Hipótesis

1.6.2.1 Lehmizidine alkaloids

The first aim of this project is to explore methodology that could in principle lead to the synthesis of lehmizidine alkaloid 50. This will employ the well established methodology within the Organic Chemistry group of the University of the Witwatersrand, in creating azabicyclic alkaloid systems via enaminone chemistry. If this can be achieved, the synthesis of the remaining lehmizidines could also be attempted. Although this would be a far more complex task, the methodology developed might be extended towards the synthesis of parvistemoline group members. The project begins with use of commercially cheap ingredients and use recently developed methods to convert them into suitable precursors for the cyclisation studies. Alternative disconnections towards pyrrolo[1,2-a]azepine 4 nucleus are shown in Scheme 20, with emphasis on alkylative and acylative ring closing mechanisms.

N N R¹

N R¹

HN

X

R²O O R¹

HN R¹

X O O

X

X X

O O

N R¹

OR² O

R¹= EWG, R²= alkyl, X = Br, Cl or H

Scheme 20: Alternative disconnections towards making pyrrolo[1,2-a]azepine core.

1.6.2.2 Strategy

The first strategy is an attempt on making the pyrrolo[1,2a]azepine 4 core, scaffold for lehmizidines and parvistemoline V. 4-Chlorobutanoyl chloride 138 can be reacted with ethyl aminobutyrate hydrochloride in the presence of a base to yield ethyl 4-(4-chlorobutanamido)butanoate 139 (Scheme 21, a). Compound 139 can then be cyclised forming a five-membered ring in the presence of a strong base to form ethyl 4-(2-oxopyrrolidin-1-yl)butanoate 141 (Scheme 21, b). On the other hand compound 141 can be achieved by the N–alkylation of pyrrolidin-2-one 140 by ethyl 4-bromobutanoate in the presence of a strong base (Scheme 21, c). A thionation reaction on compound 141 using Lawesson’s reagent or P²S5 should result in ethyl 4-(2-thioxopyrrolidin-1-yl)butanoate 142 (Scheme 21, d). The Eschenmoser sulphide contraction reaction of compound 142 would result in (E)-ethyl 4-[2-(2-ethoxy-2-oxoethylidene)pyrrolidin-1-yl]butanoate 143 (Scheme 21, e). The seven-membered ring can now be made having accessed the all important enamine 143. Compound 143 can be cyclised acylatively to yield compound 144 (Scheme 21, f) or alkylatively to yield compound 147 (Scheme 21, g). At this point a goal of making the 1-azabicyclo[5.3.0]decane 4 core would be achieved. The hydrogenation of compounds 144 and 147 would result in compounds 145 and 148 respectively (Scheme 21, h). Decarboxylation of compound 145 (Scheme 21, i) followed by the reduction reaction of the ketone on compound 146 (Scheme 21, j) would lead to compound4.

NH

Scheme 21: Synthetic strategy towards the 1-azabicyclo[5.3.0]decane core 4: (a) Acylation; (b) IntramolecularN-alkylation; (c) Intermolecular N-alkylation; (d) Thionation;

(e) Eschenmoser sulphide contraction; (f) Acylative ring closure; (g) Alkylative ring closure; (h) Hydgrogenation; (i) Decarboxylation; (j) Reduction.

a b c membered and seven-membered rings. The strategy assumes making the five-membered ring first, then later assembling the seven-five-membered ring. Ethyl 4-chloro-4-oxobutanoate 149 can be reacted with Grignard reagents marked R¹CH2

under strict conditions to yield compounds 150 (Scheme 22, a). Compounds 150 can then be reacted with ethyl 4-aminobutyrate hydrochloride which is commercially available and ethyl 4-aminopentanoate (which can be synthesized from a reaction of commercially available 5-methylpyrrolidin-2-one with sodium ethoxide, to yield compounds 151 (Scheme 22, b). Compounds 151 would require a selective reduction of the enamine double bond in order to free the amide reactivity forming compounds 152 (Scheme 22, c). Compounds 152 can then be subjected to the same conditions to those already mentioned [Scheme 21, (d – j)] to yields lehmizidine alkaloids 159. The challenge from here on would be to synthesize these alkaloids enantioselectively.

Cl O

Scheme 22: Synthetic strategy towards the Lehmizidine Alkaloids: (a) Substitution;

(b) Tandem Alkylative/Acylative ring closure; (c) Hydrogenation.

149 150 151

The second aim of this project is to synthesise models for cephalotaxine 56. This will employ a recently developed methodology within the Organic Chemistry group of the University of the Witwatersrand, in creating azabicyclic alkaloid systems via a Heck-type coupling, linking an enaminone with a brominated aryl group. This intramolecular link has assisted in forming a five-membered ring (n = 0) in these alkaloids (Scheme 23).^79,80,81 Now, this methodology will be extended towards making a seven-membered ring (n = 2). Also of interest is exploring alternatives with X = H because of the recent attention in the literature in the methods entailing to C-H activation.

N Z

H₂C_n

N

R¹= OMe R²= OMe

R¹= R²= OCH₂O n = 0

n = 2 Z = EWG X = Br, H Heck type

coupling R²

R¹

H₂C_n

Z

R¹ R²

Scheme 23: Heck type coupling.

X

1.6.2.4 Strategy

γ-Butyrolactone 13 will be reacted with homoveratrylamine 160 in an oven using a sealed tube reactor to yield lactam1-(3,4-dimethoxyphenethyl)pyrrolidin-2-one 161 (Scheme 24, a). Lactam 161 will then be reacted with bromine in acetic acid to yield 1-(2-bromo-4,5-dimethoxyphenethyl)pyrrolidin-2-one162 (Scheme 24, b).Compound 162 will then be subjected to a thionation reaction using Lawesson’s reagent or P²S5

resulting in the formation ofthiolactam1-(2-bromo-4,5-dimethoxyphenethyl)pyrrolidine-2-thione 163 (Scheme 24, c). Ethyl bromoacetate will be reacted with thiolactam163 in the Eschenmoser sulphide contraction reaction resulting in enaminone (E)-ethyl 2-(1-(2-bromo-4,5-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 164 (Scheme 23, d). At this stage the Heck-type coupling reaction would be employed to create the seven-membered ring resulting in the target molecule165 (Scheme 24, e). However, for comparison, studies in which the carbon chain between nitrogen and the aromatic ring is reduced by one or two methylene units in order to ascertain the relative ease of the cyclisation would be included. An investigation of aryl-containing pyrrolidones (without the aromatic halide) would be undertaken in order to see whether cyclisation by other C–H activation methods can be achieved.

N

Scheme 24: Synthetic strategy towards Cephalotaxus core.

a b

If the cyclisation is successful, the synthesis (Scheme 24) can be extended to compound 119 (Scheme 25, e), which was an advanced intermediate in Weinreb’s synthesis of cephalotaxine 56.^20,21 This will require the synthesis of the diketone-derived enaminone ( E)-1-(1-(2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethyl)pyrrolidin-2-ylidene)butane-2,3-dione 169 (Scheme 25, d). The uniquely fused three five-membered rings, a seven-five-membered ring and an aromatic ring of cephalotaxine 56 will be created by Heck type coupling of enaminone 169 followed by Weinreb cyclisation (Scheme 25, f) as key steps. The first few reactions use similar reaction conditions as in Scheme 24, a, b, c, d with suitable modifications to some reagents, resulting in enaminone 169 where the Heck type coupling takes centre stage in creating the five-membered ring (Scheme 25, e). Making 119 will complete a formal synthesis of cephalotaxine 56 by converging with Weinreb’s route (f, g, h Scheme 25).

N

Scheme 25: Synthetic strategy towards Cephalotaxine 56.

a b c

CHAPTER 2: APPROACHES TOWARDS THE LEHMIZIDINE