The Journal of Organic Chemistry
ARTICLE
([M ꢀ C6H11]+, 64), 55 (C4H7+, 100). EI HRMS calcd for C25H34O2
(M+) 366.2559, found 366.2566.
(c = 1.00, CHCl3). Rf = 0.3 (hexanes/EtOAc 5:1). IR (film cast, CHCl3):
3344 (m, broad), 2959 (s), 2930 (s), 2872 (m), 2858 (m), 2254 (m),
1028 (m) cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 4.23 (d, J = 5.7 Hz,
1H), 2.27 (t, J = 7.0 Hz, 2H), 1.95ꢀ1.84 (m, 2H), 1.53 (quintet, J = 7.3,
2H), 1.41ꢀ1.26 (m, 8H), 1.01 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz,
3H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 81.7, 75.5,
70.8, 68.5, 64.6, 34.8, 31.8, 29.0, 28.9, 28.3, 22.8, 19.4, 18.2, 17.6, 14.2.
EIMS m/z 220.2 (M+, 1), 177.1 ([M ꢀ i-Pr]+, 100). EI HRMS calcd for
C15H24O (M+) 220.1827, found 220.1825.
Compound 20. Compound 11h (105 mg, 0.510 mmol, 1.3 equiv)
was combined with Zn(OTf)2 (338 mg, 0.930 mmol, 2.4 equiv), (ꢀ)-N-
methylephedrine (99 mg, 0.55 mmol, 1.4 equiv), Et3N (77 μL, 56 mg,
0.55 mmol, 1.4 equiv), and isobutyraldehyde (34 μL, 28 mg, 0.38 mmol,
1.0 equiv) in PhMe (1 mL) as per the general procedure for 40 h to yield
(S)-(+)-20 (95 mg, 89%) as a yellow oil. A 91% ee was determined by
HPLC (Chiralpak AS column, 1% i-PrOH in heptane, 0.5 mL/min, λ =
254 nm, column temperature = 2.5 °C) Tminor = 20.0 min, Tmajor = 22.5
min. [R]22D = 2.35° (c = 2.00, CHCl3). Rf = 0.5 (hexanes/EtOAc 5:1).
IR (film cast, CHCl3): 3314 (m, broad), 2961 (s), 2945 (s), 2867 (s),
2219 (w), 2103 (m), 1464 (m) cmꢀ1. 1H NMR (400 MHz, CDCl3) δ
4.23 (d, J = 5.8, 1H), 1.98 (broad singlet, 1H), 1.91 (app octet, J = 6.6,
1H), 1.08 (s, 21H), 1.03 (d, J = 6.8, 3H) 1.01 (d, J = 6.9, 3H). 13C NMR
(100 MHz, CDCl3) δ 88.9, 84.4, 76.5, 70.9, 68.3, 34.6, 18.5, 18.0, 17.6,
11.2. EIMS m/z 278.2 (M+, 9), 235.2 ([M ꢀ i-Pr]+, 100); EIHRMS
calcd for C17H30OSi (M+) 278.2066, found 278.2065.
Compound 21. Compound 12a (32 mg, 0.16 mmol, 1.1 equiv) was
combined with Zn(OTf)2 (210 mg, 0.59 mmol, 4.9 equiv),34 (ꢀ)-N-
methylephedrine (81 mg, 0.45 mmol, 3.8 equiv), Et3N (60 μL, 44 mg,
0.43 mmol, 3.6 equiv), and isobutyraldehyde (11 μL, 8.7 mg, 0.12 mmol,
1.0 equiv) in PhMe (1 mL) as per the general procedure for 72 h to yield
(S)-(+)-21 (23 mg, 69%) as a beige semisolid. An 89% ee was
determined by 19F NMR analysis of the corresponding ester derived
from (R)-MTPA chloride (ꢀ71.92 ppm (major), ꢀ72.27 ppm
minor)). [R]22D = 11.42° (c = 0.50, CHCl3). Rf = 0.5 (hexanes/EtOAc
5:1). IR (film cast, CHCl3): 3359 (m, broad), 3086 (w), 3039 (w), 2964
(s), 2928 (s), 2872 (m), 2191 (m), 2103 (w), 1603 (w), 1503 (w), 1464
(m) cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.35
(d, J = 8.4 Hz, 2H), 4.27 (t, J = 5.8 Hz, 1H), 1.94 (app octet, J = 6.7 Hz,
1H), 1.81 (d, J = 5.9 Hz, 1H), 1.31 (s, 9H), 1.04 (d, J = 6.7 Hz, 3H) 1.03
(d, J = 6.7 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 153.6, 133.0, 125.7,
117.8, 79.9, 77.7, 73.8, 70.9, 68.6, 65.8, 63.6, 35.2, 34.9, 31.2, 18.2, 17.6.
EIMS m/z 278.2 (M+, 26), 235.1 ([M ꢀ i-Pr]+, 100). EI HRMS calcd for
C20H22O (M+) 278.1671, found 278.1674.
Compound 16. Compound 11d (132 mg, 0.709 mmol, 1.1 equiv)
was combined with Zn(OTf)2 (406 mg, 1.12 mmol, 1.7 equiv), (ꢀ)-N-
methylephedrine (129 mg, 0.720 mmol, 1.1 equiv), Et3N (110 μL,
77 mg, 0.76 mmol, 1.2 equiv), and isobutyraldehyde (59 μL, 47 mg,
0.65 mmol, 1.0 equiv) in PhMe (1 mL) as per the general procedure for
48 h to yield (S)-(+)-16 (138 mg, 93%) as a pale yellow semisolid. A 98%
ee was determined by HPLC analysis (Chiralcel OD column, 5%
i-PrOH in hexanes, 0.5 mL/min, λ = 254 nm, column temperature =
25 °C) Tmajor = 42.6 min, Tminor = 49.4 min. [R]22D = 2.46° (c = 0.90,
CHCl3). Rf = 0.3 (hexanes/EtOAc 5:1). IR (film cast, CHCl3): 3386
(m, broad), 2963 (s), 2933 (m), 2873 (m), 2839 (m), 2237 (m), 1604
1
(s), 1567 (w), 1510 (s) cmꢀ1. H NMR (400 MHz, CDCl3) δ 7.44
(d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 4.31 (d, J = 5.7 Hz, 1H), 3.82
(s, 3H), 1.94 (app octet, J = 6.4 Hz, 2H), 1.88 (bs, 1H), 1.06 (d, J = 6.8
Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
160.4, 134.2, 114.1, 113.4, 81.8, 78.5, 72.1, 70.5, 68.6, 55.3, 34.8, 18.1,
17.6. EIMS m/z 288.1 (M+, 37), 185.1 ([M ꢀ i-Pr]+, 100). EI HRMS
calcd for C15H16O2 (M+) 228.1150, found 228.1153.
Compound 17. Compound 11e (53 mg, 0.50 mmol, 1.3 equiv) was
combined with Zn(OTf)2 (348 mg, 0.957 mmol, 2.5 equiv), (+)-N-
methylephedrine (132 mg, 0.736 mmol, 1.9 equiv), Et3N (98 μL, 71 mg,
0.70 mmol, 1.8 equiv), and isobutyraldehyde (35 μL, 28 mg, 0.39 mmol,
1.0 equiv) in PhMe (1 mL) as per the general procedure for 60 h to yield
(R)-(ꢀ)-17 (30 mg, 43%) as a yellow oil. An 88% ee was determined by
19F NMR analysis of the corresponding ester derived from (R)-MTPA
chloride (ꢀ72.34 ppm (major), ꢀ71.97 ppm (minor)). [R]22
=
D
ꢀ3.51° (c = 0.87, CHCl3). Rf = 0.4 (hexanes/EtOAc 5:1). IR (film
cast, CHCl3): 3354 (m, broad), 2961 (s), 2934 (s), 2874 (m), 2254 (m),
1
1467 (m) cmꢀ1. H NMR (400 MHz, CDCl3) δ 4.21 (d, J = 5.7 Hz,
1H), 2.29 (dt, J = 7.0, 0.9, 2H), 1.95ꢀ1.83 (m, 2H), 1.56ꢀ1.37 (m, 4H),
1.01 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 81.4, 75.3, 70.6, 68.3, 64.4, 34.6, 30.2,
21.9, 18.9, 18.0, 17.4, 13.2. EIMS m/z 178.1 (M+, 4), 149.1 ([M ꢀ Et]+,
6), 135.1 ([M ꢀ i-Pr]+, 100). EI HRMS calcd for C12H18O (M+)
178.1358, found 178.1362.
Compound 18. Compound 11f (92 mg, 0.76 mmol, 1.2 equiv) was
combined with Zn(OTf)2 (312 mg, 0.858 mmol, 1.3 equiv), (ꢀ)-N-
methylephedrine (125 mg, 0.700 mmol, 1.1 equiv), Et3N (110 μL,
77 mg, 0.76 mmol, 1.2 equiv), and isobutyraldehyde (59 μL, 47 mg,
0.65 mmol, 1.0 equiv) in PhMe (1 mL) as per the general procedure for
60 h to yield (S)-(+)-18 (87 mg, 65%) as a yellow liquid. An 93% ee was
determined by 19F NMR analysis of the corresponding ester derived
from (R)-MTPA chloride (ꢀ71.98 ppm (major), ꢀ72.35 ppm
minor)). [R]22D = 4.16° (c = 0.25, CHCl3). Rf = 0.4 (hexanes/EtOAc
5:1). IR (film cast, CHCl3): 3361 (m, broad), 2960 (s), 2932 (s), 2872
(m), 2860 (m), 2254 (m) 1028 (m) cmꢀ1. 1H NMR (400 MHz, CDCl3)
δ 4.21 (t, J = 5.6 Hz, 1H), 2.28 (td, J = 7.1, 0.9 Hz, 2H), 1.89 (app octet,
J = 6.9 Hz, 1H), 1.79 (d, J = 5.9 Hz, 1H), 1.53 (quintet, J = 7.3 Hz, 2H),
1.42ꢀ1.24 (m, 6H), 1.01 (d, J = 6.7, Hz, 3H), 0.99 (d, J = 6.8, Hz, 3H),
0.89 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 81.5, 75.3, 70.6,
68.4, 64.4, 34.7, 31.2, 28.5, 28.1, 22.5, 19.3, 18.0, 17.5, 14.0. EIMS m/z
206.2 (M+, 2), 191.1 ([M ꢀ Me]+, 4), 177.1 ([M ꢀ Et]+, 6), 163.1
([M ꢀ i-Pr]+, 100). EI HRMS calcd for C14H22O (M+) 206.1671, found
206.1665.
Compound 19. Compound 11g (82 mg, 0.55 mmol, 1.2 equiv) was
combined with Zn(OTf)2 (210 mg, 0.58 mmol, 1.3 equiv), (ꢀ)-N-
methylephedrine (112 mg, 0.625 mmol, 1.4 equiv), Et3N (90 μL, 61 mg,
0.60 mmol, 1.3 equiv), and isobutyraldehyde (41 μL, 32 mg, 0.45 mmol,
1.0 equiv) in PhMe (1 mL) as per the general procedure for 48 h to yield
(S)-(+)-19 (76 mg, 77%) as a yellow oil. A 90% ee was determined by
19F NMR analysis of the corresponding ester derived from (R)-MTPA
chloride (ꢀ71.99 ppm (major), ꢀ72.36 ppm (minor)). [R]22D = 3.74°
Compound 22. Compound 12a (82 mg, 0.40 mmol, 1.2 equiv) was
combined with Zn(OTf)2 (182 mg, 0.501 mmol, 1.4 equiv), (ꢀ)-N-
methylephedrine (81 mg, 0.45 mmol, 1.3 equiv), Et3N (65 μL, 45 mg,
0.45 mmol, 1.3 equiv), and cyclohexanecarboxaldehyde (42 μL, 39 mg,
0.35 mmol, 1.0 equiv) in PhMe (1 mL) as per the general procedure for
90 h to yield (S)-(+)-22 (40 mg, 36%) as a pale yellow oil. A 90% ee was
determined by 19F NMR analysis of the corresponding ester derived
from (S)-MTPA chloride (ꢀ72.26 ppm (major), ꢀ71.89 ppm (minor)).
[R]22 = 7.56° (c = 1.00, CHCl3). Rf = 0.5 (hexanes/EtOAc 5:1). IR
D
(film cast, CHCl3): 3351 (m, broad), 3086 (w), 3038 (w), 2929 (s),
2854 (s), 2189 (m), 2104 (w), 1603 (w), 1503 (w) cmꢀ1. 1H NMR (500
MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 4.27
(t, J = 6.0 Hz, 1H), 1.86 (bd, J = 12.8 Hz, 2H), 1.80ꢀ1.78 (m, 3H),
1.69 (bd, J = 12.3 Hz, 1H), 1.65ꢀ1.58 (m, 1H), 1.32ꢀ1.05 (m, 14H).
13C NMR (100 MHz, CDCl3) δ 153.4, 132.8, 125.5, 117.7, 80.0,
77.5, 73.6, 70.8, 67.8, 65.4, 63.4, 44.2, 35.0, 31.0, 28.5, 28.1, 26.2,
25.80, 25.77. EIMS m/z 318.2 (M+, 61), 303.2 ([M ꢀ Me]+, 26), 235.1
([M ꢀ C6H11]+, 100). EI HRMS calcd for C23H26O (M+) 318.1984,
found 318.1987.
Compound 22 with Hunig’s Base (Table 5, entry 7).
Compound 12a (186 mg, 0.90 mmol, 1.2 equiv) was combined with
6581
dx.doi.org/10.1021/jo2008719 |J. Org. Chem. 2011, 76, 6574–6583