Stereocontrolled synthesis of the diene and triene macrolactones of oximidines I and II: Organometallic coupling versus standard macrolactonization

Article abstract of DOI:10.1021/ol016744e

(matrix presented) Stereocontrolled construction of the 12-membered diene and triene lactones 1, 2, and 3, characteristic of the antitumor agent oximidines I and II, are reported and were based on an intramolecular Castro-Stephens coupling for the construction of a cyclic enyne or dienyne followed by stereoselective reduction of the cyclic alkyne for introduction of the cis-olefin of the targets. A comparison of the effectiveness of this protocol is made with standard macrolactonization.

Full text of DOI:10.1021/ol016744e

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3487-3490
Stereocontrolled Synthesis of the Diene
and Triene Macrolactones of Oximidines
I and II: Organometallic Coupling
versus Standard Macrolactonization
Robert S. Coleman* and Rahul Garg
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
coleman@chemistry.ohio-state.edu
Received September 11, 2001
ABSTRACT
Stereocontrolled construction of the 12-membered diene and triene lactones 1, 2, and 3, characteristic of the antitumor agent oximidines I and
II, are reported and were based on an intramolecular Castro−Stephens coupling for the construction of a cyclic enyne or dienyne followed by
stereoselective reduction of the cyclic alkyne for introduction of the cis-olefin of the targets. A comparison of the effectiveness of this protocol
is made with standard macrolactonization.
Oximidines I and II (Figure 1) are members of a new family
of cytotoxic natural products isolated in 1999 from Pseudomo-
nas.1 These agents exhibit cytotoxicity at ng/mL levels that
is selective for ras and src oncogene transformed cells. The
agents effect inhibition of the cell cycle at the G1 phase,1
and recent studies have identified the cellular target of the
oximidines as mammalian vacuolar-type (H+)-ATPases.2 The
oximidines possess a functionalized and polyunsaturated
12-membered lactone that is relatively immobile as the
result of the presence of 10 contiguous sp2 or pseudo-sp2
atoms.
describe a stereocontrolled entry into the unsaturated lactone
ring systems of oximidines I and II that is based on an
intramolecular Castro-Stephens coupling reaction8,9 for
macrocycle formation.10 One of the most significant synthetic
challenges in constructing the macrocycle systems of these
agents is control of (E,Z)-diene and (E,Z,Z)-triene stereo-
chemistry. As a straightforward solution to this problem, we
have used an alkyne to (Z)-alkene transformation as a method
for olefin stereocontrol in the transformation of 2 to 1, where
There has been no synthetic work on the diene and triene
oximidine macrocycles,3 and only recently have reports
appeared4-6 on the total synthesis of the structurally related
cytotoxic agents salicylihalamides A and B.7 We now
(1) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J.
Org. Chem. 1999, 64, 153-155.
(2) 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. Pharmacol. Exp. Ther. 2001, 297, 114-120.
(3) For simplified model systems lacking the conjugated diene/triene
system, see: Scheufler, F.; Maier, M. E. Synlett 2001, 1221-1224.
Figure 1. Structures of oximidines I and II.
10.1021/ol016744e CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/28/2001

of the aldehyde of 7 (CHI3, CrCl2, THF, 0 °C, 2 h) afforded
vinyl iodide 8 (65%) as an inseparable 4.3:1 E/Z mixture of
stereoisomers. Under traditional Sonogashira coupling pro-
tocols, the cyclization partner 8 was transformed to a series
of unidentifiable compounds, not including the desired
lactone 9. Using the modified Castro-Stephens coupling
conditions of Miura and co-workers14 (catalytic CuI, Ph3P,
K2CO3, DMF, 120 °C), cyclization of 8 afforded cyclic enyne
lactone 9 in modest yields (37%), in addition to a small
amount of dimeric product (10-15%). Stereoselective reduc-
tion of the alkyne of 9 (Zn0, BrCH2CH2Br, LiBr, CuBr,
EtOH, reflux)15 afforded the (E,Z)-diene lactone 1 (71%).
Scheme 1
The modest yield for this cyclization may be a conse-
quence of the strained ring system that is formed, as similar
yields in the synthesis of strained cycloalkynes are prece-
dented.10,16 Computer modeling (MMX force field) showed
the alkyne sp-sp3 and sp-sp2 bonds of 9 to be approximately
25° from linearity (Figure 2). The source of copper (e.g.,
the cyclic enyne of 2 arises from an intramolecular copper-
promoted macrocyclization reaction between the (E)-vinyl
halide and terminal alkyne of 3 (Scheme 1). Inherent in this
plan is the issue of ring strain in the formation of macrocyclic
enyne and dienyne systems.
For the synthesis of model system 1 (Scheme 2), alkylative
Scheme 2
Figure 2. Energy minimized (MMX global minimum) cyclic enyne
9 showing distorted alkyne bonds.
CuCl vs. CuI) had little effect on the conversion of 8 to 9,
and the phosphine additive had a modest effect, with
improvement noted for bisphosphines 1,3-diphenylphosphi-
nopropane (46%) and 1,4-diphenylphosphinobutane (43%).
The reaction worked equally well in DMF, DMSO, or
N-methylpyrrolidinone (NMP) but poorly in xylenes. The
use of Cs2CO3 in place of K2CO3 had no effect.
esterification11 of phthalaldehydic acid (4) with 6-bromo-1-
hexyne (6) (aqueous KOH, n-Bu4NBr, 80 °C, 18 h, 84%),
which was prepared from 5-hexyn-1-ol (5) (Br2, Ph3P, CH3-
CN, 0 °C, 87%),12 afforded ester 7 (90%). Takai olefination13
(4) Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem., Int. Ed. 2000,
39, 4308-4310.
The more elaborate alkyne cyclization partner bearing an
additional (Z)-alkene was synthesized from 3-butyn-1-ol (10)
by iodination of the dianion of 10 (94%) to afford 11
(Scheme 3), followed by diimide reduction (2 equiv of
TsNHNH2, 3 equiv of NaOAc, 1:1 THF/H2O, reflux, 4 h,
60%) to cis-vinyl iodide 12. Sonogashira coupling of 12 with
trimethylsilylacetylene (0.04 equiv of Pd(PPh3)4, 0.16 equiv
of CuI, Et2NH, 0 °C) afforded 13 (90%). Conversion of the
(5) Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817-1820.
(6) Labrecque, D.; Charron, S.; Rej, R.; Blais, C.; Lamothe, S.
Tetrahedron Lett. 2001, 42, 2645-2648.
(7) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H.; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188-8192.
(8) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 2163. Stephens,
R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313-3315.
(9) The Castro-Stephens and Sonogashira reactions effect sp2-sp
carbon-carbon bond formation. The Castro-Stephens coupling uses
stoichiometric copper, whereas the Sonogashira variant uses catalytic
palladium and copper: Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetra-
hedron Lett. 1975, 4467-4470. Sonogashira, K. Cross-Coupling Reactions
to sp Carbon Atoms. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich , F., Stang, P. Eds.; Wiley-VCH: New York, 1998; pp 203-
229.
(13) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(14) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org.
Chem. 1993, 58, 4716-4721.
(10) There has been only a single description of the use of either coupling
reaction for the synthesis of macrolactones: Yoshimura, F.; Kawata, S.;
Hirama, M. Tetrahedron Lett. 1999, 40, 8281-8285.
(15) Aerssens, M. H. P. J.; Brandsma, L. J. Chem. Soc., Chem. Commun.
1984, 735-736.
(11) Barry, J.; Bram, G.; Decodts, G.; Loupy, A.; Orange, C.; Petit, A.;
Sansoulet, J. Synthesis 1985, 40-45.
(16) Haseltine, J. N.; Cabal, M. P.; Mantlo, N. B.; Iwasawa, N.;
Yamashita, D. S.; Coleman, R. S.; Danishefsky, S. J.; Shulte, G. K. J. Am.
Chem. Soc. 1991, 113, 3850-3866.
(12) Hanak, M.; Auchter, G. J. Am. Chem. Soc. 1985, 107, 5238-5245.
3488
Org. Lett., Vol. 3, No. 22, 2001

Intramolecular Castro-Stephens coupling of 20 under a
variety of reaction conditions failed to provide the unsatur-
ated macrolactone 21. This is not surprising given the
potential sensitivity of propargylic and allylic epoxides, and
so it appeared that this factor led to the failure of this
particular cyclization.
Scheme 3
As a syn-1,2-diol could potentially serve as a precursor to
the oximidine I cis-epoxide, this option was implemented
in the synthesis of macrolactone 26 (Scheme 6). Enyne 22
Scheme 6
hydroxyl group of 13 to the corresponding bromide (Ph3P,
CBr4, -30 °C CH2Cl2, 3 h) afforded 14 (91%).
The cyclic (E,Z,Z)-triene system of oximidine II was
constructed from bromide 14 (Scheme 4) as above to afford
Scheme 4
ester 15 (60%). Takai olefination (78%) followed by removal
of the silyl group (96%) afforded 16 as a 4:1 ratio of
stereoisomers. The enyne ester of 16 underwent cyclization
onto the vinyl iodide to afford the macrocyclic dienyne 17
in modest yield (35%), again the yield being a consequence
of ring strain (alkyne nonlinearity ca. 24°). Semireduction
of the alkyne of 17 afforded (E,Z,Z)-triene lactone 18 (64%).
For the epoxide-bearing lactone of oximidine I, the
propargylic epoxide 19 was synthesized from 14 using a
Jacobsen epoxidation (Scheme 5).17 Transformation of the
was synthesized from 3-butyn-1-ol by hydrostannylation (n-
Bu3SnH, AIBN, 90 °C, 16 h, 80%) and iodination (83%) to
afford the trans-vinyl iodide,18 which was coupled with
trimethylsilylacetylene (0.04 equiv of Pd(PPh3)4, 0.16 equiv
of CuI, Et2NH, THF, 0 °C, 1.5 h, 95%). Conversion of the
alcohol to the bromide (CBr4, Ph3P, CH2Cl2, -30 °C, 82%)
afforded 22. Sharpless asymmetric dihydroxylation19 of 22
afforded the syn-1,2-diol, which was protected as the bis-
silyl ether 23 (i-Pr3SiOTf, 2,6-lutidine, CH2Cl2, 0 °C, 92%).
Esterification of phthalaldehydic acid (63%) and Takai
olefination (72%) provided 24. The Castro-Stephens cy-
clization of 24 proceeded in 15% yield for the formation of
enyne 25, likely because of ring strain and the presence of
a potentially reactive propargylic ether. Reduction of the
alkyne of 25 afforded the (E,Z)-diene lactone 26 (76%).
Scheme 5
To understand whether the modest yields for the intramo-
lecular Castro-Stephens coupling reactions were a specific
limitation of the synthetic protocol or were the result of
features inherent in the target molecules, we examined the
complementary bond forming process of macrolactonization.
(17) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378-
4380.
(18) Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O.; de Meijere, A.
J. Org. Chem. 1998, 63, 7811-7819.
(19) Jeong, K.; Sjo¨, P.; Sharpless, K. B. Tetrahedron Lett. 1992, 33,
3833-3836.
primary alcohol of 19 to the bromide, esterification of
phthalaldehydic acid, and Takai olefination afforded 20.
Org. Lett., Vol. 3, No. 22, 2001
3489

We were especially interested in understanding the role that
bond strain played in the formation of cyclic enyne systems,
and so we undertook a comparative study of macrolacton-
ization to form cyclic enyne 9 versus cyclic (E,Z)-diene 1
(Scheme 7). The cyclization substrates chosen for study were
substrate 30 afforded 9 in 26% yield plus 12% dimer. Diene
substrate 31 afforded 1 in 23% yield with 5% dimer under
similar conditions (1.7 equiv of Ph3P, 1.4 equiv of EtO2-
CNdNCO2Et, benzene, 0.004 M, 18 h). Yields were not
increased upon extended exposure of 30 and 31 to the
reaction conditions. Protocols that rely on nucleophilic acyl
substitution such as that of Yamaguchi21 were ineffective at
providing any of the cyclized products. These results clarify
two important aspects of the present work. There was no
significant difference in the gross rate of macrolactonization
of 30 versus 31 or in isolated yield of enyne 9 compared
with diene 1, so it does not appear that the strained cyclic
alkyne of 9 is the sole limiting factor of the cyclization yields.
Rather, this seems to be an inherent feature of the unsaturated
macrocyclic systems. In addition, using the standard synthetic
strategy of macrolactonization, the yields of cyclization
products were significantly lower than with the organome-
tallic-based coupling protocol described above, indicating the
suitability of the more complex protocol for the synthesis
of these ring systems.
Scheme 7
This report is the first description of the synthesis of the
unsaturated diene and triene macrolactone ring systems of
oximidines I and II. The Castro-Stephens macrocyclization
reaction was achieved in modest yields, presumably because
of the strain present in the macrocyclic enyne and dienyne
ring systems. Several factors contribute to this being a
valuable synthetic strategy, including the simplicity of the
approach, the degree of stereocontrol achieved in the
formation of the conjugated stereogenic double bonds, and
the convergent nature of the macrocyclization process.
synthesized by Sonogashira coupling of the vinyl iodide of
27 (prepared from phthalaldehydic acid by alkylative esteri-
fication and Takai olefination) with 5-hexyn-1-ol to afford
28 (76%). Semireduction of the alkyne of 28 afforded the
(E,Z)-dienol 29 (88%). Saponification of the methyl esters
of 28 and 29 (LiOH, 4:1 MeOH/H2O, 16 h, 25 °C) afforded
the corresponding carboxylic acids 30 (95%) and 31 (94%),
respectively.
Acknowledgment. This work was supported by a grant
from the NIH (CA 65875). We thank Mr. John M. Antos
and Professor T. V. Rajanbabu for helpful discussions.
Supporting Information Available: Procedure for in-
tramolecular Castro-Stephens coupling reactions and spec-
tral characterization of cyclization precursors 8, 16, 20, and
24, cycloalkyne products 9, 17, and 25, and products 1, 18,
and 26. This material is available free of charge via the
Internet at http://pubs.acs.org.
The most effective method for performing macrolacton-
ization in these systems was the Mitsunobu protocol.20 Under
standard cyclization conditions (1.7 equiv of Ph3P, 1.4 equiv
of EtO2CNdNCO2Et, benzene, 0.004 M, 24 h, 25 °C), enyne
OL016744E
(21) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(20) Mitsunobu, O. Synthesis 1981, 1-28
3490
Org. Lett., Vol. 3, No. 22, 2001