Conservation of Helical Asymmetry N. Z. Burns chirality = helicity Term "chirality" coined in 1893, derived from Greek "cheir" (hand): I call any geometrical figure, or group of points, chiral, and say it has chirality if its image in a plane mirror, ideally realized, can not be brought to coincide with itself. -Lord Kelvin Molecular chirality often seen as solely a geometrical property, and thus enantioselection and asymmetric reaction design are rationalized using mostly steric-based arguments. Left-handed helix (LHH) For example: Ph Ph Me O Ph N Me B H2B vs. O Ph B N H2B H O H Favored Determining a point chiral molecule's helicity- Yin method: Me O Right-handed helix (RHH) d Me a C b Take a simple 5-atom chiral molecule whose groups have the following polarizability: a > b > c > d c Disfavored Because of this, any 2 bonds will be distorted dissimilarly, with larger distortions arising from more highly polarized groups. Are there alternatives? Each of the six distortions creates a micro-helix. Helical theory of chirality: (Wand, D. Z. Tetrahedron, 2005, 61, 7125; 7134) a C b David Zhigang Wang, graduate student of professor Thomas J. Katz at Columbia, puts forth a novel electronic theory of chiral interactions (can also think of as a chiral version of standard HSAB theory), that views all chiral molecules as helices. a>b a C b a C c How can a chiral center have helicity? a C d a>d a>c b>d c>d a C d b C d b>c C c C d C d a b>d a>c b c>d c Since all bonds at a chiral center are dissimilar, unbalanced electronic interactions arise. The magnitude of these interactions comes from the polarizability of the groups attached to the center. b C c b>c a>d b C c c C d a>b The end result is to deform the bonds into helices. The sum of these helices gives a chiral molecule a net helicity that is either right- or left-handed. The sum of these micro-helices creates an overall helix or net helicity. Here there are 4 RHH and 2 LHH resulting in a net RHH. 1 Conservation of Helical Asymmetry N. Z. Burns Quick and Dirty Helicity Determination: For axially chiral biaryls with polarizability X > Y: (works for simple cases) • Place least polarizable substituent coming out of plane • Travel from most to least polarizable substituent d a C c c Y X Y X Y X Y X b a b a b c RHH a C b b d c a a c (trace helix made by X–C–C–C–C–X) c LHH b Examples: (point thumb at least, move fingers from most to least) OH OH NH2 Polarizability rankings: • I > Br > SR > Cl > CN > Ar > C CN Me X (X = N, O) > C > NR2 > OR > H > D > F • transition metals (Rh, Ru, Pd, Ti, Os) > C, N LHH RHH • higher order bonded > lower order bonded C C > C C > C Me LHH OH C H > Me Ph O • strained alkyls > unstrained alkyls CH2 Ph OH N CH2 > MeO H2 C NO2 OH Me RHH LHH • for simple* alkyls, CH3 > CH2 > CH > C (* non-heteroatom containing alkyls) • for aromatics, electon rich > electron poor RHH SH PPh2 PhOMe > PhR > Ph > PhNO2 PPh2 Ph > Pyridine > thiazole > oxazole SH • epoxide O > C RHH • R3P > C 2 LHH B Conservation of Helical Asymmetry N. Z. Burns Principle of homohelicity- homohelical interactions are always lower in energy than heterohelical interactions. Helical argument: Some instances where simple steric arguments fail- R R R R O HN Trost desymmetrization of meso-allylic alcohols: P Pd Ph2 Ph2P Ph2P PPh2 NH NH O Ligands A and B should be isosteric: O HN O P Pd Ph2 P Ph2 ligand A = LHH P Ph2 ligand B = RHH PPh2 O HN Due to polarizability rankings, A and B are not isohelical! O NH NH O HN Furthermore, helicity accounts for absolute sense of stereoinduction: O O A OR B O However, TsN O Pd OR O 2.5% Pd2(dba)3 OR TsN A lig. A (LHH) interacts with LHH OR RHH 5-10% lig. A L2Pd LHH 99%, 88% e.e. OR OR B Pd OR 2.5% Pd2(dba)3 5-10% lig. B TsN OR TsN O lig. B (RHH) interacts with RHH OR OR O 94%, 88% e.e. R = CONHTs 3 O O Conservation of Helical Asymmetry N. Z. Burns PL = group of larger polarizability PS = group of smaller polarizability RL = larger group RS = smaller group Asymmetric Rh hydrogenations: RS P P Rh OMe Previous rationale based on sterics: Ph O RS R2BH RL RS (S)-cat. RHH P RS RL Me Rh OH (S)-cat. B P P RL Ph N t-Bu Rh P MeO H O Me RL CBS reductions: Me t-Bu How can steric arguments account for the following results with the (S)-cat.? RHH Me LHH OH MeO OH Two catalysts should have same relative sterics, however they give opposite absolute stereoinductions: O N MeO MeO2C LHH cat., H2 (+)-96% e.e. MeOH NHCOMe BF3 93% e.e. RHH cat., H2 OH OH Me Helicity argument: polarizability rankings- Me > t-Bu, PhOMe > Ph, thus two catalysts have opposite helicities: P Rh MeO PL PL P O Me OMe 51% e.e. PL LHH All products are RHH, matching (S)-CBS helicity. Rh P PS t-Bu P Rh Rh P P Me PS P OMe (i-PrO)2P 91% e.e. PS O OTBS (–)-99.9% e.e. MeOH Ph 97% e.e. PS Possible new model for CBS reductions: P PL t-Bu Ph Me O RHH PL Thus, Wang theory predicts opposite enantiomers for the two catalysts. 4 (S)-cat. PS RHH Ph N OH Me O PS B O H2B H PL PL PS RHH Conservation of Helical Asymmetry N. Z. Burns Asymmetric radical reductions: Homohelical point-to-axial chirality transfer: Chemists at Chirogen have discovered the following highly enantioselective free radical reaction (C&EN, July 14, 2003, 34-35): Me Me Br OEt OEt R*2SnHPh Me O MgBr2, -78˚ Me HO Ph HO Ph Me O Me 96 % e.e. Based on these results and the polarizability rankings, predict the product of the following reaction: O HN R*2SnHPh OBn Me HN MgBr2, -78˚ OMe CHCl3 Ph O O Ph 9:1 d.r. achiral CF3 Me Br Me 4-Å M.S. O CF3 Me OMe OBn PPh2 Me O Me O PPh2 H2 Ph2 Cl N P Ru P Ph2 Cl N H Ph H2N RuCl2 H2N Ph 2 Ph Ph Trost DYKAT of allenes (JACS ASAP): For allenes with X > X' and Y > Y': X Y' X X' O NH Y X' 2:1 d.r. achiral O Y HN Wang's proposed model for Sharpless AD: Y' RHH PPh2 LHH Ph2P RHH DHQD-cat. RHH ligand O Et O N EtO 1.1 eq n-C4H9 PS OEt n-C4H9 Me AcO 2.5% Pd2(dba)3 7.5% ligand 5% THACl O H 1.1 eq LHMDS H R PL H H C9 helix induces chirality MeO CO2Et Me R = PL or PS CO2Et 86 % 85 % e.e. (6 other examples follow prediction as well) 5 LHH DHQ-cat. Het. 2 N (DHQD)2-PHAL Conservation of Helical Asymmetry N. Z. Burns O H Me Leighton allylation (Leighton, ACIEE, 2003, 42, 946): P cat. L2Ru OH H2 Ph dissociation Ru P H O Ph H O OH Me O Me Ph Br homohelical interaction Homohelical adduct is lower in energy, hence less reactive leading to unreacted material. O OH N Ph H Si Ph Cl N DCM, -10˚ 98 % e.e. LHH OH O H LHH strained silacycle OH Me cat. L2Ru P H2 P Ph Ph H O [H] Ru H O Ph Me homohelical induction heterohelical interaction Br OH Me Heterohelical adduct is higher in energy, hence more reactive leading to reduction. Free enegy diagram: Helicity in kinetic resolution: O O Ph OH (R)-BINAP-Ru Me OH Me OH H2 ∆Ghom ∆Ghet OH Me Ph 49.5 % 92 % e.e. Ph 50.5 % 92 % e.e. H P Ph H O Ru P H O Me H hetero One enantiomer reacts at a faster rate with chiral catalyst resulting in product and starting material being recovered in high enantiomeric excess. P H O Ph Ru O P O H OH Me OH Me Ph O Me homo Ph OH OH OH OH Me Me Ph 6 Free energy rationale: ∆Ghom > ∆Ghet Ph Conservation of Helical Asymmetry N. Z. Burns Helicity fine-tuning: With this knowledge, rationalize the following result: (G. Bringmann, JOC, 2000, 65, 2517) Me O Me O O OH O O (S)-CBS Me n OH O PPh2 PPh2 O 0.5% Ru 1.2 % lig O Me OH H2 OMe O Me OMe BH3 Me Me H Ph Me Ph 96 % e.e. O N (S)-CBS B + unreacted atropisomer n 1 2 3 4 5 6 q 60˚ 74˚ 77˚ 88˚ 94˚ 106˚ % e.e. 90.9 90.8 97.7 99.1 97.1 96.5 Me Reaction design based on helicity? Recall that homohelical interactions are always favored. MeO PPh2 PPh2 MeO PPh2 PPh2 87˚, 97.9 % e.e For a reaction to be highly enantioselective, the overall helicity as well as the helical characters of the interacting species (i.e. catalyst and substrate) must be matched. 87˚, 98.4 % e.e. What is next for this theory? In practical term this comes down to polarizability matching. "Simple steric-based stereochemical rationals formulated AFTER one knows the experimental results are not appealing to me anymore (they abound in literature really; They are typically more arts than sciences!). I firmly believe, as expressed in that thesis chapter, there MUST be a more general scenario that is beyond steric effects." –David Zhigang Wang (personal communication) Wang proposes the following: "to design a good catalyst . . ., rather than focusing on the rigidity, bulkiness or C2–symmetry of the catalyst, one should focus more on the polarizability properties, thus the helical character, of the substrate . . . with which the catalyst will interact." 7