Preparation of protected β2- and β3- homocysteine, β2- and β3-homohistidine, and β2-homoserine for solid-phase syntheses

Article abstract of DOI:10.1002/hlca.200490280

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β-peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³-homoamino acid derivatives were obtained by Arndt-Eistert methodology from Boc-His(Ts)-OH and Fmoc-Cys(PMB)-OH (Schemes 2-4), with the side-chain functional groups' reactivities requiring special precautions. The β²-homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti-enolates to formaldehyde (generated in situ from trioxane) and subsequent functional-group manipulations. These include OH → O^tBu etherification (for β²hSer; Schemes 5 and 6), OH → STrt replacement (for β²hCys; Scheme 7), and CH ₂OH → CH₂N₃ → CH₂NH ₂ transformations (for β²hHis; Schemes 9-11). Including protection/deprotection/re-protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H- and ¹³C-NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X-ray crystal-structure analysis.

Full text of DOI:10.1002/hlca.200490280

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Preparation of Protected b2- and b3-Homocysteine, b2- and b3-Homohistidine,
and b2-Homoserine for Solid-Phase Syntheses1)
by GeÂrald Lelais2), Peter Micuch3), Delphine Josien-Lefebvre3), Francesco Rossi4), and Dieter Seebach*
Department für Chemie und Angewandte Biowissenschaften, Laboratorium für Organische Chemie der
Eidgenössischen Technischen Hochschule, ETH Hönggerberg, HCI, Wolfgang-Pauli-Strasse 10, CH-8093
Zürich (Phone: ‡4116322990, fax: ‡4116321144, e-mail: seebach@org.chem.ethz.ch)
The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins
and enzymes. For our structural and biomedical investigations of b-peptides consisting of amino acids with
proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two b3-
homoamino acid derivatives were obtained by Arndt ± Eistert methodology from Boc-His(Ts)-OH and Fmoc-
Cys(PMB)-OH (Schemes 2 ± 4), with the side-chain functional groupsꢀ reactivities requiring special precautions.
The b2-homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by
diastereoselective aldol additions of suitable Ti-enolates to formaldehyde (generated in situ from trioxane) and
subsequent functional-group manipulations. These include OH ! OtBu etherification (for b2hSer; Schemes 5
and 6), OH! STrt replacement (for b2hCys; Scheme 7), and CH2OH ! CH2N3 ! CH2NH2 transformations
(for b2hHis; Schemes 9 ± 11). Including protection/deprotection/re-protection reactions, it takes up to ten steps
to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches,
pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are
1
fully characterized by retention times (tR), melting points, optical rotations, HPLC on chiral columns, IR, H-
and 13C-NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X-ray crystal-
structure analysis.
1. Introduction. ± b-Amino acids, compared to their a-counterparts, possess one
more ꢁfreely rotatingꢀ CÀC s-bond. Intuitively, greater backbone flexibility of
oligomers built exclusively of such residues (b-peptides) might be expected to lead
to increased conformational complexity. However, this has been found to be only
partially true: depending upon the substitution pattern of the b-amino acids, several
different secondary structures have been found, e.g., five types of helices [3 ± 9], sheet
[10][11], and turn structures [10][12 ± 14]; the big surprise, however, is that these
secondary structures are present in solution with peptide chains as short as four
residues5). In addition, b-peptides turn out to be stable to rat metabolism [22], to
exhibit slow microbial degradation [23], and to be inherently stable to a range of
proteases and peptidases [3][24 ± 28], rendering them promising candidates as
peptidomimetics in drug design. b-Peptides with biological activity have been tested,
1
)
)
)
Partially published in preliminary communications [1][2].
2
3
Part of the Dissertation of G. L. (No. 15429), ETH-Zürich, 2004.
Postdoctoral Fellow at ETH-Zürich, financed by ETH Zürich and by a grant from the Swiss National
Science Foundation (No. 2000-058831.99/1).
Postdoctoral Fellow at ETH-Zürich, on leave from Pfizer, R&D, Nerviano (MI), Italy (2002/2003).
For reviews on b-peptides, see [15 ± 21].
4
5
)
)
ꢂ 2004 Verlag Helvetica Chimica Acta AG, Zürich

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so far, as somatostatin mimics [29 ± 32], for cholesterol transport inhibition [33], and as
antiproliferative [34] and antimicrobial [27][35 ± 42] compounds.
To profit as much as possible from the knowledge about a-protein chemistry and to
study the rapidly evolving field of the chemistry and biology of b-peptides, especially
towards the synthesis of what can be referred to as ꢁb-proteinsꢀ, all-b-amino acids6) with
proteinogenic side chains had to become available. It is evident that only b-amino acids
with side chains in the 2- or/and 3-position, i.e., b2- and b3-amino acids, have a high
degree of similaritiy to a-amino acids (Figure), while the cyclic b-amino acid
derivatives [4][6] are fundamentally different.
Figure. Representation of the molecular formulae of a-, b2-, and b3-amino acids
Among all ꢁproteinogenicꢀ b3-amino acids, suitably protected for solid-phase
synthesis by the Fmoc strategy7), only Fmoc-b3hHis(Tr)-OH and Fmoc-b3hCys(Tr)-
OH have not hitherto been reported in the literature and will be discussed herein. All
others are commercially available and are prepared by Arndt ± Eistert homologation of
the corresponding a-amino acids [53]. On the other hand, there is no general method
for the preparation of enantiomerically pure b2-amino acids; they are certainly not
available by any stereoselective transformation of a-amino acids. They can be prepared
via coupling of an appropriate electrophile with cyclic [54 ± 61] or acyclic [2][62 ± 70]
enolates derived from 3-aminopropanoic acid. In some of these routes, harsh
conditions8) are required to cleave auxiliary groups, and this is, of course, unsuitable
for the preparation of b2-amino acids with functionalized side chains7). In addition,
partial racemization may occur during hydrolysis steps. With Li-enolates, reactive
electrophiles are required [65], and, when two N-acyl groups (Boc2, phthalyl) are used
on the 3-aminopropanoic acid derivative, b-elimination can take place [65][67]. Thus,
most methods are applicable only to the preparation of b2-amino acids with alkyl,
benzyl, or the ± unnatural ± aryl side chains. In another approach, the amino acid side
chain is first attached to an auxiliary as part of an acyl group, followed by
‡
aminomethylation with synthetic equivalents of the [H2NCH2] cation (Mannich
reaction; Scheme 1) [2][7][31][64][71 ± 76]. Also, alkylation of an enolate with the
appropriate side chain by a haloacetate electrophile, followed by Curtius degradation,
leads to the net attachment of an aminomethyl group (a Mannich transformation [77];
Scheme 1) [76][78 ± 80].
6
)
)
For extensive reviews on syntheses of b-amino acids, see [43 ± 52].
For solid-phase synthesis by the Fmoc strategy, functionalized side chains must be protected with acid-
labile protecting groups.
7
8
)
For example, prolonged stirring or heating with acids.

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Scheme 1. Three Synthetic Approaches towards the Preparation of the b2-Amino Acid Skeleton
b2-Amino acids can also be prepared by regioselective coupling of an electrophile
containing the amino acid side chain with an unsymmetric succinic acid derivative,
which is then subjected to a regioselective Curtius rearrangement [80][81]. Asym-
metric hydrogenation has also been used in the preparation of b2-amino acids [82][83],
but high enantioselectivities were observed with only particular substrates.
We have employed hydroxymethylation for the preparation of various b2-amino
acids. This does not only lead to a b2hSer derivative [64], but, via replacement of the
OH by an STr group, provides access to a b2hCys derivative, as well. On the other hand,
substitution of the OH group with amino or azido nucleophiles gives products of an
overall attachment of an aminomethyl group (Scheme 1), thus opening another simple
route for the preparation of b2-amino acids. This strategy was successfully employed for
the preparation of a b2hHis derivative, as reported herein.
The syntheses of the title compounds by routes generally outlined in the previous
sections, in the Figure, and in Scheme 1 are described in this paper, including full
experimental details.
2. Preparation of Fmoc-b3hHis(Tr)-OH and Fmoc-b3hCys(Tr)-OH.± Histidine is a
remarkable amino acid, in which the basic 1H-imidazolyl side chain is crucial to the
biological activity of many proteins and peptides. The nucleophilic character of the
unprotected 1H-imidazole ring can be expected to be a source of difficulty in the usual
approach to a-amino-acid homologation, since the first step of the transformation

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involves the activation of the carboxy group to become a strong electrophile. A similar
assertion can be drawn if the 1H-imidazolyl group is not protected ꢁin the right wayꢀ,
using, for example, protecting-groups with donor properties (i.e., with s-donor effect).
In fact, first attempts at synthesizing the homohistidine derivatives by Arndt ± Eistert
homologation from Fmoc-His(t-BOM)-OH, Fmoc-His(t-Tr)-OH, Boc-His(t-Bn)-
OH, Boc-His(p-Bn)-OH, and Boc-His(t-BOM)-OH were unsuccessful9). Only Ts-
protected histidines reacted with CH2N2 to form the corresponding diazo ketones,
probably due to the strong electron-withdrawing effect of the tosylate, which renders
the 1H-imidazolyl N-atom less nucleophilic10). Thus, commercially available Fmoc-
His(Ts)-OH and Boc-His(Ts)-OH were converted via their mixed anhydrides (NMM/
i
ClCO2Et or NEt3/ClCO2 Bu) to the diazo ketones 1 and 2 in 56 and 86% yields,
respectively (Scheme 2). Attempts at converting diazo ketone 1 to a b3-homohistidine
derivative were shown to be ineffective, due to the insolubility of 1 in most solvents
suitable for the Wolff rearrangement (e.g., BnOH, H2O, THF, dioxane, etc.). On the
other hand, decomposition of diazo ketone 2 in the presence of the corresponding
‡
alcohol (MeOH, BnOH), by reaction with catalytic amounts of Ag (CF3CO2Ag
dissolved in Et3N) gave the Boc-protected methyl or benzyl ester as a mixture of three
‡
products in a 1:1:1 ratio. It was found that the Ag ion interacts with the 1H-imidazole
ring inducing the partial displacement of the Ts protecting group from the t-N to the p-
N, as well as the complete removal of this protecting group. With this result at hand, it
was decided to use Boc-His(Ts)-OH as starting material for conversion to the b3-amino
acid derivative Fmoc-b3hHis(Tr)-OH. To this end, a Wolff-rearrangement procedure
with in-situ deprotection of the histidine side chain had to be worked out. Four mild
cleavage conditions for the deprotection of N'-Ts-histidine derivatives are known in the
literature; they involve the treatment of the Ts-histidines with HOBt in methanolic
solutions [86], the reaction with pyridinium hydrochloride [87], the employment of Mg
in dry MeOH [88], or the use of pyridine in Ac2O[89]; the latter procedure gave the
best results, allowing isolation of the esters 3 and 4 in good yields from the diazo ketone
2 (Scheme 2)11).
Since the use of histidine derivatives with unprotected 1H-imidazolyl side chains for
peptide couplings in solution or on solid support are known to cause side reactions, we
protected the 1H-imidazolyl group of the ester 3 with a Tr group: treatment with TrCl)
and Et3N afforded compound 5 in quantitative yield. Hydrolysis of the methyl ester with
LiOH in MeOH/H2Ogave the acid 6 as a single product (Scheme 2). The Boc-b3hHis(Tr)-
O H (6) was thus prepared from a-Boc-His(Ts)-OH in ca. 75% yield over four steps.
It is known that the a-amino-acid analogue of carboxylic acid 6, as well as peptides
containing histidine, can be selectively Na-Boc- or NIm-Tr-deprotected by means of
9
)
Throughout this paper, we use the common abbreviations of peptide chemistry; see [84]. The symbols t
and p are used to define whether the protecting group is positioned at N(1) (i.e., the less-hindered
position) or N(3) of the 1H-imidazolyl ring. When no symbol is specified, the protecting group is attached
to the less-hindered N(1)-atom.
Even though the Boc group is electron-withdrawing, the attempted conversion of Fmoc-His(Boc)-OH to
the diazo ketone resulted in a complex mixture of inseparable products. This is probably due to the high
instability of urethane protecting groups when bound to the 1H-imidazolyl N-atom [85].
It should be noted that the same reaction conditions employed towards the preparation of the acid
derivative (H2O instead of MeOH or BnOH) did not prove successful.
10
)
11
)

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Scheme 2. Preparation of the b3-Homohistidine Derivative 6 by Arndt ± Eistert Homologation of Boc-His(Ts)-
OH, Followed by Tr-Protection and Saponification of the Methyl Ester Group in 5
different reaction conditions. For example, treatment with 1n HCl in 90% AcOH for
20 min at room temperature leads to cleavage of the Boc group, leaving the Tr
protection intact [90 ± 92]. When these conditions for the Boc deprotection of the b-
amino acid derivatives 5 and 6 were applied, only partial cleavage occurred even after
one day. On prolonged exposure, partial degradation was detected. More-acidic
conditions, however, caused the cleavage of both protecting groups. Therefore,
synthetic applications of carboxylic acid 6 are limited to the synthesis of peptides with
an N-terminal b-homohistidine.
Recently, Wyatt and co-workers [93] accomplished the synthesis of Boc-b3hHis-
(Boc)-OH via the Kolbe reaction, i.e., by reducing a-Mts-His(Mts)-OMe to the
corresponding amino alcohol, the OH group of which was then activated and replaced
by CN; the CN group was, in turn, hydrolyzed to the MeNH group, which was Boc-
protected to give the final product in 7% yield over five steps. The authors state that
this derivative is suitable for direct use in the synthesis of peptides, but so far no
applications are known12).
12
)
The difference in reactivity between the two Boc groups should be less pronounced than that between the
Boc and the Tr group in our case (see 6).

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The successful preparation of Fmoc-b3hHis(Tr)-OH was accomplished by using the
Boc-protected homohistidine esters 3 and 4 as starting materials. As such, Boc
deprotection, followed by saponification or hydrogenolysis of the ester groups, gave the
completely unprotected b3-homohistidine, which was then phthaloyl(Phth)-protected
and acidified to yield the HCl salt 7 in 67% yield. Subsequent tritylation and N-Phth/N-
Fmoc protecting-group exchange afforded the acid 9 in 61% yield over the three steps
(Scheme 3)13).
Scheme 3. Preparation of Fmoc-b3hHis(Tr)-OH (9) Starting from 3 or 4
In this way, the synthesis of Fmoc-b3hHis(Tr)-OH was achieved in eight steps with
an overall yield of 32%, starting from commercial Boc-His(Ts)-OH.
The non-essential amino acid cysteine is particularly abundant in the proteins of
hair, hooves, and the keratin of skin, and its importance is related to the presence of a
SH group in the side chain. This group participates in the catalytic reactions of certain
enzymes, but is also capable of combining the SH group of one cysteine residue with the
SH group of another to form a disulfide bridge, either linking two peptide chains (e.g.,
insulin) or causing a single peptide chain to fold back on itself, making a loop (e.g., zinc
fingers). This latter effect on the secondary structure of proteins is evidently of great
importance in maintaining the proper conformation of both structural proteins and
enzymes.
For the preparation of Fmoc-b3hCys(Tr)-OH, two a-cysteine derivatives with
differently protected side chains were tested as starting materials and homologated via
the Arndt ± Eistert procedure. Commercial Fmoc-Cys(PMB)-OH and Fmoc-Cys-
(Acm)-OH were first converted to the corresponding diazo ketones 10 and 11 in
moderate-to-good yields (Scheme 4). Upon ultrasonication [95] in the presence of
13
)
Direct tritylation of the completely unprotected b-homohistidine by means of TrCl, Et3N, and Me2SiCl2
[94] gave no reproduceable results; the reasons could be the less favored formation of the cyclic silyl
intermediate for b-amino acids compared to the a-analogues (six-membered ring vs. five-membered ring),
or the hampered isolation of the NIm-tritylated homohistidine by precipitation due to the discrete solubility
of the zwitterionic starting material.

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catalytic amounts of PhCO2Ag and H2O, the PMB derivative 10 smoothly underwent
Wolff rearrangement to provide the acid 12 in good yield. Interestingly, similar
conditions for the conversion of the Acm derivative 11 led to the deprotection of the
starting material [96 ± 98]; therefore, the diazo ketone 11 was transformed to the b3-
amino acid 13 in moderate overall yield by irradiation with Hg light in a MeCN/H2O
mixture. However, prolonged reaction times of up to 3 days are necessary for complete
conversion (Scheme 4).
Scheme 4. Preparation of Fmoc-b3hCys(Tr)-OH (14) Starting from Either Fmoc-Cys(PMB)-OH or Fmoc-
Cys(Acm)-OH
Since the cleavage of both the PMB and Acm S-protecting groups involves reaction
with Hg salts, the use of amino acids 12 and 13 for solid-phase peptide synthesis by
Fmoc strategy are inappropriate; this additional step for the full deprotection of a
peptide containing functionalized side chains could possibly lead to problems.
Therefore, compounds 12 and 13 were treated under Ar14) with Hg(OAc)2 in acidic
media to give Fmoc-b3hCys-OH, which was then protected in situ to afford the Tr-
protected derivative 14 in moderate-to-good yields.
Thus, Fmoc-b3hCys(Tr)-OH (14) was prepared with an overall yield of 60% and
23% over three steps, starting from Fmoc-Cys(PMB)-OH and Fmoc-Cys(Acm)-OH,
respectively. The Acm protecting group was shown to be less stable under Arndt ±
Eistert homologation conditions, and the presence of small amounts of by-products at
each step resulted in tedious purifications. The preferable route is clearly that starting
from the PMB derivative.
14
)
Both reactions have to be carried out under complete exclusion of air, due to the ease of disulfide
formation!

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3. Preparation of b2-Amino Acid Derivatives with the Side Chains of Serine,
Cysteine, and Histidine. ± As outlined in a previous work on diastereoselective aldol
additions by Hintermann and Seebach [64], direct hydroxymethylation of a chiral
homoglycine derivative with 1,3,5-trioxane appeared to be the method of choice for the
construction of the b2-homoserine skeleton. Thus, phthalyl protection of b-alanine (i.e.,
b-homoglycine), followed by treatment with oxalyl chloride and N-acylation of the
lithiated chiral auxiliary (S)-DIOZ (17), afforded the acyloxazolidinone (S)-18 in good
yield (Scheme 5). Reaction of the Ti-enolate of (S)-18 with trioxane15) gave the
hydroxymethyl derivative (S,R)-1916) in 89% yield as a single diastereoisomer17). For
the preparation of the b2-homoserine derivative, suitably protected for solid-phase
synthesis, the OH group of 19 had to be converted to the corresponding t-BuOgroup
(see 20). Thus, treatment of 19 with isobutylene and a catalytic amount of H2SO4 led to
(S,R)-20 in 95% yield18). The crystal structures19) of both (S,R)-19 and (S,R)-
20 confirmed our configurational assignments (Scheme 5).
The next step was the removal of the chiral auxiliary. Unfortunately, this step could
not be accomplished with LiOOH or NaOH, due the to opening of the phthaloyl group,
which precluded the separation of N-deprotected b-homoserine from the chiral
oxazolidinone (S)-17. To obviate this problem, compound 20 was converted to the
benzyl ester derivative (R)-21 by treatment with BnOH and BuLi in THF at 08
(Scheme 6). Interestingly, it was found that partial epimerization or racemization
occurred during this reaction. The epimerization was found to be dependent on both
the amount of BuLi used and the reaction temperature employed. By running the
reaction at 08 with 1.2 equiv. BuLi (Entry 1, Scheme 6), ca. 25% of the (S)-product was
formed. If the reaction was carried out at 08, but with 2.5 equiv. of BuLi, compound 21
was formed as a ca. 84 :16 mixture of enantiomers (Entry 2). Finally, racemization-free
conditions were obtained when the reaction was performed at À 308 with 2.5 equiv. of
BuLi (Entry 3). Even though a prolonged reaction time was required for complete
conversion, the enantiomerically pure Phth-protected b2-homoserine (R)-21 was
isolated (80%), together with the recovered oxazolidinone (S)-17 (89%). For the
synthesis of the (R)-Fmoc-b2hSer(tBu)-OH 23, the phthaloyl group was first cleaved by
treatment of (R)-21 with ethylenediamine in BuOH [99] to give the amino ester (R)-22
in 78% yield. Hydrogenation and Fmoc protection afforded the acid 23 in 80% yield
(Scheme 6). The enantiomer purity of the b2-homoserine derivatives was determined
after derivatization to the dinitrophenyl derivative (R)-24, since the ester 21 did not
show enantiomer separation on our Chiralcel OD-H column [100]. Thus, the
homoserine derivative 22 was allowed to react with Sangerꢀs reagent (1-fluoro-2,4-
15
)
)
Trioxane is ꢁdegradedꢀ by TiCl4 to give formaldehyde in situ.
16
The first configuration descriptor (S) refers to the configuration of the stereogenic center of the
oxazolidinone auxiliary group, whereas the second descriptor (R) refers to the configuration of the newly
formed stereogenic center, the a-C-atom of the b2-homoamino acid moiety.
17
18
)
)
Degradation products are formed if the reaction is not carried out under absolute exclusion of H2O, which
renders purification troublesome.
Hydroxy protection was initially carried out by treatment of 19 with tert-butyl 2,2,2-trichloroacetimidate
(TBTA) in the presence of catalytic amounts of trifluoromethanesulfonic acid, but tedious separation of
the product from the formed trichloroacetamide excluded its further use.
19
)
We are grateful to Dr. B. Schweizer of the Laboratorium für Organische Chemie, ETH-Zürich, for
determination of the X-ray crystal structures of 19, 20, and 25 (see Scheme 7).

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Scheme 5. Acylation of the Chiral Auxiliary (S)-17 with the Acid Chloride 16 to Afford the Chiral Homoglycine
Derivative (S)-18. Hydroxymethylation of (S)-18 and subsequent t-Bu protection. Crystal structures of (S,R)-19
and (S,R)-20.
dinitrobenzene; DNPF [101][102]) in alkaline solution to give the compound 24 in
moderate yield, ready for analysis on the chiral column (Scheme 6).
According to this protocol, the b2-homoserine derivative (R)-23 was obtained with
an overall yield of 34% over nine steps.
For the preparation of the b2-homocysteine20), the hydroxymethyl derivative (S,R)-
19 was chosen as suitable starting material (Scheme 7). Thus, treatment of (S,R)-19
20
)
For our ongoing projects on the synthesis of long-chain b-peptides by the thioligation methodology, we
were interested in the synthesis of the Boc-b2hCys(Tr)-OH, which is the building block for peptides with
N-terminal b2hCys residue.

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Scheme 6. Removal of the Auxiliary from (S,R)-20 and Subsequent Conversion to Afford Fmoc-(R)-
b2hSer(tBu)-OH (23). The enantiomeric purity of the b2-homoserine derivative was established (after
derivatization of compound 22 to the 2,4-dinitrophenyl derivative 24) by HPLC on a Chiralcel OD-H column
(l ˆ 390 nm, elution system: i-PrOH/hexane 5 :95).
under modified Mitsunobu conditions with TrSH, Bu3P, and azodicarboxylic dipiper-
idide (ADDP) [103], afforded the thiol ether derivative 25 in good yield, but with
substantial epimerization (dr 82 :18). The diastereoisomeric mixture was readily
separated by flash chromatography to give (S,S)- and (S,R)-25 in 71 and 16% yield,
respectively. The configurational assignment was unambiguously confirmed by crystal-
structure analysis of the major diastereomer (Scheme 7). The next step involved the
removal of the chiral auxiliary from 25, which proved, again, problematic: cleavage
with LiOOH or NaOH was unsuccessful due to the opening of the phthaloyl group. On
the other hand, cleavage with BnOLi afforded the corresponding benzyl ester, but the
following hydrogenolysis to give the free acid proved to be ineffective, most likely
because of catalyst poisoning by the sulfide group. Better results were obtained by
treating (S,S)-25 with lithium 2-(trimethylsilyl)ethanolate to afford the ester (S)-26 in
acceptable yield, which was then Phth-deprotected and Boc-protected to give the b2-
homocysteine derivative (S)-28 in good yield. Final hydrolysis with Bu4NF [104] gave
the acid (S)-29 in 84% yield (Scheme 7)21). By this approach, Boc-b2-hCys(Tr)-OH
was prepared with an overall yield of 17% over nine steps from ꢁb-alanineꢀ.
21
)
Removal of the chiral auxiliary by treatment of (S,S)-25 with MeOLi turned out to be more efficient, but
the following saponification of the methyl ester led to a completely racemized product.

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Scheme 7. Preparation of Boc-(S)-b2hCys(Tr)-OH (29) Starting from the Hydroxymethyl Derivative (S,R)-19.
Esterification of the acid 29 was necessary for enantioselectivity quantification by HPLC on a chiral column
(Chiralcel OD-H; l ˆ 220 nm, elution system: i-PrOH/hexane 2 :98). X-Ray crystal structure of the major
diastereoisomer (S,S)-25 confirmed the configurational assignment.

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To determine the enantiomeric purity of the b2-homocysteine derivatives, the acid
(S)-29 was treated with TMSCHN2 to afford the methyl ester (S)-30 in quantitative
yield, which was analyzed with a chiral HPLC column (Chiralcel OD-H) to have an
enantiomer purity of 98.3% (Scheme 7).
As pointed out above, in the syntheses of the b3-homohistidine derivatives, the
presence of the nucleophilic N-atom on the (1H-imidazolyl)methyl side chain was
found to generate undesired by-products and was expected to cause trouble in the steps
towards the preparation of the b2-analogues as well. Indeed, many routes (Scheme 8)
have been tested, and most were not successful.
Scheme 8. Retrosynthetic Analysis for the Preparation of Fmoc-b2hHis(Tr)-OH via Alkylation (route A),
Mannich-Type Reaction (route C), and Aldol Addition (routes B and D) of Chiral Acyloxazolidinones
Initial attempts of diastereoselective alkylation (cf. A in Scheme 8) of homoglycine-
derived acyloxazolidinones III (PG ˆ Phth [64]; PG ˆ Ph2C) with (1H-imidazol-4-
yl)methyl derivatives II (PG' ˆ Trt, X ˆ Cl [105]; PG' ˆ Ts, X ˆ MsO[106]) were
ineffective due to the low reactivity of both electrophiles, and modifications of II by use
of better leaving groups (X ˆ I, Br) failed, these derivatives being too unstable. In a
second approach (cf. B in Scheme 8), the aldol addition of the oxazolidinone
derivatives III with aldehydes IV (PG' ˆ Tr [107]; PG' ˆ Ts [106]), followed by
deoxygenation under Barton ± McCombie conditions [67][108][109], resulted in the
isolation of degradation products caused by retro-aldol reactions, occurring during the
deoxygenation step. Thus, the amidomethylation reaction via Ti-enolates was
attempted (cf. C in Scheme 8): treatment of the acyloxazolidinone V (PG' ˆ Tr) with

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3143
the electrophile VI [64][75] resulted in a complex mixture of inseparable products;
although the desired compound had been formed, long reaction times were required for
good conversion, causing the partial cleavage of the Tr protecting group. Thus, we
envisaged the use of a more reactive electrophile, for instance, 1,3,5-trioxane (cf. D in
Scheme 8), with subsequent OH/NH2 replacement. This route led, eventually, to the
synthesis of the desired b2-homohistidine derivative for solid-phase syntheses, and is
presented in detail in the following sections.
For the preparation of the acyloxazolidinone 35, 1H-imidazole-4-acrylic acid
(uraconic acid) was selected as the starting material. Hydrogenation of uraconic acid,
followed by esterification under acidic conditions, gave the methyl ester 32, which was
Tr-protected to give compound 33, the crude product of which was saponified to afford
the acid 34 in 73% yield over four steps (Scheme 9).
Scheme 9. Preparation of the Acyloxazolidinone (R)-35 Starting from Uraconic Acid
N-Acylation of the (R)-DIOZ (17) was accomplished by nucleophilic addition of
the lithiated auxiliary (using BuLi in THF at 08) to the pivaloyl mixed anhydride of 34
[110] to give the acyloxazolidinone (R)-35 in 60% yield (Scheme 9)22). The following
aldol reaction was effected by reaction of the Ti-enolate of 35 with 1,3,5-trioxane to
afford the hydroxymethyl derivative 36 in 70% yield (Scheme 10). The diastereose-
lectivity was ca. 9 :1 in favor of the diastereoisomer (R,S)-36 as deduced from the
1H-NMR spectra of the crude product. The absolute configuration of the newly formed
22
)
In contrast, the acylation of (R)-17 with the LiCl-activated [111] pivaloyl mixed anhydride of 34, with Et3N
as base [112] gave 35 in lower yields. A third method involving the addition of the lithiated auxiliary to the
corresponding acid chloride of 34 was not considered, since treatment of 34 with oxalyl chloride had
caused partial cleavage of the Tr protecting group!

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stereogenic center was assigned by analogy with the results from previous aldol
reactions of this type [64][72].
The next step required the replacement of the OH group of 36 by a N-substituent
by means of a Mitsunobu reaction. Thus, treatment of (R,S)-36 with Ph3P, DIAD, and
either DPPA or hydrazoic acid afforded the azide derivative (R,S)-37 in moderate-to-
good yields (55 and 89%, resp.). However, attempts to cleave the auxiliary were not
successful. Indeed, removal of the oxazolidinone group by BnOH/BuLi afforded the
elimination product 38 (Scheme 10).
Scheme 10. Diastereoselective Aldol Reaction of (R)-35 with 1,3,5-Trioxane. The following transformation
towards the formation of b2-homohistidine derivatives led, instead, to the formation of compound 38.
To circumvent this problem, the hydroxymethyl derivative 36 was first treated with
BnOH/BuLi to form23) the corresponding benzyl ester (S)-39, which was subsequently
transformed to the azide (S)-40 under Mitsunobu conditions in good yield (Scheme 11).
To verify whether both the cleavage of the auxiliary and the conversion to the azide
derivative 40 had proceeded with retention of configuration in the a-position to the
CˆOgroup, both compounds were injected into an analytical, chiral, normal-phase
HPLC column (Chiralcel OD-H). Fortunately, both compounds showed good
resolution, so that the performance of these two reactions could be validated
(Scheme 11).
Simultaneous benzyl ester cleavage and azide reduction in derivative 40 by catalytic
hydrogenation, followed by Fmoc-protection, afforded the histidine derivative (S)-41
in moderate yield (Scheme 11). It should be noted that the Tr protecting group is stable
under the hydrogenation conditions only to a certain extent; prolonged reaction times
cause complete cleavage of that group24).
23
)
)
(R)-DIOZ was recovered in 84% yield.
24
To prevent significant Tr cleavage, the hydrogenation was carried out for a period of 2 h. The solution was
then filtered over Celite, and the solvent was evaporated. The reaction progress was followed by IR
spectroscopy, using the intensive stretching vibration of the N3 group in the range 2250 ± 2080 cmÀ1. If the
reaction was not complete, the mixture was treated for a further 2 h under the hydrogenation conditions.

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3145
Scheme 11. Removal of the Auxiliary with BnOLi, Followed by Mitsunobu Reaction and Functional-Group
Modifications for the Preparation of Fmoc-(S)-b2hHis(Tr)-OH (41). The HPLC traces of the hydroxymethyl
derivative 39 and of the azide 40 demonstrate the efficiency of this approach for the preparation of
enantiomerically pure b2-homohistidine (Chiralcel OD-H, l ˆ 220 nm, elution system: i-PrOH/hexane 10 :90
for 39 and i-PrOH/hexane 5 :95 for 40).
In this way, the syntheses of (S)-Fmoc-b2hHis(Tr)-OH was achieved with an overall
yield of 11% over ten steps from 4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one (DIOZ).
4. Conclusions and Outlook. ± The preparation of Fmoc-b3hHis(Tr)-OH and Fmoc-
b3hCys(Tr)-OH were achieved via Arndt ± Eistert homologation. Thus, all 20 b3-amino
acids with proteinogenic side chains appropriately protected for solid-phase syntheses
by the Fmoc strategy have now been prepared by this method. We were also able to
develop a useful route for the preparation of three b2-amino acids making use of 4-
isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one (DIOZ) as a chiral auxiliary for a
diastereoselective aldol reaction (with trioxane). The enantiomer purity of these
amino acids was determined by HPLC on a Chiralcel OD-H column of the (R)- and
(S)-derivatives 24, 30, 39, and 40. Our protocol can easily be scaled-up to produce
multigram amounts of these amino acids in enantiomerically pure form. Ongoing work
in our laboratory is focussed in the use of the above mentioned amino acids for the
constructions of large b-peptides for structural [1][113] and biological investigations,
towards the synthesis of what can be referred to as ꢁb-proteinsꢀ.

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Experimental Part
1. General. Abbreviations: Acm: (Acetamido)methyl, ADDP: azidodicarboxylic dipiperidide, Boc: (tert-
butoxy)carbonyl, DIAD: diisopropyl azodicarboxylate, DNPF: 1-fluoro-2,4-dinitrobenzene, FC: flash chro-
matography, Fmoc-OSu: N-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)succinimide, HOBt: 1-hydroxy-1H-
benzotriazole, h.v.: high vacuum, 0.01 ± 0.1 Torr, NMM: N-methylmorpholine, PMB: para-methoxybenzyl,
TIS: tetraisopropylsilane, Ts: 4-toluenesulfonyl, Tr: trityl. Solvents for chromatography and workup procedures
were distilled from Sikkon (anh. CaSO4; Fluka) and from KOH (Et2O), resp. Et3N was distilled from CaH2 and
stored over 4-Š molecular sieves. Amino acids were purchased from Fluka or Senn. All other reagents were
used as received from Fluka. TLC: Merck silica gel 60 F254 plates; detection with UV, anisaldehyde soln. (9.2 ml
anisaldehyde, 12.5 ml conc. H2SO4, 3.75 ml AcOH, 340 ml EtOH), or ꢁMostainꢀ soln. (25 g of phosphormolybdic
acid, 10 g of Ce(SO4)2 ´ H2O, 60 ml of conc. H2SO4, 940 ml of H2O), FC: Fluka silica gel 60 (40 ± 63 mm); at ca.
0.2 bar. Anal. HPLC: Waters HPLC System (pump type 515, data module type 746, tunable absorbance detector
type 484), Chiralcel OD-H column. M.p.: Büchi-510 apparatus; uncorrected. IR Spectra: Perkin-Elmer 1600 FT-
IR spectrophotometer. NMR Spectra: Bruker AMX-II-500 (1H: 500 MHz, 13C: 125 MHz), Bruker AMX-400
(1H: 400 MHz, 13C: 100 MHz), Bruker AMX-300 (1H: 300 MHz, 13C: 75 MHz), Varian Mercury XL 300 (1H:
300 MHz, 13C: 75 MHz); chemical shifts d in ppm downfield from internal Me4Si (ˆ0 ppm); J values in Hz. MS:
IonSpec Ultima 4.7 T FT ion-cyclotron resonance (ICR, HR-MALDI, in 2,5-dihydroxybenzoic acid matrix)
spectrometer; in m/z (% of basis peak). Elemental analyses were performed by the Microanalytical Laboratory
of the Laboratorium für Organische Chemie, ETH-Zürich.
2. Synthesis of N-Fmoc- or N-Boc-Protected Diazo Ketones: General Procedure 1 (GP 1). GP 1a: Similar to
the procedure reported in [114], the N-Fmoc- or N-Boc-protected amino acid was dissolved in THF (0.2m)
under Ar and cooled to À 258. After addition of NMM (1.05 equiv.) and ClCO2Et (1.05 equiv.), the mixture was
stirred at À 258 for 30 min. The resulting white suspension was allowed to warm to 08, and a soln. of CH2N2 in
Et2Owas added until the rich yellow color persisted. Stirring was continued for 2 ± 12 h as the mixture was
allowed to warm to r.t. Excess CH2N2 was destroyed by the addition of a few drops of AcOH and vigorous
stirring. The mixture was then diluted with Et2O, and washed with sat. aq. NaHCO3 soln. (1Â), sat. aq. NH4Cl
soln. (1Â) and sat. aq. NaCl soln. (1Â). The org. layer was dried (MgSO4) and concentrated under reduced
pressure. FC afforded the pure diazo ketone.
i
GP 1b: As in GP 1a, except that Et3N (1.05 equiv.) and ClCO2 Bu (1.05 equiv.) were used instead of NMM
and ClCO2Et.
3. Preparation of Homologated Histidine: General Procedure 2 (GP 2). Similar to the procedure reported in
[114], the diazo ketone 2 (1 equiv.) was dissolved in MeOH or THF/BnOH 9 :1 (0.25m) and cooled to À 258
under Ar with the exclusion of light. A soln. of CF3CO2Ag (0.11 equiv.) in Et3N (2.3 equiv.) was added, and the
resulting mixture was slowly allowed to warm to r.t. in the dark. After completion of the reaction (TLC control,
4 ± 6 h) the solvent was removed under reduced pressure, and Ts deprotection was performed according to a
known procedure [89]: Ac2O(70 equiv.) and pyridine (1 equiv.) were added to the residue, and the mixture was
stirred until disappearance of the Ts-protecting group of the 1H-imidazole (TLC control). If necessary, Ac2O
and pyridine were added again. To the mixture was then added, at 08, MeOH (6.6 ml/mmol of 2), and stirring
was continued for another h. The solvent was concentrated under reduced pressure, the residue taken up in H2O,
and the pH was adjusted to ca. 8 by addition of solid Na2CO3. After extraction with CH2Cl2 (5Â) the combined
org. layers were dried (MgSO4) and concentrated under reduced pressure. FC afforded the pure b3-
homohistidine derivative.
4. Tr Protection: General Procedure 3 (GP 3). GP 3a: Similar to the procedure reported in [115], the amino
acid was dissolved in CHCl3 (1m) and cooled to 08. Et3N (3 equiv.), and a soln. of TrCl or TrBr (2 ± 4 equiv.) in
CHCl3 (2m) was added dropwise. Stirring was continued for 2 ± 3 d as the mixture was allowed to warm to r.t.
Thereafter, 2m AcOH (1 equiv.) was added; the CHCl3 was evaporated, and the residue was extracted with
AcOEt (3Â). The combined org. layers were dried (MgSO4) and concentrated under reduced pressure. FC
afforded the pure Tr-protected amino acid.
GP 3b: As in GP 3a, except that the amino acid dissolved in CHCl3 (0.1m) was treated with solid TrCl or
TrBr (2 ± 4 equiv.).
5. Fmoc Protection: General Procedure 4 (GP 4). GP 4a: The N-deprotected amino acid was dissolved in
0.6m Na2CO3 (3.7 equiv.) and treated with a soln. of Fmoc-OSu (1.6 equiv.) in acetone (0.2m). If necessary, the
pH was re-adjusted to 9 ± 10 with additional aq. Na2CO3 soln., and the mixture was stirred for 2.5 h. H2Owas
then added, and the mixture was extracted with Et2O(2 Â). The org. phase was re-extracted with 0.3m Na2CO3
(1Â); the combined aq. phases were carefully adjusted to pH 1 ± 2 at 08 with 1m HCl and extracted with AcOEt

Helvetica Chimica Acta ± Vol. 87 (2004)
3147
(3Â). The combined org. layers were dried (MgSO4) and concentrated under reduced pressure. FC yielded the
pure product.
GP 4b: The N-deprotected amino acid was dissolved in 0.15m Na2CO3 (2 ± 3 equiv.) and treated with a soln.
of FmocOSu (1 ± 1.2 equiv.) in acetone (0.1m). If necessary, the pH was re-adjusted to 9 ± 10 with additional aq.
Na2CO3 soln., and the mixture was stirred at r.t. for 4 h. The acetone was carefully removed under reduced
pressure at 308, and the resulting mixture was diluted with H2O. At this point, the pH of the soln. was adjusted to
9 ± 10 using 0.6m aq. Na2CO3. The aq. mixture was then extracted with Et2O(2 Â). The aq. phase was separated,
cooled to 08, and AcOEt was added to the mixture. With continuous stirring of the biphasic system at 08, the pH
of the aq. phase was adjusted to 4 ± 5 by slow addition of 10% aq. citric acid. The org. layer was separated, and
the aq. layer was extracted with AcOEt (2Â). The combined org. layers were washed with sat. aq. NaCl soln.,
dried (Na2SO4), and concentrated under reduced pressure. FC yielded the pure product.
6. Hydroxymethylation of Acyloxazolidinones: General Procedure 5 (GP 5). GP 5a: Similar to the
procedure reported in [64], the corresponding acyloxazolidinone was dissolved in CH2Cl2 (0.2m) and cooled to
ca. À 208, and TiCl4 (1.05 equiv.), quickly followed by Et3N (1.1 equiv.), was added to the soln. (T<À 108). The
formed dark red soln. was stirred for 30 min at À 108, then solid 1,3,5-trioxane (1.2 equiv.) and TiCl4 (1.1 equiv.)
were added, and the soln. was stirred for an additional 3 ± 6 h at ca. 08 (TLC control). A white suspension
formed, and the red color disappeared. The reaction was quenched with sat. aq. NH4Cl soln., diluted with Et2O,
and washed with 1m HCl (2Â), 1m NaOH (1Â), and sat. aq. NaCl soln (1Â). The org. layer was dried (MgSO4)
and concentrated under reduced pressure. FC afforded the pure product.
GP 5b: As in GP 5a, except that the reaction was quenched with 1m NaOH and diluted with Et2O. The org.
phase was separated, washed with 1m NaOH and sat. aq. NaCl soln., and each aq. phase was re-extracted with
Et2O.
7. Hydrogenolysis of Bn Esters and N3 Groups: General Procedure 6 (GP 6). GP 6a: The corresponding
substrate was dissolved in MeOH (0.17 ± 0.02m) and ca. 10% (w/w) Pd/C (10%) was added. The apparatus was
evacuated and flushed with H2 (3Â), and the soln. was stirred under an atmosphere of H2 (balloon) for 1 ± 2 h
(TLC control). Subsequent filtration through Celite and concentration under reduced pressure yielded the
crude product, which was used in the next step without further purification.
GP 6b: The corresponding substrate was dissolved in EtOH (0.1m) and ca. 10% (w/w) Pd/C was added. The
apparatus was evacuated and flushed with H2 (3Â), and the soln. was stirred under an atmosphere of H2
(balloon) for 2 h. The mixture was then filtered through Celite and concentrated under reduced pressure. For the
case of compounds containing an N3 group, the reaction progress was monitored by IR spectroscopy, since the
N3 group shows very strong asymmetric stretching vibrations in the range 2250 ± 2080 cmÀ1. If the reaction was
not complete, the mixture was treated for a further 2 h under the same conditions. The crude product was used in
the next step without further purification.
8. Phth Deprotection: General Procedure 7 (GP 7). To a soln. of the Phth-protected compound in BuOH
(0.06 ± 0.2m) at r.t., (CH2NH2)2 (4 equiv.) was added dropwise under Ar, and the mixture was stirred for 1 ± 2 h.
The solvent was then co-evaporated with toluene (3Â) and with EtOH (2Â) to give the crude deprotected
amine. FC afforded the pure compound.
9. Mitsunobu Reaction: General Procedure 8 (GP 8). GP 8a: Similar to the procedure reported in [116], a
soln. of HN3 in benzene was prepared from NaN3 and H2SO4, and its conc. was determined by titration with
NaOH on phenolphthalein. To a stirred soln. of the corresponding alcohol in benzene (0.13m) cooled at 08, solid
Ph3P (1.1 equiv.) was added, followed by dropwise addition of the HN3 soln. (1.1 equiv.) and DIAD (1.1 equiv.).
The soln. was stirred for 50 min at r.t., and the benzene was then evaporated under reduced pressure. FC gave
the pure compound.
GP 8b: To a stirred soln. of the corresponding alcohol in THF (0.1m) at 08, DIAD (1 equiv.), Ph3P (1 equiv.)
and (PhO)2P(O)N3 (1.2 equiv.) were added. The mixture was strirred at 08 for 4 h as a white precipitate formed.
The mixture was stirred for additional 14 h at r.t., and the solvent was evaporated under reduced pressure. FC
afforded the pure compound.
(S)-1-Diazo-3-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-{1-[(4-methylphenyl)sulfonyl)]-1H-im-
idazol-4-yl}butan-2-one (Fmoc-(S)-His(Ts)-CHN2 ; 1). Transformation of Fmoc-l-His(Ts)-OH (5.00 g,
9.41 mmol) according to GP 1a and FC (CH2Cl2/Et2O5 :1) yielded 1 (2.97 g, 56%). Yellow solid. Rf (CH2Cl2/
Et2O5 :1) 0.12. [ a]rD:t: ˆ À26.0 (c ˆ 0.99, CHCl3). IR (CHCl3): 3423w, 3008w, 2113s, 1720s, 1639m, 1596w, 1507m,
1476w, 1450w, 1385s, 1362s, 1175s, 1078s, 1045w. 1H-NMR (400 MHz, CDCl3): 2.37 (s, Me); 2.91 ± 3.04 (m, CH2);
4.17 (t, J ˆ 6.7, CH); 4.33 ± 4.37 (m, CH); 4.41 ± 4.45 (m, CH2O); 5.28 (br. s, CHN2); 6.19 (br. d, NH); 7.07 (s, 1 Im
H); 7.28 ± 7.33 (m, 4 arom. H); 7.37 ± 7.42 (m, 2 arom. H); 7.51 ± 7.59 (m, 2 arom. H); 7.77 (d, J ˆ 8.4, 2 arom. H);
7.92 (s, 1 Im H). 13C-NMR (100 MHz, CDCl3): 21.65 (Me); 29.75 (CH2); 47.26, 53.95, 57.56 (CH); 66.88 (CH2);

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114.98, 120.00, 125.04, 125.17, 127.10, 127.32, 127.77, 130.43 (CH); 134.79 (C); 136.37 (CH); 140.10, 141.37, 143.69,
146.39, 155.98, 193.21 (C). MALDI-MS: 578.2 (2.47), 528.2 (61.77), 414.1 (12.22), 392.2 (47.15), 390.1 (42.36),
‡
374.1 (100.00), 350.1 (53.95), 311.0 (15.44), 252.1 (43.65). HR-MALDI-MS: 528.1591 ([C29H26N3O5S] ; calc.
528.1593).
(S)-3-{[(tert-Butoxy)carbonyl]amino}-1-diazo-4-{1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl}butan-
2-one (Boc-(S)-His(Ts)-CHN2; 2). Transformation of Boc-l-His(Ts)-OH (25.0 g, 61.0 mmol) according to GP
1b and FC (CH2Cl2/Et2O 5 :1 ! CH2Cl2/Et2O1:1) yielded 2 (22.8 g, 86%). Yellow foam. Rf (CH2Cl2/Et2O 5 :1)
0.12. [a]rD:t: ˆ À21.8 (c ˆ 1.00, CHCl3). IR (CHCl3): 3428w, 3128w, 2981w, 2112s, 1708s, 1638m, 1596w, 1496m,
1382s, 1368s, 1174s, 1092w, 1079m, 1050w, 1024w. 1H-NMR (400 MHz, CDCl3): 1.42 (s, tBu); 2.43 (s, Me); 2.90
(dd, J ˆ 14.8, 5.3, 1 H, CH2); 3.01 (dd, J ˆ 14.8, 5.8, 1 H, CH2); 5.33 ± 5.48 (br. m, CHN); 5.39 (br. s, CHN2);
5.80 ± 5.90 (br. d, NH); 7.06 (s, 1 Im H); 7.35 (d, J ˆ 8.6, 2 arom. H); 7.79 (d, J ˆ 8.4, 2 arom. H); 7.92 (s, 1 Im H).
13C-NMR (100 MHz, CDCl3): 21.72, 28.32 (Me); 29.90 (CH2); 53.81, 57.12 (CH); 80.05 (C); 114.93, 127.35,
130.45 (CH); 134.94 (C); 136.35 (CH); 140.31, 146.37, 155.40, 193.81 (C). MALDI-TOF-MS: 456.1 (7.94), 434.1
(15.87), 406.1 (100.00), 356.5 (30.95), 350.1 (67.46), 270.2 (14.29), 252.1 (43.65). Anal. calc. for C19H23N5O5S
(433.49): C 52.64, H 5.35, N 16.16; found: C 52.72, H 5.36, N 15.96.
Methyl (S)-3-{[(tert-Butoxy)carbonyl]amino}-4-(1H-imidazol-4-yl)butanoate (Boc-(S)-b3hHis-OMe; 3).
A soln. of 2 (22.8 g, 52.6 mmol) in MeOH (0.25 M) was treated according to GP 2. FC(CH2Cl2/MeOH sat. with
NH3 12 :1) of the crude product yielded 3 (13.5 g, 91%). White solid. Rf (CH2Cl2/MeOH 15 :1) 0.26. [a]Dr:t:
ˆ
À5.5 (c ˆ 1.03, CHCl3). IR (CHCl3): 3436w, 2981m, 1729s, 1703s, 1503s, 1438m, 1368m, 1165s, 1050w, 824w.
1H-NMR (400 MHz, CDCl3): 1.42 (s, tBu); 2.47 (dd, J ˆ 15.4, 6.5, 1 H, CH2CO2Me); 2.56 (dd, J ˆ 15.4, 5.8, 1 H,
CH2CO2Me); 2.88 (d, J ˆ 6.1, CH2CH); 3.68 (s, MeO); 4.17 ± 4.24 (br. m, CHN); 5.53 (br. s, NH); 6.84 (s, 1 Im
H); 7.58 (s, 1 Im H). 13C-NMR (100 MHz, CDCl3): 28.38 (Me); 31.31, 38.25 (CH2); 47.60 (CH); 51.77 (Me);
79.57 (C); 135.02 (CH); 155.46, 172.20 (C). MALDI-MS: 306.1 (18.15), 284.1 (100.00), 228.1 (37.07), 184.1
(69.17). Anal. calc. for C13H21N3O4 (283.33): C 55.11, H 7.47, N 14.83; found: C 55.12, H 7.34, N 14.86.
Benzyl (S)-3-{[(tert-Butoxy)carbonyl]amino}-4-(1H-imidazol-4-yl)butanoate (Boc-(S)-b3hHis-OBn; 4).
A soln. of 2 (390 mg, 0.88 mmol) in THF/BnOH 9 :1 (0.25m) was treated according to GP 2. FC (CH2Cl2/
MeOH 12 :1) and recrystallization (CH2Cl2/hexane) of the crude product yielded 4 (276 mg, 85%). White solid.
Rf (CH2Cl2/MeOH 14 :1) 0.19. M.p. 123 ± 1248. [a]rD:t: ˆ À6.9 (c ˆ 1.02, CHCl3). IR (CHCl3): 3432w, 2982m,
1729s, 1704s, 1502s, 1456w, 1392m, 1368m, 1162s, 1048w, 824w. 1H-NMR (400 MHz, CDCl3): 1.41 (s, tBu); 2.49
(dd, J ˆ 15.4, 6.7, 1 H, CH2CO2Bn); 2.60 (dd, J ˆ 15.4, 5.8, 1 H, CH2CO2Bn); 2.85 (d, J ˆ 6.0, CH2CH); 4.21 ± 4.23
(br. m, CHN); 5.12 (s, PhCH2); 5.50 (br. s, NH); 6.77 (s, 1 Im H); 7.30 ± 7.39 (m, 5 arom. H); 7.54 (s, 1 Im H).
13C-NMR (100 MHz, CDCl3): 28.35 (Me); 31.15, 38.35 (CH2); 47.61 (CH); 66.49 (CH2); 79.52 (C); 128.30,
128.33, 128.58, 134.94 (CH); 135.69, 155.38, 171.51 (C). MALDI-MS: 398.1 (2.51), 382.2 (37.23), 360.2 (45.61),
304.1 (20.31), 282.1 (21.96), 260.1 (100.00). Anal. calc. for C19H25N3O4 (359.42): C 63.49, H 7.01, N 11.69; found:
C 63.49, H 6.94, N 11.66.
Methyl (S)-3-{[(tert-Butoxy)carbonyl]amino}-4-[1-(triphenylmethyl)-1H-imidazol-4-yl]butanoate (Boc-
(S)-b3hHis(Tr)-OMe; 5). A soln. of 3 (207 mg, 0.73 mmol) in CHCl3 (1m) was treated with Et3N (0.31 ml,
3 equiv.) and TrCl (407 mg, 2 equiv.) according to GP 3a for 55 h. FC (AcOEt/hexane 1:3 ! AcOEt/hexane
2 :1) of the crude product yielded 5 (378 mg, quant.). White foam. Rf (AcOEt/hexane 2 :1) 0.41. M.p. 123 ± 1248.
[a]Dr:t: ˆ ‡0.4 (c ˆ 2.00, CHCl3). IR (CHCl3): 3435w, 3008w, 2980w, 1728s, 1703s, 1495s, 1445m, 1367m, 1165s,
1049w, 869w. 1H-NMR (400 MHz, CDCl3): 1.40 (s, tBu); 2.39 (dd, J ˆ 15.4, 6.9, 1 H, CH2CO2Me); 2.55 (dd, J ˆ
15.4, 5.7, 1 H, CH2CO2Me); 2.80 (d, J ˆ 5.6, CH2CH); 3.61 (s, MeO); 4.18 ± 4.25 (br. m, CHN); 5.76 (br. d, NH);
6.60 (s, 1 Im H); 7.10 ± 7.14 (m, 6 arom. H); 7.31 ± 7.34 (m, 9 arom. H); 7.36 (s, 1 Im H). 13C-NMR (100 MHz,
CDCl3): 28.42 (Me); 31.91, 38.16 (CH2); 47.62 (CH); 51.54 (Me); 75.23, 79.04 (C); 119.89, 128.06, 129.75 (CH);
137.35 (C); 138.76 (CH); 142.45, 155.26, 172.09 (C). MALDI-MS: 564.2 (1.36), 548.2 (27.36), 526.3 (2.19), 448.2
(15.60), 243.1 (100.00). Anal. calc. for C32H35N3O4 (525.65): C 73.12, H 6.68, N 7.99; found: C 73.16, H 6.68, N
7.99.
(S)-3-{[(tert-Butoxy)carbonyl]amino}-4-[1-(triphenylmethyl)-1H-imidazol-4-yl]butanoic Acid (Boc-(S)-
b3hHis(Tr)-OH; 6). Similar to the procedure reported in [117], a soln. of 5 (378 mg, 0.72 mmol) in MeOH
(0.03m) was cooled to 08, treated with 0.1m LiOH (11 ml, 1.5 equiv.), and stirred at this temp. for 7 h. The
mixture was then neutralized by the addition of 10% aq. HCl soln., MeOH was removed under reduced
pressure, and the aq. layer was extracted with AcOEt (4Â). The combined org. layers were dried (MgSO4) and
concentrated under reduced pressure to yield 6 (365 mg, quant.). White foam. The product was used in the next
step without further purification. MALDI-MS: 550.2 (1.17), 534.2 (1.62), 518.2 (1.85), 410.0 (1.07), 243.1
‡
(100.00). HR-MALDI-MS: 534.2136 (C31H33N3NaO4 ; calc. 534.2369).

Helvetica Chimica Acta ± Vol. 87 (2004)
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(S)-4-(1H-Imidazol-4-yl-3-phthalimidobutanoic Acid Hydrochloride (Phth-(S)-b3hHis-OH ´ HCl; 7).
Compound 3 (13.5 g, 47.6 mmol) was dissolved in CH2Cl2 (0.5m) and cooled to 08. An equal volume of TFA
and some drops of TIS (0.01 equiv.) were added, and the mixture was stirred for 4 h at 08 (TLC control). The
solvent was evaporated, the residue was taken up in dried toluene or CHCl3 and evaporated twice. The resulting
trifluoroacetate salt was dried under h.v., identified by NMR, and used without further purification. A soln. of
the trifluoroacetate salt in 1m NaOH (200 ml, 0.24m) was cooled to 08 and stirred overnight. The mixture was
then acidified to pH 7 with 1m HCl and concentrated under reduced pressure. The oily residue was dissolved in
H2O(80 ml), and solid Na 2CO3 (13.6 g, 1 equiv.) was added. Upon dissolution, PhthNCO2Et (10.4 g, 1 equiv.)
was added at once, and the mixture was stirred for 2 h. The mixture was filtered, adjusted to pH 7 with 2m HCl,
and concentrated under reduced pressure. The green residue was taken in 300 ml of MeOH, stirred for 20 min,
and filtered. The MeOH soln. was evaporated, and the product was dissolved in H2O, and the pH was adjusted to
1 ± 2. The precipitate formed was collected by suction and washed with 2m HCl to yield 7 (10.7 g, 67%). Slightly
brownish solid. The product was used in the next step without further purification. 1H-NMR (300 MHz,
CD3OD): 2.80 (dd, J ˆ 16.5, 6.0, 1 H, CH2); 3.20 ± 3.28 (m, CH2); 3.46 (dd, J ˆ 15.2, 10.4, 1 H, CH2); 4.90 ± 5.00
(m, CHN); 7.29 (s, 1 Im H); 7.80 (s, 4 Phth H); 8.76 (s, 1 Im H).
(S)-3-Phthalimido-4-[1-(triphenylmethyl)-1H-imidazol-4-yl]butanoic Acid (Phth-(S)-b3hHis(Tr)-OH; 8).
To a suspension of 7 (10.1 g, 30 mmol) in CHCl3/DMF 2 :1 (0.5m), cooled to 08, Et3N (16.9 ml, 4 equiv.) and a
soln. of TrBr (10.7 g, 1.1 equiv.) in CHCl3/DMF 2 :1 (70 ml) were added dropwise. After TLC control (5 h
later), another portion of TrBr (9.77 g, 1 equiv.) was added as solid, and the mixture was stirred overnight.
MeOH (100 ml) was then added, and the mixture was heated at 508 for 2 h. The solvent was removed under
reduced pressure, the crude product was dissolved in AcOEt, and washed with 10% citric acid (3Â) and sat. aq.
NaCl soln. (1Â). The org. phase was dried (MgSO4) and concentrated under reduced pressure. FC (CH2Cl2 !
AcOEt/AcOH 10 :0.3) yielded 8 (12.3 g, 75%). White solid. Rf (CH2Cl2/ MeOH 9 :1) 0.37. [a]rD:t: ˆ À58.5 (c ˆ
1.04, CHCl3). IR (neat): 3058w, 2930w, 2641w, 2323w, 2050w, 1982w, 1771w, 1705s, 1607w, 1491w, 1467w, 1444w,
1390m, 1369m, 1334w, 1284w, 1215w, 1186w, 1156w, 1131w, 1107w, 1087w, 1037w, 977w, 906w, 871m, 751m, 719s,
699s. 1H-NMR (400 MHz, CDCl3): 2.82 (dd, J ˆ 15.5, 4.4, 1 H, CH2CO2H); 3.19 (dd, J ˆ 15.5, 10.3, 1 H,
CH2CO2H); 3.31 (d, J ˆ 8.1, CH2CH); 5.16 ± 5.24 (br. m, CHN); 6.33 (d, J ˆ 1.3, 1 Im H); 6.88 (d, J ˆ 7.4, 6 arom.
H); 7.10 ± 7.14 (m, 6 arom. H); 7.19 ± 7.23 (m, 3 arom. H); 7.53 (d, J ˆ 1.3, 1 Im H); 7.69 ± 7.75 (m, 4 Phth H).
13C-NMR (100 MHz, CDCl3): 29.42, 38.79 (CH2); 48.92 (CH); 75.51 (C); 119.45, 123.22, 127.95, 128.00, 129.51
(CH); 131.82 (C); 133.71 (CH); 136.19 (C); 138.22 (CH); 141.74, 167.76, 173.43 (C). MALDI-MS: 586.2 (4.64),
‡
564.2 (17.63), 322.1 (7.30), 300.1 (24.29), 243.1 (100.00). HR-MALDI-MS: 564.1896 (C34H27N3NaO4 ; calc.
564.1824).
(S)-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-4-[1-(triphenylmethyl)-1H-imidazol-4-yl]butanoic
Acid (Fmoc-(S)-b3hHis(Tr)-OH; 9). To a suspension of 8 (10.7 g, 19.7 mmol) in EtOH (0.23m) a 1m N2H4 soln.
in EtOH (19.7 ml, 1 equiv.) was added dropwise, and the mixture was stirred at r.t. for 4 h. The precipitate
formed was filtered off and washed with EtOH. The solvent was evaporated, the crude product was dissolved in
THF (200 ml) and placed in the fridge overnight. The precipitate formed was filtered, and the solvent was
concentrated under reduced pressure to give the expected product. The crude product was Fmoc-protected
according to GP 4a. FC (AcOEt/AcOH 10 :0.3) and precipitation from hexane yielded 9 (10.1 g, 81%). White
powder. Rf (CH2Cl2/ MeOH 9 :1) 0.35. M.p. 125 ± 1278. [a]rD:t: ˆ À33.0 (c ˆ 1.01, CHCl3). IR (neat): 3049w,
2930w, 2625w, 2455w, 2323w, 2051w, 1919w, 1716s, 1494w, 1446m, 1323w, 1245m, 1155w, 1129w, 1080w, 1044m,
873w, 757s, 740s, 700s, 661w, 638w. 1H-NMR (400 MHz, CD3OD): 2.53 (d, J ˆ 6.2, CH2); 2.76 (dd, J ˆ 14.7, 9.4,
1 H, CH2); 2.86 (dd, J ˆ 14.7, 4.9, 1 H, CH2); 4.04 ± 4.08 (br. t, CH); 4.12 ± 4.25 (m, 3 H, CH2, CHN); 6.88 (s, 1 Im
H); 7.06 ± 7.08 (m, 6 arom. H); 7.24 ± 7.38 (m, 13 arom. H); 7.56 (d, J ˆ 7.5, 2 arom. H); 7.68 (s, 1 Im H); 7.78 (d,
J ˆ 7.5, 2 arom. H). 13C-NMR (100 MHz, CD3OD): 33.37, 40.33 (CH2); 48.40, 48.80 (CH); 67.86 (CH2); 77.70
(C); 120.93, 121.44, 126.25, 126.33, 128.13, 128.18, 128.73, 128.79, 129.35, 129.50, 129.84, 130.83 (CH); 137.05 (C);
138.82 (CH); 142.57, 143.04, 145.19, 145.31, 158.03, 174.73 (C). MALDI-MS: 656.3 (33.64), 414.1 (8.29), 392.2
‡
(41.06), 243.1 (100.00). HR-MALDI-MS: 656.2518 (C41H35N3NaO4 ; calc. 656.2520).
(R)-1-Diazo-3-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-{[(4-methoxy)benzyl]thio}butan-2-one
(Fmoc-(R)-Cys(PMB)-CHN2; 10). Transformation of Fmoc-l-Cys(PMB)-OH (9.5 g, 20.5 mmol) according to
GP 1a for 2 h, and FC (AcOEt/hexane 3 :7) yielded 10 (9.6 g, 96%). Yellow solid. Rf (AcOEt/hexane 4 :6) 0.20.
M.p. 87 ± 918 (dec.). IR (CHCl3): 3429w, 3007w, 2975w, 2850w, 2112s, 1717s, 1609m, 1511s, 1450m, 1302w, 1248s,
1125w, 1036w, 823w. 1H-NMR (300 MHz, CDCl3): 2.76 (d, J ˆ 5.6, CH2); 3.68 (s, CH2); 3.78 (s, Me); 4.22 (t, J ˆ
6.7, CHCH2O); 4.26 ± 4.39 (m, CHN); 4.40 ± 4.57 (m, CH2O); 5.31 (s, CHN2); 4.50 (d, J ˆ 7.5, NH); 6.83 (dd, J ˆ
6.5, 1.9, 2 arom. H); 7.22 (d, J ˆ 8.1, 2 arom. H); 7.26 ± 7.43 (m, 4 arom. H); 7.59 (d, J ˆ 7.2, 2 arom. H); 7.77 (d,

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Helvetica Chimica Acta ± Vol. 87 (2004)
‡
J ˆ 7.5, 2 arom. H). MALDI-MS: 482.1(30), 362 (15), 273 (100). HR-MALDI-MS: 482.1423 (C27H25NNaO4S ;
calc. 482.1397).
(R)-4-{[(Acetamido)methyl]thio}-1-diazo-3-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)butan-2-one
(Fmoc-(R)-Cys(Acm)-CHN2; 11). Transformation of Fmoc-l-Cys(Acm)-OH (7 g, 16.9 mmol) according to GP
1a for 4 h yielded crude 11 (7.4 g). Yellow solid. The crude product was used in the next step without further
putification. The anal. data are in agreement with those reported in [98].
(R)-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-4-{[(4-methoxy)benzyl]thio}butanoic Acid (Fmoc-
(R)-b3hCys(PMB)-OH; 12). Similar to the procedure reported in [95], 10 (7.7 g, 15.8 mmol) was dissolved in
THF/H2O8 :2 (0.09 m), and PhCO2Ag (0.9 g, 4.0 mmol) was added with exclusion of light. The mixture was
ultrasonicated at r.t. for 6 h. THF was evaporated, the pH was adjusted to 1 ± 2 with 1m HCl, and Et2Owas
added. The precipitate formed was filtered off and dissolved in acetone, and the residual AgCl was filtered off
over Celite. The aq. phase was extracted with Et2O(5 Â); the combined org. layers were concentrated under
reduced pressure to give a solid residue, which was crystallized from AcOEt/hexane affording 12 (5.8 g, 77%).
White solid. Rf (AcOEt/hexane 4 :6) 0.14. M.p. 110 ± 1128. [a]rD:t: ˆ À12.5 (c ˆ 1.20, CHCl3). IR (CHCl3): 3429w,
3007w, 2975w, 2850w, 1718s, 1610m, 1512s, 1450m, 1302w, 1248s, 1125w, 1036w, 823w. 1H-NMR (500 MHz,
CDCl3): 2.65 ± 2.74 (m, 2 CH2); 3.68 (s, CH2S); 3.76 (s, Me); 4.11 ± 4.14 (m, CHN); 4.22 (t, J ˆ 6.8, CHCH2O);
4.40 (br. s, CH2O); 5.25 ± 5.31 (br. d, NH); 6.82 (d, J ˆ 7.6, 2 arom. H); 7.20 ± 7.24 (br. d, 2 arom. H); 7.30 (dt, J ˆ
7.4, 1.1, 2 arom. H); 7.39 (t, J ˆ 7.4, 2 arom. H); 7.58 (d, J ˆ7.5, 2 arom H.); 7.75 (d, J ˆ 7.5, 2 arom. H). 13C-NMR
(125 MHz, CDCl3): 34.92, 35.79, 36.91 (CH2); 47.21 (CH); 55.25 (Me); 66.88 (CH2); 77.59, 114.00, 120.00, 125.07,
127.09 (CH); 129.68 (C); 130.04 (CH); 141.33, 143.81, 155.78, 158.74, 174.66 (C). HR-MALDI-MS: 500.1508
‡
(C27H27NNaO5S ; calc. 500.1502). Anal. calc. for C27H27NO5S (477.16): C 67.90, H 5.70, N 2.93, O16.75, S 6.71;
found: C 67.87, H 5.86, N 2.94, S 6.65.
(R)-4-{[(Acetamido)methyl]thio}-3-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)butanoic Acid (Fmoc-
(R)-b3hCys(Acm)-OH; 13). Similar to the procedure reported in [98], a degassed soln. of the crude 11 (7.4 g) in
MeCN/H2O9 :1 (33 ml/g) was irradiated with a low pressure Hg vapor lamp at 0 8 for 24 ± 36 h. The solvent was
evaporated, the yellow oily residue was dissolved in sat. aq. NaHCO3 soln. (300 ml), and the mixture was
extracted with Et2O(5 Â 100 ml). The aq. phase was carefully acidified to pH 1 ± 2 with 1m HCl at 08, and
extracted with AcOEt (5 Â 100 ml). The combined org. layers were concentrated under reduced pressure.
Crystallization (AcOEt/MeOH) yielded pure 13 (3.2 g, 44% over 2 steps). White solid. Rf (AcOEt/MeOH/
AcOH 90 :10 :2) 0.41. [a]rD:t: ˆ À12.6 (c ˆ 1.20, CHCl3). The anal. data are in agreement with those reported in
[98].
(R)-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-4-[(triphenylmethyl)sulfanyl]butanoic Acid (Fmoc-
(R)-b3hCys(Tr)-OH; 14). a) Compound 12 (4.3 g, 9.0 mmol) and anisole (1.8 ml, 16.2 mmol) were dissolved in
THF (0.1m), and carefully degassed with Ar. The soln. was cooled to 08, Hg(OAc)2 (2.9 g, 9.0 mmol) was added
under Ar, and the mixture was stirred until disappearance of the starting material (TLC control, 30 ± 45 min).
THF was evaporated under reduced pressure in an O2-free atmosphere at T< 408, and the residue was dissolved
in degassed THF/H2O1:1 (200 ml). H 2S Gas was bubbled into the mixture for 5 min, the black precipitate was
filtered off on Celite under N2, and washed with degassed THF/H2O1:1 (4 Â 50 ml). THF was evaporated under
reduced pressure in an O2-free atmosphere, and the remaining aq. phase was extracted with degassed CH2Cl2.
The combined org. layers were dried (MgSO4) and concentrated under reduced pressure, in an O2-free
atmosphere. The crude Fmoc-(R)-b3hCys-OH was immediately tritylated under Ar with NMM (2.9 ml,
3 equiv.) and TrCl (8.7 g, 3 equiv.) for 15 h according to GP 3b. FC (CH2Cl2 ! CH2Cl2/AcOH 50 :1) and
precipitation from CH2Cl2/hexane yielded 14 (4.4 g, 82%). White solid.
b) Compound 13 (1.4 g, 3.3 mmol) was dissolved in THF/H2O/AcOH 2 :1:1 (0.04m) and carefully degassed
with Ar. A degassed soln. of Hg(OAc)2 (1.05 g, 3.3 mmol) in THF/H2O/AcOH 2 :1 :1 (0.3m) was added
dropwise over 2 min at r.t. The white suspension was stirred until complete disappearance of the starting
material (TLC control, 30 ± 45 min). H2S Gas was bubbled into the mixture for 5 min, the black precipitate
formed was then filtered off on Celite under N2 and washed with degassed THF/H2O/AcOH 2 :1:1 (2 Â 50 ml).
THF was evaporated under reduced pressure in an O2-free atmosphere, and the remaining aq. phase was
extracted with degassed CHCl3 (3 Â 50 ml). The combined org. layers were dried (MgSO4) and concentrated
under reduced pressure, in an O2-free atmosphere. The crude Fmoc-(R)-b3hCys-OH was immediately tritylated
under Ar with NMM (1.07 ml, 3 equiv.) and TrCl (3.3 g, 3 equiv.) for 15 h according to GP 3b. FC (CH2Cl2 !
CH2Cl2/AcOH 50 :1) and precipitation from CH2Cl2/hexane yielded 14 (1.1 g, 56%). White solid.
Data of 14: Rf (CH2Cl2/AcOH 50 :1) 0.25. M.p. 88 ± 908. [a]rD:t: ˆ ‡28.9 (c ˆ 1.00, MeOH). IR (CHCl3):
3008w, 1719s, 1508m, 1448m, 1248s, 1036w. 1H-NMR (400 MHz, CDCl3): 2.49 ± 2.52 (m, 2 CH2); 3.75 ± 3.88 (m,

Helvetica Chimica Acta ± Vol. 87 (2004)
3151
CHN); 4.18 (t, J ˆ 6.7, CHCH2O); 4.36 (d, J ˆ 6.7, CH2O); 4.90 ± 4.98 (br. d, NH); 7.18 ± 7.21 (m, 3 arom. H);
7.24 ± 7.29 (m, 8 arom. H); 7.35 ± 7.40 (m, 8 arom. H); 7.55 (d, J ˆ 7.4, 2 arom. H); 7.74 (dd, J ˆ 7.4, 3.8, 2 arom. H).
13C-NMR (100 MHz, CDCl3): 31.69, 35.82, 37.37 (CH2); 47.22 (CH); 67.19 (C); 77.22, 119.98, 125.04, 126.88,
127.07, 127.71, 128.02, 129.57 (CH); 141.33, 143.81, 144.46, 155.50, 173.95 (C). MALDI-TOF-MS: 622.0 (100.00).
Anal. calc. for C38H33NO4S (599.7): C 76.10, H 5.55, N 2.34, O10.67, S 5.35; found: C 76.14, H 5.71, N 2.34, S 5.35.
3-Phthalimidopropanoic Acid (Phth-bhGly-OH; 15). A mixture of phthalic anhydride (14.8 g, 0.10 mol)
and H-bhGly-OH (8.9 g, 1 equiv.) was heated in an open flask to 1508 for 2 h. On cooling to r.t., H2O(150 ml)
was added, and the solid was filtered and washed with additional H2O. The solid was dried (h.v.) to yield 15
(20.6 g, 94%). White solid. The product was used in the next step without further purification. 1H-NMR
(300 MHz, CDCl3): 2.76 (t, J ˆ 4.0, CH2CO2H); 3.98 (t, J ˆ 4.1, CH2N); 7.68 ± 7.72 (m, 2 Phth H); 7.81 ± 7.85 (m, 2
Phth. H).
(S)-4-(1-Methylethyl)-3-(3-phthalimidopropanoyl)-5,5-diphenyloxazolidin-2-one (18). To a soln. of 15
(20.6 g, 94.2 mmol) in CH2Cl2 (300 ml) was added a few drops of dioxane, followed by (COCl)2 (10.5 ml,
1.3 equiv.), and the suspension stirred under Ar at r.t. overnight. The resulting soln. was concentrated under
reduced pressure to give the crude acyl chloride 16 (22.4 g, quant.), which was used in the next step without
further purification. White solid. 1H-NMR (300 MHz, CDCl3): 3.35 (t, J ˆ 7.0, CH2COCl); 4.00 (t, J ˆ 7.0,
CH2N); 7.72 ± 7.74 (m, 2 Phth H); 7.84 ± 7.87 (m, 2 Phth H).
Similar to the procedure reported in [64], to an ice-bath-cooled suspension of the auxiliary (S)-17 (22.1 g,
78.5 mmol, 1 equiv.) in THF (315 ml, 0.25m), BuLi (1.6m in hexane, 49.5 ml, 1 equiv.) was added slowly. To the
resulting clear soln., the acyl chloride 16 was added in one portion. Stirring was continued for 2 d as the mixture
was slowly allowed to warm to r.t. The mixture was treated with sat. aq. NH4Cl soln., and diluted with Et2O . The
org. phase was washed with 1m HCl (2Â), 1m NaOH (2Â), and sat. aq. NaCl soln., dried (MgSO4), and
concentrated under reduced pressure. FC (Et2O/pentane 1:1) afforded 18 (32.6 g, 86%). White solid. The anal.
data are in agreement with those reported in [64].
(4S)-3-[(2R)-3-Hydroxy-2-(phthalimidomethyl)propanoyl]-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-
one (19). Compound 18 (7.00 g, 14.5 mmol) was transformed according to GP 5a for 2 ± 3 h. Crystallization
(AcOEt/hexane) and FC (Et2O/pentane 2 :1) of the crude product yielded 19 (12.9 g, 89%). White solid. The
anal. data are in agreement with those reported in [64].
(4S)-3-[(2R)-3-(tert-Butoxy)-2-(phthalimidomethyl)propanoyl]-4-(1-methylethyl)-5,5-diphenyloxazolidin-
2-one (20). A soln. of 19 (5.89 g, 11.5 mmol) in CH2Cl2 (0.23 M) was cooled to À 508 under Ar, and isobutylene
(20 ml) and conc. H2SO4 (50 ml) were added. The reaction flask (Schott bottle) was hermetically closed, warmed
to r.t., and the mixture was stirred for 3 d at r.t. The mixture was cooled again to À 508, opened to the air, slowly
warmed up to r.t., treated with sat. aq. Na2CO3 soln. (200 ml), and diluted with Et2O(400 ml). The org. phase
was washed with sat. aq. NaCl soln., dried (MgSO4), and concentrated under reduced pressure. FC (Et2O/
pentane 1:2 ! 2 :1) of the crude product yielded 20 (6.20 g, 95%). White solid. Rf (Et2O/pentane 1:2) 0.22.
M.p. 149 ± 1508. [a]rD:t: ˆ À116.6 (c ˆ 1.01, CHCl3). IR (CHCl3): 2975w, 1776s, 1718s, 1468w, 1450w, 1395m,
1364m, 1177m, 1094w, 991w. 1H-NMR (400 MHz, CDCl3): 0.75 (d, J ˆ 6.7, Me); 0.93 (d, J ˆ 7.1, Me); 1.12 (s,
tBu); 1.89 ± 1.97 (m, Me2CH); 3.68 (dd, J ˆ 8.8, 6.0, 1 H, CH2); 3.78 (dd, J ˆ 8.8, 4.7, 1 H, CH2); 3.87 (dd, J ˆ 13.9,
6.4, 1 H, CH2); 3.94 (dd, J ˆ 13.9, 6.5, 1 H, CH2); 4.33 ± 4.39 (m, CHCH2); 5.48 (d, J ˆ 2.7, CHN); 7.12 ± 7.42 (m,
10 arom. H); 7.66 ± 7.69 (m, 2 Phth H); 7.72 ± 7.75 (m, 2 Phth H). 13C-NMR (100 MHz, CDCl3): 15.89, 21.78, 27.33
(Me); 30.27 (CH); 36.62 (CH2); 43.61 (CH); 61.51 (CH2); 64.10 (CH); 73.31, 89.11 (C); 123.25, 125.66, 125.89,
127.80, 128.30, 128.37, 128.70 (CH); 132.02 (C); 133.70 (CH); 138.45, 142.20, 152.52, 167.86, 172.09 (C). MALDI-
MS: 607.2 (4.52), 591.2 (100.00), 547.3 (25.27), 469.2 (10.61), 451.2 (11.05), 238.2 (8.98). Anal. calc. for
C34H36N2O6 (568.67): C 71.81, H 6.38, N 4.93; found: C 71.65, H 6.31, N 4.95.
Benzyl (R)-3-(tert-Butoxy)-2-(phtalimidomethyl)propanoate (Phth-(R)-b2hSer(tBu)-OBn; 21). To a soln.
of BnOH (1.72 ml, 16 mmol) in THF (25 ml), BuLi (1.6m in hexane, 6.88 ml, 11 mmol) was added at À 108, and
the mixture was stirred for 20 min. After cooling to À 308, a soln. of 20 (2.46 g, 4.32 mmol) in THF (15 ml) was
added dropwise, and the mixture was stirred at À 308 for 8 h. Sat. aq. NH4Cl soln. (20 ml) was added, THF was
removed under reduced pressure, and the mixture was diluted with Et2O(50 ml). The suspension was stirred for
15 min, and the white solid was filtered off. The residue was washed with Et2O, then dried (h.v.) to yield (S)-17
(1.09 g). White solid. The filtrate was diluted with Et2O, the aq. phase was separated, and the org. phase was
washed with sat. aq. NaCl soln., dried (MgSO4), and concentrated under reduced pressure. FC (Et2O/pentane
1:2 ! 1:1) of the crude product yielded 21 (1.36 g, 80%) with e.r. > 95 :5. Colorless oil. Rf (Et2O/pentane 1:2.5)
0.22. [a]rD:t: ˆ ‡4.5 (c ˆ 1.00, CHCl3). IR (CHCl3): 2976w, 1774w, 1716s, 1469w, 1438w, 1395m, 1365m, 1177w,
1
t
1088w. H-NMR (400 MHz, CDCl3): 1.07 (s, Bu); 3.16 ± 3.22 (m, CH); 3.60 (ddd, J ˆ 13.1, 8.8, 5.9, CH2); 4.01
(ddd, J ˆ 17.6, 13.9, 7.1, CH2); 5.08 (d, J ˆ 12.3, 1 H, PhCH2); 5.15 (d, J ˆ 12.3, 1 H, PhCH2); 7.26 ± 7.31 (m, 5

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arom. H); 7.68 ± 7.70 (m, 2 Phth H); 7.80 ± 7.82 (m, 2 Phth H). 13C-NMR (100 MHz, CDCl3): 27.22 (Me); 37.14
(CH2); 45.10 (CH); 60.66, 66.61 (CH2); 73.12 (C); 123.27, 128.08, 128.21, 128.41 (CH); 132.09 (C); 133.88 (CH);
135.77, 168.13, 171.82 (C). MALDI-MS: 434.1 (2.68), 418.2 (100.00), 322.1 (8.37). Anal. calc. for C23H25NO5
(395.45): C 69.86, H 6.37, N 3.54; found: C 69.86, H 6.44, N 3.38.
Benzyl (R)-2-(Aminomethyl)-3-(tert-butoxy)propanoate (H-(R)-b2hSer(tBu)-OBn; 22). Compound 21
(190 mg, 0.48 mmol) was Phth-deprotected according to GP 7 for 1 h. FC (CH2Cl2 ! CH2Cl2/MeOH 95 :5) of
the crude product yielded 22 (100 mg, 78%). Colorless oil. Rf (CH2Cl2/MeOH 9 :1) 0.13. [a]rD:t: ˆ ‡11.2 (c ˆ 0.40,
CHCl3). 1H-NMR (400 MHz, CDCl3): 1.14 (s, tBu); 1.41 (m, NH2); 2.71 ± 2.68 (m, CHCH2); 2.96 (dd, J ˆ 13.0,
5.1, 1 H, CH2); 3.03 (dd, J ˆ 13.0, 7.2, 1 H, CH2) ; 3.55 (dd, J ˆ 8.8, 6.5, 1 H, CH2); 3.61 (dd, J ˆ 8.8, 6.1, 1 H,
CH2); 5.17 (d, J ˆ 12.4, PhCH2); 7.37 ± 7.29 (m, 5 arom. H). 13C-NMR (100 MHz, CDCl3): 27.35 (Me); 41.52
(CH2); 49.82 (CH); 60.71, 66.12 (CH2); 73.04 (C); 128.07, 128.12, 125.51 (CH); 136.09, 173.42 (C). HR-MALDI-
‡
MS: 266.1749 (C15H24NO3 ; calc. 266.1757).
(R)-3-(tert-Butoxy)-2-[({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)methyl]propanoic Acid (Fmoc-(R)-
b2hSer(tBu)-OH; 23). Transformation of compound 22 (1.10 g, 4.15 mmol) in MeOH (0.17 M) according to GP
6a for 2 h gave crude 23 (720 mg, quant.). White solid. Part of the solid (370 mg, 2.11 mmol) was then Fmoc-
protected according to GP 4b for 4 h. FC (AcOEt/pentane/AcOH 3 :7:0.02) of the crude product yielded 23
(675 mg, 80%). White solid. Rf (AcOEt/hexane/AcOH 1:1:0.01) 0.27. M.p. 59 ± 628. IR (CHCl3): 3446w, 2974m,
t
1753m, 1718s, 1513s, 1446m, 1364m, 1267w, 1092w. 1H-NMR (500 MHz, CDCl3): 1.24 (s, Bu); 2.85 ± 2.75 (m,
CHCO2H); 3.60 ± 3.45 (m, CH2); 3.60 ± 3.56 (m, 1 H, CH2); 3.70 (dd, J ˆ 8.8, 5.4, 1 H, CH2); 4.21 (t, J ˆ 7.1,
CHCH2O); 4.38 (d, J ˆ 7.1, CHCH2O); 5.46 ± 5.45 (br. t, NH); 7.31 (t, J ˆ 7.4, 2 arom. H); 7.40 (t, J ˆ 7.4, 2 arom.
H); 7.58 (d, J ˆ 7.4, 2 arom. H); 7.76 (d, J ˆ 7.4, 2 arom. H). 13C-NMR (125 MHz, CDCl3): 27.29 (Me); 39.59
(CH2); 45.57, 47.20 (CH); 60.45, 66.89 (CH2); 75.20 (C); 120.00, 125.06, 127.06, 127.71 (CH); 141.32, 143.85,
143.89, 156.58, 174.69 (C). MALDI-MS: 442.2 (10.24), 421.2 (25.30), 420.2 (100.00), 364.1 (21.95). HR-
‡
MALDI-MS: 420.1782 (C23H27NNaO5 ; calc. 420.1785). Anal. calc. for C23H27NO5 (397.47): C 69.50, H 6.85, N
3.52; found : C 69.22, H 7.21, N 3.28.
Benzyl (R)-3-(tert-Butoxy)-2-[(2,4-dinitrophenyl)amino]propanoate (24). Compound 21 (100 mg,
0.25 mmol) was Phth-deprotected according to GP 7 for 2 h. FC (CH2Cl2) afforded an oily residue that was
suspended in H2Oat 0 8. Then, NaHCO3 (25 mg, 1.2 equiv.) and a soln. of 1-fluoro-2,4-dinitrobenzene (54 mg,
1.2 equiv.) in EtOH (0.5 ml) were added to the mixture. After 10 min stirring at 08, sat. aq. NH4Cl soln. (5 ml)
and Et2O(10 ml) were added to the mixture. The org. phase was washed with sat. aq. NaCl soln., dried
(MgSO4), and concentrated under reduced pressure. FC (Et2O/pentane 1:2 ! 2 :1) of the crude product
1
t
yielded 24 (63 mg, 55%). Yellow oil. Rf (Et2O/pentane 1:3) 0.28. H-NMR (300 MHz, CDCl3): 1.18 (s, Bu);
3.03 ± 2.97 (m, CHCH2); 3.76 ± 3.63 (m, CH2); 3.85 ± 3.78 (m, CH2); 5.20 ± 5.15 (m, PhCH2); 7.02 (d, J ˆ 9.7, 1
arom. H); 7.35 ± 7.30 (m, 5 arom. H); 8.20 (dd, J ˆ 9.7, 2.8, 1 arom. H); 8.93 ± 8.90 (m, NH); 9.10 (d, J ˆ 2.8, 1
‡
arom. H). HR-MALDI-MS: 454.1580 (C21H25N3NaO7 ; calc. 454.1591).
(4S)-4-(1-Methylethyl)-5,5-diphenyl-3-{(2S)- and (2R)-2-(phthalimidomethyl)-3-[(triphenylmethyl)sulfan-
yl]propanoyl}oxazolidin-2-one (25). Bu3P (6.91 ml, 2.1 equiv.) was added dropwise at r.t. under Ar to a soln. of
the (2'S,4S)-19 (6.70 g, 13.1 mmol) and Ph3CSH (6.30 g, 2.6 equiv.) in anh. THF (300 ml). Then, ADDP (6.91 g,
2.1 equiv.) was added as a solid in one portion. The mixture was stirred at r.t. under Ar for 1 h, as the color of the
mixture changed from yellow to colorless, and a white precipitate was formed. Hexane (50 ml) was added, and
the white precipitate was filtered off (auxiliary) and washed with hexane. The filtrate was then evaporated under
reduced pressure. FC (Et2O/pentane 1:2 ! 1:1) of the crude product yielded first (2'R,4S)-25 (1.60 g, 16%)
and then (2'S,4S)-25 (7.10 g, 71%). White foams.
Data of (2'R,4S)-25: Rf (Et2O/pentane 1:2) 0.24. M.p. 151 ± 1548. [a]rD:t: ˆ À170 (c ˆ 1.00, CHCl3). IR
(CHCl3): 3062w, 3008w, 1781s, 1717s, 1493w, 1469w, 1448w, 1395m, 1366m, 1322w, 1175m, 990m. 1H-NMR
(400 MHz, CDCl3): 0.66 (d, J ˆ 7.0, Me); 0.88 (d, J ˆ 7.0, Me); 1.83 (m, Me2CH); 2.03 (dd, J ˆ 12.8, 4.0, 1 H,
CH2S); 2.83 (dd, J ˆ 12.8, 10.6, 1 H, CH2S); 2.92 (m, CHCH2); 3.60 (dd, J ˆ 14.1, 6.1, 1 H, CH2N); 3.77 (dd, J ˆ
14.1, 4.3, 1 H, CH2N); 5.27 (d, J ˆ 2.5, CHN); 6.72 ± 6.76 (m, 1 arom. H); 6.88 ± 6.93 (m, 2 arom. H); 7.06 ± 7.32
(m, 20 arom. H); 7.60 ± 7.63 (m, 2 Phth H); 7.71 ± 7.74 (m, 2 Phth H). 13C-NMR (100 MHz, CDCl3): 15.60, 21.26
(Me); 30.08 (CH); 31.84, 39.23 (CH2); 43.51, 65.00 (CH); 66.93, 89.88 (C); 123.24, 125.80, 125.85, 126.55, 127.78,
127.85, 128.07, 128.28, 128.51, 128.66, 129.53 (CH); 132.06 (C); 133.85 (CH); 138.47, 141.86, 144.43, 152.54,
167.71, 172.19 (C). MALDI-MS: 795.3 (18.70), 794.3 (53.81), 793.3 (100.00), 473.2 (27.80). HR-MALDI-MS:
‡
793.2715 (C49H42N2NaO5S ; calc. 793.2712). Anal. calc. for C49H42N2O5S (770.93): C 76.34, H 5.49, N 3.63, S
4.16; found : C 76.30, H 5.77, N 3.64, S 4.12.
Data of (2'S,4S)-25: Rf (Et2O/pentane 1:2) 0.18. M.p. 188 ± 1898. [a]rD:t: ˆ À54 (c ˆ 1.00, CHCl3). IR
(CHCl3): 3006w, 1778s, 1719s, 1493w, 1469w, 1449w, 1394m, 1363m, 1319w, 1085w, 1053w, 991m. 1H-NMR

Helvetica Chimica Acta ± Vol. 87 (2004)
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(400 MHz, CDCl3): 0.7 (d, J ˆ 6.9, Me); 0.9 (d, J ˆ 6.9, Me); 1.92 (m, Me2CH); 2.28 (dd, J ˆ 11.9, 5.9, 1 H,
CH2S); 2.66 (dd, J ˆ 11.9, 7.9, 1 H, CH2S); 3.48 (dd, J ˆ 13.8, 5.8, 1 H, CH2N); 3.68 (dd, J ˆ 13.8, 7.3, 1 H,
CH2N); 4.30 (m, CHCH2); 5.36 (d, J ˆ 2.9, CHN); 6.95 ± 7.43 (m, 25 arom. H); 7.67 ± 7.68 (m, 4 Phth H).
13C-NMR (100 MHz, CDCl3): 16.16, 21.69 (Me); 30.07 (CH); 32.54, 38.62 (CH2); 41.75, 64.70 (CH); 67.11, 89.16
(C); 123.31, 125.48, 125.84, 126.63, 127.87, 128.25, 128.32, 128.56, 129.60 (CH); 131.83 (C); 133.66 (CH); 138.19,
142.05, 144.41, 152.18, 167.34, 172.05 (C). MALDI-MS: 795.3 (18.90), 794.3 (55.23), 793.2 (100.00), 473.2
‡
(34.14), 243.1 (22.83). HR-MALDI-MS: 793.2715 (C49H42N2NaO5S ; calc. 793.2712). Anal. calc. for
C49H42N2O5S (770.93): C 76.34, H 5.49, N 3.63, S 4.16; found: C 76.28, H 5.61, N 3.59, S 4.03.
2-(Trimethylsilyl)ethyl (S)-2-(Phthalimidomethyl)-3-[(triphenylmethyl)sulfanyl]propanoate (26). To a
soln. of 2-(trimethylsilyl)ethanol (2.0 ml, 14.02 mmol) in THF (60 ml), BuLi (1.6m in hexane; 6.72 ml,
10.75 mmol) was added dropwise at À 408, and the mixture was stirred for 15 min at À 308. After cooling to
À 408, a soln. of (2'S,4S)-25 (3 g, 3.89 mmol) in THF (16 ml) was added dropwise, and the mixture was stirred for
30 min at À 408. At this point, the soln. was slowly warmed to À 308 and stirred for additional 5 h. The reaction
was monitored by TLC in order to limit the degradation formed during the reaction. As soon as degradation
occurred, the reaction was quenched although not completed. Sat. aq. NH4Cl soln. (200 ml) and Et2O(400 ml)
were added, the formed white precipitate was filtered off (free auxiliary), and the aq. phase was re-extracted
with Et2O(400 ml). The org. layers were washed with sat. aq. NaCl soln., dried (MgSO 4), and concentrated
under reduced pressure. FC (Et2O/pentane 1:3 ! 1:2) of the crude product yielded, besides the unreacted
starting material 25 (809 mg, 27%), (S)-26 (1.3 g, 55%). Colorless oil. Rf (Et2O/pentane 1:2) 0.46. [a]rD:t: ˆ ‡20
(c ˆ 2.85, CHCl3). IR (CHCl3): 3007w, 2956w, 1775m, 1719s, 1489w, 1469w, 1443w, 1396m, 1361m. 1H-NMR
(400 MHz, CDCl3): À 0.03 (s, 3 Me); 0.81 ± 0.87 (m, CH2Si); 2.15 (dd, J ˆ 12.3, 5.22, 1 H, CH2S); 2.55 ± 2.61 (m,
CHCH2); 2.66 (dd, J ˆ 12.3, 8.7, 1 H, CH2S); 3.60 (dd, J ˆ 13.8, 6.7, 1 H, CH2N); 3.73 (dd, J ˆ 13.8, 7.3, 1 H,
CH2N); 4.04 ± 4.12 (m, CH2O); 7.08 ± 7.12 (m, 3 arom. H); 7.16 ± 7.24 (m, 6 arom. H); 7.32 ± 7.36 (m, 6 arom. H);
7.67 ± 7.70 (m, 2 Phth H); 7.77 ± 7.80 (m, 2 Phth H). 13C-NMR (100 MHz, CDCl3): À 1.52 (Me); 17.20, 31.24, 39.08
(CH2); 44.55 (CH); 63.48 (CH2); 67.15 (C); 123.32, 126.66, 127.86, 129.60 (CH); 132.00 (C); 133.94 (CH); 144.51,
167.69, 171.99 (C). MALDI-MS: 793.3 (17.80), 632.2 (12.91), 631.2 (44.14), 630.2 (100.00), 602.2 (18.04), 358.1
‡
(20.33), 244.1 (12.73). HR-MALDI-MS: 630.2112 (C36H37NNaO4SSi ; calc. 630.2111). Anal. calc. for
C36H37NO4SSi (607.84): C 71.14, H 6.14, N 2.30, S 5.28; found: C 71.19, H 6.23, N 2.39, S 5.37.
2-(Trimethylsilyl)ethyl (S)-2-Aminomethyl-3-[(triphenylmethyl)sulfanyl]propanoate (H-(S)-b2hCys(Tr)-
O(CH2)2SiMe3; 27). Compound 26 (1.52 g, 2.5 mmol) was Phth-deprotected according to GP 7 for 1 h. FC
(CH2Cl2 ! CH2Cl2/MeOH 95 :5) of the crude product yielded 27 (1.02 g, 85%). Colorless oil. Rf (CH2Cl2/MeOH
9 :1) 0.62. [a]rD:t: ˆ ‡17 (c ˆ 3.15, CHCl3). IR (CHCl3): 3063w, 3007w, 2956s, 1720s, 1595w, 1489m, 1443m, 1385w,
1170m. 1H-NMR (400 MHz, CDCl3): 0.03 (s, 3 Me); 0.93 ± 1.00 (m, CH2Si, NH2); 2.15 ± 2.20 (m, CHCH2); 2.27
(dd, J ˆ 12.18, 6.93, 1 H, CH2S); 2.57 (dd, J ˆ 12.18, 7.0, 1 H, CH2S); 2.70 ± 2.82 (m, CH2N); 4.13 ± 4.18 (m,
CH2O); 7.18 ± 7.30 (m, 9 arom. H); 7.40 ± 7.44 (m, 6 arom. H). 13C-NMR (100 MHz, CDCl3): À 1.48 (Me); 17.42,
30.88, 43.28 (CH2); 48.50 (CH); 62.98 (CH2); 66.92 (C); 126.72, 127.84, 127.92, 129.63 (CH); 144.63, 173.59 (C).
MALDI-MS: 501.2 (19.28), 500.2 (55.16), 244.1 (15.31), 243.1 (100.00). HR-MALDI-MS: 500.2054
‡
(C28H35NNaO2SSi ; calc. 500.2056). Anal. calc. for C28H35NO2SSi (477.74): C 70.40, H 7.38, N 2.93, S 6.71;
found: C 70.50, H 7.19, N 3.23, S 6.61.
2-(Trimethylsilyl)ethyl (S)-2-({[(tert-Butoxy)carbonyl]amino}methyl)-3-[(triphenylmethyl)sulfanyl]pro-
panoate (Boc-(S)-b2hCys(Tr)-O(CH2)2SiMe3; 28). A soln. of di(tert-butyl) dicarbonate (510 mg, 2.33 mmol)
in dioxane (10 ml) was added to a soln. of 27 (1.00 g, 2.09 mmol) in MeOH (50 ml) at r.t. under Ar. The mixture
was stirred for 2 h. Then, sat. aq. NH4Cl soln. (40 ml) and AcOEt (80 ml) were added, the org. phase was
separated, and the aq. phase was re-extracted with AcOEt (80 ml). The combined org. layers were washed with
sat. aq. NaCl soln., dried (MgSO4), and concentrated under reduced pressure. FC (Et2O/pentane 1:5) of the
crude product yielded 28 (1.02 g, 85%). Colorless oil. Rf (Et2O/pentane 1 :5) 0.28. [a]rD:t: ˆ ‡0.5 (c ˆ 2.90,
CHCl3). IR (CHCl3): 3454w, 3063w, 3007m, 2956m, 1713s, 1595w, 1505s, 1444w, 1392w, 1368w, 1165s. 1H-NMR
(400 MHz, CDCl3): 0.03 (s, 3 Me); 0.93 ± 1.00 (m, CH2Si); 1.39 (s, tBu); 2.28 ± 2.34 (m, 2 H); 2.48 ± 2.51 (m, 1 H);
3.16 ± 3.23 (m, 2 H); 4.12 ± 4.18 (m, CH2O); 4.50 (m, NH); 7.18 ± 7.24 (m, 3 arom. H); 7.25 ± 7.30 (m, 6 arom. H);
7.36 ± 7.43 (m, 6 arom. H). 13C-NMR (100 MHz, CDCl3): À 1.48 (Me); 17.38 (CH2); 28.35 (Me); 31.00, 41.09
(CH2); 45.19 (CH); 63.28 (CH2); 66.91, 79.30 (C); 126.73, 127.94, 129.62 (CH); 144.54, 155.55, 173.02 (C).
MALDI-MS: 601.3 (41.90), 600.3 (100.00), 545.2 (20.28), 544.2 (54.52), 500.2 (44.51), 243.1 (56.34). HR-
‡
MALDI-MS: 600.2580 (C33H43NNaO4SSi ; calc. 600.2580). Anal. calc. for C33H43NO4SSi (577.86): C 68.59, H
7.50, N 2.42, S 5.55; found: C 68.57, H 7.28, N 2.62, S 5.38.
(S)-2-({[(tert-Butoxy)carbonyl]amino}methyl)-3-[(triphenylmethyl)sulfanyl]propanoic Acid (Boc-(S)-
b2hCys(Tr)-OH; 29). A soln. of Bu4NF ´ 3 H2O(1.0 g, 3.17 mmol) in THF (5 ml) was added dropwise to a

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Helvetica Chimica Acta ± Vol. 87 (2004)
soln. of 28 (950 mg, 1.64 mmol) in THF (20 ml) at 08. The mixture was then slowly warmed up to r.t. and stirred
for 4 h. Sat. aq. NH4Cl soln. (40 ml) and AcOEt (80 ml) were added, and the aq. phase was extracted. Then, the
pH of the aq. phase was adjusted to 5 by addition of a 1m HCl and extracted again with AcOEt (80 ml).
Subsequently, the pH of the aq. phase was adjusted to 1 by addition of 1m HCl and extracted again with AcOEt
(80 ml). The combined org. layers were washed with sat aq. NaCl soln., dried (MgSO4), and concentrated under
reduced pressure. 2 FC (CH2Cl2 ! CH2Cl2/MeOH 95 :5) and (AcOEt/hexane/AcOH 1:2 :0.01 ! 1:1:0.01) of
the crude product yielded 29 (657 mg, 84%). Slightly yellow foam. Rf (AcOEt/hexane/AcOH 1:2 :0.01) 0.28.
[a]Dr:t: ˆ ‡5 (c ˆ 0.55, CHCl3). IR (CHCl3): 3453w, 3060w, 2980w, 2933w, 1711s, 1600m, 1506s, 1444m, 1393w,
t
1368m, 1166s, 1084s, 1036s. 1H-NMR (400 MHz, CD3OD): 1.34 (s, Bu); 2.20 ± 2.25 (m, 1 H); 2.25 ± 2.31 (m,
1 H); 2.45 (dd, J ˆ 11.6, 7.9, 1 H); 3.05 ± 3.09 (m, 2 H); 7.14 ± 7.20 (m, 3 arom. H); 7.21 ± 7.24 (m, 6 arom. H);
7.32 ± 7.36 (m, 6 arom. H). 13C-NMR (100 MHz, CD3OD): 28.74 (Me); 32.51, 42.77 (CH2); 47.16 (CH); 67.92,
80.18 (C); 127.80, 128.92, 130.77 (CH); 146.10, 158.10, 176.75 (C). MALDI-MS: 522.2 (6.10), 500.2 (7.33), 273.0
‡
(17.74), 243.1 (100.00). HR-MALDI-MS: 500.1900 (C28H31NNaO4S ; calc. 500.1872). Anal. calc. for
C28H31NO4S (477.62): C 70.41, H 6.54, N 2.93, S 6.71; found: C 70.63, H 6.63, N 2.90, S 6.57.
Methyl (S)-2-({[(tert-Butoxy)carbonyl]amino}methyl)-3-[(triphenylmethyl)sulfanyl]propanoate (Boc-(S)-
b2hCys(Tr)-OMe; 30). To a soln. of 29 (48 mg, 0.1 mmol) in MeOH (2 ml) and toluene (0.7 ml) at r.t.,
TMSCH2N2 (2m soln. in hexane, 200 ml, 0.4 mmol) was added dropwise to the mixture. The yellow soln. was
stirred for 20 min, and AcOH (100 ml) was added. Azeotropic distillation of AcOH with toluene, followed by FC
(pentane/Et2O1:1) of the crude product, yielded 30 (50 mg, quant.). Colorless oil. er > 98 :2 (HPLC). Rf
t
(Et2O/pentane 1 :5) 0.11. [a]rD:t: ˆ ‡5.0 (c ˆ 1.63, CHCl3). 1H-NMR (300 MHz, CDCl3): 1.39 (br. s, Bu); 2.30 ±
2.39 (m, 2 H); 2.49 ± 2.54 (m, CHCH2); 3.13 ± 3.23 (m, 2 H); 3.66 (s, MeO); 4.50 (m, NH); 7.20 ± 7.30 (m, 9 arom.
H); 7.41 ± 7.43 (m, 6 arom. H).
3-(1H-Imidazol-4-yl)propanoic Acid Hydrochloride (31). Similar to the procedure reported in [118],
uraconic acid (5.01 g, 36.23 mmol) was dissolved in 0.5m NaOH (100 ml), and Pd/C (10%, 0.5 g) was added. The
apparatus was evacuated and flushed with H2 (3Â), and the mixture was stirred under an atmosphere of H2
(balloon) for 17 h at r.t. The mixture was filtered through Celite and washed with H2O; the filtrate was adjusted
to pH 2 with conc. HCl and concentrated under reduced pressure. Traces of H2Owere co-evaporated with
toluene. The white residue was dissolved in EtOH and filtered; the solvent was then evaporated under reduced
pressure to yield crude 31 (6.32 g). White solid. 1H-NMR (300 MHz, CD3OD): 2.72 (t, J ˆ 7.2, CH2); 3.00 (t, J ˆ
7.2, CH2); 7.33 (s, 1 Im H); 8.79 (s, 1 Im H). The product was used in the next step without further purification.
Methyl 3-(1H-imidazol-4-yl)propanoate Hydrochloride (32). Similar to the procedure reported in [118],
crude 31 was suspended in a soln. of sat. HCl in MeOH (70 ml) and heated at reflux for 2 h. MeOH was
evaporated under reduced pressure, followed by azeotropic distillation of MeOH/toluene and toluene/CHCl3 to
obtain crude 32 (7.87 g). The product was used in the next step without further purification. Yellow oil. The anal.
data are in agreement with those reported in [119][120].
Methyl 3-[1-(Triphenylmethyl)-1H-imidazol-4-yl]propanoate (33). Similar to the procedure reported in
[120][121], 32 was dissolved in DMF (35 ml) and cooled to 08. Et3N (20 ml, 4 equiv.) and a soln. of TrCl (10.97 g,
1.1 equiv.) in DMF (45 ml) were added dropwise. The mixture was stirred for 3 d at r.t. until a white precipitate
was formed. The mixture was poured onto ice (350 g) and extracted with CH2Cl2 (5 Â 150 ml). The combined
org. layers were washed with H2O(300 ml), dried (MgSO 4), and concentrated under reduced pressure to afford
crude 33 (15.9 g). Yellow oil. The anal. data are in agreement with those reported in [120]. The product was used
in the next step without further purification.
3-[1-(Triphenylmethyl)-1H-imidazol-4-yl]propanoic Acid (34). Similar to the procedure reported in [110],
compound 33 was dissolved in THF/H2O3 :1 (130 ml), LiOH ´ H 2O(3.5 g, 2.3 equiv.) was added, and the
mixture was stirred for 15 h at r.t. THF was evaporated under reduced pressure, the residue was diluted with
H2O(200 ml), and the resulting suspension was acidified to pH 2 ± 3 with 10% tartaric acid. The mixture was
extracted with CH2Cl2 (4 Â 100 ml); the combined org. layers were washed with 10% tartaric acid (200 ml) and
H2O(100 ml), dried (MgSO 4), and concentrated under reduced pressure. The resulting oil was dissolved in
Et2Oand evaporated several times to obtain a slightly yellow solid. Et 2O(25 ml) was added, the suspension was
stirred for 10 min, and the product was filtered off to obtain 34 (10.1 g, 73% over 4 steps). White solid. 1H-NMR
(300 MHz, CDCl3): 2.73 ± 2.78 (m, CH2); 2.83 ± 2.88 (m, CH2); 6.61 (s, 1 Im H); 7.10 ± 7.15 (m, 6 arom. H); 7.26 ±
7.37 (m, 9 arom. H); 4.49 (s, 1 Im H). The anal. data are in agreement with those reported in [110].
(R)-4-(1-Methylethyl)-5,5-diphenyl-3-{3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propanoyl}oxazolidin-2-
one (35). To a suspension of 34 (13.9 g, 36.4 mmol) in THF (0.25m) at À 308, Et3N (6.05 ml, 1.2 equiv.) and
pivaloyl chloride (4.50 ml, 1 equiv.) were added dropwise, and the mixture was stirred for 70 min at À 308.
Meanwhile, a soln. of BuLi (1.52m in hexane; 21.4 ml, 0.94 equiv.) was added to an ice-bath-cooled suspension of

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(R)-4-(1-methylethyl)-5,5-diphenyl-1,3-oxazolidin-2-one ((R)-17) (9.30 g, 0.91 equiv.) in THF (0.25 M). The
soln. formed was added to the mixed anhydride soln. prepared previously. Stirring was continued for 15 h as the
mixture was allowed to warm to r.t. The reaction was then quenched with sat. NH4Cl soln. (100 ml), and diluted
with Et2O(600 ml) and H 2O(400 ml). The org. phase was separated, washed with 10% tartaric acid (400 ml), 1m
NaOH (400 ml), and sat. aq. NaCl soln. (400 ml). Each aq. phase was re-extracted with Et2O(600 ml). The
combined org. layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was
triturated with Et2O/pentane 2 :1, and the solid was filtered off, washed with cold Et2O, and dried to yield
unreacted auxiliary 17 (1.77 g, 19%). White solid. The filtrate was concentrated under reduced pressure and FC
(CH2Cl2/MeOH sat. with NH3 45 :1) yielded (R)-35 (14.1 g, 60%). White solid. M.p. 88 ± 908. [a]rD:t: ˆ ‡115.8
(c ˆ 1.00, CHCl3). IR (CHCl3): 2969w, 1781s, 1703m, 1494m, 1449m, 1366m, 1320m, 1038w, 1001w, 638w.
1H-NMR (400 MHz, CDCl3): 0.72 (d, J ˆ 6.8, Me); 0.84 (d, J ˆ 7.0, Me); 1.90 ± 1.98 (m, Me2CH); 2.76 ± 2.90 (m,
CH2); 3.06 (ddd, J ˆ 17.1, 8.8, 6.1, 1 H, CH2); 3.28 (ddd, J ˆ 17.1, 9.2, 6.5, 1 H, CH2); 5.36 (d, J ˆ 3.3, CHN); 6.50
(d, J ˆ 1.3, 1 Im H); 7.09 ± 7.12 (m, 5 arom. H); 7.23 ± 7.37 (m, 20 arom. H); 7.43 (d, J ˆ 1.3, 1 Im H). 13C-NMR
(100 MHz, CDCl3): 16.36, 21.81 (Me); 23.39 (CH2); 29.91 (CH); 35.25 (CH2); 64.40 (CH); 75.08, 89.26 (C);
117.94, 125.59, 125.94, 127.66, 127.89, 127.93, 127.97, 128.33, 128.53, 128.88, 129.60, 129.82 (CH); 138.29 (C);
‡
138.42 (CH); 139.87, 142.37, 142.57, 152.92, 172.40 (C). HR-MALDI-MS: 668.2888 (C43H39N3NaO3 ; calc.
668.2884). Anal. calc. for C43H39N3O3 (645.79): C 79.97, H 6.09, N 6.51; found: C 79.97, H 6.03, N 6.36.
(4R)-3-{(2S)-2-(Hydroxymethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propanoyl}-4-(1-methylethyl)-
5,5-diphenyloxazolidin-2-one (36). Compound (R)-35 (5.90 g, 8.9 mmol) was transformed according to GP 5b
for 3 h. FC (hexane/AcOEt 1 :1) of the crude product yielded (2'S,4R)-36 (4.3 g, 70%). White solid. M.p. 114 ±
1168. [a]rD:t: ˆ ‡82.7 (c ˆ 0.95, CHCl3). IR (CHCl3): 3063w, 3008m, 2970m, 1778s, 1700s, 1599w, 1494m, 1450m,
1
1364m, 1319m, 1280m, 1131m, 1087w, 1051m, 1001m, 906m, 871m, 844m, 831m. H-NMR (400 MHz, CDCl3):
0.78 (d, J ˆ 6.7, Me); 0.91 (d, J ˆ 7.0, Me); 1.93 ± 2.01 (m, Me2CH); 2.61 ± 2.71 (m, CH2); 3.84 (dd, J ˆ 11.5, 5.9,
1 H, CH2); 3.90 (dd, J ˆ 11.5, 5.5, 1 H, CH2); 4.01 ± 4.08 (m, CHCH2); 5.39 (d, J ˆ 3.2, CHN); 6.32 (d, J ˆ 1.3, 1
Im H); 7.03 ± 7.13 (m, 5 arom. H); 7.27 ± 7.37 (m, 20 arom. H); 7.43 (d, J ˆ 1.3, 1 Im H). 13C-NMR (100 MHz,
CDCl3): 16.23, 21.80 (Me); 26.52 (CH2); 30.00, 45.61 (CH); 63.05 (CH2); 64.61 (CH); 75.17, 89.18 (C); 119.06,
125.51, 125.85, 127.86, 128.00, 128.33, 128.38, 128.77, 129.56, 129.65, 129.81, 130.08 (CH); 137.61 (C); 138.14
‡
(CH); 138.23, 142.40, 142.50, 152.91, 174.07 (C). HR-MALDI-MS: 698.2982 (C44H41N3NaO4 ; calc. 698.2989).
Anal. calc. for C44H41N3O4 ´ 1/2 H2O(684.82): C 77.17, H 6.18, N 6.14; found: C 77.24, H 6.21, N 6.15.
(4R)-3-{2-(Azidomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propanoyl}-4-(1-methylethyl)-5,5-di-
phenyloxazolidin-2-one (37). a) The alcohol (2'S,4R)-36 (617 mg, 0,91 mmol) was treated with Ph3P (276 mg,
1.1 equiv.), HN3 (1.03m in benzene; 1.0 ml, 1.1 equiv.) and DIAD (0.21 ml, 1.1 equiv.) according to GP 8a. FC
(Et2O/pentane 45 :55 ! 1:1) yielded (2'S,4R)-37 (571 mg, 89%). White solid.
b) The alcohol (2'S,4R)-36 (322 mg, 0.48 mmol) was treated with DIAD (98 ml, 1 equiv.), Ph3P (129 mg,
1 equiv.), and (PhO)2P(O)N3 (130 ml, 1.2 equiv.) according to GP 8b. FC (Et2O/pentane 45 :55 ! 1 :1) yielded
the (2'S,4R)-37 (182 mg, 55%). White solid.
Data of (2'S,4R)-37: M.p. 79 ± 818. 1H-NMR (400 MHz, CDCl3): 0.78 (d, J ˆ 6.7, Me); 0.94 (d, J ˆ 7.0, Me);
1.93 ± 2.02 (m, Me2CH); 2.49 (dd, J ˆ 14.7, 7.5, 1 H, CH2); 2.69 (dd, J ˆ 14.7, 5.1, 1 H, CH2); 3.60 (dd, J ˆ 12.2, 4.6,
1 H, CH2); 3.68 (dd, J ˆ 12.2, 8.0, 1 H, CH2); 4.21 ± 4.26 (m, CHCH2); 5.39 (d, J ˆ 3.1, CHN); 6.29 (d, J ˆ 1.2, 1 Im
H); 6.95 ± 7.11 (m, 10 arom. H); 7.24 ± 7.39 (m, 15 arom. H, 1 Im H). 13C-NMR (100 MHz, CDCl3): 16.20, 21.83
(Me); 27.63 (CH2); 30.02, 43.77 (CH); 52.14 (CH2); 64.78 (CH); 75.12, 89.18 (C); 119.25, 125.51, 125.86, 127.90,
128.00, 128.02, 128.37, 128.39, 128.79, 129.58, 129.83 (CH); 137.18, 138.25 (C); 138.39 (CH); 142.40, 142.48,
‡
152.65, 173.00 (C). HR-MALDI-MS: 723.3046 (C44H40N6NaO3 ; calc. 723.3054). Anal. calc. for C44H40N6O3
(700.83): C 75.41, H 5.75, N 11.91; found: C 75.36, H 5.87, N 11.79.
(S)-Benzyl 2-(Hydroxymethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propanoate (39). To a stirred
soln. of BnOH (1.7 ml, 2.2 equiv.) in THF (10 ml) at À 58 was added BuLi (1.52m in hexane; 11.1 ml, 2.2 equiv.),
and the soln. was stirred at À 108 for 10 min. After cooling to À 788, a soln. of (2'S,4R)-36 (5.20 g, 7.7 mmol) in
THF (0.37 M) was added dropwise. The mixture was stirred at À 788 for 30 min, and the temp. was allowed to
rise to À 208 over 105 min. The soln. was then stirred at À 208 for 2 h (TLC control), the reaction was quenched
with 10% tartaric acid (175 ml), and the mixture was extracted with CH2Cl2 (350 ‡ 175 ml). The combined org.
layers were washed with 10% tartaric acid (175 ml), dried (MgSO4), and concentrated under reduced pressure.
A soln. of AcOEt/hexane 2 :1 was added, and the mixture was ultrasonificated for 2 min and filtrated. Drying of
white solid (h.v.) yielded (R)-17 (1.83 g). The filtrate was concentrated under reduced pressure and purified by
FC (AcOEt/hexane 3 :1) to yield (S)-39 (2.72 g, 70%) with er > 98 :2 (HPLC). White solid. M.p. 118 ± 1208.
[a]Dr:t: ˆ ‡1.4 (c ˆ 1.00, CHCl3). IR (CHCl3): 3065w, 3005m, 2966m, 1727s, 1494s, 1446s, 1386w, 1131s, 1089w,
1050m, 1003m, 907m, 870m, 833m. 1H-NMR (500 MHz, CDCl3): 2.86 ± 3.04 (m, CHCH2, CHCH2); 3.84 (d,

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Helvetica Chimica Acta ± Vol. 87 (2004)
J ˆ 5.4, CH2OH); 4.1 ± 4.3 (br. s, OH); 5.06 (d, J ˆ 12.4, 1 H, PhCH2); 5.10 (d, J ˆ 12.4, 1 H, PhCH2); 6.55 (d, J ˆ
1.4, 1 Im H); 7.08 ± 7.15 (m, 6 arom. H); 7.27 ± 7.35 (m, 15 H, 14 arom. H, 1 Im H). 13C-NMR (125 MHz, CDCl3):
27.43 (CH2); 47.40 (CH); 62.52, 66.23 (CH2); 75.26 (C); 119.14, 127.99, 128.05, 128.14, 128.36, 128.52, 129.74
‡
(CH); 135.88, 137.95 (C); 138.32 (CH); 142.33, 173.89 (C). HR-MALDI-MS: 525.2144 (C33H30N2NaO3 ; calc.
525.2149).
(S)-Benzyl 2-(Azidomethyl)-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propanoate (40). The alcohol (S)-39
(2.66 g, 5.30 mmol) was treated with Ph3P (1.58 g, 1.1 equiv.), HN3 (1.11m in benzene; 5.3 ml, 1.1 equiv.), and
DIAD (1.19 ml, 1.1 equiv.) according to GP 8a. FC (Et2O/pentane 1 :1) yielded (S)-40 (2.31 g, 83%). Colorless
oil. Rf (AcOEt/hexane 1 :2) 0.22. [a]rD:t: ˆ ‡10.9 (c ˆ 1.00, CHCl3). IR (CHCl3): 3066w, 3008w, 2966w, 2104s,
1732s, 1600w, 1494m, 1446m, 1131m, 1087m, 1038w, 1002w, 908w, 870w, 830w. 1H-NMR (400 MHz, CDCl3): 2.80
(dd, J ˆ 14.6, 7.7, 1 H, CH2); 2.96 (ddd, J ˆ 14.6, 6.3, 0.6, 1 H, CH2); 3.02 ± 3.09 (m, CH); 3.50 ± 3.57 (m, CH2N3);
5.06, 5.12 (2d, J ˆ 12.4, PhCH2); 6.55 (t, J ˆ 0.7, 1 Im H); 7.07 ± 7.14 (m, 6 arom. H); 7.27 ± 7.34 (m, 14 arom. H);
7.35 (d, J ˆ 1.4, 1 Im H). 13C-NMR (100 MHz, CDCl3): 28.05 (CH2); 45.47 (CH); 51.68, 66.57 (CH2); 75.22 (C);
119.29, 128.05, 128.07, 128.19, 128.52, 129.40, 129.72, 130.00 (CH); 135.70, 137.51 (C); 138.72 (CH); 142.40,
‡
172.86 (C). HR-MALDI-MS: 550.2209 (C33H29N5NaO2 ; calc. 550.2214). Anal. calc. for C33H29N5O2 (527.62): C
75.12, H 5.54, N 13.27; found: C 75.10, H 5.72, N 13.30.
(S)-2-[({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)methyl]-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]-
propanoic Acid (Fmoc-(S)-b2hHis(Tr)-OH; 41). Transformation of (S)-40 (1.44 g, 2.73 mmol) according to GP
6b gave the amino acid H-(S)-b2hHis(Tr)-OH (1.26 g) as a white solid. This solid was then Fmoc-protected
according to GP 4b for 2 h. FC (CH2Cl2/MeOH 16 :1 ! 9 :1) and crystallization (AcOEt/hexane) yielded (S)-41
(1.07 g, 62%). White solid. Rf (CH2Cl2/MeOH 9 :1) 0.42. M.p. 130 ± 1338. [a]rD:t: ˆ À14.5 (c ˆ 0.97, CHCl3). IR
(CHCl3): 3444w, 3008w, 2951w, 1716s, 1513m, 1447m, 1152w, 1130w, 1087w, 1011w, 871w, 831w. 1H-NMR
(400 MHz, CD3OD): 2.68 ± 2.73 (br. dd, 1 H, CH2); 2.78 ± 2.87 (m, CHH, CHCH2); 3.25 ± 3.36 (m, CH2); 4.16 (t,
J ˆ 6.8, CHCH2O); 4.30 (d, J ˆ 6.9, CH2O); 6.74 (s, 1 Im H); 7.10 ± 7.13 (m, 6 arom. H); 7.24 ± 7.29 (m, 2 arom.
H); 7.33 ± 7.35 (m, 11 arom. H); 7.43 (s, 1 Im H); 7.60 (d, J ˆ 7.5, 2 arom. H); 7.76 (d, J ˆ 7.5, 2 arom. H). 13C-NMR
(100 MHz, CD3OD): 28.85, 43.02 (CH2); 47.62, 48.52 (CH); 61.51 (C); 67.76 (CH2); 77.11 (C); 120.94, 121.06,
126.25, 128.17, 128.79, 129.31, 129.39, 130.67, 130.92, 131.20 (CH); 138.86 (C); 139.15 (CH);142.63, 143.56,
‡
158.76, 177.88 (C). HR-MALDI-MS: 656.2518 (C26H25N3NaO2 ; calc. 656.2520).
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Received September 9, 2004