Total synthesis of pumiliotoxins 209F and 251D via late-stage, nickel-catalyzed epoxide-alkyne reductive cyclization

Article abstract of DOI:10.1021/jo071132e

(Chemical Equation Presented) Pumiliotoxins 209F and 251D were synthesized using highly selective nickel-catalyzed epoxide-alkyne reductive cyclizations as the final step. The exocyclic (Z)-alkene found in the majority of the pumiliotoxins was formed ster

Full text of DOI:10.1021/jo071132e

iminium ion-vinylsilane cyclization to this end in the first total
synthesis of pumiliotoxin 251D6a and later employed a related
iodide-promoted, iminium ion-alkyne cyclization to synthesize
more complex pumiliotoxins.4,8 Gallagher used a stereospecific
elimination of a â-hydroxylactam to install the (Z)-alkene in
the synthesis of pumiliotoxin 251D.6b In the synthesis described
herein, we have reduced the construction of the pumiliotoxins
to simultaneous and stereospecific installation of the exocyclic
Z-alkene and tertiary alcohol present in the final step of the
synthesis.
Total Synthesis of Pumiliotoxins 209F and 251D
via Late-Stage, Nickel-Catalyzed Epoxide-Alkyne
Reductive Cyclization
Katrina S. Woodin and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
tfj@mit.edu
Our strategy is based on the notion that both of these
challenges could be addressed by nickel-catalyzed reductive
cyclizations9 of epoxy alkynes previously developed in our
laboratory (Figure 1).10 However, all of the epoxides in our
earlier investigations were monosubstituted (terminal). Thus, a
major question in the context of the pumiliotoxins was whether
or not 1,1-disubstituted epoxides (e.g., 3a and 3b), which we
had previously found to be recalcitrant substrates, would undergo
reductive cyclization.11 Furthermore, in order to be used as the
final step, the regioselectivity of both alkyne addition and
epoxide ring-opening could not depend upon the use of a
directing group on the alkyne. Nevertheless, proline-derived
ketones 4a and 4b and propargyl bromides 5a and 5b were
attractive precursors and readily available. Accordingly, we
began our investigations by preparing these intermediates via
chiral ketones 4a and 4b.
ReceiVed June 6, 2007
Pumiliotoxins 209F and 251D were synthesized using highly
selective nickel-catalyzed epoxide-alkyne reductive cycliza-
tions as the final step. The exocyclic (Z)-alkene found in
the majority of the pumiliotoxins was formed stereospecifi-
cally and regioselectively, without the use of a directing
group on the alkyne, and the epoxide underwent ring opening
exclusively at the less hindered carbon to provide the
requisite tertiary alcohol. The epoxides were prepared using
diastereoselective addition of a sulfoxonium anion to a
proline-derived methyl ketone.
The pumiliotoxins were first isolated in 1967 from the
Dendrobates pumilio frogs in South America.1,2 The structure
and stereochemistry of these alkaloids were initially established
via X-ray crytallographic analysis of the hydrochloride salt of
pumiliotoxin 251D (1)3 and confirmed by total syntheses of
several members of this family of natural products.4-7 Thirty
pumiliotoxins have a (Z)-6-alkylideneindolizidine ring system
and a tertiary alcohol at C8.
FIGURE 1. Retrosynthetic analysis of the pumiliotoxins.
Several different strategies have been developed for the
synthesis of the ubiquitous (Z)-alkene. Overman used an
Treatment of carbamate-protected proline methyl esters 6a
and 6b12 with N,O-dimethylhydroxylamine hydrochloride and
trimethylaluminium afforded Weinreb amides 7a and 7b,
(1) Daly, J. W.; Myers, C. W. Science 1967, 156, 970-973.
(2) For a recent review of pumiliotoxins, see: Daly, J. W.; Spande, T.
F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556-1575.
(7) Formal syntheses of pumiliotoxins: (a) Honda, T.; Hoshi, M.; Kanai,
K.; Tsubuki, M. J. Chem. Soc., Perkin Trans. 1 1994, 2091-2101. (b)
Cossy, J.; Cases, M.; Pardo, D. G. Synlett 1996, 909-910. (c) Barrett, A.
G. M.; Damiani, F. J. Org. Chem. 1999, 64, 1410-1411. (d) Martin, S. F.;
Bur, S. K. Tetrahedron 1999, 55, 8905-8914. (e) Ni, Y.; Zhao, G.; Ding,
Y. J. Chem. Soc., Perkin Trans. 1 2000, 3264-3266. (f) Wang, B.; Fang,
K.; Lin, G.-Q. Tetrahedron Lett. 2003, 44, 7981-7984.
(8) Overman, L. E.; Sharp, M. J. Tetrahedron Lett. 1988, 29, 901-904.
(9) In the syntheses of several allopumiliotoxins, Montgomery utilized
a diastereoselective nickel-catalyzed alkyne-aldehyde reductive cyclization
to establish the (Z)-alkene and the configuration of a secondary alcohol:
(a) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098-
6099. (b) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950-
6954. (c) Review: Montgomery, J. Angew. Chem. 2004, 43, 3890-3908.
(10) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076-
8077.
(3) Daly, J. W.; Tokuyama, T.; Fujiwara, T.; Highet, R. J.; Karle, I. L.
J. Am. Chem. Soc. 1980, 102, 830-836.
(4) For a review of pumiliotoxin syntheses, see: Franklin, A. S.;
Overman, L. E. Chem. ReV. 1996, 96, 505-522.
(5) Total syntheses of pumiliotoxin 209F: (a) Overman, L. E.; Lesuisse,
D. Tetrahedron Lett. 1985, 26, 4167-4170. (b) Kibayashi, C.; Aoyagi, S.
Synth. Org. Chem. Jpn. 1999, 57, 981-992. 8-epi-Pumiliotoxin 209F: (c)
Sudau, A.; Mu¨nch, W.; Bats, J.-W.; Nubbemeyer, U. Eur. J. Org. Chem.
2002, 3315-3325.
(6) Total syntheses of pumiliotoxin 251D: (a) Overman, L. E.; Bell, K.
L. J. Am. Chem. Soc. 1981, 103, 1851-1853. (b) Fox, D. N. A.; Lathbury,
D.; Mahon, M. F.; Molloy, K. C.; Gallagher, T. J. Am. Chem. Soc. 1991,
113, 2652-2656. (c) Racemic 251D: Bargar, T. M.; Lett, R. M.; Johnson,
P. L.; Hunter, J. E.; Chang, C. P.; Pernich, D. J.; Sabol, M. R.; Dick, M. R.
J. Agric. Food Chem. 1995, 43, 1044-1051. (d) See also ref 5c.
10.1021/jo071132e CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/14/2007
J. Org. Chem. 2007, 72, 7451-7454
7451

respectively, in good yield (Scheme 1). Conversion of these
amides to ketones 4a and 4b proceeded in a similarly straight-
forward manner, setting the stage for investigation of the step
that would set the stereogenic center corresponding to the tertiary
alcohol in the natural products.13
conditions evaluated. We thus turned our attention to the Alloc
series and found that the conditions that provided high dr in
the Cbz series (NaH, trimethylsulfoxonium chloride) gave
similar results with Alloc-protected ketone 4b. However,
although the desired product had formed with high diastereo-
selectivity, it was optically inactive, suggesting that racemization
of ketone 4b had occurred prior to the epoxidation. A careful
examination of reagents and reaction conditions revealed that
the racemization could be prevented by the use of n-BuLi
(instead of NaH) at a lower reaction temperature (Scheme 3).18
This sequence provided epoxide 8b with high diastereoselec-
tivity and optical purity. Removal of the Alloc group was
effected with catalytic Pd(dba)2 and dppb in the presence of
excess diethylamine.19 The free amine was treated with prop-
argyl bromide 5a20 (Na2CO3/acetone) to form epoxy alkyne 3a,
thus setting the stage for the critical nickel-catalyzed step.
SCHEME 1. Synthesis of Proline-Derived Ketone 4
SCHEME 3. Synthesis of Epoxy Alkyne 3a (209F
Precursor)
Application of the Corey-Chaykovsky14 sulfur-ylide ep-
oxidation method provided stereochemically complementary
results, depending on which sulfonium reagent was employed.15
When Cbz-protected ketone 4a was subjected to dimethylsul-
fonium methylide, the undesired diastereomer (epoxide 8a) was
formed with high selectivity (>10:1 dr) in good yield, but both
diastereomers were optically inactiVe, suggesting rapid racem-
ization of the proline derivative prior to a highly diastereose-
lective epoxide formation (Scheme 2). Gratifyingly, when
dimethyloxosulfonium methylide was used, the desired diaste-
reomer (8a) was afforded in good yield and in a highly
diastereoselective fashion (>10:1 dr). It was further discovered
that the carbamate group was required to impart the high
diastereoselectivity during the epoxidation, as other proline-
derived ketones gave a 1:1 mixture of diastereomers.16 The
dimethylsulfonium methylide reagent often exhibits kinetic
control of stereoselectivity. In a Felkin-Ahn analysis of the
reaction at hand, the nucleophile would approach anti to the
carbamate group, leading to the observed diastereomer (8a,
undesired). Conversely, diastereoselective dimethylsulfoxonium
methylide addition reactions tend to be under thermodynamic
control. Epoxide 8a (desired) may thus be favored under these
conditions because of the reversible nature of the addition
process and a greater thermodynamic stability of either a
subsequent intermediate or of 8a itself.17
Under reaction conditions routinely used in intermolecular
nickel-catalyzed coupling reactions between alkynes and ter-
minal epoxides,9 no conversion of epoxy alkyne substrate 3a
was observed (Table 1, entry 1). However, conducting the
reaction in the absence of an additional solvent did lead to the
formation of small amounts of the desired product, pumiliotoxin
209F (2). The largest increase in yield was imparted by
(11) Molinaro, C.; Jamison, T. F. Unpublished results.
(12) (a) Cbz-Pro methyl ester is commericially available. (b) Alloc-Pro
methyl ester was prepared in quantitative yield from Pro methyl ester and
allyl chloroformate; see: Yamada, Y.; Takahashi, W.; Asada, Y.; Holiuchi,
J.; Takeda, K.; Harigaya, Y. Chem. Pharm. Bull. 2004, 52, 1082-1085.
(13) Epimerization of ketones 4a and 4b was not observed (chiral GC
analysis).
SCHEME 2
(14) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-
1364.
(15) For a discussion on kinetic vs. thermodynamic control in sulfur ylide
addition reactions, see: Johnson, C. R.; Schroeck, C. W.; Shanklin, J. R. J.
Am. Chem. Soc. 1973, 95, 7424-7431.
(16) For a discussion on sulfur-ylide epoxidation of similar pyrrolidines,
see: Fray, M. J.; Thomas, E. J.; Wallis, J. D. J. Chem. Soc., Perkin Trans.
1 1983, 395-401.
(17) For a discussion of substrate control in sulfur-ylide epoxidations,
see: Li, H-H; Dai, L-X, Aggarwal, V. K. Chem. ReV. 1997, 97, 2341-
2372 and references cited therein.
(18) Racemization could also be prevented by using less NaH (150 mol%)
and by lowering the reaction temperature, but conversion to product was
much slower. See the Supporting Information for details.
(19) Geneˆt, J. P.; Blart, E.; Savignac, M.; Lemeune, S.; Lemaire-Audoire,
S.; Bernard, J. M. Synlett 1993, 680-682.
(20) Propargyl bromide 5a was prepared by treatment of 4-methylpent-
2-yn-1-ol with CBr4 and PPh3 in CH2Cl2. See the Supporting Information
for details.
Attempts to remove the Cbz group from epoxide 8a unfor-
tunately led to a complex mixture of products under all
7452 J. Org. Chem., Vol. 72, No. 19, 2007

TABLE 1. Synthesis of Pumiliotoxin 209F via Nickel-Catalyzed
Reductive Cyclizationa
SCHEME 4. Synthesis of Epoxy Alkyne 3b (251D
Precursor)
solvent
added
Et3B
(mol %)
phosphine
additive
isolated
yield (%)
entry
T (°C)
1
2
3
4
5
6
Et2O
none
none
none
none
none
23
23
65
65
65
65
250
250
250
150
150
150
PBu3
PBu3
PBu3
PBu3
PCyp3
PMe2Ph
0
9
53
61
0
70
a See the Supporting Information for experimental details.
be required to convert a known intermediate in the 209F
synthesis to pumiliotoxin 251D.
The route to pumiliotoxin 251D thus began with synthesis
of alcohol 10 from aldehyde 925 using the Corey-Fuchs reaction
(Scheme 4).26 This alcohol was converted to bromide 5b, and
epoxide 3b was afforded by alkylation of the primary amine
prepared previously.
As was the case in the pumiliotoxin 209F studies, the final
step of the 251D synthesis, nickel-catalyzed reductive cyclization
of epoxy alkyne 3b proceeded smoothly, affording the natural
product in 82% yield as a single diastereomer and regioisomer
(Scheme 5).
conducting the reaction at slightly elevated temperature (entry
3). By lowering the amount of Et3B to 150 mol %, which also
considerably increased the concentration of the reaction,
the yield appreciated further (entry 4). The phosphine employed
also had a dramatic effect on the yield. The larger tricyclo-
pentylphosphine (PCyp3) was inferior to tributylphosphine
(PBu3), and the smaller PMe2Ph was superior to all phosphines
evaluated (entries 5 and 6).21-23 Under the optimum con-
ditions, the nickel-catalyzed reductive cyclization of epoxy
alkyne 2a proceeded in 70% yield to produce pumiliotoxin 209F
(2).
In addition to representing the first example of a successful
nickel-catalyzed cyclization between a 1,1-disubstituted epoxide
and an alkyne, a noteworthy element of selectivity was that the
six-membered ring was formed exclusively. The other alkyne
addition regioisomer would have led to a seven-membered ring
containing an alkene. This isomer was not observed, likely
because cis addition to the alkyne, a process that occurs with
very high fidelity, would lead to a highly strained trans alkene
in the seven-membered ring as the carbon-carbon bond formed.
In a similar vein, no evidence of epoxide opening at the more
hindered carbon, which would lead to a five-membered ring,
was observed. We believe that the sense of epoxide-opening
regioselectivity is largely dictated by this difference in steric
hindrance, and it is also possible that the Ni complex reacts
with the epoxide first, which in turn classifies addition to the
alkyne as a 6-exo-dig cyclization.10
SCHEME 5. Synthesis of Pumiliotoxin 251D via
Nickel-Catalyzed Reductive Cyclization
In summary, pumiliotoxin 209F was synthesized in seven
steps (longest linear sequence) in 25% overall yield, and
pumiliotoxin 251D was synthesized in nine linear steps from
commercial materials in 17% overall yield. Both syntheses
utilized a novel cyclization reaction, an intramolecular, nickel-
catalyzed reductive coupling of a 1,1-disubstituted epoxide, and
an alkyne. In this way, the tertiary homoallylic alcohol and
exocyclic trisubstituted alkene moieties present in this family
of natural products were prepared in the final step of each total
synthesis. For these reasons, this strategy shows promise for
entry into other members of the pumiliotoxin family by way of
a common intermediate.
To investigate the utility and scope of this cyclization further
and to take advantage of the high degree of convergence in
this strategy, pumiliotoxin 251D (1) was also synthesized.
Substitution of the appropriate propargyl electrophile for 5a
(Scheme 3) would provide the necessary educt for the nickel-
catalyzed reductive cyclization. In other words, after preparation
of propargyl bromide 5b,24 only two new transformations would
Experimental Section
(S)-Allyl 2-((R)-2-Methyloxiran-2-yl)pyrrolidine-1-carboxy-
late (8b). Me3SOCl (0.096 g, 0.75 mmol) was dissolved in THF
(7 mL) and n-BuLi (0.22 mL, 0.55 mmol, 2.5 M in hexanes) was
added dropwise at rt. The reaction was stirred at rt for 4.5 h and
(21) Other phosphine ligands evaluated include P(n-octyl)3, P(o-anisyl)3,
P(CH2CH2CN)3, P(OEt)Ph2, P(OEt)2Ph, and P(OEt)3.
(22) The cone angles of PBu3 and PMe2Ph are 132° and 122°,
respectively: Rahman, M. M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering,
W. P. Organometallics 1989, 8, 1-7.
(23) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes,
P. Chem. ReV. 2000, 100, 2741-2770.
(25) Synthesis of aldehyde 9 in 56% yield over four steps: Goldstein,
S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1992, 57, 1179-
1190.
(24) Preparation of bromide 5b: Okamoto, S.; Iwakubo, M.; Kobayashi,
K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 6984-6990.
(26) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769-3772.
J. Org. Chem, Vol. 72, No. 19, 2007 7453

then cooled to -20 °C, and the slurry was added to the ketone 4b
(0.099 g, 0.5 mmol), dissolved in THF (2 mL), dropwise via cannula
over 20 min. The reaction was stirred at -20 °C for 32 h and
quenched with 0.1 M NaHSO4 (10 mL).7 The aqueous layer was
extracted with ethyl acetate (3 × 10 mL), and the organic extracts
were washed with brine (50 mL) and dried over Na2SO4. The
solution was filtered and concentrated in vacuo and was purified
by flash column chromatography (3:7 EtOAc/hexanes) to give alloc-
protected epoxide 8b (0.076 g, 72% yield, 91:9 dr favoring desired
diastereomer, >98% ee, as determined by chiral GC): Rf 0.41 (1:1
dried, sealed tube, which was sealed with a rubber septum and
Teflon cap. The tube was removed from the glovebox and placed
under argon, and triethylborane (22 µL, 0.15 mmol) was added
via syringe. The resulting solution was stirred for 5 min, and the
epoxy alkyne 3a (21 mg, 0.10 mmol) was added dropwise via
microsyringe. The reaction was heated to 65 °C and allowed to
stir for 16 h. The solution was then cooled to rt, and ether (2 mL)
was added to dilute the solution at which point the septum was
removed and the reaction was stirred 30 min open to air to promote
quenching of the catalyst. The crude mixture was purified by flash
chromatography on silica gel using a solvent gradient (1:49 to 1:19
MeOH/CHCl3) to give pumiliotoxin 209F (2) as a colorless oil (14.6
1
EtOAc/hexanes); H NMR (500 MHz, CDCl3) (reported as ∼1:1
mixture of rotamers) δ 5.97-5.90 (m, 2H), 5.31 (dd, J ) 10.4, 1.1
Hz, 2H), 5.20 (dd, J ) 10.4, 1.1 Hz, 2H), 4.68-4.52 (m, 4H),
4.06 (d, J ) 6.4 Hz, 1H), 3.94 (d, J ) 6.4 Hz, 1H), 3.62-3.28 (m,
4H), 2.63 (d, J ) 4.6 Hz, 2H), 2.53 (d, J ) 4.6 Hz, 2H), 2.10-
1.67 (m, 8H), 1.35 (s, 3H), 1.33 (s, 3H); 13C NMR (125 MHz,
CDCl3) (reported as ∼1:1 mixture of rotamers) δ 155.6, 155.3,
133.3, 117.5, 117.4, 65.9, 59.5, 59.0, 52.6, 52.4, 47.7, 47.2, 29.0,
27.8, 24.6, 23.9, 19.9, 19.6; IR (thin film NaCl) 3057, 2980, 2882,
1702, 1648, 1405, 1350, 1335, 1277, 1186, 1121, 1098, 919, 774
cm-1; HRMS (ESI) m/z 234.1105 [M + Na; calcd for C11H17NO3
234.1101]; [R]D ) -80.8 (23 °C, 589 nm, 0.45 g/100 mL, CHCl3).
(S)-2-((R)-2-Methyloxiran-2-yl)-1-(4-methylpent-2-ynyl)pyr-
rolidine (3a). Pd(dba)2 (0.086 g, 0.15 mmol) and dppb (0.064 g,
0.15 mmol) were combined in a glove box. Alloc-protected epoxide
8b (0.317 g, 1.5 mmol) in THF (4 mL) was added followed by
addition of diethylamine (2.3 mL, 22.5 mmol). The reaction was
stirred at rt for 2 h and then filtered through a plug of Celite with
ether (10 mL) to removed the palladium catalyst andas concentrated
in vacuo to form free amine. The amine was dissolved in acetone
(15 mL), Na2CO3 (0.398 g, 3.75 mmol) and propargyl bromide 5a
(0.290 g, 1.8 mmol) were added, and the reaction was allowed to
stir at rt for 16 h. The solvent was removed in vacuo, and the
compound was purified by flash column chromatography using a
solvent gradient (1:19 to 3:7 EtOAc/hexanes) to give amine 3a as
a pale yellow oil (0.17 g, 55% yield over the two steps, 91:9 dr
retained): Rf 0.51 (1:1 EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) (reported as a 10:1 mixture of diastereomers, asterisk
denotes minor diastereomer) δ 3.60 (dd, J ) 16.7, 1.9 Hz, 1H),
3.49* (dd, J ) 16.7, 1.9 Hz, 0.1H), 3.41* (dd, J ) 16.7, 1.9 Hz,
0.1H), 3.31 (dd, J ) 16.7, 1.9 Hz, 1H), 3.08 (t, J ) 7.3 Hz, 1H),
2.96* (t, J ) 7.3 Hz, 0.1H), 2.77* (d, J ) 5.3 Hz, 0.1H), 2.62-
2.48 (m, 4H), 2.27 (t, J ) 7.33 Hz, 1H), 1.89-1.70 (m, 4H), 1.33
(s, 3H), 1.29* (s, 0.3H), 1.60 (d, J ) 6.9 Hz, 6H) 1.15* (d, J ) 6.9
Hz, 0.6H); 13C NMR (125 MHz, CDCl3) (major and minor peaks
reported) δ 91.2, 90.4, 74.7, 73.9, 66.8, 65.4, 58.1, 57.4, 54.0, 53.5,
53.2, 51.0, 42.6, 41.8, 28.4, 27.8, 23.6, 23.5, 23.3, 23.1, 20.8, 20.7,
16.8, 16.7; IR (thin film NaCl) 3035, 2969, 2873, 2813, 2242, 1462,
1444, 1400, 1368, 1319, 1180, 1123, 1095, 1067, 909 cm-1; HRMS
(ESI) m/z 208.1695 [M + H; calcd for C13H21NO 208.1696]; [R]D
) -40.4 (23 °C, 589 nm, 0.2 g/100 mL, CHCl3).
1
mg, 70% yield, 1 diastereomer): Rf 0.33 (1:9 MeOH/CHCl3); H
NMR (500 MHz, CDCl3) δ 5.11 (d, J ) 9.2 Hz, 1H), 3.80 (d, J )
11.9 Hz, 1H), 3.07 (t, J ) 8.3 Hz, 1H), 2.67 (s, 1H), 2.60-2.55
(m, 1H), 2.36 (d, J ) 11.9 Hz, 1H), 2.24-2.20 (m, 1H), 2.12 (d,
J ) 13.8 Hz, 1H), 2.09 (d, J ) 13.8 Hz, 1H), 1.98 (t, J ) 5.0 Hz,
1H), 1.79-1.65 (m, 4H), 1.14 (s, 3H), 0.99 (d, J ) 6.7 Hz, 3H),
0.92 (d, J ) 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 135.8,
129.4, 71.9, 68.6, 54.6, 53.1, 48.9, 26.96, 24.5, 23.7, 23.6, 23.4,
21.3; IR (thin film NaCl) 3512, 2959, 2874, 2785, 2743, 1464,
1445, 1424, 1396, 1376, 1321, 1309, 1297, 1275, 1216, 1175, 1150,
1098, 967 cm-1; HRMS (ESI) m/z 210.1852 [M + H; calcd for
C13H23NO 210.1849]; [R]D ) -12.8 (23 °C, 589 nm, 0.3 g/100
mL, CHCl3).
Pumiliotoxin 251 D (1): same experimental procedure as 2; Rf
1
0.30 (1:9 MeOH/CHCl3); H NMR (500 MHz, CDCl3) δ 5.04 (d,
J ) 9.5 Hz, 1H), 3.78 (d, J ) 12.0 Hz, 1H), 3.07-3.03 (m, 1H),
2.67 (s, 1H), 2.42-2.30 (m, 1H), 2.34 (d, J ) 12.0 Hz, 1H), 2.25-
2.15 (m, 1H), 2.15-2.12 (m, 2H), 2.00-1.90 (m, 1H), 1.78-1.60
(m, 4H), 1.32-1.10 (m, 6H), 1.14 (s, 3H), 0.97 (d, J ) 6.5 Hz,
3H), 0.87 (t, J ) 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
134.7, 130.0, 71.8, 68.4, 54.7, 53.3, 48.9, 37.6, 32.2, 29.8, 24.4,
23.3, 22.9, 21.8, 21.2, 14.2; IR (thin film NaCl) 3418, 2982, 2909,
2872, 1660, 1465, 1420, 1324, 1305, 1291, 1176, 1121, 1072, 939,
913, 871 cm-1; HRMS (ESI) m/z 252.2321 [M + H; calcd for
C16H29NO: 252.2322]; [R]D ) -9.3 (23 °C, 589 nm, 0.05 g/100
mL, CHCl3).
Acknowledgment. This work was supported by the National
Institutes of General Medical Sciences (Grant No. GM-063755).
We are grateful to Ms. Li Li for obtaining mass spectrometric
data for all compounds (MIT Department of Chemistry Instru-
mentation Facility, which is supported in part by the NSF (Grant
Nos. CHE-9809061 and DBI-9729592) and the NIH (Grant No.
1S10RR13886-01)).
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Pumiliotoxin 209F (2). In a glovebox, Ni(cod)2 (5.6 mg, 0.02
mmol) and PMe2Ph (5.7 µL, 0.04 mmol) were placed into an oven-
JO071132E
7454 J. Org. Chem., Vol. 72, No. 19, 2007