Preparation of β2-amino acid derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys, pyrrolidine-3-carboxylic acid) by using DIOZ as chiral auxiliary

Article abstract of DOI:10.1002/hlca.200590157

The title compounds were prepared from valine-derived N-acylated oxazolidin-2-ones, 1-3, 7, 9, by highly diastereoselective (≥ 90%) Mannich reaction (→ 4-6; Scheme 1) or aldol addition (→ 8 and 10; Scheme 2) of the corresponding Ti- or B-enolates as the key step. The superiority of the '5,5-diphenyl-4-isopropyl-1,3-oxazolidin-2-one' (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t-Bu-, Boc-, Fmoc-, and Cbz-protected β²-homoamino acid derivatives 11-23 (Schemes 3-6). The use of ω-bromo-acyl-oxazolidinones 1-3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic-acid derivatives.

Full text of DOI:10.1002/hlca.200590157

Helvetica Chimica Acta Vol. 88 (2005)
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Preparation of b2-Amino Acid Derivatives (b2hThr, b2hTrp, b2hMet,
b2hPro, b2hLys, Pyrrolidine-3-carboxylic Acid) by Using DIOZ as Chiral
Auxiliary1)
by Francois Gessier2)3), Laurent Schaeffer2)4), Thierry Kimmerlin5), Oliver Flˆgel6), and Dieter Seebach*
Laboratorium f¸r Organische Chemie, Department Chemie und Angewandte Biowissenschaften,
Eidgenˆssische Technische Hochschule, ETH-Hˆnggerberg, HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Z¸rich
(phone: ‡ 4116322990; fax: ‡ 4116321144; e-mail: seebach@org.chem.ethz.ch)
The title compounds were prepared from valine-derived N-acylated oxazolidin-2-ones, 1 3, 7, 9, by highly
diastereoselective ( ꢀ 90%) Mannich reaction ( ! 4 6; Scheme 1) or aldol addition ( ! 8 and 10; Scheme 2) of
the corresponding Ti- or B-enolates as the key step. The superiority of the −5,5-diphenyl-4-isopropyl-1,3-
oxazolidin-2-one× (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations
leading to various t-Bu-, Boc-, Fmoc-, and Cbz-protected b2-homoamino acid derivatives 11 23 (Schemes 3
6). The use of w-bromo-acyl-oxazolidinones 1 3 as starting materials turned out to open access to a variety of
enantiomerically pure trifunctional and cyclic carboxylic-acid derivatives.
1. Introduction. In contrast to b3-homoamino acids, which are readily available in
enantiomerically pure form from the natural proteinogenic amino acids by the Arndt
Eistert or Kolbe homologation strategy7) (18 of which are now commercially
available8)), the b2-homoamino acids are much more challaging to prepare7). From
the very beginning of our work on b-peptides containing b2-amino acids [5][6], we
decided to employ a uniform, general, synthetic approach towards derivatives of the 19
b2-amino acids with proteinogenic side chains9): the reactions of chiral oxazolidinones,
the Evans auxiliaries. With the valine-derived −5,5-diphenyl-4-isopropyl-1,3-oxazolidin-
2-one× (DIOZ ˆ 4-(1-methylethyl)-5,5-diphenyl-1,3-oxazolidin-2-one), we found a
superior auxiliary [7 9], which we used whenever possible10)11). The Li-, B-, and
1
)
)
Preliminary communication: [1].
2
Postdoctoral Researcher at ETH Z¸rich, 2001 2003, financed by ETH-Z¸rich, Swiss National Science
Foundation (Project No. 2000-058831) and Novartis Pharma AG, CH-Basel.
Present Adress: Novartis Pharma AG, LS&C, CH-Basel.
Present Adress: PrestwickChemical Inc. , F-Strasbourg.
Part of the Dissertation of T. K., ETH-Z¸rich, No. 15800 (2004), present address: Novartis NIBR, A-Wien.
3
4
5
6
)
)
)
)
Postdoctoral Researcher at ETH Z¸rich (2004/2005), financed by
a stipend of the Deutsche
Forschungsgemeinschaft.
7
8
)
)
For an extensive review article on b- and g-amino acids, and -peptide derivatives, see [2][3].
We thank Fluka AG (CH-Buchs) for generous discounts on purchases of Fmoc/acid-labile- and Boc/H2-
labile-protected b3-amino acid derivatives. The preparation of Fmoc-b3hCys(Tr)-OH and of Fmoc-
b3hHis(Tr)-OH is described in [4].
9
)
b2hGly ꢁ b3hGly ꢁ −b-alanine× does not have a side chain.
10
)
Under certain hydrogenation conditions, DIOZ can undergo cleavage [10]. Aldol additions of DIOZ-
derived enolates to aromatic aldehydes may occur with poor diastereoselectivities, vide infra, Sect. 2.
For a general review article on b2-amino acid-containing peptides and natural products, see [11].
11
)
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

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Helvetica Chimica Acta Vol. 88 (2005)
Ti-enolates of type A, B, and C were allowed to react with alkyl halides, aldehydes,
aminomethylating reagents, or benzyliodoacetate, with generation of the sterogenic
centers of the desired b2-amino acid precursors.
The steric courses of the reactions follow the generally accepted mechanistic
models [12], as confirmed by numerous X-ray crystal-structure analyses of the highly
crystalline DIOZ derivatives [1][4][7][8][13][14]. Detailed procedures for the
preparation by this method of most b2-amino acids with appropriate N-terminal and
side-chain functional-group protection for peptide syntheses have been previously
published by us (Table) [15][16]. Those specified in the title are described herein; for
nomenclature and symbols of b2-amino acids, see D, E, and F in the Table. The
incorporation into a b-peptide of all 20 b2-amino acid moieties derived from the natural
proteinogenic amino acids has been described recently [17]. For alternative enantio-
selective routes to certain b2-amino acids, we refer to references in our review articles
[2][3][11]. It is remarkable that it takes more than a dozen preparative steps to arrive
at a building block for peptide synthesis, such as for instance Fmoc-b2Gln(Tr)-OH [13],
from simple, commercially available starting materials!
Table. The Preparation of All −Proteinogenic× b2-Homoamino Acid b2hXaa Derivatives, Suitably Protected for
Solid-Phase Synthesis, Is Described in the Publications Referenced. The present paper presents new or
alternative procedures for the b2-homoamino acids, the symbols of which are marked. If we consider the b2-
homoamino acids of type E (H-b2hXaa-OH) as −true× homologs of the proteinogenic amino acids D (H-Xaa-
OH), we would have to specify the enantiomers F, as prepared by us, H-b2hdXaa-OH; according to the CIP
nomenclature, they will be H-(S)-b2hXaa-OH, with the complication that the Ser, Trp, and Cys analogs have
(R)-configuration (see also discussion in [1]).

Helvetica Chimica Acta Vol. 88 (2005)
2237
2. Preparation of the Oxazolidinones 1 10 by DIOZ-Acylations, Mannich
Reactions, and Aldol Additions. The first stepof execution of the Evans methodology
is the acylation of the chiral oxazolidinone auxiliary. Due to steric protection of the
DIOZ CˆO group, this step can be carried out simply by treating a slurry in THF with
BuLi, which leads to the soluble Li-DIOZ, and adding an acid chloride. In this way, we
obtained the 3-(w-bromoacyl)-oxazolidinones 1 3 in excellent yield (Scheme 1).
Scheme 1. Preparation of w-Bromoacyl-DIOZ Derivatives 1 3 and Mannich Reactions Thereof Rendering b2-
Amino Acid Derivatives 4 6 with w-Bromoalkyl Side Chains
a) BuLi, THF, À 308. b) Br(CH2)nCOCl, 08. c) TiCl4, Et3N, CH2Cl2, À 158. d) ZHNCH2OMe, 08. Z ˆ
PhCH2OÀCO.
For acylation with the Boc-protected 3-aminopropanoic acid, which cannot be
converted to an acid chloride, we used the bifunctional-catalysis method [18 21], i.e.,
in situ generation of a mixed anhydride and acylation in the presence of LiCl/Et3N [22]
(Scheme 2) to form the DIOZ derivative 7. The same procedure provided the classical
Evans derivative 9.
Scheme 2. Preparation of N-Boc and N-Z-3-Aminopropanoyl-DIOZ Derivatives and Aldol Additions Thereof
Precursors of b2hThr and b2hTrp Derivatives
a) BocNH(CH2)2CO2H, PivCl, Et3N, LiCl, THF, À 308. b) 2.2 equiv. Bu2BOTf, Et3N, CH2Cl2, À 788.
c) MeCHO, À 788. d) ZNH(CH2)2CO2H, PivCl, Et3N, LiCl, THF, À 308. e) [(1-Troc)indol-3-yl]CHO, À 788.
Boc ˆ tBuOÀCO, Z ˆ PhCH2OÀCO, Troc ˆ Cl3CCH2OÀCO.
From the 3-(w-bromoacyl)-oxazolidinones 1 3 Ti-enolates of type A can be
generated, which are known to be nucleophilic only towards aldehydes and iminium

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salts, but not towards alkyl halides: no cyclization to a three-, four-, or five-membered
carbocyclic ring is observed upon treatment of 1 3 with TiCl4/Et3N. Likewise, B-
enolate of type C can be generated from the the acyl-oxazolidinones 7 and 9. Reactions
of these enolate derivatives with benzyl N-(methoxymethyl)carbamate [23], acetalde-
hyde, and an N-protected indole-3-carbaldehyde, respectively, gave the b2-amino acid
derivatives 4 6, 8, and 10 in yields ranging from 90 to 94%. All products, except 10, are
crystalline and can be isolated in enantiomerically pure form by recrystallization; X-ray
crystal structures of 6, 7, and 8 have been determined [1]. The classical Evans auxiliary
(without the two Ph substituents) was used for the preparation of the b2hTrp12
)
precursor 10, because additions of DIOZ-derived B-enolates to aromatic aldehydes
take place with poor diastereoselectivities13).
3. Conversion of the Oxazolidinones 4 6 to Various Other b2-Amino Acid
Derivatives. The w-bromoalkyl b2-amino acid derivatives 4 6 are the most versatile
intermediates on the way to a variety of b2-amino acids with functionalized side chains
or with a cyclic structure: Br/SCH3 substitution in 4 provides a route to b2hMet, Br/N3
substitution in 4 provides a route to b2hOrn, and hence to b2hArg [15], the same
transformation with 6 provides a route to b2hLys, and N-deprotection, followed by
cyclization, constitutes an access to pyrrolidine-3-carboxylic acid (a b-isoproline14)) to
b2hPro, and to azepin-3-carboxylic acid [1] from 4, 5, and 6, respectively15). Four of
these transformations are described in the following sections.
Thus, treatment of ([2-(2-bromoethyl)-3-aminopropanoyl]-DIOZ 4 with MeSNa in
DMF gives the precursor 11 of H-(S)-b2hMet-OH used in the synthesis of an all-b2-
icosapeptide [17], and deprotonation of 4 leads to the N-Z-protected pyrrolidine 12
(Scheme 3).
Scheme 3. Conversion of the Bromoalkyl Derivative 4 to a Precursor for (S)-b2hMet and for Pyrrolidine-3-
carboxylic Acid
a) MeSNa, DMF. b) NaH, cat. Bu4NI, DMF, 708. Z ˆ PhCH2OÀCO.
Similarly, we have cyclized the w-bromoalkyl derivative 5 ( ! 13; Scheme 4). The
configuration of the product follows from an X-ray crystal structure of the
corresponding N-Boc-protected compound (13, Boc instead of Z [1]). To prevent
epimerization/racemization under the conditions of auxiliary removal, we used LiOH/
H2O2 [24] for the conversion to Z-b2hPro-OH (14a); normally, we hydrolize DIOZ
12
)
)
For a route to b2hTrpderivatives involving a Curtius-degradation step, see [10].
With the aldehyde used here, the selectivity of addition of the DIOZ analog of 9 is only 3:2, see also [1]
and Footnote 10.
Proposals for the nomenclature of b-iso-Xaa, see Fig. 5 and Footnote 22 in [2].
Br/CN Substitution in 4 and hydrolysis should lead to b2hGln or b2hGlu derivatives.
13
14
15
)
)

Helvetica Chimica Acta Vol. 88 (2005)
2239
derivatives with NaOH/H2O/THF [7][8]16)). Subsequent protecting-group interchang-
es provided the acids Fmoc-b2hPro-OH (14b) and Boc-b2hPro-OH (14c).
Scheme 4. Cyclization of the Bromoalkyl Derivative 5 to (S)-b2hPro-Derivatives 14
a) NaH, cat. Bu4NI, DMF, 708. b) LiOH, H2O2, H2O, THF, 08. c) H2, Pd/C, MeOH. d) (Fmoc)OSu, Na2CO3,
dioxane, H2O. e) H2, Pd/C, Boc2O, MeOH. f) Cat. CSA, EtOH. g) Pd/C, AcOH, EtOH. h) 2,4-Dinitro-1-
fluorobenzene, EtOH, H2O. Z ˆ PhCH2OÀCO, Fmoc ˆ 9H-fluoren-9-ylÀCH2ÀCO, Boc ˆ tBuOÀCO, Su ˆ N-
succinimidyl, CSA ˆ campher sulfonic acid.
The enantiomeric purities of the b2-homoproline derivatives 14a 14c were
determined by HPLC on chiral phases. Thus, compound 14b was injected into a chiral
HPLC column (ChiralpakAD-H 1151 ); in comparison with a racemic mixture, the
enantiomer ratio was 93 :717)). This is in agreement with the result of an analysis of
ester 14d, which was determined (on Chiralcel OD-H) to also have an enantiomeric
purity of 93 :7.
To further demonstrate the synthetic potential of the amido-methylated w-
bromoacyl-DIOZ derivatives, we have substituted Br by N3 in 6 ( ! 15). Reduction
of the N3 groupunder −bocylating× conditions gave the Z- b2hLys(Boc)-DIOZ 16
(Scheme 5), which had been used as the precursor for the b2-dipeptide Fmoc-b2hIle-
b2hLys(Boc)-OH employed in the b2-icosapeptide synthesis mentioned above [17].
4. Preparation of Z-(R,S)-b2Thr(t-Bu)-OH and of Fmoc-(R)-b2Trp(Boc)-OH from
the Oxazolidinones 8 and 10. The conversion of the aldol adducts 8 and 10 to building
16
)
In esterifying DIOZ removals, for instance with PhCH2OLi, we have observed extensive racemizations of
the resulting esters. When an ester must be prepared from a product of alkylation or aldol addition of an
acylated DIOZ, it is preferable to first prepare the acid and subsequently esterify it.
We thank Dr. Eric Francotte of Novartis AG, Basel, CTA/PSB, for determination of the enantiomeric
purity of 14b.
17
)

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Helvetica Chimica Acta Vol. 88 (2005)
Scheme 5. (S)-b2hLys Derivatives 15 and 16 from the Bromoalkyl Precursor 6 by Br/N3-Substitution as Key Step
a) NaN3, DMF. b) Lindlar cat., H2, Boc2O, MeOH. Boc ˆ tBuOÀCO, Z ˆ PhCH2OÀCO.
blocks suitably protected for solid-phase peptide synthesis is outlined in Scheme 6.
Thus, Boc/Z protecting-group exchange in 8 ( ! 17), tert-butylation of the OH group
( ! 18), and cleavage from the auxiliary group, this time with Bu4NOH, provided Z-
b2hThr(t-Bu)-OH (19) in an overall yield of 54%.
Scheme 6. Functional-Group Manipulations for the Conversion of DIOZ Derivatives 8 and 10 to Protected
(R,S)-b2hThr-OH 19 and (S)-b2hTrp-OH 23
a) TFA, CH2Cl2, 08. b) ZÀCl, NaHCO3. CH2Cl2, H2O. c) Isobutylene, H2SO4, CH2Cl2. d) Bu4NOH, THF, H2O.
e) BF3 ¥ Et2O, Et3SiH. f) Zn, AcOH. g) Boc2O, DMAP, MeCN. h) LiOH, H2O2, H2O, THF, 08. i) H2, Pd/C,
EtOH. j) (Fmoc)OSu, Na2CO3, acetone, H2O. Z ˆ PhCH2OÀCO, Boc ˆ tBuOÀCO, Troc ˆ Cl3CCH2OÀCO,
Fmoc ˆ 9H-fluoren-9-ylÀCH2OÀCO, Su ˆ N-succinimidyl.
Deoxygenation with silane converted compound 10 (containing five functional
groups!) to the Fmoc-b2hTrpderivative
20, which was converted to Fmoc-
b2hTrp(Boc)-OH (23) by a series of three functional-groupmaniuplations: Troc
removal and Boc introduction on the indole N-atom ( ! 21), liberation of the
carboxylic acid group( ! 22), and Z/Fmoc interchange on the amino N-atom ( ! 23),
in a total yield of 30% over six steps.
5. Conclusions. Two types of reactions have been employed for the assembly of
side-chain functionalized b2-homoamino acids with selective formation of the stereo-
genic center in the a-carbonyl position: the amidomethylation, a kind of Mannich

Helvetica Chimica Acta Vol. 88 (2005)
2241
reaction, of w-bromoacyl-DIOZ and the hydroxyalkylation, i.e., aldol addition, of N-
Boc or N-Z-protected 3-aminopropanoyl-oxazolidinones. In the first case Cl3Ti-
enolates and in the second case Bu2B-enolates were applied. Throughout, the desired
stereogenic center was created with stereoselectivities ꢀ 90%, and purification
procedures (crystallization with DIOZ derivatives) provided enantiomerically pure
samples on a preparative scale.
The usefulness of w-bromoacyl-oxazolidinones 1 3 was demonstrated; DIOZ
derivatives of this type serve as starting materials not only for the preparation of the b2-
homoamino acids described herein, but for many other targets as well, due to the fact
that there are numerous synthetically useful C-, N-, P-, S-, Se-nucleophiles, by which a
primary bromide can be substituted.
The overall benzylation-type reaction, 9 ! 10 ! 20, consisting of an aldol
addition and a deoxygenation can be superior to direct benzylations in the case of
functionalized reactants, such as the amino-acyl-oxazolidinone and the indole-
carbaldehyde. Still, it is striking to realize that the b2hTrpamino acid 23, with a single
stereogenic center and two orthogonally protected functionalized side chains, requires
nine steps to be synthesized.
Experimental Part
1. General. Abbreviations: Boc: (tert-butoxy)carbonyl, Boc2O: di-(tert-butyl) dicarbonate, Z: (benzylox-
y)carbonyl, h.v.: high vacuum, 0.01 0.1 Torr, Troc: (2,2,2-trichloroethoxy)carbonyl. Solvents for chromatog-
raphy and workup procedures were distilled from Sikkon (anh. CaSO4; Fluka) and from KOH (Et2O). Et3N was
distilled from CaH2 and stored over 4-ä molecular sieves. Amino acids were purchased from Fluka or Senn.
BuLi was used as a ca. 1.6m soln. in hexane, Bu2BOTf as 1m soln. in CH2Cl2. THF was freshly distilled over Na
under Ar before use. LiCl was dried under h.v. at 1508 overnight. 4-Bromobutanoyl chloride, 5-bromopentanoyl
chloride, and 6-bromohexanoyl chloride were freshly prepared from the corresponding carboxylic acids by
treatment with oxalyl chloride [25]. All other reagents were used as received from Fluka or Aldrich. DIOZ and
benzyl N-(methoxymethyl)carbamate (ZHNCH2OMe) were prepared according to [9] and [23], resp. TLC:
Merck silica gel 60 F254 plates; detection with UV, anisaldehyde soln. (9.2 ml of anisaldehyde, 12.5 ml of conc.
H2SO4, 3.75 ml of AcOH, 340 ml of EtOH), or −Mo-stain× soln. (25 g of phosphormolybdic acid, 10 g of
Ce(SO4)2 ¥ H2O, 60 ml of conc. H2SO4, 940 ml of H2O). Flash Chromatography (FC): Fluka silica gel 60 (40
63 mm); at ca. 0.3 bar. IR Spectra: Perkin-Elmer 1600 FT-IR spectrophotometer. NMR Spectra: Bruker AMX II
500 (1H: 500 MHz, 13C: 125 MHz), AMX-400 (1H: 400 MHz, 13C: 100 MHz), 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 ( ˆ 0 p p m)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. Acylation of the Auxiliary with Acyl Chlorides. General Procedure 1 (GP 1). To a suspension of the
auxiliary (1 equiv.) in THF (0.25m), BuLi (1.05 equiv.) was slowly added at À 308. After stirring for 10 min, a
soln. of the acyl chloride (1.2 equiv.) in THF (0.8 ml/mmol) was added. The mixture was stirred at 08 for 2 h,
allowed to warm slowly to r.t. over 14 h, hydrolyzed by the addition of sat. NH4Cl soln., and diluted with Et2O.
The org. phase was washed with 1m HCl (2 Â ), 1m NaOH (2 Â ), and brine, dried (MgSO4), and evaporated. The
crude product was purified by FC.
3. Amidoalkylation of Acyl-Oxazolidinones. General Procedure 2 (GP 2). To a soln. of the acyl-
oxazolidinone (1 equiv.) in CH2Cl2 (0.2m), TiCl4 (1.05 equiv.) and Et3N (1.10 equiv.) were added at À 158 (ice/
MeOH bath). The deep-red soln. was stirred at À 158 for 30 min, treated with a soln. of benzyl N-
(methoxymethyl)carbamate (1.05 equiv.) in CH2Cl2 (0.5m) and additional TiCl4 (1.1 equiv.). The mixture was
stirred at 08 (ice bath) for 3 h, hydrolyzed by the addition of sat. NH4Cl soln., and diluted with CH2Cl2 or Et2O.
The org. phase was washed with 1m HCl (2 Â ), 1m NaOH, and brine, dried (MgSO4), and evaporated. The crude
product was purified by FC.

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4. Acylation of the Auxiliary with Mixed Anhydrides. General Procedure 3 (GP 3). To a soln. of the
appropriate acid (1.05 equiv.) in THF (0.2m), Et3N (2.5 equiv.) and pivaloyl chloride (1 equiv.) were added at À
308. The resulting white suspension was stirred at À 308 for 2 h, LiCl (1.1 equiv.) and the auxiliary (0.95 equiv.)
were added, and stirring was continued for 1 2 d as the mixture was allowed to warm to r.t. The mixture was
diluted with Et2O, washed with sat. NH4Cl soln. (2 Â ), 1m NaOH (2 Â ), and sat aq. NaCl soln., dried (MgSO4),
and concentrated under reduced pressure. FC of the crude product yielded the pure compound.
5. Aldol Reaction via Boron-Enolate. General Procedure 4 (GP 4). To a soln. of the acyl-oxazolidinone
(1 equiv.) in CH2Cl2 (0.4m), Bu2BOTf (2.2 equiv.) and Et3N (2.4 equiv.) were added at À 788. After stirring at
À 788 for 1 h and 15 min at 08, the mixture was cooled again to À 788, treated with the appropriate aldehyde
(2.5 equiv.), and stirred at the indicated temp. and time. After addition of a phosphate buffer (pH 7, 1 ml/
mmol), MeOH (3 ml/mmol), and H2O2/MeOH 1:2 (3 ml/mmol), the mixture was stirred at r.t. for 1 h, diluted
with Et2O, washed with 0.5m HCl, sat. NaHCO3 soln., and brine. The org. phase was dried (MgSO4) and
evaporated, and the crude product was purified by FC.
6. Bromide Substitution. General Procedure 5 (GP 5). A mixture of the brominated acyl-oxazolidinone
(1 equiv.) and NaN3 (1.2 equiv.) or MeSNa (1 3 equiv.) in DMF (0.5m) was stirred at r.t. for 14 h, diluted with
Et2O, and washed with H2O (2 Â ). The org. phase was separated, dried (MgSO4), and evaporated, and the crude
product was purified by FC or recrystallization.
(4R)-3-(4-Bromo-1-oxobutyl)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (1). (R)-DIOZ (11.3 g,
40 mmol) was treated with BuLi (28.0 ml, 42 mmol) and 4-bromobutanoyl chloride (8.9 g, 48 mmol) according
to GP 1. FC (pentane/Et2O 9 :1) yielded 1 (15.59 g, 90%). Colorless solid. M.p. 105 1078. Rf (pentane/Et2O
6 :4) 0.70. [a]Dr:t: ˆ ‡ 207.9 (c ˆ 1.0, CHCl3). IR (CHCl3): 3011w, 2969w, 1779s, 1691m, 1494w, 1450m, 1399m,
1365m, 1319m, 1177m, 1092w, 1052w, 1036w, 1001w, 961w. 1H-NMR (400 MHz, CDCl3): 0.78 (d, J ˆ 6.8, Me);
0.85 (d, J ˆ 7.0, Me); 1.92 2.02 (m, Me2CH); 2.08 2.19 (m, CH2); 2.87 2.95, 3.03 3.12 (m, CH2CO); 3.38 (t,
J ˆ 6.6, CH2Br); 5.39 (d, J ˆ 3.4, CHN); 7.26 7.48 (m, 10 arom. H). 13C-NMR (100 MHz, CDCl3): 16.4, 21.7
(Me); 27.3 (CH2); 30.0 (CH); 32.3, 33.7 (CH2); 64.5 (CH); 89.2 (C); 125.8, 126.0, 128.3, 128.4, 128.5, 128.9 (CH);
‡
‡
138.4, 142.4, 153.4, 174.1 (C). MALDI-MS: 452.1 (34, [M ‡ Na] ), 372.2 (100, [M À Br ‡ Na] ). Anal. calc.
for C22H24BrNO3 (430.34): C 61.40, H 5.62, N 3.25, Br 18.57; found: C 61.38, H 5.49, N 3.23, Br 18.24.
(4R)-3-(5-Bromo-1-oxopentyl)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (2). (R)-DIOZ (20.0 g,
71 mmol) was treated with BuLi (49.7 ml, 74.6 mmol) and 5-bromopentanoyl chloride (17.0 g, 85.3 mmol)
according to GP 1. FC (pentane/Et2O 9 :1) yielded 2 (21.71 g, 87%). Colorless oil. Rf (pentane/Et2O 6 :4) 0.70.
[a]Dr:t: ˆ ‡ 172.1 (c ˆ 1.0, CHCl3). IR (CHCl3): 3025w, 2967w, 1781s, 1494w, 1450m, 1366m, 1320m, 1177m,
1
1120w, 1051w, 1002w. H-NMR (400 MHz, CDCl3): 0.76 (d, J ˆ 6.8, Me); 0.87 (d, J ˆ 7.0, Me); 1.68 1.81 (m,
2 CH2); 1.95 2.02 (m, Me2CH); 2.77 2.94 (m, CH2CO); 3.32 (t, J ˆ 6.4, CH2Br); 5.36 (d, J ˆ 3.4, CHN); 7.26
7.49 (m, 10 arom. H). 13C-NMR (100 MHz, CDCl3): 16.5, 21.8 (Me); 23.2 (CH2); 29.8 (CH); 31.8, 33.0, 34.2
(CH2); 64.6 (CH); 89.5 (C); 125.6, 125.9, 128.0, 128.4, 128.6, 128.9 (CH); 138.1, 142.3, 153.1, 172.5 (C). MALDI-
‡
MS: 468.1 (88, [M ‡ Na] ), 402.1 (21), 320.2 (41). Anal. calc. for C23H26BrNO3 (444.37): C 62.17, H 5.90, N 3.15,
Br 17.98; found: C 62.30, H 6.03, N 3.41, Br 17.96.
(4R)-3-(6-Bromo-1-oxohexyl)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (3). (R)-DIOZ (5.6 g,
20 mmol) was treated with BuLi (14.0 ml, 21 mmol) and 6-bromohexanoyl chloride (5.1 g, 24 mmol) according
to GP 1. FC (pentane/Et2O 9 :1) yielded 3 (7.82 g, 85%). Colorless solid. M.p. 74 758. Rf (pentane/Et2O 6 :4)
0.70. [a]rD:t: ˆ ‡ 165.6 (c ˆ 1.0, CHCl3). IR (CHCl3): 3026w, 2967w, 1781s, 1702s, 1494w, 1450m, 1366m, 1320m,
1
1177m, 1120w, 1051w, 1002w. H-NMR (400 MHz, CDCl3): 0.76 (d, J ˆ 6.8, Me); 0.87 (d, J ˆ 7.0, Me); 1.34
1.41 (m, CH2); 1.53 1.62 (m, CH2); 1.76 1.83 (m, CH2); 1.94 2.02 (m, Me2CH); 2.73 2.92 (m, CH2CO); 3.34
(t, J ˆ 6.8, CH2Br); 5.36 (t, J ˆ 3.4, CHN); 7.26 7.49 (m, 10 arom. H). 13C-NMR (100 MHz, CDCl3): 16.4, 21.8
(Me); 23.7, 27.4 (CH2); 29.8 (CH); 32.4, 33.4, 34.9 (CH2); 64.5 (CH); 89.4 (C); 125.6, 125.9, 127.9, 128.4, 128.6,
‡
128.9 (CH); 138.1, 142.4, 153.0, 172.8 (C). MALDI-MS: 480.1 (100, [M ‡ Na] ), 416.1 (24). Anal. calc. for
C24H28BrNO3 (458.39): C 62.89, H 6.16, N 3.06, Br 17.43; found: C 63.11, H 6.13, N 3.30, Br 17.40.
(4R)-3-[(2S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-4-bromo-1-oxobutyl]-4-(1-methylethyl)-5,5-diphe-
nyloxazolidin-2-one (4). Compound 1 (8.61 g, 20 mmol) was treated with TiCl4 (2.30 ml, 21 mmol), Et3N
(3.07 ml, 22 mmol), ZNHCH2OMe (4.1 g, 21 mmol), and additional TiCl4 (2.41 ml, 22 mmol) according to
GP 2. FC (pentane/Et2O 8 :2 ! 7:3) yielded, beside starting material 1 (1.57 g), 4 as a 89 :11 mixture with its
C(2)-epimer (7.79 g, 80%). For anal. purposes, a sample was recrystallized (pentane/Et2O). Colorless solid. M.p.
51.5 53.58. Rf (hexane/AcOEt 7:3) 0.32. [a]Dr:t: ˆ ‡ 96.1 (c ˆ 1.0, CHCl3). IR (CHCl3): 3442w, 3011w, 2968w,
1
1780s, 1719s, 1515m, 1450m, 1396w, 1364m, 1318m, 1122w, 1053w, 989w. H-NMR (500 MHz, CDCl3): 0.71 (d,
J ˆ 6.8, Me); 0.83 (d, J ˆ 7.0, Me); 1.76 1.81, 2.01 2.09 (2m, CH2); 1.96 2.01 (m, Me2CH); 2.73 2.78, 2.92
2.96 (2m, CH2Br); 3.37 3.42, 3.56 3.62 (2m, CH2NH); 3.98 4.01 (m, CHCO); 5.01 5.12 (m, PhCH2); 5.25 (s,

Helvetica Chimica Acta Vol. 88 (2005)
2243
NH); 5.34 (d, J ˆ 3.4, CHN); 7.27 7.50 (m, 15 arom. H). 13C-NMR (125 MHz, CDCl3): 16.2, 21.6 (Me); 21.6
(CH2); 29.6 (CH); 32.2 (CH2); 42.0 (CH); 43.0 (CH2); 65.6 (CH); 66.8 (CH2); 89.9 (C); 125.2, 125.5, 125.7, 128.1,
‡
128.2, 128.5, 128.9, 129.0 (CH); 136.4, 137.5, 142.1, 153.2, 156.2, 173.4 (C). MALDI-MS: 615.2 (14, [M ‡ Na] ),
‡
535.2 (100, [M À Br ‡ Na] ), 469.3 (8). Anal. calc. for C31H33BrN2O5 (593.52): C 62.73, H 5.60, N 4.72, Br 13.46;
found: C 62.76, H 5.71, N 4.70, Br 13.28.
(4R)-[(2S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-5-bromo-1-oxopentyl]-4-(1-methylethyl)-5,5-diphe-
nyloxazolidin-2-one (5). Compound 2 (20.44 g, 46 mmol) was treated with TiCl4 (5.30 ml, 48.3 mmol), Et3N
(7.05 ml, 50.6 mmol), ZNHCH2OMe (9.43 g, 48.3 mmol), and additional TiCl4 (5.55 ml, 50.6 mmol) according
to GP 2. FC (pentane/Et2O 9 :1 ! 7:3) yielded beside starting material 2 (1.63 g), 5 as a 93 :7 mixture with its
C(2)-epimer (22.1 g, 86%). Colorless glass. Rf (hexane/AcOEt 7:3) 0.31. [a]rD:t: ˆ ‡ 102.2 (c ˆ 0.9, CHCl3). IR
(CHCl3): 3448w, 3011w, 2967w, 1780s, 1719s, 1514m, 1450m, 1396w, 1364m, 1318m, 1092w, 1052w, 1001w. 1H-
NMR (500 MHz, CDCl3): 0.71 (d, J ˆ 6.8, Me); 0.83 (d, J ˆ 7.0, Me); 1.24 1.30 (m, CH2); 1.31 1.39, 1.45 1.49
(2m, CH2); 1.95 2.01 (m, Me2CH); 2.95 3.00 (m, CH2Br); 3.35 3.40, 3.51 3.56 (2m, CH2NH); 3.86 (br. s,
CHCO); 5.04 5.10 (m, PhCH2); 5.26 (s, NH); 5.32 (d, J ˆ 3.5, CHN); 7.27 7.50 (m, 15 arom. H). 13C-NMR
(125 MHz, CDCl3): 16.4, 21.6 (Me); 28.1, 29.3 (CH2); 29.5 (CH); 32.7 (CH2); 42.1 (CH); 42.7 (CH2); 65.6 (CH);
66.7 (CH2); 89.8 (C); 125.3, 125.7, 128.1, 128.2, 128.5, 128.8, 129.0 (CH); 136.5, 137.5, 142.2, 153.2, 156.2, 174.3
‡
‡
‡
(C). MALDI-MS: 645.1 (14, [M ‡ K] ), 629.2 (91, [M ‡ Na] ), 565.0 (11, [M À Br ‡ K] ), 549.2 (38, [M À
‡
Br ‡ Na] ). Anal. calc. for C32H35BrN2O5 (607.54): C 63.26, H 5.81, N 4.61, Br 13.15; found: C 63.30, H 5.77, N
4.56, Br 13.04.
(4R)-3-[(2S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-6-bromo-1-oxohexyl]-4-(1-methylethyl)-5,5-di-
phenyloxazolidin-2-one (6). Compound 3 (6.87 g, 15 mmol) was treated with TiCl4 (1.73 ml, 15.7 mmol), Et3N
(2.30 ml, 16.5 mmol), ZNHCH2OMe (3.06 g, 15.7 mmol), and additional TiCl4 (1.81 ml, 16.5 mmol) according
to GP 2. FC (pentane/Et2O 8 :2 ! 7:3) yielded beside starting material 3 (774 mg), 6 as a 94 :6 mixture with its
C(2)-epimer (6.41 g, 77%). For anal. purposes, a sample was recrystallized (pentane/Et2O). Colorless needles.
M.p. 95 988. Rf (hexane/AcOEt 7:3) 0.31. [a]Dr:t: ˆ ‡ 96.5 (c ˆ 1.0, CHCl3). IR (CHCl3): 3450w, 3026w, 2967w,
1780s, 1719s, 1514m, 1450m, 1395w, 1364m, 1318m, 1153w, 1093w, 1052w, 1002w. 1H-NMR (500 MHz, CDCl3):
0.71 (d, J ˆ 6.7, Me); 0.83 (d, J ˆ 7.0, Me); 0.88 0.92 (m, CH2); 1.18 1.27, 1.35 1.47 (2m, CH2); 1.48 1.54 (m,
CH2); 1.95 2.00 (m, Me2CH); 3.08 (t, J ˆ 6.8, CH2Br); 3.35 3.38, 3.48 3.54 (2m, CH2NH); 3.82 3.86 (m,
CHCO); 5.07 (s, PhCH2); 5.19 (br. s, NH); 5.32 (d, J ˆ 3.5, CHN); 7.26 7.51 (m, 15 arom. H). 13C-NMR
(125 MHz, CDCl3): 16.4, 21.7 (Me); 25.0, 28.6 (CH2); 29.6 (CH); 32.4, 32.8 (CH2); 42.7 (CH); 43.3 (CH2); 65.5
(CH); 66.7 (CH2); 89.7 (C); 125.4, 125.7, 128.1, 128.2, 128.4, 128.5, 129.0 (CH); 136.5, 137.6, 142.3, 153.2, 156.2,
‡
‡
174.6 (C). MALDI-MS: 659.2 (7, [M ‡ K] ), 643.2 (96, [M ‡ Na] ), 599.2 (81), 577.2 (9). Anal. calc. for
C33H37BrN2O5 (621.57): C 63.77, H 6.00, N 4.51, Br 12.86; found: C 63.56, H 5.87, N 4.48, Br 12.75.
(4R)-3-({3-[(tert-Butoxy)carbonyl]amino}-1-oxopropyl)-4-isopropyl-5,5-diphenyloxazolidin-2-one (7).
(R)-DIOZ (11.3 g, 40 mmol) was treated with pivaloyl chloride (5.7 g, 42 mmol), 3-{[(tert-butoxy)carbonyl]-
amino}propanoic acid (7.6 g, 40 mmol), Et3N (14.5 ml, 104 mmol) and dry LiCl (1.95 g, 46 mmol) according
to GP 3. FC (pentane/Et2O 9 :1 ! 8 :2) yielded 7 (13.06 g, 84%). Colorless needles. M.p. 109 1108. Rf
(pentane/Et2O 1:1) 0.25. [a]rD:t: ˆ ‡ 173.3 (c ˆ 1.0, CHCl3). IR (CHCl3): 3457w, 3005w, 2975w, 2933w, 1783s,
1708s, 1505m, 1450m, 1393m, 1368m, 1319w, 1051w, 1002w. 1H-NMR (500 MHz,CDCl3): 0.75 (d, J ˆ 6.8, Me);
0.88 (d, J ˆ 7.0, Me); 1.41 (s, t-Bu); 1.95 2.01 (m, Me2CH); 2.85 2.91 (m, CH2); 3.12 3.18 (m, CH2); 3.36
3.39 (m, CH2); 4.85 (br. s, NH); 5.36 (d, J ˆ 3.5, CHN); 7.27 7.48 (m, 10 arom. H). 13C-NMR (125 MHz,
CDCl3): 16.4; 21.8; 28.4; 29.9; 35.8; 36.0; 64.6; 79.3; 89.6; 125.2; 125.9; 128.0; 128.4; 128.7; 129.0; 138.0; 142.2;
‡
‡
152.9; 155.7; 171.9. MALDI-MS: 475.22 (42, [M ‡ Na] ), 412.2 (37), 375.2 (100, [M À Boc ‡ Na] ), 353.2 (6),
331.2 (21), 309.2 (8). Anal. calc. for C26H32N2O5 (452.55): C 69.01, H 7.13, N 6.19; found: C 69.08, H 7.28, N 6.25.
(4R)-[(2R,3S)-2-({[(tert-Butoxy)carbonyl]amino}methyl)-3-hydroxy-1-oxopropyl]-4-(1-methylethyl)-5,5-
diphenyloxazolidin-2-one (8). According to GP 4, 7 (15.0 g, 33.1 mmol) was treated with Bu2BOTf (72.9 ml,
72.9 mmol), and the formed enolate reacted with acetaldehyde (3.74 ml, 66.2 mmol) at À 788 for 1 h and at 08
for 4 h. FC (hexane/AcOEt 9 :1 ! 7:3) yielded 8 (11.15 g, 68%). Colorless needles. M.p. 137 1388. Rf
(hexane/AcOEt 7:3) 0.16. [a]rD:t: ˆ ‡ 105.2 (c ˆ 1.0, CHCl3). IR (CHCl3): 3453w, 2980w, 2934w, 1781s, 1693s,
1513m, 1450m, 1392m, 1368m, 1317m, 1289m, 1175s, 1122w, 1102w, 1052w, 990w. 1H-NMR (500 MHz, CDCl3):
0.72 (d, J ˆ 5.9, Me; 0.78 (d, J ˆ 6.8, Me); 0.87 (d, J ˆ 7.0, Me); 1.42 (s, t-Bu); 1.98 2.04 (m, Me2CH); 3.44
3.49 (m, CH2); 3.77 3.83 (m, 2 CH); 3.71 (br. s, OH); 5.06 (br. s, NH); 5.36 (d, J ˆ 3.5, CHN); 7.26 7.50 (m,
10 arom. H). 13C-NMR (125 MHz, CDCl3): 16.4; 19.7; 21.8; 28.3; 29.7; 39.1; 49.7; 65.1; 66.1; 80.0; 89.7; 125.4;
‡
125.8; 128.1; 128.5; 128.8; 128.9; 137.7; 142.2; 152.9; 156.8; 174.0. MALDI-MS: 535.2 (8, [M ‡ K] ), 519.3 (100,
‡
‡
‡
[M ‡ Na] ), 463.2 (11), 419.2 (70, [M À Boc ‡ Na] ), 397.2 (83, [M À Boc ‡ H] ), 358.1 (52). Anal. calc. for
C28H36N2O6 (496.60): C 67.72, H 7.31, N 5.64; found: C 67.82, H 7.22, N 5.60.

2244
Helvetica Chimica Acta Vol. 88 (2005)
(4R)-3-(3-{[(Benzyloxy)carbonyl]amino}-1-oxopropyl)-4-(1-methylethyl)oxazolidin-2-one (9). (R)-4-(1-
Methylethyl)oxazolidin-2-one (2.47 g, 19.12 mmol) was treated with pivaloyl chloride (3.56 ml, 28.94 mmol), 3-
{[(benzyloxy)carbonyl]amino}propanoic acid (6.4 g, 28.94 mmol), Et3N (7.4 ml, 53.53 mmol), and dry LiCl
(0.9 g, 21.98 mmol) according to GP 3. FC (AcOEt/hexane 1:2 ! 1:1) yielded 9 (3.50 g, 82%). White foam. Rf
(AcOEt/hexane 1:1) 0.58. IR (CHCl3): 3351w, 3016w, 2954w, 1771s, 1742s, 1723s, 1625m, 1503m, 1430m, 1395m,
1354m, 1328m, 1149w, 1118m, 1051w, 992w. 1H-NMR (500 MHz, CDCl3): 0.84 (d, J ˆ 6.8, Me); 0.89 (d, J ˆ 7.1,
Me); 2.22 2.31 (m, Me2CH); 3.09 (t, CH2N); 3.41 3.47 (m, CH2); 4.27 (m, CHN); 5.05 (s, CH2O); 7.29 7.33
(m, 5 arom. H). 13C-NMR (125 MHz, CDCl3): 15.3; 21.5; 25.4; 29.5; 41.6; 43.2; 64.7; 66.8; 75.6; 88.7; 95.4; 115.3;
118.8; 119.1; 122.3; 125.6; 125.8; 127.6; 128.3; 128.8; 136.5; 140.4; 155.1; 172.1. MALDI-MS: 335.1 (100, [M ‡
‡
‡
H] ), 357.2 (70, [M ‡ Na] ).
(4R)-3-[(2S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-hydroxy-3-{1-[(2,2,2-trichloroethoxy)carbonyl]-
indol-3-yl}-1-oxopropyl]-4-(1-methylethyl)oxazolidin-2-one (10). According to GP 4, 9 (4.14 g, 12.40 mmol) in
CH2Cl2 (30 ml) at À 788 was treated with Bu2BOTf (27.28 ml, 27.28 mmol) and Et3N (4.14 ml, 29.76 mmol) for
1 h, and then with 1-Troc-(1H-indole-3-carbaldehyde (9.88 g, 31 mmol) at À 788 for 3 h. FC (hexane/AcOEt
7:3) yielded 10 (5.42 g, 67%). White foam. Rf (hexane/AcOEt 7 :3) 0.36. IR (CHCl3): 3442w, 3010w, 2978w,
1777s, 1703s, 1525m, 1452m, 1388w, 1354m, 1320w, 1281w, 1106w, 1007w, 994w. 1H-NMR (500 MHz, CDCl3):
0.73 (d, J ˆ 6.8, Me); 0.75 (d, J ˆ 6.2, Me); 0.79 (d, J ˆ 6.8, Me); 2.16 2.22 (m, Me2CH); 3.17 (m, CH); 3.56
3.59 (m, CH); 3.71 (t, J ˆ 8.2, CH2N); 4.05 4.12 (m, 2 CH); 4.69 4.76 (m, CHO); 7.25 7.38 (m, 8 arom. H);
‡
7.78 (d, J ˆ 7.7, 1 arom. H); 8.20 (d, J ˆ 8.4, 1 arom. H). HR-MALDI-MS: 653.1081 (C29H31Cl3N3O8 ; calc.
653.1098).
(4R)-3-[(2S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-4-(methylsulfanyl)-1-oxobutyl]-4-(1-methylethyl)-
5,5-diphenyloxazolidin-2-one (11). Compound 4 (594 mg, 1 mmol) was treated with MeSNa (70 mg, 1 mmol),
according to GP 5. FC (pentane/AcOEt 9 :1 ! 8 :2) yielded 11 (302 mg, 54%). For anal. purposes, a sample
was recrystallized (hexane/AcOEt). Colorless needles. M.p. 131 1338. Rf (hexane/AcOEt 8 :2) 0.13. [a]Dr:t:
ˆ
‡ 101.6 (c ˆ 1.0, CHCl3). IR (CHCl3): 3443w, 3008w, 2968w, 2923w, 1779s, 1720s, 1514m, 1450m, 1395w,
1364m, 1318m, 1145w, 1092w, 1052w, 1002w. 1H-NMR (400 MHz, CDCl3): 0.71 (d, J ˆ 6.7, Me); 0.83 (d, J ˆ 7.1,
Me); 1.49 1.55, 1.73 1.77 (2m, CH2); 1.78 (s, Me); 1.94 2.02 (m, Me2CH, CH2SMe); 3.36 3.42, 3.52 3.59
(2m, CH2NH); 3.92 3.96 (m, CHCO); 5.04 5.10 (m, PhCH2); 5.24 (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 (Me); 28.8 (CH2); 29.6 (CH); 31.0 (CH2);
42.3 (CH); 43.0 (CH2); 65.4 (CH); 66.8 (CH2); 89.7 (C); 125.3, 125.7, 128.1, 128.2, 128.5, 128.8, 128.9 (CH);
‡
136.5, 137.7, 142.3, 153.2, 156.2, 174.1 (C). MALDI-MS: 583.2 (100, [M ‡ Na] ), 539.2 (59), 144.7 (23). Anal.
calc. for C32H36N2O5S (560.71): C 68.55, H 6.47, N 5.00, S 5.72; found: C 68.50, H 6.62, N 4.99, S 5.62.
(4R)-3-({(3S)-1-[(Benzyloxy)carbonyl]pyrrolidin-3-yl}carbonyl)-4-(1-methylethyl)-5,5-diphenyloxazoli-
din-2-one (12). To a soln. of 4 (2.37 g, 4.0 mmol) in DMF (20 ml), 55 wt-% NaH (210 mg, 4.8 mmol) and Bu4NI
(15 mg, 0.04 mmol) were added at r.t. The mixture was warmed to 708, stirred for 2 h, cooled again to r.t., diluted
with Et2O (100 ml), washed successively with 1m HCl (2 Â 50 ml), sat. NaHCO3 soln. (50 ml), and brine (50 ml).
The org. phase was dried (MgSO4) and evaporated. FC (pentane/Et2O 8 :2 ! 7:3) yielded 12 (1.21 g, 59%).
For anal. purposes, a sample was recrystallized (pentane/Et2O). Colorless solid. M.p. 59 608. Rf (pentane/Et2O
1:1) 0.25. [a]Dr:t: ˆ ‡ 148.6 (c ˆ 0.9, CHCl3). IR (CHCl3): 3008w, 2969w, 2933w, 2881w, 1781s, 1699s, 1495w,
1450m, 1426m, 1362m, 1346m, 1119m, 1052w, 1001w. 1H-NMR (500 MHz, CDCl3, mixture of rotamers): 0.76 (d,
J ˆ 6.7, Me); 0.86 (d, J ˆ 7.0, Me); 1.63 1.91, 2.10 2.38 (2m, CH2); 1.97 2.02 (m, Me2CH); 3.35 3.77 (m,
2 CH2); 4.03 4.11 (m, CHCO); 5.08 5.12 (m, PhCH2); 5.34 5.39 (m, CHN); 7.26 7.48 (m, 15 arom. H). 13C-
NMR (125 MHz, CDCl3): 16.4, 21.6 (Me); 27.5, 28.3, 28.8 (CH2); 29.8, 41.7, 42.7 (CH); 45.0, 45.1, 45.4, 45.6, 47.2,
47.7, 48.2, 48.8 (CH2); 64.7, 64.8 (CH); 66.8 (CH2); 89.7 (C); 125.5, 125.8, 127.9, 128.1, 128.4, 128.5, 128.9, 129.0
‡
(CH); 136.8, 136.9, 137.7, 141.9, 142.0, 152.7, 152.9, 154.5, 172.5 (C). MALDI-MS: 535.2 (100, [M ‡ Na] ), 491.2
(42), 469.3 (45), 425.3 (18). Anal. calc. for C31H32N2O5 (512.60): C 72.64, H 6.29, N 5.46; found: C 72.73, H 6.44,
N 5.37.
(4R)-3-({(3S)-1-[(Benzyloxy)carbonyl]piperidin-3-yl}carbonyl)-4-(1-methylethyl)-5,5-diphenyloxazolidin-
2-one (13). To a soln. of 5 (3.43 g, 5.65 mmol) in DMF (30 ml), 55 wt-% NaH (296 mg, 6.78 mmol) and Bu4NI
(21 mg, 0.057 mmol) were added at r.t. The mixture was warmed to 708, stirred for 3 h, cooled again to r.t.,
diluted with Et2O (130 ml), washed successively with 1m HCl (2 Â 30 ml), sat. NaHCO3 (30 ml), and brine
(30 ml). The org. phase was dried (MgSO4) and evaporated. FC (AcOEt/n-hexane 2 :1) yielded 13 (2.38 g,
80%). Colorless solid. M.p. 58 628. Rf (pentane/Et2O 1:1) 0.38. [a]rD:t: ˆ ‡ 119.3 (c ˆ 1.0, CHCl3). IR (CHCl3):
3008w, 2959w, 2933w, 2862w, 1780s, 1693s, 1496w, 1470m, 1450m, 1436m, 1391w, 1363m, 1348m, 1321w, 1140m,
1
1077w, 1052w. H-NMR (500 MHz, CDCl3, mixture of rotamers): 0.74 (d, J ˆ 6.7, Me); 0.85 (d, J ˆ 7.0, Me);
1.21 1.28, 1.43 1.49 (2m, CH2); 1.54 1.71 (m, CH2); 1.94 2.00 (m, Me2CH); 2.80 2.84, 3.95 3.99 (2m, CH2);

Helvetica Chimica Acta Vol. 88 (2005)
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3.12 3.16 and 4.18 4.22 (2m, CH2); 3.44 3.48, 3.59 3.63 (2m, CHCO); 5.08 5.13 (m, PhCH2); 5.31 (d, J ˆ
3.5, CHN); 7.26 7.46 (m, 15 arom. H). 13C-NMR (125 MHz, CDCl3): 16.2, 16.4, 21.6, 21.8 (Me); 23.9, 24.2, 26.9,
27.3 (CH2); 29.7, 29.9, 40.0, 40.7 (CH); 44.1, 45.8 (CH2); 64.8 (CH); 67.2 (CH2); 89.4 (C); 125.5, 125.6, 125.9,
127.9, 128.0, 128.4, 128.6, 128.9 (CH); 136.8, 137.9, 142.3, 152.7, 155.1, 173.6 (C). MALDI-MS: 565.2 (10, [M ‡
‡
‡
K] ), 549.2 (100, [M ‡ Na] ), 505.3 (62), 483.3 (22), 439.3 (9). Anal. calc. for C32H34N2O5 (526.63): C 72.98, H
6.51, N 5.32; found: C 72.88, H 6.70, N 5.30.
(S)-1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic Acid (14a). To a soln. of 13 (2.32 g, 4.41 mmol) in
THF/H2O (20 ml/5 ml) at 08, H2O2 (30%, 1.99 g, 17.6 mmol) and LiOH ¥ H2O (296 mg, 7.05 mmol) were added,
and the resulting mixture was stirred for 4 h at 08. The mixture was diluted with H2O, and the preticipated chiral
auxiliary was removed by filtration. After adjusting the pH of the soln. to 1 2 with 1n HCl, the aq. phase was
extracted with AcOEt (1 Â 80 ml, 2 Â 40 ml). The combined org. layers were washed with brine (40 ml), dried
(Na2SO4), and concentrated under reduced pressure. The crude product was purified by FC (AcOEt/hexane/
AcOH 50 :50 :2) to obtain 984 mg (85%) of 14a. White solid. M.p. 100 1018. Rf (AcOEt/hexane/AcOH
50 :50 :2) 0.32. [a]rD:t: ˆ ‡ 43.7 (c ˆ 1.1, CHCl3). IR (CHCl3): 3020s, 1695s, 1520w, 1472m, 1435m, 1220s, 1145m,
1080w, 1040m, 930m, 800s. 1H-NMR (400 MHz, CDCl3): 1.43 1.56 (m, 1 HÀC(5)); 1,60 1.79 (m, 1 HÀC(4),
1 HÀC(5)); 2.05 2.14 (m, 1 HÀC(4)); 2.51 (br. s, HÀC(3)); 2.94 (ddd, J ˆ 3.0, 10.8, 13.4, 1 HÀC(6)); 3.13 (br.
s, 1 HÀC(6)); 3.93 4.00 (m, 1 HÀC(6)); 4.19 (br. s, 1 HÀC(2)); AB system (dA ˆ 5.11, dB ˆ 5.16, JAB ˆ 12.4,
1 H each, PhCH2); 7.28 7.37 (m, 5 arom. H). 13C-NMR (100 MHz, CDCl3): 24.1; 27.0; 41.0; 44.2; 45.4; 67.3;
‡
127.9; 128.0; 128.5; 136.6; 155.2; 178.6. HR-ESI-MS: 286.1046 (C14H17NO4Na ; calc. 286.1050). Anal. calc. for
C14H17NO4 (263.30): C 63.87, H 6.51, N 5.32; found: C 63.72, H 6.49, N 5.42.
(S)-1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}piperidine-3-carboxylic Acid (14b). Compound 14a (263 mg,
1.00 mmol) was dissolved in MeOH (10 ml) under N2, and Pd/C (10%, 26 mg, 0.02 mmol) was added. The
apparatus was evacuated and flushed with H2 (3 Â ), and the soln. was stirred under H2 (balloon) for 1.5 h.
Subsequent filtration through Celite, washing with MeOH, and concentration under reduced pressure yielded
the crude product (148 mg). This material was dissolved in dioxane/H2O (5 ml/5 ml), and Na2CO3 (265 mg,
2.5 mmol) and FmocOSu (371 mg, 1,10 mmol) were added. The mixture was stirred for 2 h at r.t., diluted with
H2O (10 ml), and the pH of the soln. was adjusted to 1 2 with 1n HCl. The aq. phase was extracted with AcOEt
(3 Â 20 ml), and the combined org. layers were dried (Na2SO4) and concentrated under reduced pressure. The
crude product was purified by FC (AcOEt/hexane/AcOH 50 :50 :2) to give 324 mg (92%) of 14b. White solid.
M.p. 160 1618. Rf (AcOEt/hexane/AcOH 50 :50 :2) 0.46. [a]rD:t: ˆ ‡ 38.1 (c ˆ 1.2, CHCl3). IR (CHCl3): 3010w,
2950w, 1695s, 1475w, 1450m, 1260m, 1150m. 1H-NMR (400 MHz, CDCl3): 1.46 (br. s, 1 HÀC(5)); 1,61 1.77 (m,
1 HÀC(4), 1 HÀC(5)); 2.02 2.12 (m, 1 HÀC(4)); 2.43 (br. s, 1 HÀC(3)); 2.92 (ddd, J ˆ 2.9, 10.9, 13.4,
1 HÀC(6)); 3.11 (br. s, 1 HÀC(2)); 3.90 (br. s, 1 HÀC(6)); 4.09 (br. s, 1 HÀC(2)); 4.24 (t, J ˆ 6.7, 1 HÀC(9')),
4.44 (d, J ˆ 6.7, CH2O); 7.31 7.75 (m, 8 arom. H). 13C-NMR (100 MHz, CDCl3): 24.0; 27.0; 40.9; 44.2; 45.6; 47.4;
‡
67.4; 120.0; 125.0; 127.0; 127.7; 141.4; 144.0; 155.2; 178.3. HR-ESI-MS: 374.1361 (C21H21NO4Na ; calc.
374.1363). Anal. calc. for C21H21NO4 (351.41): C 71.78, H 6.02, N 3.99; found: C 71.54, H 6.14, N 4.13.
(S)-1-[(tert-Butoxy)carbonyl]piperidine-3-carboxylic Acid (14c). Compound 14a (132 mg, 0.50 mmol) was
dissolved in MeOH (5 ml) under N2, and Pd/C (10%, 20 mg, 0.02 mmol) and Boc2O (133 mg, 0.61 mmol) were
added. The apparatus was evacuated and flushed with H2 (3 Â ), and the soln. was stirred under H2 (balloon) for
2 h. The mixture was filtered through Celite, washed with AcOEt, and concentrated under reduced pressure. The
crude product was purified by FC (AcOEt/hexane/AcOH 50 :50 :2) to obtain 108 mg (94%) of 14c. White solid.
M.p. 160 1618. Rf (AcOEt/hexane/AcOH 50 :50 :2) 0.55. [a]rD:t: ˆ ‡ 44.2 (c ˆ 0.9, CHCl3). IR (CHCl3): 2980w,
2945w, 2865w, 1710m, 1685s, 1425m, 1365m, 1270m, 1170m, 1150s. 1H-NMR (400 MHz, CDCl3): 1.46 (s, t-Bu);
1.55 1.41 (m, 1 HÀC(5)); 1.59 1.76 (m, 1 HÀC(4), 1 HÀC(5)); 2.02 2.11 (m, 1 HÀC(4)); 2.44 2.54 (m,
1 HÀC(3)); 2.86 (ddd, J ˆ 2.8, 10.8, 13.4, 1 HÀC(6)); 3.05 (br. s, 1 HÀC(2)); 3.88 (br. td, J ˆ 4.0, 13.4,
1 HÀC(6)); 4.11 (br. s, 1 HÀC(2)). 13C-NMR (100 MHz, CDCl3): 24.1; 27.2; 28.4; 41.1; 43.9; 45.5; 79.9; 154.7,
‡
178.8. HR-ESI-MS: 252.1202 (C11H19NO4Na ; calc. 252.1206). Anal. calc. for C11H19NO4 (229.28): C 57.63, H
8.35, N 6.11; found: C 57.50, H 8.23, N 6.02.
Ethyl (S)-1-(2,4-dinitrophenyl)piperidine-3-carboxylate (14d). Compound 14a was dissolved in EtOH
(5 ml), and racemic camphersulfonic acid was added. After heating at reflux for 15 h sat. NaHCO3 soln. (20 ml)
was added. The soln. was extracted with AcOEt (3 Â 20 ml), dried (Na2SO4), and evaporated. The crude
material was dissolved in EtOH (5 ml) under N2, and Pd/C (10%, 20 mg, 0.02 mmol) and AcOH (57 ml) were
added. The apparatus was evacuated and flushed with H2 (3 Â ), and the solution was stirred under H2 (balloon)
for 3 h. The mixture was filtered through Celite, washed with AcOEt, and concentrated under reduced pressure.
To a soln. of this material in H2O (2 ml) was added NaHCO3 (100 mg, 1.20 mmol) under N2 at 08. Then 2,4-
dinitrofluorobenzene in EtOH (2 ml) was added. The mixture was stirred at 08 under N2 for 7 h. After addition

2246
Helvetica Chimica Acta Vol. 88 (2005)
of H2O (20 ml), the aq. phase was extracted with AcOEt (3 Â 20 ml), and the combined org. layers were dried
(Na2SO4) and concentrated under reduced pressure. The crude product was purified by FC (AcOEt/hexane
3 :1) to give 85 mg (69%) of 14d. Orange oil. 1H-NMR (400 MHz, CDCl3): 1.22 (t, J ˆ 7.1, Me); 1.65 1.88 (m,
3 CH); 2.06 2.17 (m, CH); 2.67 2.77 (m, COCH); 3.03 3.13 (m, NCH); 3.26 3.39 (m, 2 NCH), 3.53 3.61
(m, NCH); 4.12 (q, J ˆ 7.1, CH2O); 7.18 (d, J ˆ 9.3, 1 arom. H); 8.21 (dd, J ˆ 9.3, 2.8, 1 arom. H); 8.65 (d, J ˆ
2.8, 1 arom. H). 13C-NMR (100 MHz, CDCl3): 14.1; 23.8; 26.2; 40.8; 51.4; 52.4; 60.9; 119.8; 123.6; 128.1; 137.9;
138.1; 149.6; 172.518)).
(4R)-3-[(2S)-6-Azido-2-({[(benzyloxy)carbonyl]amino}methyl)-1-oxohexyl]-4-(1-methylethyl)-5,5-diphe-
nyloxazolidin-2-one (15). Compound 6 (3.91 g, 6.3 mmol) was treated with NaN3 (0.49 g, 7.6 mmol) according to
GP 5. FC (pentane/Et2O 95 :5 ! 7:3) yielded 15 (3.51 g, 95%). Colorless needles. M.p. 88 898. Rf (hexane/
AcOEt 7 :3) 0.25. [a]rD:t: ˆ ‡ 108.4 (c ˆ 1.0, CHCl3). IR (CHCl3): 3449w, 3011w, 2940w, 2099s, 1780s, 1720s,
1
1514m, 1451m, 1396w, 1364m, 1318m, 1148w, 1093w, 1052w, 1002w. H-NMR (500 MHz, CDCl3): 0.71 (d, J ˆ
6.7, Me); 0.83 (d, J ˆ 7.0, Me); 0.82 0.87 (m, CH2); 1.19 1.26, 1.33 1.36 (2m, 2 CH2); 1.94 2.01 (m, Me2CH);
2.95 (t, J ˆ 6.9, CH2N3); 3.35 3.39, 3.48 3.54 (2m, CH2NH); 3.85 (br. s, CHCO); 5.07 (s, PhCH2); 5.19 (br. s,
NH); 5.32 (d, J ˆ 3.5, CHN); 7.26 7.50 (m, 15 arom. H). 13C-NMR (125 MHz, CDCl3): 16.4, 21.7 (Me); 23.5,
28.4, 29.0 (CH2); 29.6 (CH); 42.7 (CH2); 43.4 (CH); 50.8 (CH2); 65.5 (CH); 66.7 (CH2); 89.7 (C); 125.4, 125.7,
128.1, 128.2, 128.5, 128.7, 128.9 (CH); 136.5, 137.6, 142.4, 153.1, 156.2, 174.7 (C). MALDI-MS: 606.3 (97, [M ‡
‡
‡
Na] ), 558.3 (100, [M À N2 ‡ H] ). Anal. calc. for C33H37N5O5 (583.69): C 67.91, H 6.39, N 12.00; found: C
67.79, H 6.53, N 11.95.
(4R)-3-[(2S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-6-{[(tert-butoxy)carbonyl]amino}-1-oxohexyl]-4-
(1-methylethyl)-5,5-diphenyloxazolidin-2-one (16). According to the procedure described in [5], Lindlar
catalyst (220 mg, 10 wt-%) and Boc2O (890 mg, 4.1 mmol) were added to a soln. of 15 (2.15 g, 3.7 mmol) in
MeOH (37 ml). The apparatus was evacuated and flushed with H2 (3 Â ), then the mixture was stirred at r.t. for
4 h, filtered through a Celite pad, and concentrated under reduced pressure. FC (pentane/AcOEt 8 :2 ! 7:3)
yielded 16 (2.24 g, 92%). Colorless glass. Rf (hexane/AcOEt 6 :4) 0.29. [a]rD:t: ˆ ‡ 104.0 (c ˆ 1.0, CHCl3). IR
(CHCl3): 3451w, 3008w, 2970w, 2935w, 1780s, 1710s, 1511s, 1451m, 1394m, 1366m, 1318m, 1052w, 1002w. 1H-
NMR (500 MHz, CDCl3): 0.71 (d, J ˆ 6.7, Me); 0.70 0.75 (m, CH2); 0.83 (d, J ˆ 7.0, Me); 1.09 1.26, 1.34 1.43
(2m, 2CH2); 1.45 (s, t-Bu); 1.94 2.01 (m, Me2CH); 2.83 (br. s, CH2); 3.32 3.38, 3.48 3.54 (2m, CH2); 3.80
3.84 (m, CHCO); 4.37 (br. s, NHBoc); 5.04 5.09 (m, PhCH2); 5.24 (s, NHZ); 5.32 (d, J ˆ 3.5, CHN); 7.26 7.51
(m, 15 arom. H). 13C-NMR (125 MHz, CDCl3): 16.3, 21.7 (CH3); 23.4 (CH2); 28.5 (CH); 29.0 (CH2); 29.5 (CH);
29.6, 39.9, 42.7 (CH2); 42.8, 58.4, 65.5 (CH); 66.7, 72.2 (CH2); 79.0, 89.6 (C); 125.4, 125.7, 128.1, 128.5, 128.7, 128.9
‡
(CH); 136.5, 137.6, 142.3, 153.2, 155.8, 156.2, 174.7 (C). MALDI-MS: 696.3 (20, [M ‡ K] ), 680.3 (100, [M ‡
‡
‡
‡
‡
Na] ), 624.3 (100), 595.3 (11, [M À Boc ‡ K] ), 680.3 (14, [M À Boc ‡ Na] ), 558.3 (76, [M À Boc ‡ H] ).
Anal. calc. for C38H47N3O7 (657.81): C 69.38, H 7.20, N 6.39; found: C 69.48, H 7.09, N 6.11.
(4R)-[(2R,3S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-hydroxy-1-oxopropyl]-4-(1-methylethyl)-5,5-
diphenyloxazolidin-2-one (17). A soln. of 8 (8.13 g, 16.4 mmol) in CH2Cl2 (30 ml) and TFA (30 ml) was stirred
at 08 for 1 h and evaporated under reduced pressure. To a soln. of the resulting crude product in CH2Cl2 (50 ml),
sat. NaHCO3 soln. (50 ml) and ZÀCl (2.53 ml, 18 mmol) were added at r.t. The biphasic mixture was vigorously
stirred for 1 h, decanted, and the aq. phase was extracted with CH2Cl2 (2 Â ). The combined org. fractions were
dried (MgSO4) and evaporated. FC (hexane/AcOEt 9 :1 ! 6 :4) yielded 17 (7.52 g, 86%). Colorless solid. M.p.
64 688. Rf (hexane/AcOEt 6 :4) 0.26. [a]rD:t: ˆ ‡ 111.4 (c ˆ 1.0, CHCl3). IR (CHCl3): 3448w, 3008w, 2971w,
1781s, 1700s, 1520m, 1450m, 1390w, 1364m, 1318w, 1283w, 1149w, 1102w, 1052w, 1002w, 985w. 1H-NMR
(500 MHz, CDCl3): 0.73 (d, J ˆ 6.8, Me); 0.75 (d, J ˆ 6.2, Me); 0.82 (d, J ˆ 7.0, Me); 1.95 2.01 (m, Me2CH);
3.17 (m, CH); 3.56 3.59 (m, CH); 3.72 (br. s, CHN); 3.82 3.86 (m, CH2); 5.08 (q, J ˆ 12.2, PhCH2); 5.35 (br. s,
NH); 7.26 7.49 (m, 15 arom. H). 13C-NMR (125 MHz, CDCl3): 16.2; 19.8; 21.6; 29.6; 39.5; 49.4; 65.1; 66.3; 67.0;
89.7; 125.4; 125.7; 128.1; 128.2; 128.5; 128.7; 128.9; 136.3; 137.6; 142.1; 152.9; 157.0; 173.8. MALDI-MS: 569.2 (5,
‡
‡
[M ‡ K] ), 553.2 (100, [M ‡ Na] ), 509.2 (14), 487.3 (17). Anal. calc. for C31H34N2O6 (530.62): C 70.17, H 6.46,
N 5.28; found: C 69.97, H 6.54, N 5.23.
(4R)-[(2R,3S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-(tert-butoxy)-1-oxopropyl]-4-(1-methylethyl)-
5,5-diphenyloxazolidin-2-one (18). In a Schott flask, a soln. of 17 (6.90 g, 13 mmol) in CH2Cl2 (50 ml) was cooled
to À 788, conc. H2SO4 (0.65 ml) was added, and isobutylene (ca. 50 ml) condensed. The flask was hermetically
closed, the mixture was stirred 4 d at r.t., partially evaporated, diluted with CH2Cl2, and washed with sat. K2CO3.
The org. phase was dried (MgSO4) and evaporated. FC (pentane/AcOEt 9 :1 ! 7:3) yielded 18 (5.73 g, 78%).
18
)
Anal. data are in accordance with those in [26].

Helvetica Chimica Acta Vol. 88 (2005)
2247
Colorless glass. Rf (hexane/AcOEt 7:3) 0.35. [a]rD:t: ˆ ‡ 95.8 (c ˆ 0.6, CHCl3). IR (CHCl3): 2975m, 1779s,
1718s, 1513m, 1450m, 1365m, 1319w, 1178m, 1092w, 1052m, 991w. 1H-NMR (500 MHz, CDCl3): 0.64 (d, J ˆ 6.0,
Me); 0.67 (d, J ˆ 6.7, Me); 0.84 (d, J ˆ 7.0, Me); 0.97 (s, t-Bu); 1.95 2.01 (m, Me2CH); 3.48 3.89 (m, CH2,
2 CH); 5.02 5.08 (m, PhCH2); 5.28 (br. s, NH); 5.32 (d, J ˆ 3.4, CHN); 7.22 7.53 (m, 15 arom. H). 13C-NMR
(125 MHz, CDCl3): 16.2; 21.3; 21.7; 21.8; 29.8; 41.2; 49.9; 65.9; 66.5; 67.3; 73.9; 89.3; 125.3; 125.7; 128.0; 128.1;
‡
128.4; 128.5; 128.6; 128.9; 136.7; 137.8; 142.5; 153.1; 156.1; 173.3. MALDI-MS: 625.3 (2, [M ‡ K] ), 609.3 (100,
‡
‡
[M ‡ Na] ), 587.3 (21, [M ‡ H] ), 565.3 (56), 487.3 (33), 397.2 (8), 350.2 (12). Anal. calc. for C35H42N2O6
(586.73): C 71.65, H 7.21, N 4.77; found: C 71.38, H 7.30, N 4.74.
(2R,3S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-(tert-butoxy)butanoic Acid (19). To a soln. of 18
(2.21 g, 3.77 mmol) in THF/H2O (3 :1, 40 ml), H2O2 (1.5 ml, 37.7 mmol, 30% soln. in H2O) was added at 08.
After stirring for 5 min, a soln. of Bu4NOH ¥ 30 H2O (6.02 g, 7.54 mmol) in THF (10 ml) was slowly added, and
the mixture was stirred at 08 for 1 h and at r.t. for 12 h. Sat. NH4Cl soln. (20 ml) and Et2O (20 ml) were added,
and the resulting suspension was vigorously stirred for an additional 15 min and filtered. The residue was washed
successively with H2O, cold Et2O, and pentane, and dried under h.v. to yield the chiral auxiliary. The filtrate was
diluted with Et2O, the aq. phase was separated, and the pH was adjusted to pH 2 3 by the addition of 1m HCl.
The mixture was extracted with Et2O (2 Â 20 ml), and the org. phases were combined, washed with 1m HCl and
brine, dried (MgSO4), filtered, and evaporated. FC (hexane/AcOEt/AcOH 2 :1:0.01 ! 1:1:0.01) yielded 19
(0.987 g, 81%). Colorless oil. Rf (AcOEt/hexane/AcOH 1:1:0.01) 0.42. [a]rD:t: ˆ À 2.0 (c ˆ 0.5, CHCl3). IR
(CHCl3): 3446w; 2974m, 3008s, 1749s, 1713s, 1513s, 1369m, 1133w, 1067w, 979w. 1H-NMR (400 MHz, CD3OD):
1.12 (s, t-Bu); 1.14 (d, J ˆ 6.2, MeCH); 2.53 2.59 (m, CHCO2H); 3.27 3.32 (m, 1 H, NCH2); 3.37 (dd, J ˆ 6.2,
12.2, 1 H, NCH2); 3.92 (dt, J ˆ 6.2, 12.0, MeCH); 5.03 (s, PhCH2); 6.83 6.81 (m, ZHN); 7.30 7.20 (m, 5 arom.
H). 13C-NMR (100 MHz, CD3OD): 21.6; 28.9; 40.8; 54.2; 67.4; 68.5; 75.3; 128.8; 129.0; 129.5; 138.5; 158.8; 176.6.
‡
MALDI-MS: 441.2 (11), 428.2 (7), 368.1 (22), 346.2 (100, [M ‡ Na] ), 290.1 (29), 224.1 (21). Anal. calc. for
C17H25NO5 (323.39): C 63.14, H 7.79, N 4.33; found:C 63.27, H 7.91, N 4.27.
(4R)-3-[(2S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-{1-[(2,2,2-trichloroethoxy)carbonyl]indol-3-yl}-
1-oxopropyl]-4-(1-methylethyl)oxazolidin-2-one (20). To a soln. of 10 (2.66 g, 4.07 mmol) in CH2Cl2 (50 ml),
Et3SiH (6.4 ml, 40.7 mmol) and BF3 ¥ Et2O (5.0 ml, 40.7 mmol) were added at 08. The mixture was stirred 1 h at
08, treated with a sat. NaHCO3 soln., and extracted with Et2O. The org. phase was washed with brine, dried
(MgSO4), and evaporated. The crude product was purified by FC (AcOEt/hexane 2 :8) to give 20 (1.94 g, 75%).
White foam. Rf (AcOEt/hexane 7:3) 0.51. IR (CHCl3): 3351w, 3021w, 2951w, 1768s, 1734s, 1615m, 1511m,
1
1449m, 1390m, 1351m, 1322m, 1144w, 1102m. H-NMR (500 MHz, CDCl3): 0.73 (d, J ˆ 6.8, Me); 0.81 (d, J ˆ
7.1, Me); 2.16 2.23 (m, Me2CH); 2.85 3.12 (m, CH2); 3.48 (d, J ˆ 6.5, CH2); 3.89 (t, J ˆ 8.7, CH); 4.07 4.14
(m, CH2); 4.50 4.55 (m, CH); 5.03 (q, J ˆ 8.4, PhCH2); 5.10 (s, CH2CCl3); 5.30 (d, J ˆ 3.5, CHN); 7.22 7.50
(m, 8 arom. H); 7.61 (d, J ˆ 7.7, 1 arom. H); 8.14 (d, J ˆ 7.7, 1 arom. H). 13C-NMR (125 MHz, CDCl3): 15.4;
22.3; 25.2; 28.9; 43.1; 65.2; 67.1; 75.2; 91.1; 93.2; 112.2; 117.9; 118.7; 123.3; 125.4; 128.7; 135.8; 137.3; 141.5; 151.3;
‡
155.2. HR-MALDI-MS: 638.1151 (C29H31Cl3N3O7 ; calc. 638.1149).
(4R)-3-[(2S)-2-({[(Benzyl)oxycarbonyl]amino}methyl)-3-{1-[(tert-butoxy)carbonyl]indol-3-yl}-1-oxo-
propyl]-4-(1-methylethyl)oxazolidin-2-one (21). To a soln. of 20 (1.90 g, 3.04 mmol) in AcOH (15 ml) was added
Zn powder (0.5 g), and the soln. was stirred for 1 h at r.t. The mixture was then filtered through Celite. AcOH
was then co-evaporated with toluene under reduced pressure to yield the crude product, which was used in the
next stepwithout purification. The residue was dissolved in MeCN (15 ml) and treated with Boc 2O (1.1 g,
4.6 mmol) and DMAP (24 mg, 0.2 mmol). The mixture was stirred 30 min, and diluted with Et2O (15 ml) and
sat. NH4Cl soln. (10 ml). The org. phase was separated, washed with 1m HCl (5 ml) and brine (5 ml), dried
(MgSO4), and evaporated. FC (AcOEt/hexane 2 :8 ! 3 :7) yielded 21 (1.11 g, 65% over 2 steps). Colorless oil.
Rf (AcOEt/hexane 3 :7) 0.51. [a]rD:t: ˆ À 45.6 (c ˆ 1.0, CHCl3). IR (CHCl3): 3449w, 3032w, 2975m, 1778s, 1724s,
1608w, 1514s, 1453m, 1386s, 1302s, 1157w, 1087m. 1H-NMR (400 MHz, CD3OD): 0.79 (d, J ˆ 6.9, Me); 0.86 (d,
J ˆ 7.0, Me); 1.66 (s, t-Bu); 2.25 2.33 (m, Me2CH); 2.87 2.95 (m, CH2); 3.14 (dd, J ˆ 8.1, 14.3, CH2); 3.50
3.62 (m, CH); 3.91 3.95 (m, CH2CHO); 4.09 (dd, J ˆ 2.4, 9.0, CH2CHO); 4.23 4.26 (m, CHN); 4.43 4.46 (m,
CHCO); 5.11 5.15 (m, NH); 7.20 7.32 (m, 7 arom. H); 7.42 (s, 1 arom. H); 7.55 (d, J ˆ 7.6, 1 arom. H); 8.11 (d,
J ˆ 7.4, 1 arom. H). 13C-NMR (100 MHz, CD3OD): 14.6; 18.0; 25.2; 28.2; 28.5; 43.0; 43.5; 58.9; 63.4; 66.8; 83.6;
115.2; 116.5; 119.0; 122.6; 124.1; 124.5; 128.1; 128.5; 130.2; 135.4; 136.5; 149.6; 153.8; 156.3; 174.3. HR-MALDI-
‡
MS: 586.2525 (C31H37N3O7Na ; calc. 586.2524).
(2S)-2-({[(Benzyl)oxycarbonyl]amino}methyl)-3-{1-[(tert-butoxy)carbonyl]indol-3-yl}propanoic Acid
(22). To a soln. of 21 (3.64 g, 6.46 mmol) in THF/H2O 4 :1 (50 ml) at 08, H2O2 (30% aq., 20 ml) and LiOH ¥
H2O (0.4 g) were added, and the resulting mixture stirred at 08 for 2 h before addition of a sat. aq. Na2SO3 soln.
(15 ml). The mixture was diluted with H2O, and the THF was evaporated at 258 under reduced pressure. The aq.

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soln. was cooled to 08, and the pH was adjusted to 1 2 by addition of 1m HCl. The aq. phase was extracted with
AcOEt (3 Â ), and the combined org. layers were dried (MgSO4) and concentrated under reduced pressure. FC
(pentane/AcOEt/ AcOH 100 :100 :1) yielded 22 (2.07 g, 71%). White foam. [a]rD:t: ˆ À 0.57 (c ˆ 0.6, CHCl3).
IR (CHCl3): 3448w, 2982w, 1724s, 1514m, 1453m, 1371m, 1157m, 1092w, 1040w, 1020w, 855w. 1H-NMR
(500 MHz, CDCl3): 1.66 (s, t-Bu); 2.90 2.94 (m, CH2); 3.01 3.15 (m, CH2, CHNH); 3.41 3.55 (m, 1 H, CH2);
3.56 3.64 (m, 1 H, CH2); 5.04 5.11 (m, PhCH2); 5.22 5.30 (m, NH); 7.13 7.52 (m, 9 arom. H); 8.12 (br.,
1 arom. H). 13C-NMR (125 MHz, CDCl3)): 24.9; 25.2; 28.2; 41.8; 42.3; 45.3; 45.6; 66.9; 67.3; 83.7; 115.4; 116.7;
118,7; 122.6; 123.7; 123.9; 124.5; 127.8; 128.2; 128.5; 130.2; 135.5; 136.3; 149.7; 156.5; 157.4; 157.8; 177.5; 178.4.
‡
HR-MALDI-MS: 475.1845 (C25H28N2O6Na ; calc. 475.1840).
(S)-4-{N-[(tert-Butoxy)carbonyl]-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-1H-indol-3-yl}butano-
ic Acid (23). Compound 22 (1.90 g, 3.97 mmol) was dissolved in EtOH (40 ml), and the soln. was stirred under
H2 (1 atm, balloon) with 10% Pd/C (19 mg) for 2 h at r.t. The mixture was filtered through Celite, and the filtrate
was concentrated in vacuo to yield the crude amino acid. The crude amino acid was suspended in 0.15m aq.
Na2CO3 (65 ml, 9.92 mmol) and treated with a soln. of Fmoc-OSu (2.1 g, 5.95 mmol) in acetone (30 ml). If
necessary, the pH was re-adjusted to 9 10 with additional aq. Na2CO3 soln., and the mixture was stirred for 4 h.
The aq. mixture was then extracted with Et2O (2 Â 20 ml). The aq. phase was cooled to 08, and the pH was
adjusted to 2 3 with slow addition of 1m HCl. The aq. phase was then extracted with AcOEt (3 Â 40 ml), and
the combined org. layers were dried (MgSO4) and concentrated under reduced pressure. Recrystallization
(cyclohexane/AcOEt) yielded 23 (1.92 g, 88%). Colorless solid. [a]rD:t: ˆ ‡ 5.0 (c ˆ 1.4, CHCl3). IR (CHCl3):
1
3451w, 3008w, 1725s, 1522m, 1451m, 1369w, 1142w, 1108w, 1032w. H-NMR (500 MHz, CDCl3): 1.63 (s, t-Bu);
2.85 3.05 (m, CH2, CHC(O)); 4.19 (t, J ˆ 6.8, CH); 4.32 4.38 (m, CH2); 7.17 7.40 (m, 6 arom. H); 7.48 (s,
1 arom. H); 7.56 (d, J ˆ 7.7, 1 arom. H); 7.64 (d, J ˆ 7.7, 1 arom. H). 13CÀNMR (125 MHz, CDCl3): 26.1; 28.3;
43.5; 46.9; 66.7; 84.5; 116.3; 119.5; 121.2; 123.8; 125.4; 127.2; 128.8; 130.9; 135.4; 142.5; 145.2; 150.9; 160.1. HR-
‡
MALDI-MS: 563.2465 (C32H32N2O6Na ; calc. 563.2153).
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