4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 2. Alkylation of 3-Pentanone with ACC Auxiliaries 1-7.
entry
ACC
hydrazone
allylated hydrazone
allylation yield (%)
allylation α:α’ regioselectivity [(a+b):(c+d)]
allylation dr (a:b)
>99:1
1
2
3
4
5
6
7
1
2
3
4
5
6
7
8
12
13
14
15
29
30
31
98
92
93
82
92
94
93
>99:1
96:4
94:6
97:3
96:4
>99:1
98:2
9
95:5
10
11
26
27
28
>99:1
98:2
98:2
90:10
99:1
Finally, each of the purified mixtures of allylated
hydrazones was hydrolyzed to ketone 16 under our newly
established auxiliary cleavage conditions (Table 3). In each
case the enantiomer ratio corresponded to the diastereomer
ratio determined for the allylation reaction, indicating that no
detectable epimerization was occurring during auxiliary
products, without change at the newly formed stereogenic
center.
Acknowledgments
We are grateful to the NSF (NSF 1300652), the Welch
Foundation (E-1806), and the University of Houston for
financial support. S.E.W. thanks the NSF for a Graduate
Fellowship.
removal.
This further supports the notion that the
compromised stereoselectivity observed in our earlier study
was due to epimerization during auxiliary cleavage.
Table 3. Alkylation and hydrolysis of ACC Hydrazones 8-
11 and 26-28.
Supplementary Material
Supplementary data associated with this article can be
found, in the online version, at X.
References and notes
1) For general references to enolate chemistry, see: (a)
Heathcock, C. H. Modern Enolate Chemistry: Regio- and
Steroselective Formation of Enolates and the Consequence of
Enolate Configuration on Subsequent Reactions. In Modern
Synthetic Methods, Scheffold, R., Ed.; Verlag Helvetica
Chimica Acta: Basel, Switzerland, 1992; Vol. 6, pp 1–102, (b)
Rizzacasa, M. A.; Perkins, M. Formation and Alkylation of
Enolates. Stoichiometric Asymmetric Synthesis; Sheffield
Academic Press: Sheffield, England, 2000; pp 46–71. (c)
Mekelburger, H. B.; Wilcox, C. S. Formation of Enolates. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 99–131. (d)
Evans, D. A. Stereoselective Alkylation Reactions of Chiral
Metal Enolates. In Asymmetric Synthesis, Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, pp 1–110.
2) (a) McSweeney, C. M.; Foley, V. M.; McGlacken, G. P. Chem.
Commun. 2014, 50, 14817–14819. (b) Wengryniuk, S. E.; Lim,
D.; Coltart, D. M. J. Am. Chem. Soc. 2011, 133, 8714–8720. (c)
Krenske, E. H.; Houk, K. N.; Lim, D.; Wengryniuk, S. E.;
Coltart, D. M. J. Org. Chem. 2010, 75, 8578–8584. (d) Lim,
D.; Coltart, D. M. Angew. Chem. Int. Ed. 2008, 47, 5207–5210.
(e) Enders, D.; Eichenauer, H.; Baus, U.; Schubert, H.; Kremer,
K. A. M. Tetrahedron 1984, 40, 1345–1359. (f) Enders, D. In
Asymmetric Synthesis; 1st ed.; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, p 275–339. (g) Job, A.; Janeck,
C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253–2329. (h) Enders, D.; Eichenauer, H. Angew. Chem. Int.
Ed. 1976, 15, 549–551. (i) Enders, D.; Eichenauer, H. Angew.
Chem. Int. Ed. 1979, 18, 397–399. (j) Enders, D.; Eichenauer,
H. Chem. Ber.. 1979, 112, 2933–2960. (k) Meyers, A. I.;
Williams, D. R.; Druelinger, M. J. Am. Chem. Soc. 1976, 98,
3032–3033. (l) Meyers, A. I.; Williams, D. R. J. Org. Chem.
1978, 43, 3245–3247. (m) Meyers, A. I.; Williams, D. R.;
entry ACC hydrazone alkylated
hydrazone
(R)-16:(S)-16 conversion (%)
1
2
3
4
5
6
7
8
12
13
14
15
29
30
31
99:1
93:7
97:3
93:7
96:4
93:7
3:97
>99
>99
>99
>99
>99
>99
>99
9
10
11
26
27
28
In conclusion, we have demonstrated the effectiveness of
several ACC auxiliaries, including new species 5-7, in the
asymmetric allylation of 3-pentanone. From these studies, we
have established the source of imperfect stereoselectivity for
the different auxiliaries varies. In the case of auxiliaries 2-5,
appreciable levels of competing α’-allylation were observed,
indicating that these auxiliaries are less effective in directing
the deprotonation step. For ACC auxiliaries 2 and 6, a
significantly lower lever of facial selectivity was observed for
the allylation step, in comparison with the other auxiliaries.
Several auxiliaries, most notably 1, gave both excellent
regiocontrol during the deprotonation step, and facial
selectivity during the alkylation step, such that excellent
overall levels of asymmetric induction resulted. Lastly, we
have confirmed that p-TsOH•H2O in a 4:1 (v/v) acetone-H2O
effectively causes removal of the auxiliaries from the allylated