[83876-83-9]  · C11H15LiO2  · 1-(Benzyloxymethoxy)propyllithium  · (MW 186.18)

(reagent for enantioselective nucleophilic a-hydroxyalkylation; example for several similar reagents)

Form Supplied in: in situ generation at low temperature in THF, ether, or hexane.

Preparative Method: the (preferentially enantioenriched) reagent is generated by tin-lithium exchange of [1-(benzyloxymethoxy)propyl]tributylstannane (eq 1)1 which proceeds with stereoretention. The lithium carbanion is configurationally stable in THF below approx -40 °C. The nonracemic precursor is obtained by classic1a or enzymatic2 resolution of the a-stannylalkanol, asymmetric reduction3 of acylstannanes (eq 2), or from chiral (1-chloroalkyl)boronates.4

Handling, Storage, and Precautions: solution in THF must be kept under exclusion of air or moisture below -40 °C.


Alkylation1a with Dimethyl Sulfate and carboxylation5 proceed with complete stereoretention to yield BOM-protected (S)-2-butanol1a or (S)- or (R)-2-hydroxybutanoic acid (eq 3).5 Analogously prepared (S)-1-(methoxymethoxy)propyllithium undergoes clean Michael addition to N,NŽ,NŽ-trimethylacryloylhydrazide, and the product can be converted to (S)-4-hexanolide (eq 4).6 The acylation of the (R) enantiomer by an N,N-dimethylalkanamide leads to an a-hydroxy ketone, which was converted to (+)-endo-brevicomin (eq 5).7

The addition of the lithium reagent to aldehydes gives monoprotected syn- and anti-vic-1,2-alkanediols with low diastereoselectivity (eq 6),8 which is improved in favor of the syn diastereomers by lithium-magnesium exchange and by application of b-branched analogs.8 Higher and opposite diastereoselectivity is achieved with the appropriate tributyltin or tributyllead reagents under Lewis acid catalysis; however, acetal O-protecting groups are not tolerated (eq 7).9

The cuprate reagents, derived from 1-(methoxymethoxy)alkyllithium, undergo 1,4-addition to enones10 and to enals (in the presence of Chlorotrimethylsilane) (eq 8).11 Enantioenriched reagents racemize under these conditions.12

Related Reagents.

1-Lithioalkyl N,N-dialkylcarbamates are generally accessible by direct deprotonation of alkyl carbamates,13 either in racemic form or highly enantiomerically enriched (see (-)-Sparteine) (eq 9). Sterically blocked lithiated alkyl benzoates do not permit alkyl substitution at the carbanionic center.14 Preexisting stereogenic centers in the precursor cause an efficient internal, kinetically controlled, chiral induction in the deprotonation step.15 This was demonstrated by the synthesis of (2S,4S)-2-hydroxy-4-pentanolide (eq 10)15a from (S)-2,3-butanediol and of protected (2S,3S)-2-hydroxy-3-amino acids (eq 11)15b and the chain elongation of 2-amino alkanols.15b

Racemic 1-methoxyalkyllithium16 reagents are easily obtained from monothioacetals by reductive lithiation17 with lithium salts of radical anions, such as Lithium 1-(Dimethylamino)naphthalenide (LDMAN).18 The method is particularly useful for the preparation of substituted 2-lithiotetrahydropyrans19 and 2-lithiotetrahydrofurans.19 The axial lithium compound is preferentially formed from the radical intermediate under kinetic control, irrespective of the relative configuration of the precursor; it epimerizes above -30 °C to form the more stable equatorial epimer (eq 12).19,20

Protected phenylthio- and phenylsulfonyl-2-deoxypyranosides were also subjected to these conditions and substituted by electrophiles via the 1-lithiopyranosides.21 Both a- and b-1-(3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosyl)cuprates, prepared by these methods, undergo highly stereoselective conjugate additions to enals and enones (eq 13).22

Even (3,4,6-tri-O-benzyl-2-O-lithio-a-D-glucopyranosyl)lithium can be generated and added to aldehydes (eq 14).23

4-Lithio-1,3-dioxanes19c,24 derived from chiral 1,3-diols are similarly generated and proved to be versatile building blocks in the stereoselective synthesis of polyols, such as 1,3,5,7,9,10-decanehexaol (eq 15).

The zinc-copper reagents, obtained from 1-(acetoxyalkyl)zinc bromides,25 are subjected to efficient alkylations, alkynylations, acylations, and Michael addition reactions (eq 16).

1. (a) Still, W. C.; Sreekumar, C. JACS 1980, 102, 1201. (b) Sawyer, J. S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J. JACS 1988, 110, 842.
2. Chong, J. M.; Mar, E. K. TL 1991, 32, 5683.
3. (a) Chan, P. C.-M.; Chong, J. M. JOC 1988, 53, 5584. (b) Marshall, J. A.; Gung, W. Y. T 1989, 45, 1043. (c) Marshall, J. A. Chemtracts, Org. Chem. 1992, 75.
4. Matteson, D. S.; Tripathy, P. B.; Sarkar, A.; Sadhu, K. M. JACS 1989, 111, 4399.
5. Chan, P. C.-M.; Chong, J. M. TL 1990, 31, 1985.
6. Chong, J. M.; Mar, E. K. TL 1990, 31, 1981.
7. Chong, J. M.; Mar, E. K. T 1989, 45, 7709.
8. McGarvey, G. J.; Kimura, M. JOC 1982, 47, 5420.
9. (a) Yamada, J.; Abe, H.; Yamamoto, Y. JACS 1990, 112, 6118. (b) Yamamoto, Y. Chemtracts, Org. Chem. 1991, 4, 255.
10. (a) Linderman, R. J.; Godfrey, A.; Horne, K. T 1989, 45, 495. (b) Linderman, R. J.; Godfrey, A.; Horne, K. TL 1987, 28, 3911. (c) Linderman, R. J.; Godfrey, A. TL 1986, 27, 4553.
11. Linderman, R. J.; McKenzie, J. R. JOM 1989, 361, 31.
12. (a) Linderman, R. J.; Griedel, B. D. JOC 1991, 56, 5491. (b) Linderman, R. J.; Griedel, B. D. JOC 1990, 55, 5428.
13. (a) Hoppe, D.; Hintze, F.; Tebben, P. AG 1990, 102, 1457; AG(E) 1990, 29, 1422. (b) Hintze, F.; Hoppe, D. S 1992, 1216.
14. (a) Beak, P.; Carter, L. G. JOC 1981, 46, 2363. (b) Schlecker, R.; Seebach, D.; Lubosch, W. HCA 1978, 61, 512.
15. (a) Ahrens, H.; Paetow, M.; Hoppe, D. TL 1992, 33, 5327. (b) Schwerdtfeger, J.; Hoppe, D. AG 1992, 104, 1547; AG(E) 1992, 31, 1505. (c) Guarnieri, W.; Grehl, M.; Hoppe, D. AG 1994, 106, 1815; AG(E) 1994, 33, 1724.
16. Cohen, T.; Matz, J. R. JACS 1980, 102, 6900.
17. Cohen, T.; Bhupathy, M. ACR 1989, 22, 152.
18. Cohen, T.; Sherbine, J. P.; Matz, J. R.; Hutchins, R. R.; McHenry, B. M.; Willey, P. R. JACS 1984, 106, 3245.
19. Cohen, T.; Lin, M.-T. JACS 1984, 106, 1130.
20. (a) Verner, E. J.; Cohen, T. JACS 1992, 114, 375. (b) Verner, E. J.; Cohen, T. JOC 1992, 57, 1072. (c) Rychnovsky, S. D.; Mickus, D. E. TL 1989, 30, 3011.
21. (a) Beau, J.-M.; Sinay, P. TL 1985, 26, 6185. (b) Beau, J.-M.; Sinay, P. TL 1985, 26, 6189. (c) Beau, J.-M.; Sinay, P. TL 1985, 26, 6193. (d) Fernandez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrières, A.; Sinay, P. TL 1989, 30, 2537.
22. Hutchinson, D. K.; Fuchs, P. L. JACS 1987, 109, 4930.
23. Wittmann, V.; Kessler, H. AG 1993, 105, 1138; AG(E) 1993, 32, 1091.
24. (a) Rychnovsky, S. D. JOC 1989, 54, 4982. (b) Rychnovsky, S. D.; Griesgraber, G. JOC 1992, 57, 1559.
25. Knochel, P.; Chou, T.-S.; Jubert, C.; Rajagopal, D. JOC 1993, 58, 588.

Dieter Hoppe

University of Münster, Germany

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