Total synthesis of (+)-calyculin a and (-)-calyculin B

Full text of DOI:10.1021/jo981813x

7596
J . Org. Chem. 1998, 63, 7596-7597
Sch em e 1
Tota l Syn th esis of (+)-Ca lycu lin A a n d
(-)-Ca lycu lin B
Amos B. Smith, III,* Gregory K. Friestad,
J ames J .-W. Duan, J oseph Barbosa, Kenneth G. Hull,
Makoto Iwashima, Yuping Qiu, P. Grant Spoors,
Emmanuel Bertounesque, and Brian A. Salvatore
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104
Received September 8, 1998
In the late 1980s, Fusetani and co-workers reported the
isolation and structural elucidation of calyculins A and B,1
potent serine-threonine protein phosphatase (PP1 and PP2A)
inhibitors2 endowed with remarkable cell membrane perme-
ability.3 The striking array of stereochemical and functional
elements, in conjunction with the increasing use of (-)-1 to
explore intracellular phosphorylation,4 has engendered con-
siderable interest by the synthetic community, with notable
total syntheses of the unnatural and natural antipodes of
calyculin A [i.e., (+)-1 and (-)-1] by Evans5 and Masamune,6
respectively.7 Our interest in the calyculins emanated from
the novel [5.6]spiroketal moiety, a central feature in our
phyllanthostatin-breynolide synthetic ventures.8 Herein we
disclose an efficient, convergent total synthesis of (+)-1 and
the first total synthesis of (-)-calyculin B (2).9
From the outset, we envisioned an approach that would
provide both 1 and 2 from a common advanced intermediate,
avoid extensive manipulations of the light-sensitive10
C(1-9) cyanotetraene, and permit flexibility in fragment
coupling. Accordingly, disconnections at the C(2) and C(8)
olefins led to phosphonate A (Scheme 1), possessing a latent
C(3) carbonyl for penultimate Peterson olefination to access
both 1 and 2. Disconnection of BCDE at the C(25) olefin
revealed subtargets BC, envisioned to arise via coupling acyl
anion equivalent B with epoxide C, and DE, available from
oxazole D and lactam E. Efficient stereoselective routes to
(+)-C, (-)-D, and (-)-E,11 in conjunction with a highly
diastereoselective IBr-induced iodocarbonate cyclization12
and a dithiane-epoxide coupling tactic13 to construct a
C(16-25) masked aldol en route to spiroketal C,11a were
disclosed previously.
Phosphonate A presented the intriguing possibility of
olefin σ-bond construction13 via a Suzuki14 one-pot three-
component triene synthesis (Scheme 2). In the event,
Pd-catalyzed coupling of organozinc 3, (E)-bromovinyl
boronate 4,14 and vinyl iodide 615,16 furnished the desired
triene. Methylation at C(8) completed the preparation of
A.
(1) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita, S.;
Furuya, T. J . Am. Chem. Soc. 1986, 108, 2780. Kato, Y.; Fusetani, N.;
Matsunaga, S.; Hashimoto, K.; Koseki, K. J . Org. Chem. 1988, 53, 3930.
(2) Ishihara, H.; Martin, B. L.; Brautigan, D. L.; Karaki, H.; Ozaki, H.;
Kato, Y.; Fusetani, N.; Watabe, S.; Hashimoto, K.; Uemura, D.; Hartshorne,
D. J . Biochem. Biophys. Res. Commun. 1989, 159, 871.
(3) Favre, B.; Turowski, P.; Hemmings, B. A. J . Biol. Chem. 1997, 272,
13856 and references therein.
Sch em e 2
(4) Sheppeck, J . E., II; Gauss, C.-M.; Chamberlin, A. R. Bioorg. Med.
Chem. 1997, 5, 1739 and references therein.
(5) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc. 1992,
114, 9434.
(6) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.; Noda, T.; Filla, S. A.;
Masamune, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 673.
(7) For a formal synthesis of (-)-1, see: Yokokawa, F.; Hamada, Y.;
Shioiri, T. J . Chem. Soc., Chem. Commun. 1996, 871. For other approaches
to calyculins, see: Pihko, P. M.; Koskinen, A. M. P. J . Org. Chem. 1998,
63, 92. Ogawa, A. K.; DeMattei, J . A.; Scarlato, G. R.; Tellew, J . E.; Chong,
L. S.; Armstrong, R. W. J . Org. Chem. 1996, 61, 6153. Barrett, A. G. M.;
Malecha, J . W. J . Chem Soc., Perkin Trans. 1 1994, 1901 and references
therein.
To set the stage for assembly of BCDE, we required
subtargets B and DE. For B, desilylation of the Roush
crotylboration product (+)-717 (Scheme 3), 1,3-acetonide
(8) Smith, A. B., III; Hale, K. J .; Vaccaro, H. A.; Rivero, R. A. J . Am.
Chem. Soc. 1991, 113, 2112. Smith, A. B., III; Empfield, J . R.; Rivero, R.
A.; Vaccaro, H. A.; Duan, J . J .-W.; Sulikowski, M. M. Ibid. 1992, 114, 9419
and references therein.
(9) At the start of our work, the absolute stereochemistry was unknown.
(10) Matsunaga, S.; Fujiki, H.; Sakata, D.; Fusetani, N. Tetrahedron
1991, 47, 2999.
(11) (a) Smith, A. B., III; Duan, J . J .-W.; Hull, K. G.; Salvatore, B. A.
Tetrahedron Lett. 1991, 32, 4855. (b) Smith, A. B., III; Salvatore, B. A.;
Hull, K. G.; Duan, J . J .-W. Ibid. 1991, 32, 4859. (c) Salvatore, B. A.; Smith,
A. B., III. Ibid. 1994, 35, 1329. (d) Smith, A. B., III; Iwashima, M. Ibid.
1994, 35, 6051. (e) Iwashima, M.; Kinsho, T.; Smith, A. B., III. Ibid. 1995,
36, 2199.
(12) Duan, J . J .-W.; Smith, A. B., III. J . Org. Chem. 1993, 58, 3703.
(13) For related examples, see: Smith, A. B., III; Condon, S. M.;
McCauley, J . A. Acc. Chem. Res. 1998, 31, 35.
(14) (a) Hyuga, S.; Chiba, Y.; Yamashina, N.; Hara, S.; Suzuki, A. Chem.
Lett. 1987, 1757. (b) Ogima, M.; Hyuga, S.; Hara, S.; Suzuki, A. Chem. Lett.
1989, 1959. (c) Hyuga, S.; Yamashina, N.; Hara, S.; Suzuki, A. Chem. Lett.
1988, 809.
(15) The structure assigned to each new pure compound is in accord with
its IR, 1H and 13C NMR, and high-resolution mass spectra.
(16) Phosphonate 6 was prepared from the corresponding alcohol (Rand,
C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E.-I. J . Org. Chem. 1981,
46, 4093) in two steps [MsCl, DMAP; P(OMe)3, NaI, neat; 70% yield].
10.1021/jo981813x CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/16/1998

Communications
J . Org. Chem., Vol. 63, No. 22, 1998 7597
Sch em e 5
formation, and execution of a modified Wacker oxidation
protocol18 furnished ketone 8.15 Generation of the kinetic
enol triflate,19 reaction with a mixed stannylcuprate,20 and
bromodestannylation led efficiently to acyl anion equivalent
(+)-B15 (ca. 54%; six steps).
Sch em e 3
We next addressed preparation of the DE Wittig reagent
(Scheme 4). Hydrolysis of lactam (-)-E,11b followed by
coupling with amine 9, obtained via Lindlar reduction of
azide (-)-D,11c afforded amide (+)-10.15 Deprotection, reduc-
tive methylation of the C(36) amine, and interchange of
C(34,35) diol protecting groups gave bis-diethylisopropyl-
silyl21 ether (+)-11.15 Completion of (+)-DE15 was achieved
by ester reduction, conversion to the primary chloride, and
displacement with tri-n-butylphosphine.
Sch em e 4
With the requisite subtargets in hand, we embarked upon
their union (Scheme 5). To link (+)-B with the C(14-25)
spiroketal, (+)-C11d was converted to TBS ether (+)-1215 and
exposed to the vinyl thienylcuprate22 derived from (+)-B (1.5
equiv) to furnish exclusively alcohol (+)-13 in 83% yield.
O-Methylation, olefin cleavage, and selective DIBAL reduc-
tion (â/R >12:1) afforded â alcohol (+)-14.15 Arrival at (+)-
BC15 entailed protecting group interchange, PMB removal
and phosphorylation employing the Evans protocol.5
Final assembly of the calyculin framework began with
hydrogenolysis of (+)-BC (Scheme 5), TPAP oxidation,23 and
Wittig olefination24 with (+)-DE (1.7 equiv) to provide (+)-
BCDE15 (E/Z ) 9:1; 83% yield). Removal of the pivaloate
moiety, TPAP oxidation,23 and Horner-Emmons olefination
with phosphonate A (n-BuLi, -78 °C), followed by brief
exposure to acid (0.5 N HCl), furnished trienone (+)-1715
with excellent selectivity (E/Z ) 15:1) and good overall
efficiency (67% yield). Peterson olefination (Me3SiCH2CN,
n-BuLi, -78 °C)25 then afforded protected calyculins A and
B (1:1.7, 94% yield). Careful radial chromatographic sepa-
ration (1 mm silica, 5:1 hexanes/EtOAc) and global depro-
tection with aqueous HF in CH3CN furnished pure (+)-
calyculin A (69% yield) and (-)-calyculin B (84% yield),
identical in all respects (1H and 13C NMR, IR, UV, HRMS,
TLC, and HPLC) except for chiroptic properties to authentic
1 and 2.26
In summary, an efficient, convergent total synthesis of (+)-
calyculin A and (-)-calyculin B has been achieved. The
synthesis of (-)-2 also confirms the structure of calyculin
B, previously based only on spectral comparison with caly-
culin A.
Ack n ow led gm en t. Support was provided by the Na-
tional Institutes of Health (National Cancer Institute)
through Grant CA-19033 and postdoctoral fellowships to
G.K.F. and K.G.H.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and ana-
lytical data for A, B, BC, DE, BCDE, 1, 2, 6, 8, and 10-17 and
selected experimental procedures (13 pages).
(17) Roush, W. R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc. 1990,
112, 6348.
(18) Smith, A. B., III; Cho, Y.; Friestad, G. K. Tetrahedron Lett. 1998, in
press.
(19) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(20) Piers, E.; Tillyer, R. D. J . Org. Chem. 1988, 53, 5366.
(21) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem. Soc. J pn. 1988,
61, 2369.
(22) Malmberg, H.; Nilsson, M.; Ullenius, C. Tetrahedron Lett. 1982, 23,
3823. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(23) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
J O981813X
(25) Yamakado, Y.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J . Am. Chem.
Soc. 1981, 103, 5568.
(26) We thank Professors Nobuhiro Fusetani and Shigeki Matsunaga
(University of Tokyo) for authentic samples of both natural (-)-1 and (+)-2
and for confirming that the correct [R]D for natural 2 is +15° (c 0.07, EtOH).
We also thank Professor David Evans (Harvard University) for an authentic
sample of synthetic (+)-1.
(24) Zhao, Z.; Scarlato, G. R.; Armstrong, R. W. Tetrahedron Lett. 1991,
32, 1609.