Chapter 1

Introduction

Chapter 1 2

1.1. INTRODUCTION

The Diels–Alder (DA) cycloaddition [4 + 2] reaction was first

described in 1928,1 is a pericyclic process (Fig. 1) involving an electron-

rich conjugated diene (4-electron component) and a electron-deficient

dienophile (2-electron component). The DA reaction is regio, diastereo

selective and also stereospecific. It can be used to generate a six-

membered ring, a substituted -bond, two new -bonds and up to four

contiguous stereogenic centres in one operation. And all of the atoms

constituting the starting materials appear in the product. The DA reaction

opened up new vistas in the field of synthetic organic chemistry, and it

duly established itself as a crucial synthetic tool.

Figure 1. The fundamental mechanism of Diels-Alder reaction

Mechanistically, DA reaction requires overlap of molecular orbitals

(MO). Overlap between the highest occupied molecular orbital of the diene

(HOMO) and the lowest unoccupied molecular orbital of the dienophile

(LUMO) is thermally allowed, provided the orbitals are similar in energy.

Electron-withdrawing groups on the dienophile will facilitate the reaction,

Chapter 1 3

since this will lower the energy of the LUMO. Good dienophiles often bear

one or two of the following subtituents: CHO, COR, COOR, CN, C=C, Ph,

or halogen. The diene component should be as electron-rich as possible.

DA reactions can take place either thermally, at ambient, elevated

temperatures,2 or by Lewis acids (LA) catalyst at lower temperatures.3

Figure 2. Molecular Orbital Overlap of Diels-Alder reaction

1.1.1. Regioselectivity in DA

One of the most valuable aspects of the DA reactions in organic

synthesis is high predictable regioselectivity. Although the DA reaction of

an unsymmetrical substituted diene with an unsymmetrical substituted

dienophile can give rise to a mixture of two regioisomers, one of the two

regioisomers is formed exclusively or predominantly in many cases. The

ratio of the two regio adducts depends on the nature of the reactants,

reaction conditions, and directing effects of the substituents on the diene

and dienophile components.4 DA reaction of a substituted dienes with

substituted dienophiles, substituents on the terminus of the diene unit

favor the formation of ortho adducts, whereas the same substituents on

Chapter 1 4

the terminal carbons favor formation of para adducts. The overall directing

effects of 1, 3-disubstituted dienes are synenergic as opposed to being

antagonistic for the 1, 4 or 2, 3-disubstituted dienes. Similar analogies are

applicable for the dienophile counterpart. When these regiodirecting

factors can not dictate any overall regiochemical bias in the reaction, both

regioadducts will form in comparable quantities.

Figure 3. Regioisomerism in the Diels-Alder reaction

1.1.2. Stereoselectivity in DA

Two different modes of addition, endo and exo orientations can be

envisioned for the two components of DA reaction when they approach

each other in presumably parallel planes in the transition state (TS).5

These two modes of addition and the resulting configurational outcome are

illustrated in Figure 4. As the consequence of regio and stereoisomerism,

the DA reaction of an unsymmetrical substituted achiral diene and

unsymmetrical substituted achiral dienophile give rise, in principle, to 8

isomeric adducts (Figure 5).4 Despite this, often one diastereomer is

Chapter 1 5

produced selectively over the other isomers. In cases when the selectivity

is modest, change in the reaction condition, variation of the subtituents

and connecting the reacting partners are the means to enhance the

selectivity.

Figure 4. endo and exo addition modes in Diels-Alder reaction

Figure 5. Different modes of addition of unsymmetrically substituted

diene and dieophile in Diels-Alder reaction.

1.2. Natural products synthesis

Chapter 1 6

Natural product synthesis has been a very exciting and challenging

branch of organic chemistry in view of its creativity and unlimited scope.

Natural product synthesis witnessed an exceptional growth and many

innovative developments, especially during 20th

century.6

The most

attractive feature of natural products is the inspiring structural diversity

present in them in terms of number and size of rings, extent and range of

functionalization and number of stereogenic centers. Over the past

century, the achievements in the total synthesis of natural products have

been most astonishing.7-12

1.3. Applications of Diels-Alder reaction in Natural products Synthesis

As a representative highly stereoselective cycloaddition reaction, the

Diels–Alder reaction is the most widely explored pericyclic reaction for the

assembly of functionalized six-membered carbocyclic and heterocyclic

compounds. In addition to the assembly of monocyclic six-membered

systems, polycyclic compounds containing a variety of functionalities are

also achieved by Diels–Alder approaches. The significant usefulness of

Diels–Alder reactions has been validated in many instances through the

syntheses of structurally complex natural products. Diels-alder reaction

was extensively utilized in the synthesis of various classes of natural

products. i.e. terpenoids, alkaloids, polyketides and drugs belongs to

different class of therapeutic areas.

1.3.1. Terpenoids

Chapter 1 7

Terpenoids consist of a vast, diverse group of natural products and

present in the various forms in the most of the organisms where they fulfill

a broad range of functions. Terpenoid natural products have been reported

to act as toxins, growth inhibitors, or deterrents to microorganisms and

animals that protection against enemies may indeed be their primary role

in nature. For example, various monoterpenes (C10) are toxic to insects,13

fungi14 and bacteria15 and serve as feeding deterrents to mollusks,16

insects17 and mammals.18 The synthesis of terpenoids is most challenging,

because of their complex structures. And syntheses of various terpenoids

have been achieved successfully by Diels-Alder approach.19-25

Figure 6. Terpenoids synthesized by Diels-Alder approach

1.3.2. Alkaloids

Chapter 1 8

Alkaloids are a chemically heterogenous group of basic nitrogen

containing substances found predominantly in plants, animals,

microorganisms and marine organisms. Alkaloids are chemically,

biologically and commercially significant natural products. Among the

chemical classes present in medicinal plant species, alkaloids stand as a

class of major importance in the development of new drugs and have been

identified as responsible for pharmacological properties26 of medicinal

plants. Because of their complex structure in nature synthesis of alkaloids

is very challenging and the Diels-Alder strategy has been proved to be one

of the best methods to generate various class of alkaloids.19, 27-32

Figure 7. Alkaloids synthesized by Diels-Alder approach.

1.3.3. Polyketides

Chapter 1 9

Polyketides are secondary metabolites, exhibiting significant

diversity both in terms of their structure and function. Polyketide natural

products are known to possess a wealth of pharmacologically important

activities33-38 (antimicrobial, antifungal, antiparasitic, antitumor and

agrochemical properties). The wide spectrum of acticvity of polyketides

makes them economically, clinically and industrially the most important

molecules. And the Diels-Alder strategy has been utilized extensively in the

synthesis of this class of natural products.39- 44

Figure 8. Polyketides synthesized by Diels-Alder approach.

Chapter 1 10

1.3.4. Molecules with Pharmaceutical interest (Drugs)

The Diels-Alder reaction is firmly entrenched as one of the most

versatile synthetic transformations in organic chemistry. Numerous

examples attest to its broad utility for the preparation of natural and

unnatural products. Seventy years have gone since its discovery, and yet

investigations into its mechanistic nuances and construction potential

continue unabated. Indeed [4 + 2] cycloadditions appear to be the most

widely used method for the synthesis for simple and complex natural

products and molecules with pharmaceutical interest.45-50

Figure 9. Drugs synthesized by Diels-Alder approach.

Chapter 1 11

1.3.4.1. Synthesis of (-)-Oseltamivir 35

(-)-Oseltamivir (tamiflu) is a potent inhibitor of neuraminidase and is

used worldwide as a drug for influenza of both type A and type B.51 The

recent spread of the avian virus H5N1 has prompted governments to store

tamiflu as a precautionary measure against an influenza pandemic.

However, the high cost of the drug makes it difficult for developing

countries to stock tamiflu. Currently, tamiflu is marketed by Roche and is

prepared by a semisynthetic approach starting from (-)-shikimic acid,

which has a limited resource given the massive demand.52 Therefore, the

development of alternative synthetic approaches, which start from simple

materials, has drawn extensive attention and there are numerous reports

on the development of chemical syntheses of tamiflu from simple starting

materials.52 Among them, E. J. Corey et al., and Masakatsu Shibasaki et

al. have developed an efficient Diels-Alder approaches to tamiflu.44

E. J. Corey synthesis: E. J. Corey et al.45a was the first group to report

the Diels-Alder approach to Tamiflu. They have started the synthesis with

the Diels-Alder reaction between butadiene 41 and trifluoroethyl acrylate

42 in the presence of the S-proline-derived catalyst ent - 43 to form the

adduct ent - 44. The initial Diels-Alder step is easily carried out at room

temperature on a multigram scale in excellent yield (97%) and with >97%

Chapter 1 12

ee. Followed the by synthetic manipulation of 44 in several steps, they

have achieved the total synthesis of Tamiflu (scheme 1).

Scheme 1. E. J. Corey‟s approach to Tamiflu.

Shibasaki synthesis: Masakatsu Shibasaki et al.45b have synthesized the

Hydroxydiacyl azide 50 through the Diels–Alder reaction between

commercially available 1-(trimethylsiloxy)- 1,3-butadiene 48 and fumaryl

chloride 49, followed by TMSN3 addition in the presence of a catalytic

amount of DMAP, and acidic cleavage of trimethylsilyl ether.

Subsequently, they converted the azide 50 in to Tamiflu (Scheme 2).

Chapter 1 13

Scheme 2. Masakatsu Shibasaki,s Approach to Tamiflu

1.3.4.2. Synthesis of Taxol 34.

A well-celebrated application of the Diels-Alder reaction in the

context of natural products and drugs synthesis is found in the total

synthesis of the anti cancer drug taxol 34. Nicolaou et al.9a employed two

different [4+2] cycloadditions to construct each of the two six-membered

rings (A) 57 (Scheme 3) and ring (C) 64 (Scheme 4) of the taxol. Further

synthetic manipulation between 57 and 64 gave the natural product taxol

34 (Schemes 5).

Scheme 3. Synthesis of A ring of Taxol using Diels-Alder reaction

Chapter 1 14

Scheme 4. Synthesis of C ring of Taxol using Diels-Alder reaction.

Scheme 5. Total synthesis of Taxol from intermediates 60 and 64.

From the above discussion it‟s very clear that, Diels-Alder reaction is

one of the best tools to construct main core of complex natural products,

pharmaceutically important intermedietes and drugs. Our interest in

Diels-Alder reaction encouraged us to use this unique methodology to

study its synthetic uitility in exploring to eremophilane natural products,

the fungal metabolite ascochlorin and pfizers anti smoking drug

varenicline. We would like to discuss our affords in the next upcoming

three chapters.

Chapter 1 15

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