Synthesis of d -Fagomine and Its Seven- and Eight-Membered Higher-Ring Analogues, and the Formal Synthesis of (+)-Australine from l -Xylose-Derived Chiron

Article abstract of DOI:10.1055/s-0035-1562438

The synthesis of d-fagomine and its seven- and eight-membered higher-ring analogues from commercially available l-xylose is reported. The syntheses involve elaboration of a common alkenol precursor obtained from l-xylose-derived hemiacetal. The key steps

Full text of DOI:10.1055/s-0035-1562438

SYNTHESIS
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0
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
P. Das et al.
Paper
Synthesis
Synthesis of D-Fagomine and Its Seven- and Eight-Membered
Higher-Ring Analogues, and the Formal Synthesis of (+)-Australine
from L-Xylose-Derived Chiron
Pintu Das‡
Sama Ajay‡
H
N
HO
N
HO
HO
OH
Arun K. Shaw*
HO
O
HO
OH
BnO
OH
OH
OH
Medicinal and Process Chemistry Division, CSIR-Central
Drug Research Institute (CSIR-CDRI), Sector 10, Jankipuram
Extension, Sitapur road, Lucknow-226031, U. P., India
akshaw55@yahoo.com
D-fagomine
(+)-australine
HN
HO
L-xylose
OH
HN
BnO
OBn
HO
HO
‡ These authors contributed equally to this work.
HO
OH
HO
OH
Received: 06.04.2016
Accepted after revision: 10.05.2016
Published online: 29.06.2016
H
HO
N
HN
HN
N
HO
HO
HO
OH
HO
DOI: 10.1055/s-0035-1562438; Art ID: ss-2016-t0240-op
HO
HO
OH
OH
HO
OH
OH
Abstract The synthesis of D-fagomine and its seven- and eight-mem-
bered higher-ring analogues from commercially available L-xylose is re-
ported. The syntheses involve elaboration of a common alkenol precur-
sor obtained from L-xylose-derived hemiacetal. The key steps in the
syntheses are intramolecular reductive amination and ring-closing me-
tathesis for the synthesis of D-fagomine and seven-/eight-membered
iminosugar, respectively. We have also extended our synthetic strategy
for the formal synthesis of (+)-australine using zinc-mediated fragmen-
tation reaction and ring-closing metathesis as key steps.
D-fagomine (1)
2
3
(+)-australine (4)
Figure 1 Examples of some natural and synthetic iminosugars
D-Fagomine (1; Figure 1), a polyhydroxylated piperi-
dine,6 was first isolated in 1974 from the seeds of Japanese
buckwheat Fagopyrum esculentum Moench,7 and later from
the seeds of Castanospermum australe (Leguminosae).8 In
1997, D-fagomine and 6-deoxyfagomine were also isolated
from the roots of Lycium chinense (Solanaceae).9 Although
D-fagomine is well known for its potent inhibitory activity
against mammalian intestinal glucosidases and galactosi-
dase,10 it has also been shown to exhibit strong antihyper-
glycemic effect on streptozocin-induced diabetic mice,
thereby enhancing glucose-induced insulin secretion.11
Since its first isolation, several synthetic approaches have
been reported for the synthesis of D-fagomine and its iso-
mers.12 Over the last 30 years, many synthetic efforts have
been focused on the design and synthesis of five- and six-
membered iminocyclitols, but their higher analogues, i.e.,
substituted azepanes and azocanes, have received very lit-
tle attention. Azepane iminosugars were first synthesized
by Paulsen in 1967.13 Later, Wong and co-workers in 1996
first reported the promising glycosidase inhibitory activity
of polyhydroxy azepanes against a broad range of glycosi-
dases.14 In 2004, Martin et al. first reported the synthesis
and biological evaluation of eight-membered iminoaldi-
tol.15 It has been found that eight-membered iminosugars
and their N-substituted analogues showed weak to moder-
ate glycosidase activity, thus creating a need for further
structural modifications.16,17 We report herein the total
syntheses of (–)-fagomine and higher ring analogues from
Key words D-fagomine, aminocyclitols, metathesis, (+)-australine, re-
ductive amination
Natural and synthetic polyhydroxylated pyrrolidines,
piperidines, piperazines, indolizines, etc., and higher homo-
logues, commonly known as iminosugars, can be viewed as
carbohydrate analogues in which the endocyclic oxygen
atom has been replaced with nitrogen.1 Iminocyclitols and
their derivatives are potent glycosidase inhibitors. Their po-
tency arises from the similarity of these compounds to the
oxocarbenium ion like transition state of the enzymatic re-
actions for most glycosidases. Glycosidases and glycosyl-
transferases are involved in numerous biological processes
such as metabolism, lysosomal catabolism, and glycopro-
tein processing, which, in turn, regulate many significant
biological activities such as viral infection, cell–cell recogni-
tion and inflammation.2 Potent and selective glycosidase
inhibition activities of iminocyclitols have made them at-
tractive drug candidates for a number of diseases such as
viral infections, AIDS, lysosomal storage disorders, cancer
and diabetes,3 thus making glycosidase inhibitors the sub-
ject of intense interest for nearly half a century.4 Naturally
occurring polyhydroxylated 1,2-dideoxy azasugars repre-
sent an important class of glycosidase inhibitors.5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
P. Das et al.
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Synthesis
commercially available L-xylose. We also extended our syn-
thetic strategy to the formal synthesis of bicyclic polyhy-
droxylated natural product (+)-australine18 from a common
chiron intermediate.
mide and n-BuLi (2 M in THF) at different temperatures. It
was found that performing the reaction with six equiva-
lents of methyltriphenylphosphonium bromide and three
equivalents of n-BuLi at –20 °C resulted the formation of
the desired olefin 6 in 72% yield. The preparation of 6 has
previously been described starting from arabinose, but
with more steps.21 Hydroboration–oxidation reaction of
alkene 6 with BH3SMe2 in THF at 0 °C proceeded smoothly
to give the diol 13 in 72% yield.22 The resulting diol was
then esterified with MsCl in the presence of Et3N and a cat-
alytic amount of DMAP in CH2Cl2. The crude dimesylate,
owing to its instability, was immediately subjected to cy-
clization with benzylamine at 80 °C to furnish piperidine 5
in 66% yield over two steps. Finally, debenzylation of 5 was
performed with Pd/C under a hydrogen atmosphere to give
the HCl salt of D-fagomine 1 in 90% yield.23 Its analytical
data are in complete agreement with those of previous re-
ports.24
Our retrosynthetic analysis, shown in Scheme 1, illus-
trates that the target molecule D-fagomine 1 could be ob-
tained from 5, which, in turn, could be accessible from ole-
fin 6, which could ultimately be prepared from L-xylose.
The retrosynthetic analysis for the target azepane natural
product 2 and eight-membered iminosugar 3 showed that
these compounds could be obtained from diene 7 and N-
Cbz protected diene 9, respectively. Both the latter two
compounds could be synthesized from the same olefin 6
through Mitsunobu inversion reaction.
Bn
N
H
N
BnO
BnO
HO
HO
OBn
OH
The synthesis of seven-membered iminoalditol 2 was
also initiated from L-xylose-derived olefin 6. Phthalimido
compound 15 was synthesized from 6 under Mitsunobu
conditions. Thus, alcohol 6 was treated with phthalimide
(1.5 equiv), PPh3 (1.5 equiv) and diisopropyl azodicarboxyl-
ate (DIAD; 1.5 equiv) in THF at –20 °C to room temperature
to obtain the desired inverted phthalimido compound 15 in
68% yield.25 The latter compound was then converted into
its corresponding amine by treatment with 40% aqueous
MeNH2 at 60 °C for 3 h.26 The crude primary amine was
subjected to Cbz protection by reaction with triethylamine
and benzyl chloroformate at 0 °C in CH2Cl2 to give protected
amine 16 in 65% overall yield. Allylation of 16 with allyl
bromide and NaH in THF at 0 °C furnished the diene 7 in
88% yield. With the diene assembly 7 in hand, the stage was
set for the crucial ring-closing metathesis reaction. To ac-
complish this, diene 7 was treated with 5 mol% Grubbs II
catalyst in dichloromethane under argon atmosphere to
give the protected azepane 8 in 92% yield. Finally, hydroge-
nation of 8 was achieved in the presence of Pd/C to give
azepane 2 in 90% yield (Scheme 3).27
D-fagomine (1)
5
OH
BnO
HN
HO
CbzN
BnO
L-xylose
BnO
OBn
HO
BnO
OH
OH
OBn
6
2
7
HN
HO
CbzN
BnO
HO
BnO
OBn
3
9
Scheme 1 Retrosynthetic analysis
The synthesis of fagomine 1 began with commercially
available L-xylose (Scheme 2). Selective anomeric methyla-
tion of L-xylose with acetyl chloride in methanol followed
by benzylation of the crude methylated product furnished
methyl furanoside 11.19 In the next step, 11 was converted
into its hemiacetal 12 by heating with trifluoroacetic acid
(TFA) in acetonitrile and water solvent mixture at 80 °C.20
Wittig olefination of 12 was optimized by varying the num-
ber of equivalents of methyltriphenylphosphonium bro-
OH
O
O
O
OH
BnO
OMe
OH
BnO
BnO
c
HO
d
a
b
BnO
OBn
BnO
OBn
HO
BnO
OBn
OH
11
12
6
L-xylose
.
H
HCl
Bn
N
BnO
BnO
OH
BnO
N
OH
OMs
OMs
HO
HO
BnO
BnO
f
e
BnO
OH
OBn
OBn
OBn
14
1
13
5
Scheme 2 Synthesis of D-fagomine 1. Reagents and conditions: (a) i. MeOH, AcCl, 0 °C to r.t., 2 h; ii. NaH, BnBr, DMF, 0 °C to r.t., 12 h (b) MeCN–H2O–
TFA (5:4:2), 80 °C, 4 h, 75%; (c) Ph3PCH3Br, n-BuLi, THF, –20 °C, 3 h, 72%; (d) BH3·Me2S, THF, H2O2-NaOH, 0 °C to r.t., 6 h, 72%; (e) i. MsCl, Et3N, CH2Cl2,
0 °C to r.t., 2 h; ii. BnNH2, 80 °C, 3 h, 66% for two steps; (f) H2, Pd/C, MeOH–1N HCl, 48 h, 90%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
P. Das et al.
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Synthesis
amine 9, which may be attributed to the lower basicity of
amidic N-H (Scheme 5). The same result was obtained with
Boc- and Ts-protected amines 19 and 21.
NHCbz
NPhth
b
OH
a
BnO
c
BnO
BnO
BnO
BnO
OBn
BnO
OBn
OBn
16
6
15
a or b or c
9
16
CbzN
BnO
HN
HO
CbzN
HO
NHBoc
a or b or c
BnO
BocN
e
d
BnO
BnO
BnO
BnO
BnO
OBn
BnO
OH
OBn
BnO
OBn
BnO
OBn
OBn
2
7
8
19
20
Scheme 3 Synthesis of azepane 2. Reagents and conditions: (a) PPh3,
DIAD, phthalimide, THF, –20 °C to r.t., 4 h, 68%; (b) i. 40% MeNH2,
60 °C, 3 h; ii. CbzCl, Et3N, CH2Cl2, 0 °C, 2 h, 65%, for two steps; (c) allyl
bromide, NaH, THF, 0 °C, 3 h, 88%; (d) Grubbs II (5 mol%), CH2Cl2 (0.01
M), reflux, 6 h, 92%; (e) H2, Pd/C, MeOH–1 N HCl, 48 h, 90%.
NHTs
TsN
BnO
a or b or c or d
BnO
OBn
21
22
Synthesis of eight-membered iminosugar 3 started from
phthalimido compound 15 (Scheme 4). The phthalimido
functionality was hydrolyzed with MeNH2 to afford an
amine, which was used for the next step without further
purification. The next step of the synthetic sequence in-
volved N-alkylation of the crude amine to obtain the corre-
sponding diene 17. Thus, the crude amine intermediate was
subject to N-alkylation with 4-bromobut-1-ene (1.2 equiv)
in the presence of base K2CO3 and DMF as solvent. The re-
quired N-alkylated diene 17 was obtain in 48% overall yield
in two steps.
Scheme 5 Reagents and conditions: (a) 4-bromobut-1-ene, K2CO3,
DMF, 0 °C to r.t.; (b) 4-bromobut-1-ene, Et3N, CH2Cl2, 0 °C to r.t.; (c) 4-
bromobut-1-ene, NaH, THF, TBAI, 60 °C; (d) PPh3, DIAD, phthalimide, 1-
butenol, THF.
Free amines are unsuitable substrates for ring-closing
metathesis; hence, we protected the amines with Cbz pro-
tecting groups. Ring-closing metathesis of suitably N-pro-
tected diene 9 by using 5 mol% Grubbs II catalyst proceeded
smoothly in CH2Cl2 heated to reflux, to obtain azacyclooc-
tene 18 (Scheme 4).28 Hydrogenation of the latter by using
Pd/C under hydrogen atmosphere furnished eight-mem-
bered iminosugar 3 in 90% yield.
NPhth
HN
CbzN
b
a
BnO
BnO
BnO
We were also interested to show the utility of the chiral
amide intermediate 15 in the total synthesis of polyhydrox-
ylated pyrrolizidine alkaloids. To achieve our goal, we iden-
tified (+)-australine 4, the formal synthesis of which was
envisaged from 15. Australine was isolated from Castano-
spermum austral and was found to be an inhibitor of fungal
amyloglucosidase and some glycoprotein-processing en-
zymes and also displayed antiviral activity, including anti-
HIV activity.29
Our synthetic strategy started from phthalimido inter-
mediate 15 (Scheme 6). Its iodocyclization with I2 in CH2Cl2
gave primary iodo compound 23. Zinc-mediated fragmen-
tation reaction (ring opening) of the latter in EtOH heated
to reflux furnished olefin 24 in good yield. Subsequent hy-
drolysis by heating with methylamine at 60 °C followed by
Boc-protection of the crude primary amine in CH2Cl2 using
excess triethylamine as base afforded N-Boc-protected
compound 25. We envisioned that the use of an excess of
triethylamine may lead to one-pot conversion of 25 into ox-
azolidinone 26 through simple nucleophilic attack of the al-
cohol to the carbonyl carbon of the carbamate; unfortu-
nately, no trace of oxazolidinone 26 was detected. To form
the oxazolidinone ring, we treated compound 25 with sodi-
um hydride in THF at 0 °C and, gratifyingly, obtained the
desired oxazolidinone 26 in 89% yield within three hours.
N-Alkylation of 26 was performed with sodium hydride
BnO
OBn
BnO
OBn
d
BnO
OBn
15
17
9
CbzN
HN
c
BnO
HO
BnO
OBn
HO
OH
3
18
Scheme 4 Synthesis of azocane 3. Reagents and conditions: (a) i. 40%
aq MeNH2, 60 °C, 3 h; ii. 4-bromobut-1-ene, K2CO3, DMF, 18 h, 48%
overall two steps; (b) CbzCl, Et3N, CH2Cl2, 0 °C, 2 h, 85%; (c) Grubbs II
(5 mol%), CH2Cl2 (0.01 M), reflux, 10 h, 89%; (d) H2, Pd/C, MeOH–1 N
HCl, 72 h, 90%.
In the next step compound 17 was protected as N-Cbz
by using benzyl chloroformate and triethylamine in CH2Cl2
to obtain N-Cbz protected diene 9. The poor yield of 17
could be due to the formation of dialkylated product be-
cause the mono-alkylated product was more reactive than
the free primary amine. Therefore, to avoid the dialkylation
issue, we tried to synthesize 9 through a different approach.
We first protected the free amine with a Cbz group prior to
the alkylation step to obtain mono-protected amine 16 and
then attempted the alkylation step by using 4-bromobut-1-
ene as alkylating agent in the presence of different bases.
Unfortunately alkylation did not take place with 16 to give
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
P. Das et al.
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Synthesis
and 4-bromobut-1-ene in THF to afford diene 27, the RCM
of which in CH2Cl2 heated to reflux using 5 mol% Grubbs II
catalyst afforded cyclooctene 28 in 86% yield (Scheme 6).
The spectral data and optical rotation for 28 are in complete
agreement with those reported earlier. The title natural
product 4 could be obtained from 28 in three steps by
adopting the reaction sequences reported by White et al.30
matography. All the products were characterized by 1H, 13C NMR and
IR spectroscopic analysis and by ESI-HRMS analysis. NMR spectra
were recorded with a Bruker Avance 300 MHz spectrometer at 300
MHz (1H) and 75 MHz (13C), or 400 MHz spectrometer at 400 MHz
(1H) and 100 MHz (13C). Experiments were recorded in CDCl3 and D2O
at 25 °C. Chemical shifts are given on the δ scale and are referenced
to the TMS at δ = 0.00 ppm for 1H and δ = 0.00 ppm for 13C nuclei. For
13C NMR spectra, reference CDCl3 appeared at δ = 77.40 ppm. IR spec-
tra were recorded with Perkin–Elmer 881 and FTIR-8210 PC Shimad-
zu spectrophotometers. Optical rotations were determined with an
Autopol III polarimeter and Digipol 781M6U, NOVA polarimeter using
a 1 dm cell at 17–32 °C in CHCl3/MeOH/H2O as solvents; concentra-
tions are in g/100 mL. Mass spectra were recorded with a JEOL JMS-
600H high-resolution spectrometer using EI mode at 70 eV. ESI-HRMS
were recorded with a JEOL-AccuTOF, JMS- T100LC spectrometer.
O
NPhth
NPhth
I
b
BnO
a
HO
PhthN
OBn
BnO
OBn
BnO
24
OBn
OBn
15
NHBoc
23
O
O
O
NH
N
c
HO
d
e
O
(2S,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-ol (6)
Methyltriphenyl phosphonium bromide (5.09 g, 14.27 mmol) was
taken in anhydrous THF (40 mL) and the mixture was cooled to
–20 °C. n-BuLi (2 M in cyclohexane, 3.57 mL, 7.13 mmol) was added
to the mixture dropwise under N2 atmosphere and the resulting mix-
ture was stirred for 1 h at the same temperature. Hemiacetal 12 (1 g,
2.38 mmol) in THF (20 mL) was added dropwise to the reaction mix-
ture, which was then gradually warmed to 0 °C, stirred for 1 h and for
a further 3 h at r.t. Upon completion of the reaction it was quenched
with sat. aq NH4Cl, and the mixture was extracted with EtOAc (3 × 20
mL). The combined organic layer was washed twice with brine, dried
over Na2SO4, and evaporated under reduced pressure to give a residue.
Column chromatographic purification (EtOAc/hexane, 1:7 v/v) of the
residue gave compound 6.
BnO
OBn
BnO
OBn
BnO
OBn
26
25
N
27
O
O
HO
ref: 27
N
OH
f
HO
OH
BnO
OBn
28
(+)-australine (4)
Scheme 6 Reagents and conditions: (a) I2, CH2Cl2, 0 °C to r.t., 3 h, 84%;
(b) Zn, EtOH, 80 °C, 82%; (c) i. 40% aq MeNH2, 60 °C, 3 h; ii. Boc2O,
Et3N, CH2Cl2, for two steps 66%; d. NaH, THF, 89%; (e) 4-bromobut-1-
ene, NaH, THF, cat. TBAI, 0 °C to r.t., 78%; f. Grubbs II (5 mol%), CH2Cl2
(0.01 M), reflux, 10 h, 86%.
Yield: 0.714 g (1.71 mmol, 72%); colorless oil; Rf = 0.4 (EtOAc/hexane,
1:4); [α]D28 +3.4 (c 0.53, CHCl3).
IR (neat): 3435, 3028, 2870, 1751 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.20 (m, 15 H), 5.83–5.74 (m,
1 H), 5.31–5.25 (m, 2 H), 4.78 (d, J = 11.2 Hz, 1 H), 4.56–4.46 (m, 2 H),
4.39–4.28 (m, 3 H), 4.02 (dd, J = 6.8, 7.5 Hz, 1 H), 3.84 (br s, 1 H), 3.54–
3.52 (m,1 H), 3.39–3.31 (m, 2 H), 2.41 (br s,1 H).
13C NMR (100 MHz, CDCl3): δ = 138.7, 138.6, 138.4, 135.6, 128.7,
128.7, 128.6, 128.6, 128.2, 128.1, 128.1, 128.0, 119.7, 82.5, 80.6, 75.4,
73.6, 71.5, 71.0, 70.3.
We have demonstrated a new concise total synthesis of
D-fagomine 1, azepane 2, and eight-membered iminosugar
3 from L-xylose-derived common chiron 6. Mitsunobu ami-
nation and ring-closing metathesis were the key steps for
the synthesis of D-fagomine and azepines, respectively. The
synthetic strategy discussed herein can easily be applied to
the preparation of a broad range of biologically active poly-
hydroxylated compounds or other natural product ana-
logues containing a nitrogen atom in the ring. The formal
synthesis of (+)-australine was also exemplified from the
same chiron 6. The iodocyclization reaction of 15 and zinc-
mediated fragmentation are the key steps here. The azacy-
clooctene precursor 28 was generated by ring-closing me-
tathesis. Unsaturated iminocycloheptene 8 and iminocy-
clooctene 18 will undoubtedly find applications as useful
chiral building blocks in the synthesis of a variety of biolog-
ically relevant molecules, including natural products.
HRMS (DART): m/z [M + H]+ calcd for C27H30O4: 419.2222; found:
419.2217.
(3R,4R,5R)-3,4,6-Tris(benzyloxy)hexane-1,5-diol (13)
BH3·Me2S (10 M in THF, 0.25 mL, 2.54 mmol) was added dropwise to a
solution of 6 (531 mg, 1.27 mmol) in anhydrous THF (10 mL) at 0 °C
and the solution was allowed to warm to r.t. and stirred for 3 h. Upon
complete consumption of starting material, 3 N aqueous NaOH (3 mL,
9 mmol) was added carefully at 0 °C followed by 30% aq H2O2 (0.5 mL)
and the mixture was stirred at r.t. for 3 h. The organic layer was ex-
tracted with EtOAc (4 × 10 mL), washed with brine (20 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography (EtOAc/hexane, 2:3
v/v) over 100–200 mesh silica gel to afford alcohol 13.
Organic solvents were dried by using standard methods. Analytical
TLC was performed using 2.5 × 5 cm plates coated with a 0.25 mm
thickness of silica gel (60F-254), visualization was achieved with
CeSO4 and subsequent charring over a hot plate. Silica gel (60–120
mesh, 100–200 mesh, and 230–400 mesh) was used in column chro-
Yield: 430 mg (0.99 mmol, 78%); colorless oil; Rf = 0.4 (EtOAc/hexane,
2:1); [α]D28 +29.4 (c 4.30, CHCl3).
IR (neat): 3401, 3020, 2925, 1731, 1654 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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P. Das et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.25–7.17 (m, 15 H), 4.67–4.55 (m,
2 H), 4.50–4.35 (m, 4 H), 3.87 (br s, 1 H), 3.80–3.76 (m, 1 H), 3.64–
3.61 (m, 3 H), 3.39 (ddd, J = 6.2, 9.5, 15.5 Hz, 2 H), 2.57 (br s, 1 H), 2.18
(br s, 1 H), 1.88–1.81 (m, 1 H), 1.76–1.69 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.5, 138.3, 138.2, 128.8, 128.7,
128.7, 128.5, 128.3, 128.2, 128.1, 128.1, 128.0, 79.3, 78.2, 74.8, 73.6,
73.4, 71.7, 69.6, 60.4, 33.6.
2-[(2R,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-yl]isoindoline-1,3-
dione (15)
A solution of phthalimide (684 mg, 4.66 mmol), triphenyl phosphine
(1.22 g, 4.66 mmol), and alcohol 6 (1.3 g, 3.11 mmol) in anhydrous
THF (30 mL) was cooled to –20 °C under argon atmosphere. A solution
of DIAD (0.916 mL, 4.66 mmol) in anhydrous THF (10 mL) was added
dropwise to the solution and the reaction mixture was stirred at the
same temperature for 2 h and then overnight at r.t. The reaction mix-
ture was evaporated under reduced pressure and purified by column
chromatography (EtOAc/hexane, 1:12 v/v) to give 15.
HRMS (DART): m/z [M + H]+ calcd for C27H33O5: 437.2328; found:
437.2424.
Yield: 1.15 g (2.11 mmol, 68%); colorless semisolid; Rf = 0.62 (EtOAc/
hexane, 1:4); [α]D28 +144.9 (c 0.3660, CHCl3).
(2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-[(benzyloxy)meth-
yl]piperidine (5)
IR (neat): 3432, 2924, 2852, 1453 cm–1
.
To a solution of diol 13 (380 mg, 0.87 mmol) dissolved in CH2Cl2 (8
mL) was added Et3N (0.3 mL, 2.18 mmol), methanesulfonyl chloride
(0.17 mL, 2.18 mmol), and a catalytic amount of DMAP at 0 °C. The
reaction mixture was then stirred at r.t. for 2 h. Upon completion of
the reaction (monitored by TLC) it was quenched with H2O (10 mL)
and the mixture was extracted with CH2Cl2. The organic layer was
dried over Na2SO4 and concentrated in vacuo. The crude dimesylate
product was carried on to the next step without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 2 H), 7.56–7.54 (m, 2 H),
7.22–7.00 (m, 15 H), 5.90–5.81 (m, 1 H), 5.25–5.17 (m, 2 H), 4.76–
4.62 (m, 2 H), 4.50–4.28 (m, 5 H), 4.14–4.11 (m, 1 H), 4.00 (t, J =
10.2 Hz, 1 H), 3.84–3.82 (m, 1 H), 3.78–3.74 (m,1 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 138.5, 138.1, 138.0, 135.0,
133.9, 132.4, 128.7, 128.5, 128.5, 128.4, 128.3, 128.1, 127.9, 127.7,
127.6, 123.4, 119.9, 80.6, 77.9, 74.7, 72.9, 71.0, 67.7, 51.2.
The dimesylate was dissolved in benzylamine (2 mL) and the reaction
mixture was heated at 80 °C for 3 h, then diluted with Et2O and
washed with 1 N HCl, H2O, and brine. The combined organic layer was
dried over Na2SO4, concentrated, and purified by column chromatog-
raphy (EtOAc/hexane, 1:12 v/v) to give 5.
HRMS (DART): m/z [M + H]+ calcd for C35H34NO5: 548.2437; found:
548.2449.
Benzyl [(2R,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-yl]carbamate
(16)
Yield: 290 mg (0.57 mmol, 66%); colorless oil; Rf = 0.62 (EtOAc/hex-
ane, 1:4); [α]D28 +128.6 (c 0.20, CHCl3).
A solution of 15 (520 mg, 0.95 mmol) in aq MeNH2 (10 mL, 40%), was
stirred in an open flask for 1.5 h at 50 °C, then concentrated under re-
duced pressure, dissolved in H2O (10 mL) and the mixture was ex-
tracted with EtOAc (3 × 10 mL), dried over Na2SO4, and evaporated
under reduced pressure.
IR (neat): 2924, 2853, 1453, 1092 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.14 (m, 20 H), 4.87 (d, J =
10.9 Hz, 1 H), 4.60–4.41 (m, 5 H), 4.03 (d, J = 13.7 Hz, 1 H), 3.77–3.70
(m, 2 H), 3.58–3.51 (m, 1 H), 3.41–3.35 (m, 1 H), 3.26 (d, J = 13.7 Hz,
1 H), 2.75–2.71 (m, 1 H), 2.32 (d, J = 9.1 Hz, 1 H), 1.97–1.86 (m, 2 H),
1.59–1.44 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 139.3, 139.2, 138.6, 129.5, 128.7,
128.5, 128.4, 128.4, 128.0, 127.9, 127.9, 127.8, 127.2, 82.4, 79.5, 75.3,
73.6, 71.6, 67.6, 65.6, 57.6, 49.7, 29.1.
To a solution of crude amine in CH2Cl2 (15 mL), Et3N (0.95 mmol,
0.132 mL) was added at 0 °C and, after 5 min, benzyl chloroformate
(0.11 mL, 0.95 mmol) was added dropwise at the same temperature
and the mixture was stirred for 2 h at r.t. Upon completion of the re-
action, the mixture was extracted with CH2Cl2 (3 × 10 mL) and the
combined organic layer was dried over Na2SO4, evaporated under re-
duced pressure, and the residue was purified by column chromatog-
raphy (EtOAc/hexane, 1:8 v/v) to give 16.
HRMS (DART): m/z [M + H]+ calcd for C34H38NO3: 508.2852; found:
508.2847.
Yield: 340 mg (0.62 mmol, 65% for 2 steps); colorless oil; Rf = 0.48
(EtOAc/hexane, 1:4); [α]D28 –16.3 (c 0.16, CHCl3).
(2R,3R,4R)-2-(Hydroxymethyl)piperidine-3,4-diol (1)
IR (neat): 3446, 2925, 2853, 1693, 1455 cm–1
.
A catalytic amount of 10% Pd/C (20 mg) was added to a solution of 5
(90 mg, 0.177 mmol) in a mixture of MeOH and 1 N HCl (4:1 v/v, 5
mL). A vacuum was applied briefly, then the reaction mixture was
stirred under a positive pressure of H2 in a balloon. Upon completion
of the reaction (monitored by TLC, 48 h), the catalyst was removed by
filtration, washed with MeOH twice and the combined washings was
filtered and concentrated to give the HCl salt of fagomine 1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.15 (m, 20 H), 5.90–5.81 (m,
1 H), 5.52 (d, J = 6.3 Hz, 1 H), 5.22–5.13 (m, 2 H), 4.98 (br s, 2 H), 4.53–
4.46 (m, 3 H), 4.34–4.27 (m, 2 H), 4.18–4.15 (m, 2 H), 3.90–3.88 (m,
1 H), 3.60–3.49 (m, 2 H), 3.34–3.30 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 156.5, 138.5, 138.3, 138.2, 137.1,
135.6, 128.8, 128.7, 128.7, 128.6, 128.4, 128.3, 128.1, 128.0, 119.5,
81.3, 80.0, 73.9, 73.4, 70.8, 69.2, 66.8, 51.4.
26
Yield: 17 mg (0.12 mmol, 68%); colorless semisolid; [α]D +7.9 (c
0.24, CH3OH) {Lit.22 [α]D29 +8.4 (c 0.27, CH3OH)}.
HRMS (DART): m/z [M + H]+ calcd for C35H38NO5: 552.2750; found:
552.2720.
IR (neat): 3685, 3409, 3022, 2410 cm–1
.
1H NMR (400 MHz, D2O): δ = 3.97–3.95 (m, 2 H), 3.77 (m, 1 H), 3.61–
3.48 (m, 2 H), 3.19–3.12 (m, 1 H), 2.28–2.25 (m, 1 H), 1.80–1.77 (m,
1 H).
Benzyl Allyl[(2R,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-yl]carba-
mate (7)
13C NMR (100 MHz, D2O): δ = 70.6, 69.7, 60.2, 57.9, 42.0, 28.7.
HRMS (DART): m/z [M + H]+ calcd for C6H14NO3: 148.1802; found:
A solution of amine 16 (310 mg, 0.562 mmol) in THF (5 mL) was treat-
ed sequentially with NaH (34 mg, 0.843 mmol) and allyl bromide
(0.073 mL, 0.843 mmol) at 0 °C. Upon completion of the reaction, H2O
(30 mL) was added and the mixture was extracted with EtOAc (3 × 20
mL). The combined organic layer was washed with brine, dried over
148.0969.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
P. Das et al.
Paper
Synthesis
anhydrous Na2SO4, evaporated under reduced pressure, and the resi-
due was purified by column chromatography (EtOAc/hexane, 1:9 v/v)
to give 7.
(2R,3R,4R)-1,3,4-Tris(benzyloxy)-N-(but-3-en-1-yl)hex-5-en-2-
amine (17)
Compound 15 (520 mg, 0.95 mmol) was dissolved in aq MeNH2 (15
mL, 40%), and the resulting mixture was stirred in an open flask for
1.5 h at 50 °C. The reaction mixture was then concentrated under re-
duced pressure, and the residue was dissolved in H2O (15 mL) and ex-
tracted with EtOAc (3 × 15 mL). The combined organic extracts were
washed with brine, dried over Na2SO4, and evaporated under reduced
pressure. The crude material was used for the next step without puri-
fication.
Yield: 0.312 g (0.495 mmol, 88%); yellowish oil; Rf = 0.52 (EtOAc/hex-
ane, 1:4); [α]D28 +51.1 (c 0.66, CHCl3).
IR (neat): 3402, 3019, 2866, 1633 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.18 (m, 20 H), 5.84–5.71 (m,
2 H), 5.23–4.8 (m, 6 H), 4.71–4.64 (m, 1 H), 4.48–4.20 (m, 6 H), 3.84–
3.62 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 156.6, 138.7, 136.3, 135.9, 128.8,
128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.8, 119.5, 115.9, 82.4, 82.1,
81.7, 75.1, 73.2, 70.9, 68.4, 67.6, 67.3.
To a solution of crude amine in DMF (10 mL), K2CO3 (190 mg, 1.38
mmol) was added at 0 °C and, after 5 min, 4-bromobut-1-ene (95%;
0.122 mL, 1.15 mmol) was added dropwise at the same temperature
and the mixture was stirred for 12 h at r.t. Upon completion of the
reaction, H2O was added and the mixture and was extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried over Na2SO4,
evaporated under reduced pressure and the residue was purified by
column chromatography (EtOAc/hexane, 1:7 v/v) to give 17.
HRMS (DART): m/z [M + H]+ calcd for C38H42NO5: 592.3063; found:
592.3068.
(2R,3R,4R)-Benzyl 3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-
2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (8)
Yield: 215 mg (0.46 mmol, 48% for 2 steps); colorless oil; Rf = 0.5
(EtOAc/hexane, 1:3); [α]D28 –1.5 (c 0.90, CHCl3).
To a 50 mL two-necked, oven-dried, round-bottom flask fitted with a
reflux condenser and septum was added Grubbs II catalyst (12 mg,
0.014 mmol) under argon atmosphere. Anhydrous CH2Cl2 (5 mL) was
then added and the solution was stirred. Compound 7 (171 mg, 0.289
mmol) in CH2Cl2 (20 mL) was added to the stirring reaction mixture,
which was then heated at reflux for 6 h. The temperature of the reac-
tion mixture was brought slowly to r.t. and the organic solvent was
evaporated under reduced pressure to give a black residue, which was
purified by column chromatography (EtOAc/hexane, 1:8, v/v) to give
8.
IR (neat): 3317, 2925, 1640 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.16 (m, 15 H), 5.85–5.76 (m,
1 H), 5.69–5.59 (m, 1 H), 5.22–5.18 (m, 2 H), 4.96–4.87 (m, 2 H), 4.67–
4.27 (m, 7 H), 4.07 (dd, J = 4.8, 7.5 Hz, 1 H), 3.58–3.48 (m, 1 H), 2.87–
2.83 (m, 1 H), 2.57–2.51 (m, 1 H), 2.43–2.37 (m, 1 H), 2.02 (dd, J = 6.9,
13.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 139.3, 139.0, 138.9, 137.1, 136.5,
129.0, 128.7, 128.6, 128.6, 128.4, 128.4, 128.1, 128.0, 127.9, 127.8,
127.8, 127.4, 118.6, 116.3, 81.9, 81.6, 75.2, 73.5, 71.0, 69.1, 65.8, 58.6,
47.3, 35.1.
Yield: 149 mg (0.266 mmol, 92%); colorless liquid; Rf = 0.5 (EtOAc/
hexane, 1:4); [α]D28 –23.8 (c 0.860, CHCl3).
IR (neat): 3435, 3066, 3014, 1641 cm–1
.
HRMS (DART): m/z [M + H]+ calcd for C31H38NO3: 472.2852; found:
472.2818.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.11 (m, 20 H), 5.63–5.62 (m,
2 H), 5.05–5.04 (m, 2 H), 4.87–4.81 (m, 1 H), 4.71–4.55 (m, 2 H), 4.50–
4.15 (m, 6 H), 3.79–3.63 (m, 3 H), 3.54–3.43 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ (rotamers) = 156.6, 156.4, 128.8, 128.7,
128.5, 128.3, 128.2, 128.0, 128.0, 127.9, 80.8, 80.5, 80.3, 75.2, 75.0,
74.1, 73.8, 73.3, 73.2, 69.7, 67.9, 67.7, 58.4, 58.0, 43.3.
Benzyl But-3-en-1-yl[(2S,3R,4R)-1,3,4-tris(benzyloxy)hex-5-en-2-
yl]carbamate (9)
To a solution of amine 17 (298 mg, 0.63 mmol) in CH2Cl2 (5 mL), sat.
aq sodium bicarbonate (5 mL) was added at 0 °C and, after 5 min, ben-
zyl chloroformate (0.11 mL, 0.95 mmol) was added dropwise at the
same temperature and the mixture was stirred for 2 h at r.t. Upon
completion of the reaction, the mixture was extracted with CH2Cl2
(3 × 10 mL) and the combined organic layer was dried over Na2SO4,
evaporated under reduced pressure, and purified by column chroma-
tography (EtOAc/hexane, 1:19 v/v) to give 9.
HRMS (DART): m/z [M + H]+ calcd for C36H38NO5: 564.2750; found:
564.2743.
(2R,3R,4R)-2-(Hydroxymethyl)azepane-3,4-diol (2)
A catalytic amount of 10% Pd/C (20 mg) was added to a solution of 8
(80 mg, 0.142 mmol) in a mixture of MeOH and 1 N HCl (4:1 v/v, 5
mL). A vacuum was applied briefly, then the reaction mixture was
stirred under a positive pressure of H2 in a balloon. Upon completion
of the reaction (monitored by TLC, 48 h), the catalyst was removed by
filtration, washed with MeOH twice, and the combined filtrate was
concentrated to afford the crude compound, which was purified by
column chromatography (Et2O–MeOH–NH2OH, 10:40:2 v/v/v) to give
2.
Yield: 324 mg (0.635 mmol, 84%); colorless oil; Rf = 0.5 (EtOAc/hex-
ane, 1:9); [α]D28 +10.0 (c 3.25, CHCl3).
IR (neat): 3400, 3019, 2926, 1641 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.12 (m, 20 H), 5.89–5.47 (m,
2 H), 5.22–4.59 (m, 7 H), 4.48–4.17 (m, 6 H), 3.87–3.54 (m, 4 H), 3.28–
2.99 (m, 2 H), 2.34–2.20 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 156.3, 138.7, 138.6, 137.3, 136.9,
136.1, 136.0, 135.9, 128.8, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9,
127.8, 119.4, 116.3, 82.5, 82.0, 81.6, 75.2, 73.2, 70.9, 68.6, 67.5, 67.1,
34.1.
Yield: 18 mg (0.1 mmol, 79%); colorless oil; [α]D28 +6.2 (c 1.0, CH3OH).
IR (neat): 3478, 3066, 2985, 1693 cm–1
.
1H NMR (400 MHz, D2O): δ = 4.00–3.71 (m, 4 H), 3.37–3.25 (m, 3 H),
HRMS (DART): m/z [M + H]+ calcd for C39H44NO5: 606.3219; found:
606.3213.
2.08–1.76 (m, 4 H).
13C NMR (100 MHz, D2O): δ = 73.6, 71.9, 60.2, 59.5, 45.9, 28.3, 18.9.
HRMS (DART): m/z [M + H]+ calcd for C7H16NO3: 162.1130; found:
162.1126.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
P. Das et al.
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Synthesis
(2R,3R,4R,Z)-Benzyl 3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-
3,4,7,8-tetrahydroazocine-1(2H)-carboxylate (18)
1H NMR (400 MHz, CDCl3): δ = 7.26–7.18 (m, 15 H), 5.87 (ddd, J = 8.2,
10.1, 17.8 Hz, 1 H), 5.24–5.15 (m, 3 H), 4.59–4.49 (m, 3 H), 4.33 (dd,
J = 11.9, 17.8 Hz, 2 H), 4.19 (d, J = 11.6 Hz, 1 H), 4.10 (m, 1 H), 3.91 (dd,
J = 4.4, 7.9 Hz, 1 H), 3.60 (t, J = 4.7 Hz, 1 H), 3.52–3.48 (m, 1 H), 3.32
(dd, J = 6.4, 9.6 Hz, 1 H), 1.34 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 156.0, 138.7, 138.5, 138.3, 135.7,
128.7, 128.6, 128.6, 128.5, 128.4, 128.1, 128.0, 119.4, 81.6, 80.4, 79.3,
74.0, 73.3, 70.8, 69.4, 50.7, 28.7.
To a 100 mL two-necked, oven-dried, round-bottom flask fitted with
a reflux condenser and septum was added Grubbs II catalyst (19 mg,
0.024 mmol) under argon atmosphere. Anhydrous CH2Cl2 (5 mL) was
then added and the solution was stirred. Compound 9 (271 mg, 0.446
mmol) in CH2Cl2 (40 mL) was added to the stirring reaction mixture,
which was then heated at reflux for 6 h. The temperature of the reac-
tion mixture was brought slowly to r.t. and the organic solvent was
evaporated under reduced pressure to give a black residue, which was
purified by column chromatography (EtOAc/hexane, 1:20 v/v) to give
18.
HRMS (DART): m/z [M + H]+ calcd for C32H40NO5: 518.2906; found:
518.2909.
4-Methyl-N-[(2R,3R,4R)-1,3,4-tris(benzyloxy)hex-5-en-2-yl]ben-
zenesulfonamide (21)
Yield: 149 mg (0.229 mmol, 92%); colorless liquid; Rf = 0.5 (EtOAc/
hexane, 1:9); [α]D28 +86.0 (c 0.20, CHCl3).
To a stirred solution of crude amine, obtained from hydrolysis of 15
(120 mg, 0.288 mmol) in CH2Cl2 (5 mL), Et3N (0.06 mL, 0.43 mmol)
and a catalytic amount DMAP were added at 0 °C. After 5 min, p-tol-
uenesulfonyl chloride (82 mg, 0.43 mmol) was added and the mixture
was stirred for 3 h. H2O was added to the reaction mixture, which was
then extracted with CH2Cl2, dried over Na2SO4, and concentrated un-
der reduced pressure to give a residue, which was purified by column
chromatography (EtOAc/hexane, 1:9, v/v) to give 21.
IR (neat): 3401, 3019, 2925, 1644 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.14 (m, 20 H), 5.76–5.47 (m,
2 H), 4.90–3.96 (m, 10 H), 3.84–3.65 (m, 3 H), 3.21–2.79 (m, 2 H),
2.33–1.96 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 156.4, 155.5, 139.0, 138.9, 138.7,
138.4, 137.3, 136.8, 132.7, 132.2, 129.8, 128.7, 128.7, 128.6, 128.6,
128.6, 128.5, 128.4, 128.3, 128.3, 128.1, 128.0, 127.9, 127.9, 127.8,
127.7, 127.7, 80.9, 79.9, 78.6, 74.9, 73.3, 73.2, 71.8, 71.7, 70.1, 69.3,
67.5, 66.7, 63.2, 61.7, 48.8, 27.4, 27.3.
Yield: 123 mg (0.236 mmol, 75% from crude); colorless oil; Rf = 0.5
(EtOAc/hexane, 1:4); [α]D28 –21.5 (c 0.36, CHCl3).
IR (neat): 3436, 2953, 2923, 2111 cm–1
.
HRMS (DART): m/z [M + H]+ calcd for C37H40NO5: 578.2906; found:
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.3 Hz, 2 H), 7.33–7.24 (m,
11 H), 7.16–7.13 (m, 6 H), 5.84–5.75 (m, 1 H), 5.57 (d, J = 7.1 Hz, 1 H),
5.24–5.17 (m, 2 H), 4.54 (d, J = 11.5 Hz, 1 H), 4.42–4.39 (m, 1 H), 4.32–
4.27 (m, 3 H), 4.21–4.18 (m, 1 H), 4.01 (dd, J = 3.7, 7.9 Hz, 1 H), 3.72–
3.67 (m, 1 H), 3.60–3.57 (m, 2 H), 3.22–3.18 (m, 1 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 143.4, 138.4, 138.1, 138.1, 138.0,
135.7, 129.8, 128.7, 128.7, 128.6, 128.2, 128.1, 128.0, 127.6, 119.5,
80.4, 80.2, 74.1, 73.4, 70.9, 69.0, 53.7, 21.8.
578.2903.
(2R,3R,4R)-2-(Hydroxymethyl)azocane-3,4-diol (3)
To a solution of 18 (160 mg, 0.277 mmol), in MeOH (5 mL) and concd
HCl (0.5 mL), was added Pd/C (15 mg) and the resulting mixture was
stirred under positive pressure of hydrogen for 3 days. Upon comple-
tion of reaction, the catalyst was removed by filtration and washed
twice with methanol. The solution was concentrated in vacuo and
purified by flash column chromatography (Et2O–MeOH–NH2OH,
30:20:1 v/v/v) to give 3.
HRMS (DART): m/z [M + H]+ calcd for C34H38NO5S: 572.2471; found:
572.2476.
28
Yield: 42 mg (0.244 mmol, 90%); colorless semisolid; [α]D –6.7 (c
0.75, H2O).
IR (neat): 3385, 3264, 3014, 2951 cm–1
2-[(3R,4R,5S)-4,5-Bis(benzyloxy)-6-(iodomethyl)tetrahydro-2H-
pyran-3-yl]isoindoline-1,3-dione (23)
.
1H NMR (400 MHz, D2O): δ = 4.08–3.91 (m, 4 H), 3.41–3.27 (m, 3 H),
2.03–1.75 (m, 6 H).
13C NMR (100 MHz, D2O): δ = 72.6, 68.4, 59.3, 59.0, 46.4, 28.3, 23.3,
18.4.
HRMS (DART): m/z [M + H]+ calcd for C8H18NO3: 176.1287; found:
176.1273.
To a stirred solution of 15 (1 g, 1.83 mmol) in CH2Cl2 (20 mL), I2 (702
mg, 2.74 mmol) was added at r.t. Upon completion of the reaction
(monitored by TLC), the mixture was diluted with CH2Cl2 and washed
sequentially with aq Na2S2O3 and brine. The aqueous layer was
washed with CH2Cl2 (3 × 10 mL) and the combined organic layers
were dried over Na2SO4, evaporated, and purified by column chroma-
tography (EtOAc/hexane, 1:8 v/v) to give 23.
Yield: 928 mg (1.59 mmol, 84%); pale yellow liquid; Rf = 0.4 (EtOAc/
hexane, 1:4); [α]D28 +67.4 (c 2.80, CHCl3).
tert-Butyl [(2R,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-yl]carba-
mate (19)
IR (neat): 3405, 3026, 3014, 1641 cm–1
.
To a stirred solution of crude amine obtained from hydrolysis of 15
(120 mg, 0.288 mmol) in CH2Cl2 (5 mL), Et3N (0.06 mL, 0.43 mmol)
and a catalytic amount DMAP were added at 0 °C. After 5 min,
(Boc)2O (0.1 mL, 0.43 mmol) was added to the reaction mixture and
stirring was continued for 2 h. H2O was added and the resulting mix-
ture was extracted with CH2Cl2 and the organic layer was concentrat-
ed under reduced pressure to give a residue, which was purified by
column chromatography (EtOAc/hexane, 1:9 v/v) to give 19.
1H NMR (400 MHz, CDCl3): δ = 7.75–7.17 (m, 10 H), 6.89–6.83 (m,
4 H), 4.95–4.41 (m, 5 H), 4.24–3.99 (m, 2 H), 3.90–3.72 (m, 3 H), 3.42–
3.21 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 168.5, 138.5, 137.7, 137.5,
134.5, 134.4, 134.1, 132.1, 132.0, 129.0, 128.8, 128.6, 128.5, 128.5,
128.3, 128.2, 128.2, 128.1, 128.0, 79.9, 78.8, 78.0, 76.4, 74.9, 73.4,
73.3, 72.8, 72.2, 66.9, 63.9, 49.7, 48.9, 6.1, 3.1.
HRMS (DART): m/z [M + H]+ calcd for C28H27INO5: 584.0934; found:
584.0921.
Yield: 113 mg (0.218 mmol, 76% from crude); yellowish oil; Rf = 0.5
(EtOAc/hexane, 1:4); [α]D28 –12.3 (c 5.0, CHCl3).
IR (neat): 3415, 2926, 2870, 1708 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
P. Das et al.
Paper
Synthesis
2-[(2R,3R,4R)-3,4-Bis(benzyloxy)-1-hydroxyhex-5-en-2-yl]isoin-
(R)-4-[(1R,2R)-1,2-Bis(benzyloxy)but-3-en-1-yl]oxazolidin-2-one
doline-1,3-dione (24)
(26)
To a magnetically stirred suspension of Zn dust (836 mg, 12.86 mmol)
in anhydrous MeOH (10 mL), a solution of 23 (750 mg, 1.286 mmol)
in anhydrous MeOH (10 mL) was added and the resulting solution
was heated at reflux for 2 h. The mixture was filtered through a Celite
bed and the filtrate was evaporated under reduced pressure. The resi-
due obtained was dissolved in EtOAc (25 mL) and washed with a mix-
ture of brine and water (1:1 v/v, 10 mL each). The organic layer was
dried over Na2SO4, concentrated, and purified by column chromatog-
raphy (EtOAc/hexane, 1:5, v/v) to give alcohol 24.
To an ice-cooled solution of alcohol 25 (150 mg, 0.35 mmol) in anhy-
drous THF (5 mL) was added sodium hydride (21 mg, 0.526 mmol), in
one portion, under nitrogen atmosphere and the mixture was stirred
for 1 h at the same temperature. Upon completion the reaction was
quenched by addition of sat. aq NH4Cl, and the mixture was extracted
with EtOAc (3 × 5 mL). The combined organic phase was dried
(Na2SO4) and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane, 1:5 v/v)
to give 26.
Yield: 482 mg (1.055 mmol, 82%); colorless liquid; Rf = 0.4 (EtOAc/
hexane, 1:2); [α]D28 +31.8 (c 1.25, CHCl3).
Yield: 110 mg (0.311 mmol, 89%); colorless oil; Rf = 0.4 (EtOAc/hex-
ane, 1:2); [α]D28 +24.6 (c 2.30, CHCl3).
IR (neat): 3435, 3066, 3014, 1641 cm–1
.
IR (neat): 3306, 2915, 1758, 1240 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.61–7.58 (m, 2 H), 7.56–7.53 (m, 2 H),
7.30–7.18 (m, 5 H), 7.02–6.94 (m, 5 H), 5.85 (ddd, J = 7.5, 10.5,
17.7 Hz, 1 H), 5.27–5.18 (m, 2 H), 4.68 (dd, J = 11.1, 17.6 Hz, 2 H),
4.52–4.44 (m, 2 H), 4.25 (d, J = 11.3 Hz, 1 H), 4.09–3.93 (m, 3 H), 3.88
(dd, J = 3.7, 7.5 Hz, 1 H), 2.75 (d, J = 6.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.4, 138.1, 137.9, 134.5, 134.2,
132.2, 128.8, 128.7, 128.4, 128.3, 128.2, 127.6, 123.5, 120.4, 81.1, 76.9,
74.8, 71.3, 63.1, 53.0.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.14 (m, 10 H), 5.82–5.75 (m,
1 H), 5.69 (s, 1 H), 5.33–5.28 (m, 2 H), 4.58–4.55 (m, 2 H), 4.4 (d, J =
11.5 Hz, 1 H), 4.28–4.23 (m, 2 H), 4.18–4.15 (m, 1 H), 3.94–3.92 (m,
1 H), 3.90–3.86 (m, 1 H), 3.46 (dd, J = 4.3, 6.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 159.9, 137.8, 137.6, 134.2, 128.9,
128.8, 128.4, 128.4, 128.3, 119.8, 81.1, 79.4, 74.4, 71.2, 67.7, 53.2.
HRMS (DART): m/z [M + H]+ calcd for C21H24NO4: 354.1705; found:
354.1712.
HRMS (DART): m/z [M + H]+ calcd for C28H28NO5: 458.1967; found:
458.1956.
(R)-4-[(1R,2R)-1,2-Bis(benzyloxy)but-3-en-1-yl]-3-(but-3-en-1-
yl)oxazolidin-2-one (27)
tert-Butyl [(2R,3R,4R)-3,4-Bis(benzyloxy)-1-hydroxyhex-5-en-2-
yl]carbamate (25)
A solution of oxazolidinone 26 (90 mg, 0.255 mmol) in THF (4 mL)
was treated sequentially with NaH (15 mg, 0.382 mmol) and 4-bro-
mobut-1-ene (0.093 mL, 0.383 mmol) at 0 °C, and the mixture was
stirred for 3 h at r.t. Upon completion of the reaction the mixture was
diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic extract was washed with brine, dried (Na2SO4),
evaporated under reduced pressure, and purified by column chroma-
tography (EtOAc/hexane, 1:3 v/v) to give 27.
Compound 24 (520 mg, 0.95 mmol) was dissolved in aq MeNH2 (10
mL, 40%), and the resulting mixture was stirred in an open flask for
1.5 h at 60 °C. The reaction mixture was then concentrated under re-
duced pressure, dissolved in H2O (15 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic extracts were washed with brine,
dried over Na2SO4, and evaporated under reduced pressure. The crude
amine was used for the next step without further purification.
Yield: 72 mg (0.199 mmol, 78%); colorless oil; Rf = 0.5 (EtOAc/hexane,
1:1); [α]D28 +20.8 (c 0.60, CHCl3).
To a stirred solution of crude amine in CH2Cl2 (15 mL), Et3N (0.396 mL,
2.85 mmol) and a catalytic amount DMAP were added at 0 °C. After 5
min, (Boc)2O (0.22 mL, 0.43 mmol) was added and stirring was con-
tinued for 2 h. H2O was added to the reaction mixture, which was
then extracted with CH2Cl2 and concentrated under reduced pressure
to give a residue, which was purified by column chromatography
(EtOAc/hexane, 1:8 v/v) to give 25.
IR (neat): 2981, 1748, 1425, 1370 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.17 (m, 10 H), 5.74 (ddd, J = 7.2,
10.6, 17.5 Hz, 1 H), 5.66–5.56 (m, 1 H), 5.33–5.26 (m, 2 H), 4.97–4.93
(m, 2 H), 4.65 (d, J = 11.7 Hz, 1 H), 4.57 (d, J = 5.5, 8.6 Hz, 1 H), 4.49 (d,
J = 11.7, 1 H), 4.42 (dd, J = 5.5, 8.7 Hz, 1 H), 4.27 (d, J = 11.9 Hz, 1 H),
4.05 (t, J = 8.6 Hz, 1 H), 3.86–3.82 (m, 2 H), 3.63 (dd, J = 0.7, 5.1 Hz,
1 H), 3.40–3.32 (m, 1 H), 2.54–2.48 (m, 1 H), 2.17–2.06 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.7, 138.1, 137.9, 135.0, 134.8,
128.9, 128.5, 128.4, 128.3, 128.1, 119.9, 117.7, 80.5, 76.7, 74.2, 71.2,
63.2, 56.0, 40.8, 31.7.
Yield: 268 mg (0.628 mmol, 66% from crude); colorless liquid; Rf = 0.4
(EtOAc/hexane, 1:3); [α]D28 +19.5 (c 3.50, CHCl3).
IR (neat): 3389, 2972, 2928, 1703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.22 (m, 10 H), 5.86–5.77 (m,
1 H), 5.32–5.21 (m, 3 H), 4.75–4.72 (m, 1 H), 4.56 (dd, J = 7.4, 11.6 Hz,
2 H), 4.29 (d, J = 11.7 Hz, 1 H), 3.94–3.90 (m, 1 H), 3.75–3.69 (m, 3 H),
3.52 (d, J = 8.2 Hz, 1 H), 2.74 (s, 1 H), 1.34 (s, 9 H).
HRMS (DART): m/z [M + H]+ calcd for C25H30NO4: 408.2175; found:
408.2169.
13C NMR (100 MHz, CDCl3): δ = 156.5, 138.4, 138.3, 135.0, 128.9,
128.8, 128.5, 128.3, 128.1, 120.3, 82.7, 79.8, 75.2, 70.9, 63.1, 52.6,
28.7.
HRMS (DART): m/z [M + H]+ calcd for C25H34NO5: 428.2437; found:
428.2433.
(9R,10R,10aR,Z)-9,10-Bis(benzyloxy)-5,6,10,10a-tetrahydro-1H-
oxazolo[3,4-a]azocin-3(9H)-one (28)
To a 50 mL two-necked, oven-dried, round-bottom flask fitted with a
reflux condenser and septum was added Grubbs II catalyst (6 mg,
0.007 mmol) under argon atmosphere. Anhydrous CH2Cl2 (2 mL) was
then added to the flask through a syringe and the solution was kept
stirring. Compound 27 (53 mg, 0.130 mmol) in CH2Cl2 (10 mL) was
added through a syringe to the stirring reaction mixture and the solu-
tion was heated at reflux for 6 h. The temperature of the reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
P. Das et al.
Paper
Synthesis
mixture was brought slowly to r.t. and the organic solvent was evapo-
rated under reduced pressure to give a black residue, which was puri-
fied by column chromatography (EtOAc/hexane, 1:2 v/v) to give 28.
A.; Grelli, S.; Cardona, F.; Cordero, F. M.; Mastino, A.; Brandi, A.
Glycobiology 2010, 5, 500. (q) Holman, R. R.; Cull, C. A.; Turner,
R. C. Diabetes Care 1999, 22, 960. (r) Scott, L. J.; Spencer, C. M.
Drugs 2000, 59, 521. (s) Treadway, J. L.; Mendy, P.; Hoover, D. J.
Drugs 2001, 10, 439. (t) Breuer, H. W. M. Int. J. Clin. Pharmacol.
Ther. 2003, 41, 421.
Yield: 42 mg (0.112 mmol, 86%); colorless liquid; Rf = 0.5 (EtOAc/hex-
ane, 2:1); [α]D28 +21.4 (c 0.30, CHCl3).
IR (neat): 3023, 2920, 2863, 1753, 1460 cm–1
.
(4) Dragutan, I.; Dragutan, V.; Mitan, C.; Vosloo, C. M. H.; Delaude,
L.; Demonceau, A. Beilstein J. Org. Chem. 2010, 6, 1188.
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D. J. Nat. Prod. 1988, 51, 1198.
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K.; Nash, R. J.; Molyneux, R. J. Eur. J. Biochem. 1997, 248, 296.
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(12) (a) Kallam, S. R.; Datrika, R.; Khobare, S. R.; Gajare, V. S.; Rajana,
N.; Mohan, H. R.; Babu, J. M.; Siddaiah, V.; Pratap, T. V. Tetrahe-
dron Lett. 2016, 57, 1351; and references cited therein. (b) Min,
I. S.; Kim, S. I.; Hong, S.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013,
69, 3901; and references cited therein. (c) Kundu, P. K.; Ghosh,
S. K. Tetrahedron: Asymmetry 2011, 22, 1090; and references
cited therein.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.19 (m, 10 H), 5.73–5.63 (m,
2 H), 5.04 (d, J = 11.0 Hz, 1 H), 4.64 (d, J = 11.8 Hz, 1 H), 4.51–4.41 (m,
2 H), 4.24–4.18 (m, 2 H), 4.08–4.06 (m, 1 H), 3.68 (td, J = 5.2, 13.2 Hz,
1 H), 3.44–3.35 (m, 2 H), 3.06–3.02 (m, 1 H), 2.34–2.15 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 160.1, 138.4, 138.2, 133.3, 128.9,
128.8, 128.7, 128.5, 128.4, 128.1, 128.0, 81.9, 79.0, 76.2, 71.5, 68.8,
59.1, 44.2, 27.3.
HRMS (DART): m/z [M + H]+ calcd for C23H26NO4: 380.1862; found:
380.1826.
Acknowledgment
This work was supported by the Department of Science and Technol-
ogy [DST, grant No. SB/SI/OC-28/2014]. We are thankful to Mr. A. K.
Pandey for technical assistance, and SAIF, CDRI, for providing spectral
data. P.D. and S.A. thank CSIR for the award of Senior Research Fellow-
ships. CDRI communication no. 9221.
Supporting Information
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M. C.; Wong, C.-H. Bioorg. Med. Chem. 1996, 4, 2055.
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Asano, N. Tetrahedron Lett. 2004, 45, 579. (b) Jadhav, V. H.;
Bande, O. P.; Puranik, V. G.; Dhavale, D. D. Tetrahedron 2010, 66,
2830.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562438.
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