Highly stereoselective titanium-mediated aldol reactions from chiral α-silyloxy ketones. A reliable tool for the synthesis of natural products

The additions of allylmagnesium reagents to carbonyl compounds are important methods in synthetic organic chemistry, but the mechanisms of these reactions are likely to be distinct from mechanisms followed by other organomagnesium reagents. Additions to alkyl aldehydes and ketones are likely to be concerted, proceeding through six-membered-ring transition states. These highly reactive reagents appear to react at rates that approach the diffusion limit, so chemoselectivity is generally low. Furthermore, reactions of allylmagnesium halides with carbonyl compounds are unlikely to follow stereochemical models that require differentiation between competing transition states. This Short Review discusses the current state of understanding of these reactions, including the structure of the reagent and unique aspects of the reactivity of allylmagnesium reagents.1 Introduction2 Reactions with Carbonyl Compounds2.1 Reactivity of Allylmagnesium Halides2.2 Selectivity of Addition3 Structure of Allylmagnesium Reagents3.1 Schlenk Equilibrium and Aggregation3.2 Spectroscopic Studies3.3 X-ray Crystallographic Studies3.4 Computational Studies of Structure4 Reaction Mechanism4.1 Substrate-Dependent Mechanisms4.2 Concerted Mechanisms4.3 Single-Electron Transfer Mechanisms4.4 Open, SE2′-Like Transition State4.5 Computational Studies of Mechanism5 Conclusion

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“…The high reactivity of allylmagnesium reagents with amides, even at -100 °C, can be problematic when the tertiary alcohol is not desired. 63…”

Section: Scheme 5 Addition Of Allylmagnesium Chloride To a Highly Submentioning

confidence: 99%

Reactions of Allylmagnesium Halides with Carbonyl Compounds: Reactivity, Structure, and Mechanism

et al. 2017

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“…Aldol addition of the matched pair furnished one diastereomer 30 , but the mismatched pair gave a mixture of diastereomers 31a and 31b (Scheme ) 46. This procedure was broadened to a wide range of α‐silyloxy ketones, providing an expedient tool for highly diastereoselective aldol synthesis47 and the preparation of enantiopure bioactive compounds 48. Similar high diastereoselectivity was observed in reactions between aldehydes and titanium(IV) enolates of α‐hydroxy esters 49.…”

Section: Titanium(iv) Enolates In Aldol Reactionsmentioning

confidence: 99%

Titanium Enolate Chemistry at the Beginning of the 21st Century

2016

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“…Forsyth also employed ketone 13 to synthesize an elaborate intermediate (42) en route towards azaspiracids (Scheme 11). 26 Once again, a highly stereoselective substrate-controlled aldol addition gave the anti aldol 43 with an excellent diastereoselectivity and yield (dr > 95:5, 96%).…”

Section: Short Review Syn Thesismentioning

confidence: 99%

“…12 and 13). 42 Furthermore, parallel reactions from the phenylalanine-or valine-derived α-OTBS ethyl ketones 77 with isobutyraldehyde afforded a single diastereomer of the aldol adducts 78 in high yields (Scheme 18, eq. 14).…”

Section: Short Review Syn Thesismentioning

confidence: 99%

Substrate-Controlled Aldol Reactions from Chiral α-Hydroxy Ketones

2016

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Chiral α-hydroxy ketones are valuable platforms from which highly stereoselective substrate-controlled aldol reactions may be performed. The suitable choice of the hydroxyl protecting group and the enolization conditions produce aldol adducts that can be easily manipulated to give a variety of enantiomerically pure compounds. Moreover, such aldol reactions often play a crucial role in the coupling of elaborate fragments in advanced steps of the synthesis of natural products. Together, these features confer to the α-hydroxy ketones a prominent position among the chiral substrates that are capable of providing highly asymmetric transformations. 1 Introduction 2 Pioneering Contributions 3 Boron-Mediated Aldol Reactions from α-Hydroxy Ethyl Ketones 4 Titanium-Mediated Aldol Reactions from α-Hydroxy Ethyl Ketones 5 Other Aldol Reactions from α-Hydroxy Ethyl Ketones 6 Aldol Reactions from α-Hydroxy Methyl Ketones 7 Conclusions

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Highly stereoselective titanium-mediated aldol reactions from chiral α-silyloxy ketones. A reliable tool for the synthesis of natural products

Cited by 23 publications

References 43 publications

Reactions of Allylmagnesium Halides with Carbonyl Compounds: Reactivity, Structure, and Mechanism

Reactions of Allylmagnesium Halides with Carbonyl Compounds: Reactivity, Structure, and Mechanism

Titanium Enolate Chemistry at the Beginning of the 21st Century

Substrate-Controlled Aldol Reactions from Chiral α-Hydroxy Ketones

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