Studies toward the total synthesis of sorangicins: Asymmetric synthesis of the key fragments

Article abstract of DOI:10.1055/s-2004-835661

Efficient synthesis of the key fragments of the complex antibiotics class of sorangicins (Scheme 1) is described. Starting from simple compounds fragments I, II, and IV can be synthesized. For fragment III we chose an approach via L-glucal.

Full text of DOI:10.1055/s-2004-835661

LETTER
2689
Studies toward the Total Synthesis of Sorangicins: Asymmetric Synthesis of
the Key Fragments
Studies
T
owards th
i
e
T
ota
e
l
Synthesis
t
of Sora
e
ngicins r Schinzer,* Claudia Schulz,1 Olga Krug
Chemisches Insitut, Otto-von-Guericke-Universität Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany
Fax +49(391)6712223; E-mail: dieter.schinzer@vst.uni-magdeburg.de
Received 5 August 2004
Dedicated to Professor Johann Mulzer on the occasion of his 60th birthday.
Retrosynthetic Analysis
Abstract: Efficient synthesis of the key fragments of the complex
antibiotics class of sorangicins (Scheme 1) is described. Starting
from simple compounds fragments I, II, and IV can be synthesized.
For fragment III we chose an approach via L-glucal.
The structure of sorangicins is characterized by a 31-
membered macrocyclic polyether with either 14 or 15
stereocenters. Disconnection gives four key fragments,
which can be assembled in a convergent manner: tetrahy-
dropyran fragment I, bicyclic ether fragment II, dihydro-
pyran fragment III and side chain fragment IV containing
the carboxylic acid. The tetrahydropyran rings in frag-
ments I and II have similar structures with differing ab-
solute configurations at C-27 and C-31. So, it is possible
to prepare them from the same starting material. A ring-
closing–epoxide-opening strategy by attack of a hydroxy
group on an epoxide should create the tetrahydropyran
rings.4
Key words: sorangicin, asymmetric synthesis, tetrahydropyran,
bicyclic ether, macrolide, antibiotic activity
In 1985, the research groups of G. Höfle and H. Reichen-
bach at the Gesellschaft für Biotechnologische Forschung
(GBF) in Braunschweig, Germany, reported the isolation
of the novel antibiotic sorangicin A (Scheme 1) from the
gliding bacteria Sorangium cellulosum.2 It has proved
highly active against a broad spectrum of Gram-positive
and -negative bacteria, including slow-growing or intra-
cellular bacteria and methicillin- or polyresistant clinical
isolates, e.g. mycobacteria, staphylococci, pseudomon-
ades, enterococci and neisseria. The minimal inhibitory
concentration (MIC) values against Gram-negative bacte-
ria range from 2 to >32 mg/mL. For Gram-positive bacte-
ria the MIC may be less than values of 10 ng/mL. At
values of 2–5 times the MIC bactericidal action is ob-
served. Sorangicin A has proved effective against experi-
mental staphylococcal infections in rats. The mechanism
of action has been shown to be the inhibition of the DNA-
dependent RNA polymerase in Staphylococcus aureus
and Escherichia coli. Eukaryotic cells are completely re-
sistant. In addition, sorangicin A is active in vitro against
several tumor cell lines.3
Its structure was determined by extensive use of 1H NMR
and 13C NMR, MS and UV data. Our interest in the syn-
thesis of sorangicin A and its natural variants is connected
to its unique macrolide-polyether structure. A flexible and
convergent synthetic route might open the possibility for
the synthesis of derivatives, which could improve the
biological efficacy in order to modify the pharmaceutical
and biological properties, and to gain insight into struc-
ture–activity relationships.
Tetrahydropyran Fragment I
Scheme 2 summarizes the synthesis of tetrahydropyran
fragment I starting from 1,3-propanediol. Aldehyde5 2
was obtained after selective protection of one of the hy-
droxy groups, followed by Swern oxidation.6 Asymmetric
crotylboration using the Z-alkene7 of 2, followed by
silylation8 with TIPSOTf in the presence of 2,6-lutidine
furnished the silyl ether. After dihydroxylation9 of the ter-
minal alkene moiety with OsO4, both diastereomers 4 and
5 could be isolated, which later on could be used for the
synthesis of the tetrahydropyran fragments. The use of the
Sharpless protocol with AD-mix-a or AD-mix-b10 for this
step gave no noteworthy advantage in selectivity com-
pared to OsO4. Protection of the diol as the acetonide and
selective deprotection of the primary hydroxy group was
achieved simultaneously using p-TsOH, acetone and
copper sulfate at room temperature. The resulting alcohol
was oxidized using Ley’s procedure (TPAP/NMO/MS)11
yielding aldehyde 6 in 80% yield. A Z-selective Horner–
Wadsworth–Emmons reaction of aldehyde 6 and Still–
Gennari reagent12 gave 7 as a single diastereoisomer in
92% yield, which after reduction with DIBAL13 was con-
verted into alcohol 8 in 99% yield. Selective epoxidation
of allylalcohol 8 by the Sharpless protocol14 gave epoxide,
which after protection of the primary alcohol with BnBr15
gave 9. It was then converted into 10 by a ring-closing–
epoxide-opening sequence via attack of the hydroxy
group on the protonated epoxide in 52% yield. Fragment
I could be synthesized using the same procedure starting
In this article we present our recent investigations towards
the synthesis of the key building blocks for the total syn-
thesis of sorangicins. A highly convergent, stereoselective
synthesis of four subunits is described.
SYNLETT 2004, No. 15, pp 2689–2692
0
7
.1
2
.2
0
0
4
Advanced online publication: 10.11.2004
DOI: 10.1055/s-2004-835661; Art ID: G31204ST
© Georg Thieme Verlag Stuttgart · New York

2690
D. Schinzer et al.
LETTER
O
TIPSO
O
II
OBn
O
O
O
31
O
O
10
9
O
OH
27
O
H
H
R2
OH
R1O
HO
OTBS
IV
OBn
OH
O
O
OH
O
O
O
III
I
Sorangicin A R1 = H, R2 = OH
Sorangicin B R1 = H, R2 = H
OTIPS
Scheme 1 Retrosynthetic analysis.
from diol 5. The ring-closing–epoxide-opening sequence single diastereomer 16 in 84% yield. After protection of
gave fragment I (tetrahydropyran 11) in 82% yield.
both hydroxy groups as silyl ethers, it was converted into
aldehyde 17 by dihydroxylation of the terminal alkene
moiety with AD-mix-b21 making use of the greater selec-
tivity of the chiral reagent. Protection of aldehyde 167
with orthoformic acid dimethyl ester22 gave the acetal 18
Approach to the Bicyclic Ether II
The synthesis of bicyclic fragment16 II was accomplished in 94% yield. Selective desilylation of the primary alcohol
as shown in Scheme 3. A selective protection of primary was achieved by the action of CSA in MeOH–CH2Cl2
23
alcohol 10 with TIPSCl followed by secondary alcohol leading to hydroxy compound 19, which was oxidized
with PMBCl furnished after deprotection of the silyl under Swern conditions in THF, followed by a one-pot
ethers with TBAF in THF, the primary alcohol 12. It was Grignard addition with MeMgBr. Further oxidation with
selectively protected with TIPSCl and after mesylation17 Dess–Martin periodinane24 gave the desired key fragment
gave a mixture of bicyclic ether 15 (28%) and mesylate 13 20 (III).
(59%), which could then be converted to the desired bi-
cyclic ether 1518 in two steps and an overall yield of 1%
after 19 steps.
Side Chain Fragment IV
The construction of side chain fragment IV proceeded
from 6-heptenoic acid chloride (21), which was coupled
with the Seebach auxiliary25 to obtain 22. Diastereoselec-
Dihydropyran Fragment III
Scheme 4 shows the synthesis of the dihydropyran frag- tive alkylation with MeI at –78 °C (de >99%) furnished
ment III. For this subunit we favored a precursor from the 23 (Scheme 5). Reductive removal of the auxiliary gave
‘chiral pool’, namely L-glucose, which bears the suitable alcohol 24. The use of Seebach auxiliary for the prepara-
stereochemistry at C-9 and C-10. In the one-pot, three- tion of the known alcohol 24,26 which we used in our
step procedure of Koreeda et al.,19 it can be converted to a epothilone synthesis, gave better stereoselectivity (>99%)
tri-O-acetyl-L-glucal, which was deprotected with Et3N– in comparison to Evans auxiliary (92%). The enantio-
MeOH–H2O and finally underwent a carbon Ferrier- meric excess was determined by chiral GC analyses.27
rearrangement20 with allylsilane and TMSOTf to give a
Synlett 2004, No. 15, 2689–2692 © Thieme Stuttgart · New York

LETTER
Studies toward the Total Synthesis of Sorangicins
2691
OH
O
HO
a,b
c
d,e
OTBS
OH
OH
HO
HO
OH
OH
d,e
a–c
OH
3
O
O
OTBS
OH
2
1
16
L-Glucose
OH
OH
OTBS
OTBS
+
OTBS
OTBS
OH OTIPS
OH OTIPS
f
g
5
4
f–l
O
O
f,g
OBn
OH
OTBS
OTBS
OH
O
17
O
O
O
18
O
O
OTBS
O
OTBS
OH
O
OTIPS
h–j
OTIPS
6
O
O
O
11 (I)
O
O
O
h
OH
CO2Me
19
20 (III)
i
Scheme 4 Reagents and conditions: a) HBr–HOAc–Ac2O, Zn/HO-
Ac, 81%; b) Et3N–MeOH–H2O, 100%; c) allylsilane, TMSOTf,
CH2Cl2–MeCN (2:1), 84%, de >99%; d) TBSCl, pyridine, 100%; e)
AD-mix-b, t-BuOH–H2O (1:1), NMO, NaIO4, 70%; f) HC(OMe)3,
CH2Cl2, r.t., 94%; g) CSA, CH2Cl2–MeOH (1:1), 73%; h) Swern oxi-
dation in THF; i) MeMgBr, THF, 82% after two steps; j) Dess–Martin
periodinane, 95%.
O
O
O
OTIPS
O
OTIPS
7
8
OBn
OH
OBn
O
OH
j,k
l
O
O
O
OTIPS
OTIPS
9
10
O
O
Scheme 2 Reagents and conditions: a) TBSCl, NaH, THF, 95%; b)
Swern oxidation, 83%; c) 2-dIcr2B-Z-(CH2CH=CHCH3), BF3·Et2O,
THF, –78 °C, 62%; d) TIPSOTf, 2,6-lutidine, CH2Cl2, 97%; e) OsO4,
NMO, THF, H2O, 48% of 4, 24% of 5; f) p-TsOH, CuSO4, acetone,
81%, 76% precursor for 11; g) TPAP/NMO, CH2Cl2, molecular sie-
ves, 80%, 81% precursor for 11; h) (CF3CH2O)2POCH2CO2Me, 18-
crown-6, KHMDS, THF, –78 °C, 92%, 91% precursor for 11; i) DI-
BAL-H, CH2Cl2, –78 °C, 99% for both diastereomers; j) D-DET,
Ti(Oi-Pr)4, t-BuOOH, molecular sieves, 67%, 56% precursor for 11;
k) BnBr, NaH, Bu4NI, 80% for both diastereomers; l) CSA, CH2Cl2:
i-PrOH (30:1), 52% of 10, 82% of 11.
NH
O
a
O
+
Cl
Ph
Ph
21
O
b
N
O
Ph
N
22
Ph
O
O
c
O
HO
Ph
Ph
23
OBn
OH
OBn
OBn
24 (IV)
OH
OH
OTIPS
O
O
O
Scheme 5 Reagents and conditions: a) n-BuLi, THF, 89%;
b) NaHMDS, MeI, 74% (de >99%); c) LAH, Et2O, 95%.
OPMB
OPMB
d,e
a–c
OTIPS
OH
OMs
10
12
Conclusion
13
f
+
OBn
OH
OTIPS
In this paper we have demonstrated and used a convergent
approach to synthesize the key fragments I, II, III and IV
of the novel sorangicin antibiotics. The coupling of the
key fragments and the final steps in total synthesis is
under investigation and will be reported in due course.
O
O
g
TIPSO
O
OMs
15 (II)
14
OBn
Scheme 3 Reagents and conditions: a) TIPSCl, imidazole, DMF,
91%; b) PMBCl, NaH, Bu4NI, 71%; c) TBAF, THF, 83%; d) TIPSCl,
imidazole, DMF, 91%; e) MsCl, pyridine, DMAP, CH2Cl2; f) DDQ,
CH2Cl2–H2O, 48%; g) KHMDS, THF, –78 °C, 93%.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie.
O. K. thanks the state of Sachsen-Anhalt for a fellowship.
Synlett 2004, No. 15, 2689–2692 © Thieme Stuttgart · New York

2692
D. Schinzer et al.
LETTER
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