Synthetic Approaches to (R)-Cyclohex-2-Enol

Introduction

Asymmetric synthesis starting from achiral reactants to produce synthetically useful chiral compounds  is an attractive and established branch of synthetic organic chemistry. (R)-cyclohexenol 1 serves as a versatile chiral precursor for synthesis of natural products and complex medicinally active compounds like (+) Daphmandin E 2,(1) and antiarrhythmic aminohydroisoquinocarbazole RS-2135 3 (2) respectively (Figure 1)

 

Figure 1. (R)-Cyclohexenol is a valuable building block in organic synthesis  Click here to View Figure

 

Figure 1. (R)-Cyclohexenol is a valuable building block in organic synthesis A scifinder scholar^® search of methods to synthesize (R)-cyclohexenol in February 2014 resulted in 129 hits. This mini-review discusses methods from these 129 results wherein the isolated yield for the target from commercially available reactants was in excess of 80% and the ee ranged from 99% to 26%. This mini-review is intended to present synthetic chemists with a guide for synthesis of (R)-cyclohexenol and its derivatives.

SYNTHETIC STRATEGIES TO (R)-CYCLOHEXENOL

FROM CYCLOHEXENE OXIDE

 

Scheme 1. Asymmetric transformation of cyclohexene oxide by catalyst 5.  Click here to View Scheme

 

Asami et al.(3) report conversion of cyclohexene oxide 4 to 1 (80% yield, 78% ee) using chiral catalyst – cyclohexyl[(S)-1-ethylpyrrolidin-2-yl]methylamine 5 from (Scheme 1). The mechanism involves enantioselective deprotonation of symmetrical epoxide 4 using the chiral lithium amide prepared from n-butyl lithium and 5. HMPA is used as an additive. It has been suggested that additives inhibit the formation of reactive but unselective aggregates of chiral Li-amides.(4-7)

 

Figure 2. Transtion state model for enantioselective deprotonation by 5.  Click here to View Figure

 

As lithium amide induced transformation of epoxides to allylic alcohols I supposed to proceed in a cyclic concerted manner,(8) Asami et al.(3) presume the transition states’ (TSs’) as shown in figure 2 to account for the stereoselectivity of the reaction. As indicated in transition state T1, epoxide approaches the lithium amide from the less hindered side in such a way that the steric repulsion can be avoided. Thus T1 is favored over T2, and the alcohol with R-configuration is obtained.

 

Scheme 2. Asymmetric transformation of cyclohexene oxide by catalyst 6.  Click here to View Scheme

 

Sodergren et al.(9) report conversion of cyclohexene oxide 4 to 1 (91% yield, 96% ee) using chiral catalyst – 3-aminomethyl-2-azabicyclo[2.2.1]heptane 6 (Scheme 2). DBU is used as an additive. The authors reasoned that Li-amide with a more rigid back bone would adopt a more well-ordered TS in the deprotonation reaction to afford higher asymmetric induction as the result of more strict discrimination between the enantiotopic protons in 4.

 

Scheme 3. Asymmetric transformation of cyclohexene oxide by catalyst 7. Click here to View Scheme

 

Bertilsson et al.(10) report conversion of cyclohexene oxide 4 to 1 (95% yield, 99% ee) using chiral catalyst – (1R,3R,4S)-3-(((2R,5R)-2,5-dimethylpyrrolidin-1-yl)methyl)-2-azabicyclo[2.2.1]hept-5-ene 7 (Scheme 3).

 

Figure 3. Transtion state model for enantioselective deprotonation by 7. Click here to View Figure

 

As indicated in the TS model (Figure 3), the (2R,5R)-dimethyl groups do not interfere with the favored TS II, whereas the unfavored pathway is effectively blocked by the steric repulsion between the (2R)-methyl group and the cis-g -proton of the epoxide.

 

Scheme 4. Asymmetric transformation of cyclohexene oxide by catalyst 8.  Click here to View Scheme

 

Malhotra(11) reports conversion of cyclohexene oxide 4 to 1 (82% yield, 95% ee) using chiral catalyst – C2-symmetric (−)-N,N-diisopinocampheyl- amine (DIPAM) 8 (Scheme 4). No additive was used in the reaction.

FROM 2-CYCLOHEXEN-1-ONE

 

Scheme 5. Asymmetric transformation of 2-cyclohexene-1-one by ZnEt2/pybox system. Click here to View Scheme

 

Junge et al.(12) report conversion of 2-cyclohexen-1-one 9 to 1 (88% yield, 26% ee) by asymmetric hydrosilylation with a combination of ZnEt­₂, chiral 2,6-bis((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-pyridine (pybox) catalyst 10, and polymethylhydrosiloxane (PMHS), followed by hydrolysis to the alcohol (Scheme 5).

 

Figure 4. (a) Mechanism of asymmetric hydrosilylation by ZnEt2/pybox system. (b) Catalytically active species 11 as confirmed by ESI-MS.  Click here to View Figure

 

The proposed mechanism of the asymmetric hydrosilylation process (Figure 4a) by Mimoun et al.(13,14) was confirmed by Junge et al.(12) by confirming the presence of 11 (Figure 4b) by ESI-MS studies.

FROM 1,3-CYCLOHEXADIENE

 

Scheme 6. Asymmetric transformation of cyclohexene oxide by catalyst 8.  Click here to View Scheme

 

Zaidlewicz et al.(15) report conversion of 1,3-cyclohexadiene 12 to 1 (94% yield, 68% ee) using chiral catalyst – di-(2-isocaranyl)borane (2-Icr₂-BH) 13 (Scheme 6). Mechanism involves the enantioselective hydroboration of 12 in presence of bulky dialkylboranes.

CONCLUSION

In conclusion, we present here enantioselective approaches to (R)-cyclohexanol using commercially available reactants such as cyclohexene oxide, 1,2-cyclohexenone, and 1,3-cyclohexadiene. Reactions enantioselecive deprotonation of cyclohexene oxide by chiral lithium amides, asymmetric hydrosilylation of 2-cyclohexen-1-one with chiral catalyst followed by hydrolysis, and enantioselective hydroboration of 1,3-cyclohexadiene with chiral dialkylboranes. The yields of the aforementioned methods range from 95 to 80% and the ee’s range from 99 to 26%.

ACKNOWLEDGEMENTS

Dual Therapeutics LLC, and Grant # 0249-1924 from BioMotiv, LLC, are gratefully acknowledged.

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