Epoxide-initiated electrophilic cyclization of azides: A novel route for the stereoselective construction of azabicyclic ring systems and total synthesis of (±)-indolizidine 167B and 209D

Article abstract of DOI:10.1021/ol027563v

(Matrix presented) A novel and general method for the stereoselective construction of 5-hydroxymethyl azabicyclic ring skeletons based on epoxide initiated electrophilic cyclization of azides has been developed and applied in the synthesis of (±)-indolizi

Full text of DOI:10.1021/ol027563v

ORGANIC
LETTERS
2003
Vol. 5, No. 4
583-585
Epoxide-Initiated Electrophilic
Cyclization of Azides: A Novel Route
for the Stereoselective Construction of
Azabicyclic Ring Systems and Total
Synthesis of (±)-Indolizidine 167B and
†
209D
P. Ganapati Reddy, Babu Varghese,‡ and Sundarababu Baskaran*
Department of Chemistry, Indian Institute of Technology,
Madras, Chennai-600036, India
sbhaskar@iitm.ac.in
Received December 27, 2002
ABSTRACT
A novel and general method for the stereoselective construction of 5-hydroxymethyl azabicyclic ring skeletons based on epoxide initiated
electrophilic cyclization of azides has been developed and applied in the synthesis of (±)-indolizidine 167B and 209D with an overall yield of
16.5% and 17.8%, respectively. The efficiency of this methodology is further exemplified in the synthesis of azepine skeleton via tandem
cation−olefin−azide cyclization.
Cation-induced cyclization is one of the most powerful
techniques used in the synthesis of polycyclic frameworks.1
With the advent of more efficient cation terminators, the
importance of the epoxide-initiated electrophilic cyclization
in the stereoselective synthesis of natural products is expand-
ing rapidly.2 In recent years, azide has gained remarkable
attention as a cation terminator, since the subsequent skeletal
rearrangement (Schmidt reaction) after cyclization offers a
novel approach to azabicyclic ring systems.3,4 Acid-mediated
inter- and intramolecular Schmidt reaction of azidoalkenes3
and azidoketones4 has been extensively studied; 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.5 In this family, indolizidine alkaloids are the most
important class of compounds, known for their wide range
† Dedicated with deep respect to Professor E. J. Corey on the occasion
of his 75th birthday.
‡ Correspondence regarding X-ray analysis: Regional Sophisticated
Instrumentation Center, IIT Madras, Chennai-600036, India.
(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 Syntheses; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, p 341. (c) Johnson, W. S. Tetrahedron
1991, 47 (41), xi.
(3) (a) Pearson, W. H.; Hutta, D. A.; Fang, W. J. Org. Chem. 2000, 65,
8326. (b) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang, W.;
Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183. (c) Pearson, W.
H.; Schkeryantz, J. S. Tetrahedron Lett. 1992, 33, 5291.
(4) (a) Wrobleski, A.; Sahasrabudhe, K.; Aube, J. J. Am. Chem. Soc.
2002, 124, 9974. (b) Smith, B. T.; Gracias, V.; Aube, J. J. Org. Chem.
2000, 65, 3771. (c) Forsee, J. E.; Aube, J. J. Org. Chem. 1999, 64, 4381.
(d) Milligan, G. L.; Mossman, C. J.; Aube. J. J. Am. Chem. Soc. 1995,
117, 10449.
(2) (a) Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 9999. (b) Corey, E. J.; Wood, H. B., Jr. J. Am Chem. Soc. 1996, 118,
11982. (c) Langkopf, E.; Schinzer, D. Chem. ReV. 1995, 95, 1375. (d) Corey,
E. J.; Sodeoka, M. Tetrahedron Lett. 1991, 32, 7005.
10.1021/ol027563v CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/18/2003

To explore a suitable Lewis acid for this useful transfor-
mation, an extensive investigation was carried out with
different Lewis acids (Table 1). Among all the Lewis acids
Scheme 1
Table 1. Epoxide-Initiated Electrophilic Cyclization of Azide
with Different Lewis Acids
of pharmaceutical applications (Scheme 1).6 Herein, for the
first time, we report a general and highly diastereoselective
approach for the construction of 5-hydroxymethyl azabicyclic
compounds and its application in the synthesis of indolizidine
alkaloids based on epoxide-initiated electrophilic cyclization
of azides. In addition, the hitherto unknown synthetic
potential of this cyclization, in tandem cation-olefin-azide
cyclization to the novel azepine skeleton, is further exploited.
We envisioned that the treatment of an epoxy azide 3 with
a Lewis acid would lead to the cyclization followed by
intramolecular Schmidt reaction and in situ reduction of the
intermediate iminium ion resulting in an azabicyclic alcohol
4 (Scheme 2). To test the viability of the above strategy we
entry
Lewis acid
temp, °C
% yielda
1
2
3
4
5
6
TfOH
-40
-78
-78
-25
0
25
21
50
43
25
63
TMSOTf
BF3‚OEt2
TiCl4
InCl3
EtAlCl2
-78
a Isolated yields.
studied, EtAlCl2 was found to be the ideal choice. In all cases,
isolation of the single diastereomer emphasizes the structural7
and stereochemical control8 of this reaction. The relative
stereochemistry at C5 and C9 was unambiguously established
by the single-crystal X-ray analysis of the corresponding
hydrochloride salt of p-bromobenzoate ester 7 (Figure 1).
Scheme 2. Epoxide-Initiated Electrophilic Cyclization of
Azides
have chosen a five-membered epoxyazide 3a, which can be
readily obtained from cyclopentanone (Scheme 3). Treatment
Figure 1. Single-crystal X-ray structure.
Scheme 3. Total Synthesis of Indolizidine 167 B and 209 Da
The generality of this transformation was further tested
with different ring sizes. The results are summarized in Table
2. The epoxy azides 3b and 3c were prepared by similar
strategy as shown in Scheme 3, starting from cyclohexanone
and cycloheptanone, respectively.
Interestingly, the hydroxymethyl indolizidine 4a has a
similar relative stereochemistry at C5 and C9 of indolizidine
alkaloids such as indolizidine 167B and 209D. Hence, we
anticipated that an efficient entry to this class of alkaloids
a Reagents: (a) Zn, CH2Br2, TiCl4 (1 M), CH2Cl2, 20 °C, 1 h,
71%. (b) LiAlH4, THF, 0 °C, 2 h, 95%. (c) CH3SO2Cl, Et3N,
CH2Cl2, 0 °C, 30 min, 100%. (d) NaN3, DMF, 55 °C, 4 h, 98%.
(e) mCPBA, CH2Cl2, 0.5 M NaHCO3, 0 °C, 2.5 h, 68%. (f) EtAlCl2,
CH2Cl2, -78 °C, 45 min, NaBH4 in 15% aq NaOH, 1 h, 63%. (g)
TsCl, Et3N, DMAP (cat.), 25 °C, 2 h, 94%. (h) EtMgBr, CuCN,
Et2O, - 78 °C, 62%. (i) C5H11MgBr, CuCN, Et2O, -78 °C, 67%.
(5) For a review on these natural products, see: Daly, J. W. J. Nat. Prod.
1998, 61, 162.
(6) (a) Daly, J. W.; Sande, T. F. In Alkaloids: Chemical and Biological
ProspectiVes; 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.
(7) The proton-initiated intramolecular Schmidt reaction of the azido-
alkene, leading to a mixture of regioisomeric azabicyclic products, has been
reported (ref 3b). However, under our cyclization conditions, we do not
observe any other regioisomers.
of epoxy azide 3a with 1.1 equiv of TfOH in CH2Cl2 medium
at -40 °C followed by the addition of a solution of sodium
borohydride gave hydroxymethyl indolizidine 4a in 25%
yield as a single detectable diastereomer as judged by the
1H and 13C NMR data.
(8) (a) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem.
1995, 60, 398. (b) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990,
55, 4688.
584
Org. Lett., Vol. 5, No. 4, 2003

diastereomer. The azidoalkene 11 used for this study was
prepared from geraniol.12 Regioselective epoxidation of the
azidoalkene 11 was achieved in two steps via bromohydrin.13
The remarkable stereochemical outcome of this reaction
was rationalized by invoking the similar stereoselective
reduction of the intermediate iminium ion reported in the
literature.3a,8 A plausible mechanism is shown in Scheme 5.
Table 2. Epoxide-Initiated Electrophilic Cyclization of Azides
with Different Ring Sizes
n
substrate
producta
% yield
1
2
3
3a
3bb
3cb
4a
4b
4c
63
42
47
Scheme 5. A Plausible Mechanism for Tandem Epoxide
Initiated Electrophilic Cyclization
a Single diastereomer. b Mixture of diastereomers.
could be achieved readily by further functional group
manipulation of the hydroxy group in the side chain.
Modified methylenation of the known ketoester 89 with the
CH2Br2/Zn/TiCl4 reagent system10 gave olefin ester in 71%
yield, which was converted to the corresponding azido-alkene
93b in three steps as shown in Scheme 3. Azido-alkene 9
upon exposure to mCPBA yielded the epoxyazide 3a as a
mixture of cis and trans isomers in a 1:3 ratio. Treatment of
the major diastereomer11 with EtAlCl2 at -78 °C followed
by reduction with sodium borohydride afforded azabicyclic
alcohol 4a in 63% yield. The alcohol was converted to the
corresponding tosylate 10 in 93% yield. Treatment of the
tosylate 10 with Et2CuCNMgBr in Et2O medium at - 78
°C afforded indolizidine 167B in 62% yield. Under similar
reaction conditions tosylate 10 was converted to indolizidine
209D in 67% yield upon treatment with (C5H11)2CuCNMgBr.
The spectroscopic data of these two compounds are in
complete agreement with the reported data.8b
NOE and 2D NMR studies on the corresponding acetate of
13 confirmed the relative stereochemistry at C5, C8, and C9.
In conclusion, for the first time, a novel and general
method for the stereoselective construction of 5-hydroxy-
methyl azabicyclic ring skeletons based on epoxide-initiated
electrophilic cyclization of azides has been developed and
applied in the synthesis of (()-indolizidine 167B and 209D
with an overall yield of 16.5% and 17.8% respectively,
starting from a known ketoester 8. The efficiency of this
methodology is further exemplified in tandem cation-
olefin-azide cyclization to the novel azepine skeleton.
Application of this methodology in asymmetric synthesis of
indolizidine alkaloids (alkyl and polyhydroxy indolizidines)
will be reported in due course.
The scope of this methodology was further extended to
the novel tandem cation-olefin-azide cyclization, wherein
Acknowledgment. We thank the Department of Science
and Technology, New Delhi for financial support and P.G.R.
thanks CSIR, New Delhi for a research fellowship. We are
grateful to RSIC, IIT Madras, for spectral data.
Scheme 4. Cation-Induced Tandem Cyclization of Epoxya
Azides
Note Added after ASAP Posting. The equation in Table
1 contained errors in the version posted January 18, 2003.
The corrected version was posted February 3, 2003.
a Reagents: (a) NBS, aq THF, 0 °C. (b) K2CO3, MeOH, rt, 54%
(overall). (c) EtAlCl2, CH2Cl2, -78 °C, 45 min, NaBH4 in 15% aq
NaOH, 1 h, 36%.
Supporting Information Available: Characterization
data for all the new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
the epoxyazide 12 under similar cyclization conditions
afforded the substituted azepine 13 in 36% yield as a single
OL027563V
(12) Azido olefin 11 was prepared from the known compound (4E,8E)-
ethyl 5,9-dimethyldeca-4,8-dienoate (Robinson, J. A.; Dyer, U. C. J. Chem.
Soc., Perkin Trans. 1 1988, 53) in three steps by reduction, mesylation,
and nucleophilic displacement with sodium azide.
(13) (a) Hanzlik, R. P. Organic Syntheses; Wiley: New York, 1988;
Collect. Vol. VI, p 560. (b) vanTamelen, E. E.; Sharpless, K. B. Tetrahedron
Lett. 1967, 2655.
(9) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207.
(10) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1978,
19, 2417.
(11) Surprisingly the minor diastereomer under similar cyclization
conditions failed to give the cyclized product.
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