Total synthesis of ecteinascidin 743

Article abstract of DOI:10.1021/ja026216d

The total synthesis of ecteinascidin 743 (1), an extremely potent antitumor agent, has been accomplished. The synthesis features Ugi's 4CC reaction, intramolecular Heck reaction, phenol-aldehyde cyclization, and acid-induced intramolecular sulfide formation. Copyright

Full text of DOI:10.1021/ja026216d

Published on Web 05/17/2002
Total Synthesis of Ecteinascidin 743
Atsushi Endo, Arata Yanagisawa, Masanao Abe, Shigemitsu Tohma, Toshiyuki Kan, and
Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, CREST, The Japan Science and Technology
Cooperation (JST), 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received March 18, 2002
Scheme 2a
Ecteinascidin 7431 (Et 743, 1) is an extremely potent antitumor
agent isolated from a marine tunicate, Ecteinascidia turbinata. Et
743 is currently undergoing phase II clinical trials and also attracting
considerable attention owing to its unique mechanism of action.2
The novelty of its structure, the remarkable biological activities,
and its natural scarcity make it an attractive target for total
synthesis.3 To date, Corey and co-workers have reported the only
total synthesis of 1,3a which has recently been applied to the
semisynthesis of 1 from cyanosafracin B by chemists at Pharma
Mar.3b We describe herein the efficient total synthesis of 1 that
would potentially lead to the development of a practical synthesis
of this important compound and its analogues.
Scheme 1
a Reagents and conditions: (a) TFA, CH2Cl2, -10 °C (89%); (b) Tf2O,
pyridine, CH2Cl2, 0 °C (90%); (c) NaBH4, MeOH, 0 °C (85%); (d)
TBDPSCl, imidazole, DMF, room temperature (91%); (e) MeZnCl,
PdCl2(dppf) (3 mol %), THF, reflux (97%); (f) Pb(OAc)4, CH3CN, 0 °C;
(g) NH2OH‚HCl, NaOAc, EtOH, room temperature (89% in 2 steps).
Scheme 3a
The heart of our synthetic plan is illustrated in Scheme 1. The
pentacyclic benzyl alcohol 3 was designed as the key intermediate
in our strategy. The tricyclic aldehyde 4 was envisaged as an
appropriate platform for the preparation of 3, since the intramo-
lecular ortho substitution of the phenol by the aldehyde would give
the requisite oxidation state at the C-4 position, which is essential
for constructing the unique ten-membered cyclic sulfide.
Synthesis of the left segment 9, a highly functionalized (R)-
phenylglycinol derivative, involves a Mannich-type reaction of
phenol 5 with the chiral template 64 developed recently in our
laboratories (Scheme 2). Thus, regio- and stereoselective coupling
of phenol 55 with iminolactone 6 proceeded smoothly under acidic
conditions at -10 °C to give the desired adduct 7 as a single product
(89%). Conversion of the phenol to the triflate, reductive ring
opening of the lactone, and subsequent silylation of the primary
alcohol furnished 8. Introduction of the methyl group onto the
a Reagents and conditions: (a) n-BuLi, THF, -60 °C; DMF (79%); (b)
HC(OMe)3, cat. CSA, MeOH, room temperature (94%); (c) n-BuLi, Et2O,
0 °C to room temperature; I2; (d) concentrated HCl, THF, room temperature
(72% in 2 steps); (e) BnBr, K2CO3, CH3CN, reflux (98%); (f) 12, TMG,
CH2Cl2, room temperature (93%); (g) Rh[(COD)-(S,S)-Et-DuPHOS]+OTf-,
H2 (500 psi), EtOAc, 50 °C (99%, 94% ee); (h) LiOH, MeOH-H2O-
THF, 0 °C to room temperature (quant).
aromatic ring was achieved by Pd-catalyzed cross-coupling reaction
with MeZnCl (97%).6 Oxidative cleavage of the amino alcohol
moiety was effected with Pb(OAc)4, and the resultant imine was
converted to the desired amine 9 by treatment with NH2OH.
The right segment 15, (S)-iodophenylalanine derivative, was
synthesized from commercially available 3-methylcatechol by
employing DuPHOS-mediated asymmetric hydrogenation (Scheme
3).7 The previously reported bromide 103j,8 was converted to the
* To whom correspondence should be addressed. E-mail: fukuyama@
mol.f.u-tokyo.ac.jp.
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J. AM. CHEM. SOC. 2002, 124, 6552-6554
10.1021/ja026216d CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4a
a Reagents and conditions: (a) MeOH, reflux (90%); (b) TBAF, THF, room temperature (89%); (c) Ac2O, pyridine, DMAP, room temperature (93%); (d)
TFA, anisole, CH2Cl2, room temperature; (e) EtOAc, reflux (87% in 2 steps); (f) MsCl, Py, CH2Cl2, 0 °C (91%); (g) (Boc)2O, DMAP, CH3CN, room
temperature (97%); (h) NaBH4, H2SO4, EtOH-CH2Cl2, 0 °C; (i) CSA, quinoline, toluene, reflux (88% in 2 steps); (j) Pd2(dba)3 (5 mol %), P(o-tol)3 (20 mol
%), TEA, CH3CN, reflux (83%); (k) NaOH, MeOH-H2O, reflux; (l) Ac2O, pyridine, DMAP, room temperature (93% in 2 steps); (m) TFA, CH2Cl2, room
temperature; (n) TrocCl, aq. NaHCO3-CH2Cl2, room temperature (74% in 2 steps); (o) dimethyldioxirane, MeOH-acetone, 0 °C; cat. CSA (90%); (p)
NaBH3CN, TFA-THF, 0 °C (94%); (q) TBSCl, imidazole, DMF, room temperature (92%); (r) guanidinium nitrate, NaOMe, MeOH-CH2Cl2, 40 °C (85%);
(s) BnBr, K2CO3, CH3CN, reflux (91%); (t) Red-Al, THF, 0 °C (82%); (u) TMSCN, BF3‚OEt2, CH2Cl2, 0 °C (73%); (v) Ac2O, pyridine, DMAP, room
temperature (92%); (w) HF, CH3CN, room temperature (quant); (x) Dess-Martin periodinane, CH2Cl2, room temperature (92%); (y) Pd-C, H2, THF, room
temperature (84%); (z) allyl bromide, i-Pr2NEt, CH2Cl2, reflux (89%); (aa) K2CO3, MeOH, room temperature (99%); (bb) 27, WSCD‚HCl, DMAP, CH2Cl2,
room temperature (94%); (cc) NH2NH2, CH3CN, room temperature (98%); (dd) TFA, CF3CH2OH, room temperature; (ee) Ac2O, pyridine, DMAP, room
temperature (71% in 2 steps); (ff) Zn, AcOH, Et2O, room temperature (92%); (gg) HCHO, AcOH, NaBH3CN, MeOH, room temperature (96%); (hh)
Pd(PPh3)2Cl2, AcOH, n-Bu3SnH, CH2Cl2, room temperature (89%); (ii) 4-formyl-1-methylpyridinium benzenesulfonate, DMF-CH2Cl2, room temperature;
DBU; citric acid (54%); (jj) 30, NaOAc, EtOH, room temperature (96%); (kk) AgNO3, CH3CN-H2O, room temperature (93%).
benzaldehyde by halogen-lithium exchange and subsequent treat-
ment with DMF. Regioselective introduction of the iodo substituent
was next achieved by directed ortho-lithiation9 of the corresponding
dimethylacetal followed by quenching with I2. Simultaneous
cleavage of the MOM ether and the dimethylacetal and subsequent
benzylation of the phenol afforded the iodobenzaldehyde 11, which
was then subjected to Horner-Emmons reaction with the phos-
phonate 1210 to give the (Z)-dehydrophenylalanine derivative 13.
Catalytic asymmetric hydrogenation of 13 proceeded smoothly in
the presence of Rh[(COD)-(S,S)-Et-DuPHOS]+OTf- (1.5 mol %)
under an atmosphere of hydrogen (500 psi) to afford the aminoester
14 without appreciable loss of the aromatic iodide (99%, 94% ee).
Finally, basic hydrolysis of the methyl ester gave the desired
carboxylic acid 15.
These two segments, 9 and 15, were incorporated into the
diketopiperazine 19 by means of the powerful Ugi’s four-component
condensation reaction (Scheme 4).11 A mixture of amine 9,
carboxylic acid 15, p-methoxyphenyl isocyanide (16),12 and acet-
aldehyde (17) was heated in MeOH to afford the dipeptide 18 in
90% yield, which implies that all the carbon atoms needed for the
pentacyclic key intermediate 3 were efficiently assembled in a single
step. After switching from the TBDPS ether to the acetate,
simultaneous cleavage of the Boc group and the MOM ether gave
the aminophenol, which cyclized to afford 19 upon gentle heating
in EtOAc. As in our total synthesis of saframycins,13 acyliminium
ion-mediated cyclization was extensively studied to construct the
bicyclo[3.3.1] system without success. It was therefore extremely
gratifying to find that the intramolecular Heck reaction14 of the
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C O M M U N I C A T I O N S
cyclic enamide 20 proceeded under mild conditions to give the
tricyclic nucleus as in 21 that constitutes the right half of 1. Thus,
19 was converted to the key intermediate 20 by a four-step sequence
involving mesylation of the phenol, introduction of a Boc group
onto the lactam nitrogen, partial reduction of the ring carbonyl with
NaBH4, and dehydration of the resultant hemiaminal derivative by
treatment with CSA and quinoline. The crucial Heck reaction of
20 was performed in the presence of 5 mol % of Pd2(dba)3 and 20
mol % of P(o-tol)3 to afford the desired tricycle 21 in 83%.
The next challenge in the synthesis is the construction of the
pentacyclic framework via elaboration of the tricyclic aldehyde such
as 4 while controlling the stereochemistry at the C-3 position. After
switching the protecting groups of the amine and the phenol of 21
to the corresponding N-Troc-O-Ac compound, the enamide was
oxidized with dimethyldioxirane15 in MeOH-acetone to generate
an acid-sensitive epoxide, which, without isolation, was immediately
treated with CSA to afford methoxyalcohol 22 (90%) as a single
isomer. The subsequent acyliminium ion-mediated reduction under
acidic conditions occurred from the less hindered exo-face of the
molecule to afford alcohol 23 as a single product with the correct
stereochemistry (94%). Conversion of 23 to the oxazolidine 24 was
achieved in a four-step sequence involving silylation of the alcohol,
cleavages of the two acetyl groups,16 selective benzylation of the
phenolic hydroxyl group, and partial reduction of the lactam
carbonyl with Red-Al with concomitant formation of the oxazolidine
ring. Cleavage of the oxazolidine 24 with TMSCN and BF3‚OEt2
afforded the aminonitrile as a single stereoisomer, which was
subsequently converted to aldehyde 25 by a sequence involving
acetylation of the regenerated hydroxyl group, cleavage of the TBS
ether, and oxidation of the resultant alcohol with Dess-Martin
periodinane.17 As expected from our earlier model studies, hydro-
genolysis of the benzyl ethers 25 invoked a spontaneous cyclization,
giving the desired pentacycle 26, a synthetic equivalent of 3, in
84% yield. Having succeeded in obtaining the key intermediate 26
with the correct oxidation state at the C-4 position, we then turned
our attention to the formation of the ten-membered sulfide ring.
Selective allylation of the phenols, cleavage of the acetyl group,
and condensation of the resultant alcohol with L-cysteine derivative
27 furnished ester 28. Chemoselective hydrazinolysis of the
thioacetate gave the thiol, which, upon exposure to TFA in 2,2,2-
trifluoroethanol under high dilution conditions (0.009 M), smoothly
underwent cyclization to give the ten-membered sulfide. Subsequent
acetylation of the resultant phenol gave 29 (71% in 2 steps).
With the desired ten-membered sulfide 29 in hand, all that is
necessary to complete the total synthesis of 1 is the construction
of the last tetrahydroisoquinoline moiety. Cleavage of the Troc
group followed by reductive alkylation afforded N-methyl amine,
whose Alloc group and allyl ether were simultaneously cleaved
with palladium catalyst to give the aminophenol. According to the
protocol reported by Corey,3a biomimetic transamination reaction18
afforded the known R-ketolactone,3b and subsequent Pictet-
Spengler reaction with amine 30 furnished ecteinascidin 770 (2).19
Finally, generation of the labile hemiaminal from the aminonitrile
was effected by treatment with AgNO3 in CH3CN-H2O to give
ecteinascidin 743 (1), which gave spectral data (1H NMR, 13C NMR,
IR, and HR MS) in full agreement with those of the natural product.
In conclusion, an enantioselective total synthesis of ecteinascidin
743 (1) has been accomplished. Our synthesis features Ugi’s four-
component condensation reaction for a ready access to diketopi-
perazine 19, the intramolecular Heck reaction of the cyclic enamide
20 to give tricycle 21, phenol-aldehyde cyclization to construct
the pentacyclic key intermediate 26, and acid-induced ten-membered
sulfide formation. Further modifications of the present route to
establish a truly practical synthesis of 1 and its analogues are
currently underway in our laboratories.
Acknowledgment. This research was supported in part by the
Ministry of Education, Culture, Sports, Science and Technology.
We thank Dr. Naoki Saito (Meiji Pharmaceutical University) for
providing spectral data of the natural products.
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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