Stereoselective synthesis of optically active mono and diaminoalcohols

Article abstract of DOI:10.1016/j.tet.2005.06.011

Several optically active mono and diaminopolyols have been synthesized starting from the octadienedioate 1, by regio- and stereo selective azidation of the corresponding alcohol by Mitsunobu/S_N2 substitution.

Full text of DOI:10.1016/j.tet.2005.06.011

Tetrahedron 61 (2005) 7960–7966
Stereoselective synthesis of optically active mono
and diaminoalcohols
M. Teresa Barros,a,b M. Adilia Januario Charmier, Christopher D. Maycockd,e,
b,c
*
´
and Thierry Michaudb
a
´
Departamento de Quımica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, 2825-114 Monte de Caparica, Portugal
b
´
Centro de Quımica Fina e Biotecnologica, FCT, Universidade Nova de Lisboa, 2825-114 Monte de Caparica, Portugal
c
´
Universidade Lusofona de Humanidades e Tecnologias, Av.d oCampo Grande, no 376, 1749-024 Lisboa, Portugal
d
´
Instituto de Tecnologia Quımica e Biologia, Universidade Nova de Lisboa, Apartado 127, 2780 Oeiras, Portugal
e
´
Departamento de Quımica, Universidade de Lisboa, Rua Ernesto de Vasconcelos, 1700 Lisboa, Portugal
Received 11 May 2005; revised 1 June 2005; accepted 6 June 2005
Available online 5 July 2005
Abstract—Several optically active mono and diaminopolyols have been synthesized starting from the octadienedioate 1, by regio- and stereo
selective azidation of the corresponding alcohol by Mitsunobu/SN2 substitution.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
components of important biologically active substances
such as the complex peptide antibiotic galantin I, which
exhibits powerful antibacterial properties and polyoxins
(antifungal antibiotics).
Chiral amino polyols are constituents of several compounds
and are of major importance as partial structures of
biologically active compounds covering a wide range of
biological activities from antibiotic to immunosuppressive
properties. For example, (Fig. 1) D-erythro-sphingosine and
ceramides1c–e have been shown to exhibit potent inhibitory
activity against protein kinase C. Polyhydroxylated amino
acids, like galantinic acid2 and polyoxamic acid,3 are
Within the scope of our studies on the potential of diversely
substituted octadienedioates such as 1 derived from
D-mannitol, as building blocks4a for the synthesis of
polyhydroxylated amino acids and alkaloids,4b we have
explored a versatile route to functionalised chiral mono and
Figure 1.
Scheme 1.
Keywords: Aminoalcohols; Stereoselective; Optically active.
*
Corresponding author. Tel.: C351 214469775; fax: C351 214469789; e-mail: maycock@itqb.unl.pt
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.011

M. T. Barros et al. / Tetrahedron 61 (2005) 7960–7966
7961
diamino polyols. Herein, we describe the synthesis of new
chiral protected amino alcohols in a highly enantio- and
diastereoselective fashion.
tions of the double bonds of 5 and 7 were more
diastereoselective. By adjusting the experimental conditions
(time, temperature and stoechiometry of DIBALH used (see
Table 1) it was possible to obtain the monoreduced
compound 5 in moderate yield, while the tetrol 7 could be
obtained in excellent yield (Table 1).
We have previously reported4b the preparation of the amino
diester 2 in five steps starting from the protected diene
dioate 1 (Scheme 1). We wished to test the scope of this
approach to aminoalcohols and to prepare some diamino-
alcohols stereo-and regioselectively.
The selective monoazidation (Scheme 3) of 7 under
Mitsunobu conditions using 1.2 equiv of reagents led to
the mono azide 8 and the diazide 9 that were readily isolated
by chromatography, respectively, in 52 and 19% yield. The
two silyl ether groups could be removed by treatment with
TBAF in THF. The resulting highly polar triol 10 was
benzoylated (11, 87%) in order to characterise it. Tosylation
with p-toluenesulfonic anhydride of all three hydroxyls of
10 was equally achieved in good yield (86%) to give the
rather unstable azide 12.
2. Results and discussion
We envisaged the preparation of analogous derivatives
where one or both of the ester groups would be reduced to
an alcohol. The reduction of the ester groups on the
O-isopropylidene protected diol dienedioate 3 with
DIBALH (x equiv) in THF (Scheme 2) afforded the desired
allylic mono and diol 4 and 6 in 48 and 32% yield,
respectively. The monoreduced compound 4, obtained as a
by-product during the reduction of the 2 ester groups could
be prepared up to 50% yield by quenching the reaction after
15 min. However, the lability of the O-isopropylidene
protecting group prohibited an acidic work-up, making
tedious the extraction of the final product. Disilylated
analogue 1 (Scheme 2) undergoes the same reactions but the
product is more stable to acid and subsequent functionalisa-
Finally the N-Boc protected amino alcohol 13 was obtained
in 56% yield from 8 by the two-step sequence catalytic
hydrogenation/N-protection (Scheme 4).
By using 3 equiv of reagent, the diazidation of 7 was
achieved in 78% yield (Scheme 5) and following the same
sequence as for 8, the protected bisamine was obtained in
good yield. The deprotection of the hydroxyl functions on
14 with TBAF in THF cleanly afforded the diamino diol 15.
Scheme 2.
Table 1. DIBAL reduction of diesters 1 and 3
Experimenta
Equiv of DIBALH
Reaction time
(min)
% 1 recovered
% 5
% 5 from
unreacted 1
% 7
1
2
3
2.5
2.5
2.5
5.0
5.5
6.0
10
75
130
45
315
60
72
67
57
30
0
19
13
25
30
12
0
69
39
58
47
12
0
2
4.6
16
40
66
97
4
5b
6b (K50 8C)
0
a At K78 8C except where indicated.
b Acidic work-up.
Scheme 3.

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M. T. Barros et al. / Tetrahedron 61 (2005) 7960–7966
Scheme 4.
Scheme 5.
Scheme 6.
We then turned to the preparation of more highly
oxygenated compounds (Scheme 6).
The complete attribution of the signal of the 1H NMR
spectrum of 17 was achieved by 2D (Scheme 7 for
numbering) was confirmed by the large coupling constant
J3,4Z8.72 Hz while the syn relationship between H-5 and
H-4 on one hand, H-3 and H-2 on the other hand, was
proved by the smaller coupling constants J5,4Z4.36 Hz,
J3,2Z1.24 Hz, respectively. The silyl protected allylic
secondary alcohol on 17 was selectively liberated in good
yield by treatment with HF, giving 18. An azido group was
selectively introduced at this allylic position in 90% yield by
Mitsunobu reaction. The inversion of configuration on C-5
bearing the azido group was attested by the coupling
constants J4,5ZJ4,3Z5.60 Hz in the NMR signal of H-4 that
appears as a double triplet. The resulting azido compound
19 was lightly contaminated by an unidentified rearrange-
ment product. The two steps sequence hydrogenation/
N-protection on 19 led to the expected amino polyol 20 in
moderate yield.
The dihydroxylation of one of the two C]C double bond on
7 was performed as described for the dienedioate 1.4a The
reaction was stopped before completion as we started to
observe dihydroxylation of the second double bond. A
slightly lower diastereoselectivity than for 14a was observed
and an easily separable mixture of the diastereoisomers 16a
(majoritary) and 16b as well as traces of the octitol 16c was
obtained. The stereochemistry of the thus two newly created
stereocenters on 16a was acertained after partial protection
of its four free hydroxyl functions: 16a was selectively
benzoylated by treatment with benzoyl chloride in pyridine
at rt in the presence of catalytic DMAP, affording
tribenzoate 17.
3. Conclusions
A concise stereo selective route has been developed for the
Scheme 7.

M. T. Barros et al. / Tetrahedron 61 (2005) 7960–7966
7963
synthesis of optically active polyhydroxy amino alcohols
and diamino alcohols from the readily available D-mannitol.
They are promising key intermediates in the synthesis of
attractive and potent biological units and for the synthesis
of new unnatural amino-acids; that work being in course in
our laboratory.
Anal. Calcd for C20H42O4Si2: C, 59.65; H, 10.51. Found: C,
59.20; H, 10.38.
4.1.2. 3-[(4R,5R)-5-(3-Hydroxy-1-(E)-propen-1-yl)-2,2-
dimethyl-[1,3]dioxolan-4-yl]-2-(E)-acrylic acid ethyl
ester, 4 and 3-[(4R,5R)-5-(3-hydroxy-1-(E)-propen-1-
yl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-prop-2-(E)-en-1-ol,
6. To a solution of 3 (0.513 g, 1,7 mmol) in dry THF (5 ml)
under argon was added 8.59 ml of 1 M solution of DIBALH
in THF at K78 8C. After stirring for 0.5 h, the reaction was
quenched with 10 ml of a saturated solution of NH4Cl and
allowed to stir for 20 min. After filtration and extraction of
the gel with ethyl acetate, the combined organic phase was
dried on Na2SO4 and evaporated. Purification by preparative
TLC of the crude product offered 0.058 g (11%) of
unreacted 3, 0.186 g (48%) of the monoreduced product 4
and 0.106 g (32%) of the desired 6. Compound 4; 1H NMR:
4. Experimental
4.1. General
Melting points were determined on a Bu¨chi 530 apparatus
and are uncorrected. Infrared spectra were recorded on a
Mattson 7000 FTIR spectrometer. Optical rotations were
recorded at 20 8C on an Optical activity AA 1000
polarimeter using a 0.5 dm cell. Concentrations are given
in g/100 ml. NMR spectra (1H: 400 MHz; 13C: 100 MHz)
were recorded on a Bru¨ker ARX 400 spectrometer in CDCl3
using Me4Si (1H) and the solvent peak (13C) at d 77.0 ppm
as an internal reference. Chemical shifts are expressed in
parts per million downfield. Medium pressure column
chromatography were performed on MN Silica gel 60M.
Preparative thin-layer chromatography was performed on
MN Silica gel G/UV 254 with fluorescent indicator.
Elemental analysis were performed by the Micro analytical
Laboratory, operated by the Department of Analysis at
6.75 (ddd, 1H, J5,6Z15.56 Hz, J3,2Z15.64 Hz, J3,4
5.20 Hz, H-3); 6.02 (dd, 1H, J2,3Z15.64 Hz, J2,4
0.84 Hz, H-2); 5.89 (dt, 1H, J7,6Z15.56 Hz, J7,8
4.64 Hz, H-200); 5.63 (dd, 1H, J6,7Z15.56 Hz, J6,5
Z
Z
Z
Z
7.36 Hz, H-100); 4.20–4.00 (m, 6H, OCH2CH3, H-300, H-300,
H-40, H-50); 2.98 (sl, 1H, OH); 1.35 (s, 3H, Me); 1.34 (s, 3H,
13
Me); 1.20 (t, 3H, O–CH2CH3); C00 NMR: 165.9 (C-1);
142.7 (C-3); 135.3 (C-100); 125.3 (C-2 0 ); 122.6 (C-2); 109.7
(quat., C-20); 81.4 (C-40); 79.8 (C-5 ); 61.9 (C-300); 60.5
(O–CH2CH3); 26.8, 26.6 (2CH3); 14.07 (OCH2CH3).
Compound 6: [a]D K13.66 (c 0.41, CHCl3); IR (neat,
´
Instituto Superior Tecnico (Lisbon, Portugal).
cmK1, n): 3401 (OH); 1H NMR: 5.89 (dt, 2H, J5,6
Z
15.60 Hz, JZ15.60 Hz, JZ5.00 Hz, H-2, H-200); 5.62 (m,
2H, JZ15.6000Hz, JZ3.24 Hz, 0H-3, H-100); 4.08 (m, 6H,
H-1, H-1, H-3 , H-300, H-40, H-5 ); 3.31 (s, 2H, OH); 1.40 (s,
6H, 2CH3); 13C NMR: 134.5 (C-3, C-100); 126.2 (C-2, C-200);
109.1 (quat., C-20); 81.4 (C-40, C-50); 62.2 (C-1, C-300); 27.0
(2Me). Anal. Calcd for C11H18O4: C, 61.66; H, 8.47. Found:
C, 61.73; H, 8.59.
4.1.1. (4R,5R)-4,5-Bis-(tert-butyldimethylsilanyloxy)-8-
hydroxy-octa-2(E),6(E)-dienoic acid ethyl ester, 5.
Compound 1 (1.550 g, 3.18 mmol) was dissolved under
argon in 20 ml of dry THF. DIBALH (8 ml of 1 M sol. in
THF, 2.5 equiv) was added at K78 8C and the mixture was
stirred for 2 h. A saturated solution of NH4Cl (25 ml) was
then added and the mixture was stirred for 20 min and
allowed to reach rt. The crude product was dissolved in
AcOEt, filtered and the gel was washed with AcOEt. The
organic layer was separated and dried with Na2SO4,
evaporated and the crude product separated by flash column
chromatography (Hex/AcOEt 4:1 then 3:2) to give 0.358 g
(25%) of 5, 0.876 g (57%) of unreacted 1 and 0.207 g (16%)
of the di reduced compound 7. Compound 5: [a]D C68.05
(c 1.55, CHCl3); IR (neat, cmK1, n): 3330 (OH); 1722
(C]O); 1H NMR: 7.00 (dd, 1H, JZ15.6, 3.6 Hz, H-3); 5.94
(dd, 1H, JZ15.6, 1.6 Hz, H-2); 5.78 (dtd, 1H, JZ15.6, 4.8,
4.8, 0.8 Hz, H-7); 5.63 (dd, 1H, JZ15.6, 4.8 Hz, H-6); 4.29
(m, 1H JZ2.0, 3.2, 3.6, 1.6 Hz, H-4); 4.20–4.13 (m, 3H,
OCH2CH3, H-5); 4.08 (d, 2H, H-8,80); 1.81 (sl, 1H, OH);
1.27 (t, 3H, OCH2CH3); 0.07, 0.06, 0.04, 0.036 (4s, 12H,
SiCH3); 13C NMR: 166.6 (C-1); 147.5 (C-3), 131.2 (C-6);
129.7 (C-7); 121.4 (C-2); 75.0 (C-4); 74.8 (C-5); 63.1 (C-8);
60.3 (O–CH2CH3); 25.8 (tBu); 18.2 (tBu quat.); 14.3
(OCH2CH3); K4.5, K4.8, K4.8, SiCH3. Anal. Calcd for
C22H44O5Si2: C, 59.41; H, 9.97. Found: C, 59.60; H, 10.29.
Compound 7: mp 58–60 8C. [a]D C79.44 (c 0.79, CHCl3);
IR (KBr, cmK1, n): 3330 (OH); 1H NMR: 6.97 (m, 2H, JZ
15.6 Hz, H-3, H-6); 5.97 (d, 2H, JZ15.6 Hz, H-2, H-7);
4.37 (m, 2H, H-4, H-5); 4.25–4.12 (m, 4H, OCH2CH3);
1.31–1.26 (m, 6H, OCH2CH3); 0.94 (s, 18H, tBu); 0.10
(s, 6H, Si(CH3)2); 0.08 (s 6H, Si(CH3)2)); 13C NMR: 130.9
(C-3, C-6), 130.1 (C-2, C-7); 75.2 (C-4, C-5); 63.1 (C-1,
C-8); 25.9 (tBu); 18.2 (tBu quat.); K4.5, K4.7 (SiMe).
4.1.3. (4R,5R)-4,5-Bis(tert-butyldimethylsilanyloxy)-
octa-2-(E),6-(E)-diene-1,8-diol, 7. To a solution of 1
(1.206 g, 2.48 mmol) in dry THF (8 ml) at K78 8C was
added 14.75 ml (6 equiv) of a 1 M solution of DIBALH in
THF. The temperature was allowed to reach K50 8C and the
mixture was stirred for 2 h (TLC Hex/EtOAc 1:4). The
reaction was quenched with 30 ml of a saturated solution of
NH4Cl and stirred for 20 min. The mixture was diluted with
AcOEt and carefully brought to pHZ6 by addition of 1 N
HCl until dissolution of the gel and clear separation of the 2
phases. The aqueous phase was extracted with AcOEt (5!
50 ml), The combined organic phase were dried on Na2SO4.
Evaporation of the solvent gave 1.052 g of crude product
that was purified by flash chromatography (Hex/EtOAc 1:4)
to give 0.997 g (97%) of 7 (see above for characterization).
4.1.4. (4R,5R)-8-Azido-4,5-bis-(tert-butyldimethylsilanyl-
oxy)-octa-2-(E),6-(E)-dien-1-ol,
8.
To
0.281 g
(0.70 mmol) of 7 dissolved in 12 ml of dry THF was
added triphenylphosphine (TPP) (0.220 g, 1.2 equiv). The
mixture was stirred for 20 min then HN3 (0.655 ml of a
1.28 M solution in benzene, 1.2 equiv) was added, followed
by DEAD (0.182 g in 1.5 ml of THF, dropwise). The
mixture was stirred at rt for 1 h. The solvent was evaporated;
the crude product was taken first in CH2Cl2 then AcOEt/
Hexane 1:7, filtered and the filtrate evaporated and purified

7964
M. T. Barros et al. / Tetrahedron 61 (2005) 7960–7966
by flash chromatography to give successively 0.059 g (19%)
of 9, 0.156 g (52, 74% from reacted 7) of 8 and 0.085 g
(29%) of unreacted 7. Compound 8: [a]D C68.4 (c 0.614,
stirred for 30 min at rt then HCl 1 N (2 ml) was added. The
organic phase was decanted and the aqueous phase extracted
with CH2Cl2. The combined organic phase were washed
with saturated NaHCO3, dried on Na2SO4. The crude
product (0.254 g) was purified by preparative TLC (Hex/
AcOEt 6:4) to yield 0.158 g (86%) of 12. [a]D C3.3 (c
0.484, CHCl3); IR (neat, cmK1, n): 2104 (N3); 1364, 1176
(OTs); 1H NMR: 7.76–7.67 (m, 6H, arom. tosyl); 7.38–7.29
(m, 6H, arom. tosyl); 5.69–5.60 (m, 2H, H-2, H-7); 5.57–
5.46 (m, 2H, JZ15.40, 6.28 Hz, H-3, H-6); 4.94 (m, 2H,
H-4, H-5); 4.34 (d, 2H, JZ5.12 Hz, H-1, H-10); 3.64 (d, 2H,
JZ5.40 Hz, H-8, H-80); 2.46 (s, 9H, Me); 13C NMR: 145.5,
145.5, 145.2 (quat. tosyl); 133.3, 133.24 (quat. tosyl); 131.1,
129.5, 126.3, 125.3 (C-2, C-3, C-6, C-7); 130.0, 128.1,
128.0 (arom. tosyl); 79.6, 79.3 (C-4, C-5); 68.5 (C-1); 51.5
(C-8); 21.8 (Me Tosyl).
1
CHCl3); IR (neat, cmK1, n): 3350, 2099; H NMR: 5.85–
5.65 (m, 4H, H-2,3,6,7); 4.19–4.12 (m, 4H, H-4, H-5,
H-1,10); 3.73 (AB part of ABX system, J1,1 Z13.60 Hz);
0
1.58 (sl, 1H, OH); 0.92 (s, 18H, tBu); 0.84, 0.08, 0.06, 0.06
(s, 3H each, SiCH3); 13C NMR: 135.12 (C-3), 130.64 (C-6),
130.08 (C-7), 123.68 (C-2), 74.91, 74.81 (C-4, C-5), 63.35
(C-1), 52.54 (C-8), 25.90 (tBu), 18.22 (tBu quat.), K4.52,
K4.64, K4.76 (SiCH3). Compound 9; IR (neat, cmK1, n):
2104 (N3); 1H NMR: 5.81 (dd, 2H, JZ15.60, 1.60 Hz, H-3,
H-6); 5.71 (td, 2H, JZ15.60, 6.40 Hz, H-2, H-7); 4.20 (sl,
2H, H-4, H-5); 3.73 (m, 4H, H-1, H-10, H-8, H-80); 0.93 (s,
18H, tBu); 0.10 (s, 6H, SiCH3); 0.07 (s, 6H, SiCH3); 13C
NMR: 134.5 (C-3, C-6), 124.2 (C-2, C-7), 74.6 (C-4, C-5),
52.5 (C-1, C-8), 25.9 (tBu), 18.2 (tBu quat.), K4.6, K4.8
(SiCH3).
4.1.9. (4R,5R)[4,5-Bis-(tert-butyl-dimethylsilanyloxy)-8-
hydroxy-octyl]-carbamic acid tert-butyl ester, 13.
0.131 g (0.30 mmol) of 8 were dissolved in 6 ml of absolute
ethanol and submitted to a pressure of 15 psi of hydrogen in
the presence of 32 mg of Pd/C 10% for 45 min, then 50 psi
for more 2.25 h. The catalyst was filtered off and washed
with EtOH then AcOEt; the solvent was evaporated in
vacuo to yield 0.132 g of crude product that was dissolved in
5 ml of dry DCM. (Boc)2O (0.080 g, 2.2 equiv) was added
at rt and the mixture was stirred for 1 h. The reaction was
quenched with HCl 1 N (12 ml); the organic phase was
decanted, washed successively with saturated NaHCO3 then
water, dried on Na2SO4 and the solvent was evaporated in
vacuo. Purification by medium pressure column chroma-
tography (Hex/AcOEt 5:1) yielded 0.087 g (56%) of 13 as a
4.1.5. (4R,5R)-1,8-Diazido-4,5-bis-(tert-butyldimethyl-
silanyloxy)-octa-2-(E),6-(E)-diene, 9. To 0.205 g
(0.5 mmol) of 7 dissolved in 10 ml of dry THF were
added 0.400 g (3 equiv) of TPP. The mixture was stirred for
20 min then 1 ml of a 1.58 M solution of HN3 in benzene
was added, followed by DEAD (0.265 g, 3 equiv in 2 ml of
THF, dropwise). Stirring was continued for 1.25 h. The
solvent was evaporated and the crude product purified by
medium pressure column chromatography (Hex/AcOEt 9:1)
to yield 0.179 g (78%) of 9 as a colourless oil that was
used immediately for the next step (see upper for
characterisation).
4.1.6. (4R,5R)-8-Azido-octa-2-(E),6-(E)-diene-1,4,5-triol,
10. The azide 8 (0.088 g, 0.21 mmol) in 4 ml of anhydrous
THF was stirred at rt for 45 min with 0.412 ml (2 equiv) of a
1 M solution of Bu4NF in THF. Evaporation of the solvent
followed by flash chromatography (AcOEt) gave 10
(0.034 g, 82%) as a viscous syrup. The product has been
characterized as its tribenzoate.
viscous oil. [a]D C34.54 (c 1.60, CHCl3); IR (neat, cmK1
,
n): 3356 (OH); 1694 (C]O); 1H NMR: 4.54 (br s, 1H, NH);
3.60 (m, 2H, 0H-4, H-5); 3.52 (m, 2H, H-80, H-80);03.07 (m,
2H, H-1, H-1 ); 2.01–1.20 (m, 26H, H-3,3 ; H-6,6 ; H-2,20;
H-7,70, OH, 2Boc); 0.85 0.84 (2s, 18H, SitBu); 0.01 (s, 12H,
SiCH3); 13C NMR: 156.2 (C]O), 75.3, 75.2 (C-4, C-5);
63.2 (C-8); 40.7 (C-1); 30.1 (C3, C-6); 28.3 (Boc); 27.3,
26.3 (C-2, C-7); 25.8 (SitBu); 17.9 (tBu quat.); K4.2, K4.3,
K4.7 (SiCH3). Anal. Calcd for C22H55NO5Si2: C, 59.36; H,
10.96; N, 2.77. Found: C, 59.48; H, 11.04; N, 2.66.
4.1.7. (4R,5R)-8-Azido-1,4,5-tribenzoyloxy-octa-2-(E),6-
(E)-diene, 11. Compound 10 (0.042 g, 0.21 mmol) was
dissolved in 1.5 ml of pyridine. BzCl (0.141 g, 4.5 equiv)
and a catalytic amount of DMAP were added The mixture
was stirred for 0.5 h at rt and the reaction was quenched
with 8 ml of a saturated sol. of NaHCO3. The product was
extracted with DCM (3!15 ml) and the organic phase was
dried on Na2SO4. The crude was purified by preparative
TLC (Hex/AcOEt 7:1) to give 0.068 g of 11 as an oil. [a]D
C29.3 (c 1.37, CHCl3); IR (neat, cmK1, n): 2102 (N3), 1723
(C]O); 1H NMR: 8.15–7.98 (m, 6H, arom.); 7.62–7.34 (m,
9H, arom.); 6.18 (dt, 1H, JZ5.60, 5.60, 14.96 Hz, H-2);
6.06–5.87 (m, 5H, H-30, H-4, H-5, H-6, H-7); 4.85 (d, 2H,
JZ5.60 Hz, H-1, H-1 ); 3.78 (d, 2H, JZ5.60 Hz, H-8,
H-80); 13C NMR: 166.1, 165.7 (C]O), 133.7, 133.3, 133.1,
130.2, 129.9, 129.7, 129.7, 129.7, 129.0, 128.5, 128.4,
128.3, 127.4 (C-2, C-3, C-6, C-7, arom.); 73.9 (C-4, C-5);
64.0 (C-1); 51.8 (C-8).
4.1.10. (4R,5R) [8-tert-Butoxycarbonylamino-4,5-bis-
(tert-butyldimethylsilanyloxy)-octyl]-carbamic acid tert-
butyl ester, 14. 0.179 g (0.40 mmol) of 9 dissolved in 12 ml
of absolute ethanol were hydrogenated for 30 min at 15 psi
in the presence of 43 mg of Pd/C 10%, then for 3 h at 50 psi.
The mixture was filtered on celite and concentrated in
vacuo. The crude product (0.191 g) was dissolved in 6 ml of
dry DCM. Et3N (0.25 ml, 4.4 equiv) followed by (Boc)2O
(0.196 g, 2.2 equiv) was added. The mixture was stirred for
1.5 h at rt and quenched with 12 ml of HCl (1 N). The
organic phase was decanted and the aqueous phase extracted
with CH2Cl2 (2!20 ml). The combined extracts were
washed with saturated NaHCO3 then water, dried on
Na2SO4 and concentrated in vacuo. Medium pressure
column chromatography (2!35 cm, eluent Hex/AcOEt
8:1) of the crude product (0.267 g) afforded 14 (0.179 g,
83%) as a white solid. Mp 99–101 8C. [a]D C34.0 (c 0.31,
4.1.8. (4R,5R)-8-Azido-1,4,5-tri-O-tosyl-octa-2-(E),6-(E)-
diene, 12. 0.055 g (0.28 mmol) of 10 were dissolved in 3 ml
of dry DCM. TsOTs (0.543 g, 6 equiv) and pyridine
(0.135 ml, 6 equiv) were added at 0 8C. The mixture was
1
CHCl3); IR (KBr, cmK1, n): 3357 (NH), 1694 (C]O); H
NMR: 4.52 (br s, 2H, NH); 3.500 (bd, 2H, JZ8.24 Hz, H-4,
H-5); 3.08 (br s, 4H, H-1, H-1 , H-8, H-80); 1.67–1.18 (m,

M. T. Barros et al. / Tetrahedron 61 (2005) 7960–7966
7965
26H, H-3,30; H-6,60; H-2,20; H-7,70, 2Boc); 0.85 (s, 18H,
SitBu); 0.03 (s, 12H, SiCH3); 13C NMR: 156.1 (C]O), 75.2
(C-4, C-5); 40.7 (C-1, C-8); 28.4 (Boc); 27.2 (C-2, C-3, C-6,
C-7); 25.8 (SitBu); 17.9 (tBu quat.); K4.3, K5.0 (SiCH3).
Anal. Calcd for C30H64N2O6Si2: C, 59.56; H, 10.66; N,
4.63. Found: C, 59.91; H, 10.75; N, 4.50.
phase dried on Na2SO4. Evaporation of the solvent and
purification of the crude product by flash chromatography
afforded 17 (0.495 g, 90%). [a]D C32.15 (c 2.42, CHCl3);
1
IR (neat, cmK1, n): 3483 (OH), 1724 (C]O); H NMR:
8.11 (d, 2H, JZ7.36 Hz, arom. ortho); 8.06 (d, 2H, JZ
7.48 Hz, arom. ortho); 8.0 (d, 2H, JZ7.40 Hz, arom. ortho);
7.60–7.34 (m, 9H, arom. meta, para); 6.20 (ddt, 1H, JZ
15.60, 4.36, 1.84 Hz, H-6); 6.06 (ddt, 1H, JZ15.60, 4.56,
1.24 Hz, H-7); 5.57 (dt, 1H, JZ6.24, 6.24, 1.24 Hz0, H-2);
4.92 (AB part of ABX system, JZ13.64 Hz H-8, H-8 ); 4.66
(, 2H, JZ6.36 Hz, H-1, H-10); 4.52 (m, 1H, JZ4.36,
1.88 Hz, H-5); 4.19 (br s, 1H, OH); 4.03 (dd, 1H, JZ8.72,
1.24 Hz, H-3); 3.88 (dd, 1H, JZ4.36, 8.72 Hz, H-4); 0.98 (s,
9H, tBu); 0.88 (s, 9H, tBu); 0.15 (s, 3H, SiCH3); 0.14 (s 3H,
SiCH3); 0.03 (s, 3H, SiCH3); K0.04 (s, 3H, SiCH3); 13C
NMR: 166.20, 165.85 (C]O); 133.10, 133.03, 132.89
(arom. para); 130.4 (C-7); 130.3, 130.2, 130.1 (arom. quat.);
129.8, 129.8, 129.7 (arom. ortho); 128.4, 128.3 (arom.
meta); 126.3 (C-6); 75.5 (C-2); 72.5 (C-3); 71.0 (C-5, C-4);
64.6 (C-8); 63.4 (C-1); 25.8, 25.8 (tBu); 18.2, 18.0 (tBu
quat.); K3.8, K4.7, K5.2 (SiCH3). Anal. Calcd for
C41H56O9Si2: C, 65.47; H, 7.54. Found: C, 65.73; H, 7.53.
4.1.11. (4R,5R) (8-tert Butoxycarbonylamino-4,5-di-
hydroxy-octyl)-carbamic acid tert-butyl ester, 15. Com-
pound 14 (0.133 g, 0.22 mmol) was dissolved in 5 ml of dry
THF. Then TBAF (0.115 g, 2 equiv) was added at rt. The
mixture was stirred for 5 h. Evaporation of the solvent gave
0.275 g of a crude product that was purified by medium
pressure column chromatography (Hex/AcOEt 6:1 then
AcOEt) to yield 0.078 g (94%) of 15 as a colourless viscous
syrup that crystallized on standing in fridge. Mp 81–82 8C.
[a]D C14.61 (c 0.96, CHCl3); IR (KBr, cmK1, n): 3386,
3365 (OH, NH), 1687.80 (C]O); 1H NMR: 4.92 (br s, 2H,
NH); 3.51 (br s, 2H, OH); 30.37 (br s, 2H, H-4, H-5); 3.10 (m,
4H, H-1, H-10, H-8, H-8 ); 1.72–1.35 (m, 26H, H-3,30;
H-6,60; H-2,20; H-7,70, OH, 2Boc); 13C NMR: 156.6
(C]O), 79.2 (Boc, quat.); 74.1 (C-4, C-5); 40.3 (C-1,
C-8); 30.3 (C3, C-6); 28.3 (Boc); 26.3 (C-2, C-7). Anal.
Calcd for C18H36N2O6: C, 57.42; H, 9.64; N, 7.44. Found:
C, 57.49; H, 9.71; N, 7.43.
4.1.14. (2S,3S,4R,5R)-1,2,8-Tri-benzoyloxy-4-tert-butyl-
dimethylsilanyloxy-oct-6-(E)-ene-3,5-diol, 18. Compound
17 (0.263 g, 0.35 mmol) was dissolved in 7 ml of
acetonitrile. HF (40% in water, 0.216 ml) was added and
the mixture was stirred at rt for 30 min (A longer reaction
time resulted in lower yield in expected product) until
apparition of a more polar compound (checked by TLC
Hex/AcOEt 4:1). The reaction was quenched with saturated
NaHCO3, extracted with DCM, and the organic phase dried
on Na2SO4. Evaporation of solvent and purification of the
crude product by preparative TLC gave 0.053 g (22%) of 17
and 0.174 g (73%) of 18. [a]D C12.31 (c 0.93, CHCl3); IR
4.1.12. (2S,3S,4R,5R)-4,5-Bis-(tert-butyldimethylsilanyl-
oxy)-oct-6-(E)-ene-1,2,3,8-tetraol, 16a. To 0.807 g
(2.0 mmol) of 7 dissolved in 10 ml of acetone and cooled
by an ice bath were added 0.406 g (1.5 equiv) of NMO in
0.8 ml of H2O and 5 drops of a solution of OsO4 in
acetonitrile. After 0.5 h, the stirring was continued at rt for
3 h then solid K2S2O3 was added an the mixture was stirred
for more 0.5 h, extracted with AcOEt, dried on Na2SO4 and
concentrated in vacuo. Purification of the crude by flash
chromatography gave 0.330 g (40%) of unreacted 7, 0.336 g
(39%) of 16a and 0.043 g (5%) of 16b. Compound 16a: [a]D
C57.68 (c 0.99, CHCl3); IR (neat, cmK1, n): 3326 (OH); 1H
NMR: 5.94 (m, 2H, H-6, H-7); 4.40 (m, 1H); 4.21 (m, 2H);
3.83 (dd, 1H, JZ4.36, 8.76 Hz, H-4);3.78–3.63 (m, 4H);
2.81 (br s, 4H, OH); 0.93 (s, 9H, SitBu); 0.90 (s, 9H, SitBu);
0.16, 0.14, 0.13, 0.11 (s, 3H each, SiCH3); 13C NMR: 131.19
(C-6); 128.15 (C-7); 75.72, 74.22, 71.12, 69.05, 65.53,
63.08 (C-8, C-5, C-4, C-3, C-2, C-1); 25.84, 25.80 (SitBu);
18.12, 18.02 (SitBu quat.); K4.34, K4.78, K4.92, K5.06
(SiCH3). Anal. Calcd for C20H44O6Si2: C, 55.00; H, 10.16.
Found: C; H; %. Compound 16b: [a]D C41.56 (c 0.90,
1
(neat, cmK1, n): 3456 (OH); 1723 (C]O); H NMR: 8.08
(dd, 2H, JZ8.76, 1.28 Hz, arom. ortho); 8.02 (dd, 2H, JZ
8.12, 1.28 Hz, arom. ortho); 7.97 (dd, 2H, JZ8.08, 1.24 Hz,
arom. ortho); 7.60–7.50 (m, 3H, arom para); 7.47–7.35 (m,
6H, arom. meta); 6.05 (AB part of ABMX system, JAB
Z
15.60 Hz, H-6, H-7); 5.49 (dt, 1H, JZ6.24, 1.88 Hz, H-2);
4.83 (AB part of ABX system, JZ12.76 Hz, H-8, H-80);
4.76 (dd, 1H, JZ11.24, 6.24 Hz, H-1); 4.60 (dd, 1H, JZ
11.24, 6.24 Hz, H-10); 4.43 (m, 1H, H-5); 3.96 (AB part of
ABMX system, H-3, H-4, JABZ7.48 Hz); 3.20 (br s, 2H,
OH; 0.85 (s, 9H, SitBu); 0.03 (s, 3H, SiCH3); K0.01 (s 3H,
SiCH3); 13C NMR: 166.6, 166.3, 166.0 (C]O); 133.4,
133.3, 133.0 (arom. para); 132.6 (C-6); 130.2 (arom. quat.);
130.0, 129.8, 129.7 (arom. ortho); 129.5 (arom. quat.);
128.6; 128.5, 128.4 (arom. meta); 125.9 (C-7); 73.4 (C-2);
72.8 (C-3); 72.4 (C-5); 71.3 (C-4); 64.8 (C-8); 62.7 (C-1);
25.9 (tBu); 18.0 (tBu quat.); K4.0, K4.9 (SiCH3). Anal.
Calcd for C35H42O9Si: C, 66.22; H, 6.67. Found: C, 66.50;
H, 6.50.
1
CHCl3); H NMR: 5.84 (m, 2H, H-6, H-7); 4.20 (m, 1H);
4.10 (m, 2H); 3.75 (dd, 1H, JZ3.12, 5.00 Hz, H-4); 3.71–
3.54 (m, 4H); 3.15 (br s, 4H, OH); 0.92 (s, 9H, SitBu); 0.91
(s, 9H, SitBu); 0.15, 0.14, 0.08, 0.06 (s, 3H each, SiCH3);
13C NMR: 130.6 (C-6); 129.4 (C-7); 74.3, 73.7, 72.6, 69.6,
64.0, 62.8 (C-8, C-5, C-4, C-3, C-2, C-1); 25.9 (SitBu); 18.2,
18.1 (SitBu quat.); K4.2, K4.6, K4.7, K4.8 (SiCH3).
4.1.13. (2S,3S,4R,5R)-1,2,8-Tri-benzoyloxy-4,5-bis(tert-
butyldimethylsilanyloxy)-oct-6-(E)-ene-3-ol, 17. To
0.321 g (0.74 mmol) of 16a dissolved in 5 ml of dry
pyridine at 0 8C were added 0.52 ml (4.4 mmol, 6 equiv)
of BzCl and a catalytic amount of DMAP. The mixture was
stirred at rt for 1.5 h (TLC Hex/AcOEt 4:1). The reaction
was quenched with a saturated solution of NaHCO3. The
product was extracted with DCM (4!20 ml), the organic
4.1.15. (2S,3S,4R,5R)-5-Azido-1,2,8-tri-benzoyloxy-4-
tert-butyldimethylsilanyloxy-oct-6-(E)-ene-3-ol, 19. To
0.296 g (0.47 mmol) of 18 dissolved in 9 ml of dry THF
was added TPP (0.186 g, 1.5 equiv), followed by 0.400 ml
(1.5 equiv) of a 1.7 M solution of hydrazoic acid in benzene.
The mixture was stirred at rt for 20 min then DEAD (0.124 g
in 1.7 ml of dry THF) was added dropwise. After 30 min of
stirring, the solvent was evaporated and the crude product

7966
M. T. Barros et al. / Tetrahedron 61 (2005) 7960–7966
was purified by preparative TLC (Hex/EtOAc 4:1) to give
0.277 g (90%) of 19 as a colourless syrup. [a]D K13.36 (c
1.05, CHCl3); IR (neat, cmK1, n): 3475 (OH), 2106 (N3),
(arom. para); 129.94; 129.86; 129.75 (arom. meta); 128.54,
128.42 (arom. ortho); 79.6 (quat. Boc); 73.30; 73.12 (C-1,
C-8); 68.27, 66.72, 65.78 (C-2, C-4, C-3); 49.56 (C-5);
30.22 (C-6); 28.11 (tBu, Boc); 27.32 (C-7); 25.55 (SitBu);
17.69 (SitBu quat.); K4.76, K5.11 (SiCH3). Anal. Calcd
for C40H53NO10Si: C, 65.28; H, 7.26; N, 1.90. Found: C,
64.99; H, 7.29; N, 1.85.
1
1724 (C]O); H NMR: 8.08–8.03 (m, 4H, arom. ortho);
8.00–7.97 (m, 2H, arom. ortho); 7.59–7.50 (m, 3H, arom.
para); 7.47–7.37 (m, 6H, arom. meta); 6.06 (ddd, 1H JZ
15.60, 6.24, 1.24 Hz, H-6); 5.81 (ddd, 1H, JZ15.60, 6.24,
1.24 Hz, H-7); 5.69 (ddd, 1H, JZ6.24, 5.00, 2.48 Hz, H-2);
4.63 (m, 2H, AB part of ABX system, JABZ11.84 Hz, H-8,
H-80); 4.45 (dd, 1H, JZ10.60, 3.12 Hz, H-1); 4.39 (dt, 1H,
JZ5.62, 1.24 Hz, H-4); 4.36–4.27 (m, 2H, H-10 and H-3 or
H-5); 3.87 (m, 1H, JZ5.60, 3.12 Hz, H-5 or H-3); 2.30 (br s,
1H, OH); 0.82 (s, 9H, tBu); 0.01, K0.01, K0.04 (3s, 3H
each, SiCH3); 13C NMR: 166.3, 166.2, 165.6 (C]O); 135.4
(C-6), 133.3, 133.3, 133.2 (arom. para); 129.9; 129.9; 129.8
(arom. meta); 129.5 (arom. quat.); 128.5, 128.5 (arom.
ortho); 126.7 (C-7); 73.83, 73.22, 70.51, 66.12; 63.61 (C-8);
61.74 (C-1); 25.77 (tBu); 18.06 (SitBu quat.); K4.13,
K5.00 (SiCH3).
Acknowledgements
ˆ
Fundac¸a˜o para a Ciencia e a Tecnologia POCTI/FEDER is
thanked for financial support and a grant to T.M.
References and notes
1. (a) Del Olmo, E.; Macho, A.; Alves, M. Bioorg. Med. Chem.
Lett. 2002, 12, 2621–2626. (b) Zhou, H. B.; Zhang, J.; Lu, S. M.
Tetrahedron 2001, 57, 9325–9333. (c) Vassilyeva, O. Y.;
Makhankova, V. G.; Kokozay, V. N. J. Inorg. Biochem. 2001,
86, 467. (d) Nakamura, T.; Shiozaki, M. Tetrahedron Lett.
1999, 40, 9063–9064. (e) Katsumura, S.; Yamamoto, N.;
Morita, M.; Han, Q. Tetrahedron: Asymmetry 1994, 5, 161–164.
(f) Nicholas, G. M.; Li, R. H.; MacMillan, J. B. Bioorg. Med.
Chem. Lett. 2002, 12, 2159–2162.
4.1.16. (2S,3S,4R,5R)-5-tert-Butoxycarbonylamino-1,2,8-
tri-benzoyloxy-4-tert-butyldimethylsilanyloxy-oct-6-(E)-
ene-3-ol, 20. 0.167 g (0.25 mmol) of 19 in 10 ml of EtOH
were submitted to a pressure of 15 psi of hydrogen in the
presence of 30 mg of 10% Pd/C for 0.5 h then to 55 psi for
3 h. The catalyst was filtered off and the solvent evaporated
in vacuo. The crude product was taken in DCM (5 ml) then
Et3N (0.1 ml, 2.2 equiv) was added at 0 8C followed by
(Boc)2O (63 mg, 1.1 equiv) then the mixture was stirred at rt
for 2 h. The reaction was quenched with HCl 1 N, the
product was extracted with DCM, washed with NaHCO3
sat. and dried on Na2SO4. The solvent was evaporated in
vacuo and the crude product was purified by preparative
TLC (Hex/AcOEt 3:1) to give 0.080 g (43%) of 20 as a
colourless viscous oil. [a]D C9.7 (c 1.53, CHCl3); IR (neat,
2. Ravi Kumar, J. S.; Datta, A. Tetrahedron Lett. 1999, 40,
1381–1384.
3. (a) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron lett.
¨
1994, 35, 733–736. (b) Postels, H. T.; Konig, W. A.
Tetrahedron Lett. 1994, 35, 4535. (c) Multzer, J.; Meier, A. J.
J. Org. Chem. 1996, 61, 566. (d) Wook Lee, J.; Sung Im, J.;
Kim, K. Tetrahedron Lett. 2001, 42, 2709–2711.
1
cmK1, n): 3444, 3379 (OH, NH), 1722, 1713 (C]O); H
4. (a) Barros, M. T.; Januario-Charmier, M. A.; Maycock, C. D.;
Pires, M. Tetrahedron 1996, 23, 7861–7874. (b) Barros, M. T.;
´
NMR: 8.07–7.95 (m, 6H, arom. ortho); 7.56–7.48 (m, 3H,
arom. para); 7.42–7.32 (m, 6H, arom. meta); 4.89–4.20 (m,
7H); 1.38 (s, 9H, tBu Boc); 0.88 (s, 9H, SitBu); 0.06 (s, 3H,
SiCH3); 0.03 (s 3H, SiCH3); 13C NMR: 166.54, 166.51,
166.08 (C]O Bz); 155.58 (C]O Boc); 133.49, 133.30,
´
Januario-Charmier, M. A.; Maycock, C. D.; Michaud, T.
Tetrahedron 2002, 58, 1519–1524. (c) Becker, J. M.; Covert,
N. L.; Shenbagamurthi, P. S.; Steinfeld, A.; Naider, F.
Antimicrob. Agents Chemother. 1983, 23, 926.