A simple and efficient approach to 1,3-aminoalcohols: application to the synthesis of (+)-negamycin

Article abstract of DOI:10.1016/j.tetlet.2007.03.169

A short and practical enantioselective synthesis of (+)-negamycin has been achieved in high enantio- and diastereomeric excess using an iterative Jacobsen's hydrolytic kinetic resolution as the key step.

Full text of DOI:10.1016/j.tetlet.2007.03.169

Tetrahedron Letters 48 (2007) 3793–3796
A simple and efficient approach to 1,3-aminoalcohols: application
to the synthesis of (+)-negamycin
S. Vasudeva Naidu and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 29 January 2007; revised 23 March 2007; accepted 30 March 2007
Available online 5 April 2007
Abstract—A short and practical enantioselective synthesis of (+)-negamycin has been achieved in high enantio- and diastereomeric
excess using an iterative Jacobsen’s hydrolytic kinetic resolution as the key step.
Ó 2007 Elsevier Ltd. All rights reserved.
(3R,5R)-3,6-Diamino-5-hydroxyhexanoic acid 1, is the
core fragment of the pseudo-peptide antibiotics negamy-
cin 2 and sperabillins A and C 3a and 3c (Fig. 1). (+)-
Negamycin 2 is an unusual antibiotic which contains a
hydrazine peptide linkage, and was isolated1 by Ume-
zawa et al. in 1970 from the culture filtrate of three
strains related to Streptomyces purpeofuscus, and exhib-
its very low acute toxicity (LDm-400–500 mg/kg). It
has considerable activity towards multiple drug resistant
enteric Gram-positive and Gram-negative bacteria
including Pseudomonas aerginosa.1 Negamycin also
exhibits genetic miscoding activity2 on bacterial ribo-
some systems and is a specific inhibitor of protein synthe-
sis in Escherichia coli K12.3 The structure of negamycin
was elucidated via degradation studies4 and confirmed
in 1972 by total synthesis from D-galacturonic acid.5
The sperabillin family of antibiotics isolated from the
culture broth of Pseudomonas fluoresens YK-437 shows
potential in vitro and in vivo antibacterial activity,
especially against Gram-positive pathogens, including
Me
N
O
OH
NH2
O
OH
NH2
O
H2N
H2N
N
OH
OH
H
1
negamycin 2
OH
NH2
O
NH
H
R3
N
N
H
NH2
O
R2
R1
sperabillin A (3a) : R1 = H, R2 = Me, R3 = H
sperabillin B (3b) : R1 = Me, R2 = Me, R3 = H
sperabillin C (3c) : R1 = H, R2 = H, R3 = Me
sperabillin D (3d) : R1 = Me, R2 = H, R3 = Me
Figure 1.
*
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629; e-mail: pk.tripathi@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.169

3794
S. V. Naidu, P. Kumar / Tetrahedron Letters 48 (2007) 3793–3796
multiresistant strains of Staphylococcus aureus.6 Several
approaches have been reported in the literature for the
synthesis of racemic7 as well as optically active8 negamy-
cin. Most of the enantioselective syntheses known for
negamycin derive the asymmetry from an enzymatically
derived chiral building block8a or from chiral pool start-
ing materials,8 such as D-galacturonic acid, 3R,6-diacet-
amido-5R-hydroxyhexano lactone, amino acids, D-
glucose and malic acid. However, synthetic approaches
involving achiral substrates as starting materials are
rather scarce.8j,l
negamycin 2 could be synthesized by peptide formation
between 13 and l-methylhydrazineacetic acid. The bis-
azido compound can be derived by regioselective open-
ing of epoxide 8a, which in turn could be obtained via
hydrolytic kinetic resolution of epoxide 8. Epoxide 8
could be obtained from olefin 7, which could be derived
from racemic epichlorohydrin ( )-5 via hydrolytic
kinetic resolution and vinylation. As illustrated in
Scheme 3, commercially available epichlorohydrin was
subjected to Jacobsen’s HKR by using (S,S)-salen-
Co-OAc catalyst 4 (Fig. 2) to give R-epichlorohydrin
513d as a single enantiomer, which was easily isolated
from the more polar diol 6 by distillation. With enantio-
merically pure epoxide 5 in hand our next aim was
to construct the anti-1,3-aminoalcohol. To establish
the second stereogenic centre with the required stereo-
chemistry, it was thought worthwhile to examine stereo-
selective epoxidation of a homoallylic alcohol. Thus,
R-epichlorohydrin 5 was treated with vinylmagnesium
bromide in the presence of CuI to give homoallylic
alcohol 7 in good yield.
As a part of our research programme aimed at develop-
ing enantioselective syntheses of naturally occurring lac-
tones9 and amino alcohols,10 we have recently reported
an efficient approach for the synthesis of 1,3-polyols,
which was successfully applied to the synthesis of
tarchonanthuslactone11 and cryptocarya diacetate.12
Here, we report the use of this approach for the total
synthesis of (+)-negamycin from commercially available
racemic epichlorohydrin.
Scheme 1 shows our general synthetic strategy to con-
struct the syn- and anti-1,3-aminoalcohol system which
is based on a three-step reaction sequence employing
iterative epoxidation, hydrolytic kinetic resolution
(HKR)13 and vinylation. The diastereomeric ratio in
the m-CPBA epoxidation reaction would depend on
whether the hydroxyl group is free or protected.
We then further proceeded to explore the stereoselective
outcome of the epoxidation reaction with and without
hydroxyl group protection. Towards this end, the
OH
O
O
a
+
Cl
Cl
Cl
Cl
OH
6
5
( )-5
The syn- and anti-configuration of the 1,3-polyol/
aminoalcohol moiety can be manipulated simply by
changing the Jacobsen’s catalyst in the hydrolytic kinetic
resolution step. Our synthetic strategy for the synthesis
of 2 is outlined in Scheme 2. We envisioned that (+)-
OH
OTBS
b
O
c
Cl
5
7
8
OP
OTBS OH
OTBS
O
O
vinylation
HKR
O
d
OH
Cl
Cl
+
R
R
R
*
*
8a
8b
OP
*
OP
*
NH2
*
vinylation/
NaN3
Scheme 3. Reagents and conditions: (a) S,S-salen-Co-(OAc)
4
O
HKR
(0.5 mol %), dist. H2O (0.55 equiv), 0 °C, 14 h, (46% for 5, 45% for
6); (b) vinylmagnesium bromide, ether, CuI, ꢀ78 to ꢀ40 °C, 19 h, 70%;
(c) (i) m-CPBA, CH2Cl2, 0 °C to rt, 10 h, 88%; (ii) TBDMS-Cl,
imidazole, CH2Cl2, 0 °C to rt, 4 h, 95%; (d) S,S-salen-Co-(OAc) 4
(0.5 mol %), dist. H2O (0.55 equiv), 0 °C, 24 h (46% for 8a, 45% for 8b).
R
R
*
Scheme 1. General synthetic strategy for the synthesis of 1,3-
aminoalcohols.
HKR
Me
N
O
OH
NH2
O
OTBS N3
O
H2N
N3
N
OH
OH
H
13
2
OTBS N3
OTBS
HKR
HKR
O
O
Cl
Cl
Cl
8
10
( )-5
Scheme 2. Retrosynthetic analysis of (+)-negamycin (2).

S. V. Naidu, P. Kumar / Tetrahedron Letters 48 (2007) 3793–3796
3795
OTBS OMs
OTBS OH
a
OPiv
Cl
H
H
OH
b
Cl
N
N
O
8b
Co
OTBS
t-Bu
t-Bu
O
O
OAc
Cl
t-Bu
t-Bu
8a
(S,S)-SalenCo(III)OAc complex (4)
Scheme 4. Reagents and conditions: (a) (i) PivCl, Et3N, cat. DMAP,
rt, 2 h; (ii) MsCl, Et3N, DMAP, 0 °C to rt, 1 h; (b) K2CO3, MeOH, rt,
overnight (62% for three steps).
Figure 2.
hydroxyl group of homoallylic alcohol 7 was first pro-
tected as its TBS ether, followed by epoxidation with
m-CPBA. The epoxide thus obtained was found to be
a mixture of two diastereomers (anti:syn/3:1).
Concomitant ring closure via intramolecular SN2 dis-
placement of the mesylate furnished epoxide 8a in 62%
overall yield.
With substantial amounts of 8a in hand, we proceeded
with the synthesis of 2 (Scheme 5) by opening of epoxide
8a with vinylmagnesium bromide in the presence of CuI
in THF at ꢀ20 °C to give homoallylic alcohol 9 in 86%
yield. Compound 9 was then converted into an O-mesyl
derivative, which on treatment with sodium azide in
DMF furnished azide 10 with the desired stereochemis-
try at C-3. Treatment of 10 with a large excess of NaI in
2-butanone gave iodoazide 11 in essentially quantitative
yield. Bis-azide 12 was obtained by smooth displacement
of the iodo group in 11 with sodium azide. [CAUTION:
appropriate care should be exercised when handling
azides and bis-azides]. Oxidation of the olefinic bond
using RuCl3/NaIO4 furnished the corresponding acid
in 69% yield. Hydrazide 14 was prepared in good yield
from 13 by formation of its mixed anhydride17 with
ethyl chloroformate and subsequent reaction of the acti-
vated carbonyl with benzyl (1-methylhydrazino)ace-
tate.8h In the final step, the azides were reduced to
amino groups by catalytic hydrogenation over Pd/C in
MeOH, H2O and AcOH with concomitant removal of
The desired syn isomer of 8 was obtained only as a
minor component. However, when the epoxidation
was carried out on alcohol 7 followed by hydroxy
protection as the TBS-ether, the diastereomeric epoxide
8 was formed in favour of the desired syn isomer
(syn:anti/1.2:1).14 With epoxide 8 (syn:anti/1.2:1) in
hand, our next aim was to synthesize the diastereomeri-
cally pure epoxide using Jacobsen’s hydrolytic kinetic
resolution method, the product of which could further
be elaborated to the anti-1,3-aminoalcohol moiety.
Towards this end, epoxide 8 was treated with (S,S)-
salen-Co-OAc complex 4 (0.5 mol %) and water (0.55
eq) in THF (0.55 equiv) to afford epoxide 8a as a single
diastereoisomer (determined from 1H and 13C NMR
spectral analyses)15 in 46% yield and diol 8b in 45%
yield. Epoxide 8a could easily be separated from the
more polar diol 8b through silica gel column chromato-
graphy. In order to achieve the synthesis of target
molecule 2, we required epoxide 8a in a substantial
amount. As the HKR method provided the desired
epoxide 8a along with an equal amount of diol 8b, we
therefore thought it appropriate to convert diol 8b into
the required epoxide. Thus, the diol was smoothly con-
verted into the desired epoxide 8a via internal nucleo-
philic substitution of a secondary mesylate16 (Scheme
4). Accordingly, the chemoselective pivalation of diol
8b with pivaloyl chloride followed by mesylation of
the secondary hydroxy and treatment of the crude mes-
ylate product with K2CO3 in methanol led to deprotec-
tion of the pivaloyl ester to a hydroxy group.
the benzyl and silyl protecting groups to give (+)-nega-
25
mycin 2 in 72% yield from 14; ½aꢁD +2.1 (c 0.72, H2O);
25
lit.8h ½aꢁD +1.7 (c 0.6, H2O); lit.8b +2.3 (c 4.07, H2O).
The physical and spectroscopic data of 2 were in full
agreement with the literature data.
In conclusion, we have developed a practical and
efficient strategy amenable to both syn- and anti-1,3-
aminoalcohols with high degrees of enantio- and
diastereoselectivities. The desired stereocentres can
OTBS OH
OTBS N3
OTBS N3
N3
OTBS
a
c
b
d
Cl
I
N3
Cl
8a
10
12
9
11
CH3
N
OH
NH2
O
Me
N
OTBS N3
O
OTBS
N3
O
g
f
e
CO2H
H2N
CO2Bn
N3
N3
N
N
OH
H
H
13
14
2
Scheme 5. Reagents and conditions: (a) Vinylmagnesium bromide, THF, CuI, ꢀ20 °C, 1 h, 86%; (b) (i) MsCl, Et3N, DMAP, 0 °C to rt, 1.5 h; (ii)
NaN3, DMF, 70 °C, 9 h, 89%; (c) NaI, 2-butanone, reflux, 6 h; (d) NaN3, DMF, 70 °C, 4 h; (e) RuC13 (cat.), NaIO4, CH3CN/CCl4/H2O, rt, 69%; (f)
C1CO2Et, NEt3, toluene, ꢀ5 °C, then benzyl (l-methylhydrazino) acetate, 65%; (g) H2, Pd–C, MeOH, H2O, AcOH, rt, 72%.

3796
S. V. Naidu, P. Kumar / Tetrahedron Letters 48 (2007) 3793–3796
Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett.
2004, 45, 849–851; (e) Naidu, S. V.; Gupta, P.; Kumar, P.
Tetrahedron Lett. 2005, 46, 2129–2131; (f) Kumar, P.;
Naidu, S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843–
2846; (g) Kumar, P.; Naidu, S. V. J. Org. Chem. 2005, 70,
4207–4210.
simply be achieved by changing the catalyst for the
HKR step. The synthetic protocol has been utilized
for the synthesis of (+)-negamycin 2. Further applica-
tion of this methodology to the syntheses of all the
isomers of negamycin and other biologically active
compounds for structure activity relationship studies is
currently underway in our laboratory.
10. (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000,
3447–3449; (b) Pandey, R. K.; Fernandes, R. A.; Kumar,
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Acknowledgements
S.V.N. thanks the CSIR, New Delhi for financial assis-
tance. We are grateful to Dr. M. K. Gurjar for his sup-
port and encouragement. The financial support from the
DST, New Delhi (Grant No. SR/S1/OC-40/2003) is
gratefully acknowledged. This is NCL communication
No. 6700.
11. Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett.
2005, 46, 6571–6573.
12. Kumar, P.; Gupta, P.; Naidu, S. V. Chem. Eur. J. 2006,
12, 1397–1402.
References and notes
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25
15. Spectral data of compound 8a: colourless oil, ½aꢁD +24.0
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(c 0.52, CHCl3); IR (CHCl3): mmax 3017, 2959, 2932, 1859,
1469, 1376, 1258, 1216, 1108, 1006, 935, 874, 761 cmꢀ1; 1H
NMR (200 MHz, CDCl3): d 0.12 (s, 3H), 0.13 (s, 3H), 0.91
(s, 9H), 1.69 (ddd, J = 7.3, 3.9, 2.1 Hz, 1H), 1.85 (ddd,
J = 7.3, 4.4, 2.3 Hz, 1H), 2.53 (q, J = 5.3 Hz, 1H), 2.82 (t,
J = 4.4 Hz, 1H), 3.02–3.06 (m, 1H), 3.49 (d, J = 5.4 Hz,
2H), 4.06–4.10 (m, 1H); 13C NMR (50 MHz, CDCl3): d
ꢀ4.9, ꢀ4.6, 17.9, 25.7, 38.3, 47.5, 48.5, 49.1, 70.4. Anal.
Calcd for C11H23ClO2Si (250.84): C, 52.67; H, 9.24; Cl,
14.13. Found C, 52.74; H, 9.11; Cl, 14.31. Spectral data of
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compound 9: colourless oil, ½aꢁD +32.0 (c 0.41, CHCl3);
´ ´
931–934; (c) Pierdet, A.; Nedelec, L.; Delaroff, V.; Allais,
1H NMR (200 MHz, CDCl3): d 0.04 (s, 6H), 0.80 (s, 9H),
1.61–1.95 (m, 2H), 2.13 (t, J = 10.1 Hz, 2H), 3.43 (d,
J = 5.2 Hz, 2H), 3.81–3.83 (m, 1H), 4.03–4.08 (m, 1H),
5.03–5.06 (m, 2H), 5.71–5.77 (m, 1H); 13C NMR (50 MHz,
CDCl3): d ꢀ5.1, ꢀ4.8, 13.9, 17.7, 25.5, 42.3, 47.9, 66.9,
70.2, 117.4, 134.2. Anal. Calcd for C13H27ClO2Si (278.89):
C, 55.99; H, 9.76; Cl, 12.71. Found C, 56.21; H, 9.58; Cl,
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25
12.91. Spectral data of compound 13: yellowish oil, ½aꢁD
+9.3 (c 0.61, CHCl3); IR (CHCl3): mmax 3420, 2150, 1744,
1698 cmꢀ1; H NMR (200 MHz, CDCl3): d 0.01 (s, 3H),
1
0.03 (s, 3H), 0.91 (s, 9H), 1.36–1.48 (m, 2H), 2.67 (d,
J = 7.2 Hz, 2H), 3.29 (dd, J = 13.0, 4.1 Hz, 1H), 3.52 (dd,
J = 13.0, 4.0 Hz, 1H), 3.74 (m, 1H), 3.89 (m, 1H); 13C
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