Divergent approach to the synthesis of (-)-balanol heterocycle and cis-3-hydroxypipecolic acid based on chiral 2-aminoalkanol equivalent

Article abstract of DOI:10.1016/j.tet.2020.131773

Enantioselective synthesis of the hexahydroazepine core of (?)-balanol and formal synthesis of cis-3-hydroxypipecolic acid from a common intermediate have been accomplished by a divergent path. The common intermediate was accessed from a favorably protected enantiomerically pure 2-amino-1,3,4-butanetriol (ABT) equivalent via oxidation and Wittig olefination. The synthesis of (?)-balanol heterocycle featured tandem reduction/acetal-deprotection/γ-lactonization reaction and a one-pot azide reduction followed by seven membered aza-heterocycle formation while the route to cis-3-hydroxypipecolic acid highlighted the base induced piperidine ring formation and regioselective benzylidine-acetal cleavage.

Full text of DOI:10.1016/j.tet.2020.131773

Journal Pre-proof
Divergent approach to the synthesis of (̶)-balanol heterocycle and cis-3-
hydroxypipecolic acid based on chiral 2-aminoalkanol equivalent
Subhash P. Chavan, Dinesh B. Kalbhor, Rajesh G. Gonnade
PII:
S0040-4020(20)31008-5
https://doi.org/10.1016/j.tet.2020.131773
TET 131773
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 August 2020
Revised Date: 4 November 2020
Accepted Date: 10 November 2020
Please cite this article as: Chavan SP, Kalbhor DB, Gonnade RG, Divergent approach to the synthesis
of (̶)-balanol heterocycle and cis-3-hydroxypipecolic acid based on chiral 2-aminoalkanol equivalent,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131773.
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Divergent approach to the synthesis of ( ̶ )-
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balanol heterocycle and cis-3-
hydroxypipecolic acid based on chiral 2-
aminoalkanol equivalent
Subhash P. Chavan a,b, Dinesh B. Kalbhora,b and Rajesh G. Gonnadeb,c

1
Tetrahedron
journal homepage: www.elsevier.com
Divergent approach to the synthesis of (
̶
)-balanol heterocycle and cis-3-
hydroxypipecolic acid based on chiral 2-aminoalkanol equivalent
Subhash P. Chavan a,b, Dinesh B. Kalbhora,b and Rajesh G. Gonnadeb,c
aDivision of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune-411008, India
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
cCenter for Materials Characterization (CMC), CSIR-NCL (National Chemical Laboratory), Pune-411008, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Enantioselective synthesis of the hexahydroazepine core of (–)-balanol and formal synthesis of
cis-3-hydroxypipecolic acid from a common intermediate have been accomplished by a
Received in revised form
Accepted
Available online
divergent path. The common intermediate was accessed from a favorably protected
enantiomerically pure 2-amino-1,3,4-butanetriol (ABT) equivalent via oxidation and Wittig
olefination. The synthesis of (–)-balanol heterocycle featured tandem reduction/acetal-
deprotection/γ-lactonization reaction and a one-pot azide reduction followed by seven membered
aza-heterocycle formation while the route to cis-3-hydroxypipecolic acid highlighted the base
induced piperidine ring formation and regioselective benzylidine-acetal cleavage.
Keywords:
Hexahydroazepine
Amino-alcohol
Protein kinase
Desymmetrization
Piperidine alkaloids
.
1. Introduction
(–)-Balanol (1) also known as azepinostatin, an unusual
metabolite, was first isolated from Tolypocladium
HO
OH
O
ophioglossides1 in 1977 as ophiocordine.2-4 Later in 1993 it was
isolated from the fungus Verticillium balanoides3,4 and again in
1994 from another fungus, Fusarium merismoides.5 It is known
to be a potent inhibitor of human protein kinase C (PKC)
isozymes at low concentration (IC50 ranges 4-9 nM).4 The
activation of PKC enzymes is involved in various diseases like
cancer, central nervous system disorders, cardiovascular
dysfunction, and even HIV infection and hence this family of
enzymes comprises a crucial target for development of potent
therapeutic agents for controlling various diseases.6 Several PKC
inhibitors are currently in clinical trials for different types of
cancers.7 Balanol consists of a chiral hexahydroazepine segment,
benzophenone fragment and p-hydroxy benzamide unit (Figure
1). The promising biological profile makes balanol an interesting
and important subject for chemical and pharmaceutical studies.
Soon after identification of its important biological activity, six
total syntheses of balanol8,9 were reported in quick succession.
The protected hexahydroazepine segment has been targeted in
several formal syntheses of balanol.10 Apart from synthetic
efforts, recently biosynthesis of balanol in Tolypocladium
ophioglossoides was reported.11 However, because of
unavailability of balanol in sufficient quantity when extracted
from the fungus under laboratory condition,3 balanol presents an
CH2OH
HO
O
H
OH
O
N
OH
N
O
3R
2S
NH
1
N
H
H
4R
3R
OMe
O
H
NH
HN
2
1
tetrazomine 3
OH
O
3R
2S
OH
N
H
CO2H
1
1
(-)-balanol
OH
cis-3-hydroxypipecolic
HO
OH
4R
OH
2
acid
NH2
3R
NHBoc
BocN
2
2-aminobutane-1,3,4-triol
(ABT)
1
4
hexahydroazepine
HO
OH
chiral C4 unit
is common to balanol,
tetrazomine,
conduramineand
polyhydroxyazepanes
H
N
OH
R
OH
HO
O
N
H
amino-substituted
polyhydroxylated
azepane7
HO
NH2
OH
5
(+)-conduramineF-4
HO
HO
NH2
(-)-conduramineF-4 6
Figure 1: Selected natural products comprising the azepane/piperidine
framework and conduramines and their common 2-aminoalkanol unit.
———
Corresponding author. Tel.: +91 020 25902286; e-mail: sp.chavan@ncl.res.in

2
Tetrahedron
-attractive target for synthesis. For more than two decades,
several total and formal syntheses of 1 have been reported.
Ph
HO
HO
OH
O
O
OH
N
Polyhydroxylated piperidines are also biologically important
and well-studied class of piperidine alkaloids. Their significant
pharmacological importance makes them an interesting and
attractive target for chemical and pharmaceutical studies.12
Among these piperidine alkaloids, the 3-hydroxypipecolic acids
BocN
NHBoc
H
O
NHBoc
ABT equivalent
2
cis-3-hydroxypipecolicacid
hexahydroazepine4
8
Oxidation
Wittig reaction
Ph
BnO
HO
OH
O
are
important
scaffolds.
cis-Configured
(2S,3R)-3-
N
HN
13
NHBoc
O
O
Boc
12
hydroxypipecolic acid (2, Figure 1) is a key precursor for the
synthesis of tetrazomine (3),13 an antitumor and antibiotic agent,
while reduced derivative of ent-(2) is constituent of
isofebrifugine, an antimalarial agent.14 There are several synthetic
efforts reported for 3-hydroxypipecolic acids.15 These strategies
are based on i) chiron approach,16 ii) enzymatic resolution17 and
iii) asymmetric induction.18 However, from the synthetic point of
view, there is scarcity of enantioselective approaches, and
synthetically cis derivatives are less explored as compared to
their trans counterparts.
COOEt
NHBoc
9
Regioselective
reductive
acetal cleavage
Reductive
cleavage
lactonization
FGI
common intermediate
Hydrogenation
Ph
Ph
O
O
O
2 steps
N3
O
O
O
OH
BocN
11
NHBoc
14
NHBoc
10
Optically active anti/syn-2-aminobutane-1,3,4-triol (ABT)
equivalents (Figure 1), present in various protected and freely
functionalized forms, are extremely prominent chiral C4 building
blocks for the efficient synthesis of diverse class of biologically
important compounds such as sphinganine,19 statine,20 kainic
acid,21 sphingosine22d and HIV protease inhibitor viz.
nelfinavir.22a,b Several synthetic strategies for the synthesis of
chiral ABT equivalent have appeared in literature in recent years.
ABT derivatives are accessible by these routes which follow
either functional group transformations of chiral pool,23
asymmetric synthesis22a or enzymatic method.24 From this
outlook, for practical application of ABT derivative as versatile
chiral building block, the compound should be available on large
scale, with proper relative and absolute stereochemistry, as well
as in favorably protected forms for the selective transformations
of three hydroxyl groups and amino group. However, some ABT
synthetic routes25 developed so far could not fulfil these
requirements. Exceptionally the asymmetric desymmetrization of
meso-epoxide using Ti(IV)/BINOL as a chiral catalyst and
benzylamine and its derivatives developed by Inaba et al., can be
referred as one of the efficient and robust routes to chiral ABT
equivalents.22b, 26
Scheme 1: Retrosynthetic analysis for cis-3-hydroxypipecolic
acid and aza-heterocyclic core of (–)-balanol
-saturated ester and functionalized chiral lactone used for
construction of piperidine and azepine skeleton respectively.
Retrosynthetically, azepine core of balanol and cis-3-
hydroxypipecolic acid (2, Scheme 1) can be accessed from a
common unsaturated ester 9. We envisioned that the common
intermediate ester 9 could serve as a flexible handle, enabling the
synthesis of several members of piperidine alkaloids and amino-
azepanes. Reduction of ester 9 to alcohol 10 and subsequent
mesylation of alcohol followed by base induced reaction would
deliver bicyclic piperidine acetal 11. Hydroxymethyl piperidine
12, in turn, could be obtained by the regioselective reductive
cleavage of bicyclic piperidine acetal 11 followed by functional
group manipulation to deliver cis-3-hydroxypipecolic acid (2).
On the other hand, construction of azepine ring of (–)-balanol (1)
could be achieved through one-pot azide reduction followed by
formation of lactam 13 from the corresponding azido-lactone 14.
Tandem reduction of ester 9 followed by benzylidine acetal
deprotection and lactonization would afford hydroxy lactone.
Intermediate ester 9 could be readily prepared from key
intermediate benzylidine acetal 8 which in turn could be derived
from commercially available cis-2-butene-1,4-diol (15).
The remarkable practical importance of the 2-aminobutane-
1,3,4-triol (ABT) equivalent in synthesis of biologically active
compounds prompted us to undertake a further study by
exploring Inaba’s protocol26 in the synthesis of biologically active
compounds. As a part of our ongoing interest in developing
efficient and practical strategies towards piperidine alkaloids,27 it
was decided to exploit ABT as a synthon. We herein present the
conceptually different route for the synthesis of azepine core of
(–)-balanol and piperidine ring system of cis-3-hydroxypipecolic
acid by a divergent route. Earlier, we have reported the collective
syntheses of piperidine alkaloids utilizing an aziridine derived
moiety as a common chiral synthon.28
2.1 Synthesis of common intermediate 9
As outlined in Scheme 2, synthesis began with commercially
available starting material cis-2-butene-1,4-diol (15). The trans-
amino alcohol 16 was easily prepared from cis-2-butene-1,4-diol
(15) by acetonide protection, epoxidation and asymmetric ring
opening of the corresponding meso-epoxide using chiral methyl
benzylamine by following known literature procedure.22a
However, yield was low (35-40%) for the ring opening of meso-
epoxide step. Further, to improve the yield of 16, asymmetric
aminolysis of the corresponding meso-epoxide using Ti-(IV)-
BINOL complex as a chiral catalyst was carried out with high
yield and excellent diastereoselectivity26 (see the ESI). Reduction
of the methyl benzyl group of 16 by transfer hydrogenation
followed by Boc protection of the free amine gave amino alcohol
derivative 17 in 90% yield over 2 steps. The employment of 17 as
a chiral C4 unit in the synthesis of cis-3-hydroxypipecolic acid
and balanol required differentiation of the two acetonide
protected primary hydroxyl groups. Differentiation of the primary
hydroxyl group was anticipated to be accomplished by the
deprotection of acetonide derivative 17 with catalytic p-TSA
2. Results and discussion
Based on the structural features of our target molecules 2 and
4
(Figure 1) it is necessary to modify reported ABT
equivalents.22,26 From this aspect, benzylidene acetal 8 is
expected to be a versatile intermediate by considering the
different reactivities of the three hydroxyl groups and amino
group. The key transformations in the proposed synthesis
include: (i) regioselective benzylidene acetal protection of 2-
amino-1,3,4-butanetriol (ABT), (ii) Wittig reaction to obtain
the common intermediate and (iii) Palladium-catalyzed
hydrogenation reaction of common intermediate
9 to access

3
was further transformed into desired N-Boc-protected
OH
OH
O
O
O
O
benzylidene acetal 11 with sodium hydride mediated cyclization
at 0 °C. Finally, regioselective reductive cleavage of 11 was
performed by treating with EtAlCl2 in combination with Et3SiH
in DCM at -78 °C to furnish requisite hydroxymethyl piperidine
derivative 12 in excellent yield with high degree of
regioselectivity.29 Spectral and analytical data of compound 12
thus obtained were in full accordance with the reported ones.29 As
the transformation of compound 12 into the target cis-3-
hydroxypipecolic acid (2), by the oxidation of primary alcohol
and subsequent deprotection of O-benzyl and N-Boc groups, is
reported in the literature,29 the present work constitutes the
formal synthesis of cis-3-hydroxypipecolic acid (2). While
targeting the synthesis of cis (hydroxymethyl) piperidine-3-ol
(19, Scheme 4), the cleavage of benzylidene group of 11 was
accomplished by treatment with catalytic p-TSA in methanol to
afford 19 as a white solid.
a
known
ref. 22a,26
NH OH
BocHN
OH
17
Ph
16
cis-2-butene-1,4-diol15
92% yieid and 97% de
Ph
Ph
b
c
O
O
O
O
OH
COOEt
NHBoc
NHBoc 9
8
Scheme 2: Synthesis of common intermediate 9 from ABT
equivalent, Reagents and conditions: (a) HCOONH4, Pd/C,
MeOH, reflux then Boc2O, neat, rt, 90% (2 steps); (b) p-TSA.
MeOH, rt then benzaldehyde dimethyl acetal, p-TSA, CH3CN,
rt, 64% (2 steps) (c) IBX, EtOAc, reflux, 5 h, 81% then
Ph3PCHCO2Et, CH2Cl2, rt, 4 h, 71%.
Ph
HO
a
with subsequent regioselective benzylidene acetal protection of
corresponding crude 2-amino-1,3,4-butanetriol (ABT) with
benzaldehyde dimethyl acetal catalyzed by p-TSA which resulted
in the formation of desired acetal 8 in 64% yield. The structure
and relative stereochemistry of benzylidine acetal 8 were
confirmed by a single crystal X-ray crystallography. It was found
that 1,3-hydroxyl groups get preferentially protected over 1,2-
hydroxyl groups and phenyl ring exists at thermodynamically
stable equatorial position in 8 (Figure 2). Oxidation of primary
alcohol 8 by IBX afforded aldehyde which was homologated
without further purification using Wittig reaction to furnish the
desired common intermediate 9 in high yield.
O
O
HO
N
Boc
BocN
19
11
Scheme 4: Synthesis of diol 19, Reagents and conditions: (a)
p-TSA, MeOH, rt, 24 h, 84%.
2.3 Synthesis of hexahydroazepine 4
Having
accomplished
successful
route
to
cis-3-
hydroxypipecolic acid (2), we next focused on the synthesis of
hexahydroazepine core of (–)-balanol from the common
intermediate 9. Catalytic hydrogenation of compound 9 over
Pd/C over 24 hours led to one-pot conversion via intermediates
18 and 20 to afford the corresponding functionalized desired γ-
lactone30 21 in 75% yield (Scheme 5).
2.2 Formal synthesis of cis-3-hydroxypipecolic acid (2)
With the desired common intermediate 9 in hand, attention
was focused towards the synthesis of cis-3-hydroxypipecolic acid
(2) as depicted in Scheme 3. During these studies, it was
observed that unsaturated ester 9 when subjected to palladium-
catalyzed hydrogenation reaction in methanol (monitoring this
reaction by TLC and LCMS), furnished different products
depending on time. After 1 h, the formation of saturated ester 18,
with intact benzylidene acetal group, useful in the synthesis of
cis-3-hydroxypipecolic acid (2) was observed.
Ph
Ph
O
O
COOEt
O
O
a
b
9
NHBoc
NHBoc
OH
18
10
Ph
HO
HO
BnO
HO
c
O
O
d
e
N
H
N
Boc
O
BocN
12
11
2
Scheme 3: Synthesis of cis-3-hydroxypipecolic acid,
Reagents and conditions: (a) H2, Pd/C, MeOH, rt. 1 h, 85%;
(b) NaBH4, LiCl, THF:EtOH (1:1), reflux, 73%; (c) MsCl,
Et3N, CH2Cl2, 0 °C then NaH, THF 0 °C-rt, 71% (2 steps); (d)
Et3SiH, EtAlCl2, CH2Cl2, -78 °C, 80%; (e) Ref. 29.
ORTEP of 8
(CCDC 2024030)
Successive reduction of saturated ester 18 by treatment with
LiCl/NaBH4 in THF:EtOH (1:1) system at refluxing temperature
provided primary hydroxyl compound 10 and subsequent
mesylation by treating 10 with methanesulphonyl chloride and
triethylamine in DCM furnished crude mesylate derivative which
Figure 2: ORTEP diagram of compound 8.

4
Tetrahedron
construction of azepine segment of potent protein kinase C
Ph
inhibitor (–)-balanol and cis-3-hydroxypipecolic acid precursor
with 6.1% and 9.3% overall yields respectively. It is worth
mentioning that all the key operations are catalytic in nature
including desymmetrization of meso-epoxide, one-pot
reduction/acetal-deprotection/γ-lactonization reaction sequence
and tandem azide reduction followed by seven membered aza-
heterocycle formation. The present synthetic strategy is flexible
and provides a platform for structural modification, especially by
further functionalization of the unsaturated ester 9, and thus can
enable the collective synthesis of diverse biologically active
compounds.
Ph
O
O
COOEt
O
O
a
COOEt
NHBoc
NHBoc
18
9
isolated after 1h
acetal
deprotection
O
Transesterification
OH OH COOEt
NHBoc
OH
O
4
Experimental section
NHBoc
21
20
4.1 General methods
isolated after 24 h
isolatedafter 6h
All reagents and solvents were used as received from the
manufacturer. Solvent were dried over CaH2 or sodium.
Analytical TLC was carried out using pre-coated silica gel plates
(Merck TLC silica gel 60F254) and visualized by charring after
treatment with ethanolic solution of ninhydrin or anisaldehyde.
Merck’s flash silica gel (230-400 mesh) was used for column
chromatography. IR spectra were recorded on a Perkin-Elmer
1615 FT Infrared Spectrophotometer using a NaCl cell. Melting
points of solids were measured on a Buchi melting point
apparatus. Optical rotation values were recorded on P-2000
polarimeter at 589 nm. HRMS (ESI) were recorded on
ORBITRAP mass analyzer (Thermo Scientific, Q Exactive).
Mass spectra were measured with ESI ionization in MSQ LCMS
mass spectrometer. 1H and 13C NMR spectra were recorded using
a Bruker Advance (200, 400 and 500 MHz) spectrometer.
Chemical shifts are reported in ppm relative to residual CHCl3 (δ
= 7.26) in CDCl3 for 1H NMR and CDCl3 (δ = 77.0) for 13C in the
13C NMR spectra. The diastereoselectivity was obtained by
HPLC analysis. Solvent system for HPLC analysis of compound
16 was n-Hexane: IPA (95:5), column: CHIRAL PAK IC,
detection wavelength: 254 nm, flow rate: 1.0 mL/min.
Scheme 5: One-pot reduction/deprotection/transesterification,
Reagents and conditions: (a) H2, Pd/C, cat. HCl, MeOH, rt. 24
h, 74%.
The key chiral lactone 21 acts as a handle for further
installation of second amine (Scheme 6), by converting primary
hydroxyl group in 21 to its mesylate using mesyl chloride and
triethyl amine and the mesyl group was successfully displaced by
sodium azide in DMF at 60 °C to furnish the azido-γ-lactone 14
in 82% yield (over two steps). The terminal azido group served as
a
masked amino functionality of the ϵ-caprolactam 13.
Completion of the synthesis of the azepine core involved the
hydrogenation of compound 14 which was transformed into
lactam 13 in a one-pot operation involving azide reduction
followed by ϵ-caprolactam formation. Reduction of lactam 13
with excess borane (5 equiv) followed by subsequent Boc-
protection of crude free amine furnished 4. The
hexahydroazepine 4 could be utilized for the synthesis of balanol
(1) and its analogues, and hence, the present work can be
considered as an important milestone in the synthesis of balanol
(1).
4.1.1.
4,4-Dimethyl-3,5,8-trioxabicyclo[5.1.0]octane.22a
A
mixture of 2,2-dimethyl-4,7-dihydro-1,3-dioxepine (25 g, 0.195
mol), THF (120 mL), water (120 mL) and NBS (31.3 g, 0.175
mol) was stirred at room temperature for 120 minutes. Water (50
mL) was added to the reaction mixture and extracted with ethyl
acetate (3×50 mL). The solvent was removed under reduced
pressure until the oily residue was obtained (35 g). Crude yellow
oily residue of bromohydrin (35 g, 0.156 mol) was suspended in
MeOH (500 mL) and K2CO3 (43 g, 0.312 mol) was added
successively. After stirring the mixture at room temperature for
16 h, reaction mixture was filtered and concentrated in vacuo to
give the residue to which water (200 mL) was added and
extracted with ethyl acetate (3×50 mL). The organic layer was
dried over anhydrous Na2SO4. After removal of the solvent,
distillation (88-91 °C/15 Torr) gave meso-epoxide (19 g, 84%) as
a colorless liquid. The spectral data of meso-epoxide matched
well with the reported information.22a
Ph
O
O
N3
OH
O
b
O
a
O
O
COOEt
NHBoc
NHBoc
NHBoc
9
21
14
OH
NHBoc
OH
NHBoc
c
d
O
HN
BocN
13
4
Scheme 6: Approach to aza-heterocyclic core of (–)-
balanol, Reagents and conditions: (a) H2, Pd/C, cat. HCl,
MeOH, rt. 24 h, 74%; (b) MsCl, Et3N, CH2Cl2, 0 °C then
NaN3, DMF, 80 °C, 68% (2 steps) (c) H2, Pd/C, MeOH, rt,
78%; (d) BH3.Me2S, THF, 60 °C then Boc2O, 2N NaOH,
EtOH, 61%.
4.1.2.
(5S,6R)-2,2-Dimethyl-6-[(R)-1-phenylethyl)amino]-1,3-
dioxepan-5-ol (16).22a, 26
The required trans-amino alcohol 16 was prepared from meso-
epoxide as reported earlier22a,26 (92% yield), 97% de (HPLC) as
pale yellow crystals. The absolute configuration of 16 was
3
Conclusions
Starting from the readily available cis-2-butene-1,4-diol (15), we
have demonstrated benzylidene acetal 8 to be a prominent chiral
C4 building block for 2-amino-1,3,4-butanetriol by selective
treatment of its three hydroxyl groups and an amino group.
Especially, 8 was shown to be a suitable precursor for the
25
D
determined to be (5S, 6R) by comparison of its [α] value with
that reported in the literature.26 Rf: 0.5 (pet. ether-ethyl acetate,
40:60); MP: 60-62 °C; IR (CHCl3, cm-1): νmax 3416, 1550, 1218,

5
25
25
D
3H), 5.60 (s, 1H), 5.49 (d, J = 9.2 Hz, 1H), 4.20-4.14 (m, 2H),
1048; [α] –12 (c 1.0, MeOH), {Lit.26 for ent-[α] +12 (c 1.0,
D
4.13-4.09 (m, 1H), 3.85-3.80 (m, 2H), 3.77-3.76 (m, 1H), 3.58-
3.51 (m, 1H), 1.48 (s, 9H); 13C NMR (50 MHz, CDCl3): δ 157.3,
137.4, 129.1, 128.3 (2C), 125.8 (2C), 101.3, 80.6, 78.9, 71.2,
60.7, 44.8, 28.2 (3C); HRMS (ESI) m/z: [M + Na]+ calcd for
C16H23NO5Na: 332.1468, found: 332.1460.
1
MeOH)}. H NMR (400 MHz, CDCl3): δ 7.35-7.30 (m, 4H),
7.27-7.25 (m, 1H), 3.91-3.85 (m, 2H), 3.68 (dd, J = 1.9, 12.6 Hz,
1H), 3.66-3.55 (m, 1H), 3.52-3.51 (m, 1H), 3.31 (dd, J = 5.3, 12.2
Hz, 1H), 2.53 (dt, J = 1.5, 5.3 Hz, 1H), 1.35 (d, J = 6.9 Hz, 3H),
1.32 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 146.1, 128.5 (2C),
127.1, 126.5 (2C), 101.4, 71.8, 61.6, 60.3, 59.6, 55.8, 24.7, 24.6,
24.2; HRMS (ESI) m/z: [M + Na]+ calcd for C15H22NO3Na:
288.1570, found: 288.1566.
4.1.5. Ethyl (E)-3-[(2S,4R,5R)-5-[(tert-butoxycarbonyl)amino]-2-
phenyl-1,3-dioxan-4-yl]acrylate (9). Alcohol 8 (3 g, 0.0097 mol)
was dissolved in ethyl acetate (40 mL), and IBX (3.5 g, 0.012
mol) was added. The resulting suspension was refluxed for 4 h.
Completion of reaction was monitored on TLC, the reaction was
cooled to room temperature and filtered through a medium glass
frit. The filter cake was washed with ethyl acetate (3×10 mL),
and the combined filtrates were concentrated to yield a waxy
solid aldehyde (2.5 g, 83%).
The crude aldehyde (2.5 g, 0.0081 mol) was dissolved in dry
CH2Cl2 and to this solution Ph3PCHCO2Et (5.66 g, 0.016 mol)
was added. The reaction mixture was stirred at room temperature
for 12 h. Completion of reaction was monitored by TLC. After
completion of reaction, solvent was removed under reduced
pressure and the crude product was purified using silica gel
column chromatography using pet. ether-ethyl acetate (80:20) as
eluent to furnish the common intermediate, α,β-unsaturated ester
9 (2.2 g, 71%) as a colorless thick oil. Rf: 0.5 (pet. ether-ethyl
acetate, 70:30); IR (CHCl3, cm-1): νmax 3440, 1720, 1706, 1685,
4.1.3. tert-Butyl [(5R,6S)-6-hydroxy-2,2-dimethyl-1,3-dioxepan-
5-yl]carbamate (17). A solution of the 16 (5 g, 0.018 mol) in
methanol containing 10% palladium on carbon (0.75 g) and
ammonium formate (6 g, 0.094 mol) was stirred at 60 °C. After
completion of the transfer hydrogenolysis (monitored by TLC),
the mixture was filtered through celite and the catalyst was
washed with methanol. The combined washings and filtrate was
evaporated in vacuo to oil, which was extracted into
dichloromethane (3×50 mL), the extract was washed with
saturated sodium chloride solution (3×20 mL) and dried over
anhydrous Na2SO4. The solvent was evaporated in vacuo to
afford crude oily amine (3.0 g) which was used as such for next
reaction.
To (Boc)2O (4.46 g, 0.020 mol), was added crude amine (3 g,
0.018 mol) and the mixture was stirred at room temperature for 1
h. After completion of the reaction (monitored by TLC), 40 mL
dichloromethane was added in the reaction mixture, and
concentrated under reduced pressure, 17 (4.4 g, 90% over two
steps) was obtained as a white solid which was found to be
sufficiently pure and did not require any further purification. Rf:
0.5 (pet. ether-ethyl acetate, 60:40); MP: 107-109 °C; IR (CHCl3,
25
D
1650 1506, 1040; [α] +11 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): δ 7.52 (d, J = 5.5 Hz, 2H), 7.41-7.39 (m, 3H), 6.91 (dd, J
= 3.1, 15.9 Hz, 1H), 6.17 (d, J = 15.9 Hz, 1H), 5.65 (s, 1H), 5.32
(d, J = 9.8 Hz, 1H), 4.73 (br s, 1H), 4.23-4.14 (m, 4H), 3.88 (d, J
= 9.8 Hz, 1H), 1.41 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 165.8, 155.4, 142.8, 137.3, 129.1, 128.2
(2C), 125.8, (2C), 122.4, 101.1, 79.7, 77.7, 71.3, 60.4, 47.1, 28.1
(3C), 14.1; HRMS (ESI) m/z: [M + Na]+ calcd for C20H27NO6Na:
400.1731, found: 400.1726.
25
cm-1): νmax 3442, 1706, 1218, 1048; [α] –48 (c 1.0, CHCl3); H
1
D
NMR (200 MHz, CDCl3): δ 5.18 (d, J = 7.3 Hz, 1H), 4.10-3.94
(m, 1H), 3.77 (d, J = 12.3 Hz, 1H), 3.59-3.42 (m, 4H), 3.29-3.21
(m, 1H), 1.42 (s, 9H), 1.32 (s, 6H); 13C NMR (50 MHz, CDCl3):
δ 155.3, 101.7, 79.6, 70.5, 61.3, 59.4, 54.3, 28.3 (3C), 24.6, 24.4;
HRMS (ESI) m/z: [M + Na]+ calcd for C12H23NO5Na: 284.1468,
found: 284.1460.
4.1.6. Ethyl 3-[(2S,4R,5R)-5-[(tert-butoxycarbonyl)amino]-2-
phenyl-1,3-dioxan-4-yl]propanoate (18). The α,β-unsaturated
ester 9 (0.8 g, 2.12 mmol) was dissolved in methanol (10 mL)
and to that was added catalytic amount of 10% Pd/C. The
resulting reaction mixture was stirred under hydrogen atmosphere
using balloon for 1 h. The reaction mixture was filtered through
Celite and the filtrate was concentrated in vacuo. The crude
product was purifed by flash chromatography using silica gel
(pet. ether–ethyl acetate, 80:20) to provide ester 18 (0.68 g) as a
colorless thick oil. Rf: 0.4 (pet. ether–ethyl acetate, 80:20); yield:
85%. IR (CHCl3, cm-1): νmax 3440, 1720, 1706, 1685, 1506, 1040;
4.1.4. Gram scale synthesis of tert-butyl [(2S,4S,5R)-4-
(hydroxymethyl)-2-phenyl-1,3-dioxan-5-yl]carbamate (8). To a
solution of 17 (4 g, 0.015 mol) in methanol (40 mL) was added p-
TsOH (0.29 g, 0.0015 mol). The reaction mixture was stirred at
room temperature for 24 h. Subsequently, it was neutralized with
saturated aqueous NaHCO3 (30 mL). The aqueous phase was
extracted with CH2Cl2 (3×50 mL). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, filtered
and concentrated to afford crude white solid triol (2.9 g) which
was used as such for the next reaction.
To a solution of crude triol (2.8 g, 0.012 mol) in dry acetonitrile
(30 mL) were added p-TsOH (0.24 g, 0.0012 mol) and
benzaldehyde dimethyl acetal (1.92 g, 0.012 mol). The reaction
mixture was stirred at room temperature for 3 h. Subsequently, it
was neutralized with saturated aqueous NaHCO3 (20 mL). The
organic phase was separated and the aqueous phase extracted
with CH2Cl2 (3×50 mL). The combined organic extracts were
washed with aqueous NaHCO3 and brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Silica gel
column chromatography of the crude product using pet. ether-
ethyl acetate (70:30) as eluent afforded 1, 3-protected alcohol 8,
the major product (3 g, 64% over two steps) as a white solid. Rf:
0.5 (pet. ether-ethyl acetate, 50:50); MP: 128-130 °C; IR (CHCl3,
25
D
[α] +7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.48 (dd,
J = 1.9, 8.0 Hz, 2H), 7.40-7.36 (m, 3H), 5.56 (s, 1H), 5.36 (d, J =
9.9 Hz, 1H), 4.18-4.10 (m, 4H), 4.09-4.06 (m, 1H), 3.69 (dd, J =
1.9, 10.3 Hz, 1H), 2.48 (t, J = 7.2 Hz, 2H), 1.98 (ddd, J = 7.1, 9.0,
14.3 Hz, 1 H), 1.90-1.86 (m, 1H), 1.45 (s, 9H), 1.24 (t, J = 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 173.2, 155.7, 137.8,
128.9, 128.2 (2C), 125.8 (2C), 101.4, 79.6, 78.3, 71.9, 60.3, 47.1,
29.6, 28.3 (3C), 26.8, 14.1; HRMS (ESI) m/z: [M + Na]+ calcd
for C20H29NO6Na: 402.1887, found: 402.1873.
4.1.7. tert-Butyl [(2S,4R,5R)-4-(3-hydroxypropyl)-2-phenyl-1,3-
dioxan-5-yl]carbamate (10). To a magnetically stirred solution of
ester 18 (0.5 g, 1.31 mmol) in THF: EtOH (1:1, 10 mL), LiCl
(0.11 g, 2.64 mmol) and NaBH4 (0.1 g, 2.64 mmol) were added
portionwise at 0 °C. The temperature of the reaction mixture was
allowed to rise gradually up to reflux. Then this reaction mixture
was stirred for 16 h at reflux temperature. The progress of
25
D
1
cm-1): νmax 3620, 3440, 1685, 1506; [α] +57 (c 1.0, CHCl3); H
NMR (200 MHz, CDCl3): δ 7.52-7.47 (m, 2H), 7.42-7.37 (m,

6
Tetrahedron
reaction mixture was monitored by TLC. After completion of
(CHCl3, cm-1): νmax 3418, 2930, 1676, 1420, 1416, 1216, 1178,
the reaction, it was quenched by saturated aq. NH4Cl solution at 0
°C and further stirred for 10 min. This solution was extracted
with ethyl acetate (3×50 mL). The combined organic layer was
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by a silica gel column
chromatography using pet. ether-ethyl acetate (60:40) as eluent to
furnish the reduced compound 10 (0.325 g, 73%) as a colorless
thick oil. Rf: 0.4 pet. ether–ethyl acetate (50:50); IR (CHCl3, cm-1
25
D
1154, 1096, 1042, 927, 670; [α] –65 (c 1.0, CHCl3); lit.29 {for
25
D
ent-12 [α]
+66.7 (c 1.03, CHCl3)}; 1H NMR (400 MHz,
CDCl3): δ 7.25-7.37 (m, 5H), 4.61-4.72 (m, 3H), 4.02 (dd, J =
6.0, 12.0 Hz, 1H), 3.87 (br s, 1H), 3.74 (br s, 1H), 3.61-3.64 (m,
1H), 2.75 (br s, 2H), 1.97-2.22 (m, 1H), 1.63-1.74 (m, 1H), 1.55-
1.68 (m, 1H), 1.47 (s, 9H), 1.42-1.44 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 154.9, 137.9, 128.5 (2C), 127.8, 127.6 (2C),
80.2, 73.3, 70.9, 59.1, 54.4, 39.2, 28.4 (3C), 25.7, 23.8; HRMS
(ESI) m/z: [M + Na]+ calcd for C18H27NO4Na: 344.1832, found:
344.1829.
25
): νmax 3610, 3440, 1685, 1510; [α] +6 (c 1.0, CHCl3); 1H NMR
D
(200 MHz, CDCl3): δ 7.49-7.47 (m, 2H), 7.41-7.36 (m, 3H), 5.57
(s, 1H), 5.41 (d, J = 9.9 Hz, 1H), 4.20-4.15 (m, 1H), 4.11 (s, 1H),
4.05-3.98 (m, 1H), 3.72-3.63 (m, 3H), 2.20-2.15 (m, 1H), 1.75-
;
13C NMR (50 MHz, CDCl3): δ
4.1.10. tert-Butyl (2R,3R)-3-hydroxy-2-
(hydroxymethyl)piperidine-1-carboxylate (19).
1.65 (m, 4H), 1.45 (s, 9H),
155.9, 137.8, 128.9, 128.2 (2C), 125.7 (2C), 101.4, 79.6, 79.5,
71.9, 62.4, 47.1, 28.3 (3C), 28.1 (2C); HRMS (ESI) m/z: [M +
Na]+ calcd for C18H27NO5Na: 360.1781, found: 360.1770.
To a solution of 11 (0.1 g, 0.31 mmol) in methanol (5 mL) was
added p-TsOH (6 mg, 0.031 mmol). The reaction mixture was
stirred at room temperature for 24 h. Subsequently, it was
neutralized with saturated aqueous NaHCO3 (5 mL). The aqueous
phase was extracted with CH2Cl2 (3×5 mL). The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude
product on purification by column chromatography (pet. ether-
ethyl acetate, 10:90) yielded diol 19 (60 mg, 84%) as a white
solid. Rf. 0.5 (pet. ether-ethyl acetate, 2:8), MP: 114-116 °C; IR
4.1.8. tert-Butyl (2S,4aR,8aR)-2-phenylhexahydro-5H-
[1,3]dioxino[5,4-b]pyridine-5-carboxylate (11).
To a solution of alcohol 10 (300 mg, 0.89 mmol) in anhydrous
CH2Cl2 (10 mL) was added Et3N (0.21 mL, 1.51 mmol) at 0 °C
followed by MeSO2Cl (0.1 mL, 1.33 mmol) dropwise. After
completion of reaction (monitored by TLC), reaction was
quenched with water (5 mL) and the organic layer was washed
with aq. NaHCO3 (2%, 10 mL). The organic layer was dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
compound was used directly in the next reaction.
The solution of crude mesylate (0.3 g, 0.72 mmol) was dissolved
in dry THF (5 mL), cooled to 0 °C, and NaH added (60% in
mineral oil, 49 mg, 2.16 mmol). The reaction mixture was stirred
at room temperature for 6 h and diluted with water. The mixture
was extracted with EtOAc (3 × 5 mL). The combined organic
extracts were dried over anhydrous Na2SO4, filtered and
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography using (pet. ether-ethyl acetate,
90:10) as eluent to furnish the cyclic amino compound 11 (200
mg, 71% over two steps) as a white solid. Rf: 0.4 (pet. ether–ethyl
acetate, 80:20); MP: 134-136 °C; IR (CHCl3, cm-1): νmax 3019,
25
D
(CHCl3, cm-1): νmax 3372, 2932, 1666, 1178, 1072; [α] –22.8 (c
25
1.1, MeOH), lit.16d {for ent-19 [α] +23.1 (c 1.03, MeOH)}; H
1
D
NMR (500 MHz, CDCl3): δ 4.34 (br s, 1H), 4.14 (dd, J = 6.5,
11.1 Hz, 1H), 3.99-3.97 (m, 1H), 3.79-3.78 (m, 2H), 2.92-2.84
(m, 2H), 1.83-1.74 (m, 1H), 1.73-1.69 (m, 1H), 1.68-1.64 (m,
2H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 155.6, 80.3,
69.3, 59.2, 55.9, 39.5, 28.3 (3C), 28.2, 23.7; HRMS (ESI) m/z:
[M + Na]+ calcd for C11H21NO4Na: 254.1363, found: 254.1362.
4.1.11.
Ethyl
(4R,5R)-5-[(tert-butoxycarbonyl)amino]-4,6-
dihydroxyhexanoate (20), (Intermediate of hydrogenation
reaction). Rf: 0.5 (pet. ether-ethyl acetate, 3:7); H NMR (400
1
MHz, CDCl3): δ 5.28 (d, J = 7.9 Hz, 1H), 4.14 (q, J = 7.1 Hz,
2H), 3.95 (br s, 1H), 3.82-3.78 (m, 2H), 3.58 (br s, 2H), 2.54-2.47
(m, 2H), 1.87-1.80 (m, 3H), 1.45 (s, 9H), 1.26 (t, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 174.5, 156.5, 79.7, 72.5, 65.0,
60.7, 54.8, 31.0, 29.2, 28.3 (3C), 14.1; LCMS (ESI): m/z: calcd
for C13H25NO6[M+H]: 292.2, found: 292.2.
25
D
2976, 1676, 1417, 1218, 1167, 770, 699; [α] –140 (c 1.0,
25
D
CHCl3); lit.29 {for ent-11 [α] +141.7 (c 1.03, CHCl3)}; 1H NMR
(400 MHz, CDCl3): δ 7.50-7.49 (m, 2H), 7.39-7.37 (m, 3H), 5.53
(s, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.30-4.29 (m, 1H), 4.06-3.99
(m, 2H), 3.65 (ddd, J = 18, 12.2, 6.2 Hz, 1H), 3.54 (s, 1H), 2.07-
1.90 (m, 1H), 1.83-1.76 (m, 1H), 1.76-1.74 (m, 1H), 1.66-1.60
(m, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 155.1,
138.4, 129.0, 128.3 (2C), 126.2 (2C), 101.1, 79.6, 72.0, 71.2,
49.3, 38.3, 28.5 (3C), 24.2, 18.7; HRMS (ESI) m/z: [M + Na]+
calcd for C18H25NO4Na: 342.1676, found: 342.1666.
4.1.12. tert-Butyl [(R)-2-hydroxy-1-[(R)-5-oxotetrahydrofuran-2-
yl)ethyl]carbamate (21). To a stirred solution of compound 9 (0.3
g, 0.79 mmol) in MeOH (10 mL) was added Pd/C (40 mg) and
stirred under hydrogen pressure using balloon for about 24 h. The
reaction mixture was filtered and the filtrate was concentrated
under reduced pressure. The crude compound was purified by
column chromatography over silica gel (pet. ether-ethyl acetate,
40:60) to afford pure lactone 21 (0.14 g, 74%) as a viscous liquid.
(Note: When reaction was performed on more than 0.5 g scale,
the intermediate diol 20 was isolated as the major product. To
access the desired lactone 21, cat. HCl was added and resultant
mixture was stirred for additional 12 h at room temperature). Rf:
0.5 (pet. ether-ethyl acetate, 20:80); IR (CHCl3, cm-1): νmax 3610,
4.1.9 tert-Butyl (2R,3R)-3-(benzyloxy)-2-
(hydroxymethyl)piperidine-1-carboxylate (12).
To a solution of compound 11 (100 mg, 0.31 mmol) at -78 °C in
dry DCM (20 mL) was added Et3SiH (0.06 mL, 0.375 mmol)
followed by EtAlCl2 (95 mg, 0.375 mmol) and the resultant
mixture was stirred for additional 1 h. The reaction mixture was
slowly warmed to 0 °C and then quenched with saturated
NaHCO3 solution. The reaction mixture was extracted with ethyl
acetate and the combined organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude
product on purification by column chromatography over silica gel
(pet. ether-ethyl acetate, 70:30) yielded the unreacted starting
material (14 mg, 14%) and the pure alcohol 12 (80 mg, 80%) as a
viscous liquid. Rf: 0.5 (pet. ether-ethyl acetate, 60:40); IR
25
D
3336, 2925, 1775, 1705, 1251, 1182, 1169, 1060, 910, 730; [α]
+5 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 4.91 (d, J = 7.7
Hz, 1H), 4.82-4.73 (m, 1H), 3.87-3.72 (m, 3H), 2.61-2.53 (m,
2H), 2.36-2.26 (m, 1H), 2.21-2.11 (m, 1H), 1.46 (s, 9H); 13C
NMR (125 MHz, CDCl3): δ 177.1, 156.3, 80.2, 79.6, 62.8, 54.1,

7
28.5, 28.2 (3C), 24.2; HRMS (ESI) m/z: [M + Na]+ calcd for
C11H19NO5Na: 268.1155, found: 268.1147.
solution was extracted with ethyl acetate (3×5mL) and the
extract was washed with saturated sodium chloride solution (3×5
mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using
pet. ether-ethyl acetate (80:20) as the eluent to furnish the
hexahydroazepine compound 4 (25 mg, 61% over two steps) as a
pale yellowish thick oil. Rf: 0.4 (pet. ether–ethyl acetate, 70:30);
IR (CHCl3, cm-1): νmax 3430, 2925, 2104, 1250, 1185, 1169,
4.1.13. tert-Butyl [(R)-2-azido-1-[(R)-5-oxotetrahydrofuran-2-
yl)ethyl]carbamate (14). To a solution of lactone 21 (100 mg,
0.40 mmol) in anhydrous CH2Cl2 (10 mL) was added Et3N (72
mg, 0.72 mmol) at 0 °C followed by MeSO2Cl (60 mg, 0.52
mmol) dropwise. After completion of reaction (monitored by
TLC), reaction was quenched with water (5 mL) and the organic
layer was washed with aq. NaHCO3 (2%, 10 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. The crude compound was used directly in the next
reaction.
The solution of crude mesylate (100 mg, 0.30 mmol) was
dissolved in dry DMF (5 mL) and sodium azide (40 mg, 0.61
mmol) was added at room temperature. Then reaction was stirred
for 6 h at 60 °C. The progress of reaction mixture was monitored
by TLC. After completion of the reaction, it was cooled to room
temperature. This solution was extracted with ethyl acetate (3×50
mL) and the extract was washed with saturated sodium chloride
solution (3×20 mL). The combined organic layer was dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography using (pet. ether-ethyl acetate, 80:20) as the
eluent to furnish the azido-lactone compound 14 (75 mg, 68%
over two steps) as a colorless thick oil. Rf: 0.5 (pet. ether–ethyl
acetate, 70:30); IR (CHCl3, cm-1): νmax 3336, 2925, 2104, 1777,
25
D
1060, 912, 733; [α] +22(c 1.0, CHCl3); 1H NMR (500 MHz ,
CDCl3) δ 3.83-3.75 (m, 2H), 3.64-3.62 (m, 1H), 3.15-3.05 (m,
1H), 3.04 (dd, J = 5.0, 12.6 Hz, 1H), 2.91-2.89 (m, 2H), 2.05-
1.98 (m, 1H), 1.96-1.90 (m, 1H), 1.90-1.81 (m, 1H), 1.76-1.60
(m, 2H), 1.49 (s,18 H); 13C NMR (125 MHz, CDCl3) δ 155.4,
80.0, 79.7, 72.8, 72.4, 56.3, 45.0, 44.8, 29.7, 28.4 (6C), 21.9;
HRMS (ESI) m/z: calcd for C16H30N2O5[M+H]: 331.2143, found:
331.2144.
Crystallographic data for compound 8
CCDC 2024030 contains the supplementary crystallographic data
for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
Acknowledgment
25
1705, 1251, 1182, 1169, 1060, 912, 733; [α] –21 (c 1.0,
D
D.B.K. thanks UGC, New Delhi, for award of a research
fellowship. The authors thank CSIR, New Delhi for financial
support as part of XII year plan programme under the title
ORIGIN (NO.CSC-0108) and ACT (No.CSC-0301). We
also thank Dr. H. B. Borate for carefully evaluating
manuscript and Dattatraya Kavale for help in HPLC
analysis.
CHCl3); 1H NMR (200 MHz, CDCl3): δ 4.83 (d, J = 9.6 Hz, 1H),
4.72-4.65 (m, 1H), 3.99-3.92 (m, 1H), 3.56-3.44 (m, 2H), 2.61-
2.52 (m, 2H), 2.33-2.12 (m, 2H), 1.45 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 176.6, 155.6, 80.6, 78.7, 52.5, 52.2, 28.5, 28.2
(3C), 24.1; HRMS (ESI) m/z: [M + Na]+ calcd for C11H18N4O4Na:
293.1220, found: 293.1217.
4.1.14. tert-Butyl [(3R,4R)-4-hydroxy-7-oxoazepan-
3yl]carbamate (13).
Declaration of competing interest
The azido-lactone 14 (50 mg, 0.185 mmol) was dissolved in
methanol (5 mL) and to that was added catalytic amount of 10%
Pd/C. The resulting reaction mixture was stirred under hydrogen
atmosphere using balloon for 24 h. The reaction mixture was
filtered through celite and the filtrate was concentrated in vacuo.
The crude product was purifed by flash chromatography using
silica gel (Methanol–ethyl acetate, 10:90) to provide lactam 13
(35 mg) as a colorless thick oil. Rf: 0.4 (Methanol–ethyl acetate,
20:80); yield: 78%; IR (CHCl3, cm-1): νmax 3316, 2977, 1693,
The authors declare no conflict of interest.
Supplementary Material
Supplementary data related to this article can be found at
References and notes
25
1657, 1168, 1049, 756; [α] –60 (c 1.0, MeOH); 1H NMR (400
D
MHz, CDCl3): δ 6.30 (br s, 1H), 5.18-5.17 (m, 1H), 3.90 (br s,
1H), 3.79 (d, J = 11.6 Hz, 1H), 3.61 (br s, 1H), 3.05-2.96 (m,
2H), 2.83-2.81 (m, 1H), 2.26-2.20 (m, 1H), 1.98-1.92 (m, 1H),
1.85-1.83 (m, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
179.0, 155.6, 80.1, 69.8, 53.1, 40.4, 29.3, 28.3 (3C), 26.6; LCMS
(ESI): m/z: calcd for C11H20N2O4[M+H]: 245.1, found: 245.2 and
170 (due to removal of t-BuOH).
1. Quandt, C. A.; Kepler, R. M.; Gams, W.; Araujo, J. P.; Ban, S.; Evans, H.
C.; Hughes, D.; Humber, R.; Hywel-Jones, N.; and Li, Z. IMA fungus,
2014, 5, 121.
2
Kneifel, H.; Konig, W. A.; Loeffler W.; Muller, R. Arch. Microbiol., 1977,
113, 121.
3
Kulanthaivel, P.; Hallock, Y. F.; Boros C.; Hamilton, S. M.; Janzen,W.
P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. B.; Katz, B. J. Am. Chem.
Soc., 1993, 115, 6452.
4 Boros, C.; Hamilton, S. M.; Katz, B.; Kulanthaivel, P. J. Antibiot., 1994
,
4.1.15. tert-Butyl [(3R,4R)-3-(tert-butoxycarbonyl)amino]-4-
hydroxyazepane-1-carboxylate (4).
47, 1010.
5
Ohshima, S.; Yanagisawa, M.; Katoh, A.; Fujii, T.; Sano, T.;
Matsukama, S.; Furumai, T.; Fujiu, M.; Watanabe, K.; Yokose, K.;
To the solution of lactam 13 (30 mg, 0.12 mmol) dissolved in dry
THF (5 mL), borane (1 M in DMS, 0.6 mL, 0.61 mmol) was
added at room temperature. Then reaction was stirred for 12 h at
60 °C. The progress of reaction was monitored by TLC. After
completion of the reaction, it was cooled to room temperature. To
the reaction mixture 3 mL ethanol was added and stirred for
additional 6 h, then (Boc)2O (0.1 mL) and 2 mL of 2N NaOH was
added and then reaction mixture was stirred for 12 h. This
Arisawa, M.; Okuda, T. J. Antibiot., 1994
a
,
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,

Highlights
•
•
•
Divergent approach to the synthesis of (
hydroxypipecolic acid
̶ )-balanol heterocycle and cis-3-
Benzylidene acetal is used as prominent chiral C4 building block (2-aminobutane-1,3,4-
triol)
Construction of azepine core via Tandem reduction/acetal-deprotection/γ-lactonization
reaction and a one-pot azide reduction/cyclization

Declaration of Interest statement
Subhash P. Chavan a,b, Dinesh B. Kalbhora,b and Rajesh G. Gonnadeb,c
aDivision of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune-411008, India
bAcademy of Scientific and innovative Research (AcSIR), Ghaziabad- 201002, India
cCenter for Materials Characterization (CMC), CSIR-NCL (National Chemical Laboratory), Pune-411008, India
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
D.B.K. thanks UGC, New Delhi, for award of a research fellowship. The authors thank
CSIR, New Delhi for financial support as part of XII year plan programme under the title
ORIGIN (NO.CSC-0108) and ACT (No.CSC-0301). We also thank Dr. H. B. Borate for
carefully evaluating manuscript and Dattatraya Kavale for help in HPLC analysis.
Corresponding author. Tel.: +91 020 25902286; fax: +91 020 25902629;
e-mail: sp.chavan@ncl.res.in