Asymmetric Catalytic [4+3] Cycloaddition of Oxiranes

Original Article:
Asymmetric catalytic [4+3] cycloaddition of ortho-quinone methides with oxiranes

Qingfa Tan, et al.

Chem. Commun., 2021,57, 3018-3021

10.1039/D1CC00262G

Oxiranes, also known as epoxides, are organic compounds in which one oxygen atom is bonded to two adjacent carbon atoms to form a three-membered ring. The three-membered ring in oxirane is highly strained and can be easily opened under mild conditions, which makes it widely used in organic synthesis. On the other hand, asymmetric catalytic [4+3] cyclization is a straightforward and efficient strategy for constructing seven-membered carbocycles and heterocycles. In this work, the researchers reported the ring-opening/[4+3] cyclodition reaction towards 4,5-dihydrobenzo[d][1,3]dioxepine derivatives through chiral rare earth metal complex catalysts.

Research Highlights

• Catalytic enantioselective [4+3] cycloaddition reaction between o-quinone methides and oxiranes was successfully developed by using chiral N,N'-dioxide/Tb^III complexes with good to excellent diastereo-(up to 94 : 6 dr) and enantioselectivities (up to 97% ee).
• Further transformation of the product enables the generation of a spirocyclic product with three ortho stereocenters.
• Generate a topological space map using the web application SambVca 2 to characterize the chiral pockets of N,N'-dioxide ligands around the metal ion.
• This paper proposes a possible transition state to elucidate the reaction process and chirality induction.

Experimental Key Points

1. In a preliminary study, o-QM and epoxides were selected as model reaction substrates to optimize the reaction conditions. The reaction conditions studied include metal salts, ligands, solvents, and molecular sieves, etc. The results showed that using an additive such as LiNTf₂ or NaBArF₄ was beneficial to both the yield and enantioselectivity, and the desired product could be obtained in 99% yield with 80 : 20 dr and 92% ee in the presence of 20 mol% of NaBArF₄ as the additive.

2. After establishing acceptable response conditions, the generality of the response was assessed. For example, dimethyl 3-phenyloxirane-2,2-dicarboxylates with alkyl substitution at different positions of the phenyl group were tolerant, delivering the products with high enantioselectivities and good diastereoselectivities. And 1-naphthyl or 2-naphthyl substituted oxiranes afforded the corresponding products 3ae and 3af with better enantioselectivities.

3. To test the synthetic potential of this reaction, a gram-scale synthesis of 3aa was performed. o-QM 1a reacted smoothly with the substrate 2a, yielding the corresponding [4+3] cyclodition product 3aa in 99% yield with slightly lower 88 : 12 dr and 96% ee. In this reaction, AlCl₃ promoted acetal cleavage/ C-alkylation rearrangement of 3aa, affording the spirocyclic product (3S,4S,5R)-5a in moderated yield and slight loss of enantioselectivity, but nearly only one diastereoisomer bearing three vicinal stereogenic centers was obtained within a short reaction time.

Scale-up synthesis of 3aa and further transformations of 3aa.

4. To understand the effect of steric hindrance on reactivity and enantioselectivity in chiral N,N'-dioxide-metal catalyzed reactions, Cavallo's SambVca 2 Web tool was chosen to generate topological space maps.

Chemicals Related in the Paper:

Catalog Number	Product Name	CAS Number
ACM2426075-1	1,2,7,8-Diepoxyoctane	2426-07-5
ACM2984501	1,2-Epoxyoctane purum	2984-50-1
ACM220290686	2-Oxa-6-azaspiro[3.4]octane	220290-68-6
ACM32017768	2-(4-Bromophenyl)oxirane	32017-76-8