Enantioselective preparation of β2-amino acids with aspartate, glutamate, asparagine, and glutamine side chains

Article abstract of DOI:10.1002/hlca.200490142

(S)-β²-Homoamino acids with the side chains of Asp, Glu, Asn, and Gln have been prepared and suitably protected (N-Fmoc, CO _2′Bu CONHTrt) for solid-phase peptide syntheses. The key steps of the syntheses are: N-acylation of 5,5-diphe

Full text of DOI:10.1002/hlca.200490142

Helvetica Chimica Acta Vol. 87 (2004)
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Enantioselective Preparation of b2-Amino Acids with Aspartate,
Glutamate, Asparagine, and Glutamine Side Chains1)
by Ge¬rald Lelais2), Marino A.Campo 3), Sascha Kopp4), and Dieter Seebach*
Laboratorium f¸r Organische Chemie der Eidgenˆssischen Technischen Hochschule, ETH Hˆnggerberg, HCI,
Wolfgang-Pauli-Strasse 10, CH-8093 Z¸rich
(phone: ‡41 1 632 29 90; fax: ‡41 1 632 11 44; e-mail: seebach@org.chem.ethz.ch)
(S)-b2-Homoamino acids with the side chains of Asp, Glu, Asn, and Gln have been prepared and suitably
t
protected (N-Fmoc, CO2 Bu, CONHTrt) for solid-phase peptide syntheses. The key steps of the syntheses are:
N-acylation of 5,5-diphenyl-4-isopropyl-1,3-oxazolidin-2-one (DIOZ) with succinic and glutaric anhydrides
(Scheme 2), alkylation of the corresponding Li-enolates with benzyl iodoacetate and Curtius degradation
(Scheme 4), and removalof the chiralauxiialry
(
Scheme 5). In addition, numerous functional-group
t
manipulations (CO2H > CO2 Bu, CO2Bn > CO2H, CbzNH ! FmocNH, CO2H ! CO2NH2 ! CONHTrt;
Schemes 2, 4, 5, and 6) were necessary, in order to arrive at the four target structures. The configurational
assignments were confirmed by X-ray crystal-structure determinations (Scheme 2 and Fig. 3). The enantiomeric
purities of a b2hAsn and of a b2hGln derivative were determined by HPLC on a Chiralcel column to be 99.7 :0.3
and > 99 :1, respectively (Fig. 4). Notably, it took up to twelve steps to prepare a suitably protected
trifunctional product with a single stereogenic center (overall yield of 10% from DIOZ and succinic anhydride)!
1.Introduction.
Although b3-amino acids can be conveniently synthesized from
the corresponding a-analogues by simply introducing a CH2 group between the CˆO
and the a-C-atom (i.e., ArndtÀEistert homologation)5), no such generalmethod is
known for the preparation of b2-amino acids. As outlined in Fig. 1, a wide variety of
routes have been explored for the synthesis of b2-amino acids depending upon the bond
formed in the key step.
Formation of bond ꢀ1 by diastereoselective Mannich-type reaction [1 11], i.e.,
aminomethylation of chiral acyl derivatives with synthetic equivalents of the
‡
[H2NCH2] cation, has been applied for the preparation of a large range of b2-amino
acids, most of them having alkyl or aryl side chains. The Mitsunobu reaction, instead,
was used for the conversion of 2-(hydroxymethyl)carboxylic acid esters to the
corresponding amino or azido derivatives, thus forming bond ꢀ2 [1][12][13]. Another
route is the Curtius rearrangement of enantiomerically pure monosubstituted succinic
acid derivatives [1][14][15], which were themselves synthesized by alkylation of chiral
1
)
)
)
Partially published in a preliminary communication [1].
2
3
Part of the Dissertation of G. L. (No. 15429), ETH-Z¸rich, 2004.
Postdoctoralfelow at ETH-Z¸rich, financed by a grant from the Swiss National Science Foundation (No.
200020-100182).
Part of the Master Thesis (Diplomarbeit) of S. K., ETH-Z¸rich, 2003.
With the exceptions of Fmoc-b3hHis(Trt)-OH and Fmoc-b3hCys(Trt)-OH, all −proteinogenic× b3-amino
acids, which can be prepared by ArndtÀEistert homologation of the corresponding a-amino acids, are
commercially available.
4
5
)
)

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Helvetica Chimica Acta Vol. 87 (2004)
Fig. 1. Analysis of the key CÀC-, CÀN-, or CÀH-bond-forming reactions
for b2-amino acid synthesis
N-acyloxazolidinones with bromo- or iodoacetates (bonds ꢀ1 and ꢀ2 ) [9][16 18] or by
alkylation of succinic [19] or malic acid enolates [20] with electrophiles (bonds ꢀ3 and
ꢀ2 ). Another approach is the coupling of an electrophile with cyclic [21 28] or acyclic
[1][8][29 33] chiralenoaltes derived from 3-aminopropanoic acid (bond
ꢀ3 ).
Similarly, by the enantioselective nucleophilic addition of Et2Zn to a 3-nitroacrylate
derivative, the feasibility of the process with umpolung has been demonstrated [34].
The conjugate 1,4-addition (Michael-type reaction) of chiral N-nucleophiles to 2-
substituted acrylates, followed by diastereoselective protonation, is yet another method
for their preparation, in which bonds ꢀ2 and ꢀ4 are formed [35 38]. Finally, chiral
metal complexes have permitted the isolation of enantiomerically enriched b2-amino
acids by construction of the ꢀ1 ‡ ꢀ4 [39], ꢀ4 ‡ ꢀ5 [40], or ꢀ4 ‡ ꢀ7 bonds [41], albeit
often with low enantioselectivities and, in any case, applied only for derivatives with
alkyl or aryl side chains.
The incorporation of b2-amino acids into b-peptides has uncovered intriguing
effects, leading to turn structures [42][43] or a novel type of helix, which consists of
alternating ten- and twelve-membered H-bonded rings [7][44]. For our ongoing work
on the synthesis of more complex b2/b3- and all-b2-peptides, we needed ample access to
all 19, appropriately protected6), b2-amino acids with proteinogenic side chains. At the
time this project was initiated, the above mentioned methods were only applied to the
construction of the −easy× b2-amino acids, but not much was known about the
derivatives with functionalized side chains. For this reason, the application of a method
developed in our group, relying on the use of 5,5-diphenyl-4-isopropyl-1,3-oxazolidin-
2-one (DIOZ) as a chiralauxiilary, was envisaged for the preparation of the b2-amino
acids shown in Fig. 2. Indeed, our modified Evans oxazolidinone has been shown to be
a versatile auxiliary for diastereoselective alkylations, aldol additions, 1,4-additions,
cycloadditions, and numerous other reactions [8][45 53]. Derivatives of this auxiliary
have turned out to possess several desirable properties, such as high crystallinity, ease of
removaland recovery, and good seel ctivity.
Results and Discussion. Since the aspartic and the glutamic acid side chains are
interchangeable with the corresponding amides (asparagine and glutamine, resp.), and
since they differ from each other only by a CH2 unit, it was decided to prepare all four
b2-amino acids by the same approach. As mentioned above, a prerequisite of the final
6
)
For solid-phase synthesis by the Fmoc strategy, all functionalized side chains have to be protected
orthogonally to the Fmoc group itself. They should be stable under basic conditions but labile in acidic
media, thus trityl(Trt) and tBu groups are the protecting groups of choice.

Helvetica Chimica Acta Vol. 87 (2004)
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Fig. 2. Target b2-amino acid derivatives
compounds for their use in solid-phase b-peptide synthesis is the Fmoc protection of
t
the b-amino group, and the Bu or Trt protecting group on the side chains. Thus, we
thought that 3-acyl-DIOZ derivatives of succinic and glutaric acids could serve as
precursors for the corresponding b2-homoaspartic and b2-homoglutamic acids, respec-
tively. The amino functionality would be introduced either by a diastereoselective
Mannich-type reaction (cf. bond ꢀ1 in Fig. 1) or by a carbalkoxymethylation, followed
by Curtius degradation (connections ꢀ1 ‡ ꢀ2 in Fig. 1), to give the desired amino acid
skeleton, which could be further elaborated by protecting-group exchange (Scheme 1).
Scheme 1. Retrosynthetic Analysis for the Preparation of the b2-Amino Acids with Asx and Glx Side Chains

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Helvetica Chimica Acta Vol. 87 (2004)
It should be noted that a similar approach has been previously described by Wyatt
and co-workers [15] for the synthesis of fully deprotected b2-homoaspartate; the
authors applied a diastereoselective alkylation of a −classical× Evans acyloxazolidinone
derived from pent-4-enoic acid with methyl bromoacetate as electrophile, followed by
oxidative cleavage of the double-bond, Curtius rearrangement, and removalof the
auxiliary, to give the Z-b2hAsp-OH in 97.5% enantioselectivity, but without a
protecting group on the side chain. Recently, Xue et al. [32] performed the synthesis
of an enantiomerically pure (R)-b2-homoaspartate derivative by a stereoselective
alkylation of a Bn- and Z-protected chiral b-homoglycine-oxazolidinone with tert-butyl
bromoacetate. In our approach, we started from the commercially available succinic
t
and glutaric anhydrides, which were ring-opened by refluxing in toluene with BuOH,
and catalytic amounts of 4-(dimethylamino)pyridine (DMAP), Et3N, and N-hydroxy-
succinimide (NHS) [54] to give the monoesters 1 and 2 in 70 and 24%7) yield,
respectively (Scheme 2). N-Acylation of the chiral oxazolidinone (R)-DIOZ with the
LiCl-activated [55] pivaloyl mixed anhydrides of 1 and 2 gave the desired
acyloxazolidinones 3 and 4, respectively, in excellent yields.
Scheme 2. Nucleophilic Ring Opening of the Succinic and Glutaric Anhydrides ( ! 1 and 2), N-Acylation of
(R)-DIOZ to Form the Acyloxazolidinones 3 and 4, Respectively, and X-Ray-Crystal Structure of 3
Slow evaporation of an Et2O/pentane mixture from a solution of ester 3 led to the
formation of crystals suitable for structure determination by single-crystal X-ray
diffraction; as evident from the presentation in Scheme 2, the methine H-atom of the
iPr group points towards the cis-Ph group causing a buttressing effect [49] in the face
selectivity of reactions of enolates of 3 with electrophiles.
7
)
The reaction was rather messy and the formation of polymerization products were observed.

Helvetica Chimica Acta Vol. 87 (2004)
1549
Due to the better crystallinity of compound 3 and, therefore, easier purification of
its derivatives, compared to the homologue 4, all experiments towards the construction
of the amino acid backbone, according to the approaches outlined in Scheme 1, were
performed with the former derivative. We first explored amidomethylation of the Ti-
enolate from 3 with the corresponding electrophile (N-benzyloxycarbonyl-N-
(methoxymethyl), ZNHCH2OMe) without success; the Lewis acidity of Ti4‡ caused
complete deprotection of the tert-butylester and formation of an inseparabel mixture
of products. We then switched to an allylation/double-bond oxidation/Curtius-
degradation strategy. An analogous stereoselective allylation reaction has been
successfully applied by Sibi and Deshpande [19] on a similar substrate. Treatment of
3 with 1 equiv. of sodium hexamethyldisilazide (NHMDS) in THF at À788 for 20 min,
followed by quenching with allyl bromide, furnished, in our case, the mono alkylated
derivative 5 in disappointing yields and selectivities (Entry 1, Scheme 3). Similar results
were obtained when more equivalents of allyl bromide were added to the Na-enolate
(Entry 2); however, better conversion was achieved when the more reactive iodo
derivative was used as electrophile (Entry 3). Acceptable selectivities were realized
only by running the reaction at À508 (Entry 4), while complete degradation of the
enolate resulted at 08 (Entry 5). The formation of the Li-enolate with LHMDS at À788,
Scheme 3. Optimization of the Conditions for the Diastereoselective Alkylation of 3 with Allyl Halides

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followed by quenching with allyl iodide at À508, gave the best result, with good
conversion and 96% diastereoselectivity (Entry 7). Unfortunately, purification by flash
chromatography was not sufficient to separate the diastereoisomers, and compound 5
was isolated in 66% yield and 96% diastereoselectivity. At this point, we thought that
better separation would possibly be achieved in a later stage of the synthesis, for
example, after double-bond oxidation. Ozonolysis [56] of the double bond in 5 and
oxidation with periodate (catalytic KMnO4 [57]) did, however, not lead to the desired
carboxylic acids.
Disappointed by these results, we changed our strategy and envisaged a more direct
approach of introducing the amino functionality by alkylation with benzyl iodoacetate
[58] as electrophile. We were pleased to see that, upon treatment of the Li-enolates of
the acyloxazolidinones 3 and 4 with this electrophile at À788, the alkylated products 6
and 7, respectively, could be isolated in ca. 55% yield as single diastereoisomers
(Scheme 4).
Scheme 4. Diastereoselective Alkylation of Succinic and Glutaric Acid Derivatives 3 and 4 with Benzyl
Iodoacetate. Note that the a-carbonylC-atom of 6 is a stereogenic center only due to the fact that the two ester
groups CO2R carry different OR groups (tBu and Bn)! Hydrogenolysis of the benzyl esters 6 and 7, and Curtius
degradation leads to the Z-protected derivatives 10 and 11.
Following hydrogenolysis of the benzyl ester and Curtius degradation (with DPPA
(diphenylphosphoryl azide), Et3N, and BnOH [59]), the Z-protected derivatives 10
and 11 were isolated in good yields (Scheme 4). Compound 10 formed single crystals
suitable for structure determination by X-ray crystallography (Fig. 3,a): as expected,
the newly created stereogenic center has (S)-configuration. In addition, X-ray crystal-
structure determination of the fifth crop of crystals (representing less than 4% of the
total yield) revealed that the unit cell contains 10 and epi-10 in a 1:1 ratio (Fig. 3,b).

Helvetica Chimica Acta Vol. 87 (2004)
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Fig. 3. X-Ray crystal structures of 10 (a) and of a 1:1 co-crystal of 10 and epi-10 (b)
The next step towards the synthesis of the b2-aspartate and b2-glutamate derivatives
8
involved the cleavage of (R)-DIOZ with LiOH/H2O2 ), which gave acids 12 and 13, as
well as the recovered auxiliary, in good yields (Scheme 5)9). Following Z/Fmoc
protecting-group exchange, Fmoc-b2hAsp(OtBu)-OH (14) and Fmoc-b2hGlu(OtBu)-
OH (15) were isolated in 94 and 90% yields, respectively. In this way, the Fmoc
derivatives 14 and 15 were synthesized in an overall yield of 19 and 7%10) over eight
steps starting from the corresponding anhydrides and (R)-DIOZ.
Scheme 5. Cleavage8) of the Auxiliary with LiOH/H2O2 and Subsequent Protecting-Group Exchange to Give the
Fmoc-Protected Acids 14 and 15
For the preparation of the b2hAsn and b2hGln derivatives, the acids 12 and 13 were
converted to the benzylesters 16 and 17, respectively, by treatment with BnBr and
NaHCO3 in DMF in the presence of catalytic amounts of tetrabutylammonium iodide
(TBAI; Scheme 6). It is important to note that nucleophilic cleavage of the
acyloxazolidinone 10 by BnOLi, for the direct formation of ester 16, led to partial
t
epimerization of the C(2)-centre (see above). Subsequent Bu deprotection and
nucleophilic addition of ammonia afforded amides 18 and 19, which were Trt-protected
8
)
We have claimed that a major advantage of our modified Evans auxiliary is that it can be cleaved simply
with THF/aq. NaOH and does not require LiOH/H2O2. This is not true for the application described here,
because the substrate contains ester groups, and the hydroperoxide conditions lead to much faster
cleavage.
Particular care should be taken during the workup, the tert-butylester being very sensitive to acidic
conditions. For details, see Exper. Part.
9
)
10
)
The low overall yield for this derivative is caused −essentially× by the disappointing yield obtained for the
opening of the glutaric anhydride (not optimized).

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to give the fully protected amino acids 20 and 21, respectively, in good yields.
Hydrogenolysis and Fmoc protection of the amino group led to Fmoc- and Trt-
protected b2-homoasparagine (22) and b2-homoglutamine (23; Scheme 6), respectively,
which have, thus, been synthesized over twelve steps with an overall yield of 10 and 4%,
respectively.
Scheme 6. Conversion of the Aspartate and Glutamate Derivatives 12 and 13 to Fmoc- and Trt-Protected b2-
Homoasparagine (22) and b2-Homoglutamine (23)
To verify the enantiomeric purity of the new b2-amino acid derivatives, compounds
20 and 21 were injected into a chiralHPLC coul mn ( Chiralcel OD). For comparison,
both derivatives were racemized by treatment with BnOLi at room temperature. As
shown in Fig. 4, both derivatives show only one peak, thereby confirming the purity of
all four amino acids11). Additionally, as previously mentioned, direct cleavage of the
auxiliary from acyloxazolidinone 10 with BnOLi (1 equiv. BuLi, 08, 4 h) gave ester 16.
This compound was further derivatized to give ester (R)-20, the enantiomeric purity of
which was determined to be 66% by HPLC. Since this alternative route differs from
that outlined in Scheme 3 only in the reaction involving the removal of the auxiliary, we
can conclude that the cleavage of the auxiliary with BnOLi is not always free of
epimerization/racemization8).
In conclusion, we have shown the remarkable potential of 3-acyl-DIOZ derivatives
for the preparation of b2-amino acids carrying the side chains of Asp, Asn, Glu, and
Gln. Furthermore, we have judiciously verified the enantiomeric purity of these
compounds by HPLC on a chiralstationary phase in order to ensure their utiilty as
building blocks for solid-phase peptide synthesis according to the Fmoc protocol. Our
approach can easily be scaled up to produce multigram amounts of these amino acids in
enantiomerically pure form.
11
)
Interestingly, the (S)-form of the asparagine, but the (R)-form of the glutamine derivative, is eluted first.

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Fig. 4. HPLC Traces of a) the asparagine derivative (R)-20 and of rac-20, and b) the glutamine derivative (R)-21
and rac-21 (Chiralcel OD-H, l ˆ 220 nm, mobile phase: iPrOH/hexane 20 :80 for 20 and iPrOH/hexane 15 :85
for 21). The arrows indicate the signals of the minor enantiomers. The e.r. values were determined by
integration of the corresponding peaks: (R)-20: 99.7 :0.3; (R)-21: > 99 :1. tR in min.
Experimental Part
1. General. Abbreviations: CDI: 1,1'-Carbonyldi(1H-imidazole), DIOZ: 5,5-diphenyl-4-isopropyl-1,3-
oxazolidin-2-one, DMAP: 4-(dimethylamino)pyridine, DPPA: diphenylphosphoryl azide, FC: flash chroma-
tography, h.v.: high vacuum, 0.01 0.1 Torr, LHMDS: lithium hexamethyldisilazide, NHMDS: sodium
hexamethyldisilazide, TBAI: tetrabutylammonium iodide, TES: Et3SiH. Solvents for chromatography and
workup procedures were distilled from Sikkon (anh. CaSO4; Fluka), THF was distilled from Na, CH2Cl2 and
Et3N from CaH2. LiClwas dried in h.v. at 100 8 for 1 h. All other reagents were used as received from Fluka.
TLC: Merck silica-gel 60 F254 plates; detection with UV or −Mo-stain× soln. (25 g phosphormolybdic acid, 10 g
Ce(SO4)2 ¥ H2O, 60 mlconc. H 2SO4, 940 mlH 2O). 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.: B¸chi-510 apparatus; uncorrected. Opticalrotations: Perkin-Elmer 241
polarimeter (10 cm, 1-ml cell). IR Spectra: Perkin-Elmer 1600 FT-IR spectrophotometer. NMR Spectra: Bruker
AMX-400 (1H 400 MHz, 13C 100 MHz); chemicalshifts d in ppm downfield from internal Me4Si (ˆ0 ppm); J
values in Hz. Mass Spectra: 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 f¸r Organische Chemie, ETH-Z¸rich.
2. Preparation of Diacid Mono-tert-butyl Esters: General Procedure 1 (GP 1). Similarly to the procedure
reported in [54], the corresponding anhydride was suspended in toluene (1.7m) under Ar, and treated
t
subsequently with N-hydroxysuccinimide (0.3 equiv.), DMAP (0.1 equiv.), dry BuOH (3 equiv.) and Et3N
(0.3 equiv.). The mixture was stirred for 30 min at r.t., and heated at reflux for 1 d. After cooling, AcOEt was
added, the org. phase washed with 10% citric acid (3Â) and sat aq. NaClsonl . (1 Â), dried (MgSO4), and
concentrated under reduced pressure. FC or recrystallization yielded the pure product.
3. Acylation of the Auxiliary by the Mixed Anhydride Method: General Procedure 2 (GP 2). Similarly to the
procedure reported in [8], to a soln. of the corresponding carboxylic acid in THF (0.2m) under Ar, cooled at
À308, Et3N (2.5 equiv.) and pivaloyl chloride (1 equiv.) were added dropwise. The resulting suspension was
stirred at À308 for 2 h. At this point, LiCl(1.1 equiv.) and the auxiliary (0.95 equiv.) were added at once, stirring
was continued for 1 2 d as the mixture was slowly allowed to warm to r.t. The mixture was diluted with Et2O,

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Helvetica Chimica Acta Vol. 87 (2004)
washed with sat. aq. NH4Clsonl. (2 Â), 1m NaOH (2Â), and sat. aq. NaClsonl., dried (MgSO 4), and
concentrated under reduced pressure. FC of the crude product yielded the pure compound.
4. Alkylation of Acyloxazolidinones with Benzyl Iodoacetate: General Procedure 3 (GP 3). To a soln. of the
corresponding substrate in THF (0.3m) at À788, LHMDS (1.1 equiv.) was slowly added, and the mixture was
stirred for 1 h at this temp. At this point, a soln. of benzyl iodoacetate (1.5 equiv.) in THF (1:1, v/v) was slowly
added over 1 h, and the resulting mixture was stirred for 20 h at À508. The mixture was then diluted with Et2O
and washed with sat. aq. NH4Clsoln., 5% NaHSO 3, and sat. aq. NaClsoln. The org. phase was dried (Na 2SO4),
and concentrated under reduced pressure. FC of the crude product yielded the pure compound.
5. Selective Hydrogenolysis of the Bn Ester in the Presence of DIOZ: General Procedure 4 (GP 4). The
corresponding substrate was dissolved in THF (0.02m) and ca. 10% (w/w) Pd/C (10%) was added. The apparatus
was evacuated and flushed with H2 (3Â), and the soln. stirred under an atmosphere of H2 (balloon) for 1.5 h
(TLC control). The mixture was then filtered through Celite and washed thoroughly with CH2Cl2. The filtrate
was collected and concentrated under reduced pressure. FC of the crude product yielded the pure compound.
6. Curtius Rearrangement: General Procedure 5 (GP 5). The corresponding substrate was dissolved in
toluene (0.15m) under Ar, and Et3N (1.2 equiv.), followed by DPPA (1.2 equiv), was added. The resulting
mixture was stirred for 30 min at r.t., and subsequently heated at reflux for 1.5 h. BnOH (2 equiv.) was then
added, and the mixture was refluxed for further 16 h. After cooling, the mixture was diluted with Et2O, washed
with sat. aq. NaHCO3 soln. and sat. aq. NaCl soln., dried (NaSO4), and concentrated under reduced pressure.
FC of the crude product yielded the pure compound.
7. Cleavage of the Chiral Auxiliary with LiOH/H2O2: General Procedure 6 (GP 6). To a soln. of the
corresponding substrate in THF/H2O 4 :1 (0.2m) at 08, H2O2 (30% aq., 4.0 equiv.) and LiOH ¥ H2O (1.6 equiv.)
were added, and the resulting mixture was stirred at 08 for 2 h. The mixture was diluted with H2O, and the
precipitated chiral auxiliary was removed by filtration. The THF was evaporated at 258 under reduced pressure,
the soln. was cooled to 08, and AcOEt was added to the mixture. Upon slow addition of 10% citric acid and with
continuous stirring of the biphasic system at 08, the pH of the aq. phase was adjusted to 4 5. The org. layer was
separated, and the aq. phase was extracted with AcOEt (3Â). The combined org. layers were washed with sat.
aq. NaClsoln., dried (Na 2SO4), and concentrated under reduced pressure. FC of the crude product yielded the
pure compound.
8. Hydrogenolysis of Z groups and Bn Esters: General Procedure 7 (GP 7). The corresponding substrate
was dissolved in MeOH (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.
9. Fmoc Protection: General Procedure 8 (GP 8). 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 readjusted to 9 10 with additionalaq. Na 2CO3 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 with 0.6m aq. Na2CO3. The aq. mixture was then extracted with
Et2O (2Â). 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 of
the crude product yielded the pure compound.
10. Preparation of Bn Esters: General Procedure 9 (GP 9). To a soln. of the corresponding acid in DMF
(0.2m) were added NaHCO3 (2.0 equiv.), TBAI (0.3 equiv.), and BnBr (5.0 equiv.). The resulting mixture was
vigorously stirred at r.t. for 20 h. The mixture was diluted with Et2O, and the org. phase was washed with H2O
and sat. aq. NaClsoln. The org. phase was dried (Na 2SO4) and concentrated under reduced pressure. FC of the
crude product yielded the pure compound.
t
11. Bu Ester Deprotection: General Procedure 10 (GP 10). To a soln. of the corresponding substrate in
CH2Cl2 (0.4m), TES (2.5 equiv.) and TFA (13.0 equiv.) were added dropwise, and the mixture was stirred at r.t.
for 2 h. The solvent was removed under reduced pressure at 258 and residualTFA co-evaporated with toul ene
(3Â). The product obtained was used in the next step without further purification.
12. Conversion of an Acid to an Amide: General Procedure 11 (GP 11). The corresponding acid was
dissolved in THF (0.13m), and CDI (2 equiv.) was added. After stirring for 5 h under Ar, excess NH3 gas was
bubbled through the soln. The mixture was then diluted with AcOEt, and the org. phase was washed with H2O,

Helvetica Chimica Acta Vol. 87 (2004)
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1m HCl, and sat. aq. NaCl soln. The org. phase was dried (Na2SO4) and concentrated under reduced pressure.
Crystallization yielded the pure compound.
13. N-Trt Protection: General Procedure 12 (GP 12). To a suspension of the corresponding substrate in
AcOH (0.27m), solid TrtOH (2.0 equiv.) was added, followed by a soln. of Ac2O/AcOH/H2SO4 100 :200 :3.6
(0.56 ml/mmol). The mixture was heated at 408 and stirred for 5.5 h. Et2O was then added, and the org. phase
was washed with 5% NaHCO3 and sat. aq. NaClsonl . The org. phase was dried (Na 2SO4) and concentrated
under reduced pressure. FC of the crude product yielded the pure compound.
4-(tert-Butoxy)-4-oxobutanoic Acid (1). Transformation of succinic anhydride (30 g, 0.3 mol) according to
GP 1, followed by recrystallization (Et2O/pentane), afforded 1 (36.36 g, 70%). White solid. The anal. data are in
agreement with the values reported in [54][60].
5-(tert-Butoxy)-5-oxopentanoic Acid (2). Transformation of glutaric anhydride (34.2 g, 0.3 mol) according
to GP 1, followed by FC (Et2O/pentane 1:1), afforded 2 (13.6 g, 24%). Colorless oil. The anal. data are in
agreement with the values reported in [61].
(R)-3-{3-[(tert-Butoxy)carbonyl]-1-oxopropyl}-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (3). Reac-
tion of 1 (6.0 g, 34.4 mmol) with (R)-DIOZ (9.21 g, 32.7 mmol) according to GP 2, followed by FC (Et2O/
pentane 1:5), afforded 3 (13.2 g, 92%). White solid. M.p. 149 1518. Rf (Et2O/pentane 1 :5) 0.30. [a]rD:t: ˆ ‡184.0
(c ˆ 1.00, CHCl3). IR (CHCl3): 2978w, 1782s, 1718m, 1494w, 1450w, 1368m, 1320w, 1153m, 1051w, 1001w, 941w,
t
845w. 1H-NMR (400 MHz, CDCl3): 0.77 (d, J ˆ 6.8, Me); 0.87 (d, J ˆ 7.0, Me); 1.40 (s, Bu); 1.90 2.00 (m,
Me2CH); 2.43 2.59 (m, CH2); 2.93 (ddd, J ˆ 12.3, 6.8, 5.4, 1 H, CH2); 3.26 (ddd, J ˆ 13.9, 8.2, 6.7, 1 H, CH2);
5.38 (d, J ˆ 3.3, CHN); 7.26 7.40 (m, 8 arom. H); 7.45 7.48 (m, 2 arom. H). 13C-NMR (CDCl3, 100 MHz):
16.32, 21.72, 28.00 (Me); 29.77 (CH2); 30.01 (CH); 30.88 (CH2); 64.49 (CH); 80.46, 89.46 (C); 125.68, 125.96,
128.37, 128.61, 128.92 (CH); 138.24, 142.32, 152.99, 171.32, 171.93 (C). MALDI-MS: 460.2 (44.34), 404.1
(100.00). Anal. calc. for C26H31NO5 (437.53): C 71.37, H 7.14, N 3.20; found: C 71.40, H 7.26, N 3.15.
(R)-3-{4-[(tert-Butoxy)carbonyl]-1-oxobutyl}-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (4). Reac-
tion of 2 (6.5 g, 34.5 mmol) with (R)-DIOZ (9.23 g, 32.8 mmol) according to GP 2, followed by FC (Et2O/
pentane 1:5), afforded 4 (13.3 g, 90%). White solid. M.p. 92 938. Rf (Et2O/pentane 1:5) 0.30. [a]rD:t: ˆ ‡173.0
(c ˆ 1.00, CHCl3). IR (CHCl3): 3011w, 2972w, 1781s, 1718s, 1494w, 1450m, 1368m, 1320w, 1320m, 1154m, 1050w,
1001w, 844w, 638w. 1H-NMR (400 MHz, CDCl3): 0.76 (d, J ˆ 6.8, Me); 0.87 (d, J ˆ 7.0, Me); 1.42 (s, tBu); 1.78
2.01 (m, CH2, Me2CH); 2.20 (t, J ˆ 7.4, CH2); 2.77 (ddd, J ˆ 17.0, 8.0, 6.6, 1 H, CH2); 2.96 (ddd, J ˆ 17.0, 8.2, 6.6,
1 H, CH2); 5.37 (d, J ˆ 3.4, CHN); 7.25 7.40 (m, 8 arom. H); 7.45 7.48 (m, 2 arom. H). 13C-NMR (100 MHz,
CDCl3): 16.40 (Me); 19.91 (CH2); 21.77, 28.07 (Me); 29.85 (CH); 34.31, 34.48 (CH2); 64.47 (CH); 80.27, 89.40
(C); 125.58, 125.92, 127.94, 128.36, 128.60, 128.90 (CH); 138.14, 142.29, 152.98, 172.20, 172.42 (C). MALDI-MS:
474.2 (46.16), 418.2 (98.46). Anal. calc. for C27H33NO5 (451.56): C 71.83, H 7.37, N 3.10; found: C 71.81, H 7.24,
N 3.36.
(R)-3-((R)-2-{[(tert-Butoxy)carbonyl]methyl}-1-oxopent-4-enyl)-4-(1-methylethyl)-5,5-diphenyloxazoli-
din-2-one (5). Compound 3 (150 mg, 0.34 mmol) was dissolved in THF (0.1m) and cooled to À788. LHMDS (1m
in THF, 0.38 ml, 1.1 equiv.) was added dropwise, and the mixture was stirred for 1.5 h at this temp. At this point,
allyl iodide (0.16 ml, 5 equiv.) was added slowly over 30 min, and the resulting mixture was stirred at À508 for
23 h. The mixture was quenched with sat. aq. NH4Cl soln. and diluted with Et2O. The org. phase was washed with
1m HCl, 1m NaOH, and sat. aq. NaClsoln., dried (MgSO 4), and concentrated under reduced pressure. FC (Et2O/
pentane 1:6) of the crude product yielded 5 (108 mg, 66%, d.r. 96 :4). Colorless oil. Rf (Et2O/pentane 1:6) 0.34.
t
1H-NMR (400 MHz, CDCl3): 0.72 (d, J ˆ 6.7, Me); 0.87 (d, J ˆ 7.0, Me); 1.23 (s, Bu); 1.93 2.01 (m, Me2CH);
2.27 (dd, J ˆ 16.9, 4.5, 1 H, CH2); 2.23 2.30 (m, 1 H, CH2); 2.54 (dd, J ˆ 16.9, 10.5, 1 H, CH2); 2.51 2.57 (m,
1 H, CH2); 3.95 4.02 (m, CH2CH); 5.06 5.13 (m, CH2 ˆ ); 5.45 (d, J ˆ 2.8, CHN); 5.76 5.86 (m, CHˆ); 7.25
7.51 (m, 8 arom. H); 7.44 7.49 (m, 2 arom. H). 13C-NMR (100 MHz, CDCl3): 16.18, 22.00, 28.03 (Me); 30.63
(CH); 36.18, 36.90 (CH2); 39.64, 64.61 (CH); 80.55, 89.52 (C); 118.09 (CH2); 126.14, 126.33, 128.22, 128.73,
128.89, 129.25, 135.04 (CH); 139.03, 142.97, 152.97, 171.15, 175.04 (C). MALDI-MS: 500.2 (36.73), 444.2
‡
(100.00). HR-MALDI-MS: 500.2447 ([C29H35NNaO5] ; calc. 500.2407).
(R)-3-((R)-2-{[(Benzyloxy)carbonyl]methyl}-3-[(tert-butoxy)carbonyl]-1-oxopropyl)-4-(1-methylethyl)-
5,5-diphenyloxazolidin-2-one (6). Transformation of 3 (3.2 g, 7.32 mmol) according to GP 3, followed by FC
(Et2O/pentane 1:4) afforded, beside the recovery of unreacted starting material(0.8 g, 25%), compound
6
(2.43 g, 57%). Colorless oil. Rf (Et2O/pentane 1:4) 0.24. [a]rD:t: ˆ ‡124.5 (c ˆ 0.80, CHCl3). IR (CHCl3): 3015w,
1
2974w, 2933w, 1780s, 1728s, 1703m, 1451w, 1364m, 1318w, 1330m, 1159s, 1051w. H-NMR (400 MHz, CDCl3):
0.75 (d, J ˆ 6.8, Me); 0.86 (d, J ˆ 7.0, Me); 1.30 (s, tBu); 1.91 1.99 (m, Me2CH); 2.23 (dd, J ˆ 16.5, 6.5, 1 H, CH2);
2.37 (dd, J ˆ 16.5, 7.8, 1 H, CH2); 2.62 (dd, J ˆ 16.5, 6.6, 1 H, CH2); 2.90 (dd, J ˆ 16.5, 7.3, 1 H, CH2); 4.32 4.39
(m, CH2CH); 5.11 (d, J ˆ 7.9, PhCH2); 5.38 (d, J ˆ 2.9, CHN); 7.24 7.48 (m, 15 arom. H). 13C-NMR (100 MHz,

1556
Helvetica Chimica Acta Vol. 87 (2004)
CDCl3): 16.04, 21.65, 27.92 (Me); 30.11 (CH); 35.65, 36.05 (CH2); 64.82 (CH); 66.60 (CH2); 80.72, 89.42 (C);
125.68, 125.80, 125.96, 127.91, 128.23, 128.25, 128.34, 128.54, 128.57, 128.85 (CH); 135.72, 138.29, 142.30, 152.59,
169.83, 170.86, 173.71 (C). MALDI-MS: 608.2 (44.44), 552.2 (100.00). Anal. calc. for C35H39NO7 (585.70):
C 71.78, H 6.71, N 2.39; found: C 71.95, H 6.62, N 2.44.
(R)-3-((R)-2-{[(Benzyloxy)carbonyl]methyl}-4-[(tert-butoxy)carbonyl]-1-oxobutyl)-4-(1-methylethyl)-
5,5-diphenyloxazolidin-2-one (7). Transformation of 4 (4.3 g, 9.52 mmol) according to GP 3, followed by FC
(Et2O/pentane 1:4), afforded 7 (3.14 g, 55%). Colorless oil. Rf (Et2O/pentane 1:4) 0.33. [a]rD:t: ˆ ‡112.8 (c ˆ
0.68, CHCl3). IR (CHCl3): 2930w, 1781s, 1727s, 1598m, 1451w, 1354m, 1313w, 1251w, 1239m, 1158s, 1149w.
t
1H-NMR (400 MHz, CDCl3): 0.74 (d, J ˆ 6.7, Me); 0.81 (d, J ˆ 7.0, Me); 1.31 (s, Bu); 1.41 1.68 (m, 2 CH2);
1.87 1.95 (m, Me2CH); 2.43 (dd, J ˆ 16.9, 4.4, 1 H, CH2); 2.88 (dd, J ˆ 16.9, 10.3, 1 H, CH2); 4.14 4.21 (m,
CH2CH); 5.03 (d, J ˆ 10.3, PhCH2); 5.63 (d, J ˆ 3.0, CHN); 7.15 7.38 (m, 11 arom. H); 7.43 7.44 (m, 2 arom.
H); 7.45 7.46 (m, 2 arom. H). 13C-NMR (100 MHz, CDCl3): 16.02, 21.52 (Me); 27.03 (CH2); 28.03 (Me); 30.02
(CH); 31.87, 36.37 (CH2); 37.92, 65.29 (CH); 66.49 (CH2); 80.20, 89.24 (C); 125.44, 125.78, 127.95, 128.18, 128.20,
128.43, 128.52, 128.70, 128.92 (CH); 135.78, 137.94, 142.46, 152.75, 171.38, 171.54, 174.71 (C). HR-MALDI-MS:
‡
622.2775 ([C36H41NNaO7] ; calc. 622.2781).
(R)-3-{(R)-[(tert-Butoxy)carbonyl]methyl}-4-[4-(1-methylethyl)-2-oxo-5,5-diphenyloxazolidin-3-yl]-4-oxo-
butanoic acid (8). Transformation of 6 (2.4 g, 4.1 mmol) according to GP 4, followed by FC (Et2O/pentane/
AcOH 10 :20 :0.1), afforded 8 (1.67 g, 82%). White foam. Rf (Et2O/pentane/AcOH 10 :20 :0.1) 0.31. [a]Dr:t:
ˆ
‡148.0 (c ˆ 1.00, CHCl3). IR (CHCl3): 2980w, 1780s, 1725s, 1601w, 1494w, 1450w, 1368m, 13196m, 1176m,
1153m, 1052w, 990w, 942w, 844w, 638w. 1H-NMR (400 MHz, CDCl3): 0.75 (d, J ˆ 6.7, Me); 0.86 (d, J ˆ 7.0, Me);
t
1.30 (s, Bu); 1.91 1.99 (m, Me2CH); 2.24 (dd, J ˆ 16.4, 6.5, 1 H, CH2); 2.36 (dd, J ˆ 16.4, 7.6, 1 H, CH2); 2.57
(dd, J ˆ 16.7, 6.6, 1 H, CH2); 2.86 (dd, J ˆ 16.7, 7.0, 1 H, CH2); 4.25 4.32 (m, CH2CH); 5.38 (d, J ˆ 3.0, CHN);
7.24 7.46 (m, 10 arom. H). 13C-NMR (100 MHz, CDCl3): 16.05, 21.63, 27.91 (Me); 30.08 (CH); 36.00 (CH2);
36.55, 64.81 (CH); 80.88, 89.51 (C); 125.82, 125.99, 127.91, 128.34, 128.57, 128.85 (CH); 138.24, 142.25, 152.65,
170.07, 173.72, 176.64 (C). MALDI-MS: 518.2 (68.93), 462.1 (100.00). Anal. calc. for C28H33NO7 (495.57):
C 67.86, H 6.71, N 2.83; found: C 67.74, H 6.54, N 2.76.
(R)-5-[(tert-Butoxy)carbonyl]-3-[(R)-4-(1-methylethyl)-2-oxo-5,5-diphenyloxazolidine-3-carbonyl]penta-
noic Acid (9). Transformation of 7 (2.67 g, 4.45 mmol) according to GP 4, followed by FC (Et2O/pentane/
AcOH 10 :20 :0.1), afforded 9 (2.02 g, 89%). White foam. Rf (Et2O/pentane/AcOH 10 :20 :0.1) 0.22. [a]Dr:t:
ˆ
‡121.5 (c ˆ 0.95, CHCl3). IR (CHCl3): 3015w, 2974m, 2933w, 1779s, 1718s, 1451w, 1390w, 1364m, 1318w, 1256w,
1
t
1236w, 1174m, 1149w. H-NMR (400 MHz, CD3OD): 0.78 (d, J ˆ 6.7, Me); 0.92 (d, J ˆ 7.0, Me); 1.39 (s, Bu);
1.39 1.46 (m, CH2); 1.60 1.65 (m, CH2); 2.01 2.08 (m, Me2CH); 2.45 (dd, J ˆ 17.0, 4.4, 1 H, CH2); 2.78 (dd,
J ˆ 17.0, 10.6, 1 H, CH2); 4.14 4.21 (m, CH2CH); 5.52 (d, J ˆ 2.7, CHN); 7.25 7.31 (m, 2 arom. H); 7.34 7.39
(m, 4 arom. H); 7.48 7.52 (m, 2 arom. H); 7.57-7.60 (m, 2 arom. H). 13C-NMR (100 MHz, CDCl3): 16.34, 21.93
(Me); 28.30 (CH2); 28.36 (Me); 31.46 (CH); 32.98, 37.13 (CH2); 39.29, 66.74 (CH); 81.64, 90.57 (C); 126.48,
126.82, 129.08, 129.80, 130.05 (CH); 139.54, 144.44, 154.39, 173.48, 174.99, 176.44 (C). HR-MALDI-MS:
‡
532.2306 ([C29H35NNaO7] ; calc. 532.2312).
tert-Butyl (S)-3-({[(Benzyloxy)carbonyl]amino}methyl)-4-[(R)-4-(1-methylethyl)-2-oxo-5,5-diphenyloxa-
zolidin-3-yl]-4-oxobutanoate (10). Transformation of 8 (2.0 g, 4.0 mmol) according to GP 5, followed by FC
(Et2O/pentane 1:3 ! 1:2), afforded 10 (1.84 g, 76%). White solid. M.p. 132 1348. Rf (Et2O/pentane 1:2) 0.28.
[a]Dr:t: ˆ ‡123.0 (c ˆ 1.00, CHCl3). IR (CHCl3): 3438w, 3008w, 2966w, 2992w, 1777s, 1722s, 1516m, 1450m, 1394w,
1
1368m, 1248m, 1154m, 1052w, 990w, 845w. H-NMR (400 MHz, CDCl3): 0.69 (d, J ˆ 6.7, Me); 0.84 (d, J ˆ 7.0,
Me); 1.26 (s, tBu); 1.91 1.99 (m, Me2CH); 2.30 (dd, J ˆ 16.8, 4.6, 1 H, CH2); 2.65 (dd, J ˆ 16.8, 9.9, 1 H, CH2);
3.44 4.60 (m, CH2); 4.09 4.13 (m, CH2CH); 5.07 (s, PhCH2); 5.23 (br. s, NH); 5.40 (d, J ˆ 3.0, CHN); 7.23
7.46 (m, 15 arom. H). 13C-NMR (100 MHz, CDCl3): 16.01, 21.79, 27.90 (Me); 30.01 (CH); 34.81 (CH2); 40.07
(CH); 42.80 (CH2); 64.87 (CH); 66.81 (CH2); 80.69, 89.67 (C); 125.79, 125.82, 127.93, 128.09, 128.16, 128.36,
128.48, 128.54, 128.85 (CH); 136.42, 138.25, 142.08, 153.18, 156.26, 170.13, 173.36 (C). MALDI-MS: 639.2
(3.07), 623.3 (20.11), 567.2 (100.00), 286.1 (44.30). Anal. calc. for C35H40N2O7 (600.70): C 69.98, H 6.71, N 4.66;
found: C 69.94, H 6.80, N 4.56.
tert-Butyl (S)-4-({[(Benzyloxy)carbonyl]amino}methyl)-5-[(R)-4-(1-methylethyl)-2-oxo-5,5-diphenyloxa-
zolidin-3-yl)-5-oxopentanoate (11). Transformation of 9 (5.94 g, 11.6 mmol) according to GP 5, followed by FC
(Et2O/pentane 1:3 ! 1 :2), afforded 11 (5.4 g, 75%). Colorless oil. Rf (Et2O/pentane 1 :2) 0.32. [a]rD:t: ˆ ‡75.8
(c ˆ 0.85, CHCl3). IR (CHCl3): 3015m, 2974w, 2933w, 1780s, 1718s, 1513m, 1451m, 1364m, 1313m, 1231s, 1176s,
1154s, 1050w, 990w. 1H-NMR (400 MHz, (D6)DMSO): 0.61 (d, J ˆ 6.7, Me); 0.85 (d, J ˆ 7.0, Me); 1.32 (s, tBu);
1.37 1.48 (m, 4 H, 2 CH2); 2.00 2.08 (m, Me2CH); 3.22 3.29 (m, CH2N); 3.78 3.82 (m, CH2CH); 4.93 5.02
(m, PhCH2); 5.58 (d, J ˆ 2.4, CHN); 7.24 7.41 (m, 12 H, 11 arom. H, NH); 7.57 (d, J ˆ 7.2, 2 arom. H), 7.64 (d,

Helvetica Chimica Acta Vol. 87 (2004)
1557
J ˆ 7.4, 2 arom. H). 13C-NMR (100 MHz, (D6)DMSO): 15.27, 20.90 (Me); 24.48 (CH2); 27.56 (Me); 29.21 (CH);
31.01 (CH2); 41.62 (CH); 41.99 (CH2); 64.80 (CH); 65.11 (CH2); 79.39, 88.65 (C); 124.74, 125.16, 127.54, 127.61,
127.71, 128.17, 128.26, 128.36, 128.63 (CH); 136.99, 137.80, 142.86, 152.35, 156.01, 170.87, 173.14 (C). HR-
‡
MALDI-MS: 637.2884 ([C36H42N2NaO7] ; calc. 637.2890). Anal. calc. for C36H42N2O7 (614.73): C 70.34, H 6.89,
N 4.56; found: C 70.30, H 6.75, N 4.62.
(S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-[(tert-butoxy)carbonyl]propanoic Acid (Z-b2hAsp-
(OtBu)-OH; 12). Transformation of 10 (3.0 g, 5.0 mmol) according to GP 6, followed by FC (Et2O/pentane/
AcOH 20 :10 :0.1), afforded 12 (1.5 g, 89%). Colorless oil. Rf (Et2O/pentane/AcOH 20 :10 :0.1) 0.40. [a]Dr:t:
ˆ
‡35.4 (c ˆ 0.85, CHCl3). IR (CHCl3): 3436m, 3036m, 2974m, 1718s, 1513s, 1451m, 1364m, 1148s. 1H-NMR
(400 MHz, CD3OD): 1.43 (s, tBu); 2.43 (dd, J ˆ 16.6, 5.2, 1 H, CH2); 2.55 (dd, J ˆ 16.6, 8.8, 1 H, CH2); 2.90 2.96
(m, CH2CH); 3.28 3.38 (m, 1 H, CH2N); 3.43 (dd, J ˆ 13.9, 6.3, 1 H, CH2N); 5.07 (s, PhCH2); 7.27 7.34 (m, 5
arom. H). 13C-NMR (100 MHz, CD3OD): 28.32 (Me); 36.04, 43.00 (CH2); 43.41 (CH); 67.55 (CH2); 82.07 (C),
‡
128.82, 129.00, 129.49 (CH); 138.38, 158.93, 172.75, 176.56 (C). HR-MALDI-MS: 360.1418 ([C17H23NNaO6] ;
calc. 360.1423).
(S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-4-[(tert-butoxy)carbonyl]butanoic Acid (Z-b2hGlu(OtBu)-
OH; 13). Transformation of 11 (2.7 g, 4.39 mmol) according to GP 6, followed by FC (Et2O/pentane/AcOH
20 :10 :0.1), afforded acid 13 (1.5 g, 93%). Colorless oil. Rf (Et2O/pentane/AcOH 20 :10 :0.1) 0.35. [a]rD:t: ˆ ‡2.3
(c ˆ 1.03, CHCl3). IR (CHCl3): 3446w, 2974w, 1718s, 1513m, 1451w, 1369m, 1149m. 1H-NMR (400 MHz,
t
(D6)DMSO): 1.31 (s, Bu); 1.52 1.66 (m, CH2); 2.04 2.21 (m, CH2CO); 2.36 2.40 (m, CH2CH); 2.96 3.03
(m, 1 H, CH2N); 3.11 3.18 (m, 1 H, CH2N); 4.94 (s, PhCH2); 7.21 7.31 (m, 5 arom. H); 12.25 (br. s, CO2H).
13C-NMR (100 MHz, (D6)DMSO): 24.26 (CH2); 27.63 (Me); 32.28, 41.82 (CH2); 44.26 (CH); 65.12 (CH2); 79.53
(C); 127.54, 127.63, 128.23 (CH); 137.06, 156.07, 171.54, 174.77 (C). HR-MALDI-MS: 374.1574
‡
([C18H25NNaO6] ; calc. 374.1580). Anal. calc. for C18H25NO6 (351.39): C 61.53, H 7.17, N 3.99; found: C 61.32,
H 7.13, N 4.00.
(S)-3-[(tert-Butoxy)carbonyl]-2-({[(9H-fluoren-9-yl)carbonyl]amino}methyl)propanoic Acid (Fmoc-
b2hAsp(OtBu)-OH; 14). The Z-protected acid 12 (1 g, 2.96 mmol) in MeOH (0.02m) was hydrogenated
according to GP 7. The resulting product was Fmoc-protected according to GP 8. FC (Et2O/pentane/AcOH
20 :10 :0.1) of the crude product afforded 14 (1.18 g, 94%). White solid. M.p. 109 1138. Rf (Et2O/pentane/
AcOH 20 :10 :0.1) 0.19. [a]rD:t: ˆ ‡1.4 (c ˆ 1.20, CHCl3). IR (CHCl3): 3450w, 3015m, 2981m, 1723s, 1515s, 1450m,
t
1369m, 1236s, 1153s. 1H-NMR (400 MHz, (D6)DMSO): 1.38 (s, Bu); 2.30 2.45 (m, COCH2); 2.73 2.80 (m,
CHCH2N); 3.08 3.15 (m, 1 H, CH2N); 3.25 3.30 (m, 1 H, CH2N); 4.21 (t, J ˆ 7.0 , CHCH2O); 4.30 (d, J ˆ 7.3,
CHCH2O); 7.31 7.44 (m, 4 arom. H, NH); 7.68 (d, J ˆ 7.4, 2 arom. H), 7.88 (d, J ˆ 7.5, 2 arom. H); 12.38 (br. s,
CO2H). 13C-NMR (100 MHz, (D6)DMSO): 27.60 (Me); 34.40, 41.41 (CH2); 41.62, 46.64 (CH); 65.28 (CH2);
79.76 (C); 120.01, 125.08, 126.94, 127.50 (CH); 140.63, 143.76, 156.09, 170.53, 173.97 (C). HR-MALDI-MS:
‡
448.1731 ([C24H27NNaO6] ; calc. 448.1736). Anal. calc. for C24H27NO6 (425.47): C 67.75, H 6.40, N 3.29; found:
C 67.84, H 6.39, N 3.34.
(S)-4-[(tert-Butoxy)carbonyl]-2-({[(9H-fluoren-9-yl)carbonyl]amino}methyl)butanoic Acid (Fmoc-
b2hGlu(OtBu)-OH; 15). The Z-protected acid 13 (0.2 g, 0.57 mmol) in MeOH (0.02m) was hydrogenated
according to GP 7. The resulting product was Fmoc-protected according to GP 8. FC (Et2O/pentane/AcOH
20 :10 :0.1) of the crude product afforded 15 (225 mg, 90%). Colorless oil. Rf (Et2O/pentane/AcOH 20 :10 :0.1)
0.18. [a]rD:t: ˆ ‡1.8 (c ˆ 0.85, CHCl3). IR (CHCl3): 3445w, 3010m, 2977w, 1720s, 1514m, 1448m, 1369m, 1225m,
t
1150s. 1H-NMR (400 MHz, (D6)DMSO): 1.38 (s, Bu); 1.63 1.73 (m, COCH2CH2); 2.13 2.27 (m, COCH2);
2.44 2.49 (m, CH2CH); 3.06-3.10 (m, 1 H, CH2N); 3.20 3.25 (m, 1 H, CH2N); 4.20 (t, J ˆ 5.5, CHCH2O); 4.27
(d, J ˆ 4.7, CHCH2O); 7.31 7.45 (m, 4 arom. H, NH); 7.69 (d, J ˆ 6.0, 2 arom. H), 7.88 (d, J ˆ 6.0, 2 arom. H);
12.32 (br. s, CO2H). 13C-NMR (100 MHz, (D6)DMSO): 24.25 (CH2); 27.64 (Me); 32.29, 41.78 (CH2); 44.24,
46.62 (CH); 65.33 (CH2); 79.54 (C); 119.99, 125.10, 126.95, 127.50 (CH); 140.62, 143.78, 156.05, 171.55, 174.79
‡
(C). HR-MALDI-MS: 462.1887 ([C25H29NNaO6] ; calc. 462.1893). Anal. calc. for C25H29NO6 (439.50): C 68.32,
H 6.65, N 3.19; found: C 68.33, H 6.81, N 3.19.
1-Benzyl 4-(tert-Butyl) (S)-2-([{(Benzyloxy)carbonyl]amino}methyl)butanedioate (Z-b2hAsp(OtBu)-
OBn; 16). Transformation of 12 (2.7 g, 8.0 mmol) according to GP 9, followed by FC (Et2O/pentane 1:2),
afforded 16 (3.11 g, 91%). Colorless oil. Rf (Et2O/pentane 2 :1) 0.34. [a]rD:t: ˆ ‡1.6 (c ˆ 1.03, CHCl3). IR
(CHCl3): 3446w, 3015m, 2974w, 1723s, 1513m, 1456w, 1364m, 1251m, 1149s. 1H-NMR (400 MHz, CD3OD): 1.37
t
(s, Bu); 2.45 (dd, J ˆ 16.8, 4.8, 1 H, COCH2); 2.60 (dd, J ˆ 16.8, 9.4, 1 H, COCH2); 2.97 3.03 (m, CH2CH);
3.33 3.43 (m, CH2N); 5.04 5.13 (m, 2 PhCH2); 7.27 7.36 (m, 10 arom. H). 13C-NMR (100 MHz, CD3OD):
28.25 (Me); 35.85, 43.03 (CH2); 45.58 (CH); 67.53, 67.75 (CH2); 82.13 (C); 128.80, 128.97, 129.17, 129.24, 129.45,

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Helvetica Chimica Acta Vol. 87 (2004)
‡
129.51 (CH); 138.28, 137.39, 158.83, 172.44, 174.56 (C). HR-MALDI-MS: 450.1887 ([C24H29NNaO6] ; calc.
450.1893). Anal. calc. for C24H29NO6 (427.49): C 67.43, H 6.84, N 3.28; found: C 67.18, H 6.84, N 3.53.
1-Benzyl 5-(tert-Butyl) (S)-2-([{(Benzyloxy)carbonyl]amino}methyl)pentanedioate (Z-b2hGlu(OtBu)-
OBn; 17). Transformation of 13 (3.0 g, 8.5 mmol) according to GP 9, followed by FC (Et2O/pentane 1:2),
afforded 17 (3.5 g, 93%). Colorless oil. Rf (Et2O/pentane 2 :1) 0.26. [a]rD:t: ˆ ‡5.7 (c ˆ 0.58, CHCl3). IR (CHCl3):
3446w, 3026w, 2995w, 1718s, 1513m, 1456w, 1364w, 1236m, 1149m. 1H-NMR (400 MHz, (D6)DMSO): 1.37 (s,
tBu); 1.67 1.73 (m, COCH2CH2); 2.10 2.25 (m, COCH2); 2.57 2.65 (m, CH2CH); 3.11 3.18 (m, 1 H, CH2N);
3.22 3.29 (m, 1 H, CH2N); 5.00 5.10 (m, 2 PhCH2); 7.28 7.36 (m, 10 arom. H); 7.44 (t, J ˆ 5.9, NH). 13C-NMR
(100 MHz, (D6)DMSO): 24.24 (CH2); 27.61 (Me); 32.04, 41.90 (CH2); 44.33 (CH); 65.20, 65.64 (CH2); 79.53
(C); 127.56, 127.65, 127.75, 127.87, 128.21, 128.27 (CH); 136.01, 137.00, 156.08, 171.42, 173.07 (C). HR-MALDI-
‡
MS: 464.2044 ([C25H31NNaO6] ; calc. 464.2049). Anal. calc. for C25H31NO6 (441.52): C 68.01, H 7.08, N 3.17;
found: C 61.12, H 6.97, N 3.29.
Benzyl (S)-3-(Aminocarbonyl)-2-([{(benzyloxy)carbonyl]amino}methyl)propanoate (Z-b2hAsn-OBn;
t
18). The diester 16 (0.55 g, 1.29 mmol) was Bu deprotected according to GP 10. The acid obtained was then
converted to 18 according to GP 11. Recrystallization of the crude product yielded 18 (345 mg, 72%). White
solid. M.p. 130 1318. Rf (AcOEt/Et2O 2 :1) 0.2. [a]rD:t: ˆ À18.7 (c ˆ 0.92, CHCl3). IR (CHCl3): 3518w, 3426w,
3405w, 3015w, 2954w, 1723s, 1682s, 1595w, 1513m, 1451w, 1226s, 1174w. 1H-NMR (400 MHz, (D6)DMSO): 2.28
(dd, J ˆ 15.8, 5.1, 1 H, COCH2); 2.44 (dd, J ˆ 15.8, 9.0, 1 H, COCH2); 2.90 2.97 (m, CH2CH); 3.16 3.29 (m,
CH2N); 4.97 5.07 (m, 2 PhCH2); 6.82 (br. s, 1 H, NH2); 7.28 7.37 (m, 11 H, 10 arom. H, NH2); 7.42 (t, J ˆ 6.0,
NH). 13C-NMR (100 MHz, (D6)DMSO): 34.17, 41.64 (CH2); 41.83 (CH); 65.23, 65.50 (CH2); 127.51, 127.59,
127.67, 127.70, 128.21, 128.23 (CH); 136.11, 136.97, 156.09, 171.92, 172.90 (C). HR-MALDI-MS: 393.1421
‡
([C20H22N2NaO5] ; calc. 393.1427). Anal. calc. for C20H22N2O5 (370.40): C 64.85, H 5.99, N 7.56; found: C 64.83,
H 5.95, N 7.43.
Benzyl (S)-4-(Aminocarbonyl)-2-([{(benzyloxy)carbonyl]amino}methyl)butanoate (Z-b2hGln-OBn; 19).
The diester 17 (3.5 g, 7.93 mmol) was tBu deprotected according to GP 10. The acid obtained was then converted
to 19 according to GP 11. Recrystallization of the crude product yielded 19 (2.63 g, 83%). White solid. M.p.
112 1138. Rf (EtOAc/Et2O 2 :1) 0.28. [a]rD:t: ˆ ‡2.5 (c ˆ 0.95, CHCl3). IR (CHCl3): 3528w, 3446w, 3405w, 3036w,
3005w, 2964w, 1718s, 1682s, 1590w, 1513m, 1451w, 1226m, 1164w. 1H-NMR (400 MHz, (D6)DMSO): 1.66 1.73
(m, COCH2CH2); 1.99 2.12 (m, COCH2); 2.56 2.63 (m, CH2CH); 3.13 3.29 (m, CH2N); 5.00 (s, PhCH2); 5.06
(s, PhCH2); 6.73 (s, 1 H, NH2); 7.23 (s, 1 H, NH2); 7.27 7.37 (m, 10 arom. H); 7.42 (t, J ˆ 5.9, NH). 13C-NMR
(100 MHz, (D6)DMSO): 24.75, 32.20, 42.01 (CH2); 44.79 (CH); 65.18, 65.58 (CH2); 127.56, 127.65, 127.71, 127.83,
‡
128.23, 128.28 (CH); 136.02, 137.00, 156.06, 173.27 (C). HR-MALDI-MS: 407.1577 ([C21H24N2NaO5] ; calc.
407.1583). Anal. calc. for C21H24N2O5 (384.43): C 65.61, H 6.29, N 7.29; found: C 65.67, H 6.50, N 7.37.
Benzyl (S)-2-([{(Benzyloxy)carbonyl]amino}methyl)-3-{[triphenylmethyl)amino]carbonyl}propanoate
(Z-b2hAsn(Trt)-OBn; 20). Treatment of 18 (0.3 g, 0.81 mmol) according to GP 12, followed by FC (Et2O/
pentane 3 :1), afforded 20 (421 mg, 85%). White solid. M.p. 104 1058. Rf (Et2O/pentane 3 :1) 0.29. [a]Dr:t:
ˆ
À20.8 (c ˆ 1.15, CHCl3). IR (CHCl3): 3434w, 3028w, 3020w, 1721s, 1513s, 1492s, 1446w, 1236m, 1195w, 1169w.
1H-NMR (400 MHz, (D6)DMSO): 2.45 (dd, J ˆ 15.6, 5.2, 1 H, COCH2); 2.75 (dd, J ˆ 15.6, 8.9, 1 H, COCH2);
2.83 2.90 (m, CH2CH); 3.12 3.26 (m, CH2N); 4.96 5.05 (m, 2 PhCH2); 7.14 7.34 (m, 25 arom. H); 7.38 (t, J ˆ
6.1, NH); 8.69 (s, NHTrt). 13C-NMR (100 MHz, (D6)DMSO): 35.20, 41.71 (CH2); 41.88 (CH); 65.25, 65.60
(CH2); 69.24 (C); 126.21, 127.30, 127.56, 127.62, 127.68, 127.72, 128.03, 128.22, 128.42 (CH); 136.01, 136.95,
‡
144.69, 156.08, 169.75, 172.79 (C). HR-MALDI-MS: 635.2516 ([C39H36N2NaO5] ; calc. 635.2522). Anal. calc.
for C39H36N2O5 (612.71): C 76.45, H 5.92, N 4.57; found: C 76.27, H 6.02, N 4.57.
Benzyl (S)-2-([{(Benzyloxy)carbonyl]amino}methyl)-4-{[(triphenylmethyl)amino]carbonyl}butanoate (Z-
b2hGln(Trt)-OBn; 21). Treatment of 19 (2.66 g, 6.9 mmol) according to GP 12, followed by FC (Et2O/pentane
3 :1), afforded 21 (3.81 g, 88%). White solid. M.p. 91 928. Rf (Et2O/pentane 3 :1) 0.3. [a]rD:t: ˆ À4.6 (c ˆ 0.90,
CHCl3). IR (CHCl3): 3536w, 3067w, 3035w, 3005w, 1718s, 1682m, 1512s, 1492s, 1446w, 1235m, 1164w. 1H-NMR
(400 MHz, (D6)DMSO): 1.63 1.68 (m, COCH2CH2); 2.27 2.30 (m, COCH2); 2.52 2.59 (m, CH2CH); 3.12
3.25 (m, CH2N); 4.99 (s, PhCH2); 5.07 (s, PhCH2); 7.14-7.32 (m, 25 arom. H); 7.33 (t, J ˆ 2.4, NH) 7.23 (s, NHTrt).
13C-NMR (100 MHz, (D6)DMSO): 24.89, 33.09, 41.91 (CH2); 44.73 (CH); 65.18, 65.56 (CH2); 69.10 (C); 126.19,
127.32, 127.56, 127.64, 127.67, 127.81, 128.22, 128.27 (CH); 136.04, 136.98, 144.79, 156.07, 171.09, 173.29 (C). HR-
‡
MALDI-MS: 649.2673 ([C40H38N2NaO5] ; calc. 649.2679). Anal. calc. for C40H38N2O5 (626.74): C 76.66, H 6.11,
N 4.47; found: C 76.65, H 6.16, N 4.41.
(S)-2-({[(9H-Fluoren-9-yl)carbonyl]amino}methyl)-3-{[(triphenylmethyl)amino]carbonyl}propanoic Acid
(Fmoc-b2hAsn(Trt)-OH; 22). Hydrogenation of 20 (0.39 g, 0.64 mmol) in MeOH (0.02m) according to GP 7
afforded the crude H-b2hAsn(Trt)-OH, which was Fmoc-protected according to GP 8 to give, after FC (AcOEt/

Helvetica Chimica Acta Vol. 87 (2004)
1559
pentane/AcOH 20 :10 :0.1), the acid 22 (0.36 g, 93%). White foam. Rf (AcOEt/pentane/AcOH 20 :10 :0.1) 0.4.
[a]Dr:t: ˆ À29.6 (c ˆ 1.35, CHCl3). IR (CHCl3): 3436w, 3056w, 3005w, 2995w, 1718s, 1672m, 1625w, 1513s, 1492s,
1
1446m, 1231m. H-NMR (400 MHz, (D6)DMSO): 2.36 (dd, J ˆ 15.2, 4.8, 1 H, COCH2); 2.67 (dd, J ˆ 15.2, 9.1,
1 H, COCH2); 2.72 2.75 (m, CH2CH); 3.06 3.13 (m, 1 H, CH2N); 3.18 3.26 (m, 1 H, CH2N); 4.19 4.22 (m,
CHCH2O); 4.26 4.28 (m, CH2O); 5.01 (d, J ˆ 1.8, NHCH2); 7.15 7.21 (m, 9 arom. H); 7.23 7.42 (m, 10 arom.
H); 7.68 (d, J ˆ 7.4, 2 arom. H); 7.88 (d, J ˆ 7.5, 2 arom. H); 8.64 (s, NHTrt); 12.27 (br. s, CO2H). 13C-NMR
(100 MHz, (D6)DMSO): 34.43, 41.66 (CH2); 41.80, 46.60 (CH); 65.36 (CH2); 69.20 (C); 120.00, 125.10, 126.20,
126.97, 127.30, 127.51, 127.60, 127.65, 128.23, 128.46 (CH); 137.03, 140.60, 143.74, 143.79, 144.79, 156.05, 170.07,
‡
174.53, 174.56 (C). HR-MALDI-MS: 633.2366 ([C39H34N2NaO5] ; calc. 633.2360).
(S)-2-({[(9H-Fluoren-9-yl)carbonyl]amino}methyl)-4-{[(triphenylmethyl)amino]carbonyl}butanoic Acid
(Fmoc-b2hGln(Trt)-OH; 23). Hydrogenation of 21 (0.25 g, 0.4 mmol) in MeOH (0.02m) according to GP 7
afforded the crude H-b2hGln(Trt)-OH, which was Fmoc-protected according to GP 8 to give, after FC (AcOEt/
pentane/AcOH 20 :10 :0.1), the acid 23 (0.23 g, 92%). White foam. Rf (AcOEt/pentane/AcOH 20 :10 :0.1) 0.22.
[a]Dr:t: ˆ À10 (c ˆ 0.95, CHCl3). IR (CHCl3): 3436w, 3024w, 2974w, 1713s, 1513s, 1492s, 1446m, 1236m, 1149w,
1103w. 1H-NMR (400 MHz, (D6)DMSO): 1.59 1.66 (m, COCH2CH2); 2.27 2.32 (m, COCH2); 2.41 2.45 (m,
CH2CH); 3.04 3.11 (m, 1 H, CH2N); 3.16 3.23 (m, 1 H, CH2N); 4.18 4.21 (m, CHCH2O); 4.24 4.26 (m,
CH2O); 7.15 7.34 (m, 17 arom. H, NH); 7.40 (t, J ˆ 7.4, 3 arom. H); 7.67 (d, J ˆ 7.4, 2 arom. H); 7.88 (d, J ˆ 7.5, 2
arom. H); 8.57 (s, NHTrt); 12.26 (br. s, CO2H). 13C-NMR (100 MHz, (D6)DMSO): 25.00, 33.36, 41.81 (CH2);
44.67, 46.59 (CH); 65.35 (CH2); 69.08 (C); 119.98, 125.11, 126.17, 126.96, 127.32, 127.50, 128.23, 128.41 (CH);
‡
140.60, 143.77, 144.83, 156.04, 171.29, 175.02 (C). HR-MALDI-MS: 647.2523 ([C40H36N2NaO5] ; calc. 647.2516).
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Received February 16, 2004