A Scalable Approach for the Synthesis of Epothilone Thiazole Fragment (C 12 -C 21 unit) Via Wacker Oxidation

Article abstract of DOI:10.1055/s-0036-1591942

A new scalable synthesis of the common thiazole fragment (C ₁₂ -C ₂₁ unit) of epothilone family of molecules (epothilone A-D) has been developed via palladium-catalyzed Wacker oxidation as a key step using (S)-2,2,3,3,9,9,10,10-octamethyl-5-vinyl-4,8-dioxa-3,9-disilaundecane, which has been prepared from commercially available chiral synthon (R)-ethyl-4-cyano-3-hydroxybutanoate. Then further chemical modifications using Horner-Wadsworth-Emmons reaction and Wittig reaction result in the common thiazole fragment (C ₁₂ -C ₂₁ unit) in good yields.

Full text of DOI:10.1055/s-0036-1591942

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–C
letter
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de
R. Kommera et al.
Letter
Synlett
A Scalable Approach for the Synthesis of Epothilone Thiazole
Fragment (C12–C21 unit) Via Wacker Oxidation
Rajashekar Kommeraa,b
R
(S)
O
(S)
Venkateshwer Reddy Kasireddyc
Venkat Reddy Ghojalab
Markandeya Bekkamb
S
11 steps
(R)
I
OEt
S
NC
OH
(S)
(S)
(R)
N
(S)
OH
O
O(S)
(S)
N
11% overall yield
Wacker oxidation
OTBS
1
2
Pradeep Rebellib
O
OH
O
Jayaprakash Rao Yerrabelly*d,e
thiazole fragment
(C12–C21 unit)
epothilone A, R = H
epothilone B, R = Me
a Department of Chemistry, Jawaharlal Nehru Technological
University College of Engineering, Hyderabad 500085,
India
b Department of Research and Development, MSN R&D
Center, Pashamylaram, Medak, Telangana 502307, India
c Department of Chemistry, CMR Engineering College, Jawa-
harlal Nehru Technological University, Hyderabad 501401,
India
d Department of Chemistry, University College of Science,
Saifabad, Osmania University, Hyderabad 500004, India
e Department of Organic Chemistry, Telangana University,
Nizamabad, Telangana 503322, India
yjpr_19@yahoo.com
Received: 17.12.2017
R
Accepted after revision: 29.01.2018
Published online:
DOI: 10.1055/s-0036-1591942; Art ID: st-2017-b0907-l
S
R
O
O
OH
N
S
O
Abstract A new scalable synthesis of the common thiazole fragment
(C12–C21 unit) of epothilone family of molecules (epothilone A–D) has
been developed via palladium-catalyzed Wacker oxidation as a key step
using (S)-2,2,3,3,9,9,10,10-octamethyl-5-vinyl-4,8-dioxa-3,9-disilaun-
decane, which has been prepared from commercially available chiral
synthon (R)-ethyl-4-cyano-3-hydroxybutanoate. Then further chemical
modifications using Horner–Wadsworth–Emmons reaction and Wittig
reaction result in the common thiazole fragment (C12–C21 unit) in good
yields.
OH
N
O
OH
O
O
OH
O
epothilone A, R = H
epothilone B, R = Me
epothilone C, R = H
epothilone D, R = Me
Figure 1 Structures of the epothilones A, B, C and D
Key words thiazole fragment, epothilone, Wacker oxidation, ixabepi-
lone, C12–C21 unit of epothilone
2007 by FDA for the treatment of breast cancer under the
trade name of Ixempra.
In the present study, as a part of research on ixabepilone
synthesis, we report a new scalable synthetic approach for
the preparation of common thiazole fragment 1 (C12–C21
unit) in epothilone family by involving Wacker oxidation as
a key step. This thiazole building block 1 was reported in
preceding synthesis6,7 which includes the establishment of
a chiral center at C15 carbon by Sharpless resolution. The
preparation of thiazole fragment precursor 9 was also re-
ported in literature,8–10 based on the Brown enantioselec-
tive allyl boration reaction to introduce a stereocenter at
C15 carbon or asymmetric biochemical synthesis. It is well
known to the person skilled in the art, that using a chiral
synthon will give more advantages than the resolution of
chiral center in later stages. Hence, we opted for an alter-
nate technique for the preparation of this thiazole fragment
1 by employing a chiral synthon 2 (Scheme 1).
Natural products play an important role in the drug dis-
covery, especially, in the treatment of an incurable disease
like cancer, which affects one in every three persons in the
developed countries. Around 47% of the anticancer drugs in
the market are from natural products or natural product
derived compounds.1 The epothilones, discovered by Höfle
et al.2,3 from the fermentation of myxobacterium, Sorangi-
um cellulousum, have potential anticancer properties. These
epothilones (Figure 1) have high in vivo activity but show
moderate in vitro cytotoxicity.4 However, the epothilones
are being paid much more attention towards the develop-
ment of new chemical entities due to their easy synthesis
and are more amenable to modification. Ixabepilone is one
of the semi-synthetic analogues5 of epothilone B, has been
developed by Bristol–Mayers Squibb and got approval in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

B
R. Kommera et al.
Letter
Synlett
R
(S)
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(S)
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(R)
I
OEt
S
N
15
NC
OH
(S)
(S)
(R)
N
21
18
(S)
OH
O
HN(S)
(S)
3
6
OTBS
1
1
2
O
OH
O
thiazole fragment
(C12–C21 unit)
ixabepilone
Scheme 1 Retrosynthesis of ixabepilone from chiral synthon 2
The current study (Scheme 2) was started by selecting
the (R)-ethyl-4-cyano-3-hydroxybutanoate (2) as the start-
ing material, since it is commercially available11 in the re-
quired enantiomerically pure form. This chiral synthon 2,
was reduced under the prominent reducing conditions,12
using sodium borohydride in methanol to yield the corre-
sponding diol in good yield. With the diol compound in
hand, the efforts were continued to protect the alcohol
function groups, using various protecting reagents such as
acetyl chloride, p-methoxybenzyl ether, tert-butyldimeth-
ylsilyl chloride, trimethylsilyl chloride and tert-butyldi-
methylsilyl chloride (TBDMS-Cl). Among all reagents
TBDMS-Cl protection yielded the new diprotected cyano
compound 3 in quantitative overall yield from 2 (92%). This
diprotected cyano compound 3 on further reduction with
DIBAL-H at lower temperature yielded the corresponding
aldehyde in good yield. But thus obtained aldehyde was
found to be unstable for longer periods of time; hence we
went ahead to the next stage without storing the aldehyde.
This aldehyde on reduction with sodium borohydride gave
the alcohol 4 in 70% overall yield from compound 3.
Alcohol 4 was converted to the corresponding iodide 5
by treating with iodine, triphenylphosphine and imidaz-
ole13 with 93% yield. The crude iodo compound 5 obtained
by this process was pure enough to proceed further without
purification. This iodo compound 5 on treatment with po-
tassium tert-butoxide in THF at 0 °C underwent elimination
reaction to yield the alkene product 6. This alkene 6 was
further converted into the desired methyl ketone com-
pound via Wacker oxidation, which has prominent position
in conversion of terminal alkenes to methyl ketones
(Scheme 3).
For the first attempt the reported Wacker oxidation con-
ditions14 were employed by using palladium(II) chloride
and copper(I) chloride at 25 °C under balloon pressure of
oxygen (Table 1, entry 1). Under these conditions reaction
was sluggish. To enhance the rate of reaction, the tempera-
e
OTBS
OTBS
c,d
70%
OEt
a,b
NC
HOH2C
NC
93%
OTBS
OTBS
92%
OH
O
4
3
2
S
O
O
P(OEt)2
N
OTBS
f
OTBS
10
h, 75%
g
OTBS
IH2C
66%
60%
OTBS
OTBS
OTBS
7
6
5
S
S
i,j
I
S
O
k
OTBS
N
N
84%
73%
N
OTBS
OTBS
OTBS
8
9
1
Scheme 2 Synthesis of thiazole fragment (C12–C21 unit). Reagents and conditions: (a) NaBH4, MeOH, 0 °C to r.t., 8 h; (b) TBDMS-Cl, imidazole, DMAP,
DMF, 75 °C, 7 h; (c) DIBAL-H, CH2Cl2, –78 °C, 2h; (d) NaBH4, MeOH, 0 °C to r.t., 2 h; (e) imidazole, TPP, I2, CH2Cl2, 0 °C to r.t., 1 h; (f) t-BuOK, THF, 0 °C,
2 h; (g) O2, PdCl2, Cu(OAc)2 H2O, DMA, H2O, 40 °C, 30 h, TBS-Cl, imidazole, DMAP, DMF, 75 °C, 2 h; (h) NaHMDS, THF, –78 °C to r.t., 12 h;
(i) (D)-camphor sulphonic acid, MeOH, 0°C, 4 h; (j) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 °C to r.t., 2 h; (k) ethyl triphenyl phosphonium iodide,
THF, n-BuLi, –10 °C, 30 min then I2, –78 °C to –30°C then NaHMDS, 1 h.
O
O
O
(S)
(S)
OTBS
Wacker oxidation
OTBS
(S)
(S)
OH
OH
+
+
OTBS
OTBS
OTBS
OH
6
7
7a
7b
Scheme 3 Wacker oxidation and possible impurities
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

C
R. Kommera et al.
Letter
Synlett
ture was raised to 30 °C and 40 °C (Table 1, entries 2 and 3,
respectively). At 40 °C, not surprisingly, monodeprotected
7a and dideprotected 7b products were formed in major
concentration. The basic assumption of this result was the
by-product, HCl, releasing in Wacker oxidation handled the
deprotection of 7. To conclude the assumption we tried an
experiment at 40 °C by replacing copper(I) chloride with
copper(II) chloride (Table 1, entry 4). This condition caused
the sharp increase (90%) in the concentration of didepro-
tected intermediate 7b. Based on this conclusion, we
switched over to modified Wacker oxidation condition15 re-
ported by Smith et al. in 1998, by replacing the oxidizing re-
agent, copper(I) chloride with copper(II) acetate (Table 1,
entry 5). This condition yielded the required intermediate 7
in major concentration, along with 7a and 7b in minor con-
centration. This reaction was also tried by changing the cat-
alyst, palladium(II) acetate (Table 1, entries 6 and 7), but it
did not succeed. Finally, we continued our work by doing si-
lylation of the crude reaction mass under standard TBS pro-
tection conditions to afford the compound 7 in 60% yield.
ral synthon, (R)-ethyl-4-cyano-3-hydroxybutanoate (2). In
this report, we have presented an alternative route to the
synthesis of thiazole fragment (C12–C21 unit) via Wacker ox-
idation. Moreover, the whole process for the preparation of
intermediates and final product do not require chromato-
graphic separation, allowing it to be performed on a large
scale (greater than 100-g scale in our hands) and facilely
transferable to an industrial scale.
Acknowledgment
One of the authors (Rajashekar Kommera) thanks the HOD’s Osmania
University and JNTU Hyderabad for giving opportunity to pursue
Ph.D. We express our sincere thanks to Dr. M.S.N. Reddy, S. Eswaraiah,
S.T. Rajan (MSN Laboratories pvt. Ltd.) for providing facilities to do
this research work.
This is MSNRD communication number 22.s
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591942.
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Table 1 Reaction Conditions and Reagents used for Wacker Oxidation
Reactiona
References and Notes
Entry Catalyst
(0.08 equiv)
Oxidizing reagent Temp
7
(%)
7a
(%)
7b
(%)
(1 equiv)
(°C)
(1) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461.
(2) Höfle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem. 1996, 35, 1567.
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1477.
(7) Schinzer, D.; Limberg, A.; Böhm, O. M.; Bauer, A. Chem. Eur. J.
1999, 5, 2483.
1
2
3
4
5
6
7
PdCl2
CuCl
25 °C
No reaction
No reaction
PdCl2
CuCl
30 °C
40 °C
40 °C
40 °C
40 °C
40 °C
PdCl2
CuCl
NDb
NDb
80
30
70
PdCl2
CuCl2
10
15
90
5
PdCl2
Cu(OAc)2
CuCl2
Pd(OAc)2
Pd(OAc)2
No reaction
No reaction
Cu(OAc)2
a All reactions were monitored by TLC and described results are isolated
yields after 24 h maintenance.
(8) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.;
Vallberg, H.; Finlay, M. R.V.; Yang, Z. J. Am. Chem. Soc. 1997, 119,
7974.
b ND: Not detected.
(9) Taylor, R. E.; Chen, Y. Org. Lett. 2001, 3, 2221.
(10) Reiff, E. A.; Nair, S. K.; Narayan Reddy, B. S.; Inagaki, J.; Henri, J.
T.; Greiner, J. F.; Georg, G. I. Tetrahedron Lett. 2004, 45, 5845.
(11) For the import data and price of ethyl 4-cyano-3-hydroxybuta-
noate in India (Zauba), see: https://www.zauba.com/import-
ethyl-4-cyano-3-hydroxy-butanoate-hs-code.html.
(12) Soai, K.; Oyamada, H.; Ookawa, A. Synth. Commun. 1982, 12,
463.
Compound 7 was treated with phosphonate 106 in the
presence of sodium hexamethyldisilazane (NaHMDS) under
Horner–Emmons condition giving compound 8 with 75%
yield. The intermediate 8 was then subjected to selective
deprotection by using D-camphor sulphonic acid in metha-
nol followed by oxidation with Dess–Martine periodinane
giving 9 with a good average yield (84%). Compound 9 un-
derwent Z-selective Witting reaction with 1-iodoethyl
triphenylphosphorane16 leading to the desired thiazole
fragment 1 in 60% yield as the chirally pure stereoisomer.
In conclusion, an alternate synthetic approach to thi-
azole fragment (C12–C21 unit) has been achieved in 11 steps
and 11% overall yield, by using commercially available chi-
(13) Crimmins, M. T.; Slade, D. J. Org. Lett. 2006, 8, 2191.
(14) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth., Coll. Vol. 7;
1
3
7
Wiley: New York, 1990.
(15) Smith, A. B. III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C