What Is Mislow-Evans Rearrangement?
The Mislow-Evans rearrangement, also known as the sulfoxide–sulfenate [2,3]-sigmatropic rearrangement, is a powerful and stereospecific transformation that converts allylic sulfoxides into allylic alcohols via a reversible [2,3]-sigmatropic shift. First elucidated by Kurt Mislow in the 1960s and later extensively developed by David A. Evans, this reaction has become an indispensable tool in organic synthesis.
The reaction is valued because it combines functional-group interconversion with stereochemical transfer. Properly designed allylic sulfoxides can deliver allylic alcohols with high control over alkene geometry, and the reaction has become a dependable tactic for building trans-allylic alcohols and other allylic oxygenated motifs. It is also a useful platform for asymmetric synthesis because chirality at sulfur can be relayed into carbon stereochemistry in the product.
- Reagents: Oxidants (m‑CPBA, NaIO4, MoO5·Py·HMPA) for sulfide→sulfoxide; thiophiles [P(OMe)3, P(OPh)3, PhSeH] to trap the sulfenate intermediate; thermal activation (80–170 °C) or microwave irradiation.
- Reactants: Allylic sulfoxides (or allylic sulfides that are first oxidized in situ). The sulfoxide contains a C=C–CH2–S(=O)R unit.
- Products: Allylic alcohols (after thiophilic trapping and solvolysis). In aza variants: α‑sulfenyloxy amides; in dearomative variants: benzylic alcohols from aryl sulfoxides.
- Reaction Type: Concerted, reversible [2,3]‑sigmatropic rearrangement.
- Related Reactions:
– Claisen rearrangement ([3,3]‑sigmatropic) – tandem Claisen‑Mislow‑Evans cascades exist.
– Cope rearrangement ([3,3]‑sigmatropic, often competing).
– Wittig rearrangement ([2,3]‑sigmatropic of ylides).
Fig 1. Mislow-Evans rearrangement reaction and its mechanism. [1]
Mechanism of Mislow-Evans Rearrangement
The [2,3]-Sigmatropic Shift
The Mislow-Evans rearrangement proceeds through a concerted [2,3]-sigmatropic shift via a five-membered cyclic transition state. The reaction is initiated by the isomerization of an allylic sulfoxide to the corresponding allylic sulfenate ester, with the [2,3]-shift occurring under thermal conditions. The rearrangement is a suprafacial reaction proceeding through an ordered transition state.
In the presence of a thiophile (such as P(OMe)3 or PhSeH), the intermediate allylic sulfenate is trapped, thereby driving the equilibrium toward the sulfenate and ultimately affording the allylic alcohol product.
Reversible Nature of the [2,3]-Shift
A defining feature of the Mislow-Evans rearrangement is its ready reversibility under relatively mild conditions. The [2,3]-sigmatropic rearrangement of allylic sulfoxides to allylic sulfenates is a reversible process, generally shifted toward the sulfoxide. In the presence of thiophiles, the sulfenate is trapped, and the equilibrium is forced toward the formation of allylic alcohols under mild conditions. However, with no trapping agent present, the equilibrium favors the allylic sulfoxide. At equilibrium, many allyl sulfenates are effectively completely converted to the rearranged allyl sulfoxides. This reversible nature has been exploited for the isomerization of alkenes.
Application Examples of Mislow-Evans Rearrangement
- Natural Product Total Synthesis: The Mislow-Evans rearrangement has been employed as a key stereodefining step in numerous total syntheses of complex natural products, such as (-)-13-oxyingenol, (+)-saxitoxin and 11‑saxitoxinethanoic acid, agelastatin A, myxalamide A, and pinnatoxin A spiroimine core, etc. For example, the tandem Claisen‑Mislow‑Evans rearrangement cascade developed by Zakarian efficiently forged the quaternary chiral center at the core of the characteristic spiroimine of pinnatoxin A. This tandem reaction will be employed in the synthesis of other natural products containing a cyclohexenol moiety. [2]
- Carbohydrate Chemistry: The Mislow-Evans rearrangement has proven especially valuable in carbohydrate chemistry for the construction of glycals in an iterative fashion. A short route to the synthesis of digoxose trisaccharide glycal donor via Mislow-Evans rearrangement was used to construct digitoxose‑derived glycals. The same rearrangement was iteratively performed on di‑ and trisaccharides to form the digoxose glycal donor component present in the cardenolides digitoxin, digoxin, and gitoxin. The trisaccharide synthesis was conducted on a multigram scale, demonstrating the practicality of this methodology. [3]
Fig 2. Synthetic examples via Mislow-Evans rearrangement reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Fourth Edition, 2014, 405-406.
- Pelc, Matthew J., et al. Tetrahedron letters 47.43 (2006): 7519-7523.
- Ali, Intzar, et al. The Journal of Organic Chemistry 88.16 (2023): 12105-12114.
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