Total synthesis of (+)-amphidinolide J [9]

Full text of DOI:10.1021/ja982572d

11198
J. Am. Chem. Soc. 1998, 120, 11198-11199
Scheme 1
Total Synthesis of (+)-Amphidinolide J
David R. Williams* and William S. Kissel
Department of Chemistry
Indiana UniVersity
Bloomington, Indiana 47405
ReceiVed July 20, 1998
The amphidinolides are a family of important biologically
active macrolides isolated from the marine dinoflagellate Am-
phidinium sp., a symbiotic microalga found in the Okinawan
flatworm Amphiscolops sp.1 The amphidinolides have shown
extraordinary activity against a variety of NCI tumor cell lines.
However, the fact that there are extremely limited quantities has
slowed the pace of biological studies and, in many cases,
hampered progress toward complete structural assignments of
these unusual macrolides.2 Interestingly, this family of metabolites
exhibits remarkable structural diversity with twenty-one reported
examples of amphidinolides A through S, illustrative of macro-
cycle formation ranging from twelve-membered to twenty-seven
membered systems.3 Amphidinolide J (1) was the first of the
face addition to the bis-chelated syn-s-cis conformer of 4. Further
conversions to homoallylic iodide 2 proceeded in excellent overall
yield.
Coupling reactions for stereocontrolled formation of the E-C7-
C8 alkene were undertaken using the E-vinyl iodide 10 (Scheme
2). The production of 10 utilized the base-induced elimination
of the chloro-epoxide 8, which was accessible from the Sharpless
asymmetric epoxidation product 7.10 Hydrozirconation of 9
ensured formation of the desired alkene 10 via syn-addition.11
Unfortunately, attempted alkylations of the alkenyllithium or
cuprate intermediates derived from 10 promoted facile elimina-
tions of iodide 2 to its corresponding diene. The problem was
overcome by formation of the stable homoallylic zinc reagent 2a
(Scheme 1). This novel, well-behaved alkylzinc displayed no
products of dimerization, cyclopropylcarbinyl tautomerism, or
family in which the relative and absolute stereochemistries were
defined.4 Very recently, isomeric amphidinolide R was discov-
ered as the 14-membered macrolactone formed from esterification
of the C-13 hydroxyl of a common seco acid leading to 1.5 Herein
we report the total synthesis of (+)-amphidinolide J (1), and thus
communicate the first successful route for total synthesis of a
macrolide of the amphidinolide family.
Our convergent, stereocontrolled synthesis of 1 was executed
from three subunits which were fashioned from considerations
of disconnections of C1-O (lactonization), C6-C7, and C12-C13
bonding. Current studies in our laboratories have explored recent
advances in organozinc chemistry as a significant development
for the preparation of these functionalized macrolactones.
As illustrated in Scheme 1, the first component, optically active
iodide 2, was prepared via the conjugate addition of the
Yamamoto organocopper species6,7 derived from the vinyl
bromide 3.8 Low-temperature addition to the (S)-4-phenyl-N-
enoyloxazolidinone 49 produced the imide 5 ([R]24D +31.1 (c 7.75,
CHCl3)) in 95% yield with complete diastereoselectivity. Asym-
metric induction at C-3 (2) can be attributed to the exclusive re-
t
â-elimination (formation from 2; BuLi (2 equiv), THF at -78
°C; then ZnCl2 (1 equiv), -78 °C f rt).12,13 Application of the
Negishi protocol12 for palladium-catalyzed reaction of 2a with
10 was highly successful. In this fashion, palladium coupling of
the functionalized homoallylzinc species forged a versatile and
stereospecific synthesis of the 1,5-diene 11 (Scheme 2). Utiliza-
tion of the Takai reaction15 produced alkene 12a in 77% yield
(9) Nicola´s, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766.
Hruby, V. J.; Han, Y. Tetrahedron Lett. 1997, 38, 7317. For a survey of
conjugate additions of Yamamoto-based reagents using the 4-phenyl-N-
enoyloxazolidinone auxiliary: Williams, D. R.; Kissel, W. S.; Li, J.
Tetrahedron Lett. 1998, 39, 8593.
(10) Epoxide 7 was obtained in nearly quantitative yield (de > 95%) as
previously reported: Williams, D. R.; Jass, P. A.; Tse, H.-L. A.; Gaston, R.
D. J. Am. Chem. Soc. 1990, 112, 4552.
(1) (a) Kobayashi, J.; Shigemori, H.; Ishibashi, M.; Yamasu, T.; Hirota,
H.; Sasaki, T. J. Org. Chem. 1991, 56, 5221. (b) Kobayashi, J. J. Nat. Prod.
1989, 52, 225. For a review: Kobayashi, J.; Ishibashi, M. Chem. ReV. 1993,
93, 1753.
(2) (a) Ishibashi M.; Sato, M.; Kobayashi, J. J. Org. Chem. 1993, 58, 6928.
(b) Bauer, I.; Maranda, L.; Shimizu, Y. J. Am. Chem. Soc. 1994, 116, 2657.
(3) Ishibashi, M.; Kobayashi J. Heterocycles 1997, 44, 543.
(4) Kobayashi, J.; Sato, M.; Ishibashi, M. J. Org. Chem. 1993, 58, 2645.
(5) Ishibashi, M.; Takahashi, M.; Kobayashi, J. Tetrahedron 1997, 53, 7827.
(6) Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986, 25, 947.
(7) For recent examples of related asymmetric conjugate additions in natural
product synthesis: Williams, D. R.; Li, J. Tetrahedron Lett. 1994, 35, 5113.
Rzasa, R. M.; Shea, H. A.; Romo, D. J. Am. Chem. Soc. 1998, 120, 591.
(8) Bromoboration of 4-(tert-butyldiphenylsilyloxy)-1-butyne with B-bromo-
9-borobicyclononane (CH2Cl2) followed by HOAc/NaOAc quench provided
3 in 83% yield. Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron
Lett. 1983, 24, 731.
(11) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.; King,
S. M. Tetrahedron Lett. 1987, 28, 3895. Quenching the intermediate alkenyl
zirconium species with iodine caused cleavage of the uncharacteristically labile
C-9 SEM ether.
(12) Although functionalized homoallylic zinc derivatives have received
little attention in complex molecule synthesis, the advantages of 3-butenylzincs
in coupling reactions have been discussed. Negishi, E.; Ay, M.; Gulevich, Y.
V.; Noda, Y. Tetrahedron Lett. 1993, 34, 1437.
(13) A novel methylene insertion offers opportunities for generation of
functionalized homoallylic zinc species. Knochel, P.; Singer, R. D. Chem.
ReV. 1993, 93, 2117.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156. Ireland, R.
E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(15) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497. Owing to the
presence of R-branching in the precursor aldehydes, high proportions of the
E-alkenes were obtained without the use of dioxane.
10.1021/ja982572d CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/16/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 43, 1998 11199
Scheme 2
Scheme 3
for the two-step oxidation-olefination procedure as a 15:1 ratio
of E/Z-isomers with no evidence of epimerization of the C-10
stereocenter.
As illustrated in Scheme 3, the optically active 2-methyl-1,3,4-
butanetriol derivative 1316 served as a precursor to aldehyde 15
for incorporation of the C13-C20 segment. Oxidation of 13
produced an aldehyde which suffered partial epimerization upon
flash chromatography. To avoid this problem, dilution of crude
oxidation mixtures with hexanes and filtration afforded product
which could be used directly in the subsequent Takai reaction15
to 14 (E/Z ratio 19:1). Palladium-catalyzed coupling of 14 with
n-propylzinc chloride12 led to desired aldehyde 15. Studies to
Finally, macrocyclization was achieved in 63% yield by the
Yamaguchi procedure.19 In situ generation of the mixed anhy-
dride (2,4,6-trichlorobenzoyl chloride, iPr2NEt, DMAP, CH2Cl2)
at 22 °C under high dilution conditions (0.0006 M for 18 h)
yielded the fifteen-membered macrolactone ([R]23 +76.1° (c
D
1.00, CHCl3)). Removal of the C-9 allylic SEM ether was
accomplished with mildly acidic conditions (PPTs, tBuOH, reflux),
and transesterification (MeOH, K2CO3) yielded amphidinolide J
(1) (58% for 2 steps). Comparisons of our synthetic amphi-
dinolide J demonstrated that it was identical in all respects with
spectroscopic data provided for the natural substance.20
t
join 15 and the alkenyllithium 12b (Scheme 2: BuLi (2.2 equiv),
THF at -78 °C) gave poor yields of the diastereomeric C-13
alcohols (1:1 ratio). However, conversion to dimethylalkenyl-
zincate 12c (12b; then Me2Zn (1.5 equiv)) provided exclusive
formation of 16. Although the nucleophilic behavior of similar
mixed zincates is generally not well characterized,17 the reaction
proceeded with selective transfer of the E-alkenyl group,18
producing the stereochemical result of a chelation-controlled
model. Standard operations led to intermediate aldehyde 17, and
the noteworthy DDQ deprotection of 17 to the C-14 hydroxy-
aldehyde 18 permitted selective sodium chlorite oxidation to seco-
acid 19.
Acknowledgment. The authors gratefully thank the National Institutes
of Health (GM-42897) for generous support of our work. A grant from
Merck Research Laboratories, a Division of Merck & Co., Inc., is also
gratefully acknowledged.
Supporting Information Available: Experimental procedures and
spectral data for all of the compounds of the synthesis pathway to (+)-
amphidinolide J and 1H/13C NMR spectra of 1 (26 pages, print/PDF).
See any current masthead page for ordering information and Web access
instructions.
(16) Alcohol 13 was prepared from 2R,3R-4-(tert-butyldiphenylsilyloxy)-
3-methyl-1,2-butanediol with appropriate protecting groups via slight modi-
fication of the previously reported four-step pathway; see ref 10. Also: Jass,
P. A.; Ph.D. Thesis, Indiana University, 1994.
JA982572D
(17) To our knowledge, this appears to be the first description of a mixed
zincate for natural product synthesis. For examples of triorganozincate additions
to aldehydes: Kondo, Y.; Takazawa, N.; Yoshida, A.; Sakamoto, T. J. Chem.
Soc., Perkin Trans. I 1995, 1207. Kondo, Y.; Takazawa, N.; Yamazaki, C.;
Sakamoto, T. J. Org. Chem. 1994, 59, 4717.
(19) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. For a review of macrocyclization: Meng,
W.; Hesse, M. Top. Curr. Chem. 1991, 107-176.
(20) We thank Professor Jun’ichi Kobayashi (Hokkaido University) for
providing proton and carbon NMR spectra of authentic 1. Our synthetic 1
was also consistent with the published IR and MS data of the natural product.
(18) Tu¨ckmantel, W.; Oshima, K.; Nozaki, H. Chem. Ber. 1986, 119, 1581.