The (2, 3) witting rearrangement

The [2,3]-Wittig rearrangement is a special class of [2,3]-sigma tropic rearrangement which involves an α-oxy carbanions as the migrating terminus to afford various types of homoallylic alcohols.

1. The [2,3] – Wittig Rearrangement Dr. K. RAJENDER REDDY D-206, Discovery Laboratory, Organic Chemistry Division III IICT, HYDERABAD 1

2. Contents 2 Introduction [1,2] vs [2,3]-shifts Scope and limitations [2,3]-Wittig Rearrangement: Olefinic Stereoselection Diastereoselectivity of the [2,3]-Wittig Rearrangement Asymmetric [2,3]-Wittig Rearrangement Variants of the [2,3]-Wittig rearrangement Summary and conclusions

3. Introduction The [2,3]-Wittig rearrangement is a special class of [2,3]-sigma tropic rearrangement which involves an α -oxy carbanions as the migrating terminus to afford various types of homoallylic alcohols. This type of carbanion rearrangement possesses synthetically valuble features. (a) the regiopecific carbon-carbon bond formation with allylic transposition of the oxygen function, (b) the stereoselective formation of a new olefinic bond, and (c) the stereoselective creation of vicinal centers. 2 Takeshi Nakai .; Katsuhiko Tomooka . Pure & Appl. Chem ., 1997 , 69 , 595-600

4. Mechanism After carbanion formation, the [2,3]-Wittig rearrangement is rapid and selective at low temperature . [2,3]-Sigma tropic rearrangement – general scheme Y: anion, hetero atom with lone pairs, ylide Bases: LDA, n- BuLi , PhLi , ROLi , NaNH 2 /NH 3 R should be a carbanion-stabilizing group Driving force is commonly to quench a charge or to transfer charge to a more stabilizing atom 4

5. Initial Discovery Wittig (1949) and Stevens (1960): Wittig, g., Doser, H., Lorenz, I. Leibigs Ann. Chem. 1949, 562, 192. Cast, J., Stevens, T. S., Holmes, J. J. Chem. Soc., Abstracts 1960, 9, 763. [2,3] and [1,2] – Wittig rearrangement often compete [1,2]- Wittig Rearrangement: Wittig and Löhmann (1942) 5

6. [1,2] vs [2,3]-shifts [1,2]/[2,3] rearranged product ratio depends on structural environment and reaction temperature Lower temperatures typically minimize contamination by the [1,2] – product, if the reaction mixture is allowed to reach temperatures above -60 o C, [1,2]-rearrangement becomes competitive. 6 Rautenstrach , V., J. Chem. Soc., Chem. Commum . 1970 , 4

7. Scope and Limitations The fundamental requirement for the Wittig rearrangement is, the ability to generate the appropriate carbanion in the substrate Conflicting results have been reported – rationale not completely 7 Still;, C., Mitra, A . J. Am. Chem. Soc . 1978 , 100 , 1927 .

8. [2,3]-Wittig Rearrangement: Olefinic Stereo selection In general there is a strong preference for the (E) isomer 8 Mikami, K.; Nakai, T. Chem. Rev . 1986 , 86 , 885 .

9. Mechanism TS analysis: The group attached to the carbanion can occupy either a psuedoequatorial or pseudoaxial position although the former is preferred 9

10. Olefinic stereo selection Still variant of the [2,3] – Wittig Rearrangement Useful for synthesizing Z – trisubstituted homoallylic alcohol Differs in method of anion preparation 10 Still;, C., Mitra, A. J. Am. Chem. Soc . 1978 , 100 , 1927.

11. [2,3]-Wittig-Still Rearrangement Z-selectivity only applicable to tetra substituted olefin product There is a dramatic decrease in preference for TS A when the vinyl methyl group replaced with a hydrogen atom TS analysis of Z-selectivity 11 Still, C., Mitra, A . J. Am. Chem. Soc . 1978 , 100 , 1927.

12. 12 Diastereoselectivity of the [2,3]-Wittig rearrangement Mikami, k., Azuma, K., Nakai, t. Chem. Lett . 1983, 1379 . Degree of diastereoselectivity depends on substituents R Ally propargyl ethers have illustrated remarkable levels of diastereoselectivity General trends

13. Asymmetric [2,3]-Wittig Rearrangements Chirality transfer with high E selectivity (Z)-olefins are typically more stereoselective due to A-1,3 strain 13

14. Asymmetric [2,3]- Rearrangements First example of an asymmetric [2,3]- Wittig rearrangement: 14 Nakai, T. et al. Tet. Lett . 1993 , 34 , 5923 .

15. Asymmetric [2,3]-Wittig Rearrangements 15 Synthetic applications: 1. Astrophylline synthesis 15 Blechhert . J. Org. Chem . 2003 , 68 , 2913.

16. Asymmetric [2,3]-Wittig Rearrangement 2. Stereo controlled formation of two chiral centers and one diastereomeric centre in the product based on the chiral centre and double bond geometries of the starting material. 16 Sayo , kithara, Nakai , Chem. Lett . 1984 , 259.

17. Asymmetric [2,3]-Wittig Rearrangements 17 Y.-J. Li et al. Tetrahedron: Asymmetry 2009 , 20 , 1854-1863. 3. Synthesis of (+)- Eldanolide

18. Asymmetric [2,3]-Wittig Rearrangement 4. Synthesis' of a versatile anti, anti stereotriad building block The building block was converted to the “B-2” intermediate in Miyashita’s synthesis of scytophycin C. 18 Kathyln A. Parker and Qiuzhe Xie . Org. Lett . 2008 , 10 , 1349-1352.

19. 5. synthesis of functionalized taxane skeleton 19 J. S. Yadav . et al. Tet . Lett . 1991 , 32 , 2629-2632 . Asymmetric [2,3]-Wittig Rearrangement

20. Variants of the [2,3]-Wittig Rearrangement Replacement of the allyl migrating group by a propargyl group affords allenic alcohols 20 Huche , M.; Cresson, P. Tet . Lett . 1975 , 367 . Cazes , B.; Julia, S. Synth . Commum . 1977 , 7 , 273.

21. Variants of the [2,3]-Wittig Rearrangement Aza-[2,3]-Wittig rearrangement : Reaction is slower than the oxygen variant because the N-anion is less stable than the O-anion (less thermodynamic driving force) Lewis acids can sometimes facilitate the rearrangement 21 Kessar, S. etal. Tet. Lett . 1995 , 36 , 8481.

22. Variants of the [2,3]-Wittig Rearrangement Release of ring strain can be used to accelerate the reaction Formation a N- ylide has been shown to effect the rearrangement 22 Coldham , I. et al. Tet . Lett . 1995 , 36 , 3557. Coldham , I. et al . J. Chem. Soc., Perkin Trans. I , 1998 , 2817.

23. V ariants of the [2,3]-Wittig Reaarrangement Oxonium ylide rearrangements TS analysis: 23 Marshall, J. Comp. Org. Syn ., 6, 873.

24. Summarry and Conclusions This [2,3] – Wittig rearrangement has high potential and wide applicability in asymmetric synthesis. A variety of allylic ethers undergo the Wittig rearrangement, the fundamental requirement is the ability to generate the appropriate carbanion in the substrate. The [2,3] – Wittig rearrangement provides versatile synthetic tools for various classes of highly diastereo- and enantio enriched homoallylic alcohols. When the [2,3] – Wittig rearrangement proceed with generation of two stereogenic centres , high diastereoselectivity is observed. For allyl ethers in which the activating group is a phenyl, allyl , or propargyl substient , (Z)- olefinic ethers predominantly give syn- homoallylic alcohols, while the (E) substrates afford anti products. The [2,3]- Wittig rearrangement currently enjoys widespread application in many facets of organic synthesis, particularly in the context of acyclic stereocontrol and natural product synthesis. ` 24

25. Acknowledgments 25 Dr. G. V. M. Sharma Dr. P. Radha krishna Scientists, Organic Division-III Director, IICT UGC Friends.

26. 26 THANK YOU