Studies aimed at the total synthesis of the antitumor antibiotic cochleamycin A. An enantioselective biosynthesis-based pathway to the AB bicyclic core

Article abstract of DOI:10.1021/ol0102592

Chemical equation presented A convergent, highly enantioselective synthesis of the fully functionalized AB sector of cochleamycin A is described. A pair of building blocks, crafted from L-malic and L-ascorbic acids, are conjoined in a manner that gives ri

Full text of DOI:10.1021/ol0102592

ORGANIC
LETTERS
2002
Vol. 4, No. 2
253-256
Studies Aimed at the Total Synthesis of
the Antitumor Antibiotic Cochleamycin
A. An Enantioselective
Biosynthesis-Based Pathway to the AB
Bicyclic Core
Jiyoung Chang and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received November 5, 2001
ABSTRACT
A convergent, highly enantioselective synthesis of the fully functionalized AB sector of cochleamycin A is described. A pair of building
blocks, crafted from L-malic and L-ascorbic acids, are conjoined in a manner that gives rise to an (E,Z,E)-1,6,8-nonatriene. On heating, the
latter undergoes stereocontrolled intramolecular Diels−Alder cyclization via an endo transition state.
During the period 1992-1996, a team headed by Shindo
and Kawai reported on the isolation and characterization of
a small family of architecturally novel antitumor antibiotics
named cochleamycins.1 The structures and relative stereo-
chemistries of these compounds were ascertained by mass
spectrometry and a battery of NMR spectroscopic techniques.
Of these, cochleamycin A (1) demonstrated the highest level
of cytotoxicity against P388 leukemia cells, with an IC50 of
1.2 µg/mL. Good antimicrobial activity against Gram-positive
bacteria was also uncovered.1 Independent investigations by
Abbott researchers led almost simultaneously to the discovery
of the macquarimicins.2,3 Like 1, these unique microbial
metabolites feature a cis-tetrahydroindane AB part structure
fused to a 10-membered carbocyclic ketone that is bridged
in turn with lactone functionality to set the CD ring assembly.
In neither series is the absolute configuration yet established.
In light of our longstanding interest in the construction of
biologically active natural products characterized by bridge-
head unsaturation4 and the clinical potential of 1, we have
been led to undertake its total synthesis.5 Retrosynthetically,
the intent was to utilize an intramolecular Diels-Alder
(2) (a) Jackson, M.; Karwowski, J. P.; Theriault, R. J.; Rasmussen, R.
R.; Hensey, D. M.; Humphrey, P. E.; Swanson, S. J.; Barlow, G. J.;
Premachandran, U.; McAlpine, J. B. J. Antibiot. 1995, 48, 462. (b)
Hochlowski, J. E.; Mullally, M. M.; Henry, R.; Whitern, D. M.; McAlpine,
J. B. J. Antibiot. 1995, 48, 467.
(3) For a more recent report disclosing inhibitory activity against
membrane-bound neutral sphingomyclinase from rat brain, consult: Tanaka,
M.; Nara, F.; Yamasao, Y.; Masuda-Inoue, S.; Doi-Yoshioka, H.; Kumaura,
S.; Enokita, R.; Ogita, T. J. Antibiot. 1999, 52, 670.
(1) (a) Shindo, K.; Kawai, H. J. Antibiot. 1992, 45, 292. (b) Shindo, K.;
Matsuoka, M.; Kawai, H. J. Antibiot. 1996, 49, 241. (c) Shindo, K.; Iijima,
H.; Kawai, H. J. Antibiot. 1996, 49, 244. (d) Shindo, K.; Sakakibara, M.;
Kawai, H. J. Antibiot. 1996, 49, 249.
(4) Paquette, L. A. Chem. Soc. ReV. 1995, 24, 9.
(5) A group headed by Tadano has recently disclosed their preliminary
studies toward the synthesis of the macquarimicins: Munakata, R.; Ueki,
T.; Katakai, H.; Takao, K.; Tadano, K. Org. Lett. 2001, 3, 3029.
10.1021/ol0102592 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/19/2001

cycloaddition for construction of the AB ring system in line
with the proposed biosynthesis1c (Scheme 1). Initial dis-
Scheme 2a
Scheme 1
a Reagents and conditions: (a) PMBBr, NaH, DMF (100%); (b)
HOAc, H2O, THF (1:1:1), 50-60 °C (92%); (c) PivCl, pyr, CH2Cl2
(91%); (d) CH3SO2Cl, DMAP, pyr, CH2Cl2 (97%); (e) K2CO3,
MeOH (89%); (f) O3, EtOAc, -78 °C, then Ph3P; (g) NaBH4,
MeOH, 0 °C; (h) PivCl, pyr, CH2Cl2 (77% for 3 steps); (i)
HCtCSiMe3, n -BuLi, BF3‚OEt2, THF, -78 °C; (j) (n-Bu)4NF,
THF, 0 °C (95% for 2 steps); (k) DDQ, 4 Å MS, CH2Cl2 (85%);
(l) (n-Bu)3SnH, AIBN, C6H6, ∆ (99%); (m) I2, CH2Cl2 (96%).
connection of 1 at the site of its “anti-Bredt” double bond
was visualized, thereby targeting aldehyde 2 as an advanced
intermediate. Construction of the carbocyclic network in 2
was viewed likely to be feasible by stereoselective [4 + 2]
cycloaddition within the (E,Z,E)-1,6,8-nonatriene 3.6 A key
consideration in this scenario was adherence by 3 to
appropriate transition state geometry (see below). Ultimately,
triene 3 would arise by Sonogashira coupling of 4 to 5 and
subsequent semi-hydrogenation of the alkyne link to secure
the Z-double bond geometry.
Synthesis of vinyl iodide 4 began with the four-step
conversion of L-(-)-malic acid to the hydroxy acetal 6
according to established precedent7 (Scheme 2). Protection
of the secondary hydroxyl as the p-methoxybenzyl ether8
and acidic hydrolysis of acetonide 7 furnished diol 8 in 92%
yield for the two steps. Following chemoselective pivaloyl-
ation9 to generate 9, an epoxide ring was installed10 as in
10. Subsequent double bond cleavage via ozonolysis and
accompanying reductive workup could be accomplished
without excessive intramolecular cyclization. The product
composition was defined to be 54% of 11 and 23% of 12
after esterification. The conversion of chromatographically
purified major product 11 to 13 entailed highly regioselective
nucleophilic opening of the oxirane with lithium trimethyl-
silylacetylide with subsequent fluoride ion-induced desilyl-
ation.11 This result allowed for DDQ-promoted oxidative
cyclization8c,12 to deliver 14 efficiently. This alkyne, the
configuration of which was ascertained by NOESY tech-
(6) For recent examples of intramolecular Diels-Alder reactions involv-
ing (E,Z,E)-trienes, see: (a) Back, T. G.; Nava-Salgado, V. O.; Payne, J.
E. J. Org. Chem. 2001, 66, 4361. (b) Back, T. G.; Payne, J. E. Org. Lett.
1999, 1, 663. (c) Diedrich, M. K.; Kla¨rner, F.-G. J. Am. Chem. Soc. 1998,
120, 6212. (d) Review: Roush, W. R. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, pp 513-550.
(7) (a) Carman, R. M.; Karoli, T. Aus. J. Chem. 1998, 51, 995. (b) Mori,
K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35, 933. (c) Steel, P. G.;
Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1997, 371. (d) Rodriguez, E.
B.; Scally, G. D.; Stick, R. V. Aust. J. Chem. 1990, 43, 1391. (e) Hayashi,
H.; Nakanishi, K.; Brandon, C.; Marmur, J. J. Am. Chem. Soc. 1973, 95,
8749.
(9) (a) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453. (b) Takao,
K.; Ochiai, H.; Yoshida, K.; Hashizuka, T.; Koshimura, H.; Tadano, K.;
Ogawa, S. J. Org. Chem. 1995, 60, 8179.
(10) McGarvey, G. J.; Mathys, J. A.; Wilson, K. J. J. Org. Chem. 1996,
61, 5704.
(11) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391. (b)
Mukai, C.; Kim, J. S.; Uchiyama, M.; Sakamoto, S.; Hanaoka, M. J. Chem.
Soc., Perkin Trans. 1 1998, 2903. (c) Sinha, A.; Sinha, S. C.; Sinha, S. C.;
Keinan, E. J. Org. Chem. 1999, 64, 2381. (d) Kittaka, A.; Suhara, Y.;
Takayanagi, H.; Fujishima, T.; Kurihara, M.; Takayama, H. Org. Lett. 2000,
2, 2619.
(8) (a) Ruder, S. M.; Ronald, R. C. Tetrahedron Lett. 1987, 28, 135. (b)
Nakata, M.; Ishiyama, T.; Hirose, Y.; Maruoka, H,; Tatsuta, K. Tetrahedron
Lett. 1993, 34, 8439. (c) Kochetkov, N. K.; Sviridov, A F.; Ermolenko, M.
S.; Yashunsky, D. V.; Borodkin, V. S. Tetrahedron 1989, 45, 5109.
254
Org. Lett., Vol. 4, No. 2, 2002

niques, was readily converted to the (E)-vinylstannane 15
by reaction with tri-n-butyltin hydride and AIBN in refluxing
benzene.13 Equal success was enjoyed in the generation of
iodide 4,14 quantities of which were made available in
enantiopure form by this pathway.
reduction and acetylation. Following chemoselective de-
silylation and oxidation with iodoxybenzoic acid (IBX),19
the resulting aldehyde was homologated via the Corey-
Fuchs protocol.20 Terminal alkyne 5 was formed in 88% yield
for the two steps.
Acquisition of the second cross-coupling partner took early
advantage of the readiness with which L-ascorbic acid can
be transformed into butenolide 1615 (Scheme 3). In line with
The crucial Sonagashira coupling of 4 with 5 was most
successfully implemented with Pd(PPh3)2Cl2 and CuI in
triethylamine as solvent13a,21 (Scheme 4). The clean semi-
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) (CH3)2CuLi, ether, THF, -30 °C
(89%); (b) (i-Bu)2AlH, CH2Cl2, -78 °C; (c) Ph3PdCHCO2Me,
C6H6, ∆ (100% for 2 steps); (d) PMBOC(dNH)CCl3, CSA, CH2Cl2;
(e) (i-Bu)2AlH, CH2Cl2, -78 °C (60% for 2 steps); (f) Ac2O,
DMAP, pyr, CH2Cl2 (97%); (g) (n-Bu)4NF, THF, 0 °C (100%);
(h) IBX, THF/DMSO (9:1) (90%); (i) CBr4, Ph3P, CH2Cl2, -78
°C (98%); (j) n-BuLi, THF, -78 °C (90%).
expectation,16 the conjugate addition of lithium dimethyl-
cuprate to 16 proceeded to deliver the trans adduct 17
exclusively in 89% yield. Reduction to the lactol was
followed by Wadsworth-Emmons chain extension11c,17 to
provide the E-configured open-chain R,â-unsaturated ester
with unequivocally established relative and absolute con-
figuration at the δ- and ꢀ-positions. Protection of the hydroxyl
group in 18 was accomplished via the trichloroacetimidate,18
thereby making it possible to advance to 21 via Dibal-H
a Reagents and conditions: (a) Pd(PPh3)2Cl2, CuI, Et3N (82%);
(b) H2, Lindlar catalyst, EtOAc/pyr/1-octene (10:1:1) (95%); (c)
IBX, THF/DMSO (9:1) (85%); (d) 20% BHT, toluene, sealed tube,
195 °C, 26 h; (e) NaBH4, MeOH, 0 °C (66% for 2 steps).
hydrogenation of the triple bond in 23 proved to be
challenging. Irrespective of whether catalytic quantities or
several molar equivalents of quinoline were present, mixtures
of 24 and 25 were formed. The use of 1-octene as a cosolvent
likewise did not effectively curtail the production of 25. Also,
reaction times in excess of 1 day were required. Ultimately,
recourse was made to a compromise position involving the
(12) Tsuboi, K.; Ichikawa, Y.; Jiang, Y.; Naganawa, A.; Isobe, M.
Tetrahedron 1997, 53, 5123.
(13) (a) Izzo, I.; De Caro, S.; De Riccardis, F.; Spinella, A. Tetrahedron
Lett. 2000, 41, 3975. (b) Otaka, K.; Mori, K. Eur. J. Org. Chem. 1999,
1795. (c) Deng, Y.; Salomon, R. G. J. Org. Chem. 2000, 65, 6660.
(14) (a) Drouet, K. E.; Theodorakis, E. A. Chem. Eur. J. 2000, 6, 1987.
(b) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935. (c)
Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738.
(15) (a) Andrews, G. C.; Crawford, T. C.; Bacon, B. E. J. Org. Chem.
1981, 46, 2976. (b) Hubschwerlen, C. Synthesis 1986, 962. (c) Fazio, F.;
Schneider, M. P. Tetrahedron: Asymmetry 2000, 11, 1869.
(16) Hanessian, S.; Murray, P. J. Tetrahedron 1987, 43, 5055.
(17) (a) Van Hijfte, L.; Little, R. D.; Petersen, J. L.; Moeller, K. D. J.
Org. Chem. 1987, 52, 4647. (b) Mehta, G.; Mohal, N. Tetrahedron Lett.
1999, 40, 5791. (c) Agyei-Aye, K.; Baker, D. C. Carbohydr. Res. 1988,
183, 261. (d) Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J.; Coffen,
D. L. J. Org. Chem. 1988, 53, 4780. (e) Sinha, S. C.; Sinha, S. C.; Keinan,
E. J. Org. Chem. 1999, 64, 7067.
(19) (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J.
Org. Chem. 1995, 60, 7272. (b) Frigerio, M.; Santagostino, M. Tetrahedron
Lett. 1994, 35, 8019.
(20) (a) Critcher, D. J.; Connolly, S.; Wills, M. J. Org. Chem. 1997, 62,
6638. (b) Horita, K.; Oikawa, Y.; Nagato, S.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 5143. (c) Mukai, C.; Kim, J. S.; Sonobe, H.; Hanaoka, M.
J. Org. Chem. 1999, 64, 6822. (d) Gonza´lez, I. S.; Forsyth, C. J. Org. Lett.
1999, 1, 319.
(18) (a) Nakata, M.; Ishiyama, T.; Akamatsu, S.; Hirose, Y.; Maruoka,
H.; Suzuki, R.; Tatsuta, K. Bull. Chem. Soc. Jpn. 1995, 68, 967. (b) Kawata,
S.; Yoshimura, F.; Irie, J.; Ehara, H.; Hirama, M. Synlett 1997, 250.
(21) (a) Yu, Q.; Wu, Y.; Ding, H.; Wu, Y.-L. J. Chem. Soc., Perkin
Trans. 1 1999, 1183. (b) Madec, D.; Fe´re´zou, J.-P. Tetrahedron Lett. 1997,
38, 6661.
Org. Lett., Vol. 4, No. 2, 2002
255

use of 10:1:1 ethyl acetate/pyridine/1-octene as the reaction
medium.5,22 These conditions gave rise to a 1.7-1.9:1
mixture of 24 and 25 (ES MS analysis) in 95% yield after
only 5.5 h. Since these carbinols coeluted during attempted
chromatographic separation, they were carried in admixed
form through a three-step sequence involving sequential IBX
oxidation, thermal activation in toluene at 195 °C, and
reduction with methanolic sodium borohydride. While al-
dehyde 3 derived from 24 underwent smooth intramolecular
Diels-Alder cycloaddition, the oversaturated congener did
not share in this capability and did not enter into cyclization.
The bicyclic product detected following careful chromatog-
raphy proved to be 26 (66% from 24),23 the relative (and
absolute) stereochemistry of which was elucidated by
NOESY measurements (see formula).
This excellent π-facial stereoselection, when compared with
the results of Tadano,5 supports the working assumption that
the extent of destabilization depends on the steric require-
ments of the interlinking tetrahedral carbons and their
substituents.
An (E,Z,E)-1,6,8-nonatriene such as 3 was expected
on the basis of precedent to cyclize via an endo transition
state, of which only two are possible as defined in A and
B.5,6d,24
In conclusion, the studies reported herein serve to chart
an approach to cochleamycin A that is based on the effective
use of an intramolecular Diels-Alder reaction to set all six
stereogenic centers resident in rings A and B in their proper
configuration. Current investigations are underway to de-
termine if 26 can indeed serve as a suitable precursor to 1.
The two options differ significantly in the level of
nonbonded steric interaction that must necessarily be faced
in order for diene-dienophile linkup to materialize. In A, the
methyl and OPMB substituents are projected into the region
necessarily reserved for proper positioning of the diene unit,
thereby disfavoring this arrangement. Since this level of
proximity is completely avoided in B, this transition state is
adopted in wholesale fashion and generates exclusively 27.
Acknowledgment. This research was financed by an
unrestricted grant from Aventis Pharmaceuticals.
(22) (a) Nicolaou, K. C.; Ladduwahetty, T.; Taffer, I. M.; Zipkin, R. E.
Synthesis 1986, 344. (b) Overman, L. E.; Thompson, A. S. J. Am. Chem.
Soc. 1988, 110, 2248.
(23) While this cycloadduct could not be readily separated from minor
nonisomeric impurities, it could be readily characterized as 26 on the basis
of confirmatory 1D and 2D NMR measurements. Alternate means for
producing 26 are currently under investigation.
Supporting Information Available: Experimental pro-
1
cedures and spectroscopic characterization (IR, H and 13C
NMR, HRMS) of all key compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) Ciganek, E. Org. React. 1984, 32, 1.
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