MARGINALIA TO ORGANIC CHEMICAL SYNTHESIS ...

1

MARGINALIA TO ORGANIC CHEMICAL SYNTHESIS.

INTERCONNECTIVITY OF SCIENTIFIC APPROACHES.

Zoltan G. Hajos

Formerly at the Department of Chemistry, Princeton University, Princeton, New Jersey 08540. Present address: 802-A Pompton Road, Monroe Township, NJ 08831.

Abstract

These Marginalia are the reflection of published, but lesser recognized and of some unpublished

research. The reaction of catechol and 4-methyl-catechol with racemic and optically active

glycidyl derivatives represents the latter category. MM2 and MOPAC minimizations of the

optically active intermediates predict (2R)-9b [(2R)-hydroxymethyl-6-methyl-1,4-benzodioxane]

to be the preferred reaction product.

Keywords

MOPAC and MM2 minimizations, reaction mechanism, regioselective, stereoselective, X-ray

contrast agent, 1,4-benzodioxane derivatives, glycidyl derivatives, proline catalysis, Wieland-

Miescher ketone and ketol, oxazolidines, zoapatanol, total synthesis of natural products,

heterogeneous catalysis, ion-exchange resin catalysis.

2

2 2

Introduction

The purpose of this essay is not to give an account of sixty years of research, rather to give an

insight to the approaches applied and to the interconnections of some areas of research I have

been involved over the years. Due to the character of the topic occasionally the first person

narrative may be used; the use of this style should be excused. Most of the results described have

not been published, however, they may contain interesting leads which could be investigated

further by research scientists using up to date techniques of organic chemical synthesis.

Discussion.

My first exposure to chemistry occurred at age fifteen through the lectures and experimental

demonstrations of a wonderful person named Sandor Ujhelyi. The school was associated with the

University of Sciences (nowadays ELTE), the same school that Edward Teller attended earlier at

the Trefort utca, Budapest, Hungary. Professor Ujhelyi was an excellent lecturer who could

conduct safe and successful experiments in the classroom. His experiments captured my attention.

Therefore, I decided to try to execute them in a small work room of our apartment. One

experiment stands out in my memory. It was the synthesis of “water gas” which can be generated

according to the equation: H O + C = CO + H To my good fortune the owner of a small

laboratory supply shop lived in the same apartment building as we did. He supplied all the

necessary gear for a very reasonable price. The experiment involved driving water vapor through

red hot coal in an iron tube which was heated with a Bunsen burner. The 1:1 mixture of carbon

monoxide and hydrogen was led into a test tube filled with water, and the water gas collected

3

1

above water could be ignited. It burned with a light blue flame indicating the successful

conversion according to the reaction equation shown above. This experiment and many others

were great fun; they have meant a lot more than those described in the experimental kits sold

commercially for young people Professor Ujhelyi didn’t discuss at that time the Fischer-Tropsch

synthesis in which a mixture of carbon monoxide and hydrogen is catalytically converted into

hydrocarbon fuels.

It was just natural that two years later following graduation I enrolled at the Department of

Chemical Engineering at the Technical University in Budapest, Hungary. Of the approximately

120 students in class approximately 60 passed the crucial exam to enter the second semester. It

should be noted that there was a compulsory curriculum which one had to pursue to obtain the

diploma in Chemical Engineering. After graduation I decided to stay at the Technical University

having been accepted as a demonstrator at the Organic Chemical Technological Institute. The

institute was under the leadership of Professor Zoltan Csuros who received his doctorate with

Professor Geza Zemplen. Zemplen in turn received his doctorate with Professor Emil Fischer,

who was awarded the Nobel Prize in Chemistry in 1902 "in recognition of the extraordinary

services he has rendered by his work on sugar and purine syntheses”.

One year after joining the institute as demonstrator I was appointed to assistant professor to work

under the guidance of the full professor of the institute. Some time after my appointment we were

approached by Professor Endre Kubanyi of the medical school to start a project on the synthesis

of an X-ray contrast agent which would show the presence of cancerous cells. The problem was

4

3 2 7 2 7

N H

N

SO H 3

3 2 7 2 7

N H

N

SO Na 3

3 2 7 2 7

NH 2

NH 2

HO S 3 1 2

3

4

field.

assigned to me. My concept was to synthesize a compound with a long hydrophobic chain holding

two iodides and a shorter hydrophilic entity to allow the compound to accumulate and enrich in

the vicinity of the cancerous tissues of the body. Figure 1, shows the scheme leading to the desired

X-ray contrast agent.

Figure 1.

CH (CH ) CH=CH-(CH ) -COOH

CH (CH ) CH=CH-(CH ) -

CH (CH ) CH(I)-CH(I)-(CH ) -

Compound 4 has been clinically tested by professor Kubanyi’s group, and found to be rather

promising. Unfortunately, funding at the medical school was insufficient in those days, hence the

cooperation stopped, and to my knowledge no further studies have been executed. However, I

thought to show the scheme in this essay. Someone may want to conduct further studies in the

5

2a,b

3a,b .

0

The Institute of Organic Chemical Technology has been strongly profiled towards the area of

Heterogeneous Catalysis. It was I and my coworker Jozsef Fodor who have first used ion

exchange resins in Hungary for heterogeneous catalysis . I have expanded my work on

Inhibitor effect in auto-oxidation processes into practical applications related to the paper and to

the textile industry

The direct result of the aforementioned Emil Fischer – Geza Zemplen – Zoltan Csuros scientific

line of heritage has been my investigation concerning the Stereospecific Preparation of

Glycosides from Sugar Acetates. The synthetic strategy involved Friedel-Crafts type catalysts.

The results were presented in 1952 at the Hungarian Academy of Sciences by Professor Zoltan

Csuros, a member of the Academy. This work in the field of carbohydrate chemistry determined

for a long time my interest in catalysis, stereochemistry and natural product chemistry.

Two years later at the Institute of Organic Chemistry of the Technical University a new problem

was presented to us. The task was the pharmaceutical utilization of a brown coal tar which was

available in large quantities. HPLC studies showed the tar to be rich in 4-methyl-catechol. It was

not my intention to study the pharmacological effects of 4-methyl-catechol itself therefore I

turned my attention to the synthesis of 1,4-benzodioxane derivatives of type 10. The reaction

with catechol 7 and epichlorohydrin 8 in water containing one molar equivalent of potassium

hydroxide gave a crystalline reaction product 10 (75% yield, mp 90 C). To execute the reaction I

6

4

2

used an old shaking machine and two pressure bottles at ambient temperature over a period of 16

h. There was a temporary spontaneous warming of the reaction mixture during the initial phase

of the reaction.

In order to have a good reference standard for the coal tar studies I synthesized pure 4-methyl-

catechol 6 from protocatechuic aldehyde 5 using the Clemmensen reduction. The resulting

compound 6 was then reacted with epichlorohydrin 8 in water containing one molar equivalent of

potassium hydroxide at room temperature over a period of 16 hours. It was evident that the

reaction may give two regioisomers 2-hydroxymethyl-7-methyl-1,4-benzodioxane 9a and 2-

hydroxymethyl-6-methyl-1,4-benzodioxane 9b. By using one molar equivalent potassium

hydroxide 2-hydroxymethyl-6-methyl-1,4-benzodioxane 9b was obtained as a viscous oil which

could be converted to the crystalline para toluenesulfonate 9c in good yield. I assumed the

preferred formation of the 6-methyl regioisomer 9b was due to the slightly higher acidity of the

meta cresol type 2-hydroxy group of 4-methyl catechol. This would direct the C -hydroxy group

of 4-methyl-catechol 6 to attack the epichlorohydrin 8 to render 2-hydroxymethyl 6-methyl 1,4-

benzodioxan 9b as the preferred reaction product. It was important to use only one molar

equivalent of potassium hydroxide and to work at ambient temperature. The reaction with

catechols and epichlorohydrin is shown in Figure 2.

7

OHC

OH

OH H C 3

OH

OH

R

OH

OH O

Cl

R 1

R 2

O

O

OH

+ water

KOH, 1 eq

5 6

6, R= H C 3 7, R= H

8

1 3 2 1 2 3

1 2

CH 3

O

O

OTs

9c

1 5

Figure 2.

Clemmensen

reduction

9a, R = H C, R = H; 9b, R = H, R = H C

10, R = R = H

While preparing this manuscript I found a paper published in 2013 by Aouf et al. reporting the

synthesis of a mixture of the two regioisomers 9a and 9b. The authors of the paper used two

molar equivalents of sodium hydroxide and heated the reaction mixture in order to achieve the

formation of the bis O-glycidation products. Since they used two equivalents of the base both

hydroxyl groups have been activated and they showed the presence of both regioisomers as an

approximately 1:1 mixture. They did not separate the regioisomers, but studied their mixture by

H -nmr and by CMR spectroscopy Their interest in O-glycidation products was the result of

their search for epoxy resin starting materials. The 2-hydroxymethyl-1,4- benzodioxanes were

therefore only a sideline of their studies.

8

6

The use of optically active (R) – and (S)-glycidyl sulfonates instead of the racemic

epichlorohydrin should be considered in future experiments. We have done so more recently in a

different research area using diphenyl piperidines to obtain the desired optically active synthons of

a new cardiotonic agent . Figure 3 shows the two potential reaction sites of the chiral glycidyl

sulfonates.

Figure 3.

With the diphenyl piperidine nitrogen nucleophiles attack at C-1 proceeded with retention of the

original stereochemistry while attack at C-3 proceeded with inversion of the configuration.

Through the proper choice of conditions using sodium or potassium counter ions the reaction

with nitrogen nucleophiles could be controlled to give largely sulfonate displacement at C-1 with

almost complete retention. Using lithium counter ions attack at C3 dominated to give largely

inversion of the stereochemistry. It will be interesting to see how the results obtained with

nitrogen nucleophiles will proceed with the catechol oxygen nucleophiles.

If our results with racemic 9b can be extrapolated to the optically active systems there will be no

need to selectively protect one hydroxyl group of the catechol starting material as has been done

9

7

OLi

OH

(S) O

+

OH O

(S) O

Cl

(2R)-9b

H

H

O (R)

O

OH

H

H C 3

H C 3

H C 3

by a group of Spanish and French scientists . Scheme 1 and Scheme 2 show the reaction paths

leading to optically active 9b. Based on the slightly higher acidity of the m-cresol type of

hydroxyl group of 4-methyl catechol regioismer 9b supposed to be the major reaction product in

racemic synthesis.Therefore, I undertook minimization studies of the oxirane-methyl

intermediates leading to optically active 9b. This way I wanted to pave the way of future

synthetic efforts in the area. Schemes 3, 4, 5 and 6 show the results obtained in MM2 and in

MOPAC minimizations.

Scheme 1.

Intermediate-leading-to-(2R)-9b

Reaction mechanism showing 4-methyl-catechol conversion to (2R)-9b, (2R)-CH2OH-6- Me-Benzodioxane 9b with (S)-epichlorohydrin

10

OLi

OH

(R)

O

+

OH O

(R)

O

Cl

H

H

H C 3

H C 3

O (S)

O

OH

H

H C 3

(2S)-9b

Scheme 2.

Intermediate-leading-to-(2S)-9b

Reaction mechanism showing 4-methyl-catechol conversion to (2S)-9b, (2R)-CH2OH-6-Me- Benzodioxane 9b with (R)-epichlorohydrin

11

Scheme 3.

MM2 minimized intermediate leading to (2R)-CH2OH-6-Me-Benzodioxane 9b

12

Scheme 4.

MOPAC minimized intermediate leading to (2R)-CH2OH-6-Me-Benzodioxane 9b

13

Scheme 5.

MM2 minimized intermediate leading to (2S)-CH2OH-6-Me-Benzodioxane 9b

14

8

Scheme 6.

MOPAC minimized intermediate leading to (2S)-CH2OH-6-Me-Benzodioxane 9b

The results obtained above indicate both by MM2 and by MOPAC minimizations that one will

have to use (S)-epichlorohydrine or (S)-glycidyl-sulfonate to go through a lower energy state

intermediate leading to (2R)-9b. The intermediate will be obtained with retention of the (S)

configuration, while conversion of the (S) intermediate to the reaction product (2R)-9b occurs

with inversion of configuration. The recent paper by Plata and Singleton summarizes the

philosophy of scientific interpretation in an excellent fashion by stating: “The computations aid

in interpreting observations but fail utterly as a replacement for experiment”. I have executed the

15

above described MM2 and MOPAC calculations recently in agreement with the Plata and

Singleton philosophy for the optically active series ( Schemes 1 – 6 and Table 1. ) after

having obtained the experimental results in the racemic series many years ago (Figure 2).

Table 1.

(S)-intermediate (-R)-intermediate

MOPAC -67.73092 kcal/mole -66.92446 kcal/mole

MM2 10.8222 11.6908

16

Another example of the interconnectivity of different research areas is the total synthesis of

zoapatanol analogues with a 3,8-dioxa-bicyclooctane skeleton 11 which has indeed a complex

tetrahydrofurano-dioxane structure. Its lower dioxane part relates to the synthesis of the

benzodioxane derivatives just discussed. The top tetrahydrofuran part of the molecule

interconnects to our synthesis of tetrahydro-3,4-furandione 9a, referred to in Houben-Weyl 9b

as the parent substance of a series. Before engaging in the total synthesis of compound 11 10a,b

a retro synthetic pathway has been designed starting with geranyl acetone 12 (Figure 4).

Figure 4.

11 12

The total synthesis of (+)-zoapatanol a naturally occurring compound closely related to 11 has

been achieved twenty four years later in an elegant fashion by a French research group directed

by Professor Janine Cossy utilizing the enantioselective Sharpless dihydroxylation of an

17

three steps

intermediate similar to compound 16 (Figure 6a) as the key step of their synthesis

12

11

. In order to

be able to engage in a total synthesis one has to design a scheme starting with readily available

substances, and the steps to be taken have to proceed in high individual yield. The number of

steps of the total synthesis is highly important. Even at a yield of 90% in each step the overall

yield will be 34.87% in ten steps. If there are specific stereo centers in the reaction product the

total synthesis should be designed to involve good stereo control in the multi step synthesis. The

total synthesis may involve regioselectivity, synthesis directed to the proper diastereomers and

possibly asymmetric synthesis of the desired enantiomers. It is essential that the chemist

involved in the total synthesis should be able to work on a small, milligram scale.

The total synthesis was aimed at the complex tetrahydrofurano-dioxane structure, the 3,8-dioxa-

bicyclooctane derivative 11. The (E)-Geranyl acetone (12) starting material was prepared in

from the naturally occurring terpene alcohol (E)-geraniol (Figure 5). It has sufficient

carbon atoms to construct the intermediate 3,8-dioxabicyclo [3.2.1]octane synthon (20), and the

C-5 double bond has the proper E geometry, which allows the production of the desired

stereoisomer of 20 in a stereocontrolled process.

18

Figure 5.

(E)-Geraniol.

(E)-Geranyl acetone (12) has been converted in a ten step synthesis to compound 20 involving

regiospecific epoxidation to epoxide 15, followed by periodic acid conversion to the aldehyde 16

(X=H). Jones oxidation to the carboxylic acid 16 (X=OH) was followed by epoxidation of the

remaining double bond along with gamma-lactonization to give compound 17. Conversion of the

hemiacetal with ortoformate gave a cis / trans mixture of bromomethyl methoxy acetals 18a and

18b which did not have to be separated. Ring closure with potassium hydroxide opened the

gamma-lactone ring and concomitantly closed the dioxane ring leading to the key intermediate

3,8dioxabicyclo [3.2.l]octane alcohol 20 having stereochemical integrity at all three centers of

asymmetry. Extension of the three carbon side chain of 20 and attachment of the acetic acid side

chain at C-1 in nine steps completed the geranyl acetone based total synthesis of the zoapatanol

related bicyclic acid 11. The total synthesis of 20 and 11 is being shown in Figures 6a and 6b.

19

( Figure 6b )

Figure 6a.

22

20

did not

13a,b . We a the the

14a,b . 31 and

o

Figure 6b

When designing a total synthesis sometimes unexpected problems arise. Thus, when designing

the total synthesis of steroidal compounds we planed to use the triketone 30 as the starting

material anticipate problem, because preparation of triketone 30 was

described in the scientific literature They reacted 2-methylcyclopentane-1,3-dione

methyl vinyl ketone 32 in refluxing methanol and a catalytic amount of potassium hydroxide.

They described compound 30 as a crystalline solid, mp 117-118 . Upon repeating the literature

21

o

(E)

O

H C 3

HO

H 2 C C H

C CH 3

O

+

O

O

H C 3

O

procedure we found the triketone 30 to be an oil, and confirmed its structure by ir and nmr

spectroscopy. We could also isolate a very small amount of a crystalline byproduct from the

reaction mixture, mp 121-122 . It was different from the triketone 30 by thin layer

chromatography, and corresponded to the bridged ketol 33. We found that the best way to

prepare the triketone 30 is by executing the Michael addition of the dione 31 and methyl vinyl

ketone 32 in water under slightly acidic reaction conditions due to the enolic nature of the dione

31 (Figure 7 ).

Figure 7.

31 32 30

The formation of the bridged ketol 33a or 33b from the triketone 30 is the result of enolization

of the five-membered ring ketone in the aqueous medium and bond formation via nucleophilic

attack of the enolate on the keto group in the side chain. Preferential enolization of cyclic over

aliphatic type mono ketones is well known. The reaction may be considered to proceed via 30a

to 33a or through 30b to 33b (Figure 8).

22

Figure 8.

This favorable molecular arrangement allows maximum pi-orbital overlap by an almost parallel

alignment of the enolic double bond of the five-membered ring and the carbonyl group in the

butanone side chain of the intermediate. The six-membered ring of 33a or 33b may thus be

considered the result of an almost perpendicular attack on the side-chain keto group, placing the

newly formed hydroxyl group in an equatorial arrangement. Bond formation and bond breaking

can thus occur readily, and it was therefore expected that the reverse reaction, i.e., the retro-aldol

type of ring opening of 33a to the triketone 30, should occur just as readily via the same

intermediate 30a in agreement with the principle of microscopic reversibility. We could also

conclude that the conversion of the previously described lower melting substance to the higher

melting compound should correctly be formulated as isomerization of the lower melting bridged

ketol 33a to its higher melting isomer 33b with resulting epimerization of the C-4 center. The

23

15 .

13a . It

retro-aldol ring opening of 33a proceeds via 30a to give the triketone 30, which in turn

cyclizes to the bridged ketol 33b via 30b, as shown in Figure 8. The molecular arrangement of

the enolic intermediate 33b should be less favorable than 33a, because it allows less pi-orbital

overlap. Nucleophilic attack of the enolate on the side-chain keto group places the newly formed

hydroxyl group into an axial configuration in 33b. Again, by the principle of microscopic

reversibility the bridged ketol 33b should be more stable, since its formation as well as its

potential opening to the triketone 30 would have to proceed through 33b the less favorable,

energy-rich conformation of the enolic intermediate.

Although the problem of the preparation of the starting material 30 has been discussed amongst

these “marginalia” the issue is far from being trivial. Without the daring use of water as solvent

in organic synthesis especially in a Michael addition reaction we most likely wouldn’t have been

able to uncover the proline catalyzed asymmetric ring closure. The use of water as solvent in

organic reactions has since been developed extensively

As to the Proline catalyzed asymmetric ring closure there are two other marginalia that seemed to

have been overlooked by the scientific public. These maybe worthwhile to be further investigated.

One is the reaction of triketone 30 with an equimolar amount of (-)-ephedrine (-)-34 in refluxing

benzene to give a mixture of oxazolidines 35a and 35b would be interesting to further

investigate and to separate these isomers (Figure 9).

24

25 D

0

Figure 9.

Nmr spectroscopy of the mixture of 35a and 35b showed a pair of doublets centered at

δ 5.23 and 5.08 ppm for the underlined benzal type of protons and corresponded respectively to

35a and 35b of the mixture. Thin layer chromatography indicated an approximately 60:40 mixture

of two components with Rf values of 0.63 and 0.36, respectively, in 1:l benzene-ethyl acetate. The

mixture was treated with 1 N HC1 at 20" to give a 76% weight yield of the dione 36, [α]

+54.8 , corresponding to a mixture of 57.5% of the dextrorotatory and 42.5% of the levorotatory

enantiomers of the dione 36 (Figure 10 ), which is in good agreement with the ratio for 35a to 35b

indicated by nmr spectroscopy and by tlc. The use of dione (+)-36 takes us from the area of

marginalia to total synthesis of natural products where it is a widely used starting material.

25

13b (Figure

O

O

+

O

O

11).

O

O

O

O

O OH

O

O

37 38

39

Figure 10.

(+)- 36, 57.5% ( - )-36, 42,5%

Another item which would be worthwhile to further investigate is the six-membered ring-bicyclic

ketol 38

Figure 11

Although we have completely characterized its lower homologue leading to the 6,5-bicyclic dione

(+)-36, we have not fully characterized 38 the precursor of the optically active Wieland-Miescher

ketone 39 due to my resignation in 1970. It would be interesting to see the configuration and

26

13a,b .

conformation of 38, and to obtain a single crystal for X-ray picture the way we did with its lower

homologue, the 6,5-bicyclic ketol

Conclusion

The mainstream of my research is known and well documented. These marginalia show the less

recognized or unpublished results related to my research areas. The major issues have always been

catalysis, stereochemical considerations, and total synthesis of natural products.

Acknowledgments

Thanks are due to all my coworkers whose name appears in the references, and those scientists

who were busy to analyze the compounds we synthesized.

References

1. H. Schulz "Short history and present trends of Fischer–Tropsch synthesis" Advance Catalysis,

1999, Volume 186, 3-12 doi: 10.1016/S0926-860X(99)00160-X.

2a. Catalysts XII. Effect of ion exchange resins in esterification Zoltan Csuros; Jozsef Fodor;

Zoltan Hajos, Acta Chimica Academiae Scientiarum Hungaricae (1952), 2, 459-74

2b. Hydrolysis catalyzed by ion-exchange resins, J. Fodor; Z. Hajos, Acta Chimica Academiae

Scientiarum Hungaricae (1955), 7, 133-48.

3a. Investigations on Catalysts. VIII. Zoltan Csuros, Zoltan Hajos, Acta Chimica Academiae

Scientiarum Hungaricae (1951), 1, 359-76.

27

3b. Inhibition of the fading of dyes. II. Hajos, Z.; Fodor, J. Acta Chimica Academiae

Scientiarum Hungaricae (1958), 16, 291-9.

4. Clemmensen, E. (1914). "Über eine allgemeine Methode zur Reduktion der Carbonylgruppe

in Aldehyden und Ketonen zur Methylengruppe. (III. Mitteilung.)". Chemische Berichte 47:

681–687.

5. Study of the O-glycidylation of natural phenolic compounds. The relationship between the

phenolic structure and the reaction mechanism, Chahinez Aouf, Christine Le Guerneve, Sylvain

Caillol, Helene Fulerand, Tetrahedron, 2013, 69, 1345-1353.

6. Preparation of Positive Inotropes using Glycidyl Derivatives: Influence of Metal Ions and

Solvent on Stereochemical Outcome, Donald L. Barton, Jeffery B. Press, Zoltan G. Hajos, and

Rebecca A. Sawyers, Tetrahedron: Asymmetry, 1992, 3, 1189-1196.

7. Short and Enantioselective Syntheses of (R)- and (S)-Hydroxymethyl-1,4-Benzodioxan,

Antonia Delgado, Geratd Leclerc, Cinta Lobato, David Mauleon, Tetrahedron Letters,

1988,Vo1.29,No.30,pp 3671-3674.

8. Case Study of the Mechanism of Alcohol-Mediated Morita Baylis−Hillman Reactions. The

Importance of Experimental Observations, R. Erik Plata and Daniel A. Singleton J. Am. Chem.

Soc. 2015, 137, 3811−3826.

9a. Tetrahydro-3,4-furandione I. Preparation and Properties, Edward C. Kendall and Zoltan G.

Hajos, J. Am. Chem. Soc., 1960, 82, 3219 – 3220.

9b. Houben-Weyl Methods of Organic Chemistry Vol. VI/3, 4th Edition: Ethers, Acetals

(including Orthoesters, Oxonium Salts, Cyclic Three- to Five-Membered Ethers) Pages 579,580

and 589.

28

1970).

10a. Total synthesis of 1RS,4SR,5RS-4-(4,8-dimethyl)-5-hydroxy-7-nonen-1-yl)-4-methyl-3,8-

dioxabicyclo[3.2.1]octane-1-acetic acid and Related Compounds, Zoltan G. Hajos, US 4,284,565

Aug. 18, 1981.

10b. Total synthesis of (1RS, 4SR, 5RS )-4- (5-hydroxy-4,8-dimethyl-7-nonen-l-yl)-4-methyl-

3,8-dioxabicyclo[3.2.l]octane-l-acetic acid from geraniol, Zoltan G. Hajos, Michael P. Wachter,

Harvey M. Werblood, and Richard E. Adams, J. Org. Chem. 1984, 49, 2600-2608.

11. Synthetic Approaches and Total Synthesis of Natural Zoapatanol, Catherine Taillier,

Barbara Gille, Veronique Bellosta, and Janine Cossy, J. Org. Chem. 2005, 70, 2097-2108.

12. Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc., 1955, 77, 5068.

13a. Zoltan G. Hajos, David R. Parrish, J.Org.Chem., 1974, 39, 1615-1621.

13b. Hajos, Z. G. and Parrish, D. R., Ger. Pat., July 29, 1971, DE 2102623, (priority date Jan. 21,

14a. C. B. C. Boyce and J. S. Whitehurst, J. Chem.Soc.1959, 2022.

14b. D. J. Crispin, A. E. Vanstone and J. S. Whitehurst, J. Chem. Soc. C, 1970, 10.

15. Organic Reactions in Water: Principles, Strategies and Applications, U. Marcus Lindstrom

(Editor) 424 pages, April 2007, Wiley-Blackwell.