SYNTHETIC APPROACHES FOR THE PREPARATION OF 2,5-DIHYDROPYRROLES

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CHAPTER I

SYNTHETIC APPROACHES FOR THE PREPARATION OF 2,5-DIHYDROPYRROLES

1.1. Introduction

Functionalized chiral 2,5-dihydropyrroles are recognized as potential precursors for the preparation of aza-multicyclic organic compounds, also seen among natural products such as alkaloids, and often used either as biological tools or pharmacological agents. Examples of biologically active compounds containing the 2,5-dihydropyrroles structural motifs comprehend NK1 antagonist, protein prenyltransferases inhibitor, including geranylgeranyltransferase type I inhibitor (anti-cancer agents), thrombin inhibitor and glycosidase inhibitors (e.g. pyrrolizidine alkaloids) (Figure1.1).

^1a,b,c,d

Figure 1.1. Examples of natural products containing the 2,5-dihydropyrrole moiety.

N Ts HOOC

protein geranylgeranyltransf erase type I inhibitor

N Ts HO

NK1 antagonist

HOOC NH

N O O

HN N

NH₂ NH

trombin inhibitor

N H

OH

HO OH HO

australine glycosidase inhibitor N

R R₁ R₂ R₃

R₄

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Precisely, some pyrrolizidine alkaloids present an interesting antiviral and anti- HIV activity, through an effective inhibition of the enzymatic processing of glycoproteins.

^1e

Although many of them and their derivatives have been developed for structure-activity studies, new synthetic methods to prepare a variety of analogs would be desirable to allow a better aware of structural requirements for glycosidase inhibition and to develop less toxic but more potent and selective drugs.

^1f

During the last decades, asymmetric syntheses of these compounds have been growing interest to the synthetic community.

1.2. State of Research

Based on the literature survey, the construction of 2,5-dihydropyrroles has received considerable attention over the years. After a careful retrosynthetic analysis of some pyrrolizidine alkaloids, Pyne et al.

²

have suggested an efficient and diastereroselective method for preparing 2-substituted-2,5-dihydropyrroles 1.3 in racemic and optically active form via acid catalysed or microwave assisted aminolysis of vinyl epoxides 1.1 with allyl amine followed by N-protection and Ring-Closing Methathesis (RCM),

³

a powerful tool for the formation of C-C bonds (Scheme 1.1). Although the reaction conditions appear to be quite harsh, the expected amino alcohol 1.2 is obtained with acceptable yields. The relative stereochemistry of 1.3 was established by conversion to its corresponding 4,5-cis-oxazolidinone derivative 1.4, as showed by

¹

H NMR analysis.

Thus protection of the amino group of 1.2 as its N-Boc derivative followed by RCM reaction, using commercially available Grubbs' catalyst, provided the 2,5-dihydropyrrole 1.3, via an invertion reaction at the allylic stereogenic centre.

Scheme 1.1. Synthesis of polyfunctional-2,5dihydropyrroles via vinyl epoxide aminolysis and RCM.

R O NH₂

pTsOH, 110°C 4 days

NH

R OH

1. (Boc)₂O 2. RCM N

Boc R OH

N O O

H₅ H₄R

1.1 1.2 1.3 1.4

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Years later, Mitasev and Brummond

⁴

have developed a short and efficient route to 2,5-dihydropyrroles 1.6 by using Ag(I)-catalyzed cyclization reactions of a amino allene acids 1.5 (Scheme 1.2). This result was obtained starting from a diversity-oriented synthesis (DOS) approach. This approach is based on the simultaneous synthesis of structurally diverse compounds, where a compound is subjected to varying reaction conditions that either promote or catalyze unique skeletal reorganization processes.

⁵

The cumulated double bond of an allenyl substrate is ideally suited for this type of diversification strategy. In fact, if exploited in a controlled manner, it can afford different molecular scaffolds. The participation of a number of these, easily available, allenes in metal-catalyzed C-N bond formation was also examined. These reactions generally proceed with transfer of chiral information due to coordination of the Ag(I) with the amino allene moiety.

In 2006, all four possible stereoisomeres of the 2,5-disubstituted-2,5- dihydropyrrole 1.9 were stereoselectively prepared by Trost

⁶

by two successive palladium-catalyzed asymmetric allylic alkylation (AAA) reactions of proper amine (phthalimide 1.8) with butadiene monoxide 1.7, as shown in Scheme 1.3.

The availability to access to all of the stereoisomers is given by the choice of an appropriate chiral ligand in each step of the palladium catalyzed DYKAT (dynamic kinetic asymmetric transformation) reaction. The Pd-catalyzed AAA is a specific process that generate stereogenic centres by controlling the attack of the nucleophile to a metal- coordinated allylic substrate. This procedure is able to transform racemic starting materials into products in high yield and stereoselectivity. This type of deracemization constitutes a DYKAT process. Previous research has shown that vinyl epoxides are

Scheme 1.2. Synthesis of 2,5-dihydropyrroles from α-amino allene acids

• R³ R⁴ R²

MeOOC R¹

NH₂

20 mol% AgNO₃ acetone (0.05M)

r.t. N

H R⁴ R³ R²

MeOOCR¹

1.5 1.6

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excellent electrophiles for Pd-catalyzed DYKAT with O-, C- and also some N- nucleophiles.

⁷

Initially, this rather nice synthesis starts with the first Pd-catalyzed allylic alkylation Pd-catalyzed reaction and leads to the asymmetric syntheis of vinylglycinol derivatives. Then, the protection of the free alcohol of the previously obtained oxazolydinone disfavors the likely coordination of the pendant free alcohol to the intermediate ruthenium carbene, which could shut down the catalytic cycle. Subsequently, the substrate reacts with second equivalent of butadiene monoxide for the second Pd- catalyzed reaction. Ring-Closing Metathesis reaction, basic hydrolisis of the oxazolidinone and protection of the secondary amine, as benzylcarbamate, afford 2,5- dyhydropyrroles.

In 2008, Fang and Jacobsen

⁸

have carried out research into highly enantioselective synthesis of 2-aryl-2,5-dihydropyrroles 1.12 via a phosphine-catalyzed [3 + 2] cycloaddition of electron-deficient allenoates 1.11 with imines 1.10 (Scheme 1.4).

Scheme 1.3. The possible access to all four 2,5-dihydropyrrole stereoisomers using Pd-catalyzed DYKAT reactions, with indication of the chiral ligand used.

O 1. (R,R)-ligand, Pd⁰

NH O

O

2. protecting groups 3. (R,R)-ligand, Pd⁰ 4. RCM

N (S)

(S) OR

OH

1. (R,R)-ligand, Pd⁰ 2. protecting groups 3. (S,S)-ligand, Pd⁰ 4. RCM 1. (S,S)-ligand, Pd⁰ 2. protecting groups 3. (R,R)-ligand, Pd⁰ 4. RCM

1. (S,S)-ligand, Pd⁰ 2. protecting groups 3. (S,S)-ligand, Pd⁰ 4. RCM

N (S) (R)

OH OR

N (R) (S)

OH OR

N (R )

(R) OR

OH

1.7

1.8

(R,R)-1.9

(S,R)-1.9

(S,S)-1.9

(R,S)-1.9 H

H H

H

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The presence of both H

2

O and Et

3

N as additives was found to be important for achieving optimal rates. Dual activation of both nucleophile and electrophile by the bifunctional catalyst is invoked to account for the observed high reactivity and enantioselectivity.

In this context, parallel works from Marinetti and others

⁹

have noticed a similar trend in analogous cyclizations to (S)- and (R)-1.16 promoted by achiral catalyst (PBu

₃

or PPh

3

) and the chiral binaphthophosphepine catalyst between allenoates 1.15 or 2- butynoates 1.14 and imines 1.13, according to Scheme 1.5. In addition, the use of the diphenylphosphinoyl (DPP) protecting group decreases the reactivity of the imine, as a

Scheme 1.4. Phosphine-catalyzed immine-allene [3+2] cycloaddition to 2,5-dihydropyrroles.

N P O

PhPh

Ar •

COOEt

RHN PPh₂ catalyst H₂O (20 mol%)

Et₃N (5 mol%) toluene, -30 °C

48h

N Ar DPP

COOEt

1.10 1.11 1.12

Scheme 1.5. Diastereoselective [3+2] cycloaddiction reaction of allenoates and 2-butynoates with immines.

COOMen*

N PG R₁

COOMen*

or 10 mol% cat.*

CH₂Cl₂, 24h

cat.* = PBu_3,PPh₃ or P tBu

(S)-binaphthosphepine N

PG R₁

COOMen*

PG = DPP or Ts

N PG

R₁

COOMen*

1.13

1.14

1.15 (S)-1.16 (R)-1.16

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result of a combination of steric effects and a low electrophilicity of the imine carbon.

Nevertheless, the DPP group induces high levels of asymmetric induction.

The previous asymmetric synthesis of the dihydropyrrole core is limited both for not easy preparation of the catalyst and of the allenoate substrates and for the difficult application to the synthesis of multisubstituted pyrroles. The importance of these derivatives and their potential biological properties have broadly led to the development of alternative methods in enantioselective fashion.

A convenient procedure for the preparation of optically active 2-alkyl- substituted-2,5-dihydropyrroles 1.22 was performed by Ishikawa

¹⁰

(Scheme 1.6).

This methodology is based on the preparation of aza-Baylis-Hillman adducts 1.19 from aliphatic imines 1.17 in high enantiomeric excess, although the methods requires a two-step sequence. Subsequently, chiral 2,5-dihydropyrroles are easily avaiable from N-allyl-β-amino-α-methylene esters 1.21 (obtained by alkylation of the corresponding sulphunamide 1.20) through RCM reaction catalyzed by Grubbs' second- generation catalyst.

Moreover, starting from the preparation of these compounds, the authors also have examined the synthetic application of this method to the formal synthesis of (-)- trachelanthamidine (Figure 1.2), a component of the pyrrolizidine alkaloids, which is an important class of natural products.

Scheme 1.6. RCM reaction of Aza-Baylis-Hillman adducts.

R NH

CO₂t-Bu p-Tol S

m-CPBA CH₂Cl₂

R NH

CO₂t-Bu

O

Ts

Br

K₂CO_3, DMF R N

CO₂t-Bu Ts

Grubbs' 2nd

CH₂Cl_2, reflux N R Ts

CO₂t-Bu SN

p-Tol O

R CO2t-Bu PhSMgBr

1.17 1.18 1.19

1.20 1.21 1.22

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In a similar way, Wang et al.

¹¹

have developed the asymmetric allylic substitution reaction of Morita-Baylis-Hillman (MBH) carbonates 1.24 with allylamines 1.23, using a commercially available cinchona alkaloid catalyst, which affords hightly enantioenriched N-allyl-β-amino-α-methylene esters 1.25. Then, by easily RCM reactions, the corresponding 2,5-dihydropyrrole derivatives 1.26 can be obtained smoothly in satisfactory yields (Scheme 1.7).

Their continuing interest

¹²

in chiral 2,5-dihydropyrrole synthesis has led the authors to studies on combination of a chiral secondary amine 1.28 and a transition-metal complex through a cascade iminium/enamine-metal coopertative-catalysis reaction (1.27 to 1.36), by using cheap and readily avaiable α,β-unsaturated aldehydes 1.27 and N-tosyl propargylamines 1.30, as starting materials. The cascade coperative catalytic reaction consists in the combination of organocatalysis and transition-metal catalysis in a cascade

Figure 1.2. Example of a pyrrolizidine alkaloid accessible from 2,5-dihydropyrroles 1.22.

N R

Ts

CO₂t-Bu

N H HO

(-)-trachelanthamidine 1.22

Scheme 1.7. RCM of products derived from allyl substituted Morita-Baylis-Hillman carbonates with allylamines.

NH

Ts R COOMe

OBoc quinidine (20 mol%)

p-xylene

Zhan 1-B (5 mol%) CH₂Cl₂

N N Ru

SN O O O

Cl Cl

Zhan 1-B catalyst

N R

Ts

COOMe

1.23 1.24 1.25

N R¹

R¹

Ts

R COOMe

1.26

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reaction in one process under mild conditions. The integration of the two distinct catalytic cycles into a single process facilitates the rapid and controlled production of valuable chiral dihydropyrroles 1.36 in excellent diastero- and enantioselectivities (Scheme 1.8).

In recent studies, an alternative protocol to the aza-Morita-Baylis-Hillman reaction was developed by Viso and co-workers.

¹³

This method consists in a stereoselective synthesis of 2,5-cis- or 2,5-trans-3-sulfinyl and 3-sulfonyl disubstituted dihydropyrroles 1.40 from sulfinamide intermediate 1.39.

Actually, a wide variety of 2-sulfinyl allylic sulfinamides can be obtained by lithiated vinyl and dienyl sulfoxides 1.38 with enantiopure sulfinimines 1.37. Thus, after accurate studies about different protocols for aminocyclizations to give sulfinyl and sulfonyl dihydropyrroles, the authors found that the nature of the sulfonamido group is

Scheme 1.8. Catalytic cycle for the cascade iminium/enamine-metal catalysis.

N

N R

Pd^II

Ts

N

N R

Pd^II

Ts

N

N R

Pd^II

N Ts

N R

Ts a. hydrolysis

b. isomerization

N CHO

Ts NH

H₂O H₂O CHO

R

N

R Ts N

H

Ts N

AcOH N

N R

Ts

reductive elimination

beta elimination Pd^II

iminium activation

enamine-metal cooperative

activation carbocyclization

dynamic kinetic asymmetric transformations

1.27

1.28 1.29 1.30

1.31

1.32

1.33

1.34

1.36 1.35 AcO^-

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influent on the stereochemical outcome of the halocyclization for the preparation of dihydropyrroles (S,S)- and (S,R)-1.40 through intermediate 1.39 (Scheme 1.9).

Finally, according the synthesis prepared by Shi,

¹⁴

a catalytic asymmetric construction of 2,5-dihydropyrrole scaffolds has been made through an organocatalytic 1,3-dipolar cycloaddition using α-arylglycine esters 1.41, as azomethine precursors. It takes place with concomitant creation of multiple chiral carbon centers including one quaternary stereogenic center in high yields with up to 99% ee. Additionally, further optimization has been undertaken on the catalytic asymmetric 1,3-dipolar cycloadditions of α-arylglycine ester-generated azomethine ylides with alkynes 1.42, establishing a good enatioselective method for obtaining at the same time both 2,5-dihydropyrrole diastereomers (S,R)- and (S,S)-1.43 (Scheme 1.10).

Scheme 1.9. Enantiopure dihydropyrroles from a common sulfinyl-sulfinamide intermediate.

N S O R2

R

S

R1

O p-Tol

Li S

R₁ O

p-Tol HN

S O R2

R (S)N

(S)

R

O S p-Tol X PG

(S)N

(R )

R

O S p-Tol

X PG

1.37 1.38 1.39 (S,S)-1.40 (S,R)-1.40

Scheme 1.10. Catalytic asymmetric 1,3-dipolar cycloaddition of a-arylglycine esters.

H₂N Ar¹

COOR¹ O Ar² R CHO

10 mol % *B-H, 25°C

5 Å MS, toluene (S)N

H ^(R)

R COOR¹

Ar¹ O

Ar²

(S) N H ^{( S)}

R COOR¹

Ar¹ Ar² O

O O P

O OH

9-Anthr acenyl

*B-H

1.41 1.42 (S,R)-1.43 (S,S)-1.43

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SYNTHETIC APPROACHES FOR THE PREPARATION OF 2,5-DIHYDROPYRROLES

CHAPTER I