Synthesis of terminally protected (S)-β3-H-DOPA by Arndt-Eistert homologation: An approach to crowned β-peptides

Article abstract of DOI:10.1016/j.tetasy.2004.11.089

Terminally protected Boc-(S)-β³-H-DOPA-OMe has been synthesized from l-DOPA by the Arndt-Eistert homologation procedure. During the synthesis, the side-chain catechol group was temporarily protected by benzylation. The absence of racemization w

Full text of DOI:10.1016/j.tetasy.2004.11.089

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 857–864
Synthesis of terminally protected (S)-b3-H-DOPA by
Arndt–Eistert homologation: an approach to crowned b-peptides
Anne Gaucher, Laurence Dutot, Olivier Barbeau, Wahib Hamchaoui,
Michel Wakselman and Jean-Paul Mazaleyrat*
SIRCOB, UMR CNRS 8086, University of Versailles, F-78035 Versailles, France
Received 28 October 2004; accepted 21 November 2004
Available online 22 January 2005
Abstract—Terminally protected Boc-(S)-b3-H-DOPA-OMe has been synthesized from L-DOPA by the Arndt–Eistert homologation
procedure. During the synthesis, the side-chain catechol group was temporarily protected by benzylation. The absence of racemi-
zation was demonstrated by 19F NMR analysis of the (+)-(R)- and (ꢀ)-(S)-a-methoxy-a-trifluoromethyl-a-phenyl-acetamide deriv-
atives. The catechol function of Boc-(S)-b3-H-DOPA-OMe may be used for crown-ether formation, a step towards the construction
of crowned b-peptides.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
(Maps), and has recently been exploited in the design of
Map mimetic polymers for the synthesis of nonfouling
surfaces.5 The above reports highlight the potential use-
fulness of designed analogues of L-DOPA, which could
be used as informative models in comparative studies.
As illustration, (S)-aMe-DOPA, a Ca-tetrasubstituted
analogue, is a potent inhibitor of L-DOPA decarboxyl-
ase and has become a commercial anti-hypertensive
drug.6 Herein, we report the synthesis of another ana-
logue of L-DOPA, which in our view is of the greatest
interest: the corresponding b-homo amino acid (S)-b3-
H-DOPA (Fig. 1).7–9
The naturally occurring L-3,4-dihydroxyphenylalanine
(L-DOPA) is the biosynthetic precursor of dopamine,
the most successful therapeutic agent in the treatment
of Parkinsonꢀs disease. Moreover, it seems likely that
L-DOPA has an intrinsic biological activity, different
to that of dopamine in many aspects, and ꢁꢁ ꢁ ꢁis about
to start a new career as a brain neurotransmitter sub-
stance in its own rightꢀ.1 The catechol group in itself, a
very efficient iron chelator, is a typical binding site found
in numerous siderophores, which are responsible for the
take-up and transport of metal ions through membranes
in nature.2 Catechol-containing peptides have been syn-
thesized as potential new oxidation catalysts3 and are
important targets in the design of iron chelators against
oxidative damage in biological processes.4 The catechol
side-chain of L-DOPA is also responsible for the adhe-
sive and cohesive properties of mussel adhesive proteins
The (S)-b3-H-DOPA residue belongs to the now well-
recognized and rapidly growing class of b-amino acids.
In recent years, following the pioneering studies of Gell-
man and Seebach, who have shown that b-peptides may
adopt stable secondary structures in a larger variety
than their a-peptide counterparts,10 several b-peptides
CO-
CO-
Me
CH2-CO-
H
HO
HO
HO
HO
HO
HO
H
NH-
NH-
NH-
(S)-β3-H-DOPA
L-DOPA
Figure 1. Chemical structures of L-DOPA, (S)-aMe-DOPA and (S)-b3-H-DOPA.
(S)-αMe-DOPA
*
Corresponding author. Fax: +33 01 39 25 44 52; e-mail: jean-paul.mazaleyrat@chimie.uvsq.fr
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.089

858
A. Gaucher et al. / Tetrahedron: Asymmetry 16 (2005) 857–864
as well as peptide hybrids containing both a- and b-ami-
no acids, have been synthesized and shown to possess
both biological activity and increased resistance to enzy-
mic degradation.10,11 Furthermore, Seebach and Gha-
diri have demonstrated that nanotubes based on the
self-assembly of cyclic b-peptides may behave as artifi-
cial transmembrane ion channels.12 In relation with
the above mentioned properties of b-peptides, the design
of the (S)-b3-H-DOPA residue was dictated to us by the
opportunity to take advantage of its catechol function to
introduce crown ethers on its side chain, in order to
eventually dispose of crown-carrier b-amino acids and
b-peptides,13 to be compared to the crowned a-peptides
of Voyer and co-workers,14 derived from L-DOPA, as
well as to the crowned a-peptides based on crowned
Ca-tetrasubstituted a-amino acids derived from
(S)-aMe-DOPA previously synthesized and investi-
gated by us in a joint study with Toniolo and co-
workers.13b,15
other terminally protected derivatives of L-DOPA,21
and to the previously described dibenzylation of 3,4-
dihydroxy-5-fluorobenzyl cyanide,23 resulted in a much
higher yield and a cleaner reaction. Interestingly, the
addition of n-Bu4N+Brꢀ as catalyst also resulted in a
shorter reaction time and favoured the formation of
the desired dialkylated product over the monoalkylated
intermediate. The fully protected amino acid Boc-L-DO-
25
PA[OBn]2-OMe 2 {mp 112 ꢁC, ½aꢂ ¼ þ35 (c 0.5,
D
CH2Cl2)}24 was obtained in 95% yield after chromatog-
raphy, while when the same experimental conditions
(K2CO3/NaI in refluxing acetone) were previously ap-
plied without n-Bu4N+Brꢀ catalyst,13a chromatographic
separation of the monobenzylated side-product from the
dibenzylated compound 2 had to be performed, and
then the benzylation reaction repeated in order to even-
tually obtain 2 in 85% yield (see Experimental).
Saponification of the ester function of 2 was performed
by using a slight excess of 1 M aqueous NaOH in
MeOH/THF at room temperature, which after acidifi-
cation and extraction, gave pure Boc-L-DOPA[OBn]2-
2. Results and discussion
OH 3 in 87–96% yield {mp 120 ꢁC, lit.19 mp 105–
25
107 ꢁC; lit.22 mp 139–141 ꢁC, ½aꢂ ¼ þ14:4 (c 0.4,
For the synthesis of terminally protected Boc–(S)-b3-H-
DOPA-OMe I (Fig. 2),16 we considered the classical
Arndt–Eistert homologation of either N-Boc or N-Fmoc
protected a-amino acids, previously developed by See-
bach and co-workers.17 Application of this method to
L-DOPA required the selective protection of both the
amino group and the side chain OH groups of the
catechol function. Initially, terminal protection of H-
L-DOPA-OH was achieved through conversion to H-L-
DOPA-OMeÅHCl18,19 and then to Boc-L-DOPA-OMe
119,20 {mp 135 ꢁC, lit.19 mp 133–135 ꢁC; lit.20 mp 140–
D
25
D
MeOH); lit.19 ½aꢂ ¼ þ14:2 (c 1, MeOH)}. As a possible
epimerization at the a-carbon of the present L-DOPA
derivatives could occur in the strongly basic medium re-
quired for saponification, it is important to observe that
our experimental conditions are somewhat milder than
those described in the literature for saponification of
the same compound 2 (large excess of 2 M aq NaOH
in refluxing MeOH)22 as well as for saponification of
analogue 1 (large excess of 2 M aq NaOH in MeOH).19
Epimerization could explain the difference between the
recorded melting point of our sample and that from
the literature (139–141 ꢁC),22 which is very close to the
melting point of the racemic compound 3 (140–
142 ꢁC).19 We have no explanation for the different
melting point of 3 (105–107 ꢁC) reported by Banergie
25
26
141 ꢁC, ½aꢂ ¼ þ7 (c 1.0, MeOH); lit.19, ½aꢂ ¼ þ7:6 (c
D
D
1.2, MeOH)}, by described procedures.18–22
Then, for lateral orthogonal protection of the catechol
function, compound 1 was treated with potassium car-
bonate, sodium iodide, n-Bu4N+Brꢀ as catalyst and a
large excess of benzyl bromide in refluxing acetone. In
our hands, the use of acetone as solvent instead of eth-
anol,19–22 referring to the mentioned dibenzylation of
and Ressler,19 since the specific rotation of our sample
25
D
½aꢂ
¼
þ14:4 (c 0.4, MeOH) perfectly fits with
25
the value reported by these authors: ½aꢂ ¼ þ14:2 (c 1,
D
MeOH).19
COOMe
COOMe
COOH
(v)
HO
HO
(iii)
(iv)
(i) (ii)
BnO
BnO
BnO
BnO
H
H
L-DOPA
H
NH-Boc
NH-Boc
NH-Boc
Boc-L-DOPA[OBn]2-OMe 2
Boc-L-DOPA[OBn]2-OH 3
Boc-L-DOPA-OMe 1
O
H
CH2-COOMe
H
CH2-COOMe
(vi)
(vii)
HO
HO
C
C
BnO
BnO
BnO
BnO
N2
H
H
NH-Boc
NH-Boc
NH-Boc
Boc-(S)-β3-H-DOPA[OBn]2-OMe 5
Boc-(S)-β3-H-DOPA-OMe I
Boc-L-DOPA[OBn]2-CH=N2 4
Figure 2. Synthesis of Boc-(S)-b3-H-DOPA-OMe I. Reagents and conditions: (i) SOCl2, MeOH, 0 ꢁC to rt; (ii) Boc2O, NaHCO3, H2O/THF, rt;
(iii) BnBr, K2CO3, NaI, n-Bu4N+Brꢀ (cat.), acetone, reflux; (iv) NaOH, MeOH/THF, rt; (v) (1) ClCOOEt, TEA, THF, ꢀ10 ꢁC, 15 min; (2) CH2N2,
Et2O, 0 ꢁC to rt, 18 h; (vi) AgOBz, TEA, MeOH/THF, ꢀ25 ꢁC to rt; (vii) H2, 10% Pd/C, MeOH/THF, rt.

A. Gaucher et al. / Tetrahedron: Asymmetry 16 (2005) 857–864
859
Finally, while taking into account the above discrepan-
cies, we decided to further investigate the question of
the enantiomeric purity of compounds 2 and 3, by
NMR of their Mosherꢀs amide derivatives.17a For this
purpose, the N-Boc protecting group of an aliquot of
2 was cleaved by acidolysis in TFA/dichloroethane,
which led to the amino ester H-L-DOPA[OBn]2-OMe.
In the absence of a sample of the corresponding racemic
compound, two portions of that aliquot were acylated
using a large excess of (+)-(R)-MTPA and (ꢀ)-(S)-
MTPA (a-methoxy-a-trifluoromethyl-a-phenyl-acetic
acid),25 by the EDC [N-ethyl,N0-(3-dimethylaminopro-
pyl)-carbodiimide]/HOBt [1-hydroxy-1,2,3-benzotriaz-
ole] method. This led to the diastereoisomeric amido
esters (R)-Ph(OCH3)(CF3)C-CO-L-DOPA[OBn]2-OMe
6A and (S)-Ph(OCH3)(CF3)C-CO-L-DOPA[OBn]2-OMe
6B, respectively (Fig. 3),26 having distinct CF3 signals
in 19F NMR with toluene-d8 as best solvent (Fig. 4),
which allowed determination of the diastereoisomeric
excess (de). An average >95% de was found for 6A
and 6B, as expected for an enantiomerically pure, or
nearly so, amino ester 2, taking into account the syn-
thetic nature (<100% ee) of the Mosherꢀs acids.
Figure 4. The CF3 signals in the 19F NMR spectra of the Mosherꢀs
amides (Fig. 3). Left: 6A (top), 6A+6B (center) and 6B (bottom) in
toluene-d8; right: 7A (top), 7A+7B (center) and 7B (bottom) in CDCl3.
prepared diazomethane in diethyl ether from 0 ꢁC to rt
led to the diazoketone Boc-L-DOPA[OBn]2-CHN2
4
COOMe
COOMe
BnO
BnO
BnO
BnO
25
D
{mp 127 ꢁC, ½aꢂ ¼ þ18 (c 0.5, MeOH)}, which was iso-
CF3
CF3
H
H
lated in 90% yield after chromatography, but was later
advantageously used as crude material directly in the
next step. Wolff rearrangement27 of 4 upon treatment
with silver benzoate and triethylamine in MeOH with
the exclusion of light,17 afforded the fully protected
HN
HN
OMe
OMe
Ph
Ph
O
O
6A
6B
b-amino ester (S)-Boc-b3-H-DOPA[OBn]2-OMe 5 {mp
25
D
122 ꢁC, ½aꢂ ¼ ꢀ14 (c 0.4, MeOH)} in 63–67% yield.
CH2-COOMe
CH2-COOMe
BnO
BnO
BnO
BnO
CF3
CF3
H
H
Here again, the absence of epimerization of the C-
activated mixed anhydride, was checked by 19F
NMR of the diastereoisomeric amido esters (R)-
Ph(OCH3)(CF3)C-(S)-b3-H-DOPA[OBn]2-OMe 7A and
(S)-Ph(OCH3)(CF3)C-(S)-b3-H-DOPA[OBn]2-OMe 7B
(Fig. 3),26 obtained after N-deprotection of an aliquot
of 5 in TFA/dichloroethane followed by coupling of
two portions of the resulting (S)-H-b3-H-DOPA-
[OBn]2-OMe with a large excess of (+)-(R)-MTPA
and (ꢀ)-(S)-MTPA, respectively, by the EDC/HOBt
method as above. The distinct CF3 signals in 19F
NMR with CDCl3 as best solvent (Fig. 4) allowed the
determination of the diastereoisomeric excess. An aver-
age of >95% de was found for 7A and 7B, demonstrat-
ing the absence of an appreciable racemization in the
Arndt–Eistert homologation of 3 to 5, as expected from
the previous studies of Seebach and co-workers17 rela-
tive to many other amino acid structures. Finally,
deprotection of the catechol function of 5 by hydrogen-
HN
HN
OMe
OMe
Ph
Ph
O
O
7A
7B
Figure 3. Chemical structures of the pairs of Mosherꢀs amides
(R)-Ph(OCH3)(CF3)C-CO-L-DOPA[OBn]2-OMe 6A, (S)-Ph(OCH3)-
(CF3)C-CO-L-DOPA[OBn]2-OMe 6B, and (R)-Ph(OCH3)(CF3)C-(S)-
b3-H-DOPA[OBn]2-OMe 7A, (S)-Ph(OCH3)(CF3)C-(S)-b3-H-DOPA-
[OBn]2-OMe 7B, obtained from 2 and 5, respectively.
In a second experiment, an aliquot of Boc-L-DO-
PA[OBn]2-OH 3 obtained after saponification of 2 was
re-esterified back to 2 with tetramethylsilyldiazome-
thane and then N-deprotected to the amino ester H-L-
DOPA[OBn]2-OMe of the same assumed enantiomeric
purity as its precursor 3. This aliquot was coupled with
(+)-(R)-MTPA by the EDC/HOBt method and the
resulting amido ester 6A analyzed by 19F NMR in tolu-
ene-d8 as above.26 Again >95% de was found for 6A,
demonstrating the absence of racemization in the sapon-
ification reaction of 2 to 3 under the employed exper-
imental conditions.
olysis over palladium on charcoal, afforded the desired
I
25
{½aꢂ ¼ ꢀ22 (c 0.1,
(S)-Boc-b3-H-DOPA-OMe
MeOH)} in 93–99% yield.
D
It is interesting to point out that our goal was to synthe-
size a relatively large amount of (S)-Boc-b3-H-DOPA-
OMe I in order to use this compound as starting mate-
rial for further studies. This implied carrying out each
step of the reaction sequence on a multigram scale and
repeating the experiments. Therefore, the present work
In the next Arndt–Eistert homologation step, the car-
boxylic acid group of 3 was activated to the mixed anhy-
dride Boc-L-DOPA[OBn]2-OCOOEt by treatment with
ethyl chloroformate and triethylamine in THF at
ꢀ10 ꢁC for 15 min. Subsequent reaction with freshly

860
A. Gaucher et al. / Tetrahedron: Asymmetry 16 (2005) 857–864
constitutes a practical synthesis of the novel b-amino
acid residue (S)-b3-H-DOPA, which altogether has been
obtained at a ca. 15 g scale from L-DOPA by a straight-
forward sequence devoid of appreciable racemization.
As emphasized earlier, (S)-Boc-b3-H-DOPA-OMe was
synthesized in view of its potential use as a building
block for the construction of new families of crowned-
b-peptides. However, based on the extensive studies
involving L-DOPA derivatives and/or catechol-contain-
ing derivatives and peptides, we believe that (S)-b3-H-
DOPA itself has a great future beyond our present inter-
est and we hope that it will be considered by other re-
search groups for a variety of applications and designs.
mp 140–141 ꢁC. Rf = 0.35 (F). 1H NMR (CDCl3): d
1.41 [s, 9H, CH3Boc], 2.99 and 2.90 [dd and dd,
J = 13.9, 5.6 Hz and J = 13.9, 6.8 Hz, 2H, ArCH2],
3.72 [s, 3H, OCH3], 4.53 [m, 1H, CHa], 5.08 [d,
J = 8.3 Hz, 1H, NH], 6.50 [dd, J = 9.9 and 1.7 Hz, 1H,
ArH], 6.66 [d (br), 1H, ArH], 6.75 [d, J = 8.1 Hz, 1H,
ArH]. 13C NMR (CDCl3): d 28.2 (CH3Boc), 37.7
(ArCH2), 52.4 (OCH3), 54.7 (CHa), 80.6 (O–C Boc),
115.3, 116.1, 121.3, 128.0, 143.1, 144.0 (CAr), 155.6
25
25
(CO Boc), 172.8 (CO). ½aꢂ ¼ þ7; ½aꢂ ¼ þ7;
D
578
25
546
25
436
25
365
½aꢂ ¼ þ8; ½aꢂ ¼ þ18; ½aꢂ ¼ þ43 (c 1.2, MeOH);
26
D
lit.19 ½aꢂ ¼ þ7:6 (c 1.2, MeOH). Another run gave
85% yield and mp 135 ꢁC.13a Other runs gave 88–95%
yields.
3. Experimental
3.1. General
3.3. (S)-Methyl N-(tert-butyloxycarbonyl)-3,4-bis(benz-
yloxy)phenylalanine carboxylate, Boc-L-DOPA[OBn]2-
OMe 2
Melting points were determined using either a Mettler
To a solution of 1 (10.35 g, 33.3 mmol) in acetone
(170 mL) were added K2CO3 (10 g, 73 mmol), NaI
(0.5 g, 6.6 mmol), n-Bu4N+Brꢀ (2.14 g, 6.6 mmol) and
PhCH2Br (11.9 mL, 100 mmol). The reaction mixture
was refluxed under argon atmosphere for ca. 4 h and
evaporated in vacuo. The residue was taken up in
CH2Cl2 (500 mL) and water (200 mL). After decanta-
tion, the separated aqueous phase was extracted with
CH2Cl2 (2 · 100 mL). The combined organic phase
was washed with water (2 · 100 mL), dried over MgSO4,
filtered and evaporated in vacuo. The obtained crude
product was chromatographed on a column of silica
gel with eluent (A), then (B), to afford Boc-L-DO-
PA[OBn]2-OMe 2 (15.56 g, 95%) as a white solid. Mp
112 ꢁC. Rf = 0.44 (B). 1H NMR (CDCl3): d 1.44 [s,
9H, CH3Boc], 3.00 [m (poorly resolved ABX system),
2H, ArCH2], 3.65 [s, 3H, OCH3], 4.54 [m, 1H, CHa],
4.97 [d, J = 7.9 Hz, 1H, NH], 5.30 [s, 4H, OCH2Ph],
6.65 [dd, J = 8.2 and 1.9 Hz, 1H, ArH] ; 6.74 [d,
J = 1.9 Hz, 1H, ArH]; 6.87 [d, J = 8.1 Hz, 1H, ArH];
7.41 [m, 10H, ArHOBn]. 13C NMR (CDCl3): d 28.7
(CH3Boc), 38.2 (ArCH2), 52.5 (OCH3), 54.8 (CHa),
71.7, 71.8 (OCH2Ph), 80.3 (O–C Boc); 115.6, 116.6,
122.7, 127.7, 128.2, 137.7, 148.5, 149.3 (CAr);
FP61 apparatus with a temperature raise of 3 ꢁC/min
or a Tottoli apparatus (Buchi), and are reported uncor-
¨
1
rected. H NMR and 13C NMR spectra were recorded
at 300 and 77 MHz, respectively, the solvent CDCl3
being used as the internal standard (d = 7.27 ppm for
1H and 77.00 ppm for 13C). Splitting patterns are abbre-
viated as follows: (s) singlet, (d) doublet, (t) triplet, (q)
quartet, (m) multiplet. The optical rotations were mea-
sured with an accuracy of 0.3%, in a 1 dm thermostated
cell. Analytical TLC and preparative column chroma-
tography were performed on Kieselgel F 254 and Kiesel-
gel 60 (0.040–0.063 mm) (Merck), respectively, with the
following eluent systems: 1% EtOAc (ethyl acetate)–99%
CH2Cl2 (A); 2% EtOAc–98% CH2Cl2 (B); 3% EtOAc–
97% CH2Cl2 (C); 1% MeOH–99% CH2Cl2 (D); 3%
MeOH–97% CH2Cl2 (E); 5% MeOH–95% CH2Cl2 (F);
10% MeOH–90% CH2Cl2 (G). UV light (k = 254 nm)
allowed visualization of the spots after TLC runs for
all compounds, even at low concentration. The special
apparatus used for the preparation of diazomethane
was purchased from Aldrich.
3.2. (S)-Methyl N-(tert-butyloxycarbonyl)-3,4-
bis(hydroxy)phenylalanine carboxylate, Boc-L-
DOPA-OMe 1
25
25
155.5 (CO Boc); 172.7 (CO). ½aꢂ ¼ þ35; ½aꢂ
¼
D
578
25
25
25
þ36; ½aꢂ ¼ þ42; ½aꢂ ¼ þ72; ½aꢂ ¼ þ130 (c
546
436
365
0.5, CH2Cl2), lit.21 [a]D = +25.0 (c 2, CH2Cl2) for the
corresponding ethyl ester. Anal. Calcd for C29H33NO6
(491.562): C, 70.85; H, 6.77; N, 2.85. Found: C, 70.81;
H, 6.75; N, 2.78. Other similar runs all gave ca. 90%
yield. In a previous experiment, to a suspension of
Boc-L-DOPA-OMe (11.3 g, 36.4 mmol), K2CO3
(10.56 g, 76.5 mmol) and NaI (1.1 g, 7.2 mmol) in ace-
tone (220 mL), was added PhCH2Br (8.7 mL;
76.5 mmol). The mixture was stirred at 50 ꢁC for 4 h
and evaporated in vacuo. The residue was taken up in
CH2Cl2 (500 mL), the organic solution washed with
3 · 100 mL H2O, dried over MgSO4 filtered and evapo-
rated in vacuo. The crude product was chromato-
graphed on a column of silica gel with eluent (D) to
give 10.2 g of pure dibenzylated compound 2, and a mix-
ture of mono and dibenzylated compounds. This
mixture was treated again with K2CO3 (7.5 g), NaI
(0.41 g) and PhCH2Br (6.3 mL) in refluxing acetone
In a round-bottomed flask containing MeOH (60 mL)
cooled to 0 ꢁC, was slowly added SOCl2 (10 mL) and
then H-L-DOPA-OH (5.0 g, 25.4 mmol) in small
portions. The reaction mixture was stirred at rt for
24 h and evaporated in vacuo, to afford H-L-DOPA-
OMeÆHCl (6.28 g) as a white solid. To a solution of this
compound (5.96 g, 24.1 mmol) and NaHCO3 (4.04 g,
48.2 mmol) in water (49 mL) was added a solution of
Boc2O (5.25 g, 24.1 mmol) in THF (36 mL). The mix-
ture was magnetically stirred at rt for 18 h and THF
then evaporated in vacuo. The mixture was extracted
with EtOAc (3 · 150 mL), the combined organic phase
was washed with 0.5 M HCl (2 · 25 mL), then H2O
(2 · 25 mL), dried over MgSO4 filtered and evaporated
in vacuo. The obtained white solid was crystallized from
MeOH/H2O 2.8:1, to afford Boc-L-DOPA-OMe 1
(7.36 g, 98%). Mp 138 ꢁC, lit.19 mp 133–135 ꢁC; lit.20

A. Gaucher et al. / Tetrahedron: Asymmetry 16 (2005) 857–864
861
(150 mL). After chromatography, a combined sample of
solution of diazomethane added. The reaction mixture
was allowed to warm-up to rt and then stirred for
18 h. After dilution with EtOAc (600 mL), the organic
solution was successively extracted with saturated aque-
ous solutions of NaHCO3 (100 mL), NH4Cl (100 mL)
and NaCl (100 mL), dried over MgSO4, filtered and
evaporated in vacuo. The crude product was chromato-
graphed on a column of silica gel with eluents (D), then
(E), to afford pure Boc-L-DOPA[OBn]2-CHN2 4 (5.94 g,
90%) as a white solid. Other similar runs gave 77–80%13a
yields. In other runs the crude products (89–96% yields)
were used in the next step (Wolff rearrangement to 5)
without chromatographic purification. Mp 127 ꢁC.
Rf = 0.40 (C). 1H NMR (CDCl3): d 1.43 [s, 9H,
CH3Boc], 2.91 [m, 2H, ArCH2], 4.33 [m, 1H, CHa],
5.08 [m (br), 2H, NH and CH@N2], 5.14 [s, 4H,
OCH2Ph], 6.69 [dd, J = 8.3 and 2.0 Hz, 1H, ArH], 6.80
[d (br), 1H, ArH], 6.87 [d, J = 8.3 Hz, 1H, ArH]; 7.32
[m, 10H, ArHOBn]. 13C NMR (CDCl3): d 28.3
(CH3Boc), 38.1 (ArCH2), 54.3 (CH@N2), 58.4 (CHa),
71.2, 71.3 (OCH2Ph), 80.0 (O–C Boc); 115.3, 116.2,
122.3, 127.4, 127.7, 127.8, 128.4, 128.5, 129.5, 137.1,
137.2, 148.0, 148.9 (CAr); 155.1 (CO Boc); 193.3 (CO).
25
D
pure 2 (15.30 g, 85%) was obtained, with ½aꢂ ¼ þ42 (c
0.5, CH2Cl2).13a
3.4. (S)-N-(tert-Butyloxycarbonyl)-3,4-bis(benzyloxy)-
phenylalanine carboxylic acid, Boc-L-DOPA[OBn]2-
OH 3
To a solution of 2 (14.98 g, 30.5 mmol) in MeOH
(50 mL) and THF (100 mL), cooled to 0 ꢁC, was added
a solution of aqueous NaOH (38 mL; 38 mmol). The
mixture was magnetically stirred at rt for 24 h, cooled
to 0 ꢁC and acidified to pH ꢃ2 by addition of a solution
of 0.5 M HCl (85 mL). The solution was concentrated in
vacuo in order to eliminate most of the solvents, MeOH
and THF, and then extracted with three portions of
CH2Cl2 (3 · 300 mL). The organic phase was washed
with water (200 mL), dried over MgSO4, filtered and
evaporated in vacuo, to afford pure Boc-L-DO-
PA[OBn]2-OH 3 (14.10 g, 97%) as a white solid. Other
runs gave 87% yield (crude),13a 96% yield (crude), and
89% yield (after column chromatography). Mp 120 ꢁC,
lit.19 mp 105–107 ꢁC; lit.22 mp 139–141 ꢁC. Rf = 0.54
25
25
25
25
1
(G). H NMR (CDCl3): d 1.42 [s, 9H, CH3Boc], 3.04
½aꢂ ¼ þ18; ½aꢂ ¼ þ18; ½aꢂ ¼ þ20; ½aꢂ ¼ þ36 (c
D
578
546
436
[m (poorly resolved ABX system), 2H, ArCH2], 4.52
[m, 1H, CHa]; 4.93 [d (br), 1H, NH], 5.11 [s, 4H,
OCH2Ph], 6.69 [d, J = 7.6 Hz, 1H, ArH], 6.80 [s, 1H,
ArH], 6.85 [d, J = 8.0 Hz, 1H, ArH], 7.37 [m, 10H,
ArH OBn], 8.36 [s (br), 1H, COOH]. 13C NMR
(CDCl3): d 28.2 (CH3Boc), 36.1 (ArCH2), 48.6 (CHa),
70.2, 70.2 (OCH2Ph), 77.9 (O–C Boc), 114.4, 115.7,
121.8, 127.4, 127.6, 127.7, 127.8, 128.3, 128.4, 131.2,
137.5, 146.8, 148.0 (CAr), 155.4 (CO Boc), 173.9 (CO).
0.5, MeOH). Anal. Calcd for C29H31N3O5 (501.562):
C, 69.44; H, 6.23; N, 8.38. Found: C, 69.58; H, 6.26;
N, 8.07.
3.6. (S)-Methyl N-(tert-butyloxycarbonyl)-b3-homo-3,4-
bis(benzyloxy)phenylalanine carboxylate, (S)-Boc-b3-H-
DOPA[OBn]2-OMe 5
In a three-necked round-bottomed flask containing 4
(5.94 g, 11.9 mmol) was added MeOH (360 mL) and
anhydrous THF (250 mL). The solution was magneti-
cally stirred under an argon atmosphere with exclusion
of light, and cooled to ca. ꢀ15 ꢁC (ice-salt bath). A solu-
tion of silver benzoate (0.298 g, 1.30 mmol) in anhy-
drous triethylamine (4.78 mL; 34.4 mmol) was added,
the reaction mixture allowed to slowly warm up to rt
and stirred for 3 h. The solvents were evaporated in
vacuo and the residue taken up in EtOAc (300 mL).
The organic solution was successively extracted with sat-
urated aqueous solutions of NaHCO3 (2 · 150 mL),
NH4Cl (2 · 150 mL) and NaCl (2 · 150 mL), dried over
MgSO4, filtered and evaporated in vacuo. The obtained
crude product, a brownish solid, was chromatographed
on a column of silica gel with eluent (C), to afford (S)-
Boc-b3-H-DOPA[OBn]2-OMe 5 (3.67 g, 61%) as a white
solid. Other similar runs gave 62–63%13a yields. Mp
122 ꢁC. Rf = 0.34 (C). 1H NMR (CDCl3): d 1.43 [s,
9H, CH3Boc], 2.43 [m (partly resolved ABX system),
JAB = 15.8 Hz, 2H, CH2COOMe], 2.74 [m (partly re-
solved ABX system), JAB = 13.5 Hz, 2H, ArCH2], 3.68
[s, 3H, OCH3], 4.13 [m, 1H, CHa], 4.98 [d, J = 7.7 Hz,
1H, NH], 5.13 [s, 2H, OCH2Ph], 5.14 [s, 2H, OCH2Ph],
6.68 [dd, J = 8.3 and 2.0 Hz, 1H, ArH], 6.80 [d (br), 1H,
ArH], 6.87 [d, J = 8.3 Hz, 1H, ArH], 7.40 [m, 10H, ArH
OBn]. 13C NMR (CDCl3): d 28.3 (CH3Boc), 37.4
(ArCH2), 39.7 (CH2COOMe), 48.7 (CHa), 51.5
(OCH3), 71.3, 71.4 (OCH2Ph), 79.3 (O–C Boc), 115.3,
116.4, 122.3, 127.2, 127.4, 127.6, 127.7, 128.4, 131.0,
137.2, 137.4, 147.8, 148.9 (CAr), 155.0 (CO Boc),
25
D
25
578
25
546
25
436
½aꢂ ¼ þ14:4; ½aꢂ ¼ þ15; ½aꢂ ¼ þ16; ½aꢂ
¼
25
365
25
D
þ31; ½aꢂ ¼ þ62 (c 0.5, MeOH); lit.19 ½aꢂ ¼ þ14:2 (c
1, MeOH). Anal. Calcd for C28H31NO6ÆH2O (495.552):
C, 67.85; H, 6.71; N, 2.82. Found: C, 67.76; H, 6.38;
N, 2.68.
3.5. (S)-N-(tert-Butyloxycarbonyl)-3,4-bis(benzyloxy)-
phenylalanine diazoketone, Boc-L-DOPA[OBn]2-
CHN2 4
For preparation of diazomethane [Caution: explosive.
The generation and handling with diazomethane require
special precautions]28 a solution of KOH pellets (3.70 g,
66 mmol) in water (7 mL) was introduced in a specially
designed glass apparatus (Aldrich). Carbitol (22 mL)
and diethyl ether (7 mL) were then added. The mixture
was magnetically stirred and heated at 70 ꢁC, while a
solution of Diazaldꢂ (14.1 g, 66 mmol) in diethyl ether
(95 mL) placed in an addition funnel, was added drop-
wise. The resulting distillate of an ethereal solution of
diazomethane was maintained at 0 ꢁC by means of an
ice-water cooling bath for a few minutes until its use
in the following step. In a three-necked round-bottomed
flask containing 3 (6.30 g, 13.2 mmol) was added THF
(85 mL). The solution was magnetically stirred under
an argon atmosphere and cooled to ca. ꢀ15 ꢁC (ice-salt
bath). Triethylamine (1.84 mL, 13.2 mmol) was added,
followed by ethyl chloroformate (1.25 mL, 13.2 mmol).
The resulting white suspension was stirred from ꢀ15
to 0 ꢁC for 15–20 min and the freshly prepared ethereal

862
A. Gaucher et al. / Tetrahedron: Asymmetry 16 (2005) 857–864
25
D
25
578
25
546
172.0 (CO). ½aꢂ ¼ ꢀ14; ½aꢂ ¼ ꢀ14; ½aꢂ
¼
3H, OCH3 from MTPA], 3.68 [s, 3H, OCH3], 4.85 [m,
1H, CHa], 5.14 [s, 2H, OCH2Ph], 5.15 [s, 2H, OCH2Ph],
6.66 [dd (br), J = 8.0 Hz, 1H, ArH], 6.79 [d, J = 1.5 Hz,
1H, ArH], 6.88 [d, J = 8.1 Hz, 1H, ArH], 7.2–7.5 [m,
16H, ArH OBn, ArH from MTPA and NH] (some of
the signals corresponding to the other diastereoisomer,
that is, the enantiomer of 6B, present in <5% ratio).
19F NMR (toluene-d8): d ꢀ69.14 (ca. 99%); ꢀ69.00
(ca. 1%) [de ꢃ 98%].
25
436
25
365
ꢀ17; ½aꢂ ¼ ꢀ33; ½aꢂ ¼ ꢀ58 (c 0.5, MeOH). Anal.
Calcd for C30H35NO6 (505.588): C, 71.26; H, 6.98; N,
2.77. Found: C, 71.26; H, 6.99; N, 2.74.
3.7. (S)-Methyl N-(tert-butyloxycarbonyl)-b3-homo-3,4-
bis(hydroxy)phenylalanine carboxylate, (S)-Boc-b3-H-
DOPA-OMe I
To a solution of 5 (2.00 g, 3.96 mmol) in a mixture of
MeOH (60 mL) and THF (60 mL) kept under an argon
stream was added 10% Pd/C (1.0 g). The mixture was
maintained under an H2 atmosphere and stirred at rt
for 18 h. Filtration and evaporation of the solvents in
vacuo gave a brownish oil, which was chromatographed
on a column of silica gel with eluent (F), to afford pure
(S)-Boc-b3-H-DOPA-OMe I (1.22 g, 95%) as a yellow
oil. Other similar runs gave 84–99%13a yields. Rf = 0.38
In a parallel manner, to a solution of crude H-L-DO-
PA[OBn]2-OMe (0.023 g, 0,059 mmol), (ꢀ)-(S)-MTPA
(0.021 g, 0.089 mmol) and HOBt (0.016 g, 0.12 mmol)
in CH2Cl2 (1 mL), was added EDC (0.017 g,
0.089 mmol). The solution was magnetically stirred at
rt for 18 h. Work-up as above, followed by preparative
TLC on silica gel with eluent (A),26 afforded the amido
ester (S)-Ph(OCH3)(CF3)C-CO-L-DOPA[OBn]2-OMe
1
1
(F). H NMR (CDCl3): d 1.38 [s, 9H, CH3Boc], 2.45
6B (0.018 g, 50%). H NMR (CDCl3): d 3.05 [m (partly
[m (partly resolved ABX system), JAB = 15.8 Hz, 2H,
CH2COOMe], 2.64 [m (poorly resolved ABX system),
2H, ArCH2], 3.63 [s, 3H, OCH3], 4.09 [m, 1H, CHa],
5.29 [d, J = 8.8 Hz, 1H, NH], 6.49 [dd, J = 8.1 and
1.8 Hz, 1H, ArH], 6.71 [d (br), 1H, ArH], 6.74 [d,
J = 8.1 Hz, 1H, ArH], 7.17 [s (br), 2H, ArOH]. 13C
NMR (CDCl3): d 28.1 (CH3Boc), 37.6 (ArCH2), 39.8
(CH2COOMe), 48.9 (CHa), 51.6 (OCH3), 79.9 (O–C
Boc), 115.3, 116.2, 121.2, 129.5, 142.8, 144.0 (CAr),
resolved ABX system), J = 13.9 Hz, 2H, ArCH2], 3.43
[m, 3H, OCH3 from MTPA], 3.70 [s, 3H, OCH3], 4.91
[s, 2H, OCH2Ph], 4.92 [m, 1H, CHa], 5.12 [s, 2H,
OCH2Ph], 6.42 [dd, J = 8.1 and 1.6 Hz, 1H, ArH]; 6.59
[d, J = 1.7 Hz, 1H, ArH]; 6.74 [d, J = 8.1 Hz, 1H,
ArH]; 7.2–7.5 [m, 16H, ArH OBn, ArH from MTPA
and NH] (some of the signals corresponding to the other
diastereoisomer, i.e., the enantiomer of 6A, present in
<5% ratio). 19F NMR (toluene-d8): d ꢀ69.14 (ca.
3.5%); ꢀ69.00 (ca. 96.5%) [de ꢃ 93%].
25
25
155.7 (CO Boc), 172.4 (CO). ½aꢂ ¼ ꢀ22; ½aꢂ ¼ ꢀ23;
D
578
25
546
25
436
25
365
½aꢂ ¼ ꢀ28; ½aꢂ ¼ ꢀ46; ½aꢂ ¼ ꢀ65 (c 0.1, MeOH).
Anal. Calcd for C16H23NO6 (325.352): C, 59.06; H,
7.12; N, 4.31. Found: C, 59.15; H, 7.21; N, 4.08.
In the same manner, to a solution of 3 (0.102 g,
0.21 mmol) in CH2Cl2 (2 mL) and anhydrous MeOH
(2 mL) kept under an argon atmosphere, was added by
syringe TMSCHN2 (158 lL, 0.32 mmol). The solution
was magnetically stirred at rt for 6 h and evaporated
in vacuo. The crude product was chromatographed on
a preparative TLC plate of silica gel with eluent (A),
to afford Boc-L-DOPA[OBn]2-OMe 2 (0.064 g, 62%).
In the next step, a solution of 2 (0.025 g, 0.05 mmol)
in 1,2-dichloroethane (1 mL) cooled to 0 ꢁC was treated
with TFA (0.36 mL) for 30 min. Work-up as above gave
crude H-L-DOPA[OBn]2-OMe (0.013 g, 0.03 mmol),
which was dissolved in CH2Cl2 (1 mL) and coupled with
(+)-(R)-MTPA (0.012 g, 0.05 mmol) in the presence of
EDC (0.009 g, 0.05 mmol) and HOBt (0.009 g,
0.07 mmol), at rt for 18 h. Work-up as above, followed
by preparative TLC on silica gel with eluent (A),26 af-
forded the amido ester (R)-Ph(OCH3)(CF3)C-CO-L-
DOPA[OBn]2-OMe 6A (0.008 g, 40%). 1H NMR
(CDCl3): see above. 19F NMR (toluene-d8): d ꢀ69.14
(ca. 97.5%), ꢀ69.00 (ca. 2.5%) [de ꢃ 95%].
3.8. (R)-Ph(OCH3)(CF3)C-CO-L-DOPA[OBn]2-OMe
6A and (S)-Ph(OCH3)(CF3)C-CO-L-DOPA[OBn]2-
OMe 6B obtained from 2 and 3
To a solution of 2 (0.100 g, 0.20 mmol) in 1,2-dichloro-
ethane (2 mL) cooled to 0 ꢁC was added TFA (0.72 mL).
The solution was magnetically stirred at 0 ꢁC for 30 min
and evaporated in vacuo at 25 ꢁC [Note: we have ob-
served the occurrence of a partial debenzylation of the
ArOBn groups in TFA/CH2Cl2 1:2 when the solution
is kept at room temperature for several hours]. The res-
idue was dissolved in CH2Cl2 (100 mL), the solution
then successively washed with 5% aq NaHCO3
(2 · 50 mL) and brine (2 · 50 mL), dried over MgSO4,
filtered and evaporated in vacuo, to furnish crude H-L-
DOPA[OBn]2-OMe (0.058 g, 74%). In the next step, to
a solution of this compound (0.019 g, 0.048 mmol),
(+)-(R)-MTPA (a-methoxy-a-trifluoromethyl-a-phenyl-
acetic acid) (0.017 g, 0.072 mmol) and HOBt (0.013 g,
0.096 mmol) in CH2Cl2 (1 mL), was added EDC
(0.014 g, 0.072 mmol). The solution was magnetically
stirred at rt for 18 h, diluted with CH2Cl2 (50 mL),
and successively extracted with 0.5 M HCl (2 · 25 mL),
5% NaHCO3 (2 · 25 mL) and brine (2 · 25 mL), dried
over MgSO4, filtered and evaporated in vacuo. The
crude product was chromatographed on a preparative
TLC plate of silica gel with eluent (A),26 to afford the
amido ester (R)-Ph(OCH3)(CF3)C-CO-L-DOPA[OBn]2-
3.9. (R)-Ph(OCH3)(CF3)C–(S)-b3-H-DOPA[OBn]2-
OMe 7A and (S)-Ph(OCH3)(CF3)C-(S)-b3-H-
DOPA[OBn]2-OMe 7B obtained from 5
To a solution of 5 (0.147 g; 0.29 mmol) in 1,2-dichloro-
ethane (3 mL) cooled to 0 ꢁC was added TFA (1 mL).
The solution was magnetically stirred at 0 ꢁC for
35 min and evaporated in vacuo at 25 ꢁC. The residue
was dissolved in CH2Cl2 (100 mL), the solution then
successively washed with 5% aq NaHCO3 (2 · 50 mL)
and brine (2 · 50 mL), dried over MgSO4, filtered and
1
OMe 6A (0.015 g, 51%). H NMR (CDCl3): d 3.09 [m
(poorly resolved ABX system), 2H, ArCH2], 3.19 [m,

A. Gaucher et al. / Tetrahedron: Asymmetry 16 (2005) 857–864
863
evaporated in vacuo, to furnish crude (S)-H-b3-H-DO-
PA[OBn]2-OMe (0.129 g). In the next step, to a solution
of this compound (0.051 g, 0.13 mmol), (+)-(R)-MTPA
(0.045 g, 0.19 mmol) and HOBt (0.035 g, 0.26 mmol) in
CH2Cl2 (2 mL), was added EDC (0.036 g, 0.19 mmol).
The solution was magnetically stirred at rt for 18 h, di-
luted with CH2Cl2 (50 mL), and successively extracted
with 0.5 M HCl (2 · 25 mL), 5% NaHCO3 (2 · 25 mL)
and brine (2 · 25 mL), dried over MgSO4, filtered
and evaporated in vacuo. The crude product was
chromatographed on a preparative TLC plate of silica
gel with eluent (C),26 to afford the amido ester
(R)-Ph(OCH3)(CF3)C-(S)-b3-H-DOPA[OBn]2-OMe 7A
7. It is noteworthy that the so-called (R)-b-DOPA, a natural
b-amino acid regioisomer of D-DOPA, previously isolated
as a FeIII–catechol complex present in a mushroom
pigment and synthesized in view of structural elucidation,8
as well as the known corresponding racemic compound
(R,S)-b-DOPA,9 are structurally different from the pres-
ently described b-homo DOPA derivative (S)-b3-H-
DOPA.
8. VonNussbaum, F.; Spiteller, P.; Ruth, M.; Steglich, W.;
¨
Wanner, G.; Gamblin, B.; Stievano, L.; Wagner, F. E.
Angew. Chem., Int. Ed. 1998, 37, 3292–3295.
9. Posner, T. Justus Liebigs Ann. Chem. 1912, 389, 1–120.
10. For recent review articles, see: (a) Cheng, R. P.; Gellman,
S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219–3232;
(b) Seebach, D.; Kimmerlin, T.; Sebesta, R.; Campo, M.
A.; Beck, A. K. Tetrahedron 2004, 60, 7455–7506.
11. For leading recent references, see: (a) Frackenpohl, J.;
Arvidsson, P. I.; Schreiber, J. V.; Seebach, D. ChemBio-
Chem 2001, 2, 445–455; (b) Steer, D. L.; Lew, R. A.;
Perlmutter, P.; Smith, A. I.; Aguilar, M.-I. Curr. Med.
Chem. 2002, 9, 811–822; (c) Patch, J. A.; Barron, A. E.
Curr. Opin. Chem. Biol. 2002, 6, 872–877; (d) Gelman, M.
A.; Richter, S.; Cao, H.; Umezawa, N.; Gellman, S. H.;
Rana, T. M. Org. Lett. 2003, 5, 3563–3565; (e) Arvidsson,
P. I.; Ryder, N. S.; Weiss, H. M.; Gross, G.; Kretz, O.;
Woessner, R.; Seebach, D. ChemBioChem 2003, 4, 1345–
1347; (f) Epand, R. F.; Raguse, T. L.; Gellman, S. H.;
Epand, R. M. Biochemistry 2004, 43, 9527–9535; (g)
Kritzer, J. A.; Lear, J. D.; Hodsdon, M. E.; Schepartz, A.
J. Am. Chem. Soc. 2004, 126, 9468–9469; (h) Schmitt, M.
A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004,
126, 6848–6849.
(0.048 g, 59%). 1H NMR (CDCl3):
d 2.49 [d,
J = 5.7 Hz, 2H, CH2COOMe], 2.86 [m (partly resolved
ABX system), JAB = 13.7 Hz, 2H, ArCH2], 3.25 [m,
3H, OCH3 from MTPA], 3.62 [s, 3H, OCH3], 4.47 [m,
1H, CHa], 5.15 [s, 4H, OCH2Ph], 6.70 [dd, J = 8.0 and
1.9 Hz, 1H, ArH], 6.84 [d, J = 1.9 Hz, 1H, ArH], 6.88
[d, J = 8.2 Hz, 1H, ArH], 7.2–7.5 [m, 16H, ArH OBn,
ArH from MTPA and NH] (some of the signals corre-
sponding to the other diastereoisomer, i.e., the enantio-
mer of 7B, present in <5% ratio). 19F NMR (CDCl3): d
ꢀ69.40 (ca. 1.5%), ꢀ69.31 (ca. 98.5%) [de ꢃ 97%].
In a parallel manner, to a solution of crude (S)-H-b3-
H-DOPA[OBn]2-OMe (0.051 g, 0,12 mmol), (ꢀ)-(S)-
MTPA (0.045 g, 0.19 mmol) and HOBt (0.035 g,
0.26 mmol) in CH2Cl2 (2 mL), was added EDC
(0.036 g, 0.19 mmol). The solution was magnetically stir-
red at rt for 18 h. Work-up as above, followed by pre-
parative TLC on silica gel with eluent (C),26 afforded
the amido ester (S)-Ph(OCH3)(CF3)C-(S)-b3-H-DO-
12. For review articles, see: (a) Hartgerink, J. D.; Clark, T. D.;
Ghadiri, M. R. Chem. Eur. J. 1998, 4, 1367–1372; (b)
Koert, U.; Al-Mohani, L.; Pfeifer, J. R. Synthesis 2004,
1129–1146.
1
13. Preliminary reports of this work have been published, also
mentioning the synthesis of the terminally protected
crowned residue Boc-(S)-b3-H-DOPA[18-C-6]-OMe: (a)
Gaucher, A.; Barbeau, O.; Hamchaoui, W.; Vandromme,
L.; Wright, K.; Wakselman, M.; Mazaleyrat, J.-P. Tetra-
hedron Lett. 2002, 43, 8241–8244; (b) Mazaleyrat,
J.-P.; Wright, K.; Gaucher, A.; Dutot, L.; Barbeau, O.;
Wakselman, M.; Oancea, S.; Formaggio, F.; Toniolo, C.
In Peptides 2004; Proceedings of the 28th European Peptide
Symposium, in press.
PA[OBn]2-OMe 7B (0.054 g, 72%). H NMR (CDCl3):
d 2.56 [m, 2H, CH2COOMe], 2.82 [m, 2H, ArCH2],
3.25 [m, 3H, OCH3 from MTPA], 3.70 [s, 3H, OCH3],
4.55 [m, 1H, CHa], 5.05 [s, 2H, OCH2Ph], 5.15 [s, 2H,
OCH2Ph], 6.63 [dd, J = 8.2 and 2.0 Hz, 1H, ArH], 6.78
[d, J = 1.9 Hz, 1H, ArH], 6.84 [d, J = 8.1 Hz, 1H,
ArH], 7.2–7.5 [m, 16H, ArH OBn, ArH from MTPA
and NH] (some of the signals corresponding to the other
diastereoisomer, i.e., the enantiomer of 7A, present in
<5% ratio). 19F NMR (CDCl3): d ꢀ69.40 (ca. 97.5%),
ꢀ69.31 (ca. 2.5%) [de ꢃ 95%].
14. See references cited in: Biron, E.; Otis, F.; Meillon, J.-C.;
Robitaille, M.; Lamothe, J.; Van Hove, P.; Cormier,
M.-E.; Voyer, N. Bioorg. Med. Chem. 2004, 12, 1279–
1290.
15. (a) Wright, K.; Melandri, F.; Cannizzo, C.; Wakselman,
M.; Mazaleyrat, J.-P. Tetrahedron 2002, 58, 5811–5820;
(b) Formaggio, F.; Oancea, S.; Peggion, C.; Crisma, M.;
Toniolo, C.; Wright, K.; Wakselman, M.; Mazaleyrat,
J.-P. Biopolymers (Pept. Sci.) 2003, 71, 667–674; (c)
Wright, K.; Melandri, F.; Wakselman, M.; Mazaleyrat,
J.-P.; Formaggio, F.; Oancea, S.; Crisma, M.; Toniolo, C.
In Peptide Revolution: Genomics, Proteomics and Thera-
peutics. In Proceedings of the 18th American Peptide
Symposium; Chorev, M., Sawyer, T. K., Eds.; American
Peptide Society, 2004; pp 51–52.
References
1. For leading references, see the historical review article:
Hornykiewicz, O. Amino Acids 2002, 1–6.
2. For leading references, see the review article: Albrecht, M.;
Stortz, P.; Nolting, R. Synthesis 2003, 9, 1307–1320.
3. Ashraf, M. A.; Jones, K.; Handa, S. Bioorg. Med. Chem.
Lett. 2000, 10, 1617–1620.
4. For leading references, see the review article: Galey, J.-B.
Mini Rev. Med. Chem. 2001, 1, 233–242.
5. Dalsin, J. L.; Hu, B.-H.; Lee, B. P.; Messersmith, P. B.
J. Am. Chem. Soc. 2003, 125, 4253–4258.
´
6. See, for example: (a) Leon-Romo, J. L.; Virues, C. I.;
Atvin˜a, J.; Regla, I.; Juristi, E. Chirality 2002, 14, 144–
16. The terminal protecting groups of our target Boc-(S)-b3-
H-DOPA-OMe I, were chosen because of their stability to
the basic conditions (Cs2CO3/DMF) required in the
planned further step of crown-ether formation.13–15 The
access to the corresponding Fmoc-(S)-b3-H-DOPA-OH
derivative, if needed, should be straightforward either by
Arnt–Eistert homologation of Fmoc-L-DOPA-OH with
convenient lateral protection, or from I by saponification
´
150; (b) Badorrey, R.; Cativiela, C.; Dıaz-de-Villegas, M.;
Galvez, J. A. Tetrahedron: Asymmetry 2003, 14, 2201–
´
2207; (c) Opezzo, J. A. W.; Ho¨cht, C.; Taira, C. A.
Pharmacol. Res. 2003, 48, 61–67.

864
A. Gaucher et al. / Tetrahedron: Asymmetry 16 (2005) 857–864
of the ester function, Na-Boc deprotection and Na-Fmoc
Intrasuksri, U.; McKenzie, J. L.; Feller, D. R. J. Med.
protection.
17. (a) Podlech, J.; Seebach, D. Liebigs Ann. Rec. 1995, 1217–
1228; (b) Matthews, J. L.; Overhand, M.; Kuhnle, F. N.
¨
Chem. 1990, 33, 1138–1144.
23. Clark, M. T.; Adejare, A.; Shams, G.; Feller, D. R.;
Miller, D. D. J. Med. Chem. 1987, 30, 86–90.
M.; Ciceri, P. E.; Seebach, D. Liebigs Ann. Rec. 1997,
1371–1379; (c) Matthews, J. L.; Braun, C.; Guibourden-
che, C.; Overhand, M.; Seebach, D. In Enantioselective
Synthesis of b-Amino Acids; Juaristi, E., Ed.; Wiley-VCH:
New York, 1997; pp 105–126; (d) Guichard, G.; Abele, S.;
Seebach, D. Helv. Chim. Acta 1998, 81, 187–206; (e)
Abele, S.; Vo¨gtli, K.; Seebach, D. Helv. Chim. Acta 1999,
82, 1539–1558.
24. The recorded specific rotation of compound
2
25
{½aꢂD ¼ þ35 (c 0.5, CH2Cl2)} is somewhat different to
25
the value obtained in a former experiment {½aꢂD ¼ þ42 (c
0.5, CH2Cl2)}13a and both values do not fit well with the
literature value for the corresponding ethyl ester
{[a]D = +25.0 (c 2, CH2Cl2)}.21 The reason for such
important fluctuations is probably the nature of the
solvent: CH2Cl2 is not considered as a solvent of choice
for specific rotation measurements, but was chosen by
reference to literature and because of the insolubility of 2
in methanol or ethanol.
18. Bodor, N.; Sloan, K. D.; Higuchi, T.; Sasahara, K. J.
Med. Chem. 1977, 20, 1435–1445.
19. Banerjee, S. N.; Ressler, C. J. Org. Chem. 1976, 41, 3056–
3058.
20. Rudd, E. A.; Cunningham, W. C.; Thanassi, J. W. J. Med.
Chem. 1979, 22, 233–237.
21. Kolasa, T.; Miller, M. J. J. Org. Chem. 1990, 55, 4246–
4255.
25. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543–2549.
26. Care was taken not to exercise a mechanical separation of
one of the diastereoisomers over the other.
27. Kirmse, K. Eur. J. Org. Chem. 2002, 2193–2256.
28. (a) Lombardi, P. Chem. Ind. (London) 1990, 708; (b)
Moss, S. Chem. Ind. (London) 1994, 122.
22. Miller, D. D.; Hamada, A.; Clark, M. T.; Adejare, A.;
Patil, P. N.; Shams, G.; Romstedt, K. J.; Kim, S. U.;