Total synthesis of Lucilactaene, a cell cycle inhibitor active in p53-inactive cells

Article abstract of DOI:10.1021/ja056217g

Hetero-bis-metalated 1,3-butadiene is employed in the lynchpin coupling of synthetic fragments of the side chain of the antitumor agent, lucilactaene. Sequential Stille and Suzuki-Miyaura couplings interpolate this unique boron/tin diene into the pentaene

Full text of DOI:10.1021/ja056217g

Published on Web 10/27/2005
Total Synthesis of Lucilactaene, A Cell Cycle Inhibitor Active in p53-Inactive
Cells
Robert S. Coleman,* Matthew C. Walczak, and Erica L. Campbell
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue, Columbus, Ohio 43210-1185
Received September 9, 2005; E-mail: coleman@chemistry.ohio-state.edu
Fungi of the genus Fusarium have been a rich source of
biologically active natural products. In 2001, Osada and co-workers1
reported the isolation of lucilactaene (1) from a strain of Fusarium
and demonstrated this cytotoxic natural product induced cell cycle
to arrest in a p53-independent manner in cells possessing a
temperature-sensitive p53 protein.2 Lucilactaene is related to other
Fusarium natural products, including epolactaene,3 fusarins A,4 C,5
D,6 and F,7 L-755,807,8 and NG-391,9 which possess a γ-lactam
nucleus with a polyunsaturated side chain. Hayashi and co-workers
demonstrated that lucilactaene occurs naturally as the racemate by
synthesis of 1 from NG-391 in seven steps (3.7% overall).10
stereocontrolled reaction sequence. Regioselective anti-hydrostan-
nylation19 followed by in situ iododestannylation of the resulting
vinylstannane (I2, CCl4, -10 °C, 10 min) provided allylic alcohol
9, predominantly as the Z-isomer (96:4 Z/E). Palladium-promoted
coupling of propynylmagnesium bromide and the vinylic iodide of
9 (THF, 50 °C, 4 h)20 afforded enyne 10. Syn-selective silylcupra-
tion21 of the alkyne triple bond in the presence of water to effect
protonolysis of the intermediate vinylcuprate (-10 °C, 3 h) provided
silyldiene 11 as a separable mixture of stereoisomers (85:15). Corey-
Ganem oxidation22 of 11 afforded methyl dienoate 12. Subsequent
iododesilylation of 12 (2,6-lutidine, (CF3)2CHOH, -10 °C, 90 s)23
installed the C5 iodide to afford the target 7.
The tumor suppressor gene p53 is mutated and inactive in many
human tumors.11 This gene normally controls cell cycle progression
and is responsible for a wide variety of processes that are critical
for maintenance of cell integrity, including apoptosis and DNA
repair.12 In programmed cell death, p53 provides a key link between
nuclear damage and mitochondrial release of further signaling
molecules. In cells lacking functional p53, control of cell division
is lost, and such cells are often resistant to chemotherapy because
of defects in the damage-induced apoptotic pathway due to lack of
p53 function.13 Agents that reestablish or mimic p53 function could
be useful in cancer therapy by restoring the normal apoptotic p53
response to DNA damage.14
Our strategy for the synthesis of lucilactaene was formulated to
achieve maximum convergence. Late-stage conjugate addition of
the primary alcohol of 3 would form the tetrahydrofuran ring. Under
thermodynamic control, this reaction should provide the more stable
cis-fused ring system with the pentaenone side chain in the pseu-
doequatorial position. The 2-hydroxyethyl side chain of 3 would
arise from the alkene of 4, the product of allylation of an N-pro-
tected iodomaleimide. Introduction of the pentaene side chain would
rely on a convergent series of cross-coupling reactions between
olefin partners 5, 6, and 7. Cuprate-coupling15 between C12 of acid
chloride 5 and C13 of iodide 4 would effect ketone installation;
Stille coupling16 of dienyl iodide 7 with the C6 vinyl stannane of
the dissymmetrically substituted bis-metalated 1,3-butadiene 617
would serve as a linchpin in the assembly of the terminal tetraene
fragment of 3; Suzuki-Miyaura coupling18 of the C9 vinyl boronate
of 6 with C10 of vinyl bromide 5 will accomplish construction of
the C1-C12 pentaene side chain. The synthesis of 1 would result
from an orchestrated series of sp2-sp2 bond formation events within
a triply convergent synthetic strategy [(6 + 7) + (4 + 5)]. Herein,
we report the total synthesis of lucilactaene.
The heterocyclic fragment 20 was synthesized in high yield from
bromomaleimide (16).24 Protection of the imide nitrogen with the
trimethylsilylethoxymethyl (SEM) group25 (i-Pr2NEt, DMF, -45
°C, 3 h) afforded 17. Bromide to iodide conversion (5 equiv of
NaI, acetone, reflux, 12 h) quantitatively afforded protected
iodomaleimide 18. Regioselective allylation of the carbonyl distal
to the iodine was achieved using allylindium in DMF (-15 °C, 3
days)26 to afford 19 as a separable 8:1 mixture of regioisomers.
Ozonolysis of the terminal alkene (O3, CH2Cl2, -78 °C) and
reduction of the ozonide with sodium borohydride (CH2Cl2/MeOH,
0 °C, 2 h) afforded the corresponding diol, which was protected as
the bis-triethylsilyl ether (2,6-lutidine, CH2Cl2, -45 to 25 °C, 2 h)
to provide 20 in five steps (55% overall) from bromomaleimide.
The C1-C5 terminal dienoate fragment 7 was synthesized in
five steps (36% overall) from 2-butyn-1-ol (8) by an efficient and
9
16038
J. AM. CHEM. SOC. 2005, 127, 16038-16039
10.1021/ja056217g CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
20 + acid chloride 5) + (diene 6 + diene 7)] will allow for efficient,
modular preparation of related agents for mechanistic evaluation.
Connection of the pyrroline core with the C12 acyl group of 5
was achieved using a cuprate/acid chloride coupling.15 Formation
of Grignard reagent 21 occurred upon reaction of iodide 20 with
isopropylmagnesium chloride (THF, -60 °C, 20 min); transmeta-
lation to the corresponding cuprate 22 occurred upon treatment with
cuprous cyanide (-40 °C, 20 min). Reaction of cuprate 22 with
acid chloride 527 (-40 °C, 1 min) achieved formation of the
C12-C13 bond and provided â-bromoenone 23 in good yield
(65%). Compound 23 was the result of six synthetic transformations
(36% overall) from bromomaleimide.
Acknowledgment. This work was supported by a grant from
the National Cancer Institute (NIH CA91904).
Supporting Information Available: Experimental procedures and
characterization of compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Kakeya, H.; Kageyama, S.-I.; Nie, L.; Onose, R.; Okada, G.; Beppu, T.;
Norbury, C. J.; Osada, H. J. Antibiot. 2001, 54, 850.
(2) Winters, Z. E.; Ongkeko, W. M.; Harris, A. L.; Norbury, C. J. Oncogene
1998, 17, 673.
(3) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada, H. J. Antibiot.
1995, 48, 733.
(4) Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Chem. Commun. 1985, 17, 1189.
(5) Gelderblom, W. C. A.; Marasas, W. F. O.; Steyn, P. S.; Thiel, P. G.; van
der Merwe, K. J.; van Rooyen, P. H.; Vleggaar, R.; Wessels, P. L. J.
Chem. Soc., Chem. Commun. 1984, 122.
(6) Gelderblom, W. C. A.; Thiel, P. G.; Van der Merwe, K. J. Food Chem.
Toxicol. 1988, 26, 31-6.
(7) Savard, M. E.; Miller, J. D. J. Nat. Prod. 1992, 55, 64.
(8) Lam, Y. K. T.; Hensens, O. D.; Ransom, R.; Giazobbe, R. A.; Polishook,
J.; Zink, D. Tetrahedron 1996, 52, 1481.
(9) Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839.
(10) Yamaguchi, J.; Kakeya, H.; Uno, T.; Shoji, M.; Osada, H.; Hayashi, Y.
Angew. Chem., Int. Ed. 2005, 44, 3110.
(11) (a) Slee, E. A.; O’Connor, D. J.; Lu, X. Oncogene 2004, 23, 2809. (b)
Hofseth, L. J.; Hussain, S. P.; Harris, C. C. Trends Pharmacol. Sci. 2004,
25, 177. (c) Levine, A. J.; Finlay, C. A.; Hinds, P. W. Cell 2004, 116,
S67-S69. (d) Ja¨a¨ttela¨, M. Oncogene 2004, 23, 2746.
(12) Norbury, C. J.; Zhivotovsky, B. Oncogene 2004, 23, 2797.
(13) Gasco, M.; Crook, T. Drug Resist. Updates 2003, 6, 323.
(14) Wang, W.; Rastinejad, F.; El-Deiry, W. S. Cancer Biol. Ther. 2003, 2,
S55.
Two reasonable options existed for the ordering of the final
alkene couplings as a consequence of the necessary connections
between both C5-C6 and C9-C10: [diene 6 + diene 7] + enone
23 or [enone 23 + diene 6] + diene 7. Chemoselective Stille
coupling of the vinylstannane of 628 with the vinyl iodide of 7 was
achieved using triphenylarsine as the ligand for palladium (DMF,
25 °C, 18 h), and tetraene 24 was obtained in good yield. Tetraene
24 is six steps from 2-butyn-1-ol (29% overall).
(15) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn,
T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
(16) (a) Stille, J. K.; Milstein, D. J. Am. Chem. Soc. 1978, 100, 3636. (b) Stille,
J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (c) Mitchell, T. N.
Synthesis 1992, 803. (d) Farina, V. Pure Appl. Chem. 1996, 68, 73. (e)
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(17) Coleman, R. S.; Walczak, M. C. Org. Lett. 2005, 7, 2289.
(18) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Stanforth, S.
P. Tetrahedron 1998, 54, 263. (c) Suzuki, A. J. Organomet. Chem. 1999,
576, 147.
(19) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982, 47, 404.
(20) (a) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini, P.
Tetrahedron 1998, 54, 135. (b) White, J. D.; Hanselmann, R.; Wardrop,
D. J. J. Am. Chem. Soc. 1999, 121, 1106.
Formation of the C9/C10 carbon-carbon bond by Suzuki-
Miyaura coupling18 of the vinyl boronate of tetraene 24 with the
vinyl bromide of pyrrolinone 23 afforded pentaene 25, completing
construction of the lucilactaene framework. Final treatment of 25
with trifluoroacetic acid (25 °C, 5 h) effected removal of the silyl
ethers and nitrogen protecting group, with concomitant conjugate
addition of the primary alcohol, and afforded lucilactaene (1).
The synthesis of the Fusarium metabolite lucilactaene was
achieved using a synthetic approach that is a significant departure
from existing work in the field with respect to methodology,
strategy, and synthetic efficiency.10,29 The synthesis of 1 was
achieved in eight linear steps and 17 total synthetic operations in
19% overall yield from commercially available compounds. The
convergent nature of this synthetic route wherein three organome-
tallic-based cross-coupling reactions of the four fragments [(iodide
(21) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc., Perkin Trans. 1
1981, 2527.
(22) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968, 90,
5616.
(23) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125,
7822.
(24) Nicolaus, R. A.; Nicoletti, R. Rend. Acad. Sci. Fis. Mater. (Soc. Nazl.
Sci., Napoli) 1959, 26, 148.
(25) Saito, S.; Nuckolls, C.; Rebek, J., Jr. J. Am. Chem. Soc. 2000, 122, 9628.
(26) Podlech, J.; Maier, T. C. Synthesis 2003, 633.
(27) Dzierba, C. D.; Zandi, K. S.; Mo¨llers, T.; Shea, K. J. J. Am. Chem. Soc.
1996, 118, 4711.
(28) 1,3-Butadiene 6 was prepared in 76% overall yield from propargyl
aldehyde diethyl acetal by stannylcupration and Takai olefination; see ref
17.
(29) (a) Hayashi, Y.; Narasaka, K. Chem. Lett. 1998, 313. (b) Hayashi, Y.;
Kanayama, J.; Yamaguchi, J.; Shoji, M. J. Org. Chem. 2002, 67, 9443.
(c) Kuramochi, K.; Nagata, S.; Itaya, H.; Matsubara, Y.; Sunoki, T.;
Uchiro, H.; Takao, K.-I.; Kobayashi, S. Tetrahedron 2003, 59, 9743.
JA056217G
9
J. AM. CHEM. SOC. VOL. 127, NO. 46, 2005 16039