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300 N. ZEEB ROAD, ANN ARBOR, Ml 4ÜI0G 18 BEDFORD ROW, LONDON WCIR 4EJ, ENGLAND 8100155

GANGE, DAVID MICHAEL

HELIXANES. THE FIRST PRIMARY HELICAL MOLECULES; POLYOXAPOLYSPIRO ALKANONES

The Ohio State University PH.D. 1980

University Microfilms Intern at ional300 n . Zeeb Road, Ann Arbor. MI 48106

POLYOXAPOLYSPIROALKANONES

DISSERTATION

Presented in Partial Fulfillment of the Requirements for

the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

By David M. Gange, B.S.

*****

The Ohio State University

1980

Reading Committee: Approved By Leo A. Paquette

John S. Swenton Philip D. Magnus Department of Chemistry For Sue

11 ACKNOWLEDGEMENTS

I would like to thank the National Science Foundation, the National Institutes of Health and The Ohio State

University for financial support during the time this work was done.

Dr. Charles Cottrell and Mr. John Venit are thanked for their ^^C NMR work. I would like to thank Mr. Dick Weissenberger for his mass spectral work. Ms. Dixie Fisher is thanked for typing the manuscript. Drs. Edward Ehlinger, Stevan Djuric and Malcolm Nobbs are warmly thanked for their assistance and advice. The members of the Magnus research group are thanked for their advice, criticisms and encouragement. Professor P. D. Magnus is deeply thanked for his patience and advice. I have been priviledged to work for him.

ill VITA

July 22, 1955...... Born, Royal Oak, Michigan 1977...... B.S., with Honors in Chemistry, Tulane University

1977-197...... 8 Teaching Associate, Department of Chemistry, The Ohio State University

1978-197...... 9 Research Associate, Department of Chemistry, The Ohio State University

1980...... The Ohio State University Presidential Fellow.

PUBLICATIONS

"An Unusual New Allene Cyclisation Reaction Synthesis of Dihydrofuran-3(2H)-ones." D. Gange and P. Magnus, J . Am. Chem. Soc., 100. 7746 (1978). "Helixanes. The First Primary Helical Molecules: Polyoxapolyspiroalkanones." D. Gange, P. Magnus, T. Bass, E. Arnold and J. Clardy, J . Am. Chem. Soc. , 102, 2134 (I98O)

FIELD OF STUDY

Organic Chemistry. Professor P. D. Magnus

iv TABLE OP CONTENTS

Page DEDICATION...... ü

ACKNOWLEDGEMENTS...... H i VITA...... iv

LIST OP TABLES...... vl LIST OP PIGURES...... vll ABBREVIATIONS...... vlil

CHAPTER 1 Introduction...... i CHAPTER 2 Methoxyallene Chemistry...... CHAPTER 3 Discussion...... 24 CHAPTER 4 Puran-3-one and Dlhydrofuran-3-one Synthesis...... 42

CHAPTER 5 Discussion...... %...... 55 CHAPTER 6 Discussion...... &4

CHAPTER 7 Discussion...... 76

CHAPTER 8 Experimental...... ^3 Experimental to Chapter 1...... 83

Experimental to Chapter 3...... 88

Experimental to Chapter5 ...... Experimental to Chapter 6...... i45

Experimental to Chapter7 ...... i55

References...... 180 LIST OF TABLES

Table Page

I List of Compounds...... 27 II The Reaction of Organometallic Reagents with Unsaturated Carbonyl Compounds...... 77 III The Reaction of Organometallic Reagents with Unsaturated Imino Compounds...... 77

Vi LIST OF PIGURES

Figure Page

I X-Ray Crystal Structure of Cyclopentyl[4]- helixane...... 53

vii ABBREVIATIONS nBuLl n-butyllithlum sBuLl s-butyllithlum

THF tetrahydrofuran tBuGH tert-butyl alcohol EtOAc ethyl acetate

EtzO diethyl ether DMSG dimethyl sulfoxide HMPT hexamethylphosphoric triamide TMEDA N,N,N',N’-tetramethylethylene diamine

CH2CI2 dichloromethane NaH sodium hydride KH potassium hydride LAH lithium aluminium hydride

KGtBu potassium tert-butoxide

LDA lithium diisopropylamide MgSGu magnesium sulfate

BF 3 *Et2G boron trifluoride etherate complex

Hg(GAc)2 mercuric acetate gTsGH para-toluenesulfonic acid -GTs tosyl group

-GMs mesyl group

MEM methoxyethoxymethoxy group

viii TLC thin layer chromatography nun Hg millimeters of mercury mmol millimole(s)

NMR nuclear magnetic resonance s singlet

d doublet t triplet q quartet

m multiplet

br broad IR Infrared

s strong m medium

w weak br broad

MS mass spectrum

Ix CHAPTER 1 INTRODUCTION

As part of a study of annulation reactions being conducted in our laboratories we were examining the use of the allytrimethylsilyl anion as a G-acyl anion equivalent The commercially available compound allyltrimethylsilane 1

s-BuLi/-78°C THP/TMEDA

is readily deprotonated, at low temperature in the presence of TMEDA, to give the anion 2. The anion formed is an ambident anion. Our work has shown that the allyltrlmethyl- silyl anion reacts with ketones exclusively in the y-

position to produce 6-hydroxyvinylsilanes , which are convertible, through oxidation and hydrolysis, to lactones or lactols."

We have examined methods to effect the 1,4 addition of the allyltrimethylsilyl anion to conjugated ketones. If successful, the resulting vinylsilanes 3 could be oxidized, and hydrolyzed to unmask the carbonyl 4. Aldol

condensation would complete the annulation sequence providing a new method for the synthesis of Un.B.oH ring systems.

1 1) [o] @ ■> 2) HaO

HO BASE

4 5

-78°C THF

Deprotonation of allyltrimethylsilane at low tempera ture in THF, followed by addition of 2-cyclohexen-l-one led to the formation of the 6-hydroxyvinylsilane 6. A small portion of the desired adduct 3 could, also be detected by IR. In the hope that the addition of the allyl anion might be reversible, as some allyl anion additions are. the reaction was run at a higher temperature. If the reaction was reversible, the thermodynamic product 3, would be obtained. Allyltrimethylsilane was deprotonated at low temperature, warmed to 0°C, followed by addition of 2-cyclohexen-l-one. The mixture was allowed to stir for 10 h. at G°C. The only product isolated was the 6-hydroxy

vinylsilane 6. Copper (I) complexes of alkyllithium compounds are

known to add 1,4 to conjugated ketones.? We attempted

to form the cuprate 7 of the allyltrimethylsilyl anion. Addition of purified copper (I) iodide® to a solution of the allyltrimethylsilyl anion in THF at -20°C led to the

formation of a dark solution. The addition of 2-cyclohexen- l-one to this solution resulted in the formation of the

6-hydroxyvinylsilane 6. Posner? has stated that,in cases where the cuprates of stabilized anions are formed, an equilibrium between the anion 2 and the cuprate 7 may

exist. Since the free anion is more reactive than the cuprate, the observed products are those that result from the addition of the free anion. This seems to be the case with the allyltrimethylsilyl anion.

Cul \ CuLi

1 M2/Et,0 5 S i 2 Cul n

Grignard reagents are known to add to enones in the presence of catalytic and stoichiometric amounts of copper (I) halides. ^ All of our attempts to form magnesium cuprates failed. The only compounds Isolated from these reactions were the starting enone, and a dimer 9, the product of Wurtz coupling. The prospect of finding a method to add the allyltrimethylsilyl anion 1,4 to enones was rather bleak at this point. We turned our attention to the reactions of the 6-hydroxyvlnylsllane.

Deprotonatlon of allyltrimethylsilane In ether at low temperature, followed by warming to -20°C and addition of

2-cyclohexen-l-one was the best method for the synthesis of Ô-hydroxyvlnylsllane 6. We now hoped to rearrange 6 to the 3-allyItrlmethyl- sllyl ketone 1^, via the anion accelerated (3, SU slgmatroplc shift.® Treatment of the ô-hydroxyvlnylsllane 6 with potassium hydride In THF at reflux resulted In clean conversion to the desired ketone ^ . Before we could exploit this reaction, developments In another area forced us to abandon this line of research.

Sj-C THF/A

10 While we were examining the reactions of the allyl trimethylsilyl anion, we were also exploring the chemistry

of another C3 unit methoxyallene ^ ° Heathcock has reported the cuprate of a-me.thoxyvinyllithium 1 1, and he has shown that it undergoes 1,4 addition to conjugated ketones. ^^ We planned to generate the analogous cuprate ^ hoping to achieve conjugate addition followed by hydrolysis to the enone l4. Intramolecular Michael addition would then provide the annulated product. Such a sequence would provide a useful method of synthesizing [n.3.0] 1,4 dicarbonyl systems.

CuLi CuLi

11 12

1 2---

13 1 4 ------^

Simple addition of purified copper (I) iodide® to a THF solution of a-lithiomethoxyallene does not produce

the cuprate only 1,2 adduct 1^ is formed when such

a solution is treated with 2-cyclohexen-l-one. Heathcock

observed identical behavior in the case of a-methoxyvinyl- lithium.ii However, the cuprate IJ. from a-methoxyvinyl- lithium can be formed if dimethyl sulfide is added to the reaction mixture. Unfortunately, this was not the case with a-lithiomethoxyallene. After numerous attempts we abandoned our pursuit of 12. No more than a few percent of 1,4 adduct ^ was ever observed in any experiment, even though the temperature, solvent, and order of addition of the reactants were all varied. Failing to produce the 3-allenyl ketone we decided to attempt the anion accelerated [1,3] sigmatropic shift or the anion accelerated [3,3] sigmatropic shift.® In the first case we would obtain ^ the product we had earlier hoped to synthesize via cuprate chemistry. In the second

case we would obtain an acetylenic ether ^ . Such a compound could be hydrolyzed to an ester. Intramolecular condensa tion of the ester l8 would provide a useful new method for the synthesis of [n.3.o] 3-dicarbonyl systems 19.

KH/THF/Av 16 - - - - Z [1,3]

KH/THF/A 1 6 ^ ^ [3,3] 17 18

19 8

In the event when the allenyl alcohol was treated with potassium hydride in THF at reflux, no reaction was apparent After refluxing for 3 h. only the unchanged starting material could be detected. At this time a catalytic amount of dicyclohexyl-lB-crown-6 was added to the reaction.

Crown ethers are known to be excellent chelating agents.The l8-crown-6 ether is a specific chelating agent for the potassium ion. We expected the formation a free anion, aided by the crown ether, would accelerate the rearrangement. The starting material was completely consumed

15 min. after the addition of the crown ether. However, the expected product had not formed.-^ The allene absorption (1950 cm~^) in the IR had disappeared, but no acetylene absorption (2100 cm“^) had appeared. Instead a strong absorp tion at 1650 cm“^, an enol ether, was present. The alkoxide anion had attacked the terminus of the allene to form the spirodihydrofuran ^ . Hydrolysis to the spirodihydrofuran-

3-one ^ confirmed this result. No products resulting from

the competitive [1,3] or [3,3] sigmatropic shifts were observed in this reaction.

KH/THF/A 0 > __ A + i? « IS IS » X r

20 21 9 Since we were completely surprised by this unexpected rearrangement we decided to examine the reaction in more detail. Our studies illuminated some aspects of the mechanism of the rearrangement and culiminated in the synthesis of the first primary helical molecules. CHAPTER 2

Methoxyallene Chemistry

During the past decade methoxyallene i (l-methoxypropo- diene), and other alkoxyallenes have been employed in a wide variety of synthetic methods. The lithiated species derived from methoxyallene have been especially useful. They possess a combination of high nucleophilicity and low sterlc bulk that is particularly suited to applications in synthesis.

Enones, furans, dienes and acetylenes are among the types of compounds that have been synthesized using methoxyallene.

Hoff, Brandsma and Arenswere the first group to prepare methoxyallene 1. After finding current literature methods inadequate they discovered that methoxyallene 1 and related alkoxyallenes could be prepared in excellent yields by treating neat propargyl ethers with a catalytic amount of potassium tert-butoxide. The reactions were slightly exothermic, not surprisingly since the allene is the thermo dynamically more stable isomer.

KOtBu ^ y h -c3 : - c h 2-o -’CH3

10 11

Next, they found that the allenyl ethers could be cleanly deprotonated in diethyl ether at -40°C. The a-proton was removed exclusively. Solutions of the lithio methoxy allene 2 were stable for days at -40°C, but the compound quickly decomposed to a brown tar at R.T. The a-lithio methoxyallene 2 did not undergo any type of tautomerlsm in ethereal solvents, but tautomérisation did occur in liquid ammonia, as shown by the results of deuteration and alkyla tion experiments.

1 = ® = ^ L i - Et20/-40°C 2

When a-lithio methoxyallene 2 in ether -THF solution was treated with a variety of primary bromides and iodides, the expected alkylations took place in moderate yields. These products 3 could be readily hydrolyzed to the corres ponding enones 4 with dilute aqueous acid.

EtzO/THP (1:1) 3 12

Leroux and Roman^^ were able to produce trl-substltuted enones® in a similar system. They found that the ambident anion produced upon the deprotonation of the propargylic ether could be trapped exclusively as the allene 6, if hard electrophiles were used as trapping agents. This is in contrast to the results of Coreyand Mercier who obtained a mixture of products from the alkylation of this anion.

The substituted methoxyallene 6 could then be lithiated and alkylated once more. Leroux found that his a-lithio methoxy allene was stable at 0°C and that the alkylation was accelerated by the addition of 5-10% HMPT. The products 7 were easily hydrolyzed to the enones 8.

1) BuLi ^5^11 ^ ______) n-BuLi 5H R 2) R'X ^ 5

C 5H 1 1.^ /> H3O®

II 8

Clinet and Linstrumelle^° have also studied the alkyla tion of methoxyallenes. After alkylating a-lithio methoxy allene according to the procedure of Hoff, Brandsma and Arens they found that the y—position could then be deprotonated 13

BuLi Rn _ y

R'X 10 and alkylated in excellent yield. In this case THF alone was used as the solvent instead of a THF - ether mixture.

The compounds 9 hydrolyzed exclusively to the trans enones

In the same paper Clinet and Linstrummele discussed a method for the y-deprotonation of an unsubstituted alkoxy- allene. When tert-butoxyallene 11 was deprotonated with lithium

1) LiN (Q) > 2)nBuBr / ^ 13 dicyclohexyl amide, the y-lithio compound was formed. In this way, heptenal was produced in 80% yield from the alkylation and hydrolysis of the y-lithio tert-butoxyallene.

The product ^ also contained ca. 5% the enone derived from a-alkylation. In addition to undergoing alkylation reactions, a-lithio methoxyallene adds well to ketones. Hoff, Brandsma and Arens^i were the first to examine these ketone additions. They found that ethereal solutions of a-lithio methoxy allene reacted with ketones and aldehydes to provide 14

HO 1 ) n-BuLi

_ 15

carbinols ^ in excellent yield. Again only products from a

deprotonation were observed. The a-hydroxy methoxyallenes

were conveniently hydrolyzed to the corresponding unsaturated ketols ^ in high yield. In two later papers Hoff, Brandsma and Arensstudied the base- and acid-catalyzed rearrangements of the a-hydroxy methoxyallenes. Hydroxy aliénés are known co cyclize to heterocycles under both basic ^" and acidic^® conditions.

They found that when a-hydroxy methoxyallenes l4, derived from the addition of a-lithio methoxyallene to carbonyl compounds were treated with potassium tert-butoxide in DMSO they rearranged to 3-methoxydihydrofurans ^ , which could be hydrolyzed to dihydrofuran-3-ones ^ . Also 3-hydroxy methoxy allenes ^ rearranged in a similar fashion to a mixture of two dihydrofuran isomers 19, and 20 in moderate yield. The ratio of the two products did not alter with prolonged heating. It appears to reflect the position of equilibrium between the isomers. 15

KOtBu DMSO 70°C / 7 R 16 17

KOtBu "U. DMSO/70°C 18 \ 19 20

A completely different rearrangement takes place under acidic conditions. When the 3-hydroxy methoxyallenes ^ are treated with p-toluenesulfonlc acid In THF the only products are polymeric materials. In the case of the a-hydroxy methoxy allenes l4 a considerable amount of polymr^ Is formed along with a small amount of dimer 21. The dimer Is the result of the attack of the hydroxyl groups on the y-carbon carbon of the allene. This position Is not attacked when methoxyallene Itself Is treated with an alcohol and an acid

pTSOH 14

21 16

catalyst.Instead, only a—attack is observed. The reason for the difference may be sterlc. In the formation of the dimer, the y-position is much less hindered than the

a-position.

I - > ’i — ROM I ’

The Arensgroup discovered a way to synthesize

unsaturated acetylenes 25 using methoxyallene. The a-lithio methoxyallene was produced with n-BuLi in ether at -30°C,

then alkylated with an a-chloroethyl ether. Treatment of the product 23 with potassium amide resulted in 1,4 elimination of ethoxide to give the enynes. The unsaturated acetylenes

24 were obtained as a mixture of E and Z isomers. The enynes could be easily hydrolyzed to the corresponding

acetylenic ketones 25. i

1) BuL KNHz NHa ^ t ( H 24 17

Bradsma^’’ extended the same idea to a furan synthesis by using an epoxide oxygen as the leaving group, instead of ethoxide. Treatment of an a-chloro ketone with the a-lithio methoxy allene 2, gave the carbinol?® The carbinol 26 was treated with KOH and the a-epoxy allene 27 formed. When the epoxy aliénés

KOH KOtBu DMSO ether / R

26 27

29 30

28 18 were treated with potassium tert-butoxide In DMSO, they rearranged to furans ^ , and 30 via the intermediate enyne alcohols 28. The enyne alcohols ^ could, in some cases, be isolated. They were also observed in the crude products of the rearrangement reactions. Vermeer^® used methoxyallene in a synthesis of enones

involving a 1,3 elimination. The a-lithiated methoxyallene 2 was added to a ketone to give the carbinol l4. The

alcohol was then converted to the sulfinate 3 1. When these sulfinates^ were exposed to Grignard

reagents in the presence of a stoichiometric amount of a copper (I) halide,a smooth 1,3 displacement occurred to give the dienes ^ . The addition of an equivalent of lithium bromide accelerated the reaction. Homocuprates ( RaCu MgX) could not be used in this reaction. They generally attacked the sulfur atom. The dienes ^ could

be hydrolyzed to the corresponding ketones 33 in excellent yield. No rearrangement of the double bond was observed

during hydrolysis. Vermeeralso found that terminal acetylenes ^ can

be synthesized from methoxyallene 2. Treatment of methoxy allene 2 with a Grignard reagent in the presence of a

catalytic amount of a copper (I) halide produces the terminal

acetylene 3^. Again a 1,3 displacement, this time methoxide 19

CH 14 >

31 32

Is eliminated. In the case where R Is phenyl a small portion (5%) of the product Isomerlzed to the corresponding allene under the conditions of the reaction.

RMgX H Cul (Cat)

Later Vermeer' was able to find conditions to effect the addition of Grignard reagents to methoxyallene 2 , to produce the enol ethers of aldehydes When methoxyallene 2 was treated with either the homo or heterocuprate of a Grignard reagent addition of the R group took place at the Y-posltlon. The Intermediate cuprate 36 could be 20 alkylated with Mel or allyl bromide, or worked up to give the enol ether 37 as a mixture of isomers. Hydrolysis to the aldehydes ^ was straightforward, and proceeded in excellent yields.

[r Cu(Br or R)^ MgX — -— ^ Mg X

35 Cu(R or Br

37 38

Martinhas used methoxyallene 2 as the starting point for a three carbon homologation reagent. When methoxyallene was treated with triphenylphosphonium hydrobromide addition of the phosphorus atom to the y-carbon of the allene occurred, The phosphonium salt 39 could be deprotonated with n-BuLi to generate the ylid which reacted with aldehydes and ketones in the usual manner to generate dienes ^ . The

1-methoxy-l,3-butadienes 4l could be isolated or hydrolyzed to the corresponding unsaturated aldehydes ^ in moderate yields. 21

THF/-50°C 39

H bO V H

40 R 42

The French workers Battlonl, Vo-Quang and Vo-Quang^^ have reacted methoxyallene 2 with 1,3-dipoles to obtain isoxazoles 44, pyrazoles 46, and pyrazolines 47. In the first two cases the initial products are unstable under the conditions of the reaction. They rearrange spontaneously to the observed isoxazoles # and pyrazoles ^ . The initial product 47 of the addition of diazomethane to methoxyallene

■> ©

43 22 was stable. It could be pyrolyzed to give the methoxy methylenecyclopropane presumably via the intermediate methoxy trimethylene methane 48. These reactions were run as part of the study of 1,3-dipolar additions. They are not préparâtively useful, since the indicated products are parts of 3-5 component mixtures.

45 46

I 4- >

47 49

Hoff, Bransdma and Arensobserved that methoxyallene underwent the Diels-Alder reaction with unsaturated aldehydes. Dihydropyrans ^ were produced, but only in moderate to low yields. This reaction is analogous to reactions that take place with vinyl ethers. 23

Finally Suzuki has shown that methoxyallene 2 can be used to form substituted methoxycyclopropanes . ^ ^ V/hen a-llthio methoxyallene Is treated with a borane 52 derived from an olefin and 9-BBN, an ate-complex ^ is formed.

Treatment of the borate with acetic acid results in the

formation of the substituted methoxycyclopropane 52 in good yield. These substituted cyclopropanes can be cleaved by mercuric acetate to ketones.53.

HOAc 2 + ■>

Hg(OAc) Hg OAc

52 53 CHAPTER 3 DISCUSSION

After discovering this unusual allene cyclisation reaction, we decided to investigate the reaction further.

A number of compounds containing the furan-3-one ring system possess useful biological activities . ^ We needed to know the scope and limitations of the allene cyclisation reaction. Methoxyallene 2 was conveniently prepared from propargyl methyl ether i by refluxing the neat ether over potassium tert-butoxide for 3 h ., following the procedure / 60°C

of Hoff, Brandsma, and Arens.Methoxyallene prepared in this fashion could be stored for 2-3 months at -l8°C. The allene did tend to slowly decompose even at -l8°C. Slight impurities present in the methoxyallene 2 caused the forma tion of a pale yellow color when the compound was depro tonated to the a-lithio anion 3 . Minor impurities did

24 25

not, in general, interfere with the addition of the a-

lithiomethoxyallenyl anion to ketones. No side products were ever detected. However, in the case of the addition of

the allenyl anion 2 to 3,4,5-trimethoxybenzaldehyde the purity of the reagent was important. If a-lithiomethoxyallene, prepared from freshly synthesized methoxyallene was added to 3,4,5-trimethoxybenzaldehyde at -78°C, and the reaction was then quenched and worked up in the usual manner, a crystalline product was isolated. If slightly impure methoxyallene 2 was used for the addition, the product was isolated as an oil. Spectral data on the two

samples of alcohol 13 were identical, the only difference being that one crystallized spontaneously during the work-up, and the other did not. We found that the a-lithiomethoxyallenyl anion was stable at or below -20°C, confirming the results of Hoff, Brandsma, and Arens. If a solution of the anion was warmed above -20°C, it would begin to turn dark brown

as the reagent decomposed. 26 Our usual procedure for the addition of a-lithlo- methoxyallene 3 to ketones was to cool a solution of methoxy allene 2 to -78°C in a dry ice - isopropanol bath. Addition of an equivalent amount of n-butyllithium to this solution removed the proton a to the methoxy group. Products resulting from y-deprotonation were never observed. To the clear or pale yellow solution of the anion was added the ketone as a solution in THF. After quenching at -78°C with water the reaction mixture was warmed (20°C), then worked up. This procedure worked well for the addition of a-lithiomethoxyallene to cyclohexenone 7 , 3 ,5-trimethoxybenzaldehyde 13, cyclohexanone 1^, cyclopentanone 4 , benzophenone l6 , adamantanone ^ and bicyclo[3 .3.l]nonan-9-one ^ (Table 1).

The addition of the allenyl anion 3 to the 17-keto- steroids, 3-methoxyestra-17-one and 3-methoxyandrosta- 3,5-diene-17-one required more vigorous conditions. The anion 3 was formed as before, then warmed to -20°C. The addition of either steroid, as a solution in THF, to the anion resulted in virtually quantitative formation of the desired allenyl alcohol ^ ^ . In extremely difficult cases, such as the helical polyspirofuranones to be discussed later, recycling the material through the allene addition one additional time sufficed to convert all of the ketone to the desired allenyl alcohol. 27

TABLE I List of Compounds

12 10 11

18 16 17 28 TABLE I (Continued)

19 20 21

22 2^

26 27

28 29 30 29

Our one failure with the allene addition came when we

attempted to add a-lithiomethoxy allene to 1,1-diphenyl-

dihydrofuran-3-one the furanone obtained from benzophenone. We were unable to obtain any addition product, even when large excesses of the allenyl anion, and high

temperatures were employed. The phenyl rings apparently completly shield the ketone from attack. The crude allenyl alcohols were sensitive

compounds. They stored well at -l8°C, but at R.T. traces of moisture and acid quickly distroyed them. The alcohols

derived from cyclohexenenone 7 , cyclohexanone 10, and

cyclopentanone 4 could be purified by distillation under vacuum. All of the other, solid, allenyl alcohols were used without purification, since attempted recrystallization led to decomposition, and chromatography on silica destroyed the compounds completely. Fortunately, purification was unnecessary. Side products were never observed in the

addition of a-lithiomethoxyallene 3 to ketones. All of the crude allenyl alcohols appeared >95% pure by NMR, IR, and TLC. Our original procedure for the rearrangement of a-hydroxymethoxyallenyl alcohols to 3-methoxyspirodihydro- furans was to treat a solution of the allenyl alcohol in THF, with an excess of potassium hydride and a catalytic 30 amount of dlcyclohexyl-l8-crown-6 ® This procedure worked well on a 200 mg. scale for allenyl alcohols 7 , ^ , and

4 j from 2-cyclohexen-l-one, cyclohexanone, and cyclo pentanone respectively. However, when the rearrangement of

1- (l-methoxypropadienyl)cyclopentanol 4 was attempted on a 2 g. scale, the reaction took 4 days at reflux to go to completion.

Baldwin^^ suggested that potassium tert-butoxide in tert-butyl alcohol might be a superior medium for conducting the rearrangement. In the event when the allenyl alcohol was treated with an equivalent amount of potassium tert- butoxide, tert-butyl alcohol and dicyclohexyl-l8-crown-6 at reflux the rearrangement was complete in 3 h. It occurred to us that the rearrangement might take place through the lithium alkoxide. Since the lithium alkoxide is formed during the addition of a-lithiomethoxy allene to ketones, a rearrangement using this species would eliminate a step from the reaction sequence. The crown ether 12-crown-4 is known to selectively chelate the

L'Ov

\ / 12-C-4/A

31 5 31 lithium atom/^ Addition of 12-crown-4 to a solution of the lithium alkoxide might have the same effect as the addition of dicyclohexyl l8-crown-6 has on the potassium alkoxide catalyzed rearrangement. In the event when 12- crown-4 and tert-butyl alcohol were added to a solution of

31, prepared by the addition of a-lithiomethoxyallene to cyclopentanone and the mixture was heated to reflux, no rearrangement to product was detected. The rearrangement was also attempted using lithium tert-butoxide. tert- butyl alcohol and 12-crown-4 on the allenyl alcohol with the same result. Only starting material was recovered.

Apparently the lithium alkoxide is not nucleophilic enough to attack the allene.

A consideration of the mechanism of the rearrangement reaction led us to the conclusion that an equivalent amount of base was unnecessary for the rearrangement to occur.In the event when the allenyl alcohol 4 was treated with a catalytic amount of potassium tert-butoxide tert-butyl alcohol, dicyclohexyl-l8-crown-6 and heated to reflux, a smooth rearrangement to the desired product occurred. This procedure, using a catalytic amount of base, was the most generally useful method we employed. It works well with all the allenyl alcohols we made, with the single exception of the allenyl alcohol ^ derived from adamantanone• 32

Treatment of the a-hydroxymethoxyallene obtained from the addition of a-llthlomethoxyallene to adamantanone, with potassium tert-butoxide, tert-butyl dlcohol, dlcyclohexyl-l8-crown-6 , at reflux failed to close the dlhydrofuran ring. Using either a catalytic or an equivalent amount of base made no difference. Extended periods of reflux also failed to produce any of the desired product. Since base catalysis failed In this case we tried acid catalysis. Treatment of allenyl alcohol 19 with para-toluenesulfonic acid,In benzene or toluene, at tempera tures from reflux to R.T. produced polymer.The same results were observed with BFs'EtzO. Treatment of the alcohol with mercuric acetate^® resulted In hydrolysis to the a-hydroxy enone 32.

The hydroxy enone 3^ was easily prepared from the allenyl alcohol ^ by simple hydrolysis. Baldwin®“ and Jacobson® have shown that a-hydroxy enones cycllze to

19 32 33

dlhydrofuran-3-ones under acid catalysis. Treatment the enone ^ with para-toluenesulfonic acid In benzene, toluene, or dlchloroethane, at a variety of temperatures produced none of the desired furanone 21. Mercuric acetate and boron trlfluorlde etherate also failed to effect closure of the ring. Photolysis of the enone 32 with a Hanovla medium pressure mercury lamp for 5 h. In a pyrex reactor produced a white solid. This compound proved to be Insoluble In organic solvents.

It was suggested to us by Wilson**° that the methoxy 1 oxygen may be solvating the cation In this system, as shown In 33 • Before ring closure could occur the allene

33 would have to rotate Into a position ^ suitable for attack by the alkoxide anion. If solvation of potassium by the methoxyl oxygen Is too strong the rotation may not occur.

Another possibility was that the crown ether- potassium tert-butoxide complex might not be able to approach close enough to the allenyl alcohol to deprotonate the system. 34

In order to circumvent these two difficulties we

synthesized the MEM*^ protected allene ^ . Following the procedure of Corey, propargyl alcohol was deprotonated with n-butyllithium. MEM-chloride was then added to form

the propargyl ether ^ . Rearrangement of the propargyl system to the allene ^ was straightforward. The allene"

was deprotonated as usual and 2-adamontanone was added.

The MEM protected allenyl alcohol 37 was isolated in quantitative yield.

„ — AA A /V\-A

35 ' 36

We hoped that the MEM group would act as an intra

molecular crown ether, eliminating the difficulties we had earlier experienced with the potassium tert-butoxide-

dicyclohexyl-l8-crown-6 system. In the event when the a-hydroxy MEM protected allene ^ was treated with potassium tert-butoxide in tert-butyl alcohol at reflux, no reaction occurred. 35

At this point,we considered the possibility that a stronger base was necessary. Treatment of the allenyl alcohol 19 with potassium hexamethyl disilazide in THF at reflux gave the same result as all the previous attempts.

Finally, we decided to try our original procedure, for completeness' sake, before abondoning the effort altogether. In the event„when the a-hydroxyallenyl alcohol

3^ was treated with potassium hydride, THF, dicyclohexyl- l8-crown-6 , at reflux the desired rearrangement occurred, albeit in poor yield. The initial 20% yield was eventually improved to 30%. In an attempt to improve the yield,the reaction was run in diglyme, glyme and DMSO. None of these solvents had any positive effect upon the yield of obtained.

The difficulty associated with the cyclization of the adamantyl system led us to examine the cyclization of the allenyl alcohol ^ derived from bicyclo[’3.3.1] nonan- 9-one. The structure of the ketone is similar to adamantanone, but more flexible due to the lack of the methylene bridge between carbons 3 and 7. We felt that the rearrangement would occur more readily in the less rigid system. In the event, when the allenyl alcohol ^ was treated with potassium tert-butoxide, tert-butyl alcohol, and dicyclohexyl-l8-crown-6 at reflux a clean rearrangement to 36 the vinyl epoxide 29 was observed. None of the expected dlhydrofuran was obtained. The vinyl epoxide could be hydrolyzed to the corresponding a-hydroxy enone 30, which could also be obtained by the hydrolysis of the allenyl alcohol 28.

This unusual type of rearrangement product 29 was not observed In any of the other systems that were studied. Since vinyl epoxides are known to rearrange to dlhydro- furans, this type of compound 29 may be an Intermediate In all of our rearrangements.

In contrast to the difficulty connected with the

cyclization of the adamantyl system was the ease of cyclization of the two acyclic a-hydroxymethoxyallenes IJ and ^ . These two examples are the only cases where the crown ether Is unnecessary. Both compounds cycllzed cleanly with potassium tert-butoxide In tert-butyl alcohol at reflux.

The hydrolysis of the 3-methoxysplrodlhydrofurans was usually straightforward. During the workup the aqueous basic layer would be acidified with 6 N hydrochloric acid ; shaking the acidified aqueous layer with the organic layer for 15 mln. provided the ketone. Once during a hydrolysis of the enol ether 5, a side product was formed.

It was Isolated, and Identified as the 0-ketoaldehyde 38. An examination of the hydrolysis conditions was undertaken with an eye towards eliminating the formation of the

troublesome by-product 38. 37

There are many methods available for the- hydrolysis of enol ethers and acetals.*^ A study of the following systems was made; IJi oxalic acld/THP, (1:3), IM acetic acid/

THF (1:3), 6j_ HCI/CH2CI2, IN HzSOk/CHzClz, 3J1 HaSO^/CHaCla ,

6 N HaSOu/CHaCla. The last hydrolysis using 6 n sulfuric acid In a two phase system proved to be the best. Dilute acid tends to favor the formation of the side product ^ . Substantial amounts of the keto aldehyde 54 were formed In the oxalic, acetic and IN sulfuric acid systems. We may now draw some conclusions regarding the addition of a-llthlomethoxyallene to ketones, and the mechanisms of the rearrangement and hydrolysis reactions.

The a-llthlomethoxyallenyl anion Is an extremely good nucleophile towards ketones. It adds to 17-ketosterolds In virtually quantitative yield. There are two major explanations for the observed high reactivity. 38 The a-llthlomethoxyallenyl anion Is linear. As such, It has a low sterlc demand. When the reagent approaches a ketone, groups that normally hinder or block ketone addition are simply too distant to Interact with the compact allene. It Is Interesting to note that another excellent nucleophile In ketone additions, acetylene. Is also linear. The other explanation of a-llthlomethoxyallene*s exceptional reactivity Is hard-soft acid base theory.

Both the allenyl anlon^^ and the ketone carbonyl are hard centers. This favorable Interaction no doubt aids In the ketone addition reactions of the allenyl anion 3.

The rearrangement reaction may proceed via nucleophilic attack of the alkoxide on the terminal carbon of the allene, followed by protonation of the vinyl anion. In order for the reaction to occur a very strongly basic system must be used, either potassium hydride and dlcyclohexyl-l8- crown-6 , or potassium tert-butoxide, dlcyclohexyl-l8-crown-6 ,

H 0

39 40 39

In structurally related systems, nucleophlllcity can be directly correlated with basicity.The less basic, less nucleophilic, system of the lithium alkoxide and 12-crown-4 is simply not nucleophilic enough to successfully attack the allene. Similar nucleophilic attacks have been observed in other acetylenic and allenic systems. A proton source is essential in the reaction. The vinyl anion ^ must pick up a proton from somewhere. In the small scale potassium hydride reactions the residual moisture present in solvent, reactants, and the glassware could provide the proton source. This is probably the reason the potassium hydride rearrangement fails to work well on a large scale. The protons must come from some where , the atmosphere, or gas used in maintaining an inert atmosphere, it just takes days for enough of them to enter the system during a large scale rearrangement for the reaction to go to completion. During every rearrangement the reaction mixture turned black. This may be due to the reversibility of the allene addition under the conditions necessary for the rearrange ment. Hoff, Brandsma, and Arens^z observed the formation

HO H^ _ = -S— CH^ 43 40

of the acetylenic sulfide ^ during the attempted rearrange

ment of 42. A reversal of this type in our system could cause the dark color since the allenyl anion, which would be formed, is unstable above -20°C and rapidly decomposes

to a black tar above this temperature. Steric effects are also important in the rearrangement

reaction. During the closure of the alkoxide on the allene

the bond angle 0 decreases. In order to compensate,bond

angle $ must increase somewhat.** In the case where this compensation is the easiest, the acyclic allenyl alcohols, the mildest conditions are required to effect ring closure.

In the case where compensation is diTficult, the rigid adamantane system, the most vigorous conditions are required

to effect ring closure.

The results of the rearrangement reaction of the bicyclof^S. 3. ijsystem indicate that another mechanism, consistent with the previous observations is plausible. The rearrangement may proceed via attack of the alkoxide 4l

on the near end of the allene to give the vinyl epoxide. A simgatropic shift would then provide the dihydrofuran. Protonation of the vinyl anion could occur either before

or after the sigmatropic shift had taken place. In the hydrolysis there appear to be two mechanisms operating simultaneously. Protonation can occur on the carbon of the enol ether or the ring oxygen atom. The latter reaction seems favored at low acid concentrations. Carbon-oxygen bond cleavage leads to the tertiary methoxy- allylic cation # , which after loss of a proton, and standard hydrolysis of the enol ether leads to the ketoaldehyde 38.

38 42

CHAPTER 4 Puran-3-one and Dlhydrofuran-3-one Synthesis

Furan-3-one and dihydrofuran-3-one units occur in a variety of natural products. The structure is present in sequiterpenes, such as the germacranolides, eremantholide A 1 and ciliarin 2, both of which have shown antitumor

1 2

a c t i v i t y Recently Praser-Reid has synthesized a chiral fragment 3 of these compounds from D-mannose. ^ • 43 The diterpene gieparvarln 4 also contains a furan-3- one systèmes Smith has recently synthesized this compound, which also shows antitumor activity. He states that an

Increasing number of antitumor agents possessing this ring system are being discovered.

The furan-3-one ring system has long .been Important In the area of flavor and fragrance chemistry. An example Is furaneol 5, a substance which Is a component In the flavor of strawberry and pineapple. Buchl®° Ohloff,®^ Eugsterf^ and Sllversteln*^ have all synthesized this useful compound.

H 44

An example of a reduced furan-3-one system Is muscarine 6, an alkaloid found in fly agaric. “** In their syntheses of this pharmacologically important alkaloid both Kdglfs and Eugster/® used a dihydrofuran-3-one as a stepping stone. The synthesis of Kogl is an example of a classical dihydrofuran-3-one synthesis. lodopropionic

Br 0

6 ester 7 and malic ester 8 react in the presence of silver

carbonate to form the ether 9. Dieckman condensation then provides the furanone 10 ring system.

Et * H

9 10 45

Kohler, Westhelmer and Tishler^^ were among the first to prepare furan-3-ones. They were Interested in the question of aromaticity, as it related to furan ring systems. They treated 3-acetoxytriphenylfuran y. with solution of acetic acid, water and concentrated sulfuric acid under a nitrogen atmosphere. The initially produced hydroxyfuran rapidly and irreversibly ketonized. The struc ture of furan-3-ones has been studied more recently by Eugster.58)59 He also found that the enol form is not present in detectable amounts in furan-3-ones.

11 12

When Gelin and Galliand®° attempted to synthesize some tetronic acids they found that the initially formed products were furan-3-ones l6. Treatment of the furanones with aqueous sodium carbonate rearranged them to the desired tetronic acids 17. 46

M g X C! 4" Et 30°C

13 14 15

t ® 0 H 25°C

16 17

Bien and Gillion^^ also observed a rearrangement of furan-3-ones to tetronic acids. Decomposition of the diazo compounds ^ over copper provided a modest (25-41%) yield of the furan-3-ones ^ . Treatment of the furanones with aqueous acid in a two phase system gave the tetronic acids 20 via hydrolysis and rearrangement.

H 2 Cu -> Et

19 18 20 47

During his investigations of the oxyallyl cation system 21 Hoffman®^ discovered that these compounds react with dimethylamides to form cyclic acetals 22. The acetals

rearrange upon standing to a 3-aminodihydrofuran-3-ones 23,

ZN/Cu > DMP

21 ^ ^ —24 which easily lose dimethylamine to form the furan-3-ones 24 in 68% overall yield.

Noyori®^ studied the same reaction. By using Pea(CO)g as the reducing agent instead of Zn/Cu he was able to improve the yields of furan-3-ones produced. In his system the intermediate cyclic acetal could not be detected.

Using his new procedure Noyori synthesized some 4-methyl- muscarine iodides.

Carlson ® “ has published a synthesis of furan-3-ones that depends upon an allene rearrangement. Treatment of l-thiomethyl-3-methoxyallenes with lithium diethylamide in THP at -78°C produces the 3-lithio species. The anion adds cleanly to ketones to provide the corresponding allenic carbinols ^ . Hydrolysis of the allene in aqueous aceto- nitrile at reflux provides the furan-3-one 27- 48

pTsOH 1) LlNEtz CH3CN H2O/A R

The synthesis of dlhydrofuran-3-ones has also been studied by a number of groups. Dissolving metal reduction in liquid ammonia converts furan-3-ones to dihydrofuran-3- ones.®^ By using the Birch reduction the previously discussed syntheses of furan-3-ones can also be used for the synthesis of dihydrofuran-3-ones.

Dupontreported one of the first syntheses of dihydrofuran-3-ones in 1911- He found that when acetylenic glycols 28 or epoxides ^ were treated with aqueous sulfuric acid they rearranged to form dihydrofuran-3-ones and 32. Side products ^ resulting from a pinacol reaction were also sometimes observed.

+ H

28 29 30 49

31 32

More recently, Venus-Danilova has employed a similar method for the synthesis of several dihydrofuran-

3-ones. Again, treatment of the acetylenic glycols ^ with aqueous sulfuric acid at 70°C for 6 h . resulted in the

70°C

34 33

20% H2SO*/70°C

formation of dihydrofuranones ^ . The accuracy of these results has since been questioned.®^ The reported carbonyl stretching frequency (1709 cm"^) is in sharp disagreement with values (1755-60 cm“^) reported elsewhere. 50 Bradley,®® In a British patent, described a more classical furanone synthesis. Treatment of a-hydroxyethyl acetate ^ with diethyl maleate ^ and sodium provides the dihydrofuran-3-one 39. This reaction involves a combination of 1,4 addition of the hydroxy group followed by a Dieckman condensation, and is similar to a reaction used by Eugster in a synthesis of the muscarins.

The parent compound, dihydrofuran-3-one ^ , appears to have been first synthesized by Reppe.®® Johnson’’® had previously reported a route to the compound starting from butyne-l,4-diol, but his work could not be repeated. Reppe found that treatment of butane-1,2,4-triol ^ with acid resulted in the formation of 3-hydroxytetrahydrofuran 4l. Oxidation of this compound with a copper/chromium catalyst at elevated temperatures produced the furanone 42.

H CuO'CrOa -> 250°C

40 41 42 51

Wynberg^^ reported a synthesis of dlhydrofuran-3-one that Is more amenable to use in the laboratory. He found that treatment of the hydroxytetrahydrofuran 4l with aluminium isopropoxide and benzophenone produced the ketone k2 which could be distilled directly from the reaction mixture, in moderate yield. He also attempted to use sodium dichromate to oxidize the alcohol, but found the method unsatisfactory.

The product ^ is easily overoxidized, and it is miscible with water. Because of these difficulties he could only obtain a 30% yield of product. The furanone 42 was used by Wynberg in the synthesis of some 3 substituted furans. Weiland, Dijksta, and Pik®^ were able to improve upon Wynberg’s dichromate oxidation procedure. By using an apparatus that allowed for the distillation of the pro duct 42 as it was formed and then continuously extracting the crude ketone-water mixture with ether, they were able to double Wynberg's yield. Oxidation with chromium trioxide«pyridine complex worked even better, giving a yield of 70%. Bertand, Dulcere, and Gil have published an unusual dihydrofuranone synthesis involving an oxidative allene rearrangement. They found that when a-hydroxy 1,1 disubstituted aliénés ^ were oxidized using hydrogen peroxide and benzonitrile,the dihydrofuran-3-ones 44 were produced. 52 R ^ R

H2O,/0CN. "V >

Also, the analogous oxidation of a 3-hydroxy allene 45 pro duced S-'ketotetrahydropyrans This reaction failed in cases

where the allene was not 1,1 disubstituted. The rearrange ment presumably proceeds through the epoxide and intermediate carbénium ion. R

H2O2 2 H 0-CN

Jacobson® and Baldwin^® have shown that dihydrofurans may be synthesized from a-hydroxy enones. Treatment of the protected cyanohydrin 47 with LDA at -78°C, followed'-by addition of a ketone, and subsequent hydrolysis provided the a-hydroxy enone 4^. When these enones were treated with para-toluenesulfonic acid, toluene, and 2 equivalents of methanol, at reflux, spirodihydrofuran-3-ones ^ were obtained. The presence of methanol is critical in this reaction, but its function is unclear. 53

EE EE e

2) "OH

47 49

pTSOH/A > O-CHa/MeOH

Hoff, Brandsma, and Arenshave described a furanone

synthesis that has found favor in our laboratories. When methoxyallene 51 was treated with n-butyllithium at -78°C in ether the a-lithiomethoxyallene was formed. This compound reacted readily with ketones to provide the a-hydroxymethoxyallenes ^ . When these compounds were heated in DMSG in the presence of potassium tert-butoxide, a rearrangement to the 3-methoxyspirodihydrofuran ^ took place. The enol ethers could then be easily hydrolyzed to the corresponding dihydrofuran-3-ones 54.

1) BuLl KOtBu

51 52 53 54

In view of the antitumor properties now being asso ciated with the furan-3-one system, it seems likely that interest in the synthesis of this ring system will continue. Although there has been much work done in the area, there

are few general methods for the synthesis of furan-3-ones or dihydrofuran-3-ones. One of the best procedures for the synthesis of the latter compounds is the method of

Hoff, Brandsma, and Arens. Using a modification of this procedure we were able to synthesize the first primary helical molecules. CHAPTER 5 DISCUSSION We had successfully rearranged a number of carbonyl compounds, from 3 ,5-trlmethoxybenzaldehyde 1 to 3-methoxy- estrone 2 to the corresponding spirodihydrofurans 3 which provided spirodihydrofuran-3-ones H after hydrolysis.^^ Since we began the reaction sequence with a carbonyl compound and we obtained a new carbonyl compound after hydrolysis of the annulated product, we wondered if a new ring might be spiroannulated onto the first spiro ring. To examine the possibility of executing a reiterative sequence of annulations, we attempted to prepare the bis- spiroannulated compound 8.

55 56

In the event,when 5 was treated with a-lithlomethoxy-

allene at -25°C the allenyl alcohol 6 was obtained. The

alcohol 6 was a single compound that was >95% pure. Cyclisation to the methoxydihydrospirofuran 7 was accom plished by treatment of 6 with potassium tert-butoxide, tert-butyl alcohol, and dicyclohexyl-l8-crown-6 at reflux. Hydrolysis of the enol ether 7, in the workup, followed by

chromatography, and sublimation provided the pure desired

furanone 8.

5 6

7 8

We now knew that polyspiroannulated compounds of any desired size could, in theory, be synthesized. An examina tion of molecular models (Dreiding and C.P.K.) revealed 57 that the addition of the allenyl anion to the spiro annulated furanones should be stereospecific. Only one face of the spirofuranones could be attacked, the other face was covered by the rest of the molecule. When a model of the product of twelve spiroannulations 9 was made, keeping the stereospecific formation of each successive ring in mind, an interesting fact was revealed. The compound was helical. If such compounds could be synthesized they would be the first examples of a hitherto unknown class of compounds, primary helical molecules.

In the early fifties Pauling’’^ suggested that poly peptides have an a-helix conformation, leading the way for extensive studies of helical topology, especially in biopolymers“ In particular, the double-stranded helical conformation of DNA,^* and the helical structures of many polymers® demonstrate the importance of helical molecules in macromolecular chemistry. Other molecules that possess helical topology are helical triphenyl methane:systems,?? skewed paracyclophane ® and helicene.’’® 58

All of the proceeding helical molecules owe their helical topology to secondary and tertiary interactions,

such as hydrogen bonding, hydrophobic bonding, steric repulsions, or a combination of these effects. To date,

no known compound of helical topology is helical solely because of its primary structure. We now set out to synthesize just such molecules. Addition of a-lithiomethoxyallene to cyclopentanone

provided the expected allenyl alcohol Treatment of the alcohol 10 with potassium tert-butoxide, tert-butyl

alcohol, and dicyclohexyl-l8-crown-6 at reflux gave the

enol ether 1^. It was most convenient to hydrolyze ^ and subsequent enol ethers in the workup. Such a hydrolysis provided the ketone 12. The furanone ^ could be distilled,

and when pure, the compound crystallized at low (-l8°C)

temperature.

H >

10 11 12

Cyclopentyl[i]helixane ^ was slowly added to a

solution of a-lithiomethoxyallene at -25°C, providing the allenyl alcohol ^ . The allenyl alcohol ^ was solid at low temperature (-l8°C), but our attempts to recrystallize the compound failed. 59

13 14 15

It is Interesting to compare the results of the previous allene addition to form ^ cleanly and in good yield, with the attempted homologation of 12 using the <%- chloromethyl-a-trimethylsilyl anion° Instead of the expected a,j3-epoxysilane 1^, treatment of furanone ^ with a-chloro- a-trimethylsilylethyllithium produced the aldol dimer 17. The adjacent spirocyclopentane ring prevents addition of the reagent to the carbonyl group. This result indicates the important role the nucleophilicity of a-lithiomethoxy allene plays in the success of the present synthesis.

17 6o Treatment of the allenyl alcohol 1^ with potassium tert-butoxide, tert-butyl alcohol, and dlcyclohexyl-l8- crown-6 at reflux provided the enol ether Hydrolysis of

l4 with 6n sulfuric acid gave the furanone ^ , which was the

only compound In the series that never crystallized. Even

chromatographed, distilled product remained fluid at -l8°C.

The furanone 15, cyclopentyl[2jhellxane. Is the first

furanone In the series that contains an asymmetric center.

As such. It occupies an Important place In the synthesis.

It Is the first furanone that Is potentially resolvable. Also, It provides the first test of the stereospeclflclty

of the addition of a-llthlomethoxyallene. An examination of a Dreiding model of the furanone

^ reveals that the cyclopentane ring from the starting block cyclopentanone covers one face of the carbonyl group In 1^. The cyclopentane ring should, therefore, block addition to the carbonyl group from that direction. If the addition of a-llthlomethoxyallene to the furanone 1^

Is not stereospecific, a mixture of dlasteromers would be obtained. Such a mixture would be difficult to separate, and would make the synthesis of higher homologs difficult.

If not Impossible. In the event, when cyclopentyl[2]hellxane 1^ was slowly added to a solution of a-llthlomethoxyallene at -25°C a single compound, the allenyl alcohol l8 was obtained. 61

A small amount of starting material. (<5%) was also present In the product. This was the first time we had the-

problem of Incomplete addition of the allenyl anion. Cycllzatlon as usual, with potassium tert-butoxide, tert- butyl alcohol, and dlcyclohexyl-l8-crown-6 at reflux provided the enol ether ^ . Hydrolysis, followed by chroma tography and recrystalllzatIon, gave the furanone ^ , cyclopentyl[3]hellxane. A molecular model of ^ shows that It

Is the first molecule with a structure that obviously looks

helical.

19 20

Treatment of cyclopentyl[3]hellxane ^ with a-llthlomethoxyallene at -25°C provided a single compound 21,

contaminated with ca. 25% of recovered starting material.

The product was recrystalllzed from diethyl ether to provide the pure allenyl alcohol 21, and a mixture of starting

material and product. The mixture was recycled to provide another batch of 21.

In the event when pure recrystalllzed allenyl alcohol ^ was treated with potassium tert-butoxide, tert-butyl alcohol, and dlcyclohexyl-l8-crown-6 at 25°C, the enol

ether 22 was obtained. This low temperature cycllzatlon

only occurred once with the recrystalllzed alcohol 21. 62

21 22

The reason for this unusually mild cyclisation is not clear.

Possibly the molecule is acting as its own crown ether, enhancing the nucleophilicity of the alkoxide anion, or maybe the rearrangement proceeds, in this case, by an electron transfer mechanism which is arrested by minor impurities in the starting material. Hydrolysis provided the furanone

The furanone 23 was recrystallized from diethyl ether to provide a single crystal for an X-ray diffraction study.

Cyclopentyl[4]helixane crystallized in the triclinic space group Pi with four molecules per unit cell. Accurate lattice parameters are a=13.88l (4), b=8.8532 (2),

0=13.668 (3) %=104.83 (2), 3=76.60 (2), y=78.71 °. The structure was solved by direct methods and has currently been refined to R=0.08 for the 3085 diffractometer measured intensities. Both molecules in the asymmetric unit have 63

FIGURE I X-Ray Crystal Structure of Cyclopentyljl^Jhelixane

C(I4) 0(13) C(12) C(ll)

C(I5) C(8) C(7)

CO) C(10)

0(18) 0(6)

0(19) 0(5) 0(22) 0(4)

0(20) 0(3) 0(2) 0(21) 64 the same geometry. Figure I is a computer-generated drawing of the molecule. Following the usual procedure, cyclopentyl[4]helixane was slowly added to a solution of a-lithiomethoxyallene at

-25°C. A single product was obtained contaminated with a large amount of starting material. The mixture was recycled to provide the allenyl alcohol ^ sufficiently pure for use in the next reaction. Cyclization of the alcohol 24 with potassium tert-butoxide, tert-butyl alcohol, and dicyclohexyl-l8-crown-6 at reflux provided the enol ether 25, which was hydrolyzed to cyclopentyl[5]helixane 26.

We thus completed the synthesis of the first primary helical molecules.

26 65 Our helical spiroethers are theoretically separable into enantiomers. The helices of the chiral compounds would

spiral in opposite directions. Our experience with the chiral molecules 5 and 8 indicated that chiral helixanes might show interesting optical properties. The rotation of

5 was rail Ib=-24.6° while in the case of 8 it increased to La]ll8=-60.8°.

The direct resolution of ketones is uncommon.

Usually compounds are resolved at the alcohol or acid

oxidation level. Nevertheless, we decided to attempt to resolve ^ as the Schiff base 27. In the event when cyclopentyl[2jhelixane and £-(-)-a-methylbenzylamine were refluxed in benzene, with the removal of water in a Dean- Stark trap, the Schiff base 27 was obtained as a mixture

of diastereomers. The two products were separated by medium pressure chromatography on silica gel. The faster running compound was obtained, pure by TLC, and hydrolyzed to the

chiral furanone ^ [cTjii e=+77.1° . To our knowledge this is the first time that a-methyl benzylamine has been used to resolve a ketone. Its

success in our system is due to the structure of the

27 66

furanone ^ . There are,theoretically,four possible Isomers of the Schiff base ^ . They are the two diastereomers

formed because of the chirality of the furanone, and two possible geometrical isomers about the imine single bond.

The spiro fused ring adjacent to the ketone apparently prevents the formation of the other two possible geometrical isomers. A major problem with this resolution exists, howeverj the Schiff base 27 is liquid. Since the compound could not be crystallized to a constant rotation, and

lanthanide NMR shift reagents failed to reveal the enantimeric composition,we are unsure of the purity of the

resolved furanone ^ . Although the Schiff base was pure by

TLC prior to hydrolysis, this is not an absolute indication of purity. We have successfully completed the synthesis and resolution of the first primary helical molecules. There

are three crucial aspects in the success of the synthesis.

The first is the nucleophilicity of oc-lithiomethoxyallene. A less nucleophilic reagent would have failed to add to the hindered ketones in the furanones. The second is the stereo-

specificity of the allenyl anion addition. A mixture of isomers resulting from every addition of a-lithiomethoxy-

allene to the furanones would have made the synthesis

tedious at best, and impossible at worst. Third, the

spiro linkages are all adjacent to one another. If the 67 centers were not adjacent to one another, as would be the case If the oxidative furanone synthesis of Bertrand, Dulcere, and Gil^z was employed, the molecules would not be helical. CHAPTER 6 DISCUSSION

Ajugarln I 1 Is a member of the clerodane class of rearranged diterpenes.®^ Isolated from Ajuga remota

(Labltae), ajugarln exhibits significant antifeeding activity against African army worms.®“ Many related com pounds have also been shown to act as antifeedants.®® The tructure and activity of ajugarln has been described by Nakanishi.

We decided to examine the possibility of synthesizing ajugarln and related compounds by an intramolecular

Diels-Alder reaction of the diene,dienone Our strategy was attractive in many respects. Oxygen function ality necessary for the conversion of 2 into 1 would be

68 69 introduced at the required positions. Each oxygen would be at a different oxidation level,thereby allowing selective manipulation of the oxygen functionality in subsequent

reactions. The side chain could be introduced before or

after the Diels-Alder cyclisation, whichever was more convenient. The double bond present in the B ring of 2

could be used to introduce functional groups that are present in related compounds. The synthesis is highly convergent. The diene, and butenolide fragments could

be synthesized separately, then combined to form the desired product. We first synthesized the model compound ^ to examine the intramolecular Diels-Alder reaction.. Itaconic acid 4 was treated with bromine, followed by sodium carbonate, to provide sodium aconate 5.°^ The structure of 5 was con firmed by conversion to aconic acid 7.°° Treatment of sodium aconate 5 with oxalyl chloride in benzene at reflux gave the aconyl chloride.®® Sublimation provided the pure acid chloride 6.

ClCl

7 70

The diene was synthesized from sorbic acid 8. When sorbic acid was treated with two equivalents of n-butyl-

lithium and one equivalent of HMPT, followed by the

addition of methyl iodide, another equivalent of butyllithium, and more methyl iodide the dimethylated acid 9

was obtained?®’® ^ Reduction of dimethyl sorbic acid 9 with

1) 2 eq. BuLi 2 ) Mel X LAH 3) BuLi Et:0/0°C 4) Mel

10 lithium aluminium hydride in ether at 0°C provided the alcohol ^ ^ When the alcohol was deprotonated at 0°C with sodium hydride followed by slow addition of the acid chloride 6 and stirring at R.T. (25°C) for 15 h. the diene ester ^ was obtained. We were now ready to examine the conditions required for an intramolecular Diels-Alder reaction of this compound.

1) NaH

10 11 - 71

In the event,when the diene ester 11 was treated with

Lewis acids (AICI3 , SnCl*, Cu(BP%)2, BPa'EtzO) only decom position products or recovered starting material were

obtained. Refluxing the diene in benzene, dienone, toluene, or decalin yielded only recovered starting material. However,

when the diene ester 11 was heated in a sealed tube at

200°C V II ------: / -> — sealed tube

19 200°C for 24 h., the desired product ^ , as a mixture of isomers, was obtained. The major isomer appears to be the trans compound based on the NMR. With proof that our intramolecular Diels-Alder reaction should work in hand, we set out to synthesize the carbocyclic analogue 3 of 11. We planned to convert the alcohol group of ^ into a leaving group. Displacement of the leaving group in 10 with suitable nucleophile, followed by acylation of the product with 6 would give us the desired compound. In the event, when either the tosylate®^ or the mesylate

13 were treated with the anion (Li®, Na® ) of phenylmethyl- sulfone none of the desired product was formed. Variation of the reaction temperature (0°— > 100°C) and solvent (THF, DMSO, HMPA) had no effect upon the outcome of the reaction. 72

r = M s ,T s

It seemed as If the sterlc hindrance of the neo

pentyl center might be causing our problem. We decided to

use a less hindered nucleophile, ethoxyacetylene. ®** When

either the tosylate 12 or the mesylate 13 were treated

with lithioethoxyacetylene at 0°C in THF none of the desired product was formed. Variation of the temperature (0° — ^

100°C) and the solvent (DMSO, HMPA) again failed to affect the outcome of the reaction.

Etc R

R = Ms ,Ts 13 12

At this point we abandoned the idea of using an Sn2 displacement to form our intermediate and decided instead to use a Michael addition. The Michael addition of the dianion l4 to a suitably functionalized enone ^ would provide l6. The diene,dieneone l6 would be useful since. . 73 besides bearing the functionality necessary for the Diels- Alder reaction, the acid group could be used later for the introduction of the side chain. We now attempted to synthesize the enone 15.

14 15

Treatment of the acid chloride 6 with anion of phenyl vinyl sulfone^^ under a variety of conditions resulted in no product formation.

Stork has described the use of the reagent 17 in

Michael additions under aprotic conditions.®® We attempted to synthesize the analogue 15.

— .S i

17 15 74 The addition of cuprates®’’ and Grignard reagents^® to acid chlorides are known to give ketones under certain conditions. Starting with a-bromovinylsilane we attempted these reactions on our acid chloride 6. The lithium dialkyl cuprate was produced according to the procedure

\ :Si CuLi ¥ 2

16 15 of Boeckman^® and reacted with aconyl chloride 6. None of the desired product was obtained. The addition was also attempted with the Grignard reagent. 10 0 and the alkyllithium compound with the same result. Variations in temperature, solvent, and order of addition of the reagents failed to produce the desired ^ .

Finally, feeling that perhaps the acid chloride was not a good acylating agent, we synthesized the 2-mercaptopyridyl ester l8.^°^ Treatment of 2-mercaptopyridine with

18 75 sodium hydride at 0°C followed by addition of aconyl chloride 6 gave the 2-mercaptopyridyl ester l8. In the event,when the ester ^ was treated with either the Grignard reagent or the alkyllithium compound derived from a-bromo vinylsilane none of the desired product ^ was formed. Again variation of temperature and solvent had no effect upon the outcome of the reaction.

At this point we ended our attempts to synthesize 15 • It seems that although our strategy of using an intra molecular Diels-Alder reaction to synthesize ajugarln is sound another method of synthesizing the precursor 3 must be found. CHAPTER 7 DISCUSSION

Although conjugate addition has been extensively studied,there are few general methods for the 1,4 addition of organometalllc reagents to conjugated carbonyl compounds. The most widely used reagents, cuprates, have significant shortcomings.’’ Allyltrlmethylsllylllthlum 1 and a-llthlo methoxyallene 2 are two examples of compounds whose cuprates cannot be made. Acetylenlc anions form cuprates, but the complexes are so stable the anion will not add to the enone. The shortcomings of cuprate chemistry led us to examine a new method for effecting the 1,4 addition of organometalllc reagent to unsaturated carbonyl compounds. The three most Important variables In the conjugate addition of organometalllc reagents to unsaturated carbonyl compounds are sterlc effects, the nature of the carbonyl compound, and the nature of the nucleophile. Sterlc effects are the most Important. Sterlc hindrance will override electronic effects. The search for methods to effect conjugate addition has focused on modifications of the nucleophile. We chose to examine a modification of the substrate.

Table 11 shows the mode of addition of cuprates, Grignard reagents and alkyllithium compounds to unsaturated carbonyl systems^ Cuprates undergo 1,4 addition to all 77

TABLE II THE REACTION OF ORGANOMETALLIC REAGENTS

WITH UNSATURATED CARBONYL COMPOUNDS

R ^ u L i 1,4 1.4

RMgX 1,2 1,2 + 1,4 1,2 <1,4

RLi 1,2 1,2 1,2

TABLE III

THE REACTION OF ORGANOMETALLIC REAGENTS

WITH UNSATURATED IMINO COMPOUNDS

N N

RMgX 1,4 1,4 1,4

RLi 1,2 1,2 1,4 78 three systems, but the reaction is sluggish with unsaturated esters. Grignard reagents give mixtures of 1,2 and 1,4

addition with unsaturated esters and ketones; with alde

hydes, the 1,2 addition product Is obtained. Alkyl lithium compounds add 1,2 to all three types of systems.

The same trends are visible In the reactions of Grignard reagents and alkyl lithium compounds with the unsaturated

nitrogen compounds shown In Table 111.^°^ Grignard reagents add 1,4 to unsaturated aldlmlnes, ketlmlnes, and Imlno esters. Alkyl lithium compounds add 1,4 to Imlno esters and 1,2 to unsaturated aldlmlnes and ketlmlnes. Deactivation of the unsaturated system seems to favor conjugate addition. We felt that the a-effect^^ of the adjacent nitrogen present In a hydrazone would enhance conjugate addition. To examine this possibility we prepared the hydrazone 2 from cyclohexenone.

Treatment of 2-cyclohexen-l-one with a threefold excess of N,N“dlmethylhydrazlne at reflux In benzene provided the hydrazone 1. Distillation of 1 In the presence of a

TSOH/A

0 N—N 79 catalytic amount of para-toluensulfonic acid gave the unsaturated hydrazone 2. In the event, when 2 was treated with n-butyllithium at 0°C the butylated compound 3 was obtained. Hydrolysis of 3 gave 3-n-butylcyclohexanone 4.

The success of this experiment shows that unsaturated hydrazones will indeed undergo 1,4 addition without /

o°c

resorting to the use of exotic transition metal reagents However, the reaction has limitations. When the unsaturated hydrazone 5 was treated with either n-BuLi or n-BuMgBr at a variety temperatures, followed by the

addition of allyl bromide the product 6, the result of-

N— N—

1) n-BuLi >

5 6 80 deprotonation and alkylation was obtained. Apparently the gem-dimethyl group a to double bond prevents the addition of either reagent.

Therefore, we have shown that unsaturated hydrazones can undergo 1,4 addition of organometallic reagents under certain conditions. The scope and limitations of the reaction are not known, and need to be examined in more detail. 8l GENERAL EXPERIMENTAL INFORMATION

Reaction vessels were flame dried according to the following procedure. The apparatus was evacuated (20 mm Hg), flame dried under vacuum, then flushed with dry argon. After the drying procedure was repeated two more times the apparatus was ready for use. All experiments were magneti cally stirred.

All solvents were purified before use in an experiment,

Tetrahydrofuran and diethyl ether were distilled from benzophenone ketyl. Dimethylsulfoxide and hexamethylphosphoric triamide were distilled from sodium hydride.

Tert-butyl alcohol was distilled from sodium. Ethyl acetate was distilled from sodium carbonate. Petroleum ether was distilled before being used for column chromatography.

Infrared spectra were obtained on a Perkin Elmer 26? grating infrared spectrometer. NMR spectra were obtained on a Varian EM 360 60 MHz nuclear magnetic resonance spectrometer. NMR spectra were obtained on a Brucker

WP-80 80 MHz nuclear magnetic resonance spectrometer.

Mass spectra were obtained on an AEl MS-9 double focusing mass spectrometer. Melting points were obtained on a 82 Thomas-Hoover capillary melting point apparatus and are uncorrected. Boiling points are also uncorrected. All optical rotations were measured in chloroform on a Perkin- Elmer 24l polarimeter. Microanalyses were performed by MHW Laboratories, Phoenix, Arizona.

Thin layer chromatography was performed on Merck silica gel 60P-254 sheets which were visualized with either iodine, sulfuric acid or 5% phosphomolybdic acid in ethanol. Column chromatography was performed on Davidson

100-200 mesh silica gel. CHAPTER 8

EXPERIMENTAL

Experimental to Chapter 1

l-(3-Trimethylsllylprop-2-enyl)cyclohex-2-en-l-ol(6)

Into a flame dried flask under argon was added EtsO (30 ml.) and TMEDA (2.66 g., 22.9 mmol.). The mixture was

cooled to -78°C and s-BuLi (22.9 mmol., 15.3 ml. of a 1.5 M solution In cyclohexane) was added. To the mixture at -78°C was added allyltrlmethylsllane (2.62 g., 22.9 mmol.). The mixture was warmed to -25°C for 20 mln., then 2-cyclohexen-

l-one (2.00 g., 20.8 mmol.) was added as a solution In EtgO

(5 ml.). The mixture was stirred for 30 mln., then distilled

water (2 ml.) was added to the mixture, to quench the

reaction. The mixture was allowed to warm to R.T., then

poured Into saturated aqueous ammonium chloride solution

(20 ml.), and extracted with CHgClz (4X10 ml.). The com bined organic layers were dried over MgSOu, filtered, and evaporated. The crude product was distilled to provide the

pure desired product (3.89 g., 18.5 mmol., 89%) 6 , a clear liquid. B.P.=87°-88°C at 0.75 mmHg. IR (neat, cm”^):

3350 (m), 3010 (w), 2940 (s), l6l5 (m), l440 (m), l400 (m),

1325 (m), 1250 (s), 1170 (m), 1080 (m), 1060 (m), 1025 (m),

985 (s), 965 (m), 895 (m), 860 (s), 840 (s), 765 (m), 750

(m), 735 (m), 705 (m), 690 (m). NMR (CCI*, CHCI3, 6 ):

83 . 84 0.00 (s, 9H), 1.60 (m, 7H), 2.25 (d, 6 Hz, 2H), 5.72 (m,

4H). MS: M+-H2O. C12H 20SI: Calcd. m/e: 192.133, obs. m/e: 192.1 3 4.

3-(l-Trimethylsilylprop-2-enyl)cyclohexan-l-one(10)

Into a flame dried flask under argon was introduced THF (3 ml.), and KH (9.51 mmol., 1.73 g. of a 22% dispersion in mineral oil). The KH was washed with dry THF (3X3 ml.) to remove the mineral oil, then THF (10 ml.) was added to the mixture. To the suspension of KH in THF was added l-(3- trimethylsilylprop-2-enyl)cyclohex-2-ene-l-ol (1 g., 4.75 mmol.) as a solution in THF (3 ml.). The mixture was heated to reflux and stirred. After 7 h. an aliquot was removed from the reaction mixture and worked up. An IR of the aliquot showed the complete consumption of the starting mate? rial and the formation of product. The reaction mixture was allowed to cool, then the mixture was poured into saturated aqueous ammonium chloride solution (20 ml.), and extracted with CH2CI2 (4X10 ml.). The combined organic layers were dried over MgSOu, filtered, and the solvent was removed in vacuo. The crude material was distilled to provide the pure product (400 mg., I .90 mmol., 40%) ^ . B .P.=99°-101°C at 0.75 mmHg. IR (neat, cmT^): 3070 (w), 1710 (s), 1620

(m), 1445 (m), l4l5 (m), 1375 (m), 1310 (m), 1245 (s),

1220 (m), 1150 (m), 1055 (m), 1020 (w), 1000 (m), 925 (w). 85

895 (m), 855 (s), 835 (s), 750 (m), 720 (w), 690 (m), 635

(m). NMR (CClu, CHCI3, 6): -0.07 (s, 9H), 1.80 (m, lOH),

5.20 (m, 3H). l-( l-Methox.vpcnfVTdiejiy 1 )cyclohex-‘2-ene-l-ol (16 ) Into a rianie dried flask under argon was introduced

THF (5 ml.), and niethoxypropadiene (5^7 mg. , 7.80 mmol.). The mixture was cooled to -78°C in a dry ice, isopropanol bath and n-BuM(7.80 mmol. , 5.20 ml. of a 1.5 M solution in hexane) was added. After stirring for '45 min. at -78-C,

2-cyclohexene-l-one (500 mg., 5.20 mmol.) was added to the mix ture as a solution in THF (2 ml.). The reaction was stirred for an additional '15 min. at -78°C, then distilled water

(3 ml.) was .'idded to t)ie reaction and the mixture was allowed to warm to R.T. ('25°C). The contents of the reaction vessel were poured into distilled water (15 ml.), extracted with Ft 3O (5X6 ml.), dried over MgSOu, and

filtered. After removal of the solvent vacuo the product was distilled (ti’ap to trap, bath temp. 80^C, 0.010 mmlif,. )

to provide the pure compound (820 mg. , '1.93 mmol., 955)

7, a clear liquid. IR (neat, cm~M: 3'I'10 (s), 3010

(m), 2930 (s ), 1950 (m), l'J50 (m), 1320 (m), 1250 (m ' , 1190

(s), 1150 (m), 1050 (m), 1010 (m), 960 (m), 880 (m), 85O

(m), 735 (mi, 690 (mi. NMR (CDCI3, TMS, A ) : 1 .8 1 . m, 6 ii , 86

2.54 (s, br, IH), 3.42 (s, 3H), 5.47 (s, 2H), 5.73 (m,

2H). MS! CioHii.n,: Calcd. m/^: 166.099, nbs. m/_el 166.099 ,

166(18%), 148 (22%), ]4o (15%), 115 (l4%), 111 (21%), 107

(41%), 97 (100%), 91 (30%), 79 (76%), 77 (37%), 68 (45%),

55 (50%^.

4-Methoxy-l-oxasplro 4.5 deca-3,6-dlene(20) Into a flame dried flask under argon was Introduced

potassium hydride (2.20 mmol., 220 mg. of a 22% dispersion in mineral oil) and THF (2 ml.). The dispersion was

washed with THF (3X4 ml.) to remove the mineral oil, and THF (10 ml.) was added. To the suspension of potassium

hydride was added l-(l-methoxypropadienyl) cyclohex-2- en-l-ol (200 mg., 1.20 mmol.), as a solution in THF

(2 ml.). The mixture was heated to reflux and stirred.

After 1 h. at reflux no change was apparent. At this

time dicyclohexyl-l8-crown-6 (10 mg., 0.026 mmol) was

added, and the mixture was refluxed for 30 min. At this

time an IR, of an aliquot that had been removed from

the reaction and worked up, showed the complete consumption

of starting material and the formation of product 20. The reaction mixture was allowed to cool, then poured

into distilled water (20 ml.) and extracted with CH2CI (4x6 ml.). The combined organic layers were dried over

MgSOu, filtered and the solvent was removed ^ vacuo. 87

Distillation (trap to trap, 80°C, 0.35 mmHg.) provided

the pure product 20 (1^9 mg., 0.898 mmol., 7^%), a clear

liquid. IR (neat, cm"M: 3080 (w), 3010 (m), 2930 (s),

1660 (s), 1450 (m), 1345 (m), 1240 (m), ll60 (m), 1090

(m), 1045 (m), 1010 (m), 935 (m), 750 (m). NMR (CClu,

TMS, 6): 1.51 (m, 6H), 3.40 (s, 3H), 4.31 (m, 3H), 5-42

(m, 2H). MS: CioHiuOz: calcd. m/e : 166.099, obs. m/e:

1 6 6 .1 0 0 , 166 (20%), 150 (5%), 138 (100%), 125 (5%), 123

(9%), 109 (12%), 107 (12%), 97 (34%), 96 (13%), 94 (11%),

91 (12%), 79 (42%), 77 (17%), 68 (36%), 55 (39%).

l-0xaspiro[.4 . 5"]decan-6-ene-4-one (21 )

Into a flask was introduced 4-methoxy-l-oxaspiro 4.5 deca-3,3-diene (149 mg., O.898 mmol.), methanol (5 ml.) and 6n HCl (5 ml.). The mixture was stirred overnight

(15 h.), then poured into distilled water (5 ml.) and extracted with CH2CI2 (4x4 ml.). The combined organic layers were dried over MgSOu, filtered and evaporated.

Distillation (trap to trap, 80°C, 0.75 mmHg.) provided the pure product 21 (92.4 mg., O.6 O8 mmol., 68%), a clear liquid. IR (neat, cmr^): 3020 (m), 2930 (s),

1750 (s), 1630 (m), 1440 (m), l4lO (m), 1350 (m), 1250

(m), 1190 (m), 1120 (m), 1070 (s), 1040 (s), 940 (m), 820 88

(m), 730 (m), 670 (m). NMR (CClu, TMS, 5): 1.63 (m, 6 H), 2.42 (t, 7Hz, 2H), 4.03 (t, 7Hz, 2H), 5.60 (m, 2H). "^C

(CDCla, PPM): 216.3, 123.3, 123-9, 79.0, 61.7, 36.4,

29.2, 24.6, 18.1. MS: C9H 12O2: calcd. m/e: 152.084,

obs. m/e: 152.083, 152 (3%), 124 (28%), 96 (31%), 79

(5%), 77 (5%), 68 (100%), 55 (5%). Analysis: calcd.

C, 71.03%; H, 7 .95%. Pound: C, 70.83%; H, 7.80%.

Experimental to Chapter 3

1- (1-Methoxypropadienyl ) cyclopentanol (Jl_)

Into a flame dried flask under argon was introduced

THF (50 ml.), and methoxypropadiene (6.24 g., 89-2 mmol.).

The mixture was cooled to -78°C in a dry ice,isopropanol bath, and n-BuLl (89.2 mmol., 55-7 ml. of a 1.6 M soln. in hexane) was added. After 1 h. of stirring at -78°C, cyclopentanone (5 g., 59.4 mmol.) was added dropwise as a solution in THF (10 ml.). After an hour of stirring at -78°C, distilled water (10 ml.) was added to the mixture, then the reaction was allowed to warm to R.T. Once the mixture had warmed to 25°C, the reaction mixture was worked up by being poured into distilled water (50 ml.) and extracting with CH2CI2 (4X20 ml.). The organic layers were combined and dried over MgSOu. After filtration and removal of the solvent in vacuo, distillation provided 89

the pure product (8.42 g., 54.6 mmol., 92%) ^ ,

B.P.=110°-115"C (20 mmHg.), a clear liquid. IR (neat,

cm-i): 3400 (s), 2950 (s), 1950 (m), 1450 (m), 1225 (ni),

1175 (m), 1075 (m), 890 (m). NMR (CClu, TMS, 6): 1.70

8H), 2.17 (br, s, IH), 3.43 (s, 3H), 5.49 (s, 2H). MS: CgHiuOz: calcd. m/e 154.099, obs. m/e: 154.099,

154 (3%), 128 (10%), 114 (14%), 99 (11%), 95 (l4%), 85

(100%), 67 (60%), 55 (63%), 43 (66%). Analysis: calcd.

c,70.10%' H,9.15%, Pound: 0,69.96%; H,6.39%.

, 4-Methoxy-l-oxaspiro["4 . 4]nonan-3-ene (5)

Into a flame dried flask under argon, fitted with a reflux condenser was added ^BuOH (30 ml.), dicyclohexyl- l8-crown-6 (O.98 g. , 2.6 mmol.) and l-(l-methoxypropadienyl)- cyclopentanol (4.05 g , 26.3 mmol.). Once the crown ether dissolved (about 5 min.), KOtBu (2.95 g., 26.3 mmol.) was added, and the mixture was warmed to 80°C. Immediately upon the addition of the KOtBu the mixture turned a dark brown color. After 15 h. of stirring at 80°C, an aliquot was worked up. An IR of the aliquot showed the complete con sumption of the starting material and formation of the desired product 5. The mixture was allowed to cool, poured into distilled water (50 ml.), extracted with CH2CI2

(5x15 ml.), and the combined organic layers were dried over 90

MgSOu. After filtration, and remova] of solvent in vacuo,

distillation ''0.010 mtnlîp:. , 40^C, trap to trap).' gave the

desired product (2.25 g., 15 mmol., 55%) 11, a clear liquid.

IR (neat, ciirV): 1070 (w), 2950 (s), 165O (s', l^^O (m),

1340 (s), 1235 (s), 1180 (m), 1080 (m), 1050 (m), 1010 (m),

940 (m), 740 (m). NMR (001%, TMS, 6): 1.50 (s, 8H), 3.45

(s, 3H), 4.27 (s, hr, 3H). MS: OgHiwOg: calcd. m/e:

154.099, obs. m/e: 154.099, 154 (30%), 125 (100%), 123

(28%), 111 (11%), 97 (11%), 83 (6%), 67 (8%), 55 (30%).

l-0xaspiro[4.4]nonan-4-one (^

Into a flame dried flask under argon was introduced l-(l-methoxypropadienyl)cyclopentanol (8.34 g., 54 mmol.), dicyclohexyl-l8-crown-6 (1.01 g., 2.7 mmol,), and tBuGH (10 ml.). The mixture was stirred at R.T. for 1 min., then

KOtBu (1.21 g ., 10.8 mmol) was added and the mixture was warmed to 80°0. Immediately upon the addition of KOtBu the mixture turned dark brown. After 15 h . of stirring at 80°0,an aliquot was removed from the mixture and worked up. An IR of the aliquot showed that the reaction had gone to completion. The mixture was allowed to cool, then worked up. After the mixture was poured into distilled water,

(70 ml.), the solution was extracted with CRUClz (4X20 ml.).

The combined organic layers were then washed for 15 min. 91

with 6 n HzSOtt (30 ml.). After being washed the layers were

separated, the aqueous layer was extracted twice with CH2CI2

(6 ml.), and the combined organic layers were dried over MgSOu. After removal of the solvent vacuo, distillation

provided the pure product (5.32 g, 44.4 mmol., 82%) 1 2.

The product crystallizes at -l8°C. B .P.=35°-36°C at 0.010 mm Hg. IR (neat, cm“M: 2950 (s), 1750 (s), l440 (m), 1350

(m), 1250 (m), II50 (m), 1120 (m), 1050 (s), IO90 (m), 940

(m), 925 (m). MMR (CCI*, TMS, 5): I .70 (s, br, 8h), 2.39

(t, 5Hz, 2H), 4.03 (t, 5Hz, 2H). " NMR (CDCI3 , PPM):

218.3, 89.5, 52.2, 36 .4, 35.0 (2 carbons), 25.2, (2 carbons). Analysis: calcd: C, 58.55; H, 8.53. Found:

C, 58.54%, H, 8.84%. MS : CeHizOz: calcd: m/e : 140.084,

obs. m/e: 140.084, l40 (11%), 112 (28%), 84 (100%), 67

(7%), 56 (36%), 55 (82%).

1-(1-Methoxypropadienyl)cyclohex-2-en-l-ol (7)

Into a flame dried flask under argon was introduced

THF (5 ml.), and methoxypropadiene (547 mg., 7.80 mmol.). The mixture was cooled to -78°C in a dry ice, isopropanol

bath and n-BuLi(7.80 mmol., 5.20 ml. of a 1.5 M solution

in hexane) was added. After 45 min. of stirring.at -78°C,

2-cyclohexen-l-one (500 mg., 5.20 mmol.) was added to the mix ture as a solution in THF (2 ml.). The reaction mixture was 92

stirred for an additional 45 min. at -78°C, then distilled water (3 ml.) was added to the reaction and the mixture was

allowed to warm to R.T. (25°C). The contents of the

reaction vessel were poured into distilled water (15 ml.), extracted with EtgO (5X6 ml.), dried over MgSOi*, and

filtered. After removal of the solvent vacuo the product was distilled (trap to trap, bath temp. 80°C, 0.010 mmHg.)

to provide the pure compound (820 mg., 4.93 mmol., 95%) 7, a clear liquid. IR (neat, cm"M: 3440 (s), 3010

(m), 2930 (s), 1950 (m), 1450 (m), 1320 (m), 1250 (m), 1190 (s), 1150 (m), 1050 (m), 1010 (m), 960 (m), 880 (m), 850

(m), 735 (m), 690 (m). NMR (CDCla, TMS, 6): 1.8l (m, 6H),

2.54 (s, br, IH), 3.42 (s, 3H), 5.47 (s, 2H), 5.73 (m,

2H). MS: CioHikOg: calcd. m/e: 166.099, obs. m/el 166.099, 166(18%), 148 (22%), 140 (15%), 115 (14%), 111 (21%), 107

(41%), 97 (100%), 91 (30%), 79 (76%), 77 (37%), 68 (45%), 55 (50%).

4-Methoxy-l-oxaspiro[4 .^deca-3,6-diene(8)

Into a flame dried flask under argon was introduced tBuOH (5 ml.), dicyclohexyl-l8-crown-6 (314 mg., 0.842 mmol.) and 7“ (1-methoxypropadienyl)cyclohex-2-en-l-ol (700 mg., 4.21 mmol.). The mixture was stirred for 1 min. then

KOtBu (94.5 mg., 0.842 mmol.) was added and the mixture 93

was heated to 80°C. After 12 h. of stirring an IR of

an aliquot, removed from the reaction and worked up, showed

that the cyclisation had gone to completion. The reaction mixture was allowed to cool, then poured into distilled water

(20 ml.). The mixture was extracted with EtgQ (4X6 ml.), and the combined organic layers were dried over MgSOi,.

After filtration and the removal of the solvent vacuo, distillation (trap to trap, bath temp. 80°C, 0.010 mmHg.) provided the pure product (520 mg., 3.13 mmol., 74%),

8, a clear liquid. IR (neat, cm“^)I 3080 (w), 3010

(m), 2930 (s), 1660 (s), 1450 (m), 1345 (m), 1240 (m), ll60

(m), 1090 (m), 1045 (m), 1010 (m), 935 (m), 750 (m). NMR

(CCI*, TMS, 5): 1.51 (m, 6h ), 3.40 (s, 3H), 4.31 (m, 3H), 5.42 (m, 2H). MS : CioHiuOal calcd. m/e : 166.099, obs. m/e: 166.100, l66 (20%), 150 (5%), 138 (100%),125 (5%),

123 (9%), 109 (12%), 107 (12%), 97 (34%), 96 (13%), 94 (11%), 79 (42%), 77 (17%), 68 (36%), 55 (39%).

1-Oxaspiro[4 .5]dec-6-en-4-one (9 ) Into diethyl ether (10 ml.) was added 4-methoxy-l- oxaspiro[4.5]deca -3,6-diene (520 mg., 3.13 mmol.). The solution was placed in a separatory funnel and washed for

15 min. with 6n HgSO* (5 ml.). At this time the layers were separated, the aqueous layer was extracted with 94

diethyl ether (2X4 ml.), and the organic layers were combined.

After-being dried over MgSOu, the solution was filtered, evaporated and the crude product was distilled (trap to trap, bath temp! 80°C, 0.75 mmHg.) to provide the pure desired compound (380 mg., 2.50 mmol., 80%) 9, a clear liquid. IR

(neat, cm"M: 3020 (m), 2930 (s), 1750 (s), 1630 (m), l440

(m), 1410 (m), 1350 (m), 1250 (m), 1190 (m), 1120 (m), 1070

(s), 1040 (s), 940 (m), 820 (m), 730 (m), 670 (m). NMR

(CClu, TMS, Ô): 1.63 (m, 6 H), 2.42 (t, 7Hz, 2H), 4.03

(t, 7Hz, 2H), 5.60 (m, 2H). (CDCI3, PPM): 216.3,

134.3, 123.9, 79.0, 61.7 , 36.4, 29.2, 24.6, 18.2. MS:

C9H 12O2: calcd. m/e: 152.083, obs. 152.084, 152 (3%),

124 (28%), 96 (31%), 79 (5)%, 77 (5%), 68 (100%), 55 (5%). Analysis: calcd: C, 71.03%j H, 7.95%. Pound: C, 70.83%j

H, 7 .80%. l-(l-Methoxypropadlenyl)cyclohexan-l-ol(10) Into a flame dried flask under argon was Introduced

THF (5 ml.), and methoxypropadiene (714 mg., 10.2 mmol.). The mixture was cooled to -Yd°C andji-BuLl (10.2 mmol., 6.79 ml. of a 1.5 M solution in hexane) was added. The resulting pale yellow solution was allowed to stir for 1 h. at -78°C.

At this time cyclohexanone (500 mg., 5.09 mmol.) was added to the mixture as a solution in THF (2 ml.). After 1 h. of 95

stirring at -78°C,distilled water (3 ml.) was added to the reaction and the temperature was allowed to rise to 20°C.

The solution was poured into distilled water (15 ml.), then extracted with EtaO (5X6 ml.). The combined organic layers were dried over MgSO*, and the solvent was removed in vacuo. Distillation (trap to trap, bath temp. 75°C, 0.15 mmHg.) provided the pure product (820 mg., 4.87 mmol., 95%)

10 , a clear liquid, which froze to a white crystalline solid at -18°C. IR (neat, cm“M: 3440 (m), 2940 (s), 1950 (w),

1450 (m), 1380 (m), 1350 (m), 1255 (m), 1200 (s), 1150 (s),

1050 (s), 960 (s), 890 (m), 675 (m). NMR (CCI*, TMS, 6):

1.61 (s, br, 8H), 1.96 (s, br, IH), 3.47 (s, 3H), 5-52

(s, 2H). MS: CioHieOz: calcd. m/e: 168.115, obs. m/e:

168.115, 168 (17%), 153 (5%), 125 (22%), 111 (11%), 99

(24%), 97 (20%), 91 (13%), 87 (l4%), 8l (40%), 79 (23%),

77 (11%), 70 (15%), 67 (26%), 55 (100%).

4-Methoxy-l-oxaspiro[4 .5] dec-3-ene (11)

Into a flame dried flask under argon was introduced tBuOH (5 ml.), dicyclohexyl-l8-crown-6 (319 mg., O.856 mmol.) and l-(l-methoxypropadienyl)cyclohexan-l-ol (720 mg., 4.28 mmol.). The mixture was stirred briefly and KOtBu (96.1 mg.,

0.856 mmol.) was added. The solution was then heated to 80°C and stirred. After 10 h. of stirring an aliquot was removed from the reaction mixture and worked up. An IR of the 96 aliquot showed that the reaction had gone to completion.

At this time the mixture was allowed to cool, then poured distilled water (15 ml.) and extracted with EtaO (5X6 ml.).

The combined ether layers were dried over MgSOi,, filtered, and evaporated. Distillation (trap to trap, bath temp. 80°C, 0.10 mmHg.) provided the pure product (350 mg., 2.08 mmol., HS%) Ijr, a clear liquid. IR (neat, cm~^) 3080 (w), 2920 (s), l660 (s), 1450 (m), 1345 (m), 1240 (m), 1150 (m), 1090 (m), 1055 (m), 1010 (m), 970 (m), 940 (m),

840 (m), 750 (m), 700 (m). NMR (CDCI3, TMS, 6): 1.50

(m, 8H), 3.56 (s, 3H), 4.47 (m, 3H). MS: CioHisOz: calcd. m/e: 168.115, obs. m/e: 168.115, 168 (27%), 153 (4%),

140 (6%), 138 (13%), 125 (100%), 111 (9%), 97 (13%),

91 (3%), 81 (14%), 79 (8%), 67 (9%), 55 (25%).

1-Oxaspiro[4.5]decan-4-one(^)

Into a separatory funnel was added diethyl ether (10 ml.),

4-methoxy-l-oxaspiro[4.5]dec-3-ene (300 mg., I.78 mmol.), and

6n HaSOu (5 ml.). The mixture was shaken for 15 min., then the layers were separated. The aqueous layer was extracted with diethyl ether (2X4 ml.) and the ether layers were combined, After being dried over MgSO*, filtration, and removal of the solvent vacuo, distillation (trap to trap, bath temp. 80°C, 0.010 mmHg.) provided the pure product (230 mg.,

1.49 mmol., 84%) 12, a clear liquid. IR (neat, cm~M: 97

2930 (s), 1750 (s), 1450 (m), l4lO (m), 1360 (m), 1255 (m), 1230 (m), 1190 (m), 1150 (m), 1110 (m), 1060 (s), 970 (m), 940

(m), 910 (m), 830 (m). NMR (CCI*, TMS, 5): li45 (m, BH), 2.32 (t, 7Hz, 2H), 3.97 (t, 7Hz, 2H). Analysis’, calcd: C, 70.10%; H,9.15%, Pound: C,69.87%; H, 9.41%. MS: CgHi^Og: calcd: m/e: 154.099, obs. m/e: 154.099, 154 (20%), 126 (24%), 98 (100%), 82 (5%), 80 (3%), 79 (11%), 70 (l6%), 69 (22%), 55 (42%).

1-(3,4,5-trlmethoxyphenyl)-2-methoxybuta-2,3-dlen-l-ol ( ^ ) Into a flame dried flask under argon was introduced methoxypropadiene (268 mg., 3.82 mmol.) and THF (5 ml.). The solution was cooled to -78°C and n^-BuLi (3.82 mmol., 2.55 ml. of a 1.5 M solution in hexane) was added. The mixture was stirred for 30 min. To the clear solution of the anion was added 3,4,5-trimethoxybenzyladehyde (500 mg., 2.55 mmol.) as a solution in THF (3 ml). The reaction mixture was allowed to stir at -78°C for 1 h. then distilled water (4 ml.) was added and the mixture was allowed to warm to 20°C. The solution was poured into distilled water (15 ml.) and extracted with diethyl ether (5X6 ml.). After the combined ether layers were dried over MgSO«, and filtered, removal of the solvent in vacuo provided the desired product (620 mg., 2.32 mmol., 91%) 13, a yellow solid. M.P.=66°-70°C. IH (neat, cm“ M :

3450 (m), 2940 (m), 1950 (w), 1590 (s), 1500 (m), l460 (m). 98

1420 (m), 1330 (m), 1240 (m), 1190 (m), 1125 (m), 1050 (m),

1010 (m), 960 (w), 850 (w), 760 (w). NMR (CCI*, TMS, 6):

3.30 (s, 3H), 3.70 (s, 3H), 3.73 (s, 6H), 5.42 (d, 2Hz, 2H),

6.50 (s, 2H). MS: C1UH17O5: calcd: m/e: 266.115, obs. m/e:

266 .116, 266 (3%), 254 (2%), 237 (5%), 212 (5%), 196 (38%),

181 (25%), 169 (7%), 154 (4%), 138 (5%), 125 (10%), 121 (27%),

119 (92%), 117 (100%), 110 (8%), 101 (15%), 84 (15%), 82 (23%),

77 (7%), 65 (5%), 57 (8%).

2,5-Dlhydro-3-methoxy-2-(3 ,4 ,5-trlmethoxyphenyl ) furan (14) Into a flame dried flask under argon was introduced tBuOH (5 ml.), THF (5 ml.), dicyclohexyl-l8-crown-6 (173 mg., 0.466 mmol.) and l-(3,4,5-trimethoxyphenyl)-2-methoxybuta-2,3-dien- l-ol (620 mg., 2.33 mmol.). The mixture was stirred for 1 min. and KOtBu (52.3 mg., 0.466 mmol.) was added. The mixture was heated to 80°C and stirred. After 13 h.,the initially brown solution had turned orange, and an aliquot was removed and worked up. An IR of the aliquot showed that the reaction had gone to completion. The mixture was allowed to cool, then poured into distilled water (10 ml.) and extracted with diethyl ether (5X6 ml.). The combined ether layers were dried over MgSOu, filtered, and evaporated. The crude pro duct was chromatographed on silica gel (20 g., eluted with

20% EtOAc- 80% petroleum ether) to provide the desired compound (470 mg., 1.77 mmol., 76 %)14, a yellow oil. IR 99

(neat, cm-M: 2930 (s), I66 O (s), 1590 (s), 1500 (s), l460

(s), 1420 (s), 1330 (s), 1240 (s), 1130 (s), 1010 (m), 96O

(w), 830 (m), 750 (m), 720 (m). NMR (CCI*, TMS, 6): 3.57

(s, 3H), 3.70 (s, 3H), 3.80 (s, 6H), 4.63 (d, 1.5Hz, 2H),

4.72 (t, 1.5Hz, IH), 5.20 (m, IH), 6.43 (s, 2H). MS:

CiuHirOs. calcd. ]J^/s_" 266.115, obs. : 266.155j 266

(100%), 249 (23%), 235 (23%), 226 (12%), 219 (10%), 203

(22%), 196 (18%), 195 (22%), 191 (14%), 181 (13%), 168

(36%), 153 (24%), 143 (8%), 125 (8%), 99 (11%), 93 (8%),

91 (8%), 89 (8%), 81 (16%), 79 (8%), 77 (12%), 55 (67%).

2-(3,4,5-trlmethoxyph6nyl)dlhydrofuran-3(2H)-one(^) Into a flame dried flask under argon was introduced tBuOH (15 ml.), KOtBu (545 mg., 4.46 mmol.) and 1-(3,4,5- trimethoxyphenyl)-2-methoxybuta-2,3-dien-l-ol (1.19 g., 4.46 mmol.). The mixture was heated to reflux and the progress of the reaction was followed by IR. After 2 h. the reaction was finished. The mixture was allowed to cool, then poured into distilled water (15 ml.) and extracted with

CH2CI2 (5x6 ml.). The combined organic layers were washed for 15 min. with 6j^ HCl (10 ml.). The layers were separated and

the aqueous layer was extracted with CH2CI2 (2X4 ml.). The combined organic layers were dried over MgSOi*, filtered, and evaporated. The resulting brown oil was chromatographed on silica gel (20 g., eluted with 50% diethyl ether, 50% 100

petroleum ether). The product obtained from the column was. recrystallized from diethyl ether and pentane to provide the

pure desired product (585 mg., 2.32 mmol., 52%) 15, a white solid. A portion of the product was sublimed for an elemental analysis. M.P.=65°-6?° C. IR (Nujol, cm”^): 2930 (s), 1750

(s), 1590 (m), 1500 (m), 1460 (m), 1420 (m), 1350 (m), 1240 (m),

1125 (s), 1000 (m), 950 (m), 88O (m), 835 (m). NMR (CDCI3,

TMS, Ô): 2.52 (t, 7Hz, 2H), 3.75 (s, 3H), 3.80 (s, 6h), 4.22

it, 7Hz, 2H), 4.59 (s, IH). Analysis: calcd. C,61.89%;

H,6.39%, Pound: C,6l.6l%; H,6.4l%. MS: CiaHieOsI calcd. m/e: 252.100, obs. m/e: 252.099, 252 (34%), 224 (1%),

212 (1%), 197 (100%), 181 (42%), 177 (1%), 153 (4%), 135

(4%), 125 (12%), 110 (7%), 95 (6%), 93 (7%), 79 (4%),

77 (5%), 65 (6%), 58 (7%).

I ,l-Diphenyl-2-methoxy-2,3-butadien-l-ol ( ^ )

Into a flame dried flask under argon was introduced

THF (5 ml.) and methoxypropadiene (288 mg., 4.12 mmol.). The mixture was cooled to -78°C and n^BuLi (4.12 mmol.,

2.74 ml. of a 1.5 Ü solution in hexane) was added. The resulting pale yellow solution was stirred at -78°C for 1 h.

At this time,benzophenone (500 mg., 2.74 mmol.) was added slowly to the reaction as a solution in THF (4 ml.). The mixture was allowed to stir for 1 h. at -78°C, then distilled water (2 ml.) was added and the reaction mixture was allowed 101

to warm to R.T. The mixture was poured Into distilled water (10 ml.) and was extracted with diethyl ether (4x6 ml.). After drying over MgSO#, and filtration, the removal of the solvent

in vacuo provided the desired product (6 lO mg., 2.42 mmol., 89%) 16, a waxy solid. M.P.=4l°-47°C. IR (CCI*, cm"M:

3540 (s), 3060 (m), 3020 (m), 2930 (m), 1950 (w), 1600 (w),

1490 (m), 1450 (s), 1350 (m), 1280 (m), 1210 (s), 1170 (s),

1100 (s), 1030 (s), 900 (m), 755 (s), 700 (s), 665 (m).

NMR (CCI*, TMS, 6 ): 3.45 (s, 3H), 5.22 (s, 2H), 7.20 (m,

lOH). MS: C17H16O2. calcd. m/e: 252.115, obs. m/e:

252.116, 252 (16%), 234 (16%), 220 (33%), 192 (17%), 191

(18%), 183 (23%), 175 (11%), 166 (15%), 165 (19%), 147

(13%), 115 (17%), 105 (100%), 77 (57%).

l,l-Diphenyl-3-methoxy-5(H)-furan(IJ ) Into a flame dried flask under argon was introduced

tBuOH (5 ml.), dicyclohexyl-l8-crown-6 (192 mg., 0.515 mmol.),

THF (3 ml.), and l,l-diphenyl-2-methoxy-2,3-butadiene-l-ol

(610 mg., 2.42 mmol.). The mixture was stirred briefly, then

KOtBu (57.8 mg., 0.515 mmol.) was added. The mixture was heated to 80°C and stirred. After 10 h. at 80°C an IR of an aliquot, removed from the reaction mixture and worked up, showed the complete formation of product. The mixture was

allowed to cool, then poured into distilled water (15 ml.) and extracted with EtaO (5X6 ml.). The combined organic 102

layers were dried over MgSO*, filtered and evaporated. The crude product was chromatographed on silica gel (20 g., eluted with 20% EtOAc- 80% petroleum ether) to provide the pure product (4lO mg., 1.62 mmol., 67%) ^ , a white solid. M.P.=89°-90°C. IR (CCI*, TMS, 5): 3090 (m), 3070 (m),

3010 (m), 1660 (s), l600 (m), 1490 (m), l440 (s), 1350 (s),

1305 (s), 1280 (m), 1245 (s), 1200 (s), ll80 (s), ll60 (s),

1040 (s), 995 (m), 960 (m), 940 (m), 915 (m), 900 (m), 760

(s), 700 (s). NMR (CCI4, TMS, 6): 3.71 (s, 3H), 4.71

(m, 3H), 7.23 (m, lOH). MS: C17H1GO2: calcd. m/e:

252.115, obs, m/e: 252.116, 252 (34%), 221 (5%), 191 (6%),

175 (100%), 165 (7%), 147 (14%), 143 (9%), 115 (l6%), 105

(24%), 91 (7%), 77 (24%), 55 (21%). l,l-Diphenyl-5(H)-furan-3-one(1^) Into a flask was introduced THF (20 ml), 1,1-diphenyl-

3-methoxy-5(H)-furan (300 mg., 1.19 mmol.) and 6n HaSOi*

(10 ml.). The mixture was stirred for 15 h. At this time both TLC, and an IR of an aliquot that had been removed from the reaction mixture and worked up, indicated that the hydro lysis had gone to completion. The mixture was poured into distilled water (10 ml.), and extracted with CH2CI2 (5X6 ml.). The combined organic layers were dried over MgSOu, filtered and evaporated. The crude product was recrystallized from Et20 -petroleum ether to provide the pure product 103

(l67 mg., 0.702 mmol., 59%) ^ , a pale pink solid. M.P.=

65°-68°C. IR (CCI*, cm-"): 305O (m), 2880 (m), 1750(s),

1600 (w), 1560 (w), 1490 (m), 1440 (m), 1395 (m), 1350 (w),

1310 (w), 1260 (m), 1140 (s), 1040 (m), 1020 (m), 930 (w),

900 (w), 810 (w), 760 (m), 700 (m). NMR (CCI*, TMS, 5):

2.54 (t, 7Hz, 2H), 4.18 (t, 7Hz, 2H), 7.26 (m, lOH).

Analysis: calcd: C,80.65%; H,5.92%, Found: 0, 79.28%;

H, 6.16%. MS! calcd. m/e’.238.099, obs. m/e_: 238.099, 238 (5%), 210 (40%), 182 (43%), 165 (7%), 152 (2%), 106 (10%), 105 (100%), 82 (4%), 77 (33%), 63 (2%), 51 (13%).

2-(l-Methoxypropadienyl)adamantan-2-ol(^) Into a flame dried flask under argon was introduced

methoxypropadiene (1.12 g ., 16.O mmol.) and THF (10 ml.). The mixture was cooled to -78°C and n-BuLi (16.0 mmol., 10 ml. of a 1.6 M solution in hexane) was added. After stirring

for 45 min. at -78°C 2-adamantanone (2.00 g. , 13.3 mmol.)

was added dropwise as a solution in THF (6 ml.). After 1 h.

of stirring at *?8°C, distilled water (6 ml.) was added to the reaction mixture and the mixture was allowed to warm to 20°C.

At this time the reaction was poured into saturated aqueous

NaHCOg solution (15 ml.) and extracted with CH2CI2 (4x8 ml.). The organic layers were combined, dried over MgSO*, filtered,

and evaporated to provide the desired product (2.83 g.,

12.8 mmol., 97%) 19, a yellow solid. M.P.=80°-89°C. IR 104

(Nujol, cm-i): 3500 (m), 2900 (s), 1950 (w), 1450 (s), 1380

(m), 1350 (m), 1330 (m), 1270 (m), ll80 (s), 1100 (m), 1085

(m), 1070 (m), 1050 (m), 1020 (s), 995 (m), 940 (s), 890 (s),

840 (w), 700 (m). NMR (CDCI3 , TMS, 6): 1.73 (m, 14h), 3.35

(s, 3H), 5.50 (q, 7Hz, 2H). MS: Ci^HzoOz: calcd. m/e:

220.146, obs. m/e: 220.145, 220 (9.7%), 194 (15%), 165 (24%),

161 (12%), 150 (100%), 134 (15%), 117 (23%), 105 (17%), 101

(20%), 93 (33%), 91 (49%), 85 (26%), 8l (51%), 80 (73%), 79

(85%), 78 (34%), 77 (30%), 75 (30%), 72 (50%), 71 (4l%), 69

(33%), 67 (33%), 57 (87%), 56 (68%), 55 (53%).

Spiro[’adamantane-2,2^(5'H)-3^methoxyfuranl (20 ) Into a flame dried flask under argon was introduced

KH (6.81 mmol., I.I6 g. of a 23.5% dispersion in mineral oil) and THF (2 ml.). The mixture was stirred briefly then allowed to sit quietly until the KH settled (about 5 min.) The solvent was carefully removed. This washing procedure was repeated 3 more times, using THF (2 ml) each time.

THF (5 ml.) was added to the KH, along with dicyclohexyl- l8-crown-6 (3.38 g., O.908 mmol.). To the reaction mixture was added 2-(1-methoxypropadienyl)adamantan-2-ol (1 g .,

4.54 mmol.) as a solution in THF (3 ml.). The mixture bubbled vigorously upon the addition of the allenyl alcohol, and turned a deep brown color. The mixture was heated to 80°C and stirred. After 12 h. of refluxing an IR of an aliquot. 105

removed from the reaction mixture and worked up, showed

that the cycllzation had gone to completion. The mixture

was allowed to cool and %&g^4.^-led water (6 ml.) was added very carefully to the mixture. The solution was poured into

distilled water (20 ml.) and extracted with CH2CI2 (5X6 ml.). The combined organic layers were dried over MgSO*, filtered, and evaporated. The crude product was chromatographed on

silica gel (20 g., eluted with 20% EtOAc - 80% petroleum

ether) to provide the pure product (320 mg., 1.45 mmol.,

32%) 20, a yellow oil. IR (neat, cm""): 2920 (s), I65O (s),

1450 (s), 1335 (s), 1240 (s), 1100 (m), IO8O (m), 1055 (m),

1020 (5), 915 (m), 865 (m). NMR (CCI*, TMS, Ô): 1.69

(m, 14H), 3.62 (s, 3H), 4.38 (d, 2Hz, 2H), 4.53 (t, 2Hz,

IH). MS I Ci*H2o02.‘ calcd. m/e_; 220.146, obs. n/e_I

220.147, 220 (42%), 207 (6%), 191 (10%), 178 (6%), I6 I

(5%), 150 (100%), 132 (3%), 117 (7%), 103 (5%), 99 (10%),

93 (6%), 91 (12%), 80 (22%), 79 (26%), 72 (8%), 67 (9%), 55 (17%). 106

Splro[[adamantane-2,2*-(5’H)furan-3 '-one] (21)

Into a separatory funnel was placed diethyl ether (20 ml.), and spiro[adamantane-2,2^(5^H)-3^-methoxyfuran]

(300 mg., 1.36 mmol.), and 6N H2SO» (10 ml.). The mixture was shaken for 30 min., then the layers were separated. The aqueous layer was extracted with diethyl ether (3X2 ml.) and the combined organic layers were washed with saturated brine. After the ether solution had been dried over MgSOu, it was filtered, and evaporated. The crude product was sublimed (O.OO5 mmHg., 25°C) to provide the pure product

(273 mg., 1.32 mmol., 91%) 21, a waxy solid. M.P.=36°-38°C, IR (neat, cm"M: 2940 (s), 1750 (s), 1470 (m), 1455 (s),

1415 (m), 1360 (m), 1270 (m), II80 (s), II50 (s), 1110 (s),

1080 (s), 1040 (m), 1010 (m), 98O (m), 940 (m), 875 (m),

820 (m), 680 (m). NMR (CClu, TMS, 5): 1.70 (m, 14H),

2.52 (t, 7Hz, 2H), 4.07 (t, 7Hz, 2H). MS: CisHieOz: calcd.m/e: 206.131, obs. m/e: 206.131, 206 (5.3%), 178

(5%), 150 (100%), 132 (2%), 117 (5%), 114 (4%), 91 (5%), 80

(21%), 79 (18%), 72 (7%), 67 (4%), 53 (4%). Analysis: calcd: 0,75.69%; H,8.80%, Found: 0,75.47%*, H,8.91%. 107 3-Methoxyestpa-17(1-methoxypropadienyl)-17g-ol (22) Into a flame dried flask under argon was introduced methoxypropadiene (370 mg., 5.27 mmol.), and THF (4 ml.). The mixture was cooled to -78°C in a dry ice -isopropanol bath, and n-BuLi (5.27 mmol., 3.52 ml. of a 1.5 M solution in hexane) was added. The resulting pale yellow solution was stirred for 1 h. Next, estrone (500 mg., 1.76 mmol.) was added slowly to the reaction as a solution in THF (10 ml.). The reaction was stirred for an additional hour at -78°C, then distilled water (4 ml.) was added to the solution and the temperature was allowed to rise to 20°C. The mixture was poured into distilled water (15 ml.), then extracted with diethyl ether (5X6 ml.). The combined ether layers were dried over MgSOu, filtered, then evaporated to provide the product (610 mg., 1.72 mmol., 98%) 22, a yellow foam.

M.P.=97°-106°C. IR (CCI4, cm-i): 3560 (m)., 2930 (s), 19^5

(w), 1600 (m), 1495 (m), 1450 (m), 1340 (m), 1280 (m), 1250

(m), 1230 (m), 1180 (m), II50 (m), IO7 O (m), 1040 (m), 900

(m). NMR (CDCI3, TMS, 6 ): 0.90 (s, 3H), 1.57 (m, 15H),

2.74 (s, br, IH), 3.44 (5, 3H), 3.68 (s, 3H), 5.48 (q, 7Hz,

2H), 6.82 (m, 3H). MS: C23H 30O3: calcd. m/e: 354.219, obs. m/e: 354.220, 354 (37%), 342 (7%), 340 (12%), 332

(4%), 284 (21%), 268 (13%), 240 (50%), 227 (53%), 225

(21%), 213 (8%), 199 (16%), 186 (12%), 174 (28%), 173

(3%%), 171 (22%), 160 (17%), 147 (39%), 143 (31%), 121 (28%),

119 (92%), 117 (66%), 101 (27%), 91 (19%), 84 (80%), 75

(44%), 69 (40%), 57 (100%). 108

3-Methoxyspiro(^estrane-17’2’ (5’H)3 ’ -methoxyfurarT} (23 )

Into a flame dried flask under argon was introduced tBuOH (5 ml.), THF (5 ml.), dicyclohexyl-l8-crown-6 (156 mg.,

0.42 mmol.), and 3-methoxyestra-17(1-methoxypropadienyl)-

173-01 (740 mg., 2.1 mmol.). The mixture was stirred briefly, and KOtBu (46.9 mg., 0.42 mmol.) was added. The reaction mixture was heated to 80°C and stirred. After 11 h. of stirring, an aliquot was removed from the reaction mixture and worked up. An

IR of the aliquot showed that the reaction had gone to comple tion. The mixture was allowed to cool, then poured into distilled water (20 ml.). After extraction with diethyl ether (5X6 ml.), the combined organic layers were dried over MgSOi,, filtered, and evaporated. The crude product was chromatographed on silica gel (20 g., eluted with 20% EtOAc-

80% petroleum ether) to provide the desired product (200 mg., 0.564 mmol., 27%) 23, a yellow oil. IR (neat, cm"^)I 2920

(s), 1650 (s), 1600 (m), 1570 (w), 1490 (s), 1450 (m), 1370

(m), 1340 (m), 1240 (s), ll40 (m), 1090 (m), 1040 (m), 1010

(m), 945 (w), 870 (w), 735 (m). NMR (CCI*, TMS, 6 ): 0.84

(s, 3H), 1.62 (m, 15H), 3.63 (s, 3H), 3.69 (s, 3H), 4.34

(d, 2Hz, 2H), 4.53 (t, 2Hz, IH), 6.68 (m, 3H). MS: 354

(4%), 340 (64%), 284 (13%), 240 (12%), 237 (100%), 213 (4%),

199 (7%), 186 (6 %), 174 (11%), 160 (8%), l47 (10%), 119

(14%), 117 (14%), 91 (8%), 81 (17%), 68 (21%). 109 3-Methoxysplrofestran-17,2^(5 ^H)-furan-3^-one](24) Into a flame dried flask under argon was introduced tBuOH (15 ml), dioyclohexyl-l8-crown-6 (100 mg., 0.268 mmol.), and 3-methoxyestra-17(l-methoxypropadienyl)-173-ol (1.20 g., 3.39 mmol.). The mixture was stirred for 5 min. and KOtBu

(1.90 g., 16.9 mmol.) was added. The mixture was heated to 80°C and stirred. After 15 h. an aliquot was removed from the reaction mixture and worked up. An IR of the aliquot showed that the reaction had gone to completion. The mixture was allowed to cool, then poured into saturated aqueous NaHCOs solution

(20 ml.). The mixture was extracted with CH2CI2 (4X10 ml.) and the organic layers were combined. After washing the combined organic layers for 15 min. with 6 N HCl (20 ml.), the layers were separated and the aqueous layer was extracted with CH2CI2 (2x4 ml.). The combined organic layers were dried over MgSO I,, filtered, evaporated, and the resulting brown oil was chromatographed on silica gel (20 g., 20% diethyl ether,

80% petroleum ether). The chromatographed product was recrystallized from MeOH and pentane to provide the pure product (679 mg., 1.99 mmol., 59%) 24, a white solid. A portion was sublimed (100°C, O.OO5 mmHg.) to provide a sample for elemental analysis. M.P.=ll8°-119°C. IR (Nujol, cm“^)I

3010 (w), 2950 (s), 1740 (m), 1610 (m), 1585 (m), 1500 (m),

1450 (m), 1405 (m), 138O (m), 136O (m), 1320 (m), 1290 (m),

1240 (m), 1190 (m), 1170 (m), 1135 (m), IO85 (m), 1040 (m),

1010 (m), 970 (w), 910 (m), 865 (m), 85O (m), 825 (m), 795 110 (m). NMR (CDCI3, TMS, ô): 0.90 (s, 3H), I .70 (m, 15H),

2.^3 (t, 7Hz, 2 H ) , 3.70 (s, 3H), 4.06 (t, 7Hz, 2H), 6 .80

3H). Analysis: calcd. C, 77.61%; H, 8.29%. Found.

C, 77 .62%, H, 8.50%. MS : CsaHzeOa: calcd. m/e :

340.204, obs, m/e: 340.205, 340 (100%), 284 (8%), 240

(9%), 227 (81%), 213 (3%), 199 (5%), 1B 6 (3%), 174 (6%),

173 (6 %), 160 (4%), 149 (6%), 147 (6 %), 128 (3%), 115

(3%), 91 (5%), 72 (7%), 58 (8%), 57 (8%). [a]##8=-24.6°, c=0.500 g/100 ml. in chloroform.

17-(l-Methoxypropadienyl)-3-methoxyandrosta-3 >5-dlen-

173-01(25) Into a flame dried flask under argon was introduced

THF (5 ml.) and methoxypropadiene (700 mg., 9.99 mmol.). The mixture was cooled to -78°C and n-BuLi (9.99 mmol.,

6.66 ml. of a 1.5 M solution in hexane) was added. The solution was stirred at -78°C for 30 min., then 3-methoxyandrosta-3,5-dlen-17-one (1 g . , 3.33 mmol.) was slowly added as a solution in THF (10 ml.). Upon the completion of the addition, the mixture was allowed to stir at -78°C for

1 h. At this time the reaction was quenched,* at -78°C, with distilled water (4 ml.), and allowed to warm to R.T. The mixture was then poured into distilled water (15 ml.) and extracted with diethyl ether (4x6 ml.). The combined ether layers were dried over MgSOu, filtered, and evaporated to provide the product (1.22 g ., 3.29 mmol., 98%) 25, a pale Ill

yellow foam. M.P.=115°-125°C. IR (neat, cm"M: 3^50 (m),

2940 (s), 1950 (w), 1660 (s), I63O (m), 1460 (m), 1390 (m),

1240 (s), 1170 (s), 1080 (m), 1040 (m), 880 (m). NMR

(CDCI3 , TMS, 6 ): 0.90 (s, 3H), 0.96 (s, 3H), 1.52 (m, 1?H).,

3.45 (8, 3H), 3.56 (s, 3H), 5.03 (m, 2H), 5-52 (q, 7Hz, 2H).

MS : C2UH34O3I calcd. m/e : 370.250, obs. m/e: 370.249,

370 (100%), 355 (23%), 338 (5%), 300 (33%), 284 (23%), 256

(34%), 243 (18%), 189 (20%), 173 (11%), 150 (20%), 133 (l8%),

111 (18%), 105 (16%), 97 (16%), 91 (23%), 79 (15%), 71 (20%),

67 (13%), 59 (28%), 55 (66%).

3-Methoxyspiro[androstane-17,2^X3"-methoxy-5 ^H)furan]- 3 ,5-dlene (26)

Into a flame dried flask under argon was Introduced

17-(1-methoxypropadienyl)-3-methoxyandrosta-3,5-dien-17B-ol (1.22 g ., 3.29 mmol.), tBuOH (5 ml.), and dicyclohexyl-l8- crown-6 (251 mg., 0.675 mmol.). The mixture was stirred for

1 min. and KOtBu (75.7 mg., 0.675 mmol.) was added. The mixture was heated to 80°C and stirred. After 13 h. of stirring an aliquot was removed from the reaction mixture and worked up. An IR of the aliquot showed ■ the complete consump tion of starting material and the formation of the desired product 2^. The reaction mixture was allowed to cool and was then poured into distilled water (10 ml). The mixture was extracted 112

with diethyl ether (5X4 ml.), then the ether layers were combined, dried over MgSO*, and filtered. After evaporation of the solvent In vacuo the crude product was chromatographed

on silica gel (20 g., eluted with 20% EtOAc-80% petroleum ether) to provide the desired product (251 mg., O.678 mmol,

21%) 2^, a yellow oil. IR (neat, c m " M : 2930 (s), 1650 (s),

1630 (m), 1450 (m), 1380 (m), 1230 (m), II70 (m), 1040 (m),

950 (m), 870 (m). NMR (CCI*, TMS, Ô): 0.92 (s, 6 h), 1.53

(m, 17H), 3.50 (s, 6 H), 5.02 (m, 6 h). MS: 370 (0.3%), 356

(3%), 342 (7%), 286 (7 %), 242 (5%), 229 (3%), 164 (4%),

152 (9%), 128 (13%), 121 (50%), 119 (100%), 117 (100%),

105 (18%), 91 (32%), 84 (127%), 82 (40%).

(173)-4" ,5'*-Dlhydrosplro|Jandrost-4- en -17 ,2^-furan-3' -on^-

3-one (27) Into a flame dried flask under argon was Introduced _tBuOH

(15 ml.), dlcyclohexyl-l8-crown-6 (100 mg., 0.268 mmol.), and 17-(l-methoxypropadlenyl-3-methoxyandrosta-3,5-dlen-176-ol

(2 g., 5-40 mmol.). The mixture was stirred briefly and

KOtBu (3.03 g., 27.0 mmol.) was added. The mixture was heated to 80°C and stirred. After 4 h. an IR of an aliquot, that had been removed from the react! n mixture and worked, showed that

the reaction had gone to completion. The mixture was allowed

to cool, then poured Into saturated aqueous NaCHOs solution (20 ml.) and extracted with CHsCla (5X10 ml.). The organic 113

layers were combined and washed for 20 min. with 6n HCl (20 ml.). The layers were separated, then the aqueous layer

was extracted with CH2CI2 (2X4 ml.). The combined organic

layers were dried over MgSO*, filtered, evaporated, chromato

graphed on silica gel (20 g., eluted with 50% EtgO- 50%

petroleum ether), and then recrystallized (MeOH - pentane)

to provide the desired product (863 mg., 2.52 mmol., 47%) 27, a white solid. A portion of the product was sublimed (90°C,

0.005 mmHg.) for an elemental analysis. M.P.=l67°-l68°C.

IR (Nujol, cm-M; 2900 (s), 1740 (s), l675 (s), 1620 (m),

1450 (s), 1375 (s), 1280 (m), 1230 (m), II90 (m), 1170 (m),

1130 (m), 1085 (m), 1060 (m), 950 (m), 885 (m), 815 (m),

675 (m). NMR (CDCI3, TMS, 5): 1.00 (s, 3H), 1.22 (s, 3H), 1.68 (m, 17H), 2.37 (m, 4H), 4.10 (t, 7Hz, 2H), 5.72 (s, br,

IH). Analysis: calcd. C, 77-16%; H, 8.83%. Pound:

C, 77 .34%; H, 8.92%. MS: C22H30O3. calcd. m/e: 342.219, obs. m/e: 342.220, 342 (60%), 237 (102), 309 (4%),

286 (10%), 258 (10%), 224 (100%), 242 (64%), 229 (91%),

219 (16%), 211 (14%), 201 (21%), 196 (21%), 187 (l8%), l47

(18%), 159 (22%), 149 (33%), 136 (39%), 124 (56%), 105

(49%), 93 (45%), 91 (73%), 79 (64%), 67 (44%), 58 (68%),

56 (62%). (a]ile=-4.67 °, c=0.300 g/100 ml. in chloroform. 114 9-(l-Methoxypropadlenyl )blcyclo[j3. 3. llnonan-9-ol (28 ) Into a flame dried flask under argon was Introduced 1-methoxypropadiene (380 mg., 5.43 mmol.), and THF

(5 ml.). The mixture was cooled to -78°C and n-butyllithium

(5.43 mmol., 3.62 ml. of a 1.5 M solution in hexane) was added. The mixture was stirred at -78°C for 45 min. then bicycloCS • 3. ij|nonan-9-one (500 mg., 3-62 mmol.) was slowly added as a solution in THF (5 ml.). The mixture was stirred for 45 min., the distilled water (5 ml.) was added and the mixture was allowed to warm to 20°C. The solution was poured onto distilled water (10 ml.) and extracted with diethyl ether (4x6 ml.). The combined organic layers were dried over MgSO*, filtered, and evaporated to provide the product (690 mg., 3.31 mmol., 92%) a pale yellow waxy solid. M.P.=63°-70°C. IR (CCI*, cm"M: 3340 (m),

2920 (s), 1950 (w), 1485 (w), 1450 (s), l400 (w), 136O (w),

1325 (w), 1270 (w), 1235 (w), 1200 (s), 1190 (s), 1170 (s),

1125 (m), 1100 (m), 1070 (m), 1040 (s), 1020 (m), 985 (m),

945 (m), 900 (m), 885 (m), 69O (w). NMR (CCI*, TMS, 6):

1.66 (m, 14h), 3.43 (s, 3H), 5.52 (s, 2H). MS: C13H20O2: calcd. m/e: 208.146, obs. m/e: 208.147, 208 (12%), 190

(8.5%), 178 (7%), 165 (10%), 161 (8.5%), 149 (13%), 147

(12%), 139 (100%), 122 (41%), 121 (100%), 111 (24%), 110

(27%), 93 (54%), 91 (39%), 8l (39%), 80 (39%), 79 (74%),

67 (58%). 115 lO-Methoxy-9-oxasplro[2.6]bicyclop.3.Ijdodec-ll-ene ( ^ )

Into a flame dried flask under argon was Introduced 9-(l-methoxypropadlenyl)bicyclo 3.3.1 nonan-9-ol, (600 mg, 2.88 mmol.), KOtBu (64.6 mg., 0.58 mmol.), dicyclohexyl- l8-crown-6 (215 mg., 0.58 mmol.) and tBuOH (10 ml.). The mixture was heated to reflux. After being stirred at 80°C for 10 h. an IR of an aliquot, removed from the reaction mixture and worked up, showed the formation of product. The mixture was allowed to cool, then poured into distilled water (20 ml) and extracted with EtaO

(4x6 ml.). The combined organic layers were dried over MgSOij, filtered, and evaporated to give the product (380 mg., l8.2 mmol., 63%) 29, a yellow oil. IR (neat, cm-i): 3080 (w), 2920 (s), 1445 (m), l400 (m), 1355 (w),

1285 (w), 1260 (w), 1235 (m), 1205 (m), 1150 (s), 1125 (s), 1065 (s), 1025 (m), 995 (m), 945 (m), 905 (m), 885 (m). NMR (CCI*, TMS, 6): 1.6? (m, br, 14H), 3.30 (s, 3H),

5.50 (m, 3H). NMR (CDCla, PPM)I 131.0, 121.0, 90.6,

74.8, 52.5, 31.1, 31.6, 30.9 (2 carbons), 28.8, 28.4,

21.3, 21.0.

9-Acroloylbicyclo[3.3. l]nonan-9-ol (^ )

Into a separatory funnel was placed Et2Û (20 ml.) and g_(l_methoxypropadienyl)bicyclo[3.3.1]nonan-9-ol (500 mg.,

2.40 mmol.) and 6n sulfuric acid (5 ml.). The mixture was shaked for 20 min. then the layers were separated. 116

The aqueous layer was extracted with EtgO (3X6 ml.) and the organic layers were combined. The combined organic

layers were dried over MgSO*, filtered, and evaporated to provide the product (320 mg., l6.7 mmol., 8%) a yellow foam. IR (neat, cmT^): 3400 (s), 2900 (s),

1675 (s), 1600 (s), 1480 (w), 1445 (m), l400 (s), 1350

(m), 1330 (m), 1315 (w), 1290 (w), 1260 (w), 1230 (m),

1210 (m), 1190 (m), ll60 (s), 1120 (m), 1100 (m), 1040

(s), 1020 (m), 995 (m), 985 (m), 960 (m), 900 (m),

860 (m), 805 (w), 775 (w), 700 (w). NMR (CCI*, TMS, 6 ): 1.67 (m, 14h), 6.50 (m, 3H).

2-Acroloyladamantan-2-ol (32)

Into a separatory funnel was placed EtaO (20 ml.),

2(1-methoxypropadienyl)adamantan-2-ol (1 g., 4.54 mmol.)

and 6 n HaSOu (10 ml.). The mixture was shaken for 15 mln, then the layers were separated. The aqueous layer was

extracted with EtaO (3X4 ml.) and the organic layers were combined. The combined organic layers were dried over

MgSOi*, filtered, and evaporated. The crude product was

chromatographed on silica gel (15 g ., eluted 20% EtOAc-

80% petroleum ether) to give the pure product (78O mg.,

3.77 mmol. , 83%) a yellow foam.

IR (CCI*, cm-'): 3400 (m), 2920 (s), I69O (s), I6 IO (m),

1455 (m), 1410 (m), 1375 (m), 1355 (m), 1340 (m), 1290 117 (m), 1210 (m), 1160 (m), 1105 (m), 1050 (m), 1015 (m),

1000 (m), 965 (m), 9H0 (m), 910 (m), 885 (w), 86O (w),

840 (m), 810 (m), 795 (m), 740 (m). NMR (CCI*, TMS, 6):

1.70 (m, 15H), 6.10 (m, 3H). MS: 206 (3%), 151 (100%),

133 (5%), 107 (6%), 93 (8%), 91 (14%), 81 (12%), 79 (l4%),

74 (18%), 67 (8%), 59 (29%).

3-Methoxyethoxymethoxypropyne (35)

Into a flame dried flask under argon was introduced

THF (30 ml.), and propargyl alcohol (5 g-, 89.2 mmol.). The mixture was cooled to 0°C and n-BuLi (89.2 mmol., 55.7 ml. of a 1.6 M solution in hexane) was added dropwise to the mixture. The addition of the n-BuLi was accompanied by a large amount of spattering. The mixture was stirred at 0°C for 15 min. upon the completion of the addition of the nj-BuLi, and MEM chloride (13.3 g. , 107 mmol.) was added to the reaction mixture. The mixture was allowed to stir for 2 h ., warming slowly to 25°C. During this period a fine white precipitate formed. After 2 h. of stirring the reaction mix ture was worked up by being poured into distilled water

(50 ml.) and extracting with CH2CI2 (4X15 ml.). The combined organic layers were dried over MgSO*, filtered, and the solvent was removed ^ vacuo. The crude product was distilled to provide the pure desired product (12.5 g .,

86.5 mmol., 97%) 35, a clear liquid. B.P.=35°-40°C at 118 0.01 mmHg. IR (neat, cm“M: 3240 (s), 2900 (s), 2100 (w), 1440 (m), 1400 (w), 1350 (m), 1270 (m), 1230 (m), 1190 (m),

1160 (s), 1100 (s), 1040 (s), 980 (s), 925 (m), 885 (m), 840 (m). NMR (CCI*, TMS, 6): 2.30 (t, 2Hz, IH), 3.27

(s, 3H), 3.47 (m, 4H), 4.10 (d, 2Hz, 2H), 4.65 (s, 2H).

MS: 144 (0%), 105 (8%), 99 (6%), 89 (25%), 73 (29%), 69

(100%), 59 (71%), 58 (54%).

3-Methoxyethoxymethoxypropdiene (36) Into a flame dried flask under argon fitted with a reflux condenser was added 3-methoxyethoxymethoxypropyne

(12.5 g., 86.5 mmol.). KOtBu (1.49 g., 13*3 mmol.) was added and the mixture was heated to 60°C. After 3 h. at 60°C the mixture was allowed to cool, then the crude product was distilled from the reaction vessel to give to desired product (9.89 g., 68.6 mmol., 79%) 36, a clear liquid. B.P.=48°-51°C at 20 mmHg. IR (neat, cm"M: 3010

(w), 2900 (s), 1045 (w), 1440 (m), l400 (w), 1360 (w),

1340 (m), 1275 (w), 1230 (w), 1175 (m), 1150 (m), 1100

(m), 1000 (m), 950 (w), 925 (w), 88O (m), 840 (m). NMR

(CCI*, TMS, 6): 3.27 (s, 3H), 3.45 (m, 4h), 4.73 (s, 2H),

5.27 (d,' 2H, 6Hz ), 6.46 (t, IH, 6Hz). MS: l44 (0%), 105

(8%), 89 (41%), 76 (8%), 73 (6%), 69 (6%), 59 (100%). 119 2-(3-Met'hoxyethoxymethoxypropadienyl)adamantan-2-ol (37)

Into a flame dried flask under argon was introduced

THF (5 ml.), and 1-methyleneoxyethoxymethoxypropadiene (1.15 g., 7.99 mmol.). The mixture was cooled to -78°C and n-BuLi (7.99 mmol., 4.99 ml. of a 1.6 M solution in hexane) was added. The mixture immediately turned brown and a precipitate formed. After 1 h. of stirring at -78°C, 2-adamantanone (1.00 g., 6.66 mmol.) was added a solution in THF (3 ml.). The mixture was stirred at

-78°C for 1 h. During this time the precipitate disappeared and the solution became a clear brown color. After being

stirred for 1 h. at -78,0, the reaction mixture was quenched by the addition of distilled water (2 ml.) and allowed to warm to R.T., 25°C. The mixture was then poured into distilled

water (15 ml.) and extracted with CH2CI2 (4x6 ml.). The combined organic layers were dried over MgSO*, filtered and evaporated to provide the product (1.84 g. , 6.26 mmol.,

94%) a pale yellow foam. IR (CCI*, cm"^): 3380 (m),

3010 (w), 2900 (s), 1940 (w), 1440 (m), l4lO (w), 1380 (w),

1355 (w), 1325 (w), 1260 (m), 1230 (w), 1220 (w), 1190 (m),

1160 (s), 1130 (m), 1100 (m), 1090 (m), IO6 O (m), 1040 (m),

1000 (s), 980 (m), 925 (m), 89O (w). NMR (CCI*, TMS, 6 ): 7.86 (s, br, 9H), 5.52 (d, 3Hz, IH), 8.10 (d, 3Hz, IH). MS:

256 (0.04%), 150 (55%), 117 (9%), 105 (13%), 89 (60%), 80

(31%), 79 (32%), 69 (14%), 59 (100%). 120 3-Oxo-3-cyclopentyl-propanal (38)

Into a flame dried flask under argon was introduced 1-(1-methoxypropadienyl)cyclopentanol (2.00 g., 13.0 mmol), dieyclohexyl-lB-crown-6 (1.3 mmol.), and jfcBuOH (10 ml.).

KOtBu (2.l8 g., 19.5 mmol.) was added and the mixture was heated to reflux (80°C). The reaction was complete after 14 h.j as shown by an IR of an aliquot that had been removed from the reaction mixture and worked up. The mixture was cooled, then poured into distilled water (15 ml.), extracted with CH2CI2 (5x6 ml.) and dried over MgSO%. After filtra- tration, evaporation of solvent, and distillation (0.010 mmHg.) the enol ether (950 mg., 6.2 mmol., 46%) was obtained. The enol ether was dissolved in THF (30 ml.), 1 M oxalic acid (10 ml.) was added and the mixture was stirred for

12 h. A TLC of the hydrolysis showed the presence of the desired ketone plus a side product. The crude material was separated by preparative plate chromatography (eluted with 15% EtOAc - 85% petroleum ether 60°-90°C) to give the side product (70 mg., 0.49 mmol., 8.1%) 38, a clear liquid. IR (neat, cm"'): 3420 (m), 3040 (w), 2940 (s), 1695 (s),

1550 (s), 1430 (m), 1350 (m), 1240 (m), 1190 (m), 1120 (m), 1040 (m), 1000 (m), 950 (m), 780 (m). NMR (CCI*, TMS, 6):

7.86 (s, br, 9H), 5.52 (d, 3Hz, IH), 8.10 (d, 3Hz, IH). 121

Experimental to Chapter 3

3-Methoxyspiroj3estra -1 7 ,2'(5"H)furan-3 "( 1-methoxypro-

padlenyl)-3■'-olD (6 ) Into a flame dried flask under argon was introduced

methoxypropadiene (231 mg., 3.30 mmol.) and THF (5 ml.). The mixture was cooled to -78°C and n-BuLi (3.30 mmol.,

2.07 ml. of a 1.6 M solution in hexane). The resulting pale

yellow solution was stirred at ~7d°C for 1 h., then warmed

to “25°C. At this time,3-methoxyspiro[estra-17,2^(5^H)-

furan-3^-onej (562 mg., 1.65 mmol.) was added slowly as a solution in THF (5 ml.). The mixture was allowed to stir at -25°C for 1 h., then distilled water (4 ml.) was added and

the reaction was allowed to warm to H.T. (25°C). The mixture

was poured into distilled water (20 ml.) and extracted with

CH2CI2 (5x6 ml.). The combined organic layers were dried

over MgSOi*, filtered and evaporated to give the desired

product (643 mg., 1.57 mmol., 95%) 6 , a yellow oil. IR

(neat, cm"'): 3450 (m), 2930 (s), 1950 (w), 16OO (m), 1570

(m), 1500 (s), 1450 (m), 1380 (m), 1350 (m), 1310 (m), 1280

(m), 1250 (m), 1150 (m), 1070 (m), 1040 (m), 89O (m), 870

(m). NMR (CClu, TMS, 5): O.87 (s, 3H), 1.67 (m, 15H), 2.37

(t, 7Hz, 2H), 3.43 (s, 3H), 3.70 (s, 3H), 4.03 (t, 7Hz, 2H),

5.54 (s, 2H), 6.73 (m, 3H). MS: 4lO (not seen), 340 (7%),

284 (1%), 239 (2%), 227 (16%), 161 (6%), 143 (6%), 121 (71%), 122

119 (100%), 117 (100%), 111 (14%), 101 (16%), 84 (38%), 82

(63%), 75 (14%), 69 (23%).

(13R*,17S*)-4",5",6,7,8,9,ll,12,13,l4,15,l6-Dodecahydro-3- me thoxy-13~me t hy ldi spiro|jL7H-cy clop enta [ojphenanthrene- 17,1’-cyclopentane-2',2"(3"H)furan]-3"-one (8)

Into a flame dried flask under argon was introduced tBuOH (10 ml.), dicyclohexyl-l8-crown-6 (100 mg., 0.268

mmol.), and 3-methoxyspiro[estran-17,2'(5^H)furan-3^(l-

methoxypropadienyl)-3"-ol] (643 mg., 1,57 mmol.). The mixture was stirred briefly and KOtBu (176 mg., 1.57 mmol.) was added. The mixture was heated to 80°C and stirred. After 11 h. of stirring at 80°C an aliquot was removed

from the reaction mixture and worked up. An IR of the aliquot

showed that the reaction had gone to completion. The mixture was allowed to cool, then it was poured into distilled water

(20 ml.) and extracted with CH2CI2 (4x8 ml.). The combined organic layers were washed for 20 min. with 6n HCl (20 ml.).

The layers were separated, the aqueous layer was extracted

with CH2CI2 (2X4 ml.), and the combined organic layers were

dried over MgSOu• After filtration, and evaporation the product was chromatographed on silica gel (20 g., eluted with 40% Et20-60% petroleum ether), then sublimed (0.005 mmHg.,

l40°C) to provide the pure desired product (348 mg., O .878

mmol., 56%) 8 , a white solid. M.P.=197°-199°C. IR (Nujol, 123

cm M : 3030 (w), 2920 (s), 1750 (s), l6lO (m), 1575 (m),

1490 (m), 1450 (m), l400 (m), 1380 (m), 1360 (m), 1340 (m),

1280 Cm), 1250 Cm), 1220 Cm), ll80 Cm), 1160 Cm), ll40 Cm),

1110 Cm), 1080 Cm), 1060 Cm), 1030 Cm), 970 (w), 950 Cw),

930 Cw), 880 Cm), 820 Cm), 785 Cm). NMR CCDCI3, TMS, 6):

0.90 Cs, 3H), 1.63 Cm, 15H), 2.08 Ct, 7Hz, 2H), 2.49 Ct,

7Hz, 2H), 3.70 Cs, 3H), 3.84 Ct, 7Hz, 2H), 4.23 Cm, 2H),

6.77 Cm, 3H). Analysis: calcd. C, 75.70%; H, 8.13%. Pound: C, 75.97%; H, 8.21%. MS: CasHazO*: calcd. m/e*.

396.230, obs. m/e: 396.230, 396 C13%), 340 Cl%), 284

(9%), 267 (9%), 242 (4%), 227 (44%), 199 (4%), I86 (4%),

174 (10%), 171 (7%), 167 (7%), 160 (5%), 147 (6%), 130

(3%), 121 (3%), 112 (100%), 91 (3%), 81 (2%), 79 (2%),

77 (2%), 67 (2%), 58 (4%), 56 (7%). [a]##8=-60.8°, c=0.375 g/100 ml. In chloroform.

1-C1-Methoxypropadienyl)cyclopentanol (10)

Into a flame dried flask under argon was introduced

THF C50 ml.), and methoxypropadiene (6.24 g . , 89.2mmol.). The mixture was cooled to -78°C in a dry ice,isopropanol bath, and n-BuLi (89.2 mmol., 55.7 ml. of a 1.6 M soln. in hexane) was added. After 1 h. of stirring at -78°C, cyclopentanone (5 g., 59.4 mmol.) was added dropwise as a solution in THF (10 ml.). After an hour of stirring at

-78°C, distilled water (10 ml.) was added to the mixture. 124

then the reaction was allowed to warm to R.T. Once the mixture had warmed to 25°C, the reaction mixture was worked up by being poured into distilled water (50 ml.) and extracting with CH2CI2 (4X20 ml.). The organic layers were combined and dried over MgSO«. After filtration and removal of the solvent iui vacuo, distillation provided the pure product (8.42 g., 54.6 mmol., 92%) ^ ,

B .P.=110°-115°C (20 mmHg.), a clear liquid. IR (neat, cm-i): 3400 (s), 2950 (s), 1950 (m), l450 (m), 1225 (m),

1175 (m), 1075 (m), 89O (m). NMR (CCI*, TMS, 5): 1.70

(s, 8H), 2.17 (br, s, IH), 3.43 (s, 3H), 5.49 (s, 2H).

MS I C9H 1UO2I calcd. m/e^: 154.099, obs. m/e_: 154.099,

154 (3%), 128 (10%), 114 (14%), 99 (11%), 95 (14%), 85

(100%), 67 (60%), 55 (63%), 43 (66%). Analysis: calcd.

0,70.10%; H,9.15%. Found: 0,69.96%; H,6.39%.

4-Methoxy-l-oxaspiro[4.4]nonan-3-ene (11)

Into a flame dried flask under argon, fitted with a reflux condenser was added tBuOH (30 ml.), dicyclohexyl- l8-crown-6 (0.98 g., 2.6 mmol.) and 1-(1-methoxypropadienyl)- cyclopentanol (4.05 g, 26.3 mmol.). Once the crown ether dissolved (about 5 min.), KOtBu (2.95 g., 26.3 mmol.) was added, and the mixture was warmed to 80°C. Immediately upon the addition of the KOtBu the mixture turned a dark brown color. After 15 h . of stirring at 80,C, an aliquot was 125 worked up. An IR of the aliquot showed the complete con sumption of the starting material and formation of the desired product 11. The mixture was allowed to cool, poured into distilled water (50 ml.), extracted with CH2CI2

(5x15 ml.), and the combined organic layers were dried over MgSOu. After filtration, and removal of solvent ^ vacuo, distillation (0.010 mmHg., 40°C, trap to trap), gave the desired product (2.25 g., 15 mmol., 55%) y., a clear liquid,

IR (neat, cm"M: 3070 (w), 2950 (s), I65O (s), l440 (m),

1340 (s), 1235 (s), 1180 (m), 1080 (m), 1050 (m), 1010 (m),

940 (m), 740 (m). NMR (CCI*, TMS, 6): 1.50 (s, 8H), 3.45

(s, 3H), 4.27 (s, br, 3H). MSI CgHinOgl calcd. m/e :

154.099, obs. m/e: 154.099, 154 (30%), 125 (100%), 123

(28%), 111 (11%), 97 (11%), 83 (6%), 67 (8%), 55 (30%).

l-0xaspiro[4.4]nonan-4-one (12)

Into a flame dried flask under argon was introduced

l-(1-methoxypropadienyl)cyclopentanol (8.34 g., 54 mmol.),

dicyclohexyl-l8-crown-6 (1.01 g., 2.7 mmol,), and tBuOH (10 ml.). .The mixture was stirred at R.T. for 1 min., then KOtBu (1.21 g ., 10.8 mmol) was added and the mixture was warmed to 80°C. Immediately upon the addition of KO^Bu, the mixture turned dark brown. After 15 h. of stirring at 80°C,and aliquot was removed from the mixture and worked 126 up. An IR of the aliquot showed that the reaction had gone to completion. The mixture was allowed to cool, then worked up. After the mixture was poured into distilled water

(70 ml.), the solution was extracted with CH2CI2 (4X20 ml.). The combined organic layers were then washed for 15 min. with 6N H2S0u (30 ml.). After being washed the layers were separated, the aqueous layer was extracted twice with CH2CI2 (6 ml.), and the combined organic layers were dried over MgSOu. After removal of the solvent vacuo, distillation provided the pure product (6.32 g, 44.4 mmol., 82%) ^ .

The product crystallizes at -l8°C. B.P.=35°-36°C at 0.010 mmHg. IR (neat, cm""): 2950 (s), 1750 (s), l44o (m), 136O

(m), 1260 (m), 1150 (m), 1120 (m), IO6 O (s), 1090 (m), 940

(m), 925 (m). NMR (CCI*, TMS, 5): 1.70 (s, br, 8h), 2.39

(t, 6Hz, 2H), 4.03 (t, 6Hz, 2H). "^C NMR (CDCla, PPM):

218.3, 89.6 , 62.2, 36 .4 , 36.0 (2 carbons), 25.2 (2 carbons).

Analysis: calcd. C, 68.55%;H, 8.63%. Found: C, 68.54%;

H, 8.84%. MS; CaHizOg: calcd. m/e: l40.048, obs. m/e:

140.048, 140 (11%), 112 (28%), 84 (100%), 67 (7%), 56

(36%), 55 (82%). 127 4-(1-Methoxypropadienyl)-l-oxaspiroQ•d nonan-3-ol(^) Into a flame dried flask under argon was added methoxy propadiene (5 g., 71.3 mmol.) and THF (20 ml.). The mixture was cooled to -J8°C and n_-BuLi (71.3 mmol., 44.6 ml. of a 1.6 M solution in hexane) was added. After 45 min. of stirring at -78°C the mixture was warmed to -25°C. After 30 min. of stirring at -25°C, 1-oxaspiro jj . 4jnonan-4-one

(5 g., 35.7 mmol.) was added, as a solution in THF (5 ml.), over a period of 10 min. Upon completion of the addition of the ketone, the mixture was allowed to stir at -25°C for 1 h. At the end of this period water (15 ml.) was added to the mixture and the reaction mixture was allowed to warm to R.T. After the reaction mixture was poured into distilled water (75 ml.), the product was extracted into CH2CI2 (5X20 ml.). The combined organic layers were dried over MgSO^, filtered, and the solvent was removed dji vacuo. After storage over night at -25°C, needlelike crystals of the product formed. These were separated from the mother liquor and an attempt to recrystallize the compound from diethyl ether was made.

After several tries,no recrystallization at low temperature could be effected. The solvent was removed iui vacuo, and once more crystals formed overnight at -25°C. These crystals were isolated to provide the desired product (5.90 g ., 28.0 mmol., 79%) 13. M.P.=5°-12°C. IR (neat, cm-"): 3440 (s),

2960 (s), 1950 (w), 1450 (m), 1350 (m), 1280 (m), 1230 (s). 128 1110 (m), 1065 (s), 985 (m), 900 (w). NMR (CCI*, TMS, ô):

1.70 (m, lOH), 2.57 (s, br, IH), 3.40 (s, 3H), 3-70 (m, 2H),

5.53 (s, 2H). MSI CizHieOaZ calcd. m/e: 210.126, obs.

m/e/ 210.126, 210 (1%), 196 (1%), 183 (3%), l44 (26%),

141 (20%), 112 (100%), 95 (20%), 85 (59%), 84 (50%), 67

(28%), 56 (46%), 55 (67 %). Analysis: calcd: 0,68.54%;

H,8.63%. Found! 0,61.99%, 61.78%; H,7.24%, 7.34%.

4-Methoxyl-l,ll-dloxasplro[4.0.4.3]trldec-3-ene (l4) Into a flame dried flask under argon was introduced

4-( 1-methoxypropadienyl )-l-oxaspiroQ4 .4]] nonan-3-ol (350 mg., I.66 mmol.), tBuOH (10 ml.), and dicyclohexyl-l8-crown-6

(62 mg., 0.17 mmol.). The mixture was stirred for 5 min.

at 25°0, then KOtBu (I87 mg., 1.66 mmol.) was added. When the KOtBu was added the reaction mixture immediately turned

a dark brown color. The mixture was warmed to 75°C and stirred for 17 h. At the end of this time an aliqu'ot was

removed from the reaction mixture and worked up. An IR of the

aliquot showed complete consumption of the starting material

and formation of the desired product ^ . The mixture was allowed to cool, and then poured into distilled water (20 ml.)

The resulting solution was extracted with CH2CI2 (4X10 ml.). The combined organic layers were dried over MgSO%. After filtration, the solvent was removed ^ vacuo. The crude product was chromatographed on silica gel (15 g., eluted with 20% diethyl ether -80% petroleum ether) to give the 129

desired product (221 mg., 1.05 mmol., 63%) Ij} , a clear liquid,

IR (neat, cm"'): 3080 (w), 2940 (s), 1650 (s), l440 (m),

1345 (s), 1245 (s), 1125 (s), 1060 (s), 1010 (s), 980 (m),

950 (m), 750 (m). NMR (CDCI3, TMS, 5): I .60 (s, br, BH),

2.17 (m, 2H), 3.67 (s, 3H), 3.77 (m, 2H), 4.50 (d, 2Hz,

2H), 4.63 (t, 2Hz, IH). MS: CizHiaOs: calcd. m/e; 210.126, obs. m/e: 210.126, 210 (1.3%), 152 (1.5%), 126 (100%), 111

(27%), 97 (36%), 83 (55%), 67 (14%), 55 (56%). l,ll-Dloxadlsplro[4.0.4.3]trldecan-4-one(15)

Into a flame dried flask under argon was Introduced

4-(l-methoxypropadlenyl)-l-oxasplro[4.4]nonan-3-ol (8.73 g., 41.5 mmol.), jtBuOH (10 ml.), and dlcyclohexyl-l8-crown-6

(773 mg., 2.08 mmol.). To the mixture was added KOtBu

(466 mg., 4.15 mmol.). The reaction turned dark brown upon the addition of the KOtBu. The mixture was warmed to 80°C and stirred overnight. After 13 h . of stirring at 80°C, an aliquot was removed from the reaction mixture and worked up. An IR of the aliquot showed that the reaction had gone to completion. The mixture was allowed to cool. The contents of the reaction vessel were poured Into water

(70 ml.) and the resulting solution was extracted with

CH2CI2 (5x20 ml.). The organic layers were combined and washed for 15 mln. with 6N H2SOU (30 ml.). The layers were separated, and the aqueous phase was extracted with 130

CHzCla (2X6 ml.). The organic layers were combined^ dried over MgSOi,, and filtered. The crude product was chromato

graphed on silica gel (15 g., 10% diethyl ether - 90% petroleum ether) to give the desired product (5-70 g .,

29.1 mmol., 70%) ^ , a clear liquid. B.P.=92°-95°C at 0.020 mmHg. IR (neat, cmT"): 2950 (s), 1750 (s), 1435

(m), 1410 (m), 1350 (w), 1330 (w), 1250 (m), 1220 (m),

1115 (m), 1070 (s), 1035 (m), 990 (w), 940 (w), 83O (w).

NMR (CCI4, TMS, 6): 1.63 (s, br, 8H), 1.97 (t, 6Hz, IH),

2.03 (t, 6Hz, IH), 2.49 (t, 6Hz, 2H), 3.80 (t, 6Hz, 2H),

4.06 (t, 6Hz, IH), 4.13 (t, 6Hz, IH). “ C NMR (CDCI3,

PPM): 214.9, 94.0, 88.2, 63 .6 , 62.8, 37.5, 36.0, 33.4,

32.9, 24.1, 23.5. MS: CiiHasOa: calcd. m/e: 196.110,

obs. m/e: 196.110, 196 (0.51%), 167 (0.85%), l40 (0.85%),

123 (0.85%), 112 (100%), 84 (8.8%), 67 (4.4%), 56 (68%).

Analysis: calcd. C, 67.32%; H, 8.22%. Pound: C, 67 .06%;

H, 8.49%.

4-Acetyl-l-oxasplro[4.4]nonane ( ^ ) (not produced) Into a flame dried flask under argon was Introduced

THF (3 ml.), and a-chloroethyltrlmethylsllane (0.33 ml., 2.0 mmol.). The mixture was cooled to -78°C and s-butyl- llthlum (2.0 mmol., 1.5 ml. of a 1.4 M solution In cyclohexane) was added, followed by slow addition of TMEDA 131

(0.31 ml., 2.0 mmol.). The mixture was warmed to -55°C over a period of 1 h., recooled to -78°C, and treated with 1-oxasplro[4.^]nonan-4-one (200 mg., 1.4 mmol.) was added as a solution in THF (2 ml.). After being stirred for 30 min. at

-78°C,the mixture was poured in saturated aqeuous ammonium chloride solution (20 ml) and extracted with ethyl acetate (2X20 ml.). The combined organic layers were washed with distilled water (4X5 ml.), and saturated brine

(2X5 ml.), then dried over MgSOi*. The removal of the solvent vacuo followed by preparative layer chromato graphy (30% EtOAc -70% petroleum ether) gave the pure product (100 mg., 0.70 mmol., 50%) ^ . M.P.=71°-73°C.

IR (Nujol, cm-i): 3480 (s), 2960 (s), 2880 (s), 1750 (s), 1640 (w), 1460 (m), 1450 (m), 1430 (m), l4lO (m),

1370 (m), 1350 (w), 1330 (w), 1240 (m), 1190 (w), 1120 (m), 1060 (s), 1030 (m), 990 (m), 9^0 (w), 930 (m), 840

(w), 780 (w), 730 (s). NMR (90 MHz, CCI*, CHCls, 6):

1.70 (m, 17H), 2.45 (m, 3H), 3.77 (m, 2H), 4.10 (d of d, 4Hz, 8Hz, 2H). MS: CieHauOi,: calcd. m/e : 280.167, obs. m/e: 280.168, 280 (0.7%), 262 (1.7%), 234 (1.6%), 205

(1.1%), 197 (9%), 186 (26%), 178 (4%), l69 (6%), 150 (9%),

140 (18%), 139 (25%), 125 (44%), ll6 (31%), 114 (100%).

Analysis: calcd: 0,68.59%; H,8.63%. Pound: 0,68.32%;

H,8.49%. 132

4-(l-Methoxypropadienyl)-l,ll-dloxadisplro[4.0.4. bJ— trldecan-4-ol (l8)

Into a flame dried flask under argon was Introduced methoxypropadiene (1.79 g., 25.5 mmol.), and THF (15 ml.). The mixture was cooled to -78°C, In a dry Ice, Isopropanol bath, and n-BuLl (25.5 mmol., 15.9 ml. of a 1.6 M soltulon In hexane) was added. The mixture was stirred at -78°C for 45 mln., then warmed to -25°C. After 20 mln. of stirring at -25°C, 1 ,11-dloxadlsplro[4.0.4. 3Htrldecan-4-one

(1.0 g., 5-1 mmol.) was added as a solution In THF (5 ml.).

The mixture was allowed to stir for 45 mln. at -25°C, then distilled water (15 ml.) was added. The mixture was allowed to warm to 20°C, then poured Into distilled water

(20 ml.). The resulting mixture was extracted with CH2CI2

(5x10 ml.). The organic layers were combined, dried over MgSOu, and filtered. After removal of the solvent vacuo, the desired product (1.29 g., 4.8 mmol., 95%) ^ , a white solid contaminated with a small amount of starting material was obtained. A portion was sublimed at 0.005 mmHg., 60°C, for analysis. M.P.=133°-137°C. IR (Nujol mull, cm"M:

3375 (s), 2920 (s), 1950 (w), 1450 (m), 1375 (m), 1350 (m),

1275 (m), 1230 (m), 1190 (m), 1135 (m), IO5O (s), 1015 (m),

960 (m), 940 (m), 890 (m). NMR (CDCI3, TMS, 5): 1.65

(m, 13H), 3.48 (s, 3H), 3.83 (m, 4h), 5.63 (s, 2H). MS:

C15H22OU: calcd. m/e: 266.152, obs. m/e: 266.152, 266 133 (4.2%), 213 (2.2%), 197 (1.3%), 182 (13.3%), 165 (83%),

155 (57%), 123 (40%), 112 (27%), 96 (20%), 84 (30%), 67

(22%), 55 (100%). Analysis: calcd: 0,67.65%: H,8.33%. Pound: 0,67.80%; H,8.37%.

4-Methoxy-l,12,15-trloxatrispiro[4.0.0.4.3. 3]heptadecan- 3-ene (1^)

Into a flame dried flask under argon was introduced dicyclohexyl-l8-crown-6 (207 mg., O.56 mmol.), and tBuGH

(5 ml.). To this mixture was added 4-(l-methoxypropadienyl)- l,ll-dioxadispiro[4.0.4.3]tridecan-4-ol (740 mg., 2.78 mmol.) as a solution in THF (5 ml.). KOtBu (62.4 mg., O .56 mmol.) was then added to the mixture which was heated to 80°C. After l4 h. of stirring at 80°C, an aliquot was removed and worked up. An IR of the aliquot showed that the reaction had gone to completion. The mixture was allowed to cool, then poured into distilled water (20 ml.). The resulting mixture was extracted with diethyl ether (5X6 ml.). The organic layers were combined, dried over MgSO*, and filtered. After removal of solvent vacuo, the remaining brown oil was chromatographed over silica gel (20 g., eluted with 20% EtOAc,-80% petroleum ether) to give the product (440 mg., 1.65 mmol., 59%) 19, a white solid.

M.P.=43°-47°C. IR (Nujol, cm-i): 3080 (w), 2940 (s), 1650

(s), 1440 (s), 1350 (s), 1290 (m), 1250 (s), IO6 O (s), 950

(m), 750 (m). NMR (CCI*, TMS, 6): 1.54 (m, 12H), 3.58 134

(s, 3H), 3.75 (m, 4H), 4.38 (d, 2Hz, 2H), 4.60 (t, 2Hz, IH).

MS : CisHaaOu^ calcd. m/e: 266 .152, obs. m/e : 266 .151,

266 (7%), 190 (3%), 182 (12%), 167 (4%), 165 (7%), 153

(30%), 126 (100%), 111 (21%), 97 (25%), 86 (19%), 84 (29%),

83 (33%), 70 (9%), 69 (9%), 67 (10%), 57 (8%), 55 (50%).

1,12,15-Trloxatrlspiro[4.0.0.4.3.3]heptadecan-4-one(20) Into a flame dried flask under argon was introduced

4-(1-methoxypropadienyl-l,ll-dioxadispiro[4.0.4. 3Htridecan-

4-01 (3.0 g., 11.3 mmol.), tBuOH (10 ml.), and dicyclohexyl- l8-crown-6 (210 mg., O.56 mmol.). After 2 min. of stirring

at R.T., KOtBu (130 mg., 1.13 mmol.) was added, then the mixture was warmed to 90°C. After 9 h. of stirring at 90°C,an aliquot of the dark brown reaction mixture was removed and worked up. An IR of the aliquot showed the presence of a large enol ether peak at I65O cm“ ^ and no allene at 1950 cm“^. The reaction mixture was allowed to cool, then was quenched by being poured into distilled water (30 ml.). The mixture was extracted with CH2CI2

(5x10 ml.). The combined organic layers were washed for

20 min. with 6 n R^SO* (25 ml.). After the acid wash the layers were separated, the aqueous layer was extracted with

CH2CI2 (2X6 ml.), and the organic layers were combined. After drying over MgSOu, and filtration, the solvent was removed in vacuo. The crude product was chromatographed 135 on silica gel (15 g., eluted with 10% diethyl ether - 90% petroleum ether), then recrystallized from diethyl ether to give the desired ketone (1.90 g., 7-53 mmol., 67%) a white solid. A portion of the product was sublimed (70°C, 0.005 mmHg.) for analysis. M.P.=88.5°-90°C. IR (CCI*, cm"^):

2940 (s), 1745 (s), 1430 (m), l400 (m), 1345 (w), 1190 (m),

1060 (s), 1020 (m), 900 (m). NMR (CCI*, TMS, 6): 2.10

(m, 14h), 3.90 (m, 6H). "^C NMR (CDCI3, PPM): 214.0,

94.4, 94.3, 88.2, 64.6, 63 .2, 61.4, 37.0,

36 .5, 36 .5, 34.1, 33.6 , 26.3, 24.2. MS: CiwHzoO*: calcd. m/e_: 252.136, obs. m/e : 252.136, 252

(0.2%), 221 (0.1%), 193 (0.1%), 177 (0.4%), 168 (4l%), 151

(7%), 140 (10%), 123 (7%), 112 (100%), 98 (3%), 84 (3%), 67

(4%), 56 (42%), 4l (8%). Analysis: calcd: C,66.64%;

H, 7.99%. Found: 0,66.78%; H 8.12%.

4-(1-Methoxypropadienyl)-1,12,15-trioxatrispiro[4.0.0.4.3.3] heptadecan-4-ol(21)

Into a flame dried flask under argon was introduced methoxypropadiene (1.17 g., I6.6 mmol.), and THF (10 ml.).

The mixture was cooled to -78°C and n-BuLi (I6.6 mmol., 10.4 ml. of a 1.6 M_ solution in hexane) was added. The resulting pale yellow solution was stirred at -78°C for

45 min. The reaction mixture was then warmed to -25°C. After the reaction mixture had been stirred for 15 min. 136

a solution of 1,12 ,l6-trioxatrispiro[[4.0. 0.4. 3 • Slheptadecan- 4-one (1.4 g., 5*55 mmol.) In THF (10 ml.) was added

dropwise to the reaction mixture over a period of 20 min. The reaction mixture was stirred for an additional

30 min. upon completion of the addition of the ketone. At

this time, distilled water (10 ml.) was added to the reaction mixture which was allowed to warm to 20°C. The contents (20 ml.) and extracted with CH2CI2 (5X10 ml.). The organic layers were combined and dried over MgSO*. After removal of the solvent vacuo the crude product was recrystallized from diethyl ether to give the pure product (8OO mg.,

2.5 mmol., 45%) a white solid, and a mixture of starting material and product (750 mg.). This mixture was recycled to give another batch of product (8OO mg., 2.5 mmol., 45%) 21 , suitable for further use, providing a total overall yield of

90%. M.P.=92°-99°C. IR (CClk, cm-i): 3300 (s), 2940 (s), 1945 (w), 1455 (m), 1435 (m), 1275 (m), 1220 (s), II90 (s),

1150 (s), 1070 (s), 1015 (s), 965 (m), 880 (m). NMR (CCI*,

TMS, 6): 1.72 (m, 14H), 3.42 (s, 3H), 3.70 (m, 6h), 4.88

(s, br, IH), 5.53 (q, 7Hz, 2H). MSI Ci8H2605l calcd. m/e:

322.178, obs. m/e: 322.178, 322 (0.9%), 277 (2%), 238 (7%),

220 (4%), 193 (7%), 182 (10%), 165 (53%), 143 (31%), 126

(20%), 112 (100%), 95 (34%), 67 (29%), 55 (66%). Analysis: calcd: 0,67-06%; H,8.13%. Pound! 0,65.27%, 64.89%; H, 7.77%,

7 .88%. 137 4-Methoxy-ljl3 jl6,19-tetraoxatetrasplro[4.0.0.0.4.3.3.3] heneicos -3-ene (22 ) Into a flame dried flask under argon was introduced tBuOH (2 ml.), dicyclohexyl-l8-crown-6 (112 mg., 0.30 mmol.), and a solution of 4-(l-methoxypropadienyl)-l,12,15-trioxatrispiro[4.0.0.4.3.3]heptadecan-4-ol (970 mg., 3.01 mmol.), in

THF (2 ml.). The mixture was stirred briefly, then KOtBu (67.5 mg., 0.60 mmol.) was added. The reaction mixture was heated to 80°C for 1 h. At this time an IR, of an aliquot that had been removed from the reaction mixture and worked up, showed that the cyclisation had gone to completion. The mixture was cooled and poured into distilled water (20 ml). The aqueous mixture was extracted with CH2CI2 (5X10 ml.). The combined organic layers were dried over MgSO*, filtered, and the solvent was removed jni vacuo. The crude product was chromatographed on silica gel (15 S*> eluted with 10% diethyl ether..-90% petroleum ether) to give the desired product (350 mg., 1.09 mmol., 36%) 22, a pale yellow, waxy

solid. M.P.=96°-102°C. IR (CHCI3, c m " M : 3000 (s), I65O

(s), 1510 (w), 1430 (m), 1210 (s), IO6 O (s), 950 (m), 920 (m). NMR (CCI*, TMS, 5): 1.55 (m, 14H), 3-72 (m, 6H),

3.72 (s, 3H), 4.53 (d, 2Hz, 2H), 4.72 (t, 2Hz, IH). MS:

C18H 26O9: calcd. m/e: 322.178, obs. m/e : 322.178, 322 (1%),

277 (0.2%), 252 (1%), 238 (7%), 210 (6%), 193 (10%), I81

(5%), 151 (10%), 126 (100%), 125 (90%), 111 (14%), 97 (19%),

83 (21%), 67 (10%), 55 (2%). 138 1,13,16,19-TetraoxatetrasplroC/i .0.0.0.4.3. 3. 3lhenelcosan- 4-one (23 )

Into a flame dried flask under argon was introduced 4-(1-methoxypropadlenyl)-l,12,15-trioxatrlspiro[4.0.0.4.3.3] heptadecan-4-ol (700 mg., 2.17 mmol.), tBuOH (5 ml.), THF

(4 ml.), and dicyclohexyl-l8-crown-6 (80.9 mg., .22 mmol.). The mixture was stirred for 1 min., then KOtBu (48.7 mg.,

0.43 mmol.) was added. The mixture was allowed to stir overnight at R.T. After 12 h. of stirring at 25°C an aliquot was removed from the clear colorless reaction mixture and worked up. An IR of the aliquot showed that the reaction had gone to completion. The mixture was poured into distilled water (20 ml.), and extracted with CH2CI2 (5X6 ml.). The combined organic layers were washed for 30 min. with 6 N, H2SO4 (20 ml.). The layers were separated and the aqueous layer was extracted twice with CH2CI2 (6 ml.). The combined organic layers were dried over MgSOu, filtered and the solvent was removed vacuo. The crude product was recrystallized from diethyl ether to give the pure product (150 mg., 1.46 mmol., 67 %) ^ , a white solid. The crystal for the X-ray diffraction was also obtained by recrystallization from diethyl ether. M.P.=123°-124°C. IR (CCI*, cm“M : 2930

(5), 1745 (s), 1430 (m), 1400 (m), 1345 (w), 1190 (m), 1150

(m), 1065 (5 ), 1015 (m), 970 (w), 940 (m), 915 (m). NMR (CDCla, TMS, 6): 2.10 (m, 16H), 3.93 (m, 8H), "^C NMR 139 (CDCla, PPM): 213.6, 97.1, 94.5, 92.9, 87.8, 64.2, 64.1,

63.6, 60.8, 37.2, 36.4, 35.7, 35.0 (2 carbons), 34.2,

24.9, 23.5. MS: 308 (0.4%), 224 (20%), 196 (5%), l68

(112), 151 (5%), 140 (7%), 112 (100%), 84 (17%), 66 (l6%),

56 (24%). Analysis: calcd. C, 66.22%; H, 7.84%. Pound:

C, 66 .49%; H, 7 .97%.

4-(l-Methoxypropadlenyl)-l,13,l6,19-tetraoxatetraspiro-

Qj.0.0.0.4.3.3.3]heneicosan-4-ol(24) Into a flame dried flask under argon was introduced methoxypropadiene (239 mg., 3.41 mmol.) and THF (5 ml.). The mixture was cooled to -78°C in a dry ice isopropanol bath, and n-BuLi (3.41 mmol., 2.13 ml. of a 1.6 M solution in hexane) was added. The mixture was stirred at -78°C for

45 min., then it was warmed to -25°C and stirred for 15 min. At this time,a solution of 1,13,16,19-tetraoxatetraspiro-

[4 .0. 0. 0. 4 . 3 . 3. 3l] heneicosan-4-one (350 mg., I.l4 mmol.) in

THF (5 ml.), was added dropwise to the reaction over a period of 15 min. After being stirred at -25°C for an additional 30 min. the react 1 n mixture wsa quenched by the addition of distilled water (5 ml.), and allowed to warm to R.T. The mixture was then poured into distilled water (15 ml.) and extracted with

CH2CI2 (5x6 ml.). The combined organic layers were dried over MgSOi, and filtered. After removal of the solvent in vacuo, an IR of the crude product showed the presence of a major amount of starting material. The crude product was recycled using exactly the same conditions as before to 140

provide the desired product (400 mg., 1.06 mmol., 93%) 24, a yellow oil. IR (neat, cm“M: 3350 (m), 2940 (s), 1950 (w),

1745 (w), 1440 (m), 1345 (w), 1270 (m), 1220 (m), II85 (m),

1145 (m), 1060 (s), 950 (w), 890 (m). NMR (CDCI3 , TMS, 6):

1.60 (m, 17H), 3.44 (s, 3H), 3.80 (m, 8H), 5.64 (s, 2H).

4-Methoxy-l,l4,17,20,23-pentaoxapentasplro [^.0.0.0.0.4.3, 3.3.8]pentacos-3-ene ( ^ )

Into a flame dried flask under argon was Introduced tBuOH (2 ml.), dlcyclohexyl-l8-crown-6 (19.7 mg., 0.053 mmol.), and a solution of 4-(l-methoxypropadlenyl)-

1,13,16,19-tetraoxatetrasplro[4.0.0.0.4.3.3.3]henelconsan-4-ol

(100 mg., 0.26 mmol) In THF (2 ml.). The mixture was stirred

for 1 mln. and then KOtBu (29.6 mg., 0.26 mmol.) was added.

The mixture was warmed to 80°C and stirred for 12 h. At

this time an IR of an aliquot, which had been removed from the reaction mixture and worked up, showed that the cycllzatlon was

complete. The mixture was cooled, then poured Into distilled

water (15 ml.). The solution was extracted with CH2CI2

(7x6 ml.). The combined organic layers were dried over

MgSOi», filtered, and the solvent was removed vacuo. The crude product was purified by chromatography on two

analytical TLC plates (E. Merck, aluminium backed, silica

gel 60, P-254, 0.2 mm. thick, eluted with a mixture of 40%

EtOAc- 60% petroleum ether (60°-90°C fraction),double

development) to give the desired product (60 mg., O.I6 mmol.. l4l

60%) 25, a yellow oil.' IR (neat, cm~M: 2930 (s), 165O

(m), 1450 (m), 1350 (m), 1290 (m), 1250 (s), 1100 (s), 990

(m), 915 (m). NMR (CDCla, TMS, 6): I .56 (m, 16H), 3.67 (s,

3H), 3.67 (m, 8h), 4.56 (d, 2Hz, 2H), 4.72 (t, 2Hz, IH). MS:

C21H30OG. calcd. ^/e_. 378.204 , obs. m/e_: 378.205, 378 (3%),

372 (2%), 355 (1%), 310 (1%), 294 (7%), 280 (2%), 253 (4%),

231 (3%), 187 (17%), 181 (29%), 173 (17%), 169 (47%), 153

(20%), 151 (53%), 143 (48%), 126 (95%), 112 (25%), 99

(74%), 98 (42%), 97 (39%), 89 (48%), 81 (100%), 73 (38%),

67 (30%), 55 (67 %).

1,14,17,20,23-Pentaoxapentaspiro[4.0.0.0.0.4.3.3.3.3] pentacosan-4-one(26)

Into a flame dried flask under argon was Introduced

tBuOH (1.5 ml.), dlcyclohexyl-l8-crown-6 (39.5 mg., 0.11 mmol.), and a solution of 4-(l-methoxypropadlenyl)-

1,13,16,19-tetraoxatetrasplro[4.0.0.0.4.3.3. 3]henelcosan- 4-ol (400 mg., 1.04 mmol.) In THF (1.5 ml.). The mixture was stirred for 1 mln., then KOtBu (23.8 mg., 0.21 mmol.)

was added. The mixture was heated to 80°C for 1 h. At

this time an IR of an aliquot, removed from the reaction mixture

and worked up, showed that the cycllzatlon had gone to completion. The reaction moxtlre was cooled and poured Into

distilled water (20 ml.). The mixture was extracted with

CH2CI2 (6X6 ml.). The combined organic layers were then 142 washed for 1 h. with ôl^HaSOu (30 ml.). The layers were then separated. The aqueous layer was extracted with

CH2CI2 (2X6 ml.). The organic layers were combined, dried over MgSOu, filtered, and then the solvent was removed in vacuo. The crude product was purified on a preparative plate (eluted with 40% EtOAc- 60% petroleum ether) to give the desired product (212 mg., O.58 mmol., 55%) 26, a white solid. A portion was recrystallized from diethyl ether for analysis. M.P.=195°-197°C. IR (CCI*, cm'i): 2930 (s),

1745 (m), 1440 (m), 1350 (m), 1260 (m), 1130 (s), 1070 (s),

990 (m), 920 (m), 735 (m). NMR (CDCI3, TMS, 6 ): I .60

(m, I8H), 3.70 (m, lOH). NMR (CDCI3, PPM): 213-3,

97.8, 95.8, 95.6 , 93.5, 88.0, 64.7, 64.1, 64.0, 63 .8,

60.8, 38.7, 36 .9, 36 .1, 35.8, 35.3, 34.9 (2 carbons),

25.5, 24.5. Analysis: calcd. C, 65-92%; H, 7-74%. Found: C, 66.14%; H, 7.95%. MS: calcd. m/e: 364.189, obs. m/e: 364.191, 365 (0.2%), 310 (0.6%), 28l (3%),

280 (3%), 205 (10%), 187 (13%), 168 (16%), 142 (39%),

112 (52%), 99 (65%), 89 (45%), 81 (100%), 73 (42%), 67

(35%), 55 (61%). 143 1,ll-Dloxa8plro[\.0.4.3]trldecan-4-(1-Methylbenzyl)- Imine (27 ) Into a flask under argon, fitted with a reflux condenser,

was added l,ll-dloxasplro[4.0.4.3]trldecan-4-one (1 g., 5.10 mmol.), £(-)a -methylbenzylamlne (1.23 g., 10.2 mmol.), and dry benzene (30 ml.). A small portion of CaHa was

suspended In the reflux condenser. Inside a funnel of filter

of the reaction mixture was heated to reflux. The progress

of the reaction was monitored by TLC (20% EtOAc - 80% petroleum ether). Almost Immediately 2 new spots (Rf=0.3,

0.25) began to appear. After a reflux period of several hours, the starting material was still present, but no more pro gress In the reaction could be seen. At this point more

£(-) a-methylbenzylamlne (1.23 g., 10.2 mmol.) was added. The reaction mixture was allowed to reflux for 12 h. At this time, TLC still showed the presence of the starting ketone, and another batch of amine (1.23 g.) was added. After 48 h.

at reflux TLC showed that the reaction had gone to comple tion. The mixture was allowed to cool then poured Into distilled water (20 ml.). The solution was extracted with diethyl ether (5X10 ml.), then the combined organic layers were washed with saturated NHuCl solution (2X10 ml.), and dried over MgSO*. The mixture of dlastereomers was chromatographed (Lobar pre-packed column, size B (310-25), packed with LI Chroprep SI 60 (40-63 mm), eluted with a 144 mixture of 10^ EtOAc - 90% petroleum ether, at a pressure of

90 Ibs./sq. in.). Fractions were taken every 5' ml. Two isomers (540 mg., 1.80 mmol., 35%) were isolated. Of these

the higher Rf material (155 mg., 0.52 mmol., 10%) appeared

to be pure by TLC. The product was a pale yellow oil. IR (neat, cm-'): 3020 (w), 2960 (s), 1675 (m), l600 (w),

1490 (m), 1445 (m), 1365 (m), 1350 (m), 1325 (m), 1260 (m),

1180 (m), 1130 (s), 1100 (s), 1060 (s), 1040 (m), 1010 (m), 970 (m), 900 (w), 760 (m), 740 (m), 700 (s). NMR (CCI*,

TMS, Ô): 1.56 (m, 15H), 3.93 (m, 5H), 7.21 (m, 5H). MS:

C19H25NO2: calcd. m/e: 299.188, obs. m/e: 299-189, 299

(23%), 256 (62%% 215 (6%), 200 (11%), 186 (6%), 152 (4%),

112 (100%), 110 (20%), 105 (65%), 79 (11%), 77 (10%), 56 (32%).

l,ll-Dioxadispiro[4.0.4.3]tridecan-4-one (chiral)(^) Into diethyl ether (4 ml.) was dissolved 1,11-dioxadi-

spiro[4.0.4.3Htridecan-4-(1-methylbenzyl)imine (155 mg., 0.52

mmol.). The solution was washed with 6 n H2SO* (4 ml.) until the

starting imine had disappeared by TLC (80% petroleum ether -

20% EtOAc), about 20 min. The layers were separated, the aqueous layer was extracted with diethyl ether (3X2 ml.), and the combined organic layers were dried over MgSO*. After filtration and removal of the solvent ^ vacuo the product (100 mg., 0.509 mmol., 98%) ^ was isolated. The

TLC, IR, NMR of chiral and achiral materials appeared to be identical. The rotation of the material was measured in 145

chloroform. [0Q 5 8 9 =+77.10, c=0.240 g./lOO ml. An attempt to determine the enantiomeric composition through the use of tris-[3-(trifluoromethylhydroxymethylene)-d-camphoratq]- europium (III), a chiral lanthanide NMR shift reagent, failed.

Although the peaks did shift in position they did not split into 2 sets, one for each enantiomer, when either the chiral ketone or the racemic ketone was used.

Experimental to Chapter 6

Aconyl Chloride(6)

Into a flame dried flask under argon was introduced sodium aconate (500 mg., 3-33 mmol.), and dry benzene

(5 ml.). To this mixture was added oxalyl chloride (634 mg., 5.00 mmol.). A vigorous bubbling took place upon the addition of the oxalyl chloride. The mixture was heated to reflux upon the completion of the addition of the oxalyl chloride. After being refluxed for 2 h. the reaction mix ture was cooled, filtered, and evaporated. After sublimation (50°C, 0.010 mmHg.) the desired product (312 mg., 2.13 mmol.,

64%) 6 was obtained. M.P. (sealed tube) =73°-75°C (liti-=

75-5°C). IR (Nujol, cm'i): 308O (w), 2900 (s), 1750 (br, s), 1630 (m), i460 (w), 1435 (m), 1370 (w), 1350 (m), 1315

(m), 1175 (m), 1130 (m), 1100 (m), 1030 (m), 990 (w), 925

(m), 890 (m), 780 (m), 730 (m), 645 (m), 640 (m). NMR 146

(CCDCla, TMS, 5): 5.02 (d, 2Hz, 2H), 6.90 (t, 3Hz, IH).

MS: CsHaOa^^Ci: calcd. m/e: 145.977, obs. m/e: 145.977,

148 (3%), 146 (9%), 120 (4%), 119 (3%), 118 (12%), 117 (7%),

112 (6 %), 111 (100%), 110 (6 %), 91 (5%), 89 (l4%), 83 (12%),

82 (8%), 81 (14%), 55 (18%), 54 (11%), 53 (60%), 44 (25%).

Aconic Acid (7)

Into distilled water (15 ml.) was added sodium aconate

(200 mg., 1.33 mmol.), and 6N H2SO4 (2 ml.). The mixture was continiously extracted with diethyl ether for 2 days.

At this time, the extraction was stopped and the ether layer was dried over MgSO*. After filtration and the removal of the ether ^ vacuo,aconic acid (l40 mg., 1.09 mmol., 82%) 7

was obtained, a white sublimable solid. M.P.=155°-l60°C

(Lit ."® = 156°0 . IR (Nujol, cm""): 2900 (br, s), 1700 (br, s),

1330 (w), 1220 (s), 1180 (s), 1090 (s), 1020 (s), 990 (w),

900 (s), 830 (m), 765 (w), 725 (s), 700 (s). NMR (TPA, TMS,

6): 5.30 (d, 3HZ, 2H), 7.08 (t, 3Hz, IH). MS: C5H 4O4: calcd.

m/e: 128.011, obs. m/e: 128.011, 128 (23%), 110 (22%),

99 (92%), 81 (20%), 74 (23%), 69 (41%), 59 (37%), 57 (18%),

55 (25%), 53 (39%), 45 (100%). 147

2j2-Dimethylhexadlenolc Acid (9)

Into a flame dried flask under argon was introduced THF (20 ml.),and diisopropyl amine (3.97 g., 39.2 mmol.). The mixture was cooled to -25°C in a CC1%, dry ice bath, and n-BuLi (39.8 mmol., 24.5 ml. of a 1.6 M solution in hexane) was added dropwise, taking care to keep the temperature below -10°C. The mixture was stirred for 15 min. at -25°C upon the completion of the addition of the n-BuLi. A solution of sorbic acid (2 g., 17.8 mmol.) in THF (20 ml.) was added dropwise to the reaction mixture through an addition funnel. The mixture turned a deep reddish, brown color and a small amount of white precipitate formed upon the addition of the acid to the reaction. Once the addition of the sorbic acid was completed, HMPT (3.20 g. , 17.8 mmol.) was added, which caused the reaction mixture to become homogeneous and more deeply colored. The mixture was allowed to warm to R.T.(25°C),over a period of 45 min. At this time Mel

(2.79 g . 5 19.6 mmol.) was added to the reaction. This caused the reaction to warm to 40°C and turn a clear pale yellow color. After being stirred for 30 min., the mixture was ip cooled to -25°C, and n-BuLi (19.6 mmol., 12.3 ml. of a 1.6 M solution in hexane) was added. The dark reddish brown color returned once the n-BuLi was added. The mix ture was allowed to warm to R.T., 25°C over a period of

45 min. At this time Mel (2.79 g., 19.6 mmol.) was added to 148

the reaction mixture. As before, the mixture warmed up and

decolorized. The mixture was allowed to stir for 2 h., then worked up by pouring the contents of the reaction vessel Into distilled water (20 ml.). The layers were separated, the organic layer was washed with distilled water (3X6 ml.) then thrown away. The combined aqueous layers were acidified with 6n HgSO*. The aqueous mix ture was then extracted with EtaO (5X10 ml.). The combined organic layers were washed for 20 mln. with 6N HgSO*

(20 ml.) to Insure hydrolysis of the HMPT. The layers were separated, the aqueous layer was extracted with EtaO (2X6 ml.) and the combined organic layers were dried over MgSOu. After filtration, and the removal of the solvent ^ vacuo, and distillation, the desired product (2.12

g., 15.1 mmol., 85%) 9, was obtained, a clear liquid. B.P.=

83°-86°C (0.10 mmHg., Llt?°B.P.=158°C at 5 mmHg). IR (neat,

cm-"): 2960 (br, s), 1700 (s), 1645 (m), I6OO (w), 1455 (m),

1410 (m), 1375 (w), 1280 (m), 1260 (m), 1200 (m), 1170

(m), 1130 (m), 1030 (w), 1000 (m), 950 (m), 900 (m), 845

(m). NMR (CClu, TMS, 6): 1.35 (s, 6H), 5.10 (m, 2H),

6.00 (m, 3H). MS: CeHizOz: calcd. m/e: l40.084, obs. m/e: 140.084, l40 (19%), 125 (5.2%), 111 (1%), 95 (79%),

81 (13%), 79 (16%), 77 (9%), 72 (7%), 71 (9%), 67 (25%),

56 (100%), 55 (34%), 53 (13%). 149 2.2-Dlmethyl-3,5-hexadlenol(^)

Into a flame dried flask under argon was introduced dry diethyl ether and LAH (574 mg., 15.1 mmol.). The mixture was cooled to 0°C in an ice -water bath and

2.2-dimethyl-3,5-hexadienoic acid (2.12 g., 15.1 mmol.) was added dropwise to the mixture as a solution in dry diethyl ether (10 ml.). Vigorous bubbling took place when each drop of the acid solution mixed with the LAH suspension. When the addition of the acid was complete, the mixture was allowed to warm to R.T., 25°C. After being stirred for 30 min. the mixture was recooled to 0°C and the excess LAH was care fully quenched by the addition of distilled water (10 ml.) to the reaction. After the LAH had been quenched, 6N HzSO*

(4 ml.) was added to the mixture. The viscous material, which had formed when the LAH had been quenched now dissolved, and the mixture was extracted with EtzO (4X20 ml.). The organic layers were combined, dried over MgSO*, filtered, and evaporated to give the crude product (1.56 g., 12.4 mmol., 82%) 1^. The compound was distilled to give the product (l.lB g., 9-36 mmol., 62%) ^ , a clear liquid.

B.P.=45°-48°C at 0.005 mmHg. IR (neat, cm“M : 3350 (s),

3080 (w), 2460 (s), l640 (w), l600 (w), l460 (m), 1385 (m),

1360 (m), 1280 (w), 1135 (s), 1045 (s), 1005 (s), 950 (m),

900 (m), 850 (m). NMR (CCI*, TMS, 6 ) : 1.00 (s, 6H), 3.21 150 (s, 2H), 5.50 (m, 5H). MS: CaHxuO: calcd. m/e: 126.10%, obs. m / & : ^126.105, 126 (9%), 108 (1%), 96 (10%), 95 (100%),

93 (12%), 91 (5%), 81 (8%), 79 (10%), 77 (12%), 71 (5%),

67 (50%), 55 (38%), 53 (16%).

2 ,2-Dlmethyl-3,5-hexadienyl Aconate(11)

Into a flame dried flask under argon was Introduced

NaH (0.4% mmol., 17.6 mg. of a 59.3% dispersion in mineral oil) and dry THF (2 ml.). The sodium hydride was washed with dry THF (3X2 ml.) to remove the mineral oil. Once the oil had been removed 2,2-dimethyl-3,5-hexadienol (50 mg., 0.396 mmol.) was added as a solution in THF (2 ml.). A vigorous bubbling ensued upon the addition of the diene alcohol to the NaH suspension. When the bubbling stopped, aconyl chloride (ll6 mg., 0.79 mmol.) was added to the mixture as a solution of THF (1 ml.). Immediately upon the addition of the acid chloride,the reaction mixture turned a turbid yellow color and a large quantity of precipitate formed. A TLC (80% petroleum ether -20% EtOAc) of the reaction mixture at this point showed no product formation. The mixture was stirred at R.T. for 15 h. At this time,TLC indicated that the reaction had gone to completion. The reaction mixture was quenched by the careful addition of saturated NaHCOs solution (1 ml.), then poured into saturated NaHCOa solution (% ml.), and extracted with diethyl ether (%X6 ml.). The combined organic layers were washed with saturated NaHCOs solution 151

ml.), saturated brine (4 ml.), and dried over MgSOu. After filtration, evaporation, and recrystallization from EtaO, petroleum ether gave the desired product (60.7 mg.,

0.26 mmol., 65%) 11. M.P.=57°-59°C, IR (CHCI3, cm"'): 3100

(w), 3070 (w), 2950 (m), 1775 (8), 1720 (s), 1630 (w), I6 OO

(w), 1450 (w), 1390 (w), 1370 (m), 1325 (w), 13OO (m), 1220

(m), 1140 (m), 1090 (m), 1025 (m), 1000 (m), 950 (w), 900

(w), 880 (m), 760 (m), 640 (w). NMR (CCI*, TMS, 5): 1.10

(s, 6 h), 4.00 (s, 2H), 4.90 (d, 3Hz, 2H), 5.60 (m, 5H),

6.60 (t, 3Hz, IH). MS: CisHieOu: calcd. m/e: 236.105, obs. n/ej 236.106, 236 (12%), 198 (1%), l82 (2%), I68 (1%),

149 (1%), 139 (1%), 111 (29%), 108 (9%), 95 (100%), 93

(21%), 91 (7%), 83 (7%), 79 (8%), 77 (8%), 67 (15%), 55 (11%), 53 (6%).

4,6a,7,B-Tetrahydro-7,7-dimethyl-lH,10H-furo D,4-iJ [ 2 ] - benzopyran-3,10(3aH)-dione (1^)

Into a glass tube (thick walled, 28 cm long, I .30 cm. dia.) was introduced 2,2-dimethyl-3,5-hexadienyl aconate dissolved in dry benzene (4 ml.), and hydroquinone (5 mg.).

The tube was immersed in a dry ice filled dewar, evacuated (20 mmHg.) and sealed with a torch. The tube was then placed in an iron pipe and heated to 200°C for 24 h. At the end of this time, the reaction mixture was allowed to cool 152 to R.T.j about 2 h., then the tube was opened. The solution was filtered, evaporated, and the products were purified on an analytical TLC plate (eluted with 70% petroleum ether-

30% EtOAc) to provide two compounds. The first compound 19E,

Rf=0.23, was obtained In 30% yield (15 mg., O.063 mmol.).

M.P.=163°-164.5°C. IR (CHCI3, cmr'): 3010 (m), 2960 (m),

2920 (m), 2890 (m), 1780 (s), 1725 (s), 1475 (m), 1430 (w),

1400 (w), 1375 (m), 1340 (w), 13OO (w), 1280 (w), 1265 (w),

1255 (w), 1225 (m), 1185 (m), 1170 (m), ll40 (m), 1090 (w),

1060 (m), 1030 (m), 1010 (w), 1000 (w), 985 (w), 900 (w),

810 (w), 785 (w). NMR (CDCI3, TMS, 6 ): 1.07 (s, 3H),

1.31 (s, 3H), 2.55 (m, 3H), 3.50 (m, IH), 4.10 (s, 2H), 4.37 (q, 8Hz, 2H), 5-90 (m, 2H). MS: CigHieO*: calcd. m/e: 236.105, obs. m/e: 236.105, 236 (l4%), 218 (3%), 205

(3%), 203 (3%), 191 (31%), 177 (11%), 173 (27%), 16% (9%),

149 (12%), 145 (13%), 137 (13%), 136 (37%), 135 (30%),

123 (22%), 119 (12%), 105 (26%), 93 (23%), 92 (81%), 85

(20%), 83 (31%), 79 (36%), 77 (40%), 65 (21%), 56 (42%).

The second compound,Rf=0.16, 19S, was obtained In 20% yield (10 mg., 0.042 mmol.). M.P.-153°-156°C. IR (CHCI3, cm"M: 3005

(w), 2960 (m), 1775 (s), 1730 (s), 1465 (w), l44o (w), l400

(w), 1380 (m), 1370 (m), 1300 (w), 1280 (m), 1270 (m), 1230

(s), 1190 (s), 1155 (m), 1070 (m), 1060 (m), 1040 (m), 1025

(m), 1005 (m), 910 (w), 840 (w), 800 (w). NMR (CDCI3, 153

TMS, 6); 1.22 (s, 6H), 2.53 (m, 3H), 3.50 (m, IH), 4.13

(s, 2H), 4.33 (q, 9Hz, 2H), 6.07 (m, 2H). MS: CiaHzeO*:

calcd.m/e_: 236.105, obs. m/e: 236.105, 236 (33%), 206

(102), 194 (10%), 191 (17%), 190 (26%), l88 (77%), 187

(46%), 173 (15%), 159 (17%), 149 (29%), 136 (29%), 123

(29%), 119 (21%), 105 (45%), 95 (31%), 93 (29%), 92 (4l%),

91 (100%), 85 (29%), 83 (41%), 79 (45%), 77 (50%), 67

(29%), 65 (24%), 56 (52%), 55 (43%).

2,2-Dlmethyl-3,5-hexadienyl Tosylate(^) Into a flask was added dry pyridine (2 ml.) and 2,2-dlmethyl-3,5-hexadienol (100 mg., 0.79 mmol.). The mixture was cooled to 0°C in an ice bath and tosyl chloride

(302 mg., 1.58 mmol.) was added. The mixture was held at -2°C for 20 h. At this time,a dense precipitate of white needles had formed. The mixture was poured into distilled water (25 ml.) which had been cooled to 0°C, and extracted with EtzO (5X10 ml.). The ether layers were combined and washed with 6w HzSO* (4X5 ml.), then saturated NaHCOs solution (3X5 ml.). The organic layer was then dried

over MgSOu, filtered, and evaporated, to give the product

(215 mg., 0.77 mmol., 97%) ^ , a pale brown oil. IR

(neat, cm“M: 2960 (m), 1595 (m), l440 (w), 1450 (m), 1355

(s), 1305 (w), 1290 (w), 1210 (w), 1190 (s), 1170 (s),

1095 (m), 1005 (m), 965 (s), 915 (m), 840 (s), 81O (s),

780 (m), 660 (s). NMR (CClu, TMS, 5): 1.03 (s, 6H), 2.43 154

(s, 3H), 3.67 (s, 2H), 5.43 (m, 5H), 7.4? (q, lOHz, 4h ).

MS: C15H20O3S: calcd. m/e: 280.113, obs. m/e: 280.114,

280 (%), 226 (1%), 172 (3%), 154 (23%), 139 (1%), 124

(2%), 110 (17%), 108 (43%), 95 (100%), 93 (34%), 91 (53%), .

81 (17), 79 (16%), 77 (14%), 67 (15%), 65 (l4%), 55 (21%).

2 ,2-Dimethy1-3,5-hexadienyl Mesylate(^) Into a flask was added dry pyridine (4 ml.), and 2,2- dimethyl-3,5-hexadienol (210 mg., 1.66 mmol.). The mixture was cooled to 0°C in an ice bath and mesyl chloride (38I mg., 3.33 mmol.) was added. The mixture was held at -2°C for 20 h. At this time,the mixture was poured into distilled water (15 ml.) which had been cooled to 0°C. The mixture was extracted with diethyl ether (5X6 ml.), then the combined ether layers were washed with 6N H2SO4 (2X6 ml.) and saturated NaHCOa solution (2X6 ml.). The organic layer was then dried over MgSO*, filtered, and evaporated to give the desired product (254 mg., 1.25 mmol.,

75%) a clear liquid. IR (neat, cmT^): 308O (w), 2960

(s), 1645 (w), 1600 (w), 1470 (m), l4lO (w), 1390 (w),

1350 (s), 1175 (s), 1135 (m), 1005 (s), 960 (s), 915 (m),

840 (s), 780 (w), 750 (m). NMR (CDCI3, TMS, 6): I .13 (s,

6H), 2.97 (s, 3H), 3.93 ( 5 , 2H), 5.55 (m, 5H). MS: C9H 26O3S: calcd. m/e : 204.082, obs, m/e: 204.081, 204

(6%), 150 (1%), 122 (1%), 108 (22%), 95 (100%), 93 (45%),

91 (22%), 79 (23%), 77 (27%), 67 (31%), 55 (35%). 155

Experimental to Chapter 7

Cyclohex-2-ene-l-one-N,N-dimethylhydrazone (2) Into a flask under argon was Introduced cyclohexenone

(1 g., 10.4 mmol.), p-toluenesulfonic acid (198 mg., 1.04 mmol.), benzene (20 ml.,), and N,N-dimethylhydrazlne

(625 mg., 10.4 mmol.). The mixture was heated to reflux, and the water from the reaction was collected In a Dean- Stark trap. After being refluxed for 3 h., the reaction mix ture ceased the azeotroplc distillation of water. A TLC showed the presence of product along with major amounts of starting material. At this point N,N-dlmethylhydrazlne (625 mg., 10.4 mmol.) was added to the reaction mixture. Almost at once water began to be collected again In the Dean-Stark trap. After 2 h. the same problem as before arose. No more water was being removed from the reaction, but the starting material was still present. At this point, N,N-dlmethylhydrazlne (625 mg., 10.4 mmol.) was added to the reaction mixture. After 2 h. at reflux the reaction was judged to be complete by TLC (20% EtOAc - 80% petroleum ether). The mixture was allowed to cool, then poured Into saturated aqueous NaHCOs solution (15 ml.), shaken, and extracted with CH2CI2

(4X10 ml.). The organic layers were dried over MgSOi*, filtered and evaporated to give the product (2.05 g., 126%). An NMR of this product showed that It contained no vinyl protons. Apparently 2 equivalents of M,N-dlmethylhydrazlne had added to the cyclohexenone. This material was placed In 156 a flask with p-toluenesulfonlc acid (10 mg., 0.053 mmol.) and the excess N,N-dlmethylhydrazine was removed by distil lation. After being heated at 70°C for 45 min., N,N-dimethyl- hydrazine stopped distilling. The mixture was cooled, placed under vacuum, then distilled to give the desired product (800 mg., 5-78 mmol., 55%) 2, a yellow liquid. B.P.=83°-B5°C at 20 mmHg. IR (neat, cm“M : 3030 (m), 2920 (s), 1630 (m), 1590 (m), 1470 (s), 1435 (s), 1390 (m), 1340

(w), 1250 (m), 1200 (m), 1155 (m), 1145 (m), 1130 (m), 1050

(m), 1020 (s), 990 (s), 970 (s), 950 (m), 870 (m), 845 (w),

750 (m), 735 (m). NMR (CDCI3, TMS, 6): 2.00 (m, 6H), 2.43

(s, 3H), 2.47 (s, 3H), 6.40 (m, 2H). MS: CaHiuNal calcd. m/e: 138.116, obs. m/e: 138.II6 .

3-n-Butylcyclohexanone -N,N-dimethylhydrazone (3) Into a flame dried flask under argon was introduced

THF (3 ml.) and cyclohex-2-ene-l-one-N,N-dimethylhydrazone

(315 mg., 2.28 mmol.). The mixture was cooled to 0°C and n-BuLi (4.56 mmol., 2.84 ml. of a 1.6 M solution in hexane) was added dropwise over 1 min. Immediately upon the addition of the n-BuLi the reaction mixture turned a dark reddish brown.

The reaction mixture was allowed to stir for 15 min. at

0°C, then poured into saturated aqueous NaHCOs solution

(10 ml.), and extracted with CH2CI2 (4x4 ml.)’. The com bined organic layers were dried over MgSOu, filtered and evaporated to provide the desired product (240 mg., 1.22 mmol., 55%) 3, a yellow liquid. IR (neat, cm"M: 3020 157

(w), 2930 (s), 1630 (m), 1470 (s), 1380 (m), 1350 (w),

1275 (m), 1225 (m), 1200 (m), 1155 (m), 1100 (m), IO7 O

(m), 1020 (m), 970 (m), 910 (m), 87O (w), 85O (w), 740

(m). NMR (CDCI3, TMS, 5): I .30 (m, 8H), 2.40 (s, 3H),

2.47 (s, 3H).

3-n-Butylcyclohexanone (4)

Into a mixture of aqueous sulfuric acid (pH=3, 46 ml.), and cupric acetate (924 mg., 4.63 mmol.) was added 3-n-butyl-

cyclohexane-one-N,N-dimethylhydrazone (240 mg., 1.22 mmol.) as a solution in THF (46 ml.). The mixture was allowed to stir at 25°C. Immediately upon the addition of the hydrazone the mixture turned dark brown and the pH went up to 7- After being stirred for 12 h., the mixture was worked up by extracting with CH2CI2 (4X10 ml.). The combined organic layers were washed with pH=8 aqueous NH4OH/NH4CI solution

(3x10 ml.) then dried over MgSOu. After filtration, and removal of the solvent ^ vacuo, the product was distilled (80°C, 0.010 mmHg., trap to trap) to give the desired product (100 mg., 0.648 mmol., 53%) 4, a clear liquid. IR (neat, cm“"): 2920 (s), 1710 (s), l460 (m), l430 (m),

1280 (m), 1245 (m), 1215 (m), 1265 (m), 1230 (m), 1120 (s),

1050 (m), 950 (w), 880 (w), 740 (m). NMR (CDCI3, TMS, 5):

1.70 (m, 18h). MS: CioHisO: calcd. m/e: 154.136, obs. m/e: 154.136. 158 ^J^-Dimethylcyclopent-2-en-l-one-NjN-dlmethylhydrazone (5) Into a flask was Introduced 4,4-dimethylcyclopent-

2-en-l-one (4.4 g., 40.0 mmol.), diethyl EtzO (50 ml.),

N,N-dimethylhydrazlne (3.84 g., 63.8 mmol.) and silica gel

(10 g.). The mixture was stirred at 25°C for 48 h. At this time an IR of a aliquot showed complete consumption of the starting material. The mixture was filtered, evaporated and distilled from para-toluenesulfonic acid

(5 mg.) to provide the pure product 5 (5.28 g., 34.7 mmol. 87%). B.P.=182°-184°C. IR (neat, cm"M: 3060

(w), 3020 (w), 2940 (s), 2850 (s), 2800 (s), 2760 (s),

1710 (w), 1625 (s), 1465 (s), 1360 (m), 1275 (m), 1240

(w), 1215 (w), 1190 (m), 1150 (m), IO90 (w), 1070 (m),

1015 (m), 975 (s), 910 (w), 865 (w), 785 (s), 730 (w).

NMR (CCI*, TMS, Ô): 1.13 (s, 6H, 2.32 (s, 2H), 2.38

(s, 6H), 6.10 (m, 2H). MS: CgHi^Ng: calcd. m/e: 152.131, obs. m/e: 152.132, 153 (10%), 137 (100%), 120 (12%), 110

(15%), 108 (29%), 94 (80%), 79 (39%), 77 (37%), 67 (73%), 53 (38%), 44 (100%).

5-Allyl-l,4-dimethylcyclopent-2-ene-1-one-N,N-dimethylhydrazone (6) Into a flame dried flask under argon was introduced 4,4-dimethylcyclopent-2-ene-1-one-N,N-dimethylhydrazone (308 mg., 2.00 mmol.) and diethyl ether (6 ml.). The mixture was cooled to 0°C and n-butyllithium (2.20 mmol., 1.38 159

ml. of a 1.6 solution in hexane) was added. After the mix ture had been stirred for 1 h. at 0°C allyl bromide (484 mg., 4 mmol.) was added. After being stirred at 0°C for 15 h., the mixture was poured into distilled water (10 ml.) and extracted with diethyl ether (4x6 ml.). The combined organic layers were dried over MgSOu, filtered and distilled (trap to trap, 90°C, 0.10 mmHg.) to provide the pure product (360 mg.,

1.87 mmol., 93%) 6. IR (neat, cm"'): 3060 (m), 3020 (w), 2940 (s), 2840 (s), 2800 (m), 2760 (m), 1625 (s),

1465 (s), 1355 (m), 1255 (w), 1205 (w), 1145 (w), 1070 (w), 1010 (m), 990 (m), 960 (m), 900 (m), 790 (s), 730 (w). NMR (CClu, TMS, 6): 1.10 (m, 6H), 2.40 (m, 9H),

5.50 (m, 5H). MS: C12H20N 2. calcd. m/e: 192.163, obs. m/e: 192.163. REFERENCES

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