Novel Synthetic Approach to
Nine-Membered Diallylic Amides: Stereochemical Behavior
and Utility as Chiral Building Block

Katsuhiko Tomooka; Masaki Suzuki; Kazuhiro Uehara; Maki Shimada; Toshiyuki Akiyama

doi:10.1055/s-2008-1078235

LETTER

Novel Synthetic Approach to Nine-Membered Diallylic Amides: Stereochemical Behavior and Utility as Chiral Building Block

Katsuhiko Tomooka*^a,b, Masaki Suzuki^b, Kazuhiro Uehara^a, Maki Shimada^b, Toshiyuki Akiyama^b
^a Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-koen 6-1, Kasuga-shi, Fukuoka 816-8580, Japan
Fax: +81(92)5837810; e-Mail: ktomooka@cm.kyushu-u.ac.jp;
^b Department of Applied Chemistry, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo 152-8552, Japan

Abstract

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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

References and Notes

For reviews, see:

1a Marshall JA. Acc. Chem. Res. 1980, 13: 213

1b Nakazaki M. Yamamoto K. Naemura K. Top. Curr. Chem. 1984, 125: 1

1c Schlögl K. Top. Curr. Chem. 1984, 125: 27

1d Eliel EL. Wilen SH. Mander LN. Stereochemistry of Organic Compounds Wiley; New York: 1994. p.1172-1175

For recent studies on planar chiral medium-sized rings, see:

2a Sudau A. Münch W. Nubbemeyer U. J. Org. Chem. 2000, 65: 1710

2b Nubbemeyer U. Eur. J. Org. Chem. 2001, 1801 ; and references cited therein

2c Deiters A. Mück-Lichtenfeld C. Fröhlich R. Hoppe D. Chem. Eur. J. 2002, 8: 1833

2d Gauvreau D. Barriault L. J. Org. Chem. 2005, 70: 1382

2e Larionov OV. Corey EJ. J. Am. Chem. Soc. 2008, 130: 2954

3a Tomooka K. Komine N. Fujiki D. Nakai T. Yanagitsuru S. J. Am. Chem. Soc. 2005, 127: 12182

3b Tomooka K. Suzuki M. Shimada M. Yanagitsuru S. Uehara K. Org. Lett. 2006, 8: 963

For ring-closing-metathesis-based seven-membered lactam synthesis, see:

4a Fu GC. Nguyen ST. Grubbs RH. J. Am. Chem. Soc. 1993, 115: 9856

4b Vo-Thanh G. Boucard V. Sauriat-Dorizon H. Guibé F. Synlett 2001, 37

5

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).

7

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]⁺.

8

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.

9

The absolute configurations of 2b and 2c were speculated on the basis of the similarity of the CD spectra of 2a and 2d.

10

Enantioenriched 2 can be prepared via the fractional crystallization of its ammonium salt with chiral carboxylic acid, see ref. 3b.

11

The detailed transition-state analysis of racemization by ab initio calculation is in progress.

12

The enantiopurity of 2a-d remains unchanged in the solid state(crystal) at -30 ˚C for at least one year.

13 Pd(II)-catalyzed Cope rearrangement, see: Overman LE. Jacobsen EJ. J. Am. Chem. Soc. 1982, 104: 7225

14

The absolute stereochemistry of 10 was deduced from the configuration of 2b and the steric course of the reactions.

In general, the aza-Wittig rearrangement is considerably slower than the corresponding oxa-Wittig rearrangement. To enhance the reactivity of the aza-Wittig rearrangement, several contrivances have been developed. For reviews, see:

15a Vogel C. Synthesis 1997, 497

15b Tomooka K. In The Chemistry of Organolithium Compounds Vol. 2: Rappoport Z. Marek I. John Wiley and Sons; Chichester: 2004. p.749-828

The X-ray crystal structure analysis shows that the distance between C4 and C9 of 2a is 3.8 Å (Figure 2). The present rearrangement should proceed via a deprotonation of the C9 equatorial proton and an inversion of the configuration at the carbanion chiral center. It has been reported that [2,3]-Wittig rearrangement proceeds with inversion of configuration at the migrating terminus, see:

16a Verner EJ. Cohen T. J. Am. Chem. Soc. 1992, 114: 375

16b Tomooka K. Igarashi T. Watanabe M. Nakai T. Tetrahedron Lett. 1992, 33: 5795

17 (+)-γ-Lycorane was obtained by Kotera in his degradation studies of lycorine, see: Kotera K. Tetrahedron 1961, 12: 248

Six different asymmetric syntheses of γ-lycorane(12) have been reported thus far, see:

18a Yoshizaki H. Satoh H. Sato Y. Nukui S. Shibasaki M. Mori M. J. Org. Chem. 1995, 60: 2016

18b Ikeda M. Ohtani S. Sato T. Ishibashi H. Synthesis 1998, 1803

18c Banwell MG. Harvey JE. Hockless DCR. J. Org. Chem. 2000, 65: 4241

18d Dong L. Xu Y.-J. Cun L.-F. Cui X. Mi A.-Q. Jiang Y.-Z. Gong L.-Z. Org. Lett. 2005, 7: 4285

18e Fujioka H. Murai K. Ohba Y. Hirose H. Kita Y. Chem. Commun. 2006, 832

18f Chapsal BD. Ojima I. Org. Lett. 2006, 8: 1395

19

Mori and co-workers constructed the C ring of γ-lycorane by a Pd-catalyzed Mizoroki-Heck reaction, see ref. 18a.