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Scope and Facial Selectivity of the Prins-Pinacol Synthesis of Attached Rings

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Scope and Facial Selectivity of the Prins-Pinacol Synthesis of Attached Rings Scope and Facial Selectivity of the Prins-Pinacol Synthesis of Attached Rings By Larry E. Overman and Emile J. Velthuisen Leading Reference”J. Org. Chem. 2006, 71, 1581-1587 Presented by Zhenyu Zhong Journal Club Presentation April 3rd 2006 Presentation Outline ¾ Overview of the Prins-Pinacol Reaction ¾ Early developments of the acid-promoted Prins-pinacol rearrangement and its potential to be the key strategic element in the total synthesis of heterocyclic and carbocyclic natural products ¾ Exploration of the scope of the Prins-pinacol reaction for assembling attached rings with various sizes and ring substitutions ¾ Rationalization of facial stereoselection in the Prins cyclization ¾ Summary ¾ Future Work Zhenyu Zhong Journal Club 2 Prins Reaction: • The acid-catalyzed condensation of alkenes with aldehyde O Nuc OH OH O O H H R R R R + H 1)H2O O Nuc 2)H+ H H OH OH R H H R carbocation Condensation of formaldehyde with some unsaturated compounds H. J. Prins, Chemisch Weekblad, 16, 64, 1072, 1510 1919 Pinacol Rearrangement HO OH HO O Lewis Acid 1,2-shift R4 R1 R4 R1 R4 R 1 R3 R2 R3 R2 R3 R2 Migratory aptitude: aryl > tBu>> cyclopropyl > 2° alkyl > 1° alkyl R. Fittig. Justus Liebigs Ann. Chem. 110, 23–45 (1859). Zhenyu Zhong Journal Club 3 Serendipitous discovery of the Prins-Pinacol Reaction OH K-10 Clay OHC Acetone O OH Reflux O Pinnacol O Rearrangment H Prins cyclization HO HO O O Oxocarbenium ion β-hydroxy carbenium ion Results two C-C bonds, one C-O bond and two new stereocenters Completely Stereoselective Martinet, P.; Mousset, G.; Michel, M. C. R. Acad. Sci. Paris, Ser. C 1969, 268, 1303-1306 Zhenyu Zhong Journal Club 4 Other Examples of Prins-Pinacol Reaction R R2 3 R O R R 1 SnCl4 1) Prins Cylization 3 1 O R R1 R4 O 2) Pinacol Rearrangement R3 O R4 O R4 R and R2= CH3 or O Overman et al. J. Am. Chem. Soc. 1987, 109, 4748-4749 MeO SnCl MeO MeO 4 OTIPS H CHO MeNO2 0° C 75% Overman et al Can. J. Chem. 2000, 78, 732 Zhenyu Zhong Journal Club 5 Natural Products Containing Attached Rings • Rings joined by a C-C σ bond are prevalent in many oxacyclic and carbocyclic natural products. • Prins-Pinacol reaction, like many sequential, tandem, cascade, or domino reactions, allows the construction of such rings with high stereoselective from relatively simple starting materials. Zhenyu Zhong Journal Club 6 Early Study on Prins-Pinacol Reaction ¾ Due to A1,3 minimized chair conformer of the Z-alkene, a greater regio-selectivity can be achieved to form the desired Prins-Pinacol products as a mixture of methoxy epimers. ¾ Prins-Pinacol reaction on E-alkene shows less regio-selectivity. Zhenyu Zhong Journal Club 7 Preparation of the Prins-Pinacol Precursors MeO MeO 3 OMe OMe PdCl (dppf) 1) LAH 2 O OTIPS 2)TIPSOTf OH OTf NaOH/THF n n t-BuLi O O n=1, 65% 2steps 20: n=1, 43% 2steps Hexanes n=2, 58% 2steps 21: n=2, 42% 2steps n Tf2O n n=3, 79% 2steps 22: n=3, 27% 2steps 1a: n=1 1b: n=2 1c: n=3 4 1d: n=0 PdCl (dppf) 2 MeO 1) LAH MeO MeO NaOH/THF O MeO 2)TIPSOTf OTIPS 4= (MeO)2HC n B n n=0, 39% 2steps n=2, 66% 2steps 31: n=0, 40% 2steps n=3, 46% 2steps 32: n=2, 64% 2steps 3= 33: n=3, 50% 2steps (MeO)2HC B ¾ Relatively short sequence to prepare the (Z)alkylidenecycloalkylnols ¾ Low overall yield Zhenyu Zhong Journal Club 8 Results for Various Attached Rings systems Scope and limitations: When the starting ring is Five membered, the cation produced upon Prins cyclization would not undergo Pinacol ring contraction, due to high ring constrain associated with forming of cyclobutane ring. Zhenyu Zhong Journal Club 9 Effect of Ring substitution upon Prins-Pinacol reaction Preparation of the Precursors OH 1) t-BuLi 1) LAH Hexanes, then Tf2O MeO MeO O MeO MeO 2) 4 O 2)TIPSOTf OTIPS PdCl2(dppf) NaOH/THF 9 32% over 2 steps 73% over 2steps OH 1) t-BuLi 1) LAH Hexanes, then Tf2O O MeO MeO MeO MeO 2) 4 O 2)TIPSOTf OTIPS PdCl2(dppf) NaOH/THF 55% over 2 steps 10 87% over 2 steps OH 1) t-BuLi 1) LAH Hexanes, then Tf O O 2 MeO MeO MeO MeO 2) 4 O 2)TIPSOTf OTIPS PdCl2(dppf) NaOH/THF 11 58% over 2 steps 69% over 2 steps Zhenyu Zhong Journal Club 10 Effect of Ring substitution upon Prins-Pinacol reaction cont’d Geminally disubstituted precursor (48) give desire Prins- Pinacol products in moderate yield. Whereas the precursor (49) affords the Prins-Pinacol in a higher yield. Zhenyu Zhong Journal Club 11 Effect of Ring Substitution upon Prins-Pinacol reaction cont’d Disfavoring ring contraction of carbocation was due to the developing steric interactions between the axial methyl and pseudoaxial cyclohexyl subsitituent, thus, resulting lower yield for the desired Prins-Pinacol product. Zhenyu Zhong Journal Club 12 Prins-Pinacol Reaction on Enatiomerically Riched Precursor Zhenyu Zhong Journal Club 13 Analysis of stereochemical outcome Zhenyu Zhong Journal Club 14 Summary ¾ A variety of attached ring systems were prepared using Prins-pinacol reaction on simple precursors, cyclohexyl- and cyclopentyl triisopropylsiloxy ethers bearing (2Z)-(6,6-dimethoxyhexylidene) or (2Z)-(6,6-dimethoxyhexylidene) side chains. ¾ The facial selectivity of Prins reaction was rationalized by the through-space electrostatic stabilizing interactions between the α-alkyloxycarbenium ion and an axially positioned oxygen subsituent. Future Work ¾ Improve the efficiency for preparation of precurors of Prins-pinacol reaction. Zhenyu Zhong Journal Club 15 Acknowledgements •Dr. Wipf • All members of Chem 2320 Thank you! Zhenyu Zhong Journal Club 16.
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