An enantiopure building block for naturally occurring hydroporphyrins and vitamin B 12 from Hagemann´s ester

Enantiomerically pure ring building block for naturally occurring hydroporphyrins and possibly vitamin B 12 was synthesized starting from methylated Hagemann´s ester. Originally, this ester was utilized to investigate preparation of ring building blocks for vitamin B 12 in Eschenmoser´s and Woodward´s syntheses. Hagemann´s ester furnished methyl 4-acetoxy-2,3-dimethylcyclohex-2-en-1-carboxylate in racemic form. Kinetic enzymatic resolution of the cyclohexene acetate led to the enantiopure hydroporphyrin building block methyl {(1 S ,2 S ,5 S ,3 Z )-3-(2-t -butoxy-2-oxoethylidene)-1.


Introduction
Since its discovery in 1893 Hagemann´s ester rac-1 has become an important building block in organic synthesis. 1,2Based on its unique multifunctional reactivity Hagemann´s ester rac-1 was in particular utilized as starting material for numerous syntheses of natural products. 2Also in the course of vitamin B12 syntheses [3][4][5][6][7] Hagemann´s ester was successfully applied by Eschenmoser for synthesis of a building block in racemic form (rac-3) for rings A and B of the macrotetracycle. 3,8,9][10] Today this rearrangement is known as the Meerwein-Eschenmoser rearrangement [8][9][10] which represents a gentle synthetic tool together with Johnson´s ortho-ester Claisen rearrangement 11 and Ireland´s ester enolate rearrangement. 12heme 1. Eschenmoser´s amide acetal approach leading to a lactone lactam intermediate rac-3 for Vitamin B12 synthesis. 3,8,94][15][16][17][18][19] These hydroporphyrins and also chlorophyll a exhibit partial structures identical or closely related to structure patterns present in vitamin B12.Therefore, building blocks applied in vitamin B12 synthesis could play a role as suitable common educts for the preparation of hydroporphyrins.To achieve a common building block with the desired absolute configuration we considered transformation of the original Hagemann´s ester approach from vitamin B12 synthesis into a chirogenic enantioselective route.
Alcohol 5 was transformed into its N-tosylproline derivatives 15 for determination of its enantiopurity (Figure 2). 1 H NMR spectrum of a diastereomeric mixture of N-tosylproline derivatives 14/15 derived from rac-5 shows two methyl ester signals, one for each diastereomer.In contrast, for N-tosyl derivative 15 formed from 5 only one signal was observed thus confirming its enantiopurity.Absolute configuration of alcohol 5 follows from its further transformation into compounds of known absolute configuration in the course of subsequent synthesis.Conservation of enantiopurity of intermediates in the course of synthesis was proven by NMR experiments with chiral shift reagents (Figure 2).Enantiomerically pure alcohol 5 underwent Meerwein-Eschenmoser-Claisen rearrangement with N,Ndimethylacetamide dimethyl acetal to give cyclohexene carboxylate 2 (Scheme 3).Rearrangement product 2 is completely (> 99%) enantiopure as confirmed by NMR experiments with chiral europium shift reagent [Eu(TFC)3] (Figure 2).Formation of a trace amount of diastereomeric trans-2 can be attributed to equilibration of the carbomethoxy group induced by the slightly basic rearrangement reaction conditions or by a minimally decreased streoselectivity of the rearrangement process itself.Since trans-diastereomer of 2 is formed in that case enantiopurity of 2 is not affected.
Ozonolysis of N,N-dimethylamide ester 2 followed by oxidative workup in the presence of acid cleaved the cyclohexene double bond giving keto and a carboxylic acid functions.Proposed intermediate 7 afforded dilactone acid 8 which was further transformed via lactone lactam 9 into lactone lactam ester 3. The whole reaction sequence was elaborated during work on vitamin B12 3,[8][9] to give racemic lactone lactam ester rac-3 (rac-2 _ rac-7 _ rac-8 _ rac-9 _ rac-3).Therefore a detailed characterization of intermediates was not performed.However, for dilactone carboxylic acid rac-8 and its epimer epi-rac-8 crystals suitable for X-ray analysis were obtained (see Supplementary Material).As mentioned before, for syntheses of vitamin B12 [3][4][5] an alternative approach was applied to achieve enantiopure lactone lactam ester 3. Comparison of lactone lactam 3 derived from allylalcohol 5 with 3 from vitamin B12 synthesis revealed its absolute configuration and therefore those of intermediates of the synthesis route.Conversion of lactam 3 into its thiolactam 10 was originally achieved by treatment with P4S10. 3,21,22Actually, sulfuration was performed with Lawesson´s reagent to give a separable 10 : 1 mixture of 10 and its epimer 2-epi-10.Thiolactam 10 was transformed by the sulfide contraction method 3,22,23 into the target compound 12. Thiolactam 10 reacted with bromo malonic diester 11 [24][25][26] in the presence of DBU to yield coupling product 13.Crude 13 was heated in triethyl phosphite for sulfur extrusion and contracted diester intermediate was allowed to react further without purification to give 12 with allyl ester cleavage and decarboxylation.Allylic ester function is selectively cleaved with piperidine catalyzed by tetrakis(triphenylphosphane)palladium(0) and the carboxylic acid decarboxylates spontaneously via an intermediate imine tautomer. 25,27As observed in previous investigations [24][25][26]28 12 is formed exclusively with Zconfiguration at the double bond, due to a stabilizing intramolecular hydrogen bond between ring NH and ester carbonyl group. X-ay structure confirmed relative configurations of all the stereogenic centers of 12. Enantiopurity was checked by NMR shift experiments with [Eu(TFC)3](Figure 2) which demonstrated that methyl ester signals of rac-12 were split off whereas 12 shows only one methyl ester signal as expected.
Cleavage of the γ-lactone ring of 12 with potassium cyanide in methanol should give more stable lactam derivatives compared to lactone lactam (Scheme 4).Whereas imine derivative 19 is formed by lactone ring cleavage of 12 under gentle basic reaction conditions, cyanide elimination from 16-18 requires drastic reaction conditions.Therefore cyano adducts could be beneficial for further reaction steps in the course of syntheses.Cyanide addition was performed with rac-12 to furnish a diastereomeric mixture of cyano adducts rac-16a and rac-16b in an 8 : 2 ratio.Prior to cyanide addition the γ-lactone ring is cleaved to form an imine intermediate rac-19.As demonstrated for a similar case cyanide attack to imine intermediate rac-19 is directed by the carboxylic acid function preferring cis-isomer rac-16. 26The formed acetic acid side chain was esterified with diazomethane (rac-17a,b) resp.with chloroacetonitrile (rac-18a,b).In the latter case the differentiation of the acid side chain is preserved for possible subsequent regioselective transformations.

Conclusions
An enantioselective synthetic route forms lactam lactone diester 12 in seven synthesis steps starting from methylated Hagemann´s ester rac-4 in overall yield of 9.4%.Key step for preparation of enantiomerically pure Hagemann´s alcohol 5 is a kinetic enzymatic resolution of acetoxy derivative rac-6.Enantiopurity of alcohol 5 (> 98%) is completely preserved along the synthetic route.

Figure 1 .
Figure 1.A common building block for naturally occurring tetrapyrrolic pigments.

Figure 2 .
Figure 2. (a) Determination of enantiomeric excess of cis-alcohol 5 by 1 H NMR of its diastereomeric tosyl proline derivatives 14 and 15 (methyl ester signals).(b) Determination of enantiomeric purity of rearrangement product 2 by 1 H NMR shift experiment with chiral Eu(TFC)3 (methyl ester signals).(c) Determination of enantiomeric purity of building block 12 by 1 H NMR shift experiment with chiral Eu(TFC)3 (methyl ester signals).