[81725-22-6]  · C11H20LiNO2  · (E)-1-(N,N-Diisopropylcarbamoyloxy)crotyllithium  · (MW 205.23)

(homoenolate reagent for the stereoselective introduction of the butyric acid b-enolate synthon onto aldehydes and ketones;1,2a,2b prototype of several analogous reagents)

Preparative Method: prepared in situ from (E)-2-butenyl N,N-diisopropylcarbamate3a,3b by deprotonation at -78 °C with n-Butyllithium in the presence of N,N,N,N-Tetramethylethylenediamine (TMEDA) in ether or hexane (eq 1).

Handling, Storage, and Precautions: must be prepared and handled under inert gas (Ar or N2) to exclude oxygen and moisture;3a solutions in ether decompose slowly above -60 °C.

Diastereoselective Homoaldol Reaction.1

The lithium-TMEDA complex adds g-selectively to aldehydes and ketones3 to give anti-(Z)-4-hydroxy-1-(N,N-diisopropylcarbamoyloxy)-1-alkenes as a consequence of the intervention of a five-membered chelate (eq 1). The stereoselectivity is enhanced to >97% ds by in situ metal exchange with Titanium Tetraisopropoxide.4-6 The pure (E)-carbamate (>97%)3 must be used for achieving high stereoselectivities.5b,6 2-Enals react with clean 1,2-regioselectivity.4,7

Enantiopure aldehydes furnish 1:1 diastereomeric mixtures due to the reagent-controlled chirality transfer5b,5c and the configurational stability8 of the racemic titanium intermediate (eq 2). The enantiomerically enriched reagent is also available (see (-)-Sparteine).9 The O-(4-hydroxy-1-alkenyl) carbamates were converted by hydroxy-directed epoxidation via stable O-(1,2-epoxy-4-hydroxyalkyl) carbamates5b,10 to methyl 3-deoxy-3-C-methylhexofuranosides (eqs 3 and 4)5b,5c and to 2-heterosubstituted g-lactones.10b

The mercury(II) salt-catalyzed methanolysis furnishes 2-methoxytetrahydrofurans, which can be oxidized to trans-3,4-disubstituted g-lactones (eq 5).3a,5a 1,4-Alkanediols are accessible by a hydroboration sequence.11

The enol carbamates can be used for further C-C coupling reactions. The Lewis acid-catalyzed condensation with carbonyl compounds leads to stereochemically homogeneous tetrahydrofuran-3-carbaldehydes.12 Both the acidic vinylic proton6,13 and the carbamate group in enol carbamates undergo stereospecific substitution reactions.6,13a The racemic reagent has also been applied in the total synthesis of rifamycin S intermediates14 and of doubly C-branched sugar analogs.7

Alkylation does not offer useful levels of regioselectivity.3a The reaction with p-toluenesulfonyl fluoride yields (E)-1-(N,N-diisopropylcarbamoyloxy)-1-(4-methylphenylsulfonyl)-2-butene,15 which is a useful reagent for nucleophilic crotonoylation.15b (Z)-1-(N,N-Diisopropylcarbamoyloxy)butenyllithium reacts, after metal exchange by diisobutylaluminum methanesulfonate, with modest syn-(E) diastereoselectivity.16

Related Reagents.

Up to three alkyl groups, aryl groups, and several types of hetero substitutents in the allyl moiety are permitted in 1-lithio-2-alkenyl carbamates.1a,3a The addition of 1-(1-cyclopentenyl)-1-(N,N-diisopropylcarbamoyloxy)methyllithium11 or of 3-(dimethylphenylsilyl)-1-(N,N-diisopropylcarbamoyloxy)-2-propenyllithium17 to (S)-2-aminoalkanals was utilized to prepare several dipeptide isosteres. A higher analog was used in the total synthesis of (±)-anisomelic acid.18 The homoaldol adducts from 1-(N,N-diisopropylcarbamoyloxy)-3-(trimethylsilyl)-2-propenyllithium offer a flexible and highly diastereoselective access to all four possible geometric isomers of 1,3-alkadienyl carbamates.19 Enantiomerically enriched 1,3-disubstituted 1-lithio-2-alkenyl carbamates, such as (1S,2E)- or (1R,2Z)-1-(N,N-diisopropylcarbamoyloxy)-1-methyl-2-butenyllithium20 are configurationally stable below -70 °C in ether or hexane and are prepared by deprotonation of the nonracemic carbamate esters21 (see also (-)-Sparteine). Trapping these by trialkylstannyl chlorides proceeds with SE anti stereochemistry22 to provide enantiomerically enriched (Z)-1-methyl-3-trialkylstannyl-1-butenyl N,N-diisopropylcarbamates, which are valuable chiral homoenolate reagents.23

Alternative reagents for some of the transformations described above include (E)-1-methoxycrotylboronates24 and (1-alkoxycrotyl)tributylstannanes.25

1. (a) Hoppe, D. AG 1984, 96, 930; AG(E) 1984, 23, 932. (b) Hoppe, D.; Krämer, T.; Schwark, J.-R.; Zschage, O. PAC 1990, 62, 1999.
2. (a) Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990, 155, 1. (b) Crimmins, M. T.; Nantermet, P. G. OPP 1993, 25, 41.
3. (a) Hoppe, D.; Hanko, R.; Brönneke, A.; Lichtenberg, F.; van Hülsen, E. CB 1985, 118, 2822. (b) Hoppe, D.; Hanko, R.; Brönneke, A.; Lichtenberg, F. AG 1981, 93, 1106; AG(E) 1981, 20, 1024.
4. Hanko, R.; Hoppe, D. AG 1982, 94, 378; AG(E) 1982, 21, 372.
5. (a) Hoppe, D.; Brönneke, A. TL 1983, 24, 1687. (b) Hoppe, D.; Tarara, G.; Wilckens, M. S 1989, 83. (c) Hoppe, D.; Tarara, G.; Wilckens, M.; Jones, P. G.; Schmidt, D.; Stezowski, J. C. AG 1987, 99, 1079; AG(E) 1987, 26, 1034.
6. Kocienski, P.; Dixon, N. J. SL 1989, 52.
7. Peschke, B.; Lüssmann, J.; Dyrbusch, M.; Hoppe, D. CB 1992, 125, 1421.
8. Hoffmann, R. W.; Lanz, J.; Metternich, R.; Tarara, G.; Hoppe, D. AG 1987, 99, 1196; AG(E) 1987, 26, 1145.
9. Zschage, O.; Hoppe, D. T 1992, 48, 5657.
10. (a) Hoppe, D.; Lüssmann, J.; Jones, P. G.; Schmidt, D.; Sheldrick, G. M. TL 1986, 27, 3591. (b) Lüssmann, J.; Hoppe, D.; Jones, P. G.; Fittschen, C.; Sheldrick, G. M. TL 1986, 27, 3595.
11. Hanko, R.; Rabe, K.; Dally, R.; Hoppe, D. AG 1991, 103, 1725; AG(E) 1991, 30, 1690.
12. Hoppe, D.; Krämer, T.; Freire Erdbrügger, C.; Egert, E. TL 1989, 30, 1233.
13. (a) Pimm, A.; Kocienski, P.; Street, S. D. A. SL 1992, 886. (b) Kocienski, P.; Barber, C. PAC 1990, 62, 1933. (c) Paulsen, H.; Hoppe, D. T 1992, 48, 5667. (d) Le Menez, P.; Firmo, N.; Fargeas, V.; Ardisson, J.; Pancrazi, A. SL 1994, 995.
14. Tarara, G.; Hoppe, D. S 1989, 89.
15. (a) Reggelin, M.; Tebben, P.; Hoppe, D. TL 1989, 30, 2915. (b) Tebben, P.; Reggelin, M.; Hoppe, D. TL 1989, 30, 2919.
16. Hoppe, D.; Lichtenberg, F. AG 1984, 96, 241; AG(E) 1984, 23, 239.
17. (a) Rehders, F.; Hoppe, D. S 1992, 859. (b) Rehders, F.; Hoppe, D. S 1992, 865.
18. Marshall, J. A.; DeHoff, B. S. T 1987, 43, 4849.
19. van Hülsen, E.; Hoppe, D. TL 1985, 26, 411.
20. (a) Hoppe, D.; Krämer, T. AG 1986, 98, 171; AG(E) 1986, 25, 160. (b) Krämer, T.; Hoppe, D. TL 1987, 28, 5149.
21. Schwark, J.-R.; Hoppe, D. S 1990, 291.
22. Marshall, J. A. Chemtracts, Org. Chem. 1992, 75.
23. (a) Krämer, T.; Schwark, J.-R.; Hoppe, D. TL 1989, 30, 7037. (b) Zschage, O.; Schwark, J.-R.; Krämer, T.; Hoppe, D. T 1992, 48, 8377.
24. Andersen, M. W.; Hildebrandt, B.; Hoffmann, R. W. AG 1991, 103, 90; AG(E) 1991, 30, 97.
25. (a) Jephcote, V. J.; Pratt, A. J.; Thomas, E. J. CC 1984, 800. (b) Jephcote, V. J.; Pratt, A. J.; Thomas, E. J. JCS(P1) 1989, 1529. (c) Marshall, J. A.; Yashunsky, D. V. JOC 1991, 56, 5493.

Dieter Hoppe

University of Münster, Germany

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