Carene synthesis

Kauffman GS, Harris GD, Dorow RL, Stone BR, Parsons RL Jr, Pesti JA, Magnus NA, Fortunak JM, Confalone PN, Nugent WA (2000) An efficient chiral moderator prepared from inexpensive (+)-3-carene synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963. Org Lett 2 3119-3121... 

Among chiral dialkylboranes, diisopinocampheylborane (8) is the most important and best-studied asymmetric hydroborating agent. It is obtained in both enantiomeric forms from naturally occurring a-pinene. Several procedures for its synthesis have been developed (151—153). The most convenient one, providing product of essentially 100% ee, involves the hydroboration of a-pinene with borane—dimethyl sulfide in tetrahydrofuran (154). Other chiral dialkylboranes derived from terpenes, eg, 2- and 3-carene (155), limonene (156), and longifolene (157,158), can also be prepared by controlled hydroboration. A more tedious approach to chiral dialkylboranes is based on the resolution of racemates. /n j -2,5-Dimethylborolane, which shows excellent enantioselectivity in the hydroboration of all principal classes of prochiral alkenes except 1,1-disubstituted terminal double bonds, has been... 

Menthol can also be synthesized from optically active terpenoids such as (+)-citroneUal, (-)- P-pheUandrene, and (+)-3-carene. The synthesis from (+)-3-carene has already been discussed in the section on hydrocarbons. Such methods must avoid any racemization during the course of a usually multiple-step synthesis. One disadvantage of such methods is that the other menthol diastereoisomers must be equilibrated and recycled. 

M (+)-trans-2-carene oxide (2-epoxycarene), 1M olivetol or analog, 0.05 M p-toluenesulfonic acid in 10L benzene reflux two hours and evaporate in vacuum (or can separate the unreacted olivetol as above) to get about 30% yield THC. Olivetol can also be separated as described below. For synthesis of 2-epoxycarene (A4 carene oxide) from A4 carene (preparation given later) see p-methadieneol preparation (Method 2). 3-carene oxide gives 20% yield of AH6) THC. 

The same authors 83) used the chiral ketone (46) as substrate for the preparation of optically active cyclohexanol derivatives (47) which may be useful intermediates in the synthesis of chiral natural products, such as (—)-mesenbranoene, (+)-2-carene etc. 

The oxidation of 3-carene to 3-caren-5-one (Figure 3.46) is a key step in the synthesis of the pyrethroid ester insecticide Deltamethrin [162,163]. This reaction is performed with air as the oxidant, catalyzed by 2 mol% of a Cr-pyridine complex (the catalyst precursors are CrCl3 and pyridine). Table 3.1 shows the turnover frequencies obtained using various Cr/pyridine ratios. 

In the course of our earlier studies on terpenylboranes we developed a simple transformation of a- into 3-pinene," and a stereoselective synthesis of allylic alcohols by the reduction of vinylic epoxides.12 An extension of these studies to contrathermo-dynamic isomerization of a-thujene, 2- and 3-carene,13 and kinetic resolution of vinylic epoxides by the reduction with terpenylboranes,14 is described. 

SYNTHESIS OF (+)-3(10>CARENE, (+)-SABINENE, AND KINETIC RESOLUTION OF VINYLIC EPOXIDES... 

Several years ago, we developed a contrathermodynamic isomerization of a- to 3-pinene via diethylmyrtenylborane obtained from a-pinene by metalation-transmetalation.11 Later, (+)-p-pinene of > 99 % ee was prepared by this method.22 Extending this work to other bicyclic monoterpenes, the isomerization of (+)-2-, (+)-3-carene, and (-)-a-thujene, was studied.13 Among bicyclic monoterpene olefins with an exocyclic double bond, 3(10)-carene is a rare compound reported only a few times in the long history of terpene chemistry, and its rotation is still controversial.23,24 Sabinene is isolated from the oil of savin, and no convenient synthesis of an optically active sabinene is known. 

The synthesis of 8- and 9-substituted carenes (320) and (321) from the epoxide (322) has been described. 

W.J. Kerr and co-workers carried out the total synthesis of (+)-taylorione starting from readily available (+)-2-carene and using a modified Pauson-Khand annulation with ethylene gas as the key step. The key terminal alkyne intermediate was prepared by the Corey-Fuchs reaction. Interestingly, the ketal protecting group was sensitive to the excess of CBr4, so the addition of this reagent had to be monitored carefully to cleanly transform the aldehyde to the desired dibromoolefin. 

A highly stereoselective total synthesis of racemic sesquicarene, a sesquiterpene analogous to d -carene was accomplished by the photochemical transformation of a bicyclo[3.3.2]nona-3,6-dien-2-one. ... 

Vinylcyclopropane-cyclopentene rearrangement (VCP-CP) reaction under thermal conditions is a useful transformation and has been extensively utilized in the synthesis of number of cyclopentanoid natural products.However, cw-alkyl-vinylcyclopropanes pose a serious problem since the retro-ene reaction, a lower energy pathway occurs readily instead. To obviate this problem, we sought to explore the excited state chemistry of c/s-alkyl-vinylcyclopropanes.t ] Thus, sensitized photolysis of (+)-A -carene readily afforded the VCP-CP product exclusively in a preparative yield. The obtention of a racemic product can be rationalized by involving a diradical intermediate.l l... 

An amino ether 46, presumably derived from (+)-3-carene [( + )-40], has been used for asymmetric alkylation of azaenolates via imines (SectionD.1.1.1,4.1., ref 40). No details were given on the synthesis of 46, but it can be prepared by methylation of the corresponding amino alcohol which was probably obtained from the epoxide of ( + )-3-carene by ring opening with trimethylsilyl azide, followed by catalytic hydrogenation41,... 

Indian turpentine is rich in 3-carene and this can be used as a starting material for synthesis of menthol. The overall scheme is shown in Figure 4.23. 

The final stage of the synthesis is hydrogenation of the ketone function. The major product of this hydrogenation is the all equatorial /-menthol but some of the opposite enantiomers at the 3-position are obtained. The overall yield of the desired isomer from the /-menthone/d-isomenthone mixture is only about 50%. A little simple arithmetic shows that the overall yield of this synthesis is only about 13% based on the starting 3-carene. This serves to illustrate two important factors in synthesis planning. Firstly, long syntheses with numerous steps will inevitably lead to low overall yields. Even if every yield is 90%, a six stage process will still have a yield of only 50% overall. Secondly, low yields are particularly... 

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