9202
J. Am. Chem. Soc. 1996, 118, 9202-9203
tylaluminum hydride in CH2Cl2 at -78 °C for 1 h) to give the
chiral aldehyde 8 (>90% yield).
Enantioselective Total Synthesis of Ecteinascidin
743
The next stage of the synthesis, which involved the combina-
tion of the building blocks 6 and 8 and subsequent elaboration
to construct the key monobridged pentacyclic intermediate 10,
commenced with the reaction of 6 and 8 in HOAc containing
25 equiv of KCN at 23 °C for 18 h to give a coupled phenolic
R-amino nitrile (61%) and subsequent O-allylation to give allyl
ether 9 in 87% yield (2 equiv of Cs2CO3 and 5 equiv of allyl
bromide in DMF at 23 °C for 1 h). Treatment of 9 with 1.2
equiv of diisobutylaluminum hydride in toluene at -78 °C for
5 h effected the selective conversion of the lactone function to
a lactol which was desilylated by exposure to excess KF‚2H2O
in CH3OH at 23 °C for 20 min and cyclized to pentacycle 10
by internal Mannich bisannulation with 20 equiv of CH3SO3H
in CH2Cl2 in the presence of 3 Å molecular sieves at 23 °C for
5 h (55% overall from 9). Selective trifluoromethanesulfonation
of the least hindered phenolic hydroxyl (5 equiv of Tf2NPh,
Et3N, 4-(dimethylamino)pyridine (DMAP) in CH2Cl2 at 23 °C
for 6 h; 72% yield) was followed by (1) selective silylation of
the primary hydroxyl (excess tert-butyldiphenylsilyl chloride-
DMAP in CH2Cl2 at 23 °C for 13 h; 89%), (2) protection of
the remaining phenolic group as the methoxymethyl ether
(MeOCH2Br and i-Pr2NEt in CH2Cl2 at 23 °C for 20 min; 92%),
(3) double deallylation (Bu3SnH, catalytic Cl2Pd(PPh3)2, excess
HOAc in CH2Cl2 at 23 °C for 15 min; 100%), (4) reductive
N-methylation (excess Formalin, NaBH3CN, HOAc in CH3CN
at 23 °C for 30 min; 95%), and (5) replacement of CF3SO3 by
CH3 (excess Me4Sn, Cl2Pd(Ph3P)2, LiCl, DMF, 80 °C, 2 h) to
give 11 in 83% yield. Oxidation of the phenol 11 with 1.1
equiv of (PhSeO)2O in CH2Cl2 at 23 °C for 15 min effected
position-selective angular hydroxylation to yield after desily-
lation (2 equiv of Bu4NF in THF at 23 °C for 10 min) the
dihydroxy dienone 12 (75% from 11).
The last three rings of ecteinascidin 743, the 10-membered
lactone bridge and the spiro tetrahydroisoquinoline subunit, were
then added in the final stage of the synthesis of 1 by a novel
sequence of reactions. The primary hydroxyl function of 12
was esterified with (S)-N-((allyloxy)carbonyl)-S-(9-fluorenyl-
methyl)cysteine using 5 equiv of 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride and 5 equiv of DMAP in
CH2Cl2 at 23 °C for 30 min to form 13 (91%). Compound 13
was then transformed in one flask to the bridged lactone in 79%
overall yield by the following operations: (1) reaction of 13
with the in situ-generated Swern reagent from excess triflic
anhydride and DMSO at -40 °C for 30 min,8a (2) addition of
i-Pr2NEt and warming to 0 °C for 30 min to form the exendo
quinone methide,8b (3) quenching with tert-butyl alcohol (to
destroy excess Swern reagent), (4) addition of excess N-tert-
butyl-N′,N′,N′′,N′′-tetramethylguanidine9 to convert the 9-fluo-
renylmethyl thiolether to the thiolate ion and to promote
nucleophilic addition of sulfur to the quinone methide to
generate the 10-membered lactone bridge, and (5) addition of
excess Ac2O to acetylate the resulting phenoxide group. The
N-((allyloxy)carbonyl) group of 14 was cleaved (excess Bu3-
SnH, HOAc, and catalytic Cl2Pd(PPh3)2 in CH2Cl2 at 23 °C
for 5 min; 84%), and the resulting R-amino lactone was oxidized
to the corresponding R-keto lactone by transamination with the
methiodide of pyridine-4-carboxaldehyde, 1,8-diazabicyclo-
[6.4.0]undec-7-ene (DBU), and DMF in CH2Cl2 at 23 °C for
40 min to give 15 (70%). Reaction of 15 with 2-[3-hydroxy-
E. J. Corey,* David Y. Gin, and Robert S. Kania
Department of Chemistry, HarVard UniVersity
Cambridge, Massachusetts 02138
ReceiVed July 18, 1996
Described herein is the first total synthesis of ecteinascidin
743 (1),1 an exceedingly potent and rare marine-derived
antitumor agent which is slated for clinical trials when adequate
quantities become available.2,3 The synthesis is enantio- and
stereocontrolled, convergent and short (Scheme 1).
The R,â-unsaturated malonic ester 2, prepared as a mixture
of E and Z isomers from 2-(benzyloxy)-3-methyl-4,5-(meth-
ylenedioxy)benzaldehyde4a and allyl 2,2-dimethoxyethyl malo-
nate4b (2 equiv of piperidine and 4 equiv of acetic acid in C6H6
or C7H8 at 23 °C for 18 h; 99%), was subjected to selective
allyl ester cleavage (Et3N-HCOOH, catalytic Pd(PPh3)4, 23 °C,
4 h; 94% yield), Curtius rearrangement (1.2 equiv of (PhO)2P-
(O)N3, 4 equiv of Et3N, in C7H8 containing 4 Å molecular sieves
at 70 °C for 2 h), and reaction of the intermediate isocyanate
with benzyl alcohol at 23 °C for 1 h to form 3 stereospecifically
(93% yield).5 Hydrogenation of 3 at 3 atm with Rh[(COD)-
(R,R)-DIPAMP]+BF4- as catalyst at 23 °C for 16 h afforded 4
in 97% yield and 96% ee.6 Acetal cleavage of 4 (10 equiv
BF3‚Et2O and 10 equiv of H2O in CH2Cl2 at 0 °C for 10 min),
isolation, and exposure of the resulting aldehyde to BF3‚Et2O
(17 equiv) and 4 Å molecular sieves in CH2Cl2 at 23 °C for 18
h gave the bridged lactone 5 in 73% yield.7 Hydrogenolysis of
5 (1 atm H2, 10% Pd/C, EtOAc, 23 °C, 6 h) produced the free
amino phenol 6 in 100% yield. The protected R-amino ester 7
was synthesized by an analogous route, starting with 3,5-bis-
((tert-butyldimethylsilyl)oxy)-4-methoxybenzaldehyde and meth-
yl hydrogen malonate, and then reduced (2 equiv of diisobu-
(1) The pioneering research in this area is due to Prof. Kenneth L.
Rinehart and his group, see: (a) Rinehart, K. L.; Shield, L. S. In Topics in
Pharmaceutical Sciences; Breimer, D. D., Crommelin, D. J. A., Midha, K.
K., Eds.; Amsterdam Medical Press: Noordwijk, The Netherlands, 1989;
pp 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.;
Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.;
Shield, L. S.; Seigler, D. S.; Li, L. H.; Martin, D. G.; Grimmelikhuijzen,
C. J. P.; Ga¨de, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai,
R.; Holt, T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G.
R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.;
Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.;
Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D.
A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O.
J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.;
Wang, H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
(2) Science 1994, 266, 1324.
(3) The current clinical plan calls for the administration of three 0.5 mg
doses of 1 per patient; personal communication from Dr. Glynn Faircloth,
PharmaMar USA, Cambridge, MA.
(4) (a) Prepared from 3,4-(methylenedioxy)phenyl methoxymethyl ether
by the sequence: (1) lithiation at C-2 (3 equiv of BuLi, 3 equiv of
tetramethylethylene diamine in hexane at 0 °C for 4 h) and reaction with
CH3I (6 equiv at -78 f 23 °C over 15 min) to afford exclusively the
2-methyl derivative (87%); (2) ortho lithiation (2 equiv of BuLi in THF at
-30 °C for 13 h) and subsequent formylation with 4 equiv of DMF (64%
yield); (3) cleavage of the MeOCH2 protecting group (0.55 equiv of CH3-
SO3H in CH2Cl2 at 0 °C; (4) treatment of the resulting 3-methyl-4,5-
(methylenedioxy)salicylaldehyde with 1.5 equiv of NaH in DMF at 0 °C
for 5 min and 2 equiv of benzyl bromide at 23 °C for 40 min (86% overall).
(b) Prepared from the monoallyl ester of malonic acid by conversion to the
mixed anhydride with BOP chloride (Aldrich) and reaction with 2,2-
dimethoxyethanol.
(5) This step, which involves isomerization possibly of the intermediate
isocyanate, represents a generally useful process for the stereospecific
synthesis of such compounds.
(6) Koenig, K. E. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press, Inc.: Orlando, FL, 1985; Vol. 5, p 71.
(7) The conversion 4 f 5 demonstrates a method for control of
stereochemistry in the tetrahydroisoquinoline series.
(8) (a) This step converts the tertiary hydroxyl group of 13 to the
O-dimethylsulfonium derivative. The use of oxalyl chloride-DMSO as
reagent is unsatisfactory due to interference by chloride in the subsequent
steps of quinone methide formation and addition. (b) This step generates
the quinone methide probably by cycloelimination of the Swern type
oxosulfonium ylide intermediate.
(9) Barton, D. H. R.; Elliott, J. D.; Ge´ro, S. D. J. Chem. Soc., Perkin
Trans. 1 1982, 2085.
S0002-7863(96)02480-8 CCC: $12.00 © 1996 American Chemical Society
Corey
