are perfectly suited to this problem, since the chirality at
carbon forces the N-methyl groups to exist primarily in one
of the two possible conformations and thus effectively moves
the chirality one atom closer to the reaction site. Now the
two diastereomeric transition states, 5a,b, are somewhat
dissimilar in energy, with the former experiencing steric
hindrance from the N-methyl group while the latter lacks
this interaction. Thus, one would expect to achieve reasonable
asymmetric induction favoring the isomer 6 as shown. We
now report the preparation of such fully substituted optically
active aminals by an interesting route and their use in
achieving good asymmetric induction.
It has been reported that N,N-dialkyl-1,2-diamines react
well with aldehydes but do not react with ketones (presum-
ably due to steric hindrance) although the simple 1,2-
diamines do.3,4 Therefore, we devised a different strategy
for the preparation of the very hindered aminals 4, as shown
in Scheme 2. The readily available optically active diol 7
which was converted into the imidazolinium salt 12 on
treatment with methyl iodide. After several failed attempts
to add various nucleophiles to 12, we found that the simple
silylated acetylide anion added extremely well to give, after
desilylation, the acetylene 13.9 This step forms the required
hindered quaternary center and represents a new way to pre-
pare fully substituted aminals of ketones. The aldehyde 14
was then prepared from 13 in two steps, catalytic hydrogena-
tion and then Swern oxidation, in nearly quantitative yield.
With aldehyde 14 in hand, we began to examine various
intramolecular cyclizations to determine whether one could
observe good asymmetric induction in this system. Thus,
treatment of 14 with tosylhydrazide followed by reaction with
tert-butoxide at 50 °C afforded an 82% yield of the
pyrazoline 16 as the only isomer isolated (Scheme 3). The
Scheme 3
Scheme 2a-i
structure of 16 was proven by a single-crystal X-ray
determination.10 Thus, the intermediate diazo compound 15
undergoes intramolecular dipolar cycloaddition only from
the bottom side of the alkene to give solely the isomer with
the R ring juncture hydrogens in agreement with the picture
shown in 5a,b.11 However, the difference in diastereomeric
transition states is not always so clear-cut. For example,
cyclization of the nitrone 17 derived from 14 is not very
stereoselective (Scheme 4). Reaction of 14 with N-benzyl
hydroxylamine afforded a 91% yield of a 1:1.2 mixture of
(4) (a) Alexakis, A.; Mangeney, P.; Lensen, N.; Tranchier, J. P.; Gosmini,
R.; Raussou, S. Pure Appl. Chem. 1996, 68, 531. (b) Alexakis, A.; Tranchier,
J. P.; Lensen, N.; Mangeney, P. J. Am. Chem. Soc. 1995, 117, 10767. (c)
Alexakis, A.; Lensen, N.; Tranchier, J. P.; Mangeney, P.; Feneaudupont,
J.; DeClercq, J. P. Synthesis 1995, 1038. (d) Alexakis, A.; Frutos, J. C.;
Mangeney, P. Tetrahedron: Asymmetry 1993, 4, 2431. (e) Commerc¸on,
M.; Mangeney, P.; Tejero, T.; Alexakis, A. Tetrahedron: Asymmetry 1990,
1, 287. (f) For a good review, see: Alexakis, A.; Mangeney, P. In AdVanced
Asymmetric Synthesis; Stephenson, G. R., Ed., Chapman and Hall: London,
1996; Chapter 5, pp 93-110.
a (a) Reaction conditions: (a) K2OsO4 (H2O)2, (DHQD) Phal,
2
NMO, H2O, t-BuOH, 100%, 92% ee; (b) SOCl2, Et3N, CCl4/H2O/
CH3CN, then RuCl2‚3(H2O) 2 (cat.), NaIO4, 81%; (c) acetylamidine,
toluene, reflux, 16 h, 54.2%; (d) n-BuLi, MeI, THF, -78 °C, 99%;
(e) n-BuLi, ICH2CH2OTBS, THF, -78 °C, 93%; (f) MeI, THF,
100%; (g) LiCCTMS, THF, -78 °C to rt, then 1 equiv of TBAF,
85%; (h) 5% Pd/BaSO4 (cat.), H2 (1 atm) TBAF, THF, 20 h, 98%;
(i) DMSO, (COCl) , Et3N, THF, -78 °C, 100%.
2
(5) Oi, R.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 999.
(6) Perrin, C. L.; Nun˜ez, O. J. Am. Chem. Soc. 1987, 109, 522.
(7) Gruseck, U.; Heuschmann, M. Chem. Ber. 1987, 120, 2053.
(8) (a) Anderson, M. W.; Jones, R. C. F. Tetrahedron Lett. 1981, 22,
261. (b) Anderson, M. W.; Jones, R. C. F.; Saunders, J. J. Chem. Soc.,
Perkin Trans. 1 1986, 205. (c) Gruseck, U.; Heuschmann, M. Tetrahedron
Lett. 1987, 28, 2681.
(9) Jones reported the addition of nucleophiles to such salts to give the
products of hydrolysis of the presumed dialkylated imidazolidines. Anderson,
M. W.; Jones, R. C. F.; Saunders, J. J. Chem. Soc., Perkin Trans. 1 1986,
1995.
(prepared by Sharpless asymmetric dihydroxylation of (E)-
stilbene) was converted into the known optically active cyclic
sulfate 85 and then reacted with acetamidine6 to give the
imidazoline 9 in 54% overall yield. Monomethylation of the
lithium anion of 9 with 1 equiv of methyl iodide gave a
quantitative yield of 10.7 Formation of the anion of the
C-methyl group of 10 and alkylation (by the method of
Jones)8 with 2-iodoethanol TBS ether gave the imine 11
(10) We thank Dr. Saeed Khan for his assistance in obtaining this crystal
structure.
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Org. Lett., Vol. 2, No. 17, 2000