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DOI: 10.1055/s-2008-1078235
Novel Synthetic Approach to Nine-Membered Diallylic Amides: Stereochemical Behavior and Utility as Chiral Building Block
Publication History
Publication Date:
22 August 2008 (online)
Abstract
An efficient approach to nine-membered diallylic cyclic amides having a variety of substituents has been developed. The synthesized amides have stable planar chirality at ambient temperature. The transformation of the enantiomerically enriched amides provides optically active compounds containing stereogenic centers in a stereospecific fashion. As a demonstration of the synthetic utility of the amides, we have synthesized (+)-γ-lycorane using such an optically active amide as a chiral building block.
Key words
atropisomerism - amides - asymmetric synthesis - alkaloids - planar chirality
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References and Notes
The ¹H NMR analysis of 6a and 6b revealed a trace amount of the aldehyde tautomer was contained (<5%).
6
General Procedure
of the Synthesis of Amide 2 from 9
To a solution of
Ph3P (96.2 mg, 0.368 mmol) in anhydrous THF (10 mL) at
0 ˚C was added DEAD (0.166 mL of 40 wt% in
toluene, 0.366 mmol) and 9b (42.4 mg, 0.137
mmol) dissolved in anhydrous THF (4 mL). The resulting mixture was
stirred at that temperature for 4 h, concentrated in vacuo, and
the residue was purified by silica gel chromatography (hexane-EtOAc,
10:1 to 5:1) to afford 30.7 mg (77%) of 2b as
a white solid and a trace amount of dimerized product (<1%,
analyzed by ¹H NMR).
All new compounds were fully characterized
by ¹H NMR, ¹³C
NMR, and IR spectroscopy.
Data for
Selected Compounds
Compound 2b: ¹H
NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 8.4 Hz,
2 H), 7.31 (d, J = 8.4
Hz, 2 H), 5.47 (ddd, J = 11.4,
10.8, 4.2 Hz, 1 H), 5.43-5.34 (m, 1 H), 5.24 (dd, J = 11.4,
4.5 Hz, 1 H), 4.26 (d, J = 9.9
Hz, 1 H), 3.89 (dd, J = 14.1,
4.2 Hz, 1 H), 3.05 (dd, J = 14.1,
10.8 Hz, 1 H), 3.00 (d, J = 9.9
Hz, 1 H), 2.44 (s, 3 H), 2.22-2.06 (m, 2 H), 1.99-1.70
(m, 2 H), 1.55 (s, 3 H). ¹³C NMR (75
MHz, CDCl3): δ = 143.0,
136.3, 134.2 (2 C), 132.2, 131.1, 129.7, 127.1, 59.0, 44.3, 27.0,
26.5, 21.7, 17.3. IR (reflection): 2934, 1597, 1452, 1324, 1158,
1095, 1023, 960, 869, 821, 767, 714, 658, 596 cm-¹.
Mp 123 ˚C. For R-isomer
(>98% ee): [α]D
²7 -65.3 (c 0.80, CHCl3); for S-isomer (>98% ee): [α]D
²7 +67.7
(c 0.88, CHCl3). Anal. Calcd
for C16H21NO2S: C, 65.95; H, 7.26;
N, 4.81; S, 11.00. Found: C, 65.55; H, 7.24; N, 4.70; S, 11.52.
Compound 2c: ¹H NMR (300 MHz,
CDCl3): δ = 7.66 (d, J = 8.1
Hz, 2 H), 7.30 (d, J = 8.1
Hz, 2 H), 5.47-5.24 (m, 3 H), 4.40 (dd, J = 10.2,
3.9 Hz, 1 H), 3.82 (dd, J = 14.2,
4.2 Hz, 1 H), 3.00 (dd, J = 10.2,
9.9 Hz, 1 H), 2.80 (dd, J = 14.2, 11.9
Hz, 1 H), 2.43 (s, 3 H), 2.33-2.28 (m, 1 H), 2.03-1.96 (m,
1 H), 1.91-1.83 (m, 1 H), 1.69 (s, 3 H), 1.67-1.52
(m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 143.0,
138.1, 135.9, 132.8, 129.6, 128.4, 127.1, 126.1, 53.2, 45.0, 32.1,
29.4, 25.3, 21.6. IR (neat): 2934, 1319, 1149, 983, 893, 815, 734, 655,
597, 547 cm-¹. For R-isomer
(>98% ee): [α]D
²8 -88.8
(c 1.23, CHCl3); for S-isomer (>98% ee): [α]D
²9 +88.5
(c 1.60, CHCl3). Anal. Calcd
for C16H21NO2S: C, 65.95; H, 7.26;
N, 4.81. Found: C, 65.92; H, 7.26; N, 4.68.
Compound 2d: ¹H NMR (300 MHz,
CDCl3): δ = 7.67 (d, J = 8.1
Hz, 2 H), 7.31 (d, J = 8.1
Hz, 2 H), 5.63 (dddd, J = 11.4,
11.1, 4.8, 1.2 Hz, 1 H), 5.40-5.24 (m, 3 H), 4.41 (dd, J = 9.9, 3.3
Hz, 1 H), 3.83 (dd, J = 14.1,
4.2 Hz, 1 H), 3.00 (dd, J = 9.9,
9.9 Hz, 1 H), 2.84 (dd, J = 14.1,
11.7 Hz, 1 H), 2.43 (s, 3 H), 2.37-2.30 (m, 1 H), 2.26-2.17
(m, 1 H), 1.77-1.65 (m, 1 H), 1.58-1.45 (m, 1
H). ¹³C NMR (75 MHz, CDCl3): δ = 143.1,
136.9, 135.8, 131.7, 129.7, 128.8, 127.1, 126.1, 53.4, 44.0, 30.2,
26.6, 21.7. IR (reflection): 3016, 2934, 2869, 1920, 1806, 1661,
1596, 1459, 1347, 988 cm-¹. For R-isomer (>98% ee): [α]D
²5 -114.2
(c 1.21, CHCl3); for S-isomer (>98% ee): [α]D
²6 +118.9
(c 1.97, CHCl3). Anal. Calcd
for C15H19NO2S: C, 64.95; H, 6.90;
N, 5.05; S, 11.56. Found: C, 65.22; H, 7.07; N, 4.92; S, 11.25.
Compound
(3S,4R)-10: ¹H NMR (300 MHz,
CDCl3): δ = 7.72 (d, J = 8.1
Hz, 2 H), 7.32 (d, J = 8.1
Hz, 2 H), 5.53 (dd, J = 17.4,
10.8 Hz, 1 H), 5.43 (ddd, J = 17.1,
10.5, 8.4 Hz, 1 H), 5.04 (dd, J = 10.5,
1.5 Hz, 1 H), 4.98 (dd, J = 17.1,
1.5 Hz, 1 H), 4.98 (d, J = 10.8
Hz, 1 H), 4.88 (d, J = 17.4
Hz, 1 H), 3.50 (dd, J = 9.9,
7.5 Hz, 1 H), 3.44 (d, J = 9.6
Hz, 1 H), 3.16 (dd, J = 9.9,
9.9 Hz, 1 H), 3.01 (d, J = 9.6
Hz, 1 H), 2.44 (s, 3 H), 2.33-2.24 (m, 1 H), 1.02 (s, 3
H). ¹³C NMR (75 MHz, CDCl3): δ = 143.3,
139.1, 134.1, 133.8, 129.6, 127.3, 118.2, 114.2, 58.2, 53.3, 51.0,
47.0, 21.8, 21.7. IR (neat): 2965, 1346, 1155, 1094, 1052, 922,
813, 711, 663, 587 cm-¹. [α]D
¹9 -6.5
(c 1.03, CHCl3).
Compound
(R,R)-11d: ¹H NMR (300 MHz,
CDCl3): δ = 7.75 (d, J = 8.1
Hz, 2 H), 7.29 (d, J = 8.1
Hz, 2 H), 5.83-5.69 (m, 2 H), 5.36-5.32 (m, 1
H), 5.07 (dd, J = 9.0,
0.9 Hz, 1 H), 5.00 (dd, J = 17.1,
0.6 Hz, 1 H), 4.54 (d, J = 9.6
Hz, 1 H), 3.92-3.84 (m, 1 H), 2.42 (s, 3 H), 2.37-2.29
(m, 1 H), 2.12-1.88 (m, 2 H), 1.77-1.67 (m, 1
H), 1.58-1.47 (m, 1 H). ¹³C
NMR (75 MHz, CDCl3): δ = 143.3, 138.4,
137.2, 130.2, 129.7, 127.3, 127.2, 117.6, 51.5, 41.8, 24.8, 22.8,
21.6. IR (neat): 3278, 2925, 1433, 1331, 1160, 1084, 915, 814, 709,
660 cm-¹. [α]D
²5 -86.1
(c 1.27, CHCl3).
Compound 13: ¹H NMR (300 MHz,
CDCl3): δ = 7.76 (d, J = 8.1
Hz, 2 H), 7.29 (d, J = 8.1
Hz, 2 H), 5.65 (ddd, J = 9.6, 3.6,
3.3 Hz, 1 H), 5.12 (ddd, J = 9.6,
4.5, 2.1 Hz, 1 H), 4.95-4.85 (m, 1 H), 3.79-3.62
(m, 3 H), 2.42 (s, 3 H), 2.04-1.75 (m, 5 H), 1.63-1.42
(m, 2 H), 1.36-1.23 (m, 1 H). ¹³C
NMR (75 MHz, CDCl3): δ = 143.2, 138.3,
130.9, 129.6, 126.9, 126.4, 60.9, 51.1, 34.9, 34.2, 24.8, 24.2,
21.6. IR (neat): 3274, 2928, 1598, 1432, 1327, 1159, 1094, 1021,
915, 815, 663 cm-¹. [α]D
²6 -153.5
(c 1.10, CHCl3).
Compound 14: ¹H NMR (300 MHz,
CDCl3): δ = 7.69 (d, J = 8.1
Hz, 2 H), 7.28 (d, J = 8.1
Hz, 2 H), 5.83-5.70 (m, 2 H), 3.96 (d, J = 6.9
Hz, 1 H), 3.45 (ddd, J = 14.1,
7.5, 4.5 Hz, 1 H), 3.17 (ddd, J = 9.9,
8.4, 7.5 Hz, 1 H), 2.40 (s, 3 H), 2.03-1.89 (m, 3 H), 1.80-1.49
(m, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 143.1,
134.8, 129.5, 128.2, 127.5, 127.3, 57.5, 47.3, 36.5, 27.8, 22.9,
21.6, 20.9. IR (neat): 2924, 1598, 1450, 1343, 1161, 1092, 848,
817, 659, 593 cm-¹. [α]D
²5
-98.6
(c 1.31, CHCl3).
Compound 17; 60:40 rotamer
ratio (# denotes major,
* denotes
minor rotamer signals): ¹H NMR (300 MHz, CDCl3):
d = 6.96* (s, 1 H), 6.95# (s,
1 H), 6.76* (s, 1 H), 6.71# (s, 1 H),
6.04# (d, J = 10.2
Hz, 1 H), 5.99-5.96* (m, 1 H), 5.96 (s, 2 H),
5.80-5.73# (m, 1 H), 5.68-5.63* (m,
1 H), 5.23* (d, J = 9.9
Hz, 1 H), 4.62# (dd, J = 4.8,
2.1 Hz, 1 H), 4.04-3.98* (m, 1 H), 3.64# (dd, J = 9.0, 6.0
Hz, 1 H), 3.32-3.13 (m, 1 H), 2.54-2.37 (m, 1
H), 2.14-1.58 (m, 6 H). ¹³C NMR
(75 MHz, CDCl3): δ = 167.1*,
167.0#, 148.6*, 148.5#, 147.4#,
147.3*, 132.6#, 132.4*, 129.0,
128.0, 125.8*, 125.0#, 112.7#,
109.8*, 108.0*, 107.3#, 102.1*,
102.0#, 57.0*, 55.3#, 47.0#,
44.8*, 36.6*, 35.6#, 27.6#,
25.3*, 22.7#, 22.1*, 21.0#, 20.2*.
IR (neat): 2922, 1631, 1482, 1440, 1374, 1239, 1109, 1035, 932,
863, 732, 617 cm-¹. [α]D
²5 -146.4
(c 0.86, CHCl3).
Compound 18: ¹H NMR (300 MHz,
CDCl3): δ = 7.52 (s, 1 H), 6.69 (s,
1 H), 5.99 (d, J = 1.2
Hz, 1 H), 5.98 (d, J = 1.2 Hz,
1 H), 5.70-5.63 (m, 1 H), 5.36 (dd, J = 9.9,
2.4 Hz, 1 H), 4.02 (dd, J = 5.7,
4.8 Hz, 1 H), 3.69 (d, J = 9.6
Hz, 1 H), 3.67 (d, J = 9.6
Hz, 1 H), 3.62-3.56 (m, 1 H), 2.53-2.44 (m, 1
H), 2.29-2.18 (m, 1 H), 2.07-1.70 (m, 3 H). ¹³C
NMR (75 MHz, CDCl3): δ = 161.8, 150.5,
146.9, 135.6, 125.9, 125.3, 123.0, 107.6, 107.4, 101.6, 56.6, 42.4,
37.1, 34.2, 30.0, 25.2. IR (neat): 2885, 1645, 1609, 1465, 1387,
1349, 1269, 1244, 1036, 933, 770, 703 cm-¹. [α]D
²4 -111.4
(c 0.38, CHCl3).
Compound 12: ¹H NMR (300 MHz,
CDCl3): δ = 6.61 (s, 1 H), 6.49 (s,
1 H), 5.89 (d, J = 1.2
Hz, 1 H), 5.88 (d, J = 1.2 Hz,
1 H), 4.02 (d, J = 14.1
Hz, 1 H), 3.37 (ddd, J = 9.3,
9.0, 3.6 Hz, 1 H), 3.22 (d, J = 14.1
Hz, 1 H), 2.75 (ddd, J = 11.7, 4.5,
4.5 Hz, 1 H), 2.39 (dd, J = 4.8,
4.5 Hz, 1 H), 2.25-2.11 (m, 2 H), 2.08-1.97 (m,
1 H), 1.80-1.60 (m, 3 H), 1.55-1.30 (m, 4 H). ¹³C
NMR (75 MHz, CDCl3): δ = 146.0, 145.6, 133.1,
127.3, 108.4, 106.3, 100.7, 63.0, 57.2, 53.9, 39.6, 37.5, 31.9,
30.6, 29.5, 25.4. IR (neat): 2925, 1505, 1483, 1376, 1318, 1230,
1138, 1040, 938, 867 cm-¹. [α]D
²5 +15.0 (c 0.44, EtOH) {lit.¹7 [α]D
²0 +17.1
(c 0.25, EtOH)}. MS (ESI+): m/z = 258 [M + H]+.
Analytical and semipreparative-scale HPLC were carried out with a chiral stationary column [CHIRALCEL OD-H (4.6 × 250 mm or 20 × 250 mm)] equipped with a UV detector and a CD spectropolarimeter.
9The absolute configurations of 2b and 2c were speculated on the basis of the similarity of the CD spectra of 2a and 2d.
10Enantioenriched 2 can be prepared via the fractional crystallization of its ammonium salt with chiral carboxylic acid, see ref. 3b.
11The detailed transition-state analysis of racemization by ab initio calculation is in progress.
12The enantiopurity of 2a-d remains unchanged in the solid state(crystal) at -30 ˚C for at least one year.
14The absolute stereochemistry of 10 was deduced from the configuration of 2b and the steric course of the reactions.
19Mori and co-workers constructed the C ring of γ-lycorane by a Pd-catalyzed Mizoroki-Heck reaction, see ref. 18a.