Enantiospecific total synthesis of macrolactone Sch 725674

Article abstract of DOI:10.1021/ol5018678

The enantiospecific total synthesis of 14-membered macrolactone Sch 725674 was accomplished from tartaric acid. Key reactions in the synthesis include the Ley's dithiaketalization of an alkynone derived from the bis-Weinreb amide of tartaric acid, Boord o

Full text of DOI:10.1021/ol5018678

Letter
pubs.acs.org/OrgLett
Enantiospecific Total Synthesis of Macrolactone Sch 725674
Amit K. Bali, Sunil K. Sunnam, and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
S
* Supporting Information
ABSTRACT: The enantiospecific total synthesis of 14-membered macrolactone Sch
725674 was accomplished from tartaric acid. Key reactions in the synthesis include the
Ley’s dithiaketalization of an alkynone derived from the bis-Weinreb amide of tartaric
acid, Boord olefination, and ring-closing metathesis of an acrylate ester.
ch 725674 (1) is a 14-membered macrolactone isolated
from the culture of Aspergillus by chemists at the Schering-
Scheme 1. Retrosynthesis for Sch 725674 (1)
S
Plough Co.1 Structurally, the macrolactone possess three free
hydroxy groups (two of them contiguous) and a (E)-α,β-
unsaturated ester (Figure 1). A solitary total synthesis of Sch
Figure 1. Macrolactone Sch 725674 (1).
725674 was reported by the Curran group using their
trademark fluorous tagging technology, which also established
the absolute stereochemistry of the chiral centers present in
macrolactone.2 Recently, we disclosed an approach to the
macrolactone core of Sch 725674 from chiral furyl carbinol.3 In
continuation of our efforts, herein, we report the total synthesis
of Sch 725674.
We anticipated the formation of 1 by ring-closing metathesis
of the acryloyl ester 2 possessing three free hydroxy groups.
Although RCM is widely used for macrolactone formation, the
use of acryloyl esters in the formation of macrolactones of a
higher ring size is not so common.4 Synthesis of the acryloyl
ester 2 was envisaged from the iodide 3 via Boord olefination
followed by subsequent deprotection of the 1,3-acetonide. The
synthesis of 3 was planned by elaboration of the 1,3-
dithianylketone 4, the synthesis of which was envisioned by
Ley dithiaketalization5 of the alkynone in 5 with 1,3-
propanedithiol. Desymmetrization of the bis-Weinreb amide 6
derived from tartaric acid by controlled addition of alkynyl
Grignard reagent was envisaged for the synthesis of the
alkynone 5 (Scheme 1).
Accordingly, the synthetic sequence commenced with the
addition of hex-5-en-1-ynylmagnesium chloride (prepared in
situ from propargyl bromide and allylmagnesium chloride) to
the bis-Weinreb amide 66 to afford the alkynyl ketone 5 in 63%
yield.7 Ley’s dithianylation5 of the alkynyl ketone 5, involving
the addition of 1,3-propanedithiol, afforded the 1,3-dithianyl
ketone in 97% yield. Olefin cross-metathesis of the alkene in 4
with the chiral homoallylic alcohol 78 furnished the extended
alkene 8 in 67% (87% brsm) yield.9 Stereoselective reduction of
the ketone in 8 with excess NaBH4 not only afforded the
secondary alcohol but also reduced the Weinreb amide to the
corresponding primary alcohol to yield the triol 9 in 95%
yield.10 Deprotection of the dithiane in 9 using MeI/CaCO3
produced the corresponding β-hydroxy ketone 10 which, on
reduction with tetramethylammoniumtriacetoxy borohydride11
Received: June 27, 2014
Published: July 17, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
(Evans’ reagent), furnished the 1,3-anti-diol 11 in 84% yield.
Hydrogenation of the olefin in 11 produced the saturated tetrol
12 in 94% yield (Scheme 2).
Scheme 3. Total Synthesis of Sch 725674 (1)
Scheme 2. Synthesis of the Tetrol 12
2.6% overall yield from the bis-Weinreb amide of tartaric acid.
Key steps include the synthesis of a chiral alkynone from the
desymmetrization of a tartaric acid amide with a functionalized
alkynyl Grignard reagent and a Ley dithiaketalization of the
alkynone. Ring-closing metathesis of the acryloyl ester was used
to assemble the macrolactone.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and copies of the NMR spectra of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
After successfully assembling the tetrol 12, the primary
alcohol in 12 was selectively transformed to the iodide 3, via
the formation of the tosylate 13, iodination of the tosylate, and
1,3-diol protection as its corresponding acetonide in 73% yield.
Acryloylation of the free alcohol in 3 furnished the acrylate 14
in 78% yield. The key Boord olefination reaction of 14 with
zinc dust in ethanol at reflux produced the required acryloyl
ester 2 in 57% yield along with the allyl alcohol 15 (8% yield)
and the 1,2-acetonide 16 (19% yield). Ring-closing metathesis
of the acryloyl ester 2 with Grubbs’ second-generation catalyst
furnished the macrolactone Sch 725674 (1) in 36% yield,12 the
spectral and physical data of which were in complete agreement
with those reported by the Curran group2 (Scheme 3).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: prasad@orgchem.iisc.ernet.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.K.B. thanks the Council of Scientific and Industrial Research,
New Delhi, India, for a research fellowship. We thank Prof.
Dennis P. Curran, University of Pittsburgh, for providing us
copies of the theses of Dr. J. D. Moretti and Dr. X. Wang.
In conclusion, the total synthesis of the macrolactone natural
product Sch 725674 has been accomplished in 12 steps and
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Letter
DEDICATION
■
This paper is dedicated with warmth and respect to Prof.
Franklin A. Davis, Temple University, on the occasion of his
75th birthday.
REFERENCES
■
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(7) Compound 5a was also isolated in 23% yield in the reaction
arising from the Michael addition of the released Weinreb amine to the
ynone 5.
(8) Homoallylic alcohol 7 was prepared by Keck allylation of hexan-
1-al with allyltributyltin according to the procedure described
previously. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am.
Chem. Soc. 2003, 125, 1708. (b) Also, see ref 3..
(9) The dimer resulting from the dimerization of the homoallylic
alcohol 7 is also formed. See the Supporting Information for
characterization of the dimer.
(10) Formation of the other diastereomer was not observed within
detectable limits in 1H NMR spectrum. Attempted selective reduction
of the keto group in 8 was always accompanied by formation of the
1,4-diol 9, and the purification was very cumbersome. Hence, both
keto and the amide groups were reduced to the 1,4-diol 9 with excess
NaBH4.
(11) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
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(12) Performing the reaction at higher dilution with the slow
addition of either 2 to the catalyst or catalyst to the ester 2 (with the
aid of syringe pump) did not improve the yield of the reaction. In
addition, performing the reaction with Hoveyda−Grubbs’ second-
generation metathesis catalyst did not yield the desired product and
resulted in a number of unidentifiable mixture of products.
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