Chiron approach towards the synthesis of (2S,3R)-3-hydroxyornithine, (2S,3R)-3-hydroxylysine and tetrahydroazepine core of (?)-balanol

Article abstract of DOI:10.1016/j.tet.2016.06.021

D-Glucose derived synthon 4 was successfully utilized for the synthesis of (2S,3R)-β-hydroxyornithine 1, (2S,3R)-β-hydroxylysine 2 and tetrahydroazepine core of balanol 3.

Full text of DOI:10.1016/j.tet.2016.06.021

Accepted Manuscript
Chiron approach towards the synthesis of (2S,3R)-3-hydroxyornithine, (2S,3R)-3-
hydroxylysine and tetrahydroazepine core of (-)-balanol
Rajendra Rohokale, Dilip Dhavale
PII:
S0040-4020(16)30534-8
10.1016/j.tet.2016.06.021
TET 27835
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 April 2016
Revised Date: 3 June 2016
Accepted Date: 6 June 2016
Please cite this article as: Rohokale R, Dhavale D, Chiron approach towards the synthesis of (2S,3R)-3-
hydroxyornithine, (2S,3R)-3-hydroxylysine and tetrahydroazepine core of (-)-balanol, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.06.021.
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Chiron approach towards the synthesis of (2S,3R)-3-Hydroxyornithine, (2S,3R)-3-Hydroxylysine
Leave this area blank for abstract info.
and tetrahydroazepine core of (-)-Balanol
Rajendra Rohokale and Dilip Dhavale*
Department of Chemistry, Garware Research Centre,
Savitribai Phule Pune University, (formerly Univesity of Pune) Pune-411 007, India.
Email: ddd@chem.unipune.ac.in

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Chiron approach towards the synthesis of (2S,3R)-3-Hydroxyornithine, (2S,3R)-
3-Hydroxylysine and tetrahydroazepine core of (-)-Balanol
Rajendra Rohokale and Dilip Dhavale*
Department of Chemistry, Garware Research Centre,
Savitribai Phule Pune University, (formerly Univesity of Pune) Pune-411 007, India.
Email: ddd@chem.unipune.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
D
-Glucose derived synthon
(2S,3R)− −hydroxyornithine 1, (2S,3R)−
balanol 3. 2009 Elsevier Ltd. All rights reserved
4
was successfully utilized for the synthesis of
β
β
−hydroxylysine 2 and tetrahydroazepine core of
.
Available online
Keywords:
balanol
carbohydrate
hydroxy amino acids
non-proteinogenic
protein kinase
ring closing metathesis
1. Introduction
The non-proteinogenic β−hydroxy amino acids are important
building blocks in the biosynthesis of peptides, protein scaffolds
and antibiotics1 as well as in the synthesis of complex natural
products.2 For example, threo-3-hydroxy-
L-ornithine 1 (Figure 1)
is an intermediate for the synthesis of the tuberculostatic cyclic
peptide antibiotic capreomycidine as well as a biosynthetic
precursor for β−lactamase inhibitor proclavaminic acid,
clavulanic acid and anticancer agent acivicin.3 One carbon
homologated analogue of 1 is 3-hydroxylysine 2 which is a
crucial marker in the oxidation of proteins.4 Glycosylated
derivatives of 5-hydroxylysine were found to be
immunodominant T cell Epitope in murine of Type II collagen-
the main protein part of articular cartilage associated with
rheumatoid arthritis.5 Moreover 3-hydroxylysine 2 is used as a
synthetic intermediate for fungal metabolite balanol 3 which is an
effective inhibitor of human protein kinase C (PKC)6,7 in cellular
signal transduction.8 The PKC enzyme is also involved in the
progression of diseases such as cardiovascular dysfunction,
asthma, cancer, inflammation, central nervous system disorders,
diabetic complications as well as HIV infection.9 Thus, high
selectivity and potency of balanol 3 towards the protein kinase
enzymes renders it as an attractive target for new therapeutic
agents.10 The structural framework of balanol 3 contains the
central chiral hexahydroazepine core that contains β−hydroxyl
amine functionality in which the stereochemistry at carbons
carrying amino and hydroxyl groups is exactly matching to that
of carbons having amino-hydroxyl functionality in 1 and 2.
Figure 1:
β
−Hydroxy−α−amino acids 1, 2 and (−)−balanol 3.
The synthetic approaches to 1, 2 and 3 involve both
asymmetric as well as chiron approaches. The asymmetric
pathways to
1 are based on the Sharpless asymmetric
epoxidation,11a dihydroxylation11b and asymmetric aldol
reaction.12a While chiron approaches make use of amino acids
such as vinyl glycinate and
D
-serine.12b-d Also, the methods for
the synthesis of 2 are reported in literature.6,7,13 The synthesis of
balanol 3 is focused on the synthesis of hexahydroazepine core14
wherein the main challenge is to obtain required
β−hydroxyamino
functionality
with
defined
absolute
stereochemistry. Amongst the reported total synthesis of
(−)−balanol 3, asymmetric methods are based on (i) resolutions
of the racemic mixtures15a-g or dynamic kinetic resolutions of
allylic alcohols,15h desymmetrization reactions15i,j (ii) asymmetric
epoxidation of unsaturated esters as well as allylic alcohols,16a-c
aminohydroxylation of unsaturated aryl esters.16d (iii) asymmetric
aziridination15i (iv) intramolecular stereo selective addition of
sulfonium
ylide
to
N-tbutylsulfinyl
imine.16e

2
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 1: Retrosynthetic analysis of 1, 2 and 3.
In addition, some reports for the synthesis of 3 have been based
16f-k
on the chiral templates i.e
D-serine
and L
-ascorbic acid.16l
As a part of our continuous interest in the synthesis of chiral
amino acids17 and iminosugars,18 we now report hitherto
unknown and an efficient chiron approach for the synthesis of
3−hydroxyornithine 1, 3-hydroxylysine 2 and tetrahydroazepine
core of balanol 3 using the common precursor 4 obtained from D-
glucose.
hydroxylysine 2, the sugar olefin 4 was subjected for the cross
metathesis reaction using the -NCbz protected allylamine in the
presence of Grubb’s second generation catalyst that afforded
diamino sugar olefin derivative 9 in 70% yield. In the next step,
treatment of 9 with TFA: H2O (9:1) afforded an anomeric
mixture of hemiacetal that was treated with NaIO4 in acetone:
H2O (to get C2 aldehyde) followed by the Pinnick oxidation to
get acid 10 in 68% yield over three steps. In the final step,
deprotection of both the -NCbz functionalities,-O-formyl group
and reduction of the carbon-carbon double bond in one pot using
catalytic 10% Pd/C provided bishydrochloride salt of 2 in 81%
yield. The spectral and analytical data of 2 was found to be
Results and discussion: As shown in the retrosynthetic
analysis (Scheme 1), we visualized -glucose type of hidden
D
symmetry in the target molecules. The acid functionality of the
target molecules 1 and 2 could be obtained by excision of the
anomeric carbon in compound 7 followed by oxidation. The α-
amino functionality of 1 and 2 could be derived from the double
o
inversion of C3-hydroxy group of
D-glucose and in case of 1 and
identical with that of reported {mp 190-191 C, [reported6a 188–
2
the terminal amino functionality could be derived by
192 oC]; [α]D28 +15.8, (c 1.88, CH3OH), reported6a [α]D25 +16.90,
(c 1.83, CH3OH)}.
functionalization of C5-C6 carbon-carbon double bond in 4. For
balanol 3, the functionalized azepine core could be accessed
through ring closing metathesis (RCM) of acyclic diene precursor
14 (Scheme 1) that could be obtained by SN2 displacement of
tosyloxy group in 13 with allylamine. The 1,2 acetonide
functionality in 4 could be manipulated to get 13. Absolute
configurations of C3 and C4 in 4 are identical with that of target
molecules 1, 2 and 3 justifying its use as common synthon.
Synthesis of tetrahydroazepine core of 3: For the synthesis
of protected tetrahydoazepine core of balanol 3, sugar olefin 4
was treated with TFA: H2O (9:1) to get hemiacetal that on
reaction with NaIO4 followed by reduction of in situ generated C-
2 aldehyde with NaBH4 afforded 1,3 diol 11. The primary
hydroxyl group in diol 11 was selectively converted into tosyloxy
derivative by treatment with TsCl in TEA using cat. amount of
nBu2SnO to get tosyl derivative 12 in 85% yield. In the next step,
free allylic hydroxyl group in 12 was protected as a MOM ether
using MOM chloride in the presence of DIPEA in
dichloromethane under reflux condition to get 13 in 82% yield.
Further, the SN2 displacement of the tosyloxy group in 13 with
Synthesis of 1 and 2: The requisite 3-benzylcarbamate-3,5,6-
trideoxy-1,2-O-isopropylidene-α-
prepared according to the earlier report from our laboratory in
79% yield from
-glucose17b (Scheme 2). Hydroboration with
D-gluco-hexofuran-5-ene 4 was
D
B2H6 (in situ generated from NaBH4/I2) followed by oxidation
(H2O2, NaOH) of sugar olefin 4 gave primary alcohol 5 in 80%
yield.19 In the next step, the primary alcohol is converted into O-
mesyl derivative 6 (MsCl/TEA) and subsequently reacted with
NaN3 in DMF to get 6-azido-sugar derivative 7. Deprotection of
1,2-acetonide functionality in 7 with TFA-water (9:1) afforded an
anomeric mixture of hemiacetal that on oxidative cleavage using
sodium metaperiodate in acetone–water followed by the Pinnick
oxidation (NaClO2, NaH2PO4) provided acid 8 as a viscous oil.20
Finally, one pot reduction of azide functionality and deprotection
of –NCbz as well as removal of -O-formyl group using 10% Pd/C
in MeOH-HCl afforded mono-hydrochloride salt of (2S,3R)-β-
hydroxyornithine 1 as a solid in 68% yield. The spectral and
analytical data of 1 was found to be in consonance with that
reported {[mp 194-195 °C (lit.12d mp 123 °C)]; [α]D28 +3.2 (c 2.9,
o
allylamine in methanol at 60 C followed by reaction with Ac2O
in pyridine afforded N-acetyl protected divinyl derivative 14. In
the final step, ring closing metathesis (RCM) of 14 using the
Grubbs second-generation catalyst in dichloromethane at reflux
conditions afforded the tetrahydroazepine core 15 that could be
utilized for the synthesis of balanol 3 and its analogues (Scheme
3).
In summary, we have demonstrated the judicious
manipulation of hydroxyl functionalities in
D
-glucose derived
for the synthesis of (2S,3R)-β-
(2S,3R)-β-hydroxylysine and
common synthon
hydroxyornithine
4
1,
2
tetrahydroazepine core of balanol 3. The use of easily available
reagents, mild reaction conditions and high yielding steps make
our approach practicable for the synthesis of target molecules.
25
H2O) [lit.12d [α]D +2.9 (c 3.0, H2O)]}. For the synthesis of 3-

3
ACCEPTED MANUSCRIPT
Scheme 2: Synthesis of 1 and 2. Reagents and conditions: (a) NaBH4, I2, NaOH/H2O2; (b) MsCl, Et3N, DCM; (c) NaN3, DMF; (d) i.
TFA/H2O; ii. NaIO4; iii. NaClO2, H2O2; (e) H2, Pd/C, MeOH:HCl (4:1); (f) NCbzallyl amine, Grubbs IInd (10 mol %), DCM.
1,2-O-isopropylidene-3-(N-benzyoxycarbonyl)-amino-
3,5-
dideoxy-α-D-gluco-1,4-furanose (5): To a stirred suspension of
NaBH4 (0.26 g, 6.9 mmol) in dry THF (25 mL) was added iodine
(0.87 g, 3.44 mmol) in dry THF (15 ml) under nitrogen
o
atmosphere over a period of 1 h at 0 C. To this cooled solution
was added solution of 4 (2.2 g, 15 mmol) in THF (10 mL) and
o
the reaction mixture was stirred at 25 C. After 3 h, reaction
o
mixture was cooled to 0 C and 3N NaOH (30 mL) and 30%
H2O2 (30 mL) were added slowly and stirred for 20 min. The
organic layer was separated and the aqueous layer was extracted
with diethyl ether (20 mL × 3). The combined organic extract
was washed with water, brine and dried over anhydrous Na2SO4.
Evaporation of solvent and purification by silica gel column
chromatography using (pet. ether/ EtOAc = 7/3) afforded alcohol
5 (1.85 g, 80%) as a thick liquid; Rf = 0.5 (30% EtOAc/pet.
ether); [α]D20 −14.8 (c 0.4, CHCl3); IR (neat) ν max: 3200–3600
Scheme 3: Synthesis of 15. Reagents and conditions: (a)
i.TFA:H2O (9:1); ii. NaIO4, CH3COCH3: H2O; iii. NaBH4, THF:
H2O (4:1); (b) TsCl, nBu2SnO, TEA, DCM; (c) MOMCl,
o
DIPEA, DCM, reflux; (d) i. allyl amine, MeOH, 60 C; ii. Ac2O,
Py, DCM; (e) Grubb's IInd, DCM, reflux.
1
(br), 1695 cm-1; H NMR (300 MHz, CDCl3): δ 7.50-7.20 (5H,
Experimental section
General experimental methods:
All reactions were carried out with distilled and dried solvents
m, Ar-H), 5.80 (1H, d, J = 3.8 Hz, H-1), 5.13 (2H, AB quartet, J
= 12.0 Hz, O-CH2Ph), 4.88-4.72 (2H, br m, NH, D2O), 4.53 (1H,
d, J = 3.8 Hz, H-2), 4.44- 4.32 (1H, m, H-4), 4.20 (1H, d, J = 3.0
Hz, H-3), 3.86-3.69 (2H, m, H-6), 1.92-1.72 (2H, m, H-5), 1.53
(3H, s, -CH3), 1.30 (3H, s, -CH3). 13C NMR (75 MHz, CDCl3): δ
155.8, 136.0, 130.9, 128.5, 128.3, 111.9, 26.0, 103.9, 84.5, 67.2,
60.0, 58.2, 30.8, 29.7, 26.3. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd. for C17H23NO6Na, 360.1425; found 360.1424.
using oven-dried glassware. Specialized reagents were purchased
from commercial sources (Aldrich or fluka). 1H NMR
(300MHz/400MHz/500MHz)
and
13C
NMR
(75MHz/100MHz/125MHz) were recorded in CDCl3 and D2O as
solvents. Chemical shifts were reported in δ unit (parts per
million) with reference to TMS as an internal standard (In case of
D2O, HDO peak at δ 4.86). IR spectra were obtained using FTIR
spectrophotometer as a thin film or using KBr pellets and
recorded in cm-1. High-resolution mass spectra were obtained
1,2-O-isopropylidene-3-(N-benzyoxycarbonyl)-amino-3,5-
dideoxy-6-O-mesyl-α-D-gluco-1,4-furanose (6): To an ice
cooled solution of alcohol 5 (2 g, 5.93 mmol) in dichloromethane
(15 mL) was added triethylamine (2.5 mL, 17.78 mmol) and
DMAP (0.01 g) followed by methanesulphonyl chloride (0.56
mL, 7.11 mmol) in dichloromethane (10 mL) over a period of 10
min and the resultant reaction mixture was stirred at the same
temperature for 3 h. The reaction mixture was quenched by
adding water (20 mL) and organic layer was separated. Usual
work up and purification by column chromatography using pet.
ether/ EtOAc = 8/2 gave 6 (2.4 g, 98%) as a thick liquid; Rf = 0.7
with
a HRMS Thermo-scientific Bruker Daltonic GmbH
Germany Impact II UHR-TOF mass spectrometer ESI. Melting
points were recorded using Thomas Hoover melting point
apparatus and are uncorrected. Optical rotations were measured
on a digital polarimeter with sodium light (589.3 nm) at 24–30
°C. Thin layer chromatography was performed on pre-coated
plates (0.25 mm, silica gel 60 F254). Column chromatography
was carried out with silica gel (100-200 mesh). After
neutralization workup involves washing of combined organic
layer with water, brine, drying over anhydrous sodium sulphate
and evaporation of solvent under reduced pressure.
20
(30% EtOAc/pet. ether); [α]D −8.7 (c 0.75, CHCl3); IR
(neat) ν max: 1710, 1440, 1350, 1170 cm−1; 1H NMR (300 MHz,
CDCl3): δ 7.40-7.20 (5H, br. m, Ar-H), 5.71 (1H, d, J = 3.8 Hz,
H-1), 5.04 (2H, AB quartet, J = 12.5 Hz, O-CH2Ph), 4.92-4.82

4
Tetrahedron
ACCEPTED MANUSCRIPT
(1H, br,-NH), 4.43 (1H, d, J = 3.8 Hz, H-2), 4.33-4.10 (4H, m,
1H NMR (300 MHz, CDCl3): δ 7.97 (1H, s, -OCHO), 7.41-7.20
H-6, H-3, H-4), 2.92 (3H, s, -OMs), 2.01-1.84 (2H, m, H-5), 1.43
(3H, s, -CH3), 1.22 (3H, s, -CH3); 13C NMR (75 MHz, CDCl3):
155.7, 135.9, 130.9, 128.8, 128.6, 128.4, 128.2, 112.0, 103.7,
84.6, 74.7, 67.2 , 66.8, 57.9, 37.2, 28.3, 26.3, 26.0; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C18H25NO8SNa 438.1200; found
438.1199.
(5H, m, Ar-H), 6.09-6.06 and 5.80-5.71 (1H, d, J = 8.9 Hz, 9.9
Hz, two rotamers) 5.20-5.05 (2H, m), 4.64-4.61 and 4.41-4.25
(3H, m, two rotamers), 3.49–3.12 (2H, m), 1.80–1.45 (1H, m).
13C NMR (75 MHz, CDCl3) δ 174.2, 160.2, 157.1 and 156.7 (two
rotamers) 135.8, 128.5, 128.6, 128.3, 128.1, 128, 71.1, 69.1, 67.7
and 67.5 (two rotamers), 58.2, 47.9 and 47.2 (two rotamers),
1
1,2-O-isopropylidene-3-(N-benzyoxycarbonyl)-amino-3,5-
32.3, 30.5; (The H and 13C NMR spectra of 8 showed doubling
of signals due to the presence of -NHCbz group resulting into
restricted rotation around C=N bond); HRMS (ESI TOF) m/z
calcd. for C14H16N4O6Na [M + Na]+ 359.0968, found 359.0964.
trideoxy-6-azido-α-D-gluco-1,4-furanose (7): To a stirred
solution of 6 (2 g, 4.81 mmol) in DMF (10 mL) was added
sodium azide (0.63 g, 9.63 mmol) and the reaction mixture was
ο
(2S,3R)-2,5-diamino-3-hydroxy-pentanoic acid.HCl (1):
A
refluxed. After 1 h the solution was cooled to 25 C, DMF was
steel pressure vessel containing 8 (0.2 g, 0.68 mmol) in MeOH (4
mL) and absolute HCl (1 mL) was purged with argon for 15 min
and Pd/C (0.02g, 0.13 mmol) was added to this solution. The
tube was pressurized to 100 psi with hydrogen gas. The reaction
was stirred at room temperature for 4 days. The catalyst was
removed by filtration through celite. The celite pad was washed
several times with a MeOH:H2O (2:1) solution. The water
volume was reduced on high vacuum and brought to pH 6.5 with
NH4OH. Addition of EtOH resulted in a white precipitate that
was collected by filtration and dried to yield 0.06 g (68%) of 1 as
the mono-HCl salt; Rf = 0.4 (n-butanol /H2O/AcOH = 4/2/1); mp
removed on rotary evaporator and the crude mixture was
dissolved into EtOAc/H2O (40 mL, 1:1). The organic layer was
separated and aqueous phase was extracted with ethyl acetate
(3×10 mL). Usual workup and column purification (pet. ether/
EtOAc = 9/1) afforded 7 (1.6 g, 91%) as a thick liquid; Rf = 0.54
(10% EtOAc/pet. ether); [α]D28 −13.4 (c 0.11, CHCl3); IR (neat)
ν max: 2160, 1680, 1456, 1377 cm−1; 1H NMR (500 MHz, CDCl3
): δ 7.56–7.01 (5H, m, Ar-H), 5.75 (1H, d, J = 3.7 Hz), 5.08 (2H,
AB quartet, J = 12.1 Hz), 4.99 (1H, d, J = 9.6 Hz), 4.47 (1H, d, J
= 3.1 Hz), 4.29–4.21 (1H, m), 4.21–4.13 (1H, m), 3.38 (2H, t, J =
9.6 Hz), 1.88 –1.70 (2H, m), 1.49 (3H, s), 1.26 (3H, s); 13C NMR
(125 MHz, CDCl3): δ 155.7, 135.9, 128.5, 128.3, 128.1, 111.9,
103.7, 84.5, 75.6, 67.1, 57.8, 48.2, 28.1, 26.3, 25.9; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C17H22N4O5Na, 385.1488 found
385.1489.
28
194-195 °C (dec.), (lit.12d mp 123 °C; [α]D +3.2 (c 2.9, H2O)
[lit.12d [α]D25+2.9 (c 3.0, H2O)]; IR (neat) ν max: 3350 (br), 2950,
1
1640, 1572, 1540 cm˗1; H NMR (300 MHz, D2O) δ 4.20 (1H,
ddd, J = 8.4, 5.3, 3.5 Hz), 3.73 (1H, d, J = 4.2 Hz), 3.30-3.07
(2H, sym m), 2.09 –1.71 (2H, m); 13C NMR (75 MHz, D2O) δ
172.8, 68.2, 59.8, 32.9, 31.8.; HRMS (ESI TOF) m/z calcd. for
C5H12N2O3Na [M + Na]+ 171.0746, found 171.0750.
(2S,3R)-2-(N-benzyoxycarbonyl)-amino-5-azido-3-O-formylo-
pentanoic acid (8): An ice-cold solution of 7 (1 g, 2.76 mmol) in
TFA-H2O (20 mL, 9:1) was stirred for 15 min and at 25 °C for 7
h. Trifluoroacetic acid was co-evaporated with toluene at rotary
evaporator using high vacuum to furnish hemiacetal as a thick
liquid (crude wt = 0.9 g). To an ice-cooled solution of hemiacetal
(0.9 g, 2.79 mmol) in acetone/water (10 mL, 5:1) was added
sodium metaperiodate (0.89 g, 4.19 mmol), and the solution was
stirred for 30 min at 25 °C. Ethylene glycol (0.2 mL) was added,
solvent was evaporated on rotary evaporator and the residue was
extracted with chloroform (3 × 15 mL). Usual workup afforded
α-aminal as a thick liquid (1.5 g). To a stirred solution of above
product (0.64 g, 2 mmol) in acetonitrile (5 mL) was added the
solution of sodium dihydrogen phosphate (0.08 g, 0.59 mmol) in
water (3 mL) and 30% H2O2 (0.24 mL, 2.4 mmol). Reaction
mixture was stirred and cooled at −10 °C. To this solution,
NaClO2 (0.20 g, 2.4 mmol) in water (3.5 mL) was added drop
wise over a period of 30 min and stirred at 15 °C, (the reaction
was monitored by the evolution of oxygen with a bubbler
connected to the apparatus). After 10 h, the reaction was
decomposed by addition of a small amount of Na2SO3 (0.1 g) and
acidified with 10% aq. HCl (5 mL). The organic layer was
separated and aqueous layer was extracted with ethyl acetate (4 ×
5 mL). Combined organic layer was evaporated, and the residue
was dissolved in 10% NaHCO3 solution (25 mL). The
bicarbonate layer was washed with ethyl acetate (15 mL) and
then made acidic to pH 2 and extracted with ethyl acetate (3 × 15
mL). Usual workup gave 8 (0.64 g, 79% over 3 steps) as a sticky
3,7-(N-benzyoxycarbonyl)-amino-1,2-O-isopropylidene-
3,5,6,7-tetradeoxy-α-D-xylo-hept-5-ene-furanose (9): To a
solution of 4 (0.3 g, 0.94 mmol) in dry dichloromethane (25 mL)
was added NCbz protected allylamine (0.54 g, 2.82 mmol)
followed by 10 mol % Grubbs IInd generation catalyst (0.01 g,
0.01 mmol), the resulting reaction mixture was stirred for 72 h
and solvent evaporation to get crude product (dark oil).
Purification by column chromatography (pet. ether/ EtOAc = 6/4)
gave 9 as a thick liquid (0.32 g, 70%); Rf = 0.4 (50% EtOAc/pet.
28
ether); [α]D −30.2 (c 1.9, CHCl3); IR ν max: 3350 (br), 1733,
1
1650 cm-1; H NMR (500 MHz, CDCl3): δ 7.41-7.28 (10H, m),
5.97-5.86 (1H, m), 5.82 (1H, d, J = 3.7 Hz), 5.63-5.49 (1H, m),
5.19-4.92 (6H, m), 4.79 (1H, br. s), 4.61 (1H, br. s), 4.14 (1H, dd,
J = 7.2, 2.3 Hz), 3.86-3.65 (2H, m), 1.53 (3H, s), 1.30 (3H, s);
13C NMR (125 MHz, CDCl3): δ 156.2, 155.9, 136.5, 136.1,
131.0, 128.6, 128.5, 128.3, 128.1, 127.0, 124.8, 111.9, 103.9,
84.4, 77.6, 67.1, 66.8, 58.5, 42.5, 26.5, 26.1.; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C26H30N2O7Na, 505.1951; found
505.1946.
(2S,3R)-2,6-(N-benzyoxycarbonyl)-amino-3-O-formylo-hex-4-
ene-oic acid (10): 9 afforded 10 as sticky gum (0.16 g, 68% over
3 steps) using similar procedure as described for the synthesis of
8 from 7. Rf = 0.2 (40% EtOAc/pet. ether); [α]D28 -48.3 (c 1.8,
1
CHCl3). IR ν max: 3350 (br), 2850, 1737, 1648, 1040 cm-1; H
NMR (300 MHz, CDCl3): δ 8.20 (1H, s, -OCHO), 7.41-7.28 (10
H, m), 5.98 (1H, br. d, J = 5.4 Hz, -NH) 5.8-5.01 (3H, m), 5.60
(1H, d, J = 9.6 Hz), 5.30-5.10 (6H, m, two rotamers), 4.70 (1H,
28
gum; Rf = 0.45 (40% EtOAc/pet. ether); [α]D +24.4 (c 0.1,
CHCl3); IR (neat) ν max: 3389-2800 (br), 2150, 1721, 1460 cm˗1;

5
dd, J = 6.2, 3.2 Hz), 4.31 (1H, d, J = 6.2 Hz), 3.81-3.60 (2H, m);
13C NMR (75 MHz, CDCl3): δ 170.3, 169.9 (two rotamers),
162.8, 157.1, 157.0, 136.2, 133.4, 130.1, 128.8, 128.7, 128.6,
128.4, 128.3, 128.2, 127.7, 127.0, 68.5, 68.2 (two rotamers),
67.1, 65.4, 42.3, 41.7.; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C23H24N2O8Na, 479.1430; found 479.1431.
extracted with dichloromethane (10 mL × 3) and concentrated.
ACCEPTED MANUSCRIPT
Purification by column chromatography (pet. ether/ EtOAc = 8/2)
gave 12 (0.69 g, 85%) as a thick liquid; Rf = 0.6 (40%
EtOAc/pet. ether); [α]D25 −2.41 (c 1.9, CHCl3); IR (neat) ν max:
3341 (br), 1658, 1427, 1350, 1092, 756, 660 cm−1; 1H NMR (500
MHz, CDCl3): δ 7.81 (2H, d, J = 8.1 Hz), 7.90-7.20 (7H, m),
5.86 -5.76 (1H, m), 5.32 (1H, d, J = 17.2 Hz), 5.28 (1H, d, J =
12.5 Hz), 5.20 (1H, br, s, exchange with D2O), 5.11 (2H, s), 4.40
(1H, s, -NH), 4.10 (1H, dd, J = 9.7 Hz, 7.0 Hz), 4.09 (1H, dd, J =
9.8 Hz, 5.4 Hz), 4.01-3.80 (1H, m), 2.45 (3H, s); 13C (125 MHz,
CDCl3) NMR: δ 156.4, 145.2, 136.5, 136.1, 132.4, 130.0, 128.6,
128.2, 128.0, 127.9, 117.2, 70.1, 68.1, 67.1, 53.5, 21.7.; HRMS
(ESI TOF) m/z calcd. for C20H23NO6SNa [M + Na]+ 428.1144,
found 428.1139.
(2S,3R)-2,6-Diamino-3-hydroxy-hexanoic acid. 2HCl (2):
Compound 10 (0.16 g, 0.35 mmol) and 10% Pd/C (20% mole,
0.01 g, 0.07 mmol) in MeOH/HCl (4:1 mL) was stirred under a
H2 atmosphere at 100 psi for 12 h at 25 oC in pressure vessel. The
catalyst was filtered through a pad of celite. The filtrate was
concentrated, washed using EtOAc and purified using column
chromatography using (H2O/MeOH = 9.5/0.5) to afford 2 as a
white powder (0.9 g, 81%); Rf = 0.06 (n-butanol /H2O/AcOH =
4/1/1); mp 190–191 oC (The compound gets decomposed at
(2R,3R)-2-(((benzyloxy)-carbonyl)-amino)-3-
o
28
metling point temperature) [reported6a mp 188–192 C]; [α]D
(methoxymethyl)-pent-4-en-1-yl-4-methylbenzenesulfonate
(13): DIPEA (0.44 mL, 2.52 mmol) was added at 0 oC to a
cooled solution of the alcohol 12 (0.51 g, 1.26 mmol) in dry
dichloromethane (15 mL) followed by MOM chloride (0.14 mL,
1.89 mmol). The reaction mixture was refluxed for 4 h. After
completion of the reaction, solvent was evaporated and the
residue was diluted with ethyl acetate. The organic layer was
washed with water and brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by column
chromatography (pet. ether/ EtOAc = 6/4) to give 13 (0.47 g
+15.8, (c 1.88, CH3OH); reported6a +16.9 (c 1.83, CH3OH); IR
(neat) ν max: 3355 (br), 1735 cm-1; 1H NMR (300 MHz, D2O): δ
4.34-4.14 (1H, m), 4.06 (1H, s), 3.07 (2H, t, J = 6.9 Hz), 1.59–
1.95 (4H, m); 13C NMR (75 MHz, D2O): δ 170.5. 68.4, 57.7,
38.9, 29.9, 23.3.; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C6H14N2O3Na, 185.0902; found 185.0910.
((2R,3R)-1,3-dihydroxypent-4-en-2-yl)-carbamate (11): An
ice-cold solution of 4 (2 g, 5.74 mmol) in TFA-H2O (20 mL, 9:1)
was stirred for 15 min and at 25 °C for 4 h. Trifluoroacetic acid
was co-evaporated with toluene at rotary evaporator using high
vacuum to furnish hemiacetal as a thick liquid 1.8 g. To an ice-
cooled solution of hemiacetal (1.8 g, 6.44 mmol) in
acetone/water (20 mL, 5:1) was added sodium metaperiodate
(2.07 g, 9.67 mmol), and the solution was stirred for 1.5 h at 25
°C. The solvent was evaporated on rotary evaporator, and the
residue was extracted with EtOAc (3 × 15 mL). To an ice-cooled
solution of crude aldehyde (1.5 g, 5.41 mmol) in THF-water (10
mL, 4:1) was added sodium borohydride (0.31 g, 8.11 mmol) in
two portions. Reaction mixture was stirred for 30 min and
quenched by adding saturated aq. NH4Cl solution (5 mL). THF
was evaporated under reduced pressure, extracted with
chloroform (20 mL × 3) and concentrated. Purification by
column chromatography (pet. ether/EtOAc = 7/3) gave 11 (1.2 g,
90%) as a thick colourless liquid; Rf = 0.45 (40% EtOAc/pet.
ether); [α]D25 −2.12, (c 1.8, CHCl3); IR (neat) ν max: 3389 (br),
1636, 1460, cm−1; 1H NMR (500 MHz, CDCl3): δ 7.42-7.24 (5H,
m), 5.92-5.75 (1H, m), 5.62 (1H, d, J = 8.2 Hz), 5.38 (1H, d, J =
17.2 Hz), 5.26 (1H, br. d, J = 10.5 Hz), 5.11 (2H, br. s, CH2O-),
4.41 (1H, br, s, -NH), 3.87-3.67 (3H, m), 3.45 (2H, br. s,
exchange with D2O); 13C (125 MHz, CDCl3) NMR: δ 157.0,
137.4, 136.3, 128.5, 128.2, 128.0, 116.5, 72.8, 72.5, 67.1, 63.5,
55.6; HRMS (ESI TOF) m/z calcd. for [C13H17NO4Na M + Na]+
274.1055, found 274.1057.
25
82%) as thick liquid; Rf = 0.6 (40% EtOAc/pet. ether); [α]D
−1.5 (c 1.64, CHCl3); IR (neat) ν max: 1717, 1596, 1455, 1402,
1024 cm−1; H NMR (500 MHz, CDCl3): δ 7.80-7.61 (2H, d, J =
1
8.1 Hz), 7.39-7.29 (7H, m), 5.75-5.65 (1H, m), 5.33-5.27 (2H,
m), 5.11 (1H, br, s, -NH), 5.09 (2H, s, -OCH2OMe), 4.65 (1H, d,
J = 6.7 Hz, -OCH2Ph), 4.5 (1H, d, J = 6.7 Hz, -OCH2Ph), 4.26- 4.
22 (1H, m, -CH2OTs), 4.15 (1H, dd, J = 9.4 Hz, J = 7 Hz), 4.10
(1H, dd, J = 9.5 Hz, J = 5 Hz), 4.05-3.90 (1H, m), 3.33 (3H, s, -
OCH3), 2.46 (3H, s, -PhCH3); 13C (125 MHz, CDCl3) NMR: δ
155.9. 145.0, 136.2, 133.6, 132.7, 129.1, 128.5, 128.2, 128.0,
127.9, 120.3, 94.1, 74.8, 67.8, 67.0, 55.9, 53.1, 21.6.; HRMS
(ESI TOF) m/z calcd. for C22H27 NO7SNa [M + Na]+ 472.1406,
found 472.1412.
((2R,3R)-1-(N-allylacetamido)-3-(methoxymethyl)-pent-4-en-
2-yl)-carbamate (14): The tosylated compound 13 (0.35 g, 0.78
mmol), was stirred in a sealed tube with allylamine (5 mL) in
methanol (5 mL) at 65 C for 6 h. The reaction mixture was
concentrated and the residue was dissolved in dichloromethane (5
o
o
mL). Pyridine (1.0 mL) was added at 0 C, followed by acetic
anhydride (0.15 g, 0.99 mmol). The reaction mixture was stirred
for 12 h. After completion of the reaction, it was diluted with
ethyl acetate and organic layer was washed with sat. solution of
CuSO4. Organic layer concentrated in vaccum. The residue was
chromatographed over silica gel (pet. ether/EtOAc = 7/3) to give
divinyl product 14 (0.54 g, 93%) as colourless thick liquid; Rf =
0.7 (40% EtOAc/pet. ether); [α]D25−0.44 (c 0.56, CHCl3); IR
(neat) ν max: 2105, 1713, 1628, 1475, 1417, 1023 cm−1; 1H NMR
(500 MHz, CDCl3): δ 7.42-7.30 (6H, m), 5.80-5.60 (2H, m),
5.50-5.01 (6H, m, two rotamers), 4.70 (1H, d, J = 6.7 Hz, -
OCH2Ph), 4.59 (1H, d, J = 6.7 Hz, -OCH2Ph), 4.17-3.80 (5H, m,
two rotamers), 3.41 (3H, s, -OCH3), 3.16 (1H, d, J = 10 Hz), 1.99
(3H, s, -NCOCH3); 13C (125 MHz, CDCl3) NMR: δ 172.2, 156.6,
(2R,3R)-2-(((benzyloxy)carbonyl)-amino)-3-hydroxypent-4-
en-1-yl-4-methylbenzenesulfonate (12): To a stirred solution of
11 (0.5 g, 1.99 mmol) in dry dichloromethane, was added triethyl
amine (0.08 mL, 5.97 mmol) and tosyl chloride (0.42 g, 2.19
mmol) and catalytic amount of di-nbutyl tinoxide (nBu2SnO)
o
(0.01 g, 0.039 mmol) at 0 C. The reaction mixture was stirred
for 2 h at room temperature. Reaction mixture was quenched with
water (5 mL). Organic layer was separated and aqueous layer was

6
Tetrahedron
ACCEPTED MANUSCRIPT
Fugger, L. Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 7574. (b)
136.8, 134.1, 132.6, 128.6, 128.4, 128.0, 119.4, 116.7, 94.3,
Backlund, J.; Treschow, A.; Bockermann, R.; Holm, B.; Holm, L.;
Issazadeh-Navikas, S.; Kihlberg, J.; Holmdahl, R.; Eur. J.
Immunol. 2002, 32, 3776.
66.5, 55.9, 53.5, 51.0, 45.9, 21.2. (The spectrum showed
additional peaks due to its rotamers); HRMS (ESI TOF) m/z
calcd. for C20H28N2O5Na [M + Na]+ 399.1896, found 399.1896.
((3R,4R)-1-acetyl-4-(methoxymethyl)-2,3,4,7-tetrahydro-1H-
azepin-3-yl)-carbamate (15): Grubbs catalyst IInd generation 10
mol % (0.03 g, 0.04 mmol) was added in two portions (after 1 h
each) to a solution of 14 compound (0.15 g, 0.40 mmol) in dry
CH2Cl2 (20 mL) and the reaction mixture was refluxed for 16 h.
After completion of the reaction, solvent was removed and the
residue was chromatographed over silica gel to furnish the
tetrahydroazepine core (0.11 g, 78%); Rf = 0.3 (40% EtOAc/pet.
6. (a) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu,
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25
ether). [α]D −1.6 (c 1.9, CHCl3); IR (neat) ν max: 2924, 1710,
1630, 1447, 1237cm−1; 1H NMR (500 MHz, CDCl3): δ 7.45-7.29
(8H, m), 6.24 (1H, d, J = 7.4 Hz), 6.10-6.03 (1H, m), 5.80-5.71
(2H, m), 5.62-5.01 (1Η, m), 5.17 (1H, d, J = 12.2 Hz, -
OCH2OMe), 5.14-5.09 (1H, m), 5.06-5.03 (1H, d, J = 12.3 Hz, -
OCH2OMe), 4.71 (1H, d, J = 10.3 Hz, -OCH2Ph), 4.65-4.60 (1H,
m), 4.50 (1H, d, J = 10.3 Hz, -OCH2Ph), 4.35-4.05 (3H, m, two
rotamers), 3.93-3.80 (3H, m, two rotamers), 3.38 (3H, s, -OCH3),
2.15 (3H, s, -NCOCH3); 13C (125 MHz, CDCl3) NMR: δ 171.5
and 170.5 (two rotamers), 156.2 and 155.6 (two rotamers), 136.8,
136.1, 132.8, 130.2, 128.6, 128.4, 128.2, 127.9, 126.2, 95.7, 75.6,
67.1, 67.05, 55.8, 55.5, 55.0, 52.8, 50.9, 49.2 21.3 and 21.1 (two
rotamers) (The spectrum showed additional peaks due to its
rotamers14h); HRMS (ESI TOF) m/z calcd. for C18H24N2O5Na [M
+ Na]+ 371.1583, found 371.1582.
Acknowledgments:
We are thankful to the Department of Science and
Technology, New Delhi (Project File No. EMR/2014/000873) for
providing financial support. R.S.R. is thankful to CSIR, New
Delhi for providing a Senior Research Fellowship. We are
thankful to Central Instrumentation Facility (CIF) of SPPU for
spectral analysis.
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7
M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J. Org. Chem.
ACCEPTED MANUSCRIPT
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