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ABSTRACTASYMMETRIC SYNTHESIS OF 6,7-EPOXYCITRONELLYLPIVALATE: OPTIMIZING THE SYNTHESIS OF THECALIFORNIA RED SCALE PHEROMONEThe title compound, an important intermediate in the multi-step synthesis ofthe active component in the sex pheromone of Aonidiella aurantii (California RedScale), was synthesized asymmetrically from citronellyl pivalate. The key to thesynthesis was the use of a recently discovered coordination compound (Jacobsen’scatalyst) used for epoxide formation. Under the previous protocols, a mixture ofdiastereomers is created during formation of the epoxide. Analysis of thediastereomeric mixture was accomplished using GC/MS and NMR.Diastereoselectivity of the reaction utilizing Jacobsen’s catalyst was also studiedby GC/MS and NMR. The asymmetric epoxide produced by this method can thenbe converted to the active stereoisomer of the pheromone in four steps. The totalsynthetic efficiency is thus dramatically increased. Use of “higher order cuprates”,as a possible synthetic route to the California Red Scale Pheromone, was alsoinvestigated.James Anthony MirandaAugust 2001

ASYMMETRIC SYNTHESIS OF 6,7-EPOXYCITRONELLYLPIVALATE: OPTIMIZING THE SYNTHESIS OF THECALIFORNIA RED SCALE PHEROMONEbyJames Anthony MirandaA thesissubmitted in partialfulfillment of the requirements for the degree ofMaster of Science in Chemistryin the College of Science and MathematicsCalifornia State University, FresnoAugust 2001

NOTE:THIS PAGE IS OPTIONAL, AND REQUIRES PAYMENT OFAN EXTRA $45 COPYRIGHTING FEE.Copyright © 2000 Student’s Name as it appears on title page

APPROVED FOR FINAL DRAFT SUBMISSIONFor the Department of Chemistry:Ronald L. Marhenke (Chair)ChemistrySaeed AttarChemistryBarbara J. MayerChemistry

APPROVEDFor the Department of Chemistry:Ronald L. Marhenke (Chair)ChemistrySaeed AttarChemistryBarbara J. MayerChemistryFor the Graduate Committee:Dean, Division of Graduate Studies

AUTHORIZATION FOR REPRODUCTIONOF MASTER'S THESISI grant authorization for the reproduction of this thesis in part orin its entirety without further authorization from me, on thecondition that the person or agency requesting reproductionabsorbs the cost and provides proper acknowledgment ofauthorship.Permission to reproduce this thesis in part or in its entirety mustbe obtained from me.Signature of thesis writer:

ACKNOWLEDGMENTSI would like to thank Dr. Ron Marhenke for his guidance and supportthroughout the past two years.I also thank Dr. Saeed Attar and Dr. Barbara Mayer, members of my thesiscommittee, for challenging and guiding me.I express gratitude to my parents, Mr. Luis Miranda and Mrs. ImeldaMiranda, for their continued support of my education.I am grateful to Christina Berris for her caring and understanding. Her loveinspires me to reach for my dreams.The 1999-2000 Faculty Sponsored Research Award and the 2000-2001California Graduate Equity Fellowship supported the author during the researchand writing of this thesis.

TABLE OF CONTENTSPageLIST OF FIGURES . . . . . . . . . . . . . . . . . viiINTRODUCTION . . . . . . . . . . . . . . . . . 1Asymmetric Synthesis of (3S,6S)-6,7-Epoxycitronellyl Pivalate. . . . 1Use of Higher Order Cuprates in the Synthesis of the California Red ScalePheromone. . . . . . . . . . . . . . . . . . . 20RESULTS AND DISCUSSION . . . . . . . . . . . . . 24Synthesis of (3S) Citronellyl Pivalate . . . . . . . . . . . 24Synthesis of (3S,6RS)-6,7-Epoxycitronellyl Pivalate . . . . . . . 24Separation of epoxide diastereomers using EC-WAX capillary GC column 32Asymmetric Synthesis of (3S,6S)-6,7-Epoxycitronellyl Pivalate. . . . 39Ring opening of 6,7-Epoxycitronellyl Pivalate using Higher Order MixedOrganocuprates . . . . . . . . . . . . . . . . . 47EXPERIMENTAL . . . . . . . . . . . . . . . . . 54Synthesis of (3S) Citronellyl Pivalate . . . . . . . . . . . 54Synthesis of (3S,6RS)-6,7-Epoxycitronellyl Pivalate . . . . . . . 56Asymmetric Synthesis of (3S,6S)-6,7-Epoxycitronellyl Pivalate. . . . 57Synthesis of Bu 2 Cu(CN)Li 2 . . . . . . . . . . . . . . 58Ring opening of epoxide using Bu 2 Cu(CN)Li 2 and (3S,6SR)-6,7-Epoxycitronellyl Acetate. . . . . . . . . . . . . . . 59Synthesis of Butenyl Lithium, using Butenyl Bromide and Li wire . . . 59Synthesis of Pentyl Lithium, using Chloropentane and Li wire . . . . 60REFERENCES . . . . . . . . . . . . . . . . . . 62

FigureLIST OF FIGURESPage1. California Red Scale (Aonidiella aurantii) . . . . . . . 32. California Red Scale Pheromone trap in the field. . . . . . 43. Current commercial reaction scheme of California Red ScalePheromone (3S,6RS)-3-Methyl-6-isopropenyl-9-decen-1-ylAcetate . . . . . . . . . . . . . . . . 64. Proposed New Reaction Scheme of the California Red ScalePheromone (3S,6R)-3-Methyl-6-isopropenyl-9-decen-1-ylAcetate . . . . . . . . . . . . . . . . 85. (S,S) Jacobsen’s catalyst . . . . . . . . . . . . 96. Two step catalytic epoxidation cycle . . . . . . . . . 107. Asymmetric Epoxidation Mechanism . . . . . . . . . 108. Asymmetric epoxidation mechanism applied to citronellyl pivalate 129. (R,R) Jacobsen’s catalyst 3-D top view . . . . . . . . 1310. (R,R) Jacobsen’s catalyst 3-D flat view . . . . . . . . 1311. Citronellyl Pivalate 3-D Structure . . . . . . . . . . 1412. Trans-Alkene approach produces steric repulsion 13-15 . . . . 1513. Tri-substituted alkenes are good substrates for a Jacobsenepoxidation . . . . . . . . . . . . . . . 1614. Partial radical formation during the step-wise addition of oxygen toalkene . . . . . . . . . . . . . . . . . 1615. Ring opening of epoxide by Grignard reagent. . . . . . . 2116. Ring opening of epoxide using Higher Order Cuprates . . . . 2317. IR spectrum of (3S) Citronellyl Pivalate taken as neat sample . . 2518.1 H NMR Spectrum of (3S) Citronellyl Pivalate in CDCl 3 . . . 2619. GC/MS trace of [(3S,6RS)-6,7-Epoxycitronellyl Pivalate] + [(3S)Citronellyl Pivalate] Co-injection (gradient 150 °C → 230 °C,∆T = 5 °C/min) . . . . . . . . . . . . . . 27

viii20. GC/MS trace of (3S) Citronellyl Pivalate (gradient 150 °C → 230°C, ∆T = 5 °C/min), starting material . . . . . . . . 2821. GC/MS trace of (3S,6RS)-6,7-Epoxycitronellyl Pivalate (gradient150 °C → 230 °C, ∆T = 5 °C/min), product . . . . . . 2922.1 H NMR Spectrum of (3S,6RS)-6,7-Epoxycitronellyl Pivalate inCDCl 3 . . . . . . . . . . . . . . . . . 3023. IR Spectrum of (3S,6RS)-6,7-Epoxycitronellyl Pivalate taken asneat sample . . . . . . . . . . . . . . . 3124. GC/MS trace of (3S,6RS)-6,7-Epoxycitronellyl Pivalateisothermal 150 °C. . . . . . . . . . . . . . 3325. GC/MS trace of (3S,6RS)-6,7-Epoxycitronellyl Pivalateisothermal 125 °C . . . . . . . . . . . . . 3426. GC/MS trace of (3S, 6RS)-6,7-Epoxycitronellyl Pivalateisothermal 115 °C . . . . . . . . . . . . . 3527. GC/MS trace of (3S,6RS)-6,7-Epoxycitronellyl acetateisothermal 150 °C . . . . . . . . . . . . . 3628. GC/MS trace of (3S,6RS)-6,7-Epoxycitronellyl acetateisothermal 115 °C . . . . . . . . . . . . . 3729. GC/MS trace of (3S,6RS)-6,7-Epoxycitronellyl acetateisothermal 105 °C . . . . . . . . . . . . . 3830. Integration of GC/MS peak corresponding to(3S,6RS)-6,7-Epoxycitronellyl acetate isothermal 115 °C . . 3931. Integration of GC/MS peak corresponding to(3S,6RS)-6,7-Epoxycitronellyl acetate isothermal 105 °C . . 3932. GC/MS trace of [(3S,6RS)-6,7-Epoxycitronellyl Pivalate]+ [(3S,6S)-6,7-Epoxycitronellyl Pivalate] Co-injection(gradient 150 °C → 230 °C, ∆T = 5 °C/min) . . . . . . 4133.1 H NMR Spectrum of (3S,6RS)-6,7-Epoxycitronellyl Pivalate inCDCl 3 . . . . . . . . . . . . . . . . . 4234. IR Spectrum of (3S,6S)-6,7-Epoxycitronellyl Pivalate taken asneat sample . . . . . . . . . . . . . . . 4235.36.13 C NMR Spectrum of (3S,6RS)-6,7-Epoxycitronellyl Pivalate inCDCl 3 . . . . . . . . . . . . . . . . . 4313 C NMR Spectrum of (3S,6RS)-6,7-Epoxycitronellyl Pivalate(58 ppm – 67 ppm) in CDCl 3 . . . . . . . . . . 44

37.38.39.ix13 C NMR Spectrum of (3S,6RS)-6,7-Epoxycitronellyl Pivalate(18 ppm – 39 ppm) in CDCl 3 . . . . . . . . . . 4513 C NMR Spectrum of (3S,6S)-6,7-Epoxycitronellyl Pivalate inCDCl 3 . . . . . . . . . . . . . . . . . 4613 C NMR Spectrum of (3S,6S)-6,7-Epoxycitronellyl Pivalate inCDCl 3 (57 ppm – 66 ppm) . . . . . . . . . . . 4740. GC/MS trace of reaction mixture showing 5 methyl-5 nonanol(top) and unreacted epoxide (bottom) gradient 150 °C → 230°C, ∆T = 5 °C/min . . . . . . . . . . . . . 4941. 5-methyl-5-nonanol . . . . . . . . . . . . . . 4842. Results of GC/MS library search conclusively identified5-methyl-5 nonanol . . . . . . . . . . . . . 5043. GC/MS trace of reaction mixture showing two diastereomers of(3S,6SR)-6-(1 Hydroxy-1-methyl ethyl)–3-methyl-decan-1-yl-2,2acetate, gradient 150 °C → 230 °C, ∆T = 5 °C/min . . . . 5144. GC/MS trace of reaction mixture showing two diastereomers of(3S, 6SR) 6-(1 Hydroxy-1-methyl ethyl) –3-methyl decan-1-yl 2,2Pivalate (from aqueous layer) gradient 150 °C → 230 °C, ∆T = 5°C/min . . . . . . . . . . . . . . . . . 53

INTRODUCTIONAsymmetric Synthesis of (3S,6S)-6,7-EpoxycitronellylPivalateThe California Red Scale, Aonidiella aurantii, is the most destructive citruspest in the United States, Australia, and the Mediterranean. 1,2In the United States,the California Red Scale is common in orange groves in California, Arizona,Texas, and Florida. These are states that lie within the tropical and subtropicalzone, with temperatures and humidity conducive to the growth of the CaliforniaRed Scale. The adult female Red Scale is characterized by a circular shape andslightly convex central area. The color of the female is reddish and the entire bodyis covered with a protective “scale”. This scale covering is firmly attached to theleaf, wood, or fruit substrate of a citrus tree throughout the entire life of the insect.The female Red Scale then causes damage to all parts of the tree by sucking on theplant tissue for food. The farmer suffers economic losses because infested fruitmust be removed at the packinghouse and serious damage to the citrus tree itselfmay occur.The length of the female is between 1.6 and 2.2 mm. The adult male RedScale is smaller (0.6 – 0.8 mm long, 1.5 mm wing span) and is orange-yellowcolored. The adult male Red Scale lives for only about 6 hours and has the solepurpose of mating with the female Red Scale. Because male Red Scale arenocturnal insects and must fly to mate with the female Red Scale, search for thefemale Red Scale during reproduction is expedited by a pheromone released by thefemale. The male Red Scale antennae are covered with numerous chemical senseorganswhich are large and well developed. The presence of large antennae

2support the contention that the female pheromone is the dominant factor in malefemalesearching. Figure 1 shows both female and male California Red Scale.Current methods of controlling California Red Scale include both pesticidetreatment and biological control. 3,4 The most common pesticide treatment usesbroad spectrum organophosphate and carbamate insecticides. These sweepingpesticides have two main disadvantages. First, they kill natural predators ofCalifornia Red Scale and second, some California Red Scale have becomeresistant to all forms of pesticide. Another method of controlling California RedScale is biological control. This type of control is characterized by controlledrelease of natural predators to California Red Scale. The most important naturalpredator is the parasitic wasp, Aphytis melinus. In the San Joaquin Valley, atypical release rate of Aphytis is 100,000 parasites per acre per year. Thedisadvantages to this method of control are cost and time.Pheromone traps are used to trap male Red Scale in flight seeking toreproduce with the female Red Scale. 3 Important information is obtained by maleRed Scale pheromone trap counts including determination of when male flights areoccurring, which citrus orchards have high levels of Red Scale infestation, andhow to time insecticide applications. The pheromone trap is charged with asample of synthetic female California Red Scale pheromone which lures the maleto the trap. The pheromone trap, therefore, serves two purposes: (a) it providesinformation on Red Scale population and (b) the control of Red Scale populationby the prevention of reproduction. Figure 2 shows a pheromone trap in the field.In 1977, the active components of the California Red Scale female sexpheromone were discovered by collaborative effort between the United StatesDepartment of Agriculture and Zoecon Corporation of Palo Alto, California. 5These components were 3-methyl-6-isopropenyl-9-decen-1-yl acetate and (Z)-3-

3a. Adult Female California Red Scaleb. Adult Male California Red ScaleFigure 1. California Red Scale (Aonidiella aurantii)

Figure 2. California Red Scale pheromone trap in the field4

5methyl-6-isopropenyl-3,9-decadien-1-yl acetate. Both components are effective inattracting male California Red Scale.One of the components, 3-methyl-6-isopropenyl-9-decen-1-yl acetate,possesses two chiral centers. A non-stereoselective synthesis plan, giving nocontrol over stereochemistry, of the pheromone would yield 4 differentstereoisomers of the pheromone, only one of which is biologically active. In alater study (1980) by Anderson of Zoecon Corporation, it was discovered that theconfiguration of the active stereoisomer of the pheromone was (3S,6R). 6,7Anderson synthesized all four possible stereoisomers of the final pheromone (3RS,6RS). Chromatography showed that upon co-injection of the synthesizedisomers and the naturally isolated pheromone, only the (3S,6R) isomer co-elutedwith the natural pheromone. However, it is important to note that the other threeisomers present in the mixture do not inhibit biological activity of the (3S,6R)isomer.The purpose of this study was to effect control over the stereochemistry atthe C 6 chiral center. Effective control over the creation of this key chiral centerwould increase the efficiency of the overall pheromone synthesis dramatically.During the total synthesis scheme of 3-methyl-6-isopropenyl-9-decen-1-yl acetate,pure (3S) citronellyl pivalate is currently reacted with m-chloroperoxybenzoic acidto give a mixture of (3S,6R) and (3S,6S)-6,7-epoxycitronellyl pivalate. Figure 3shows the currently used reaction scheme for the total synthesis of California RedScale pheromone. This ~ 1:1 mixture of diastereomers is usually then carried infour steps to the pheromone and shipped for field trials. Because of Anderson’sstudy, it is known that the biologically active stereoisomer has an (R)configuration at the C 6 chiral center. 6,7An asymmetric synthesis during the

6creation of the chiral center at C 6 would then yield a single diastereomer. Sincethe C 6 chiral center is6*3 OH(3S) citronelloltrimethylacetylchloride, pyridine6*3 OOm-chloroperoxybenzoic acid indichlorometthaneHO* 6*3OO(3S) citronellyl pivalate(3S, 6SR) Epoxycitronellyl pivalateMgBrCuITetrahydrofuran at -40 COH*6*3 OOOHH*6*3 OMethanesulfonlyl chlorideTriethylamine, 0 C(3S, 6RS)inversion at C-6KOH in methanolH*6*3 OHacetyl chloridepyridineH*6*3 OAc(3S, 6RS) 3-Methyl-6-isopropenyl-9-decen-1-ylacetateFigure 3. Current commercial reaction scheme of California Red Scale pheromone(3S,6RS)-3-Methyl-6-isopropenyl-9-decen-1-yl acetate

7created early in the total synthesis, a mixture of diastereomeric epoxides wouldtheoretically cause the wastage of 50% of the reagents used in the last four steps ofthe synthesis. Half of the reagents used during the last four steps of the synthesiswould be consumed making the inactive (3S,6S) isomer of the pheromone.Because of inversion of configuration at C 6 during the step after epoxidation, thecorrect configuration of the epoxide created is (3S,6S). The (6S) epoxidestereoisomer would yield the biologically active (6R) pheromone. Figure 4 showsthe proposed new reaction scheme, incorporating an asymmetric synthesis of theepoxide at step two.Epoxides are very important structures in organic synthesis. 8 The strainenergy present in the three-membered ring lends an epoxide to react readily with awide variety of nucleophiles. For example, the next step after epoxidation in thetotal synthesis of the California Red Scale pheromone, is the nucleophilic attack ofbutenyl magnesium bromide, a Grignard reagent that opens the epoxide ring tocreate a tertiary alcohol. Another important feature of epoxide formation is thecreation of a chiral carbon. If the synthesis of a particular target compound callsfor a chiral carbon to be created, an epoxide synthetic pathway is a natural choice.The epoxidation of a prochiral alkene will yield a chiral carbon.The first catalytic asymmetric epoxidations were performed on allylicalcohols by Katsuki and Sharpless. 9 They utilized a chiral enantioselectivetitanium-tartrate-complex to carry out such a reaction. By using anenantiomerically pure dialkyl tartrate, Katsuki and Sharpless were able to controlthe attack upon the alkene to afford an enantiomerically pure epoxy alcohol.

8During the early 1990s Professor Eric Jacobsen of Harvard Universitydeveloped a method for asymmetric epoxidations using a Mn(III) complex. 10complex [N,N’-Bis (3,5-di-t-butylsalicylidene)-1,2-cyclohexanediamino-The6*3 OH(3S) citronelloltrimethylacetylchloride, pyridine6*3 OO(S, S) Jacobsen's catalyst,NaOCl,4-phenylpyridine N-oxideHO* 6*3OO(3S) citronellyl pivalate(3S, 6S) Epoxycitronellyl pivalateMgBrCuITetrahydrofuran at -40 COH*6*3 OOOHH*6*3 OMethanesulfonlyl chlorideTEA, 0 C(3S, 6R)inversion at C-6KOH in methanolH*6*3 OHacetyl chloridepyridineH*6*3 OAc(3S, 6R) 3-Methyl-6-isopropenyl-9-decen-1-ylacetateFigure 4. Proposed new reaction scheme of the California Red Scale pheromone(3S,6R)-3-Methyl-6-isopropenyl-9-decen-1-yl acetate

9manganese (III) chloride] is readily and cost effectively prepared in three steps andis commercially available. 11,12 Asymmetric synthesis of (3S,6S)-6,7-epoxycitronellyl pivalate is made possible by the use of this reagent. Figure 5shows the structure of Jacobsen’s catalyst. This catalyst is reported to work beston synthesizing enantiomerically rich epoxides from cis-alkenes. 13-15t-BuHNOt-BuMnClHNOt-But-BuFigure 5. (S,S) Jacobsen’s catalystThe mechanism of the epoxidation and source of stereochemical selectivity13, 16has been proposed by Jacobsen and Houk. Duringthe addition of the oxygenatom across the double bond of an alkene, attack is only made possible in oneconfiguration due to the stereochemistry of the particular Jacobsen’s catalyst beingused (R,R or S,S). A stoichiometric amount of NaOCl (sodium hypochlorite,commonly known as bleach) is used during the epoxidation. This is the source ofthe oxygen atom. The proposed catalytic cycle for the Jacobsen’s catalyst isshown in Figure 6. 16As shown in Figure 7, due to the presence of two bulky t-butyl groups oneach side of the Manganese-oxo intermediate, attack of the alkene is only possible

10across the top of the molecule, after first passing across the cyclohexane ring.Attack of the alkene across the top of the molecule is dictated by the structure ofOR CH 3NaClMn (V)H CH 3alkeneNaOClMn (III)RH*OCH 3CH 3epoxideFigure 6. Two-step catalytic epoxidation cycleLHSHL=large substituentS=small substituentt-BuHNOt-BuOMnH*= axial HydrogenH*NOt-But-BuLOS(S,S) Jacobsen's catalystFigure 7. Asymmetric epoxidation mechanism

11the particular alkene substrate. 17 The alkene will have a “large” substituentconnected to it and a “small” substituent connected to it (Figure 7). Jacobsen’scatalyst has two chiral centers on the cyclohexane ring whose configurations areeither (R,R) or (S,S). Depending upon the configuration, the axial hydrogenconnected to those two chiral centers will be on either the left side of the catalyst(R,R) or on the right side of the catalyst (S,S). When the alkene adds across thetop of the Manganese-oxo species, it will attack in a way that the “large”substituent on the alkene will situate itself in a position remote to the axialhydrogen. This selective approach is the source of the stereoselectivity of theepoxidation.By applying this mechanism to citronellyl pivalate, it can be shown that the“large” substituent would approach the manganese-oxo complex in a way remoteto the axial hydrogen on Jacobsen’s catalyst and the “small” substituent would bebetter accommodated closer to the axial hydrogen (Figure 8). This mechanism canalso be used to predict the stereochemistry of the newly synthesized epoxide. 17 Byusing the (S,S) Jacobsen’s catalyst, we can make the needed (3S,6S)-6,7-epoxycitronellyl pivalate.3-D images generated by the molecular modeling program PC Spartanfurther validate this proposed mechanism. Figure 9 shows a 3-D view ofJacobsen’s catalyst from the top. From this view, it can readily be seen that thebulky t-butyl groups prevent approach to the centrally located manganese-oxogroup. It can also be seen that the axial hydrogen controls approach from acrossthe cyclohexane ring on top. Figure 10 shows Jacobsen’s catalyst from a flatperspective. This figure displays the prominent oxygen atom at the top of the

12molecule and also shows that the axial hydrogen on the cyclohexane ring plays adominant role in approach of an alkene towards that oxygen. Figure 11 shows a 3-PivalateOLSHH*3PivalateOL=large substituentS=small substituentH6*3t-BuHNOHO NMnOt-Bu36H O4 12(3S, 6S)6,7-epoxycitronellyl pivalatet-But-Bu(S,S) Jacobsen's catalystFigure 8. Asymmetric epoxidation mechanism applied to citronellyl pivalate

Figure 9. (R,R) Jacobsen’s catalyst 3-D top view13

14Figure 10. (R,R) Jacobsen’s catalyst 3-D flat viewFigure 11. Citronellyl pivalate 3-D structureD image of our starting material, citronellyl pivalate. From this figure, it can beseen that the molecule’s “large” substituent must be aligned in a way that wouldprevent interaction with the axial hydrogen of Jacobsen’s catalyst.It can be discerned from this mechanism that cis-alkenes are idealmolecules for this type of epoxidation and that trans-alkenes are not. 13-15 Transalkeneswould prevent the necessary correct approach to the manganese-oxocomplex, and therefore would be poor substrates for this type of epoxidation(Figure 12).

15The starting material for our epoxide is citronellyl pivalate, a tri-substitutedalkene. Based upon the previously described mechanism, one would think thatthis compound would be a poor epoxidation substrate for Jacobsen’s catalyst,however Jacobsen has described this very approach to the reaction. 18 According tothisR1 R2R1OO R2Mncis alkene-epoxide transition stateMntrans alkene-epoxide transition stateFigure 12. Trans-Alkene approach produces steric repulsion 13-15paper, tri-substituted alkenes are indeed excellent substrates for a Jacobsenepoxidation and many such reactions have been carried out with high reactionrates and enantioselectivity. Figure 13 includes the six tri-substituted alkeneswhich showed promising yields and enantiomeric excesses. Also included inFigure 13 is the one unconjugated tri-substituted alkene that underwent Jacobsenepoxidation.In order to explain these seemingly contradictory results, Jacobsen had tore-evaluate his proposed mechanism for epoxidation. 18 This new theory involveda “side-on” skewed attack of the alkene upon the manganese-oxo complex thatinvolved the formation of two possible intermediates. With a cis-alkene, one lowenergy activated complex and one high energy activated complex are possible.With trans-alkenes, both possible activated complexes are high energy speciesbecause either approach of the alkene would produce the same steric repulsion.Therefore a trans-alkene would not proceed with appreciable yield and

16stereoselectivity. With tri-substituted alkenes, one transition state is significantlyless hindered than the other, therefore allowing a possible route for the reaction toproceed to completion. A proposed radical mechanism serves to explain why trisubstitutedalkenes are suitable substrates for a Jacobsen epoxidation. 18 Duringthe step-wise addition of an alkene to the manganese-oxo catalyst, a partial radicalis created (Figure 14). If a tri-Me PhPh87% yield, 88% e.e.61% yield, 86% e.e.Ph PhPh97% yield, 92% e.e.Ph MePh91% yield, 95% e.e.Ph75% yield, 86% e.e.Ph69 % yield, 93% e.e.Me40% e.e.Figure 13. Tri-substituted alkenes are good substrates for a Jacobsen epoxidationR1R2R1δ.R2δ.OR2OMndi-substituted alkeneepoxidationMntri-substituted alkeneepoxidation

17Figure 14. Partial radical forms during the step-wise addition of oxygen to alkenesubstituted alkene is used, this partial radical is a tertiary radical, as opposed to asecondary radical formed when a di-substituted alkene is used. Tertiary radicalsare relatively more stable than secondary radicals, 19 therefore tri-substitutedalkenes can be included in the list of suitable substrates for Jacobsen epoxidations.Furthermore, tri-substituted conjugated alkenes produced epoxides with highyields and high enantioselectivity, while tri-substituted non-conjugated alkenesproduced epoxides with low yields and low enantioselectivity. Conjugatedradicals are relatively more stable than non-conjugated radicals, serving to validatethe step-wise, radical intermediate mechanism. 18It was theorized that even though citronellyl pivalate is not a conjugatedalkene, it may still be a suitable substrate for asymmetric epoxidation. Since it is atri-substituted alkene, a relatively stable tertiary radical will form during the stepwiseaddition of oxygen across the alkene. Also the remote chiral center C 3 mayalso play a role in the approach of the substrate to the manganese-oxo complex.Since we are starting with pure (3S) citronellyl pivalate, approach of the alkenemay be favored in only one orientation, precluding the synthesis of an asymmetricepoxide.Characterization of the asymmetric 6,7-epoxycitronellyl pivalate was achallenge. Gas Chromatography-Mass Spectrometry was the preferred method ofcharacterization. We wanted to prove that we had synthesized only one (3S,6S)diastereomer and not the unwanted diastereomer (3S,6R). Diastereomers areisomers that have different physical properties. Enantiomers have identical

18physical properties (except optical rotation) and therefore cannot be separated bytraditional GC columns. Chiral columns must be used to separate enantiomers.But since diastereomers have different melting points, different boiling points, anddifferent solubilities, a chiral column is not needed. When separating andcharacterizing the stereoisomers of the California Red Scale pheromone in 1980,Anderson used a Carbowax 20M capillary column. 6 We used an EC-WAX 30Mcolumn purchased from Alltech to separate and characterize the diastereomers.Both columns have polyethylene glycol as their packing material. Separation ofthe epoxide mixture of diastereomers is needed in order to characterize theasymmetric epoxide. Once two peaks (each peak corresponding to a diastereomerof the epoxide) can be discerned from the mixture of diastereomers, then theasymmetric epoxide can be characterized.Another method of characterizing the asymmetric epoxide is by NuclearMagnetic Resonance (NMR). Chiral shift reagents can be used to characterize theasymmetric epoxide in a mixture of diastereomers. 20-22 Tris (trifluoroacetyl-dcamphorato)Praseodymium(III), abbreviated Pr(facam) 3 , is one such chiral shiftreagent. Since diastereomeric hydrogens are situated differently in space and havedifferent surroundings, diastereomeric hydrogens connected to a chiral centerwould give different 1 H NMR peaks. This difference in chemical shift would bevery small and quite difficult to measure. A chiral shift reagent, when added to amixture of diastereomers, would preferentially complex to only one of thediastereomers. When an NMR experiment is run on this mixture, the hydrogenpeaks corresponding to the complexed molecule (chiral shift reagent + epoxide)are shifted upfield or downfield. By identifying a peak that has a differentchemical shift for each of the diastereomers, a measure of diastereomeric puritycan be made by integrating the area under these peaks. 20 Carbon NMR can also be

19used to characterize the asymmetric epoxide. A peak corresponding to a singlecarbon that is split into two close peaks indicates that a mixture of diastereomers ispresent. The height of each peak would give an indication of the ratio ofdiastereomers present.A review of literature showed that this is the first to attempt toasymmetrically synthesize the California Red Scale pheromone by use ofJacobsen’s catalyst.Anderson in 1979 published the first synthesis of the California Red Scalepheromone. 6 His method used (3S) citronellol as starting material and employedthe use of m-chloroperoxybenzoic acid as the reagent for epoxidation. Andersonsynthesized a mixture of diastereomers at C 6 and then proceeded to separate thediastereomers by High Performance Liquid Chromatography (HPLC).Baudouy in 1987 synthesized the California Red Scale pheromoneenantioselectively using trans (-)-dihydrocarvone as starting material. 23 Thisstarting material already has the correct configuration at C 3 and C 6 . The problemfor Baudouy was the preservation of both chiral centers during the synthesis of thenecessary butenyl and acetate groups. This was accomplished by theregioselective ozonolysis of the (-)-dihydrocarvone to allow for preservation ofboth chiral centers in the final pheromone product.Becker in 1988 published the first enantioselective synthesis of theCalifornia Red Scale pheromone. 24 (R)- Limolene was used as starting material.In Becker’s method, the correct C 6 configuration is already in place by using (R) –Limolene. The problem for Becker was the synthesis of the correct C 3stereochemistry. A mixture of diastereomers at C 3 resulted in the steps thatfollowed.

20Calo in 1990 published a method of synthesizing the California Red Scalepheromone using (S)(-) citronellyl benzyl ether as starting material. 25 Caloreported an overall yield of 71% for the final pheromone product. This synthesisdid not attempt to synthesize the pheromone asymmetrically and also resulted in amixture of diastereomers at C 6 .The most recent published synthesis of the California Red Scale pheromonewas in 1994 by Keflas 26 . The synthesis was a three-step process starting from S-citronellyl acetate with an overall yield of 30%. The C 3 chiral center was alreadyconfigured in the starting material and the Keflas synthetic route resulted in amixture of diastereomers at C 6 .After an extensive literature review utilizing Chemical Abstracts, it wasconcluded that this study was the first to use the Jacobsen’s catalyst in an attemptto asymmetrically synthesize the California Red Scale pheromone in the correctand proven biologically active configuration of (3S,6R).Use of Higher Order Cuprates in the Synthesis of theCalifornia Red Scale PheromoneThe ease of preparing organomagnesium compounds (or Grignard reagents)from organic halides and their high reactivity towards polar organic functionalgroups make them excellent reagents in organic synthesis. 27Under the currentlyused synthesis scheme for the commercial production of the California Red Scalepheromone, a Grignard reagent is reacted with an epoxide to yield an alcohol, asrepresented in Figure 15.Epoxides are structures prone to nucleophilic attack due to the inherentstrain in a three-membered ring, as well as the electron deficiency at the site ofattack due to the presence of an electronegative oxygen atom. This reaction addsthe necessary butenyl group to the carbon skeleton of the pheromone, as well as

21making a tertiary alcohol. The reaction is a nucleophilic substitution that proceedsvia an S N 2-like pathway, with inversion of stereochemical configuration. Thistertiary alcohol is then ready for dehydration to an alkene, another necessaryelement in the final CRS pheromone structure. Grignard reagents have theadvantages of synthetic accessibility, excellent solubility, and stability in storageOMgBr+OOCuITetrahydrofuran at -40 COOOHFigure 15. Ring opening of epoxide by Grignard reagentover lengthy periods of time in diethyl ether or tetrahydrofuran (THF).During the synthesis of butenyl MgBr, butenyl bromide is reacted withmagnesium metal. There are inherent problems with the synthesis of alkenylicGrignard reagents. 27 When alkenylic bromides are used in typical Grignardprocedures, yields of the Grignard reagent are low because of the ease ofdimerization with which the generated magnesium compound couples with R-X toform R-R. This unwanted coupling can be minimized by slow introduction of the

22halide into an excess of magnesium. Another problem with handling alkenylichalides is that they are lachrymators and skin irritants. A good fume hood isneeded when handling these reagents. As with other organometallic reactions, theTHF solvent must be thoroughly dried, by distilling over Na metal andbenzophenone.One key disadvantage to the Grignard reagent synthetic route in the CRSpheromone synthesis is the non-selectivity of the Grignard reagent in attackingelectrophilic carbons. The final CRS pheromone structure has an acetatecomponent. A bulky protecting group is needed to prevent attack at the acylcarbon by the Grignard reagent. A smaller acetate group in the same place wouldnot effectively prevent the Grignard reagent from attacking the acyl carbon.Because of this fact, the starting material citronellol must be converted tocitronellyl pivalate. If another method could be used to add the butenylcomponent and open the epoxide ring as a Grignard reagent does, but has betterselectivity towards attacking the C 6 epoxide ring, instead of the acetate, thepivalate protecting group would not be needed. A step could be removed from thetotal synthesis scheme, saving both time and money.In 1984, Dr. Bruce Lipschutz of the University of California at SantaBarbara published a study in which higher order, mixed organocuprates(R 2 Cu(CN)Li 2 ) were allowed to react with epoxides to yield alcohols. 28,29 It washypothesized that perhaps these higher order cuprates could be used to replace theGrignard reagent utilized in the synthesis of CRS pheromone. The theorizedreaction is shown in Figure 16.Reaction of higher order cuprates with 6,7-epoxycitronellyl acetate wasstudied to see if this would be a viable synthetic route. Synthesis of the higher

23order cuprate from Cu(CN) and R-Li was also studied. 30studied starting with an allylic halide with lithium metal. 31Synthesis of R-Li wasOButenyl 2Cu(CN)Li 2+OOOOOHFigure 16. Ring opening of epoxide using Higher Order Cuprates

RESULTS AND DISCUSSIONSynthesis of (3S) Citronellyl PivalateSynthesis of this compound was necessary to provide the starting materialfor the epoxidation reactions to follow. (3S) Citronellol is a good choice ofstarting material as it contains many features in the carbon skeleton of theCalifornia Red Scale pheromone. (3S) Citronellol already has a C 3 chiral carbonthat can be commercially obtained in high optical purity. Citronellol was reactedwith trimethylacetyl chloride to yield Citronellyl pivalate. The desired productwas primarily characterized by Infrared spectroscopy (IR), showing a strongabsorption band at 1729.24 cm -1 , characteristic of a carbonyl group present, wherethere was none in citronellol (Figure 17). The NMR spectrum showed a tripletpeak at 4.10 ppm, characteristic of an ester group created by acylation ofcitronellol (Figure 18). The yield of this reaction is good at 90%.Synthesis of (3S,6RS)-6,7-Epoxycitronellyl PivalateThe synthesis of this mixture of diastereomers was necessary in order tocharacterize the single diastereomer synthesized by using Jacobsen’s catalyst.Citronellyl pivalate was then epoxidized with m-chloroperoxybenzoic acid to givea mixture of diastereomers. Characterization of the epoxide mixture ofdiastereomers was done primarily by GC/MS (Figure 19, 20, 21). The progress ofthe reaction was monitored by disappearance of peaks due to starting material andappearance peaks due to product on the GC trace. Product characterization wasdone by 1 H NMR (Figure 22). A peak at 2.65 ppm (triplet) showed that theepoxide had formed, while disappearance of the alkene triplet at 5.10 ppm in thestarting

material showed that the alkene was gone. (Figure 23) Product also identified by25Figure 17. IR spectrum of (3S) citronellyl pivalate taken as neat sample

Figure 18. 1 H NMR spectrum of (3S) citronellyl pivalate in CDCl 326

Figure 19. GC/MS trace of [(3S,6RS)-6,7-epoxycitronellyl pivalate] + [(3S)citronellyl pivalate] co-injection (gradient 150 °C → 230 °C, ∆T = 5 °C/min)27

Figure 20. GC/MS trace of (3S) citronellyl pivalate (gradient 150 °C → 230 °C,∆T = 5 °C/min), starting material28

Figure 21. GC/MS trace of (3S,6RS)-6,7-epoxycitronellyl pivalate(gradient 150 °C → 230 °C, ∆T = 5 °C/min), product29

Figure 22. 1 H NMR spectrum of (3S,6RS)-6,7-epoxycitronellyl pivalate in CDCl 330

Figure 23. IR spectrum of (3S,6RS)-6,7-epoxycitronellyl pivalate taken as neatsample31

32IR spectroscopy .Separation of Epoxide Diastereomers Using EC-WAXCapillary GC ColumnIn order to characterize the asymmetric epoxide and confirm that a singlediastereomer is synthesized, separation of the mixture of diastereomers must beaccomplished on GC-MS. Since diastereomers have different physical properties,a chiral column is not needed for separation. The original synthesis of CaliforniaRed Scale pheromone by Anderson used a capillary GLC (20 m x 0.25 mm ID)Carbowax 20M column. 6This is a polar column using polyethylene glycol asliquid phase material. In theory, polar molecules will be retained on this type ofcolumn longer than non-polar molecules. A column was needed that wouldperform in a similar fashion to the Carbowax 20M capillary column used byAnderson. Due to the high cost of Carbowax 20M capillary columns, an EC-WAX (30 m x 0.25 mm ID) column from Alltech was purchased. The ECproduct line of capillary columns from Alltech are mass-produced columns that areeconomical.The next set of experiments was done in order to optimize the GC-MSconditions for the separation of the diasteromeric mixture. A series of isothermalinjections of (3S,6RS)-6,7-epoxycitronellyl pivalate was performed to achieve thistask, starting at 150° C, 125° C, 115° C. (Figure 24,25,26). Even though retentiontime of the epoxide progressively became longer as expected, the epoxide stayedin one peak. After these discouraging results, the same set of experiments wasperformed upon the acetate analog of the previous compound. A series ofisothermal injections of (3S,6RS)-6,7-epoxycitronellyl acetate were performed,starting at 150° C, 115° C, 105° C. (Figure 27,28,29) Partial separation wassuccessful at 115° C and 105° C. Even though the two peaks were not ideally

Figure 24. GC/MS trace of (3S,6RS)-6,7-epoxycitronellyl pivalateisothermal 150 °C33

Figure 25. GC/MS trace of (3S,6RS)-6,7-epoxycitronellyl pivalateisothermal 125 °C34

Figure 26. GC/MS trace of (3S, 6RS)-6,7-epoxycitronellyl pivalateisothermal 115 °C35

Figure 27. GC/MS trace of (3S,6RS)-6,7-epoxycitronellyl acetateisothermal 150 °C36

Figure 28. GC/MS trace of (3S,6RS)-6,7-epoxycitronellyl acetateisothermal 115 °C37

Figure 29. GC/MS trace of (3S,6RS)-6,7-epoxycitronellyl acetateisothermal 105 °C38

39resolved, it was apparent that there were two diastereomers in the mixture. Anintegration of the two diastereomeric peaks from the isothermal 115° C GC run(Figure 29) provides a way to calculate the ratio of diastereomers. The ratio ofdiastereomers was calculated to be 63:36, according to these GC conditions. Asimilar integration of the two diastereomeric peaks from the isothermal 105° C GCrun revealed a diastereomeric ratio of 59:41. From these results it is shown thatthe acetate analog of the epoxide can be separated by using an EC-WAX GCcolumn using isothermal temperature runs, but that the pivalate epoxide wouldprove to be more difficult to characterize.Figure 30. Integration of GC/MS peak corresponding to (3S,6RS)-6,7-Epoxycitronellylacetate isothermal 115 °CFigure 31. Integration of GC/MS peak corresponding to (3S,6RS)-6,7-epoxycitronellylacetate isothermal 105 °CAsymmetric Synthesis of (3S,6S)-6,7-EpoxycitronellylPivalateSynthesis of this compound would show whether or not this was a viablesynthetic route for the California Red Scale pheromone. The reaction wascomplete after one day and monitored by the disappearance of the GC-MS peak

40due to the starting material (3S) citronellyl pivalate and the appearance of that dueto the product. Confirmation of the epoxide was done by co-injection of theepoxide formed using Jacobsen’s catalyst with the diastereomeric mixture createdby m-chloroperoxybenzoic acid (Figure 32). As can be seen from the GC trace,the two epoxides co-eluted. Analysis of the NMR spectra from the asymmetricepoxide confirmed the structure of the epoxide (Figure 33). The triplet at 2.69ppm is characteristic of an epoxide, while the triplet at 4.10 ppm is characteristicof an acyl ester present in the compound. IR spectra also confirmed the structureof the epoxide (Figure 34). Purification was necessary to separate the Jacobsen’scatalyst from the epoxide. There were examples in the literature of the epoxidebeing distilled from the mixture. However, these epoxides were typically lowboiling epoxides with lower molecular weights than the epoxide used in this work.An attempt to distill (3S,6S)-6,7-Epoxycitronellyl pivalate from the mixture usingvacuum distillation proved unsuccessful. Separation of the catalyst from epoxidewas successful using flash chromatography, with silica gel as the stationary phaseand a methanol/dichloromethane mixture as eluent.Use of a chiral shift reagent was unsuccessful in characterizing theasymmetric epoxide. None of the peaks in the 1 H NMR spectrum split into twodistinguishable peaks, corresponding to the two diastereomers present in themixture. Although the peaks shifted noticeably upfield, only peak broadening wasapparent.Although 1 H NMR experiments proved unsuccessful in characterizing theasymmetric epoxide, 13 C NMR experiments were successful. Figures 35, 36, and37 show the 13 C NMR spectrum of (3S,6RS)-6,7-Epoxycitronellyl pivalate.Splitting of peaks is readily apparent at 58 ppm, 35 ppm, 33 ppm, 30 ppm, and 19

Figure 32. GC/MS trace of [(3S,6RS)-6,7-epoxycitronellyl pivalate] + [(3S,6S)-6,7-epoxycitronellyl pivalate] co-injection (gradient 150 °C → 230 °C, ∆T = 5°C/min)41

42Figure 33. 1 H NMR spectrum of (3S,6RS)-6,7-epoxycitronellyl pivalate in CDCl 3Figure 34. IR spectrum of (3S,6S)-6,7-epoxycitronellyl pivalatetaken as neat sample

Figure 35. 13 C NMR spectrum of (3S,6RS)-6,7-epoxycitronellyl pivalate in CDCl 343

Figure 36. 13 C NMR spectrum of (3S,6RS)-6,7-epoxycitronellyl pivalate(58 ppm – 67 ppm) in CDCl 344

45Figure 37. 13 C NMR Spectrum of (3S,6RS)-6,7-Epoxycitronellyl Pivalate (18 ppm– 39 ppm) in CDCl 3ppm. This splitting is due to the presence of a diastereomeric mixture. The peakheights show an approximately 1:1 mixture of diastereomers.The 13 C NMR spectrum of (3S,6S)-6,7-Epoxycitronellyl pivalate shows thatthe same peaks have split (Figure 38, 39, and 40). Due to the asymmetric natureof the synthesis, the split peak heights show an approximately 1:2 mixture ofdiastereomers.

46Figure 37. 13 C NMR Spectrum of (3S,6S)-6,7-Epoxycitronellyl Pivalate in CDCl 3Figure 38. 13 C NMR Spectrum of (3S,6S)-6,7-Epoxycitronellyl Pivalate in CDCl 3(57 ppm – 66 ppm)

47Figure 39. 13 C NMR Spectrum of (3S,6S)-6,7-Epoxycitronellyl Pivalate in CDCl 3(18 ppm – 40 ppm)Ring opening of 6,7-Epoxycitronellyl Pivalate usingHigher Order Mixed OrganocupratesThe study was first carried out using butyl lithium, not butenyl lithium.This was done to save the expensive butenyl lithium until we knew that thereaction had some probability of success. It was theorized that butenyl lithiumwould react in a similar fashion to butyl lithium. We had available to us butyllithium which was reacted with Cu(CN) to form the higher order mixed cuprateBu 2 Cu(CN)Li 2 . This was then reacted with 6,7-epoxycitronellyl acetate.After the first attempt to synthesize the tertiary alcohol and to add the butylgroup, there were two interesting results. First, an unwanted byproduct showed a

48major peak by GC/MS (Figure 40). It was concluded that this product was 5-methyl-5-nonanol, MW=158.17 (Figure 41).OHFigure 41. 5-methyl-5-nonanolComparison of the sample with a mass spectrometry library searchconclusively identified the peak as 5-methyl-5-nonanol. (Figure 42)At first glance, it seems that the two butyl groups from the cuprate specieshave reacted to form a dimer. This shows a significant attack on the acetatecarbonyl. One possible conclusion to this observation is that, indeed, the pivalateprotecting group was needed to prevent attack of the cuprate on the acyl groupinstead of the intended epoxide ring.The second observation was that the reaction was successful in forming thedesired product. The GC/MS trace showed two discernible peaks representing thetwo diastereomers present in the mixture (Figure 43). During the previousepoxidation step, at the chiral center C 6 , a mixture of diastereomers is formed andthis mixture is carried to the final pheromone mixture. A workup procedure forthe ring opening reaction was devised, since there were different workupprocedures in literature. The workup procedure was intended to keep the productin the organic layer (hexane), which was then evaporated to yield the product.During this experiment, however, it was found that a small portion of the productremained in the aqueous layer as shown in the GC/MS trace was of the aqueouslayer. This

Figure 40. GC/MS trace of reaction mixture showing 5 methyl-5 nonanol (top)and unreacted epoxide (bottom) gradient 150 °C → 230 °C, ∆T = 5 °C/min49

Figure 42. Results of GC/MS library search conclusively identified 5-methyl-5nonanol50

Figure 43. GC/MS trace of reaction mixture showing two diastereomers of(3S,6SR)-6-(1 Hydroxy-1-methyl ethyl)–3-methyl-decan-1-yl-2,2 acetate, gradient150 °C → 230 °C, ∆T = 5 °C/min51

52GC/MS trace showed that only intended product was present, without the 5-methyl-5-nonanol impurity (Figure 44). The overall yield of this reaction was37%From these results it was concluded that the use of higher order cuprates inthe CRS pheromone synthesis is a viable option, but that the introduction of apivalate protecting group on the acyl side of the carbon skeleton was needed. Thisprotecting group is also needed for the current synthetic scheme using theGrignard reagent to add the butenyl group and open the epoxide to form a tertiaryalcohol. Therefore there is no advantage to using the higher order cuprates in thering opening step, other than if a cost analysis reveals that using higher ordercuprates instead of Grignard reagents is less expensive.The final experiment done in this study was to see if butenyl bromide couldreact with lithium metal to form butenyl Lithium. After all, butenyl Lithium wasneeded to add the necessary butenyl group to the carbon skeleton and not butyllithium. This experiment showed that butenyl bromide would not react withlithium metal at all to form butenyl lithium. Although an argon atmosphere wasused instead of nitrogen (N 2 ) atmosphere would react with Li metal to formlithium nitride), it appeared that a black film was forming on the surface of thelithium metal during reaction. Also there was no observable temperature changethat would show that a reaction has taken place. There must have been a leak inthe system, letting nitrogen in or perhaps the Br leaving group would not work inthe formation of the alkenyllithium. This was tested by reacting chloropentanewith lithium metal to see if a reaction would occur. During this reaction, bubblingand a temperature change of 10 degrees was observed, evidence of a reactionoccurring.

Figure 44. GC/MS trace of reaction mixture showing two diastereomers of (3S,6SR) 6-(1 Hydroxy-1-methyl ethyl) –3-methyl decan-1-yl 2,2 Pivalate (fromaqueous layer) gradient 150 °C → 230 °C, ∆T = 5 °C/min53

EXPERIMENTALAll 1 H Nuclear Magnetic Resonance (NMR) Spectroscopy were performedusing a Gemini 200 Mhz. All 13 C Nuclear Magnetic Resonance Spectroscopywere performed using a Gemini 50 Mhz. The samples were dissolved in CDCl 3 ,which was used as internal standard.All Infrared (IR) spectroscopy were performed using an Avatar 320 FT-IR.The samples were prepared neat.All Gas Chromatography-Mass Spectrometry (GC/MS) were performedusing a Hewlett Packard Model 5890 GC using helium as carrier gas connected toa Hewlett Packard 5988A Mass Spectrometer using electron impact as theionization method. An EC-WAX 30 m x 0.25 mm I.D. capillary column was used.Samples were dissolved in methanol and 1uL of sample in methanol was theinjection volume.All reactions were carried out in a well ventilated hood and ultra high puritygrade N 2 gas was used as inert atmosphere where indicated. Argon gas was usedas inert atmosphere where N 2 was not suitable.Synthesis of (3S) Citronellyl Pivalate(3S) l-citronellol was purchased from Bush Boake Allen, trimethylacetylchloride was purchased from Acros Organics, pyridine was purchased from AcrosOrganics.(3S) l-citronellol, 50 grams (0.320 mol), was added to a 2-neck, 250 mlround bottom flask equipped with an addition funnel and thermometer. Pyridinedried by molecular sieves (115 ml) was added and the solution was cooled to 1-2°C using an ice-water bath. Trimethylacetyl chloride, 41.4 ml (1.05 equivalent,

550.336 ml), was added dropwise through an addition funnel equipped with a dryingtube. The temperature was kept below 10 °C at all times during the 1.5 hoursrequired for the addition. During this time, pyridine hydrochloride was observedto precipitate in the reaction flask. The reaction was allowed to warm to roomtemperature and stirred overnight.The workup was done by solid precipitate of pyridine hydrochlorideremoval by vacuum filtration. Reaction flask and filter cake were washed 5 x 30ml ethyl ether. The filtrate (organic layer) was funneled into a 500 ml separatoryfunnel and extracted with 3 x 100 ml 2 M HCl. The combined aqueous layerswere extracted with 1 x 50 ml ethyl ether. This ethyl ether layer was combinedwith the previous organic layer, washed with 1 x 50 ml 10% NaHCO 3 , and then 1x 50 ml saturated ammonium chloride. The combined organic layers were placedinto a 500 ml Erlenmeyer flask and dried overnight over MgSO 4 .The ether solvent was evaporated away using a rotary evaporator to yieldproduct. The product had some pyridine still present, therefore vacuum distillationwas necessary to purify the citronellyl pivalate. The product was distilled at 20torr, 140 °C to yield 76.8 grams of citronellyl pivalate (90% yield). The productwas characterized by NMR, IR and GC/MS. NMR confirmed a trace of startingmaterial citronellol was present (triplet at 3.69 ppm).1 H NMR (200 MHz, CDCl 3 , δ): 5.09 (t, 1H, RHC=CRR), 4.10 (t, 2H,CH 2 CH 2 0COCH 3 ), 1.30 (s, 9H, -CH 3 )IR (cm -1 ): 2960.45, 2873.20, 1728.17, 1480.61, 1461.04GC-MS m/z (ion, %relative intensity): 157 (1), 138 (90), 123 (90), 95 (90),81 (90), 69 (70), 57 (70).

56Synthesis of (3S,6RS)-6,7-Epoxycitronellyl Pivalate3-Chloroperoxybenzoic acid was purchased from Acros. The (3S)citronellyl pivalate used was synthesized from (3S) citronellol and describedpreviously.Into a 500 ml 3-neck round bottom flask, equipped with mechanical stirrer,40.4 grams of (3S) Citronellyl pivalate (0.168 mol) was added to 294 ml ofdichloromethane, along with 14.76 grams of NaHCO 3 (0.176 mol, 1.05equivalent). The round bottom flask was then immersed in an ice/salt water bathto maintain a temperature of between 0° C and 10° C. 3-chloroperoxybenzoic acid(28.94 grams, 0.168 mol, 1 equivalent) was added to the stirred solution slowly tokeep the temperature below 10° C. After 1 hour, addition of 3-chloroperoxybenzoic acid was complete. Ice/salt water bath was then removed,the reaction mixture was allowed to warm to room temperature, and was stirredovernight.The dichloromethane layer was washed 2 x sat. NaHSO 3 , 2 x sat. NaHCO 3 ,and 2 x sat. NaCl. The dichloromethane layer was then dried over MgSO 4 in a500 ml Erlenmeyer flask. The organic layer was then filtered to remove MgSO 4and the dichloromethane was evaporated to yield the product. 29.80 grams ofproduct was isolated corresponding to a 69.3% yield. The product was confirmedby NMR, IR, and GC/MS. NMR confirmed a trace of starting material citronellolwas present (triplet at 3.69 ppm).1 H NMR (200 MHz, CDCl 3 , δ): 4.10 (t, 2H, CH 2 CH 2 0COCH 3 ), 2.60 (t, H,-epoxide H), 1.30 (s, 9H, -CH 3 )IR (cm -1 ): 2960.45, 2873.20, 1728.17, 1480.61, 1461.04GC-MS m/z (ion, %relative intensity): 241 (1), 171 (1), 154 (10), 103 (40),85 (90), 57 (100).

Asymmetric Synthesis of (3S,6S)-6,7-EpoxycitronellylPivalate5.25% in water commercial bleach (NaOCl), Good Day brand, waspurchased from Albertson’s Food Store, (S,S) Jacobsen’s catalyst was purchasedfrom Aldrich, 4-phenylpyridine N-oxide was purchased from Acros. The (3S)citronellyl pivalate used was synthesized from (3S) citronellol and describedpreviously.A solution of 0.05 M Na 2 HPO 4 (16.8 ml) was added to 42 ml (0.03 mol, 1.5equivalent) of commercial bleach (0.709 M or 5.25%). One drop of 1 M NaOHwas added to make a basic solution, confirmed by pH paper. Citronellyl pivalate(0.02 mol), (S,S) Jacobsen’s catalyst (0.002 mol, 0.1 equivalent), 4-phenylpyridineN-oxide (0.004 mol, 0.2 equivalent), were all dissolved in ~20 ml dichloromethane(DCM) in a 100 ml round bottom flask). The buffered bleach solution was thenadded slowly to the citronellyl pivalate solution via an addition funnel (heating isobserved). The reaction was a two phase (aqueous/organic) reaction. The mixturewas allowed to stir overnight and monitored by GC/MS (disappearance of startingmaterial, citronellyl pivalate, was observed). A GC/MS sample was taken fromthe reaction mixture as follows: stirring for the reaction is stopped, a glass pipetwas used to take a sample from the bottom organic layer, and the sample wasdiluted with methanol to run a GC/MS.After one day, the completion of the reaction was observed by GC/MStrace. All starting material has disappeared. ~75 ml of DCM was added to thereaction mixture. The organic and aqueous layers were then separated via aseparatory funnel. The DCM layer was washed 2 x sat. NaCl and then dried overNa 2 SO 4 . After drying, the solution was filtered and the organic solvent evaporatedto yield the epoxide product. The theoretical yield of epoxide was 5.13 grams,experimental yield was 8.43 grams. This indicated that there was Jacobsen’s57

58catalyst in the product. Another indicator that there was Jacobsen’s catalyst in theproduct was the purple color of the product, indicating that manganese waspresent, as well as the multiple spots on TLC. There were two ways to purify theepoxide, flash chromatography and vacuum distillation.Flash chromatography was performed upon the product in order to separatethe epoxide from the Jacobsen’s catalyst. The solvent system used was 5%methanol in dichloromethane. Baker Silica gel (40 micrometer particle diameter)was used and the column dimensions were 4 cm (width) x 10 inches (length).Purified epoxide eluted first from the column. All fractions were checked forpurity by TLC. Jacobsen’s catalyst and 4-phenylpyridine N-oxide were elutedwhen the column was washed with 100% methanol.1 H NMR (200 MHz, CDCl 3 , δ): 4.10 (t, 2H, CH 2 CH 2 0COCH 3 ), 2.60 (t, H,-epoxide H), 1.30 (s, 9H, -CH 3 )IR (cm -1 ): 2960.45, 2873.20, 1728.17, 1480.61, 1461.04GC-MS m/z (ion, %relative intensity): 154 (5), 139 (5), 113 (10), 97 (100),81 (100), 68 (50), 57 (100).Synthesis of Bu 2 Cu(CN)Li 2A 100 mL round bottom flask was oven dried at 120° C and flushed withN 2 . Cu(CN) (0.8956 g, 0.01 mol, 1 eq) was dissolved in 10 mL dry THF, theslurry was cooled to –78 ° C. A dry ice-acetone bath was used to cool to theneeded temperature. Butyl Lithium (8 mL, 0.02 mol, 2 eq) was added to anaddition funnel connected to the round bottom flask via N 2 pressured double endedneedle. The Butyl Lithium was a 2.5 M solution in hexanes (d=0.0693 g/mL).The Butyl Lithium was added dropwise to the THF/Cu(CN) mixture and the

temperature was allowed to rise slowly to 0° C, over a period of two hours. Theproduct was immediately used for the next step.59Ring opening of epoxide using Bu 2 Cu(CN)Li 2 and(3S,6SR)-6,7-Epoxycitronellyl acetateIn a 50 mL round bottom flask cooled to –78 ° C, 2.175 g (0.01 mol, 1 eq)Bu 2 Cu(CN)Li 2 was added to 2.13 g (0.01 mol, 1 eq) of 6,7-epoxycitronellylacetate via an N 2 pressurized double ended needle. The reaction mixture wasgradually warmed to 0 ° C and monitored by disappearance of starting material onGC/MS. The reaction mixture was allowed to mix overnight at room temperature.The reaction was quenched with 10% NH 4 OH and saturated NH 4 Cl. The reactionmixture (THF + aqueous) was then filtered through Celite to remove solidspresent. Reaction mixture was then washed with hexane. The organic layer waswashed 1 x saturated NH 4 Cl and 1 x saturated NaCl, then dried over MgSO 4 andevaporated to yield product. 0.82 grams of product isolated, 2.72 gramstheoretical yield. The percent yield was 37%. Product was characterized byGC/MS.GC-MS m/z (ion, %relative intensity): 157 (5), 113 (5), 99 (5), 85 (25), 71(25), 59 (100).Synthesis of Butenyl Lithium, using Butenyl Bromideand Li wirePetroleum ether was dried by refluxing using Na metal and benzophenone.50 mL of dry petroleum ether was placed into an oven dried, Argon gas flushed 3neck 100 mL round bottom flask. Lithium wire (3.1 cm, 0.02 mol, 139 mg, 2 eq)was measured out (45 mg/cm wire), rinsed with dry pet ether and added into thedry pet ether in the round bottom flask. 1.35 g (0.01 mol, 1 eq) butenyl bromidewas then added dropwise to the lithium metal in pet. ether mixture. No reaction

60was observed and no temperature change. Boiling chips were added and themixture was heated to ~40° C and allowed to reflux. Still no reaction wasobserved. The reaction mixture was allowed to stir overnight. Another equivalentof lithium was added. Before it was added, the lithium was pounded into flatchips and the first lithium layer was sanded before adding to the reaction mixture.This was done to remove any lithium that may have reacted with nitrogen in theatmosphere to form a lithium nitride coating. No reaction was observed.Synthesis of Pentyl Lithium, using chloropentane andLi wireDry pentane was prepared by distillation over Na metal and benzophenone.15 ml dry pentane was placed into a three neck 25 mL round bottom flask. 1.06 g(0.01 mol, 1 eq) of 1-chloropentane was added to the dry pentane. 3.1 cm (0.02mol, 139 mg) Li wire was cut, pounded into chips, and sanded. The lithium wasthen placed into the reaction flask. After 15 mins, the chips disintegrated and thetemperature rose from 20 °C to 30

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