IE. Allylations & CrotylationsI. Basic PrinciplesReviews:Marek, I.; Sklute, G., "Creation of quaternary stereocenters in carbonyl allylation reactions."Chem. Commun. 2007, 1683-1691.Merino, P.; Tejero, T.; Delso, J. I.; Mannucci, V. "Stereoselective allylation reactions of iminesand related compounds." Curr. Org. Synth. 2005, 2, 479-498.Kennedy, J. W. J.; Hall, D. G. "Recent advances in the activation of boron and siliconreagents for stereocontrolled allylation reactions." Angew. Chem., Int. Ed. 2003, 42, 4732-4739.Denmark, S. E.; Fu, J. P. "Catalytic enantioslelective addition of allylic organometallicreagents to aldehydes and ketones." Chem. Rev. 2003, 103, 2763-2793.Roush, W. R. Comprehensive Organic Synthesis 1991, vol. 2, p. 1.MXDr. P. WipfPage 1 of 601/26/2008M = B, Al, Si, Ti, Cr, Zr, Zn, Sn, In, Ba,.....Retrosynthetic SchemeHOROHMH ROHOROHMH ROROHHOROHMH RO+NaIO4/OsO4 (J-L) or O3allylmetalation+syn-crotylmetalation+anti-crotylmetalationDr. P. WipfPage 2 of 601/26/2008Early WorkPioneering papers on the stereocontrolled use of allylicorganometallics were reported by• Hiyama - Buse and Heathcock, THL 1978, 1865. Cr• Brown - Hoffmann and Zeiss, Angew. Chem. Int. Ed. Engl. 1982, 18, 306.B• Yamamoto et al., JACS 1980, 102, 306. SnDr. P. WipfPage 3 of 601/26/2008Boeckmann’s Synthesis of Calcimycin (JACS 1987, 7553)OCH3OHONHNONHCH3HO2CDr. P. WipfPage 4 of 601/26/2008Lowe, J. T.; Wrona, I. E.; Panek, J. S., "Total Synthesis ofBistramide A." Org. Lett. 2007, 9, 327-330.SiMe2PhCO2MeOTMS(Z)-(2S, 3S)-Crotylsilane[4+2]-Annulation[4+2]-AnnulationOOHNHHNOHOH OOOOHCO2MeOTMSSiMe2Ph(E)-(2S, 3S)-Crotylsilanebistramide AChelation-ControlledCrotylationCO2MeSiMe2Ph(E)-(3R)-CrotylsilaneDr. P. WipfPage 5 of 601/26/2008OOH HONHHNOHOOOOHbistramide A94131522393431Peptide couplingWittig olefinationOOH HOOH9413H2NOTIPSTBSO O15OOOTBS22393431H2NSpirocyclizationCO2MeOTMSSiMe2PhCO2MeSiMe2PhCO2MeSiMe2PhOTMSO CHOBnOH OMe22OTBS3934PMBOPh3P31Dr. P. WipfPage 6 of 601/26/2008Preparation of cis- and trans-Silyl Epoxy EstersSiMe2PhOTHP1) PPTS, THF2) m-CPBA, CH2Cl23) PS-D Lipase, vinyl acetateOPhMe2SiOAcOPhMe2SiOH1) MeOH, K2CO32) RuCl3-H2O, NaIO4, CH3CN/CCl4/H2O3) DCC, DMAP, CH2Cl2, MeOH 3 steps 76%OPhMe2Si CO2MeLowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 3231-3234.Al(Et)2Hexanes80%OHCO2MeSiMe2Ph1) 5%Pd/C-CaCO3-PbO, EtOAc2) TMSOTf, 2,6-lutidine, CH2Cl2 2 steps 82%CO2MeOTMSSiMe2PhDr. P. WipfPage 7 of 601/26/2008Preparation of cis- and trans-Silyl Epoxy EstersAl(Et)2Hexanes74%OHCO2MeSiMe2Ph1) 5%Pd/C-CaCO3-PbO, EtOAc2) TMSOTf, 2,6-lutidine, CH2Cl2 2 steps 85%CO2MeOTMSSiMe2PhOPhMe2SiOH1) RuCl3-H2O, NaIO4, CH3CN/CCl4/H22) DCC, DMAP, CH2Cl2, MeOH 2 steps 77%OPhMe2SiCO2MeDr. P. WipfPage 8 of 601/26/2008Comparison of (E)- and (Z)-Crotylsilanes in [4+2]-AnnulationOTMSCO2MeSiMe2PhEHSiR3HRHHO RMeO2CHH5,6-trans2,6-transSiMe2PhOTMSCO2MeEHSiR3HRMeHSevere A 1,3 interactionO RMeO2CHH5,6-cis2,6-cisHR3SiHEHHRMinimize A 1,3E = CO2MeSiR3 = SiMe2PhDr. P. WipfPage 9 of 601/26/2008OTMSCO2MeSiMe2Phanti-(Z)-crotylsilaneR-CHOOMeO2C RH H5,6-cis2,6-cisOTMSCO2MeSiMe2Phsyn-(Z)-crotylsilaneR-CHOOMeO2C RH H5,6-cis2,6-transComparison of (E)- and (Z)-Crotylsilanes in [4+2]-AnnulationDr. P. WipfPage 10 of 601/26/2008OTMSCO2MeSiPhMe2OH OBnTMSOTf,CH2Cl2, -50 oC66% dr 12:1O OBnH HMeO2C(dr=12/1)1) H2, PtO2, MeOH2) TBDPSCl, Et3N, CH2Cl23) LiBH4, Et2O 3 steps 74%OH HOTBDPS1) (CH3O)3P+CH3 -I2)S S, n-BuLi,HMPA, THF2 steps 86%SSOH HOTBDPSOH1) Dess-Martin2) HF, CH3CN 2 steps 69%OH HOHOCrO3, H5IO4CH3CN/H2O85%OH HOHOOSynthesis of the C1-C13 Fragment of Bistramide ADr. P. WipfPage 11 of 601/26/2008Regioselectivity of AllylationYanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H., "Allylbarium reagents:Unprecedented regio- and stereoselective allylation reactions of carbonylcompounds." J. Am. Chem. Soc. 1994, 116, 6130-6141.MPhCHO, -78 °CPhOH!-product+Ph"-productOHM: Li: 47 : 53K: 67 : 33Mg: 1 : 99Ca: 12 : 88Sr: 54 : 46Cu: 45 : 55Ce: 72 : 28Ba: 92 : 8Dr. P. WipfPage 12 of 601/26/2008The stereochemical outcome of allyl-metal additions can be classified intothree groups:- I. the syn/anti ratio of the products reflects the Z/E geometry of thecrotyl moiety (B, Al, Sn, Si (Δ-reactions)).- II. syn-selective irrespective of olefin geometry (Sn, Si, Ti).- III. anti-selective irrespective of olefin geometry (Ti, Cr, Zr, In, Zn).Dr. P. WipfPage 13 of 601/26/2008Caveat:SnBu3CHO+TiCl4OH+OHadd stannane last: 93 : 7add aldehyde last: 5 : 95→ transmetalation, and allyl-Ti is type I reagent! (THL 1984, 25, 3927):Dr. P. WipfPage 14 of 601/26/2008configurational stability: important for synthesis of type IorganometallicsMgBrMgBrviaMgBrfastLiLifastKKslow in absence of O2e.g.KtBuOKBuLiKtBuOKBuLiDr. P. WipfPage 15 of 601/26/2008I. the syn/anti ratio of the products reflects the Z/E geometryof the crotyl moiety (B, Al, Sn, Si (Δ-reactions)).chair TS‡Met+ RCHOOMetLLHRHROHMet+ RCHOOMetLLHRHROH(rac!)Dr. P. WipfPage 16 of 601/26/2008The dialkylcrotylboranes are the most reactive but also the leastconfigurationally stable of the allylborane reagents (borderline type III).anti synCO2ROBEt2O, -76 °C(CO2R is eq.)RO2COH+RO2CHOR = MeR = Ph73 : 2780 : 20100 : 0Dr. P. WipfPage 17 of 601/26/2008Ph HOBIpc2PhOH88% ee (>98% de)BIpc2PhOH88% ee (>98% de)JOC 1986, 51, 432JACS 1986, 108, 5919OBHRHHHOBHRHLMSSLMlargesmallminimizes steric interactions Brown’s Allylboranes:Dr. P. WipfPage 18 of 601/26/2008CH3H3C CH3(1R)-(+)-!-Pinene91.3% ee=CH3H3B•S(CH3)2THF, 0 oC72 h, 72%CH3BH2(-)-Ipc2BH98.9% eeCH3OH, 1 h0 oC, 100%CH3BOCH3298.9% eeMgBr-78 25 oC25 oC, 1 hCH3B298.9% eeProlonged incubation at 0 °C affords enantiomerically enriched Ipc2BH,due to the equilibration of Ipc4B2H2 with α-pinene and Ipc3B2H3; thesymmetrical dimer crystallizes preferentially.Dr. P. WipfPage 19 of 601/26/2008H3CCH3n-BuLi, KOt-BuTHF-45 oCKCH3(-)-Ipc2BOCH3-78 oCCH3B2OCH3CH3K+BF3•OEt2-78 oCCH3B2CH3RCHO-78 oCNaOH, H2O2ROHCH3ROHCH3The crotylboranes are used immediately after methoxide decomplexationfrom the ate complex by boron trifluoride at -78 °C to avoid crotylisomerization.Dr. P. WipfPage 20 of 601/26/2008ROHCH3ROHCH3A B-pinene aldehyde yield (%) A:B ee (%) + CH3CHO 78 95:5 90 - CH3CHO 76 4:96 92 + C2H5CHO 70 95:5 90 - C2H5CHO 69 4:96 92 + CH2=CHCHO 65 95:5 90 + C6H5CHO 79 94:6 88 Dr. P. WipfPage 21 of 601/26/2008Hoffmann, 1979:
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