Design, synthesis, and application of enantioselective coupling reagent with a traceless chiral auxiliary

Article abstract of DOI:10.1021/ol802691x

(Chemical Equation Presented) Stable chiral N-triazinylbrucinium tetrafluoroborate enantioselectively activates racemic carboxylic acids yielding enantiomerically enriched amides, esters, and dipeptides with er from 8:92 to 0.5:99.5. Due to the departure

Full text of DOI:10.1021/ol802691x

ORGANIC
LETTERS
2009
Vol. 11, No. 3
765-768
Design, Synthesis, and Application of
Enantioselective Coupling Reagent with
a Traceless Chiral Auxiliary
Beata Kolesinska* and Zbigniew J. Kaminski
Institute of Organic Chemistry, Lodz UniVersity of Technology, Zeromskiego 116,
90-924 Lodz, Poland
beata.kolesinska@p.lodz.pl
Received December 8, 2008
ABSTRACT
Stable chiral N-triazinylbrucinium tetrafluoroborate enantioselectively activates racemic carboxylic acids yielding enantiomerically enriched
amides, esters, and dipeptides with er from 8:92 to 0.5:99.5. Due to the departure of a chiral auxiliary after the activation of the carboxylic
function, all of the subsequent stages of the coupling reaction proceed without any perturbation caused by a chirality discriminator (traceless).
Therefore, the advantageous coupling conditions, configuration, and enantiomeric purity of the final product are entirely predictable from the
model experiment.
The rapid development of the methods of combinatorial
chemistry in the systematic exploration of molecular diversity
and in the search for improved activities and properties of a
broad range of synthetic materials have resulted in a
vigorously growing demand for numerous new chiral sub-
strates with diversified structural features.
research groups as some of the first efficient enantioselective
reagents for condensation involving racemic amino as well
as carboxylic components, but none found acceptance. More
promising results were obtained in kinetic resolution of
racemic acylated components, mostly amines and alcohols.
In several cases, high er’s were obtained using the chiral
component in catalytic amounts. The most spectacular results
In most cases, enantiomerically active substrates are
needed only in tiny amounts. Therefore, an approach based
on the enantiodifferentiating transformation of usually easily
available racemic substrates would be valued as advantageous
and less time-consuming than the classic procedure involving
racemate resolution or asymmetric synthesis. Such an ap-
proach would be considered the most convenient in the case
of coupling chiral building blocks like amino acids used for
the construction of more complex molecules.
(1) (a) Takeda, K.; Tsuboyama, K.; Suzuki, A.; Ogura, H. T. Chem.
Pharm. Bull. 1985, 33, 2545. (b) Teramoto, T.; Deguchi, M.; Kurosaki, T.
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ka, J. Pol. J. Chem. 1994, 68, 1973. (e) Kricheldorf, H. R.; Au, M.; Mang,
T. Int. J. Peptide Protein Res. 1985, 26, 149. (f) Kricheldorf, H. R.; Mang,
T. Makromol. Chem. 1982, 183, 2093.
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T.; Yokoyama, Y. Tetrahedron Lett. 1997, 38, 3751. (b) Kondo, K.;
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Maezaki, N.; Furusawa, A.; Uchida, S.; Tanaka, T. Tetrahedron 2001, 57,
9309.
Several chiral coupling reagents were proposed for the
synthesis of enantiomerically enriched peptides directly from
racemic substrates. Optically active N-hydroxysuccinimide1
and diacylamine2 derivatives were evaluated by several
10.1021/ol802691x CCC: $40.75
Published on Web 01/07/2009
2009 American Chemical Society

were obtained using chiral DMAP analogues,3,4 N-meth-
ylimidazole,5 benzotetramisol,6 tertiary amines,7 phosphines,8
and others9 used as a chiral auxiliary. Thus far, however,
none of the proposed enantioselective coupling method was
accepted for the condensations of complex molecules with
stereogenic centers in both reacting components because of
the unpredictable yield, purity, and configuration of the final
product.
Scheme 2
Therefore, in the presence of three chiral centers (two in
both condensed substrates and one in chiral reagent or
catalyst, see Scheme 1), for each pair of coupled substrates
Scheme 1
as those obtained in a reaction involving a well-known,
classic achiral reagent 2 with well-recognized scope and
synthetic limitations (see Scheme 2). Moreover, due to the
departure of the chiral auxiliary after activation, all further
stages of the coupling procedure should remain free of the
disturbances caused by the presence of the third chiral center,
and therefore the configuration and enantiomeric purity, once
established during the activation, should remain essentially
intact in all the syntheses involving this carboxylic compo-
nent and reagent. Thus, for the every one racemic carboxylic
component all the final results of the syntheses could be
predicted from the single model experiment.
The enantioselective condensing reagent was prepared in
a phase transfer reaction by the treatment of 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT) (1) with brucine tetrafluo-
roborate (7) in the presence of sodium bicarbonate.12 The
postulated primary reaction product, unstable and unisolated
chiral quaternary N-triazinylbrucinium chloride 8 bearing a
chiral nitrogen atom, exchanged counterions and produced
appropriate stable chiral tetrafluoroborate 9 in high yield (see
Scheme 3).
it is inevitable to select the suitable auxiliary and optimize
the reaction conditions acceptable for the given synthetic
goal. This limitation, which is both risky and tedious, makes
this method unacceptable for the coupling of complex,
expensive molecules such as peptides.
In order to overcome all the difficulties in coupling a
racemic carboxylic component with a chiral nucleophile, the
method of synthesis should be predictable and controllable
with respect to efficiency, configuration, and enantiomeric
enrichment and be applicable to the broadest possible range
of substrates. Moreover, all the mentioned requirements
should meet the high standards of the classic methodology
of synthesis, in particular, the criterion of high enantiomeric
homogeneity.10
In this paper, we propose an entirely new approach to
enantioselective incorporation of the substrate into the chiral
molecule involving a novel design of the coupling reagent.
In order to remove the unpredictability of coupling results
involving three chiral components, enantioselective reagents
with traceless chiral auxiliary were proposed, designed, and
used in experiments of kinetic resolution of racemic car-
boxylic component (see Scheme 2).
Scheme 3
According to the concept, the traceless enantioselective
coupling reagent 4 is a binary system consisting of a chiral
auxiliary (L*) active during the enantiodiscriminating activa-
tion of the carboxylic component and subsequently departing
after the completion of the process.
Thus, the structure, reactivity, and properties of the
activated carboxylic component 3 should be exactly the same
(3) (a) Garret, C. E.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 7479. (b)
Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001,
40, 234. (c) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.;
Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925. (d) Mermerian, A. H.; Fu,
G. C. Angew. Chem., Int. Ed. 2005, 44, 949
.
(4) (a) Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest,
R. L. J. Org. Chem. 2003, 68, 7379. (b) Kawabata, T.; Stragies, R.; Fukaya,
T.; Nagaoka, Y.; Schedel, H.; Fuji, K. Tetrahedron Lett. 2003, 44, 1545.
(c) Priem, G.; Pelotier, B.; Madonald, S. J. F.; Anson, M. S.; Campbell,
I. B. J. Org. Chem. 2003, 68, 3844. (d) Dalaigh, C. O.; Hynes, S. J.; O’Brien,
J. E.; McCabe, T.; Maher, D. J.; Watson, G. W.; Connon, S. J. Org. Biomol.
Chem. 2006, 4, 2785. (e) Anstiss, M.; Nelson, A. Org. Biomol. Chem. 2006,
It has been proven in model experiments involving 2,2-
dimethylpropionic acid and 4-methoxybenzoic acid that
reaction with 9 gave the expected11 “superactive esters”
4, 4135
.
766
Org. Lett., Vol. 11, No. 3, 2009

Table 1. Configuration and Enantiomeric Enrichment of Protected Peptides Obtained from Racemic Carboxylic Components with 9
Used as a Coupling Reagent
a
entry
racemic component
Z-DL-Phe
acylated component
product prepared
Z-L-Phe-L-Ala-OMe
Z-L-Phe-L-Leu-OMe
Z-L-Phe-L-Trp-OMe
Z-L-Phe-L-Val-OMe
Z-L-Phe-L-Ile-OBut
Z-L-Phe-L-Ser-OMe
Z-L-Phe-L-Tyr-OEt
Z-L-Phe-L-His-OMe
Z-L-Phe-L-Pro-OMe
Z-L-Phe-Gly-OEt
Z-L-Phe-NH-(CH2)3CH3
Z-L-Phe-NH-CH2-C6H5
Z-L-Phe-OMe
Fmoc-L-Phe-L-Ala-OMe
Fmoc-L-Phe-L-Leu-OMe
Fmoc-L-Phe-Gly-OEt
Fmoc-L-Phe-NH-(CH2)3CH3
Z-L-Tyr-L-Leu-OMe
Z-L-Tyr-L-Val-OMe
yield (%)
er D/L
1
2
3
4
5
6
7
8
HCl·L-Ala-OMe
HCl·L-Leu-OMe
HCl·L-Trp-OMe
HCl·L-Val-OMe
HCl·L-Ile-OBut
HCl·L-Ser-OMe
HCl·L-Tyr-OEt
2HCl·L-His-OMe
HCl·L-Pro-OMe
HCl·Gly-OEt
NH2-(CH2)3CH3
NH2-CH2C6H5
CH3OH
HCl·L-Ala-OMe
HCl·L-Leu-OMe
HCl·Gly-OEt
NH2-(CH2)3CH3
HCl·L-Leu-OMe
HCl·L-Val-OMe
HCl·L-Ile-OBut
HCl·L-Ala-OMe
HCl·L-Trp-OMe
HCl·L-Phe-OMe
HCl·Gly-OMe
CH3OH
HCl·L-Phe-OMe
HCl·L-Leu-OMe
HCl·L-Trp-OMe
HCl·L-Val-OMe
HCl·L-Ile-OBut
HCl·L-Ser-OMe
HCl·L-Tyr-OEt
2HCl·L-His-OMe
HCl·L-Pro-OMe
HCl·Gly-OEt
HCl·Aib-OMe
NH2-(CH2)3CH3
CH3OH
HCl·L-Phe-OMe
HCl·L-Leu-OMe
HCl·Gly-OEt
NH2-(CH2)3CH3
HCl·Gly-OMe
NH2-(CH2)3CH3
HCl·Gly-OMe
NH2-(CH2)3CH3
HCl·Gly-OMe
NH2-(CH2)3CH3
HCl·Gly-OMe
NH2-(CH2)3CH3
HCl·Gly-OMe
NH2-(CH2)3CH3
NH2-C6H5
95
94.5
91
98
98
98
97
94
98
85
87
88
98
97
98
90
89
99
98
98
99
97
96
97
98
94
93
88
96
95
93
89
88
92
85
88
86
96
92
93
87
86
93
90
91
89
92
88
93
94
89
90
90
3/97
1/99
0.5/99.5
0.5/99.5
0.5/99.5
0.5/99.5
05/99.5
0.5/99.5
2/98
0.5/99.5
0.5/99.5
0.5/99.5
2/98
05/99.5
0.5/99.5
0.5/99.5
0.5/99.5
1/99
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Fmoc-DL-Phe
Z-DL-Tyr
0.5/99.5
2/98
Z-L-Tyr-L-Ile-OBut
Z-L-Tyr-L-Ala-OMe
Z-L-Tyr-L-Trp-OMe
Z-L-Tyr-L-Phe-OMe
Z-L-Tyr-Gly-OMe
3/97
0.5/99.5
0.5/99.5
1.5/98.5
2/98
Z-L-Tyr-OMe
Z-DL-Ala
Z-D-Ala-L-Phe-OMe
Z-D-Ala-L-Leu-OMe
Z-D-Ala-L-Trp-OMe
Z-D-Ala-L-Val-OMe
Z-D-Ala-L-Ile-OBut
Z-D-Ala-L-Ser-OMe
Z-D-Ala-L-Tyr-OEt
Z-D-Ala-L-His-OMe
Z-D-Ala-L-Pro-OMe
Z-D-Ala-Gly-OEt
Z-D-Ala-Aib-OMe
Z-D-Ala-NH-(CH2)3CH3
Z-D-Ala-OMe
Fmoc-D-Ala-L-Phe-OMe
Fmoc-D-Ala-L-Leu-OMe
Fmoc-D-Ala-Gly-OEt
Fmoc-D-Ala-NH(CH2)3CH3
Z-D-Val-Gly-OMe
96/4
93/7
96/4
98/2
92/8
95/5
99.6/0.4
92/8
97/3
98/2
94/6
99/1
97/3
96/4
92/8
96/4
Fmoc-DL-Ala
95/5
Z-DL-Val
99.5/0.5
99/1
Z-D-Val-NH-(CH2)3CH3
Z-D-Leu-Gly-OMe
Z-DL-Leu
99/1
99/1
95/5
94/6
90/10
91/9
5/95
Z-D-Leu-NH-(CH2)3CH3
Z-D-nor-Leu-Gly-OMe
Z-D-nor-Leu-NH-(CH2)3CH3
D-Z-NH-CH((CH2)4CH3)CO-Gly-OMe
D-Z-NH-CH((CH2)4CH3)CONH-(CH2)3CH3
Z-L-Ser-Gly-OMe
Z-DL-nor-Leu
DL-Z-NH-CH((CH2)4CH3)COOH
Z-DL-Ser
Z-L-Ser- NH-(CH2)3CH3
(S)-C2H5CH(C6H5)CO-NH-C6H5
5.5/94.5
rac-C2H5CH(C6H5)COOH
6/94b
a er13 determined by GC on a ChirasilVal capillary column. b Determined by polarimetric method; for (S)-2-phenylbutanoic acid anilide [R]25D ) +106
(c ) 1.0, EtOH).
2-acyloxy-4,6-dimethoxy-1,3,5-triazines 3, which were iden-
tical with the products prepared with an achiral triazine
coupling reagent.12 In all enantioselective coupling experi-
ments, 9 was treated with 2 equiv of a racemic carboxylic
component and then, after activation, in reaction with a
nucleophile, gave the final product of the condensation. After
Org. Lett., Vol. 11, No. 3, 2009
767

the completion of the reaction, the chiral auxiliary, nonre-
acted stereodiscriminated enantiomer, and triazine byproduct
were removed from the reacting mixture by the typical
washing procedure. It has been found that under these
conditions a high yield of HPLC pure acylated products was
obtained (see Table 1).
coupling, and workup procedure, we did not expect identical
ee’s to be obtained. The most divergent ee values were found
in coupling of alanine with sterically hindered substrates
(entries 27 (Leu), 30 (Ile), 36 (Aib), 40 (Leu)) and acylation
of less nucleophilic methanol (entries 13, 25, and 38). In
the latter case, the negative effects of lowered nucleophilicity
were suppressed by modification of reaction conditions and
using a less reactive component in large excess.
Nevertheless, enantiomeric enrichment after coupling with
9 in all cases gave very similar results within the range of
er 8/92 to er 1/99%. This documented that the departure of
the chiral auxiliary prior to the acylation of the nucleophile
consists a crucial advantage of 9 because this transformation
substantially eliminated the unpredictable diastereomeric
discriminations caused by the presence of an chiral auxiliary
in reacting molecules at the coupling stage and its influence
on the subsequent stages of the acylation process involving
the temporary creation of new stereogenic centers in the
tetrahedral intermediate.
The configuration and optical purity of isolated products
were established after hydrolytic degradation to amino acids
and the subsequent derivatization and separation of enanti-
omers by GC on a Chirasil Val capillary column. The
chromatographic data confirmed that the configuration of the
preferred enantiomer was identical in all the cases studied
and did not depend on the structure of the acylated amino
component, as it was anticipated. For N-protected aromatic
amino acids, i.e., phenylalanine and tyrosine (Table 1, entries
1-25) and N-protected serine (entries 51-52), in all the
experiments the L configuration was preferred. Moreover, it
has to be anticipated that in all other couplings involving
mentioned racemic N-protected amino acids and any kind
of acylated nucleophile the L enantiomer of carboxylic
component should be favored during activation, yielding a
final product with er in the range 0.5/99.5 to 3/97.
For N-protected alanine (entries 26-42), valine, leucine,
norleucine, and 2-aminoheptanoic acid, the D configuration
was preferred (entries 43-50). Considering adverse effects
such as unavoidable diastereoselection during acylation of
chiral nucleohiles, diversified reaction yields altering racemic
substrate/stereoselector ratio, and side reactions such as
participation of anhydrides, partial racemization during
Thus, the predictable configuration, comparable enantio-
meric purity, and convenient and highly resourceful prepara-
tive procedure confirm the efficiency of the presented
approach in the synthesis of enantiomerically enriched
peptides, amides, and esters of carboxylic acids from racemic
carboxylic components.
Acknowledgment. This study was supported by the Polish
State Committee for Scientific Research under Project PBZ-
KBN-126/T09/15.
Supporting Information Available: Full experimental
details and spectral data for all compounds described in Table
1. This material is available free of charge via the Internet
at http://pubs.acs.org.
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