Total synthesis of (+)-epiquinamide and (?)-epiepiquinamide from D-mannose

Article abstract of DOI:10.1016/j.tet.2017.11.016

The total synthesis of (+)-epiquinamide and (?)-epiepiquinamide has been achieved starting from a 3,5-dihydroxyfuranoside synthon derived from D-mannose. The methods featured Bernet-Vasella reaction followed by Horner-Wadsworth-Emmons (HWE) reaction to provide a new chiral building block diene as the key steps. The bicyclic framework of this quinolizidine was constructed by using ring-closing metathesis, selective reduction of ester and intramolecular nucleophilic substitution-cyclization.

Full text of DOI:10.1016/j.tet.2017.11.016

Accepted Manuscript
Total synthesis of (+)-epiquinamide and (−)-epiepiquinamide from D-mannose
Withsakorn Sangsuwan, Boonsong Kongkathip, Pitak Chuawong, Ngampong
Kongkathip
PII:
S0040-4020(17)31152-3
10.1016/j.tet.2017.11.016
TET 29096
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 August 2017
Revised Date: 31 October 2017
Accepted Date: 6 November 2017
Please cite this article as: Sangsuwan W, Kongkathip B, Chuawong P, Kongkathip N, Total synthesis
of (+)-epiquinamide and (−)-epiepiquinamide from D-mannose, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.11.016.
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Total synthesis of (+)-epiquinamide
Leave this area blank for abstract info.
and (−)-epiepiquinamide from ᴅ-mannose
Withsakorn Sangsuwan, Boonsong Kongkathip,* Pitak Chuawong and Ngampong Kongkathip
Natural Products and Organic Synthesis Research Unit (NPOS), Department of Chemistry and Center of
Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok 10900,
Thailand

1
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Tetrahedron
journal homepage: www.elsevier.com
Total synthesis of (+)-epiquinamide and (−)-epiepiquinamide from ᴅ-mannose
Withsakorn Sangsuwan, Boonsong Kongkathip, Pitak Chuawong and Ngampong Kongkathip
Natural Products and Organic Synthesis Research Unit (NPOS), Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of
Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The total synthesis of (+)-epiquinamide and (−)-epiepiquinamide has been achieved
starting from a 3,5-dihydroxyfuranoside synthon derived from -mannose. The methods
featured Bernet-Vasella reaction followed by Horner-Wadsworth-Emmons (HWE) reaction
to provide a new chiral building block diene as the key steps. The bicyclic framework of
this quinolizidine was constructed by using ring-closing metathesis, selective reduction of
ester and intramolecular nucleophilic substitution-cyclization.
ᴅ
Available online
Keywords:
epiquinamide
2009 Elsevier Ltd. All rights reserved
.
epiepiquinamide
quinolizidine alkaloids
ᴅ-mannose
Bernet-Vasella
ring-closing metathesis
1. Introduction
NHAc
OBn
OBn
RCM
H
N
H
N
H
(+)-Epiquinamide (1) is a quinolizidine alkaloid isolated
from the skin extracts of an Ecuadorian poisonous frog,
Epipedobates tricolor.1 This compound has been reported to
possess nicotinic agonistic activity and considered as a lead
compound for a new nicotinic agent. Due to the low availability
of the isolated product, many research groups have synthesized
this alkaloid as a single enantiomer2 and a racemic mixture3 in
order to identify its absolute configurations and examine the
biological activities.3a Several asymmetric compounds including
amino acids,2a,2b cyclic amines,3a,2c and a reduced monosac-
charide2e were employed as chiral starting materials. In 2009, the
reinvestigation of its biological activity revealed that (+)-
epiquinamide and its stereoisomers are inactive to α4β2 nicotinic
receptor subtypes up to 100 µM.3a,4 The activity previously
discovered is due to the contamination with epibatidine in the
isolation steps. However, other biological activities have not yet
to be examined.
NH
O
O
X
(+)-Epiquinamide (1)
18
OBn
OBn
Bernet-Vasella
HWE
O
CO2Et
NHBoc
NHBoc
12
13
I
HO
5
O
OH
OH
HO
HO
O
O
OMe
OMe
5
2
3
3
2
2
3
BocHN
OBn
HO
OBn
OH
2)
D-Mannose (
11
3
Scheme 1. Retrosynthesis of (+)-epiquinamide from ᴅ-mannose.
Recently, a new method to synthesize oseltamivir phosphate
(Tamiflu®), an anti-influenza drug, has been developed by our
group.5 Commercially available monosaccharides including,
ᴅ-mannose5b,5c and ᴅ-glucose5a,5d were used as starting materials.
The key features involved reductive ketal ring opening, Bernet-
Vasella reaction, and ring-closing metathesis.
In this work, we have applied our reported key reactions for
the asymmetric synthesis of (+)-epiquinamide (1) from ᴅ-
mannose. An important core structure of (+)-epiquinamide would
be useful for the modification in the synthesis of other bioactive
alkaloids. The key reactions and synthetic methodologies could
be a practical guideline for the application of monosaccharides in
the synthesis of bioactive compounds which is very essential for
drug development.
———
Corresponding author. Tel.: +662 5625444 ext.647585; fax: +662 5790658; e-mail: fscibsk@ku.ac.th

2
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 2. Synthetic approach to 3-N-protected-5-iodo-β-aminofuranoside (11) from ᴅ-mannose.
2. Results and discussion
As depicted in Scheme 1, we envisaged to obtain epiquina-
mide from diene 13. This key intermediate should provide a
bicyclic skeleton after an intramolecular cyclization and ring-
closing metathesis. For the synthesis of 13, we relied on our
recently developed strategy involving reductive benzylidene ring
opening and Bernet-Vasella reaction followed by Horner-
Wadsworth-Emmons (HWE) reaction of the 5-iodofuranoside 11.
The intermediate 11 could be obtained from diol 3, which could
be derived from ᴅ-mannose using a modified method previously
reported by our group.6
The synthesis of 11 began with protection of the primary
alcohol of 3 as TBDPS to provide furanoside 4 (Scheme 2). To
replace the hydroxyl group at C-3 of 4 by amino group with
retention configuration, oxidation of the hydroxyl group to a
ketone, immediately followed by the conversion to oxime 5 were
attempted. Unfortunately, a general reduction of oxime to amine
using NaBH4/MoO3 provided only a trace amount of the desired
amino product 6 along with an unidentified complex mixture. To
overcome this problem, we decided to introduce the amino group
via SN2 substitutions with sodium azide. Firstly, the configuration
of 3-OH of 4 was inverted by activating with Tf2O followed by
treating with sodium nitrite to afford 7 in moderate yield.7 Once
the 3-α-OH of 7 was activated again by the same manner, the
resulting crude triflate was treated with NaN3 to afford azide 8,
which established the 2,3-cis-stereochemistry. The corresponding
azido group was mildly reduced to an amine by Staudinger
reaction [PPh3, THF then NEt3, H2O] and subsequently protected
Scheme 3. Synthesis of bicycliclactam 19 via Bernet-Vasella
reaction, Horner-Wadsworth-Emmons reaction, and ring-closing
metathesis.
as NHBoc to give 9 in an excellent yield. After the removal of
the silyl group, the corresponding hydroxyl group was converted
to an iodide by using I2/PPh3/im in THF at room temperature to
give 11 in modest yield.
Zn-mediated Bernet-Vasella reaction was employed for the
opening of the furanoside ring of 11 as shown in scheme 3. This
step was promoted by acetic acid. The crude aldehyde 12 was
directly subjected to HWE reaction to afford α,β-unsaturated
ester 13. Boc protecting group was removed with TFA and the
resulting amine was coupled with vinylacetic acid to provide
triene 14 in good yield. Cyclization of 14 by ring-closing
metathesis using the 2nd generation Hoveyda-Grubbs catalyst
provided lactam 15 in good yield. Both double bonds of 15 were
hydrogenated by NaBH4/NiCl2 in MeOH at room temperature.
Transesterification occurred during the reduction to give a
mixture of esters 16a and 16b (ratio = 1:1.8).
Selective reduction of the ester containing a lactam ring was
investigated using various reducing agents and conditions
including NaBH4 in the presence of Lewis acids (LiCl and
CaCl2), DIBAL-H, LiBH4, and LiAlH4 at low temperature. None
of the above mentioned reagents gave satisfactory results. Only

3
small amount of alcohol product was observed, along with a high
ACCEPTED MANUSCRIPT
polar complex mixture. The best result was obtained by using
NaBH4 in EtOH at room temperature for 24 h to give the alcohol
product 17 in 51% yield.
The second ring of the quinolizidine skeleton was constructed
by intramolecular nucleophilic substitution. Thus, the hydroxyl
group of 17 was activated by converting to a mesylate, followed
by treatment with NaH in THF to afford bicyclic compound 18.
The benzyl protecting group of 18 was easily cleaved by
hydrogenolysis to give alcohol 19 (Scheme 3).
Scheme 5. A proposed mechanism for the azide substitution of
20 with retention of configuration.
OMs
H
NaN3, DMF
C9a
MsCl, Et3N, CH2Cl2
C1
1.54
19
N
100 °C, 24 h
90%
0 °C, 1 h, 78%
O
20
N3
N3
H
N
H
N
1) LiAlH4, THF
reflux, 12 h
+
2) Ac2O, NaOH
dioxane/H2O
rt, 2 h
O
O
21a
21b
Figure 1. Optimized geometry (distance, Å) of the aziridinium
ion intermediate 20a for the substitution of 20 with NaN3. The
optimization was performed at DFT(B3LYP)/6-311G (d,p) level
of theory.
21a:21b = 5:2
NHAc
H
NHAc
H
+
N
N
Lithium aluminium hydride reduction of the azide mixture
followed by acetylation provided the desired (+)-epiquinamide
(1) in 68% along with the (−)-epiepiquinamide (22) in 27% yield
after chromatographic separation. The physical and spectroscopic
data of compound 1 and 22 are in full agreement with the
literature.8,2d,2b,2a
(–)-Epiepiquinamide (22)
( )-Epiquinamide (1)
27%
68%
The overall yield of (+)-1 and (–)-22
from 3 are 0.61% and 0.24%
Scheme 4. Completion of the synthesis of (+)-epiquinamide (1)
and (−)-epiepiquinamide (22).
3. Conclusion
We have developed a new asymmetric approach to access
both (+)-epiquinamide and (−)-epiepiquinamide from the
commercially available and inexpensive starting material, ᴅ-
mannose. Bernet-Vasella and Horner-Wadsworth-Emmons
(HWE) reactions were used as the key steps to provide a new
chiral building block 13 from the intermediate compound 3.
Compound 13 from this synthetic pathway can be used as an
important chiral building block for the total synthesis of
iminosugars with potentially useful biological activities, which is
currently under investigation in our laboratory.
For the synthesis of (+)-epiquinamide (1), 19 was mesylated
to give 20. The subsequent SN2 reaction of 20 with sodium azide
was carried out in DMF for 24 h to yield the desired azido
product 21a, along with 21b as an inseparable diastereomeric
1
mixture in 5:2 ratio. (determined by H and 13C NMR). The
stereochemistry was ultimately proven by completion of the total
synthesis and comparison of the spectra to the reported data of
(+)-epiquinamide2a and (−)-epiepiquinamide2d (Scheme 4). This
observation is in contrast to the previous publication in which the
authors reported 21a as a single isomer in 50% yield in the trans-
formation from alcohol 19.2e
4. Experimental
4.1. General
In the course of our investigation on the azidation of 20,
DMSO was selected as a solvent due to improved solubility of
sodium azide. The reaction at 80 C for 12 h provided the same
o
result as that of DMF.
Starting materials and reagents were obtained from
commercial sources and used without further purification.
Solvents were dried by distillation from appropriate drying
reagents immediately prior to use. Dry methanol, tetrahydrofuran
and dichloromethane were distilled from magnesium,
sodium/benzophenone and calcium hydride, respectively under
nitrogen atmosphere. Moisture- and air-sensitive reactions were
carried out under an atmosphere of nitrogen. Reaction flasks
were oven dried overnight. Unless otherwise stated,
We have proposed the mechanism for the transformation of
20 to 21a and 21b. The product 21a was obtained via an SN2
reaction; whereas the diastereomer 21b was generated through
the aziridinium ion intermediate 20a, which was presumably
formed upon the dissociation of the mesylate leaving group
(Scheme 5). The latter mechanism is supported by the DFT
calculations. Upon geometry optimization, the structure of the
intermediate indicated a short distance between the nitrogen atom
and the C1 carbon (1.54 Å in Figure 1), indicative of the
formation of aziridinium ion (20a) through the neighboring group
participation from the nitrogen lone pair electrons.
concentration under reduced pressure refers to
a rotary
evaporator with water aspirator. Analytical thin-layer
chromatography (TLC) was conducted using MERCK pre-coated
TLC plates (silica gel 60 F-254). Compounds were visualized
under ultraviolet light followed by heating the plate after dipping
in 3% solution of vanillin in 0.1 M H2SO4 in EtOH and/or 1%

4
Tetrahedron
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KMnO4 in 0.4 M K2CO3 and 0.025 M NaOH. Flash column
4.2.2. Methyl 2,3-O-benzylidene-α-ᴅ-lyxofuranoside6
chromatography was carried out using SiliaFlash® irregular
silica gels, F60, 40–63 µm (230–400 mesh). Proton and carbon
nuclear magnetic resonance (NMR) spectra were obtained using
Bruker Avance NanoBay 400 Mz spectrometer in CDCl3.
Chemical shifts were recorded as δ values in ppm. The peak due
To a solution of methyl 2,3-O-benzylidene-α-ᴅ-mannofura-
noside (1.83 g, 6.50 mmol) in MeOH (40 mL) was added a
solution of NaIO4 (1.53 g, 7.15 mmol) in water (10 mL). The
reaction mixture was stirred at room temperature for 30 min. The
white solid was filtered off through celite and the filtrate was
concentrated under reduced pressure. The residue was dissolved
in CH2Cl2, washed with water, dried (Na2SO4) and concentrated
to afford a crude aldehyde as a colorless oil. To a solution of the
crude aldehyde in EtOH (38 mL) was added NaBH4 (305 mg,
8.06 mmol) and then stirred at room temperature for 3 h. EtOAc
(6 mL) was added and the reaction mixture was concentrated
under reduced pressure. The residue was quenched with satd aq
NaHCO3, extracted with CH2Cl2, dried (Na2SO4) and concen-
trated. The crude product was purified by silica gel flash column
chromatography (30% EtOAc/hexane) to afford the alcohol
product (Methyl 2,3-O-benzylidene-α-ᴅ-lyxofuranoside) (1.51 g,
92%) as a colorless oil; a mixture of two isomers (ratio 1:0.87);
Rf 0.35 (40% EtOAc/hexane); FTIR (neat) νmax, cm−1: 3444,
to residual CHCl3 (7.26 ppm for H and 77.16 ppm for 13C) was
1
used as the internal reference. Coupling constant (J) values were
given in Hertz (Hz), and multiplicity was defined as follows: br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublets, dt = doublet of triplets, td = triplet of
doublets, ddd = doublet of doublet of doublets, dtd = doublet of
triplet of doublets and m = multiplet. The specific rotations
(
[α]TD ) were measured with Polax-2L polarimeter and reported
with the concentration in g/100 cm3. Infrared (IR) spectra were
recorded in cm−1 on Perkin-Elmer system 2000 FT-IR
spectrometer. The high resolution mass spectra (HRMS) were
recorded from Bruker, microTOF (Bruker Daltonics, Bremen,
Germany) in the electrospray positive ionization mode (ESI+).
Melting points (mp) were determined on Electrothermal
MelTemp® 1002 melting point apparatus and reported in degrees
Celcius (oC).
1
3066, 2937, 1723, 1602, 1460; For the major isomer: H NMR
(400 MHz, CDCl3) δ 7.51–7.36 (m, 5H), 5.75 (s, 1H), 5.12 (s,
1H), 4.84 (dd, J = 6.2, 3.7 Hz, 1H), 4.67 (d, J = 6.2 Hz, 1H), 4.16
(td, J = 5.4, 3.7 Hz, 1H), 4.05–3.93 (m, 2H), 3.38 (s, 3H), 2.26
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 135.8, 130.1, 128.6,
127.1, 106.8, 106.5, 85.8, 81.1, 79.6, 61.1, 54.9; For the minor
isomer: 1H NMR (400 MHz, CDCl3) δ 7.49–7.36 (m, 5H), 5.94
(s, 1H), 5.10 (s, 1H), 4.87 (dd, J = 5.5, 3.7 Hz, 1H), 4.74 (d, J =
5.5 Hz, 1H), 4.14 (td, J = 5.4, 3.7 Hz, 1H), 4.02 (d, J = 5.4 Hz,
2H), 3.38 (s, 3H), 2.20 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ
136.4, 129.9, 128.6, 126.7, 107.3, 105.8, 84.9, 80.2, 80.1, 61.1,
54.8; HRMS (ESI-TOF), m/z calcd for C13H16NaO5 [M+Na]+
275.0890, found 275.0894.
4.2. Experimental procedure
4.2.1. Methyl 2,3-O-benzylidene-α-ᴅ-mannofuranoside6
To a suspension of ᴅ-mannose (2) (1.0 g, 5.56 mmol) in dry
MeOH (8 mL) was added benzaldehyde dimethylacetal (6 mL,
40 mmol) followed by p-TsOH (200 mg, 1.16 mmol). The
mixture was stirred at room temperature for 20 min. Hexane
(5 mL) was added and the reaction mixture was refluxed with
Dean-Stark apparatus until the solvents were removed by
azeotropic distillation. The reaction mixture was cooled and
neutralized by satd aq NaHCO3 (10 mL), extracted with CH2Cl2,
dried (Na2SO4) and concentrated under reduced pressure. The
crude product was used in the next step without purification; Rf
0.30 (10% EtOAc/hexane).9 A solution of crude methyl 2,3,5,6-
di-O-benzylidene-α-ᴅ-mannofuranoside in MeOH (20 mL) was
added 1.5% HCl (6 mL). The reaction mixture was stirred at
room temperature for 3 h and then neutralized with ammonia
solution. Solvent was removed under reduced pressure and the
residue was extracted with CH2Cl2. The organic layer was
collected, dried (Na2SO4) and concentrated to obtain a yellow oil.
Purification by silica gel flash column chromatography (50%
EtOAc/hexane) gave the diol product (Methyl 2,3-O-
benzylidene-α-ᴅ-mannofuranoside) (1.2 g, 76%) as a colorless
oil; a mixture of two isomers (ratio = 1:0.87); Rf 0.15 and 0.17
(40% EtOAc/hexane); FTIR (neat) νmax, cm−1: 3417, 3067, 2935,
4.2.3. Methyl 2-O-benzyl-α-ᴅ-lyxofuranoside (3)10,6
BH3 SMe2 (1.7 mL, 18.24 mmol) was added dropwise to a
cooled solution of methyl 2,3-O-benzylidene-α-ᴅ-lyxofuranoside
(1.51 g, 5.99 mmol) in dry THF (30 mL) under nitrogen atmos-
phere. The mixture was stirred for 30 min at room temperature.
Cu(OTf)2 (325 mg, 0.898 mmol) was added and the reaction
mixture was stirred for 1 h. Satd aq NaHCO3 was slowly added
and the mixture was concentrated under reduced pressure. The
residue was extracted with CH2Cl2, dried (Na2SO4), concen-
trated, and purified by silica gel flash column chromatography
(50% EtOAc/hexane) to give diol 3 (1.08 g, 71%) as a colorless
oil; Rf 0.15 (40% EtOAc/hexane);
[α
]
25 +33.3 (c 0.75, CH2Cl2);
D
FTIR (neat) νmax, cm−1: 3434, 3063, 2932, 1606, 1454; H NMR
(400 MHz, CDCl3) δ 7.39–7.29 (m, 5H), 4.94 (d, J = 1.5 Hz, 1H),
4.70 (d, J = 11.6 Hz, 1H), 4.65 (d, J = 11.6 Hz, 1H), 4.47 (dt, J =
7.2, 5.5 Hz, 1H), 4.12 (dt, J = 5.5, 4.0 Hz, 1H), 3.91 (dd, J = 5.5,
1.5 Hz, 1H), 3.90–3.86 (m, 2H), 3.35 (s, 3H), 3.16 (d, J = 7.2 Hz,
1H,), 2.64 (t, J = 5.9 Hz, 1H,); 13C NMR (100 MHz, CDCl3) δ
137.0, 128.8, 128.4, 128.0, 105.9, 82.6, 79.2, 73.4, 72.0, 61.7,
55.4; HRMS (ESI-TOF), m/z calcd for C13H18NaO5 [M+Na]+
277.1046, found 277.1061.
1
1
1723, 1602, 1460; For the major isomer: H NMR (400 MHz,
CDCl3) δ 7.50–7.34 (m, 5H), 5.75 (s, 1H), 5.06 (s, 1H), 4.87 (dd,
J = 6.2, 3.6 Hz, 1H), 4.63 (d, J = 6.2 Hz, 1H), 4.06 (ddd, J = 8.3,
6.2, 3.3 Hz, 1H), 4.01 (dd, J = 8.3, 3.6 Hz, 1H), 3.85 (dd, J =
11.5, 3.3 Hz, 1H), 3.71 (dd, J = 11.5, 6.2 Hz, 1H), 3.33 (s, 3H),
3.00 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 135.7, 130.1,
128.6, 127.1, 106.9, 106.3, 85.3, 80.9, 79.2, 70.3, 64.6, 54.8; For
1
the minor isomer: H NMR (400 MHz, CDCl3) δ 7.50–7.34 (m,
5H), 5.92 (s, 1H), 5.05 (s, 1H), 4.92 (dd, J = 5.6, 3.6 Hz, 1H),
4.71 (d, J = 5.6 Hz, 1H), 4.07 (ddd, J = 8.3, 5.8, 3.2 Hz, 1H),
3.95 (dd, J = 8.3, 3.6 Hz, 1H), 3.88 (dd, J = 11.5, 3.2 Hz, 1H),
3.70 (dd, J = 11.5, 5.8 Hz, 1H), 3.32 (s, 3H), 3.00 (br s, 2H); 13C
NMR (100 MHz, CDCl3) δ 136.3, 129.9, 128.6, 126.7, 107.4,
105.8, 84.5, 80.1, 79.7, 70.1, 64.5, 54.6; HRMS (ESI-TOF), m/z
calcd for C14H18NaO6 [M+Na]+ 305.0996, found 305.1006.
4.2.4. Methyl 2-O-benzyl-5-O-(tert-butyldiphenyl)silyl-α-ᴅ-lyxo
furanoside (4)
TBDPSCl (0.94 mL, 3.61 mmol) was added to a solution of
diol 3 (764 mg, 3.01 mmol), imidazole (408 mg, 6.01 mmol), and
DMAP (36 mg, 0.30 mmol) in dry CH2Cl2 (30 mL) under
nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 3 h and then quenched with satd aq NH4Cl,
extracted with CH2Cl2, dried (Na2SO4) and concentrated under

5
reduced pressure. The crude product was purified by silica gel
flash column chromatography (5–10% EtOAc/hexane) to give
alcohol 4 (1.37 g, 93%) as a colorless oil; Rf 0.35 (10% EtOAc/
reduced pressure. The crude product was purified by silica gel
ACCEPTED MANUSCRIPT
flash column chromatography (10–20% EtOAc/hexane) to give
alcohol 7 (1.02 g, 69%) as a colorless oil; Rf 0.20 (10% EtOAc/
hexane);
[α
]
25 +86.5 (c 0.17, CH2Cl2); FTIR (neat) νmax, cm−1:
hexane); [α]
25 −13.0 (c 0.39, CH2Cl2) (reported +34 (c 0.2,
D
D
3520, 3069, 2930, 1777, 1589, 1471; 1H NMR (400 MHz,
CDCl3) δ 7.80–7.64 (m, 4H), 7.50–7.32 (m, 11H), 4.98 (d, J =
2.7 Hz, 1H), 4.67 (s, 2H), 4.34 (td, J = 5.0, 3.8 Hz, 1H), 4.16 (td,
J = 5.6, 3.8 Hz, 1H), 4.05 (dd, J = 10.6, 5.6 Hz, 1H), 3.96 (dd, J
= 5.0, 2.7 Hz, 1H), 3.92 (dd, J = 10.6, 5.6 Hz, 1H), 3.38 (s, 3H),
2.82 (d, J = 5.0 Hz, 1H), 1.07 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 137.3, 135.8, 135.7, 133.6, 133.5, 129.8, 128.7, 128.2,
128.1, 127.8, 107.2, 84.3, 80.8, 73.0, 70.9, 62.5, 55.6, 26.9, 19.4;
HRMS (ESI-TOF), m/z calcd for C29H36NaO5Si [M+Na]+
515.2224, found 515.2218.
CHCl3)); FTIR (neat) νmax, cm−1: 3452, 3070, 2955, 1589, 1427;
1H NMR (400 MHz, CDCl3) δ 7.78–7.63 (m, 4H), 7.51–7.26 (m,
11H), 4.92 (d, J = 1.1 Hz, 1H), 4.59 (d, J = 11.8 Hz, 1H), 4.55 (d,
J = 11.8 Hz, 1H), 4.18 (ddd, J = 7.5, 5.2, 2.7 Hz, 1H), 4.11 (dt, J
= 6.9, 5.2 Hz, 1H), 3.91 (dd, J = 2.7, 1.1 Hz, 1H), 3.88 (dd, J =
10.4, 5.2 Hz, 1H), 3.77 (dd, J = 10.4, 6.9 Hz, 1H), 3.37 (s, 3H),
2.39 (d, J = 7.5 Hz, 1H), 1.08 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 137.7, 135.7, 133.4, 129.9, 128.6, 127.9, 127.8, 107.2,
88.4, 84.7, 76.9, 72.0, 64.5, 55.1, 27.0, 19.4; HRMS (ESI-TOF),
m/z calcd for C29H36NaO5Si [M+Na]+ 515.2224, found 515.2233.
4.2.5. Methyl 2-O-benzyl-3-oxime-3-deoxy-5-O-(tert-butyldi
4.2.7.
Methyl
2-O-benzyl-3-azido-3-deoxy-5-O-(tert-butyl
phenyl)silyl-α-ᴅ-lyxofuranoside (5)
diphenyl)silyl-α-ᴅ-lyxofuranoside (8)
To a cooled suspension of TCCA (188 mg, 0.81 mmol) in
CH2Cl2 (2 mL) was added TEMPO (2.5 mg, 16 ꢀmol). The
solution of alcohol 4 (200 mg, 0.41 mmol) in CH2Cl2 (2 mL) was
added dropwise and the reaction mixture was stirred at 0 °C for
30 min. The white solid was removed by filtration through celite
and the filtrate was concentrated under reduced pressure to
provide a crude ketone as a yellow oil; Rf 0.42 (10%
EtOAc/hexane). The crude ketone was dissolved in EtOH (1
mL), and NH2OH HCl (50 mg, 0.72 mmol) was then added,
followed by pyridine (0.3 mL, 3.72 mmol). The reaction mixture
was stirred at room temperature for 2 h. The solvent was
removed under reduced pressure. The residue was dissolved in
CH2Cl2, washed with water, dried (Na2SO4), concentrated and
purified by silica gel flash column chromatography (10%
EtOAc/hexane) to provide two isomers of oximes (174 mg, 85%)
To a solution of alcohol 7 (261 mg, 0.53 mmol) and pyridine
(0.09 mL, 1.14 mmol) in dry CH2Cl2 (1.32 mL) at −15 °C was
added Tf2O (0.1 mL, 0.58 mmol). After stirring for 1 h, a few
drops of MeOH was added. The mixture was quenched with
water, extracted with CH2Cl2, dried (Na2SO4) and concentrated
under reduced pressure to give a crude triflate as a yellow oil.
The crude triflate was dissolved in DMF (0.88 mL). NaN3 (171
mg, 2.63 mmol) was added and the reaction mixture was stirred
at room temperature for 12 h. Water was added and the resulting
mixture was extracted with CH2Cl2. The organic layer was
combined, dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purified by silica gel flash
column chromatography (5% EtOAc/hexane) to give azide 8
(214 mg, 78%) as a colorless oil; Rf 0.35 (5% EtOAc/hexane);
[α
]
25 −34.5 (c 0.15, CH2Cl2); FTIR (neat) νmax, cm−1: 3070, 2955,
D
as a colorless oil; Rf 0.25 (10% EtOAc/hexane); FTIR (neat) νmax
,
1
2108, 1589, 1427; H NMR (400 MHz, CDCl3) δ 7.76–7.63 (m,
4H), 7.52–7.29 (m, 11H), 4.96 (d, J = 3.8 Hz, 1H), 4.69 (d, J =
11.8 Hz, 1H), 4.66 (d, J = 11.8 Hz, 1H), 4.25 (ddd, J = 7.1, 6.0,
3.2 Hz, 1H), 4.14 (dd, J = 5.1, 3.8 Hz, 1H), 4.01 (dd, J = 5.1, 3.2
Hz, 1H), 3.92 (dd, J = 10.3, 7.1 Hz, 1H), 3.87 (dd, J = 10.3, 6.0
Hz, 1H), 3.38 (s, 3H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 137.3, 135.7, 133.4, 129.9, 128.6, 128.1, 127.9, 107.5, 85.6,
79.4, 73.0, 63.2, 62.3, 56.2, 26.9, 19.4; HRMS (ESI-TOF), m/z
calcd for C29H35N3NaO4Si [M+Na]+ 540.2289, found 540.2296.
cm−1: 3354, 3070, 2931, 1589, 1472; oxime isomer I: 1H NMR
(400 MHz, CDCl3) δ 8.37 (s, 1H), 7.81–7.68 (m, 4H), 7.48–7.33
(m, 6H), 7.34–7.21 (m, 5H), 5.06 (s, 1H), 4.70–4.56 (m, 4H),
3.99 (dd, J = 11.0, 6.6 Hz, 1H), 3.92 (dd, J = 11.0, 4.2 Hz, 1H),
3.39 (s, 3H), 1.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 159.0,
137.9, 135.9, 135.8, 133.7, 133.5, 129.7, 128.4, 127.9, 127.8,
127.7, 106.5, 77.8, 75.8, 72.7, 66.3, 54.6, 26.9, 19.4; oxime
isomer II: 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.87–7.65
(m, 4H), 7.47–7.34 (m, 6H), 7.32–7.17 (m, 5H), 5.10 (s, 1H),
4.97 (dd, J = 6.2, 2.9 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.48 (d,
J = 12.0 Hz, 1H), 4.21–4.07 (m, 2H), 4.03 (dd, J = 10.9, 6.2 Hz,
1H), 3.41 (s, 3H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
159.0, 137.4, 135.9, 135.8, 133.7, 133.5, 129.7, 128.5, 128.1,
127.8, 127.7, 106.1, 79.7, 77.4, 70.3, 64.0, 54.8, 26.9, 19.4;
HRMS (ESI-TOF), m/z calcd for C29H35NNaO5Si [M+Na]+
528.2177, found 528.2171.
4.2.8. Methyl 2-O-benzyl-3-amino-3-deoxy-5-O-(tert-butyldiphe-
nyl)silyl-α-ᴅ-lyxofuranoside (6)
Method A: reduction of oxime 5. To a cooled solution of
oxime 5 (100 mg, 0.20 mmol) and MoO3 (40 mg, 0.28 mmol) in
MeOH (2 mL) was added NaBH4 (75 mg, 1.98 mmol)
portionwise. After stirring at room temperature for 30 min, the
starting material was completely consumed and a trace amount of
the amine product was formed along with an unidentified
complex mixture.
4.2.6. Methyl 2-O-benzyl-5-O-(tert-butyldiphenyl)silyl-α-ᴅ-arabi-
nofuranoside (7)7
Method B: Staudinger reduction of azide 8. To a solution of
azide 8 (102 mg, 0.197 mmol) in THF (3.5 mL) was added PPh3
(103 mg, 0.39 mmol). The reaction mixture was stirred at room
temperature for 2 h. Et3N (0.08 mL, 0.59 mmol) and water (0.3
mL) were added and the mixture was stirred at room temperature
for 24 h and then poured into water and extracted with EtOAc.
The organic layer was combined, dried (Na2SO4) and
concentrated under reduced pressure. The crude product was
purified by silica gel flash column chromatography (50%
EtOAc/hexane) to give amine 6 (80.1 mg, 83%) as a colorless
To a −15 °C solution of alcohol 4 (1.46 g, 2.97 mmol) and
pyridine (0.63 mL, 7.72 mmol) in dry CH2Cl2 (9 mL) was added
Tf2O (0.60 mL, 3.56 mmol). The reaction mixture was stirred at
the same temperature for 1 h. A few drops of MeOH were added
followed by water. The organic layer was combined, dried
(Na2SO4) and concentrated under reduced pressure to give a
crude triflate as a yellow oil. The crude triflate was dissolved in
DMF (7.4 mL) and NaNO2 (246 mg, 3.56 mmol) was added. The
reaction mixture was stirred at 40 °C for 24 h. Water was added
and the resulting mixture was extracted with CH2Cl2. The organic
layer was combined, dried (Na2SO4) and concentrated under
oil; Rf 0.45 (50% EtOAc/hexane); [α]
25 +21.3 (c 0.24, CH2Cl2);
D

6
Tetrahedron
FTIR (neat) νmax, cm−1: 3394, 3329, 3069, 2930, 1589, 1427; 1H
pressure. The crude product was purified by silica gel flash
ACCEPTED MANUSCRIPT
NMR (400 MHz, CDCl3) δ 7.72–7.65 (m, 4H), 7.47–7.27 (m,
11H), 4.94 (d, J = 2.6 Hz, 1H), 4.65 (d, J = 11.8 Hz, 1H), 4.58 (d,
J = 11.8 Hz, 1H), 4.19 (ddd, J = 6.6, 5.9, 5.1 Hz, 1H), 3.95 (dd, J
= 10.6, 6.6 Hz, 1H), 3.89 (dd, J = 10.6, 5.9 Hz, 1H), 3.88 (dd, J =
5.1, 2.6 Hz, 1H), 3.66 (t, J = 5.1 Hz, 1H), 3.38 (s, 3H), 1.36 (br s,
2H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 137.9, 135.7,
133.6, 133.5, 129.8, 128.5, 127.9, 127.8, 106.9, 84.8, 80.3, 72.7,
63.0, 55.7, 53.7, 27.0, 19.4; HRMS (ESI-TOF), m/z calcd for
C29H38NO4Si [M+H]+ 492.2565, found 492.2575.
column chromatography (10% EtOAc/hexane) to give iodide 11
(227 mg, 61%) as a white solid (recrystallized from hexane; mp
83–84 °C); Rf 0.28 (10% EtOAc/hexane); [α]
25 +185.2 (c 0.38,
D
CH2Cl2); FTIR (film) νmax, cm−1: 3367, 3064, 2977, 1714, 1520;
1H NMR (400 MHz, CDCl3) δ 7.42–7.29 (m, 5H), 5.03 (d, J =
8.5 Hz, 1H), 4.92 (d, J = 0.7 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H),
4.51 (d, J = 11.5 Hz, 1H), 4.54–4.48 (m, 1H), 4.37 (ddd, J = 9.1,
6.1, 4.4 Hz, 1H), 3.98 (dd, J = 5.6, 0.7 Hz, 1H), 3.36 (s, 3H), 3.25
(dd, J = 10.2, 4.4 Hz, 1H), 3.16 (dd, J = 10.2, 9.1 Hz, 1H), 1.44
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.6, 137.0, 128.7,
128.2, 128.0, 104.9, 83.0, 80.1, 79.5, 72.9, 55.2, 53.2, 28.4, 3.6;
HRMS (ESI-TOF), m/z calcd for C18H26INNaO5 [M+Na]+
486.0748, found 486.0756.
4.2.9. Methyl 2-O-benzyl-3-(tert-butoxycarbonyl)amino-3-deoxy-
5-O-(tert-butyldiphenyl)silyl-α-ᴅ-lyxofuranoside (9)
To a solution of amine 6 (623 mg, 1.26 mmol) in MeOH (5
mL) was added Boc2O (412 mg, 1.89 mmol) at room tempera-
ture. After stirring for 2 h, the solvent was removed under
reduced pressure. The residue was quenched with water,
extracted with CH2Cl2, dried (Na2SO4), concentrated and purified
by silica gel flash column chromatography (10% EtOAc/hexane)
to give 9 (735 mg, 98%) as a colorless oil; Rf 0.25 (10%
4.2.12. (4R,5S,E)-ethyl 4-(benzyloxy)-5-((tert-butoxycarbonyl)
amino)hepta-2,6-dienoate (13)
Iodide 11 (445 mg, 0.96 mmol) was dissolved in THF/H2O
(2:1 v/v, 7.3 mL). Activated zinc dust (630 mg, 9.63 mmol) was
added followed by 50% acetic acid (0.15 mL, 1.31 mmol). The
reaction mixture was sonicated for 30 min and then filtered
through celite. The filtrate was extracted with CH2Cl2. The
organic layer was combined, dried (Na2SO4) and concentrated
under reduced pressure to afford crude aldehyde 12 as a colorless
oil; Rf 0.15 (10% EtOAc/hexane). To a suspension of NaH (60 %
dispersion in mineral oil, 57 mg, 1.44 mmol) in dry THF (2 mL)
at 0 °C was added triethyl phosphonoacetate (0.23 mL, 1.15
mmol) dropwise. After stirring for 15 min, a solution of crude
aldehyde 12 in dry THF (1 mL) was added dropwise. The
reaction mixture was stirred at 0 °C for 1 h. Water was slowly
added and the mixture was extracted with CH2Cl2. The organic
layer was combined, dried (Na2SO4), and concentrated under
reduced pressure. The crude product was purified by silica gel
flash column chromatography (10% EtOAc/hexane) to give ester
13 (211.2 mg, 58 %) as a white solid (recrystallized from hexane;
EtOAc/hexane); [α] ,
25 +26.3 (c 0.57, CH2Cl2); FTIR (neat) νmax
D
cm−1: 3420, 3070, 2958, 1715, 1504; 1H NMR (400 MHz,
CDCl3) δ 7.74–7.67 (m, 4H), 7.48–7.26 (m, 11H), 5.50 (d, J =
8.9 Hz, 1H), 4.89 (s, 1H), 4.62–4.54 (m, 1H), 4.57 (s, 2H), 4.25
(dt, J = 6.6, 5.2 Hz, 1H), 3.95 (d, J = 5.7 Hz, 1H), 3.91 (dd, J =
11.1, 5.2 Hz, 1H), 3.75 (dd, J = 11.1, 5.2 Hz, 1H), 3.33 (s, 3H),
1.41 (s, 9H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.9,
137.8, 135.8, 133.5, 133.3, 129.8, 129.7, 128.5, 127.9, 127.8,
106.1, 82.5, 79.5, 78.4, 73.0, 63.8, 55.1, 52.8, 28.5, 26.8, 19.3;
HRMS (ESI-TOF), m/z calcd for C34H45NNaO6Si [M+Na]+
614.2908, found 614.2915.
4.2.10. Methyl 2-O-benzyl-3-(tert-butoxycarbonyl)amino-3-deoxy
-α-ᴅ-lyxofuranoside (10)
TBAF solution (1 M in THF, 1.35 mL, 1.35 mmol) was added
dropwise to a cooled solution of 9 (666 mg, 1.12 mmol) in THF
(10 mL). The reaction mixture was stirred at room temperature
for 4 h. Satd aq NH4Cl was added and the mixture was extracted
with CH2Cl2. The organic layer was combined, dried (Na2SO4),
and concentrated under reduced pressure. The crude product was
purified by silica gel flash column chromatography (20–40%
EtOAc/hexane) to give alcohol 10 (330 mg, 83%) as a colorless
mp 78.0–78.5 °C); Rf 0.42 (20% EtOAc/hexane); [α]
25 +47.1 (c
D
0.32, CH2Cl2); FTIR (film) νmax, cm−1: 3362, 3065, 2979, 1716,
1
1497; H NMR (400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 6.82
(dd, J = 15.8, 5.9 Hz, 1H), 6.09 (d, J = 15.8 Hz, 1H), 5.83 (ddd, J
= 16.8, 10.5, 6.0 Hz, 1H), 5.26–5.19 (m, 2H), 4.84 (d, J = 6.3 Hz,
1H), 4.64 (d, J = 11.9 Hz, 1H), 4.41 (d, J = 11.9 Hz, 1H), 4.34 (br
s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.17–4.11 (m, 1H), 1.42 (s, 9H),
1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9,
155.3, 144.3, 137.7, 133.7, 128.6, 128.0, 127.9, 124.3, 117.6,
79.9, 71.6, 60.8, 55.7, 28.5, 14.3; HRMS (ESI-TOF), m/z calcd
for C21H29NNaO5 [M+Na]+ 398.1938, found 398.1956.
oil; Rf 0.25 (30% EtOAc/hexane);
[
α
]
25 −48.4 (c 0.10, CH2Cl2);
D
FTIR (neat) νmax, cm−1: 3433, 3064, 3031, 2976, 1712, 1504; H
NMR (400 MHz, CDCl3) δ 7.42–7.28 (m, 5H), 5.34 (d, J = 7.7
Hz, 1H), 4.87 (d, J = 0.9 Hz, 1H), 4.63 (d, J = 11.6 Hz, 1H), 4.56
(d, J = 11.6 Hz, 1H), 4.51 (ddd, J = 7.7, 6.3, 5.5 Hz, 1H), 4.23
(ddd, J = 6.3, 5.2, 3.7 Hz, 1H), 3.96 (dd, J = 5.5, 0.9 Hz, 1H),
3.71 (dd, J = 12.0, 5.2 Hz, 1H), 3.62 (dd, J = 12.0, 3.7 Hz, 1H),
3.33 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.8,
136.9, 128.7, 128.3, 128.0, 105.5, 81.8, 80.3, 78.8, 73.1, 60.9,
55.2, 52.5, 28.4; HRMS (ESI-TOF), m/z calcd for C18H27NNaO6
[M+Na]+ 376.1731, found 376.1754.
1
4.2.13. (4R,5S,E)-ethyl 4-(benzyloxy)-5-(but-3-enamido)hepta-
2,6-dienoate (14)
To a cooled solution of ester 13 (188 mg, 0.50 mmol) in
CH2Cl2 (2 mL) was added TFA (1 mL, 13.06 mmol). The
reaction mixture was stirred at room temperature for 1 h. Satd aq
NaHCO3 was added and the mixture was extracted with CH2Cl2.
The organic layer was combined, dried (Na2SO4), concentrated
under reduced pressure. The crude amine was dissolved in
CH2Cl2 (5 mL). DCC (124 mg, 0.60 mmol) and DMAP (6 mg,
0.05 mmol) were added followed by vinylacetic acid (0.05 mL,
0.59 mmol). The reaction mixture was stirred at room tempera-
ture for 20 min. The white solid was filtered off through celite.
The filtrate was quenched with satd aq NaHCO3, extracted with
CH2Cl2, dried (Na2SO4) and concentrated under reduced pressure.
The crude product was purified by silica gel flash column
chromatography (30% EtOAc/hexane) to give amide 14 (151 mg,
4.2.11. Methyl 2-O-benzyl-3-(tert-butoxycarbonyl)amino-3-deoxy
-5-iodo-5-deoxy-α-ᴅ-lyxofuranoside (11)
To a cooled solution of alcohol 10 (281 mg, 0.79 mmol), PPh3
(500 mg, 1.97 mmol), and imidazole (162 mg, 2.38 mmol) in dry
THF (3.2 mL) was added portionwise I2 (484 mg, 1.91 mmol).
After stirring for 12 h, the reaction mixture was poured into satd
aq Na2S2O3 and extracted with CH2Cl2. The organic layer was
combined, dried (Na2SO4), and concentrated under reduced

7
87%) as a white solid (recrystallized from hexane; mp 58.0–58.5
4.2.16. (S)-6-((R)-1-(benzyloxy)-4-hydroxybutyl)piperidin-2-one
(17)
ACCEPTED MANUSCRIPT
°C); Rf 0.27 (30% EtOAc/hexane);
[
α
]
25 −99.3 (c 0.25, CH2Cl2);
D
FTIR (film) νmax, cm−1: 3296, 3065, 2983, 1720, 1654, 1538; H
NMR (400 MHz, CDCl3) δ 7.40–7.28 (m, 5H), 6.82 (dd, J =
15.8, 5.8 Hz, 1H), 6.10 (dd, J = 15.8, 1.4 Hz, 1H), 5.91–5.77 (m,
3H), 5.24–5.16 (m, 4H), 4.68–4.63 (m, 1H), 4.65 (d, J = 11.9 Hz,
1H), 4.34 (d, J = 11.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.15
(ddd, J = 5.8, 3.4, 1.4 Hz, 1H), 2.92 (d, J = 6.9 Hz, 2H), 1.31 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 165.9,
144.0, 137.5, 132.8, 131.2, 128.7, 128.2, 128.1, 124.4, 120.1,
118.3, 79.4, 71.6, 60.8, 54.1, 41.7, 14.3; HRMS (ESI-TOF), m/z
calcd for C20H25NNaO4 [M+Na]+ 366.1676, found 366.1697.
1
To a cooled solution of ester 16 (363 mg 1.15 mmol) in EtOH
(10 mL) was added NaBH4 (437 mg, 11.5 mmol) portionwise.
The reaction mixture was stirred at room temperature for 12 h.
NH4Cl was added followed by a small amount of water and the
solvent was removed under reduced pressure. The residue was
dissolved with EtOAc, washed with water, dried (Na2SO4) and
concentrated. The crude product was purified by silica gel flash
column chromatography (5% MeOH/CH2Cl2) to provide alcohol
17 as a colorless oil (163 mg, 51%); Rf 0.35 (5% MeOH/CH2Cl2);
[α
]
25 +16.5 (c 2.42, CHCl3); FTIR (neat) νmax, cm−1: 3298, 2948,
D
1
4.2.14. (R,E)-ethyl 4-(benzyloxy)-4-((S)-6-oxo-1,2,5,6-tetrahydro-
pyridin-2-yl)but-2-enoate (15)
1651; H NMR (400 MHz, CDCl3) δ 7.40–7.20 (m, 5H), 6.81 (s,
1H), 4.56 (d, J = 11.4 Hz, 1H), 4.51 (d, J = 11.4 Hz, 1H), 3.73–
3.54 (m, 3H), 3.40 (q, J = 5.1 Hz, 1H), 2.66 (br s, 1H), 2.44–2.33
(m, 1H), 2.33–2.20 (m, 1H), 1.93–1.79 (m, 2H), 1.78–1.45 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 173.4, 137.9, 128.6, 128.0,
80.4, 72.0, 62.6, 54.3, 31.5, 28.1, 25.6, 24.3, 19.7; HRMS (ESI-
TOF), m/z calcd for C16H23NNaO3 [M+Na]+ 300.1570, found
300.1564.
To a solution of amide 14 (45 mg, 0.13 mmol) in dry CH2Cl2
(4 mL) was added Hoveyda-Grubbs catalyst 2nd generation (4
mg, 6.7 µmol, 5 mol%). The reaction mixture was stirred at 40
°C for 2 h under argon atmosphere. The solvent was removed
under reduced pressure. The crude product was purified by silica
gel flash column chromatography (3% MeOH/CH2Cl2) to give
lactam 15 (31 mg, 74%) as a white solid (recrystallized from
25
4.2.17. (9R,9aS)-9-(benzyloxy)hexahydro-1H-quinolizin-4(6H)-
one (18)
hexane; mp 109–110 °C); Rf 0.37 (3% MeOH/CH2Cl2); [α]
D
−122.4 (c 0.082, CH2Cl2); FTIR (film) νmax, cm−1: 3224, 3045,
To a cooled solution of alcohol 17 (150 mg, 0.54 mmol) and
Et3N (0.15 mL, 1.07 mmol) in CH2Cl2 (1.5 mL) was added
dropwise MsCl (60 µL, 0.78 mmol). The white precipitate was
formed and the reaction mixture was stirred at 0 °C for 30 min.
Water was added and the organic layer was combined, dried
(Na2SO4), and concentrated under reduced pressure to provide a
yellow oil. To a cooled suspension of NaH (60%, 43 mg, 1.07
mmol) in dry THF (1.3 mL) was added dropwise a solution of the
crude mesylate in dry THF (1.3 mL). The reaction mixture was
stirred for 30 min at 50 °C. After cooling to 0 °C, water was
added dropwise to destroy excess NaH. The mixture was extract-
ed with CH2Cl2, dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purified by silica gel flash
column chromatography (1% MeOH/CH2Cl2) to afford 18 as a
colorless oil (106 mg, 75%); Rf 0.60 (2% MeOH/CH2Cl2);
1
2984, 1718, 1663, 1455; H NMR (400 MHz, CDCl3) δ 7.40–
7.16 (m, 5H), 6.71 (dd, J = 15.8, 6.3 Hz, 1H), 6.32 (s, 1H), 6.02
(dd, J = 15.8, 1.2 Hz, 1H), 5.79 (dtd, J = 10.1, 3.5, 1.8 Hz, 1H),
5.69–5.48 (m, 1H), 4.56 (d, J = 11.8 Hz, 1H), 4.35 (d, J = 11.8
Hz, 1H), 4.29–4.20 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.97 (ddd,
J = 6.3, 3.9, 1.2 Hz, 1H), 2.90–2.75 (m, 2H), 1.22 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 165.5, 142.1, 137.2,
128.6, 128.1, 127.8, 125.9, 125.0, 120.6, 79.9, 71.5, 60.8, 57.1,
31.6, 14.2; HRMS (ESI-TOF), m/z calcd for C18H21NNaO4
[M+Na]+ 338.1363, found 338.1377.
4.2.15. (R)-Methyl 4-(benzyloxy)-4-((S)-6-oxopiperidin-2-yl)
butanoate (16a) and (R)-Ethyl 4-(benzyloxy)-4-((S)-6-oxo
piperidin-2-yl)butanoate (16b)
[α
]
25 −116.8 (c 1.67, CHCl3); FTIR (neat) νmax, cm−1: 3030, 2938,
D
NaBH4 (200 mg, 5.26 mmol) was added portionwise to a
cooled solution of lactam 15 (210 mg, 0.66 mmol) and NiCl2 (42
mg, 0.33 mmol) in MeOH (10 mL). Color gradually changed
from yellow to brown and then black. The reaction mixture was
stirred overnight at room temperature and then quenched with
satd aq NH4Cl. The solvent was removed under reduced pressure.
The residue was extracted with CH2Cl2, dried (Na2SO4),
concentrated and purified by silica gel flash column chromato-
graphy (80% EtOAc/hexane) to give a mixture of lactam 16a and
16b (ratio 1:1.8, 109 mg, 51%) as a colorless oil; Rf 0.23 (80%
EtOAc/hexane); FTIR (film, mixture) νmax, cm−1: 3394, 3031,
1
1644; H NMR (400 MHz, CDCl3) δ 7.39–7.27 (m, 5H), 4.77–
4.70 (m, 1H), 4.68 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz,
1H), 3.25–3.09 (m, 2H), 2.48–2.28 (m, 4H), 2.21–2.11 (m, 1H),
1.84–1.75 (m, 2H), 1.74–1.66 (m, 1H), 1.65–1.53 (m, 1H), 1.49–
1.35 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.2, 138.2,
128.6, 128.0, 78.3, 71.1, 61.3, 42.6, 32.7, 30.2, 25.5, 23.4, 18.3;
HRMS (ESI-TOF), m/z calcd for C16H21NNaO2 [M+Na]+
282.1464, found 282.1464.
4.2.18. (9R,9aS)-9-hydroxyhexahydro-1H-quinolizin-4(6H)-one
1
(19)
2950, 1731, 1660; H NMR (400 MHz, CDCl3, 16a) δ 7.38–7.25
(m, 5H), 6.07 (s, 1H), 4.58 (d, J = 11.4 Hz, 1H), 4.43 (d, J = 11.4
Hz, 1H), 3.77–3.70 (m, 1H), 3.61 (s, 3H), 3.46–3.40 (m, 1H),
2.52–2.21 (m, 4H), 1.98–1.43 (m, 6H); 1H NMR (400 MHz,
CDCl3, 16b) δ 7.38–7.25 (m, 5H), 6.07 (s, 1H), 4.58 (d, J = 11.4
Hz, 1H), 4.44 (d, J = 11.4 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H),
3.77–3.70 (m, 1H), 3.46–3.40 (m, 1H), 2.52–2.21 (m, 4H), 1.98–
1.43 (m, 6H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3, 16a + 16b) δ 174.0, 173.5, 172.5, 137.7, 137.6, 128.6,
128.0, 127.9, 79.4, 79.3, 72.0, 71.9, 60.6, 53.9, 51.7, 31.7, 30.1,
29.9, 24.4, 24.1, 20.2, 14.3; HRMS (ESI-TOF), m/z calcd for
C17H24NO4 [M+H]+ 306.1702, found 306.1700 and C18H26NO4
[M+H]+ 320.1862, found 320.1856.
To a solution of lactam 18 (100 mg, 0.386 mmol) in MeOH
(4 mL) was added 10% Pd/C (70 mg, 66 µmol). The reaction
mixture was stirred at room temperature for 2 h under hydrogen
atmosphere and then filtered through celite. The filtrate was
concentrated and the crude product was purified by silica gel
flash column chromatography (2% MeOH/CH2Cl2) to afford
alcohol 19 (56 mg, 85%) as a white solid (recrystallized from
hexane/CH2Cl2; mp 156–157 °C) (reported mp 156–157 °C,
ent);11 Rf 0.50 (5% MeOH/CH2Cl2); 25 −73.3 (c 0.75, CHCl3)
[α]
D
(reported +73.7 (c 0.58, CHCl3, ent));11 FTIR (film) νmax, cm−1:
1
3282, 2947, 1598; H NMR (400 MHz, CDCl3) δ 4.80–4.64 (m,

8
Tetrahedron
ACCEPTED MANUSCRIPT
1H), 3.36 (td, J = 9.4, 4.4 Hz, 1H), 3.06 (dt, J = 9.4, 6.1 Hz,
extracted with CH2Cl2. The organic layer was combined, dried
1H), 2.43–2.32 (m, 3H), 2.30 (s, 1H), 2.21–2.06 (m, 2H), 1.90–
1.78 (m, 2H), 1.77–1.71 (m, 1H), 1.70–1.60 (m, 1H), 1.55–1.38
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.0, 71.9, 62.6, 42.4,
34.3, 32.8, 25.4, 23.6, 18.4; HRMS (ESI-TOF), m/z calcd for
C9H15NNaO2 [M+Na]+ 192.0995, found 192.0999.
(Na2SO4) and concentrated under reduced pressure. The crude
product was purified by silica gel flash column chromatography
(2% MeOH/CH2Cl2–6% MeOH/CH2Cl2 + 3% NH3 sol.) to give
(+)-epiquinamide (1) (50 mg, 68%) and (−)-epiepiquinamide (22)
(20 mg, 27%); For (+)-1:2b white solid (recrystallized from
hexane/CH2Cl2; mp 130–131 °C) (reported mp 130 °C); Rf 0.64
4.2.19. (1R,9aS)-6-oxooctahydro-1H-quinolizin-1-yl methane
(6% MeOH/CH2Cl2 + 3% NH3 sol.); [α]
25 +26.8 (c 0.56, CHCl3)
sulfonate (20)2e
D
(reported +24 (c 0.1, CDCl3)); FTIR (film) νmax, cm−1: 3326,
2937, 1660; 1H NMR (400 MHz, CDCl3) δ 6.29 (br s, 1H), 3.95–
3.85 (m, 1H), 2.83–2.69 (m, 2H), 2.04–1.89 (m, 6H), 1.86–1.78
(m, 1H), 1.75–1.63 (m, 2H), 1.61–1.53 (m, 1H), 1.53–1.37 (m,
4H), 1.37–1.13 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.7,
64.5, 56.9, 48.3, 29.8, 29.2, 25.7, 24.2, 23.6, 20.7; HRMS (ESI-
TOF), m/z calcd for C11H21N2O [M+H]+ 197.1648, found
197.1645;
To a cooled solution of alcohol 19 (50 mg, 0.29 mmol) and
Et3N (0.12 mL, 0.85 mmol) in CH2Cl2 (1.5 mL) was added
dropwise MsCl (50 µL, 0.65 mmol). The white precipitate was
formed and the reaction mixture was stirred at 0 °C for 1 h.
Water was added and the mixture was extracted with CH2Cl2,
dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by silica gel flash column chromato-
graphy (0–2% MeOH/CH2Cl2) to afford mesylate 20 (57 mg,
78%) as a white solid (recrystallized from hexane/CH2Cl2; mp
For (−)-22:2d white solid; mp 190 °C (dec) (reported mp 190
ºC (dec)); Rf 0.28 (6% MeOH/CH2Cl2 + 3% NH3 sol.); [α]
25 −9.5
D
108–109 °C); Rf 0.33 (2 % MeOH/CH2Cl2);
[
α
]
25 −61.7 (c 0.95,
(c 0.11, CHCl3) (reported −2.9 (c 0.6, CH2Cl2); FTIR (film) νmax
,
D
1
cm−1: 3422, 2931, 1635; H NMR (400 MHz, CDCl3) δ 5.17 (br
CHCl3); FTIR (film) νmax, cm−1: 2953, 1633, 1347; 1H NMR (400
MHz, CDCl3) δ 4.82–4.68 (m, 1H), 4.40 (td, J = 10.4, 4.8 Hz,
1H), 3.31 (dt, J = 10.4, 6.1 Hz, 1H), 3.05 (s, 3H), 2.47–2.28 (m,
4H), 2.21–2.04 (m, 1H), 1.92–1.76 (m, 3H), 1.76–1.61 (m, 2H),
1.61–1.47 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 169.7, 80.0,
59.8, 42.0, 39.2, 32.7, 32.0, 25.4, 23.5, 18.1; HRMS (ESI-TOF),
m/z calcd for C10H17NNaO4S [M+Na]+ 270.0770, found
270.0766.
s, 1H), 3.71 (dtd, J = 11.8, 9.5, 4.4 Hz, 1H), 2.84 (br d, J = 11.0
Hz, 1H), 2.76 (br d, J = 11.0 Hz, 1H), 2.03–1.94 (m, 3H), 1.96 (s,
3H), 1.85–1.47 (m, 7H), 1.35–1.03 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 169.5, 67.5, 56.5, 55.8, 51.2, 32.0, 29.0, 25.4,
24.4, 23.8, 23.7; HRMS (ESI-TOF), m/z calcd for C11H21N2O
[M+H]+ 197.1648, found 197.1648.
4.3. Computational Details
4.2.20.
(9S,9aS)-9-azidohexahydro-1H-quinolizin-4(6H)-one
(21a)2e and its diastereoisomer (21b)
The geometrical structure of aziridinium ion intermediate 20a
was optimized using the hybrid density functional B3LYP
method. The basis set for all atoms was 6-311G (d,p), the charge
was 1, and the spin state was singlet. The calculations were
performed using the Gaussian03 package.12
To a solution of mesylate 20 (200 mg, 0.81 mmol) in DMF (8
mL) was added NaN3 (263 mg, 4.05 mmol). The reaction mixture
was stirred at 100 °C for 24 h under argon atmosphere. After
cooling to room temperature, the reaction mixture was diluted
with EtOAc and washed with water. The organic layer was
combined, dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purified by silica gel flash
column chromatography (2% MeOH/CH2Cl2) to give azide 21a
as the major product along with its diastereomer 21b (colorless
oil, 140 mg, 90%, ratio 1:0.4); Rf 0.35 (2% MeOH/CH2Cl2);
FTIR (neat) νmax, cm−1: 2943, 2097, 1633; For 21a: 1H NMR (400
MHz, CDCl3) δ 4.84–4.73 (m, 1H), 3.68–3.59 (m, 1H), 3.38 (td,
J = 7.5, 1.9 Hz, 1H), 2.48–2.24 (m, 3H), 2.18–2.10 (m, 1H),
1.97–1.82 (m, 3H), 1.78–1.67 (m, 2H), 1.65–1.50 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 170.4, 60.7, 58.2, 41.8, 32.8, 28.6,
Acknowledgements
W.S. is
a M.Sc. student under Science Achievement
Scholarship of Thailand (SAST). We are grateful for financial
support from the Center of Excellence for Innovation in
Chemistry (PERCH-CIC), Commission on Higher Education,
Ministry of Education and Kasetsart University Research and
Development Institute (KURDI).
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new and
important known compounds, and atomic coordinates for
optimized structure of 20a) related to this article can be found
at………
1
26.6, 19.6, 19.0; For 21b: H NMR (400 MHz, CDCl3) δ 4.84–
4.73 (m, 1H), 3.14–2.98 (m, 2H), 2.48–2.24 (m, 3H), 2.18–2.10
(m, 1H), 1.97–1.82 (m, 3H), 1.78–1.67 (m, 2H), 1.65–1.50 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 169.5, 62.7, 60.4, 41.9, 32.8,
30.2, 26.3, 23.6, 18.3.
References and notes
4.2.21. (+)-Epiquinamide (1)2b and (−)-epiepiquinamide (22)2d
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