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. 2014 Dec 16;47(12):3655-64.
doi: 10.1021/ar500330x. Epub 2014 Dec 3.

The domestication of ortho-quinone methides

Wen-Ju Bai  1 , Jonathan G David, Zhen-Gao Feng, Marisa G Weaver, Kun-Liang Wu, Thomas R R Pettus
Affiliations

The domestication of ortho-quinone methides

Wen-Ju Bai et al. Acc Chem Res. .

Abstract

CONSPECTUS: An ortho-quinone methide (o-QM) is a highly reactive chemical motif harnessed by nature for a variety of purposes. Given its extraordinary reactivity and biological importance, it is surprising how few applications within organic synthesis exist. We speculate that their widespread use has been slowed by the complications that surround the preparation of their precursors, the harsh generation methods, and the omission of this stratagem from computer databases due to its ephemeral nature. About a decade ago, we discovered a mild anionic triggering procedure to generate transitory o-QMs at low temperature from readily available salicylaldehydes, particularly OBoc derivatives. This novel reaction cascade included both the o-QM formation and the subsequent consumption reaction. The overall transformation was initiated by the addition of the organometallic reagent, usually a Grignard reagent, which resulted in the formation of a benzyloxy alkoxide. Boc migration from the neighboring phenol produced a magnesium phenoxide that we supposed underwent β-elimination of the transferred Boc residue to form an o-QM for immediate further reactions. Moreover, the cascade proved controllable through careful manipulation of metallic and temperature levers so that it could be paused, stopped, or restarted at various intermediates and stages. This new level of domestication enabled us to deploy o-QMs for the first time in a range of applications including diastereocontrolled reactions. This sequence ultimately could be performed in either multipot or single pot processes. The subsequent reaction of the fleeting o-QM intermediates included the 1,4-conjugate additions that led to unbranched or branched ortho-alkyl substituted phenols and Diels-Alder reactions that provided 4-unsubstituted or 4-substituted benzopyrans and chroman ketals. The latter cycloadducts were obtained for the first time with outstanding diastereocontrol. In addition, the steric effects of the newly created stereocenters in subsequent reactions of chroman ketals and acetals were studied and proved predictable. Through the use of a chiral auxiliary, Diels-Alder products were deployed in numerous enantioselective reactions including several complex natural products syntheses. In this Account, we summarize our efforts, which we hope have contributed to the synthetic renaissance for this venerable species.

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Figures

Figure 1
Figure 1
Plausible canonical representation of o-QMs.
Figure 2
Figure 2
Synthetic methods to generate o-QMs.
Figure 3
Figure 3
Applications of o-QM generation protocols.
Figure 4
Figure 4
ortho-Alkylated polyhydridic phenolic motifs.
Scheme 1
Scheme 1. Construction of Unbranched ortho-Aliphatic Phenols
Scheme 2
Scheme 2. Construction of Branched ortho-Aliphatic Phenols
Scheme 3
Scheme 3. Construction of 4-Unsubstituted Benzopyrans and Chroman Ketals from β-Unsubstituted o-QMs
Scheme 4
Scheme 4. Stereocontrol Emanating from Y Substituent at the C3-Position
Scheme 5
Scheme 5. Construction of 4-Substituted Benzopyrans and Chroman Ketals from β-Substituted o-QMs
Scheme 6
Scheme 6. Stereocontrol Emanating from R1 at the C4-Position
Scheme 7
Scheme 7. o-QM Production Triggered under Other Salty Conditions
Scheme 8
Scheme 8. Some Future Explorations
See this image and copyright information in PMC

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