Divergent and Stereocontrolled Synthesis of the Enamide Side Chains of Oximidines I/II/III, Salicylihalamides A/B, Lobatamides A/D, and CJ-12,950

Article abstract of DOI:10.1021/ol036381d

(Matrix presented) A unified strategy for the divergent and stereocontrolled introduction of the (E)- and (Z)-enamide side-chains of oximidines I, II, and III, salicylihalamides A and B, lobatamides A and D, and CJ-12,950 is detailed. The synthesis relied on the copper-promoted C-N coupling of (E)-and (Z)-vinyl iodides with a protected maleimide hemiaminal followed by deprotection and reaction of the resulting (E)- or (Z)-enelactam hemiaminals with O-methylhydroxylamine or propylidenetriphenylphosphorane.

Full text of DOI:10.1021/ol036381d

ORGANIC
LETTERS
2004
Vol. 6, No. 4
577-580
Divergent and Stereocontrolled
Synthesis of the Enamide Side Chains
of Oximidines I/II/III, Salicylihalamides
A/B, Lobatamides A/D, and CJ-12,950
Robert S. Coleman* and Pei-Hua Liu
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
coleman@chemistry.ohio-state.edu
Received December 5, 2003
ABSTRACT
A unified strategy for the divergent and stereocontrolled introduction of the (E)- and (Z)-enamide side-chains of oximidines I, II, and III,
salicylihalamides A and B, lobatamides A and D, and CJ-12,950 is detailed. The synthesis relied on the copper-promoted C−N coupling of (E)-
and (Z)-vinyl iodides with a protected maleimide hemiaminal followed by deprotection and reaction of the resulting (E)- or (Z)-enelactam
hemiaminals with O-methylhydroxylamine or propylidenetriphenylphosphorane.
The family of natural products known as the benzolactone
enamides includes a diverse array of structures characterized
by a benzo-fused macrolactone bearing an N-acylated
enamine side-chain (Figure 1).1 Members of this family
include: (1) oximidines I, II, and III, isolated from Pseudomo-
nas sp. that arrest the cell cycle in ras or src-transformed
cells;2 (2) salicylihalamides A and B, marine natural products
isolated from the sponge Haliclona sp. that display a unique
profile of differential cytotoxicity;3 and, (3) the lobatamides,
characterized by lobatamides A and D, isolated from
Aplidium tunicates,4,5 which exhibit activity similar to that
of the salicylihalamides. These agents inhibit mammalian
vacuolar ATPases, enzyme systems that are distributed
widely in eukaryotic tissues and are involved in the regulation
of pH gradients within intracellular compartments and
secretory vesicles.6 These agents have attracted considerable
attention as important targets for total synthesis and as lead
compounds for drug development.1
These antitumor agents share a common enamide side
chain of variable stereochemistry at the enamine and R,â-
unsaturated amide stereogenic double bonds. There have been
a number of reports detailing synthetic routes to specific side
chains,7 but there is no general method for introduction of
the oximidine, salicylihalamide, or lobatamide side-chains
using a common synthetic strategy.
(1) For a review, see: Yet, L. Chem. ReV. 2003, 103, 4283.
(2) Oximidines I and II: Kim, J. W.; Shin-ya, K.; Furihata, K.;
Hayakawa, Y.; Seto, H. J. Org. Chem. 1999, 64, 153. Oximidine III:
Hayakawa, Y.; Tomikawa, T.; Shin-ya, K.; Arao, N.; Nagai, K.; Suzuki,
K.-i.; Furihata, K. J. Antibiot. 2003, 56, 905. For an approach to the triene
lactone system of oximidine II, see: Coleman, R. S.; Garg, R. Org. Lett.
2001, 3, 3487. For the first total synthesis of oximidine II, see: Wang, X.;
Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040.
In this communication, we report a stereocontrolled
method for the divergent synthesis8 of model enamide side-
(3) Erickson, K. L., Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188.
(4) McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J. H., II;
Laakso, J.; Ireland, C. M.; Murray, L.; Capon, R. J.; Boyd, M. R. J. Org.
Chem. 1998, 63, 7805. Galinis, D. L.; McKee, T. C.; Pannell, L. K.;
Cardellina, J. H., III; Boyd, M. R. J. Org. Chem. 1997, 62, 8968.
(5) For a recent report on the total synthesis of lobatamide C and
simplified analogues, see: Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman,
B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889.
(6) Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J. W.;
Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E.
J. J. Exp. Pharm. Exp. Therapeut. 2001, 297, 114.
10.1021/ol036381d CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/28/2004

Figure 1. Structures of the benzolactone enamide antitumor agents.
chains (E)-5, characteristic of oximidine III, the lobatamides
and CJ-12,950, (Z)-5, characteristic of oximidine I and II,
(E)-6, present in salicylihalamide A, and (Z)-6, present in
salicylihalamide B, all starting from isovaleraldehyde via the
readily prepared vinyl iodides (E)-2 and (Z)-2 (Scheme 1).
Our strategy uses cyclic hemiaminal 3, presumably in equi-
librium with acyclic aldehyde 4: oxime formation provides
5, whereas Wittig olefination provides 6. The key intermedi-
ate 3 is synthesized by a stereospecific copper-promoted
C-N bond formation7f,9 between suitably protected precursor
1 and vinyl iodides (E)-2 and (Z)-2. A central feature of this
strategy is the recognition that the common cis stereochem-
istry found in the R,â-unsaturated amide alkene of side-chains
of 5 and 6 could be introduced with total stereocontrol from
within the cyclic framework of maleimide. Vinyl iodides
(E)-2 and (Z)-2 can be prepared in a stereodivergent fashion
from isovaleraldehyde by Takai10 or Stork-Zhao11 olefina-
tion, respectively.
Scheme 1
(7) (a) Vinyl cuprate addition to an isocyanate: Snider, B. B.; Song, F.
Org. Lett. 2000, 2, 407. (b) Vinyllithium addition to an isocyanate: Wu,
Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J. K. J. Am. Chem. Soc.
2002, 124, 3245. (c) Nonstereocontrolled elimination of bis-acylated
aminal: Labrecque, D.; Charron, S.; Rej, R.; Blais, C.; Lamothe, S.
Tetrahedron Lett. 2001, 42, 2645. (d) Acylation of a Teoc-protected
enamine: Smith, A. B., III; Zheng, J. Tetrahedron 2002, 58, 6455. (e) From
an acyl azide via a Curtius rearrangement and subsequent addition of a
vinyllithium reagent: Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett
2000, 397. (f) Copper-promoted coupling of a vinyl iodide with a primary
amide: Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333.
(8) For the origin of the concept of a divergent synthesis, i.e., the use of
a common intermediate to prepare diverse members of a class of synthetic
targets or family of natural products, see: Boger, D. L.; Mullican, M. L. J.
Org. Chem. 1984, 49, 4045.
(9) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421. (c) Mallesham, B.; Rajesh, B. M.;
Reddy, P. R.; Srinivas, D.; Trehan, S. Org. Lett. 2003, 5, 963. (d) Fu¨rstner,
A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem. Eur. J. 2001, 7, 5286. (e)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (f) Wolter, M.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
Reduction of maleimide12 with NaBH4 in the presence of
CeCl3 (MeOH, 0 °C, 1 h, 40% unoptimized) and protection
of the resulting hemiaminal (t-BuMe2SiCl imidazole, DMF,
25 °C, 12 h, 85%) afforded the central fragment 7 (Scheme
2). Copper-promoted coupling of 7 with vinyl iodides (Z)-
213 or (E)-213a effected C-N bond formation to provide (Z)-8
(56%) and (E)-8 (72%), respectively, in good yields that were
comparable with those reported by other workers7c (Table
1). Cleavage of the silyl ether of (Z)-8 and (E)-8 occurred
(12) Mase, N.; Nishi, T.; Hiyoshi, M.; Ichihara, K.; Bessho, J.; Yoda,
H.; Takabe, K. J. Chem. Soc., Perkin Trans. 1 2002, 707,
(13) (a) Stamos, D. P.; Tayler, A. G.; Kishi, Y. Tetrahedron Lett. 1996,
37, 8647. (b) Imoga¨ı, H.; Petit, Y.; Larcheveˆque, M. Synlett 1997, 615.
(10) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(11) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
578
Org. Lett., Vol. 6, No. 4, 2004

base, and 1,4-dioxane as the solvent proved to be effective
for the coupling of lactam 7 and cis-vinyl iodide (Z)-2 (Table
1). An excess of amide 7 was necessary to effect complete
consumption of the vinyl iodide, which is a favorably dis-
posed ratio based on our intended use as the end game of a
total synthesis. The (Z)- or (E)-configuration of the double
bond of vinyl iodide was fully retained.
Scheme 2
Screening of reaction conditions revealed copper(I), in the
form of CuTc or recrystallized CuI,18 to be the most effective
metal catalysts, where improved yields were obtained by
using CuTc. 1,2-Diamine ligands are excellent for promoting
C-N bond formation in this system, but no coupling prod-
ucts were formed when triphenylphosphine or 1,10-phenan-
throline was used as a ligand. Little difference was seen
between K3PO4, Cs2CO3, or Rb2CO3 as bases, but K2CO3
was less effective and the reaction required a longer time to
proceed to completion. Polar solvents such as DMF, DMA,
NMP, or 1,2-cyclohexanediamine gave no desired coupling
product; toluene was moderately effective, and 1,4-dioxane
and THF proved to be the most generally useful solvents
for the coupling.19
With optimized reaction conditions, the trans-vinyl iodide
(E)-2 provided higher yields in the C-N bond formation
(72%) compared to the cis-vinyl iodide (Z)-2 (56%). Pal-
ladium was completely unsuccessful as a catalyst for this
C-N bond formation, and a variety of Pd catalysts and lig-
ands were employed, including palladium sources such as
Pd2(dba)3, Pd(PPh3)4, and Pd(OAc)2 and ligands such as dppf,
BINAP, and xantphos, uniformly without success.14,20
Treatment of the hemiaminals (Z)-3 and (E)-3 with
O-methylhydroxylamine hydrochloride led to the forma-
tion of the corresponding ring-opened O-methyloxime ether
(Z)-5 (78%), characteristic of oximidines I and II, (E)-5
(71%), characteristic of oximidine III, lobatamides A and
D, and CJ-12,950 (Scheme 3).
A hemiaminal is less reactive than the typically used
hemiacetal or aldehyde, and to the best of our knowledge,
this is the first report of the ring-opening reaction of a
hemiaminal to form the corresponding oxime. The reaction
of hemiaminal (E)-3 bearing the trans-alkenyl group with
O-methylhydroxylamine hydrochloride is sluggish compared
to the corresponding hemiaminal (Z)-3 bearing the cis-alkenyl
Table 1. Copper-Promoted C-N Bond Formationa
metal
ligand/base
solvent/temp/time
%
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
CuTC
CuTC
CuTC
CuI
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC +
Pd2(dba)3
dppf/Cs2CO3
xantphos/Cs2CO3
xantphos/NaOt-Bu toluene/100 °C/10 h
BINAP/Cs2CO3
dppf, NaOt-Bu
dppf/Cs2CO3
Ph3P or 1,10-phen
diamine/K3PO4
DMED/K3PO4
diamine/K3PO4
diamine/K3PO4
diamine/K3PO4
diamine/K3PO4
diamine/Rb2CO3
diamine/K2CO3
diamine/K3PO4
dioxane/100 °C/10 h
dioxane/100 °C/10 h
dioxane/100 °C/10 h
toluene/100 °C/10 h
dioxane/100 °C/10 h
dioxane/90 °C/24 h
dioxane/90 °C/24 h
dioxane/90 °C/24 h
dioxane/90 °C/24 h
THF/70 °C/24 h
toluene/90 °C/24 h
NMP, DMF, or DMA
dioxane/90 °C/24 h
dioxane/90 °C/24 h
dioxane/90 °C/24 h
56
42
46
42
21
42
33
<5
(14) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(b) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (c) Browning, R. G.;
Mahmud, H.; Badarinarayana, V.; Lovely, C. J. Tetrahedron Lett. 2001,
42, 7155. (d) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035.
(15) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991, 1443.
(16) (a) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2748. (b) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62,
2312.
a CuTC ) copper(I) thiophenecarboxylate;16 diamine ) trans-N,N′-
dimethyl-1,2-cyclohexanediamine; DMED ) N,N′-dimethylethylenediamine;
dppf ) diphenylphosphinoferrocene; xantphos ) 4,5-bis(diphenylphos-
phino)-9,9-dimethylxanthene; dba ) dibenzylidene acetone.
(17) Betschart, C.; Schmidt, B.; Seebach, D. HelV. Chim. Acta. 1988,
71, 1999.
(18) Dieter, R. K.; Silks, L. A.; Fishpaugh, J. A.; Kastner, M. E. J. Am.
Chem. Soc. 1985, 107, 4679.
smoothly using n-Bu4NF (THF, -20 °C, 10 min) to afford
hemiaminals (Z)-3 and (E)-3, respectively.
(19) In examples of amide coupling with a trans-vinyl iodide reported
by Porco7f and Fu¨rstner,9d the reaction was performed without ligands and
polar aprotic solvents were used, contrasting our reaction conditions.
(20) (a) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem.
Commun. 2002, 2362. (b) MacNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J. J.;
Snieckus, V. Synlett 1998, 419. (c) Deboves, H. J. C.; Hunter, C.; Jackson,
R. F. W. J. Chem. Soc., Perkin Trans. 1 2002, 733. (d) Maes, B.; Jonckers,
T.; Lemie`re, G.; Rombouts, G.; Pieters, L.; Haemers, A.; Dommisse, R.
Synlett 2003, 615. (e) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L.
Tetrahedron 1996, 52, 7525.
N-Arylation or N-vinylation of amides and lactams is often
difficult, and there are surprisingly few reports of this reac-
tion.9b,c,f,14 There is a single report of the N-vinylation of
the potassium salt of a lactam.15 We found that the combina-
tion of Liebeskind’s copper(I) thiophenecarboxylate (CuTc),16
trans-N,N′-dimethyl-1,2-cyclohexanediamine,17 K3PO4 as the
Org. Lett., Vol. 6, No. 4, 2004
579

Scheme 3
Scheme 4
Starting from isovaleraldehyde, installation of the enamide
side-chains of the natural products oximidines I, II, and III,
salicylihalamides A and B, lobatamides A and D, and
CJ-12,950 was accomplished in an efficient, four-step reac-
tion sequence. The synthetic sequence proceeds with two
points of introduction of diversity. Stereodivergent installa-
tion of the corresponding cis- or trans-vinyl iodides by Takai
or Stork-Zhao olefinations afforded (Z)-2 and (E)-2, which
were carried through a stereospecific copper-promoted C-N
bond formation to afford (Z)-8 and (E)-8. The second point
of diversity introduction occurred at the stage of the cyclic
hemiaminals (Z)-3 and (E)-3 via chemodivergent oxime
formation or Wittig olefination. The methodology reported
herein, while ingenuous in its formulation, proved to be
effective when implemented. This work provides a unified
synthetic strategy for enamide introduction for the total
synthesis of the benzolactone family of antitumor agents.
group, and this reaction required an extended reaction time
to reach completion. The success of this ring-opening is
dependent upon the identity of the base used to neutralize
the hydrochloride salt: with amine bases such as Et3N, the
desired oxime ethers (Z)-5 or (E)-5 were obtained in 78 and
71% yields, respectively. In the presence of stronger bases
such as KOH, ring opening at the CO-N acyl bond and
isomerization of the double bond of the resulting hydrox-
amate occurred. In the absence of base or in the presence of
acetic acid, the reaction is not productive.
Cis-selective Wittig olefination of hemiacetals has been
reported and proceeds effectively,21 but to the best of our
knowledge, there are no reports of the Wittig reaction of
cyclic hemiaminals. The Wittig cis olefination of (Z)-3 and
(E)-3 (Scheme 4) using propylidenetriphosphorane (gen-
erated from propyltriphenylphosphonium bromide by treat-
ment with KN(SiMe3)2 in THF at -20 °C) proceeded
uneventfully (THF, -78 to 0 °C, 30 min) and afforded (Z)-
6, characteristic of salicylihalamide B, and (E)-6, charac-
teristic of salicylihalamide A, in 94 and 90% yields,
respectively.
Acknowledgment. This work was supported by a grant
from the National Cancer Institute (R01 CA91904).
Supporting Information Available: Experimental pro-
cedures and spectral characterization of intermediates and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) For representative examples, see: Busato, S.; Scheffold, R. HelV.
Chim. Acta. 1994, 77, 92. Chauhan, K.; Aravind S.; Lee S.-G.; Falck, J.
R.; Capdevila, J. H. Tetrahedron Lett. 1994, 35, 6791. Roush, W. R.;
Blizzard, T. A. J. Org. Chem. 1983, 48, 758.
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