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FINE, SPECIALTY

& PERFORMANCE

CHEMICALS

Chemoselectiveand stereoselective

reductionswith modifiedborohydride reagents

GUY WINDEY 1*KARL SEPER 2JOHN H. YAMAMOTO 2

1. Rohm and Haas CompanyAnkerrui 9b5B 2000 Antwerpen, BelgiumTel +32-3-4513624Fax +32-3-4513630

2. Rohm and Haas Company60 Willow StreetNorth Andover, MA 01845, USA

* Corresponding author

FINE, SPECIALTY E PERFORMANCE CHEMICALS SEPTEMBER 2002 15

INTRODUCTION

Sodium Borohydride (NaBH4) is thepreferred reducing agent forchemoselective reductions ofaldehydes and ketones (1). It issometimes forgotten, however, thatSodium Borohydride can be easilymodified to form either a stronger ormore selective reducing agent (2).And under the appropriateconditions, this versatility expands toinclude stereoselective reductions(3). This article will examine a few

typical industrial examples showingSodium Borohydride as achemoselective and stereoselectivereducing agent.

IMIDE REDUCTIONS

Reductions of esters, carboxylicacids, imides and amides are oftencarried out with very strong reducingagents such as Lithium AluminumHydride (LiAlH4) (4). However, the

strength of aluminum hydridereducing agents can cause loss ofchemoselectivity or regioselectivity.In cases requiring selectivity, it maybe beneficial to use NaBH4 or itsderivatives.

An applicable industrial exampleis the borohydridereduction step inSumitomos synthesis ofd-Biotin (Figure 1). Biotin,also known as vitamin H,is an important nutritionadditive for both humans

and animals (5a).Reductive opening of theimide (with surprisingregioselectivity) results information of thehydroxyamide in 65%

yields after recrystallization (5b) Thechiral R-group attached to thenitrogen atom of the imide inducesthe regioselectivity observed in thisreaction. Thirty years after its initialapplication, this Sodium Borohydridereaction is still used industriallybecause of its cost-effectiveness.

CHEMOSELECTIVE

HYDROXY ESTER

REDUCTIONS

There are many laboratory methodsand reducing agents to selectivelyreduce hydroxy esters (6). In theexample shown in Figure 2, a-hydroxymethyl ester is selectivelyreduced in the presence of anothermethyl ester (7). The chemoselectivityof this reaction is directed bycondensation of the LithiumTriethylborohydride (LiBHEt3) reagentwith the hydroxyl function, forming asix-member transition state.

LiBHEt3 is prepared by the reaction

of triethyl boron with lithium hydride ina THF solution. Unfortunately, both thereaction conditions and the cost of thereducing agent limit large-scaleapplication of this interestingconversion.

For these reasons, BASF

Figure 1


2/4FINE, SPECIALTY E PERFORMANCE CHEMICALSSEPTEMBER 200216

investigated alternative methods forthe selective hydroxy ester reduction intheir synthesis of R-Lipoic acid. Theirretrosynthetic analysis relied upon theselective reduction of a hydroxyester to an ester diol as shown inFigure 3 (8).

Using NaBH4 in this applicationresulted in a cost-effective synthesisroute suitable for large-scale

production. This chemistry relies oninitial reaction between NaBH4 and theOH-group, forming an alkoxyborohydride intermediate (Figure 4).The electron donation by the alkoxygroup results in a nucleophilicactivation of the B-H bond. Thisactivation makes the alkoxyborohydride a significantly strongerreducing agent than uncoordinatedSodium Borohydride.

For this reason, the estergroup in the -position to the

hydroxyl group is selectively

reduced versus the non-substituted ester. At ambienttemperature the reaction iscomplete within 4-8 hours, withyields in excess of 90%. Furtherrefinement of the reduction willenable BASF to carry out thisreduction with virtually no excessborohydride.

STEREOSELECTIVE HYDROXYKETONE REDUCTIONS

A nearby electron-donating group canalso enhance borohydridesstereoselectivity. In the example in

Figure 5, a chiral centerexists - to both thecarbonyl and hydroxylgroups. Addition of ZincBorohydride [Zn(BH4)2]results in a carbonylreduction with highdiastereomeric excess(Table I) (9).

The stereoselectivity

can be explained byformation of a six-membered chair-conformation transitionstate. As shownin Figure 6,geometricfactorsdetermine thepreferentialattack ofborohydride toyield a syn-diol.

The presence

of a chiral methylgroup adjacent tothe carbonyl andalcohol functionsdrives thestereoselectivity. Themethyl group forcesthe chair

conformation used for hydrideinsertion.

Zinc borohydride is also a well-known chemoselective reducing agent in

academic research. A barrier to itscommercial use as a reducing agent isits limited storage stability. Fortunatelyfor the industrial chemist, Zn(BH4)2 canbe preparedin situ by addition of ZnCl2to either a THF slurry of NaBH4 or to aNaBH4 glyme solution (10).

STATIN-TYPECHEMISTRY (11)

Some of the todays largest sellingdrugs are a series of HMG-CoA

reductase inhibitors or statins, suchas fluvastatin, atorvastatin orpravastatin. All of these anti-cholesterol drugs contain an identicalside chain, -ene-,-dihydroxy-methyl ester. For a number of the

statins, this synthon isobtained by SodiumBorohydride reduction of thecorresponding -ene--hydroxy--carboxy-methylester (Figure 7).

The hydroxy ketonechemistry described in theprevious section is inadequatefor this application due to theabsence of a stereocenteradjacent to the ketone andhydroxyl groups. Narasaka andothers have published an

alternative technology that addressesthis synthesis problem (12). Hediscovered that a combination ofNaBH4 with an organoboranecompound, such as Bu3B or Et3B(Figure 8), produces diastereomericyields exceeding 80% (Table II).

The stereoselectivity can beexplained by either preferential axialNaBH4 attack on a six-member ringtransition-state intermediate (thecyclohexanone model, orbital

perturbation), or by the steric hindrance

R1 R2 Syn:Anti

- Ph - H 25:1

- CH2=CMe - H 25:1

Table I

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7


3/4FINE, SPECIALTY E PERFORMANCE CHEMICALS SEPTEMBER 2002 17

from the butyl groups of the borane

(Figure 9).Researchers at Pfizer (Warner

Lambert), Bayer and Novartis havedeveloped the NaBH4/organoborane combination fordiastereoselective hydroxy ketonereductions to where this approachdominates reduction methods forstatin-type molecules (12b). TheNaBH4/ organoborane combinationproduces excellent diastereoselectiveyields, without requiring transitionmetal separation (necessary when

using catalytic hydrogenation) It also

does not require the use andrecovery of chiral auxiliary ligands.

STEREOSELECTIVE ENAMINE

KETONE REDUCTIONS

Abbott Laboratories uses a similartechnique in the production ofritonavir, which requires reducing bothan enamine and a carbonyl functionwith the creation of two chiral centers.

Both reductions use SodiumBorohydride in a one-potsequence (13).

The enamine reduction uses aborane reagent, which is generatedin situ from Sodium Borohydrideupon addition of methanesulfonicacid (Figure 10). The postulatedborane reagent is DME:BH3 (DME= dimethoxyethane ormonoglyme), an unstable boranecomplex that readily exchanges withthe R-NH2 group to form anR-NH2:BH3 complex.

Commercially available boranesused for large-scale industrialapplications are mainly THF:BH3 and[amine]:BH3. The first reduction step ofthe above ritonavir sequence revealsone of the disadvantages of borane

chemistry. Someinteresting boranecomplexes, such asDME:BH3 in the caseof ritonavir, cannotbe offeredcommercially due totheir limited stability.In situ generation of

boranes from NaBH4 overcomes this

hurdle and expands the range ofavailable BH3-complexing solvents.

As for the second step, the li teratureprovides many alternatives that exploitthe presence of a chiralOH-group, or as in this caseNH2-group, in -position forthe diastereoselectivereduction of the carbonylgroup.

In the example inFigure 11, thediastereomeric excess appears to be

high (> 98%) for a large number of

substitutents (Table III). However thechemical yield never exceeds 80%,

despite using a large excess (8 hydride

equivalents) of Sodium Borohydride.The low yields might be caused by the

way the compound isisolated; as thehydrochloridesolid (14).

Researchers atAbbott Laboratorieshave investigated thesynthesis problem of

obtaining both good chemical yield

and good diastereoselectivity. They

showed that addition of a proticco-solvent, e.g. 2-propanol,improved diastereoselectivity(Figure 12). It is believed thatafter hydroboration of the C-Cdouble bond, the boron remainsbonded to the molecule andforms a propoxyamino borane.The propoxyamino boraneserves as a stereodriver in the

subsequent NaBH4 ketonereduction (15). The isolated yield is

96%.

R T Time A/B YieldC h %

Bz 2 98:2 94n-Bu -100 3 96:4 74

-78 2 88:12 73C6H11 -100 6 84:16 90

-78 6 73:27 94-78 36 88:12 84

Table IIFigure 8

Figure 9

Figure 10

Figure 11

Figure 12

Ar R Temperature Yield Syn/AntiC %

Ph Bz 20 77 >97:34-MeOC6H4 Bz 18 79 96:44-MeOC6H4 2-Furylmethyl 20 65 >97:33-Me-4-MeOC6H4 Bz 20 70 >97:32-Thienyl Bz 20 76 >97:35-Me-2-Thienyl 2-Furylmethyl 20 60 97:3Ph (S)-1-phenylethyl 2-5 80 97:3

Ph (+)-1-phenylethyl 2-5 76 >97:34-MeOC6H4 (S)-1-phenylethyl 2-5 63 97:34-MeOC6H4 (+)-1-phenylethyl 2-5 75 >97:33-Me-4-MeOC6H4 (S)-1-phenylethyl 2-5 80 >97:33-Me-4-MeOC6H4 (+)-1-phenylethyl 2-5 78 97:3

Table III


4/4FINE, SPECIALTY E PERFORMANCE CHEMICALSSEPTEMBER 200218

CONCLUSION

Borohydride chemistry hasdeveloped far beyond simplealdehyde and ketone reductions.The above examples demonstratethat modified borohydridereagents can reduce not only esterfunctions but also selectivelyreduce hydroxy esters in the

presence of non-substitutedesters. Other surprisingchemoselective andstereoselective reductions can beobtained using SodiumBorohydride and its derivatives.Finally, through thein situgeneration of boranes,electrophilic reduction chemistry ispossible using SodiumBorohydride.

Rohm and Haas Company is theworlds largest and most experienced

supplier of Sodium Borohydride. Wesupport the synthesis community withMor-Care technical and safety supportservices to help you select theappropriate reduction technology.

We invite you to contact Rohm and Haas

(www.hydridesolutions.com) to learn more about

how this versatile reducing agent can solve your

reduction chemistry challenges.

REFERENCES

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b FIAOUZABADI, H.; ZEYNIZADEH, B.Iranian J. Sci. Tech. 1995, 19, 103

3) SEYDEN-PENNE, J. Reductions by Alumino-and Borohydride in Organic Synthesis, 2ndEdn.; 1997

4) ASHBY, E.C. Advances in InorganicChemistry and Radio Chemistry 1966, 282

5) a AOKI, Y.; SUZUKI H.; AKANO, S.; US Pat.3,876,656, April 8, 1975; Chem. Abstr.1974, 80, 9595lz

b OUTTEN, R.A. Biotin in: Kirk-OthmerEncyclopedia of Chemical Technology,

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b CRABBE, P.; GARCIA, G.A.; RIUS, C. J.Chem. Soc. Perkin Trans. 1 1973, 810

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c REPI, O.; PRASAD, K.; LEE, G.T.Organic Process Research & Development

2001, 5, 519-52713) STONER, E.J.; COOPER, A.J.; DICKMAN,

D.A.; KOLACZKOWSKI, L.; LALLAMAN, J.E.;LIU, J.-H.; OLIVER-SHAFFER, P. A.; PATEL,K. M.; PATERSON, J. B., JR.; PLATA, D. J.;RILEY, D. A.; SHAM, H. L.; STENGEL, P. J.;TIEN, J.-H. J. Org. Process Res. Dev. 2000,4, 264

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