Synthesis of (±)-calicheamicinone by two related methods

Full text of DOI:10.1021/ja9602004

4
904
J. Am. Chem. Soc. 1996, 118, 4904-4905
Communications to the Editor
Scheme 1a
Synthesis of (()-Calicheamicinone by Two Related
Methods
D. L. J. Clive,* Yunxin Bo, Yong Tao, Sylvain Daigneault,
Yong-Jin Wu, and G e´ rard Meignan
Chemistry Department, UniVersity of Alberta
Edmonton, Alberta, Canada T6G 2G2
ReceiVed January 22, 1996
1
We report the synthesis of (()-calicheamicinone (1), the
2
aglycon (in racemic form) of the antitumor agent calicheamicin
I
3
4
γ1 . Ester exchange of â-keto ester 2 with ClCH2CH2OH [Ti-
5
(
OPr-i)4, 63%], followed by treatment with K2CO3, gave ketene
6
acetal 3 (80-87%) (Scheme 1). Deprotonation [(Ph2MeSi)2NLi ]
to the Z-enolate and trapping with Me3SiCl afforded triene 4,
7
which underwent Diels-Alder cycloaddition with methyl (E)-
8
9
3
-nitropropenoate (4 f 5 ; 56% from 3). Reduction of 5 with
NaBH4 gave a 2:1 mixture of C(5) epimeric alcohols [only the
major one (6) is shown]. These were separated after silylation
[
3
t-BuMe2SiOTf, 2,6-lutidine, 65% (from 5) of 5R-isomer 7, and
9
3% (from 5) of corresponding 5â-isomer ]. Both isomers were
independently converted into 14 by identical routes; only the
procedure for the major isomer is shown, but yields for the 5â-
series are also given in the scheme. Reduction (DIBAL-H;
9
9%) of ester 7 generated primary alcohol 8, and the carbon-
carbon double bond of 8 was then cleaved (OsO4, NaIO4; 99%).
The resulting equilibrium mixture of lactols (9) afforded (96%)
a single pivaloate (10) in the presence of t-BuCOCl and pyridine.
Next, the nitro group was reduced10 (NiCl2, NaBH4, ultrasound,
9
5%) and protected (allyloxycarbonyl chloride, pyridine; 94%)
(10 f 11 f 12). Desilylation (12 f 13; TBAF; 97%) and
PCC oxidation (13 f 14; 91%) now set the stage for
9
introduction of the first acetylene unit (14 f 15 ). This was
(
1) (a) Haseltine, J. N.; Paz Cabal, M.; Mantlo, N. B.; Iwasawa, N.;
Yamashita, D. S.; Coleman, R. S.; Danishefsky, S. J.; Schulte, G. K. J.
Am. Chem. Soc. 1991, 113, 3850. (b) 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. (c) Aiyer, J.; Hitchcock, S. A.;
Denhart, D. J.; Liu, K. K.-C.; Danishefsky, S. J.; Crothers, D. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 855.
(
2) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Siegel, M. M.; Morton, G.
O.; Ellestad, G. A.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc.
992, 114, 985.
3) Seebach, D.; Hungerb u¨ hler, E.; Naef, R.; Schnurrenberger, P.;
1
(
Weidmann, B.; Z u¨ ger, M. Synthesis 1982, 138.
(
4) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
5) cf.: (a) Broadhurst, M. D. J. Org. Chem. 1985, 50, 1117. (b) Eid,
(
C. N., Jr.; Konopelski, J. P. Tetrahedron 1991, 47, 975.
(
6) Made from the amine (BuLi, THF, 0 °C; 20 min); Zhinkin, D. Y.;
a
Bu-t; yields in brackets refer to 5â series. b Yield after
Z ) SiMe
2
Mal’nova, G. N.; Gorislavskya, Zh. V. J. Gen. Chem. USSR 1968, 38, 2702.
equilibration: 71% (see text).
(
7) cf.: Masamune, S.; Ellingboe, J. W.; Choy, W. J. Am. Chem. Soc.
982, 104, 5526.
8) Danishefsky, S.; Prisbylla, M. P.; Hiner, S. J. Am. Chem. Soc. 1978,
1
accomplished by reaction with cerium trimethylsilylacetylide11
(
(1:1.2 Me3SiCtCLi, CeCl3; THF, -78 °C; 91%), the acetylene
1
00, 2918. cf.: Danishefsky, S. Acc. Chem. Res. 1981, 14, 400. Banville,
J.; Brassard, P. J. Chem. Soc., Perkin Trans. 1 1976, 1852. Schechter, H.;
Conrad, F.; Daulton, A. L.; Kaplan, R. B. J. Am. Chem. Soc. 1952, 74,
being introduced anti to the nitrogen. Protection of the hydroxyl
group (15 f 16; t-BuMe2SiOTf, 2,6-lutidine; 93%), removal
of the pivaloyl group (16 f 17; DIBAL-H; 96%), and Collins
oxidation (17 f 18; 97%) then brought the work to a point
3
052.
(
(
9) Structure confirmed by x-ray analysis.
10) Osby, J. O.; Ganem, B. Tetrahedron Lett. 1985, 26, 6413.
S0002-7863(96)00200-4 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4905
Scheme 2a
Scheme 3a
a
2
Z ) SiMe Bu-t.
where we needed to introduce double bonds at C(4)-C(7) and
C(2)-C(3) and attach an acetylene unit at C(9).
Compound 18 was desaturated at C(4)-C(7) [18 f 19; LDA,
PhSeBr; dimethyldioxirane; 85%), deprotected at nitrogen [19
f 20; Pd(PPh3)4, dimedone;12 93%], desaturated at C(2)-C(3)
a
Z ) SiMe
2
2 6 4
Bu-t; A ) CH OC H OMe-p.
hydrolysis (TsOH, H2O, 84%) served to disengage the two
remaining protecting groups and so give synthetic (()-cali-
cheamicinone (1).
We have also converted racemic 8 (represented in Scheme 3
by the enantiomer 8a) into ketone 33 by procedures
type used in the first route. Treatment of 33 with cerium
trimethylsilylacetylide (1:1.4 Me3SiCtCLi, CeCl3; THF, -78
°C; 91%) serves to introduce the acetylene syn to the nitrogen
33 f 34), and further elaboration
aldehyde 35. This reacts with cerium trimethylsilylacetylide
1:1.3 Me3SiCtCLi, CeCl3, THF, -78 °C) to give alcohol 36
71%), which is easily convertible
(
20 f 21; t-BuOCl, DBU; 81%), and methoxycarbonylated (21
f 22; triphosgene, pyridine; MeOH; 91%). Next, free radical
bromination at C(9) [22 f 23; NBS, (PhCO)2O2, 100 W
tungsten lamp], followed by hydrolysis (H2O, AgNO3, 23 f
1
a,b
1
9,20
1
3
of the
2
4 ) and esterification (CH2N2), gave aldehyde ester 25 (77%
from 22). This reacted with cerium trimethylsilylacetylide
(
1:1.3 Me3SiCtCLi, CeCl3, THF, -78 °C), affording 26 (91%).
9
Finally, desilylation (TBAF) yielded 27 (46%). During this
2
0,21
(
took the route as far as
step, epimerization occurs at C(9); however, treatment of the
easily separated anti-isomer14 (42% isolated from 26) with Bu4-
(
(
NOAc gives quantitatively a 6:4 mixture in favor of 27.
Therefore, by equilibrating the anti-diyne once, it is possible
to convert 26 into 27 in 71% yield.
22 20,23
into lactone 37 and then,
similar to that used earlier, into 27.
2
0,24
by a procedure
The only stereogenic center in 18 and 34 that is preserved
after elaboration to (()-calicheamicinone is C(5). Therefore,
in a synthesis of material with the natural stereochemistry (as
actually depicted in diagram 1), intermediates corresponding
to 5 with (2S) absolute configuration would have to be processed
as in Scheme 1, while the reactions of Scheme 3 would be used
for the (2R)-isomer.
The acetylenic hydrogens of 27 were now replaced by iodine
(
27 f 28; NIS, AgNO3; 89%], and the cyclic enediyne was
1
5
then generated (Scheme 2, 28 f 29; 72%) by Pd-mediated
1
6
condensation with (Z)-1,2-bis(trimethylstannyl)ethene [Pd-
(
PPh3)4, 60 °C]. From 29, the last steps were guided by
1
a,b,17
established
principles. Reduction with DIBAL (98%),
desilylation (TBAF, 94%), and further reduction (76%) with
NaBH4 gave triol 30. Silylation of the primary and secondary
hydroxyls (Et3SiOTf, 2,6-lutidine, 95%) and selective hydrolysis
Acknowledgment. We thank NSERC, the Merck Frosst Therapeutic
Research Centre, and the Alberta Cancer Board for financial support,
Drs. G. V. J. da Silva, N. Selvakumar, and Y.-Z. Hu for assitance,
Professor W. A. G. Graham for hexamethylditin, Professor D. N. Harpp
for advice, and Dr. R. McDonald for x-ray measurements. Y.T. held
an AHFMR Postdoctoral Fellowship, Y.-J.W. a NSERC Postdoctoral
Fellowship, S.D. a 1967 NSERC Graduate Fellowship, and G.M. a
Postdoctoral Scholarship (Minist e` re de la Recherche et de la Tech-
nologie, France).
(
3
3:6:1 AcOH, THF, H2O; 94%) then afforded allylic alcohol
1, from which point elaboration of the trisulfide (31 f 32)
1
a,18
was accomplished
by successive reaction with diisopropyl
azodicarboxylate, Ph3P, and AcSH (94%) and DIBAL-H and
N-(methyldithio)phthalimide (88% over two steps). Finally, acid
(11) cf.: (a) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett.
1
1
984, 25, 4233. (b) Suzuki, M.; Kimura, Y.; Terashima, S. Chem. Lett.
984, 1543. (c) Jung, P. M. J.; Burger, A.; Biellmann, J.-F. Tetrahedron
Supporting Information Available: Spectral data for most com-
pounds and annotated flow chart for the second route (42 pages).
Ordering information is given on any current masthead page.
Lett. 1995, 36, 1031.
(
12) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Edn. Engl. 1984, 23,
36.
13) The SiMe3 group is removed during hydrolysis. Compound 24
4
(
JA9602004
exists as two hydroxyl lactones, epimeric at C(9).
(
14) CtCH units at C(5) and C(9) anti.
(19) OH f OCOBu-t; CHdCH2 f CHO f CH2OH f CH2OCH2-
OC6H4OMe-p; NO2 f NH2 f NHCO2allyl; CHOSiMe2Bu-t f CHOH f
CdO. The C(5) epimer of 8a was also converted into 33.
(
15) cf.: Shair, M. D.; Yoon, T.; Danishefsky, S. J. J. Org. Chem. 1994,
5
9, 3755. Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa,
N.; Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419. Barrett, A. G. M.;
Boys, M. L.; Boehm, T. L. J. Chem. Soc., Chem. Commun. 1994, 1881.
Pattenden, G.; Thom, S. M. Synlett 1993, 215.
(20) See supporting information for details of these efficient procedures.
(21) OH f OSiMe2Bu-t; CH2OCOBu-t f CH2OH f CHO.
(22) The C(9) epimer (18%) is convertible (PCC; NaBH4; ca. 90%
overall) into an 11.6:1 isomer mixture in favor of 36.
(
16) Mitchell, T. N.; Amamria, A.; Killing, H.; Rutschow, D.; J.
Organomet. Chem. 1986, 304, 257.
17) Magnus, P.; Lewis, R. T.; Bennett, F. J. Chem. Soc., Chem. Commun.
989, 916 and references therein.
18) CH2OH f CH2SAc f CH2SH f CH2SSSMe.
(23) OH f OCOCH2Cl; CH2OCH2OC6H4OMe-p f CH2OH f CHO;
OCOCH2Cl f OH; Collins oxidation of lactols.
(
1
(24) Desaturation at C(4)-C(7), nitrogen deprotection, desaturation at
C(2)-C(3), nitrogen methoxycarbonylation, acetylene desilylation.
(