Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Syntheses of Indolizidine Alkaloids (-)-205A, (-)-207A, and (-)-235B

Article abstract of DOI:10.1021/jo971448u

Concise asymmetric syntheses of indolizidine alkaloids (-)-205A, (-)-207A, and (-)-235B were accomplished with a high degree of stereocontrol in eleven steps. Addition of 4-(1-butenyl)-magnesium bromide to 1-acylpyridinium salt 5, prepared in situ from 4-methoxy-3-(triisopropylsilyl)-pyridine and the chloroformate of (+)trans-2-(α-cumyl)cyclohexanol, gave a 91% yield of diastereomerically pure dihydropyridone 6. Oxidative cleavage of 6 and subsequent reduction provided alcohol 7 in 81% yield. Removal of the chiral auxilliary and TIPS group (NaOMe; 10% HCl), N-acylation with BnOCOCCl, and treatment with NCS/Ph₃P gave chloride 10. Methylation at C-3, copper-mediated conjugate addition of 4-(benzyloxy)butylmagnesium bromide, and vinyl triflate formation provided 13 in a stereoselective fashion. Catalytic reduction of the vinyl triflate moiety, simultaneous cleavage of the benzyl ether and Cbz groups, and cyclization to give amino alcohol 14 was effected via a one-pot reaction. Oxidation of 14 with the Dess-Martin reagent gave a 97% yield of amino aldehyde 4. Synthesis of each of the three title alkaloids was accomplished in one step from 4. The Seyferth-Gilbert reaction provided a 41% yield of (-)-205A. The appropriate Wittig olefination of 4 gave indolizidines (-)-207A and (-)-235B in 70% and 86% yield, respectively.

Full text of DOI:10.1021/jo971448u

8182
J . Org. Chem. 1997, 62, 8182-8187
En a n tiop u r e N-Acyld ih yd r op yr id on es a s Syn th etic In ter m ed ia tes:
Asym m etr ic Syn th eses of In d olizid in e Alk a loid s (-)-205A, (-)-207A,
a n d (-)-235B
Daniel L. Comins,* Donald H. LaMunyon, and Xinghai Chen
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
Received August 4, 1997X
Concise asymmetric syntheses of indolizidine alkaloids (-)-205A, (-)-207A, and (-)-235B were
accomplished with a high degree of stereocontrol in eleven steps. Addition of 4-(1-butenyl)-
magnesium bromide to 1-acylpyridinium salt 5, prepared in situ from 4-methoxy-3-(triisopropylsilyl)-
pyridine and the chloroformate of (+)-trans-2-(R-cumyl)cyclohexanol, gave a 91% yield of diaste-
reomerically pure dihydropyridone 6. Oxidative cleavage of 6 and subsequent reduction provided
alcohol 7 in 81% yield. Removal of the chiral auxilliary and TIPS group (NaOMe; 10% HCl),
N-acylation with BnOCOCCl, and treatment with NCS/Ph3P gave chloride 10. Methylation at C-3,
copper-mediated conjugate addition of 4-(benzyloxy)butylmagnesium bromide, and vinyl triflate
formation provided 13 in a stereoselective fashion. Catalytic reduction of the vinyl triflate moiety,
simultaneous cleavage of the benzyl ether and Cbz groups, and cyclization to give amino alcohol
14 was effected via a one-pot reaction. Oxidation of 14 with the Dess-Martin reagent gave a 97%
yield of amino aldehyde 4. Synthesis of each of the three title alkaloids was accomplished in one
step from 4. The Seyferth-Gilbert reaction provided a 41% yield of (-)-205A. The appropriate
Wittig olefination of 4 gave indolizidines (-)-207A and (-)-235B in 70% and 86% yield, respectively.
The indolizidine ring system is found in many biologi-
alkaloids containing the 5-substituted 8-methylindolizine
ring system were isolated from skin extracts of neotro-
pical members of the Dendrobatidae family of frogs.5
These 5,8-disubstituted indolizidines appear to represent
an atypical and potent class of noncompetitive blockers
for muscle-type and ganglionic nicotinic receptor-
channels.5c In this paper we report the asymmetric
synthesis of three of these indolizidine alkaloids, (-)-
205A (1), (-)-207A (2), and (-)-235B (3), from a common
intermediate 4.
cally active and structurally interesting alkaloids.1 Al-
though numerous preparations of these alkaloids have
been reported,2 the development of concise enantioselec-
tive approaches is still a worthy synthetic goal. We have
found that chiral N-acyl-2,3-dihydro-4-pyridones are
excellent synthetic building blocks due to their facile
preparation, the functionality present, their availability
in either enantiomerically pure form, good air stability,
and the ease of introducing ring substituents in a regio-
and stereocontrolled manner.3 Various alkaloids have
been prepared in our laboratories via dihydropyridone
intermediates, including indolizidines (()-209B,4a (+)-
209D,2c (+)-elaeokanine A,4b (+)-elaeokanine C,4b (-)-
septicine,4c and (-)-tylophorine.4c Recently, several new
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) Reviews: (a) Suffness, M.; Cordell, G. A. In The Alkaloids; Brossi,
A., Ed.; Academic Press: Orlando, FL, 1985; Vol. 25, Chapter 1, pp
3-355. (b) Gellert, E. In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; J ohn Wiley & Sons: New York, 1987; Vol.
5, p 55. (c) Takahata, H.; Momose, T. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press, Inc.: San Diego, 1993; Vol. 44, Chapter 3. (d)
Michael, J . P. Nat. Prod. Rep. 1997, 14, 21-41.
(2) For recent examples of and leading references to the synthesis
of indolizidine natural products see: (a) Angle, S. R.; Breitenbucher,
J . G. In Studies in Natural Products Chemistry; Stereoselective
Synthesis, Atta-ur-Rahman, Ed.; Elsevier: New York, 1995; Vol. 16,
Part J , pp 453-502. (b) Okano, T.; Sakaida, T.; Eguchi, S. Heterocycles
1997, 44, 227-236. (c) Comins, D. L.; Zhang, Y. M. J . Am. Chem. Soc.
1996, 118, 12248-12249. (d) Michael, J . P.; Gravestock, D. Synlett
1996, 981-982. (e) Thanh, G. V.; Ce´le´rier, J . P.; L’hommet, G.
Tetrahedron Asymmetry 1996, 7, 2211-2212. (f) Chan, C.; Cocker, J .
D.; Davies, H. G.; Gore, A.; Green, R. H. Bioorg. Med. Chem. Lett. 1996,
6, 161-164. (g) Li, Y. W.; Marks, T. J . J . Am. Chem. Soc. 1996, 118,
707-708. (h) Takahata, H.; Bandoh, H.; Momose, T. Heterocycles 1996,
42, 39-42.
(3) (a) Comins, D. L.; J oseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J ., Ed.; J AI Press: Inc.: Greenwich, CT, 1996;
Vol. 2, pp 251-294. (b) Comins, D. L.; J oseph, S. P.; Chen, X.
Tetrahedron Lett. 1995, 36, 9141. (c) Comins, D. L.; J oseph, S. P.;
Peters, D. D. Tetrahedron Lett. 1995, 36, 9449. (d) Comins, D. L.;
J oseph, S. P.; Zhang, Y. Tetrahedron Lett. 1996, 37, 793. (e) Comins,
D. L.; Guerra-Weltzien, L. Tetrahedron Lett. 1996, 37, 3807. (f) Comins,
D. L.; Chen, X.; J oseph, S. P. Tetrahedron Lett. 1996, 37, 9275.
(4) (a) Comins, D. L.; Zeller, E. Tetrahedron Lett. 1991, 32, 5889.
(b) Comins, D. L.; Hong, H. J . Am. Chem. Soc. 1991, 113, 6672. (c)
Comins, D. L.; Chen, X.; Morgan, L. A. J . Org. Chem. 1997, submitted.
Our plan for synthesizing key intermediate 4 (Scheme
1) called for a regio- and stereoselective construction
starting with chiral 1-acylpyridinium salt 5, prepared in
(5) (a) Daly, J . W.; Spande, T. F. In Alkaloids: Chemical and
Biological Perspectives, Ed.; Pelletier, S. W., Wiley: New York, 1986;
Vol. 4, Chapter 1, pp 1-274. (b) Daly, J . W.; Garraffo, H. M.; Spande,
T. F. In The Alkaloids; Cordell, G. A.; Ed.; Academic Press: San Diego,
1993; Vol. 43, pp 185-288. (c) Daly, J . W.; Nishizawa, Y.; Padgett, W.
L.; Tokuyama, T.; Smith, A. L.; Holmes, A. B.; Kibayashi, C.; Aronstam,
R. S. Neurochem. Res. 1991, 16, 1213-18.
S0022-3263(97)01448-5 CCC: $14.00 © 1997 American Chemical Society

Enantiopure N-Acyldihydropyridones
J . Org. Chem., Vol. 62, No. 23, 1997 8183
Sch em e 1
F igu r e 1. Stereoelectronically preferred axial attack on the
chair conformation of 11.
hydride, or ozonolysis of the terminal alkene followed by
reductive workup, resulted in low yields (∼25%) of the
desired alcohol 7. Removal of the chiral auxiliary with
sodium methoxide in refluxing methanol, subsequent
addition of aqueous 10% HCl to effect protodesilylation,
and anhydrous workup afforded 89% of the amino alcohol
8 as a white solid. The chiral auxiliary ((+)-TCC) was
recovered in 96% yield. Selective N-acylation of 8 was
effected by deprotonation with 1.05 equiv of n-BuLi in
THF at -78 °C and addition of benzyl chloroformate to
give dihydropyridone 9. The alcohol to chloride conver-
sion was achieved in 94% yield under mild conditions by
treatment of 9 with triphenylphosphine and N-chloro-
succinimide to give 10. Enolate formation using LHMDS
in THF and reaction with methyl iodide gave 96% of
trans-2,3-dihydro-4-pyridone 11. No cis-product or in-
1
tramolecular alkylated product was evident from the H
NMR spectrum of the crude product.8 Treatment of 11
with BF3‚OEt2, CuBr‚DMS, and [4-(benzyloxy)butyl]-
magnesium bromide provided an 89% yield of (2S,3S,6R)-
piperidone 12. Presence of the C-2,C-6 trans-diastere-
omer could not be detected by 1H NMR or by HPLC
analysis, and none was found during purification by
chromatography. Preference for the formation of the cis-
diastereomer 12 via attack at C-6 of 11 was anticipated
based on stereoelectronic arguments and previous results
from our laboratories.3a,9 Due to a strong A(1,3) strain
between the alkyl substituent at C-2 and the N-acyl
group of 11, the C-2 and C-3 substituents are forced into
an axial orientation of a chairlike conformation (see
Figure 1). Stereoelectronically preferred axial attack by
the organocuprate at C-6 of 11 leads to the observed
diastereospecificity.
Since the vinyl triflate 13 was needed, several unsuc-
cessful attempts were made to trap the resulting enolate
from the conjugate addition of 11 with triflating re-
agents.10 Although vinyl triflates have been prepared by
in situ trapping of enolates prepared from copper-
mediated conjugate addition reactions,10,11 the presence
of BF3‚OEt2 in our reaction prevented vinyl triflate
formation. Since the use of BF3‚OEt2 was needed to
obtain a high yield and the desired stereoselectivity in
the formation of 12,9 an additional step was used to
situ from 4-methoxy-3-(triisopropylsilyl)pyridine6 and the
chloroformate of (+)-trans-2-(R-cumyl)cyclohexanol(TCC).7
The Grignard reagent prepared from commercially avail-
able 4-bromo-1-butene was added to 1-acylpyridinium
salt 5 using our standard conditions. After workup with
aqueous acid, the crude dihydropyridone 6 was obtained
in 90% de. Recrystallization from methanol and chro-
matography of the mother liquor gave a 91% yield of
diastereomerically pure 6. Oxidative cleavage using
catalytic OsO4 and subsequent reduction of the crude
aldehyde with L-Selectride provided alcohol 7 in 81%
yield. In contrast, reductive workup with sodium boro-
(8) A similar stereoselective transformation has been reported,
see: (a) Al-awar, R. S.; J oseph, S. P.; Comins, D. L. Tetrahedron Lett.
1992, 33, 7635. (b) Al-awar, R. S.; J oseph, S. P.; Comins, D. L. J . Org.
Chem. 1993, 58, 7732. (c) ref 4a.
(9) Brown, J . D.; Foley, M. A.; Comins, D. L. J . Am. Chem. Soc. 1988,
110, 7445.
(10) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299. (b) Comins, D. L.; Dehghani, A.; Foti, C. J .; J oseph, S. P. Org.
Synth. 1996, 74, 77.
(11) (a) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(b) For a recent review on vinyl and aryl triflates, see: Ritter, K.
Synthesis 1993, 735-761.
(6) Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem. Soc.
1994, 116, 4719.
(7) (a) Comins, D. L.; Salvador, J . M. Tetrahedron Lett. 1993, 34,
801. (b) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656.

8184 J . Org. Chem., Vol. 62, No. 23, 1997
Comins et al.
Exp er im en ta l Section 6
Sch em e 2
(+)-(2S)-2-(3′-Bu ten yl)-1-[(((1S,2R)-tr a n s-2-(r-cu m yl)cy-
cloh exyl)oxy)ca r bon yl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-
4-p yr id on e (6). Magnesium turnings (5.48 g, 225.4 mmol)
were mechanically stirred at rt overnight under argon, and
then 50 mL of anhydrous THF was added to the flask. Neat
4-bromo-1-butene (7.65 mL, 75.35 mmol) was added dropwise
at 0 °C. The mixture was stirred 20 min at rt, 1 h at 0 °C,
and 2 h at rt to form the Grignard reagent.
Into a separate flask containing a solution of 4-methoxy-3-
(triisopropylsilyl)pyridine (10.0 g, 37.7 mmol) in 280 mL of
anhydrous toluene was added a solution of the chloroformate
of (+)-trans-2-(R-cumyl)cyclohexanol (11.63 g, 41.44 mmol) in
80 mL of anhydrous toluene at -42 °C. The reaction mixture
was stirred at -42 °C for 1.5 h, and then 70 mL of THF was
added. The mixture was cooled to -78 °C. The previously
prepared Grignard reagent was transferred dropwise via a
double-tipped stainless steel needle to the flask containing the
newly formed chiral N-acylpyridinium salt solution, and the
mixture was stirred at -78 °C for 4 h. Saturated aqueous
oxalic acid (100 mL) was added, and the reaction mixture was
warmed to rt and then was stirred overnight. The aqueous
layer was extracted with diethyl ether. The combined organic
extracts were washed with brine and dried over anhydrous
K2CO3. Filtration and concentration in vacuo gave 23.24 g (de
90%) of the crude product. Crystallization from 5% H2O/
MeOH yielded 15.24 g (de 100%) of the desired (2R)-2,3-
dihydro-4-pyridone 6. The mother liquor was concentrated
and purified by radical PLC (silica gel, 2-5% EtOAc/hexanes)
prepare vinyl triflate 13. Regiospecific enolate formation
was accomplished by deprotonation of 12 with 1.1 equiv
of LHMDS in THF at -78 °C. Subsequent addition of
N-(2-pyridyl)triflimide10 provided the vinyl triflate 13 in
87% yield. At this point, the synthetic plan called for
complete reduction of the vinyl triflate moiety of 13,
simultaneous cleavage of the benzyl ether and Cbz
groups, and cyclization to give the amino alcohol 14. We
were able to accomplish this via a one-pot reaction.
Catalytic hydrogenation of the vinyl triflate in EtOH
using 5% Pt/C and 20% Pd(OH)2/C as catalysts, and then
heating the mixture with Na2CO3 for 1 h, afforded the
desired indolizidine 14 in 82% yield. Oxidation of 14 with
the Dess-Martin periodinane12 gave a 97% yield of amino
aldehyde 4. The synthesis of each of the three target
indolizidine alkaloids was completed in one step from
amino aldehyde 4 as shown in Scheme 2. Using the
Seyferth-Gilbert reaction,13 treatment of 4 with methyl
diazomethyl phosphate and potassium tert-butoxide pro-
vided a 41% yield of indolizidine 205A (1). Wittig
olefination of 4 with methylenetriphenylphosphorane
gave indolizidine 207A (2) in 70% yield. Finally, treat-
ment of 4 with 2.5 equiv of n-propylenetriphenylphos-
phorane under high dilution and “salt free” conditions14
at -78 °C f rt provided an 86% yield of (-)-indolizidine
235B (3). All three synthetic alkaloids exhibited IR and
1H and 13C NMR spectral data in agreement with the
reported values for the natural products.5 Samples of our
synthetic alkaloids had identical MS and FTIR spectra
and GC retention times as the natural compounds (see
Acknowledgment).
In summary, a strategy for the synthesis of the
5-substituted 8-methylindolizidine ring system has been
developed and utilized in the preparation of indolizidines
(-)-205A, (-)-207A, and (-)-235B.15 These three natural
products were constructed enantioselectively in eleven
steps from readily available 4-methoxy-3-(triisopropyl-
silyl)pyridine via the common amino aldehyde intermedi-
ate 4. The three stereocenters of the indolizidines are
formed with a high degree of control of relative and
absolute stereochemistry. The route is general and
broadens the scope of 1-acyl-2,3-dihydro-4-pyridones as
chiral building blocks for the enantioselective preparation
of various alkaloid natural products.
to yield another 3.68 g (de 99.8%) of 6: [R]25 +62.9 (c 0.34,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.71 (s, 1 H), 7.20-7.39
(m, 5 H), 7.11 (t, 1 H, J ) 6.6 Hz), 5.63 (br s, 1 H), 4.77-5.15
(m, 3 H), 2.76 (br s, 1 H), 1.60-2.50 (series of m, 8 H), 1.12-
1.45 (series of m, 15 H), 1.05 and 1.01 (two d, 18 H, J ) 7.3
Hz); 13C NMR (CDCl3, 75 MHz) δ 196.7, 152.5 and 152.1 (due
to rotamers), 147.4, 137.1, 128.1, 125.1, 115.2, 110.2, 78.0, 51.0,
40.1, 39.4, 33.5, 30.7, 29.9, 29.5, 26.8, 25.8, 24.6, 21.7, 18.82,
18.77, 11.1; IR (KBr): 3085, 3020, 1712, 1660 cm-1
. Anal.
Calcd for C34H53NO3Si: C, 74.00; H, 9.68; N, 2.54. Found: C,
73.93; H, 9.68; N, 2.53.
(+)-(2S)-1-[(((1S,2R)-tr a n s-2-(r-Cu m yl)cycloh exyl)oxy)-
ca r bon yl]-2-(3′-h yd r oxyp r op yl)-5-(tr iisop r op ylsilyl)-2,3-
d ih yd r o-4-p yr id on e (7). A stirred solution of 6 (1.04 g, 1.88
mmol) in 80 mL of H2O/THF (1:1) was treated with NaIO4 (3.66
g, 17.1 mmol) and OsO4 (0.12 mL, 1.88 × 10-2 mmol, 4 wt %
in H2O) and stirred for 19 h at rt. The reaction mixture was
filtered through Celite and extracted with methylene chloride.
The extracts were dried over anhydrous K2CO3. Filtration and
concentration gave a clear oil that was dissolved in THF (40
mL) and treated with L-Selectride (2.1 mL, 2.1 mmol, 1.0 M
solution in THF) at -78 °C. After stirring for 1 h, 5.0 mL of
water and 1 g of sodium perborate tetrahydrate (NaBO3‚4H2O)
was added, and stirring was continued for 3 h as the reaction
mixture warmed to rt. Drying over anhydrous K2CO3, filtra-
tion, concentration, and purification by radial PLC (silica gel,
30-50% EtOAc/hexanes) gave 0.85 g (81%) of the desired
dihydropyridone 7 as a white solid: mp 119-121 °C; [R]27.5
D
1
+66.2 (c 0.52, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.71 (br
s, 1 H), 7.19-7.40 (m, 5 H), 7.11 (t, 1 H, J ) 6.7 Hz), 4.85 (br
s, 1 H), 3.49 (d, 3 H, J ) 5.5 Hz), 2.66 (br s, 1 H), 1.65-2.50
(series of m, 7 H), 1.08-1.45 (m, 17 H), 1.01 and 1.04 (two
(15) For enantioselective syntheses of these indolizidines, see: (a)
(-)-205A, (-)-235B: Polniaszek, R. P.; Belmont, S. E. J . Org. Chem.
1991, 56, 4868. Shishido, Y.; Kibayashi, C. J . Chem. Soc., Chem.
Commun. 1991, 1237. (b) (-)-205A, (-)-207A, (-)-235B: Shishido, Y.;
Kibayashi, C. J . Org. Chem. 1992, 57, 2876. (c) Satake, A.; Shimizu, I.
Tetrahedron: Asymmetry 1993, 4, 1405. (d) (-)-207A, (-)-235B:
Momose, T.; Toyooka, N. J . Org. Chem. 1994, 59, 943; Toyooka, N.;
Tanaka, K.; Momose, T.; Daly, J . W.; Garraffo, H. M. Tetrahedron 1997,
53, 9553. (e) (-)-207A: Taber, D. F.; Rahimizadeh, M.; You, K. K. J .
Org. Chem. 1995, 60, 529. (f) Also, for the first synthesis of a
5,8-disubstituted indolizidine ((-)-209B), see: Smith, A. L.; Williams,
S. F.; Holmes, A. B.; Hughes, L. R.; Swithenbank, C.; Lidert, Z. J . Am.
Chem. Soc. 1988, 110, 8696.
(12) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277. (c)
Ireland, R. E.; Lin, L. J . Org. Chem. 1993, 58, 2899.
(13) (a) Gilbert, J . C.; Weerasooriya, U. J . Org. Chem. 1979, 44, 4997.
(b) Brown, D. G.; Velthuisen, E. J .; Commerford, J . R.; Brisbois, R. G.;
Hoye, T. R. J . Org. Chem. 1996, 61, 2540.
(14) (a) Miyano, S.; Izumi, Y.; Hashimoto, H. J . Chem. Soc., Chem.
Commun. 1978, 446. (b) Corey, E. J .; Achiwa, K.; Katzenellenbogen,
J . A. J . Am. Chem. Soc. 1969, 91, 4318.
(16) Burgstahler, A. W.; Weigel, L. O.; Sanders, M. E.; Shaefer, C.
G. J . Org. Chem. 1977, 42, 566.

Enantiopure N-Acyldihydropyridones
J . Org. Chem., Vol. 62, No. 23, 1997 8185
doublets due to rotamers, 18 H, J ) 7.6 Hz); 13C NMR(CDCl3,
75 MHz) δ 196.9, 152.7 and 152.1 (doublet due to rotamers),
147.4, 128.0, 125.0, 110.1, 78.1, 62.1, 51.2 and 50.9 (doublet
due to rotamers), 40.2, 39.3, 33.4, 30.9, 28.5, 26.8, 25.8, 24.6,
21.3, 18.8, 18.7, and 11.0; IR (KBr) 3434, 3088, 3022, 1717,
1658 cm-1. Anal. Calcd for C33H53NO4Si: C, 71.30; H, 9.61;
N, 2.52. Found: C, 71.36; H, 9.58; N, 2.48.
methyl iodide (1.70 mL, 27.3 mmol) was added dropwise.
Stirring was continued for 2 h at -78 °C, the reaction mixture
was slowly warmed to -10 °C and was then stored in a freezer
overnight (-5 to -10 °C). After warming to rt, 25 mL of water
was added, and the crude mixture was extracted with diethyl
ether. The combined organic extracts were dried over anhy-
drous K2CO3 for 15 min (drying over K2CO3 for longer times
may cause epimerization at C-3). Filtration and concentration
in vacuo gave 3.18 g of the crude product. Purification by
radial PLC (silica gel, 10-30% EtOAc/hexanes) yielded 2.82
(-)-(2S )-2-(3′-H y d r o x y p r o p y l)-2,3-d ih y d r o -4-p y r i-
d on e (8). To a stirred solution of 7 (4.30 g, 7.74 mmol) in 20
mL of MeOH was added sodium methoxide (7.0 mL, 30.9
mmol, 4.37 M (25%) in MeOH). After refluxing for 3.5 h, and
cooling to rt, aqueous HCl (16.9 mL, 46.4 mmol, 2.74 M (10%))
was added. The mixture was stirred at rt for 15 min, and then
the methanol was removed in vacuo (0 °C). An aqueous
workup was avoided by adding THF and drying the mixture
with anhydrous K2CO3. Filtration and concentration yielded
3.56 g of the crude product. Purification by radial PLC (silica
gel, 10% MeOH/EtOAc/1% TEA) gave 3.25 g (96%) of the chiral
auxiliary ((+)-TCC) and 1.064 g (89%) of the desired 2,3-
dihydro-4-pyridone 8 as a white semisolid: [R]27D -430 (c 0.30,
MeOH); 1H NMR (CDCl3 300 MHz) δ 7.16 (t, 1 H, J ) 6.9 Hz),
5.35 (br s, 1 H), 5.02 (d, 1 H, J ) 7.3 Hz), 3.60-3.72 (m, 3 H),
2.30-2.51 (m, 2 H), 1.18-1.82 (series of m, 5 H); 13C NMR
(CDCl3, 75 MHz) δ 193.2, 151.4, 98.6, 62.3, 53.2, 42.1, 31.0,
g (96%) of the desired 2,3-dihydropyridone 11 as a clear oil:
1
[R]27.5 +29.7 (c 0.385, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
7.72 (br s, 1 H), 7.39 (s, 5 H), 5.28 (shoulder at 5.24) (s, 3 H),
4.32 (br s, 1 H), 3.46 (br s, 2 H), 2.38 (apparent q, 1 H, J ) 6.7
and 7.2 Hz), 1.55-1.95 (m, 4 H, J ) 6.6 and 7.1 Hz), 1.20 (d,
3 H, J ) 7.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 196.8, 152.9,
139.9, 134.7, 128.5, 128.2, 105.2, 68.9, 58.6, 44.0, 43.8, 28.6,
28.2, 16.7; IR (NaCl, neat): 3090, 3066, 3034, 1726, 1668, 1602
cm-1. Anal. Calcd for C17H20NO3Cl: C, 63.45; H, 6.26; N, 4.35.
Found: C, 63.39; H, 6.27; N, 4.38.
1-Br om o-4-(ben zyloxy)bu ta n e.16
Sodium hydroxide (20.0
g, 505 mmol) was carefully added to 40 mL of deionized water
at 0 °C. To the solution was added benzyl alcohol (10.35 mL,
100 mmol), 1,4-dibromobutane (59.7 mL, 500 mmol), and
tetrabutylammonium hydrogen sulfate (1.70 g, 5.0 mmol). The
reaction mixture was stirred at rt overnight, poured into 500
mL of H2O, and was extracted with hexanes. The organic
extracts were washed with brine, dried over anhydrous K2-
CO3, and concentrated in vacuo. The crude product was
purified by distillation (bp 101-105 °C, 0.40 mmHg) to yield
20.72 g (85%) of the desired product [67.2 g of 1,4-dibromobu-
tane was recovered (bp 31-41 °C, 0.35-0.5 mmHg)]: 1H NMR
(CDCl3, 300 MHz) δ 7.20-7.45 (m, 5 H), 4.50 (s, 2 H), 3.51 (t,
2 H, J ) 6.2 Hz), 3.44 (t, 2 H, J ) 6.8 Hz), 1.98 (quintet, 2 H,
J ) 7.9 Hz), 1.76 (quintet, 2 H, J ) 6.0 Hz).
(-)-(2S,3S,6R)-1-[(ben zyloxy)ca r bon yl]-2-(3′-ch lor op r o-
p yl)-3-m eth yl-6-[4′-(ben zyloxy)bu tyl]-4-p ip er id on e (12).
To a mixture of freshly ground magnesium turnings (0.457 g,
18.8 mmol) in 20 mL of anhydrous THF at rt was added 1,2-
dibromoethane (0.15 mL, 1.71 mmol). After stirring at rt for
1 h, the MgBr2/THF solution was removed and discarded.
Residual MgBr2 was removed by washing the magnesium with
anhydrous THF. Fresh THF (40 mL) and a portion of
4-(benzyloxy)-1-bromobutane (3.24 mL, 17.1 mmol) were added
to the flask. When the reaction initiated, the flask was cooled
to 0 °C and the remainder of 4-(benzyloxy)-1-bromobutane was
added. The mixture was stirred until most of the magnesium
had reacted. Additional magnesium (0.21 g, 8.5 mmol) was
added, and stirring was continued for 1 h at rt to give the
Grignard reagent.
28.4; IR (NaCl, neat): 3266, 3044, cm-1
C8H13NO2 155.09460 (M+), found 155.09442.
. HRMS calcd for
(+)-(2S)-1-[(Ben zyloxy)ca r bon yl]-2-(3′-h yd r oxyp r op yl)-
2,3-d ih yd r o-4-p yr id on e (9).4a To a stirred solution of 8
(0.992 g, 6.39 mmol) in THF at -78 °C was added n-
butyllithium (2.10 mL, 6.71 mmol, 3.19 M solution in n-
hexane). After stirring at -78 °C for 1 h, benzyl chloroformate
(0.91 mL, 6.39 mmol) was added, and the reaction mixture
was stirred for 1.5 h. Because TLC analysis of the reaction
mixture indicated the presence of starting dihydro-4-pyridone,
an additional portion of benzyl chloroformate (0.30 mL, 2.1
mmol) was added. Stirring was continued for an additional
30 min, 0.2 mL of water was added, and the reaction mixture
was warmed to rt. The crude solution was dried over K2CO3,
filtered, and concentrated to give 2.41 g of the crude product.
Purification by radial PLC (silica gel, EtOAc/hexanes) yielded
1.457 g (79%) of the desired hydroxy 2,3-dihydro-4-pyridone 9
1
as a clear oil: [R]25.5 +103 (c 0.37, CHCl3); H NMR (CDCl3,
D
300 MHz) δ 7.76 (d, 1 H, J ) 7.7 Hz), 7.40 (s, 5 H), 5.18-5.38
(m, 3 H), 4.66 (apparent q, 1 H, J ) 5.9 Hz), 3.60 (apparent t,
2 H, not resolved adequately to obtain J values), 2.83 (dd, 1
H, J ) 6.6 and 16.6 Hz), 2.46 (d, 1 H, J ) 16.7 Hz), 1.35-1.90
(m, 5 H); 13C NMR (CDCl3, MHz) δ 192.9, 152.3, 141.4, 134.7,
128.5 (2 carbons), 128.2, 106.9, 68.8, 61.7, 53.0, 39.5, 28.4, 26.9;
IR (NaCl, neat): 3427, 3089, 3067, 1724, 1663, 1600 cm-1
.
(+)-(2S)-1-[(Ben zyloxy)ca r b on yl]-2-(3′-ch lor op r op yl)-
2,3-d ih yd r o-4-p yr id on e (10). Triphenylphosphine (3.88 g,
14.8 mmol) was added in one portion to a solution of 9 (2.85 g,
9.86 mmol) in 30 mL of anhydrous CH2Cl2 at -42 °C, and the
mixture was stirred until homogeneous. N-Chlorosuccinimide
(1.98 g, 14.8 mmol) was added in one portion, and the mixture
was stirred at -42 °C for 30 min after becoming homogeneous.
After warming to rt, the stirring was continued for 4 h, 0.5
mL of anhydrous methanol was added, and the mixture was
stirred for 20 min. The solvents were removed in vacuo, and
the residue was redissolved in diethyl ether, filtered through
Celite, and concentrated. The crude product was purified by
radial PLC to yield 2.85 g (94%) of the desired dihydropyridone
In a separate flask, copper(I) bromide-dimethyl sulfide
complex (3.51 g, 17.1 mmol) was added to 70 mL of anhydrous
THF and cooled to -78 °C. The Grignard of 4-(benzyloxy)-1-
bromobutane was added slowly via a double-tipped stainless
steel needle. Stirring for 1 h at -78 °C produced an orange
solution that appeared to be almost homogeneous. Boron
trifluoride etherate (2.10 mL, 17.1 mmol) was added, and
stirring was continued for 5 min. To the newly formed BF3‚-
OEt2/organocopper complex was added (over a 1.5 h period) a
solution of 11 (2.75 g, 8.55 mmol) in 35 mL of anhydrous THF.
After stirring for 2 h at -78 °C, 40 mL of aqueous 20% NH4-
Cl/NH4OH (50:50) was added, and the mixture was allowed
to warm to rt. After exposure to air and stirring for several
min, the mixture turns blue. The crude mixture was extracted
with diethyl ether. The organic extracts were washed with
brine and dried over anhydrous K2CO3 for 15 min. Filtration
and concentration in vacuo gave 5.26 g of the crude product
as a dark oil. Purification by radial PLC (silica gel, 10-30%
10 as a clear oil: [R]27.5 +111.6 (c 0.43, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.76 (d, 1 H, J ) 7.6 Hz), 7.39 (s, 5 H),
5.15-5.40 (m, 3 H), 4.63 (br s, 1 H), 3.46 (br s, 2 H), 2.84 (dd,
1 H, J ) 6.5 and 16.6 Hz), 2.41 (d, 1 H, J ) 16.5 Hz), 1.55-
1.95 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ 192.4, 152.4, 141.2,
134.8, 128.8, 128.7, 128.5, 107.3, 69.1, 52.7, 44.1, 40.0, 28.7,
28.1; IR (NaCl, neat): 3089, 3066, 1725, 1670, 1603 cm-1; Anal.
Calcd for C16H18NO3Cl: C, 62.44; H, 5.89; N, 4.55. Found: C,
62.31; H, 5.91; N, 4.55.
EtOAc/hexanes) yielded 3.70 g (89%) of the desired 2,6-cis-
1
piperidone 12 as a clear oil: [R]24.5 -3.0 (c 0.46, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 7.20-7.45 (m, 10 H), 5.08-5.22
(appears as a doublet at 5.15 ppm with sidebands at 5.20 and
5.11 ppm, 2 H, J ) 2.2 Hz), 4.50 (br s, 1 H), 4.47 (s, 2 H), 4.35
(br s 1 H), 3.48 (br s, 2 H), 3.42 (t, 2 H, J ) 5.2 Hz), 2.81 (dd,
1 H, J ) 9.2 and 15.8 Hz), 2.40 (q, 1 H, J ) 6.6 Hz), 2.31 (dd,
1 H, J ) 4.5 and 15.5 Hz), 1.25-1.90 (series of m, 10 H), 1.18
(+)-(2S,3S)-1-[(Ben zyloxy)car bon yl]-2-(3′-ch lor opr opyl)-
3-m eth yl-2,3-d ih yd r o-4-p yr id on e (11). Lithium bis(trim-
ethylsilyl)amide (10.9 mL, 10.9 mmol, 1.0 M solution in THF)
was added dropwise to a solution of 10 (2.80 g, 9.08 mmol) in
100 mL of THF at -78 °C. After stirring for 1 h at -78 °C,

8186 J . Org. Chem., Vol. 62, No. 23, 1997
Comins et al.
(d, 3 H, J ) 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 210.3, 156.1,
138.4, 136.2, 128.4, 128.1, 128.0, 127.8, 127.4, 127.3, 72.6, 69.7,
67.5, 58.5, 52.7, 47.8, 44.2, 40.2, 37.0, 33.7, 29.6, 29.1, 23.1,
16.6; IR (NaCl, neat): 3088, 3063, 3031, 1715, 1694, 1605,
reaction mixture was extracted with diethyl ether. The
combined organic extracts were washed with brine and dried
over anhydrous K2CO3. Filtration through Celite and concen-
tration yielded 0.406 g (97%) of the desired amino aldehyde 4
as a dark oil, which was used without further purification.
[R]25D -86.0 (c 0.24, MeOH); 1H NMR (CDCl3, 300 MHz) δ 9.77
(s 1 H), 3.23 (t, 2 H, J ) 6.8 Hz), 2.44 (t, 2 H, J ) 7.1 Hz),
1.83-2.10 (m, 4 H), 1.10-1.83 (m, 10 H), 0.96 (dq, 1 H, J )
4.1 and 13.4 Hz), 0.87 (d, 3 H, J ) 6.4 Hz); 13C NMR (CDCl3,
75 MHz) δ 202.2, 71.3, 63.0, 51.7, 44.1, 36.4, 34.0, 33.5, 31.0,
29.0, 20.3, 18.7, 18.3; IR (NaCl, neat): 2950, 2871, 2781, 1726,
1694 cm-1. HRMS calcd for [C13H23NO + H] 210.18580 [(M
+ H)+], found, 210.18568.
cm-1
.
HRMS calcd for C28H36NO4Cl 485.23330 (M+), found
485.23252.
(-)-(2S,3S,6R)-6-[4′-(Ben zyloxy)bu tyl]-1-[(ben zyloxy)-
c a r b o n y l]-2-(3′-c h lo r o p r o p y l)-3-m e t h y l-4-[(t r iflu o -
r om eth a n esu lfon yl)oxy]-1,2,3,6-tetr a h yd r op yr id in e (13).
To a stirred solution of LHMDS (8.31 mL, 8.31 mmol, 1.0 M
solution in THF) in 25 mL of anhydrous THF at -78 °C was
added dropwise a solution of 12 (3.673 g, 7.556 mmol) in 11
mL of anhydrous THF via a double-tipped stainless steel
needle. After the reaction mixture was stirred at -78 °C for
1.5 h, a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]-
pyridine10 (4.06 g, 11.3 mmol) in 8.0 mL of THF was added
via a double-tipped stainless steel needle (Note: The N-(2-
pyridyl)triflimide was pumped under high vacuum for 1 h prior
to use). The reaction was stirred for 2 h at -78 °C, and 0.25
mL of water was added. The mixture was diluted with diethyl
ether and dried over anhydrous K2CO3. Filtration through
Celite and silica gel and concentration in vacuo gave 9.04 g of
the crude vinyl triflate. Purification in three separate portions
by radial PLC (silica gel, CH2Cl2/hexanes, CH2Cl2, then 20%
EtOAc/hexanes) yielded 4.08 g (87%) of the desired vinyl
(-)-(5R,8R,8a S)-5-(4′-P en tyn yl)-8-m eth ylocta h yd r oin -
d olin e [(-)-In d olizid in e 205A] (1). To a stirred slurry of
potasium tert-butoxide (15 mg, 0.13 mmol) in 1.0 mL of
anhydrous THF (-78 °C) was added a solution of methyl
diazomethyl phosphonate (20 mg, 0.13 mmol) in 2.0 mL of
anhydrous THF. The reaction mixture was stirred at -78 °C
for 5 min. A solution of crude 4 (25 mg, 0.118 mmol) in 2.0
mL of anhydrous THF was added via a double-tipped stainless
steel needle. The reaction mixture was stirred at -70 °C for
14 h, and then 20 mL of H2O was added. The resulting
mixture was extracted with dichloromethane (3 × 25 mL). The
combined extracts were dried over anhydrous K2CO3, filtered
through Celite, and concentrated. Purification by column
chromatography (neutral alumina, 0-1% EtOAc/hexanes) gave
triflate 13 as a clear oil: [R]23.7 -74.1 (c 0.885, CHCl3); 1H
D
NMR (CDCl3, 300 MHz) δ 7.33 (s, 10 H), 5.73 (dd, 1 H, J )
3.4 and 22.0 Hz), 5.05-5.23(m, 2 H), 4.19-4.72 (m, 4 H), 3.32-
3.60 (m, 4 H), 2.39 (apparent sextet, 1 H, J ) 7.4 Hz), 1.21-
1.90 (m, 10 H), 1.16 and 1.11 (two d due to rotamers, 3 H, J )
7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 156.0 and 1.55 (due to
rotamers), 149.8 and 149.3 (due to rotamers), 138.5, 136.2,
128.5, 128.3, 128.2, 127.9, 127.5, (124.8, 120.5, 116.3, 112.0)
(CF3), 116.0 and 115.4 (due to rotamers), 72.8, 69.8 and 69.7
(due to rotamers), 67.7 and 67.5 (due to rotamers), 56.2 and
55.7 (due to rotamers), 52.0 and 51.7 (due to rotamers), 44.3
and 44.1 (due to rotamers), 37.7 and 37.6 (due to rotamers),
36.0, 35.2, 31.4 and 31.3 (due to rotamers), 29.3, 23.2, 17.6;
IR (NaCl, neat): 3089, 3065, 3032, 1701, 1604 cm-1. HRMS
calcd for C29H35NO6SClF3 618.19040 (M+), found 618.18840.
(-)-(5R,8R,8a S)-5-(4′-H yd r oxyb u t yl)-8-m et h yloct a h y-
d r oin d olin e (14). A flask containing a solution of 13 (305
mg, 0.493 mmol) in 5 mL of absolute EtOH at rt was purged
with argon. To this solution was added 122 mg (40 wt %) of
5% platinum on carbon. The mixture was stirred overnight
under a hydrogen atmosphere at balloon pressure. The flask
was again purged with argon and 61 mg (20 wt %) of palladium
hydroxide (Pearlman’s catalyst, 20% on carbon/31% H2O) was
added. The reaction mixture was stirred for 13 h at rt under
a hydrogen atmosphere at balloon pressure, and then argon
was bubbled through the solution for 5 min. Sodium carbonate
(105 mg, 0.99 mmol) was added, and the reaction mixture was
heated at reflux for 1.5 h. After cooling to rt, the solution was
filtered through Celite and concentrated in vacuo. The crude
residue was dissolved in methylene chloride, filtered through
Celite, and purified by column chromatography (basic alumina,
0-50% EtOAc/hexanes) to give 85 mg (82%) of the desired
10 mg (41%) of (-)-indolizidine 205A (1) as a clear oil: [R]27.5
D
-82.3 (c 0.26, MeOH); lit.15c [R]24 -81.7 (c 0.36, MeOH); H
1
D
NMR (CDCl3, 300 MHz) δ 3.26 (dt, 1 H, J ) 2.1 and 8.7 Hz),
2.19 (apparent dt, 2 H, J ) 2.5 and 6.8 Hz), 2.05-1.14 (series
of m, 16 H), 0.95 (apparent dt, 1 H, J ) 3.6 and 12.4 Hz), 0.87
(d, 3 H, J ) 6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 84.4, 71.4,
68.3, 63.0, 51.8, 36.5, 33.8, 33.7, 31.3, 29.1, 24.8, 20.4, 18.83,
18.79; IR (NaCl, neat) 3313, 2951, 2119 cm-1
.
(-)-(5R,8R,8a S)-5-(4′-P en ten yl)-8-m eth ylocta h yd r oin -
d olin e [(-)-In d olizid in e 207A] (2). To a stirred solution of
methyltriphenylphosphonium bromide (0.114 g, 0.319 mmol)
in 3.0 mL of anhydrous THF at rt was added potassium bis-
(trimethylsilyl)amide (0.64 mL, 0.319 mmol, 0.5 M solution
in toluene). The yellow reaction mixture was stirred for 20
min at rt and cooled to 0 °C. Then crude 4 (22.3 mg, 0.106
mmol) in 3.0 mL of anhydrous THF was slowly added via a
double-tipped stainless steel needle. The reaction mixture was
slowly warmed to rt and stirred for 15 min. The organic
solvents were removed in vacuo. The crude residue was
dissolved in methylene chloride and filtered through Celite.
Concentration in vacuo gave the crude product. Purification
by radial PLC (silica gel, 15% THF/hexanes/1% TEA) gave 15.4
mg (70%) of (-)-indolizidine 207A (2) as a clear oil: [R]22.5
D
-103.2 (c 0.47, CHCl3); lit.15b [R]28 -86.5 (c 0.95, CHCl3); H
1
D
NMR (CDCl3, 300 MHz) δ 5.70-5.90 (m, 2 H), 4.86-5.08 (m,
2 H), 3.26 (dt, 1 H, J ) 2.0 and 8.7 Hz), 1.12-2.15 (series of
m, 17 h), 0.95 (m, 1 H, J ) 4.5 and 13.8 Hz), 0.87 (d, 3 H, J )
6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 138.8, 114.4, 71.3, 63.3,
51.8, 36.5, 34.1 (2 carbons), 33.6, 31.2, 29.0, 25.1, 20.3, 18.9.
(-)-(5R,8R,8aS)-8-Meth yl-5-[4(Z)-h epten yl]octah ydr oin -
d olid in e [(-)-In d olizid in e 235B] (3). To a stirred solution
of n-propyltriphenylphosphonium bromide (0.175 g, 0.454
mmol) in 15.0 mL of anhydrous THF (rt) was added sodium
bis(trimethylsilyl)amide (0.45 mL, 0.454 mmol, 1.0 M solution
in THF). After stirring for 1 h at rt, the orange reaction
mixture was cooled to -78 °C, and crude 4 (38.0 mg, 0.182
mmol) in 50 mL of anhydrous THF was added dropwise via a
double-tipped stainless steel needle. The reaction mixture was
stirred at -78 °C for 3 h, slowly warmed to rt, and stirred
overnight. Methanol (1.0 mL) was added, the solution was
stirred for 1 h, water (0.5 mL) was added, and the crude
mixture was dried over anhydrous K2CO3. Filtration and
concentration in vacuo gave 0.162 g of the crude product.
Purification by radial PLC (silica gel, 20% EtOAc/hexanes/0.5%
NH4OH) yielded 36.9 mg (86%) of (-)-indolizidine 235 B (3)
as a clear oil: [R]24 - 88.0 (c 1.0, MeOH); lit.15b [R]28 -85.4
amino alcohol 14 as a dark oil: [R]24 -95.1 (c 0.45, MeOH);
D
1H NMR (CDCl3, 300 MHz) δ 3.64 (t, 2 H, J ) 6.3 Hz), 3.32
(dt, 1 H, J ) 2.1 and 7.0 Hz), 1.20-2.25 (series of m, 18 H),
0.95 (dq, 1 H, J ) 4.4 and 11.8 Hz), 0.89 (d, 3 H, J ) 6.6 Hz);
13C NMR (CDCl3, 75 MHz) δ 71.1, 63.3, 61.4, 51.3, 35.6, 33.6,
33.0, 32.6, 30.4, 28.4, 21.8, 19.8, 18.4; IR (NaCl, neat): 3353
(br), 2932, 1699 (br) cm-1. HRMS calcd for C13H25NO 211.19360
(M+), found 211.19279.
(-)-(5R,8R,8a S)-5-(3-F or m ylp r op yl)-8-m et h yloct a h y-
d r oin d olin e (4). A solution of 14 (0.423 g, 2.00 mmol) in 20
mL of anhydrous CH2Cl2 was transferred via a double-tipped
stainless steel needle into a solution of 1,1,1-triacetoxy-1,1-
dihydro-1,2-benziodoxol-3-(1H)-one (1.10 g, 2.6 mmol) (the
Dess-Martin 12-I-5 triacetoxyperiodinane)12 in 20 mL of CH2-
Cl2 at rt. After stirring for 2.5 h at rt, the reaction mixture
was transferred via a double-tipped needle into a stirred
solution of 10 mL of saturated aqueous NaHCO3 and 2.5 g of
sodium thiosulfate (Na2S2O3‚5H2O). Stirring was continued
at rt until the solution appeared homogeneous. The crude
D
D
(c 0.79, MeOH); 1H NMR (CDCl3, 300 MHz) δ 5.21-5.43 (m, 2
H), 3.26 (dt, 1 H, J ) 1.8 and 8.1 Hz), 1.80-2.10 (m, 8 H),
1.55-1.80 (m, 5 H), 1.14-1.55 (m, 7 H), 0.95 (t, 3 H, J ) 7.5

Enantiopure N-Acyldihydropyridones
J . Org. Chem., Vol. 62, No. 23, 1997 8187
Hz), 0.87 (d, 3 H, J ) 6.6 Hz); 13C NMR (CDCl3, 75 MHz) δ
131.8, 129.0, 71.4, 63.4, 51.8, 36.6, 34.3, 33.7, 31.3, 29.1, 27.4,
26.0, 20.5, 20.4, 18.9, 14.3; IR (NaCl, neat): 3004, 2961, 2932,
2871, 2850, 2778, 2700, 1457, 1374, 1332, 1242, 1220, 1163,
and the National Science Foundation (CHE-9121380).
Special thanks to Dr. Thomas F. Spande of the National
Institutes of Health for comparing our synthetic alka-
loids to the authentic compounds.
1132, 975 cm-1
.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1-3, 8, and 12-14 (14 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Ack n ow led gm en t. We express appreciation to the
National Institutes of Health (Grant GM 34442) for
financial support of this research. The 1H and 13C NMR
spectra and mass spectra were obtained at NCSU
instrumentation laboratories, which were established
by grants from the North Carolina Biotechnology Center
J O971448U