Chemoselective and stereoselective reductions with modified borohydride reagents

INTRODUCTION

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Sodium Borohydride (NaBH4) is the

preferred reducing agent for chemoselective reductions of aldehydes and ketones (1). It is sometimes forgotten, however, that Sodium Borohydride can be easily modified to form either a stronger or more selective reducing agent (2). And under the appropriate conditions, this versatility expands to include stereoselective reductions (3). This article will examine a few typical industrial examples showing Sodium Borohydride as a chemoselective and stereoselective reducing agent.

yields after recrystallization (5b) The chiral R-group attached to the nitrogen atom of the imide induces the regioselectivity observed in this reaction. Thirty years after its initial application, this Sodium Borohydride reaction is still used industrially because of its cost-effectiveness.

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

1. Rohm and Haas Company Ankerrui 9b5 B 2000 Antwerpen, Belgium Tel +32-3-4513624 Fax +32-3-4513630 2. Rohm and Haas Company 60 Willow Street North Andover, MA 01845, USA * Corresponding author

CHEMOSELECTIVE HYDROXY ESTER REDUCTIONS

There are many laboratory methods

and reducing agents to selectively reduce hydroxy esters (6). In the example shown in Figure 2, a -hydroxymethyl ester is selectively reduced in the presence of another methyl ester (7). The chemoselectivity of this reaction is directed by condensation of the Lithium Triethylborohydride (LiBHEt3) reagent with the hydroxyl function, forming a six-member transition state. LiBHEt3 is prepared by the reaction of triethyl boron with lithium hydride in a THF solution. Unfortunately, both the reaction conditions and the cost of the reducing agent limit large-scale application of this interesting conversion. For these reasons, BASF

IMIDE REDUCTIONS

Reductions of esters, carboxylic acids, imides and amides are often carried out with very strong reducing agents such as Lithium Aluminum Hydride (LiAlH4) (4). However, the strength of aluminum hydride reducing agents can cause loss of chemoselectivity or regioselectivity. In cases requiring selectivity, it may be beneficial to use NaBH4 or its derivatives. An applicable industrial example is the borohydride reduction step in Figure 1 Sumitomos synthesis of d-Biotin (Figure 1). Biotin, also known as vitamin H, is an important nutrition additive for both humans and animals (5a). Reductive opening of the imide (with surprising regioselectivity) results in formation of the hydroxyamide in 65%
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investigated alternative methods for the selective hydroxy ester reduction in their synthesis of R-Lipoic acid. Their retrosynthetic analysis relied upon the selective reduction of a hydroxy ester to an ester diol as shown in Figure 3 (8). Using NaBH4 in this application resulted in a cost-effective synthesis route suitable for large-scale production. This chemistry relies on initial reaction between NaBH4 and the OH-group, forming an alkoxy borohydride intermediate (Figure 4). The electron donation by the alkoxy group results in a nucleophilic activation of the B-H bond. This activation makes the alkoxy borohydride a significantly stronger reducing agent than uncoordinated Sodium Borohydride. For this reason, the ester group in the -position to the hydroxyl group is selectively
Figure 4

Figure 5, a chiral center Figure 2 exists - to both the carbonyl and hydroxyl groups. Addition of Zinc Borohydride [Zn(BH4)2] results in a carbonyl reduction with high diastereomeric excess (Table I) (9). The stereoselectivity can be explained by formation of a sixmembered chairconformation transition state. As shown Figure 3 in Figure 6, geometric factors determine the preferential attack of borohydride to yield a syn-diol. The presence statins, this synthon is obtained by Sodium Borohydride reduction of the corresponding -ene-hydroxy--carboxy-methyl ester (Figure 7). The hydroxy ketone chemistry described in the previous section is inadequate for this application due to the absence of a stereocenter adjacent to the ketone and hydroxyl groups. Narasaka and others have published an alternative technology that addresses this synthesis problem (12). He discovered that a combination of NaBH4 with an organoborane compound, such as Bu3B or Et3B (Figure 8), produces diastereomeric yields exceeding 80% (Table II). The stereoselectivity can be explained by either preferential axial NaBH4 attack on a six-member ring transition-state intermediate (the cyclohexanone model, orbital perturbation), or by the steric hindrance

Figure 5

Table I R1 - Ph - CH2=CMe R2 -H -H Syn:Anti 25:1 25:1

reduced versus the nonsubstituted ester. At ambient temperature the reaction is complete within 4-8 hours, with yields in excess of 90%. Further refinement of the reduction will enable BASF to carry out this reduction with virtually no excess borohydride.

of a chiral methyl group adjacent to the carbonyl and alcohol functions drives the stereoselectivity. The methyl group forces the chair conformation used for hydride insertion. Zinc borohydride is also a wellknown chemoselective reducing agent in academic research. A barrier to its commercial use as a reducing agent is its limited storage stability. Fortunately for the industrial chemist, Zn(BH4)2 can Figure 6 be prepared in situ by addition of ZnCl2 to either a THF slurry of NaBH4 or to a NaBH4 glyme solution (10).

STATIN-TYPE CHEMISTRY (11)

Figure 7

STEREOSELECTIVE HYDROXY KETONE REDUCTIONS

A nearby electron-donating group can also enhance borohydrides stereoselectivity. In the example in
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Some of the todays largest selling drugs are a series of HMG-CoA reductase inhibitors or statins, such as fluvastatin, atorvastatin or pravastatin. All of these anticholesterol drugs contain an identical side chain, -ene-,-dihydroxymethyl ester. For a number of the
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Figure 8

from the butyl groups of the borane (Figure 9). Researchers at Pfizer (Warner Lambert), Bayer and Novartis have developed the NaBH4 / organoborane combination for diastereoselective hydroxy ketone reductions to where this approach dominates reduction methods for statin-type molecules (12b). The NaBH4 / organoborane combination produces excellent diastereoselective yields, without requiring transition metal separation (necessary when using catalytic hydrogenation) It also
Figure 10

chemistry. Some interesting borane complexes, such as DME:BH3 in the case of ritonavir, cannot be offered commercially due to their limited stability. In situ generation of boranes from NaBH4 overcomes this hurdle and expands the range of available BH3-complexing solvents. As for the second step, the literature provides many alternatives that exploit the presence of a chiral OH-group, or as in this case Figure 9 NH2-group, in -position for the diastereoselective reduction of the carbonyl group. In the example in Figure 11, the diastereomeric excess appears to be high (> 98%) for a large number of
Figure 12

Table II R Bz n-Bu C6H11 T C -100 -78 -100 -78 -78 Time h 2 3 2 6 6 36 A/B 98:2 96:4 88:12 84:16 73:27 88:12 Yield % 94 74 73 90 94 84

equivalents) of Sodium Borohydride. The low yields might be caused by the way the compound is isolated; as the hydrochloride solid (14). Researchers at Abbott Laboratories have investigated the synthesis problem of obtaining both good chemical yield and good diastereoselectivity. They

does not require the use and recovery of chiral auxiliary ligands.

Figure 11

STEREOSELECTIVE ENAMINE KETONE REDUCTIONS

Abbott Laboratories uses a similar technique in the production of ritonavir, which requires reducing both an enamine and a carbonyl function with the creation of two chiral centers. Both reductions use Sodium Borohydride in a one-pot sequence (13). The enamine reduction uses a borane reagent, which is generated in situ from Sodium Borohydride upon addition of methanesulfonic acid (Figure 10). The postulated borane reagent is DME:BH3 (DME = dimethoxyethane or monoglyme), an unstable borane complex that readily exchanges with the R-NH2 group to form an R-NH2:BH3 complex. Commercially available boranes used for large-scale industrial applications are mainly THF:BH3 and [amine]:BH3. The first reduction step of the above ritonavir sequence reveals one of the disadvantages of borane
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substitutents (Table III). However the chemical yield never exceeds 80%, despite using a large excess (8 hydride

showed that addition of a protic co-solvent, e.g. 2-propanol, improved diastereoselectivity (Figure 12). It is believed that after hydroboration of the C-C double bond, the boron remains bonded to the molecule and forms a propoxyamino borane. The propoxyamino borane serves as a stereodriver in the subsequent NaBH4 ketone reduction (15). The isolated yield is 96%.

Table III Ar Ph 4-MeOC6H4 4-MeOC6H4 3-Me-4-MeOC6H4 2-Thienyl 5-Me-2-Thienyl Ph Ph 4-MeOC6H4 4-MeOC6H4 3-Me-4-MeOC6H4 3-Me-4-MeOC6H4 R Bz Bz 2-Furylmethyl Bz Bz 2-Furylmethyl (S)-1-phenylethyl (+)-1-phenylethyl (S)-1-phenylethyl (+)-1-phenylethyl (S)-1-phenylethyl (+)-1-phenylethyl Temperature C 20 18 20 20 20 20 2-5 2-5 2-5 2-5 2-5 2-5 Yield % 77 79 65 70 76 60 80 76 63 75 80 78 Syn/Anti >97:3 96:4 >97:3 >97:3 >97:3 97:3 97:3 >97:3 97:3 >97:3 >97:3 97:3

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CONCLUSION

Borohydride chemistry has

developed far beyond simple aldehyde and ketone reductions. The above examples demonstrate that modified borohydride reagents can reduce not only ester functions but also selectively reduce hydroxy esters in the presence of non-substituted esters. Other surprising chemoselective and stereoselective reductions can be obtained using Sodium Borohydride and its derivatives. Finally, through the in situ generation of boranes, electrophilic reduction chemistry is possible using Sodium Borohydride. Rohm and Haas Company is the worlds largest and most experienced supplier of Sodium Borohydride. We support the synthesis community with Mor-Care technical and safety support services to help you select the appropriate 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.

7) 8) 9) 10)

REFERENCES
1) 2) BROWN, H.C. Boranes in Organic Chemistry; Cornell University, 1972 a PERISASAMY, M.; TIRUMALAIKUMAR, M. J. Organomet. Chem. 2000 609, 137 b FIAOUZABADI, H.; ZEYNIZADEH, B. Iranian J. Sci. Tech. 1995, 19, 103 SEYDEN-PENNE, J. Reductions by Aluminoand Borohydride in Organic Synthesis, 2nd Edn.; 1997 ASHBY, E.C. Advances in Inorganic Chemistry and Radio Chemistry 1966, 282 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-Othmer Encyclopedia of Chemical Technology, 1998 a SOAI, K.; OYAMADA, H. Synthesis 1984, 605 b DALLA, V.; CATTEAU, J.P.; PALE, P. Tet. Lett. 1999, 40, 5193

11) 12)

3)

4) 5)

13)

6)

14) 15)

RODRIGO et al. J. Org. Chem. 1989, 54, 4280 BALKENHOHL, F.; PAUST, J. US 5,530,143 June 25, 1996 NAKATA, T.; TANI, Y.; HATOZAKI, M.; OISHI, T. Chem. Pharm. Bull. 1984, 32, 1411 a GENSLER, W.J.; JOHNSON, F. SLAON, A.D.B. J. Am. Chem. Soc. 1960, 82, 6074 b CRABBE, P.; GARCIA, G.A.; RIUS, C. J. Chem. Soc. Perkin Trans. 1 1973, 810 REPIC, O.; PRASAD, K.; LEE, G.T. Org. Proc. Res. Dev. 2001, 5, 519 a NARASAKA, K.; PAI, F.C. Tetrahedron 1984, 40, 2233 b CHEN, K.M.; HARDTMANN, G.E.; PRASAD, K.; REPIC, O.; SHAPIRO, M. Tet Lett. 1987, 28, 155 c REPI, O.; PRASAD, K.; LEE, G.T. Organic Process Research & Development 2001, 5, 519-527 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 BERAKES, D.; KOLAROVIC, A.; POVAZANEC, F. Tetrahedron Lett. 2000, 41, 5257 HAIGHT, A.R. et al. Organic Process Research & Development 1999, 3, 94-100

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