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DOI: 10.1055/s-0031-1290074
Intramolecular Conjugate Addition of α,β-Unsaturated Lactones Having an Alkanenitrile Side Chain: Stereocontrolled Construction of Carbocycles with Quaternary Carbon Atoms
Publication History
Publication Date:
03 January 2012 (online)
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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
- Supporting Information for this article is available online:
- Supporting Information
- 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
References and Notes
The configurations of 4a and 4b were unambiguously determined by ¹H NMR NOE experiments. See Supporting Information for details.
8The 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.
9It 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] ).
![](https://www.thieme-connect.de/media/synlett/201202/u548_s7.gif)
Scheme 7
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%).
See Supporting Information for the synthesis.
12Controlled experiments showed that neither TMSOTf nor Et3N alone promoted this carbocyclization.
13General 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%).