Concise synthesis of indolizidines: Total synthesis of (-)-coniceine

Article abstract of DOI:10.1039/b002621m

The Ti-mediated allylsilane addition to bicyclic lactams occurs with high stereoselectivity and combined with a ring closure metathesis provides the title compounds in high ee.

Full text of DOI:10.1039/b002621m

Concise synthesis of indolizidines: total synthesis of (2)-coniceine
Michael D. Groaning and A. I. Meyers*
Department of Chemistry, Colorado State University, Ft. Collins, Colorado 80523-1872, USA.
E-mail: aimeyers@lamar.colostate.edu
Received (in Corvallis, OR, USA) 30th March 2000, Accepted 27th April 2000
Published on the Web 25th May 2000
The Ti-mediated allylsilane addition to bicyclic lactams
occurs with high stereoselectivity and combined with a ring
closure metathesis provides the title compounds in high ee.
Indolizidines represent an important class of biologically active
compounds, including such alkaloids as slaframine, castano-
spermine (a potent glycosidase inhibitor) and a number of
poisonous-frog alkaloids typified by pumiliotoxin B1 (Fig. 1).
Development of a general method to access these 1-azabicyclo-
[4.3.0]nonanes would provide a useful tool in studying a host of
derivatives.
Fig. 1
Scheme 1 Reagents and conditions: i, allyltrimethylsilane, TiCl4, 68–79%
6+1–11+1 dr; ii, Ca/NH3, 73–89%; iii, NaH/allylbromide, 81–92%; iv, cat.
7 (10 mol%), 89–93%; v, H2, Pd(OH)2, 92–96%; vi, LiAlH4, 83–89%.
The construction of optically pure heterocycles using the
bicyclic lactam template has been of great interest in our group,2
and over the years we have published3 applications of the
[4.3.0] bicyclic lactam to access a variety of alkaloids (e.g.
1-deoxy-6-epicastanospermine and coniceine), Fig. 2.
was identical with a sample previously reported from these
laboratories.3a
To further illustrate the versatility of this methodology, the
oxygenated derivatives of 6 were obtained by dihydroxylation
of metathesis product 5b providing the 3,4-dihydroxy in-
dolizidinone 8 as a 4+1 mixture of diastereomers which were
separable by column chromatography (Scheme 2). In order to
simplify the purification and reduce water solubility of the diol
8, it was protected as the acetonide 9 and reduced to the
indolizidine 10 using lithium aluminium hydride. This route
provides enantiomerically pure hydroxylated derivatives of
1-azabicyclo[4.3.0]nonanes.
Fig. 2
In summary, a general method for the construction of a
variety of optically pure indolizidines using the chiral non-
racemic [3.3.0] bicyclic lactams 1a–d in combination with ring-
closing metathesis has been illustrated. The utility of this
method is exemplified by the synthesis of (2)-coniceine with
excellent stereocontrol and overall yield.5
We now report a general protocol utilizing bicyclic lactams
1a–d for the construction of a variety of enantiomerically pure
indolizidines (Scheme 1) including the naturally occurring
parent ring system, (2)-coniceine 6a.
The synthetic route to the 1-azabicyclic systems 6 began by
the addition of allyltrimethylsilane to a dichloromethane
solution of the enantiomerically pure bicyclic lactam and
titanium tetrachloride to furnish the 5-substituted pyrrolidinone
2 with diastereomeric ratios ranging from 6+1 to 11+1. After the
diastereomers in 2 were separated (silica gel column chroma-
tography) the chiral auxiliary was removed by dissolving metal
reduction using calcium metal (NH3, 278 to 230 °C over 4 h)
affording 3. It is noteworthy that for compound 2d containing
two possible benzylic cleavage sites only the exocyclic N-
benzyl bond was cleaved. Introduction of the N-allyl group to
give 4 proceeded smoothly by addition of allyl bromide to the
sodium salt of the pyrrolidinone. The bis-olefin 4 was subjected
to a ring-closing metathesis (10 mol% 7 as catalyst, 25 °C,
1,2-dichloroethane) to afford the indolizidinones 5 in excellent
yields.4 Hydrogenation of the olefinic bond and reduction of the
lactam carbonyl provided the target compounds 6a–d in
32–51% overall yield. In the case where R = H, the reaction
sequence provided a 49% overall yield of (2)-coniceine, which
Scheme 2 Reagents and conditions: i, OsO4/NMO, 73% 4+1 dr; ii,
2,2-dimethoxypropane, TsOH, 94%; iii, LiAlH4, 89%.
DOI: 10.1039/b002621m
Chem. Commun., 2000, 1027–1028
This journal is © The Royal Society of Chemistry 2000
1027

°C and TiCl4 (9 ml of 1.0 M solution in dichloromethane, 1.6 equiv.) was
slowly added via syringe followed by allyltrimethylsilane (1.3 mL, 1.5
equiv.). The solution was stirred under an argon atmosphere and allowed
to warm to r.t. over a 4 h period. A solution of saturated NH4Cl (50 mL)
was added in one portion and the layers were separated. The aqueous
layer was washed with dichloromethane (3 3 50 mL), the combined
organic layers were dried over Na2SO4 and concentrated to an oil. 1H
NMR analysis of the crude material was used to analyze the diaster-
eomeric ratio. Column chromatography (SiO2, EtOAc) provided 1.25 g
of 2c (76%) as a colorless solid: mp 98 °C; [a]D 2177 (c 1.9, CHCl3); dH
(300 MHz, CDCl3) 0.97 (t, J 7 Hz, 3H), 1.26–1.45 (m, 4H), 1.58–1.71 (m,
2H), 1.89–2.06 (m, 4H), 2.49 (t, J 9 Hz, 2H), 4.08–4.27 (m, 3H),
4.70–4.97 (m, 3H), 5.36 (dddd, J 17, 13, 10, 7 Hz, 1H), 7.24–7.43 (m,
5H); dC (75 MHz, CDCl3) 14.0, 22.9, 25.5, 27.6, 30.4, 37.7, 44.7, 60. 3,
65.5, 68.2, 199.0, 127.2, 127.7, 128.2, 132.3, 139.1, 177.4; IR(film)
n/cm21 1658, 3351. Anal. Calc. for C18H27NO2: C, 75.71; H, 9.03.
Found: C, 75.44; H, 9.03%. A dichloroethane solution of the bis-olefin
4c (200 mg, 0.9 mmol) was added to a solution of catalyst 7 (74 mg, 10
mol%). The purple solution slowly changed to brown. After 6 h the
reaction was concentrated in vacuo to an oil and chromatographed (SiO2,
EtOAc) to provide 5c (179 mg, 92%) as a colorless solid: mp 63 °C; [a]D
258 (c 1.0, CHCl3); dH (300 MHz, CDCl3) 0.91 (t, J 7 Hz, 3H),
1.12–1.39 (m, 4H), 1.48–1.82 (m, 3H), 2.01–2.21 (m, 3H), 2.38–2.53 (m,
2H), 3.40 (d, J 9 Hz, 1H), 4.38 (d, J 9 Hz, 1H), 5.71 (m, 2H); dC (75 MHz,
CDCl3) 14.1, 23.1, 25.9, 27.8, 29.9, 30.3, 36.0, 38.4, 60.0, 122.8, 123.8,
173.5; IR(film) n/cm21 1692.
We are grateful to the National Institutes of Health for
financial support. An ACS-Organic Division Graduate Fellow-
ship to MDG (sponsored by Merck) is also warmly acknowl-
edged.
Notes and references
1 For a review on indolizidines, see: J. P. Michael, Nat. Prod. Rep., 1999,
16, 675; for a review on slaframine and castanospermine, see: R. J.
Molyneux and L. F. James, Mycotoxins Phytoalexins, 1991, 637; for a
review on pumiliotoxins, see: A. S. Franklin and L. E. Overman, Chem.
Rev., 1996, 96, 505.
2 G. P. Brengel and A. I. Meyers, Chem. Commun., 1998, 1 and references
therein.
3 (a) M. J. Munchhof and A. I. Meyers, J. Org. Chem., 1995, 60, 7084; (b)
A. I. Meyers, C. J. Andres, J. E. Resek, C. C. Woodall, M. A.
McLaughlin, P. H. Lee and D. A. Price, Tetrahedron, 1999, 55, 8931.
4 For a review on olefin metathesis, see: R. H. Grubbs and S. Chang,
Tetrahedron 1998, 54, 4413; for a review on applications of the ring-
closing metathesis reaction to the construction of a wide variety of
nitrogen containing ring systems, see: U. K. Pandit, H. S. Overkleeft,
B. C. Borer and H. Bieraugel, Eur. J. Org. Chem., 1999, 5, 959.
5 Typical procedure; the synthesis of 5c from 1c: A dichloromethane
solution of the bicyclic lactam 1c (1.4 g, 5.48 mmol) was cooled to 278
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Chem. Commun., 2000, 1027–1028