Hydrangenol synthesis

Substituted 3,4-dihydroisocoumarins are produced by the radical-promoted reaction between ethyl 2-bromomethylbenzoates and aldehydes. A total synthesis of naturally-occurring hydrangenol has been achieved in this way <07TL4131 >. 

The directed metalation of aromatic systems that was discussed in Section 2.1.3.3 has one ramification that was not mentioned there the directed lithiation of an o-methyl group. Although the resultant species is formally a resonance-stabilized anion, and therefore covered in Volume 2 of this series, we mention it here for consistency with the other topics covered. In particular, the examples that have appeared in recent years involve substrates having a methyl ortho to a tertiary amide. Intentional use of such a directed lithiation has been used in the synthesis of the isocoumarin natural products hydrangenol and pyllodul-cin.137,138 Interestingly, the directed metalation of 5-methyl-oxazoles and -thiazoles occurs in preference to deprotonation at a 2-methyl group (azaenolate) (Scheme 33). ... 

Knoevenagel condensation. DBU was used as the base for the condensation of dimethyl 3-hydroxyhomophthalate (1) with p-benzyloxybenzaldehyde (2). Note that this reaction is not successful with p-hydroxybenzaldehyde. The condensation was the first step in a synthesis of hydrangenol (4), a component of a variety of Hydrangea Hortensia D.C. ... 

The construction of isocoumarin natural products offers another instructive comparison between DoM and more conventional methodologies. Thus, in the synthesis of hydrangenol 37 (Scheme 12), [31a] a five-step, one-pot process directly furnishes the heteroannelated product 36, a sequence involving a low-temperature DoM of a dimethyl amide, an LDA-induced chain extension, and a base-mediated cyclization. BBr3 treatment leads to the natural product 37 in good overall yield. The chosen classical alternative, [31b] involving Claisen condensation of 39 with 40 to give 38, is achieved in low over l yield due to the an inefficient preparation of the homophthalic ester 39 (from 3-nitrophthalic anhydride), a memento of an earlier DoM- classical route comparison (Scheme 3). 

Watanabe, M., M. Sahara, M. Kubo, S. Furkawa, R.J. Billedeau, and V. Snie-KUS Ortho-lithiated Tertiary Benzamides. Chain Extension via f>-Toluamide Anion and General Synthesis of Isocoumarins Including Hydrangenol and Phyllodulcin. J. Organ. Chem. (USA) 49, 742 (1984). 

---