2,3-Sigmatropic Rearrangements in Organic Synthesis

Transcription

1 2,3-igmatropic Rearrangements in rganic ynthesis ctober 25, 2006 Matt aley Crimmins roup

2 igmatropic Rearrangements -concerted pericyclic reactions traditionally thought to be governed by orbital symmetry -a group attached by a sigma bond migrates to the terminus of an adjacent pi-electron system 2,3-sigmatropic rearrangements: -can be defined as a thermal isomerization that proceeds through a six-electron, five-membered cyclic transition state -thermally allowed sigmatropic process according to the Woodward-offman Rule* X X Y X Y Y 5-membered cyclic transition state 2,3-sigmatropic rearrangements discussed: -2,3-Wittig rearrangements -Mislow-Evans rearrangement -Additional 2,3 rearrangements *Chem. Rev. 1986, 86,

3 2,3-Wittig Rearrangement (anionic) -regiospecific carbon-carbon bond formation and allylic transposition of oxygen function -generation of specific olefin geometries -stereoselective creation of vicinal chiral centers -transfer of chirality -competition is seen with 1,2-shift, dependent on substrate structure and rxn temperature Diastereoselection tudy = C C C = Ph C C C TM n-buli TF, -85 C n-buli TF, -85 C 99% ee 99% ee 95~98% ee 100% ee 100% ee threo erythro A general trend is observed that E-alkenes show threo selection and Z-alkenes show Erythro selection. Exceptions include ubstrates where = C 2 and Ph Chem. Rev. 1986, 86,

4 Diastereoselectivity: Proposed Transition tates akai and Mikami Marshall, ouk, and Wu Transition structure based on MP2/6-31+ computations: endo exo erythro threo Cation plays large role π-acceptors like carbonyls and electropositive groups like silyl ethers prefer endo position sterics place substituents preferentially in the exo position Chem. Rev. 1986, 86, J. rg. Chem. 1990, 55,

5 C arcodonin -diterpenoid from the cyathane family -characterized by Ayer and Taube in anti-fungal and promotes synthesis of nerve growth factor CA (equil.) 71% (2 s teps) 1. K DA, 3 e I 2. A c, aa c, 2 69% (2 steps ) 3 e 1. a, 66% 2. LDA, I, 85% 3. I, 90% 4. BuLi, 86% K, Bu 3 nc 2 I nbu 3 Piers, et al. rganic Letters, 2000, 2,

6 BuLi quench 88% (2 steps) Piers, et al. rganic Letters, 2000, 2,

7 Completion of arcodonin 1. K, PMB Cl, 96% 2. s 4, ai 4, 65% 3. a, (Et) 2 C, 74% PM B TBA F; C 2 I 2 C 2 E t 78% PM B I C 2 E t mi 2 PM B C 2 E t P MB 1. DIB Al 1. piper idine, P h ecl 2. DM P 2. KI 4, 78% (2 steps) C 2 Et 86% (2 steps) PM B C 3. DB, 95% 4. DDQ, 91% C Piers, et al. rganic Letters, 2000, 2,

8 Mislow-Evans (neutral) R 3 P: R R R -it is proposed that the rearrangement proceeds exclusively through a concerted mechanism -equilibrium lies largely to the left, sulfonate not detectable by MR -increased heating can result in 1,3-shift of sulfoxide: Ph! Ph Acc. Chem. Res. 1974, 7,

9 lefin eometry R 4 R 1 R 2 R 3 X R 4 R 1 s R 2 R 3 X R 2 R 1 R 4 R 3 X R 1 > R 2 There is a very high E-olefin selectivity when there is substitution β to the sulfoxide (substitution at R 1 ) J. rg. Chem. 1989, 54,

10 ynthesis of the Imine Ring ystem of Pinnatoxins R Pinnatoxins: A: R = C 2 C: R = B: R = C C 2 - -pinnatoxins structurally elucidated by Uemura et al. in structurally unique cyclic imine, stable to aqueous acids Piv PMB cascade Claisen-Mislow-Evans PMB Piv PMB Ac rganic Letters, 2005, 7,

11 Construction of Cascade Reaction Precursor Piv TIP from ascorbic acid 1. MgB r, 93% 2. s 4, ai 4 3. TP AP, M, 68% ( 2 s teps) TIP 1. LA, 98% 2. a, PivCl 3. I 2, Ph 3 P, Im, 74% (2 steps) Piv 1. LDA; Et 2 Zn; A, DM PU 2. P htf 2, KMD 80% (2 steps ) A I Tf TIP Piv 1. P MB C 2 C 2 C 2 ZnX, Pd 0, 75% 2. TB AF, 91% Piv Tf TIP 3. wern 4. ( )-m ethyl p- tolyl s ulfox ide, LDA 5. TM Cl, K M D 6. LDA, 65% (4 steps) PMB rganic Letters, 2005, 7,

12 Cascade Claisen-Mislow-Evans Piv PMB (Et) 3 P, s-collidine C 2 C 2 C C, 15h, ~90% PMB Piv A r() R 1 P iv P iv R 2 P MB A r P MB A r Piv Piv Ac PMB PMB PMB Ar can be done in microvave in 20 min with ~10% yield hit (Et) 3 P: rganic Letters, 2005, 7,

13 Additional 2,3-igmatropic Rearrangements ynthesis of (+)-Milbemycin D (+)-Milbemycin D TIP TM TB + P h 3 P TB DP -milbemycins first reported in 1975 by Mishima -among the most potent antiparasitic and insecticidal agents known -notable synthetic challenges include spiroketal moiety and hexahydrobenzofuran Crimmins et al. J. Am. Chem. oc. 1996, 118,

14 Preparation of 2,3-Rearrangement Precursor 1. P h 3 P=CC 2 Et, 98% 2. LA 3. TB Cl, 95% (2 steps ) TB 1. C CC, 98% 2. LA, 98% TB + TB 1. AE 2. wern 3. MgCl 4. wern 73% ( 4 steps) TB + TB 1.5 : 1 TB LDA, TM Cl TM TM TB m CPB A 60% (2 steps ) TB PheCl, 78% TM R TB ep h Crimmins et al. J. Am. Chem. oc. 1996, 118,

15 Rearangement and Endgame R TB 2 2 ep h 66% ( 2 steps) R TB Ph e R e Ph TB Ph e TM TB wor kup TM TB TM TB TIP TM TB + P h 3 P TB DP 1. Li-LiBr 2. I 2 (73% 2 steps ) T IP TM TB T BDP Crimmins et al. J. Am. Chem. oc. 1996, 118,

16 Additional 2,3-igmatropic Rearrangements Cont d ynthesis of Bakkenolide A Bakkenolide A -Approximately 50 bakkanes isolated from plants to date -they are sesquiterpenoids possessing a cis-hydrindane skeleton with two quat. centers -biological activities include selective cytotoxicity, antifeedant effects and inhibition of platelet aggregation rganic Letters, 2004, 6, 3345 J. Am. Chem. oc. 1977, 99, 5453

17 ynthesis of Bakkenolide A CnC 4 9 Cl KotBu 84% CnC 4 9 K 78% + s 4, ai 4 46% only s yn pdt taken on 1. K tbu, 63% 2. 2 /Pd-C, 93% 60% Li PB r 3 Br Br a C C 3 75% (2 steps) C 3 Ts J. Am. Chem. oc. 1977, 99, 5453

18 2,3-igmatropic Rearrangement ynthesis of Bakkenolinde A a C 3 Ts 62% Ts C 3 T s C 3 Ts C 3 C 3 C 3 g, gcl 2, 2 C 3 2 e 3

19 Additional Interesting 2,3 Rearrangements Ar= Fe 2 ear* mcpba or Ti(iPr) 2, DIPT Ts ( ) n Cu(acac)2 ( ) m C 6 6, reflux 2 ( ) n ( ) m R = Ph er, tbucl, then TsLi * Ts 90% ee 2 Cu(acac) 2 C 6 6, reflux Angew. Chem. Int. Ed. 2000, 39, 3740 J. Chem. oc., Perkin Trans , 3325