26.7 Terpenes: The Isoprene Rule - Columbia University

1 : The Isoprene RuleTerpenes: The Isoprene RuleTerpenesTerpenesTerpenes are natural products that are Terpenes are natural products that are structurally related to related to ororIsopreneIsoprene(2(2--methylmethyl-- 1,31,3--butadiene)butadiene)TerpenesTerp enesMyrcene Myrcene (isolated from oil of bayberry) (isolated from oil of bayberry) is a typical a typical ororThe Isoprene UnitThe Isoprene UnitAn Isoprene unit is the carbon skeleton of An Isoprene unit is the carbon skeleton of Isoprene (ignoring the double bonds) Isoprene (ignoring the double bonds) Myrcene contains two Isoprene contains two Isoprene units. The Isoprene UnitThe Isoprene UnitThe Isoprene units of myrcene are joined "headThe Isoprene units of myrcene are joined "head--toto--tail.

2 "tail." headheadtailtailtailtailheadheadTable of carbon atomsNumber of carbon atomsMonoterpeneMonoterpene1010 SesquiterpeneSesquiterpene1515 DiterpeneDiterpene2020 SesterpeneSesterpene2525 TriterpeneTriterpene3030 TetraterpeneTetraterpene4040 Classification of TerpenesClassification of TerpenesFigure MonoterpenesRepresentative Monoterpenes --PhellandrenePhellandrene(eucalyptus)(e ucalyptus)MentholMenthol(peppermint)(pep permint)CitralCitral(lemon grass )(lemon grass ) OOHH OHOHF igure MonoterpenesRepresentative Monoterpenes --PhellandrenePhellandrene(eucalyptus)(e ucalyptus)MentholMenthol(peppermint)(pep permint)CitralCitral(lemon grass )(lemon grass ) OOHH OHOH Figure MonoterpenesRepresentative Monoterpenes --PhellandrenePhellandrene(eucalyptus)(e ucalyptus)MentholMenthol(peppermint)(pep permint)CitralCitral(lemon grass )(lemon grass ) Figure SesquiterpenesRepresentative Sesquiterpenes --SelineneSelinene(celery)(celery) HHFigure SesquiterpenesRepresentative Sesquiterpenes --SelineneSelinene(celery)(celery) HH Figure SesquiterpenesRepresentative Sesquiterpenes --SelineneSelinene(celery)(celery)

3 Figure DiterpenesRepresentative DiterpenesVitamin AVitamin A OHOHF igure DiterpenesRepresentative DiterpenesVitamin AVitamin A OHOH Figure DiterpenesRepresentative DiterpenesVitamin AVitamin A Figure TriterpeneRepresentative TriterpeneSqualeneSqualene(shark liver oil)(shark liver oil) tailtail--toto--tail linkage of Isoprene unitstail linkage of Isoprene Pyrophosphate:Isopentenyl Pyrophosphate:The Biological Isoprene UnitThe Biological Isoprene UnitThe Biological Isoprene UnitThe Biological Isoprene UnitThe Isoprene units in terpenes do not come from The Isoprene units in terpenes do not come from come from isopentenyl come from isopentenyl pyrophosphate (5 carbons) comes Isopentenyl pyrophosphate (5 carbons) comes from acetate (2 carbons) via mevalonate (6 from acetate (2 carbons) via mevalonate (6 carbons).)

4 Carbons).The Biological Isoprene UnitThe Biological Isoprene UnitCHCH33 COHCOHOO33 HOCCHHOCCH22 CCHCCH22 CHCH22 OHOHCHCH33 OHOHOOM evalonic acidMevalonic acidHH22 CCCCHCCH22 CHCH22 OPOPOHOPOPOHCHCH33 OOOOI sopentenyl Isopentenyl pyrophosphatepyrophosphateIsopentenyl PyrophosphateIsopentenyl PyrophosphateHH22 CCCCHCCH22 CHCH22 OPOPOHOPOPOHCHCH33 OOOOI sopentenyl Isopentenyl pyrophosphatepyrophosphateoror OPPOPPI sopentenyl and Dimethylallyl PyrophosphateIsopentenyl and Dimethylallyl PyrophosphateIsopentenyl pyrophosphate is interconvertible withIsopentenyl pyrophosphate is interconvertible with22--methylallyl pyrophosphate. OPPOPP OPPOPPD imethylallyl pyrophosphate has a leaving Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is group (pyrophosphate) at an allylic carbon.

5 It is reactive toward nucleophilic substitution at this reactive toward nucleophilic substitution at this pyrophosphateIsopentenyl pyrophosphateDimethylallyl pyrophosphateDimethylallyl Bond Formation in Carbon Bond Formation in Terpene BiosynthesisTerpene BiosynthesisCarbonCarbon--Carbon Bond FormationCarbon Bond FormationThe key process involves the double bond of The key process involves the double bond of isopentenyl isopentenyl pyrophosphatepyrophosphateacting as a nucleophile acting as a nucleophile toward the allylic carbon of dimethylallyl toward the allylic carbon of dimethylallyl ++OPPOPP OPPOPPC arbonCarbon--Carbon Bond FormationCarbon Bond Formation ++OPPOPPOPPOPP ++OPPOPP OPPOPPA fter CAfter C C Bond Bond ++OPPOPPThe carbocation The carbocation can lose a proton can lose a proton to give a double to give a double CAfter C C Bond Bond ++OPPOPP OPPOPPThe carbocation The carbocation can lose a proton can lose a proton to give a double to give a double ++After CAfter C C Bond Bond OPPOPPThis compound is called geranyl pyrophosphate.

6 It This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil).geraniol (rose oil).After CAfter C C Bond Bond OPPOPP OHOHG eraniolGeraniolHH22 OOFrom 10 Carbons to 15 From 10 Carbons to 15 ++OPPOPP OPPOPP Geranyl pyrophosphateGeranyl pyrophosphate++OPPOPP From 10 Carbons to 15 From 10 Carbons to 15++OPPOPP HH ++ OPPOPPFrom 10 Carbons to 15 From 10 Carbons to 15 OPPOPPThis compound is called farnesyl This compound is called farnesyl of the pyrophosphate ester gives the Hydrolysis of the pyrophosphate ester gives the alcohol farnesol (Figure ).

7 Alcohol farnesol (Figure ).From 15 Carbons to 20 From 15 Carbons to 20 OPPOPPF arnesyl pyrophosphate is extended by another Farnesyl pyrophosphate is extended by another Isoprene unit by reaction with isopentenyl Isoprene unit by reaction with isopentenyl OPPOPPC yclizationCyclizationRings form by intramolecular carbonRings form by intramolecular carbon--carbon carbon bond formation. OPPOPP OPPOPP ++EEdouble double bondbondZZdouble double bondbond ++ OHOHHH ++HH22 OOLimoneneLimonene --TerpineolTerpineolBicyclic TerpenesBicyclic Terpenes ++ ++ ++ --PinenePinene++ Pathway from Acetate to The Pathway from Acetate to Isopentenyl PyrophosphateIsopentenyl PyrophosphateRecallRecallCHCH33 COHCOHOO33 HOCCHHOCCH22 CCHCCH22 CHCH22 OHOHCHCH33 OHOHOOM evalonic acidMevalonic acidHH22 CCCCHCCH22 CHCH22 OPOPOHOPOPOHCHCH33 OOOOI sopentenyl Isopentenyl pyrophosphatepyrophosphateBiosynthesis of Mevalonic AcidBiosynthesis of Mevalonic AcidCHCH33 CCHCCH22 CSCoACSCoAOOOOSS--AcetoacetylAcetoacetyl coenzyme Acoenzyme AIn a sequence analogous to the

8 Early steps of In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is fatty acid biosynthesis, acetyl coenzyme A is converted to converted to SS--acetoacetyl coenzyme coenzyme of Mevalonic AcidBiosynthesis of Mevalonic AcidCHCH33 CSCoACSCoAOO++CHCH33 CCHCCH22 CSCoACSCoAOOOOIn the next step, SIn the next step, S--acetoacetyl coenzyme A acetoacetyl coenzyme A reacts with acetyl coenzyme with acetyl coenzyme addition of acetyl coenzyme A Nucleophilic addition of acetyl coenzyme A (probably via its enol) to the ketone carbonyl of (probably via its enol) to the ketone carbonyl of SS--acetoacetyl coenzyme A coenzyme A of Mevalonic AcidBiosynthesis of Mevalonic AcidCHCH33 CSCoACSCoAOOCHCH33 CCCHCH22 CSCoACSCoACHCH22 COHCOHHOHOOOOO++CHCH33 CCHCCH22 CSCoACSCoAOOOOB iosynthesis of Mevalonic AcidBiosynthesis of Mevalonic AcidCHCH33 CCCHCH22 CSCoACSCoACHCH22 COHCOHHOHOOOOONext, the Next.

9 The acyl coenzyme A acyl coenzyme A function is is product of this reduction is mevalonic product of this reduction is mevalonic of Mevalonic Acid to Conversion of Mevalonic Acid to Isopentenyl PyrophosphateIsopentenyl PyrophosphateCHCH33 CCHCCH22 CHCH22 OOHHCHCH22 COHCOHHHOOOOThe two hydroxyl groups of mevalonic acid The two hydroxyl groups of mevalonic acid undergo Conversion of Mevalonic Acid to Conversion of Mevalonic Acid to Isopentenyl PyrophosphateIsopentenyl PyrophosphateCHCH33 CCHCCH22 CHCH22 OOPPPPCHCH22 Phosphorylation is followed by a novel Phosphorylation is followed by a novel elimination involving loss of COelimination involving loss of CO22and POand PO4433.

10 OOPOPO3333 CHCH33 CCHCCH22 CHCH22 OOPPPPCHCH22 OOOOPOPO3322 CCOO OOCCOOC onversion of Mevalonic Acid to Conversion of Mevalonic Acid to Isopentenyl PyrophosphateIsopentenyl PyrophosphateThe product of this elimination is isopentenyl The product of this elimination is isopentenyl pathway is based on Biosynthetic pathway is based on experiments with experiments with 1414CC--labeled acetatelabeled acetateCCHH33 COHCOHOOHOCHOCCCHH22 CCCCHH22 CHCH22 OHOHCCHH33 OHOHOOM evalonic acidMevalonic acidHH22 CCCCCCHH22 CHCH22 OPOPOHOPOPOHCCHH33 OOOOI sopentenyl Isopentenyl pyrophosphatepyrophosphateBiosynthetic pathway is based on Biosynthetic pathway is based on experiments with experiments with 1414CC--labeled acetatelabeled acetateCCHH33 COHCOHOOC itronellal biosynthesized using Citronellal biosynthesized using 1414CC--labeled labeled acetate as the carbon source had the labeled acetate as the carbon source had the labeled carbons in the positions in the positions OOHH