Houk Hydroboration Tet

7/28/2019 Houk Hydroboration Tet

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Terrahrd rm Vol. 40. No. 12, pp. 2251 IO 2274. 1984Printed in Great Britain. aMo4mp s3.00+.00FWpwa h Ltd.

THEORETICAL STUDIES OF STEREOSELECTIVEHYDROBORATIONSK. N. HOUK*, NELWN G. RONDAN,YUN-DONG WV, JA~IEST. MJDZ andMICHAELN. PADDON-ROWDepartment of Chemistry, University of Pittsburgh, Pittsburgh PA 15260, U.S.A.

(Receiued n Japan 23 September 1983)

Ahatra~-Asymmetric hydroborations of alkenes are outstanding examples of reactions which proceedwith high acyclic stereoselection to give synthetically useful functionality. We have undertaken com-putational studies of these reactions as a part of our more general studies of stereoselective organicreactions. We wish to develop understanding of those factors which control stemoselectivity in knowncases, and to develop both qualitative and quantitative methods to predict stereoselectivities of cases notyet investigated. Here, we detail our progress in understanding hydroborations, and in subsequentpublications, we will report similar studies for other types of organic reactions, such as intermolecularand intramolecular cycloadditions, epoxidations, radical reactions, nucleophilic additions, and aldolcondensations.

Stereoselective hydroborations of alkenes have beenemployed in the synthesis of many natural products.*Hydroboration with optically active boranes fol-lowed by oxidation gives optically active alcohols,often with high enantiomeric excess.3 An example isgiven in Fig. l(a). Chiral alkenes undergo attack byachiral boranes preferentially from one side of thedouble bond. This occurs when the chiral center isattached to the C which is attacked by boron (Fig.1b),4 or when the chiral center is attached to the C towhich hydride is transferred (Fig. Ic).~.~ High asym-metric induction is found even when the chiral centeris one atom removed from the C to which hydride isbeing transferred (Fig. Id). Thus, chiral centersattached to boron or to either alkene C can promotehighly stereoselective reactions.What factors cause these reactions to be stereo-selective? Can the modest stereoselectivity observedin some of these cases be enhanced by alternativesubstituents on reagents or substrates? Can thesestereochemical control features be incorporated intoother organic reactions to produce useful stereo-selectivities?. Is it possible to predict the stereoisomerratios in such reactions? Our computational studieshave addressed these questions, and in this manu-script, we report the results of our initial in-vestigations.Ab initio calculations can be used to locate thetransition structures of various organic reactions. Weuse the word structure in the sense advocated byPople, to emphasize that the calculations give astructure which corresponds to a saddle point on theelectronic energy surface, not a real state as is impliedby the word, state. These calculations can also givedetailed information about the geometries, energies,and vibrational motion of transition structures. How-ever, computations with sufficiently large basis setsand adequate correlation energy corrections can stillonly be carried out practically with relatively smallsystems. Many insights can be achieved by appropri-

ate calculations on small model systems, but mostorganic reactions involve quantum mechanicallymonstrous systems, which cannot (yet) be studied bydirect ab initio calculations. Nevertheless, it is de-sirable to compute quantitative information about allof the electronic and steric effects which mayinfluence the rates of reactions of such large systems.We have explored small model systems at the ab initiolevel, and have devised a modified force field modelbased upon Allingers MM2 method, which hasproven useful for the computational study of highlysubstituted systems.Ab initio transition structures

The hydroboration of ethylene with BH3 has beenstudied theoretically with a variety of techniques.4Both ab initio and semiempirical techniques predictthat BH, and ethylene will form a weakly boundn-complex in the gas phase, and that the conversionof this complex to the addition product is the higherbarrier to be surmounted in the addition reaction.The transition structure corresponding to the highestbarrier is a four-center one, which avoids orbitalsymmetry forbiddenness since it is a pseudopericyclicreaction having little or no cyclic four-electronconjugation.9

However, in noncoordinating solvents, boranedimerizes to diborane, while Lewis basic solventsform complexes with borane. Thus, in solution, mono-meric borane is not the actual hydroborating re-agent, although some sterically hindered di-alkylboranes do react as monomeric species. Howthen can gas phase calculations on monomeric BH,reactions have any relevance to solution experiments?Clark, Wilhelm and Schleyer have carried out atheoretical study which suggests that gas phase andsolution hydroboration transition structures are verysimilar to each other. They studied the reaction of aBH,-water complex with ethylene, as a model forsolution hydroboration reactions.r3 The ncomplex of

225-l


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2258 K. N. HOUK et al.

Ipc2BH(R) -I-butanol

98.4% ee

85% yield

(=I1) BH3,THF2) H202,0H-

Fig. 1. Examples of several stereoselective hydroboration reactions.

BHr and ethylene is no longer an energy minimumdue to stronger coordination of BH, with water thanwith ethylene. The single transition state which nowseparates reactants from products is similar in itsmain geometrical features to that calculated for theBHr-ethylene reaction, with the solvent molecule,water, nearly completely displaced from BH, in thetransition state. The activation energy is greatlyincreased by coordination of the BH,, and the transi-tion state is somewhat later in terms of CB bondformation. Nevertheless, the details of the four-centered transition state are quite similar in gas phaseand these model solution phase reactions. For thatreason, as well as for reasons of practicality, we havenot attempted to include solvent explicitly in ourcalculations.Location of the transition states for substitutedcases also indicates a relative insensitivity of thetransition structure to substituents and reveals a newconformational feature. The transition structure thatwe have obtained for the parent reaction using the3-21G basis setI and gradient optimizationtechniques is shown in Fig. 2. Transition structuresfor the hydroboration of propene in both the pre-ferred (anti-Markovnikov) and disfavored (Mar-kovnikov) directions were published recently,14 and

are shown for comparison. We have also obtained thetransition structure for the hydroboration of ethyleneby methylborane. This is also shown in Fig. 2.Various conformers and configurations of transitionstructures for the hydroboration on ally1 alcohol byborane will be described later.The activation energies, without zero-point energycorrections, are shown below each drawing in Fig. 2.These numbers are the total energies, in kcal/mol,relative to the isolated monomeric reactants. Theactivation energies calculated at the 3-21G level areall too high, since the reaction of BH, with ethylenein the gas phase has an activation energy of only2-3 kcal/mol.* Morokuma et al. have shown that useof polarization functions and CI lowers the calculatedbarrier to a more reasonable 5.6 kcal/mol.2 It isprobable that relocation of the transition state withCI would give an earlier transition state, while inclusionof solvent would give a later transition state. Becauseof neglect of these two counteracting influences, our3-21G results may be fortuitously close to actualsolution transition structures.As shown in Fig. 2, a Me substitucnt at the alkeneterminus away from boron lowers the activationenergy slightly, and gives a slightly more advanced,or later, transition structure. These results are


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Theoretical studies of stereoselective hydroborations 2259

Fig. 2. Transition structures (3-21G) for hydroborations of ethylene by BH,, ethylene by MeBH,, andpropane by BH, in two orientations.

compatible with expectation for an electrophilic pro-cess. A Me at the alkene terminus near boron raisesthe activation energy, primarily, we assume, for stericreasons.O.s The Me on boron raises the activationenergy, primarily by stabilizing the isolated boranerelative to the transition state. None of the geometriesof the Me-substituted transition structures are verydifferent from that found for the parent reaction. Thebond angles in the four-center transition structures atewithin a few degrees of each other, and the formingand breaking bond lengths change at most by severalhundredths of an Angstrom.Each transition structure has the Me CH bondsstaggered with respect to the partially formed orbroken bonds, and with respect to the bonds of thepartially pyramidal&d alkene carbons or nearlytetrahedral boron. This staggering is shown moreclearly by the Newman structures given in Fig. 3. Thisstaggering effect follows our earlier gener-alization,4.9.20 and the deduction made for nucleo-philic additions by Felkin and subsequently sup-ported theoretically by Anh. A 180 rigid rotationof the Me group in any of these structures causes anincrease in energy of 2.6-3.0 kcal/mol. We have alsoevaluated these transition state rotational barriersin several more sophisticated ways for the Markov-nikov addition of BH, to propane and found onlyslight changes from the values evaluated by rigidrotation.14 Thus, the barriers to rotation of groupsattached to atoms undergoing bonding changes aresimilar to those of the products, even though theseare relatively early transition structures. We conclude

that alkyl substituent conformations in transitionstructures are of similar rigidity to those of alkylgroups in alkanes. This simple conclusion allowspowerful predictions about transition structures.These predictions are always quantitatively differentfrom those based upon an assumption that substitu-ents in transition structures adopt reactant-like con-formations, and these predictions may even lead toqualitatively different predictions in some cases.In hydroborations such as the first three shownin Fig. 1, one atom attached to boron or to eitheralkene C is a chiral center. Figure 3 shows that bondsto the chiral center will be staggered with respect topartially formed bonds. In order to predict the stereo-selectivity of an asymmetric hydroboration, it is alsonecessary to know which of the three nonequivalentstaggered positions for each type of chiral centerwill be preferentially occupied by a given type ofsubstituent.Model calculations which assess the steric require-ments of an alkyl substituent in each location aresummarized in Fig. 4. The relative energies ofdifferent Et group conformations were obtained withthe 3-2lG basis set by substituting a standard Megroup (rcu = 1.09A, r, = 1.54A,


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H H

H- -H \ P

H

J+ 4

iH H

WH HH H

Fig. 3. Newman projections of the four transition structures shown in Fig. 2.Max6--u /

: I8 ,&--7 ai-7I :,L---- l---~ :____ JE,~,hLm 0 + 0.4 + 0.8

-_- -f+ 7I III* Ma

0Fig. 4. Relative energies (3-21G) of model transition structures for hydroboration of ethylene byethylborane and of I-butene by BH, in both orientations. Energies were calculated for geometries obtainedby substitution of a standard methyl group for a hydropn.


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Theoretical studies of stereoselective hydroborations

Fig. 5. Qualitative models for asymmetric hydroborations with groups of different size, but no specificelectronic effects.

positions are clearly the sterically least crowded pos-itions in each case. The outside positions (awayfrom the alkene double bond) are somewhat morecrowded, while the Me groups inside the four-centered transition structure are clearly in the mostcrowded locations.Based on these results, we can make qualitativepredictions about stereochemically preferred transi-tion structures when the chiral centers consist ofgroups which interact with other atoms or groupssterically, but do not interact in any other specificelectronic way. Alkyl groups are presumably closestto this steric ideal. Figure 5 shows these steric models.It is tempting to ascribe the stereoselectivity shown inFig. 1b to the steric model, with fury1 = L (large),Me = M (medium), and hydrogen = S (small). In

fact, we have succumbed to this temptation! How-ever, as described later, the fury1 and Me groupsdiffer very little in effective size, so that we also investi-gated the possible electronic role of the homoallylicoxygen present in the fury1 group and alkoxymethylgroups present in analogous examples from Kishislaboratories.4 For computational mnomy, we at-tached a standard hydroxymethyl group with theCCOH dihedral angle fixed at 180 in place of one theCH bonds of Me in the Markovnikov propene_BH,transition state. This model mimics the conformationabout the CO bond expected for ethers. We thencalculated the energies of the nine possible con-formations obtained by 120 rotations about C,C, orC2C, bonds. The results of single point 3-21G calcu-lations are shown in Fig. 6.

anti 0.0 1.6 1.1

OutaIde 0.9 1.4 7.1

Inrldo 23.2 7.4 4.3

C+OH-anil-=ccco=f&

Fig. 6. Relative energies (kcal/mol) of model transition structuxs for hydroborations of homoallyl ethers.The preferred conformation is shown, and the energies of nine additional transition structures aresummarized in the table.


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2262 K. N. HOUKet al.The preferred conformation has the CH,OH group

ant i o the partially-formed BC bond, and has the CObond in that gauche conformation which places the 0atom nearest the alkene. Although the distances fromthe homoallylic 0 to the alkene carbons are 2.9 and3.1 A, there is apparently a considerable interactionwhich stabilizes the transition state. Full optimizationmight lead to closer approach of the oxygen to thedouble bond, and a further preference for this con-formation.Since BHS is an electrophilic species, the doublebond should become somewhat electron-deficient inthe transition state of the reaction. A neighboringoxygen can stabilize the transition state either electro-statically, or by through-space interaction of anoxygen lone-pair orbital with the 1~ orbitals of thealkene. Accelerations of electrophilic additions toalkenes by through-space interactions of an etherwith alkene n-bonds have been noted previously inmore rigid systemsThese calculations show why a homoallylic ethergroup prefers the ant i conformation in hydro-borations. Although a CH, and a CH2CH20R groupare essentially identical in steric requirements (seelater), the latter can stabilize the transition state whenant i . Thus, Kishis many examples of the general

type shown in Fig. l(b) result from an electronicpreference for the homoallylic ether to be anti, alongwith a steric preference for Me to be outside ratherthan inside.Figure l(c) shows another type of asymmetricsynthesis in which a hydroxyl group is located on theallylic C adjacent to the alkene C to which hydrideis delivered upon hydroboration. To investigate thepossible electronic effect of an allylic alcohol on thesereactions, we carried out ub i n i t i o calculations on thehydroboration of ally1 alcohol by BHJ. Six differenttransition states were calculated, and these are shownin Fig. 7. The two transition structures shown at thetop of Fig. 7 with OH oursideor ins ide are preferred,and have activation energies slightly lower than thatfor hydroboration of propene. These preferred ally1alcohol transition states have the OH directed so thatit can hydrogen bond with the alkene, as is preferredfor ally1 alcohol itself. In fact, when calculations werecarried out on the ally1 alcohol fragments of thesetransition states (i.e. with BH, removed), the relativeenergies are in the same order, although the energydifferences between conformers are smaller.Thethreehighest energy transition structures, shownat the bottom of Fig. 7, should be good models forthe hydroboration of allylic ethers. The relative ener-

Ethaf mod&

Fig. 7. 3-2lG Transition structures for hydroboration of ally1 alcohol. Activation energies (kcal/mol) areshown below each structure. The three ether models, which started at geometries with < HOCC = 180.are less stable than the alcohol models. The lowest ether model is 1.9 kcal/mol higher in energy than thelowest energy alcohol model.


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Theoretical studies of stereoselective hydroborations 2263gies increase in the order: outside < inside


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2264 K. N. HOUK et al.mended MM2 values. Van der Waals interactionsbetween all atoms on substituents and those involvedin bonding changes are also included.The treatment of bonds to boron is somewhatproblematical, since parameters for tetracoordinatedboron are not available. We have assumed thatsubstituent atoms which are attached directly toboron have distances and angles fixed at the valuesfor the CH,BH+thylene transition state. This makesthe model too inflexible about boron, and futuremodels will utilize ab in i f io force constants calculatedfor the transition state to provide more quantitativepredictions.

SPFCIFIC CASES1. Asymmetri c hydroborati ons w it h isopinocampheyland dik opi nocampheyl boranesBrown et al. have explored the use of optically activeboranes for the enantioselective synthesis of alcoholsfrom alkenes. Diisopinocampheylborane, knownalso as di-3-pinanylborane, prepared from a-pinene,and mono-3-pinanylborane show high stereo-selectivities with some types of alkenes. Figure 8 sum-

marizes the stereoselectivities observed with these re-agents and various types of alkenes. Withtransdisubstituted and trisubstituted alkenes, loss ofa-pinene from the di-pinanyl reagent accompanieshydroboration,3 so that the ratios of enantiomers withdi-3-pinanylborane are probably a result of hydro-boration by the mono-pinanyl compound, di-pinanylcompound, and the 3-pinanyl-alkylborane, where thealkyl group is derived from the alkene being reduced.Examples of stereoselective hydroboration-oxidationof additional alkenes, as well as allenes, will be described later.Many models have been proposed to rationalizethese and related results.3-3s Our conclusions differ insignificant ways from all of these, since we have beenable to numerically evaluate the preferred con-formation of the pinanyl groups in these reactions. Abrief comparison with previous models will be madelater.We have applied the model described in the pre-vious section to the study of these asymmetric hydro-borations. The calculated preferred conformations ofmono- and di-pinanyl borane are shown in Fig. 9,%

IpcSH, l RCH=cHR

CHzR 5) I-* I CM (R)Rq&-alkanemalkomatrisubetltuted

20-24% . . . 76-98.4% l e.70-92% (13%) s i.lpcBn:52-100% (14-22X) S lab&

Fig. 8. Preparations of mono- and di-3-pinanylboranes (IpcBH, and I~QBH) from ( + )-a-pinene, andsummary of stereoselectivities of alkene hydroboration-oxidations with these reagents.


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Fig. 9. The MM2 structures of ( + )-a-pinene and mono- and di-3-pinanylboranes. The shorthandnotation used in later figures is given at the bottom.

along with sketches of the starting ( + >a-pinene fromwhich these reagents are derived, and a shorthand forthe chiral center as proposed by Brown et al., and usedin a variety of models for this reaction which have beenproposed in the literature. Although the conventionaldrawing of the 3-pinanyl group suggests a chair con-formation with Me and boron equatorial on the 3-Cbridge, the MM2 calculations suggest a much moreflattened ring, which must arise from both the pres-ence of the cyclobutane ring, which opens up theC7-Cl-C2 and C7-CS-C4 angles, and becauseflattening of the ring relieves eclipsing around theCl-C2 and C4-CS bonds.Several of the previous models have concentratedon the preferred conformation of the starting boraneor borane dimer. Our model focusses directly on the

preferred transition state conformation, since not onlyis the reactant conformation irrelevant in principle,but it is found here not to correspond to the preferredconformation in the transition state.

Mono-3-pinanylborane reactions. For the reactionof a simple alkene such as cis-2-butene with mono-pinanylborane, there are a large number of minimumenergy conformations possible in the transition state.As we have described earlier in this paper, there isalways a preference for staggering about the bondfrom boron to the substituent. Thus, the pinanylgroup can have three distinct staggered con-formations about this B-C bond. The alkene can thenapproach the borane from above or below the boronplane. Finally, there are two possible orientations ofthe butene Me groups with respect to the pinanyl


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2266 K. N. HOUK er al.

Smajor

TS

Fig. 10. The preferred conformation of the MM2[3-21G] transition structure of the reaction of3-pinanylborane (from ( + )-a-pinene) with cb-Zbutene. This leads to the S (major) alcohol.

group. Thus, for cis-Zbutene there are twelve reason-able staggered conformations, which served as thestarting points for our transition state computations.Six of these would give the S-alcohol after oxidationof the borane product, while the other six would givethe R alcohol. The lowest energy transition structureleading ultimately to the S alcohol is shown in Fig.10. This, and the preferred transition structure forformation of the R (minor) alcohol (Fig. ll), bothhave the pinanyl group anti to both alkene Megroups. The lower energy transition state, which givesthe S alcohol, has the best arrangement possible forthe pinanyl group: the smallest group on the chiralcenter, H, is inside, the medium-sized group, -CH,-,is outside, and the largest group, -CHMe+, is anti.The preferred transition structure for formation ofthe minor (R) alcohol is quite similar, but when thebutene attacks from the other face of the borane, thebest possible pinanyl arrangement has the largestgroup, -CHMe-, outside, and the medium-sizedgroup, -CH,-, wfi. This is higher in energy than thatshown in Fig. 10 because the methyl group of CHMenow experiences non-bonded repulsions with theneighboring atoms of cis-Zbutene.The calculated difference in energy between the twotransition structure models shown in Figs. 10 and 11is 1.1 kcal/mol, favoring formation of the.S alcohol.

This agrees with experiment qualitatively, but thedifference in energy is higher than expected from theratio found experimentally, undoubtedly due to therigidity built into our model around the B atom, andthe inflexibility of the alkene Hs and the four atomsinvolved in bonding changes. We have also calculatedthe energies of the other ten minimum energy con-formations, and the energies of all twelve transitionstructures were used to calculate a predicted ratio ofdiastereomers of 74% S and 26% R, or 48% en-antiomeric excess. The only transition structuressufficiently low in energy to contribute significantly tothese ratios are those in which the pinanyl group andthe butene Me groups are anti. For the preferredtransition state, which leads to the S-alcohol, thetransition structures involving _ 120 and 240 rota-tion of the pinanyl group are 2.6 and 1.9 kcal/molhigher in energy than that shown in Fig. 10. For thetransition state leading to the R-product, 120 and_ 240 rotations give transition states only 0.4 and0.7 kcal/mol less stable than the best R-transitionstate. Thus, the R-transition states are always higherin energy than the best S-transition state, but thereare several conformations of the R-transition statewhich are similar in energy, so that stereoselectivityis only modest.Experimentally, the stereoselectivity observed with


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H M4 ---_-HL :IPCBH~ d /-;yL___~ -TS H.F minorRR

Fig. I I. The preferred MM2[ 3- 21)ransition structure for formation of the R (minor) alcohol.

trans-alkenes and mono-3-pinanylborane is muchhigher than that with c&-alkenes. The drawings oftransition states for the rrans-butene reaction, shownin Figs. 12 and 13, are very similar to those shown inFigs. 10 and Il. The preferred transition state has theMe at the butene C becoming bonded to borondisposed anti to the pinanyl group. This, of necessity,forces the other butene Me to be syn to the pinanylgroup. This Me causes the conformations with H(inside) to be much more stable than those with M orL (inside). The two transition states shown in Figs. 12and 13 are 1 O kcal/mol different in energy, and thereare no other conformations of either R or S transitionstates which are within 1.3 kcal/mol of the besttransition state. The predicted ratio for t ram-2-butene is 78% S + 22% R, 56% enantiomeric excess,somewhat higher than that predicted for cis-2-butene. Our model predicts only a small increase inselectivity, whereas experimentally the selectivity ismore than doubled.The high stereoselectivity observed experimentallywith rrans-alkenes is paralleled by that found fortrisubstituted alkenes. We have not calculated modelsfor these cases, but they are expected to be verysimilar to those for the trans-tbutene case, with the

Me group syn to the pinanyl producing strong prefer-ence for the transition state with the H inside, andM and L preferring the outside and ant i arrange-ments.LX-pimnylborune. The most obvious difference be-tween the mono- and di-pinanylborane reactions isthat the former (from ( + )-a-pinene) preferentiallyforms S-alcohols, while the latter gives R predom-inantly. The reason for this is shown quite clearly inthe transition structure for the reaction of di-pinanylborane with cb-Zbutene, shown in Fig. 14.

Only one of the pinanyl groups can achieve the idealconformation with the H in sid e, the -CHr-- ourside,and the -CHMe- ant i .T he second pinanyl group, which is in back ofboron in Fig. 14, assumes a conformation whichplaces the largest group, -CHMe-, inside! The reasonfor this unexpected behavior is clearly the directinteraction between the two pinanyl groups. Thisconformation is also predicted to be favored for thedipinanylborane-ethylene transition state. It relievessteric repulsion between M and L, or L and L, on thetwo pinanyl groups. The preferred transition struc-

ture now clearly makes the two pinanyl groupseffectively very different in size. The Me group at the


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2268 K. N. HOUK et al.Ld---_+R I

5I I

IpcBHZ , I--R -Rf~__--__


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(R) -alcohol maj or

Fig. 14. Preferred MM2[3-2lG] transition structure for hydroboration of cb-Zbutene with di-3-pinanylborane. The computer drawing on the left shows the front pinanyl group connected to thetransition state atoms, while the drawing at the right shows only the back pinanyl attached to BH.

alkene C becoming bonded to boron prefers to benear the (front) pinanyl group which is in the pre-ferred conformation. In this way, it is near the CH,(M) and H of the front pinanyl group, rather thannear the CH, (M) and the CHMe(L) of the backpinanyl. The stereoselectivity with ci.r-alkenes is nowvery high because the transition structure shown is3.7 kcal/mol lower in energy than the best one leadingto the S product. The S transition structure (notshown) has the Hs of both pinanyls inside, to relievethe repulsions between the butene methyl and the Lgroup of the back pinanyl.trans-Alkenes and trisubstituted alkenes react verysluggishly with dipinanylborane, and a-pinene isfrequently displaced when hydroboration occurs.Thus, hydroborations of rruns or hindered alkenesoccur not by a simple reaction of dipinanylboranewith the alkene, but by the reaction of mono-pinanylborane, pinanyl-alkylborane (where the alkylgroup is formed from the alkene), and perhaps bysome reaction of dipinanylborane, as well. We predictthat the S-product should be slightly favored withdipinanylborane and trans-butene, but by a smallamount, since all conformations are similar, andquite high in energy. The reason for the low reactivityof the dipinanyl reagent with tram or trisubstitutedTf!T Vol. 40. No. L---F

alkenes is the severe crowding between the alkenealkyl group which is syn to the effectively largerpinanyl group. Some of this repulsion can be relievedby rotation of the back pinanyl group to the con-formation with H inride, but only at the expense ofincreased pinanyl-pinanyl repulsions.I-Alkenes also form alcohols stereoselectivelywhen a D label is present on the alkene to establishthe direction of attack of the borane. Figure 15 showsthe preferred transition structures for formation ofthe major product. As with cb-Zbutene, the majorfactors controlling preference for this product are thepreferred conformation of the pinanyl groups, whichmakes the back group effectively larger, and theplacement of the alkene alkyl group near theeffectively smaller pinanyl group.Although we have not yet carried out com-putations on other systems, the model developedabove can be applied to understand the stereo-chemistry of reactions of dipinanylborane with1,ldisubstituted alkenes and with allenes, as well.Figure 15 shows the transition states which we pro-pose for these reactions. For 1,ldisubstituted al-kenes, the larger of the two alkyl groups prefers to beaway from the effectively larger pinanyl group. Thisleads to the prediction of formation of the R-alcohol,


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2270 K. N. HOUK r uf.

II I&__- _._A_$ HO H

-%

20-30X s.&(s)Me mono?

R L

I III :H~--__--__~H + S-~stmled faster

R S-alleneFig. 15. Expected transition structures for hydroboration of I-alkenes, 1,ldisubstituted alkenes, and1,3-disubstituted allenes with dipinanylborane.

whereas a modest preference for S is actually ob-served. We believe that this must arise from displace-ment of a-pinene, and reaction with mono-pinanylborane or monopinanyl-alkylborane, as fortruns- and trisubstituted alkenes.Caserio and Moore have found that S-allenes arehydroborated faster than R-allenes. Our model,shown in Fig. 15, shows the origin of this preference.The least hindrered approach leads to fastest reac-tion. The R-allene could only be hydroboratedthrough a transition state with one of the alkyls in amore hindered location than in the transition state forreaction of the S-allene.How does our model differ from those suggestedearlier? The major advance afforded by our model isthe relative certainty about transition structure con-formations achieved by the model ab ini tio calcu-lations, and the heretofore unrecognized preferencefor staggering about the forming CB and breakingBH bonds in the transition states of these reactions.There is a relatively simple and obvious way thatsubstituents attach to this transition state in a ste-rically least-hindered fashion. Other models generallyconsidered the conformation of the starting boraneand attempted to deduce how an olefin approachesthe borane.

For dipinanylborane, our model implies that ste-reochemical preferences arise from repulsions be-tween alkyl substituents and the small (H) group onthe front pinanyl group versus the large (CHMe)on the back. Browns model and Streitwiesers attrib-uted stereoselectivity to competition between Meinteractions with S or M.** Varma and Caspi alsoattributed differences to S and L, as in our model,although the preferred conformation of the borane inthe transition state was not the staggered one wepropose. The McKenna model uses the dimer,% butis otherwise like the Brown model, while Mooresmodel for allenes uses a non-planar transition state.3sNeither of these subtleties are necessary to explainstereoselectivity.Chid centers on C . . B. Kishi has discovered avariety of examples of hydroborations of this type,and has proposed a model to rationalize these re-sults. Figure 16 summarizes the stereoselectivitiesobserved for several reactions of this type, along withKishis model to rationalize these results. Kishi pro-posed that the alkene would align itself in the con-formation shown, which is expected to be thatfavored for the ground state of alkenes, with thesmallest of the groups (H) on the chiral centereclipsed with the alkene double bond. The borane


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71 29

75 25

92 8

89 11

Fig. 16. Stereoselectivities of hydroborations of chiral homoallylic ethers. Kishis reactant-conformer,steric-approach model is shown at the bottom.

then approaches from the side of the medium-sizedsubstituent (Me) rather than the side of the hugerG-containing substituent.Our version of this steric model, which is staggered,but otherwise similar to Kishis, has been describedearlier in this paper (Fig. 5) and in an earlier article.However, we were concerned about why groups suchas 2-fury) or alkoxymethyl should be substantiallylarger than methyl, since most of the bulk of thesegroups could easily be directed away from the remain-ing atoms involved in the transition state.Indeed, when various model systems were calcu-lated with our MM2 technique, we could find essen-tially no difference in steric effects for the preferredconformation of transition states for r e or si attackfor such molecules. Figure 17 shows the relativeenergies of several diastereomeric transition statescalculated by MM2. The generalizations made earlierdo hold for groups which are clearly different in size,such as H, Me and t-Bu. We predict moderatestereoselectivities in such cases, as shown by therelative energies of diastereomeric transition statesgiven in Fig. 17. However, the two types of substitu-ents attached to the chiral center in Kishis reactions

are too similar to exert any significant steric effect onstereoselectivity, as shown in the last three cases.However, the ab i n i t i o alculations described ear-lier for homoallyl ether interactions in the hydro-boration transition state show that there can be asignificant stabilizing interaction between a homo-ally1 ether and the alkene when this substituent is m t i .Since this interaction is a unique electronic inter-action (anchimeric assistance) in the transition statewhich is not accounted for by MM2, our model willnot reproduce these results. However, we can correctour MM2 model in the following way to give reason-able qualitative rationalizations of Kishis results. Asnoted previously, 3-21G calculations indicate that ana n t i alkoxymethyl group prefers the a n t i con-formation over the outside by 0.9 kcal/mol. The cor-responding difference is only 0.4 kcal/mol for the Megroup. Thus, the alkoxymetbyl a n t i preference is0.5 kcal/mol greater than the Me u n t i preference,and the ratio of products from A and B should beapprox. 70:30, somewhat lower than is observed(Fig. 16).

These results also suggest that homoallylic aminesand sulfides, and to a lesser extent, halides, will


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R AL x Es- EAt-Bu H n 0.501-b Me H 0.21

=v H H 0.03-CP n Me 0.04-v Me n 0.08

Fig. 17. Preferred transition structures and relative energies according to the MM2[3-21G] model forhydroborations of 3,4,4-trimethyl-I-pentene, 4-methoxy-3-methyl-I-butene, and methyl derivatives.

exhibit the same stereochemical preferences shown bythe homoallylic ethers, since these atoms are alsocapable of this type of anchimeric assistance.Chir al center at the H----C terminusI. Al kyd substituents. We already described a qual-itative model for pure alkyl cases. Although simpleexamples have not been tested experimentally, Mid-land has reported several cases involving a steroidnucleus as the chiral moiety.5 The results fit ourqualitative model satisfactorily. Examples of chiralketone reductions are also known5 and can be ratio-nalized by a similar model.2. Al lyli c alcohols and ethers. For the parent sys-tem, we have described calculations which indicate apreference for an ahylic OH substituent to be insideor outside, while an allylic ether prefers the outsideconformation. An MM2 model constructed in theusual way provides the same prediction, but alsoallows us to compute how alkyl substituents onboron, or additional substituents on the alkene, willinfluence stereoselectivity. Figure 18 compares somecalculated results obtained from the MM2 model toexperimental results obtained by Still6 For com-putational simplicity, we substituted Et groups inplace of the Bu groups present in Stills examples, andwe placed Mes on boron to model the dialkylboranesused in some experiments.For the 3-hydroxyalkenes with an unsubstitutedterminus, or those with a rrans-Bu-substituted termi-nus at C-l, little stereochemical preference is ob-tained upon hydroboration with diborane. This isalso found computationally. When a dialkylborane isused, or when there is a cis substituent at C-l of thealkene, a strong preference for formation of the

diastereomer arising from the H-inside, OH-outside,R-anti transition state is found. In these cases, theinside conformation is sterically hindered, so the OHstrongly prefers the outside position. With ethers, theOR outside conformation is always preferred, al-though here the calculations underestimate the degreeof preference.3. 1,3-Asymmetric induction. Finally, Evans et al.have reported several hydroborations involving mol-ecules with chiral centers which are homoallylic to thedisubstituted terminus of an alkene (Fig. Id). Wehave applied our MM2 model to an example of thistype, and the best transition states for formation ofthe major and minor diastereomers are shown in Fig.19. These differ in energy by 0.8 kcal/mol, predictinga ratio of -80:20 at room temperature, in goodagreement with the ratios found experimentally.Our calculations indicate that the origin of this1,3-asymmetric induction is precisely that proposedby Evans. The forming C---H bond causes the largeallylic substituent to move into the sterically leastcrowded anti position, while the two allylic hydrogensare located in the inside and outside positions. Thereis staggering around the C(allylic)-C(homoallylic)bond, and the largest substituent on the homoallylicC is aligned unti to the bond to the alkene C. In thepreferred (R,S>transition state, the homoallylic Mesubstituent is away from the alkene Me, while in the(S,S)-transition state, the homoallylic Me and alkeneMe experience significant repulsion. The double-headed arrows show these different interactions in thetwo transition structures.Since similar effects are operative for chiral centersat either alkene terminus or even on boron, otherexamples of 1,3-asymmetric induction are likely to be


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q_____-_I II I

E,., (kcalhol)P E! a hzH H 0 -0.1

W(R) 0 0.9

!mWt(ti H 0 -0.1 1 :1 0M&t) 0 0.8 8-9:1 1.2-1.3

Gia+d I+ 0 0.5Ma00 0 0.4

R

Expermentat~etk A&z*lZl.4 -0.2

2.5-ll:l Q5-1.4

6:l 1.1>15:1 > 1.6

Fig. IS. Comparisons of MM2[3-21G)predicted diastereomer ratios, and Stills experimental results forrelated cases.

found. Indeed, the chiral center in longifolylborane,a useful optically active hydroborating magent, islocated /I to the boron.

CONCLUSIONSWe have identified a number of conformational,steric. and electronic factors which lead to stereo-selectivities in a variety of known hydroborations.

Having identified these, and developed a numericalmethod which provides good estimates of stereo-selectivity, we are in a position to undertake real chal-lenge, the prediction of the unknown! The ideas devel-oped here allow us to develop reliable design criteria tobe used in arriving at promising new avenues of experi-mental study. In subsequent papers, we will use theprinciples and methods reported here to predict usefulnew stereoselective reagents.

0

2

%%

1 */

%S20Fig. 19. Computed transition structures for formation of R,S (major) and S,S (minor) products in Evanshydroborations.


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2274 K. N. HOUK el alAcknowledgements-We are grateful to the National Insti-tutes of Health for financial support of this research, and tothe National Science Foundation for an equipment grantwhich made acquisition of the Chemistry Department Har-ris 800 minicomputer possible. Computer graphics weremade possible by the National Institutes of HealthPROPHET Computer System. K. N. H. is indebted to theAlexander von Humboldt Stiftung for a U.S. Senior Sci-entist Award, which made valuable discussions of thissubject with European scientists possible.

REFERENCES AND NOTESPermanent address: New South Wales Institute of Tech-nology, New South Wales, Australia.2J. D. Morrison and H. S. Mosher, Asymmefric OrganicReactions. Prentice-Hall, New York (1971); P. A. Bartlett,Tefrahedron 36, 2 (1980).H. C. Brown, P. K. Jadhav and A:K. Mandal, Tetrahedron37, 3547 (1981); H. C. Brown and P. K. Jadhav, J. Org.Chem. 46, 5047 (1981); H. C. Brown, M. C. Desai and P.K. Jadhav. J. Org. C/rem. 47,5065 (1982); H. C. Brown, A.K. Mandal. N. M. Yoon. B. Sinaaram. B. Schwier and P.K. Jadhav, i. Org. Chem47.5069 (1982); H. C. Brown, P.K. Jadhav and A. K. Mandal, J. Org. Chem. 47, 5074(1982); and refs therein.Y. Kishi, Aldrichimica Acra 13,23 (1980); H. Nagaoka andY. Kishi, Tetrahedron 37, 3873 (1981); and refs therein.M. M. Midland and Y. C. Kwon, J. Am. Chem. Sot. 105,3725 (1983).6W. C. Still and J. C. Barrish, J. Am. Chem. Sot. 105,2487(1983).D. A. Evans, J. Bartroli and T. Godel, Tefrahedron Lefters.23, 4577 (1982).*U. Burkert and N. L. Allinger, Molecular Mechanics.American Chemical Society, Washington, D.C. (1982); N.L. Allinger, J. Am. Chem. Sot. 79, 8127 (1977); QuantumChemistry Program Exchange No. 406.9M. J. S. Dewar and M. L. McKee, Irwrg. Chem. 17, 1075(1978).OG.D. Graham, S. C. Freilich and W. N. Lipscomb, J. Am.Chem. Sot. 103. 2546 (1983).T. Clark and P. v. R. Sohleydr, J. Org. Chem. 150, (1978).*S. Nagase., N. K. Ray and K. Morokuma, J. Am. Chem.Sot. 102,4536 (1980).T. Clark, D. Wilhelm and P. v. R. Schleyer, J. Chem. Sot.Chem. Commun. 606 (1983).

IM. N. Paddon-Row. N. G. Rondan and K. N. Houk. J.Am. Chem. Sot. 104;7162 (1982).lJH. C. Brown, Hydroborufion. Benjamin, New York (1962);Boranes h Organic Chemistry. Cornell University Press,Ithaca (I 972).J. S. Binkley, J. A. Pople and W. J. Hehre, J. Am. Chem.Sot. 102,939(1980).J. S. Binkley, R. A. Whiteside, R. Krishnan, R. Seeger, D.J. DeFrees, H. B. Schlegel, H. B. Topiol, L. R. Kahn andJ. A. Pople, GAUSSIAN 82. Carnegie-Mellon University,Pittsburgh, Pennsylvania (1983).

sT. P. Fehlner, J. Am. Chem. Sot. 93, 6366 (1971).i9P. Caramella, N. G. Rondan, M. N. Paddon-Row and K.N. Houk, 1. Am. Chem. Sot. 103, 2438 (1981).mN. G. Rondan, M. N. Paddon-Row, P. Caramella, J.Mareda, P. H. Mueller and K. N. Houk, J. Am. Chem. Sot.104, 4974(1982).2M. Cherest, H. Felkin and N. Prudent, Tetrahedron Lams2199, 2205 (1968).22N.T. Anh and 0. Eisenstein, Norm. J. Chim. 1,61 (1977);N. T. Anh, Forrschr. Chem. Forsch. 88, I45 (1980).231. McCary, M. N. Paddon-Row and R. N. Warrener,Tetrahedron Lerrers 1401 (1972); M. N. Paddon-Row andR. N. Warrener, Tetrahedron Lerrers 1405 (1972); M. N.Paddon-Row, H. K. Patney and R. N. Warrener, J. Org.Chem. 44, 3908 (1979).%. R. Moses, Y.-D. Wu, N. G. Rondan, K. N. Houk, R.Schohe, V. Jager and F. Fronczek, submitted for publica-tion.2JR. C. Bin&m and P. v. R. Schleyer, J. Am. Chem. Sot.93, 3189 (1971); J. L. Fry, E. M. Engler and P. v. R.Schlever. Ibid. 94. 4628 (19721: W. L. Parker. R. L.Tranier, C. I. F. Watt, L: W. K. Chang and P. v. R.Schleyer, Ibid. 96, 7121 (1974).%D. F. DeTar, J. Am. Chem. Sot. 96, 1254, 1255 (1974); D.F. DeTar and C. J. Tenpes, Ibid. 93, 4567 (1976).21J.-C. Perlberger and P. Muller, J. Am. Chem. Sot. 99.6316(1977); and refs. therein.mP. Miiller, J. Blanc and D. Lenoir, Helu. Chim. Acra 66,I21 2 (1982); P. Miiller, J. Blanc and J.-C. Perlberger, Ibid.65, 1418 (1982).9w. C. Still and I. Galynker, J. Am. Chem. Sot. 104, 1774(1982).uE. W. Garbisch, Jr., S. M. Schildcrout, D. B. Pattersonand C. M. Sprecher, 1. Am. Chem. Sot. 87, 2932 (1965).G. Zweifel, W. R. Ayyangar and H. C. Brown, J. Am.Chem. Sot. 84. 4342 (i96f).J2A. Streitwieser, Jr., L. Verbit and R. Bittman, J. Org.Chem. 32, 1530 (1967).33K. R. Varma and E. Caspi, Tetrahedron 24, 6365 (1968).D. R. Brown. S. F. A. Kettle. J. McKenna and J. M.McKenna, &em. Commwt. 667 (1967).W. L. Waters, W. S. Linn, M. C. Caserio, J. Am. Chem.SOC. 90,674l (1968); W. R. Moore, H. W. Anderson andS. D. Clark, J. Am. Chem. Sot. 95, 835 (1973).MThe figures are drawn from calculations in which theboron and three attached atoms were constrained to lie ina plane. Calculations in which this constraint was removedresulted in conformations very similar to those shown, butwith a pyramidal borane group. The parameters used inthese calculations were normal, except for boron, forwhich force constants for stretching, bending, and torsionwere set equal to those of sp2 carbon. The equilibrium CBand CH bond lenaths and CBC. CBH and HBH analeswere taken from ub inirio calculations on methylbor&eand dimethylborane. The van der Waals radius of boronwas used in the calculation of van der Waals repulsionsinvolving the B atom.

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