Highly anti-selective conjugate addition of arylcuprates to a γ-alkoxy-α,β-enoate. A new method to address stereochemical challenges presented by Amaryllidaceae alkaloids

Article abstract of DOI:10.1016/j.tetlet.2005.05.006

Various substituted arylcuprates undergo stereocontrolled additions to a d-mannitol-derived γ-alkoxy-α,β-enoate with exclusive anti-selectivity. The method is well suited for the preparation of a broad range of biologically active Amaryllidaceae alkaloids

Full text of DOI:10.1016/j.tetlet.2005.05.006

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4433–4437
Highly anti-selective conjugate addition of arylcuprates to a
c-alkoxy-a,b-enoate. A new method to address
stereochemical challenges presented by Amaryllidaceae alkaloids
Madhuri Manpadi and Alexander Kornienko*
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA
Received 12 March 2005; revised 1 May 2005; accepted 3 May 2005
Abstract—Various substituted arylcuprates undergo stereocontrolled additions to a D-mannitol-derived c-alkoxy-a,b-enoate with
exclusive anti-selectivity. The method is well suited for the preparation of a broad range of biologically active Amaryllidaceae alka-
loids and their aromatic analogues. A model accounting for the stereochemical outcome of this process is presented.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Isoquinoline alkaloids, isolated from plants of the Ama-
ryllidaceae family, have attracted broad interest from
synthetic chemists, biologists, and pharmacologists.1
Many of these natural products have been found to dis-
play various medicinally useful physiological effects
including anticancer, antiviral, immunostimulatory, acet-
ylcholinesterase inhibitory, and antimalarial activities.
On the basis of the carbon framework, Amaryllidaceae
alkaloids are classified into several structural types,
examples being the narciclasine, lycorine, and lycorenine
families (Fig. 1).
According to a recent comprehensive review, over 100
alkaloids that fall into one of these three groups have
been isolated.2 Despite potent biological activities asso-
ciated with some of these Amaryllidaceae constituents,
OH
OH
MeN
OH
1
HO
*
10b
MeO
MeO
*
*
O
O
*
O
O
OH
O
NH
N
OH
Lycorenine
OH
O
Lycorine
OH
Narciclasine
OH
MeN
HO
1
OH
OH
HO
OH
OH
*
10b
*
*
O
O
*
O
O
O
OH
O
NH
NH
O
O
OH
O
O
Hippeastrine
Pancratistatin
7-Deoxy-pancratistatin
Figure 1.
Keywords: Acyclic stereoselection; Arylcuprate; Amaryllidaceae alkaloids.
*
Corresponding author. Tel.: +1 505 835 5884; fax: +1 505 835 5364; e-mail: akornien@nmt.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.006

4434
M. Manpadi, A. Kornienko / Tetrahedron Letters 46 (2005) 4433–4437
their medicinal evaluation is hampered due to low natu-
ral abundance, hence insufficient quantities available
from isolation. For example, pancratistatin (narciclasine
type) is a potent anticancer, antiviral, and antiparasitic
agent that has been in various stages of preclinical devel-
opment for over 18 years. This lengthy time period is in
great part due to availability issues.3 Cytotoxic alkaloids
hippeastrine4 (lycorenine type) and 7-deoxypancratista-
tin5 (narciclasine type) serve as additional examples of
this problem. It should be noted that 7-deoxypancratist-
atin has been shown to exhibit promising therapeutic in-
dexes in antiviral assays and represents a rare example
of chemotherapeutic efficacy in a Japanese Encephalitis
virus infected mouse model.6
we were uncertain about the contribution of d and
e-benzyloxy groups in enoate 1 toward this high selectiv-
ity. This is an important issue since successful applica-
tion of this arylcuprate chemistry in various settings
requires that efficient stereocontrol be exerted by a single
c-alkoxy group.
Examination of the literature reports of organocopper
addition processes with c-alkoxy-a,b-enoates reveals
that although the anti-stereochemical outcome is
cwell-precedented, the selectivities range from moderate
to high and are seldom exclusive.12 While various c-
oxygen protecting groups have been found to favor
the formation of anti-products, Hanessian and his co-
workers systematically studied Me2CuLi addition to a
glyceraldehyde-derived enoate and found that selectivi-
ties were highest with methoxymethyl (10:1) and benzyl-
oxymethyl (14:1) groups.12d Although Ph2CuLi reagent
was only moderately (4.5:1) anti-selective with a
c-MOMO-a,b-enoate,12d the same research group
reported later that the reaction of Ph2CuMgBr with
These issues have led to a worldwide effort aimed at
developing synthetic pathways to these natural products
for systematic study of their biology and generation of
analogues with medicinal potential. The complexity of
these structures stems in part from dense stereochemis-
try of the cyclitol moiety. Thus, installation of the aro-
matic ring with the required stereochemistry in
pancratistatin (position C10b) has significantly under-
mined the efficiencies of its published syntheses.7 Conse-
quently, pancratistatinÕs practical chemical preparation,
which will provide the required quantity of material for
clinical trials, still captivates the minds of the synthetic
community.8 In contrast, much shorter synthetic ap-
proaches have been developed to narciclasine, which
has no stereocenter at position C10b.9
a
c-BOMO-a,b-enoate displayed very high anti-
selectivity.12k These, to our knowledge, represent the
only examples of utilization of arylcuprates in this
methodology.
The above-mentioned reports prompted us to prepare
enoate 3 utilizing literature procedures reported for a re-
lated compound12d,13 and investigate its reactions with
various substituted arylcopper reagents, including those
derived from alkoxy aromatics (Scheme 2). We were
pleased to find that under the reaction conditions previ-
ously developed for enoate 1, these additions proceed
with exclusive anti-diastereoselectivities14 with all of
the arylcuprates studied.15,16
Our recently disclosed synthetic strategy for a practical
synthesis of pancratistatin involves an arylcuprate con-
jugate addition process to c,d,e-trialkoxyenoate 1
(Scheme 1) as an efficient way to install the C10b stereo-
center.10 We found that this reaction affords exclusive
anti-selectivity, independent of the substitution pattern
on the aromatic ring. While the anti-stereochemical out-
come of this process makes it potentially applicable to
the synthesis of lycorine and lycorenine alkaloid types,11
The anti-stereochemistry was confirmed by converting
the phenyl addition product 4a to known lactone 6,
1
whose H and 13C NMR had been previously reported
(Scheme 3).17
A number of transition state models, which may ac-
count for anti-selective addition of alkyl, vinyl, and allyl
cuprates to c-alkoxy-a,b-enoates, have been discussed
by various investigators.12b,d,e Clearly, because of the
complex and diverse nature of organocopper reagents,
no single mechanistic model generally explains or pre-
dicts the outcome of these reactions. In addition, the re-
sults of recent mechanistic investigations strongly
support the involvement of large cluster frameworks in
these conjugate additions.18 Thus, the reason for the
strong anti-stereochemical preference may be totally dif-
ferent for arylcuprates. The rather unusual (for acyclic
systems) high degree of stereocontrol observed here
leads us to favor a Ômodified Felkin-AnhÕ19 interpreta-
tion (Fig. 2), in which allylic 1,3-strain20 greatly destabi-
lizes transition state B that leads to syn-products. This
destabilization is augmented by the ÔacuteÕ angle of at-
tack in a copper-enoate p-complex, whose formation is
evidenced by recent experimental and theoretical work
(Fig. 2).18,21 To our knowledge, there has been no discus-
sion of factors determining stereochemical outcome of
such reactions after the new mechanistic understanding
OBn
OBn
BnO
HO
OBn
BnO
OBn
Ar2CuMgBr
TMSCl, THF
CO2Me
CO2Me
1
OH
OBn
OH
OH
BnO
OBn
3 steps
NH
O
Pancratistatin and its
aromatic analogues
O
O
O
O
Ar =
MeO
OMe
97%
200:1
95%
200:1
95%
200:1
97%
200:1
Scheme 1.

M. Manpadi, A. Kornienko / Tetrahedron Letters 46 (2005) 4433–4437
4435
1. AcOH, H2O
2 steps
OCH2OCH3
CO2Et
O
2. t-BuPh2SiCl, DMAP,
imidazole, DMF
D-mannitol
O
t-BuPh2SiO
70%
ref. 13
CO2Et
3. CH3OCH2Cl, (i-Pr)2NEt
79% overall
2
3
OSiPh2t-Bu
H3COH2CO
lycorine
OCH2OCH3
Ar2CuMgBr
TMSCl, THF
-78 oC
rt
t-BuPh2SiO
3
lycorenine
type alkaloids
CO2Et
Ar
4a-f
CO2Et
O
b)
MeO
a)
c)
e)
f)
O
O
H3CO
H3CO
d)
O
Ar =
F
OMe
75%
200:1
80%
200:1
78%
200:1
79%
200:1
75%
200:1
76%
200:1
Scheme 2.
complex substances. Two particular aspects of this
method are noteworthy. Firstly, the observed exclusive
stereocontrol is an important factor in evaluating the
potential scalability of any synthetic method, since nor-
mally difficult chromatographic separation of acyclic
stereoisomers is not required. Secondly, the lack of
dependence of this stereochemical outcome on the sub-
stitution pattern on the aromatic ring makes this process
applicable to the generation of aromatic analogues of
these natural products, an area which has been little
explored.22
OCH2OCH3
CO2Et
t-BuPh2SiO
Me2BBr, CH2Cl2;
NaHCO3, H2O/THF
63%
4a
O
O
O
O
1. Bu4NF, THF
2. Ac2O, py
64%
OAc
OSiPh2t-Bu
6
5
Further efforts are underway in this area to apply this
chemistry to the synthesis of Amaryllidaceae constitu-
ents and to refine the presented stereochemical model.
Scheme 3.
Br
Ar
Ar
III
Ar
Mg
Acknowledgments
Cu
Ar
Br
Cu
Mg
O
R
H
H
We thank Professor Patrick S. Mariano for generously
giving his time and numerous helpful suggestions. This
work is supported by the US National Institutes of
Health (RR-16480) under the BRIN/INBRE program
of the National Center for Research Resources.
OEt
anti
H
MOMO
(A)
1,3-strain
MOMO
H
R
syn
H
H
OEt
Ar
O
Supplementary data
Mg
Br
Ar
III
Cu
Cu
Mg
Br
Ar
The supplementary data, which include the copies of 1H
and 13C NMR spectra of compounds 3 and 4a–f, are
available online with the paper in ScienceDirect. Supple-
mentary data associated with this article can be found,
in the online version at doi:10.1016/j.tetlet.2005.05.006.
Ar
(B)
Figure 2.
of organocopper conjugate addition process, includ-
ing the intermediacy of CuIII species, has emerged.
References and notes
1. Martin, S. F. The Amaryllidaceae Alkaloids. In The
Alkaloids; Brossi, A. R., Ed.; Academic: New York, 1987;
Vol. 30, pp 251–376.
2. Hoshino, O. The Amaryllidaceae Alkaloids. In The
Alkaloids; Cordell, G. A., Ed.; Academic: London, 1998;
Vol. 51, pp 323–376.
We believe that the chemistry described in this letter will
find general utility in procedures for the installation of
aromatic subunits with required stereochemistry in
pathways to a large number of medicinally promising
Amaryllidaceae alkaloids and other stereochemically

4436
M. Manpadi, A. Kornienko / Tetrahedron Letters 46 (2005) 4433–4437
3. For recent discussion, see: Pettit, G. R.; Melody, N.;
Herald, D. L. J. Nat. Prod. 2004, 67, 322.
4. Antoun, M. D.; Mendoza, N. T.; Rios, Y. R.; Proctor, G.
R. J. Nat. Prod. 1993, 56, 1423.
5. Ghosal, S.; Singh, S.; Kumar, Y.; Srivastava, R. S.
Phytochemistry 1989, 28, 611.
6. Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kefauver,
D. F.; Pettit, G. R.; Groszek, G.; Hollingshead, M.; Kirsi,
J. J.; Shannon, W. M.; Shubert, E. M.; Dare, J.; Ugarkar,
B.; Ussery, M. A.; Phelan, M. J. J. Nat. Prod. 1992, 55,
1569.
aryl bromide was added dropwise to allow a gentle
reaction. The reaction mixture was allowed to cool to
room temperature and was cannulated to a slurry of CuI
(3.52 mmol, 0.67 g) in THF (10 mL) at ꢀ78 ꢁC. The
mixture was stirred at ꢀ78 ꢁC for 40 min (in the synthesis
of 4e the mixture was stirred at 0 ꢁC for 2 h, as no trans-
metallation occurred at ꢀ78 ꢁC). Me3SiCl (7.03 mmol,
0.76 g) and enoate 3 (0.703 mmol, 0.311 g in 10 mL of
THF) were added sequentially at ꢀ78 ꢁC. The yellow-
brown suspension was stirred overnight while slowly
warming up to room temperature. The reaction mixture
was quenched with a mixture of concd. NH4OH and satd
NH4Cl (1:9, 30 mL) and extracted with ether (3 · 30 mL).
The combined organic layers were washed with brine,
dried with MgSO4, and concentrated under reduced
pressure. The residue was absorbed on silica gel and
purified by column chromatography (5–10% EtOAc/hex-
anes) to yield 4a–f as an oil.
7. For total syntheses of pancratistatin see: (a) Danishefsky,
S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829; (b) Tian,
X.; Hudlicky, T.; Ko¨nigsberger, K. J. Am. Chem. Soc.
1995, 117, 3643; (c) Hudlicky, T.; Tian, X.; Ko¨nigsberger,
K.; Maurya, R.; Rouden, J.; Fan, B. J. Am. Chem. Soc.
1996, 118, 10752; (d) Trost, B. M.; Pulley, S. R. J. Am.
Chem. Soc. 1995, 117, 10143; (e) Magnus, P.; Sebhat, I. K.
J. Am. Chem. Soc. 1998, 120, 5341; (f) Magnus, P.; Sebhat,
I. K. Tetrahedron 1998, 54, 15509; (g) Rigby, J. H.;
Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc.
2000, 122, 6624; (h) Doyle, T. J.; Hendrix, M.; VanDer-
veer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997,
53, 11153; (i) Pettit, G. R.; Melody, N.; Herald, D. L.
J. Org. Chem. 2001, 66, 2583; (j) Kim, S.; Ko, H.; Kim, E.;
Kim, D. Org. Lett. 2002, 4, 1343; (k) Ko, H.; Kim, E.;
Park, J. E.; Kim, D.; Kim, S. J. Org. Chem. 2004, 69, 112.
8. For recent discussion, see: Rinner, U.; Hudlicky, T.
Synlett 2005, 365.
9. For total syntheses of narciclasine, see: (a) Rigby, J. H.;
Mareo, M. E. J. Am. Chem. Soc. 1997, 119, 12655; (b)
Gonzales, D.; Martinot, T.; Hudlicky, T. Tetrahedron
Lett. 1999, 40, 3077; (c) Keck, G. E.; Wager, T. T.;
Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176; (d)
Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am.
Chem. Soc. 2000, 122, 6624; (e) Elango, S.; Yan, T.-H.
J. Org. Chem. 2002, 67, 6954; (f) Hudlicky, T.; Rinner, U.;
Gonzalez, D.; Akgun, H.; Schilling, S.; Siengalewicz, P.;
Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002, 67,
8726.
16. Characterization data: 3: Rf 0.64 (20% EtOAc/hexanes);
21
1
½aꢁD +12.3 (c 1.7, CHCl3); H NMR (CDCl3) d 7.38–7.69
(m, 10H), 6.85 (dd, 1H, J = 5.5, 15.7 Hz), 6.06 (dd, 1H,
J = 1.4, 15.7 Hz), 4.72 (d, 1H, J = 6.6 Hz), 4.65 (d, 1H,
J = 6.6 Hz), 4.32 (m, 1H), 4.16 (q, 2H, J = 7.1 Hz), 3.71
(dd, 1H, J = 6.6, 10.5 Hz), 3.63 (dd, 1H, J = 5.2, 10.7 Hz),
3.35 (s, 3H), 1.26 (t, 3H, J = 7.1 Hz), 1.05 (s, 9H); 13C
NMR (CDCl3) d 166.2, 145.2, 135.7, 133.2, 129.9, 127.8,
122.9, 95.3, 76.0, 66.1, 60.5, 55.7, 26.8, 19.3, 14.3; HRMS
m/z (ESI) calcd for C25H34O5SiNa (M+Na+) 465.2067,
found 465.2063. 4a: Rf 0.58 (20% EtOAc/hexanes);
21
½aꢁD ꢀ43.9 (c 0.5, CHCl3); 1H NMR (CDCl3) d 7.19–
7.60 (m, 15H), 4.68 (d, 1H, J = 6.9 Hz), 4.51 (d, 1H,
J = 6.9 Hz), 3.97 (q, 2H, J = 7.2 Hz), 3.75 (m, 1H), 3.46
(m, 3H), 3.27 (s, 3H), 2.97 (dd, 1H, J = 5.2, 15.6 Hz), 2.64
(dd, 1H, J = 10.2, 15.6 Hz), 1.08 (t, 3H, J = 7.2 Hz), 1.03
(s, 9H); 13C NMR (CDCl3) d 172.8, 141.3, 135.5, 133.2,
129.8, 128.5, 127.8, 126.9, 96.4, 81.0, 63.9, 60.0, 56.0, 43.1,
37.2, 26.8, 19.2, 14.0; HRMS m/z (ESI) calcd for
C31H40O5SiNa (M+Na+) 543.2537, found 543.2530. 4b:
21
Rf 0.45 (20% EtOAc/hexanes); ½aꢁD ꢀ45.7 (c 0.2, CHCl3);
1H NMR (CDCl3) d 6.76–7.60 (m, 14H), 4.52 (d, 1H,
J = 6.9 Hz), 4.69 (d, 1H, J = 6.9 Hz), 3.98 (q, 2H,
J = 7.0 Hz), 3.77 (s, 3H), 3.75 (m, 1H), 3.42 (m, 3H),
3.29 (s, 3H), 2.96 (dd, 1H, J = 5.2, 15.4), 2.59 (dd, 1H,
J = 10.5, 15.4 Hz), 1.07 (t, 3H, J = 7.0 Hz), 1.03 (s, 3H);
13C NMR (CDCl3) d 172.7, 158.4, 135.7, 135.6, 133.4,
133.2, 129.7, 129.3, 127.7, 116.1, 114.8, 113.8, 96.4, 81.1,
63.7, 60.2, 56.1, 55.3, 42.6, 37.4, 26.9, 19.3, 14.2; HRMS
m/z (ESI) calcd for C32H42O6SiNa (M+Na+) 573.2642,
10. Nadein, O. N.; Kornienko, A. Org. Lett. 2004, 6, 831.
11. Relative cis-configuration of an aromatic ring and an
adjacent oxygen stereocenter (marked with asterisks in
Fig. 1) is conserved throughout these alkaloid types and it
translates to anti-stereochemistry in an open-chain
precursor.
12. For key reports, see: (a) Nicolaou, K. C.; Pavia, M. R.;
Seitz, S. P. J. Am. Chem. Soc. 1981, 103, 1224; (b) Roush,
W. R.; Lesur, B. M. Tetrahedron Lett. 1983, 24, 2231; (c)
Yamamoto, Y.; Nishii, S.; Ibuka, T. Chem. Commun.
1987, 464; (d) Hanessian, S.; Sumi, K. Synthesis 1991,
1083; (e) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka,
T.; Kitahara, H. J. Am. Chem. Soc. 1992, 114, 7652; (f)
Hanessian, S.; Gai, Y.; Wang, W. Tetrahedron Lett. 1996,
7473; (g) Hanessian, S.; Wang, W.; Gai, Y. Tetrahedron
Lett. 1996, 37, 7477; (h) Hanessian, S.; Wang, W.; Gai, Y.;
Olivier, E. J. Am. Chem. Soc. 1997, 119, 10034; (i) Ziegler,
F. E.; Wang, Y. J. Org. Chem. 1998, 63, 426; (j) Ziegler, F.
E.; Wang, Y. J. Org. Chem. 1998, 63, 7920; (k) Hanessian,
S.; Ma, J.; Wang, W. Tetrahedron Lett. 1999, 40, 4627.
13. Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K.
Synthesis 1986, 403.
21
found 573.2630. 4c: Rf 0.48 (20% EtOAc/hexanes); ½aꢁD
1
ꢀ37.8 (c 0.6, CHCl3); H NMR (CDCl3) d 7.63–6.92 (m,
14H), 4.67 (d, 1H, J = 6.9 Hz), 4.50 (d, 1H, J = 6.9 Hz),
3.99 (q, 2H, J = 7.1 Hz), 3.71 (m, 1H), 3.52 (m, 3H), 3.27
(s, 3H), 2.97 (dd, 1H, J = 4.9, 15.7 Hz), 2.60 (dd, 1H,
J = 10.5, 15.7 Hz), 1.07 (t, 3H, J = 7.1 Hz), 1.03 (s, 3H);
13C NMR (CDCl3) d 172.4, 136.9, 135.7, 135.5, 133.3,
133.1, 129.9, 129.8, 127.7, 115.4, 115.1, 96.4, 80.8, 63.6,
60.3, 56.1, 42.6, 37.1, 31.0, 26.9, 19.2, 14.2; HRMS m/z
(ESI) calcd for C31H39FO5SiNa (M+Na+) 561.2443,
21
found 561.2422. 4d: Rf1 0.46 (20% EtOAc/hexanes); ½aꢁD
ꢀ35.59 (c 0.2, CHCl3); H NMR (CDCl3) d 7.59–7.30 (m,
10H), 6.66 (m, 3H), 5.91 (s, 2H), 4.70 (d, 1H, J = 6.9 Hz),
4.53 (d, 1H, J = 6.9 Hz), 4.0 (q, 2H, J = 7.2 Hz), 3.69 (m,
1H), 3.51 (m, 3H), 2.94 (dd, 1H, J = 4.95, 15.4 Hz), 2.56
(dd, 1H, J = 10.2, 15.4 Hz), 1.12 (t, 3H, J = 7.2 Hz), 1.03
(s, 9H); 13C NMR (CDCl3) d 172.5, 147.8, 146.3, 135.6,
133.7, 129.7, 127.7, 121.8, 108.3, 108.0, 100.9, 96.5, 81.7,
64.0, 60.3, 56.0, 35.8, 34.7, 31.7, 26.9, 25.3, 22.7, 14.2;
HRMS m/z (ESI) calcd for C32H40O7SiNa (M+Na+)
587.2435, found 587.2421. 4e: Rf 0.38 (20% EtOAc/
14. We were unable to detect the presence of syn isomers in
reaction product mixtures.
15. General procedure for the arylcuprate additions: ca. 1 mL
of a required aryl bromide (7.03 mmol) was added to
crushed Mg turnings (7.03 mmol, 0.17 g) in THF (10 mL)
under nitrogen atmosphere. Once the reaction started, the
solution warmed up and slightly darkened. The rest of the

M. Manpadi, A. Kornienko / Tetrahedron Letters 46 (2005) 4433–4437
4437
21
1
hexanes); ½aꢁD ꢀ26.8 (c 0.4, CHCl3); H NMR (CDCl3) d
43.4, 37.4, 26.8, 19.2, 14.2; HRMS m/z (ESI) calcd for
C33H42O8SiNa (M+Na+) 617.2541, found 617.2551.
17. Ha, H.-J.; Yoon, K.-N.; Lee, S.-Y.; Park, Y.-S.; Lim,
M.-S.; Yim, Y.-G. J. Org. Chem. 1998, 63, 8062.
18. For a recent review, see: Nakamura, E.; Mori, S. Angew.
Chem., Int. Ed. 2000, 39, 3750.
19. Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987,
109, 3353.
20. For a review, see: Hoffmann, R. W. Chem. Rev. 1989, 89,
1841.
21. For recent discussion and relevant references, see Nak-
anishi, W.; Yamanaka, M.; Nakamura, E. J. Am. Chem.
Soc. 2005, 127, 1446.
22. Synthesis and in vitro anticancer activity of two aromatic
pancratistatin analogues have been reported recently:
Rinner, U.; Hillebrenner, H. L.; Adams, D. R.; Hudlicky,
T.; Pettit, G. R. Bioorg. Med. Chem. Lett. 2004, 14, 2911;
(b) Rinner, U.; Hudlicky, T.; Gordon, H.; Pettit, G. R.
Angew. Chem., Int. Ed. 2004, 43, 5342.
7.63–7.28 (m, 10H), 6.73 (m, 3H), 4.69 (d, 1H, J = 6.9 Hz),
4.52 (d, 1H, J = 6.9 Hz), 3.99 (q, 2H, J = 7.7 Hz), 3.85 (s,
3H), 3.78 (s, 3H), 3.73 (m, 1H), 3.52 (m, 3H), 3.30 (s, 3H),
2.97 (dd, 1H, J = 4.9, 15.4 Hz), 2.61 (dd, 1H, J = 10.5,
15.4 Hz), 1.11 (t, 3H, J = 7.7 Hz), 1.03 (s, 9H); 13C NMR
(CDCl3) d 172.7, 148.7, 147.7, 135.6, 133.7, 133.4, 133.1,
129.8, 127.7, 120.3, 111.5, 111.0, 96.4, 81.0, 63.7, 60.2,
56.1, 55.9, 43.0, 37.6, 26.9, 19.3, 14.2; HRMS m/z (ESI)
calcd for C33H44O7SiNa (M+Na+) 603.2748, found
21
603.2764. 4f: Rf 0.56 (40% EtOAc/hexanes); ½aꢁD ꢀ27.2
1
(c 0.2, CHCl3); H NMR (CDCl3) d 7.61–7.30 (m, 10H),
6.38 (m, 2H), 5.92 (s, 2H), 4.69 (d, 1H, J = 6.7 Hz), 4.52
(d, 1H, J = 6.7 Hz), 4.02 (q, 2H, J = 6.9 Hz), 3.79 (s, 3H),
3.68 (m, 1H), 3.50 (m, 3H), 3.29 (s, 3H), 2.94 (dd, 1H,
J = 4.9, 15.4 Hz), 2.56 (dd, 1H, J = 10.2, 15.4 Hz), 1.13 (t,
3H, J = 6.9 Hz), 1.04 (s, 9H); 13C NMR (CDCl3) d 172.5,
148.7, 143.3, 135.8, 135.7, 135.5, 133.9, 133.3, 133.1, 129.7,
127.7, 107.7, 102.1, 101.4, 96.4, 80.9, 63.7, 60.3, 56.4, 56.1,