Ring-closing metathesis in flavonoid synthesis, part 1: flavenes

Tebbe methylenation and ring-closing metathesis with Grubbs second generation catalyst were investigated as key steps in the synthesis of flav-2-enes with natural substitution patterns. The effect of aromatic substituents on the electron densities of the allyl and vinyl moieties and the effect thereof on methylenation and ring-closing metathesis, is discussed.


Introduction
The flavonoid group is the most diverse group of secondary metabolites in plants.Based on two aryl rings linked by a 3-carbon chain, the basic flavonoid structure is commonly referred to as a C6-C3-C6 skeleton.Though some flavonoids have an acyclic C3 moiety, the vast majority of flavonoids are of the phenylchroman type.Depending on the position of the phenyl substituent (B-ring) on the heterocyclic ring (C-ring), the flavonoids are divided into three subclasses, i.e. the flavonoid subgroup 1 with a 2-phenyl substituent, and the isoflavonoids 2 and neoflavonoids 3 with this substituent at carbons 3 and 4, respectively. 1Additional variety stem from the degree of unsaturation and oxidation of the heterocyclic ring, thus allowing for further subclassification.A variety of substituents (e.g.hydroxy, methoxy, acetoxy and glycosyl) and substitution patterns contribute to further structural diversification and accompanying biological properties, e.g., anti-cancer, antimutagenic, vasodilatory, anti-inflammatory, anti-allergenic, anti-microbial, anti-viral, neuroprotective, antioxidant, etc. 1 Chart 1. Basic skeletons of the flavonoid 1, isoflavonoid 2 and neoflavonoid 3 subclasses.
The flavonoid subgroup 1 is most commonly prepared via the chalcone (1,3-diaryl-2-propen-1-one) route.In this regard, the aldol condensation is the most prevalent, followed by Friedel-Crafts acylation, the Fries reaction, the Wittig reaction, Julia-Kocienski olefination or acid-catalysed condensation of benzaldehydes and phenylacetylenes.Catalytic methodologies exploited in the synthesis of flavonoids include the Suzuki-Miyaura, Heck and Sonogashira reactions. 2,3n alignment with modern catalytic methodologies in the synthesis of natural products, and as a continuation of our endeavours into the use of olefin metathesis as strategy for the formation of natural and other products, [4][5][6] we decided to investigate the possibility of applying ring closing metathesis to the preparation of flavonoids.Since this would imply unsaturation in the heterocyclic ring of the flavonoid unit, flav-2-enes 4, which can then be advanced to the more stable flav-3-enes 5 [7][8][9] and/or other saturated and oxygenated analogues, were selected as target molecules to give entry into the series of flavonoid compounds (Scheme 1).Scheme 1. Proposed flav-2-ene transformation into selected members of the flavonoid 1 subclass.
Herein, we disclose our results on the role of metathesis in the formation of flav-2-enes (2-phenyl-4Hchromenes) 4 with natural substitution patterns (Scheme 2).This investigation was inspired by the assembly of the benzochroman skeleton by the De Koning group 10 and is an extension of the application of ring-closing metathesis in the synthesis of the basic flavonoid and neoflavonoid skeletons previously reported by us. 4 The esterification of appropriately substituted 2-hydroxy allylbenzenes 14 with benzoyl chlorides 13 thus gave access to the 2-allylphenyl benzoates 12, where after olefination and subsequent cross-metathesis gave various flav-2-enes 4 in good yield.Scheme 2. Retrosynthetic approach to flav-2-enes (2-phenyl-4H-chromenes) 4 with natural substitution patterns.Note: As the A-and B-rings of the flav-2-ene 4 originated from the allylbenzene 14 and benzoyl chloride 13, respectively, the A/B ring labelling system was also applied to the intermediates.
5][16] As this step previously resulted in allyl methylation and selectivity could be improved by lowering the temperature, 4 the methylenation reaction on the first substrate 12aa was initially performed at -40 °C.Although the desired 2allylphenyl 1-(phenyl)vinyl ether (11aa) was obtained, the yield was low (9%) (Table 2, entry 1).The reaction mixture was subsequently allowed to warm up to room temperature from -40 °C, which led to a lower yield of only 5% (Table 2, entry 2).The reaction was therefore started at 0 °C, allowed to warm up to room temperature and eventually heated to reflux (66 °C) to give the desired product in 81% yield (Table 2, entry 3).With a high-yielding method in place, methylenation of the 2-allylphenyl benzoates 12 also gave access to 2allylphenyl 1-(phenyl)vinyl ethers 11 with methoxy substituents on the 4-(11ab), 3,4-(11ac) and 3,4,5positions (11ad) of the B-ring in combination with an unsubstituted A-ring (Table 2, entries 3-6), as well as derivatives that combine the 3,4-and 3,4,5-B-ring substitution with a resorcinol-type A-ring (5-substituted) (Table 2, entries 7 & 8).The method could unfortunately not be extended to the phloroglucinol-type A-ring compounds (Table 2, entries 9 & 10).Analogous methylenation options (TiCp2Cl2 with the Nysted reagent 17 and TiCl4/Zn/PbCl2 with CH2Br2 18 ) also failed with these substrates (12cc & 12cd).As neither the B-ring nor the A-ring substitution patterns had a significant influence on the chemical shift of the carbonyl carbon (Table 3, δC 164.8-165.1)and thus the electronic properties of the carbonyl group, the failed methylenation of the phloroglucinol-type substrates, 12cc and 12cd, may be ascribed to the steric influence of the methoxy group ortho to the allyl group, most likely forcing the latter into a conformation that restricts interaction of the carbonyl with the Tebbe reagent.Oxygenation of the A-ring in the positions para and ortho to the allyl group furthermore shielded the allylic H-2'' [Table 3, δ 5.94, 5.91 and 5.83 for 2allylphenyl 3,4-dimethoxybenzoates 12ac, 12bc and 12cc (line 6) and δ 5.96, 5.91 and 5.85 for 2-allylphenyl 3,4,5-trimethoxybenzoates 12ad, bd and cd (line 8) with unsubstituted, 5-methoxy and 3,5-dimethoxy substituted A-rings, respectively], thus reflecting an increase in the electron density of the allyl double bond.A repelling interaction between the electron clouds of the Tebbe cyclopentadienyl rings and the electron-rich phloroglucinol-type allylbenzene 12 may also inhibit interaction between the titanium carbene and the carbonyl group.When the vinyl methylene resonances of unsubstituted 11aa and 4''-methoxy substituted 2-allylphenyl 1-(phenyl)vinyl ether 11ab are compared, it is evident that the vinyl methylene carbon (C-2) of 11ab is shielded (Table 5, lines 1 & 4: δC 89.2 vs 88.2 for 11aa & 11ab, respectively).The introduction of 3''-and 5''-methoxy substituents on the B-ring resulted in the deshielding of C-2 (Table 5, lines 4, 7 and 10: δC 88.2, 88.5 and 89.5 for 11ab, 11ac and 11ad, respectively), thus reflecting the negative inductive effects of the 3''-and 5''methoxy groups.A similar trend was observed for the analogous 2-allyl-5-methoxyphenyl 1-(phenyl)vinyl ethers 11bc and 11bd, with the vinyl methylene carbon of the 3'',4'',5''-trimethoxy derivative being deshielded with respect to that of the 3'',4''-dimethoxy analogue ( The yields obtained for the ring-closing metathesis products 4 proved to be related to the chemical shift of the vinyl methylene carbon and thus the electron density thereof.In the case of analogues with an unsubstituted A-ring, a decrease in yield was observed with the introduction of an activating para methoxy group into the B-ring and a subsequent increase in yield with the introduction of deactivating meta methoxy groups.The introduction of a 5'-methoxy group to the A-ring also resulted in a deshielding of the =CH2 group with an accompanying decrease in yield.

Conclusions
Various flav-2-enes 4 with natural substitution patterns were prepared via Tebbe methylenation and ringclosing metathesis with Grubbs second generation catalyst (GII).A distinctive trend between the electron density of the phenyl allyl moiety and the yield of the methylenation products was observed.This suggested increased repulsion between the electron clouds of this moiety and the cyclopentadienyl rings of the Tebbe reagent to the extent that a phloroglucinol A-ring was not tolerated.Ring-closing metathesis was influenced negatively by an activating p-methoxy group and positively by deactivating m-methoxy groups on the B-ring.An A-ring methoxy group meta to the vinyl ether moiety deshielded the vinyl methylene, but shielded the para allyl, cumulating into an overall deleterious impact on metathesis.With the viability of this catalytic approach towards flav-2-enes 4 being demonstrated, problems with the phloroglucinol A-ring may be addressed by using alternative olefination method and metathesis catalysts.With the flav-2-ene 4 in hand, isomerization, epoxidation, reduction and benzylic oxidation may give access to the various members of the flavonoid 1 subclass.The application of metathesis as common methodology towards the synthesis of the other two flavonoid subclasses, i.e. the iso-(2) and neoflavonoids (3), will be reported on in subsequent papers.

Table 1 .
Benzoylation of 2-hydroxy allylbenzenes 17 a In these cases, acylation in pyridine/DMAP resulted in a gummy inseparable reaction mixture and aq.NaOH (2.0 M), rt was thus used.

Table 3 .
In the final step, ring-closing metathesis of the 2-allylphenyl 1-(phenyl)vinyl ethers 11, catalysed by the Grubbs second generation catalyst (GII) in dichloromethane heated at reflux, gave the desired flav-2-enes 4 in acceptable to excellent yields (Table4, 41-96%).The introduction of a 5-methoxy group to the A-ring resulted in a marked decrease in the efficiency of the metathesis reaction (Table4, entry 3 vs 5 & entry 4 vs 6).
13C and 1 H NMR chemical shifts (δ) of the carbonyl and allyl resonances of 2-allylphenyl benzoates with resorcinol-and phloroglucinol-type A-rings in combination with catechol-and pyrogallol-type B-rings [600 MHz, (CD3)2CO] at 20 °C in relation to the yield of methylenation products 11
C and 1 H NMR chemical shifts (δ) of the vinyl and allyl resonances of 2-allylphenyl 1-(phenyl)vinyl ethers 11 with unsubstituted and resorcinol-type A-rings in combination with unsubstituted, p-methoxy, catechol-and pyrogallol-type B-rings [600 MHz, (CD3)2CO] at 20 °C in relation to the yield of the ring-closing metathesis products 4 Injections were made in the split mode.The initial column temperature of 50 °C was kept for 3 min, where after it was increased to 250 °C at 10 °C/min and kept at this temperature for the rest of the analysis.
Alternatively, MS was performed with a Matrix Assisted Laser Desorption Ionization Time-Of-Flight (MALDI-TOF) Bruker Microflex LRF20 in either the positive or negative mode with the minimum laser power required to observe signals.High resolution MS (EI-MS, 70 eV) was performed by PMBMS, University of KwaZulu-Natal.Melting points were determined with a Barloworld Scientific Stuart Melting Point (SMP3) apparatus and are uncorrected.Microwave reactions were carried out in a CEM Discover® SP microwave reactor utilising the dynamic irradiation program (fixed temperature, variable power) with continuous cooling and the power set to a maximum of 200 W.