Studies on the syntheses of benzoquinone ansamycin antibiotics. Syntheses of the C(5)-C(15) subunits of macbecin I, geldanamycin, and herbimycin A

Article abstract of DOI:10.1021/ol0607995

A general and convergent route to the C(5)-C(15) subunits of the benzoquinone ansamycin antibiotics macbecin I, geldanamycin, and herbimycin A is described. Each subunit is prepared by the stepwise coupling of differentially functionalized aldehydes with

Full text of DOI:10.1021/ol0607995

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2409-2412
Studies on the Syntheses of
Benzoquinone Ansamycin Antibiotics.
Syntheses of the C(5)−C(15) Subunits of
Macbecin I, Geldanamycin, and
Herbimycin A
Justin K. Belardi and Glenn C. Micalizio*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
glenn.micalizio@yale.edu
Received April 3, 2006
ABSTRACT
A general and convergent route to the C(5)−C(15) subunits of the benzoquinone ansamycin antibiotics macbecin I, geldanamycin, and herbimycin
A is described. Each subunit is prepared by the stepwise coupling of differentially functionalized aldehydes with a pentenyl dianion equivalent
derived from diastereoselective pentynylation and regioselective reductive coupling.
The benzoquinone ansamycin antibiotics, including the
macbecins, herbimycins, and geldanamycin, are a family of
benzoquinone-containing ansa-bridged macrocyclic lactams
that possess a significant range of antitumor, antibacterial,
antifungal, and antiprotozoal activities (Figure 1).1 Binding
of the ansamycin antibiotics to Hsp-90 results in a significant
decrease in cellular levels of various oncogenic tyrosine
kinases, while not affecting levels of the serine/threonine
kinases PKA or PKC.2 As such, members of the ansamycin
class of natural products have been targets for total synthesis,3
and have been explored as leads for the development of novel
anticancer therapeutics, with 17-allylaminogeldanamycin
currently in phase-II clinical trials.4 To date, the search for
more effective members of this class has been dominated
by semisynthesis (from derivatization of geldanamycin) and
engineered biosynthesissapproaches that are limited in their
ability to provide structurally diverse ansamycins.5 Although
a number of elegant syntheses of members of this class have
been described,3 new strategies are needed that enable the
preparation of diversely functionalized synthetic benzo-
quinone ansamycins to fuel the discovery of novel thera-
peutics.4
With the long-term goal of developing a synthetic pathway
of use for the discovery of novel benzoquinone ansamycins
with unique biological profiles, we initiated research aimed
(1) DeBoer, C.; Meulman, P. A.; Wnuk, R. J.; Peterson, D. H. J. Antibiot.
(Tokyo), 1970, 23, 442-447.
(2) Goetz, M. P.; Toft, D. O.; Ames, M. M.; Erlichman, C. Ann. Oncol.
2003, 14, 1169-1176.
Figure 1. Structures of benzoquinone ansamycin antibiotics.
10.1021/ol0607995 CCC: $33.50
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Published on Web 05/04/2006

at developing a general route to the stereochemically dense
region of these targets. Central to this goal was to define a
synthetic pathway that could address the natural structural
perturbations observed among the members of this class
(Figure 2), as well as to provide possibilities for additional
skeletal diversification.
Figure 3. Group 4 metal alkoxide-mediated coupling reactions for
polyketide assembly.
Figure 2. Structural diversity in the C(5)-C(14) segments of the
natural benzoquinone ansamycins: C(6), C(11), and C(15).
stereoselective pentynylation (5 f 6), in conjunction with a
titanium alkoxide-mediated coupling (6 f 7)7 can provide
general and flexible access to complex polyketides.
Herein, we describe a succinct and convergent approach
to the preparation of the stereochemically dense regions of
these natural productssthe C(5)-C(15) subunits of macbecin
I, geldanamycin, and herbimycin A (8)sby the convergent
assembly of functionalized aldehyde 9 with either the
R-methyl-â-silyloxy aldehyde 11 or glyceraldehyde acetonide
12 (Figure 4).
Recently, we reported a two-step process for ene-1,5-diol
synthesis based on the coupling of differentially function-
alized carbonyl electrophiles with a formal pentenyl dianion
equivalent (Figure 3).6 Our studies revealed that a dia-
(3) For total syntheses of members of the benzoquinone ansamycin family
of natural products, see: (a) Baker, R.; Castro, J. L. J. Chem. Soc., Chem.
Commun. 1989, 378-381. (b) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin
Trans. 1 1990, 47-65. (c) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.;
Tamai, T.; Tatsuta, K. Tetrahedron Lett. 1991, 32, 6015-6018. (d) Evans,
D. A.; Miller, S. J.; Ennis, M. D.; Ornstein, P. L. J. Org. Chem. 1992, 57,
1067-1069. (e) Evans, D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem.
1993, 58, 471-485. (f) Panek, J. S.; Xu, F. J. Am. Chem. Soc. 1995, 117,
10587-10588. (g) Panek, J. S.; Xu, F.; Rondon, A. C. J. Am. Chem. Soc.
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L.; Sekhar, B. B. V. S.; Hicken, E. J. Org. Lett. 2002, 4, 3549-3552. (i)
Aqndrus, M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B. L.; Glancey,
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G.; Panek, J. S. J. Am. Chem. Soc. 2005, 127, 15026-15027. For formal
syntheses, or partial syntheses, see: (l) Coutts, S. J.; Whittman, M. D.;
Kallmerten, J. Tetrahedron Lett. 1990, 31, 4301-4304. (m) Coutts, S. J.;
Kallmerten, J. Tetrahedron Lett. 1990, 31, 4305-4308. (n) Eshelman, J.
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Limberakis, C.; Burgess, L. E.; Hartmann, M. Tetrahedron 1999, 55, 3561-
3572.
Figure 4. Synthetic strategy for the C(5)-C(15) subunit of the
benzoquinone ansamycin antibiotics.
Our initial efforts focused on the synthesis of the macbecin
I C(5)-C(15) fragment 18 (Figure 5). Myers’ alkylation8 of
the Roche iodide 13,9 followed by LAB reduction (BH3‚
NH3, LDA, THF)8 of the amide provided the stereochemi-
cally defined primary alcohol 15 (dr 9:1). Oxidation to the
aldehyde (Dess-Martin periodinane, CH2Cl2),10 followed by
a double asymmetric11 pentynylation with the allenylstannane
(4) Uehara, Y. Curr. Cancer Drug Targets 2003, 3, 325-330.
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Schnur, R. C.; Corman, M. L.; Gallaschun, R. J.; Cooper, B. A.; Dee, M.
F.; Doty, J. L.; Muzzi, M. L.; Moyer, J. D.; DiOrio, C. I.; Barbacci, E. G.;
Miller, P. E.; O’Brien, A. T.; Morin, M. J.; Foster, B. A.; Pollack, V. A.;
Savage, D. M.; Sloan, D. E.; Pustilnik, L. R.; Moyer, M. P. J. Med. Chem.
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J.; Cooper, B. A.; Dee, M. F.; Doty, J. L.; Muzzi, M. L.; DiOrio, C. I.;
Barbacci, E. G.; Miller, P. E.; Pollack, V. A.; Savage, D. M.; Sloan, D. E.;
Pustilnik, L. R.; Moyer, J. D.; Moyer, M. P. J. Med. Chem. 1995, 38, 3813-
3820. (c) Tian, Z.-Q.; Liu, T.; Zhang, D.; Wang, Z.; Dong, S. D.; Carreras,
C. W.; Zhou, Y.; Rastelli, G.; Santi, D. V.; Myles, D. C. Bioorg. Med.
Chem. 2004, 12, 5317-5329. (d) Rastelli, G.; Tian, Z.-Q.; Wang, Z.; Myles,
D.; Lium Y. Bioorg. Med. Chem. Lett. 2005, 15, 5016-5021. (e) Le
Brazidec, J.-Y.; Kamal, A.; Busch, D.; Thao, L.; Zhang, L.; Timony, G.;
Grecko, R.; Trent, K.; Lough, R.; Salazar, T.; Khan, S.; Burrows, R.; Boehm,
M. F. J. Med. Chem. 2004, 47, 3865-3873. For an example of engineered
biosynthesis of geldanamycin analogues, see: (f) Patel, K.; Piagentini, M.;
Rascher, A.; Tian, Z.-Q.; Buchanan, G. O.; Regentin, R.; Hu, Z.; Hutchinson,
C. R.; McDaniel, R. Chem. Biol. 2004, 11, 1625-1633.
(6) (a) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc.
2005, 127, 3694-3695. (b) Bahadoor, A. B.; Micalizio, G. C. Org. Lett.
2006, 8, 1181-1184.
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alkynes and aldehydes, see: (a) Harada, K.; Urabe, H.; Sato, F. Tetrahedron
Lett. 1995, 36, 3203-3206. (b) Sato, F.; Urabe, H.; Okamoto, S. Chem.
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(8) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(9) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292-5800.
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2410
Org. Lett., Vol. 8, No. 11, 2006

Figure 6. Synthesis of C(5)-C(15) segments of herbimycin A
and geldanamycin.
BF3‚OEt2 and 12), oxidation (Dess-Martin periodinane,
CH2Cl2),10 and diastereoselective reduction (L-Selectride,
THF; ds g 20:1).14 In a similar fashion, the geldanamycin
fragment 22 was prepared via conversion of 17 to the
corresponding PMB ether (NaH, PMBCl, DMF), regio-
selective reductive coupling, oxidation, and diastereoselective
reduction.
In summary, we have defined a synthetic pathway to the
C(5)-C(15) polyketide fragments of the benzoquinone ansa-
mycin antibiotics macbecin I, geldanamycin, and herbimycin
A. The route is highly convergent, providing the stereo-
chemically dense region of these natural products by the
stepwise construction of three C-C bonds (C(12)-C(13),
C(10)-C(11), and C(7)-C(8)). Overall, the sequence pro-
ceeds in just six to eight steps from the Roche iodide 13,
and features a Myers’ alkylation, a diastereoselective pentyn-
ylation, and a regioselective titanium-mediated coupling
reaction with a functionalized aldehyde. On the basis of the
generality of these bond constructions, and the convergent
nature of the pathway to the ansa chains of these targets
(Figure 7), we expect that this pathway will be useful for
Figure 5. Synthesis of the C(5)-C(15) segment of macbecin I.
16 (BF3‚OEt2, CH2Cl2, -78 °C) provided the homopropar-
gylic alchol 17 (50% yield over two steps).12 Conversion to
the methyl ether (NaH, MeI, THF), followed by a regio- and
diastereoselective titanium alkoxide-based reductive coupling
with the R-methyl-â-silyloxy aldehyde 1113 (ClTi(Oi-Pr)3,
c-C5H9MgCl, -78 to -30 °C, then -78 °C, BF3‚OEt2 and
11) provided the fully functionalized C(5)-C(15) subunit
of macbecin I 18 (rs ) 9:1, ds ) 2.5:1). Although the product
was formed as a 2.5:1 mixture of diastereomers (favoring
the desired isomer), realization of this bond construction
results in a six-step linear synthesis of this complex
polyketide from the Roche iodide 13.9 Importantly, the pure
Felkin isomer was obtained by simple column chromatog-
raphy of the diastereomeric mixture of products.
Next, we examined the flexibility of this synthetic pathway
for the preparation of fragment precursors to the ansa chains
of herbimycin A and geldanamycin. As previously discussed,
the structural differences between these targets reside at three
positions in the ansa chain: C(6), C(11), and C(15). On the
basis of our synthetic route to the macbecin subunit 18,
substitution at C(6) can be varied by coupling of the
homopropargylic ether with a differentially functionalized
carbonyl electrophile, whereas the nature of the C(11)
substituent can be varied simply by protection of the
homopropargylic alcohol 17. These simple modifications of
our pathway are described in Figure 6.
First, the C(5)-C(15) subunit of herbimycin A (20) was
prepared from homopropargylic alcohol 17 by methyl-
ation (NaH, MeI, THF), regioselective reductive coupling
(ClTi(Oi-Pr)3, c-C5H9MgCl, -78 to -30 °C, then -78 °C,
(11) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1-30.
(12) (a) Marshall, J. A.; Wang, X. J. Org. Chem. 1992, 57, 1242-1252.
For a review of chiral allenylmetal reagents, see: (b) Marshall, J. A. Chem.
ReV. 1996, 96, 31-47. For the synthesis of allenylstannanes, see: (c)
Marshall, J. A.; Chobanian, H. Org. Synth. 2005, 82, 43-54.
(13) Heathcock, C. H.; Young, S. D.; Hagan, J. P.; Pilli, R.; Badertscher,
U. J. Org. Chem. 1985, 50, 2095-2105
Figure 7. Summary and future direction.
Org. Lett., Vol. 8, No. 11, 2006
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total syntheses of each member of this natural product class,
as well as for the synthesis of diverse benzoquinone
ansamycins. Progress made along these lines will be reported
in due course.
Arnold and Mabel Beckman Foundation, Boehringer Ingel-
heim, Eli Lilly & Co., and Yale University.
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge financial
support of this work by the American Cancer Society, the
(14) Sun, C.; Bittman, R. J. Org. Chem. 2004, 69, 7694-7699.
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