Preparation of sugar amino acids by Claisen-Johnson rearrangement: Synthesis and incorporation into enkephalin analogues

Article abstract of DOI:10.1002/ejoc.200400166

We have developed a convenient route for the synthesis of an unsaturated branched sugar bearing a carboxylic acid and an amino group (masked as an azide group) by employing a totally stereoselective Claisen-Johnson rearrangement as the key step. Several M

Full text of DOI:10.1002/ejoc.200400166

FULL PAPER
Preparation of Sugar Amino Acids by Claisen-Johnson Rearrangement:
Synthesis and Incorporation into Enkephalin Analogues[‡]
[a]
[a]
[a]
´
Ana Montero, Enrique Mann,* and Bernardo Herradon*
Keywords: Amino acids / Carbohydrates / Enkephalin / Peptidomimetics / Sigmatropic rearrangement
We have developed a convenient route for the synthesis of
an unsaturated branched sugar bearing a carboxylic acid and
an amino group (masked as an azide group) by employing a
totally stereoselective Claisen−Johnson rearrangement as
the key step. Several Met- and Leu-enkephalin analogues
with different substitution patterns at the N- and C-termini
were prepared by incorporating this sugar amino acid (SAA)
as a substitute for the central Gly−Gly fragment of the par-
ent pentapeptides.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
The design and development of new amino acids and
peptidomimetics has attracted considerable attention due to
the pharmacological limitations (such as conformational
flexibility and in vivo instability) of bioactive peptides.[1]
Sugar amino acids (SAAs), carbohydrate derivatives con-
taining a carboxylic acid and amino functionality, have em-
erged as an attractive option to be used as building blocks
for the preparation of new analogues designed in order to
circumvent those limitations.[2] The conformationally bi-
ased furan or pyran rings of these molecules make them
suitable candidates for non-peptide scaffolds in peptidomi-
metics where they can easily be incorporated using their
carboxyl and amino termini. SAAs occur in nature as subu-
nits of oligosasaccharides in cell walls of bacteria (e.g. neur-
aminic acid[3]) and in some antibiotics as A40926[4] (Fig-
ure 1). Furthermore, in recent years, different unnatural
SAAs have been prepared by Kessler (A),[5] Fleet (B),[6]
Overhand[7] (C) and Hirschman[8] (D) among others,[9] and
have found broad applications in different topics, for ex-
ample, in the synthesis of peptidomimetics[10] or in the
preparation of linear and cyclic oligomers designed to act
as foldamers and host molecules (Figure 1).[11]
Figure 1. Natural and unnatural sugar amino acids (SAAs)
at the contiguous position of the endocyclic oxygen atom
present in the sugar framework and is usually obtained by
direct oxidation of the primary hydroxyl group attached to
that position. Furthermore, the presence of additional func-
tional groups is generally limited to several protected- or
free hydroxyl groups that are difficult to manipulate inde-
pendently. Thus, it would be desirable to develop new syn-
thetic approaches in order to expand the diversity of SAA-
like structures.
In connection with ongoing projects on the synthesis,
structure and properties of peptidic compounds,[12] we have
been interested in the preparation of new peptide deriva-
tives that employ unsaturated carbohydrates as scaffolds
(peptide-carbohydrate hybrids).[13] Herein we report our re-
A review of the different SAAs already reported shows
that the carboxylic acid functionality is located, in general,
[‡]
Taken in part from the Ph. D. thesis of E. M. (Universidad
´
Autonoma, Madrid, 2002) and the projected Ph. D. thesis of
A. M.
Dedicated to Prof. J. L. Soto (Universidad Complutense,
Madrid) on the occasion of his retirement from the chair of
Organic Chemistry
[a]
´
´
Instituto de Quımica Organica General, C.S.I.C.,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (internat.) ϩ34-91-5644-853
E-mail: herradon@iqog.csic.es
ictm317@ictp.csic.es
Eur. J. Org. Chem. 2004, 3063Ϫ3073
DOI: 10.1002/ejoc.200400166
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3063

´
A. Montero, E. Mann, B. Herradon
FULL PAPER
sults on the design and synthesis of a novel SAA with a to the sugar amino acid template H with the use of conven-
3,6-dihydro-2H-pyran structure (E, Figure 2), using a tional peptide chemistry. This conveniently functionalized
ClaisenϪJohnson rearrangement as the key step. Although derivative of 3,6-dihydro-2H-pyran should be obtainable
the application of the Claisen rearrangement in carbo- from commercially available 3,4,6-tri-O-triacetyl -glucal
hydrate chemistry has proven to be a valuable method for (1), by employing ClaisenϪJohnson and Ferrier rearrange-
the realization of complex synthetic schemes,[14] it has not ments as key steps.
been used previously for the preparation of SAAs. Ad-
The synthesis of the key intermediate 7 started from 1,[18]
ditionally, we have incorporated this SAA into Leu- and which was subjected to a Ferrier rearrangement[19] using al-
Met-enkephalin analogues (F). Although the enkephalins lyl alcohol as nucleophile (Scheme 1). Two methods were
(G) are potent analgesic natural peptides that act on the compared to perform the transformation, employing either
[20]
[21]
opioid receptor,[15] their pharmacological utility is limited, I2
or FeCl3
as catalysts. Although similar high yields
and this is what makes the search for enkephalin analogues (81% with I2, 91% with FeCl3) and identical anomeric ratios
an active research field.[16] Most enkephalin analogues have of the glycosides 2α and 2β (α/β ratio ϭ 8:1) were obtained
been prepared with the aim to increase their enzymatic sta- with both methods, it was easier to purify the resulting
bility as well as to restrict their conformational mobility. product when FeCl3 was used. Our choice of the allyloxy
The non-peptidic fragment of compounds of type F re- group as the substituent at the anomeric position was based
places the conformationally flexible GlyϪGly sequence in on the possibility of providing an additional site for poten-
the corresponding enkephalins (G) that are known to adopt tial chemoselective modifications. Since the two anomers
different conformations depending on the binding environ- proved difficult to separate chromatographically, the syn-
ment (Figure 2).[17] The cis stereochemistry of the SAA thetic sequence was carried out with the mixture. Meth-
would allow suitable interactions between the amino acid anolysis of the diacetate 2 gave the diol 3 (98% yield) with
residues that flank the non-peptidic scaffold. Furthermore, erythro configuration, which underwent a double Mitsu-
the presence of additional functional groups (the endocyclic nobu reaction[22] with benzoic acid as the nucleophile to
carbonϪcarbon double bond and RЈ) in molecules of type give dibenzoate 4 (95% yield), with threo configuration, as
F provides sites to generate molecular diversity.
a ca 8:1 mixture of anomers. The dibenzoate 4 was treated
with sodium methoxide to afford the diol 5, which was
selectively protected with tert-butyldiphenylsilyl chloride
(TBDPSCl) to give the allylic alcohol 6 (77% yield). At this
stage, the minor anomer was separated by chromatography.
ClaisenϪJohnson rearrangement was accomplished by re-
fluxing compound 6 in triethyl orthoacetate in the presence
of propanoic acid and hydroquinone,[23] and this gave the
corresponding γ,δ-unsaturated ester 7 as the only product
in excellent yield. Furthermore, the reaction took place in
a completely stereoselective way, as is expected for such su-
prafacial allyl rearrangements. The stereochemistry in com-
pound 7 was confirmed by 1H NMR spectroscopic analysis,
which showed that the anomeric proton (H-2) signal res-
onated as a singlet.[24] This data is in agreement with the
empirical rule reported by Ferrier for similar 3-substituted
3,6-dihydro-2H-pyrans, which relates the value of the coup-
ling constant between the protons H-2 and H-3 (J2,3) to
their relative stereochemistry: a value of J2,3 ഠ 0 Hz is in-
dicative of a trans-relationship.[25] The pseudo axial dispo-
sition of the free hydroxy group at C-3 in 6 seems to play
an important role in the outcome of the rearrangement. Re-
cently, Krohn et al. reported the ClaisenϪJohnson re-
arrangement of a related substrate that is epimeric at C-3
(the erythro diastereoisomer with pseudo-equatorial confor-
mation of the OH);[26] their results show a moderate conver-
sion (55%) after refluxing for two days. The different be-
havior of 6 and its epimer in the ClaisenϪJohnson re-
arrangement reflects the poor tendency of the last com-
pound to adopt a suitable arrangement of the allylic CϪC
and the intermediate ketene ketal double bonds (structure
non-shown).[27]
Figure 2. Structures of the SAA (E), the target enkephalin ana-
logues (F), and natural Met- and Leu-enkephalins (G)
Results and Discussion
The preparation of enkephalin analogues of type F has
been approached through the retrosynthetic correlation
summarized in Figure 3. Peptidic chains could be attached
Having established a convenient route to the ester 7,[28]
the last step for the synthesis of the target SAA was per-
Figure 3. Retrosynthetic analysis of target molecules F
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Preparation of Sugar Amino Acids by Claisen-Johnson Rearrangement
FULL PAPER
as catalyst, and DMF as solvent.[29] The protocol followed
for the synthesis of the enkephalin analogues 16 and 18 is
depicted in Scheme 3. Reaction of acid 12 with dipeptides
HϪPheϪMetϪOMe and HϪPheϪLeuϪOMe gave inter-
mediates 13 (75%) and 14 (72%), respectively. Reduction of
the azido group was performed by the Staudinger reac-
tion,[30] with the use of triphenylphosphane and water in
refluxing benzene. The resulting amines, which were used
without any purification, were coupled to BocϪTyrϪOH
with peptide coupling conditions described above to give
compounds 15 (72%) and 17 (84%). Final saponification of
the methyl esters (LiOH) afforded enkephalin analogues 16
and 18 in quantitative yields.
Scheme 1. Reagents and conditions: (a) I2, CHϭCHCH2OH, THF,
room temp., 81% (b) FeCl3, CHϭCHCH2OH, CH3CN, 91%. (c)
KOH, MeOH, room temp., 99% (d) PPh3, benzoic acid, DIAD,
THF, room temp., 95% (e) MeONa/MeOH, 99% (f) TBDPSCl,
Et3N, DMAP, CH2Cl2, 0 °C to room temp., 77% (g) CH3C(OEt)3,
CH3CH2CO2H, hydroquinone, 140 °C, 20 h, 85%
formed as follows (Scheme 2). Desilylation of compound 7
with tetrabutylammonium fluoride (TBAF) afforded al-
cohol 8 (91% yield) that, in turn, was reacted with meth-
anesulfonyl chloride in the presence of triethylamine to give
the methanesulfonate 9 in excellent yield (98%). Compound
9 was converted into compound 10 by reaction with sodium
azide (76% yield). Since the direct hydrolysis of ethyl ester
10 to the acid 12 with lithium hydroxide was sluggish and
gave variable yields and side products, we performed this
transformation in a two-step sequence: first the transesteri-
fication to the methyl ester 11 by reaction with sodium me-
thoxide in methanol (72% yield), followed by treatment
with lithium hydroxide to afford acid 12 (93% yield).
Scheme 3. Reagents and conditions: (a) CF3CO2H·HϪPheϪ
MetϪOMe for 13 or CF3CO2H·HϪPheϪLeuϪOMe for 14, EDC,
HOBt, Et3N, DMAP, DMF, 75% for 13, 72% for 14 (b) (i) Ph3P,
H2O, benzene, reflux (ii) BocϪTyrϪOH, EDC, HOBt, Et3N,
DMAP, DMF, 72%for 15, 84% for 17 (c) LiOH, THF/H2O, 99%
for 16 and 18
Finally, since the biological activity of many peptides and
analogues is dependent of the C and N-terminal substitu-
ents,[31] we have explored the synthesis of peptide-carbo-
hydrate hybrids related to enkephalins with different substi-
tution patterns at these positions. Synthesis of derivatives
20؊24, presenting the N-methyl amide functionality at the
Scheme 2. Reagents and conditions: (a) TBAF·3H2O, THF, room
temp., 95% (b) MsCl, Et3N, CH2Cl2, 0 °C, 98% (c) NaN3, DMF,
60 °C, 76% (d) MeONa/MeOH, 72% (e) LiOH, THF/H2O, 93%
With the key sugar amino acid 12 in hand, we explored C-termini and the amino group of the tyrosine residue acyl-
the incorporation of this scaffold into longer peptides that ated with several groups, was accomplished in a similar fa-
have sequences that are similar to those of Leu- and Met- shion as that described for 16 and 18 (Scheme 4). Coupling
enkephalin. All the peptide bonds were formed by standard of acid 12 with dipeptide HϪPheϪMetϪNHMe (EDC/
solution methods with 1-ethyl-3-[3-(dimethylamino)propyl]- HOBt/Et3N/DMAP) gave intermediate 19 in 74% yield.
carbodiimide hydrochloride (EDC) and 1-hydroxybenzo- After Staudinger reduction of the azido group, the resulting
triazole (HOBt) as coupling reagents, Et3N as base, DMAP free amine underwent condensation reactions five different
Eur. J. Org. Chem. 2004, 3063Ϫ3073
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A. Montero, E. Mann, B. Herradon
FULL PAPER
otherwise indicated, were used as received. Anhydrous solvents
were purchased from Aldrich or Fluka and kept over molecular
sieves under argon. 1H NMR and 13C NMR spectra were recorded
on Varian UNITY 500, Varian INOVA 400 or Varian INOVA 300
spectrometers; chemical shifts (δ) are reported in parts per million
N-acylated tyrosine derivatives to give the corresponding
enkephalin analogues 20؊24 (49Ϫ69%).
1
and the coupling constants are indicated in Hz. H NMR spectra
were referenced to the chemical shift of either TMS (δ ϭ 0.00 ppm)
or the residual proton in the deuterated solvent. 13C NMR spectra
were referenced to the chemical shift of the deuterated solvent. The
IR spectra were measured on a PerkinϪElmer-Spectrum One FT-
IR spectrometer; the units in the IR spectra are indicated in cmϪ1
.
MS analyses were recorded on a Hewlett Packard 5973 MSD (EI)
or on a Hewlett Packard1100 MSD (ESI) spectrometer. Combus-
tion analyses were measured on a Carlo Erba EA 1180-Elemental
Analyzer. Optical rotations were determined with a PerkinϪElmer
241 MC polarimeter at room temperature (ca. 295 K). Melting
points were measured on a Kofler hot-stage apparatus. All the pre-
parative chromatography was done with silica gel (40Ϫ63 nm)
using the technique of flash chromatography.
(2R,3S,6S)-6-Allyloxy-2-(acetoxymethyl)-3,6-dihydro-2H-pyran-3-
yl acetate (2): A 1  solution of FeCl3 in CH3CN (6.9 mL,
6.98 mmol) was added to a stirred solution of 3,4,6-tri-O-acetyl--
glucal 1 (19.0 g, 69.8 mmol) and allyl alcohol (5.2 mL, 76.8 mmol)
in anhydrous CH3CN (250 mL) under argon. The mixture was
stirred for 30 min and saturated solution of NaHCO3 was added.
The aqueous phase was thoroughly extracted with CH2Cl2, and the
combined organic phases were dried (MgSO4). Solvent evaporation
and purification of the residual product by flash chromatography
gave diacetate 2 (17.11 g, 91%) as a mixture of anomers (α/β ra-
tio ϭ 8:1). White solid; m.p. 44Ϫ45 °C. [α]2D2 ϭ ϩ109 (c ϭ 1.0,
Scheme 4. Reagents and conditions: (a) CF3CO2H·HϪPheϪ
MetϪNHMe, EDC, HOBt, Et3N, DMAP, DMF, 74% (b) (i) Ph3P,
H2O, benzene, reflux (ii) 2-BiphCOϪTyrϪOH for 20 (67%),
BzϪTyrϪOH for 21 (51%), CF3COϪTyrϪOH for 22 (49%),
CH3(CH2)2COϪTyrϪOH for 23 (69%), CH3CO-TyrϪOH for 24
(65%), EDC, HOBt, Et3N, DMAP, DMF
CHCl3). IR (KBr): ν˜ ϭ 2902, 1744, 1371, 1235, 1043 cmϪ1 1H
.
NMR (300 MHz, CDCl3): δ ϭ 2.08 (s, 3 H, COCH3), 2.10 (s, 3 H,
COCH3), 4.07 (dd, J ϭ 12.7 and J ϭ 4.7 Hz, 1 H, CHHCHϭCH2),
4.09 (m, 1 H, 2-H), 4.21 (m, 2 H, CH2OAc), 4.30 (dd, J ϭ 12.7
and J ϭ 6.9 Hz, 1 H, CHHCHϭCH2), 5.07 (s, 1 H, 6-H), 5.20 (m,
Jcis-H ϭ 10.3 Hz, 1 H, ϭCH2 cis), 5.30 (m, Jtrans-H ϭ 17.4 Hz, 1
H, ϭCH2 trans), 5.31 (m, 1 H, 3-H), 5.89 (m, 2 H, 4-H, 5-H), 6.00
(m, 1 H, CHϭCH2) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 21.7
(q, COCH3), 21.9 (q, COCH3), 64.0 (t, CH2OAc), 66.4 (d, C-3),
68.1 (d, C-2), 70.3 (t, CH2CHϭCH2), 94.7 (d, C-6), 118.4 (t, CHϭ
CH2), 128.8 (d, C-5), 130.3 (d, C-4), 135.2 (d, CHϭCH2), 171.2 (s,
CO), 171.6 (s, CO) ppm. MS (EI): m/z (%) ϭ 270 (Ͻ 1) [Mϩ], 213
(10), 168 (20), 153 (13), 126 (78), 111 (35), 97 (11), 85 (45), 43 (100).
C13H18O6 (270.28): calcd. C 57.77, H 6.71; found C 57.69, H 7.07.
Conclusion
In summary, we have developed a practical route for the
synthesis of a new sugar amino acid derived from 2-alkoxy-
3,6-dihydro-2H-pyran through
a totally stereoselective
ClaisenϪJohnson rearrangement. Compounds 7؊12 can be
considered as unsaturated branched sugars that are useful
synthetic intermediates.[32] In this context, the azido acid
12, as a masked amino acid, was incorporated in peptidom-
imetics that resemble the structure of enkephalins. Ad-
ditionally, further transformations of the endocyclic
carbonϪcarbon double bond by well-established reactions
employed in similar substrates[33] might constitute a method
to generate molecular diversity[34] by providing compounds
with modulated pharmacological properties.
Work is in progress to determine, by solution and compu-
tational techniques, the conformational preferences induced
by template 12 when introduced into a peptidic chain, as
well as the biological activity of the resulting enkephalin
analogues.
(2R,3S,6S)-6-Allyloxy-2-(hydroxymethyl)-3,6-dihydro-2H-pyran-3-
ol (3): KOH (100 mg) was added to a solution of diacetate 2
(16.50 g, 61.08 mmol) in MeOH (150 mL). The mixture was stirred
for 2 h. The solvent was evaporated, and the residual product was
purified by flash chromatography using hexane/EtOAc (2:8) as elu-
ent. Diol 3 was obtained (11.30 g, 99%) as a mixture of anomers
(α/β ratio ϭ 9.5:1).White solid; m.p. 69Ϫ70 °C. [α]2D2 ϭ ϩ72 (c ϭ
1.2, CHCl3). IR (KBr): ν˜ ϭ 3391, 2879, 1396, 1043 cmϪ1. 1H NMR
(300 MHz, CDCl3): δ ϭ 2.90 (br. s, 1 H, OH), 3.41 (br. s, 1 H,
OH), 3.66 (dt, J ϭ 9.1 and J ϭ 4.0 Hz, 1 H, 2-H), 3.81 (m, 2 H,
CH2OAc), 4.04 (dd, J ϭ 12.7 and J ϭ 4.7 Hz, 1 H, CHHCHϭ
CH2), 4.16 (m, 1 H, 3-H), 4.22 (dd, J ϭ 12.7 and J ϭ 6.9 Hz, 1 H,
CHHCHϭCH2), 4.99 (s, 1 H, 6-H), 5.17 (m, Jcis-H ϭ 10.4 Hz, 1
H, ϭCH2 cis), 5.27 (m, Jtrans-H ϭ 17.2 Hz, 1 H, ϭCH2 trans), 5.72
(ddd, J ϭ 10.1, J ϭ 2.7 and J ϭ 2.1 Hz, 1 H, 5-H), 5.88 (m, 1 H,
CHϭCH2), 5.94 (dd, J ϭ 10.1 and J ϭ 1.3 Hz, 1 H, 4-H) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 62.6 (t, CH2OAc), 64.1 (d, C-3),
69.2 (t, CH2CHϭCH2), 71.6 (d, C-2), 93.6 (d, C-6), 117.5 (t, CHϭ
Experimental Section
General Methods: All the reactions with sensitive materials were
carried out using dry solvents under an argon atmosphere. All the
solvents and reagents were commercially available and, unless
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Preparation of Sugar Amino Acids by Claisen-Johnson Rearrangement
FULL PAPER
CH2), 126.0 (d, C-5), 133.7 (d, C-4), 134.3 (d, CHϭCH2) ppm. MS (300 MHz, CDCl3): δ ϭ 1.06 [s, 9 H, (CH3)3C], 1.92 (d, J ϭ 8.5 Hz,
(EI): m/z ϭ 185 (1) [Mϩ Ϫ 1], 129 (23), 126 (48), 97 (27), 85 (100),
1 H, OH), 3.90 (m, 3 H, 3-H, CH2OTBDPS), 4.03 (dd, J ϭ 12.7
83 (22), 69 (23), 57 (48), 55 (27). C9H14O4 (186.21): calcd. C 58.05, and J ϭ 4.7 Hz, 1 H, CHHCHϭCH2), 4.13 (dt, J ϭ 6.2 and J ϭ
H 7.58; found C 57.87, H 7.71.
2.2 Hz, 1 H, 2-H), 4.24 (dd, J ϭ 12.7 and J ϭ 6.9 Hz, 1 H,
CHHCHϭCH2), 5.06 (d, J ϭ 2.8 Hz, 1 H, 6-H), 5.17 (m, Jcis-H
ϭ
(2R,3R,6S)-6-Allyloxy-2-(benzoyloxymethyl)-3,6-dihydro-2H-pyran-
3-yl benzoate (4): DIAD (18.7 mL, 94.5 mmol) was added dropwise
to a well stirred solution of diol 3 (8.0 g, 43.0 mmol), Ph3P (24.7 g,
94.5 mmol), and benzoic acid (11.5 g, 94.5 mmol) in anhydrous
THF (60 mL) under argon. Stirring was continued for 2 h, after
which the solvent was evaporated, and the residual product was
purified by flash chromatography using hexane/EtOAc (9:1) as elu-
ent. Compound 4 was obtained (16.0 g, 95%) as a mixture of ano-
mers (α/β ratio ϭ 9.5:1). Colorless thick oil. [α]2D2 ϭ Ϫ189 (c ϭ 1.0,
CHCl3). IR (KBr): ν˜ ϭ 2904, 1721, 1451, 1315, 1266, 1097, 1026
10.3 Hz, 1 H, ϭCH2 cis), 5.25 (m, Jtrans-H ϭ 17.2 Hz, 1 H, ϭCH2
trans), 5.90 (m, 1 H, CHϭCH2), 5.91 (dd, J ϭ 9.9 and J ϭ 2.8 Hz,
1 H, 5-H), 6.16 (ddd, J ϭ 9.9, J ϭ 5.5 and J ϭ 0.9 Hz, 1 H, 4-H),
7.38 (m, 6 H, Ar-H), 7.70 (m, 4 H, Ar-H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 19.7 [s, (CH3)3C], 27.3 (q, 3C, (CH3)3C],
62.4 (t, CH2OTBDPS), 64.0 (d, C-3), 69.1 (t, CH2CHϭCH2), 71.3
(d, C-2), 93.1 (d, C-6), 117.9 (t, CHϭCH2), 128.2 (d, 4C, CAr),
129.0 (d, C-5), 130.2 (s, 2C, CAr; d, C-4), 134.9 (d, CHϭCH2),
136.1 (d, 4C, CAr) ppm. MS (EI): m/z (%) ϭ 309 (18) [Mϩ Ϫ 115],
241 (100), 223 (28), 199 (50), 181 (17), 163 (61), 135 (16).
C25H32SiO4 (424.60): calcd. C 70.72, H 7.60; found C 70.47, H
7.42.
cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 4.05 (dd, J ϭ 12.7 and
.
J ϭ 4.7 Hz, 1 H, CHHCHϭCH2), 4.29 (dd, J ϭ 12.7 and J ϭ
6.9 Hz, 1 H, CHHCHϭCH2), 4.52 (m, 1 H, CHHOBz), 4.67 (m, 2
H, 2-H, CHHOBz), 5.17 (m, Jcis-H ϭ 10.4 Hz, 1 H, ϭCH2 cis), 5.20
(d, J ϭ 3.1 Hz, 1 H, H-6), 5.25 (m, Jtrans-H ϭ 17.2 Hz, 1 H, ϭCH2
trans), 5.37 (dd, J ϭ 5.4 and J ϭ 1.6 Hz, 1 H, 3-H), 5.94 (m, 1 H,
CHϭCH2), 6.12 (dd, J ϭ 10.0 and J ϭ 3.1 Hz, 1 H, 5-H), 6.30
(dd, J ϭ 10.0 and J ϭ 5.4 Hz, 1 H, 4-H), 7.43 (m, 4 H, Ar-H),
7.56 (m, 2 H, Ar-H), 8.05 (m, 4 H, Ar-H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 63.8 (d, t, 2C, C-3, CH2OBz), 67.6 (d, C-
2), 69.2 (t, CH2CHϭCH2), 93.4 (d, C-6), 117.9 (t, CHϭCH2), 125.6
(d, C-4), 128.6 (d, 2C, CAr), 128.7 (d, 2C, CAr), 129.9 (d, 2C, CAr),
130.0 (s, d, d, 3C, CAr), 130.4 (s, CAr), 131.1 (d, C-5), 133.4 (d,
CAr), 133.6 (d, CAr), 134.3 (d, CHϭCH2), 166.1 (s, CO), 166.4 (s,
CO) ppm. MS (EI): m/z (%) ϭ 337 (6) [Mϩ Ϫ 57], 230 (37), 215
(18), 105 (100), 77 (53).
Ethyl
2-{(2S,3S,6S)-2-Allyloxy-6-[(tert-butyldiphenylsilanyloxy)-
methyl]-3,6-dihydro-2H-pyran-3-yl}acetate (7): A mixture of alcohol
6 (5.0 g, 11.8 mmol) and triethyl orthoacetate (22.1 mL, 118 mmol)
was heated to 100 °C, and then hydroquinone (129 mg, 1.18 mmol)
and propionic acid (0.09 mL, 1.18 mmol) were added. The mixture
was stirred for 20 h at 140 °C (EtOH formed during the reaction
was eliminated periodically with a rotavapor). The solvent was eva-
porated, and the residual product was purified by flash chromatog-
raphy using hexane/EtOAc (9:1). Ester 7 was obtained (4.93 g, 85%)
as a colorless thick oil. [α]2D2 ϭ ϩ41 (c ϭ 1.2, CHCl3). IR (neat):
ν˜ ϭ 2931, 2858, 1735, 1428, 1264, 1113, 1031 cmϪ1 1H NMR
.
(300 MHz, CDCl3): δ ϭ 1.07 [s, 9 H, (CH3)3C], 1.25 (t, J ϭ 7.2 Hz,
3 H, CO2CH2CH3), 2.34 (dd, J ϭ 16.1 and J ϭ 6.0 Hz, 1 H,
CHHCO2Et), 2.46 (dd,
J ϭ 16.1 and J ϭ 8.7 Hz, 1 H,
(2R,3R,6S)-6-Allyloxy-2-(hydroxymethyl)-3,6-dihydro-2H-pyran-3-
ol (5): A solution of dibenzoate 4 (6.0 g, 15.2 mmol) in MeOH
(130 mL) was added to a solution of sodium methoxide (16.4 mg,
0.3 mmol) in MeOH (10 mL), and the mixture was stirred for 2 h.
The solvent was evaporated, and the residual product was purified
by flash chromatography using hexane/EtOAc (4:6). Diol 5 was ob-
tained (2.8 g, 99%) as a mixture of anomers (α/β ratio ϭ 9.5:1).
White solid; m.p. 85Ϫ87 °C. [α]2D2 ϭ Ϫ101 (c ϭ 1.0, CHCl3). IR
CHHCO2Et), 2.60 (m, 1 H, 3-H), 3.70 (dd, J ϭ 10.4 and J ϭ
5.3 Hz, 1 H, CHHOTBDPS), 3.76 (dd, J ϭ 10.4 and J ϭ 5.8 Hz,
1 H, CHHOTBDPS), 4.06 (dd, J ϭ 12.8 and J ϭ 4.9 Hz, 1 H,
CHHCHϭCH2), 4.14 (q, J ϭ 7.2 Hz, 2 H, CO2CH2CH3), 4.22 (dd,
J ϭ 12.8 and J ϭ 6.4 Hz, 1 H, CHHCHϭCH2), 4.23 (m, 1 H, 6-
H), 4.80 (s, 1 H, 2-H), 5.18 (m, Jcis-H ϭ 10.2 Hz, 1 H, ϭCH2 cis),
5.28 (m, Jtrans-H ϭ 17.2 Hz, 1 H, ϭCH2 trans), 5.79 (m, 2 H, 5-H,
4-H), 5.92 (m, 1 H, CHϭCH2), 7.40 (m, 6 H, Ar-H), 7.68 (m, 4 H,
Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.5 (q, CH2CH3),
19.5 [s, C(CH3)3], 27.1 (q, 3C, C(CH3)3], 35.9 (d, C-3), 38.1 (t,
CH2CO2Et), 60.7 (t, CO2CH2), 66.4 (t, CH2OTBDPS), 68.7 (t,
CH2CHϭCH2), 69.6 (d, C-6), 98.4 (d, C-2), 117.5 (t, CHϭCH2),
126.2 (d, C-4), 127.1 (d, C-5), 127.9 (d, 4C, CAr), 129.9 (d, 2C,
CAr), 133.7 (s, CAr), 133.8 (s, CAr), 134.5 (d, CHϭCH2), 135.8 (d,
2C, CAr), 135.9 (d, 2C, CAr), 172.1(s, CO) ppm. ESI-MS: m/z (%) ϭ
517 (100) [MNa]ϩ.
(KBr): ν˜ ϭ 3430, 2905, 1189, 1094, 1064 cmϪ1 1H NMR
.
(300 MHz, CDCl3): δ ϭ 2.65 (bd, J ϭ 8.2 Hz, 1 H, OH), 2.76 (br.
s, 1 H, OH), 3.89 (m, 3 H, CH2OH, 3-H), 4.04 (m, 1 H, 2-H), 4.05
(dd, J ϭ 12.7 and J ϭ 4.7 Hz, 1 H, CHHCHϭCH2), 4.24 (dd, J ϭ
12.7 and J ϭ 6.9 Hz, 1 H, CHHCHϭCH2), 5.07 (d, J ϭ 3.1 Hz, 1
H, 6-H), 5.18 (m, Jcis-H ϭ 10.3 Hz, 1 H, ϭCH2 cis), 5.27 (m, Jtrans-
H ϭ 17.2 Hz, 1 H, ϭCH2 trans), 5.90 (dd, J ϭ 10.0 and J ϭ 3.1 Hz,
1 H, 5-H), 5.92 (m, 1 H, CHϭCH2), 6.12 (dd, J ϭ 10.0 and J ϭ
5.5 Hz, 1 H, 4-H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 63.0 (t,
CH2OH), 63.2 (d, C-3), 69.3 (t, CH2CHϭCH2), 70.7 (d, C-2), 94.0
(d, C-6), 117.9 (t, CHϭCH2), 129.8 (d, C-5), 131.4 (d, C-4), 134.7
(d, CHϭCH2) ppm. MS (EI): m/z (%) ϭ 186 (Ͻ 1) [Mϩ], 126 (37),
85 (100), 69 (14), 55 (27). C9H14O4 (186.21): calcd. C 58.05, H 7.58;
found C 57.91, H 7.76.
Ethyl 2-[(2S,3S,6S)-2-Allyloxy-6-(hydroxymethyl)-3,6-dihydro-2H-
pyran-3-yl]acetate (8): Tetrabutylammonium fluoride trihydrate
(6.76 g, 21.44 mmol) was added to a solution of ester 7 (8.21 g,
16.49 mmol) in THF (100 mL). The mixture was stirred for 2 h at
room temperature. The solvent was evaporated, and the residual
(2R,3R,6S)-6-Allyloxy-2-[(tert-butyldiphenylsilanyloxy)methyl]-3,6- product was purified by flash chromatography using hexane/EtOAc
dihydro-2H-pyran-3-ol (6): tert-Butyldiphenylsilyl chloride (10 mL,
38.61 mmol), Et3N (5.86 mL, 42.13 mmol), and DMAP (643 mg,
0.15 mmol) were added to a solution of diol 5 (6.54 g, 35.11 mmol)
in dry CH2Cl2 (100 mL) at 0 °C under argon. The mixture was
(1:1). Alcohol 8 was obtained (4.0 g, 95%) as a colorless thick oil.
[α]2D2 ϭ ϩ126 (c ϭ 1.2, CHCl3). IR (neat): ν˜ ϭ 3446, 2929, 1733,
1268, 1182, 1114, 1051 cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ
.
1.25 (t, J ϭ 7.2 Hz, 3 H, CO2CH2CH3), 2.43 (m, 2 H, CH2CO2),
stirred overnight and allowed to warm to room temperature. The 2.64 (m, 1 H, 3-H), 3.61 (m, 1 H, CHHOH), 3.77 (m, 1 H,
solvent was evaporated, and the residue was purified by flash chro-
matography using hexane/EtOAc (6:4) to afford compound 6
(11.48 g, 77%). Colorless oil. [α]2D2 ϭ Ϫ63 (c ϭ 1.0, CHCl3). IR
CHHOH), 4.10 (m, 1 H, CHHCHϭCH2), 4.14 (q, J ϭ 7.2 Hz, 2
H, CO2CH2CH3), 4.28 (m, 2 H, 6-H, CHHCHϭCH2), 4.85 (s, 1
H, 2-H), 5.19 (m, Jcis-H ϭ 10.4 Hz, 1 H, ϭCH2 cis), 5.30 (m, Jtrans-
(KBr): ν˜ ϭ 3446, 2931, 2857, 1427, 1113, 1031 cmϪ1
.
1H NMR
ϭ 17.2 Hz, 1 H, ϭCH2 trans), 5.66 (d, J ϭ 10.4 Hz, 1 H, 5-H),
H
Eur. J. Org. Chem. 2004, 3063Ϫ3073
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3067

´
A. Montero, E. Mann, B. Herradon
FULL PAPER
5.86 (m, 1 H, CHϭCH2), 5.92 (m, 1 H, 4-H), ppm. 13C NMR
by flash chromatography using hexane/EtOAc (9:1) to afford ester
(75 MHz, CDCl3): δ ϭ 14.3 (q, CH2CH3), 35.8 (d, C-3), 38.0 (t, 11 (680 mg, 72%) as a colorless oil. [α]2D2 ϭ ϩ40 (c ϭ 0.4, CHCl3).
CH2CO2), 60.7 (t, CO2CH2CH3), 65.0 (t, CH2OH), 68.6 (t, IR (neat): ν˜ ϭ 3382, 2922, 2099, 1736, 1437, 1267, 1168, 1115,
1
CH2CHϭCH2), 69.2 (d, C-6), 98.3 (d, C-2), 117.5 (t, CHϭCH2),
1057, 1021 cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 2.38 (dd, J ϭ
125.8 (d, C-5), 127.1 (d, C-4), 134.2 (d, CHϭCH2), 171.8 (s, CO) 16.2 and J ϭ 6.6 Hz, 1 H, CHHCO2Me), 2.48 (dd, J ϭ 16.2 and
ppm. ESI-MS: m/z (%) ϭ 279 (100) [MNa]ϩ.
J ϭ 8.0 Hz, 1 H, CHHCO2Me), 2.58 (m, 1 H, 3-H), 3.25 (dd, J ϭ
12.8 and J ϭ 3.6 Hz, 1 H, CHHN3), 3.34 (dd, J ϭ 12.8 and J ϭ
6.3 Hz, 1 H, CHHN3), 3.65 (s, 3 H, CO2CH3), 4.07 (dd, J ϭ 13.0
and J ϭ 4.9 Hz, 1 H, CHHCHϭCH2), 4.22 (dd, J ϭ 13.0 and J ϭ
6.4 Hz, 1 H, CHHCHϭCH2), 4.33 (m, 1 H, 6-H), 4.81 (s, 1 H, 2-
Ethyl 2-{(2S,3S,6S)-2-Allyloxy-6-[(methylsulfonyloxy)methyl]-3,6-
dihydro-2H-pyran-3-yl}acetate (9): Et3N (0.57 mL, 4.10 mmol) was
added to a solution of alcohol 8 (450 mg, 1.71 mmol) in dry
CH2Cl2 (20 mL) at 0 °C under argon. After 5 minutes of stirring,
a solution of methylsulfonyl chloride (0.17 mL, 2.22 mmol) in dry
CH2Cl2 (5 mL) was added. The reaction mixture was allowed to
warm up to room temperature for 1 h and quenched by addition
of saturated solution of NaHCO3. The organic phase was washed
with water, HCl (5%) and brine, dried (MgSO4), and the solvents
evaporated. Purification of the residue by flash chromatography
using hexane/EtOAc (7:3) afforded compound 9 (512 mg, 98%) as
a colorless thick oil. 1H NMR (300 MHz, CDCl3): δ ϭ 1.24 (t, J ϭ
7.2 Hz, 3 H, CO2CH2CH3), 2.35 (dd, J ϭ 16.1 and J ϭ 6.7 Hz, 1
H, CHHCO2), 2.45 (dd, J ϭ 16.1 and J ϭ 8.1 Hz, 1 H, CHHCO2),
2.61 (m, 1 H, 3-H), 3.04 (s, 3 H, OSO2CH3), 4.10 (m, 3 H,
H), 5.17 (m, Jcis-H ϭ 10.4 Hz, 1 H, ϭCH2 cis), 5.28 (m, Jtrans-H
ϭ
17.2 Hz, 1 H, ϭCH2 trans), 5.63 (d, J ϭ 10.4 Hz, 1 H, 4-H), 5.84
(m, 1 H, 5-H), 5.89 (m, 1 H, CHϭCH2) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 35.4 (d, C-3), 37.3 (t, CH2CO2Me), 51.6 (q, CO2CH3),
54.0 (t, CH2N3), 67.8 (t, CH2CHϭCH2), 68.5 (d, C-6), 98.1 (d, C-
2), 117.4 (t, CHϭCH2), 125.6 (d, C-4), 127.4 (d, C-5), 133.9 (d,
CHϭCH2), 172.0 (s, CO) ppm. ESI-MS: m/z (%) ϭ 507 (86) [2(M
Ϫ
N)H]ϩ, 529 (100) [2(M N)Na]ϩ, 290 (92) [MNa]ϩ.
Ϫ
C12H17N3O4 (267.28): calcd. C 53.92, H 6.41, N 15.72; found C
53.85, H 6.74, N 15.62.
2-[(2S,3S,6S)-2-Allyloxy-6-(azidomethyl)-3,6-dihydro-2H-pyran-3-
yl]acetic Acid (12): LiOH (197 mg, 4.68 mmol) was added to a solu-
tion of ester 11 (624 mg, 2.34 mmol) in a THF/H2O (1:1, 10 mL)
mixture. After standing for 3.5 h at room temperature, the mixture
was treated with 5% aqueous HCl until pH 1Ϫ2 was reached. The
organic solvent was removed at reduced pressure, and the aqueous
phase was thoroughly extracted with EtOAc. The combined or-
ganic phases were washed with brine and dried (MgSO4). Solvent
evaporation afforded pure acid 12 (578 mg, 93%). Colorless thick
oil. [α]2D2 ϭ ϩ115 (c ϭ 0.5, MeOH). IR (neat): ν˜ ϭ 2926, 2100,
CO2CH2CH3, CHHCHϭCH2), 4.27 (m,
3 H, CH2OSO2,
CHHCHϭCH2), 4.45 (m, 1 H, 6-H), 4.83 (s, 1 H, 2-H), 5.19 (m,
Jcis-H ϭ 10.4 Hz, 1 H, ϭCH2 cis), 5.31 (m, Jtrans-H ϭ 17.2 Hz, 1
H, ϭCH2 trans), 5.66 (d, J ϭ 10.4 Hz, 1 H, 5-H), 5.88 (m, 2 H, 4-
H, CHϭCH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.3 (q,
CH2CH3), 35.5 (d, C-3), 37.7 (q, OSO2CH3), 37.8 (t, CH2CO2),
60.7 (t, CO2CH2CH3), 66.9 (d, C-6), 68.8 (t, CH2CHϭCH2), 70.7
(t, CH2OSO2), 98.3 (d, C-2), 117.7 (t, CHϭCH2), 123.9 (d, C-5),
128.5 (d, C-4), 134.0 (d, CHϭCH2), 171.6 (s, CO) ppm.
1711, 1412, 1271, 1165, 1114, 1055, 1016 cmϪ1 1H NMR
.
Ethyl 2-[(2S,3S,6S)-2-Allyloxy-6-(azidomethyl)-3,6-dihydro-2H-py-
ran-3-yl]acetate (10): NaN3 (8.57 g, 131.90 mmol) was added to a
solution of mesylate 9 (4.41 g, 13.19 mmol) in dry DMF (40 mL)
under argon, and the mixture was stirred at 60 °C overnight. The
solvent was concentrated in vacuo, EtOAc was added to the residue
and washed with H2O (twice). The organic phase was dried
(MgSO4), and the solvent was evaporated. Purification of the re-
sidual product by flash chromatography using hexane/EtOAc (9:1)
afforded azide 10 (3.20 g, 76%) as a colorless oil. [α]2D2 ϭ ϩ130 (c ϭ
(300 MHz, CDCl3): δ ϭ 2.52 (m, 2 H, CH2CO2H), 2.62 (m, 1 H,
3-H), 5.92 (m, 1 H, CHϭCH2), 3.28 (dd, J ϭ 12.9 and J ϭ 3.6 Hz,
1 H, CHHN3), 3.37 (dd, J ϭ 12.9 and J ϭ 6.3 Hz, 1 H, CHHN3),
4.10 (dd, J ϭ 12.9 and J ϭ 4.9 Hz, 1 H, CHHCHϭCH2), 4.26 (dd,
J ϭ 12.9 and J ϭ 6.4 Hz, 1 H, CHHCHϭCH2), 4.36 (m, 1 H, 6-
H), 4.86 (s, 1 H, 2-H), 5.19 (m, Jcis-H ϭ 10.5 Hz, 1 H, ϭCH2 cis),
5.30 (m, Jtrans-H ϭ 17.1 Hz, 1 H, ϭCH2 trans), 5.66 (d, J ϭ 10.5 Hz,
1 H, 4-H), 5.89 (m, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 35.2 (d, C-3), 37.3 (t, CH2CO2H), 54.1 (t, CH2N3), 67.9 (t,
CH2CHϭCH2), 68.6 (d, C-6), 98.1 (d, C-2), 117.5 (t, CHϭCH2),
125.9 (d, C-4), 127.2 (d, C-5), 133.9 (d, CHϭCH2),176.9 (s, CO)
ppm. ESI-MS: m/z (%) ϭ 228 (100) [M Ϫ 25], 732 (72) [(3M Ϫ
N2)H]ϩ.
0.25, CHCl3). IR (neat): ν˜ ϭ 2099, 1733, 1267, 1114 cmϪ1 1H
.
NMR (300 MHz, CDCl3): δ ϭ 1.23 (t, J ϭ 7.1 Hz, 3 H,
CO2CH2CH3), 2.37 (dd, J ϭ 16.1 and J ϭ 6.6 Hz, 1 H, CHHCO2),
2.48 (dd, J ϭ 16.1 and J ϭ 8.0 Hz, 1 H, CHHCO2), 2.60 (m, 1 H,
3-H), 3.26 (dd, J ϭ 12.8 and J ϭ 3.6 Hz, 1 H, CHHN3), 3.36 (dd,
J ϭ 12.8 and J ϭ 6.3 Hz, 2 H, CHHN3), 4.11 (m, 1 H, CHHCHϭ
CH2), 4.12 (q, J ϭ 7.1 Hz, 2 H, CO2CH2), 4.23 (m, 1 H, CHHCHϭ
Peptidyl Azide 13: HOBT (395 mg, 2.92 mmol), Et3N (0.9 mL,
6.75 mmol), EDC (560 mg, 2.92 mmol), and DMAP (28 mg,
CH2), 4.33 (m, 1 H, 6-H), 4.83 (s, 1 H, 2-H), 5.19 (m, Jcis-H
ϭ
0.01 mmol) were added to
a solution of acid 12 (570 mg,
10.4 Hz, 1 H, ϭCH2 cis), 5.31 (m, Jtrans-H ϭ 17.2 Hz, 1 H, ϭCH2
trans), 5.63 (d, J ϭ 10.3 Hz, 1 H, 5-H), 5.86 (m, 1 H, 4-H), 5.89
(m, 1 H, CHϭCH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.4
(q, CH2CH3), 35.7 (d, C-3), 37.9 (t, CH2CO2), 54.3 (t, CH2N3),
60.8 (t, CO2CH2), 68.1 (d, C-6), 68.8 (t, CH2CHϭCH2), 98.4 (d,
C-2), 117.6 (t, CHϭCH2), 125.8 (d, C-5), 127.8 (d, C-4), 134.2 (d,
CHϭCH2), 171.8 (s, CO) ppm. ESI-MS: m/z (%) ϭ 198 (100) [MH
Ϫ N2 Ϫ OAllyl]ϩ. C13H19N3O4 (281.31): calcd. C 55.50, H 6.81, N
14.94; found C 55.65, H 6.79, N 14.82.
2.25 mmol) and dipeptide TFA·HϪPheϪMetϪOMe (1.10 g,
2.92 mmol) in dry DMF (8 mL) under argon. After stirring over-
night at room temperature, the reaction mixture was concentrated,
and the residue was taken in EtOAc. The organic phase was treated
with 5% aqueous solution of HCl, saturated aqueous NaHCO3,
brine, and dried (MgSO4) and concentrated. Purification by silica
gel column chromatography using hexane/EtOAc (1:1) as eluent
afforded compound 13 (922 mg, 75%) as a white solid; m.p.
1
108Ϫ109 °C. [α]2D2 ϭ ϩ95 (c ϭ 0.5, CHCl3). H NMR (300 MHz,
Methyl 2-[(2S,3S,6S)-2-Allyloxy-6-(azidomethyl)-3,6-dihydro-2H-
pyran-3-yl]acetate (11): A solution of ester 10 (1.00 g, 3.55 mmol)
in MeOH (15 mL) was added to a solution of NaOMe (0.21 mmol,
generated from 5 mg of Na in 15 mL of MeOH). The reaction mix-
ture was stirred for 3 h at room temperature. The solvent was re-
moved at reduced pressure, and the resulting residue was purified
CDCl3): δ ϭ 1.91 (m, 1 H, CHHβMet), 2.05 (s, 3 H, CH3S), 2.09
(m, 1 H, CHHβ Met), 2.32 (m, 2 H, CH2CONHPhe), 2.41 (m, 2 H,
CH2S), 2.66 (m, 1 H, 3-H), 3.06 (m, 2 H, CH2βPhe), 3.25 (dd, J ϭ
12.9 and J ϭ 3.4 Hz, 1 H, CHHN3), 3.44 (dd, J ϭ 12.9 and J ϭ
5.8 Hz, 1 H, CHHN3), 3.72 (s, 3 H, CO2CH3), 4.03 (dd, J ϭ 12.9
and J ϭ 5.3 Hz, 1 H, CHHCHϭCH2), 4.21 (dd, J ϭ 12.9 and J ϭ
3068
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3063Ϫ3073

Preparation of Sugar Amino Acids by Claisen-Johnson Rearrangement
FULL PAPER
6.0 Hz, 1 H, CHHCHϭCH2), 4.37 (m, 1 H, 6-H), 4.61 (m, 1 H, 4.8 Hz, 1 H, CHHβPhe), 3.17 (m, 2 H, CH2NH), 3.62 (s, 3 H,
CHα Met), 4.66 (s, 1 H, 2-H), 4.67 (m, 1 H, CHαPhe), 5.18 (m, Jcis- CO2CH3), 3.85 (dd, J ϭ 13.1 and J ϭ 5.6 Hz, 1 H, CHHCHϭ
H. ϭ 10.3, 1 H, ϭCH2 cis), 5.29 (m, Jtrans-H ϭ 17.2 Hz, 1 H, ϭCH2 CH2), 4.07 (m, 3 H, 6-H, CHαTyr, CHHCHϭCH2), 4.41 (m, 1 H,
trans), 5.64 (d, J ϭ 10.4 Hz, 1 H, 5-H), 5.87 (dd, J ϭ 10.4 and J ϭ
5.9 Hz, 1 H, 4-H), 5.90 (m, CHϭCH2), 6.11 (d, J ϭ 7.8 Hz, 1 H,
CHαMet), 4.45 (s, 1 H, 2-H), 4.57 (m, 1 H, CHαPhe), 5.11 (m, Jcis-
ϭ 10.5 Hz, 1 H, ϭCH2 cis), 5.21 (m, Jtrans-H ϭ 17.3 Hz, 1 H, ϭ
H
NHPhe), 6.41 (d, J ϭ 7.9 Hz, 1 H, NHMet), 7.25 (m, 5 H, Ar-H) CH2 trans), 5.76 (m, 2 H, 4-H, 5-H), 5.84 (m, 1 H, CHϭCH2), 6.62
ppm.13C NMR (75 MHz, CDCl3): δ ϭ 15.6 (q, CH3S), 30.0 (t,
(m, 2 H, Ar-HTyr), 6.86 (d, J ϭ 8.5 Hz, 1 H, NHTyr), 7.03 (m, 2 H,
CH2βMet), 31.6 (t, CH2S), 35.9 (d, C-3), 38.4 (t, CH2βPhe), 39.9 (t, Ar-HTyr), 7.25 (m, 5 H, Ar-HPhe), 7.96 (t, J ϭ 6.1 Hz, 1 H,
CH2CONHPhe), 51.8 (d, CHαMet), 52.8 (q, CO2CH3), 54.2 (t, CH2NHCO), 8.17 (d, J ϭ 8.3 Hz, 1 H, NHPhe), 8.46 (d, J ϭ 7.6 Hz,
CH2N3), 54.4 (d, CHαPhe), 68.2 (t, CH2CHϭCH2), 68.9 (d, C-6),
98.4 (d, C-2), 117.2 (t, CHϭCH2), 125.9 (d, C-5), 127.3 (d, CAr), [D6]DMSO): δ ϭ 14.9 (q, CH3S), 28.5 (q, 3C, (CH3)3C], 29.8 (t,
127.3 (d, C-4), 129.0 (d, 2C, CAr), 129.5 (d, 2C, CAr), 134.2 (d, CH2S), 30.9 (t, CH2βMet), 36.0 (d, C-3), 31.1 (t, CH2βTyr), 37.8 (t,
1 H, NHMet), 9.17 (s, 1 H, OH) ppm. 13C NMR (75 MHz, 40 °C,
CHϭCH2), 136.5 (s, CAr), 170.8 (CO), 170.9 (CO), 171.9 (CO) CH2βPhe), 38.8 (t, CH2CO), 42.6 (t, CH2NH), 51.3 (d, CHαMet),
ppm. ESI-MS: m/z (%) ϭ 568 (100) [MNa]ϩ. C26H35N5O6S 52.3 (q, CO2CH3), 53.9 (d, CHαPhe), 56.5 (d, CHαTyr), 66.9 (d, C-
(545.65): calcd. C 57.23, H 6.47, N 12.83; found C 57.44, H 6.39,
N 12.80.
6), 67.7 (t, CH2CHϭCH2), 78.3 [s, C(CH3)3], 98.0 (d, C-2), 115.1
(d, 2C, CAr), 116.8 (t, CHϭCH2), 126.6 (d, C-5), 126.8 (d, C-4),
128.4 (d, 2C, CAr), 128.6 (d, CAr), 129.4 (d, 2C, CAr), 130.4 (d, 2C,
CAr), 131.2 (s, CAr), 135.1 (d, CHϭCH2), 138.2 (s, CAr), 155.6 (s,
CAr), 156.0 (s, CO), 170.5 (s, CO), 171.9 (s, CO), 172.4 (s, 2C, CO)
ppm. ESI-MS: m/z (%) ϭ 783 (100) [MH]ϩ. C40H54N4O10S
(782.94): calcd. C 61.36, H 6.71, N 7.16, S 4.10; found C 61.18, H
7.02, N 7.17, S 3.95.
Peptidyl Azide 14: Acid 12 (658 mg, 2.59 mmol) was coupled to
dipeptide TFA·HϪPheϪLeuϪOMe (1.32 g, 3.37 mmol) as de-
scribed for 13. The crude product was purified by column chroma-
tography using hexane/EtOAc (7:3) as eluent to afford 14 (976 mg,
72%) as a white solid; m.p. 128Ϫ129 °C. [α]2D2 ϭ ϩ84 (C ϭ 0.2,
1
CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 0.90 (d, J ϭ 5.9 Hz, 6
H, CH(CH3)2], 1.53 (m, 3 H, CH2βLeu, CH(CH3)2], 2.32 (m, 2 H,
Boc؊Tyr؊SAA؊Phe؊Met؊OH
(16):
LiOH
(10.7 mg,
CH2CO), 2.65 (m, 1 H, 3-H), 3.07 (m, 2 H, CH2βPhe), 3.25 (dd, 0.250 mmol) was added to a solution of ester 15 (100 mg,
J ϭ 12.9 and J ϭ 3.4 Hz, 1 H, CHHN3), 4.43 (dd, J ϭ 12.9 and 0.127 mmol) in a THF/H2O (1:1, 2 mL) mixture. After standing for
J ϭ 5.8 Hz, 1 H, CHHN3), 3.71 (s, 3 H, CO2CH3), 4.04 (dd, J ϭ 1 h at room temperature, the mixture was treated with 5% aqueous
12.9 and J ϭ 5.3 Hz, 1 H, CHHCHϭCH2), 4.21 (dd, J ϭ 12.9 and HCl. The organic solvent was removed at reduced pressure, and
J ϭ 6.0 Hz, 1 H, CHHCHϭCH2), 4.38 (m, 1 H, 6-H), 4.53 (m, 1 the aqueous phase was thoroughly extracted with EtOAc. The com-
H, CHαLeu), 4.67 (s, 1 H, 2-H), 4.68 (m, 1 H, CHαPhe), 5.19 (m, bined organic phases were washed with brine and dried (MgSO4).
Jcis-H ϭ 10.3 Hz, 1 H, ϭCH2 cis), 5.30 (m, Jtrans-H ϭ 17.3 Hz, 1 Solvent evaporation afforded pure acid 16 (97 mg, 99%) as a white
H, ϭCH2 trans), 5.63 (d, J ϭ 10.5 Hz, 1 H, 5-H), 5.84 (dd, J ϭ solid; m.p. 146Ϫ147 °C. [α]2D2 ϭ ϩ25 (c ϭ 0.21, MeOH). IR (KBr):
10.2 and J ϭ 5.9 Hz, 1 H, 4-H), 5.90 (m, 1 H, CHϭCH2), 6.16 (m, ν˜ ϭ 3429, 2928, 1647, 1516, 1368, 1249, 1166, 1052 cmϪ1. 1H NMR
2 H, NHLeu, NHPhe), 7.27 (m, 5 H, Ar-H) ppm. 13C NMR (400 MHz, CDCl3, 40 °C): δ ϭ 1.38 [s, 9 H, (CH3)3C]), 2.03 (s, 3
(75 MHz, CDCl3): δ ϭ 21.9 (q, CHCH3), 22.7 (q, CHCH3), 24.7 H, SCH3), 1.98 (m, 1 H, CHHβMet), 2.15 (m, 2 H, CHHCO,
[t, CH(CH3)2], 35.6 (d, C-3), 38.1 (t, CH2βPhe), 39.8 (t, CH2CO),
CHHβMet), 2.22 (d, J ϭ 14.7 Hz, 1 H, CHHCO), 2.42 (m, 2 H,
41.4 (t, CH2βLeu), 50.8 (d, CHαLeu), 52.3 (q, CO2CH3), 53.9 (t, CH2S), 2.49 (m, 1 H, 3-H), 2.96 (m, 3 H, CH2βTyr, CHHβPhe), 3.10
CH2N3), 54.3 (d, CHαPhe), 67.9 (d, C-6), 68.7 (t, CH2CHϭCH2), (dd, J ϭ 14.1 and J ϭ 4.8 Hz, 1 H, CHHβPhe), 3.32 (m, 2 H,
98.2 (d, C-2), 117.4 (t, CHϭCH2), 125.6 (d, C-5), 127.1 (d, 1C, CH2NH), 3.95 (dd, J ϭ 12.9 and J ϭ 5.3 Hz, 1 H, CHHCHϭ
CAr), 127.7 (d, C-4), 129.7 (d, 2C, CAr), 129.3 (d, 2C, CAr), 133.9 CH2), 4.12 (dd, J ϭ 12.9 and J ϭ 5.6 Hz, 1 H, CHHCHϭCH2),
(d, CHϭCH2), 136.3 (s, CAr), 170.4 (CO), 170.5 (CO), 172.6 (CO) 4.19 (m, 1 H, 6-H), 4.36 (m, 1 H, CHαTyr), 4.48 (m, 1 H, CHαMet),
ppm. ESI-MS: m/z (%) ϭ 470 (100) [M Ϫ OAllyl]ϩ, 550 (94)
4.59 (s, 1 H, 2-H), 4.81 (m, 1 H, CHαPhe), 5.11 (m, Jcis-H ϭ 11.6 Hz,
[MNa]ϩ, 528 (49) [MH]ϩ. C27H37N5O6 (527.61): calcd. C 61.46, H 1 H, ϭCH2 cis), 5.23 (m, Jtrans-H ϭ 17.3 Hz, 1 H, ϭCH2 trans),
7.07, N 13.27; found C 61.27, H 6.89, N 13.10.
5.28 (bd, 1 H, NHTyr), 5.45 (d, J ϭ 10.4 Hz, 1 H, 5-H), 5.69 (dd,
J ϭ 10.4 and J ϭ 4.9 Hz, 1 H, 4-H), 5.85 (m, 1 H, CHϭCH2), 6.39
(bt, CH2NH), 6.72 (d, J ϭ 8.5 Hz, 2 H, Ar-HTyr), 7.01 (d, J ϭ
8.3 Hz, 2 H, Ar-HTyr), 7.14 (bd, NHPhe), 7.19 (m, 5 H, Ar-HPhe; 1
H, NHMet) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 15.3 (q, SCH3),
28.4 (q, 3C, (CH3)3C], 30.0 (t, CH2S), 30.7 (t, CH2βMet), 35.7 (d,
C-3), 38.1 (t, t, 2C, CH2βPhe, CH2βTyr), 39.4 (t, CH2CO), 42.6 (t,
CH2NH), 51.9 (d, CHαMet), 54.5 (d, CHαPhe), 56.2 (d, CHαTyr),
66.5 (d, C-6), 68.6 (t, CH2CHϭCH2), 80.6 [s, C(CH3)3], 98.4 (d, C-
2), 115.8 (d, 2C, CAr), 117.5 (t, CHϭCH2), 126.2 (d, C-4), 127.1 (s,
CAr), 127.2 (d, C-5), 127.9 (d, 1C, CAr), 128.7 (d, 2C, CAr), 129.3
(d, 2C, CAr), 130.6 (d, 2C, CAr), 134.1 (d, CHϭCH2), 136.4 (s, CAr),
155.4 (s, CAr), 156.1 (s, CO), 171.8 (s, CO), 172.3 (s, CO), 172.7 (s,
CO), 174.1 (s, CO) ppm. ESI-MS: m/z (%) ϭ 769 (100) [MH]ϩ.
C39H52N4O10S (768.92): calcd. C 60.92, H 6.82, N 7.29, S 4.17;
found C 60.73, H 7.02, N 6.99, S 3.98.
Boc؊Tyr؊SAA؊Phe؊Met؊OMe (15): A mixture of azide 13
(922 mg, 1.69 mmol), Ph3P (886 mg, 3.78 mmol), and H2O
(0.06 mL) in benzene (20 mL) was refluxed overnight. The solvent
was evaporated, and the residue was dissolved in dry DMF (5 mL).
BocϪTyrϪOH (618 mg, 2.19 mmol), HOBT (297 mg, 2.19 mmol),
Et3N (0.7 mL, 5.07 mmol), EDC (421.2 mg, 2.19 mmol), and
DMAP (21 mg, 0.219 mmol) were added sequentially. The reaction
mixture was stirred for 21 h at room temperature. The solvent was
removed at reduced pressure, and the residue was purified by silica
gel column chromatography using hexane/EtOAc (7:3) as eluent to
afford compound 15 (957 mg, 72%) as a white solid; m.p. 183Ϫ184
°C. [α]2D2 ϭ ϩ26 (c ϭ 0.25, CHCl3). IR (KBr): ν˜ ϭ 3429, 1739,
1644, 1517, 1445, 1367, 1166 cmϪ1
.
1H NMR (500 MHz,
[D6]DMSO, 40 °C): δ ϭ 1.29 [s, 9 H, (CH3)3C], 1.92 (m, 2 H,
CH2βMet), 2.03 (s, 3 H, SCH3), 2.07 (dd, J ϭ 14.6 and J ϭ 6.9 Hz,
1 H, CHHCO), 2.16 (dd, J ϭ 14.6 and J ϭ 7.7 Hz, 1 H, CHHCO), Boc؊Tyr؊SAA؊Phe؊Leu؊OMe (17): The azide 14 (954 mg,
2.28 (m, 1 H, 3-H), 2.46 (m, 2 H, CH2S), 2.58 (m, 1 H, CHHβTyr), 1.81 mmol) was reduced and coupled to BocϪTyrϪOH (662 mg,
2.75 (dd, J ϭ 13.9 and J ϭ 3.9 Hz, 1 H, CHHβPhe), 2.77 (dd, J ϭ
2.35 mmol) as described for 15. The crude product was purified by
15.3 and J ϭ 4.3 Hz, 1 H, CHHβTyr), 3.00 (dd, J ϭ 13.9 and J ϭ column chromatography using hexane/EtOAc (7:3) as eluent to af-
Eur. J. Org. Chem. 2004, 3063Ϫ3073
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3069

´
A. Montero, E. Mann, B. Herradon
FULL PAPER
ford 17 (762 mg, 84%) as a white solid; m.p. 107Ϫ110 °C. [α]2D2
ϭ
Methyl Amide 19: The acid 12 (790 mg, 3.12 mmol) was coupled
ϩ20 (c ϭ 0.25, CHCl3). IR (KBr): ν˜ ϭ 3420, 2959, 1652, 1516, to dipeptide TFA·HϪPheϪMetϪNHCH3 (1.72 g, 4.05 mmol) as
1442, 1367, 1250, 1167, 1052, 1019, 700 cmϪ1. 1H NMR (400 MHz,
described for 13. The crude product was purified by column chro-
[D6]DMSO): δ ϭ 0.84 (d, J ϭ 6.6 Hz, 3 H, CHCH3), 0.89 (d, J ϭ matography using hexane/EtOAc (1:1) as eluent to afford 19
6.3 Hz, 3 H, CHCH3), 1.29 (m, 1 H, CHHβLeu), 1.29 [s, 9 H, (1.25 g, 74%) as a white solid; m.p. 138Ϫ141 °C. [α]2D2 ϭ ϩ37 (c ϭ
C(CH3)3], 1.54 [m, 2 H, CH(CH3)2, CHHβLeu), 2.12 (m, 2 H, 0.25, MeOH). IR (KBr): ν˜ ϭ 3429, 3288, 2922, 2100, 1632, 1537,
CH2CO), 2.28 (m, 1 H, 3-H), 2.59 (m, 1 H, CHHβTyr), 2.75 (dd, 1415, 1271, 1123, 1065, 1017, 703 cmϪ1
J ϭ 13.7 and J ϭ 10.1 Hz, 1 H, CHHβPhe), 2.77 (m, 1 H,
.
1H NMR (300 MHz,
CDCl3): δ ϭ 1.92 (m, 1 H, CHHβMet), 2.05 (m, 1 H, CHHβMet),
CHHβTyr), 3.03 (dd, J ϭ 13.7 and J ϭ 4.2 Hz, 1 H, CHHβPhe), 2.04 (s, 3 H, CH3S), 2.32 (m, 2 H, CH2CO), 2.45 (m, 2 H, CH2S),
3.19 (m, 1 H, CHHN3), 3.61 (s, 3 H, CO2CH3), 3.87 (dd, J ϭ 13.0
and J ϭ 5.3 Hz, 1 H, CHHCHϭCH2), 4.07 (m, 4 H, 6-H, CHαTyr
2.62 (m, 1 H, 3-H), 2.73 (d, J ϭ 4.9 Hz, 3 H, NHCH3), 3.06 (m, 2
H, CH2βPhe), 3.24 (dd, J ϭ 12.9 and J ϭ 3.5 Hz, 1 H, CHHN3),
,
CHHCHϭCH2, CHHN3), 4.30 (m, 1 H, CHαLeu), 4.49 (s, 1 H, 2- 3.42 (dd, J ϭ 12.9 and J ϭ 5.7 Hz, 1 H, CHHN3), 4.05 (dd, J ϭ
H), 4.60 (m, 1 H, CHαPhe), 5.10 (m, Jcis-H ϭ 10.5 Hz, 1 H, ϭCH2 12.9 and J ϭ 4.9 Hz, 1 H, CHHCHϭCH2), 4.20 (dd, J ϭ 12.9 and
cis), 5.20 (m, Jtrans-H ϭ 18.7 Hz, 1 H, ϭCH2 trans), 5.74 (m, 2 H,
J ϭ 6.4 Hz, 1 H, CHHCHϭCH2), 4.36 (m, 1 H, 6-H), 4.48 (m, 1
4-H, 5-H), 5.85 (m, 1 H, CHϭCH2), 6.62 (m, 2 H, Ar-HTyr), 6.69 H, CHαMet), 4.63 (m, 1 H, CHαPhe), 4.68 (s, 1 H, 2-H), 5.17 (m,
(d, J ϭ 6.5 Hz, 1 H, NHTyr), 7.03 (m, 2 H, Ar-HTyr), 7.25 (m, 5 H,
Ar-HPhe), 7.98 (t, J ϭ 6.1 Hz, 1 H, CH2NH), 8.16 (d, J ϭ 8.6 Hz,
Jcis-H ϭ 10.5 Hz, 1 H, ϭCH2 cis), 5.28 (m, Jtrans-H ϭ 17.1 Hz, 1
H, ϭCH2 trans), 5.63 (d, J ϭ 10.5 Hz, 1 H, 5-H), 5.81 (m, 1 H, 4-
1 H, NHPhe), 8.42 (d, J ϭ 7.5 Hz, 1 H, NHLeu), 9.16 (s, 1 H, OH) H), 5.89 (m, 1 H, CHϭCH2), 6.07 (q, J ϭ 4.9 Hz, 1 H, NHCH3),
ppm. 13C NMR (75 MHz, [D6]DMSO, 40 °C): δ ϭ 22.0 (q, 6.13 (d, J ϭ 8.0 Hz, 1 H, NHPhe), 6.66 (d, J ϭ 8.0 Hz, 1 H, NHMet),
CHCH3), 23.5 (q, CHCH3), 24.9 [d, CH(CH3)2], 29.8 (q, 3C, 7.16 (m, 2 H, Ar-HPhe), 7.26 (m, 3 H, Ar-HPhe) ppm. 13C NMR
(CH3)3C], 36.4 (d, C-3), 37.5 (d, CH2βTyr), 38.0 (t, CH2βPhe), 38.3 (75 MHz, CDCl3): δ ϭ 15.1 (q, SCH3), 26.3 (q, NHCH3), 30.1 (t,
(t, CH2CO), 38.5 (t, CH2βLeu), 43.2 (t, CH2NH), 51.0 (d, CHαLeu), CH2S), 30.3 (t, CH2βMet), 35.6 (d, C-3), 38.0 (t, CH2βPhe), 39.6 (t,
52.6 (q, CO2CH3), 54.1 (d, CHαPhe), 55.7 (d, CHαTyr), 67.3 (d, C-
CH2CO), 52.4 (t, CHαMet), 53.9 (t, CH2N3), 54.8 (d, CHαPhe), 68.0
6), 68.1 (t, CH2CHϭCH2), 78.6 [s, C(CH3)3], 98.4 (d, C-2), 115.5 (d, C-6), 68.7 (t, CH2CHϭCH2), 98.2 (d, C-2), 117.5 (t, CHϭCH2),
(d, 2C, CAr), 117.2 (t, CHϭCH2), 126.9 (d, d, 2C, CAr, C-5), 128.2 125.8 (d, C-5), 127.3 (d, CAr), 127.6 (d, C-4), 128.8 (d, 2C, CAr),
(d, C-4), 128.7 (d, 2C, CAr), 129.8 (d, 2C, CAr), 129.0 (s, CAr), 130.9 129.2 (d, 2C, CAr), 133.9 (d, CHϭCH2), 136.0 (s, CAr), 170.7 (s,
(s, CAr), 135.5 (d, CHϭCH2), 138.6 (s, CAr), 155.7 (s, CAr), 156.4
(s, CO), 170.8 (s, CO), 172.3 (s, CO), 172.8 (s, CO), 173.5 (s, CO) (100) [M
ppm. ESI-MS: m/z (%) ϭ 765 (100) [MH]ϩ. C41H56N4O10 (764.90): C26H36N6O5S (544.67): calcd. C 57.33, H 6.66, N 15.43, S 5.89;
CO), 170.8 (s, CO), 171.0 (s, CO) ppm. ESI-MS: m/z (%) ϭ 487
Ϫ
OAllyl]ϩ, 545 (13) [MH]ϩ, 567 (40) [MNa]ϩ.
calcd. C 64.38, H 7.38, N 7.32; found C 64.17, H 7.68, N 7.02.
found C 57.50, H 6.97, N 15.61, S 6.04.
Boc؊Tyr؊SAA؊Phe؊Leu؊OH (18): Compound 17 was hy-
drolyzed as described for 16 to afford acid 18 (99%) as a white
solid; m.p. 142Ϫ145 °C (previous softening). [α]2D2 ϭ ϩ18 (c ϭ 0.1,
MeOH). IR (KBr): ν˜ ϭ 3416, 2958, 1649, 1516, 1439, 1367, 1248,
1168, 1121, 1051 cmϪ1. 1H NMR (400 MHz, [D6]DMSO): δ ϭ 0.86
(d, J ϭ 6.2 Hz, 3 H, CH3CH), 0.88 (d, J ϭ 6.2 Hz, 3 H, CH3CH),
1.30 [s, 9 H, (CH3)3C], 1.45 (m, 1 H, CHHβLeu), 1.56 (m, 1 H,
CHHβLeu), 1.66 [m, 1 H, CH(CH3)2], 2.07 (dd, J ϭ 14.4 and J ϭ
6.8 Hz, 1 H, CHHCO), 2.17 (dd, J ϭ 14.4 and J ϭ 7.7 Hz, 1 H,
CHHCO), 2.30 (m, 1 H, 3-H), 2.64 (m, 1 H, CHHβTyr), 2.77 (m,
2 H, CHHβPhe, CHHβTyr), 3.07 (dd, J ϭ 13.9 and J ϭ 10.1 Hz, 1
H, CHHβPhe), 3.19 (m, 2 H, CH2NH), 3.87 (dd, J ϭ 12.8 and J ϭ
General Procedure for the Synthesis of Compounds 20؊24: A mix-
ture of azide 19 (200 mg, 0.37 mmol), Ph3P (198 mg, 0.73 mmol),
and H2O (0.02 mL) in benzene (4 mL) was refluxed for 1 h. The
solvent was evaporated and the residue was dissolved in dry DMF
(3 mL). The corresponding N-acylated-TyrϪOH derivative
(0.48 mmol), HOBT (64.4 mg, 0.48 mmol), Et3N (0.15 mL,
1.1 mmol), EDC (91 mg, 0.48 mmol), and DMAP (4.5 mg,
0.037 mmol) were added sequentially. The reaction mixture was
stirred for 20 h at room temperature. The solvent was removed at
reduced pressure, and the residue was purified by silica gel column
chromatography to afford the desired compounds 20؊24.
5.3 Hz, 1 H, CHHCHϭCH2), 4.07 (m, 4 H, CHHCHϭCH2, 2-(Biph)؊Tyr؊SAA؊Phe؊Met؊NHMe (20): Azide 19 was cou-
CHαTyr, 6-H, CHαLeu), 4.48 (s, 1 H, 2-H), 4.53 (m, 1 H, CHαPhe),
5.11 (m, Jcis-H ϭ 10.2 Hz, 1 H, ϭCH2 cis), 5.22 (m, Jtrans-H
pled to 2-(Biph)ϪTyrϪOH according to the general procedure de-
scribed above to afford, after purification by flash chromatography,
ϭ
17.2 Hz, 1 H, ϭCH2 trans), 5.55 (m, 2 H, 4-H, 5-H), 5.85 (m, 1 H, compound 20 (67%) as a white solid; m.p. 118Ϫ120 °C. [α]2D2
ϭ
CHϭCH2), 6.64 (d, J ϭ 8.3 Hz, 2 H, Ar-HTyr), 6.84 (d, J ϭ 7.9 Hz,
ϩ63 (c ϭ 0.55, MeOH). IR (KBr): ν˜ ϭ 3412, 3062, 2920, 1646,
1 H, NHTyr), 7.01 (d, J ϭ 8.3 Hz, 2 H, Ar-HTyr), 7.16 (m, 2 H, Ar- 1516, 1449, 1231, 1192, 1111, 1008, 747, 700 cmϪ1 1H NMR
.
HPhe), 7.24 (m, 3 H, Ar-HPhe), 7.60 (bd, 1 H, NHLeu), 8.00 (bt, 1 (400 MHz, [D6]DMSO, 40 °C): δ ϭ 1.59 (m, 2 H, CH2βMet), 1.87
H, CH2NH), 8.17 (d, J ϭ 8.7 Hz, 1 H, NHPhe), 9.16 (s, 1 H, OH) (m, 1 H, CHHS), 2.01 (m, 1 H, CHHS), 1.95 (s, 3 H, SCH3), 2.13
ppm. 13C NMR (75 MHz, [D6]DMSO, 40 °C): δ ϭ 22.1 (q, (m, 1 H, CHHCO), 2.24 (m, 1 H, CHHCO), 2.34 (m, 1 H, 3-H),
CHCH3), 23.3 (q, CHCH3), 24.8 [d, CH(CH3)2], 29.9 (q, 3C, 2.55 (d, J ϭ 4.5 Hz, 3 H, NHCH3), 2.72 (m, 3 H, CHHβPhe
,
(CH3)3C], 36.3 (d, C-3), 37.5 (t, CH2βTyr), 37.9 (t, CH2βPhe), 39.7 CH2βTyr), 2.84 (m, 1 H, CHHβPhe), 3.24 (m, 2 H, CH2NH), 3.88
(t, CH2CO), 42.0 (t, CH2βLeu), 42.7 (t, CH2NH), 53.0 (d, CHαLeu), (m, 1 H, CHHCHϭCH2), 4.02 (m, 2 H, 6-H, CHHCHϭCH2), 4.13
54.0 (d, CHαPhe), 56.2 (d, CHαTyr), 67.5 (d, C-6), 67.9 (t, CH2CHϭ (m, 1 H, CHαMet), 4.40 (m, 1 H, CHαPhe), 4.48 (m, 1 H, CHαTyr),
CH2), 78.5 [s, C(CH3)3], 98.6 (d, C-2), 115.7 (d, 2C, CAr), 117.1 (t, 4.57 (s, 1 H, 2-H), 5.08 (m, Jcis-H ϭ 10.4 Hz, 1 H, ϭCH2 cis), 5.19
CHϭCH2), 126.9 (d, d, 2C, CAr, C-5), 128.2 (d, C-4), 128.7 (d, 2C, (m, Jtrans-H ϭ 17.1 Hz, 1 H, ϭCH2 trans), 5.59 (m, 2 H, 4-H, 5-H),
CAr), 129.0 (d, CAr), 129.1 (d, 2C, CAr), 130.9 (s, CAr), 135.4 (d,
CHϭCH2), 138.0 (s, CAr), 155.3 (s, CAr), 155.6 (s, CO), 171.1 (s, (d, J ϭ 8.4 Hz, 2 H, Ar-HTyr), 7.29 (m, 8 H, Ar-H), 7.34 (m, 4 H,
CO), 171.2 (s, CO), 171.5 (s, CO), 171.7 (s, CO) ppm. ESI-MS: Ar-H), 7.47 (m, 2 H, Ar-H), 7.79 (bq, J ϭ 4.5 Hz, 1 H, NHCH3),
m/z (%) ϭ 751 (100) [MH]ϩ, 773 (31) [MNa]ϩ. C40H54N4O10 7.90 (t, J ϭ 6.1 Hz, 1 H, CH2NH), 8.25 (d, J ϭ 8.3 Hz, 1 H,
5.83 (m, 1 H, CHϭCH2), 6.68 (d, J ϭ 8.3 Hz, 2 H, Ar-HTyr), 7.08
(750.88): calcd. C 63.98, H 7.25, N 7.46; found C 63.71, H 7.45,
N 7.56.
NHMet), 8.30 (d, J ϭ 8.3 Hz, 1 H, NHPhe), 8.52 (d, J ϭ 8.7 Hz, 1
H, NHTyr), 9.19 (s, 1 H, OH) ppm. 13C NMR (75 MHz,
3070
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3063Ϫ3073

Preparation of Sugar Amino Acids by Claisen-Johnson Rearrangement
FULL PAPER
[D6]DMSO, 40 °C): δ ϭ 14.8 (q, CH3S), 25.9 (q, NHCH3), 29.8 (t,
Jtrans-H ϭ 17.1, 1 H, ϭCH2 trans), 5.56 (m, 2 H, 4-H, 5-H), 5.83
CH2S), 31.3 (t, CH2βMet), 36.0 (t, CH2βTyr), 36.8 (t, CH2βPhe), 37.6 (m, 1 H, CHϭCH2), 6.60 (d, J ϭ 8.4 Hz, 2 H, Ar-HTyr), 7.02 (d,
(t, CH2CO), 38.6 (d, C-3), 42.3 (t, CH2NH), 52.1 (d, CHαMet), 55.3 J ϭ 8.3 Hz, 2 H, Ar-HTyr), 7.21 (m, 5 H, Ar-HPhe), 7.69 (bq, 1 H,
(d, CHαTyr; d, CHαPhe), 67.2 (d, C-6), 67.8 (t, CH2CHϭCH2), 98.1 NHMe), 8.03 (d, J ϭ 8.1 Hz, 1 H, NHMet), 8.13 (d, J ϭ 8.3 Hz, 1
(d, C-2), 115.2 (d, 2C, CAr), 116.8 (t, CHϭCH2), 126.7 (d, C-4; d,
H, NHTyr), 8.22 (bt, 1 H, CH2NH), 9.06 (s, 1 H, OH), 9.44 (d, J ϭ
C-5), 127.0 (d, CAr), 127.1 (d, CAr), 127.2 (d, CAr), 127.3 (d, CAr), 8.4 Hz, 1 H, NHPhe) ppm. 13C NMR (75 MHz, [D6]DMSO, 40 °C):
127.4 (d, CAr), 127.6 (d, CAr), 128.2 (d, 2C, CAr), 128.4 (d, 2C, δ ϭ 14.5 (q, CH3S), 25.5 (q, NHCH3), 29.5 (t, CH2CO), 31.7 (t,
CAr), 128.6 (d, CAr), 128.7 (d, CAr), 129.5 (d, 2C, CAr), 129.9 (d,
CH2βMet), 35.6 (t, C-3), 37.1 (t, CH2βTyr), 38.4 (t, CH2βPhe), 38.4
CAr), 130.2 (d, CAr), 130.5 (d, 2C, CAr), 135.1 (d, CHϭCH2), 135.2 (t, CH2S), 42.2 (t, CH2NH), 51.7 (d, CHαMet), 51.8 (d, CHαTyr),
(s, CAr), 136.8 (s, CAr), 137.6 (s, CAr), 139.6 (s, CAr), 140.3 (s, CAr), 53.9 (d, CHαPhe), 66.5 (d, C-6), 67.3 (t, CH2CHϭCH2), 97.7 (d, C-
156.2 (s, CAr), 169.3 (s, CO), 171.3 (s, CO), 171.6 (s, CO), 171.7 2), 114.7 (d, 2C, CAr), 116.3 (t, CHϭCH2), 125.9 (d, C-5), 126.1
(s, CO), 171.8 (s, CO) ppm. ESI-MS: m/z (%) ϭ 699 (33) [(M Ϫ
(d, CAr), 126.6 (d, C-4), 127.9 (d, 2C, CAr), 128.9 (d, 2C, CAr),
Biph)NH4]ϩ, 862 (100) [MH]ϩ, 884 (26) [MNa]ϩ. C48H55N5O8S 129.9 (d, 2C, CAr), 131.8 (s, CAr), 134.6 (d, CHϭCH2), 137.8 (s,
(861.38): calcd. C 66.88, H 6.43, N 8.12, S 3.72; found C 66.88, H CAr), 155.7 (s, CAr), 169.8 (s, COCF3), 170.0 (s, CO), 170.4 (s, CO),
6.50, N 8.21, S 3.58.
171.0 (s, CO), 171.1 (s, CO) ppm. ESI-MS: m/z (%) ϭ 720 (20) [M
Ϫ OAllyl]ϩ, 778 (100) [MH]ϩ, 800 (67) [MNa]ϩ. C37H46F3N5O8S
(777.30): calcd. C 57.13, H 5.96, N 9.00, S 4.12; found C 57.21, H
6.20, N 8.94, S 3.95.
Bz؊Tyr؊SAA؊Phe؊Met؊NHMe (21): Azide 19 was coupled to
BzϪTyrϪOH according to the general procedure described above
to afford, after purification by flash chromatography, compound
21 (51%) as a white solid; m.p. 107Ϫ110 °C. [α]2D2 ϭ ϩ46 (c ϭ 0.8,
CH3(CH2)2CO؊Tyr؊SAA؊Phe؊Met؊NHMe (23): Azide 19 was
coupled to CH3(CH2)2COϪTyrϪOH according to the general pro-
cedure described above to afford, after purification by flash chro-
1
MeOH). H NMR (300 MHz, [D6]DMSO, 40 °C): δ ϭ 1.62 (m, 1
H, CHHβMet), 1.88 (m, 1 H, CHHβMet), 1.97 (s, 3 H, SCH3), 2.13
(m, 3 H, CHHCO, CH2S), 2.26 (m, 1 H, CHHCO), 2.34 (m, 1 H, matography, compound 23 (69%) as a white solid; m.p. 101Ϫ103
3-H), 2.56 (d, J ϭ 4.5 Hz, 3 H, NHCH3), 2.81 (d, J ϭ 13.5 Hz, 1 °C. [α]2D2 ϭ ϩ58 (c 0.1, MeOH). 1H NMR (400 MHz,
H, CHHβTyr), 2.91 (m, 2 H, CHHβPhe, CHHβTyr), 2.98 (dd, J ϭ [D6]DMSO, 40 °C): δ ϭ 0.73 (t, J ϭ 7.3 Hz, 3 H, CH3CH2), 1.40
13.9 and J ϭ 4.8 Hz, 1 H, CHHβPhe), 3.35 (m, 2 H, CH2NH), 3.88 (m, 2 H, CH2CH2CO), 1.76 (m, 1 H, CHHβMet), 1.90 (m, 1 H,
ϭ
(dd, J ϭ 13.1 and J ϭ 4.9 Hz, 1 H, CHHCHϭCH2), 4.10 (m, 2 H, CHHβMet), 2.01 (m, 2 H, CH2CONHTyr), 2.02 (s, 3 H, SCH3), 2.10
6-H, CHHCHϭCH2), 4.18 (m, 1 H, CHαMet), 4.45 (m, 1 H, (m, 1 H, CHHS), 2.19 (m, 1 H, CHHS), 2.39 (m, 3 H, 3-H,
CHαTyr), 4.58 (s, 1 H, 2-H), 4.63 (m, 1 H, CHαPhe), 5.08 (m, Jcis-
CH2CONHPhe), 2.56 (d, J ϭ 4.6 Hz, 3 H, NHCH3), 2.63 (m, 1 H,
CHHβTyr), 2.77 (dd, J ϭ 13.9 and J ϭ 3.9 Hz, 1 H, CHHβPhe),
ϭ 10.4 Hz, 1 H, ϭCH2 cis), 5.19 (m, Jtrans-H ϭ 17.2 Hz, 1 H, ϭ
H
CH2 trans), 5.61 (m, 2 H, 4-H, 5-H), 5.82 (m, 1 H, CHϭCH2), 6.62 2.84 (d, J ϭ 14.1 Hz, 1 H, CHHβTyr), 3.02 (dd, J ϭ 13.9 and J ϭ
(d, J ϭ 8.4 Hz, 2 H, Ar-HTyr), 7.11 (d, J ϭ 8.4 Hz, 2 H, Ar-HTyr),
7.20 (m, 5 H, Ar-HPhe), 7.43 (t, J ϭ 7.8 Hz, 2 H, Ar-HBz), 7.50 (t,
4.8 Hz, 1 H, CHHβPhe), 3.19 (m, 2 H, CH2NH), 3.88 (dd, J ϭ 12.9
and J ϭ 5.6 Hz, 1 H, CHHCHϭCH2), 4.07 (m, 1 H, 6-H), 4.08
J ϭ 7.4 Hz, 1 H, Ar-HBz), 7.74 (bq, J ϭ 4.5 Hz, 1 H, NHMe), 7.79 (dd, J ϭ 13.1 and J ϭ 6.0 Hz, 1 H, CHHCHϭCH2), 4.27 (m, 1 H,
(d, J ϭ 7.1 Hz, 2 H, Ar-HBz), 8.02 (t, J ϭ 5.8 Hz, 1 H, CH2NH), CHαMet), 4.44 (m, 1 H, CHαTyr), 4.51 (s, 1 H, 2-H), 4.55 (m, 1 H,
8.19 (d, J ϭ 8.4 Hz, 1 H, NHMet), 8.25 (d, J ϭ 6.8 Hz, 1 H, NHTyr), CHαPhe), 5.12 (m, Jcis-H ϭ 10.2 Hz, 1 H, ϭCH2 cis), 5.22 (m,
8.43 (d, J ϭ 8.4 Hz, 1 H, NHPhe), 9.06 (s, 1 H, OH) ppm. 13C
Jtrans-H ϭ 17.3 Hz, 1 H, ϭCH2 trans), 5.56 (m, 2 H, 4-H, 5-H), 5.86
NMR (75 MHz, [D6]DMSO, 40 °C): δ ϭ 15.2 (q, CH3S), 26.3 (q, (m, 1 H, CHϭCH2), 6.62 (d, J ϭ 8.3 Hz, 2 H, Ar-HTyr), 7.01 (d,
NHCH3), 30.2 (t, CH2S), 31.8 (t, CH2βMet), 36.5 (t, CH2βPhe), 37.1 J ϭ 8.5 Hz, 2 H, Ar-HTyr), 7.22 (m, 5 H, Ar-HPhe), 7.49 (q, J ϭ
(t, CH2βTyr), 38.0 (t, CH2CO), 39.0 (d, C-3), 43.0 (t, CH2NH), 52.5 4.6 Hz, 1 H, NHMe), 7.84 (t, J ϭ 5.8 Hz, 1 H, CH2NH), 7.87 (d,
(d, CHαMet), 55.5 (d, CHαTyr), 56.0 (d, CHαPhe), 67.5 (d, C-6), 68.1 J ϭ 8.3 Hz, 1 H, NHTyr), 7.98 (d, J ϭ 8.0 Hz, 1 H, NHMet), 8.11
(t, CH2CHϭCH2), 98.5 (d, C-2), 115.6 (d, 2C, CAr), 117.1 (t, CHϭ
CH2), 127.0 (d, C-4; d, C-5), 127.2 (d, CAr), 128.1 (d, 2C, CAr),
(d, J ϭ 7.8 Hz, 1 H, NHPhe), 9.04 (s, 1 H, OH), ppm. 13C NMR
(75 MHz, [D6]DMSO, 40 °C): δ ϭ 13.3 (q, CH3CH2), 14.5 (q,
128.7 (d, 2C, CAr), 128.8 (d, 2C, CAr), 129.1 (s, CAr), 129.8 (d, 2C, CH3S), 18.4 (t, CH2CH2CO), 25.4 (q, NHCH3), 29.5 (t,
CAr), 130.7 (d, 2C, CAr), 131.9 (d, CAr), 134.8 (s, CAr), 135.5 (d, CH2CONHPhe), 31.7 (t, CH2βMet), 35.5 (d, C-3), 36.7 (t, CH2βTyr),
CHϭCH2), 138.0 (s, CAr), 156.4 (s, CAr), 167.0 (s, COBz), 171.6 (s, 37.0 (t, CH2βPhe; t, CH2CH2CO), 38.4 (t, CH2S), 42.1 (t, CH2NH),
CO), 171.9 (s, CO), 172.0 (s, CO), 172.3 (s, CO) ppm. ESI-MS:
m/z (%) ϭ 786 (100) [MH]ϩ, 808 (48) [MNa]ϩ. C42H51N5O8S
(785.35): calcd. C 64.18, H 6.54, N 8.91, S 4.08; found C 63.85, H
6.80, N 8.69, S 3.73.
51.8 (d, CHαMet), 53.8 (d, CHαPhe), 54.1 (d, CHαTyr), 66.5 (d, C-
6), 67.3 (t, CH2CHϭCH2), 97.7 (d, C-2), 114.6 (d, 2C, CAr), 116.2
(t, CHϭCH2), 126.1 (d, C-4; d, C-5), 126.4 (d, CAr), 127.8 (d, 2C,
CAr), 127.9 (s, CAr), 128.9 (d, 2C, CAr), 129.8 (d, 2C, CAr), 134.7
(d, CHϭCH2), 137.7 (s, CAr), 155.5 (s, CAr), 170.3 (s, CO), 170.9
(s, CO), 171.0 (s, CO), 171.5 (s, CO), 171.8 (s, CO) ppm. ESI-
MS: m/z (%) ϭ 752 (100) [MH]ϩ, 774 (43) [MNa]ϩ C39H53N5O8S
(751.36): calcd. C 62.30, H 7.10, N 9.31, S 4.26; found C 62.12, H
7.37, N 9.22, S 3.98.
CF3CO؊Tyr؊SAA؊Phe؊Met؊NHMe (22): Azide 19 was cou-
pled to CF3COϪTyrϪOH according to the general procedure de-
scribed above to afford, after purification by flash chromatography,
compound 22 (49%) as a white solid; m.p. 116Ϫ118 °C. [α]2D2
ϩ31 (c ϭ 0.2, MeOH), H NMR (400 MHz, [D6]DMSO, 40 °C):
ϭ
1
δ ϭ 1.59 (m, 2 H, CH2βMet) 1.59 (m, 2 H, CH2βMet), 1.87 (m, 1 H, Ac؊Tyr؊SAA؊Phe؊Met؊NHMe (24): Azide 19 was coupled to
CHHS), 2.05 (s, 3 H, CH3S), 2.09 (m, 1 H, CHHS), 2.14 (m, 1 H, AcϪTyrϪOH according to the general procedure described above
CHHCO), 2.21 (m, 1 H, CHHCO), 2.32 (m, 1 H, H-3), 2.53 (d, to afford, after purification by flash chromatography, compound
J ϭ 4.5 Hz, 3 H, NHCH3), 2.78 (m, 3 H, CHHβPhe, CHHβTyr), 24 (65%) as a white solid. m.p. 106Ϫ109 °C. [α]2D2 ϭ ϩ61 (c ϭ 0.5,
1
2.90 (m, 2 H, CHHβPhe, CHHβTyr), 3.22 (m, 2 H, CH2NH), 3.88 MeOH). H NMR (400 MHz, [D6]DMSO, 40 °C): δ ϭ 1.75 (s, 3
(m, 1 H, CHHCHϭCH2), 4.05 (m, 2 H, 6-H, CHHCHϭCH2), 4.12 H, COCH3), 1.76 (m, 1 H, CHHβMet), 1.89 (m, 1 H, CHHβMet),
(m, 1 H, CHαMet), 4.24 (m, 1 H, CHαTyr), 4.47 (m, 1 H, CHαPhe), 2.02 (s, 3 H, SCH3), 2.11 (m, 3 H, CHHS, CH2CO), 2.38 (m, 2 H,
4.58 (s, 1 H, 2-H), 5.07 (m, Jcis-H ϭ 10.4, 1 H, ϭCH2 cis), 5.18 (m, 3-H, CHHS), 2.56 (d, J ϭ 4.6 Hz, 3 H, NHCH3), 2.63 (m, 1 H,
Eur. J. Org. Chem. 2004, 3063Ϫ3073
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3071

´
A. Montero, E. Mann, B. Herradon
FULL PAPER
Hoffmann, H. Kessler, J. Am. Chem. Soc. 1996, 118,
CHHβTyr), 2.82 (m, CH2βPhe, 3 H, CHHβTyr), 3.19 (m, 2 H,
CH2NH), 3.89 (m, 1 H, CHHCHϭCH2), 4.07 (m, 1 H, 6-H), 4.14
(m, 1 H, CHHCHϭCH2), 4.28 (m, 1 H, CHαMet), 4.42 (m, 1 H,
CHαTyr), 4.51 (s, 1 H, 2-H), 4.55 (m, 1 H, CHαPhe), 5.12 (m,
Jcis-H ϭ 10.2 Hz, 1 H, ϭCH2 cis), 5.22 (m, Jtrans-H ϭ 17.3 Hz, 1
H, ϭCH2 trans), 5.56 (m, 2 H, 4-H, 5-H), 5.87 (m, 1 H, CHϭCH2),
6.62 (d, J ϭ 8.5 Hz, 2 H, Ar-HTyr), 7.00 (d, J ϭ 8.3 Hz, 2 H, Ar-
[10b]
10156Ϫ10167.
T. K. Chakraborty, S. Ghosh, S. Jayaprak-
ash, J. A. R. P. Sharma, V. Ravikanth, P. V. Diwan, R. Nagaraj,
A. C. Kunwar, J. Org. Chem. 2000, 65, 6441Ϫ6457. [10c] B. Agu-
ilera, G. Siegal, H. S. Overkleeft, N. J. Meeuwenoord, F. P. J.
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[10d]
1541Ϫ1547.
R. M. van Well, H. S. Overkleeft, G. A. van
HTyr), 7.23 (m, 5 H, Ar-H), 7.49 (bq, J ϭ 4.6, 1 H, NHMe), 7.87
der Marel, D. Bruss, G. Thibault, P. G. de Groot, J. H. van
Boom, M. Overhand, Bioorg. Med. Chem. Lett. 2003, 13,
331Ϫ334.
(t, J ϭ 5.6 Hz, 1 H, CH2NH), 7.98 (d, J ϭ 8.3 Hz, 1 H, NHTyr; d,
J ϭ 8.3 Hz, 1 H, NHMet), 8.11 (d, J ϭ 7.8 Hz, 1 H, NHPhe), 9.08
(s, 1 H, OH) ppm. 13C NMR (75 MHz, [D6]DMSO, 40 °C): δ ϭ
14.6 (q, CH3S), 22.5 (q, COCH3), 25.6 (q, NHCH3), 29.5 (t, CH2S),
31.8 (t, CH2βMet), 35.6 (t, CH2βTyr), 35.7 (t, CH2βPhe), 36.9 (t,
CH2CO), 38.4 (d, C-3), 42.1 (t, CH2NH), 51.8 (d, CHαMet), 53.9
(d, CHαPhe), 55.5 (d, CHαTyr), 66.6 (d, C-6), 67.4 (t, CH2CHϭ
CH2), 97.7 (d, C-2), 114.8 (d, 2C, CAr), 116.5 (t, CHϭCH2), 126.2
(d, C-5), 126.3 (d, C-4), 126.6 (d, CAr), 128.1 (d, 2C, CAr), 129.1
(d, 2C, CAr), 129.2 (d, CAr), 130.0 (d, 2C, CAr), 134.8 (d, CHϭ
CH2), 137.2 (s, CAr), 137.9 (s, CAr), 155.7 (s, CAr), 169.1 (s, CO),
170.4 (s, CO), 171.2 (s, CO), 171.3 (s, CO), 171.7 (s, CO) ppm. ESI-
MS: m/z (%) ϭ 724 (100) [MH]ϩ, 746 (96) [MNa]ϩ. C37H49N5O8S
(723.33): calcd. C 61.39, H 6.82, N 9.67, S 4.43; found C 61.21, H
6.97, N 9.70, S 4.35.
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acknowledged. AM thanks CSIC for an EPO-fellowship. We thank
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