Total synthesis of clerocidin via a novel, enantioselective homoallenylboration methodology

Full text of DOI:10.1021/jo981331l

6774
J . Org. Chem. 1998, 63, 6774-6775
Tota l Syn th esis of Cler ocid in via a Novel,
En a n tioselective Hom oa llen ylbor a tion
Meth od ology
Alan X. Xiang, Donald A. Watson, Taotao Ling, and
Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, University of
CaliforniasSan Diego, 9500 Gilman Drive,
La J olla, California 92093-0358
Received J uly 9, 1998
Clerocidin (1),1 terpentecin (2),2 and UCT4B (3)3 (Figure
1) are recently isolated diterpenoid antibiotics that exhibit
very promising antitumor activities in vitro and in vivo.4 It
has been postulated that their antitumor properties arise
through interference with topoisomerase II, a nuclear en-
zyme implicated in DNA metabolism and cell proliferation.5
In addition to their remarkable biological profile, these
compounds possess a challenging molecular architecture,
beckoning the development of synthetic methodology.6 Their
common structural motif consists of a highly functionalized
side-chain (C11-C16) attached at the C9 carbon of a trans-
decalin core. Undoubtedly, this side chain is the most
provocative part of the molecule, both from a structural and
biological standpoint. Structurally, its high degree of oxy-
genation and strong electrophilic nature give rise to several
forms in equilibrium (Figure 1) and present a formidable
synthetic endeavor. Biologically, this side chain is believed
to be responsible for the observed “topoisomerase II poison”
activity.5 Our interest in these aspects of this class of
compounds led us to undertake the total synthesis of
clerocidin (1).
F igu r e 2. Strategic bond disconnections of clerocidin (1).
construction of clerocidin’s carbon framework (Figure 2).
This reaction sequence constitutes the first total synthesis
of any of these natural products, proves the absolute
stereochemistry of 1, and provides the first demonstration
of the versatility of the asymmetric homoallenylboration
reaction, in total synthesis.7
Our synthetic strategy was designed to target the keto
aldehyde form (open form) of clerocidin (1), which exists in
equilibrium with its hemiacetal form. This retrosynthetic
analysis reveals that the entire carbon skeleton of 1 can be
constructed by an asymmetric addition of a 1,3-butadienyl
unit on the carbonyl carbon of 5 (Figure 2). To this end,
application of the novel homoallenylboration methodology,
recently developed by Brown and co-workers, appeared to
be the best reaction candidate.8 Conceptually, this reaction
involves treatment of an aldehyde 7 with a chiral homoal-
lenylboronate ester 8 to furnish alcohol 10.9 The stereo-
chemical outcome at the C* center (ultimately C12 in
clerocidin) is dictated by the chirality of the boronate ester
8 and transferred to the product via a putative six-membered
transition state 9 (Figure 3). Use of this method was
expected to produce alcohol 4, which could then be trans-
formed to clerocidin (1) via the use of Sharpless’s asymmetric
epoxidation10 and dihydroxylation11 methodologies (Figure
2). Application of this plan to the synthesis of clerocidin (1)
F igu r e 3. Brown’s asymmetric homoallenylboration.
F igu r e 1. Structures of clerocidin (1), terpentecin (2), and UCT4B
(3).
is shown in Scheme 1.
Herein, we disclose a chemical synthesis of 1 employing
a key asymmetric homoallenylboration reaction for the
The synthesis of clerocidin (1) commenced with the
optically active alcohol 11, which is readily available by a
* Corresponding author’s full mailing address: Emmanuel A. Theodor-
akis, Assistant Professor of Chemistry, University of CaliforniasSan Diego,
Department of Chemistry & Biochemistry, 9500 Gilman Dr., Dept. 0358,
La J olla, CA 92093-0358; Tel: 619-822-0456; Fax: 619-822-0386; email:
etheodor@ucsd.edu.
(1) Andersen, N. R.; Lorck, H. O. B.; Rasmussen, P. R. J . Antibiot. 1983,
36, 753. Andersen, N. R.; Rasmussen, P. R.; Falshaw, C. P.; King, T. J .
Tetrahedron Lett. 1984, 25, 469. Andersen, N. R.; Rasmussen, P. R.
Tetrahedron Lett. 1984, 25, 465. McCullough, J . E.; Muller, M. T.; Howells,
A. J .; Maxwell, A.; O’Sullivan, J .; Summerill, R. S.; Parker, W. L.; Wells, J .
S.; Bonner, D. P.; Fernandes, P. B. J . Antibiot. 1993, 46, 526.
(2) Tamamura, T.; Sawa, T.; Isshiki, K.; Masuda, T.; Homma, Y.; Iinuba,
H.; Naganawa, H.; Hamada, M.; Takeuchi, T.; Umezawa, H. J . Antibiot.
1985, 38, 1664. Isshiki, K.; Tamamura, T.; Takahashi, Y.; Sawa, T.;
Naganawa, H.; Takeuchi, T.; Umezawa, H. J . Antibiot. 1985, 38, 1819.
(3) Uosaki, Y.; Kawada, S.-Z.; Nakano, H.; Saitoh, Y.; Sano, H. J . Antibiot.
1993, 46, 235.
(4) Kawada, S.-Z.; Yamashita, Y.; Fujii, N.; Nakano, H. Cancer Res. 1991,
51, 2922.
(5) Sehested, M.; J ensen, P. B. Biochem. Pharmacol. 1996, 51, 879.
Binaschi, M.; Zagotto, G.; Palumbo, M.; Zunico, F.; Farinosi, R.; Carpanico,
G. Cancer Res. 1997, 57, 1710.
(6) J acquet, J . P.; Bouzard, D.; Remuzon, P. Tetrahedron Lett. 1993, 34,
823. Tokoroyama, T. J . Synth. Org. Chem. J pn. 1993, 51, 1164. Bailey, M.;
Marko, I. E.; Ollis, W. D.; Rasmussen, P. R. Tetrahedron Lett. 1990, 31,
4509. Bailey, M.; Staton, I.; Ashton, P. R.; Marko, I. E.; Ollis, W. D.;
Rasmussen, P. R. Tetrahedron Asymmetry 1991, 2, 495. Takao, K.; Aiba,
Y.; Ito, H.; Kobayashi, S. Chem. Lett. 1996, 931. Takao, K.; Kobayashi, S.
Tetrahedron Lett. 1997, 38, 6685.
(7) The resulting 1,3-butadienyl-2-carbinols are commonly used as Diels-
Alder dienes. For selected examples see: Wender, P. A.; Tebbe, M. J .
Synthesis 1991, 1089. Bloch, R.; Chaptal-Gradoz, N. J . Org. Chem. 1994,
59, 4162.
(8) Soundararajan, R.; Li, G.; Brown, H. C. J . Org. Chem. 1996, 61, 100.
S0022-3263(98)01331-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/12/1998

Communications
Sch em e 1. Tota l Syn th esis of Cler ocid in (1)a
J . Org. Chem., Vol. 63, No. 20, 1998 6775
sphere and Pd(0) catalysis13 gave rise to the R,â unsaturated
aldehyde 13 (88% yield). 9-BBN-mediated reduction14 of the
C18 aldehyde afforded allylic alcohol 14, which was protected
as the corresponding p-methoxybenzyl ether 15 (two steps,
74%). Fluoride-induced desilylation of 15, followed by PCC
oxidation of the resulting alcohol, yielded the desired alde-
hyde 5 (two steps, 89% yield) (Scheme 1).
The stage was now set for the construction of alcohol 4.
Thus, reaction of (L)-diisopropyl tartrate (DIPT) boronate 6
with aldehyde 5 (toluene, molecular sieves (4 Å MS), -78
°C, 72 h) afforded 4 in 83% yield and 6:1 ratio at C12 in
favor of the desired diastereomer.8,15 Sharpless asymmetric
epoxidation10 of the C13-C16 double bond, using (-) diethyl
tartrate (DET) as the chiral ligand, followed by silylation of
the C12 hydroxyl group gave rise to 17 via alcohol 16 (85%
yield). Conversion of 16 to the corresponding (S)- and (R)-
1
Mosher esters and subsequent H NMR analysis confirmed
the correct R-stereochemistry of the C12 hydroxyl group.16
Our attention was then focused on the dihydroxylation of
the terminal olefin of 17. This was accomplished by first
converting 17 to the R,â unsaturated aldehyde 18, which
upon dihydroxylation (1% (DHQD)2PHAL)11 afforded diol 19
in 67% yield over three steps (3:1 ratio at C14, in favor of
the indicated isomer). Swern oxidation of 19,17 followed by
in situ desilylation of the C12 silyl ether, gave rise to
synthetic clerocidin, which was isolated as its C14 methanol
adduct (20) upon methanolic workup (76% yield). Synthetic
20 exhibited identical spectroscopic and analytical data with
the natural compound. Compound 20 is known to exist in
equilibrium with 1,1 and its complete conversion to 1 was
accomplished by dissolving 20 in methylene chloride and
evaporating the solvent. Further evidence confirming the
structure of synthetic 1 was obtained by treating 1 with
o-phenylenediamine to produce the phthalazine adduct 21,
which also exhibited identical spectroscopic data to the one
derived from natural clerocidin.
In summary, the first total synthesis of clerocidin (1) has
been designed and executed in an enantioselective fashion.
The cornerstone of our strategy involves the use of asym-
metric homoallenylboration8 for the assembly of the clero-
cidin’s framework. Our strategy provides the first synthetic
application of this method and clearly demonstrates its
utility for the construction of complex 1,3-butadienyl-2-
carbinols. In addition, our synthesis proves unambiguously
the absolute stereochemistry of clerocidin (1) and should
allow access to a variety of potentially bioactive analogues.
a
Reagents and conditions: (a) 1 N HCl, THF, 25 °C, 2 h, 98%; (b)
1.1 equiv TIPSCl, 2.0 equiv imid, CH2Cl2, 25 °C, 2 h, 91%; (c) 1.5 equiv
NaHMDS, 2.0 equiv PhNTf2, THF, -78 °C, 1 h, 100%; (d) 10%
Pd(PPh3)4, CO, 3.0 equiv LiCl, 1.1 equiv Bu3SnH, THF, 50 °C, 4 h,
88%; (e) 1.05 equiv 9-BBN, THF, 0 °C, 2 h; MeOH, 10 equiv NaOH, 10
equiv H2O2, 89%; (f) 1.5 equiv NaH, 1.5 equiv PMBCl, 0.2 equiv of
(Bu4N)+I-, DMF, 25 °C, 6 h, 83%; (g) 1.5 equiv TBAF‚THF 25 °C, 2 h,
98%; (h) 1.5 equiv PCC/Celite, CH2Cl2, 25 °C, 1.5 h, 91%; (i) 2.0 equiv
6, toluene, MS, -78 °C, 72 h, 83% (71% de); (j) 0.25 equiv D-(-)-DET,
0.22 equiv Ti(iPrO)4, 2.0 equiv tBuOOH, MS, CH2Cl2, -20 °C, 88%
(86% de); (k) 1.1 equiv TESOTf, 2.0 equiv 2,6-lutid, CH2Cl2, 25 °C, 0.5
h, 97%; (l) 1.5 equiv DDQ, wet CH2Cl2, 25 °C, 3 h, 95%; (m) 1.3 equiv
Dess-Martin periodinane, 3.0 equiv pyrid, CH2Cl2, 25 °C, 4 h, 98%;
(n) 0.01 equiv (DHQD)2PHAL, 0.01 equiv K2OsO2(OH)4, 3.0 equiv
K3Fe(CN)6, 3.0 equiv K2CO3, tBuOH, H2O, 0 °C, 7 h, 72% (50% de); (o)
5.0 equiv (COCl)2, 8.0 equiv DMSO, CH2Cl2, -78 °C then 16 equiv
Et3N, 2 h, -78 °C to 25 °C then 1.5 equiv TBAF‚THF, MeOH, 25 °C,
1 h, 76%; (p) 2.0 equiv 1,2-phenylenediamine, CH3CN/H2O, 25 °C, 1
h, 73%.
Ack n ow led gm en t. This research was supported by the
Cancer Research Coordinating Committee, the Hellman
Foundation, the donors of the Petroleum Research Funds
administered by the American Chemical Society, and
Pfizer, Inc. (Undergraduate Research Fellowship to D.A.W.).
We also thank Dr. P. R. Rasmussen (Leo Pharmaceutical
Products, Denmark) and Dr. S. -Z. Kawada (Kyowa Hakko
Kogyo Co, J apan) for generously providing us a sample and
spectral data of natural clerocidin, respectively.
modification of the reported procedure.12 Acid-induced
deprotection of the C4 acetal, followed by silylation of the
C12 primary alcohol afforded 12 in 89% yield. Ketone 12
was then converted to the corresponding enol triflate, which
upon treatment with tributyltin hydride under CO atmo-
Su p p or tin g In for m a tion Ava ila ble: Selected experimental
procedures and spectral data for compounds 1, 4, 5, and 11-21
(28 pages).
J O981331L
(9) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J .; Park, J . C. J . Org. Chem.
1990, 55, 4109. Roush, W. R.; Hoong, L. K.; Palmer, M. A. J .; Straub, J . A.;
Parkowitz, A. D. J . Org. Chem. 1990, 55, 4117.
(10) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 5976.
(11) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483. Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995,
51, 1345.
(14) Krishnamurthy, S.; Brown, H. C. J . Org. Chem. 1977, 42, 2, 1197.
(15) Use of chiral substituents on the boron was indispensable for the
observed diastereoselectivity, since use of the isopropyl boronate yielded
alcohol 4 with complete scrambling of the stereochemistry at the C12 center,
while use of the (D)-DIPT boronate afforded preferentially 4 with the
unwanted stereoisomer at C12.
(12) Takahashi, S.; Kusumi, T.; Kakisawa, H. Chem Lett. 1979, 515. See
the Supporting Information for more details.
(13) Baillargeon, V. P.; Stille, J . K. J . Am. Chem. Soc. 1986, 108, 452.
(16) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am. Chem.
Soc. 1991, 113, 4092.
(17) See: Ireland, R. E.; Norbeck, D. W. J . Org. Chem. 1985, 50, 2198.