Towards functionalized silicon-containing α-amino acids: Asymmetric syntheses of sila analogs of homoserine and homomethionine

Article abstract of DOI:10.1002/hlca.200490152

The homoserine and homomethionine sila analogs, (R)-HOSi(Me ₂)CH₂CH(NH₂)CO₂H ((R)-21) and (R)-MeSCH₂Si(Me₂)CH₂CH(NH₂)CO ₂H ((R)-24), respectively, were each synthesized in nine steps and in 30 and 23% overall yield, respectively, from commercially available ClSiMe ₂CH₂Cl. The key step of both syntheses was the asymmetric α-bromination of an Evans amide to introduce the stereogenic center of the amino acids with defined absolute configuration. While the preparation of the homomethionine analog (R)-24 followed the expected pathway, the sila analog of homoserine, (R)-21, was unexpectedly formed during the catalytic hydrogenation of an N₃CH₂-substituted silane derivative.

Full text of DOI:10.1002/hlca.200490152

Helvetica Chimica Acta Vol. 87 (2004)
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Towards Functionalized Silicon-Containing a-Amino Acids: Asymmetric
Syntheses of Sila Analogs of Homoserine and Homomethionine
by Richard J. Smith1) and Stefan Bienz*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
(phone: ‡4116354245; fax. ‡4116356812; e-mail: sbienz@oci.unizh.ch)
Dedicated to Dr. G¸nther Ohloff on the occasion of his 80th birthday
The homoserine and homomethionine sila analogs, (R)-HOSi(Me2)CH2CH(NH2)CO2H ((R)-21) and (R)-
MeSCH2Si(Me2)CH2CH(NH2)CO2H ((R)-24), respectively, were each synthesized in nine steps and in 30 and
23% overall yield, respectively, from commercially available ClSiMe2CH2Cl. The key step of both syntheses was
the asymmetric a-bromination of an Evans amide to introduce the stereogenic center of the amino acids with
defined absolute configuration. While the preparation of the homomethionine analog (R)-24 followed the
expected pathway, the sila analog of homoserine, (R)-21, was unexpectedly formed during the catalytic
hydrogenation of an N3CH2-substituted silane derivative.
Introduction.
Nonproteinogenic and unnatural amino acids are important
building blocks for peptide chemistry [1 3], and, among such compounds, sila amino
acids are of increasing interest [3 13]. With their large hydrophobic groups, they are
expected and have been shown to offer several advantages over classical amino acids
when incorporated into peptides, such as prevention of hydrophobic-pocket collapse,
higher lipophilicity, and enhanced stability towards proteolytic enzymatic degradation
[2][9].
Several approaches towards enantiomerically pure sila amino acids have been
reported. Apart from resolution or dynamic resolution of racemic mixtures [3][5 7],
several stereoselective syntheses have been performed. In these syntheses, either the
Si-containing side chains were introduced by diastereoselective alkylation of chiral
glycine anion synthons [3][8 10] or by b-substitution of serine derivatives [11].
Alternatively, the amino acids were prepared by stereoselective a-amination of b-
silylated carboxylic acids [7][12]. While most of the previous studies targeted rather
simple trialkyl- or trialkyl/triarylsilanes, Tacke et al. reported the first enantioselective
synthesis of Si-containing amino acids that are hetero-functionalized at a Si-containing
side chain [10]. However, the hetero group, an amino function, was introduced early in
the synthetic scheme, limiting the versatility of the method. In continuation of our
investigations [6][7][13], we were looking for a more flexible route to functionalized
sila amino acids, considering halogenomethyl-substituted silanes such as 4 as precursors.
Results and Discussion. According to the reaction sequence already described for
the preparation of other sila amino acids [7], we prepared b-silylated Evans amide 4 to
1
)
Part of the Ph.D. thesis of R. J. S., University of Zurich.

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be converted to differently functionalized amino acids by appropriate substitution at
the ClCH2 group and stereoselective a-amination of the amide.
Chloro(chloromethyl)dimethylsilane (1) was thus treated with but-3-enyl magne-
sium bromide to afford (but-3-enyl)silane 2 in 53% yield (Scheme 1). This compound
was converted in a single step, in 95% yield, to carboxylic acid 3 by reaction with NaIO4
in the presence of RuCl3 [14]. The alternative route through ozonolysis of 2 in MeOH/
NaOH, followed by hydrolysis of the intermediary ester with aqueous LiOH [7], was
less satisfactory: this reaction sequence yielded merely 27% of compound 3. Synthesis
of Evans amide 4 was completed in 84% yield by successive treatment of acid 3 with
NaH (formation of the sodium carboxylate), 2,2-dimethylpropanoyl chloride (for-
mation of a mixed anhydride), and the lithium salt of (R)-4-benzyloxazolidin-2-one
(ˆ Evans-Ox).
Scheme 1
From compound 4, two possible paths were open to form functionalized a-amino
acids. The ClCH2 group at the Si-atom could be manipulated in a first stage by
replacement of the Cl-atom with an appropriate nucleophile before the required a-
amino group would be introduced (path A; cf. Scheme 2) or vice versa (path B; cf.
Scheme 5).
We first studied path A with the initial replacement of the Cl-atom in compound 4
with N-nucleophiles. Treatment of 4 with amines such as 3-phenylpropanamine,
PhCH2NH2, Et2NH, (i-Pr)2NH, and piperidine, however, revealed immediately that
the ClCH2 group in 4 is not sufficiently reactive for the attempted transformations2)
(Scheme 2). Even when the Cl-atom was exchanged by an I-atom, substitution at the
halogenomethyl group was ineffective: ICH2-substituted silane 5, obtained by
Finkelstein reaction from 4, remained unchanged when treated with most of the
amines mentioned above. Only when piperidine was used, the expected substitution
2
)
Sieburth et al. reported a successful transformation of (chloromethyl)(trimethyl)silane into (benzyl)-
[(trimethylsilyl)methyl]amine in DMSO at 808 [15]. These reaction conditions led, in our case, to
decomposition of the starting material 4.

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Scheme 2
product 6 was formed in 73% yield. Successful were also the substitution reactions
performed with the N,N,N',N'-tetramethylguanidinium azide (TMG-N3) and with
potassium phthalimide (PhthNK; at 608 for 14 d). Reaction with these nucleophiles
delivered azide 7 and phthalimide 8 in excellent 94 and 99% yields, respectively.
Interestingly, while the azide anion reacted quite efficiently with 5, the equally small
cyanide ion was ineffective for substitution.
Unfortunately, neither of the two compounds 7 or 8 could be converted stereo-
selectively to the amino acid 9 possessing the NH2CH2 group at the Si-atom. Reduction
of 7 with Ph3P in the presence of H2O or by catalytic hydrogenation led to the six-
membered silalactam 11 in 99% yield
a compound that was not amenable to
stereoselective amination rather than to the desired amino compound 10 (Scheme 3).
The lactam 11 was most probably formed via compound 10, which cyclized with
substitutive expulsion of the Evans auxiliary.
Without prior release of the protected amino groups, the two compounds 7 and 8
were also treated with dibutylboron triflate/EtN(i-Pr)2, followed by N-bromosuccin-
imide (NBS) to effect stereoselective a-bromination of the Evans amides. While
compound 7 led to the desired bromides 12a/12b (78% yield, ratio 4 :1; Scheme 3), the
corresponding bromides 14a/14b from 8 were not obtained (Scheme 4). Instead,
propenoyl-oxazolidinone 15 was produced quantitatively. Apparently, the initially
formed bromides 14a/14b rapidly underwent elimination, possibly supported by the
neighboring phthalimido groups as indicated in Scheme 4. We observed the same
elimination with compound 16, which possesses, like the phthalimides 14a/14b, a
carboxylic O-atom in position 5 with respect to the Si-atom, and which delivered 15 as
the sole product upon bromination, too. We have, however, no further evidence for the
proposed mechanism.
In an attempt to complete the enantioselective synthesis of amino acid 9, the two
isomers (4R,2'R)-12a and (4R,2'S)-12b were separated by chromatography, and the

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Scheme 3
major diastereoisomer, (4R,2'S)-12b, was reacted with TMG-N3 to replace the Br-atom.
The substitution reaction proceeded smoothly (85% yield), however, not stereo-
specifically: the diastereoisomeric diazides 13a/13b, which were not separable by
chromatography, were formed in virtually equal amounts. The reason for this unspecific
formation of the diazides 13a/13b is not clear. Until now, a similar nonspecific reaction
course has not been observed with analogous compounds, which possess groups other
than N3CH2 attached to the Si-atom (see also below).
Since functionalized sila amino acids were not accessible in enantiomerically
enriched form through path A, the alternative route B, in which the order of
functionalization at the ClCH2 group and at the a-position to the Evans amide were
reversed, was tested.
Starting with compound 4, we easily prepared bromo compounds 17a/17b (80%
yield, ration 4 :1) by bromination of the Evans amide via its boron enolate as described
above (Scheme 5). The two diastereoisomers (4R,2'R)-17a and (4R,2'S)-17b, were
readily separated by chromatography, and the isomer (4R,2'S)-17b, the structure of
which was established by a single-crystal X-ray-analysis (cf. Fig. in Exper. Part), was
converted to the azide (4R,2'R)-18a (99% yield) by treatment with TMG-N3. In
contrast to the analogous reaction with (4R,2'S)-12b, no epimerization was observed
this time. Subsequent Finkelstein reaction exchanged the Cl-atom of the ClCH2 group
by an I-atom to afford the iodinated compound (4R,2'R)-19a (96% yield). This
compound was treated with a number of N-nucleophiles. Again, most of the

Helvetica Chimica Acta Vol. 87 (2004)
1685
Scheme 4
nucleophiles did not give the desired substitution products. Neither the cyanide and
phthalimide anions nor 3-phenylpropanamine, PhCH2NH2, Et2NH, (i-Pr)2NH, or
piperidine provided the desired substitution products. Either no reaction occurred or,
under forcing conditions, (4R,2'R)-19a decomposed. Only the azide anion was able to
introduce an N-functionality into the compound. Treatment of (4R,2'R)-19a with
TMG-N3 produced the diazide (4R,2'R)-13a in 95% yield.
With compound (4R,2'R)-13a at hand, the synthesis of the desired sila analog of
ornithine, (R)-9, was planned to be completed by hydrolytic removal of the Evans
auxiliary and reductive conversion of the two N3 into NH2 groups.
According to the procedure described in [7], hydrolysis of the Evans auxiliary with
aqueous LiOH produced readily and in the excellent yield of 99% the carboxylic acid
(R)-20. The subsequent catalytic hydrogenation of (R)-20, however, did not give the
desired sila-ornithine (R)-9. To our astonishment, the homoserine analog (R)-21 was
formed instead. We have not been able to determine the enantiomeric purity of this
compound yet, but the sample of (R)-21 arose at least in optically active and, thus,
20
D
enantiomerically enriched form (‰aŠ ˆ ‡7.8( c ˆ 1.90, H2O)). The mechanism for the
conversion of the N3CH2 to the HOSi(Me)2 group is not clear. It is possible that an
intermediate hydrosilane is formed by hydrogenolysis, which would deliver the
corresponding silanol in the presence of transition-metal catalysts and H2O, as is well-
known in the literature [16].
With compound (4R,2'R)-19a at hand, we were also able to synthesize the
enantiomerically pure homomethionine analog (R)-24 (Scheme 5). Hydrolytic remov-
al of the Evans auxiliary from diastereoisomerically pure (2R)-19a by treatment with

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 5

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1687
aqueous LiOH in THF afforded acid (R)-22 in 89% yield. The ICH2 group remained
unaffected during this basic hydrolysis. Reaction with MeSNa, on the other side,
converted compound (R)-22 efficiently (even at low temperatures) to methylsulfanyl
derivative (R)-23 (95% yield). The reduction of the N3 group to obtain the desired
amino acid (R)-24 was performed by hydrogenation of (R)-23 in aqueous EtOH in the
presence of PtO2 as catalyst (85% yield). The enantiomer purity (ee > 99%) of the
amino acid (R)-24 obtained was determined with its N-carbamoyl derivative by means
of HPLC analysis on a chiral column by the method described in [7].
Conclusions.
We have shown with the preparation of the sila analogs of
homoserine and homomethionine, (R)-21 and (R)-24, respectively, that functionalized
silicon-containing amino acids can be prepared divergently starting from chloro(chloro-
methyl)dimethylsilane (1). Two major problems arose: 1) the substitution of the
halogen atom at the halogenomethyl group attached to the Si-atom was inefficient,
even when the Cl-atom was exchanged by an I-atom, and 2) b-elimination occurred too
readily with a-brominated, b-silylated carboxylic acid derivatives during our attempts
to synthesize sila analogs of ornithine and glutamic acid, possibly due to neighboring-
group participation.
Experimental Part
1. General. Unless otherwise stated, all chemicals were of reagent grade and purchased from Fluka Chemie
AG or Merck AG. Chemical manipulations were carried out under Ar in oven-dried glass equipment. For
reactions, Et2O and THF were freshly distilled from Na with benzophenone ketyl as indicator; dry CH2Cl2 was
purchased from Merck AG and stored over molecular sieves. Extracts were washed with sat. aq. NH4Cl soln. and
brine, and were dried (MgSO4). Chromatography: Merck silica gel 60 (40 63 mm). Optical Rotation: Perkin-
Elmer Polarimeter 241. M.p.: Mettler FP5/FP52. IR Spectra: neat liquid films between NaCl plates for liquids
and as KBr presslings for solids; Perkin-Elmer 297 or 781; in cmÀ1. 1H-NMR spectra in CDCl3; Bruker AC-300
(300 MHz), ARX-300 (300 MHz), or AMX-600 (600 MHz); d in ppm rel. to CHCl3 (d 7.26), J in Hz. 13C-NMR
Spectra: in CDCl3; Bruker ARX-300 (75.5 MHz); d in ppm rel. to CDCl3 (d 77.0); multiplicities from DEPT-135
and DEPT-90 experiments; the interpretation of the NMR spectra is based on cross-correlation with a number
of reference samples. Mass spectrometry (MS): Finnigan MAT 95, Finnigan SSQ 700, or Finnigan TSQ 700;
electron impact (EI) at 70 eV; chemical ionization (CI) with NH3 as the reactant gas; electrospray-ionization
(ESI) with MeOH as the solvent; molecular ions, quasi-molecular ions, and characteristic fragments either with
interpretation or ꢀ 20 rel.%; in m/z (rel.%). Elemental Analysis: Elementar Vario EL.
2. (But-3-enyl)(chloromethyl)dimethylsilane (2). 4-Bromobut-1-ene (22.13 g, 163.9 mmol) in Et2O (50 ml)
was added dropwise at 238 to a suspension of Mg (3.94 g, 161.9 mmol) in Et2O (250 ml). After the exothermic
reaction ceased, it was stirred for another 3 h at 238. Chloro(chloromethyl)dimethylsilane (1; 23.04 g,
161.0 mmol) in Et2O (50 ml) was added dropwise, the mixture was warmed to reflux for 36 h, and the reaction
was quenched with an excess of H2O. Extraction with Et2O and distillation (808, 45 Torr) via a Vigreux column
afforded 2 (13.98g, 53%). Colorless liquid. IR: 3075 w, 2995w, 2970m, 2960m, 2920m, 2840w, 1640m, 1445w,
1
1415w, 1395m, 1250s, 1175w, 995m, 910s, 900s, 8 45s, 8 35s, 8 10s, 790s, 650m, 605s. H-NMR: 5.87 (ddt, J ˆ 16.5,
10.1, 6.3, CHˆ); 5.01 (ddd, J ˆ 17.0, 3.5, 1.7, 1 H, CH2ˆ); 4.92 (ddd, J ˆ 10.1, 3.2, 1.4, 1 H, CH2ˆ); 2.79
(s, ClCH2); 2.15 2.06 (m, CH2CHˆ); 0.79 0.73 (m, CH2Si); 0.12 (s, Me2Si). 13C-NMR: 143.0 (d, CHˆ); 115.2
(t, CH2ˆ); 32.3 (t, CH2Cl); 29.6 (t, CH2CHˆ); 14.8( t, SiCH2); À 2.5 (q, Me2Si). EI-MS: 113 (100, [M À
‡
‡
CH2Cl] ), 107 (15, [M À C4H7] ), 93 (14), 85 (48), 81 (26), 79 (71), 63 (18), 59 (77).
3. 3-[(Chloromethyl)(dimethyl)silyl]propanoic Acid (3). A mixture of 2 (2.07 g, 12.77 mmol) and NaIO4
(11.25 g, 52.6 mol) in CCl4 (25 ml), MeCN (25 ml), and H2O (39 ml) was stirred at 238 for 2 min. RuCl3 ¥ H2O
(70 mg, 0.30 mmol) was added, and the resultant biphasic mixture was stirred vigorously for 2 h at 238. After the
exothermic reaction ceased, CH2Cl2 (100 ml) was added, the phases were separated, and the aq. phase was
extracted three times with CH2Cl2 (50 ml). Chromatography (Et2O/hexan 1:2) afforded 3 (2.20 g, 95%).
Yellowish liquid. IR: 3030m, 2955s, 2920s, 2895m, 2660m, 1710s, 1425m, 1410m, 1330w, 1295m, 1250s, 1180m,

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Helvetica Chimica Acta Vol. 87 (2004)
1130w, 1105w, 1040w, 920m, 8 45s, 8 15m, 795m, 700w, 640m. 1H-NMR: 2.80 (s, ClCH2); 2.44 2.38( m, CH2CO);
1.03 0.97 (m, SiCH2); 0.14 (s, Me2Si). 13C-NMR: 180.7 (s, CO); 29.8( t, ClCH2); 28.3 (t, CH2CO); 8.6
‡
(t, SiCH2); À 4.8( q, Me2Si). CI-MS: 163 (11), 162 (100 [M À Cl ‡ NH4] ), 145 (5). Anal. calc. for C6H13ClO2Si
(180.70): C 39.88, H 7.25; found: C 40.13, H 7.04.
4. (R)-4-Benzyl-3-{3-[(chloromethyl)(dimethyl)silyl]propanoyl}-1,3-oxazolidin-2-one (4). A dispersion of
NaH (60% in oil, 1.28g, 32.0 mmol) was added at 23 8 to a soln. of 3 (5.63 g, 31.13 mmol) in THF (200 ml), and
the resulting suspension was cooled to 08. Pivaloyl chloride (3.80 g, 31.50 mmol) was added, and the mixture was
stirred for 2 h and then cooled to À 788 (soln. A). In a separate flask, BuLi (1.6m in hexane, 19.9 ml, 31.80 mmol)
was added slowly at À 788 to a soln. of (R)-4-benzyloxazolidin-2-one (5.56 g, 31.40 mmol) in THF (80 ml), and
the mixture was stirred for 30 min (soln. B). Soln. B was then transferred by syringe into soln. A at À 788. After
stirring at À 788 for 2 h and at 238 for 2 h, the reaction was quenched with H2O, and the mixture was extracted
20
D
with Et2O and chromatographed (AcOEt/hexane 1:9) to give 4 (8.92 g, 84%). Colorless oil. ‰aŠ ˆ À40.3 (c ˆ
1.49, CHCl3). IR: 3060w, 3030w, 2955m, 2920m, 1780s, 1700s, 1605w, 1495m, 1480m, 1455m, 1385s, 1355s, 1290m,
1250s, 1210s, 1200s, 1180m, 1160m, 1100s, 1075m, 1050m, 1030m, 1015m, 975m, 920w, 8 45s, 8 15m, 78 5m, 760m,
750m, 740m, 705s, 635m. 1H-NMR: 7.37 7.18( m, 5 arom. H); 4.71 4.62 (sym. m, 8lines, HCN); 4.24 4.13
(m, H2CO); 3.31 (dd, J ˆ 13.6, 3.3, 1 H, PhCH2); 3.06 2.88 (m, CH2CˆO); 2.84 (s, CH2Cl); 2.77 (dd, J ˆ 13.4,
9.6, 1 H, PhCH2); 1.07 0.99 (m, CH2Si); 0.18( s, Me2Si). 13C-NMR: 174.1 (s, CON); 153.4 (s, COO); 135.3
(s, arom. C); 129.4, 128.9 (2d, 4 arom. C); 127.3 (d, arom. C); 66.2 (t, CH2O); 55.2 (d, HCN); 37.9 (t, PhCH2);
30.1 (t, CH2CO); 30.0 (t, ClCH2); 8.2 (t, SiCH2); À 4.7 (q, Me2Si). CI-MS: 360 (8), 359 (39), 358 (18), 357 (100,
‡
‡
[M ‡ NH4] ), 340 (11, [M ‡ H] ). Anal. calc. for C16H22ClNO3Si (339.89): C 56.54, H 6.52, N 4.12; found: C
56.84, H 6.67, N 3.97.
5. (R)-4-Benzyl-3-{3-[(iodomethyl)(dimethyl)silyl]propanoyl}-1,3-oxazolidin-2-one (5). A soln. of
4
(1.14 g, 3.34 mmol) in acetone (20 ml) was added to a suspension of NaI (0.53 g, 3.54 mmol) in acetone
(80 ml), and the resulting mixture was stirred at 658 for 48h. Evaporation of the solvent and chromatography
20
D
(AcOEt/hexane 1:9) afforded 5 (1.40 g, 97%). Colorless oil. ‰aŠ ˆ À29.4 (c ˆ 3.17, CHCl3). IR: 3085w, 3060w,
3025w, 2955m, 2925w, 2900w, 2860w, 1780s, 1695s, 1605w, 1585w, 1495w, 1480w, 1455m, 1440w, 1385s, 1350s,
1330m, 1290m, 1250s, 1215s, 1195s, 1180m, 1160m, 1105m, 1075m, 1050m, 1030w, 1010m, 975m, 920w, 905w, 8 40s,
1
805m, 78 5m, 760m, 750m, 735m, 705s, 610m. H-NMR: 7.37 7.18( m, 5 arom. H); 4.71 4.62 (sym. m, 8lines,
HCN); 4.24 4.16 (m, CH2O); 3.30 (dd, J ˆ 13.3, 3.0, 1 H, PhCH2); 2.99 2.91 (AB of ABX, CH2CˆO); 2.77
(dd, J ˆ 13.4, 9.6, 1 H, PhCH2); 2.06 (s, ICH2); 1.09 1.01 (m, CH2Si); 0.20 (s, Me2Si). 13C-NMR: 174.1
(s, CON); 153.4 (s, COO); 135.2 (s, arom. C); 129.4, 128.9 (2d, 4 arom. C); 127.3 (d, arom. C); 66.2 (t, CH2O);
55.2 (d, HCN); 37.9 (t, PhCH2); 30.1 (t, CH2CO); 9.3 (t, SiCH2); À 3.2 (q, Me2Si); À 14.2 (t, ICH2). CI-MS: 450
‡
‡
(24), 449 (100, [M ‡ NH4] ), 432 (16, [M ‡ H] ), 382 (9), 381 (51), 359 (8), 357 (21), 324 (8), 323 (37), 301
(20), 300 (27), 284 (10), 267 (11), 210 (12), 195 (18), 73 (11). Anal. calc. for C16H22INO3Si (431.34): C 44.55, H
5.14, N 3.25; found: C 44.32, H 5.27, N 3.05.
6. (R)-4-Benzyl-3-(3-{dimethyl[(piperidin-1-yl)methyl]silyl}propanoyl)-1,3-oxazolidin-2-one (6). EtN(i-
Pr)2 (39 mg, 0.30 mmol) and piperidine (26 mg, 0.30 mmol) were added at 238 to a soln. of 5 (98mg, 0.21 mmol)
in MeCN (10 ml). The mixture was stirred for 66 h at 238, concentrated in vacuo, and chromatographed (NH3/
20
D
EtOH/CHCl3, 1:2 :97) to afford 6 (51 mg, 73%). Pale-brownish oil. ‰aŠ ˆ À30.4 (c ˆ 2.29, CHCl3). IR: 3085w,
3060w, 3025m, 2930s, 2850m, 2775m, 2740m, 2700m, 2670w, 1765s, 1700s, 1605w, 1570w, 1495w, 1480w, 1455m,
1440m, 1385s, 1365s, 1325m, 1295m, 1250s, 1225s 1215s, 1200m, 1180m, 1160m, 1105s, 1075w, 1050m, 1040m,
1
1030w, 1015w, 995w, 975w, 915w, 8 60m, 8 40s, 78 0m, 760m, 750m, 735m, 705s. H-NMR: 7.36 7.17 (m, 5 arom.
H); 4.71 4.61 (sym. m, 8lines, HCN); 4.23 4.12 ( m, CH2O); 3.29 (dd, J ˆ 13.4, 3.3, 1 H, PhCH2); 3.04 2.85
(m, CH2CˆO); 2.76 (dd, J ˆ 13.4, 9.6, 1 H, PhCH2); 2.40 2.30 (m, 2 NCH2); 1.96 (s, NCH2Si); 1.62 1.53
(m, (CH2CH2)2N); 1.42 1.33 (m, CH2(CH2CH2)2N); 1.03 0.86 (m, SiCH2); 0.11 (s, Me2Si). 13C-NMR: 174.7
(s, CON); 153.4 (s, COO); 135.3 (s, arom. C); 129.4, 128.9 (2d, 4 arom. C); 127.3 (d, arom. C); 66.1 (t, CH2O);
58.4 (t, 2 NCH2); 55.2 (d, CHN); 50.0 (t, NCH2Si); 37.9 (t, PhCH2); 30.3 (t, CH2CO); 26.0 (t, 2CH2CH2N); 23.6
‡
(t, CH2(CH2CH2)2N); 10.0 (t, SiCH2); À 2.9 (q, Me2Si). CI-MS: 391 (8), 390 (22), 389 (100, [M ‡ H] ), 338(6),
‡
290 (7, [M À C6H12N] ); 258(24). Anal. calc. for C 21H32N2O3Si (388.58): C 64.91, H 8.30, N 7.21; found: C 64.91,
H 8.29, N 7.17.
7. (R)-3-{3-[(Azidomethyl)(dimethyl)silyl]propanoyl}-4-benzyl-1,3-oxazolidin-2-one (7).
A soln. of
N,N,N',N'-tetramethylguanidinium azide (TMG-N3; 0.52 g, 3.28mmol) in MeCN (10 ml) was added at 23 8 to
stirred soln. of 5 (0.35 g, 0.82 mmol) in MeCN (10.0 ml), and the mixture was stirred for 48 h at 238. It was
concentrated in vacuo, and the residue was dissolved in AcOEt. The mixture was washed with H2O, dil. aq.
Na2S2O3 soln., and brine. Chromatography (AcOEt/hexane 1:9) afforded 7 (0.28g, 94%). Pale-yellowish oil.
20
D
‰aŠ ˆ À42.8( c ˆ 1.68, CHCl3). IR: 3085w, 3060w, 3030w, 2960m, 2920m, 2895m, 2180m, 2090s, 1780s, 1700s,

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1605w, 1495m, 1480m, 1455m, 1440m, 1385s, 1350s, 1330m, 1290s, 1250s, 1215s, 1195s, 1180s, 1160m, 1100s,
1075m, 1050m, 1030m, 1010m, 975m, 910m, 8 50s, 795m, 760s, 750m, 735s, 705s. 1H-NMR: 7.37 7.19 (m, 5 arom.
H); 4.71 4.62 (sym. m, 8lines, HCN); 4.26 4.13 ( m, CH2O); 3.30 (dd, J ˆ 13.3, 3.3, 1 H, PhCH2); 3.00 2.92
(AB of ABX, CH2CˆO); 2.86 (s, N3CH2); 2.77 (dd, J ˆ 13.4, 9.6, 1 H, PhCH2); 1.04 0.96 (m, SiCH2); 0.16
(s, Me2Si). 13C-NMR: 174.0 (s, CON); 153.4 (s, COO); 135.2 (s, arom. C); 129.4, 128.9 (2d, 4 arom. C); 127.3
(d, arom. C); 66.2 (t, CH2O); 55.2 (d, HCN); 41.0 (t, N3CH2); 37.9 (t, PhCH2); 30.0 (t, CH2CO); 8.5 (t, SiCH2);
‡
À 4.4 (q, Me2Si). CI-MS: 292 (7), 291 (25), 290 (100, [M À CH2N3] ), 239 (24), 211 (10), 167 (6), 108(12).
Anal. calc. for C16H22N4O3Si (346.46): C 55.47, H 6.40, N 16.17; found: C 55.40, H 6.47, N 16.17.
8. 2-[({3-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}(dimethyl)silyl)methyl]-1H-isoindole-
1,3(2H)-dione (8). A soln. of potassium phthalimide (0.44 g, 2.37 mmol) in MeCN (20 ml) was added at 238
to a stirred soln. of 5 (0.68g, 1.58mmol) in MeCN (50.0 ml), and the mixture was stirred for 48h at 23 8. The
mixture was warmed to 608 and stirred for an additional 14 d. The solvent was removed, and the residue was
20
D
chromatographed (AcOEt/hexane 1:4) to give 8 (0.71 g, 99%). Colorless oil. ‰aŠ ˆ À31.3 (c ˆ 1.77, CHCl3).
IR: 3085w, 3060w, 3030w, 2950m, 2910m, 2250w, 1780s, 1730m, 1710s, 1700s, 1610w, 1495w, 1480w, 1465m, 1455m,
1410s, 1385s, 1305m, 1285m, 1250s, 1225s, 1215s, 1195m, 1185s, 1155m, 1100m, 1060s, 1040w, 1010m, 970m, 910m,
885s, 8 4s5, 8 1m0 , 790m, 760m, 730s, 720s, 700s. 1H-NMR: 7.83 7.77 (m, 2 arom. H (Phth)); 7.70 7.64
(m, 2 arom. H (Phth)); 7.36 7.17 (m, 5 arom. H); 4.69 4.60 (sym. m, 10 lines, HCN); 4.23 4.13 (m, CH2O);
3.28( dd, J ˆ 13.4, 3.3, 1 H, PhCH2); 3.25 (s, PhthCH2N); 3.03 2.97 (sym. m, 6 lines, CH2CˆO); 2.75 (dd, J ˆ
13.3, 9.7, 1 H, PhCH2); 1.07 0.96 (m, SiCH2); 0.15, 0.14 (2s, Me2Si). 13C-NMR: 174.2 (s, CON); 168.5 (s, CO
(Phth)); 153.4 (s, COO); 135.3 (s, arom. C); 133.6 (d, 2 arom. C (Phth)); 132.2 (s, 2 arom. C (Phth)); 129.4,
128.9 (2d, 4 arom. C); 127.3 (d, arom. C); 122.9 (d, 2 arom. C (Phth)); 66.1 (t, CH2O); 55.2 (d, HCN); 37.8
(t, PhCH2); 30.0 (t, CH2CO); 27.8( t, PhthNCH2); 9.0 (t, SiCH2); À 3.68, À 3.72 (2q, Me2Si). CI-MS: 470 (10),
‡
‡
469 (35), 468(100, [ M ‡ NH4] ), 451 (21), 449 (24), 323 (17), 291 (13), 290 (12, [M À CH2NPhth] ), 251 (11),
249 (8), 235 (15), 218 (11), 195 (37), 175 (61). Anal. calc. for C24H26N2O5Si (450.56): C 63.98, H 5.82, N 6.22;
found: C 63.87, H 5.87, N 6.13.
9. 3,3-Dimethyl-1-aza-3-silacyclohexan-6-one (11). A soln. of 7 (0.27 g, 0.79 mmol) in THF (10 ml) was
treated at 238 for 24 h with Ph3P (0.21 g, 0.80 mmol) and H2O (0.02 g, 1.1 mmol). The solvent was removed, and
the residue was chromatographed (MeOH/CH2Cl2, 1:12) to afford 11 (0.11 g, 99%). Colorless crystals. M.p.
44.8 54.3 8 (CH2Cl2). IR: 3200m, 3060w, 2955m, 2930m, 2900m, 2860m, 1750w, 1660s, 1470m, 1435m, 1415m,
1385m, 1245m, 1225m, 1210m, 1190w, 1135s, 1120m, 1080w, 930w, 8 45s, 8 10s, 760m, 720m, 700m. 1H-NMR: 6.87
(br. s, NH); 2.27 (d, J ˆ 3.8, NCH2Si); 2.10 2.02 (m, COCH2); 0.55 0.48( m, SiCH2); À 0.21 (s, Me2Si).
13C-NMR: 176.8( s, CON); 30.5 (t, CH2CO); 29.9 (t, CH2N); 7.5 (t, SiCH2); À 3.6 (q, Me2Si). CI-MS: 289 (9),
‡
288 (24), 287 (100), 145 (8), 144.2 (60, [M ‡ H] ). Anal. calc. for C6H13NOSi (143.26): C 50.30, H 9.15, N 9.78;
found: C 50.21, H 9.33, N 9.65.
10. (4R)-3-{(2R)-3-[(Azidomethyl)(dimethyl)silyl]-2-bromopropanoyl}-4-benzyl-1,3-oxazolidin-2-one and
(4R)-3-{(2S)-3-[(Azidomethyl)(dimethyl)silyl]-2-bromopropanoyl}-4-benzyl-1,3-oxazolidin-2-one ((4R,2'R)-
12a and (4R,2'S)-12b, resp.). EtN(i-Pr)2 (0.16 g, 1.24 mmol) and a soln. of dibutylboryl trifluoromethanesul-
fonate (Bu2BOTf; 1m in CH2Cl2, 1.2 ml, 1.2 mmol) were added subsequently at À 788 to a soln. of 7 (0.304 g,
0.88 mmol) in CH2Cl2 (4.0 ml). The mixture was allowed to warm to 08, kept at this temp. for 4 h, and was re-
cooled to À 788, before the mixture was transferred with a double-tipped needle (insulated to maintain the
temp.) to a soln. of N-bromosuccinimide (NBS; 0.21 g, 1.17 mmol, freshly recrystallized from H2O) in CH2Cl2
(10 ml) at À 788. After 1 h, sat. aq. NaHCO3 soln. (3.2 ml) was added to the dark red soln., and the mixture was
allowed to warm to 238. Extraction with CH2Cl2 and chromatography (AcOEt/hexane, 5 :95) afforded (4R,2'R)-
12a (58mg, 16%) and (4 R,2'S)-12b (232 mg, 62%) as yellowish oils.
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D
Data of (4R,2'R)-12a: ‰aŠ ˆ À40.72 (c ˆ 1.01, CHCl3). IR: 3085w, 3060m, 3030m, 3000m, 2960m, 2920m,
2180m, 2090s, 1780s, 1705s, 1605w, 1585w, 1495m, 1480m, 1455m, 1380s, 1350s, 1290s, 1260s, 1210s, 1200s, 1175s,
1
1105s, 1075m, 1045m, 1030m, 1015m, 1000w, 970m, 910w, 8 50s, 8 00m, 760s, 750s, 735m, 705m. H-NMR: 7.39
7.21 (m, 5 arom. H); 5.95 (dd, J ˆ 9.7, 6.2, BrHC); 4.71 4.62 (m, HCN); 4.28 4.16 ( m, CH2O); 3.41 (dd, J ˆ
13.2, 3.4, 1 H, PhCH2); 2.90 (s, N3CH2); 2.70 (dd, J ˆ 13.2, 10.4, 1 H, PhCH2); 1.95 (dd, J ˆ 14.4, 9.7, 1 H, SiCH2);
1.60 (dd, J ˆ 14.4, 6.2, 1 H, SiCH2); 0.21, 0.20 (2s, 2 MeSi). 13C-NMR: 169.6 (s, CON); 152.5 (s, COO); 135.0
(s, arom. C); 129.4, 129.1 (2d, 4 arom. C); 127.5 (d, arom. C); 66.4 (t, CH2O); 56.1 (d, HCN) 41.4 (d, BrCH);
‡
41.2 (t, N3CH2); 37.9 (t, PhCH2); 21.4 (t, SiCH2); À 3.6, À 3.8(2 q, 2 MeSi). CI-MS: 444 (30, [M ‡ NH4] ), 442
‡
‡
‡
(28, [M ‡ NH4] ), 371 (21), 370 (100, [M À CH2N3] ), 369 (21), 368(97, [ M À CH2N3] ), 291 (17), 290 (78), 279
(36), 250 (9), 249 (64), 195 (38).
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D
Data of (4R,2'S)-12b: ‰aŠ ˆ À39.87 (c ˆ 1.63, CHCl3). IR: 3085w, 3060w, 3030w, 3000w, 2960m, 2920m,
2870w, 1780s, 1705s, 1605w, 1585w, 1495w, 1480w, 1455m, 1445w, 1385s, 1350m, 1290m, 1260s, 1210s, 1200s,

1690
Helvetica Chimica Acta Vol. 87 (2004)
1175m, 1105m, 1075m, 1045m, 1030w, 1015m, 1000w, 975m, 920w, 8 75m, 8 45s, 8 00w, 760m, 750m, 735m, 705m,
1
645m, 600m. H-NMR: 7.38 7.16 ( m, 5 arom. H); 5.96 (dd, J ˆ 10.1, 5.8, BrHC); 4.79 4.64 (m, HCN); 4.27
4.18( m, CH2O); 3.32 (dd, J ˆ 13.6, 3.7, 1 H, PhCH2); 2.88 (s, N3CH2); 2.79 (dd, J ˆ 13.7, 9.6, 1 H, PhCH2); 1.95
(dd, J ˆ 14.4, 10.1, 1 H, SiCH2); 1.61 (dd, J ˆ 14.4, 5.8, 1 H, SiCH2); 0.18, 0.17 (2s, 2 MeSi). 13C-NMR: 169.4
(s, CON); 152.4 (s, COO); 134.8( s, arom. C); 129.4, 129.0 (2d, 4 arom. C); 127.4 (d, arom. C); 66.2 (t, CH2O);
55.1 (d, HCN) 41.6 (d, BrCH); 41.1 (t, N3CH2); 37.0 (t, PhCH2); 21.5 (t, SiCH2); À 3.7, À 4.0 (2q, 2 MeSi). CI-
‡
‡
‡
MS: 444 (32, [M ‡ NH4] ), 442 (29, [M ‡ NH4] ), 371 (19), 370 (100, [M À CH2N3] ), 369 (23), 368(98, [ M À
‡
CH2N3] ), 291 (12), 290 (83), 279 (29), 250 (11), 249 (66), 195 (42). Anal. calc. for C16H21BrN4O3Si (425.35): C
45.18, H 4.98, N 13.17; found: C 45.04, H 4.92, N 12.93.
11. (4R)-3-{(2R)-2-Azido-3-[(azidomethyl)(dimethyl)silyl]propanoyl}-4-benzyl-1,3-oxazolidin-2-one and
(4R)-3-{(2S)-2-Azido-3-[(azidomethyl)(dimethyl)silyl]propanoyl}-4-benzyl-1,3-oxazolidin-2-one ((4R,2'R)-
13a and (4R,2'S)-13b, resp.). A soln. of TMG-N3 (0.66 g, 4.2 mmol) in MeCN (30 ml) was added at 08 to a
stirred soln. of (4R,2'S)-12b (0.38g, 0.89 mmol) in MeCN (20.0 ml). The mixture was stirred for 4 h at 0 8, and
sat. aq. NaHCO3 soln. (2 ml) was added. The mixture was extracted with Et2O and chromatographed (AcOEt/
hexane, 1:4) to afford an inseparable mixture (4R,2'R)-13a/(4R,2'S)-13b (ratio 1:1, 0.29 g, 85%). Colorless oil.
Data of (4R,2'R)-13a/(4R,2'S)-13b: IR: 3085w, 3060w, 3025m, 2960w, 2920w, 2180w, 2095s, 1780s, 1705s,
1605w, 1495w, 1480w, 1455w, 1385s, 1370m, 1350m, 1290m, 1245s, 1210s, 1195m, 1110m, 1070w, 1045w, 1030w,
1015w, 990w, 8 95w, 8 8w0, 8 50w, 8 10w, 760m, 735w, 705m. 1H-NMR: 7.38 7.28 ( m, 6 arom. H); 7.24 7.19
(m, 4 arom. H); 4.98( dd, J ˆ 8.1, 6.9, N3CH (13a)); 4.87 (dd, J ˆ 10.9, 4.1, N3CH (13b)); 4.77 4.64 (m, 2 HCN);
4.31 4.21 (m, 2 CH2O); 3.38 3.26 ( m, PhCH2); 2.95, 2.93 (2s, 2 N3CH2); 2.84 (dd, J ˆ 13.5, 9.4, 1 H, PhCH2);
2.81 (dd, J ˆ 13.4, 9.6, 1 H, PhCH2); 1.30 1.24 (m, 2 SiCH2); 0.26, 0.25 (2s, 2 Me2Si). 13C-NMR: 172.05, 171.95
(2s, 2 CON); 152.8( s, 2 COO); 134.70, 134.65 (2s, 2 arom. C); 129.41, 129.38, 129.05, 129.02 (4d, 8arom. C);
127.57, 127.53 (2d, 2 arom. C); 66.9, 66.6 (2t, 2 CH2O); 57.16, 57.14 (2d, 2 N3CH); 55.4, 55.1 (2d, 2 HCN) 41.0
(t, 2 N3CH2); 37.67, 37.64 (2t, 2 PhCH2); 17.0, 16.9 (2t, 2 SiCH2); À 4.0, À 4.3 (2q, 2 Me2Si). ESI-MS 410 (100,
‡
[M ‡ Na] ), 397 (31), 331 (9).
12. (R)-4-Benzyl-3-(prop-2-enoyl)-1,3-oxazolidin-2-one (15). From 8 (EtN(i-Pr)2 (0.29 g, 2.25 mmol) and a
soln. of Bu2BOTf (1m in CH2Cl2, 2.2 ml, 2.2 mmol) were added subsequently at À 788 to a soln. of 8 (0.72 g,
1.60 mmol) in CH2Cl2 (20 ml). The mixture was allowed to warm to 08, kept at this temp. for 4 h, and was re-
cooled to À 788, before the mixture was transferred with a double-tipped needle (insulated to maintain the
temp.) to a soln. of NBS (0.35 g, 1.95 mmol, freshly recrystallized from H2O) in CH2Cl2 (20 ml) at À 788. After
1 h, sat. aq. NaHCO3 soln. (3.2 ml) was added, and the mixture was allowed to warm to 238. Extraction with
CH2Cl2 and chromatography (AcOEt/hexane, 5 :95) afforded 15 (0.34 g, 99%). Colorless crystals.
From 16. The same reaction performed with (4R,4'R)-3,3'-[(dimethylsilanediyl)bis(1-oxopropane-3,1-
diyl)]bis(4-benzyl-1,3-oxazolidin-2-one) (16; 1.13 g, 2.16 mmol [17]) delivered quantitatively 15. Spectroscopic
data of 15 are in agreement with those given in [18].
13. (4R)-4-Benzyl-3-{(2R)-2-bromo-3-[(chloromethyl)(dimethyl)silyl]propanoyl}-1,3-oxazolidin-2-one
and
(4R)-4-Benzyl-3-{(2S)-2-bromo-3-[(chloromethyl)(dimethyl)silyl]propanoyl}-1,3-oxazolidin-2-one
((4R,2'R)-17a and (4R,2'S)-17b, resp.). EtN(i-Pr)2 (0.50 g, 3.83 mmol) and a soln. of Bu2BOTf (1m in CH2Cl2,
3.8ml, 3.80 mmol) were added subsequently at À 788 to a soln. of 4 (0.93 g, 2.74 mmol) in CH2Cl2 (10 ml). The
mixture was allowed to warm to 08, kept at this temp. for 4 h, and was re-cooled to À 788, before the mixture was
transferred with a double-tipped needle (insulated to maintain the temp.) to a soln. of NBS (0.65 g, 3.64 mmol,
freshly recrystallized from H2O) in CH2Cl2 (20 ml) at À 788. After 1 h, sat. aq. NaHCO3 soln. (10 ml) was added
to the reddish soln., and the mixture was allowed to warm to 238. Extraction with CH2Cl2 and chromatography
(AcOEt/hexane 5 :95) afforded a mixture of (4R,2'R)-17a (0.18g, 0.43 mmol, 16%) and (4 R,2'S)-17b (0.74 g,
64%) as a colorless oil and as colorless crystals, respectively.
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D
Data of (4R,2'R)-17a: ‰aŠ ˆ À36.73 (c ˆ 2.86, CHCl3). IR: 3085w, 3060w, 3030w, 3000w, 2960m, 2920m,
2870w, 1780s, 1705s, 1605w, 1585w, 1495m, 1480w, 1455m, 1445w, 1385s, 1350s, 1290m, 1260s, 1210s, 1200s, 1175m,
1105m, 1075m, 1045m, 1030m, 1015m, 1000w, 970m, 920w, 8 75m, 8 45s, 8 00w, 760m, 750m, 735m, 705m, 645m,
625m, 600m. 1H-NMR: 7.39 7.20 (m, 5 arom. H); 5.94 (dd, J ˆ 9.6, 6.3, BrHC); 4.71 4.62 (m, HCN); 4.28
4.16 (m, CH2O); 3.41 (dd, J ˆ 13.3, 3.4, 1 H, PhCH2); 2.83 (AB of AB, JAB ˆ 5.4, ClCH2); 2.71 (dd, J ˆ 13.3, 10.3,
1 H, PhCH2); 1.98( dd, J ˆ 14.5, 9.6, 1 H, SiCH2); 1.66 (dd, J ˆ 14.5, 6.3, 1 H, SiCH2); 0.23, 0.22 (2s, 2 MeSi).
13C-NMR: 169.6 (s, CON); 152.5 (s, COO); 135.0 (s, arom. C); 129.4, 129.1 (2d, 4 arom. C); 127.5 (d, arom. C);
66.4 (t, CH2O); 56.1 (d, HCN); 41.5 (d, BrHC); 37.9 (t, PhCH2); 30.0 (t, ClCH2); 21.3 (t, SiCH2); À 3.9, À 4.1
‡
‡
(2q, 2 MeSi). CI-MS: 439 (30), 438(24), 437 (100, [ M ‡ NH4] ), 436 (18), 435 (73, [M ‡ NH4] ), 357 (9), 338
‡
(6, [M À Br] ), 249 (30), 195 (9), 164 (28), 147 (34), 115 (9). Anal. calc. for C16H21BrClNO3Si (418.79): C 45.89,
H 5.05, N 3.34; found: C 46.11, H 4.93, N 3.33.

Helvetica Chimica Acta Vol. 87 (2004)
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Data of (4R,2'S)-17b: Crystals suitable for X-ray crystal-structure determination were obtained from
20
D
hexane. M.p. 99.2 100.08 (hexane). ‰aŠ ˆ À39.48( c ˆ 1.35, CHCl3). IR: 3085w, 3060w, 3030w, 3000w, 2960m,
2920m, 2870w, 1780s, 1705s, 1605w, 1585w, 1495w, 1480w, 1455m, 1445w, 1385s, 1350m, 1290m, 1260s, 1210s,
1200s, 1175m, 1105m, 1075m, 1045m, 1030w, 1015m, 1000w, 975m, 920w, 8 75m, 8 45s, 8 00w, 760m, 750m, 735m,
705m, 645m, 600m. 1H-NMR: 7.37 7.22 (m, 5 arom. H); 5.90 (dd, J ˆ 9.8, 6.1, BrHC); 4.76 4.67 (m, HCN);
4.27 4.18( m, CH2O); 3.32 (dd, J ˆ 13.5, 3.4, 1 H, PhCH2); 2.83 (s, ClCH2); 2.79 (dd, J ˆ 13.5, 9.6, 1 H, PhCH2);
1.97 (dd, J ˆ 14.5, 9.9, 1 H, SiCH2); 1.67 (dd, J ˆ 14.4, 6.0, 1 H, SiCH2); 0.21, 0.20 (2s, 2 MeSi). 13C-NMR: 169.5
(s, CON); 152.4 (s, COO); 134.8( s, arom. C); 129.4, 129.0 (2d, 4 arom. C); 127.4 (d, arom. C); 66.2 (t, CH2O);
55.2 (d, HCN); 41.6 (d, BrCH); 37.0 (t, PhCH2); 30.1 (t, ClCH2); 21.3 (t, SiCH2); À 3.9, À 4.2 (2q, 2 MeSi). CI-
‡
‡
MS: 440 (7), 439 (29), 438(25), 437 (100, [ M ‡ NH4] ), 436 (19), 435 (73, [M ‡ NH4] ), 359 (6), 357 (17), 338
‡
(9, [M À Br] ), 250 (9), 249 (55), 195 (12). Anal. calc. for C16H21BrClNO3Si (418.79): C 45.89, H 5.05, N 3.34;
found: C 45.97, H 5.13, N 3.31. For X-ray crystal-structure determination, see Sect. 23.
14. (4R)-3-{(2R)-2-Azido-3-[(chloromethyl)(dimethyl)silyl]propanoyl}-4-benzyl-1,3-oxazolidin-2-one
((4R,2'R)-18a). A soln. of TMG-N3 (4.49 g, 28.4 mmol) in MeCN (300 ml) was added dropwise at 08 to a
soln. of (4R,2'S)-17b (3.21 g, 7.67 mmol) in MeCN (50.0 ml). After 4 h, the mixture was concentrated, and H2O
(50 ml) was added. The mixture was extracted with Et2O and chromatographed (AcOEt/hexane 1 :9) to afford
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D
(4R,2'R)-18a (2.89 g, 99%). Pale-yellowish oil. ‰aŠ ˆ À19.5 (c ˆ 2.35, CHCl3). IR: 3085w, 3060w, 3025m,
2960m, 2925m, 2855w, 2105s, 1780s, 1705s, 1605w, 1500m, 1480m, 1455m, 1390s, 1365s, 1350s, 1290m, 1245s,
1210s, 1195s, 1110s, 1075m, 1050m, 1020m, 995m, 8 95s, 8 8 0s, 8 45s, 8 10m, 760s, 735s, 705s, 665m, 630m. 1H-NMR:
7.37 7.29 (m, 3 arom. H); 7.23 7.20 (m, 2 arom. H); 4.87 (dd, J ˆ 10.3, 4.2, N3CH); 4.77 4.68( m, HCN); 4.32
4.22 (m, CH2O); 3.29 (dd, J ˆ 13.4, 3.1, 1 H, PhCH2); 2.90 (s, ClCH2); 2.82 (dd, J ˆ 13.7, 9.5, 1 H, PhCH2); 1.38
1.18( m, SiCH2); 0.29, 0.27 (2s, 2 MeSi). 13C-NMR: 172.1 (s, CON); 152.8( s, COO); 134.6 (s, arom. C); 129.4,
129.0 (2d, 4 arom. C); 127.5 (d, arom. C); 66.8( t, CH2O); 57.1 (d, N3CH); 55.1 (d, HCN); 37.6 (t, PhCH2); 30.0
(t, ClCH2); 16.8( t, SiCH2); À 4.4, À 4.7 (2q, 2 MeSi). CI-MS: 401 (9), 400 (39), 399 (25), 398(100, [ M ‡
‡
‡
‡
NH4] ), 357 (6), 355 (11), 354 (6), 353 (28), 340 (6), 338 (13, [ M À N3] ), 331 (10, [M À CH2Cl] ), 284 (7), 249
(7), 247 (5), 195 (11), 176 (9). Anal. calc. for C16H21ClN4O3Si (380.90): C 50.45, H 5.56, N 14.71; found: C 50.35,
H 5.57, N 14.68.
15. (4R)-3-{(2R)-2-Azido-3-[(iodomethyl)(dimethyl)silyl]propanoyl}-4-benzyl-1,3-oxazolidin-2-one
((4R,2'R)-19a). A soln. of (4R,2'R)-18a (1.77 g, 4.6 mmol) in acetone (50 ml) was added to a suspension of
NaI (0.72 g, 4.8mmol) in acetone (100 ml). The mixture was stirred for 2 h at 23 8 and for another 24 h at 648.
Evaporation of the solvent and chromatography (AcOEt/hexane 1:9) afforded (4R,2'R)-19a (2.07 g, 96%).
20
D
Yellow oil. ‰aŠ ˆ À15.1 (c ˆ 2.11, CHCl3). IR: 3090w, 3060w, 3030w, 2960m, 2925m, 2860w, 2110s, 1785s, 1705s,
1605w, 1500w, 1480w, 1455m, 1390s, 1375s, 1350m, 1290m, 1245s, 1215s, 1195s, 1110s, 1075m, 1050m, 1030m,
1
1015m, 995m, 8 95m, 8 8 m0 , 8 40s, 8 00m, 760m, 740m, 705m, 665m, 630m. H-NMR: 7.38 7.28( m, 3 arom. H);
7.23 7.19 (m, 2 arom. H); 4.85 (dd, J ˆ 9.9, 5.1, N3CH); 4.77 4.68( m, HCN); 4.33 4.21 (m, CH2O); 3.29
(dd, J ˆ 13.7, 3.3, 1 H, PhCH2); 2.82 (dd, J ˆ 13.4, 9.5, 1 H, PhCH2); 2.13 (s, ICH2); 1.38 1.25 ( m, SiCH2); 0.31,
0.30 (2s, 2 MeSi). 13C-NMR: 172.2 (s, CON); 152.8( s, COO); 134.6 (s, arom. C); 129.4, 129.0 (2d, 4 arom. C);
127.6 (d, arom. C); 66.8( t, CH2O); 57.2 (d, N3CH); 55.1 (d, HCN); 37.7 (t, PhCH2); 17.9 (t, SiCH2); À 2.8, À 2.9
‡
(2q, 2 SiMe); À 14.4 (t, ICH2). CI-MS: 492 (6), 491 (24), 490 (100, [M ‡ NH4] ), 445 (12), 400 (8), 398 (21), 331
‡
(14, [M À CH2I] ), 319 (20), 317 (16), 302 (8), 290 (10), 249 (6), 247 (8), 195 (23). Anal. calc. for C16H21IN4O3Si
(472.35): C 40.68, H 4.48, N 11.86; found: C 40.83, H 4.55, N 11.90.
16. (4R)-3-{(2R)-2-Azido-3-[(azidomethyl)(dimethyl)silyl]propanoyl}-4-benzyl-1,3-oxazolidin-2-one
((4R,2'R)-13a). A soln. of TMG-N3 (1.67 g, 10.6 mmol) in MeCN (20 ml) was added at 238 to a stirred soln.
of (4R,2'R)-19a (1.25 g, 2.65 mmol) in MeCN (20.0 ml). The soln. was stirred for 48h at 23 8, sat. aq. NaHCO3
soln. (2 ml) was added, and the mixture was extracted with Et2O. The org. phase was concentrated in vacuo, and
20
D
chromatography of the residue (AcOEt/hexane, 1:4) afforded (4R,2'R)-13a (0.97 g, 95%). Colorless oil. ‰aŠ
ˆ
À15.7 (c ˆ 2.95, CHCl3). IR: 3085w, 3060w, 3025m, 2960w, 2920w, 2180w, 2095s, 1780s, 1705s, 1605w, 1495w,
1480w, 1455w, 1385s, 1370m, 1350m, 1290m, 1245s, 1210s, 1195m, 1110m, 1070w, 1045w, 1030w, 1015w, 990w,
895w, 8 8 0w, 8 50w, 8 10w, 760m, 735w, 705m. 1H-NMR: 7.38 7.27 ( m, 3 arom. H); 7.24 7.19 (m, 2 arom. H); 4.86
(dd, J ˆ 10.9, 4.1, N3CH); 4.77 4.64 (m, HCN); 4.32 4.21 (m, CH2O); 3.29 (dd, J ˆ 13.4, 3.3, 1 H, PhCH2); 2.94
(s, N3CH2); 2.81 (dd, J ˆ 13.4, 9.6, 1 H, PhCH2); 1.34 1.24 (m, 2 SiCH2); 0.26 (s, Me2Si). 13C-NMR: 172.0
(s, CON); 152.8( s, COO); 134.6 (s, arom. C); 129.4, 129.0 (2d, 4 arom. C); 127.5 (d, 1 arom. C); 66.8( t, CH2O);
57.1 (d, N3CH); 55.1 (d, HCN); 41.0 (t, N3CH2); 37.6 (t, PhCH2); 17.0 (t, SiCH2); À 4.1, À 4.3 (2q, Me2Si). ESI-
‡
MS: 410 (100, [M ‡ Na] ), 397 (31), 331 (9). Anal. calc. for C16H21N7O3Si (387.47): C 49.60, H 5.46, N 25.30;
found: C 49.40, H 5.51, N 25.20.

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Helvetica Chimica Acta Vol. 87 (2004)
17. (R)-2-Azido-3-[(azidomethyl)(dimethyl)silyl]propanoic Acid ((R)-20). A mixture of (4R,2'R)-13a
(890 mg, 2.29 mmol) and LiOH ¥ H2O (0.20 g, 4.75 mmol) in THF/H2O (48ml, 3 :1) was stirred at 0 8 for 1 h. Sat.
aq. NaHCO3 soln. (10 ml) was added, and the THF was evaporated. Extraction of the aq. residue with CH2Cl2 to
remove the auxiliary, acidification with aq. HCl soln. (1m) to pH 2, extraction with AcOEt, and filtration through
20
D
a plug of SiO2 afforded (R)-20 (518mg, 99%). Colorless oil. ‰aŠ ˆ À22.2 (c ˆ 2.09, CHCl3). IR: 2960s, 2900s,
2640m, 2180s, 2100s, 1720s, 1410s, 1335m, 1290s, 1255s, 1230s, 1200s, 1150m, 1060m, 1040m, 945m, 8 90s, 8 50s,
810s, 705m. 1H-NMR: 10.90 (br. s, COOH); 3.97 (X of ABX, JAX ˆ 6.3, JBX ˆ 9.1, N3CH); 2.91 (s, N3CH2); 1.32,
1.25 (AB of ABX, JAB ˆ 14.9, JAX ˆ 6.3, JBX ˆ 9.1, SiCH2); 0.21 (s, Me2Si). 13C-NMR: 177.2 (s, COOH); 58.8
(d, N3CH); 41.1 (t, N3CH2); 17.0 (t, SiCH2); À 4.0, À 4.1 (q, Me2Si). CI-MS: 190 (11), 189 (93, [M ‡ NH4 À
‡
‡
CH2N3 À H] ), 149 (11), 148(100, [ M ‡ NH4 À CH2N3 À N3] ), 144 (11), 131 (11), 92 (10), 91 (8). Anal. calc. for
C6H12N6O2Si (228.28): C 31.57, H 5.30, N 36.81; found: C 31.43, H 5.47, N 36.73.
18. (R)-2-Amino-3-[hydroxy(dimethyl)silyl]propanoic Acid ((R)-21).
A soln. of (R)-20 (0.46 g,
2.01 mmol) in EtOH/H2O (30 ml, 1:1) was treated at 238 for 14 h with PtO2 ¥ H2O (0.079 g, 0.32 mmol) under
H2 (1 atm). The catalyst was removed by filtration through a plug of cotton, and evaporation of the solvent
20
D
afforded pure (R)-21 (0.323 g, 98%). Colorless solid. ‰aŠ ˆ ‡7.8( c ˆ 1.90, H2O). M.p. 194.08 (start of dec.). IR:
3420m, 3040s, 1605s, 1585s, 1510s, 1420s, 1390s, 1345m, 1310m, 1255s, 1185w, 1135m, 1040s, 8 45s, 825s, 795s, 720w.
1H-NMR (D2O): 3.80 (X von ABX, JAX ˆ 6.0, JBX ˆ 9.5, NCH); 1.22, 1.13 (AB von ABX, JAB ˆ 14.7, JAX ˆ 6.0,
JBX ˆ 9.5, SiCH2); 0.19, 0.18(2 s, 2 MeSi). 13C-NMR (D2O): 174.7 (s, COOH); 51.7 (d, NCH); 19.2 (t, SiCH2); À
‡
‡
1.7, À 2.2 (2q, 2 MeSi). ESI-MS: 331 (18), 309 (25 [2M ‡ H À H2O] , Siloxan), 186 (21), 164 (96 [M ‡ H] ), 146
‡
‡
(28[ M ‡ H À H2O] ), 129 (100 [M ‡ H À H2O À NH3] ), 92 (12), 75 (28).
19. (R)-2-Azido-3-[(iodomethyl)(dimethyl)silyl]propanoic Acid ((R)-22). A mixture of (4R,2'R)-19a
(0.90 g, 1.90 mmol) and LiOH ¥ H2O (0.24 g, 5.72 mmol) in THF/H2O (32 ml, 3 :1) was stirred for 1 h at 08. Sat.
aq. NaHCO3 soln. (10 ml) was added, and the THF was evaporated. Extraction of the aq. residue with CH2Cl2 to
remove the auxiliary, acidification with aq. HCl soln. (1m) to pH 2, extraction with AcOEt, and filtration
20
D
through a plug of SiO2 afforded (R)-22 (0.53 g, 89%). Yellow oil. ‰aŠ ˆ À12.3 (c ˆ 2.14, CHCl3). IR: 2965m,
2950m, 2910m, 2630w, 2120s, 1730s, 1420m, 1405m, 1400m, 1380m, 1300m, 1260s, 1235s, 1210m, 1090w, 1030w,
1
950m, 8 90m, 8 45s, 8 15s, 735w, 710m. H-NMR: 10.46 (s, COOH); 3.99 3.87 (m, N3CH); 2.07 (s, ICH2); 1.44
1.30 (m, SiCH2); 0.25 (s, Me2Si). 13C-NMR: 177.4 (s, COOH); 58.8 (d, N3CH); 17.8( t, SiCH2); À 2.8( q, Me2Si);
‡
À 14.7 (t, ICH2). CI-MS: 216 (6), 204 (14), 203 (100, [M À I ‡ NH3] ), 195 (21), 189 (30), 162 (8), 158 (14), 148
(32), 131 (9). Anal. calc. for C6H12IN3O2Si (313.17): C 23.01, H 3.86, N 13.42; found: C 23.22, H 3.92, N 13.32.
20. (R)-2-Azido-3-{dimethyl[(methylsulfanyl)methyl]silyl}propanoic Acid ((R)-23). NaSMe (0.30 g,
4.28mmol) was added at 0 8 to a soln. of (R)-22 (0.58g, 1.85 mmol) in MeOH (10 ml), and the mixture was
stirred for 2 h. The solvent was evaporated, and the residue was dissolved in H2O, acidified with aq. HCl soln.
(1m) to pH 2, and extracted with AcOEt. Chromatography (MeOH/CH2Cl2 1:20) afforded (R)-23 (0.41 g,
20
D
95%). Pale-yellowish oil. ‰aŠ ˆ À19.4 (c ˆ 3.44, CHCl3). IR: 2970s, 2925s, 2900s, 2120s, 1720s, 1430s, 1420s,
1320m, 1255s, 1235s, 1205s, 1150m, 1070w, 1050w, 965m, 8 9s0, 8 4s5, 8 1s0, 8 0m0 , 700m. 1H-NMR: 9.78
(s, COOH); 3.95 (X of ABX, JAX ˆ 6.3, JBX ˆ 9.5, HCN3); 2.16 (s, MeS); 1.87 (s, CH2S); 1.32, 1.25 (AB of
ABX, JAB ˆ 14.8, JAX ˆ 6.3, JBX ˆ 9.5, SiCH2); 0.19 (s, Me2Si). 13C-NMR: 177.4 (s, COOH); 59.9 (d, N3CH); 20.3
‡
(q, MeS); 20.0 (t, CH2S); 17.7 (t, SiCH2); À 3.0, À 3.1 (2q, Me2Si). CI-MS: 251 (30, [M ‡ H ‡ NH3] ), 235 (7),
‡
234 (47, [M ‡ H] ), 208 (8), 206 (15), 203 (11), 193 (11), 191 (23), 190 (12), 189 (100), 177 (9), 164 (6), 163 (8),
162 (63), 157 (7), 146 (9), 144 (5), 136 (37), 117 (6), 116 (8). Anal. calc. for C7H15N3O2SSi (233.36): C 23.01, H
3.86, N 13.42; found: C 23.22, H 3.92, N 13.32.
21. (R)-2-Amino-3-{dimethyl[(methylsulfanyl)methyl]silyl}propanoic Acid ((R)-24). A soln. of (R)-23
(0.07 g, 0.32 mmol) in EtOH/H2O (20 ml, 1:1) was treated with PtO2 ¥ H2O (0.05 g, 0.22 mmol) and H2 (1 atm)
for 5 h. The catalyst was removed by filtration through a plug of cotton, and evaporation of the solvent afforded
20
D
pure (R)-24 (0.06 g, 85%). Colorless solid. ‰aŠ ˆ ‡9.9 (c ˆ 1.55, H2O). M.p. 1868 (start of dec.). IR: 3440m,
3060m, 2960m, 2920m, 1630s, 1610s, 1530m, 1515s, 1430s, 1395s, 1355m, 1325m, 1260s, 1190w, 1140w, 1065s, 970w,
850s, 8 30s, 795s, 700w. 1H-NMR (DMSO/DCl): 3.80 (X of ABX, JAX ˆ 4.6, JBX ˆ 11.6, HCN); 2.07 (s, MeS); 1.82
(s, CH2S); 1.20, 1.11 (AB of ABX, JAB ˆ 14.4, JAX ˆ 4.6, JBX ˆ 11.6, CH2Si); 0.11, 0.09 (2s, Me2Si). 13C-NMR
(DMSO/DCl): 171.3 (s, COOH); 50.0 (d, NCH); 19.6 (q, MeS); 19.4 (t, CH2S); 17.3 (t, SiCH2); À 2.7, À 3.0
‡
‡
(2q, Me2Si). ESI-MS: 236 (12), 230 (24 [M ‡ Na] ), 209 (8), 208 (50 [ M ‡ H] ), 191 (25), 151 (24), 147 (14),
137 (100), 119 (19).
22. Determination of the Enantiomeric Purity of (R)-24. A mixture of (R)-24 (70 mg, 0.36 mmol) and
KOCN (0.03 g, 0.38mmol) in H 2O (5 ml) was stirred for 3 h at 708. The mixture was cooled to 108, and AcOH
(2 ml) was added. The precipitated product was collected by filtration and dried at 10À2 Torr to yield (R)-2-
[(aminocarbonyl)amino]-3-{dimethyl[(methylsulfanyl)methyl]silyl}propanoic acid (60 mg, 0.23 mmol, 63%) as

Helvetica Chimica Acta Vol. 87 (2004)
1693
20
D
a colorless solid. ‰aŠ ˆ ‡4.0 (c ˆ 1.21, MeOH). M.p. 133.6 143.48. IR: 3400s, 3260m, 2935s, 2360w, 2480w,
1690s, 1630s, 1560s, 1540s, 1470m, 1420m, 1310m, 1220m, 1185m, 1135m, 1025s, 910w, 8 60m, 8 20m, 750w, 725w,
710w, 695w. 1H-NMR (MeOH): 4.12 (dd, J ˆ 9.4, 5.6, HCN); 2.07 (s, MeS); 1.80 (s, CH2S); 1.25 0.94
(m, SiCH2); 0.082, 0.078 (2s, Me2Si). 13C-NMR (MeOH): 176.0 (s, COOH); 158.1 (s, CON); 52.8( d, NCH);
‡
21.3 (t, CH2S); 20.9 (t, SiCH2); 20.4 (q, MeS); À 2.6, À 2.7 (2q, Me2Si). CI-MS: 268(27, [ M ‡ NH4] ), 251 (100,
‡
‡
‡
[M ‡ H] ), 233 (11, [M ‡ H À H2O] ), 208(83, [ M ‡ H À CONH] ). The enantiomeric purity of this material
was established as > 99% by chiral RP-HPLC with ET 200/4 Nucleodex b-PM (5 mm, 200 Â 4 mm, Macherey-
Nagel, CH-Oensingen), mobile phase: 3 g of H3PO4 (85%), 842 ml of H2O, 400 ml of MeOH, flow: 0.6 ml minÀ1
tR ((R)-isomer) 12.4 min, tR ((S)-isomer) 10.4 min; UV detection at 215 nm.
23. X-Ray Crystal-Structure Determination for Compound (4R,2'R)-17b3). The data collection and
refinement parameters are summarized in the Table, and a view of the molecule is shown in Figure. All
measurements were performed on a Nonius KappaCCD diffractometer [19] with graphite-monochromated
;
Table. Crystallographic Data of Compound (4R,2'S)-17b
Crystallized from
hexane
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Crystal temp. [K]
C16H21BrClNO3Si
418.78
colorless, prism
0.20 Â 0.25 Â 0.25
160 (1)
]
Radiation, wavelength [ä]
Crystal system
Space group
Z
MoKa, 0.71073
orthorhombic
P212121 (#19)
4
Reflections for cell determination
25249
2q Range for cell determination [8]
4 50
Unit-cell parameters a [ä]
8.5646 (1)
10.3502 (1)
21.1820 (2)
90
b [ä]
c [ä]
a [8]
b [8]
90
g [8]
V [ä3]
90
1877.69 (3)
1.481
Dx [g cmÀ3
m [mmÀ1
]
]
2.414
Absorbtion corrections (min; max)
2q(max) [8]
0.547; 0.673
50
Total reflections measured
Symmetry-independent reflections
Reflections used [I > 2q(I)]
Parameters refined
35012
3298
3162
219
Reflection/parameter ratio
R
14.4
0.0286
0.0303
0.005
wR
Weights: p in w ˆ [s 2(Fo) ‡ ( pFo)2]À1
Goodness-of-fit s
2.484
Secondary extinction coefficient
Final Dmax/s
1.46 (8) Â 10À6
0.0009
0.28; À 0.26
D1(max; min) [e äÀ3
]
3
)
Crystallographic data (excluding structure factors) for 17b has been deposited with the Cambridge
Crystallographic Data Center as supplementary publication No. CCDC-189270. Copies of the data can be
obtained free of charge on application to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: ‡44-
(0)-1223-336033; email: deposit@ccdc.cam.ac.uk).

1694
Helvetica Chimica Acta Vol. 87 (2004)
Figure. ORTEP Plots [30] of the two disordered conformations of the structure (4R,2'S)-17b (50% probability
ellipsoids; H-atoms given arbitrary displacement parameters for clarity)
MoKa radiation (l 0.71073 ä) and an Oxford Cryosystems Cryostream 700 cooler. The unit-cell constants and an
orientation matrix for data collection were obtained from a least-squares refinement of the setting angles of
25249 reflections in the range 48 < 2q < 508. The mosaicity was 0.453 (1)8. A total of 356 frames were collected
by using w scans with k offsets, 18-s exposure time, and a rotation angle of 1.88 per frame, and a crystal-detector
distance of 33.0 mm.
Data reduction was performed with HKL Denzo and Scalepack [20]. The intensities were corrected for
Lorentz and polarization effects, and a numerical absorption correction [21] was applied. Standard reflection
intensities were not monitored. The space group was uniquely determined by the systematic absences.
Equivalent reflections, other than Friedel pairs, were merged.
The structure was solved by direct methods using SIR92 [22], which revealed the positions of all non-H-
atoms. The ClCH2 group and one of the other Me substituents on the Si-atom group are disordered over two

Helvetica Chimica Acta Vol. 87 (2004)
1695
conformations such that these groups appear to have switched positions in the alternate conformation. The
major conformation occurs in 56% of the molecules. The non-H-atoms were refined anisotropically. All of the
H-atoms were fixed in geometrically calculated positions (d(CÀH) ˆ 0.95 ä), and each was assigned a fixed
isotropic displacement parameter with a value equal to 1.2 Ueq of its parent atom. Refinement of the structure
was carried out on F using full-matrix least-squares procedures, which minimized the function Sw(j Fo jÀj Fc j )2.
The weighting scheme was based on counting statistics and included a factor to downweight the intense
reflections. Plots of Sw(j Fo jÀj Fc j )2 vs. j Fo j , reflection order in data collection, sinq/l, and various classes of
indices showed no unusual trends. A correction for secondary extinction was applied. The refinement of the
absolute structure parameter [23] yielded a value of À 0.007(5), which confidently confirms that the refined
coordinates.
Neutral-atom scattering factors for non-H-atoms were taken from [24], and the scattering factors for H-
atoms were taken from [25]. Anomalous dispersion effects were included in Fc [26]; the values for f' and f'' were
those of [27]. The values of the mass attenuation coefficients are those of [28]. All calculations were performed
using the teXsan crystallographic software package [29].
We thank A. Guggisberg for helpful discussions and the analytical laboratories of our institute for spectra
and analyses, especially Dr. G. Hopp-Rentsch, N. Walch, and S. Jurt for NMR spectra, N. Bild and M. Tzouros for
mass spectra, A. Deambrosi for elemental analyses, and Dr. A. Linden for the X-ray crystal-structure analysis.
Financial support from the Swiss National Science Foundation and the Novartis Stipendienfonds are also
gratefully acknowledged.
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Received March 17, 2004