Synthetic explorations in the saframycin-ecteinascidin series: Construction of major chiral subunits through catalytic asymmetric induction

Article abstract of DOI:10.1016/S0040-4039(00)00105-2

The major subunits needed to reach the titled targets have been assembled by chemistry, which included p-Claisen rearrangement, asymmetric epoxidation and asymmetric dihydroxylation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00105-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2039–2042
Synthetic explorations in the saframycin-ecteinascidin series:
construction of major chiral subunits through catalytic
asymmetric induction
Bishan Zhou,a Scott Edmondson,a Juan Padron a and Samuel J. Danishefsky a,b,∗
aThe Department of Chemistry, Columbia University, Havemeyer Hall, New York, NY 10027, USA
bThe Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Ave., New York,
NY 10024, USA
Received 7 July 1999; revised 17 December 1999; accepted 19 December 1999
Abstract
The major subunits needed to reach the titled targets have been assembled by chemistry, which included p-
Claisen rearrangement, asymmetric epoxidation and asymmetric dihydroxylation. © 2000 Elsevier Science Ltd.
All rights reserved.
The screening of natural product sources for new drug candidates with useful therapeutic margins has
led to a variety of novel structures. One of the most fascinating and promising of these is ecteinascidin 743
(1=ET 743) derived from the marine tunicate Ecteinascidia turbinata.1 The novel structure of ET 743, its
difficult availability, and its exceedingly potent cytotoxicity (as well as its advancement to clinical trials)
conspire to render it an attractive target for total synthesis. This goal was undertaken and accomplished
in a most interesting fashion by Corey and co-workers.2 Follow-up studies by Corey, Schreiber3 and
co-workers resulted in the demonstration that a significantly simplified version of 1 (ie: phthalascidin)
retains the cytotoxicity of the natural product.
Our interest in ET 743 was much influenced by the considerations described above, with an additional
caveat. Some years ago, well before the ecteinascidins were known, we had accomplished what was then
the only total synthesis of quinocarcinol.4 We wondered whether the central Mannich-like envelopment
strategy, which was our take home lesson in the quinocarcin series, could be adapted to the ET problem.
This matter will be considered in greater detail in the subsequent letter.5
We undertook to test these and other relevant questions in the context of a synthesis directed to systems
of the type 3. From the perspective of its two aromatic sectors, 3 can be viewed as more closely related
to the saframycin series (2) than to ET.6 Indeed, the aromatic rings in 3 can be regarded as modified
hydroquinone versions of the quinone moieties of saframycin, with the important proviso that 3 also
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00105-2
tetl 16384

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contains a 4-oxo group. This function, in the context of appropriate aromatic domains, is potentially
valuable for synthesizing ET and a new range of analogs thereof.
Our approach to 3 contemplated the merger of two moieties, 16 and 25, wherein each component
would bear the absolute configuration appropriate to the goal system in high enantiomeric excess. In
this disclosure, we describe the pathways, which we followed for reaching the key building blocks. Our
inquiry was directed to the applicability of catalytic oxidative asymmetric induction to these targets, and
was strongly influenced by precedents from Sharpless.7a–c
Scheme 1. (a) 1.1 equiv. BrCH2CH_CHCH2OTBS, 1.5 equiv. K2CO3, CH3CN, reflux, 5 h, 100%; (b) 1.1 equiv. 30%, H2O2,
cat. SeO2, t-BuOH, 40°C, 5 h, then Et3N, MeOH, 85%; (c) 1.1 equiv. MOMCl, 1.5 equiv. (i-Pr)2NEt, CH2Cl2, 80°C, 12 h, 100%;
(d) 1.1 equiv. Me2NPh, toluene, 210°C, 12 h, 96%; (e) MeI(xs), 1.5 equiv. K2CO3, CH3CN, reflux, 12 h, 87%; (f) 1.5 equiv.
TBAF, THF, 1 h; (g) 1.1 equiv. PivCl, pyridine:CH2Cl2 (1:20), 3 h; (h) 3N HCl, THF–i-PrOH (2:1), 12 h, 99% for three steps; (i)
3 equiv. Et2AlCl, (CH2O)n(xs), CH2Cl2, 12 h, 96%; (j) MeI(xs), 1.5 equiv. K2CO3, CHCl3:MeOH (2:1), reflux, 12 h, 90%; (k)
1.2 equiv. TBSCl, 1.5 equiv. imidazole, cat. DMAP, CH2Cl2, 1 h, 99%; (l) 2.5 equiv. DIBAL-H, CH2Cl2, −78°C, 30 min, 94%;
(m) 8% (D)-DET, 5.6% Ti(OiPr)4, 2 equiv. t-BuOOH, m.s. 4 Å, −20°C, 1 day, 98% (95% ee); (n) 3.5 equiv. Ti(OiPr)2(N3)2,
PhH, 80°C, 76% (single isomer); (o) (MeO)2CMe2:acetone (1:2), cat. p-TsOH·H2O, 10 min, 100%; (p) H2, Pd/C, EtOAc, 1.2
equiv. (Boc)2O, 5 h, 100%; (q) 1.5 equiv. TBAF, THF, 1 h; (r) 1.2 equiv. PMBCl, 2 equiv. NaH, cat. n-BuN+I−, THF:DMF
(5:1), 5 h, 96% for two steps; (s) MeI(xs), 5 equiv. NaH, THF:DMF (5:1), 12 h, reflux, 93%; (t) (i) 80% AcOH, 12 h; (ii) 0.2
equiv. KMnO4, 4 equiv. NaIO4, 0.5 equiv. Na2CO3, dioxane:H2O (2.5:1), 10 h, 95%
We begin with the route followed to reach 16 (Scheme 1). The starting material was the readily acces-
sible 4,8 obtained from the commercially available 2,4-dimethoxy-3-methyl benzaldehyde. Compound 4
was converted by O-alkylation, as shown to ether 5. Dakin-like9 oxidative cleavage of the aryl aldehyde
linkage generated a formate, which was deacylated by trans esterification. Protection of the resultant

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phenol afforded 6. It will be recognized that the allylic ether had served to protect the C2 hydroxyl
group while the substituent at C1 was being adjusted in a constructive way. At this point, p-Claisen
rearrangement and sequential protection of the phenol and primary allylic alcohol functions, as indicated,
led to 7 and thence 8. Cleavage of the MOM group was now readily accomplished and the resultant phenol
function was exploited to bring about O-hydroxymethylation (see compound 9). Selective methylation
of the phenolic hydroxyl and silylation of the primary benzylic alcohol led to 10.
The setting was in place to introduce the L-amino acid functionality. An allylic alcohol (see structure
11) was exposed on cleavage of the pivaloate. Sharpless K. B.,7a under the conditions shown, led to
12 in high ee (>95%). Azidolysis of the oxirane linkage under titanium mediated direction7c afforded a
t
diol. To allow for building the required N-methyl Boc linkage, the diol was protected as its acetonide
(see structure 13). From that point, the azide linkage was reductively cleaved in the presence of Boc
anhydride to afford 14. Subsequent to cleavage of the TBS group and installation of a p-methoxybenzyl
function, 15 was in hand. Following N-methylation, hydrolysis of the acetonide, and oxidative cleavage
of the diol,10 compound 16 was secured.
The synthesis of 25, with the suitable S configuration at the future C13, commenced with the
known and readily available benzaldehdye 17,11 which was converted to 18 (Scheme 2). Asymmetric
dihydroxylation7b of the styrene like double bond through the action of AD mix-α gave rise to 19 (>95%
ee), from which the epoxide 20 was derived as shown. Azidolysis of the epoxide compound, under the
conditions indicated, resulted in a 6.5:1 preference for attack at the benzylic, as opposed to primary
carbon. The major product, 21, was converted to its O-benzyl derivative 22.
Scheme 2. (a) 1.6 equiv. Ph3P_CH2Li, THF, 0°C, 1 h, 96%; (b) 1.1 equiv. AD-mix-α, t-BuOH:H2O (1:1), 0°C, 3 d, 99%; (c)
1.1 equiv. TsCl, pyridine:CH2Cl2 (1:1), 1 d, 95%; (d) 2 equiv. K2CO3, MeOH, 4 h, 95%; (e) 4 equiv. NaN3, 15 equiv. LiClO4,
CH3CN, 60°C, 5 h, (2°:1°=6.5:1); (f) 1.1 equiv. BnBr, 5 equiv. NaH, cat. n-BuN+I−, THF, 5 h, 90% for 2 steps; (g) H2, Pd/C,
EtOAc, 1.2 equiv. (Boc)2O, 5 h, 100% (h) TFA:CH2Cl2 (1:2), then NaHCO3 (i) 4 equiv. K2CO3, 5 equiv. BrCH2CH(OEt)2,
CH3CN, reflux, 3 d, 80% for 2 steps; (j) 12N HCl:THF (1:1), then NaOH, 88% (β-OH:α-OH=4:1)
t
The azide linkage was reduced in the presence of Boc anhydride to afford 23. The Boc protection
maneuver was conducted for convenience in the isolation process. Cleavage of the Boc group of 23
was followed by monoalkylation of the resultant amine function with diethylbromoacetal in high yield
(see compound 24). Finally, the tetrahydroisoquinole ring was produced by the Pomerantz–Fritsch type
cyclization of 24.12 Product 25 was obtained as a 4:1 mixture of β,α stereoisomers at the future C4. As
will be seen,5 this stereochemical issue is without consequence, since this center is destined to become a
ketone in short order.

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In summary, we have shown that a suitably directed p-Claisen rearrangement followed by Sharpless
K. B.7a can be used to generate a significantly functionalized tyrosine (see compound 16) analog.
Furthermore, Sharpless K. B.7b followed in due course by a modified Pomerantz–Fritsch cyclization,
has been used to reach a valuable heavily functionalized tetrahydroisoquinoline subtype 25 in high ee.
Acknowledgements
This work was supported by the National Institutes of Health (Grant Nos CA-28824 and HL-25848
(S.J.D.). B.Z. gratefully acknowledges the Pharmacia-Upjohn Corporation for a predoctoral Fellowship.
S.D.E. gratefully acknowledges the N.I.H. for a postdoctoral Fellowship (Grant No. GM18335). We
thank Vinka Parmakovich and Barbara Sporer (Columbia University) for mass spectral analyses.
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