New enantiomerically enriched amino allyl- and allenylsilanes derived from naturally occurring amino acids

Tetrahedron: Asymmetry 19 (2008) 2882–2886

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New enantiomerically enriched amino allyl- and allenylsilanes derived from naturally occurring amino acids Gianna Reginato *, Alessandro Mordini, Alice Tenti, Michela Valacchi  , Julie Broguiere CNR ICCOM—Dipartimento di Chimica Organica ‘U. Schiff’ Università di Firenze, via della Lastruccia, 13, 50119 Sesto Fiorentino, Italy

a r t i c l e

i n f o

Article history: Received 16 October 2008 Accepted 10 December 2008 Available online 29 January 2009

a b s t r a c t Some enantiomerically enriched Z-amino allylsilanes and allenylsilanes have been obtained selectively through the synthetic elaboration of naturally occurring amino acids. Fluorodesilylation with SelectfluorÒ has been proved as an easy way for preparing allylic fluorides bearing an amino or an amino acid moiety on the lateral chain. In particular, a new unsaturated fluorinated amino acid has been obtained, albeit as a diastereomeric mixture. Ó 2009 Elsevier Ltd. All rights reserved.

1. Introduction Allylsilanes have proved to be very versatile silicon-containing carbon nucleophiles, often showing a high level of stereocontrol in reactions with electrophiles.1,2 The exploitation of these reagents in the synthesis of complex molecular structures is obviously related to their availability as multifunctional and enantiomerically enriched compounds, and this prompted the development of a number of preparative methods which have been reported and used successfully.3 Naturally occurring amino acids have been used, for instance, for the preparation of chiral amino silanes,4,5 and recently we have shown a very efficient way for obtaining enantiomerically enriched allysilanes bearing an amino acid moiety, using commercially available L-serine as starting material.6 Our approach is based on the silylcuprate displacement of an allylic acetate, a well-established procedure for allylsilanes synthesis.7 The reaction is anti stereospecific, and was performed on acetate 2a to provide oxazolidine 3a in high yield and selectivity, as a direct precursor of the desired E-amino acid 4 (Scheme 1). Aminosilanes can be of great interest for their biological activity, given that some silylated derivatives have been recently developed in order to exploit new opportunities of silicon chemistry for drug design.8 Moreover, they can be regarded as highly valuable optically active starting materials. Compound 3a, for instance, has been recently shown as a key intermediate for the synthesis of fluorinated sphingosine analogues via fluorodesilylation.9 It was prepared, in reasonable yield, from (S)-Garner’s aldehyde following a two-step procedure based on Wittig olefination and

N

1) ClMg

Boc

O

0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2008.12.025

Boc

O

O 1

OAc

2a

(Me3Si)2CuLi*CuCN

Boc NHBoc MeO

N O

SiMe 3 O

SiMe 3

4

3a Scheme 1.

cross-metathesis, albeit with 6/1 selectivity. Compared with the reported data, our procedure represents a real improvement as the final allylsilane is obtained with high diastereomeric purity. This prompted us to extend our procedure to the synthesis of two new aminoallylsilanes and to verify if a similar approach could be also applied to the synthesis of allenylsilanes, using a propargyl acetate as starting material (Scheme 2).

N

Boc

(Me3Si)2CuLi*CuCN

N O

O OAc

Boc

H SiMe3

• 6

5 * Corresponding author. Tel.: +39 0554573558; fax: +39 0554573580. E-mail address: gianna.reginato@unifi.it (G. Reginato).   Present address: Medicinal Chemistry 1, SienaBiotech S.p.A, via Fiorentina, 153100 Siena, Italy.

N

2) CH3COCl, Et3N

Scheme 2.

Finally, since fluorodesilylation of allylsilanes with SelectfluorÒ has been established as a very efficient and useful process,10 and

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fluorinated compounds have a remarkable importance in medicinal chemistry,11 we decided to test the reactivity of our substrates, aiming to show an easy way to prepare allylic fluorides bearing an amino or an amino acid moiety on the lateral chain (Scheme 3).

NHBoc SiMe 3

R

NHBoc

Selectfluor R R

F

R = COOMe, CH(CH3 )2 , CH 2Ph Scheme 3.

2. Results and discussion Amino aldehydes have been prepared as reported,12 starting from commercially available t-Boc protected L-valine and L-phenylalanine. According to the literature data,13 addition of vinyl magnesium chloride onto aldehydes and esterification with acetylchloride gave acetates 2b,c with low selectivity (syn:anti = 60:40), good yields and without racemization (Scheme 4).

NHBoc R

NHBoc

NHBoc

COOH

N

R

R O 1b,c

R=

It is known that silylcupration of propargylic acetates affords stereospecifically allenylsilanes via an anti-SN2 process.1 Thus silylcupration of anti-5 gave allene (R,R)-6 as the only isomer, which could be clearly identified in the crude mixture by recording the 1H NMR experiment at 50 °C, in order to obtain the averaged spectrum of the slowly interconverting rotamers. Pure (R,R)-6 was then obtained in 44% yield after purification and full characterization. However, analysis of the crude mixture revealed the presence of some by-products due to a second addition of silylcuprate on allene 6.18 Two products of syn addition were clearly distinguished in the 1H NMR spectra by the chemical shift of the olefinic proton, from which the geometry of the double bond could be easily determined by comparison with data reported in the literature for similar compounds (Scheme 6).19 Compound 7, bearing both an allyl and a vinylsilane moiety on the lateral chain of the oxazolidine ring, might be of high synthetic value. In order to select optimal conditions, we then performed the reaction using an excess of silylcuprate and leaving the reaction mixture for 4 h at room temperature. These conditions allowed us to recover compound 7 as the major product and to isolate it in 54% yield, after purification (Scheme 7).

MgBr

OAc 2b,c

CH3COCl

NHBoc

N

R

Boc

O

3b,c

(Me3Si)2CuLi*CuCN (1eq) -78°C, 30 min

SiMe3

Boc

H

•

(R,R)-6

OAc syn-5

Scheme 4.

N O

OAc anti-5

(Me3Si)2CuLi*CuN

1c = (Phe)

(Me3Si)2CuLi*CuCN (1eq) -78°C, 10 min

O

1b =(Val)

SiMe3

Boc

N

[α]24 = -168.1 D (c 1.16, CHCl3 ) Boc

O

H SiMe 3

•

not 24 (R,S)-6 [α] D = recorded Scheme 6.

As expected, trimethylsilyl cyanocuprate reacted at low temperature with acetates 2b,c to afford, after hydrolytic work-up, allylsilanes 3b,c as a 95/5 mixture of E and Z isomers, as determined by 1H NMR analysis of the crude mixture. From this crude, pure isomers 3b,c were obtained in 68% and 74% yield after chromatography. The double bond trans geometry was easily confirmed from the coupling constant of 15.3 and 15.4 Hz, for 3b and 3c, respectively, that we observed for the olefinic protons in the 1H NMR spectra. To verify if this approach could also be extended to the synthesis of allenylsilanes, we prepared propargylic acetate 5 using (S)-Garner aldehyde14,15 1a as a starting material. Addition of commercially available ethynyl-MgCl was performed in the presence of anhydrous ZnBr2 as chelating agent, in order to raise the amount of the syn isomer.16,17 Under these conditions, no selectivity was observed, and a 1:1 diastereomeric mixture of syn and anti propargylic alcohols was obtained. These were converted into the corresponding acetates and were separated by flash column chromatography (Scheme 5).

N

Boc

O

O

Boc MgBr

1a O

O

N

ZnBr2

Boc O OH

syn- 5 [α]24 D = -29.2 (c 1.0,CHCl3 )

(CH3CO)2O Et3N, DMAP

N

Boc

5 OAc syn/anti=1/1

anti-5 [α]25 = -90.8 (c 1.0,CHCl3 ) D

Scheme 5.

N

Boc

SiMe3

O SiMe 3

OAc

anti-5

7 Scheme 7.

Finally, silylcupration of syn-5 gave allene (R,S)-6 (Scheme 6), however, this isomer resulted to be less stable and slowly decomposed, even at 0 °C. Fluorodesilylation of allylsilanes 3b–c and 4 was then carried out. The reaction with SelectfluorÒ in acetonitrile in the presence of Na2CO3 occurred smoothly at room temperature and afforded the corresponding allyl fluorides anti-8a–c and syn-8a–c with high yield. In all cases the two diastereoisomers were formed, as expected, as roughly a 1:1 mixture (Scheme 8).20

NHBoc N

(Me3Si)2CuLi*CuCN (1.5 eq) -78°C to RT

R

Selectfluor R SiMe3 R

NHBoc

3b,c and 4

a = CH(CH 3) 2 98% b = CH 2Ph 97% F 8a-c c = COOMe 68%

Scheme 8.

To the best of our knowledge, the procedure reported here is the most expeditious route to these compounds.21 Unfortunately, the mixture of diastereoisomers 8a–c could not be separated using standard chromatographic techniques.

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Recent studies with fluorinated amino acids have shown that these compounds are useful tools in proteins and peptidomimetics design.22,23 To demonstrate that fluoro amino ester 8c is capable of undergoing typical reactions associated with peptide synthesis we tried to hydrolyze the ester in the presence of LiOH, but only compound 9, derived by HF elimination, was recovered. To circumvent this problem, oxazolidine 10 was prepared by reaction of allylsilane 3a with SelectfluorÒ and then deprotected with TFA and oxidized with HIO3/CrO324 to give the corresponding amino acid (Scheme 9). The crude compound showed sufficient purity for further uses and was coupled with PheOMeHCl in the presence of the EDC/HOBT coupling system. Finally, dipeptide 11 was recovered as a roughly 1:1 diastereomeric mixture, in 30% overall yield after chromatography.

NHBoc

NHBoc

TFA HIO3/CrO3

O

HOOC

MeOOC F

F

8c

PheOMe*HCl EDC/HOBT, DMF

LiOH NHBoc MeOOC 9

O MeOOC

NBoc F 10

F

NH NHBoc

11

Scheme 9.

3. Conclusion In conclusion, we have reported the synthesis of two new chiral amino allylsilanes through the silylcuprate displacement of allylacetates derived from amino acids and shown that this synthetic approach can be extended to the synthesis of chiral allenylsilanes. Moreover, a new unsaturated, fluorine containing amino acid has been obtained, albeit as a diastereomeric mixture. The transformation of serine derived allenylsilanes to the corresponding amino acid and its further synthetic elaboration are currently under investigation. 4. Experimental 4.1. General methods and materials Starting materials 2b,25,26 2c,25,13 1a,15 3a6 and 46 were prepared according to the literature. All reactions were carried out under a positive pressure of dry nitrogen. THF was dried by distillation over sodium benzophenone ketyl. Ethereal extracts were dried with Na2SO4. Reactions were monitored by TLC on SiO2; detection was made using a KMnO4 basic solution. Flash column chromatography27 was performed using glass columns (10– 50 mm wide) and SiO2 230–400 mesh. Petroleum ether, unless specified, is the 40–70 °C boiling fraction. 1H NMR spectra were recorded at 200 or 400 MHz. 13C NMR spectra were recorded at 50.3 or 100 MHz. 19F NMR were recorded at 188 MHz. Chemical shifts were determined relative to the residual solvent peak (CHCl3 d 7.26 for 1H NMR; CHCl3 d 77.0 for 13C NMR). For those compounds which are present as slowly interconverting rotamers, 1H NMR experiments were performed at 50 °C (CDCl3) and signals of the averaged spectrum are reported when possible. Coupling constants (J) are reported in Hertz. When necessary, J value has been obtained through selective decoupling. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br s

(broad singlet) and br m (broad multiplet). Mass spectra were obtained at a 70 eV ionization potential and are reported in the form m/z (intensity relative to base = 100). Polarimetric measurements were performed in CHCl3 solution at k = 589 nm, and the temperature is specified case by case. 4.2. General procedure for acetate displacement for the synthesis of allylsilanes Trimethylsilylcyanocuprate was prepared according to the general route,28 using hexamethyldisilane (642 mg, 4.4 mmol), MeLi (1,5 mL, 1.6 M solution in THF, 2.2 mmol) and CuCN (94 mg, 1.1 mmol) and was cooled to 78 °C. Amino acetate 2b (270 mg, 1 mol) was dissolved in THF, added at 78 °C and left at this temperature for 30 min. The reaction mixture was hydrolyzed with NH4Cl/NH4OH buffer solution, extracted with Et2O, then washed with brine and dried over Na2SO4. The crude product obtained after evaporation was purified by flash chromatography. 4.2.1. (S,E)-1-Isopropyl-4-trimethylsilanyl-but-2-enyl-carbamic acid tert-butyl ester 3b Acetate 2b (937 mg, 3.5 mmol) was reacted to give, after purification, 668 mg of 3b as a colourless oil (yield: 68%). Eluent: petroleum ether/ethyl acetate = 20/1. 1H NMR (200 MHz) d: 5.62–5.47 [m, 1H]; 5.16–5.05 [ddapp, Jtrans = 15.3 Hz, J = 6.9 Hz, 1H]; 4.60–4.35 [m, 1H]; 3.90–3.76 [m, 1H]; 1.78–1.62 [m, 1H]; 1.45–1.40 [m, 2H]; 1.43 [s, 9H]; 0.87 [d, J = 6.6 Hz, 2H]; 0.01 [s, 9H]. 13C NMR (50.3 MHz) d: 155.1; 128.3; 126.9; 78.7; 58.2; 32.6; 28.4; 22.8; 18.6; 1.8. MS m/e: 242 (23); 73 (100); 57 (87). ½a26 D ¼ 24:5 (c 1.25, CHCl3). Anal. Calcd for C15H31NO2Si: C, 63.10; H, 10.94; N, 4.91. Found: C, 63.22; H, 10.90; N, 4.86. 4.2.2. (S,E)-1-Benzyl-4-trimethylsilanyl-but-2-enyl-carbamic acid tert-butyl ester 3c Acetate 2c (600 mg, 1.9 mmol) was reacted to give, after purification, 464mg of 3c as a colourless oil (yield: 74%). Eluent: petroleum ether/ethyl acetate = 7/1. 1H NMR (200 MHz) d: 7.32–7.09 [m, 5H]; 5.54–5.42 [m, 1H]; 5.21–5.09 [ddapp, Jtrans = 15.4 Hz, J = 6.6 Hz, 1H]; 4.46–4.25 [m, 1H+1H]; 2.90–2.71 [m, 2H]; 1.49–1.31 [m, 2H]; 1.41 [s, 9H]; 0.08 [s, 9H]. 13C NMR (50.3 MHz) d: 154.7; 137.6; 129.2; 128.7; 127.9; 126.5; 125.9; 78.8; 53.7; 42.0; 28.3; 22.6; 1.9. MS m/e: 276 (14); 73 (100); 57 (92). ½a26 D ¼ 8:5 (c 1.17, CHCl3). Anal. Calcd for C19H31NO2Si: C, 68.42; H, 9.37; N, 4.20. Found: C, 68.36; H, 9.32; N, 4.15. 4.3. 2,2-Dimethyl-4-(1-acetoxy-prop-2-inyl)-oxazolidine-3carbamic acid tert-butyl ester 5 Aldehyde 1a (430 mg, 1.9 mmol) was dissolved in dry toluene (15 mL) together with ZnBr2 (430 mg, 2.0 mmol), cooled to 78 °C and reacted with ethynyl magnesium chloride (0.5 M, THF solution, 4.0 mL). The reaction mixture was warmed to room temperature and stirred overnight, then quenched with a NH4Cl saturated solution (30 mL), extracted with ether and dried. After evaporation of the solvent crude alcohol was obtained as a 1:1 diastereomeric mixture. The crude was dissolved into CH2Cl2 (10 mL), cooled to 0 °C and reacted with triethylamine (225 mg, 2.2 mmol), DMAP (10 mg) and acetic anhydride (200 mg, 2.3 mmol) for 3 h. After hydrolysis with a NaHCO3 saturated solution (20 mL), extraction and washing with brine, the organic phase was dried and evaporated to afford acetate 5 as a 1:1 diastereomeric mixture. The two diastereomers were separated by column chromatography. The purification was performed twice (first eluent: petroleum ether/ethyl acetate = 20/1, second eluent: petroleum ether/ethyl acetate = 10/1) to give 265 mg of (S,R)-anti-5 as a colourless oil (yield: 42%) and 182 mg of (S,S)-syn-5 (yield 29%).

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(S,R)-anti-5: 1H NMR (400 MHz, C6D6, 60 °C) d: 6.23–6.18 [br m, 1H]; 4.23 [br d, J = 7.6 Hz, 1H]; 3.98–3.82 [br m, 1H]; 3.81–3.77 [m, JAB = 8.8 Hz, JAX = 7.4 Hz, 1H]; 1.96 [d, J = 2.4 Hz, 1H]; 1.68 [s, 3H]; 1.58 [br s, 3H; 1.43–1.38 [br m, 3H+9H]. 13C NMR (50.3 MHz) d: 169.4; 152.1; 94.9; 80.7; 78.9; 75.0; 64.2; 62.4; 59.6; 28.4; 25.9; 23.3; 21.0. MS m/e: 238 (16); 59 (63); 57 (100). ½a25 D ¼ 90:8 (c 1.0, CHCl3). Anal. Calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.51; H, 7.73; N, 4.73. (S,S)-syn-5: 1H NMR (400 MHz, C6D6, 60 °C) d: 6.21–6.18 [br m, 1H]; 4.27 [m, JAB = 9.2 Hz, JAX = 2.6 Hz, 1H]; 4.12–3.98 [br m, 1H]; 3.74 [m, JAB = 9.2 Hz, JBX= 3.7 Hz, 1H]; 1.97 [d, J = 2.4 Hz, 1H]; 1.88 [br s, 3H]; 1.66–1.46 [br m, 6H+9H]. 13C NMR (50.3 MHz) d: 168.8; 151.4; 94.9; 80.6; 78.9; 75.1; 63.5; 62.3; 59.1; 28.3; 26.9; 24.6; 20.8. MS m/e: 238 (9); 59 (83); 57 (100). ½a25 D ¼ 29:2 (c 1.00, CHCl3). Anal. Calcd for C15H23NO5: C. 60.59; H, 7.80; N, 4.71. Found: C, 61.57; H, 7.84; N, 4.77. 4.4. (R,R)-2,2-Dimethyl-4-[3-trimethylsilanyl-propa-1,2dienyl]-oxazolidine-3-carbamic acid tert-butyl ester (R,R)-6 Trimethylsilylcuprate (1.1 equiv) was prepared according to the general route,28 and the solution was cooled to 78 °C. Acetate (S,R)-anti-5 (150 mg, 0.5 mmol) was dissolved in THF (2.5 mL) and added dropwise. The reaction mixture was stirred for 10 min. Work-up and purification gave 105mg of (R,R)-6 as a colourless oil (yield: 67%). Eluent: petroleum ether/ethyl acetate = 30/1. 1H NMR (400 MHz, 50 °C) d: 5.12–5.06 [m, JAB = 7.0 Hz, 1H]; 5.03 [m, JAB = 7.0 Hz, J = 5.2 Hz, 1H]; 4.45–4.35 [m, 1H]; 3.97 [m, JAB = 8.6 Hz, JAX = 1.8 Hz, 1H]; 3.86 [m, JAB = 8.6 Hz, JBX = 2.2 Hz, 1H]; 1.47–1.45 [br s, 6H+9H]; 0.10 [s, 9H]. 13C NMR (100.0 MHz, C6D6) d: 208.5; 151.7; 93.3; 86.3; 79.3; 68.1; 65.3; 56.6; 28.4; 26.7; 25.1; -1.0. MS m/e: 311 (2); 73 (11); 57 (100). IR (CCl4, KBr): 1940 cm1. ½a26 D ¼ 168:1 (c 1.16, CHCl3). Anal. Calcd for C16H29NO3Si: C. 61.69; H. 9.38; N. 4.50; Found: C. 61.62; H. 9.33; N. 4.44. 4.5. (R,S)-2,2-Dimethyl-4-[3-trimethylsilanyl-propa-1,2-dienyl]oxazolidine-3-carbamic acid tert-butyl ester (R,S)-6 Trimethylsilylcuprate (1.1 equiv) was prepared according to the general route,28 and the solution was cooled to 78 °C. Acetate (S,S)-syn-5 (80 mg, 0.3 mmol) was dissolved in THF (1.5 mL) and added dropwise. The reaction mixture was stirred for 30 min. Work-up and purification gave 34 mg of (R,S)-6 as a colourless oil (yield: 39%). Compound (R,S)-6 must be stored at 20 °C, as rapidly decomposes at room temperature. Eluent: petroleum ether/ethyl acetate = 30/1. 1H NMR (400 MHz, 50 °C) d: 5.14–4.92 [br m, 2H]; 4.35 [br s, 1H]; 4.02– 3.97 [m, 1H]; 3.87 [m, JAB = 8.8 Hz, JAX = 2.0 Hz, 1H]; 1.51–1.43 [br s, 6H+9H]; 0.11 [s, 9H]. 13C NMR (100.0 MHz, C6D6) d: 203.6; 154.2; 95.2; 93.6; 81.8; 63.9; 61.5; 57.0; 28.3; 26.5; 24.3; -0.4. MS m/e: 310 (1); 73 (23); 57 (100). 4.6. (R,E)-2,2-Dimethyl-4-[2,3-bis-trimethylsilanyl-prop-1enyl]-oxazolidine-3-carbamic acid tert-butyl ester 7 Trimethylsililcuprate (1.5 equiv) was prepared according to the general route,28 and the solution cooled to 78 °C. Acetate (S,R)anti-5 (80 mg, 0.3 mmol) was dissolved in THF (1.5 mL) and added dropwise. The reaction mixture was warmed to room temperature and stirred for 4 h. Work-up and purification gave 54 mg of 7 as a pale yellow oil (yield 54%). Eluent: petroleum ether/ethyl acetate = 40/1. 1H NMR (400 MHz, 50 °C) d: 5.60 [d, J = 9.2 Hz, 1H]; 4.57–4.49 [br m, 1H]; 4.06 [m, JAB = 8.4 Hz, JAX = 6.0 Hz, 1H]; 3.65 [m, JAB =8.4 Hz, JBX=

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2.8 Hz, 1H]; 1.47–1.43 [br s, 6H+9H]; 1.28 [br s, 2H], 0.08 [s, 9H]; 0.02 [s, 9H]. 13C NMR (50.0 MHz) d: 151.7; 139.8; 135.6; 79.6; 68.8; 63.8; 54.8; 28.7; 27.0; 24.2; 0.2; 0.8. MS m/e: 312 (5); 73 (100); 57 (81). ½a26 D ¼ þ89:8 (c 1.00, CHCl3). Anal. Calcd for C19H39NO3Si2: C, 59.17; H, 10.19; N, 3.63. Found: C, 59.25; H, 9.98; N, 3.66. 4.7. General procedure for fluorination with Selectfluor Allylsilane 3 or 4 (1 equiv) was dissolved into acetonitrile (5 mL) and reacted at room temperature with SelectfluorÒ (1.1 mmol) and NaHCO3 for 18 h. The solvent was evaporated and the crude filtered on SiO2. 4.7.1. (1S),(2S,R)-2-Methyl-3-tert-butoxycarbonylamino-4fluoro-5-hexene 8a Allylsilane 3b (96 mg, 0.3 mmol) gave 75 mg of fluoride 8a as a 60/40 diastereomeric mixture. Oil (yield 98%). 4.7.1.1. Major diastereoisomer. 1H NMR (400 MHz) d: 5.98–5.79 [m, 1H]; 5.43–5.25 [m, 2H]; 4.86 [dm, JHF = 47.6 Hz, 1H]; 4.55 [br d, J = 9.6 Hz, 1H], 3.76–3.67 [m, 1H]; 2.01–1.93 [m, 1H]; 1.42 [s, 9H], 0.94 [d, J = 6.8 Hz, 3H]; 0.89 [d, J = 6.8 Hz, 3H]. 13C NMR (50.0 MHz) d: 155.6; 133.0 (d, JCF = 78.8 Hz]; 118.3 (d, JCF = 48.6]; 91.4 (d, JCF = 215.6 Hz); 79.3; 57.3 (d, JCF = 91.0 Hz); 29.7; 28.4; 20.4. 19F NMR (200 MHz) d: 187.8. MS m/e: 172 (9); 57 (100). 4.7.1.2. Minor diastereoisomer. 1H NMR (400 MHz) d: 5.98–5.79 [m, 1H]; 5.43–5.25 [m, 2H]; 5.06 [dm, JHF = 47.6 Hz, 1H]; 4.64 [br d, J = 9.4 Hz, 1H]; 3.53–3.49 [m, 1H]; 1.89–1.80 [m, 1H]; 1.41 [s, 9H]; 1.00 [d, J = 6.8 Hz, 3H]; 0.96 [d, J = 6.8 Hz, 3H]. 13C NMR (50.0 MHz) d: 155.6; 133.9 (d, JCF = 78.8 Hz]; 117.5 (d, JCF = 48.6]; 93.3 (d, JCF = 215.6 Hz); 79.1; 58.5 (d, JCF = 91.0 Hz); 30.5; 28.4; 17.1. 19F NMR (200 MHz) d: 196.3. MS m/e: 172 (5); 57 (100). Anal. Calcd for C12H22FNO2: C, 62.31; H, 9.59; N, 6.06; Found: C, 62.26; H, 9.56; N, 6.04. 4.7.2. (1S),(2S,R)-1-Phenyl-2-tert-butoxycarbonylamino-3fluoro-4-pentene 8b Allylsilane 3c (218 mg, 0.6 mmol) gave 177 mg of fluoride 8b as a 60/40 diastereomeric mixture. White solid (yield 97%). 4.7.2.1. Major diastereoisomer. 1H NMR (200 MHz) d: 7.31–7.20 (m, 5H); 5.96–5.71 [m, 1H]; 5.38–5.25 [m, 2H]; 4.86 [dm, JHF = 47.3 Hz, 1H]; 4.69 [br s, 1H], 4.13–3.91 [m, 1H]; 2.96–2.86 [m, 2H]; 1.39 [s, 9H]. 13C NMR (50.0 MHz) d: 155.4; 137.4; 133.3 (d, JCF = 76.4 Hz); 129.3; 128.5; 126.6; 118.1 (d, JCF = 51.0 Hz); 93.7; 79.5; 54.5 (d, JCF = 76.6 Hz); 38.0; 28.3. 19F NMR (200 MHz) d: 192.40 (m). MS m/e: 220 (2); 57 (100). 4.7.2.2. Minor diastereoisomer. 1H NMR (400 MHz) d: 1H NMR (200 MHz) d: 7.31–7.20 (m, 5H); 6.05–5.80 [m, 1H]; 5.48–5.32 [m, 2H]; 4.83 [dm, JHF = 47.6 Hz, 1H]; 4.58 [br s, 1H]; 4.18–3.98 [br m, 1H]; 2.99–2.90 [m, JAB = 14.6 Hz, JAX = 4.8 Hz, 1H]; 2.79– 2.67 [m, JAB = 14.6 Hz, JBX= 9.2 Hz, 1H]; 1.33 [s, 9H]. 13C NMR (50.0 MHz) d: 155.0; 137.1; 132.9 (d, JCF = 75.8 Hz]; 129.2; 128.3; 126.4; 118.5 (d, JCF = 48.6 Hz); 92.2; 79.5; 54.2 (d, JCF = 91.0 Hz); 35.1; 28.3. 19F NMR (200 MHz) d: 197.98 (m). MS m/e: 220 (4); 57 (100). Anal. Calcd for C16H22FNO2: C, 68.79; H, 7.94; N, 5.01. Found: C, 68.74; H, 7.99; N, 5.03. 4.7.3. (2R),(3S,R)-2-tert-Butoxycarbonylamino-3-fluoro-pent-4enoic acid methyl ester 8c Allylsilane 4 (95 mg, 0.3 mmol) gave 53 mg of fluoride 8c as a 60/40 diastereomeric mixture. Oil (yield 68%).

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4.7.3.1. Major diastereoisomer. 1H NMR (200 MHz) d: 5.94–5.76 [m, 1H]; 5.46–5.31 [m, 2H]; 5.31–5.01 [m, 1H+1H]; 4.68–4.53 [m, 1H]; 3.76 [s, 3H]; 1.44 [s, 9H]. 13C NMR (50.0 MHz) d: 168.8;ß154.6; 131.4 (d, JCF = 75.8 Hz]; 119.1 (d, JCF = 24.4 Hz]; 94.2; 80.4; 56.6 (d, JCF = 94.0 Hz); 52.5; 28.3. 19F NMR (200 MHz) d: 190.0 (m). MS m/e: 188 (5); 57 (100). 4.7.3.2. Minor diastereoisomer. 1H NMR (200 MHz) d: 5.98–5.80 [m, 1H]; 5.48–5.33 [m, 2H]; 5.31–5.01 [m, 1H+1H]; 4.56–4.52 [m, 1H]; 3.79 [s, 3H]; 1.44 [s, 9H]. 13C NMR (50.0 MHz) d: 168.8; 155.3; 131.6 (d, JCF = 75.8 Hz]; 119.3 (d, JCF = 24.4 Hz]; 90.6; 80.4; 57.1 (d, JCF = 94.0 Hz); 52.8; 28.3. 19F NMR (200 MHz) d: 191.6 (m). MS m/e: 188 (3); 57 (100). Anal. Calcd for C11H18FNO4: C, 53.43; H, 7.34; N, 5.66; Found: C, 53.48; H, 7.31; N, 5.63. 4.8. (2S),(2R),(3S,R)-2-(2-tert-Butoxycarbonylamino-3-fluoropent-4-enoylamino)-3-phenyl-propionic acid methyl ester 11 A solution of oxazolidine 10 (128 mg, 0.8 mmol) in MeOH (2 mL) was cooled to 0 °C and reacted with CF3COOH for 12 h. Volatile components were evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, then dried over Na2SO4 and evaporated to afford a crude which was dissolved in wet acetonitrile and cooled to 0 °C. Then HIO3 (460 mg, 2 mmol) and CrO3 (5 mg) were added and after 30 min the mixture was diluted with ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. The solvent was evaporated to give the crude amino acid, which was dissolved in DMF (2 mL), cooled at 0 °C and reacted with PheOMeHCl (170 mg, 0.8 mmol), DIPEA (112 mg, 0.9 mmol), EDCI (167 mg, 0.9 mmol) and HOBT (32 mg, 0.2 mmol). The reaction mixture was warmed to room temperature and stirred for 12 h. After dilution with ethyl acetate (5 mL) the organic phase was washed with a HCl (1 M) solution, then with a NaOH (1 M) solution and with brine. Evaporation of the solvent and purification afforded 96 mg of dipeptide 11 as a yellow solid (yield 30%). 4.8.1. Major diastereoisomer 1 H NMR (400 MHz) d: 7.30–7.23 (m, 3H); 7.19–7.11 (m, 2H); 6.63 (br d, J = 7.4 Hz, 1H); 5.87–5.75 [m, 1H]; 5.44–5.31 [m, 2H]; 5.31 [dm, J = 46.5 Hz, 1H]; 5.20–5.15 [m, 1H]; 4.90–4.84 [m, 1H]; 4.52–4.53 [m,1H]; 3.71[s, 3H]; 3.16–3.10 [m, 2H]; 1.43 [s, 9H]. 13 C NMR (50.0 MHz) d: 171.4; 167.9; 155.2; 135.4; 131.8 (d, JCF = 29.1 Hz]; 129.2; 128.6; 127.2; 119.6 (d, JCF = 12.3 Hz]; 91.2

(d, JCF = 177.9); 80.5; 56.9; 53.2 (d, JCF = 9.2 Hz); 52.3; 37.9; 28.1. MS m/e: 303 (8); 59 (100). 4.8.2. Minor diastereoisomer 1 H NMR (200 MHz) d: 7.30–7.23 (m, 3H); 7.11–7.01 (m, 2H); 6.72 (br d, J = 7.8 Hz, 1H); 5.77–5.65 [m, 1H]; 5.44–5.18 [m, 2H+1H+1H]; 4.92–4.86 [m, 1H]; 4.33–4.45 [m, 1H]; 3.71 [s, 3H]; 3.14–3.06 [m, 2H]; 1.44 [s, 9H]. 13C NMR (50.0 MHz) d: 171.4; 167.9; 155.9; 135.4; 131.5 (d, JCF = 9.1 Hz]; 129.2; 128.6; 127.2; 119.1 (d, JCF = 12.3 Hz]; 91.6 (d, JCF = 177.9); 80.5; 57.1; 53.2 (d, JCF = 9.2 Hz); 52.3; 37.7; 28.2. MS m/e: 303 (4); 59 (100). Anal. Calcd for C20H27FN2O5: C, 60.90; H, 6.90; N, 7.10. Found: C, 60.84; H, 6.88; N, 7.07. References 1. Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063. 2. Chabaud, L.; James, P.; Landais, Y. Eur. J. Org. Chem. 2004, 3173. 3. Suginome, M.; Iwanami, T.; Ohmori, Y.; Matsumoto, A.; Ito, Y. Chem.: A Eur. J. 2005, 11, 2954, and references cited therein. 4. Franciotti, M.; Mann, A.; Mordini, A.; Taddei, M. Tetrahedron Lett. 1993, 34, 1355. 5. Franciotti, M.; Mordini, A.; Taddei, M. Synlett 1992, 137. 6. Reginato, G.; Mordini, A.; Meffre, P.; Tenti, A.; Valacchi, M.; Cariou, K. Tetrahedron: Asymmetry 2006, 17, 922. 7. Fleming, I.; Higgins, D.; Lawrence, N. J.; Thomas, A. P. J. Chem. Soc., Perkin Trans. 1 1992, 24, 3331. 8. Bains, W.; Tacke, R. Curr. Opin. Drug Discovery Dev. 2003, 6, 526. and references cited therein. 9. Teare, H.; Huguet, F.; Tredwell, M.; Thibaudeau, S.; Luthra, S.; Gouverneur, V. Arkivoc 2007, 232. 10. Tredwell, M.; Governeur, V. Org. Biomol. Chem. 2006, 4, 26. 11. Purser, S.; Moore, P. R.; Swallow, S.; Governeur, V. Chem. Soc. Rev. 2008, 37, 320. 12. Feherencs, J. A.; Castro, B. Synthesis 1983, 676. 13. Hanson, G. J.; Lindberg, T. J. Org. Chem. 1985, 50, 5399. 14. Garner, P.; Park, J. M. Org. Synth. 1992, 70, 18. 15. Dondoni, A.; Perrone, D. Org. Synth. 1997, 77, 64. 16. Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60, 8199. 17. Coleman, R. S.; Carpenter, A. J. Tetrahedron Lett. 1992, 33, 1697. 18. Barbero, A.; Pulido, F. J. Acc. Chem. Res. 2004, 37, 817, and references cited therein. 19. Smith, J. G.; Drozda, S. E.; Petraglia, S. P. J. Org. Chem. 1984, 49, 4142. 20. Tredwell, M.; Tenza, K.; Pacheco, M. C.; Governeur, V. Org. Lett. 2005, 7, 4495. 21. Ohba, T.; Ikeda, E.; Takei, H. Bioorg. Med. Chem. Lett. 1996, 6, 1875. 22. Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31, 335. 23. Jackel, C.; Koksch, B. Eur. J. Org. Chem. 2005, 4483. 24. Zhao, M.; Li, J. S.; Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. Tetrahedron Lett. 1998, 39, 5323. 25. Gryco, D.; Urbanczyk-Lipkowska, Z.; Jurczak, J. Tetrahedron: Asymmetry 1998, 8, 4059. 26. Petrini, M.; Profeta, R.; Righi, P. J. Org. Chem. 2002, 67, 4530. 27. Still, W. C.; Kahn, M. K.; Mitra, A. J. Org. Chem. 1978, 43, 293. 28. Reginato, G.; Mordini, A.; Valacchi, M.; Grandini, E. J. Org. Chem. 1999, 64, 9545.