography over silica gel
eluting with 95:5 hexanes/Et2O to give 21 (333 mg, 93%). Mp 103-
3,13-Dioxo-5-[(tert-butyldimethylsilyl)oxy]-12â-hydroxybicyclo-
[7.3.1]trideca-6,10-diyn-1,8-diene 26. To a solution of 23 (240 mg,
0.53 µmol) in tetrahydrofuran (4.9 mL) and water (1.8 mL) was added
trifluoromethanesulfonic acid (610 µL), and the mixture stirred at 25
°C for 3 h. The mixture was quenched with saturated aqueous NaHCO3
(5 mL) and diluted with Et2O (5 mL). The dried (MgSO4) extract was
evaporated in Vacuo, and the residue purified by chromatography over
silica gel eluting with 20% Et2O/hexanes to give 26 (157 mg, 87%).
Mp 113-115 °C (Et2O/hexanes). IR (thin film) 3509, 2957, 2929,
105 °C (Et2O). IR (CHCl3) 2955, 2929, 2856, 1722 cm-1 1H NMR
.
(300 MHz, CDCl3) δ 6.30 (1H, m), 5.84 (1H, d, J ) 9.8 Hz), 5.80
(1H, d, J ) 9.8 Hz), 5.43 (1H, s), 2.46 (2H, m), 2.25 (1H, m), 2.11
(1H, m), 0.94 (9H, s), 0.91 (9H, s), 0.22 (3H, s), 0.18 (3H, s), 0.14
(6H, s). 13C NMR (75 MHz, CDCl3) δ 190.5, 138.8, 137.4, 122.7,
101, 97.1, 90.9, 87.3, 74.9, 69.5, 34.6, 26, 25.9, 24.5, 18.4, -2.8, -3.2,
-4.6, -4.7. Anal. Calcd for C25H38O3Si2: C, 67.84; H, 8.66.
Found: C, 67.92; H, 8.71.
2858, 1712, 1692 cm-1 1H NMR (300 MHz, CDCl3) δ 6.34 (1H, d,
.
J ) 1 Hz), 5.90 (2H, s), 5.35 (1H, d, J ) 11 Hz), 4.44 (1H, d, J ) 11
Hz), 3.21 (1H, dd, J ) 17.4, 1 Hz), 2.96 (1H, d, J ) 17.4 Hz), 0.88
(9H, s), 0.19 (3H, s), 0.16 (3H, s). 13C NMR (75 MHz, CDCl3) δ 194,
193, 148, 132, 124, 123, 99, 95, 93, 89, 75, 68, 50, 26, 18, -3, -4.
HRMS calcd for C19H22O4Si (M+) 342.1287. Found 342.1288.
3,13-Dioxo-2-amino-5-[(tert-butyldimethylsilyl)oxy]-12â-
hydroxybicyclo[7.3.1]trideca-6,10-diyn-1,8-diene 27. Freshly dehy-
drated diphenylsulfilimine (350 mg, 1.75 mmol, 2.0 equiv) was added
to a solution of 26 (300 mg, 0.87 mmol, 1.0 equiv) in tetrahydrofuran
(20 mL) at room temperature. The mixture was stirred under argon
for 12 h, diluted with hexanes (10 mL), filtered through a silica plug,
and washed with Et2O (10 mL). The crude amine was purified by
chromatography over silica gel eluting with 40% Et2O/hexanes to give
27 (204 mg, 65%). The amine slowly decomposes and is best stored
in the freezer in petroleum ether. Mp 82-84 °C (Et2O). IR (thin film)
Bis-Selenide 22. A solution of 21 (600 mg, 1.35 mmol) in
anhydrous dichloromethane (14 mL) was stirred at room temperature
under argon in the dark (flask wrapped in foil). Freshly-prepared
N-(phenylselenenyl)phthalimide (820 mg, 2.71 mmol, 2 equiv) was
added in one portion, followed by DBU (4.05 mL, 27.1 mmol, 20
equiv). The mixture was stirred for 1.5 h at room temperature, after
which time TLC (hexanes/EtOAc, 90:10) showed the complete
consumption of starting material and formation of one new less polar
product plus diphenyl diselenide. The mixture was concentrated in
Vacuo (water bath temperature below 30 °C), and the residue triturated
with Et2O and filtered through Florisil eluting with Et2O. The filtrate
was concentrated in Vacuo (bath below 30 °C) to give the crude product,
which was purified by chromatography over silica gel eluting with 95:5
hexanes/Et2O to afford 22 (800 mg, 79%). 1H NMR (300 MHz, C6D6)
δ 7.57 (2H, m), 7.39 (2H, m), 7.03 (3H, m), 5.91 (1H, d, J ) 2.9 Hz),
5.37 (1H, dd, J ) 9.5, 1.5 Hz), 5.33 (1H, d, J ) 9.5 Hz), 4.88 (1H, d,
3459, 3354, 2953, 2928, 2855, 1704, 1622 cm-1 1H NMR (300 MHz,
.
CDCl3) δ 5.79 (2H, s), 5.74 (1H, d, J ) 10.0 Hz), 5.37 (1H, d, J )
10.0 Hz), 4.93 (2H, bs), 3.22 (1H, ABq, J ) 17.4 Hz), 2.98 1H, ABq,
J ) 17.4 Hz), 0.86 (9H, s), 0.19 (3H, s), 0.16 (3H, s). 13C NMR (75
MHz, CDCl3) δ 193.7, 190.2, 141.7, 124.8, 124.2, 123.3, 115.0, 99.7,
96.8, 91.3, 85.0, 74.6, 63.1, 48.9, 25.6, 18.3, 16.4, -3.0, -3.3. HRMS
calcd for C19H24NO4Si (M+ + 1) 358.1475. Found 358.1459.

Synthesis of a Protected (()-Calicheamicinone DeriVatiVe
J. Am. Chem. Soc., Vol. 119, No. 29, 1997 6747
3,13-Dioxo-2-amino-5-[(tert-butyldimethylsilyl)oxy]-12â-[(2-
hydroxyethyl)oxy]bicyclo[7.3.1]trideca-6,10-diyn-1,8-diene 28. Cam-
phor sulfonic acid (24 mg, 0.104 mmol, 2.5 equiv) was added in one
portion to a dioxane (0.5 mL) solution of 27 (15 mg, 0.042 mmol, 1.0
equiv) containing ethylene glycol (0.5 mL). The mixture was stirred
at room temperature for 90 min, quenched with triethylamine (2 drops),
diluted with saturated aqueous NaCl, and extracted with EtOAc (5.0
mL). The extract was dried (Na2SO4) and evaporated in Vacuo, and
the residue purified by plc (70:30 CHCl3/acetone) to give 28 (11 mg,
65%). Mp 205 °C (EtOAc/hexanes). IR (NaCl) 3436, 3349, 2928,
solution at 0 °C. The mixture was stirred at 0 °C for 2 h and quenched
with water (20 mL). The organic layer was separated, dried (MgSO4),
and evaporated in Vacuo. The residue was purified by chromatography
over silica gel to give 32 (665 mg, 88%). IR (film) 2980, 2931, 1798,
1768, 1732, 1605 cm-1 1H NMR (300 MHz, CDCl3) δ 6.15 (1H, d,
.
J ) 9 Hz), 6.08 (1H, s), 6.02 (1H, d, J ) 9 Hz), 6.01 (1H, s), 5.90
(1H, s), 1.47 (9H, s), 1.46 (9H, s), 1.31 (9H, s), 0.94 (9H, s), 0.28 (3H,
s), 0.26 (3H, s). 13C NMR (75 MHz, CDCl3) δ 161.4, 154.1, 150.1,
148.5, 142.8, 129.4, 124.8, 122.1, 120.1, 119.7, 114.3, 113.9, 97.5,
95.9, 94.9, 93.7, 90.1, 84.5, 84.0, 70.0, 67.5, 27.4, 25.8, 18.1, -3.0.
ΗRMS calcd for C36H48NO10Si (M+ + 1) 682.3047. Found 682.3037.
2860, 1693, 1620 cm-1 1H NMR (300 MHz, CDCl3) δ 5.88 (1H, d,
.
J ) 9.5 Hz), 5.82 (1H, d, J ) 9.7 Hz), 5.41 (1H, s), 5.01 (2H, bs),
3.87-3.62 (4H, m), 3.26 (1H, ABq, J ) 17.6 Hz), 2.97 (1H, ABq, J
) 17.6 Hz), 0.88 (9H, s), 0.22 (3H, s), 0.18 (3H, s). 13C NMR (75
MHz, CDCl3) δ 190.3, 189.4, 143.7, 124.1, 123.5, 114.9, 97.4, 96.7,
89.9, 86.9, 75.5, 71.4, 71.3, 69.3, 61.9, 49.1, 25.8, 18.4, -3.4, -2.1.
HRMS calcd for C21H28NO5Si (M+ + 1) 402.1737. Found 402.1727.
Allylic Alcohol 33. A solution of 32 (439 mg, 0.644 mmol) in
MeOH (7.83 mL) and water (17 drops) at 0 °C under argon was treated
with NaBH4 (400 mg), the mixture stirred for 30 min, and further
NaBH4 (240 mg) added. The mixture was then stirred at 0 °C for
1.25 h, diluted with Et2O (10 mL), and washed with saturated aqueous
NH4Cl (10 mL). The extracts were dried (MgSO4) and evaporated in
Vacuo, and the residue taken up in MeOH (10 mL) and left for 15 min
at room temperature. The solution was evaporated in Vacuo, and the
residue again taken up in MeOH (10 mL) and left for 10 min. After
evaporation of the solution in Vacuo the residue was purified by plc
eluting with 60% Et2O/hexanes to give 33 (356 mg, 81%). IR (film)
3,13-Dioxo-2-amino-5-[(tert-butyldimethylsilyl)oxy]-12â-
[(triethylsilyl)oxy]bicyclo[7.3.1]trideca-6,10-diyn-1,8-diene 29.
A
solution of 27 (105 mg, 0.294 mmol) in dichloromethane (2 mL) under
argon at 0 °C was treated with triethylamine (70 µL), followed by
triethylsilyl trifluoromethanesulfonate (100 µL). The mixture was
stirred at 0 °C for 10 min and warmed to room temperature for a further
10 min. The mixture was diluted with Et2O (5 mL) and washed with
aqueous NH4Cl (5 mL). After drying (MgSO4) and evaporation in
Vacuo, the product was purified by plc, eluting with 30% Et2O/hexanes
to give 29 (125 mg, 90%). IR (film) 3371, 2954, 2880, 1695, 1614
3414, 2932, 1786, 1764 cm-1 1H NMR (300 MHz, CDCl3) δ 6.46
.
(1H, dd, J ) 5.2, 5.3 Hz), 6.05 (1H, d, J ) 9.5 Hz), 5.94 (1H, dd, J )
9.5, 1.4 Hz), 5.77 (1H, s), 5.73 (1H, d, J ) 1.4 Hz), 4.35 (1H, dd, J )
5.3, 13.2 Hz), 4.22 (1H, dd, J ) 5.2, 13.2 Hz), 1.49 (9H, s), 1.44 (9H,
s), 1.35 (9H, s), 0.93 (9H, s), 0.27 (3H, s), 0.21 (3H, s). 13C NMR (75
MHz, CDCl3) δ 150.5, 150.2, 149.4, 143.2, 138.4, 136.9, 134.4, 128.0,
126.4, 125.2, 124.8, 124.5, 122.6, 120.5, 100.2, 99.5, 88.9, 87.2, 83.9,
83.5, 83.0, 71.4, 62.9, 60.3, 27.9, 27.6, 25.8, 18.4, -2.9. ΗRMS calcd
for C36H51NO10Si (M+) 685.3282. Found 685.3272.
cm-1 1H NMR (300 MHz, CDCl3) δ 5.84 (1H, d, J ) 9.5 Hz), 5.80
.
(1H, d, J ) 9.5 Hz), 5.63 (1H, s), 4.67 (2H, s), 3.22 (1H, d, J ) 17.2
Hz), 2.92 (1H, d, J ) 17.2 Hz), 1.01-0.91 (9H, t, J ) 7.9 Hz), 0.89
(9H, s), 0.68 (6H, q, J ) 7.9 Hz), 0.23 (3H, s), 0.18 (3H, s). 13C
NMR (75 MHz, CDCl3) δ 191.1, 187.8, 141.1, 123.7, 123.5, 123.4,
118.4, 99.5, 97.7, 89.4, 85.6, 75.8, 62.5, 49.2, 26.1, 18.4, 6.9, 4.7.
ΗRMS calcd for C25H37NO4Si2 (M+) 471.2261. Found 471.2264.
2,4-Dinitrosulfenate Ester 34. To a solution of 33 (381 mg, 0.556
mmol) and 2,4-dinitrophenylsulfenyl chloride (157 mg) in dichlo-
romethane (10.16 mL) under argon at 0 °C was added pyridine (15
drops), and the mixture stirred for 5 min, after which it was diluted
with dichloromethane (10 mL). After washing with saturated aqueous
NaHCO3 (10 mL) and saturated aqueous CuSO4 (10 mL), the organic
layer was dried (MgSO4) and evaporated in Vacuo. Purification of the
residue by plc eluting with 45% Et2O/hexanes gave 34 (359 mg, 73%).
13-Oxo-2-[bis(tert-butoxycarbonyl)amino]-3-[(tert-butoxycarbo-
nyl)oxy]-5-[(tert-butyldimethylsilyl)oxy]-12â-[(triethylsilyl)oxy]bicyclo-
[7.3.1]trideca-6,10-diyn-1,3,8-triene 30. A solution of 29 (292 mg,
0.62 mmol) in dichloromethane (1.78 mL) under argon was treated
with triethylamine (180 µL), followed by Boc2O (534 mg) and
4-(dimethylamino)pyridine (160 mg). After 5 min the mixture was
loaded onto a column of silica gel and eluted with 15% Et2O/hexanes
to give 30 (453 mg, 95%) as a pale yellow foam. IR (film) 2955,
IR (film) 3448, 2933, 1787, 1760, 1593, 1521 cm-1 1H NMR (300
.
MHz, CDCl3) δ 9.07 (1H, d, J ) 2.3 Hz), 8.51 (1H, dd, J ) 2.3, 9.1
Hz), 7.95 (1H, d, J ) 9.1 Hz), 6.58 (1H, dd, J ) 5.5, 8 Hz), 6.07 (1H,
d, J ) 9.5 Hz), 5.96 (1H, dd, J ) 9.5, 1.6 Hz), 5.73 (1H, s), 5.70 (1H,
dd, J ) 1.6, 6.3 Hz), 4.72 (2H, m), 2.28 (1H, d, J ) 6.3 Hz), 1.48 (9H,
s), 1.41 (9H, s), 1.35 (9H, s), 0.86 (9H, s), 0.24 (3H, s), 0.18 (3H, s).
13C NMR (75 MHz, CDCl3) δ 154.7, 149.3, 144.5, 143.5, 139.1, 132.6,
128.3, 127.1, 125.6, 124.6, 124.3, 122.5, 120.8, 120.7, 99.7, 89.0, 88.2,
83.9, 83.7, 74.7, 71.3, 65.8, 62.6, 27.8, 27.6, 25.6, 18.2, 15.2, -3.0.
ΗRMS calcd for C42H54N3O14SiS (M+ + 1) 884.3096. Found
884.3108.
2879, 1798, 1768, 1729 cm-1 1H NMR (300 MHz, CDCl3) δ 6.06
.
(1H, s), 6.00 (1H, d, J ) 7.1 Hz), 5.95 (1H, dd, J ) 7.1, 1.3 Hz), 5.78
(1H, d, J ) 1.3 Hz), 1.46 (9H, s), 1.45 (9H, s), 1.35 (9H, s), 0.96 (9H,
t, J ) 8 Hz), 0.92 (9H, s), 0.69 (6H, m), 0.20 (3H, s), 0.15 (3H, s). 13
C
NMR (75 MHz, CDCl3) δ 190.0, 149.9, 149.0, 148.8, 141.0, 135.0,
134.1, 125.1, 124.3, 122.5, 100.4, 95.0, 91.1, 87.8, 84.1, 84.0, 75.5,
62.1, 27.6, 27.5, 25.9, 18.4, 6.8, 5.0, -3.1, -3.2. ΗRMS calcd for
C40H62NO10Si2 (M+ + 1) 772.3912. Found 772.3914.
13-Oxo-2-[bis(tert-butoxycarbonyl)amino]-3-[(tert-butoxycarbo-
nyl)oxy]-5-[(tert-butyldimethylsilyl)oxy]-12â-hydroxybicyclo[7.3.1]-
trideca-6,10-diyn-1,3,8-triene 31. To a solution of 30 (906 mg) in
tetrahydrofuran (10.6 mL) under argon at room temperature was added
aqueous trifluoromethanesulfonic acid [(1.37 mL) was added to water
(3.87 mL)] with stirring. This solution was added dropwise by cannula
to the substrate. The mixture was stirred for 10 min, diluted with Et2O
(50 mL), and washed with saturated aqueous NaHCO3 (20 mL). After
drying (MgSO4) and evaporation of solvents in Vacuo, the product was
purified by chromatography over silica gel eluting with 20% Et2O/
hexanes to yield 31 (730 mg, 95%). IR (film) 3499, 2932, 2858, 1798,
12â-Carbonate Derivative 35. A solution of 34 (264 mg, 0.3
mmol) in dichloromethane (6.4 mL) under argon at 0 °C was treated
with methyl chloroformate (500 µL), followed by pyridine (500 µL),
and the mixture stirred at 0 °C for 45 min. After dilution with
dichloromethane (10 mL), the solution was washed with saturated
aqueous NaHCO3 (10 mL) and saturated aqueous CuSO4 (10 mL), dried
(MgSO4), and evaporated in Vacuo. Purification by plc eluting with
40% Et2O/hexanes gave 35 (208 mg, 74%). IR (film) 2981, 2933,
2858, 1798, 1767, 1594, 1520 cm-1 1H NMR (300 MHz, CDCl3) δ
.
9.07 (1H, d, J ) 2.6 Hz), 8.52 (1H, dd, J ) 2.3, 9.0 Hz), 7.89 (1H, d,
J ) 9.0 Hz), 6.57 (1H, dd, J ) 3.9, 9.0 Hz), 6.39 (1H, d, J ) 1.3 Hz),
6.11 (1H, d, J ) 9.5 Hz), 5.96 (1H, dd, J ) 9.5, 1.3 Hz), 5.78 (1H, s),
4.77 (1H, dd, J ) 3.9, 12.9 Hz), 4.57 (1H, dd, J ) 9.0, 12.9 Hz), 3.79
(3H, s), 1.49 (9H, s), 1.36 (9H, s), 1.33 (9H, s), 0.89 (9H, s), 0.26 (3H,
s), 0.20 (3H, s). 13C NMR (75 MHz, CDCl3) δ 154.6, 154.0, 150.4,
149.3, 148.9, 144.5, 143.2, 139.2, 137.6, 128.9, 128.4, 128.1, 126.4,
125.7, 124.4, 124.3, 123.4, 120.8, 120.7, 99.1, 95.9, 89.3, 88.9, 84.1,
83.9, 83.8, 74.8, 71.1, 67.2, 65.8, 55.4, 27.9, 27.6, 25.7, 18.3, 15.3,
-2.9. ΗRMS calcd for C44H55N3O16SiS (M+) 941.3072. Found
941.3042.
1768, 1730, 1694, 1601 cm-1 1H NMR (300 MHz, CDCl3) δ 6.07
.
(1H, s), 6.02 (2H, s), 5.47 (1H, d, J ) 11.2 Hz), 4.40 (1H, d, J ) 11.2
Hz), 1.47 (9H, s), 1.46 (9H, s), 1.34 (9H, s), 0.93 (9H, s), 0.20 (3H, s),
0.17 (3H, s). 13C NMR (75 MHz, C6D6) δ 197, 150.6, 148.4, 148.3,
142.3, 136.0, 132.8, 127.8, 126.0, 123.6, 101.2, 94.4, 92.7, 87.8, 84.2,
84.0, 83.4, 63.6, 27.5, 25.8, 18.6, -2.7, -3.0. ΗRMS calcd for C34H48-
NO10Si (M+ + 1) 658.3047. Found 658.3057.
Lactone 32. To a solution of trimethylphosphonoacetate (450 µL)
in tetrahydrofuran (5.1 mL) under argon at 0 °C was added dropwise
1 M lithium bis(trimethylsilyl)amide (2.74 mL), and the mixture stirred
at 0 °C for 5 min. A solution of 31 (730 mg, 1.11 mmol) in
tetrahydrofuran (17.6 mL) was added dropwise by cannula to the above
14-Alcohol 36. To a solution of 35 (283 mg, 0.3 mmol) in
tetrahydrofuran (2 mL) under argon at room temperature was added

6748 J. Am. Chem. Soc., Vol. 119, No. 29, 1997
Magnus et al.
thiophenol (100 µL) followed by pyridine (100 µL). After stirring at
room temperature for 45 min, the mixture was diluted with Et2O (10
mL) and washed with saturated aqueous NaHCO3 (5 mL) and saturated
aqueous CuSO4 (5 mL). The organic layer was dried (MgSO4) and
evaporated in Vacuo to give a residue which was purified by plc eluting
with 60% Et2O/hexanes to give 36 (195 mg, 87%). IR (film) 3544,
3-Oxotrisulfide 41 and 12,14-Cyclic Sulfide 42. To a solution of
39 (3 mg, 3.5 µmol) in dichloromethane (150 µL) under argon at room
temperature was added triethylamine (1 drop), followed by triethylsilyl
trifluoromethanesulfonate (2 drops). After 15 min the mixture was
diluted with Et2O (1.0 mL) and washed with water (1.0 mL). After
drying (MgSO4) and concentration the products were purified by plc,
eluting with 50% Et2O/hexanes to give 42 (1 mg, 49%) and the trisulfide
2988, 2933, 2858, 1796, 1762 cm-1 1H NMR (300 MHz, CDCl3) δ
.
6.49 (1H, dd, J ) 7.2, 8.0 Hz), 6.48 (1H, d, J ) 1.7 Hz), 6.12 (1H, d,
J ) 9.5 Hz), 5.95 (1H, dd, J ) 9.5, 1.7 Hz), 5.78 (1H, s), 4.35-4.22
(1H, m), 4.12-3.98 (1H, m), 2.0 (1H, t, J ) 5 Hz), 1.45 (9H, s), 1.43
(9H, s), 1.35 (9H, s), 0.94 (9H, s), 0.28 (3H, s), 0.23 (3H, s). 13C
NMR (75 MHz, CDCl3) δ 153.9, 150.2, 149.3, 149.2, 143.1, 134.7,
130.7, 128.9, 128.4, 126.7, 124.0, 123.2, 114.4, 99.8, 96.0, 88.9, 88.8,
83.8, 71.1, 67.3, 60.3, 55.6, 27.9, 27.6, 25.8, 18.4, -2.9. ΗRMS calcd
for C38H53NO12Si (M+) 743.3337. Found 743.3340.
41 (1 mg, 39%). IR (film) 2959, 2929, 2855, 1799, 1764, 1695 cm-1
.
1H NMR (300 MHz, CDCl3) δ 6.57 (1H, dd, J ) 5.0, 9.0 Hz), 6.43
(1H, d, J ) 1.3 Hz), 6.00 (1H, d, J ) 9.4 Hz), 5.81 (1H, dd, J ) 9.4,
1.3 Hz), 3.84 (3H, s), 3.79 (1H, dd, J ) 5.0, 12.8 Hz), 3.60 (1H, dd,
J ) 9.0, 12.8 Hz), 3.16 (1H, d, J ) 18 Hz), 2.70 (1H, d, J ) 18 Hz),
2.51 (3H, s), 1.46 (9H, s), 1.40 (9H, s), 0.96 (9H, s), 0.28 (3H, s), 0.26
(3H, s). ΗRMS calcd for C34H47NO9SiS3 (M+) 737.2182. Found
737.2176.
14-Mesylate 37. A solution of 36 (153 mg, 0.205 mmol) in
dichloromethane (2.52 mL) under argon at 0 °C was treated with
methanesulfonic anhydride (115 mg) and triethylamine (140 µL), and
the mixture stirred at 0 °C for 1 h. Purification by plc gave 37 (139
11,14-Cyclic Sulfide 44. To a solution of 38 (2.5 mg, 3.12 µmol)
in MeOH (100 µL) at 0 °C under argon was added solid NaBH4. The
mixture was stirred for 2.5 h, quenched with acetone (1 mL), and
purified by plc, eluting with 60% Et2O/hexanes to give 44 (1 mg, 42%).
mg, 83%). IR (film) 2957, 2939, 1798, 1760 cm-1
.
1H NMR (300
IR (film) 2932, 1795, 1760 cm-1 1H NMR (300 MHz, CDCl3) δ 6.38
.
MHz, CDCl3) δ 6.49 (1H, d, J ) 1.4 Hz), 6.41 (1H, dd, J ) 3.1, 8.2
Hz), 6.10 (1H, d, J ) 9.5 Hz), 5.96 (1H, dd, J ) 9.5, 1.4 Hz), 5.81
(1H, s), 5.08 (1H, dd, J ) 3.1, 14 Hz), 4.87 (1H, dd, J ) 8.2, 14 Hz),
3.84 (3H, s), 2.96 (3H, s), 1.46 (9H, s), 1.44 (9H, s), 1.36 (9H, s), 0.95
(9H, s), 0.28 (3H, s), 0.23 (3H, s). 13C NMR (75 MHz, CDCl3) δ
154.0, 150.1, 149.1, 149.0, 143.0, 137.3, 129.1, 128.0, 126.4, 124.7,
124.3, 122.8, 99.2, 95.8, 89.5, 89.1, 84.1, 83.9, 71.2, 68.7, 67.2, 55.5,
37.7, 27.8, 27.6, 25.8, 18.3, 3.0, -2.9. ΗRMS calcd for C39H56NO14-
SiS (M+ + 1) 822.3191. Found 822.3201.
(1H, dd, J ) 3.2, 10.7 Hz), 6.29-6.20 (2H, m), 6.04 (1H, s), 5.90
(1H, s), 5.59 (1H, dd, J ) 2.1, 10.7 Hz), 3.78 (3H, s), 3.76 (1H, dd, J
) 9.2, 12.2 Hz), 2.78 (1H, dd, J ) 9.2, 12.2 Hz), 1.50 (9H, s), 1.44
(9H, s), 1.43 (9H, s), 0.93 (9H, s), 0.20 (6H, s). ΗRMS calcd for
C38H54NO11SiS (M+ + 1) 760.3187. Found 760.3193.
3-Oxo-12,14-cyclic Sulfide 42. A solution of 39 (2 mg, 2.4 µmol)
in dichloromethane (135 µL) and dioxane (15 µL) under argon at room
temperature was treated with methane sulfonic acid (2 drops). After
30 min, the mixture was diluted with Et2O (0.5 mL) and washed with
aqueous NaHCO3 (1 mL). After drying (MgSO4) and evaporation in
Vacuo, the product was purified by plc eluting with 20% Et2O/hexanes
14-Thioacetate 38. To a solution of 37 (139 mg, 0.17 mmol) in
acetone (1.24 mL) under argon at 0 °C was added a suspension of
potassium thioacetate (40 mg) in acetone (2.18 mL) in one portion by
pipet. The mixture was warmed to room temperature, stirred for 2.5
h, diluted with Et2O (5 mL), washed with water (5 mL) and saturated
aqueous NaHCO3 (5 mL), and dried (MgSO4). Evaporation in Vacuo,
followed by purification of the residue by plc eluting with 60% Et2O/
hexanes, gave 38 (110 mg, 81%). Mp 170-171 °C (from Et2O/
to give 42 (1 mg, 86%). IR (film) 2919, 2850, 1727, 1673 1615 cm-1
.
1H NMR (300 MHz, CDCl3) δ 6.18 (1H, t, J ) 4.3 Hz), 5.73 (2H, m),
4.58 (1H, s), 3.90 (1H, bs), 3.66 (1H, dd, J ) 4.3, 18 Hz), 3.35 (1H,
dd, J ) 4.3, 18 Hz), 2.92 (2H, ABq, J ) 16.3 Hz), 1.23 (9H, s), 0.94
(9H, s), 0.23 (6H, s). ΗRMS calcd for C26H33NO4SiS (M+) 483.1900.
Found 483.1900.
hexanes, dec). IR (film) 2980, 2956, 2931, 1797, 1760, 1694 cm-1
.
2-Amino-3-keto-12,14-cyclic Sulfide 43. A solution of 39 (9 mg,
0.011 mmol) in dichloromethane (200 µL) under argon was treated
with 2,6-lutidine (1 drop) followed by triethylsilyl trifluoromethane-
sulfonate (2 drops). After 20 min at room temperature, further
triethylsilyl trifluoromethanesulfonate (2 drops) was added. The
mixture was stirred for another 20 min, extracted into Et2O (2 mL),
and washed with water (2 mL). After drying (MgSO4) and evaporation
in Vacuo, the residue was purified by plc, eluting with 40% Et2O/
hexanes, to give 43 (3.1 mg, 76%). IR (film) 3371, 2929, 2856, 1732,
1H (300 MHz, CDCl3) δ 6.53 (1H, d, J ) 1.3 Hz), 6.26 (1H, dd, J )
7.2, 8.9 Hz), 6.06 (1H, d, J ) 9.3 Hz), 5.93 (1H, dd, J ) 9.3, 1.3 Hz),
5.77 (1H, s), 3.82 (3H, s), 3.73 (2H, dd, J ) 9.2, 8.9 Hz), 2.28 (3H, s),
1.43 (9H, s), 1.42 (9H, s), 1.35 (9H, s), 0.91 (9H, s), 0.25 (3H, s), 0.18
(3H, s). 13C (75 MHz, CDCl3) δ 195.3, 172.3, 154.3, 150.1, 149.1,
142.7, 134.7, 129.2, 128.9, 127.2, 126.2, 124.2, 122.9, 99.9, 96.2, 89.1,
88.8, 83.7, 83.6, 71.4, 67.6, 55.3, 30.3, 29.1, 27.8, 27.6, 25.7, 18.4,
-2.9. HRMS calcd for C40H55NO12SiS (M+) 801.3214. Found
801.3198.
1667, 1615 cm-1 1H (300 MHz, CDCl3) δ 6.17 (1H, t, J ) 4.4 Hz),
.
Protected Trisulfide 39. To a solution of 38 (10.3 mg, 0.013 mmol)
in tetrahydrofuran (370 µL) under argon at -78 °C was added
DIBAL-H (200 µL of a 1 M solution in dichloromethane), and the
mixture stirred at -78 °C for 1.3 h. The reaction was quenched by
addition of MeOH (4 drops) and diluted with EtOAc (1 mL). The
mixture was washed with Rochelle’s salt (2 mL), and the organic layers
were dried (MgSO4) and concentrated in Vacuo. The residue was
dissolved in dichloromethane (1 mL), and Harpp’s reagent (5 mg)
added. After 30 min the mixture was concentrated in Vacuo, and the
residue purified by plc eluting first with 60% Et2O/hexanes, reloaded,
and eluted with Et2O/dichloromethane/hexanes (10:20:70) to give 39
(5.7 mg, 52%, 90% based on 5.3 mg recovered starting material). IR
5.72 (2H, s), 4.58 (1H, s), 3.91 (2H, bs), 3.65 (1H, dd, J ) 4.4, 18.3
Hz), 3.35 (1H, dd, J ) 4.4, 18.3 Hz), 2.92 (2H, ABq, J ) 16.4 Hz),
0.92 (9H, s), 0.22 (6H, s). ΗRMS calcd for C21H25NO2SiS (M+ + 1)
384.1454. Found 384.1453.
Acknowledgment. The National Institutes of Health (CA
50512), National Science Foundation, Bristol-Myers Squibb and
The Robert A. Welch Foundation are thanked for their support
of this research. Dr. Vince Lynch (University of Texas at
Austin) is thanked for the X-ray crystal structures of 28 and
38.
(film) 2931, 1796, 1761 cm-1 1H NMR (300 MHz, CDCl3) δ 6.58
.
Supporting Information Available: Complete experimental
details and spectral information for compounds 6 and 9 and
X-ray crystallographic data for 28 and 38 (42 pages). See any
current masthead page for ordering and Internet access
instructions.
(1H, dd, J ) 6.4, 8.9 Hz), 6.53 (1H, d, J ) 1.3 Hz), 6.08 (1H, d, J )
9.4 Hz), 5.94 (1H, dd, J ) 9.4, 1.3 Hz), 5.79 (1H, s), 3.87 (1H, dd, J
) 6.4, 14.7 Hz), 3.82 (3H, s), 3.69 (1H, dd, J ) 8.9, 14.7 Hz), 2.52
(3H, s), 1.44 (9H, s), 1.43 (9H, s), 1.36 (9H, s), 0.96 (9H, s), 0.28 (3H,
s), 0.23 (3H, s). ΗRMS calcd for C39H55NO11SiS3 (M+ + 1) 838.2785.
Found 838.2774.
JA970743T