Asymmetric synthesis of proline-based conformationally constrained tryptophan mimetic

Article abstract of DOI:10.1039/c0ob00118j

The synthesis of an optically pure proline-based tryptophan mimetic is described. The strategy involves the in situ generation of an unprecedented allylmetal species containing the indole moiety, and its coupling with a chiral imine. The construction of the 3-substitued proline skeleton is then achieved through a hydrozirconation/iodination sequence applied to the resulting homoallylic amine.

Full text of DOI:10.1039/c0ob00118j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of proline-based conformationally constrained
tryptophan mimetic†
Pierre-Olivier Delaye, Jean-Luc Vasse* and Jan Szymoniak
Received 13th May 2010, Accepted 17th June 2010
First published as an Advance Article on the web 30th June 2010
DOI: 10.1039/c0ob00118j
The synthesis of an optically pure proline-based tryptophan
mimetic is described. The strategy involves the in situ gen-
eration of an unprecedented allylmetal species containing
the indole moiety, and its coupling with a chiral imine.
The construction of the 3-substitued proline skeleton is then
achieved through a hydrozirconation/iodination sequence
applied to the resulting homoallylic amine.
Substituted prolines exhibit significant biological activity, and are
Scheme 1
of marked interest for medicinal chemistry.1 Among them, proline
chimeras, incorporating proteinogenic amino acid chains at the
3-position, are valuable tools for biological investigations.2 Such
compounds are used as probes in SAR studies of biologically active
peptides.3 For example, their incorporation into peptides already
proved to be an efficient approach to mimicking the natural b-
turn of types I, II and II¢ found in proteins.4 They have also been
employed with a view to developing protein–protein interaction
inhibitors.5 Although several syntheses of proline chimeras have
been reported,6 the development of efficient synthetic methods
opening the way to optically pure compounds, and particularly
those possessing an aromatic substituent at the 3-position, is
valuable.
Scheme 2
As part of our work on a hydrozirconation-based asym-
metric approach to 5- and 6-membered N-heterocycles,7 we
recently developed an efficient synthesis of optically pure cis-2,3-
disubstituted pyrrolidines.8 In pursuit of this work, we describe
herein a simple method for the diastereoselective construction of
proline chimeras having an indolic fragment at the 3-position.
The synthetic strategy applied for this purpose involves: (i)
diastereoselective allylation of a chiral phenylglycinol-derived
imine; (ii) hydrozirconation of the resulting homoallylic amine,9
followed by iodination to promote pyrrolidine ring formation; (iii)
direct oxidation of the 2-substituent to a CO2H group (Scheme 1).
Following this approach, the possibility of synthesizing proline-
phenylalanine mimetic 5 was first checked out (Scheme 2). In
the beginning, Barbier-type cinnamylation of cinnamaldehyde-
derived imine 1 was performed in THF at room temperature,
by using cinnamyl bromide (2.5 equiv.), Zn powder (2.5 equiv.)
and a catalytic amount of CeCl3.10 As a result, homoallylic
amine 2 was obtained as the sole (branched) regioisomer in
a highly diastereoselective fashion (≥95% de) in 64% isolated
yield. Subsequent Pb(OAc)4-mediated chiral auxiliary removal
and Boc-protection11 provided 3.12 Selective hydrozirconation of
the terminal C C double bond, and in situ iodination gave the
iodo intermediate, which after treatment with NaHMDS afforded
the compound 4. The successive Ru-mediated oxidation of the
cinnamyl group, followed by diazomethane esterification provided
the target proline-phenylalanine derivative 5 in the orthogonally
protected form. Compound 5 was obtainedas a unique syn (2S,3R)
stereoisomer, based on the literature data (1H, 13C NMR and
[a]D).13
We initially envisioned to start the synthesis of a (3-
indolyl)proline analogue in the way similar to that followed for the
preparation of 5, i.e. by employing a Barbier-type protocol for the
allylation step. Thus, the synthesis of 3-bromo-3-indolylpropene
was first undertaken. However, all attempts to prepare this
previously unreported starting material (in the N-Boc or N-Bn
protected form) failed, presumably due to its instability resulting
from the strong electron-donating effect of the indolyl moiety.
We then turned to another possible way of generating allylmetal
species, which would bypass the use of an unstable bromide. It was
based on the Taguchi and Hanzawa protocol for the preparation
of allylic zirconium species by reaction of a zirconocene equivalent
“Cp2Zr” with allylic ethers.14,15 This reaction typically uses Cp2Zr-
butene, generated in situ from Cp2ZrCl2 and 2 equiv. of n-BuLi,
and involves the formation of zirconacyclopropane through ligand
exchange followed by b-alkoxy elimination (Scheme 3).
ICMR, CNRS-UMR 6229, Universite´ de Reims Champagne-Ardenne,
BP 1039, 51687, Reims Cedex 2, France. E-mail: jl.vasse@univ-reims.fr;
Fax: +00(0)3 2691 3166; Tel: 00(0)3 2691 3431
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of new compounds. See DOI: 10.1039/c0ob00118j
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Scheme 3
Scheme 4
The indole-containing allylic ether 6 was easily prepared in
3 steps in 75% overall yield, from indole-3-carboxaldehyde (see
ESI†). Compound 6 was added to the mixture of Cp2ZrCl2 (1
equiv.) and n-BuLi (2 equiv.) at -78 ◦C, and the temperature was
raised to rt within 3 h. To check whether the allylic zirconocene A
was efficiently generated, benzaldehyde was added. The expected
homoallylic alcohol 7 was obtained in 86% yield as 4.7 : 1 anti/syn
mixture of diastereomers (Scheme 4). Allylic metals bearing a
heteroaromatic moiety are uncommon; to our knowledge, no
allylmetals bearing the indole moiety have been reported. The
formation and possible synthetic uses of A are worthy of note.
The preparation of a corresponding homoallylic amine was next
envisioned, in the light of only a few examples involving allylzir-
conocene additions with imines.16,17 Although the low reactivity of
A towards imines could be anticipated,18 the possibility of carrying
out the reaction and preparing the syn adduct might be however
achieved through transmetalation.19 According to Taguchi’s recent
work on Cu(I) mediated addition of dialkoxyallylic zirconium
species with imines,20 we first examined the possibility of carrying
out the reaction in Zr-to-Cu transmetalation conditions. These
reactions were conducted in THF by using CuI, CuBr or CuCN
as additive. However, no allylation product was obtained but only
complex reaction mixtures were formed in all cases.
Scheme 5
Scheme 6
the allylation step can be explained by a classical six-membered
chair-like transition state.
The homoallylic amine 8 in hand, the target prolino-tryptophan
analogue 11 was obtained in 4 steps (Scheme 6). The one-
pot hydrozirconation–iodination sequence starting from 8 (4.5 : 1
mixture of diastereomers) afforded 10 in 61% isolated yield.
At this stage the major isomer was easily isolated by flash
chromatography. The simultaneous N- and O- debenzylation with
ammonium formate25 followed by Fmoc protection and oxida-
tion provided enantiopure and orthogonally protected amino
acid 11.
Recent advances in Zr-to-Zn transmetalations (typically
using Me2Zn or Et2Zn) from alkenylzirconocenes,21a and
allylzirconocenes,21b led to a number of synthetically useful trans-
◦
formations. Thus, Et2Zn was added to 0 C to in situ generated
allylzirconocene A, prior to the addition of 1¢,22 and the reaction
was carried out at room temperature for 6 h. In these conditions,
the expected compound 8 was formed and isolated in 61% yield
as a mixture of two diastereomers (dr = 4.5 : 1) (Scheme 5). The
use of Me2Zn instead of Et2Zn gave identical result. We noticed
that the reaction took also place when using ZnBr2 as additive,
however with a lower yield of 42%. Moreover, the size of the OR
group has been demonstrated to not affect the diastereoselectivity
which remains almost constant for R = Me, Bn and TBDMS.23
The syn stereochemistry in 8 was unambiguously established after
conversion of the mixture of diastereomers 8 into the piperidine
8¢ (Scheme 5). First, 8¢ was obtained as a single isomer, thus
indicating a unique relative configuration in 8. Secondly, the syn
stereochemistry was deduced from coupling constant values and
NOESY experiment performed on compound 8¢. Finally, the
Conclusions
In summary, we have described a diastereoselective method for
the preparation of an optically pure proline-based tryptophan
mimetic. The key steps are (i) diastereoselective allylmetallation of
phenylglycinol-derived imines via Zr to Zn transmetallation of an
in situ generated allylzirconocene, and (ii) the pyrrolidine ring con-
struction through a hydrozirconation–iodination sequence. Other
pyrrolidine (proline) derivatives with heteroaromatic substituents
at the b-carbon could be available. The possibility of using allylic
zirconiums bearing a heteroaromatic moiety opens the way to
various synthetic applications.
1
2R,3R configuration was assigned to compound 8 based on H
NMR data for the a-methoxy-a-phenylacetic amides (MPA) 9a
and 9b (for details, see ESI†).24 The observed facial selectivity in
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We thank the Ministere de la Recherche et de l¢Enseignement
Supe´rieur and the Agence Nationale de Recherche (ANR) for
their financial support.
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