6
Tetrahedron
4.2.13. Ethyl (S)-2-[(4-methoxyphenyl)amino]-2-
Hz, 1H), 3.66 – 3.45 (m, 1H), 3.29 (t, J = 6.5 Hz, 1H), 2.42 (d,
ACCEPTED MANUSCRIPT
[(R)-2-oxocycloheptyl]acetate (5m)7 b
J = 2.8 Hz, 2H), 1.54 – 1.35 (m, 3H), 1.30 – 0.95 (m, 12H), 1.00
– 0.70 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 142.99, 138.52,
129.48, 127.01, 61.08, 56.06, 42.64, 33.62, 32.02, 31.65, 29.05,
28.08, 27.10, 25.58, 22.55, 22.49, 14.08. νmax (neat, cm-1): 3390,
2953, 2856, 1723, 1465, 1377, 1330. HRMS (ESI) m/z calcd. for
C18H30NO5S [M+H]+): 372.1829; Found: 372.1834. Enantiomeric
excess of 6i was determined by chiral stationary phase HPLC
analysis using a ChiralPak IC column (90:10 hexanes/i-PrOH at
1.0 mL/min, λ = 254 nm), major enantiomer: tR = 34.1 min;
minor enantiomer: tR = 29.6 min.
Yellow oil; 54.4 mg, 85% yield; 84:16 dr, 59% ee, [α]25
=
D
1
+35.8 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ 6.79 (d,
J = 8.9 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 4.18 (t, J = 7.1 Hz,
2H), 3.76 (d, J = 1.5 Hz, 3H), 3.11 – 3.00 (m, 1H), 2.56 (d, J =
3.7 Hz, 2H), 2.19 (s, 1H), 2.10 – 1.86 (m, 4H), 1.57 (dd, J = 11.3,
2.6 Hz, 2H), 1.48 – 1.33 (m, 2H), 1.28 – 1.20 (m, 4H); 13C NMR
(125 MHz, CDCl3): δ 214.20, 172.60, 152.74, 140.99, 115.24,
114.89, 77.29, 77.03, 76.78, 61.31, 60.71, 55.74, 54.39, 43.90,
30.94, 29.93, 29.04, 27.21, 24.26, 14.18, 14.15. Enantiomeric
excess of 5m was determined by chiral stationary phase HPLC
analysis using a ChiralPak IC column (80:20 hexanes/i-PrOH at
1.0 mL/min, λ = 254 nm), major enantiomer: tR = 17.7 min;
minor enantiomer: tR = 15.2 min.
4.2.10. Ethyl (2S,3R)-3-acetyl-2-[(4-
methoxyphenyl)amino]hexanoate (5j)7 b
Colorless oil; 47.8 mg, 76% yield; 80:20 dr, 84% ee, [α]25
=
D
1
Acknowledgements
-36.5 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ 6.78
(ddd, J = 9.4, 4.9, 2.1 Hz, 2H), 6.73 – 6.60 (m, 2H), 4.21 – 4.10
(m, 3H), 3.76 (t, J = 1.9 Hz, 3H), 3.10 – 2.97 (m, 1H), 2.53 (ddd,
J = 7.5, 5.4, 2.0 Hz, 2H), 1.63 – 1.50 (m, 3H), 1.27 – 1.16 (m,
5H), 0.92 (td, J = 7.4, 5.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 214.19, 172.59, 152.74, 140.99, 115.24, 114.89, 77.29, 77.03,
76.78, 61.31, 60.71, 55.74, 54.39, 43.90, 30.94, 29.93, 29.04,
27.21, 24.26, 14.18. νmax (neat, cm-1): 3335, 2957, 1727, 1699,
1510, 1464, 1362, 1286. HRMS (ESI) m/z calcd. for C17H26NO4
([M+H]+): 308.1856; Found: 308.1861. Enantiomeric excess of
5j was determined by chiral stationary phase HPLC analysis
using a ChiralPak IC column (80:20 hexanes/i-PrOH at 1.0
mL/min, λ = 254 nm), major enantiomer: tR = 8.8 min; minor
enantiomer: tR = 11.3 min.
The generous financial support of this research by the Welch
Foundation (Grant No. AX-1593) and the National Science
Foundation (Grant No. CHE 1664278) was gratefully
appreciated. Some of the NMR data reported in this paper were
collected on an NMR spectrometer acquired with the funding
from the NSF (Grant No. CHE-1625963). The HRMS used in
this research was supported by a grant from the National Institute
on Minority Health and Health Disparities (G12MD007591)
from the National Institutes of Health. The authors also thank Dr.
Wendell P. Griffith for help with the HRMS analysis of the
samples.
Appendix A. Supplementary data
4.2.11. Ethyl (S)-2-[(4-methoxyphenyl)amino]-2-
Supplementary data related to this article can be found at
[(R)-2-oxocyclohexyl]acetate (5k):7 b
Colorless oil; 59.4 mg, 90% yield; 92:8 dr, 86% ee, [α]25
=
D
1
+32.8 (c = 1.0, CH2Cl2). H NMR (300 MHz, CDCl3): δ 6.93 –
6.69 (m, 2H), 6.70 – 6.54 (m, 2H), 4.28 – 4.04 (m, 2H), 3.98 (d, J
= 4.1 Hz, 1H), 3.74 (d, J = 2.4 Hz, 3H), 3.21 – 3.03 (m, 1H), 2.60
– 2.23 (m, 2H), 2.23 – 2.01 (m, 2H), 2.02 – 1.83 (m, 2H), 1.88 –
1.56 (m, 3H), 1.36 – 1.15 (m, 3H); 13C NMR (125 MHz, CDCl3):
δ 211.00, 173.10, 152.74, 142.15, 115.64, 115.61, 114.74, 61.22,
59.18, 59.01, 55.79, 55.62, 53.62, 41.85, 30.56, 26.87, 24.57,
14.25, 14.18, 14.10. Enantiomeric excess of 5k was determined
by chiral stationary phase HPLC analysis using a ChiralPak IC
column (80:20 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm),
major enantiomer: tR = 17.5 min; minor enantiomer: tR = 16.3
min.
References
1. For some general reviews, see: (a) Akiyama, T., C-C Bond
Formation: Mannich Reaction. In Comprehensive Chirality,
Carreira, E. M., Yamamoto, H., Ed. Elsevier B.V.: Amsterdam,
2012; Vol. 6, pp 69-96. (b) Akiyama, T., The bimolecular and
intramolecular Mannich and related reactions. In Comprehensive
Organic Synthesis 2nd ed.; Knochel, P. M., Gary A, Ed. Elsevier
B.V.: Amsterdam, Neth, 2014; Vol. 2, pp 629-681. (c) Kobayashi,
S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111,
2626-2704. (d) Hart, D. J.; Ha, D. C. Chem. Rev. 1989, 89, 1447-
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L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29-41. (f)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094.
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L.-Z. J. Am. Chem. Soc. 2007, 129, 3790-3791. (b) Juhl, K.;
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2995-2997. (c) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am.
Chem. Soc. 2002, 124, 5640-5641. (d) Trost, B. M.;
Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc. 2006, 128,
2778-2779. (e) Yoshida, T.; Morimoto, H.; Kumagai, N.;
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Soc. 1998, 120, 431-432. (g) Sun, B.; Balaji, P. V.; Kumagai, N.;
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Tsogoeva, S. B.; Shubina, T. E.; Martynova, I. M.; Clark, T.
Angew. Chem. Int. Ed. 2008, 47, 6624-6628.
4.2.12. Ethyl (S)-2-[(4-methoxyphenyl)amino]-2-
[(S)-4-oxotetrahydro-2H-pyran-3-yl]acetate
(5l):7 b
Colorless oil; 54 mg, 78% yield; 70:30 dr, 44% ee, [α]25
=
D
1
+46.3 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ 6.82 –
6.74 (m, 2H), 6.74 – 6.58 (m, 2H), 4.34 – 3.97 (m, 6H), 3.97 –
3.85 (m, 1H), 3.86 – 3.77 (m, 1H), 3.74 (d, J = 2.2 Hz, 3H), 3.25
(dt, J = 9.5, 5.2 Hz, 1H), 2.67 – 2.54 (m, 1H), 2.48 (dt, J = 14.9,
3.9 Hz, 1H), 1.30 – 1.16 (m, 3H); 13C NMR (125 MHz, CDCl3):
δ 208.19, 172.15, 153.19, 141.27, 116.22, 115.91, 114.82, 70.07,
69.58, 68.07, 67.84, 61.54, 61.49, 56.64, 55.68, 54.45, 53.84,
42.09, 42.03. Enantiomeric excess of 5l was determined by chiral
stationary phase HPLC analysis using a ChiralPak IC column
(80:20 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major
enantiomer: tR = 19.2 min; minor enantiomer: tR = 17.9 min.
3. (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337. (b) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002,
124, 827-833.