Concise synthesis of (-)-anisomycin

Article abstract of DOI:10.1016/j.cclet.2012.03.029

The antibiotic (-)-anisomycin was synthesized starting from d-tyrosine using Sharpless asymmetric epoxidation as a key reaction followed by formation and hydrolysis of oxazoline set up all chiral center.

Full text of DOI:10.1016/j.cclet.2012.03.029

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 647–649
www.elsevier.com/locate/cclet
Concise synthesis of (À)-anisomycin
Ji Li a, Yan Hua Feng a, Xin Bai Li a, Wei Han a, Huan Qiu Liu a,
Guo Guang Shao b
*
,
a Department of Anesthesiology, The First Hospital of Jilin University, Changchun 130021, China
b Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 130021, China
Received 6 January 2012
Available online 12 May 2012
Abstract
The antibiotic (À)-anisomycin was synthesized starting from D-tyrosine using Sharpless asymmetric epoxidation as a key
reaction followed by formation and hydrolysis of oxazoline set up all chiral center.
# 2012 Huan Qiu Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Anisomycin; D-Tyrosine; Sharpless asymmetric epoxidation; Oxazoline
Anisomycin 1 was first isolated from the fermentation broths of Streptomyces griseolus and Streptomyces
roseochromogenes by Sobin and Tanner in 1954 [1]. The absolute configuration of 1 was determined by chemical
studies and X-ray crystallographic analysis [2,3]. (À)-Anisomycin exhibits remarkably selective activity against
pathogenic protozoa and fungi [4]. It has also been shown to exhibit antiviral and antitumor activities due to apoptotic
activity, such as mammalian cell lines HBL 100, RAS A and MCF 7 in the nanomolar region [5]. It is currently being
used in clinical trials for the treatment of amoebic dysentery and Trichomonas Vaginitis.
Because of its promising biological profile, anisomycin has attracted much synthetic interest over the past 30 years,
with over 20 syntheses of anisomycin and its analogues being reported in the literature [6]. However, many of the
published procedures suffer from inefficient protecting group operation in the later stages.
We wish to develop a new and efficient synthetic routes to investigate the total synthesis of (À)-anisomycin (1).
Sharpless asymmetric epoxidation and subsequent formation of oxazoline can introduce the required chiral center. At
the same time the hydrolysis of oxazoline afford the acetyl protection to avoid a series of protection and deprotection
steps. We now report an enantioselective synthesis of 1 in accordance with these strategies. Our retrosynthetic analysis
is shown in Fig. 1.
The synthesis of the requisite syn allyl alcohol was commenced with commercial obtained D-tyrosine 2 as shown in
Scheme 1. Compound 3 was obtained in 70% yield from D-tyrosine by protecting the amino functionality using acetic
anhydride, followed by methylation of the acid and phenolic hydroxyl group with MeI/K2CO3. Reduction of ester 3
with lithium borohydride furnished the alcohol 4 in 81% yield. A Swern oxidation gave aldehyde 5, which was reacted
* Corresponding author.
E-mail address: liuhuanqiu@yahoo.com.cn (H.Q. Liu).
1001-8417/$ – see front matter # 2012 Huan Qiu Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.03.029

648
J. Li et al. / Chinese Chemical Letters 23 (2012) 647–649
O
AcO
OH
MeO
O
N
N
H
MeO
OH
COOH
NH2
NHAc
HO
MeO
Fig. 1.
COOMe
COOH
c
b
a
OH
NHAc
OH
NHAc
NH2
MeO
MeO
MeO
HO
4
3
2
OH
d
e
O
NHAc
NHAc
NHAc
MeO
MeO
6
5
7
Scheme 1. Reagents and conditions: (a) i: Ac2O, NaOAc, 0 8C; ii: MeI, K2CO3, acetone, 65%; (b) LiBH4, EtOH, rt, 81%; (c) Dess–Martin
periodinane, 92%; (d) i: PPh3, CBr4, CH2Cl2; ii: BuLi, (CH2O)n, À78 8C, 82%; (e) H2, Lindlar cat, 97%.
OH
OH
O
OAc
O
c
a
b
OH
O
OH
N
BocHN
NHAc
MeO
MeO
NHAc
MeO
MeO
OAc
MeO
10
7
8
9
AcO
OH
AcO
OH
f
e
d
OMs
MeO
OH
N
H
MeO
BocHN
N
Boc
1
12
11
Scheme 2. Reagents and conditions: (a) (+)-DIPT, Ti(OiPr)4, TBHP, DCM, À20 8C, 86%; (b) MsCl/Et3N, 0 8C – reflux, 69%; (c) i: 2 mol/L HCl/
THF; ii: NaHCO3, Boc2O, 79%; (d) MsCl/Et3N, 0 8C, 88%; (e) NaH, DMF, 73%; (f) HCl/MeOH, 78%.
with PPh3 and CBr4 to provide dibromoalkene. The resultant was treated with BuLi and then paraformaldehyde to give
propargyl alcohol 6 [7]. Partial reduction of 6 in the presence of Lindlar catalyst afforded the (Z)-olefin 7 in 97% yield.
The next stage for our synthesis of (À)-anisomycin was now faced to asymmetric epoxidation of the allylic alcohol
moiety. Sharpless asymmetric epoxidation which was carried out with (+)-DIPT, Ti(OiPr)4, TBHP at À20 8C to afford
epoxy alcohol 8 in 86% yield (>99% ee) (Scheme 2) [8]. With compound 8 in hand the next step was the key inversion
of the configuration of the hydroxyl in C 3. To our delight, the mesylated compound was obtained with MsCl and

J. Li et al. / Chinese Chemical Letters 23 (2012) 647–649
649
DIEA [9] in CH2Cl2 and the mixture was heated to reflux for 2 h without more process to give the oxazoline
accompanied by the open of C-3 epoxide and the generation of new epoxide in the end. The procedure completed
inversion of configuration at C-3 during the formation of oxazoline. Instead of reductive ring opening to form
benzylamine, we hydrolyzed the oxazoline 9 under acidic conditions to give a acetate and liberated the primary amino
group, which were in turn protected with Boc2O to afford 10 [10]. Along with hydrolysis of the oxazoline, the end
epoxide was regioselectively opened once again under the same acidic conditions in 79% yield. At this stage the
required stereogenic centers and the acetyl protection of C-3 hydroxyl in the target molecule had already been set up
unambiguously. Chemoselective mesylation of primary hydroxyl in diol 10 using MsCl and Et3N furnished the
monomethanesulfonate, which was subjected to cyclization using NaH/DMF at room temperature to furnish the N-
Boc protected piperidine 12. Removal of N-Boc afforded (À)-anisomycin in 78% yield, whose spectral data were in
full agreement with those reported [11].
In summary, a concise and efficient synthesis of (À)-anisomycin was accomplished in 9% overall yields from a
common commercially available amino acid. The synthesis relies upon a key Sharpless asymmetric epoxidation
followed by formation of oxazoline and hydrolysis to afford the correct stereochemistry, which has been shown to
proceed in high yield. These methods devoid a series of protection and deprotection steps in the later stages.
Acknowledgment
We are grateful for financial support from The First Hospital of Jilin University.
References
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(b) A.P. Grollman, J. Biol. Chem. 242 (1967) 3226.
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(c) Y.S. Lee, R.D. Wurster, Cancer Lett. 93 (1995) 157.
[6] (a) J.H. Kim, M.J. Crutis-Long, W.D. Seo, et al. J. Org. Chem. 70 (2005) 4082, and references therein;
(b) A.N. Hulme, E.M. Rosser, Org. Lett. 4 (2002) 265, and references therein.
[7] Y. Kozawa, M. Mori, J. Org. Chem. 68 (2003) 8068.
[8] C. Srivari, G.S. Kiran, D.K. Mohapatra, Eur. J. Org. Chem. 11 (2011) 2057.
[9] R.H. Liu, K. Fang, B. Wang, et al. J. Org. Chem. 73 (2008) 3307.
[10] G.R. Cook, P.S. Shanker, J. Org. Chem. 66 (2001) 6818.
[11] White needles: m.p. 143–144 8C. [a]D À31.5 (c 0.66, MeOH). 1H NMR (300 MHz, CDCl3): d 2.15 (s, 3H), 2.65–2.9 (m, 3H), 3.43 (dd, 1H,
23
J = 11.4, 6.6 Hz), 3.50 (m, 1H), 3.78 (s, 3H), 4.19 (dd, 1H, J = 6.6, 5.1 Hz), 4.72 (br d, 1H, J = 4.8 Hz), 6.85 (d, 2H, J = 8.7 Hz), 7.12 (d, 2H,
J = 8.7 Hz), 13C NMR (CDCl3, 75 MHz): d 21.1, 34.6, 52.5, 55.3, 61.8, 77.8, 82.4, 114.1, 129.8, 131.1, 158.3, 171.6. HR-ESI-MS: Calcd. for
C
14H19NO4 (M+H+) 266.1392, Found 266.1385.