Enantioselective [2,3]-Wittig rearrangement via sparteine-mediated lateral metalation of N,N-dialkyl-o-allyloxymethylbenzamides and o-substituted benzyl prenyl ethers

Article abstract of DOI:10.1055/s-1998-1978

The (-)-sparteine-mediated enantioselective [2,3]-Wittig rearrangement of N,N-dialkyl-o-allyloxymethylbenzamides and o-substituted benzyl prenyl ethers has been investigated. With N,N-diethyl-o-allyloxymethylbenzamide, enantiomeric excess up to 60% was observed in pentane. These results suggest that the carbamoyl group can effectively assist the transfer of stereoinformation by coordinating with the (-)-sparteine-n-BuLi complex. Other functional groups (OMe, OCONR₂, OMOM, F) were impotent to the enantiodifferentiation of this rearrangement.

Full text of DOI:10.1055/s-1998-1978

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Enantioselective [2,3]-Wittig Rearrangement via Sparteine-Mediated Lateral Metalation of
N,N-Dialkyl-o-allyloxymethylbenzamides and o-Substituted Benzyl Prenyl Ethers
Takeshi Kawasaki, and Tetsutaro Kimachi*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8304, Japan
Fax +81 75 761 2689; E-mail tkimachi@pharmsun.pharm.kyoto-u.ac.jp
Received 26 August 1998
Abstract: The (-)-sparteine-mediated enantioselective [2,3]-Wittig
rearrangement of N,N-dialkyl-o-allyloxymethylbenzamides and o-
substituted benzyl prenyl ethers has been investigated. With N,N-
diethyl-o-allyloxymethylbenzamide, enantiomeric excess up to 60%
was observed in pentane. These results suggest that the carbamoyl group
can effectively assist the transfer of stereoinformation by coordinating
with the (-)-sparteine-n-BuLi complex. Other functional groups (OMe,
rearrangement of benzyl allyl ethers. We wish to report here the (-)-
sparteine-mediated enantioselective [2,3]-Wittig rearrangement of N,N-
dialkyl-o-allyloxymethylbenzamides 3a, 3b and o-substituted benzyl
prenyl ethers 8b-8g initiated by enantioselective lateral metalation.
OCONR , OMOM, F) were impotent to the enantiodifferentiation of
2
this rearrangement.
Enantioselective and diastereoselective reactions of [2,3]-Wittig
rearrangement are powerful tools in the synthesis of natural products for
the introduction of more than one chiral carbon center. While a number
of successful studies have reported for the diastereoselective [2,3]-
Wittig rearrangement1, the enantioselective version of [2,3]-Wittig
rearrangement is still an underdeveloped field2. Recently, Manabe has
reported that [2,3]-Wittig rearrangement of unsubstituted benzyl prenyl
ether mediated by (-)-sparteine proceeded in moderate chemical yield
(70 %) but in low enantiomeric excess (19%)2c.
Scheme 1
Among the well studied heteroatomic substituents promoted lateral
metalation-substitution reactions3, the enantioselective metalation of
N,N-dialkyl-o-ethylbenzamides mediated by (-)-sparteine, studied by
Beak’s group4, is a successful example. Based on these results, we
started to study the effects of the carbamoyl and other functional groups,
located at the ortho position of benzyl allyl ethers and presumably
involved in coordination with a ligand and a base, on [2,3]-Wittig
Initial studies, summarized in Scheme 1 and Table 1, concerned the
synthesis and (-)-sparteine-mediated [2,3]-Wittig rearrangement of N,N-
dialkyl o-allyloxymethylbenzamides (3a, 3b). Compounds 3a and 3b
were synthesized by the reaction of allyl bromide with 2a, 2b which
were prepared by ortho metalation methodology followed by sodium

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borohydride reduction5, 6(Scheme 1). The reaction with no ligand
afforded substantial amounts of aryl butyl ketone 5 resulting from
nucleophilic attack of n-BuLi on the amide carbonyl (Table 1, entry 1).
The [2,3]-Wittig rearrangement proceeded by the addition of N,N,N’,N’-
tetramethylethylenediamine (TMEDA) (entry 2) to give 4a. These
results prompted us to examine a series of reactions using (-)-sparteine
as a chiral ligand7.
Table 1 also shows that the enantioselectivity was influenced by the
solvent used. In diethyl ether, low enantiomeric excess was observed
with the opposite sense of selectivity compared with that in pentane
(entry 5), although in toluene poor enantioselectivity was observed with
the same sense of selectivity as shown in pentane (entry 6). Use of 2.2
equivalents of n-BuLi and (-)-sparteine in pentane at -95°C afforded the
best selectivity (60 % ee) without recovery of the starting material
(entry 9).
The % ee's were obtained by HPLC analysis on a chiralcel OD column
(250 X 4.6 mm, I. D.) using n-hexane : i-PrOH = 200 : 1 as eluent (flow
rate 0.5 ml / min) at 254 nm. It is noteworthy that the reaction using
N,N-diisopropyl o-allyloxymethylbenzamide (3b) as a starting material
at -78°C showed the similar enantioselectivity in yielding 4b (37% ee)
but with the opposite sense of selectivity (entry 10). The reason for the
opposite selectivity between N,N-diisopropylcarbamoyl group and N,N-
diethylcarbamoyl group is not clear.
Acknowledgements. We wish to thank Professor Victor Snieckus
(Department of Chemistry, Queen's University, Canada) for informative
discussions and advice.
References and Notes
Scheme 2
(1) (a) Nakai, T.; Mikami, K. Org. React. ; John Wiley & Sons, Inc.:
N. Y., 1994; Vol.46, 105. (b) Nakai, T.; Tomooka, K. Pure and
Appl. Chem. 1997, 69, 595. (c) Enders, D.; Backhaus, D. Synlett.
1995, 631. (d) Enders, D.; Backhaus, D.; Runsink, J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2098. (e) Takahashi, O.; Mikami,
K.; Nakai, T. Chem. Lett. 1987, 69. (f) Mikami, K.; Takahashi, O.;
Kasuga, T.; Nakai, T. Chem. Lett. 1985, 1729. (g) Mikami, K.;
Fujimoto, K.; Kasuga, T.; Nakai, T. Tetrahedron Lett. 1984, 25,
6011.
Next, attention was focused on the preparation and the reaction of a
series of o-substituted benzyl prenyl ethers (8b-8g) as shown in Scheme
2
and Table 2. As can be seen, N,N-diethyl o-(3-methyl-2-
butenyl)oxymethylbenzamide (8b) gave the highest enantioselectivity
(62% ee) (entry 2). The presence of o-methoxy and o-OCON(i-Pr)
2
groups, both of which are known to be strongly directing metalation
groups, did not enhance the enantioselectivities (entries 3, 5). o-
Methoxymethoxy adduct (9f) was obtained in 20% ee. o-Fluoro
derivative (8g) gave a product with 16% ee. These results suggest that
the carbamoyl group can effectively assist the stereoinformation transfer
by coordinating with the (-)-sparteine-n-BuLi complex, though it is not
yet determined whether the enantioselectivity is introduced at the
deprotonation step or after the deprotonation. In conclusion, the N,N-
diethylcarbamoyl group acts as an efficient director in the (-)-sparteine-
mediated enantioselective [2,3]-Wittig rearrangement of o-substituted
benzyl allyl ethers. The presence of N,N-diisopropylcarbamoyl group
gave a product with a similar but opposite enantioselectivity to that of
N,N-diethylcarbamoyl group. The presence of functional groups other
than carbamoyl group did not show significant enantioenrichment in
this system.
(2) (a) Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron Lett. 1998,
39, 5513. (b) Gibson, S. E.; Ham, P.; Jefferson, G. R. J. Chem.
Soc., Chem. Commun. 1998, 123. (c) Manabe, S. Chem. Pharm.
Bull. 1998, 46, 335. (d) Manabe, S. J. Chem. Soc., Chem.
Commun. 1997, 737. (e) Marshall, J. A.; Wang, X. J. Org. Chem.,
1992, 57, 2747. (f) Marshall, J. A.; Lebreton, J. J. Am. Chem. Soc.,
1988, 110, 2925.
(3) Clark, R. D.; Jahangir, A. Org. React.; John Wiley & Sons, Inc.:
N. Y., 1995; Vol. 47., 1.
(4) (a) Thayumanavan, S.; Basu, A.; Beak, P. J. Am. Chem. Soc. 1997,
119, 8209. (b) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552.
(5) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231.

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1
(6) All new compounds show analytical and spectral ( H-NMR,
HRMS) data consistent with the depicted structure.
(8) Takahashi, H.; Tsubuki, T.; Higashiyama, K. Chem. Pharm. Bull.
1991, 39, 3136.
(7) Typical procedure: To a stirred solution of a ligand (1.1 or 2.2
equiv.) and n-BuLi (1.1 or 2.2 equiv.) in the solvent (15 ml) at -78
or -95°C, substrates (3, 8a—8g) (200 mg) in dry solvent (5 ml)
was slowly added via cannula. After 3h stirring at -78 or -95 °C,
(9) For example, the (S) absolute configuration of 4a (Table 1, entry
4) was determined as follows.
the reaction mixture was quenched with sat. NH Cl aq. and
4
extracted with AcOEt. Purification by flash chromatography
afforded the compounds listed in Table 1 and Table 2.