Organoboranes for Synthesis—Substitution with Retention

Organoboranes for synthesis—substitution with retention

HerbertC. Brown and Bakthan Singararn

H. C. Brown and R. B. Wetherill Laboratories of Chemistry Purdue University, West Lafayette, Indiana 47907, U.S.A.

Abstract -Thefacile reaction of olefins, dienes and acetylenes with various hydroborating agents made a vast array of organoboranes readily available. Organoboranes tolerate many functional groups and are often formed in a stereosnecific manner. The boron atom in these organoboranes can be readily substituted with a variety of functional qroups to give organic compounds under mild conditions such that organoboranes now appear to be among the most versatile internediates available for organic synthesis. Exploration of these substitution reactions revealed that the organoboranes transfer the alkyl group to essentially most of the other elements of synthetic and biological interest, includinci carbon, with complete maintenance of stereochemical integrity. Consequently, the organic groups that are formed stereospecifically by the hydrohoration reaction can be readily incorporated into organic molecules. A recent development -preparationof optically pure orqanohorane intermediates -makespos- sible the synthesis of essentially any comnound containina a chiral center in both optical isomers in essentially 100% optical purity. Thus, our research program has taken boranes from an exotic material of little interest to a reagent widely used in organic synthesis, greatly assisting chemists in overcoming synthetic difficulties.

INTRODUCTION

The remarkably facile addition of diborane in ether solvents to alkenes and alkynes was discovered in 1956 (ref. 1). For the next decade a major portion of the research effort of my students and associates was devoted to systematic studies of the scope and characteristics of hydroboration reaction. These established that hydroboration is essentially quantitative, involves a cia anti—tlarkovnikov addition from the less hindered side of the double bond and can tolerate essentially all functional groups (ref. 2). When we were exploring the hydroboration reaction, many individuals expressed skepticism to me as to the wisdom of devoting so much research effort to this reaction. After all, hydroboration produced organoboranes. At the time we started, only three things were really known about organohoranes: (1) they were oxidized by air; (2) they were stable to later; (3) they formed addition compounds with bases. Besides, relatively little new chemistry of organoboranes had appeared since the original classic publication by Frankland in 1862 (ref. 3). iany individuals took the position that the lack of published material in this area meant that there was little of value there. In this case, it is now clear that this position is not correct. After our exploration of the hydrohoration reaction had proceeded to the place where we felt we understood the reaction and could apply it with confidence to new situations, we began a systematic exploration of the chemistry of organoboranes, with emphasis on reactions of synthetic utility. A systematic study of the reactions of organohoranes revealed their exceptional versatility (ref. 2). Our studies have established that these oroanoboranes transfer the alkyl aroun to essentially most of the other elements of synthetic and hioloqical interest with complete maintenance of stereochemical integrity. Typical transformations are indicated in Fig. 1. It is not possible here to give more than a taste of the rich chemistry. Consequently, this article is restricted to some of the substitution reactions of oroanohoranes that proceed with retention of configuration.

879 880 H. C. BROWN AND B. SINGARAM

RCH=CHCHCHR' air, cis cis, trans trans,trans ROH etc.

R—C2 .RNH2 CH

RR CHNH2 RCeCR'

Fiq. 1. Chart summar- izinci representative substitution reactions of orqanoboranes

RRCOH RCH2COR

PROTONOLYSIS

The organoboranes are remarkably stable to water, aqueous bases, and aqueous mineral acids. However, they are susceptible to protonolysis bycarboxylicacids. Trialkylboranes require relatively vigorous cnnditions. In general, they must he heated under reflux with excess propionic acid in diglyme for 2 to 3 hours (ref. 4). This provides a convenient non-catalytic means of hydrogenating double bonds in comnounds where the usual catalytic hydrogenation is difficult (1). EtCO,)H RSCH CHCH - — RSCHCH CH 2 2 RSCH 2L3CHnCH (1) ,B A

Vinylboranes undergo protonolysis with particular ease, providinn a simole route to cis— olefins from the corresnondinq acetylenes (ref. 5)(2).

R R R P. RCCR HB \j (2) HB- H H /

Protonolysis of organoboranes proceed with retention of configuration (ref. 4). Thus one can take advantage of the unique properties of the hydroboration reaction to achieve stereospecific hydrogenations (ref. 6, Fig. 2).

CH2—)3B CH3

trans-Pi nane Fin. 2. Hvdroboration_I5rotonolvsis B CH—)B of -pinene to provide either cis-. or trczns-ginane as desired EtCO2H 33 A cj8—Pi nane Organoboranes for synthesis—substitution with retention 881

Protonolysis also makes possible the stereospecific synthesis of deuterium derivatives (Fig. 3).

EtCO9D 5/3ZIII2)B BD3 EtCO2H /IiI2B Fig. 3. Hydroboration-orotonolysis of protonolysis BD''\ Z2__D EtCO2D

The high reactivity of organoboranes with carboxylic acid is unexpected, althouah not un reasonable. This reactivit" may be ascribed to an initial coordination of the electron-rich carbonyl oxygen of the acid with electron-deficient boron (3).

+ (3) EtCO2D 'B' D DA

OXIDATION Thereaction of alkaline hydrogen neroxide with ornanohoranes is a remarkably clean reaction of wide generality (ref. 7, 8). It is essentially quantitative and takes place readily in the presence of the usual hydroboration media and can accommodate all groups which tolerate hydroboration. Alternative reagents include buffered peroxide, trimethylamine oxide and m- chloroperbenzoicacid (ref. 0-11). Hydroboration-oxidation studies with cyclic and bicyclic alkenes led to the generalization that the reaction proceeds with complete retention of configuration (Fig. 4, ref. 12).

OH HB + 00H +ThH

jB H OH + r

Fin.5. Proposedmechanismfor the oxidation HO 2.OH ofB—R by alkaline hydrogen peroxide ' NaOH

Fin. 4. Representative iydroborations-oxidations which establish retention in the oxidation stage

Consequently, hydroboration, followed by in situ oxidation with alkaline hydrooen peroxide, provides a simple, broadly applicable procedure to achieve the cia—, anti—1arkovnikov hydra- tion of double bonds (4).

HOOH + —÷ 00H+ oil 1120 r (4) \ oifl B—R+ OOH —p B +ROH / L 01J 882 H. C. BROWN AND B. SINGARAM

FORMYLATION Carbonylation to aldehydes Treatment of organoboranes with carbon monoxide in the presence of certain hydride reagents providan intermediate which is oxidized to the aldehyde or hydrolyzed to the homologated alcohol derivative. The use of B-alkyl-9-BBH derivatives is especially effective in permitting complete utilization of the alkyl groups (Fig. 6, ref. 15,16).

9-BBN > RCH=CH2 9-BBN 1. Co 2. tlH 6'B RCH2CH2CHON KOH

RCH2CH2B -, Li Al H4 / TsC1 6NOH RCH2CH2CH2OH trans

Fig. 6. Conversion of R—BZvia Fiq. 7. Pronosed mechanism for the carbonylation of carbonylation into aldehydes or organoboranes to aldehydes or methylols with coenlete nethylol derivatives retention of confiauration

The stereospecificity realized in thehydrohoration reaction is retained durinci the reaction (Fin. 7, ref. 17).

A possible mechanism for this reaction is that the acyldialkylborane, the first alkyl minrated product in the carbonylation.reaction of trialkylboranes, is trapned by the hydride reducinq agent to provide the a-alkoxy intermediate (Fin. 6).

Aldehydes from boronate esters

Alkylboronate esters are readily converted into the correspondinq aldehydes by successive treatment with methoxy(phenylthio)-methyllithium (lIPIIL), mercuric chloride and buffered hydrogen peroxide (ref. 18) (5).

—1.__FIPML ______RCHO RB(OR')2 RCH(Orle)B(OR')2 (5) 2. HgC12

The reaction proceeds with retention of configuration at the minrating carbon atom, as observed in other related reactions of organoboranes. Thus, the trans geometry obtained by hydroboration of 1-methylcyclohexene is retained in the product (Fig. 8).

OMe

1. RHBr2 1.MPHL a á# 2. ) HnC12 2. ( Fig. 8. Transformation \__ OH [0] ofthe hydroboration productfrom 1-methylcyclohexene into trans- LiA1H 2-methyl cycl ohexane OTs 1. 4 - 4_ B1S c5CH0 carboxaldehyde with 2. TsCl completeretention of a confi ciurati on trans Organoboranes for synthesis—substitution with retention 883

The reaction proceeds through the intermediate formation of a stable ate complex. Addition of mercuric chloride induces the alkyl qroun of migration, presumably by coordinatinq with the sulfur atom. The c-methoxyboronate ester, upon oxidation, furnishes the aldehyde (Fio. 9).

B') MPFIL .+ ó.10D1Li a CH(01e)Sj

,HgCl2 Fig. 9. Intermediates in the conversion of boron intermediates into the OMe aldehyde by the 1P!1L reaction

-CHO H202 o# 8

OXYCARBONYLATION

Treatmentof alkylthioboronic esters with trichloromethyllithium provides an intermediate which is oxidized to the carboxylic acids or hydrolyzed to the aldehyde thioacetals (Fin. 10, ref. 19).

1. BHBr2 r - RCH=CH2 RCH9CH2B( 1.LiCC1 rSLi ______2.1 L_ SLi 2. 65°C jLiCCl3 /[o] RCH2CH2C02H 0— RCH CH CB' 2 RCH2CH2CH aOH pure trans by 13C NMR

Fin. 10. Conversion of organoboranes Fig. 11. Evidence that the conversion Oforcianoborane into carboxylic acids intermediates into carboxylic acids by the MPML reac tion proceeds with retention

The configuration attained by hydroboration of 1-methylcyclonentene is retained in the nroduct (Fig. 11).

This reaction apparently proceeds throunh the following mechanism (Fiq. 12).

SR . ESRI 1 / LiCC13 + -LiCl / RB RBCC13 Li * RCC12B SR L'J F Fig. 12. Proposed mech- ITH anism for the conversion of organoborane SR SR intermediates into the / THF ______[0] RCB RCC1B' corresponding carboxy- RCO2H I \ Cl \ lic acids SR' 0 SR

Alternatively,the aldehydes obtained from the formylation of organoboranes can be easily oxidized by the two-phase chromic acid procedure to furnish carboxylic acids (ref. 20). 884 H. C. BROWN AND B. SINGARAM

HOMOLOGATION TO METHYLOL DERIVATIVES

Reactionof alkylboronic esters with dichioromethyllithium (the Ilatteson reaction), followed by reduction of the intermediates with potassium triisopropoxyborohydride (KIPBH), gives the corresponding one-carbon homologated boronic esters. Oxidation provides methylol derivatives (ref. 21) (6).

O\ 1. LiCHC1 2 [0] RB RCH B RCH OH (6) 2 2 2. KIPBH _,,

In this reaction also, the transfer of the alkyl group from boron to carbon proceeds with stereochemical integrity (Fig. 13). The mechanism of the reaction is given in Fig. 14.

1. BHBr2

/0H ______2.( áBc) LiCHC12 \—OH 1. LiCHC12 KIPBH KIPBH

OHBQ KC1 + Fig.13. Homologation of boronic Fig. 14. Proposed mechanism homologation esters into the hiqher boronic esters of horonic esters with retention with retention

Alternatively, a one-carbon homolonation of organoboranes can be achieved by the reaction with chloromethyllithium generated insitu fromeither C1CH2I and n—BuLi (ref. 22) or C1CH2Br and n—BuLi (ref. 23).

AMINATION

Primaryamines Eitherchloramine or O—hydroxylamine sulfonic acid (HSA) can be used to convert organoboranes into the corresponding amines (ref. 24). The use of dimethylalkylboranes is especially effective in permitting essentially complete utilization of the alkyl groups (ref. 25) (7). NH2OSO H RBMe2 RNH2 (7) The reaction proceeds with retention of configuration, making it possible to retain the remark- able stereospecificity of the hydroboration reaction (Fig. 15). The reaction is believed to involve a mechanism similar to that postulated for oxidation with hydrogen peroxide (Fig. 16).

. LifieBH - 2. ciii rle3SiCl j.#Bt1e2 + ,j, NH2OSO3H IIe2BR +:NH2OSO3H— Me2B—NH2—OSO3H NH2 1. H20 ,,J NH2BMe2 2. NaOH HO - L.,,,) OSO3H + ______2 fle2B—NH2 OSO3H trans R!H2H2SO4 Me2BOH

Fia.15. Amination of orqanoborane inter— Fig. 16. Proposed mechanism for the mediates with retention of confiouration amination reaction Organoboranes for synthesis—substitution with retention 885

Secondaryamines Thereaction of orianic azides with organoboranes, preferably the monoalkyldichloroboranes, provides a convenient route to secondary amines (ref. 26) (8).

HBC12 BBCl2 RN3 (8)

This procedure provides a simple route to pure N—exo—norbornyl aniline, correspondinq to retention in the reaction of the exo—norbornyl boron moiety produced in the hydroboration (Fig. 17). Experimental data for this reaction is consistent with a mechanism involving Lewis acid complexation (Fig. 18).

HBC1 2) BC12 N RBC1 +RN — C1B—N—R' 2

H20

NBC12 H,,O Ph Ph B(OH)3 +HNRR' Cl1—N—R' Cl

Fig. 17. Synthesis of secondary amines Fii. 18. 1echanism for the synthesis of with retention from orcianoborane inter- secondary amines mediates and organic azides

ACETYLENE SYNTHESIS

The ate complex formed by the reaction of an orcianoborane with a lithium acetylide reacts readily with iodine at -78°C to give the corresponding acetylene (ref. 27) (9).

-78°C LiCECR'—* R3B + [R3BCC]Li RCCR' (9) 12 The reaction makes possible the ready synthesis of some acetylenes that would otherwise be difficult to prepare (Fig. 19).

+ LiCECC(CH3)3 ThxBHC1 +alkene—*ThxBRC1 5F1e2 S•1e2

ThxBRC1.SMe2+ NaOCH3—ThxBR(OCH3) +NaC1 + Me25 - Li )3BECC(CH3)3 ThxBR(OCH3) +LiCECR' Li ThxECR'

OCH3 I,J-78°C —

I -78°C

D—CC_C(CH3)3 RCECR'

Fig. 19. Simnle synthesis of rihen,l— Fig. 20. Improved procedure for the synthesis of tert—butyl-acetylene acetylenes avoidina the R groups

This procedure involves the loss of two of the three organic groups on boron. Fortunately, a recent development allows one to avoid such loss (Fig. 20, ref. 28). 886 H. C. BROWNAND B. SINGARAM

Use oflithium acetylide-ethylene diamine makes possible the synthesis of simple acetylenes (ref. 27). Application of the reaction to 1-methylcyclopentene established that the reaction proceeds with complete retention of confiriuration (Fig. 21). LiCCH Li Là]c óc5: : 90%yield pure trans Fig.21. Acetylene synthesis proceeds withretention

SUBSTITUTIONWITHOUT RETENTION Whereasthe nreat maiority of the substitution reactions of orqanoboranes proceed with complete retention, a few reactions are known, which nroceed with loss of stereochemical intenrity or with inversion.

Oxidationby oxygen Orqanoboranescan be quantitatively converted into alcohols by the controlled treatment with air or molecular oxygen (10, ref. 29).

1.5 —- 3 ROH R3B + 02 _(R02)15BR15 (10) The formation of the peroxy intermediate proceeds throuah free radical intermediate, resultina in a loss of the stereochemical integrity of the final product (Fin. 22). —÷R R3B +02 R + _ 02 R02• —p + etc. R02 +R3B RO2BR2 R, HB )3B 1. 1.5 02'0H + 2.NaOH OH Fig. 22. Oxidation of l4/ 86% organoboranes by molecular ,,3 1. 1.5 02 oxyqen pro- HB (1N0H 2. NaOH \.__J1 loss of stereochemical 81% 19% identity

It is important that the oxidation by alkaline hydrogen peroxide, which proceeds with complete retention of confiquration (ref. 8) be carried out with complete exclusion of atmos- pheric oxygen.

REACTION OF R3BWITH CONJUGATED ALDEHYDES AND KETONES Thetreatment of orqanoboranes with acrolein or other a,-unsaturated carbonyl compounds like- wise proceeds through free radical intermediates (11, ref. 30,31).

R3B + —* CH2=CHCHO RCH2CH2CHO (11) The reaction appears to involve an interestinri type of chain reaction (Fin. 23). 02 R R3B R+ —÷ — CH2=CHCHO RCH2CHCHO RCH2CH=CH0

—* +R• RCH2CH=CHO +R3B RCH2CH=CHOBR2

Fig. 23. Proposed mechanism for the 20 reaction of ornanoboranes with RCH2CH2CHO conjugated aldehydes and ketones Organoboranes for synthesis—substitution with retention 887

Although this point does not anpear to have been examined critically, it is probable that the reaction will involve the same kind of loss of stereochemical identity in the alkyl oroups as has been established for the reaction of ornanoboranes with oxygen.

CONVERSION OF ORGANOBORANES TO HALIDES In the presence of alkali, organoboranes, R3B, readily react with bromine or iodine to aive the corresponding halides, RBr and RI (12,13, ref. 32,33).

212 -* 2 2Hal + (12) (RCH2CH2)3B RCH2CH2I + RCH2CH2B(OH)2 2 NaOH

2 Br2 - 3NaBr (13) (RCH2CH2)3B - 3RCH2CH2Br + 2 NaOCH3

The reaction is more sluqaish for secondary alkyl nrouns. Somewhat surprisina, the bromina- tion of exo—norbornyl boron derivatives proceeds with predominant inversion to yield endo— norbornyl bromide, the inverted product (Fin. 24).

HO HOSO2NH2- H if HO H2N"" U U

(R)— (—)—,

87%e.e. 75% e.e. 112/OCH3 Br2 1NaOCH3

84% e.e. H

Fig. 25. An examnle of inversion as contrasted to oredominant retention in the substitution Fig. 24. Inversion in the conversion reactions of orcianoboranes of exo-norbornyl boron intermediate into the norbornyl bromide

As a final example, it may be mentioned that the observation that the chiral intermediate, 2- butyldiisopinocampheylborane, is readily converted into optically active 2-butanol (ref. 35) and optically active 2-aminobutane (ref. 36), both with complete retention of configuration, but into 2-iodobutane (ref. 37) with comnlete inversion of confiquration (Fin. 25).

A GENERAL ASYMMETRIC SYNTHESIS The realization that the great majority of the substitution reactions of orpanoboranes proceed with retention made it evident that if we could learn to achieve the synthesis of optically active groups attached to boron, we could transfer those proups to carbon and other elements to permit a general synthesis of optically pure enantiomers.

Our approach has been to emphasize the synthesis of optically active hydroborating agents by practical hydroboration of appropriate terpenes. These reanents are then used to hydroborate alkenes to produce the desired optically active alkyl group attached to boron (ref. 38). 4n alternative approach has been utilized by D. S. !latteson and his coworkers (ref. 39). They have synthesized esters of boronic acids, RB(OH)2, with appropriate chiral diols and then treated these esters with lithium dichloromethide. Subsequent treatment of the intermediate with R'Li or R.1gX provides the optically active intermediate, RR'C*HB(OH)2. Since 1atteson is presenting his approach at I1EBORON VI, we shall concentrate on the hydroboration anproach in the present treatment. 888 H. C. BROWN AND B. SINGARAM

ASYMMETRIC HYDROBORATION—Ipc2BH

Inour original study of hydroborations with optically active Ipc2BH (ref. 35), we used reagent prepared from commercial c-pinene of relatively low enantiomeric purity (93%). How- ever, we have now learned to prepare reacient of high enantiomeric purity from such ct-pinene. The reagent is equilibrated at 0°C with 15% excess a-ninene. The major isomer becomes incorporated into the crystalline reagent, leaving the minor isomer in solution (Fiq. 26, ref. 40).

THF 2 +BH J,2BH O°C/3 days 2 + BH3.SMe2 j 94.7%e.e. (+)-ct-pinene 91.3% ee 91.3% ee excess (15% excess) J._)2BH ji5%

e.e. minor isomer O0% ,)2BH looc — Fig.26. Preparation of pure diiso- 2 3 CH5CH0 + pinocamnheylborane 20 h 98.9% em 98.9%cc

Fig.27. Preparation of a-pinene of high optical purity

Treatment of Ipc2BH with benzaldehyde liberates c-pinene of 100% ee. Thus the two reactions provide a convenient procedure for upgrading commercial c-pinene to an enantiomeric purity of essentially 100% ee (Fig. 27, ref. 41,42).

Improved asymmetric results were realized in the hydroboration of cis—alkenes with this improved reagent and a somewhat lower hydroboration temperature (-25°C) (Fig. 28, ref. 43).

Bnz

OH 0H OH HO HO HO HO nz 98.4% e.e. 92.3% e.e. 93% e.e. 83%e.e. 100%ee 100% ee 100% ee 86% ee

Fiq.28. Asymmetric hydroboration of cis- Fig. 29. Asymmetric hydroboration of alkenes with Ipc2BH some heterocyclic alkenes

Hydroboration of heterocyclic olefins with Ipc2BH is both highly regio- and enantioselective. Thus asymmetric hydroboration of 2,3-dihydrofuran, followed by oxidation of the intermediate, provides 3-hydroxytetrahydrofuran in essentially 100% ee (Fig. 29, ref. 44,45).

Diisopinocampheylborane handles cis-alkenes very effectively. However, it is not an effective asymmetric hydroborating agent for 2-methyl-l-alkenes, trans—alkenes and trisubstituted alkenes. Evidently the steric requirements of 2-methyl-l-alkenes are too low to provide a good steric fit with the reagent. On the other hand, the steric requirements of trans—andtn- substituted alkenes appear too larcie for the reagent. It appeared that monoisopinocampheyl- horane, IpcBH2, might be more effective for the latter types of alkenes (Fig. 30).

2-METHYL-1-ALKEHE ' 20%e.e.

n cis—ALKENES '100%e.e.

trczna-ALKENES '20% e.e. 5 TRISUBSTITUTED ALKENES " )0 20% Fig.30. Ipc2BH handles only one class Will IpcBH2 handle more hindered classes? effectively Organoboranes for synthesis—substitution with retention 889

ASYMMETRIC HYDROBORATION—IpcBH2

Itis difficult to halt the hydroboration of c-pinene at the monoalkylborane stage. Conse- quently, IpcBH2 must be prepared by an indirect route. Treatment of Ipc2BH with one-half molar equivalent of NN,N',N'—tetramethylethylenediamine (T1ED) provides 2 IpcBH2TI1ED. The diastereomeric adduct crystallizes out in enantiomerically pure form. The pure reagent, IpcBH2, is readily liberated by treating the adduct with boron trifluoride etherate (Fig. 31, ref. 46).

)BH

+ 2 2 2 BH3SMe2

1TMED

2 2 IpcBH2 ±!—— IpcBH2'NH2BIPC + 100% e.e. 100%e.e. -- HO H0 H0 Fig.31. Synthesis of IpcBH2 in 100% ee H H (S)—(+)—, (S)—(+)—,

73%e.e. 75% e.e. 92% e.e. 75% e.e.

Fig.32. Asymmetric hydroboration of trans-alkeneswith IpcBH2

Monoisopinocampheylborane is very effective for the asymmetric hydroboration of trans—alkenes (Fig. 32, ref. 47).

Similarly, the hydroboration of trisubstituted alkenes with IpcF3H2, followed by oxidation of the intermediate organoboranes, provides the correspondinq alcohols in 53-72% ee (Fig. 33, ref. 48,49).

HO'1'J HO'iJ HO 110 1'h H0h1 (2S 3S)-(-)— (25,3S)-(÷)—, (1S,2R)—(+)—, (1S,2R)—(+)—, (S)—(+)—, (R)—(+)—, (1S,2s)—(+)—, (1S,2s)—(÷)—, 53% e.e. 62% e.e. 66% e.e. 72% e.e. 82% ee 85%ee 85% ee 97% ee

Fiq.33. Asymmetric hydroboration of tn- Fig. 34. Asymmetric hy'iiroboration of tn- substituted alkenes with IpcBH2 substituted alkenes with a phenyl sub- stituent by IpcBH2

For some reason, the asymmetric hydroboration of the phenyl derivatives nrovides considerably improved asymmetric synthesis. For examnle, 1-phenylcyclopentene provides the hydroboration product in 85% ee. Possibly the cireater steric requirements of the phenyl groun or the r- cloud provide a more optimum fit with the reagent (Fig. 34, ref. 50,51).

It appears that Ipc2E3H and IpcBH2 are complementary to each other. Excellent results are realized in the case of unhindered cis—olefins by using a reanent with large steric requirements, IPc2BH. On the other hand, hydroboration of olefins with lamer steric requirements is more favorable with a reagent of lower steric requirements, IpcBH2. These two reaqents handle three of the four major classes of alkenes. There remains a need for a reagent which will provide access to products of high ee from alkenes of relatively low steric requirements such as the 2-methyl-l-alkenes (Fici. 35). However, as discussed later, tie have developed an alternative solution to this problem. 890 H. C. BROWNAND B. SINGARAM

CLASS Ipc2BH IpcBH2 " ' ,2_METHYL_1-ALKENE 20%'e.e. 1% "100%e.e. '25% CCi—ALKENES '-trans-ALKENES "20%e.e. 70-90% e.e. . Fiq.35. Range of applicability of Ipc2BH cTRISUBSTITUTED ALKENES '20%e.e. 60-100% e.e. and IpcBH2

ANEW ASYMMETRIC HYDROBORATING REAGENT

Recently1asamune and coworkers have reported an alternative approach to asymmetric hydroborating agents (ref. 52). Instead of relying on optically active terpenes to provide the active R2BH reagents, they undertook to synthesize such a reagent. 2,5-Dibromohexane was converted into the di-Grignard reagent. This was treated with C12BNEt2 to form the three isomeric B—methoxy-2,5-dimethylborinanes. Byappropriateuse of three complexina agents, N,N—dimethylethanolamine, (+)-prolinol and (-)-valinol, these three isomers were separated and resolved (Fig. 36). - I &le Me Me MgBr ?lgBr : * ER,S] [R)R] [s,sJ

OH OH H HO NMe NH2

Fig.36. Synthesis of a new asymmetrichydroborating B --.[J)_— J)_— aaent O\) [R,SJ [RJRJ [s,s]

Utilizing a reaction to be discussed later, theyconvertedthe desired isomer into an pntic- ally active hydroborating agent.

[R,RJ

This reagent yielded excellent results in the hydroboration of three of the four representative classes of olefins. Only 2-methyl-l-alkenes proved resistant (Fig. 37). \/

1.4%ee 95% ee 97% ee 94% ee

Fig. 37. Asymmetric hydroboration with the Masamune reagent

It has not yet been established whether this new hydroborating agent can be recycled in the manner to be discussed later for diisopinocamoheylhorane. Organoboranes for synthesis—substitution with retention 891

ASYMMETRIC BORONIC AND BORINIC ACIDS Initially,the application of chiral organoboranes was limited primarily to alcohols because of the presence of the isopinocampheyl groups on boron in the product. Recently we discovered that these groups can be selectively eliminated by treatment of the mixed chiral organoboranes with acetaldehyde, regeneratinn c-pinene, and providing the optically active boronate as the product. In this way, 2-butyldiisopinocampheylborane is readily converted into diethyl 2-butylboronate in 97% ee (Fig. 38, ref. 53).

BH 2 + ___ BH3.SMe2 +

92%ee 99% ee 15% excess 100% ee recrystal 1 izedj2 cH3CHO/25c/6

HO- + 2 _)2B11,__.____ (EtO)2B.,/

100% ee 100%cc 100% cc 97%cc [ct] +25.4 Fig. 38. Asymmetric hydroboration with Ipc2BH with regeneration of the -pinene Fig. 39. Asymmetric hydroboration with IpcBH2with regeneration of c-pinene

Similarly, diethyl trans—2-phenylcyclopentylboronate can be obtained in 100% ee (ref. 51). The elimination of the isopinocampheyl group is highly selective. Indeed, in all cases we have studied thus far, this group is eliminated in preference to the desired chiral group (Fig. 39, ref. 53,51).

It should be noted that in this synthetic approach the chiral auxiliary, c-pinene, is readily recovered and recycled (Fig. 40)

8H2

%,O11n-A

Fig. 40. Easy recycle of the chiral auxiliary 4>N%CHCPIO B

C2H5

Itwasapparentthat if we could control the hydroboration step to yield boron intermediates of 100% ee this chemistry would provide a major synthetic route to the preparation of optically pure enantiomers.

GENERAL ASYMMETRIC SYNTHESIS A recent development in our laboratories offers promise of a general synthesis of essentially any organic compound containing an asymmetric center in 100% ee. Either of the two enantiomers can be produced as desired. Consequently, it would appear that for the first time we have within our grasp a rational synthesis of almost any organic compound with an asymmetric center in 100% ee.

As discussed earlier, asymmetric hydroboration of alkenes with either Ipc2BH or IpcBH2 as appropriate provides the correspondino chiral organoborane containing the new alkyl group R* in from 53 to 100% ee. While this is encouraging, it would be more desirable to have the alkyl group R* available in all cases in 100% ee. Once the group is on boron, it can be transferred to carbon and many other elements of interest with essentially complete retention of activity. 892 H. C. BROWN AND B. SINGARAM

Itwas noted that the hydroboration products of both Ipc2BH and IpcBH2 are often solids. Consequently, instead of oxidizing the entire reaction product, providing us with the total ee achieved, we undertook to separate the crystalline product from the total hydroboration product. We achieved organoboranes containing the R* group in essentially 100% ee (Fig. 41, ref. 54).

BH2 olefin R* ,- Ph crystalline B(OR)2 B(OR)2 J,,,,,H cII:7—

B(OR)2 ROH ct— 53-100% ee PhJ'H( 2 100% e

Fig.41. riajor improvement in optical Fig. 42. Optically pure boronic esters purity afforded by recrystallization of the hydroboration product

We are now in position to obtain both the initial hydroboration product, IpcR*BH, and the derived horonic esters in a state of high optical purity, essentially 100% ee (Fig. 42,ref.54).

It should be noted that we achieve predominant formation of the desired optical isomer by utilizing the appropriate hydroborating agent from either (+)- or (—)-ct-pinene. We then bring it to 100% ee by a crystallization of the hydrohorating product. Once we obtain the boron intermediate, IpcR*BH or Ipc2P.*B, optically pure, we can remove the Ipc groups by treatment with an appropriate aldehyde. This provides us with chiral boronic esters in 100% ee (Fig. 42).

Fortunately, there are now a number of reactions which can be applied to boronic esters. Thus they are readily converted into aldehydes, R*CHO, and these can either be reduced to alcohols, R*CH2OH, or oxidized to carboxylic acids, R*CO2H (Fig. 43, ref. 55). These chiral boronic esters of 100% ee can be converted into chiral ketones of 100% ee (Fiq. 44, ref. 56).

o / \ _1 UCH(OMe)SPh RU—+ R* RCHO R*B(OR)2 + LiR*RB(OR)2 RRBOR J 2.HgC12 1. [o1 HC12COMe(DCME) R*RIBOR R*OU R*CH2OH 2. LiO—t—Bu RR 3.H202,pH 8 Itoj IBMS /o___\ _____ P R*B\0J R*1u: Me HhCØ R*CO2H > 99%ee >99%ee >99%ee >99%ee Fic;rc 5o0pc Fig. 44. Synthesis of optically active aldehydes, acids and methylol deriva- e ones 0 essen ia y 00/ ee tives of essentially 100% ee

We can adopt the 4atteson homologation reaction to achieve the synthesis of optically active horonic esters, making available the -chiral boionic esters (ref. 57). A second operation provides the y-chiral boronic ester (Fig. 45).

Treatment of boronic esters with lithium aluminum hydride provides the optically active boro- hydrides, LiR*BH3. By an appropriate choice of the ester oroup, the aluminum by-product, HA1(OR)2, readily precipitates from solution (Fig. 46, ref. 58).

We are now in position to make all of the boron reagents we had previously found valuable to achieve syntheses via organoboranes without loss of alkyl groups (Fig. 47, ref. 59). Toillustrate, in the past the synthesis of amines from organoboranes invariably resulted in the loss of approximately 50% of the organic groups attached to boron. Such a loss is highly undesirablefor 100% ee organic groups. We can avoid any loss by the procedure indicated (Fig. 48, ref. 60). Organoboranes for synthesis—substitution with retention 893

R*CH OH R*OH +— R*BI —EE R*CHO R*CO2H Ii.LiCHC12 2. KIPBH R*BH2 +

R*CH2CH2OH R*CH2OH R*CH2B(II R*CH2CHO R*CH2CO2H + 1.ucHcl2 R*BH2 + R*_B 2.KIPBH R*CH CH r ,0 2 2 2 Fig.47. Synthesisof optically active R*CH2CH2OH R*CH2CH2B\ —'E R*CH2CH2CHO thexyland 9-BBN derivatives R*CH2CH2CO2H Fig. 45. Synthesisof optically active derivativesviasuccessivehomologations

0 O\ LiA1H4 ) LiRBH+HAl1 R* 0 R*B( 1. MeLi \ / 0—, B R*B2. R*BH22 +H CH3COC1 Me' 2 HX R* 0 R*BHX + 1.NH OSO H LiR*BH3 H2 \/ 7 C 2 B R*NH 2 3HX 2. H20 R*BX2 +H2 Me' Fig. 46. Conversion of optically active Fig. 48. Procedure for the synthesis of boronic acids into optically active boro- primary amines in high enantiomeric purity hydrides and derived boranes

IMPLICATIONS

Now we are in position to obtain by relatively simple procedures a wide variety of orqanic groups of 100% ee attached to boron, R*FLZ . Wehave simple procdures to convert these into our comon reagents, R*B(OR)2, LiR*BH3, R*BH2, R*BHX, R*BX2, R*E3)), R*HBI_j, R*RBOR, LiR*RBH2, R*RBH and R*RBX.

An important characteristic of the reactions of organoboranes and ofthese organoboron reagents is that in almost all reactions the organic group transfersfrom boron to other elements, including carbon, with complete retention of confiquration. Consequently, it should be possible to duplicate Fig. 1 in optically active form, Fig. 49. This is now the main center of our efforts.

R*CH=CHCH=CH R cis cia cia, trans R*OH trans , etc.\

R*NH2

R*RCHNH2

Fig. 49. Borane chemistry makes possible a general synthesis of optically pure enanti omers 1768 'H '3 NMOi8 GNV '8 V%JV}dV9NIS

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