A straightforward synthesis of both enantiomers of α-vinylalanine and α-ethynylalanine

Article abstract of DOI:10.1016/S0957-4166(99)00533-9

This report describes the synthesis of enantiomerically pure (S)- and (R)-α-vinylalanines and (S)- and (R)-α-ethynylalanines, four quaternary α- amino acids, using a straightforward synthetic route and starting from (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00533-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4653–4661
A straightforward synthesis of both enantiomers of
α-vinylalanine and α-ethynylalanine
Alberto Avenoza,a,∗ Carlos Cativiela,b,∗ Jesús M. Peregrina,a David Sucunza a and
María M. Zurbano a
aDepartamento de Química, Universidad de La Rioja, Grupo de Síntesis Química de la Rioja, U.A.-C.S.I.C.,
26001 Logroño, Spain
bDepartmento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-C.S.I.C.,
50009 Zaragoza, Spain
Received 19 November 1999; accepted 23 November 1999
Abstract
This report describes the synthesis of enantiomerically pure (S)- and (R)-α-vinylalanines and (S)- and (R)-α-
ethynylalanines, four quaternary α-amino acids, using a straightforward synthetic route and starting from (S)- and
(R)-N-Boc-N,O-isopropylidene-α-methylserinals. © 1999 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
The α-alkyl α-amino acids are an important class of non-proteinogenic amino acids used to increase
conformational restrictions in peptides and thereby change their biological activity and stability.1 They
have attracted a great deal of research interest and a number of interesting approaches have been
developed.2 In this context, one of us recently published a review that covers the literature related to
the synthesis of α-substituted quaternary α-amino acids with an acyclic backbone.3
β,γ-Unsaturated amino acid derivatives have received special attention since they are important en-
zyme inhibitors,4 for example, α-vinyl amino acids are known to inhibit pyridoxal phosphate-dependent
enzymes, and in particular, amino acid decarboxylases.5 They are also potential precursors to new α-
branched α-amino acids as building blocks for de novo peptide design.6 Moreover, α-ethynyl amino
acids are of interest as potential suicide inhibitors of glutamic acid decarboxylase; in particular, ethynyl-
glycine (FR-900130) is a well-known natural antibiotic, and is a suicide substrate for alanine racemase.7
Given this background, we have focused our attention on the synthesis of β,γ-unsaturated α-methyl
α-amino acids, particularly α-vinylalanine and α-ethynylalanine. To the best of our knowledge, there
∗
Corresponding authors. E-mail: alberto.avenoza@dq.unirioja.es
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00533-9
tetasy 3168

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are three methods in the literature for the synthesis of racemic α-vinylalanine8 and four strategies for the
preparation of its enantiomerically pure forms,9 while the asymmetric synthesis of (S)-ethynylalanine
was only reported by Hegedus.9c The asymmetric synthesis of (R)-vinylalanine and (R)-ethynylalanine
methyl esters was described by Schöllkopf using the well-known bis-lactim ether method.10
In this context and as a part of our research program on the synthesis of new conformationally
constrained α-amino acids,11 we have recently reported the synthesis of (S)- and (R)-2-amino-2-
methylbutanoic acids starting from both enantiomers of N-Boc-N,O-isopropylidene-α-methylserinal (1
and 2) (Fig. 1).12
Fig. 1. (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals 1 and 2
In this paper, in order to demonstrate the synthetic utility of both compounds 1 and 2 as chiral
building blocks in the synthesis of enantiomerically pure α-substituted alanines, we now describe a more
convenient synthesis of (R)- and (S)-α-vinylalanines 5 and 8 and (R)- and (S)-α-ethynylalanines 11 and
14.
2. Results and discussion
Starting from (S)- and (R)-N-Boc-α-methylserinal acetonides 1 and 2, and using six steps, we obtained
both enantiomers of α-vinylalanine with an excellent overall yield (49%) (Scheme 1).
Scheme 1. Synthesis of both enantiomers of α-vinylalanine (5 and 8)
The initial step involved Wittig methylenation of (S)-α-methylserinal 1 and was carried out
under salt-free Wittig conditions13 using methyltriphenylphosphonium bromide and potassium
bis(trimethylsilyl)amide (KHMDS) as the base, obtaining olefin 3 in 93% yield. Starting from this
compound, several attempts to carry out the selective deprotection of the acetonide moiety of 3 failed
(p-TsOH, BF3·AcOH14). However, using Sc(OTf)3 (10 mol%) as a Lewis acid catalyst15 we obtained
compound 4 in a 25% yield. All attempts to improve the yield by increasing the temperature were
unsuccessful, since at 40°C we observed partial deprotection of the N-Boc group.
Since we could not obtain an acceptable yield via the selective cleavage of the acetonide moiety of
3, we decided to try acid hydrolysis using hydrochloride acid. After 2 h at 25°C, the cleavage of the
acetonide moiety and the hydrolysis of the N-Boc group took place in almost quantitative yield. The
corresponding aminoalcohol hydrochloride was then protected with Boc2O in the presence of sodium
carbonate to give 4 (88% from 3).

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4655
In order to transform this compound into the required quaternary amino acid 5, it was oxidized with
Jones’ reagent,16 hydrolyzed using a mixture of concentrated HCl and THF at room temperature and
finally treated with propylene oxide in ethanol at reflux to give (R)-α-vinylalanine 5 in a 60% yield. The
spectral data and optical activity of this compound proved to be identical to those previously reported9c
(Scheme 1).
The enantiomer (S)-α-vinylalanine 8 was obtained using the same strategy but starting from (R)-α-
methylserinal 2. The spectral data of compound 8 were identical to those previously obtained for amino
acid 5, but with an optical rotation of opposite sign (Scheme 1).
The syntheses of (R)- and (S)-α-ethynylalanines 11 and 14 also start from (S)- and (R)-methylserinals
1 and 2, respectively, and involve seven steps with an overall yield of 32% (Scheme 2).
Scheme 2. Synthesis of both enantiomers of α-ethynylalanine 11 and 14
The aldehyde-to-acetylene conversion protocol can be undertaken using either of two strategies: in
one step by ethynylation of the aldehyde with dimethyl-1-diazo-2-oxopropyl phosphonate17 or in two
steps using a dibromovinyl intermediate (the Corey–Fuchs strategy).18 The literature reports that when
this transformation was carried out on N-protected serinal acetonides, the second method gave better
results.19 We, therefore, decided to obtain the α-alkynyl-α-methylamino acids 11 and 14 by using the
Corey–Fuchs transformation. In this way, (R)- and (S)-methylserinals 1 and 2 were converted into the
corresponding alkynes 10 and 13, using the vinyl intermediates 9 and 12 (Scheme 2).
Initially, we attempted the olefination of aldehyde 1 using a recently reported modification of the
Corey–Fuchs method, involving the presence of Et3N at low temperature (CBr4, PPh3, Et3N, 14 h,
10°C).20 Unfortunately, this method provided dibromoolefin 9 only in a 49% yield. We attempted the
olefination using the original Corey–Fuchs conditions (CBr4, PPh3, Zn, 14 h, rt), obtaining dibromoolefin
9 in a 57% yield. However, the best result was obtained by preparation of the dibromomethyl phosphorane
t
using bromoform with BuOK in the presence of PPh3,21 followed by addition of aldehyde 1 at rt in
toluene, giving a 79% yield of 9 and recovering a 15% yield of 1 (Scheme 2).
Treatment of dibromoolefin 9 with two equivalents of n-BuLi at −78°C gave the corresponding
acetylene derivative, which was hydrolyzed, without purification, by the action of concentrated HCl,
obtaining the 1,2-aminoalcohol hydrochloride. Protection of this compound with Boc2O in the presence
of sodium carbonate gave 10 (54% from 9). The conversion of compound 10 into the desired (R)-
ethynylalanine 11 was achieved in the same way as described above for the preparation of amino acid 5
from alcohol 4 (Scheme 2).
The synthesis of (S)-ethynylalanine 14 was performed using the same strategy described for its
enantiomer 11, but starting from aldehyde 2 (Scheme 2).
The enantiomeric purity of the intermediates in the synthesis of the four quaternary amino acids was
examined by preparation of the Mosher esters of alcohols 4 and 10 (Scheme 3).

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Scheme 3. Determination of enantiomeric purity of 4 and 10
In accordance with the protocol described in the literature,22 alcohol 4 was coupled with (R)-(+)- and
(S)-(−)-methoxytrifluorophenylacetic acid [(R)-(+)- and (S)-(−)-MTPA] in the presence of DCC and
DMAP to give Mosher esters 15 and 16, respectively. Analysis of the NMR spectra of esters 15 and 16
showed that the enantiomeric purity of compound 4 was at least 96% (only one isomer was observed in
the 1H and 19F NMR spectra). Similarly, the synthesis of Mosher esters 17 and 18 was carried out using
the same methodology, but now starting from alcohol 10 (Scheme 3).
In conclusion, we have developed a methodology that offers a straightforward route to the synthesis of
β,γ-unsaturated α-methyl α-amino acids. In this way, we have achieved the synthesis of four interesting
quaternary α-amino acids in enantiomerically pure form: (R)- and (S)-vinylalanines 5 and 8 and (R)- and
(S)-ethynylalanines 11 and 14, thus demonstrating that (S)- and (R)-N-Boc-α-methylserinal acetonides 1
and 2 are valuable chiral building blocks in the enantioselective synthesis of α-methyl α-amino acids.
3. Experimental
Solvents were purified according to standard procedures. Analytical TLC was performed using
Polychrom SI F254 plates. Column chromatography was performed using silica gel 60 (230–400 mesh).
1H and 13C NMR spectra were recorded on a Bruker ARX-300 spectrometer. 1H and 13C NMR spectra
were recorded in CDCl3 with TMS as the internal standard and in CD3OD with TMS as the external
standard using a coaxial microtube (chemical shifts are reported in ppm on the δ scale, coupling
constants in Hz). The assignment of all separate signals in the 1H NMR spectra was made on the basis of
coupling constants, selective proton–proton homonuclear decoupling experiments, proton–proton COSY
experiments and proton–carbon HETCOR experiments. Melting points were determined on a Büchi
SMP-20 melting point apparatus and are uncorrected. Optical rotations were measured on a Perkin–Elmer
341 polarimeter in 1 and 0.5 dm cells of 1 and 3.4 mL capacity, respectively. Microanalyses were carried
out on a CE Instruments EA-1110 analyser and are in good agreement with the calculated values. IR
spectra were recorded on a Perkin–Elmer FT-IR Spectrum 1000 spectrometer.
3.1. (R)-2-((tert-Butoxycarbonyl)amino)-2-methyl-3-buten-1-ol 4
Concentrated HCl (10 mL) was added to (R)-N-(tert-butoxycarbonyl)-4-vinyl-2,2,4-trimethyl-3-
oxazolidine 3 (274 mg, 1.13 mmol), which was previously obtained according to the procedure described
by us in the literature,12 and the solution was stirred, at rt, for 2 h. The HCl was then removed to give
the corresponding 1,2-aminoalcohol as an orange oil. This compound was dissolved in (1:5) H2O:THF
(6 mL) and then Na2CO3·10H2O (812 mg, 2.83 mmol) and Boc2O (306 mg, 1.36 mmol) were added.

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4657
The mixture was stirred at rt for 14 h and the reaction was quenched with saturated NH4Cl (10 mL) and
extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous MgSO4,
filtered and concentrated. The residue was purified by flash silica gel chromatography (hexane:ethyl
acetate, 8:2) to give compound 4 (200 mg, 88%) as a white solid. Mp: 41–43°C. [α]D25=+10.9 (c 1.13,
MeOH); 1H NMR (CDCl3): δ 1.29 (s, 3H, CH3), 1.40 (s, 9H, (CH3)3C), 3.52 (d, 1H, J=11.4 Hz, CH2O),
3.59 (d, 1H, J=11.4 Hz, CH2O), 4.97 (br s, 1H, NHCO), 5.12 (d, 1H, J=6.6 Hz, CH2_CH), 5.17 (s,
1H, CH2_CH), 5.85 (dd, 1H, J=17.1 Hz, J=11.1 Hz, CH2_CH); 13C NMR (CDCl3): δ 22.8 (CH3),
28.2 ((CH3)3C), 58.3 (C(CH3)NH), 69.3 (CH2O), 79.8 ((CH3)3C), 113.9 (CH2_CH), 140.4 (CH2_CH),
155.9 (OCON); ESI+ (m/z)=202.3. Anal. calcd for C10H19NO3: C, 59.68; H, 9.52; N, 6.96. Found: C,
58.91; H, 10.01; N, 6.92.
3.2. (R)-2-Amino-2-methyl-3-butenoic acid 5
To a solution of compound 4 (165 mg, 0.82 mmol) in acetone (10 mL) at 0°C was added a 1.5-fold
excess of Jones’ reagent, drop by drop over 5 min. The mixture was stirred at 0°C for 3 h and then at
rt for a further 3 h. The excess of Jones’ reagent was destroyed with 2-propanol. The mixture was then
diluted with water (10 mL) and extracted with ethyl acetate (4×20 mL). The combined organic extracts
were dried with anhydrous Na2SO4 and concentrated in vacuo. The residual yellow oil (150 mg) was
dissolved in THF (15 mL) and was treated with concentrated HCl (2 mL). The mixture was stirred at rt
for 6 h. The solvent was removed and the residual oil partitioned between water (10 mL) and ethyl acetate
(10 mL). The aqueous phase was concentrated in vacuo to give (R)-α-vinylalanine hydrochloride as a
white solid (103 mg, 83%). This compound was dissolved in (3:1) EtOH:propylene oxide (4 mL) and the
mixture heated under reflux for 2 h, after which time the amino acid partially precipitated as a white solid
(35 mg). The filtrate was concentrated and the residue dissolved in distilled water and eluted through a
C18 reverse-phase Sep-Pak cartridge to give, after removal of the water, 21 mg of (R)-α-vinylalanine 5 as
a white solid. Total amount: 56 mg (72%, 60% from 4). [α]D25=−27.4 (c 0.62, H2O); ESI− (m/z)=116.2.
Anal. calcd for C5H9NO2: C, 52.16; H, 7.88; N, 12.17. Found: C, 52.21; H, 7.33; N, 12.20. Spectral data
were identical to those reported in the literature (Ref. 9c).
3.3. (S)-2-((tert-Butoxycarbonyl)amino)-2-methyl-3-buten-1-ol 7
In a similar way to that described for its enantiomer 4, compound 7 (202 mg, 88%) was obtained from
oxazolidine 6 (272 mg, 1.13 mmol). [α]D25=−10.5 (c 1.08, MeOH). Anal. calcd for C10H19NO3: C,
59.68; H, 9.52; N, 6.96. Found: C, 59.00; H, 9.97; N, 7.01.
3.4. (S)-2-Amino-2-methyl-3-butenoic acid 8
In a similar way to that described for its enantiomer 5, (S)-α-vinylalanine 8 (54 mg, 58%) was obtained
from alcohol 7 (160 mg, 0.82 mmol). [α]D25=+27.3 (c 0.63, H2O). Anal. calcd for C5H9NO2: C, 52.16;
H, 7.88; N, 12.17. Found: C, 52.33; H, 7.21; N, 12.17.
3.5. (R)-N-(tert-Butoxycarbonyl)-4-(20,20-dibromoethenyl)-2,2,4-trimethyl-3-oxazolidine 9
CHBr3 (2.57 g, 9.88 mmol) was rapidly added dropwise to a 1 M solution of tBuOK in THF (10 mL,
10.00 mmol) and PPh3 (2.62 g, 9.88 mmol) in toluene (30 mL) at −20°C, followed after 15 min by
aldehyde (S)-N-(tert-butoxycarbonyl)-4-formyl-2,2,4-trimethyl-3-oxazolidine 1 (600 mg, 2.47 mmol) in

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toluene (15 mL). After 15 min, the cooling bath was removed and the reaction mixture was allowed to
warm to rt. After 17 h, the reaction mixture was diluted with ethyl ether (50 mL), filtered and concentrated
in vacuo. The crude product was purified by silica gel chromatography (hexane:ethyl acetate, 19:1) to
1
give the required compound 9 (780 mg, 79%) as a colourless oil. [α]D25=−95.1 (c 1.18, CHCl3); H
NMR (CDCl3): δ 1.48–1.69 (m, 18H, (CH3)3C, CH3, (CH3)2C), 3.92, 4.03 (2d, 1H, J=8.7 Hz, J=8.7
Hz, CH2O), 4.15, 4.16 (2d, 1H, J=8.7 Hz, J=8.7 Hz, CH2O), 6.83, 7.11 (2s, 1H, CH_CBr2); 13C NMR
(CDCl3): δ 22.0, 23.8, 24.8, 25.6, 26.2, 27.3 (CH3, (CH3)2C), 28.4 ((CH3)3C), 64.2, 65.1 (C(CH3)N),
72.6, 72.8 (CH2O), 80.3, 80.5 ((CH3)3C), 86.7, 86.8 (CH_CBr2), 94.4, 95.5 ((CH3)2C), 142.1, 142.3
(CH_CBr2), 151.0, 151.3 (OCON); ESI+ (m/z)=400.1. Anal. calcd for C13H21Br2NO3: C, 39.12; H,
5.30; N, 3.51. Found: C, 39.22; H, 5.28; N, 3.48.
3.6. (R)-2-((tert-Butoxycarbonyl)amino)-2-methyl-3-butyn-1-ol 10
A solution of oxazolidine 9 (304 mg, 0.76 mmol) in THF (15 mL) was cooled at −78°C and a 2 M
solution of n-BuLi in hexane (0.8 mL, 1.60 mmol) was added dropwise. After 3.5 h, the cooling bath
was removed, the mixture was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate
(2×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated
in vacuo. Concentrated HCl (10 mL) was added to this mixture and the solution was stirred, at rt, for 2
h. The HCl was then removed to give the corresponding aminoalcohol (orange oil). This compound was
dissolved in (1:5) H2O:THF (6 mL) and then Na2CO3·10H2O (545 mg, 1.90 mmol) and Boc2O (206
mg, 0.91 mmol) were added to the solution. The mixture was stirred at rt for 14 h. The reaction was
quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3×30 mL). The combined
organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified
by flash silica gel chromatography (hexane:ethyl acetate, 7:3) to give compound 10 (82 mg, 54%) as
1
a yellow oil. [α]D25=−9.4 (c 1.05, MeOH); H NMR (CDCl3): δ 1.42 (s, 9H, (CH3)3C), 1.51 (s, 3H,
CH3), 2.37 (s, 1H, C^CH), 3.50 (br s, 1H, OH), 3.63 (d, 1H, J=10.8 Hz, CH2O), 3.74 (d, 1H, J=10.8 Hz,
CH2O), 5.12 (br s, 1H, NHCO); 13C NMR (CDCl3): δ 24.2 (CH3), 28.3 ((CH3)3C), 52.2 (C(CH3)NH),
69.4 (CH2O), 71.3 (C^CH), 80.4 ((CH3)3C), 84.4 (C^CH), 155.2 (OCON); ESI+ (m/z)=200.2. Anal.
calcd for C10H17NO3: C, 60.28; H, 8.60; N, 7.03. Found: C, 60.39; H, 8.88; N, 7.13.
3.7. (R)-2-Amino-2-methyl-3-butynoic acid 11
To a solution of alcohol 10 (95 mg, 0.48 mmol) in acetone (10 mL) at 0°C a 1.5-fold excess of Jones’
reagent was added, drop by drop, over 5 min. The mixture was stirred at 0°C for 3 h and then at rt for a
further 3 h. The excess of Jones’ reagent was destroyed with 2-propanol. The mixture was then diluted
with water (10 mL) and extracted with ethyl acetate (4×20 mL). The combined organic extracts were
dried with anhydrous Na2SO4 and concentrated in vacuo. The residual yellow oil (82 mg) was dissolved
in THF (15 mL) and was treated with concentrated HCl (2 mL). The mixture was stirred at rt for 6
h. The solvent was removed and the residual oil partitioned between water (10 mL) and ethyl acetate
(10 mL). The aqueous phase was concentrated in vacuo to give (R)-α-ethynylalanine hydrochloride as
a white solid (57 mg). This compound was dissolved in (3:1) EtOH:propylene oxide (4 mL) and the
mixture heated under reflux for 2 h after which time the amino acid partially precipitated as a white solid
(15 mg). The filtrate was concentrated, the residue dissolved in distilled water and eluted through a C18
reverse-phase Sep-Pak cartridge to give, after removal of the water, 26 mg of (R)-α-ethynylalanine 11
as a white solid. Total amount: 41 mg (76%). [α]D25=−43.1 (c 0.74, H2O); ESI− (m/z)=114.2. Anal.

A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 4653–4661
4659
calcd for C5H7NO2: C, 53.09; H, 6.24; N, 12.38. Found: C, 52.44; H, 7.05; N, 13.09. Spectral data were
identical to those reported in the literature (Ref. 9c).
3.8. (S)-N-(tert-Butoxycarbonyl)-4-(20,20-dibromoethenyl)-2,2,4-trimethyl-3-oxazolidine 12
In a similar way to that described for its enantiomer 9, compound 12 (783 mg, 79%) was obtained
from aldehyde 2 (602 mg, 2.47 mmol). [α]D25=+96.0 (c 1.06, CHCl3). Anal. calcd for C13H21Br2NO3:
C, 39.12; H, 5.30; N, 3.51. Found: C, 39.25; H, 5.39; N, 3.55.
3.9. (S)-2-((tert-Butoxycarbonyl)amino)-2-methyl-3-butyn-1-ol 13
In a similar way to that described for its enantiomer 10, compound 13 (80 mg, 54%) was obtained
from oxazolidine 12 (303 mg, 0.76 mmol). [α]D25=+10.0 (c 1.05, MeOH). Anal. calcd for C10H17NO3:
C, 60.28; H, 8.60; N, 7.03. Found: C, 60.36; H, 8.90; N, 7.10.
3.10. (S)-2-Amino-2-methyl-3-butynoic acid 14
In a similar way to that described for its enantiomer 11, (S)-α-ethynylalanine 14 (39 mg, 73%) was
obtained from alcohol 13 (94 mg, 0.48 mmol). [α]D25=+43.4 (c 0.78, H2O). Anal. calcd for C5H7NO2:
C, 53.09; H, 6.24; N, 12.38. Found: C, 52.53; H, 6.96; N, 12.98.
3.11. (2R,20R)-20-((tert-Butoxycarbonyl)amino)-20-methyl-30-butenyl 2-methoxy-2-(trifluoromethyl)-2-
phenylacetate 15
To a solution of alcohol 4 (20 mg, 0.20 mmol), DCC (41 mg, 0.20 mmol) and DMAP (2.5 mg, 0.02
mmol) in dry CH2Cl2 (6 mL) was added a solution of (R)-(+)-MTPA (52 mg, 0.22 mmol) in dry CH2Cl2
(4 mL). After stirring the mixture at rt for 6 h, the resulting white suspension was filtered to remove the
N,N0-dicyclohexylurea. The filtrate was concentrated in vacuo to give a white slurry, to which Et2O was
added. The resulting suspension was filtered to remove the acylurea and the solvent was evaporated. The
residue was purified by column chromatography (hexane:ethyl acetate, 7:3) to give 15 (51 mg, 65%) as
an oil. [α]D25=+31.0 (c 1.43, CHCl3); 1H NMR (CDCl3): δ 1.33 (s, 3H, CH3), 1.40 (s, 9H, (CH3)3C),
3.53 (s, 3H, OCH3), 4.44 (d, 1H, J=10.8 Hz, CH2O), 4.59 (d, 1H, J=10.8 Hz, CH2O), 4.60 (br s, 1H,
NHCO), 5.14 (d, 1H, J=7.2 Hz, CH2_CH), 5.18 (br s, 1H, CH2_CH), 5.90 (dd, 1H, J=17.4 Hz, J=10.8
Hz, CH2_CH), 7.40 (m, 3H, Ph), 7.51 (m, 2H, Ph); 13C NMR (CDCl3): δ 22.8 (CH3), 28.3 ((CH3)3C),
55.4 (C(CH3)NH), 55.5 (OCH3), 68.9 (CH2O), 79.7 ((CH3)3C), 114.7 (CH2_CH), 121.3 (C(CF3)), 125.2
(CF3), 127.4, 128.4, 129.6, 132.0 (Ph), 139.4 (CH2_CH), 154.2 (OCON), 166.1 (CCO2CH2); 19F NMR
(CDCl3): δ −71.8; ESI+ (m/z)=418.3. Anal. calcd for C20H26F3NO5: C, 57.55; H, 6.28; N, 3.36. Found:
C, 56.92; H, 6.62; N, 3.43.
3.12. (2S,20R)-20-((tert-Butoxycarbonyl)amino)-20-methyl-30-butenyl 2-methoxy-2-(trifluoromethyl)-2-
phenylacetate 16
In a similar way to that described for compound 15, Mosher ester 16 (54 mg, 69%) was obtained
from alcohol 4 (22 mg, 0.20 mmol) and (S)-(−)-MTPA (52 mg, 0.22 mmol). [α]D25=−22.2 (c 0.82,
1
CHCl3); H NMR (CDCl3): δ 1.34 (s, 3H, CH3), 1.40 (s, 9H, (CH3)3C), 3.53 (s, 3H, OCH3), 4.39 (d,
1H, J=10.8 Hz, CH2O), 4.58 (br s, 1H, NHCO), 4.63 (d, 1H, J=10.8 Hz, CH2O), 5.13 (d, 1H, J=5.4 Hz,

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CH2_CH), 5.18 (d, 1H, J=1.5 Hz, CH2_CH), 5.91 (dd, 1H, J=17.4 Hz, J=10.8 Hz, CH2_CH), 7.40 (m,
3H, Ph), 7.51 (m, 2H, Ph); 13C NMR (CDCl3): δ 22.7 (CH3), 28.3 ((CH3)3C), 55.4 (C(CH3)NH), 55.5
(OCH3), 69.0 (CH2O), 79.7 ((CH3)3C), 114.7 (CH2_CH), 121.3 (C(CF3)), 125.2 (CF3), 127.4, 128.4,
129.6, 132.0 (Ph), 139.4 (CH2_CH), 154.2 (OCON), 166.1 (CCO2CH2); 19F NMR (CDCl3): δ −71.8;
ESI+ (m/z)=418.3. Anal. calcd for C20H26F3NO5: C, 57.55; H, 6.28; N, 3.36. Found: C, 56.90; H, 6.57;
N, 3.49.
3.13. (2R,20R)-20-((tert-Butoxycarbonyl)amino)-20-methyl-30-butynyl 2-methoxy-2-(trifluoromethyl)-2-
phenylacetate 17
In a similar way to that described for compound 15, Mosher ester 17 (51 mg, 61%) was obtained from
alcohol 10 (19 mg, 0.20 mmol) and (R)-(+)-MTPA (51 mg, 0.22 mmol). [α]D25=+32.2 (c 0.95, CHCl3);
1H NMR (CDCl3): δ 1.42 (s, 9H, (CH3)3C), 1.54 (s, 3H, CH3), 2.37 (s, 1H, C≡CH), 3.55 (s, 3H, OCH3),
4.50 (d, 1H, J=10.8 Hz, CH2O), 4.69 (d, 1H, J=10.8 Hz, CH2O), 4.70 (br s, 1H, NHCO), 7.41 (m, 3H, Ph),
7.53 (m, 2H, Ph); 13C NMR (CDCl3): δ 24.6 (CH3), 28.2 ((CH3)3C), 49.7 (C(CH3)NH), 55.4 (OCH3),
68.5 (CH2O), 71.8 (C≡CH), 80.4 ((CH3)3C), 82.9 (C≡CH), 121.3 (C(CF3)), 125.1 (CF3), 127.4, 128.4,
129.7, 132.0 (Ph), 153.7 (OCON), 165.9 (CCO2CH2); 19F NMR (CDCl3): δ −71.9; ESI+ (m/z)=416.2.
Anal. calcd for C20H24F3NO5: C, 57.83; H, 5.82; N, 3.37. Found: C, 57.02; H, 6.10; N, 3.48.
3.14. (2S,20R)-20-((tert-Butoxycarbonyl)amino)-20-methyl-30-butynyl 2-methoxy-2-(trifluoromethyl)-2-
phenylacetate 18
In a similar way to that described for compound 16, Mosher ester 18 (46 mg, 55%) was obtained from
alcohol 10 (20 mg, 0.20 mmol) and (S)-MTPA (50 mg, 0.22 mmol). [α]D25=−28.0 (c 1.18, CHCl3); 1H
NMR (CDCl3): δ 1.43 (s, 9H, (CH3)3C), 1.52 (s, 3H, CH3), 2.37 (s, 1H, C≡CH), 3.55 (s, 3H, OCH3),
4.50 (d, 1H, J=10.8 Hz, CH2O), 4.67 (br s, 1H, NHCO), 4.71 (d, 1H, J=10.8 Hz, CH2O), 7.41 (m, 3H, Ph),
7.53 (m, 2H, Ph); 13C NMR (CDCl3): δ 24.6 (CH3), 28.2 ((CH3)3C), 49.8 (C(CH3)NH), 55.5 (OCH3),
68.5 (CH2O), 71.8 (C≡CH), 80.4 ((CH3)3C), 82.9 (C≡CH), 121.3 (C(CF3)), 125.1 (CF3), 127.4, 128.4,
129.7, 132.0 (Ph), 153.7 (OCON), 165.8 (CCO2CH2); 19F NMR (CDCl3): δ −71.9; ESI+ (m/z)=416.2.
Anal. calcd for C20H24F3NO5: C, 57.83; H, 5.82; N, 3.37. Found: C, 57.21; H, 6.06; N, 3.50.
Acknowledgements
This work was supported by the Dirección General de Enseñanza Superior (project PB97-0998-C02-
02) and the Universidad de La Rioja (project API-99/B02).
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