Synthesis of caryophyllene

The total synthesis of caryophyllene and its Z-isomer involved a photochemical [2 + 2] cycloaddition reaction to generate the 4-membered ring and a fragmentation process Helv. Chim. Acta, 1951, 34, 2338) to establish the 9-membered ring. Caryophyllene and various oxygenated derivatives protect plants against insects. 

Therefore, a rational synthesis of caryophyllenes should be designed in such a way that after proceeding through a series of common intermediates at a given step they may offer the opportunity to exert a stereochemical control in the formation of the endocyclic double bond. In this context, the synthesis reported by Corey as early as 1964 [1] is still more efficient than more recent syntheses in which only one isomer (isocaryophyllene, lb) is formed [2] or that require parallel synthetic sequences which start from compounds which are only remotely related to each other [3]. 

Corey Eaton, de Mayo - and many others began to investigate the various synthetic and mechanistic ramifications of the photocycloaddition which resulted in the total synthesis of caryophyllene " and bour-bonene" as well as a proposed mechanistic rationale for the reaction. Subsequently, numerous natural and unnatural products have been prepared by synthetic routes which have a [2 -t- 2] photocycloaddition as a crucial step in their synthesis, and the reaction has become recognized as an important transformation in the repertoire of the synthetic organic chemist. 

Corey utilized the reaction of apprc riately substituted 1,3-hydrindanediol monotosylates for the introduction of the cyclononene moiety in an elegant synthesis of caryophyllene and its isomers (Scheme 2) Some further examples will be found in two recent reviews. ... 

Propose a mechanistic pathway for the bio,synthesis of caryophyllene, a substance found in clove oil. 

The synthesis of caryophyllene was another major challenge for the synthetic chemist and again it was E. J. Corey who rose to meet it.7 18,7 19... 

Both inter- and intramolecular [2-1-2] cycloaddition reactions have been used in synthesis. In intermolecular reactions, a common problem is that mixtures of regioisomers (sometimes referred to as head-to-tail and head-to-head products) in addition to more than one stereoisomer may be formed. In general, the head-to-tail regioisomer is the major product using an electron-rich alkene, whereas the head-to-head regioisomer is favoured using an electron-deficient alkene. For example, the first step in Corey s synthesis of caryophyllene involved addition of cyclohexenone to isobutene to give predominantly the trans-cyclobutane (head-to-tail) derivative 151 (3.107). 05... 

When trans-cyclododecen-3-ol is subjected to CH2l2-Cu/Zn treatment the trans,anti-bicyclotridecane (66) is produced in a highly stereoselective manner. The Simmons-Smith cyclopropanation procedure has also been employed in a new synthesis of (+ )-caryophyllene and in the preparation of the parent cyclohepta[a]acenaphthyl-enyl cation. ... 

To give you an idea of the kind of thinking required for the synthesis of a complicated molecule, we will look at the S5mlhesis of lysergic acid, which was done by R. B. Wo ward, and the synthesis of caryophyllene, which was done by E. J. Corey. Woodward (in 1965) and Corey (in 1990) both received the Nobel Prize for their contributions to synthetic organic chemistry. 

The potential of this type of reaction, as a key step in the synthesis of natural products, was first shown by Corey in his landmark synthesis of caryophyllene (Eq. (72.2)). ... 

The synthesis of hydroxy ketone A, via a different reduction process as shown below ... 

The sesquiterpenoids caryophyllene and its geometrical isomer occur naturally in the oil of cloves. Plan a synthesis of a suitable starting material containing a four membered ring ... 

A new elegant stereoselective synthesis of humulene (192) has been achieved by a route (Scheme 22) in which the 11-membered-ring framework [cf. (191)] is produced by cyclization of the 11-allylpalladium complex derived from intermediate (190). Buddledin-A (193), -B (194), and -C (195) are new piscicidal sesquiterpenoids which have recently been isolated from the root bark of Buddleja davidiC The caryophyliane framework of these compounds has been established by spectroscopic data and X-ray analysis of the mono-bromohydrin (196) derived from buddledin A (193). An extension of previous studies on the cyclization of the epoxy-ketone (197) derived from caryophyllene has shown that the base-catalysed cyclization of the isomeric epoxy-ketones (198) and (199) provides compounds... 

Compounds in which two donor atoms are linked by a three-carbon chain undergo C-C bond cleavage readily. Well-known reactions are the retro-aldolization, retro Claisen, retro-Michael, and retro-Mannich reactions. Significant application of such processes to synthesis of complex natural products include approaches to caryophyllene [80], nootkatone [81], trihydroxydecipiadiene [82], hybridalactone [83], and mesembrine [84],... 

Analysis TM290 was used by Corey ( . Amer. Chem. Soc,, 196, 86, 1652) in his synthesis of a-caryophyllene alcohol. Again, only one disconnection is very productive ... 

Though the rearrangement step transforms a stable tertiary cation into a less stable secondary cation, relief of strain in expansion from a four- to a five-membered ring makes the alkyl migration favourable. In 1964, E.J. Corey published a synthesis of the natural product a-caryophyllene alcohol that made use of a similar ring expansion. Notice the photochemical [2+2] cycloaddition (Chapter 35) in the synthesis of the starting material. 

This cycloalkanone synthesis furnishes a short synthesis of isocaryophyllenc (1), the (Z)-isomer of natural caryophyllene. In this example, the double bond isomerizes during the keto cyclization. ... 

The ready availability of four-membered rings of defined stereochemistry from enone-alkene photocycloadditions has been the origin of several syntheses which employ Wagner-Meerwein rearrangements in subsequent steps. This is exemplified by a neat and very short synthesis of a-caryophyllene alcohol (40) from cyclopentene and 3-methylcyclohexenone which was described some years ago (see Scheme 15). The rearrangement in 40% sulfuric acid proceeded remarkably smoothly. A short synthesis of iso-comene (41 Scheme 16) also Illustrates this strategy... 

Carbomethoxylation. In one stage of a total synthesis of dZ-caryophyllene, Corey et al.1 treated the cyclic ketone (1), 7,7-dimethylbieyclo[4.2.0]octanone-2, in dioxane with sodium hydride and dimethyl carbonate at 80-85° and obtained the /3-keto ester (2) in high yield. 

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