Vernolepin synthesis

Synthesis of a m-decalin system by the asymmetric cyclization[38] has been carried out with high enantioselectivity[142,143,147,148], Using BINAP as a chiral ligand, 91% ee was achieved in the asymmetric cyclization of 177 to give 178. In order to achieve an efficient asymmetric cyclization, selection of the reaction conditions is crucial, and sometimes added Ag salts play an important role[148], A catalytic asymmetric cyclization of 179 to prepare the key intermediate enone 180 for vernolepin synthesis has been carried out[149]. Highly efficient asymmetric cyclization of 181 to give the tetralin system 182 has been applied to the synthesis of (-)-eptazocine (183)[150], Hydrindans are synthesized in 86% ee[151]. 

Example Compound (27) was needed for synthesis of analogues of vernolepin, an anti-tumour compound. Robinson disconnection suggests unsymmetrical ketone (28)... 

Complete details of the previously reported total synthesis of the antitumour elemanolides vernolepin (363) and vernomenin (364) (Vol. 7, p. 97) have been published.Other research groups have reported the synthesis of compounds (365)—(367) which could be of considerable value as intermediates in alternative synthetic routes to vernolepin and vernomenin.The antitumour activity of... 

In one of the last transformations in a multistep synthesis of 1,2-dihydro-8-ep/-vernolepin (43), nucleophilic intramolecular substitution at an iodomethyl group was promoted by heating an ester precursor with an equivalent of NaOAc in DMF (Equation (18)) <95TL3ii>. Molecular mechanics analysis of the precursor produced a minimum energy conformer that showed the hydroxyl substituent too distant from the iodomethyl group to have interfered with this high yield transformation. 

In their search for suitable synthetic applications of their methodology, Shibasaki and coworkers spared no efforts and carried out an 18-step synthesis of lactone 35, which represents an early intermediate of Danichefsky s synthesis of (-i-)-vernolepin (Scheme 10) [14]. First, the ester 31 is transformed via 32 into the allylic alcohol 33, which is then cyclized with good enantioselectivities to yield the enone 34 (which is initially formed as an enol by /i-H-elimination). 

Scheme 10 Formal total synthesis of (+)-vernolepine according to M. Shibasaki.

This (formal) total synthesis of vernolepin deserves attention because of the elegance of the key step, which generates 34 in non-racemic form. However, the long and inefficient overall sequence impairs the competitiveness of the synthesis. 

This chemistry is part of a synthesis of the antitumour agent vernolepin by S. Danishefsky and group, J. Am. Chem. Soc., 1976, 98, 3028,... 

Depending on the catalytic species, palladium-catalyzed mono- and dicarbonyl-ation of alkynes may be achieved. Monocarbonylation of acetylenic alcohols in the presence of thiourea is an elegant route to a-methylene-7-butyrolactone 202, the structure of which is widely distributed in certain natural products98,99). The synthesis of a vernolepine derivative (203) has been attempted by this method 100l Pro-... 

Epoxides - The first indication of the synthetic utility of metalated carboxylic acids resulted from efforts to prepare steroidal aldosterone inhibitors from spiroepoxides.39 Model studies indicated that the reaction fails as a result of severe steric hindrance in either the epoxide or carboxylic acid and that monosubstitution occurs for the same reason.39 The reaction has been used in a key step of an elegant synthesis of vernolepin, 5. 40 Forcing conditions are required, and, in contrast to acid dianions, anions of unactivated esters fail to react with epoxides.39 41... 

The significant antitumour and cytotoxic properties of vernolepin (436) and, to a lesser extent, vernomenin (437) have stimulated general interest in the natural occurrence and total synthesis of 2,3-secoeudesmanolides or elemanolides cf. Vol. 8, p. 111). Two new alternative multi-step syntheses of vernolepin (436) have recently been accomplished by independent research groups using the reaction sequences outlined in Schemes 41 and 42. 

Pratt and Raphael needed the cyclohexenone (1) for a synthesis of the antitumour compound vernolepin. Disconnection of the a ,0 bond reveals the basic skeleton (2) no FGI is needed as all the FGs are carbonyl groups. 

In section 4.2.C.ii, LiAlH4 was used to reduce ozonides to the alcohol (sec. 4.2.C.ii). Sodium borohydride can be used in an identical manner,127 as seen in the ozonolysis of 95, where borohydride reduction gave 96 without reduction of the sensitive trimethylsilyl ester. 128 Subsequent hydrolysis gave lactone 97, a key intermediate in Heathcock s synthesis of vernolepin.128... 

The selective cleavage of a cyclopropane ring has also been used in a stereo-controlled total synthesis of the antitumor lactone vernolepin (10). A key step involved reaction of 4 with sodium p-methoxythiophenoxide, which was used rather than sodium thiophenoxide because the corresponding sulfoxide is less prone to i yw-elimination than a phenyl sulfoxide in the next step, 5 6. Remaining steps involved epoxidation and reduction to the diol (9). Conversion of 9 to 10 included hydrolysis, lactonization, and methylenation, accomplished in 227 yield. See structure on page 422. 

Cleavage of silyloxyalkenes. In the course of studies on the synthesis of vernolepin prototypes, Clark and Hcathcock encountered a novel ozonization of a silyloxyalkene (equation I). When the amount of O3 is controlled, no attack... 

Specific examples of the synthesis of natural products containing a-methylene-butyrolactone functions are to be found in the full reports from Danishefsky s group" and from Grieco s group " on the total synthesis of ( )-vernolepin (79) and its isomer, vernomenin Grieco et al. have also reported a synthesis of ( )-desoxyvernolepin " and demonstrated the use of the selenenation method for the introduction of an a-methylene substituent with a neat total synthesis of (+)-costunolide (80) from santonin," together with a general, stereochemically-... 

Kondo, K., Sodeoka, M., Mori, M. and Shibasaki, M. (1993) Asymmetric Heck reaction. A catalytic asymmetric synthesis of the key intermediate for vernolepin. Tetrahedron Lett., 34, 4219-22. 

The enantiotopic alkene approach was used in a synthesis of vernolepin 5.128, with p-hydride elimination proceeding away from the original alkene site, leading to a ketone 5.124 after tautomerization (Scheme 5.38). After a series of functional group interconversions and protecting group manipulation steps, a known intermediate 5.127 for vernolepin could be synthesized. When taken through to the end, this work also served to determine the absolute stereochemistry of this natural product. 

To provide an example of the use of a non-metal in synthesis, Grieco and coworkers have applied selenium chemistry twice in their synthesis of ( )-vernolepin... 

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