Convergent approach to pumiliotoxin alkaloids. Asymmetric total synthesis of (+)-pumiliotoxins A, B, and 225F

Article abstract of DOI:10.1021/jo0200466

A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation-cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh3)4 catalyst to give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.

Full text of DOI:10.1021/jo0200466

Con ver gen t Ap p r oa ch to P u m iliotoxin Alk a loid s. Asym m etr ic
Tota l Syn th esis of (+)-P u m iliotoxin s A, B, a n d 225F
Sakae Aoyagi, Shintaro Hirashima, Kosuke Saito, and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi,
Hachioji, Tokyo 192-0392, J apan
kibayasi@ps.toyaku.ac.jp
Received J anuary 18, 2002
A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed
employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl
iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was
synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrro-
lidine followed by a palladium-catalyzed intramolecular carbonylation-cyclization sequence. This
synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-
iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and
subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh3)4 catalyst to
give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided
(+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into
the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with
the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.
In tr od u ction
Neotropical poison-dart frogs of the family Dendro-
batidae have been a rich source of a remarkable variety
of alkaloids with structurally unique features and bio-
logical significance.1 Among these natural products,
pumiliotoxins A (6) and B (7), isolated as the major toxic
alkaloids from skin extracts of the Panamanian poison
frog Dendrobates pumilio in 1967,2 were the first repre-
sentatives of the pumiliotoxin class. In the late 1970s, a
simpler congener, pumiliotoxin 251D (3), was isolated
from another dendrobatid frog.3 These dendrobatid al-
kaloids had been thought to be unique to frogs of the
dendrobatid genera. However, during the screening of
skin extracts from various genera of other amphibian
families, the pumiliotoxin class of alkaloids has been
found to have a wide distribution in nondendrobatid frogs
and toads, and the number of this class of natural
products detected so far now totals up to more than 20.1d
They are all characterized structurally by a (Z)-6-alkyl-
idene-8-hydroxy-8-methylindolizidine ring system differ-
ing in only the alkylidene side chain.1 These molecules
have been shown to have modulatory effects on voltage-
dependent sodium channels, therefore displaying, in
some cases, potent cardiotonic and myotonic activity.4 For
F IGURE 1. Representative pumiliotoxin class alkaloids.
the synthesis of the pumiliotoxins, one significant chal-
lenge is the stereoselective incorporation of the (Z)-
alkylidene side chain at C-6 of the indolizidine nucleus.
The selective generation of (E)- and (Z)-exocyclic olefins
has traditionally been attained via π-bond construction
employing the Wittig reaction or aldol condensation, but
these methods have often been less than satisfactory. In
(1) (a) Daly, J . W.; Spande, T. F. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1986;
Vol. 4, pp 1-274. (b) Daly, J . W.; Garraffo, H. M.; Spande, T. F.
Alkaloids 1993, 43, 185-288. (c) Daly, J . W. Alkaloids 1998, 50, 141-
169. (d) Daly, J . W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Perga-
mon: Amsterdam, 1999; Vol. 13, pp 1-161.
(2) Daly, J . W.; Myers, C. W. Science 1967, 156, 970-973.
(3) Daly, J . W.; Tokuyama, T,; Fujiwara, T.; Highet, R. J .; Karle, I.
L. J . Am. Chem. Soc. 1980, 102, 830-836.
(4) Gusovsky, F.; Padget, W. L.; Creveling, C. R.; Daly, J . W. Mol.
Pharmacol. 1992, 42, 1104-1108 and references therein, and also ref
1.
10.1021/jo0200466 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/28/2002
J . Org. Chem. 2002, 67, 5517-5526
5517

Aoyagi et al.
SCHEME 1
the search for control of the exocyclic alkene geometry
as well as the piperidine ring construction, comprehen-
sive efforts by the Overman group5 have led to the
development of the total synthesis of pumiliotoxins 251D
(3), A (6), and B (7) via two fundamental approaches
based on iminium ion-vinylsilane and iminium ion-alkyne
cyclizations. After these pioneering studies, the synthesis
of pumiliotoxin 251D (3) was reported by Gallagher and
co-workers,6 in which an aldol condensation of a bicyclic
lactam was employed to introduce the alkylidene side
chain. This intermediate bicyclic lactam was later syn-
thesized by other routes,7-11 which thus represent formal
syntheses of pumiliotoxin 251D. Our own approach to the
structural problem presented by this class of alkaloids
has thus been to focus on developing stereoselective
construction of the (Z)-alkylidene indolizidine as a com-
mon key intermediate and subsequent assembly of a
variety of side chains by means of an organozinc-based
homoallyl-vinyl cross-coupling reaction promoted by a
palladium(0) catalyst. This process is relevant to a
convergent entry into the total synthesis of pumiliotoxins
225F (2), A (6), and B (7).12
Resu lts a n d Discu ssion
Syn t h et ic St r a t egy. Since the presence of the (Z)-
alkylidene indolizidine moiety is the common structural
motif shared by not only pumiliotoxins A (6) and B (7)
but also all other pumiliotoxin alkaloids, the strategic
disconnection of this class of alkaloids at the C-12-C-13
bond of the alkylidene side chain should be the most
appropriate for the efficient and flexible synthesis of
these natural products. Our synthetic plan for pumilio-
toxins A (6) and B (7) thus called for connecting two
fragments, a metal species 8 of the (Z)-alkylidene in-
dolizidine and the alkenyl halides 9, by cross-coupling
reaction (Scheme 1). This approach utilizing 8 with a
common fundamental structural unit of the pumiliotoxin
alkaloids allows a convergent and general entry into this
class of alkaloids. The organic moiety of 8 was anticipated
to be obtained through stereoselective addition of a
silylallene 14 to (S)-acetylpyrrolidine (13) followed by a
sequence involving an intramolecular carbonylation of a
vinyl iodide 11 and cyclization to the indolizidine skeleton
as outlined in Scheme 1.
metal-catalyzed homoallyl-alkenyl coupling would be the
tendency of the homoallylic metal compounds to undergo
â-elimination.13 This problem was overcome by Negishi,14
who subjected homoallylic organozincs to the palladium-
catalyzed conjugate substitution reaction with alkenyl
halides to effect the construction of 1,5-dienes. We
envisioned that this coupling chemistry associated with
the organozincs effects the combination of 8 and 9
through a homoallyl-alkenyl coupling process to yield the
1,5-diene unit, which was expected to be adopted for
incorporation of appropriate alkylidene side chains cor-
responding to pumiliotoxins A and B.
Syn th esis of th e (Z)-Iod oa lk ylid en e In d olizid in e
In ter m ed ia te. According to the above discussion, syn-
thesis of the common intermediate (Z)-iodoalkylidene
indolizidine (34 in Scheme 5) needed for the preparation
of the corresponding zinc reagent was our initial objec-
tive. The synthesis began with the dibromo olefin 16,
prepared from O-monosilylated (2S)-2-methyl-1,3-pro-
panediol (15)15 via Swern oxidation15c followed by treat-
In the critical cross-coupling process between 8 and 9,
one potential problem associated with the transition
(5) (a) Overman, L. E.; Bell, K. L. J . Am. Chem. Soc. 1981, 103,
1851-1853. (b) Overman, L. E.; Bell, K. L.; Ito, F. J . Am. Chem. Soc.
1984, 106, 4192-4201. (c) Overman, L. E.; Lin, N.-H. J . Org. Chem.
1985, 50, 3669-3670. (d) Overman, L. E.; Sharp, M. J . Tetrahedron
Lett. 1988, 29, 901-904. (e) Lin, N.-H.; Overman, L. E.; Rabinowitz,
M. H.; Robinson, L. A.; Sharp, M. J .; Zablocki, J . J . Am. Chem. Soc.
1996, 118, 9062-9072.
(6) Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molloy, K. C.;
Gallagher, T. J . Am. Chem. Soc. 1991, 113, 2652-2656.
(7) (a) Honda, T.; Hoshi, M.; Tsubuki, M. Heterocycles 1992, 34,
1515-1518. (b) Honda, T.; Hoshi, M.; Kanai, K.; Tsubuki, M. J . Chem.
Soc., Perkin Trans. 1 1994, 2091-2101.
(8) (a) Cossy, J .; Cases, M.; Gomez-Pardo, D. Synlett 1996, 909-
910. (b) Cossy, J .; Cases, M.; Gomez-Pardo, D. Bull. Soc. Chim. Fr.
1997, 134, 141-144.
(13) Negishi, E. Acc. Chem. Res. 1982, 15, 340-348.
(14) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J . Am. Chem. Soc.
1980, 102, 3298-3299. (b) Kobayashi, M.; Negishi, E. J . Org. Chem.
1980, 45, 5223-5225.
(15) Prepared by a chiron approach from commercial methyl (R)-3-
hydoxy-2-methylpropionate: (a) Schmittberger, T.; Uguen, D. Tetra-
hedron Lett. 1995, 36, 7445-7448. (b) Schmittberger, T.; Uguen, D.
Tetrahedron Lett. 1997, 38, 2837-2840. (c) Matsushima, T.; Mori, M.;
Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi, J .; Yonemitsu, O.
Chem. Pharm. Bull. 1999, 47, 308-321.
(9) Barrett, A. G. M.; Damiani, F. J . Org. Chem. 1999, 64, 1410-
1411.
(10) Martin, S. F.; Bur, S. K. Tetrahedron 1999, 55, 8905-8914.
(11) Ni, Y.; Zhao, G.; Ding, Y. J . Chem. Soc., Perkin Trans. 1 2000,
3264-3266.
(12) Part of this work has been published in a preliminary form:
Hirashima, S.; Aoyagi, S.; Kibayashi, C. J . Am. Chem. Soc. 1999, 121,
9873-9874.
5518 J . Org. Chem., Vol. 67, No. 16, 2002

Convergent Approach to Pumiliotoxin Alkaloids
SCHEME 2
SCHEME 4
SCHEME 3
SCHEME 5
ment with CBr4/PPh3,16 which was converted to the
propargylic alcohol 17 upon treatment with BuLi and
paraformaldehyde (Scheme 2). Construction of the alle-
nylsilane 19 was successfully achieved using Fleming’s
method17 by conversion to the mesylate 18 and subse-
quent treatment with the bis(dimethylphenylsilyl)cuprate
reagent at -85 °C in a very short reaction time (3 min).
The trifluoroacetate salt of (S)-2-acetylpyrrolidine (13),
available from the N-Boc derivative 2018 by deprotection
with trifluoroacetic acid, was subjected to titanium(IV)
chloride-mediated nucleophilic addition19 of 19 to afford
the desired homopropargylic alcohol 22, which was
isolated as the N-Boc derivative 23, with complete
stereocontrol in 71% overall yield; no trace of the other
diastereomer was detected by NMR analysis. When the
reaction was performed using hafnium(IV) chloride as a
Lewis acid, it yielded 23 as a single product more cleanly
and in excellent overall yield (92%). The stereochemistry
of 22 was determined by a NOESY experiment of the
bicyclic carbamate 24 derived from 23 by base treatment.
The facial selectivity realized in these propargylations
can be rationalized by invoking a Lewis acid-chelate cyclic
intermediate 21 involving the chelation of the NH and
carbonyl groups with the metal.
Radical-initiated hydrostannylation of 23 proceeded
with complete trans selectivity to give the pure (Z)-3′-
stannyl alkene 25 (60%) after chromatographic separa-
(16) Panek, J . S.; Hu, T. J . Org. Chem. 1997, 62, 4912-4913.
(17) Fleming, I.; Terrett, N. K. J . Organomet. Chem. 1984, 264, 99-
118.
(18) For preparation of N-Boc-(S)-2-acetylpyrrolidine (20) from
N-Boc-L-proline, see: (a) Trost, B. M.; Scanlan, T. S. J . Am. Chem.
Soc. 1989, 111, 4988-4990. (b) Goldstein, S. W.; Overman, L. E.;
Rabinowitz, M. H. J . Org. Chem. 1992, 57, 1179-2290.
(19) For the TiCl4-mediated addition of allenylsilanes to carbonyl
compounds, see: (a) Danheiser, R. L.; Carini, D. J . J . Org. Chem. 1980,
45, 3925-3927. (b) Danheiser, R. L.; Carini, D. J .; Kwasigroch, C. A.
J . Org. Chem. 1986, 51, 3870-3878.
J . Org. Chem, Vol. 67, No. 16, 2002 5519

Aoyagi et al.
SCHEME 6
tion from the 4′-stannyl regioisomer 26 (28%) (Scheme
4). The assignment of the (Z)-stereochemistry of 25 was
made on the basis of the large coupling constant (89.3
Hz) between Sn and the vinylic proton.20 The regiocontrol
of this hydrostannylation process would be rationalized
by assuming coordination of a Ph3Sn• radical to the OH
group21 and preferential attack of the Ph3Sn• radical at
the less hindered C-3′. Upon exposure of 25 to N-
iodosuccinimide, iodolysis took place with complete re-
tention of the (Z)-configuration to give the vinyl iodide
27. Palladium-catalyzed carbonylation22 of 27 smoothly
occurred when treated with carbon monooxide and tribu-
tylamine in the presence of catalytic Pd(OAc)2 (2 mol %)
and PPh3 (10 mol %) in HMPA at 100 °C,23 furnishing
the lactone 28 in excellent yield (97%). Compound 28 was
converted to the amine 29 by N-Boc deprotection with
TFA.
(E)-vinyl iodide 42 in the homochiral form, which was
needed as a coupling partner for the synthesis of (+)-
pumiliotoxin A (6). Commercially available (R)-glycidol
(35) was protected as the THP ether and underwent
copper(I)-catalyzed epoxide ring-opening using methyl-
magnesium bromide to yield the (S)-2-butanol derivative
37 (Scheme 6). After O-benzylation of the secondary
alcohol followed by deprotection of the THP group, the
resulting primary alcohol 39 was oxidized by the Swern
procedure to give the aldehyde 40, which was converted
to (3S)-3-(benzyloxy)-2-pentanone (41)27 by the Grignard
reaction (MeMgBr) and Swern oxidation sequence. This
ketone 41 was subjected to iodo-olefination using the
Takai protocol28 of treatment with CrCl2 and iodoform
to produce stereoselectively the chromatographically
separable (E)-vinyl iodide 42 (63%) and the (Z)-isomer
(7%).
Preliminary experiments were performed in order to
determine the feasibility of this vinyl iodide 42 as the
coupling partner in the Pd(0)-catalyzed cross-coupling
reaction with the organozinc compound.29 Hence, the (R)-
iodide 43, prepared by iodination of the above-described
(S)-alcohol 15,30 underwent halogen-metal exchange
with 2 equiv of t-BuLi at -78 °C, followed by transmeta-
lation with 1 equiv of ZnCl2. Subsequent one-pot treat-
ment of the in situ generated alkylzinc reagent 44 with
the iodide 42 in the presence of catalytic Pd(PPh3)4 at
room temperature led to the cross-coupled product 45 in
55% yield with complete retention of the (E)-geometry
(Scheme 7).
With the (Z)-alkylidene lactone 29 in hand, we next
envisaged the construction of the indolizidine framework
with the (Z)-alkylidene appendage. Thus, after DIBAL-H
reduction, the resulting diol 30 underwent smooth in-
tramolecular cyclodehydration using carbon tetrabromide
24
and PPh3 to form the (Z)-alkylidene indolizidine 31 in
85% yield (Scheme 5). Subsequent removal of the TBDPS
protecting group with tetrabutylammonium fluoride re-
sulted in the first total synthesis of (-)-pumiliotoxin 225F
(2). The synthetic material displayed spectral properties
(13C NMR and MS) that matched those of the natural
product.25 However, the observed rotation of synthetic 2
([R]24D -25.3 (c 0.25, CHCl3)) was significantly lower than
the reported value ([R]D -87.4 (c 0.23, CHCl3)).25 The
reason for this discrepancy in the optical rotation is
unclear at present, although it might be attributed to
contamination by a small amount of a highly optically
active impurity in the natural sample.
For the formation of the key intermediate (Z)-iodoalkyl-
idene indolizidine 34, 31 was protected as the TBDMS
ether 32. The selective deprotection of the primary
TBDPS ether was successfully achieved by using difluoro-
trimethylsilicate (TAS-F)26 to provide the primary alcohol
33, which was then iodinated (I2, PPh3, imidazole) to give
34.
P r elim in a r y Exp er im en ts of Cr oss-Cou p lin g Re-
a ction s w ith th e Vin yl Iod id e. Having established an
efficient route for the synthesis of the indolizidine frag-
ment 34 bearing the 6-alkylidene side chain with the
required (Z)-configuration, we next examined the prepa-
ration of the C-13-C-17 vinylic side chain segment, i.e.,
Syn th esis of (+)-P u m iliotoxin A. The stage was
then set for the critical homoallyl-vinyl coupling with the
(Z)-iodoalkylidene indolizidine 34 and the (E)-vinyl iodide
42 under conditions similar to those described above.
Thus, 34 was subjected to halogen-metal exchange (t-
BuLi, THF, -110 °C) followed by transmetalation with
ZnCl2 to generate the homoallylzinc derivative 46 in situ,
which underwent cross-coupling reaction with 42 in the
presence of catalytic Pd(PPh3)4 to give the cross-coupled
(20) In our earlier study, smaller coupling constants (ca. 35 Hz) were
observed for (E)-stannyl alkenes prepared by syn selective palladium-
catalyzed hydrostannylation in a nonradiacal manner. See: Aoyagi,
S.; Wang, T.-C.; Kibayashi, C. J . Am. Chem. Soc. 1993, 115, 11393-
11409.
(21) Nativi, C.; Taddei, M. J . Org. Chem. 1988, 53, 820-826.
(22) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318-3326. (b) Schoenberg, A.; Heck, R. F. J . Org. Chem. 1974,
39, 3327-3331.
(23) Procedure according to Mori, M.; Chiba, K.; Ban, Y. J . Org.
Chem. 1978, 43, 1684-1687.
(24) For intramolecular cyclodehydration of amino alcohols via
alkoxyphosphonium salts, see: (a) Stoilova, V.; Trifonov, L. S.; Ora-
hovats, A. S. Synthesis 1979, 105-106. (b) Shishido, Y.; Kibayashi, C.
J . Org. Chem. 1992, 57, 2876-2883.
(25) Tokuyama, T.; Tsujita, T.; Garraffo, H. M.; Spande, T. F.; Daly,
J . W. Tetrahedron 1991, 47, 5415-5424.
(26) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J . Org. Chem. 1998, 63, 6436-6437.
(27) For an alternative synthesis of the ketone 41 from (S)-2-methyl-
1-penten-3-ol available by Sharpless kinetic resolution, see: ref 5e.
(28) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408-7410
(29) For recent reviews on cross-coupling reactions of zinc organo-
metallics, see: (a) Erdik, E. Tetrahedron 1992, 48, 9577-9648. (b)
Diederich, F., Stang, P. J ., Eds. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, Germany, 1998.
(30) For the conversion of the alcohol 15 into the iodide 43, see the
literature cited as 15a,b in ref 15.
5520 J . Org. Chem., Vol. 67, No. 16, 2002

Convergent Approach to Pumiliotoxin Alkaloids
SCHEME 7
SCHEME 9
SCHEME 8
next directed our efforts toward the synthesis of (+)-
pumiliotoxin B (7) by applying this approach. In this case,
the (E)-vinyl iodide 50 was needed as a C-13-C-17 side
chain fragment for the coupling reaction. Thus, (3S,4R)-
3,4-(isopropylidenedioxy)-2-propanone (49)33 was trans-
formed via iodoolefination using the Takai protocol
(CrCl2, CHI3)28 into the desired (E)-vinyl iodide 50 (56%)
along with the (Z)-isomer (11%). To test the possibility
of exploiting the (E)-iodide 50 for the organozinc-based
cross-coupling reaction, the above-described alkylzinc
chloride 44 was allowed to react with 50 under catalytic
Pd(PPh3)4 in a manner similar to that described above
for the coupling reaction of the (E)-vinyl iodide 42 with
the alkylzinc 44. However, this procedure resulted in the
formation of the desired coupled product 51 in low yield
(28%) together with a complex mixture (Scheme 9).
The low yield in the formation of the cross-coupled
product 51 was presumably due to accompanying cleav-
age of the isopropylidene acetal group by a Lewis acidic
zinc halide (IZnCl), which would be generated during the
coupling process corresponding to the transmetalation
between the palladium(II) complex, R′PdIL2, and alkyl-
zinc chloride, RZnCl, as indicated in eq 1 wherein X )
Cl.34 An alternative coupling approach was then consid-
ered, and it was envisioned that the generation of the
zinc halide, IZnCl, could be avoided by use of diorgano-
zincs, R2Zn (X ) R in eq 1), which are claimed to be more
reactive than organozinc halides and undergo transmeta-
lation reactions more readily.35 Nevertheless, only few
reports36 concerning the palladium-catalyzed37 cross-
coupling reaction using the diorganozinc reagents have
been published, and application of this reaction to
construction of complex molecules such as natural prod-
ucts had never been described.38 However, recent reports
by Smith et al.39 demonstrated in natural product syn-
product 47 in 60% yield from 34 with complete retention
of configuration of the stereocenter(s) and (Z)-geometry
(Scheme 8). When deprotection of the TBDMS group of
47 was carried out using tetrabutylammonium fluoride
in DMF at 60 °C, the reaction was very slow and was
not complete after 2 days, resulting in 66% yield of the
secondary alcohol 48 along with 18% recovery of 47.
However, the use of triethylamine tris(hydrogen fluo-
ride)31 (MeCN, 60 °C, 24 h) proved to be effective for the
silyl deprotection and provided 48 ([R]22 -2.7 (c 0.59,
D
CHCl3), lit.5c [R]25 -2.1 (c 0.70, CHCl3)) in 88% yield.
D
Subsequent cleavage of the benzyl ether through the
Overman protocol (Li, NH3, MeOH)5b produced (+)-
pumiliotoxin A (6) ([R]25 +16.7 (c 0.84, CHCl3), lit.5b
D
[R]23 +14.9 (c 0.65, CHCl3)). The H and 13C NMR data
of synthetic 6 were identical with those of natural
1
D
pumiliotoxin A.32
Syn th esis of (+)-P u m iliotoxin B. Having achieved
the total synthesis of (+)-pumiliotoxin A (6) based on the
homoallyl-vinyl cross-coupling strategy utilizing the (Z)-
iodoalkylidene indolizidine 34 as a key intermediate, we
(31) Review: McClinton, M. A. Aldrichim. Acta 1995, 28, 31-35.
(32) Tokuyama, T.; Daly, J . W.; Highet, R. J . Tetrahedron 1984, 40,
1183-1190.
(33) For the preparation of 49, see the literature cited in ref 20.
(34) Cf. ref 29b.
(35) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117-2188.
J . Org. Chem, Vol. 67, No. 16, 2002 5521

Aoyagi et al.
SCHEME 10
thesis the efficiency of a functionalized dialkylzinc de-
rivative for the alkyl-vinyl coupling based on the modified
Negishi cross-coupling reaction.
In view of this protocol, we considered employing the
dialkylzinc instead of the alkylzinc chloride for the cross-
coupling reaction of the vinyl iodide 50. Hence, the mixed
dialkylzinc 52 was prepared in situ by addition of a THF
solution containing 1 equiv of ZnCl2 to a solution of the
alkyl iodide 43 in ether at -90 °C followed by addition
of 3 equiv of t-BuLi. After being warmed to room
temperature, the resulting mixture was treated with the
(E)-vinyl iodide 50 along with Pd(PPh3)2 catalyst, fur-
nishing the cross-coupled product 51 in 50% yield (Scheme
9).
With these results, we were poised to incorporate the
homoallyl-vinyl coupling utilizing the diorganozinc for the
synthesis of pumiliotoxin B (7). Accordingly, we subjected
the (Z)-iodoalkylidene indolizidine 34 as the homoallylic
fragment to the same conditions (1 equiv of ZnCl2, and
then 3 equiv of t-BuLi) used above in the preparation of
the dialkylzinc 52, leading to the in situ formation of the
homoallyl-tert-butyl organozinc intermediate 53 (Scheme
10). Subsequent treatment with the (E)-vinyl iodide 50
under the palladium(0) catalyst resulted in the desired
cross-coupled product 54 in 51% yield. Deprotection of
the TBDMS group with Et3N‚3HF gave the free second-
ary alcohol 55, which was then treated with hydrochloric
acid to remove the acetonide protecting group to provide
(+)-pumiliotoxin B (7) ([R]26D +22.1 (c 0.34, MeOH), lit.5e
[R]20D +20.1 (c 1.0, MeOH)), which gave spectral data (IR,
on a palladium(0)-based cross-coupling reaction employ-
ing homoallylic zinc molecules derived from the (Z)-
iodoalkylidene indolizidine which served as an advanced
common synthetic intermediate, leading to an efficient
approach to the asymmetric synthesis of (+)-pumiliotox-
ins A and B. To the best of our knowledge, this study
provides the first example of utilization of highly func-
tionalized nitrogenous organozinc derivatives in the
homoallylic cross-coupling strategy for the natural prod-
ucts synthesis.40
1
MS, and H and 13C NMR) identical with those reported
in the literature.5b
Exp er im en ta l Section
ter t-Bu tyl (2S)-2-[(1S,5S)-5-{[ter t-Bu tyl(d ip h en yl)silyl]-
oxy}-1-h yd r oxy-1,5-d im et h yl-3-h exyn yl]-1-p yr r olid in e-
ca r boxyla te (23). To a solution of 20 (157 mg, 0.736 mmol)
in CH2Cl2 (4 mL) was added trifluoroacetic acid (588 mg, 5.16
mmol). The mixture was stirred at room temperature for 3 h
and then concentrated in vacuo to give (S)-2-acetylpyrrolidine
trifluoroacetate (13‚TFA) as a pale yellow oil. The trifluoro-
acetate obtained was redissolved in CH2Cl2 (2 mL) and then
added to a solution of HfCl4 (708 mg, 2.21 mmol) in CH2Cl2 (3
mL) at -78 °C. After stirring for 30 min, a solution of 19 (1.04
g, 2.21 mmol) in CH2Cl2 (2 mL) was added dropwise over 5
min, and the reaction mixture was allowed to warm very
slowly to 0 °C over 2 h. To this was added 30% aqueous K2-
CO3 (5 mL) followed by di-tert-butyl dicarbonate (482 mg, 2.21
mmol). After being stirred at room temperature for 12 h, the
mixture was extracted with CHCl3 (3 × 30 mL). The combined
extracts were washed with water (10 mL) and brine (20 mL),
dried (MgSO4), and concentrated in vacuo. Purification of the
residual oil by chromatography (20:1 hexane-AcOEt) provided
23 (374 mg, 92%) as a colorless oil: [R]24D -26.6 (c 0.28, CHCl3);
IR (neat) 3348, 1666 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.11
Con clu sion
The new strategy developed herein has served to
demonstrate the potential of the homoallyl-vinyl coupling
protocol for a general entry into the convergent asym-
metric synthesis of the pumiliotoxin alkaloids. It relies
(36) (a) Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 83-
86. (b) Nakamura, E.; Sekiya, K.; Kuwajima, I. Tetrahedron Lett. 1987,
28, 337-340. (c) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.;
Kuwajima, I. J . Am. Chem. Soc. 1987, 109, 8056-8066.
(37) In these coupling reactions between the zinc homoenolate and
aryl (or vinyl) halides, the Pd(II)Cl2 has been used as a catalyst instead
of Pd(0).
(38) For some recent examples of applications of palladium-catalyzed
couplings using organozinc halides in natural products synthesis,
see: (a) Wipf, P.; Lim, S. J . Am. Chem. Soc. 1995, 117, 558-559. (b)
Amat, M.; Hadida, S.; Pshenichnyi, G.; Bosch, J . J . Org. Chem. 1997,
62, 3158-3175. (c) Smith, A. B., III; Friestad, G. K.; Duan, J . J .-W.;
Barbosa, J .; Hull, K. G.; Iwashima, M.; Qiu, Y.; Spoors, P. G.;
Bertounesque, E.; Salvatore, B. A. J . Org. Chem. 1998, 63, 7596-7597.
(d) Hu, T.; Panek, J . S. J . Org. Chem. 1999, 64, 3000-3001. (e) Sasaki,
M.; Koike, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett. 2000, 41,
3923-3926. (f) Masaki, H.; Mizozoe, T.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Tetrahedron Lett. 2000, 41, 4801-4804. (g) Thompson,
C. F.; J amison, T. F.; J acobsen, E. N. J . Am. Chem. Soc. 2001, 123,
9974-9983.
(40) Only
a limited number of applications of the palladium-
catalyzed homoallyl-alkenyl coupling strategy in natural product
synthesis have been published, using non-nitrogenous homoallylic zinc
halides. See ref 14 and also: (a) McMurry, J . F.; Bosch, G. K. J . Org.
Chem. 1987, 52, 4885-4893. (b) Asao, K.; Iio, H.; Tokoroyama, T.
Tetrahedron Lett. 1989, 30, 6401-6404. (c) William, D. R.; Kissel, W.
S. J . Am. Chem. Soc. 1998, 120, 11198-11199.
(39) (a) Smith, A. B., III; Qiu, Y.; J ones, D. R.; Kobayashi, K. J . Am.
Chem. Soc. 1995, 117, 12011-12012. (b) Smith, A. B., III; Beauchamp,
T. J .; LaMarche, M. J .; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; J ones,
D. R.; Kobayashi, K. J . Am. Chem. Soc. 2000, 122, 8654-8664.
5522 J . Org. Chem., Vol. 67, No. 16, 2002

Convergent Approach to Pumiliotoxin Alkaloids
(9H, s), 1.09 (3H, s), 1.21 (3H, d, J ) 6.8 Hz), 1.46 (9H, s),
1.60-1.87 (3H, m), 2.03 (1H, br s), 2.30 and 2.35 (2H, AB q, J
) 16.8 Hz), 2.61-2.72 (1H, m), 3.17 (1H, ddd, J ) 11.0, 7.2,
7.2 Hz), 3.52 (1H, A part of ABX, J ) 9.5, 7.9 Hz), 3.63 (1H,
br s), 3.72 (1H, B part of ABX, J ) 9.5, 5.5 Hz), 4.05 (1H, dd,
J ) 7.8, 5.7 Hz), 5.68 (1H, br s), 7.35-7.44 (6H m), 7.66-7.69
(4H, m,); 13C NMR (100.6 MHz, CDCl3) δ 17.8, 19.3, 22.1, 24.3,
26.9, 28.3, 28.5, 29.2, 31.4, 48.2, 65.4, 68.0, 74.8, 77.5, 80.5,
84.3, 127.7, 129.6, 133.8, 135.6, 157.7; CIMS (isobutane) m/z
550 (MH+); EIMS m/z (rel intensity) 549 (M+, 0.02), 448 (0.7),
436 (5), 392 (17), 379 (6), 358 (11), 314 (10), 199 (18), 135 (14),
114 (100). Anal. Calcd for C33H47NO4Si: C, 72.09; H, 8.62; N,
2.55. Found: C, 71.74; H, 8.52; N, 2.62.
54.3, 64.8, 67.3, 77.1, 80.5, 98.7, 127.6, 129.5, 133.8, 135.7,
142.8, 158.1; CIMS (isobutane) m/z 678 (MH+); EIMS m/z (rel
intensity) 677 (M+, 0.2), 620 (0.4), 576 (6), 564 (14), 520 (100),
486 (69), 429 (48). Anal. Calcd for C33H48INO4Si: C, 58.48; H,
7.14; N, 2.07. Found: C, 58.13; H, 7.06; N, 1.99.
ter t-Bu tyl (2S)-2-[(2S,4Z)-4-((2S)-3-{[ter t-Bu tyl(d ip h en -
yl)silyl]oxy}-2-m et h ylp r op ylid en e)-2-m et h yl-5-oxot et -
r a h yd r o-2-fu r a n yl]-1-p yr r olid in eca r boxyla te (28). To a
solution of 27 (409 mg, 0.603 mmol) in hexamethylphosphora-
mide (6.0 mL) were added palladium(II) acetate (3.0 mg, 0.012
mmol), triphenylphosphine (16.0 mg, 0.0603 mmol), and tribu-
tylamine (134 mg, 0.723 mmol). The air in the reaction vessel
was evacuated, and a balloon of carbon monoxide gas was
attached. The mixture was heated to 100 °C and stirred for 4
h. After being cooled, the mixture was diluted with AcOEt (100
mL) and washed successively with 1 N aqueous HCl (10 mL),
water (3 × 10 mL), and brine (10 mL). The organic layer was
dried (MgSO4), concentrated in vacuo, and chromatographed
(10:1 hexane-AcOEt) to afford 28 (338 mg, 97%) as a colorless
ter t-Bu tyl (2S)-2-[(1S,3Z,5S)-6-{[ter t-Bu tyl(d ip h en yl)-
silyl]oxy}-1-h yd r oxy-1,5-d im eth yl-3-(tr ip h en ylsta n n yl)-
3-h exyn yl]-1-p yr r olid in eca r boxyla te (25). To a solution of
23 (708 mg, 1.29 mmol) in benzene was added triphenyltin
hydride (2.26 g, 6.44 mmol) followed by triethylborane (1.06
M solution in hexane, 0.608 mL, 0.644 mmol), and the mixture
was stirred at room temperature. After 5 days, the mixture
was diluted with AcOEt (100 mL), washed with water (10 mL)
and brine (10 mL), and dried (MgSO4). Removal of the solvent
by evaporation in vacuo followed by chromatography (100:1
hexane-AcOEt) afforded 25 (707 mg, 60%) as a white amor-
oil: [R]28 -32.2 (c 0.52, CHCl3); IR (neat) 1755, 1688 cm-1
;
D
1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 1.10 (3H, d, J ) 6.6
Hz), 1.26 (6H, br s), 1.37 (3H, br s), 1.44 (3H, br s), 1.71 (1H,
br s), 1.88 (1H, br s), 1.95-2.12 (2H, br m), 2.48 (1H, dd, J )
16.4, 1.9 Hz), 2.92 (1H, br s), 3.30-3.65 (4H, m, including dd
at 3.59 ppm, J ) 9.5, 4.5 Hz), 3.90 (1H, br s), 4.00 (1H, d, J )
8.3 Hz), 5.95 (1H, d, J ) 9.9 Hz), 7.35-7.41 (6H, m), 7.65-
7.67 (4H, m); 13C NMR (100.6 MHz, CDCl3) δ 17.2, 19.3, 24.7,
25.2, 26.5, 26.9, 28.3, 28.5, 34.3, 39.0, 47.3, 63.2, 67.8, 79.7,
85.8, 126.3, 127.6, 129.5, 133.6, 133.9, 135.7, 143.0, 156.4,
169.0; CIMS (isobutane) m/z 578 (MH+); EIMS m/z (rel
intensity) 578 (M+ + 1, 0.1), 521 (0.2), 504 (2), 464 (58), 446
(18), 420 (23), 402 (12), 386 (26), 342 (45), 204 (33), 199 (39),
170 (18), 135 (42), 114 (100). Anal. Calcd for C34H47NO5Si: C,
70.67; H, 8.20; N, 2.42. Found: C, 70.43; H, 8.08; N, 2.39.
phous powder: [R]26 +21.4 (c 0.43, CHCl3); IR (neat) 3303,
D
1663 cm-1; H NMR (400 MHz, CDCl3) δ 0.94 (3H, d, J ) 6.5
1
Hz), 1.05 (3H, s), 1.07 (9H, s), 1.48 (9H, s), 1.50-1.76 (3H, m),
1.94 (1H, br s), 2.42 and 2.60 (2H, AB q, J ) 12.5 Hz), 2.44-
2.61 (1H, m), 3.04 (1H, br s), 3.45 (2H, s), 3.58 (1H, br s), 3.80
(1H, br t, J ) 7.0 Hz), 5.43 (1H, br s), 6.25 (1H, d, J ) 9.9 Hz,
J Sn-H ) 89.3 Hz) 7.33-7.46 (15H, m), 7.61-7.75 (10H, m); 13
C
NMR (100.6 MHz, CDCl3) δ 17.8, 19.3, 21.3, 24.2, 26.9, 28.0,
28.4, 41.9, 48.1, 49.2, 66.2, 68.4, 76.9, 80.2, 127.5, 127.9, 128.1,
128.3, 129.4, 133.8, 134.0, 135.7, 137.2, 137.4, 137.6, 141.9,
149.2, 157.7; EIMS m/z (rel intensity) 824 (M+ - Ph, Sn120
,
(3Z,5S)-3-((2S)-3-{[ter t-Bu tyl(d ip h en yl)silyl]oxy}-2-m e-
th ylp r op ylid en e)-5-m eth yl-5-[(2S)-p yr r olid in yl]d ih yd r o-
2(3H)-fu r a n on e (29). To a solution of 28 (693 mg, 1.20 mmol)
in CH2Cl2 (8.0 mL) was added trifluoroacetic acid (1.37 g, 12.0
mmol), and the resulting solution was stirred at room tem-
perature. After 2 h, the mixture was made basic by addition
of 30% aqueous K2CO3 (10 mL) and extracted with CHCl3 (3
× 50 mL). The combined extracts were washed with brine (10
mL), dried (MgSO4), and concentrated in vacuo. Purification
of the residual oil by chromatography (700:10:1 CHCl3-
MeOH-29% NH4OH) provided 29 (534 mg, 93%) as a colorless
11), 822 (M+ - Ph, Sn118, 9), 724 (6), 653 (100). Anal. Calcd
for C51H63NO4SiSn: C, 68.00; H, 7.05; N, 1.55. Found: C,
67.71; H, 6.99; N, 1.62.
Further elution provided the (Z)-4′-stannyl regioisomer 26
(1.29 g, 28%) as a white amorphous powder: [R]26 -41.7 (c
D
0.44, CHCl3); IR (neat) 3349, 1663 cm-1; H NMR (400 MHz,
1
CDCl3) δ 0.72 (3H, s), 1.02 (9H, s), 1.09 (3H, d, J ) 6.7 Hz),
1.34-1.50 (4H, m), 1.45 (9H, s), 2.08-2.17 (2H, m), 2.81 (1H,
sextet, J ) 6.7 Hz), 2.94 (1H, dt, J ) 10.6, 7.0 Hz), 3.45 (1H,
dd, J ) 9.6, 7.7 Hz), 3.49 (1H, br s), 3.66-3.70 (2H, m), 6.00
(1H, br s), 6.76 (1H, br s, J Sn-H ) 88.7 Hz), 7.28-7.43 (15H,
m), 7.48-7.63 (10H, m); 13C NMR (100.6 MHz, CDCl3) δ 18.3,
19.3, 20,8, 24.0, 26.9, 27.8, 28.4, 45.1, 46.8, 48.1, 66.2, 68.6,
75.7, 80.5, 127.5, 127.6, 128.2, 128.5, 128.7, 129.4, 134.0, 135.6,
137.0, 137.2, 137.4, 139.4, 139.9, 145.3, 158.0; EIMS m/z (rel
intensity) 824 (M+ - Ph, Sn120, 4), 822 (M+ - Ph, Sn118, 3),
770 (6), 750 (11), 653 (100). Anal. Calcd for C51H63NO4SiSn:
C, 68.00; H, 7.05; N, 1.55. Found: C, 67.63; H, 7.14; N, 1.61.
oil: [R]28 +36.4 (c 1.06, CHCl3); IR (neat) 3361, 1749 cm-1
;
D
1H NMR (400 MHz, CDCl3) δ 1.040 (3H, d, J ) 6.6 Hz), 1.043
(9H, s), 1.38 (3H, s), 1.47-1.57 (1H, m), 1.71-1.89 (3H, m),
2.55 (1H, dd, J ) 16.3, 2.2 Hz), 2.83-2.95 (3H, m), 3.17 (1H,
t, J ) 7.8 Hz), 3.58 (1H, A part of ABX, J ) 9.7, 6.1 Hz), 3.61
(1H, B part of ABX, J ) 9.7, 5.3 Hz), 3.89-3.99 (1H, m), 6.05
(1H, dt, J ) 10.0, 2.2 Hz), 7.35-7.44 (6H, m), 7.63-7.68 (4H,
m); 13C NMR (100.6 MHz, CDCl3) δ 16.8, 19.4, 24.2, 26.0, 26.5,
26.9, 34.1, 38.8, 47.2, 65.6, 68.2, 84.4, 125.9, 127.7, 129.6, 133.8,
135.7, 146.1, 169.2; CIMS (isobutane) m/z 478 (MH+); EIMS
m/z (rel intensity) 477 (M+, 0.4), 420 (8), 342 (4), 204 (9), 199
(10), 135 (13), 70 (100); HRMS (EI) calcd for C29H39NO3Si (M+)
477.2699, found 477.2703.
ter t-Bu tyl (2S)-2-[(1S,3Z,5S)-6-{[ter t-Bu tyl(d ip h en yl)-
silyl]oxy}-1-h yd r oxy-3-iod o-1,5-d im et h yl-3-h exyn yl]-1-
p yr r olid in eca r boxyla te (27). To an ice-cooled, stirred solu-
tion of 25 (656 mg, 0.728 mmol) in CH2Cl2 (7.3 mL) was added
solid N-iodosuccinimide (492 mg, 2.18 mmol) in one portion.
After being stirred for 30 min, the mixture was diluted with
Et2O (150 mL), washed successively with 5% aqueous NaHSO3
(10 mL), water (10 mL), and brine (10 mL), and dried (MgSO4).
After concentration in vacuo, the residue was purified by
chromatography (20:1 hexane-AcOEt) to give 27 (409 mg,
(3Z,5S)-3-((2S)-3-{[ter t-Bu tyl(d ip h en yl)silyl]oxy}-2-m e-
t h ylp r op ylid en e)-4-[(2S)-p yr r olid in yl]-1,4-p en t a n ed iol
(30). To a cooled (-30 °C), stirred solution of 29 (449 mg, 0.940
mmol) in toluene (7 mL) was added dropwise diisobutylalu-
minum hydride (1.01 M solution in toluene, 2.79 mL, 2.82
mmol). After the mixture was stirred at -30 °C for 30 min,
30% aqueous K2CO3 (1 mL) was added, and the mixture was
stirred at room temperature for 1 h. The resulting cloudy
solution was dried over MgSO4, filtered, and concentrated in
vacuo to give a crude oil, which was purified by chromatog-
raphy (300:10:1 CHCl3-MeOH-29% NH4OH) to provide 30
83%) as a colorless oil: [R]26 +5.3 (c 0.57, CHCl3); IR (neat)
D
3345, 1665 cm-1; H NMR (400 MHz, CDCl3) δ 1.06 (12H, s),
1
1.07 (3H, d, J ) 6.3 Hz), 1.47 (9H, s), 1.66-1.77 (2H, m), 1.78-
1.91 (1H, m), 1.99-2.09 (1H, m), 2.67-2.85 (3H, m), 3.23 (1H,
dt, J ) 11.0, Hz), 3.54-3.65 (3H, m, including dd at 3.56 ppm,
J ) 9.7, 6.4 Hz, and dd at 3.63 ppm, J ) 9.7, 5.8 Hz), 4.05
(1H, dd, J ) 8.1, 3.7 Hz), 5.41 (1H, br s), 5.61 (1H, d, J ) 8.1
Hz) 7.36-7.43 (6H, m), 7.67-7.69 (4H, m); 13C NMR (100.6
MHz, CDCl3) δ 16.0, 19.3, 22.4, 24.3, 26.9, 28.5, 44.8, 48.2,
(321 mg, 71%) as a colorless oil: [R]24 -4.0 (c 0.53, CHCl3);
D
IR (neat) 3307 cm-1; H NMR (400 MHz, CDCl3) δ 0.98 (3H,
1
d, J ) 6.7 Hz), 1.05 (9H, s), 1.09 (3H, s), 1.49-1.66 (2H, m),
J . Org. Chem, Vol. 67, No. 16, 2002 5523

Aoyagi et al.
1.70-1.79 (2H, m), 2.24 and 2.30 (2H, AB q, J ) 13.6 Hz),
2.75-2.85 (3H, m), 3.05 (1H, dd, J ) 8.1, 7.2 Hz), 3.47 (1H, A
part of ABX, J ) 9.7, 6.9 Hz), 3.52 (1H, B part of ABX, J )
9.7, 6.1 Hz), 3.8 (2H, br), 4.06 and 4.17 (2H, AB q, J ) 12.4
Hz), 5.11 (1H, d, J ) 9.5 Hz), 7.36-7.44 (6H, m), 7.65-7.67
(4H, m); 13C NMR (100.6 MHz, CDCl3) δ 17.7, 19.3, 23.6, 26.6,
26.7, 26.9, 35.2, 46.8, 49.9, 61.3, 66.0, 68.8, 73.0, 127.6, 129.6,
133.8, 135.4, 135.6, 136.4; CIMS (isobutane) m/z 482 (MH+);
EIMS m/z (rel intensity) 481 (M+, 0.3), 424 (9), 406 (6), 199
J ) 12.4 Hz), 2.60-2.71 (1H, m), 3.00-3.04 (1H, m), 3.38 and
3.42 (2H, AB q, J ) 10.2 Hz), 3.68 (1H, d, J ) 12.0 Hz), 4.85
(1H, d, J ) 9.4 Hz), 7.34-7.43 (6H, m), 7.64-7.66 (4H, m);
13C NMR (100.6 MHz, CDCl3) δ -1.7, 17.5, 18.6, 19.3, 21.3,
23.5, 26.2, 26.9, 28.0, 34.9, 48.3, 52.8, 54.5, 68.9, 72.5, 72.8,
127.6, 128.3, 129.5, 133.3, 134.1, 135.7; EIMS m/z (rel inten-
sity) 577 (M+, 10), 520 (9), 388 (3), 280 (100), 176 (10), 135
(16); HRMS (EI) calcd for C35H55NO2Si2 (M+) 577.3771, found
577.3793.
(15), 137 (11), 114 (15), 70 (100); HRMS (EI) calcd for C29H43
-
(2S,3Z)-3-((8S,8a S)-8-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-
8-m eth ylh exa h yd r o-6(5H)-in d olizin ylid en e)-2-m eth yl-1-
p r op a n ol (33). To an ice-cooled, stirred solution of 32 (241
mg, 0.417 mmol) in DMF (2.6 mL) was added tris(dimethyl-
amino)sulfur (trimethylsilyl)difluoride (1.30 M solution in
DMF, 0.481 mL, 0.625 mmol), and the resulting solution was
stirred at 0 °C for 1 h and then at room temperature for an
additional 6 h. After addition of saturated aqueous NaHCO3
(10 mL) followed by extraction with AcOEt (3 × 40 mL), the
combined extracts were washed with brine (10 mL), dried
(MgSO4), and concentrated in vacuo to give a residue, which
was purified by chromatography (300:10:1 CHCl3-MeOH-
29% NH4OH) to provide 33 (120 mg, 85%) as a colorless oil:
NO3Si (M+) 481.3012, found 481.3017.
(6Z,8S,8a S)-6-((2S)-3-{[ter t-Bu tyl(d ip h en yl)silyl]oxy}-
2-m eth ylp r op ylid en e)-8-m eth ylocta h yd r o-8-in d olizin ol
(31). To an ice-cooled, stirred solution of 30 (51.0 mg, 0.106
mmol) in CH2Cl2 (0.7 mL) was added triphenylphosphine (42.0
mg, 0.159 mmol) followed by carbon tetrabromide (49.0 mg,
0.148 mmol). After being stirred at room temperature for 1 h,
the mixture was diluted with CHCl3 (50 mL), washed with 1
N aqueous NaOH (3 mL) and brine (10 mL), and dried
(MgSO4). Evaporation of the solvent in vacuo and purification
of the residue by chromatography (500:50:1 CHCl3-MeOH-
29% NH4OH) provided 31 (42.0 mg, 85%) as a colorless oil:
[R]24 +25.6 (c 1.14, CHCl3); IR (neat) 3507, 2787 cm-1
;
1H
[R]24 -21.4 (c 0.45, CHCl3); IR (neat) 3331, 2774 cm-1 1H
;
D
D
NMR (400 MHz, CDCl3) δ 1.01 (3H, d, J ) 6.7 Hz), 1.04 (9H,
s), 1.12 (3H, s), 1.61-1.73 (4H, m), 1.90-1.98 (1H, m), 2.06
and 2.14 (2H, AB q, J ) 13.7 Hz), 2.10-2.21 (1H, m), 2.24
(1H, d, J ) 12.0 Hz), 2.55-2.68 (2H, m), 2.79-3.07 (1H, m),
3.38 (1H, A part of ABX, J ) 9.7, 6.5 Hz), 3.43 (1H, B part of
ABX, J ) 9.7, 7.1 Hz), 3.65 (2H, d, J ) 12.0 Hz), 5.02 (1H, d,
J ) 9.3 Hz), 7.35-7.44 (6H, m), 7.63-7.65 (4H, m); 13C NMR
(100.6 MHz, CDCl3) δ 17.7, 19.3, 21.1, 23.2, 24.3, 26.9, 35.0,
48.8, 53.2, 54.6, 68.4, 68.7, 71.7, 127.6, 129.6, 130.8, 132.2,
134.0, 135.6; CIMS (isobutane) m/z 464 (MH+); EIMS m/z (rel
intensity) 463 (M+, 5), 406 (10), 328 (2), 199 (13), 166 (100).
NMR (400 MHz, CDCl3) δ 0.08 (3H, s), 0.09 (3H, s), 0.85 (9H,
s), 0.96 (3H, d, J ) 6.7 Hz), 1.17 (3H, s), 1.59-1.80 (4H, m),
1.94 (1H, dd, J ) 7.6, 6.4 Hz), 2.10-2.21 (1H, m), 2.11 and
2.27 (2H, AB q, J ) 14.4 Hz), 2.49 (1H, d, J ) 12.2 Hz), 2.63-
2.74 (1H, m), 3.00-3.06 (1H, m), 3.27 (1H, A part of ABX, J )
10.4, 8.3 Hz), 3.45 (1H, B part of ABX, J ) 10.4, 5.7 Hz), 3.80
(1H, d, J ) 12.2 Hz), 4.89 (1H, d, J ) 9.5 Hz); 13C NMR (100.6
MHz, CDCl3) δ -1.7, 17.1, 18.6, 21.3, 23.5, 26.1, 28.0, 35.0,
48.3, 52.6, 54.5, 68.0, 72.3, 72.9, 127.9, 135.3; EIMS m/z (rel
intensity) 339 (M+, 24), 324 (8), 282 (60), 207 (53), 176 (100),
84 (97); HRMS (EI) calcd for C19H37NO2Si (M+) 339.2594, found
339.2577.
(6Z,8S,8a S)-8-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-6-[(2S)-
3-iod o-2-m eth ylp r op ylid en e]-8-m eth ylocta h yd r oin d oliz-
in e (34). To an ice-cooled, stirred solution of 33 (241 mg, 0.417
mmol) in CH2Cl2 (1.5 mL) were successively added imidazole
(30.0 mg 0.442 mg), triphenylphosphine (116 mg, 0.368 mmol),
and iodine (93.0 mg, 0.368 mmol), and the mixture was
warmed to room temperature. After the mixture was stirred
for 8 h, saturated aqueous Na2SO3 (5 mL) was added, and the
mixture was extracted with AcOEt (4 × 10 mL). The combined
extracts were washed with saturated aqueous Na2SO3 (3 mL)
followed by brine (3 mL) and dried (MgSO4). Concentration in
vacuo followed by purification by chromatography (1500:30:1
CHCl3-MeOH-29% NH4OH) provided 34 (63.0 mg, 95%) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.07 (3H, s), 0.08
(3H, s), 0.85 (9H, s), 1.09 (3H, d, J ) 6.5 Hz), 1.16 (3H, s),
1.60-1.80 (4H, m), 1.86-1.93 (1H, m), 2.08-2.16 (1H, m), 2.10
and 2.26 (2H, AB q, J ) 14.0 Hz), 2.48 (1H, d, J ) 12.3 Hz),
2.65-2.75 (1H, m), 3.01-3.05 (1H, m), 3.05 (2H, d, J ) 6.6
Hz), 3.74 (1H, d, J ) 12.3 Hz), 4.89 (1H, d, J ) 9.2 Hz); 13C
NMR (100.6 MHz, CDCl3) δ -1.7, 15.9, 18.6, 21.3, 21.6, 23.4,
26.1, 27.9, 34.5, 48.2, 52.8, 54.6, 72.4, 72.7, 128.7, 134.3.
(6Z,8S,8a S)-6-[(2R,4E,6S)-6-(Ben zyloxy)-2,5-d im eth yl-
4-octen ylid en e]-8-{[ter t-bu tyl(d im eth yl)silyl]oxy}-8-m e-
th ylocta h yd r oin d olizin e (47). A pentane solution of t-BuLi
(1.54 M, 0.122 mL, 0.188 mmol) was added to cooled (-110
°C) Et2O (0.20 mL), and to this solution was added a solution
of 34 (42.0 mg, 0.0934 mmol) in Et2O (0.20 mL). After the
mixture was stirred at -110 °C for 30 min, zinc chloride (0.50
M solution in THF, 0.187 mL, 0.0935 mmol) was introduced
slowly and the resulting mixture was allowed to warm slowly
to room temperature over 2 h. To this mixture was added a
solution containing 42 (38.0 mg, 0.121 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (10.8 mg, 0.00935 mmol) in
benzene (0.50 mL). After being stirred at room temperature
for 3 h, the mixture was diluted with AcOEt (50 mL), washed
with water (10 mL) and brine (10 mL), dried (MgSO4), and
concentrated in vacuo. The crude product obtained was puri-
(-)-P u m iliotoxin 225F (2). To a stirred solution of 31 (45.0
mg, 0.097 mmol) in THF (1.0 mL) was added tetrabutylam-
monium fluoride (1.0 M solution in THF, 0.194 mL, 0.194
mmol), and the mixture was stirred at room temperature. After
2 h, the mixture was diluted with CHCl3 (50 mL), washed with
brine (5 mL), dried (MgSO4), and concentrated in vacuo. The
crude product obtained was purified by chromatography (400:
10:1 CHCl3-MeOH-29% NH4OH) to afford 2 (18.5 mg, 84%)
as a colorless oil: [R]24D -25.5 (c 0.33, CHCl3); IR (neat) 3407,
1
2794 cm-1; H NMR (400 MHz, CDCl3) δ 0.99 (3H, d, J ) 6.7
Hz), 1.14 (3H, s), 1.64-1.78 (4H, m), 1.97-2.03 (1H, m), 2.15
and 2.20 (2H, AB q, J ) 14.1 Hz), 2.19-2.28 (1H, m), 2.41
(1H, d, J ) 12.0 Hz), 2.62-2.73 (2H, m), 3.04-3.08 (1H, m),
3.29 (1H, A part of ABX, J ) 10.5, 8.2 Hz), 3.46 (1H, B part of
ABX, J ) 10.5, 5.9 Hz), 3.84 (1H, d, J ) 12.0 Hz), 5.04 (1H, d,
J ) 9.5 Hz); 13C NMR (100.6 MHz, CDCl3) δ 17.3, 21.1, 23.2,
24.3, 35.2, 49.0, 53.3, 54.5, 67.8, 68.5, 71.7, 130.3, 134.2; CIMS
(isobutane) m/z 226 (MH+); EIMS m/z (rel intensity) 225 (M+,
11), 194 (16), 166 (79), 112 (16), 70 (100); HRMS (EI) calcd for
C
13H23NO2 (M+) 225.1729, found 225.1720.
(6Z,8S,8a S)-8-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-6-((2S)-
3-{[ter t-bu tyl(d ip h en yl)silyl]oxy}-2-m eth ylp r op ylid en e)-
8-m eth ylocta h yd r oin d olizin e (32). To an ice-cooled, stirred
mixture of 31 (213 mg, 0.459 mmol), 4-(dimethylamino)-
pyridine (6.0 mg, 0.046 mmol), and 2,6-lutidine (151 mg, 1.41
mmol) in CH2Cl2 (1.5 mL) was added tert-butyldimethylsilyl
trifluoromethanesulfonate (364 mg, 1.38 mmol). The resulting
mixture was stirred at 0 °C for 30 min, and the reaction was
quenched by addition of 1 N aqueous NaOH (10 mL). After
extraction with Et2O (3 × 40 mL), the combined extracts were
washed with water (10 mL) and then brine (10 mL), dried
(MgSO4), and concentrated in vacuo. Purification of the residue
by chromatography (750:50:1 CHCl3-MeOH-29% NH4OH)
gave 32 (241 mg, 91%) as a colorless oil: [R]22 +17.5 (c 1.14,
D
CHCl3); IR (neat) 2773 cm-1
;
1H NMR (400 MHz, CDCl3) δ
0.069 (3H, s), 0.074 (3H, s), 0.85 (9 H, s), 1.00 (3H, d, J ) 6.6
Hz), 1.04 (9H, s), 1.14 (3H, s), 1.59-1.82 (5H, m), 2.02 and
2.20 (2H, AB q, J ) 14.5 Hz), 2.02-2.08 (1H, m), 2.28 (1H, d,
5524 J . Org. Chem., Vol. 67, No. 16, 2002

Convergent Approach to Pumiliotoxin Alkaloids
fied by chromatography (1500:30:1 CHCl3-MeOH-29% NH4-
OH) to provide 47 (28.5 mg, 60%) as a colorless oil: [R]21D -4.1
(6Z,8S,8a S)-8-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-8-m eth -
yl-6-{(2R,4E)-2-m et h yl-5-[(4R,5R)-2,2,5-t r im et h yl-1,3-d i-
oxola n -4-yl]-4-h exen ylid en e}oct a h yd r oin d olizin e (54).
To a cooled (-90 °C), stirred solution of 34 (55.0 mg, 0.122
mmol) in Et2O (0.5 mL) was added zinc chloride (0.50 M
solution in THF, 0.244 mL, 0.122 mmol), and the mixture was
stirred at -90 °C. After 30 min, t-BuLi (1.60 M solution in
pentane, 0.229 mL, 0.366 mmol) was added dropwise, and the
resulting mixture was allowed to warm slowly to room tem-
perature over 2 h. The flask was then covered completely with
aluminum foil to afford protection from light, and a solution
containing 50 (25.1 mg, 0.0889 mmol) and tetrakis(triphenyl-
phosphine)palladium(0) (14.1 mg, 0.0122 mmol) in benzene
(0.6 mL) was added. The mixture was stirred in the dark for
3 h and then diluted with Et2O (10 mL) and water (10 mL).
The aqueous layer was separated and extracted with Et2O (3
× 10 mL), and the combined organic layers were washed with
brine (5 mL) and dried (MgSO4). Concentration in vacuo
followed by chromatography (1000:10:1 CHCl3-MeOH-29%
(c 1.05, CHCl3); IR (neat) 2773 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 0.08 (3H, s), 0.09 (3H, s), 0.83 (3H, d, J ) 7.5 Hz),
0.86 (9H, s), 1.00 (3H, d, J ) 6.6 Hz), 1.13 (3H, s), 1.45-1.55
(1H, m), 1.55 (3H, s), 1.61-1.80 (5 H, m), 1.87 (1H, br s), 1.96-
2.16 (3H, m), 2.02 and 2.22 (2H, AB q, J ) 14.4 Hz), 2.43 (1H,
br d, J ) 12.1 Hz), 2.47-2.59 (1H, m), 3.05 (1H, br t, J ) 6.2
Hz), 3.52 (1H, t, J ) 7.0 Hz), 3.80 (1H, d, J ) 12.2 Hz), 4.20
and 4.43 (2H, AB q, J ) 12.0 Hz), 4.94 (1H, d, J ) 9.5 Hz),
5.28 (1H, t, J ) 7.0 Hz), 7.23-7.35 (5H, m); 13C NMR (100.6
MHz, CDCl3) δ -1.72, -1.68, 10.5, 10.7, 18.6, 21.1, 21.3, 23.5,
26.2, 26.5, 28.0, 32.4, 35.8, 48.2, 52.7, 54.5, 69.5, 72.3, 72.8,
87.0, 127.3, 127.7, 127.8, 128.3, 131.1, 131.6, 134.8, 139.3;
CIMS (isobutane) m/z 512 (MH+); EIMS m/z (rel intensity) 511
(M+, 22), 454 (24), 420 (45), 404 (85), 307 (31), 280 (72), 176
(45), 91 (100); HRMS (EI) calcd for C32H53NO2Si (M+) 511.3846,
found 511.3838.
NH4OH) provided 54 (30.0 mg, 51%) as a colorless oil: [R]24
(6Z,8S,8a S)-6-[(2R,4E,6S)-6-(Ben zyloxy)-2,5-d im eth yl-
4-octen ylid en e]-8-m eth ylocta h yd r o-8-in d olizin ol (48). To
a solution of 47 (11.5 mg, 0.0225 mmol) in acetonitrile (4.0
mL) was added triethylamine tris(hydrogen fluoride) (363 mg,
2.25 mmol) followed by Et3N (27 mg, 0.27 mmol). This mixture
was stirred and heated to 60 °C, and stirring was continued
for 24 h. After the mixture was cooled, saturated aqueous
NaHCO3 (5 mL) was added, and the resulting mixture was
extracted with AcOEt (3 × 10 mL). The combined extracts were
washed with brine (5 mL), dried (MgSO4), and concentrated
in vacuo to give a crude oil, which was purified by chroma-
tography (1000:10:1 CHCl3-MeOH-29% NH4OH), affording
48 (7.8 mg, 88%) as a colorless oil: [R]22D -2.7 (c 0.59, CHCl3);
IR (neat) 3507, 2787 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.83
(3H, J ) 7.4 Hz), 1.02 (3H, d, J ) 6.6 Hz), 1.11 (3H, s), 1.45-
1.78 (6H, m), 1.55 (3H, s), 1.93 (1H, m), 1.96-2.10 (2H, m),
2.05 and 2.25 (2H, AB q, J ) 13.9 Hz), 2.16-2.25 (1H, m),
2.34 (1H, d, J ) 11.8 Hz), 2.46-2.57 (1H, m), 2.65 (1H, br s),
3.06 (1H, m), 3.51 (1H, t, J ) 7.0 Hz), 3.79 (1H, d, J ) 11.8
Hz), 4.20 and 4.43 (2H, AB q, J ) 12.0 Hz), 5.10 (1H, d, J )
9.6 Hz), 5.27 (1H, t, J ) 7.1 Hz), 7.24-7.35 (5H, m); 13C NMR
(100.6 MHz, CDCl3) δ 10.4, 10.8, 21.1, 21.4, 23.3, 24.3, 26.5,
32.6, 35.6, 48.9, 53.3, 54.6, 68.4, 69.5, 71.7, 86.9, 127.3, 127.5,
127.7, 128.3, 130.4, 133.9, 135.0, 139.2; CIMS (isobutane) m/z
398 (MH+); EIMS m/z (rel intensity) 397 (M+, 5), 306 (45), 290
(74), 206 (27), 193 (49), 166 (92), 91 (100), 70 (72); HRMS (EI)
calcd for C26H39NO2 (M+) 397.2981, found 397.2987.
D
-14.7 (c 0.91, CHCl3); IR (neat) 2778 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.080 (3H, s), 0.083 (3H, s), 0.85 (9H, s), 0.96 (3H, d,
J ) 6.6 Hz), 1.16 (3H, s), 1.21 (3H, d, J ) 5.7 Hz), 1.42 (6H,
s), 1.62 (3H, s), 1.57-1.80 (5H, m), 1.91-2.17 (4H, m), 2.23
(1H, 1/2AB q, J ) 14.2 Hz), 2.40-2.55 (2H, m), 3.03 (1H, td,
J ) 7.2, 1.0 Hz), 3.77 (1H, d, J ) 12.3 Hz), 3.80-3.90 (2H, m,
including d at 3.84 ppm, J ) 3.3 Hz), 4.93 (1H, d, J ) 9.2 Hz),
5.44 (1H, td, J ) 7.2, 0.7 Hz); 13C NMR (100.6 MHz, CDCl3) δ
-1.72, -1.69, 11.7, 17.1, 18.6, 20.9, 21.3, 23.5, 26.2, 27.0, 27.5,
28.0, 32.2, 35.8, 48.0, 52.2, 54.2, 72.0, 72.9, 74.4, 88.8, 107.9,
128.6, 130.8, 131.5, 131.8; EIMS m/z (relative intensity) 477
(M+, 30), 462 (11), 420 (14), 391 (13), 357 (12), 334 (30), 307
(74), 280 (44), 253 (60), 225 (31), 176 (59), 162 (50), 148 (44),
91 (66), 84 (94), 73 (100); HRMS (EI) calcd for C28H51NO3Si
(M+) 477.3643, found 477.3638.
(6Z,8S,8a S)-8-Met h yl-6-{(2R,4E)-2-m et h yl-5-[(4R,5R)-
2,2,5-t r im et h yl-1,3-d ioxola n -4-yl]-4-h exen ylid en e}oct a -
h yd r o-8-in d olizin ol (55). The silyl ether 54 (28.0 mg, 0.0586
mmol) was treated with triethylamine tris(hydrogen fluoride)
(944 mg, 5.86 mmol) and Et3N (70 mg, 0.69 mmol) as described
above for desilylation of 47. Workup and chromatography (500:
10:1 CHCl3-MeOH-29% NH4OH) afforded 55 (18.0 mg, 85%)
as a colorless oil: [R]27 +6.4 (c 0.88, CHCl3); IR (neat) 3509,
D
2788 cm-1; H NMR (400 MHz, CDCl3) δ 0.98 (3H, d, J ) 6.6
1
Hz), 1.13 (3H, s), 1.20 (3H, d, J ) 5.6 Hz), 1.41 (6H, s), 1.61
(3H, s), 1.64-1.77 (4H, m), 1.91-2.05 (3H, m), 2.09 and 2.14
(2H, AB q, J ) 14.7 Hz), 2.17-2.26 (1H, m), 2.35 (1H, d, J )
11.8 Hz), 2.40-2.53 (1H, m), 2.55-2.75 (1H, br s), 3.06 (1H,
m), 3.77 (1H, d, J ) 11.8 Hz), 3.79-3.89 (2H, m, including d
at 3.84 ppm, J ) 3.2 Hz), 5.08 (1H, d, J ) 9.5 Hz), 5.43 (1H,
td, J ) 7.2, 0.7 Hz); 13C NMR (100.6 MHz, CDCl3) δ 11.7, 17.1,
21.1, 23.2, 24.3, 27.0, 27.5, 32.4, 35.7, 48.8, 53.2, 54.5, 68.4,
71.7, 74.4, 88.7, 107.9, 128.4, 130.4, 131.7, 133.8; EIMS m/z
(relative intensity) 363 (M+, 29), 348 (16), 206 (32), 194 (44),
166 (100), 91 (14), 70 (46); HRMS (EI) calcd for C22H37NO3
(M+) 363.2773, found 363.2782.
(+)-P u m iliotoxin A (6). A solution of 48 (13.4 mg, 0.0337
mmol) in THF (2 mL) was added to liquid NH3 (1 mL) at -78
°C. To this was added excess lithium in several small portions
until the blue color persisted. Once the blue color persisted
for 2 min, the reaction mixture was quenched by addition of
MeOH (0.5 mL) followed by saturated aqueous NH4Cl (1 mL),
and the ammonia was allowed to evaporate at room temper-
ature. To the resulting slurry was added saturated aqueous
NaHCO3 (5 mL), and the mixture was extracted with CHCl3
(3 × 10 mL). The combined extracts were washed with brine
(2 mL), dried (MgSO4), and concentrated in vacuo. The crude
product obtained was purified by chromatography (500:10:1
CHCl3-MeOH-29% NH4OH) to give 6 (8.4 mg, 81%) as a
colorless oil: [R]25D +16.7 (c 0.84, CHCl3); IR (neat) 3421, 2791
cm-1; 1H NMR (400 MHz, CDCl3) δ 0.84 (3H, J ) 7.4 Hz), 0.99
(3H, d, J ) 6.6 Hz), 1.12 (3H, s), 1.49-1.78 (6H, m), 1.56 (3H,
s), 1.88-2.05 (3H, m), 2.08 and 2.14 (2H, AB q, J ) 13.9 Hz),
2.17-2.25 (1H, m), 2.33 (1H, d, J ) 11.8 Hz), 2.42-2.53 (1H,
m), 2.64 (1H, br s), 3.05 (1H, m), 3.77 (1H, d, J ) 11.8 Hz),
3.88 (1H, t, J ) 6.7 Hz), 5.07 (1H, d, J ) 9.5 Hz), 5.30 (1H, t,
J ) 7.1 Hz); 13C NMR (100.6 MHz, CDCl3) δ 10.1, 11.3, 21.1,
21.2, 23.2, 24.3, 27.7, 32.5, 35.5, 48.8, 53.3, 54.6, 68.4, 71.7,
79.5, 125.0, 130.3, 133.8, 137.7; EIMS m/z (rel intensity) 307
(M+, 13), 290 (6), 278 (4), 193 (19), 166 (100), 70 (38); HRMS
(EI) calcd for C19H33NO2 (M+) 307.2511, found 307.2517.
(+)-P u m iliotoxin B (7). To a solution of 55 (16.0 mg,
0.0440 mmol) in THF (0.34 mL) was added 10% aqueous HCl
(0.34 mL) at room temperature. After the mixture was stirred
for 30 min, saturated aqueous NaHCO3 (2 mL) was added, and
the resulting mixture was extracted with CHCl3 (3 × 5 mL).
The combined extracts were washed with brine (3 mL), dried
(MgSO4), and concentrated in vacuo. Purification of the crude
product by chromatography (100:10:1 CHCl3-MeOH-29%
NH4OH) afforded 7 (10.0 mg, 70%) as a colorless oil: [R]26
D
+22.1 (c 0.34, MeOH); IR (neat) 3401, 2793 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 1.00 (3H, d, J ) 6.6 Hz), 1.11 (3H, d, J )
6.2 Hz), 1.13 (3H, s), 1.58 (3H, s), 1.65-1.78 (4H, m), 1.89-
2.07 (3H, m), 2.09 and 2.14 (2H, AB q, J ) 13.8 Hz), 2.18-
2.26 (1H, m), 2.35 (1H, d, J ) 11.8 Hz), 2.44-2.55 (1H, m),
2.65 (1H, br s), 3.05 (1H, m), 3.70 (1H, d, J ) 7.1 Hz), 3.71-
3.80 (2H, m), 5.06 (1H, d, J ) 9.6 Hz), 5.39 (1H, t, J ) 7.2
J . Org. Chem, Vol. 67, No. 16, 2002 5525

Aoyagi et al.
Hz); 13C NMR (100.6 MHz, CDCl3) δ 12.2, 18.9, 21.1, 21.3, 23.2,
24.3, 32.5, 35.5, 48.8, 53.2, 54.5, 68.4, 68.8, 71.7, 82.7, 127.5,
130.5, 133.7, 135.2; EIMS m/z (relative intensity) 323 (M+, 53),
306 (17), 278 (46), 206 (27), 194 (41), 193 (29), 176 (21), 166
(100), 70 (16); HRMS (EI) calcd for C19H33NO3 (M+) 323.2460,
found 323.2457.
istry of Education, Sports and Culture of J apan (No.
10671999) to which we are grateful.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures for the preparation of compounds 17-19,
1
24, 36-42, 45, 50, and 51 and copies of H NMR spectra for
compounds 2, 6, 7, 29-34, 40, 45, 47, 48, 50, (Z)-50, 51, 54,
and 55. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Science Research from the Min-
J O0200466
5526 J . Org. Chem., Vol. 67, No. 16, 2002