Enantioselective synthesis of unsaturated amino acids using p- methoxybenzylamine as an ammonia equivalent

Article abstract of DOI:10.1016/S0957-4166(99)00525-X

A versatile, non-alkylative enantioselective synthesis of unsaturated α-amino acids based on the Sharpless asymmetric epoxidation has been developed. Enantiomerically enriched trans epoxy alcohols bearing unsaturated substituents were prepared and submitted to regio- and stereospecific ring- opening with p-methoxybenzylamine as a nucleophile, leading to anti-3-(p- methoxybenzylamino)-1,2-diols which were further protected by reaction with Boc₂O. The 1,2-diol fragment was then oxidatively cleaved by a sequential treatment with sodium periodate and sodium chlorite to afford the corresponding amino acid. Using this methodology, doubly N-protected (p- methoxybenzyl and Boc) allyl glycine, 3-butenyl glycine and 4-pentenyl glycine have been prepared in three synthetic steps from the corresponding allyl alcohols. As a demonstration of the orthogonal nature of the nitrogen protection, both protecting groups have been selectively removed from the fully protected amino ester. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00525-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4639–4651
Enantioselective synthesis of unsaturated amino acids using
p-methoxybenzylamine as an ammonia equivalent
Montserrat Alcón, Albert Moyano, Miquel A. Pericàs ∗ and Antoni Riera ∗
Unitat de Recerca en Síntesi Asimètrica, Departament de Química Orgànica, Universitat de Barcelona,
c/ Martí i Franquès, 1-11, 08028 Barcelona, Spain
Received 18 November 1999; accepted 19 November 1999
Abstract
A versatile, non-alkylative enantioselective synthesis of unsaturated α-amino acids based on the Sharpless
asymmetric epoxidation has been developed. Enantiomerically enriched trans epoxy alcohols bearing unsaturated
substituents were prepared and submitted to regio- and stereospecific ring-opening with p-methoxybenzylamine
as a nucleophile, leading to anti-3-(p-methoxybenzylamino)-1,2-diols which were further protected by reaction
with Boc2O. The 1,2-diol fragment was then oxidatively cleaved by a sequential treatment with sodium periodate
and sodium chlorite to afford the corresponding amino acid. Using this methodology, doubly N-protected (p-
methoxybenzyl and Boc) allyl glycine, 3-butenyl glycine and 4-pentenyl glycine have been prepared in three
synthetic steps from the corresponding allyl alcohols. As a demonstration of the orthogonal nature of the nitrogen
protection, both protecting groups have been selectively removed from the fully protected amino ester. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
The increasing interest of modified peptides in biological studies and as therapeutic agents1 is fostering
the research of methodologies directed to the synthesis of unnatural amino acids in enantiomerically pure
form.2 Unsaturated α-amino acids are key components in the synthesis of biologically active peptides3
and peptide isosteres.4 They are also useful chiral synthons5 and, as with many other unsaturated
substrates, their synthetic interest has recently increased with the advent of the ring-closing metathesis
(RCM) methodologies.6 In combination with this reaction, they have been used as precursors of dicarba
analogs of macrocyclic peptides,7 isosteric cystine dipeptide bis-amino diacids,8 physiologically active
meso-diaminopimelic acid derivatives,9 unsaturated heterocycles10 or cyclic protease inhibitors.11
Among the α-amino acids bearing an unsaturated alkene-type residue, allyl glycine 1a is the most
important and widely used3–10,12 although other specimens of the same family such as 3-butenyl glycine
∗
Corresponding author. Fax: 34-933397878; e-mail: mpb@ursa.qo.ub.es, are@ursa.qo.ub.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00525-X
tetasy 3160

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1b13 or 4-pentenyl glycine 1c5e,10,11,13b,c,14 have also shown high synthetic utility. The syntheses des-
cribed for these compounds include enzymatic resolutions,3e,12b,15 alkylation of alanine synthons13b,c,16
and asymmetric synthesis using the chiral auxiliary approach17 but, to the best of our knowledge, no
practical catalytic asymmetric synthesis18 has been developed to date for this important type of amino
acids.
Recently, we have set out the principles of a general methodology based on the catalytic Sharpless
epoxidation19 which allows the completely stereocontrolled synthesis of amino acids of different structu-
ral types in enantiomerically pure form20 (Scheme 1). Our method relies on the regio- and stereospecific
ring-opening of epoxy alcohols I by a synthetic equivalent of ammonia to provide, after hydrogenation
and protection, N-Boc-3-amino-1,2-diols II; until now we have used benzhydrylamine or azide reagents
for this purpose. Whereas our approach has been successfully applied to the preparation of a wide range
of biologically important amino acids,20 the need of reductive protocols for the actualization of the amino
function (I→II) poses some limitations to the scope of the method. Thus, amino acids containing side
chains with olefinic double bonds could not be efficiently prepared by our original procedure, due to
the difficulties encountered in the chemoselective reduction of the benzhydryl group and the low yields
obtained in the preparation of non-aromatic unsaturated 3-azido-1,2-diols.21
Scheme 1. The regio- and stereospecific ring-opening of epoxy alcohols I by a reductively cleavable synthetic equivalent of
ammonia provides N-Boc-3-amino-1,2-diols II which have been used as starting materials in the preparation of several structural
types of amino acids
The failure of our early efforts21 directed towards developing a high-yield synthesis of unsaturated
N-Boc-3-amino-1,2-diols [II, R_(CH2)n-CH_CH2] through non-hydrogenative reduction of the benz-
hydryl or azido groups drove our attention towards the use of an alternative amino synthon that could
be unmasked by oxidative methods. p-Methoxybenzylamine appeared as an attractive candidate for
this purpose. Although p-methoxybenzylamine has been used as a nitrogen source in the preparation
of amides from lactones22 and the p-methoxybenzyl group is a well known protecting group,23 to the
best of our knowledge p-methoxybenzylamine has never been used in epoxide chemistry as a vehicle
for the introduction of the amino group. We report herein a new and efficient methodology for the
preparation of unsaturated α-amino acids, orthogonally protected at nitrogen, based on the use of p-
methoxybenzylamine as ammonia surrogate.

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2. Results and discussion
Our initial study of the Lewis acid assisted, regioselective ring-opening of chiral epoxy alcohols by
primary amines24 already showed that p-methoxybenzylamine was an excellent reagent for this process,
leading, under titanium tetraisopropoxide catalysis,25 to the corresponding C-3 ring-opened products in
good yields and excellent regioselectivities. According to this precedent, and bearing in mind the easy
oxidative cleavage of the p-methoxybenzyl group23,26 this amine was selected as a promising ammonia
source for our study. N-Protected derivatives of (S)-allyl glycine 1a, (S)-3-butenyl glycine 1b, and (S)-
4-pentenyl glycine 1c which, as we have already mentioned, are the most representative examples of
unsaturated α-amino acids, were selected as the targets.
According to the planned strategy (Fig. 1), these amino acids would come from N-protected 3-amino-
1,2-diols 2 which, in turn, would arise from epoxy alcohols 3, readily accessible by Sharpless epoxidation
of allyl alcohols 4.
Fig. 1. Retrosynthetic analysis of unsaturated amino acids
Whereas the synthesis and even the asymmetric epoxidation of (E)-2,5-hexadien-1-ol 4a27 and
(E)-2,7-octadien-1-ol 4c28,29 were already described in the literature, (E)-2,6-heptadien-1-ol 4b was
previously unknown. Nevertheless, it could be prepared in multigram scale from commercially available
4-penten-1-ol 5 by a sequence of Swern oxidation, Wittig olefination and DIBALH reduction, to provide
diastereomerically pure 4b in 66% overall yield.
The catalytic Sharpless epoxidation of 4a–c took place uneventfully, leading to 3a–c in good yield.
The enantiomeric excess of these epoxy alcohols was determined to be 91–94% by HPLC analysis of the
corresponding p-toluenesulfonates (Scheme 2). Optimization of conditions for the ring-opening process
and nitrogen protecting group manipulation was performed with readily available epoxy alcohol 3b.
Thus, treatment of this epoxy alcohol with 2 equivalents of p-methoxybenzylamine and 3 equivalents
of titanium tetraisopropoxide in methylene chloride at reflux afforded p-methoxybenzylaminodiol 7b in
80% yield, although the removal of excess of p-methoxybenzylamine proved to be very troublesome.
Significantly, and contrary to what happened with 3-benzhydrylamino-1,2-diols,30 the nucleophilicity of
the amino group in 7b allowed its further protection with a tert-butoxycarbonyl group. In effect, when
a solution of compound 7b in methanol was sonicated in the presence of Boc2O and NaHCO3,31 the
orthogonally protected aminodiol 2b was obtained in 80% yield (Scheme 2). The difficulties encountered
in the purification of 7b could be overcome by submitting the reaction crude (still containing some p-
methoxybenzylamine) to the Boc protection conditions. In this way, 2b was obtained in 60% overall
yield. When the same optimized experimental protocol was applied to epoxy alcohols 3a and 3c, the
doubly protected aminodiols 2a and 2c were obtained in good overall yields.

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Scheme 2. Reaction conditions: (a) tert-Butyl hydroperoxide, D-(−)-DIPT (cat), Ti(OiPr)4 (cat), 4 Å sieves, −20°C. (b)
p-Methoxybenzylamine, Ti(OiPr)4, CH2Cl2, reflux. (c) (Boc)2O, NaHCO3, MeOH, sonication. (d) (i) NaIO4, THF, H2O; (ii)
NaClO2, ButOH, 2-methyl-2-butene. (e) MeI, DMF, KHCO3. (f) Ceric ammonium nitrate (CAN), CH3CN, H2O. (g) HCl, THF
On the way to the target amino acids, removal of the PMB protection could in principle be performed at
the stage of aminodiols 2a–c, since all of the remaining operations are compatible with the presence of the
terminal double bond. Unfortunately, however, the oxidative deprotection of 2b, using ceric ammonium
nitrate (CAN), gave N-Boc-3-amino-5-hepten-1,2-diol 8b in low and poorly reproducible yields (Scheme
2). The failure of this reaction was probably due to the presence of the oxidatively labile 1,2-diol
functionality; to avoid this problem, we decided to proceed to the orthogonally protected unsaturated
amino acids before cleavage of the PMB group.
The oxidative cleavage of the 1,2-diol fragment in the presence of two oxidatively sensitive groups,
like the double bond and the p-methoxybenzylamino substituent, required a careful selection of reaction
conditions. After some experimentation on 2a, we found an appropriate protocol: the 1,2-diol fragment
was first cleaved with sodium periodate to the corresponding aldehyde,32 which was immediately
oxidized by sodium chlorite33 to the PMB/Boc protected amino acid 9a in 81% yield. This sequence
was also applied to 2b and to 2c which afforded the doubly N-protected (S)-butenyl glycine 9b and
(S)-pentenyl glycine 9c, respectively, also in good yields.
Given the intermediacy of a labile α-amino aldehyde in the synthetic sequence, special attention
was paid to the control of stereochemical integrity of the stereogenic center along the sequence. In
practice, the periodate oxidation was performed quickly, and the intermediate aldehyde was submitted
to chlorite oxidation without purification. In order to check the enantiomeric purity of 9a–c, the methyl
ester derivatives were prepared by treatment with MeI/KHCO3 in DMF, providing 10a–c in good yields
(82–86%). HPLC analysis of these compounds (Chiralcel OD column) showed ee values essentially
identical to those of the starting epoxy alcohols (91, 93 and 94% ee, respectively) although we could

M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
4643
confirm by analysis of a sample that was stored overnight, that the intermediate aldehyde racemized on
standing.
As a demonstration of the orthogonal nature of the nitrogen protection, all three amino acids were
esterified and both protecting groups were selectively removed. The cleavage of the p-methoxybenzyl
group in 10a–c took place cleanly with CAN, affording the Boc-amino esters 11a–c, in good yields
(Scheme 2). On the other hand, the Boc group in 10b could be readily removed with HCl/MeOH, leading
to the PMB-protected (S)-butenyl glycine methyl ester 12b in 81% yield
In summary, we have developed a new methodology for the synthesis of unsaturated α-amino acids
from epoxy alcohols using p-methoxybenzylamine as an ammonia equivalent. As representative ex-
amples of this interesting class of compounds we have described the preparation of enantiomerically
enriched, fully protected, allyl, butenyl and pentenyl glycines in only three separate steps from the corres-
ponding allyl alcohols. The intrinsic characteristics of our methodology, which uses a Sharpless catalytic
epoxidation as the sole source of chirality, make it extendable to amino acids of both enantiomeric series
bearing carbon–carbon double bonds at the side chain. Moreover, the protection of the amino function
with two orthogonal groups (p-methoxybenzyl and Boc) confers to the intermediates in the sequence a
great potential as synthetic intermediates. Results on the evaluation of this potential will be reported in
due course.
3. Experimental
3.1. General
Optical rotations were recorded at room temperature (23°C) (concentration in g/100 mL. Infrared
spectra were recorded using film NaCl technique. 1H NMR were obtained at 200 or 300 MHz (s=singlet,
d=doublet, t=triplet, q=quartet, dt=double triplet, m=multiplet, b=broad and bd=broad doublet). 13C
NMR were obtained at 50.3 MHz or 75.4 MHz. Carbon multiplicities have been assigned by distor-
tionless enhancement by polarization transfer (DEPT) experiments. Low resolution mass spectra were
recorded in CI mode using ammonia. High-resolution mass spectra (CI) were performed by the Servicio
de Espectrometría de Masas, Universidad de Córdoba using methane. Elemental analyses were performed
by the ‘Servei d’Anàlisis Elementals del CSIC de Barcelona’. Dichloromethane was distilled from CaH2
under nitrogen prior to use. Chromatographic separations were carried out using NEt3 pre-treated (2.5%
v/v) SiO2 (70–230 mesh). (E)-2,5-Hexadien-1-ol 4a27 and (E)-2,7-octadien-1-ol 4c28 were prepared
according to the procedures described in the literature.
3.2. (E)-2,6-Heptadienoic acid methyl ester 6
To a solution of oxalyl chloride (4.2 mL) in anhydrous dichloromethane (90 mL) at −60°C were
sequentially added, dropwise and under stirring, dimethyl sulfoxide (7.1 mL) in anhydrous dichlorome-
thane (22.5 mL) and a solution of 4-penten-1-ol 5 (3.5 g, 40.7 mmol) in anhydrous dichloromethane
(37.7 mL). After 15–20 min, triethylamine (28.6 mL) was added dropwise and stirring was continued at
the same temperature. After 20–25 min, the reaction mixture was allowed to warm to room temperature.
Then, water (188 mL) was added and phases were separated. The aqueous layer was extracted with
dichloromethane and the combined organic phases were washed with 5% hydrochloric acid and brine,
dried over magnesium sulfate and concentrated (to ca. 100 mL) under reduced pressure without heating.
To this solution (containing mainly 4-pentenal), was added methyl triphenylphosphoranylacetate (15 g,

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M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
44.8 mmol) with stirring and the mixture was heated at reflux for 2 h. The solvent was removed in vacuo
and the residual oil extracted with hexanes. The hexane solution was evaporated and the resulting oil
purified by column chromatography eluting with hexanes:ethyl acetate (95:5) to afford 4.56 g of 6 (80%
1
yield) as an oil. IR (NaCl) ν 3090, 1730, 1660 cm−1. H NMR (200 MHz, CDCl3) δ 6.95 (m, 1H),
5.9–5.7 (m, 2H), 5.1–4.95 (m, 2H), 3.73 (s, 3H), 2.26 (m, 4H) ppm. 13C NMR (50 MHz, CDCl3) δ 167.0
(C), 148.6 (CH), 137.0 (CH), 121.2 (CH), 115.5 (CH2), 51.4 (CH3), 32.0 (CH2), 31.4 (CH2).
3.3. (E)-2,6-Heptadien-1-ol 4b
To a solution of 6 (2.6 g, 18 mmol) in diethyl ether (24 mL) at 0°C, DIBALH (46.3 mL, 1 M in hexanes)
was added dropwise. The reaction mixture was allowed to warm up to room temperature, and stirred for
1.5 h, diluted with diethyl ether (77 mL), cooled to 0°C and quenched with careful addition of brine
(60 mL). Then, 4 M HCl was added dropwise under stirring until two clear phases were formed (ca. 46
mL). The aqueous layer was extracted with diethyl ether and the combined organic phases were washed
with brine, dried (sodium sulfate) and evaporated. The residue was purified by column chromatography
eluting with hexanes/ethyl acetate mixtures yielding 1.7 g of 4b (82% yield) as an oil. IR (NaCl) ν 3332,
1
3
3079, 1642 cm−1. H NMR (200 MHz, CDCl3) δ 5.9–5.6 (m, 3H), 5.0 (m, 2H), 4.07 (d, J(H,H)=4.4
Hz, 2H), 2.2–2.1 (m, 5H). 13C NMR (50 MHz, CDCl3) δ 138.0 (CH), 132.1 (CH), 129.3 (CH), 114.7
(CH2), 63.4 (CH2), 32.2 (CH2), 31.4 (CH2).
3.4. (2R,3R)-2,3-Epoxy-5-hexen-1-ol 3a
In a 250 mL round-bottomed flask were placed anhydrous powdered 4 Å molecular sieves (1.1 g)
and anhydrous dichloromethane (107 mL) under nitrogen. After cooling to −20°C (CO2/CCl4 bath) the
following reagents were introduced sequentially via cannula under stirring: D-(−)-diisopropyl tartrate
(1.0 g, 4.3 mmol) in dichloromethane (1 mL), titanium tetraisopropoxide (1.07 mL, 3.55 mmol) and
a 2.78 M solution of tert-butyl hydroperoxide in isooctane (25.8 mL, 94.6 mmol). The mixture was
stirred for 1 h at –20°C and a solution of 4a (3.5 g, 35.7 mmol) (previously distilled and stored for 24
h over 4 Å molecular sieves) in dichloromethane (18 mL) was added dropwise. After 3.5 h stirring at
that temperature, the reaction was quenched by addition of 10% NaOH solution saturated with NaCl
(2.86 mL) and diethyl ether (17 mL). The mixture was then allowed to warm up to 10°C, and anhydrous
MgSO4 (2.86 g) and Celite (0.36 g) were added. After 15 min stirring at room temperature the mixture
was filtered through a short pad of Celite, the solvents were evaporated in vacuo and the excess of
tert-butyl hydroperoxide removed by azeotropic distillation with toluene. The crude product was then
purified by column chromatography eluting with hexanes/ethyl acetate mixtures to yield 3.33 g of 3a
1
(82% yield) as an oil. [α]D23=+35.4 (c=1.2, CHCl3); [lit.27 [α]D23=+23.2 (c=10, CH3OH)]. H NMR
(200 MHz, CDCl3) δ 5.8 (m, 1H), 5.2–5.0 (m, 2H), 3.95 (d, 3J(H,H)=12 Hz), 3.65 (d, 3J(H,H)=12 Hz,
1H), 3.0 (m, 2H), 2.37 (m, 2H), 1.8 (s, 1H). 13C NMR (50 MHz, CDCl3): δ=132.8 (CH), 117.7 (CH2),
61.7 (CH2), 58.2 (CH), 54.8 (CH), 35.6 (CH2). The enantiomeric excess was determined to be 92% by
HPLC analysis of its p-toluenesulfonate ester. HPLC (Chiralcel® OD column; 25 cm): 30°C, 254 nm;
0.5 mL/min; hexane 90%/isopropyl alcohol 10%; tR (2R,3R)=17.37 min; tR (2S,3S)=18.58 min.
3.5. (2R,3R)-2,3-Epoxy-6-hepten-1-ol 3b
Following the procedure described for the preparation of 3a but starting from 4b (5.3 g, 47.3 mmol),
5.57 g of 3b (92% yield) were obtained as an oil. Bp 125°C/18 torr.34 [α]D23=+34.5 (c=2, CHCl3). IR

M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
4645
(NaCl) ν 3423, 2981, 2929, 1642 cm−1. 1H NMR (200 MHz, CDCl3) δ 5.9 (m, 1H), 5 (m, 2H), 3.9 (m,
1H), 3.63 (m, 1H), 2.95 (m, 2H), 2.2 (m, 2H), 1.8–1.6 (m, 2H). 13C NMR (50 MHz, CDCl3) δ 137.3
(CH), 115.2 (CH2), 61.7 (CH2), 58.7 (CH), 55.4 (CH), 30.8 (CH2), 30.0 (CH2). MS (CI-NH3): m/z (%):
163 (33) [M+35]+, 146 (100) [M+18]+. The enantiomeric excess was determined to be 94% by HPLC
analysis of its p-toluenesulfonate. HPLC (Chiralcel® OD column; 25 cm): 30°C, 254 nm; 0.5 mL/min;
hexane 90%/isopropyl alcohol 10%; tR (2R,3R)=17.37 min; tR (2S,3S)=18.70 min.
3.6. (2R,3R)-2,3-Epoxy-7-octen-1-ol 3c
Following the procedure described for the preparation of 3a but starting from 4c (6.4 g, 50 mmol),
6.1 g of 3c (85% yield) were obtained as an oil. [α]D23=+38.6 (c=1.8, CHCl3). IR (NaCl) ν 3425, 2979,
2935, 1642 cm−1. 1H NMR (200 MHz, CDCl3) δ 5.8 (m, 1H), 5 (m, 2H), 3.89 (m, 1H), 3.58 (m, 1H), 3
(m, 3H), 2.1 (m, 2H), 1.6 (m, 4H). 13C NMR (50 MHz, CDCl3) δ 137.9 (CH), 114.7 (CH2), 61.7 (CH2),
58.6 (CH), 55.8 (CH), 33.2 (CH2), 30.8 (CH2), 25.0 (CH2). The enantiomeric excess was determined to
be 91% by HPLC analysis of its p-toluenesulfonate. HPLC (Chiralcel® OD column; 25 cm): 30°C, 254
nm; 0.5 mL/min; hexane 90%/isopropyl alcohol 10%; tR (2R,3R)=16.48 min; tR (2S,3S)=17.94 min.
3.7. (2S,3S)-3-[tert-Butoxycarbonyl-(4-methoxybenzyl)-amino]hex-5-en-1,2-diol 2a
To a solution of freshly distilled 3a (1.0 g, 9 mmol) in anhydrous dichloromethane (12 mL), titanium
tetraisopropoxide (9.3 mL, 31.3 mmol) was added. The mixture was briefly stirred and a solution of
p-methoxybenzylamine (2.87 g, 20.9 mmol, freshly distilled) in anhydrous dichloromethane (12 mL)
was added via cannula. The reaction mixture was then heated at reflux with stirring for 24 h, allowed
to cool down to room temperature and quenched by addition of 10% NaOH solution saturated with
NaCl (36.2 mL). The mixture was stirred for 5 h, filtered through a short pad of Celite and washed
thoroughly with dichloromethane. The aqueous layer was extracted with dichloromethane and the
combined organic phases were dried (MgSO4) and evaporated. The crude product (a mixture of (2S,3S)-
3-(4-methoxybenzylamino)-5-hexene-1,2-diol and p-methoxybenzylamine) was directly used in the next
step.
To a solution of the previously obtained reaction crude in MeOH (105 mL), Boc2O (5.92 g, 27.2
mmol), and NaHCO3 (5.22 g) were added. The suspension was sonicated in a cleaning bath until the
evolution of CO2 ceased (ca. 4 h). The solids were then filtered and the solvent evaporated. Addition
of 105 mL of ether provoked the precipitation of small quantities of salts that were also filtered off.
Evaporation of the solvent afforded a crude product that was purified by column chromatography eluting
with hexanes/ethyl acetate mixtures to yield 2.26 g of 2a (72% overall yield). [α]D23=+3.2 (c=1.5,
CHCl3). IR (NaCl) ν 3419, 3076, 1665, 1613 cm−1. 1H NMR (200 MHz, CDCl3) δ 7.16 (d, 3J(H,H)=8.5
Hz, 2H), 6.83 (d, 3J(H,H)=8.5 Hz, 2H), 5.7 (m, 1H), 5.1–4.9 (m, 2H), 4.29 (m, 2H), 3.78 (s, 3H), 4.1–3.0
(m, 4H), 2.57 (m, 2H), 1.48 (s, 9H). 13C NMR (50 MHz, CDCl3) δ 158.9 (C), 156.5 (C), 135.4 (CH),
130.4 (C), 129.1 (CH), 116.9 (CH2), 113.8 (CH), 80.8 (C), 73.8 (CH), 63.4 (CH2), 59.4 (CH), 55.1 (CH3),
50.3 (CH2), 31.7 (CH2), 28.3 (CH3). MS (CI-NH3): m/z (%): 352 (100) [M+1]+, 369 (1) [M+18]+, 296
(3), 297 (1). HRMS calcd for C19H29NO5: 351.2030, found 351.2046.
3.8. (2S,3S)-3-[(4-Methoxybenzyl)amino]hept-5-en-1,2-diol 7b
To a solution of freshly distilled 3b (4.9 g, 38.3 mmol) in anhydrous dichloromethane (44 mL),
titanium tetraisopropoxide (34.5 mL, 115 mmol) was added. The mixture was stirred for several

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M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
minutes, a solution of p-methoxybenzylamine (10.5 g, 76.5 mmol, freshly distilled) in anhydrous
dichloromethane (44 mL) was added via cannula and the mixture was heated to reflux. After 48 h
reflux, the reaction mixture was allowed to cool down to room temperature, quenched (5 h stirring)
with 10% NaOH solution saturated with NaCl (134 mL), filtered through a short pad of Celite and
thoroughly washed with dichloromethane. The aqueous layer was extracted with dichloromethane and
the combined organic phases were extracted with 0.1N HCl. The organic phase was dried (MgSO4)
and evaporated to afford 1.58 g of pure 7b. The combined aqueous layers were brought to pH 9 with
2N NaOH and extracted with dichloromethane. The organic phase was dried (MgSO4), concentrated in
vacuo, and the residue dissolved in diethyl ether. To this solution, solid CO2 was added to precipitate the
excess p-methoxybenzylamine as the carbonate. The precipitate was filtered off and washed with ether
saturated with CO2. Evaporation of this ether solution afforded 8.43 g of crude 7b (containing 23% of
p-methoxybenzylamine) that was used in the next step without further purification. The estimated overall
yield was 80%. [α]D23=+10.2 (c=2.1, CHCl3). IR (NaCl) ν 3361, 2935, 1640, 1613 cm−1. 1H NMR (200
MHz, CDCl3) δ 7.22 (d, 3J(H,H)=8.5 Hz, 2H), 6.87 (d, 3J(H,H)=8.5 Hz, 2H), 5.8 (m, 1H), 5.1–4.95 (m,
2H), 3.8 (s, 3H), 3.8–3.6 (m, 5H), 2.8 (m, 1H), 2.1 (m, 2H), 1.6 (m, 2H). 13C NMR (50 MHz, CDCl3) δ
158.7 (C), 137.8 (CH), 131.9 (C), 129.3 (2CH), 115.2 (CH2), 113.8 (2CH), 71.4 (CH), 64.3 (CH2), 59.9
(CH), 55.2 (CH3), 51.7 (CH2), 30.2 (CH2), 29.6 (CH2). MS (CI-NH3): m/z (%): 266 (100) [M+1]+, 204
(3). HRMS calcd for C15H24NO3: 266.1756, found 266.1713.
3.9. (2S,3S)-3-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]hept-5-en-1,2-diol 2b
From pure 7b: A mixture of 7b (100 mg, 0.38 mmol), Boc2O (100 mg, 0.456 mmol), and NaHCO3
(94 mg) in MeOH (1.9 mL) was sonicated in a cleaning bath until the evolution of CO2 ceased (ca. 4 h).
The solids were then filtered off, and the solvent evaporated. The crude product was purified by column
chromatography eluting with hexanes/ethyl acetate mixtures to afford 110 mg of 2b (80% yield).
From crude 7b: Following the procedure described above but starting from 2 g of crude 7b containing
23% of p-methoxybenzylamine, 1.6 g of 2b (75% yield) were obtained as an oil. [α]D23=−8.9 (c=1.6,
CHCl3). IR (NaCl) ν 3423, 1663, 1613, 1586 cm−1. 1H NMR (200 MHz, CDCl3) δ 7.19 (d, 3J(H,H)=8.5
Hz, 2H), 6.84 (d, 3J(H,H)=8.5 Hz, 2H), 5.7 (m, 1H), 5.0–4.9 (m, 2H), 4.3 (s, 2H), 3.78 (s, 3H), 3.8–3.2
(m, 4H), 2.1–1.8 (m, 4H), 1.49 (s, 9H). 13C NMR (50 MHz, CDCl3) δ 158.8 (C), 157.2 (C), 137.8 (CH),
130.4 (C), 129.1 (CH), 114.9 (CH2), 113.8 (CH), 80.9 (C), 73.5 (CH), 63.2 (CH2), 58.4 (CH), 55.2
(CH3), 49.0 (CH2), 30.6 (CH2), 28.4 (CH3), 26.4 (CH2). MS (CI-NH3): m/z (%): 366 (100) [M+1]+, 383
(3) [M+18]+. Anal. calcd for C20H31NO5: C 65.73, H 8.55, N 3.83; found C 65.64, H 8.63, N 3.91.
3.10. (2S,3S)-3-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]oct-7-en-1,2-diol 2c
Following the procedure described for the preparation of 2a, but starting from 3c (6.0 g, 42.2 mmol),
9.0 g of 2c (56% yield) were obtained as an oil. [α]D23=–10.5 (c=1.9, CHCl3). IR (NaCl) ν 3419, 1663,
1613, 1586 cm−1. 1H NMR (200 MHz, CDCl3) δ 7.18 (d, 3J(H,H)=8.5 Hz, 2H), 6.84 (d, 3J(H,H)=8.5
Hz, 2H), 5.75 (m, 1H), 5 (m, 2H), 4.3 (m, 3H), 3.8 (s, 3H), 3.7–3 (m, 3H), 2.1–1.8 (m, 4H), 1.5 (s,
9H), 1.3 (m, 2H). 13C NMR (50 MHz, CDCl3) δ 158.8 (C), 157.3 (C), 138.4 (CH), 130.5 (C), 129.1
(CH), 114.6 (CH2), 113.8 (CH), 81.1 (C), 73.5 (CH), 63.1 (CH2), 58.8 (CH), 55.2 (CH3), 49.0 (CH2),
33.6 (CH2), 28.5 (CH3), 26.6 (CH2), 26.0 (CH2). HRMS calcd for C21H34NO5 (M+1): 380.2437, found
380.2436.

M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
4647
3.11. (2S,3S)-3-[(tert-Butoxycarbonyl)amino]-5-hepten-1,2-diol 8b
To a solution of 2b (200 mg, 0.55 mmol) in CH3CN:H2O (3:1) (2.2 mL), ceric ammonium nitrate (600
mg, 1.1 mmol) was added. After 0.5 h, the mixture was diluted with dichloromethane (82 mL) and the
organic layer was washed with saturated aqueous NaHCO3 (41 mL). The combined organic phases were
dried with MgSO4 and evaporated. The crude product was purified by column chromatography eluting
with hexanes/ethyl acetate mixtures to afford 72 mg of 8b (54% yield). [α]D23=–6.4 (c=3.1, CHCl3). IR
(NaCl) ν 3355, 1684 cm−1. 1H NMR (200 MHz, CDCl3) δ 5.8 (m, 1H), 5.1–4.9 (m, 2H), 3.75 (b, 1H),
3.9–3.2 (m, 4H), 2.3–1.8 (m, 4H), 1.45 (s, 9H). 13C NMR (50 MHz, CDCl3) δ 157.1 (C), 137.6 (CH),
115.2 (CH2), 80.2 (C), 74.5 (CH), 63.1 (CH2), 51.9 (CH), 30.2 (CH2), 28.3 (CH3), 26.4 (CH2).
3.12. (2S)-2-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-4-pentenoic acid 9a
To a solution of 2a (675 mg, 1.9 mmol), in 7.5 mL THF:H2O (1:3) was added NaIO4 (616 mg, 2.9
mmol). After 2 h stirring at room temperature, the solution was diluted with water and dichloromethane
until two clear phases formed. The aqueous layer was extracted with dichloromethane and the combined
organic phases were dried over Na2SO4 and concentrated in vacuo without heating. The crude product
(557 mg) was placed in a pressure tube, immediately dissolved in tBuOH (8.9 mL) and a solution of 2-
methyl-2-butene (0.38 mL, 6.63 mmol) in THF (1.4 mL) and a solution of sodium chlorite (80% purity,
257 mg, 2.28 mmol) and NaH2PO4 (252 mg, 2.1 mmol) in H2O (2.2 mL) were sequentially added to this
solution. The reaction flask was hermetically sealed and the mixture was vigorously stirred at 25°C for 15
h. Then, it was extracted with dichloromethane (2×61 mL) and the organic phase was washed with 0.1
M NaHSO4 (41 mL) and water (28 mL). Solvent evaporation in vacuo afforded 518 mg of acid 9a (81%
1
yield). [α]D23=–28.0 (c=2, CHCl3). IR (NaCl) ν 3080, 1744, 1700, 1613 cm−1. H NMR (200 MHz,
CDCl3) δ 7.21 (bd, 2H), 6.84 (d, 3J(H,H)=8.8 Hz, 2H), 5.6 (m, 1H), 5.0 (m, 2H), 4.7–4.0 (m, 3H), 3.79
(s, 3H), 2.67 (m, 2H), 1.45 (s, 9H). 13C NMR (50 MHz, CDCl3) δ 176.9–175.6* (C), 158.9 (C), 134.3
(CH, C), 120.0 (CH), 129.0 (CH), 117.9 (CH2), 113.7 (CH), 81.3 (C), 64.4–59.1* (CH), 55.2 (CH3), 51.4
(CH2), 34.7–33.7* (CH2), 28.3 (CH3) (signals marked with an asterisk correspond to a rotamer). HRMS
calcd for C18H25NO5: 335.1716, found 335.1733.
3.13. (2S)-2-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-4-pentenoic acid methyl ester 10a
To a solution of 9a (518 mg, 1.55 mmol) in dimethylformamide (1.5 mL), were added under nitrogen
KHCO3 (317 mg, 3.1 mmol) and methyl iodide (150 mL, 2.4 mmol). The mixture was stirred for 16
h at room temperature and then the reaction was quenched by addition of water (6.2 mL). The product
was extracted with (1:1) benzene:ethyl acetate mixtures. The combined organic phases were successively
washed with water, 5% Na2SO3 and brine, dried over MgSO4 and evaporated. The crude product was
purified by chromatography eluting with hexanes:ethyl acetate (95:5) to afford 458 mg of 10a (84%
yield). [α]D23=–44.2 (c=1.8, CHCl3). IR (NaCl) ν 2979, 1744, 1698, 1613, 1588 cm−1. 1H NMR (200
MHz, CDCl3) δ 7.22 (bd, 2H), 6.84 (d, 3J(H,H)=8.5 Hz, 2H), 5.8–5.5 (m, 1H), 5.0 (m, 2H), 4.6–4.3 (m,
3H), 3.79 (s, 3H), 3.59 (s, 3H), 2.8–2.4 (m, 2H), 1.45 (s, 9H). 13C NMR (50 MHz, CDCl3): δ=171.5 (C),
158.7 (C), 152.1 (C), 134.4 (CH, C), 129.9 (CH), 128.8 (CH), 117.5 (CH2), 113.5 (CH), 80.5 (C), 59.1*
(CH), 55.2 (CH3), 51.8 (CH3), 51.0–49.8* (CH2), 34.9–33.9* (CH2), 28.3 (CH3) (signals marked with
an asterisk correspond to a rotamer). MS (CI-NH3): m/z (%): 367 (10) [M+18]+, 350 (100) [M+1]+, 311
(11), 294 (11). HRMS calcd for C19H27NO5: 349.1889, found 349.1895. The enantiomeric excess was

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M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
determined to be 91% by HPLC (Chiralcel® OD column; 25 cm): 30°C; 254 nm; 0.5 mL/min; hexane
99%/isopropyl alcohol 1%; tR (2R)=25.35 min; tR (2S)=27.65 min.
3.14. (2S)-2-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-5-hexenoic acid 9b
Following the procedure described for the preparation of 9a but starting from 2b (527 mg, 1.44 mmol),
437 mg of 9b (87% yield) were obtained. [α]D23=–32 (c=1.1, CHCl3). IR (NaCl) ν 3250, 1700, 1613,
1586 cm−1. 1H NMR (200 MHz, CDCl3) δ 7.21 (bd, 2H), 6.85 (d, 3J(H,H)=8.8 Hz, 2H), 5.65 (m, 1H),
5.1–4.8 (m, 2H), 4.55 (b, 1H), 4.5–4.1 (m, 2H), 3.8 (s, 3H), 2.2–1.6 (m, 4H), 1.46 (s, 9H). 13C NMR
(50 MHz, CDCl3) δ 175.0 (C), 159.0 (C), 157.0 (C), 137.2 (CH), 130.0 (CH, C), 115.6 (CH2), 113.8
(CH), 81.3 (C), 59 (CH), 55.3 (CH3), 51.1 (CH2), 30.5 (CH2), 29.7 (CH2), 28.3 (CH3). HRMS calcd for
C19H27NO5: 349.1896, found 349.1889.
3.15. (2S)-2-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-5-hexenoic acid methyl ester 10b
Following the procedure described for the preparation of 10a but starting from 9b (437 mg, 1.25
mmol), 372 mg of 10b (82% yield) were obtained. [α]D23=–49.7 (c=1.8, CHCl3). IR (NaCl) ν 1744,
1698, 1613 cm−1. 1H NMR (200 MHz, CDCl3) δ 7.22 (bd, 2H), 6.84 (d, 3J(H,H)=8.8 Hz, 2H), 5.7 (m,
1H), 5.1–4.8 (m, 2H), 4.4 (m, 3H), 3.79 (s, 3H), 3.59 (s, 3H), 2.2–1.7 (m, 4H), 1.45 (s, 9H). 13C NMR
(50 MHz, CDCl3) δ 172.1 (C), 158.8 (C), 155.6 (C), 137.4 (CH), 129.7 (CH, C), 115.3 (CH2), 113.6
(CH), 80.5 (C), 58.4 (CH), 55.2 (CH3), 51.8 (CH3), 50.3 (CH2), 30.5 (CH2), 29.6 (CH2), 28.3 (CH3).
MS (CI-NH3): m/z (%): 381 (10) [M+18]+, 364 (100) [M+1]+, 325 (11%). Anal. calcd for C20H29NO5
C 66.09, H 8.04, N 3.85; found: C 66.05, H 8.12, N 4.10. The enantiomeric excess was determined to
be 93% by HPLC (Chiralcel® OD column; 25 cm): 30°C; 254 nm; 0.5 mL/min; hexane 99%/isopropyl
alcohol 1%; tR (2R)=23.11 min; tR (2S)=24.13 min.
3.16. (2S)-2-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-5-heptenoic acid 9c
Following the procedure described for the preparation of 9a but starting from 2c (802 mg, 2.12 mmol),
556 mg of 9c (72% yield) were obtained. [α]D23=–24.6 (c=2.1, CHCl3). IR (NaCl) ν 3078, 1698, 1613,
1
3
1588 cm−1. H NMR (200 MHz, CDCl3) δ 7.2 (bd, 2H), 6.84 (d, J(H,H)=8.8 Hz, 2H), 5.8–5.5 (m,
1H), 5.0–4.8 (m, 2H), 4.6–4.1 (m, 3H), 3.79 (s, 3H), 2.1–1.6 (m, 4H), 1.45 (s, 9H), 1.4–1.2 (m, 2H). 13
C
NMR (50 MHz, CDCl3) δ 176.2–177.5* (C), 158.8 (C), 155.6 (C), 138.0 (CH), 129.8 (CH, C), 128.8
(CH), 114.7 (CH2), 113.7 (CH), 81.2 (C), 60.3–59.1* (CH), 55.2 (CH3), 50.8 (CH2), 33.2 (CH2), 29.7
(CH2), 28.3 (CH3), 25.7 (CH2) (signals marked with an asterisk correspond to a rotamer). HRMS calcd
for C20H29NO5 (M+): 363.2046, found 363.2045.
3.17. (2S)-2-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-5-hexenoic acid methyl ester 10c
Following the procedure described for the preparation of 10a but starting from 9c (395 mg, 1.09
mmol), 397 mg of 10c (86% yield) were obtained. [α]D23=–38.0 (c=2.0, CHCl3). IR (NaCl) ν 1744,
1698, 1613 cm−1. 1H NMR (200 MHz, CDCl3) δ 7.2 (bd, 2H), 6.84 (d, 3J(H,H)=8.4 Hz, 2H), 5.8–5.5
(m, 1H), 5.0–4.8 (m, 2H), 4.6–4.2 (m, 3H), 3.79 (s, 3H), 3.58 (s, 3H), 2.0–1.6 (m, 4H), 1.45 (s, 9H),
1.5–1.2 (m, 2H). 13C NMR (50 MHz, CDCl3) δ 172 (C), 158.5 (C), 156 (C), 138.1 (CH), 129.8 (CH, C),
128.7 (CH), 114.6 (CH2), 113.5 (CH), 80.5 (C), 59.1–58.5* (CH), 55.2 (CH3), 51.8 (CH3), 50.4–49.1*
(CH2), 33.3 (CH2), 29.7 (CH2), 28.3 (CH3), 25.6 (CH2) (signals marked with an asterisk correspond to

M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
4649
a rotamer). HRMS calcd for C21H32NO5 (M+1+): 378.2280, found, 378.2294. The enantiomeric excess
was determined to be 94% by HPLC (Chiralcel® OD column; 25 cm): 30°C; 254 nm; 0.42 mL/min;
hexane 99%/isopropyl alcohol 1%; tR (2R)=26.71 min; tR (2S)=29.08 min.
3.18. (2S)-2-[(tert-Butoxycarbonyl)amino]-4-pentenoic acid methyl ester 11a
To a solution of 10a (425 mg, 1.22 mmol) in CH3CN:H2O (3:1) (4.9 mL), ceric ammonium nitrate
(1.34 mg, 2.44 mmol) was added. After 20–30 min stirring, dichloromethane (182 mL) was added and
the organic layer was washed with saturated aqueous NaHCO3 (91 mL). The combined organic phases
were dried (MgSO4) and evaporated. The crude product was purified by column chromatography eluting
with hexanes/ethyl acetate mixtures to afford 269 mg of 11a (75% yield). [α]D23=–7.9 (c=1.3, MeOH)
1
(lit.13b [α]D23=–9 (c=2, MeOH), ee>95%). IR (NaCl) ν 3367, 1748, 1719 cm−1. H NMR (200 MHz,
CDCl3) δ 5.67 (m, 1H), 5.1 (m, 2H), 4.35 (m, 1H), 3.71 (s, 3H), 2.5 (m, 2H), 1.41 (s, 9H). 13C NMR (50
MHz, CDCl3) δ 172.4 (C), 155.0 (C), 132.2 (CH), 119.0 (CH2), 79.8 (C), 52.8 (CH), 52.2 (CH3), 36.7
(CH2), 28.3 (CH3). MS (CI-NH3): m/z (%): 247 (100) [M+18]+, 230 (71) [M+1]+, 191 (28), 174 (10).
3.19. (2S)-2-[(tert-Butoxycarbonyl)amino]-5-hexenoic acid methyl ester 11b
Following the procedure described for the preparation of 11a but starting from 10b (324 mg, 0.89
mmol), 168 mg of 11b (77% yield) were obtained. [α]D23=–14.5 (c=1.2, MeOH) (lit.13b,c [α]D23=–17
(c=1.2, MeOH), ee>95%). IR (NaCl) ν 3367, 1717, 1642 cm−1. 1H NMR (200 MHz, CDCl3) δ 5.8 (m,
1H), 5.1–5.0 (m, 2H), 4.3 (m, 1H), 3.73 (s, 3H), 2.1 (m, 2H), 2–1.6 (m, 2H), 1.44 (s, 9H). 13C NMR (50
MHz, CDCl3) δ 173.1 (C), 155.2 (C), 136.8 (CH), 115.6 (CH2), 79.8 (C), 52.9 (CH), 52.2 (CH3), 31.9
(CH2), 29.4 (CH2), 28.3 (CH3).
3.20. (2S)-2-[(tert-Butoxycarbonyl)amino]-5-heptenoic acid methyl ester 11c
Following the procedure described for the preparation of 11a but starting from 10c (182 mg, 0.48
mmol), 54 mg of 11c (44% yield) were obtained. [α]D23=–10.6 (c=1.3, CHCl3). IR (NaCl) ν 3367,
1
1719, 1642 cm−1. H NMR (200 MHz, CDCl3) δ 5.9–5.6 (m, 1H), 5.1–4.9 (m, 2H), 4.4–4.2 (m, 1H),
3.74 (s, 3H), 2.07 (m, 2H), 1.9–1.2 (m, 4H), 1.45 (s, 9H). 13C NMR (50 MHz, CDCl3) δ 173.3 (C), 155.2
(C), 137.9 (CH), 115.0 (CH2), 79.8 (C), 53.3 (CH), 52.2 (CH3), 33.2 (CH2), 32.2 (CH2), 28.3 (CH3), 24.5
(CH2).
3.21. (2S)-2-[(4-Methoxybenzyl)amino]-5-hexenoic acid methyl ester 12b
A solution of 10b (60 mg, 0.165 mmol), in 2.78 M HCl in MeOH (3 mL) was stirred for 6 h. The
solvent was removed in vacuo and the crude was dissolved in saturated NaHCO3. Then the solution was
extracted with diethyl ether and the combined organic phases were dried over MgSO4 and evaporated
to afford 35 mg of 12b (81% yield). [α]D=–24.9 (c=1.1, CHCl3). IR (NaCl) ν 3332, 3078, 2931, 2838,
1737, 1613 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.17 (d, J=8.7 Hz, 2H), 6.78 (d, J=8.7 Hz, 2H), 5.7 (m,
1H), 4.9 (m, 2H), 3.72 (s, 3H), 3.67 (d, J=12.6 Hz, 1H), 3.65 (s, 3H), 3.48 (d, J=12.6, 1H), 3.2 (t, J=7 Hz,
1H), 2.1 (m, 2H), 1.7 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 176.0 (C), 158.7 (C), 137.7 (CH),
132.0 (C), 129.4 (CH), 115.2 (CH2), 113.8 (CH), 60.0 (CH), 55.3 (CH3), 51.6 (CH3, CH2), 32.7 (CH2),
30.0 (CH2) ppm.

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M. Alcón et al. / Tetrahedron: Asymmetry 10 (1999) 4639–4651
Acknowledgements
Financial support from CIRIT (1996SGR-00013 and 1998SGR-00005) and from DGICYT (PB98-
1246 and PB97-0939) is gratefully acknowledged. M.A. thanks CIRIT (Generalitat de Catalunya) for a
fellowship.
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