Synthesis of the Enantiomers of Tedanalactam and the First Total Synthesis and Configurational Assignment of (+)-Piplaroxide

Article abstract of DOI:10.1021/acs.jnatprod.5b01041

Highlighting the recently established methodology for the direct synthesis of glycidic amides from tertiary allyl amines, the synthesis of the enantiomers of tedanalactam were completed in two steps from the corresponding chiral dihydropiperidine. Additio

Full text of DOI:10.1021/acs.jnatprod.5b01041

Note
pubs.acs.org/jnp
Synthesis of the Enantiomers of Tedanalactam and the First Total
Synthesis and Configurational Assignment of (+)-Piplaroxide
Julio Romero-Ibanez, Leonardo Xochicale-Santana, Leticia Quintero, Lilia Fuentes,*
̃
and Fernando Sartillo-Piscil*
Centro de Investigacion
Claudio, Colonia San Manuel, 72570 Puebla, Mex
́
de la Facultad de Ciencias Químicas, Benemer
́ ́
ita Universidad Autonoma de Puebla (BUAP), 14 Sur Esq. San
́
ico
S
* Supporting Information
ABSTRACT: Highlighting the recently established method-
ology for the direct synthesis of glycidic amides from tertiary
allyl amines, the synthesis of the enantiomers of tedanalactam
were completed in two steps from the corresponding chiral
dihydropiperidine. Additionally, the (+)- and (−)-enantiomers
of piplaroxide were obtained from their respective tedana-
lactam precursor, and the absolute configuration of the
naturally occurring (+)-piplaroxide was determined. The
present approach represents not only the shortest synthesis
of (−)-tedanalactam but also the first total synthesis of
(+)-piplaroxide, a repellent against the leafcutter ant Atta cephalotes.
he 3,4-epoxy-2-piperidone motif is not only a versatile
for the synthesis of compounds 1−4 is highly desirable. Herein,
1
Tbuilding block for total synthesis but also a common a more efficient approach to the synthesis of the enantiomers of
tedanalactam and the first total synthesis and determination of
the absolute configuration of (+)-piplaroxide, a repellent
against the leafcutter ant Atta cephalotes, are described.
skeleton encountered in numerous biologically active com-
pounds such as (−)-tedanalactam (1)2 (isolated from the
sponge Tedania ignis2a and the leaves of Piper crassinervium2b),
(+)-kaousine (2)3 (isolated from the aerial parts of Piper
capense L.f), (−)-3,4-epoxy-5-pipermethystine (3)4 (isolated
from the aerial parts of kava, Piper methysticum), and
(+)-piplaroxide (4)5 (isolated from the leaves of Piper
tuberculatum) (Figure 1). Despite the interesting biological
activity of the naturally occurring 3,4-epoxy-2-piperidones
depicted in Figure 1, in which, for instance, alkaloid 23 showed
antiplasmodial activity and (+)-piplaroxide (4)5 showed
repellency activity against the leafcutter ant Atta cephalotes,
(−)-tedanalactam (1) is the only alkaloid that has been
synthesized and has had its absolute configuration defined.6
Since the epoxidation of α,β-unsaturated amides in some
cases is difficult to achieve,7 organic chemists have chosen
longer strategies for the elaboration of the 3,4-epoxy-2-amide
moiety.1,8 For example, in order to prepare the 3,4-epoxy-2-
piperidone motif of (−)-tedanalactam (1), Tilve and co-
workers6a employed Wittig olefination to introduce the α,β-
unsaturated ester functionality, which was dihydroxylated under
Sharpless conditions, followed by monotosylation, SN2
cyclization, and lactamization under basic conditions. On the
other hand, Nagarapu and co-workers6b took advantage of the
hydroxy groups at C-3 and C-4, and C-2 of the diacetone-D-
glucose to form the oxirane ring and the carbonyl group,
respectively (Scheme 1).
In 2012, the first chemical method for preparing 2,3-
epoxyamides (glycidic amides) was reported (Scheme 2).9
Since NaClO2 is the sole oxidizing reagent used in the double
sequential oxidation of the tertiary allyl amines, this method-
ology not only reduces the cost for preparing glycidic amides
but also considerably reduces the environmental impact; that is,
C−H oxidation and olefinic epoxidation are generally mediated
by transition metals, which are more expensive and toxic than
NaClO2. Additionally, this synthetic methodology has shown its
utility in the synthesis of norbalasubramide10 and the synthesis
of a potent inhibitor of glycolipid biosynthesis.11 Thus, the best
way to construct the 3,4-epoxy-2-piperidone motif of
(−)-tedanalactam (1) and subsequently (+)-piplaroxide (4)
would be by applying this straightforward methodology to
chiral dihydropiperidine 5. Since the absolute configuration of
naturally occurring (−)-tedanalactam (1) is known, the
absolute configurational assignment of (+)-piplaroxide (4)
can be deduced by chemical correlation with the acylation
products from the reaction between either (−)-1 or (+)-1 and
propanoyl chloride derivative 6 (Scheme 3).
The synthesis started with the (S)-α-methylbenzylamine 7,
which was converted in three steps into the dihydropiperidine
(S)-5. Homoallylation of (S)-7, followed by allylation of (S)-8,
and subsequent ring-closing metathesis (RCM) of the
As seen in Scheme 1, in order to achieve the relatively simple
structure of (−)-tedanalactam (1), up to or more than 10 steps
have been required. Therefore, a shorter and an efficient route
Received: November 20, 2015
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.5b01041
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Note
Figure 1. Representative naturally occurring compounds containing the 3,4-epoxy-2-piperidone motif.
Scheme 1. Synthesis Strategies toward Naturally Occurring (−)-Tedanalactam (1)
Scheme 2. Direct Synthesis of 2,3-Epoxyamides from
Tertiary Amines Mediated by NaClO2
Scheme 4. Initial Approach for the Synthesis of (−)- and
(+)-Tedanalactams
Scheme 3. Synthesis Plan for (−)-1 and (+)-1 and for the
First Total Synthesis and Absolute Configurational
Assignment of (+)-Piplaroxide (4)
(Scheme 4). Since the removal of the chiral auxiliary under
reductive conditions was problematic,14 a reasonable solution
would be the preparation of a chiral dihydropiperidine that
could be debenzylated under oxidative conditions. Accordingly,
chiral piperidine (S)-11, which contains the (S)-4-methoxy-α-
methylbenzylamine chiral auxiliary (12) and can be removed
under mild oxidizing condition, e.g., in the presence of ceric
ammonium nitrate,15 was prepared in similar yields following
the same route as for (S)-5 (Scheme 5).
Like the allyl amine (S)-5, the application of the tandem
oxidation to allyl amine (S)-11 gave a similar yield and
diastereomeric ratio of (S)-13a and (S)-13b (73% and ∼1:1
ratio). Glycidic amides 13a and 13b were separately treated
with ceric ammonium nitrate (CAN) in aqueous MeCN to
corresponding hydrochloride of (S)-9 with the second-
generation Hoveyda−Grubbs catalyst12 afforded the target
cyclic amine (S)-5 in excellent overall yield (70%). RCM
attempts with the free amine (S)-9 were unsuccessful.13
The treatment of (S)-5 with NaClO29 afforded an equimolar
diastereomeric mixture of glycidic amides 10a and 10b in 83%
combined yield (Scheme 4). However, debenzylation either
under Birch conditions or Pd-catalyzed hydrogenolysis did not
afford the target (−)- and (+)-tedanalactams (1), but led to
degradation of the starting material or no reaction at all
B
DOI: 10.1021/acs.jnatprod.5b01041
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Journal of Natural Products
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Scheme 5. Five-Step Synthesis of (−)-Tedanalactam and Its Enantiomer and the First Total Synthesis and Absolute
Configurational Assignment of Naturally Occurring (+)-Piplaroxide (4)
materials, unless otherwise stated. NMR spectra were recorded on a
afford [(3S,4S)]-(−)-tedanalactam 1 (natural enantiomer) from
(S)-13b and [(3R,4R)]-(+)-tedanalactam 1 (unnatural) from
(S)-13a. While acylation of naturally occurring (−)-1 with acyl
chloride 6 and n-BuLi at −78 °C gave the naturally occurring
[(3S,4S)]-(+)-piplaroxide (4) in moderate yield, the synthetic
enantiomer 4 [(3R,4R)-(−)-4] was obtained from unnatural
(+)-tedanalactam [(+)-1] in moderate yield (Scheme 5). The
spectroscopic data and specific rotation of (+)-piplaroxide (4)
are in full agreement with the compound isolated from the air-
dried leaves of P. tuberculatum by Wiemer and Capron5 and
also defined the absolute configuration of (+)-4 as 3S,4S.
Additionally, this chemical correlation also suggests that
(−)-tedanalactam [(−)-1] might be the biosynthetic precursor
of (+)-piplaroxide [(+)-4] (Scheme 5).
In summary, taking advantage of the tandem oxidation of
tertiary allyl amines to glycidic amides mediated by NaClO2 led
to the development of an affordable and efficient five-step
synthesis of (−)-tedanalactam [(−)-1]. In addition, the first
total synthesis and absolute configurational assignment of the
naturally occurring (+)-piplaroxide [(+)-4] has also been
achieved.
1
Bruker Ascend 500 NMR spectrometer operating at 500 MHz for H
and 125 MHz for 13C nuclei. Chemical shifts are reported in parts per
1
million (ppm) using tetramethylsilane as internal reference for H (δ
1
0.00 ppm) and CDCl3 for 13C (δ 77.00 ppm). H NMR shift values
are reported as chemical shifts δ, relative integral, multiplicity, and
coupling constant (J in Hz). High-resolution mass spectra (HRMS)
were recorded on a Jeol MStation JMS-700 spectrometer using FAB-
QMS (fast atom bombardment). Melting points were recorded on a
Fischer Scientific 12-144 melting point apparatus and are uncorrected.
Optical rotations were obtained on a PerkinElmer 341 polarimeter.
General Procedure for N-Homoallylation. To a stirred
suspension of K2CO3 (3.07 g, 22.2 mmol) in MeCN (30 mL) at
room temperature was added either (S)-(−)-α-methylbenzylamine or
(S)-(−)-4-methoxy-α-methylbenzylamine (17.8 mmol). The mixture
was stirred for 15 min before adding 4-bromobut-1-ene (2.0 g, 14.8
mmol) in MeCN (5 mL) and was then heated at reflux for 6 h. Upon
completion, the mixture was cooled to 25 °C, solids were filtered, and
the resultant organic phase was evaporated under reduced pressure.
The residue was purified by column chromatography (SiO2, hexanes/
EtOAc, 3:1) to afford the corresponding product.
(S)-N-(1-Phenylethyl)but-3-en-1-amine [(S)-8]: 2.25 g of a light
1
yellow oil (87%); [α]25 = −21.4 (c 0.86, CHCl3); H NMR (500
D
MHz, CDCl3) δ 1.36 (d, J = 6.5 Hz, 3H), 1.78 (bs, 1H), 2.23
(apparent q, J = 7.0 Hz, 2H), 2.50 (dt, J = 11.5, 6.5 Hz, 1H), 2.57 (dt, J
= 11.5, 6.5 Hz, 1H), 3.76 (q, J = 6.5 Hz, 1H), 5.02 (m, 1H), 5.07 (m,
1H), 5.74 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H), 7.28 (m, 5H); 13C NMR
(125 MHz, CDCl3) δ 24.2, 34.2, 46.6, 58.2, 116.3, 126.5, 126.8, 128.4,
136.4, 145.5; HRMS (FAB-QMS) m/z 176.1403 [M + H]+ (calcd for
C12H18N, 176.1439).
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions were carried
out under an inert argon atmosphere and anhydrous conditions, unless
otherwise noted. Reagents of the highest commercial quality were
purchased and used without further purification. Solvents were used as
technical grade and freshly distilled prior to use. Yields refer to
chromatographically and spectroscopically (1H NMR) homogeneous
(S)-N-[(1-(4-Methoxyphenyl)ethyl)]but-3-en-1-amine [(S)-(8-
OMe)]: 2.52 g of a light yellow oil (83%); [α]25 = −42.5 (c 1.0,
D
C
DOI: 10.1021/acs.jnatprod.5b01041
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Note
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.33 (d, J = 6.5 Hz, 3H), 1.57
(bs, 1H), 2.22 (apparent qq, J = 7.0, 1.5 Hz, 2H), 2.49 (dt, J = 11.5,
7.0, Hz, 1H), 2.55 (dt, J = 11.5, 7.0 Hz, 1H), 3.72 (q, J = 6.5 Hz, 1H),
3.80 (s, 3H), 5.01 (ddt, J = 10.0, 2.0, 1.0 Hz, 1H), 5.06 (apparent dq, J
= 17.0, 1.5 Hz, 1H), 5.74 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H), 6.86
(apparent d, J = 8.5 Hz, 2H), 7.22 (apparent d, J = 8.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 24.2, 34.2, 46.6, 55.2, 57.5, 113.7 (2C),
116.3, 127.5 (2C), 136.5, 137.6, 158.4; HRMS (FAB-QMS) m/z
206.1541 [M + H]+ (calcd for C13H20NO, 206.1539).
General Procedure for N-Allylation. To a stirred suspension of
K2CO3 (2.08 g, 15.1 mmol) and (S)-8 (2.20 g, 12.6 mmol) in MeCN
(30 mL) at room temperature was added dropwise over 10 min allyl
iodide (2.53 g, 15.1 mmol) in MeCN (5 mL). The mixture was stirred
at room temperature for 1.5 h. Upon completion, the mixture was
filtered, and the solvent was removed under reduced pressure. The
residue was purified by column chromatography (SiO2, hexanes/
EtOAc, 4:1) to afford the corresponding product.
(S)-1-[(1-(4-Methoxyphenyl)ethyl)]-1,2,3,6-tetrahydropyridine
[(S)-11]: 2.16 g of a brown oil (98%); [α]25 = −4.6 (c 1.0, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 1.39 (d, J = 7.0 Hz, 3H), 2.06 (m,
1H), 2.14 (m, 1H), 2.37 (ddd, J = 11.0, 7.5, 5.0 Hz, 1H), 2.59 (dt, J =
11.0, 5.0, 1H), 2.86 (ddt, J = 16.5, 5.5, 3.0 Hz, 1H), 3.14 (ddt, J = 16.5,
5.5, 3.0 Hz, 1H), 3.40 (q, J = 7.0 Hz, 1H), 3.80 (s, 3H), 5.65 (m, 1H),
5.73 (m, 1H), 6.85 (apparent d, J = 8.5 Hz, 2H), 7.25 (apparent d, J =
8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 20.0, 26.5, 47.1, 50.3,
55.2, 64.1, 113.4 (2C), 125.2, 125.6, 128.6 (2C), 136.0, 158.4; HRMS
(FAB-QMS) m/z 218.1541 [M + H]+ (calcd for C14H20NO,
218.1539).
General Procedure for the Synthesis of 2,3-Epoxyamides.
Dihydropiperidine (S)-5 (1.52 g, 8.11 mmol) and NaH2PO4·H2O
(11.2 g, 81.2 mmol) were dissolved in a mixture of t-BuOH/THF/
H2O (7:3:3) (104 mL), and the mixture was vigorously stirred at room
temperature until the NaH2PO4 was completely dissolved. The
mixture was cooled to 0 °C followed by the addition of 2-methyl-2-
butene (17.8 g, 243.5 mmol); then, NaClO2 (5.87 g, 51.9 mmol)
dissolved in H2O (10 mL) was added. After 12 h of stirring, the phases
were separated, and the aqueous phase was extracted with EtOAc (3 ×
50 mL). The combined organic phases were dried over Na2SO4 and
filtered, and the solvent was removed under reduced pressure. The
residue was purified by column chromatography (SiO2, hexanes/
EtOAc, 2:1) to give the diastereomeric glycidic amides 10a and 10b.
(1R,6R)-3-[(S)-1-Phenylethyl)]-7-oxa-3-azabicyclo[4.1.0]heptan-
(S)-N-Allyl-N-(1-phenylethyl)but-3-en-1-amine [(S)-9]: 2.40 g of a
light yellow oil (89%); [α]25D = −29.9 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 1.34 (d, J = 7.0 Hz, 3H), 2.19 (m, 2H), 2.48 (ddd, J =
13.0, 8.5, 7.0 Hz, 1H), 2.58 (ddd, J = 13.0, 8.5, 7.0 Hz, 1H), 3.04 (dd, J
= 14.5, 7.0 Hz, 1H), 3.12 (dd, J = 14.5, 7.0 Hz, 1H), 3.87 (q, J = 7.0
Hz, 1H), 4.95 (ddt, J = 10.5, 2.0, 1.0 Hz, 1H), 5.00 (dq, J = 17.0, 1.5
Hz, 1H), 5.08 (m, 1H), 5.16 (dq, J = 17.0, 1.5 Hz, 1H), 5.75 (ddt, J =
17.0, 10.5, 7.0 Hz, 1H), 5.84 (ddt, J = 17.0, 10.5, 7.0 Hz, 1H), 7.28 (m,
5H); 13C NMR (125 MHz, CDCl3) δ 17.0, 31.9, 49.0, 53.1, 58.8,
115.2, 116.4, 126.6, 127.6, 128.0, 136.9, 137.1, 144.3; HRMS (FAB-
QMS) m/z 216.1751 [M + H]+ (calcd for C15H22N, 216.1752).
(S)-N-Allyl-N-[(1-(4-methoxyphenyl)ethyl)]but-3-en-1-amine [(S)-
2-one (10a): 0.56 g of a white solid (43%); mp = 84−85 °C; [α]25
=
D
1
−148.0 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 1.49 (d, J =
7.0 Hz, 3H), 1.66 (ddd, J = 14.0, 12.5, 6.0 Hz, 1H), 2.17 (m, 1H), 2.72
(dd, J = 12.5, 5.5 Hz, 1H), 3.18 (td, J = 12.5, 4.0 Hz, 1H), 3.56
(apparent s, 2H), 5.99 (q, J = 7.0 Hz, 1H), 7.30 (m, 5H); 13C NMR
(125 MHz, CDCl3) δ 15.6, 24.2, 34.3, 50.4, 51.1, 52.6, 127.1, 127.4,
128.4, 139.9, 166.4; HRMS (FAB-QMS) m/z 218.1179 [M + H]+
(calcd for C13H16NO2, 218.1181).
(9-OMe)]: 2.83 g of a light yellow oil (95%); [α]25 = −24.5 (c 1.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.32 (d, J = 6.5 Hz, 3H), 2.19
(apparent qq, J = 7.0, 1.5 Hz, 2H), 2.46 (ddd, J = 13.0, 8.5, 6.5 Hz,
1H), 2.56 (ddd, J = 13.0, 8.5, 6.5 Hz, 1H), 3.02 (ddt, J = 14.5, 6.5, 1.5
Hz, 1H), 3.10 (ddt, J = 14.5, 6.5, 1.5 Hz, 1H), 3.80 (s, 3H), 3.83 (q, J
= 6.5 Hz, 1H), 4.95 (ddt, J = 10.0, 2.0, 1.5 Hz, 1H), 5.00 (dq, J = 17.0,
1.5 Hz, 1H), 5.07 (ddt, J = 10.0, 2.0, 1.5 Hz, 1H), 5.15 (dq, J = 17.0,
1.5 Hz, 1H), 5.75 (ddt, J = 17.0, 10.0, 6.5 Hz, 1H), 5.83 (ddt, J = 17.0,
10.0, 6.5 Hz, 1H), 6.85 (apparent d, J = 9.0 Hz, 2H), 7.27 (apparent d,
J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 16.9, 31.9, 48.9, 53.0,
55.2, 58.0, 113.3 (2C), 115.2, 116.3, 128.6 (2C), 136.2, 137.1, 137.2,
138.2; HRMS (FAB-QMS) m/z 246.1856 [M + H]+ (calcd for
C16H24NO, 246.1852).
(1S,6S)-3-[(S)-1-Phenylethyl)]-7-oxa-3-azabicyclo[4.1.0]heptan-2-
one (10b): 0.52 g of a white solid (40%); mp = 99−101 °C; [α]25
=
D
1
−138.3 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 1.48 (d, J =
7.0 Hz, 3H), 1.89 (ddd, J = 15.0, 11.0, 9.0 Hz, 1H), 2.24 (apparent dq,
J = 15.0, 2.5 Hz, 1H), 2.77 (m, 2H), 3.57 (m, 2H), 5.95 (q, J = 7.0 Hz,
1H), 7.29 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 15.3, 24.5, 35.3,
50.5, 51.1, 52.8, 127.2, 127.4, 128.4, 139.2, 166.4; HRMS (FAB-QMS)
m/z 218.1179 [M + H]+ (calcd for C13H16NO2, 218.1181).
(1R,6R)-3-[(S)-1-(4-Methoxyphenyl)]ethyl-7-oxa-3-azabicyclo-
General Procedure for the Ring-Closing Metathesis. To a
stirred solution of (S)-9 (2.0 g, 9.29 mmol) in THF (30 mL) at room
temperature was added dropwise 5 N HCl until a pH ∼1 was reached
(3 mL). After the addition of HCl was completed, the reaction mixture
was stirred for 10 min, and the solvent was evaporated under reduced
pressure. Then, H2O (30 mL) was added, and the aqueous layer was
extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were dried over Na2SO4, filtered, and concentrated in vacuo to afford
2.30 g of a yellow oil, which was used directly for the next step without
purification. To a stirred solution of crude hydrochloride salt of (S)-9
in anhydrous CH2Cl2 (15 mL) at room temperature was added
second-generation Hoveyda−Grubbs catalyst (0.174 g, 0.29 mmol) in
CH2Cl2 (10 mL). The resulting mixture was stirred for 3 h; then, 10
mL of H2O and a saturated solution of NaOH (pH > 12) were added.
The biphasic mixture was extracted with EtOAc (3 × 50 mL), and the
combined organic phases were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, hexanes/EtOAc, 1:1) to yield the correspond-
ing product.
(S)-1-(1-Phenylethyl)-1,2,3,6-tetrahydropyridine [(S)-5]: 1.56 g of a
brown oil (90%); [α]25D = +6.5 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 1.40 (d, J = 7.0 Hz, 3H), 2.05 (m, 1H), 2.16 (m, 1H), 2.38
(ddd, J = 12.5, 7.5, 5.0 Hz, 1H), 2.60 (dt, J = 11.0, 5.0, 1H), 2.87 (ddt,
J = 16.5, 5.5, 3.0 Hz, 1H), 3.17 (apparent ddt, J = 16.5, 5.5, 3.0 Hz,
1H), 3.42 (q, J = 7.0 Hz, 1H), 5.66 (m, 1H), 5.74 (m, 1H), 7.28 (m,
5H); 13C NMR (125 MHz, CDCl3) δ 20.2, 26.5, 47.3, 50.4, 64.9,
125.3, 125.6, 126.8, 127.6, 128.2, 144.2; HRMS (FAB-QMS) m/z
188.1478 [M + H]+ (calcd for C13H18N, 188.1439).
[4.1.0]heptan-2-one [(S)-13a]: 0.88 g of a white solid (39%); mp =
1
54−55 °C; [α]25 = −164.2 (c 1.0, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 1.45 (d, J = 7.0 Hz, 3H), 1.62 (ddd, J = 15.0, 11.0, 6.0 Hz,
1H), 2.16 (ddt, 15.0, 4.0, 2.0 Hz, 1H), 2.72 (apparent dd, J = 12.5, 6.0
Hz, 2H), 3.15 (td, J = 12.5, 4.0 Hz, 1H), 3.55 (m, 2H), 3.80 (s, 3H),
5.94 (q, J = 7.0 Hz, 1H), 6.86 (apparent d, J = 9.0 Hz, 2H), 7.20
(apparent d, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 15.8,
24.2, 34.0, 49.9, 51.1, 52.6, 55.2, 113.7 (2C), 128.3 (2C), 131.9 158.8,
166.3; HRMS (FAB-QMS) m/z 248.1284 [M + H]+ (calcd for
C14H18NO3, 248.1281).
(1S,6S)-3-[(S)-1-(4-Methoxyphenyl)]ethyl-7-oxa-3-azabicyclo-
[4.1.0]heptan-2-one [(S)-13b]: 0.77 g of a light yellow solid (34%);
mp = 110−111 °C; [α]25D = −120.41 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 1.45 (d, J = 7.0 Hz, 3H), 1.88 (ddd, J = 15.0, 11.0, 8.0
Hz, 1H), 2.23 (apparent d, J = 14.0 Hz, 1H), 2.75 (m, 2H), 3.56 (m,
2H), 3.79 (s, 3H), 5.89 (q, J = 7.0 Hz, 1H), 6.86 (apparent d, J = 8.5
Hz, 2H), 7.17 (apparent d, J = 8.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 15.5, 24.4, 35.2, 50.0, 51.1, 52.8, 55.1, 113.7 (2C), 128.4
(2C), 131.2, 158.7, 166.2; HRMS (FAB-QMS) m/z 248.1283 [M +
H]+ (calcd for C14H18NO3, 248.1281).
General Procedure for the N-Debenzylation under Oxida-
tive Conditions. Glycidic amide 13b (0.51 g, 2.06 mmol) was
dissolved in MeCN (40 mL), and the solution was cooled to 0 °C
followed by the addition of CAN (3.37 g, 6.18 mmol) dissolved in
H2O (10 mL) (previously cooled). The mixture was stirred at 0 °C for
4 h. Upon completion, the mixture was warmed to 25 °C, and brine
(30 mL) was added. The phases were separated, and the aqueous
phase was extracted with EtOAc (3 × 50 mL). The combined organic
D
DOI: 10.1021/acs.jnatprod.5b01041
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Journal of Natural Products
Note
phases were dried over Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The residue was purified by column
chromatography on silica gel (hexanes/EtOAc, 1:2) to afford 0.170 mg
(2) (a) Cronan, J. M. L.; Cardellina, J. H., II Nat. Prod. Lett. 1994, 5,
85−88. (b) Lago, J. H. G.; Kato, M. J. Nat. Prod. Res. 2007, 21, 910−
914.
(3) Mohamed, A. K.; Valerie, M. L.; Cecile, C.; Laurent, D. S. H.;
Nadine, A. E. O. Fitoterapia 2010, 81, 632−635.
(4) Dragull, K.; Yoshida, W. Y.; Tang, C.-S. Phytochemistry 2003, 63,
193−198.
(5) Capron, M. A.; Wiemer, D. F. J. Nat. Prod. 1996, 59, 794−795.
(6) (a) Majik, M. S.; Parameswaran, P. S.; Tilve, S. G. J. Org. Chem.
2009, 74, 6378−6381. (b) Konda, S.; Kurva, B.; Nagarapu, L.;
Dattatray, A. M. Tetrahedron Lett. 2015, 56, 834−836.
(7) (a) Johansen, M. B.; Leduc, A. B.; Kerr, M. A. Synlett 2007, 2007,
2593−2595. (b) Li, B.; Smith, M. B. Synth. Commun. 1995, 25, 1265−
1275.
(73%) of (−)-tedanalactam [(−)-1] as a yellow oil: [α]25 = −9.7 (c
D
6
1
1.0, MeOH); lit. = [α]27 = −7.6 (c 0.13, MeOH); the H and 13C
D
NMR data matched the literature values.6
(+)-Tedanalactam [(+)-1]: 0.185 mg (88%) of a pale yellow oil;
[α]25D = +6.4 (c 1.0, MeOH); lit.2 = [α]30D = +8.7 (c 0.118, MeOH);
6a
1
the H and 13C NMR data matched the literature values.
3-(3,4-Dimethoxyphenyl)propanoyl chloride (6). To a stirred
solution of 3-(3,4-dimethoxyphenyl)propanoic acid (0.08 g, 0.38
mmol) in CH2Cl2 (6 mL) at room temperature were added CH2Cl2 (3
mL) and DMF (22 μL). The resultant mixture was cooled to 0 °C
followed by the addition of oxalyl chloride (0.24 g, 1.9 mmol). The ice
bath was removed, and the mixture was stirred at room temperature
for 1 h. The resulting clear, pale yellow solution was concentrated in
vacuo to afford crude 6 as a yellow oil, which was used immediately for
the next reaction without further purification.
(8) See representative example: Sarabia, F.; Vivar-García, C.; García-
Ruiz, C.; Martín-Ortiz, L.; Romero-Castro, A. J. Org. Chem. 2012, 77,
1328−1339.
́
(9) Fuentes, L.; Osorio, U.; Quintero, L.; Hopfl, H.; Vazquez-
̈
To a stirred solution of (−)-tedanalactam [(−)-1] (16.4 mg, 0.145
mmol) in anhydrous THF (1.5 mL) at −78 °C was added dropwise n-
BuLi (12 mg, 0.19 mmol). The reaction mixture was stirred for 40 min
before adding acyl chloride 6 (0.38 mmol) dissolved in THF (1.5 mL),
and stirred at −78 °C for 6 h. Upon completion, the mixture was
warmed to 25 °C, H2O (2 mL) was added, the phases were separated,
and the aqueous phase was extracted with EtOAc (3 × 10 mL). The
combined organic phases were dried over Na2SO4, and the solvent was
removed under reduced pressure. The residue was purified by column
chromatography on silica gel (hexanes/EtOAc, 3:1) to afford 21.2 mg
of (+)-piplaroxide [(3S,4S)-(+)-4] as a white solid (48%): mp = 86−
87 °C; [α]25 = +62.6 (c 0.8, CHCl3); lit.5 [α]25 = +67.7 (c 0.8,
Cabrera, N.; Sartillo-Piscil, F. J. Org. Chem. 2012, 77, 5515−5524.
(10) Fuentes, L.; Hernandez-Juarez, M.; Teran, J. L.; Quintero, L.;
Sartillo-Piscil, F. Synlett 2013, 24, 878−882.
(11) Gomez-Fosado, C. G.; Quintero, L.; Fuentes, L.; Sartillo-Piscil,
́
́
́
́
F. Tetrahedron Lett. 2015, 56, 5607−5609.
(12) Hoveyda, A. H. J. Org. Chem. 2014, 79, 4763−4792.
(13) Since the basic amino group is incompatible with most of the
metathesis catalysts, the amino group should generally be protected.
See: Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 2003, 3693−
3712.
(14) It is difficult to remove a benzyl group from amides. See:
Moriyama, K.; Nakamura, Y.; Togo, H. Org. Lett. 2014, 16, 3812−
3815.
(15) Yoshimura, J.; Yamaura, M.; Suzuki, T.; Hashimoto, H. Chem.
Lett. 1983, 1001−1002.
D
D
CHCl3); the 1H and 13C NMR data matched those reported by
Capron and Wiemer.5
(−)-Piplaroxide[(3R,4R)-(−)-4]: 17 mg of a white solid (42%); mp =
85−87 °C; [α]25 = −61.8 (c 1.0, CHCl3).
D
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.5b01041.
1
Copies of H NMR and 13C NMR of new compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: fuenliliates@hotmail.com (L. Fuentes).
*E-mail: fernando.sartillo@correo.buap.mx (F. Sartillo-Piscil).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support provided by
CONACyT (project number 179074) and Benemer
́
ita
Universidad Auton
́
oma de Puebla (BUAP-VIEP). L.F. acknowl-
edges CONACyT for a graduate scholarship (grant number
332449). We thank Dr. A. Cordero-Vargas for helpful
comments and suggestions.
REFERENCES
■
(1) Representative examples: (a) Fu, R.; Ye, J.-L.; Dai, X.-J.; Ruan, Y.-
P.; Huang, P.-Q. J. Org. Chem. 2010, 75, 4230−4243. (b) Fisyuk, A. S.;
Poendaev, N. V. Molecules 2002, 7, 119−123. (c) Marson, C. M.;
Grabowska, U.; Fallah, A. J. Org. Chem. 1994, 59, 291−296.
(d) Jespersen, T. M.; Bols, M. Tetrahedron 1994, 50, 13449−13460.
E
DOI: 10.1021/acs.jnatprod.5b01041
J. Nat. Prod. XXXX, XXX, XXX−XXX