Epoxide-Initiated Cationic Cyclization of Azides: A Novel Method for the Stereoselective Construction of 5-Hydroxymethyl Azabicyclic Compounds and Application in the Stereo- and Enantioselective Total Synthesis of (+)- and (-)-Indolizidine 167B and 209D

Article abstract of DOI:10.1021/jo035258x

A novel and general method has been developed for the stereoselective construction of 5-hydroxymethyl azabicyclic ring skeletons based on epoxide-initiated cationic cyclization of azides. The key cyclization reaction was systematically studied with the mo

Full text of DOI:10.1021/jo035258x

Ep oxid e-In itia ted Ca tion ic Cycliza tion of Azid es: A Novel Meth od
for th e Ster eoselective Con str u ction of 5-Hyd r oxym eth yl
Aza bicyclic Com p ou n d s a n d Ap p lica tion in th e Ster eo- a n d
En a n tioselective Tota l Syn th esis of (+)- a n d
(-)-In d olizid in e 167B a n d 209D†
P. Ganapati Reddy and Sundarababu Baskaran*
Department of Chemistry, Indian Institute of Technology, Madras, Chennai-600036, India
sbhaskar@iitm.ac.in
Received August 28, 2003
A novel and general method has been developed for the stereoselective construction of 5-hydroxy-
methyl azabicyclic ring skeletons based on epoxide-initiated cationic cyclization of azides. The key
cyclization reaction was systematically studied with the model compound, 3-(1-oxa-spiro[2.4]hept-
4-yl)propyl azide 3a , and EtAlCl2 was found to be an ideal choice as the catalyst. The generality of
this transformation was further tested with different ring sizes, where six- and seven-membered
epoxyazides 3b,c underwent smooth cyclization to give 5-hydroxymethyl azepine 4b and 5-hy-
droxymethyl azocine 4c, respectively, as a single detectable diastereomer. This novel methodology
was elegantly applied in the stereoselective total synthesis of indolizidine alkaloids 167B and 209D.
Further, the enantioselective total synthesis of natural and unnatural indolizidine alkaloids 167B
and 209D was accomplished by using Sharpless asymmetric dihydroxylation as a key step.
In tr od u ction
the stereoselective synthesis of nitrogen containing al-
kaloids.4,5 Cation-induced inter- and intramolecular elec-
trophilic cyclization of azidoalkenes4 and azidoketones5
has been extensively studied with different protic and
Lewis acids; however, the synthetic potential of the
corresponding epoxide-initiated Schmidt reaction is yet
to be explored.
The azabicyclic ring skeleton is an important structural
subunit present in numerous biologically active natural
products.6 In this family, indolizidine alkaloids are the
most important class of compounds, known for their wide
range of pharmaceutical applications (Figure 1).7 For
example, alkylindolizidine alkaloids isolated from the
skin secretions of neotrophical amphibians, mostly from
frogs belonging to the dendrobatidae family, are found
to function as noncompetitive blockers of neuromuscular
transmission.8 The potent biological activity is due to the
interaction of basic indolizidine nucleus with the gangli-
onic nicotinic acetylcholine receptor-ion channels.7b The
agonist activity on the nicotinic receptors is similar to
Cation-induced cyclization reactions are major re-
sources for the synthesis of fused polycyclic ring systems.1
The need for stereo- and enantioselective construction of
carbocyclic ring systems of biological origin has evoked
considerable interest in the design and development of
novel chiral initiating species and selective terminators.2,3
While the cation-induced cyclization terminated by the
attack of carbon nucleophiles is used widely for the
preparation of carbocyclic ring systems, the termination
by heteroatom has become a popular technique for the
synthesis of heterocyclic compounds.1b Oxygen and ni-
trogen nucleophiles are extensively studied as hetero-
atom terminators. Aube and Pearson have developed a
novel method for the synthesis of azabicyclic ring systems
using azide as a heteroatom terminator and applied in
† Dedicated to Professor S. Swaminathan on the occasion of his 80th
birthday.
(1) (a) Sutherland, J . K. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I. Eds.; Pergamon: Oxford, UK, 1991; Vol. 3, p 341.
(b) Bartlett, P. A. In Asymmetric Synthesis Morrison, J . D., Ed.;
Academic Press: London, UK, 1984; Vol. 3, p 341. (c) J ohnson, W. S.
Tetrahedron 1991, 47, No. 41, xi and references cited therein.
(2) (a) J ohnson, W. S.; Bartlett, W. R.; Czeskis, B. A.; Gautier, A.;
Lee, C. H.; Lemoine, R.; Leopold, E. J .; Luedtke, G. R.; Bancroft, K. J .
J . Org. Chem. 1999, 64, 9587. (b) Langkopf, E.; Schinzer, D. Chem.
Rev. 1995, 95, 1375. (c) Fish, P. V.; J ohnson, W. S.; J ones, G. S.; Tham,
F. S.; Kullnig, R. K. J . Org. Chem. 1994, 59, 6150. (d) J ohnson, W. S.;
Telfer, S. J .; Cheng, S.; Schubert, U. J . Am. Chem. Soc. 1987, 109,
2517. (e) J ohnson, W. S.; Chen, Y.-Q.; Kellog, M. S. J . Am. Chem. Soc.
1983, 105, 6653. (f) J ohnson, W. S.; Lyle, T. A.; Daub, G. W. J . Org.
Chem. 1982, 47, 161.
(3) (a) Huang, A. X.; Xiong, Z.; Corey, E. J . J . Am. Chem. Soc. 1999,
121, 9999. (b) Corey, E. J .; Wood, H. B., J r. J . Am. Chem. Soc. 1996,
118, 11982. (c) Fish, P. V.; J ohnson, W. S. Tetrahedron Lett. 1994, 35,
1469. (d) Fish, P. V.; Sudhakar, A. R.; J ohnson, W. S. Tetrahedron
Lett. 1993, 34, 7849. (e) Sarkar, T. K.; Ghosh, S. K.; Subba Rao, P. S.
V.; Satapathi, T. K.; Mamdapur, V. R. Tetrahedron 1992, 48, 6897. (f)
Corey, E. J .; Sodeoka, M. Tetrahedron Lett. 1991, 32, 7005.
(4) (a) Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57, 5081.
(b) Pearson, W. H.; Hutta, D. A.; Fang, W.-k. J . Org. Chem. 2000, 65,
8326. (c) Pearson, W. H.; Fang, W.-k. J . Org. Chem. 2000, 65, 7158.
(d) Pearson, W. H.; Fang, W.-k. J . Org. Chem. 1995, 60, 4960. (e)
Pearson, W. H.; Walavalkar, R.; Schkeryantz, J . M.; Fang, W.;
Blickensdorf, J . D. J . Am. Chem. Soc. 1993, 115, 10183. (f) Pearson,
W. H.; Schkeryantz, J . S. Tetrahedron Lett. 1992, 33, 5291.
(5) (a) Wrobleski, A.; Sahasrabudhe, K.; Aube, J . J . Am. Chem. Soc.
2002, 124, 9974. (b) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman,
C.; Milligan, G. L.; Aube, J . J . Am. Chem. Soc. 2000, 122, 7226. (c)
Smith, B. T.; Gracias, V.; Aube, J . J . Org. Chem. 2000, 65, 3771. (d)
Forsee, J . E.; Aube, J . J . Org. Chem. 1999, 64, 4381. (e) Milligan, G.
L.; Mossman, C. J .; Aube. J . J . Am. Chem. Soc. 1995, 117, 10449. (f)
Aube, J .; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993, 35, 1141.
(g) Aube, J .; Milligan, G. L.; Mossman, C. J . J . Org. Chem. 1992, 57,
1635. (h) Aube, J .; Milligan, G. L. J . Am. Chem. Soc. 1991, 113, 8965.
(6) For a review on these natural products, see: Daly, J . W. J . Nat.
Prod. 1998, 61, 162.
10.1021/jo035258x CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/03/2004
J . Org. Chem. 2004, 69, 3093-3101
3093

Reddy and Baskaran
SCHEME 1. Ep oxid e-In itia ted Ca tion ic
Cycliza tion of Azid es
F IGURE 1.
that of phencyclidine, quinacrine, chlorpromazine, and
various local anesthetics.6
Owing to their wide variety of biological activity, the
indolizidine alkaloids have attracted much attention from
synthetic chemists. Several total syntheses of indolizidine
alkaloids 167B and 209D have been reported in the
literature.9 Indeed, many of the syntheses have utilized
naturally occurring chiral starting materials. Stepwise
annulations and consecutive amination reactions are the
most commonly used strategies for the synthesis of
indolizidine alkaloids. Aube and Pearson independently
reported an interesting and convergent synthetic method
for this class of alkaloids by electrophilic cyclization of
azidoketones5a,b and azidoalkenes4b-e with concurrent
intramolecular Schmidt reaction. Recently, we have
reported the synthetic potential of the epoxide-initiated
electrophilic cyclization of azides in the stereoselective
construction of azabicyclic compounds and its application
in the stereoselective total synthesis of (()-indolizidine
alkaloids 167B and 209D.10 In this article, we report a
detailed study on epoxide-initiated cationic cyclization of
azides and enantioselective total synthesis of both natu-
ral and unnatural indolizidine alkaloids 167B and 209D.
B, and in situ reduction9e of B would give 5-hydroxy-
methyl azabicyclic compound 4 (Scheme 1). To test the
viability of this strategy, a five-membered epoxyazide 3a
was chosen as a model substrate, which was readily
synthesized from cyclopentanone as shown in Scheme 2.
Initial trials at the preparation of olefinester 6a from
known ketoester11 5a using Wittig olefination were poor
yielding due to the basic conditions. However, by using
a modification of the relatively neutral titanium carbene
reagent developed by Takai,12 derived from Zn/TiCl4/
CH2X2 where CH2Br2 has replaced the relatively expen-
sive CH2I2, the olefinester 6a could be isolated in 61%
yield after workup and distillation. The olefinester 6a
thus obtained was treated with LAH in THF to furnish
the corresponding alcohol 7a in 95% yield. Alcohol 7a was
converted to the corresponding mesylate in quantitative
yield by treatment with CH3SO2Cl/Et3N and the crude
mesylate was reacted with excess NaN3 in dry DMF to
furnish azidoolefin 8a in 98% overall yield. Azidoolefin
8a on exposure to mCPBA, in the presence of 0.5 M
aqueous NaHCO3, in CH2Cl2 afforded epoxyazide 3a as
a mixture of cis and trans diastereomers.13 The mixture
was separated by column chromatography to furnish
trans-3a and cis-3a in 51% and 17% isolated yields,
respectively. Similarly, epoxyazides 3b14 and 3c were
prepared as shown in Scheme 2, with an overall yield of
41% and 12%, starting from cyclohexanone and cyclo-
heptanone, respectively. Unlike five-membered epoxyazide
3a , 3b and 3c were obtained as an inseparable mixture
of cis- and trans-isomers (Scheme 2).
Resu lts a n d Discu ssion
On the basis of the pioneering work of Aube and
Pearson on intramolecular Schmidt reaction of alkyl
azides,4,5 we envisioned that the treatment of epoxyazide
3 with a Lewis acid would lead to cyclization to give
aminodiazonium intermediate A, followed by intramo-
lecular Schmidt reaction resulting in bicyclic iminium ion
(7) (a) Daly, J . W.; Sande, T. F. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1986;
Vol. 4, Chapter 1. (b) Aronstam, R. S.; Daly, J . W.; Spande, T. F.;
Narayanan, T. K.; Albuquerque, E. X. Neurochem. Res. 1986, 11, 1227.
(c) Michael, J . P. In The Alkaloids: Chemistry and Pharmacology;
Cordell, G., Ed.; Academic Press: New York, 2001; Vol. 55, p 91. (d)
Michael, J . P. Nat. Prod. Rep. 2002, 19, 719. (e) Lourenco, A. M.;
Maximo, P.; Ferreira, L. M.; Pereira, M. M. A. Stud. Nat. Prod. Chem.
2002, 27 (Bioactive Natural Products (part H)), 233. (f) Michael, J . P.
Nat. Prod. Rep. 2003, 20, 458.
Our earlier efforts on epoxide-initiated cationic cycliza-
tion of azide 3a in THF with a catalytic, as well as a
stoichiometric, amount of Lewis acids were not successful
and resulted in the isolation of a complex mixture of
(8) (a) Daly, J . W. Prog. Chem. Org. Nat. Prod. 1982, 41, 205. (b)
Daly, J . W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25, 1023. (c)
Erspamer, V.; Melchiorri, P. Trends Pharmacol. Sci. 1980, 1, 391.
(9) For enantioselective total synthesis of indolizidine 167B please
see: (a) Chenevert, R.; Ziarani, G. M.; Dasser, M. Heterocycles 1999,
51, 593. (b) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J .-
C.; Canet, I. Tetrahedron Lett. 1999, 40, 1661. (c) Angel, S. R.; Henry,
R. M. J . Org. Chem. 1997, 62, 8549. (d) Weymann, M.; Pfrengle, W.;
Schollmeyer, D.; Kunz, H. Synthesis 1997, 1151. (e) Polniaszek, R. P.;
Belmont, S. E. J . Org. Chem. 1990, 55, 4688. For enantioselective total
synthesis of indolizidine 209D please see: (f) Kim, G.; J ung, S.-D.; Kim,
W.-J . Org. Lett. 2001, 3, 2985. (g) Back, T. G.; Nakajima, K. J . Org.
Chem. 2000, 65, 4543. (h) Chenevert, R.; Ziarani, G. M.; Morin, M. P.;
Dasser, M. Tetrahedron: Asymmetry 1999, 10, 3117. (i) Comins, D. L.;
Zhang, Y.-m. J . Am. Chem. Soc. 1996, 118, 12248. (j) Nukui, S.;
Sodeoka, M.; Sasai, H.; Shibasaki, M. J . Org. Chem. 1995, 60, 398. (k)
Ahman, J .; Somfai, P. Tetrahedron 1995, 51, 9747.
(11) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J .;
Terrell, R. J . Am. Chem. Soc. 1963, 85, 207.
(12) (a) Hibino, J .-I.; Okazoe, T.; Takai, K.; Nozaki, H.Tetrahedron
Lett. 1985, 26, 5579. (b) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1978, 19, 2417. (c) Lombardo, L. Tetrahedron Lett.
1982, 23, 4293. (d) Lombardo, L. Org. Synth. 1987, 65, 81.
(13) R-Substituted cyclopentanone on treatment with sulfur ylide
[(a) Rajan Babu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1994, 116,
986] or Li-CH2-Cl [(b) Gansauer, A.; Pierobon, M.; Bluhm, H.
Synthesis 2001, 2500] is expected to undergo highly diastereoselective
nucleophilic attack from the less hindered side to give cis-epoxide. The
reported chemical shift values of these epoxy methylene protons are
found to be very similar to those of our minor isomer of 3a . On the
basis of the chemical shift values, we concluded that our minor
epoxyazide 3a is cis.
(10) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5,
583.
(14) Reddy, P. G.; Pratap, T. V.; Kumar, G. D. K.; Mohanty, S. K.;
Baskaran, S. Eur. J . Org. Chem. 2002, 3740.
3094 J . Org. Chem., Vol. 69, No. 9, 2004

Epoxide-Initiated Cationic Cyclization of Azides
SCHEME 2. Syn th esis of Ep oxya zid es 3a -c
TABLE 1. Ep oxid e-In itia ted Ca tion ic Cycliza tion of
tr a n s-Ep oxya zid e 3a w ith Differ en t Lew is Acid s
entry
Lewis acida
temp (°C)
timeb(min)
yieldc (%)
1
2
3
4
5
6
TfOH
-40
-78
-78
-25
0
30
30
45
30
60
45
25
21
50
43
25
63
TMSOTf
BF3.OEt2
TiCl4
InCl3
EtAlCl2
F IGURE 2. NOE experiments to confirm relative stereo-
chemistry at C5 and C9.
-78
1.1 equiv was used in all the cases. b Lewis acid step. c Isolated
a
yields
standard acylation conditions (Figure 2). Irradiation of
the equatorial proton at C3 resulted in the enhancement
of intensities of side chain methylene protons by 3.6%
and 0.9%. This clearly reveals that the side chain is
equatorial. Considerable NOE between the proton at C5
and C9 (7.4%) shows that they are cis to each other.
Though significant NOE between C5 and C3 axial
hydrogens was observed, the exact magnitude could not
be calculated since they are very close to each other.
Furthermore, the structure and relative stereochem-
istry of the cyclized product was unambiguously con-
firmed by single-crystal X-ray analysis. Since the 5-hy-
droxymethyl indolizidine 4a is a viscous liquid a crystalline
p-bromobenzoate hydrochloride salt 11 was prepared and
recrystallized from nitromethane to afford good size and
quality crystals suitable for X-ray analysis. As revealed
in Figure 3, the p-bromobenzoate hydrochloride salt 11
possesses the indolizidine basic skeleton and the two
hydrogens at C5 and C9 are cis to each other. It is
apparent from the X-ray structure that the side chain at
C5 is equatorial while six- and five-membered rings are
in trans-fused chair and envelop conformations, which
are presumed to be stable conformations of the indolizi-
dine skeleton. The remarkable stereochemical outcome
of this reaction was rationalized by invoking a similar
stereoselective reduction of the intermediate iminium ion
in the indolizidine skeleton already reported by several
groups.9e,17 It has been proposed that the high selectivity
is a result of stereoelectronic effects and a similar
products along with unreacted starting material. The
first successful cyclization reaction was realized when the
reaction was carried out in CH2Cl2. Treatment of the
major trans-3a with 1.1 equiv of TfOH in CH2Cl2 at -40
°C for 30 min followed by the addition of NaBH4 in a 15%
aqueous NaOH solution at 0 °C afforded 5-hydroxymethyl
indolizidine 4a in 25% yield as a single detectable
diastereoisomer as judged by the H and 13C NMR data
1
(Table 1, entry 1). An extensive investigation was carried
out with different Lewis acids to optimize this transfor-
mation and the results are summarized in Table 1. Lewis
acids such as InCl3, TMSOTf, and TfOH are found to give
the cyclized product as a single diastereoisomer, albeit
in low yields. Though BF3‚OEt2 and TiCl4 are proved to
be potential Lewis acid catalysts, EtAlCl2 is found to be
an excellent catalyst, in which case the isolated yield is
always more than 60%. The high yield with EtAlCl2 could
be due to the minimization of side reactions, such as
pinacol rearrangement and formation of 1,2-diol or ha-
lohydrin, as it would not allow the formation of any protic
acid by virtue of its inherent ability to scavenge adventi-
tious protons.3f,15 Surprisingly, the minor cis-epoxyazide
3a under similar cyclization conditions failed to give any
cyclized product.16
The relative stereochemistry of the cyclized product
was confirmed by NOE experiments on the corresponding
acetate 9a , which was readily prepared from 4a by using
(15) (a) Snider, B. B. In Selectivities in Lewis Acid Promoted
Reactions; Schinzer, D., Ed.; Kluwer: Dordrecht, The Netherlands,
1989, Chapter 8. (b) Cartaya-Marin, C. P.; J ackson, A. C.; Snider, B.
B. J . Org. Chem. 1984, 49, 2443. (c) Snider, B. B.; Rodini, D. J .; Kirk,
T. C.; Cordova, R. J . Am. Chem. Soc. 1982, 104, 555. (d) Snider, B. B.
Acc. Chem. Res. 1980, 13, 426.
(16) The intramolecular opening of Lewis acid-activated epoxide by
azide is believed to take place via the SN2 rather than the SN1
mechanism leading to amino-diazonium intermediate A (Scheme 1).
It is clear from the conformational analysis that the cis-epoxyazide
would resist undergoing cyclization via the SN2 mechanism due to
stereochemical constrains.
J . Org. Chem, Vol. 69, No. 9, 2004 3095

Reddy and Baskaran
SCHEME 4. Tota l Syn th esis of In d olizid in e
Alk a loid s
F IGURE 3. ORTEP diagram of the hydrochloride salt of
p-bromobenzoate 11.
TABLE 2. Ep oxid e-In itia ted Ca tion ic Cycliza tion of
Azid es w ith Differ en t Rin g Sizes
group in the side chain. The 5-hydroxymethyl indolizidine
4a was converted to the corresponding tosylate 12, using
TsCl and Et3N in the presence of a catalytic amount of
DMAP, in 83% yield.
After surveying several solvents and additives with use
of Bu2Cu(CN)Li2 a smooth cuprate displacement of the
tosylate was realized when the reaction was carried out
in Et2O medium. Thus, treatment of tosylate 12 with Bu2-
Cu(CN)Li2, generated in situ from readily available
CuCN and n-BuLi, in Et2O at - 78 °C afforded 5-pentyl
indolizidine 13 in 53% yield, which is an analogue of
natural indolizidine alkaloids 167B and 209D (Scheme
4). Intriguingly, reaction of the tosylate 12 with Et2Cu-
(CN)MgBr, in Et2O medium at -78 °C, afforded indolizi-
dine 167B in 62% yield. Under similar reaction conditions
indolizidine 209D was prepared in 67% yield upon
treatment of 12 with (C5H11)2Cu(CN)MgBr (Scheme 4).
The spectroscopic data of these two natural products are
in complete agreement with the reported data.9e
En a n tioselective Tota l Syn th esis of (+)- a n d (-)-
In d olizid in e Alk a loid s 167B a n d 209D. The successful
stereoselective synthesis of indolizidine alkaloids 167B
and 209D motivated us to explore the enantioselective
synthesis of these alkaloids. Chiral indolizidine 167B and
209D can be achieved readily by our well-established
synthetic protocol starting from optically active ep-
oxyazide 3a . We envisaged the synthesis of optically
active epoxyazide 3a via Sharpless asymmetric dihy-
droxylation20 of the racemic azidoolefin 8 as shown in
Scheme 5.
n
substrate
producta
yield (%)
1
2
3
trans-3a
3bb
4a
4b
4c
63
42
47
3cb
a
b
Single diastereomer. Mixture of diastereomers.
SCHEME 3. Syn th esis of th e Hyd r och lor id e Sa lt
of p-Br om oben zoa te 11 for X-r a y An a lysis
explanation can be given for the reduction of our iminium
ion B generated from 3a (Scheme 1).
The generality of this transformation was further
tested with different ring sizes. Under standard cycliza-
tion conditions as described earlier, the mixture of
epoxyazide 3b afforded 5-hydroxymethyl azepine 4b as
a single diastereomer in 42% yield. Similarly, epoxyazide
3c furnished a single diastereomer of 5-hydroxymethyl
azocine 4c in 47% yield.18 The results are summarized
in Table 2. The relative stereochemistry of 4b and 4c was
assigned by NOE experiments.19
Ster eoselective Syn th esis of (()-In d olizid in e Al-
k a loid s 167B a n d 209D. Interestingly, the 5-hydroxy-
methyl indolizidine 4a has similar relative stereochem-
istry at C5 and C9 of the indolizidine alkaloids such as
indolizidine 167B and 209D. Hence, we anticipated that
an efficient entry to this class of alkaloids could be
achieved readily from 5-hydroxymethyl indolizidine 4a
by simple functional group manipulation of the hydroxy
Asymmetric dihydroxylation (ADH)21 of the racemic
azidoolefin 8 with OsO4 (0.5 mol %) in the presence of
K3[Fe(CN)6], CH3SO2NH2, and (DHQD)2PHAL (5 mol %)
as a chiral ligand afforded azidodiol 14 as an inseparable
mixture of diastereoisomers (cis:trans ) 1:1.3, calculated
based on NMR data) in 95% yield. Selective mesylation
of the primary hydroxyl group of the cis and trans
mixture of 14 with CH3SO2Cl and Et3N, followed by
treatment with K2CO3 afforded epoxyazide 3a as a
(19) In the case of the acetate of 4b, irradiation of equatorial
hydrogen at C3 enhanced the signal intensities of side chain methylene
hydrogens by 3.1% and 0.4%, indicating that the side chain and C3-H
(equatorial) are on the same side of the molecule. Although similar
results were not observed in the case of 4c, however, considerable NOE
between the hydrogens at C3 (axial), C5, and C11 upon irradiation of
C5-H clearly shows that they are syn to each other.
(20) For reviews please see: (a) Kolb, H. C.; VanNieuwenhze, M.
S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (b) J ohnson, R. A.;
Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH
Publishers: New York, 1993. (c) Sharpless, K. B. Tetrahedron 1994,
50, 4235.
(17) (a) Stevens, R. V.; Lee, A. W. M. J . Chem. Soc., Chem. Commun.
1982, 102. (b) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289. (c)
Polniaszek, R. P.; Belmont, S. E. J . Org. Chem. 1991, 56, 4868. (d)
Satake, A.; Shimizu, I. Tetrahedron: Asymmetry 1993, 4, 1405.
(18) By analogy based on the earlier observation, in the case of
epoxyazide 3a , it is believed that the cyclization products isolated are
derived from the corresponding trans-epoxyazides.
3096 J . Org. Chem., Vol. 69, No. 9, 2004

Epoxide-Initiated Cationic Cyclization of Azides
SCHEME 5. En a n tioselective Tota l Syn th esis of Un n a tu r a l (+)-(5S,9S)-In d olizid in e 167B a n d 209D
SCHEME 6. En a n tioselective Tota l Syn th esis of Na tu r a l (-)-(5R,9R)-In d olizid in e167B a n d 209D
separable mixture of cis-(+)-3a and trans-(-)-3a in 1:1.5
ratio, respectively (Scheme 5). The major trans-(-)-3a
was subjected to the standard cyclization conditions to
give the key intermediate 5-hydroxymethyl indolizidine,
which was immediately converted to the corresponding
tosylate (+)-12. Column chromatography of the crude
tosylate (+)-12 over deactivated silica gel (Et3N) afforded
optically active pure tosylate (+)-12 in 52% overall yield.
The enantiomeric excess (ee) of tosylate (+)-12 was
determined by HPLC analysis, using chiral column
(chiralcel OD-H), and found to be 77%. The moderate ee
observed for (+)-12 is due to the poor selectivity in the
ADH step of azidoolefin 8.21,22 Treatment of the tosylate
(+)-12 with Et2Cu(CN)MgBr led to the isolation of
indolizidine 167B in 68% yield with 78% ee. The spectral
data of our synthetic material are found to be in complete
agreement with those of the natural (-)-(5R,9R)-indolizi-
dine 167B except in the sign of rotation. So, the absolute
configuration of our synthetic indolizidine 167B was
assigned as unnatural (+)-(5S,9S)-indolizidine 167B. On
the basis of this observation, we could unambiguously
assign the absolute configuration of the trans-(-)-3a as
(3R,4S)-4-(3-azidopropyl)-1-oxa-spiro[2.4]heptane, whereas
the cis-(+)-3a is assigned as (3R,4R)-4-(3-azidopropyl)-
1-oxa-spiro[2.4]heptane. Similarly, unnatural (+)-(5S,9S)-
indolizidine 209D was achieved in 74% yield with 75%
ee, upon reaction of (+)-tosylate 12 with (C5H11)2Cu(CN)-
MgBr (Scheme 5).
As expected, the enantioselective synthesis of trans-
(+)-epoxyazide 3a required for the synthesis of natural
(-)-(5R,9R)-indolizidine 167B and 209D was readily
achieved by using the chiral ligand (DHQ)2PHAL instead
of (DHQD)2PHAL in the Sharpless asymmetric dihy-
droxylation step. Following a similar synthetic sequence
as described earlier, the natural (-)-(5R,9R)-indolizidine
167B was prepared in 75% ee, whereas (-)-(5R,9R)-
indolizidine 209D was achieved with 74% ee starting
from trans-(+)-(3S,4R)-3a (Scheme 6).
(21) The 1,1-dialkyl-substituted olefins are known to give moderate
ee in the Sharpless asymmetric dihydroxylation reaction. For ADH of
1,1-disubstituted olefins please see: (a) Hale, K. J .; Manaviazar, S.;
Peak, S. A. Tetrahedron Lett. 1994, 35, 425. (b) Crispino, B. A.; J eong,
K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B. J . Org. Chem.
1993, 58, 3785. (c) Wang, Z.-M.; Sharpless, K. B. Synlett 1993, 603.
(d) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, A.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768.
(22) Selective tosylation of the primary hydroxyl group of the cis
and trans mixture of 14 using p-TsCl and Et3N afforded a separable
mixture of the corresponding monotosylate (please see the Supporting
Information). The ee of the monotosylate of trans-14 was found to be
78% by HPLC analysis, using chiral column (Chiralcel OJ -H). In
addition, treatment of the monotosylate of trans-14 with K2CO3 in
MeOH afforded trans-(-)-3a with optical rotation identical with that
of the material obtained via mesylation as described in Scheme 5.
Con clu sion s
A novel and general method for the stereoselective
construction of 5-hydroxymethyl azabicyclic compounds
has been developed based on epoxide-initiated cationic
cyclization of azides. The cyclization reaction was thor-
oughly studied with different Lewis acids and ethyl
aluminum dichloride was found to be the most efficient
Lewis acid catalyst for this novel transformation. The
structure and relative stereochemistry of the cyclization
product, 5-hydroxymethyl indolizidine, was unambigu-
ously confirmed by NMR and X-ray analysis. The gen-
erality of this methodology was further tested with
J . Org. Chem, Vol. 69, No. 9, 2004 3097

Reddy and Baskaran
on silica gel with use of 10% EtOAc in hexane as an eluent
afforded pure hydroxyolefin 7a (8.04 g, 95% yield) as a colorless
oil.
different ring sizes, where six- and seven-membered
epoxyazides underwent smooth cyclization to give 5-hy-
droxymethyl azepine and azocine, respectively. The 5-hy-
droxymethyl indolizidine has been realized as a potential
precursor for the synthesis of biologically important
indolizidine alkaloids, such as indolizidine 167B and
209D. Thus, the novel methodology was elegantly applied
in the stereoselective total synthesis of indolizidine
alkaloids 167B and 209D. Enantioselective total synthe-
sis of both natural and unnatural indolizidine alkaloids
167B and 209D was readily achieved by using Sharpless
asymmetric dihydroxylation as a key step.
3-(2-Meth ylen ecyclop en tyl)p r op a n -1-ol (7a ): IR (neat)
1
3331 (broad), 1651 cm-1; H NMR (400 MHz, CDCl3) δ 4.88
(br s, 1H), 4.79 (br s, 1H), 3.65 (t, J ) 6.4 Hz, 2H), 2.24-2.33
(m, 3H), 2.08 (br s, 1H), 1.87-1.93 (m, 1H), 1.47-1.76 (m, 5H),
1.16-1.31(m, 2H); 13C NMR (100 MHz, CDCl3) δ 156.7, 104.2,
62.9, 43.7, 33.1, 32.7, 30.9, 30.4, 24.1.
3-(2-Meth ylen ecycloh exyl)p r op a n -1-ol (7b): Purification
by column chromatography (10% EtOAc in hexane) on silica
gel afforded 7b in 87% yield (31.8 mmol scale) as a colorless
liquid. IR (neat) 3342 (broad), 1644 cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.58 (s, 1H), 4.49 (s, 1H), 3.55 (t, J ) 7.1 Hz, 2H),
2.28 (br s, 1H), 2.11-2.19 (m, 1H), 1.94-1.97 (m, 2H), 1.15-
1.73 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 152.7, 105.6, 63.0,
42.9, 34.6, 33.8, 30.7, 28.8, 28.1, 24.1.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r e for th e P r ep a r a tion
of Olefin ester s (6a -c). A modified literature procedure12 was
used for the preparation of olefinesters as followed. To a stirred
slurry of zinc (16 g, 0.245 mol) in dry THF (300 mL) was added
CH2Br2 (8.6 mL, 0.122 mol) at room temperature and the
resultant mixture was stirred for about 30 min. The reaction
mixture was cooled to 0 °C and then treated dropwise with a
1 M solution of TiCl4 (89.7 mL, 89.7 mmol) in CH2Cl2. After
completion of the addition, the resultant dark brown color
solution was allowed to warm to room temperature over a
period of 20 min. Ketoester 5a (15 g, 81.5 mmol) was added to
the reaction mixture at room temperature and the solution
was allowed to stir for an additional 1 h. The mixture was
diluted with EtOAc and then poured in to ice cold 1 M HCl.
The mixture was stirred for 15 min and then the layers were
separated. The organic layer was washed with a 1 M HCl
solution and water and dried over anhydrous Na2SO4. The
organic layer was concentrated under reduced pressure and
the crude product was distilled under vacuum (bp 70-75 °C
at 1 mm) to give pure olefinester 6a (9.05 g, 61% yield) as a
colorless liquid.
3-(2-Meth ylen ecycloh ep tyl)p r op a n -1-ol (7c): Purifica-
tion by column chromatography (10% EtOAc in hexane) on
silica gel afforded 7c in 93% yield (1.81 mmol scale) as a
colorless liquid. 1H NMR (400 Hz, CDCl3) δ 4.79 (br s, 1H),
4.67 (d, J ) 1.9 Hz, 1H), 3.59 (t, J ) 6.4 Hz, 2H), 1.10-2.24
(m, 16H); 13C NMR (100 MHz, CDCl3) δ 154.6, 111.6, 62.9,
45.8, 34.3, 33.1, 32.1, 31.2, 30.7, 30.3, 26.3.
Gen er a l Exp er im en ta l P r oced u r e for th e P r ep a r a tion
of Azid oolefin s (8a -c). To a stirred solution of hydroxyolefin
7a (8.4 g, 60 mmol) in dry CH2Cl2 (150 mL) at 0 °C was added
Et3N (17 mL, 0.12 mol) followed by a dropwise addition of CH3-
SO2Cl (5.6 mL, 72 mmol) over a period of 10 min. After being
stirred for an additional 15 min at 0 °C, the mixture was
diluted with CH2Cl2 and the organic layer was washed with
water and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to give the corresponding
mesylate as a pale yellow liquid (13.08 g, quantitative yield).
The crude mesylate (13.0 g, 59.6 mmol) was redissolved in dry
DMF (200 mL) and treated with NaN3 (7.7 g, 0.119 mol). The
resultant mixture was stirred at 50 °C for about 3 h. The
reaction mixture was poured into ice-cold water and extracted
with hexane, then the combined hexane extracts were washed
with water and dried over anhydrous Na2SO4. Hexane was
removed under reduced pressure to give pure azidoolefin 8a
(9.66 g, 98% yield) as a colorless oil.
Eth yl 3-(2-m eth ylen ecyclop en tyl)p r op ion a te (6a ): IR
(neat) 1736, 1651 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.90 (br
s, 1H), 4.81 (br s, 1H), 4.13 (q, J ) 7.1 Hz, 2H), 2.28-2.42 (m,
5H), 1.50-1.99 (m, 6H), 1.26 (t, J ) 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.8, 155.7, 105.0, 60.2, 43.4, 33.1, 32.6,
32.5, 29.4, 24.2, 14.3.
3-(2-Meth ylen ecyclopen tyl)pr opyl azide (8a): The physi-
cal and spectral data were identical with those previously
Eth yl 3-(2-m eth ylen ecycloh exyl)p r op ion a te (6b): Pur-
ification by column chromatography (gradient elution with
0-5% EtOAc in hexane) on silica gel afforded 6b in 71% yield
1
reported for this compound.4e IR (neat) 2095, 1652 cm-1; H
NMR (400 MHz, CDCl3) δ 4.90 (br s, 1H), 4.78 (d, J ) 1.47
Hz, 1H), 3.25-3.30 (m, 2H), 2.24-2.33 (m, 3H), 1.87-1.95 (m,
1H), 1.48-1.76 (m, 5H), 1.22-1.34 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 156.0, 104.3, 51.5, 43.3, 32.9, 32.5, 31.2, 27.0,
24.0; MS (EI) m/z (rel intensity, %) 166 (M+ + 1, 2.5), 124 (100).
3-(2-Meth ylen ecycloh exyl)pr opyl azide (8b): Under simi-
lar reaction conditions azidoolefin 8b was isolated in 95% yield
(33.6 mmol scale). The physical and spectral data were
identical with those previously reported for this compound.4b
IR (neat) 2095, 1644 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.67
(br s, 1H), 4.56 (br s, 1H), 3.28(t, J ) 6.6 Hz, 2H), 2.17-2.26
(m, 1H), 1.98-2.06 (m, 2H), 1.23-1.80 (m, 10H); 13C NMR (100
MHz, CDCl3) δ 152.3, 105.9, 51.7, 42.8, 34.5, 33.9, 29.1, 28.8,
26.9, 24.1; MS (EI) m/z (rel intensity, %) 179 (M+ - 2, 2.5), 67
(100).
(50 mmol scale) as a colorless liquid. IR (neat) 1737, 1644 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.60 (br s, 1H), 4.50 (br s, 1H),
4.05 (q, J ) 7.1 Hz, 2H), 2.22 (t, J ) 7.7 Hz, 2H), 2.10-2.19
(m, 1H), 1.82-2.02 (m, 3H), 1.34-1.70 (m, 6H), 1.19-1.28 (m,
1H), 1.18 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.9, 151.6, 106.4, 60.1, 42.6, 34.2, 33.6, 32.4, 28.6, 27.1, 23.8,
14.2.
Eth yl 3-(2-m eth ylen ecycloh ep tyl)p r op ion a te (6c): Pur-
ification by column chromatography (gradient elution with
0-5% EtOAc in hexane) on silica gel afforded 6c in 39% yield
(4.72 mmol scale) as a colorless liquid. IR (neat) 1734, 1635
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.82 (s, 1H), 4.67 (s, 1H),
4.11 (q, J ) 7.1 Hz, 2H), 2.17-2.32 (m, 4H), 1.52-1.98 (m,
7H), 1.25 (t, J ) 7.1 Hz, 3H), 1.12-1.35 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 173.9, 153.5, 112.4, 60.0, 45.7, 34.2, 32.9,
32.4, 31.3, 30.8, 30.5, 26.2, 14.2.
3-(2-Meth ylen ecycloh ep tyl)p r op yl a zid e (8c): Under
similar reaction conditions azidoolefin 8c was isolated in 94%
yield (1.63 mmol scale). The physical and spectral data were
identical with those previously reported for this compound.4b
Gen er a l Exp er im en ta l P r oced u r e for th e P r ep a r a tion
of Hyd r oxyolefin s (7a -c). To a stirred suspension of LAH
(3.42 g, 90 mmol)) in dry THF (200 mL) was added olefinester
6a (11 g, 60 mmol) at room temperature and the resultant
mixture was stirred at the same temperature for 2 h. The
excess LAH was quenched with hydrated Na2SO4 (solid) at 0
°C. The white solid separated was filtered through a pad of
Celite, and the filtrate was dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give crude compound.
Column chromatographic purification of the crude compound
1
IR (neat) 2095 cm-1; H NMR (400 MHz, CDCl3) δ 4.81 (br s,
1H), 4.68 (br s, 1H), 3.25 (t, J ) 6.9 Hz, 2H), 2.16-2.22 (m,
2H), 1.85-2.15 (m, 1H), 1.80-1.84 (m, 2H), 1.48-1.68 (m, 4H),
1.08-1.46 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 154.0, 111.8,
51.5, 45.7, 34.4, 33.0, 32.1, 31.1, 30.1, 26.9, 26.4.
Gen er a l Exp er im en ta l P r oced u r e for th e P r ep a r a tion
of Ep oxya zid es (3a -c). To a solution of 3-(2-methylene
yclopentyl)propyl azide 8a (2.2 g, 13.3 mmol) in CH2Cl2 (30
3098 J . Org. Chem., Vol. 69, No. 9, 2004

Epoxide-Initiated Cationic Cyclization of Azides
mL) was added 0.5 M aqueous NaHCO3 solution (30 mL). The
resultant two-phase mixture was cooled to 0 °C and mCPBA
(50% suspension, 5.0 g, 14.5 mmol) was added portion-wise.
The mixture was stirred at the same temperature for about 2
h and then diluted with CH2Cl2. The organic layer was washed
with saturated aqueous NaHCO3 solution, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to
give the crude compound as a mixture of diastereomers. The
mixture was separated by column chromatography over de-
activated (Et3N) silica gel by using 5% EtOAc in hexane as an
eluent to afford pure cis-epoxyazide 3a (410 mg, 17% yield)
and trans-epoxyazide 3a (1.24 g, 51% yield) as colorless liquids.
2.5), 124 (100). Anal. Calcd for C9H17NO: C, 69.63; H, 11.04;
N, 9.02. Found: C, 69.72; H, 11.09; N, 9.32.
5-(H yd r oxym e t h yl)oct a h yd r op yr r olo[1,2-a ]a ze p in e
(4b): Purification by column chromatography (gradient elution
with 0-15% EtOAc in hexane) over basic alumina afforded
pure compound 17b in 42% yield (2 mmol scale) as a colorless
syrup. IR (neat) 3268 (broad), 2831, 2735 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.61 (dd, J ) 5.4, 10.3 Hz, 1H), 3.46 (dd, J )
4.2, 10.3 Hz, 1H), 3.40-3.58 (br s, 1H), 3.14-3.22 (m, 1H),
2.94 (dq, J ) 2.0, 8.0 Hz, 1H), 2.61-2.66 (m, 1H), 2.45 (ca. q,
J ) 8.0 Hz, 1H), 1.34-2.01 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ 64.7, 63.6, 61.4, 52.9, 35.9, 33.4, 30.6, 26.8, 24.7, 23.1;
MS (EI) m/z (rel intensity, %) 169 (M+, 1.6), 138 (100). Anal.
Calcd for C10H19NO: C, 70.96; H, 8.28; N, 8.28. Found: C,
71.04; H, 11.62; N, 8.54.
5-(H yd r oxym et h yl)d eca h yd r op yr r olo[1,2-a ]a zocin e
(4c): Purification by column chromatography (gradient elution
with 0-20% EtOAc in hexane) over basic alumina afforded
pure compound 17c in 47% yield (1 mmol scale) as a colorless
syrup. 1H NMR (400 MHz, CDCl3) δ 3.59 (dd, J ) 5.4, 10.4
Hz, 1H), 3.46 (dd, J ) 5.3, 10.4 Hz, 1H), 3.25-3.19 (m, 1H),
3.17-3.05 (m, 1H), 2.97-3.33 (br s, 1H), 2.81-2.86 (m, 1H),
2.52 (ca. q, J ) 8.3 Hz, 1H), 1.40-1.97 (m, 14H); 13C NMR
(100 MHz, CDCl3) δ 63.7, 61.8, 61.1, 50.7, 35.8, 32.6, 29.1, 26.7,
24.3, 24.2, 23.9; MS (EI) m/z (rel intensity, %) 183 (M+, 5.5),
152 (100). Anal. Calcd for C11H21NO: C, 72.08; H, 11.55; N,
7.64. Found: C, 72.38; H, 11.64; N, 7.84.
3-(1-Oxa -sp ir o[2.4]h ep t-4-yl)p r op yl a zid e (3a ): Ma jor
d ia ster eom er (tr a n s-3a ): IR (neat) 2095 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.26 (m, 2H), 2.90 (d, J ) 4.4 Hz, 1H), 2.71 (d,
J ) 4.9 Hz, 1H), 1.16-2.17 (m, 11H); 13C NMR (100 MHz,
CDCl3) δ 67.8, 51.5, 50.3, 42.5, 32.2, 31.1, 28.7, 27.2, 22.6; MS
(EI) m/z (rel intensity, %) 153 (M+ - 28, 1.5), 95 (100). Anal.
Calcd for C9H15N3O: C, 59.64; H, 8.34; N, 23.19. Found: C,
60.01; H, 8.14; N, 23.25. Min or d ia ster eom er (cis-3a ): IR
1
(neat) 2095 cm-1; H NMR (400 MHz, CDCl3) δ 3.25 (t, J )
7.3 Hz, 2H), 2.81 (d, J ) 4.9 Hz, 1H), 2.71 (d, J ) 4.9 Hz, 1H),
1.16-2.03 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 65.4, 51.3,
50.1, 40.5, 32.2, 31.4, 27.1, 25.6, 22.3.
3-(1-Oxa -sp ir o[2.5]oct-4-yl) p r op yl a zid e (3b): Purifica-
tion by column chromatography on silica gel (deactivated with
Et3N) with 5% EtOAc in hexane as an eluent afforded pure
title compound 3b in 91% yield (2.5 g scale) as a colorless liquid
5-(Acetoxym eth yl)in d olizid in e (9a ): To a stirred solution
of alcohol 4a (1.4 g, 9.03 mmol) in CH2Cl2 (15 mL) was added
Et3N (2.5 mL, 18.06 mmol) followed by Ac2O (1 mL, 10.84
mmol) and the resultant mixture was stirred at room temper-
ature for 3 h. The reaction mixture was diluted with CH2Cl2,
washed with aqueous NaHCO3 solution, dried over anhydrous
MgSO4, and concentrated under reduced pressure to give crude
compound. Column chromatographic purification of the crude
compound (gradient elution with 0-2.5% EtOAc in hexane)
on basic alumina furnished pure acetate 9a (1.62 g, 91% yield)
(inseparable mixture of diastereomers). IR (neat) 2095 cm-1
;
1H NMR (400 MHz, CDCl3) δ 3.26 (m, 2H), 2.67 (t, J ) 6.6
Hz, 1H), 2.52 (t, J ) 5.8 Hz, 1H), 1.06-1.95 (m, 13H); 13C NMR
(100 MHz, CDCl3) δ 61.1, 53.5, 51.6, 51.4, 40.8, 40.1, 32.8, 31.7,
30.1, 29.4, 26.9, 26.8, 26.4, 25.6, 25.0, 23.1, 22.1; MS (EI) m/z
(rel intensity, %) 196 (M+ - 1, 1.5), 79 (100). Anal. Calcd for
C
10H17N3O: C, 61.51; H, 8.78; N, 21.52. Found: C, 61.75; H,
8.44; N, 21.85.
3-(1-Oxa -sp ir o[2.6]n on -4-yl)p r op yl a zid e (3c): Purifica-
tion by column chromatography on silica gel (deactivated with
Et3N) with 5% EtOAc in hexane as an eluent afforded pure
title compound 3c in 82% yield (1.5 mmol scale) as a colorless
liquid (inseparable mixture of diastereomers). IR (neat) 2093
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.27 (m, 2H), 2.59 (m, 2H),
1.20-2.04 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 62.9, 62.7,
55.2, 54.1, 52.0, 51.9, 44.2, 43.7, 33.2, 32.8, 31.8, 31.6, 30.1,
29.5, 29.4, 29.3, 27.3, 27.2, 25.9, 25.3, 25.1, 24.6. Anal. Calcd
for C11H19N3O: C, 63.13; H, 9.15; N, 20.08. Found: C, 63.24;
H, 9.21; N, 20.50.
as a colorless oil. IR (neat) 1740 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 4.20 (dd, J ) 4.9, 11.2 Hz, 1H), 4.04 (dd, J ) 5.4,
11.2 Hz, 1H), 3.24 (dt, J ) 2.4, 8.8 Hz, 1H), 2.21-2.27 (m,
1H), 2.05-2.14 (m, 1H), 2.07 (s, 3H), 1.63-1.95 (m, 7H), 1.16-
1.48 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.3, 67.6, 65.3,
62.4, 52.1, 30.8, 30.2, 29.1, 24.4, 21.3, 20.9; MS (EI) m/z (rel
intensity, %) 197 (M+, 0.5), 124 (100). Anal. Calcd for C11H19
-
NO2: C, 66.97; H, 9.71; N, 7.10. Found: C, 67.03; H, 9.41; N,
7.42.
4-Br om o(in d olizid in -5-ylm eth yl)ben zoa te (10): To a
stirred solution of alcohol 4a (155 mg, 1 mmol) in CH2Cl2 was
added Et3N (0.278 mL, 2 mmol) followed by p-bromobenzoyl
chloride (241 mg, 1.1 mmol) at room temperature. The result-
ant mixture was stirred for about 3 h. The reaction mixture
was diluted with CH2Cl2 and washed with aqueous NaHCO3
solution, then the organic layer was dried over anhydrous
MgSO4. Solvent was removed under reduced pressure and the
crude compound was purified by column chromatography over
silica gel (deactivated with Et3N), using 15% EtOAc in hexane
as an eluent, to afford pure title compound 10 (289 mg, 86%
yield) as a colorless low-melting solid. 1H NMR (400 MHz,
CDCl3) δ 7.90 (d, J ) 8.8 Hz, 2H), 7.57 (d, J ) 8.3 Hz, 2H),
4.43 (dd, J ) 5.9, 11.2 Hz, 1H), 4.29 (dd, J ) 5.4, 11.2 Hz,
1H), 3.30 (dt, J ) 1.96, 8.8 Hz, 1H), 2.39 (m, 1H), 2.18 (ca. q,
J ) 8.8, 9.3 Hz, 1H), 1.67-1.95 (m, 7H), 1.23-1.47 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 165.4, 131.6, 130.9, 128.9, 127.9,
68.4, 64.8, 61.9, 52.0, 30.5, 29.8, 28.9, 24.0, 20.6. Anal. Calcd
for C16H20BrNO2: C, 56.82; H, 5.96; N, 4.14. Found: C, 56.98;
H, 6.04; N, 4.52.
Gen er a l Exp er im en ta l P r oced u r e for th e P r ep a r a tion
of 5-Hyd r oxym eth yl Aza bicyclic Com p ou n d s (4a -c). To
a stirred solution of trans-(()-3a (181 mg, 1 mmol) in dry CH2-
Cl2 (5 mL) at - 78 °C was added EtAlCl2 (1.8 M solution in
toluene, 0.611 mL, 1.1 mmol) dropwise. The resultant mixture
was stirred for 45 min at -78 °C and then allowed to warm to
room temperature. After being stirred for additional 5 min at
room temperature, the mixture was cooled to 0 °C and treated
with a solution of NaBH4 (266 mg, 7 mmol) in 15% aqueous
NaOH (3 mL). The reaction mixture was allowed to warm to
room temperature and stirred for 1.5 h. The layers were
separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with water, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure to give a crude compound that was purified by column
chromatography on basic alumina (gradient elution with
0-10% EtOAc in hexane) to afford pure 5-hydroxymethyl
indolizidine 4a (97 mg, 63% yield) as a colorless syrup.
5-(H yr oxym et h yl)in d olizid in e (4a ): IR (neat) 3362
Hyd r och lor id e sa lt of 4-br om o(in d olizid in -5-ylm eth -
yl)ben zoa te (11): Dry HCl gas was passed through a solution
of 4-bromo(indolizidin-5-ylmethyl)benzoate 10 (100 mg, 0.296
mmol) in dry Et2O (10 mL) at 0 °C for 2 min. The white solid
that separated was filtered and washed with Et2O (10 mL).
The solid was azeotropically dried with toluene (2 × 5 mL)
1
(broad), 2788, 2358 cm-1; H NMR (400 MHz, CDCl3) δ 3.65
(dd, J ) 4.4, 10.7 Hz, 1H), 3.47 (dd, J ) 2.9, 10.7 Hz, 1H),
3.15 (dt, J ) 2.2, 8.8 Hz, 1H), 2.90 (br s, 1H), 1.04-2.0 (m,
13H); 13C NMR (100 MHz, CDCl3) δ 64.9, 64.8, 64.5, 51.5, 30.8,
30.4, 28.4, 24.5, 20.8; MS (EI) m/z (rel intensity, %) 155 (M+,
J . Org. Chem, Vol. 69, No. 9, 2004 3099

Reddy and Baskaran
TABLE 3. Op tica l Rota tion s a n d Absolu te Con figu r a -
tion s for 4-(3-Azid op r op yl)-1-oxa -sp ir o[2.4]h ep ta n es
under high vacuum at room temperature to give pure title
compound 11 as a white solid (108 mg, 97% yield). Recrystal-
ization of 11 from nitromethane (50 mg/10 mL) by slow
evaporation technique at room temperature afforded good size
and quality crystals (colorless needles) suitable for X-ray
diffraction studies (please see the Supporting Information for
X-ray crystallographic data).
2-(3-Azid op r op yl)-1-h yd r oxym eth ylcyclop en ta n ol (14):
To a stirred solution of olefinazide 8 (825 mg, 5 mmol) in a
1:1 mixture of t-BuOH-water (30 mL) were added sequentially
K3[Fe(CN)6] (4.94 g, 15 mmol), K2CO3 (2.07 g, 15 mmol),
(DHQD)2PHAL (195 mg, 0.25 mmol), CH3SO2NH2 (475 mg, 5
mmol), and OsO4 (0.250 mL of a 0.1 M solution in t-BuOH,
0.025 mmol). The resulting mixture was stirred at 6 °C for
3.5 h. Na2S2O5 (30 mg) was added to the reaction mixture and
stirred for an additional 45 min at room temperature. The
reaction mixture was diluted with EtOAc and filtered through
a pad of Celite and the filter cake was thoroughly washed with
EtOAc. The combined filtrates were dried over anhydrous
MgSO4 and concentrated under reduced pressure. The crude
compound was purified by column chromatography over silica
gel with us eof 20-40% EtOAc in hexane solvent gradient to
afford a diastereomeric mixture of azidodiols 14 (945 mg, 95%
isolated epoxyazide obsd optical rotation
ligand used in
ADH reaction of
(abs config)
(c 1.0, CH2Cl2)
S. No. azidoolefin 8
trans
cis
trans
cis
(-)-3a
(+)-3a
1
2
(DHQD)2PHAL (3R,4S) (3R,4R)
-52.8
+51.4
+34.4
-32.3
(+)-3a
(3S,4R) (3S,4S)
(-)-3a
(DHQ)2PHAL
reduced pressure and the crude compound was purified over
deactivated silica gel (Et3N) with 25% EtOAc in hexane as
eluent to give pure tosylate 12 (1.65 g, 83% yield) as a colorless
1
oil. IR (neat) 2861, 2791 cm-1; H NMR (400 MHz, CDCl3) δ
7.78 (d, J ) 8.3 Hz, 2H), 7.34 (d, J ) 8.3 Hz, 2H), 4.09 (dd, J
) 5.4, 9.8 Hz, 1H), 3.89 (dd, J ) 5.4, 9.8 Hz, 1H), 3.04 (dt, J
) 2.4, 8.5 Hz, 1H), 2.44 (s, 3H), 2.23-2.28 (m, 1H), 2.04 (q, J
) 9.0 Hz, 1H), 1.61-1.87 (m, 7 H), 1.07-1.38 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 144.7, 132.6, 129.7, 127.8, 72.9, 64.6, 61.5,
51.6, 30.3, 29.8, 28.5, 23.7, 21.5, 20.5; MS (EI) m/z (rel
yield) as a colorless syrup. IR (neat) 3408 (broad), 2112 cm-1
;
1H NMR (400 MHz, CDCl3) δ 3.62 (dd, J ) 11.2, 17.2 Hz, 1H),
3.48 (ca. t, J ) 11.2, 12.4 Hz, 1H), 3.28-3.30 (m, 2H), 2.78 (br
s, 1H), 2.39 (br s, 1H), 1.13-2.06 (m, 11H); 13C NMR (100 MHz,
CDCl3) d 83.2, 82.1, 69.0, 65.5, 51.7, 51.6, 48.4, 45.6, 37.6, 35.6,
30.7, 29.5, 27.9, 27.8, 26.9, 26.6, 21.6, 20.9. Anal. Calcd for
C9H17N3O2: C, 54.25; H, 8.60; N, 21.09. Found: C, 54.25; H,
8.48; N, 21.29.
intensity, %) 309 (M+, 1.7), 124 (100). Anal. Calcd for C16H23
-
NO3S: C, 62.11; H, 7.49; N, 4.53. Found: C, 62.32; H, 7.56;
N, 4.73.
P r ep a r a tion of (+)-(5R,9S)- a n d (-)-(5S,9R)-5-(p-tolu -
en esu lfon yloxym eth yl)in d olizid in e (12). Under similar
reaction conditions as described above trans-(-)-epoxyazide
16a was converted to the corresponding (+)-(5R,9S)-5-(p-
toluenesulfonyloxymethyl)indolizidine (12) {[R]26D +32.4 (c 1.0,
CH2Cl2)} in 52% overall yield with 77% ee (determined by
HPLC analysis on a chiral column). Similarly, trans-(+)-
epoxyazide 3a was converted to the corresponding (-)-(5S,9R)-
Gen er a l P r oced u r e for th e P r ep a r a tion of Op tica lly
Active 4-(3-Azid op r op yl)-1-oxa -sp ir o[2.4]h ep ta n e (3a ). To
a stirred solution of a diastereomeric mixture of azidodiol 14
(597 mg, 3 mmol, prepared by the Sharpless ADH reaction of
azidoolefin 8 with (DHQD)2PHAL as a chiral ligand) in dry
CH2Cl2 (15 mL) was added Et3N (0.835 mL, 6 mmol) followed
by CH3SO2Cl (0.285 mL, 3.6 mmol) at 0 °C. The mixture was
stirred for 1 h at the same temperature and then it was diluted
with CH2Cl2. The organic layer was washed with water and
dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure to give crude compound. The crude
monomesylate was redissolved in methanol (15 mL) and
treated with K2CO3 (828 mg, 6 mmol) at room temperature
and the resultant mixture was stirred for 45 min. Solvent was
removed under reduced pressure and the residue was diluted
with EtOAc. The organic layer was washed with water, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure to give crude epoxyazide 3a as a mixture of diaster-
eomers. The mixture was separated by column chromatogra-
phy over silica gel with use of 0-2.5% EtOAc in hexane solvent
gradient as eluent to give pure trans-(-)-3a (168 mg, 31%
yield) and cis-(+)-3a (114 mg, 21% yield).
Under similar reaction conditions, trans-(+)-3a and cis-(-)
-3a were obtained in 23% and 30% yield, respectively (total
53% yield, 3.52 mmol scale), from the azidodiol 14, which in
turn was prepared by the Sharpless ADH reaction of racemic
olefinazide 8 with (DHQ)2PHAL as a chiral ligand. 1H and 13C
NMR data for trans-(+)-3a and (-)-3a are in complete agree-
ment with those of trans-(()-3a obtained by mCPBA oxidation
of olefinazide 8. Similarly, spectral data for cis-(+)-3a and (-)-
3a are comparable with those of cis-(()-3a .
5-(p-toluenesulfonyloxymethyl)indolizidine (12) {[R]26 -31.2
D
(c 1.0, CH2Cl2)} in 53% overall yield with 75% ee (determined
by HPLC analysis on a chiral column). Spectral data for (+)-
and (-)-tosylate 12 were found to be identical in all respects
with those of the racemic tosylate 12. HPLC (chiral) column:
Chiralcel OD-H (0.46 × 25 cm2); λ ) 222 nm. Mobile phase:
0.5% isopropyl alcohol in hexane at 0.5 mL/min flow rate.
Retention times: 32.64 min [(+)-(5R,9S)-12], 35.05 min [(-)-
(5S,9R)- 12].
P r ep a r a tion of 5-P en tylin d olizid in e w ith Bu 2Cu (CN)-
Li2 in Et2O (13). CuCN (119 mg, 1.33 mmol) was placed in a
dry two-neck round-bottom flask and azeotropically dried with
toluene (2 × 5 mL) at room temperature under vacuum. The
powder was placed under argon and dry Et2O (5 mL) was
introduced. The slurry was cooled to - 78 °C and then n-BuLi
(2.5 mL of 1.1 M solution in hexane, 2.65 mmol) was added
dropwise. The heterogeneous mixture was allowed to warm
to 0 °C to give a homogeneous solution and then recooled to -
78 °C. A solution of tosylate 12 (82 mg, 0.265 mmol) in dry
Et2O (2 mL) was added dropwise and the resultant mixture
was allowed to stir for 2 h at - 78 °C. Aqueous ammonia
solution (10 mL, 25%) was added to the reaction mixture and
extracted with EtOAc. Combined organic extracts were washed
with water, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude compound was purified by
column chromatography (gradient elution with 0-10% EtOAc
in hexane) over silica gel (deactivated with Et3N) to afford pure
5-pentyl indolizidine 13 (27 mg, 53% yield) as a colorless liquid.
IR (neat) 2928, 2864 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.27
(dt, J ) 2.0, 8.8 Hz, 1H), 1.98 (q, J ) 8.8 Hz, 1H), 1.61-1.92
(m, 9H), 1.11-1.50 (m, 11H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 65.0, 63.9, 51.5, 34.6, 32.3, 30.9, 30.8, 30.5,
25.5, 24.7, 22.6, 20.4, 14.0; MS (EI) m/z (rel intensity, %) 195
(M+, 12.5), 124 (100).
5-(p-Tolu en esu lfon yloxym eth yl)in dolizidin e (12): trans-
3a (1.81 g, 10 mmol) was subjected to standard cyclization
conditions to afford pure 5-hydroxymethylindolizidine 4a (1.0
g, 63% yield) as a colorless syrup. To a stirred solution of
alcohol 4a (1.0 g, 6.45 mmol) in dry CH2Cl2 (20 mL) at room
temperature were added Et3N (1.8 mL, 12.9 mmol) and TsCl
(1.35 g, 7.1 mmol) followed by a catalytic amount of DMAP.
The mixture was allowed to stir for 3 h and then diluted with
CH2Cl2, washed with saturated aqueous NaHCO3 and water,
and dried over anhydrous Na2SO4. Solvent was removed under
3100 J . Org. Chem., Vol. 69, No. 9, 2004

Epoxide-Initiated Cationic Cyclization of Azides
Gen er a l P r oced u r e for th e P r ep a r a tion of In d olizi-
d in e Alk a loid s 167B a n d 209D (1, 2) w it h Ma gn esiu m
Cu p r a tes. To a slurry of azeotropically dried CuCN (671 mg,
7.5 mmol) in dry Et2O (5 mL) was added a solution of EtMgBr
(15 mmol, generated from 360 mg of magnesium and 1.12 mL
of ethyl bromide) in 10 mL of dry Et2O. The heterogeneous
mixture was allowed to warm to -10 °C (a dark yellow color
suspension was observed) at which temperature it was stirred
for about 10 min and then recooled to -78 °C. A solution of
tosylate 12 (309 mg, 1 mmol) in dry Et2O (5 mL) was added
and the resultant mixture was allowed to warm to 0 °C over
a period of 2 h. Quenching of the reaction mixture with
saturated aqueous NH4Cl (20 mL) followed by standard
workup and purification, as described for 5-pentylindolizidine
13, furnished pure (()-indolizidine alkaloid 167B 1 (104 mg,
62%) as a colorless liquid. The physical and spectral data were
identical with those previously reported for this compound.9e
IR (neat) 2870, 2780 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.28
(dt, J ) 2.4, 8.8 Hz, 1H), 1.99 (q, J ) 9.0 Hz, 1H), 1.62-1.92
(m, 9H), 1.14-1.49 (m, 7H), 0.91 (t, J ) 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 65.0, 63.7, 51.4, 36.8, 30.9, 30.7, 30.4, 24.6,
20.3, 19.0, 14.4; MS (EI) m/z (rel intensity, %) 167 (M+, 14.5),
124 (100). Anal. Calcd for C11H21N: C, 78.97; H, 12.65; N, 8.37.
Found: C, 78.59; H, 12.86; N, 8.39.
by column chromatography (gradient elution with 0-25%
EtOAc in hexane) on deactivated silica gel (Et3N) afforded pure
title compound as a colorless liquid in 67% yield (500 mg scale).
IR (neat) 2857, 2780 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.25
(dt, J ) 2.0, 8.8 Hz, 1H), 1.96 (q, J ) 9.0 Hz, 1H), 1.61-1.90
(m, 10H), 1.09-1.49 (m, 12H), 0.88 (t, J ) 6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 65.3, 64.1, 51.8, 34.8, 32.1, 31.2,
31.1, 30.8, 30.0, 26.0, 24.9, 22.9, 20.6, 14.3; MS (EI) m/z (rel
intensity, %) 209 (M+, 8.5), 124 (100). Anal. Calcd for
C9H15N3O: C, 80.31; H, 13.00; N, 6.69. Found: C, 80.70; H,
12.94; N, 6.85.
En a n tioselective Syn th esis of (+)-(5S,9S)- a n d (-)-
(5R,9R)-In d olizid in e Alk a loid 209D (2). Under similar
reaction conditions as described above (+)-(5R,9S)-tosylate 12
was converted to the corresponding unnatural (+)-(5S,9S)-
indolizidine 209D {[R]26D +59.7 (c 1.0, CH2Cl2, 75% ee)} in 74%
yield. Similarly, (-)-(5S,9R)-tosylate 12 was converted to the
corresponding natural (-)-(5R,9R)-indolizidine 209D {[R]26
D
-59.5 (c 1.0, CH2Cl2); lit.9e [R]26 -80.4 (c 1.0, CH2Cl2), 74%
D
ee)} in 74% yield. Spectral data of unnatural and natural
indolizidine alkaloid 209D were found to be identical in all
respects with those of the racemic indolizidine alkaloid 209D.
Ack n ow led gm en t. We thank DST, New Delhi and
DRDO, New Delhi for financial support and P.G.R.
thanks CSIR, New Delhi and IIT Madras for research
fellowships. We are grateful to RSIC, IIT Madras, for
spectral data.
En a n tioselective Syn th esis of (+)-(5S,9S)- a n d (-)-
(5R,9R)-In d olizid in e Alk a loid 167B (1). Under similar
reaction conditions as described above, (+)-(5R,9S)-tosylate 12
was converted to the corresponding unnatural (+)-(5S,9S)-
indolizidine 167B {[R]26 +86.6 (c 1.3, CH2Cl2), 78% ee)} in
D
68% yield. Similarly, (-)-(5S,9R)-tosylate 12 was converted to
the corresponding natural (-)-(5R,9R)-indolizidine 167B
{[R]26 -83.5 (c 1.3, CH2Cl2; lit.9e [R]26 -111.3 (c 1.3, CH2-
Cl2), 75% ee)} in 68% yield. Spectral data of unnatural and
natural indolizidine alkaloid 167B were found to be identical
in all respect with those of the racemic indolizidine alkaloid
167B 1.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods, representative 1H and 13C NMR spectra for all
the new compounds, chiral HPLC reports of 12, monotosylate
of trans-14, and X-ray crystallographic data for 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
D
D
(()-In d olizid in e-209D (2): Under similar conditions (()-
indolizidine 209D was prepared with C5H11MgBr. Purification
J O035258X
J . Org. Chem, Vol. 69, No. 9, 2004 3101