Diastereoselective Diels Alder Reactions: Chiral Dienes. Diastereoselective Attack of Electrophiles on Chiral Olefins. 01-Diels-Alder 3/19/02 2:03 PM

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1 Diastereoselective Diels lder eactions: hiral Dienes Diastereoselective ttack of Electrophiles on hiral lefins 1. Diels lder reactions 2. alogenation and related electrophilic additions 3. eactions of allylsilanes 4. ydroborations 5. smylations Mick Dart Evans Group Seminar Tues. Jan. 18, 1994 ther dienophiles also give adducts derived from endo addition to the hydroxyl D. Jones, J.. S. hem. omm. 1980, 739. ehre's Proposal: Based solely on electrostatic considerations Electron ich Substituents have lone pairs (, N 2, S, S 2 ) Electron Poor Substituents: Si 3 (electropositive) Electron ich Electron Poor Syn nti Kahn & ehre, J. m. hem. Soc. 1987, 109, PhN (99%) NPh Stereocontrol: (1,3) strain Diastereoselection 91 : 9 (73%) Diastereoselection >95 : 5 pposite diastereofacial selectivity is observed with acrolein. Trost, J. rg. hem, 1989, 54, Diels-lder 3/19/02 2:03 PM

2 Diastereoselective Diels lder eactions: hiral Dienes Si 2 Ph PhN Ph, 60 2 days (96%) NPh Si 2 Ph Si 2 Ph NPh 2 2 Si 2 Ph Ph, days (72%) 2 2 Si 2 Ph 2 2 Si 2 Ph Fleming, JS Perkin Trans, 1989, Diastereoselection 82 : 18 Fleming, JS Perkin Trans, 1989, Diastereoselection >99 : 1 Si 3 PhN Ph, rt 10 days (90%). Franck, J. m. hem. Soc. 1988, 110, 3257 ationalization for diastereofacial selectivity: Si 3 NPh Diastereoselection 12 : 88 Si 3 NPh Ph, days (62%) Si 3 Si 3 Si 3. Franck, J. m. hem. Soc. 1988, 110, 3257 Diastereoselection 27 : 73 llylsilane llylic her inside outside Si 2 Ph Si 2 Ph Si 2 Ph 2 2 Si 2 Ph Ph 2 Si Ph 2 Si 2 Favored diene conformers in reactions with acetylenic dienophiles 2 3 Si Si 3 Si 2 Si 3 3 Si See ouk & o-workers Science, 1986, 221, Diels-lder 3/19/02 1:59 PM lso see. Kozikowski, J. m. hem. Soc. 1987, 109,

3 onditions Kinetic Thermodynamic odolactonization NS, l 3, 25 3 equiv 2, N, (cis : trans) 75 : 25 9 : 91 2, /TF 3 = 2-2 Gauche B is more destabilizing than gauche B 2-2 odolactonization of allylic alcohols Substrate Bartlett, J. m. hem. Soc. 1978, 100, Major Product = = = = Selectivity 93 : 7 95 : : : : : : 5 Yield (%) Kinetic conditions: 3 equiv 2, aq Na 2 3, 2, 0 Bartlett's "thermodynamic conditions" produced complex mixtures Protection of the hydroxyl group (TBS or c) does not affect selectivity hamberlin, J. m. hem. Soc. 1983, 105, odolactonization 3/19/02 2:00 PM = t- V(acac) 2 (1,2) strain 2, /TF 3 Gauche is now more destabilizing than gauche B preference for "inside alkoxy" is observed in these cyclizations - 2 B K 2 3 Lactonization atio = 96 : 4 Epoxidation atio = 3 : 97 2 atio >95 : 5 (49%) low yield due to δ-lactone formation hamberlin, J. m. hem. Soc. 1983, 105, ow can the above results be rationalized? atio 96 : 4 (85%) - 2 2

4 odo diol formation from allylic alcohols Substrate Major Product Selectivity Yield (%) c 98 : 2 78 c 95 : 5 90 c 94 : 6 85 ' 2, gc Gauche B is more energetically destabilizing than gauche Model for Stereoinduction? B major nalysis: D.. Evans, hem. 115, Lecture 23, Dec. 16, 1993 c ' ' ' c c minor c ' 80 : 20 Prevost conditions: 2 equiv 2, 2 equiv gc, TF, 78 0 ther conditions: 2, TF/phosphate buffer; 2, TF, aq Na 2 3 provide 1,3 diols in very high selectivity 2, gc 2 B 2 igh selectivities are also observed with allylic ethers (, Bn, TBS) hamberlin, Tetrahedron 1984, 40, Gauche is now more destabilizing than gauche B ytovaricin Synthesis TPS 2, TF aq K 2 P 4 TPS Diastereoselection 96 : 4 atio 80 : 20 perfect regioselectivity Place the medium size group ( ) outside and the small group ( ) inside 04-ododiol formation 3/19/02 2:00 PM Evans, Kaldor, Jones, J. m. hem. Soc. 1990, 112, , /TF 3 Poor regioselectivity affords a mixture of products

5 complete turnover in olefin diastereofacial selectivity is observed when adding internal and external nucleophiles For a review of elctrophilic induced olefin cyclization reactions see: G. ardillo & M. rena, Tetrahedron 1990, 46, "Facial preferences in electrophilic addition reactions are not invariant with respect to the location of the transition state along the reaction coordinate." cis : trans 95 : 5 hamberlin & ehre's ationalization ratio 99 : 1 General bservation: For electrophiles that react via onium intermediates ( 2, Br 2, g(c) 2, PhSel), the major diastereomer from electrophile-induced cyclization is opposite to that observed in the analogous intermolecular electrophilic addition. Favored groundstate conformer More reactive ground-state conformer ehre's nalysis Nu Disfavored π complex Nu 2 2 Favored π complex ddition product Favored iodonium ion Disfavored iodonium ion hange in diastereoselectivity is a consequence of a change in the rate-limiting step ddition reactions: Formation of an onium ion intermediate (subsequently trapped by a Nu from the medium) yclization reactions: ntramolecular attack on a π complex (not an onium ion) nalysis of the stereoselectivity of electrophilic addition to chiral olefins: 1. elative abundances of conformational minima 2. elative reactivities of the available forms 3. Stereoselectivies of the individual conformers hamberlin & ehre, J. m. hem. Soc. 1987, 109, For a review of the halogenation reaction see: ndy atz, Evans Group Seminar, Synthetic and chanistic eview of Electrophilic alogenation, May 7, odolact/ehre 3/19/02 2:00 PM yclization product ouk: rgument for the "inside alkoxy effect" in π complex formation π complex cyclizes if contains a Nu and its formation is rate determining nium ion formation is rate determing in the addition reactions "The presence or absence of an internal nucleophile acts to determine the stereochemical outcome of the reaction by modifying the nature (timing) of transition state.

6 Diastereoselective Functionalization of (E) llylic lcohols alogenation xymercuration Sulfenylation ydroboration D.. Evans, hem. 115, Lecture 23, Dec. 16, , gc Gauche B is more energetically destabilizing than gauche n- g(c) 2 PhS l 2 Zn Til 4 PhS l 2 Zn Til 4 major hamberlin, Tetrahedron 1984, 40, TBS ' Ph S eetz, ngew. hem. nt. Ed. 1987, 26, n- 06-xymercuration 3/19/02 2:01 PM n- ThexylB B g TBS c ' ' ' c c SPh minor atio = 99 : 1 (40%) TBS n- atio = 50 : 50 (77%) c : = 80 :20 t least 3 major products SPh SPh ' gc xymercuration of cyclic allylic alcohols: g(c) 2 ' Giese, Tet. Lett. 1985, 26, 1197 L g(c) 2 NaB 4 g(c) 2 odohydroxylation of these substrates is not regioselective NaB 4 gc ' ' atio yield - 76 : 24 65% - 93 : 07 72% -Ph 88 : 12 66% -t 98 : 02 70% -acetate participation will turn over the stereochemical course of the rxn Bz Disfavored L g L L Bz g : = 77 : 23 Favored ehre's model could be invoked to explain turnover in π facial selectivity ' L g ' gc L Bz g L L ' L gc

7 Stereochemical Model For Electrophilic ttack on llylsilanes Electrophilic ttack on llylsilanes Model assumes: 1. Electrophilic attack to the silyl moiety 2. The silyl group is the "large" substituent Epoxidation Ph 2 Si mpb Ph 2 Si Ph 2 Si Path Si 3 ' Path B The products on the left correspond to attack by Path i Pr P atio 61 : 39 >95 : : 11 ' ' yclopropanation Ph 2 Si l 3 Ph 2 Si Ph 2 Si Si 3 Si El ' El El El ' Si 3 Si 3 smylation i Pr P atio 58 : 42 >95 : : 09 Ph 2 Si s 4 Ph 2 Si Ph 2 Si El El f, then Path dominates due to (1,3) strain f =, then Path B can compete 07-llylsilanes 3/19/02 2:01 PM ' Scott J. Miller Evans Evening Seminar, "The hemistry of llylsilanes and the β Silicon Effect," Dec 11, 1990, p 45. Paddon-ow, ondan, and ouk JS , ' i Pr P atio 34 : : : 08 Larger groups result in higher selectivity The size of is more important in locking the substrate into the conformation leading to Path than in shieldieng the El Fleming, JS Perkin Trans, 1992,

8 Model for Diastereoselective ydroborations Dave Evans, hem 115, Lecture 22, Dec 14, 1993 Diastereoselective ydroboration Examples L M 2 B Bad M L B Worse B M L 2 B Favored product for dialkyl borane reagents L M L M M. M. Midland & o-workers, J. m. hem. Soc. 1983, 105, B B 3 DMS ThexylB 2 9 BBN (hx) 2 B Selectivity 50 : : : : 04 turnover in diastereofacial selectivity is sometimes observed using B 3 ydroboration of allylic alcohols (ethers) ' M B B ' 9 BBN B 3 M M L 2 2 ' L L L M M L W.. Still & J.. Barrish, J. m. hem. Soc. 1983, 105, B 3 TF n ipr n n n ' Selectivity 92 : : 04 TMS 91 : 09 c 88 : : 58 ssume (') = m and results are consistent with the model K. N. ouk, M. N. Paddon-ow, & o-workers, Tetrahedron 1984, 40, ydroboration Models 3/19/02 2:01 PM

9 Diastereoselective ydroborations Erythronolide thesis: nnette Kim TBS 3 ThexylB 2 TF, 0 rt 12 h Diastereoselection 93 : 7 2:1 mixture of the lactol:lactone was obtained. This mixture was oxidized to the keto-lactone in 73% overall yield from the olefin. Lonomycin thesis: ndy atz (60%) TBS TBS P Diastereoselection > 95 : 5 () Bn. Paterson & J. hannon Tetrahedron Lett., 1992, 33, Bn 5 Diastereoselective ydroborations Bn Bn Bn Bn Bn B 3 TF unexpectedly provided the isomer in high selectivity Bn Bn B 3 TF B 3 TF : 85 : : 95 Bn : 95 : 05 >95 : 05 Bn Bn yield 70% 84% yield 74% 89% P nti selective hydroborations with borane B 3 DMS (85%) Diastereoselection 92 : 8 () The sense of asymmetric induction is completely turned over in ndy's reaction when using 2 B B 3 P K. Mori Tetrahedron 1979, 32, B 3 TF Diastereoselection 92 : 8 () Bn Bn Bn B 3 TF Nakata, Tatsuta & o-workers, ll. hem. Soc. Jpn., 1992, 65, (hx) 2 B B 3 DMS : 82 : : 83 yield 80% 99% Bn ikawa & o-workers Tetrahedron Lett., 1983, 19, Bn = Diastereoselection 6.8 : 1 () = Bn Diastereoselection 6.6 : 1 () 09-ydroboration-2 3/19/02 2:02 PM

10 The atalyzed ydroboration lefin binding to metal is irreversible for 1,1-disubstituted allylic alcohol derivatives lefin catalyst complexation is the stereochemistry-determining step Evans & Fu J 1990, 55, 2280 and Evans, Fu, nderson JS 1992, 114, The atalyzed vs Uncatalyzed ydroboration eactions Stereochemical Model i-pr TF 20 i-pr nti i-pr Syn hl n ' h cat B ' h cat B ' hl n onditions nti : Syn Si(t-)Ph 2 Si(t-) 2 h(pph 3 ) 3 l / B h(pph 3 ) 3 l / B h(pph 3 ) 3 l / B 95 : 5 3 : : 5 15 : : 4 50 : 50 Yield (%) ' omplexation involves back-donation from a filled metal d orbital π* = The EWG (alkoxy substituent) is aligned perpendicular to the olefin (π σ* ) This stereoelectronic interaction lowers the energy of π* The small group is placed "inside", the most sterically congested site ' omplementary diastereoselectivity for the catalyzed and uncatalyzed reactions is observed for a wide range of substrates. The uncatalyzed variant: El El Evans, Fu, & oveyda JS 1988, 110, 6917 and JS 1992, 114, ' ' ' ' ' 10-at ydroboration 3/19/02 2:02 PM K. rgess & o-workers, J. rg. hem. 1991, 56,

11 (z) lefins Bn () () Diastereoselective smylations s 4 Bn 2 Bn s 4 Bn Bn selectivity 50 : : 14 (z) lefins s 4 Diastereoselective smylations s 4 ddition occurs to the allylic heteroatom functionality selectivity Ph 2 Si 78 : 22 PhS 2 80 : 20 PhS 83 : 17 TBS 62 : 38 c 70 : 30 Vedejs argues that hyperconjugative effects are not important because both EDG and EWG provide the same sense of induction Kishi's Empirical Model: rrange olefin in the stable ground state conformer s 4 attacks to the allylic oxygen substituent Works for both (Z) and (E) allylic ethers (alchols) (E) lefins s 4 (E) lefins Bn s 4 Bn s 4 Kishi Model Ph 2 Si PhS 2 PhS TBS c selectivity 34 : : : : : 38 llylic oxygen protecting group:, Bn, Si 3, acetonides all work well cetates give lower selectivity Bn selectivity 60 : : 19 Kishi & o-workers Tetrahedron Lett., 1983, 24, 3943 and Tetrahedron, 1984, 40, James Barrow, Evans Group Seminar, "smium diated Dihydroxylation: chanism and pplication" pril 21, Vedejs Model s 4 s 4 = TBS, = S, S 2, Si 3 11-smylations 3/19/02 2:02 PM E. Vedejs &. Mclure JS, 1986, 108, 1094.

12 Diastereoselective smylations Ph 2 Si Ph 2 Si s 4 Ph 2 Si i Pr P Ph 2 Si atio 34 : : : 08 s 4 Fleming, JS Perkin Trans, 1992, Vedejs model breaks down or ipr, Ph > 2 PhSi ouk Model: Staggered transition states s 4 "inside alkoxy" s 4 xygen avoids "outside" position to avoid repulsive electrostatic interactions with the incoming s 4 ouk, JS, 1986, 108, smylation 3/19/02 2:02 PM