Synthesis of the pyridine core of cyclothiazomycin

Article abstract of DOI:10.1021/ol201682k

A highly convergent synthesis of the pyridine core of the thiopeptide antibiotic cyclothiazomycin has been developed based on a [2 + 2 + 2] cyclotrimerization key step. The regioselective assembly of the heterocyclic center of this important class of anti

Full text of DOI:10.1021/ol201682k

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4352–4355
Synthesis of the Pyridine Core of
Cyclothiazomycin
Yan Zou, Qingyang Liu, and Alexander Deiters*
North Carolina State University, Department of Chemistry, Raleigh, North Carolina
27695-8204, United States
alex_deiters@ncsu.edu
Received June 22, 2011
ABSTRACT
A highly convergent synthesis of the pyridine core of the thiopeptide antibiotic cyclothiazomycin has been developed based on a [2 þ 2 þ 2]
cyclotrimerization key step. The regioselective assembly of the heterocyclic center of this important class of antibiotics takes advantage of a
temporary silicon tether and the ruthenium-catalyzed cyclotrimerization reaction of a diyne and an electron-poor thiazole nitrile.
Thiopeptide antibiotics have attracted considerable at-
tention due to their intriguing architecture and their inhi-
bition of bacterial protein synthesis, preventing the growth
of gram-positive bacteria, including methicillin-resistant
S. aureus.1 Cyclothiazomycin (1) is 1 of 76 structurally
distinct actinomycete thiopeptide antibiotics (Figure 1).1
thiopeptide antibiotics, including berninamycins, gen-
inthiocin, promothiocins, radamycin, and thioxamycin.
However, previous syntheses of thiopeptide antibiotics
have often struggled with the assembly of the pyridine
core. Several groups have developed sophisticated and
specially designed approaches, including aza-DielsꢀAlder
reactions2,3 and heteroannulations.4,5 To date, three synth-
eses of the pyridine motif present in cyclothiazomycin (1)
have been reported.6ꢀ8 However, only one of the three
approaches is a stereospecific synthesis8 and utilizes a
BohlmannꢀRahtz reaction to assemble the trisubstituted
pyridine ring from an enantiomerically pure β-ketoester
and ethyl 2-(propynoyl)thiazole-4-carboxylate. No total
synthesis of cyclothiazomycin is known.
[2 þ 2 þ 2] Cyclotrimerization reactions have been
applied as efficient tools in the construction of highly
(2) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C. J. J. Am.
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Figure 1. Structure of cyclothiazomycin (1), a representative
thiopeptide antibiotic.
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The peptide 1 bears a central 2,3,6-trisubstituted pyr-
idine motif, which is also found in a number of other
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r
10.1021/ol201682k
Published on Web 07/15/2011
2011 American Chemical Society

functionalized benzene and pyridine rings.9ꢀ14 The [2 þ 2
þ 2] cyclotrimerization reaction tolerates a variety of
functional groups, which allows for its application in the
facile synthesis of multisubstituted carbo- and heteroaro-
matic ring systems in a single step.15ꢀ30 Based on our
previous successes in applying cyclotrimerization reactions
in the synthesis of important, naturally occurring structur-
al motifs,31ꢀ36 we are reporting a regioselective approach
to the formation of the pyridine domain of thiopeptide
antibiotics via a transition-metal-catalyzed [2 þ 2 þ 2]
cyclotrimerization reaction as the key step. Two different
retrosynthetic analyses of 2 are shown in Scheme 1. We
first envisioned that 2 could be assembled from the cyclo-
trimerization of the enantiopure alkynylnitrile 3 and the
thiazole alkyne 4 (route 1). Although this route is highly
convergent, this approach potentially entails several pit-
falls: (1) Alkynylnitriles are traditionally poor substrates in
cyclotrimerization reactions due to the possibility of sev-
eral undesired side reactions.17,37,38 (2) The cyclotrimeriza-
tionprecursor 3 can exist as two different amide isomers, of
which only the one shown can undergo the desired reac-
tion. (3) The cyclotrimerization reaction can yield mixtures
of regioisomers,17 a problem that could possibly be solved
through the installation of a temporary regiodirecting
group R2.
Scheme 1. Retrosynthetic Analysis of 2
However, the cyclotrimerization reaction of the alkynyl-
nitrile 3 (R1 = Ac, R2 = TMS) and the thiazole alkyne 4
did not proceedasexpected(datanot shown). Eventhough
a wide range of conditions were explored, a number of
catalysts were investigated at different temperatures, with
and without microwave irradiation, the product yields
were generally below 15%.
Based on our39 and others40ꢀ43 recent successes in
constructing highly substituted benzenes and pyridines
via a silyl-tethered [2 þ 2 þ 2] cyclotrimerization reaction,
we applied a similar approach to the synthesis of the
pyridine core 2 of cyclothiazomycin (1) (Scheme 1, route
2). The silyl tether transforms an otherwise intermolecular
cyclotrimerization reaction into an intramolecular one,
providing enhanced regio- and chemoselectivity. Here,
the application of a silyl tether enabled switching of the
synthetic approach from a notoriously difficult17,38 to
cyclotrimerize alkynylnitrile to a regular diyne cyclotri-
merization precursor. The linker can be easily and selec-
tively removed in a traceless fashion, delivering the desired
product.
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We envisioned that 2 could be obtained from the oxida-
tion of the alcohol 5, which in turn could be synthesized
through removal of the silyl group from 6. The pyridine
ring 6 could be assembled by a [2 þ 2 þ 2] cyclotrimeriza-
tion reaction of the enantiopure diyne 7 and the
Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem.
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Org. Lett., Vol. 13, No. 16, 2011
4353

thiazolecarbonitrile 8. The diyne 7 could be synthesized
from the known dibromoalkene 9.
product 22 was obtained in good yield and with excellent
regioselectivity. This was the first time a thiazole nitrile was
employed in a [2 þ 2 þ 2] cyclotrimerization reaction. The
successful reaction between the silyl-tethered diyne solved
potential regioselectivity problems and previously encoun-
tered reactivity problems of alkynylnitriles. These discov-
ered results were subsequently applied to the synthesis of
the pyridine core of cyclothiazomycin (1).
We first investigatedthe ability toreact various silylether
diynes in [2 þ 2 þ 2] cyclotrimerization reactions. Two
model substrates, silylether diynes 10 and 11, were synthe-
sized (Scheme 2). The diyne 10 was prepared in one step
from the commercially available alcohol 14 and freshly
prepared alkynylsilyl bromide 15.40 The synthesis of the
diyne 11 was accomplished in two steps via an SN2 reaction
of N-benzyl-p-toluene sulfonamide with 4-hydroxybut-2-
ynyl methanesulfonate, followed by reacting 13 with alky-
nylsilyl bromide to form 11 in good yields. The known
thiazolecarbonitrile 8 was prepared in one step from
commercially available ethyl 2-bromothiazole-4-carboxy-
late (16) in 59% yield.44
Table 1. Cyclotrimerization Reactions of Model Substrates
Scheme 2. Synthesis of Model Cyclotrimerization Substrates
With the model diynes and nitriles in hand, we investi-
gated the cyclotrimerization reactions under different re-
action conditions (Table 1). The CpCo(CO)2 catalyst was
the first used due to its wide application in the formation of
pyridines.9,13,45,46 However, no product was obtained from
the diynes 10ꢀ11 and benzonitrile or thiazolecarbonitrile 8
under microwaveirradiation (entries 1, 2, and 4). Whenthe
cyclotrimerization reaction between 10 and benzonitrile
was thermally heated to 150 °C in the presence of CpCo-
(CO)2, only 39% of the desired product 18 was obtained
(entry 3). Yamamoto et al.47 succefully used Cp*RuCl-
(COD) as the catalyst for cyclotrimerization reactions of
electron-deficient nitriles. Gratifyingly, the diyne17under-
went a smooth cyclotrimerization reaction with the elec-
tron-poor thiazolecarbonitrile 8 in the presence of
Cp*RuCl(COD) at either room temperature or 60 °C
(entries 6 and 7), furnishing the desired pyridine 21 in
excellent yields. The cyclotrimerization reaction between
diyne 11 and thiazolecarbonitrile 8 was successful and the
a CpCo(CO)2, toluene, MW 300 W. b CpCo(CO)2, xylene, 150 °C, 16
h. c CpCo(COD), 150 °C, 16 h. d Cp*RuCl(COD), DCM, rt, 20 h.
e Cp*RuCl(COD), DCE, 60 °C, 20 h.
The synthesis of 2 commences with the known dibro-
moalkene 9 which was synthesized in three steps from (R)-
2-aminopropan-1-ol following a literature procedure.48
The dibromoalkene 9 was deprotonated with n-BuLi
and reacted with DMF to the corresponding aldehyde
which was directly reduced to the propargyl alcohol 23
(Scheme 3).49 The alcohol 23 was alkylated with freshly
prepared alkynylsilyl bromide,40 producing the silylether-
tethered cyclotrimerization precursor 7 in 84% yield. As
expected from the model studies, the diyne 7 underwent an
efficient [2 þ 2 þ 2] cyclotrimerization reaction with the
thiazolecarbonitrile 8 in the presence of Cp*RuCl(COD),
delivering the tetrasubstituted pyridine 6 in 82% yield.
Importantly, the reaction proceeded with complete regio-
and chemoselectivity, as no other cyclotrimerization
(44) Toogood, P. L.; Hollenbeck, J. J.; Lam, H. M.; Li, L. Bioorg.
Med. Chem. Lett. 1996, 6, 1543.
(45) Varela, J. A.; Saa, C. J. Organomet. Chem. 2009, 694, 143.
(46) Turek, P.; Kotora, M. Targets Heterocycl. Syst. 2009, 13, 175.
(47) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Oku-
da, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2004, 127, 605.
(48) Hoveyda, H.; Fraser, G. L.; Benakli, K.; Beauchemin, S.;
Brassard, M.; Drutz, D.; Marsault, E.; Ouellet, L.; Peterson, M. L.;
Wang, Z. U.S. Pat. Appl. Publ., 20080194672A1, 2008.
(49) Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.;
Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904.
4354
Org. Lett., Vol. 13, No. 16, 2011

pyridine core of cyclothiazomycin was efficiently assembled
in regio- and enantiomerically pure form. The stereochemical
information was retained throughout the entire synthesis, as
the optical rotation of 2 ([R]20D þ51.9 (c 0.54, CHCl3)) is in
þ48.1 (c 0.54, CHCl3)).8 The lactam 2 has previously been
converted to the hydrolysate 24 of cyclothiazomycin.8 Even
though our synthetic approach is slightly longer than Bagley’s
published route,8 the overall efficiency of both synthesis is
comparable, with our approach being more easily adaptable
to the synthesis of structural analogs.
Scheme 3. Synthesis of the Cyclothiazomycin Core 2
excellent agreement with the literature reported value ([R]24
D
In summary, we have described an effective and regio-
selective approach to the pyridine core of cyclothiazomy-
cin (1). The key step of the synthesis is a transition-metal-
catalyzed [2 þ 2 þ 2] cylotrimerization reaction of a diyne
and a nitrile. The electron-deficient nature of the thiazole-
bearing nitrile enables ruthenium catalysis under mild
reaction conditions with excellent yields. Complete chemo-
and regioselectivity in the construction of the trisubstituted
pyridine core were achieved by applying a temporary silyl
tether. We believe that this approach, of tethering functio-
nalized alkynes and cyclotrimerizing them with heterocyc-
lic nitriles, will be applicable to a wide range of pyridine
motifs found in natural products and pharmacologically
relevant molecules.
Acknowledgment. Financial support from the National
Science Foundation is acknowledged (CAREER Award
CH0846756).
products were observed. The silylether linkage was removed
by treatment with TBAF, generating the alcohol 5 in 97%
yield. The alcohol was subsequently oxidized to the corre-
sponding carboxylic acid using Jones’ reagent and the Boc
group was removed through treatment with TFA, which
delivered the lactam 2 in 80% yield over both steps. Thus, the
Supporting Information Available. Experimental pro-
tocols and analytical data, as well as 1H NMR spectra for
compounds 2, 5ꢀ8, 10, 11, 13, 18, and 21ꢀ23. This
information is available free of charge via the Internet
at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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