A Direct Approach to Enantiopure Propionate Derivatives from Ethyl Lactate

Article abstract of DOI:10.1055/s-0035-1562449

The S-propargyl xanthate derived from ethyl (S)-lactate reacts upon heating with various acidic substances to give the propionate transfer product in high yield and with complete inversion of configuration.

Full text of DOI:10.1055/s-0035-1562449

SYNTHESIS
0
0
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8
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1
1
4
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7
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2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
D. Clemente-Tejeda et al.
Paper
Synthesis
A Direct Approach to Enantiopure Propionate Derivatives from
Ethyl Lactate
Me
O
David Clemente-Tejeda
Juan Carlos Ortiz Lara1
Samir Z. Zard*
H
CO2Et
R
S
CO2H
CO2Et
H
H
H
O
O
Me
S
S
toluene, reflux
Laboratoire de Synthèse Organique associé au CNRS, Ecole
Polytechnique, 91128 Palaiseau, France
samir.zard@polytechnique.edu
inversion
70%
* 16 examples, 35–100% yield
* not limited to carboxylic acids
OH
OH
This paper is dedicated with respect and affection to the
memory of Professor Jean Normant.
Received: 01.06.2016
Accepted after revision: 06.06.2016
Published online: 13.07.2016
H
H
H
Me
Me
CO2H
Me
CO2H
CO2H
DOI: 10.1055/s-0035-1562449; Art ID: ss-2016-c0375-op
MeO
Abstract The S-propargyl xanthate derived from ethyl (S)-lactate re-
acts upon heating with various acidic substances to give the propionate
transfer product in high yield and with complete inversion of configura-
tion.
naproxen (2)
Me
Me
ibuprofen (1)
Ph
O
ketoprofen (3)
H
Me
O
Me
H
H
O
Me
O
Me
CO2H
Key words S-propargyl xanthate, sigmatropic rearrangement, esters,
inversion, propionates
O
CO2H
CO2H
O
Cl
F
Cl
mecoprop (4)
N
N
haloxyfop (6)
cyhalofop (5)
The propionate side chain is arguably one of the most
important pharmacophores. It is a key element of the wide-
ly used nonsteroidal anti-inflammatory drugs (NSAIDs),
such as compounds 1–3 (Figure 1).2a These are the more
popular representatives and are produced on a scale of
thousands of tons. The propionate motif is also central to
the so-called aryloxyphenoxypropionate (AOPP or fop) class
of herbicides, as illustrated by compounds 4–9 displayed in
Figure 1. These substances act by inhibiting a particular en-
zyme in the plant, namely acetyl-CoA carboxylase (AC-
Case).2b It is presumed that the free carboxylic acid is the
active entity, but the ester precursors (e.g., 8 and 9) are
sometimes better absorbed by the leaf and then hydrolyzed
into the corresponding acid in vivo.
In view of the importance of this motif, numerous
methods have been devised for its introduction. Essentially
all known techniques have been exploited to obtain the op-
tically active form, ranging from classical resolution to en-
antioselective protonation of ketene intermediates, to the
use of asymmetric catalytic hydrogenation and enzymatic
resolution based approaches.3 Optically active alkylating
agents derived from chloropropionates and lactates have
played a prominent role in this respect.4 The now classical
Mitsunobu reaction, allowing the direct use of lactate esters
H
CN
O
Me
CF3
O
H
CO2H
O
Me
O
Cl
F
clodinafop (7)
CO2Et
N
O
fenoxaprop-ethyl (8)
H
Cl
Cl
N
N
O
Me
CO2Et
quizalofop-ethyl (9)
O
Figure 1 Examples of biologically active propionate derivatives
as partners in alkylations with inversion, has logically also
been used in this context.5 Indeed, the synthesis of AOPP
herbicides, which have an R absolute configuration, from
abundant and cheap (S)-lactic acid derivatives by alkylation
of a suitable phenol with inversion of configuration is par-
ticularly attractive. We now describe an alternative ap-
proach relying on a novel method for creating a powerful
leaving group on the alcohol function of ethyl (S)-lactate.
In the course of our studies on various aspects of the
chemistry of xanthates, in particular related to radical
transformations,6 we found that moderate heating (≥80 °C)
of an S-propargyl xanthate 10 causes its isomerization into
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
D. Clemente-Tejeda et al.
Paper
Synthesis
the corresponding S-allenyl isomer 11, which is in equilibri-
um with the betaine 12 (Scheme 1).7 The latter represents a
new reactive species for which only indirect evidence could
be obtained. The equilibrium largely favors allene 11 and
the concentration of betaine 12 is too small to allow its di-
rect spectroscopic observation. When the thermal rear-
rangement is conducted in the presence of a weak acid HA,
13, an irreversible protonation of the betaine occurs to give
an ion pair 14, which rapidly collapses into dithiolone 15
and alkylated species 16.8 Thus, protonation transforms the
betaine motif into a powerful leaving group with the count-
er-anion being the nucleophile itself.
Me
S
CO2Et
H
O
17
H
1) NaH, CS2, THF
2) propargyl bromide
O
Me
PhCO2H 19a
R
H
O
CO2Et
Me
toluene, reflux
S
CO2Et
(R)-20a 100%
H
O
CO2H
CO2Et
Me
S
S
S
CF3
O
O
O
(S)-18
R
H
S
Me
(S)-19b
CF3
O
Me
(S,R)-20b 80%
toluene, reflux
R
O
R
O
S
O
S
S
Scheme 2 Formation of a benzoate and a Mosher ester from natural
(S)-ethyl lactate
R
O
heat
S
S
S
12
10
11
H—A
13
R
O
the reaction in Scheme 2. The transformation had therefore
occurred with complete inversion and no racemization had
taken place during the preparation of the xanthate reagent
(S)-18.
A
inversion at R
A
R*
16
+
S
S
S
S
14
15
Scheme 1 Formation and capture of a betaine from an S-propargyl xan-
thate
δ
H = 1.51 (d)
δH = 1.58 (d)
Me
The overall process represents an alkylation with inver-
sion of configuration under quite mild conditions. It was
therefore tempting to extend this chemistry to a lactic acid
derivative, since this would allow the direct introduction of
the chiral propionate group.
CH3
CO2Et
CH3
CO2Et
H
CO2Et
O
O
O
O
O
(S)-19b
R
R
+
H
H
S
S
S
S
toluene
reflux
CF3
CF3
Ph
Ph
O
O
(S,R)-20b
(S,S)-20b
CH3
CH3
(R,S)-18
Our main concern from the outset was that the synthe-
sis of the required reagent 10, which entails the treatment
of (S)-ethyl lactate with base followed by carbon disulfide
and propargyl bromide, and which may not proceed with-
out some degree of racemization. In the event, our worries
were unfounded and the preparation of 10 proceeded with-
out any noticeable erosion of the original optical purity of
the lactate (Scheme 2). Thus, upon heating of xanthate 18
with benzoic acid (19a), the expected known benzoate of
ethyl (R)-lactate 20a was obtained in quantitative yield. The
optical rotation of the product corresponded to the report-
ed literature value and indicated that clean inversion had
δ
H = 3.65 (q)
δ
H = 3.57 (q)
Scheme 3 Formation of Mosher esters from racemic ethyl lactate
A series of esters 20 of the ethyl (R)-lactate esters were
prepared in the same manner in generally high yield
(Scheme 4). The formation of Boc-protected proline ester
20e is especially interesting. Equally noteworthy is the
clean formation of esters 20d and 20f, despite the presence
of an unprotected phenol. The large difference in acidity
between the two functional groups ensures that intermedi-
ate betaine 12 (Scheme 1) is protonated to give species 14
with a carboxylate and not a phenolate counter-anion.
There is thus no need to protect phenols (or alcohols) if
they are part of the substrate. Phenols and other functional
groups can nevertheless react with intermediate betaine 12
if they are sufficiently acidic to protonate it. This is demon-
strated by the examples in Scheme 5. Phenols 13a and 13b
and hydroxypyridine 13c reacted smoothly under the usual
conditions to give aryl ethers 21a, 21b, and 21c, respective-
ly. Disappointingly, the somewhat less acidic phenol 13h
furnished quizalofop-ethyl (9) only in modest yield. This
transformation was complicated by the very low solubility
17
indeed taken place {[α]D25 –13.2 (c 1.2, CHCl3); Lit.9 [α]D
–14.9 (c = 1.2, CHCl3)}.
A more accurate method for measuring the enantiomer-
ic purity involved making the corresponding Mosher ester
(S,R)-20b from commercial Mosher acid (S)-19b (Scheme 2)
and comparing its NMR spectrum with those of the two
diastereoisomers (S,R)-20b and (S,S)-20b obtained by reac-
tion of the same Mosher acid (S)-19b with racemic ethyl
lactate (see relevant chemical shifts in Scheme 3). Not a
trace of diastereoisomer (S,S)-20b was observed in the
high-field NMR spectrum of the Mosher ester obtained by
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
D. Clemente-Tejeda et al.
Paper
Synthesis
of phenol 13h, and toluene had to be replaced by benzoni-
trile and the temperature had to be raised to 130 °C, which
caused slow decomposition of reagent 18. Phenols substi-
tuted with alkyl groups, such as estrone, did not react
cleanly.
CO2Et
H
(S)-18
H
13
A
A
R
toluene, reflux
21
Me
CO2Et
H
O
NC
OH
NC
Me
13a
21a 87%
Cl
Cl
O
Cl
Cl
CO2Et
H
CO2Et
Me
H
O
(S)-18
R-CO2H
19
R
O
R
OH
13b
toluene, reflux
20
Me
21b 64%
O
CO2Et
H
CO2H
S
S
CO2Et
Me
H
O
O
Cl
Cl
OH
20c 100%
Me
19c
N
N
OH
OH
21c 65%
13c
CN
Et
Et
CN
19d
20d 76%
CO2Et
Me
H
13d
21d 81%
CO2Et
N
H
H
H
CO2H
N
O
O
Me
N
CO2Et
H
Me
Me
O
N
CO2H
N
N
Me
21e, 68%
CO2Et
O
20e 71%
13e
N
H
19e
N
Boc
Boc
Me
Me
O
CO2H
H
CO2Et
Me
Me
H
O
H
O
O
H
CO2Et
Me
N
O
N
OH
13f
21f 83%
19f
20f 70%
O
O
OH
N
N
OH
N
N
N
O
H
H
CO2Et
Me
NH
CO2Et
21g 100%
CO2H
N
N
O
13g
Me
H
H
H
H
N
O
13h
OH
20g 80%
H
H
H
H
Cl
N
HO
HO
H
19g
H
N
N
O
H
CO2Et
Me
CO2Me
CO2H
CO2Me
CO2Et
Me
Cl
O
H
H
H
O
quizalofop-ethyl (9) 35%
H
H
O
Scheme 5 Reaction of propargylic xanthate (S)-18 with various acidic
AcO
AcO
20h 90%
19h
derivatives
H
H
Scheme 4 Examples of ester formation with inversion from ethyl lactate
In summary, we have described a simple method for
producing optically pure propionate derivatives from natu-
ral ethyl lactate. In the present context, this approach com-
pares very favorably with the more traditional Mitsunobu
reaction: it is more atom economical, since only one trivial
shelf-stable reagent (S)-18 is needed and much less waste is
generated; no hazardous and expensive diazo coupling
agent is involved; the experimental procedure is very sim-
ple and calls for mere heating of the acidic substance with
xanthate (S)-18 in refluxing toluene or other solvents with
a similar boiling point; and the purification of the products
is often very easy since the co-product, dithiolone 15, is
fairly volatile and the majority is in fact eliminated upon
evaporation of the solvent. Numerous propionate deriva-
tives can thus be prepared quickly and conveniently. Last,
No difficulties were encountered with N-hydroxy-
phthalimide (13f) or with ‘acidic’ nitrogen derivatives: 3-
cyanoindole (13d), benzimidazole 13e, and phenyltetrazole
13g (Scheme 5). The last three may be considered as aza an-
alogues of the nonsteroidal anti-inflammatory drugs 1–4 in
Figure 1 and could exhibit useful biological activities.10
Interestingly, we observed the formation of only one re-
gioisomer in the reaction of hydroxypyridine 13c and
phenyltetrazole 13g. This was not the case with saccharin
(13i) and sulfonimide 13j (Scheme 6). The reaction in both
cases furnished a quantitative yield of a 1:1 mixture of N-
and O-alkylated regioisomers 21i/21′i and 21j/21′j, respec-
tively.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
D. Clemente-Tejeda et al.
Paper
Synthesis
Propionates 9, 20, and 21 Derived from the Propargyl Xanthate of
(S)-(–)-Ethyl Lactate; General Procedure
CO2Et
Me
H
O
O
O
CO2Et
Me
H
Propargyl xanthate (S)-18 (1 equiv) and the acidic substrate HA (2
equiv) were dissolved in toluene, unless stated otherwise (10
mL/mmol of propargyl xanthate). The mixture was refluxed under an
argon atmosphere and followed by TLC until total conversion of the
starting material (2–6 h). Then, the solvent was removed under re-
duced pressure and the crude was purified by flash column chroma-
tography. Due to the low solubility of compounds 13d, 13e, 19d, and
19f in toluene, chlorobenzene was used as a solvent in the reactions.
In the experiment involving 13h, benzonitrile was used as a solvent
and the reaction was carried out at 130 °C. Finally, a few of the exper-
iments were also carried out using the acid partner HA as the limiting
reagent. No significant changes in yields were observed.
(S)-18
NH
N
+
N
toluene
reflux
S
S
S
O
O
O
O
O
O
13i
21i + 21'i 100%
O
H
CO2Et
N
HN
+
O
SO2 Me
(S)-18
toluene, reflux
NH
SO2
HN
CO2Et
Me
H
13j
O
Ethyl (R)-2-{4-[(6-Chloroquinoxalin-2-yl)oxy]phenoxy}propa-
N
noate (Quizalofop-p-Ethyl; 9)
HN
SO2
According to the general procedure, (S)-18 (0.34 mmol) and 13h (0.68
mmol) were dissolved in benzonitrile. After purification, the product
was isolated as a grey solid.
21j + 21'j 100%
Scheme 6 Formation of regioisomers from sulfonimides
Yield: 45 mg (0.12 mmol, 35%); mp 87–88 °C.
1H NMR (400 MHz, CDCl3): δ = 8.59 (s, 1 H), 7.96 (d, J = 2.4 Hz, 1 H),
7.60 (d, J = 8 Hz, 1 H), 7.52 (dd, J = 8, 2.4 Hz, 1 H), 7.10 (d, J = 8 Hz, 2 H),
6.88 (d, J = 8 Hz, 2 H), 4.68 (q, J = 8 Hz, 1 H), 4.18 (q, J = 8 Hz, 2 H), 1.57
(d, J = 8 Hz, 3 H), 1.21 (t, J = 8 Hz, 3 H).
but not least, this transformation reveals yet another fasci-
nating mechanistic facet of the chemistry of S-propargyl
xanthates.
13C NMR (100 MHz, CDCl3): δ = 172.1, 157.2, 155.1, 146.5, 140.1,
139.7, 138.5, 132.8, 131.1, 128.8, 127.9, 123.0, 122.4, 116.0, 73.1, 61.3,
18.6, 14.1.
Solvents were used as received. Merck Geduran SI 60 Å silica gel (35–
70 μm) was used for column chromatography. IR spectra were record-
ed on a Perkin-Elmer 1420 spectrometer. 1H NMR and 13C NMR spec-
tra were recorded using 400 MHz ARX 400 Bruker spectrometers.
Chemical shifts are given in ppm, referenced to the residual proton
resonances of the solvents.
HRMS: m/z calcd: 372.0877; found: 372.0865, 299.0342 [M – CO2Et].
(R)-1-Ethoxy-1-oxopropan-2-yl Benzoate [(R)-20a]
According to the general procedure, (S)-18 (1.8 mmol) and 19a (0.9
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
Ethyl (S)-2-{[(Prop-2-yn-1-ylthio)carbonothioyl]oxy}propanoate
[(S)-18]
Yield: 378 mg (0.91 mmol, 100%).
1H NMR (400 MHz, CDCl3): δ = 8.10 (m, 2 H), 7.59 (m, 1 H), 7.46 (m, 2
H), 5.32 (q, J = 7 Hz, 1 H), 4.24 (q, J = 7 Hz, 2 H), 1.64 (d, J = 7 Hz, 3 H),
1.29 (t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 166.0, 133.3, 129.9, 129.5,
128.4, 69.2, 61.4, 17.1, 14.1.
Ethyl (S)-(–)-lactate (17; 4 mL, 35.3 mmol) and CS2 (21.22 mL, 352.94
mmol) were dissolved in anhyd THF (120 mL). The solution was
cooled to 0 °C in an ice bath and NaH (1.016 g, 42.36 mmol) was add-
ed portionwise. The mixture was stirred for 30 min at r.t. and, after
this time, again cooled to 0 °C in an ice bath. Then, propargyl bromide
(9.43 mL, 105.9 mmol) was added dropwise. The reaction mixture
was stirred at r.t. and followed by TLC until total absence of starting
ethyl lactate. H2O was carefully added, the solution was stirred for 20
min, and the solvent was removed under reduced pressure. The resi-
due was extracted with Et2O, dried (MgSO4), and purified by flash col-
umn chromatography (silica gel, PE–EtOAc, 9:1).
MS (IC, NH3): 223 [M + H+].
(R)-1-Ethoxy-1-oxopropan-2-yl (S)-3,3,3-Trifluoro-2-methoxy-2-
phenylpropanoate [(S,R)-20b]
According to the general procedure, (S)-18 (0.5 mmol) and (S)-19b (1
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
Yield: 5.74 g, 24.7 mmol, 70%).
1H NMR (400 MHz, CDCl3): δ = 5.77–5.61 (q, J = 7 Hz, 1 H), 4.23 (q, J =
7 Hz, 2 H), 3.91 (dd, J = 4.4, 2.8 Hz, 2 H), 2.24 (t, J = 2.8 Hz, 1 H), 1.65
(d, J = 7 Hz, 3 H), 1.28 (t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.8, 169.3, 76.8, 76.7, 72.0, 61.6,
24.2, 17.0, 14.1.
Yield: 130 mg (0.39 mmol, 80%).
1H NMR (400 MHz, CDCl3): δ = 7.61 (m, 2 H), 7.42 (m, 3 H), 5.28 (q,
J =8 Hz, 1 H), 4.21 (q, J = 8 Hz, 2 H), 3.57 (d, J = 1.2 Hz, 3 H), 1.58 (d, J =
8 Hz, 3 H), 1.25 (t, J = 8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.5, 166.0, 131.6, 129.7, 128.3 (2C),
127.7, 124.5, 121.7, 84.6 (q), 70.4, 61.7, 55.4, 16.7, 14.0.
MS (IC, NH3): 233 [M + H+].
19F NMR (300 MHz, CDCl3): δ = 67.41 (s).
HRMS: m/z calcd: 334.1028; found: 265.1076 [M – CF3].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
D. Clemente-Tejeda et al.
Paper
Synthesis
(R)-1-Ethoxy-1-oxopropan-2-yl Thiophene-2-carboxylate (20c)
(R)-1-Ethoxy-1-oxopropan-2-yl (4R)-4-[(3R,5R,10S,13R,17R)-3-Hy-
droxy-10,13-dimethylhexadecahydro-1H-cyclopenta[α]phenan-
thren-17-yl]pentanoate (20g)
According to the general procedure, (S)-18 (1.56 mmol) and 19c (0.78
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
According to the general procedure, (S)-18 (0.5 mmol) and 19g (1
mmol) were dissolved in toluene. After purification, the product was
isolated as a pale white-yellow solid.
Yield: 178 mg (0.78 mmol, 100%).
1H NMR (400 MHz, CDCl3): δ = 7.89 (dd, J = 5.2, 3.5 Hz, 1 H), 7.61 (dd,
J = 6, 2 Hz, 1 H), 7.13 (dd, J = 5.2, 3.5 Hz, 1 H), 5.28 (q, J = 7 Hz, 1 H),
4.25 (q, J = 7 Hz, 2 H), 1.62 (d, J = 7 Hz, 3 H), 1.29 (t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.1, 160.4, 123.7, 121.9, 116.4,
110.6, 68.6, 61.4, 17.2, 14.1.
Yield: 191 mg (0.40 mmol, 80%); mp 59–60 °C.
1H NMR (400 MHz, CDCl3): δ = 5.04 (q, J = 8 Hz, 1 H), 4.19 (q, J = 8 Hz,
2 H), 3.60 (m, 1 H), 2.60 (d, J = 12 Hz, 1 H), 1.99 (s, 3 H), 1.39 (d, J = 8
Hz, 3 H), 1.22 (t, J = 8 Hz, 3 H), 1.18 (s, 3 H), 0.80 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.0, 172.6, 170.7, 170.6, 73.4, 68.5,
61.2, 54.2, 51.9, 51.9, 45.3, 44.3, 36.3, 35.7, 35.6, 33.7, 33.5, 31.8, 28.1,
27.2, 21.4, 19.5, 16.8, 16.6, 14.0, 11.9.
MS (IC, NH3): 229 [M + H+].
(R)-1-Ethoxy-1-oxopropan-2-yl 3-Ethyl-4-hydroxybenzoate (20d)
HRMS: m/z calcd: 480.2723; found: 480.2729.
According to the general procedure, (S)-18 (0.5 mmol) and 19d (1
mmol) were dissolved in chlorobenzene. After purification, the prod-
uct was isolated as a thick yellow oil.
1-[(R)-1-Ethoxy-1-oxopropan-2-yl] 2-Methyl (1S,2S,4βS,7S,8αS)-7-
Acetoxy-2,4β-dimethyltetradecahydrophenanthrene-1,2-dicar-
boxylate (20h)
Yield: 100 mg (0.38 mmol, 76%).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 4 Hz, 1 H), 7.71 (dd, J = 8, 2
Hz, 1 H), 6.86 (br s, 1 H), 6.71 (d, J = 8 Hz, 1 H), 5.28 (q, J = 8 Hz, 1 H),
4.25 (q, J = 8 Hz, 2 H), 2.61 (q, J = 8 Hz, 1 H), 1.63 (d, J = 8 Hz, 3 H), 1.29
(t, J = 8 Hz, 3 H), 1.20 (t, J = 8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.9, 166.4, 158.8, 131.3, 130.3,
129.5, 120.9, 114.9, 68.9, 61.7, 22.8, 17.1, 14.0, 13.6.
According to the general procedure, (S)-18 (0.5 mmol) and 19h (1
mmol) were dissolved in toluene. After purification, the product was
isolated as a white-pink solid.
Yield: 214 mg (0.45 mmol, 90%); mp 81–82 °C.
1H NMR (400 MHz, CDCl3): δ = 4.95 (q, J = 8 Hz, 1 H), 4.66 (m, 1 H),
4.14 (q, J = 8 Hz, 2 H), 3.64 (s, 3 H), 2.42 (m, 1 H), 2.30–2.22 (m, 2 H),
1.93 (d, J = 12 Hz, 1 H), 1.46 (d, J = 8 Hz, 3 H), 1.25 (t, J = 8 Hz, 3 H),
0.90 (d, J = 12 Hz, 3 H), 0.90 (s, 3 H), 0.62 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.6, 170.9, 71.8, 68.4, 61.3, 56.4,
55.9, 42.7, 42.0, 40.4, 40.1, 36.3, 35.8, 35.4, 35.3, 34.5, 30.9, 30.7, 30.4,
28.1, 27.1, 26.4, 24.2, 23.3, 20.8, 18.2, 16.9, 14.1, 12.0.
HRMS: m/z calcd: 266.1154; found: 266.1145.
1-tert-Butyl 2-[(R)-1-Ethoxy-1-oxopropan-2-yl] (S)-Pyrrolidine-
1,2-dicarboxylate (20e)
According to the general procedure, (S)-18 (0.5 mmol) and 19e (1
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
HRMS: m/z calcd: 476.3502; found: 458.3386 [M – H2O].
Yield: 111 mg (0.35 mmol, 71%). The main rotamer is described.
Ethyl (R)-2-(4-Cyanophenoxy)propanoate (21a)
1H NMR (400 MHz, CDCl3): δ = 5.04 (q, J = 8 Hz, 1 H), 4.26 (dd, J = 8, 4
Hz, 1 H), 4.16 (q, J = 8 Hz, 2 H), 3.49 (m, 2 H), 2.20 (m, 1 H), 2.04 (m, 2
H), 1.86 (m, 1 H), 1.45 (d, J = 8 Hz, 3 H), 1.39 (s, 3 H), 1.24 (t, J = 8 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 170.3, 153.7, 79.9, 68.8, 61.3,
59.2, 46.3, 30.7, 28.3, 23.4, 16.9, 14.0.
According to the general procedure, (S)-18 (5 mmol) and 13a (2.5
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
Yield: 480 mg (2.19 mmol, 87%).
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8
Hz, 2 H), 4.80 (q, J = 7 Hz, 1 H), 4.21 (q, J = 7 Hz, 2 H), 1.66 (d, J = 7 Hz,
3 H), 1.25 (t, J = 7 Hz, 3 H).
HRMS: m/z calcd: 315.1682; found: 315.1678.
13C NMR (100 MHz, CDCl3): δ = 171.0, 160.8, 118.9, 115.6, 104.7, 72.5,
61.6, 18.3, 14.0.
MS (IC, NH3): 220 [M + H+].
(R)-1-Ethoxy-1-oxopropan-2-yl (1S,4αS,10αR)-6-Hydroxy-1,4α-di-
methyl-1,2,3,4,4α,9,10,10α-octahydrophenanthrene-1-carboxyl-
ate (20f)
According to the general procedure, (S)-18 (0.5 mmol) and 19f (1
mmol) were dissolved in chlorobenzene. After purification, the prod-
uct was isolated as a pale yellow solid.
Ethyl (R)-2-(3,5-Dichlorophenoxy)propanoate (21b)
According to the general procedure, (S)-18 (1.2 mmol) and 13b (0.60
mmol) were dissolved in toluene. After purification, the product was
isolated as a colorless oil.
Yield: 129 mg (0.35 mmol, 70%); mp 125–127 °C.
1H NMR (400 MHz, CDCl3): δ = 6.91 (d, J = 8 Hz, 1 H), 6.73 (d, J = 4 Hz,
1 H), 6.58, (dd, J = 8, 4 Hz, 1 H), 5.06 (q, J = 8 Hz, 1 H), 4.56 (br s, 1 H),
4.20 (q, J = 8 Hz, 2 H), 2.84 (dd, J = 16, 4 Hz, 1 H), 2.71 (m, 1 H), 2.30
(m, 1 H), 2.20 (m, 2 H), 2.00 (m, 2 H), 1.62 (m, 1 H), 1.57 (dd, J = 12, 4
Hz, 1 H), 1.48 (d, J = 8 Hz, 3 H), 1.36 (s, 3 H), 1.27 (t, J = 8, 8 Hz, 3 H),
1.07 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.0, 171.1, 153.8, 149.3, 130.0,
127.3, 113.1, 112.1, 68.4, 61.4, 52.7, 44.0, 39.4, 38.7, 37.7, 31.4, 28.3,
23.2, 21.2, 19.8, 16.9, 14.0.
Yield: 103 mg (0.39 mmol, 64%).
1H NMR (400 MHz, CDCl3): δ = 6.95 (d, J = 2 Hz, 1 H), 6.77 (d, J = 2 Hz,
2 H), 4.72 (q, J = 7 Hz, 1 H), 4.25 (q, J = 7 Hz, 2 H), 1.62 (d, J = 7 Hz, 3 H),
1.28 (t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.2, 158.6, 135.5, 121.9, 114.2, 73.0,
61.6, 18.4, 14.2.
MS (IC, NH3): 263 [M + H+].
HRMS: m/z calcd: 374.2093; found: 374.2103.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
D. Clemente-Tejeda et al.
Paper
Synthesis
Ethyl (R)-2-[(5-Chloropyridin-2-yl)oxy]propanoate (21c)
1H NMR (400 MHz, CDCl3): δ = 8.18 (m, 2 H), 7.52 (m, 3 H), 5.67 (q, J =
7.2 Hz, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 2.04 (d, J = 7.2 Hz, 3 H), 1.25 (t, J =
7.2 Hz, 3 H).
According to the general procedure, (S)-18 (4.6 mmol) and 13c (2.3
mmol) were dissolved in toluene. After purification, the product was
isolated as a brown oil.
13C NMR (100 MHz, CDCl3): δ = 168.1, 130.4, 128.9, 127.3, 127.0, 62.2,
61.2, 16.7, 14.0.
Yield: 343 mg (1.49 mmol, 65%).
MS (IC, NH3): 247 [M + H+].
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 9.98 Hz, 1 H), 7.29 (dd, J =
9.98, 2.93 Hz, 1 H), 6.56 (d, J = 9.98 Hz, 1 H), 5.53 (q, J = 7.6 Hz, 1 H),
4.23 (q, J = 7 Hz, 2 H), 1.65 (d, J = 7.6 Hz, 3 H), 1.29 (t, J = 7 Hz, 3 H).
Ethyl (R)-2-[1,1-Dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl]propa-
noate (21i)
13C NMR (100 MHz, CDCl3): δ = 170.2, 161.0, 140.6, 132.6, 121.5, 99.8,
According to the general procedure, (S)-18 (2 mmol) and 13i (1
mmol) were dissolved in toluene. After purification, the product was
isolated as a brown solid.
64.1, 54.0, 16.7, 14.4.
MS (IC, NH3): 230 [M + H+].
Yield: 140 mg (0.49 mmol, 50%); mp 90–93 °C.
Ethyl (R)-2-(3-Cyano-1H-indol-1-yl)propanoate (21d)
1H NMR (400 MHz, CDCl3): δ = 8.07 (m, 1 H), 7.94–7.83 (m, 3 H), 4.86–
4.30 (q, J = 7.6 Hz, 1 H), 4.24 (q, J = 7.2 Hz, 2 H), 1.87 (d, J = 7.6 Hz, 3 H),
1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.6, 154.8, 135.0, 134.4, 125.4,
121.0, 62.3, 49.9, 14.8, 14.1.
According to the general procedure, (S)-18 (0.5 mmol) and 13d (1
mmol) were dissolved in chlorobenzene. After purification, the prod-
uct was isolated as a brown oil.
Yield: 96 mg (0.405 mmol, 81%). Only one rotamer is described.
1H NMR (400 MHz, CDCl3): δ = 8.18 (s, 1 H), 7.71–7.64 (m, 2 H), 7.25
(m, 2 H), 4.64 (q, J = 8 Hz, 1 H), 4.25 (q, J = 8 Hz, 2 H), 1.52 (d, J = 8 Hz,
3 H), 1.23 (t, J = 8 Hz, 3 H).
MS (IC, NH3): 283 [M + H+].
Ethyl (R)-2-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)oxy]propanoate
(21′i)
13C NMR (100 MHz, CDCl3): δ = 172.1, 134.2, 133.8, 124.0, 123.0,
120.3, 119.7, 115.3, 114.9, 88.3, 72.0, 61.5, 18.8, 14.1.
According to the general procedure, (S)-18 (2 mmol) and 13i (1
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
HRMS: m/z calcd: 242.1055; found: 242.1045.
Ethyl (R)-2-(5,6-Dimethyl-1H-benzo[δ]imidazol-1-yl)propanoate
(21e)
Yield: 142 mg (0.50 mmol, 50%).
1H NMR (400 MHz, CDCl3): δ = 7.91–7.71 (m, 4 H), 5.53 (q, J = 7.2 Hz, 1
H), 4.27 (q, J = 7.2 Hz, 2 H), 1.75 (d, J = 7.2 Hz, 3 H), 1.31 (t, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 161.8, 161.6, 143.6, 134.4, 133.6,
126.4, 123.6, 122.1, 75.2, 65.1, 17.2, 14.1.
MS (IC, NH3): 283 [M + H+].
According to the general procedure, (S)-18 (0.5 mmol) and 13e (1
mmol) were dissolved in chlorobenzene. After purification, the prod-
uct was isolated as a brown solid.
Yield: 83 mg (0.34 mmol, 68%); mp 80–84 °C.
1H NMR (400 MHz, CDCl3): δ = 8.74 (s, 1 H), 8.04 (s, 1 H), 7.52 (s, 1 H),
5.86 (q, J = 8 Hz, 1 H), 4.29 (q, J = 8 Hz, 2 H), 2.39 (s, 3 H), 2.36 (s, 3 H),
1.81 (d, J = 8 Hz, 3 H), 1.32 (t, J = 8 Hz, 3 H).
Ethyl (2R)-2-(4-Benzyl-1,1-dioxido-3-oxo-1,2,5-thiadiazolidin-2-
yl)propanoate (21j)
13C NMR (100 MHz, CDCl3): δ = 184.0, 169.3, 143.2, 135.0, 134.1,
129.7, 121.0, 116.2, 75.8, 61.9, 20.8, 20.2, 17.1, 14.1.
According to the general procedure, (S)-18 (0.9 mmol) and 13j (0.44
mmol) were dissolved in toluene. After purification, the product was
isolated as a white solid.
HRMS: m/z calcd: 246.1368; found: 246.1358.
Ethyl (R)-2-[(1,3-Dioxoisoindolin-2-yl)oxy]propanoate (21f)
Yield: 72 mg (0.22 mmol, 50%); mp 117–119 °C.
According to the general procedure, (S)-18 (3.6 mmol) and 13f (1.8
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H), 4.91 (d, J = 7.0 Hz, 1
H), 4.66 (q, J = 7 Hz, 1 H), 4.39 (m, 1 H), 4.21 (q, J = 7 Hz, 2 H), 3.33–
3.13 (m, 2 H), 1.73 (d, J = 7 Hz, 3 H), 1.26 (t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.4, 168.1, 134.8, 129.6, 129.1,
127.8, 62.4, 61.3, 51.3, 36.6, 14.1, 14.0.
Yield: 404 mg (1.534 mmol, 83%).
1H NMR (400 MHz, CDCl3): δ = 7.85 (m, 2 H), 7.77 (m, 2 H), 4.87 (q, J =
7 Hz, 1 H), 4.23 (q, J = 7 Hz, 2 H), 1.65 (d, J = 7 Hz, 3 H), 1.29 (t, J = 7 Hz,
3 H).
MS (IC, NH3): 327 [M + H+].
13C NMR (100 MHz, CDCl3): δ = 169.7, 163.3, 134.6, 128.8, 123.7, 81.3,
61.7, 16.4, 14.0.
MS (IC, NH3): 264 [M + H+].
Ethyl (2R)-2-[(4-Benzyl-1,1-dioxido-4,5-dihydro-1,2,5-thiadiazol-
3-yl)oxy]propanoate (21′j)
According to the general procedure, (S)-18 (0.9 mmol) and 13j (0.44
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
Ethyl (R)-2-(5-Phenyl-2H-tetrazol-2-yl)propanoate (21g)
According to the general procedure, (S)-18 (0.4 mmol) and 13g (0.2
mmol) were dissolved in toluene. After purification, the product was
isolated as a yellow oil.
Yield: 71 mg (0.22 mmol, 50%).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.24 (m, 5 H), 5.29 (d, J = 7.0 Hz, 1
H), 4.99 (q, J = 7 Hz, 1 H), 4.71–4.63 (m, 1 H), 4.27 (q, J = 7 Hz, 2 H),
3.29–2.95 (m, 2 H), 1.65 (d, J = 7 Hz, 3 H), 1.30 (t, J = 7 Hz, 3 H).
Yield: 49 mg (0.198 mmol, 100%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
D. Clemente-Tejeda et al.
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 176.3, 168.8, 135.1, 129.3, 129.0,
127.7, 76.2, 67.7, 62.3, 37.9, 17.1, 14.1.
MS (IC, NH3): 327 [M + H+].
(4) See, for example: (a) Barrett, A. G. M.; Braddock, C. D.; James, R.
A.; Koike, N.; Procopiou, P. A. J. Org. Chem. 1998, 63, 6273.
(b) King, J. F.; Loosmore, S. M.; Aslam, M.; Lock, J. D.; McGarrity,
M. J. J. Am. Chem. Soc. 1982, 104, 7108.
(5) (a) Dirlam, N. L.; Moore, B. S.; Urban, F. J. J. Org. Chem. 1987, 52,
3587. (b) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301.
(c) For a review of the Mitsunobu reaction, see: Hughes, D. L.
Org. React. 1992, 42, 335.
(6) For recent reviews, see: (a) Quiclet-Sire, B.; Zard, S. Z. Pure Appl.
Chem. 2011, 83, 519. (b) Quiclet-Sire, B.; Zard, S. Z. Top. Curr.
Chem. 2006, 264, 201. (c) Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J.
2006, 12, 6002. (d) For an account of the discovery of this pro-
cess, see: Zard, S. Z. Aust. J. Chem. 2006, 59, 663.
Acknowledgment
We thank the ANR for financial support and CONACyT (Mexico) for a
scholarship to one of us (JCOL).
Supporting Information
(7) (a) Boivin, J.; Tailhan, C.; Zard, S. Z. J. Am. Chem. Soc. 1991, 113,
5874. (b) Boivin, J.; Tailhan, C.; Zard, S. Z. Tetrahedron Lett. 1992,
33, 7853. (c) Boivin, J.; Henriet, E.; Tailhan, C.; Zard, S. Z. Tetra-
hedron Lett. 1993, 34, 2763. (d) Boivin, J.; Henriet, E. B.; Zard, S.
Z. Tetrahedron Lett. 1995, 36, 5171. (e) Poelert, M. A.; Zard, S. Z.
Synlett 1995, 325. (f) Poelert, M.; Roger, W.; Zard, S. Z. Chem.
Commun. 1996, 743. (g) Tromeur-Fauré, M.; Zard, S. Z. Tetrahe-
dron Lett. 1999, 40, 1305. (h) Harrington, R.; Wright, D.; Zard, S.
Z. Heterocycles 2012, 86, 965.
(8) (a) Boivin, J.; Henriet, E. B.; Zard, S. Z. J. Am. Chem. Soc. 1994,
116, 9739. (b) Tromeur-Fauré, M.; Zard, S. Z. Tetrahedron Lett.
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(9) Otera, J.; Nakazawa, K.; Secoguchi, K.; Orita, A. Tetrahedron
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(10) See, for example: (a) Kaila, N.; Follows, B.; Leung, L.; Thomason,
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562449.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G