E. Kwan, C.M. Gampe Acyclic Stereocontrol Chem 106 Acyclic Stereocontrol Eugene E. Kwan, Christian M. Gampe 1 Ke Re dy ROHR Scope of Lecture halofunctionalization carbonyl of olefins directed reaction additions — of olefins acyclic stereocontrol } Fekivson Z vs. chelate ——— allylic strain in model inside hydroxy sterecontrol conformation Helpful References 1. "Classics in Stereoselective Synthesis", E. M. Carreira, L. Kvaerno, Wiley-VCH 2010. 2. "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", M. B. Smith, J. March, Wiley Interscience 2007, 3 G. Fu, Chom, Rev. 1993, 93, 1307. 4, "Acyclic Stereocontrol Induced by Allylic Alkoxy Groups” J.K. Cha, N-S. Kim, Chem. Rev. 1995, 95, 1761 Substrate Directable Reactions’, A. H. Hoveyda, D. A. Evans, 5. "Allylic 1,3-Strain as a Controlling Factor in Stereoselective Transformations", Chem, Rev. 1989, 89, 1841 6. "Stereoselective Cyclopropanation Reactions" Chem. Rev. 2003, 103, 97. Key Questions 1. How do allylic and homoallylic steregenic centers influence the stereochemical outcome of these reactions? 2, How can we explain the following? oms. © oPMB ° BFIOEY Mer H Pr — "= er Pr ite 95:5 dr tite ‘OH OPME: ono OH OH Me. Me NaBH(OAC), Mo. A Me HORE Me te Me Me Ne Me 98:2 dr : Lecture notes edited by Richard LiuE. Kwan, C.M. Gampe Acyclic Stereocontrol Chem 106 ‘cycle Stereocontrel T yroboration Highly dastereoselecive reactions controle ony by substrate | Hydroboration used to be an important reaction for eonvertng Storoschemisty have become an invaluable tool ganic | akenes to alohols, Nowadaye te termediate Srgancborenes synthesis, In 1005 before er prvalence, Woodward are Nighy use in thomwsivos ana con partcipas erase. famously remarked thet he foal synthesis ofthe erthvonoldes, | eoupinge,addlon-migratonrescons ang halogenatona ttamiy ofmacrocyeanbiote eompounds, was “hopelessly , oo complex” on account of its multiple contiguous stereocenters. RH H:02 Rs 4 4 workup bo ooo, “EE whom erythromycin i rR Sodium perborate oxidation/workup (milder alternative): Kalbalka JOC 1989 54 5930 Regioselectivity is generally moderate with BH,°THF, but good with bulkier reagents lke 9-BBN: meme (we it tt tt tt BH, = 94:68 81:19 87:43 50:50 9-BBN 99.9:0.1 98.5:1.5 98.8:0.2 80:20 Only 34 years later, a recent synthesis of 6-deoxyerythronolide by the White group sets every stereocenter except one by acyclic stereocontrol, using reactions that have become standard in the field Evans aldol sem Myers alkyation Meo MO 6 decxyerynronalide Evans aldol ‘Common hydroboration reagents: Me Me Shiver odo Mo Me ue 0 9 ZZ 3 ketoimide aldo Me Xoy, MS ey" om Wnt aye oxidation oq site-directed the Me Me I, That siagpk Ceatechaborane CTrexyborere) _(Disiamyborane) ‘Nat. Chom, 20091 547 | General trend of the rate of hydroboration: R R R RR bt Gt de? fe oA?” KR K RoR d Kok & In this lecture, we will explore some reactions that proceed under substrate stereocontrol and some models for their selectivity based on principles of acyclic conformational analysis. Next lecture, we will discuss aldol-tike reactions in more detailE. Kwan, C. M. Gampe Acyclic Stereocontrol Chem 106 Hydroborations Controlled by Ay,2 Strai Let's look at a 1,1-disubstituted olefin, Still has reported a study (on the hydroboration of allylic alechals (JACS 1983 105 2487). Hydroboration controlled by A, strain Houk Tetrahedron 1984 40 2257 Consider this reaction in Kish’s Monensin synthesis (JACS 1979 101, 260; JACS 1979, 101, 262.) He notes that BH, displays only poor diastereoselectvity ry B.HyTHF 7 ! However, if 9-BBN is used, good selectivities are obtained and oS onn Ho, 0 ‘08 _ the stereoinduction is reversed. So what is going on here? 5 Again, a conformational analysis is revealing fie Me et dr whe Me This result can be rationalized by conformational analysis. ‘The reactive conformation of the starting material is Me Be Me on Me the one inwhich A; stainis minimized. BH, then approaches | A. —= BH AOH + Buy Lon from the face opposite to the larger substituent. on bn bn 0-H ah Biisdn 114 RinoH or SABBN: de 111 WE oe Me r a oh | small boranes: reactive rotamer Re OR ‘Aya strain reactive fay strain voramer In this case the severe A, 5 strain of the 1,1,2-trisubstitued olefin RL Me dictates the reactive conformation. What is your prediction for oD Rs AUR tho stereochemistry of this reaction? (-OH does not direct normal Wey X boranes.}, Wey 2 e Me Me This 02 ers 10" ‘or; | In E-1,1,2trisubstituted olefins A, 2 strain in conformer | will favor or Moe Su Sa Oe conformer Il. A small borane reagent can now come in from either { side and will have to pass either Ryy or R,, which explains the Still, W. C. JACS 1983 105 2487 | poor selectivity. In general, selecting between Ry, and Ris We could do the conformational analysis again (you should), or | gyways much more dificult than selecting between Ryy and H. we can just do this by analogy to the upper example. Pick an orientation for the central hydroxyl (let's say *up"). Now clearly the borane approaches from the top face of both olefins to give: Me Me Toor OH OH 6HE. Kwan, C. M. Gampe Acyclic Stereocontrol Chem 106 large boranes: IFlarge borane reagents are used conformer i will stil be favored." bu bus Bu pu Big den However, severe steric clash between Ry and the borane will SS we S-BBN: die. 15:1 prevent the reaction with rotamer Il. Instead, the less stable rotamer becomes the reactive one, reversing the observed selectivity On Bu OH OH Avzstrain TH asian Ry reactive | Thus far, the substrate controlled-selectivity we have discussed rotamer { has relied on repulsive steric interactions. However, substrate ! control can also derive from attractive non-covalent interactions such as hydrogen-bonding or Lewis acid/base complexation. ‘The resulting association of the substrate and reagent induces a conformational bias in the ground state that translates to highly | organized transition states, and hence, high selectivity. on Interestingly, the substrate-reagent interaction can also increase the rate of reaction as well. For example, in hydroxyl-directed Peracid epoxidations, the carbonyl oxygen becomes more negatively charged in the transition state. As a result, hydrogen ! bonding is stronger in the transition state than the ground state, and the overall rate is faster (J. Chem. Soc. 1957 1958; Proc. | Chem. Soc. 1963 159; JACS 1997 119 3385). Another instructive example was reported by Midland (JACS 1983, 105, 3725): Bis: die = 191 9-BBN: ay. = 14:1 (CoH yshoBHt ar. = 26:1 Competing Ay,s and A;2 strain In Z-4,1,2 substituted olefins both conformers I and Il will suffer on R from A;.2- and A;.s-strain, respectively. The following experiment & reagent via by Still shows that Ay,3 strain dominates Ay strain and 0 reactive conformer lis favored despite the Ay,» energy. Note that the steric clash with bulky borane reagents favors I as well; moPea an=928 both effects work in concert to give pronounced stereoinduction. | {8u00H, VO(acac)y J. = 96:2 (JACS 1983 105 2487)E. Kwan, C. M. Gampe Sharpless carried out an instructive study of acyclic stereocontrol Acyclic Stereocontrol Chem 106 ‘Stereoinduction using m-CPBA is highest if the dihedral angle is in the epoxidation of allylic alcohols. ‘As you can see, we perform ! around 120°. In contrast the V(V) species prefers to be directed the same type of conformational analysis using allylic strain, but now the electrophile approaches from the hydroxyl side, rather than the least hindered side. He ‘OH OH ; HOH A strain moran ane (eas olin ador Voteae, nse Shes, we we (9H eeoacaton Me OH Me OH Me Sharpless model (Aldrichimica Acta 1979 63): epoxidation tovowses arcs eae Aca san 2 ors ~ dominates epoxidation J ea 60° ify stain dominates epoxidation — on forperacés aH tmereay (we pit itayastain SE Rt s dominates a 120" 7 10 Aya strain dominates by a hydroxy group that forms a dihedral angle of ca. 50°. Homoallylic alcohols have as well been reported to react in highly diastereoselective epoxidation reactions. Direction of the metal ! reagent by the hydroxyl group in a cyclic transition structure was proposed, in which most substituents occupy the equatorial { position (JACS 1981, 7690). ‘OH vor a 9784 _ z ow, Lk Te he de Cyclopropanation ! Directed cyclopropanation of allylic alcohols can also be quite stereoselective, but the mechanism is not as well understood, ‘The cyclopropanation of E-allylic alcohols is highly dependant {on the reaction conditions. Furukawa's conditions (Et,Zn, CHoI,) | generally give higher d.r. than the Simmons-Smith procedure or the samarium carbenoid ‘OH OH we weve Znou Cre EYO sea EtzZn,CHaly CHCl, 86:14 Sm(tig), CHola, THE 25:74 on Me ‘The fact that samarium carbenoids often give complementary stereoinduction to zinc carbenoids is difficult to explain.E. Kwan, CM. Gampe Acyclic Stereocontrol Chem 106 On the other hand, Z-aliylic alcohols or trisubstituted olefins _ Halofunctionalizations react under a variety of conditions to give the syn-products in Good selectivities, usualy >:1 | We conclude our discussion of stereoselective olefin / functionalization with a discussion of reactions that proceed on R! oH RY on R* oH | through halonium ions. First, we will need some background, gt - i - ‘Typically, the bromination of an olefin is trans-selective. In 2 2 pte ° e) Rt | jons are intermediates: ‘Sm oF Zn-reagents ‘Sm- of Zn-reagents : termediate cytorropanation : & er ‘With a few exceptions, the directing HO i Hag ~ HAL, effects of basic groups that PD poh? vou b wear: J oes ae do not reside on a stereogenic center TSR ‘on af is rather poor. : Axa strain miaeizey’ | However, this picture is gravely lacking in mechanistic detail. | ttnow appears that, Ike in yéroboration, w-complanes ars Since this droctng ofc reins on rtracon wih he metal ten important intermediates. The exet mechanism depends directed by many more Lewis basic functionalities than are | also on the solvent. In aprotic solvents: Use for peroxide-promoted epoxdation For tance, alvlc | a biyl ethers and acetals ean be viable drectng groups, / . i Mo Mo | | a ZnEty, CHa : go (CH2Cl)p + : a4 24 - or n-complex. n-complex aN i ~ fT wd We wd © Be. wapping by Numerous chica auxiliaries have been developed. selection of | = pucleopilos eso aula ie depleted below for a good overview, see" bromonium Cee eons are ne velom fora good \ oe Chem. Eur, J. 2003 9 1037-1044 | (Complexes of 3:1 stoichiometry or higher are possible.) | Nucleophiles can attack any of these intermediates, giving | tise to very complex mechanistic behavior. These x-complexes | were examined by Mulliken (Molecular Complexes, 1969, | Wiley Interscience). Moe yy Rt Bue ° 0 ve tS ne e Pr0xe 1986 9487° Ccharete, ACS 1991 1738166 Imai, soc 1990 4986E. Kwan, C.M. Gampe Acyclic Stereocontrol Chamberlin and Hehre have noted that the stereoselectivity of trapping reactions on allylic alcohol-derived bromonium ions depends on whether the nucleophile is internal or external (JACS 1983 105 5819; JACS 1987 109 672)! With internal nucleophiles, the product seems to derive from ‘a conformer in which the allyl alcohol occupies the on jo ° 95:5 dr With external nucleophiles, the product seems to derive from ‘a conformer in which the allylic alcohol occupies the normal, outside position: Tae aS This is rationalized by considering a change in the rate- determining step: (1) when the nucleophile is internal, the more stable complex is trapped quickly. (2) when the nucleophile is external, trapping is slow, and cannot occur directly via the 7-complex, 80 the more iodonium is trapped. Chem 106 { Heme : ROH favored "OH outside" more reactive ground state conformer conformer complex rds (internal | formation nucleophiles) internal R — nucleophiles Ho trap this : favored "OH inside” complex disfavored (6c0" cannot withdraw } complex density from the roc) \ I Favored iodonium fon : rds (external) lodine comes in opposite the bulky | external nucleophiles 9f0up to form the x-complex in trap this both cases, (3) the "OH inside" complex is favored becase |, does not ‘compete with co" for the reg electron density. (4) the left-hand iodonium ion is favored because the C-O inductively stabilizes the iodonium ion. (6) evidently there is a considerable barrier to go } from the x-complex to the iodonium ion (reactions in Et,0)E. Kwan, C. M. Gampe Configurational Stabilit Interestingly, one bromonium ion can exchange with another (Brown ACR 1997 30 131): e A me ok determined by NMR lineshape analysis. Apparently, there is an intermediate in this process: of Halonium lons at 80°C ~ product chelate slows down reaction chelate ——= ketone —> product (1) Ifthe chelate is just an unproductive side equilibrium, then it will just stabilize the ground state and slow down the reaction, (2) Conversely, the chelate might just form in the transition state, | lowering its energy and speeding up the reaction Itis found that chelation significantly accelerates addition rate (10? Mt s*t) ° m Me, OH ve — eet Mo / 051 Phe THF,-70°C PR {atenvation is not store SL op __MesMa HO Me 1000 (R=Me) oy eo ery 0.45 (R=TIPS) Me Me (@) a-Akoxyketones and magnesium bromide do not visibly coordinate by NMR. This is expected, since THF is quite 2 good ligand for magnesium. However, in CD,Cly, there isa substantial sit. oye RO 9 Ma, LL soon —e REP eke Le Re The extent of chelation in CD;Cl, depends on the protecting group. (4) The reaction is first order in ketone and Me2Mg, energy This means that the scenario Is: ketone —= chelate —~ product If we want to draw an energy diagram, we can can compare the competing chelated and unchelated transition states: tr JB inselective ™ ketone + R09 MeMg (fo alkoxide “NR alkoxide product product There is no differentiation between forming major and minor products on this diagram. Thus, we have to think of each transition state as really representing a pair of transition states, cone for the major and one for the minor product. Interestingly, f-alkoxy ketones do not seem to experience any rate acceleration. This is consistent with other literature precedents, which suggest that 5-membered chelates are more reactive than 6- membered chelates. However, 6-membered chelates do give high selectivity (Evans JACS 2001 123 10840): gms Mie gawk : @ gH gon Hy A y —. cam PS Me,AICl or Tick, 97:3. drE. Kwan, D. A. Evans Acyclic Stereocontrol Chem 106 Intrinsic vs Chelate Selectivity Before analyzing the outcomes of these chelate-controlled additions in more detail, it is important to realize that there is an intrinsic selectivity that is being turned over when chelation ‘occurs (Evans JACS 2001 123 10840): “intrinsic selectivity” 2 on i Tih wows OHO, 78°C Mase ‘ores Me ‘TMS enolsiane Me 93:7 dr “Cram chelate selectivity” 2 On i Tok 1 roen Cio, TES Mase ~Y~o8n Me ‘TMS enoisiane Me 5:95 dr ‘The idea here is that going from a bulky protecting group, TBS, toa less hindered, coordinating protecting group, Bn, gives chelate control, But where does the intrinsic selectivity come from? Felkin-Anh-Eisenstein Model In the Felkin model, one assumes: (1) all ground state rotamers are accessible (Curtin-Hammett) (70m clockwise = g (dk rotation uty —totation__ ‘ QR, “airotamers” Ab R accessible R (2) the transition states are very early (exothermic reaction) (3) both the major and minor transition states place the largest substituent anti to to the incoming nucleophile (4) the major transition state minimizes torsional interactions between the C-R bond in the front and the C-M group in the back (L=large, M=medium, S=small): = Lis opposite Nuc - the torsional interaction between C-Rand C-S is small Nuc - also could imagine that S/Nuc interactions are small - Lis stil opposite Nuc - the C-R/C-M interaction is bad - 80 is the Nuc/M interaction Nuc This model works for the vast majority of aldehydes and ketones and is generally accepted. However, it does seem to fail in some pathological cases, such as sterically unbiased ketones which are nonetheless slightly electronically biased. Effect of Electronegative Subst jonts In the above analysis, it was tacitly assumed that all three substituents were alkyl; ie., not electronically biased. Anh and Eisenstein showed that polar substituents X can take the place of the large group: major TS minor TS M so ly hy TBs. iDE. Kwan, 0. A. Evans Acyclic Stereocontrol Chem 106 Effect of Electronegative Substituents The work of Anh and Eisenstein (Nouv J Chem 1977 1 61) was seminal because it showed that computational chemistry could be a powerful tool for analyzing real problems in organic chemistry. Even though their work was, in today's terms, at a very crude level of theory (HF/STO-3G), itis telling that it gives the right predictions most of the time. In their study, they analyzed the reduction of 2-chloropropanal with hydride. The distance between the hydride and the carbonyl carbon was fixed at 1.5 A, and the Cl-C-C=0 dihedral angle was varied. Bachrach (page 303 of his book) has recomputed their results at a more modern (BLYPI6=31++g(d)) level of theory: pote +H ote & 180 Dinedral angle (1) The solid line (circles) represents configurations that lead to the major product; dashed (squares) lead to minor product. 270 | (2) The minimum energy structures of the solid and dashed lines correspond to the rotamers depicted: 0 Me HO ; | (8) Notice that the nucleophile approaches at the Burgi-Dunitz angle. Hydride is not a very realistic nucleophile, but the | Burgi-Dunitz constraint is stil realized (4) Why does the C-X bond take the place of the large group? Explanation 1. Donation from the forming a(C-Nuc) into the '(C=0). However, this is a very early TS, so there is very litle density in «(C-Nuc); NBO analysis shows that this is not a very significant interaction, | Explanation 2. The x*( a better acceptor: ) and «*(C-Cl) combine to form -— ot(C-Cl) (C=O) — docroasod _ HOMOLUMO HOMO Nuc gap | (6) The possibilities of asymmetric x* lobes (i.., bigger on one | diastereofacial surface) and electrostatic minimization (Comforth model) have been examined.E. Kwan, D. A. Evans Practice with Stereochemical Models From a practical standpoint, what is the stereochemical outcome of a Felkin-controlled 1,2-addition? Let's analyze the reaction from before: ° Tiel, ioe wy ons “oe, eo wee ~oras we TMS ehaltane te 93:7 dr ‘The major TS positions the large CH,OTBS group anti to the nucleophile, which comes over the smallest group: Q Me HO Me TBSO, TBS, ‘ ch ‘ ere Hw Nuc RAH Notice that in the product, we have the R and the CH,OTBS inthe "zig-zag." So the Me and the OH are syn, as is, observed. (if the R and CH,OTBS weren't anti to each other, then we would need to rotate the Newman projection first.) hy Felkin contrat Me What is the expected Felkin product of this addition (Keck, TL 1984 25 265)? Zs on 9 BF,OEt, BF CHCl, 78°C ‘mes ores 95:5 dr (When there's a polar group involved, we use the ‘polar Folkin-Anh(-Eisenstein) model.”) Acyclic Stereocontrol Chem 106. | The OTBS takes the place of the large group (itis interesting that the electronegative substituent seems to override the ! bulkiness of the cyclohexyl group): GO 3 O reso = 90S 4 Notice that we need to have the allyl nucleophile and the cyclohexyl group anti to each other in the Newman projet to decide if the product is 1,2-syn or 1,2-ant "9 a reso-(SCnive folate, teso-(y oH mH ws Nud ' CHCh,-7eC ¥ OTBS ores i 95:5 dr ! A Half-Chair Model for Chelate Control | With 1,2-chelates, the nucleophile simply adds from the face opposite the o-substituent: roo Ho of Lyne Ste a OR ROR The kinetic data on this is unclear (Retz, ACR 1993 26 462), and its possible than nucleophile transfer can be either intra- or inter-molecular, depending on the situation. But this is stil a useful model for predicting stereoselectivity.E. Kwan, D. A. Evans Chem 106 For 1,3-chelate induction, a half chair model has been proposed by Evans (JACS 2001 123 10840). In some cases, a 2:1 bidentate chelate is observable in the ground state; in others, a monodentate 1:1 complex. So given the lack of kinetic data, it is unclear whether one can view all of these reactions as adding a nucleophile to a chelated complex. However, if one assumes this, then the performance of the stereochemical model is very good Ifone assumes a boat-like chelate, then the nucleophile comes in opposite the R grou WR QH OP rot ieee Nuc R eo Nuc If it’s a half-chair, the same prediction is obtained R uo, Moon PS? S84 oR Nuc. Nuc disfavored favored As usual the Furst-Plattner rule dictates chair-axial opening, Interestingly, even if a monodentate carbonyl-Lewis acid complex is formed, the same outcome is observed. A polar 1,3-stereoinduction model predicts this (Evans JACS 1996 118 4322). We will discuss this in the next lecture. | Directed Reductions | These are among the most useful of the chelate-controlled | addition reactions. What happens in this reaction? Me Me ph _2n(BHade Ph 97:3 dr wed 6 Meo OH Chelate control wins out over Felkin control. What is the stereochemical outcome of this reaction? Me Mo : Ph. Ph LAs PRA PD ga:12 dr NH, O NH, OH | evans has also developed (JACS 1988 110 3560) reductions where chelation overrides Felkin selectivity: oH oO oH On Me Me MeBHOAE we AA, Me 98:2 dr Y HOAG Me the Me Me fe Me ‘one re n : R70; one REP eG one i RR RP favored TS disfavored TS Note that 1,3-diaxial interactions are much worse on the top than on the bottom, where Ry is the only axial substituent. In contrast, when Re is axial in the disfavored TS, it interacts with the acetate and axial hydrogen on the top face,