SYNTHESIS OF ENANTIOMERICALLY PURE cis-2,5-DISUBSTITUTED-2,5-DIHYDROPYRROLES

CHAPTER III

SYNTHESIS OF ENANTIOMERICALLY PURE cis-2,5-DISUBSTITUTED-2,5-DIHYDROPYRROLES

3.1. Introduction

Multisubstitued 2,5-dihydropyrroles are found in significantly important pharmaceuticals, bioactive natural products and building blocks in organic and diversely oriented synthesis, because scaffolds of molecules characterized by important biological activity (see Chapter I).

As a natural extension of the interest in heterocyclic compounds and in the synthesis of compounds with potential biological activity, the possibility of the construction of an enantiomerically pure 2,5-disubstituted-2,5-dihydropyrrole system was envisaged starting from D -allal 2.2-Ms

and D -galactal-derived N-mesyl aziridine 2.2- Ms.

In particularly the use of a type of a particular type of C-nuclophile, as a metal enolate, never tried before, in the reaction with 2.2-Ms and 2.2-Ms, could determine the occurrence of an opening-closing process with ring contraction and the formation of a 2,5-dihydropyrrole system. Three points were necessary for such a rearrangement process to occur: a) the use of a C-nucleophile characterized by the presence of two C-H bonds with a consistent acidity, as an active methylene compound, b) the formation of a corresponding syn- and/or anti-1,4-addition product, and c) the presence in the reaction intermediate of a sufficiently acid N-H bond, e.g. MsN-H.

3.2. Reactions of vinyl aziridines 2.2a-Ms and 2.2b-Ms with metal enolates of methylene active compounds.

In order to check the validity of the new approach to 2,5-dihydropyrroles,

initially the reaction of N-mesyl aziridines 2.2 and 2.2 was examined, with metal

enolates of dimethyl malonate, as the active methylene compound.

Scheme 3.1. Synthesis of N-mesyl aziridines 2.2-Ms and 2.2-Ms.

O

OAc AcO

AcO

2.5

2.1

BnO O

O O

OH BnO

MsO

2.4

t-BuOK

BnO O

MsO OH

THF

O

OH BnO

HO

2.23

Bu

N

Me

SiO

BnO O

Ms N

BnO O

MsO

NHMs

O

NHMs BnO

MsO

BnO O

2.2

Ms N O

NH

BnO HO

2.45

O

NH

BnO

HO

2.45

BnO O

HO N

TMGA

PS-PPh

MsCl Py

K

CO

O

OTBS BnO

HO

MsCl Py

O

OTBS BnO

MsO TBAF

THF

BnO O

O

TMGA BnO O

HO N

PS-PPh

MsCl Py K

CO

3.5

3.8

3.6

3.7

O

OH HO

HO O

OH BnO

HO O

OTBS BnO

HO O

OTBS BnO

MsO

MeOH MeO

Na

LHMDS/THF DMF/ BnBr TBSCl

Imidazole DMF MsCl

Py

3.1 3.3 3.2

3.4

TBAF

THF

TBSCl Imidazole

DMF

t-BuOK

N-mesyl aziridines 2.2

and 2.2

were prepared as previously described, starting from the corresponding epoxide with opposite configuration 2.1 and 2.1, respectively.

Epoxide 2.1 was prepared starting from epoxide 2.1, on its own prepared starting from tri-O-acetyl- D -glucal (+)-2.5 (Scheme 3.1).

As reported briefly in the first part of this thesis, N-mesyl aziridines 2.2-Ms and 2.2-Ms are not stable and can be prepared only in situ by cyclization of the corresponding stable precursors, the trans N-mesyl-O-mesyltates (+)-2.32 and (+)- 2.32, respectively and immediately left to react with the appropriate nucleophile (2.5-3 equiv) in a non-nucleophilic solvent (protocol B).

Under protocol B reaction conditions, the reaction of N-mesyl aziridine 2.2

with the K-enolate of dimethyl malonate (by t-BuOK, 2.5 equiv) in dry toluene, afforded a crude reaction product consisting of the highly functionalized (2R,5S,6S)-2- (dimethoxycarbonylmethyl)-5-(2-benzyloxy-1-hydroxy-ethyl)-N-mesyl-2,5-dihydro- pyrrole [(+)-3.9, 32%], as expected, in a mixture with the anti-1,2-addition product, the trans 4-(N-mesylamino-)-3-(dimethoxycarbonyl-methyl)- D -glucal derivative (–)-3.10 (68%) which were separated by SiO

flash chromatography (Scheme 3.2).

The structure of compounds 3.9 and 3.10 and configuration at C(3) in 3.10 and at C(2) carbon in 3.9 were determined by examination of their

H and

C NMR spectra and by appropriate NOE experiments which also confirmed that the configuration at C(4) and C(5) carbons in 3.10 and 3.9, respectively, corresponds to that at C(4) carbon of the starting aziridine 2.2.

Since we thought that 2,5-dihydropyrrole derivative (+)-3.9 derived from the

Scheme 3.2. Reaction of aziridine 2.2 with the K- and Li-enolates of dimethyl malonate.

BnO O

MeO OMe

O O

base toluene

N Ms

CH(CO

Me)

MsHN

CH(CO

Me)

BnO

OH

+ BnO O

Ms N

1) K -enolate (2.5 equiv, t-BuOK) 2) Li-enolate (3.0 equiv, LiH)

32%

74%

68%

26%

2R 5S

6S 5S

4S 4S

3S

2.2 (+)-3.9 (-)-3.10

corresponding syn- 3.11 and/or anti-1,4-addition product 3.11 (Scheme 3.3), if the amount of these 1,4-adducts could be increased also the amount of the rearranged product would have been reasonably and correspondently increased in the final crude reaction mixture. In this sense, the reactions of glycal-derived aziridines 2.2 and 2.2 with other nucleophiles had previously demostrated that the corresponding syn-1,4-addition product/

anti-1,2-addition product ratio could be increased by favoring the occurrence of a coordination between the nucleophile and the aziridine nitrogen.

It is worth noting that this behavior appears to be typical of these glycal-derived heterocyclic systems, having been observed also with epoxides 2.1a and 2.1b.

For this reason, we repeated the reaction of aziridine 2.2 with the Li-enolate of dimethyl malonate (generated by LiH, 3.0 equiv, in dry toluene) in order to have in the reaction mixture a cation, as Li

, more coordinating than the previously used K

(from t-BuOK). Actually, under these modified reaction conditions, 2,5-dihydropyrrole (+)-3.9 turned out to be the main reaction product (74%) accompanied by a reduced amount of anti-1,2-addition product (–)-3.10 (26%), as desired (Scheme 3.2).

In a rationalization of the entire process, the formation of 2,5-dihydropyrrole (+)- 3.9 indifferently starts from syn- 3.11 and/or anti-1,4-addition product 3.11 (primary reaction products) by base-catalyzed deprotonation (a small excess of base is present in the reaction mixture) of the residual acid C-H bond of the (dimethoxycarbonyl)-methyl group with generation of the corresponding enolate species 3.12 (Scheme 3.3).

Scheme 3.3. Rationalization of the formation of 2,5-dihydropyrrole (+)-3.9 from aziridine 2.2.

(+)-3.9 N Ms

CHY2

BnO OH

2R 5S 6S

BnO O

MsHN

C O OMe O OMe

 



BnO O MsHN

CY₂ BnO O

MsHN

CHY2

4S

5S E₁cb

MeO OMe

O O

base +

3.13

3.14a anomers 3.11and3.11

(not isolated)

base syn- and anti-

1,4-addition pr oducts

3.14b

Y Y H BnO

MsN -

HO NMs

O

H O CO₂Me

OMe

H

H -

H BnO Re

Y = CO₂Me

2.2 (-)-3.10

3.12

Subsequent E1cb-type elimination, with an intramolecular alcoholate species acting as the leaving group, leads to formation of the intermediate ,-,-unsaturated ester system 3.13. Acid-base equilibration between the alcoholate and the acid MsN-H group present in 3.13 leads to the new species 3.14 bearing the hydroxy group and the weaker base MsN

. Intramolecular nucleophilic attack by the MsN

group, in a conjugate fashion, to the ,-unsaturated system through the folded conformer 3.14b leads to the regio- and stereoselective formation of cis-2,5-disubstituted-2,5-dihydropyrrole (+)-3.9.

Actually, in 3.14b the conjugate system assumes an s-cis conformation in order to form a hydrogen bond between the carbonyl oxygen and the secondary hydroxy functionality.

This makes the nucleophilic MsN

group appropriately disposed for a favored, completely facial selective attack on the Re face of the ,-conjugated system, with consequent complete cis-steroselectivity (Scheme 3.3).

When the same reaction was repeated, under the same reaction conditions (dimethylmalonate/t-BuOK, 2.5 equiv, dry toluene), with the diastereoisomeric aziridine 2.2 (Scheme 3.4), the corresponding anti-1,2-addition product, the trans 4-(N- mesylamino)-3-(dimethoxycarbonylmethyl)- D -gulal derivative (+)-3.16 was practically the only reaction product, accompanied by only a small amount (7%) of a rearranged product which turned out to be (2S,5R,6S)-2-(dimethoxycarbonylmethyl)-5-(2-benzylozy- 1-hydroxy-ethyl)-N-mesyl-2,5-dihydropyrrole (+)-3.15, a diastereoisomer of (+)-3.9. As expected, by changing the base from t-BuOK to LiH and finally to t-BuOLi, the amount of the 2,5-dihydropyrrole (+)-3.15 increased to 15 and 41%, respectively (Scheme 3.4).

Also in this case, 2,5-dihydropyrrole (+)-3.15 reasonably derives from both the corresponding syn- and/or anti-1,4-addition product 3.17 and 3.17 through

Scheme 3.4. Reaction of aziridine 2.2 with the K- and Li-enolates of dimethyl malonate.

1) K-enolate (2.5 equiv, t-BuOK) 2) Li-enolate (3.0 equiv, LiH) 3) Li-enolate (3.0 equiv, t-BuOLi)

MeO OMe

O O

base toluene 2.2 

BnO O

Ms N

5S

O

BnO

(+)-3.15 (+)-3.16

N Ms

CH(CO

Me)

MsHN

CH(CO

Me)

BnO

OH

+

6S

7%

15%

41%

93%

85%

59%

correspondly intermediate species 3.18-3.20 (Scheme 3.5). In this case, intramolecular nucleophilic attack selectively occurs at the Si face of the intermediate ,-conjugated system, as shown in 3.20b (Scheme 3.5). As found for 3.11 and 3.11 from aziridine 2.2, syn- and/or anti-1,4-addition products 3.17 and 3.17 are not found in the crude product, due to their evidently rapid rearrangement.

Necessarily having the same (S)-configuration at C(6) of the (1-hydroxy-2- benzyloxyethyl)- side chain, the diastereoisomeric relationship between 2,5- dihydropyrroles (+)-3.15 from aziridine 2.2 and (+)-3.9 from aziridine 2.2 is due to the opposite configuration at C(4) in the starting aziridine and, as a consequence, at C(4) in the corresponding 1,4-addition products (Schemes 3.2-3.4). This determines an opposite configuration at C(5) carbon of the corresponding 2,5-dihydropyrrole and the occurrence of a completely Re- and Si-face-selective conjugate addition by the internal nucleophile (intermediates 3.14b from 2.2 and 3.20b from 2.2, Schemes 3.3 and 3.5), respectively and, consequently, an opposite configuration at C(2) carbon in 2,5-dihydropyrroles (+)- 3.9 and (+)-3.15.

To check the scope of this new protocol for the construction of highly functionalized 2,5-disubstituted-2,5-dihydropyrroles, dibenzoyl methane K-enolate [from CH

(PhCO)

and t-BuOK (2.5 equiv) in dry toluene (protocol B)] was taken as an appropriate further C-nucleophile for the rearrangement reaction to occur and, initially,

Scheme 3.5. Rationalization of the formation of 2,5-dihydropyrrole (+)-3.15 from aziridine 2.2 . 

(+)-3.15 N Ms

CHY₂ BnO

OH

2S 5R 6S

BnO O MsHN

C O OMe O OMe

 



BnO O MsHN

CY₂ BnO O

MsHN

CHY₂

4R

5S

E

cb

MeO OMe

O O

base +

3.19

3.20a anomers 3.17and 3.17

(not isolated)

base syn- and anti-

1,4-addition pr oducts

3.20b

Y Y H BnO

MsN -

HO Y = CO₂Me

2.2 (+)-3.16

3.18

O

H H CO₂Me

BnO

H

-

NMs H O OMe

Si

we checked this possibility with aziridine 2.2. A clean reaction occurred leading to a crude reaction product consisting of (2R,5S,6S)-2-(dibenzoylmethyl)-5-(2-benzylozy-1- hydroxy-ethyl)-N-mesyl-2,5-dihydropyrrole [(+)-3.21, 42%] in a mixture with the corresponding anti-1,2-addition product, the trans 4-(N-mesylamino)-3- (dibenzoylmethyl)- D -glucal-derivative (–)-3.22 (42%) and a small amount of an anti-1,4- addition product, the -C-glycoside 3.23 (16%) which were separated by SiO

flash chromatography (Scheme 3.6).

When dry THF was used as the solvent, an increased amount of the rearranged product (+)-3.21 (60%) was obtained, accompanied only by the anti-1,2-addition product (–)-3.22 (40%). More interestingly, and superior to any reasonable expectation, it was the result obtained when the corresponding Li-enolate (3 equiv, by t-BuOLi) was used under a partially modified protocol. Under the new protocol, t-BuOLi (3 equiv) was used only for the preventive generation of the Li-enolate of dibenzoylmethane, whereas aziridine 2.2a (or 2.2b) was formed in situ by cyclization of trans-N,O-dimesylate 2.2a (or 2.2b) by t-BuOK (1.5 equiv). Under the new conditions, the 2-(dibenzoylmethyl)-substituted dihydropyrrole (+)-3.21 (66%) and the corresponding 2-(benzoylmethyl)-derivative (+)- 3.24 (34%) (vide infra) were the only reaction products (Scheme 3.6). For the formation of (+)-3.24, see following Scheme 3.7 and the related discussion. No trace of anti-1,2- addition product (–)-3.22 was found.

As for the reaction mechanism of formation of 2,5-dihydropyrrole (+)-3.21, a rationalization of the same type as admitted for corresponding 2,5-dihydropyrrole (+)-3.9, is reasonably applied (Scheme 3.7).

Scheme 3.6. Reaction of aziridine 2.2 with the K- and Li-enolates of dibenzoylmethane.

BnO O O

BnO

3.23

Ph Ph

O O

base solvent

N Ms

R

MsHN

CH(COPh)₂

CH(COPh)₂

MsHN BnO

OH

+ +

1) K -enolate (2.5 equiv, t-BuOK)/ toluene 2) K -enolate (2.5 equiv, t-BuOK)/ THF 3) Li-enolate (3.0 equiv, t-BuOLi)/¹⁰THF

42% (3.21) 42% 16%

>99% (3.21 : 3.24 = 66 : 34) R = CH(COPh)₂

R = CH₂COPh

60% (3.21)

– –

40% –

2.2

(+)-3.21,

(+)-3.24, (-)-3.22

Treatment of -C-glycoside 3.23, the anti-1,4-addition product from the reaction of aziridine 2.2 (entry 1, Scheme 3.6), with t-BuOK/toluene afforded, after 24 h at room temperature, the same 2,5-dihydropyrrole (+)-3.21 already present in the crude reaction mixture (Schemes 3.6 and 3.8). This result confirmed the validity of the proposed mechanism of formation of 2,5-dihydropyrroles by our protocol (Schemes 3.3, 3.5 and 3.7).

In the course of this control reaction, we found that if the 2,5-dihydropyrrole (+)- 3.21 was left in contact with the base (t-BuOK, 50% molar excess, toluene) for 48 h at rt, a haloform-like reaction occurred, with formation of the corresponding 2,5- dihydropyrrole (+)-3.24 in which the 2-(dibenzoylmethyl)-substitution of (+)-3.21 was transformed into the simpler 2-(benzoylmethyl)-group (a mono-debenzoylation reaction had occurred, see Scheme 3.9). The same transformation was observed also with the isomeric anti-1,2-addition product (–)-3.22, with the obtainment of the corresponding 3- (benzoylmethyl)-derivative (–)-3.25 (Scheme 3.9).

Scheme 3.8. The treatment of -C-glycoside 3.23 with t-BuOK.

Scheme 3.7. Rationalization of the formation of 2,5-dihydropyrrole (+)-3.21 from aziridine 2.2 . 

Y = COPh

Ph Ph

O O

(+)-3.21 N Ms

CH(COPh)2

BnO OH

5S 2R 6S

BnO O

MsHN

C O Ph O Ph

 



BnO O MsHN

CY₂ BnO O

MsHN

CHY₂

4S

5S

E

cb

base +

anomers 3.23and 3.23

(not isolated)

base syn- and anti-

1,4-addition pr oducts

Y Y H BnO

MsN -

HO NMs

O

H O COPh

Ph

H

H -

H BnO Re

2.2 (-)-3.22

N Ms

CH(COPh)

(+)-3.21 BnO O

MsHN

CH(COPh)

3.23

toluene

t-BuOK BnO

OH

Addition of the K-enolate of dibenzoyl methane (1.5 equiv) to the diastereoisomeric N-mesyl aziridine 2.2 afforded only the corresponding anti-1,2- addition product, the trans 4-(N-mesylamino)-3-(dibenzoylmethyl)- D -gulal derivative (+)-3.26. The treatment with t-BuOK transformed compound (+)-3.26 into corresponding 2-(benzoylmethyl)-derivative (-)-3.27 (Scheme 3.9), and no 2,5-dihydropyrroles were observed (Scheme 3.10). However, when the addition reaction was repeated with the corresponding, more coordinating Li-enolate (3 equiv, by t-BuOLi), the anti-1,2-adduct (–)-3.27 (58%) was accompanied by a consistent amount of 2,5-dihydropyrrole derivative (–)-(3.29) (42%). To note that under these conditions, both reaction products 3.27 and 3.29 bear the simplified 2-(benzoylmethyl)-substitution.

On the basis of the experimental evidence obtained for 3.26/3.27 and by a reasonable extension to 3.29 of what previously found for 3.24 (Scheme 3.9), the (benzoylmethyl)-substituted reaction products 3.27 and 3.29 derive from the corresponding (dibenzoylmethyl)-substituted derivatives 3.26 and 3.28 (the primary reaction products) which were not isolated due to their, evidently fast, monodebenzoylation process under the alkaline reaction conditions (entry 2, Scheme 3.10).

Scheme 3.9. The transformation of compounds (+)-3.21 and (-)-3.22 into the corresponding mono- debenzoylated derivatives (+)-3.24 and (-)-3.25.

N Ms

HC OH

(+)-3.21

t-BuOK N

Ms O C

O-t-Bu Ph

N Ms

CH

COPh OH

(+)-3.24 O

Ph

Ph O t-BuO

O Ph

BnO BnO

BnO O

CH(COPh)

MsHN

(–)-3.22

t-BuOK

BnO O

CH

COPh MsHN

(–)-3.25

On the basis of what previously admitted for the corresponding reaction with metal enolates of dimethyl malonate (Schemes 3.3 and 3.5) and experimental evidences obtained with aziridine 2.2 and related products (Schemes 3.7 and 3.9), a detailed rationalization of the formation of 2,5-dihydropyrrole (-)-3.29 and glycal-derivative

Scheme 3.10. Reaction of aziridine 2.2 with the K- and Li-enolates of dibenzoylmethane.

Scheme 3.11. Rationalization of the formation of 2,5-dihydropyrrole (-)-3.29 and glycal-derivative (-)-3.27 in the reaction of aziridine 2.2b with metal enolates of dibenzoyl methane by the t-BuOK/

t-BuOLi protocol.

Y H Y BnO

MsN

OH O

H H COPh

BnO

H -

NMs H O Ph

Si (+)-3.28

N Ms

CHY₂ BnO

OH

2S 5R 6S

BnO O

MsHN

C O Ph O Ph

 



BnO O

MsHN

CY₂ BnO O

MsHN

CHY₂

4R

5S E1cb

Ph Ph

O O +

anomers 3.30 and 3.30

(not isolated) syn- and anti- -1,4-addition products

Y = COPh

t-BuOK/t-BuOLi

(-)-3.29 N Ms

CH₂COPh BnO

OH

2S 5R 6S

t-BuOK BnO O

MsHN

CH₂COPh

t-BuOK t-BuOLi

t-BuOLi t-BuOK 2.2 (-)-3.26

(-)-3.27

BnO O

(3.28), R = CH(COPh)

Ph Ph

O O

base solvent

N Ms

R MsHN

CH(COPh)

BnO OH +

1) K -enolate (2.5 equiv, t-BuOK)/ toluene 2) Li-enolate (3.0 equiv, t-BuOLi)/¹⁰THF

2.2

(-)-3.27

>99% – –

– 58% 42%

BnO O

MsHN

CH

COPh +

(+)-3.26

(-)-3.29, R = CH

COPh

toluene