Application of crystallization-induced asymmetric transformation to a general, scalable method for the resolution of 2,8-disubstituted Troeger's base derivatives

Article abstract of DOI:10.1021/jo401873x

A general method for the gram scale resolution of 2-substituted and 2,8-disubstituted Troeger's base (TB) derivatives in 63-91% yield has been achieved through the application of crystallization-induced asymmetric transformation (CIAT). Enantiomeric ratios of the resolved TB derivatives range from 99.1:0.9 to >99.5:0.5. Among the Troeger's base compounds resolved are four synthetically valuable bromo and iodo derivatives.

Full text of DOI:10.1021/jo401873x

Note
pubs.acs.org/joc
Application of Crystallization-Induced Asymmetric Transformation to
a General, Scalable Method for the Resolution of 2,8-Disubstituted
̈
Troger’s Base Derivatives
Donald L. Jameson,* Thomas Field, Monica R. Schmidt, Alyson K. DeStefano, Christopher J. Stiteler,
Vincent J. Venditto, Brooke Krovic, Christopher M. Hoffman, Matthew T. Ondisco,
and Matthew E. Belowich†
Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania 17325, United States
S
* Supporting Information
ABSTRACT: A general method for the gram scale resolution of 2-substituted and 2,8-disubstituted Troger’s base (TB)
̈
derivatives in 63−91% yield has been achieved through the application of crystallization-induced asymmetric transformation
(CIAT). Enantiomeric ratios of the resolved TB derivatives range from 99.1:0.9 to >99.5:0.5. Among the Troger’s base
̈
compounds resolved are four synthetically valuable bromo and iodo derivatives.
roger’s base (TB, 1) (Figure 1), a chiral, tetracyclic
diamine possessing a rigid, V-shaped structure, has
Of particular interest are TB derivatives with substituents in the
2- and 8-positions, which are projected at roughly a 90° angle,
making these ideal “corner” structural components.
̈
T
Warnmark’s method for preparing halogenated derivatives8
̈
was a leap forward in enabling cross-coupling strategies for the
modification of the TB core. However, the absence of an
efficient way to resolve these synthetically useful iodo and
bromo derivatives hampers the preparation of homochiral
molecules or assemblies possessing multiple TB fragments.
While individual TB derivatives have been resolved by either
diastereomeric salt formation or chiral HPLC, no general
method for the scalable chemical resolution of this class of
molecules has been reported.
The resolution of TB 1 and its derivatives and the
assignment of absolute configuration have had a somewhat
convoluted history. In 1944, Prelog and Wieland reported the
Figure 1. (a) The two enantiomers of TB 1 showing atomic
numbering scheme. (b) The architecture of the enantiomers of TB 1,
showing the mechanism of acid-catalyzed racemization.
partial resolution of 6 g of racemic Troger’s base 1 on 270 g of
̈
D-lactose giving only 5.5% yield of each pure enantiomer.9 The
paper also described unsuccessful attempts to resolve 1 as
diastereomeric salts of both (1R)-(−)-10-camphorsulfonate and
(1R)-(endo,anti)-(+)-3-bromo-camphor-8-sulfonate. This
coupled with their finding that chiral 1 racemizes in acid
received considerable attention as a scaffold for the
construction of supramolecular assemblies.1−5 The renaissance
in TB chemistry originated with the work of Wilcox, who used
the molecule for the design of chiral molecular clefts.6 Recent
research involves applications as diverse as TB fragments that
have been incorporated into new materials for gas separation.7
Received: August 23, 2013
Published: October 11, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
(Figure 1) led to the widely held belief that resolution via
diastereomeric salt formation was not feasible.
yields of 70−80%. This was not entirely surprising given the
capacity for TB to racemize under acidic conditions (Figure 1)
and Wilen’s observation of CIAT in the resolution of 1. These
observations prompted us to explore the possibility of using
CIAT to improve the efficiency of our resolution by heating
TB-DBTA mixtures while varying time and temperature.
Solubility of the individual dyads varied with temperature: 2,
3, 5, 6, and 7 precipitated rapidly at the boiling point of DCE,
while dyads of 1 and 4 remained in solution at reflux and
precipitated only slowly from cooled solutions. It was
determined that heating TB-DBTA mixtures of 1 and 4 at
45−50 °C and 2, 3, 5, 6, and 7 at 55−60 °C for 120 h resulted
in the isolation of dyads in yields ranging from 63 to 91%
In 1991, Wilen et al. refuted that hypothesis when they
described the resolution of 1 via the (−)-[1,1′-binaphthalene]-
2,2′-diyl phosphate salt.10 The absolute configuration of the
resolved 1 was confirmed as the (5S,11S)-(+) isomer by X-ray
crystallography (settling earlier competing assignments).11,12
The yield of the salt (from ethanol) was 93%, considerably
higher than the theoretical 50% yield, which lead to the
conclusion that a crystallization-induced asymmetric trans-
formation (CIAT) had taken place. Troger’s bases 113 and 214
̈
(as O,O′-dibenzoyl-L-tartaric acid complexes) and a naphthyl
derivative15 (as an O,O′-ditoluoyl-L-tartaric acid complex) have
been resolved. The tartaric acid based resolutions have all used
acetone as the solvent, and in no case was CIAT observed.
Despite these successes, synthetically more useful halogen-
ated TB have resisted chemical resolution. Chiral HPLC has
been used to resolve a dibromo-TB derivative (in 10 mg
batches)16 and diiodo-TB 4 (in 40 mg17 and 200 mg18
batches). Finally, several dihalogenated TB derivatives have
been resolved using recycling chiral HPLC to increase peak
resolution.19
(based on total TB). Troger’s base 8, bearing no substituents,
̈
1
deposited a 1:1 TB-DBTA dyad (as determined by H NMR),
but recovered TB exhibited low enantiomeric ratios (<80:20).
Troger’s base derivatives 9 and 10, bearing substituents in
̈
positions other than 2- and 8-, did not deposit crystalline dyads
under the conditions of this procedure. This is particularly
disappointing for compound 9, whose value lies in its decreased
tendency for acid-catalyzed racemization. We postulate that the
varying yields for the TB dyads reflect a fine balance between
solubility of the dyads, temperature of the CIAT, and time. It
was our goal to devise a straightforward, general resolution
method with as few variables as possible. It is possible that
extension of reaction times and/or closer examination of
temperature control for individual TB could result in marginally
higher yields of dyads of TB 1−7.
The lack of a general and scalable method for the resolution
of Troger’s base derivatives (particularly halogenated deriva-
̈
tives) prompted us to explore solutions to this problem. Our
approach was to utilize the proven ability of O,O′-dibenzoyl-
tartaric acid (DBTA) to form complexes with Troger’s base and
̈
screen solvents that would lead to selective precipitation of
Enantiopure TB derivatives were recovered from the dyads in
>95% yield by extraction from methylene chloride and aqueous
sodium carbonate. The enantiopurity of the resolved TB
derivatives was determined by HPLC. The efficiency of the
resolution is shown in Figure 3, which depicts the chiral HPLC
traces of ( )-3, (+)-S,S-3, and (−)-R,R-3. Enantiomeric ratios
(er) of ≥99:1 were observed for resolved TB 1−7, with er
>99.5:0.5 for most derivatives. HPLC analysis revealed that the
TB-DBTA dyads of TB bearing electron-withdrawing sub-
stituents possess a high degree of stereointegrity upon storage:
enantiopure TB 4 recovered from dyad stored ∼60 days at rt,
showed no measurable decrease in er. On the other hand, TB 1
from a dyad stored 45 days showed a slight decrease in er from
99:1 to 95:5. As a result, it is generally advantageous to recover
the TB shortly after isolation of the dyads. In general, the high
er observed for recovered TB indicates that racemization in the
presence of DBTA, under these conditions, does not interfere
with resolution.
diastereomeric salts/complexes. Troger’s base derivatives 1−
̈
1020−23 (Figure 2) possess a variety of substituents and include
symmetrically dihalogenated TB and unsymmetric monohalo-
genated TB.
Figure 2. Troger’s base derivatives investigated in this study.
̈
Specific rotations of both enantiomers of 1,10,13 2,14 3,18 and
417,18 were in agreement with literature values and allowed for
the assignment of absolute configuration. In these cases, (−)-L-
DBTA consistently formed dyads with (R,R)-(−)-TB, while
(+)-D-DBTA formed dyads with (S,S)-(+)-TB. In addition,
(S,S)-(+)-TB derivatives consistently eluted before (R,R)-
(−)-TB derivatives under the conditions of chiral HPLC. On
the basis of analogous behavior of TB 5, 6, and 7, these (−)-TB
stereoisomers were tentatively assigned R,R absolute config-
uration and the (+)-TB stereoisomers were tentatively assigned
S,S absolute configuration. The results of the resolution of TB
derivatives 1−8 are summarized in Table 1.
Solvent polarity was seen as a potential factor that could
improve the chances of successful resolution of TB with DBTA;
lower solvent polarity would be expected to decrease the
stability of charged intermediates leading to racemization
(Figure 1). Our search revealed 1,2-dichloroethane (DCE) to
be suitable for the resolution of TB 1−7. Treatment of a 1:1
mixture of the TB derivative and DBTA in boiling DCE
resulted in crystals that were deposited over periods ranging
from minutes to hours, depending on the derivative. The
resulting solids were resuspended in DCE and filtered to give
complexes, which were revealed by H NMR and elemental
analysis to be 1:1 TB-DBTA dyads.
During the course of our investigation, two apparently
anomalous observations were noted. Dyads of TB 2
consistently gave >50% yields (based on total TB) and
concentration of dyad filtrates of TB 4 at elevated temperatures
deposited second and even third crops of crystals giving total
1
Caution should be exercised in assigning absolute config-
urations of Troger’s base derivatives. The relationship between
̈
the chiroptical properties and absolute configuration is sensitive
to the structure of the chromophore.16 Lutzen et al.19
̈
determined the absolute configuration of a series of three 2,8-
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The Journal of Organic Chemistry
Note
bromo- and iodo-Troger’s bases should stimulate research on
̈
enantiopure derivatives in general and homochiral molecules/
assemblies possessing multiple TB fragments in particular.
EXPERIMENTAL SECTION
■
General Information. NMR spectra were obtained on a 400 MHz
spectrometer. Chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane (TMS) with reference to internal
solvent for 1H NMR and 13C NMR spectra. Multiplicities are
abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), and broad (br). Optical rotations were obtained at a
wavelength of 589 nm. The concentration “c” has units of g/100 mL.
Enantiomeric purities were determined as enantiomeric ratios (er)
using a Chiralpak 1A chiral column using HPLC detecting at 254 nm.
The mobile phase was 100% ethanol at a flow rate of 0.800 mL/min.
HPLC traces of resolved TB were compared to racemic samples.
Column chromatography was performed using neutral alumina
(activity III). (−)-O,O′-Dibenzoyl-L-tartaric acid monohydrate
((−)-L-DBTA•H2O) and (+)-O,O′-dibenzoyl-D-tartaric acid ((+)-D-
DBTA) were purchased from commercial sources and used as
received. Preparations of Troger’s base derivatives ( )-1
̈
(( )-Me2TB),20 ( )-2 (( )-MeO2TB),20 ( )-3 (( )-I2TB),20
( )-4 (( )-Br2TB),20 ( )-5 (( )-Cl2TB),20 ( )-6 (( )-HITB),21
(
)-7 (( )-HBrTB),2 1 )-8 (( )-H2 TB),2 0
( ( )-9
(( )-I2Me2TB),22 and ( )-10 (( )-3,9-Cl2TB)23 have been reported
in the literature.
̈
Representative Procedure for the Preparation of a Troger’s
Base-DBTA Dyad. (−)-R,R-2,8-Dibromo-6,12-dihydro-5,11-
methanodibenzo[b,f ][1,5]diazocine•(−)-O,O′-dibenzoyl-L-tar-
taric acid dyad, [(−)-Br2TB•(−)-L-DBTA]. A 300 mL round-bottom
flask charged with 11.60 g (30.83 mmol) of (−)-O,O′-dibenzoyl-L-
tartaric acid monohydrate and 130 mL of dichloroethane (DCE) was
heated to boiling, and the water of hydration and residual water (either
from the solvent or as water of hydration) was carefully removed
azeotropically. ( )-Br2TB (11.40 g; 25.00 mmol) was added, and the
solution heated to boiling. Crystals of the complex deposited almost
immediately. The suspension was stirred at 55−60 °C for 120 h. The
mixture was cooled and allowed to stand for 16 h, whereupon the solid
was collected by filtration and washed with 3 × 15 mL of DCE to give
20.08 g of fine white crystals. The solid was resuspended in 70 mL of
DCE, stirred for 30 min, filtered and washed with 3 × 15 mL of DCE
to give 19.76 g (89%) of product as a white solid. The solid was dried
under a vacuum at rt for 24 h: mp 173−174 °C (dec); 1H NMR (400
MHz, DMSO-d6) δ 4.19 (d, J = 17.2 Hz, 2H), 4.21 (s, 2H), 4.60 (d, J
= 17.2 Hz, 2H), 5.92 (s, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 2.0
Hz, 2H), 7.30 (dd, J = 8.8, 2.4 Hz, 2H), 7.58−7.63 (m, 4H), 7.71−
7.76 (m, 2H), 8.03−8.06 (m, 4H), 13.95 (br s, 2H); 13C NMR (100
MHz, DMSO-d6) δ 57.6, 65.7, 71.4, 115.3, 126.9, 128.4, 129.0, 129.39,
129.43, 129.9, 130.5, 134.1, 147.1, 164.64, 167.1. Anal. Calcd for
C33H26Br2N2O8: C, 53.68; H, 3.55; N, 3.79. Found: C, 53.59; H, 3.27;
N, 3.76.
Note: The complexes of MeO2TB, Br2TB, Cl2TB, HITB, and
HBrTB deposited precipitates almost immediately, while the solution
was still boiling. The complexes of Me2TB and I2TB often gave solid
only after prolonged heating. Seed crystals and/or sonication often
aided in the deposition of crystals. In these cases, once substantial
crystallization occurs, the prolonged heating of the suspension can
commence.
(+)-S,S-2,8-Dibromo-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine•(+)-O,O′-dibenzoyl-D-tartaric acid dyad,
[(+)-Br2TB•(+)-D-DBTA]. ( )-Br2TB (7.60 g; 20.0 mmol) and
(+)-O,O′-dibenzoyl-D-tartaric acid (7.34 g; 20.5 mmol) heated to
55−60 °C for 120 h yielded 13.0 g (88%) of the complex as a white
solid: mp 172−173 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 4.19
(d, J = 17.2 Hz, 2H), 4.21 (s, 2H), 4.60 (d, J = 17.2 Hz, 2H), 5.91 (s,
2H), 7.07 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 2.4 Hz, 2H), 7.30 (dd, J =
8.8, 2.4 Hz, 2H), 7.58−7.63 (m, 4H), 7.71−7.76 (m, 2H), 8.03−8.06
(m, 4H), 13.95 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ57.6,
65.7, 71.4, 115.3, 126.9, 128.4, 129.0, 129.39, 129.43, 129.9, 130.5,
Figure 3. HPLC traces of racemic 3 (top), (+)-S,S-3 (middle) and
(−)-R,R-3 (bottom). The er for both (+)-S,S-3 and (−)-R,R-3 is
>99.5:0.5. HPLC conditions: Chiralpak 1A column, flow 0.8 mL/min,
100% ethanol.
dihalogenated TB molecules bearing additional substituents,
and in each case the (−)-R,R-TB and (+)-S,S-TB relationship
persisted (in agreement with the established absolute
configuration of TB 1−4 and our tentative assignment for
TB 5−7). Troger’s base derivatives where the relationship
̈
between the absolute configuration and the specific rotation is
reversed possess halogens in positions other than 2- and 8-.16,19
Several other 2,8-disubstituted TB (nonhalogenated) maintain
the (−)-R,R-TB and (+)-S,S-TB relationship.16,18 Finally, in
Lutzen’s series of halogenated TB,19 the chiral HPLC order was
̈
consistent with the absolute configuration/specific rotation
relationship; for the three examples of (−)-R,R-TB and (+)-S,S-
TB, the (−)-R,R-TB stereoisomer eluted first. In the example
where the halogens were not 2,8-disubstituted and possessed a
(+)-R,R-TB relationship, the R,R isomer still eluted first.
In conclusion, we have described a general method for the
resolution of five different 2,8-disubstituted and two different 2-
substituted Troger’s base derivatives. Control of time and
̈
temperature results in yields of TB-DBTA dyads of >50%
(based on total TB) and demonstrate the participation of a
crystallization-induced asymmetric transformation (CIAT).
The results contradict the widely held belief that a general
procedure for the resolution of TB analogues via complexes
with acids is not feasible. The method provides derivatives in
multigram quantities, and access to the synthetically versatile
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The Journal of Organic Chemistry
Note
a
Table 1. Results for the resolution of TB 1−8
d
Troger’s
TB-DBTA yield g
isolated resolved TB
(yield)
er
̈
b
c
25
entry
base
X
Y
DBTA
(%)
[α]D (c)
lit. [α]D
(major:minor)
e
h
1
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
)-1
)-1
)-2
)-2
)-3
)-3
)-4
)-4
)-5
)-5
)-6
)-6
)-7
)-7
)-8
)-8
Me
Me
MeO
MeO
Br
Br
I
Me
Me
MeO
MeO
Br
Br
I
(−)-L-DBTA
(+)-D-DBTA
(−)-L-DBTA
(+)-D-DBTA
(−)-L-DBTA
(+)-D-DBTA
(−)-L-DBTA
(+)-D-DBTA
(−)-L-DBTA
(+)-D-DBTA
(−)-L-DBTA
(+)-D-DBTA
(−)-L-DBTA
(+)-D-DBTA
(−)-L-DBTA
(+)-D-DBTA
32.0 (66)
22.3 (63)
16.9 (88)
13.2 (83)
19.8 (89)
13.0 (88)
15.9 (76)
13.2 (79)
14.8 (91)
8.90 (91)
6.36 (90)
6.21 (88)
4.53 (69)
(−)-R,R-1(96%)
(+)-S,S-1(98%)
(−)-R,R-2(97%)
(+)-S,S-2(98%)
(−)-R,R-3(97%)
(+)-S,S-3(98%)
(−)-R,R-4(98%)
(+)-S,S-4(98%)
(−)-R,R-5(97%)
(+)-S,S-5(97%)
(−)-R,R-6(98%)
(+)-S,S-6(96%)
(−)-R,R-7(98%)
(+)-S,S-7(98%)
−276 (0.112)
+282 (0.112)
−240 (0.110)
+236 (0.110)
−383 (0.117)
+379 (0.114)
−441 (0.114)
+443 (0.116)
−396 (0.110)
+393 (0.114)
−323 (0.110)
+326 (0.114)
−302 (0.110)
+302 (0.109)
−301
+279
99.1:0.9
e
h
2
>99.5:0.5
>99.5:0.5
99.1:0.9
i
3
4
−242
i
+236
f
j
5
−394
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
f
j
6
+393
g
j
7
−454
g
j
8
I
I
+445
9
Cl
Cl
I
Cl
Cl
H
10
11
12
13
14
15
16
I
H
Br
Br
H
H
H
5.20 (79)
k
H
k
H
H
a
b
c
Conditions: [TB] = [DBTA] ∼ 0.20−0.25 M in DCE at 55−60 °C for 120 h. DBTA: O,O′-dibenzoyltartaric acid. c = g/100 mL; performed in
d
e
CHCl3. er = enantiomeric ratio. HPLC conditions: Chiralpak 1A column, flow 0.8 mL/min, 100% ethanol. [TB] = [DBTA] ∼ 0.50 M; T = 45−50
°C. [TB] = [DBTA] ∼ 0.30 M. T = 45−50 °C. ref 10. ref 14. ref 18. Deposited 1:1 dyad, but recovered TB had er <80:20.
f
g
h
i
j
k
134.1, 147.1, 164.64, 167.1. Anal. Calcd for C33H26Br2N2O8: C, 53.68;
H, 3.55; N, 3.79. Found: C, 53.60; H, 3.20; Br; N, 3.76.
(dd, J = 8.8, 3.2 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 7.59−7.64 (m, 4H),
7.72−7.77 (m, 2H), 8.02−8.05 (m, 4H), 13.94 (br s, 2H); 13C NMR
(100 MHz, DMSO-d6) d 55.0, 58.3, 66.6, 71.5, 110.6, 113.7, 125.6,
128.5, 128.8, 129.0, 129.4, 134.1, 140.8, 155.3,164.7, 167.2. Anal. Calcd
for C35H32N2O10: C, 65.62; H, 5.03; N, 4.37. Found: C, 65.55; H,
5.00; N, 4.38.
(−)-R,R-2,8-Dimethyl-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine•(−)-O,O′-dibenzoyl-L-tartaric acid dyad,
[(−)-Me2TB•(−)-L-DBTA]. ( )-Me2TB (20.00 g; 80.00 mmol) and
(−)-O,O′-dibenzoyl-L-tartaric acid monohydrate (30.52 g; 81.12
mmol) heated to 45−50 °C for 120 h yielded 32.04 g (66%) of the
complex as a white solid: mp 162−164 °C (dec); 1H NMR (400 MHz,
DMSO-d6) δ 2.15 (s, 6H), 4.00 (d, J = 16.8 Hz, 2H), 4.19 (s, 2H),
4.54 (d, J = 16.8 Hz, 2H), 5.91 (s, 2H), 6.71 (s, 2H), 6.92 (dd, J = 8.0,
1.6 Hz, 2H), 6.98 (d, 8.4 Hz, 2H), 7.58−7.63 (m, 4H), 7.72−7.76 (m,
2H), 8.03−8.06 (m, 4H), 13.97 (br s, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 20.3, 58.2, 66.4, 71.5, 124.4, 127.0, 127.6, 127.7, 128.5,
129.0, 129.4, 132.2, 134.1, 145.5, 164.7, 167.2. Anal. Calcd for
C35H32N2O8: C, 69.07; H, 5.30; N, 4.60. Found 68.82; H, 5.34; N,
4.56.
(+)-S,S-2,8-Dimethyl-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine•(+)-O,O′-dibenzoyl-D-tartaric acid dyad,
[(+)-Me2TB•(+)-D-DBTA]. ( )-Me2TB (15.00 g; 60.00 mmol) and
(+)-O,O′-dibenzoyl-D-tartaric acid (21.86 g; 61.00 mmol) heated to
45−50 °C for 120 h yielded 22.26 g (63%) of the complex as a white
solid: mp 161−162 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 2.15
(s, 6H), 4.00 (d, J = 16.8 Hz, 2H), 4.19 (s, 2H), 4.54 (d, J = 16.8 Hz,
2H), 5.91 (s, 2H), 6.71 (s, 2H), 6.92 (dd, J = 8.0, 1.6 Hz, 2H), 6.98 (d,
8.0 Hz, 2H), 7.58−7.63 (m, 4H), 7.71−7.76 (m, 2H), 8.03−8.06 (m,
4H), 13.97 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 20.3, 58.2,
66.4, 71.5, 124.4, 127.0, 127.6 (2 carbons), 128.5, 129.0, 129.4, 132.3,
134.1, 145.4, 164.7, 167.2. Anal. Calcd for C35H32N2O8: C, 69.07; H,
5.30; N, 4.60. Found 68.97; H, 5.32; N, 4.59.
(+)-S,S-2,8-Dimethoxy-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine•(+)-O,O′-dibenzoyl-D-tartaric acid dyad,
[(+)-MeO2TB•(+)-D-DBTA]. ( )-MeO2TB (7.06 g; 25.0 mmol) and
(+)-O,O′-dibenzoyl-D-tartaric acid (9.14 g; 25.5 mmol) heated to 55−
60 °C for 120 h yielded 13.22 g (83%) of the complex as a white solid:
1
mp 172−173 °C (dec); H NMR (400 MHz, DMSO-d6) d 3.64 (s,
6H), 4.00 (d, J = 16.8 Hz, 2H), 4.18 (s, 2H), 4.55 (d, J = 16.8 Hz, 2H),
5.90 (s, 2H), 6.51 (d, J = 2.8 Hz, 2H), 6.72 (dd, J = 8.8, 3.2 Hz, 2H),
7.02 (d, J = 8.8 Hz, 2H), 7.59−7.63 (m, 4H), 7.71−7.77 (m, 2H),
8.02−8.05 (m, 4H), 13.92 (br s, 2H); 13C NMR (100 MHz, DMSO-
d6) d 55.0, 58.3, 66.6, 71.5, 110.6, 113.7, 125.6, 128.5, 128.8, 129.0,
129.4, 134.1, 140.8, 155.3, 164.7, 167.2. Anal. Calcd for C35H32N2O10:
C, 65.62; H, 5.03; N, 4.37. Found: C, 65.40; H, 4.83; N, 4.31.
(−)-R,R-2,8-Diiodo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine•(−)-O,O′-dibenzoyl-L-tartaric acid dyad,
[(−)-I2TB•(−)-L-DBTA]. ( )-I2TB (11.85 g; 25.00 mmol) and
(−)-O,O′-dibenzoyl-L-tartaric acid monohydrate (9.80 g; 26.0 mmol)
heated to 45−50 °C for 120 h yielded 15.88 g (76%) of the complex as
a white solid: mp 170−171 °C (dec); 1H NMR (400 MHz, DMSO-d6)
δ 4.09 (d, J = 17.2 Hz, 2H), 4.19 (s, 2H), 4.56 (d, J = 16.8 Hz, 2H),
5.89 (s, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 2.0 Hz, 2H), 7.45
(dd, J = 8.4, 2.0 Hz, 2H), 7.59−7.64 (m, 4H), 7.72−7.77 (m, 2H),
8.02−8.05 (m, 4H), 13.93 (br s, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 57.4, 65.6, 71.4, 87.4, 127.1, 128.4, 129.0, 129.4, 130.9, 134.1,
135.3, 135.6, 147.7, 164.6, 167.1. Anal. Calcd for C33H26I2N2O8: C,
47.62; H, 3.15; N, 3.37. Found: C, 47.60; H, 2.77; N, 3.32.
(−)-R,R-2,8-Dimethoxy-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine•(−)-O,O′-dibenzoyl-L-tartaric acid dyad,
[(−)-MeO2TB•(−)-L-DBTA]. ( )-MeO2TB (8.47 g; 30.0 mmol) and
(−)-O,O′-dibenzoyl-L-tartaric acid monohydrate (11.44 g; 30.40
mmol) heated to 55−60 °C for 120 h yielded 16.88 g (88%) of the
complex as a white solid: mp 174−175 °C (dec); 1H NMR (400 MHz,
DMSO-d6) d 3.64 (s, 6H), 4.00 (d, J = 16.8 Hz, 2H), 4.17 (s, 2H),
4.54 (d, J = 16.8 Hz, 2H), 5.90 (s, 2H), 6.51 (d, J = 3.2 Hz, 2H), 6.72
(+)-S,S-2,8-Diiodo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine•(+)-O,O′-dibenzoyl-D-tartaric acid dyad,
[(+)-I2TB•(+)-D-DBTA]. ( )-I2TB (9.48 g; 20.0 mmol) and
(+)-O,O′-dibenzoyl-D-tartaric acid (7.34 g; 20.5 mmol) heated to
45−50 °C for 120 h yielded 13.16 g (79%) of the complex as a white
11593
dx.doi.org/10.1021/jo401873x | J. Org. Chem. 2013, 78, 11590−11596

The Journal of Organic Chemistry
Note
solid: mp 166−167 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 4.09
(d, J = 17.2 Hz, 2H), 4.19 (s, 2H), 4.56 (d, J = 17.2 Hz, 2H), 5.90 (s,
2H), 6.92 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 1.6 Hz, 2H), 7.45 (dd, J =
8.4, 2.0 Hz, 2H), 7.59−7.63 (m, 4H), 7.71−7.76 (m, 2H), 8.02−8.05
(m, 4H), 13.94 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 57.5,
65.6, 71.4, 87.4, 127.1, 128.4, 129.0, 129.4, 130.9, 134.1, 135.3, 135.6,
147.7, 164.6, 167.2. Anal. Calcd for C33H26I2N2O8:C, 47.62; H, 3.15;
N, 3.37. Found: C, 47.51; H, 2.78; N, 3.35.
(−)-R,R-2,8-Dichloro-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine•(−)-O,O′-dibenzoyl-L-tartaric acid dyad,
[(−)-Cl2TB•(−)-L-DBTA]. ( )-Cl2TB (7.28 g; 25.0 mmol) and
(−)-O,O′-dibenzoyl-L-tartaric acid monohydrate (9.52 g; 25.3 mmol)
heated to 55−60 °C for 120 h yielded 14.76 g (91%) of the complex as
a white solid: mp 173−174 °C (dec); 1H NMR (400 MHz, DMSO-d6)
d 4.12 (d, J = 16.8 Hz, 2H), 4.21 (s, 2H), 4.59 (d, J = 16.8 Hz, 2H),
5.91 (s, 2H), 7.05 (d, J = 2.4 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.18
(dd, J = 8.8, 2.4 Hz, 2H), 7.58−7.63 (m, 4H), 7.71−7.76 (m, 2H),
8.02−8.05 (m, 4H), 13.95 (br s, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 57.8, 65.8, 71.5, 126.5, 126.6, 127.0, 127.2, 128.5, 129.0, 129.4,
130.0, 134.1, 146.7, 164.6, 167.2. Anal. Calcd for C33H26Cl2N2O8: C,
61.03; H, 4.04; N, 4.31. Found: C, 60.91; H, 3.80; N, 4.29.
(+)-S,S-2,8-Dichloro-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine•(+)-O,O′-dibenzoyl-D-tartaric acid dyad,
[(+)-Cl2TB•(+)-D-DBTA]. ( )-Cl2TB (4.37 g; 15.0 mmol) and
(+)-O,O′-dibenzoyl-D-tartaric acid (5.45 g; 15.2 mmol) heated to
55−60 °C for 120 h yielded 8.90 g (91%) of the complex as a white
solid: mp 173−174 °C (dec); 1H NMR (400 MHz, DMSO-d6) d 4.12
(d, J = 17.2 Hz, 2H), 4.21 (s, 2H), 4.59 (d, J = 16.8 Hz, 2H), 5.92 (s,
2H), 7.04 (d, J = 2.4 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.18 (dd, J =
8.4, 2.4 Hz, 2H), 7.58−7.63 (m, 4H), 7.71−7.76 (m, 2H), 8.03−8.06
(m, 4H), 13.95 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 57.8,
65.8, 71.5, 126.5, 126.5, 127.0, 127.2, 128.5, 129.0, 129.4, 130.0, 134.1,
146.6, 164.6, 167.2. Anal. Calcd for C33H26Cl2N2O8: C, 61.03; H, 4.04;
N, 4.31. Found: C, 61.06; H, 3.82; N, 4.28.
(−)-R,R-2-Iodo-6,12-dihydro-5,11-methanodibenzo[b,f ][1,5]-
diazocine•(−)-O,O′-dibenzoyl-L-tartaric acid dyad,
[(−)-HITB•(−)-L-DBTA]. ( )-HITB (3.48 g; 10.0 mmol) and
(−)-O,O′-dibenzoyl-L-tartaric acid monohydrate (3.84 g; 10.2 mmol)
heated to 55−60 °C for 120 h yielded 6.36 g (90%) of the complex as
a white solid: mp 172−173 °C (dec); 1H NMR (400 MHz, DMSO-d6)
δ4.09 (d, J = 17.2 Hz, 1H), 4.14 (d, J = 17.2, 1H), 4.16−4.23 (m, 2H),
4.59 (d, J = 16.8 Hz, 1H), 4.62 (d, J = 16.8 Hz, 1H), 5.90 (s, 2H),
6.94−6.96 (m, 2H), 7.07−7.10 (m, 2H), 7.12−7.18 (m, 2H), 7.29 (dd,
J = 8.8, 2.4 Hz, 1H), 7.59−7.64 (m, 4H), 7.72−7.77 (m, 2H), 8.02−
8.05 (m 4H), 13.95 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ
57.5, 58.1, 65.8, 71.4, 87.2, 123.5, 124.7, 126.9, 127.0, 127.1, 127.8,
128.4, 129.0, 129.4, 131.1, 134.1, 135.3, 135.5, 147.8, 148.0. Anal.
Calcd for C33H27IN2O8: C, 56.10; H, 3.85; N, 3.97. Found: C, 56.05;
H, 3.36; N, 3.97.
2H), 4.59 (d, J = 16.8 Hz, 1H), 4.62 (d, J = 16.8 Hz, 1H), 5.90 (s, 2H),
6.94−6.96 (m, 2H), 7.07−7.10 (m, 2H), 7.12−7.18 (m, 2H), 7.29 (dd,
J = 8.8, 2.4 Hz), 7.59−7.63 (m, 4H), 7.72−7.77 (m, 2H), 8.02−8.05
(m, 4H), 13.95 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 57.8,
58.1, 65.9, 71.5, 115.1, 123.5, 124.8, 126.9, 127.1, 127.8, 128.5, 129.0,
129.4, 129.7, 130.8, 134.1, 147.5, 147.7, 164.7, 167.2. Anal. Calcd for
C33H27BrN2O8: C, 60.10; H, 4.13; N, 4.25. Found: C, 60.05; H, 3.97;
N, 4.21.
(+)-S,S-2-Bromo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine•(+)-O,O′-dibenzoyl-D-tartaric acid dyad,
[(+)-HBrTB•(+)-D-DBTA]. ( )-HBrTB (3.01 g; 10.0 mmol) and
(+)-O,O′-dibenzoyl-D-tartaric acid (3.65 g; 10.2 mmol) heated to 55−
60 °C for 120 h yielded 5.20 g (79%) of the complex as a white solid:
mp 163−164 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ4.09 (d, J =
17.2 Hz, 1H), 4.14 (d, J = 17.6 Hz, 1H), 4.17−4.25 (m, 2H), 4.60 (d, J
= 17.2 Hz, 1H), 4.62 (d, J = 16.8 Hz, 1H), 5.91 (s, 2H), 6.94−6.96 (m,
2H), 7.07−7.10 (m, 2H), 7.12−7.18 (m, 2H), 7.29 (dd, J = 8.4, 2.4
Hz), 7.58−7.63 (m, 4H), 7.71−7.76 (m, 2H), 8.03 (d, J = 1.2 Hz, 4H),
13.95 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 57.8, 58.1, 65.9,
71.4, 115.1, 123.5, 124.8, 126.9, 127.1, 127.8, 128.5, 129.0, 129.4,
129.7, 130.8, 134.1, 147.5, 147.7, 164.6, 167.1. Anal. Calcd for
C33H27BrN2O8: C, 60.10; H, 4.13; N, 4.25. Found: C, 60.15; H, 3.85;
N, 4.18.
Representative Procedure for the Recovery of Resolved TB
from TB•DBTA Complex. (−)-R,R-2,8-Dibromo-6,12-dihydro-
5,11-methanodibenzo[b,f ][1,5]diazocine, [(−)-R,R-3; (−)-R,R-
Br2TB]. (−)-Br2TB•(−)-L-DBTA (5.00 g; 6.77 mmol) was suspended
in 50 mL of CH2Cl2 and extracted with 50 mL of 5% aqueous
Na2CO3. The organic layer was separated, and the aqueous layer
extracted with 2 × 10 mL of CH2Cl2. The combined organic extracts
were dried over MgSO4 and passed through a 2 × 8 cm column of
activity III neutral alumina. Evaporation of the eluate gave a white
solid, which was dried under a vacuum at rt for 24 h (2.49 g; 97%): mp
1
173−174 °C; H NMR (400 MHz, CDCl3) d 4.80 (d, J = 16.8 Hz,
2H), 4.23 (s, 2H), 4.62 (d, J = 16.8 Hz, 2H), 6.90, (d, J = 8.4 Hz, 2H),
7.03 (d, J = 2.4 Hz, 2H), 7.26 (dd, J = 8.4, 2.4, 2H); 13C NMR (100
MHz, CDCl3) δ58.3, 66.4, 116.8, 126.7, 129.68, 129.72, 130.6, 146.8;
25
[α]D = −383 (c, 0.117, CHCl3). The er was measured by HPLC
Chiralpak 1A column, flow 0.8 mL/min, 100% ethanol, 254 nm, tR =
8.5 min (minor = 0.2%), tR = 11.0 min (major = 99.8%) for an er
>99.5:0.5.
All resolved TB derivatives were recovered from their DBTA
complexes in the same way in yields >95%.
(+)-S,S-2,8-Dibromo-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine, [(+)-S,S-3; (+)-S,S-Br2TB]. From 5.00 g (6.77
mmol) of (+)-Br2TB•(+)-D-DBTA, 2.52 g (98%) (+)-S,S-Br2TB as a
1
white solid: mp 172−173 °C (dec); H NMR (400 MHz, CDCl3) d
4.80 (d, J = 16.8 Hz, 2H), 4.24 (s, 2H), 4.63 (d, J = 16.8 Hz, 2H), 6.90,
(d, J = 8.4 Hz, 2H), 7.04 (d, J = 2.4 Hz, 2H), 7.26 (dd, J = 8.4, 2.4,
2H); 13C NMR (100 MHz, CDCl3) δ58.3, 66.4, 116.8, 126.7, 129.68,
129.72, 130.6, 146.8; [α]D25 = +379 (c, 0.114, CHCl3); HPLC tR = 8.5
min (major = 99.9%), tR = 11.2 min (minor = 0.1%) for an er
>99.5:0.5.
(+)-S,S-2-Iodo-6,12-dihydro-5,11-methanodibenzo[b,f ][1,5]-
diazocine•(+)-O,O′-dibenzoyl-D-tartaric acid dyad,
[(+)-HITB•(+)-D-DBTA]. ( )-HITB (3.48 g; 10.0 mmol) and
(+)-O,O′-dibenzoyl-D-tartaric acid (3.65 g; 10.2 mmol) heated to
55−60 °C for 120 h yielded 6.21 g (88%) of the complex as a white
(−)-R,R-2,8-Dimethyl-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine, [(−)-R,R-1; (−)-R,R-Me2TB]. From 5.00 g (8.22
mmol) of (−)-Me2TB•(−)-L-DBTA, 1.98 g (96%) (−)-R,R-Me2TB as
1
solid: mp 172−173 °C (dec); H NMR (400 MHz, DMSO-d6) δ4.09
(d, J = 16.4 Hz, 1H), 4.12 (d, J = 16.4, 1H), 4.14−4.23 (m, 2H), 4.57
(d, J = 16.8 Hz, 1H), 4.61 (d, J = 16.8 Hz, 1H), 5.90 (s, 2H), 6.92−
6.96 (m, 2H), 7.07−7.10 (m, 2H), 7.12−7.18 (m, 2H), 7.29 (dd, J =
8.8, 2.4 Hz, 1H), 7.59−7.63 (m, 4H), 7.72−7.77 (m, 2H), 8.02−8.05
(m, 4H), 13.95 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 57.5,
58.1, 65.8, 71.4, 87.2, 123.5, 124.7, 126.9, 127.0, 127.1, 127.8, 128.5,
129.0, 129.4, 131.1, 134.1, 135.3, 135.5, 147.8, 148.0. Anal. Calcd for
C33H27IN2O8: C, 56.10; H, 3.85; N, 3.97. Found: C, 55.99; H, 3.43; N,
3.95.
1
a white solid: mp 128−129 °C; H NMR (400 MHz, CDCl3) δ 2.20
(s, 6H), 4.10 (d, J = 16.8 Hz, 2H), 4.29, s, 2H), 4.63 (d, J = 16.8 Hz,
2H), 6.69, s, 2H), 6.96 (dd, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 20.9, 58.7, 67.1, 124.8, 127.3, 127.6,
128.2, 133.4, 145.5; [α]D25 = −276 (c, 0.112, CHCl3); HPLC tR = 6.2
min (minor = 0.9%), tR = 9.1 min (major = 99.1%) for an er =
99.1:0.9.
(+)-S,S-2,8-Dimethyl-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine, [(+)-S,S-1; (+)-S,S-Me2TB]. From 5.00 g (8.22
mmol) of (+)-Me2TB•(+)-D-DBTA, 2.02 g (98%) (+)-S,S-Me2TB as a
white solid: mp 129−130 °C; 1H NMR (400 MHz, CDCl3) δ 2.20 (s,
6H), 4.10 (d, J = 16.8 Hz, 2H), 4.29, s, 2H), 4.63 (d, J = 16.8 Hz, 2H),
6.69, s, 2H), 6.96 (dd, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 20.9, 58.7, 67.1, 124.8, 127.3, 127.6, 128.2,
(−)-R,R-2-Bromo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine•(−)-O,O′-dibenzoyl-L-tartaric acid dyad,
[(−)-HBrTB•(−)-L-DBTA]. ( )-HBrTB (3.01 g; 10.0 mmol) and
(−)-O,O′-dibenzoyl-L-tartaric acid monohydrate (3.84 g; 10.2 mmol)
heated to 55−60 °C for 120 h yielded 4.53 g (69%) of the complex as
a white solid: mp 163−164 °C (dec); 1H NMR (400 MHz, DMSO-d6)
δ4.09 (d, J = 17.2 Hz, 1H), 4.14 (d, J = 17.2 Hz, 1H), 4.16−4.25 (m,
25
133.4, 145.5; [α]D = +282 (c, 0.112, CHCl3); HPLC tR = 6.3 min
11594
dx.doi.org/10.1021/jo401873x | J. Org. Chem. 2013, 78, 11590−11596

The Journal of Organic Chemistry
Note
(major = 100%), tR = 9.0 min (minor = 0%; none detected) for an er
>99.5:0.5.
(+)-HITB•(+)-D-DBTA, 1.45 g (98%) (+)-S,S-HITB as a white solid:
mp 130−131 °C; 1H NMR (400 MHz, CDCl3) δ 4.11 (d, J = 16.8 Hz,
2H), 4.19−4.30 (m, 2H), 4.59 (d, J = 16.8 Hz, 1H), 4.66 (d, J = 16.8
Hz, 1H), 6.85−6.89 (m, 2H), 6.97 (td, J = 7.6, 1.2, 1H), 7.10 (dd, J =
8.0, 1.2 Hz, 1H), 7.13−7.20 (m, 2H), 7.41 (dd, J = 8.4, 2.0, 1H); 13C
NMR (100 MHz, CDCl3) δ 58.2, 58.7, 66.7, 87.5, 124.2, 125.1, 127.0,
127.1, 127.56, 127.60, 130.6, 135.7, 136.3, 147.7, 148.0; [α]D25 = +326
(c, 0.114, CHCl3); HPLC tR = 7.6 min (major = 100%), tR = 9.3 min
(minor = 0.0%; none detected) for an er >99.5:0.5.
(−)-R,R-2,8-Dimethoxy-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine, [(−)-R,R-2; (−)-R,R-MeO2TB]. From 5.00 g
(7.80 mmol) of (−)-MeO2TB•(−)-L-DBTA, 2.14 g (97%) (−)-R,R-
1
MeO2TB as a white solid: mp 141−142 °C; H NMR (400 MHz,
CDCl3) δ 3.70 (s, 6H), 4.08 (d, J = 16.8 Hz, 2H), 4.29 (s, 2H), 4.64
(d, J = 16.8 Hz, 2H), 6.42 (d, J = 2.8 Hz, 2H), 6.73 (dd, J = 8.8, 2.8,
2H), 7.06 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 55.4,
25
58.9, 67.3, 110.9, 114.0, 126.0, 128.6, 140.9, 156.1; [α]D = −240 (c,
(−)-R,R-2-Bromo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine, [(−)-R,R-7; (−)-R,R-HBrTB]. From 3.00 g (4.55
mmol) of (−)-HBrTB•(−)-L-DBTA, 1.34 g (98%) (−)-R,R-HBrTB
as a white solid: mp 162−163 °C; 1H NMR (400 MHz, CDCl3) δ 4.11
(d, J = 16.8 Hz, 1H), 4.13 (d, J = 16.8 Hz, 1H), 4.22−4.32 (m, 2H),
4.63 (d, J = 17.6 Hz, 1H), 4.67 (d, J = 17.2 Hz, 1H), 6.89 (dd, J = 7.6,
0.4 Hz, 1H), 6.95−7.02 (m, 3H), 7.09−7.19 (m, 2H), 7.22−7.26 (m,
0.110, CHCl3); HPLC tR = 9.8 min (major = 99.8%) for an er
>99.5:0.5.
(+)-S,S-2,8-Dimethoxy-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine, [(+)-S,S-2; (+)-S,S-MeO2TB]. From 5.00 g (7.80
mmol) of (+)-MeO2TB•(+)-D-DBTA, 2.16 g (98%) (+)-S,S-MeO2TB
as a white solid: mp 140−141 °C; 1H NMR (400 MHz, CDCl3) δ 3.69
(s, 6H), 4.07 (d, J = 16.8 Hz, 2H), 4.29 (s, 2H), 4.64 (d, J = 16.8 Hz,
2H), 6.42 (d, J = 2.8 Hz, 2H), 6.73 (dd, J = 8.8, 2.8, 2H), 7.05 (d, J =
8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 55.4, 58.9, 67.3, 110.9,
1H); 13C NMR (100 MHz, CDCl3) δ 58.4, 58.7, 66.7, 116.5, 124.2,
25
125.1, 126.8, 127.0, 127.6, 129.7, 130.1, 130.4, 147.2, 147.7; [α]D
=
−302 (c, 0.110, CHCl3); HPLC tR = 7.3 min (minor = 0.0%; none
detected), tR = 9.0 min (major = 100%) for an er >99.5:0.5.
25
114.0, 126.0, 128.6, 140.9, 156.1; [α]D = +236 (c, 0.110, CHCl3);
HPLC tR = 7.9 min (major = 99.1%), tR = 9.7 min (minor = 0.9%) for
an er = 99.1:0.9.
(+)-S,S-2-Bromo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine,[(+)-S,S-7; (+)-S,S-HBrTB]. From 3.00 g (4.55 mmol)
of (+)-HBrTB•(+)-D-DBTA, 1.32 g (96%) (+)-S,S-HBrTB as a white
(−)-R,R-2,8-Diiodo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine, (−)-R,R-4; (−)-R,R-I2TB]. From 6.00 g (7.21 mmol)
of (−)-I2TB•(−)-L-DBTA, 3.36 g (98%) (−)-R,R-I2TB as a white
1
solid: mp 162−163 °C; H NMR (400 MHz, CDCl3) δ 4.12 (d, J =
16.8 Hz, 1H), 4.14 (d, J = 16.8 Hz, 1H), 4.22−4.33 (m, 2H), 4.64 (d, J
= 17.2 Hz, 1H), 4.68 (d, J = 16.8 Hz, 1H), 6.89 (dd, J = 7.6, 0.4 Hz,
1H), 6.96−7.03 (m, 3H), 7.09−7.19 (m, 2H), 7.23−7.26 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 58.4, 58.7, 66.7, 116.5, 124.2, 125.1, 126.8,
127.0, 127.5, 129.7, 130.1, 130.4, 147.2, 147.7; [α]D25 = +302 (c, 0.109,
CHCl3); HPLC tR = 7.2 min (major = 100%), tR = 9.0 min (minor =
0.0%; none detected) for an er >99.5:0.5.
1
solid: mp 203−204 °C; H NMR (400 MHz, CDCl3) δ 4.08 (d, J =
16.8 Hz, 2H), 4.23 (s, 2H), 4.61 (d, J = 16.8 Hz, 2H), 6.86 (d, J = 8.4
Hz, 2H), 7.22−7.24 (m, 2H), 7.45 (dd, J = 8.4, 2.0, 2H); 13C NMR
(100 MHz, CDCl3) δ 58.1, 66.5, 87.6, 127.0, 130.2, 135.7, 136.5,
147.6; [α]D25 = −441 (c, 0.114, CHCl3); HPLC tR = 9.9 min (minor =
0.1%), tR = 11.3 min (major = 99.9%) for an er >99.5:0.5.
(+)-S,S-2,8-Diiodo-6,12-dihydro-5,11-methanodibenzo[b,f ]-
[1,5]diazocine, [(+)-S,S-4; (+)-S,S-I2TB]. From 6.00 g (7.21 mmol)
of (+)-I2TB•(+)-D-DBTA, 3.35 g (98%) (+)-S,S-I2TB as a white solid:
mp 204−205 °C; 1H NMR (400 MHz, CDCl3) δ 4.07 (d, J = 16.8 Hz,
2H), 4.23 (s, 2H), 4.61 (d, J = 16.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H),
ASSOCIATED CONTENT
* Supporting Information
NMR spectra of dyads and isolated TB, and chiral HPLC traces
of racemic and resolved TB derivatives. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
7.22−7.24 (m, 2H), 7.45 (dd, J = 8.4, 2.0, 2H); 13C NMR (100 MHz,
25
CDCl3) δ 58.1, 66.5, 87.6, 127.0, 130.2, 135.7, 136.5, 147.6; [α]D
=
+443 (c, 0.116, CHCl3); HPLC tR = 9.7 min (major = 99.9%), tR =
11.2 min (minor = 0.1%) for an er >99.5:0.5.
AUTHOR INFORMATION
Corresponding Author
*E-mail: djameson@gettysburg.edu.
■
(−)-R,R-2,8-Dichloro-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine, [(−)-R,R-5; (−)-R,R-Cl2TB]. From 5.00 g (7.70
mmol) of (−)-Cl2TB•(−)-L-DBTA, 2.18 g (97%) (−)-R,R-Cl2TB as a
white solid: mp 117−118 °C; 1H NMR (400 MHz, CDCl3) δ 4.07 (d,
J = 16.8 Hz, 2H), 4.23 (s, 2H), 4.62 (d, J = 16.8 Hz, 2H), 6.88 (J = 2.4
Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 7.12 (dd, J = 8.8, 2.4, 2H); 13C
NMR (100 MHz, CDCl3) δ 58.5, 66.7, 126.4, 126.8, 127.7, 129.1,
Present Address
†The Dow Chemical Company, 727 Norristown Road, Spring
House, Pennsylvania 19477, United States.
Notes
25
129.2, 146.3; [α]D = −396 (c, 0.110, CHCl3); HPLC tR = 7.6 min
The authors declare no competing financial interest.
(minor = 0.1%), tR = 10.0 min (major = 99.9%) for an er >99.5:0.5.
(+)-S,S-2,8-Dichloro-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine, [(+)-S,S-5; (+)-S,S-Cl2TB]. From 5.00 g (7.70
mmol) of (+)-Cl2TB•(+)-D-DBTA, 2.17 g (97%) (+)-S,S-Cl2TB as a
white solid: mp 117−118 °C; 1H NMR (400 MHz, CDCl3) δ 4.08 (d,
J = 16.8 Hz, 2H), 4.23 (s, 2H), 4.62 (d, J = 16.8 Hz, 2H), 6.88 (J = 2.4
Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 7.12 (dd, J = 8.8, 2.4, 2H); 13C
NMR (100 MHz, CDCl3) δ 58.5, 66.7, 126.4, 126.8, 127.7, 129.1,
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the Mary
Catherine Albaugh (Class of 1954) Chemistry Fund for
Student Research.
REFERENCES
25
■
129.2, 146.3; [α]D = +393 (c, 0.114, CHCl3); HPLC tR = 7.5 min
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̈
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