First stereoselective synthesis of potassium aeschynomate and its no-natural stereomers

Article abstract of DOI:10.1016/j.tet.2005.11.051

The synthesis of potassium aeshynomate and its non-natural stereomers was achieved using the Sharpless catalytic asymmetric dihydroxylation of (Z) or (E) vinylogous glycine as the key step. The resulting γ-amino α,β-dihydroxyester stereomer was deprotected and coupled with the caffeic acid to afford stereoselectively potassium aeshynomate or its stereomers. A detailed study of the NMR data of the different stereomers is reported that corrects the literature data.

Full text of DOI:10.1016/j.tet.2005.11.051

Tetrahedron 62 (2006) 1787–1798
First stereoselective synthesis of potassium aeschynomate
and its no-natural stereomers
a
Stephanie Claudel, Tomasz Krzysztof Olszewski, Pierre Mutzenardt, Christie Aroulanda,
b
c
c
´
Philippe Coutrota and Claude Grisonb,
*
a
´ ´ ´
Laboratoire de Chimie Organique Biomoleculaire, UMR 7565, Universite Henri Poincare, Nancy 1,
` ´
BP 239, 54506 Vandoeuvre-les-Nancy cedex, France
b
´
Laboratoire de Chimie Biomoleculaire, UMR 5032, ERT 5, 8 rue de l’Ecole Normale, 34296 Montpellier, France
c
´
´
´
`
´
Laboratoire de Methodologie RMN, UMR 7565, Universite Henri Poincare, Nancy 1, BP 239, 54506 Vandoeuvre-les-Nancy cedex, France
Received 19 October 2005; revised 17 November 2005; accepted 21 November 2005
Available online 20 December 2005
Abstract—The synthesis of potassium aeshynomate and its non-natural stereomers was achieved using the Sharpless catalytic asymmetric
dihydroxylation of (Z) or (E) vinylogous glycine as the key step. The resulting g-amino a,b-dihydroxyester stereomer was deprotected and
coupled with the caffeic acid to afford stereoselectively potassium aeshynomate or its stereomers. A detailed study of the NMR data of the
different stereomers is reported that corrects the literature data.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
These authors have established that the diol entity of 1
possessed the anti-relation on the basis of a variety of NMR
techniques.1 Nonetheless, the absolute stereochemistry of
the natural molecule was not assigned.
Recently, potassium aeshynomate 1 was identified as a leaf-
opening substance in a nyctinastic plant, Aeshynomene
indica L. Among the different bioactive molecules that
control the leaf-movement of Leguminosae plants, 1 was
found to be a new type of leaf-opening substances. Efforts
have been realized by Yamamura and co-workers to isolate
potassium aeshynomate 1 in small quantities from
Aeshynomene indica L. and to determinate the correspon-
ding structure (Fig. 1).
In the present work, we report the first stereoselective
syntheses of 1 and its three stereomers in the order to obtain
practically and conveniently these potent ‘clean’ herbicide
compounds and to confirm the structure of the isolated
natural compound.
2. Results and discussion
OH
OH
Retrosynthetically, potassium aeshynomate can be devised
into the two components caffeic acid and an appropriate
a,b-dihydroxy-g-aminoester 3 (Scheme 1). The synthetic
design of the chiral part was based on an initial
stereoselective Horner reaction for the elaboration of the
a,b-unsaturated-g-aminoester precursor 5 followed by the
Sharpless asymmetric dihydroxylation (SAD) of
the ethylenic double bond using the AD-mix system.2 The
stereoselective olefination–SAD sequence allows theoreti-
cally an enantioselective syn or anti diastereocontrol. In this
paper, we use the designation syn/anti to differentiate the
pairs of diastereomers, but a difficulty arises for a simple
appellation of the different enantiomers, since the absolute
configuration of the natural product is unknown and cannot
serve of reference. Thus, for facilitating the discussion, we
CH3
OH
OK
O
N
H
H
OH
O
Figure 1. Potassium aeshynomate 1.
Keywords: Potassium aeshynomate; Vinylogous peptides; Aminoalde-
hydes; Horner reaction; Asymmetric dihydroxylation; Natural product.
Corresponding author. Tel./fax: C33 467 144342;
e-mail: cgrison@univ-montp2.fr
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.051

1788
S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
OH
OH
OH
OH
OH
OH
H3C OH
COOR2
H3C OH
H3C OH
OK
COOR2
+
O
N
H2N
O
N
H
O
OH
H
OH
O
O
OH
OH
O
Caffeic acid
2a β-anti 2b α-syn
2b β-syn
1α-syn
3b α-syn
3b β-syn
3b α-anti
3b β-anti
3a β-anti
1β-syn
1α-anti
1β-anti
2b α-anti
2b β-anti
H3C OH
R1
COOR2
R1
R1
N
CH3
COOR2
N
N
O
H
H
H
H
O
OH
5bE
5bZ
5aZ
4a β-anti 4b α-syn
6a
6b
4b β-syn
4b α-anti
4b β-anti
a: R1= Boc and / or R2= Et
b: R1= Z and / or R2= t-Bu
Scheme 1. Retrosynthetic analysis.
Me
N
R1
(i)
R1
(ii), (iii)
R1
OH
H
N
OMe
N
N
H
H
O
H
O
O
6a,R1 = Boc
6b,R1 = Z
Scheme 2. Synthesis of Boc or Z-glycinal 6a,b: (i) (MeO)NHMe$HCl, BOP, Et3N, CH2Cl2, rt, 2 h, 85%; (ii) LiAlH4 1 M/Et2O, O 8C, 20 min; (iii) KHSO4/H2O.
assign a or b to the enantiomeric diols 4 which are prepared
respectively from AD-mix-a or AD-mix-b.2
phosphate (BOP) as coupling reagent. The reduction of
the N0-methoxy-N0-methylamide led to a lithium salt
intermediate which was stabilized by intramolecular
complexation. The desired aldehyde 6a,b was obtained
upon hydrolysis of the reaction mixture in excellent yield
(82, 85% overall yields, respectively) (Scheme 2).
Two approaches were studied. The first strategy used ethyl
g-N-Boc-amino-a,b-dihydroxy ester 4ab-anti as the chiral
intermediate precursor but was unsuccessful as a result of a
surprising fragility of the carboxamide bond, especially
during the basic hydrolysis of the ester 2ab-anti in the last
step of the reaction sequence. Although this approach
brought useful information concerning the stability of the
potassium aeschynomate and its precursors in basic or
acidic medium, this excluded the use of a ethyl ester
protecting group that needed a basic deprotection step.
Thus, a synthetic plan using protecting groups cleavable by
acidolysis (t-butyl ester) and hydrogenolysis (Z-NH group)
was adopted in the second successfully approach using
t-butyl g-N-Z-amino-a,b-dihydroxy esters 4b as the chiral
intermediate precursors.
On the basis of our previous works concerning the syntheses
of vinylogous peptides,4 the lithium anion derived from
ethyl 2-diethylphosphonopropanoate reacted with the
N-Boc-glycinal 6a to afford stereoselectively the unsatu-
rated ethyl ester 5a. Similarly, the lithium anion derived
from t-butyl 2-diethylphosphonopropanoate reacted with
the N-Z-glycinal 6b to provide stereoselectively the
unsaturated t-butyl ester 5b (Scheme 3).
Me
COOR
R1
(i)
R1
H
The starting compounds N-protected glycinal 6a and 6b
were prepared according to the method of Castro et al. in
which a Weinreb amide derived from a N-Boc aminoacid
is reduced with lithium aluminium hydride.3 The N-t-
butyloxycarbonyl glycine N0-methoxy N0-methylamide and
N-benzyloxycarbonyl glycine N0-methoxy N0-methylamide
were prepared by reaction between the Boc or Z-glycine
and O,N-dimethylhydroxylamine hydrochloride, respect-
ively, in the presence of triethylamine and benzotriazol-
1-yloxytris(dimethylamino)phosphonium hexafluoro
N
2
N
H
H
O
5aE / 5aZ
5bE / 5bZ
6a
6b
R1 = Boc R2 = Et
R1 = Z R2 = t-Bu
Scheme 3. Preparation of the vinylogous ethyl glycinate 5a and t-Butyl
glycinate 5b: (i) (EtO)2P(O)CHLiCOOEt, THF or (EtO)2P(O)CHLiCOOt-
Bu, THF, respectively.

S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
1789
Pure Z or E vinylogous glycine derivatives 5a or 5b
necessary for the different syntheses of the stereomers of
potassium aeschynomate were easily obtained after a
chromatographic separation.
substrates. Thus, we studied successively the osmium-
catalyzed asymmetric dihydroxylation of the trisubstituted
vinylogous glycine derivative 5aZ, using the commercially
available ‘AD-mix b’ that afforded 4ab-anti. Similarly, 5bE
should lead to 4ba-syn or its enantiomer 4bb-syn, using
the commercially available ‘AD-mix a’ or ‘AD-mix b’
respectively, whereas 5bZ should provide 4ba-anti or its
enantiomer 4bb-anti, using the same reagents. The
enantiomeric excesses of the different stereomers 4a,b
were evaluated by NMR analysis of the corresponding
Mosher ester derivatives 7a,b/70a,b. They were confirmed
by NMR analysis of the diasteromers 8a/80a and 8b/80b
produced by coupling the carboxylic acid issued from 4a
with H-Phe-OBn and by coupling the carboxylic acid issued
from 4b with H-Leu-OMe, respectively (Scheme 4,
Table 2).
It was noted that the nature of the N-protecting group
combined with the steric hindrance of the phosphonate have
a marked effect on the stereoselectivity of the olefination. Z
selectivity could be obtained with the N-Boc-glycinal 6a
and ethyl 2-diethylphosphonoacetate,4 whereas a E pre-
ference was observed with N-Z-glycinal 6b and the lithiated
t-butyl 2-diethylphosphonopropanoate (Table 1).
The following step of the strategy was the construction of
the diol entity via the Sharpless catalytic asymmetric
dihydroxylation2 of pure Z or E vinylogous glycine deriv-
ative 5. Recent works relate the asymmetric dihydroxylation
of trans-1,2-disubstituted g-amino-a,b-unsaturated ester
derivatives,5 but, to our knowledge, no reports concern
the asymmetric dihydroxylation of E- and Z-trisubstituted
Dihydroxylation was very slow. However, the 5bZ
derivative underwent dihydroxylation faster (48 h) than
the 5bE stereomer (192 h).
Table 1. Preparation of the vinylogous alkyl Z- or E-glycinate 5b and 5a from aminoaldehyde 6
6
Horner reagent
Reaction conditions
5 (Yield %)
Z/Ea
6a
6b
(EtO)2P(O)CHLiCOOEt
(EtO)2P(O)CHLiCOOt-Bu
3 h at K78 8C/hydrolysis at K78 8C
3 h at K78 8C/hydrolysis at K78 8C
1.5 h at K78 8C/hydrolysis at K78 8C
0.75 h at K78 8C/hydrolysis at K78 8C
1 h at K78 8C/0.75 h at 20 8C/hydrolysis at K78 8C
5a (63%)
5b (60%)
5b (40%)
5b (40%)
5b (60%)
86/14
55/45
40/60
48/62
20/80
1
a Z/E ratio was determined by H NMR on the crude product.
CH3
CH3 OH
R1
a: R1 = Boc R2 = Et
b: R1 = Z R2 = t-Bu
OR2
R1
(i)
COOR2
NH
NH
O
OH
4a β-anti
4b α-syn
5aZ
5bE
5bZ
4b β-syn
4b β-anti
4b α-anti
(v), (vi)
b
(ii)
(iii), (iv)
a
CH3 OH
O
R1
CH3 OH
OR2
Z
NH
NH
OMe
NH
O
O
O
OH
Ph
OMe
O
8b/8'b
CF3
7a/7'a
7b/7'b
O
CH3 OH
Boc
NH
OBn
NH
O
OH
Bn
8a/8'a
Scheme 4. Asymmetric dihydroxylation of vinylogous glycine derivatives 5aZ, 5bE or 5bZ: (i) AD-mix a or AD-mix b, MeSO2NH2, t-BuOH/H2O; (ii) (S)-
MTPA-Cl/pyridine/CH2Cl2, 25 8C, 2 days; (iii) NaOH/EtOH/H2O; (iv) H-Phe-OBn$HCl, Et3N, BOP, CH2Cl2, 25 8C, 2 h; (v) TFA, 25 8C, 30 mn; (vi) H-Leu-
OMe$HCl, Et3N, BOP, CH2Cl2, 25 8C, 2 h.

1790
S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
Table 2. Asymmetric dihydroxylation of vinylogous glycine derivatives 5aZ, 5bE or 5bZ
5
Reaction conditions
4a
eeb (Yield%)c
61 (83)
7
de (yield %)c
60 (72)
8
de (Yield %)c
62 (85)
7a/70a b-anti
8a/80a b-anti
5aZ
AD-mix-b t-BuOH/H2O, 0 8C,
MeSO2NH2/72 h
4a b-anti
7b/70b a-syn
7b/70b b-syn
7b/70b a-anti
7b/70b b-anti
8b/80b a-syn
8b/80b b-syn
8b/80b a-anti
8b/80b b-anti
5bE
5bE
5bZ
5bZ
AD-mix-a t-BuOH/H2O, 0 8C,
MeSO2NH2/192 h
AD-mix-b t-BuOH /H2O, 0 8C,
MeSO2NH2/192 h
AD-mix-a t-BuOH /H2O, 0 8C,
MeSO2NH2/48 h
AD-mix-b t-BuOH /H2O, 0 8C,
MeSO2NH2/48 h
4b a-syn
4b b-syn
4b a-anti
4b b-anti
22 (85)
9 (82)
24 (69)
8 (70)
20 (80)
10 (82)
30 (85)
62 (82)
29 (90)
61 (85)
28 (72)
60 (68)
a Major product.
b ee is deduced from the average between the two values of de.
c Yields after chromatographic purification.
In the case of 5bE the reaction rate can be compared
favourably with the SAD of trans-1,2-disubstituted
g-amino-a,b-unsaturated ester (168 h), being done the
trisubstitution of the double bond in 5bE.5 Surprisingly,
the yields were even better. The transformation of the diols
4a,b into the Mosher esters 7a,b/70a,b was also slow and
was stopped after 48 h, leading to 7a,b/70a,b accompanied
with approximately 30% of the starting compound 4a,b. In
these conditions the estimation of the enantiomeric excesses
was questionable, as kinetic resolution could arise with one
of the two enantiomers of 4a,b. Therefore a second method
based on the transformation of 4a,b into dipeptides 8a,b/
80a,b was tested. After hydrolysis of the ethyl ester 4a with
NaOH or cleavage of the t-butyl ester of 4b with pure TFA,
the resulting acid was coupled with respectively H-Phe-OBn
hydrochloride or H-Leu-OMe hydrochloride in the presence
of BOP as coupling reagent. After 2 h, the reaction was
complete and led to the desired dipeptide diastereomers
8a,b/80a,b in high yield after a chromatographic
purification.
hydrogenolysis into 4b, the resulting crude ethyl amino-
a,b-dihydroxy ester 3ab-anti hydrochloride or t-butyl
amino-a,b-dihydroxy ester 3ba-syn, 3bb-syn, 3ba-anti, or
3bb-anti, was coupled with caffeic acid using BOP as
coupling reagent to provide the corresponding product 2a
or b in good yields (Scheme 5).
In the first approach,6 the hydrolysis of the ethyl ester
moiety of 2ab-anti to obtain the desired product 1ab-anti
was the last troublesome step. The monitoring by TLC of a
stirred mixture of KOH/MeOH, 1 M (1 equiv) and 2ab-anti
dissolved in MeOH/THF (1/2) indicated a complete
disappearance of the starting compound after 30 min.
After a classical acidic treatment of the aqueous phase at
pHZ4 and successive extractions with ether and dichloro-
methane, the 1H and 13C NMR analyses of the crude product
allowed to identify caffeic acid and the g-aminoacid 9.
Similar NMR analyses of the product issued from the
organic phase revealed the presence of the lactame 10 which
formally resulted from a cyclization of the g-aminoester
3ab-anti (Scheme 6).
Beforehand, the ratio of the so-obtained diastereomers 8a/
1
80a and 8b/80b was determined by H NMR on the crude
Thus, the amide bond presented an unusual fragility, being
hydrolysed concurrently to the ethyl ester group in a basic
medium. A hydrogen bond between the C]O of the amide
and one of the neighbouring OH (or a aromatic OH via an
intermolecular H-bond) can favour this hydrolysis by
electrophilic assistance (Fig. 2a). Another possible expla-
nation is a mechanism where the nitrogen of the amide at
the g-C relatively to the ethyl ester involves a easy
intramolecular cyclisation into lactame 10 and makes
product and compared to the Mosher esters ratio. The results
accorded and shown that kinetic resolution did not probably
arise. However, the enantiomeric excesses were modest.
AD-mix-b and 5aZ, 5bZ gave the best result (in the 60% ee
range), while 5bE olefin revealed the much poorest
substrate.
After removal of Boc in 4ab-anti by bubble of gaseous
HCl in anhydrous ether or removal of
Z
by
OH
OH
H3C OH
H3C OH
R1
OR2
OR2
ii
i
N
H2N
H
O
OH
4a β-anti
O
OH
H3C OH
OR2
3b α-syn
3b β-syn
3b α-anti
3b β-anti
O
N
3a β-anti
4b α-syn
4b β-syn
4b α-anti
4b β-anti
H
OH
O
2b α-syn (67%)a
2b β-syn (70%)a
2b α-anti (75%)a
2b β-anti (80%)a
2a β-anti (73%)a
a: R1 = Boc R2 = Et
b: R1 = Z R2 = t-Bu
Scheme 5. Deprotection of 4 and coupling with caffeic acid: (i) 4ab-anti: bubble of gaseous HCl in anhydrous ether provided 3ab-anti,HCl; 4b: H2 (30 bars),
Pd/C 10%, MeOH, 20 8C, 12 h; (ii) caffeic acid, Et3N, BOP, DMF, 25 8C, 2 h; Yield of purified products from 4.
a

S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
1791
OH
OH
OH
OH
OH
OH
O
H3C
OH
O
CH3
H3C
HO
KOH / MeOH (1M)
OH
OEt
+
+
H2N
O
O
N
H
MeOH / THF
(1 / 2)
30 min, rt
HO H
O
OH
HO
N
H
H
2a β-anti
Scheme 6. Break of the amide bond in basic medium.
Caffeic acid
9
10
O
O
(a)
O
(b)
O
H
H
O
O
H
Caffeic acid + 9 + 10
2a β-anti
O
N
H
OH
CH3
O
NH
O
H
O
CH3
OH
EtO
OH
O
H
OEt
2a β-anti
Figure 2. The hydrogen bonding between C]O of the amide bond and the neighbouring OH favours the hydrolysis of the amide link (a). Concerted
mechanism (b).
simultaneous hydrolysis easier for the amide bond in a fully
concerted mechanism (Fig. 2b).
decreased reactivity was not sufficient to insure the
complete stability of the amide link in the basic medium.
With the aim to remove the possible H-bond assistance to
the amide hydrolysis, a novel synthesis similar to that
described above to obtain 2ab-anti was then carried out to
obtain 12 with a complete protection of OH. Starting from
the commercially available 3,4-dimethoxycinnamic acid,
the compound 12 was obtained as described in Scheme 7.
Indeed, the steric hindrance was also responsible of the
difficult hydrolysis of the methyl ester moiety of 13, so that
both slow hydrolyses of the methyl ester and the amide
occurred competitively.
Thus, it seems particularly difficult to carry out a
chimioselective basic hydrolysis of ethyl or methyl ester
without a competitive hydrolysis of the amide bond in the
case of the structures 2ab-anti and 12.
The saponification of ethyl ester 12 was attempted in the
same precedent conditions that for 2ab-anti. A transes-
terification into the methyl ester 13 was only observed after
30 min at rt. A prolonged reaction time shown a slow
hydrolysis of the methyl ester intermediate 13 into
3,4-dimethoxycinnamic acid and aminoacid 14 until 72 h
when the amide bond was entirely hydrolysed (Scheme 8).
As a result, the chemoselective acidic hydrolysis of the ethyl
ester moiety of 2ab-anti was studied. In a previous work we
describe the use of trimethylbromosilane in methanol to
hydrolyse a isopropyl ester linked to a tri-substituted
hindered carbon bearing notably a tertiary alcohol.7
However, whatever the different attempts using various
amounts of Me3SiBr onto 2ab-anti, only a partial
transesterification into the corresponding methyl ester was
observed. No trace of the expected acid was detected,
Consequently, the absence of a free OH or the steric
hindrance of the ketal moiety involves a cleanly reduced
rate of the amide bond hydrolysis and can explain this
relative decrease of the amide reactivity. However, this
OMe
OMe
OMe
OMe
OMe
OMe
OMe
BOP / Et3N / DMF
85 %
OMe
OH
O
APTS / MeOH
72 %
H3C
OH
O
H3C
Cl
H3N
H3C
OEt
OEt
OEt
O
N
O
OH
O
N
H
H
HO
O
O
O
HO
H
H
H
3a β-anti
Scheme 7. Preparation of the ethyl ester 12 with protected OH.
11
12

1792
S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
OMe
OMe
O
H3C
KOH / MeOH (1M)
13
OMe
OMe
MeOH / THF
(1 / 2)
30 min, rt
O
N
OMe
H
O
O
H
100 %
O
H3C
OEt
O
N
H
OMe
O
O
OMe
OH
H
O
H3C
12
OH
14
KOH / MeOH (1M)
+
H2N
MeOH / THF
(1 / 2)
72 h, rt
O
O
H
O
Scheme 8. Basic hydrolysis of ethyl ester 12.
neither hydrolysis of the amide bond. As the molecule
2ab-anti was difficult to dissolve in another solvent than
methanol or THF, a classical hydrolysis with a 1 N aqueous
solution of sulphuric acid (2 equiv) in THF (3 mL) was also
realized, but unsuccessfully, the starting compound being
recovered.
OH
OH
OH
OH
i,ii
H3C OH
OK
H3C OH
Ot-Bu
O
N
H
O
N
H
Consequently, the study of the second strategy using
precursors with a t-Bu ester protection such as stereomers 2b
was justified by the possible releasing of the carboxylic acid in
acidic medium which could preserve the amide bond.
Nevertheless, the removal of the t-Bu ester into 2b revealed
also troublesome.
O
OH
OH
O
[α]D22= -6.2b
[α]D22= +1.7b
[α]D22= -4.0b
1 α-syn (95%)a
1 β-syn (95%)a
1 α-anti (93%)a
2b α-syn
2b β-syn
2b α-anti
2b β-anti
[α]D22= +5.0b
1 β-anti (98%)a
This t-Bu ester 2b presented, as the potassium aeschynomate
1, a low solubility in most of the used solvents and was
practicallyonlysolubleinMeOHorTHF,thatcomplicatedthe
different attempts. A degradation occurred when 2b was
treated with formicacid.8 The treatment of 2bwithMe3SiBr in
MeOH only yielded the corresponding methyl ester (100%
yield). Other attempts using a bubble of gaseous HCl in ether/
THF or in ether in the same conditions that those used for the
removal of Boc did not succeed. It has to be noted that similar
difficulties in the hydrolysis of t-Bu ester have been
mentioned.9 Finally, the reaction of 2 with neat trifluoroacetic
acid for 30 min at 25 8C succeeded and led to the expected
carboxylic acid (100% yield). A subsequent treatment of the
acid with a titrated solution of MeOK in MeOH (0.13 M,
1 equiv) yielded the potassium salt 1. It was noted that this last
step required a careful control to avoid the cleavage of the
carboxamide bond (Scheme 9).
Scheme 9. Removal of the t-butyl ester of 2b and preparation of the
stereomers of potassium aeschynomate 1: (i) TFA, 25 8C, 30 min; (ii)
MeOK/MeOH (0.13 M, 1 equiv), 25 8C, 5 mn; ayield of purified product
from 2; b[a]2D2 (c 0.24, 50% MeOH aq.).
chemical shifts of stereomers are the consequence of the
necessity of a change of solvent for the NMR analysis.
The reader is referred to the Figure 3 for the structure and
numeration of the hydrogens and carbons into 1 and 2. The
hydrogens are labeled the same the carbon they are linked
to, in particular the two diastereotopic hydrogens bounded
to the carbon 40 are noted H4 a and H4 b hereafter.
0
0
The structures of the four stereomers 1 were assigned from
their NMR data and from their comparison with the NMR
data of the natural potassium aeshynomate. Assignments
have been made on all the stereomers synthesized using 1H,
and 13C 1D experiments, 1H–1H 2D COSY, 1H–13C gradient
enhanced inverse HSQC and HMBC experiments. Due to
the fragility of the carboxamide group, HMBC experiments
are a valuable tool for establishing the connectivity between
the caffeyl and the a,b-dihydroxy-g-aminoacid moieties in
the carboxylate compounds 1.
NMR studies of 1 and 2 were carried out at 400 MHz. The
solvents (MeOH-d4/D2O: 1/1 or MeOH-d4) and the
concentration (c 0.24) were chosen for a sake of comparison
with the results reported in Ref. 1 However, the potassium
salts 1 revealed weakly soluble in MeOH-d4/D2O: 1/1 or
D2O, even at 35 8C, contrary to the data of Yamamura et al.1
This observed little solubility has constituted a real
difficulty in this study, particularly with the diastereomers
syn. Sometimes, the small differences observed in the
1
A small J-correlation between the 13C carbonyl and the H
methylene group 40 through the NH group allows to
demonstrate the existence of this amide link.

S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
1793
OH
OH
4
4
H
H
OH
H
H
OH
5
5
3
3
2
2
6
6
H
H
H
H
1
1
β
β
5'
5'
HO
HO
H
H
Me
Me
H
H
α
H
α
H
Me
Me
OK
O
Me
3'
2'
3'
4'
HO
2'
4'
HO
O
N
H
O
N
H
1'
1'
H
O
H
O
1
2
Figure 3. Schemes and generic cartbon and hydrogen labels of diols 1 and 2.
1
Table 3. H and 13C NMR chemical shifts (d, ppm) of 1
0
0
0
H5
H3
H4
Ha
Hb
H2
H5
H6
1a-syna
1b-synb
1a-antia
1b-antib
3.73
3.74
3.80
3.82
3.34
3.23
3.43
3.37
4.25
1.48
1.47
1.37
1.36
1.40
6.41
6.45
6.40
6.44
6.35
7.38
7.38
7.36
7.37
7.60
7.01
7.09
7.02
7.08
6.95
6.76
6.85
6.75
6.84
6.85
6.90
7.02
6.88
7.00
7.02
Natural aeschynomateb 4.03
0
0
0
0
0
C5
C1
C2
C3
C4
C(O)NH
Ca
Cb
C1
C2
C3
C4
C5
C6
1a-syna
1b-synb
1a-antia
1b-antib
181.8
76.0
42.7
42.5
42.9
42.5
66.5
23.4
23.4
23.3
23.5
23.3
169.8
169.3
170.0
170.0
170.3
118.2 142.3 128.1 115.5 148.9 148.9 117.2 122.3
118.6 142.7 128.1 115.5 145.3 147.9 117.1 123.2
118.6 142.3 128.2 115.1 147.0 149.9 116.6 122.3
118.5 142.0 128.5 115.5 145.7 147.9 117.0 123.0
115.3 147.0 127.9 115.9 145.4 148.3 117.1 123.5
181.8 78.0
181.9 77.7
181.5 78.0
75.5
76.1
75.5
74.3
Natural aeschynomatec 181.3 77.6
a Solvent: MeOH-d4.
b Solvent: MeOH-d4/D2O:1/1.
c D2O (See Ref. 1).
As it can be observed in Table 3, the NMR chemical shifts
of the different stereomers 1 are very close, and it is difficult
to differentiate the diastereomers 1-syn and 1-anti in 1H and
13C NMR. All chemical shifts are in a good agreement with
those of the natural potassium aeshynomate described by
The detailed study of the NMR data has been hence
made more likely on the t-butyl ester precursors 2b
(Table 4). These compounds are indeed slightly more
soluble than the salts 1 and their spectra present a best
resolution. HSQC and HMBC experiments show also
clearly the link between the two moieties caffeic acid
and a,b-dihydroxy-g-amino ester. In these cases, it is
noteworthy that the identification of the diastereomers
2-syn and 2-anti can be easily established by NMR from
0
Yamamura except for the chemical shifts of C4 and H4
0
which are practically identical in the case of the four
products 1 prepared by us from four different syntheses, and
cleanly different from the values reported by Yamamura.
The corresponding assignments have been safely deter-
0
the resonance signals of H4 a which are cleanly different
0
mined using HSQC and HMBC correlations with both H4 ,
0
and with H3 respectively.
in MeOH-d4 or MeOH-d4/D2O: 1/1 (3.72 ppm for 2-syn,
3.54 for 2-anti).
1
Table 4. H and 13C NMR chemical shifts (d, ppm) of 2
0
0
0
0
H5
2
H3
H4a
H4b
C(CH3)3
Ha
Hb
H2
H5
H6
2a-syna
2b-syna
2a-antia
2b-antib
3.88
3.88
3.82
3.82
3.72
3.72
3.54
3.54
3.21
3.21
3.23
3.25
1.34
1.34
1.39
1.34
1.48
1.48
1.50
1.45
6.40
6.40
6.38
6.38
7.39
7.39
7.38
7.40
7.00
7.00
6.99
7.00
6.75
6.75
6.75
6.75
6.90
6.90
6.89
6.90
0
0
0
0
0
C5
C1
C2
C3
C4
C(Me)3
C(CH3)3 C(O)NH Ca
Cb
C1
C2
C3
C4
C5
C6
2a-syna
2b-syna
175.9 78.3
175.9 78.3
75.6
75.6
75.6
74.4
42.2
42.2
42.8
41.6
22.6
22.6
23.2
22.1
83.2
83.2
83.5
82.6
28.3
28.3
28.3
27.2
169.9
169.9
169.8
168.8
118.5 142.5 128.4 115.2 146.8 148.9 117.2 122.3
118.5 142.5 128.4 115.2 146.8 148.9 116.6 122.3
118.6 142.4 128.5 115.2 146.8 148.9 116.6 122.2
117.3 141.5 127.3 114.1 147.5 147.8 115.5 121.2
2a-antia 175.7 77.8
2b-antib 174.7 76.7
a Solvent: MeOH-d4.
b Solvent: MeOH-d4/D2O: 1/1.

1794
S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
In conclusion, the synthetic way leading to the natural
isomer can be deduced from the known stereochemical
added Et3N (3.86 g, 38.2 mmol), benzotriazol-1-yloxytris
(dimethylamino)phosphonium hexafluorophosphate (BOP)
(16.9 g, 38.2 mmol) and N,O-dimethylhydroxylamine
hydrochloride (4.1 g, 42.02 mmol). The mixture was stirred
for 5 min and an extra portion of Et3N (w1 equiv) was
added to obtain pH 9–10. The reaction was stirred for 2 h
and then diluted with 50 mL of CH2Cl2 before phase
separation. The organic phase was washed with 3 M HCl aq.
(3!15 mL) and aq. NaCl sat. (1!20 mL) then with aq.
NaHCO3 sat. (3!15 mL) and aq. NaCl sat. (3!20 mL).
The organic layer was dried over MgSO4. After evaporation
the resulting oil was purified by chromatography (Hexane/
EtOAc 2:1) to give the pure product as a white solid, 8.20 g,
85%, mp 75–78 8C, Rf (0.33 Hexane/EtOAc 1:1). 1H NMR
(250 MHz, CDCl3) 7.36 (s, 5H, Ph), 5.56 (m, 1H, NH), 5.14
(s, 2H, CH2Ph), 4.15 (d, 2H, JZ4.3 Hz, NH–CH2), 3.72 (s,
3H, N–OCH3), 3.21 (s, 3H, N–CH3). 13C/{1H} NMR
(62.9 MHz, CDCl3) 170.0 (CO–N–OMe), 155.7
(CO–NH), 136.2 (Ph), 128.6 (Ph), 128.4 (Ph), 128.3 (Ph),
67.1 (Ph–CH2–O), 61.2 (N–OCH3), 41.4 (NH–CH2), 31.9
(N–CH3). IR (cmK1) 3310, 1715, 1660.
0
0
relationship anti of both C2 –OH and C3 –OH into the
natural compound and from the comparison between the
specific rotations measured for the products 1a-syn, 1b-syn,
1a-anti, or 1b-anti and that of the natural compound ([a]D22
K3.39 c 0.24, 50% MeOH aq.).1 Data of Table 3 cleanly
indicate the compound 1a-anti ([a]2D2 K4.0 c 0.24, 50%
MeOH aq.), which presents the nearest specific rotation, as
being the stereomer corresponding to the natural potassium
aeschynomate. Consequently, the asymmetric dihydroxy-
lation of the ‘cis’-vinylogous glycine derivative precursor
5bZ with the system AD-mix-a appears as the correct
combination to obtain the natural potassium aeshynomate.
Thus, the structure of the potassium aeschynomate which
has been established by Yamamura et al. from NMR and
SM spectroscopic data is confirmed by the syntheses of the
natural compound and its three no-natural stereomers.
However, the absolute chemistry of these different
stereomers remains a problem to be studied, since the
stereomers or their precursors described here have not
crystallised and therefore X-ray analysis has not been
possible.
3.1.2. N-Benzyloxycarbonyl-glycinal 6b. To a solution of
N-benzyloxycarbonyl glycine N0-methoxy-N0-methylamide
(3.5 g, 14.0 mmol) in dry THF (65 mL) at 0 8C was added
drop wise a 1 M ethereal solution of lithiumaluminium
hydride (14.0 mL, 14.0 mmol) during 25 min. The reaction
was stirred for additional 20 min at 0 8C and quenched by
aq. KHSO4 (3.74 g in 15 mL H2O) followed by extraction
with CH2Cl2 (3!30 mL). The organic layer was then
washed with 3 N HCl (3!15 mL), aq. NaCl sat. (1!
10 mL), aq. NaHCO3 (3!15 mL) and aq. NaCl sat. (3!
15 mL). The organic layer was dried over MgSO4. After
evaporation a resulting colourless oil was obtained, 2.27 g,
85%, Rf (0.42 AcOEt/Hexane 1:1). The crude product was
used in further transformations. 1H NMR (250 MHz
CDCl3): 9.67 (s, 1H, CHO), 7.37 (s, 5H, Ph), 5.45 (m, 1H,
NH), 5.15 (s, 2H, CH2–Ph), 4.17 (d, 2H, JZ4.8 Hz,
NH–CH2). 13C (62.9 MHz, CDCl3) 196.5 (CHO), 158.1
(NH–CO), 136.3 (Ph), 128.7 (Ph), 128.5 (Ph), 128.3 (Ph),
67.4 (CH2–Ph), 51.8 (NH–CH2). IR (cmK1) 3320, 1725,
1690.
3. Experimental
3.1. General
NMR experiments were recorded on Bruker spectrometers
(AC 250, AM 400, DRX 400) and internal references used
were TMS when available (1H NMR, 13C NMR), CCl3F
(19F NMR) or H3PO4 (31P NMR). The NMR signals of the
solvent, methanol-d4, have been used as internal reference
for the calibration of the spectra for the compounds
generically labeled 1 and 2 (3.30 ppm for the remaining
–CD2H resonance in proton, and 49.15 ppm in C-13 for the
seven-lines CD3 for the methanol-d4 whenever used).
Inverse experiments have been recovered on a Bruker
DRX 400 equipped with a 5 mm TBI-Z probe. Chemical
shifts are reported in d ppm values and J values in
1
Hertz (Hz). Isomer ratios were determined by H NMR
and 19F NMR on the crude products. IR spectra were
recorded on a Nicolet 210 FT-IR spectrometer, nmax are
given in cmK1. Mass spectra (EI) were obtained with a
Waters 2615 Micromass/zq spectrometer. Merck silica gel
60 (230–400 mesh) was used as stationary phase for column
chromatography. TLC (Merck Kieselgel 60, F254) were
viewed on UV light or with the Cifonelli and Smith reagent
for the diol structures: (a) 0.1% aq. solution of sodium
metaperiodate; (b) solution of benzidine (1.8 g of benzidine,
50 mL H20, 50 mL EtOH, 20 mL of acetone and 10 mL
0.2 M aq. HCl; diols gave a white spot.10 Melting points
were measured in a capillary tube on Electrothermal IA
9000. Optical rotations were measured on a Perkin-Elmer
241 polarimeter. All reactions were carried out under
nitrogen atmosphere. All solvents were purified prior to use
using the standard techniques.
3.1.3. t-Butyl-4-[(benzyloxycarbonyl)amino]-2-methyl-2-
butanoate 5bZ, 5bE. To a solution of t-butyl 2-diethylphos-
phonopropanoate (2.93 g, 11.0 mmol) in dry THF (50 mL)
at K78 8C was added drop wise n-BuLi 1.4 M sol. in hexane
(8.0 mL). The reaction was stirred at this temperature for
30 min and N-benzyloxycarbonyl-glycinal 6 in 10 mL THF
was added (2.08 g, 11.0 mmol). The reaction mixture was
stirred for 3 h at K78 8C and then hydrolysed with 25 ml aq.
NH4Cl sat. The phases were separated and the aqueous
phase was extracted with Et2O (3!20 mL). The organic
phases were combined, dried over MgSO4 and evaporated to
give a yellow syrup which was purified by flash
chromatography (Hexane/EtOAc 7:1), 1.97 g, 60%, 5bZ:
1
Rf (0.48 EtOAc/Hexane 2:1), H NMR (250 MHz, CDCl3)
7.36 (s, 5H, Ph), 5.94 (t, 1H, JZ6.3 Hz, CHZC(CH3)), 5.12
(s, 2H, PhCH2), 4.10 (t, 2H, JZ6.4 Hz, NH–CH2), 1.87 (s,
3H, CH]C(CH3)), 1.50 (s, 9H, C(CH3)3), 13C/{1H} NMR
(62.9 MHz, CDCl3) cis 168.4 (COOt-Bu), 158.1 (NH–CO),
137.6 (CH]), 135.3 (]C(CH3)), 128.6 (Ph), 128.4 (Ph),
128.2 (Ph), 80.9 (C(CH3)3), 67.4 (Ph–CH2), 39.0
3.1.1. N-Benzyloxycarbonyl glycine N0-methoxy-N0-
methylamide. To a solution of Z-glycine (8.0 g,
38.2 mmol) in dry CH2Cl2 (25 mL) at room temp. were

S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
1795
1
(NH–CH2), 28.3 (C(CH3)3), 20.4 (C(CH3)). 5bE: Rf (0.39
EtOAc/Hexane 2:1), H NMR (250 MHz, CDCl3): 7.36 (s,
[a]2D2 K4.0 (c 0.4 CH2Cl2). H NMR (250 MHz, CDCl3)
7.36 (s, 5H, Ph), 5.08–5.22 (m, 1H, NH), 5.11 (s, 2H,
Ph–CH2), 3.65–3.77 (m, 1H, CH2CH), 3.49 (s, 1H, OH),
3.42–3.56 (m, 1H, NH–CH2), 3.12 (ddd, 1H, JZ13.9, 9.1,
4.0 Hz, NH–CH2), 2.42 (m, 1H, OH), 1.52 (s, 9H, C(CH3)3),
1.43 (s, 3H, C(CH3)).
1
5H, Ph), 6.55 (t, 1H, JZ6.5 Hz, CH]C(CH3)), 5.12 (s, 2H,
PhCH2), 4.85 (m, 1H,NH–CH2), 3.95 (m, 2H, NH–CH2),
1.82 (s, 3H, CH]C(CH3)), 1.48 (s, 9H, C(CH3)3), 13C/{1H}
NMR (62.9 MHz, CDCl3) trans 166.8 (COOt-Bu), 156.4
(NH–CO), 136.4 (CH]), 131.1 (]C(CH3)), 128.5 (Ph),
128.1 (Ph), 126.9 (Ph), 80.5 (C(CH3)3), 66.8 (Ph–CH2), 39.3
3.2.4. t-Butyl-4-[N-(benzyloxycarbonyl)amino]-2,3-di-
hydroxy-2-methyl butanoate 4b. b-anti. White solid,
1.31 g, 85%, Rf 0.21 (EtOAc/Hexane 1:2), [a]2D2 C9.5 (c
0.4 CH2Cl2). 1H NMR (250 MHz CDCl3) 7.36 (s, 5H, Ph),
5.08–5.22 (m, 1H, NH), 5.11 (s, 2H, Ph–CH2), 3.65–3.77
(m, 1H, CH2CH), 3.49 (s, 1H, OH), 3.42–3.56 (m, 1H,
NH–CH2), 3.12 (ddd, 1H, JZ13.9, 9.1, 4.0 Hz, NH–CH2),
2.42 (m, 1H, OH), 1.52 (s, 9H, C(CH3)3), 1.43 (s, 3H,
C(CH3)). 13C/{1H} NMR (62.9 MHz, CDCl3) 174.5
(COOtBu), 157.7 (NH–CO), 135.8 (Ph), 127.8 (Ph), 128.7
(Ph), 128.3 (Ph), 83.6 (C(CH3)3), 74.2 (CH–OH), 67.0
(C(CH3), CH2–Ph), 42.3 (NH–CH2), 28.0 (C(CH3)3), 22.8
(C(CH3)), IR (cmK1) 3610–3130, 1755–1645, 1140, 1080.
HR MS (FAB): m/z Calcd for C17H25NO6 [M]C 339.39,
found 340.30 [MC1]C, 50%), 284.20 ([MC1–tBu]C,
100%), ([MC1–t-BuOC(O)]C, 50%).
(NH–CH2), 28.0 (C(CH3)3), 12.5 (C(CH3)). IR (cmK1
)
3345, 1800–1705, 1650. HR MS (FAB): m/z Calcd for
C17H23NO4 [M]C 305.37, found 306.30 ([MC1]C, 45%),
250.20 ([MC1–t-Bu]C, 100%).
3.2. Asymmetric dihydroxylation of vinylogous glycine
derivative 5
General procedure. To 50 mL of a solution of H2O/t-BuOH
(1/1) was added AD-mix (6.41 g) followed by methane
sulfonamide (440 mg, 4.58 mmol) and this was stirred until
total homogenising. The reaction mixture was then cooled
to 0 8C and stirred for 15 min until orange solid precipitated.
Olefin 5 (1.4 g, 4.58 mmol) was added to this mixture and
the reaction mixture was left stirring for an additional 1 h at
0 8C, then allowed to warm to room temperature. Stirring
was continued for 48 h in the case of olefin 5bZ, and for
192 h in the case of 5bE. Then, the reaction was quenched
with solid Na2S2O5 (6.9 g) and stirred for 1 h. The phases
were separated and the aqueous layer was extracted with
EtOAc (3!20 mL) The organic phases were combined,
washed with aq. KOH 2 M (3!5 mL), dried over MgSO4,
and evaporated to give an oil which was purified by
chromatography (Hexane/EtOAc 1:1, then EtOAc).
3.3. General procedure for the hydrogenolysis
of the ZNH group of 4
Deprotection of the N-benzyloxycarbonyl function was
carried out in standard conditions using Pd/C 10% and H2
(30 bars). The protected molecule (1.03 g, 3.03 mmol) was
dissolved in dry MeOH (15 mL). Pd/C was added (40 mg)
and after 12 h under H2 (30 bars) the mixture was filtered
through celite and evaporated to give crude 3 which was
used directly in further reactions without any purification.
3.2.1. t-Butyl-4-[N-(benzyloxycarbonyl)amino]-2,3-dihy-
droxy-2-methyl butanoate 4b. a-syn. White solid, 1.31 g
85%, mp 87–90 8C, Rf 0.28 (EtOAc/Hexane 1:1), [a]D22
K4.4 (c 0.4 CH2Cl2). 1H NMR (250 MHz, CDCl3) 7.36 (s,
5H, Ph), 5.20–5.37 (m, 1H, NH), 5.12 (s, 2H, Ph–CH2), 3.82
(dd, 1H, JZ8.5, 3.2 Hz, CH2CH), 3.59 (s, 1H, OH), 3.57
(m, 1H, NH–CH2), 3.15 (ddd, 1H, JZ14.3, 8.1, 3.2 Hz,
NH–CH2), 2.46 (m, 1H, OH), 1.51 (s, 9H, C(CH3)3), 1.35 (s,
3H, C(CH3)), IR (cmK1) 3600–3140, 1760–1645, 1150,
1080. HR MS (FAB): m/z Calcd for C17H25NO6 [M]C
339.39, found 340.30 [MC1]C, 42%), 284.20 ([MC
1–tBu]C, 100%), ([MC1–t-BuOC(O)]C, 50%).
3.3.1. Coupling reaction of 3 with caffeic acid. The caffeic
acid (621.0 mg, 3.45 mmol) was dissolved in dry DMF
(15 mL) and Et3N (0.48 mL, 3.45 mmol) was added
followed by the addition of BOP (1.52 g, 3.45 mmol) and
the appropriate diol 3 (710.0 mg, 3.45 mmol). The mixture
was stirred for 5 min and an extra portion of Et3N
(w1 equiv) was added to obtain pH 9–10. The reaction
mixture was stirred for 2 h, then evaporated to dryness and
the crude product was purified by column chromatography
(Hexane/EtOAc 1:2, then EtOAc) to obtain pure product 2.
3.2.2. t-Butyl-4-[N-(benzyloxycarbonyl)amino]-2,3-di-
hydroxy-2-methylbutanoate 4b. b-syn. White solid,
1.27 g, 82%, mp 90–92 8C, Rf 0.28 (EtOAc/Hexane 1:1),
3.3.2. t-Butyl-4-[[(2E)-3-(3,4-dihydroxyphenyl)-1-oxo-2-
propenyl]amino]-2,3-dihydroxy-2-methylbutanoate 2b.
a-syn. White solid, 0.85 g, 67%, mp 92–95 8C, Rf 0.32
(EtOAc/Hexane 5:1), [a]2D2 K4.17 (c 0.21 CH3OH). 1H
NMR (400 MHz, MeOH-d4): 7.39 (d, 1H, JZ15.7 Hz, Hb),
1
[a]2D2 C2.33 (c 0.4 CH2Cl2). H NMR (250 MHz, CDCl3)
7.36 (s, 5H, Ph), 5.20–5.37 (m, 1H, NH), 5.12 (s, 2H,
Ph–CH2), 3.82 (dd, 1H, JZ8.5, 3.2 Hz, CH2CH), 3.59 (s,
1H, OH), 3.57 (m, 1H, NH–CH2), 3.15 (ddd, 1H, JZ14.3,
8.1 Hz, JZ3.2 Hz, NH–CH2), 2.46 (m, 1H, OH), 1.51 (s,
9H, C(CH3)3), 1.35 (s, 3H, C(CH3)). 13C/{1H} NMR
(62.9 MHz, CDCl3) 174.8 (COOt-Bu), 157.1 (NH–CO),
136.1 (Ph), 128.6 (Ph), 128.3 (Ph), 128.2 (Ph), 83.6
(C(CH3)3), 75.3 (CH–OH), 67.0 (C(CH3), CH2–Ph), 43.0
(NH–CH2), 28.2 (C(CH3)3), 22.8 (C(CH3).
3
4
7.00 (d, 1H, JZ1.9 Hz, H2), 6.90 (dd, 1H, JZ8.2, JZ
1.9 Hz, H6), 6.75 (d, 1H, JZ8.2 Hz, H5), 6.40 (d, 1H, JZ
0
15.7 Hz, Ha), 3.88 (dd, 1H, JZ9.0, 2.9 Hz, H3 ), 3.72 (dd,
0
1H, JZ13.9, 2.9 Hz, H4 a), 3.21 (dd, 1H, JZ13.9, 9.0 Hz,
H4 b), 1.48 (s, 9H, t-Bu), 1.34 (s, 3H, H5 ), 13C/{1H} NMR
0
0
0
(100 MHz, MeOH-d4) 175.9 (C1 ), 169.9 (CONH), 148.9
(C4), 146.8 (C3), 142.5 (Cb), 128.4 (C1), 122.3 (C6), 118.5
0
(Ca), 116.6 (C5), 115.2 (C2), 83.2 (C(Me)3), 78.3 (C2 ), 75.6
K1
0
(C3 ), 42.2 (C4 ), 28.3 (C(CH3)3), 22.6 (C5 ), IR (cm
0
0
3.2.3. t-Butyl-4-[N-(benzyloxycarbonyl)amino]-2,3-di-
hydroxy-2-methyl butanoate 4b. a-anti. White solid,
1.39 g, 90%, mp 78–80 8C, Rf 0.21 (EtOAc/Hexane 1:2),
)
3670–3615, 1730, 1640, 1110, 1075, HR MS (FAB): m/z
Calcd for C18H25NO7 [M]C 367.39, found 368.30

1796
S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
[MC1]C, 78%), 312.20 ([MC1–t-Bu]C, 53%), ([MC1–
NH–CH2–CH(OH)–C(CH3) (OH)–C(O)Ot-Bu]C, 100%).
3.4.1. Preparation of the potassium salt 1 from 4-[[(2E)-
3-(3,4-dihydroxyphenyl)-1-oxo-2-propenyl]amino]-2,3-
dihydroxy-2-methyl butanoic acid. The free acid (85 mg,
0.27 mmol) was dissolved in dry MeOH (5 mL) and a
0.15 M solution of potassium methanolate in methanol was
added drop wise (1.8 mL, 0.27 mmol). The reaction was
stirred for 5 min and evaporated to dryness to give the
desired product 1 as a solid.
3.3.3. t-Butyl-4-[[(2E)-3-(3,4-dihydroxyphenyl)-1-oxo-2-
propenyl]amino]-2,3-dihydroxy-2-methylbutanoate 2b.
b-syn. White solid, 0.89 g, 70%, mp 94–96 8C, Rf 0.33
(EtOAc/Hexane 5:1), [a]2D2 C2.78 (c 0.21 CH3OH). 1H
NMR (400 MHz, MeOH-d4) 7.39 (d, 1H, JZ15.7 Hz, Hb),
7.00 (d, 1H, JZ1.9 Hz, H2), 6.90 (dd, 1H, JZ8.2, 1.9 Hz,
H6), 6.75 (d, 1H, JZ8.2 Hz, H5), 6.40 (d, 1H, JZ15.7 Hz,
3.4.2. 4-[[(2E)-3-(3,4-Dihydroxyphenyl)-1-oxo-2-pro-
penyl]amino]-2,3-dihydroxy-2-methyl butanoate potas-
sium salt 1. a-syn. White-yellow solid, 90.0 mg, 95%, mp
140–143 8C, [a]2D2 K6.25 (c 0.24 50% MeOH aq.). 1H NMR
(400 MHz, MeOH-d4) 7.38 (d, 1H, JZ15.6 Hz, Hb), 7.01
(d, 1H, JZ1.8 Hz, H2), 6.90 (dd, 1H, JZ8.2, 1.8 Hz, H6),
6.76 (d, 1H, JZ8.2 Hz, H5), 6.41 (d, 1H, 3JZ15.6 Hz, Ha),
0
Ha), 3.88 (dd, 1H, JZ9.0, 2.9 Hz, H3 ), 3.72 (dd, 1H, JZ
0
0
13.9, 2.9 Hz, H4 a), 3.21 (dd, 1H, JZ13.9, 9.0 Hz, H4 b),
1.48 (s, 9H, t-Bu), 1.34 (s, 3H, H5 ). 13C/{1H} NMR
0
0
(100 MHz, MeOH-d4): 175.9 (C1 ), 169.9 (CONH), 148.9
(C4), 146.8 (C3), 142.5 (Cb), 128.4 (C1), 122.3 (C6), 118.5
0
(Ca), 116.6 (C5), 115.2 (C2), 83.2 (C(Me)3), 78.3 (C2 ), 75.6
0
3.73 (unresolved signal, 1H, H3 ), 3.34 (unresolved signal,
0
0
(C3 ), 42.2 (C4 ), 28.3 (C(CH3)3), 22.6 (C5 ).
0
0
2H, H4 ), 1.48 (s, 3H, H5 ). 13C/{1H} NMR (100 MHz,
0
0
MeOH-d4/D2O: 1/1) 181.8 (C1 ), 169.8 (CONH), 148.9
3.3.4. t-Butyl-4-[[(2E)-3-(3,4-dihydroxyphenyl)-1-oxo-2-
propenyl]amino]-2,3-dihydroxy-2-methylbutanoate 2b.
a-anti. White solid, 0.95 g, 75%, mp 86–89 8C, Rf 0.30
(EtOAc/Hexane 5:1), [a]2D2 K3.95 (c 0.21 CH3OH). 1H
NMR (400 MHz, MeOH-d4) 7.38 (d, 1H, JZ15.7 Hz, Hb),
(C4), 146.8 (C3), 142.3 (Cb), 128.1 (C1), 122.3 (C6), 118.2
0
0
0
(Ca), 117.2 (C5), 115.5 (C2), 76.0 (C2 ), (C3 ), 42.7 (C4 ),
0
23.4 (C5 ); IR (cmK1) 3630–2640, 1645, 1595, 1285, 1125,
1080; HR MS (ESK): m/z Calcd for C14H16NO7K [MKK]K
310.1, found 310.1[MKK]K, 100%).
3
4
6.99 (d, 1H, JZ1.9 Hz, H2), 6.89 (dd, 1H, JZ8.2, JZ
1.9 Hz, H6), 6.75 (d, 1H, JZ8.2 Hz, H5), 6.38 (d, 1H, JZ
3.4.3. 4-[[(2E)-3-(3,4-Dihydroxyphenyl)-1-oxo-2-pro-
penyl]amino]-2,3-dihydroxy-2-methyl butanoate potas-
sium salt 1. b-syn. Yellow-green solid, 87.0 mg, 92%, mp
135–137 8C, [a]2D2 C1.67 (c 0.24 50% MeOH aq.). 1H NMR
(400 MHz, MeOH-d4/D2O: 1/1) 7.38 (d, 1H, JZ15.6 Hz,
Hbb), 7.09 (d, 1H, JZ1.7 Hz, H2), 7.02 (dd, 1H, JZ8.2,
1.7 Hz, H6), 6.85 (d, 1H, JZ8.2 Hz, H5), 6.45 (d, 1H, JZ
0
15.7 Hz, Ha), 3.82 (dd, 1H, JZ9.1, 3.2 Hz, H3 ), 3.54 (dd,
0
1H, JZ13.7, 3.2 Hz, H4 a), 3.23 (dd, 1H, JZ13.7, 9.1 Hz,
H4 b), 1.50 (s, 9H, t-Bu), 1.39 (s, 3H, H5 ). 13C/{1H} NMR
0
0
0
(100 MHz, MeOH-d4): 175.7 (C1 ), 169.8 (CONH), 148.9
(C4), 146.8 (C3), 142.4 (Cb), 128.5 (C1), 122.2 (C6), 118.6
0
(Ca), 116.6 (C5), 115.2 (C2), 83.5 (C(Me)3), 77.8 (C2 ), 75.6
K1
0
(C3 ), 42.8 (C4 ), 28.3 (C(CH3)3), 23.2 (C5 ), IR (cm
0
0
)
0
15.6 Hz, Ha), 3.74 (unresolved signal, 1H, H3 ), 3.23
0
3675–3610, 1720, 1650, 1120, 1080, HR MS (FAB): m/z
Calcd for C18H25NO7 [M]C 367.39, found 368.30 [MC
1]C, 78%), 312.20 ([MC1–t-Bu]C, 53%), ([MC
1–NH–CH2–CH(OH)–C(CH3)(OH)–C(O)Ot-Bu]C, 100%).
(unresolved signal, 2H, H4 ), 1.47 (large s, 3H, H5 ). 13C/
0
1
{ H} NMR (100 MHz, MeOH-d4/D2O: 1/1) 181.8 (C1 ),
0
169.3 (CONH), 147.9 (C4), 145.3 (C3), 142.7 (Cb), 128.1
(C1), 123.2 (C6), 118.6 (Ca), 117.1 (C5), 115.5 (C2), 78.0
0
(C2 ), 75.5 (C3 ), 42.5 (C4 ), 23.4 (C5 ).
0
0
0
3.3.5. t-Butyl-4-[[(2E)-3-(3,4-dihydroxyphenyl)-1-oxo-2-
propenyl]amino]-2,3-dihydroxy-2-methylbutanoate 2b.
b-anti. White solid, 1.01 g, 80%, mp 99–100 8C, Rf 0.91
(Acetone/MeOH 8:2), [a]2D2 C5.2 (c 0.21 CH3OH). 1H
NMR (400 MHz, MeOH-d4/D2O: 1/1) 7.40 (d, 1H, JZ
15.5 Hz, Ph–CH], noted Hb), 7.00 (d, 1H, JZ2.0 Hz, Ph,
noted H2), 6.90 (dd, 1H, JZ8.8, 2 Hz, Ph, noted H6), 6.75
(d, 1H, JZ8.8 Hz, Ph, noted H5), 6.38 (d, 1H, JZ15.5 Hz,
]CH–Ph, noted Ha), 3.82 (dd, 1H, JZ9, 3.5 Hz, noted
3.4.4. 4-[[(2E)-3-(3,4-Dihydroxyphenyl)-1-oxo-2-pro-
penyl]amino]-2,3-dihydroxy-2-methyl butanoate potas-
sium salt 1. a-anti. Brown-yellow solid, 88.0 mg, 93%,
1
[a]2D2 K4.0 (c 0.24 50% MeOH aq.). H NMR (400 MHz,
MeOH-d4) 7.36 (d, 1H, 3JZ15.8 Hz, Hb), 7.02 (enlarged s,
1H, H2), 6.88 (enlarged d, 1H, JZ8.2 Hz, H6), 6.75 (d, 1H,
JZ8 Hz, H5), 6.40 (d, 1H, JZ15.8 Hz, Ha), 3.80 (m, 1H,
H3 ), 3.43 (unresolved m, 2H, H4 ), 1.37 (s, 3H, H5 ). 13C/
0
0
0
1
{ H} NMR (100 MHz, MeOH-d4) 181.9 (C1 ), 170.0
(CONH), 149.9 (C4), 147.0 (C3), 142.3 (Cb), 128.2 (C1),
0
0
H3 ), 3.54 (dd, 1H, JZ13.9, 3.5 Hz, noted H4 a), 3.25 (dd,
0
0
1H, JZ13.9, 9.0 Hz, noted H4 b), 1.45 (s, 9H, t-Bu), 1.34 (s,
3H, H5 ), 13C/{1H} NMR (100 MHz, MeOH-d4/D2O: 1/1)
0
0
122.3 (C6), 118.6 (Ca), 116.6 (C5), 115.1 (C2), 77.7 (C2 ),
0
174.7 (C1 ), 168.8 (CONH), 147.8 (C4), 145.7 (C3), 141.5
(Cb), 127.3 (C1), 121.2 (C6), 117.3 (Ca), 115.5 (C5), 114.1
0
76.1 (C3 ), 42.9 (C4 ), 23.3 (C5 ).
0
0
0
(C2), 82.6 (C(Me)3),76.7 (C2 ), 74.4 (C3 ), 41.6 (C4 ), 27.2
0
(C(CH3)3), 22.1 (C5 ).
0
0
3.4.5. 4-[[(2E)-3-(3,4-Dihydroxyphenyl)-1-oxo-2-pro-
penyl]amino]-2,3-dihydroxy-2-methyl butanoate potas-
sium salt 1. b-anti. Brown solid, 93.0 mg, 98%, [a]2D2 C5.4
1
3.4. Typical procedure for the deprotection of the
t-butyl-ester 2
(c 0.24 50% MeOH aq.). H NMR (400 MHz, MeOH-d4/
D2O: 1/1) 7.37 (d, 1H, JZ15.7 Hz, Hb), 7.08 (d, 1H, JZ
1.9 Hz, H2), 7.00 (dd, 1H, JZ8.2, 1.9 Hz, H6), dZ6.84 (d,
1H, JZ8.2 Hz, H5), 6.44 (d, 1H, JZ15.7 Hz, Ha), 3.82 (m,
The t-butyl ester 2 (200 mg, 0.545 mmol) was dissolved in
4 mL of pure TFA and the mixture was stirred for 30 min at
rt. The evaporation of TFA followed by co-evaporation with
toluene gave the free acid as a solid, which was used directly
in the further reaction without any purification.
0
0
0
1H, H3 ), 3.37 (unresolved m, 2H, H4 ), 1.36 (s, 3H, H5 ).
13C/{1H} NMR (100 MHz, MeOH-d4/D2O: 1/1) 181.5
0
(C1 ), 170.0 (CONH), 147.9 (C4), 145.7 (C3), 142.0 (Cb),
128.5 (C1), 123.0 (C6), 118.5 (Ca), 117.0 (C5), 115.5 (C2),

S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
1797
K1
0
0
0
0
78.0 (C2 ), 75.5 (C3 ), 42.5 (C4 ), 23.5 (C5 ); IR (cm
)
CDCl3) 7.58–7.21 (m, 10H, Ph), 5.47 (m, 1H, CH), 5.05 (m,
2H, CH2Ph), 3.41 (s, 3H, OCH3), 3.56–3.58 (m, 2H, CH2),
1.44 (s, 9H, C(CH3)3), 1.36 (s, 1H, C(CH3)). 19F NMR
(235.4 MHz, CDCl3) K71.58 (s, 3F, CF3). Diastereomer 2:
1H NMR (250 MHz, CDCl3) 7.29 (m, 10H, Ph), 5.47 (m, 1H,
CH), 5.05 (m, 2H, CH2Ph), 3.41 (s, 3H, OCH3), 3.19–3.06 (m,
2H, CH2), 1.49 (s, 9H, C(CH3)3), 1.29 (s, 1H, C(CH3)). 19F
3635–2640, 1655, 1600, 1280, 1120, 1080; HR MS (ESK):
m/z Calcd for C14H16NO7K [MKK]K 310.1, found
310.1[MKK]K, 100%).
3.4.6. Preparation of Mosher’s esters 7b/70b. Dry pyridine
(1.2 mL) and (S)-(C)-a-Methoxy-a-(trifluoromethyl)-phe-
nylacetyl chloride [(S)-MTPA-Cl] were dissolved in 5 mL
of dry CH2Cl2 and appropriate t-butyl-4-[N-(Benzyloxy-
carbonyl)amino]-2,3-dihydroxy-2-methylbutanoate 4b
(80 mg, 0.235 mmol) was added. The reaction mixture
was stirred for 48 h, then diluted with 20 mL of CH2Cl2,
successively washed with 1 N aq. HCl (2!5 mL), sat. aq.
NaHCO3 (3!5 mL), sat. aq. NaCl (3!5 mL), dried over
MgSO4 and evaporated to give the crude product as an oil.
NMR (235.4 MHz, CDCl3) K71.89 (s, 3F, CF3), IR (cmK1
)
3580–3150, 1750, 1720, 1515, 1250, 1170, 1070.
3.4.7. Preparation of dipeptides 8b/80b. To a solution of 4-
[N-(Benzyloxycarbonyl)amino]-2,3-dihydroxy-2-methylbu-
tanoic acid(440 mg, 1.55 mmol) indryCH2Cl2 (25 mL), were
added successively Et3N (0.22 mL, 1.55 mmol), BOP
(680 mg, 1.55 mmol) and H-Leu-OMe$HCl (310 mg,
1.705 mmol). The mixture was stirred for 5 min and Et3N
(w1 equiv) was added up to obtain pH 9–10. Stirring was
continued for 2 h, before the reaction mixture was evaporated
to dryness to provide a crude oil which was purified by column
chromatography (Hexane/EtOAc 2:1, then EtOAc) to obtain
pure product 8b.
7b/70b b-anti. Colourless syrup, 89.0 mg, 68.0%, Rf 0.84
(EtOAc/Hexane 1:1), Diastereomer 1: 1H NMR (250 MHz,
3
CDCl3) 7.62–7.31 (m, 10H, Ph), 5.41 (dd, 1H, JHH
Z
3
7.9 Hz, JHHZ4.0 Hz, CH), 5.08 (m, 2H, CH2Ph),
4.93–5.10 (m, 1H, NH), 3.49 (s, 3H, OCH3), 3.37–3.71
(m, 2H, CH2), 3.42 (s, 1H, OH), 1.50 (s, 9H, C(CH3)3), 1.28
(s, 1H, C(CH3)). 19F NMR (235.4 MHz, CDCl3) K71.77 (s,
8b/80b b-anti. White solid, 520.0 mg, 82.0%, Rf 0.21
(EtOAc/Hexane 1:1), Diastereomer 1: 1H NMR
(250 MHz, acetone-d6) 7.76 (bs, 1H, NH–CH–C(O)), 7.30
(m, 5H, Ph), 6.48 (bs, 1H, NH–CH2–Ph), 5.08 (s, 2H,
CH2Ph), 4.50 (m, 2H, NH–CH and OH), 3.89 (bs, 1H, CH),
3.70 (s, 3H, OCH3), 3.18 (m, 3H, NH–CH2 and OH), 1.45
(m, 3H, CH2CH), 1.45 (s, 3H, CH3), 0.91 (m, 6H, (CH3)2).
Diastereomer 2: 1H NMR (250 MHz, acetone-d6) 7.76 (bs,
1H, NH–CH–C(O)), 7.30 (m, 5H, Ph), 6.48 (bs, 1H,
NH–CH2–Ph), 4.86 (s, 2H, CH2Ph), 4.50 (m, 2H, NH–CH
and OH), 3.89 (bs, 1H, CH), 3.68 (s, 3H, OCH3), 3.18 (m,
3H, NH–CH2 and OH), 1.45 (m, 3H, CH2CH), 1.43 (s, 3H,
CH3), 0.91 (m, 6H, (CH3)2). MS (FAB): m/z Calcd for
C20H30N2O7 [M]C 410.2, found 411.3 [MC1]C (100%).
1
3F, CF3). Diastereomer 2: H NMR (250 MHz, CDCl3):
7.62–7.31 (m, 10H, Ph), 5.36–5.46 (m, 1H, CH), 5.08 (m,
2H, CH2Ph), 4.56–5.76 (m, 1H, NH), 3.57 (s, 3H, OCH3),
3.37–3.52 (m, 2H, CH2), 3.42 (s, 1H, OH), 1.50 (s, 9H,
C(CH3)3), 1.30 (s, 1H, C(CH3)), 19F NMR (235.4 MHz,
CDCl3) K71.87 (s, 3F, CF3), 13C/{1H} NMR (62.9 MHz,
CH3OD) 179.7 (C(O)), 175.6 (C(O)O-t-Bu), 158.2
(NHC(O)), 129.9 (Ph), 128.6 (Ph), 128.3 (Ph), 127.6 (Ph),
84.6 (C(OH)), 77.8 (CF3), 75.3 (CH(O)), 67.1 (Ph–CH2)
55.8, 55.6 (OCH3 from dia. 1 and 2), 41.4 (NHCH2), 27.9
(C(CH3)3), 23.6, 23.3 (C(CH3)) from dia. 1 and 2).
7b/70b a-anti. Colourless syrup, 94.0 mg, 72.0%, Rf 0.84
(EtOAc/Hexane 1:1), Diastereomer 1: 1H NMR (250 MHz,
CDCl3) 7.60–7.20 (m, 10H, Ph), 5.41 (m, 1H, CH), 5.08 (m,
2H, CH2Ph), 4.86 (m, 1H, NH), 3.55 (s, 3H, OCH3), 3.42
(m, 2H, CH2), 1.49 (s, 9H, C(CH3)3), 1.41 (s, 1H, C(CH3)).
19F NMR (235.4 MHz, CDCl3) K71.74 (s, 3F, CF3).
Diastereomer 2: 1H NMR (250 MHz, CDCl3) 7.28 (m,
10H, Ph), 5.15 (m, 1H, CH), 5.08 (m, 2H, CH2Ph), 4.86 (m,
1H, NH), 3.49 (s, 3H, OCH3), 3.42 (m, 2H, CH2), 1.49 (s,
9H, C(CH3)3), 1.26 (s, 1H, C(CH3)). 19F NMR (235.4 MHz,
CDCl3) K72.07 (s, 3F, CF3). MS (FABC): m/z Calcd for
C27H32F3NO8 [M]C 555.2, found 556.2 [MC1]C (100%).
8b/80b a-anti. White solid, 540.0 mg, 85.0%, Rf 0.21
(EtOAc/Hexane 1:1), Diastereomer 1: 1H NMR
(250 MHz, acetone-d6) 7.76 (bs, 1H, NH–CH–C(O)), 7.30
(m, 5H, Ph), 6.48 (bs, 1H, NH–CH2–Ph), 5.08 (s, 2H,
CH2Ph), 4.50 (m, 2H, NH–CH and OH), 3.89 (bs, 1H, CH),
3.70 (s, 3H, OCH3), 3.18 (m, 3H, NH–CH2 and OH), 1.45
(m, 3H, CH2CH), 1.45 (s, 3H, CH3), 0.91 (m, 6H, (CH3)2),
13C NMR (62.9 MHz, acetone-d6)175.5 (C(O)–NH), 173.1
(C(O)CH3), 157.6 (C(O)CH2Ph), 137.7 (Ph), 128.7 (Ph),
128.2 (Ph), 76.7 (C–CH3), 74.7 (CHOH), 66.3 (CH2–Ph),
52.0 (O–CH3), 50.6 (CH–CO), 43.1 (CH2CH(CH3)2), 40.6
(NH–CH2), 25.0 (CH(CH3)2), 22.8 ((CH3)2), 21.3 (CH3).
Diastereomer 2: 1H NMR (250 MHz, acetone-d6) 7.76 (bs,
1H, NH–CH–C(O)), 7.30 (m, 5H, Ph), 6.48 (bs, 1H,
NH–CH2–Ph), 4.86 (s, 2H, CH2Ph), 4.50 (m, 2H, NH–CH
and OH), 3.89 (bs, 1H, CH), 3.68 (s, 3H, OCH3), 3.18 (m,
3H, NH–CH2 and OH), 1.45 (m, 3H, CH2CH), 1.43 (s, 3H,
CH3), 0.91 (m, 6H, (CH3)2), 13C NMR (62.9 MHz, acetone-
d6)175.5 (C(O)–NH), 173.1 (C(O)CH3), 157.6
(C(O)CH2Ph), 137.7 (Ph), 128.7 (Ph), 128.2 (Ph), 76.8
(C–CH3), 74.7 (CHOH), 66.3 (CH2–Ph), 52.0 (O–CH3),
50.6 (CH–CO), 43.1 (CH2CH(CH3)2), 40.6 (NH–CH2), 25.0
(CH(CH3)2), 22.9 ((CH3)2), 21.30 (CH3).
7b/70b b-syn. Colourless syrup, 91.0 mg, 70.0%, Rf 0.90
(EtOAc/Hexane 1:1), Diastereomer 1: H NMR (250 MHz,
1
CDCl3) 7.63–7.25 (m, 10H, Ph), 5.48 (m, 1H, CH), 5.08 (m,
2H, CH2Ph), 4.86 (m, 1H, NH), 3.52 (s, 3H, OCH3), 3.12–3.24
(m, 2H, CH2), 1.49(s, 9H, C(CH3)3), 1.46(s, 1H, C(CH3)). 19
F
NMR (235.4 MHz, CDCl3) K71.43 (s, 3F, CF3). Diaster-
eomer 2: 1H NMR (250 MHz, CDCl3) 7.28 (m, 10H, Ph), 5.38
(m, 1H, CH), 5.08 (m, 2H, CH2Ph), 4.86 (m, 1H, NH), 3.49 (s,
3H, OCH3), 3.12–3.24 (m, 2H, CH2), 1.49 (s, 9H, C(CH3)3),
1.41 (s, 1H, C(CH3)). 19F NMR (235.4 MHz, CDCl3) K71.61
(s, 3 F, CF3). MS (FAB): m/z Calcd for C27H32F3NO8 [M]C
555.2, found 556.1 [MC1]C (100%).
7b/70b a-syn. Colourless syrup, 90.0 mg, 69.0%, Rf 0.90
(EtOAc/Hexane 1:1), Diastereomer 1: H NMR (250 MHz,
8b/80b b-syn. White solid, 490.0 mg, 82.0%, Rf 0.50
(EtOAc/Hexane 1:1), Diastereomer 1: 1H NMR
1

1798
S. Claudel et al. / Tetrahedron 62 (2006) 1787–1798
(250 MHz, acetone-d6) 7.60 (bs, 1H, NH–CH–C(O)), 7.31
(m, 5H, Ph), 6.27 (bs, 1H, NH–CH2–Ph), 5.06 (s, 2H,
CH2Ph), 4.46 (m, 1H, NH–CH), 3.70 (m, 1H, CH), 3.67 (s,
3H, OCH3), 3.58 (m, 1H, NH–CH2), 3.12 (m, 1H,
NH–CH2), 1.64 (m, 3H, CH2CH), 1.43 (s, 3H, CH3), 0.89
(m, 6H, (CH3)2). Diastereomer 2: 1H NMR (250 MHz,
acetone-d6) 7.60 (bs, 1H, NH–CH–C(O)), 7.31 (m, 5H, Ph),
6.27 (bs, 1H, NH–CH2–Ph), 5.06 (s, 2H, CH2Ph), 4.46 (m,
1H, NH–CH), 3.70 (m, 1H, CH), 3.67 (s, 3H, OCH3), 3.58
(m, 1H, NH–CH2), 3.12 (m, 1H, NH–CH2), 1.64 (m, 3H,
CH2CH), 1.40 (s, 3H, CH3), 0.89 (m, 6H, (CH3)2).
grateful to Dr. A. van Dorsselaer, University Louis Pasteur,
Strasbourg, France, for mass measurements.
References and notes
1. Ueda, M.; Hiraoka, T.; Niwa, M.; Yamamura, S. Tetrahedron
Lett. 1999, 40, 6777–6780.
2. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547.
3. Fehrentz, J. A.; Castro, B. Synthesis 1983, 676–678.
8b/80b a-syn. White solid, 509.0 mg, 80.0%, Rf 0.50 (EtOAc/
Hexane 1:1), Diastereomer 1: H NMR (250 MHz, CDCl3)
1
`
4. (a) Grison, C.; Coutrot, P.; Geneve, S.; Didierjean, C.;
7.27 (m, 6H, NH–CH–C(O)) and Ph), 5.59 (bs, 1H, NH–CH2–
Ph), 5.03 (s, 2H, CH2Ph), 4.50 (m, 1H, NH–CH), 4.26 (bs, 2H,
OH), 3.49 (m, 1H, CH), 3.66 (s, 3H, OCH3), 3.55 (m, 1H,
NH–CH2),3.18(m, 1H,NH–CH2),1.64(m, 3H, CH2CH),1.47
(s, 3H, CH3), 0.89 (m, 6H, (CH3)2), 13C NMR (62.9 MHz,
acetone-d6) 176.9 (C(O)–NH), 173.4 (C(O)CH3), 157.8
(C(O)CH2Ph), 137.5 (Ph), 128.30 (Ph), 128.2 (Ph), 76.0
(C–CH3), 75.7 (COH), 66.5 (CH2–Ph), 52.3 (O–CH3), 50.9
(CH–CO), 42.7 (CH2CH(CH3)2), 40.7 (NH–CH2), 25.0
(CH(CH3)2), 22.9 ((CH3)2), 21.4 (CH3). Diastereomer 2: 1H
NMR (250 MHz, CDCl3) 7.27 (m, 6H, NH–CH–C(O)) and
Ph), 5.59(bs, 1H, NH–CH2–Ph), 5.03(s, 2H, CH2Ph), 4.50(m,
1H, NH–CH), 4.26 (bs, 2H, OH), 3.49 (m, 1H, CH), 3.65 (s,
3H, OCH3), 3.55 (m, 1H, NH–CH2), 3.18 (m, 1H,
NH–CH2),1.64 (m, 3H, CH2CH), 1.39 (s, 3H, CH3), 0.89
(m, 6H, (CH3)2), 13C NMR (62.9 MHz, acetone-d6) 176.9
(C(O)–NH), 173.4 (C(O)CH3), 157.8 (C(O)CH2Ph), 137.5
(Ph), 128.3 (Ph), 128.2 (Ph), 76.0 (C–CH3), 75.7 (COH), 66.5
(CH2–Ph), 52.3 (O–CH3), 50.9 (CH–CO), 42.7 (CH2-
CH(CH3)2), 40.5 (NH–CH2), 25.0 (CH(CH3)2), 22.9
((CH3)2), 21.4 (CH3). MS (FAB): m/z Calcd for
C20H30N2O7 [M]C 410.2, found 411.2 [MC1]C (100%).
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The authors thank the French Ministry of National
Education (MENESR) for financial support. We are very