The reaction of carbohydrate-derived alkoxyaldehydes with methoxycarbonylmethylenetriphenylphosphorane: stereoselective synthesis of β-unsaturated esters

Unequivocal Experimental Evidence for a Unified Lithium Salt-Free Wittig Reaction Mechanism for All Phosphonium Ylide Types: Reactions with β-Heteroatom-Substituted Aldehydes Are Consistently Selective for cis-Oxaphosphetane-Derived Products

“…2,88 In many of these examples, the carbonyl and the -substituent of the aldehyde are substituents on a ring, and high Z-selectivity is observed only if the carbonyl and -heteroatom are oriented cis with respect to each other, and it is highest in alcohol solvents. High E-selectivity is observed for similar aldehydes in which the carbonyl and -heteroatom have trans relative orientation 89,90,91,92,93 or if there is no -heteroatom. 89,90 We chose the aliphatic aldehyde, 1,2-O-isopropylidene-3-Omethyl-α-D-xylopentodialdofuranose-(1,4) 94 (65, see Chart 2) as our non-benzaldehyde test and we reacted it under our standard reaction conditions with some of the same ylides used in the reactions described above.…”

“…High E-selectivity is observed for similar aldehydes in which the carbonyl and -heteroatom have trans relative orientation 89,90,91,92,93 or if there is no -heteroatom. 89,90 We chose the aliphatic aldehyde, 1,2-O-isopropylidene-3-Omethyl-α-D-xylopentodialdofuranose-(1,4) 94 (65, see Chart 2) as our non-benzaldehyde test and we reacted it under our standard reaction conditions with some of the same ylides used in the reactions described above. The carbonyl group of this aldehyde is a substituent on a five-membered ring and there is a -methoxy substituent oriented cis with respect to the carbonyl.…”

“…This is consistent with earlier reports of non-epimerization of this and other related aliphatic aldehydes in Wittig reactions carried out under similar conditions. 89,90,91,92,93,97 Comparing phospholium ylides 50 and 78, it is noticeable that there is a much greater shift from E to Z selectivity for the semi-stabilized analogue 78 in its respective reactions with 66 and 65. Thus it shows complete E-selectivity in its reaction with 66, 98 but very high Z-selectivity in its reaction with 65 (albeit not quite as high as the MePh 2 P-derived analogue), demonstrating a very dramatic shift in the energy of the cisselective TS as a consequence of the presence of the heteroatom.…”

“…similarly disposed relative to the carbonyl as the ortho-heteroatoms in benzaldehydes). 88 There are literature examples of this phenomenon (although in these, the mechanistic origin of the high Zselectivity has not been identified), most involving stabilized ylides, 2,14,89,90 but there are also some examples involving a semi-stabilized ylides. 2,88 In many of these examples, the carbonyl and the -substituent of the aldehyde are substituents on a ring, and high Z-selectivity is observed only if the carbonyl and -heteroatom are oriented cis with respect to each other, and it is highest in alcohol solvents.…”

“…Such a TS should benefit from both the phosphorus-heteroatom bond and the advantageous anti-parallel orientation of the carbonyl C-O and ylide C-R 2 bond dipoles that is normally only present in a trans-selective TS. Apart from its precedence in organophosphorus chemistry, factors that argue for the existence of phosphorus -heteroatom bonding in the cycloaddition TS are: (i) the effect is observed for both aromatic and aliphatic aldehydes bearing a suitablyoriented remote heteroatom -aldehydes with no such heteroatom substituent do not show such high Z-selectivity; 89,90 (ii) the effect is seen for benzaldehydes with both electron donating and with electron withdrawing ortho-heteroatom substituents but hardly at all with a methyl substituent; (iii) the effect increases as the heteroatom polarizability increases and electronegativity decreases -in the order F, OMe, Cl, Br, I (e.g. see Table 1, entries 1-4 and 6 and Table 3 entries 4-13) which would correlate with the ability of the heteroatom to bond to phosphorus -this has precedent in the reported structures of 1,8-selenylsubstituted naphthalenes, 101,102 where the magnitude of the proposed 3c4e selenium-heteroatom bonding interaction also appears to increase in the order F < Cl < Br; (iv) related to point (iii) is the fact that cis-selectivity also increases in line with the bond length of the carbon-heteroatom bond of the aldehyde -the longer this bond and the larger and more polarizable the heteroatom, the closer the heteroatom can approach to phosphorus in the TS, thus facilitating stronger phosphorusheteroatom bonding; (v) when the heteroatoms are switched (Table 1 entry 19 and footnote d), the effect is stronger for the bromo aldehyde than the fluoro; (vi) there must be some significant effect lowering in the energy of the cis-OPA selective cycloaddition TS particularly to make Z-alkene formation predominant in the reactions of ester-stabilized ylides.…”