New efficient synthesis of (3R,4S)-3-methyl-3-hydroxy-4-phenyl-β-lactam

Article abstract of DOI:10.1016/S0957-4166(99)00288-8

A method is described for the chiral synthesis of (3R,4S)-3-methyl-3-hydroxy-4-phenyl-β-lactam, a useful precursor for the semi-synthesis of 2'-methyl-taxoids. This protocol follows Seebach's synthetic principle of 'self-regeneration of stereocenters' (SR

Full text of DOI:10.1016/S0957-4166(99)00288-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2765–2773
New efficient synthesis of (3R,4S)-3-methyl-3-hydroxy-
4
-phenyl-β-lactam
a
a,∗
a
a
Gaetano Barbaro, Arturo Battaglia, Fabio Di Giuseppe, Patrizia Giorgianni,
a
b
c
Andrea Guerrini, Carlo Bertucci and Silvano Geremia
a
Istituto CNR dei Composti del Carbonio Contenenti Eteroatomi ‘I.Co.C.E.A .’ , via Gobetti 101, I-40129 Bologna, Italy
b
CNR, Centro Studi Macromolecole Stereordinate ed Otticamente Attive, Dipartimento di Chimica e Chimica Industriale,
Università di Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
c
Dipartimento Scienze Chimiche, Università di Trieste, via Gorgieri 1, I-34127 Trieste, Italy
Received 11 June 1999; accepted 9 July 1999
Abstract
A method is described for the chiral synthesis of (3R,4S)-3-methyl-3-hydroxy-4-phenyl-β-lactam, a useful
0
precursor for the semi-synthesis of 2 -methyl-taxoids. This protocol follows Seebach’s synthetic principle of
self-regeneration of stereocenters’ (SRS) and has been applied to addition reactions of the (2S)-chiral enolates
‘
of dioxolan-4-ones, derived from the acetalization of (S)-α-lactic acid and tert-butylaldehyde or pinacolone, to
N-trimethylsilylphenyl aldimine. © 1999 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Taxol (paclitaxel) and its semi-synthetic derivative docetaxel (Taxotere) exhibit outstanding activity
1
2
with various types of cancer. In fact, paclitaxel inhibits cell replication in the mitotic phase of the cycle
1
d,f,3
by promoting polymerization of microtubules which are stable and resistant to depolymerization.
Structure–activity relationship studies (SARs) have shown that the phenylisoserine side-chain at
position 13 of taxanes with proper 2 R,3 S configuration is essential. However, treatment with these drugs
often results in various undesired side effects as well as multidrug resistance (MDR). For this reason,
1,4
0
0
5
6
a number of N,O-protected (2R,3S)-isoserine analogues have been synthesized to be appended to C-
1
3 of taxanes to improve MDR. Alternatively, (3R,4S)-1-acyl-3-hydroxy-4-phenyl-β-lactam derivatives
7
bearing a suitable protecting substituent at the C-3 oxygen atom have also been designed, and they
8
9
have been directly appended to C-13 of taxanes via Holton’s chemistry. Kant reported that taxoids,
which bear an additional methyl substituent at the C-2 position of the phenylisoserine, display higher
cytotoxic activity compared to the parents docetaxel and paclitaxel when evaluated in in vitro assays
∗
Corresponding author. E-mail: battaglia@area.bo.cnr.it
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00288-8

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G. Barbaro et al. / Tetrahedron: Asymmetry 10 (1999) 2765–2773
using HCT116 human colon carcinoma cell lines. The enhanced potency is probably the result of
0
0
a reduction in the degree of freedom at the C2 –C3 bond of the isoserine appendant or of some
additional hydrophobic interactions between the methyl substituent and the microtubule binding sites.
10
9
11
Greene, Kant, and Ojima independently developed different approaches for the synthesis of synthons
of the enantiopure C-2 methylated phenylisoserine. Greene synthesized, via a multistep process, the
2,4-dimethoxyphenyl-substituted oxazolidine free acid (2S,3R)-I (Scheme 1). Instead, Kant and Ojima
independently synthesized enantiopure O-protected-1-acyl-3-methyl-β-lactam derivatives III and V.
However, their synthesis requires non-readily available and expensive chiral inductors such as VI, and
enantiopure β-lactam precursors such as II and IV. Moreover, both III and V are obtained in moderate to
low (35–5%) yields via multi-step processes which require several deprotection–reprotection sequences.
Recently, we have developed a new synthetic protocol for the asymmetric construction of trisubstituted
3
-hydroxy-β-lactams in a versatile and predictable manner using easily available lithium enolates of
12
acetal-type derivatives of (S)-α-hydroxy-substituted carboxylic acids and imines as starting reagents.
To achieve our target, we have applied the synthetic principle called ‘self-regeneration of stereocenters’
developed by Seebach to the addition reactions of lithium enolates of the (2S,5S)-2-(tert-butyl)-5-
methyl-1,3-dioxolan-4-one 1a and (2S,5S)-2-(tert-butyl)-2,5-dimethyl-1,3-dioxolan-4-one 1b (Fig. 1) to
N-trimethylsilylphenyl aldimine.
13
Scheme 1.

G. Barbaro et al. / Tetrahedron: Asymmetry 10 (1999) 2765–2773
2767
2. Results and discussion
Diastereomeric (2S,5S)-cis:(2R,5S)-trans mixtures of 1a (97:3)14a and 1b (93:7)14b were prepared
according to standard procedures. Even the single (1S,2S)-diastereomer of 1a and 1b can be easily
obtained via recrystallization at low temperatures,1 for our study the cis:trans mixtures of dioxolanones
were directly converted into the corresponding enolates (2S:2R)-3a=97:3 and (2S:2R)-3b=93:7 (Fig. 1)
by reaction with lithium bis(trimethylsilyl)amide (LHMDS) or lithium diisopropylamide (LDA) in THF
4b
15
at low temperatures. The imine was prepared from benzaldehyde and LHMDS, and reacted in situ
or purified according to standard methodologies.1
2c,15
Depending on the type of base used and on the
structure of the enolate, different results were obtained.
Figure 1. (2S,5S)-2-(tert-Butyl)-5-methyl-1,3-dioxolan-4-ones 1a and 1b and their lithium enolates (2S)-3a and (2S)-3b
2.1. Reaction of enolate (2S)-3a and imine 2
2.1.1. Reaction with LHMDS
Best results were obtained when LHMDS, HMPA and a THF solution of dioxolanone 1a were
sequentially added at −90°C to an excess of aldimine 2 (THF:HMPA=85:15). The reaction gave an 8.8:1
0
0
mixture of imino-dioxolanone derivatives (1 S,2S,5R)-4 and (1 R,2S,5R)-5 (Scheme 2). The mixture
of compounds 4 and 5 was directly hydrolyzed with 1N HCl at 20°C affording the amino-lactones
0 0
16
(
1 S,2S,5R)-6 (37%) and (1 R,2S,5R)-7 (4%). MeMgBr-induced cyclization of amino-lactone 6 under
17
Birkofer conditions gave the β-lactam (3R,4S)-8 in 68% yield.
Scheme 2. Synthesis of β-lactams 8 and 9. Reagents and conditions: (i) LHMDS, THF:HMPA=85:15, −90°C, 4 h; (ii) HCl 1N,
acetone:H O=1:1, 20°C, 6 h; (iii) K CO , 20°C, 1 h; (iv) MeMgBr, Et O, 25°C, 1 h
2 2 3 2

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G. Barbaro et al. / Tetrahedron: Asymmetry 10 (1999) 2765–2773
Chiral HPLC analysis showed that amino-lactones 6 and 7 were obtained in 94% enantiomeric excess
ee), corresponding to that expected on the basis of the diastereomeric excess (de) of the starting
(
dioxolanone 1a. This result indicated that the cycloaddition occurred under total facial diastereocontrol.
The electrophilic imine approaches the enolate from the face opposite to the tert-butyl substituent
(
Scheme 2) in agreement with the mechanism proposed by Seebach for the addition of electrophiles to
18
0
enolates having (2S)-chirality. The relative 1 S,2S,5R stereoconfiguration of compound 6 was assessed
by X-ray analysis whose ORTEP drawing is reported in Fig. 2. The sign (positive) of the circular
dichroism band of (3R,4S)-8 at 225 nm allowed the assessment of its absolute configuration.1 Moreover,
the β-lactam (3R,4S)-8 was chemically correlated with its ODMPS derivative (3R,4S)-10 (Scheme 3)
which has been synthesized by Ojima via a different route.11
2b
0
Figure 2. ORTEP of (1 S,2S,5R)-6
Scheme 3. (3R,4S)-β-Lactam 10
2.1.2. Reaction with LDA
Next, we investigated the reaction of aldimine 2 with enolate 3a using LDA as the base in the
mixed solvent THF:HMPA=85:15. The addition reaction proved to be non-reproducible. In fact, variable
mixtures of 3-hydroxy- and 3-trimethylsilyloxy-3-methyl-4-phenyl-β-lactams and imino-dioxolanones 4
and 5 were obtained in low yields with deleterious competing side reactions.19
2.2. Reaction of enolate (2S)-3b and imine 2
2.2.1. Reaction with LHMDS
Aldimine 2 was added at −90°C to the enolate of dioxolanone 1b obtained with LHMDS
in a THF:HMPA=85:15 mixed solvent. The reaction gave a mixture of imino-dioxolanones

G. Barbaro et al. / Tetrahedron: Asymmetry 10 (1999) 2765–2773
2769
0
0
0
(
1
(
1 S,2S,5R)-11:(1 R,2S,5R)-12=2:1 (22%), a mixture of the corresponding amino-lactones (1 S,2S,5R)-
0
3:(1 R,2S,5R)-14=9:1 (4%) (Fig. 3), a mixture of β-lactams (3R,4S)-8:(3R,4R)-9=4:1 (7%), and
3R,4S)-15:(3R,4R)-16=10:1 (44%) (Fig. 4).
0
0
Figure 3. (2S,5R)-1 -Imino-dioxolanones 11, 12 and (2S,5R)-1 -amino-dioxolanones 13, 14
Figure 4. β-Lactams 15, 16
2
.2.2. Reaction with LDA
Aldimine 2 was slowly added to the enolate 3b obtained with LDA in the mixed solvent
THF:HMPA=85:15 at −90°C. The reaction gave a mixture of the β-lactams (3R,4S)-15:E:(3R,4R)-
0
0
1
6=6:1 (63%) and a 1:1 mixture of β-imino-lactones (1 S,2S,5R)-11 and (1 R,2S,5R)-12 (6%).
20
Compound 15 was isolated by column chromatography (SiO , n-pentane:EtOAc, 8:2). Alternatively,
2
TBAF-induced O-desilylation of the crude reaction mixture, followed by chromatography, allowed the
isolation of the β-lactams (3R,4S)-8 (59%) and (3R,4R)-9 (9%). It is worth noting that the reaction
occurred with total enantiofacial selectivity. In fact, β-lactams (3R,4S)-15 and (3R,4R)-16 were obtained
in 86% ee which is identical to the expected one on the basis of the de of the starting dioxolanone 1b.
3. Conclusion
The above-described methodology appears to be a fairly direct approach to the synthesis of (3R,4S)-
β-lactams 15 and 8 when they are synthesized from enolate 3b using LDA as the base. In fact, 15 or
are obtained in good yields and with good Z:E diastereoselectivity (86:14). This is due to the greater
8
stability of enolate 3b compared to enolate 3a in the presence of LDA. The methodology is quite useful to
achieve complete (3R)-stereocontrol in the β-lactams since the single (1S,2S)-diastereomer of the starting
reagents 1a and 1b can be easily obtained via recrystallization from pentane at −78°C1 and the addition
reaction of the corresponding enolates 3a and 3b to imine 2 occurs from the face opposite to the tert-
butyl substituent with full control of stereochemistry. The use of LHMDS as the base seems to inhibit the
cyclization process, thus favoring the formation of the β-imino-dioxolanones with both enolates 3a and
4b
3
b. It is worth noting that β-imino-dioxolanones are in turn suitable intermediates for the synthesis of
β-lactams via their facile hydrolysis to the corresponding amino-lactones followed by MeMgBr-induced
cyclization.

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G. Barbaro et al. / Tetrahedron: Asymmetry 10 (1999) 2765–2773
4. Experimental
Solvents were dried according to published methods and distilled prior to use. All other reagents
1
were commercially available compounds of highest purity. Melting points are uncorrected. H and
13
C NMR spectra were recorded on a 200 MHz VXR Varian spectrometer with Me Si or CHCl (in
4
3
CDCl ) as internal standards. Mass spectra were recorded on a Finnigan ion trap spectrometer with
3
an ionization potential of 70 eV. Infrared spectra were recorded on a Nicolet 205-FT spectrometer.
The dioxolanones were prepared according to the literature and were purified by distillation under
vacuum. N-Trimethylsilylphenyl aldimine 2 was prepared according to literature procedures.15 The
HPLC system consisted of a Jasco PU 980 pump. UV and CD detection were obtained by a Jasco
MD-910 multiwavelength detector and a Jasco J 710 spectropolarimeter. Enantioselective analysis was
performed on a Chiralcel OD column (Daicel 25×0.46 cm, I.D.). The mobile phase was n-hexane:2-
propanol (97.5:2.5, v/v), at 1 mL/min, with UV and CD detection at 230 nm. CD spectra of (3R,4S)-β-
lactams 8 and 15 (8 mM, solvent 2-propanol, 0.1 mm cell, room temperature) were obtained on a Jasco
J 600 spectropolarimeter.
0 0 0 0
.1. (1 S,2S,5R)- and (1 R,2S,5R)-2-(tert-Butyl)-5-(1 -benzylideneamino-1 -phenylmethyl)-5-methyl-
,3-dioxolan-4-ones [(1 S,2S,5R)-4 and (1 R,2S,5R)-5]
4
1
0
0
A THF solution (10 mL) of benzaldehyde (0.8 g, 7.83 mmol, 1 equiv.) was added to a THF solution
(10 mL) of LHMDS (1.2 equiv.) at −10°C. Trimethylchlorosilane (7.80 mmol, 1.0 equiv.) was added
after 20 min under stirring at 0°C. The resulting solution was cooled at −90°C and 3.8 mL of 1.0
M THF solution of LHMDS and 7.0 mL of HMPA were sequentially added. Finally, a THF solution
(9.0 mL) of dioxolanone 1 (0.15 g, 3.16 mmol) was added over 4.0 h at −90°C via a syringe pump
under stirring. The reaction mixture was treated with an aqueous solution of NH Cl. The organic layer
4
was extracted two times with brine, dried over Na SO , and the solvent evaporated under reduced
2
4
0
0
1
pressure. The (1 S,2S,5R):(1 R,2S,5R)=8.8:1 product distribution was calculated by H NMR analysis
of the residue. Chromatography (SiO , EtOAc:n-hexane, 1:10) gave 0.45 g (1.28 mmol, 40.6%) of a
2
0
0
−1
+
mixture of (1 S,2S,5R)-4 and (1 R,2S,5R)-5. IR (CDCl ) cm : 1780, 1643; MS, m/z 351 (M ), 336, 307,
3
2
94, 238, 194. Anal. calcd for C H NO : C, 75.19; H, 7.17; N, 3.99. Found: C, 75.05; H, 7.11; N, 4.06.
22 25 3
0
1
(
1 S,2S,5R)-4: H NMR (CDCl ): δ 0.98 (s, 9H), 1.32 (s, 3H), 4.65 (s, 1H), 5.64 (s, 1H), 7.25–7.90 (m,
3
13
1
1
4
3
0H), 8.17 (s, 1H); C NMR (CDCl ): δ 21.4, 23.4, 34.5, 79.2, 83.4, 110.5, 128.1, 128.3, 128.4, 128.6,
3
0
1
29.6, 131.1, 163.2, 175.7. (1 R,2S,5R)-5: H NMR (CDCl ): δ 0.86 (s, 9H), 1.39 (s, 3H), 4.69 (s, 1H),
3
.58 (s, 1H), 7.25–7.90 (m, 10H), 8.31 (s, 1H); 13C NMR (CDCl ) relevant resonances at: δ 21.0, 23.3,
3
4.6, 80.2, 82.8, 109.5, 163.3, 174.1.
0 0 0 0
.2. (1 S,2S,5R)- and (1 R,2S,5R)-2-(tert-Butyl)-5-(1 -amino-1 -phenylmethyl)-5-methyl-1,3-dioxolan-
-ones [(1 S,2S,5R)-6 and (1 R,2S,5R)-7]
4
4
0
0
0
0
An 8.8:1 mixture of (1 S,2S,5R)-4 and (1 R,2S,5R)-5 (0.60 g, 1.70 mmol) in 5.0 mL of acetone was
treated at 20°C with 5.0 mL of a 1N aqueous solution of HCl under stirring for 6 h. The reaction mixture
was diluted with 30 mL of acetone and the lactone amine chloridrate was filtered. The crude material was
dissolved in 10 mL of an aqueous solution of 0.12 g of K CO and stirred for 1 h. The aqueous solution
2
3
was extracted with CH Cl . The organic layer was dried over Na SO , and the solvent evaporated under
2
2
2
4
0
reduced pressure. Chromatography (SiO , n-pentane:EtOAc, 2:1) gave 0.264 g of (1 S,2S,5R)-6 (37%)
and 0.032 g of (1 R,2S,5R)-7 (4%). (1 S,2S,5R)-6: mp 66–67°C; H NMR (CDCl ): δ 0.95 (s, 9H), 1.23
s, 3H), 1.70 (b, 2H), 4.07 (s, 1H), 5.30 (s, 1H), 7.30–7.40 (m, 5H); C NMR (CDCl ): δ 22.2, 23.3, 34.8,
2
0
0
1
3
13
(
3

G. Barbaro et al. / Tetrahedron: Asymmetry 10 (1999) 2765–2773
2771
−1
6
(
5
3
6
2.1, 83.6, 110.8, 127.8, 128.0, 128.5, 141.2, 176.0; IR (CDCl ) cm : 3500–3400, 1778; [α]D25=+68.2
3
+
c=1.37, CDCl ); MS, m/z 263 (M ), 219, 207, 106. Anal. calcd for C H NO : C, 68.42; H, 8.04; N,
3
15 21
3
0
1
.32. Found: C, 68.55; H, 8.11; N, 5.23. (1 R,2S,5R)-7: oil; H NMR (CDCl ): δ 0.86 (s, 9H), 1.49 (s,
3
13
H), 2.0 (b, 2H), 4.20 (s, 1H), 4.64 (s, 1H), 7.30–7.40 (m, 5H); C NMR (CDCl ): δ 21.2, 23.2, 34.6,
3
0.3, 83.3, 109.6, 127.8, 128.1, 128.3, 140.1, 174.6; [α]D25=+44.9 (c=1.60, CDCl3).
0
4
.3. Reaction of amino-dioxolanone (1 S,2S,5R)-6 and MeMgBr
0
MeMgBr (3.0 M in Et O, 0.6 mL, 1.8 mmol) was added to a solution of (1 S,2S,5R)-6 (0.15 g, 0.57
2
mmol in 4 mL of Et O) at 0°C. The mixture was stirred at 25°C for 60 min. There was obtained 0.069 g
2
(0.39 mmol, 68%) of (3R,4S)-8.
4.4. Reaction of enolate 3b and aldimine 2
A solution of 2.9 mmol of dioxolanone 2b (cis:trans=93:7) in 6.0 mL of THF was added at −78°C to a
solution of 4.35 mmol of LDA in 13.0 mL of THF. After 30 min the reaction mixture was cooled to −90°C
and 5.0 mL of HMPA and 4.20 mmol of imine 2 were sequentially added over 60 min. The temperature
was allowed to warm up to −60°C over a period of 2 h. The reaction was quenched at this temperature
with a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The
1
organic layer was dried over Na SO , and the solvent evaporated under reduced pressure. A H NMR
2
4
spectrum of the crude reaction mixture revealed the presence of a mixture of (3R,4S)-15:E:(3R,4R)-
0
0
1
6=6:1, and trace amounts of a 1:1 mixture of β-imino-lactones (1 S,2S,5R)-11 and (1 R,2S,5R)-12. The
TBAF-induced O-desilylation of the crude reaction mixture followed by chromatography allowed the
isolation of the β-lactams (3R,4S)-8 (59%) and (3R,4R)-9 (9%).
4.5. (3R,4S)- and (3R,4R)-3-Hydroxy-3-methyl-4-phenyl-β-lactams [(3R,4S)-8 and (3R,4R)-9]
−
1
1
(
3R,4S)-8 from 1b: mp 171–173°C; IR (CDCl ) cm : 3650, 3411, 1771; H NMR (CD COCD ):
3 3 3
13
δ 1.58 (s), 2.75–2.85 (b, 1H), 4.61 (s, 1H), 7.20–7.60 (m, 6H); C NMR (CD COCD ): δ 22.7, 65.6,
3
3
+
8
6.8, 128.2, 128.8, 139.1, 172.1; [α]D25=+101 (c=0.5, CD COCD ); MS, m/z 177 (M ), 134, 106. Anal.
3
3
calcd for C H NO : C, 67.75; H, 6.25; N, 7.90. Found: C, 67.84; H, 6.12; N, 7.83. (3R,4R)-9 from 1b:
H NMR (CD COCD ): δ 0.89 (s, 3H), 2.75–2.85 (b, 1H), 4.64 (s, 1H), 7.20–7.60 (m, 6H); C NMR
CD COCD ): δ 19.0, 66.3, 88.0, 126.8, 128.3, 129.3, 139.2, 172.3.
10
11
2
1
13
3
3
(
3
3
4.6. (3R,4S)-3-Dimethylphenylsilyloxy-3-methyl-4-phenyl-β-lactam [(3R,4S)-10]
A CH Cl solution (5 mL) of a mixture of β-lactam (3R,4S)-8 (0.05 g, 0.28 mmol), chlorodimethyl-
2
2
phenylsilane (0.09 g, 0.53 mmol), triethylamine (0.08 g, 1.30 mmol) and 4-(dimethylamino)pyridine
(0.005 g, 0.04 mmol) was reacted under stirring at 25°C for 5 h. The reaction mixture was treated with
an aqueous solution of NH Cl. The organic layer was extracted two times with brine, dried over Na SO ,
4
2
4
and the solvent evaporated under reduced pressure. Chromatography (SiO , EtOAc:n-hexane, 1:10) gave
2
−1
1
0
0
0
.078 g (0.25 mmol, 91%) of (3R,4S)-10: oil; IR (CDCl ) cm : 1765; H NMR (CDCl ): δ 0.18 (s, 3H),
3
3
13
.31 (s, 3H), 1.62 (s, 3H), 4.55 (s, 1H), 6.30 (bs, 1H), 7.20–7.40 (m, 10H); C NMR (CDCl ): δ −0.1,
3
25
.2, 23.3, 40.9, 65.8, 87.5, 127.4, 127.5, 127.9, 128.2, 129.3, 133.2, 137.0, 138.3, 172.0; [α]D =+30
+
(c=0.5, CDCl ); MS, m/z 311 (M ), 268, 176. Anal. calcd for C H NO Si: C, 69.41; H, 6.80; N,
3 18 21 2
11
−1
4.50. Found: C, 69.84; H, 6.72; N, 4.56. Lit. (private communication): oil; IR (neat) cm : 1763.5,
1
1235.7, 1120.5; H NMR (CDCl ): δ 0.16 (s, 3H), 0.30 (s, 3H), 1.62 (s, 3H), 4.54 (s, 1H), 6.58 (bs, 1H),
3

2772
G. Barbaro et al. / Tetrahedron: Asymmetry 10 (1999) 2765–2773
7
1
.17–7.38 (m, 10H); 13C NMR (CDCl ): δ −0.1, 0.2, 23.3, 40.9, 65.8, 87.5, 127.4, 127.5, 127.9, 128.2,
3
20
29.3, 133.2, 137.0, 138.3, 172.0; [α]D =+31.1 (c=0.74, CHCl3).
4
.7. (3R,4S)- and (3R,4R)-3-Trimethylsilyloxy-3-methyl-4-phenyl-β-lactams [(3R,4S)-15 and
(3R,4R)-16]
−
1
1
(
3R,4S)-15 from 1b: mp 86–88°C; IR (CDCl ) cm : 1764, 1236; H NMR (CDCl ): δ −0.09 (s, 9H),
3
3
13
1
1
.64 (s, 3H), 4.50 (s, 1H), 6.4–6.8 (b, 1H), 7.20–7.60 (m, 5H); C NMR (CDCl ): δ 1.1, 23.3, 65.8, 87.3,
3
25
+
27.5, 127.8, 127.9, 137.1, 171.6; [α]D =48.0 (c=0.79, CDCl ); MS, m/z 249 (M ), 234, 206, 191, 73.
3
Anal. calcd for C H NO Si: C, 62.71; H, 7.68; N, 5.62. Found: C, 62.84; H, 7.72; N, 5.53. (3R,4R)-16:
13
19
2
1
H NMR (CDCl ): δ 0.25 (s, 9H), 1.00 (s, 3H), 4.63 (s, 1H), 6.30–6.40 (b, 1H), 7.20–7.40 (m, 5H).
3
4.8. X-Ray crystallography
0
Analyses were carried out on a single crystal of (1 S,2S,5R)-6 obtained after slow evaporation of
an ethyl acetate solution. Crystal data were collected at 293 K using an Enraf–Nonius CAD4 single
crystal diffractometer with Mo-Kα radiation (λ=0.71073 Å). The structure was solved by direct methods
2
using SHELXS. Refinements were carried out by full-matrix least squares of F for all 2367 data using
SHELXL-97. The refined Flack parameter did not allow the unambiguous experimental assignment of
the absolute structure.
0
(
1 S,2S,5R)-6 (C H NO , M=263.33) monoclinic, space group P2 , a=8.478(2) Å, b=6.3715(5) Å,
15
21
3
1
3
3
−1
c=14.363(4) Å, β=103.00(2)°, V=756.0(3) Å , Z=2, D =1.157 g/cm , µ(Mo-Kα)=0.080 mm , final R1,
c
wR2 and S are 0.058, 0.148 and 1.02 for 177 parameters and 1418 unique observed reflections with
I>2σ(I). Tables of crystal data and structural refinement, final positional parameters, anisotropic thermal
parameters, bond lengths and angles are available as supplementary material.
References
1
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1
15. Colvin, E. W.; McGarry, D.; Nugent, M. J. Tetrahedron 1988, 44, 4157–4172.
16. Trace amounts (<5%) of a mixture of (3R,4S)- and (3R,4R)-3-hydroxy-3-trimethylsilyl-hydroxy-4-phenyl-β-lactams were
also formed.
1
7. Birkofer, L.; Schramm, J. Liebigs Ann. Chem. 1975, 2195.
0
18. Compound (1 R,2S,5R)-5 is formed through a Zimmermann–Traxler transition state with the hydrogen of the imine, rather
0
than the phenyl substituent, over the face of the dioxolanone ring. The formation of (1 S,2S,5R)-4 as the major isomer may
be due to the steric repulsion between the methyl substituent of the enolate of (2S,5S)-1a and the phenyl substituent of the
imine 2. See: Zimmermann, H.; Traxler, M. J. Am. Chem. Soc. 1957, 79, 1920.
19. For a detailed description of these side products see: (a) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313–1324; (b) see Ref. 12c.
2
0. It is worth noting that the O-TMS protected β-lactam 15 can be easily transformed into the corresponding N-t-Boc-
protected 2-methyl-phenylisoserine methyl ester via acylation at the nitrogen atom with di-tert-butyl dicarbonate followed
by methanolysis. See Ref. 11.