Total synthesis of the Hsp90 inhibitor geldanamycin

Article abstract of DOI:10.1021/ol800749w

(Chemical Equation Presented) An enantioselective synthesis of the Hsp90 inhibitor geldanamycin was achieved in 20 linear steps and 2.0% overall yield from 2-methoxyhydroquinone. The synthesis is highlighted by a regio- and stereoselective hydroboration r

Full text of DOI:10.1021/ol800749w

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2477-2479
Total Synthesis of the Hsp90 Inhibitor
Geldanamycin
Hua-Li Qin and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
panek@bu.edu
Received April 2, 2008
ABSTRACT
An enantioselective synthesis of the Hsp90 inhibitor geldanamycin was achieved in 20 linear steps and 2.0% overall yield from 2-methoxyhydroquinone.
The synthesis is highlighted by a regio- and stereoselective hydroboration reaction; a Sc(OTf)3/Et3SiH-mediated pyran ring-opening reaction; an
enantioselective crotylation to simultaneously install the C8–C9 (E)-trisubstituted olefin, the C10 and C11 stereocenters; a chelation-controlled asymmetric
metallated acetylide addition; and an intramolecular copper(I)-mediated aryl amidation reaction to close the 19-membered macrolactam.
Heat shock protein 90 (Hsp90) is a molecular chaperone that
regulates folding, transport, and degradation of client proteins.
It also plays a key role in the conformational maturation of
oncogenic signaling proteins.1 Hsp90 ATPase binding region’s
role in cancer and protein maintenance as well as its broad range
of functions make it a significant therapeutic target for anticancer
drug development.1d,e
Geldanamycin, a natural product isolated from Streptomyces
hygroscopicus var. geldanus var. noVa in 1970,2 is the first
reported Hsp90 inhibitor. It is currently under development as
a therapeutic agent for cancers associated with abnormally
elevated levels of receptor tyrosine kinase activity.3a Studies
have shown that the Hsp90 client proteins can be destabilized
when geldanamycin binds to the ATP-binding site of Hsp90
and inhibits the chaperone activity of the protein.3 Accordingly,
several geldanamycin analogues are in various stages of
(1) (a) Rutherford, S. L.; Lindquist, S. Nature 1998, 396, 336. (b) Young,
J. C.; Moarefi, I.; Hartl, F. U. J. Cell Biol. 2001, 154, 267. (c) Picard, D.
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Dodge, J. A.; Burgess, L. E.; Limberakis, C.; Hartmann, M. Tetrahedron
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(5) For syntheses of herbimycin, see: (a) Nakata, M.; Osumi, T.; Ueno,
A.; Kimura, T.; Tatsuta, K. Tetrahedron Lett. 1991, 32, 6015. (b) Nakata,
M.; Osumi, T.; Ueno, A.; Kimura, T.; Tatsuta, K Bull. Chem. Soc. Jpn.
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(7) For the synthesis of reblastatin, see: Wrona, I. E.; Gabarda, A. E.;
Evano, G.; Panek, J. S. J. Am. Chem. Soc. 2005, 127, 15026.
10.1021/ol800749w CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society

development as novel antitumor agents and as chemotherapeutic
agents in a number of diseases.4
chemistry while simultaneously creating the C8-C9 (E)-
trisubstituted olefin.
Recently, we have reported the selective hydridic opening
of aryl C-glycosides using a Sc(OTf)3/Et3SiH-mediated reduc-
tion of the benzylic C-O σ-bond resulting in the formation of
a stereochemically well-defined acyclic system.10
Geldanamycin, together with herbimycin A,5 macbecin I,6
and reblastatin,7 are members of the ansamycin class of natural
products (Figure 1). Geldanamycin differs at C6, C11, C15,
The synthesis of the C6-C21 fragment 7 (Scheme 2) started
from functionalized aromatic aldehyde 10, which was easily
Scheme 2. Synthesis of Aromatic C6-C21 Fragment 7
Figure 1. Geldanamycin and related ansamycin antibiotics.
and C17 from macbecin I and herbimycin A. Presently, one
total synthesis of geldanamycin has been described.8 Herein,
we report the total synthesis of geldanamycin as part of our
ongoing studies of ansamycins.
Our strategy for the synthesis of geldanamycin (1) is shown
in Scheme 1. We envisioned the 19-membered macrocycle
Scheme 1. Retrosynthetic Analysis of Geldanamycin
obtained in three steps from commercially available 2-meth-
oxyhydroquinone in 55% overall yield. [4 + 2]-Annulation of
this aldehyde with silane 11 provided a mixture of dihydropy-
rans 12 and 13 in 84% yield (trans/cis: 4:1).11 Regio- and
stereoselective hydroboration of the pyran double bond provided
the secondary alcohol, which was subsequently methylated with
Meerwein’s reagent to provide tetrahydropyran 14 in good yield
and excellent selectivity (dr > 20:1). Reductive opening of
pyran 14 with Sc(OTf)3/Et3SiH gave a mixture of 15 (which
was easily converted to 16 in 95% yield) and 16 in excellent
yield, essentially deoxygenating C15 (cf. macbecin). Reduction
of ester 16 with LiBH4 afforded the 1,2-diol, which was
subjected to oxidative cleavage using sodium periodate to
furnish the R-methoxyaldehyde 9.
would be formed from the acylic amide 5 through an intramo-
lecular aryl amidation reaction similar to that described in our
synthesis of reblastatin.7,9 The (E,Z)-diene could be installed
by reduction of the enyne from alkynylation of precursors 6
and 7 which could be generated from easily accessible
aldehyde 9 and chiral silane reagent 8. Organosilane 8 has
unique features as it establishes the C10-C11 syn stereo-
At this point, we turned toward the generation of the C7,
C10, and C11 stereocenters and the installation of the trisub-
stituted alkene. Gratifyingly, after a variety of conditions were
explored, a double-stereodifferentiating crotylation12 of silane
8 and aldehyde 9 promoted by BF3·OEt2 provided benzyloxy
(8) (a) Andrus, M. B.; Meredith, E. L.; Simmons, B. L.; Sekhar,
B. B. V. S.; Hicken, E. J. Org. Lett. 2002, 4, 3549. (b) Andrus, M. B.;
Meredith, E. L.; Hicken, E. J.; Simmons, B. L.; Glancey, R. R. J. Org.
Chem. 2003, 68, 8162.
(10) Qin, H.-L.; Lowe, J. T.; Panek, J. S. J. Am. Chem. Soc. 2007, 129,
38.
(11) (a) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 1529. (b) Huang,
H.; Panek, J. S Org. Lett. 2003, 5, 1991. (c) Huang, H.; Panek, J. S. J. Am.
Chem. Soc. 2000, 122, 9836.
(9) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421
.
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Org. Lett., Vol. 10, No. 12, 2008

homoallylic ether bearing not only the three desired stereo-
centers and trisubstituted alkene, but also a benzylic ether
protecting group at C11. The reaction proceeded in 70% yield
with high selectivity (dr ) 9:1). Reduction of the product methyl
ester with DIBAL-H yielded aldehyde 7.
To access (E,Z)-unsaturated macrocycle 19 through the
intermediacy of bromo ester 17, aldehyde 7 was homologated
through diastereoselective addition13 of a metallated acetylide
(Scheme 3). Accordingly, fragment 17 was obtained through
intramolecular copper(I)-mediated aryl amidation reaction to
provide the desired macrocyclic lactam in 81% yield. Depro-
tection of the MOM ether was achieved utilizing anhydrous
HCl/Et2O/MeOH to obtain the secondary alcohol in nearly
quantitative yield without affecting other protecting groups. The
secondary alcohol was then converted to the desired carbamate
19 in 88% yield.7,18 Finally, deprotection of both the diiso-
propyl and benzyl ethers was accomplished with AlCl3 in
the presence of anisole19 to generate dihydrogeldanamycin,
which was immediately treated with catalytic palladium on
carbon20 (10%) under air atmosphere to give geldanamycin
in 55% yield over two steps. The spectroscopic data obtained
for synthetic material were in agreement with those for
authentic geldanamycin (optical rotation, 1H and 13C NMR,
IR, and HRMS).21
Scheme 3. Completion of the Total Synthesis of Geldanamycin
In summary, we achieved the total synthesis of geldanamycin
in 20 linear steps and 2.0% overall yield from commercially
available 2-methoxyhydroquinone. Notable features of our
synthetic route include the following: a concise synthesis of
the C11-C21 fragment through reductive pyran-opening ap-
proach; an efficient and selective crotylation with silane 8 that
simultaneously set two stereocenters (C10, C11), created an (E)-
trisubstituted olefin, and put the stereocenter C7 in place; an
asymmetric alkynylation to install stereocenter C6; and the first
example of synthesis of the E,Z-diene of ansamycins through
Lindlar reduction of the enyne precursor.22 An intramolecular
copper(I)-mediated amidation reaction was used to close the
19-membered macrolactam.
Acknowledgment. Financial support for this research is
obtained from NIH CA56304. J.S.P. is grateful to Amgen,
AstraZeneca, Johnson & Johnson, Merck Co., Novartis, Pfizer,
and GSK for financial support of our programs. We are grateful
to Pfizer for the providing an authentic sample of geldanamycin.
We are grateful to Mr. Jason Lowe (Boston University) and
Ms. Iwona Wrona (Boston University) for helpful discussions.
Supporting Information Available: Experimental details
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
chelation-controlled coupling of acetylene 6 and aldehyde 7 in
76% yield (dr ) 10:1).14,15
OL800749W
To complete the synthesis, methylation of propargylic alcohol
17 using NaH and MeI occurred with simultaneous dealkylation
of the ester to the corresponding acid16 and gave the enyne-acid
18 in 87% yield, which was subjected to Lindlar reduction.17
The resulting acid was subsequently converted to the (E,Z)-
unsaturated amide 5. The amide 5 was then subjected to an
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propargylic alcohols were unsuccessful with the illustrated reaction partners:
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1321 Other conditions such as BCl3, AlCl3 alone, BCl3·SMe2, BBr3, and
other Lewis acids or hydrolysis were screened which resulted in either
incomplete reaction or decomposition.
(20) (a) Luly, J. R.; Rapoport, H. J. Org. Chem. 1984, 49, 1671. (b)
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(21) Authentic geldanamycin was provided by Pfizer, and experiments
to obtain spectroscopic data were carried out at Boston University Chemical
Instrumentation Center.
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J. K.; Micalizio, G. C. Angew. Chem. Int. Ed 2008, 47, Early View.
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