An efficient synthesis of (-)-deacetylanisomycin starting from D-tyrosine1

Article abstract of DOI:10.1055/s-2002-33904

The antibiotic (-)-deacetylanisomycin was synthesized starting from D-tyrosine using Sharpless asymmetric dihydroxylation as a key reaction.

Full text of DOI:10.1055/s-2002-33904

PAPER
1867
An Efficient Synthesis of (–)-Deacetylanisomycin Starting from D-Tyrosine1
Synthesis of (–
.
)-Deacetyla
C
Indian Institute of Chemical Technology, Hyderabad - 500 007, India
Fax +91(40)7160512; E-mail: srivaric@iict.ap.nic.in
Received 11 April 2002; revised 10 June 2002
its high biological profile. Our continued interest in the
development of new and efficient synthetic routes to clin-
ically significant amino compounds prompted us to inves-
tigate the total synthesis of (–)-deacetylanisomycin (2).8
We wish to report herein the synthesis of 2 from D-ty-
rosine, which also constitutes a formal total synthesis of 1.
It appeared to us that an expedient approach to 2 from D-
tyrosine would involve a reaction sequence outlined as be-
low (Scheme 1).
Abstract: The antibiotic (–)-deacetylanisomycin was synthesized
starting from D-tyrosine using Sharpless asymmetric dihydroxyla-
tion as a key reaction.
Key words: anisomycin, (–)-deacetylanisomycin, D-tyrosine,
Sharpless asymmetric dihydroxylation
Anisomycin (1) is an antibiotic that has been isolated from
fermentation broth filtrates of various species of Strepto-
myces.2 X-ray crystallographic analysis3 and chemical
studies4 reveal the structure and relative stereochemistry
of anisomycin to be that depicted in structure 1 (Figure 1).
The absolute stereochemistry was established as 2R,3S,4S
by chemical correlation studies.5 Anisomycin possesses
strong and selective activity against pathogenic protozoa
and fungi and has been proved successful clinically in the
treatment of amoebic dysentry and trichomonas vagini-
tis.6 It has been shown to block ribosomal peptide synthe-
sis.6
Compound 4 was obtained in 70% yield from D-tyrosine
by protecting the amino functionality using di-tert-butyl
dicarbonate, followed by methylation of the acid and phe-
nolic hydroxyl group with MeI/K2CO3. Reduction of ester
4 with lithium borohydride9 furnished the alcohol 5
(72%). A Swern oxidation10 followed by Wittig reaction
with (ethoxycarbonylmethylene)triphenylphosphorane in
CH2Cl2 yielded the trans , -unsaturated ester 6 (73%). In
order to avoid or minimize any possible racemization at
the chiral centre, the aldehyde was used immediately
without purification.
OR
HO
Our strategy required that the olefination product 6 con-
tained the desired trans geometry at the double bond for
the subsequent creation of chiral diol via Sharpless asym-
metric dihydroxylation. Upon reacting the N-Boc-protect-
ed -amino- , -unsaturated ester 6 with the modified
Sharpless asymmetric dihydroxylation conditions using
AD-mix- ,11 the expected (2R,3S,4R) configured ester 7
(60%) was obtained with high stereoselectivity
(Scheme 2). This result has precedence.12,13
MeO
N
H
1 R = COCH3
2 R = H
Figure 1 The structure of Anisomycin (1)
Although a few total synthesis of (–)-anisomycin have
been reported7 previously, the molecule still continues to
attract the attention of synthetic organic chemists owing to
COOH
NH2
1) NaOH/Dioxane/H2O
Boc2O
COOMe
LiBH4
NHBoc
Et2O/MeOH
reflux
2) MeI/Acetone
K2CO3
HO
MeO
4 (70%)
D-tyrosine
O
1) (COCl)2, DMSO
DCM, Et3N, -78 °C
OH
OEt
NHBoc
5 (72%)
NHBoc
2) Ph3P=CHCOOEt
CH2Cl2, r.t.
MeO
MeO
6 (73%)
Scheme 1
Synthesis 2002, No. 13, Print: 20 09 2002.
Art Id.1437-210X,E;2002,0,13,1867,1870,ftx,en;Z06502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1868
S. Chandrasekhar et al.
PAPER
OH
O
OH
O
AD-mix- α
OEt
OEt
6
+
OH
OH
NHBoc
t-BuOH/H2O, 0 °C
NHBoc
MeO
MeO
7 (60%)
7a
(2S, 3R, 4R)
(2R, 3S, 4R)
7:7a = 95:5
Scheme 2
Then diol 7 was subjected to acetonation with 2,2-
dimethoxypropane (2,2-DMP) in the presence of a cata-
lytic amount of camphorsulfonic acid (CSA) in anhydrous
CH2Cl2 to afford the acetonide 8 (72%). Then 8 was re-
duced to the corresponding alcohol 9 (68%) with LiBH4
(Scheme 3).
were dried over sodium and benzophenone. All reactions were car-
ried out under N2 using dry glassware.
Methyl (2R)-2-(tert-Butoxycarbonyl)amino-3-(4-methoxy-
phenyl)propanoate (4)
A solution of D-tyrosine (3 g, 16.5 mmol) in a mixture of dioxane
(30 mL), H2O (20 mL) and aq 1 M NaOH (20 mL) was stirred and
cooled in an ice-water bath. Di-tert-butyl dicarbonate (3.97 g, 18.2
mmol) was added and stirring was continued at r.t. for 30 min. The
solution was concentrated in vacuo to about 10–15 mL, cooled in an
ice-water bath, covered with a layer of EtOAc (30 mL) and acidified
with dilute aq KHSO4 solution to pH 2–3. The aqueous phase was
The alcohol 9 was converted to its corresponding bromide
10 (65%) via the tosylate (TsCl/Py) using LiBr/DMF. The
above obtained Boc-amine 10 was subjected to acidolysis
using TFA and the resulting amine was in situ treated with
triethylamine, thereby facilitating cyclisation to the de-
sired (–)-deacetylanisomycin 2 (70%). The sample had
identical spectral data, to that previously reported in the
literature14 (Scheme 3).
extracted with EtOAc (2
50 mL). The EtOAc extracts were
pooled, washed with H2O (2 30 mL), dried (Na2SO4) and evapo-
rated in vacuo. To a solution of this crude N-Boc protected amino
acid (3 g, 10.6 mmol) in acetone (100 mL) were added anhyd
K2CO3 (7.35 g, 53.3 mmol) and MeI (4.55 g, 32 mmol). The result-
ing mixture was refluxed for 8 h, cooled to r.t. and filtered. The fil-
trate was concentrated and purified by column chromatography
(hexane–EtOAc, 7:3) to give 4 (2.3 g, 70%) as a colorless viscous
oil; [ ]D25 –58.4 (c = 1, CHCl3).
1H NMR (CDCl3): = 1.45 (s, 9 H), 3.05 (d, J = 4.65 Hz, 2 H), 3.7
(s, 3 H), 3.8 (s, 2 H), 4.05 (m, 1 H), 4.9 (br d, 1 H, NH), 6.8 (d,
J = 8.3 Hz, 2 H), 7.05 (d, J = 8.3 Hz, 2 H).
The present work offers an alternative route to the antibi-
otic in enantiomerically pure form. It is to be noted that a
completely different approach to the synthesis of (–)-
deacetylanisomycin has been achieved starting from the
chiral pool D-tyrosine. Further work on the synthesis of
anisomycin analogues utilizing the above method is in
progress and will be reported in due course.
EIMS: m/z = 192 (M+ – 117), 121, 57.
Crude products were purified by column chromatography on silica
gel (60–120 mesh). 1H NMR were obtained in CDCl3 at 200 MHz.
Chemical shifts are given in ppm, with respect to internal TMS; J
values are quoted in Hz. DMSO, Et3N and CH2Cl2 were distilled
from CaH2 and stored over molecular sieves. Benzene and Et2O
(2R)-2-(tert-Butoxycarbonyl)amino-3-(4-methoxyphenyl)pro-
pan-1-ol (5)
To a stirred solution of ester 4 (2 g, 6.4 mmol) in anhyd Et2O (100
mL) were added LiBH4 (0.57 g, 25.5 mmol) and MeOH (10 mL) at
O
O
LiBH4
2, 2-DMP
OEt
7
BocHN
CSA, CH2Cl2
O
Et2O/MeOH
reflux
MeO
8 (72%)
O
O
OH
Br
1. TsCl/Py
BocHN
BocHN
O
O
2. LiBr/DMF
MeO
MeO
OH
10 (65%)
9 (68%)
HO
MeO
1. TFA/CH2Cl2
2. Et3N, MeOH
N
H
(-)-Deacetyl anisomycin
2 (70%)
Scheme 3
Synthesis 2002, No. 13, 1867–1870 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of (–)-Deacetylanisomycin
1869
0 °C. The reaction mixture was then refluxed for 5 h and quenched
by adding an aq sat. NH4Cl solution. The aqueous phase was ex-
tracted with EtOAc (2 50 mL) and the combined organic layers
were washed with brine (2 25 mL), and dried (Na2SO4). The vol-
atiles were removed under reduced pressure and the residue purified
by column chromatography (hexane–EtOAc, 6.5:3.5) to afford 5
(1.3 g, 72%) as a syrupy liquid; [ ]D25 +12.58 (c = 1, CHCl3).
1H NMR (CDCl3): = 1.45 (s, 9 H), 2.48 (m, 1 H), 2.78 (d, J = 4.55
Hz, 2 H), 3.55 (m, 2 H), 3.8 (s, 3 H), 4.75 (br d, 1 H, NH), 6.8 (d,
J = 6.8 Hz, 2 H), 7.1 (d, J = 6.8 Hz, 2 H).
1H NMR (CDCl3): = 1.12 (t, J = 4.75 Hz, 3 H), 1.30 (s, 6 H), 1.35
(s, 9 H), 2.8 (m, 3 H), 3.7 (s, 3 H), 4.1 (m, 4 H), 4.7 (br d, 1 H, NH),
6.75 (d, J = 7.1 Hz, 2 H), 7.1 (d, J = 7.1 Hz, 2 H).
FABMS: m/z = 424 (M+1).
(1R,4S,5R)-5-[1-(tert-Butoxycarbonyl)amino-2-(4-methoxyphe-
nyl)ethyl]-2,2-dimethyl-1,3-dioxolan-4-ylmethanol (9)
To a stirred solution of the protected ester 8 (0.5 g, 1.18 mmol) in
anhyd Et2O (50 mL) were added LiBH4 (0.1 g, 4.72 mmol) and
MeOH (5 mL) at 0 °C. The reaction mixture was then refluxed for
5 h and quenched by the addition of aq sat. NH4Cl solution. The
aqueous phase was extracted with EtOAc (2 20 mL) and the com-
bined organic layers were washed with brine (2 10 mL), dried
(Na2SO4). The volatiles were removed under reduced pressure and
the residue was purified by column chromatography (hexane–
EtOAc, 7:3) to afford 9 (0.375 g, 68%) as a syrupy liquid;
[ ]D25 +7.75 (c = 1.5, CHCl3).
HRMS: m/z calcd for C15H23NO4: 281.1627 (M+), observed:
281.1628 (M+).
Ethyl (2E,4R)-4-(tert-Butoxycarbonyl)amino-5-(4-methoxy-
phenyl)pent-2-enoate (6)
To a stirred solution of oxalyl chloride (1.2 g, 9.6 mmol) in CH2Cl2
(15 mL) at –78 °C under N2 was added DMSO (0.75 mL, 10 mmol)
dropwise. After stirring for 30 min, a solution of the amino alcohol
5 (1.5 g, 5.33 mmol) in CH2Cl2 (25 mL) was added over 15 min. The
mixture was warmed to –45 °C and stirring was continued for 1 h
at this temperature, then Et3N (2.7 g, 26.6 mmol) was added.
The reaction mixture was brought to 0 °C and maintained at this
temperature for 15 min, then a solution of (ethoxycarbonylmethyl-
ene)triphenylphosphorane (2.2 g, 6.4 mmol) in benzene (15 mL)
was added and the resulting solution was stirred for 15 h at r.t. The
solvent was removed under vacuum; the residue was washed with
H2O, brine and dried (Na2SO4). The residue was purified by column
1H NMR (CDCl3): = 1.4 (2 s, 9 H + 6 H), 2.65 (m, 1 H), 2.8 (d,
J = 5.1 Hz, 2 H), 3.68 (m, 2 H), 3.78 (s, 3 H), 3.88 (m, 2 H), 4.86 (br
d, 1 H, NH), 6.85 (d, J = 5.5 Hz, 2 H), 7.17 (d, J = 5.5 Hz, 2 H).
FABMS: m/z = 382 (M + 1).
(1R,4R,5R)-1-[N-(tert-Butoxycarbonyl)]-1-(5-bromomethyl-2,2-
dimethyl-1,3-dioxolan-4-yl)-2-(4-methoxyphenyl)ethan-1-
amine (10)
To a solution of compound 9 (0.2 g, 5.3 mmol) in anhyd CH2Cl2 (15
mL) containing anhyd pyridine (0.062 g, 7.9 mmol) at 0 °C under
N2 was added a solution of tosyl chloride (0.12 g, 6.3 mmol) in
CH2Cl2 (5 mL) and the reaction mixture was stirred for 10 h at r.t..
The mixture was washed with aq sat. CuSO4 solution (20 mL) and
extracted with CH2Cl2 (2 20 mL). The organic phase was dried
(Na2SO4) and concentrated under reduced pressure. To the above
obtained crude tosyl compound (0.2 g, 0.37 mmol) in anhyd DMF
(15 mL) was added LiBr (0.1 g, 1.12 mmol) and the reaction mix-
ture was stirred for 10 h at 80 °C. The mixture was cooled to r.t. and
diluted with H2O (20 mL), the resulting mixture was extracted with
Et2O (2 25 mL) and dried (Na2SO4) and concentrated. The crude
product was purified by column chromatography (hexane–EtOAc,
8.5:1.5) to afford the bromo compound 10 (0.107 g, 65%) as a yel-
low liquid; [ ]D25 +6.65 (c = 0.5, CHCl3).
chromatography (hexane–EtOAc, 8:2) to yield the amino , -unsat-
25
urated ester 6 (1.35 g, 73%) as a pale yellow viscous liquid; [ ]D
5.25 (c = 2, CHCl3).
–
1H NMR (CDCl3): = 1.3 (t, J = 5.1 Hz, 3 H), 1.4 (s, 9 H), 2.85 (d,
J = 4.0 Hz, 2 H), 3.8 (s, 3 H), 4.2 (q, J = 5.1 Hz, 2 H), 4.45 (m, 1 H),
4.55 (br d, 1 H, NH), 5.82 (d, J = 13.5 Hz, 1 H), 6.85 (m, 3 H), 7.08
(d, J = 6.2 Hz, 2 H).
FABMS: m/z = 372 (M+ + 23).
Ethyl (2R,3S,4R)-4-(tert-Butoxycarbonyl)amino-2,3-dihydroxy-
5-(4-methoxyphenyl)pentanoate (7)
A mixture of 6 (0.4 g, 1.15 mmol) and the Sharpless AD-mix- (1.6
g) modified by additional (DHQ)2PHAL (35.65 mg) and potassium
osmate (3.45 mg) in tert-butyl alcohol (11.5 mL) and H2O (11.5
mL) was stirred at r.t. for 18 h. The mixture was treated with
Na2SO3 (2.3 g). After 0.5 h, EtOAc (100 mL) was added and the or-
ganic phase separated and washed twice with aq 1 M KHSO4 (100
mL) and aq 5% NaHCO3. The organic phase was filtered through
silica gel and dried (MgSO4). The residue was purified by column
chromatography (hexane–EtOAc, 6:4) to yield 7 (0.26 g, 60%) as a
semi-solid; [ ]D25 +9.12 (c = 1, CHCl3).
1H NMR (CDCl3): = 1.3 (t, J = 3.1 Hz, 3 H), 1.4 (s, 9 H), 2.85 (m,
2 H), 3.35 (m, 2 H), 3.68 (m, 1 H), 3.75 (s, 3 H), 3.92 (m, 1 H), 4.2
(m, 3 H), 4.9 (m, 1 H, NH), 6.8 (d, J = 6.1 Hz, 2 H), 7.1 (d, J = 6.1
Hz, 2 H).
1H NMR (CDCl3): = 1.35 (2 s, 9 H + 6 H), 2.85 (m, 3 H), 3.38 (d,
J = 2.9 Hz, 2 H), 3.76 (s, 3 H), 3.95 (m, 2 H), 4.8 (br d, 1 H, NH),
6.8 (d, J = 7.2 Hz, 2 H), 7.15 (d, J = 7.2 Hz, 2 H).
FABMS: m/z = 467 (M + 23).
(–)-Deacetylanisomycin (2)
To a solution of compound 10 (0.23 g, 0.6 mmol) in CH2Cl2 (5 mL)
were added trifluoroacetic acid (1 mL) and H2O (0.5 mL) and the
reaction mixture was stirred at r.t. for 10 h. After concentration of
the solvent under reduced pressure, benzene (5 mL) was added to
the residue and the solvents were removed under vacuo. The crude
residue was dissolved in MeOH (5 mL) and cooled to 0 °C. Et3N
(0.15 g, 1.5 mmol) was added slowly to the mixture and it was
stirred at r.t. for 5 h. Removal of solvent under reduced pressure,
followed by purification of the crude residue by column chromato-
graphy (CH2Cl2–MeOH, 9:1) afforded compound 2 (0.07 g, 70%)
as a solid; [ ]D25 –22.5 (c = 1, MeOH).13
1H NMR (DMSO-d6): = 2.36 (dd, 1 H, J = 2.1, 11.8 Hz, H-5), 2.52
(dd, 1 H, J = 6.5, 13.2 Hz, CH2Ar), 2.71 (dd, 1 H, J = 7.4, 13.2 Hz,
CH2Ar), 2.96 (ddd, 1 H, J = 3.5, 6.8, 7.6 Hz, H-2), 3.15 (dd, 1 H,
J = 5.5, 11.8 Hz, H-5), 3.45–3.47 (m, 1 H, H-3), 3.70 (s, 3 H,
OCH3), 3.82–3.85 (m, 1 H, H-4), 4.56 (br s, 1 H, OH), 4.61 (br s, 1
H, OH), 6.81 (d, 2 Harom, J = 8.3 Hz), 7.16 (d, 2 Harom, J = 8.3 Hz).
HRMS m/z calcd for C19H29NO7: 383.1944 (M+), observed:
383.1946 (M+).
Ethyl (1R,4R,5R)-5-[1-(tert-Butoxycarbonyl)amino-2-(4-meth-
oxyphenyl)ethyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate (8)
To a stirred solution of 7 (0.25 g, 2.4 mmol) in CH2Cl2 (10 mL) were
added 2,2-dimethoxypropane (1.25 g, 12 mmol) and a catalytic
amount of camphorsulfonic acid (15 mg) at 0 °C. The mixture was
left stirring at r.t. for 2–3 h under N2. The progress of the reaction
was monitored by TLC. The solvent was removed under vacuo and
the residue was purified by column chromatography (hexane–
EtOAc, 8:2) to give the desired compound 8 (0.2 g, 72%) as a yel-
low viscous oil; [ ]D25 +14.22 (c = 1, CHCl3).
HRMS: m/z calcd for C12H17NO3: 224.1286 (M + 1), observed:
224.1286 (M + 1).
Synthesis 2002, No. 13, 1867–1870 ISSN 0039-7881 © Thieme Stuttgart · New York

1870
S. Chandrasekhar et al.
PAPER
(8) (a) Chandrasekhar, S.; Mohapatra, S. Tetrahedron Lett.
Acknowledgement
1998, 39, 6415. (b) Chandrasekhar, S.; Mohapatra, S.;
Yadav, J. S. Tetrahedron 1999, 55, 4763.
(c) Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56,
1111.
Two of us (TRC and MVR) thank CSIR, New Delhi for financial as-
sistance.
(9) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J.
Org. Chem. 1987, 52, 1252.
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Synthesis 2002, No. 13, 1867–1870 ISSN 0039-7881 © Thieme Stuttgart · New York