The first formal asymmetry synthesis of phorbol

Full text of DOI:10.1021/ja9706256

J. Am. Chem. Soc. 1997, 119, 7897-7898
7897
Scheme 1
The First Formal Asymmetric Synthesis of Phorbol
Paul A. Wender,* Kenneth D. Rice, and Mark E. Schnute†
Department of Chemistry, Stanford UniVersity
Stanford, California 94305
ReceiVed February 26, 1997
Phorbol (1) is a tigliane diterpene whose 12,13-diesters play
a principal role in efforts to understand a range of cellular
processes at the molecular level, including most notably
carcinogenesis and signal transduction.1 The highly potent
biological activity of phorbol esters is attributed to their ability
to avidly bind to and activate isozymes of the protein kinase C
(PKC) family.2 Although many such 12,13-diesters are potent
tumor promoters, other derivatives possessing the phorbol
skeleton hold promise as chemotherapeutic leads due to their
antitumor and anti-HIV activity.3 In 1989, we reported the first
synthesis of phorbol in racemic form.4,5 To identify therapeutic
targets in the PKC signaling pathway and to elucidate the
structural basis for their biological activity, we have now
developed an efficient asymmetric synthesis of 2 (Scheme 1),
a highly flexible synthetic precursor to phorbol analogues
possessing the ABC-ring skeleton. The utility of this intermedi-
ate is further demonstrated by its transformation to phorbol in
racemic form, thereby establishing the first formal asymmetric
synthesis of phorbol.
Scheme 2
Our approach to the phorbol BC-ring system was designed
around an intramolecular oxidopyrylium-alkene [5 + 2]
cycloaddition (12 to 13).6 As a consequence, the control of
absolute stereochemistry rested on stereocontrolled installation
of the pro-C(11) center in the sequence leading to the cycload-
dition precursor (12). This was achieved through a chiral
oxazolidinone-based asymmetric aldol reaction7 between alde-
hyde 5, prepared in two steps from furfuryl alcohol 3 by
silylation (99%)4a and formylation of the corresponding furyl
lithium (75%), and N-propionyl oxazolidinone 67b (Scheme 2).
The aldol reaction occurred with high diastereoselectivity (98%
de) to provide upon column chromatography alcohol 7 as a
single diastereomer in 96% yield. Introduction of the alkene
subunit into the tether was accomplished through transamination
of 7 to provide Weinreb amide 8 (86%) along with recovered
chiral auxiliary (88%). Addition of 3-butenylmagnesium bro-
mide (4 equiv) to 8 afforded hydroxy ketone 9 (82%).
Reduction of 9 with DIBAL gave diol 10 (Scheme 3) in 85%
yield and high diastereoselectivity (30.6/1), consistent with
Scheme 3
† National Institutes of Health Postdoctoral Fellow.
(1) (a) Evans, F. J., Ed. Naturally Occurring Phorbol Esters; CRC
Press: Boca Raton, FL, 1986. (b) Hecker, E.; Schmidt, R. Fortschr. Chem.
Org. Naturst. 1974, 31, 377.
(2) For a general review on PKC, see: (a) Lester, D. S., Ed. Protein
Kinase C Current Concepts and Future PerspectiVes; Ellis Harwood, Ltd.:
West Sussex, 1992. (b) Wender, P. A.; Cribbs, C. M. AdV. Med. Chem.
1992, 1, 1. (c) Nishizuka, Y. Nature 1988, 334, 661.
(3) (a) Kupchan, S. M.; Baxter, R. L. Science 1975, 187, 652. (b)
Gustafson, K. R.; Cardellina, J. H.; McMahon, J. B.; Gulakowski, R. J.;
Ishitoya, J.; Szallasi, Z.; Lewin, N. E.; Blumberg, P. M.; Weislow, O. S.;
Beutler, J. A.; Buckheit, R. W., Jr.; Cragg, G. M.; Cox, P. A.; Bader, J. P.;
Boyd, M. R. J. Med. Chem. 1992, 35, 1978.
formation of a six-membered aluminum chelate.8 Initial at-
tempts to perform a ring expansion of the furan at this stage
were unsatisfactory.9 Therefore, selective acetylation of the
potentially interfering C(12) hydroxyl was conducted by treat-
ment of 10 with trimethylsilylimidazole to first effect silylation
of the more reactive furfuryl alcohol9a followed by in situ
acetylation. Subsequent deprotection of the transient trimeth-
ylsilyl ether afforded 11 in 82% yield. Oxidative ring expansion
of 11 with VO(acac)2/t-BuOOH followed by acetylation of the
(4) (a) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D. J.
Am. Chem. Soc. 1989, 111, 8954. (b) Wender, P. A.; Kogen, H.; Lee, H.
Y.; Munger, J. D., Jr.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc.
1989, 111, 8957. (c) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc.
1990, 112, 4956. (d) Rice, K. D. Ph.D. Thesis, Stanford University, Stanford,
CA, 1993; for the synthesis of rac-2, see Supporting Information.
(5) For a review of synthetic approaches toward tigliane diterpenes,
see: (a) Rigby, J. H. Stud. Nat. Prod. Chem. 1993, 12, 233. For a strategy
toward synthetic scalemic phorbol analogs see: (b) Tokunoh, R.; Tomiyama,
H.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 2449. (c) Sugita,
K.; Sawada, D.; Sodeoka, M.; Sasai, H.; Shibasaki, M. Chem. Pharm. Bull.
1996, 44, 463. (d) Sugita, K.; Neville, C. F.; Sodeoka, M.; Sasai, H.;
Shibasaki, M. Tetrahedron Lett. 1995, 36, 1067.
(8) Kiyooka, S.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986, 27,
3009.
(9) Complex mixtures of products were obtained presumably due to
hemiketal formation and spiroketalization, see: (a) Paterson, I.; Lister, M.
A.; Ryan, G. R. Tetrahedron Lett. 1991, 32, 1749. (b) Martin, S. F.;
Gluchowski, C.; Campbell, C. L.; Chapman, R. C. J. Org. Chem. 1984,
49, 2512.
(6) (a) Ullman, E. F.; Milks, J. E. J. Am. Chem. Soc. 1962, 84, 1315. (b)
Sammes, P. G. Gazz. Chim. Ital. 1986, 116, 109.
(7) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
S0002-7863(97)00625-2 CCC: $14.00 © 1997 American Chemical Society

7898 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Communications to the Editor
Scheme 4
Scheme 5
crude hydroxy pyranones afforded 12 in 88% yield as an
inconsequential mixture (2/1) of C(6) epimers.
Intramolecular oxidopyrylium-alkene cycloaddition occurred
upon treatment of an acetonitrile solution of epimers 12 with
DBU (2.0 equiv), affording cycloadduct 13 in 79% yield as a
single diastereomer. The high stereoselectivity of this trans-
formation can be rationalized by the PM3 semiempirical
representation of the proposed transition state (i), in which the
tether between the reactive subunits adopts a chair-like confor-
mation with the C(11) methyl group equatorially disposed to
minimize steric interactions with the pyranone carbonyl. Thus,
the chirality installed at C(11) effectively controls stereogenesis
at C(8) and C(9).
Elaboration of cycloadduct 13 to intermediate 2 (Scheme 4)
next required C(4) oxygenation and annelation of the A ring
through zirconocene-mediated enyne cyclization. For this
purpose, the cycloadduct was first hydrogenated to afford the
corresponding ketone (95%), which underwent subsequent
Wittig olefination (79%) and allylic oxygenation (89%) to afford
enone 14. Conjugate addition of vinyl cuprate to 14 followed
by stereoselective (axial) protonation of the intermediate enolate
afforded 15 as a single diastereomer in 83% yield. The addition
of lithium phenylacetylide to 15 in the presence of lithium
bromide followed by HMPA (6 equiv)10 and TMSCl gave
exclusively the â-addition product 16 in 75% yield, thus
establishing the required trans A/B ring fusion. Zirconocene-
mediated enyne cyclization11 proceeded with fortuitous depro-
tection of the C(12) acetate to afford alcohol 17 (93%).
Subsequent PCC oxidation (94%) provided the desired ent-2
in 16 steps (9.0% yield) overall from furfuryl alcohol 3.
The selection of 2 as a target in the above studies was based
on the demonstration as described below that rac-24d serves as
an effective precursor of rac-1 (Scheme 5). This new sequence
provides a more concise and efficient solution to previously
encountered problems4 attending elaboration of the C,D-ring
system, B-ring ether cleavage, and introduction of the A-ring.
This sequence started with phenyl sulfenylation of the kinetically
generated silyl enol ether of 2 (96%) followed by oxidation with
lead tetraacetate12 to provide a diastereomeric mixture of C(13)
acetoxy phenyl sulfides (84%). Further oxidation and thermal
sulfoxide elimination afforded the corresponding 13-acetoxy
enone (88%). Diphenylisopropylsulfonium ylide addition oc-
curred with â-face stereoselectivity, thereby introducing the
D-ring and providing tigliane 18 in 80% yield. Deprotection
of the C(20) silyl ether (96%) followed by ozonolysis of the
benzylidene (89%) unmasked the C(3) carbonyl to provide
diketone 20. Cleavage of the ether bridge was accomplished
by conversion of 20 to the corresponding iodide (67%), which
underwent elimination in the presence of activated zinc to afford
alkene 21 (61%). Allylic oxidation of 21 occurred preferentially
at the C(7) carbon to afford allylic alcohol 22 (54%). Subse-
quent treatment with thionyl chloride followed by silver-assisted
nucleophilic substitution gave diacetate 24 (71%, 2 steps).
Hydroxyl (C(9)) directed reduction of the C(12) ketone with
sodium triacetoxyborohydride provided the desired â-alcohol
25 in 92% yield, which was subsequently acetylated to provide
triacetate 26 (89%). Installation of the C1,2 olefin was achieved
in a two-step sequence by bromination of the corresponding
silyl enol ether of 26 (63%) followed by endocyclic halide
elimination of the resulting bromide to provide the desired R,â-
unsaturated ketone 27 in 56% yield. Finally, deprotection of
the C(4) silyl ether (88%) and exhaustive acetate hydrolysis
(62%) afforded racemic phorbol in 17 steps from the intermedi-
ate rac-2. Current efforts are directed at utilizing 2 as a
cornerstone intermediate to prepare phorbol and daphnane
derivatives as required to explore and exploit these novel
families of highly potent biological probes and therapeutic leads.
Acknowledgment. Support of this research by the National Cancer
Institute through grant CA31841 is gratefully acknowledged. M.E.S.
thanks the National Institutes of Health for a Postdoctoral Fellowship
(GM17351-02).
(10) The use of HMPA as additive was found to be essential for efficient
trapping of the intermediate alkoxide.
Supporting Information Available: Experimental details, full
characterization data for 1, 2, 5, and 7-28, and the synthesis of rac-2
(40 pages). See any current masthead page for ordering and Internet
access instructions.
(11) (a) RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P. J. J.
Am. Chem. Soc. 1988, 110, 7128. (b) Negishi, E.; Holmes, S. J.; Tour, J.
M.; Miller, J. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am.
Chem. Soc. 1989, 111, 3336.
(12) Trost, B. M.; Massiot, G. S. J. Am. Chem. Soc. 1977, 99, 4405.
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