Stereoselective synthesis of unsaturated and functionalized L-NHBoc amino acids, using wittig reaction under mild phase-transfer conditions

Article abstract of DOI:10.1021/jo3013622

The stereoselective synthesis of a new amino acid phosphonium salt was described by quaternization of melting triphenylphosphine with the β-iodo NHBoc-amino ester, derived from l-aspartic acid. The deprotection of the carboxylic acid function to afford the phosphonium salt with a free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid-liquid phase-transfer conditions in chlorobenzene and in the presence of K₃PO₄ as weak base, to afford the corresponding unsaturated amino acids without racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids, directly usable for the synthesis of customized peptides.

Full text of DOI:10.1021/jo3013622

Article
pubs.acs.org/joc
Stereoselective Synthesis of Unsaturated and Functionalized
L‑NHBoc Amino Acids, Using Wittig Reaction under Mild Phase-
Transfer Conditions
Emmanuelle Remond, Jerome Bayardon, Marie-Joelle Ondel-Eymin, and Sylvain Juge*
́
́
̂
́
̈
†Institut de Chimie Molec
BP47870, 21078 Dijon Cedex, France
́
ulaire de l’Universite
́
de Bourgogne (ICMUB- Ster
́
eo
́
chIM-UMR CNRS 6302), 9 avenue A. Savary
S
* Supporting Information
ABSTRACT: The stereoselective synthesis of a new amino
acid phosphonium salt was described by quaternization of
melting triphenylphosphine with the γ-iodo NHBoc-amino
ester, derived from L-aspartic acid. The deprotection of the
carboxylic acid function to afford the phosphonium salt with a
free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the
Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid−liquid phase-transfer conditions in
chlorobenzene and in the presence of K3PO4 as weak base, to afford the corresponding unsaturated amino acids without
racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of
the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid
Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid
phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids,
directly usable for the synthesis of customized peptides.
1). In a pioneering work, Itaya et al. described the use of the
phosphonium salt 1a derived from L-serine, for the synthesis of
unusual amino acids by reaction with an aldehyde.19 Likewise,
an alternative route was reported by Sibi et al., using the
phosphonium salt 2 derived from alaninol.20 Another approach
is based on the reaction of a phosphonium ylide with an
aldehyde prepared from L-glutamic acid. However, in this case
the method involves preparing a new Wittig reagent for each
unsaturated amino acid synthesized.21 On the other hand, the
preparation of enone derived amino acids can be achieved in
good yields using a Horner−Wadsworth−Emmons reaction
between the β-ketophosphonate esters 3 and aldehydes.22
Anyway, the Wittig reaction involving an amino acid moiety
is rarely described in the literature, probably due to the
difficulty to prepare α-amino acid phosphonium salts, which are
demanding of strategies, and also the uncertainties on the
chemo- and enantioselectivity. As an example of constraint, the
phosphonium salt 1a was obtained by hydrogenolysis of the
benzyl ester only in the case of the chloride, which must be
prepared by counterion exchange.19 In a previous work, we
have reported an efficient preparation of phosphonium salt 1b
bearing a free carboxylic acid function by ring opening of
oxazolidine derived from L-serine.23 Unfortunately, its use in a
Wittig reaction with an aldehyde gave poor reactivity, and the
unsaturated amino acid was obtained as a racemic mixture.23
Therefore, we envisaged to synthesize a new class of α-amino
acid Wittig reagents, derived from L-aspartic acid 5,24 having
INTRODUCTION
■
The synthetic peptide market emerged in the recent past, and
today several dozen of these compounds are used for their
therapeutic applications.1 One of the reasons for this success is
that the pharmaceutical companies focus more and more on
biomolecules and customized peptide drugs with specific
properties, a field in full growth, on which intellectual property
is still widely available.1b On the other hand, numerous
challenging research subjects that are related to the current
vaccines, antibiotics, neurohormones, or biomarkers topics
involve also modified peptides.2,3 Therefore, the demand for
efficient sources of unusual amino acids useful for the high-
throughput synthesis of customized peptides is of crucial
interest to date.2 In this field, unsaturated amino acids3 are very
interesting and useful non-proteinogenic analogues that can be
functionalized by various chemical processes such as Diels−
Alder reactions,4 cycloadditions,5 and catalytic transformations
including hydroformylation,6 metathesis,7 Heck,8 or Suzuki−
Miyaura cross-coupling reactions.9 Furthermore, these com-
pounds are often used in peptide chemistry to confer a “β-turn”
secondary structure to induce new properties.10 Finally, several
unsaturated amino acids were used as enzyme inhibitors,11
antibiotics,12 markers,13 and intermediates in the total synthesis
of products of biological interest.14 Unusual amino acids
bearing a CC bond are mainly prepared using cationic,15
anionic,16 or radical17 equivalent of amino acids as well as by
metathesis7 or rearrangement.18
Another method is to synthesize the unsaturated amino acids
by CC bond formation on the lateral chain, using a Wittig−
Horner−Wadsworth−Emmons α-amino acid reagent (Figure
Received: July 2, 2012
Published: August 7, 2012
© 2012 American Chemical Society
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Figure 1. Wittig−Horner−Wadsworth−Emmons amino acid reagents.
a
Scheme 1. Synthesis of Chiral Amino Acid Wittig Reagent 4
a
Reagents and conditions: (a) (i) SOCl2, MeOH, 85%; (ii) Boc2O, Na2CO3, 75%; (iii) AllBr, K2CO3, 85%; (b) (i) Boc2O, DMAP, 98%; (ii) DIBAL
then NaBH4, 75%; (iii) Ph3P, I2, Imd, 91%.
both a free carboxylic function and the phosphonium moiety in
the γ-position of the lateral chain. The goal was to avoid
racemization or phosphine elimination, by deprotonation of the
carboxylic acid or in the α-position or still on the amide group,
respectively. We present herein the stereoselective synthesis of
the phosphonium salt 4 from L-aspartic acid 5 and its
application as Wittig reagent for the preparation of enantiopure
γ,δ-unsaturated NHBoc-amino acids.24b
n-BuLi, or t-BuLi, the corresponding unsaturated amino acids
11a were obtained with low yields and partially racemized. As
the phosphonium salt 4 may act as a phase-transfer agent, we
have envisaged to perform the reaction in heterogeneous
conditions, using an inorganic weak base (Scheme 2, Table
1).33
Table 1. Reaction of Wittig Reagent 4 with Benzaldehyde
a
10a under Phase-Transfer Conditions
RESULTS AND DISCUSSION
b
c
■
entry
base
solvent
% yield
% ee
99
Chiral amino acid phosphonium salt 4 was prepared in 60%
overall yield by quaternization of triphenylphosphine with the
γ-iodo NHBoc-amino allyl ester 8 and then deprotection to the
free carboxylic acid using palladium-catalyzed conditions
(Scheme 1).25 The γ-iodo amino ester 8 was previously
prepared from L-aspartic acid 5, according to modified literature
procedures with 75−98% chemical yield by step (Scheme
1).26−31 It should be noted that the iodide 7 was prepared as a
N,N-diBoc-amino ester derivative and then monodeprotected
to its derivative 8, by reaction with iodide ions in the presence
of cerium salt,31 in order to partially avoid this reaction by
quaternization with the phosphine. The enantiomeric purities
of the phosphonium salt allyl ester 9 and acid derivative 4 were
checked using the chiral hexacoordinated phosphorus BIN-
PHAT (Λ,R)-(1,1′-binaphthalene-2,2′diolato)(bis(tetrachlor-
1,2-benzenediolato)phosphat(V)) anion.32
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Li3PO4
EtOH
THF
6
8
DMF
PhCl
PhCl
PhCl
dioxane
PhCl
33
d
65
6
5
e
NaH
f
K2CO3
K3PO4
58
99
99
g
70
a
Reactions were performed at 90 °C during 15 h in 1.5 mL of solvent
and with ratio 4/10a/base = 1:1.5:6. Isolated yield after purification
b
c
by column chromatography. Determined by HPLC on chiral column
after esterification using TMSCHN2.34 Reaction time 48 h. Ratio 4/
d
e
f
10a/base = 1:1.5:.3 Water is added to the medium with a ratio H2O/4
= 0.8. 11a was obtained as a mixture of Z/E isomers with a 30:70
g
ratio.
When the amino acid phosphonium salt 4 is heated during
15 h in EtOH or THF with the benzaldehyde 10a in the
presence of Cs2CO3 as base, the corresponding γ,δ-unsaturated
amino acids 11a were obtained in low yields (entries 1, 2). If
the reaction was performed in DMF or chlorobenzene at 90 °C,
the γ,δ-unsaturated amino acid 11a was isolated with 33% and
65% yields, respectively (entries 3, 4). The use of Li3PO4 or
NaH as base in chlorobenzene at 90 °C did not lead to the
formation of the product 11a (entries 5, 6). When K2CO3 is
used in 1,4-dioxane and in the presence of 0.8 equiv of water,33
11a was obtained in 58% yield (entry 7). Finally, the best result
was obtained when the amino acid phosphonium salt 4 is
heated during 15 h in chlorobenzene with benzaldehyde 10a in
The Wittig reaction conditions of the amino acid
phosphonium salt 4 were first investigated with the
benzaldehyde 10a (Scheme 2). When the experiments were
performed in THF, using a strong base such as LiHMDS, LDA,
Scheme 2. Reaction of the Amino Acid Wittig Reagent 4
with Benzaldehyde 10a
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the presence of dry K3PO4 (entry 8).24b In these conditions, the
corresponding γ,δ-unsaturated NHBoc amino acid 11a was
obtained in 70% yield, as a Z/E mixture in the ratio 30:70, and
with 99% ee for both geometric isomers (entry 8).
Table 2. Reaction of Wittig Reagent 4 with Various Carbonyl
Derivatives 10
f
Interestingly, in these conditions, the phosphonium salt 4 has
the double role to be a phase-transfer agent and to stabilize the
α-carbanion (ylide 12), as shown in Figure 2. Thus, the
Figure 2. Proposed mechanism of the Wittig reaction in solid−liquid
phase-transfer conditions.
phosphonium salt 4 interacts at the surface of the inorganic
base, which deprotonates on one hand the carboxylic acid
function and on the other hand the methylene substituent to
afford the ylide 12 (Figure 2). In chlorobenzene, a non-
dissociative solvent, the presence of phosphonium salt 4 must
also help the formation of an ion pair with the carboxylate
moiety, which allows better solubility and reactivity of the ylide
12 with the benzaldehyde 10a (Figure 2). Despite the fact that
12 is a not stabilized ylide, the predominant formation of (E)-
γ,δ-unsaturated NHBoc-amino acid 11a was explained by the
thermal isomerization under the reaction conditions (15 h, 90
°C).35 Interestingly, the Z/E mixture 11a was isomerized with
unprotected carboxylic moiety, in pure (E)-γ,δ-unsaturated
NHBoc-amino acid 11a, by simple heating in the presence of
diphenylsulfide (Scheme 2).36 It should be noted that the
unsaturated amino acid 11a, which is obtained with a free
carboxylic acid and a Boc protecting group, could be directly
used in peptide synthesis.
The amino acid phosphonium salt 4 was used for the Wittig
reaction with various aromatic or aliphatic aldehydes 10b−m
and 2,2,2-trifluoroacetophenone 10n (Scheme 3, Table 2). In
the optimized conditions, the reaction with the 4-trifluoro-
methyl, 4-nitro, 4-cyano, or 4-methoxy benzaldehydes 10b−e
leads to the corresponding γ,δ-unsaturated amino acids 11b−e
as a mixture of Z/E isomers in a ratio close to 20: 80 and yields
a
Enantiomeric purity of each unsaturated amino acid 11b−n was
determined by HPLC on chiral column after esterification with
TMSCHN2 and was superior to 99%. Isolated yield after
34
b
c
1
purification by column chromatography. Determined by H NMR.
d
e
f
Not determined.40 Yield as methyl ester. The reactions were
performed at 90°C during 15h in 1.5 mL of solvent and with the ratio
3/10/K3PO4 = 1:1.5:6.
Scheme 3. Synthesis of Unsaturated Amino Acids 11 Using
Wittig Reagent 4
ranging from 67% to 98% (entries 1−4). The reaction of the
furfural 10f or ferrocene carboxaldehyde 10g affords then the
corresponding product 11f (or 11g) in 80% and 51% yield,
respectively (entries 5, 6). The enantiomeric purity for both Z/
E isomers 11b−g was determined by HPLC on chiral column
after esterification using TMSCHN2 and was superior to 99%
(entries 1−6). Moreover, when aliphatic aldehydes were used
in this Wittig reaction, the corresponding γ,δ-unsaturated
amino acids were also isolated in satisfactory yields. Thus, the
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Reactions were monitored by thin-layer chromatography (TLC) using
0.25 mm E. Merck precoated silica gel plates. Flash chromatographies
were performed with the indicated solvents using silica gel 60 (60AAC,
35−70 μm). NMR spectra (1H, 13C, 31P) were recorded with 300 and
500 MHz apparatus, at ambient temperature using TMS as internal
reaction of 4 with the 3-phenylpropanal 10h afforded the γ,δ-
unsaturated amino acids 11h in 57% yield, whereas in the case
of the paraformaldehyle 10i, the NHBoc-allylglycine 11i was
obtained in 55% yield (entries 7, 8). The excellent reactivity of
the Wittig reagent 4 toward aromatic aldehydes allows the
synthesis of α-amino acids bearing functional groups. Thus,
when 4 reacts with the 4-boronato-benzaldehyde 10j, the
corresponding unsaturated amino acid 11j was obtained in 57%
yield as a Z/E mixture in a ratio 25:75 (entry 9). Obviously, the
boronato derivative 11j presents a particular interest for the
synthesis of modified amino acids using Suzuki−Miyaura cross-
coupling reactions.9,37 Noteworthy, the reaction of 2 equiv of 4
with the m-phthaldialdehyde 10k leads to the corresponding
bis-amino acid 11k in 85% isolated yield (entry 10). On an
other hand, when α,β-unsaturated aldehydes were used, the
Wittig reaction with the phosphonium salt 4 leads to the
corresponding amino acid derivatives bearing a diene pattern
on the lateral chain.
Very few exemples of diene α-amino acids derivatives are
reported to date.38 Thus, the reaction of the trans-
cinnamaldehyde 10l or its azido derivative 10m in the Wittig
reaction with 4 led to the corresponding dienic α-amino acids
11l (or 11m) in 77% and 57% yield, respectively (entries 11
and 12). Again, it is interesting to note that the azido α-amino
acid 11m is a new useful building block for click chemistry.39
Finally, in the reaction conditions developed, the Wittig reagent
4 reacts with the trifluoroacetophenone 10n to afford the
trifluoromethyl amino acid derivative 11n as a Z/E mixture in a
ratio of 37:63 and 81% yield (entry 13).
1
reference for H and 13C NMR and 85% phosphoric acid as external
reference for 31P NMR. Data are reported as s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet, br.s = broad singlet, coupling
constant(s) in Hertz, integration. Infrared spectra were recorded on a
FTIR instrument. Melting points were measured on a Kofler melting
points apparatus and are uncorrected. Optical rotation values were
determined at 20 °C on a polarimeter at 589 nm (sodium lamp). Mass
spectroscopies were performed under (ESI) conditions with a micro
Q-TOF or HR/AM-MS detector. Elemental analyses were measured
with a precision superior to 0.3% on a CHNS-O instrument apparatus.
Li3PO4, K3PO4, and Cs2CO3 were previously dried by heating at 200
°C under vacuum, during 5 min. Chlorobenzene 99%, 1,4-doxane 99%,
aldehydes 10a−h, 10k−m, paraformaldehyde 95% 10i, 2,2,2-
trifluoroacetophenone 10n, L-aspartic acid 5, 4-formylbenzeneboronic
acid 10j, and tris(dibenzylideneacetone)dipalladium were purchased
from commercial sources and used without purification. Boc-L-β-
methyl-aspartic acid was prepared in two steps from L-aspartic acid 5,
according to the procedures described in the literature.26,27
(S)-2-(tert-Butyloxycarbonylamino), 1-Allyl-4-methyl-succi-
nate (6). This compound was prepared from Boc-L-β-methyl-aspartic
acid, according to a modified literature procedure changing benzyl
bromide versus allyl bromide.28 To a solution of Boc-L-β-methyl-
aspartic acid (5.62 g, 22.7 mmol) in 70 mL of DMF were introduced
K2CO3 (7.53 g, 54.5 mmol) and allyl bromide (3.9 mL, 45.4 mmol).
After the mixture was stirred overnight, 70 mL of water was added, the
aqueous layer was extracted with 3 × 75 mL of ethyl acetate, and the
combined organic layers were dried over MgSO4. After evaporation of
the solvent, the residue was purified by chromatography using a
mixture petroleum ether/ethyl acetate (4:1) as eluent to afford the
allyl ester 6 as a colorless oil (5.15 g, 79%). Rf: 0.29 (ethyl acetate/
CONCLUSION
■
1
In summary, the stereoselective synthesis of a new amino acid
phosphonium salt 4, by quaternization of melting triphenyl-
phosphine with the γ-iodo NHBoc-amino ester 8, derived from
L-aspartic acid 5, has been described. The deprotection of the
carboxylic acid function to afford the phosphonium salt 4 with a
free carboxylic acid group was achieved in 80% yield by a
palladium-catalyzed desallylation reaction. The use of 4 in the
Wittig reaction with aromatic or aliphatic aldehydes and
trifluoroacetophenone, under unusual solid−liquid phase-trans-
fer conditions in chlorobenzene and in the presence of K3PO4
as weak base, affords the corresponding unsaturated amino
acids 11 without racemization and in yield up to 98%. The γ,δ-
unsaturated amino acids 11, which are obtained as a Z/E
mixture, can be isomerized by simple heating in the presence of
diphenylsulfide. By reaction with substituted aldehydes, the
Wittig reagent 4 thus makes it possible to graft various
functionalized groups such as trifluoromethyl, cyano, nitro,
ferrocenyl, boronato, or azido on the lateral chain of the amino
acids 11. In addition the reaction of 4 with α,β-unsaturated
aldehydes leads to rarely described amino acids bearing a diene
on the lateral chain. Finally, the phosphonium 4 appears to be a
powerful new tool for the preparation of unsaturated and non-
proteinogenic α-amino acids, directly usable for the synthesis of
customized peptides.
petroleum ether 1:4); [α]D = +17.7 (c 0.7, CHCl3). H NMR (300
MHz, CDCl3) δ 5.92−5.79 (m, 1H), 5.28 (dq, 1H, J = 1.4, 17.2 Hz),
5.20 (dq, 1H, J = 1.2, 10.4 Hz), 4.60 (dt, 2H, J = 1.3, 5.7 Hz), 4.57−
4.53 (m, 1H), 3.65 (s, 3H), 2.98 (dd, 1H, J 4.6, 17.1 Hz), 2.79 (dd,
1H, J = 17.0, 4.7 Hz), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
171.4, 170.7, 155.4, 131.5, 118.6, 80.1, 66.2, 52.0, 50.0, 36.6, 28.3.
FTIR (neat) cm−1 3370, 2980, 1716, 1502, 1439, 1367, 1339, 1286,
1246, 1209, 1161, 1049, 1026, 992. Analysis calcd for C13H21NO6
(227.14): C 54.35, H 7.37, N 4.88. Found: C 54.50, H 7.38, N 4.93.
(S)-2-[Bis(tert-Butyloxycarbonyl)amino], Allyl-4-iodobuta-
noate (7). This compound was prepared from the aspartic ester
derivative 6, via compounds I then II, according to a modified
literature procedure.29,30
(S)-2-[Bis(tert-Butyloxycarbonyl)amino], 1-Allyl-4-methyl-succi-
nate (I). This compound was prepared from the allyl ester 6,
according to a modified literature procedure.29,30 To a solution of the
allyl ester 6 (4.86 g, 16.9 mmol) in 80 mL of acetonitrile were added
successively DMAP (643 mg, 5.2 mmol) and Boc2O (9.3 g, 42.6
mmol). After the mixture was stirred overnight at room temperature,
the solvent was evaporated, and the residue was purified by
chromatography with a mixture of petroleum ether/ethyl acetate
(4:1) to afford the N,N-diBoc diester I as a colorless oil (5.76 g, 88%).
Rf: 0.32 (ethyl acetate/petroleum ether 1:4); [α]D = −54.1 (c 0.7,
1
CHCl3). H NMR (300 MHz, CDCl3) δ 5.90−5.79 (m, 1H), 5.47−
5.42 (m, 1H), 5.28 (dq, 1H, J = 1.5, 17.2 Hz), 5.19 (dq, 1H, J = 1.3,
10.5 Hz), 4.59 (dt, 2H, J = 1.3, 5.6 Hz), 3.67 (s, 3H), 3.23 (dd, 1H, J =
7.1, 16.4 Hz), 2.71 (dd, 1H, J = 8.5, 16.4 Hz), 1.47 (s, 18H); 13C NMR
(75 MHz, CDCl3) δ 171.0, 169.5, 151.6, 131.5, 118.3, 83.5, 66.1, 55.0,
51.9, 35.6, 27.9. FTIR (neat) cm−1 2982−2954, 1742, 1702, 1458,
1439, 1368, 1314, 1269, 1243, 1168, 1142, 1116, 993, 934. Analysis
calcd for C18H28NO8 (387.19): C 55.80, H 7.54, N 3.62. Found: C
56.16, H 7.75, N 3.53.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were carried out
under inert atmosphere. Solvents were dried and purified by
conventional methods prior to use. Tetrahydrofuran (THF) and
diethyl ether were distilled from sodium/benzophenone and stored
under argon. Dimethylformamide (DMF), acetonitrile (ACN), and
ethanol (EtOH) were distilled from CaH2 under argon prior to use.
(S)-2-[Bis(tert-Butyloxycarbonyl)amino], Allyl-4-hydroxybuta-
noate (II). This compound was prepared from diester I according to
a modified literature procedure.29,30 To a solution of diester I (2.2 g,
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5.7 mmol) in 60 mL of distilled diethyl ether was introduced DIBAL
(9 mL, 9 mmol) under argon at −78 °C. The mixture was stirred 1 h
at −78 °C and hydrolyzed with 10 mL of distilled water at 0 °C. After
5 min, the mixture was filtered on Celite and washed with 3 × 25 mL
of diethyl ether. After removal of the solvent, the crude product
containing the aldehyde intermediate and traces of the corresponding
alcohol II was dissolved in 50 mL of a mixture THF/H2O (4:1), and
NaBH4 (225 mg, 5.9 mmol) was added. The mixture was stirred 30
min at 0 °C, and the aqueous layer was extracted with 3 × 75 mL of
ethyl acetate. The organic layer was dried over MgSO4, filtered and
evaporated. The crude product was purified by chromatography with
ethyl acetate/petroleum ether (1:4, then 3:7, and finally 1:1) as eluent,
to afford the alcohol II as a colorless oil (1.27 g, 75%). Rf: 0.31 (ethyl
acetate/petroleum ether 1:2); [α]D = −27.9 (c 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3) δ 5.92−5.81 (m, 1H), 5.30 (dq, 1H, J = 1.5, 17.2
Hz), 5.20 (dq, 1H, J = 1.3, 10.4 Hz), 4.99 (dd, 1H, J = 4.7, 9.8 Hz),
4.59 (dt, 2H, J = 1.4, 5.5 Hz), 3.73−3.68 (m, 1H), 3.61−3.54 (m, 1H),
2.44−2.36 (m, 1H), 2.07−1.97 (m, 1H) 1.47 (s, 18H); 13C NMR (75
MHz, CDCl3) δ 170.5, 152.5, 131.7, 118.2, 83.6, 65.8, 59.0, 55.6, 32.8,
27.9. FTIR (neat) cm−1 3524, 2980−2934, 1740, 1700, 1457, 1368,
1272, 1254, 1144, 1119, 1049, 989. Analysis calcd for C17H29NO4
(359.19): C 56.81, H 8.13, N 3.90. Found: C 56.52, H 8.32, N 3.93.
(S)-2-[Bis(tert-Butyloxycarbonyl)amino], Allyl-4-iodobutanoate
(7).29b,30 In a first flask, containing a solution of alcohol II (1.33 g,
3.7 mmol) in 20 mL of dry THF, was added imidazole (600 mg, 8.8
mmol). In a second flask containing Ph3P (1.52 g, 5.8 mmol) in 15 mL
of dry THF was added iodine (1.55 g, 6.1 mmol). The first solution
was then added, and the resulting mixture was stirred for 2 h at room
temperature. The reaction mixture was then hydrolyzed with 100 mL
of 20% aqueous NaCl. The aqueous layer was extracted by 3 × 50 mL
ethyl acetate. After drying over MgSO4, filtration, and evaporation, the
crude product was purified by chromatography using a mixture of ethyl
acetate/petroleum ether (1:9) as eluent, to afford the iodo aminoester
7 as a colorless oil (1.6 g, 91%). Rf: 0.75 (ethyl acetate/petroleum
ether 1:9); [α]D = −44.6 (c 0.7, CHCl3). 1H NMR (300 MHz,
CDCl3) δ 5.97−5.84 (m, 1H), 5.33 (dq, J = 1.5, 17.2 Hz, 1H), 5.24
(dq, 1H, J = 1.3, 10.5 Hz), 5.03 (dd, 1H, J = 5.5, 8.5 Hz), 4.63 (dt, 2H,
J = 1.4, 5.5 Hz), 3.25−3.16 (m, 2H), 2.78−2.66 (m, 1H), 2.48−2.36
(m, 1H), 1.52 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 167.9, 150.2,
129.8, 116.5, 87.7, 64.1, 52.8, 32.6, 26.2, 0.0. FTIR (neat) cm−1 2981−
2936, 1747, 1704, 1479, 1457, 1368, 1236, 1171, 1131, 988. Analysis
calcd for C17H29NO6I (469.10): C 43.51, H 6.01, N 2.98. Found: C
43.31, H 6.24, N 2.92.
(S)-2-(tert-Butyloxycarbonylamino), Allyl-4-iodobutanoate
(8).24b Finally, this compound was obtained from the iodo aminoester
7 according to a modified literature procedure.31 To the solution of 7
(1.6 g, 3.4 mmol) in 20 mL of acetonitrile were added CeCl3.7H2O
(1.3 g, 3.4 mmol) and NaI (513 mg, 3.4 mmol). The reaction mixture
was stirred overnight at room temperature and hydrolyzed with 20 mL
of water. The aqueous layer was extracted with 3 × 20 mL of ethyl
acetate, and the organic layer was dried over MgSO4. After
evaporation, the crude product was purified by chromatography
using a mixture of ethyl acetate/petroleum ether (1:4) as eluent. The
iodo aminoester 8 was obtained as a pale yellow oil (831 mg, 86%). Rf:
0.31 (ethyl acetate/petroleum ether 1:4); [α]D = +11.7 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3) δ 5.95−5.82 (m, 1H), 5.31 (dd, 1H, J =
1.4, 17.2 Hz), 5.24 (dd, 1H, J = 1.1, 10.4 Hz), 5.05 (d, 1H, J = 6.2 Hz),
4.62 (d, 2H, J = 5.8 Hz), 4.34−4.32 (m, 1H), 3.18−3.13 (m, 2H),
2.43−2.37 (m, 1H) 2.23−2.10 (m, 1H), 1.42 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 171.9, 155.9, 132.0, 119.8, 80.9, 66.9, 55.0, 37.8, 28.9,
0.0. FTIR (neat), cm−1 2981−2936, 1747, 1704, 1479, 1457, 1368,
1236, 1171, 1131, 988, 930, 853. Analysis calcd for C12H20NO4I
(369.09): C 39.04, H 5.46, N 3.79. Found: C 39.14, H 5.59, N 3.84.
(S)-2-[(tert-Butyloxycarbonyl)amino]-4-triphenylphospho-
nium, Allyl-butanoate (9). A mixture of iodo aminoester 8 (1.1 g,
3.1 mmol) and triphenylphosphine (1.9 g, 7.1 mmol) was stirred
without solvent under argon at 80 °C. After 2 h, 5 mL of toluene was
added, followed by 30 mL of diethyl ether, after cooling to room
temperature. The white solid was washed with 2 × 25 mL of diethyl
ether and purified by column chromatography using acetone and
petroleum ether (7: 3) as eluent to afford phosphonium salt 9 as a pale
yellow solid (1.22 g, 72%). Rf: 0.57 (acetone/petroleum ether 7: 3);
mp 84−86 °C; [α]D = −17.5 (c 0.4, CHCl3). H NMR (300 MHz,
1
CDCl3) δ 7.83−7.65 (m, 15H), 6.32 (d, 1H, J = 7.5 Hz) 5.89−5.78
(m, 1H), 5.29−5.15 (m, 2H), 4.60−4.53 (m, 3H), 3.95−3.79 (m, 1H)
3.73−3.58 (m, 1H), 2.30−2.26 (m, 2H) 1.39 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 170.7, 135.7, 135.2 (d, J = 3.0 Hz) 133.6 (d, J = 9.8
Hz) 131.7, 130.6 (d, J = 12.8 Hz), 118.6, 117.8 (d, J = 86.0 Hz), 80.0,
66.2, 53.2 (d, J = 17.3 Hz), 28.3, 23.8, 20.3 (d, J = 53.6 Hz); 31P NMR
(121 MHz, CDCl3) δ +25.2 (s). FTIR (neat) cm−1 3249, 3053−2870,
1699, 1648, 1587, 1508, 1486, 1437, 1391, 1366, 1340, 1309, 1251,
1229, 1158, 1111, 1052, 995. HRMS (ESI-Q-TOF) calcd for
C30H35N1O4P1 [M − I]+: 504.2298, found 504.2278. The enantio-
meric excess (>99%) was determined by 31P NMR analysis using the
BINPHAT as chiral reagent.32
(S)-2-(tert-Butyloxycarbonyl)amino]-4-triphenylphospho-
nium Butanoic Acid (4).24b The desallylation of 9 was realized
according to a modified literature procedure.25 To a solution of
phosphonium salt 9 (1.28 g, 2 mmol) in 20 mL of dry THF were
successively added under argon Pd2dba3 (46 mg, 0.05 mmol) and dppe
(40 mg, 0.1 mmol). After 5 min of stirring, HNEt2 (0.42 mL, 4.2
mmol) was introduced, and the mixture was stirred at room
temperature overnight. After hydrolysis, the crude product was
extracted with CH2Cl2, and the combined organic layers were dried
over MgSO4, evaporated under vacuum, and purified by column
chromatography with acetone and methanol (1:1) as eluent to afford
the phosphonium salt 4 as a white solid (946 mg, 80%). Rf: 0.50
(acetone/MeOH 1:1); mp 151−153 °C; [α]D = +48.5 (c 0.4, CHCl3).
1H NMR (300 MHz, CDCl3) δ 7.77−7.70 (m, 3H), 7.64−7.52 (m,
12H), 6.27 (d, 1H J = 2.7 Hz), 4.08 (t, 1H, J = 3.6 Hz), 3.30−3.13 (m,
2H), 2.32−2.13 (m, 2H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
172.6, 156.0, 135.1 (d, J = 3.0 Hz), 133.3 (d, J = 9.8 Hz), 130.5 (d, J =
12.8 Hz), 118.3 (d, J = 86.0 Hz), 78.6, 54.9 (d, J = 17.3 Hz), 28.4, 25.7,
18.4 (d, J = 9.8 Hz); 31P NMR (121 MHz, CDCl3) δ +24.3 (s). FTIR
(neat) cm−1 3387, 3060−2932, 1695, 1605, 1483, 1438, 1386, 1365,
1251, 1161, 1112, 1053, 1025; HRMS (ESI-Q-TOF) calcd for
C27H31N1O4P1 [M − I]+ 464.1985, found 464.1958.
Typical Procedure To Prepare γ,δ-Unsaturated Amino Acids
(11) Using the Wittig Reagent (4).24b Aldehyde 10 (0.3 mmol)
and dry K3PO4 (254 mg, 1.2 mmol) were successively added to a
solution of phosphonium salt 4 (120 mg, 0.2 mmol) in chlorobenzene
(1.5 mL). The reaction mixture was stirred for 15 h at 90 °C. After
cooling to room temperature, the solution was hydrolyzed with
distilled water (5 mL) and extracted with diethyl ether (3 × 5 mL).
The aqueous layer was then acidified with KHSO4 (1 M) to pH 3 and
extracted with AcOEt (3 × 5 mL). The combined organic layers were
dried over anhydrous MgSO4 and evaporated. The crude residue was
purified by chromatography on silica gel with a mixture of ethyl
acetate/petroleum ether (3:7) containing 1% AcOH as eluent to afford
the corresponding unsaturated α-amino acid 11.
(S)-2-(tert-Butyloxycarbonylamino)-5-phenylpent-4-enoic Acid
(11a). In the above conditions, 120 mg of phosphonium salt 3 and
42.4 mg of benzaldehyde 10a afford the unsaturated α-amino acid 11a
as a pale yellow uncrystallized compound (42 mg, 72%) with a Z/E
ratio 30:70; Rf: 0.52 (ethyl acetate/petroleum ether 3:7 + 1% acetic
1
acid); H NMR (300 MHz, CDCl3) δ 7.38−7.22 (m, 5H), 6.63 (d,
0.3H, J = 11.7 Hz), 6.50 (d, 0.7H, J = 15.9 Hz), 6.23−6.08 (m, 0.7H),
5.69−5.60 (m, 0.3H), 5.12 (d, 0.7H, J = 7.8 Hz), 5.05 (d, 0.3H, J = 8.1
Hz), 4.51−4.49 (m, 0.7H), 4.38−4.28 (m, 0.3H), 2.98−2.92 (m,
0.6H), 2.81−2.65 (m, 1.4H), 1.45 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 176.5, 155.6, 136.8, 134.2, 132, 130.2, 129.7, 128.7, 128.6,
128.5, 128.4, 128.3, 127.6, 127.1, 126.4, 126.3, 125.6, 123.5, 80.4, 80.2,
53.1, 35.8, 31.1, 28.3. FTIR (neat) cm−1 3422, 3026−2930, 1711,
1496, 1450, 1395, 1368, 1249, 1163, 1053, 1026, 966. HRMS (ESI-Q-
TOF) calcd for C16H21N1Na1O4 [M + Na]+ 314.1363, found
314.1343. The enantiomeric excess >99% was determined by HPLC
after esterification with TMSCHN2 (Lux 5 μm cellulose-2, hexane/i-
PrOH 98:2, 1.3 mL min−1, λ = 210 nm, 20 °C, tR(Z)‑(S)= 13.1 min,
tR(E)‑(S) = 16.5 min, tR(Z)‑(R) = 23.3 min, tR(E)‑(R) = 32.2 min).
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(E)-(S)-2-(tert-Butyloxycarbonylamino)-5-phenylpent-4-enoic
Acid (11a). To a solution of unsaturated amino acid 11a (20 mg, 0.07
mmol) in 5 mL of dry THF was added (PhS)2 (3 mg, 0.014 mmol).
The mixture was heated under reflux for 15 h, to afford the
corresponding (E)-unsaturated amino acid 11a as a colorless
uncrystallized compound (19 mg, 95%); Rf: 0.53 (ethyl acetate/
petroleum ether 3:7 + 1% acetic acid); [α]D = +61.0 (c 0.2, CHCl3).
1H NMR (300 MHz, CDCl3) δ 7.29−7.12 (m, 5H), 6.41 (d, 1H, J =
tR(Z)‑(S) = 16.2 min, tR(E)‑(S) = 20.4 min, tR(Z)‑(R) = 22.1 min, tR(E)‑(R) =
34.2 min).
(S)-2-(tert-Butyloxycarbonylamino)-5-(4-methoxyphenyl)pent-4-
enoic Acid (11e). In the above conditions, 120 mg of phosphonium
salt 4 and 4-methoxybenzaldehyde 10e (136 mg, 1 mmol) afford the
amino acid 11e as a pale yellow uncrystallized compound (43 mg,
67%), with a Z/E ratio 24: 76. Rf: 0.42 (ethyl acetate/petroleum ether
1
3:7 + 1% acetic acid); H NMR (300 MHz, CDCl3) δ 7.32−7.29 (m,
1H), 7.22−7.17 (m, 1H), 6.89−6.83 (m, 2H), 6.54 (d, 0.24H, J = 11.4
Hz), 6.43 (d, 0.76H, J = 15.6 Hz), 6.02−5.93 (m, 0.76H), 5.58−5.52
(m, 0.24H), 5.13−5.03 (m, 1H), 4.43−4.33 (m, 1H), 3.81 (s, 3H),
2.99−2.94 (m, 0.5H), 2.79−2.56 (m, 1.5H), 1.44 (s, 9H). 13C NMR
(75 MHz, CDCl3) δ 176.8, 159.2, 158.6, 155.8, 137.9, 133.7, 132.2,
130.0, 129.7, 129.0, 128.3, 127.5, 125.3, 123.9, 121.1, 114.0, 113.8,
80.6, 80.5, 55.3, 53.1, 35.7, 31.1, 28.3. FTIR (neat) cm−1 3288, 2978−
2838, 1713, 1578, 1512, 1456, 1441, 1394, 1368, 1289, 1248, 1174,
1111, 1043. HRMS (ESI-Q-TOF) calcd for C17H23N1Na1O5 [M +
Na]+ 344.1468, found 344.1448. The enantiomeric excess >99% was
determined by HPLC on chiral column after esterification with
TMSCHN2 (Lux 5 μm cellulose-2, hexane/i-PrOH 95:5, 1.5 mL
min−1, λ = 254 nm, 20 °C, tR(Z)‑(R) = 8.3 min, tR(E)‑(R) = 10.4 min,
tR(Z)‑(S) = 13.1 min, tR(E)‑(S) = 16.7 min).
15.9 Hz), 6.14−5.99 (m, 1H), 5.01 (d, 1H, J = 6.9 Hz), 4.40 (d, 1H, J
= 3.3 Hz), 2.72−2.57 (m, 2H), 1.35 (s, 9H).
(S)-2-(tert-Butyloxycarbonylamino)-5-[4-trifluoromethyl)phenyl]-
pent-4-enoic Acid (11b). In the above conditions, 120 mg of
phosphonium salt 4 and 69.6 mg of 4-trifluoromethylbenzaldehyde
10b afford the unsaturated α-amino acid 11b as a white solid (57 mg,
98%) with a Z/E ratio 10:90; Rf: 0.33 (ethyl acetate/petroleum ether
1
3:7 + 1% acetic acid); H NMR (300 MHz, CDCl3) δ 7.58−7.53 (m,
2H), 7.43 (d, 2H, J = 8.1 Hz), 7.35 (d, 0.2H, J = 7.8 Hz), 6.62 (d,
0.1H, J = 11.4 Hz), 6.52 (d, 0.9H, J = 15.6 Hz), 6.27−6.22 (m, 0.9H),
5.88−5.71 (m, 0.1H), 5.17 (d, J = 7.8 Hz, 0.9H), 4.52−4.30 (m, 0.89
H), 4.23−4.21 (m, 0.1H), 2.80−2.76 (m, 1H), 2.70−2.68 (m, 1H),
1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 176.5, 176.0, 156.8,
155.5, 132.8, 129.6, 129.5, 128.8, 128.6, 128.2, 127.7, 126.6, 126.4,
125.3 (q, J = 6.8 Hz), 125.3 (q, J = 271.7 Hz), 82.1, 80.6, 54.4, 53.0,
34.3, 28.2, 27.2. FTIR (neat) cm−1 3352, 2973−2925, 1710, 1681,
1615, 1521, 1433, 1415, 1392, 1367, 1326, 1287, 1267, 1252, 1159,
1108, 1084, 1069, 1046, 1025. HRMS (ESI-Q-TOF) calcd for
C17H19F3NO4 [M − H]− 358.1272, found 358.1256. The enantio-
meric excess >99% was determined by HPLC on chiral column after
esterification with TMSCHN2 (Lux 5 μm cellulose-2, hexane/i-PrOH
95:5, 1 mL min−1, λ = 210 nm, 20 °C, tR(Z)‑(S) = 6.9 min, tR(E)‑(S) = 8.2
min, tR(Z)‑(R) = 10.6 min, tR(E)‑(R) = 17.2 min).
(S)-2-(tert-Butyloxycarbonylamino)-5-furylpent-4-enoic Acid
(11f). In the above conditions, 120 mg of phosphonium salt 4 and
38.4 mg of 2-furaldehyde 10f afford the unsaturated amino acid 11f as
a pale yellow uncrystallized compound (45 mg, 80%). Rf: 0.40 (ethyl
1
acetate/petroleum ether 3:7 + 1% acetic acid); H NMR (300 MHz,
CDCl3) δ 7.36 (dd, 1H, J = 1.2, 21.9 Hz), 7.20−7.17 (m, 0.4H), 6.41−
6.35 (m, 3H), 6.10−6.00 (m, 0.6H), 6.21 (d, 1H, J = 3.3 Hz), 5.54−
5.45 (m, 0.4H), 5.14−5.12 (m, 0.6H), 4.48−4.34 (m, 0.6H), 4.27−
4.20 (m, 0.4H), 3.16- 2.90 (m, 1H), 2.78−2.58 (m, 1H), 1.45 (s,
9H).13C NMR (75 MHz, CDCl3) δ 176.8, 176.3, 155.7, 155.5, 152.6,
152.3, 142.0, 141.8, 123.1, 122.6, 122.2, 120.5, 111.2, 111.1, 110.2,
107.5, 81.7, 80.4, 53.1, 54.5, 35.5, 31.8, 28.3. FTIR (neat) cm−1 3338,
2978−2931, 1780, 1694, 1511, 1455, 1393, 1367, 1254, 1157, 1349,
1017, 925, 863, 811, 735, 702, 653. HRMS (ESI-Q-TOF) calcd for
C14H18N1O5 [M − H]− 280.1190, found 280.1188. The enantiomeric
excess >99% was determined by HPLC after esterification by
TMSCHN2 (Lux 5 μm cellulose-2, hexane/i-PrOH 95:5, 1 mL
(S)-2-(tert-Butyloxycarbonylamino)-5-(4-cyanophenyl)pent-4-
enoic Acid (11c). In the above conditions, 120 mg of phosphonium
salt 4 and 52 mg of 4-cyanobenzaldehyde 10c afford the unsaturated
amino acid 11c as a white solid (60 mg, 96%), with a ratio Z/E 20:80;
Rf: 0.31 (ethyl acetate/petroleum ether 3:7 + 1% acetic acid); 1H
NMR (300 MHz, CDCl3) δ 7.27−7.24 (m, 2H), 7.20−7.17 (m, 2H),
6.72 (d, 0.2H, J = 6.3 Hz), 6.59 (d, 0.2H, J = 11.4 Hz), 6.50 (d, 0.8H, J
= 15.6 Hz), 6.34−6.24 (m, 0.8H), 5.86−5.73 (m, 0.2H), 5.21 (d, 0.8H,
J = 8.1 Hz), 4.52−4.48 (m, 0.8H), 4.32−4.30 (m, 0.2H), 2.88−2.78
(m, 1H), 2.72−2.62 (m, 1H), 1.43 (s, 9H) ; 13C NMR (75 MHz,
CDCl3) δ 174.9, 155.4, 140.2, 132.3, 131.5, 131.4, 131.1, 130.1, 128.5,
128.3, 127.8, 127.1, 126.5, 125.8, 117.8, 117.9, 109.7, 109.6, 81.0, 79.6,
53.1, 51.9, 35.0, 29.0, 27.2. FTIR (neat) cm−1 3416, 3135−2865, 2221,
1737, 1662, 1604, 1522, 1457, 1442, 1412, 1396, 1371, 1334, 1305,
1252, 1210, 1157, 1442, 1412, 1396, 1371, 1334, 1305, 1252, 1210,
1086, 1027. HRMS (ESI-Q-TOF) calcd for C17H20N2NaO4 [M +
Na]+ 339.1315, found 339.1299. The enantiomeric excess >99% was
determined by HPLC after esterification with TMSCHN2 (Lux 5 μm
cellulose-2, hexane/i-PrOH 85:15, 1 mL min−1, λ = 210 nm, 20 °C,
min−1, λ = 254 nm, 20 °C, tR(Z)‑and (E)‑(S) = 10.2 min, tR(Z)‑or (E)‑(R)
14.5 min, tR(E)‑or (Z)‑(R) = 16.0 min).
=
(S)-Methyl-2-(tert-Butyloxycarbonylamino)-5-ferrocenylpent-4-
enoate (11g). A 120 mg portion of phosphonium salt 4 and 214 mg
(1 mmol, 5 equiv) of ferrocene-carboxaldehyde 10g were stirred at 90
°C with 254 mg (1.2 mmol, 6 equiv) of K3PO4 during 16 h. The
reaction mixture was hydrolyzed with distillated water (5 mL) and
extracted with diethyl ether (3 × 5 mL). The aqueous layer was
acidified with KHSO4 (1 M) until pH = 3 and extracted with ethyl
acetate (3 × 5 mL). The combined organic layers were dried over
magnesium sulfate, and the solvent was evaporated. The residue was
dissolved in 2 mL of a mixture of toluene/methanol (3:2), and 0.13
mL (0.25 mmol) of TMSCHN2 was added. The reaction mixture was
stirred 30 min at room temperature, and the solvent was evaporated.
The residue was purified by chromatography with ethyl acetate/
petroleum ether (3:7) as eluent. Methyl ester 11g was obtained as an
orange uncrystallized compound (30 mg, 51%) with a Z/E ratio 50:50.
tR(Z)‑(S) = 16.3 min, tR(E)‑(S) = 19.2 min, tR(Z)‑(R) = 23.8 min, tR(E)‑(R)
=
32.1 min).
(S)-2-(tert-Butyloxycarbonylamino)-5-(4-nitrophenyl)pent-4-
enoic Acid (11d). In the above conditions, 120 mg of phosphonium 4
and 60.4 mg of 4-nitrobenzaldehyde 10d afford the unsaturated amino
acid 11d as a yellow uncrystallized compound (50 mg, 75%) with a Z/
E ratio 15:85; Rf: 0.33 (ethyl acetate/petroleum ether 3:7 + 1% acetic
1
Rf: 0.42 (ethyl acetate/petroleum ether 1:4); H NMR (300 MHz,
1
acid); H NMR (300 MHz, CDCl3) δ 8.14 (d, 2H, J = 8.4 Hz), 7.46
CDCl3) δ 6.22 (d, J = 15.6 Hz, 0.5H), 6.26 (d, J = 11.8 Hz, 0.5H),
5.39−5.33 (m, 1H), 5.68−5.58 (m, 1H), 5.12−5.06 (m, 1H), 4.47−
4.38 (m, 1H), 4.35−4.30 (2 m, 2H), 4.24−4.20 (2 m, 2H), 4.14−4.12
(2s, 5H), (2s, 3H), 2.87−2.47 (2 m, 2H), 1.47−1.46 (2s, 9H). 13C
NMR (75 MHz, CDCl3) δ 173, 172.6, 155.3, 155.2, 131.8, 130.1,
121.7, 120.4, 82.7, 81.0, 69.3, 69.0, 68.9, 68.8, 68.7, 68.6, 66.7, 66.6,
53.1, 53.0, 52.4, 52.3, 35.8, 31.7, 28.3. IR (cm−1) 3390, 2927−2854,
1779, 1695, 1509, 1455, 1392, 1366, 1251, 1158, 1106, 1048, 1023,
1001, 821, 734, 662. HRMS (ESI-Q-TOF) calcd for C21H27FeNNaO4
[M + Na]+ 436.1182, found 436.1193. The enantiomeric excess was
determined by HPLC (Lux 5 μm cellulose-2, hexane/i-PrOH 97:3, 0.8
mL min−1, λ = 254 nm, 20 °C, tR(Z)‑(S) = 27.4 min, tR(E)‑(S) = 30.7 min,
tR(Z)‑and (E)‑(R) = 43.1 min).
(d, 2H, J = 8.8 Hz), 7.16 (d, 0.15H, J = 7.8 Hz), 6.68 (d, 0.15H, J =
11.4 Hz), 6.56 (d, 0.85H, J = 15.6 Hz), 6.54−6.30 (m, 0.85H), 5.82−
5.78 (m, 0.15H), 5.20 (d, 0.85H, J = 7.8 Hz), 4.56−4.54 (m, 1H),
2.89−2.83 (m, 1H), 2.78−2.65 (m, 1H), 1.43 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 175.3, 174.9, 155.8, 154.4, 149.9, 145.9, 145.6, 142.2,
133.8, 131.1, 130.2, 129.8, 128, 125.8, 122.9, 122.6, 81.3, 79.6, 53.2,
51.9, 35.1, 28.7, 27.2. FTIR (neat) cm−1 3487, 3059−2817, 1703,
1484, 1453, 1436, 1413, 1386, 1366, 1311, 1220, 1167, 1107, 1064,
1024, 1002. HRMS (ESI-Q-TOF) calcd for C16H20N2NaO6 [M +
Na]+: 359.1214; found 359.1228. The enantiomeric excess >99% was
determined by HPLC after esterification with TMSCHN2 (Lux 5 μm
cellulose-2, hexane/i-PrOH 90:10, 1 mL min−1, λ = 210 nm, 20 °C,
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(S)-2-(tert-Butyloxycarbonylamino)-7-phenylhept-4-enoic Acid
(11h). In the above conditions, 120 mg of phosphonium salt 4 and
120 mg (0.88 mmol, 4.4 equiv) of 3-phenylpropanal 10h afford the
unsaturated amino acid 11h as an orange solid (36 mg, 57%); Rf: 0.48
determined by HPLC after esterification with TMSCHN2 and
hydrogenation (Lux 5 μm cellulose-2, hexane/i-PrOH 90: 10, 1 mL
min−1, λ = 210 nm, 20 °C, tR(S,S) = 14.3 min, tR(R,S) + (S,R) = 21.7 min,
tR(R,R) = 32.2 min).
(S)-2-(tert-Butyloxycarbonylamino)-7-phenylhept-4,6-dienoic
Acid (11l). In the above conditions, 120 mg of phosphonium salt 4 and
53 mg of trans-cinnamaldehyde 9l afford the unsaturated amino acid
11l as a white solid (42 mg, 66%); Rf: 0.53 (ethyl acetate/petroleum
ether 3:7 + 1% acetic acid); 1H NMR (300 MHz, CDCl3) δ 7.36−7.18
(m, 5H), 7.03 (dd, 0.3H, J = 11.4, 15.6 Hz), 6.76 (dd, 0.7H, J = 10.2,
15.6 Hz), 6.62−6.49 (m, 1H), 6.38−6.27 (m, 0.7H), 5.73−5.70 (m,
0.3H), 5.45−5.42 (m, 0.7H), 5.20−5.04 (m, 1H), 4.53−4.45 (m,
0.7H), 4.33−4.14 (m, 0.3H), 2.94−2.47 (m, 2H), 1.47−1.44 (2s, 9H);
13C NMR (75 MHz, CDCl3) δ 175.5, 175.2, 155.7, 154.5, 136.8, 136.1,
133.6, 133.5, 133, 131.9, 131.4, 130.9, 128, 127.6, 127.4, 127.2, 126.7,
126.5, 125.5, 125.3, 124.3, 124.0, 123.8, 122.5, 80.8, 79.4, 54.6, 53.1,
35.6, 31.9, 27.3. FTIR (neat) cm−1 3319, 3083−3053, 1710, 1496,
1450, 1393, 1368, 1251, 1159, 1056, 1027, 989, 948, 920, 857, 807,
778, 752, 731, 694. HRMS (ESI-Q-TOF) calcd for C18H22NO4 [M −
H]− 316.1554, found 316.1560. The enantiomeric excess >99% was
determined by HPLC after esterification with TMSCHN2 (Lux 5 μm
cellulose-2, hexane/i-PrOH, 95:5, 1 mL min−1, λ = 210 nm, 20 °C,
tR(Z)‑or (E)‑(S) = 20.1 min, tR(E)‑or (Z)‑(S) = 29 min, tR(Z)‑or (E)‑(R) = 32.2
min, tR(E)‑or (Z)‑(R) = 61.2 min).
1
(ethyl acetate/petroleum ether 3:7 + 1% acetic acid); H NMR (300
MHz, CDCl3) δ 7.34−7.27 (m, 2H), 7.23−7.11 (m, 3H), 5.68−5.62
(m, 1H), 5.40−5.32 (m, 1H), 4.95 (d, 1H, J = 7.2 Hz), 4.38−4.35 (m,
1H), 2.72−2.57 (m, 3H), 2.49−2.34 (m, 3H), 1.46 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 176.9, 155.8, 141.6, 134.8, 133.4, 128.7, 128.5,
128.3, 125.9, 123.3, 79.2, 53.0, 35.7, 34.3, 32.0, 30.9, 29.7, 29.2, 28.3.
FTIR (neat) cm−1 3235, 3077−2808, 2326, 1652, 1497, 1454, 1394,
1368, 1055, 983, 817, 736, 698, 649. HRMS (ESI-Q-TOF) calcd for
C18H25NNaO4 [M + Na]+ 342.1676, found 342.1647. The
enantiomeric excess >99% was determined by HPLC after
esterification with TMSCHN2 (Lux 5 μm cellulose-2, hexane/i-
PrOH 95:5, 1 mL min−1, λ = 254 nm, 20 °C, tR(Z)‑or (E)‑(S) = 6.9 min,
tR(E)‑or (Z)‑(S) = 7.8 min, tR(Z)‑or(E)‑(R) = 10.2 min, tR(E)‑or (Z)‑(R) = 12.7
min).
(S)-2-(tert-Butyloxycarbonylamino)-4-pentenoic Acid (11i). In the
above conditions, 120 mg of phosphonium salt 4 and 12 mg of
paraformaldehyde 10i afford the unsaturated amino acid 11i as a
colorless uncrystallized compound (24 mg, 55%); Rf: 0.39 (ethyl
acetate/petroleum ether 3:7 + 1% acetic acid); [α]D = +13.5 (c 0.2,
CHCl3), lit.41 [α]D = +14.5. H NMR (300 MHz, CDCl3) δ 6.12 (d,
1
0.3H, J = 7.5 Hz). 5.87−5.69 (m, 1H), 5.36−5.16 (m, 2H), 5.04 (d,
0.7H, J = 7.5 Hz), 4.42−4.10 (m, 1H), 2.67−2.57 (m, 2H), 1.46 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 175.7, 155.5, 131.1, 118.4, 79.3,
51.8, 35.3, 27.4. FTIR (neat) cm−1 3313, 3082−2932, 1703, 1662,
1509, 1439, 1394, 1368, 1250, 1157, 1050, 1024, 993, 920, 855, 778,
754, 739, 655. HRMS (ESI-Q-TOF) calcd for C10H17NNaO4 [M +
Na]+ 238.1050, found 238.1039. The enantiomeric excess >99% was
determined by HPLC after esterification with TMSCHN2 (Lux 5 μm
cellulose-2, hexane/i-PrOH 98:2, 1 mL min−1, λ = 210 nm, 20 °C, tR(S)
= 12.2 min, tR(R) = 20.2 min).
(S)-2-(tert-Butyloxycarbonylamino)-7-(4-azidophenyl)hept-4,6-
dienoic Acid (11m). In the above conditions, 120 mg of phosphonium
salt 4 and 69.2 mg of (E)-4-azidophenylprop-2-enal 10m afford the
diene amino acid 11m as a red solid (40 mg, 56%); Rf: 0.43 (ethyl
1
acetate/petroleum ether 3:7 + 1% acetic acid); H NMR (300 MHz,
CDCl3) δ 7.38 (dd, 2H, J = 8.4, 13.2 Hz). 6.70−6.65 (m, 0.53H),
6.56−6.42 (m, 1H), 6.97 (dd, 2H, J = 8.4, 3.0 Hz), 6.38−6.24 (m,
1H), 5.77−5.67 (m, 0.5H), 5.50−5.42 (m, 0.55H), 4.46−4.44 (m,
0.75H), 4.33−4.26 (m, 0.25H), 2.90−2.62 (m, 2H), 1.46−1.43 (2s,
9H); 13C NMR (75 MHz, CDCl3) δ 175.3, 154.5, 138.1, 137.9, 133.5,
133.1, 132.3, 131.7, 131.6, 130.0, 128.1, 127.2, 126.9, 126.5, 124.3,
124.0, 122.2, 118.2, 79.4, 52.1, 29.5, 28.7, 27.3. FTIR (neat) cm−1
3346, 2925−2854, 2114, 1706, 1598, 1504, 1454, 1393, 1367, 1284,
1259, 1157, 1127, 1053. HRMS (ESI-Q-TOF) calcd for
C18H21N4Na2O4 [M − H + 2Na]+ 403.1358, found 403.1333. The
enantiomeric excess >99% was determined by HPLC after
esterification with TMSCHN2 (Lux 5 μm cellulose-2, hexane/i-
PrOH 95:5, 1 mL min-1, λ = 254 nm, 20 °C, tR(Z)‑or (E)‑(S) = 12.2 min,
tR(E)‑or(Z)‑(S) and (Z)‑or (E)‑(R) = 16.2 min, tR(E)‑or (Z)‑(R) = 30.4 min).
(S)-2-(tert-Butyloxycarbonylamino)-5-trifluoromethyl-5-phenyl-
pent-4-enoic Acid (11n). In the above conditions, 120 mg of
phosphonium salt 4 and 35 mg of 2,2,2-trifluoroacetophenone 10n
afford the unsaturated amino acid 11n as a yellow solid in 81% yield
with a Z/E ratio 37:63; Rf: 0.62 (ethyl acetate/petroleum ether 3:7 +
(S)-2-(tert-Butyloxycarbonylamino)-5-[4-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)]-pent-4-enoic Acid (11j). In the above
conditions, 120 mg of phosphonium salt 4 and 93 mg of 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 10j, previously pre-
pared by reaction of pinacol with 4-formylbenzeneboronic acid,42
afford the unsaturated amino acid 11j as a colorless uncrystallized
compound in 57% yield with a Z/E ratio 25:75; Rf: 0.40 (ethyl
1
acetate/petroleum ether 3:7 + 1% acetic acid); H NMR (300 MHz,
CDCl3) δ 7.41−7.15 (m, 4H), 6.63 (d, 0.25H, J = 12.3 Hz), 6.51 (d,
0.75H, J = 15.6 Hz), 6.25−6.10 (m, 0.75H), 5.73−5.61 (m, 0.25H),
6.18−5.16 (m, 1H), 5.13−4.48 (m, 1H), 2.80−2.67 (m, 2H), 1.44 (s,
9H), 1.36 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 176.1, 155.6,
139.5, 137.9, 135.1, 134.8, 134.2, 132.5, 131.6, 129.4, 129.0, 128.2,
128.0, 126.4, 125.6, 125.3, 124.8, 116.0, 83.8, 54.4, 53.1, 35.9, 31.2,
28.3, 24.8. FTIR (neat) cm−1 3346, 2979−2931, 1714, 1608, 1515,
1496, 1455, 1397, 1358, 1321, 1270, 1214, 1143, 1089, 1052, 1019.
HRMS (ESI) calcd for C22H32BNNaO6 [M + Na]+ 440.2219, found
440.2215. The enantiomeric excess >99% was determined by HPLC
after esterification with TMSCHN2 (Lux 5 μm cellulose-2, hexane/i-
PrOH 90:10, 1 mL min−1, λ = 210 nm, 20 °C, tR(E)‑(S) = 6.9 min,
tR(Z)‑(S) = 7.8 min, tR(E)‑(R) = 10.2 min, tR(Z)‑(R) = 12.7 min,.
Bis-1,3-[(S)-2-(tert-Butyloxycarbonylamino)pent-4-enoic acid]-
benzene (11k). In the above conditions, 120 mg of phosphonium
salt 4 and 13.4 mg (0.1 mmol, 0.5 equiv.) of m-phthaldialdehyde 10k
afford the unsaturated amino acid 11k as a white solid (86 mg, 85%);
Rf: 0.23 (ethyl acetate/petroleum ether 3:7 + 1% acetic acid); 1H
NMR (300 MHz, CDCl3) δ 7.18−7.14 (m, 2H). 7.11−7.08 (m, 2H),
7.07−7.01 (m, 1H), 6.54−6.35 (m, 2H), 6.06−6.01 (m, 1H), 5.71−
5.63 (m, 1H), 5.32−5.26 (m, 1H), 4.70−4.14 (m, 2H), 2.89−2.59 (m,
4H), 1.44 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 175.9, 156.8,
155.6, 137.9, 137.1, 137.0, 134.1, 132.4, 129.0, 128.5, 128.3, 127.9,
127.5, 126.1, 126.0, 125,3, 80.4, 54.5, 53.1, 35.7, 31.3, 28.3. FTIR
(neat) cm−1 3555, 3407, 3056−3407, 2326, 2244, 2030, 1949, 1583,
1573, 1493, 1471, 1462, 1431, 1296, 1273, 1241, 1180, 1129, 1108,
1070, 1022. HRMS (ESI-Q-TOF) calcd for C26H36N2NaO8 [M +
Na]+ 527.2364, found 527.2372. The enantiomeric excess >99% was
1
1% acetic acid); H NMR (300 MHz, CDCl3) δ 7.31−7.08 (m, 5H),
6.28 (t, 0.37H, J = 7.5 Hz), 5.90 (t, 0.63H, J = 7.5 Hz), 5.07 (d, 0.63H,
J = 6.3 Hz), 4.36−4.17 (m, 1H), 2.99−2.84 (m, 0.63H), 2.84−2.74
(m, 0.63H), 2.56−2.50 (m, 0.37H), 2.38−2.35 (m, 0.37H), 1.18 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 175.7, 174.8, 156.6, 155.5, 135.9,
135.1, 134.7, 131.6, 129.6, 129.1, 129, 108.7, 128.6, 128.4, 128.3, 128.2,
125.5 (q, J = 10.8 Hz), 125.3 (q, J = 276.2 Hz), 82.3, 80.6, 53.0, 52.7,
32, 31.5, 29.7, 29.3, 28.2, 22.7. FTIR (neat) cm−1 3348, 2965−2918,
1731, 1678, 1587, 1518, 1501, 1432, 1376, 1334, 1319, 1272, 1261,
1244, 1154, 1110, 1080, 1066, 1041, 1018. HRMS/MS (ESI) calcd for
C17H19F3N1O4 [M − H]− 358.1264, found 358.1261. The
enantiomeric excess was determined by HPLC on chiral column
after esterification with TMSCHN2 (Lux 5 μm cellulose-2, hexane:i-
PrOH 97:0.7 mL min−1, λ = 254 nm, 20 °C, tR(E)‑or (Z)‑(S) = 10.7 min,
tR(Z)‑or (E)‑(S) = 11.9 min, tR (E)‑and (Z)‑(R) = 21 min).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 31P NMR spectra of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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The Journal of Organic Chemistry
Article
(16) (a) Schollkopf, U.; Neubauer, H.-J. Synthesis 1982, 861.
(b) Genet, J. P.; Juge, S.; Achi, S.; Mallart, S.; Ruiz Montes, J.;
̂ ́ ̀
̈
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sylvain.juge@u-bourgogne.fr.
Notes
The authors declare the following competing financial
interest(s): This work is international patent pending US 61/
528,376 (2011 august 29th), Fr 11 59112 (2011 october
10th).PCT 2012.
Levif, G. Tetrahedron 1988, 44, 5263. (c) Sasaki, A. N.; Hashimoto, C.;
Pauly, R. Tetrahedron Lett. 1989, 30, 1943. (d) Dunn, M. J.; Jackson, R.
F. W.; Pietruzka, J.; Turner, D. J. Org. Chem. 1995, 60, 2210.
(e) O’Donnell, M. J.; Delgado, F.; Hostettler, C.; Schwesinger, R.
Tetrahedron Lett. 1998, 39, 8775. (f) Hashimoto, T.; Maruoka, K.
Chem. Rev. 2007, 107, 5656.
(17) (a) Baldwin, J. E.; Adlinton, R. M.; Birch, D. J.; Crawford, J. A.;
Sweeney, J. B. J. Chem. Soc., Chem. Commun. 1986, 1339. (b) Hamon,
D. P. G.; Massy-Westropp, R.; Razzino, P. Tetrahedron 1995, 51, 4183.
(c) Baldwin, J. E.; Fieldhouse, R.; Russell, A. T. Tetrahedron Lett. 1993,
34, 5491.
ACKNOWLEDGMENTS
■
The authors are grateful for the E. R. fellowship and financial
support, provided by the “Minister
de la Recherche”, the CNRS (Centre National de la Recherche
Scientifique) and the “Conseil Regional de Bourgogne”. It is
also a pleasure to thank Miss F. Chaux and M. J. Penouilh for
their technical assistance.
̂
(18) (a) Mehmandoust, M.; Petit, Y.; Larcheveque, M. Tetrahedron
̀
e de l’Education Nationale et
Lett. 1992, 33, 4313. (b) Bakke, M.; Ohta, H.; Kazmaier, U.; Sugai, T.
Synthesis 1999, 9, 1671. (c) Kazmaier, U.; Mues, H.; Krebs, A.
Chem.Eur. J. 2002, 8, 1850.
(19) (a) Itaya, T.; Mizutani, A. Tetrahedron Lett. 1985, 26, 347.
(b) Itaya, T.; Shimomichi, M.; Ozasa, M. Tetrahedron Lett. 1988, 29,
4129. (c) Itaya, T.; Mizutani, A.; Iida, T. Chem. Pharm. Bull. 1991, 39,
1407. (d) Itaya, T.; Iida, T.; Shimizu, S.; Mizutani, A.; Morisue, M.;
Sugimoto, Y.; Tachinaka, M. Chem. Pharm. Bull. 1993, 41, 252.
(20) (a) Sibi, M. P.; Renhowe, P. A. Tetrahedron Lett. 1990, 31, 7407.
(b) Sibi, M. P.; Li, B. Tetrahedron Lett. 1992, 33, 4115. (c) Sibi, M. P.;
Christensen, J. W. J. Org. Chem. 1999, 64, 6434. (d) Sibi, M. P.;
Rutherford, D.; Renhowe, P. A.; Li, B. J. Am. Chem. Soc. 1999, 121,
7509.
REFERENCES
■
(1) (a) Pichereau, C.; Allary, C. Eur. Biopharm. Rev. 2005, 88−91.
(b) Genet. Eng. Biotechnol. News 2006, 26, issue 13.
(2) Amino Acids, Peptides and Proteins in Organic Chemistry; Hughes,
A.B., Ed.; Wiley-VCH: Weinheim, 2009; Vol. 2.
(3) (a) Kazmaier, U. Liebigs Ann./Recueil 1997, 285. (b) Berkowitz,
D. B.; Chisowa, E.; McFadden, J. M. Tetrahedron 2001, 57, 6329.
(c) Kazmaier, U.; Deska, J.; Watzke, A. Angew. Chem., Int. Ed. 2006,
45, 4855. (d) Kazmaier U. In Amino Acids, Peptides and Proteins in
Organic Chemistry; Hughes, A.B., Ed.; Wiley-VCH: Weinheim, 2009;
Vol. 2, pp 3-34.
(4) (a) Kohta, S. Acc. Chem. Res. 2003, 36, 342. (b) Kotha, S.; Ghosh,
A. K. Synthesis 2004, 4, 558.
(5) Aveoza, A.; Busto, J. H.; Canal, N.; Peregrina, J. M.; Per
Fernandez, M. Org. Lett. 2005, 7, 3597.
(21) (a) Baldwin, J. E.; Adlington, R. M.; Robinson, N. G. J. Chem.
Soc., Chem. Commun. 1987, 153. (b) Padron, J. M.; Kokotos, G.;
Martin, T.; Markidis, T.; Gibbons, W. A.; Martin, V. S. Tetrahedron:
Asymmetry 1998, 9, 3381. (c) Rose, N. G. W.; Blaskovich, M. A.;
Wong, A.; Lajoie, G. A. Tetrahedron 2001, 57, 1497. (d) Wasserman,
H. H.; Long, Y. O.; Zhang, R.; Parr, J. Tetrahedron Lett. 2002, 43,
3351.
(22) (a) Gosselin, F.; Lubell, W. D. J. Org. Chem. 1998, 63, 7463.
(b) Werner, R. M.; Williams, L. M.; Davis, J. T. Tetrahedron Lett. 1998,
39, 9135. (c) Fowler, L. S.; Ellis, D.; Sutherland, A. Org. Biomol. Chem.
2009, 7, 4309. (d) Fowler, L. S.; Thomas, L. H.; Ellis, D.; Sutherland,
A. Chem. Commun. 2011, 47, 6569.
́
ez-
(6) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995, 60,
7078.
(7) (a) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997,
38, 677. (b) Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc.,
Perkin Trans. 1998, 1, 2485. (c) Nolen, E. G.; Kurish, A. J.; Wong, K.
A.; Orlando, M. D. Tetrahedron Lett. 2003, 44, 2449. (d) Gardiner, J.;
Anderson, K. H.; Downard, A.; Abell, A. D. J. Org. Chem. 2004, 69,
3375. (e) Kaul, R.; Surprenant, S. W. D.; Lubell. J. Org. Chem. 2005,
70, 3838. (f) Mutlak, H.; Hassan, A.; Brown, F. K. Chem. Commun.
2010, 46, 3013.
(23) (a) Meyer, F.; Uziel, J.; Papini, A. M.; Juge,
2001, 42, 3981. (b) Meyer, F.; Laaziri, A.; Papini, A. M.; Uziel, J.; Juge,
S. Tetrahedron: Asymmetry 2003, 14, 2229.
́
S. Tetrahedron Lett.
́
(24) (a) Both enantiomers of aspartic acid are commercially
available and are among the cheapest amino acids. (b) This work is
international patent pending: US 61/528,376 (2011 august 29th), Fr
11 59112 (2011 october 10th), PCT/EP 2012.
(25) Genet, J. P.; Blart, E.; Savignac, M.; Lemeune, S.; Lemaire-
̂
Audoire, S.; Bernard, J. M. Synlett 1993, 680.
(8) (a) Crisp, G. T.; Gebauer, M. G. Tetrahedron 1996, 52, 12465.
(b) Gurjar, M. K.; Talukdar, A. Synthesis 2002, 3, 315. (c) Collier, P.
N.; Patel, I.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43, 3401.
(26) Brown, F. K.; Brown, P. J.; Bickett, D. B.; Chambers, C. L.;
Davies, H. G.; Deaton, D. N.; Drewry, D.; Foley, M.; McElroy, A. B.;
Gregson, M.; McGeehan, G. M.; Myers, P. L.; Norton, D.; Salovich, J.
M.; Schoenen, F. J.; Ward, P. J. Med. Chem. 1994, 37, 674.
(27) Ramalingam, K.; Woodard, R. W. J. Org. Chem. 1988, 53, 1900.
(28) Stein, K. A.; Toogood, P. L. J. Org. Chem. 1995, 60, 8110.
(29) (a) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron:
Asymmetry 1999, 10, 775. (b) Adamczyk, M.; Johnson, D. D.; Reddy,
R. E. Tetrahedron: Asymmetry 2000, 11, 3063.
(30) Sutherland, A.; Caplan, J. F.; Vederas, J. C. Chem. Commun.
1999, 555.
(31) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S. Synlett 2002, 3, 468.
(32) Hebbe, V.; Londez, A.; Goujon-Ginglinger, C.; Meyer, F.; Uziel,
(9) Krebs, A.; Ludwig, V.; Pfitzer, J.; Durner, G.; Gobel, M. W.
̈
̈
Chem.Eur. J. 2004, 10, 544.
(10) Duggan, H. M. E.; Hitchcock, P. B.; Young, D. W. Org. Biomol.
Chem. 2005, 3, 2287.
(11) (a) Tolman, V.; Sedmera, P. Tetrahedron Lett. 1988, 29, 6183.
(b) Keith, D. D.; Tortora, J. A.; Ineichen, K.-S.; Leimgruber, W.
Tetrahedron 1975, 31, 2633.
(12) Yonezawa, Y.; Shimizu, K.; Yoon, K.-S; Shin, C.-G. Synthesis
2000, 5, 634.
(13) (a) Sasaki, N. A.; Potier, P.; Savignac, M.; Jaouen, G.
Tetrahedron Lett. 1988, 29, 57592. (b) Guillena, G.; Kruithof, C. A.;
Casado, M. A.; Egmond, M. R.; Van Koten, G. J. Organomet. Chem.
2003, 668, 3. (c) Van Staveren, D. R.; Metzler-Nolte, N. Chem. Rev.
2004, 104, 5931. (d) Albrecht, M.; Stortz, P. Chem. Soc. Rev. 2005, 34,
496. (e) Ojida, A.; Honda, K.; Shinmi, D.; Kiyonaka, S.; Mori, Y.;
Hamachi, I. J. Am. Chem. Soc. 2006, 128, 10452.
́
J.; Juge, S.; Lacour, J. Tetrahedron Lett. 2003, 44, 2467.
(33) For a pertinent article on the Wittig reaction under phase
transfer conditions, see: Moussaoui, Y.; Saïd, K.; Ben Salem, R.
ARKIVOC 2006, xii, 1.
(14) (a) Krebs, A.; Ludwig, V.; Pfitzer, J.; Durner, G.; Gobel, M. W.
̈
̈
Chem.Eur. J. 2004, 10, 544. (b) Chavan, S. P.; Sivappa, R.
(34) Presser, A.; Hufner, A. Monatsh. Chem. 2004, 135, 1015.
̈
Tetrahedron Lett. 2004, 45, 3941.
(35) For a pertinent review on the stereochemistry of the Wittig
reaction, see: Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(36) Ali, M. A.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40, 2842.
(15) Bajgrowicz, J. A.; Hallaoui, A.; Jacquier, R.; Pigier
̀
e, C.;
Viallefont, P. Tetrahedron 1985, 41, 1833.
7586
dx.doi.org/10.1021/jo3013622 | J. Org. Chem. 2012, 77, 7579−7587

The Journal of Organic Chemistry
Article
(37) (a) Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.;
Taylor, R. J. K. J. Org. Chem. 2002, 67, 1802. (b) Krebs, A.; Ludwig, V.;
Pfitzer, J.; Durner, G.; Gobel, M. W. Chem.Eur. J. 2004, 10, 544.
̈
̈
(c) Harvey, J. E; Kenworthy, M. N.; Taylor, R. J. K. Tetrahedron Lett.
2004, 45, 2467.
(38) (a) Baldwin, J. E.; Flinn, A. Tetrahedron Lett. 1987, 28, 3605.
(b) Miller, E. D.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Org.
Chem. 2007, 72, 323.
(39) (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36,
1249. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004.
1
(40) The Z/E ratios were not determined, because the olefinic H
NMR signals appear in massif as the result of many coupling or
superimposed with other signals, or due to the formation of (E,E),
(Z,Z), and (E,Z) stereoisomers.
(41) Kaul, R.; Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70,
3838.
(42) Oehlke, A.; Auer, A. A.; Jahre, I.; Walfort, B.; Ruffer, T.; Zoufala,
P.; Lang, H.; Spange, S. J. Org. Chem. 2007, 72, 4328.
7587
dx.doi.org/10.1021/jo3013622 | J. Org. Chem. 2012, 77, 7579−7587