Eight-step synthesis of routiennocin

Article abstract of DOI:10.1002/adsc.200700537

Routiennocin is a member of a family of polycyclic pyrrole ether antibiotics that simultaneously uncouple oxidative phosphorylation and inhibit ATPase as a result of selective complexation of divalent metal ions. We describe a concise synthesis of routien

Full text of DOI:10.1002/adsc.200700537

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DOI: 10.1002/adsc.200700537
Eight-Step Synthesis of Routiennocin
Kenji Matsumotoa and Sergey A. Kozmina,*
a
Department of Chemistry, University of Chicago, 5735 S. Ellis Ave, Chicago, IL 60637, USA
Fax : (+1)-773-7020805; e-mail: skozmin@uchicago.edu
Received: November 12, 2007; Published online: February 18, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Routiennocin is a member of a family of
polycyclic pyrrole ether antibiotics that simultane-
ously uncouple oxidative phosphorylation and in-
hibit ATPase as a result of selective complexation
of divalent metal ions. We describe a concise syn-
thesis of routiennocin with the longest linear se-
quence of 8 steps. Our synthesis features a unique
bi-directional strategy, which entails a sequential
ring-opening/cross metathesis of a highly strained
cyclopropenone acetal. This approach enables rapid
and highly convergent assembly of the fully extend-
ed polyketide subunit of this natural product from
readily available homoallylic alcohol precursors.
metal ions perturbs normal mitochondrial function by
altering the endogenous levels of calcium and magne-
sium.[2] The unique biochemistry of pyrrole ether anti-
biotics stimulated considerable interest in the assem-
bly of this class of natural products, which enabled
one to test the power of synthetic methods for the
construction of polyketide-derived spiroketals.[14] Sev-
eral syntheses of calcimycin have been reported by
Evans,[15] Grieco,[16] Ogawa,[17] Kishi,[18] Boeckman[19]
and Ziegler.[20] In contrast to calcimycin, the only syn-
thesis of routiennocin was described by Ley and co-
workers in 1992.[21] The assembly of the spiroketal
was based on the sulfone alkylation tactic and deliv-
ered the final target with the longest linear sequence
of 16 steps.
We have recently devised a highly convergent strat-
egy for polyketide assembly, which exploits the
unique reactivity of cyclopropenone acetals in provid-
ing rapid synthetic access to spiroketal-containing nat-
ural products, such as bistramide A[22] and spirofungin
A.[23] Herein, we provide another important demon-
Keywords: antibiotics; asymmetric synthesis; meta-
thesis; natural products; ruthenium; spiro com-
pounds
Polycyclic pyrrole ether antibiotics comprise a family stration of the generality and the convergency of our
of divalent ionophores produced by different species metathesis-based strategy by describing the develop-
of Streptomyces.[1] Selective complexation of metal ment of a concise synthesis of routiennocin. The as-
ions by this class of natural products has been linked sembly process takes a full advantage of the excep-
to their ability to simultaneously uncouple oxidative tional functional group compatibility of Ru-based
phosphorylation and to inhibit ATPase in rat liver mi- olefin metathesis[24] in enabling coupling of complex
tochondria.[2] Routiennocin (1) is a representative synthetic fragments en route to the final target, which
member of this family of antibiotics, which also in- is assembled with the longest linear sequence of only
cludes calcimycin (A-23187),[3] cezomycin,[4] X- 8 steps.
14885A[5] and AC7230.[6] Routiennocin was originally
Our strategy for the rapid assembly of routiennocin
designated as CP-61,405 and isolated by fermentation (1) is outlined in Scheme 1. The unique feature of our
of a previously unknown microbial species Streptomy- approach is the assembly of a fully elaborated spiro-
ces routienii Huang sp. nov. (ATCC 39446).[7] The nat- ketalization precursor 2 containing both heterocyclic
ural product was found to display potent activity subunits prior to the spiroketalization event. This
against a wide spectrum of Gram-positive and anaero- strategy was expected to significantly facilitate the
bic bacteria.[7] Structural analysis of routiennocin re- end game of the synthesis, providing a fully conver-
vealed the presence of carboxylic acid, benzoxazole gent entry to the final target 1. Ketone 2 would
and ketopyrrole groups. The three functional groups derive from dienone 3 by hydrogenation and concom-
comprise the ionophore subunit, that enables triden- itant hydrogenolysis of two benzyl ethers. The assem-
tate coordination of divalent cations, such as Mn2+, bly of dienone 3 would entail a sequential ring-open-
Ca2+, Mg2+, Fe2+, resulting in the formation of octahe- ing/cross metathesis of highly strained cycloprope-
dral 2:1 complexes.[8–13] Such effective scavenging of none acetal 4 with terminal alkenes 5 and 6. The most
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557

Kenji Matsumoto and Sergey A. Kozmin
COMMUNICATIONS
challenging aspect of the synthesis entailed develop-
ing an efficient set of conditions that would enable
the coupling of 5 and 6 in the presence of fully elabo-
rated heterocyclic moieties.
The synthesis began with Roush crotylboration[25]
of a well-known aldehyde 7[26] to give alcohol 9 in
93% yield and
a
diastereoselection of 91:9
(Scheme 2). Treatment of alcohol 9 with KHMDS and
BnBr furnished the requisite benzyl ether 10. Jones
oxidation of the primary TBS ether, followed by con-
version of the resulting carboxylic acid to the corre-
sponding thiopyridyl ester and in situ addition of the
pyrrolemagnesium bromide delivered the first requi-
site alkene 5 (4 steps, 46% overall yield).[27]
Assembly of the second metathesis partner 6 com-
menced with oxidation of hydroquinone 11 to qui-
none 12 with silver oxide (96% yield). Regioselective
installation of the azide moiety was realized by treat-
ing quinone 12 with TMSN3 in MeOH at À788C. Diol
13 was next coupled with carboxylic acid 14, which
was prepared in 3 steps by Keck allylation[28] of 3-
(tert-butyldimethylsiloxy)propanal, followed by ben-
zylation of the homoallylic alcohol and Jones oxida-
tion of primary silyl ether. Subsequent treatment of
the resulting ester with P(OEt)3 in THF triggered the
G
intramolecular Staudinger reaction to give benzoxa-
zole 6 (70% yield, 2 steps).[29]
Scheme 1. Retrosynthetic analysis of routiennocin (1).
Scheme 2. Eight-step synthesis of routiennocin (1).
558
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Eight-Step Synthesis of Routiennocin
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The final metathesis sequence began with the ring- Routiennocin Methyl Ester (23)
opening of cyclopropenone acetal 4[30] with alkene 5
A solution of dienone 3 (80 mg, 0.12 mmol) in methanol
in the presence of Grubbsꢁ catalyst 15.[31] Following
the in situ removal of the acetal under acidic condi-
tions, which is required to enable the second produc-
tive metathesis step, the resulting enone was treated
with the benzoxazole-contaning alkene 6, again in the
presence of catalyst 15, to deliver the fully extended
enone 3. Subjection of dienone 3 to heterogeneous
hydrogenation with concomitant hydrogenolysis of
benzyl ethers, followed by saponification of the
methyl ester according to the Leyꢁs protocol[21] deliv-
(2 mL) was treated with Pd-C (25 mg, 10 wt%) and stirred
at room temperature for 7h under an atmosphere of H 2 (1
atm). The resulting mixture was filtered and the filtrate was
concentrated under vacuum and the residue was purified by
preparative TLC (ethyl acetate:hexane=1:1) to afford rou-
tiennocin methyl ester 23 as a pale brown foam; yield:
36 mg (62%). For complete analytical characterization, see
Supporting Information.
Routiennocin (1)
1
ered the final target (1). The 500 MHz H NMR and
A
solution of routiennocin methyl ester 23 (10 mg,
125 MHz 13C NMR spectra of synthetic routiennocin
(1), as well as the optical rotation were in excellent
agreement with those reported previously.[7,21]
In closing, we have developed a concise synthetic
access to routiennocin (1) with a longest linear se-
quence of 8 steps, which significantly exceeds the effi-
ciency of any of the existing synthetic approaches to
naturally occurring polycyclic pyrrole ether antibiot-
ics. Such rapid assembly of routiennocin provides an-
other demonstration of the power of the cycloprope-
none acetal metathesis-based strategy for rapid as-
sembly of complex spiroketal-containing natural prod-
ucts.
0.020 mmol) in THF-H2O (10:1, 1 mL) was treated with lith-
ium hydroxide monohydrate (14 mg, 0.33 mmol) and stirred
at room temperature for 48 h. The reaction mixture was
acidified by careful addition of 2N HCl and then diluted
with chloroform. The resulting mixture was washed with
H2O and brine, dried over Na2SO4. The solvent was evapo-
rated and the residue was chromatographed over silica gel
(ethyl acetate: Et2O=1:5) to afford carboxylic acid 1 as a
colorless form; yield: 8.0 mg (82%). For complete analytical
characterization, see Supporting Information.
Supporting Information
Full characterization of all new compounds and experimen-
tal procedures are given in the Supporting Information.
Acknowledgements
Experimental Section
S.A.K thanks the Alfred P. Sloan Foundation, the Dreyfus
Foundation, Amgen and GlaxoSmithKline for financial sup-
port of this work.
Ring-Opening/Cross Metathesis Sequence
Grubbsꢁ catalyst 15 (25 mg, 0.030 mmol) was dissolved in an-
hydrous THF (2 mL) and treated dropwise with solution of
alkene 5 (90 mg, 0.30 mmol) and cyclopropenone acetal 4
(84 mg, 0.60 mmol) in THF (3 mL) at room temperature.
After 1.5 h, the reaction mixture was cooled to 08C, treated
with HClO4 (0.050 mL, 30% solution in water) and stirred
for 10 min at 08C until TLC indicated complete consump-
tion of the starting material. The reaction mixture was
quenched with saturated NaHCO3 solution and diluted with
ethyl acetate-hexane. The resulting mixture was washed
with brine and dried over MgSO4. The solvent was evaporat-
ed and the residue was purified by flash chromatography on
silica gel (ethyl acetate: hexane=1:5 to 1:3) to give the cor-
responding dienone as a pale brown oil; yield: 53 mg (50%).
For complete analytical characterization, see Supporting In-
formation.
Next, Grubbsꢁ catalyst 15 (13 mg, 0.015 mmol) and the
above dienone (64 mg, 0.18 mmol) were dissolved in THF
(2 mL) and treated dropwise (30 min) with a solution of
alkene 6 (38 mg, 0.10 mmol) in THF (3 mL) at room tem-
perature. After 6 h, the solvent was removed under vacuum
and the residue was purified by flash chromatography on
silica gel (ethyl acetate: hexane=1:1) to yield dienone 3 as
a brown oil; yield: 42 mg (59%). For complete analytical
characterization, see Supporting Information.
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