A novel generation of coupling reagents. Enantiodifferentiating coupling reagents prepared in situ from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and chiral tertiary amines

Article abstract of DOI:10.1021/jo0101499

Coupling of racemic N-protected amino acids with amino components by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in the presence of chiral tertiary amines such as strychnine, brucine, and sparteine proceeds enantioselectively, affording appropriate amides or dipeptides in 69-85% yield. The configuration of the preferred enantiomer and enantiomeric enrichment depend on the structures of the amine and carboxylic acid. Calculated Kagan enantioselectivity parameters (s) are in the range 1.6-195. Chiral triazinylammonium chlorides formed in situ from CDMT and chiral tertiary amines are postulated as reactive intermediates involved in the process of enantioselective activation of N-protected amino acids.

Full text of DOI:10.1021/jo0101499

6276
J . Org. Chem. 2001, 66, 6276-6281
A Novel Gen er a tion of Cou p lin g Rea gen ts. En a n tiod iffer en tia tin g
Cou p lin g Rea gen ts P r ep a r ed in Situ fr om
2-Ch lor o-4,6-d im eth oxy-1,3,5-tr ia zin e (CDMT) a n d Ch ir a l Ter tia r y
Am in es
Zbigniew J . Kamin´ski,*,† Beata Kolesin´ska,† J anina E. Kamin´ska,‡ and J o´zef Go´ra‡
Institute of Organic Chemistry and Institute of General Food Chemistry,
Technical University of Ło´dz´, ul. Z˙ eromskiego 116, 90-924 Ło´dz´, Poland
kaminsz@ck-sg.p.lodz.pl
Received February 6, 2001
Coupling of racemic N-protected amino acids with amino components by means of 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT) in the presence of chiral tertiary amines such as strychnine,
brucine, and sparteine proceeds enantioselectively, affording appropriate amides or dipeptides in
69-85% yield. The configuration of the preferred enantiomer and enantiomeric enrichment depend
on the structures of the amine and carboxylic acid. Calculated Kagan enantioselectivity parameters
(s) are in the range 1.6-195. Chiral triazinylammonium chlorides formed in situ from CDMT and
chiral tertiary amines are postulated as reactive intermediates involved in the process of
enantioselective activation of N-protected amino acids.
In tr od u ction
system, formed in situ from two readily accessible compo-
nents just before the enantiodiscriminating process.
An advantage of the proposed reagents results from
the presence of the chiral component only at the activa-
tion stage. Thus, after departure of the auxiliary, the
activated carboxylic acid forms acylating reagent, identi-
cal with the product of the classical activation performed
using a standard achiral coupling reagent. This precludes
additional studies on scope and limitation on the acyl-
ation procedure. Moreover, the absence of chiral auxiliary
simplifies the prediction of diastereomeric discrimina-
tions in the course of the acylation step. This results from
the elimination of unpredictable disturbances of coupling
of two chiral substrates, by the presence of the additional
chiral center of the auxiliary. It should be also expected
that the chiral auxiliary could be recovered after enan-
tioselective activation of the carboxyl group and used
again in the enantiodiscriminating syntheses.
A strong demand for molecular diversity of peptides,
necessary for successful structure-activity relationships
studies and construction of libraries of compounds, has
stimulated progress in the preparation of optically active
analogues of proteinogenic amino acids. An approach
based on the application of enantiodiscriminating cou-
pling reagents is considered as a particularly versatile
tool1 for SAR screening studies because it opens access
to chiral amino acids without relying on laborious resolu-
tion of racemates or de novo asymmetric syntheses. Thus,
once prepared, enantiodifferentiating reagents might be
successively applied in the condensation of a broad range
of substrates, thereby facilitating SAR screening studies.
A new, convenient approach leading from racemates
to optically active products is presented in this paper.
This is based on the application of known, achiral
condensing reagents acting as enantiodifferentiating
species in the presence of an appropriate chiral auxiliary.
According to this concept, the reagent consists of a binary
Resu lts a n d Discu ssion
To accomplish the above strategy, an enantioselective
condensing reagent was generated in situ by the treat-
ment of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)2
(1) with a chiral tertiary amine (2a -c). According to
previous studies3 this affords the chiral quarternary
triazinium salt 3a -c, which seems to be the obligatory
reactive intermediate for the successful formation of
triazine active esters 4a -d (Scheme 1).
Throughout all condensation experiments a 2-fold
excess of the racemic carboxylic acid 5a -d was used.
Activation as well as coupling was performed following
conditions of standard procedure.4 Due to the weakly
* To whom correspondence should be addressed. Tel: (048-42) 6-31-
31-51. Fax: (048-42) 6-36-55-30.
† Institute of Organic Chemistry.
‡ Institute of General Food Chemistry.
(1) (a) Ie, Y.; Fu, G. C. Chem. Commun. 2000, 119-120. (b) Spivey,
A. C.; Fekner, T.; Spey, S. E. J . Org. Chem. 2000, 65, 3154-3159 and
refs cited therein. (c) Vedejs, E.; Daugulis, O. J . Am. Chem. Soc. 1999,
121, 5813-5814. (d) Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem.
Lett. 1999, 265-266. (e) Ruble, J . C.; Fu, G. C. J . Am. Chem. Soc. 1998,
120, 11532-11533. (f) Somfai, P. Angew. Chem., Int. Ed. 1997, 36,
2731-2733. (g) Evans, D. A.; Anderson, J . C.; Taylor, M. K. Tetra-
hedron Lett. 1993, 34, 5563-5566. (h) Burk, M. J .; Feaster, J . E.;
Nugent, W. R.; Harlow, R. L. J . Am. Chem. Soc. 1993, 115, 10125-
10126. (i) Benoiton, N. L.; Lee, Y. C.; Chen, F. M. F. Int. J . Pept. Protein
Res. 1991, 38, 574-579. (j) Guenster, E. J .; Schulz, R. C. Makromol.
Chem. 1980, 181, 643-649. (k) Teramoto, T.; Deguchi, M.; Kurosaki,
T.; Okawara, M. Tetrahedron Lett. 1981, 22, 1109-1112. (l) Teramoto,
T.; Kurosaki, T.; Okawara, M. Tetrahedron Lett. 1977, 18, 1523-1526.
(m) Wickramasinghe, S. M. D.; Lacey, J . C., J r. Bioorg. Chem. 1992,
20, 265-268. (n) Takeda, K.; Tsuboyama, K.; Suzuku, A.; Ogura, H.
Chem. Pharm. Bull. 1985, 33, 2545-2548. (o) Markowicz, S. W.;
Karolak-Wojciechowska, J . Pol. J . Chem. 1994, 68, 1973-1981.
(2) For the review on triazine condensing reagents see Kamin´ski,
Z. J . Biopolymers (Pept. Sci.) 2000, 55, 140-164.
(3) Kamin´ski, Z. J .; Paneth, P.; Rudzin´ski, J . J . Org. Chem. 1998,
63, 4248-4255.
(4) a) Kamin´ski, Z. J . Tetrahedron Lett. 1985, 26, 2901-2904. (b)
Kamin´ski, Z. J . Synthesis 1987, 917-920.
10.1021/jo0101499 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/22/2001

Enantiodifferentiating Coupling Reagents
J . Org. Chem., Vol. 66, No. 19, 2001 6277
Sch em e 1
Sch em e 2
isolated and identified6 as the expected triazine ester 4e.
Ethanolysis of 4e proceeding in the absence of any chiral
additive7 gave a mixture of appropriate ethyl esters 18
(Scheme 2), and the ratio of enantiomers was determined
on chiral GC stationary phase to be R/ S ) 42/58 (Table
1, entry 13).
The end result of enantioselective activation is pre-
defined optical purity and configuration at the chiral
center at this reaction step. This particular feature
strongly facilitates application of triazine enantio-
differentiating reagents 3a -c for the preparation of
diastereomeric compounds. Due to the departure of chiral
auxiliary after activation, the coupling stage involves
substrates identical to those used in the standard pro-
cedure. This means that effects of diastereoselection8
always accompanying coupling of two chiral sub-
strates9 are essentially independent of the structure of
the chiral auxiliary.
Determination of the configuration and diastereomeric
ratio of dipeptides obtained by acylation of optically pure
substrate with rac-5a activated by CDMT in the presence
of strychnine (2a ) (entry 6) or brucine (2b) (entry 7)
unequivocally confirmed that the preferred configuration
at the alanine10 residue is the same as in the case of the
achiral substrates (entries 1, 2). Also, acylation of opti-
cally pure L-alanine methyl ester with racemic Z-Phe-
OH (rac-5d ) in the presence of strychnine (2a ) confirmed
the preference for the same configuration of the phenyl-
alanine leading predominantly to the L,L diastereomeric
dipeptide 12 (entry 12).
To elucidate more precisely the enantioselectivity in
coupling by 3a -c and to estimate its diversification,
Kagan’s enantioselectivity parameters (s) have been
calculated.11 In the most favorable (i.e., strychnine)
circumstances the parameters (s) are in the range 98-
195. These values, although exceedingly high, are still
basic properties of all triazine derivatives and the basic
character of the chiral auxiliary, simple washing of the
crude reaction mixture with dilute aqueous acid gave
neutral products in 52-95% yield, sufficiently pure so
that there was no need for any additional purification
procedures prior to determination of enantioselectivity.
The structure of all products 6-12 obtained in the
condensation was confirmed by the comparison of their
spectra with appropriate data of authentic samples
obtained by the standard method.4
The enantioselectivity of the condensation mediated by
5
2a -c was determined by GC on a chiral stationary
phase, HPLC analysis of diastereomer 12, or 13C NMR
of diastereomer 8, formed in reaction with optically pure
amino component. All methods gave essentially consist-
ent results and showed that configuration and optical
purity of the product depends on the structure of chiral
auxiliaries 2a -c, and the substrates 5a -d .
(6) IR and 1H NMR spectroscopic data of 3e were identical with
spectra of the authentic sample obtained according to the standard
procedure: (a) Kamin´ski, Z. J . J . prakt. Chem. 1990, 332, 579-584.
(b) Kamin´ski, Z. J . Pol. J . Chem. 1991, 65, 2077-2079;
(7) Kamin´ska, J . E.; Kamin´ski, Z. J .; Go´ra J . Synthesis 1999, 593-
596,
(8) Although these effects are usually of minor importance, in some
cases their influence should not be neglected; for a review on control
of diastereoselectivity through diastereomeric equilibriation, see: Beak,
P.; Anderson, D. R.; Curtis, M. D.; Laumer, J . M.; Pippel, D. J .;
Weisenburger, G. A. Acc. Chem. Rev. 2000, 33, 715-727.
(9) a) Weygand, F.; Steglich, W. Tetrahedron, Suppl. 1966, 8, 9-13.
(b) Benoiton, N. L.; Kuroda, K.; Chen, F. M. F. Tetrahedron Lett. 1981,
22, 3361-3364.
In condensations involving strychnine (2a ) as chiral
auxiliary, the D configuration of the preferred enantiomer
was determined for alanine and leucine, but the opposite
selectivity was found for phenylalanine (D enantiomer
was less reactive, entry 11). Use of sparteine (2c) as
auxiliary resulted in faster conversion of the alanine
derivative of L configuration (entries 3 and 5).
We were able to prove that enantiodifferentiation
proceeds in the stage of activation. Thus, treatment of
2-ethylhexanoic acid with CDMT in the presence of
strychnine (2a ) gave weakly basic product, which was
(10) For entry 1, the less reactive enantiomer Z-Ala-OH was
recovered and opposite, S configuration (enantiomer R/S ratio 2/98)
was determined by GC on Permabond L-Chirasil-Val capillary column.
(11) Kagan, H. B.; Fiaud, J . C. Topics Stereochem. 1988, 18, 250-
265.
(5) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; pp 214-295.

6278 J . Org. Chem., Vol. 66, No. 19, 2001
Kamin´ski et al.
Ta ble 1. Op tica lly Active Am id es a n d Dip ep tid es 6-12, Obta in ed in th e Con d en sa tion Med ia ted by Ch ir a l Tr ia zin e
Cou p lin g Rea gen ts 3a -c, P r ep a r ed in Situ fr om Ach ir a l CDMT (1) a n d Ch ir a l Ter tia r y Am in es 2a -cf
carboxylic
component
amine
product
yield [%]
[R]
config
DL/LL or D/L
s
1
2
3
4
5
6
7
8
9
10
11
12
13
14
rac-5a
rac-5a
rac-5a
rac-5a
rac-5a
rac-5a
rac-5a
rac-5b
rac-5c
rac-5c
rac-5d
rac-5d
rac-5e
rac-5a
2a
2b
2c
2a
2c
2a
2b
2a
2a
2b
2a
Z-D-Ala-NH-Ph (6)
Z-D-Ala-NH-Ph (6)
Z-L-Ala-NH-Ph (6)
82
81.5
85
82
75
87
84
77
76
72
69
80
-
+36.3 (c ) 1.5, EtOH)
+23.0 (c ) 0.9, EtOH)
-36.1 (c ) 1.0, EtOH)
+23.8 (c ) 0.9, EtOH)
-23.1 (c ) 1.2, EtOH)
-
D
D
L
98/2a
98
79/21a
2/98a
5.5
104
98
Z-D-Ala-Gly-OEt (7)
Z-L-Ala-Gly-OEt (7)
Z-D-Ala-L-Ala-OMe (8)
Z-D-Ala-L-Ala-OMe (8)
Z-D-Leu-NH-Ph (9)
Boc-D-Leu-Gly-OEt (10)
Boc-D-Leu-Gly-OEt (10)
Z-L-Phe-NH-Ph (11)
Z-L-Phe-L-Ala-OMe (12)
C4H9CH(C2H5)COOEt (18)
Z-DL-Ala-NH-Ph (6)
D
L
98/2a
10/90a
98/2b
14.4
109
4.2
16.8
11.6
1.6
6.8
195
-
D
D
D
D
D
L
-
85/15b
91/9a
+42.5 (c ) 1, CHCl3)
+26.6 (c ) 1.0, EtOH)
+10.9 (c ) 1.0, EtOH)
-3.7 (c ) 1, CHCl3)
-
1.1 (c ) 1, EtOH)
0.05 (c ) 1.5, EtOH)
88/12a
59/41a
16/84a
1/99c
2a
L
2e
S
DL
42/58d
50/50a
NMMe
93
0
a
Enantiomer composition of hydrolysate has been determined by GC on Permabond L-Chirasil-Val (25m × 0.25 mm capillary column).
Diastereomer ratio determined by 13C NMR: average from diagnostic signals of CH3 and CH. c Diastereomer ratio determined by HPLC
b
(Vydac C-18; acetonitrile/water). Enantiomer ratio determined by GC on CP-Chirasil-Dex (25m × 0.25 mm capillary column). e NMM )
d
N-methylmorpholine. f A twofold excess of racemic substrates rac-5a -d was used in all experiments.
Sch em e 3
in the range described in the literature11 for kinetic
resolutions. Moreover, in the case of Z-Ala-OH, the same
range of values was found throughout the whole family
of reactions involving acylation of broad variety of
substrates by the same acylating intermediate 4a . Thus,
for the activation of racemic Z-Ala-OH (5a ) by CDMT in
the presence of strychnine (2a ) the s parameter reaches
value in the range 98-109.
However, the enantiomeric enrichment calculated from
the HPLC diastereomeric composition of dipeptide 12
showed that the presence of an additional chiral center
in the amino component affects the purity of diastereo-

Enantiodifferentiating Coupling Reagents
J . Org. Chem., Vol. 66, No. 19, 2001 6279
meric products,12 substantially enhancing D/L ratio from
16/84 (entry 11) to, DL/LL ) 1/99 (entry 12). This means
that diastereoselection accompanying coupling of two
chiral substrates cannot be abandoned (at least in some
cases) in the interpretation of enrichment process.
Many questions arise concerning the mechanism or
reactions affording this efficient enantiodiscrimination.
It seems enantiodiscrimination proceeds in two succes-
sive stages. In the first, the chiral triazinylammonium
chloride (3a -c) equilibrates13 rapidly with racemic car-
boxylate anion to yield two diastereomeric ion-pairs
14a -c and 15a -c (Scheme 3).
In the next reaction step, ion-pairs 14a -c and 15a -c
form transition state diastereomeric addition products
16a -c and 17a -c and then yield enantiomerically
enriched triazine esters 3a -c when the chiral auxiliary
departs. Therefore, if the process proceeds in these two
successive stages, in all experiments involving preference
for the same enantiomer in both stages, relatively high
stereoselectivities are expected, but respectively low in
all cases of unmatched enantiomeric preference.
It is noteworthy that the chiral auxiliary departs after
the activation step, affording real acylating species,
triazines 4a -e, identical with the intermediates in the
typical activation of carboxylic acids with the triazine
condensing reagent.14
capillary column (25 m × 0.25 mm, film 0.25 µm), carrier-gas
- nitrogen; pressure - 90 kPa.
Strychnine and brucine have been purchased from BDH,
and (-)-sparteine from Aldrich, and have been used without
further purification.. Acetonitrile, Baker - HPLC grade, has
been used for analytical purposes.
En a n tiod iffer en tia tin g Cou p lin g. Gen er a l P r oced u r e.
To the vigorously stirred solution of CDMT (1.76 g; 10 mmol)
in THF (20 mL), cooled to 0 °C, was added chiral amine (10
mmol), and after 30 min, the resulting suspension was treated
with the appropriate racemic carboxylic acid (20 mmol). The
stirring was continued for additional 30 min, amino component
(11 mmol) was added, and the mixture was left for an
additional 2 h at 0 °C and overnight at room temperature. The
solvent was evaporated under reduced pressure, and the
residue dissolved in ethyl acetate (30 mL) was then washed
successively with water, 1 M aqueous HCl, water, 1 M aqueous
NaHCO3, and water again. The organic layer was dried with
MgSO4, filtered, and concentrated to dryness. The residue was
dried in a vacuum desiccator under P2O5 and KOH, affording
appropriate neutral products. This preparation has been used
in all further studies without any additional purification.
Hyd r olysis of Am id es a n d Dip ep tid es to Am in o Acid .
Gen er a l P r oced u r e. Amide or peptide (5 mg) was treated
with redistilled, constant boiling HCl in the sealed tube at 103
°C for 20 h. The solution was concentrated to dryness, and
the residue was dissolved with redistilled water and concen-
trated again. This procedure was repeated twice. Remaining
salt was dried overnight in a vacuum desiccator under P2O5
and then treated with anhydrous methanol saturated with HCl
(2 mL) for 4 h at room temperature. Methanol was evaporated,
and the residue was suspended in dichloromethane and treated
with trifluoroacetic acid anhydride (50 µL) for 12 h at room
temp. The solution was analyzed on a Chirasil-Val capillary
column (25m × 0.25 mm); split 1:50; helium as carrier-gas has
been used.
Cou p lin g of Z-DL-Ala -OH (r a c-5a ) w ith An ilin e by
Mea n s of CDMT (1) in th e P r esen ce of Str ych n in e (2a ).
CDMT (1.76 g; 10 mmol) in THF (20 mL) was treated with 2a
(3.34 g; 10 mmol) at 0 °C, and after 30 min rac-5a (4.46 g; 20
mmol) was added followed by addition of aniline (1.1 mL, 11
mmol). Synthesis was performed under standard conditions
yielding Z-D-Ala-NH-Ph (2.45 g, 82%); mp 136-138 °C. 1H
NMR (CDCl3) δ ) 1.46 (d, 3H, J ) 7 Hz); 4.40 (q, 1H, J ) 7
Hz); 5.14 (AB system, 2H, J ) 12 Hz); 5.19 (d, 1H, J ) 7.5
Hz); 7.00-7.70 (m 10H); 8.29 (broad s, 1H). GC: hydrolysate
was derivatized according to standard procedure: chromatog-
raphy conditions: 80 °C, 4°/min. tR ) 2.66 (D-Ala); tR ) 2.89
(L-Ala); D/L ) 98/2.
Con clu sion s
The above approach based on the in situ preparation
of enantiodifferentiating coupling reagents from readily
accessible precursors is of general synthetic utility. It has
been successfully applied in the synthesis of optically
active amides, esters, and dipeptides.
Two (2a and 2c) of three common chiral amines 2a -c
has been found to serve as useful chiral auxiliaries.
Bearing in mind easy modification of the structure of
triazine condensing reagents,15 as well as easy access to
a broad range of other chiral tertiary amines, the present
approach provides an access to tailor-made combinations
of a binary system of substrates most suited for the
configuration needed in any synthetic goal.
Recover y of Excess of Z-Ala -OH (5a ). The crude prepa-
ration obtained after the coupling step was concentrated to
dryness, and the remaining residue was partitioned between
ethyl acetate (50 mL) and water (20 mL). The organic layer
was washed with saturated aq NaHCO3 solution (4 × 30 mL).
Aqueous phases were combined, washed with ethyl acetate,
acidified with 5 N HCl to pH 1, and then extraced with ethyl
acetate (3 × 20 mL). Combined organic extracts were dried
and concentrated to dryness. The residue was dried in a
vacuum desiccator, affording Z-L-Ala-OH (2.14 g; 96%); mp 81-
Exp er im en ta l Section
Gen er a l. HPLC: C-18, 250 mm column, detection 220 nm,
gradient acetonitrile/water (0.1%TFA). GC: FID (H2/air); split
1:50; Chirasil-Val capillary column (25 m × 0.25 mm) carrier-
gas - helium; pressure - 135 kPa, and CP Chirasil-Dex CB;
(12) Preference for isotactic (LL/DD) diastreomer was observed in
the coupling of racemic Z-Phe-OH with racemic H-Ala-OMe by means
of CDMT in the presence of NMM.
(13) Kamin´ski, Z. J .; Darski, S. Presented at the XLII Annual
Meeting of Polish Chemical Society, Rzeszow, Poland, Sep 7-8, 1999;
p 60.
82 °C, lit.16 mp 81.5-82.5 °C. [R]20 -14.3 (c ) 4.3; AcOH).
D
GC: hydrolysate was derivatized according to standard pro-
cedure: chromatography conditions: 60 °C, 4°/min. tR ) 4.54
(L-Ala); D/L ) 2/98.
(14) (a) Kaminski, Z. J . Int. J . Pept. Protein Res. 1994, 43, 312-
319. (b) Taylor, E. C.; Dowling, J . E. J . Org. Chem. 1997, 62, 1599-
1603. (c) Kuciauskas, D.; Lindell, P. A.; Hung, S.; Lin, S.; Stone, S.;
Seely, G. R.; Moore, A. L.; Moore, T. A.; Gust, D. J . Phys. Chem. 1997,
101, 429-440. (d) Svete, J .; Mateja, A.-R.; Branko, S. J . Heterocycl.
Chem. 1997, 34, 177-193. (e) Cronin, J . S.; Ginah, F. O.; Murray, A.
R.; Copp, J . D. Synth. Commun. 1996, 26, 3491-3494. (f) Kiec´-
Kononowicz, K.; Cegła, M. T. Pharmazie 1998, 53, 518-521. (g) Masala,
S.; Taddei, M. Org. Lett. 1999, 1, 1355-1357 and refs cited therein.
(15) (a) Kamin´ski, Z. J .; Kolesin´ska, B. 26th EPS, Montpellier, Sep
10-15, 2000. J . Pept. Sci. 2000, supplement to vol. 6, 96. (b) Kamin´ski,
Z. J .; Markowicz, S. W.; Kolesin´ska, B.; Martynowski, D.; Gło´wka, M.
L. Synth. Commun. 1998, 28, 2689-2696. (c) Kamin´ski, Z. J .; Koles-
in´ska, B.; Markowicz, S. W.; Pokrzeptowicz, K. Pol. J . Chem. 1999,
73, 1965-1968.
Syn t h esis of St a n d a r d Z-L-Ala -NH -P h (6). Enantio-
merically homogeneous Z-L-Ala-NH-Ph was obtained from Z-L-
Ala-OH (2.23 g, 10 mmol) CDMT (1.76 g, 10 mmol), and NMM
(1.1 mL, 10 mmol) under standard procedure.4 After crystal-
lization from ethyl acetate/petroleum ether, Z-L-Ala-NH-Ph
(2.48 g, 83%) was obtained. Mp 159-160 °C, [R]24 -37.0 (c )
D
1, EtOH); lit.17 tt)161-162 °C; [R]24D -37.0 (c ) 1, EtOH). 1H
NMR (CDCl3) δ ) 1.46 (d, 3H, J ) 7 Hz); 4.40 (q, 1H, J ) 7
(16) Wipf, P.; Heimgartner, H. Helv. Chim. Acta 1988, 71, 140-
154.
(17) Abernethy, J . L. Tetrahedron 1975, 31, 2659-2662.

6280 J . Org. Chem., Vol. 66, No. 19, 2001
Kamin´ski et al.
Hz); 5.14 (AB system, 2H, J ) 12 Hz); 5.19 (d, 1H, J ) 7.5
Hz); 7.00-7.70 (m 10H); 8.29 (broad s, 1H). GC: hydrolysate
was derivatized according to standard procedure: chromatog-
raphy conditions: 80 °C, 4°/min. tR ) 2.89 (L-Ala).
conditions: temperature: 60 °C, 4 °C/min. tR ) 4.43 (D-Ala);
tR ) 4.53 (L-Ala); D/L ) 10/90.
Cou p lin g of Z-DL-Ala -OH (r a c-5a ) w ith H-L-Ala -OMe‚
HCl by Mea n s of CDMT (1) in th e P r esen ce of Str ych -
n in e (2a ). CDMT (0,352 g; 2 mmol) in THF (20 mL) was
treated under standard conditions4 with 2a (0.789 g; 2 mmol)
at 0 °C, and after 30 min rac-5a (0.892 g; 4 mmol) was added
followed by addition of H-L-Ala-OMe‚HCl (0.307 g, 2.2 mmol)
and triethylamine (0.306 mL; 2.2 mmol). Z-D-Ala-L-Ala-OMe
(0.536 g) was obtained in 87% yield; mp106-107 °C. 1H NMR
(DMSO) δ ) 1.26 (d, 3H, J ) 7 Hz); 1.33 (d, 3H, J ) 8 Hz);
3.60 (s, 3H); 4.07 (q, 1H, J ) 8 Hz); 4,24 (q, 1H, J ) 7 Hz);
5.02 (AB system, 2H, J ) 10 Hz); 7,44 (broad s, 5H); 8,26 (d,
1H, J ) 7 Hz). 13C NMR (DMSO) diagnostic for Z-Alav-Alaw-
Cou p lin g of Z-DL-Ala -OH (r a c-5a ) w ith An ilin e by
Mea n s of CDMT (1) in th e P r esen ce of Br u cin e (2b).
CDMT (0,352 g; 2 mmol) in THF (20 mL) was treated with 2b
(0.789 g; 2 mmol) at 0 °C, and after 30 min rac-5a (0.892 g; 4
mmol) was added followed by addition of aniline (0.220 mL,
2.2 mmol). Synthesis was performed under standard conditions
yielding Z-D-Ala-NH-Ph (0.486 g, 82%); mp 137-138 °C. 1H
NMR (CDCl3) δ ) 1.45 (d, 3H, J ) 7 Hz); 4.36 (q, 1H, J ) 7
Hz); 5.14 (AB system, 2H, J ) 12 Hz); 5.41 (d, 1H, J ) 7 Hz);
7.00-7.70 (m, 10H); 8.26 (broad s, 1H). GC: hydrolysate was
derivatized according to standard procedure: chromatography
conditions: temperature: 60 °C, 4 °C/min. tR ) 4.32 (D-Ala);
tR ) 4.45 (L-Ala); D/L ) 79/21.
Cou p lin g of Z-DL-Ala -OH (r a c-5a ) w ith An ilin e by
Mea n s of CDMT (1) in th e P r esen ce of Sp a r tein e (2c).
CDMT (0,352 g; 2 mmol) in THF (20 mL) was treated with 2c
(0.234 g; 1 mmol) at 0 °C, and after 30 min rac-5a (0.892 g; 4
mmol) was added followed by addition of aniline (0.220 mL,
2.2 mmol). Synthesis was performed under standard conditions
yielding Z-L-Ala-NH-Ph (0.507 g, 85%); mp 136-138 °C.
1H NMR (CDCl3) the same as the standard of Z-L-Ala-NH-
Ph.
w
OMe: heights of signals for DL, δ ) 17.82 (CH3)DL +19.14
v
w
v
v
(CH3)DL +48.56 (CH)DL +50.55 (CH)DL + 171.99 (CO)DL
+
173.08 (CO)DLw/heights of signals for LL, δ ) 17.48 (CH3)LL
+
w
18.79 (CH3)LLv +48.23 (CH)LLw +50.84 (CH)LLv +172.70 (CO)LL
v
w
+ 172.81 (CO)LL ) 98:2.
Cou p lin g of Z-DL-Ala -OH (r a c-5a ) w ith H-L-Ala -OMe‚
HCl by Mea n s of CDMT (1) in th e P r esen ce of Br u cin e
(2b). CDMT (0,352 g; 2 mmol) in THF (20 mL) was treated
under standard conditions with 2a (0.789 g; 2 mmol) at 0 °C,
and after 30 min rac-5a (0.892 g; 4 mmol) was added followed
by addition of H-L-Ala-OMe (0.307 g, 2.2 mmol) and triethyl-
amine (0.306 mL; 2.2 mmol). Z-D-Ala-L-Ala-OMe (0.518 g) was
GC: hydrolysate was derivatized according to standard
procedure: chromatography conditions: temperature: 80 °C,
4 °C/min. tR ) 2.62 (D-Ala); tR ) 2.75 (L-Ala); R/ S)2/98.
Coupling of Z-DL-Ala-OH (rac-5a) with H-Gly-OEt.HCl by
Means of CDMT (1) in the Presence of strychnine (2a).
CDMT (0,352 g; 2 mmol) in THF (20 mL) was treated under
standard conditions with 2a (0.789 g; 2 mmol) at 0 °C and after
30 min rac-5a (0.892 g; 4 mmol) was added followed by
addition of H-Gly-OEt‚HCl (0.307 g, 2.2 mmol) and triethyl-
amine (0.306 mL; 2.2 mmol). Z-D-Ala-Gly-OEt (0.567 g) was
obtained in 92% yield; mp 98-99 °C. 1H NMR (CDCl3) δ )
1.29 (t, 3H, J ) 7 Hz); 1.42 (d, 3H, J ) 7.5 Hz); 4.02 (d, 2H, J
) 5 Hz); 4.22 (q, 2H, J ) 6.5 Hz); 5.25 (AB system, 2H, J ) 10
Hz); 5.18 (broad s, 1H); 6.47 (broad s, 1H); 7.30-7.35 (m, 5H).
GC: hydrolysate was derivatized according to standard pro-
cedure: chromatography conditions: temperature: 60 °C, 4
°C/min. tR ) 4.32 (D-Ala); D/L ) 98/2.
1
obtained in 84% yield; mp115-116 °C. H NMR (DMSO) δ )
1.175 (d, 3H, J ) 7 Hz); 1.21 (d, 3H, J ) 6 Hz); 3.60 (s, 3H);
4.23 (q, 1H, J ) 7 Hz); 4,49 (q, 1H, J ) 6 Hz); 5.07 (AB system,
2H, J ) 10 Hz); 7,34 (broad s, 5H); 8,26 (d, 1H, J ) 7 Hz). 13C
NMR (DMSO) diagnostic for Z-Alav-Alaw-OMe: heights of
w
v
signals for DL, δ ) 17.15 (CH3)DL +18.48 (CH3)DL +47.57
w
v
v
w
(CH)DL +49.89 (CH)DL 171.34 (CO)DL + 172.42 (CO)DL
/
w
v
heights of signals for LL, δ ) 16.90 (CH3)LL + 18.13 (CH3)LL
w
v
v
+47.90 (CH)LL +50.18 (CH)LL +172.02 (CO)LL + 172.15
w
(CO)LL ) 85:15.
Cou p lin g of Z-DL-Leu -OH (r a c-5b) w ith An ilin e by
Mea n s of CDMT (1) in th e P r esen ce of Str ych n in e (2a ).
CDMT (0.352 g; 2 mmol) in THF (10 mL) was treated with 2a
(0.789 g; 2 mmol) at 0 °C, and after 30 min rac-5b (1.061 g; 4
mmol) was added followed by addition of aniline (1.1 mL, 2.2
mmol). Synthesis was performed under standard conditions,
yielding Z-D-Leu-NH-Ph (0.524 g, 77%); mp 133-134 °C. 1H
NMR (CDCl3) δ ) 0.96 (d, 6H, J ) 7.5 Hz); 1.56-1.81 (m, 3H);
4.31 (q, 1H, J ) 5 Hz); 5.17 (AB system, 2H, J ) 10 Hz); 7.06-
7.49 (m, 10H,); 8.19 (broad s, 1H). GC: hydrolyzate was
derivatized according to standard procedure: chromatography
conditions: temperature: 60 °C, 4 °C/min. tR ) 9.02 (D-Leu);
tR ) 9.19 (L-Leu); D/L ) 91/9.
Syn th esis of Op tica lly P u r e Z-L-Leu -NH-P h (9). Z-L-
Leu-OH (2.65 g, 10 mmol) was activated with CDMT (1.76 g;
10 mmol) in THF (20 mL) in the presence of NMM (1.10 mL,
10 mmol) under standard procedure4 and then treated with
aniline (10 mL, 10 mmol), yielding Z-L-Leu-NH-Ph (2.68 g,
82%). mp 135-136 °C; [R]25D -23.9 (c ) 1, CHCl3). Literature20
mp 138-141 °C; [R]25D -47.6 (c ) 2, CHCl3).211H NMR (CDCl3)
δ ) 0.95 (d, 6H, J ) 6 Hz); 1.56-1.81 (m, 3H); 4.32 (q, 1H, J
) 5 Hz); 5.10 (AB system, 2H, J ) 9 Hz); 5.28 (d, 1H, J ) 7.5
Hz); 7.06-7.19 (m, 10H); 8.19 (broad s, 1H). GC: hydrolysate
was derivatized according to standard procedure: chromatog-
raphy conditions: temperature: 60 °C, 4 °C/min. tR ) 9.19 (L-
Leu).
Standard of optically pure Z-L-Ala-Gly-OEt (7).
Z-L-Ala-OH (0.446 g, 2 mmol) was activated with CDMT
(0.358 g, 2 mmol) in THF (10 mL) in the presence of NMM
(0.22 mL, 2 mmol) under standard procedure,4 then treated
with H-Gly-OEt.HCl (0,279 g, 2 mmol) and NMM (0.22 mL, 2
mmol) yielding Z-L-Ala-Gly-OEt (0.573 g, 93%). Mp 99-100
°C; [R]D25 -24.1 (c ) 1, EtOH); lit.18 mp)95-96 °C; [R]25D -23.8
(c ) 1, EtOH).191H NMR (CDCl3) δ ) 1.29 (t, 3H, J ) 6.5 Hz);
1.41 (d, 2H, J ) 7 Hz); 4.20 (dAB system, 2H, J ) 5.2 Hz);
4.21 (q, 2H, J ) 6.5 Hz); 4.24 (q, 1H, J ) 7 Hz); 5.12 (AB
system, 2H, J ) 8 Hz); 7.36 (broad s, 5H). GC: hydrolysate
was derivatized according to standard procedure: chromatog-
raphy conditions: temperature: 60 °C, 4 °C/min. tR ) 4.53 (L-
Ala).
Cou p lin g of Z-DL-Ala -OH (r a c-5a ) w ith H-Gly-OEt‚HCl
by Mea n s of CDMT (1) in th e P r esen ce of Sp a r tein e (2c).
CDMT (0,352 g; 2 mmol) in THF (20 mL) was treated with 2c
(0.234 g; 1 mmol) at 0 °C, and after 30 min rac-5a (0.892 g; 4
mmol) was added followed by addition of H-Gly-OEt‚HCl
(0.307 g, 2.2 mmol) and triethylamine (0.306 mL; 2.2 mmol).
Synthesis was performed under standard conditions yielding
Z-L-Ala-Gly-OEt (0.462 g, 75%); mp 108-109 °C. 1H NMR
(CDCl3) δ ) 1.28 (t, 3H, 7,5 Hz); 1.44 (d, 3H, J ) 10 Hz); 4.02
(d, 2H, J ) 5 Hz); 4.27 (q, 2H, J ) 7,5 Hz); 4.30 (q, 1H, J )
7,5 Hz); 5.11 (AB system, 2H, J ) 10 Hz); 5.18 (broad s, 1H);
6.54 (broad s, 1H); 7.33 (broad s, 5H). GC: hydrolysate was
derivatized according to standard procedure: chromatography
Cou p lin g of Boc-DL-Leu -OH (r a c-5b) w ith H-Gly-OEt‚
HCl by Mea n s of CDMT (1) in th e P r esen ce of Str ych -
n in e (2a ). CDMT (0.352 g; 2 mmol) in THF (10 mL) was
treated with 2a (0.789 g; 2 mmol) at 0 °C, and after 30 min
rac-5b (0.925 g, 4 mmol) was added followed by addition of
H-Gly-OEt‚HCl (0.307 g, 2.2 mmol) and triethylamine (0.306
mL; 2.2 mmol). Synthesis was performed under standard
conditions yielding Boc-D-Leu-Gly-OEt (0.481 g, 76%); mp
(18) Bertno, J . N.; Loffet, A.; Pinel, C.; Reuther, F.; Sennyey, G.
Tetrahedron Lett. 1991, 32, 1303-1306.
(19) Takeda, K.; Saweda, I.; Suzuki, A.; Ogura, H. Tetrahedron Lett.
1983, 24, 4451-4454.
(20) Fox, S. W.; Wax, H. J . Am. Chem. Soc. 1950, 72, 5087-5089.
(21) Siemion, I. Z. Roczn. Chem. 1969, 43, 513-518.

Enantiodifferentiating Coupling Reagents
J . Org. Chem., Vol. 66, No. 19, 2001 6281
103-104 oC. Literature22 mp 96-98 °C; [R]25 -34.1 (c ) 1,
(0.22 mL, 2 mmol), yielding Z-L-Phe-L-Ala-OMe (0.631 g, 82%).
D
EtOH).231H NMR (CDCl3) δ ) 0.95 (d, 6H, J ) 5 Hz); 1.28 (t,
3H, J ) 7 Hz); 1.49 (s, 9H); 1.56-1.76 (m, 3H); 4.03 (d, 2H, J
) 6 Hz); 4.18 (q, 2H, J ) 7 Hz); 4.90 (broad s, 1H); 6.67 (broad
s, 1H). GC: hydrolyzate was derivatized according to standard
procedure: chromatography conditions: temperature: 60 °C,
4 °C/min. tR ) 9.02 (D-Leu); tR ) 9.19 (L-Leu); D/L ) 88/12.
Cou p lin g of Boc-DL-Leu -OH (r a c-5b) w ith H-Gly-OEt‚
HCl by Mea n s of CDMT (1) in th e P r esen ce of br u cin e
(2b). CDMT (0.352 g; 2 mmol) in THF (10 mL) was treated
with 2b (0.789 g; 2 mmol) at 0 °C, and after 30 min rac-5b
(0.925 g, 4 mmol) was added followed by addition of H-Gly-
OEt.HCl (0.307 g, 2.2 mmol) and triethylamine (0.306 mL; 2.2
mmol). Synthesis was performed under standard conditions
yielding Boc-D-Leu-Gly-OEt (0.456 g, 72%); mp 111-112 °C.
1H NMR (CDCl3) δ ) 0.93 (d, 6H, J ) 5 Hz); 1.25 (t, 3H, J )
7 Hz); 1.46 (s, 9H); 1.55-1.73 (m, 3H); 4.04 (d, 2H, J ) 6 Hz);
4.18(q, 2H, J ) 7 Hz); 4.89 (broad s, 1H); 6.66 (broad s, 1H).
GC: hydrolysate was derivatized according to standard pro-
cedure: chromatography conditions: temperature: 60 °C, 4
°C/min. tR ) 9.02 (D-Leu); tR ) 9.19 (L-Leu); D/L ) 59/41.
Cou p lin g of Z-DL-P h e-OH (r a c-5d ) w ith An ilin e by
Mea n s of CDMT (1) in th e P r esen ce of Str ych n in e (2a ).
CDMT (0,352 g; 2 mmol) in THF (20 mL) was treated with 2a
(0.789 g; 2 mmol) at 0 °C, and after 30 min rac-5d (1.197 g; 4
mmol) was added followed by addition of aniline (0.220 mL,
2.2 mmol). Synthesis was performed under standard condi-
tions, yielding Z-L-Phe-NH-Ph (0.517 g, 69%); mp 165-167 °C.
1H NMR (CDCl3) δ ) 3.23 (dd, 2H, J ) 5 Hz); 4.52 (q, 1H, J )
5 Hz); 5.10 (AB system, 2H, J ) 11 Hz); 5.42 (broad s, 1H);
7.09-7.33 (m, 15H). GC: hydrolysate was derivatized accord-
ing to standard procedure: chromatography conditions: tem-
perature: 100 °C, 4 °C/min. tR ) 10.85 (D-Phe); tR ) 10.97 (L-
Phe); D/L ) 16/84.
mp 104-106 °C; [R]25 -23.3 (c ) 1.2, EtOH); lit.25 mp )96-
D
97 °C; lit.26 [R]25D -24 (c ) 1, EtOH). 1H NMR (CDCl3) δ)1.33
(d, 3H, J ) 7 Hz); 3.08 (dd, 2H, J ) 7 Hz); 3.71 (s, 3H); 4.47
(q, 1H, J ) 7 Hz); 4.80 (t, 1H, J ) 7 Hz); 5.09 (AB system, 2H,
J ) 10 Hz); 7.17-7.35 (m, 10H). HPLC: tR ) 22.74 min.
Syn t h esis of Op t ica lly H om ogen eou s Z-L-P h e-D-Ala -
OMe (LD-12). Z-L-Phe-OH (0.597 g, 2 mmol) was activated
with CDMT (0.358 g, 2 mmol) in THF (10 mL) in the presence
of NMM (0.22 mL, 2 mmol) under standard procedure and then
treated with H-D-Ala-OMe‚HCl (0,279 g, 2 mmol) and NMM
(0.22 mL, 2 mmol), yielding Z-L-Phe-D-Ala-OMe (0.615 g, 80%).
mp 119-121 °C; [R]25 +4.0 (c ) 1.1, EtOH). Literature27 mp
D
116-117 °C; [R]25D -1 (c ) 1, MeOH). 1H NMR (CDCl3) δ)1.21
(d, 3H, J ) 7 Hz); 3.06 (dd, 2H, J ) 7.7 Hz); 3.71 (s, 3H); 4.44
(q, 1H, J ) 7 Hz); 4.47 (t, 1H, J ) 7.7 Hz); 5.09 (AB system,
2H, J ) 10 Hz); 6.18 (d,1H, J ) 7.5 Hz); 7.21-7.35 (m, 10H).
HPLC: tR ) 23.44 min.
Eth yl 2-Eth ylh exa n oa te (18). (a) Activation: CDMT (0.88
g, 5 mmol) was dissolved in THF (20 mL) and treated with
strychnine (2a ) (1.67 g, 5 mmol) for 0.5 h at 0 °C, and then
rac-2-ethylhexanoic acid (1.59 mL, 10 mmol) in THF (20 mL)
was added dropwise. The solution was stirred at 0 °C for
additional 5 h, concentrated to dryness, and then partitioned
between dichloromethane and water. The organic layer was
washed successively with ice-cold water, 1 M NaHSO4, brine,
0.5N aq NaHCO3, and brine again and dried with MgSO4,
filtered, and concentrated to dryness, yielding 2-(2-ethyl-
hexanoyloxy)-4,6-dimethoxy-1,3,5-triazine (4e) (1.23.g, 87%) as
1
a pale yellow oil. H NMR (CDCl3) δ) 0.84 (t, 3H, J ) 7 Hz);
1.00 (t, 3H, J ) 12 Hz); 1.10-1.95 (m, 8H); 2.45 (q, 1H, J ) 7
Hz), 4.01 (s, 6H). IR (film): 1780 cm-1 (CdO).
(b) Alcoholysis: 2-(2-ethylhexanoyloxy)-4,6-dimethoxy-1,3,5-
triazine (376 mg, 1.33 mmol) was dissolved in ethanol (5 mL)
and stirred for 3 days at r.t. in according to standard prepara-
Syn th esis of Op tica lly Hom ogen eou s Z-L-P h e-NH-P h
(11). Z-L-Phe-OH (2.99 g, 10 mmol) was activated with CDMT
(1.76 g; 10 mmol) in THF (20 mL) in the presence of NMM
(1.10 mL, 10 mmol) under standard procedure and then
treated with aniline (10 mL, 10 mmol) yielding Z-L-Phe-NH-
tive procedure.7 [R]23 +1.1 (c ) 1, EtOH), lit.28 for (R)-ethyl
D
2-ethylhexanoate [R]25 -3.38 (neat); n15 ) 1.4179 29GLC
D
D
(Chirasil-Dex CB; 25 m; 100 f 200 °C, 4 °C/min); tR ) 10.32
(58%); tR ) 10.44 (42%); R/S)42/58.
Ph (3.07 g, 82%). mp 167-169 °C; lit24 mp 169-170 °C; [R]25
D
1
-3.7 (c ) 3, CHCl3). H NMR (CDCl3) δ ) 3.21 (dd, 2H, J )
(c) Hydrolysis to 2-ethylhaxanoic acid: 2-(2-ethylhexanoyl-
oxy)-4,6-dimethoxy-1,3,5-triazine (4e) (376 mg, 1.33 mmol) was
dissolved in ethanol (5 mL) and immediately treated with 1
N NaOH (5 mL) for 2 h at room temperature. Solution is
diluted with water (5 mL), treated with NaHSO4 to pH 1, and
extracted with dichloromethane. Collected organic phases were
dried (MgSO4), and the solvent was evaporated under reduced
pressure affording a pale yellow oil (125 mg, 65%). [R]23D +2.40
(c ) 0.52, CHCl3). Literature30 for (S)-2-ethylhexanoic acid
[R]20 +3.2 (c ) 3.3, CHCl3). n25 )1.4229.28 GLC (Chirasil-
5.5 Hz); 4.55 (q, 1H, J ) 5 Hz); 5.12 (AB system, 2H, J ) 9
Hz); 5.49 (broad s, 1H); 7.09-7.33 (m, 15 H). GC: hydrolysate
was derivatized according to standard procedure: chromatog-
raphy conditions: 80 °C, 4°/min. tR ) 15.03 (L-Phe).
Cou p lin g of Z-DL-P h e-OH (r a c-5d ) w ith H-L-Ala -OMe‚
HCl by Mea n s of CDMT (1) in th e P r esen ce of Str ych -
n in e (2a ). CDMT (0,352 g; 2 mmol) in THF (20 mL) was
treated under standard conditions with 2a (0.789 g; 2 mmol)
at 0 °C, and after 30 min rac-5d (1.197 g; 4 mmol) was added
followed by addition of H-L-Ala-OMe (0.307 g, 2.2 mmol) and
triethylamine (0.306 mL; 2.2 mmol). Z-L-Phe-L-Ala-OMe (0.615
g) was obtained in 80% yield; mp114-116 °C. 1H NMR (CDCl3)
δ ) 1.32 (d, 3H, J ) 7,2 Hz); 3.10 (dd, 2H, J ) 7 Hz); 3.74 (s,
3H); 4.46 (q, 1H, J ) 7.2 Hz); 4,56 (t, 1H, J ) 7 Hz); 5.08 (AB
system, 2H, J ) 10 Hz); 5.36(d,1H,J ) 6.75 Hz); 6.40 (d, 1H,
J ) 5,75 Hz); 7.20-7.34 (m, 10H). HPLC: gradient 35:40%B,
25 min, tR ) 22.69 min. (Z-L-Phe-L-Ala-OMe/Z-D-Phe-L-Ala-
OMe)>99/1.
D
D
Dex CB; 25 m; 100 f 200 °C, 4 °C/min.); tR ) 14.06; tR ) 14.30,
R/S ) 66:34. Coinjection with racemic sample: GLC (Chirasil-
Dex CB; 25 m; 100 f 200 °C, 4 °C/min); tR ) 13.96; tR ) 14.21.
Ack n ow led gm en t. The study was supported by the
Polish State Committee for Scientific Research under
the Project 3 T09A 029 16.
J O0101499
Syn th esis of Op tica lly Hom ogen eou s Z-L-P h e-L-Ala -
OMe (LL-12). Z-L-Phe-OH (0.597 g, 2 mmol) was activated
with CDMT (0.358 g, 2 mmol) in THF (10 mL) in the presence
of NMM (0.22 mL, 2 mmol) under standard procedure and then
treated with H-L-Ala-OMe‚HCl (0,279 g, 2 mmol) and NMM
(25) Krasobrizhii, N. Ya.; Scholudenko, L. I.; Kovalenko, L. G. J .
Org. Chem. 1975, 11, 300-303.
(26) Katoh, A.; Ohkanda, J .; Itoh, Y.; Mitsuhashi, K. Chem. Lett.
1992, 10, 2009-2012.
(27) Nicolaides, E.; DeWald, H.; Westland, R.; Lipnik, M.; Posler,
J . J . Med. Chem. 1968, 11, 74-79.
(22) Pasaribu, S. J . Aust. J . Chem. 1980, 33, 2427-2440.
(23) Odake, S.; Nakahashi, K.; Morikawa, T.; Takebe, S.; Kobashi,
K. Chem. Pharm. Bull. 1992, 40, 2764-2768.
(24) Anderson, G. W.; Blodinger, J .; Young, R. W.; Welcher, A. D.
J . Am. Chem. Soc. 1952, 74, 5304-5309.
(28) Levene; P. S.; Rothen; L.; Meyer, J . J . Biol. Chem. 1936, 115,
405-411.
(29) Kenyon; J .; Young, D. P. J . Chem. Soc. 1940, 216-218.
(30) Larcheveque, M., et al. J . Organomet. Chem. 1979, 177, 5-15.