Access to enantiomerically enriched cis-2,3-disubstituted azetidines via diastereoselective hydrozirconation

Article abstract of DOI:10.1021/ol200323r

An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case

Full text of DOI:10.1021/ol200323r

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1793–1795
Access to Enantiomerically Enriched
cis-2,3-Disubstituted Azetidines via
Diastereoselective Hydrozirconation
Tarun K. Pradhan, K. Syam Krishnan, Jean-Luc Vasse,* and Jan Szymoniak*
ꢀ
Institut de Chimie Moleculaire de Reims, CNRS (UMR 6229) and Universite de Reims,
51687 Reims Cedex 2, France
ꢀ
jean-luc.vasse@univ-reims.fr; jan.szymoniak@univ-reims.fr
Received February 2, 2011
ABSTRACT
An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting
diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case, they have been
transformed into enantiomerically enriched cis-2,3-disubstituted azetidines through a iodination/cyclization sequence.
Azetidines are valuable building blocks for the prepara-
tion of both naturally occurring1 and synthetic molecules2
of biological interest and for the design of new organo-
catalysts3 or ligands.4 One of the modern mimicking
approaches to enhance recognition of biological receptors
is based on conformational constraint. Therefore, small-
size rings, and among them the azetidine framework,
constitute potent tools for SAR studies.5 Although several
syntheses of azetidine derivatives have been reported,6 the
development of simplesyntheticstrategiesopening the way
to optically pure compounds is still important.
The hydrozirconation of alkenes with the Schwartz
reagent, Cp2Zr(H)Cl, is a well-known reaction with
important synthetic potential, owing to wide functional
group tolerance, as well as marked regioselectivity and syn-
stereoselectivity.7,8 It represents one of the most practical
methods for the formation of C-Zr bonds, which can be
further transmetalated, linking zirconium chemistry with
that of many other metals. In this context, an almost total
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r
10.1021/ol200323r
2011 American Chemical Society
Published on Web 03/08/2011

lack of alkene asymmetric hydrozirconation is surprising.
To our knowledge, the only reported reactions deal with
the hydrozirconation of enantiopure 1-alkenyl boranes to
afford optically active 1,1-bimetallic species.9 An efficient
asymmetric hydrozirconation, particularly applied to the
generation of functionalized organozirconium intermedi-
ates, would open new routestoa number ofoptically active
molecules.
Our recent discovery that the hydrozirconation reaction
can be carried out in the presence of secondary amino
groups made it possible to develop new stereoselective
approaches to pyrolidines (Scheme 1).10 However, with
this strategy, the formation of the stereogenic carbon
center(s) is controlled prior to the hydrozirconation step.
CH2Cl2 at room temperature.12 Treatment of the hydrozir-
conated intermediate with iodine afforded the corresponding
iodocarbamate, isolated in 65% yield. Subsequent addition
of NaHMDS in THF to promote the cyclization afforded 2
in 55% yield over the two steps, thus validating the strategy
to build the azetidine. The diastereoselectivity of the hydro-
zirconation reaction was next studied by using a simple
amine 3a with two methyl groups. In this case, the hydro-
zirconation reaction was found to be effective in toluene at 80
°C,13 and the azetidine 4a was obtained with almost total
diastereoselectivity in favor of the cis isomer14 (dr g95:5) in
65% isolated yield (Scheme 3).
Scheme 3. Diastereoselective Access to Azetidine 4a
Scheme 1. Synthesis of 2,3-Disubstituted Pyrrolidines
The methodology was further explored by employing a
series of enantiomerically enriched substituted allylic
amines 3. These compounds were easily obtained from
the corresponding natural N-Boc protected L-amino acids
or derivatives, following the sequence15-17 shown in
Scheme 4 (see the Supporting Information for details).
We report herein that hydrozirconation can proceed
with high diastereofacial selectivity, making the prepara-
tion of optically pure 2,3-disubstituted azetidines possible.
We first checked the feasibility of building the azetidine
framework, starting from an amine with a protecting
group that could further stereodirect the approach of the
Schwartz reagent. For this purpose, we decided to use
N-Boc protected allylamine11 1 (Scheme 2).
Scheme 4. Synthesis of Boc-Protected Allylamines 3
Scheme 2. Construction of the Azetidine Skeleton
In a model experiment, 1 was first hydrozirconated
within 1 h by using 3 equiv of the Schwartz reagent in
(7) For selected reviews of hydrozirconation, see: (a) Wipf, P.; Jahn,
H. Tetrahedron 1996, 40, 12853. (b) Lipshutz, B. H.; Pfeiffer, S. S.;
Noson, K.; Tomioka, T. Titanium and Zirconium in Organic Synthesis;
Wiley: Weinheim, Germany, 2002. (c) Wipf, P.; Kendall, C. Topics in
Organometallic Chemistry 08; Springer-Verlag: Berlin, Germany, 2005.
(d) In addition to the widely used Cp2Zr(H)Cl, some other hydrozirconation
agents such as Cp2Zr(H)OTf or the hydrogen-transfer hydrozirconation agent
iBuZrCp2Cl are available.
(8) For some recent synthetic applications, see: (a) Pu, X.; Ready,
J. M. J. Am. Chem. Soc. 2008, 130, 10874. (b) De Benedetto, M. V.;
Green, M. E.; Wan, S.; Park, J.-H.; Floreancig, P. E. Org. Lett. 2009, 11,
835. (c) Lu, C.; Xiao, Q.; Floreancig, P. E. Org. Lett. 2010, 12, 5112. (d)
Kuninobu, Y.; Ureshino, T.; Yamamoto, S.; Takai, K. J. Chem. Soc.,
Chem. Commun. 2010, 46, 5310. (e) Joosten, A.; Lambert, E.; Vasse, J.-
L.; Szymoniak, J. Org. Lett. 2010, 12, 5128.
Applied to 3a-f, the hydrozirconation/iodination se-
quence and a subsequent NaHMDS-promoted cyclization
afforded cis-2,3-disubstituted azetidines 4a-f (Table 1).
(12) When using 1 or 2 equiv of the Schwartz reagent, the starting
material was recovered.
(13) When using CH2Cl2 as solvent, the hydrozirconation does not
take place.
(14) The cis stereochemistry in 4a was assigned based on the NOESY
experiment (see the Supporting Information).
(9) Zheng, B.; Srebnik, M. Tetrahedron Lett. 1994, 35, 6247.
(10) (a) Ahari, M.; Joosten, A.; Vasse, J.-L.; Szymoniak, J. Synthesis
2008, 61. (b) Delaye, P.-O.; Pradhan, T. K.; Lambert, E.; Vasse, J.-L.;
Szymoniak, J. Eur. J. Org. Chem. 2010, 3395.
(11) Hydrozirconation of Boc-protected propargylic amines was
reported, see: Hauske, J. R.; Dorff, P.; Julin, S.; Martinelli, G.; Busso-
lari, J. Tetrahedron Lett. 1992, 33, 3715.
(15) For amides preparation, see: Shimizu, M.; Kume, M.; Fujisawa,
T. Tetrahedron Lett. 1995, 36, 5227.
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Org. Lett., Vol. 13, No. 7, 2011

Table 1. Synthesis of Azetidines 4
entry
R1
R2
drc
compd (yield)
1a
2
Me
Bn
Bn
i-Pr
Ph
Me
Bu
Me
Me
Me
Me
94:6
96:4
95:5
50:50
73:27
92:8
4a (65%)
4b (75%)
4c (65%)
4d (68%)
4e (80%)
4f (65%)
3
4
5b
6
CH2OTBS
a Reaction carried out starting from a racemic substrate. b Reaction
carried out starting from (R)-enantiomer. c Determined by 1H NMR of
the crude reaction mixture.
Figure 1. Plausible Origin of the Stereoselectivity.
moiety in a number of natural products and derivatives,18
and the recent use of such acids for preparing the conforma-
tionally constrained peptides has to be underlined.19 Rapid
access to nonracemic azetidine-2-carboxylic acids is exempli-
fied here by a simple preparation of the amino acid 5, a rigid
valine analogue, from 4f through alcohol deprotection and
ruthenium-based oxidation (Scheme 5).
Thus, azetidines bearing two alkyl groups (entries 1-4, 6)
and also an alkyl (R2) and an aryl (R1) substituent (entry 5)
were prepared. These reactions proceeded with high diaster-
eoselectivity except for 3d and 3e (R1 = i-Pr, Ph, R2 = Me,
entries 4 and 5). The lack of stereoselectivity in these cases is
not entirely clear at present, but might be due to steric rea-
sons. The reaction did not take place starting from the
allylamine with R2 = Ph. A possible explanation could
involve a thermodynamically favored dehydrozirconation.
Due to the 3 equiv of the Schwartz reagent required to
perform the CdC bond hydrozirconation, one may as-
sume that the first equivalent acts as a base, and the second
coordinates to the N-Boc (on the O or N). Therefore, a
protecting group-assisted approach of the hydride is prob-
ably not involved.
Scheme 5
To account for the observed stereoselectivity, we as-
sumed that conformations locating the large Zr-coordinated
N-Boc fragment in a pseudoaxial orientation with respect to
the double CdC bond plan prevail when R1 is a medium-
sized substituent. The selectivity may thus be rationalized by
a more favorable accessibility of the Re face (Figure 1). This
scenario is altered if the stereogenic center bears two large
groups (R1 = i-Pr or Ph and N-Boc). In such a case, their
competition to adopt the pseudoaxial position renders the
above simple conformationnal duality less likely.
In conclusion, we have presented an asymmetric variant
of the hydrozirconation reaction applied to N-Boc protected
allylamines. The organozirconium species thus generated
appear as versatile intermediates for synthetic applications,
as exemplified by the stereoselective synthesis of cis-2,3-dis-
ubstituted azetidines.
Acknowledgment. We gratefully acknowledge ANR for
financial support of this work (SAACoude).
The introduction of an alkoxy group at the R carbon of
the chain (in R1, entry 6) opens the way for further functio-
nalizations. The presence of an azetidine-2-carboxylic acid
Supporting Information Available. Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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