New crown-carrier Cα,α-disubstituted glycines derived from α-methyl-(L)-DOPA

Article abstract of DOI:10.1016/S0040-4020(02)00566-5

The side-chain catechol function of α-methyl-(L)-DOPA was utilized for the synthesis of a new series of crown-carrier C^α,α-disubstituted glycines. During N-protection of α-methyl-(L)-DOPA methyl ester (H-Mdp-OMe) with Boc anhydride, the formation of N,O-di-Boc derivatives was observed. Selective aminolysis of the catechol tert-butyl carbonate group was achieved using pyrrolidine as nucleophile. Treatment of the resulting Boc-Mdp-OMe by Cs₂CO₃ in MeOH, followed by bis-O-alkylation with cyclization using various polyethyleneglycol ditosylates or catechol-derived bis-polyethyleneglycol ditosylates in DMF at 60°C, led to the derivatives Boc-[15-C-5]-Mdp-OMe, Boc-[18-C-6]-Mdp-OMe, Boc-[benzo-18-C-6]-Mdp-OMe, Boc-[benzo-24-C-8]-Mdp-OMe and then after saponification, to the corresponding N^α-protected amino acids. The tripeptides Fmoc-Ala-[18-C-6]-Mdp-Ala-OMe and Boc-Aib-[18-C-6]-Mdp-Ala-OMe were prepared in solution by using Ala and Aib UNCAs for coupling at the N terminus of the [18-C-6]-Mdp residue and the EDC/HOAt method for coupling Ala at its C terminus.

Full text of DOI:10.1016/S0040-4020(02)00566-5

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5811±5820
New crown-carrier Ca,a-disubstituted glycines derived from
a-methyl-(l)-DOPA
Karen Wright, Francesca Melandri, Caroline Cannizzo, Michel Wakselman
and Jean-Paul Mazaleyratp
Ã
University of Versailles, SIRCOB, ESA CNRS 8086, Bat. Lavoisier, 45Avenue des Etats-Unis, F-78000 Versailles cedex, France
Received 19 March 2002; accepted 31 May 2002
AbstractÐThe side-chain catechol function of a-methyl-(l)-DOPA was utilized for the synthesis of a new series of crown-carrier Ca,a
-
disubstituted glycines. During N-protection of a-methyl-(l)-DOPA methyl ester (H-Mdp-OMe) with Boc anhydride, the formation of N,O-
di-Boc derivatives was observed. Selective aminolysis of the catechol tert-butyl carbonate group was achieved using pyrrolidine as
nucleophile. Treatment of the resulting Boc-Mdp-OMe by Cs2CO3 in MeOH, followed by bis-O-alkylation with cyclization using various
polyethyleneglycol ditosylates or catechol-derived bis-polyethyleneglycol ditosylates in DMF at 608C, led to the derivatives Boc-[15-C-5]-
Mdp-OMe, Boc-[18-C-6]-Mdp-OMe, Boc-[benzo-18-C-6]-Mdp-OMe, Boc-[benzo-24-C-8]-Mdp-OMe and then after saponi®cation, to the
corresponding Na-protected amino acids. The tripeptides Fmoc-Ala-[18-C-6]-Mdp-Ala-OMe and Boc-Aib-[18-C-6]-Mdp-Ala-OMe were
prepared in solution by using Ala and Aib UNCAs for coupling at the N terminus of the [18-C-6]-Mdp residue and the EDC/HOAt method for
coupling Ala at its C terminus. q 2002 Elsevier Science Ltd. All rights reserved.
Within the current developing strategies for peptide-based
nanotechnology, synthetic a-amino acids bearing a crown
ether are of great interest for the preparation of ion selective
molecular receptors and arti®cial ion channels, since they
can be easily assembled in structurally well-de®ned
nanometer-scale architectures of bis-crown as well as
polymeric crown compounds with a peptidic framework.1
In the past few years, a series of crown-carrier derivatives of
(l)-DOPA,1,2 lysine3 or glutamic acid,4 have been synthe-
sized for the construction of peptidic molecular speci®c
receptors for alkali metal, ammoniums and di-ammonium
ions. Application of this strategy to Ca-tetrasubstituted
a-amino acids should result in more de®ned and predictable
peptidic structures, according to their well-established
ability to induce folded (helical) conformations of the
peptide backbone.5 In this view, we have previously
described the synthesis of the ®rst crown-carrier, axially
dissymmetric
a,a-disubstituted glycine: [20-C-6]-Bip,
C
with a 2,20,6,60-tetrasubstituted-1,10-biphenyl frame, and
of some of its peptides (Fig. 1).6±8 However, we could not
prepare this amino acid in an enantiomerically pure state,
because of extensive racemization occuring at several stages
of the synthesis.8 Following a route previously established
by Voyer et al.1,2 in the case of (l)-DOPA, we have now
taken advantage of the catechol function of the com-
mercially available a-methyl-(l)-DOPA to prepare a new
series of crown-carrier Ca,a-disubstituted glycines with
a-carbon chirality instead of axial chirality: [15-C-5]-Mdp
(1), [18-C-6]-Mdp (2), [benzo-18-C-6]-Mdp (3) and [benzo-
24-C-8]-Mdp (4). Achiral, indane-based Ca,a-disubstituted
amino acid derivatives with a crown-ether side chain have
also been recently synthesized.9
Figure 1. Structure of the title crown-carrier Ca,a-disubstituted glycines.
Keywords: crown-ethers; Ca,a-disubstituted glycines; a-methyl-(l)-DOPA.
Corresponding author. Fax: 133-01-39-25-44-52; e-mail: jean-paul.mazaleyrat@chimie.uvsq.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00566-5

5812
K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
Figure 2. Synthesis of Boc-Mdp-OMe (I) from (l)-a-methyl-DOPA. (i) SOCl2; MeOH; 608C; 7 days, (ii) Boc2O; NaHCO3; tert-BuOH/DMF; 608C; 2days,
(iii) Boc2O; NaHCO3; H2O/THF; rt; 5 days, (iv) Boc2O; TEA; CH3CN/THF; rt; 6 days, (v) pyrrolidine; CH2Cl2; rt; 3 h.
1. Results and discussion
salt was freed from methanol and then reacted with (i) tetra-
ethyleneglycol ditosylate, (ii) pentaethyleneglycol ditosyl-
ate, (iii) 1,2-bis(5-tosyloxy-3-oxa-1-pentyloxy)-benzene19b
or (iv) 1,2-bis(8-tosyloxy-3,6-dioxa-1-octyloxy)-benzene,
in DMF at 608C, to give the expected fully protected
crown-carrier a-methyl-(l)-DOPA derivatives (Fig. 3) (i)
Boc-[15-C-5]-Mdp-OMe 1a (49%), (ii) Boc-[18-C-6]-
Mdp-OMe 2a (44%), (iii) Boc-[benzo-18-C-6]-Mdp-OMe
3a (9%), and (iv) Boc-[benzo-24-C-8]-Mdp-OMe 4a
(32%), respectively, in variable yields (not optimized).
Saponi®cation of the ester function of 1a, 2a and 4a was
performed using a large excess of aqueous 1N NaOH/
MeOH at 608C for several hours, as usually required for
a,a-disubstituted-amino esters,20 and furnished the corre-
sponding N a-protected amino acids Boc-[15-C-5]-Mdp-
OH 1b (87%), Boc-[18-C-6]-Mdp-OH 2b (95%) and Boc-
[benzo-24-C-8]-Mdp-OH 4b (88%).
1.1. Synthesis of terminally protected a-methyl-(l)-
DOPA
Although numerous protected a-methyl-(l)-DOPA (Mdp)
derivatives have been reported, including H-Mdp-
OMe´HCl,10,11 Boc-Mdp-OH,10±12 Boc-[OMe]2-Mdp-OH,11
Boc-[OBzl]2-Mdp-OH,11
Z-[O,O-diphenylmethylene]-
Mdp-OR,13 H-[OBzl]2-Mdp-OBzl,14 Z-[OZ]2-Mdp-OH,15
and others, there is no report of a fully characterized Mdp
residue with differential protection of the a-amino and car-
boxyl groups but leaving the side-chain catechol OH groups
free, as necessary in order to proceed with crown-ether
formation. The N-protected amino ester Boc-Mdp-OMe
(I) (Fig. 2) which ful®lls the above requirements, was
previously obtained as a synthetic intermediate (not char-
acterized) upon treatment of H-Mdp-OMe´HCl with Boc2O
in DMF/tert-BuOH 1:1 and NaHCO3 at 608C for 5 days.11
However in our hands, performing the reaction either in the
same experimental conditions, or with Boc2O and NaHCO3
in H2O/THF at room temperature as previously described in
the case of (l)-DOPA,16 or with Boc2O and Et3N in THF/
CH3CN at room temperature,17 always led to mixtures of I
and the two isomers of Boc-[O-Boc,O-H]-Mdp-OMe (IIA
and IIB) resulting from a further acylation of one of the
catechol OH groups. Such competition between O and
N-acylation is not surprising, because of the lower nucleo-
philicity of the sterically hindered Na amino group of
a-methyl-(l)-DOPA compared to (l)-DOPA. The desired
compound I could be easily separated from (IIA1IIB) by
chromatography but was obtained in a rather low yield,
highlighting the need for a selective deacylation of the
OBoc group with regard to both the NHBoc and the
COOMe groups in order to convert (IIA1IIB) back into I.
We considered pyrrolidine as a reagent of choice for a selec-
tive aminolysis of the OBoc group, according to the
previously described selective deacetylation of aromatic
acetates using this amine.18 Indeed, treatment of the crude
mixture I1IIA1IIB by pyrrolidine in dichloromethane at
room temperature, ef®ciently led to pure I in ca. 67%
yield after chromatography.
1.2. Synthesis of the crown-ethers
In a similar manner as previously reported for (l)-DOPA
itself,2b,e the N a-protected amino ester Boc-Mdp-OMe (I)
was reacted with Cs2CO3 in MeOH. The resulting di-cesium
Figure 3. Synthesis of the crown-carrier N a-protected amino esters 1a±4a
and amino acids 1b±4b from N a-tert-butyloxycarbonyl-a-methyl-(l)-
DOPA methyl ester (I). (i) 1. aq. NaOH/MeOH; 608C 2 . H .
1

K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
5813
([18-C-6]-Mdp-Ala) 7, isolated in 23% yield, in competition
with the slow coupling reaction. Therefore, another strategy
was applied in order to supress the possibility of such a
cyclization side reaction: 2b was ®rst N-deprotected in
TFA/CH2Cl2 1:3 to give the free amino acid tri¯uoroacetate
2d, which could be successfully acylated at its N terminus
without C-protection using Boc-Aib-NCA, to afford the
dipeptide Boc-Aib-[18-C-6]-Mdp-OH 8b in 78% yield.
Then, coupling of 8b with H-Ala-OMe by the EDC/HOAt
method as above gave 9a in 86% yield.
Chain elongation applied to 6a and 9a will afford peptides
rich in Aib and/or Ala residues both known to be helix
inducers,5 and containing two or more [18-C-6]-Mdp resi-
dues also expected to be easily accomodated in 310 helices
because of their Ca-tetrasubstitution.5 In these expected
short-chain peptide helices, positioning of the [18-C-6]-
Mdp residues at i and i13 positions of the main chain
should allow a parallel orientation of their side-chain
crown-ether receptors, with the opportunity for cooperative
binding.1,2 Solution synthesis of similar peptides based on
the [15-C-5]-Mdp, [benzo-18-C-6]-Mdp and [benzo-24-C-
8]-Mdp residues, is also under way, to examine their confor-
mational analysis as well as their complexing abilities.
Figure 4. Solution synthesis of the tripeptides Fmoc-Ala-[18-C-6]-Mdp-
Ala-OMe (6a) and Boc-Aib-[18-C-6]-Mdp-Ala-OMe (9a). (i) H-Ala-
OMe´HCl; NMM; EDC; HOAt; CH2Cl2; rt, (ii) TFA/CH2Cl2 1:3, (iii)
Fmoc-Ala-NCA; DIPEA; THF, (iv) Boc-Aib-NCA; DIPEA; THF.
2. Experimental
1.2.1. Peptide coupling conditions in solution: synthesis
of tripeptides based on the [18-C-6]-Mdp residue. As a
®rst step to the synthesis of peptides based on these new
crown-carrier Ca,a-disubstituted glycines, the tripeptides 6a
and 9a (Fig. 4) based on the [18-C-6]-Mdp residue were
prepared in order to ®nd suitable coupling conditions in
solution.21 The EDC/HOBt method,22 generally recognized
to be ef®cient for coupling at the C-terminus of Ca,a-di-
substituted glycines,21 including Ca,a-diphenylglycine,23
was chosen ®rst for the coupling of 2b with H-Ala-OMe,
but gave the dipeptide Boc-[18-C-6]-Mdp-Ala-OMe 5a in
only 28% yield. Using the CIP/HOAt method previously
shown to allow the coupling between two Aib residues,24
5a was obtained in 40% yield. Finally, in our hands, the
EDC/HOAt25 method was found to be the most ef®cient,
giving 5a in 69% yield after puri®cation. Furthermore,
the crude reaction product, obtained after extraction in
ca. 98% yield, consisted of almost pure 5a, contaminated
only by traces of a side product which was identi®ed by
1H NMR as 1-chloromethyloxy-7-aza-1,2,3-benzotriazole
(ClCH2OAt) resulting from substitution of the reaction
solvent CH2Cl2 by HOAt. This crude product could be
used directly in the next step, in which urethane-protected
amino acid N-carboxy anhydrides (UNCAs),26 previously
employed with success in the coupling of Phe with Aib27a
and of Aib with Aib in THF,27b were utilized for coupling of
both Ala and Aib at the N terminus of the [18-C-6]-Mdp
residue. In this way, crude 5a was N-deprotected in TFA/
CH2Cl2 1:3 to give 5c, which again was not isolated but
directly coupled with an excess of Fmoc-Ala-NCA in the
presence of DIPEA, to afford the tripeptide Fmoc-Ala-[18-
C-6]-Mdp-Ala-OMe 6a in 67% overall yield from 2b after
chromatography. However, coupling of 5c with the more
hindered Boc-Aib-NCA gave the desired Boc-Aib-[18-C-
6]-Mdp-Ala-OMe 9a in an only moderate yield (33%),
because of cyclization of 5c to the diketopiperazine cyclo-
2.1. Abbreviations
(l)-DOPA, b-3,4-dihydroxyphenyl-(l)-alanine; a-methyl-
(l)-DOPA (Mdp), a-methyl-b-3,4-dihydroxyphenyl-(l)-
alanine; [15-C-5]-Mdp, a-methyl-b-3,4-(15-crown-5)-
phenyl-(l)-alanine; [18-C-6]-Mdp, a-methyl-b-3,4-(18-
crown-6)-phenyl-(l)-alanine; [benzo-18-C-6]-Mdp, a-methyl-
b-3,4-(benzo-18-crown-6)-phenyl-(l)-alanine; [benzo-24-
C-8]-Mdp, a-methyl-b-3,4-(benzo-24-crown-8)-phenyl-
(l)-alanine; Aib, a-aminoisobutyric acid; Boc, tert-butoxy-
carbonyl; Fmoc, 9-¯uorenylmethoxycarbonyl; CIP, 2-chlo-
ro-1,3-dimethylimidazolidinium hexa¯uorophosphate;
EDC, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide;
HOBt, 1-hydroxy-1,2,3-benzotriazole; HOAt, 1-hydroxy-
7-aza-1,2,3-benzotriazole; NCA, N-carboxy anhydride;
UNCA, urethane protected a-amino acid N-carboxy
anhydride; TFA, tri¯uoroacetic acid; Me, methyl; Et,
ethyl; nBu, n-butyl; tBu, tert-butyl; TEA, triethylamine;
NMM, N-methylmorpholine; DIPEA, diisopropylethyl-
amine; THF, tetrahydrofuran; DMF, N,N-dimethylforma-
mide; EtOAc, ethyl acetate; TLC, thin layer
chromatography.
2.2. General
Melting points were determined by means of a capillary
tube immersed in an oil bath (Tottoli apparatus, BuÈchi)
and are uncorrected. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz, respectively, the solvent CDCl3 or
CD3OD being used as internal standard (dˆ7.27 or
3.31 ppm for 1H and 77.00 or 49.00 ppm for 13C). Splitting
patterns are abbreviated as follows: (s) singlet, (d) doublet,
(t) triplet, (q) quartet, (m) multiplet. The optical rotations
were measured with an accuracy of 0.3%, in a 1 dm thermo-
statted cell. Analytical TLC and preparative column

5814
K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
chromatography were performed on Kieselgel F 254 and on
Kieselgel 60 (0.040±0.063 mm) (Merck), respectively, with
the following eluent systems: 2.5% MeOH±97.5% CH2Cl2
(A); 5% MeOH±95% CH2Cl2 (B); 10% MeOH±90%
CH2Cl2 (C); 20% MeOH±80% CH2Cl2 (D); 50% MeOH±
50% CH2Cl2 (E); 5% EtOAc±95% CH2Cl2 (F); CH2Cl2±
nBuOH±EtOAc±MeOH±AcOH±H2O 8:4:3:2.5:1:0.5 (G).
The TLC chromatograms were visualized by UV
¯uorescence (254 nm) and/or developed by ninhydrin/
TFA reaction, as appropriate. 3-(3,4-Dihydroxyphenyl)-2-
methyl-(l)-alanine sesquihydrate, tetraethyleneglycol
ditosylate and pentaethyleneglycol ditosylate, were
purchased from Aldrich. Fmoc-(l)-alanine N-carboxy
anhydride (Fmoc-Ala-NCA) and Boc-a-methyl-alanine
N-carboxy anhydride (Boc-Aib-NCA) were purchased
from Fluka and Isochem, respectively.
added. The solution was stirred at room temperature for
3 h, diluted with CH2Cl2 (100 mL), extracted with 0.5N
HCl (3£100 mL), and then H2O (2£100 mL), dried
(MgSO4), ®ltered and evaporated in vacuo. The crude
product presented only one UV-positive TLC-spot of
Rfˆ0.30 (B) corresponding to (I), and a second ninhydrin/
TFA positive TLC-spot of Rfˆ0.60 (B) corresponding to
N-Boc-pyrrolidine. Chromatography on
a
2.3£53 cm
column of silica gel with eluent (A) gave 0.987 g of analyti-
cally pure Boc-Mdp-OMe (I) as a white amorphous solid,
for a total of 1.733 g (53%). In a duplicate run, a mixture of
crude H-Mdp-OMe´HCl obtained after esteri®cation of
H-Mdp-OH´1.5H2O (5.00 g; 21.0 mmol) (vide supra),
Boc2O (7.50 g; 34.4 mmol) and Et3N (4.5 mL; 32mmol)
in CH3CN (60 mL) and THF (30 mL) was reacted in the
same experimental conditions as above. The crude product
obtained after work-up was directly treated with pyrrolidine
(8.5 mL; 102mmol) in CH 2Cl2 (150 mL) at room tempera-
ture for 3 h. Extraction as above followed by repeated
column chromatography, afforded 4.55 g of pure (I) (67%
overall yield from a-methyl-(l)-DOPA). In another run, a
2.2.1.
a-Methyl-b-3,4-dihydroxyphenyl-(l)-alanine
methyl ester hydrochloride. SOCl2 (37.5 mL) was added
dropwise to an ice-cold suspension of a-methyl-(l)-DOPA
sesquihydrate H-Mdp-OH´1.5H2O (11.90 g; 50 mmol) in
MeOH (125 mL). The resulting clear yellow solution was
stirred at 658C for 6 days, and then evaporated in vacuo, the
residue being repeatedly evaporated to dryness from H2O/
acetone, as previously described.10,11 The obtained crude
H-Mdp-OMe´HCl (13.80 g) was pure by NMR and was
mixture of H-Mdp-OMe´HCl (0.32g; 1.2mmol), Boc O
2
(0.54 g; 2.5 mmol) and NaHCO3 (0.58 g; 6.9 mmol) in
DMF (1 mL) and tert-BuOH (1 mL) was stirred at 608C
for 5 days, as previously described.11 Extraction as above
gave a crude product presenting two main TLC-spots of
Rfˆ0.50 and 0.30 (B), corresponding to (IIA1IIB) and (I),
respectively (vide supra). In another run, a mixture of crude
H-Mdp-OMe´HCl obtained after esteri®cation of H-Mdp-
OH´1.5H2O (0.883 g; 3.71 mmol), Boc2O (0.890 g;
4.08 mmol) and NaHCO3 (0.620 g; 7.4 mmol) in H2O
(7.5 mL) and THF (5 mL) was stirred at room temperature
for 5 days, as previously described in the case of (l)-
DOPA.16 The crude product obtained after work-up was
chromatographed on a 2.3£30 cm column of silica gel
with eluent (A), to give (i) 0.454 g of pure (I) and (ii)
0.508 g of a mixture (I1IIA1IIB) which was treated with
pyrrolidine (0.5 mL) in CH2Cl2 (25 mL) at room tempera-
ture for 3 h, extracted as above and chromatographed on a
2.3£46 cm column of silica gel with eluent (A), to give
0.287 g of pure (I) for a total of 0.741 g (62% overall).
Mpˆ1408C. Rfˆ0.30 (B). 1H NMR (CDCl3): 6.74 [d,
Jˆ8.1 Hz, 1H, ArH5], 6.60 [d, Jˆ1.8 Hz, 1H, ArH2], 6.46
[dd, Jˆ8.1, 1.8 Hz, 1H, ArH6], 5.19 [s (broad), 1H, NH],
3.74 [s, 3H, OCH3], 3.15 [d (broad), 1H] and 3.04 [d,
1
used in the next step without further puri®cation. H NMR
(CD3OD): 6.76 [d, Jˆ8.0 Hz, 1H, ArH5], 6.62[d, Jˆ2.1 Hz,
1H, ArH2], 6.51 [dd, Jˆ8.0, 2.1 Hz, 1H, ArH6], 3.84 [s, 3H,
OCH3], 3.16 [d, Jˆ14.2Hz, 1H] and 2.95 [d, Jˆ14.2Hz,
b
b
1H, ArCH2 ], 1.60 [s, 3H, CH3 ]. 13C NMR (CD3OD): 172.4
[CvO], 146.8, 146.5 [CAr±O], 125.3, 122.6, 118.0, 116.7
[CAr], 62.0 [Ca], 53.8 [OCH3], 43.6 [ArCH2 ], 22.5 [CH3 ].
b
b
2.2.2.
Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-di-
hydroxyphenyl-(l)-alanine methyl ester (I). To an ice-
cold solution of H-Mdp-OMe´HCl (2.615 g; 10 mmol) and
Boc2O (3.04 g; 14 mmol) in CH3CN (40 mL)/THF (20 mL)
(13.80 g) was added TEA (2mL; 14 mmol). The solution
was stirred at room temperature for 5 days, and then evapo-
rated in vacuo. The residue was solubilized in H2O/EtOAc.
The separated organic phase was washed with 0.5N HCl
(3£50 mL), then H2O (2£200 mL), dried (MgSO4), ®ltered
and evaporated in vacuo. The crude product which
presented two TLC-spots of Rfˆ0.50 and 0.30 (B), was
chromatographed on a 3£68 cm column of silica gel with
eluent (B), to give (i) 1.550 g (37%) of a ca. 1:1 mixture of
b
b
Jˆ13.0 Hz, 1H, ArCH2 ], 1.51 [s (broad), 3H, CH3 ], 1.46
[s, 9H, (CH3)3 Boc]. 13C NMR (CDCl3): 174.9 [CvO],
154.8 [CvO Boc], 143.8, 143.1 [CAr±O], 128.0, 122.1,
117.0, 115.1 [CAr], 80.0 [O±C Boc], 60.2[C a], 52.5
isomers
(IIA1IIB)
of
Boc-[OBoc;OH]-Mdp-OMe,
1
{Rfˆ0.50 (B). H NMR (CDCl3): <7.1 [m (broad), 1H,
ArOH], 6.96 [d, Jˆ8.2Hz, 0.5H, ArH 5 of 1 isomer], 6.80
[d, Jˆ1.8 Hz, 0.5H, ArH2 of 1 isomer], 6.78 [d, Jˆ8.2Hz,
0.5H, ArH5 of 1 isomer], 6.72[dd, Jˆ8.2, 1.8 Hz, 0.5H,
ArH6 of 1 isomer], 6.65 [d, Jˆ1.8 Hz, 0.5H, ArH2 of 1
isomer], 6.53 [dd, Jˆ8.2, 1.8 Hz, 0.5H, ArH6 of 1 isomer],
5.20 [s, 0.5H, NH of 1 isomer], 5.17 [s, 0.5H, NH of 1
isomer], 3.68 [s, 1.5H, OCH3 of 1 isomer], 3.67 [s, 1.5H,
OCH3 of 1 isomer], 3.10 [m (broad d and d), 2H, ArCH2b of
b
b
[OCH3], 41.7 [ArCH2 ], 28.2 [(CH3)3 Boc], 23.3 [CH3 ].
25
25
25
[a]589 ˆ235.08, [a]578 ˆ239.28, [a]546 ˆ244.98,
25
25
[a]436 ˆ281.38, [a]365 ˆ2133.68 (c 0.2; MeOH). Anal.
for C16H23NO6´0.5H2O: calcd C 57.47, H 7.23, N 4.18;
found C 57.43, H 6.89, N 3.81.
2.2.3.
Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-(15-
crown-5)-phenyl-(l)-alanine methyl ester (1a). Similar
experimental conditions as those previously reported by
Voyer et al.2b,e were applied: a solution of Boc-Mdp-OMe
(I) (1.625 g; 5 mmol) and Cs2CO3 (1.792g; 5.5 mmol) in
degassed MeOH (20 mL) was stirred under argon atmo-
sphere at 458C for 15 min, then evaporated to dryness in
vacuo to leave a brown foam. DMF (5 mL) was added
2isomers], 1.47 [s, 9H, OCOOC(CH ) of 2isomers], 1.40
3 3
b
[s, 12H, NHCOOC(CH3)3 and CH3 of 2isomers]}, (ii)
0.257 g of (I) contaminated by (IIA1IIB) and (iii) 0.746 g
(23%) of pure (I). The combined fractions containing the
mixture (IIA1IIB) (1.55010.257 g) were dissolved in
CH2Cl2 (50 mL) and pyrrolidine (1.5 mL; 18 mmol) was

K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
5815
and the resulting mixture was evaporated to dryness under
high vacuum at 458C in order to completely remove the
residual methanol. The residue was re-dissolved in DMF
(50 mL) and the mixture heated at 608C under argon
atmosphere. A solution of tetraethyleneglycol ditosylate
(2.767 g; 5.5 mmol) in DMF (20 mL) was added dropwise
over a 2h period. The mixture was magnetically stirred at
608C for 16 h and then evaporated to dryness under high
vacuum. The residue was taken up in CH2Cl2 (250 mL) and
5% NaHCO3 (100 mL). The decanted CH2Cl2 solution was
washed with 5% NaHCO3 (2£100 mL), then with H2O
(2£100 mL), dried (MgSO4), ®ltered and evaporated in
vacuo. The crude product was chromatographed on a
3£66 cm column of silica gel with eluent (G). The fractions
containing the desired product were combined and the solu-
tion was evaporated to dryness in vacuo at 458C. Aqueous
5% NaHCO3 (200 mL) was added to the residue and the
mixture was again evaporated to dryness in vacuo at 458C
in order to completely remove the eluent components
nBuOH and AcOH. The residue was taken up in CH2Cl2
(250 mL) and H2O (200 mL). The basic aqueous NaHCO3
phase obtained after shaking and decantation was extracted
with CH2Cl2 (50 mL). The combined CH2Cl2 phase was
washed with H2O (3£150 mL), dried (MgSO4), ®ltered
and evaporated in vacuo, to afford 1.177 g (49%) of pure
Boc-[15-C-5]-Mdp-OMe 1a as a pale yellow glass. Rfˆ0.30
(G). 1H NMR (CDCl3): 6.77 [d, Jˆ8.5 Hz, 1H, ArH5], 6.61
[dd, Jˆ8.1, 1.8 Hz, 1H, ArH6], 6.60 [d, Jˆ1.8 Hz, 1H,
ArH2], 5.13 [s (broad), 1H, NH], 4.11 [m, 4H, OCH2],
3.90 [m, 4H, OCH2], 3.76 [s (broad), 8H, OCH2], 3.74 [s,
3H, OCH3], 3.26 [d (broad), Jˆ13.6 Hz, 1H] and 3.11 [d,
(relative intensity): 1077 (1) [2M,Na]1, 566 (2) [M,K]1,
550 (100) [M,Na]1. Anal. for C26H41NO10: calcd C 59.19,
H 7.83, N 2.65; found C 59.34, H 7.89, N 2.31.
2.2.5. Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-(benzo-
18-crown-6)-phenyl-(l)-alanine methyl ester (3a). Cate-
chol (5.50 g; 50 mmol) and sodium hydroxide (4.00 g;
100 mmol) were added to nBuOH (100 mL) previously
degassed under an argon stream. The mixture was heated
under an argon atmosphere at 808C for 90 min. until no solid
remained. Chloro-ethoxy-ethanol (12.6 mL; 120 mmol) was
slowly added in portions, and the mixture was stirred at
1108C for 72h. The solvent was evaporated in vacuo, the
residue was triturated with CH2Cl2 and the resulting suspen-
sion was ®ltered through a bed of Celite on a sintered glass
®lter. The ®ltrate was evaporated in vacuo and the residue
puri®ed by chromatography on a 5£38 cm column of silica
gel with eluent (B), to give 6.40 g (45%) of 1,2-bis(5-
hydroxy-3-oxa-1-pentyloxy)-benzene19 as a yellow syrup.
1
Rfˆ0.40 (C). H NMR (CDCl3): 6.80 [s, 4H, ArH], 4.02
[m (t-like), 4H, OCH2], 3.85 [s (broad), 2H, OH], 3.76 [m,
4H, OCH2], 3.64 [m, 4H, OCH2], 3.55 [m (t-like), 4H,
OCH2]. 13C NMR (CDCl3): 148.3 [CAr±O], 121.3, 113.8
[CAr], 72.5, 69.1, 68.4, 61.2 [OCH2]. The diol (3.20 g;
11.2mmol) was dissolved in 20 mL dry pyridine and cooled
to 2108C on an ice/salt bath. Toluenesulphonyl chloride
(5.54 g; 29.0 mmol) was dissolved in 10 mL dry pyridine,
and added slowly in portions to the diol solution. The
mixture was left at 48C for 18 h, diluted with ice cold
CH2Cl2 and poured onto iced water. The two phases were
separated and the aqueous phase was extracted twice with
cold CH2Cl2. The combined organic phases were washed
twice with iced 2N HCl and once with iced brine. The
solution was dried over MgSO4, ®ltered and evaporated in
vacuo. The residue was puri®ed by chromatography on a
3£40 cm column of silica gel with eluent (F), to give 2.50 g
(37%) of 1,2-bis(5-tosyloxy-3-oxa-1-pentyloxy)-benzene19
b
b
Jˆ13.6 Hz, 1H, ArCH2 ], 1.54 [s (broad), 3H, CH3 ], 1.46
[s, 9H, (CH3)3 Boc]. 13C NMR (CDCl3): 174.6 [CvO],
154.5 [CvO Boc], 148.9, 148.3 [CAr±O], 129.5, 123.0,
116.3, 113.8 [CAr], 79.7 [O±C Boc], 71.2, 70.7, 69.8, 69.1
[OCH2], 60.6 [Ca], 52.6 [OCH3], 41.5 [ArCH2 ], 28.6
b
b
25
25
25
[(CH3)3 Boc], 23.8 [CH3 ]. [a]589 ˆ231.88, [a]578
ˆ
25
25
1
233.58, [a]546 ˆ239.68, [a]436 ˆ271.88, [a]365
ˆ
as a yellow syrup. Rfˆ0.35 (F). H NMR (CDCl3): 7.76
2113.88 (c 0.29; MeOH). ESI1 MS m/z (relative intensity):
522 (6) [M,K]1, 506 (100) [M,Na]1. Anal. for C24H37NO9:
calcd C 59.61, H 7.71, N 2.89; found C 59.16, H 7.71, N 2.67.
[d, Jˆ8.5 Hz, 4H] and 7.28 [d, Jˆ8.5 Hz, 4H, ArH Tos],
6.88 [m, 4H, ArH], 4.15 [m, 4H, OCH2], 4.04 [m, 4H,
OCH2], 3.75 [m, 8H, OCH2], 2.38 [s, 6H, CH3 Tos]. Treat-
ment of (I) (0.940 g; 2.89 mmol) and Cs2CO3 (1.03 g;
3.18 mmol) with this ditosylate (1.89 g; 3.18 mmol) in
DMF (45 mL), under the same experimental conditions,
work-up and puri®cation as for the preparation of 1a, led
to 0.143 g (9%) of pure Boc-[benzo-18-C-6]-Mdp-OMe 3a
as a pale yellow glass. Rfˆ0.60 (G). 1H NMR (CDCl3): 6.88
(m, 4H, ArH), 6.75 [d, Jˆ7.7 Hz, 1H, ArH5 Mdp], 6.60 [dd,
Jˆ7.7, 1.8 Hz, 1H, ArH6 Mdp], 6.59 [d, Jˆ1.8 Hz, 1H,
ArH2 Mdp], 5.12[s (broad), 1H, NH], 4.16 [m, 8H,
2.2.4.
Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-(18-
crown-6)-phenyl-(l)-alanine methyl ester (2a). Treatment
of (I) (1.625 g; 5 mmol) and Cs2CO3 (1.792g; 5.5 mmol)
with pentaethyleneglycol ditosylate (3.006 g; 5.5 mmol) in
DMF (70 mL), under the same experimental conditions,
work-up and puri®cation as for the preparation of 1a, led
to 1.172g (44%) of pure Boc-[18-C-6]-Mdp-OMe 2a as a
pale yellow glass. Rfˆ0.35 (G). 1H NMR (CDCl3): 6.72[d,
Jˆ8.6 Hz, 1H, ArH5], 6.56 [dd, Jˆ8.5, 1.8 Hz, 1H, ArH6],
6.56 [d, Jˆ1.8 Hz, 1H, ArH2], 5.12[s (broad), 1H, NH],
4.08 [m, 4H, OCH2], 3.86 [m, 4H, OCH2], 3.74±3.69 [m,
4H, OCH2], 3.69 [s, 3H, OCH3], 3.69±3.64 [m, 4H, OCH2],
3.64 [s (broad), 4H, OCH2], 3.20 [d (broad), 1H] and 3.06
OCH2], 4.02[m, 8H, OCH ], 3.74 [s, 3H, OCH3], 3.27 [d
2
b
(broad), 1H] and 3.11 [d, Jˆ13.6 Hz, 1H, ArCH2 ], 1.53 [s
(broad), 3H, CH3 ], 1.46 [s, 9H, (CH3)3 Boc]. 13C NMR
b
(CDCl3): 174.6 [CvO], 154.5 [CvO Boc], 148.9 [CAr±
O], 148.5, 147.9 [CAr±O Mdp], 129.4, 122.9, 121.5,
115.6, 113.7, 113.2[C Ar], 79.7 [O±C Boc], 70.1, 68.9
b
b
[d, Jˆ13.6 Hz, 1H, ArCH2 ], 1.49 [s (broad), 3H, CH3 ],
1.42[s, 9H, (CH 3)3 Boc]. 13C NMR (CDCl3): 174.2[C vO],
154.1 [CvO Boc], 148.3, 147.8 [CAr±O], 129.1, 122.6,
115.9, 113.5 [CAr], 79.2[O±C Boc], 70.6, 70.5, 69.5,
69.4, 68.9, 68.8 [OCH2], 60.1 [Ca], 52.3 [OCH3], 41.1
[OCH2], 60.6 [Ca], 52.6 [OCH3], 41.6 [ArCH2 ], 28.6
b
b
25
25
[(CH3)3 Boc], 23.8 [CH3 ]. [a]589 ˆ227.78, [a]578
ˆ
25
25
25
228.88, [a]546 ˆ234.28, [a]436 ˆ260.48, [a]365 (abs)
<2968 (c 0.26; MeOH). ESI1 MS m/z (relative intensity):
598 (100) [M,Na]1, 576 (12) [M,H]1. Anal. for
C30H41NO10´0.5H2O: calcd C 61.63, H 7.24, N 2.39; found
C 61.69, H 7.42, N 2.01.
b
b
25
25
[ArCH2 ], 28.2 [(CH3)3 Boc], 23.4 [CH3 ]. [a]589
ˆ
25
25
232.18, [a]57285 ˆ233.88, [a]546 ˆ240.88, [a]436
ˆ
273.58, [a]365 ˆ2121.28 (c 0.32; MeOH). ESI1 MS m/z

5816
K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
2.2.6. Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-(benzo-
24-crown-8)-phenyl-(l)-alanine methyl ester (4a). Treat-
ment of catechol (1.10 g; 10 mmol) and sodium hydroxide
(0.80 g; 20 mmol) in degassed nBuOH (20 mL) with chloro-
ethoxy-ethoxy-ethanol (3.48 mL; 24 mmol) under the
same experimental conditions and work-up as for the
preparation of 1,2-bis(5-hydroxy-3-oxa-1-pentyloxy)-ben-
zene, followed by chromatography on a 3£42cm column
of silica gel with eluent (B), and then (C), gave 2.208 g
(59%) of 1,2-bis(8-hydroxy-3,6-dioxa-1-octyloxy)-benzene
as a yellow syrup. Rfˆ0.35 (C). 1H NMR (CDCl3): 6.91 [s,
4H, ArH], 4.17 [m (t-like), 4H, OCH2], 3.87 [m (t-like), 4H,
OCH2], 3.69 [m, 12H, OCH2], 3.60 [m (t-like), 4H, OCH2],
3.29 [s (broad), 2H, OH]. 13C NMR (CDCl3): 148.7 [CAr±
O], 121.5, 114.6 [CAr], 72.5, 70.6, 70.2, 69.6, 68.6, 61.3
[OCH2]. Treatment of this diol (2.20 g; 5.88 mmol) with
toluenesulphonyl chloride (2.91 g; 15.28 mmol) in dry
pyridine (15 mL) under the same experimental conditions
and work-up as for the preparation of 1,2-bis(5-tosyloxy-3-
oxa-1-pentyloxy)-benzene, followed by chromatography on
a 3£40 cm column of silica gel with eluent (A), gave 3.09 g
(77%) of 1,2-bis(8-tosyloxy-3,6-dioxa-1-octyloxy)-benzene
as a yellow syrup. Rfˆ0.65 (A). 1H NMR (CDCl3): 7.79 [d,
Jˆ8.2Hz, 4H] and 7.33 [d, Jˆ8.5 Hz, 4H, ArH Tos], 6.91
[s, 4H, ArH], 4.14 [m, 8H, OCH2], 3.82[m (t-like), 4H,
OCH2], 3.68 [m, 8H, OCH2], 3.61 [m, 4H, OCH2], 2.42
[s, 6H, CH3 Tos]. [Note: in a duplicate experiment, the
diol (3.526 g; 9.43 mmol) was reacted with toluene-
sulphonyl chloride (4.67 g; 24.5 mmol) under the same
experimental conditions and work-up as above, to give
5.42g of crude product consisting in a mixture of 1,2-
column of silica gel with eluent (G). The fractions contain-
ing the desired product were combined, the solution was
evaporated to dryness in vacuo at 458C and the residue
worked-up as in the preparation of 1a, to afford 1.025 g
(32%) of pure Boc-[benzo-24-C-8]-Mdp-OMe 4a as a
yellow glass. A duplicate initial experiment in which (I)
(1.418 g; 4.36 mmol) and Cs2CO3 (1.56 g; 4.80 mmol)
were reacted with 3.09 g (4.53 mmol) of NMR pure 1,2-
bis(8-tosyloxy-3,6-dioxa-1-octyloxy)-benzene, under the
same experimental conditions and work-up as above, gave
0.349 g (12%) of pure 4a. Rfˆ0.55 (G). 1H NMR (CDCl3):
6.83 [m (s-like), 4H, ArH], 6.71 [d, Jˆ8.8 Hz, 1H, ArH5
Mdp], 6.56 [dd, <Jˆ8, 1.8 Hz, 1H, ArH6 Mdp], 6.55 [d,
Jˆ2.0 Hz, 1H, ArH2 Mdp], 5.14 [s (broad), 1H, NH], 4.08
[m, 8H, OCH2], 3.85 [m, 8H, OCH2], 3.78 [s, 8H, OCH2],
3.68 [s, 3H, OCH3], 3.20 [d (broad), 1H] and 3.06 [d,
b
b
Jˆ13.6 Hz, 1H, ArCH2 ], 1.48 [s (broad), 3H, CH3 ], 1.41
[s, 9H, (CH3)3 Boc]. 13C NMR (CDCl3): 174.1 [CvO],
154.0 [CvO Boc], 148.6 [CAr±O], 148.2, 147.6 [CAr±O
Mdp], 129.1, 122.6, 121.1, 115.8, 113.8, 113.3 [CAr], 79.1
[O±C Boc], 70.9, 69.6, 69.2, 69.1 [OCH2], 60.0 [Ca], 52.1
b
b
[OCH3], 41.0 [ArCH2 ], 28.1 [(CH3)3 Boc], 23.3 [CH3 ].
25
25
25
[a]589 ˆ227.88, [a]578 ˆ229.68, [a]546 ˆ233.38,
[a]436 ˆ259.78 (c 0.21; MeOH). ESI1 MS m/z (relative
25
intensity): 686 (100) [M,Na]1, 664 (35) [M,H]1. Anal. for
C34H49NO12´0.5H2O: calcd C 60.70, H 7.49, N 2.08; found
C 60.46, H 7.48, N 1.75.
2.2.7.
Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-(15-
crown-5)-phenyl-(l)-alanine (1b). To a solution of 1a
(1.151 g; 2.38 mmol) in MeOH (75 mL) was added 1N
NaOH (75 mL), and the mixture was stirred at 608C for
24 h. Methanol was evaporated in vacuo at 408C with
portions of H2O added. The resulting aqueous basic solution
(ca. 150 mL) was extracted with Et2O (150 mL), cooled by
addition of ice, then acidi®ed by addition of a large excess
of 0.5N HCl and extracted with CH2Cl2 (4£50 mL). The
combined CH2Cl2 phases were washed with H2O
(200 mL), dried (MgSO4), ®ltered and evaporated in
vacuo, to afford 0.968 g (87%) of pure Boc-[15-C-5]-
Mdp-OH 1b as a pale yellow glass. Rfˆ0.25 (G). 1H
NMR (CDCl3): 8.47 [s (broad), 1H, COOH], 6.68 [d
(broad), Jˆ8.8 Hz, 1H, ArH5], 6.62[m (broad s), H2,
ArH6 and ArH2], 5.32[s (broad), 1H, NH], 4.02[m
(broad), 4H, OCH2], 3.81 [m (broad), 4H, OCH2], 3.68 [s
(broad), 8H, OCH2], 3.26 [d (broad), 1H] and 3.08 [d,
bis(8-tosyloxy-3,6-dioxa-1-octyloxy)-benzene
TsO±X±
OTs and TsO±X±Cl resulting from substitution of one of
the tosyl groups by a chloride anion present in the reaction
mixture.28 These two compounds of very close Rf could
not be completely separated by conventional chromato-
graphy and presented identical or very similar chemical
1
shifts in H NMR, but their ratio could be estimated by
integration of the aromatic protons signals of the tosyl
group(s) compared to integration of the aromatic protons
of the catechol moiety. The following fractions were
obtained after chromatography on a 4.5£24 cm column of
silica gel with gradient elution from CH2Cl2 to eluent (A):
(i) 0.199 g (4%) (TsO±X±OTs/TsO±X±Cl<1:3) (ii)
0.856 g (15%) (TsO±X±OTs/TsO±X±Cl <1:1) (iii)
1.591 g (26%) (TsO±X±OTs/TsO±X±Cl<3:1). These
mixtures were used as well as the pure ditosylate for
O-alkylation of (I) with crown-ether formation (see
later).] Treatment of (I) (0.989 g; 3.04 mmol) and Cs2CO3
(1.09 g; 3.35 mmol) with 1. 992g (3.04 mmol) of a mixture
of 1,2-bis(8-tosyloxy-3,6-dioxa-1-octyloxy)-benzene TsO±
X±OTs (80% mol/mol by 1H NMR i.e. 2.43 mmol) and the
corresponding TsO±X±Cl (vide supra) (20% mol/mol by
1H NMR i.e. 0.61 mmol) in DMF (50 mL), under the
same experimental conditions and work-up as for the
preparation of 1a, led to a crude product which presented
the same TLC pro®le as the crude product obtained upon
treatment of (I) (0.564 g; 1.74 mmol) and Cs2CO3 (0.622 g;
1.91 mmol) with 1. 055 g (1.74 mmol) of a mixture of TsO±
X±OTs (45% mol/mol by 1H NMR i.e. 0.78 mmol) and the
b
b
Jˆ13.6 Hz, 1H, ArCH2 ], 1.51 [s (broad), 3H, CH3 ], 1.40
[s, 9H, (CH3)3 Boc]. 13C NMR (CDCl3): 176.6 [COOH],
154.2[C vO Boc], 148.2, 147.6 [CAr±O], 129.5, 122.6,
115.7, 113.2[C Ar], 79.0 [O±C Boc], 70.5, 70.1, 69.3,
b
68.5, 68.4 [OCH2], 59.9 [Ca], 40.5 [ArCH2 ], 28.2 [(CH3)3
b
25
25
Boc], 23.4 [CH3 ]. [a]589 ˆ29.18, [a]578 ˆ29.18,
25
25
25
[a]546 ˆ211.98, [a]436 ˆ218.88, [a]365 ˆ228.18 (c
0.21; MeOH). Anal. for C23H35NO9: calcd C 58.83, H
7.51, N 2.98; found C 58.45, H 7.55, N 2.75.
2.2.8.
Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-(18-
crown-6)-phenyl-(l)-alanine (2b). Saponi®cation of 2a
(0.927 g; 1.76 mmol) in MeOH (75 mL) and 1N NaOH
(75 mL) under the same experimental conditions (608C;
24 h) and work-up as for the preparation of 1b, led to
0.856 g (95%) of pure Boc-[18-C-6]-Mdp-OH 2b as a
1
corresponding TsO±X±Cl (55% mol/mol by H NMR i.e.
0.95 mmol) in DMF (35 mL). The combined crude products
1
were puri®ed by repeated chromatography on a 3£66 cm
pale yellow glass. Rfˆ0.25 (G). H NMR (CDCl3): 9.06 [s

K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
5817
(broad), 1H, COOH], 6.69 [d, Jˆ8.5 Hz, 1H, ArH5], 6.64 [s
(broad), 1H, ArH2 Mdp], 6.63 [d (broad), <Jˆ8 Hz, 1H,
ArH6 Mdp], 5.30 [s (broad), 1H, NH], 4.06 [m (broad),
4H, OCH2], 3.83 [m (broad), 4H, OCH2], 3.75±3.64 [m
(broad), 8H, OCH2], 3.63 [s, 4H, OCH2b], 3.27 [d (broad),
1H] and 3.10 [d, Jˆ13.4 Hz, 1H, ArCH2 ], 1.53 [s (broad),
176.7 [COOH], 154.3 [CvO Boc], 148.0, 147.3 [CAr±O],
129.6, 122.6, 115.5, 113.0 [CAr], 79.1 [O±C Boc], 70.4,
70.3, 69.35, 69.30, 68.5, 68.4 [OCH2], 60.1 [Ca], 40.6
0.43 mmol) in CH2Cl2 (5 mL), was added DIPEA
(0.410 mL; 2.32 mmol) and then CIP (0.119 g;
0.43 mmol). The mixture was stirred at room temperature
for 24 h and evaporated to dryness in vacuo. The residue
was extracted as above, to give 0.125 g of a crude product
which consisted of almost pure 5a, only contaminated by a
3H, CH3 ], 1.41 [s, 9H, (CH3)3 Boc]. 13C NMR (CDCl3):
side product (ca. 15% mol/mol by H NMR) identi®ed as
b
1
1-chloromethyloxy-7-aza-1,2,3-benzotriazole (ClCH2OAt)
(vide infra). Puri®cation was achieved by preparative TLC
on silica gel with eluent (G). The silica gel from the TLC
zone containing the desired product was ®nely ground and
extracted by the solvent mixture (E) (200 mL) with
magnetic stirring. The mixture was ®ltered on a sintered
glass ®lter and the solution was evaporated in vacuo. The
residue was dissolved in CH2Cl2 (200 mL) and the solution
was washed as above with aqueous NaHCO3 (100 mL), then
with H2O (2£200 mL), dried (MgSO4), ®ltered and evapo-
rated in vacuo, to give 0.093 g (40%) of pure 5a (vide infra).
(3) By the EDC/HOAt method, to a suspension of 2b
b
b
25
[ArCH2 ], 28.3 [(CH3)3 Boc], 23.5 [CH3 ]. [a]589
ˆ
25
25
25
25.88, [a]578 ˆ25.88, [a]546 ˆ27.18, [a]436 ˆ213.88,
[a]365 ˆ216.78 (c 0.24; MeOH). ESI1 MS m/z (relative
25
intensity): 1065 (2)) [2M,K]1, 1049 (11)) [2M,Na]1, 552
(15) [M,K]1, 536 (100) [M,Na]1. Anal. for
C25H39NO10´1.5H2O: calcd C 55.54, H 7.83, N 2.59; found
C 55.91, H 7.46, N 2.04.
2.2.9. Na-tert-Butyloxycarbonyl-a-methyl-b-3,4-(benzo-
24-crown-8)-phenyl-(l)-alanine (4b). Saponi®cation of
4a (1.364 g; 2.06 mmol) in MeOH (85 mL) and 1N NaOH
(85 mL) under the same experimental conditions (608C;
24 h) and work-up as for the preparation of 1b, led to
1.177 g (88%) of pure Boc-[benzo-24-C-8]-Mdp-OH 4b
(0.237 g;
0.46 mmol),
HCl´H-Ala-OMe
(0.194 g;
1.39 mmol) and HOAt (0.126 g; 0.93 mmol) in CH2Cl2
(5 mL), was added NMM (0.205 mL; 1.85 mmol) and
then EDC (0.133 g; 0.69 mmol). The mixture was stirred
at room temperature for 48 h and evaporated to dryness in
vacuo. The residue was extracted as above, to give 0.257 g
of a crude product which, by 1H NMR, was constituted of a
mixture of pure 5a and traces (ca. 5% mol/mol) of the side
product ClCH2OAt. The crude product was puri®ed by
preparative TLC followed by the same extraction procedure
as above, to give (i) 0.0041 g of pure 1-chloromethyloxy-7-
aza-1,2,3-benzotriazole (ClCH2OAt), Rfˆ0.90 (G), identi-
1
as a pale yellow glass. Rfˆ0.40 (G). H NMR (CDCl3):
7.91 [s (broad), 1H, COOH], 6.86 (m, 4H, ArH), 6.72[d,
Jˆ8.3 Hz, 1H, ArH5 Mdp], 6.66 [s (broad), 1H, ArH2 Mdp],
6.65 [d (broad), <Jˆ8 Hz, 1H, ArH6 Mdp], 5.28 [s (broad),
1H, NH], 4.11 [m, 8H, OCH2], 3.88 [m, 8H, OCH2], 3.80 [s,
8H, OCH2], 3.28 [d (broad), 1H] and 3.06 [d, Jˆ13.2Hz,
b
b
1H, ArCH2 ], 1.54 [s (broad), 3H, CH3 ], 1.44 [s, 9H,
(CH3)3 Boc]. 13C NMR (CDCl3): 176.8 [COOH], 154.2
[CvO Boc], 148.6 [CAr±O], 148.1, 147.5 [CAr±O Mdp],
129.5, 122.7, 121.2, 115.8, 113.8, 113.3 [CAr], 79.1 [O±C
1
®ed by H NMR (CDCl3): 8.79 [dd, Jˆ4.5, 1.4 Hz, 1H,
ArH6], 8.43 [dd, Jˆ8.4, 1.4 Hz, 1H, ArH4], 7.47 [dd,
1
Jˆ8.4, 4.4 Hz, 1H, ArH5], 6.28 [s, 2H, OCH2Cl] and H
b
Boc], 70.9, 69.6, 69.0 [OCH2], 59.9 [Ca], 40.5 [ArCH2 ],
NMR (CD3OD): 8.79 [dd, Jˆ4.5, 1.4 Hz, 1H, ArH6], 8.43
[dd, Jˆ8.4, 1.4 Hz, 1H, ArH4], 7.47 [dd, Jˆ8.4, 4.4 Hz, 1H,
ArH5], 6.28 [s, 2H, OCH2Cl], and (ii) 0.191 g (69%) of pure
25
b
25
28.2 [(CH3)3 Boc], 23.4 [CH3 ]. [a]589 ˆ24.28, [a]578
ˆ
25
25
25
24.68, [a]546 ˆ26.98, [a]436 ˆ211.98, [a]365 ˆ214.98
(c 0.26; MeOH). Anal. for C33H17NO12´H2O: calcd C 59.35,
H 7.39, N 2.10; found C 59.05, H 7.17, N 1.75.
1
5a as a pale yellow glass. Rfˆ0.30 (G). H NMR (CDCl3):
6.84 [d (broad), Jˆ6.6 Hz, 1H, NH Ala], 6.77 [d, Jˆ8.6 Hz,
1H, ArH5], 6.65 [dd, <Jˆ8, 1.8 Hz, 1H, ArH6], 6.64 [d,
Jˆ1.8 Hz, 1H, ArH2], 4.80 [s (broad), 1H, NH Mdp], 4.57
[dq, <Jˆ7.2, 7.2 Hz, 1H, Ha Ala], 4.11 [m, 4H, OCH2],
3.89 [m, 4H, OCH2], 3.74 [m (partly masked), 4H,
2.2.10. Boc-[18-C-6]-Mdp-Ala-OMe (5a). (1) By the EDC/
HOBt method, to a suspension of 2b (0.221 g; 0.43 mmol),
HCl´H-Ala-OMe (0.180 g; 1.29 mmol) and HOBt (0.117 g;
0.86 mmol) in THF (3 mL) and CH2Cl2 (3 mL), was added
TEA (0.180 mL; 1.29 mmol) and then a solution of EDC
(0.124 g; 0.65 mmol) in CH2Cl2 (2mL). The mixture was
stirred at room temperature for 48 h and evaporated to
dryness in vacuo. The residue was solubilized in EtOAc
(150 mL) and 0.5N HCl (50 mL) with stirring. The sepa-
rated organic phase was extracted with 0.5N HCl
(4£50 mL), H2O (100 mL), 5% NaHCO3 (4£50 mL), H2O
(2£100 mL), dried (MgSO4), ®ltered and evaporated in
vacuo. The crude product was chromatographed on a
1.5£10 cm column of silica gel with eluents (B)±(E),
successively. The fractions containing the desired product
were combined and the solution was evaporated to dryness
in vacuo at 458C. The residue was taken up in CH2Cl2
(200 mL) and aqueous NaHCO3 (100 mL). The decanted
CH2Cl2 phase was washed with H2O (2£200 mL), dried
(MgSO4), ®ltered and evaporated in vacuo, to give 0.073 g
(28%) of pure 5a (vide infra). (2) By the CIP/HOAt method,
to a suspension of 2b (0.198 g; 0.38 mmol), HCl´H-Ala-
OMe (0.162g; 1.16 mmol) and HOAt (0.058 g;
OCH2], 3.72[s, 3H, OCH ], 3.70 [m (partly masked), 4H,
3
OCH2], 3.66 [s, 4H, OCH2], 3.32[d, Jˆ14.0 Hz, 1H] and
2.98 [d, Jˆ13.8 Hz, 1H, ArCH2b Mdp], 1.45 [s, 9H, (CH3)3
b
Boc], 1.38 [d, Jˆ7.2Hz, 3H, CH 3b Ala], 1.35 [s, 3H, CH3
Mdp]. 13C NMR (CDCl3): 173.5, 173.4 [CvO Ala and
Mdp], 154.4 [CvO Boc], 148.4, 147.8 [CAr±O], 129.2,
123.3, 116.4, 113.6 [CAr], 80.2[O±C Boc], 70.7, 70.6,
69.5, 68.9, 68.8 [OCH2], 59.8 [Ca Mdp], 52.3 [OCH3],
48.1 [Ca Ala], 40.3 [ArCH2 Mdp], 28.2 [(CH3)3 Boc],
b
b
b
25
24.0 [CH3 Mdp], 18.3 [CH3 Ala]. [a]58295 ˆ250.58,
25
25
[a]578 ˆ252.08, [a]546 ˆ261.58, [a]436 ˆ2109.08,
25
[a]365 ˆ2187.08 (c 0.2; MeOH). ESI1 MS m/z (relative
intensity): 1219 (2) [2M,Na]1, 637 (4) [M,K]1, 621 (100)
[M,Na]1. Anal. for C29H46N2O11: calcd C 58.18, H 7.74, N
4.68; found C 57.76, H 7.61, N 4.38. In a duplicate experi-
ment, 2b (0.340 g; 0.66 mmol) was coupled with HCl´H-
Ala-OMe (0.277 g; 1.99 mmol) in the presence of NMM
(0.300 mL; 2.73 mmol), by the EDC (0.190 g;
0.99 mmol)/HOAt (0.180 g; 1.32mmol) method, in
CH2Cl2 (5 mL), under the same experimental conditions

5818
K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
and work-up as above, to give 0.387 g (<98%) of a crude
mixture consisting in pure 5a with traces (ca. 6% mol/mol
by H NMR) of the side product ClCH2OAt. This mixture
ESI1 MS m/z (relative intensity): 830 (2) [M,K]1, 814
(100) [M,Na]1. Anal. for C42H53N3O12´0.5H2O: calcd C
62.98, H 6.80, N 5.25; found C 62.77, H 6.47, N 5.15.
1
was used in the next coupling step without further puri®ca-
tion (vide infra).
2.2.12. Diketopiperazine c([18-C-6]-Mdp-Ala) (7). Crude
5a (0.467 g; <0.78 mmol), contaminated by ClCH2OAt (ca.
9% mol/mol by 1H NMR) (vide supra) was N-deprotected in
TFA (5 mL)/CH2Cl2 (15 mL), and then the obtained crude
TFA´H-[18-C-6]-Mdp-Ala-OMe (5c) (not characterized)
(<0.78 mmol) was directly reacted with Boc-Aib-NCA
(0.715 g; 3.12mmol) and DIPEA (0.300 mL; 1.72mmol)
in THF (1 mL) at room temperature for 96 h, under the
same experimental conditions as for the preparation of 6a.
The obtained THF suspension was ®ltered on a BuÈchner
funnel (water aspirator), the precipitate was washed with 5
portions of 2mL THF and air dried, to afford 0.155 g (43%)
of crude 7 as a white powder. The ®ltrate was evaporated in
vacuo. The residue was dissolved in CH2Cl2 (150 mL), the
solution was washed with 0.5N HCl (2£100 mL), H2O
(2£100 mL), dried (MgSO4), ®ltered and evaporated in
vacuo. The crude product was chromatographed on a
2.3£34 cm column of silica gel with eluent (G) and the
combined fractions containing the desired product were
treated as in the preparation of 1a to give 0.173 g (33%)
of pure Boc-Aib-[18-C-6]-Mdp-Ala-OMe (9a) (vide infra).
The crude diketopiperazine 7 was chromatographed on a
1.3£29 cm column of silica gel with eluent (G), the
combined fractions containing the desired product being
treated as in the preparation of 1a, to give 0.083 g (23%)
of pure 7 as a pale yellow solid. The solid was dissolved in
CH2Cl2 (10 mL) and EtOAc (25 mL) was added. The clear
solution was re¯uxed, concentrated to ca. 15 mL (CH2Cl2
off) and left at room temperature overnight, resulting in
crystallization. The crystals were ®ltered on a BuÈchner
funnel, abundantly washed with EtOAc and air dried, to
afford 0.057 g of pure c([18-C-6]-Mdp-Ala) (7) as white
crystals. Mpˆ2288C. Rfˆ0.15 (G). 1H NMR (CDCl3):
6.94 [s, 1H, NH Mdp], 6.81 [d, Jˆ7.9 Hz, 1H, ArH5],
6.75 [s (broad), 1H, ArH2], 6.73 [dd, <Jˆ8, 1.9 Hz, 1H,
ArH6], 6.66 [d (broad), 1H, NH Ala], 4.11 [m, 4H,
OCH2], 3.94 [dq, Jˆ7.2, 1.8 Hz, 1H, Ha Ala], 3.88 [m,
4H, OCH2], 3.74 [m, 4H, OCH2], 3.70 [m, 4H, OCH2],
3.67 [s, 4H, OCH2], 3.21 [d, Jˆ13.6 Hz, 1H] and 2.72 [d,
2.2.11. Fmoc-Ala-[18-C-6]-Mdp-Ala-OMe (6a). To an
ice-cold solution of crude 5a (0.175 g; <0.29 mmol),
contaminated by ClCH2OAt (ca. 6% mol/mol by 1H
NMR) (vide supra) in CH2Cl2 (7.5 mL) was added TFA
(2.5 mL). The solution was stirred from 08C to room
temperature for 4 h and evaporated in vacuo at 308C. The
residue was repeatedly dissolved in CH2Cl2 and the solution
evaporated in vacuo. The residue was repeatedly triturated
with Et2O and the mixture evaporated in vacuo, to yield
crude TFA´H-[18-C-6]-Mdp-Ala-OMe (5c) (not character-
ized). The crude dipeptide 5c (<0.29 mmol) was dissolved
in THF (3 mL), the solution was magnetically stirred at 08C
and DIPEA (0.180 mL; 1.03 mmol) was added, followed by
solid Fmoc Ala-NCA (0.296 g; 0.88 mmol). The solution
was stirred from 08C to room temperature for 64 h and
evaporated in vacuo at 408C. The residue was dissolved in
CH2Cl2 (150 mL), the solution was washed with 0.5N HCl
(2£75 mL), H2O (2£100 mL), dried (MgSO4), ®ltered and
evaporated in vacuo. The crude product was chromato-
graphed on preparative TLC plates of silica gel with eluent
(G). The silica gel from the TLC zone containing the desired
product was ®nely ground and extracted by the solvent
mixture (E) (200 mL) with magnetic stirring. The mixture
was ®ltered on sintered glass and the solution was evapo-
rated in vacuo. The residue was dissolved in CH2Cl2
(200 mL) and the solution was washed as above with
aqueous NaHCO3 (2£100 mL), then with H2O (2£
200 mL), dried (MgSO4), ®ltered and evaporated in vacuo,
to give 0.160 g (69%) (67% overall yield from 2b) of pure
Fmoc-Ala1-[18-C-6]-Mdp-Ala2-OMe (6a). Rfˆ0.50 (G);
1
0.60 (D). H NMR (CDCl3): 7.75 [d, Jˆ7.3 Hz, 2H, ArH
Fmoc], 7.58 [m (t-like), 2H, ArH Fmoc], 7.39 [m (t-like),
2H, ArH Fmoc], 7.30 [m (split t-like), 2H, ArH Fmoc], 7.00
[d (broad), Jˆ7.0 Hz, 1H, NH Ala2], 6.69 [d, Jˆ8.1 Hz, 1H,
ArH5], 6.61 [dd, Jˆ8.1, 1.9 Hz, 1H, ArH6], 6.64 [d,
Jˆ1.8 Hz, 1H, ArH2], 6.54 [s (broad), 1H, NH Mdp], 5.52
[d (broad), Jˆ6.1 Hz, 1H, NH Ala1], 4.51 [dq, <Jˆ7.1,
7.1 Hz, 1H, Ha Ala2], 4.39 [dd, Jˆ7.0, 10.3 Hz, 1H] and
4.28 [dd (broad), <Jˆ7.0, 10.3 Hz, 1H, CH2O Fmoc], 4.19
[m (t-like), <Jˆ7.0 Hz, 1H, Ar±CH Fmoc], 4.06 [m, 4H,
OCH2], 4.03 [dq (partly masked), <Jˆ7, 7 Hz, 1H, Ha
Ala1], 3.83 [m, 4H, OCH2], 3.70 [m (partly masked), 4H,
OCH2], 3.69 [s, 3H, OCH3], 3.66 [m (partly masked), 4H,
OCH2], 3.64 [s, 4H, OCH2], 3.37 [d, Jˆ13.8 Hz, 1H] and
b
b
Jˆ13.6 Hz, 1H, ArCH2 Mdp], 1.56 [s, 3H, CH3 Mdp],
b
0.84 [d, Jˆ7.1 Hz, 3H, CH3 Ala]. 13C NMR (CDCl3):
169.7, 168.2[C vO Ala and Mdp], 148.8, 148.3 [CAr±O],
128.1, 123.5, 116.7, 114.0 [CAr], 70.7, 70.6, 70.5, 69.5, 69.4,
69.1, 69.0 [OCH2], 60.6 [Ca Mdp], 51.0 [Ca Ala], 46.6
b
b
b
[ArCH2 Mdp], 27.6 [CH3 Mdp], 20.3 [CH3 Ala].
25
25
25
[a]589 ˆ135.98, [a]57285 ˆ136.38, [a]546 ˆ142.68,
b
b
25
[a]436 ˆ183.08, [a]365 ˆ1156.38 (c 0.22; MeOH).
3.11 [d, Jˆ13.9 Hz, 1H, ArCH2 Mdp], 1.53 [s, 3H, CH3b
Mdp], 1.35 [d (broad, partly masked), <Jˆ7 Hz, 3H, CH3
Anal. for C23H34N2O8´0.5H2O: calcd C 58.08, H 7.42, N
5.89; found C 57.84, H 7.31, N 5.71.
Ala1], 1.33 [d, Jˆ7.2Hz, 3H, CH 3 Ala2]. 13C NMR
b
(CDCl3): 173.2, 172.9, 171.8 [CvO Ala1, Ala2 and Mdp],
156.2[C vO Fmoc], 148.4, 147.9 [CAr±O Mdp], 143.7,
2.2.13. Boc-Aib-[18-C-6]-Mdp-OH (8b). A solution of 2b
(0.529 g; 1.03 mmol) in CH2Cl2 (15 mL) was treated with
TFA (5 mL) under the same experimental conditions and
work-up as for the N-deprotection of 5a (see preparation
of 6a), to afford crude TFA´H-[18-C-6]-Mdp-OH (2d) (not
characterized) (1.03 mmol) which was directly reacted with
Boc-Aib-NCA (0.945 g; 4.12mmol) and DIPEA
(0.720 mL; 4.12 mmol) in THF (7.5 mL) at 558C for 30 h.
Extraction followed by preparative TLC of the crude
Ar
143.6, 141.2[C
Fmoc], 128.9 [CAr Mdp], 127.7, 127.1,
127.0, 125.0, 124.9, 119.9 [CAr Fmoc], 123.0, 116.3,
113.3 [CAr Mdp], 70.5, 69.4, 68.8, 68.7 [OCH2], 67.0 [O±
CH2 Fmoc], 60.4 [Ca Mdp], 52.3 [OCH3], 51.4, 48.3 [Ca
Ala1 and Ala2], 47.0 [Ar±CH Fmoc], 40.8 [ArCH2 Mdp],
b
b
b
23.9 [CH3 Mdp], 17.9, 17.7 [CH3 Ala1 and Ala2].
25
25
25
[a]589 ˆ268.38, [a]578 ˆ272.38, [a]546 ˆ279.28,
25
25
[a]436 ˆ2146.08, [a]365 ˆ2242.68 (c 0.1; MeOH).

K. Wright et al. / Tetrahedron 58 (2002) 5811±5820
5819
Tetrahedron 1995, 51, 9241±9284. (b) Voyer, N. Topics in
Current Chemistry, Vol. 184; Springer: Berlin, 1996 pp 1±37.
2. (a) Berthet, M.; Sonveaux, E. Biopolymers 1986, 25, 189±
204. (b) Voyer, N. J. Am. Chem. Soc. 1991, 113, 1818±
1821. (c) Voyer, N.; Roby, J. Tetrahedron Lett. 1991, 32,
product on silica gel with eluent (G) and then product
extraction from silica gel, using the same work-up pro-
cedure as in the preparation of 6a, gave 0.481 g (78%) of
pure Boc-Aib-[18-C-6]-Mdp-OH (8b). Rfˆ0.25 (G). 1H
NMR (CDCl3): 7.39 [s (broad), 1H, COOH], 7.03 [s, 1H,
NH Mdp], 6.69 [s (broad), 1H, ArH2], 6.68 [d (partly
masked), Jˆ8.4 Hz, 1H, ArH5], 6.64 [d (broad),
Jˆ8.4 Hz, 1H, ArH6], 5.29 [s (broad), 1H, NH Aib], 4.06
[m, 4H, OCH2], 3.83 [m, 4H, OCH2], 3.69 [m, 8H, OCH2],
3.64 [s, 4H, OCH2], 3.38 [d, Jˆ13.8 Hz, 1H] and 3.16 [d,
Ã
331±334. (d) Voyer, N.; Deschenes, D.; Bernier, J.; Roby, J.
J. Chem. Soc., Chem. Commun. 1992, 134±136. (e) Voyer, N.;
Ã
Roby, J.; Deschenes, D.; Bernier, J. Supramol. Chem. 1995, 5,
Â
61±69. (f) Voyer, N.; Guerin, B. J. Chem. Soc., Chem.
Commun. 1997, 2329±2330. (g) Voyer, N.; Potvin, L.;
Rousseau, E. J. Chem. Soc., Perkin Trans. 2 1997, 1469±
1471. (h) Meillon, J.-C.; Voyer, N. Angew. Chem., Int. Ed.
Engl. 1997, 36, 967±969. (i) Biron, N.; Voyer, J.-C.; Meillon,
M.-E.; Cormier, M. A. Biopolymers 2000, 55, 364±372.
(j) Meillon, J.-C.; Voyer, N.; Biron, E.; Sanschagrin, F.;
Stoddart, J. F. Angew. Chem., Int. Ed. Engl. 2000, 39, 143±
145.
b
b
Jˆ13.8 Hz, 1H, ArCH2 Mdp], 1.61 [s, 3H, CH3 Mdp],
b
1.40 [s, 3H] and 1.36 [s (masked), 3H, CH3 Aib], 1.36 [s,
9H, (CH3)3 Boc]. 13C NMR (CDCl3): 175.9, 174.2[COOH
Mdp and CvO Aib], 154.7 [CvO Boc], 148.2, 147.6 [CAr±
O], 129.4, 122.7, 115.7, 113.2 [CAr], 79.9 [O±C Boc], 70.4,
69.42, 69.39, 68.63, 68.58 [OCH2], 60.8 [Ca Mdp], 56.7 [Ca
b
b
Aib], 40.8 [ArCH2 Mdp], 28.1 [(CH3)3 Boc], 25.8 [CH3
b
25
25
25
Â
3. Voyer, N.; Guerin, B. Tetrahedron 1994, 50, 989±1010.
Mdp], 24.9, 23.0 [CH3 Aib]. [a]589 ˆ18.88, [a]578
ˆ
25
25
4. Anzai, J.; Ueno, A.; Osa, T. Makromol. Chem., Rapid
Commun. 1982, 3, 55±58.
19.78, [a]546 ˆ111.98, [a]436 ˆ126.98, [a]365
ˆ
162.18 (c 0.23; MeOH). Anal. for C29H46N2O11´0.5H2O:
calcd C 57.31, H 7.80, N 4.61; found C 57.28, H 7.73, N 4.19.
5. For leading references see: (a) Toniolo, C.; Benedetti, E.
Macromolecules 1991, 24, 4004±4009. (b) Toniolo, C.;
Benedetti, E. Trends. Biochem. Sci. 1991, 16, 350±353.
(c) Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.;
2.2.14. Boc-Aib-[18-C-6]-Mdp-Ala-OMe (9a). (1) To a
suspension of 8b (0.092g; 0.15 mmol), HCl´H-Ala-OMe
(0.065 g; 0.46 mmol) and HOAt (0.042g; 0.0.30 mmol) in
CH2Cl2 (2mL), was added NMM (0.070 mL; 0.62mmol)
and then EDC (0.044 g; 0.23 mmol). The mixture was stir-
red at room temperature for 72h, and then diluted with
CH2Cl2 (150 mL) and 0.5N HCl (100 mL). The separated
organic phase was extracted with 0.5N HCl (100 mL), H2O
(100 mL), 5% NaHCO3 (2£100 mL), H2O (2£100 mL),
dried (MgSO4), ®ltered and evaporated in vacuo, to give
Â
Cavicchioni, G.; Precigoux, G.; Aubry, A.; Kamphuis, J.
Biopolymers 1993, 33, 1061±1072. (d) Toniolo, C.; Benedetti,
E. In Molecular Conformation and Biological Interactions,
Balaram, P., Ramaseshan, S., Eds.; Indian Academy of
Sciences: Bangalore, 1991; pp 511±521. (e) Benedetti, E.
Biopolymers 1996, 40, 3±44. (f) Karle, I. L.; Balaram, P.
Biochemistry 1990, 29, 6747±6756. (g) Karle, I. L.
Biopolymers 1996, 40, 157±180. (h) Karle, I. L. Acc. Chem.
Res. 1999, 32, 693±701. (i) Bolin, K. A.; Millhauser, G. L.
Acc. Chem. Res. 1999, 32, 1027±1033.
1
0.091 g (<86%) of a crude product which, by H NMR,
consisted of a mixture of 9a and traces (ca. 6% mol/mol)
of the side product ClCH2OAt. This mixture could be
directly used in further experiments. (2) From 5a, a sample
of pure 9a was obtained after separation of the side product
Ï
6. Mazaleyrat, J. P.; Gaucher, A.; Goubard, Y.; Savrda, J.;
Wakselman, M. Tetrahedron Lett. 1997, 38, 2091±2094.
7. Mazaleyrat, J.-P.; Goubard, Y.; Azzini, M.-V.; Wakselman,
M.; Crisma, M.; Formaggio, F.; Toniolo, C. In Peptides 2000,
Martinez, J., Fehrentz, J.-A., Eds.; EDK: Paris, France, 2001;
pp 185±186.
1
7 (vide supra). Rfˆ0.25 (G). H NMR (CDCl3): 7.72[d
(broad), Jˆ6.2Hz, 1H, NH Ala], 6.74 [d, Jˆ7.9 Hz, 1H,
ArH5], 6.65 [d (broad), <Jˆ2Hz, 1H, ArH 2], 6.62[dd
(broad), Jˆ8.1 Hz and <Jˆ2Hz, 1H, ArH 6], 6.20 [s, 1H,
NH Mdp], 4.95 [s, 1H, NH Aib], 4.53 [dq, <Jˆ7.2, 7.2 Hz,
1H, Ha Ala], 4.11 [m, 4H, OCH2], 3.89 [m, 4H, OCH2],
3.77±3.67 [m, 8H, OCH2], 3.70 [s, 3H, OCH3], 3.67 [s,
4H, OCH2], 3.54 [d, Jˆ13.8 Hz, 1H] and 3.06 [d,
8. Mazaleyrat, J.-P.; Goubard, Y.; Azzini, M.-V.; Wakselman,
M.; Peggion, C.; Formaggio, F.; Toniolo, C. Eur. J. Org.
Chem. 2002, 1232±1247.
9. Kotha, S.; Brahmachary, E. Indian J. Chem. 2001, 40B, 1±4.
10. Hu, M.; Subramanian, P.; Mosberg, H. I.; Amidon, G. L.
Pharm. Res. 1989, 6, 66±70.
b
b
Jˆ13.9 Hz, 1H, ArCH2 Mdp], 1.47 [s, 3H, CH3 Mdp],
b
1.43 [d, Jˆ7.2Hz, 3H, CH 3 Ala], 1.40 [s, 9H, (CH3)3
11. Hsieh, K.-H.; deMaine, M. M. Synthesis 1991, 59±62.
12. Saari, W. S.; Halczenko, W.; Cochran, D. W.; Dobrinska,
M. R.; Vincek, W. C.; Titus, D. C.; Gaul, S. L.; Sweet, C. S.
J. Med. Chem. 1984, 27, 713±717.
Boc], 1.38 [s, 3H] and 1.34 [s, 3H, CH3 Aib]. 13C NMR
b
(CDCl3): 173.8, 173.6, 172.8 [CvO Aib, Mdp and Ala],
155.5 [CvO Boc], 148.2, 147.8 [CAr±O], 129.8, 123.6,
117.1, 113.3 [CAr], 81.0 [O±C Boc], 70.6, 70.5, 69.5,
69.0, 68.8 [OCH2], 59.6 [Ca Mdp], 57.1 [Ca Aib], 52.0
13. Saari, W. S.; Freedman, M. B.; Hartman, R. D.; King, S. W.;
Raab, A. W.; Randall, W. C.; Engelhardt, E. L.; Hirschmann,
R.; Rosegay, A.; Ludden, C. T.; Scriabine, A. J. Med. Chem.
1978, 21, 746±753.
b
[OCH3], 48.4 [Ca Ala], 39.1 [ArCH2 Mdp], 28.1 [(CH3)3
b
Boc], 26.8 [CH3b Mdp], 24.9, 23.9 [CH3b Aib], 17.0 [CH3
25
25
25
Ala]. [a]589 ˆ226.88, [a]578 ˆ228.88, [a]546 ˆ236.28,
14. Arakawa, K.; Hirata, M.; Watanabe, K.; Kuga, H.; Hattori, E.
Chem. Pharm. Bull. 1979, 27, 1030±1033.
25
[a]436 ˆ259.18 (c 0.15; MeOH). Anal. for C33H53N3O12:
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