Intramolecular Conjugate Addition of α,β-Unsaturated Lactones Having an Alkanenitrile Side Chain: Stereocontrolled Construction of Carbocycles with Quaternary Carbon Atoms

Abstract

An efficient method for constructing carbocycles with all-carbon quaternary stereocenters has been developed on the basis of a stereoselective cyclization reaction of α,β-unsaturated lactones having an alkanenitrile side chain. Treatment of the substrate with lithium hexamethyldisilazide (LiHMDS) in the presence of triisopropylsilyl chloride (TIPSCl) led to the generation of the corresponding α-cyano carbanion species which readily underwent an intramolecular conjugate addition reaction. It was found that the combined use of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and triethylamine is also effective for the cyclization ­reaction without using a strong base. Interestingly, different ste­reochemical outcomes were observed in the two cyclization methods.

Key words

carbocycles - cyclization - Michael addition - nitriles - stereoselective synthesis

References and Notes

• For representative reviews of the stereoselective construction of all-carbon quaternary stereogenic centers, see:
• 1a Christoffers J. Baro A. Adv. Synth. Catal.  2005,  347:  1473 
• 1b Denissova I. Barriault L. Tetrahedron  2003,  59:  10105 
• 1c Fuji K. Chem. Rev.  1993,  93:  2037 
• 2a Shiina Y. Tomata Y. Miyashita M. Tanino K. Chem. Lett.  2010,  39:  835 
• 2b Tanino K. Tomata Y. Shiina Y. Miyashita M. Eur. J. Org. Chem.  2006,  328 
• There are a few examples of the intramolecular conjugate addition reaction involving an α-cyano carbanion intermediate:
• 3a Condon S. El Ouarradi A. Métay E. Léonel E. Bourdonneau M. Nédélec J.-Y. Tetrahedron  2008,  64:  9388 
• 3b Shia K.-S. Jan N.-W. Zhu J.-L. Ly TW. Liu H.-L. Tetrahedron Lett.  1999,  40:  6753 
• 4 The intramolecular alkylation reactions of nitriles provide useful carbocyclization method. For an excellent review of nitrile anion cyclization, see: Fleming FF. Shook BC. Tetrahedron  2002,  58:  1 
• 5 Eliel EL. Wilen SH. Mander LN. Stereochemistry of Organic Compounds   Wiley; New York: 1994.  p.696-697  
• 6 Clavier H. Nolan SP. Chem. Eur. J.  2007,  13:  8029 
• 14 We could not detect any silyl ketene imine intermediates in the cyclization of 3 by using the TMSOTf/Et₃N system when monitoring the reaction by ^¹H NMR and ^¹³C NMR spectroscopy. In this context, Denmark and Wilson have recently reported the Lewis base catalyzed intermolecular conjugate addition of silyl ketene imines to α,β-unsaturated carbonyl compounds, see: Denmark SE. Wilson TW. Synlett  2010,  1723 

7

The configurations of 4a and 4b were unambiguously determined by ^¹H NMR NOE experiments. See Supporting Information for details.

8

The use of sterically demanding silylating reagent is of critical importance in this reaction. For example, the reaction in the presence of the less bulky triethylsilyl chloride (TESCl) was accompanied by the formation of the α-silyl nitrile through trapping of the α-cyano carbanion before cyclization.

9

It should be noted that the use of a nitrile group was indispensable for the LiHMDS/TIPSCl-mediated cyclization. For example, when a nitrile group was replaced to an ester group, the reaction did not proceed efficiently; the bicyclic lactone was obtained only in 15% yield along with the recovery of the starting material in 63% yield (Scheme  [7] ).

Scheme 7

10

General Experimental Procedure for the Carbocyclization by Using the LHMDS/TIPSCl System
To a cooled mixture of α,β-unsaturated lactone 3 (32.4 mg, 0.156 mmol), TIPSCl (49.8 µL, 0.235 mmol), and HMPA (136 µL, 0.782 mmol) in THF (1.6 mL) was slowly added a freshly prepared 1.0 M THF solution of LiHMDS (312 µL, 0.312 mmol) at -78 ˚C. After stirred at this temperature for 7 h, the reaction was quenched with aq 1 M HCl (1.6 mL). The mixture was stirred at r.t. for 1.5 h and then diluted with EtOAc. After the layers were separated, the aqueous layer was extracted with EtOAc. The combined organic layers were washed successively with H₂O and brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane-EtOAc = 5:1 to 1:1) to afford 4a (27.3 mg, 84%) and 4b (2.9 mg, 9%).

11

See Supporting Information for the synthesis.

12

Controlled experiments showed that neither TMSOTf nor Et₃N alone promoted this carbocyclization.

13

General Experimental Procedure for the Carbocyclization by Using the TMSOTf/Et ₃ N System To a mixture of α,β-unsaturated lactone 3 (18.5 mg, 89.0 µmol) and Et₃N (50.2 µL, 0.357 mmol) in DCE (0.45 mL) was added TMSOTf (32.3 µL, 0.179 mmol) at r.t. After stirred at 50 ˚C for 1.5 h, the mixture was cooled to r.t., and a sat. aq NaHCO₃ solution was added. The layers were separated, and then the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane-EtOAc = 5:1 to 1:1) to afford 4a (5.1 mg, 28%) and 4b (10.3 mg, 56%).