Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (-)-norsecurinine, and phyllanthine

Article abstract of DOI:10.1021/jo000260z

A new strategy for enantiospecific construction of the Securinega alkaloids has been developed and applied in total syntheses of (+)-14,15-dihydronorsecurinine (8), (-)-norsecurinine (6), and phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids originated from trans-4-hydroxy-L-proline (10), which was converted to ketonitrile 13 via a high-yielding eight-step sequence. Treatment of this ketonitrile with SmI₂ afforded the 6-azabicyclo-[3.2.1]octane B/C-ring system 14, which is a key advanced intermediate for all three synthetic targets. Annulation of the A-ring of (-)-norsecurinine (6) with the required C2 configuration via an N-acyliminium ion alkylation was accomplished using radical-based amide oxidation methodology developed in these laboratories as a key step, providing tricycle 33. Annulation of the D-ring onto α-hydroxyketone 33 with the Bestmann ylide 45 at 12 kbar gave (+)-14,15-dihydronorsecurinine (8). In the securinine series, the D-ring was incorporated using an intramolecular Wadsworth-Horner-Emmons olefination of phenylselenylated α-hydroxyketone 47. The C14,15 unsaturation was installed late in the synthesis by an oxidative elimination of the selenoxide derived from tetracyclic butenolide 50 to give (-)-norsecurinine (6). The A-ring of phyllanthine (2) was formed from hydroxyketone 14 using a stereoselective Yb(OTf)₃-promoted hetero Diels-Alder reaction of the derived imine 34 with Danishefsky's diene, affording adduct 35. Conjugate reduction and stereoselective equatorial ketone reduction of vinylogous amide 35 provided tricyclicintermediate 36, which could then be elaborated in a few steps to stable hydroxyenone 53 via α-selenophenylenone intermediate 52. The D-ring was then constructed, again using an intramolecular Wadsworth-Horner-Emmons olefination reaction to give phyllanthine (2).

Full text of DOI:10.1021/jo000260z

VOLUME 65, NUMBER 20
OCTOBER 6, 2000
© Copyright 2000 by the American Chemical Society
Articles
Tota l Syn th eses of th e Secu r in ega Alk a loid s
(+)-14,15-Dih yd r on or secu r in in e, (-)-Nor secu r in in e, a n d
P h ylla n th in e†
Gyoonhee Han, Matthew G. LaPorte, J ames J . Folmer, Kim M. Werner, and
Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
smw@chem.psu.edu
Received February 24, 2000
A new strategy for enantiospecific construction of the Securinega alkaloids has been developed
and applied in total syntheses of (+)-14,15-dihydronorsecurinine (8), (-)-norsecurinine (6), and
phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids
originated from trans-4-hydroxy-L-proline (10), which was converted to ketonitrile 13 via a high-
yielding eight-step sequence. Treatment of this ketonitrile with SmI2 afforded the 6-azabicyclo-
[3.2.1]octane B/C-ring system 14, which is a key advanced intermediate for all three synthetic
targets. Annulation of the A-ring of (-)-norsecurinine (6) with the required C2 configuration via
an N-acyliminium ion alkylation was accomplished using radical-based amide oxidation methodology
developed in these laboratories as a key step, providing tricycle 33. Annulation of the D-ring onto
R-hydroxyketone 33 with the Bestmann ylide 45 at 12 kbar gave (+)-14,15-dihydronorsecurinine
(8). In the securinine series, the D-ring was incorporated using an intramolecular Wadsworth-
Horner-Emmons olefination of phenylselenylated R-hydroxyketone 47. The C14,15 unsaturation
was installed late in the synthesis by an oxidative elimination of the selenoxide derived from
tetracyclic butenolide 50 to give (-)-norsecurinine (6). The A-ring of phyllanthine (2) was formed
from hydroxyketone 14 using a stereoselective Yb(OTf)3-promoted hetero Diels-Alder reaction of
the derived imine 34 with Danishefsky’s diene, affording adduct 35. Conjugate reduction and
stereoselective equatorial ketone reduction of vinylogous amide 35 provided tricyclic intermediate
36, which could then be elaborated in a few steps to stable hydroxyenone 53 via R-selenophenylenone
intermediate 52. The D-ring was then constructed, again using an intramolecular Wadsworth-
Horner-Emmons olefination reaction to give phyllanthine (2).
In tr od u ction a n d Ba ck gr ou n d
produce a group of tetracyclic compounds classified as
the Securinega alkaloids.1 Securinine (1), the major
alkaloid isolated from the leaves of Securinega suffruc-
Various plants of the Euphorbiaceae family, particu-
larly those of the Securinega and Phyllanthus genera,
(1) For excellent reviews, see: (a) Snieckus, V. The Securinega
Alkaloids. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press:
New York, 1973; Vol. 14, p 425. (b) Beutler, J . A.; Brubaker, A. N.
Drugs Fut. 1987, 12, 957.
† Dedicated to the memory of Professor Arthur G. Schultz, a superb
chemist and friend.
10.1021/jo000260z CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/13/2000

6294 J . Org. Chem., Vol. 65, No. 20, 2000
Han et al.
F igu r e 1.
ticosa, was structurally characterized in the early 1960s
and is the most common member of this family (Figure
1).2 Around the same time, allosecurinine (4), the C2
epimer of securinine, was isolated in minor quantities
from the same plant and later from a Phyllanthus
species.1 Interestingly, the enantiomers of both of these
compounds (i.e., virosecurinine (3) and viroallosecurinine)
were subsequently discovered in related Euphorbiaceae
species. During the succeeding years, a number of other
Securinega alkaloids were found, including the A-ring
methoxylated compounds phyllanthine (2)3 and securi-
tinine (5).4 Moreover, the A-ring contracted alkaloids (-)-
norsecurinine (6),5 its enantiomer (+)-norsecurinine, and
4-methoxynorsecurinine (7)6 have also been reported. In
addition, a number of saturated congeners such as (+)-
14,15-dihydronorsecurinine (8)7 have been described. To
date, approximately 20 different members of this family
of alkaloids have been isolated and characterized.
malarial,9a an antibacterial agent,9b and causes apoptosis
in leukemia cells.9c
Considering the extensive body of work in the litera-
ture on alkaloid total synthesis, it is surprising that
relatively little research has been directed toward these
interesting compounds, particularly in view of their wide
profile of biological activity. In 1966, starting from (()-
pipecolic acid as the source of the A-ring, Horii and co-
workers completed a nonstereoselective, low-yielding
total synthesis of racemic securinine, which could be
resolved by classical procedures into securinine and
virosecurinine.10 The field lay dormant for over 15 years
until synthetic work resumed, when Heathcock et al. in
1983 described the first total synthesis of norsecurinine
(6) starting from L-proline.11 The intent was to have this
scalemic amino acid provide the A-ring and the C2
absolute stereochemistry of the alkaloid. Unfortunately
a racemization occurred during the synthesis, which
eventually led to racemic 6. A few years later, J acobi and
co-workers devised an elegant oxazole/acetylene intramo-
lecular Diels-Alder-based strategy to both (+)- and (-)-
norsecurinine starting from L- and D-proline, respec-
tively.12 Once again, the amino acids provided the A-ring
and C2 absolute stereochemistry. Shortly thereafter,
Magnus et al. reported a total synthesis of racemic
norsecurinine,13 along with the related Securinega alka-
loid nirurine,14 starting from 3-hydroxypyridine as the
A-ring precursor. This synthetic route to norsecurinine
The Securinega alkaloids display an impressive range
of biological activity.1b The most widely studied of these
alkaloids, securinine, is a specific GABA receptor an-
tagonist8 and has been found to have significant in vivo
CNS activity. The compound has been studied clinically
in treating paralysis following Bell’s palsy and poliomy-
elitis, and in treatment of the symptoms of ALS and
chronic aplastic anemia.1b More recently, reports have
appeared indicating that securinine is also an anti-
(9) (a) Weenen, H.; Nkunya, M. H. H.; Bray, D. H.; Mwasumbi, L.
B.; Kinabo, L. S.; Kilimali, V. A.; Wijnberg, J . B. Planta Med. 1990,
56, 371. (b) Mensah, J . L.; Lagarde, I.; Ceschin, C.; Michel, G.; Gleye,
J .; Fouraste, I. J . Ethnopharmacol. 1990, 28, 129. (c) Dong, N. Z.; Gu,
Z. L.; Chou, W. H.; Kwok, C. Y. Chung Kuo Li Hsueh Pao 1999, 20,
267; Chem Abstr. 1999, 130, 346993n.
(10) Saito, S.; Yoshikawa, H.; Sato, Y.; Nakai, H.; Sugimoto, N.;
Horii, Z.; Hanaoka, M.; Tamura, Y. Chem. Pharm. Bull. 1966, 14, 313.
See also: Horii, Z.; Imanishi, T.; Tanaka, T.; Mori, I.; Hanaoka, M.;
Iwata, C. Chem. Pharm. Bull. 1972, 20, 1768. Horii, Z.; Imanishi, T.;
Hanaoka, M.; Iwata, C. Chem. Pharm. Bull. 1972, 20, 1774.
(11) (a) Heathcock, C. H.; J ennings, R. A.; von Geldern, T. W. J .
Org. Chem. 1983, 48, 3428. (b) Heathcock, C. H.; von Geldern, T. W.
Heterocycles 1987, 25, 75. (c) Heathcock, C. H.; von Geldern, T. W.;
Librilla, C. B.; Maier, W. F. J . Org. Chem. 1985, 50, 968.
(12) (a) J acobi, P. A.; Blum, C. A.; DeSimone, R. W.; Udodong, U.
E. S. Tetrahedron Lett. 1989, 30, 7173. (b) J acobi, P. A.; Blum, C. A.;
DeSimone, R. W.; Udodong, U. E. S. J . Am. Chem. Soc. 1991, 113,
5384. (c) We are grateful to Professor J acobi for providing spectra of
authentic norsecurinine.
(2) Saito, S.; Kodera, K.; Shigematsu, N.; Ide, A.; Sugimoto, N.; Horii,
Z.; Hanaoaka, M.; Yamawaki, Y.; Tamura, Y. Tetrahedron 1963, 19,
2085 and references cited.
(3) Parello, J . Bull. Soc. Chim. Fr. 1968, 1117. Arbain, D.; Birkbeck,
A. A.; Byrne, L. T.; Sargent, M. V.; Skelton, B. W.; White, A. H. J .
Chem. Soc., Perkin Trans. 1 1991, 1863.
(4) Horii, Z.; Ikeda, M.; Hanaoka, M.; Yamauchi, M.; Tamura, Y.;
Saito, S.; Tanaka, T.; Kodera, K.; Sugimoto, N. Chem. Pharm. Bull.
1967, 15, 1633 and references cited.
(5) J oshi, B. S.; Gawad, D. H.; Pelletier, S. W.; Kartha, G.; Bhandary,
K. J . Nat. Prod. 1986, 49, 614 and references cited.
(6) Mulchandani, N. B.; Hassarajani, S. A. Planta Med. 1984, 50,
104.
(7) (a) Saito, S.; Tanaka, T.; Kotera, K.; Nakai, H.; Sugimoto, N.;
Horii, Z.-I.; Ikeda, M.; Tamura, Y. Chem. Pharm. Bull. 1964, 12, 1520.
(b) Saito, S.; Tanaka, T.; Kotera, K.; Nakai, H.; Sugimoto, N.; Horii,
Z.-I.; Ikeda, M.; Tamura, Y. Chem. Pharm. Bull. 1965, 13, 786.
(8) (a) Rognan, D.; Boulanger, T.; Hoffmann, R.; Vercauteren, D.
P.; Andre, J .-M.; Durant, F.; Wermuth, C.-G. J . Med. Chem. 1992, 35,
1969. (b) Galvez-Ruano, E.; Aprison, M. H.; Robertson, D. H.; Lipko-
witz, K. B. J . Neurosci. Res. 1995, 42, 666.
(13) Magnus, P.; Rodriguez-Lopez, J .; Mulholland, K.; Matthews, I.
Tetrahedron 1993, 49, 8059.

Total Syntheses of the Securinega Alkaloids
J . Org. Chem., Vol. 65, No. 20, 2000 6295
Sch em e 1
Sch em e 2a
featured a clever biogenetically inspired15 rearrangement
of an azabicyclo[2.2.2]octane to an azabicyclo[3.2.1]octane
system.
Syn th etic Str a tegy
a
Reagents: (a) TBSCl, imid., CH2Cl2, 88%; (b) DIBALH, PhMe,
The goal of this program was to devise a new general
synthetic strategy to the Securinega alkaloids that would
allow a simple entry to any of the compounds of the
family in enantiomerically pure form starting from a
common advanced intermediate.16,17 We recognized that
most members of this group differ only in the A-ring size
and functionality, as well as the C2 configuration (cf.
1-8), and thus, we attempted to devise a strategy with
the flexibility to allow for the variations in this portion
of the molecules. Also, since in most instances both
enantiomers of a given alkaloid are known, we felt the
approach should in principle provide access to either
antipode starting from readily available chiral pool
compounds. We therefore investigated the retrosynthetic
plan shown in Scheme 1. The idea was to first generate
a 6-azabicyclo[3.2.1]octane B/C moiety like 9 starting
from enantiomerically pure trans-4-hydroxyl-L-proline
(10), or its commercially available D-enantiomer, which
would provide the B-ring and the absolute chirality at
C7. It might be noted that for the Heathcock11 and
J acobi12 strategies to produce the more common enan-
tiomeric alkaloid series related to securinine D-proline
is required, whereas our proposed approach would use
the less expensive L-amino acid. Our objective was to then
develop methodology to annulate an appropriate A-ring
onto the pivotal bicycle 9, followed by the D-ring. This
order was chosen since the conjugated dienic γ-lactone
functionality, particularly in the case of norsecurinine,
adds an element of instability to the system, and it
seemed prudent to leave introduction of this sensitive
array until the final stages of the synthesis. In this paper,
we descibe the successful application of this strategy to
enantiospecific total syntheses of three Securinega alka-
loids (+)-14,15-dihydronorsecurinine (8), (-)-norsecuri-
nine (6), and phyllanthine (2).
-78 °C to rt, 98%; (c) DMSO, (COCl)2, NEt3, CH2Cl2, -78
°C/Ph3PdCHCN, CH2Cl2, -78 °C to rt, 90%; (d) 1 atm H2, 10%
Pd-C, EtOAc, 98%; (e) Bu4NF, THF, rt, 100%; (f) J ones reagent,
Me2CO, rt, 84%; (g) SmI2, MeOH, THF, -78 °C to rt; then H3O+,
78%.
Sch em e 3a
a
Reagents: (a) TBSOTf, i-Pr2NEt, CH2Cl2, 0 °C to rt, 91%; (b)
(CH2OH)2, p-TsOH, PhH, ∆, 100%; (c) TsNHNH2, MeOH, 0 °C to
rt; NaH, PhMe, ∆, 78%.
access an enantiomerically pure B/C ring intermediate
such as 9. Our starting material was the known ester
sulfonamide 11,18 easily prepared from trans-4-hydroxy-
L-proline (10). This compound was first converted to the
TBS ether, and after ester reduction followed by Swern
oxidation the resulting aldehyde was subjected to a
Wittig reaction to produce R,â-unsaturated nitrile 12 as
a 7:2 mixture of E/Z isomers (Scheme 2). Catalytic
hydrogenation of isomer mixture 12, silyl ether removal,
and alcohol oxidation led to the ketonitrile 13 in high
overall yield. We were pleased to find that upon subjec-
tion of compound 13 to samarium diiodide in THF
containing methanol as a proton source, followed by
acidic hydrolysis, the desired azabicyclic R-hydroxyketone
14 was formed in 78% isolated yield.19
Since we entertained a number of possibilities for
eventual annulation of the D-ring (vide infra), it was
decided to prepare two differently functionalized C-ring
systems for future study. Therefore, hydroxyketone 14
was first silylated to produce TBS ether 15, which could
then be converted to ketal 16 in high yield (Scheme 3).
The second system was produced by conversion of ketone
15 to the corresponding tosylhydrazone, which cleanly
Resu lts a n d Discu ssion
Con str u ction of a 6-Aza bicyclo[3.2.1]octa n e B/C
Rin g Syn th on . The first objective of the project was to
(14) Petchnaree, P.; Bunyapraphatsara, N.; Cordell, G. A.; Cowe,
H. J .; Cox, P. J .; Howie, R. A.; Patt, S. L. J . Chem. Soc., Perkin Trans.
1 1986, 1551.
(15) For studies on the biosynthesis of the Securinega alkaloids,
see: Parry, R. J . Bioorg. Chem. 1978, 7, 277 and references cited.
(16) Preliminary accounts of portions of this research have ap-
peared: (a) Weinreb, S. M. J . Heterocycl. Chem. 1996, 33, 1437. (b)
Han, G.; LaPorte, M. G.; Folmer, J . J .; Werner, K. M.; Weinreb, S. M.
Angew. Chem., Int. Ed. Engl. 2000, 39, 237.
(17) This work is taken in part from: (a) Folmer, J . J . Ph.D. Thesis,
The Pennsylvania State University, 1994. (b) Han, G. Ph.D. Thesis,
The Pennsylvania State University, 1997. (c) LaPorte, M. G. Ph.D.
Thesis, The Pennsylvania State University, 2000.
(18) Andreatta, R. H.; Nair, V.; Robertson, A. V.; Simpson, W. R. J .
Aust. J . Chem. 1967, 20, 1493.
(19) cf. Molander, G. A.; Wolfe, C. N. J . Org. Chem. 1998, 63, 9031
and references cited.

6296 J . Org. Chem., Vol. 65, No. 20, 2000
Han et al.
Sch em e 4a
Sch em e 5a
a
a
Reagents: (a) Na, naphthalene, DME, -78 °C; (b) isatoic
Reagents: (a) Na, naphthalene, DME, -78 °C; (b) isatoic
anhydride, MeCN, DMAP, 0 °C to rt, 79% from 17; (c) NaNO2,
HCl, CuCl (20 mol %); MeOH, rt, 61%; (d) allyltrimethylsilane,
TiCl4, CH2Cl2, -78 °C to rt, 91%; (e) disiamylborane, THF; H2O2,
NaOH; TsCl, DMAP, NEt3, CH2Cl2, 0 °C to rt, 64%; (f) DIBALH,
PhMe, -70 to -15 °C; (g) NaI, NEt3, PhMe, ∆, 59% from 22.
anhydride, DMAP, MeCN, rt, 87% from 16; (c) NaNO2, HCl, CuCl
(100 mol %), MeOH, rt; (d) allylmagnesium bromide, BF3-Et2O,
THF, -78 to 0 °C; (e) (Boc)2O, NEt3, CH2Cl2, reflux, 68% from
27/28; (f) disiamyl borane, THF, 0 °C to rt/H2O2, NaOH; (g) TsCl,
DMAP, NEt3, CH2Cl2, 71% from 30; (h) 0.8 N HCl, MeOH, 60 °C,
81%; (i) 3 N aqueous HCl, 95 °C, 74%.
afforded the bicyclic olefin 17 using a modification of the
Shapiro reaction described by J ung.20
Sch em e 6
An n u la tion of th e Nor secu r in in e A-Rin g. With
azabicyclics 16 and 17 in hand, we next turned to
studying routes for annulation of the norsecurinine
pyrrolidine A-ring. It was our intention here to make use
of our recently developed radical-based methodology for
generation of N-acyliminium ions from simple secondary
amines.21 Thus, the sulfonamide group of 17 was reduc-
tively cleaved to afford the corresponding amine, which
was acylated with isatoic anhydride to yield o-amino-
benzamide 18 (Scheme 4). When this compound was
subjected to diazotization conditions in the presence of
CuCl (∼20 mol %) in methanol, the desired R-methoxy-
benzamide 19 was formed regioselectively (61%). Treat-
ment of 19 with allyltrimethylsilane and TiCl4 then led
to a single stereoisomeric allylation product 21 in high
yield. We believe that 21 results from exo attack on an
intermediate N-acyliminium salt 20. Although the ster-
eochemistry of 21 was not firmly established, this trans-
formation is in accord with later results discussed below.
To complete annulation of the A-ring, olefin 21 was
hydroborated and the resulting primary alcohol was
converted to tosylate 22. However, all attempts to remove
the N-benzoyl group by basic hydrolysis failed. Alterna-
tively, it was possible to reduce the benzoyl substituent
with DIBALH to give ammonium salt 23, which without
characterization was dealkylated with sodium iodide,
affording the requisite norsecurinine tricyclic amine 24.
We have also investigated a similar annulation strat-
egy in the C-ring ketal azabicyclic series. Therefore,
sulfonamide 16 was first converted to amine 25 and then
to o-aminobenzamide 26 (Scheme 5). Interestingly, the
conversion of 26 to the desired R-methoxybenzamide
proved messy under our standard conditions and required
a significantly larger amount of CuCl than we have
usually employed, perhaps due to complexation of the
catalyst by the ketal moiety.21 The reaction could be
promoted by using 100 mol % of CuCl, but under these
conditions the product consisted of a nearly 1:1 mixture
of the R-methoxybenzamide 28 and the R-chloro com-
pound 27. However, it was possible to effect the next step
in the sequence using the mixture of 27 and 28. Treat-
ment of this mixture with a large excess of allylmagne-
sium bromide in the presence of boron trifluoride etherate
afforded the allylated product 29 and also conveniently
led to removal of the benzoyl group. Amine 29 is a single
stereoisomer, whose C2 configuration was eventually
proven to be exo by X-ray crystallography (vide infra).
This amine was next converted to the Boc-protected
derivative 30 which, after hydroboration of the olefin,
could be transformed to tosylate 31. Finally, acidic
cleavage of the Boc group and in situ cyclization led to
tricycle 32. Further hydrolysis of the TBS and ketal
groupings, which required more stringent conditions,
yielded R-hydroxyketone 33.
An alternative and more convenient route has also
been developed to convert secondary amine 25 to inter-
mediate 30 (Scheme 6). It was found that 25 could be
cleanly oxidized to chromatographically stable imine 34
(20) J ung, M. E.; Gomez, A. V. Tetrahedron Lett. 1991, 34, 2891.
(21) (a) Han, G.; McIntosh, M. C.; Weinreb, S. M. Tetrahedron Lett.
1994, 35, 5813. (b) Han, G.; LaPorte, M. G.; McIntosh, M. C.; Weinreb,
S. M. J . Org. Chem. 1996, 61, 9483.

Total Syntheses of the Securinega Alkaloids
J . Org. Chem., Vol. 65, No. 20, 2000 6297
Sch em e 7a
Sch em e 8
a
Reagents: (a) Danishefsky’s diene, Yb(OTf)3, MeCN, 84%, or
CH2Cl2, 12 kbar, 71%; (b) L-Selectride (2 equiv), THF, -78 °C, 85%;
(c) NaH, MeI, THF, 0 °C to rt, 87%; (d) 3 N HCl, reflux, 78%.
using iodosobenzene.22,23 Attempts to allylate 34 with
allyltributylstannane and ytterbium triflate as the cata-
lyst led to about a 30% yield of 29 along with 60% of
unreacted starting material.24 However, the imine could
be cleanly alkylated with allylmagnesium bromide/boron
trifluoride etherate to produce amine 29, which was then
Boc protected to yield 30 (82% from 34).
An n u la tion of th e P h ylla n th in e A-Rin g. Our strat-
egy of choice for annulating the phyllanthine A-ring was
to effect a hetero Diels-Alder reaction using imine 34
as a dienophile.25 We had some initial concerns about the
feasibility of this approach since this unactivated bicyclic
imine is more complex than any imino dienophile previ-
ously used for this type of cycloaddition, and we felt it
was possible that it might be too sterically hindered to
participate effectively in the reaction. Initial experiments
with imine 34 and Danishefsky’s diene using a variety
of common Lewis acid catalysts (e.g., SnCl4, TiCl4, etc.)
produced only low yields of the desired cycloadduct 35
(Scheme 7), possibly due in part to the sensitivity of the
ketal and silyl ether functionality to strong acids. How-
ever, it was eventually discovered that ytterbium triflate
catalyzes the [4 + 2]-cycloaddition affording 35 in 84%
yield.24 It was also found that the Diels-Alder reaction
can be run without a catalyst at high pressure (12 kbar,
71% yield). The structure of tricycle 35 was confirmed
by X-ray crystallography, indicating that as had been
anticipated the diene attacks the imine from the less
congested exo direction with the regiochemistry shown,
thereby setting the correct C2 stereochemistry of phyl-
lanthine (see the Supporting Information).
reduction.26 It is possible here that the second reduction
step actually occurs upon enolate protonation during the
aqueous workup. Finally, O-methylation of alcohol 36
afforded the corresponding methyl ether, which upon acid
hydrolysis led to the desired tricyclic R-hydroxyketone
37.
D-Rin g Mod el Stu d ies w ith Aza bicyclic Olefin 17.
An attractive strategy which we wished to explore was
the possibility of utilizing a metal-catalyzed atom transfer
radical reaction27 to construct the requisite Securinega
alkaloid D-ring, and we opted to investigate the basic
approach using bicyclic olefin 17 as a model system. In
our initial experiments, the silyl ether group of 17 was
removed with TBAF to give the tertiary alcohol, which
could then be acylated with dichloroacetyl chloride to
afford ester olefin 38 (Scheme 8). Exposure of this
compound to a catalytic amount of ruthenium dichloride
tris-triphenylphosphine at 165 °C in a sealed tube indeed
led to the desired R,γ-dichlorolactone 40. However, we
have been unable to effect a double elimination to
produce the desired diene 44. The only characterizable
product obtained in any of these experiments was R-chlo-
robutenolide 42, which could not be converted to 44.
In an attempt to circumvent the elimination problem,
compound 17 was converted to the R-chloro-R-thiophen-
ylacetate 39. Ruthenium-catalyzed cyclization of this
intermediate proceeded cleanly to afford the expected
lactone 41, which could be oxidized to the sulfoxide and
thermally eliminated to give γ-chloro butenolide 43.
Unfortunately, we have been unable to eliminate HCl
To further elaborate the A-ring functionality, vinylo-
gous amide 35 was treated with 2 equiv of L-Selectride,
leading to stereoselective formation of the axial alcohol
36 in high yield. This result was rather surprising since
one would anticipate that conjugate reduction of 35
produces an enolate which should be resistant to further
(22) Muller, P.; Gilabert, D. M. Tetrahedron 1988, 44, 7171. Larsen,
J .; J orgensen, K. A. J . Chem. Soc., Perkin Trans. 2 1992, 1213.
(23) This transformation could also be effected, but less conveniently,
with diphenylseleninic anhydride: Czarny, M. R. J . Chem. Soc., Chem.
Commun. 1976, 81. Czarny, M. R. Synth. Commun. 1976, 6, 285.
(24) Kobayashi, S.; Nagayama, S. J . Am. Chem. Soc. 1997, 119,
10049.
(25) For reviews of the imino Diels-Alder reaction, see: (a) Boger,
D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic
Synthesis; Academic Press: Orlando, 1987; Chapter 2. (b) Weinreb, S.
M. Heterodienophile Additions to Dienes. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 4, p 401.
(26) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J . J . Org.
Chem. 1999, 64, 2184 and references cited.
(27) For lead references, see: (a) Ishibashi, H.; Nakatani, H.; Iwami,
S.; Sato, T.; Nakamura, N.; Ikeda, M. J . Chem. Soc., Chem. Commun.
1989, 1767. (b) Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Wash-
iyama, M.; Itoh, K. J . Org. Chem. 1993, 58, 464. (c) Iwamatsu, S.;
Matsubara, K.; Nagashima, H. J . Org. Chem. 1999, 64, 9625.

6298 J . Org. Chem., Vol. 65, No. 20, 2000
Han et al.
Sch em e 9
from 43 to form diene lactone 44. Moreover, it has not
been possible to displace the chlorine in tricycle 43 with
any nucleophile. In view of these disappointing results,
we decided to abandon the idea of using an olefin as a
handle to elaborate the D-ring and have instead concen-
trated on the compounds bearing a C-ring ketone sub-
stituent.
Syn th esis of (+)-14,15-Dih yd r on or secu r in in e (8)
a n d (-)-Nor secu r in in e (6). At this point, we chose to
return to the tricyclic R-hydroxyketone 33 and investigate
the D-ring annulation of this key intermediate via a
strategy based upon the methodology of Bestmann.28
Thus, treatment of hydroxyketone 33 with the Bestmann
ylide 45 under the usual conditions for butenolide forma-
tion (CH2Cl2, reflux, NEt3) gave 14,15-dihydronorsecuri-
nine (8) but in only ∼25% yield (eq 1). This reaction has
benzamides 27/28 (Scheme 5) had occurred exo as was
assumed (see Supporting Information).
Several attempts were made to directly oxidize the
dihydro compound 8 to (-)-norsecurinine (6) using re-
agents such as DDQ, or by a Saegusa-type oxidation.
However, in all cases either starting material was
recovered unchanged or complete decomposition occurred.
It therefore became necessary to introduce the norse-
curinine C-ring double bond at the tricycle stage using
ketone 33 or a related compound. Effecting this trans-
formation in fact turned out to be much more difficult
than was envisioned.
A number of experiments were conducted using both
R-hydroxyketone 33 and model bicyclic ketone 14, along
with some alcohol-protected derivatives, with the idea of
generating an enolate which could then be selenylated
or sulfenylated.30 In no case, however, could any useful
product be isolated in acceptable yield. We were also
unable to prepare a silylenol ether from any of these
ketones.17
Since these compounds did not appear to form well-
behaved metal enolates, we turned to an alternative
neutral method for R-phenylselenation of ketones de-
scribed by Sharpless.31 Surprisingly, refluxing hydroxy-
ketone 33 in ethyl acetate in the presence of excess
phenylselenyl chloride did not produce the desired R-
phenylselenyl ketone 47, but in fact gave the R-phenyl-
selenoenone 46 (Scheme 9). However, the reaction was
sluggish, requiring several days of heating, and moreover,
yields of product 46 were quite variable. It was eventually
found that addition of pyridine increased the rate of the
reaction and also led to a reproducible 67% yield of the
apparently not been used previously with a tertiary
R-hydroxyketone, and it is possible that the initial alcohol
acylation step with 45 is slow with substrate 33. How-
ever, we were pleased to find that if the reaction is run
at 12 kbar in the absence of an added base, alkaloid 8 is
formed in 89% yield. 14,15-Dihydronorsecurinine was
isolated in 1964 from the root bark of Securinega virosa,
but only scant data are provided for this alkaloid.7 In fact,
no D-line optical rotation is available for the natural
material, but rather an ORD spectrum was reported. The
ORD spectrum of our synthetic material is in accord with
that described, thereby confirming the assigned absolute
configuration.29 Furthermore, X-ray analysis of the hy-
drochloride salt of 8 unambiguously established the
structure of our synthetic material, and also confirmed
that the allylation of the N-acyliminium salt derived from
(28) Bestmann, H. J .; Sandmeier, D. Chem Ber. 1980, 113, 274.
Nickisch, K.; Klose, W.; Bohlmann, F. Chem Ber. 1980, 113, 2038.
(29) We are indebted to Dr. C. J . Easton and J . Kelly (Australian
National University) for recording the ORD spectrum of synthetic (+)-
14,15-dihydronorsecurinine (8).
(30) Reich, H. J .; Wollowitz, S. Org. React. 1993, 44, 1.
(31) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J . Am. Chem.
Soc. 1973, 95, 6137.

Total Syntheses of the Securinega Alkaloids
J . Org. Chem., Vol. 65, No. 20, 2000 6299
Sch em e 10
selenoenone 46. Liotta and co-workers32a have previously
investigated the reaction of this combination of PhSeCl/
pyridine with some enolizable ketones, and observed
direct formation of R,â-unsaturated ketones. To explain
these results, it was suggested that initial ketone R-phen-
ylselenylation occurs, followed by a “nonoxidative” elimi-
nation to an R,â-unsaturated ketone. However, the
reaction does not occur with simple ketones such as
cyclohexanone, and it is not clear why this transformation
seems to be happening with R-hydroxyketone 33. Liotta
has also found that R,â-unsaturated ketones react with
PhSeCl/pyridine to produce R-selenophenylenones analo-
gous to 46, thus suggesting transient formation of the
enone 48.32b
Syn th esis of 14,15-Dih yd r op h ylla n th in e (51) a n d
P h ylla n th in e (2). To test the D-ring annulation in the
phyllanthine series, R-hydroxyketone 37 was reacted
under high pressure with the Bestmann ylide 45, provid-
ing 14,15-dihydrophyllanthine (51) in 80% yield (eq 2).
Inexplicably, when the base used for the selenylation
step was changed from pyridine to triethylamine, R-phen-
ylselenyl ketone 47 was formed from ketone 33 (mixture
of epimers, 60%) rather than the selenoenone 46. How-
ever, despite some considerable effort we have been
unable to convert either 46 or 47 to the requisite enone
48. We believe that the difficulty here is that 48 is
probably unstable and polymerizes, as is the case with
the free base of norsecurinine itself. Based upon this
supposition, we chose to delay introduction of the C14,15
double bond until after butenolide formation.
Attempts were first made to combine hydroxyketone
47 with the Bestmann reagent 45, but in no case did we
detect the desired butenolide 50. Alternatively, tricyclic
selenide alcohol 47 was esterified with commercially
available diethylphosphonoacetic acid to produce phos-
phonate 49 in high yield. Exposure of 49 to potassium
carbonate/18-crown-6 in toluene led to an efficient in-
tramolecular Wadsworth-Horner-Emmons cyclization,
giving the tetracyclic butenolide 50 (95%) as a chromato-
graphically separable mixture of selenide epimers. To
complete the total synthesis all that remained was to
effect a selenide oxidation/elimination sequence. Disap-
pointingly, the usual selenide oxidants (m-CPBA, H2O2,
NaIO4, Oxone, ozone, tert-butylhydroperoxide, etc.)30 all
led to only poor yields (<30%) of norsecurinine. In
addition, there was no discernible improvement in yield
by first converting 50 to an amine salt. It was finally
found that oxidation of the mixture of selenides 50 with
dimethyldioxirane at -78 °C produces (-)-norsecurinine
(6) in moderate 39% yield.33 To our knowledge, this
reagent has not previously been used for the oxidation
of selenides to selenoxides.30 Our synthetic material had
spectral data identical with those of an authentic sample
of norsecurinine.12c
Although this compound is not a natural product, it has
been previously prepared by partial reduction of phyl-
lanthine (2).3 Our compound had data in good accord with
those reported for naturally derived material.
Some of the same problems as described above for
norsecurinine arose with regard to introducing C-ring
unsaturation into the phyllanthine intermediate. Once
again, enolate chemistry with hydroxyketone 37 and
derivatives proved fruitless. More surprising was the fact
that exposure of 37 to the selenation procedures used for
33 (Scheme 9) gave complex mixtures of products. In
exploring other neutral or acidic methods for R-phenylse-
lenylation of ketones, we turned to the procedure of
Sonoda et al.34 Thus, ketone 37 was treated with diphen-
yldiselenide, selenium dioxide, and methanesulfonic acid,
leading to selenoenone 52 in 58% yield (Scheme 10). This
was an unexpected result since the Sonoda protocol has
been used previously for forming an R-phenylselenoke-
tone from a ketone, but direct formation of an R-sele-
nophenylenone has apparently not been observed. For-
(32) (a) Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar,
H. S., III. J . Org. Chem. 1981, 46, 2920. (b) Zima, G.; Liotta, D. Synth.
Commun. 1979, 9, 697.
(33) A byproduct in this reaction has been tentatively identified as
the phenylselenonorsecurinine i. We are uncertain as to the genesis
of this compound.
(34) Miyoshi, N.; Yamamoto, T.; Kambe, N.; Murai, S.; Sonoda, N.
Tetrahedron Lett. 1982, 23, 4813. Watanabe, M.; Awen, B. Z.; Kato,
M. J . Org. Chem. 1993, 58, 3923.

6300 J . Org. Chem., Vol. 65, No. 20, 2000
Han et al.
1/9) to give the silyl ether as a white solid (14.1 g, 88%):
tunately, in a crucial experiment selenoenone 52 could
be converted to the stable tricyclic enone 53 using NaI/
BF3 etherate in 84% yield.35,36 This procedure has previ-
ously been used for dehalogenation of an R-bromoenone,
but not for deselenylation.
Attempted condensation of hydroxyenone 53 with the
Bestmann reagent 45 under a variety of conditions did
not produce any phyllanthine, and it was therefore
necessary to pursue a Wadsworth-Horner-Emmons
approach for annulation of the D-ring. Thus, hydroxy-
enone 53 was first converted to the phosphonate 54,
which upon exposure to potassium carbonate/18-crown-6
yielded phyllanthine (2). Although we could not obtain a
sample of the natural alkaloid, the synthetic phyllanthine
had spectral data in close agreement with those pub-
lished.3
[R]20 ) -82.2 (c 0.64, CDCl3); mp 45-47 °C; IR (film) 2950,
D
2840, 1750, 1595 cm-1; H NMR (300 MHz, CDCl3) δ 7.75 (d,
1
J ) 8.3 Hz, 2H), 7.30 (d, J ) 8.2 Hz, 2H), 4.42-4.32 (m, 1H),
4.24 (t, J ) 7.9 Hz, 1H), 3.78 (s, 3H), 3.66 (dd, J ) 4.3, 10.7
Hz, 1H), 3.18 (dd, J ) 1.9, 10.8 Hz, 1H), 2.40 (s, 3H), 2.11-
2.04 (m, 2H), 0.69 (s, 9H), -0.072 (s, 3H), -0.084 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 172.6, 143.6, 134.3, 129.6, 127.7, 70.3,
59.7, 56.7, 52.5, 40.2, 25.5, 21.5, 17.8, -5.0, -5.1; EIMS m/z
(relative intensity) 412 (M+ - H, 0.1), 356 (M+ - t-Bu, 100).
Anal. Calcd for C19H31NO5SSi: C, 55.17; H, 7.55; N, 3.39.
Found: C, 55.19; H, 7.62; N, 3.32.
To a -78 °C solution of the silyl ether (15.0 g, 36.3 mmol)
in 450 mL of dry toluene was added neat DIBALH (20.0 mL,
0.11 mol) dropwise over 30 min. The solution was stirred at
-78 °C for 1 h and then warmed to 0 °C. The reaction mixture
was diluted with 100 mL of saturated sodium potassium
tartrate (Rochelle salt). Ethyl acetate (100 mL) was added, and
the cloudy mixture was stirred at room temperature for 2 h.
The organic layer was washed with saturated Rochelle salt
solution and brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash chromatography
(ethyl acetate/hexanes, 1/3) to give the alcohol as a white solid
Con clu sion
Described here is a conceptually new, general strategy
for enantiospecific construction of the biologically active
Securinega family of plant alkaloids starting from trans-
L-4-hydroxyproline (10). Total syntheses of (+)-14,15-
dihydronorsecurinine (8) and (-)-norsecurinine (6), along
with the first total synthesis of phyllanthine (2) have
been achieved via this approach. Novel chemical steps
include: (1) an intramolecular pinacol-type coupling of
ketonitrile 13 using samarium diiodide to efficiently
generate the pivotal B/C azabicyclo[3.2.1]octane nucleus
14 common to all these alkaloids; (2) application of our
recently developed radical-based methodology for regio-
selective generation of N-acyliminium ions from simple
amines as a key step in the syntheses of the norsecuri-
nine series; and (3) stereoselective imino Diels-Alder
reaction catalyzed by Yb(OTf)3 of the hindered, highly
functionalized bicyclic imine 34 for efficient annulation
of the A ring of phyllanthine. We also hope to modify the
approach described here so that A-rings bearing the endo
C2 stereochemistry found in allosecurinine (4) and se-
curitinine (5) can be annulated onto key bicyclic hydroxy-
ketone 14.
(13.7 g, 98%): [R]20 ) -26.8 (c 0.55, CDCl3); mp 83-85 °C;
D
IR (film) 3510-3480, 2930, 2810, 1595 cm-1
;
1H NMR (200
MHz, CDCl3) δ 7.74 (d, J ) 8.3 Hz, 2H), 7.31 (d, J ) 8.0 Hz,
2H), 4.30-4.23 (m, 1H), 3.92-3.87 (m, 1H), 3.73-3.62 (m, 3H),
3.22 (dt, J ) 1.7, 11.2 Hz, 1H), 3.09-3.00 (m, 1H), 2.42 (s,
3H), 1.91-1.86 (m, 1H), 1.79-1.75 (m, 1H), 0.71 (s, 9H),
-0.078 (s, 3H), -0.098 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
143.7, 133.1, 129.7, 127.8, 69.4, 65.2, 60.9, 58.6, 38.7, 25.6, 21.5,
17.9, -5.0, -5.1; EIMS m/z (relative intensity) 384 (M+ - H,
0.3), 370 (M+ - Me, 4), 354 (M+ - CH2OH, 64), 328 (M+
-
t-Bu, 100). Anal. Calcd for C18H31NO4SSi: C, 56.07; H, 8.10;
N, 3.63. Found: C, 55.98; H, 8.05; N, 3.71.
To a solution of oxalyl chloride (12.0 mL, 2.0 M in CH2Cl2)
in 50 mL of dry CH2Cl2 at -78 °C was added a solution of
DMSO (4.0 mL, 56.3 mmol) in 7.0 mL of CH2Cl2. The mixture
was stirred for 10 min, and a solution of the above alcohol (5.3
g, 13.8 mmol) in 30 mL of dry CH2Cl2 was added dropwise
over 30 min. The mixture was stirred for an additional 30 min,
and triethylamine (9.0 mL, 64.7 mmol) was added over 10 min.
The solution was stirred for 35 min, and (triphenylphospho-
ranylidene)acetonitrile (9.4 g, 31.2 mmol) in 100 mL of dry
CH2Cl2 was added via cannula. The reaction mixture was
stirred for an additional 3 h at room temperature and was
diluted with 50 mL of brine. The organic layer was washed
twice with brine, dried over MgSO4, and concentrated in vacuo.
The residue was dissolved in ethyl acetate and hexanes (1/4),
filtered through a silica gel plug, and concentrated. The residue
was purified by flash chromatography (ethyl acetate/hexanes,
1/8) to give (E)-olefin (3.9 g, 70%) and (Z)-olefin (1.1 g, 20%)
(12) as white solids.
Exp er im en ta l Section
Gen er a l Meth od s. Reactions were run under an atmo-
sphere of argon. Low-resolution mass spectra were obtained
at 50-70 eV by electron impact (EIMS). Chemical ionization
mass spectra (CIMS) were obtained using isobutane as a
carrier gas. Optical rotations were obtained at ambient tem-
perature. Reactions under high pressure were conducted in a
LECO model PG-200-HPC apparatus at room temperature.
Flash chromatography was performed using EM Sciences silica
gel 60 (25-40 mm). Preparative TLC was done with EM Silica
Gel 60 PF254. Melting points are uncorrected. Combustion
analyses were carried out by Atlantic Microlab.
Syn th esis of r,â-Un sa tu r a ted Nitr ile 12. To a solution
of trans-4-hydroxy-L-proline-derived alcohol sulfonamide 1118
(11.6 g, 38.7 mmol) in 300 mL of CH2Cl2 at 0 °C was added
imidazole (6.3 g, 92.5 mmol), followed by tert-butyldimethyl-
silyl chloride (8.4 g, 55.7 mmol). The mixture was stirred at 0
°C for 45 min and then at room temperature for 16 h. The
solution was concentrated under reduced pressure, and the
residue was filtered through a silica gel plug eluting with ethyl
acetate. The eluent was concentrated in vacuo, and the residue
was purified by flash chromatography (ethyl acetate/hexanes,
(E)-Olefin: mp 84-87 °C; IR (CCl4) 2952, 2856, 2224, 1738
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.68 (d, J ) 8.0 Hz, 2H),
7.34 (d, J ) 8.0 Hz, 2H), 6.72 (dd, J ) 7.2, 16.2 Hz, 1H), 5.58
(dd, J ) 1.3, 16.2 Hz, 1H), 4.25 (m, 1H), 4.17 (q, J ) 7.5 Hz,
1H), 3.62 (dd, J ) 4.4, 11.1 Hz, 1H), 3.19 (d, J ) 11.1 Hz, 1H),
2.41 (s, 3H), 1.86-1.80 (m, 2H), 0.70 (s, 9H), -0.09 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 154.5, 143.9, 133.7, 129.8, 127.7,
116.7, 100.2, 69.5, 59.6, 57.4, 41.9, 25.5, 21.5, 17.8, -5.0, -5.2;
CIMS m/z (relative intensity) 407 (MH+, 33), 349 (M+ - t-Bu,
15); EIMS m/z (relative intensity) 391 (M+ - Me, 3), 349
(M+ - t-Bu, 100).
(Z)-Olefin: mp 98-100 °C; IR (CCl4) 2950-2856, 2218, 1733
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.71 (d, J ) 8.0 Hz, 2H),
7.31 (d, J ) 8.0 Hz, 2H), 6.66 (dd, J ) 9.1, 10.9 Hz, 1H), 5.40
(d, J ) 10.9 Hz, 1H), 4.44 (m, 1H), 4.23 (m, 1H), 3.66 (dd, J )
3.6, 11.3 Hz, 1H), 3.14 (d, J ) 11.3 Hz, 1H), 2.37 (s, 3H), 2.02-
1.88 (m, 1H), 1.87-1.72 (m, 1H), 0.61 (s, 9H), -0.14 (s, 3H),
-0.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.1, 143.9, 133.7,
129.8, 127.9, 115.7, 98.9, 69.7, 58.5, 58.3, 41.8, 25.4, 21.4, 17.6,
-5.0, -5.2; CIMS m/z (relative intensity) 407 (MH+, 57), 349
(M+ - t-Bu, 27); EIMS m/z (relative intensity) 391 (M+ - Me,
2), 349 (M+ - t-Bu, 100).
(35) Mandal, A. K.; Mahajan, S. W. Tetrahedron 1988, 44, 2293.
(36) Attempted application of this procedure to convert norsecuri-
nine intermediate 46 to enone 48 failed.

Total Syntheses of the Securinega Alkaloids
J . Org. Chem., Vol. 65, No. 20, 2000 6301
P r ep a r a tion of Keton itr ile 13. To a solution of an E/ Z
mixture of unsaturated nitriles 12 (10.4 g, 25.6 mmol) in 200
mL of ethyl acetate was added 3 g of 10% Pd/C. The mixture
was stirred under 1 atm of H2 for 12 h and filtered through a
short plug of Celite which was washed with ethyl acetate. The
filtrate was concentrated in vacuo, and the residue was
purified by flash chromatography (ethyl acetate/hexanes, 1/3)
to give the saturated nitrile as a white solid (10.2 g, 98%):
with CH2Cl2 (3 × 100 mL). The combined organic extract was
washed with saturated NaHCO3 solution and brine, dried over
MgSO4, and evaporated. The residue was purified by flash
column chromatography (ethyl acetate/CH2Cl2, 1/8) to give
R-hydroxyketone 14 as a white solid (1.65 g, 78%): [R]20
)
D
-13.3 (c 0.052, CDCl3); recrystallization of the solid (benzene/
hexanes, 1/1) gave material with mp 199-202 °C dec; IR (film)
3480, 2971, 2877, 1717, 1598 cm-1; 1H NMR (200 MHz, CDCl3)
δ 7.77 (d, J ) 8.2 Hz, 2H), 7.36 (d, J ) 8.1 Hz, 2H), 4.39-4.30
(m, 1H), 3.91 (s, 1H), 3.45 (d, J ) 10.0 Hz, 1H), 3.19 (d, J )
10.0 Hz, 1H), 2.71-2.61 (m, 2H), 2.44 (s, 3H), 1.95-1.78 (m,
1H), 1.75-1.65 (m, 1H), 1.63 (s, 1H), 1.58 (d, J ) 13.2 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 208.9, 144.0, 134.7, 130.0,
127.2, 80.8, 57.4, 53.9, 41.5, 33.4, 33.0, 21.6; 13C NMR DEPT
(75 MHz, CDCl3) δ 130.0 (CH), 127.2 (CH), 57.4 (CH), 53.9
(CH2), 41.5 (CH2), 33.4 (CH2), 33.0 (CH2), 21.5 (CH3); CIMS
m/z (relative intensity) 296 (MH+, 100). Anal. Calcd for
C14H17NO4S: C, 56.93; H, 5.80; N, 4.74. Found: C, 56.68; H,
5.71; N, 4.83.
[R]29 ) -64.6 (c 0.55, CDCl3); mp 83-87 °C; IR (KBr) 2958,
D
2852, 2246, 1599 cm-1; H NMR (300 MHz, CDCl3) δ 7.70 (d,
1
J ) 8.3 Hz, 2H), 7.30 (d, J ) 8.3 Hz, 2H), 4.25 (ddd, J ) 3.9,
4.3, 4.3 Hz, 1H), 3.71-3.62 (m, 1H), 3.58 (dd, J ) 4.6, 11.2
Hz, 1H), 3.16 (dd, J ) 1.1, 11.2 Hz, 1H), 2.60-2.44 (m, 2H),
2.40 (s, 3H), 2.26-2.20 (m, 1H), 2.18-2.01 (m, 1H), 1.81-1.74
(m, 2H), 0.69 (s, 9H), -0.10 (s, 3H), -0.12 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 143.7, 133.4, 129.7, 127.8, 119.6, 69.4, 57.7,
57.3, 40.5, 30.6, 25.5, 21.5, 17.8, 13.2, -5.0, -5.1; CIMS m/z
(relative intensity) 409 (MH+, 80), 351 (M+ - t-Bu, 34). Anal.
Calcd for C20H32N2O3SSi: C, 58.79; H, 7.89; N, 6.86. Found:
C, 58.85; H, 7.92; N, 6.82.
P r ep a r a tion of Silyl Eth er 15. To a solution of hydroxy-
ketone 14 (1.40 g, 4.74 mmol) in 120 mL of dry CH2Cl2 was
added N,N-diisopropylethylamine (2.60 mL, 14.96 mmol),
followed by tert-butyldimethylsilyl trifluoromethanesulfonate
(1.20 mL, 5.23 mmol) at 0 °C. The solution was stirred at 0 °C
for 2 h and at room temperature for 15 h. Another portion of
tert-butyldimethylsilyl trifluoromethanesulfonate (0.70 mL,
3.05 mmol) was added at 0 °C, and the solution was stirred at
0 °C for 2 h and at room temperature for 15 h. The reaction
mixture was diluted with 2 mL of methanol, and the solvent
was removed in vacuo. The residue was filtered through a silica
gel pad, eluting with ethyl acetate/hexanes (1/2), and the
filtrate was concentrated in vacuo. The residue was purified
by flash chromatography (ethyl acetate/hexanes, 1/4) to give
the silyl ether 15 as a white solid (1.76 g, 91%): [R]20D ) -11.2
(c 0.55, CDCl3); mp 69-72 °C; IR (CCl4) 2955, 2887, 1731, 1598
To a solution of the saturated nitrile (8.0 g, 19.6 mmol) in
200 mL of THF was added tetrabutylammonium fluoride (1
M in THF, 20 mL) at room temperature. The amber solution
was stirred at room temperature for 0.5 h and concentrated.
The residue was diluted with brine and extracted with CH2Cl2
(3 × 50 mL). The extract was washed with brine, dried with
MgSO4, and concentrated. The residue was then purified by
flash chromatography (ethyl acetate/CH2Cl2, 1/2) to give the
hydroxynitrile as a white solid (5.7 g, 100%): [R]20 ) -56.3
D
(c 0.52, CDCl3); mp 101-103 °C; IR (film) 3506 (br), 2939, 2852,
1
2247, 1732 cm-1; H NMR (300 MHz, CDCl3) δ 7.72 (d, J )
8.3 Hz, 2H), 7.31 (d, J ) 8.3 Hz, 2H), 4.37-4.28 (m, 1H), 3.85-
3.76 (m, 1H), 3.52 (dd, J ) 4.1, 12.0 Hz, 1H), 3.31 (ddd, J )
1.6, 2.6, 12.0 Hz, 1H), 2.58-2.44 (m, 2H), 2.41 (s, 3H), 2.24-
2.13 (m, 1H), 2.03-1.91 (m, 1H), 1.89-1.85 (m, 1H), 1.82-
1.73 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 144.0, 133.6, 129.7,
127.8, 119.5, 69.4, 57.5, 56.9, 39.9, 31.1, 21.5, 13.4; 13C NMR
DEPT (75 MHz) δ 129.7 (CH), 127.8 (CH), 69.4 (CH), 57.5
(CH), 56.9 (CH2), 39.9 (CH2), 31.1 (CH2), 21.5 (CH3), 13.4 (CH2);
EIMS m/z (relative intensity) 294 (M+, 3), 240 (M+ - C3H4N,
100).
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.75 (d, J ) 8.3 Hz, 2H),
7.35 (d, J ) 8.2 Hz, 2H), 4.32 (m, 1H), 3.50 (d, J ) 7.8 Hz,
1H), 3.15 (d, J ) 7.8 Hz, 1H), 2.48-2.40 (m, 5H), 2.38-2.22
(m, 1H), 1.70-1.58 (m, 3H), 0.72 (s, 9H), 0.039 (s, 3H), 0.012
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.2, 143.9, 134.7, 129.9,
127.1, 83.8, 57.8, 56.1, 42.9, 34.6, 32.4, 25.6, 21.4, 18.4, -3.4;
CIMS m/z (relative intensity) 410 (MH+, 100), 352 (M+ - t-Bu,
83).
To a solution of the hydroxynitrile (7.2 g, 24.5 mmol) in 200
mL of acetone was added J ones reagent (0.91 M, 32 mL, 29
mmol). The mixture was stirred at room temperature for 30
min, and 5 mL of 2-propanol was then added. The mixture
was concentrated in vacuo and extracted with CH2Cl2 (3 × 100
mL). The combined organic extract was washed with saturated
NaHCO3 solution and brine, dried over MgSO4, and concen-
trated to give ketonitrile 13 as a white solid (6.0 g, 84%) which
was recrystallized from ethyl acetate/hexanes (1/1): mp 165-
166 °C; IR (CDCl3) 2926, 2254, 1766, 1597 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.72 (d, J ) 8.2 Hz, 2H), 7.36 (d, J ) 8.1 Hz,
2H), 4.32-4.21 (m, 1H), 3.83 (d, J ) 19.3 Hz, 1H), 3.66 (d,
J ) 19.5 Hz, 1H), 2.69-2.60 (m, 2H), 2.45 (s, 3H), 2.20-2.08
(m, 2H), 1.94-1.86 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 208.6,
144.9, 133.8, 130.4, 127.3, 118.9, 56.4, 52.7, 42.1, 31.3, 21.5,
14.2; 13C NMR DEPT (75 MHz, CDCl3) δ 130.4 (CH), 127.3
(CH), 56.4 (CH), 52.7 (CH2), 42.1 (CH2), 31.3 (CH2), 21.5 (CH3),
14.2 (CH2); EIMS m/z (relative intensity) 292 (M+, 29), 155
(p-MePhSO2, 100); HRMS (C14H16N2O3S) calcd 292.0882, found
292.0901. Anal. Calcd for C14H16N2O3S: C, 57.52; H, 5.52; N,
9.58. Found: C, 57.41; H, 5.49; N, 9.51.
Cycliza tion of Cya n ok eton e 13 to r-Hyd r oxyk eton e 14.
To a slurry of Sm powder (stored and weighed in a glovebox
and then flame dried under Ar, 2.9 g, 19.3 mol) in THF (200
mL) was added CH2I2 (1.40 mL, 17.4 mmol) dropwise at 0 °C.
After the mixture was stirred for 30 min, the ice bath was
removed. The reaction mixture was stirred for an additional
2 h at room temperature and cooled to -78 °C. To the SmI2
solution was added dropwise a solution of ketonitrile 13 (2.10
g, 7.19 mmol) in THF (100 mL) and MeOH (0.90 mL) over 30
min via cannula. The reaction mixture was allowed to warm
to room temperature overnight, diluted with saturated NaH-
CO3 solution (50 mL), and concentrated at reduced pressure.
The residue was acidified with 5% HCl solution and extracted
Syn th esis of Keta l 16. A solution of the TBS ether ketone
15 (1.23 g, 3.01 mmol), ethylene glycol (1.50 mL, 26.9 mmol),
and p-toluenesulfonic acid monohydrate (126 mg, 0.66 mmol)
in 60 mL of dry benzene was heated at reflux for 15 h. After
being cooled to room temperature, the reaction mixture was
concentrated. The residue was purified by flash chromatog-
raphy (ethyl acetate/hexanes, 1/4) to give ketal 16 as a white
solid (1.36 g, 100%): [R]20 ) 8.8 (c 1.2, CH2Cl2); mp 103-105
D
°C; IR (CCl4) 2957, 1356 cm-1; H NMR (300 MHz, CDCl3) δ
1
7.73 (d, J ) 8.3 Hz, 2H), 7.31 (d, J ) 8.2 Hz, 2H), 4.14 (t, J )
5.7 Hz, 1H), 4.04-3.84 (m, 4H), 3.54 (d, J ) 9.9 Hz, 1H), 2.92
(d, J ) 9.9 Hz, 1H), 2.39 (s, 3H), 1.90-1.78 (m, 2H), 1.70-
1.61 (m, 2H), 1.53-1.36 (m, 2H), 0.72 (s, 9H), -0.11 (s, 3H),
-0.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.4, 135.5, 129.8,
127.1, 110.6, 82.8, 65.9, 65.5, 58.0, 54.4, 40.3, 30.5, 30.1, 25.7,
21.5, 18.0, -2.8, -2.9; CIMS m/z (relative intensity) 454 (MH+,
100), 396 (M+ - t-Bu, 23); HRMS (C22H35NO5SiS) calcd
453.2005, found 453.1995.
P r ep a r a tion of Olefin 17. To a solution of TBS ether
ketone 15 (1.7 g, 4.23 mmol) in 90 mL of dry methanol was
added p-toluenesulfonylhydrazine (0.94 g, 45.05 mmol) at 0
°C. The solution was stirred at 0 °C for 2 h and at room
temperature for 18 h. The solvent was removed, and the
residue was dried in vacuo. The crude tosylhydrazone was used
without further purification.
To a solution of the crude tosylhydrazone in 100 mL of dry
toluene was added NaH (0.97 g, 0.95%, 38.4 mmol). The
mixture was heated at reflux for 3 h, cooled to 0 °C, and diluted
with brine/aqueous NH4Cl solution (10 mL/10 mL). The
aqueous layer was extracted with ethyl acetate (2 × 40 mL).
The combined organic extract was washed with brine, dried
over MgSO4, and concentrated. The residue was purified by

6302 J . Org. Chem., Vol. 65, No. 20, 2000
Han et al.
flash chromatography (ethyl acetate/hexanes, 1/8) to give
5H), 6.05-5.91 (m, 2H), 5.52-5.39 (m, 1H), 5.18-5.02 (m, 1H),
4.79-4.72 (m, 1H), 4.55-3.85 (m, 2H), 2.81-2.69 (m, 1H),
2.47-1.26 (m, 9H), 0.20-0.11 (m, 6H); CI MS m/z (relative
intensity) 384 (MH+), 368 (M+ - Me); EIMS m/z (relative
intensity) 383 (M+, 13), 342 (M+ - allyl, 74), 326 (M+ - t-Bu,
24); HRMS (C23H33NO2Si) calcd 383.2280, found 383.2283.
P r ep a r a tion of Tosyla te 22. To a solution of BH3‚THF
(1.8 mL, 1 M in ether, 1.8 mmol) in 5 mL of THF was added
2-methyl-2-butene (1.8 mL, 2 M in THF, 3.6 mmol) dropwise
at 0 °C. The solution was stirred at 0 °C for 2 h and cooled to
-23 °C. To the borane solution was added dropwise olefin 21
(130 mg, 0.34 mmol) in 5 mL of THF over 10 min. The reaction
mixture was stirred at -23 °C for 2 h and allowed to warm to
room temperature. H2O2 (2.3 mL, 30%, 22.9 mmol) and
aqueous NaOH solution (2M, 2.3 mL) were added at room
temperature, and the mixture was stirred for 30 min. Aqueous
2 M NaHSO3 solution was added until effervescence ceased.
The mixture was extracted with ethyl acetate (30 mL × 3),
and the combined organic extract was washed with 2M
NaHSO3, solution and brine, dried over MgSO4 and concen-
trated. The crude alcohol was used without further purifica-
tion.
alkene 17 as a light yellow solid (1.3 g, 78%): mp 67-69 °C;
[R]20 ) -15.1° (c 0.67, CDCl3); IR (CCl4) 2956, 2858 cm-1; 1H
D
NMR (200 MHz/CDCl3) δ 7.68 (d, J ) 8.3 Hz, 2H), 7.28 (d,
J ) 8.2 Hz, 2H), 5.90-5.83 (m, 1H), 4.29-4.21 (m, 1H), 3.50
(d, J ) 7.9 Hz, 1H), 3.00 (d, J ) 7.9 Hz, 1H), 2.40 (s, 3H),
2.38-2.11 (m, 2H), 1.73 (d, J ) 10.0 Hz, 1H), 1.62-1.54 (m,
1H), 0.79 (s, 9H), 0.00 (s, 3H), -0.037 (s, 3H); 13C NMR (75
MHz/CDCl3) δ 143.2, 137.3, 135.7, 129.6, 127.1, 123.9, 61.3,
57.4, 53.4, 40.9, 35.3, 25.5, 21.4, 17.7, -2.8; HRMS (C20H31
NO3SSi) calcd 393.1793, found 393.1769.
-
P r ep a r a tion of o-Am in oben za m id e 18. A solution of
sodium naphthalenide was made by adding sodium metal (0.3
g, 13 mol) to a solution of naphthalene (2.1 g, 16.4 mmol) in
10 mL of dry DME at room temperature. The dark blue
solution was stirred at room temperature for 3 h and added
dropwise to a -78 °C solution of the sulfonamide olefin 17 (0.82
g, 2.09 mmol) in 40 mL of dry DME until a dark blue color
persisted. The mixture was stirred at -78 °C for 15 min and
quenched with 10 mL of saturated aqueous NH4Cl solution.
The aqueous layer was extracted with ethyl acetate (3 × 40
mL). The combined organic extract was dried over MgSO4 and
concentrated, and the residue was dried in vacuo. The crude
amine was used without further purification.
To a solution of the crude alcohol in 25 mL of CH2Cl2 were
added DMAP (20 mg, 0.16 mmol) and triethylamine (1 mL,
7.2 mmol) followed by p-toluenesulfonyl chloride (168 mg, 0.88
mmol) at 0 °C. After being stirred for 2 h at 0 °C, the reaction
mixture was allowed to warm to room temperature and stirred
for 16 h. The reaction was diluted with 1 mL of MeOH, and
the solvent was removed in vacuo. The residue was filtered
through a silica gel pad which was washed with ethyl acetate/
hexanes (1/2), and the filtrate was concentrated. The residue
was purified by preparative TLC (ethyl acetate/hexanes, 1/3)
to give tosylate 22 as a colorless oil (120 mg, 64%): IR (film)
2954, 2856 1738, 1633 cm-1; 1H NMR (200 MHz/CDCl3) δ 7.77
(d, J ) 8.0 Hz, 1H), 7.68 (d, J ) 8.0 Hz, 1H), 7.40-7.28 (m,
7H), 5.90 (d, J ) 9.7 Hz, 1H), 5.60 and 5.36 rotamers (br d, J
) 9.1 Hz, 1H), 4.65 and 4.29 rotamers (br d, J ) 8.4 Hz, 1H),
4.05 (m, 2H), 3.50 (m, 1H), 2.59-2.24 (m, 5H), 1.83-1.76 (m,
5H), 1.51-1.30 (m, 1H), 0.85 and 0.77 rotamers (m, 9H), 0.06
To a solution of isatoic anhydride (0.84 g, 5.2 mmol) and
DMAP (61 mg, 0.5 mmol) in 50 mL of dry MeCN was added a
solution of the above crude amine in 50 mL of dry MeCN at 0
°C. The mixture was stirred at 0 °C for 2 h and at room
temperature for 2 d. The solvent was removed in vacuo, and
the residue was filtered through a silica gel pad, eluting with
ethyl acetate/hexanes (1/1), and the filtrate was concentrated.
The residue was purified by column chromatography (ethyl
acetate/hexanes, 1/3) to give amide 18 as a yellow oil (0.59 g,
1
79%): IR (film) 3451, 3349, 2953, 2856, 1737, 1613 cm-1; H
NMR (300 MHz/DMSO-d6, 75 °C) δ 7.10-7.07 (m, 2H), 6.72
(d, J ) 8.0 Hz, 1H), 6.57 (t, J ) 7.4 Hz, 1H), 5.91 (d, J ) 9.9
Hz, 1H), 5.53 (d, J ) 9.5 Hz, 1H), 4.93 (br s, 2H), 4.43 (m,
1H), 3.33 (d, J ) 9.3 Hz, 1H), 2.24-2.12 (m, 3H), 1.91 (d, J )
9.9 Hz, 1H), 0.87 (s, 9H), 0.11 (s, 6H); EIMS m/z (relative
intensity) 358 (M+, 20); HRMS (C20H30N2O2Si) calcd 358.2076,
found 358.2098.
(s, 6H); EIMS m/z (relative intensity) 555 (M+, 4), 498 (M+
-
t-Bu, 44), 105 (PhCO+, 100); HRMS (C30H41NO5SSi) calcd
555.2475, found 555.2485.
Oxid a tion of o-Am in oben za m id e 18. To a solution of
amide 18 (230 mg, 0.64 mmol) in 30 mL of dry MeOH at room
temperature were added NaNO2 (96 mg, 1.41 mmol), CuCl (14
mg, 0.14 mmol), and 3.9 mL of an 0.83 M solution of HCl in
MeOH. The mixture was stirred at room temperature for 1 h
and diluted with 5 mL of saturated NaHCO3 solution. The
MeOH was removed at reduced pressure, and the aqueous
layer was extracted with ethyl acetate (3 × 30 mL). The
combined organic extract was washed with brine, dried over
MgSO4, and concentrated. The crude product was purified by
preparative TLC (ethyl acetate/hexanes, 1/3) to give R-meth-
P r ep a r a tion of Tr icycle 24. To a -78 °C solution of
benzamide tosylate 22 (190 mg, 0.34 mmol) in 25 mL of dry
toluene was added DIBALH (1.7 mL, 1 M in hexanes, 1.7
mmol) dropwise over 30 min. The solution was stirred at -78
°C for 1 h and was allowed to warm to room temperature. The
reaction was quenched with 1 mL of MeOH, and the mixture
was stirred at room temperature for 4 h. The mixture was
diluted with 10 mL of ethyl acetate, filtered through a Celite
pad, and concentrated in vacuo. The crude compound was used
without further purification.
oxybenzamide 19 as a yellow solid (138 mg, 59%): [R]20
)
To a solution of the above crude product in 25 mL of dry
toluene were added NaI (50 mg, 0.33 mmol) and triethylamine
(1 mL, 9.67 mol). The solution was heated at reflux for 17 h
and cooled to room temperature. The reaction mixture was
concentrated in vacuo, and the residue was filtered through a
silica gel pad which was washed with ethyl acetate/triethyl-
amine (9/1). After concentration of the filtrate, the residue was
purified by flash column chromatography (ethyl acetate/
CH2Cl2/triethylamine, 4/4/1) to give tricycle 24 as a yellow oil
(56 mg, 59%): IR (CCl4) 2958, 2858 cm-1; 1H NMR (300 MHz/
CDCl3) δ 6.00 (dddd, J ) 7.4, 2.1, 2.1, 2.1 Hz, 1H), 5.45 (dddd,
J ) 7.4, 4.4, 4.4, 2.1 Hz, 1H), 3.49-3.40 (m, 1H), 3.38-3.28
(m, 1H), 3.05-2.98 (m, 1H), 2.21 (m, 2H), 2.01-1.92 (m, 1H),
1.81-1.51 (m, 6H), 0.88 (s, 9H), 0.08 (s, 6H); 13C NMR (75
MHz/CDCl3) δ 140.7, 123.3, 77.3, 62.3, 57.4, 35.9, 35.1, 29.2,
26.4, 25.7, 18.0, -2.6, -2.8; EIMS m/z (relative intensity) 279
(M+, 88); HRMS (C16H29NOSi) calcd 279.2018, found 279.2029.
P r ep a r a tion of o-Am in oben za m id e 26. A solution of
sodium naphthalenide was made by adding sodium metal (0.3
g, 13 mol) to a solution of naphthalene (2.1 g, 16.4 mmol) in
10 mL of dry DME at room temperature. The dark blue
solution was stirred at room temperature for 3 h and added
dropwise to a -78 °C solution of the sulfonamide 16 (1.5 g,
D
-7.1° (c 0.46, CDCl3); mp 74-78 °C; IR (CCl4) 2955, 2858 1651
cm-1; 1H NMR (300 MHz/DMSO, 75 °C) δ 7.45-7.39 (m, 5H),
5.82-5.72 (m, 1H), 5.62-5.52 (m, 1H), 4.71-4.64 (m, 1H), 4.19
(s, 1H), 2.94 (s, 3H), 2.61-2.48 (m, 1H), 2.40-2.29 (m, 1H),
2.21-2.10 (m, 1H), 1.79 (d, J ) 10.1 Hz, 1H), 0.88 (s, 9H),
0.11 (s, 6H); EIMS m/z (relative intensity) 373 (M+, 4), 316
(M+ - t-Bu, 60); HRMS (C21H31NO3Si) calcd 373.2073, found
373.2075.
Allyla tion of r-Meth oxyben za m id e 19. To a solution of
R-methoxyamide 19 (141 mg, 0.38 mmol) in 30 mL of dry
CH2Cl2 at -78 °C was added allyltrimethylsilane (0.8 mL, 5.03
mmol), followed by TiCl4 (0.8 mL, 1 M in CH2Cl2, 0.8 mmol).
After the mixture was stirred for 4 h at -78 °C, the bath was
removed and the solution was stirred for 2 d at room temper-
ature. The reaction mixture was diluted with 10 mL of
saturated NaHCO3 solution at 0 °C and the aqueous layer was
extracted with CH2Cl2 (3 × 30 mL). The combined organic
extract was washed brine, dried over MgSO4, and concen-
trated. The crude product was purified by preparative TLC
(ethyl acetate/hexanes, 1/3) to give olefin 21 as a colorless oil
(132 mg, 91%): [R]20D ) -57.9° (c 0.50, CDCl3); IR (film) 2954,
1
2856 1633 cm-1; H NMR (300 MHz/CDCl3) δ 7.48-7.35 (m,

Total Syntheses of the Securinega Alkaloids
J . Org. Chem., Vol. 65, No. 20, 2000 6303
3.31 mmol) in 80 mL of dry DME until a dark blue color
persisted. The mixture was stirred at -78 °C for 15 min and
quenched with 10 mL of saturated aqueous NH4Cl solution.
The aqueous layer was extracted with ethyl acetate (3 × 40
mL). The combined organic extract was dried over MgSO4 and
concentrated, and the residue was dried in vacuo. The crude
amine 25 was used without further purification.
(s, 3H); EIMS m/z (relative intensity) 439 (M+, 8), 382 (M+
-
t-Bu, 3), 105 (PhCO+, 100); HRMS (C23H41NO5Si) calcd
439.2754, found 439.2726.
F or m a tion of Im in e 34. Amine 25 (570 mg, 1.91 mmol)
in 20.0 mL of CH2Cl2 was treated with iodosobenzene (928 mg,
4.22 mmol, obtained from TCI) at room temperature. After 3.5
h, the solution was filtered through Celite, rinsed with CH2Cl2
(3 × 50 mL), and concentrated in vacuo. Purification of the
residue by flash chromatography (ethyl acetate/hexanes, 1/3)
afforded imine 34 (496 mg, 87%) as a yellow oil: IR (neat)
To a solution of isatoic anhydride (0.60 g, 3.7 mmol) and
DMAP (86 mg, 0.7 mmol) in 80 mL of dry MeCN was added a
solution of the amine 25 in 50 mL of dry MeCN at 0 °C. The
mixture was stirred at 0 °C for 2 h and at room temperature
for 3 d. The solvent was removed in vacuo, and the residue
was filtered through a silica gel pad, eluting with ethyl acetate/
hexanes (1/1), and the filtrate was concentrated. The residue
was purified by flash column chromatography (CH2Cl2 to 5%
MeOH/CH2Cl2) to give benzamide 26 as a yellow oil (1.2 g,
1
1604, 1472 cm-1; H NMR (300 MHz, CDCl3) δ 7.81 (s, 1H),
4.35 (m, 1H), 4.15-3.80 (m, 4H), 2.09-2.01 (m, 2H), 1.72-
1.62 (m, 4H), 0.89 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 173.4, 108.0, 89.9, 66.3, 65.9, 65.6, 45.4,
31.3, 25.7, 22.9, 18.0, -2.6, -2.7; CIMS m/z (relative intensity)
298 (MH+, 100); HRMS (C15H27NO3Si) calcd 297.1760, found
297.1754.
87%): IR (film) 3469, 3372, 2957, 1630 cm-1 1H NMR (300
;
MHz, CDCl3, 62 °C) δ 8.18-8.11 (m, 1H), 7.70-7.61 (m, 1H),
7.58-7.48 (m, 1H), 7.35 (d, J ) 7.8 Hz, 1H), 4.08-3.81 (m,
5H), 3.62-3.51 (m, 1H), 3.26 and 2.92 rotamer (d, J ) 8.2 Hz,
1H), 2.08-1.97 (m, 2H), 1.83-1.18 (m, 6H), 0.88 and 0.71
rotamer (s, 9H), 0.070, 0.063 and -0.023 rotamer (s, 6H);
EIMS m/z (relative intensity) 418 (M+, 10), 361 (M+ - t-Bu,
11), 120 (o-NH2PhCO+, 100); HRMS (C22H34N2O4Si) calcd
418.2288, found 418.2267.
P r ep a r a tion of Boc Ca r ba m a te 30 fr om Im in e 34. To a
solution of imine 34 (150 mg, 0.51 mmol) in THF (2 mL) at 0
°C was added BF3‚etherate (64 µL, 0.51 mmol) followed by
allylmagnesium bromide (1.52 mL, 1 M in Et2O). After 1.5 h,
the reaction mixture was warmed to room temperature and
stirred for 3 h. The reaction was quenched with saturated
aqueous NH4Cl solution and extracted with ethyl acetate
(3 × 5 mL). The organic layers were combined, dried over
MgSO4, and concentrated. Purification of the residue by flash
chromatography (CH2Cl2 to 2.5% NH4OH/10% MeOH/87.5%
CH2Cl2 gradient) gave the amine as a yellow oil. To a solution
of this amine in CH2Cl2 (2.5 mL) was added di-tert-butyl
dicarbonate (110 mg, 0.50 mmol). The reaction mixture stirred
at room temperature for 16 h and was then concentrated in
vacuo. The crude residue was purified by flash chromatography
(3 to 6% ethyl acetate/hexanes) to afford 183 mg (82%) of
carbamate 30 as a yellow oil.
P r ep a r a tion of Tosyla te 31. To a solution of BH3-THF
complex (5 mL, 1 M in ether, 5 mmol) in 5 mL of THF was
added 2-methyl-2-butene (5 mL, 2 M in ether, 10 mmol)
dropwise at 0 °C. After 2 h at 0 °C, carbamate 30 (165 mg,
0.38 mmol) in 5 mL of THF was added dropwise to the borane
solution over 10 min. The reaction mixture was stirred at 0
°C for 1 h and allowed to warm to room temperature. After 9
h at room temperature, H2O2 (2 mL, 30%, 20 mmol) and 1 N
aqueous NaOH solution (2 mL) were added at room temper-
ature, and the mixture was stirred for 50 min. Aqueous 1 M
Na2S2O3 solution was added until effervescence ceased. The
mixture was extracted with ethyl acetate (30 mL × 3). The
combined organic layer was washed with 1 M Na2S2O3 solution
and brine, dried over MgSO4 and concentrated. The crude
alcohol was used without further purification.
Oxid a tion of o-Am in oben za m id e 26. To a solution of
amide 26 (590 mg, 1.41 mmol) in 40 mL of dry MeOH at room
temperature were added NaNO2 (195 mg, 2.82 mmol), CuCl
(140 mg, 1.41 mmol), and 16 mL of methanolic HCl (0.81 M).
The mixture was stirred at room temperature for 15 min and
diluted with 5 mL of saturated NaHCO3 solution. The MeOH
was removed in vacuo, and the aqueous layer was extracted
with CH2Cl2 (3 × 30 mL). The combined organic layer was
washed with brine, dried over MgSO4, and concentrated. The
crude product was purified by column chromatography (ethyl
acetate/CH2Cl2, 1/4) to give R-methoxybenzamide 28 (178 mg,
30%) and R-chlorobenzamide 27 (157 mg, 26%).
Data for 28: [R]20 ) -54.3 (c 1.3, CH2Cl2); IR (CCl4) 2956,
D
1703, 1650 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.55-7.38 (m,
5H), 4.28-3.82 (m, 6H), 3.52 and 3.75 (d, rotamers, 1H), 3.66
and 2.79 (s, rotamers, 3H), 2.28-1.78 (m, 3H), 1.68-1.46 (m,
2H), 0.85 (two s, 9H), 0.11 (four s, 6H); EIMS m/z (relative
intensity) 433 (M+, 60), 376 (M+-t-Bu, 92), 105 (PhCO+, 100);
HRMS (C23H35NO5Si) calcd 433.2284, found 433.2270.
Data for 27: IR (CCl4) 2953, 1658 cm-1; 1H NMR (200 MHz,
CDCl3) δ 7.63-7.39 (m, 5H), 4.11-3.86 (m, 3H), 3.76-3.47 (m,
rotamers, 2H), 3.08 and 2.36 (m, rotamers, 2H), 2.62 (s, 1H),
2.02-1.22 (m, 4H), 0.88 (s, 9H), 0.16 (s, 3H), 0.07 (s, 3H); EIMS
m/z (relative intensity) 437 (M+, 4), 439 (M+ + 2, 2), 402
(M+ - Cl, 8), 105 (PhCO+, 100).
To a solution of the above crude alcohol in 25 mL of CH2Cl2
was added DMAP (150 mg, 1.20 mmol) and followed by
p-toluenesulfonyl chloride (155 mg, 0.81 mmol) at 0 °C. After
being stirred for 1 h at 0 °C, the reaction mixture was allowed
to warm to room temperature and stirred for 16 h. The reaction
mixture was diluted with 1 mL of MeOH, and the solvent was
removed in vacuo. The residue was filtered through a silica
gel pad, eluting with ethyl acetate/hexanes (1/2), and the
filtrate was concentrated in vacuo. The residue was purified
by flash column chromatography (ethyl acetate/hexanes, 1/4)
Allyla tion of r-Meth oxyben za m id e 28 a n d r-Ch lo-
r oben za m id e 27. To a solution of a mixture of R-methoxy-
benzamide 28 and R-chlorobenzamide 27 (251 mg, 0.58 mmol)
in THF (20 mL) at -78 °C was added allyltrimethylsilane as
a fluoride ion scavenger (1.6 mL, 10.1 mmol), followed by
BF3‚etherate (0.8 mL, 6.31 mmol) and allylmagnesium bromide
(1 M in ether, 8 mL, 8.0 mmol). After 2 h at -78 °C, the
reaction mixture was allowed to warm to -5 °C, and diluted
with saturated NH4Cl solution (20 mL), and the aqueous layer
was extracted with ethyl acetate (3 × 40 mL). The combined
organic layer was dried over MgSO4 and concentrated. The
crude product was used without further purification.
To a solution of crude secondary amine 29 in CH2Cl2 (20
mL) were added di-tert-butyl dicarbonate (0.8 mL, 3.48 mmol)
and triethylamine (2.0 mL, 14.3 mmol) at room temperature.
The reaction mixture was refluxed for 14 h and concentrated.
The residue was diluted with brine (30 mL) and extracted with
ethyl acetate (2 × 30 mL). The combined organic extract was
dried over MgSO4 and concentrated. The residue was purified
by flash column chromatography (ethyl acetate/hexanes, 1/8)
to give tosylate 31 as a colorless oil (164 mg, 71%): [R]20
)
D
-32.9 (c 1.1, CH2Cl2); IR (film) 2961, 1694, 1360 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J ) 8.3 Hz, 1H), 7.33 (d, J ) 8.2
Hz, 2H), 4.03-3.82 (m, 8H), 2.40 (s, 3H), 2.10-1.24 (m, 11H),
1.36 (s, 9H), 0.82 and 0.79 (s, rotamers, 9H), 0.09 (s, 6H); EIMS
m/z (relative intensity) 611 (M+, 10); HRMS (C30H49NO8SSi)
calcd 611.2948, found 611.2950.
P r ep a r a tion of Tr icycle 32 fr om Tosyl Ca r ba m a te 31.
To a solution of the tosylate 31 (155 mg, 0.25 mmol) in 20 mL
of MeOH was added methanolic HCl (0.8 N, 0.9 mL, 0.73
mmol) at room temperature. The reaction mixture was heated
at 60 °C for 9 h. After being cooled to room temperature, the
mixture was concentrated and the residue was purified by
flash column chromatography (ethyl acetate/CH2Cl2/triethyl-
amine, 4/4/1) to give the tricyclic ketal 32 (69 mg, 81%) as a
to give carbamate 30 as a light yellow oil (180 mg, 68%):
1
[R]20 ) -48.9 (c 1.3, CH2Cl2); IR (film) 2958, 1694 cm-1; H
D
NMR (300 MHz, CDCl3) δ 6.00-5.80 (m, 1H), 5.11-4.91 (m,
2H), 4.08-3.89 (m, 6H), 2.61-2.48 (m, 1H), 2.30-1.90 (m, 6H),
1.74-1.62 (m, 1H), 1.45 (s, 9H), 0.89 (s, 9H), 0.15 (s, 3H), 0.13
colorless oil: [R]20 ) -38.4 (c 0.96, CH2Cl2); IR (CCl4) 2960,
D

6304 J . Org. Chem., Vol. 65, No. 20, 2000
Han et al.
1
1694, 1360 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.09-3.83 (m,
4H), 3.46-3.25 (m, 2H), 2.93 (m, 1H), 2.50-2.40 (m, 1H), 1.97-
1.34 (m, 10H), 0.85 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 111.8, 85.4, 68.6, 65.1, 64.2, 60.9, 56.7, 34.7,
30.5, 30.2, 29.4, 26.4, 26.2, 18.4, -1.5, -2.8; EIMS m/z (relative
intensity) 339 (M+, 51), 282 (M+-t-Bu, 66), 169 (100); HRMS
(C18H33NO3Si) calcd 339.2230, found 339.2221.
2957, 1713, 1579 cm-1; H NMR (400 MHz, CDCl3) δ 7.59 (d,
J ) 6.6 Hz, 2H), 7.27 (m, 3H), 4.43 (dd, J ) 11.4, 8.8 Hz, 1H),
3.50 (br s, 1H), 3.33 (t, J ) 7.6 Hz, 1H), 3.27 (t, J ) 8.0 Hz,
1H), 3.07 (m, 1H), 2.58 (ddd, J ) 11.3, 9.6, 5.6 Hz, 1H), 2.48
(dddd, J ) 12.5, 8.8, 3.7, 3.7 Hz, 1H), 2.33 (ddd, J ) 12.0, 5.2,
3.0 Hz, 1H), 1.93 (m, 1H), 1.86-1.66 (m, 4H), 1.50 (d, J ) 12.0
Hz, 1H);13C NMR (100 MHz, CDCl3) δ 208.9, 135.8, 129.1,
128.2, 127.2, 85.1, 68.2, 60.7, 57.3, 45.1, 42.5, 37.2, 28.5, 26.4;
CIMS m/z (relative intensity) 205 (MH+, 12), 180 (M+ - SePh,
65), 70 (100); HRMS (C16H19NO2Se) calcd 338.0659, found
338.0658.
Syn th esis of Hyd r oxyk eton e 33. A solution of TBS ether
ketal 32 (40 mg, 0.12 mmol) in 3 N HCl (20 mL) was heated
at 95 °C for 17 h. After being cooled to room temperature, the
reaction mixture was concentrated in vacuo. The resulting HCl
salt was converted to the free amine by ion-exchange chro-
matography (Dowex 1 × 8-400 ion-exchange resin, MeOH
eluant). After concentration, the residue was purified by flash
column chromatography (MeOH/triethylamine/CH2Cl2, 1/1.5/
20) to give hydroxyketone 33 (16 mg, 74%, white solid): mp
118-119 °C; [R]20D ) -62.6 (c 0.35, CH2Cl2); IR (CDCl3) 3479,
Bu ten olid e 50. A solution of epimeric R-phenylselenoke-
tones 47 (47 mg, 0.14 mmol) in 1 mL of CH2Cl2 was cooled to
0 °C. To this mixture was added diethylphosphonoacetic acid
(45 µL, 0.28 mmol) followed by 1-cyclohexyl-3-(2-morpholino-
ethyl)carbodiimide metho-p-toluenesulfonate (130 mg, 0.31
mmol), and the solution was warmed to room temperature
overnight. After 20 h, the solution was diluted with water (5
mL) and extracted with CH2Cl2 (3 × 5 mL). The combined
organic layers were dried over Na2SO4 and concentrated. The
crude mixture was purified by flash chromatography (4%
MeOH/CH2Cl2) to give 63 mg (88%) of phosphonate 49 as a
mixture of diastereomers.
1
2955, 1713 cm-1; H NMR (400 MHz, CDCl3) δ 3.80 (s, 1H),
3.34 (t, J ) 7.8 Hz, 1H), 3.20 (t, J ) 7.8 Hz, 1H), 3.11 (br s,
1H), 2.75-2.56 (m, 2H), 2.51 (dd, J ) 7.8, 16.1 Hz, 1H), 2.32-
2.26 (m, 1H), 2.14-2.09 (m, 1H), 1.92-1.88 (m, 1H), 1.79-
1.61 (m, 4H), 1.47 (d, J ) 12.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 212.4, 84.8, 68.3, 60.6, 57.4, 36.9, 33.9, 32.8, 28.5,
26.4; EIMS m/z (relative intensity) 181 (M+, 53), 96 (100);
HRMS (C10H15NO2) calcd 181.1103, found 181.1097.
A solution of phosphonate 49 (63 mg, 0.12 mmol) in toluene
(3 mL) was added to a suspension of 18-crown-6 (97 mg, 0.37
mmol) and K2CO3 (67 mg, 0.49 mmol) in 7 mL of toluene at 0
°C which had been stirred at room temperature for 15 min.
After 4 h, the mixture was diluted with saturated NaHCO3 (5
mL) and extracted with Et2O (3 × 5 mL). The combined organic
layers were dried over Na2SO4 and concentrated. The crude
residue was purified by flash chromatography (4% MeOH/
CH2Cl2) to give 42 mg (95%) of butenolide 50 as a mixture of
diastereomers which was separated by preparative TLC (2
elutions with 4% MeOH/ CH2Cl2) for characterization.
Major diastereomer: IR (CDCl3) 2942, 1752, 1628 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 7.41-7.30 (m, 3H),
4.81 (s, 1H), 4.31 (d, J ) 8.1 Hz, 1H), 3.88 (t, J )7.7 Hz, 1H),
3.38 (ddd, J ) 8.7, 5.7, 2.6 Hz, 1H), 3.19 (m, 1H), 2.63 (ddd,
J ) 5.8, 5.8, 4.0 Hz, 1H), 2.51 (ddd, J ) 10.9, 5.9, 1.4 Hz, 1H),
2.43 (br d, J ) 14.8 Hz, 1H), 2.19 (ddd, J ) 14.8, 8.2, 2.3 Hz,
Syn th esis of (+)-14,15-Dih yd r on or secu r in in e (8). A
solution of hydroxyketone 33 (6 mg, 0.033 mmol) and the
Bestmann reagent 4528 (25 mg, 0.083 mmol) in toluene/CH2Cl2
(1.5 mL/1.5 mL) was subjected to 12 kbar of pressure for 21 h
at room temperature. After removal of the solvent, the residue
was purified by preparative TLC (CH2Cl2/MeOH/NH4OH
(concd), 92.5/5/2.5 and then ethyl acetate/triethylamine, 9/1)
to give (+)-14,15-dihydronorsecurinine (8) as a white solid (6
mg, 89%): mp 124-127 °C (lit.7 mp 135-136 °C); ORD in
dioxane (c ) 0.25); [R]500 -20°, [R]300 -910°; [R]20 ) +10 (c
D
0.35, dioxane); IR (CDCl3) 2955, 1752 cm-1; 1H NMR (300 MHz,
CDCl3) δ 5.60 (s, 1H), 3.34 (t, J ) 7.9 Hz, 1H), 3.20-3.11 (m,
2H), 2.87-2.50 (m, 5H), 2.09-1.38 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 174.7, 129.7, 109.3, 92.2, 66.5, 60.8, 57.2, 34.8, 31.5,
29.0, 26.6, 22.8; EIMS m/z (relative intensity) 205 (M+, 17),
96 (100).
1H), 1.94 (m, 2H), 1.78 (m, 2H), 1.40 (d, J ) 10.9 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 173.1, 172.5, 135.8, 130.9, 129.4,
128.9, 108.4, 91.8, 68.1, 61.4, 57.7, 39.4, 34.8, 34.7, 29.2, 26.6;
EIMS m/z (relative intensity) 362 (MH+, 6), 206 (MH+ - SePh,
33), 70 (100); HRMS (C18H19NO2Se) calcd 362.0659, found
362.0641.
The HCl salt of 8 was prepared by 5-7 cycles of dissolution
in CHCl3 and removal of solvent under reduced pressure.37 The
crude solid was dried in vacuo for 10 h to give a white solid.
Recrystallization of the crude solid by dissolving in 1 mL of
CH2Cl2 and addition of hexanes by slow diffusion gave crystals
suitable for X-ray analysis (see Supporting Information).
Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.59 (m,
2H), 7.34-7.30 (m, 3H), 5.94 (d, J ) 2.4 Hz, 1H), 4.33 (t, J )
8.9 Hz, 1H), 3.36 (m, 1H), 3.24 (m, 1H), 3.16 (m, 1H), 2.62-
2.50 (m, 3H), 1.98-1.90 (m, 2H), 1.77-1.68 (m, 3H), 1.42 (d,
J ) 11.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 175.4, 171.7,
134.6, 129.4, 128.3, 127.7, 112.9, 91.7, 66.7, 61.3, 57.2, 40.6,
34.8, 34.6, 28.9, 26.5.
P r ep a r a tion of r-Selen op h en ylen on e 46. To a solution
of hydroxyketone 33 (9.0 mg, 0.050 mmol) in 5 mL of ethyl
acetate was added phenylselenyl chloride (38 mg, 0.20 mmol)
followed by pyridine (20 µL, 0.25 mmol). The reaction mixture
was heated at reflux, stirred for 16 h, and then concentrated.
The crude residue was purified by column chromatography
(CH2Cl2 to 2.5% NH4OH (concd)/10% MeOH/87.5% CH2Cl2
gradient) to give 11.3 mg (67%) of vinylselenide 46 as a dark
(-)-Nor secu r in in e (6). To a solution of butenolides 50 (19
mg, 0.053 mmol) in CH2Cl2 at -78 °C was added dimethyl-
dioxirane (1.16 mL, 0.059 M in acetone). After 1 h, the reaction
was quenched with dimethyl sulfide (40 µL, 0.54 mmol)
followed by triethylamine (10 µL, 0.071 mmol). The mixture
was concentrated and the residue was purified by flash
chromatography (9% MeOH/CH2Cl2) to give 4.2 mg (39%) of
1
yellow oil: IR (CDCl3) 3491, 2971, 1679 cm-1; H NMR (200
MHz, CDCl3) δ 7.62-7.57 (m, 2H), 7.48-7.34 (m, 3H), 6.78
(d, J ) 7.0 Hz, 1H), 3.46 (dd, J ) 7.2, 4.8 Hz, 1H), 3.27-3.18
(m, 2H), 2.55-2.42 (m, 1H), 2.32 (dd, J ) 12.7, 4.8 Hz, 1H),
2.04-1.80 (m, 6H); CIMS m/z (relative intensity) 336 (MH+,
31), 332 (MH+ + 2, 10), 267 (100).
r-P h en ylselen ok eton e 47. To a solution of hydroxyketone
33 (60 mg, 0.33 mmol) in 6.5 mL of ethyl acetate was added
phenylselenyl chloride (190 mg, 0.99 mmol) followed by tri-
ethylamine (184 µL, 1.32 mmol). The solution was heated at
86 °C for 48 h and concentrated. The residue was purified by
flash chromatography (0-5% MeOH/CH2Cl2 gradient) to give
67 mg (60%) of R-phenylselenoketone 47 as a mixture of
diastereomers. The major diastereomer was separated by
preparative TLC (two elutions with 4% MeOH/ CH2Cl2) for
characterization: [R]20D ) -65.1 (c 0.55, CHCl3); IR (film) 3477,
(-)-norsecurinine (6) as a yellow oil: [R]20 ) -256 (c 5.6,
D
EtOH) (lit.12b [R]20 ) -262 (c 0.06, EtOH)); IR (neat) 1748,
D
1633, 1455 cm-1; H NMR (400 MHz, CDCl3) δ 6.76 (dd, J )
1
9.0, 6.5 Hz, 1H), 6.51 (d, J ) 9.0 Hz, 1H), 5.68 (s, 1H), 3.67 (t,
J ) 5.5 Hz, 1H), 3.30 (m, 1H), 3.19 (t, J ) 7.7 Hz, 1H), 2.61-
2.50 (m, 2H), 2.10-1.94 (m, 3H), 1.84-1.74 (m, 2H), 1.72 (d,
J ) 11.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.7, 168.2,
143.5, 120.6, 108.0, 91.6, 65.1, 59.8, 55.3, 35.8, 29.3, 26.8;
ESIMS m/z (relative intensity) 204 ([M + H]+, 100); HRMS
calcd for C12H14NO2 204.1025, found 204.1018; UV (EtOH) λmax
255 nm.
(-)-Norsecurinine hydrochloride was prepared by dissolving
(-)-norsecurinine (6) in CH2Cl2 and adding HCl (1 N in Et2O)
1
until the pH reached 2: mp 220 °C dec; H NMR (400 MHz,
(37) Formation of the amine hydrochloride by this procedure was
fortuitous but was not planned.
CD3OD) δ 7.02 (d, J ) 9.1 Hz, 1H), 6.80 (dd, J ) 9.0, 6.3 Hz,

Total Syntheses of the Securinega Alkaloids
J . Org. Chem., Vol. 65, No. 20, 2000 6305
1H), 6.12 (s, 1H), 4.54 (t, J ) 5.5 Hz, 1H), 4.01 (t, J ) 8.6 Hz,
1H), 3.90 (dd, J ) 11.6, 6.8 Hz, 1H), 3.25 (dt, J ) 11.9, 5.7 Hz,
1H), 3.01 (dd, J ) 12.3, 4.9 Hz, 1H), 2.38-2.15 (m, 3H), 2.21
(d, J ) 12.1 Hz, 1H), 1.97-1.83 (m, 1H).
Dih yd r op yr id in on e 35. P r oced u r e A. A solution of imine
34 (56 mg, 0.19 mmol) in 0.50 mL of CH2Cl2 and Danishefsky’s
diene (75 mg, 0.44 mmol, distilled prior to use at 65-66 °C/6
mmHg) in 1.0 mL of CH2Cl2 was sealed in a 5 mL plastic
Luerlock syringe and subjected to 12 kbar of pressure for 48
CDCl3) δ 4.04-3.81 (m, 4H), 3.68 (dddd, J ) 2.7, 2.9, 3.7, 3.7
Hz, 1H), 3.29 (s, 3H), 3.27 (dd, J ) 2.9, 12.4 Hz, 1H), 3.06 (m,
1H), 2.85 (ddd, J ) 3.6, 8.9, 11.2 Hz, 1H), 2.66 (ddd, J ) 5.4,
5.4, 10.9 Hz, 1H), 2.06-2.01 (m, 1H), 1.91-1.64 (m, 7H), 1.40-
1.24 (m, 2H), 0.88 (s, 9H), 0.12 (s, 3H), 0.073 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 112.5, 84.6, 74.2, 65.2, 64.5, 59.4, 58.4, 55.8,
44.4, 38.8, 31.2, 30.4, 30.3, 28.8, 26.2, 18.6, -1.4, -2.7; 13C
NMR DEPT (75 MHz, CDCl3) δ 74.2 (CH), 65.2 (CH2), 64.5
(CH2), 59.4 (CH), 58.4 (CH), 55.8 (CH3), 44.4 (CH2), 38.8 (CH2),
31.2 (CH2), 30.4 (CH2), 30.3 (CH2), 28.8 (CH2), 26.2 (CH3), -1.4
(CH3), -2.7 (CH3); CIMS m/z (relative intensity) 383 (M+, 40),
326 (M+-t-Bu, 70); HRMS (C20H37NO4Si) calcd 383.2492, found
383.2491. Anal. Calcd for C20H37NO4Si: C, 62.62; H, 9.72; N,
3.65. Found: C, 62.77; H, 9.85; N, 3.70.
h
at room temperature. The resulting red solution was
concentrated in vacuo, and the residue was purified by flash
chromatography (hexanes/acetone, 1/1) to give 49 mg (71%) of
dihydropyridinone 35 as a tan solid: [R]20 ) -327 (c 0.554,
D
CH2Cl2); mp 149-151 °C; IR (CDCl3) 1634, 1567 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.08 (d, J ) 6.8 Hz, 1H), 4.90 (d, J ) 6.8
Hz, 1H), 4.11-3.83 (m, 6H), 2.37-2.30 (m, 2H), 2.24-2.17 (m,
2H), 1.85-1.69 (m, 3H), 1.67-1.49 (m, 1H), 0.88 (s, 9H), 0.14
(s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 191.9, 149.2,
110.9, 97.8, 82.6, 65.4, 64.8, 61.3, 59.6, 40.8, 36.8, 30.1, 29.3,
26.1, 18.4, -1.2, -2.7; 13C NMR DEPT (75 MHz, CDCl3) δ
149.2 (CH), 97.8 (CH), 65.4 (CH2), 64.8 (CH2), 61.3 (CH), 59.6
(CH), 40.8 (CH2), 36.8 (CH2), 30.1 (CH2), 29.3 (CH2), 26.1 (CH3),
-1.2 (CH3), -2.7 (CH3); CIMS m/z (relative intensity) 366
(MH+, 100); HRMS (C19H31NO4Si) calcd 365.2022, found
365.2018; Anal. Calcd for C19H31NO4Si: C, 62.43; H, 8.55; N,
3.83. Found: C, 61.98; H, 8.72; N, 3.71. A sample of 35 was
recrystallized from ethyl acetate/hexanes for X-ray analysis
(see Supporting Information).
To a solution of the methyl ether (26 mg, 0.068 mmol) was
added 3 N HCl (8.0 mL). The solution was heated to reflux,
stirred for 26 h, and concentrated in vacuo. The residue was
dissolved in MeOH and filtered through ion-exchange resin
(Dowex-strongly basic, 1 × 8-400, 200-400 mesh) eluting with
MeOH (20 mL), and the eluent was concentrated. Purification
of the residual oil by flash chromatography (CH2Cl2/MeOH/
NH4OH (concd), 92.5/5/2.5) gave hydroxyketone 37 (12 mg,
78%) as an amorphous solid: [R]20 ) 24.9 (c 0.167, CH2Cl2);
D
IR (neat) 3367, 1711 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.67
(m, 1H), 3.29 (s, 3H), 3.28-3.27 (m, 1H), 3.07 (dd, J ) 3.2,
12.2 Hz, 1H), 3.02 (ddd, J ) 3.6, 9.2, 11.7 Hz, 1H), 2.74-2.65
(m, 2H), 2.51 (dd, J ) 8.0, 17.4 Hz, 1H), 2.38 (ddd, J ) 2.7,
5.4, 11.4 Hz, 1H), 2.13-2.08 (m, 1H), 1.84-1.72 (m, 3H), 1.66-
1.62 (m, 1H), 1.60 (d, J ) 11.3 Hz, 1H), 1.53 (dddd, J ) 1.8,
P r oced u r e B. A solution of imine 34 (299 mg, 1.0 mmol)
in 20.0 mL of dry CH3CN was treated with Yb(OTf)3 (134 mg,
0.22 mmol) and Danishefsky’s diene (253 mg, 1.47 mmol) in
10.0 mL of CH3CN at 0 °C. The solution was allowed to warm
to room temperature overnight and then concentrated. The
residue was extracted with CH2Cl2 (3 × 50 mL), washed with
saturated NaHCO3, dried over K2CO3, and concentrated in
vacuo. Purification of the residual oil by flash chromatography
(hexanes/acetone, 2/1) provided dihydropyridinone 35 as tan
solid (308 mg, 84%).
1
3.5, 12.2, 12.2 Hz, 1H); H NMR (500 MHz, C6D6) δ 3.80 (bs,
1H), 3.38 (dddd, J ) 4.1, 4.1, 4.1, 4.1 Hz, 1H), 3.17 (dd, J )
3.2, 12.0 Hz, 1H), 3.04 (s, 3H), 2.95 (dddd, J ) 3.3, 3.3, 9.8,
9,8 Hz, 1H), 2.74-2.73 (m, 1H), 2.37-2.29 (m, 2H), 2.24 (ddd,
J ) 2.7, 5.5, 11.2 Hz, 1H), 2.17 (dd, J ) 8.0, 17.2 Hz, 1H),
1.93 (dddd, J ) 1.4, 1.4, 3.0, 13.9 Hz, 1H), 1.64-1.55 (m, 2H),
1.52-1.45 (m, 2H), 1.24 (d, J ) 11.2 Hz, 1H), 1.04-0.98 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 212.6, 83.7, 73.9, 59.4, 58.0,
56.3, 44.5, 39.8, 34.3, 31.2, 29.9, 29.6; 13C NMR DEPT (75 MHz,
CDCl3) δ 73.9 (CH), 59.4 (CH), 58.0 (CH), 56.3 (CH3), 44.5
(CH2), 39.8 (CH2), 34.3 (CH2), 31.2 (CH2), 29.9 (CH2), 29.6
(CH2); CIMS m/z (relative intensity) 226 (MH+, 50); HRMS
(C12H19NO3) calcd 225.1365, found 225.1372.
Syn th esis of P ip er id in ol 36. To a -78 °C solution of
dihydropyridinone 35 (153 mg, 0.42 mmol) in 20.0 mL of dry
THF was added L-Selectride (1.0 mL, 1.0 M in THF). After 30
min, the solution was diluted with brine (10 mL), warmed to
room temperature, and extracted with EtOAc (3 × 50 mL).
The combined organics were dried with K2CO3 and concen-
trated in vacuo. Purification of the oil by flash chromatography
(CH2Cl2/MeOH/NH4OH (concd), 92.5/5/2.5) afforded 132 mg
14,15-Dih yd r op h ylla n th in e (51). A solution of tricyclic
hydroxyketone 37 (11 mg, 0.049 mmol) and the Bestmann
reagent 45 (30 mg, 0.099 mmol) in 4.0 mL of PhMe/CH2Cl2
(1/1) was sealed in a 5 mL Luerlock syringe and subjected to
12 Kbar of pressure for 25 h at room temperature. The solution
was then concentrated, and the residue was purified by flash
chromatography (ether/acetone, 2/1) followed by preparative
TLC (1% TEA/ethyl acetate) to give dihydrophyllanthine (51,
(85%) of alcohol 36 as an orange oil: [R]20 ) +12.4 (c 0.294,
D
CH2Cl2); IR (neat) 3403 cm-1; H NMR (300 MHz, CDCl3) δ
1
4.23 (m, 1H), 4.06-3.83 (m, 5H), 3.30 (dd, J ) 2.6, 12.3 Hz,
1H), 3.13 (m, 1H), 2.93 (ddd, J ) 3.5, 9.3, 11.3 Hz, 1H), 2.67
(m, 1H), 2.10-2.04 (m, 1H), 1.98-1.85 (m, 2H), 1.80-1.63 (m,
5H), 1.56-1.38 (m, 2H), 0.88 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 112.6, 84.1, 65.1, 65.0, 64.5, 59.4,
58.5, 44.1, 39.2, 34.9, 32.7, 31.3, 28.1, 26.2, 18.5, -1.4, -2.7;
13C NMR DEPT (75 MHz, CDCl3) δ 65.1 (CH2), 65.0 (CH), 64.5
(CH2), 59.4 (CH), 58.5 (CH), 44.1 (CH2), 39.2 (CH2), 34.9 (CH2),
32.7 (CH2), 31.3 (CH2), 28.1 (CH2), 26.2 (CH3), -1.4 (CH3), -2.7
(CH3); CIMS m/z (relative intensity) 370 (MH+, 100), 352 (M+-
OH, 60); HRMS (C19H35NO4Si) calcd 369.2335, found 369.2333.
Anal. Calcd for C19H35NO4Si: C, 61.75; H, 9.55; N, 3.79.
Found: C, 61.63; H, 9.52; N, 3.73.
9.8 mg, 80%) as a tan solid: [R]20 ) -12° (c ) 0.85, CHCl3)
D
(lit. [R]20D ) -8.5° (c 0.94, CHCl3)), mp 55-58 °C (lit.3 mp 66-
68 °C), IR (neat) 2929, 1758 cm-1; 1H NMR (300 MHz) δ 5.60
(s, 1H), 3.73 (m, 1H), 3.30 (s, 3H), 3.24 (dd, J ) 3.8, 12.6 Hz,
1H), 3.11 (ddd, J ) 3.6, 7.9, 11.8 Hz, 1H), 2.79-2.71 (m, 2H),
2.69-2.60 (m, 2H), 2.05-1.96 (m, 1H), 1.91-1.71 (m, 3H),
1.67-1.56 (m, 2H), 1.52-1.46 (m, 2H); 13C NMR (125 MHz) δ
173.0, 171.3, 109.0, 89.0, 70.3, 60.4, 55.5, 55.1, 44.3, 35.9, 29.9,
27.0, 26.8, 21.8; CIMS m/z (relative intensity) 250 (MH+, 60);
HRMS (C14H19NO3) calcd 249.1365, found 249.1371.
F or m a tion of Vin ylselen id e 52. To a solution of hydroxy-
ketone 37 (21 mg, 0.093 mmol) in 3.0 mL of dry CH2Cl2 was
added methanesulfonic acid (12 µL, 0.19 mmol) at room
temperature. After 20 min, the solution was cooled to 0 °C and
then treated with selenium dioxide (13 mg, 0.12 mmol) and
diphenyl diselenide (31 mg, 0.099 mmol). The mixture was
slowly warmed to room temperature overnight. The solution
was diluted with saturated NaHCO3 (10 mL) and extracted
exhaustively with CH2Cl2 (3 × 50 mL). The aqueous layer was
back-extracted with Et2O (20 mL) and ethyl acetate (20 mL).
The combined organics were dried with K2CO3 and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography (ethyl acetate/hexanes, 2/1) provided vinylselenide
52 as a yellow oil (20.3 mg, 58%): IR (neat) 3474, 2926, 2819,
1682, 1567 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.59-7.57 (m,
P r ep a r a tion of Keton e Meth yl Eth er 37. To a solution
of alcohol 36 (59 mg, 0.16 mmol) in 15.0 mL of dry THF was
added NaH (12 mg, 60% dispersion in mineral oil) at room
temperature. After 10 min, a solution of CH3I in THF (0.20
M, 2.0 mL) was slowly added via syringe pump (20 min). After
1 d, TLC indicated starting material remained. An additional
1.0 mL of CH3I in THF (0.20 M) was slowly added. After being
stirred at room temperature overnight, the solution was
diluted with brine and extracted with EtOAc (3 × 25 mL). The
combined organics were dried with K2CO3 and concentrated
in vacuo. Purification of the residue by flash chromatography
(CH2Cl2/MeOH/NH4OH (concd), 92.5/5/2.5) gave the methyl
ether (53 mg, 87%) as a yellow oil: [R]20 ) +19.7 (c 0.206,
D
CH2Cl2); IR (neat) 2928, 1472, 1462 cm-1; 1H NMR (300 MHz,

6306 J . Org. Chem., Vol. 65, No. 20, 2000
Han et al.
2H), 7.38-7.33 (m, 3H), 6.37 (d, J ) 5.6 Hz, 1H), 3.74 (t, J )
4.8 Hz, 1H), 3.64 (m, 1H), 3.29 (s, 3H), 2.75-2.71 (m, 1H),
2.54-2.47 (m, 2H), 2.25 (dd, J ) 5.1, 10.1 Hz, 1H), 1.97-1.92
(m, 2H), 1.83-1.79 (m, 1H), 1.75-1.60 (m, 3H); 13C NMR
DEPT (100 MHz, CDCl3) δ 198.4, 143.6 (CH), 136.1 (CH),
133.1, 129.7 (CH), 129.3 (CH), 126.5, 82.4, 74.6 (CH), 59.2
(CH), 56.1 (CH3), 55.2 (CH), 45.7 (CH2), 44.9 (CH2), 31.1 (CH2),
30.3 (CH2); CIMS m/z (relative intensity) 380 (MH+, 3).
P r ep a r a tion of Hyd r oxy En on e 53. A solution of vinylse-
lenide 52 (14.5 mg, 0.038 mmol) and sodium iodide (22 mg,
0.15 mmol) in 3.0 mL of dry CH3CN was cooled to 0 °C and
treated with freshly distilled boron trifluoride etherate (12 µL,
0.098 mmol). The yellow solution immediately turned orange.
After 1.5 h, the reaction mixture was diluted with 10% NaOH
(10 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined
organics were dried over K2CO3 and concentrated in vacuo.
Purification of the residual oil by flash chromatography
(CH2Cl2-CH2Cl2/MeOH/NH4OH (concd), 92.5/5/2.5) to give
hydroxyenone 53 as a yellow oil (7.1 mg, 84%): IR (neat) 3465,
mL of dry PhMe was stirred at room temperature for 15 min.
To this mixture was added ester 54 (7.3 mg, 0.018 mmol) in
dry PhMe (2.0 mL) at 0 °C. The solution was allowed to warm
to room temperature overnight. After 20 h, the mixture was
diluted with saturated NaHCO3 (10 mL) and extracted with
Et2O (3 × 50 mL). The combined organics were dried over
K2CO3 and concentrated. Purification of the residual oil by
flash chromatography (4% MeOH in CH2Cl2) provided phyl-
lanthine (2, 3.7 mg, 84%) as a yellow oil: [R]20 ) -791 (c
D
0.090, CHCl3) (lit.3 [R]20 ) -898 (c 0.98, CHCl3)); IR (neat)
D
1754, 1663, 1456, 1101 cm-1 1H NMR (400 MHz, CDCl3) δ
;
6.58 (d, J ) 9.2 Hz, 1H), 6.43 (dd, J ) 5.3, 9.2 Hz, 1H), 5.55(s,
1H), 3.80 (t, J ) 4.7 Hz, 1H), 3.63 (dddd, J ) 3.0, 3.0, 3.1, 3.1
Hz, 1H), 3.26 (s, 3H), 2.79 (ddd, J ) 3.3, 5.4, 10.6 Hz, 1H),
2.67 (ddd, J ) 3.8, 10.2, 10.2 Hz, 1H), 2.59 (dd, J ) 2.4, 12.2
Hz, 1H), 2.52 (dd, J ) 4.1, 9.3 Hz, 1H), 1.94 (dddd, J ) 1.4,
2.5, 2.5, 13.1 Hz, 1H), 1.87-1.73 (m, 2H), 1.78 (d, J ) 8.9 Hz,
1H), 1.68 (ddd, J ) 2.9, 12.4, 12.4 Hz, 1H); 13C NMR DEPT
(100 MHz, CDCl3) δ 140.7 (CH), 122.1 (CH), 105.8 (CH), 74.7
(CH), 59.2 (CH), 56.7 (CH), 56.5 (CH3), 44.9 (CH2), 42.4 (CH2),
31.5 (CH2), 31.1 (CH2); CIMS m/z (relative intensity) 248 (MH+,
8).
1
1689, 1457 cm-1; H NMR (300 MHz, CDCl3) δ 6.83 (dd, J )
5.7, 9.4 Hz, 1H), 6.19 (d, J ) 9.4 Hz, 1H), 3.87 (t, J ) 4.5 Hz,
1H), 3.66 (m, 1H), 3.62 (s, 1H), 3.28 (s, 3H), 2.83 (ddd, J )
2.3, 3.0, 10.2 Hz, 1H), 2.57 (ddd, J ) 3.4, 7.5, 10.9 Hz, 1H),
2.44 (dd, J ) 2.3, 12.1 Hz, 1H), 2.26 (dd, J ) 4.1, 10.9 Hz,
1H), 1.97-1.60 (m, 5H); CIMS m/z (relative intensity) 224
(MH+, 23).
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-32299) for financial support
of this research. We thank Dr. M. Parvez (University
of Calgary) for the crystal structure determination of
synthetic alkaloid 8 and Dr. M. Shang (University of
Notre Dame) for the X-ray structure of intermediate 35.
We also thank Gerald and Minde Artman for design of
the cover art and Murray Fagg (Australian National
Botanic Gardens, Canberra) for use of the copyrighted
photo of Phyllanthus calycinus.
F or m a tion of Ester 54. A solution of hydroxyenone 53 (6.0
mg, 0.027 mmol) in 2.0 mL of dry THF was cooled to 0 °C. To
this mixture was added diethylphosphonoacetic acid (35 mg,
0.18 mmol) in THF (1.5 mL) followed by DCC (26 mg, 0.13
mmol). The solution was allowed to warm to room temperature
overnight. After 20 h, the solution was diluted with saturated
NaHCO3 (10 mL) and extracted with ethyl acetate (3 × 50 mL).
The combined organics were dried over K2CO3 and concen-
trated. Purification of the residue by flash chromatography
(CH2Cl2/ethyl acetate, 1/1 CH2Cl2/MeOH/NH4OH (concd), 92.5/
5/2.5) followed by preparative TLC (acetone/CH2Cl2, 2/1)
afforded ester 54 (7.3 mg, 67%) as a yellow oil: 1H NMR (200
MHz, CDCl3) δ 6.75 (dd, J ) 4.4, 9.5 Hz, 1H), 6.17 (d, J ) 9.7
Hz, 1H), 4.26-4.11 (m, 4H), 3.90 (t, J ) 4.9 Hz, 1H), 3.66-
3.62 (m, 1H), 3.28 (s, 3H), 3.13 (d, J ) 7.2 Hz, 1H), 3.02 (d,
J ) 7.2 Hz, 1H), 2.89-2.52 (m, 3H), 2.24-2.12 (m, 1H), 1.88-
1.60 (m, 5H), 1.35 (t, J ) 7.0 Hz, 6H).
Su p p or tin g In for m a tion Ava ila ble: Copies of proton and
carbon NMR spectra of new compounds and X-ray data
including ORTEP drawings for compounds 35 and 8‚HCl. Also
included are experimental details for the reactions in Scheme
8. This material is available free of charge via the Internet at
http://pubs.acs.org.
P r ep a r a tion of P h ylla n th in e (2). A solution of 18-crown-6
(16 mg, 0.061 mmol) and K2CO3 (12 mg, 0.087 mmol) in 2.0
J O000260Z