Stereocontrolled synthesis and functionalization of cyclobutanes and cyclobutanones

Abstract

In the last decade a certain number of new cyclobutane and cyclobutanone synthesis and functionalization protocols have been published. Organo- and biocatalyzed eco-friendly approaches to cyclobutane-containing molecules have been developed with interesting results. Also, successful new total synthesis of bioactive compounds and drugs have been recently reported where a four membered ring represented the key intermediate. Therefore, the rising interest in this field represents a great point of discussion for the scientific community, disclosing the synthetic potential of strained four membered ring carbocyclic compounds. Herein we report a critical survey on the literature concerning the enantiocontrolled synthesis and functionalization of cyclobutane derivatives, with particular attention to metal-free, low impact methodologies, published during the period 2000-2013.

Figure 1

Cyclobutane containing natural products and synthetic intermediates.

Scheme 1

Stereoselective synthesis of (cis/trans)-2-hydroxycyclobutane amino acids.

Scheme 2

Cyclobutenone as a highly reactive dienophile in Diels-Alder reactions.

Scheme 3

[2+2] Cycloaddition of chiral keteniminium salts in the synthesis of cyclobutanones.

Scheme 4

Synthesis of enantiopure α-chlorocyclobutanones.

Scheme 5

Enantioselective access to pyrrolidinoindoline alkaloids.

Scheme 6

Stereoselective synthesis of cis- and trans-γ-cyclobutane amino acids.

Scheme 7

Use of a chiral allene in the synthesis of substituted cyclobutenones.

Scheme 8

[2+2] enantioselective vinylogous cycloaddition of esters with dihydrofuran.

Scheme 9

Enantioselective [2+2] cycloaddition of unactivated alkenes with α-acyloxyacroleins.

Scheme 10

Asymmetric formal [2+2] cycloadditions via bifunctional dienamine catalysis.

Scheme 11

Asymmetric formal [2+2] cycloadditions via enamine catalysis.

Scheme 12

Asymmetric vinylogous formal [2+2] cycloadditions via enamine catalysis.

Scheme 13

Intermolecular [2+2] cycloaddition of isoquinolone via a chiral H-bonding template.

Scheme 14

Bifunctional Brønsted acids based desymmetrization of meso cyclobutaneanidrides.

Scheme 15

Desymmetrization of 3-substituted cyclobutanones via organocatalyzed aldol reactions.

Scheme 16

Organocatalyzed synthesis of chiral 4-substituted γ-lactams.

Scheme 17

Enzymatic transesterification of cyclobutanols.

Scheme 18

Stereoselective enzymatic esterification and hydrolysis of cyclobutanols.

Scheme 19

Enantioselective α-alkylation of cyclobutanone via SOMO catalysis.

Scheme 20

Asymmetric S_N1 α-alkylation of cyclobutanone catalyzed by chiral ionic liquids.

Scheme 21

Enantioselective organocatalyzed synthesis of cyclobutanone aldol derivatives.

Scheme 22

Enantioselective organocatalyzed synthesis of cyclobutanone aldol derivatives.

Scheme 23

Enantioselective organocatalyzed synthesis of cyclobutanone aldol derivatives.

Scheme 24

Enantioselective organocatalyzed synthesis of syn- and anti-cyclobutanone diols.

Figure 2

Rationalized transition states A and B for the L-Thr (TS_A) and L-Trp (TS_B) catalyzed aldol reaction of hydroxycyclobutanone 92 with aromatic aldehydes.

Scheme 25

Enantioselective organocatalyzed Mannich reaction of cyclobutanone with glycolates.

Scheme 26

Enantioselective organocatalyzed Mannich reaction of cyclobutanone with glycolates.

Scheme 27

Organocatalyzed Michael reaction of cyclobutanone with nitrostyrenes.

Scheme 28

Enantioselective functionalization of 2-substituted cyclobutanones via Michael reaction.

Scheme 29

Heteroatom functionalization of cyclobutanone with azodicarboxylates.

Scheme 30

Enantiomerically enriched cyclobutane diols ring enlargement and spiranization.

Scheme 31

Acid catalyzed ring expansion of enantiomerically enriched cyclobutanols.

Scheme 32

Enantioselective synthesis of 2-aryl cyclopentanones.

Scheme 33

Enantioselective construction of chiral quaternary stereocentres in spirocyclic diketones.

Scheme 34

Synthesis of spirocycloalkanediones by organocatalytic asymmetric epoxidation.

Scheme 35

Enantioselective acid catalyzed ring expansion of cyclobutanols.

Scheme 36

Enantioselective fluorination-induced cyclopropane and cyclobutane ring expansion.

Scheme 37

Enantio- and diastereoselective Bayer-Villiger oxidation of cyclobutanones.

Figure 3

chemo- and enantioselective cyclobutanone Bayer-Villiger metal-free catalysts.

Scheme 38

Organocatalyzed enantioselective cyclobutanone Bayer-Villiger oxidation.

Scheme 39

Biocatalytic enantioselective cyclobutanone Bayer-Villiger oxidation.

Scheme 40

PAMO-mutants biocatalytic cyclobutanone Bayer-Villiger oxidation.