Earlier, we had reported on the use of the Pomeranz-
Fritsch reaction to gain access to optically pure tetra-
hydroisoquinoline substrates.7 The enantiomeric definition
at C1 arose from Sharpless asymmetric dihydroxylation8 of
the starting styrene 12 en route to optically defined amine
13. Cleavage of the acetal set into motion the cyclization
reaction that led to 14. In this product, C1 is enantiomerically
homogeneous, but C4 emerges as a mixture of diastereomers.
After the NH function was protected as a urethane (see 15),
cleavage of the primary ether function afforded 16 in 99%
yield. Our first encouraging finding was that treatment of
this mixture with TFA in the presence of molecular sieves
provided 17. We construed this cyclization to a six-membered
ring as an encouraging precedent for the more ambitious case
we had in mind (cf. 10 f 11, Scheme 2).
as shown (Scheme 4). The route started from phenol 18,
known from earlier work in our laboratory on an unrelated
problem.9 It continued through bromocatechol 19 and thence
to styrene 20, which was advanced as above to amine 21
and thence to diastereomer mixture 22. Following protection
of the NH group as a Boc derivative and silylation of the
secondary hydroxyl group, the primary ether was debenzy-
lated as shown (see intermediates 23).
Following precedents of the Corey-Gin synthesis, the
alcohols 23 were coupled to freshly prepared cysteine acid
24.4,10 The desired esters 25 were produced in excellent yield
(see Scheme 5). Subsequent deprotection of the PMB group
Scheme 5a
Scheme 3a
a Reagents and conditions: (a) EDC, DMAP, CH2Cl2, 95%; (b)
Hg(O2CCF3)2, 80% AcOH, 80%; (c) TFA, 4 Å molecular sieves,
CH2Cl2, 95%.
a Reagents and conditions: (a) 6N HCl, THF, H2O, 80%; (b)
Boc2O, Et3N, EtOAc, >90%; (c) H2 (1 atm), 10% Pd/C, EtOAc,
99%; (d) TFA, 4 Å mol sieves, CH2Cl2, 80%.
occurred smoothly to afford 26 and 27. These two easily
separable, potential cyclization substrates were advanced
individually for the purpose of gaining insight into the role
of C4 stereochemistry on the possibilities of cyclization. In
the event, 26 and 27 were each treated with TFA in dry CH2-
Cl2 in the presence of activated 4 Å molecular sieves.
Remarkably, in less than 5 min, each substrate produced the
same product, 28, in comparably high yields.
For this purpose, we turned to the Et743 related ring A
tetrahydroisoquinoline 22, which was smoothly synthesized
Scheme 4a
Our final subgoal was to reach compounds such as 32 and
33 where the C, D and E rings of ET743 have been deleted.
We also hoped to explore the issue of stereoselectivity in
the Pictet-Spengler reaction leading to 32 (vide infra).
Toward these ends, the N-allyloxycarbonyl group of 28 was
cleaved by treatment with Bu3SnH and Pd(PPh3)2Cl2 in the
presence of excess of AcOH (Scheme 6). The resulting
(7) (a) Zhou, B.; Edmondson, S.; Padron, J.; Danishefsky, S. J.
Tetrahedron Lett. 2000, 41, 2039. The experimental procedures for the
conversion of 20 f 21 are provided as Supporting Information. For recent
applications of the Pomeranz-Fritsch reaction, see: (b) Ponzo, V. L.;
Kaufman, T. S. J. Chem. Soc., Perkin Trans. 1 1997, 3131. (c) Scott, J. D.;
Williams, R. M. Angew. Chem., Int. Ed. 2001, 40, 1463.
(8) Sharpless, K. B.; Hartung, J.; Jeong, K.; Kwong, H.; Morikawa, K.;
Wang, Z.; Xu, D.; Zhang, X. J. Org. Chem. 1992, 57, 2768.
(9) Danishefsky, S. J.; Doehner, R. Tetrahedron Lett. 1977, 35, 3031.
(10) Zhou, B. Ph.D. Thesis, Columbia University, 2001.
a Reagents and conditions: (a) Br2, K2CO3, CH2Cl2, -78 °C,
80%; (b) AlCl3, CH2Cl2, 99%; (c) BrCH2Cl, Cs2CO3, MeCN, reflux,
82%; (d) vinyltributyltin, Pd(PPh3)4, toluene, reflux, 90%; (e) 6 N
HCl, dioxane, H2O, 86%; (f) Boc2O, Et3N, EtOAc, >90%; (g)
TBSCl, DMAP, imidazole, CH2Cl2, 81%; (h) H2 (1 atm), 10% Pd/
C, EtOAc, 99%.
Org. Lett., Vol. 4, No. 1, 2002
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