Synthesis of the cytotrienin A core via metal catalyzed C-C coupling

Article abstract of DOI:10.1021/ol200160p

A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core.

Full text of DOI:10.1021/ol200160p

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1482–1485
Synthesis of the Cytotrienin A Core via
Metal Catalyzed C-C Coupling
€
Michael Rossle, David J. Del Valle, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin,
Texas 78712, United States
mkrische@mail.utexas.edu
Received January 18, 2011
ABSTRACT
A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium
catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the
stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed
acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core.
Beginning with the discovery of the antibacterial rifa-
mycin B, ansamycin antibiotics continue to evoke interest
as antibiotic and antineoplastic agents.1 An important
ansamycin subclass is represented by the ansatrienins,
which are classified as triene-containing C17-benzene an-
samycins. Members of this subclass, which are produced
from various Streptomyces and Bacillus species, include
the mycotrienins and mycotrienols,2 the trienomycins,3
and the cytotrienins (Figure 1).4 Whereas the mycotrienins
exhibit potent antifungal activity,2d,e the trienomycins and
cytotrienins display antineoplastic properties.3a,5 For
(4) For isolation of cytotrienin A-D, see: (a) Zhang, H.-P.; Kakeya,
H.; Osada, H. Tetrahedron Lett. 1997, 38, 1789. (b) Kakeya, H; Zhang,
H.-P.; Kobinata, K.; Onose, R.; Onozawa, C.; Kudo, T.; Osada, H.
J. Antibiot. 1997, 50, 370. (c) Osada, H.; Kakeya, H.; Zhang, H.-P.;
Kobinata, K. PCT Int. Appl. WO 9823594, 1998.
(5) (a) Komiyama, K.; Hirokawa, Y.; Yamaguchi, H.; Funayama, S.;
Masuda, K.; Anraku, Y.; Umezawa, I.; Omura, S. J. Antibiot. 1987, 40,
1768. (b) Funayama, S.; Anraku, Y.; Mita, A.; Yang, Z. B.; Shibata, K.;
Komiyama, K.; Umezawa, I.; Omura, S. J. Antibiot. 1988, 41, 1223. (c)
Kakeya, H.; Zhang, H.-p.; Kobinata, K.; Onose, R.; Onozawa, C.;
Kudo, T.; Osada, H. J. Antibiot. 1997, 50, 370.
(6) For stereochemical assignment of the trienomycins and myco-
trienins, see: (a) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.;
Rizzo, C. J. J. Am. Chem. Soc. 1990, 112, 7425. (b) Smith, A. B., III;
Wood, J. L.; Omura, S. Tetrahedron Lett. 1991, 32, 841. (c) Smith, A. B.,
III; Barbosa, J.; Hosokawa, N.; Naganawa, H.; Takeuchi, T. Tetrahe-
dron Lett. 1998, 39, 2891. (d) Smith, A. B., III; Wood, J. L.; Wong, W.;
Gould, A. E.; Rizzo, C. J.; Barbosa, J.; Funayama, S.; Komiyama, K.;
Omura, S. J. Am. Chem. Soc. 1996, 118, 8308.
(7) For the total and formal syntheses of triene-ansamycins, see: (a)
Trienomycins A and F and thiazinotrienomycin E: Smith, A. B., III;
Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1995, 117, 10777.
(b) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1996, 118, 8316. (c) Smith, A. B., III; Wan, Z. J. Org. Chem. 2000,
65, 3738. (d) Mycotrienol I and mycotrienin I: Panek, J. S.; Masse, C. E.
J. Org. Chem. 1997, 62, 8290. (e) Masse, C. E.; Yang, M.; Solomon, J.;
Panek, J. S. J. Am. Chem. Soc. 1998, 120, 4123. (f) Cytotrienin A:
Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamaru, T.; Imai,
H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Angew. Chem.,
Int. Ed. 2008, 47, 6657.
(1) For selected reviews on ansamycin natural products, see: (a)
Wrona, I. E.; Agouridas, V.; Panek, J. S. C. R. Acad. Sci., Paris 2008,
11, 1483. (b) Funayama, S.; Cordell, G. A. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: New York, 2000; Vol. 23, pp
51-106.
(2) For isolation of mycotrienols I and II and mycotrienins I and II
(ansatrienins A and B), see: (a) Weber, W.; Zuehner, H.; Damberg, M.;
Russ, P.; Zeeck, A. Zbl. Bakt. Hyg., Abt. Orig. C2 1981, 122. (b) Zeeck,
A.; Damberg, M.; Russ, P. Tetrahedron Lett. 1982, 23, 59. (c) Sugita, M.;
Furihata, K.; Seto, H.; Otake, N.; Sasaki, T. Agric. Biol. Chem. 1982, 46,
1111. (d) Sugita, M.; Natori, Y.; Sasaki, T.; Furihata, K.; Shimazu, A.;
Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1460. (e) Sugita, M.; Sasaki, T.;
Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1467. (f) Sugita,
M.; Natori, Y.; Sueda, N.; Furihata, K.; Seto, H.; Otake, N. J. Antibiot.
1982, 35, 1474. (g) Sugita, M.; Hiramoto, S.; Ando, C.; Sasaki, T.;
Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1985, 38, 799.
(3) For isolation of trienomycins A-F, see: (a) Umezawa, I.;
Funayama, S.; Okada, K.; Iwasaki, K.; Satoh, J.; Masuda, K.; Komiyama,
K. J. Antibiot. 1985, 38, 699. (b) Hiramoto, S.; Sugita, M.; Ando, C.;
Sasaki, T.; Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1985, 38, 1103.
(c) Funayama, S.; Okada, K.; Komiyama, K.; Umezawa, I. J. Antibiot.
1985, 38, 1107. (d) Funayama, S.; Okada, K.; Iwasaki, K.; Komiyama,
K.; Umezawa, I. J. Antibiot. 1985, 38, 1677. (e) Nomoto, H.; Katsumata,
S.; Takahashi, K.; Funayama, S.; Komiyama, K.; Umezawa, I.; Omura,
S. J. Antibiot. 1989, 42, 1677. (f) Smith, A. B., III; Wood, J. L.; Gould,
A. E.; Omura, S.; Komiyama, K. Tetrahedron Lett. 1991, 32, 1627.
r
10.1021/ol200160p
Published on Web 02/16/2011
2011 American Chemical Society

Figure 1. Representative ansatrienins: C17-benzene triene-ansamycin antibiotics.
example, cytotrienin A induces apoptosis in human acute
promyelocytic leukemia HL-60 cells (ED50 = 7.7 nM).5c
Scheme 1. Retrosynthetic Analysis of C17-Benzene Triene-
Ansamycins via Metal Catalyzed C-C Coupling
Following their stereochemical assignment,6 total synthe-
ses of trienomycins A and F and thiazinotrienomycin E
were reported by Smith,7a-c total syntheses of mycotrienol
I and mycotrienin I were reported by Panek,7d,e and a total
synthesis of cytotrienin A was reported by Hayashi.7f
Finally, Kirschning and Panek reported syntheses of the
ansatrienol and cytotrienin cores, respectively.8 Here, we
report initial efforts toward the development of a synthetic
approach to triene-containing C17-benzene ansamycins
featuring C-C bond forming hydrogenations and transfer
hydrogenations developed in our laboratory.9
closing metathesis, as established by Panek,8b would deliver
the C17-benzene triene-ansamycin core (Scheme 1).
Synthesis of fragment A, which embodies the character-
istic C17-benzene ansamycin stereotriad, begins with direct
carbonyl crotylation of allylic alcohol 1a10 mediated by
R-methyl allyl acetate 1b under the conditions of iridium
catalyzed transfer hydrogenation.11 High levels of anti-
diastereo- and enantioselectivity are obtained using the
isolated ortho-cyclometalated iridium C,O-benzoate preca-
talyst modified by (S)-SEGPHOS. As efforts toward corre-
sponding syn-diastereoselective processes are underway,11d
the present first-generation synthesis requires conversion of
the anti-adduct to the syn-diastereomer via Mitsunobu
inversion employing p-nitrobenzoic acid12 to deliver the
crystalline p-nitrobenzoate 3. Saponification of 3 followed
by Williamson ether synthesis provides the p-methoxyben-
zyl ether 5. Catalytic dihydroxylation to furnish 6 followed
by conversion to the acetonide completes the synthesis of
fragment A (Scheme 2).
The synthesis of fragment B begins with the Suzuki-
Molander coupling of 1-bromo-2,5-dimethoxy-3-nitro-
benzene with potassium ethenyltrifluoroborate.13 Hydro-
boration of the resulting vinylarene under standard con-
ditions employing 9-BBN occurred regioselectively, but
subsequent Suzuki coupling to produce 7 was problematic.
For this reason, Miyaura’s method for iridium catalyzed
Retrosynthetically, it was envisioned that diverse C17-
benzene ansamycins may be accessed through modular
assembly of fragments A-D. Specifically, Suzuki cross-
coupling of vinyl bromide A and the organoboron building
block B would deliver an arene-containing C11-C17 sub-
structure. Chelation-controlled pentadienylation of the
latent C11-aldehyde employing reagent C followed by
reduction of the nitroarene and amidation of the resulting
aniline with carboxylic acid D would provide a bis(diene),
which upon macrocyclization via ruthenium catalyzed ring
(8) For syntheses of the ansatrienol and cytotrienin cores, see: (a)
Kashin, D.; Meyer, A.; Wittenberg, R.; Schoning, K.-U.; Kamlage, S.;
Kirschning, A. Synthesis 2007, 304. (b) Evano, G.; Schaus, J. V.; Panek,
J. S. Org. Lett. 2004, 6, 525.
(9) For selected reviews on C-C bond forming hydrogenation and
transfer hydrogenation, see: (a) Ngai, M.-Y.; Kong, J. R.; Krische, M. J.
J. Org. Chem. 2007, 72, 1063. (b) Skucas, E.; Ngai, M.-Y.; Komanduri,
V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394. (c) Patman, R. L.;
Bower, J. F.; Kim, I. S.; Krische, M. J. Aldrichimica Acta 2008, 41, 95. (d)
Shibahara, F.; Krische, M. J. Chem. Lett. 2008, 37, 1102. (e) Bower, J. F.;
Kim, I. S.; Patman, R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48,
34. (f) Han, S. B.; Kim, I. S.; Krische, M. J. Chem. Commun. 2009, 7278.
(g) Bower, J. F.; Krische, M. J. Top. Organomet. Chem. 2011, 43, 107.
(10) Alcohol 1a was prepared using a variation of the literature
procedure: Fang, G.-H.; Yan, J.-Z.; Yang, J.; Deng, M.-Z. Synthesis
2006, 1148. Experimental details are included in the Supporting
Information.
(11) For enantioselective iridium catalyzed carbonyl crotylation
from the alcohol oxidation level, see: (a) Kim, I. S.; Han, S. B.; Krische,
M. J. J. Am. Chem. Soc. 2009, 131, 2514. (b) Itoh, J.; Han, S. B.; Krische,
M. J. Angew. Chem., Int. Ed. 2009, 48, 6313. (c) Bechem, B.; Patman,
R. L.; Hashmi, A. S. K.; Krische, M. J. J. Org. Chem. 2010, 75, 1795. (d)
Zbieg, J. R.; Fukuzumi, T. Adv. Synth. Catal. 2010, 352, 2416. (e) Han,
S. B.; Hassan, A.; Kim, I.-S.; Krische, M. J. J. Am. Chem. Soc. 2010, 132,
15559.
(12) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(13) For recent reviews, see: (a) Molander, G. A.; Figueroa, R.
Aldrichimica Acta 2005, 38, 49. (b) Molander, G. A.; Sandrock, D. L.
Curr. Opin. Drug Discovery Dev. 2009, 12, 811.
(14) Yamamoto, Y.; Fujikawa, R.; Umemoto, T.; Miyaura, N.
Tetrahedron 2004, 60, 10695.
Org. Lett., Vol. 13, No. 6, 2011
1483

Scheme 2. Synthesis of the Stereotriad-Containing Fragment A and Suzuki Cross-Coupling with Fragment Ba
a See Supporting Information for detailed experimental procedures.
acylation of the resulting amine 11 using cyclohexene
carboxylic acid delivers 12 (Scheme 4).
Scheme 3. Synthesis of Fragment Ba
Elaboration of 12 to the cytotrienin A core requires
preparation of diene-containing carboxylic acid D. Pre-
viously, carboxylic acid D was produced in 12 steps in 16%
overall yield.7f Hydrogen-mediated C-C coupling of
acetylene18 to the p-toluenesulfonate of hydroxy acetalde-
hydedeliversthe indicatedproductof (Z)-butadienylation,
which upon O-methylation and isomerization of the
diene19 provides the indicated (E)-homoallylic sulfonate.
Displacement of the p-toluenesulfonate by cyanide and,
finally, hydrolysis of the resulting nitrile furnishes car-
boxylic acid D in 7 steps from allyl alcohol in 32% overall
yield (Scheme 5). With carboxylic acid D in hand, com-
pound 12 is transformed to bis(diene) 13 via reduction of
a See Supporting Information for detailed experimental procedures.
hydroboration employing pinacol borane was used, which
delivered fragment Bin a regioselective fashion (Scheme 3).14
The Suzuki coupling of fragments A and B was espe-
cially challenging. However, after screening numerous
palladium sources and phosphine ligands, a remarkably
simple protocol was identified, in which fragments A and B
were exposed to Pd(dppf)Cl2 in the presence of sodium
hydroxide to furnish the product of C-C coupling 7 in
75% isolated yield (Scheme 2).
At this point, elaboration of 7 to the cytotrienin core was
set as an initial goal of our first-generation synthetic
approach to the C17-benzene triene-ansamycins. Toward
this end, exposure of 7 to periodic acid in ethyl acetate
solvent directly provides aldehyde 8,15 which was subjected
immediately to conditions for chelation-controlled16 pen-
tadienylation.17 Gratifyingly, the desired adduct 9 was
formed in a stereoselective fashion. To install the cytotrienin
side chain, Hayashi’s protocol was employed.7f Specifically,
alcohol 9 was converted to the R-azido-cyclopropane car-
boxylic ester 10. Reduction of the azide followed by
20
the nitroarene employing NaBH2S3 followed by acyla-
tion of the resulting aniline (Scheme 4).
Initial exploration of the ruthenium catalyzed ring-closing
metathesis (RCM) reaction of bis(diene) 13 and related
model systems revealed exceptional sensitivity to both the
catalyst and the substituent at C11. For example, in model
studies involving the corresponding C11 TBS-ether of
bis(diene) 13, RCM using the Grubbs-Hoveyda-II cata-
lyst occurred to deliver the diene product exclusively.
Eventually, itwasfoundthatdieneformationissuppressed
for O-acyl derivatives at C11 and, gratifyingly, the actual
cytotrienin A side chain proved to be ideal. Thus, using the
indenylidene analogue of the first generation Grubb’s
metathesis catalyst,21 bis(diene) 13 is converted to the
cytotrienin A core in 43% yield. Difficulties encountered
(18) (a) Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2006, 128,
16040. (b) Skucas, E.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc.
2007, 129, 7242. (c) Han, S. B.; Kong, J.-R.; Krische, M. J. Org. Lett.
2008, 10, 4133. (d) Williams, V. M.; Kong, J.-R.; Ko, B.-J.; Mantri, Y.;
Brodbelt, J. S.; Baik, M.-H.; Krische, M. J. J. Am. Chem. Soc. 2009, 131,
16054.
(19) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627.
(20) Lalancette, J. M.; Freche, A.; Brindel, J. R.; Laliberte, M.
Synthesis 1972, 526.
(15) (a) Wu, W.-L.; Wu, Y.-L. J. Org. Chem. 1993, 58, 3586. (b) Xie,
M.; Berges, D. A.; Robins, M. J. J. Org. Chem. 1996, 61, 5178. (c) Curti,
C.; Zanardi, F.; Battistini, L.; Sartori, A.; Rassu, G.; Azzas, L.; Roggio,
A.; Pinna, L.; Casiraghi, G. J. Org. Chem. 2006, 71, 225.
(16) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, Craig, E.
J. Am. Chem. Soc. 2001, 123, 10840.
€
(17) Seyferth, D.; Pornet, J.; Weinstein, R. M. Organometallics 1982,
1, 1651.
(21) Furstner, A.; Grabowski, J.; Lehmann, C. W. J. Org. Chem.
1999, 64, 8275.
1484
Org. Lett., Vol. 13, No. 6, 2011

Scheme 4. Elaboration of Suzuki Cross-Coupling Product 7 to the Cytotrienin Corea
a See Supporting Information for detailed experimental procedures.
In summary, we report a first-generation approach to the
C17-benzene triene-ansamycins, as demonstrated by the
synthesis of the cytotrienin A core in 17 steps from alcohol
1a (longest linear sequence). This study serves as a prelude
to second-generation routes of greater step economy, which
will incorporate syn-diastereo- and enantioselective carbo-
nyl crotylation of alcohol 1a and the use of phenolic
protecting groups amenable to late-stage cleavage.
Scheme 5. Synthesis of Diene-Containing Carboxylic Acid D via
Hydrogen-Mediated C-C Couplinga
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM069445), and the University of Texas at Austin,
Center for Green Chemistry and Catalysis for partial sup-
port of this research. The Humboldt Foundation is ac-
knowledged for postdoctoral fellowship support (M.R.).
a See Supporting Information for detailed experimental procedures.
Supporting Information Available. Characterization
data for all new compounds (1H NMR, 13C NMR, IR,
HRMS, [R]). This material is available free of charge via
the Internet at http://pubs.acs.org.
in the removal of the methyl ether functionality prevented
conversion of this material to the natural product.
Org. Lett., Vol. 13, No. 6, 2011
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