Synthetic studies aimed at (-)-cochleamycin A. Evaluation of late-stage macrocyclization alternatives

Article abstract of DOI:10.1021/jo049084a

An efficient route to the fully functionalized ABC ring systems of the unnatural enantiomer of cochleamycin A was developed. L-(-)-Malic and L-(-)-ascorbic acids served well as starting materials for the two building blocks used to construct an (E,Z,E)-1,

Full text of DOI:10.1021/jo049084a

Syn th etic Stu d ies Aim ed a t (-)-Coch lea m ycin A. Eva lu a tion of
La te-Sta ge Ma cr ocycliza tion Alter n a tives
Leo A. Paquette,* J iyoung Chang, and Zuosheng Liu
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received J une 1, 2004
An efficient route to the fully functionalized ABC ring systems of the unnatural enantiomer of
cochleamycin A was developed. L-(-)-Malic and L-(-)-ascorbic acids served well as starting materials
for the two building blocks used to construct an (E,Z,E)-1,6,8-nonatriene intermediate. The AB
part structure was assembled by way of a stereocontrolled intramolecular Diels-Alder cycloaddition
via adoption of an endo transition state. From this vantage point, two general pathways were
subsequently explored as to their suitability for elaboration of the CD rings. Initially examined
was a protocol involving 10-membered carbocycle construction. When this approach was demon-
strated not to be workable, attention was directed to 10-membered macrolactonization as an
alternative tactic. Although assembly of the C-ring in this manner was easily achieved, ultimate
closure of the six-membered ring to form ring D remains an unsolved problem.
In 1992, Shindo and Kawai reported from the Kirin
Brewery Co. the discovery of a small group of novel
antibiotics, chief among which was cochleamycin A (1).1
Interest in this substance grew as its appreciable anti-
tumor and antimicrobial properties came to be known.2
Detailed NMR studies indicated its ring system to consist
of a fused 5-6-10-6 tetracyclic core. The assignment
of the relative configuration was initially made possible
at that time. Only in mid-2003 was the absolute config-
uration of 1 established as that shown in the illustrated
formula.3 The source of cochleamycin A was a soil sample
collected in Aomori, J apan. Almost simultaneously, Ab-
bott scientists succeeded in isolating from strains of
Micromonospora chalcea several metabolites, the prin-
cipal component of which was defined as 2 by X-ray
analysis and called macquarimicin A.4 The cytotoxic
properties of 2 and its ability to serve as a selective
inhibitor of membrane-bound neutral sphingomyelinase
have been well documented.5 Still more recently, an-
nouncements have emerged of the isolation and charac-
cochleamycin A was initiated in this laboratory.8 Herein,
we detail this early effort together with a comparative
terization of the closely related cytotoxic agents hexacy-
clinic acid (3)6 and FR182877 (4).7
evaluation of more advanced end-game macrocyclization
Several years ago when the absolute configuration of
strategies targeting (-)-1. This enantiomer is antipodal
1 was still unknown, an enantioselective synthesis of
to the natural material. Impressive independent routes
to (+)-1 have recently been reported by Tatsuta and co-
(1) Shindo, K.; Kawai, H. J . Antibiot. 1992, 45, 292.
(2) (a) Shindo, K.; Matsuoka, M.; Kawai, H. J . Antibiot. 1996, 49,
workers and by the Roush group.3 These accomplish-
241. (b) Shindo, K.; Iijima, H.; Kawai, H. J . Antibiot. 1996, 49, 244.
ments define the three-dimensional structure of the
cochleamycins. Finally, attention is called to the elegant
completed total syntheses of 2 by Tadano9 and of 4 in
the hands of Evans10 and Sorensen.11
(c) Shindo, K.; Sakakibara, M.; Kawai, H.; Seto, H. J . Antibiot. 1996,
49, 249.
(3) (a) Tatsuta, K.; Narazaki, F.; Kashiki, N.; Yamamoto, J .; Nakano,
S. J . Antibiot. 2003, 56, 584. (b) Dineen, T. A.; Roush, W. R. Org. Lett.
2004, 6, 2043.
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Premachandran, U.; McAlpine, J . B. J . Antibiot. 1995, 48, 462. (b)
Hochlowski, J . E.; Mullally, M. M.; Henry, R.; Whittern, D. M.;
McAlpine, J . B. J . Antibiot. 1995, 48, 467.
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Yoshioka, H.; Kumakura, S.; Enokita, R.; Ogita, T. J . Antibiot. 1999,
52, 670.
Retr osyn th etic P er cep tion s. Despite the presence
of bridgehead unsaturation in 1,12 we envisioned that the
(7) (a) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.;
Hino, M.; Hashimoto, S.; Terano, H. J . Antibiot. 2000, 53, 123. (b) Sato,
B.; Nakajima, H.; Hori, Y.; Hino, M.; Hashimoto, S.; Terano, H. J .
Antibiot. 2000, 53, 204. (c) Yoshimura, S.; Sato, B.; Kinoshita, T.;
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39, 3258.
(8) Chang, J .; Paquette, L. A. Org. Lett. 2002, 4, 253.
10.1021/jo049084a CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/24/2004
J . Org. Chem. 2004, 69, 6441-6448
6441

Paquette et al.
SCHEME 1
SCHEME 2
intramolecular [4 + 2] cycloaddition via a single low-
energy endo-transition-state arrangement.19 Encourag-
ingly, the two available options (see A and B in Scheme
2) were seen to differ significantly in the levels of
nonbonded steric interaction (particularly A1,3 strain) that
builds up as C-C bond formation progresses. 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 skirted in B, the
latter transition state was expected to be adopted with
exclusive formation of 7.
To implement this plan, 8 was to be generated by the
Sonagashira coupling20 of 9 to 10, followed by semihy-
drogenation of the alkyne link to secure the Z double
bond geometry. The latent functionality in 8 was to be
exploited as well by macrolactonization of hydroxy acid
12 (Scheme 3). For the macrocyclization pathway, reduc-
tive cyclization of bromo lactone 11 with intramolecular
displacement involving a Weinreb amide side chain11 or
aldehyde capture would establish the final C-C bond
connection. Although the unnatural enantiomer was
targeted, the strategy outlined herein is, of course, also
viable for the dextrorotatory form with only minor
modification.
tetrahydroindane 7 might serve well as a common
advanced intermediate along two reasonably flexible
pathways involving different approaches to medium-ring
construction. In the first (Scheme 1), the focus of atten-
tion was to be directed toward elaboration of the car-
bocyclic 10-membered subunit that was destined to
become rings C and D of the target. This goal was
expected to be realized by structural modification of both
pendant chains as illustrated in 6.13,14 Cyclization by
either the Nozaki-Hiyama-Kishi protocol15 or samarium
iodide-mediated ring closure would follow.16 The continu-
ation of this analysis requires a viable route from 6 to
an R-iodo enone as typified by 5,17 the carbonylation of
which in the presence of an appropriate transition metal18
would generate the complete ABCD framework.
A key consideration in this scenario was the requisite
participation of the (E,Z,E)-1,6,8-nonatriene 8 in an
(9) (a) Munakata, R.; Hatakai, H.; Ueki, T.; Kurosaka, J .; Takao,
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6442 J . Org. Chem., Vol. 69, No. 19, 2004

Sythetic Studies Aimed at (-)-Cochleamycin A
SCHEME 3
alate 16 made possible generation of the terminal epoxide
ring resident in 17.24 Ozonolytic cleavage of the double
bond in 17 could, under properly controlled conditions,
be accomplished without excessive intramolecular cy-
clization. For convenience, the aldehydes so formed were
sequentially reduced with sodium borohydride and es-
terified with pivaloyl chloride. At this point, the product
composition could be readily defined as 54% 18 and 23%
19 after chromatographic separation.
Highly regioselective nucleophilic opening of the ox-
irane ring in purified 18 with lithium trimethylsily-
lacetylide and subsequent fluoride ion-induced desilyla-
tion25 provided carbinol 20, whose DDQ-promoted cyc-
lization26 gave rise to benzylidene acetal 21. At this
juncture, configurational analysis was readily accom-
plished by NOESY techniques as indicated. Treatment
of 21 with tri-n-butyltin hydride in refluxing benzene27
resulted in formation of the (E)-vinylstannane 22, thereby
making possible the generation of vinyl iodide 2328 in
enantiopure form.
SCHEME 4 a
Construction of the second cross-coupling partner
commenced with butenolide 24, which was prepared from
L-(-)-ascorbic acid via an established six-step sequence.29
Conjugate addition of lithium dimethylcuprate to 24
furnished the trans 1,4-adduct 2530 (Scheme 5). Reduc-
tion of 25 to the lactol followed by Wittig chain exten-
sion31 generated alcohol 26, which was transformed into
27 through deployment of trichloroacetimidate technol-
ogy.32 The acquisition of this ester set the stage for
reduction and acetylation in advance of desilylation and
oxidation with iodoxybenzoic acid (IBX).33 The aldehyde
so formed was then homologated according to the Corey-
Fuchs protocol13 to provide alkyne 10.
The all-important Sonagashira coupling of 10 to 23 was
successfully accomplished with Pd(PPh3)2Cl2 and CuI in
(22) (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.
(23) (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.
(24) McGarvey, G. J .; Mathys, J . A.; Wilson, K. J . J . Org. Chem.
1996, 61, 5704.
(25) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(b) Sinha, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Org. Chem. 1999,
64, 2381. (c) Kittaka, A.; Suhara, Y.; Takayanagi, H.; Fujishima, T.;
Kurihara, M.; Takayama, H. Org. Lett. 2000, 2, 2619.
(26) Tsuboi, K.; Ichikawa, Y.; J iang, Y.; Naganawa, A.; Isobe, M.
Tetrahedron 1997, 53, 5123.
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 three steps); (i) HCtCSiMe3,
n-BuLi, BF3‚OEt2, THF, -78 °C; (j) (n-Bu)4NF, THF, 0 °C (95%
for two steps); (k) DDQ, 4 Å molecular sieves, CH2Cl2 (85%); (l)
(n-Bu)3SnH, AIBN, C6H6, ∆ (99%); (m) I2, CH2Cl2, 0 °C (96%).
(27) (a) Izzo, I.; De Caro, S.; De Riccardis, F.; Spinella, A. Tetrahe-
dron 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.
(28) (a) Drouet, K. E.; Theodorakis, E. A. Chem.sEur. 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.
(29) (a) Andrews, G. C.; Crawford, T. C.; Bacon, B. E. J . Org. Chem.
1981, 46, 2976. (b) Hubschwerlen, C. Synthesis 1986, 962. (c) Hub-
schwerlen, C.; Specklin, J .-L.; Higelin, J . Org. Synth. 1993, 72, 1. (d)
Fazio, F.; Schneider, M. P. Tetrahedron: Asymmetry 2000, 11, 1869.
(30) Hanessian, S.; Murray, P. J . Tetrahedron 1987, 43, 5055.
(31) (a) Messenger, B. T.; Davidson, B. S. Tetrahedron Lett. 2001,
42, 801. (b) Miyaoka, H.; Sagawa, S.; Nagaoka, H.; Yamada, Y.
Tetrahedron: Asymmetry 1995, 6, 587. (c) Barrett, A. G. M.; Carr, R.
A. E.; Attwood, S. V.; Richardson, G.; Walshe, N. D. A. J . Org. Chem.
1986, 51, 4840. (d) Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Org. Chem.
1999, 64, 7067.
p lin g. The synthesis commenced by transforming L-
(-)-malic acid into hydroxy acetal 13 by way of a
predescribed four-step sequence (Scheme 4). Masking
of the hydroxyl functionality as the p-methoxybenzyl
ether22 followed by acidic hydrolysis of the acetonide
subunit provided diol 15 in highly efficient fashion (92%).
Selective conversion23 of primary alcohol 15 to the piv-
21
(21) (a) Carman, R. M.; Karoli, T. Aust. 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.
(32) (a) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahe-
dron Lett. 1988, 29, 4139. (b) Nakata, M.; Ishiyama, T.; Akamatsu,
S.; Hirose, Y.; Maruoka, H.; Suzuki, R.; Tatsuta, K. Bull. Chem. Soc.
J pn. 1995, 68, 967. (c) Kawata, S.; Yoshimura, F.; Irie, J .; Ehara, H.;
Hirama, M. Synlett 1997, 250.
J . Org. Chem, Vol. 69, No. 19, 2004 6443

Paquette et al.
SCHEME 5 a
SCHEME 6 a
a
Reagents and conditions: (a) (CH3)2CuLi, Et2O, THF, -30 °C
(89%); (b) (i -Bu)2AlH, CH2Cl2, -78 °C; (c) Ph3PdCHCO2Me, C6H6,
∆ (100% for two steps); (d) PMBOC(dNH)CCl3, CSA, CH2Cl2; (e)
(i-Bu)2AlH, CH2Cl2, -78 °C (60% for two 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%).
the presence of triethylamine as solvent20 (Scheme 6).
The semihydrogenation of 31 over Lindlar’s catalyst
proved to be rather problematical, in that the coproduc-
tion of overreduced product 33 invariably occurred.34
Since carbinols 32 and 33 coeluted during chromatogra-
phy, the mixture was subjected directly to sequential IBX
oxidation, heating to 195 °C in toluene, and borohydride
reduction. The Diels-Alder product 34 formed uniquely
from 32 was now amenable to purification, and its
stereochemical features were deduced by NOE measure-
ments on both aldehyde 34 and carbinol 35 (see the
illustrations).
a
Reagents and conditions: (a) Pd(PPh3)2Cl2, CuI, Et3N (82%);
(b) H2, Lindlar’s catalyst, EtOAc/pyr/1-octene (10:1:1); (c) IBX,
THF/DMSO (9:1); (d) 20% BHT, toluene, sealed tube, 150-160 °C,
24 h (32% for three steps); (e) NaBH4, MeOH, 0 °C (82%).
P u r su it of 10-Mem ber ed Ca r bocycle F or m a tion .
To construct the CD ring system of cochleamycin A,
attention was first directed to the generation of aldehyde
6 (Scheme 7). This task was readily accomplished by
application of the Corey-Fuchs chain extension to 3413
and ensuing treatment with iodine and morpholine.14
Standard oxidation with pyridinium chlorochromate
completed the four-step sequence. It was hoped that 6
would be responsive to one or another modification of the
Nozaki-Hiyama-Kishi reaction.15 Accordingly, this iodo
aldehyde was treated with CrCl2 and NiCl2 in THF or
DMF under various conditions including ultrasonication,
but to no avail. Additionally, numerous attempts to bring
about cyclization through the agency of samarium io-
dide16 failed to generate 37.
In the end, both of these substrates produced complex
mixtures when exposed to several ruthenium catalyst
systems including 41.35 A contributing factor to the
foregoing results may well be the presence of a 1,3-
dioxane ring in the longer of the two side chains and its
associated conformational restrictions. The same struc-
tural considerations are not present in the contingency
plan outlined in Scheme 3, and we therefore proceeded
next in this direction.
In vestiga tion of th e Ma cr ola cton iza tion Alter n a -
tive. The exploration of this alternative pathway re-
quired utilization of a different subset of protecting
groups. Therefore, MEM ether 44 was prepared in a
manner paralleling that employed earlier for 17. Nucleo-
philic opening of the oxirane ring in 44 could then be
realized regioselectively with lithium trimethylsilylacetyl-
ide to furnish 45 after desilylation and masking of the
hydroxyl group with tert-butyldimethylsilyl chloride
(Scheme 8). Equally uneventful was the ensuing chemose-
lective ozonolysis that cleaved the terminal olefinic
π-bond of 45, sodium chlorite oxidation of the resulting
aldehyde to the carboxylic acid level,36 and generation of
In light of these reverses, this approach was abandoned
in favor of an alternative involving ring-closing metath-
esis. Toward this end, we turned to the structural
modification of 35 such that allylic alcohol 39 and its
conjugated keto analogue 40 would be made available.
(33) (a) Frigerio, M.; Santagostino, M.; Sputore, S. J . Org. Chem.
1999, 64, 4537. (b) Frigerio, M.; Santagostino, M.; Sputore, S.;
Palmisano, G. J . Org. Chem. 1995, 60, 7272. (c) Frigerio, M.; Santa-
gostino, M. Tetrahedron Lett. 1994, 35, 8019.
(34) (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.
(35) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) Nevalainen, M.; Koskinen, A. M. P. J . Org. Chem.
2002, 67, 1554. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
6444 J . Org. Chem., Vol. 69, No. 19, 2004

Sythetic Studies Aimed at (-)-Cochleamycin A
SCHEME 7 a
SCHEME 8 a
a
Reagents and conditions: (a) HCtCTMS, n-BuLi, BF3‚OEt2,
THF, -78 °C (90%); (b) TBAF, THF, 0 °C (94%); (c) TBSU,
imidazole, DMAP, CH2Cl2 (quant); (d) O3, Ref 23, CH2Cl2/MeOH
(1:1); Ph3P (81%); (e) NaClO2, NaH2PO4, CH3CHdC(CH3)2,
t-BuOH, H2O; (f) CH2N2, Et2O (91% for two steps); (g)
MeNH(OMe)‚HCl, i-PrMgCl, THF, -15 °C (77%); (h) n-Bu3SnH,
AIBN, C6H6, reflux; (i) I2, CH2Cl2, 0 °C (60% for two steps); (j) 10,
Pd(PPh3)2Cl2, CuI, Et3N (82%); (k) Zn dust, Cu(OAc)2‚H2O, AgNO3,
MeOH/H2O (1:1), 65 °C (70%); (l) IBX, THF/DMSO (9:1) (97%);
(m) BHT, toluene, sealed tube, 170 °C (91%); (n) (CF3CH2O)2P(O)-
CHBrCO2Me, NaHMDS, THF, 5-10 °C (81%); (o) 52, CH2Cl2, -78
°C (81%).
a
Reagents and conditions: (a) CBr4, Ph3P, pyr, CH2Cl2, 0 °C
(98%); (b) n-BuLi, THF, -78 °C (86%); (c) I2, morpholine, C6H6,
50-60 °C (90%); (d) PCC, NaOAc, 4 Å molecular sieves, CH2Cl2
(78%); (e) Ph3PCH3+Br-, n-BuLi, THF, -78 °C (76%); (f) n-BuLi,
THF, -78 °C (80%); (g) PCC, NaOAc, 4 Å molecular sieves, CH2Cl2,
0 °C (76%); (h) CH2dCHMgBr, THF, -78 to 0 °C (96%); (i) PCC,
NaOAc, 4 Å molecular sieves, CH2Cl2, 0 °C (82%).
nol proved notably effective in transforming the conju-
gated enyne into the targeted trienol (70% yield). Fol-
lowing the IBX oxidation of this intermediate, heating
in toluene containing BHT to 170 °C under sealed tube
conditions promoted efficient intramolecular Diels-Alder
cycloaddition as before and formation of 49. To set the
proper geometry in R-bromo ester 50, reliance was placed
on the utilization of methyl bis(2,2,2-trifluoroethoxy)-
bromophosphonoacetate.40 In line with previous prece-
dent, 50 was formed as the major isomeric product (81%
isolated in a 7:1 epimeric ratio).
The chemical reactivity of advanced intermediate 50
was soon determined to be rather unfavorable. Selective
deprotection of the MEM group in the presence of the
TBS functionality could be achieved. However, no reac-
tion was observed following treatment with trimethyla-
luminum or diethylaluminum chloride in CH2Cl2 at 0 °C
to rt. In contrast, cerium trichloride in refluxing CH3CN41
Weinreb amide 46 from the methyl ester.37 The viability
of the hydrostannylation approach to vinyl iodide 47 was
easily demonstrated, as was the now familiar protocol
for the Sonagashira coupling of 47 to 10.
Prior to unmasking of the carboxaldehyde group,
partial reduction of the triple bond to the (Z)-alkene was
necessary. When hydrogenation over Lindlar’s catalyst
generated a mixture of compounds, reductive decomplex-
ation of the dicobalt hexacarbonyl-ligated acetylene38 was
examined but proved unrewarding. A broader search of
metal-promoted reductions was then undertaken. Of
these, the action of zinc dust previously activated with
copper(II) acetate and silver nitrate39 in aqueous metha-
(36) Hase, T.; Wa´ha´la´, K. In Encyclopedia of Reagents for Organic
Synthesis, Paquette, L. A.; Editor-in-Chief; Wiley: Chichester, U.K.,
1995; p 4533.
(37) (a) Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. J . Am.
Chem. Soc. 1985, 107, 7790. (b) Nahm, S.; Weinreb, S. M. Tetrahedron
Lett. 1981, 22, 3815. (c) Paterson, I.; Florence, G. J .; Gerlach, K.; Scott,
J . P.; Sereinig, N. J . Am. Chem. Soc. 2001, 123, 9535.
(38) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609.
(39) (a) Boland, W.; Schroer, N.; Sieler, C. Helv. Chim. Acta 1987,
70, 1025. (b) Avignon-Tropis, M.; Pougny, J . R. Tetrahedron Lett. 1989,
30, 4951.
(40) (a) Tago, K.; Kogen, H. Org. Lett. 2000, 2, 1975. (b) Tago, K.;
Kogen, H. Tetrahedron 2000, 56, 8825.
J . Org. Chem, Vol. 69, No. 19, 2004 6445

Paquette et al.
SCHEME 9 a
or trimethylchlorosilane and sodium iodide in CH2Cl2 at
-20 °C42 acted on both protecting groups and returned
only the diol. Ultimately, clean chemoselectivity was
realized with 2-chloro-1,3,2-dithioborolane (52) as pre-
pared from boron trichloride and ethanedithiol.43 This
reagent, dissolved in CH2Cl2 and cooled to -78 °C,
afforded the desired alcohol 51 in 81% yield.44
Under the assumption that 51 would be amenable to
ester hydrolysis, attempts were made to bring about con-
version to the acid under mild saponification conditions
or by SN2 dealkylation.45 Extensive decomposition was
seen under both sets of conditions. When the use of potas-
sium trimethylsilanolate46 gave comparable results, the
decision was made to transform the methyl ester into an
allyl ester via conventional exchange conditions (K2CO3,
allyl alcohol, H2O). However, this routing was unwieldy
and only modestly efficient (46-78% yield of 54).
To overcome these complications, aldehyde 49 was
condensed directly with phosphonate ester 53.47 Usefully,
54 was formed in 79% yield. Subsequent recourse to the
chloroborolane reagent 52 proved as before to be an
appropriate means for effecting specific cleavage of the
MEM group (Scheme 9). With 55 in hand, this substance
was found to be amenable to deesterification in the
presence of palladium acetate, triphenylphosphine, and
dimedone in THF solution.48 At this juncture, the hydroxy
carboxylic acid was subjected to the Yamaguchi condi-
tions for macrolactonization.49 This approach to in situ
activation afforded 56 cleanly.
The next hurdle involved the transformation of 56 into
keto lactone 58 via a reductive carbon-carbon-bond-
forming process.11,50 To this end, 56 was treated with tert-
butyllithium in THF at -78 °C. Disappointingly, ineffi-
cient conversion to 57 was observed. Through careful
exposure of 56 to (n-Bu)3SnSiMe3 and benzyltriethylam-
monium chloride in DMF,51 the loss of bromine could be
achieved almost quantitatively. Reaction with samarium
iodide in THF containing either HMPA or Fe(acac)3
elicited an entirely parallel result in 93% yield.52
a
Reagents and conditions: (a) Pd(OAc)2, Ph3P, dimedone, THF;
(b) 2,4,6-Cl3C6H2COCl, Et3N, THF; DMAP, toluene, ∆ (73% for
two steps); (c) (n-Bu)3SnTMS, BnEt3NCl, DMF (97%) or SmI2,
HMPA, THF (93%).
These observations suggested that anion formation was
occurring, but that ring closure was inoperative as a
consequence of either the low reactivity of the Weinreb
amide functionality or the buildup of conformational
inflexibility during the projected ring closure. In a move
designed to reduce hindrance, 56 was successfully desi-
lylated to produce 59. However, no means was found for
(41) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Srividya, R.; Yadav, J .
S. Org. Lett. 2001, 3, 1149.
(42) Rigby, J . H.; Wilson, J . Z. Tetrahedron Lett. 1984, 25, 1429.
(43) (a) Williams, D. R.; Sakdarat, S. Tetrahedron Lett. 1983, 24,
3965. (b) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J . Am. Chem. Soc. 1994, 116, 11287.
(44) Although an 81% yield was realized on one occasion, a lesser
efficiency (30-80%) was frequently encountered.
(45) (a) McMurry, J . Org. React. 1976, 24, 187. (b) Haslam, E.
Tetrahedron 1980, 36, 2409.
(46) Marshall, J . A.; Adams, N. D. J . Org. Chem. 2002, 67, 733.
(47) Reagent 53 was prepared from allyl bis(2,2,2-trifluoroethyl)-
phosphonoacetate48a by Kogen’s protocol.40
(48) (a) Boeckman, R. K., J r.; Weidner, C. H.; Perni, R. B.; Napier,
J . J . J . Am. Chem. Soc. 1989, 111, 8036. (b) Casy, G.; Sutherland, A.
G.; Taylor, R. J . K.; Urben, P. G. Synthesis 1989, 767. (c) Auberson,
Y.; Vogel, P. Tetrahedron 1990, 46, 7019. (d) Arnould, J . C.; Landier,
F.; Pasquet, M. J . Tetrahedron Lett. 1992, 33, 7133. (e) Guibe´, F.
Tetrahedron 1998, 54, 2967.
(49) (a) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. J pn. 1979, 52, 1989. (b) Hoffmann, R. W.; Ditrich,
K. Liebigs Ann. Chem. 1990, 23. (c) Meng, Q.; Hesse, M. Top. Curr.
Chem. 1992, 161, 107.
successfully reattaching a smaller protecting group (Me,
PMB). Selective reduction of the Weinreb amide to the
aldehyde level in the presence of a lactone ring53 gave
equally disappointing results. When this reaction was
performed on a small scale (2 mg of 56), 60 was obtained
in acceptable yield. On a larger scale, an unidentified
product (not resulting from reduction of the lactone) was
(50) (a) Flann, C. J .; Overman, L. E. J . Am. Chem. Soc. 1987, 109,
6115. (b) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059.
(c) Ruiz, J .; Sotomayor, N.; Lete, E. Org. Lett. 2003, 5, 1115.
6446 J . Org. Chem., Vol. 69, No. 19, 2004

Sythetic Studies Aimed at (-)-Cochleamycin A
SCHEME 10 a
SCHEME 11 a
a
Reagents and conditions: (a) HCtCSiMe3, n-BuLi, BF3‚OEt2,
THF, -78 °C (90%); (b) (n-Bu)4NF, THF, 0 °C (94%); (c) TBSU,
imidazole, DMAP, CH2Cl2 (100%); (d) CBr4, i-PrOH, reflux (94%);
(e) BzCl, DMAP, Et3N, CH2Cl2 (95%); (f) HF‚pyr, THF/pyr (5:1)
(96%); (g) PMBOC(dNH)CCl3, CSA, CH2Cl2; (h) O3, Ref 23, -78
°C, MeOH/CH2Cl2 (1:1), Ph3P; (i) NaBH4, MeOH (62% for three
steps); (j) TBSU, NH4NO3, DMF (100%); (k) DDQ, CH2Cl2/H2O
(18:1) (91%); (l) TBSU, DMAP, imidazole, CH2Cl2 (96%); (m)
(n-Bu)3SnH, AIBN, C6H6, reflux; (n) I2, CH2Cl2 (94% for two steps);
(o) 10, Pd(PPh3)2Cl2, CuI, Et3N (87%); (p) Zn dust, AgNO3,
Cu(OAc)2‚H2O, THF/H2O (1:1), reflux (87%); (q) IBX, THF/DMSO
(9:1) (93%); (r) BHT, toluene, sealed tube, 150-160 °C (64%).
a
Reagents and conditions: (a) (CF3CH2O)2P(O)CHBrCO2AlI,
NaHMDS, THF, -78 to -15 °C (64%); (b) Pd(OAc)2, PPh3,
dimedone, THF (88%); (c) (i-Bu)2AlH, CH2Cl2, -78 °C; (d) 2,4,6-
Cl3C6H2COCl, Et3N, THF, DMAP, toluene, reflux (54% for two
steps); (e) (n-Bu)4NF-HOAc (1:1), DMF-THF (1:1) (83%); (f) PCC,
NaOAc, 4 Å MS, CH2Cl2 (73%).
treatment with a 1:1 mixture of TBAF and acetic acid in
1:1 DMF/THF.57 Ensuing PCC oxidation delivered alde-
hyde 60 in preparation for six-membered ring closure.
The yields realized were rather variable (67-98%),
chiefly because of the instability of 60 to chromatography
on silica gel. However, pure product was acquired when
Florisil was used instead. Our first attempts to bring
about the 60 f 67 conversion by the Nozaki-Hiyama-
Kishi reaction made use of relatively high ratios of NiCl2
to CrCl2 (from 1:258 to 1:559) as well as high dilution
conditions. In all instances, decomposition of the starting
material was uniformly observed. An increase in reaction
temperature to 40 °C as well as the use of a large excess
(100 equiv) of CrCl211c did not rectify matters. When the
number of equivalents of NiCl2 was decreased, quantities
of 60 ranging from 22% to 36% were recovered, but no
67 was seen. This inability to achieve cyclizatioin of the
bromo aldehyde was likewise observed in the presence
of Rieke zinc.60
These unsatisfactory results have been traced to two
contributing factors. The first is the critical instability
of 60. Its â-acyloxy part structure is seemingly conducive
to â-elimination at 30-40 °C such that survival for long
periods of time at modestly elevated temperatures is not
seen under a variety of conditions. In addition, molecular
mechanics calculations61 (Monte Carlo simulation in
MacroModel version 5.0) give evidence that the more
generated efficiently. These issues were avoided by
preparing 60 instead from a protected alcohol precursor.
As reflected in Scheme 10, a different subset of protect-
ing groups was introduced for the new intermediates.
Although compatibility issues did surface, they were dealt
with properly.54 The more notable steps involved in this
series of transformations include (d) the chemoselective
unmasking of an MEM ether with carbon tetrabromide
in refluxing isopropyl alcohol (94%)55 and (j) the use of
mild reagents (NH4NO3, DMF) to install a TBDPS
group56 to avoid the possibility of benzoyl group migration
under the basic conditions.
At this point, the conversion of 64 to 65 and then
crafting into lactone 66 (Scheme 11) went well. Controlled
removal of the primary TBDPS group in the presence of
the secondary TBS group was subsequently achieved by
(57) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.;
Shirahama, H.; Nakata, M. Synlett 2000, 1306.
(58) (a) McCauley, J . A.; Nagasawa, K.; Lander, P. A.; Mischke, S.
G.; Semones, M. A.; Kishi, Y. J . Am. Chem. Soc. 1998, 120, 7647. (b)
Chen, C.; Tagami, K.; Kishi, Y. J . Org. Chem. 1995, 60, 5386.
(59) Goldring, W. P. D.; Pattenden, G. Org. Biomol. Chem. 2004,
466.
(60) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J . Org. Chem. 1991,
56, 1445.
(61) These calculations were performed by David G. Hilmey. Note
that the PMB group was replaced by OPh and OTBS by OCH3 to
simplify the approximations.
(51) Mori, M.; Kaneta, N.; Isono, N.; Shibasaki, M. Tetrahedron Lett.
1991, 32, 6139.
(52) Molander, G. A.; McKie, J . A. J . Org. Chem. 1993, 58, 7216.
(53) (a) Sheppeck, J . E., II; Liu, W.; Chamberlin, A. R. J . Org. Chem.
1997, 62, 387. (b) Sorensen et al. mentioned a similar transformation
briefly in ref 11c. They kindly provided us with the detailed experi-
mental procedure.
(54) For a detailed discussion of the relevant issues, see: Chang, J .
Ph.D. Dissertation, The Ohio State University, 2004; Chapter 4.
(55) Lee, A. S.-Y.; Hu, Y.-I.; Chu, S.-F. Tetrahedron 2001, 57, 2121.
(56) Hardinger, S. A.; Wijaya, N. Tetrahedron Lett. 1993, 34, 3821.
J . Org. Chem, Vol. 69, No. 19, 2004 6447

Paquette et al.
and carboxaldehyde functionalities are too distal to
become covalently bonded. The proximity factor is no
longer an issue with conformer B, but this structural
arrangement is 9 kcal/mol less stable than A. Conformer
C is higher in energy than A by only 1 kcal/mol. However,
in this example the lactone bridge is improperly oriented
toward the â-face and would therefore lead to an un-
wanted diastereomer. Consequently, the conformational
inflexibility of the macrolactone ring in 60 disallows
proximity of the two reaction sites and renders ring
closure slow and inefficient.
In summary, a strategy has been developed for the
synthesis of stereochemically well defined seco ring D in-
termediates related to cochleamycin A. The sequence of
steps leading to lactones 57, 59, and 60 involves adapta-
tion of the Sonagashira coupling reaction and an intra-
molecular Diels-Alder cycloaddition, alongside stereo-
controlled chain extensions. However, the reaction cen-
ters positioned external to the macrocycle appear not to
be able to approach each other because of unanticipated
conformational constraints. These findings teach that
topological changes in macrocyclic lactones are not neces-
sarily low-energy processes and merit up-front considera-
tion when being contemplated in retrosynthetic planning.
Ack n ow led gm en t. This work was supported in part
by the Yamanouchi USA Foundation.
F IGURE 1. Conformational analysis of 60.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
populated, lower energy conformations of 60 are not
particularly conducive to ring closure, the kinetics of
which should therefore be slowed (Figure 1). The com-
putational analysis indicates the global minimum-energy
conformer to be A. In this structure, the vinyl bromide
1
tails and H/13C NMR spectral data for all compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O049084A
6448 J . Org. Chem., Vol. 69, No. 19, 2004