Synthetic studies toward ecteinascidin 743

Article abstract of DOI:10.1021/jo050408k

An efficient synthesis of a fully functionalized tetracycle (A-B-C-H) 7 containing a 1,4-bridged 10-membered lactone was developed. Phenolic aldol condensation between 2-methylsesamol (15) and Garner's aldehyde provided the protected amino diol 16, which

Full text of DOI:10.1021/jo050408k

Synthetic Studies toward Ecteinascidin 743
Xiaochuan Chen, Jinchun Chen, Michael De Paolis, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
zhu@icsn.cnrs-gif.fr
Received March 3, 2005
An efficient synthesis of a fully functionalized tetracycle (A-B-C-H) 7 containing a 1,4-bridged 10-
membered lactone was developed. Phenolic aldol condensation between 2-methylsesamol (15) and
Garner’s aldehyde provided the protected amino diol 16, which was converted to free amine 11 in
excellent yield. A Pictet-Spengler reaction between 11 and ethyl glyoxylate under carefully
controlled conditions (LiCl, toluene, 1,1,1,3,3,3-hexafluoro-2-propanol, room temperature) provided
the acid-sensitive tetrahydroisoquinoline (18) in high yield, which was converted to the amino alcohol
9. Enantioselective alkylation of a glycine template in the presence of a catalytic amount of chiral
cinchonidium salt was the key step for the access of enantiomerically pure amino aldehyde 10.
Union of the two fragments 9 and 10 via oxazolidine intermediate afforded amino nitrile 39, which
upon esterification of the primary alcohol with (R)-N-(S-4,4′,4′′-trimethoxyltrityl) Cys (42) afforded
43. Cyclization of 43 (1% trifluoroacetic acid in trifluoroethanol) provided compound 44 by a domino
process involving (a) unmasking of the S-trimethoxytrityl group, (b) fragmentation of dioxane
assisted by an electron-rich aromatic ring, and (c) formation of a 1,4-bridged 10-membered lactone
via formation of a sulfide linkage. Treatment of 7, obtained in two steps from 44b, under acidic
conditions (0.5% methyl sulfonic acid in acetonitrile) afforded the pentacyclic compound 51 via
fragmentation of the 10-membered cyclic sulfide followed by an intramolecular Pictet-Spengler
reaction.
Introduction
rodent tumors and human tumor xenografts in vivo.2 One
of its members, ecteinascidin 743 (Et 743, 1a, Figure 1)
is currently in phase II/III clinical trials in Europe and
the United States for ovarian, endometrial, and breast
cancer and several types of sarcoma. It showed particu-
larly high activity in cases of advanced sarcoma that had
relapsed or were resistant to conventional therapy. The
antiproliferative activity of Et 743 is greater than that
of taxol, camptothecin, adriamycin, mitomycin C, cispl-
atin, bleomycin, or etopside by 1-3 orders of magnitude.
Et 743 binds to the minor groove of the DNA by way of
three hydrogen bond contacts between the A- and E-ring
of Et 743 and the three base pairs recognition sequence,
the most critical being the interaction of the E-subunit
The ecteinascidins, a family of tetrahydroisoquinoline
alkaloids isolated from the Caribbean tunicate Ectein-
ascidia turbinate,1 possess potent cytotoxic activity against
a variety of tumor cell lines in vitro and against several
(1) (a) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera,
S. P.; Koehn, F. E.; McConnell, O. J. J. Org. Chem. 1990, 55, 4508-
4512. (b) 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,
4512-4515. (c) 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. 1991,
56, 1676. (d) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, A. H. J. Proc.
Nat. Acad. Sci. U.S.A. 1992, 89, 11456-11460. (e) Sakai, R.; Jares-
Erijman, E. A.; Manzanares, I.; Elipe, M. V. S.; Rinehart, K. L. J. Am.
Chem. Soc. 1996, 118, 9017-9023. (f) Suwanborirux, K.; Charupant,
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10.1021/jo050408k CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/28/2005
J. Org. Chem. 2005, 70, 4397-4408
4397

Chen et al.
is of utmost importance for the antitumor activity of Et
743. Indeed, it has been shown that modifying the F-G
subunit changes the drug’s ability to inhibit cell division.
For example, Et 736 (1c) with a tetrahydro-â-carboline
residue instead of a tetrahydroisoquinoline at the F-G
part has a different bioactivity profile relative to Et 743.
It is only slightly active against M5076 ovarian sarcoma
and an MX-1 human mammary carcinoma xenograft but
shows a higher level of activity in vivo in mice against
P388 leukemia.1d,8 Et 637 (1e) and Et 594 (1f), lacking
the F-G subunit, are generally 10-50 times less active
than Et 743 against MEL 28 and CV-A cell lines.1e
Structurally, Et 743 is composed of three tetra-
hydroisoquinoline systems interconnected via two bridged
ring systems. Specifically, ring A-B and ring D-E are
fused together, producing an additional six-membered
ring (ring C) and a labile carbinolamine functional group
that serves to alkylate the DNA. In addition, ring A-B is
linked to the third tetrahydroisoquinoline (F-G) by a 10-
membered lactone having a 1,4-bridged benzylic sulfide
linkage. Overall seven stereocenters and eight rings are
found in Et 743. Et 743 is structurally related to the
saframycin class of antibiotics,9 the noticeable difference
being the higher oxidation state of the C-4 carbon in Et
743 compared to that in saframycin (2, 3). The same
difference can be recognized in two other structurally
related natural products, naphthyridinomycin (4)10 and
lemonomycin (5, Figure 1).11
The restricted natural availability of ecteinascidins
(1 g from 1 ton of tunicate) in conjunction with their
potent antiproliferative activities and complex molecular
architecture has made them attractive synthetic tar-
gets.12 To date, two total syntheses have been ac-
complished by Corey13 and Fukuyama,14 respectively. A
semisynthesis from cyanosafracin B (3)15 has been de-
veloped by Cuevas, Manzanares, and co-workers at
PharmaMar. In addition, other synthetic approaches
have been reported from a number of research groups,
including those of Kubo,16 Danishefsky,17 Williams,18
FIGURE 1. Structures of ecteinascidin 743 and related
natural products.
with the base located 3′ to the modification site. In
addition, through intramolecular acid-catalyzed dehydra-
tion of the carbinolamine moiety, Et 743 forms a covalent
bond with the exocyclic 2-amino group of guanine.3 It was
demonstrated that the formation of Et 743/DNA complex
is reversible under nondenaturing conditions and that
Et 743 can migrate from the nonfavored bonding se-
quence (e.g., 5′-AGT) to the favored DNA target site (e.g.,
5′-AGC), leading to the observed site-specificity.4 In the
Et 743/DNA adduct, the double helix bends toward the
major groove and the third domain (ring F-G) of Et 743
positions itself outside the complex, making it available
to interact with proteins and at the same time disrupting
DNA-protein binding.5-7 Although the F-G subunit has
little contact with the minor groove of DNA, its presence
(6) Seaman, F. C.; Hurley, L. H. J. Am. Chem. Soc. 1998, 120,
13028-13041.
(7) (a) Takebyashi, Y.; Pourquier, P.; Zimonjic, D. B.; Nakayama,
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Popescu, N.; Kraemer, K. H.; Pommier, Y. Nat. Med. 2001, 7, 961-
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Hurley, L. H. Chem. Biol. 2001, 8, 1033-1049.
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Acad. Sci. U.S.A. 2000, 97, 6775-6779. (b) Minuzzo, M.; Marchini, S.;
Broggini, M.; Faircloth, G.; D’Incalci, M.; Mantovani, R. Proc. Nat.
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Press: New York, 1983; Vol. 21, pp 55-100.
(10) Itoh, J.; Omoto, S.; Inouye, S.; Kodama, Y.; Hisamatsu, T.;
Niidda, T.; Ogawa, Y. J. Antibiot. 1982, 35, 642-644.
(11) He, H.; Shen, B.; Carter, G. T. Tetrahedron Lett. 2000, 41,
2067-2071.
(12) For a recent comprehensive review of the field, see: Scott, J.
D.; Williams, R. M. Chem. Rev. 2002, 102, 1669-1730.
(13) (a) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996,
118, 9202-9203. (b) Martinez, E. J.; Corey, E. J. Org. Lett. 2000, 2,
993-996.
(14) (a) Endo, A.; Kann, T.; Fukuyama, T. Synlett 1999, 1103-1105.
(b) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T. J. Am. Chem. Soc. 2002, 124, 6552-6554.
(3) (a) Pommier, Y.; Kohlhagen, G.; Bailly, C.; Waring, M.; Mazum-
der, A.; Kohn, K. W. Biochemistry 1996, 35, 13303-13309. (b) Moore,
B. M., II.; Seaman, F. C.; Wheelhouse, R. T.; Hurley, L. H. Am. Chem.
Soc. 1998, 120, 2490-2491.
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Chem. 1999, 42, 2493-2497. (c) Garc´ıa-Nieto, R.; Manzanares, I.;
Cuevas, C.; Gago, F. J. Med. Chem. 2000, 43, 4367-4369. (d) Garc´ıa-
Nieto, R.; Manzanares, I.; Cuevas, C.; Gago, F. J. Am. Chem. Soc. 2000,
122, 7172-7182.
(15) (a) Cuevas, C.; Pe´rez, M.; Martin, M. J.; Chicharro, J. L.;
Ferna´ndez-Rivas, C.; Flores, M.; Francesch, A.; Gallego, P.; Zarzuelo,
M.; De La Calle, F.; Grac´ıa, J.; Polanco, C.; Rodriguez, I.; Manzanares,
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4398 J. Org. Chem., Vol. 70, No. 11, 2005

Synthetic Studies toward Ecteinascidin 743
Magnus,19 and Liu et al.20 A simpler synthetic analogue
of Et 743 named phthalascidin (Pt-650) that displayed
virtually the same biological activities as the natural
product has been discovered by Corey and Schreiber.21
We have been investigating an alternative synthetic
approach that is retrosynthetically depicted in Scheme
1. It was anticipated that cyclization of suitably protected
carbinolamine 7, which embodies all of the requisite
functionalities to Et 743, would afford the desired hexacy-
clic compound 6 whose conversion to the natural product
is known. Compound 7 could be traced back to the amino
alcohol 8, which in turn could be prepared by assemblage
of fully functionalized tetrahydroisoqunoline 9 and amino
aldehyde 10. The C-4 hydroxy group was strategically
positioned in 9 to facilitate the formation of the 10-
membered lactone via an intramolecular carbon-sulfur
bond forming process. One concern associated with this
approach is the compatibility of the benzyl sulfide bond
with the acidic conditions that would be required for the
subsequent transformations. Moreover, the steric hin-
drance imposed by the pre-existing 10-membered mac-
rolactone may potentially hamper the nucleophilic attack
of the aromatic ring (E) onto the incipient iminium
intermediate from the same side (â-face) defined by the
macrolactone. Nevertheless, the overall approach is at-
tractive for its convergency. We detail herein the suc-
cessful synthesis of compound 7 and results of its
subsequent cyclization reaction.22
SCHEME 1. Retrosynthetic Analysis of Et 743
Results and Discussion
Synthesis of Highly Functionalized Tetrahy-
droisoquinoline 9 and Macrolactone 27. The synthe-
sis of tetrahydroisoquinoline 18 is shown in Scheme 2.
Protection of sesamol (13) as the MOM ether followed
by regioselective ortho-lithiation and methylation gave
14,23 which was cleanly unmasked (TMSCl, NaI in
MeCN) to provide free phenol 15. Phenolic aldol conden-
sation between 15 and Garner’s aldehyde24 according to
Casiraghi25 provided, after column chromatography, the
(16) (a) Saito, N.; Tashiro, K.; Maru, Y.; Yamaguchi, K.; Kubo, A.
J. Chem. Soc., Perkin Trans. 1 1997, 53-69. (b) Saito, N.; Kamayachi,
H. Tachi, M.; Kubo, A. Heterocycles 1999, 51, 9-12. (c) Saito, N.; Tachi,
M.; Seki, R.; Kamayachi, H. Kubo, A. Chem. Pharm. Bull. 2000, 48,
1549-1557.
(17) (a) Zhou, B.; Edmondson, S.; Padron, J. Danishefsky, S. J.
Tetrahedron Lett. 2000, 41, 2039-2042. (b) Zhou, B.; Guo, J.; Dan-
ishefsky, S. J. Tetrahedron Lett. 2000, 41, 2043-2046. (c) Zhou, B.;
Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43-46.
(18) (a) Herberich, B.; Kinugawa, M.; Vazquez, A.; Williams, R. M.
Tetrahedron Lett. 2001, 42, 543-546. (b) Jin, W.; Williams, R. M.
Tetrahedron Lett. 2003, 44, 4635-4639. (c) Jin, W.; Metobo, S.;
Williams, R. M. Org. Lett. 2003, 5, 2095-2098.
syn amino diol 16 in 98% yield as the only diastereomer.
Compound 16 was converted into the 1,3-dioxane 17 in
a three-step sequence involving (a) selective allylation
of phenol, (b) selective hydrolysis of oxazolidine, and (c)
selective ketalization of 1,3-diol. Finally, selective depro-
tection of N-tert-butyloxy carbamate following Ohfune’s
procedure proceeded smoothly to provide the free amine
11 in 90% yield.26
The benzylic hydroxy group in compound 11 is par-
ticularly vulnerable under acidic conditions as a result
of the presence of an electron-rich aromatic ring. This
acid-sensitivity posed a significant challenge in the
realization of the subsequent Pictet-Spengler (P-S)
reaction for the synthesis of tetrahydroisoquinolines.27
Indeed, condensation between 11 and ethyl glyoxalate
(19) Magnus, P.; Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5,
2181-2184.
(20) Tang, Y.-F.; Liu, Z.-Z.; Chen, S.-Z. Tetrahedron Lett. 2003, 44,
7091-7094.
(21) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc.
Natl. Acad. Sci. U.S.A. 1996, 96, 3496-3501.
(22) Preliminary results have been communicated: (a) De Paolis,
M.; Chiaroni, A.; Zhu, J. J. Chem. Soc., Chem. Commun. 2003, 2896-
2897. (b) De Paolis, M.; Chen, X.; Zhu, J. Synlett 2004, 729-731.
(23) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101-
2108.
(24) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361-2364.
(b) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979-2984. (c)
Garner, P.; Park, J. M., Malecki, E. J. Org. Chem. 1988, 53, 4395-
4398. For a review, see: (d) Liang, X.; Andersch, J.; Bols, M. J. Chem.
Soc., Perkin Trans. 1 2001, 2136-2157.
(25) Casiraghi, G.; Cornia, M.; Rassu, G. J. Org. Chem. 1988, 53,
4919-4922.
(26) (a) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870-
876. (b) Zhang, A. J.; Russel, D. H.; Zhu, J.; Burgess, K. Tetrahedron
Lett. 1998, 39, 7439-7442.
(27) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797-1842.
J. Org. Chem, Vol. 70, No. 11, 2005 4399

Chen et al.
TABLE 1. Synthesis of Tetrahydroisoquinoline 18 by
Pictet-Spengler Reaction of 1 with ethyl glyoxylate
SCHEME 2. Synthesis of Highly Oxygenated
Acid-sensitive Tetrahydroisoquinoline 18a
entry
promotera
solvent
temp
yieldb
1
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
Tol
80 °C
60 °C
60 °C
80 °C
70 °C
80 °C
rt
40-50%c
40%c
0%d
2
Tol
3
THF
4
DME
0%d
5
EtOAc
0%d
6
Tol/TFE (4/1)
Tol/HFIP (4/1)
Tol/HFIP (4/1)
Tol
40-50%e
25%f
38%f
0%d
7
8
40 °C
80 °C
80 °C
40 °C
40 °C
rt
9
10
11
12
13
14
15
16
17
18
19
20
Tol/HFIP (4/1)
Tol/HFIP (8/1)
Tol/HFIP (16/1)
Tol/HFIP (4/1)
Tol/HFIP (4/1)g
Tol/EtOH (4/1)
Tol/HFIP (4/1)
Tol/HFIP (4/1)
ClCH2CH2Cl
toluene
10%
60%c
58%c
65%c
85%c
0%
rt
rt
rt
0%
85 °C
85 °C
rt
50%
phenolh
AcOH
50%f
0%
TFE
80 °C
0%d
a Three equivalents were used except for entry 18. b Isolated
yield after flash chromatography. c trans isomer only. d The cor-
responding imine was formed. e trans/cis ) 1/2. f trans/cis ) 6/1.
g Molecular sieves were added, reaction time was 48 h. h 2,6-Di-
tert-butyl-4-methyl phenol, 0.1 equiv. Abbreviations: TFE ) tri-
fluoroethanol; HFIP ) hexafluoroisopropanol; rt ) room temper-
ature.
roethanol (TFE, pKa ) 12.4)31 as cosolvent of toluene
changed the reaction selectivity to give predominantly
the desired cis isomer (trans/cis ) 1/2, entry 6). Interest-
ingly, employing 1,1,1,3,3,3-hexafluoro-2-propanol (pKa
) 9.3)31 allowed the reaction to be performed at room
temperature, although the conversion remained low
(entry 7, reaction time 24 h). Under these conditions, the
trans isomer again became the major product (trans/cis
) 6/1). Heating the reaction mixture to 40 °C improved
the conversion but also inevitably caused the decomposi-
tion of the desired product. It was observed that in the
course of this reaction, the color of the reaction mixture
gradually changed from colorless to brown, probably due
to the generation of bromine and/or related species. Since
we speculated that these species would be responsible
for the degradation of starting materials as well as P-S
product, we switched the lithium bromide to lithium
chloride and found the change highly rewarding (entries
9-14). As a weaker Lewis acid than LiBr, LiCl did not
promote the P-S reaction in toluene (entry 1 vs 9).
Nevertheless, the cooperative effect between LiCl and
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) allowed the P-S
reaction of 11 and ethyl glyoxylate to proceed cleanly at
room temperature (entry 13). While adding molecular
sieves can further increase the reaction efficiency (entry
a Reaction conditions: (a) NaH, MOMCl, Et2O-DMF, 0 °C, 90%;
(b) BuLi, TMEDA, hexane, 0 °C, then MeI, Et2O, -78 °C to rt,
93%; (c) TMSCl (1.2 equiv), NaI (5 equiv), MeCN, 0.05 M, -30 °C,
then KOH, 85-90%; (d) MeMgCl, in THF, then Garner’s aldehyde,
CH2Cl2, 98%; (e) Cs2CO3, NaI, DMF, AllylBr; (f) pTsOH (0.1 equiv),
MeOH, 0 °C; (g) dimethoxypropane, pTsOH (0.05 equiv), 70% for
three steps; (h) TBDMSOTf, lutidine, -60 to 0 °C, then MeOH,
KF, rt, 90%; (i) Table 1; (j) Pd(PPh3)4, Bu3SnH, CH2Cl2, 90%.
led either to the decomposition of reactants under a
variety of acidic conditions or to the recovery of starting
materials under mild neutral conditions. Consequently,
Lewis acid promoted Pictet-Spengler cyclization was
next examined. After a survey of reaction conditions
varying the Lewis acids [Yb(OTf)3, Sc(OTf)3, LiBr, Ti(Oi-
Pr)4],28 the solvents (CH2Cl2, DMF, toluene, ethanol,
dimethoxyethane), the temperatures, and the additives
(base for lanthanide triflate, Na2SO4, molecular sieves),
we found that the reaction performed in toluene in the
presence of LiBr provided the desired tetrahydroiso-
quinoline (18) as a single diastereomer in about 40%
yield. The stereochemistry of 18 was determined to be
1,3-trans-3,4-cis by the X-ray analysis of phenol 19 (cf.
Supporting Information), obtained by deallylation of the
former under Guibe´’s conditions [Pd(PPh3)4, Bu3SnH,
CH2Cl2, 90%].29,30
(30) Crystal data for 19: colorless crystal (0.075 × 0.20 × 0.80
mm3). C18H23NO7, Mw ) 365.37. Orthorombic system, space group
P212121, Z ) 4, a ) 5.513(6), b ) 12.528(14), c ) 26.192(23) Å; V )1809
Å3, Dc ) 1.342 g‚cm-3, F(000) ) 776, l (Mo KR) ) 0.71073 Å, m ) 0.104
mm-1; 6899 data measured (q range 1.55-31.4°) on Nomius Kappa-
CCD area-detector diffractometer. Refinement with SHELXL93. R1-
(F) ) 0.0457 for the 2135 observed reflections and wR2(F2) ) 0.1441
for all the 2554 unique data. GOF S )1.072. Residual electrons density
between -0.13 and 0.12 e Å3. The detailed X-ray date has been
deposited at The Cambridge Crystallographic Data Centre (CCDC
217803).
The promising results obtained with LiBr in toluene
prompted us to further optimize the reaction conditions,
and the results are summarized in Table 1. It was found
that solvents dramatically influenced the reaction out-
come. Whereas the Pictet-Spengler (P-S) reaction did
not occur in EtOAc, THF, and DME, addition of trifluo-
(28) Srinivasan, N.; Ganesan, A. J. Chem. Soc., Chem. Commun.
2003, 916-917.
(29) Guibe´, F. Tetrahedron 1998, 54, 2967-3042.
(31) (a) Filler, R.; Schure, R. M. J. Org. Chem. 1967, 32, 1217-1219.
(b) Matesich, M. A.; Knoefel, J.; Feldman, H.; Evans, D. F. J. Phys.
Chem. 1973, 77, 366-369.
4400 J. Org. Chem., Vol. 70, No. 11, 2005

Synthetic Studies toward Ecteinascidin 743
SCHEME 3
14), increasing the reaction temperature was detrimental
due most probably to product decomposition (entries 10-
12). Although the exact role of HFIP was unclear, its
weak Brønsted acidity (pKa ) 9.3), strong ionizing
power,32 and hydrogen bond donor ability33 may be
relevant to its unique role in this transformation. Indeed,
no reaction occurred when the same reaction was per-
formed using ethanol as cosolvent under otherwise
identical conditions (entry 15). Furthermore, the action
of both Lewis acid (LiCl) and Brønsted acid (HFIP) might
be synergistic, since in the absence of LiCl no reaction
occurred at room temperature under otherwise identical
conditions (entry 16). Nevertheless, it is worthy of noting
that by heating the reaction mixture to 85 °C, the Pictet-
Spengler reaction took place in a mixture of solvents
(toluene/HFIP ) 1/4) in the absence of Lewis acid (entry
17). Apparently, at this temperature, the acidity of HFIP
is enough to promote the P-S reaction.34 Parallel to this
observation, it was found that 2,6-di-tert-butyl-4-methyl
phenol (0.1 equiv) was also capable of catalyzing the
reaction to provide the trans isomer (9) in 50% yield
(entry 18). On the other hand, acetic acid is too strong
an acid and led only to the degradation of the materials
(entry 19). Overall, under the optimized conditions (LiCl,
toluene/HFIP ) 4/1, room temperature, molecular sieves
4 Å, 48 h, entry 14), the desired Pictet-Spengler reaction
took place smoothly to provide exclusively the trans
isomer (18) in 85% yield. This protocol is highly reliable
and can be performed on a multigram scale without
erosion of the yield and diastereoselectivity.
Conversion of imine to the corresponding iminium by
acylation is often an efficient way to increase its electro-
philicity. Since the imino ester (20) resulting from the
condensation of 11 and ethyl glyoxylate is isolable, we
briefly examined its reaction with a chloroformate with
the hope to obtain directly the N-acylated tetrahydroiso-
quinoline.35 However under a set of conditions varying
the solvents (toluene, dichloromethane, acetonitrile), the
additives (NaI, DMAP, AgNO3), and the temperatures
(-40 °C to room temperature), only the simple N-Troc
derivative 21 (N-2,2,2-trichloroethyloxycarbonyl), prob-
ably resulting from a sequence of acylation-hydrolysis,
was isolated (Scheme 3).
SCHEME 4. Epimerization of 1,3-trans
Tetrahydroisoquinoline 18 to 1,3-cis Isomer 24a
a Reaction conditions: (a) TrocCl, CH2Cl2, aq NaHCO3; (b) DBU,
THF; (c) Zn, AcOH-Et2O (1/10), rt, 90%.
Baumann conditions provided 22. Gratifyingly, stirring
a THF solution of 22 in the presence of DBU for 12 h
provided exclusively the cis isomer 23. Reductive removal
of the N-Troc function was initially problematic because
of the epimerization of the C-1 center. After careful
examination of the reaction parameters, it was ultimately
found that by decreasing the quantity of acetic acid, the
cis isomer 24 was produced exclusively. Under these
optimized conditions, purification of intermediate 22 and
23 was not required and the cis isomer 24 was obtained
from the trans isomer 18 in 90% yield for this three-step
sequence.
Taking into consideration the X-ray structure of 19,
the epimerization via N-acylated intermediate 22 can be
rationalized as shown in Scheme 5. The compound 22
can exist in two conformations. The conformer 22b
wherein the N-acyl residue is positioned in a pseudo-
equatorial position should be more stable than 22a, the
latter being destabilized by severe steric repulsions.
Enolization of the ester (22b) followed by protonation
from the side opposite to the C-3 substituent would give
the desired cis isomer 23, which upon reductive removal
of N-Troc function provided the all-cis compound 24.
With compound 18 in hand, epimerization of the C-1
center was next examined.18a All attempts with this
substrate being uniformly unsuccessful, a three-step
sequence was developed (Scheme 4). Thus N-acylation
of 18 with trichloroethyl chloroformate under Schotten-
(32) Schadt, F. L.; Bentley, T. W.; Schleyer, P. V. R. J. Am. Chem.
Soc. 1976, 98, 7667-7674.
(33) Eberson, L.; Hartshorn, M. P.; Persson, O.; Radner, F. J. Chem.
Soc. Chem. Commun. 1996, 2105-2112.
(34) Selected recent leading references on HFIP-assisted transfor-
mations. (a) Diels-Alder reaction: Cativirla, C.; Garc´ıa, J. I.; Majoral,
J. A.; Salvatella, L. Can. J. Chem. 1994, 72, 308-311. (b) Ring opening
of epoxides: Kesavan, V.; Bonnet-Delpon, D.; Be´gue´, J.-P. Tetrahedron
Lett. 2000, 41, 2895-2898. Das, U.; Crousse, B.; Kesavan, V.; Bonnet-
Delpon, D.; Be´gue´, J.-P. J. Org. Chem. 2000, 65, 6749-6751. Rodrigues,
I.; Bonnet-Delpon, D.; Be´gue´, J.-P. J. Org. Chem. 2001, 66, 2098-2103.
Magueur, G.; Crousse, B.; Oure´vitch, M.; Be´gue´, J.-P.; Bonnet-Delpon,
D. J. Org. Chem. 2003, 68, 9763-9766. (c) Epoxidation and Baeyer-
Villiger reaction: Neimann, K.; Neumann, R. Org. Lett. 2000, 2, 2861-
2863. (d) Guanidinylation: Snider, B. B.; O’Hare, S. M. Tetrahedron
Lett. 2001, 42, 2455-2458. (e) Ring opening of cyclic sulfate: Johnston,
B. D.; Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto, B. M. J. Am.
Chem. Soc. 2002, 124, 8245-8250. (f) Oxidative amidation of phenol:
Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175-177.
(35) Wang, H.; Ganesan, A. Tetrahedron Lett. 1997, 38, 4327-4328.
With an efficient synthesis of 24 being developed, the
construction of the 1,4-bridged macrolactone was next
envisaged (Scheme 6). Reduction of amino ester 24 with
LAH afforded the amino alcohol 9, which was chemo-
selectively O-acylated with (R)-N-Troc-(S-trityl) cysteine
(25, EDCI, DMAP) to give ester 26 in 83% yield. The C-4
hydroxy group in tetrahydroisoquinoline (24) was stra-
tegically introduced with the aim to facilitate the forma-
tion of the benzylic sulfide bond, Indeed, parallel to the
present studies, we have demonstrated that reaction of
alcohol 16 with thiol in the presence of TFA gave the
J. Org. Chem, Vol. 70, No. 11, 2005 4401

Chen et al.
SCHEME 5. Conformation Analysis on the
Based-catalyzed Epimerization of 22
SCHEME 7. Enantioselective Synthesis of Amino
Aldehyde 10a
SCHEME 6. Construction of 10-membered
Macrolactonea
a Reagents and conditions (a) 31 (0.1 equiv), CsOH‚H2O (0.1
equiv), CH2Cl2, -78 °C; (b) THF/H2O/AcOH (1:1:1), 87% for two
steps; (c) LiBH4, MeOH, Et2O, rt, then aq 2 N NaOH, EtOH, 80
°C; (d) AllocCl, aq NaHCO3/CH2Cl2 (1:1); 78% from 32; (e) AllylBr,
NaHCO3, acetone, 92%; (f) TBSCl, imidazole, DMF, then 2 N HCl,
91% overall yield from 34; (g) Swern oxidation, 92%.
produced as a result of the inherent higher ring strain
of the trans counterpart. Compound 28 was transformed
into 27 in high yield under reductive conditions (HCOOH,
Et3SiH). Parallel to this work, a similar strategy has been
independently developed by the group of Danishefsky.17c
Synthesis of Amino Aldehyde 10. The protected L-3-
hydroxy-4-methoxy-5-methyl phenylalanal (10) was pre-
pared featuring a key enantioselective alkylation step
(Scheme 7).37-41 Following Corey’s procedure, alkylation
of N-(diphenylmethylene) glycine tert-butyl ester 30 by
3-tosyloxy-4-methoxy-5-methyl benzyl bromide 29 in the
presence of a catalytic amount of O-(9)-allyl-N-(9′-an-
thracenylmethyl)cinchonidium bromide 31 (0.1 equiv)
a Reagents and conditions: (a) LAH, THF, -20 to 0 °C, 85%;
(b) (R)-N-Troc-(S-trityl)cysteine (25), EDCI, DMAP, CH2Cl2, 83%;
(c) TFA/toluene 1/1, 0 °C, 70%; (d) HCOOH, Et3SiH, CH2Cl2, 92%.
corresponding sulfide in excellent yield.36 Indeed, by
simply dissolving 26 in toluene in the presence of TFA
(v/v ) 1/1) at 0 °C, we were able to isolate the macrocycle
27 in 70% yield, together with small amount of its
O-tritylated derivative 28. In this experimentally simple
procedure, a sequence of domino processes involving
initial sulfide deprotection, fragmentation of dioxane,
C-S bond formation with the concurrent macrocycliza-
tion, and O-tritylation occurred at the expense of other
competitive processes. Only one stereoisomer (1,4-cis) was
(37) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414-12415.
(38) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
8595-8598. (b) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518-
525.
(39) (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999,
121, 6519-6520. (b) Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37,
526-533.
(40) (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 505-517.
(41) For an alternative synthesis of this amino acid, see ref 18b.
(36) De Paolis, M.; Blankenstein, J.; Bois-Choussy, M.; Zhu, J. Org.
Lett. 2002, 4, 1235-1238.
4402 J. Org. Chem., Vol. 70, No. 11, 2005

Synthetic Studies toward Ecteinascidin 743
filtration and evaporation of the filtrate, the crude
residue was treated with TMSCN in the presence of BF3‚
OEt2 at -30 °C to afford aminonitrile (39) in 80% overall
yield as two separable diastereoisomers in a ratio of 3/1.
The reaction temperature of the second step should be
carefully controlled (below -20 °C) in order to avoid the
competitive ring-opening of the dioxane. Indeed, when
the same reaction was performed at 0 °C, the dicyanide
40 was isolated in about 30% yield as a mixture of four
diastereomers whose structure was deduced from 1H
NMR and mass spectroscopic data.
FIGURE 2. Assignment of absolute configuration of amino
alcohol 35b.
The major isomer of the amino nitrile 39 (vide infra
for configuration assignment) was engaged in the sub-
sequent transformation. Coupling of (R)-N-Troc (S-trityl)
Cys 25 with 39a provide ester 41 in 80% yield. Treatment
of 41 under a variety of conditions led only to degradation
and failed to produce even trace amounts of the desired
macrocycle. This is in sharp contrast to the cyclization
of compound 26 where an excellent yield of 27 was
obtained. We reasoned that in the case of 41, the
fragmentation of the dioxane function preceded depro-
tection of the S-trityl function, leading to the unstable
ortho quinone methide intermediate that degraded in the
absence of an appropriate nucleophile. To ensure the
occurrence of the desired domino process, the timing of
S-trityl deprotection and dioxane fragmentation needed
to be carefully readjusted. While switching the protective
group into a base-sensitive function and proceeding via
the same transformation in two separable steps, i.e.,
S-deprotection and cyclization, is an obvious choice, we
nevertheless preferred an acid-sensitive protecting group
since this option would allow us to realize the deprotec-
tion-cyclization in one step. From experimental results,
it is evident that a protective group that is even more
acid-labile than trityl would be required in order to
maximize the chance of success. Toward this end, a
trimethoxytrityl group was envisaged.44 Coupling of 39a
or 39b with (R)-N-Troc-(S-4,4′,4′′-trimethoxyltrityl) Cys
(42)45 under standard conditions afforded the compound
43a or 43b in 75-80% yield, respectively. Gratifyingly,
by simply dissolving 43a in TFE containing 1% TFA, the
desired domino sequence took place smoothly to afford
the bridged macrocycle 44a in 55-65% yield. By the same
sequence, compound 43b was converted into 44b under
identical conditions in 65% yield. The TBS ether survived
under such mild acidic conditions. The formation of
S-trimethoxytrityl derivative 45 was observed and iden-
tified. However, its isolation was not necessary since
unmasking the O-trimethoxytrityl function proceeded
smoothly under the cyclization conditions upon prolong-
ing the reaction time. It was known that for each methoxy
group introduced, acid-lability of the trityl group in-
creased by about 1 order of magnitude.46 We thus
suspected that under mild acidic conditions, deprotection
of the S-4,4′,4′′-trimethoxyltrityl group would lead to 46
and the stabilized carbenium cation 47. The fragmenta-
afforded, after chemoselective hydrolysis of the imine
function (THF-H2O-AcOH), the amino ester 32 in 87%
overall yield. Reduction of ester to alcohol followed by
detosylation under basic conditions gave the amino
alcohol 33. Selective N-acylation with allyl chloroformate
afforded N-Alloc derivative 34. Masking of phenol as allyl
ether followed by oxidation of the primary alcohol pro-
vided amino aldehyde 10a in 64% overall yield from 32.
Alternatively, simultaneous protection of the phenol and
the primary hydroxy group as TBDMS ethers followed
by selective removal of the TBDMS group from the
primary alcohol gave the amino alcohol 35b, which was
oxidized (Swern oxidation) to provide the expected amino
aldehyde 10b.
The (S) configuration of amino ester 32 was assigned,
taking for granted the Corey-Lygo empirical model. To
confirm this assignment, both (S)- and (R)-O-methyl
mandelic amides 36 and 37 were synthesized (Figure 2).
The calculated chemical shift differences (∆δArCH (36-
2
37) ) -0.08 ppm; ∆δTBDMSOCH (36-37) ) 0.09 ppm) are
2
in accord with the S configuration of the amino alcohol
and hence that of the amino ester 32.42 In addition,
analysis of 1H NMR spectra of compounds 36 and 37
indicated that the de of 36 and 37, and hence the ee of
their precursor 32, is higher than 90%.
Assemblage of Two Fragments and Cyclization
Studies. Our initial efforts focused on the union of
lactone 27 and amino aldehyde 10a by way of a Strecker
reaction. This would represent the most convergent
approach following our projected synthetic scheme. Un-
fortunately, all attempts under a variety of conditions43
failed to provide the desired amino nitrile, probably
because of the steric hindrance around the secondary
amine. We then turned our attention to the condensation
between 9 and 10. The acid-lability of 9 was a primary
concern at the outset since the Strecker reaction is
usually performed under acidic conditions. Indeed, initial
efforts on the reaction of 9, 10, and cyanide (KCN or
TMSCN) in the presence of either Lewis acids or Brøn-
sted acids were uniformly unsuccessful. After much
experimentation, a two-step sequence was developed.
Thus, mixing of 9 and 10a (or 10b) in toluene in the
presence of 3 Å molecular sieves gave the oxazolidine 38
as a mixture of two diastereomers (Scheme 8). After
(42) (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994,
59, 4202-4205. (b) Helmchen, G.; Sauber, K. Tetrahedron Lett. 1972,
3873-3878.
(43) The following conditions have been tested: (a) AcOH, KCN, (b)
KCN, MeCN, H2O, (c) TMSCN, MeOH, CH2Cl2, ZnI2 (0.1 equiv), (d)
TMSCN, MeOH, CH2Cl2, (e) TMSCN, MeOH, Et2O, LiClO4, (f) LiBr,
KCN, toluene, trifluoroethanol, and (g) Yb(OTf)3, TMSCN, CH2Cl2,
However, none of them provided the desired amino nitrile. In most
cases, starting materials were recovered or decomposed under forcing
conditions (longer reaction time, higher reaction temperature).
(44) Myers, A. G.; Dragovich, P. S. J. Am. Chem. Soc. 1992, 114,
5859-5860.
(45) Synthesized from commercial available (R)-N-(S-4,4′,4′′-tri-
methoxyltrityl) Cys (25) in three steps: (a) TrocCl, NaHCO3, H2O/1,4-
dioxane, 45 °C; (b) Et3SiH, TFA, CH2Cl2; (c) (p-4-MeOPh)3CCl, CH2Cl2;
76% overall yield for three steps.
(46) (a) Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G.
J. Am. Chem. Soc. 1962, 84, 430-440. (b) Shchepinov, M. S.; Korshun,
V. A. Chem. Soc. Rev. 2003, 32, 170-180.
J. Org. Chem, Vol. 70, No. 11, 2005 4403

Chen et al.
SCHEME 8. Assemblage and Construction of Macrolactonea
a Reagents and conditions: (a) toluene, 3Å molecular sieves, 40 °C; (b) TMSCN, BF3‚Et2O, CH2Cl2, -30 °C, 70-80% for two steps
(dr ) 3:1); (c) EDCI, DMAP, CH2Cl2, (R)-N-Troc(trityl) Cys (25), 78% or (R)-N-Troc-(trimethoxy trityl) Cys (42), 74%; (d) 1% TFA in TFE,
0 °C to rt, 65%.
tion of dioxane assisted by the electron-rich aromatic ring
would produce the ortho quinone methide intermediate
48, which would suffer the intramolecular nucleophilic
addition of thiol to produce the 1,4-bridged 10-membered
ring.47,48 The primary alcohol revealed upon fragmenta-
tion of the dioxane would be partially tritylated, leading
to 45 that may ultimately be converted to compound 44.
Compound 44b has all of the requisite functionalities
for construction of the missing C and D rings. Our final
efforts toward this goal are summarized in Scheme 9.
Swern oxidation of 44b provided the aldehyde that was
intercepted directly by the tethering carbamate function
to provide the stable aminal 49 in 74% yield. Removal of
TBS ether under carefully controlled conditions afforded
the phenol 7 that was ready for the pivatol cyclization
step.49 After much experimentation, a clean transforma-
tion was observed when a MeCN solution of 7 was treated
(48) For recent examples of formation/trapping of o-quinone methide,
see: (a) Van de Water, R. W.; Magdziak, D. J.; Chau, J. N. C.; Pettus,
T. R. R. J. Am. Chem. Soc. 2000, 122, 6502-6503. (b) Lindsley, C. W.;
Chan, L. K.; Goess, B. C.; Joseph, R.; Shair, M. D. J. Am. Chem. Soc.
2000, 122, 422-423. (c) Pande, P.; Shearer, J.; Yang, J.; Greenberg,
W. A.; Rokita, S. E. J. Am. Chem. Soc. 1999, 121, 6773-6779. (d) Angle,
S. R.; Rainier, J. D.; Woytowicz, C. J. Org. Chem. 1997, 62, 5884-
5892. (e) Taing, M.; Moore, H. W. J. Org. Chem. 1996, 61, 329-340
(47) For the quinone methide initiated cyclization for the synthesis
of five- and six-membered rings, see: (a) Angle, S. R.; Turnbull, K. D.
J. Am. Chem. Soc. 1989, 111, 1136-1138. (b) Angle, S. R.; Rainier, J.
D. J. Org. Chem. 1992, 57, 6883-6890. (c) Angle, S. R.; Arnaiz, D. O.;
Boyce, J. P.; Frutos, R. P.; Louie, M. S.; Mattson-Arnaiz, H. L.; Rainier,
J. D.; Turnbull, K. D.; Yang, W. J. Org. Chem. 1994, 59, 6322-6337.
4404 J. Org. Chem., Vol. 70, No. 11, 2005

Synthetic Studies toward Ecteinascidin 743
SCHEME 9. Construction of Pentacyclic Ring Systema
a Reagents and conditions: (a) Swern oxidation, 74%; (b) KF, AcOH, MeOH, 89%; (c) 0.5% CF3SO3H in CH3CN, 0 °C, 78%; (d) MsCl,
CH2Cl2, Et3N, 40 °C.
with trifluoromethanesulfonic acid (0.5 vol %), providing
the one single compound 51a. The 1H NMR spectrum of
51a displayed only one aromatic proton at δ 6.68 ppm.
High-resolution mass spectrometry indicated a molecular
formula of C38H39Cl3N4O11S (M + Na+, calcd for C38H39-
Cl3N4O11SNa 887.1299 and 889.1270, found 887.1311 and
889.1298) corresponding to a dehydration product of 7.
The analysis of 1H NMR spectra recorded at room
temperature was complicated as a result of the presence
of interchangeable conformers within the NMR time
scale. However, by recording the spectra at 253 K, two
1
well distinguishable sets of peaks appeared in the H
NMR and 13C spectra. From detailed NMR studies
(COSY, HMBC, HMQC, NOESY), the structure 51a was
proposed as shown in Scheme 9. The presence of long-
distance C-H correlation between H-4 signals (at δ 6.26
and 6.23 ppm for two rotamers) and the 13C signals of
C-11, C-10, C-9, C-3, C-8, and C-5 is indicative of the
1
presence of a benzylic proton, whereas H-13C correla-
tions observed between H-15 and C-16, between 18-Me
protons and C-19, and between H-11 and C-19 indicated
that the nucleophilic addition to acyliminium intermedi-
FIGURE 3. Structure determination of pentacyclic compound
51a.
ate occurred at C-19 rather than the expected C-15
(Figure 3). Interestingly, the regioselectivity observed is
opposite to that observed by Williams in a related
system.18c The observation of NOE correlation between
H21 and H14 indicated the R-configuration of C-21, which
corresponded to the configuration of the natural product.
Compound 44a was similarly converted to pentacyclic
compound 52 following the same synthetic sequence as
detailed for 44b.
(49) Veerman, J. J. N.; Bon, R. S.; Hue, B. T. B.; Girones, D.; Rutjes,
F. P. J. T.; Van Maaresveen, J. H.; Hiemstra, H. J. Org. Chem. 2003,
68, 4486-4494.
J. Org. Chem, Vol. 70, No. 11, 2005 4405

Chen et al.
cyclization via formation of the carbon-sulfur bond with
concomitant formation of the 10-membered ring. Al-
though compound 7 was responsive to the intramolecular
Pictet-Spengler reaction, a destructive ring opening of
the 1,4-bridged lactone also occurred, leading to the
formation of a pentacyclic compound, 51. In the course
of this study, it was discovered that a combination of a
mild Lewis acid (LiCl) and a mild Brønsted acid (HFIP)
constituted excellent reagents for performing the Pictet-
Spengler reaction of a highly acid-sensitive substrate. We
are currently investigating the potential application of
these conditions to other reactions, as well as an alterna-
tive strategy for the total synthesis of Et 743.
FIGURE 4. Structure of cribrostatin IV.
The formation of compound 51a could be rationalized
as follows. Dehydration of aminal under acidic conditions
would produce the acyliminium interemediate 52. The
nucleophilic addition of phenol onto this electrophilic
species would produce the expected product 50. However,
the fact that the nucleophile must approach the iminium
from the same face as that occupied by the adjacent
macrocycle might significantly retard this process. There-
fore, an alternative iminium-enamine tautomerization
would take place to produce enamine 53a. Cleavage of
the C-S bond assisted by the lone pair electron of
nitrogen would then produce the conjugated acyliminium
54a.50 Alternatively, ring opening of the macrolactone
could also be assisted by the electron-rich aromatic ring,
leading to oxonium 55, which would tautomerize to the
acyl iminium 54a. Whatever the mechanism of fragmen-
tation, the â-face of the acyliminium is now sterically
more accessible, and nucleophilic addition of phenol could
take place to provide the observed compound 51a.
Interestingly, the thiol function was quite stable and did
not dimerize upon flash column chromatography. Alter-
natively, the enamine 53b was prepared by treatment
of 49 with MsCl under basic conditions (MsCl, Et3N, CH2-
Cl2, 40 °C).51 However, when it was submitted to acidic
conditions (CF3SO3H, MeCN), the same sequence of
fragmentation-cyclization occurred, leading to 51b in 87%
yield.
The pentacyclic compound 51 with a double bond at
C-3 and C-4 positions possesses the correct oxidation level
for the formation the 10-membered cycle. Furthermore,
we thought that chemistry developed herein would be
useful for the development of a short synthesis of cri-
brostatin IV (Figure 4), another member of the tetrahy-
droisoquinoline class of natural products.52 An elegant
total synthesis of this alkaloid has very recently been
accomplished by Danishefsky.53
In summary, a strategy has been developed for the
access of tetracycle 7 that embodies all of the requisite
functionalities en route to the natural product Et 743.
The synthesis is highly convergent and has been carried
out on a multigram scale featuring the following key
steps: (a) union of two fragments 9 and 10 via an
oxazolidine intermediate, and (b) acid-promoted macro-
Experimental Section
Compound 16. To a solution of phenol 15 (1.8 g, 11.8 mmol)
in anhydrous THF (20 mL) was added CH3MgCl in THF (22
wt %, 4.2 mL, 12.6 mmol) at room temperature. After 5 min
of stirring, a solution of Garner’s aldehyde (3.0 g, 13.0 mmol,
in 25 mL CH2Cl2) was introduced dropwise and the resulting
reaction mixture was stirred overnight at room temperature.
The reaction was quenched by addition of saturated aqueous
NH4Cl and the aqueous phase was extracted with CH2Cl2. The
combined organic extracts were washed with brine and dried
over Na2SO4 and the volatile was evaporated under reduced
pressure. The crude product was purified by flash column
chromatography to afford 16 (4.5 g, 11.6 mmol, 98%) as a
colorless oil. [R]2D3 ) -10 (c 0.4, CHCl3); IR (CHCl3) ν 3242,
1
1651, 1468, 1406 cm-1; H NMR (250 MHz CDCl3, 293 K) δ
8.39 (br‚s, 1H), 6.62 (br‚s, 1H), 6.31 (s, 1H), 5.86 (d, J ) 1.0
Hz, 1H), 5.84 (d, J ) 1.0 Hz, 1H), 4.66 (d, J ) 8.4 Hz, 1H),
4.32 (m, 1H), 3.64 (m, 2H), 2.08 (s, 3H), 1.57 (s, 3H), 1.51 (s,
9H), 1.47 (s, 3H); 13C NMR (62.5 MHz CDCl3, 293 K) δ 155.8,
149.8, 146.6, 139.6, 114.8, 109.3, 105.4, 100.8, 94.7, 82.2, 80.2,
65.1, 62.4, 28.3 (×3), 27.0, 24.4, 8.6; LRMS (ESI-) m/z 379.9
(M - H).
Tetrahydroisoquinoline 18. A suspension of amine 11
(1.0 g, 3.1 mmol), LiCl (410.0 mg, 9.4 mmol), molecular sieves
4 Å (200.0 mg), and ethyl glyoxalate (350.0 mg, 3.4 mmol) in
toluene/HFIP (4:1, v/v, 10 mL) was stirred at room tempera-
ture for 48 h. The reaction mixture was then diluted with CH2-
Cl2 and filtered through a short pad of Celite. The filtrate was
evaporated to dryness and the residue was purified by flash
column chromatography to afford 18 (1.07 g, 2.6 mmol, 85%)
as a colorless oil. Mp 122 °C; [R]2D3 ) +24° (c 1.9, CHCl3); IR
1
(CHCl3) ν 2985, 1746, 1475, 1157, 1092 cm-1; H NMR (300
MHz CDCl3, 293 K) δ 6.08 (ddt, J ) 17.3, 10.8, 5.5 Hz, 1H),
5.95 (d, J ) 1.3 Hz,1H), 5.90 (d, J ) 1.3 Hz, 1H), 5.46 (dq, J
) 17.5, 2.8 Hz, 1H), 5.28 (dq, J ) 10.9, 1.3 Hz, 1H), 5.06 (d, J
) 1.4 Hz, 1H), 4.79 (s, 1H), 4.52 (ddt, J ) 12.4, 5.2, 1.4 Hz,
1H), 4.29-4.22 (m, 4H), 3.93 (dd, J ) 12.4, 1.3 Hz, 1H), 2.93
(m, 1H), 2.15 (s, 3H), 1.60 (s, 3H), 1.39 (s, 3H), 1.27 (t, J ) 7.3
Hz, 3H); 13C NMR (75 MHz CDCl3, 293 K) δ 171.3, 151.2,
146.2, 139.8, 133.8, 120.5, 116.4, 113.2, 112.6, 101.4, 98.8, 75.0,
64.5, 61.0, 60.0, 54.5, 46.3, 29.8, 18.7, 13.9, 9.3; LRMS (ESI+)
m/z 405.9 (M + H)+, 428.0 (M + Na)+; HRMS (ESI+) m/z calcd
for C21H27NO7Na (M + Na)+ 428.1685, found 428.1651.
N-Troc-1,3-trans-Tetrahydroisoquinoline 22. To a bi-
phasic solution of amine 18 (220.0 mg, 0.54 mmol) in CH2Cl2
(5.0 mL) and saturated aqueous NaHCO3 (5.0 mL) was added
TrocCl (0.083 mL, 0.6 mmol) at room temperature. After being
stirred at room temperature for 2 h, the reaction mixture was
diluted with CH2Cl2 and the organic phase was separated. The
aqueous phase was extracted with CH2Cl2, and the combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography to afford 22 (311.0
mg, 98%) as a colorless oil. [R]2D3) +40° (c 1.3, CHCl3); IR
(50) For a related example, see: Rikimaru, K.; Mori, K.; Kan, T.;
Fukuyama, T. J. Chem. Soc., Chem. Commun. 2005, 394-396.
(51) Saito, N.; Tanitsu, M.-A.; Betsui, T.; Suzuki, R.; Kubo, A. Chem.
Pharm. Bull. 1997, 45, 1120-1129.
(52) (a) Petti, G. R.; Knight, J. C.; Collins, J. C.; Herald, D. L.; Pettit,
R. K.; Boyd, M. R.; Young, V. G. J. Nat. Prod. 2000, 63, 793-798. (b)
Saito, N.; Sakai, H.; Suwanborirux, K.; Pummangura, S.; Kubo, A.
Hetereocycles 2001, 55, 21-28.
(53) Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.;
Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 4596-4598.
(CHCl3) ν 2955, 2934, 1742, 1461, 1385, 1167, 1037, 939 cm-1
;
4406 J. Org. Chem., Vol. 70, No. 11, 2005

Synthetic Studies toward Ecteinascidin 743
1H NMR (300 MHz CDCl3, 293 K) δ 6.13 (ddt, J ) 17.3, 10.8,
5.7 Hz, 1H), 6.06 (s, 1H), 6.03 (d, J ) 1.1 Hz, 1H), 5.95 (d, J
) 1.1 Hz, 1H), 5.44 (dq, J ) 17.6, 2.8 Hz, 1H), 5.28 (dq, J )
10.8, 1.5 Hz, 1H), 5.12 (d, J ) 3.1 Hz, 1H), 4.83 (d, J ) 12.1
Hz, 1H), 4.80 (d, J ) 12.1 Hz, 1H), 4.48 (ddt, J ) 13.2, 5.4, 0.9
Hz, 1H), 4.36 (dd, J ) 13.3, 3.8 Hz, 1H), 4.26 (ddt, J ) 13.2,
5.4, 1.9 Hz, 1H), 4.20 (q, J ) 7.1 Hz, 3H), 3.78 (m, 1H), 2.15
AcOEt and filtered. The combined filtrate was concentrated
in vacuo to furnish the crude oxazolidine 38a. To the solution
of the crude 38a in CH2Cl2 (2.4 mL), cooled to -30 °C, were
added TMSCN (93.0 mg, 126.0 µL, 0.94 mmol) and BF3.OEt2
(33.0 µL, 0.26 mmol), successively. After being stirred at -30
°C for 1.5 h, the reaction was quenched with saturated
NaHCO3 and extracted with AcOEt. The organic phase was
dried over Na2SO4 and concentrated under reduced pressure.
The resulting crude product was purified by flash column
chromatography to afford the aminonitrile 39a as two sepa-
rable diastereomers. The major isomer (96.0 mg, 0.14 mmol,
(s, 3H), 1.60 (s, 3H), 1.39 (s, 3H), 1.27 (t, J ) 7.1 Hz, 3H); 13
C
NMR (62.5 MHz CDCl3, 293 K) δ 171.1, 169.5, 151.3, 147.2,
140.0, 133.7, 118.1, 116.9, 114.2, 110.1, 101.6, 99.9, 95.1, 75.4,
74.9, 63.1, 62.0, 61.5, 55.3, 52.2, 27.7, 20.9, 14.1, 9.5; LRMS
(ESI+) m/z 602.0, 604.0 (M + Na)+; HRMS (ESI+) m/z calcd
for C24H28NO9NaCl3 (M + Na)+ 602.0727 and 604.0698, found
602.0728 and 604.0701.
23
60% for two steps): [R]D ) -24° (c 0.47 CHCl3); IR (CHCl3)
ν 3447, 3019, 2959, 2929, 2401, 1719, 1511, 1232 cm-1 1H
;
NMR (300 MHz CDCl3, 293 K) δ 6.68 (s, 1H), 6.66 (s, 1H),
6.11 (m, 2H), 6.06 (d, J ) 1.3 Hz, 1H), 5.98 (d, J ) 1.3 Hz,
1H), 5.90 (m, 1H), 5.47 (br.d, 1H), 5.41-5.23 (m, 6H), 5.02 (d,
J ) 7.9 Hz, 1H), 4.55 (m, 5H), 4.45 (m, 1H), 4.39 (ddt, J )
12.1, 5.1, 1.2 Hz, 1H), 4.31 (ddt, J ) 12.1, 4.9, 1.0 Hz, 1H),
4.12 (m, 2H), 3.95 (m, 1H), 3.85 (m, 5H), 3.32 (dd, J ) 13.9,
3.1 Hz, 1H), 3.11 (m, 1H), 2.97 (dd, J ) 13.5, 10.2 Hz, 1H),
2.54 (m, 1H), 2.24 (s, 3H), 2.16 (s, 3H), 1.60 (s, 3H), 1.40 (s,
3H); 13C NMR (75 MHz CDCl3, 293 K) δ 155.8, 151.5, 150.1,
147.1, 146.4, 139.7, 133.6, 133.4, 132.6, 132.5, 132.0, 123.8,
118.8, 117.7, 117.4, 117.1, 116.9, 114.0, 112.9, 112.6, 101.7,
99.3, 75.7, 69.3, 66.3, 65.8, 63.0, 62.5, 61.4, 60.1, 55.8, 55.4,
54.2, 35.8, 29.3, 19.2, 15.9, 9.3; HRMS (ESI+) m/z calcd for
C38H47N3O10Na (M + Na)+ 728.3159, found 728.3167. The
1,3-cis-Tetrahydroisoquinoline 24. To a solution of N-
Troc amine 22 (326.0 mg, 0.56 mmol) in dry THF (3.0 mL)
was added DBU (0.134 mL, 1.13 mmol) dropwise. After being
stirred at room temperature for 14 h, the reaction mixture was
diluted with water and extracted with Et2O. The combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The crude product
was used directly for next step. To a solution of crude 1,3-cis-
N-Troc amine 23 in Et2O/AcOH (10:1, v/v, 6.0 mL) was added
Zn powder (2.7 g, 42.0 mmol). After being stirred at room
temperature for 1 h, the reaction mixture was diluted with
diethyl ether (100 mL) and filtered with a short pad of Celite.
The filtrate was washed with saturate aqueous NaHCO3,
brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography to afford amine 24 (205.0 mg, 0.51 mmol, 90%) as a
colorless oil. [R]2D3 ) -2° (c 0.4, CHCl3); IR (CHCl3) ν 3018,
1738, 1458, 1382, 1223, 1103 cm-1; 1H NMR (300 MHz CDCl3,
293 K) δ 6.11 (ddt, J ) 16.9, 10.3, 5.5 Hz, 1H), 5.94 (d, J ) 1.2
Hz, 1H), 5.91 (d, J ) 1.2 Hz, 1H), 5.43 (dq, J ) 17.1, 2.8 Hz,
1H), 5.27 (dq, J ) 10.9, 1.3 Hz, 1H), 5.09 (d, J ) 1.0 Hz, 1H),
4.71 (s, 1H), 4.56 (ddt, J ) 12.5, 5.3, 1.7 Hz, 1H), 4.32-4.28
(m, 3H), 4.24 (m, 1H), 3.94 (dd, J ) 11.4, 1.1 Hz, 1H), 2.53 (m,
1H), 2.15 (s, 3H), 1.66 (s, 3H), 1.44 (s, 3H), 1.32 (t, J ) 7.1 Hz,
3H); 13C NMR (62.5 MHz CDCl3, 293 K) δ 171.2, 151.2, 146.4,
139.3, 133.9, 120.9, 116.3, 113.1, 112.8, 101.2, 98.8, 75.2, 64.6,
61.4, 60.1, 57.5, 49.3, 29.6, 18.7, 13.9, 9.1; HRMS (ESI+) m/z
calcd for C21H27NO7Na (M + Na)+ 428.1685, found 428.1714.
Amino Ester 32. To a solution of imine 30 (3.4 g, 11.2
mmol) and O(9)-allyl-N-(9-anthracenylmethyl) cinchonidinium
bromide 31 (0.6 g, 1.1 mmol) in CH2Cl2 (12 mL) were added
CsOH‚H2O (18.8 g, 111.7 mmol) and a CH2Cl2 (8 mL) solution
of bromide 29 (4.3 g, 11.2 mmol) dropwise at -78 °C. After
being stirred vigorously at -78 °C for 30 h, the suspension
was diluted with ether, washed with water, dried over Na2-
SO4, filtered and concentrated in vacuo. The residue was
dissolved in HOAc/THF/H2O (1:1:1, 57 mL) and the resulting
solution was stirred at room temperature for 2 h. The solution
was then made basic by addition of solid NaHCO3 and water.
The aqueous phase was extracted with AcOEt. The combined
organic extracts were washed with brine and dried over Na2-
SO4. After concentration and column chromatography, the
amino ester 32 (4.3 g, 87%) was isolated as a colorless oil.
[R]2D3 ) +13° (c 0.8, CHCl3); IR (CHCl3) ν 3382, 3034, 2981,
2938, 1725, 1598, 1495, 1370, 1293, 1218, 1178 cm-1; 1H NMR
(250 MHz CDCl3, 293 K) δ 7.78 (d, J ) 7.6 Hz, 2H), 7.32 (d, J
) 7.5 Hz, 2H), 6.90 (s, 1H), 6.79 (s, 1H), 3.67 (s, 3H), 3.51-
3.45 (dd, J ) 7.3, 5.5 Hz, 1H), 2.92-2.84 (dd, J ) 13.7, 5.5
Hz, 1H), 2.71-2.63 (dd, J ) 13.7, 7.7 Hz, 1H), 2.44 (s, 3H),
2.19 (s, 3H), 1.42 (s, 9H); 13C NMR (75 MHz CDCl3, 293 K) δ
174.0, 149.3, 145.1, 142.2, 133.2, 133.1, 132.8, 130.4, 129.5
(×2), 128.4 (×2), 121.8, 81.2, 60.5, 56.0, 40.2, 27.9 (×3), 21.6,
15.9; HRMS (ESI+) m/z calcd for C22H30NO6S + H (M + H)+
436.1795, found 436.1789.
23
minor isomer (36.0 mg, 0.05 mmol, 22% for two steps): [R]D
) -2° (c 0.51 CHCl3); IR (CHCl3) ν 3434, 3013, 2929, 2399,
1715, 1496, 1232 cm-1; H NMR (300 MHz CDCl3, 293 K) δ
1
6.64 (s, 1H), 6.63 (s, 1H), 6.11 (m, 2H), 6.02 (d, J ) 1.5 Hz,
1H), 6.00 (d, J ) 1.5 Hz, 1H), 5.90 (m, 1H), 5.63 (d, J ) 5.9
Hz, 1H), 5.46 (dd, J ) 16.9, 2.2 Hz, 2H), 5.33 (d, J ) 2.9 Hz,
1H), 5.35-5.20 (m, 4H), 4.58 (m, 4H), 4.39 (ddt, J ) 12.5, 5.1,
1.5 Hz, 2H), 4.31 (ddt, J ) 12.5, 5.9, 1.5 Hz, 1H), 4.07-4.01
(m, 2H), 3.87 (m, 1H), 3.85 (s, 3H), 3.70 (br.d, J ) 12.5 Hz,
1H), 3.58 (m, 1H), 3.17 (dd, J ) 14.0, 4.4 Hz, 1H), 3.10 (dd, J
) 14.0, 8.8 Hz, 1H), 2.51 (m, 1H), 2.26 (s, 3H), 2.16 (s, 3H),
1.56 (s, 3H), 1.41 (s, 3H); 13C NMR (75 MHz CDCl3, 293K) δ
156.0, 151.4, 150.1, 147.0, 146.6, 139.5, 133.6, 133.3, 132.6,
132.1, 131.9, 124.0, 118.9, 117.6, 117.4, 117.2, 117.1, 113.9,
113.0, 112.9, 101.6, 99.2, 75.7, 69.4, 65.9, 65.7, 62.9, 62.5, 60.1,
58.7, 55.8, 55.7, 54.6, 29.7, 29.1, 19.2, 15.9, 9.3; HRMS (ESI+)
m/z calcd for C38H47N3O10Na (M + Na)+ 728.3159, found
728.3132.
Aminonitrile 39b. In a manner similar to that used in the
preparation of 39a, treatment of 10b (824.0 mg, 2.02 mmol)
and 9 (490.0 mg, 1.35 mmol) gave 39b (590.0 mg, 0.75 mmol,
56% for the major isomer) as a colorless oil. [R]2D3 ) -29° (c
1.0 CHCl3); IR (CHCl3) ν 3447, 3016, 2930, 2229, 1719 (forte),
1585, 1490, 1384, 1200, 1113 cm-1; 1H NMR (300 MHz CDCl3,
293 K) δ 6.66 (s, 1H), 6.58 (s, 1H), 6.07 (m, 1H), 5.99 (d, J )
1.2 Hz, 1H), 5.95 (d, J ) 1.2 Hz, 1H), 5.85 (m, 1H), 5.17-5.45
(m, 4H), 5.37 (d, J ) 2.6 Hz, 1H), 5.03 (d, J ) 6.8 Hz, 1H),
4.54 (m, 2H), 4.43 (m, 1H), 4.39 (m, 1H), 4.25 (ddt, J ) 12.1,
5.1, 1.0 Hz, 1H), 3.96-4.16 (m, 3H), 3.73-3.92 (m, 3H), 3.73
(s, 3H), 3.29 (dd, J ) 13.6, 3.1 Hz, 1H), 3.11 (m, 1H), 2.93 (dd,
J ) 13.5, 10.2 Hz, 1H), 2.51 (br.s, 1H), 2.22 (s, 3H), 2.14 (s,
3H), 1.58 (s, 3H), 1.42 (s, 3H), 0.97 (s, 9H), 0.16 (s, 6H); 13C
NMR (75 MHz CDCl3, 293 K) δ 156.5, 150.9, 149.5, 149.3,
147.9, 140.5, 134.5, 134.4, 133.4, 133.2, 125.2, 120.7, 119.6,
118.6, 118.0, 117.7, 114.8, 113.7, 102.5, 100.1, 76.6, 67.1, 66.6,
63.8, 63.4, 62.1, 60.6, 56.7, 56.3, 55.1, 36.2, 30.1, 26.5 (×3),
20.0, 19.1, 16.8, 10.1, -4.2 (×2); LRMS (ESI+) m/z 802.4 (M +
Na)+; HRMS (ESI+) m/z calcd for C41H57N3O10SiNa (M + Na)+
802.3711, found 802.3704.
Macrolactone 44a. To a solution of the ester 43a (55.0 mg,
0.42 mmol) in TFE (5.0 mL) at 0 °C was added a solution of
TFA (60.0 µL) in TFE (1.0 mL) and the resulting mixture was
stirred at room temperature for 2 h. The reaction mixture was
quenched with saturated NaHCO3 and extracted with EtOAc.
The organic phase was dried over Na2SO4 and concentrated
Aminonitrile 39a. To a solution of amino alcohol 9 (85 mg,
0.23 mmol) and aldehyde 10a (117.0 mg, 0.35 mmol) in toluene
(1.2 mL) was added 3 Å molecular sieves (260.0 mg). After
being stirred at 40 °C overnight, the mixture was diluted with
J. Org. Chem, Vol. 70, No. 11, 2005 4407

Chen et al.
under reduced pressure. The residue was purified by flash
column chromatography to afford the macrocycle 44a (25.0 mg,
0.027 mmol, 65%) as a colorless oil. [R]2D3 ) +10° (c 0.86
CHCl3); IR (CHCl3) ν 3524, 3422, 3016, 2928, 2362, 1732, 1506,
calculated C44H55N4O12SiKSCl3 (M + K)+ 1035.2009 and
1037.1979, found 1035.2009, 1037.1953.
Phenol 7. To a solution of hemiacetal 49 (74.0 mg, 0.074
mmol) in MeOH (4.0 mL) was added a solution of KF‚2H2O
(21.0 mg, 0.22 mmol) in MeOH (4.0 mL), AcOH (4.5 µL, 0.076
mmol), and H2O (0.2 mL). After being stirred at room tem-
perature for 4 h, the mixture was partitioned between AcOEt
and saturated NaCl/H2O/saturated NaHCO3 (1:1:0.2). The
organic phase was washed with brine, dried over Na2SO4 and
concentrated. The residue was purified by flash column
chromatography to afford phenol 7 (58.0 mg, 0.066 mmol, 89%)
as a pale yellow powder. [R]2D3 ) -21° (c 1.0 CHCl3); IR
(CHCl3) ν 3533, 3421, 3013, 2929, 1735, 1683, 1502, 1432, 1099
cm-1; 1H NMR (300 MHz CDCl3, 293 K) δ 6.78 (d, J ) 1.4 Hz,
1H), 6.67 (s, 1H), 6.11 (s, 1H), 6.09 (m, 1H), 5.99 (s, 1H), 5.98
(d, J ) 6.6 Hz, 1H), 5.67 (d, J ) 11.3 Hz, 1H), 5.66 (m, 1H),
5.49 (dd, J ) 8.1, 1.6 Hz, 1H), 5.47 (dd, J ) 17.1, 2.0 Hz, 1H),
5.30 (dd, J ) 10.9, 2.1 Hz, 1H), 5.18 (m, 2H), 5.10 (d, J ) 1.4
Hz, 1H), 4.71 (d, J ) 1.3 Hz, 2H), 4.56 (m, 3H), 4.26 (m, 3H),
4.15 (dd, J ) 11.4, 2.0 Hz, 1H), 3.94 (d, J ) 2.4 Hz, 1H), 3.79
(m, 1H), 3.77 (s, 3H), 3.21 (m, 3H), 2.51 (dd, J ) 2.4, 8.1 Hz,
1H), 2.47 (dd, J ) 14.7, 3.0 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H);
13C NMR (75 MHz CDCl3, 293 K) δ 166.9, 155.2, 152.2, 149.1,
147.1, 145.3, 142.7, 137.2, 131.9, 131.7, 129.9, 129.2, 122.5,
117.4, 116.8, 116.4, 115.3, 112.9, 111.8, 111.5, 100.3, 93.6, 75.5,
73.1, 72.6, 65.0, 65.0, 63.8, 59.0, 58.8, 56.3, 55.2, 53.5, 37.1,
33.3, 30.8, 14.3, 8.3; LRMS (MALDI) m/z 905.2, 907.2 (M +
Na)+; HRMS (MALDI) m/z calcd for C38H41N4O12NaSCl3 (M +
Na)+ 905.1405, 907.1375, found 905.1415, 907.1364.
1
1101 cm-1; H NMR (300 MHz CDCl3, 293 K) δ 6.78 (s, 1H),
6.74 (s, 1H), 6.09 (s, 1H), 6.05 (m, 2H), 5.99 (s, 1H), 5.93 (d, J
) 6.6 Hz, 1H), 5.92 (m, 1H), 5.51-5.20 (m, 6H), 4.95 (d, J )
9.6 Hz, 1H), 4.82 (d, J ) 2.2 Hz, 1H), 4.69 (s, 2H), 4.57-4.50
(m, 8H), 4.43 (m, 1H), 4.25 (ddt, J ) 11.0, 6.6, 1.5 Hz, 1H),
4.08 (br.d, J ) 8.8 Hz, 1H), 3.89 (dd, J ) 12.5, 3.7 Hz, 1H),
3.82 (m, 4H), 3.45 (br.d, J ) 11.0 Hz, 1H), 3.10 (dd, J ) 14.7,
2.2 Hz, 1H), 3.03 (m, 1H), 2.90 (dd, J ) 13.2, 8.8 Hz, 1H), 2.41
(dd, J ) 14.7, 2.9 Hz, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.61 (s,
3H), 1.47 (s, 3H); 13C NMR (75 MHz CDCl3, 293 K) δ 169.0,
155.7, 153.7, 151.6, 150.5, 147.0, 146.7, 138.8, 133.4, 133.3,
133.1, 132.4, 132.2, 131.8, 123.9, 117.8, 117.6, 117.3, 116.7,
113.3, 113.0, 112.9, 101.9, 95.1, 74.7, 74.0, 69.4, 66.6, 66.0, 65.5,
62.0, 60.4, 60.1, 57.7, 55.4, 55.3, 52.3, 43.3, 29.7, 16.1, 9.9;
LRMS (ESI+) m/z (M + Na)+ 947.3, 949.3.
Macrolactone 44b. In a manner similar to that used for
the preparation of 44a, treatment of 43b (180.0 mg, 0.13 mmol)
gave 44b (82.0 mg, 0.081 mmol, 63%) as a colorless oil. [R]D23
) +40° (c 1.0 CHCl3); IR (CHCl3) ν 3420, 3019, 2931, 2857,
1
1735, 1505, 1257, 1107 cm-1; H NMR (300 MHz CDCl3, 293
K) δ 6.74 (s, 1H), 6.69 (s, 1H), 6.08 (s, 1H), 5.97 (s, 1H), 6.1-
5.8 (m, 3H), 5.5-5.1 (m, 5H), 4.93 (d, J ) 8.8 Hz, 1H), 4.83 (d,
J ) 2.4 Hz, 1H), 4.67 (s, 2H), 4.6-4.4 (m, 6H), 4.4-4.0 (m,
2H), 3.85 (br.d, J ) 14.5,Hz, 1H), 3.73 (m, 4H), 3.50 (br.d, J )
13.8 Hz, 1H), 3.11 (dd, J ) 14.9, 1.7 Hz, 1H), 3.04 (m, 1H),
2.81 (dd, J ) 13.6, 8.7 Hz, 1H), 2.37 (dd, J ) 15.1, 3.0 Hz,
1H), 2.23 (s, 3H), 2.19 (s, 3H), 0.99 (s, 9H), 0.18 (s, 3H), 0.17
(s,1H); 13C NMR (75 MHz CDCl3, 293 K) δ 169.3, 158.6, 156.0,
154.1, 150.9, 149.1, 147.4, 139.2, 137.1, 133.7, 132.8, 130.9,
124.8, 120.4, 119.0, 118.1, 118.0, 117.1, 113.7, 113.3, 102.3,
95.5, 75.1, 74.4, 67.1, 66.4, 65.8, 62.3, 60.2, 58.0, 55.7, 55.6,
52.7, 43.6, 33.2, 33.2, 25.7 (×3), 18.4, 16.1, 9.8, -4.2 (×2);
LRMS (ESI+) m/z 1021.3, 1023.3 (M + Na)+; HRMS (ESI+)
m/z calcd for C44H57N4O12Si NaSCl3 (M + Na)+ 1021.2426,
1023.2449, found 1021.2441, 1023.2443.
Thiol 51a. To a solution of 7 (20.0 mg, 0.023 mmol) in
MeCN (3.0 mL) was added a solution of trifluoromethane-
sulfonic acid (25.0 µL) in MeCN (2.0 mL) at 0 °C, and the
mixture was stirred at 0 °C for 40 min. The reaction was
quenched by addition of saturated NaHCO3 and extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4 and concentrated. The residue was purified by flash
column chromatography to afford 51a (16.0 mg, 0.019 mmol,
84%) as a colorless oil: [R]2D3 ) + 77° (c 1.0 CHCl3); IR
(CHCl3) ν 3530, 3419, 2928, 1733, 1702, 1683, 1420, 1251, 1100
1
N,O-Hemiacetal 49. To a stirred solution of oxalyl chloride
(7.0 µL, 0.079 mmol) in CH2Cl2 (0.15 mL) cooled to -78 °C
was added a solution of DMSO (14.0 µL, 0.20 mmol) in CH2-
Cl2 (0.15 mL). After 5 min of stirring at -78 °C, a solution of
alcohol 44b (66.0 mg, 0.066 mmol) in CH2Cl2 (0.50 mL) was
added and the mixture was stirred at the same temperature
for 1 h. TEA (46.0 µL, 0.33 mmol) was added, the reaction was
then allowed to warm to 0 °C, and stirring was continued for
another 30 min. The mixture was diluted with CH2Cl2, washed
with saturated NaHCO3, brine and dried over Na2SO4. After
concentration and column chromatography, the hemiacetal 49
(49.0 mg, 0.049 mmol, 74%) was isolated as a colorless oil.
[R]2D3 ) -28° (c 1.0 CHCl3); IR (CHCl3) ν 3421, 2958, 1735,
cm-1; H NMR (300 MHz CDCl3, 293 K) two rotamers δ 6.69
& 6.67 (s, 1H), 6.29 & 6.23 (br.s, 1H), 6.10 (m, 1H), 6.01 (s,
1H), 5.90 (m, 1H), 5.88 (s, 1H), 5.81 (d, J ) 7.2 Hz, 1H), 5.62
& 5.54 (br.s, 1H), 5.45 (dd, J ) 17.0, 1.4 Hz, 1H), 5.32 (br.d, J
) 10.0 Hz, 1H), 5.3-5.2 (m, 2H), 4.95-4.80 (m, 3H), 4.73-
4.52 (m, 4H), 4.51 (d, J ) 3.7 Hz, 1H), 4.35-4.25 (m, 2H), 3.72
(s, 3H), 3.70 (m, 1H), 3.46 (dd, J ) 4.2, 10.9 Hz, 1H), 3.36 (br.d,
1H), 3.02(m, 2H), 2.28 (br.s, 3H), 2.14 (s, 3H); 13C NMR (75
MHz CDCl3, 293 K) δ 168.7, 154.1, 153.7 & 153.3, 148.2, 147.5,
146.2, 144.2, 139.4, 134.9 & 134.8, 133.6, 132.2, 128.9 & 128.6,
127.9 &127.5, 126.1 & 125.8, 118.6, 118.0, 117.9, 117.1, 116.3,
114.0, 112.8 & 112.5, 104.2, 102.9 & 102.4, 101.6, 95.2, 75.2,
75.1, 66.8, 64.2, 61.0, 56.7 & 56.4, 55.5, 53.1 & 52.2, 52.7, 49.8
& 48.8, 29.4 & 29.1, 11.3, 9.4; LRMS (ESI+) m/z 887.1, 889.2;
HRMS (ESI+) m/z calcd for C38H39N4O11NaSCl3 (M + Na)+
887.1299, 889.1270, found 887.1311, 889.1298.
1
1684, 1462, 1303, 1099 cm-1; H NMR (300 MHz CDCl3, 293
K) δ 6.73 (d, J ) 1.1 Hz, 1H), 6.69 (s, 1H), 6.11 (d, J ) Hz,-
1H), 6.09 (m, 1H), 5.99 (d, J ) 1.1 Hz, 1H), 5.92 (d, J ) 6.7
Hz, 1H), 5.68 (m, 1H), 5.67 (d, J ) 11.3 Hz, 1H), 5.49 (dd, J )
8.2, 1.5 Hz, 1H), 5.47 (dd, J ) 16.9, 2.1 Hz, 1H), 5.30 (dd, J )
10.9, 2.1 Hz, 1H), 5.24-5.14 (m, 1H), 5.11 (d, J ) 1.8 Hz, 1H),
4.70 (s, 2H), 4.58 (m, 3H), 4.27 (m, 3H), 4.16 (dd, J ) 11.5, 2.0
Hz, 1H), 3.94 (d, J ) 2.4 Hz, 1H), 3.80 (m, 1H), 3.73 (s, 3H),
3.3-3.1 (m, 3H), 2.53 (dd, J ) 8.2, 2.3 Hz, 1H), 2.46 (dd, J )
14.8, 3.0 Hz, 1H), 2.25 (s, 3H), 2.22 (s, 3H), 1.03 (s, 9H), 0.24
(s, 6H); 13C NMR (75 MHz CDCl3, 293 K) δ 168.7, 157.0, 154.0,
151.0, 148.8, 148.6, 147.1, 139.0, 133.5, 132.4, 132.3, 131.8,
125.2, 120.6, 119.0, 118.6, 118.1, 117.1, 113.5, 113.3, 102.1,
95.3, 77.0, 74.9, 74.4, 66.7, 65.6, 60.5, 59.9, 58.0, 56.9, 55.3,
55.3, 39.5, 34.8, 32.7, 25.9 (×3), 18.5, 16.2, 10.0, -4.2, -4.4;
LRMS (MALDI) m/z 1035.24, 1037.25; HRMS (MALDI) m/z
Acknowledgment. We thank CNRS and this insti-
tute for financial support. A doctoral fellowship from
the “Ministe`re de l’Enseignement Supe´rieur et de la
Recherche” to M.D.P. is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedure and spectroscopic data of compounds 9, 10a,b, 11, 15,
17, 19, 26-28, 34, 35a,b, 36, 37, 41, 43a,b, 51b, and 53b;
synthesis of bromide 29 from methyl catechol; and X-ray data
for compound 19 in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO050408K
4408 J. Org. Chem., Vol. 70, No. 11, 2005