Enantioselective total syntheses of allopumiliotoxins 267A, 323B', and 339A. Application of iodide-promoted iminium ion-alkyne cyclizations for forming allopumiliotoxin A alkaloids

Article abstract of DOI:10.1021/ja961640y

A concise, stereocontrolled strategy for the total synthesis of allopumiliotoxin A alkaloids is described. A much improved second generation total synthesis of enantiopure (+)-allopumiliotoxin 267A (3) was accomplished in 10 steps and 11% overall yield from the commercially available oxazolidinone precursor of alcohol 32 and 17 steps and 4% overall yield from N-[(benzyloxy)carbonyl]-L-proline. The first synthesis of (+)-allopumiliotoxin 323B' (4) rigorously confirms the complete stereostructure of 4 and establishes that the major C(15) epimer isolated from dendrobatid frogs has the 15S configuration. The total synthesis of 4 was realized in 5 steps and 17% overall yield from alkyne 39 and aldehyde 20; the synthesis proceeded in 13 steps and 6% overall yield from (S)-2-methyl-1-penten-3-ol and 17 steps and 3.5% overall yield from N-[(benzyloxy)carbonyl]-L-proline, the precursors, respectively, of alkyne 39 and pyrrolidine aldehyde 20.The first total synthesis of allopumiliotoxin 339A (5) also confirmed the full stereostructure of this alkaloid. The synthesis of enantiopure 5 was achieved in 5 steps and 32% overall yield from alkyne 45 and pyrrolidine aldehyde 20; the synthesis proceeded in 17 steps and ~7% overall yield from N-[(benzyloxy)carbonyl]-L-proline and 16 steps and ~6% overall yield from the commercially available oxazolidinone precursor of 45. These syntheses provide the best illustrations to date of the substantial utility of iodide-promoted iminium ion-alkyne cyclizations for constructing highly functionalized nitrogen heterocycles.

Full text of DOI:10.1021/ja961640y

J. Am. Chem. Soc. 1996, 118, 9073-9082
9073
Enantioselective Total Syntheses of Allopumiliotoxins 267A,
323B′, and 339A. Application of Iodide-Promoted Iminium
Ion-Alkyne Cyclizations for Forming Allopumiliotoxin A
Alkaloids
Christian Caderas,1a Renee Lett,1b Larry E. Overman,* Michael H. Rabinowitz,1c
Leslie A. Robinson,1d Matthew J. Sharp,1c and Jeffery Zablocki1e
Contribution from the Department of Chemistry, UniVersity of California,
IrVine, California 92717-2025
ReceiVed May 16, 1996X
Abstract: A concise, stereocontrolled strategy for the total synthesis of allopumiliotoxin A alkaloids is described.
A much improved second generation total synthesis of enantiopure (+)-allopumiliotoxin 267A (3) was accomplished
in 10 steps and 11% overall yield from the commercially available oxazolidinone precursor of alcohol 32 and 17
steps and 4% overall yield from N-[(benzyloxy)carbonyl]-L-proline. The first synthesis of (+)-allopumiliotoxin 323B′
(4) rigorously confirms the complete stereostructure of 4 and establishes that the major C(15) epimer isolated from
dendrobatid frogs has the 15S configuration. The total synthesis of 4 was realized in 5 steps and 17% overall yield
from alkyne 39 and aldehyde 20; the synthesis proceeded in 13 steps and 6% overall yield from (S)-2-methyl-1-
penten-3-ol and 17 steps and 3.5% overall yield from N-[(benzyloxy)carbonyl]-L-proline, the precursors, respectively,
of alkyne 39 and pyrrolidine aldehyde 20. The first total synthesis of allopumiliotoxin 339A (5) also confirmed the
full stereostructure of this alkaloid. The synthesis of enantiopure 5 was achieved in 5 steps and 32% overall yield
from alkyne 45 and pyrrolidine aldehyde 20; the synthesis proceeded in 17 steps and ∼7% overall yield from
N-[(benzyloxy)carbonyl]-L-proline and 16 steps and ∼6% overall yield from the commercially available oxazolidinone
precursor of 45. These syntheses provide the best illustrations to date of the substantial utility of iodide-promoted
iminium ion-alkyne cyclizations for constructing highly functionalized nitrogen heterocycles.
Amphibians have proven to be a rich source of structurally
unique and pharmacologically active alkaloids.2 The majority
of these alkaloids have been isolated from neotropical poison
frogs of the family Dendrobatidae. Several members of the
pumiliotoxin A class of dendrobatid alkaloids, which now
numbers more than 40 alkaloids, display potent cardiotonic and
myotonic activities.2 The pumiliotoxin A alkaloids are char-
acterized by the bicyclic 8-hydroxy-8-methyl-6-alkylidenein-
dolizidine ring system found in pumiliotoxins A (1) and B (2),
the first representatives of this group to be isolated (Figure 1).3
The allopumiliotoxins contain oxidation at both C(7) and C(8)
of the indolizidine ring and are the most complex pumiliotoxin
A alkaloids. As of 1993, 15 alkaloids were recognized as
members of this subgroup of pumiliotoxin A alkaloids.2a
The trans-diaxial arrangement of the 7,8-diol of allopumil-
iotoxins 267A (3), 323B′ (4), 323B′′ (the C(15) epimer of 4),
and 339A (5) was established through 1H NMR studies and the
failure of these alkaloids to form phenyl boronides or react with
periodic acid.4 The cis arrangement of the 7,8-diol is less
X Abstract published in AdVance ACS Abstracts, September 1, 1996.
(1) (a) Postdoctoral fellow of the Swiss National Science Foundation;
current address: CPPS 68/802, Sandoz AG, 4000 Basel, Switzerland. (b)
NIH NRSA Postdoctoral fellow (GM 09850); current address: DuPont
Agricultural Products Division, Elkton Rd., Newark, DE 19714. (c) Current
address: Glaxo Wellcome Research Institute, 5 Moore Drive, Research
Triangle Park, NC 27709. (d) Current address: Ciba-Geigy Pharmaceuticals,
556 Morris Ave., Summit, NJ 07901. (e) NIH NRSA Postdoctoral fellow
(GM 11456); current address: Amgen Boulder Inc., 3200 Walnut St.,
Boulder, CO 80301.
(2) For recent reviews, see: (a) Daly, J. W.; Garraffo, H. M.; Spande,
T. F. Alkaloids 1993, 43, 185. (b) Daly, J. W.; Spande, T. F. In Alkaloids:
Figure 1. Representative pumiliotoxin A alkaloids.
Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New
common.2 The ready formation of a diboronide upon reaction
York, 1986; Vol. 4, Chapter 1.
of allopumiliotoxin 339B (6) with phenylboronic acid as well
(3) Daly, J. W.; Myers, C. W. Science 1967, 156, 970.
(4) Tokuyama, T.; Daly, J. W.; Highet, R. J. Tetrahedron 1984, 40, 1183.
1
as diagnostic H NMR signals demonstrated that this alkaloid
S0002-7863(96)01640-X CCC: $12.00 © 1996 American Chemical Society

9074 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Caderas et al.
has the cis-7,8-diol stereochemistry.2,4 That the side chains of
3-6 are identical to those found in pumiliotoxins 251D, A (1),
Scheme 1
1
and B (2) was surmised initially from correlations of H and
13C NMR spectra.4 The correctness of this assignment for 3
and 6 was confirmed by our initial total syntheses of these
alkaloids.5,6 Allopumiliotoxins containing the trans-diaxial
arrangement of the 7,8-diol display greater biological activity
than their 7R epimers, with allopumiliotoxin 339A (5) being
the only alkaloid of the pumiliotoxin A family to be more
effective than pumiliotoxin B in stimulating sodium influx and
phosphoinositide breakdown in guinea pig cerebral cortical
synaptoneurosomes.7
Since the allopumiliotoxins are found in only minute amounts
in dendrobatid frogs,2 chemical total synthesis has played a role
in their structure elucidation and been essential in providing
samples of natural alkaloids and analogs for pharmacological
studies.7 The first allopumiliotoxin total syntheses were reported
from our laboratories in 1984.5 In these initial syntheses of 3
and 6, an aldol reaction was employed to couple indolizidine
and side chain fragments while thermodynamic equilibration
of an enone intermediate was exploited to establish the proper
stereochemistry of the exocyclic alkylidene side-chain.5,6 How-
ever, this approach did not achieve a practical entry to the
allopumiliotoxin alkaloids. As a result, we turned to the
potential application of iodide-promoted iminium ion-alkyne
cyclizations for constructing the allopumiliotoxins, since ef-
ficient syntheses of several simpler pumiliotoxin A alkaloids
had been realized in this way.8 In 1992, we reported the first
total synthesis of (+)-allopumiliotoxin 339A (5) using an iodide-
promoted iminium ion-alkyne cyclization as the key step.9 This
synthesis confirmed the full stereostructure of 5 and provided
the first practical sequence for obtaining useful amounts of the
allopumiliotoxins. In this paper, we summarize the evolution
of this improved approach for preparing the allopumiliotoxin
alkaloids and document with full details enantioselective total
syntheses of (+)-allopumiliotoxin 267A (3), (+)-allopumil-
iotoxin 323B′ (4), and (+)-allopumiliotoxin 339A (5).6,10
Scheme 2
Results and Discussion
Synthesis Plan. A plan for assembling allopumiliotoxins that
contain the trans-diaxial arrangement of the 7,8-diol is sum-
marized in Scheme 1. The central issue in this strategy is the
viability of the pivotal iodide-promoted iminium ion-alkyne
cyclization (8 f 7) with substrates containing a potentially labile
and inductively deactivating propargylic hydroxyl group. The
cyclization precursor 8 would come from combination of a
proline-derived aldehyde unit 9 with a side-chain acetylide
nucleophile. If the C(8) alkoxy substituent of 9 was engaged
through chelate organization, the desired R stereochemistry at
C(7) would result from this coupling step.
Preparation of Pyrrolidine Aldehyde 20. After preliminary
examination of several possibilities for the pyrrolidine aldehyde
fragment, 20 emerged as a viable formulation (Scheme 2). The
cyanomethyl protecting group for the pyrrolidine nitrogen was
chosen (a) to disfavor, through inductive electron withdrawal,
competitive chelation of the carbonyl oxygen and the pyrrolidine
nitrogen during the metal acetylide addition step11 and (b) to
serve as a source for the formaldiminium ion during the key
cyclization step.12 Oxazolidinone 12 was a logical starting point
for preparing 20, since this intermediate incorporates the
required oxidation at C(8). Crystalline iodide 12 is available
by stereoselective iodocyclization of propenylpyrrolidine car-
bamate 11, which in turn is readily prepared on a large scale in
two steps and 54% overall yield from N-[(benzyloxy)carbonyl]-
L-proline methyl ester.13
(5) (a) Overman, L. E.; Goldstein, S. W. J. Am. Chem. Soc. 1984, 106,
5360. (b) Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org.
Chem. 1992, 57, 1179.
(6) For a recent review of total synthesis of pumiliotoxin A alkaloids,
see: Franklin, A.; Overman, L. E. Chem. ReV. 1996, 96, 505.
(7) (a) Daly, J. W.; Gusovsky, F.; McNeal, E. T.; Secunda, S.; Bell, M.;
Creveling, C. R.; Nishizawa, Y.; Overman, L. E.; Sharp, M. J.; Rossignol,
D. P. Biochem. Pharmacol. 1990, 40, 315. (b) Daly, J. W.; McNeal, E. T.;
Gusovsky, F.; Ito, F.; Overman, L. E. J. Med. Chem. 1988, 31, 477.
(8) See the preceding paper in this issue for a full account of these
investigations.
(9) Overman, L. E.; Robinson, L. A.; Zablocki, J. J. Am. Chem. Soc.
1992, 114, 368.
(10) For syntheses of allopumiliotoxins 267A and 339A by Kibayashi
and co-workers and a synthesis of allopumiliotoxin 339B by Trost and
Scanlon, see: (a) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J. Am. Chem.
Soc. 1992, 114, 10653. (b) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J. Am.
Chem. Soc. 1993, 115, 11393. (c) Trost, B. M.; Scanlan, T. S. J. Am. Chem.
Soc. 1989, 111, 4988.
(11) The pKa of aminoacetonitrile is 4.5: Soloway, S.; Lipschitz, A. J.
Org. Chem. 1958, 23, 613.
(12) We often have employed the cyanomethyl group to both protect
nitrogen and serve as a formaldiminium source; see, for example: Overman,
L. E.; Jacobsen, E. J. Tetrahedron Lett. 1982, 23, 2355.

Synthesis of Allopumiliotoxins
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9075
Table 1. Addition of 1-Hexynyl Nucleophiles to Aldehyde 20
Scheme 3
propargylic
alcohol products
syn:antia yield, %b
reaction conditions
metal solvent
temp, °C
-78 f 0
ZnBr
ZnBr
Li
Et2O
ndc
nd
85
(90)
86
(81)
nd
Et2O-THF (15:1) -78 f rt
THF
Et2O
PhMe
C6H14
THF
THF
-78
3.2:1
2.2:1
1:1
Li
Li
Li
-20
-40
-40
2.2:1
CeCl2
MgBr
-78 f rt
-78
1.8:1
>10:1
61
80
Ti(O-i-Pr)3 THF
-50
1
a Ratio of 26:27 determined by H NMR analysis. b Yield of the
mixture of propargylic alcohols after purification on silica gel. Yields
in parentheses refer to unpurified crude product. c Not detected.
example water, to R-alkoxyaldehyde 20. After much experi-
mentation, we found that this critical oxidation could be
accomplished satisfactorily in the following way. Alcohol 25
was treated at -78 °C with the Swern reagent,15 and the reaction
was allowed to gradually warm to room temperature. Concen-
tration, dilution of the residue with acetone to precipitate the
bulk of triethylamine hydrochloride, followed by chromatog-
raphy of the concentrated filtrate gave 20, [R]D +24.7, as a
colorless oil. Using this nonaqueous workup, pyrrolidine
aldehyde 20 was obtained in yields that ranged, depending upon
scale, from 72 to 90%.
Initial Optimization Studies. Preparation of Nor-11-
Methylallopumiliotoxin 253A (31). The critical side-chain
addition and Mannich cyclization steps were examined in detail
using 1-hexyne as a model side-chain component. Since the
reaction of simple R-alkoxyaldehydes with alkynyltitanium21,22
and alkynylzinc23 nucleophiles had been shown to proceed with
high levels of chelate organization, the condensation of these
derivatives of 1-hexyne, as well as the corresponding lithium
and Grignard reagents, with pyrrolidine aldehyde 20 was
examined (eq 1, Table 1).
An initial attempt to prepare pyrrolidine aldehyde 20 from
iodide 12 is summarized in Scheme 2. Although direct
oxidation of 12 to the corresponding aldehyde was undermined
by the low reactivity of this neopentyl electrophile,13 the desired
conversion could be accomplished efficiently through a three-
step sequence. Thus, heating 12 with 3 equiv of AgNO3 in
refluxing acetonitrile cleanly provided nitrate ester 13. Reduc-
tion of this latter intermediate with Zn afforded primary alcohol
14 in crystalline form in 95% overall yield from 12. Swern
oxidation14 of 14, followed by direct acetalization of the crude
aldehyde product 15 delivered acetal 16 in 63% yield. Base
hydrolysis of 16 then provided the corresponding amino alcohol,
which was treated directly with formalin to yield cyclopentaox-
azolidine 17. Reaction of 17 with TMS-CN occurred readily
15
in the presence of ZnBr2 to deliver 18 in 54% yield after
cleavage of the intermediate silyl ether. Protection of the tertiary
alcohol of 18 with a benzyl group then yielded 19. However,
acetal 19 did not prove to be a viable precursor of 20. All
attempts to cleave the acetal group of 19 under mildly acidic
conditions that were expected to be compatible with the
cyanomethylamine group returned only starting material.16,17
Attempts to remove the group by dealkylation (e.g., with TMSI)
led to complex reaction mixtures.18,19
Deferring oxidation of the primary alcohol to the last step
allowed pyrrolidine aldehyde 20 to be prepared successfully
from 14 by a closely related sequence (Scheme 3). Conversion
of 14 to the corresponding SEM ether 2120 followed by base
hydrolysis provided amino alcohol 22. Alkylation of this
intermediate with iodoacetonitrile yielded cyanomethylamine
23 whose potassium salt could be selectively alkylated on
oxygen with benzyl bromide to give 24. Cleavage of the SEM
group with LiBF4 in wet acetonitrile17 provided primary alcohol
25 in 62% overall yield from 14. Oxidation of 25 to aldehyde
20 was complicated by facile addition of nucleophiles, for
The reaction of 1-hexynylzinc bromide with 20 in ether at
-78 to 0 °C, according to the general procedure of Mead,23
did not produce any of the corresponding propargylic alcohols
26 and 27. Changing the solvent to 15:1 Et2O-THF to increase
the solubility of the zinc reagent also failed to promote addition.
Aldehyde 20 is significantly more complex than the R-alkoxy
aldehydes studied by Mead and is apparently too hindered to
react with a weakly nucleophilic alkynylzinc nucleophile.24 The
related organocerium reagent, prepared according to Imamoto’s
general procedure,25 also failed to react with aldehyde 20 in
THF at -78 °C to room temperature.24 1-Hexynyllithium
reacted with 20 within 1 h at -78 °C in THF to give syn and
(13) (a) Overman, L. E.; McCready, R. J. Tetrahedron Lett. 1982, 23,
4887. (b) Overman, L. E.; Bell, K. L.; Ito, F. J. Am. Chem. Soc. 1984, 104,
4192.
(14) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(15) Evans, D. A.; Hoffman, J. M.; Truesdale, L. K. J. Am. Chem. Soc.
1973, 95, 5822.
(21) Krause, N.; Seebach, D. Chem. Ber. 1987, 120, 1845.
(22) For an earlier report of chelate organization in the addition of
alkynyltitanium nucleophiles to tartrate-derived aldehydes, see: Tabusa,
F.; Yamada, T.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1984, 405.
(23) Mead, K. T. Tetrahedron Lett. 1987, 28, 1019.
(24) Under identical conditions 1-hexynylzinc and 1-hexynylcerium
reagents added in good yield to cyclohexancarboxaldehyde.
(25) Imamoto, T.; Sugiura, Y.; Tagiyama, N. Tetrahedron Lett. 1984,
25, 4233.
(16) Conditions examined included: PPTS, acetone, H2O, rt; oxalic acid,
acetone, rt; LiBF4, MeCN, H2O.17
(17) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267.
(18) Jung, M. E.; Andrus, W. A.; Ornstein, P. L. Tetrahedron Lett. 1977,
18, 4175.
(19) Standard abbreviations employed are defined in: J. Org. Chem.
1996, 61, 22A.
(20) Lipshutz, B. H.; Tegram. J. J. Tetrahedron Lett. 1980, 21, 3343.

9076 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Caderas et al.
Scheme 4
Scheme 5
anti propargylic alcohols 26 and 27 in high yield and a ratio of
3.2:1 (see Table 1). Stereoselectivity with this nucleophile was
less in Et2O, hexanes, or toluene where higher temperatures were
required.26 Addition of 1-hexynylmagnesium bromide, prepared
from reaction of 1-hexynyllithium with MgBr2‚Et2O, with 20
in THF also proceeded with low stereoselectivity. Finally, the
titanium nucleophile prepared from reaction of 1-hexynyllithium
with chlorotitanium triisopropoxide in THF at -50 °C added
to aldehyde 20 with excellent stereoselectivity (>10:1) to give
syn diastereomer 26 in 80% yield. Unfortunately, with more
elaborate alkyne side chains that contained ether and an acetal
functionality, addition of the derived titanium triisopropoxide
nucleophiles took place with markedly reduced efficiency (Vide
infra). As a result, we have employed the lithium salt of the
side-chain nucleophile in our syntheses of the more complex
allopumiliotoxins.
Iodide-promoted cyclization of 26 in H2O at 100 °C in the
presence of 10 equiv of NaI and 1 equiv of camphorsulfonic
acid27 provided the desired (Z)-alkylideneindolizidine 28 in 36%
yield (Scheme 4).28 Attempted cyclization under non-aqueous
conditions ((n-Bu)4NI, CSA, MeCN, 100 °C, sealed tube)
yielded none of the cyclized product.27,29 The efficiency of the
conversion of 26 to 28 was increased by first exposing 26 to 1
equiv of AgNO3 in EtOH to give cyclopentaoxazine 29.
Subsequent reaction of 29 in refluxing H2O with 10 equiv of
NaI, 1 equiv of camphorsulfonic acid, and 2 equiv of paraform-
aldehyde provided 28, as a single alkylidene stereoisomer, in
71% yield. The structure of this product was secured by
treatment of 28 with 4 equiv of n-BuLi followed by protonolysis
with MeOH to yield 30, which upon careful debenzylation with
Li/NH3 at -78 °C gave the nor-11-methyl analog 31 of
allopumiliotoxiin 253A in 76% overall yield from 28. The
identity of this product with an authentic sample of 31 that we
had prepared earlier, using our original vinylsilane-iminium
ion cyclization strategy,30 confirmed both the expected syn
preference in the reaction of 1-hexynyllithium with 20 and the
antarafacial stereochemistry of the iodide-promoted iminium
ion-alkyne cyclization.
Enantioselective Total Synthesis of (+)-Allopumiliotoxin
267A (3). This synthesis begins with readily available (R)-2-
methylhexanol (32) (Scheme 5).5b,31 Swern oxidation15 of 32
followed by dibromethylenation32 of the derived crude aldehyde
provided 34 in 65% yield. Treatment of 34 with 2.2 equiv of
n-BuLi at -78 °C in THF to generate the corresponding lithium
acetylide followed by addition of aldehyde 20 and chromato-
graphic purification provided the major syn adduct 35 in 41%
yield. The minor anti diastereomer was isolated in 14% yield.
Although this one-step sequence was convenient, the yield of
35 undoubtedly would have been higher if the lithium reagent
had been generated free of LiBr from the corresponding alkyne
(Vide infra). Reaction of 35 with just less than 1 equiv of
AgNO3 in EtOH produced cyclopentaoxazine 36 in high yield.
Iodide-promoted cyclization of this intermediate proceeded
efficiently using the conditions developed during our earlier
model study to deliver alkylideneindolizidine 37 as a single
stereoisomer in 80% overall yield from 35. Conversion of 37
to the corresponding dilithio derivative by treatment with 3.5
equiv of s-BuLi at -78 °C in THF, followed by protonolysis
provided 38 in 76% yield.34 Careful debenzylation with Li/
NH3 at -78 °C delivered (+)-allopumiliotoxin 267A(3) in 84%
(26) The requirement for higher reaction temperatures in these cases is
likely in part due to the lower solubility of 1-hexynyllithium in these
solvents.
(27) Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110, 612.
(28) For a brief review of iminium ion-initiated cyclizations, see:
Overman, L. E.; Ricca, D. J. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, U.K., 1991;
Vol. 2, Chapter 4.4.
(30) Lett, R. M.; Overman, L. E.; Zablocki, J. Tetrahedron Lett. 1988,
29, 6541.
(31) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506.
(32) Corey, E. J.; Fuchs, P. Tetrahedron Lett. 1972, 36, 3769.
(33) Overman, L. E.; Lin, N.-H. J. Org. Chem. 1985, 50, 3669.
(29) Overman, L. E.; Sarkar, A. K. Tetrahedron Lett. 1992, 33, 4103.

Synthesis of Allopumiliotoxins
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9077
Scheme 6
formaldiminium ion-alkyne cyclization was at least 80%.
Deiodination of 43 by sequential treatment with n-BuLi and
MeOH afforded dibenzyl allopumiliotoxin 323B′ (44) in 83%
yield. Careful debenzylation of 44 with Li/NH3 at -78 °C then
afforded (+)-allopumiliotoxin 323B′ (4) in 86% yield. It was
critical to quench the reductive debenzylation with solid NH4-
Cl after 2 min to avoid reductive scission of the axial C(7) allylic
hydroxyl group.36 Synthetic 4 was indistinguishable from an
authentic specimen of (+)-allopumiliotoxin 323B′ by TLC,
capillary GLC, and 500 MHz 1H NMR comparisons. The
optical rotation of synthetic 4 was [R]23D +23.8 (c 0.42, CHCl3),
which compares closely to the rotation reported for material
isolated from Dendrobates pumilio (a 2:1 mixture of C(15)
epimers): [R]D +22.3 (c 1.0, MeOH).4
This first synthesis of 4 rigorously confirms the complete
stereostructure of 4 and establishes that the major C(15) epimer
isolated from dendrobatid frogs has the 15S configuration.2 This
synthesis was realized in five steps and 17% overall yield from
alkyne 39 and aldehyde 20.37 The synthesis proceeded in 13
steps and 6% overall yield from (S)-2-methyl-1-penten-3-ol and
17 steps and 3.5% overall yield from N-[(benzyloxy)carbonyl]-
L-proline, the precursors respectively of alkyne 39 and pyrro-
lidine aldehyde 20.
Enantioselective Total Synthesis of (+)-Allopumiliotoxin
339A (5). In a similar fashion, the first synthesis of 5 was
completed from pyrrolidine aldehyde 20 and the side-chain
alkyne 45 (Scheme 7).8 The lithium salt of 45 added to aldehyde
20 with the highest degree of chelate organization (4.5:1) we
had observed with an alkynyllithium nucleophile. After chro-
matographic separation, the syn adduct 46 was obtained in 68%
yield and the minor anti isomer 47 in 15% yield. Attempts to
improve selectivity by treating the lithium derivative of 45 with
Ti(O-i-Pr)3Cl at -50 °C in THF prior to reaction with 20
provided alcohol 46 in a disappointing 10% yield.21,22 Uncon-
verted aldehyde 20 was isolated from this reaction in 70% yield,
although the recovery of alkyne 45 was <40%. This result
indicates that this more highly functionalized alkynyltitanium
reagent was not stable at the temperatures required to promote
its condensation with 20.
Several conditions were investigated for converting 46 to
cyclopentaoxazine 48. Treatment of 46 with 1 equiv of AgNO3
in EtOH at rt provided 48 in low yield (36%), possibly due to
competitive degradation of the side chain. The yield of 48 was
improved to 60% when 2 equiv of Cu(OTf)2 in THF was
employed; however, the reaction required 20 h to go to
completion. Best results were realized upon exposure of 46 to
2.3 equiv of AgOTf in THF, which provided cyclopentaoxazine
48 in 94% yield within 2 h. The yield of this step was quite
sensitive to the purity of AgOTf and was significantly lower
when older samples of this salt, which undoubtedly contained
triflic acid, were employed.
yield. This sample showed [R]20D +31 (c 0.2, MeOH), which
is slightly higher than the rotation reported for a dilute solution
of the natural isolate, [R]25D +24.7 (c 0.2, MeOH).4 Synthetic
3 was identical by spectroscopic and chromatographic com-
parisons with an authentic sample of the natural alkaloid and a
sample of 3 prepared earlier in our laboratories.5
This much improved second-generation total synthesis of
(+)-3 was accomplished in 10 steps and 11% overall yield from
the commercially available oxazolidinone precursor of alcohol
32 and 17 steps and 4% overall yield from N-[(benzyloxy)-
carbonyl]-L-proline.
Enantioselective Total Synthesis of (+)-Allopumiliotoxin
323B′ (4). The first total synthesis of 4 was accomplished in
a similar fashion (Scheme 6). Addition of the alkynyllithium
reagent derived from enantiopure alkyne 39 (a 5:1 mixture of
C(11) epimers)8 to aldehyde 20 provided a 3:1 a mixture of
syn and anti alcohols 40 and 41 in 71% combined yield after
chromatographic resolution. The major diastereomer 40 was
converted in 68% yield to cyclopentaoxazine 42 upon exposure
to 2 equiv of Cu(OTf)2 in THF.35 The yield for this step was
less if AgNO3 in EtOH was employed.
Cyclization of 42 occurred cleanly under standard aqueous
conditions in the presence of NaI to afford iodoalkylidenein-
dolizidine 43 as a single stereoisomer in 66% yield. At this
stage, the C(11) epimer of 43, which resulted from the low
diastereomeric purity of alkyne 39, could be separated by flash
chromatography. Since the C(11) epimer of 43 was isolated in
14% yield, the efficiency of the pivotal iodide-promoted
Cyclization of 48 using the standard aqueous conditions we
had employed to prepare allopumiliotoxins 3 and 4 provided a
mixture of cyclopentaoxazine diol 49 and cyclized triol vinyl
iodide 51. Only traces of the alkylideneindolizidine product
50 that retained the acetonide were isolated. The conversion
(36) Reaction of 44 with Li/NH3 for >5 min at -78 °C produced the
internal alkene a as the major product.
(34) Although either n- or s-BuLi can be employed, s-BuLi is preferable
since a smaller excess is required to obtain optimum yields.
(35) The contaminating amount of the C(11) epimer could not be removed
until the alkylideneindolizidine ring was formed.
(37) The overall yield was 21% when corrected for the isomeric purity
of 39.

9078 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Caderas et al.
Scheme 7
and 125 MHz 13C NMR comparisons. Since 1H NMR spectra
of this indolizidene triol are markedly concentration dependent,
identity of the synthetic and natural samples was confirmed by
1
500 MHz H NMR analysis of a 1:1 mixture of these samples
in CDCl3 and CD3OD. The optical rotation of synthetic 5,
[R]23D +68 and [R]23546 +90 (c 0.5 and 1.0, CHCl3), was slightly
higher than the rotation we measured for a small sample of the
natural toxin: [R]23D +52.0 and [R]23546 +75.0 (c 0.5, CHCl3).
This first total synthesis of allopumiliotoxin 339A also
confirmed the full stereostructure of this alkaloid. The total
synthesis of enantiopure 5 proceeded in five steps from alkyne
45 and pyrrolidine aldehyde 20. The synthesis was achieved
in 17 steps and ∼7% overall yield from N-[(benzyloxy)-
carbonyl]-L-proline and 16 steps and ∼6% overall yield from
the commercially available oxazolidinone precursor of 45.
Conclusion. The first total syntheses of 4 and 5, and a much
improved synthesis of the simpler 3, were accomplished. The
former two syntheses rigorously establish the full stereostructure
of these complex pumiliotoxin A alkaloids. The synthetic
approach to the allopumiliotoxins documented here is suf-
ficiently concise to provide these scarce alkaloids in quantities
(10-100 mg) far in excess of that available by isolation.
Pharmacological studies of these samples, as well as some
simple congeners, have highlighted the sensitivity of biological
activity to the stereochemistry of the allopumiliotoxin side
chain.7a,38 The syntheses documented here, together with those
described in the accompanying account,8 underscore the sub-
stantial utility of iodide-promoted iminium ion-alkyne cycliza-
tions in constructing highly functionalized nitrogen heterocycles.
Experimental Section39
(1R,7aS)-Tetrahydro-1-methyl-1-(nitratomethyl)-1H,3H-pyrrolo-
[1,2-c]oxazol-3-one (13). A solution of AgNO3 (7.2 g, 43 mmol),
iodide 12 (4.0 g, 14 mmol), and dry MeCN (15 mL) was heated at
reflux for 16 h, during which time AgI precipitated. After cooling to
rt, the resulting slurry was filtered and the filtrate was concentrated.
Trituration of the gummy residue with EtOAc (7 × 20 mL) left a yellow
powder. The combined EtOAc extracts were washed with brine, dried
(K2CO3), and concentrated to give 3.0 g (∼100% yield) of crude
nitratocarbamate 13 as a pale yellow oil, which was used directly in
the next step: [R]23D -50.9 (c 3.4, CHCl3); 1H NMR (250 MHz, CDCl3)
δ 4.61 and 4.55 (AB, JAB ) 11.1 Hz, 2H), 3.70 (m, 1H), 3.62 (m, 1H),
3.23 (m, 1H), 2.11 (m, 1H), 1.89 (m, 2H), 1.58 (m, 1H), 1.48 (s, 3H);
13C NMR (63 MHz, CDCl3) 159.4, 78.8, 75.9, 65.0, 45.7, 26.3, 25.4,
18.6 ppm; IR (CHCl3) 1760, 1647, 1277, 830 cm-1; MS (isobutane,
CI) m/z 217 (MH), 172; HRMS (EI) m/z 216.0744 (216.0746 calcd for
C8H12N2O5).
(1R,7aS)-Tetrahydro-1-(hydroxymethyl)-1-methyl-1H,3H-pyrrolo-
[1,2-c]oxazol-3-one (14). Zinc powder (2.7 g, 41 mmol) was added
over 2 min to a stirring solution of nitrate 13 (1.77 g, 8.19 mmol),
NH4OAc (3.2 g, 41 mmol), and MeOH (35 mL) at 0 °C. After 30 min
at 0 °C, the slurry was filtered, the zinc residue was washed with MeOH
(3 × 50 mL), and the filtrate was concentrated. The resulting residue
was partitioned between saturated aqueous NH4Cl (25 mL) and EtOAc,
the organic layer was separated, and the aqueous layer was extracted
with ethyl acetate (2 × 200 mL). The combined organic extracts were
dried (K2CO3) and concentrated to afford 1.34 g (95%) of alcohol 14
as a pale yellow oil that solidified upon standing and was sufficiently
pure to be used directly in the next step: mp 90-92.5 °C; [R]23D -69.7
(c 3.0, CHCl3); 1H NMR (250 MHz, CDCl3) δ 3.73 (dd, J ) 10.3, 5.5
Hz, 1H), 3.60 and 3.57 (AB, JAB ) 11.8 Hz, 2H), 3.50 (app dt, J )
11.5, 3.5 Hz, 1H), 3.30 (br s, 1H), 3.13 (m, 1H), 1.99 (m, 1H), 1.88
(m, 1H), 1.76 (m, 1H), 1.55 (m, 1H), 1.30 (s, 3H); 13C NMR (63 MHz,
CDCl3) 160.4, 77.4, 67.4, 64.1, 45.0, 26.1, 25.3, 17.9 ppm; IR (CHCl3)
to 51 was much improved by the addition of acetone (10%) to
improve the solubility of 48 and 49. Although extensive
optimization studies were not undertaken, the cyclization could
be reliably conducted on a small scale by heating a mixture of
48, 3 equiv of camphorsulfonic, 5 equiv of paraformaldehyde,
and a 10:1 mixture of H2O-acetone in a sealed vial at 100 °C
for 2 h. Basic workup, followed by chromatographic purifica-
tion provided the sensitive vinyl iodide diol 51 in 81% yield.
Unfortunately, when the cyclization was conducted on a 50 mg
scale, the yield of 51 was reduced. The reason for this
difference in yield is not understood; however, the expedience
of conducting several simultaneous cyclizations on a 10 mg scale
allowed 50 mg of 51 to be obtained.
Since 51 was quite sensitive to light, it was immediately
deiodinated by treatment with a large excess of n-BuLi at -78
°C in THF followed by protonolysis with MeOH to deliver
benzyl allopumiliotoxin 339A (52) in 81% yield. Careful
debenzylation of this intermediate then provided (+)-allopu-
miliotoxin 339A (5) in 76% yield. Synthetic 5 was indistin-
guishable from a natural specimen by TLC, 500 MHz 1H NMR,
(38) Bessard, Y.; Daly, J.; Overman, L. E.; Sharp, M. J.; Zablocki, J.,
manuscript in preparation.
(39) For general experimental details, see: Deng, W.; Overman, L. E.
J. Am. Chem. Soc. 1994, 116, 11241.

Synthesis of Allopumiliotoxins
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9079
3605, 3420, 1735, 1400, 1350, 1060 cm-1; MS (isobutane, CI) m/z
172 (MH), 114; HRMS (EI) m/z 171.0904 (171.0895 calcd for C8H13-
NO3). Anal. Calcd for C8H13NO3: C 56.13; H, 7.65; N, 8.18.
Found: C, 55.97; H, 7.69; N, 8.16.
15.2, -1.5 ppm; IR (film) 2231, 1249, 836 cm-1; MS (CI, isobutane)
m/z 405 (MH), 378, 248, 147; HRMS (EI) m/z 404.2504 (404.2495
calcd for C22H36N2O3Si).
(R)-r-Methyl-r-(hydroxymethyl)-1-cyanomethyl-2(S)-pyrrolidine-
(benzyloxy)methane (25). Following the general procedure of Lip-
shutz,17 a mixture of 24 (419 mg, 1.04 mmol), LiBF4 (1.9 g, 20 mmol),
and 10:1 MeCN-H2O (5 mL) was maintained at 70 °C for 2 h and
then concentrated. The residue was dissolved in EtOAc (100 mL),
and this solution was washed with brine (2 × 30 mL). After drying
(K2CO3) and concentration, purification of the residue by radial
chromatography (silica gel, 1 mm plate, 3:2 hexane-EtOAc) gave 222
(1R,7aS)-Tetrahydro-1-methyl-1-[[2-(trimethylsilyl)ethoxy]methoxy]-
methyl-1H,3H-pyrrolo[1,2-c]oxazol-3-one (21). A solution of alcohol
14 (800 mg, 4.68 mmol), SEM-Cl (1.7 mL 9.4 mmol), i-Pr2NEt (2.5
mL, 14 mmol), and CH2Cl2 (20 mL) was maintained at room
temperature for 14 h. The reaction was poured into saturated aqueous
NaHCO3 (75 mL), and the aqueous layer was extracted with CH2Cl2
(2 × 200 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (75 mL), dried (K2CO3), and concentrated
to a clear oil. Purification of this residue on silica gel (1:1 hexane-
EtOAc) gave 1.40 g (∼100%) of 21, which solidified upon standing:
mp 48-49 °C; [R]23D -44.7, [R]578 -46.3, [R]546 -52.8, [R]435 -89.0,
mg (78%) of 25 as a colorless oil: [R]23 -46.7, [R]578 -48.4, [R]546
D
-55.1, [R]435 -93.9, [R]365 -148 (c 1.2, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.29-7.38 (m, 5H), 4.51 (ABq, J ) 11.2 Hz, ∆ ) 7.8 Hz,
2H) 3.82 (ABq, J ) 17.2 Hz, ∆ ) 154.4 Hz, 2H), 3.81 (dd, J ) 12.1,
3.0 Hz, 1H), 3.48 (dd, J ) 12.1, 8.0 Hz, 1H), 3.15 (m, 1H), 3.09 (m,
1
[R]365 -139 (c 3.1, CHCl3); H NMR (500 MHz, CDCl3) δ 4.71 (s,
2H), 3.75 (m, 1H), 3.55 (m, 5H), 3.21 (m, 1H), 1.35-2.05 (m, 4H),
1.38 (s, 3H), 0.94 (t, J ) 8.1 Hz, 2H), 0.02 (s, 9H); 13C NMR (125
MHz, CDCl3) 160.3 (s), 95.0 (t), 80.4 (s), 72.6 (t), 65.2 (t), 64.9 (d),
45.5 (t), 26.4 (t), 25.5 (t), 18.9 (q), 17.9 (t), -1.6 (q) ppm; IR (film)
1729, 1250, 835 cm-1; MS (CI, isobutane) m/z 302 (MH), 274, 244,
172; HRMS (EI) m/z 286.1476 (286.1474 calcd for C13H24NO4Si, M
- Me). Anal. Calcd for C14H27NO4Si: C, 55.81; H, 8.97; N, 4.65.
Found: C, 55.76; H, 9.08; N, 4.59.
1H), 2.71 (m, 1H), 2.65 (m, 1H), 1.76-2.02 (m, 4H), 1.23 (s, 3H); 13
C
NMR (125 MHz, CDCl3) 138.6, 128.5, 127.5, 127.2, 116.5, 80.4, 66.4,
65.2, 63.8, 54.8, 43.6, 27.4, 23.8, 15.8 ppm; IR (film) 3625-3200,
2231 cm-1; MS (CI, isobutane) m/z 275 (MH), 249, 248; HRMS (EI)
m/z 248.1671 (248.1650 calcd for C15H22NO2, M - CN). Anal. Calcd
for C16H22N2O2: C, 70.07; H, 8.03; N, 10.22. Found: C, 70.02; H,
8.11, N, 10.17.
(R)-r-Methyl-r-formyl-1-(cyanomethyl)-2(S)-pyrrolidine(benz-
(R)-r-Methyl-r-[[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1-
(cyanomethyl)-2(S)-pyrrolidinemethanol (23). A carefully degassed
solution of 21 (650 mg, 2.2 mmol), KOH (2.4 g, 43 mmol), EtOH (10
mL), and H2O (2.0 mL) was heated at 80 °C for 16 h under Ar. After
cooling to 23 °C, EtOH was removed on a rotary evaporation and the
aqueous layer was extracted with THF (100 mL). The organic extract
was dried (K2CO3) and concentrated to afford crude secondary amine
yloxy)methane (20). Following the general procedure of Swern,14
a
stirring solution of oxalyl chloride (270 mg, 2.1 mmol, freshly distilled)
and dry CH2Cl2 (11 mL) was cooled to -78 °C and DMSO (300 µL,
4 mmol, distilled from CaH2 and stored over 4 Å sieves) was added
dropwise over 3 min. The resulting mixture was stirred at -78 °C for
10 min, and a solution of alcohol 25 (238 mg, 0.87 mmol) and CH2Cl2
(1 mL) was added dropwise over 2 min. The reaction was maintained
at -78 °C for an additional 30 min, and then Et3N (750 µL) was added
dropwise over 3 min. The resulting slurry was stirred at -78 °C for
10 min and allowed to gradually warm to room temperature over 20
min. Concentration, dilution of the residue with acetone (25 mL),
filtration, and a second concentration gave the crude aldehyde as a
yellow oil that was contaminated with DMSO and Et3N‚HCl. Purifica-
tion of this residue on silica gel (4:1 hexane-ethyl acetate) gave 183
1
22 (570 mg) as a pale yellow oil that was homogeneous by H NMR
analysis: (300 MHz, CDCl3) δ 4.63 (s, 2H), 3.56 (t, J ) 7.9 Hz, 2H),
3.36 (s, 2H), 3.12 (m, 1H), 2.90 (m, 1H), 1.52-1.83 (m, 4H), 1.09 (s,
3H), 0.89 (t, J ) 7.9 Hz, 2H), -0.03 (s, 9H).
Iodoacetonitrile (450 mg, 2.7 mmol) was added over 1 min to a
solution of this sample of 22 (570 mg), Et3N (840 mg, 8.3 mmol), and
THF (10 mL) at room temperature. After 2 h at room temperature,
the reaction was diluted with saturated aqueous NaHCO3 (30 mL) and
extracted with EtOAc (3 × 80 mL); the organic extract was washed
with brine (15 mL), dried (K2CO3), and concentrated. The resulting
residue was purified in a silica gel (3:2 hexane-EtOAc) to give
cyanomethylamine 23 (610 mg, 88% from 14) as a pale yellow oil:
[R]23D -38.7, [R]578 -40.2, [R]546 -45.8, [R]435 -77.6, [R]365 -122 (c
mg (77%) of nearly pure 20 as a colorless oil: [R]23 +24.7, [R]578
D
+27.3, [R]546 +37.2, [R]435 +144 (c 2.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 9.64 (s, 1H), 7.29-7.39 (m, 5H), 4.45 (ABq, J ) 11.4 Hz,
∆ ) 96.8 Hz, 2H) 3.86 (ABq, J ) 17.3 Hz, ∆ ) 193.5 Hz, 2H), 3.20
(m, 1H), 3.07 (m, 1H), 2.71 (m, 1H), 1.55-1.87 (m, 4H), 1.34 (s, 3H);
13C NMR (125 MHz, CDCl3) 203.5, 137.7, 128.2, 116.0, 86.4, 66.7,
63.6, 54.0, 42.9, 26.3, 23.8, 11.9 ppm; IR (film) 2237, 1731 cm-1; MS
(CI, isobutane) m/z 273 (MH); HRMS (EI) m/z 246.1498 (246.1494
calcd for C15H20NO2, M - CN).
1
3.1, CHCl3); H NMR (300 MHz, CDCl3) δ 4.68 (s, 2H), 3.90 (ABq,
J ) 17.2 Hz, ∆ ) 132.5 Hz, 2H), 3.63 (m, 2H), 3.40 (ABq, J ) 10.0
Hz, ∆ ) 28.5 Hz, 2H), 3.04 (m, 1H), 2.90 (m, 1H), 2.70 (m, 1H),
1.21-1.95 (m, 4H), 1.11 (s, 3H), 0.94 (m, 2H), 0.02 (s, 9H): 13C NMR
(75 MHz, CDCl3) 116.5, 95.5, 75.3, 74.7, 65.9, 65.6, 54.5, 43.3, 27.5,
23.5, 18.9, 18.0, -1.5 ppm; IR (film) 3616-3567, 3515-3300, 2232
cm-1; MS (CI, isobutane) m/z 315 (MH), 288, 158; HRMS (EI) m/z
314.2010 (314.2025 calcd for C15H30N2O3Si). Anal. Calcd for
C15H30N2O3Si: C, 57.32; H, 9.55; N, 8.92. Found C, 57.61; H, 9.67;
N, 8.90.
(R)-r-Methyl-r-[[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1-
(cyanomethyl)-2(S)-pyrrolidine(benzyloxy)methane (24). A solution
of alcohol 23 (1.50 g, 4.78 mmol), benzyl bromide (1.6 g, 9.6 mmol),
and THF (4 mL) was added dropwise over 3 min to a rapidly stirred
suspension of KH (∼0.3 g, 7.2 mmol, prewashed with 4 mL of dry
hexane) and THF (4 mL). The solution exotherms to reflux upon
combination of the reagents. After 30 min, the reaction mixture was
added dropwise to EtOAc (300 mL), and the organic solution was
washed with brine (2 × 50 mL). After drying (K2CO3) and concentra-
tion, the residue was purified on silica gel (4:1 hexane-EtOAc) to
give 1.76 g (91%) of 24 as a pale yellow oil: [R]D -42.9, [R]578 -44.6,
[R]546 -50.9, [R]435 -86.8 (c 3.1, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.29-7.38 (m, 5H), 4.68 (s, 2H), 4.56 (ABq, J ) 11.3 Hz, ∆ ) 16.7
Hz, 2H), 3.86 (ABq, J ) 17.1 Hz, ∆ ) 123.5 Hz, 2H), 3.61 (m, 2H),
3.62 (ABq, J ) 11.1 Hz, ∆ ) 71.9 Hz, 2H), 3.20 (m, 1H), 3.06 (m,
1H), 2.71 (m, 1H), 1.57-2.03 (m, 4H), 1.20 (s, 3H), 0.94 (t, J ) 8.5
Hz, 2H), 0.01 (s, 9H); 13C NMR (125 MHz, CDCl3) 139.2, 128.2, 127.2,
127.1, 116.9, 95.0, 81.0, 70.2, 65.3, 64.7, 54.6, 43.5, 27.6, 23.6, 18.1,
(R)-1,1-Dibromo-3-methylheptene (34). Following the general
procedure of Swern,14 a solution of oxalyl chloride (410 mg, 3.3 mmol)
and CH2Cl2 (7 mL) was cooled to -78 °C and a solution of DMSO
(460 µL, 6.5 mmol) and CH2Cl2 (2 mL) was added dropwise; the
resulting solution was allowed to stir for 3 min. A solution of (R)-2-
methylhexanol5b (342 mg, 2.95 mmol) and CH2Cl2 (4 mL) was added
dropwise at -78 °C, and after 15 min, Et3N (570 µL, 4.1 mmol) was
added slowly. After 5 min, the cooling bath was removed and the
reaction was allowed to warm to room temperature. The reaction
mixture then was washed 1:1 H2O-brine (2 × 20 mL), dried (MgSO4),
and concentrated to give 375 mg of crude aldehyde 33, which was
immediately used in the next step.
Following the general procedure of Corey and Fuchs,32 a solution
of Ph3P (3.09 g, 11.8 mmol) and CH2Cl2 (7.5 mL) was added dropwise
at -15 °C to a solution of CBr4 (1.96 g, 5.90 mmol; passed through
activity 1 alumina immediately prior to use) and CH2Cl2 (6 mL). After
20 min at -10 °C, the orange solution was cooled to -78 °C.
A
solution of this sample of crude aldehyde 33 and CH2Cl2 (3 mL) then
was added dropwise, and the resulting solution was maintained at
-78°C for 10 min and then at -20 °C for 30 min. The solution was
poured into pentane (150 mL), and the resulting mixture was filtered
through Celite. The gummy residue was taken up in CH2Cl2 (10 mL),
pentane was added, and the resulting mixture was filtered. This process
was repeated 3×, and the combined filtrates were concentrated (0 °C
bath; 20 mm). This residue was suspended in pentane (50 mL), and

9080 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Caderas et al.
after 3 h at -15 °C, this mixture was filtered. The concentrated filtrate
(rotary evaporation at 0 °C, 20 mm) was purified on silica gel (pentane)
to give 522 mg (65% for two steps) of 34 as a colorless, nonviscous
liquid: 1H NMR (50 MHz, CDCl3) δ 6.17 (d, J ) 9.0 Hz, 1H), 2.42
(m, 1H), 1.4-1.2 (m, 6H), 1.00 (d, J ) 6.5 Hz, 3H), 0.89 (t, J ) 6.8
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 144.5, 87.1, 38.3, 35.8, 29.3,
the residue on silica gel (20:1.0:01 CHCl3-MeOH-NH4OH) provided
80 mg (88%) of the unstable vinyl iodide 37: IR (film) 3418, 3363,
1
1636 cm-1; H NMR (300 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 4.90 (s,
1H), 4.64 (AB, J ) 12.3 Hz, 1H), 4.60 (AB, J ) 12.3 Hz, 1H), 4.03
(d, J ) 12.9 Hz, 1H), 3.09 (m, 1H), 2.87 (d, J ) 12.9 Hz, 1H), 2.52
(dd, J ) 9.6, 6.0 Hz, 1H), 2.32-2.18 (m, 2H), 2.1-1.9 (m, 1H), 1.9-
1.8 (m, 1H), 1.7 (br s, 3H), 1.4-1.1 (m, 4H), 1.29 (s, 3H), 1.02 (d, J
) 6.3 Hz, 3H), 0.89 (t, J ) 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
140.2, 138.2, 128.0, 127.1, 126.9, 123.3, 81.1, 76.7, 66.3, 65.5, 53.5,
51.0, 38.9, 36.9, 29.3, 22.8, 22.7, 21.2, 19.0, 14.1 ppm.
22.7, 19.2, 14.0 ppm; IR (CCl4) 2962, 2929, 2873, 1457, 732 cm-1
;
HRMS (EI) m/e 269.9465 (269.9442 calcd for C8H1479Br81Br, MH).
(S)-2-[(1R,2R,5R)-1-(Benzyloxy)-1,5-dimethyl-2-hydroxy-3-nony-
nyl]-1-(cyanomethyl)pyrrolidine (35). A hexane solution of n-BuLi
(0.35 mL, 0.76 mmol, 2.2 M) was added dropwise at -78 °C to a
solution of dibromoalkene 34 (98 mg, 0.36 mmol) and 1.3 mL of THF.
After 2 h, this solution was added via cannula to a -78 °C solution of
aldehyde 20 (90 mg, 0.33 mmol, azeotropically dried with toluene 3×
prior to use) and THF (2 mL). After the temperature was maintained
at of -78 °C for 0.5 h, the reaction was placed in a -50 °C bath and
was maintained at this temperature for an additional 8 h. Saturated
aqueous NH4Cl (2 mL) was added, and the resulting mixture was
partitioned between ether (20 mL) and H2O (2 mL). The aqueous layer
was extracted with ether (3 × 10 mL), and the combined organic layers
were dried (Na2SO4) and concentrated. Purification of the residue on
silica gel (10:1 hexanes-EtOAc) gave 18 mg (14%) of the anti alcohol
as a colorless oil followed by the major syn isomer 35 (51 mg, 41%):
1H NMR (300 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 5.01 (AB, J ) 11.0
Hz, 1H), 4.66 (AB, J ) 11.0 Hz, 1H), 4.33 (d, J ) 7.8 Hz, 1H), 3.86
(AB, J ) 17.1 Hz, 1H), 3.62 (AB, J ) 17.1 Hz, 1H), 3.18 (m, 1H),
3.08 (m, 1H), 2.93 (d, J ) 8.1 Hz, 1H), 2.70 (m, 1H), 2.48 (m, 1H),
1.98 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.2 (m, 4H), 1.42 (s, 3H), 1.18
(d, J ) 6.9 Hz, 3H), 0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (125 MHz,
benzene-d6) 139.6, 128.7, 116.8, 91.6, 82.3, 80.4, 67.2, 66.6, 66.4, 54.8,
43.7, 36.9, 30.0, 27.9, 26.4, 24.2, 22.9, 21.2, 15.6, 14.3 ppm; IR (neat)
3478, 2872, 2860, 2830, 1497, 1454, 1377 cm-1; MS (CI, isobutane)
m/e 383 (MH), 356, 257, 232, 192, 107; HRMS (CI, isobutane) m/e
383.2677 (383.2698 calcd for C24H35N2O2, MH).
A cyclohexane solution of s-BuLi (0.47 mL, 0.58 mmol) was added
dropwise at -78 °C to a solution of the vinyl iodide 37 (80 mg, 0.17
mmol) and THF (3.5 mL). After 1.75 h, MeOH (0.2 mL) was added
and the resulting solution was allowed to warm to room temperature
and then was diluted with EtOAc (10 mL). This solution was washed
with saturated aqueous NH4Cl (2 × 1 mL), 1 M aqueous Na2CO3 (2 ×
1 mL), and brine, dried (K2CO3), and concentrated. Purification of
the residue on silica gel (20:1:0.1 CHCl3-MeOH-NH4OH) gave 45
mg (76%) of benzyl ether 38 as an amorphous solid: 1H NMR (500
MHz, CDCl3) δ 7.4-7.2 (m, 5H), 5.27 (d, J ) 10.0 Hz, 1H), 4.59
(AB, J ) 12.5 Hz, 1H), 4.56 (AB, J ) 12.5 Hz, 1H), 4.07 (s, 1H),
3.71 (d, J ) 12.5 Hz, 1H), 3.12 (app t, J ) 7.5 Hz, 1H), 2.74 (d, J )
12.5 Hz, 1H), 2.43 (m, 2H), 2.15 (m, 1H), 1.97 (m, 1H), 1.9-1.6 (m,
5H), 1.4-1.1 (m, 3H), 1.26 (s, 3H), 1.00 (d, J ) 6.5 Hz, 3H), 0.87 (t,
J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) 140.3, 136.7, 134.0,
128.0, 127.2, 126.9, 76.4, 76.2, 66.5, 64.5, 54.4, 48.7, 37.4, 31.8, 29.6,
22.8, 21.0, 20.8, 18.8, 14.1 ppm; HRMS (EI) m/e 357.2691 (357.2668
calcd for C23H35NO2, M).
(+)-Allopumiliotoxin 267A (3). Lithium wire (4 mg, 0.5 mmol,
containing 1% Na) was added in small pieces to a solution of benzyl
ether 38 (12 mg, 0.034 mmol), THF (2 mL), and NH3 (4 mL, freshly
distilled) at -78 °C. After the last piece of Li was added, the reaction
was stirred for 6 min, the cooling bath was removed, and the clear
solution was stirred vigorously until a deep blue color developed (1
min). After an additional 30 s, dry MeOH (1 mL) was added followed
by saturated aqueous NH4Cl (1 mL). The NH3 was allowed to
evaporate, and the residue was taken up in EtOAc (5 mL) and washed
with saturated aqueous NaHCO3 and brine. The organic layer was
separated, the aqueous layer was extracted with CHCl3 (3 × 1 mL),
the combined organic extracts were dried and (K2CO3) concentrated,
and the residue was purified on silica gel (20:1:0.1 CHCl3-MeOH-
NH4OH) to give 8.2 mg (90%) of 3, which was 93% pure by capillary
GLC analysis: [R]20D +31; [R]405 +87, [R]435 +68, [R]546 +50, [R]577
+40 (c 0.22, MeOH). Synthetic 3 showed TLC mobility and 250 MHz
1H NMR, 125 MHz 13C NMR, and mass spectra that were indistin-
guishable from those of a natural specimen.
(S)-2-[(1R,2S,5R)-1-(Benzyloxy)-1,5-dimethyl-2-hydroxy-3-nonynyl]-
1
1-(cyanomethyl)pyrrolidine: H NMR (300 MHz, CDCl3) δ 7.4-7.2
(m, 5H), 5.84 (s, 1H), 4.67 (s, 1H), 4.63 (AB, J ) 11.0 Hz, 1H), 4.45
(AB, J ) 11.0 Hz, 1H), 4.29 (AB, J ) 17.4 Hz, 1H), 3.57 (AB, J )
17.4 Hz, 1H), 3.57 (m, 1H), 3.15 (m, 1H), 2.77 (m, 1H), 2.50 (m, 1H),
2.1-1.8 (m, 4H), 1.6-1.3 (m, 4H), 1.27 (s, 3H), 1.20 (d, J ) 6.9 Hz,
3H), 0.91 (t, J ) 6.9 Hz, 3H); IR (CCl4) 3480, 2965, 2932, 2875, 1485,
1457 cm-1; HRMS (CI, isobutane) m/e 383.2677 (383.2698 calcd for
C24H35N2O2, MH).
(7R,8R,8aS)-8-(Benzyloxy)-8-methyl-7-[(3R)-3-methyl-1-heptynyl]-
6-oxaocthydroindolizidine (36). A solution of alcohol 35 (71 mg,
0.19 mmol), AgNO3 (30 mg, 0.18 mmol) and ethanol (3 mL) was stirred
in the dark at room temperature for 20 h. The reaction mixture then
was diluted with EtOAc (15 mL) and was washed with 1 M NaOH (5
mL), H2O (5 mL), and brine, dried (K2CO3), and concentrated. The
resulting oil was purified on silica gel (3:1 hexanes-EtOAc) to give
60 mg (90%) of oxazine 36 as a colorless oil: [R]20D -87, [R]405 -655,
[R]435 -589, [R]546 -535, [R]577 -482 (c 0.11, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.2-7.4 (m, 5H), 5.21 (d, J ) 11.5 Hz, 1H), 4.82 (d,
J ) 11.5 Hz, 1H), 4.78 (d, J ) 10.0 Hz, 1H), 4.42 (d, J ) 10.0 Hz,
1H), 4.13 (d, J ) 1.0 Hz, 1H), 3.43 (app q, J ) 7.5 Hz, 1H), 2.77 (dd,
J ) 7.0, 3.5 Hz, 1H), 2.62 (m, 1H), 2.47 (m, 1H), 2.12 (m, 1H), 1.9-
1.7 (m, 3H), 1.5-1.2 (m, 4H), 1.26 (s, 3H), 1.15 (d, J ) 7.0 Hz, 3H),
0.85 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 140.3, 128.1,
127.0, 126.8, 92.6, 82.0, 76.4, 75.1, 74.6, 67.5, 67.2, 49.6, 36.3, 29.6,
26.1, 25.3, 22.9, 22.5, 20.7, 18.6, 14.0 ppm; IR (neat) 2964, 2931, 2871,
1454, 1167 cm-1; MS (CI, isobutane) m/e 356 (MH), 354, 256, 248,
192, 165, 147; HRMS (CI, isobutane) m/e 356.2566 (356.2589 calcd
for C23H34NO2, MH).
(7S,8R,8aS)-8-(Benzyloxy)-7-hydroxy-8-methyl-6-(E)-[(2R)-2-me-
thylpentylidene]octahydroindolizidine (38). A mixture of oxazine
36 (67 mg, 0.19 mmol), camphorsulfonic acid monohydrate (CSA; 50
mg, 0.20 mmol), NaI (283 mg, 1.89 mmol), paraformaldehyde (14 mg,
0.47 mmol), H2O (2 mL), and a stir bar was sealed in a 5 mL pressure
bottle, immersed in a preheated (100 °C) oil bath, and vigorously stirred
for 1 h. The mixture was allowed to cool to room temperature and
was partitioned between brine and CH2Cl2; the organic layer was
washed with brine, dried (MgSO4), and concentrated. Purification of
(S)-2-[(1R,2R,5R,7E,9S)-1,9-(Dibenzyloxy)-2-hydroxy-1,5,8-tri-
methyl-7-undecen-2-ynyl]-1-(cyanomethyl)pyrrolidine (40). A hex-
ane solution of n-BuLi (0.45 mL, 2.05 M) was added dropwise to a
solution of alkyne 39 (244 mg, 0.953 mmol, previously dried by
azeotroping 2× with benzene) and THF (2 mL) over 3 min at 0 °C.
After an additional 40 min at 0 °C, the reaction was cooled to -78 °C
and a solution of aldehyde 20 (162 mg, 0.596 mmol, previously dried
by azeotroping with benzene) and THF (3 mL) was added dropwise.
After 1.5 h at -78 °C, the reaction was allowed to warm to -40 °C
over 20 min and then was recooled to -78 °C and quenched by the
addition of saturated aqueous NH4Cl (1.5 mL). After allowing the
reaction to warm to room temperature, it was diluted with brine (20
mL) and extracted with EtOAc (2 × 100 mL). After drying (K2CO3)
and concentration, the residue was purified by radial chromatography
(silica gel, 2 mm plate, 9:1-3:1 hexane-EtOAc) to give 165 mg (53%)
of the major syn diastereomer 40 as a colorless oil and 56 mg (18%)
of the minor anti diastereomer 41. Characterization data for 40: [R]23
D
-90.1, [R]577 -94.3, [R]546 -107.6, [R]435 -184 [R]405 -221 (c 2.3,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.27-7.37 (m, 10H), 5.44 (br
t, J ) 7.0 Hz), 4.85 (ABq, J ) 10.9 Hz, ∆ν ) 175.8 Hz), 4.36 (ABq,
J ) 11.8 Hz, ∆ν )124.5 Hz), 4.30 (br s, 1H), 3.73 (ABq, J ) 17.2
Hz, ∆ν ) 118.0 Hz, 2H), 3.56 (t, J ) 7.0 Hz, 1H), 3.18 (m, 1H), 3.08
(m, 1H), 2.96 (br s, 1H), 2.70 (m, 2H), 1.48-1.98 (m, 6H), 1.61 (s,
3H), 1.41 (s, 3H), 1.22 (d, J ) 6.9 Hz, 3H), 0.85 (t, J ) 7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 138.9 (s), 138.6 (s), 136.3 (s), 128.5
(d), 128.2 (d), 127.6 (d), 127.5 (d), 127.3 (d), 126.0 (d), 125.8 (d),
116.7 (s),

Synthesis of Allopumiliotoxins
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9081
91.4 (s), 86.6 (d), 82.3 (s), 79.4 (s), 69.6 (t), 66.8 (d), 66.5 (t), 66.3
(d), 54.9 (t), 44.0 (t), 34.5 (t), 27.8 (t), 26.4 (t), 26.3 (d), 24.1 (t), 20.3
MHz, CDCl3) δ 7.34-7.20 (m, 10H), 5.37-5.28 (m, 3H), 4.57 (ABq,
J ) 12.8 Hz, ∆ν ) 8.3 Hz, 2H), 4.36 (ABq, J ) 11.9 Hz, ∆ν ) 60.9
Hz, 2H), 4.07 (s, 1H), 3.72 (d, J ) 13.3 Hz, 1H), 3.55 (t, J ) 7.0 Hz,
1H), 3.12 (t, J ) 8.2 Hz, 1H), 2.75 (d, J ) 12.2 Hz, 1H), 2.62-2.40
(m, 2H), 1.58 (s, 3H), 1.26 (s, 3H), 1.04 (d, J ) 6.5Hz, 3H), 0.84 (t,
J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) 140.2, 138.9, 136.0,
135.4, 134.1, 128.2, 128.0, 127.7, 127.3, 127.2, 126.9, 126.9, 86.8,
76.5, 75.9, 69.6, 66.3, 64.5, 54.3, 48.5, 35.4, 32.2, 26.2, 22.8, 20.9,
20.5, 18.7, 10.9, 10.4 ppm; MS (CI, isobutane) m/e 504 (MH), 396,
380, 288, 272, 107, 91; HRMS (EI) m/e 412.2845 (412.2852 calcd for
C26H38NO3, M - PhCH2).
(q), 14.9 (q), 10.8 (q), 10.3 (q) ppm; IR (film) 3606-3250, 2244 cm-1
;
MS (CI, isobutane) m/e 529 (MH), 502; HRMS (EI) m/e 528.3346
(528.3352 calcd for C34H44N2O3).
Minor anti diastereomer 41: 1H NMR (500 MHz, CDCl3) δ 7.27-
7.38 (m, 10H), 5.44 (t, J ) 7.1 Hz, 1H), 4.20-4.65 (m, 6H), 3.06 (m,
1H, 2H), 2.71 (m, 1H), 2.62 (m, 1H), 2.30 (m, 2H), 1.48-2.10 (m,
6H), 1.63 (s, 3H), 1.25 (d, J ) 7.0 Hz, 3H), 1.24 (s, 3H), 0.86 (t, J )
7.5 Hz, 3H).
(7R,8R,8aS)-8-(Benzyloxy)-7-[(3R,5E,7S)-7-(benzyloxy)-3,6-di-
methyl-5-decen-1-ynyl]-8-methyl-6-oxaoctahydroindolizidine (42).
A solution of alcohol 40 (60 mg, 0.11 mmol), Cu(OTf)2 (82 mg, 0.23
mmol), and dry THF (3 mL) was stirred at room temperature. A gray
precipitate formed slowly over a 19 h period. The reaction then was
quenched by the addition of saturated aqueous NaHCO3 (20 mL), and
the resulting mixture was extracted with EtOAc (100 mL). The organic
layer was washed with saturated aqueous NaHCO3 (20 mL), dried (K2-
CO3), and concentrated. Purification of the residue by radial chroma-
tography on silica gel (1 mm plate, 2:1 hexane-EtOAc) gave 38 mg
(+)-Allopumiliotoxin 323 B′ (4). A solution of 44 (15 mg, 0.030
mmol), THF (1.0 mL), and NH3 (5 mL, freshly distilled) was cooled
to -78 °C and treated with excess Li until the blue color persisted for
2 min. The reaction was then quenched by the addition of solid NH4-
Cl. This mixture was allowed to warm to room temperature and then
was diluted with 1 M aqueous Na2CO3 (10 mL) and extracted with
CHCl3 (3 × 15 mL). After drying (K2CO3) and concentration, the
residue was purified on silica gel (15:1:0.1 CHCl3-MeOH-NH4OH)
to give 6.5 mg (86%) of 4 as a colorless oil: [R]23D +23.8, [R]577 +19.8,
[R]546 +25.0, [R]435 +52.9, [R]405 +66.2 (c 0.42 CHCl3). Synthetic 4
(68%) of 42 as a clear oil: [R]23 -89.0, [R]577 -93.5, [R]546 -106,
D
1
showed TLC mobility and 250 MHz H NMR, 125 MHz 13C NMR,
[R]435 -181, [R]405 -217 (c 2.1, CHCl3); IR (film) 2237 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.23-7.39 (m, 10H), 5.41 (m, 1H), 5.01 (ABq,
J ) 11.6 Hz, ∆ν ) 198.1 Hz, 2H), 4.54 (ABq, J ) 10.0 Hz, ∆ν )
197.2 Hz, 2H), 4.34 (ABq, J ) 11.9 Hz, ∆ν ) 130.3 Hz, 2H), 4.07 (br
s, 1H), 3.53 (t, J ) 6.9 Hz, 1H), 3.42 (m, 1H), 2.72 (m, 1H), 2.55-
2.65 (m, 2H), 2.3 (m, 2H), 1.48-2.01 (m, 6H), 1.58 (s, 3H), 1.25 (s,
3H), 1.17 (d, J ) 6.9 Hz, 3H), 0.83 (t, J ) 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) 140.1 (s), 139.0 (s), 136.2 (s), 128.2 (d), 128.0 (d),
127.6 (d), 127.2 (d), 127.0 (d), 126.8 (d), 126.1 (d), 92.0 (s), 86,6 (d),
81.8 (t), 76.6 (s), 74.9 (d), 74.5 (s), 69.5 (t), 67.3 (d), 67.2 (d), 49.4 (t),
34.5 (t), 26.4 (t), 26.3 (d), 25.2 (t), 22.8 (t), 20.1 (q), 18.5 (q), 10.7 (q),
10.3 (q) ppm; MS (CI, isobutane) m/e 502 (MH), 394; HRMS (EI)
m/e 410.2682 (410.2695 calcd for C26H36NO3 M - PhCH2).
and mass spectra that were indistinguishable from those of a natural
specimen.
(S)-2-[(1R,2R,5R,7E,9R,10R)-1-(Benzyloxy)-2-hydroxy-9,10-O-iso-
propylidene-1,5,8-trimethyl-7-undecen-3-ynyl]-1-(cyanomethyl)pyr-
rolidine (46). Following the procedure described for preparation of
40, a solution of the alkyne 45 (150 mg, 0.68 mmol) and THF (1.4
mL) was treated with n-BuLi (300 µL, 2.2 M in hexanes, 0.66 mmol)
at -15 °C. The resulting dark anion solution was maintained at -15
°C for 15 min and then cooled to -78 °C. A solution of aldehyde 20
(140 mg, 0.51 mmol) and THF (1.6 mL) was added dropwise, and the
resulting solution was maintained at -78 °C for 2.5 h. Workup
provided a dark oil that was purified on silica gel (8:1 hexane-EtOAc)
to give 43 mg (17%) of the anti diastereomer 47 and 172 mg (68%) of
the syn isomer 46. Also isolated were recovered alkyne 45 (51 mg,
34%) and aldehyde 20 (21 mg, 15%). Characterization data for 46:
[R]22D -73.6, [R]577 -73.5, [R]546 -79.4, [R]435 -118 (c 0.9, CHCl3);
(7R,8R,8aS)-8-(Benzyloxy)-7-hydroxy-8-methyl-6-(Z)-[(2R,4E,6S)-
6-(benzyloxy)-2,5-dimethyl-1-iodo-4-octenylidene]octahydroindoliz-
idine (43). A solution of 41 (88 mg, 0.18 mmol), camphorsulphonic
acid (44 mg, 0.18 mmol), paraformaldehyde (11 mg, 0.35 mmol), NaI
(260 mg, 1.8 mmol), and H2O (4.5 mL) was heated in a sealed vial at
100 °C for 1 h. The resulting mixture was allowed to cool to room
temperature and then was partitioned between CH2Cl2 (50 mL) and 1
M NaHCO3 (30 mL). The aqueous layer was extracted with CH2Cl2
(20 mL), and the combined organic layers were dried (K2CO3) and
concentrated. Purification of the residue on silica gel (50:1:0.1 CHCl3-
MeOH-NH4OH) gave 73 mg (66%) of 43 as a colorless oil that was
homogeneous by TLC analysis (high Rf) and 15 mg (14%) of the C(11)
epimer (low Rf). Characterization data for 43: IR (film) 3387, 2968,
1
IR (film) 3463, 2982, 2250, 1455, 1379, 1239, 1103, 1036 cm-1; H
NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, ArH, 5H), 5.57 (dt, J )
7.1, 0.9 Hz, 1H), 4.82 (ABq, JAB ) 10.9 Hz, ∆νAB ) 98.3, 2H), 4.31
(br d, J ) 4.9 Hz, 1H), 3.86 (m, 2H), 3.73 (ABq, JAB ) 17.2 Hz, ∆νAB
) 74.4 Hz, 2H), 3.18 (dd, J ) 8.9, 5.1 Hz, 1H), 3.07 (dt, J ) 3.7, 5.7
Hz, 1H), 2.99 (br d, J ) 7.3 Hz, OH, 1H), 2.69 (m, 1H), 2.59 (dq, J
) 7.0, 1.7 Hz, 1H), 2.25 (m, 2H), 1.97 (m, 2H), 1.83-1.68 (m, 2H),
1.65 (s, 3H), 1.42 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H), 1.20 (d, J ) 4.5
Hz, 3H), 1.18 (d, J ) 6.9 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) 138.6,
132.9, 128.4, 127.5, 127.0, 116.7, 107.9, 91.1, 88.4, 82.3, 79.6, 74.2,
66.8, 66.5, 66.2, 54.8, 43.9, 34.6, 27.8, 27.4, 26.8, 26.0, 24.0, 20.2,
16.9, 14.9, 11.7 ppm; MS (CI, isobutane) m/e 495 (MH), 468, 437,
410, 304, 246; HRMS (CI) m/e 495.3225 (495.3223 calcd for
C30H43N2O4, MH).
1
2931, 2875, 1456, 1056, 912 cm-1; H NMR (300 MHz, CDCl3) δ
7.25-7.09 (m, 10H), 5.13 (bt, J ) 7.3 Hz, 1H), 4.75 (br s, 1H), 4.51
(ABq, J ) 12.2 Hz, ∆ν ) 14.4 Hz, 2H), 4.25 (ABq, J ) 11.8 Hz, ∆ν
) 64.9 Hz, 2H), 3.90 (d, J ) 12.8 Hz, 1H), 3.43 (t, J ) 6.9 Hz, 1H),
2.98 (br t, J ) 7.0 Hz, 1H), 2.80 (d, J ) 12.8 Hz, 1H), 2.45-2.29 (m,
2H), 2.17-1.33 (m, 8H), 1.53 (s, 3H), 1.16 (s, 3H), 0.97 (d, J ) 6.3
Hz, 3H), 0.74 (t, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) 140.0,
138.9, 138.5, 136.1, 128.2, 128.0, 127.7, 127.3, 127.1, 126.9, 125.6,
121.9, 86.6, 80.8, 76.8, 69.7, 66.1, 65.5, 53.4, 50.8, 39.2, 35.4, 26.3,
22.8, 22.4, 21.2, 18.9, 11.2, 10.3 ppm; MS (CI, isobutane) m/e 630
(MH), 522, 502, 410, 396, 364, 300, 147, 107, 91; HRMS (EI) m/e
538.1806 (538.1818 calcd for C26H37NO3I, M - PhCH2).
Diastereomer 47: [R]22 -20.8, [R]577 -24.7, [R]546 -25.6, [R]435
D
-32.4 (c 2.0, CHCl3); IR (film) 3438, 3294, 2982, 2250, 1455, 1380,
1239, 1038 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, ArH,
5H), 5.94 (br s, OH, 1H), 5.59 (t, J ) 7.2 Hz, 1H), 4.65 (d, J ) 1.2
Hz, 1H), 4.53 (ABq, JAB ) 10.8 Hz, ∆νAB ) 52.9 Hz, 2H), 3.92 (ABq,
JAB ) 17.3 Hz, ∆νAB ) 204.9 Hz, 2H), 3.88 (m, 2H), 3.54 (dd, J )
8.3, 4.4 Hz, 1H), 3.15 (m, 1H), 2.77 (dt, J ) 10.2, 7.0 Hz, 1H), 2.61
(dq, J ) 6.9, 1.6 Hz, 1H), 2.27 (m, 2H), 2.05 (m, 2H), 1.90 (m, 2H),
1.68 (s, 3H), 1.42 (s, 6H), 1.26 (s, 3H), 1.23 (d, J ) 5.5 Hz, 3H), 1.21
(d, J ) 6.9 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 138.9, 133.0,
128.3, 128.1, 127.4, 127.1, 127.0, 117.1, 107.9, 91.5, 88.3, 80.3, 79.1,
74.3, 69.5, 66.7, 63.7, 55.1, 44.4, 34.7, 27.4, 27.0, 26.8, 26.0, 24.9,
20.3, 18.6, 17.0, 11.6 ppm; MS (CI, isobutane) m/e 495, 468, 437,
410, 304; HRMS (CI) m/e 495.3223 (495.3223 calcd for C30H43N2O4
(MH).
(7R,8R,8aS)-8-(Benzyloxy)-7-hydroxy-8-methyl-6-(E)-[(2R,4E,6S)-
6-(benzyloxy)-2,5-dimethyl-4-octenylidine]octahydroindolizidine (44).
A hexane solution of n-BuLi (0.28 mL, 2.05 M, 0.58 mmol) was added
dropwise to a solution of 43 (66 mg, 0.11 mmol) and dry THF (4.0
mL) at -78 °C. This solution was maintained at -78 °C for 1 h and
MeOH (100 mL) was added. The resulting solution was allowed to
warm to room temperature and then was partitioned between CHCl3
(50 mL) and brine (30 mL). The organic layer was separated, dried
(K2CO3), and concentrated. Purification of the residue on silica gel
(50:1:0.1 CHCl3-MeOH-NH4OH) gave 44 mg (83%) of 44 as a
(7R,8R,8aS)-8-(Benzyloxy)-7-[(3R,5E,7R,8R)-3,6-dimethyl-7,8-O-
isopropylidene-5-decen-1-ynyl]-8-methyl-6-oxaoctahydroindolizi-
dine (48). Silver triflate (25 mg, 0.097 mmol) was added in one portion
to a solution of the alcohol 46 (20 mg, 0.041 mmol) and THF (1.5
mL) at room temperature. The reaction was protected from light and
colorless oil that was homogeneous by TLC analysis: [R]23 +2.5,
D
[R]577 +5.6, [R]546 +5.4, [R]435 +10.6, [R]405 +14.1 (c 1.1 CHCl3); IR
1
(film) 3431, 2962, 1456, 1093, 1056, 750, 700 cm-1; H NMR (300

9082 J. Am. Chem. Soc., Vol. 118, No. 38, 1996
Caderas et al.
was stirred at room temperature for 3h. The resulting mixture was
diluted with saturated aqueous NaHCO3 (2 mL) and then basified (pH
9) with 12 M NH4OH (∼5 drops). This mixture was extracted into
EtOAc (4 × 5 mL), the organic phase was dried (K2CO3) and
concentrated, and the residue was and purified on silica gel (3:2
hexane-EtOAc) to give 18 mg (94%) of oxazine 48 as a clear oil:
[R]22D -66.5, [R]577 -67.7, [R]546 -75.8, [R]435 -118 (c 2.2, CHCl3);
[R]23D +3.6, [R]577 -33.6, [R]546 -30.9 (c 1.0, CHCl3); IR (film) 3380
1
(br), 2958, 2798, 1455, 1374, 1217, 1028 cm-1; H NMR (300 MHz,
CDCl3) δ 7.35-7.28 (m, ArH, 5H), 5.38 (m, 1H), 5.23 (d, J ) 10.1
Hz, 1H), 4.55 (m, 2H), 4.09 (s, 1H), 3.76 (m, 1H), 3.67 (m, 1H), 3.50
(d, J ) 12.3 Hz, 1H), 3.00 (m, 1H), 2.88 (d, J ) 12.1 Hz, 1H), 2.72-
2.33 (m, 3H), 2.10-1.65 (m, 6H), 1.56 (s, 3H), 1.29 (s, 3H), 1.12 (d,
J ) 6.2 Hz, 3H), 1.08 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
140.6, 135.8, 135.0, 134.4, 128.8, 128.1, 128.0, 127.9, 127.7, 83.0,
75.9, 69.1, 66.8, 65.1, 55.1, 49.3, 36.2, 33.3, 30.4, 23.5, 21.8, 19.8,
19.2, 14.8, 13.0 ppm; MS (CI, isobutane) m/e 430, 338, 267, 236, 186;
HRMS (CI) m/e 430.2953 (430.2957 calcd for C26H40NO4, MH).
Allopumiliotoxin 339A (5). Following the procedure described for
the formation of 4, Li (38 mg, 6 mmol, containing 2% Na) was added
at -78 °C to a stirring solution of benzyl ether 52 (11 mg, 0.026 mmol)
and 2:1 NH3-THF (19 mL). The solution became deep blue within 3
min, 30 s later MeOH (3.5 mL) was added, and 3 min thereafter
saturated aqueous NH4Cl (7 mL) was added. The crude residues from
two identical reactions were combined and purified on silica gel (9:1:
0.15 CHCl3-MeOH-NH4OH) to give 13.5 mg (76%) of 5 as a
colorless oil: [R]22D +68.2, [R]577 +75.0, [R]546 +90.0 (c 1.0, CHCl3).
A natural sample isolated from D. pumilio showed [R]22D +52.0, [R]577
+60.3, [R]546 +75.0 (c 0.5, CHCl3), while a rotation of +29.4 (c 1.0,
MeOH) is reported for allopumiliotoxin 339A.4 Synthetic 5 exhibited
TLC mobility and 13C NMR and mass spectra indistinguishable from
those of the natural product. Moreover, a 1:1 mixture of synthetic and
natural 5 was homogeneous by TLC comparisons and by 500 MHz 1H
NMR analysis in CDCl3 and CD3OD.
1
IR (film) 3026, 2980, 2244, 1455, 1378, 1239, 1174, 1030 cm-1; H
NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, ArH, 5H), 5.57 (t, J ) 7.0
Hz, 1H), 5.0 (ABq, JAB ) 11.6 Hz, ∆νAB ) 115.5 Hz, 2H), 4.60 (ABq,
JAB ) 10.0 Hz, ∆νAB ) 106.4 Hz, 2H), 4.12 (d, J ) 1.8 Hz, 1H), 3.84
(m, 2H), 3.43 (dd, J ) 15.1, 7.7 Hz, 1H), 2.78 (dd, J ) 7.2, 3.7 Hz,
1H), 2.60 (m, 2H), 2.23 (m, 2H), 2.02 (m, 2H), 1.82 (m, 2H), 1.63 (s,
3H), 1.41 (s, 3H), 1.40 (s, 3H), 1.27 (s, 3H), 1.19 (d, J ) 5.2 Hz, 3H),
1.14 (d, J ) 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) 140.5, 133.3,
128.4, 127.4, 127.2, 127.1, 108.2, 92.1, 88.7, 82.3, 75.4, 74.9, 74.7,
67.8, 67.6, 49.9, 34.8, 27.8, 27.2, 26.4, 25.6, 23.2, 20.3, 18.9, 17.4,
12.0 ppm; MS (CI, isobutane) m/e 468, 410, 304, 246, 165; HRMS
(CI) m/e 468.3096 (468.3113 calcd for C29H42NO4, MH).
(7R,8R,8aS)-8-(Benzyloxy)-7-hydroxy-8-methyl-6-(E)-[(2R,6R,7R)-
6,7-dihydroxy-2,5-dimethyl-4-(E)-octenylidene]octahydroindoliz-
idine (52). A mixture of oxazine 48 (9 mg, 0.019 mmol), CSA (14
mg, 0.056 mmol), paraformaldehyde (3 mg, 0.10 mmol), NaI (28 mg,
0.19 mmol), H2O (750 µL), acetone (75 µL), and a small stirring bar
was placed in a 20 dr sealable vial. The vial was tightly capped,
lowered into a hot (100 °C) oil bath, and stirred for 2 h. After being
cooled to room temperature, the vial was carefully opened, diluted with
1 M aqueous Na2CO3 (2 mL), and extracted with CH2Cl2 (5 × 5 mL).
The organic phase was dried (K2CO3) and concentrated, and the residue
was purified on silica gel (9:1:0.15 CHCl3-MeOH-NH4OH) to give
8.5 mg (81%) of indolizidine iodide 51 as a colorless oil. This product
decomposed rapidly upon storage or in room light and was immediately
deiodinated. Diagnostic data for 51: IR (film) 3401 (br), 2975, 1455,
1216, 1052 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, ArH,
5H), 5.25 (dd, J ) 10.3, 4.2 Hz, 1H), 4.77 (s, 2H), 4.59 (s, 2H), 3.89
(d, J ) 12.9 Hz, 1H), 3.82 (t, J ) 6.0 Hz, 1H), 3.67 (d, J ) 5.9 Hz,
1H), 3.01 (d, J ) 12.7 Hz, 1H), 2.95 (dt, J ) 8.0, 3.0 Hz, 1H), 2.70
(dd, J ) 10.2, 3.5 Hz, 1H), 2.52-1.67 (m, 7H), 1.68 (s, 3H), 1.28 (s,
3H), 1.13 (d, J ) 6.4 Hz, 3H), 1.10 (d, J ) 6.2 Hz, 3H); 13C NMR
(125 MHz, MeOH-d4) 139.8, 138.4, 136.6, 127.8, 127.1, 125.8, 125.0,
82.9, 80.1, 78.3, 68.9, 66.3, 65.6, 53.0, 50.2, 39.4, 35.1, 22.5, 22.0,
21.8, 20.8, 18.7, 18.1, 11.5 ppm.
Acknowledgment. This paper is dedicated with respect and
affection to Nelson Leonard on the occasion of his 80th birthday.
This research was supported by grants from the National Heart,
Lung, and Blood Institute of the National Institutes of Health
(HL-25854). NMR and mass spectra were determined at Irvine
with instrumentation acquired with the assistance of the NSF
Shared Instrumentation program. We particularly thank Dr.
John Daly, Chief, Laboratory of Bioorganic Chemistry NIDDK,
NIH, for samples of natural allopumiliotoxins 267A, 323B′ and
339A.
Supporting Information Available: Experimental proce-
dures and characterization data for compounds 26-31 (4 pages).
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A hexane solution of n-BuLi (580 µL, 2.1 M) was added dropwise
to a stirring solution of a comparable sample of vinyl iodide 51 (27
mg, 0.049 mmol) and THF (6 mL) at -78 °C. After 1.5 h, the reaction
was quenched by the addition of MeOH (2 mL) and the resulting
solution was allowed to warm to room temperature. After concentra-
tion, the residue was purified on silica gel (9:1:0.15 CHCl3-MeOH-
NH4OH) to give 17 mg (81%) of indolizidine triol 52 as a clear oil:
JA961640Y