Studies on the synthesis of the inostamycin natural products: A reductive aldol/reductive claisen approach to the C10-C24 ketone fragment

Article abstract of DOI:10.1021/ol0516115

(Chemical Equation Presented) An approach to the C₁₀-C ₂₄ ketone fragment of the inostamycin family of polyether antibiotics is described. The synthetic strategy utilizes an asymmetric Rh-catalyzed reductive aldol reaction and a ster

Full text of DOI:10.1021/ol0516115

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4867-4869
Studies on the Synthesis of the
Inostamycin Natural Products: A
Reductive Aldol/Reductive Claisen
Approach to the C10−C24 Ketone
Fragment
Nathan O. Fuller and James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories, The UniVersity of North
Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
morken@unc.edu
Received July 9, 2005
ABSTRACT
An approach to the C10−C24 ketone fragment of the inostamycin family of polyether antibiotics is described. The synthetic strategy utilizes an
asymmetric Rh-catalyzed reductive aldol reaction and a stereoselective Rh-catalyzed reductive Claisen rearrangement as the key steps in
formation of alkene and vinyl iodide synthons, respectively.
In the process of screening for inhibitors of phosphatidyl
inositol turnover, Imoto and Umezawa isolated inostamycin
A (Figure 1) from the culture broth of a microorganism from
and C from the culture broths of the same microorganism.2
The three inostamycins differ only in the functionality
occurring at the C2 position. Inostamycin A elicits a wide
range of pharmacological effects, showing inhibitory action
toward both phosphatidyl inositol turnover and inositol
transferase, while also possessing anti-HIV activity at 0.17
µM concentration, and anticancer activity against RPMI-8826
(GI50 ) 10 nM), HL-60 (GI50 ) 25 nM), and CCRF-CEM
(GI50 ) 32 nM) leukemia cell lines and some non-small cell
lung carcinoma cell lines.3 Inostamycins B and C also show
activity against Gram-positive bacteria in vitro comparable
to that of inostamycin A, and also show cytocidal activity
against src-NIH-3T3 cells, albeit with less potency than
Figure 1. The inostamycin natural products.
(1) Imoto, M.; Umezawa, K.; Takahashi, Y.; Naganawa, H.; Iitaka, Y.;
Nakamura, H.; Koizumi, Y.; Sasaki, Y.; Hamada, M.; Sawa, T.; Takeuchi,
T. J. Nat. Prod. 1990, 53, 825.
(2) Odai, H.; Shindo, K.; Odagawa, A.; Mochizuki, J.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1994, 47, 939.
the genus Streptomyces sp. MH816-AF15.1 Several years
later, Shindo et al. reported the isolation of inostamycins B
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hyde and phenyl crotonate, which provided â-hydroxy ester
5 in 76% yield and with 4.3:1 diastereoselectivity and 88%
enantioselectivity (Scheme 2).6 The phenyl ester was then
Scheme 1
Scheme 2
converted to the derived Weinreb amide and subsequently
treated with 2-lithiopropene to form R,â-unsaturated ketone
6.8 Protection of the free alcohol as a methoxymethyl ether
followed by chelation controlled reduction of the ketone9
(10:1 diastereoselectivity) and protection of the resulting free
alcohol as TBS-ether furnished protected allylic ether 3.
Our plan for the synthesis of vinyl iodide 4 involved the
application of the reductive Claisen rearrangement to install
the correctly configured C18 stereocenter.7 While our previous
studies found that this reaction proceeded with a high degree
of diastereoselectivity, no investigations into the level of
chirality transfer in the rearrangement process have been
carried out. To test the feasibility of this strategy in the
context of the inostamycin synthesis, we prepared allylic
acrylate 7. This was accomplished by Grignard addition to
2-ethylacrolein followed by Sharpless kinetic resolution10 and
esterification with acryloyl chloride (Scheme 3). Treatment
inostamycin A (IC50 values of 0.5 versus 0.07 µg/mL for
inostamycin A).2
While no synthetic endeavors toward the inostamycin
family of compounds have been reported, close structural
relatives ferensimycin B and lysocellin have been synthesized
by Evans4 and Yonemitsu and Horita,5 respectively. In their
report on ferensimycin B, Evans and co-workers utilized an
aldol coupling strategy as the final step to form the C9-
C10 bond between the ethyl ketone and aldehyde fragments
with the desired anti-aldol product being favored. An
analogous aldol coupling strategy was employed by Yone-
mitsu and Horita in their total synthesis of lysocellin. In our
approach to the inostamycin family of natural products, we
intended to make a similar aldol disconnection rendering a
C1-C9 aldehyde and a C10-C24 ketone as subtargets in the
total synthesis. The structural complexity and functionality
inherent in these fragments provided an excellent opportunity
to explore the synthetic utility of both reductive aldol6 and
reductive Claisen7 methodologies developed in our lab. In
this paper, we describe our approach to the C10-C24 ketone
fragment of the inostamycins, which we envisioned arising
from the oxidative transformation of diene 2 obtained from
tandem hydroboration/B-alkyl Suzuki coupling of alkene 3
and vinyl iodide 4 (Scheme 1).
Scheme 3
The synthesis of ketone 1 began with the Rh-catalyzed
asymmetric reductive aldol reaction between propionalde-
(3) (a) Umezawa, K. AdV. Enzyme Regul. 1995, 35, 43. (b) Baba, Y.;
Tsukuda, M.; Mochimatsu, I.; Furukawa, S.; Kagata, H.; Nagashima, Y.;
Sakai, N.; Koshika, S.; Imoto, M.; Kato, Y. Clin. Exp. Metastasis 2000,
18, 273. (c) Baba, Y.; Tsukuda, M.; Mochimatsu, I.; Furukawa, S.; Kagata,
H.; Nagashima, Y.; Koshika, S.; Imoto, M.; Kato, Y. Cell Biol. Int. 2001,
25, 613.
(4) Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.;
Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613.
(5) (a) Horita, K.; Inoue, T.; Tanaka, K.; Yonemitsu, O. Tetrahedron
1996, 52, 531. (b) Horita, K.; Inoue, T.; Tanaka, K.; Yonemitsu, O.
Tetrahedron 1996, 52, 551.
(6) (a) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc.
2000, 122, 4528. (b) Zhao, C. X.; Duffey, M. O.; Taylor, S. J.; Morken, J.
P. Org. Lett. 2001, 3, 1829. (c) Russell, A. E.; Fuller, N. O.; Taylor, S. J.;
Aurriset, P.; Morken, J. P. Org. Lett. 2004, 6, 2309. (d) Fuller, N. O.;
Morken, J. P. Synlett 2005, 9, 1459.
of compound 7 with [Rh(cod)Cl]2 in the presence of Cl2-
MeSiH and (S,S)-Me-DuPhos led to the formation of 9 in
88% yield and with 86% ee.11 Thus the reductive Claisen,
(8) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.
(7) Miller, S. P.; Morken, J. P. Org. Lett. 2002, 4, 2743.
(9) Boger, D. L.; Curran, T. T. J. Org. Chem. 1992, 57, 2235.
4868
Org. Lett., Vol. 7, No. 22, 2005

in this instance, occurred with 92% chirality transfer, a level
consistent with previously reported levels of diastereoselec-
tivity in the reductive Claisen rearrangement.7 Presumably,
the reaction proceeds through the intermediacy of an (E)-
silyl ketene acetal as is generated from allylic acrylates upon
reduction with Rh/Duphos and Cl2MeSiH.12 Subsequent
rearrangement via a six-membered chair transition state such
as 8 is consistent with the observed stereochemical outcome
of the reaction (Scheme 3). At this point, it is not clear
whether the small amount of erosion in enantiomeric purity
arises from a competing boat transition structure in the
Claisen rearrangement or from imperfect E/Z selectivity in
reduction of the acrylate to the silylketene acetal.
Scheme 5
The γ,δ-unsaturated carboxylic acid 9 obtained from the
reductive Claisen rearrangement was then converted to
aldehyde 10 via a reduction/oxidation sequence and thereafter
converted to alkyne 11 by the Corey-Fuchs reaction
(Scheme 4).13 Analysis of the enantiomeric purity at this stage
Scheme 4
12 with a 6:1 diastereomer ratio. Fortuitously, subsequent
epoxidation of bishomoallylic alcohol 12 was sufficiently
slow, relative to the oxidation of starting material 2, that the
monooxidation adduct could be isolated. This allowed for
protecting group manipulation in preparation for oxidation
of the remaining alkene.18 Under acidic conditions, the MOM
protecting group was removed to give 13 and at this stage
the relative stereoinduction in the epoxidation/cyclization
sequence was determined by NOESY analysis. Subsequently,
both free alcohols were then protected as TES-ethers,
providing 14. With the C10-C24 carbon framework con-
structed, and easily removable alcohol protecting groups in
place, current efforts are being directed toward developing
the oxidation strategy for the C20-C21 alkene and conversion
to 1.
In summary, we have described an expeditious and
convergent route that constructs the requisite carbon skeleton
of the C10-C24 ketone fragment of the inostamycin natural
products. This pathway involves the use of two Rh-catalyzed
methodologies developed in our lab and showcases their
utility in the rapid construction of a complex structural
subunit of an important natural product. Further studies on
the synthesis of the inostamycin family of natural products
will be reported in due course.
indicates that the allylic stereocenter was not racemized
during the reaction sequence. Hydrozirconation of the methyl
alkyne with Schwartz’ reagent and iodinolysis of the vinyl
zirconium intermediate with iodine provided vinyl iodide 4.14
The union of subunits 3 and 4 was accomplished by
carrying out a stereoselective hydroboration15 of alkene 3
with 9-BBN and effecting a Suzuki-Miyaura coupling of
the intermediate alkyl borane with vinyl iodide 4 to provide
diene 2 in a 91% yield for the tandem process (Scheme 5).16
Initial exploratory studies of the oxidative cyclization were
conducted. In the event, deprotection of the TBS-ether 2
was then followed by a bis-homoallylic alcohol directed
vanadium-catalyzed epoxidation.17 As expected based on
Evans’ studies in the ferensimycin synthesis, the intermediate
epoxide underwent cyclization to provide trisubstituted furan
Acknowledgment. This work is supported by the NIH
(GM-64451), Bristol-Myers Squibb, and a fellowship for
Scientists and Engineers from the David and Lucile Packard
Foundation.
(10) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(11) As expected, the same level of chirality transfer occurs regardless
of which enantiomer of chiral ligand is employed.
(12) Zhao, C. X.; Bass, J.; Morken, J. P. Org. Lett. 2001, 3, 2839.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron 1972, 13, 3769.
(14) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679.
(15) Still, W. C.; Barish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
(16) (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369. (b) Review: Chemler, S. R.; Trauner, D.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2001, 40, 4544.
Supporting Information Available: Characterization
data, spectra, and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0516115
(17) (a) Fukuyama, T.; Vranesic, B.; Negri, D. P.; Kishi, Y. Tetrahedron
Lett. 1978, 19, 2741. (b) Review: Hoveyda, A. H.; Evans, D. A.; Fu, G. C.
Chem. ReV. 1993, 93, 1307.
(18) Evans has shown that oxidation of the C20-C21 alkene is a delicate
task, and great care must be taken to avoid irreversible formation of a
bicyclic ketal (see ref 4).
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