Vemolepin synthesis

The usefulness of this cis-decalin synthesis was demonstrated by an enantioselective synthesis of the sesquiterpene (+)-vemolepin 6.4 (Scheme 8G.6). Thus, Heck cyclization of the... 

Asymmetric cyclization using chiral ligands offers powerful synthetic methods for the preparation of optically active compounds [39]. After early attempts [40,41], satisfactory optical yields have been obtained in a number of cases. Synthesis of the optically active cA-decalin system [42] was carried out with high enantioselectivity based on the differentiation of enantiotopic C=C double bonds [43]. The cyclization of the triflate 93 gave the cA-decalin 94 with 95% ee in 78% yield using (i )-BINAP. A mixture of 1,2-dichloroethane and f-BuOH is the best solvent, and the asymmetric synthesis of vemolepin (96) via Danishefsky s key intermediate 95 has been achieved [44]. 

We could look at every possible C-C carbonyl disconnection and decide which we prefer. For any even moderately complex molecule, this can be an exhausting process and we shall do it for just one target molecule. Thereafter we shall choose disconnections as we go along and go back to the target only if that strategy proves poor. Pratt and Raphael1 needed the keto-diester 1 for a synthesis of the anti-tumour compound vemolepin. Our first disconnection is easy as the a, 3-unsaturated carbonyl unit suggests the classic aldol la disconnection to 2. 

Some fine examples of the synthetic use of this reagent are available in the literature for example in a total synthesis of vemolepin, intermediate (70), containing a fairly sensitive lactol ether unit, was selectively prepared by the use of chromium trioxide-dimethylpyrazole with formation of only 5% of the allylically rearranged product (equation 36). 

Deaminomethylation of terpenoid Mannich bases is frequently applied (Table 23, Chap. II, A.2) in order to create an unsaturated moiety in the molecule. The reaction has been carried out on the Mannich bases of c7.v-4-caranone, 2-pinene-4-one and sesquiterpene lactones, the.se last compounds being intermediates in the synthesis"- of tumor inhibitors vemolepin and vemomenin, which have a structure of typ 491. 

Heathcock and cowoikers in the course of their synthesis of vemolepin reacted the oxirane (8) with the diethylaluminum alkynide (9), when regiospecific ring opening of the oxirane occurred, leading to (10 Scheme 19). Interestingly, the stereoisomer (11) did not react under the same conditions. 

Other polycyclic systems that incorporate an activated cyclopropane structure reacted in a similar fashion when treated with sodium benzenethiolate or 4-methoxybenzenethio-late. This reaction was used in the total synthesis of ( )-vemolepin (20)/ ... 

The alkene that is attacked is an enol ether and is much more nucleophilic than the other simple alkene. Similarly nucleophilic reagents attack only alkenes that are conjugated with an electron-withdrawing group. Chemoselective epoxidation is usually straightforward. The peracid epoxidation is stereospeciiic the alkene 22 is E and so the epoxide 23 is trans (or anti). The other epoxidation is stereoselective as it is a two stage process and gives the more stable trans (or anti) epoxide 21 by choice. There is an example later in the synthesis of vemolepin. 

In connection with a synthesis of the hydroazulenic sesquiterpene kessanol (304), Knoevenagel condensation of photocitral-A (302) with ethyl cyanoacetate was found to give (303) as a single isomer. The following sequence includes an intramolecular Prins reaction initiated with SnCU. In Isobe s synthesis of vemolepin (307) the two carbons of the -y-iactone are introduced by a Knoevenagei condensation. Reaction of ketone (305) with di-f-butyl maionate followed by treatment with DBU affords (306), which is transformed to the a,a -dihydroxy compound (308). Hydrolysis of the esters foliowed by decarboxy-iation, formation of the y-lactone, Mannich reaction and elimination yields vemolepin (307 Scheme 58).3"... 

Geijerone (465) and y-elemene (466) have both been synthesized by reductive fragmentation of the keto-mesylate (468) which is readily available from the Wieland-Miescher ketone (467). Another synthesis of the key vemolepin... 

The first examples of intramolecular AHRs were reported by Shibasaki et al. [123] and Overman et al. [124] in 1989. The Shibasaki group carried out cycliza-tion of achiral alkenyl iodide or triflate 300 to give the chiral tetrahydronaph-thalene system 301 by differentiation of enantiotopic C=C double bonds using (i )-BINAP without using a silver salt [123]. Subsequently, the reaction has been improved [125]. The chiral hexahydronaphthalene system 304 with 86% ee was obtained by AHR of the bisallylic alcohol 302 via syn j6-H elimination from the intermediate 303, and 304 was converted to the key intermediate 305 in the synthesis of vemolepin (306). Use of a mixed solvent of 1,2-dichloroethane and r-BuOH is important [126]. 

Another reaction that has been successfully employed as an enantioselective desymmetrization processes is the Heck reaction. The Heck reaction, which is described in more detail in Chapter 19, couples an aryl or vinyl electrophile with an olefin. As shown in Equation 14.19, this reaction can be run as a desymmetrization in which the catalyst reacts preferentially at one of the enantiotopic olefins over the other to generate the intermediate enol that undergoes isomerization to the ketone product. This ketone as formed in 76% yield and 86% enantioselectivity and was an intermediate in the synthesis of vemolepin. ... 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treatment) from a total synthesis of ( )-physostigmine 203 (Scheme 31).The reaction occurs in 84% yield with 95% ee, which is remarkably efficient for the construction of a quaternary center. Reaction conditions that favor the neutral manifold of the Heck reaction are employed. Examination of the scope of the oxindole synthesis and mechanistic analysis have appeared. " Group selective reactions are also powerful reactions in carbopalladation asymmetric synthesis.From a synthesis of (+)-vemolepin 206, alkenyl triflate 204 is... 

In an early application, the aqueous Diels-Alder reaction of diene carboxy-lates was used to effect a very concise synthesis of the vemolepin precursor 5.2 [60]. This compound had previously been prepared by Schlessinger via another route in 11 steps from ethyl crotonate [61]. Reaction of the substituted methacrolein 5.3 with sodium ( )-3,5-hexadienoate (5.4) in water proceeded at 50 C to give the Diels-Alder endo adduct 5.5 along with a minor amount of the exo adduct (not shown) quantitatively in a ratio of 10/1 (Scheme 1.4). Sodium borohydride was added directly to this reaction mixture to produce the 6-hydroxycarboxylate 5.6, which lactonized spontaneously upon acidic workup. This one-pot operation resulted in the isolation of vemolepin AB-ring... 

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