CIAT with simultaneous epimerization at two stereocenters. Synthesis of substituted β-methyl-α-homophenylalanines

Article abstract of DOI:10.1039/b613103d

Diastereoselective aza-Michael additions of phenylethylamine to 3-aroylbutenoic acids are reported. During these processes, efficient control over two new stereogenic centers on the Michael acceptor has been possible via crystallization-induced asymmetric

Full text of DOI:10.1039/b613103d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
CIAT with simultaneous epimerization at two stereocenters. Synthesis of
substituted b-methyl-a-homophenylalanines†
Dusˇan Berkesˇ,*a Pavol Jakubec,a Dagmar Winklerova´,a Frantisˇek Povazˇaneca and Adam Daich*b
Received 11th September 2006, Accepted 31st October 2006
First published as an Advance Article on the web 23rd November 2006
DOI: 10.1039/b613103d
Diastereoselective aza-Michael additions of phenylethylamine to 3-aroylbutenoic acids are reported.
During these processes, efficient control over two new stereogenic centers on the Michael acceptor has
been possible via crystallization-induced asymmetric transformation (CIAT). As an application, a
convenient two-step synthesis of anti-b-methylhomophenylalanines is also described.
phenomenon, whereby simultaneous epimerization occurred at
Introduction
two stereogenic centers. This resulted in the formation of only one
Crystallization-induced asymmetric transformation (CIAT)
of the four possible stereoisomers in high yield, as well as excellent
diastereomeric and enantiomeric purity.17 Such CIAT applications
are very rare in the literature.18,19
of diastereomers or crystallization-induced diastereomer
transformation1 is an efficient tool for stereoselective synthesis
based on thermodynamic control. Because it is not necessary to
work at low temperature and readily available chiral auxiliaries or
chirality mediators can be used to build a new stereogenic center,
CIAT is an effective means to develop highly diastereoselective
processes especially on an industrial scale.2 In spite of the
exceptional effectiveness of CIAT processes the number of
known applications is relatively low. The critical point in the
CIAT development is the compatibility of the epimerization
(racemization) conditions in the solution with the conditions for
the crystal growth and nucleation.3,4 More than half of the papers
on racemization deal with amino acids or their derivatives.5
c-Oxo substituted derivatives of amino acids are derivatives with
high potential for further development, and their synthesis has ac-
cordingly been lately studied in considerable detail. The principal
strategies thereby pursued were as follows: catalytic, enantiose-
lective Mannich-type reactions,6,7 “chiral pool” syntheses from
available amino acids, mainly of the L-series,8–10 and alternatively
using the tandem reaction sequence, consisting of aza-Michael
addition of chiral N-nucleophiles to aroylacrylic acids, followed by
crystallization-induced asymmetric transformation (CIAT). The
latter route, owing to its technological robustness and simplicity
of operation, was successfully used for accessing enantiomerically
pure precursors of ACE inhibitors.11,12
Here we would like to present an interesting application of this
concept to the synthesis of anti-b-methyl-a-homophenylalanines
and their c-hydroxy derivatives with high diastereoselectiv-
ity control over two new stereogenic centers. b-Methyl-a-
homophenylalanine forms a vital part of cytotoxic depsipeptide
kulokekahilide-1.20 Interestingly, the same constrained amino
acid (4-phenylvaline) can be found in the potential anti-
cancer agent dolastatin-16 and also in the cyclic depsipep-
tide homodolastatin-16.21,22 The stereochemistry of 2-amino-3-
methyl-4-phenylbutanoic acid in the last two natural species
remains unassigned. In addition, c-hydroxy substituted b-methyl-
a-homophenylalanines can be found in many biologically active
substances like antifungal nikkomycins23 and immunosuppresive
cymbimycins.24
Results and discussion
The starting unsaturated acids 2a–c have been prepared by
modified acid catalyzed condensation of the corresponding pro-
piophenones 1a–c with glyoxylic acid (Scheme 1).25 The Friedel–
Crafts reaction of aromatics with citraconic anhydride exhibits low
regioselectivity and stereoselectivity and the formation of the (Z)-
stereomer in the form of cyclic tautomeric lactone was observed.26
In our optimized conditions the desired (E)-stereomers 2a–c were
prepared in yields ranging from 51 up to 73% and in E : Z ratio
more than 81 : 19, which can be increased up to 96 : 4 by one
crystallization. 4-Methoxy substituted propiophenones 2b,c were
prepared by highly regioselective LiClO4-catalyzed acylation.27
Our research program is focused on applications of CIAT to
the synthesis of c-oxo and c-hydroxy substituted a-amino acids.
The success of such transformations is based on the formation of
amino acids only slightly soluble at their isoelectric point and on
reversible aza-Michael addition, the retro-Michael being catalyzed
by excess of the base.13–16 Recently we have described a remarkable
aDepartment of organic chemistry, Slovak University of Technology,
Radlinske´ho 9, SK-81237, Bratislava, Slovakia. E-mail: dusan.berkes@
stuba.sk; Fax: +421 2 52968560; Tel: +421 2 52968560
bLaboratoire de Chimie, URCOM, UFR des Techniques de l’Universite´ du
Havre, 25, rue Philippe Lebon, B.P.: 540, F-76058, Le Havre Cedex, France.
E-mail: adam.daich@univ-lehavre.fr; Fax: +33 02-32-74-43-91; Tel: +33
02-32-74-44-03
† Electronic supplementary information (ESI) available: Experimental
procedures, 1H NMR and 13C NMR spectra are provided for all the
products reported herein. See DOI: 10.1039/b613103d
Scheme 1 (i) HOOC-CHO·H2O, H2SO4, dioxane, reflux, 1.5 h.
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Two new stereogenic centres are formed by conjugated addition
of amines on Michael acceptors 2a–c. For the design of a successful
CIAT process the conditions for an effective equilibrium between
all the possible stereomers in solution and the phase equilibria in
heterogeneous mixture between the precipitated solid and solution
have to be precisely ascertained.
Firstly, the conditions for the addition of benzylamine to
unsaturated acid 2a were optimized. Stirring the starting 0.21 M
aqueous solution of 2a with benzylamine (1.1 equiv.) at 40 ◦C
caused slow precipitation of both adducts and an effective
epimerization between them in alkaline solution (Fig. 1). After
several days the filtration of the reaction suspension allows one
to obtain only one of two possible diastereomers in high yield
and with excellent diastereomeric purity (anti-3a; 70%; dr 97 : 3).
As can be gleaned from Fig. 1A), the ratio of the diastereomeric
adducts at the initial stages is the opposite (anti : syn = 17 : 83 after
2 h). A similar reaction course (with small alteration of the solvent
concentration) has been observed for the unsaturated acids 2b,c
(Scheme 2).
Having in hand the optimized process for the benzylamine
addition the reactions of chiral (S)-phenylethylamine ((S)-PEA)
and (R)-phenylglycinol in tandem with an effective CIAT process
have been studied. The best results were obtained with (S)-PEA in
conditions consistent with benzylamine addition (water, 0.26 M
solution, 40 ◦C, 7 days). Only one of the four possible isomers
has been separated from the reaction mixture by simple filtration
(4a: 70% yield, dr 99 : 0 : 1 : 0; 4b: 60% yield, dr 99 : 0 : 1 : 0
Fig. 1 Diastereomer distribution (HPLC experiments) A) 0.21 M of 2a
◦
ꢀ
in water with benzylamine (1.1 equiv.) at 40 C ꢀ 3a, syn-diastereomer;
B) 0.26 M of 2b in water with (S)-PEA (1.1 equiv.) at 40 ◦C ꢀ 4b, ꢁ other
diastereomers.
in HPLC succession). In the case of (R)-phenylglycinol only
dichloromethane has been found to be a suitable solvent for the
CIAT process with 2a, however, the yield of precipitated product
was low (4aꢀ:18% after 14 days, dr 1 : 99 : 0 : 0).
The course of the CIAT process for the (S)-PEA addition on
acid 2b is outlined on Fig. 1B). Also in this case at the initial
stages of the transformation the kinetically favoured diastereomers
predominated in the reaction mixture. This is in agreement with
the benzylamine addition. However as the CIAT progressed in
time 4b clearly became a major product with concomitant decline
of the content of all other isomers in the reaction suspension.
The prepared c-oxo-a-amino acids 3a–c or 4a,b are stable
as solids, however they decompose slowly especially in alkaline
solution. The reduction of the carbonyl group has been found as a
tool for the stabilization of the newly formed stereogenic centers.28
A stereodivergent route to both diastereomeric c-hydroxy-a-
amino acids 5a,b and 6a,b was developed (Scheme 3) using sodium
borohydride in convenient reaction conditions. The application of
Scheme 2 aza-Michael addition of amine and CIAT process. (i) 1.1 equiv.
of BnNH2, water, 40 ◦C, 7 days, filtration; (ii) 4a,b: 1.1 equiv. of (S)-PEA,
water, 40 ◦C, 7 days, filtration; 4a: 1.1 equiv. of (R)-phenylglycinol, CH2Cl2,
25 ◦C, 14 days, filtration.
Scheme 3 Stereodivergent reduction and catalytic hydrogenation of oxoamino acids 4. (i) NaBH4, MeOH, 0–5 ◦C, 5 : 6 > 92 : 8; (ii) NaBH4, MnCl2,
MeOH, 0–5 ◦C, 5 : 6 > 5 : 95; (iii) 1 equiv. HBr, H2/Pd–C, MeOH–H2O, 25 ◦C; (iv) 3 equiv. HBr, H2/Pd–C, MeOH–H2O, 40 ◦C, 24 h.
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sodium borohydride in methanol produces the 3,4-syn-isomers
5a,b in high yield and excellent diastereomeric purity via 1,2-
stereoinduction and it is in agreement with the known results
on related systems.29 The 3,4-anti-isomers 6a,b were prepared
using our previously reported catalytic reduction with NaBH4–
cat. MnCl2·4H2O system in methanol by 1,3-asymmetric
induction via Mn2+ chelation.28 The chemoselective catalytic N-
debenzylation of 5a,b and 6a,b produces the 2-amino-4-aryl-4-
hydroxy-3-methylbutanoic acids 7a,b and 8a,b, the non-natural
analogues of N-terminal amino acid of nikkomycins.
Absolute configuration assignment of the carbons C-2 and C-
3 of the parent adducts 4a,b and 4aꢀ was made by their trans-
formation to intermediates of biologically important compounds
and at the same time the relative configuration was also tested.
Pd-catalyzed hydrogenation proceeds smoothly in an EtOH–H2O
combination with excess of HBr. No epimerization to the (2S,3S)-
2-amino-3-methyl-4-phenylbutanoic acid 9a has been observed.
The NMR spectral data and optical properties are in agreement
with those published by Kimura et al. in the kulokekahelide
studies.20
Furthermore, the methoxy substituted hydroxyamino acids
7b,8b were transferred to the known Boc-protected lactones
12b,13b30 (Scheme 5)—intermediates of the nikkomycin-B
synthesis—and their NMR spectral data as well as their specific
optical rotation confirm the (2S,3R,4S)-12b or (2S,3R,4R)-13b
configuration and conclude the absolute and relative structural
assignment of methoxy substituted derivatives given above.
Elucidation of the relative and absolute configuration
Determination of the relative configuration on the newly formed
stereogenic centres was based on the results obtained from NOE
experiments, which were performed on cyclic derivatives 10a,b and
11a,b.
Acid-catalyzed lactonization of the phenyl substituted hydrox-
yamino acids 5a,6a under simple stirring in diluted HCl led to
the corresponding crystalline lactones 10a,11a in high yield. One
recrystallization seems to be sufficient to obtain these nicely crys-
talline hydrochlorides in excellent stereochemical homogeneity
(dr > 99 : 1). In the case of methoxy substituted derivatives 5b,6b
the lactonization took place smoothly under mild conditions (3 M
HCl, 4 h, rt), however, in both cases the all cis-isomer 10b was
isolated in excellent both yield and purity. Such a result accords
with our recently described CIAT application on closely related
derivatives.16
Scheme 5 Lactone 12b,13b synthesis, absolute configuration elucidation.
(i) a: 12 M HCl, rt, 1 h, filtration, 100%; b: (Boc)2O, NEt3, dioxane, 50%,
12 : 13 ratio 98 : 2; (ii) a: Boc2O, NEt3, CH2Cl2, 30 ◦C, b: DCC, CH2Cl2,
5 min (dr 81 : 19), chromatography, 28% of 13b, 12 : 13 ratio 2 : 98.
Gratifyingly, the employment of DCC in our previously de-
scribed conditions allowed us to prepare the desired lactone
11b under mild conditions (Scheme 4). As expected, the NOE’s
observed between protons at C-2, C-3 and C-4 testified to
the relative all cis-configuration of 10b (Scheme 4). Similarly
the NOE data clearly confirmed the expected 3,4-trans-relative
configuration on the lactone 11b. The relative configurations of
all hydroxyamino acids 5,6 and corresponding lactones 10a,11a
were tentatively assigned on the basis of these results.
Conclusions
We have successfully broadened the scope of CIAT in the conjugate
addition of N-nucleophiles to substituted aroylacrylic acids. We
have demonstrated an efficient CIAT methodology, enabling an
efficient stereocontrol over two new stereogenic centers. We report
herein a two-step and inexpensive preparation of the 4-aryl
substituted 2-amino-3-methylbutanoic acids and their 4-hydroxy
substituted derivatives, respectively, with high degree of both
diastereomeric and enantiomeric purity.
Acknowledgements
Financial support by the Slovak Grant Agency No. 1/2469/05
and NMR measurements provided by the Slovak State Programme
Project No. 2003SP200280203 are gratefully acknowledged.
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