Substrate stereocontrol in the intramolecular organocatalyzed tsuji-trost reaction: Enantioselective synthesis of allokainates

Article abstract of DOI:10.1021/ol4028557

Organocatalyzed Tsuji-Trost cyclization of 3b proceeds with asymmetric induction and allows for stereoselective synthesis of (+)-allokainic acid. The stereochemical outcome of the cyclization was predicted by calculations.

Full text of DOI:10.1021/ol4028557

Letter
pubs.acs.org/OrgLett
Substrate Stereocontrol in the Intramolecular Organocatalyzed
Tsuji−Trost Reaction: Enantioselective Synthesis of Allokainates
Bojan Vulovic,† Maja Gruden-Pavlovic,† Radomir Matovic,‡ and Radomir N. Saicic*,†
†Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 51, 11158 Belgrade 118, Serbia
‡ICTM, Center for Chemistry, Njegoseva 12, Belgrade, Serbia
S
* Supporting Information
ABSTRACT: Organocatalyzed Tsuji−Trost cyclization of 3b
proceeds with asymmetric induction and allows for stereo-
selective synthesis of (+)-allokainic acid. The stereochemical
outcome of the cyclization was predicted by calculations.
he terms organotransition-metal catalysis1 and organo-
catalysis2 refer to two distinct ways to promote organic
domoic, or acromelic acids, which show potent neuroexcitatory,
anthelmintic and insecticidal activity.9 Interesting biological
activity, coupled with a synthetic challenge of three contiguous
stereocenters in a pyrrolidine core, have attracted considerable
attention from the synthetic community: fourteen enantiose-
lective10 and five racemic11 syntheses of allokainic acid have
been reported to date. Our retrosynthetic blueprint is
represented in Scheme 2. The key step is the disconnection
T
reactions. Recently, a concept of dual catalysis has emerged3
that uses a synergic combination of both types of catalyst in a
single reaction, thus overcoming some limitations of the parent
reactions.4 A promising class of reactions that hinge on this
principle combine organotransition-metal catalysis and amino-
catalysis or, more precisely, enamine−metal catalysis. In the
presence of secondary amine and palladium complexes,
carbonyl compounds can be allylated with allyl acetate via a
mechanism that involves alkylation of transient enamine with a
π-allylpalladium complex.5 We have applied this principle at the
intramolecular level for the construction of five- and six-
membered rings in the organocatalyzed Tsuji−Trost reaction
(Scheme 1).6 In a subsequent study, we have shown that the
Scheme 2. Retrosynthetic Analysis of (+)-Allokainic Acid
Scheme 1. Organocatalyzed Tsuji−Trost Cyclization
reaction can also be performed as a catalytic asymmetric
reaction with high levels of diastereo- and enantioselectivity.7
Enantioselective annulations with chiral amines have also been
described.8 The diastereoselective outcome of the reaction
indicated an organized transition state, where an efficient
transfer of stereochemical information from the reactant to the
product occurred. Therefore, we set out to explore the
possibility of a substrate-controlled, organocatalyzed Tsuji−
Trost cyclization that would use a substrate with one
stereogenic center and transform it into a cyclic product
containing three stereocenters of defined absolute configu-
ration. We decided to test this concept experimentally in the
stereoselective synthesis of (+)-allokainic acid and its
analogues.
of the pyrrolidine ring in 2 with simultaneous cleavage of two
stereocenters by an organocatalyzed Tsuji-Trost cyclization
transform. Further simplification of the cyclization precursor 3
by the N-alkylation transform gives known allylglycine
derivative 4.
The syntheses of both allokainic acid 1 and its desmethyl
derivative 15 are represented in Scheme 3. (S)-(−)-tert-Butyl
allylglycinate 4 was obtained by alkylation of glycine derivative
5 under chiral phase-transfer conditions (PTC), with an optical
purity of 80% ee,12 as described by Lygo.13 N-Tosylated
Allokainic acid 1 belongs to kainoids, a group of naturally
occurring nonproteinogenic amino acids, such as kainic,
Received: October 3, 2013
© XXXX American Chemical Society
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Letter
Scheme 3. Synthesis of (+)-Allokainic 1 and (+)-Desmethylallokainic Acid 15
derivative 6 was subjected to ozonolysis, followed by
acetalization,14 to give protected aldehyde 8 in 85% yield. For
the alkylation of 8 with 1,4-dihalo-2-alkenes 9 to be successful,
inverse addition was required (i.e., a solution of the amide
anion was slowly added into excess dihalide); otherwise, with
1,4-dibromo-2-butene 9a the diamide product was obtained (2-
butene-1,4-diyl bridging two amide units). Preliminary experi-
ments have shown that bromides are better cyclization
precursors than chlorides; therefore, chloride displacement
with bromide was performed to give 11b. The crucial
cyclization step was performed by submitting 3 to the
simultaneous action of tetrakis(triphenylphosphine)palladium
(7 mol %) and pyrrolidine (50 mol %), in the presence of
triethylamine, in THF at rt; under these conditions, both 3a
and 3b were converted into cyclic products 2a and 2b in good
yields, as mixtures of three diastereoisomers in a ratio of
(2S,3S,4R):(2S,3S,4S):(2S,3R,4S) = 10:1:1.15,16 Homologation
of aldehydes 2 was performed with (methoxymethylidene)-
triphenylphosphorane. Interestingly, the use of tert-butyllithium
as a base was essential for the success of the reaction. Jones
oxidation of 13 was accompanied by a partial hydrolysis of tert-
butyl ester. Therefore, its hydrolysis was completed with TFA,
and the dicarboxylic acids thus obtained were esterified with
diazomethane and isolated as dimethyl esters 14 in 77−83%
overall yield. Hydrolysis with lithium hydroxide, followed by
detosylation with lithium in liquid ammonia,17 completed the
synthesis of (+)-allokainic acid (1), whose spectral data were
identical with the natural compound. The optical purity of 1
could not be determined by chiral HPLC.18 Therefore, H
1
NMR spectra were recorded in the presence of a Sm-based,
water-soluble chiral shift reagent,19 which indicated the level of
optical purity of 80% ee. Given the fact that the enantiomeric
enrichment of the starting compound 4 was 80% ee, we
conclude that chirality transfer from the initial stereocenter to
the newly created stereocenters in the final product had
efficiently occurred, and that the stereochemical integrity of all
the intermediates was preserved throughout the synthetic
sequence, without epimerization/racemization in any of the
steps involved. Starting from 14a, the same sequence of
deprotective steps gave a non-natural (+)-desmethyl allokainic
acid 15 in quantitative yield.
Prior to this work, we were aware of two synthetic
applications of the organocatalyzed Tsuji−Trost cyclization
with substrates containing a stereogenic center. Whereas the
formation of a six-membered ring in the total synthesis of
(−)-atrop-abyssomicin C proceeded stereoselectively,20 the 5-
exo-cyclization in the total synthesis of (−)-englerin A
produced a mixture of diastereoisomers.21 Therefore, we also
set out to develop a method that would enable us to rationalize
the stereochemical outcome of the cyclization, as well as to
B
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Figure 1. Calculated geometries and transition states for the cyclization.
predict the outcome of other substrate-controlled dually
catalyzed cyclizations of this type. Intuitively, we considered
the cyclization as an irreversible, kinetically controlled process,
and indeed, the relative thermodynamic stabilities of the
products cannot rationalize the observed 10:1:1 ratio. There-
fore, to explain the diastereoselectivity of the crucial cyclization
step (3→2), we employed density functional theory (DFT)
calculations of transition states (TS) on the model systems.22
For three diastereoisomeric intermediate products in this
reaction step (before obtaining products of type 2 upon
hydrolysis) TS have been located. The geometries and relative
energies obtained with scalar relativistic zeroth-order regular
approximation (ZORA) calculations at BLYP-D3/TZP level of
theory within solvation model are depicted in Figure 1. Energy
differences between TS of model systems are sufficient to assert
that 3,4-trans-(2,3-trans) TS isomer is predominant. Even
though some approximations we introduced in the model lead
to minimization of steric effects, model calculations confirmed
that diastereoselectivity is kinetically controlled, and the
calculated ratio between diastereoisomers is corroborated by
experimental findings.
believe that the described chemistry can find a place in the
armamentarium of methods for stereoselective synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data for all new
1
compounds, copies of H/13C NMR spectra, computational
details, and Cartesian coordinates. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rsaicic@chem.bg.ac.rs.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Serbian Ministry of Education,
Science and Technological Development (Project No. 172027).
The authors gratefully acknowledge the support of the
Municipality of Stari Grad.
To summarize, an organocatalyzed intramolecular Tsuji−
Trost reaction with substrates possessing a stereogenic center
proceeds stereoselectively with substrate control, as exemplified
in the synthesis of (+)-allokainic acid and its non-natural
analogue. The stereochemical outcome of the reaction was
predicted on the basis of DFT calculations. Therefore, we
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