Preparation of (S,S)-Fmoc-β2hIle-OH, (S)-Fmoc-β 2hMet-OH, and (S)-Fmoc-β2hTyr(tBu)-OH for Solid-Phase Syntheses of β2- and β2/β 3-Peptides

Article abstract of DOI:10.1002/hlca.200390337

The preparation of three new N-Fmoc-protected (Fmoc=[(9H-fluoren-9-yl)methoxy]carbonyl) β²-homoamino acids with proteinogenic side chains (from Ile, Tyr, and Met) is described, the key step being a diastereoselective amidomethylation of the corresponding Ti-enolates of 3-acyl-4-isopropyl-5,5-diphenyloxazolidin-2-ones with CbzNHCH₂OMe/TiCl₄ (Cbz=(benzyloxy)carbonyl) in yields of 60-70% and with diastereoselectivities of > 90%. Removal of the chiral auxiliary with LiOH or NaOH gives the N-Cbz-protected β-amino acids, which were subjected to an N-Cbz/N-Fmoc (Fmoc=[(9H-fluoren-9-yl)methoxy]carbonyl) protective-group exchange. The method is suitable for large-scale preparation of Fmoc-β²hXaa-OH for solid-phase syntheses of β-peptides. The Fmoc-amino acids and all compounds leading to them have been fully characterized by melting points, optical rotations, IR, ¹H- and ¹³C-NMR, and mass spectra, as well as by elemental analyses.

Full text of DOI:10.1002/hlca.200390337

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Preparation of (S,S)-Fmoc-b2hIle-OH, (S)-Fmoc-b2hMet-OH, and (S)-Fmoc-
b2hTyr(tBu)-OH for Solid-Phase Syntheses of b2- and b2/b3-Peptides1)
by Radovan Sebesta2) and Dieter Seebach*
Laboratorium f¸r Organische Chemie der Eidgenˆssischen Technischen Hochschule Z¸rich,
Hˆnggerberg-HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Z¸rich
Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday
The preparation of three new N-Fmoc-protected (Fmoc ˆ [(9H-fluoren-9-yl)methoxy]carbonyl) b2-
homoamino acids with proteinogenic side chains (from Ile, Tyr, and Met) is described, the key step being a
diastereoselective amidomethylation of the corresponding Ti-enolates of 3-acyl-4-isopropyl-5,5-diphenylox-
azolidin-2-ones with CbzNHCH2OMe/TiCl4 (Cbz ˆ (benzyloxy)carbonyl) in yields of 60 70% and with
diastereoselectivities of > 90%. Removal of the chiral auxiliary with LiOH or NaOH gives the N-Cbz-protected
b-amino acids, which were subjected to an N-Cbz/N-Fmoc (Fmoc ˆ [(9H-fluoren-9-yl)methoxy]carbonyl)
protective-group exchange. The method is suitable for large-scale preparation of Fmoc-b2hXaa-OH for solid-
phase syntheses of b-peptides. The Fmoc-amino acids and all compounds leading to them have been fully
characterized by melting points, optical rotations, IR, 1H-and 13C-NMR, and mass spectra, as well as by
elemental analyses.
Introduction. In recent years, there has been considerable interest in the design
and synthesis of non-natural oligomers that form secondary structures [2]. In this class
of compounds, peptides consisting exclusively of b-amino acids have emerged as a
promising new class of compounds that form helices, hair-pin turns, or pleated-sheets in
solution with only a few b-amino acid residues, a field that has already been reviewed
[3].
Almost all b3-amino acids with proteinogenic side chains are now commercially
available3). Except for b2-homoalanine and b2-homoproline, however, no other b2-
amino acids of this type are on the market in enantiomerically pure form. In the past
few years, the preparation of b2-amino acids, mainly with simple alkyl side chains, was
published by several groups [5]4).
For our ongoing projects on the synthesis of b2/b3-and all- b2-peptides, we need to
have ample access to the b2-amino acid building blocks with proteinogenic side chains
and N-Fmoc protection. With the exceptions of b2hLys and b2hTrp, only Fmoc-
protected b2-amino acids with nonfunctionalized and achiral side chains have, so far,
been published [7]. We describe here, in detail, the preparation of three new b2-amino
acid derivatives, with the side chains of isoleucine, tyrosine, and methionine.
1
)
)
Partially published in a preliminary communication [1].
Postdoctoral fellow at ETH-Z¸rich, financed by the Swiss National Science Foundation (Grant No. 2000-
58831).
For review on their synthesis, see [4].
For a recent review article on b-amino acids synthesis, see [6].
2
3
4
)
)

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Results and Discussion. Acylation of (R)-4-isopropyl-5,5-diphenyloxazolidin-2-
one (1; DIOZ; derived from (R)-valine) can be achieved by two methods. The standard
Evans procedure [8] involves reaction of lithiated 1 (generated with BuLi) with an acid
chloride. The second possibility is the mixed-anhydride method introduced by Ho and
Mahre [9] (Scheme 1), which is more convenient when the corresponding acid chloride
is commercially or otherwise not available.
Scheme 1. Acylation of( R)-DIOZ
The carboxylic acid for the synthesis of b2-homoisoleucine was actually prepared
from isoleucine itself by reductive removal of the amino group with H2NOSO3H [10].
3-{4-[(tert-Butyl)diphenylsilyl]phenyl}propanoic acid was obtained from 3-(4-hydroxy-
phenyl)propanoic acid by silylation of both the phenolic and the carboxylic function
with (t-Bu)Ph2SiCl (TBDPSCl), and subsequent deprotection of the carboxylic acid
group [11]. 4-(Methylsulfanyl)butanoic acid was prepared by nucleophilic opening of
g-butyrolactone with MeSNa in DMSO [12].
Amidomethylations of Ti-enolates of acyl-DIOZ precursors 2, 3, and 4 were
effected with benzyl (methoxymethyl)carbamate as the electrophile [13]. Amido-
methylation of 2 proceeded with a high diastereoselectivity of 96%, despite the
presence of two stereogenic centers in the enolate. The product 5 was freed from the
auxiliary by the action of LiOH in a THF/H2O mixture. Cbz-b2-Homoisoleucine 6 was
obtained in 66% yield after crystallization (Scheme 2). Use of NaOH in MeOH/THF
resulted in substantial methyl ester formation. Hydrogenolysis of the Cbz group and
introduction of the Fmoc group were achieved according to standard procedures [7] to
give Fmoc-b2-homoisoleucine 7 in 90% yield.
The X-ray crystal structure of Cbz-b2hIle-OH (6) was determined to establish the
relative configuration of the stereogenic centers as shown in Scheme 2, confirming that
the stereochemical course of the amidomethylation is the same as with nonchiral acyl
groups on DIOZ (Fig. 1).
For the preparation of b2-homotyrosine, we eventually needed t-Bu protection of
the phenolic OH group. However, it turned out that a phenolic t-BuO group is unstable
under the condition of amidomethylation in the presence of TiCl4. We, therefore, used
the TBDPS group, one of the most-acid-stable protecting groups for this step. The
amidomethylation proceeded smoothly, and the Mannich product 8 was obtained in
62% yield and with 91% diastereoselectivity. The TBDPS group was then removed
with Bu4NF (TBAF) in THF [14] to give the hydroxy derivative 9, and the resulting OH
group was protected by treatment with isobutylene/CF3SO3H in CH2Cl2 to afford the

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4063
Fig. 1. X-Ray crystal structure (MolMol presentation) of( S,S)-N-Cbz-b2hIle-OH ((S,S)-6). Color code: C:
grey, H: white, N: blue, O: red. The structure was determined by Dr. B. W. Schweizer.
Scheme 2. Preparation of( S,S)-N-Fmoc-b2hIle-OH (ds ˆ diastereoselectivity)
ether 105). Cleavage of the chiral auxiliary from 10 proceeded smoothly to give the acid
11. Deprotection of the NH2 group and Fmoc protection afforded the desired N-Fmoc-
b2hTyr(tBu)-OH (12) in good yield (Scheme 3).
Amidomethylation of the methylsulfanyl derivative 4 resulted in two major
products, the benzyl carbamate 13 (30%) and methyl carbamate 14 (33%), with 93%
diastereoselectivity. From both of these compounds, the chiral auxiliary was removed
easily to provide the acids 15 and 16, respectively. Hydrogenolytic cleavage of the Cbz
group from 15 is problematic; several common hydrogenation procedures were tried
without success; with Me3SiI, S-demethylation occured. Deprotection by removal of
both the [(benzyloxy)carbonyl]amino and (method by the action of HBr in AcOH, in
the presence of EtSMe to minimize formation of sulfonium salts from liberated BnBr
5
)
The commonly used H2SO4 was replaced by CF3SO3H to minimize side reactions [15].

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Scheme 3. Preparation of( S)-N-Fmoc-b2hTyr(tBu)-OH
and MeBr [16]. The product (a free amino acid) could be purified by ion-exchange
chromatography, and the Fmoc group was finally introduced to give N-Fmoc-
b2hMethionine 17 (Scheme 4).
The enantiomer purity of unprotected b2hIle and b2hTyr(tBu) was confirmed by
1H-NMR spectroscopy of the diastereoisomeric Pd complexes, as shown in Scheme 5
and Fig. 2. This method has been demonstrated to be reliable for determining the
enantiomer purity of other b2-, b3-, and g-amino acids [17].
In the case of b2hMet, it was not possible to confirm enantiomer purity by the
1
method mentioned above (the H-NMR spectrum was not interpretable). So, we
derivatized the unprotected b2-homomethionine for HLPC analysis on a chiral
stationary phase. In two steps, (S)-N-(2,4-dinitrophenyl)-b2-homomethionine methyl
ester was prepared, and part of the compound was deliberately racemized with
MeONa/MeOH. The samples thus obtained were analyzed by HPLC on a chiral
stationary phase. In Fig. 3, the overlaid chromatograms of an enantiomerically enriched
and of a racemic sample are shown.
Although we describe herein the preparation of only a few hundred miligrams of
the three N-Fmoc-b2-amino acids 7, 12, and 17, we know that gram amounts are
accessible by the optimized procedures given in the Exper. Part.

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Scheme 4. Preparation of( S)-N-Fmoc-b2hMet-OH
Scheme 5. Preparation ofPd Complexes of b2-Amino Acids for Determination of Enantiomeric Purity
Experimental Part
1. General. Abreviations: FC: flash chromatography, h.v.: high vacuum, < 50 Pa, TBDPS: (t-Bu)Ph2Si.
Solvents for chromatography and workup procedures were distilled from Sikkon (anh. CaSO4; Fluka), THF was
distilled from Na, CH2Cl2 and Et3N from CaH2. LiCl was dried in h.v. at 1008 for 1 h. All other reagents were
used as received from Fluka. TLC: Merck silica gel 60 F254 plates, detection with UVand phosphomolybdic acid.
FC: Fluka silica gel 60 (40 63 mm). HPLC: Waters HPLC system (pump type 515, data module type 746,
tunable absorbance detector type 484), Daicel Chiralpack OD-H column. M.p.: B¸chi 510 apparatus;
uncorrected. Optical rotations: Perkin-Elmer 241 polarimeter (10 cm, 1-ml cell). IR Spectra: Perkin-Elmer 782
1
spectrometer. NMR Spectra: Bruker AMX-500 (500 MHz for H, 125 MHz for 13C), AMX-400 (400 MHz for
1H, 100 MHz for 13C), Varian Gemini 2000 (300 MHz for 1H, 75 MHz for 13C); chemical shifts d in ppm
downfield from internal Me4Si (ˆ0 ppm); J values in Hz. MS: IonSpec Ultima-Maldi FT/ICR mass
spectrometer, matrix DHB or DCTB, 4.7 T, N2 laser at 337 nm. Elemental analyses were performed by the
Microanalytical Laboratory of the Laboratorium f¸r Organische Chemie, ETH-Z¸rich.
2. Acylation of( R)-DIOZ by Mixed-Anhydride Method: General Procedure 1 (GP 1). To the soln. of
corresponding carboxylic acid (1.05 equiv.) in THF (200 ml), Et3N (2.6 equiv.) was added. The mixture was
cooled to À308, and pivaloyl chloride (1.05 equiv.) was added dropwise, and the resulting white suspension was
stirred for 1.5 h at this temp. Anh. LiCl (1.15 equiv.) and (R)-DIOZ (1.0 equiv.) were added, and the mixture
was then stirred overnight, allowing to warm to 258. The mixture was diluted with Et2O, and sat. NH4Cl soln. was

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 2. Proofofenantiomer purity of b2hIle and b2hTyr by 1H-NMR spectra oftheir Pd complexes. By analogy
with already described examples [17], the signal of the enantiomer should have been observed further upfield
from the quadruplet of the corresponding CH group.
Fig. 3. Determination ofenantiomer purity of b2hMet by HPLC, by using the chiral stationary phase Daicel
Chiralpack OD-H

Helvetica Chimica Acta Vol. 86 (2003)
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added. The org. phase was washed with 1n HCl (2Â), 1m NaOH, and sat. NaCl, then dried (MgSO4), and
evaporated. The crude product was purified by FC or recrystallization.
3. Amidoalkylation of N-Acyl-oxazolidin-2-ones: General Procedure 2 (GP 2). To a soln. of acyl (R)-DIOZ
(1 equiv.) in CH2Cl2 (0.2m), TiCl4 (1.05 equiv.) was added at À158 (ice/MeOH). To the yellow-orange soln.,
Et3N (1.1 equiv.) was added, and the resulting dark red soln. was stirred at ca. À158 for 30 min. The
corresponding electrophile (1.1 equiv.) was mixed with TiCl4 (1.1 equiv.) in CH2Cl2 (0.5m) in an ice-bath, and the
resulting soln. was added to the mixture via cannula. The mixture was stirred at 08 (ice-bath) for 3 4 h, treated
with sat. NH4Cl soln., and diluted with CH2Cl2. The org. phase was washed with 1n HCl (2Â), 1m NaOH, and
sat. NaCl soln., dried (MgSO4), and evaporated. The resulting crude product was purified by FC.
4. Cleavage ofthe Chiral Auxiliary: General Procedure 3 (GP 3). To a soln. of amidomethylated acyl DIOZ
(1 equiv.) in MeOH/THF (1:1, 0.2m), 1m aq. NaOH (1.6 equiv.) was added, and the mixture was stirred for 2.5 h
(in case of Ile, 24 h were required) at 258. MeOH/THF was evaporated, Et2O was added, and the resulting
suspension was stirred for 15 min and filtered. The residue was washed with 1m NaOH soln., H2O, Et2O, and
pentane, and dried to give the auxiliary as a white powder. The filtrate was diluted with Et2O, the aq. phase was
separated and washed with Et2O, pH adjusted to 1 2 with 6n HCl, and extracted with AcOEt (3Â). Combined
org. extracts washed with sat. NaCl soln., dried (MgSO4), and evaporated. The resulting Cbz-protected amino
acids were used in the next steps without further purification.
5. Cleavage ofCbz Group: General Procedure 4 (GP 4). The Cbz-protected amino acid (1 equiv.) was
dissolved in MeOH (0.06m), the flask was purged with N2, Pd/C (10 wt.-%) was added, then the flask was
evacuated and flushed with H2 (3Â), and the mixture was stirred at 258 for 2 h under H2 atmosphere (balloon).
The catalyst was filtered off with the help of Celite and washed thouroughly with MeOH. The filtrate was
evaporated and dried under h.v. The resulting product was pure enough for the next reaction.
6. Fmoc Protection: General Procedure 5 (GP 5). The unprotected amino acid (1 equiv.) was dissolved in
0.15m aq. Na2CO3 soln. (2 equiv.). To this soln. was added FmocOSu (1.2 equiv.) in acetone (0.1m) at 258. The
mixture was stirred at r.t. for 2 h, acetone was evaporated, and the residue was diluted with H2O and extracted
with Et2O (2Â). The aq. phase was acidified to pH 1 with 6n HCl and extracted with AcOEt (3Â). The
combined org. extracts were washed with sat. NaCl soln., dried (MgSO4), and evaporated. The resulting product
was purified by FC (AcOEt/hexane 1:2 ‡0.5% AcOH).
7. Preparation ofAcyloxazolidinone Starting Materials 2 4. (R)-4-Isopropyl-3-[(S)-3-methyl-1-oxopentyl]-
5,5-diphenyloxazolidin-2-one ((R,S)-2). Compound 2 was prepared according GP 1. Recrystallization from
hexane yielded (R,S)-2 (7.0 g, 74%). Colorless needles. M.p. 89 908. Rf (AcOEt/hexane 3 :7) 0.61. [a]D25
ˆ
‡206.4 (c ˆ 0.69, CHCl3). IR (CHCl3): 2966m, 1781s, 1699s, 1450m, 1366m, 1320m, 1177m, 1156w, 990w.
1H-NMR (300 MHz, CDCl3): 0.767 (d, J ˆ 6.9, 3 H, Me2CH); 0.77 (t, J ˆ 7.2, MeCH3); 0.82 (d, J ˆ 6.9, 3 H,
Me2C); 0.89 (d, J ˆ 6.9, MeCH); 1.0 1.3 (m, MeCH2); 1.70 1.84 (m, MeCH); 1.92 2.04 (m, Me2CH); 2.65
(dd, J ˆ 15.6, 7.8, 1 H, CH2CO); 2.80 (dd, J ˆ 15.6, 6.2, 1 H, CH2CO); 5.37 (d, J ˆ 3.4, CHN); 7.27 7.50
(m, 10 arom. H). 13C-NMR (75 MHz, CDCl3): 11.3; 16.6; 19.1; 21.9; 29.2; 29.9; 31.6; 41.8; 64.7; 89.2; 125.5;
‡
125.8; 127.8; 128.3; 128.4; 128.8; 138.0; 142.3; 153.0; 172.5. HR-MALDI-MS: 402.2039 ([C24H29NNaO3] ; calc.
402.2040). Anal. calc. for C24H29NO3 (379.5) C 75.96, H 7.70, N 3.69; found: C 76.07, H 7.81, N 3.72.
3-{4-[(tert-Butyl)diphenylsilyl]phenyl}propanoic Acid. 3-(4-hydroxyphenyl)propanoic acid (1.66 g,
10 mmol) and 1H-imidazole (3.0 g, 44 mmol) were dissolved in DMF (20 ml). To this soln., TBDPSCl
(6.04 g, 22 mmol, 5.64 ml) was added dropwise at 258, and the resulting soln. was stirred for 5 h at this temp. The
mixture was diluted with sat. NaCl soln. (250 ml) and extracted with Et2O (3Â). The combined extracts were
washed with ice-cold 1n HCl and brine, dried (MgSO4), and evaporated. The residue was redissolved in THF/
MeOH (1:1; 80 ml), and 10% aq. K2CO3 soln. (10 ml) was added, and the mixture was stirred at 258 for 1 h, then
concentrated, diluted with brine (100 ml), acidified with 1n HCl, and extracted with Et2O (3Â). The combined
extracts were washed with brine, dried (MgSO4), and evaporated. Crude product was purified by FC (Et2O/
pentane 1:4 ‡0.5% AcOH) to yield the acid (3.12 g, 77%). Colorless oil. Rf (AcOEt/hexane/AcOH 5 :5 :0.5)
0.55. IR (CHCl3): 2933m, 2860m, 1712s, 1609m, 1510s, 1472w, 1428m, 1257s, 1114m, 1042w, 921m, 835m, 822m.
1H-NMR (300 MHz, CDCl3): 1.10 (s, t-Bu); 2.59 (t, J ˆ 8.4, PhCH2); 2.83 (t, J ˆ 8.1, COCH2); 6.69 (d, J ˆ 8.4,
2 arom. H); 6.92 (d, J ˆ 8.7, 2 arom. H); 7.26 7.43 (m, 6 arom. H); 7.72 (m, 4 arom. H). 13C-NMR (75 MHz,
CDCl3): 19.5; 26.6; 29.8; 35.8; 119.6; 127.6; 128.8; 129.7; 132.4; 132.9; 135.4; 153.9; 178.7. HR-MALDI-MS:
‡
427.1703 ([C25H28NaO3Si] ; calc. 427.1700). Anal. calc. for C25H28O3Si (404.6) C 74.22, H 6.98; found: C 74.31, H
7.01.
(R)-3-{3-[4-(tert-Butyl)diphenylsilyl)phenyl]-1-oxopropyl}-4-isopropyl-5,5-diphenyloxazolidin-2-one
((R)-3). Compound 3 was prepared according to GP 1. FC (AcOEt/hexane 1:1) yielded pure (R)-3 (7.5 g,
79%). White solid. M.p. 120 1228. Rf (AcOEt/hexane 3 :7) 0.57. [a]2D5 ˆ ‡106.6 (c ˆ 1.0, CHCl3). IR (CHCl3):

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Helvetica Chimica Acta Vol. 86 (2003)
2963m, 2932m, 2859m, 1780s, 1701s, 1510s, 1372m, 1114m, 921m, 823m. 1H-NMR (400 MHz, CDCl3): 0.70
(d, J ˆ 6.8, 3 H, Me2CH); 0.81 (d, J ˆ 7.0, 3 H, Me2CH); 1.08 (s, t-Bu); 1.94 (m, (Me2CH); 2.68 2.82
(m, COCH2CH2), 2.92 2.99 (m, 1 H, COCH2); 3.11 3.19 (m, 1 H, COCH2); 5.34 (d, J ˆ 3.4, NCH); 6.62
(d, J ˆ 8.7, 2 arom. H); 6.84 (d, J ˆ 8.7, 2 arom. H); 7.20 7.73 (m, 20 arom. H). 13C-NMR (100 MHz, CDCl3):
16.4; 19.5; 21.7; 26.6; 29.6; 29.8; 36.9; 64.5; 89.4; 119.5; 125.6; 127.7; 127.9; 128.4; 128.6; 128.9; 129.0; 129.8; 132.7;
‡
133.1; 134.8; 135.5; 138.2; 142.3; 153.0; 153.9; 172.3. HR-MALDI-MS: 690.3017 ([C43H45NNaO4Si] ; calc.
690.3010 ). Anal. calc. for C43H45NO4Si (667.9) C 77.33, H 6.79, N 2.10; found: C 77.19, H 6.88, N 2.17.
(R)-4-Isopropyl-3-[(S)-4-methylsulfanyl-1-oxobutyl]-5,5-diphenyloxazolidin-2-one ((R)-4). Compound 1
was acylated according to GP 1. FC (AcOEt/hexane 1:1) yielded (R)-4 (9.0 g, 86%) White solid. M.p. 71 728.
Rf (AcOEt/hexane 3 :7) 0.53. [a]2D5 ˆ ‡196.2 (c ˆ 0.78, CHCl3). IR (CHCl3): 2970m, 2923w, 1781s, 1702s, 1450m,
1
1366m, 1320m, 1177m, 1049w, 1002w. H-NMR (300 MHz, CDCl3): 0.76 (d, J ˆ 6.5, 3 H, Me2CH); 0.88 (d, J ˆ
7.2, 3 H, Me2CH); 1.82 2.02 (m, (Me2CH, COCH2CH2); 2.04 (s, MeS); 2.45 (t, J ˆ 7.2, CH2S); 2.81 3.07
(m, COCH2); 5.37 (d, J ˆ 3.4, CHN); 7.28 7.49 (m, 10 arom. H). 13C-NMR (75 MHz, CDCl3): 15.4; 16.5; 21.9;
23.9; 30.0; 33.3; 34.1; 64.5; 89.4; 125.5; 125.8; 127.9; 128.3; 128.5; 128.8; 138.0; 142.2; 152.9; 172.3. HR-MALDI-
‡
MS: 420.1607 ([C23H27NNaO5S] ; calc. 420.1604). Anal. calc. for C23H27NO5S (397.5) C 69.49, H 6.85, N 3.52, S
8.07; found: C 69.60, H 6.92, N 3.61, S 8.06.
8. Preparation of( S,S)-N-Fmoc-b2hIle-OH (7). (R)-3-[(2S,3S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-
3-methyl-1-oxopentyl]-4-isopropyl-5,5-diphenyloxazolidin-2-one ((R,S,S)-5). Compound 2 was amidomethyl-
ated according to GP 2. FC (AcOEt/hexane 1:2) yielded (R,S,S)-5 (5.10 g, 66%). Colorless oil. Rf (AcOEt/
hexane 3 :7) 0.34. [a]2D5 ˆ ‡117.0 (c ˆ 0.53, CHCl3). IR (CHCl3): 3452w, 2969m, 1781s, 1718s, 1514s, 1451m,
1364m, 1178m, 1051m, 989w. 1H-NMR (400 MHz, CDCl3): 0.49 (t, J ˆ 7.2, MeCH2); 0.55 (d, J ˆ 6.7, 3 H,
Me2CH); 0.59 0.86 (m, CH2); 0.66 (d, J ˆ 6.7, 3 H, Me2CH); 0.78 (d, J ˆ 6.9, MeCH); 1.38 (m, CHCH2); 1.93
(m, Me2CH); 3.31 3.64 (m, CH2N); 3.74 (m, COCH); 5.01 (s, CH2O); 5.06 (br. s, NH); 5.25 (d, J ˆ 3.5, CHN);
7.19 7.47 (m, 10 arom. H). 13C-NMR (100 MHz, CDCl3): 11.1; 15.0; 16.5; 21.7; 27.0; 29.6; 34.9; 40.0; 47.4; 65.9;
66.6; 89.5; 125.3; 125.7; 128.0; 128.1; 128.45; 128.49; 128.6; 128.8; 128.9; 136.6; 137.7; 142.4; 153.2; 156.2; 175.1.
‡
HR-MALDI-MS: 565.2680 ([C33H38N2NaO5] ; calc. 565.2673). Anal. calc. for C24H29NO3 (542.7) C 73.04, H
7.06, N 5.16; found: C 73.14, H 7.02, N 5.06.
(2S,3S)-2-{[(Benzyloxy)carbonyl]amino}methyl-3-methylpentanoic Acid ((S,S)-6). Chiral auxiliary was
cleaved from 5 according to GP 3. Recrystallization from (i-Pr)2O/hexane yielded (S,S)-6 (203 mg, 66%).
Colorless needles. M.p. 74 768. Rf (AcOEt/hexane/AcOH 5 :5 :0.5) 0.58. [a]2D5 ˆ ‡25.7 (c ˆ 0.61, CHCl3). IR
(CHCl3): 3466w, 2966m, 1714s, 1514s, 1454w, 1256m, 1141w, 1066w, 974w. 1H-NMR (500 MHz, (D6)DMSO):
0.84 0.98 (m, 2 Me); 1.11 1.18 (m, 1 H, MeCH2); 1.36 1.44 (m, 1 H, MeCH2); 1.61 1.66 (m, CH); 2.40 2.50
(m, CHCO); 3.12 3.34 (m, CH2N); 3.57 (br. s, NH); 5.00 (s, CH2O); 7.23 7.37 (m, 5 arom. H) ; 12.19
(br. s, OH). 13C-NMR (125 MHz, (D6)DMSO): 11.4; 16.0; 26.3; 34.5; 39.3; 49.6; 65.0; 127.5; 127.6; 128.2;
‡
137.1; 156.0; 175.1. HR-MALDI-MS: 302.1360 ([C15H21NNaO4] ; calc. 302.1368). Anal. calc. for C15H21NO4
(279.3) C 64.50, H 7.58, N 5.01; found: C 64.71, H 7.37, N 4.87.
(2S,3S)-2-[({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)methyl]-3-methylpentanoic Acid ((S,S)-7).
Compound 6 was deprotected according to GP 4 and Fmoc-protected according to GP 5. FC (AcOEt/hexane
1:2 ‡0.5% AcOH) yielded (S,S)-7. (279 mg, 90%). Colorless oil. Rf (AcOEt/hexane/AcOH 5 :5 :0.5) 0.48.
[a]2D5 ˆ ‡15.5 (c ˆ 0.42, CHCl3). IR (CHCl3): 3446w, 2964m, 1713s, 1513s, 1451m, 1144m, 1082w, 1041w, 990w.
1H-NMR (400 MHz, (D6)DMSO): 0.86 (t, J ˆ 7.3, MeCH2); 0.88 (d, J ˆ 6.8, MeCH); 1.11 1.19 (m, 1 H, CH2);
1.37 1.44 (m, 1 H, CH2); 1.63 (m, MeCH); 2.44 (m, CHCO); 3.24 (m, CH2N); 4.18 4.29 (m, OCHCH2); 7.30
7.43 (m, 4 arom. H); 7.68 (d, J ˆ 7.3, 1 arom. H); 7.69 (d, J ˆ 7.2, 1 arom. H); 7.89 (d, J ˆ 7.4, 2 arom. H).
13C-NMR (100 MHz, (D6)DMSO): 11.4; 16.1; 26.3; 34.6; 46.6; 49.6; 65.3; 120.0; 125.1; 127.0; 127.5; 140.6; 143.77;
‡
143.81; 156.0; 175.1. HR-MALDI-MS: 390.1679 ([C22H25NNaO4] ; calc. 390.1676). Anal. calc. for C22H25NO4
(367.4) C 71.91, H 6.86, N 3.81; found: C 72.16, H 6.81, N 3.66.
9. Preparation of( S)-N-Fmoc-b2hTyr(tBu)-OH (12). (R)-3-((S)-2-{[(Benzyloxy)carbonyl]amino})methyl-
3-[4-(tert-butyl)diphenylsilyl)phenyl]-1-oxopropyl)-4-isopropyl-5,5-diphenyloxazolidin-2-one ((R,S)-8). Com-
pound 3 was amidomethylated according to GP 2. The crude product purified by FC (AcOEt/hexane 1 :4) to
yield (R,S)-8 (11.1 g, 62%). White foam. M.p. 74 778. Rf (AcOEt/hexane 3 :7) 0.35. [a]2D5 ˆ ‡68.5 (c ˆ 0.95,
CHCl3). IR (CHCl3): 3444w, 2964w, 2921w, 1779s, 1721s, 1510s, 1450w, 1363m, 1114m, 921m, 822s. 1H-NMR
(400 MHz, CDCl3): 0.69 (d, J ˆ 6.7, 3 H, Me2CH); 0.82 (d, J ˆ 7.0, 3 H, Me2C); 1.09 (s, t-Bu); 1.94 (m, (Me2CH);
2.36 (m, 1 H, CHCH2); 2.59 (m, 1 H, CHCH2); 3.33 3.67 (m, CH2N); 4.06 (m, COCH); 5.05 (s, CH2O); 5.11
(br. s, NH); 5.30 (d, J ˆ 3.4, NCH); 6.48 (d, J ˆ 8.5, 2 arom. H); 6.58 (d, J ˆ 8.6, 2 arom. H); 7.11 7.70
(m, 25 arom. H). 13C-NMR (100 MHz, CDCl3): 16.3; 19.5; 21.7; 26.6; 29.7; 34.3; 42.2; 44.7; 65.0; 66.6; 89.5;
119.6; 125.3; 125.8; 127.7; 128.01; 128.03; 128.12; 128.4; 128.5; 128.6; 128.9; 129.4; 129.84; 129.85; 133.1; 135.53;

Helvetica Chimica Acta Vol. 86 (2003)
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‡
135.54; 137.9; 138.0; 152.9; 154.0; 173.9. HR-MALDI-MS: 853.3653 ([C52H54N2NaO6Si] ; calc. 853.3643). Anal.
calc. for C52H54N2O6Si (831.1) C 75.15, H 6.55, N 3.37; found: C 75.15, H 6.53, N 3.49.
(R)-3-[(S)-2-({[(Benzyloxy)carbonyl]amino})methyl)-3-(4-hydroxyphenyl)-1-oxopropyl]-4-isopropyl-
5,5-diphenyloxazolidin-2-one ((R,S)-9). Compound ((R,S)-8 (1.63 g, 1.96 mmol) was dissolved in THF (15 ml),
and TBAF (682 mg, 2.16 mmol, 1.1 equiv.) in THF (10 ml) was added, and the mixture was stirred at 258 for 4 h.
The soln. was diluted with AcOEt (120 ml), and washed with H2O and sat. NaCl soln. Aq. phases were extracted
with AcOEt. Combined org. extracts were dried (MgSO4) and evaporated. FC (AcOEt/hexane 1:2) yielded
(R,S)-9 (1.08 g, 93%). For anal. purposes, a sample was recrystallized from AcOEt/hexane. Colorless needles.
M.p. 153 1548. Rf (AcOEt/hexane 3 :7) 0.10. [a]2D5 ˆ ‡95.5 (c ˆ 0.78, CHCl3). IR (CHCl3): 3599m, 3443m,
3008m, 2971m, 1779s, 1717s, 1515s, 1450m, 1364m, 1318m, 1149m, 1051m, 990m, 826w. 1H-NMR (500 MHz,
CDCl3): 0.71 (d, J ˆ 6.7, 3 H, Me2CH); 0.84 (d, J ˆ 7.0, 3 H, Me2CH); 1.99 (m, (Me2CH); 2.41 (m, 1 H, CHCH2);
2.58 (m, 1 H, CHCH2); 3.38 3.50 (m, CH2N); 4.16 (m, COCH); 5.07 (s, CH2O); 5.26 (br. s, NH); 5.32 (d, J ˆ
3.3, NCH); 5.62 (s, OH); 6.52 (d, J ˆ 8.3, 2 arom. H); 6.75 (d, J ˆ 8.3, 2 arom. H); 7.25 7.38 (m, 15 arom. H).
13C-NMR (125 MHz, CDCl3): 16.3; 21.7; 29.7; 34.4; 42.1; 44.8; 65.1; 66.8; 89.6; 115.3; 125.3; 125.8; 128.0; 128.1;
128.2; 128.4; 128.5; 128.6; 129.0; 129.1; 129.8; 136.4; 138.8; 141.9; 153.1; 154.4; 156.3; 174.2. HR-MALDI-MS:
‡
615.2461 ([C36H36N2NaO6] ; calc. 615.2466). Anal. calc. for C36H36N2O6 (592.7) C 72.95, H 6.12, N 4.73; found:
C 72.93, H 6.13, N 4.64.
(R)-3-[(S)-2-({[(Benzyloxy)carbonyl]amino})methyl-3-[4-(tert-butoxy)phenyl]-1-oxopropyl]-4-is oprop-
yl-5,5-diphenyloxazolidin-2-one ((R,S)-10). Isobutylene (15 ml) was dissolved in CH2Cl2 (10 ml) at À788. At
À308, CF3SO3H (0.11 ml, 1.25 mmol, 10 mol-%) was added to this soln. followed by 9 (7.4 g, 12.5 mmol) in
CH2Cl2 (50 ml). The resulting red soln. was stirred for 5 h at À308. Et3N (0.17 ml, 1.25 mmol) was added, and the
mixture was allowed to warm slowly to 258, the solvent was then evaporated, and the crude product was purified
by FC (AcOEt/hexane 3 :7), and then recrystallized from Et2O/pentane to give the (R,S)-10 (5.88 g, 73%).
White amorphous solid. M.p. 97 998. Rf (AcOEt/hexane 3 :7) 0.32. [a]2D5 ˆ ‡94.4 (c ˆ 0.64, CHCl3). IR
(CHCl3): 3444w, 2980m, 1779s, 1719s, 1507s, 1450m, 1366m, 1177m, 1180m, 1016m, 895w. 1H-NMR (500 MHz,
CDCl3): 0.71 (d, J ˆ 6.7, 3 H, Me2CH); 0.84 (d, J ˆ 7.0, 3 H, Me2CH); 1.29 (s, t-Bu); 1.97 (m, Me2CH); 2.45
(dd, J ˆ 14.0, 7.6, 1 H, CHCH2); 2.65 (dd, J ˆ 14.2, 6.2, 1 H, CHCH2); 3.39 (m, 1 H, CH2NH); 3.49 (m, 1 H,
CH2NH); 4.13 (m, COCH); 5.06 (s, CH2O); 5.15 (br. s, NH); 5.35 (d, J ˆ 3.3, NCH); 6.71 (d, J ˆ 8.2,
2 arom. H); 6.80 (d, J ˆ 8.5, 2 arom. H); 7.25 7.41 (m, 15 arom. H). 13C-NMR (125 MHz, CDCl3): 16.3; 21.7;
28.9; 29.7; 34.5; 42.2; 44.7; 65.0; 66.7; 78.1; 89.6; 124.0; 124.2; 125.4; 125.8; 128.03; 128.05; 128.1; 128.4; 128.5;
128.7; 128.96; 129.05; 136.5; 137.9; 142.0; 153.0; 153.9; 156.1; 174.0. HR-MALDI-MS: 671.3099
‡
([C40H44N2NaO6] ; calc. 671.3092). Anal. calc. for C40H44N2O6 (648.8) C 74.05, H 6.84, N 4.32; found: C
74.22, H 6.86, N 4.32.
(S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-[4 -(tert-butoxy)phenyl]propanoic Acid ((S)-11). The
chiral auxiliary was cleaved from 10 according to GP 3. The resulting product (S)-11 (376 mg, 94%) was
pure enough for next reaction. White solid. For anal. purposes, a sample was recrystallized from Et2O/pentane.
M.p. 112 1138. Rf (AcOEt/hexane/AcOH 5 :5 :0.5) 0.46. [a]2D5 ˆ ‡3.3 (c ˆ 0.43, CHCl3). IR (CHCl3): 3444w,
2980m, 1719s, 1507s, 1455m, 1367m, 1160m, 895m. 1H-NMR (400 MHz, CD3OD): 1.30 (s, t-Bu); 2.74 2.91
(m, CHCH2); 3.28 3.47 (m, CH2NH); 5.06 (s, CH2O); 6.88 (d, J ˆ 8.4, 2 arom. H); 7.11 (d, J ˆ 8.4, 2 arom. H);
7.27 7.34 (m, 5 arom. H). 13C-NMR (100 MHz, CD3OD): 29.2; 36.2; 43.5; 67.5; 79.5; 125.2; 128.8; 129.0; 129.5;
‡
130.5; 135.4; 138.4; 155.0; 158.9; 177.5. HR-MALDI-MS: 408.1787 ([C22H27NNaO5] ; calc. 408.1781). Anal.
calc. for C22H27NO5 (385.5) C 68.55, H 7.06, N 3.63; found: C 68.45, H 6.99, N 3.61.
(S)-2-[({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)methyl]-3-[4-(tert-butoxy)phenyl]propanoic Acid
((S)-12). Compound 11 was deprotected according to GP 4 and the resulting product was Fmoc-protected
according to GP 5. The crude product was purified by FC (AcOEt/hexane 1 :2 ‡0.5% AcOH) to give final
compound (S)-12 (203 mg, 71%). White foam. M.p 58 608. Rf (AcOEt/hexane/AcOH 5 :5 :0.5) 0.48. [a]D25
ˆ
‡5.4 (c ˆ 0.37, CHCl3). IR (CHCl3): 3466w, 3008m, 2979m, 1719s, 1507s, 1450m, 1367m, 1160m, 1082w, 1041w,
1
894m. H-NMR (400 MHz, CD3OD): 1.30 (s, t-Bu); 2.73 2.91 (m, CHCH2); 3.31 (m, CH2N); 4.20 (t, J ˆ 6.8,
CH); 4.33 (d, J ˆ 6.1, CH2); 6.89 (d, J ˆ 8.4, 2 arom. H); 7.11 (d, J ˆ 8.4, 2 arom. H); 7.27 7.39 (m, 4 arom. H);
7.63 (d, J ˆ 7.5, 2 arom. H); 7.78 (d, J ˆ 7.5, 2 arom. H). 13C-NMR (100 MHz, CD3OD): 29.2; 36.1; 43.4; 48.5;
49.1; 67.8; 79.4; 120.9; 125.2; 126.2; 128.1; 128.8; 130.5; 135.4; 142.6; 145.3; 155.0; 158.8; 177.5. HR-MALDI-MS:
‡
496.2099 ([C29H31NNaO5] ; calc. 496.2094). Anal. calc. for C29H31NO5 (473.6) C 73.55, H 6.60, N 2.96; found: C
73.38, H 6.64, N 2.77.
10. Preparation of( S)-N-Fmoc-b2hMet-OH (17). (R)-3-[(S)-2-{[(Benzyloxy)carbonyl]amino}methyl)-4-
(methylsulfanyl)-1-oxobutyl]-4-isopropyl-5,5-diphenyloxazolidin-2-one ((R,S)-13) and (R)-4-Isopropyl-3-((S)-
2-{[(methoxycarbonyl)amino]methyl}-4-(methylsulfanyl)-1-oxobutyl)-5,5-diphenyloxazolidin-2-one ((R,S)-

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14). Amidomethylation of (R)-4 was carried out according to GP 2. Two major products, (R,S)-13 and (R,S)-14,
were separated by FC (Et2O/pentane 1:1).
Data for (R,S)-13: 0.70 g, 30%. White solid. M.p. 130 1318. Rf (AcOEt/hexane 3 :7) 0.24. [a]2D5 ˆ ‡99.6
(c ˆ 0.83, CHCl3). IR (CHCl3): 3446w, 2968m, 2921m, 1779s, 1719s, 1515s, 1450m, 1364m, 1181m, 1145m, 1052m,
1002m. 1H-NMR (400 MHz, CDCl3): 0.71 (d, J ˆ 6.7, 3 H, Me2CH); 0.83 (d, J ˆ 6.9, 3 H, Me2CH); 1.53
(m, Me2CH); 1.74 (m, 1 H, CHCH2); 1.79 (s, MeS); 1.99 (m, 3 H, CH2S, CHCH2); 3.39 (m, 1 H, CH2N); 3.74
(m, 1 H, CH2N); 3.95 (m, COCH); 5.07 (s, CH2O); 5.17 (br. s, NH); 5.35 (d, J ˆ 3.4, CHN); 7.26 7.50
(m, 15 arom. H). 13C-NMR (100 MHz, CDCl3): 15.1; 16.3; 21.6; 28.8; 29.7; 31.0; 42.3; 43.0; 65.4; 66.8; 89.7;
125.4; 125.7; 128.06; 128.09; 128.2; 128.3; 128.5; 128.8; 128.9; 136.5; 137.7; 142.3; 153.2; 156.2; 174.1. HR-
‡
MALDI-MS: 583.2244 ([C32H36N2NaO5S] ; calc. 583.2237). Anal. calc. for C32H36N2O5S (560.7) C 68.55, H 6.47,
N 5.00, S 5.72; found: C 68.51, H 6.53, N 4.99, S 5.71.
Data for 14: 0.68 g, 33%. White solid. M.p. 103 1048. Rf (AcOEt/hexane 3 :7) 0.18. [a]2D5 ˆ ‡114.8 (c ˆ
0.40, CHCl3). IR (CHCl3): 3446w, 2964w, 1780s, 1718s, 1518s, 1451m, 1364m, 1318m, 1051w, 990w. 1H-NMR
(400 MHz, CDCl3): 0.76 (d, J ˆ 6.8, 3 H, Me2CH); 0.86 (d, J ˆ 7.0, 3 H, Me2CH); 1.51 (m, 1 H, CHCH2); 1.70
(m, 1 H, CHCH2); 1.80 (s, MeS); 2.03 (m, CH2S, Me2CH); 3.34 3.56 (m, CH2N); 3.63 (s, MeO); 3.93
(m, COCH); 5.16 (br. s, NH); 5.36 (d, J ˆ 3.5, NCH); 7.26 7.51 (m, 10 arom. H). 13C-NMR (100 MHz, CDCl3):
15.1; 16.3; 21.6; 28.8; 29.7; 31.1; 42.4; 43.0; 52.1; 65.4; 89.7; 125.4; 125.7; 128.1; 128.5; 128.8; 128.9; 137.7; 142.3;
‡
153.2; 156.9; 174.2. HR-MALDI-MS: 507.1919 ([C26H32N2NaO5S] ; calc. 507.1924). Anal. calc. for C26H32N2O5S
(484.6) C 64.44, H 6.66, N 5.78, S 6.62; found: C 64.45, H 6.79, N 5.86, S 6.47.
(S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-4-(methylsulfanyl)butanoic Acid ((S)-15). The chiral aux-
iliary was cleaved from 13 according to GP 3. Compound 15 (2.05 g, 97%) was pure enough for the next
reaction. A sample was recrystallized from Et2O/pentane. White solid. M.p. 77 798. Rf (AcOEt/hexane/AcOH
5 :5 :0.5) 0.50. [a]D25 ˆ ‡0.3 (c ˆ 0.74, CHCl3). IR (CHCl3): 3448m, 3025m, 2920m, 1717s, 1515s, 1454m, 1260m,
1
1142m, 1089w, 1040m, 980w, 913w. H-NMR (400 MHz, (D6)DMSO): 1.63 1.84 (m, CHCH2); 2.01 (s, MeS);
2.37 2.60 (m, CH2S, CH); 3.08 3.25 (m, CH2N); 3.27 (br. s, NH); 5.02 (s, CH2O); 7.28 7.38 (m, 5 arom. H);
12.3 (br. s, OH). 13C-NMR (100 MHz, (D6)DMSO): 14.4; 28.5; 30.7; 41.8; 44.2; 65.1; 127.5; 127.6; 128.2; 137.1;
‡
156.1; 174.8. HR-MALDI-MS: 320.0930 ([C14H19NNaO4S] ; calc. 320.0927). Anal. calc. for C14H19NO4S (297.4)
C 56.55, H 6.44, N 4.71; found: C 56.58, H 6.30, N 4.79.
(S)-2-{[(Methoxycarbonyl)amino]methyl}-4-(methylsulfanyl)butanoic Acid ((S)-16). The chiral auxiliary
was cleaved from 14 according to GP 3. FC (AcOEt/hexane 1 :1 ‡0.5% AcOH) yielded 16 (1.16 g, 82%).
Colorless oil. Rf (AcOEt/hexane/AcOH 5 :5 :0.5) 0.25. [a]2D5 ˆ À4.5 (c ˆ 0.42, CHCl3). IR (CHCl3): 3682w,
3446m, 3005m, 2923m, 1718s, 1518s, 1446m, 1144m, 1087m, 1041w. 1H-NMR (400 MHz, CD3OD): 1.29 1.93
(m, CHCH2); 2.07 (s, MeS); 2.47 2.59 (m, CH2S); 2.71 (m, CH); 3.24 3.38 (m, CH2N); 3.62 (s, MeO).
13C-NMR (100 MHz, CD3OD): 15.1; 30.1; 32.5; 43.2; 46.0; 52.5; 159.6; 177.5. HR-MALDI-MS: 244.0617
‡
([C8H15NNaO4S] ; calc. 244.0614). Anal. calc. for C8H15NO4S (221.3) C 43.42, H 6.83, N 6.33; found: C 43.71, H
6.98, N 6.16.
(S)-2-(Aminomethyl)-4-(methylsulfanyl)butanoic Acid. Compound 16 (1.07 g, 4.84 mmol) (or 15) was
mixed with EtSMe (1.84 g, 2.18 ml, 24.2 mmol, 5 equiv.), and HBr/HOAc (5.7m, 5 ml) was added at 258, and the
mixture was stirred for 18 h (2 h in case of 15), protected from moisture with CaCl2 drying tube. Et2O (20 ml)
was added, and the oily residue was separated and triturated with Et2O (3Â), and dried in h.v. The resulting
crude product was used directly in the next step.
(S)-2-[({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)methyl]-4-(methylsulfanyl)butanoic Acid ((S)-17).
Crude product from the previous reaction was Fmoc-protected according GP 5. FC (AcOEt/hexane 3 :7 ‡0.5%
AcOH) yielded 17 (337 mg, 36%). White solid. M.p. 138 1408. Rf (AcOEt/hexane/AcOH 5 :5 :0.5) 0.52.
[a]2D5 ˆ ‡3.8 (c ˆ 0.40, CHCl3). IR (CHCl3): 3446w, 3005m, 2923w, 1718s, 1513s, 1451m, 1144m, 1087w, 1041w,
985w. 1H-NMR (400 MHz, CD3OD): 1.72 1.93 (m, CHCH2); 2.05 (s, MeS); 2.48 2.58 (m, CH2S); 2.73
(m, COCH); 3.25 3.40 (m, CH2N); 4.20 (t, J ˆ 6.9, CH); 4.33 (d, J ˆ 7.0, CH2O); 7.17 (br. s, NH); 7.28 7.40
(m, 4 arom. H); 7.64 (d, J ˆ 6.7, 2 arom. H); 7.78 (d, J ˆ 7.5, 2 arom. H). 13C-NMR (100 MHz, CD3OD): 15.2;
30.1; 32.5; 43.2; 46.0; 48.5; 67.8; 121.0; 126.2; 128.2; 128.8; 142.6; 145.4; 158.9; 177.6. HR-MALDI-MS: 408.1242
‡
([C21H23NNaO4S] ; calc. 408.1240). Anal. calc. for C21H23NO4S (385.5) C 65.43, H 6.01, N 3.63, S 8.32; found: C
65.48, H 5.98, N 3.66, S 8.18.
11. Determination ofEnantiomer Purity of b2-Homoamino Acids. Preparation ofPd Complexes ofr
Determination ofEnantiomer Purity of b2hIle and b2hTyr. Unprotected amino acid (0.1 mmol) was dissolved in
MeOH (10 ml); to this soln. 1m MeONa in MeOH (0.2 mmol, 0.2 ml) was added dropwise, and the mixture was
stirred for 15 min at r.t. To the resulting solution, di-m-chlorobis{2-[1-(dimethylamino)-cN-ethyl]phenyl-
cC}palladium (58 mg, 0.1 mmol) in CH2Cl2 (3 ml) was added, and the mixture was stirred for 1.5 h at r.t. The

Helvetica Chimica Acta Vol. 86 (2003)
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org. solvents were then evaporated, and the residue was redissolved in CHCl3 and washed with H2O, sat. aq.
NaHCO3 soln., and again with H2O. CHCl3 was then evaporated in vacuo, and the residue was analyzed by
1H-NMR.
{(2S,3S)-2-[(Amino-cN)methyl]-(3-methylpentanoato-cO} {(1S)-2-[1-(dimethylamino-cN)ethyl]phenyl-
cC}palladium. 1H-NMR (300 MHz, CD3OD): 0.92 (d, J ˆ 6.7, MeCH2); 0.99 (t, J ˆ 7.3, Me); 1.30 (m, 1 H,
CH2); 1.48 (d, J ˆ 6.6, Me); 1.55 (m, 1 H, CH2); 2.24 (m, MeCH); 2.42 2.55 (m, CHCO); 2.52 (s, MeN); 2.75
2.89 (m, NH2CH2); 2.80 (s, MeN); 3.97 (q, J ˆ 6.6, CHN); 4.09 (br. s, 1 H, NH2); 4.47 (br. s, 1 H, NH2); 6.74
7.00 (m, 4 arom. H).
{(2S)-2-[(Amino-cN)methyl]-3-[4-(tert-butoxy)phenyl]propanoato-cO} {(1S)-2-[1-(dimethylamino-cN)-
ethyl]phenyl-cC}palladium. 1H-NMR (300 MHz, CD3OD): 1.30 (s, t-Bu); 1.51 (d, J ˆ 6.6, MeCH); 2.53
(s, MeN); 2.70 (m, CH2); 2.77 2.87 (m, CH2N); 2.82 (s, MeN); 3.37 (m, CHCO); 3.92 (q, J ˆ 6.5, NCH);
4.14 (br. s, 1 H, NH2); 4.46 (br. s, NH2); 6.67 7.21 (m, 8 arom. H).
Preparation of N-(2,4-dinitrophenyl)-b2homomethion ine Methyl Ester for Determination of Enantiomer
Purity of b2hMet by HPLC. b2-Homomethionine (1.74 mmol) was dissolved in sat. aq. NaHCO3 soln. (10 ml),
the resulting soln. was cooled in an ice-bath, and 2,4-dinitrofluorobenzene (389 mg, 2.09 mmol) in EtOH
(10 ml) was added. The mixture was stirred for 3 h at 08. The soln. was diluted with Et2O, washed with 1n HCl
and sat. aq. NH4Cl soln., dried, and evaporated. The residue was dissolved in toluene (20 ml) and Me3SiCHN2
(2m soln. in hexane, 1.29 ml, 2.58 mmol) was added dropwise and the resulting mixure stirred for 15 min at r.t. At
this point, AcOH (2 ml) was added slowly. Org. solvents were evaporated, and the residue was purified by FC
(AcOEt/hexane 3 :7) to give the product as yellow solid (153 mg, 26%). Part of this material was racemized by
treating it with 1m MeONa in MeOH overnight at r.t. HPLC (hexane/i-PrOH 4 :1, flow 0.8 ml/min): tR 28.8 and
31.3 min. 1H-NMR (300 MHz, CDCl3): 1.88 (m, 1 H, CH2); 2.12 (s, MeS); 2.18 (m, 1 H, CH2); 2.59 (m, CH2S);
3.05 (m, CH); 3.64 (m, CH2N); 3.77 (s, MeO); 6.97 (d, J ˆ 9.5, 1 arom. H); 8.30 (dd, J ˆ 9.6, 2.8, 1 arom. H);
8.82 (br. s, NH); 9.15 (d, J ˆ 2.7, 1 arom. H).
X-Ray Crystal-Structure Determination of 66). The intensities were collected on Nonius KappaCCD
diffractometer with graphite-monochromated MoKa radiation (l ˆ 0.71073). The structure was solved by direct
methods with SIR 97 [18] and refined by full-matrix least-squares refinement on F2 with SHELXL-97 [19]. The
H-atoms were fixed at calculated positions. Crystallization from (i-Pr)2O/hexane, colorless needles, C15H21NO4,
Mr ˆ 279.336, a ˆ 6.7708 (3), b ˆ 16.0378 (9), c ˆ 28.379 (2) ä, a ˆ 90, b ˆ 90, g ˆ 908, Vˆ 3081.7 (3) ä3,
orthorhombic space group P212121, Z ˆ 8, Dx ˆ 1.204 g cmÀ3, q Range 0.998 22.9868, m ˆ 0.087 mmÀ1; 4286
reflections measured, 4260 independent, 3368 reflections observed (I > 2s(I)), 362 parameters, 0 restraints,
R(F) ˆ 0.0625, wR(F2) ˆ 0.1581, S(ref) ˆ 1.193, D1max ˆ 0.155 e ä3, D1min ˆ À0.166 e ä3.
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deposit@ccdc.cam.ac.uk).

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Received September 3, 2003