Intramolecular schmidt reaction involving primary azidoalcohols under nonacidic conditions: Synthesis of indolizidine (-)-167B

Article abstract of DOI:10.1021/ja908933s

(Chemical Equation Presented) A powerful intramolecular Schmidt reaction starting from primary azidoalcohols is reported. This approach involves a nonacidic activation of the alcohol via triflation. The synthetic potential offered by the mild reaction con

Full text of DOI:10.1021/ja908933s

Published on Web 11/20/2009
Intramolecular Schmidt Reaction Involving Primary Azidoalcohols under
Nonacidic Conditions: Synthesis of Indolizidine (-)-167B
Ajoy Kapat, Erich Nyfeler, Guy T. Giuffredi, and Philippe Renaud*
UniVersity of Berne, Department of Chemistry and Biochemsitry, Freiestrasse 3, CH-3012 Berne, Switzerland
Received October 20, 2009; E-mail: philippe.renaud@ioc.unibe.ch
In the early 1990s, Aube´ and Pearson independently reported
the intramolecular Schmidt rearrangement reaction of alkyl azides
with ketones1 and tertiary carbocations2,3 generated from alkenes
and alcohols under acidic reaction conditions. This reaction rapidly
proved to be a powerful tool for the rapid assembly of complex
nitrogen containing heterocycles.4 From a mechanistic point of view,
the reaction takes place between an alkyl azide with either an
oxocarbenium ion (obtained by protonation of a ketone, acid
catalyzed opening of a ketal, etc.) or a secondary/tertiary carbenium
ion (obtained by protonation of an alkene or acid promoted
heterolysis of a secondary/tertiary alcohol). The synthesis of
5-phenylindolizidine represents a typical example of the carboca-
tionic rearrangement.3 However, when the same approach was
attempted for preparation of 5-methylindolizidine (Scheme 1), a
model system for several natural products such as indolizidine 209D
and 167B, a 1:1 mixture of regioisomers is obtained due to a rapid
rearrangement of the intermediate carbenium ion followed by a
nonselective 1,2-migration (A, pathways (a) and (b)).6 Different
strategies to overcome this lack of regioselectivity have been
investigated but are still relying on acidic reaction conditions.6-8
treatment with triflic anhydride and sodium hydride at -78 °C and
allowed to warm up to room temperature, nitrogen extrusion was
observed, and after addition of diisobutylaluminum hydride (DIBALH),
clean formation of the octahydropyrroloazepine 2 was observed (77%
yield, dr 95:5) (Scheme 2). The use of NaBH4 or NaBH3CN instead
of DIBALH afforded 2 in similar yields but with lower diastereose-
lectivities (dr e70:30). The reaction involves likely a nucleophilic
substitution of the triflate by the azide leading to the intermediate
aminodiazonium B followed by a 1,2-alkyl migration leading to the
iminium ion that is finally reduced by the hydride. To the best of our
knowledge, this is the first example of an intramolecular Schmidt
reaction involving a primary electrophilic carbon center.
Scheme 2
Scheme 1
Scheme 3
As part of our ongoing research program directed toward the
synthesis of various biologically active alkaloids, we recently
developed a method for the radical carboazidation of alkenes.9-12
This process represents a unique source of γ-azidoesters and, after
ester reduction, of primary 4-azidoalcohols. We report here a
modified version of the intramolecular Schmidt reaction involving
such primary azidoalcohols. This process is run under nonacidic
conditions, and it allows resolution of the regioselectivity problems
caused by rearrangement of carbenium ions described in Scheme
1. The utility of the method is demonstrated by a concise synthesis
of dendrobate alkaloid (-)-indolizidine 167B.
The 4-azidoalcohol 1 was chosen as a model system for the
development of the Schmidt reaction with a primary alcohol.
Compound 1 is easily prepared from 4-phenylmethylenecyclohexane
via carboazidation and reduction of the intermediate azidoester with
LiBH4 (see Supporting Information). Activation of the alcohol with
triflic acid according to Pearson’s conditions3 as well as conversion
to the corresponding iodide, tosylate, and nosylate followed by
heating failed to give the desired rearranged product. Gratifyingly,
when the alcohol was converted into the corresponding triflate by
The reaction of primary 4-azidoalcohols 3-5 was examined next
(Scheme 3). The acid sensitive acetal 3 gave the expected
octahydropyrroloazepine 6 in 78% yield. The 1-azido-2-propylcy-
clopentane 4 gave a 1:1 mixture of the two indolizidines 7a and
7b. Compound 7a can be obtained in an analytically pure form by
further chromatography and is identical to the known alkaloid
indolizidine 167B, a natural product isolated from the skin the frog
Dendrobates speciosus.13-15 The lack of regioselectivity of this
rearrangement is reminiscent of the reaction reported by Pearson
described in Scheme 1.3,16 Remarkably, the 2-tert-butyl-substituted
azidocyclopentane 5 afforded a single regio- and diastereomer of
5-tert-butylindolizidine 8 in 63% yield.17
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17746 J. AM. CHEM. SOC. 2009, 131, 17746–17747
10.1021/ja908933s  2009 American Chemical Society

C O M M U N I C A T I O N S
Since the 4-azidoalcohol 4 affords a mixture of 7a/7b, another
approach for selective synthesis of indolizidine 167B was envisaged.
As proposed by Pearson,3 a piperidinodiazonium salt of type D
should lead to the desired product with high regioselectivity
(Scheme 4). However, Pearson’s approach did not afford the desired
product due to the unexpected carbocationic rearrangement. Inter-
estingly, activation of the primary carbon atom of 5-azidoalcohol
11 should lead exclusively to the piperidinodiazonium salt D and
therefore to a fully regioselective synthesis of indolizidine 167B.
The synthesis of (-)-indolizidine 167B is depicted in Scheme
4. The starting methylenecyclopentane 9 was readily prepared
from 1-chloromethylcyclopentene in 65% yield and 99% ee using
Alexakis enantioselective copper(I) catalyzed allylic substitu-
tion.18 The carboazidation of 9 afforded the azidoester 10 in 81%
yield as a 1:1 mixture of diastereomers. Since both diastereomers
of 10 are expected to give the desired product, no separation was
performed. The propyl side chain was installed by reduction of the
ester to the primary alcohol with LiBH4 followed by tosylation and,
finally, reduction of the primary tosylate with LiBH4. After removal
of the tert-butyl protecting group with cerium(III) chloride in the
presence of NaI,19 the primary 5-azidoalcohol 11 was obtained in
65% overall yield from 10. The azidoalcohol 11, as a 1:1 mixture
of diastereomers, was treated with triflic anhydride in the presence
of sodium hydride at -78 °C, and the reaction mixture was allowed
to warm up to room temperature overnight. The intermediate
iminium ion was reduced in situ with NaBH4 (7 equiv) to afford
(-)-indolizidine 167B in 79% yield as a single regio- and
diastereomer. The optical purity of the final product (ee g 98%)
matches the one of the starting material. (-)-Indolizidine 167B has
been synthesized in 7 steps and 27% overall yield starting from
1-chloromethylcyclopentene and 42% overall yield from methyl-
enecyclopentane 9.20 Remarkably, even if the carboazidation
reaction delivers a 1:1 mixture of diastereoisomers, the whole
process is fully stereoselective and takes place with complete
retention of the absolute configuration.
complementary to the rich chemistry mediated by secondary and
tertiary carbocations developed by Pearson. The synthetic advan-
tages offered by the mild reaction conditions were unambiguously
demonstrated by the regio- and stereoselective synthesis of (-)-
indolizidine 167B.
Acknowledgment. Dedicated to Prof. Alexandre Alexakis for
his 60th birthday. We thank the Swiss National Science Foundation
for financial support. A.K. is very grateful to the Federal Com-
mission for Scholarships for Foreign Students (FCS) for generous
support. We thank Prof. J. Aube´ for providing us a review article
at the galley proof level.
Supporting Information Available: Experimental procedures,
1
characterization data, and copies of H and 13C NMR spectra of all
new compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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5-propylindolizidine of unknown configuration on the basis of a GC-MS
analysis; see ref 14.
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Scheme 4
(16) The reaction was reapeated with diastereomercially pure cis-4 and trans-4
and both diastereomers gave the same 1:1 mixture of 7a/7b.
(17) The regioselectivity may be due to a favorable conformation of the
aminodiazonium salt or to a higher inherent migration ability of the tert-
butyl substituted carbon atom.
(18) Falciola, C. A.; Tissot-Croset, K.; Alexakis, A. Angew. Chem., Int. Ed.
2006, 45, 5995. Falciola, C. A.; Tissot-Croset, K.; Reyneri, H.; Alexakis,
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(19) Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003, 2101.
(20) Shorter syntheses of indolizidine 167B are reported; however, they rely
on starting material containing either the pyrrolidine or the piperidine rings.
See for instance ref 14h and 14j. Our synthesis compares well with syntheses
where both heterocycles are synthesized; see for instance ref 14e (11 steps
from cycloheptadiene) and ref 14i (25% overall yield from a noncommer-
cially available starting material).
In conclusion, we have developed a powerful intramolecular
Schmidt reaction starting from primary azidoalcohols. This approach
involves a nonacidic activation of the alcohol via triflation and is
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