Chiron approach to callipeltin A: First synthesis of fully protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxy heptanoic acid

Article abstract of DOI:10.1016/S0957-4166(01)00400-1

Stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihyroxy heptanoic acid, which is present as a side chain attached to the main macrocyclic depsidecapeptide backbone of callipeltin A (a potent, cytotoxic, anti-HIV and anti-fungal agent) s

Full text of DOI:10.1016/S0957-4166(01)00400-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2315–2321
Chiron approach to callipeltin A: first synthesis of fully
protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxy heptanoic acid†
S. Chandrasekhar,* T. Ramachandar and B. Venkateswara Rao
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 July 2001; accepted 11 September 2001
Abstract—Stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxy heptanoic acid, which is present as a side
chain attached to the main macrocyclic depsidecapeptide backbone of callipeltin A (a potent, cytotoxic, anti-HIV and anti-fungal
agent) starting from a carbohydrate, is described. © 2001 Published by Elsevier Science Ltd.
1. Introduction
from a shallow water sponge of the Callipelta species. The
compound showed marked activity in cytotoxic assays
against KB and P388 cells and in anti-HIV and antifungal
tests. The structure of callipeltin A was determined by
interpretation of spectral data, chemical degradation, and
evaluation of the amino acids obtained by acid hydrolysis.
Cyclic depsidecapeptides have emerged as a very impor-
tant class of bioactive compounds isolated from marine
natural products.1 In 1996, Minale et al. reported the
isolation of a cyclic depsidecapeptide, callipeltin A 1,2
CONH2
L-dlMe-Gln
2R, 3R, 4S AGDHE
OH
O
NH
OH
O
H
N
L-Thr
O
NH
N
H
H2N
N
H
N
H
L-Thr
O
HN
D-Arg
OH
NH
NH2
N
H
O
O
H2NOC
O
L-Ala
O
NH
O
Me
L-MeAla
HN
N
N
Me
O
O
L-Leu
MeO
O
N
H
L-MeGln
OH
β-MeOTyr
OH
Callipeltin A 1
* Corresponding author. Fax: +91-40-7170512; e-mail: srivaric@iict.ap.nic.in
†
IICT Communication No. 4856.
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00400-1

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S. Chandrasekhar et al. / Tetrahedron: Asymmetry 12 (2001) 2315–2321
In our efforts to synthesize a series of bioactive
molecules, we have chosen callipeltin A as a target
molecule due to its interesting anti-HIV properties
and its novel amino acid residues: b-methoxy-tyrosine
2. Results and discussion
D
-Glucose 6 was converted into the dialdo derivative
5 by a sequence of reactions reported earlier.4 Subse-
(b-OMeTyr),
dihydroxyheptanoic acid (AGDHE) and (3S,4R)-3,4-
dimethyl- -glutamine. Recently, Joullie et al. reported
the synthesis of one of the unusual amino acids,
(3S,4R)-3,4-dimethyl-
-glutamine.3 As a part of our
(2R,3R,4S)-4-amino-7-guanidino-2,3-
quent
olefination
with
(carboethoxymethylene)
triphenylphosphorane5 yielded the a,b-unsaturated
ester 7. The geometry of the double bond in 7 was of
little consequence as it was further reduced in the
subsequent step. Reduction with LiAlH4 furnished the
saturated alcohol 8. The alcohol was converted into
its azide 9 via the tosylate using TsCl/Py and NaN3/
DMF. Azide 9, thus obtained, was reduced to the
amine using LiAlH4 and protected as its Boc deriva-
tive 10 (Scheme 2).
L
L
studies on the total synthesis of callipeltin A, we now
describe the first synthesis of fully protected
(2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid.
Our synthetic approach to the AGDHE fragment
involves a chiron approach via replenishable source of
carbohydrates using
rial. As the first step of retrosynthetic analysis, inver-
sion of the C(3) hydroxyl group of -glucose was
D
-glucose as the starting mate-
The inversion of configuration at C(3) in 10 was
effected in four steps involving an oxidation–
reduction6 protocol to give 14. Under acidic condi-
tions (MeOH/AcCl), compound 14 underwent
isopropylidene cleavage, which was followed by
methyl glycosidation and protection of the secondary
alcohol as its benzyl ether 16. Hydrolysis of the O-
D
achieved by an oxidation–reduction procedure, fol-
lowed by the lactol ring opening and inversion of the
configuration at C(4) was achieved by tosylation and
subsequent azide displacement (Scheme 1).
NH
OH
O
O
O
PG1
5
7
PG1
2
6
4
CALLIPELTIN A
1
3
H2N
N
H
OH
N
PG2
OMe
OH
NH2
HN
PG2
O
PG1
(2R,3R,4S)-AGDHE
PG1 = Bn
PG2 = Boc
3
1
2
PG1
N
PG2
O
O
OH
OHC
O
D-GLUCOSE
O
OPG1
G1PO
G1PO
4
6
5
Scheme 1.
O
O
O
O
OHC
a
O
O
HO
b
ref 4
EtO
O
O
O
6
BnO
HO
O
BnO
BnO
8
7
5
O
O
O
e
c
d
O
O
HN
O
HN
Boc
N3
Boc
O
O
O
BnO
BnO
9
11
10
Scheme 2. Reagents and conditions: (a) Ph3PꢀCHCOOEt, benzene, rt 4 h, 90%; (b) LAH, THF, 0°C, 6 h, 85%; (c) (i) TsCl, Py,
6 h; (ii) NaN3, DMF, 80°C, 12 h, 68% (two steps); (d) (i) LAH, THF, 0°C, 12 h; (ii) NaOH, (Boc)2O, 3 h, 43% (two steps); (e)
Na/liq. NH3, THF, −78°C, 2 h, 80%.

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 12 (2001) 2315–2321
2317
O
O
O
O
c
O
O
HN
Boc
a
b
BnN
Boc
HN
Boc
11
O
O
O
O
O
HO
BnO
13
14
12
O
O
OMe
OBn
OMe
OH
OBn
d
e
BnN
Boc
BnN
Boc
f
BnN
Boc
BnO
BnO
OH
BnO
15
16
4
Scheme 3. Reagents and conditions: (a) PDC, DCM, 0°C, 4 h; (b) NaBH4, MeOH, 0°C, 2 h, 38%; (c) NaH, BnBr, DMF, 0°C,
1 h, 74%; (d) (i) MeOH, CH3COCl (cat.), reflux, 6 h; (ii) Et3N, (Boc)2O, 3 h, 40% (two steps); (e) NaH, BnBr, DMF, 0°C, 1 h,
75%; (f) (i) 60% AcOH, conc. HCl (cat.), 4 h; (ii) Et3N, (Boc)2O, 3 h, 40% (two steps).
OBn
OBn
OBn
b
a
BnN
Boc
OH
BnN
Boc
OTBDMS
4
OBn
OH
OH
18
17
OBn
OBn
c
e
d
BnN
Boc
OTBDMS
BnN
Boc
OTBDMS
OBn
BocNH
N3
OBn
OBn
19
20
OBn
COOMe
OBn
f
BnN
Boc
BnN
Boc
OH
BocNH
OBn
BocNH
21
3
Scheme 4. Reagents and conditions: (a) NaBH4, MeOH, 0°C, 1 h, 80%; (b) imidazole, TBDMSCl, DCM, 0°C, 6 h, 85%; (c) (i)
MsCl, Et3N, DCM, 0°C, 5 h; (ii) NaN3, DMF, 80°C, 12 h, 29% (two steps); (d) (i) PPh3, H2O, benzene, 11 h; (ii) Et3N, (Boc)2O,
12 h, 63% (two steps); (e) TBAF, THF, 0°C, 3 h, 70%; (f) (i) Jones oxidation; (ii) CH2N2, dry ether, 41% (two steps).
glycosidic bond of 16 using 60% acetic acid and cata-
lytic conc. HCl at 50°C afforded the corresponding
lactols 4 (Scheme 3).
4. Experimental
Crude products were purified by column chromatogra-
phy on silica gel of 60–120 mesh. H and 13C NMR
1
Reduction of hemiketal 4 (NaBH4, MeOH) then
afforded the open chain diol 17. The primary alcohol
was then protected selectively using TBDMSCl/imida-
zole and the free secondary alcohol in 18 was converted
to its azide 19 via the mesylate ester (MsCl/Py; NaN3/
DMF).
spectra were recorded in CDCl3 solution on a Varian
Gemini-200 MHz spectrometer, and chemical shifts are
reported in ppm unless otherwise stated. Mass spectra
were recorded on VG micromass-7070H (70 eV). The
optical rotations were recorded on Jasco Dip 360 digi-
tal polarimeter. Infrared spectra were obtained neat
and only the most significant absorptions in cm−1 are
indicated. All solvents used were purified by a known
procedure. All reactions were carried out under an
atmosphere of nitrogen using dry glassware.
Azide 19 was reduced with triphenylphosphine/ben-
zene/H2O and the resulting free amine was protected as
its Boc derivative 20. After obtaining the diamine func-
tionality, the TBDMS ether was deprotected using
TBAF. Finally, the free alcohol 21 was subjected to
oxidation with Jones’ reagent to yield the acid, which
was protected as its methyl ester 3 using ethereal dia-
zomethane (Scheme 4).
4.1. Ethyl 5,6-dideoxy-1,2-O-isopropylidene-3-O-benzyl-
a- -xylo-hept-5-enofuranuronoate 7
D
Aldehyde 5 (10 g, 0.036 mol) was dissolved in benzene
(100 mL) at 0°C and (carboethoxymethylene)triphenyl-
phosphorane (12.53 g, 0.0359 mol) was added portion
wise under a nitrogen atmosphere. The reaction mix-
ture was allowed to stir at rt for 4 h and benzene was
evaporated under reduced pressure and purification by
column chromatography yielded conjugated ester 7
3. Conclusion
In conclusion, we have developed an efficient protocol
for the synthesis of the fully protected AGDHE frag-
ment, utilizing
D-glucose as the chiral raw material.
1
This synthetic approach is flexible and other analogues
can be synthesized by changing the starting sugar or by
varying the length of the Wittig reagent.
(11.24 g, 90%). IR (neat): 1760 and 960 cm−1; H NMR
(200 MHz, CDCl3): l 1.24–1.38 (m, 6H, OCH2CH3,
CH3), 1.48 (s, 3H, CH3), 3.92 (d, J=2.38 Hz, 1H) 4.20

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S. Chandrasekhar et al. / Tetrahedron: Asymmetry 12 (2001) 2315–2321
4.4. 3-O-Benzyl-7-tert-butoxycarbonylamino-1,2-O-iso-
propylidene-5,6,7-trideoxy-a- -xylo-heptofuranose 10
(q, J=4.76 Hz, 2H, OCH2CH3), 4.42–4.65 (m, 3H),
4.70–4.78 (m, 1H), 5.95 (d, J=4.76 Hz, 1H, C1-H),
6.12 (d, J=14.3 Hz, 1H, olefinic), 6.90 (dd, J=4.8,
14.3 Hz, 1H, olefinic), 7.20–7.38 (m, 5H, aromatic);
EI MS: m/z 348 (M+); [h]D −27.2 (c 1, CHCl3).
D
To a cooled suspension of lithium aluminium hydride
(0.54 g, 0.014 mol) in dry THF (25 mL) at 0°C under
a nitrogen atmosphere, was added azide 9 (4 g, 0.012
mol). The reaction mixture was allowed to warm to
rt and stirred for 12 h, then cooled to 0°C and
quenched with 1N NaOH solution and extracted with
ethyl acetate. The combined organic extracts were
concentrated to give amine (2.0 g) as syrup.
4.2. 5,6-Dideoxy-3-O-benzyl-1,2-O-isopropylidene-a-
xylo-heptofuranose 8
D-
To a suspension of lithium aluminium hydride (1.08
g, 0.028 mol) in dry THF (100 mL) at 0°C under a
nitrogen atmosphere was added a solution of the con-
jugated ester 7 (5 g, 0.014 mol) in THF (25 mL) and
stirred at rt for 6 h. The reaction mixture was
quenched with a saturated solution of Na2SO4 at 0°C
and extracted with ethyl acetate. The combined
organic extracts were washed with water, brine, dried
(anhydrous, Na2SO4), concentrated and on purifica-
tion by column chromatography afforded saturated
alcohol 8 (3.74 g, 85%). IR (neat): 3400, 3030 cm−1;
1H NMR (200 MHz, CDCl3): l 1.30 (s, 3H, CH3),
1.48 (s, 3H, CH3) 1.54–1.94 (m, 4H, 2×CH2), 3.63 (t,
J=3.25 Hz, 2H, CH2OH), 3.75 (d, J=2.3 Hz, 1H,
C3-H), 4.10–4.20 (m, 1H, C4-H), 4.60 (d, J=2.8 Hz,
1H, C2-H), 4.40–4.70 (AB quartet, 2H, benzylic
CH2), 5.85 (d, J=2.8 Hz, 1H, C1-H), 7.20–7.40 (m,
5H, aromatic); EI MS: m/z 308 (M+); [h]D −15.2 (c 1,
CHCl3).
The above obtained crude amine (2 g, 0.006 mol) was
dissolved in dry CH2Cl2 (50 mL) cooled to 0°C, tri-
ethylamine (1.25 g, 0.012 mol) followed by Boc2O
(1.62 g, 0.078 mol) was added under a nitrogen atmo-
sphere and allowed to stir at rt for 3 h. The reaction
mixture was then extracted with DCM. The combined
organic extracts were washed with water, brine, dried
over anhydrous Na2SO4, concentrated and on purifi-
cation by column chromatography yielded protected
amine 10 (2.10 g, 43% overall) as a viscous liquid. IR
1
(neat): 1690 cm−1; H NMR (400 MHz, CDCl3): l 1.3
(s, 3H, CH3), 1.43 (s, 9H, 3×CH3), 1.46 (s, 3H, CH3),
1.52–1.70 (m, 3H), 1.72–1.85 (m, 1H), 3.14 (m, 2H,
CH2-NH-Boc), 3.72 (d, 1H, C3-H), 4.08 (m, 1H, C4-
H), 4.40–4.65 (AB quartet, 2H, benzylic CH2), 4.58
(d, 1H, C2-H), 5.85 (d, J=4 Hz, 1H, C1-H), 7.14–
7.19 (m, 5H, aromatic); 13C NMR (50 MHz, CDCl3):
l 25.3, 26.2, 26.7, 28.4, 40.5, 71.7, 79.0, 80.0, 82.1,
82.2, 104.6, 111.2, 127.7, 127.9, 128.4, 137.5, 155.9;
FAB MS: m/z 408 (M+1)+; [h]D−32.2 (c 1.25,
CHCl3).
4.3. 7-Azido-3-O-benzyl-1,2-O-isopropylidene-5,6,7-
trideoxy-a- -xylo-heptofuranose 9
D
To a stirred solution of alcohol 8 (2.5 g, 0.008 mol)
was added a solution of pyridine (1.3 g, 0.016 mol) in
dry CH2Cl2 (50 mL) at 0°C under a nitrogen atmo-
sphere. Tosyl chloride (2.3 g, 0.012 mol) was added
slowly and the reaction mixture was allowed to stir at
rt for 6 h. The reaction mixture was extracted with
CH2Cl2, washed with a CuSO4 solution, water, brine,
dried over anhydrous Na2SO4, concentrated and on
purification by column chromatography afforded
tosylate as a viscous liquid.
4.5. 7-tert-Butoxycarbonylamino-1,2-O-isopropylidene-
5,6,7-trideoxy-a- -xylo-heptofuranose 11
D
To liquid NH3 (100 mL) at −78°C, was added the
protected amine 10 (2 g, 0.0051 mol) in THF (10
mL), followed by metallic sodium (0.46 g, 0.0204
mol). After 2 h, ammonia was allowed to completely
evaporate by warming the reaction mixture to rt.
Then saturated NH4Cl was added and extracted with
CH2Cl2. The organic layers were washed with water,
brine, dried over anhydrous Na2SO4, concentrated
and purified by column chromatography to afford the
debenzylated alcohol 11 (1.25 g, 80%) as a syrupy
liquid. IR (neat): 3410, 1695 cm−1; 1H NMR (200
MHz, CDCl3): l 1.3 (s, 3H, CH3), 1.45 (s, 9H, 3×
CH3), 1.5 (s, 3H, CH3), 1.55–1.80 (m, 4H, 2×CH2),
3.10–3.23 (m, 2H, CH2-NH-Boc), 4.0–4.10 (m, 2H,
C3-H, C4-H), 4.48 (d, J=2.4 Hz, 1H, C2-H), 4.70
(bs, 1H, NH), 5.82 (d, J=2.4 Hz, 1H, C1-H); 13C
NMR (50 MHz, CDCl3): l 24.8, 26.1, 26.6, 26.7,
28.3, 40.5, 75.1, 79.3, 80.3, 85.3, 104.2, 111.2, 156.3;
EI MS: m/z 201 (M−116)+; [h]D −9.29 (c 1, CHCl3).
The above tosylate (2.5 g, 0.005 mol) was dissolved in
dry DMF (40 mL) and heated at 90°C with NaN3
(1.05 g, 0.015 mol) for 12 h. The reaction mixture
was brought to rt and diluted with water and
extracted with ether. The combined ethereal layers
were washed with water, brine, dried (anhydrous
Na2SO4), concentrated and on purification by column
chromatography yielded azide 9 (1.2 g, 68%). IR
(neat): 2097 cm−1; 1H NMR (400 MHz, CDCl3): l
1.30 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.50–1.58 (m,
1H), 1.60–1.75 (m, 2H), 1.76–1.85 (m, 1H), 3.20–3.36
(m, 2H, CH2N3), 3.75 (d, 1H, C3-H), 4.10 (m, 1H,
C4-H), 4.45–4.70 (AB quartet, 2H, benzylic CH2),
4.56 (d, 1H, C2-H), 5.86 (d, 1H, C1-H), 7.13–7.19 (m,
5H, aromatic); 13C NMR (50 MHz, CDCl3): l 25.3,
25.7, 26.1, 26.7, 51.4, 71.7, 79.7, 82.1, 82.2, 104.7,
111.3, 127.7, 127.9, 128.4, 137.5; EI MS: m/z 333
(M+); [h]D−49.1 (c 1, CHCl3).
4.6. 7-tert-Butoxycarbonylamino-1,2-O-isopropylidene-
5,6,7-trideoxy-a- -ribo-heptofuranose 13
D
To compound 11 (3 g, 0.01 mol) was added pyridinium
dichromate (7.11 g, 0.02 mol) in dry CH2Cl2 (70 mL) at

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 12 (2001) 2315–2321
2319
0°C and the mixture was stirred for 4 h. The mixture
was concentrated in vacuo and the residue was dis-
solved in ether and filtered through a small pad of silica
gel. The combined ether layers were washed with 1N
NaOH, dil. HCl and a satd. NaHCO3 solution, dried
over anhydrous Na2SO4 and concentrated to give com-
pound 12 (1.5 g) as a liquid, which was used without
any further purification.
without any further purification. The proton NMR
spectra of the residue indicated the absence of Boc peak
and therefore the crude free amine was protected as its
Boc derivative using Boc2O (0.525 g, 0.0024 mol) and
Et3N (0.4 g, 0.004 mol) in dry CH2Cl2 at 0°C under an
inert atmosphere. The reaction mixture was stirred at rt
for 3 h, extracted with CH2Cl2, washed with water,
brine, dried and concentrated. The residue was purified
by column chromatography to furnish compound 15
(0.38 g, 40%) as an a,b-mixture. IR (neat): 3400, 1167,
The above ketone 12 (1.5 g, 0.005 mol) was dissolved in
methanol (50 mL), cooled to 0°C and NaBH4 (0.32 g,
0.01 mol) was added in small portions under a nitrogen
atmosphere. After complete addition, the reaction mix-
ture was brought to rt and allowed to stir for 2 h,
methanol was removed under reduced pressure, and the
residue was dissolved in water and extracted with chlo-
roform. The combined organic layers were washed with
aqueous sodium bicarbonate, water, brine, dried over
anhydrous Na2SO4 and concentrated to afford inverted
alcohol 13 as a white solid (1.14 g, 38% overall yield).
IR (neat): 3500, 1695 cm−1; 1H NMR (200 MHz,
CDCl3): l 1.35 (s, 3H, CH3), 1.45 (s, 9H, 3×CH3), 1.55
(s, 3H, CH3), 1.60–1.80 (m, 4H, 2×CH2), 2.30 (bs, 1H,
OH), 3.10–3.24 (m, 2H, CH2-NH-Boc), 3.50–3.60 (m,
1H, C3-H), 3.61–3.75 (m, 1H, C4-H), 4.50 (t, J=2.4
Hz, 1H, C2-H), 4.65 (bs, 1H, NH), 5.75 (d, J=2.4 Hz,
1H, C1-H); EI MS: m/z 201 (M−116)+; [h]D +10.0 (c
1.1, CHCl3).
1
1023 cm−1; H NMR (200 MHz, CDCl3): l 1.20–1.70
(m, 13H), 2.5 (s, 1H, OH), 3.10–3.28 (m, 2H, CH2-
NBn), 3.31 (s, 3H, O-CH3), 3.80 (m, 3H, C2-H, C3-H,
C4-H), 4.40 (m, 2H, N-CH2-Ph), 4.55 (m, 2H, O-CH2-
Ph), 4.78 (m, 1H, C1-H), 7.05–7.40 (m, 10H, aromatic);
13C NMR (50 MHz, CDCl3): l 24.6, 28.5, 32.8, 46.4,
54.8, 72.9, 73.3, 79.5, 80.8, 82.8, 96.2, 108.4, 127.1,
127.3, 127.4, 128.0, 128.3, 128.4, 128.6, 137.1, 138.6;
FAB MS: m/z 471 (M+); [h]D +10.2 (c 1, CHCl3).
4.9. Methyl 7-N-benzylamino-7-tert-butoxycarbonyl-
amino-2,3-di-O-benzyl-5,6,7-trideoxy-a/b- -ribo-
D
heptofuranoside 16
To an ice cooled solution of compound 15 (2 g, 0.0042
mol) in dry DMF (40 mL), NaH (0.2 g, 60% dispersion
in oil, 0.0084 mol) was added and the mixture stirred at
rt for 1 h under a nitrogen atmosphere. Benzyl bromide
(0.87 g, 0.0051 mol) was added and the reaction mix-
ture was stirred overnight. Excess NaH was quenched
with a saturated ammonium chloride solution and
extracted with ether. The organic layer was washed
with brine, dried, concentrated and on purification by
column chromatography afforded the benzyl derivative
4.7. N-Benzyl-3-O-benzyl-7-tert-butoxycarbonylamino-
1,2-O-isopropylidene-5,6,7-trideoxy-a- -ribo-heptofura-
D
nose 14
To an ice cold solution of compound 13 (1 g, 0.003
mol) in dry DMF (20 mL) was added NaH (0.3 g, 60%
dispersion in oil, 0.012 mol) and the mixture stirred at
rt for 1 h. Benzyl bromide (1.19 g, 0.007 mol) was then
added at 0°C and the reaction mixture was stirred over
night. Excess NaH was quenched with saturated NH4Cl
and extracted with ethyl acetate, washed with water,
brine, dried (anhydrous Na2SO4), concentrated and on
purification by column chromatography afforded ben-
zyl derivative 14 (1.16 g, 74%). IR (neat): 1695 cm−1; 1H
NMR (200 MHz, CDCl3): l 1.35 (s, 3H, CH3), 1.45 (s,
9H, 3×CH3), 1.55 (s, 3H, CH3), 1.60–1.75 (m, 4H,
2×CH2), 3.05–3.25 (m, 2H, CH2-NBn), 3.26–3.38 (m,
1H, C3-H), 3.88–4.0 (m, 1H, C4-H), 4.34–4.44 (m, 2H,
-N-CH2-Ph), 4.45–4.80 (AB quartet, 2H, benzylic CH2),
4.53 (m, 1H, C2-H), 5.65 (d, J=2.8 Hz, 1H, C1-H),
7.15–7.40 (m, 10H, aromatic); FAB MS: m/z 497 (M+);
[h]D +48.5 (c 1, CHCl3).
1
16 (1.78 g, 75%). IR (neat): 1696, 1120, 1067 cm−1; H
NMR (200 MHz, CDCl3): l 1.40–1.70 (m, 13H), 3.10–
3.20 (m, 2H, CH2-NBn), 3.30 (s, 3H, OCH3), 3.65–3.80
(m, 2H, C3-H, C4-H), 4.0–4.10 (m, 1H, C2-H), 4.40 (m,
2H, -N-CH2-Ph), 4.50–4.70 (AB quartet, 4H, 2×O-CH2-
Ph), 4.80 (s, 1H, C1-H), 7.10–7.40 (m, 15H, aromatic);
FAB MS: m/z 561 (M+); [h]D +12.3 (c 1, CHCl3).
4.10. N-Benzyl-7-tert-butoxycarbonylamino-2,3-di-O-
benzyl-5,6,7-trideoxy-a/b- -ribo-heptofuranose 4
D
Compound 16 (1.5 g, 0.0027 mol) was hydrolysed using
60% acetic acid (15 mL) and catalytic conc. HCl (2–4
drops) and heating the mixture at 80°C for 4 h. The
reaction mixture was cooled to rt, neutralized with solid
sodium bicarbonate and extracted with ethyl acetate.
The combined ethyl acetate layers were washed with
brine and dried over Na2SO4. The volatiles were evapo-
rated and the residue was used without further purifica-
tion. The proton NMR spectra of the residue indicated
the absence of Boc peak and therefore the crude free
amine was protected as its Boc derivative using Boc2O
(0.7 g, 0.0032 mol) and Et3N (0.54 g, 0.0054 mol) in dry
CH2Cl2 at 0°C under an inert atmosphere. The reaction
mixture was stirred at rt for 3 h, extracted with CH2Cl2,
washed with water, brine, dried and concentrated. The
residue was purified by column chromatography to
4.8. Methyl 7-N-benzyl-3-O-benzyl-7-tert-butoxycar-
bonylamino-5,6,7-trideoxy-a/b-
D
-ribo-heptofuranoside
15
Compound 14 (1 g, 0.002 mol) was dissolved in dry
methanol (50 mL) and cooled to 0°C, to which a
catalytic amount of acetyl chloride (2–4 drops) was
added. It was allowed to warm to rt and then stirred
under reflux for over a period of 6 h. The reaction
mixture was cooled, filtered and washed with methanol.
The filtrate was evaporated and the residue was used

2320
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 12 (2001) 2315–2321
furnish compound 4 (0.58 g, 40%) as an a,b-mixture of
lactol. IR (neat): 3450 cm−1; 1H NMR (200 MHz,
CDCl3): l 1.40–1.70 (m, 13H), 3.10–3.20 (m, 2H, CH2-
NBn), 3.50–3.60 (bs, 1H, OH), 3.65–3.75 (m, 2H, C3-
H, C4-H), 4.10 (m, 1H, C2-H), 4.40 (m, 2H,
-N-CH2-Ph), 4.50–4.75 (m, 4H, 2×O-CH2-Ph), 5.2 (d,
1H, anomeric), 7.10–7.35 (m, 15H, aromatic); FAB
MS: m/z 548 (M+1); [h]D +25.1 (c 1, CHCl3).
ice and extracted with CH2Cl2. The combined organic
extracts were washed with water, brine, dried over
anhydrous Na2SO4 and concentrated to yield the mesyl-
ate (0.5 g) as a pale reddish solution. The product was
used without any further purification.
A solution of mesylate (0.5 g, 0.007 mol) in dry DMF
(10 mL) was heated at 90°C with NaN3 (0.175 g, 0.0028
mol) for 12 h. The reaction mixture was allowed to cool
to rt and diluted with water and extracted with ether.
The combined ethereal layers were washed with water,
brine, dried over anhydrous Na2SO4, concentrated and
the residue purified by column chromatography to
4.11. (4R,5R,6S)-1-N-Benzyl-N-(tert-butoxycarbonyl)-
5,6-di-benzyloxy-4,7-dihydroxy-heptylamine 17
To a solution of the mixture 4 (1 g, 0.0018 mol) in
methanol (30 mL) was added sodium borohydride
(0.075 g, 0.0022 mol) at rt. After 1 h, the reaction
mixture was neutralised with saturated ammonium
chloride and the resulting solution was extracted with
dichloromethane and washed with brine. The combined
organic layers were dried over anhydrous Na2SO4, and
concentrated under vacuo and purification by column
chromatography yielded the open chain diol 17 (0.8 g,
80%). IR (neat): 3500 cm−1; 1H NMR (400 MHz,
CDCl3): l 1.4–1.75 (m, 13H), 2.80 (bs, 2H, 2×OH)
3.10–3.30 (m, 2H, CH2-NBn), 3.45 (m, 1H), 3.64–3.92
(m, 4H), 4.30–4.40 (m, 2H, N-CH2-Ph), 4.50–4.75 (m,
4H, 2×O-CH2-Ph), 7.15–7.38 (m, 15H, aromatic); FAB
MS: m/z 550 (M+1)+; [h]D +16.3 (c 1.5, CHCl3).
1
afford azide 19 (0.30 g, 29%). IR (neat): 2095 cm−1; H
NMR (400 MHz, CDCl3): l 0.10 (s, 6H, Si-2×CH3),
0.90 (s, 9H, 3×CH3), 1.50 (bs, 11H), 1.60–1.80 (m, 2H),
3.05–3.20 (m, 2H, CH2-NBn), 3.40–3.45 (m, 1H, CH-
N3), 3.56 (m, 2H), 3.80–3.90 (dd, 2H), 4.35–4.42 (m,
2H, N-CH2-Ph), 4.50–4.64 (AB quartet, 2H, O-CH2-
Ph), 4.70–4.78 (m, 2H, O-CH2-Ph), 7.10–7.38 (m, 15H,
aromatic); FAB MS: m/z 327 [(M+23)−384]+; [h]D−6.2
(c 0.5, CHCl3).
4.14. (4S,5R,6S)-1N-Benzyl-N-(tert-butoxycarbonyl)-
5,6-di-benzyloxy-7-(tert-butyldimethylsilyloxy)-4-(tert-
butoxycarbonylamino)-heptylamine 20
To a stirred solution of compound 19 (0.3 g, 0.43
mmol) in benzene (10 mL) at 45°C was added
triphenylphosphine (0.23 g, 0.87 mmol). After 30 min,
water (0.8 mL, 43 mmol) was added and stirring was
continued at 45°C for 11 h. The mixture was cooled to
rt and extracted with ethyl acetate, washed with a
saturated ammonium chloride solution, dried over
anhydrous Na2SO4, filtered and concentrated to give
the amine product (0.28 g), which was contaminated
with triphenylphosphine oxide. This impurity was
removed after the next step.
4.12. (4R,5R,6S)-1-N-Benzyl-N-(tert-butoxycarbonyl)-
5,6-di-benzyloxy-4-hydroy-7-(tert-butyldimethylsilyloxy)-
heptylamine 18
To a solution of 17 (1.5 g, 0.0027 mol) in dry CH2Cl2
(30 mL) was added imidazole (0.28 g, 0.0041 mol) and
tert-butyldimethylsilyl chloride (0.45 g, 0.003 mol) and
the temperature was maintained at 0°C. The reaction
mixture was stirred for 6 h at rt after which it was
diluted with CH2Cl2. The organic layer was washed
with water, brine and dried over anhydrous Na2SO4.
The volatiles were removed under reduced pressure.
The crude product was purified by column chromatog-
raphy to afford the silyl ether 18 as a viscous liquid
(1.54 g, 85%). IR (neat): 3500 cm−1; 1H NMR (400
MHz, CDCl3): l 0.20 (s, 6H, Si-2×CH3), 0.90 (s, 9H,
3×CH3), 1.40 (s, 9H), 1.43–1.65 (m, 4H), 3.05–3.20 (m,
2H, CH2-NBn), 3.45 (m, 1H), 3.60–3.78 (m, 3H), 3.82–
4.0 (m, 1H), 4.38–4.42 (m, 2H, N-CH2-Ph), 4.50–4.78
(m, 4H, 2×O-CH2-Ph), 7.10–7.38 (m, 15H, aromatic);
FAB MS: m/z 506 (M−158+1)+; [h]D +10.2 (c 0.5
CHCl3).
To a solution of the above crude amine (0.28 g, 0.42
mmol) in dry THF (10 mL) were added Et3N (0.128 g,
1.26 mmol) and (Boc)2O (0.11 g, 0.05 mmol) at 0°C.
The mixture was stirred at rt for 12 h. The solvent was
evaporated in vacuo and the residue was purified by
column chromatography to give compound 20 (0.21 g,
63% overall). IR (neat): 3300, 1695 cm−1; 1H NMR (400
MHz, CDCl3): l 0.10 (s, 6H, Si-2×CH3), 0.90 (s, 9H,
3×CH3), 1.50 (bs, 20H), 1.58–1.70 (m, 2H), 3.10–3.14
(m, 2H, CH2-NBn), 3.48 (m, 1H), 3.58 (d, 1H), 3.78–
3.98 (dd, 2H), 4.0–4.08 (m, 1H), 4.36–4.44 (m, 2H),
4.50–4.60 (m, 2H), 4.64–4.72 (m, 2H), 4.96 (d, J=3.55
Hz, 1H, NH), 7.20–7.44 (m, 15H, aromatic); FAB MS:
m/z 762 (M+); [h]D −3.0 (c 0.5, CHCl3).
4.13. (4S,5R,6S)-1-N-Benzyl-N-(tert-butoxycarbonyl)-
4-azido-5,6-di-benzyloxy-7-(tert-butyldimethylsilyloxy)-
heptylamine 19
4.15. (4S,5R,6S)-1N-Benzyl-N-(tert-butoxycarbonyl)-
5,6-di-benzyloxy-7-hydroxy-4-(tert-butoxycarbony-
lamino)-heptylamine 21
A stirred solution of alcohol 18 (1 g, 0.0015 mol) in dry
CH2Cl2 at 0°C under a nitrogen atmosphere was
treated with triethylamine (0.46 g, 0.0045 mol) and a
catalytic amount of DMAP. Methanesulphonyl chlo-
ride (0.2 g, 0.0018 mol) was added to the mixture very
slowly. The reaction mixture was allowed to stir at rt
for 5 h. The reaction mixture was poured into crushed
To a stirred solution of compound 20 (0.2 g, 0.26
mmol) in THF (10 mL) at 0°C was added TBAF (0.14
g, 1 M solution in THF, 0.52 mmol). The reaction
mixture was allowed to warm to rt and stirred for a
further 3 h. The reaction mixture was quenched with a

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 12 (2001) 2315–2321
2321
saturated NH4Cl solution, extracted with ethyl acetate
and washed with water and brine. The organic layer
was dried over anhydrous Na2SO4 and the volatiles
were removed under reduced pressure. The crude
product thus obtained was purified by column chro-
matography to afford compound 21 as a colorless
viscous oil (0.13 g, 70%). IR (neat): 3500, 3300, 1695
3H, OCH3), 3.95 (m, 2H), 4.30–4.45 (m, 2H, N-CH2-
Ph), 4.50–4.70 (m, 4H, 2×O-CH2-Ph), 5.0 (d, 1H, NH-
Boc), 7.16–7.40 (m, 15H, aromatic); FAB MS: m/z 545
(M+1−131)+; [h]D −17.2 (c 0.5, CHCl3).
Acknowledgements
1
cm−1; H NMR (400 MHz, CDCl3): l 1.45 (bs, 20H),
1.52–1.70 (m, 2H), 2.10 (bs, 1H, OH), 3.08–3.12 (m,
2H, CH2-NBn), 3.40–3.60 (m, 2H), 3.65–3.90 (m, 2H),
3.92–4.08 (m, 1H), 4.40 (m, 2H), 4.5–4.76 (m, 4H,
2×O-CH2-Ph), 4.86 (bd, 1H, NH-Boc), 7.20–7.44 (m,
15H, aromatic); FAB MS: m/z 648 (M+); [h]D−14.8 (c
0.7, CHCl3).
T.R. thanks CSIR, New Delhi for financial support.
References
4.16. Methyl (2R,3R,4S)-7-N-benzyl-N-(tert-butoxycar-
bonyl)-2,3-di(benzyloxy)-4-(tert-butoxycarbonylamino)-
heptanoate 3
1. Ireland, C. M.; Molinski, T. F.; Roll, D. M.; Zabriskie, T.
M.; McKee, T. C.; Swersey, J. C.; Foster, M. P. In Natural
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Heidelberg, 1989; pp. 1–46.
2. (a) Zampella, A.; Valeria D’Auria, M.; Gomez Paloma, L.;
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Chem. Soc. 1996, 118, 6202; (b) Valeria D’Auria, M.;
Zampella, A.; Gomez Paloma, L.; Minale, L. Tetrahedron
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The alcohol 21 (0.1 g, 0.15 mmol) was dissolved in dry
acetone (10 mL) at 0°C and treated with Jones reagent,
then stirred for 15 min at the same temperature. The
reaction mixture was diluted with water and extracted
with ethyl acetate. The combined organic extracts were
washed with water, brine, dried over anhydrous
Na2SO4 and concentrated to furnish the acid (0.066 g).
3. Bo, L.; Carroll, P. J.; Joullie, M. M. Org. Lett. 2000, 2,
4157.
The above acid (0.066 g, 0.099 mmol) was immediately
dissolved in dry ether at 0°C and treated with ethereal
diazomethane. After 0.5 h, ether was removed and the
residue on purification by column chromatography
afforded amino acid ester 3 (0.043 g, 41%) as a syrup.
4. Wolfrom, M. L.; Hanessian, S. J. Org. Chem. 1962, 27,
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5. Sueda, N.; Ohrui, H.; Kuzuhara, H. Tetrahedron Lett.
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1
IR (neat): 3500, 1745, 1695 cm−1; H NMR (200 MHz,
CDCl3): l 1.30 (s, 9H), 1.40 (s, 9H), 1.43–1.65 (m, 4H),
3.10–3.33 (m, 3H, CH-NH-Boc, CH2-NBn), 3.80 (s,