Camphor, Synthesis

The synthesis of camphor (80% optical purity) by heating optically pure di-hydrocarvone at 400 °C for 20 h is reminiscent of Money s racemic camphor synthesis (Vol. 1, p. 39) in that both correspond to a biogenetic-type synthesis via enol formation. Further synthetic work on deuteriated camphors (see references therein and Vol. 3, p. 67 Vol. 4, p. 48 Vol. 7, p. 38 for earlier work) includes syntheses of optically pure [8- Hi]-, [8- H2]-, and [8- H3]-(—)-camphor (204) by modification of known reactions (Scheme 5) and the use of an improved Zn-Cu... 

Further examples and elimination types will undoubtedly be added to the hitherto known ones and it appears highly versatile that our classification system is not limited to complex eliminations, but also covers complex additions (e.g. the so called benzilic acid rearrangement 36a) in terms of a complex [l,2,3]-addition 170) of water to benzil) and complex substitutions. Thus, the well known technical camphor synthesis starting with a-pinene (Scheme 9) is the result of a sequence of a [l,2,3]-addition 170), [l,2,3]-elimination, (l,2,3]-addition, and finally saponification and oxidation. This appears to be a highly economic description of the underlying chemical processes. 

H2S04 added dropwise to ice-cooled 2-e i/o-3-ejco-dimethyl-3-en /o-hydroxy-2-ejco-norbornanecarboxylic acid, and stirred 17 hrs. at room temp. 1,7-di-methylnorbornane-7-carbo-2-lactone. Y 88%. - This is one stage of a high-yield 9-step ( )-camphor synthesis, whidi allows the individual labeling of each of the 3 methyl groups. O. R. Rodig and R. J. Sysko, J. Org. Chem. 36, 2324 (1971). 

Many notable examples of the synthesis of complex natural products from optically pure starting materials have been reported (70). One synthesis of considerable interest is that of taxol [33069-62-4] (74), a potent antitumor agent used clinically. The starting material (73) used ia the first total synthesis of taxol is produced ia enantiomericaHy pure form from inexpensive and readily available /-camphor [464-48-2] (72) (73). 

Another monoterpene used as a starting material for taxol analogues is camphor (43), which is readily available naturally or can be produced synthetically (201,202). Total synthesis of taxol analogues may be the answer toward finding new compounds for the treatment of many types of cancer. 

The cyclized analog of meralluride is prepared by a similar synthesis. Thus, condensation of camphoric acid (42) (obtained by oxidation of camphor) with ammonia gives the bicyclic succinimide (44). Reaction with allyl isocyanate followed by ring opening and then reaction with mercuric acetate affords the mercury derivative (45) as the acetate rather than the hydroxide as above. Reaction with sodium chloride converts that acetate to the halide (46). Displacement on mercury with the disodium salt of thioglycollic acid affords the diuretic mercaptomerine (47). ... 

When distilled with phosphorus pentoxide, camphor yields cymene, and with iodine, carvacrol. Both of these bodies are para-derivatives of benzene. On oxidation with nitric acid camphor yields many acids, of which the chief are camphoric acid, CjgHjgO, camphanic acid, CjoHj O, and camphoronic acid, CgHj Og. The constitution of these acids has an important bearing on that of camphor. Many formulae have been suggested for camphor during the past few years, but that of Bredt is now universally accepted, and has received complete confirmation by Komppa s synthesis of camphoric acid. This synthesis confirms the formula for camphoric acid as—... 

The Gabriel-Cromwell aziridine synthesis involves nucleophilic addition of a formal nitrene equivalent to a 2-haloacrylate or similar reagent [29]. Thus, there is an initial Michael addition, followed by protonation and 3-exo-tet ring-closure. Asymmetric variants of the reaction have been reported. N-(2-Bromo)acryloyl camphor-sultam, for example, reacts with a range of amines to give N-substituted (azir-idinyl)acylsultams (Scheme 4.23) [30]. 

The asymmetric 1,4-addition of the dienolate of the optically active camphor derived 3-methyl-3-butenoate to 2-cyclopentenone gives a mixture of four diastereomers. The major adduct was applied in the synthesis of (—)-khusimone188. 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

In 2006, Wang et al. reported the synthesis of a new camphor-derived disulfonamide ligand based on L-tartaric acid that was employed in similar reactions to those described above, giving rise to enantioselectivities of up to 83% ee by using 5 mol% of catalyst loading (Scheme 3.43). ... 

In addition, these authors have reported the synthesis of other A -sulfony-lated amino alcohols derived from camphor that have been examined as ligands... 

The camphor sultam derivative 21A was used in a synthesis of epothilone. The stereoselectivity of the aldol addition was examined with several different aldehydes. Discuss the factors that lead to the variable stereoselectivity in the three cases shown. 

An enantiospecific synthesis of longifolene was done starting with camphor, a natural product available in enantiomerically pure form (Scheme 13.31) The tricyclic ring was formed in Step C by an intramolecular Mukaiyama reaction. The dimethyl Multistep Syntheses substituents were formed in Step E-l by hydrogenolysis of the cyclopropane ring. 

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

As early as 1900 Pope and Peachey 5a> reported the synthesis of (+)-methyl-ethylpropyltin iodide, (+)- (7), via the corresponding (+)-camphor- 3-sulfonate (7 )... 

Sulfur ylides are a classic reagent for the conversion of carbonyl compounds to epoxides. Chiral camphor-derived sulfur ylides have been used in the enantioselective synthesis of epoxy-amides <06JA2105>. Reaction of sulfonium salt 12 with an aldehyde and base provides the epoxide 13 in generally excellent yields. While the yield of the reaction was quite good across a variety of R groups, the enantioselectivity was variable. For example benzaldehyde provides 13 (R = Ph) in 97% ee while isobutyraldehyde provides 13 (R = i-Pr) with only 10% ee. These epoxy amides could be converted to a number of epoxide-opened... 

Hoye and Richardson have published an ingeneous synthesis of the tricyclic iridoid sarracenin (170) which relied on the Paterno-Buchi cycloaddition between acetaldehyde and cyclopentadiene as the intial step (Scheme 38)79. This reaction provided a 5 1 mixture of adducts 166a and 166b. The major adduct was opened with camphor-10-sulfonic acid (CSA) in methanol and the alcohol was tosylated to give 167. Displacement with malonate 168 and decarboalkoxylation/demethylation steps gave 169. Ozonolysis, reductive workup and acid-catalyzed acetalization then furnished 170. 

Studies of the intramolecular cyclization of P-amino acids have included the use of camphor-derived oxazoline A-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, OOEJOC1595>. A diastereoselective synthesis of a ip-methylcarbapenem intermediate utilises a cyclization of a P-amino acid <99CC2365>. 

The synthesis of camphor-derived nitrones (87), of spin traps containing alkyl-phenylphosphoryl (36a,b) (88) and diethoxyphosphoryl substituents (37-39) requires m-CPBA as an oxidant (Fig. 2.3) (89, 90). 

For a review of sultam chemistry, interested readers can refer to Oppolzer s article57 on Camphor as a Natural Source of Chirality in Asymmetric Synthesis. ... 

Camphor sultam derivatives have proved to be effective chiral auxiliaries in many different types of asymmetric reactions. As shown in Scheme 5-44, chiral camphor sulfam can be applied in the synthesis of (—)-pulo upone precursor 151 using an intramolecular Diels-Alder reaction. A Wittig reaction of 148 with 147 connects the chiral auxiliary to the substrate, and subsequent intramolecular Diels-Alder reaction via transition state 150 affords product 151. Compound 151 already has the stereochemistry of (—)-pulo upone 153.72... 

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