2,3-Wittig rearrangement
Encyclopedia
The [2,3]-Wittig rearrangement is the transformation of an allylic ether
into a homoallylic alcohol
via a concerted, pericyclic process
. Because the reaction is concerted, it exhibits a high degree of stereocontrol, and can be employed early in a synthetic route to establish stereochemistry. The Wittig rearrangement requires strongly basic conditions, however, as a carbanion intermediate is essential. [1,2]-Wittig rearrangement
is a competitive process.
and Y an alkoxide
, the rearrangement is called the [2,3]-Wittig rearrangement and the products are pent-1-en-5-ols. The [1,2]-Wittig rearrangement, which produces isomeric pent-5-en-1-ols, is a competitive process that takes place at high temperatures. Because of the high atom economy and stereoselectivity
of the [2,3]-rearrangement, it has gained considerable synthetic utility. The carbanion is generated by direct lithiation of moderately acidic substrates, tin transmetallation, or reductive lithiation of O,S-acetals. Stereoselective methods employing chiral starting materials have been used to effect either asymmetric induction or simple diastereoselection
(1)
(2)
The postulated transition state possesses a five-membered, envelope-like structure. The group attached to the carbanion (G) can occupy either a pseudoequatorial or pseudoaxial position, although the former is usually preferred. Large substituents on the other side of the ether oxygen prefer to occupy the exo position (RE) to avoid A1,3 strain. These restrictions lead to a preference for the syn product from (Z) isomers and anti products from (E) isomers; however, some exceptions to this rule are known.
(3)
(4)
The asymmetric induction
approach relies on stereocenters already set in the starting material that are unaffected by the reaction (chiral auxiliaries). The most success has been achieved by placing these stereocenters either in the G group or in a substituent attached to the terminal end of the double bond. Diastereomeric ratios in excess of 90:10 are common for these reactions; however, removal of the chiral auxiliary is sometimes difficult.
(5)
The use of chiral bases has afforded enantioenriched rearrangement products in a few cases, although this method does not appear to be general. Enantioselectivity in these reactions is often low, suggesting that the association between the conjugate acid of the base and the rearranging carbanion is likely weak.
(6)
(7)
When an alkene is used as the anion-stabilizing group G, issues of selectivity arise concerning the site of the carbanion. Anion-stabilizing groups such as (trimethyl)silyl or methylthio provide essentially complete site selectivity.
(8)
Carbonyl groups may also be used as the anion-stabilizing group; carbonyl groups are particularly useful for asymmetric rearrangements that employ chiral auxiliaries.
(9)
A highly enantioselective method employing chromium carbonyl complexes involves the use of the acidified phenyl ring as an anion-stabilizing group.
(10)
That the substrate must contain acidic hydrogens adjacent to the ether oxygen was a significant limitation of the original reaction. Thus, the development of transmetallation methods that allowed the selective generation of carbanions from carbon-tin bonds represented a profound methodological advance. The scope of the groups that could be attached to the anionic center expanded dramatically as a result.
(11)
, affording δ,ε-unsaturated carbonyls. This tandem sigmatropic strategy has been employed in the synthesis of some natural products, including brevicomine and oxocrinal.
(12)
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
into a homoallylic alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
via a concerted, pericyclic process
Pericyclic reaction
In organic chemistry, a pericyclic reaction is a type of organic reaction wherein the transition state of the molecule has a cyclic geometry, and the reaction progresses in a concerted fashion. Pericyclic reactions are usually rearrangement reactions...
. Because the reaction is concerted, it exhibits a high degree of stereocontrol, and can be employed early in a synthetic route to establish stereochemistry. The Wittig rearrangement requires strongly basic conditions, however, as a carbanion intermediate is essential. [1,2]-Wittig rearrangement
1,2-Wittig rearrangement
A 1,2-Wittig rearrangement is a categorization of chemical reactions in organic chemistry, and consists of a 1,2-rearrangement of an ether with an alkyllithium compound. The reaction is named for Nobel Prize winning chemist Georg Wittig....
is a competitive process.
Introduction
[2,3]-Sigmatropic rearrangements occur for a variety of groups X and Y (see below). When X is a carbanionCarbanion
A carbanion is an anion in which carbon has an unshared pair of electrons and bears a negative charge usually with three substituents for a total of eight valence electrons. The carbanion exists in a trigonal pyramidal geometry. Formally a carbanion is the conjugate base of a carbon acid.where B...
and Y an alkoxide
Alkoxide
An alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They can be written as RO−, where R is the organic substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands...
, the rearrangement is called the [2,3]-Wittig rearrangement and the products are pent-1-en-5-ols. The [1,2]-Wittig rearrangement, which produces isomeric pent-5-en-1-ols, is a competitive process that takes place at high temperatures. Because of the high atom economy and stereoselectivity
Stereoselectivity
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during the non-stereospecific creation of a new stereocenter or during the non-stereospecific transformation of a pre-existing one...
of the [2,3]-rearrangement, it has gained considerable synthetic utility. The carbanion is generated by direct lithiation of moderately acidic substrates, tin transmetallation, or reductive lithiation of O,S-acetals. Stereoselective methods employing chiral starting materials have been used to effect either asymmetric induction or simple diastereoselection
(1)
Prevailing mechanism
After carbanion formation, the [2,3]-Wittig rearrangement is rapid and selective at low temperatures. However, if the reaction mixture is allowed to reach temperatures above -60 °C, [1,2]-rearrangement becomes competitive.(2)
The postulated transition state possesses a five-membered, envelope-like structure. The group attached to the carbanion (G) can occupy either a pseudoequatorial or pseudoaxial position, although the former is usually preferred. Large substituents on the other side of the ether oxygen prefer to occupy the exo position (RE) to avoid A1,3 strain. These restrictions lead to a preference for the syn product from (Z) isomers and anti products from (E) isomers; however, some exceptions to this rule are known.
(3)
Stereoselective variants
Stereoselective variants of the [2,3]-Wittig rearrangement have employed three strategies: diastereoselection based on an existing, established stereocenter, placement of a chiral auxiliary on the starting material whose configuration is unaffected by the reaction, and the use of a chiral base. The relative diastereoselection strategy works well only for a limited number of G groups, but usually results in high yields because no chiral auxiliary group needs to be removed or modified. The stereocenter opposite the carbanion usually must be tertiary (rather than quaternary) in order to enforce the placement of he largest substituent in the RE position.(4)
The asymmetric induction
Asymmetric induction
Asymmetric induction in stereochemistry describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment...
approach relies on stereocenters already set in the starting material that are unaffected by the reaction (chiral auxiliaries). The most success has been achieved by placing these stereocenters either in the G group or in a substituent attached to the terminal end of the double bond. Diastereomeric ratios in excess of 90:10 are common for these reactions; however, removal of the chiral auxiliary is sometimes difficult.
(5)
The use of chiral bases has afforded enantioenriched rearrangement products in a few cases, although this method does not appear to be general. Enantioselectivity in these reactions is often low, suggesting that the association between the conjugate acid of the base and the rearranging carbanion is likely weak.
(6)
Scope and limitations
A variety of allylic ethers undergo the Wittig rearrangement—the fundamental requirement is the ability to generate the appropriate carbanion in the substrate. This demands either acidic hydrogens, a reducible functional group, or a carbon-metal bond. Historically, alkenyl, alkynyl, and phenyl groups have been used to acidify the α position. Free terminal alkynes are tolerated, although yields are higher when silyl-protected alkynes are used.(7)
When an alkene is used as the anion-stabilizing group G, issues of selectivity arise concerning the site of the carbanion. Anion-stabilizing groups such as (trimethyl)silyl or methylthio provide essentially complete site selectivity.
(8)
Carbonyl groups may also be used as the anion-stabilizing group; carbonyl groups are particularly useful for asymmetric rearrangements that employ chiral auxiliaries.
(9)
A highly enantioselective method employing chromium carbonyl complexes involves the use of the acidified phenyl ring as an anion-stabilizing group.
(10)
That the substrate must contain acidic hydrogens adjacent to the ether oxygen was a significant limitation of the original reaction. Thus, the development of transmetallation methods that allowed the selective generation of carbanions from carbon-tin bonds represented a profound methodological advance. The scope of the groups that could be attached to the anionic center expanded dramatically as a result.
(11)
Synthetic applications
The products of the [2,3]-Wittig rearrangement of bis(allylic) ethers are 1,5-dien-3-ols. These substrates may undergo the oxy-Cope rearrangement upon deprotonationDeprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...
, affording δ,ε-unsaturated carbonyls. This tandem sigmatropic strategy has been employed in the synthesis of some natural products, including brevicomine and oxocrinal.
(12)