Chiral Cleft Compounds
FULL PAPER
leaving a thick, brown oil. CC on the crude product (n-heptane/CH
2
Cl
2
-
18x), 4.32 (d, J=18 Hz, 1H; H-9x), 4.29 (d, J=13 Hz, 1H; H-25b), 4.28
(d, J=18 Hz, 1H; H-18n), 4.24 (d, J=13 Hz, 1H; H-25a), 4.21 (d, J=
17 Hz, 1H; H-12n), 4.20 (d, J=17 Hz, 1H; H-6n), 4.19 (d, J=13 Hz, 1H;
H-26a), 4.17 (d, J=14 Hz, 1H; H-27a), 4.14 (d, J=17 Hz, 1H; H-24n),
4.12 (d, J=14 Hz, 1H; H-27b), 4.10 (d, J=13 Hz, 1H; H-26b), 3.93 (d,
J=17 Hz, 1H; H-9n), 3.92 (d, J=18 Hz, 1H; H-21n), 2.21 (s, 3H; Me-7),
2.20 (s, 3H; Me-19), 2.17 (s, 3H; Me-13), 2.14 ppm (s, 3H; Me-1);
C NMR (125 MHz, CDCl ): d=143.75 (C-19a), 143.66 (C-7a), 143.38
3
(C-16a), 143.24 (C-4a), 139.79 (C-22a), 139.59 (C-10a), 134.17 (C-13),
134.04 (C-1), 131.53 (C-3), 131.51 (C-15), 130.38 (C-12a), 130.35 (C-24a),
(
5:95)) gave 81% yield of compound 6 (224 mg, 0.510 mmol) as a pale-
1
f 2 2
yellow solid. R =0.23 (n-heptane/CH Cl (5:95)); H NMR (400 MHz,
CDCl
3
): d=7.52 (s, 1H), 7.09 (s, 1H), 4.46 (d, J=17.6 Hz, 1H; H-6x),
.41 (d, J=17.6 Hz, 1H; H-12x), 4.26 (d, J=17.2 Hz, 1H; H-6n), 4.25 (s,
H; H-13), 4.23 (d, J=18.4 Hz, 1H; H-12n), 2.19 (s, 3H), 1.97 ppm (s,
4
2
3
1
5
4
1
3
H); C NMR (100 MHz, CDCl
3
): d=143.11, 140.47, 135.10, 134.26,
1
3
31.61, 130.18, 130.13, 127.66, 127.57, 126.12, 120.49, 117.99, 66.32, 54.86,
4.11, 17.78, 11.95 ppm; HRMS (FAB+): calcd for
C
17
H
14BrCl
2
N
5
:
36.9810; found: 436.9811.
1
1
9
5
29.36 (C-19), 129.31 (C-7), 127.57 (C-16), 127.50 (C-4), 127.50 (C-6a),
27.41 (C-18a), 125.72 (C-10), 125.35 (C-22), 125.22 (C-21a), 124.88 (C-
a), 120.43 (C-2), 120.37 (C-14), 66.61 (C-26), 66.56 (C-25), 66.30 (C-27),
5.03 (C-21), 54.78 (C-9), 54.74 (C-24), 54.74 (C-12), 54.19 (C-6), 54.02
2
-Amino-8-bromo-4,10-dichloro-1,7-dimethyl-6H,12H-5,11-methano-
dibenzo[b,f][1,5]diazocine (7): To a solution of compound 7 (487 mg,
1
.11 mmol) in anhydrous THF (40 mL) was added NaBH
4
(210 mg,
6
.99 mmol) in small portions at room temperature. The mixture was
(
C-18), 17.73 (Me-13), 17.71 (Me-1), 11.98 (Me-7), 11.81 ppm (Me-19);
HRMS (FAB+): calcd for C37 : 857.9809; found: 857.9790; el-
emental analysis calcd (%) for C37 Cl (862.3): C 51.54, H 3.74, N
heated to reflux and MeOH (1.1 mL) was added dropwise over 50 min.
After refluxing for 4 h, the reaction mixture was allowed to come to
room temperature. Concentrated HCl (37%, 2 mL) was added giving a
white precipitate. The reaction mixture was made alkaline (pH 10) by
H
2 l4 6
32Br C N
H
32Br
2
4 6
N
9
.75; found: C 51.62, H 3.67, N 9.66.
using aqueous NaOH (10m) at 08C. H
were separated and the aqueous layer was extracted with EtOAc. The
combined organic layers were dried over MgSO , filtered, and evaporat-
ed in vacuo to give 510 mg of a yellow solid. CC (EtOAc/n-heptane
15:85) gave a white solid of compound 7 in 93% yield (430 mg,
.04 mmol). =0.21 (EtOAc/n-heptane (15:85)); m.p. 190–1928C;
H NMR (400 MHz, CDCl ): d=7.51 (s, 1H), 6.70 (s, 1H), 4.17–4.50 (m,
H), 3.50 (s, 2H), 2.18 (s, 3H), 1.90 ppm (s, 3H); C NMR (100 MHz,
CDCl ): d=143.4. 141.9, 134.9, 134.2, 131.3, 130.6, 128.7, 127.4, 127.1,
20.2, 118.1, 115.4, 66.4, 55.0, 54.3, 17.8, 11.5 ppm; IR (KBr): n˜ =3456,
2
O (10 mL) was added. The layers
Compound 1b: R
at about 2508C); H NMR (500 MHz, CDCl
4.43 (d, J=17 Hz, 2H; H-12x/24x), 4.40 (d, J=17 Hz, 2H; H-6x/18x),
4.37 (d, J=18 Hz, 2H; H-9x/21x), 4.30 (d, J=17 Hz, 2H; H-6n/18n), 4.24
(d, J=17 Hz, 2H; H-12n/24n), 4.22 (d, J=13 Hz, 2H; H-25a/27a), 4.19
(d, J=13 Hz, 2H; H-25b/27b), 4.09 (s, 2H; H-26), 4.03 (d, J=18 Hz, 2H;
f
=0.23 (EtOAc/CH
2
Cl
2
(5:95)); m.p.>4008C (darkened
): d=7.52 (s, 2H; H-3/15),
1
3
4
(
1
R
f
1
H-9n/21n), 2.22 (s, 6H; Me-7/Me-19), 2.18 ppm (s, 6H; Me-1/Me-13);
3
1
3
13
6
3
C NMR (125 MHz, CDCl ): d=143.74 (C-7a/19a), 143.46 (C-4a/16a),
139.76 (C-10a/22a), 134.18 (C-1/13), 131.51 (C-3/15), 130.38 (C-12a/24a),
129.24 (C-7/19), 127.59 (C-4/16), 127.46 (C-6a/18a), 125.43 (C-10/22),
125.08 (C-9a/21a), 120.36 (C-2/14), 66.37 (C-26), 66.31 (C-25/27), 54.97
(C-9/21), 54.77 (C-12/24), 54.08 (C-6/18), 17.75 (Me-1/Me-13), 11.84 ppm
3
1
3
ꢀ
1
2 2 3
352 cm (NH ); HRMS (FAB+): calcd for C17H16BrCl N : 410.9905;
found: 410.9907.
-Amino-8-bromo-4,10-dichloro-1,7-dimethyl-6H,12H-5,11-methano-
dibenzo[b,f][1,5]diazocine·HCl (7·HCl): Compound 7 (50 mg, 0.12 mmol)
was dissolved in the smallest amount possible of CH Cl (4 mL) and HCl
(
2 l4 6
Me-7/Me-19); HRMS (FAB+): calcd for C37H32Br C N : 857.9809;
2
found: 857.9809.
f 2 2
Compound 1c: R =0.20 (EtOAc/CH Cl
at about 2508C); H NMR (500 MHz, CDCl ): d=7.50 (s, 2H; H-3/15),
(5:95)); m.p.>4008C (darkened
2
2
1
in dioxane (4m, 500 mL, 2 mmol) was added swiftly resulting in a white
3
precipitate. The solid was filtered and dissolved in the smallest amount
4.47 (d, J=17 Hz, 2H; H-6x/18x), 4.45 (d, J=17 Hz, 2H; H-9x/21x), 4.39
(d, J=17 Hz, 2H; H-12x/24x), 4.25 (d, J=12 Hz, 2H; H-25b/27b), 4.20
(d, J=12 Hz, 2H; H-25a/27a), 4.19 (d, J=17 Hz, 2H; H-6n/18n), 4.18 (s,
2H; H-26), 4.08 (d, J=17 Hz, 2H; H-12n/24n), 3.84 (d, J=17 Hz, 2H; H-
9n/21n), 2.21 (s, 2H; Me-7/Me-19), 2.08 ppm (s, 2H, Me-1/Me-13);
possible of MeOH (1 mL) and then Et
a precipitate. The mixture was filtered, washed with cold Et
to give a white solid of 7·HCl (43 mg, 0.096 mmol). Elemental analysis
calcd (%) for C17 17BrCl (449.6): C 45.41, H 3.81, N 9.35; found: C
5.36, H 3.74, N 9.27.
,14-Dibromo-4,10,16,22-tetrachloro-1,7,13,19-tetramethyl-9H,21H-8,20-
2
O (8 mL) was added resulting in
2
O, and dried
H
3 3
N
1
3
4
3
C NMR (125 MHz, CDCl , 310 K): d=143.59 (C-7a/19a), 143.39 (C-4a/
1
2
2
5
1
8
6a), 139.92 (C-10a/22a), 134.22 (C-1/13), 131.57 (C-3/15), 130.21 (C-12a/
4a), 129.69 (C-7/19), 127.76 (C-4/16), 127.32 (C-6a/18a), 125.42 (C-10/
2), 125.39 (C-9a/21a), 120.51 (C-2/14), 66.78 (C-26), 66.55 (C-25/27),
4.74(C-9/21), 54.68 (C-12/24), 54.18 (C-6/18), 17.74 (Me-1/Me-13),
1.93 ppm (Me-7/Me-19); HRMS (FAB+): calcd for C37H32Br C N :
2 l4 6
57.9809; found: 857.9812.
2
methanobis(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine)[b-2,3;f-
’,9’][1,5]diazocine (1): To a mixture of compound 7 (430 mg, 1.04 mmol)
8
and paraformaldehyde (80 mg, 2.7 mmol) at ꢀ108C, TFA (3 mL) was
added dropwise over 20 min. After the addition of TFA, the reaction
mixture was allowed to come to room temperature and the resulting so-
lution was stirred in the dark for 72 h. TFA was removed in vacuo, result-
Isomerizations
ing in a brown oil. H
ed aqueous NH (28%, 4 mL), resulting in a pink gummy solid. The reac-
tion mixture was first extracted with CH Cl (210 mL), and then with
4
CHCl (35 mL). The combined CHCl layers were dried over MgSO ,
filtered, and evaporated under reduced-pressure to give compound 1b as
a white solid in 13% yield (64 mg, 0.074 mmol). The same procedure was
2
O (5 mL) was added to this oil followed by saturat-
General Procedure 1: The isomers, syn–anti 1a, anti–anti 1b, and syn–syn
1c (5 mg, 5.8 mmol) were dissolved in TFA (1 mL) in three separate
flasks and the flasks were sealed. The resulting solutions were stirred for
72 or 144 h. To each reaction mixture was added water (2 mL) and the
resulting mixture was then made alkaline by the addition of saturated
aqueous NH3 (28%). The mixture was extracted with CHCl3 (35 mL)
and the combined organic layers were washed with water, dried over
3
2
2
3
3
followed with the combined CH
2 2
Cl layers, giving a pale yellow solid. CC
(
EtOAc/CH Cl (5:95)) gave compounds 1a and 1c as separate fractions,
2
2
MgSO , filtered, and evaporated.
4
and a mixed fraction of compounds 1a, 1b, and 1c (66 mg, 0.076 mmol).
The combined fractions containing each of compounds 1a and 1c, respec-
tively, were evaporated to dryness in vacuo. The mixed fraction was not
further purified due to its low solubility in the eluent. Compound 1a was
Condition 1A: 72 h at RT. No isomerization occurred for any of the
three isomers.
Condition 1B: 72 h at 608C. No isomerization occurred for any of the
three isomers.
reprecipitated by dissolving it in the smallest amount possible of CHCl
followed by addition of Et O giving pure compound 1a as a white solid
in 32% yield (157 mg, 0.182 mmol). Compound 1c was further purified
twice by preparative TLC (EtOAc/CHCl (15:85)) giving pure compound
c as a white solid in 8% yield (28 mg, 0.032 mmol).
Compound 1a: R =0.33 (EtOAc/CH Cl (5:95)); m.p.>4008C (darkened
at about 2508C); H NMR (500 MHz, CDCl ): d=7.51 (s, 1H; H-15),
.49 (s, 1H; H-3), 4.46 (d, J=17 Hz, 1H; H-6x), 4.44 (d, J=17 Hz, 1H;
H-21x), 4.40 (d, J=17 Hz, 2H; H-12x/H-24x), 4.36 (d, J=17 Hz, 1H; H-
3
Condition 1C: 144 h at 608C. No isomerization occurred in any of the
three isomers.
2
3
Condition 1D: 144 h at 958C. No isomerization occurred in any of the
three isomers.
1
f
2
2
General Procedure 2: The isomers, syn–anti 1a, anti–anti 1b, and syn–syn
1c (5 mg, 5.8 mmol) were dissolved in TFA (1 mL) in three separate
flasks and the flasks were sealed. The solutions were stirred for 72 or
144 h. To each reaction mixture was added water (2 mL) and the result-
1
3
7
Chem. Eur. J. 2006, 12, 2692 – 2701
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2699