3-Vetivone synthesis

Two additional synthetic routes to ( )-j8-vetivone (350) have been developed. In one of these a suitably substituted spirocyclic system [cf. (349)] is constructed by addition of Me2CuLi to the fulvene derivative (348)/ Subsequent functional group modification (cf. Scheme 32) provides ( )-j8 -vetivone (350). In the other total synthesis d the well-known intramolecular alkylation of para-substituted phenols has been used to produce a spirocyclic intermediate (353) which can be converted into ( )-/3-vetivone (350) (cf. Scheme 33). 

In a total synthesis of (—)-/J-vetivone, the key step involves intramolecular alkylation of the bromo ketone 108 to give spiro ketone 111 (equation 47)169. The 5-Eto-Tet... 

This stereoselective Michael reaction provides a synthesis of (- )-vetivone (3) from a cyclohexenone (l).2... 

An excellent review of the isolation, structural elucidation, total synthesis, and postulated biosynthesis of sesquiterpenoids based on the spiro[4,5]decane (vetis-pirane) skeleton has been published." Further studies on the development of alternative routes to the vetispirane sesquiterpenoids have been described. In one report100 the spirocyclic acetal (217), previously used as an intermediate in the synthesis of (—)-a-acorenol (218),101,102 has been converted into (—)-agarospirol (219) and (-)-/3-vetivone (220) by the reaction sequence outlined in Scheme 26. 

The a./y alkylation ratio of the intramolecular nucleophilic substitution reaction of an a,y9-unsaturated cyclohexenone tosylate can also be controlled by the right choice of solvent. The desired y-alkylation - the final step of the total synthesis of the sesquiterpene yS-vetivone - is favoured by NaOH in CH3SOCH3/H2O, in contrast to (CH3)3C0K/(CH3)3C0H, which promotes a-alkylation [670],... 

Solvent effects. The final step of a total synthesis of 3-vetivone (2) involves the intramolecular y-alkylation of the -unsaturated ketone 1. Under a variety of base-solvent combinations 1 is converted into 4, the product of kinetically favored o-alkylation (70% using KO-t-Bu, t-BuOH). However, alkylation takes the desired course with NaOH in DMSO-HjO mixtures, the ratio 4/2 being dependent on the amount of water present. Best results are obtained with 25% aqueous DMSO (4/2 = 7 93). Actually, the /3-vetivone as obtained contains 7% of the lt)-epimer (3). 

A key step in the synthesis of 3-vetivone, a major constituent of vetiver, a perennial grass found in tropical and subtropical regions of the world, involved the reaction of compound A and dihalide B with two equivalents of LDA to form C. Draw a stepwise mechanism for this reaction. 3-Vetivone contains a spiro ring system—that is, two rings that share a single carbon atom. 

The last step in the synthesis of p-vetivone (Problem 23.55) involves treatment of C with CHsLi to form an intermediate X, which forms p-vetivone with aqueous acid. Identify the structure of X and draw a mechanism for converting X to p-vetivone. 

In this kind of cyclopropane ring-opening olefins are currently generated by elimination. An approach to spiro-vetivones and a synthesis of indole alkaloids (equation 48) take advantage of this property. 

In the l960s, Kropp showed that fused bicyclic dienones structurally related to santonin could potentially serve as synthetically useful precursors to either spirocyclic skeletons or hydroazulenones. One of these cases, 91, was successfully used by Marshall and Johnson as the starting point in an elegant synthesis of the spirocyclic sesquiterpene )6-vetivone (Scheme 23). More recently, a variety of bicyclic cyclohexadienones have been studied by Caine and coworkers. For example, bicyclic dienone 92 could be photochemically rearranged to the oxygenated bicyclo[4.3.0]nonenone system 93, along with other rearrangement products, via acetic acid solvolysis of the cyclopropyl ketone intermediate. ... 

By the use of appropriate dialkylating agents, it is possible to spiroannulate cyclohex-2-enones at the 6-position via kinetic lithium dienolates. This method was used by Stork et alP to prepare the enone (67), a key intermediate for the total synthesis of ( )-3-vetivone (Scheme 32). In the cycloalkylation step the cross-conjugated dienolate presumably adopts a conformation with the S-methyl group quasiaxial to the ring to avoid A -strain and the new C—C bond is formed trans to this group. 

Fluoride-induced desilylation-cyanation studies have been undertaken 138) with several electrophilic cyanogen type reagents. The best results were attained 138) when the 1-silyl-l-vinylcyclopropane shown in Scheme 65 was heated in a THF solution containing 4 equivalents of phenylcyanate. This reaction has been used 138> as a key step for the synthesis of ( )-hinesol and of (+)-P-vetivone (Scheme 65). 

Spiroketones have also been prepared from this aldehyde, such as spirovetivane, a constituent of Vetiver oil used in the perfume industry, and key intermediate for the synthesis of biogenetically related compounds such as a-vestipirene, -vetivone, hinesol, agarospirol. 

Robinson annelation. Marshall et al.2 achieved the total synthesis of racemic isonootkatone (a-vetivone, formula 12) as follows. Diethyl isopropylidenemalonate... 

On the basis of both synthetic and degradative studies, Marshall and co-workers have shown that the structure of -vetivone based on a bicyclo-[5,3,0]decane skeleton is untenable and subsequent work dictated the structure (326) incorporating a spiro[4,5]decane skeleton, and this they have confirmed by total synthesis. The method employed was the selective introduction of an isopropylidene group in a stepwise fashion starting with the keto-olefin (327), which was obtained via photolysis of the known dienone (328). 

A new general synthetic procedure for constructing cyclopentene derivatives [c/. (529)—(532)] has been illustrated by the completion of new synthetic routes to ( )-a-cuparenone (140) (Scheme 51) and ( )-/S-vetivone (538) (Scheme 52) 170.171 pyjj Qf tjjg previously reported synthesis of (+)-hinesol (540)t... 

This reaction has been developed into a synthesis of a number of spiroveti-vones. The first step involves the reaction of the sodium enolate of (4) with (1) to give the spiro ester (5) in 38% yield. The product was converted by known reactions into several known spirovetivones, for example, dZ- 3-vetivone (6) and d/-0 -vetispirene (7). 

The use of elegance in design can enable complex structures to be synthesised in a very efficient way, as demonstrated by Gilbert Stork s synthesis of p-vetivone. 

The dienone (7.26) is the key for both the synthesis of (7.25) as above and in Marshall s total synthesis of p-vetivone and its stereochemistry is important in the subsequent steps of the syntheses. Hence, it is... 

The structure of p-vetivone appeared as (7.21) in Figure 7.6 but this showed no stereochemistry. Figure 7.11 shows the stereochemical detail as (7.50). A brief inspection of the architecture of the molecule reveals two main challenges in its total synthesis. The first is the construction of the spirane system and the second is the introduction of both the methyl and isopropylidene groups in the correct relative stereochemical relationship to each other, i.e. both must be on the same side of the plane of the six-membered ring. 

There have been many syntheses of p-vetivone since that of Marshall and Johnson but perhaps the one that provides the greatest contrast is that of Gilbert Stork.710 One striking feature of Stork s synthesis is that it is essentially a two-pot synthesis. In one ingenious step, he builds the spirane system and does so with the correct stereochemistry. His reaction scheme, realised in collaboration with his co-workers Rick Danheiser and Bruce Ganem, is shown in Figure 7.13. 

The starting material for Stork s synthesis of 3-vetivone was shown in Chapter 7 to be prepared as shown in Figure PI9. Write a mechanism for this reaction. Why is the mono-enol form of the product more stable than the diketone ... 

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