Asymmetric synthesis of indolizidine alkaloids by ring-closing-ring-opening metathesis

Article abstract of DOI:10.1039/b004106h

Asymmetric Pd(0) catalyzed allylic amination followed by a Ru catalyzed RCM-ROM sequence converted an easily accessible racemic cyclopentenol 2 to the functionalized tetrahydropyridine 9 which can be used for the asymmetrical synthesis of indolizidine 13.

Full text of DOI:10.1039/b004106h

Asymmetric synthesis of indolizidine alkaloids by ring-closing–ring-opening
metathesis
Huib Ovaa,a Roland Stragies,b Gijs A. van der Marel,a Jacques H. van Booma and Siegfried Blechert*b
a Leiden Institute of Chemistry, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leiden, The Netherlands
b Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 135, 10623 Berlin, Germany.
E-mail: Blechert@chem.tu-berlin.de
Received (in Liverpool, UK) 19th May 2000, Accepted 21st June 2000
Published on the Web 19th July 2000
Asymmetric Pd(0) catalyzed allylic amination followed by a
Ru catalyzed RCM–ROM sequence converted an easily
accessible racemic cyclopentenol 2 to the functionalized
tetrahydropyridine 9 which can be used for the asymmetrical
synthesis of indolizidine 13.
Polyhydroxylated indolizidine alkaloids are widespread in
nature and possess very diverse and important physiological
properties.1 Consequently, development of general method-
ologies for their construction is an important challenge.
Recently we published a paper in which ruthenium catalyzed
ring-rearrangement (i.e. sequential ring-closing–ring-opening
metathesis) is described.2 The herein reported ring-rearrange-
ment opens the way to converting readily accessible carbo-
cycles into stereodefined heterocycles containing highly func-
tionalized side chains. In order to illustrate the general
applicability of this reaction it was decided to synthesize (see
Scheme 1) 1,2,3,5,6,8a-hexahydroindolizine-1,2-diol
(RNH).
A
Scheme 2 Reagents and conditions: a ClCO2Me, CH2Cl2, pyridine, 0 °C,
30 min, 97%; b H2CNCH(CH2)2NHNs, Pd2dba3 CHCl3 (1 mol%), ligand 6,
Et3N, THF, 18 h, 210 to 0 °C, 93%, 99.5% ee.
·
Retrosynthetic analysis reveals that the target compound A
can be attained from functionalised tetrahydropyridine B which,
in turn, can be obtained from cyclopentenylamine C via
ruthenium catalyzed ring-rearrangement. Asymmetric Pd-cata-
lyzed allylic amination3 of the racemic alcohol 2, readily
accessible from cyclopentadiene 1,4 leads to the optically pure
metathesis precursor C.
It was expected that palladium(0) catalyzed allylic amination
of a cyclopentenyl donor derived from 2 would be an
appropriate way to introduce the desired nitrogen nucleophile.
We now report an asymmetric synthesis of hexahydroindoli-
zine 13 starting from 1 using a ring-rearrangement as the key
step (see Scheme 2).
In order to provide a good leaving group for the oxidative
addition event of the palladium catalyzed allylic amination,
alcohol 2 was converted into its corresponding methyl carbon-
ate 3. In the first instance a solution of optically pure 3† in THF–
triethylamine was subjected to palladium(0) catalysis, using
dppb as a ligand and o-nitrophenylsulfonyl5 (Ns) protected
homoallylamine as the nitrogen nucleophile. Work-up and
purification gave cyclopentenylamine 5 as a racemic mixture in
95% yield.
It is well established that the palladium catalyzed reaction
proceeds through the symmetrical p-allyl palladium complex 4.
This indicates that the use of asymmetric ligands would open
the way to the synthesis of both enantiomers of 5. To this end
ligand 6, developed by Trost and co-workers,6 was selected for
this purpose because of its proven reliability in terms of yield
and enantioselectivity. Gratifyingly, the reaction of 3 with
ligand (R,R)-6 led to the isolation of (2)-5‡ in good yield with
> 99.5% enantiomeric excess.§
At this stage, enantiomerically pure cyclopentenylamine
(2)-5 was now subjected to ruthenium catalyzed ring-re-
arrangement using a catalytic amount of 87 in the presence of
ethylene (Scheme 3). It was established that 5 was inert under
the reaction conditions, however, the corresponding TBDMS
protected derivative 7 gave 9 quantitatively. It is also worth
mentioning that no reaction was observed in the absence of
ethylene.
It turned out that differentiation between the internal and
terminal double bonds in 9 could be realized via regioselective
dihydroxylation of the terminal double bond resulting in the
corresponding diol in 80% yield as a single diastereoisomer.
Periodate cleavage and in situ reduction of the newly generated
aldehyde function gave alcohol 10. Alcohol 10 was tosylated to
provide 11, setting the stage for an intended cyclisation–
cleavage procedure. Deprotection of the Ns group was accom-
panied by concomitant cyclisation resulting in the 1,2,3,5,6,8a-
hexahydroindolizine 12. Removal of the TBDMS groups led to
the unprotected indolizidine 13 in 87% yield based on 11.
Scheme 1
DOI: 10.1039/b004106h
Chem. Commun., 2000, 1501–1502
This journal is © The Royal Society of Chemistry 2000
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the reaction mixture at 210 °C. The reaction mixture was stirred for an
additional 18 h at 0 °C. The solution was concentrated and purified by
column chromatography (0 ? 5% MeOH in CH2Cl2) to afford 2.54 g, 93%
of (2)-5. n cm21: 3078 (m), 2986 (m), 2936 (m), 1544 (s), 1372 (s), 1163
(s); dC (100.6 MHz, CDCl3): 148.0 (Cq), 136.6 (CH), 134.1 (CH), 133.6
(CH), 133.4 (Cq), 131.6 (CH), 131.5 (CH), 130.9 (CH), 124.0 (CH), 117.4
(CH2), 111.5 (Cq), 84.1 (CH), 83.2 (CH), 70.5, (CH), 46.2 (CH2), 34.9
1
(CH2), 27.1 (CH3), 25.4 (CH3); H-NMR (400 MHz, CDCl3) d: 8.08, (m,
1H), 7.67 (m, 2H), 7.58 (m, 1H), 6.02 (ddd, J 7, 4, 2 Hz, 1H), 5.65 (m, 1H),
5.20 (m, 1H), 5.04 (m, 1H), 5.01 (m, 1H), 4.81 (d, J 1 Hz, 1H), 4.51 (d, J
4 Hz, 1H), 4.36 (m, 1H), 2.99 (m, 1H), 2.26 (m, 2H), 1.36 (s, 3H), 1.24 (s,
3H); HRMS: calc. for C17H19N2O6S [M+ 2 CH3] 379.0964, found
379.09622. [a]2D0 (c, 1, CHCl3) 233.3 °; 9: 245 mg of 7 (0.42 mmol) were
dissolved in 15 mL of CH2Cl2 and 20 mL of ethylene were bubbled through
the solution. 14 mg (4 mol%) of catalyst 8 were added and the solution was
stirred overnight. The reaction mixture was concentrated and purified by
column chromatography (0 ? 20% MeOtBu in hexane) to give 245 mg
(100%) of 9. IR: n cm21: 2955 (m), 2929 (m), 2894 (w), 2857 (m), 1547 (s),
1372 (m), 1361 (m), 1171 (m); 13C-NMR (126.8 MHz, CDCl3) d: 148.3
(Cq), 137.7 (CH), 134.5 (Cq), 133.3 (CH), 131.3 (CH), 130.4 (CH), 125.9
(CH), 125.6 (CH), 123.8 (CH), 116.5 (CH2), 78.9 (CH), 76.6 (CH), 57.2
(CH), 40.2 (CH2), 26.1 (CH3), 22.9 (CH2), 18.4 (Cq), 18.3 (Cq), 24.0
(CH3), 24.4 (CH3), 24.5 (CH3), 24.6 (CH3); 1H-NMR (500 MHz, CDCl3)
d: 7.91 (m, 1H), 7.62 (m, 2H), 7.51 (m, 1H), 5.94 (ddd, J 17, 10, 8 Hz, 1H),
5.77 (m, 1H), 5.67 (m, 1H), 5.22 (d, J 17 Hz, 1H), 5.10 (d, J 10 Hz), 4.50
(s, 1H), 4.35 (d, J 6 Hz), 3.97 (dd, J 14, 4 Hz, 1H), 3.87 (d, J 5 Hz, 1H), 3.41
(ddd, J 16, 10, 6 Hz), 1.82 (m, 2H), 0.91 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H),
0.08 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H); HRMS: calc. for C26H43N2O6SSi2
[M+ 2 CH3] 567.2380, found 567.2388; [a]D20 (c, 1, CHCl3) +189.4°.
§ For determination of the enantiomeric excess the Ns group was replaced
by a tosyl group (i, PhSH, K2CO3, DMF; ii, TsCl, pyridine) in order to
facilitate separation of the enantiomers on a Chiralcel OD Gold column
(0.5% iPrOH in hexane, 0.9 mL min21, 218 nm).
Scheme 3 Reagents and conditions: a, HOAc, H2O, 80 °C, 30 min;
TBDMSCl, imidazole DMF, rt, overnight, 75% (two steps); b,
Cl2(PCy3)2RuNCHPh (8) (4 mol%), H2CNCH2, CH2Cl2, rt, overnight,
·
100%; c, K2OsO4 2H2O cat., NMO, acetone–H2O, rt, 48 h, 80%; d, NaIO4,
MeOH/H2O, 0 °C, 30 min, then NaBH4(aq), 0 °C, 3 min, 99%; e, TsCl,
pyridine, DMAP, rt, overnight, 71%; f, PhSH, K2C2O3, DMF, 0 °C, 30 min,
100%; g, TBAF, THF, rt, overnight, 88%.
In conclusion, it has been shown that asymmetric palladium
catalyzed introduction of a nitrogen nucleophile proceeds with
a high degree of enantioselectivity. The resulting stereodefined
platform serves as a suitable substrate for an ensuing ruthenium
catalyzed ring-rearrangement leading to an azacycle carrying a
highly functionalized side chain amenable to further manip-
ulations.
This work was supported by the Council for Chemical
Sciences of the Netherlands Organization for Scientific Re-
search (CW-NWO) and the Fonds der Chemischen Industrie,
Germany.
1 For a recent review article on indolizidine and quinolizidine alkaloids
see: J. P. Michael, Nat. Prod. Rep., 1999, 16, 675; in Iminosugars as
Glycosidase Inhibitors, ed. A. E. Stu¨tz, Wiley-VCH, Weinheim, 1999,
p. 1–397.
2 R. Stragies and S. Blechert, Tetrahedron, 1999, 55, 8179; J. A. Adams,
J. G. Ford, P. J. Stamatos and A. H. Hoveyda, J. Org. Chem., 1999, 64,
9690.
3 N. S. Sirisoma and P. M. Woster, Tetrahedron Lett., 1998, 39, 1489;
B. M. Trost and D. E. Patterson, Chem. Eur. J., 1999, 5, 3279; B. M.
Trost and R. C. Bunt, J. Am. Chem. Soc., 1994, 116, 4089.
4 G. Wolczunowicz, F. G. Cocu and T. Posternak, Helv. Chim. Acta,
1970, 53, 2275.
5 T. Fukayama, C. Jow and M. Cheung, Tetrahedron Lett., 1995, 36,
6373.
6 For a review on asymmetric transition metal-catalyzed allylic alkyla-
tions see: B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996, 96,
395.
7 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996, 118,
100.
8 H. Ovaa, J. D. C. Codée, B. Lastdrager, H. S. Overkleeft, G. A. van der
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Notes and references
† Optically pure carbonate 3 was obtained from (
is not a requirement that 3 be optically pure.
D
)-mannose.8 However, it
‡ All new compounds were fully characterized by 1H NMR, 13C NMR, IR
spectroscopy, high resolution mass spectrometry and optical rotation.
Relevant data and experimental details for the compounds 5 and 9 are as
follows: 5: 1.50 g (6.94 mmol) of carbonate 3 and 2.00 g (7.80 mmol) of N-
but-3-enyl o-nitrobenzenesulfonamide were dissolved in 25 mL of THF and
3 mL of Et3N. This solution was degassed and cooled to 210 °C. 100 mg
of ligand (R,R)-6 and 50 mg of Pd2dba3·CHCl3 were dissolved in THF (1
mL) and stirred for one hour, after which this solution was slowly added to
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Chem. Commun., 2000, 1501–1502