Short, Tin-Free Synthesis of All Three Inthomycins

Article abstract of DOI:10.1002/chem.201803794

The inthomycins are a family of structurally and biologically rich natural products isolated from Streptomyces species. Herein the implementation of a modular synthetic route is reported that has enabled the enantioselective synthesis of all three inthomycins. Key steps include Suzuki and Sonogashira cross-couplings and an enantioselective Kiyooka aldol reaction.

Full text of DOI:10.1002/chem.201803794

DOI: 10.1002/chem.201803794
Communication
&
Natural Products
Short, Tin-Free Synthesis of All Three Inthomycins
[
a]
Manjeet Kumar, Liam Bromhead, Zoe Anderson, Alistair Overy, and Jonathan W. Burton*
product showed little biological activity. However, a close ana-
[
7]
Abstract: The inthomycins are a family of structurally and
biologically rich natural products isolated from Streptomy-
ces species. Herein the implementation of a modular syn-
thetic route is reported that has enabled the enantioselec-
tive synthesis of all three inthomycins. Key steps include
Suzuki and Sonogashira cross-couplings and an enantiose-
lective Kiyooka aldol reaction.
logue (23) was found to have proteasome inhibition activity.
Apart from their biological significance, the structures of the
inthomycins are particularly striking in that they contain a
methylene interrupted oxazolyl-triene moiety including a tri-
substituted alkene and a chiral allylic b-hydroxy carbonyl
moiety. Moreover, the full structural motif of the inthomycins is
found within a number of more complex natural products in-
cluding the oxazolomycins, 16-methyloxazolomycin, curromyci-
n A and B, and KSM 2690.
Given their wide ranging biological activities and interesting
structures, the inthomycins have attracted considerable atten-
tion from the synthetic community, although their deceptively
simple structures belie the challenge associated with their syn-
thesis. To date, synthetic effort has primarily focused on intho-
mycin C with only one report on the enantioselective synthesis
of inthomycin A and only two on the enantioselective synthe-
sis of inthomycin B. The first synthesis of inthomycin A (1) in
The inthomycins A–C (1–3, Figure 1), also known as the
phthoxazolins, are a family of oxazole triene natural products
isolated from Streptomyces culture that display both interesting
structures and a wide range of biological activities. The isola-
[1]
¯
tion of inthomycin A was first reported by Omura in 1990
who subsequently reported the isolation of inthomycins B and
[
2]
C in 1995. Between these dates, Zeek had reported the reiso-
lation of inthomycin A and the first isolation of inthomycins B
[8]
racemic form was disclosed by Whiting in 1999 with the only
[
3]
and C. Inthomycin A was discovered in a screen for inhibitors
of cellulose biosynthesis, however, not only does inthomycin A
enantioselective synthesis of 1 being reported by Hatakeyama
[9]
in 2012 who disclosed the enantioselective synthesis of in-
[
1,4]
inhibit cellulose biosynthesis, but it also shows both herbici-
thomycins B 2 and C 3 in the same publication. In 2006 Taylor
[
4,5]
[4]
[6]
[10]
dal,
and antifungal activity, and both inthomycin A and
reported the first enantioselective synthesis of inthomycin B
[
6b]
inthomycin B
inhibit prostate cancer cell growth. Very re-
2 followed by a report of the enantioselective synthesis of in-
[11]
cently the cytotoxicity of inthomycin C against a range of
human cancer cell lines has been investigated but the natural
thomycin C 3 and of racemic inthomycin A 1 in 2008. In
2010, Ryu reported an enantioselective synthesis of inthomy-
[12]
cin C 3 which was followed by Hale’s reports on the enantio-
[13]
selective synthesis of 3. Very recently the Donohoe group
[7]
published an enantioselective synthesis of inthomycin C 3. All
[7]
of the syntheses of the inthomycins bar one, feature a Stille
cross-coupling as a key step with the inherent problems asso-
ciated with the toxicity and disposal of stoichiometric organo-
tin waste. Herein we report short (9/10 steps, longest linear se-
quence), tin-free syntheses of all three inthomycins using
Suzuki or Sonogashira couplings as key steps and a Kiyooka
aldol to set the necessary asymmetry.
We envisaged that inthomycins A–C (1–3), could all be pre-
pared through cross-coupling of the (E)- or (Z)-alkenyl iodides
5
with the (E,E)- or (E,Z)-dienylboronic esters 4 (Figure 2). The
dienylboronic esters 4 were to be prepared by syn or anti hy-
droboration of the enyne oxazole 6 with the enyne oxazole 6
being prepared from alkylation of oxazole 8 with an electro-
phile derived from commercially available (E)-pent-2-en-4-yn-1-
ol (7). The iodides 5 were to be prepared using an enantiose-
Figure 1. Inthomycin natural products.
[
a] Dr. M. Kumar, Dr. L. Bromhead, Dr. Z. Anderson, A. Overy, Dr. J. W. Burton
Department of Chemistry, University of Oxford, Chemistry Research Labora-
tory
[14]
lective Kiyooka aldol reaction between the silylketene acetal
and the known (E)- or (Z)-iodoaldehydes 10, which can
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: jonathan.burton@chem.ox.ac.uk
9
be readily prepared from propargyl alcohol 11. This modular
route allowed the ready synthesis of all three inthomycins A–C
1–3.
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/chem.201803794.
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&
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1
4, the desired product 6, and fully desilylated material. Ulti-
[20]
mately, we found that modifying Basak’s procedure by using
sodium sulfide in a mixture of THF and water, gave the desired
mono-desilylated product 6 without allene formation although
the reaction did not reach completion; the product 6 could be
obtained in 85% yield after one recycle. Zirconium catalyzed
hydroboration of the terminal acetylene in 6 gave the desired
(
E,E)-dienylboronic ester 15 in good yield and with complete
[21]
stereocontrol.
The necessary Suzuki coupling partners for the dienylboronic
ester 15 were prepared from the known (Z)- and (E)-iodoal-
kenes (Z)-16 and (E)-16 (Scheme 2). Thus, propargyl alcohol 11
Figure 2. Retrosynthesis of the inthomycins 1.
Our synthesis commenced with the preparation of the
enyne oxazole 6 (Scheme 1). Commercially available (E)-pent-2-
[
15]
en-4-yn-1-ol 7 was readily converted into the known bro-
[
16]
mide 12 in two simple steps. After careful optimization we
I
Scheme 2. Synthesis of the alkenyl iodides (Z)- and (E)-17. a) MeMgBr, Cu I,
[17]
found that lithiation of the known silyl-protected oxazole 13
with n-butyllithium followed by addition to CuCN·LiCl and ad-
dition of the bromide 12 gave the desired coupled product 14
THF, À108C then I
2
, À10 to À58C, 66%; b) MnO
2 2 2 3
, CH Cl ; c) BH ·THF, 18, 9,
CH Cl , À788C then HCl, (Z)-5, 68% (2 steps), 89% ee, (E)-5, 61% (2 steps),
2
2
8
9% ee; d) Et
3
SiCl, imidazole, CH
2
Cl
2
, 08C to RT, (Z)-17 93%, (E)-17 91%;
, À78 8 to RT, 61%.
[
18]
e) Me Al, (C
3
5
H
5
)
2
ZrCl , CH Cl , 08C to RT then I
2
2
2
2
in 81% yield.
The next stage in the synthesis involved the seemingly
simple selective silyl group removal from 14 which proved un-
expectedly challenging. Commonly used basic conditions for
trimethylsilyl group deprotection failed to give the desired
product with allene formation being the major reaction path-
was readily converted into the (Z)- and (E)-alkenyl iodides (Z)-
[8,22]
[23]
16
and (E)-16 using Negishi’s protocols. The (Z)- and (E)-
alkenyl iodides (Z)-16 and (E)-16 were individually oxidized
with manganese dioxide to the corresponding aldehydes 10
and subjected to the enantioselective Mukaiyama aldol reac-
[
19]
way. The use of silver(I) salts to promote acetylene deprotec-
tion resulted in the formation of mixtures of starting material
[14]
tion developed by Kiyooka using the ketene acetal 9 in the
[24]
presence of l-N-tosylvaline (18). This gave the corresponding
aldols (Z)-5 (68% yield, 94.5:5.5 er) and (E)-5 (61% yield,
94.5:5.5 er) which were converted into the corresponding silyl
ethers (Z)-17 and (E)-17 under standard conditions.
Having established reliable routes to both the dienylboronic
ester 15 and the two alkenyl iodides (Z)-17 and (E)-17, we next
[25]
addressed the key Suzuki coupling reaction (Scheme 3).
After extensive experimentation we found that the use of pal-
ladium(II) acetate and triphenylphosphine in the presence of
1
m aqueous sodium bicarbonate allowed the union of the di-
enylboronic ester 15 with the (Z)-alkenyl iodide (Z)-17 to pro-
ceed with complete stereochemical fidelity to give the corre-
sponding coupled product 19 in 64% yield. Double deprotec-
[9]
tion of the triene 19 with HF in acetonitrile gave the alcohol
0 which was converted into inthomycin B 2 via aminolysis of
2
Scheme 1. Synthesis of dienylboronic ester 15. a) nBuLi, Me
then 2m HCl, 08C to RT, 62%; b) PPh , N-bromosuccinimide, CH
1%; c) nBuLi, iPr
SiOTf, THF, À788C to RT, 82%; d) 13, nBuLi, CuCN·2LiCl,
THF, À788C then add 12, 81%; e) Na S, THF:H O (1:1), 08C to RT, 85%, after
one recycle.; f) pinacol borane, (C ZrHCl, Et N, 608C, 84%. RT=room
temperature, Tf=SO CF , THF=tetrahydrofuran.
3
SiCl, THF, À788C
the corresponding pentaflurorophenyl ester 21. Our synthetic
inthomycin B 2 had spectroscopic properties in accord with
that of both natural and synthetic inthomycin B 2.
For the synthesis of inthomycin C 3, the Suzuki coupling be-
tween the (Z,Z)-dienyl boronate 15 and the (E)-alkenyl iodide
3
2
Cl
2
, À308C,
8
3
2
2
5
H
5
)
2
3
2
3
&
&
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therefore investigated the semi-hydrogenation of the
alcohol 26 formed by double deprotection of 25.
Pleasingly the use of Zn(Cu/Ag) couple in methanol
at above room temperature gave the desired (Z,Z,E)-
[27]
triene 27 in 80% yield. As before, the methyl ester
7 was readily transformed into the corresponding
2
amide target inthomycin A 1 via the pentafluoro-
1
phenyl ester 28. Careful analysis of the H and
13
C NMR spectra of 1 indicated that it was contami-
nated with a small amount (<10%) of inthomycin B
which appears to arise during conversion of the
2
ester 27 into inthomycin A 1.
All of our synthesized inthomycins had spectro-
scopic properties in accord with the natural and pre-
viously synthesized compounds. Importantly, the ab-
solute configuration of inthomycin C 1 has been the
subject of much confusion and debate in the litera-
ture. However, recently these ambiguities have been
[13b]
laid to rest by Hale and Hatakeyama
with the ab-
solute configuration of inthomycin C 1 being firmly
established as (R) confirming the original assignment
[3]
by Henkel and Zeek. We had assigned the absolute
configuration of the alkenyl iodides (Z)-5 and (E)-5 as
[28]
(
S) using Kakisawa’s extension of Mosher’s method
Scheme 3. Synthesis of inthomycins B and C. a) (Z)-17 or (E)-17, Pd(OAc)
THF, H O, 19 64%, 22 65%; b) HF·pyridine, CH CN, 08C to RT, 20 80%, 23 97%; c) LiOH,
O, THF, MeOH, 08C to RT; d) C OH, EDCI·HCl, DMAP, CH Cl , 21 80% (2 steps), 24
7% (2 steps); e) NH OH, THF, 08C to RT, 2 95%, 3 94%. EDCI=1-ethyl-3-(3-dimethylami-
nopropyl)carbodiimide).
2 3 2 3
, PPh , Na CO ,
which translates into the absolute configuration of all
of the inthomycins being (R), and our optical rotation
for 3 was in agreement with the recently remeasured
2
3
H
8
2
6
H
5
2
2
4
[13b]
values.
(
E)-17 required further optimization. Ultimately, we found that
the concentration of aqueous base proved crucial with the use
of 0.25m sodium bicarbonate giving the coupled product 22
in 65% yield. In a similar manner to the synthesis of inthomy-
cin B 2, inthomycin C 3 was prepared from the triene 22 by
the same reaction sequence. Our synthetic inthomycin C 3 had
spectroscopic properties in accord with that of both natural
and synthetic inthomycin C 3.
Having successfully synthesized inthomycins B 2 and C 3 we
turned our attention to inthomycin A 1 (Scheme 4). We had
originally aimed to prepare inthomycin A 1 by the same strat-
egy namely Suzuki cross-coupling of a (Z,E)-dienylboronic acid
(
Z,E)-15, however, rhodium(I) catalyzed anti-selective hydrobo-
[
26]
ration of the enyne 6 gave the corresponding (Z,E)-dienyl-
boronic ester (Z,E)-15 in low yields (<40%) under a number of
conditions. We therefore altered our synthetic strategy and in-
vestigated a Sonogashira/semi-hydrogenation sequence. Pleas-
ingly, the Sonogashira reaction of the alkenyl iodide (Z)-17
with the enyne 6 proceeded smoothly under standard condi-
tions to give the coupled product 25 in 62% yield. The next
challenge was the semi-hydrogenation of the alkyne to give
the (Z,Z,E)-triene required for completion of the synthesis of in-
thomycin A. Semi-hydrogenation of 25 under a variety of con-
ditions [Pd, CaCO , quinoline; Pd, CaCO ; Pd, BaSO ; nickel
I
Scheme 4. Synthesis of inthomycin A. a) (Z)-17, Pd(PPh
b) HF·pyridine, CH CN, 08C to RT, 91%; c) Zn-Cu-Ag couple, MeOH, 358C,
0%; d) LiOH, H O, THF, MeOH, 08C to RT; e) C OH, EDCI·HCl, DMAP,
CH Cl , 78% (2 steps); f) NH OH, THF, 08C to RT, 89%.
3 4 3
) , CuI, Et N, 62%;
3
8
2
6 5
H
2
2
4
In summary, we have developed efficient modular enantiose-
lective total syntheses of all three inthomycins, which proceeds
in only 9/10 steps from commercially available materials. The
key steps include Suzuki and Sonogashira cross-couplings, and
an enantioselective Kiyooka aldol reaction. Our modular route
has allowed the efficient syntheses of these biologically active
3
3
4
boride; Zn (Cu/Ag)] gave mixtures of the desired product, over
reduced products and starting material and we were unable to
isolate the desired triene in synthetically useful yields. We
Chem. Eur. J. 2018, 24, 1 – 5
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natural products and we will use this synthetic sequence in
our assault on the synthesis of the oxazolomycins.###
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Acknowledgements
[
1
991, 56, 2276–2278.
We thank the EPSRC and the European Union (H2020-MSCA-IF-
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J. Chem. Soc. Perkin Trans. 1 1983, 1553–1571.
2015-708354) for funding this work.
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Conflict of interest
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The authors declare no conflict of interest.
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Keywords: inthomycin · phthoxazolin · total synthesis
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Version of record online: && &&, 0000
&
&
Chem. Eur. J. 2018, 24, 1 – 5
www.chemeurj.org
4
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
The inthomycins are a family are struc-
turally and biologically rich natural
products isolated from Streptomyces
species. Herein a modular synthetic
route is reported which enables the
enantioselective synthesis of all three in-
thomycins. Key steps include Suzuki and
Sonogashira cross-couplings and an
enantioselective Kiyooka aldol reaction.
&
Natural Products
M. Kumar, L. Bromhead, Z. Anderson,
A. Overy, J. W. Burton*
&
& – &&
Short, Tin-Free Synthesis of All Three
Inthomycins
Chem. Eur. J. 2018, 24, 1 – 5
www.chemeurj.org
5
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ