Carba-methylephedrine and carba-pseudo-methylephedrine as tools for probing the role of the nitrogen atom of chiral amino alcohols in asymmetric synthesis

Article abstract of DOI:10.1055/s-1999-3092

As part of our on-going program on the use of chiral alkoxides as chiral bases in asymmetric synthesis, we report that carba-ephedrine analogues of N- methylephedrines, with a simple change of bridging nitrogen for CH, served to probe the role of the nitrogen atom in the discrimination of enantiotopic protons by means of the derived alkoxides. We suggest reasons why in the pseudo ephedrine series the asymmetric induction is retained while in the ephedrine series the enantioselectivity is strongly affected.

Full text of DOI:10.1055/s-1999-3092

960
LETTER
Carba-Methylephedrine and Carba-pseudo-Methylephedrine as Tools for
Probing the Role of the Nitrogen Atom of Chiral Amino Alcohols in
Asymmetric Synthesis
Dominique Cahard, Laurent Ferron, Jean-Christophe Plaquevent*
Université de Rouen, UPRES-A 6014 et Institut de Recherche en Chimie Organique Fine (IRCOF), 76821 Mont Saint-Aignan Cedex,
France
E-mail: Jean-Christophe.Plaquevent @univ-rouen.fr
Received 25 January 1999
thyl iodide. Reduction of the resulting ketone 2 was first
Abstract: As part of our on-going program on the use of chiral
realized at room temperature with sodium borohydride in
alkoxides as chiral bases in asymmetric synthesis, we report that
methanol to afford the alcohol 3 in excellent yield as a di-
astereomeric mixture (88:12). Lowering the reaction tem-
carba-ephedrine analogues of N-methylephedrines, with a simple
change of bridging nitrogen for CH, served to probe the role of the
nitrogen atom in the discrimination of enantiotopic protons by perature to -70°C allowed the isolation of a single
means of the derived alkoxides. We suggest reasons why in the
diastereomer. The Felkin-Anh formulation of Cram’s rule
pseudo ephedrine series the asymmetric induction is retained while
predicts the (R*, R*) configuration for the major stereoi-
in the ephedrine series the enantioselectivity is strongly affected.
Key words: chiral alkoxide, ephedrine, carba-ephedrine, enantiose-
lective dehydrohalogenation
Chiral amino alcohols are powerful chiral auxiliaries in
various asymmetric reactions. For example, their use as
chiral ligands to render enantioselective a nucleophilic ad-
dition onto a prochiral electrophilic unit is well document-
ed.1 In this particular case, both heteroatoms (N and O) are
involved in the coordination of the metal ion, suggesting
that the difunctional character of the auxiliary is probably
the main reason for the success in asymmetric synthesis.
Another application of chiral amino alcohols has been re-
cently examined by our group, i.e. the enantioselective de-
hydrohalogenation by means of potassium N-
methylephedrinate.2 During these studies, we wondered if
the dimethylamino moiety of the chiral base was involved
in coordination or played only a steric role. This prompted
us to explore the induction ability of carba-derivatives in
which the nitrogen atom is replaced by a CH group.
Figure 1
The carbon skeleton of carba-ephedrine3 was built by ad-
dition of 2-methylpropylmagnesium chloride to benzoni-
trile and subsequent hydrolysis with sulfuric acid
Scheme 1
followed by methylation of the enolate of ketone 1 by me-
Synlett 1999, S1, 960–962 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Carba-Methylephedrine as Tools in Asymmetric Synthesis
961
somer. The racemic mixture was derivatized as its (1S)-
(-)-camphanic ester and separated by preparative HPLC.
Then the diastereoisomeric esters were saponified in
aqueous sodium hydroxide to generate the pure enanti-
omers (1R, 2R) and (1S, 2S) carba-pseudo-methylephe-
drine 4 and 5. The absolute configuration of each
enantiomer was unambiguously established by single
crystal X-ray analysis of the camphanic esters.4
In order to obtain the two enantiomers 6 and 7 of the car-
ba-methylephedrine one needs the inversion of one of the
stereogenic centers of the pseudo-derivative. Racemic
carba-pseudo-methylephedrine 3 was subjected to Mit-
sunobu conditions to afford esters in which the original
configuration at C-1 was inverted.5 Reduction (DIBAL)
and separation of the enantiomers by derivatization and
preparative HPLC as previously described gave pure (1R,
2S) and (1S, 2R) enantiomers of carba-methylephedrine 6
and 7. As in the carba-pseudo-methylephedrine series, X-
ray analysis of a single crystal of camphanic ester gave ac-
cess to the absolute configuration of the compounds.4 In
order to confirm X-ray analysis, enantiomerically pure
(1S, 2S) carba-pseudo-methylephedrine 5 was subjected
to the Mitsunobu inversion and saponification to give pure
(1R, 2S) carba-methylephedrine 6 with specific rotation
data allowing the assignment of the absolute configura-
tion of each enantiomer.
In order to probe the role of the nitrogen atom of potassi-
um ephedrinates, we have carried out enantioselective de-
hydrohalogenation of prochiral dibrominated dioxanes 11
using alkoxides obtained either from the amino alcohol or
the carba derivatives. Table 1 shows the asymmetric in-
duction obtained in both cases.
coordinate the potassium ion. One can propose that this
coordination leads the alkoxide to adopt an eclipsed con-
formation due to the ionic radius of the metallic ion. This
eclipsed conformation is sterically disfavored in the pseu-
do-ephedrine series, with respect to the ephedrine series.
The chelated alkoxide would be responsible of asymmet-
ric induction, which consequently would be inferior in the
case of the pseudo-ephedrine series.
Scheme 2
The major and striking feature of these data is the opposite
behaviour in the ephedrine and pseudo-ephedrine series.
While in the latter case, the replacement of the nitrogen
atom by a CH moiety does not change significantly the
asymmetric induction (and even enhances it to a small ex-
tent. Table 1, entries 1, 2, 5, 6), one can observe that a dra-
matic decrease of enantiomeric excess is obtained in the
former case (Table 1, entries 3, 4, 7). Thus a clear conclu-
sion is that carbon cannot replace nitrogen without a loss
of enantioselectivity in the ephedrine series.
Figure 2
Replacement of the nitrogen by a CH moiety would not
change the conformation in the pseudo-ephedrine series,
thus giving similar ee’s. On the other hand, the same mod-
ification would not allow coordination in the ephedrine
series; this would be the reason for the dramatic decrease
in enantioselection.
In conclusion, the present study describes the synthesis
and the determination of the absolute configuration of the
four stereoisomers of carba-methylephedrine. Their use in
asymmetric synthesis makes it possible to readily probe
the role of the nitrogen atom.6
As usually assumed, one can expect that the more rigid the
chiral auxiliary is, the more efficient the asymmetric in-
duction. Thus, one possible explanation for the differenc-
es discussed above could be the ability of the alkoxide to
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962
D. Cahard et al.
LETTER
(3) This trivial nomenclature is preferred to the systematic one to
readily allow a direct comparison with the amino alcohol
series.
(4) The full details of the X-ray crystallographic data have been
deposited at the Cambridge Crystallographic Data Centre
(CCDC 113910).
Acknowledgement
The authors thank Dr L. Toupet (University of Rennes, France) for
the determination of crystal structures.
References and Notes
(5) Mitsunobu, O. Synthesis 1981, 1.
(6) For related studies using chiral alkoxides as Brønsted bases,
see: Jones, C.D.; Simpkins, N.S.; Giblin, G.M.P. Tetrahedron
Lett. 1998, 39, 1023. Hodgson, D.M.; Gibbs, A.R.
Tetrahedron Asymmetry, 1996, 7, 407. Kumamoto, T.; Aoki,
S.; Nakajima, M.; Koga, K. Tetrahedron Asymmetry, 1994, 5,
1431. Milne, D.; Murphy, P.J. J. Chem. Soc., Chem.
Commun., 1993, 884. Willems, J.G.H.; De Vries, J.G.; Nolte,
R.J.M.; Zwanenburg, B. Tetrahedron Lett., 1995, 36, 3917.
(1) See for examples : Gawley, R.E.; Aube, J. Principles of
Asymmetric Synthesis, Pergamon, Oxford 1996.
(2) Vadecard, J.; Plaquevent, J-C.; Duhamel, L.; Duhamel, P. J.
Chem. Soc., Chem. Commun., 1993, 116. Vadecard, J.;
Plaquevent, J-C.; Duhamel, L.; Duhamel, P.; Toupet, L. J.
Org. Chem. 1994, 59, 2285. Amadji, M.; Vadecard, J.;
Plaquevent, J-C.; Duhamel, L.; Duhamel, P. J. Am. Chem.
Soc., 1996, 118, 12483. Amadji, M.; Vadecard, J.; Cahard, D.;
Duhamel, L.; Duhamel, P.; Plaquevent, J-C. J. Org. Chem.,
1998, 63, 5541.
Article Identifier:
1437-2096,E;1999,0,S1,0960,0962,ftx,en;W03299ST.pdf
Synlett 1999, S1, 960–962 ISSN 0936-5214 © Thieme Stuttgart · New York