Enantioselective Synthesis of DIANANE, a Novel C2-Symmetric Chiral Diamine for Asymmetric Catalysis

Article abstract of DOI:10.1021/jo035841d

DIANANE (endo,endo-2,5-diaminonorbornane) is a novel chiral C ₂-symmetric diamine, based on the rigid bicyclo[2.2.1]heptane scaffold. Schiff-base ligands derived from DIANANE have already found use in asymmetric catalysis, e.g., in the highly e

Full text of DOI:10.1021/jo035841d

En a n tioselective Syn th esis of DIANANE, a Novel C2-Sym m etr ic
Ch ir a l Dia m in e for Asym m etr ic Ca ta lysis†
Albrecht Berkessel,* Michael Schro¨der, Christoph A. Sklorz, Stefania Tabanella, Nadine Vogl,
J ohann Lex, and J o¨rg M. Neudo¨rfl
Institut fu¨r Organische Chemie, Universita¨t zu Ko¨ln, Greinstrasse 4, D-50939 Ko¨ln, Germany
berkessel@uni-koeln.de
Received December 18, 2003
DIANANE (endo,endo-2,5-diaminonorbornane) is a novel chiral C2-symmetric diamine, based on
the rigid bicyclo[2.2.1]heptane scaffold. Schiff-base ligands derived from DIANANE have already
found use in asymmetric catalysis, e.g., in the highly enantioselective Nozaki-Hiyama-Kishi
reaction. We herein describe a practical synthesis of enantiomerically pure DIANANE, starting
from norbornadiene in four steps: (i) Pd-MOP catalyzed Hayashi-hydrosilylation/Tamao-Fleming
oxidation, (ii) oxidation to norbornane-2,5-dione, (iii) endo-selective reductive amination with
benzylamine, and (iv) hydrogenolytic debenzylation. None of the steps involves chromatographic
purification. For the Tamao-Fleming oxidation, the use of hydrogen peroxide in the form of its
urea clathrate instead of aqueous solution proved beneficial. By the above sequence, enantiomerically
pure (ee g99%) DIANANE was obtained from norbornadiene in 40-50% overall yield. The relative
and absolute configuration of DIANANE was confirmed by X-ray crystallography of the DIANANE
bis-tosylamide, and of its bis-camphorsulfonamide. Furthermore, the synthesis and X-ray crystal
structure of the Schiff-base ligand derived from DIANANE and 3,5-di-tert-butyl salicylic aldehyde
are reported.
In tr od u ction
ligand 2, which is based on endo,endo-2,5-diaminonor-
bornane (DIANANE, 3) as the diamine component, is a
very effective catalyst for the asymmetric Nozaki-
Hiyama-Kishi (NHK) reaction.6 DIANANE (3) is C2-
symmetric and it has a rigid backbone and a larger N-N
distance compared to 1,2-diaminocyclohexane. In the
NHK reaction, the Cr complex of the salen ligand 2
provided enantiomeric excesses up to 92% (Scheme 1).6
Furthermore, substrates such as vinyl triflates and
iodides, which are usually not reactive in the catalytic
enantioselective NHK reaction using the salen ligand 1,
readily underwent addition to aldehydes to form the
expected NHK products. These encouraging results and
the great potential of DIANANE (3) as a novel C2-
symmetrical diamine prompted us to search for an
efficient synthesis of this chiral building block.
In the search for new and ever more efficient chiral
transition metal catalysts, the design of novel ligands is
one of the major research objectives. Chiral salen ligands
are among the so-called “privileged ligands” that effect
remarkable enantioselectivity for a broad range of trans-
formations.1 As one of the first examples, J acobsen et al.2
reported in 1990 on the use of the manganese complex
of N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohex-
anediamine (1) for the asymmetric epoxidation of un-
functionalized olefins (Scheme 1). Since then, a variety
of transition metal complexes of ligands of this type have
been developed for various asymmetric transformations.
Among those, chromium Schiff base complexes have been
used successfully in Diels-Alder and hetero-Diels-Alder
reactions,3 the kinetic resolution of racemic epoxides,4
and the Nozaki-Hiyama-Kishi (NHK) reaction.5 We
have recently reported that the Cr-complex of the salen
Resu lts a n d Discu ssion
† Dedicated to Professor Hisashi Yamamoto on the occasion of his
60th birthday.
(1) Yoon, T. P.; J acobsen, E. N. Science 2003, 299, 1691-1693.
(2) Zhang, W.; Loebach, J . L.; Wilson, S. R.; J acobsen, E. N. J . Am.
Chem. Soc. 1990, 112, 2801-2803.
(3) (a) Gademann, K.; Chavez, D. E.; J acobsen, E. N. Angew. Chem.
2002, 114, 3185-3187; Angew. Chem., Int. Ed. 2002, 41, 3059-3061.
(b) Aikawa, K.; Irie, R.; Katsuki, T. Tetrahedron 2001, 57, 845-851.
(c) Schaus, S. E.; Brånalt, J .; J acobsen, E. N. J . Org. Chem. 1998, 63,
403-405.
Our initial synthetic approach toward DIANANE (3)
started from the known bis-oxime rac-57 of the racemic
diketone rac-48 (Scheme 2). We intended to reduce the
bis-oxime rac-5 in an endo-selective fashion directly to
(6) Berkessel, A.; Menche, D.; Sklorz, C. A.; Schro¨der, M.; Paterson,
I.; Angew. Chem. 2003, 115, 1062-1065; Angew. Chem., Int. Ed. 2003,
42, 1032-1035.
(4) J acobsen, E. N. Acc. Chem. Res. 2000, 33, 421-431.
(5) (a) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Chem. Commun.
2002, 919-927. (b) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.
Polyhedron 2000, 19, 537-539. (c) Bandini, M.; Cozzi, P. G.; Mel-
chiorre, P.; Umani-Ronchi, A. Angew. Chem. 1999, 111, 3558-3561;
Angew. Chem., Int. Ed. 1999, 38, 3357-3359.
(7) (a) Marchand, A. P.; Sharma, R.; Zope, U. R.; Watson, W. H.;
Kashyap, R. P. J . Org. Chem. 1993, 58, 759-762. (b) Olah, G. A.;
Ramaiah, P.; Prakash, G. K. S.; Gilardi, R. J . Org. Chem. 1993, 58,
763-765.
(8) Hawkins, R. T.; Hsu, R. S.; Wood, S. G. J . Org. Chem. 1978, 43,
4648-4650.
10.1021/jo035841d CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/08/2004
3050
J . Org. Chem. 2004, 69, 3050-3056

Enantioselective Synthesis of DIANANE
SCHEME 1
SCHEME 2a
racemic DIANANE (rac-3). Unfortunately, of the numer-
ous reduction conditions tried (catalytic hydrogenation
with a variety of heterogeneous catalysts, B- and Al-based
hydride reagents), only NaBH4 in combination with NiCl2
gave a reasonable yield of diamine of satisfactory purity
(Scheme 2). This reduction product proved to be a
mixture of endo/exo-isomers, the bis-endo-diamine rac-3
being the major component (ca. 70%).
a
Reaction conditions: (a) H2N-OH‚HCl (ref 7); (b) NaBH4,
NiCl2, 80%; (c) TosCl, NEt3, crystallization from MeOH; (d) Li,
NH3, -35 °C; (e) air; (f) prep. HPLC on Daicel Chiralpak AD; (g)
3,5-di-tert-butylsalicylic aldehyde, EtOH; (h) (1S)-(+)-camphor-
sulfonyl chloride, NEt3.
For the separation of the desired bis-endo-isomer,
conversion of the crude mixture to the bis-tosylates and
crystallization from methanol proved successful: Under
these conditions, the bis-endo sulfonamide rac-6 was
obtained in 35% yield. The separation of the enantiomers
6 and ent-6 was achieved by preparative HPLC on a
Daicel Chiralpak AD column (see the Supporting Infor-
mation for the X-ray crystal structure of the enantio-
merically pure bis-tosylate ent-6). Detosylation of the
sulfonamides 6 and ent-6 (or rac-6) proceeded smoothly
with lithium in liquid ammonia (85%, Scheme 2), afford-
ing the enantiomerically pure diamines 3 and ent-3,
respectively (or racemic DIANANE, rac-3, if racemic bis-
tosylate rac-6 was employed). The X-ray crystal structure
of DIANANE ent-3 is shown in Figure 1, top. For the
determination of the absolute configuration, DIANANE
3 was converted to the bis-(1S)-camphorsulfonamide 8
(Scheme 2). X-ray structural analysis of the crystalline
bis-sulfonamide 8 unambiguously established the con-
figuration of the DIANANE moiety in 8 to be (1R,4R)
(Scheme 2, see the Supporting Information for the X-ray
crystal structure of 8). We observed that DIANANE rac-3
slowly reacts with carbon dioxide when exposed to air,
affording the crystalline carbamic acid rac-7 (Scheme 2).
The constitution of the latter was again unambiguously
proven by X-ray crystallography (see the Supporting
Information for the X-ray crystal structure of the racemic
carbamic acid rac-7). In summary, the synthetic route
shown in Scheme 2 allows the preparation of enantio-
merically pure DIANANE 3 or ent-3, but the chromato-
graphic separation step limits the quantities of DI-
ANANE (3, ent-3) accessible by this method.
For the synthesis of larger amounts of both enanti-
omers of DIANANE, it was necessary to develop an
alternative route in which both enantiomers can be
generated selectively at an early stage. Scheme 3 sum-
marizes our optimized synthesis of enantiomerically pure
DIANANE 3. Norbornadiene (9) served as the starting
material. In the first step, norbornadiene (9) was sub-
jected to a palladium-catalyzed hydrosilylation with
trichlorosilane at -3 °C according to Hayashi et al.9 The
Pd catalyst is generated in situ from bis(allylpalladium
chloride) and the axially chiral phosphine ligand [(R)-
MOP], which is commercially available or can readily be
prepared according to literature procedures.10
The hydrosilylation is exothermic, and careful temper-
ature control is necessary to keep the proportion of the
undesired meso-isomer (11, Scheme 3) low. The hydrosi-
lylation product was subjected to a Tamao-Fleming
oxidation,9b,d,11 which afforded the bis-exo-diol 10 in up
(9) (a) Hayashi, T. Acta Chem. Scand. 1996, 50, 259-266. (b)
Hayashi, T.; Uozumi, Y. Pure Appl. Chem. 1992, 64, 1911-1916. (c)
Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185-
7188. (d) Uozumi, Y.; Hayashi, T. J . Am. Chem. Soc. 1991, 113, 9887-
9888.
(10) Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J . Org. Chem.
1993, 58, 1945-1948.
J . Org. Chem, Vol. 69, No. 9, 2004 3051

Berkessel et al.
SCHEME 3a
F IGURE 1. X-ray crystal structures of DIANANE hemihy-
drate (ent-3, top) and the DIANANE-salen ligand 2 (bottom).
to 58% yield (from norbornadiene). In this oxidation step,
the hydrosilylation product is first treated with methanol
and triethylamine to convert the chlorosilane into a
methyl silicate. Direct oxidation of the bistrichlorosilane
with 30% aqueous H2O2 in the presence of KF/KHCO3
according to the literature procedure9b,d led, in our hands,
to rather poor yields of the diol 10. Optimal yields of the
diol 10 (ca. 60%, vide supra) were achieved by using
urea-H2O2 as the oxidant. Usually, the diol 10 was
obtained with an enantiomeric excess of 99%, together
with ca. 4% of the meso-compound 11. Clearly, the
opposite enantiomer ent-10 can be synthesized in the
same way by using (S)-MOP as the chiral ligand.
Efforts to synthesize the endo,endo-diamine DIANANE
(3) from the exo,exo-diol 10 via nucleophilic substitution
to the endo,endo-bis-azide 13, followed by reduction, were
unsuccessful (Scheme 3, bottom). Utilizing a number of
variations of the Mitsunobu reaction (HN3 as the acid
component), the expected bisazide 13 could not be
prepared. The latter was obtained, however, when the
bistosylate 12 (see the Supporting Information for the
X-ray crystal structure of the enantiomerically pure
bistosylate 12) was treated with sodium azide in DMF
under harsh reaction conditions. The bisazide 13 was
formed in trace quantities, together with two unidentified
side products, and could not be isolated in pure form.
Therefore, this approach was abandoned. Although we
never experienced any problems in the course of the
above experiments, it should be noted that the azide 13
may be explosive due to its high nitrogen content (ca. 47%
a
Reaction conditions: (a) HSiCl3 (2.4 equiv), 0.05 mol %
[Pd(C3H5)Cl]2, 0.2 mol % (R)-MOP, -3 °C; (b) (1) MeOH, NEt3, (2)
KHF2, H2O2‚urea; (c) PCC, CH2Cl2, rt; (d) Bn-NH2 (2.5 equiv),
NaBH(OAc)3; (e) H2 (1 atom), Pearlman-catalyst; (f) 3,5-di-tert-
butylsalicuylic aldehyde, EtOH; (g) TosCl (2.2 equiv), pyridine, 4
°C.
by mass). For the thermal behavior of the isomeric bis-
exo-azide, see ref 12.
From the enantiomerically pure diketone 4,13a,e which
can be easily obtained by either Swern- (79% yield)13b or
PCC-oxidation (78% yield)13c,d of the bis-exo-diol 10, we
tried to reach the target molecule DIANANE (3) by
reductive amination. As the direct amination with NH4-
OAc following a literature procedure14 did not afford
detectable quantities of DIANANE (3), we attempted the
condensation with benzylamine. In this reaction, the bis-
(benzylimine) is readily formed. To exclusively obtain the
endo/endo-bis(benzylamine) 14 (Scheme 3), the in situ
reduction of the bisimine had to be endo-selective. This
was not the case, e.g., for the heterogeneous hydrogena-
tion employing palladium on charcoal as catalyst, which
(12) Marchand, A. P.; Sorokin, V. D.; Rajagopal, D.; Bott, S. G.
Synth. Commun. 1994, 24, 3141-3147.
(13) (a) Smith, B. T.; Wendt, J . A.; Aube´, J . Org. Lett. 2002, 4, 2577-
2579. (b) Omura, K.; Sharma, A. K.; Swern, D. J . Org. Chem. 1976,
41, 957-962. (c) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975,
2647-2650. (d) Piancatelli, G.; Scettri, A.; D’Auria, M. Synthesis 1982,
245-258. (e) The enantiomerically pure diketone has recently been
used as a building block for chiral ligands. See: Hayashi, T.; Ueyama,
K.; Tokunaga, N.; Yoshida, K. J . Am. Chem. Soc. 2003, 125, 11508-
11509.
(11) (a) Fleming, I. Chemtracts-Org. Chem. 1996, 9, 1-64. (b)
Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983,
2, 1694-1696. (c) J ones, G. R.; Landais, Y. Tetrahedron 1996, 52,
7599-7662.
(14) Borch, R. F.; Bernstein, M. D.; Dupont Durst, H. J . Am. Chem.
Soc. 1971, 93, 2897-2904.
3052 J . Org. Chem., Vol. 69, No. 9, 2004

Enantioselective Synthesis of DIANANE
yielded a ca. 1:1:1 mixture of the endo- and exo-isomers.
The problem was solved, however, by using triacetoxy-
borohydride as the reducing agent,15 which is known to
stereoselectively produce endo-reduction products for a
number of norbornane-like substrates.15b Bisimine forma-
tion of the diketone 4 and subsequent endo-selective
reduction could be carried out in one step, providing the
bisbenzylamine 14 in 98% yield and with an endo-
selectivity of 97% (3% of endo-exo-bisbenzylamine were
formed). Debenzylation of 14 by hydrogenolysis with
Pearlman’s catalyst16 finally afforded the target molecule
DIANANE (3) quantitatively. The use of this particular
catalyst was crucial because the debenzylation step did
not work in a satisfactory manner with standard com-
mercially available palladium-on-charcoal catalysts. How-
ever, two palladium-on-charcoal catalysts optimized for
hydrogenolytic debenzylation worked just as well as the
Pearlman catalyst.17 Enantiomerically pure DIANANE
ent-3 was characterized by X-ray crystallography (in the
form of its hemihydrate), and the result is shown in
Figure 1, top. As mentioned before, DIANANE 3 tends
to form the carbamate 7 upon prolonged contact with air.
In practice, we found it convenient to store DIANANE 3
in the bisbenzyl-protected form 14.
Finally, DIANANE (3) was condensed with 2 equiv of
3,5-bis-tert-butylsalicylic aldehyde to afford the DIANANE-
salen ligand 2 (Schemes 1 and 3). In the course of the
crystallization, the few percent of impurities (meso-isomer
formed in the hydrosilylation of norbornadiene; exo-amine
formed in the reductive amination step) are lost, and the
crystalline Schiff base ligand is g99% pure (HPLC,
NMR). The Schiff base ligand 2 was subjected to X-ray
structural analysis as well, and the result is shown in
Figure 1, bottom. In particular the latter crystal structure
nicely reveals that the N,N distance is significantly larger
in DIANANE-Schiff base ligands (3.59 Å in 2) than in
those ligands derived from trans-1,2-diaminocyclohexane,
such as 1 (2.91 Å, Scheme 1).18
Con clu sion
In this article, we describe a practical synthesis for
both enantiomers 3 and ent-3 of DIANANE, starting from
readily available norbornadiene (9). With large quantities
of DIANANE available in both enantiomeric forms, it is
expected that this novel C2-symmetric diamine will find
many applications in asymmetric synthesis and catalysis,
e.g., in the design of novel salen-type ligands such as 2.
Exp er im en ta l Section
Gen er a l Meth od s. HSiCl3 was distilled from quinoline.
Norbornadiene was passed through neutral alumina (activity
I) and subsequently distilled. NEt3 and pyridine were distilled
from CaH2. Other commercially available reagents were used
as purchased. Racemic bicyclo[2.2.1]heptane-2,5-dione-dioxime
(15) (a) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G.
Tetrahedron Lett. 1990, 31, 5595-5598. (b) McGill, J . M.; LaBell, E.
S.; Williams, M. Tetrahedron Lett. 1996, 37, 3977-3980.
(16) Bernotas, R. C.; Cube, R. V. Synth. Commun. 1990, 20, 1209-
1212.
(17) Catalysts were received from ENGELHARD ITALIANA SPA:
(a) Sample code: 43958, 10% Pd on carbon powder, moisture content:
54.66% and (b) Sample code: 43959, 5% Pd on carbon powder, moisture
content: 55.00%.
(18) Yoon, J . W.; Yoon, T.-S.; Shin, W. Acta Crystallogr. Sect. C:
Cryst. Struct. Commun. 1997, 53, 1685-1687.
J . Org. Chem, Vol. 69, No. 9, 2004 3053

Berkessel et al.
was prepared according to a literature method.7 Axially chiral
MOP ligands were prepared according to a literature method.10
Debenzylation catalysts17 were kindly provided by Engelhard
Inc., NJ . All solvents were distilled prior to use. Dry solvents
were freshly distilled under argon from either CaH2 or Na/
benzophenone. Melting points were determined in an open
capillary and are uncorrected.
g, 3.00 mmol), and NH3 (ca. 150 mL) was condensed at -78
°C with magnetical stirring. The mixture was allowed to warm
to -33 °C and solid Li (220 mg, 31.7 mmol) was added
gradually. The suspension turned blue and the reaction was
quenched after 80 min by dropwise addition of brine (0.5 mL).
NH3 was evaporated and the residue was diluted with H2O
(10 mL) and concentrated in vacuo until the condensation of
water was observed. The residue was diluted with H2O (10
mL), acidified with concentrated HCl, and extracted with CH2-
Cl2. The aqueous phase was concentrated in vacuo until a
white precipitate formed. 25% aq NaOH (15 mL) was added
and the aqueous solution was extracted with CH2Cl2 in a
liquid/liquid extractor for 42 h. Concentration of the organic
phase yielded 321 mg (85%) of DIANANE rac-3 as a colorless
oil or semisolid. Bp 110 °C, 12 mbar. IR (film) 3359, 3282, 2941,
en d o,en d o-2,5-Dia m in ob icyclo[2.2.1]h ep t a n e (m ix-3,
m ixtu r e of ster eoisom er s). Bicyclo[2.2.1]heptane-2,5-dione-
dioxime rac-5 (9.25 g, 60.0 mmol) in dry MeOH (100 mL) was
added to a suspension of anhydrous NiCl2 (15.6 g, 120 mmol)
in dry MeOH (400 mL) with stirring. The mixture was cooled
to -35 °C and NaBH4 (45.0 g, 1.20 mol) was added over a
period of 1 h in small portions to maintain a temperature
beetween -20 and -35 °C. After completion of the addition,
the mixture was allowed to warm to rt and concentrated in
vacuo. The dark brown residue was extracted with 15% aq
NaOH (100 mL) and CH2Cl2 in a liquid/liquid extractor. After
2-3 d the yellow organic suspension was filtered and concen-
trated in vacuo. Distillation of the residue at 13 mbar, 130
°C, yielded 5.5 g of a colorless oil that solidified upon cooling.
This material was shown by GC to be ca. 80% pure and was
used in the next step without further purification. GC/MS
(capillary column HP-5MS 0.25 mm × 30 m, cross-linked 5%
PH ME Siloxane 0.25 µm; He, 1 mL/min; 80 °C, 10 min, 5 °C/
min, 100 °C, 10 min, 20 °C/min, 260 °C, 10 min) τR 9.8-9.9
min (3 isomers with identical m/z) 126 M+, 125 (M - H)+, 109
(M - NH3)+, 94 (M n -2 NH2)+, 82 (C6H10)+, 68 (C5H8)+.
en d o,en d o-2,5-Bis[4(4-m et h ylp h en yl)su lfon yla m id o]-
bicyclo[2.2.1]h ep ta n e (r a c-6). To a solution of the crude 2,5-
diaminobicyclo[2.2.1]heptane mix-3 (9.3 g, 74 mmol) and NEt3
(22.0 mL, 158 mmol) in dry CH2Cl2 (300 mL) at -78 °C was
added TosCl (28.6 g, 150 mmol) in small portions with vigorous
stirring. The temperature was maintained for 3 h, then the
suspension was allowed to warm to rt overnight. The yellow
to red brown suspension was washed with 3 × 80 mL of 2 M
aq HCl, 2 × 80 mL of H2O, and 80 mL of brine and dried over
MgSO4. After evaporation of the solvent in vacuo, the residue
was extracted with a mixture of Et2O and n-pentane (1/1, v/v)
several times. The crude product was crystallized from MeOH
and treated with activated charcoal in boiling acetic acid.
Crystallization from acetic acid and subsequently from MeOH
gave 11.1 g (35%) of colorless crystals of rac-6. Mp 188-190
°C. IR (CsI) 3260, 2964, 1302-1337, 1162, 1092, 813 cm-1. 1H
NMR (300 MHz, CDCl3) δ 7.70 (d, J ) 8.4 Hz, 4H), 7.23 (d, J
) 8.4 Hz, 4H), 5.70 (br d, J ) 6.9 Hz, 2H), 3.42-3.53 (m, 2H),
2.39 (s, 6H), 2.05-2.10 (m, 2H), 1.50-1.63 (m, 2H), 1.28 (br s,
2H), 1.18-1.26 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 143.3
(s), 137.4 (s), 129.6 (d), 127.1 (d), 54.2 (d), 41.0 (d), 36.9 (t),
28.4 (t), 21.5 (q). MS (FAB) 457 (M + Na)+, 435 (M + H)+, 279
(M + H - Tos - H2)+, 264 (M + H - TosNH2)+, 262 (M + H
- TosNH2 - H2)+. HRMS (ESI) calcd for C21H26N2O4S2 + H+
435.141, found 435.141. Anal. Calcd for C21H26N2O4S2: C,
58.04; H, 6.03; N, 6.45. Found: C, 57.93; H, 5.93; N, 6.41.
2871, 1604, 1452, 887 cm-1 1H NMR (300 MHz, CDCl3) δ
.
3.26-3.30 (m, 2H), 1.95 (br s, 2H), 1.60-1.71 (m, 2H), 1.40
(centered multiplet, 2H), 1.17-1.24 (m, 2H). 13C NMR (75
MHz, CDCl3) δ 52.7 (d), 43.8 (d), 38.9 (t), 30.2 (t). HRMS (EI)
calcd for C7H14N2 126.116, found 126.116.
en d o,en d o-(5-Am in obicyclo[2.2.1]h ep ta n -2-yl)ca r ba m -
ic Acid (r a c-7). When a solution of DIANANE rac-3 in CH2-
Cl2/MeOH was allowed to stand open to air, off-white crystals
of carbamic acid rac-7 precipitated gradually, which were
subjected to X-ray structural analysis.
(1S,2S,4S,5S)-2,5-Dia m in ob icylo[2.2.1]h ep t a n e (DIA-
NANE, (S)-3) by Detosyla tion of (S)-6. The bissulfonamide
(S)-6 was subjected to the detosylation procedure described
above for rac-6. As an alternative to the liquid/liquid extraction
of the acidified residues from the first extraction, this crude
material was treated with a large excess of solid KOH and
extracted with CH2Cl2 in a Soxhlett extractor. Evaporation of
the solvent in vacuo yielded 107 mg (96%) of DIANANE (S)-3
as a colorless oil or semisolid.
(1S,1′S,4R,4′R)-N,N′-(1R,2R,4R,5R)-Bicyclo[2.2.1]h eptan -
2,5-d iylb is[7,7-d im et h yl-2-oxob icyclo[2.2.1]h ep t a n e-1-
m eth a n esu lfon a m id e] [(R)-8]. A solution of DIANANE (R)-3
(35 mg, 280 µmol) and NEt3 (77 µL, 560 µmol) in dry CH2Cl2
(10 mL) was cooled to -78 °C and (1S)-(+)-camphorsulfonyl
chloride (147 mg, 590 µmol) was added. After 1 h, the
suspension was allowed to warm to rt and stirred overnight.
The reaction mixture was washed with H2O, 2 M aq HCl (2×),
and brine (2×) and dried over MgSO4. A small amount of
MeOH was added and the mixture was evaporated until a
colorless pecipitation occurred. This material was filtered off
and recrystallized twice from MeOH to yield 10 mg (7%) of
the product (R)-8 as colorless crystals, suitable for X-ray
structural analyis. Mp 204-205 °C. IR (CsI) 3338, 2961, 1742,
1458, 1323, 1142, 1045, 910 cm-1. 1H NMR (300 MHz, CDCl3)
δ 5.68-5.71 (m, 2H), 3.80-3.88 (m, 2H), 3.44 (d, J ) 15 Hz,
2H), 2.91 (d, J ) 15 Hz, 2H), ca. 2.44 (centered multiplet, 2H),
ca. 2.44 (centered multiplet, 2H), 2.19-2.27 (m, 2H), 2.09-
2.12 (m, 2H), ca. 2.01 (centered multiplet, 2H), ca. 2.00
(centered multiplet, 2H), ca. 1.93 (centered multiplet, 2H), ca.
1.92 (centered multiplet, 2H), 1.51 (br s, 2H), ca. 1.47 (centered
multiplet, 2H), ca. 1.44 (centered multiplet, 2H), 1.00 (s, 6H),
0.91 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 217.7 (s), 59.2 (s),
54.7 (d), 50.3 (t), 48.9 (s), 43.1 (t), 42.7 (d), 42.3 (d), 36.9 (t),
28.6 (t), 27.0 (t), 26.5 (t), 19.9 (q), 19.5 (q). HRMS (ESI) calcd
for C27H42N2O6S2 + Na+ 577.237, found 577.238.
(1R,2R,4R,5R)- a n d (1S,2S,4S,5S)-2,5-Bis[(4-m eth ylp h e-
n yl)su lfon yla m id o]bicyclo[2.2.1]h ep t a n e [(R)- a n d (S)-
6]. The two enantiomers of sulfonamide rac-6 were separated
by chiral preparative HPLC on a Daicel Chiralpak AD column
(50 mm i.d. × 500 mm L) with n-hexane/i-PrOH (60/40, v/v),
P 12 bar, flow 80 mL/min, τR 24.0-33.0 min [(R)-6], 46.5-
62.5 min [(S)-6]. A 100-200 mg sample of rac-6 in 10 mL of
hot EtOH were injected per run. The fractions were concen-
trated in vacuo and the residue was crystallized from MeOH.
2,2′-[en d o,en d o-Bicyclo[2.2.1]h ep ta n -2,5-d iylbis(n itr ilo-
m eth ylid in e)]bis-4,6-d i-ter t-bu tylp h en ol (r a c-2). 2,5-Di-
tert-butylsalicylaldehyde (1.13 g, 4.83 mmol) was dissolved in
dry EtOH (40 mL) and added to a solution of racemic
DIANANE rac-3 (290 mg, 2.30 mmol) in dry EtOH (20 mL).
After being stirred at rt for 30 min, the solution was heated
to reflux and then stirred at rt overnight. The yellow needles
formed were filtered off, washed with MeOH, and recrystal-
lized from MeOH/CH2Cl2 to yield 1.11 g (86%) of the product
rac-2 as bright yellow needles. Mp 286-287 °C. IR (CsI) 2955,
(R)-6: Mp 175-176 °C. [R]20 +12.3 (CHCl3, c 1.00). CD
D
(EtOH) ∆ꢀ205 +3.5, ∆ꢀ223 +0.2, ∆ꢀ233 +1.1, ∆ꢀ248 -0.3. Anal.
Calcd for C21H26N2O4S2: C, 58.04; H, 6.03; N, 6.45. Found: C,
58.11; H, 6.13; N, 6.50. (S)-6: Mp 174-176 °C. [R]20 -12.3
D
(CHCl3, c 1.00). CD (EtOH) ∆ꢀ205 -4.0, ∆ꢀ223 -0.4, ∆ꢀ233 -1.8,
∆ꢀ248 +0.1. Anal. Calcd for C21H26N2O4S2: C, 58.04; H, 6.03;
N, 6.45. Found: C, 58.06; H, 6.02; N, 6.48.
en do,en do-2,5-Diam in obicylo[2.2.1]h eptan e (DIANANE)
(r a c-3). A flask was charged with the sulfonamide rac-6 (1.31
2906, 2873, 1628, 1468, 1439, 1272, 1250, 1069, 880, 772 cm-1
1H NMR (300 MHz, CDCl3) δ 13.69 (br s, 2H), 8.43 (s, 2H),
.
3054 J . Org. Chem., Vol. 69, No. 9, 2004

Enantioselective Synthesis of DIANANE
7.35 (d, J ) 2.3 Hz, 1H), 7.08 (d, J ) 2.4 Hz, 2H), 3.80-3.84
(m, 2H), 2.39 (br t, J ) 4.0 Hz, 2H), 2.04 (dd, J ) 13.5, 4.5,
2H), 1.85-1.94 (m, 2H), 1.71 (s, 2H), 1.41 (s, 18H), 1.30 (s,
18H). 13C NMR (75.5 MHz, CDCl3) δ 165.0 (d), 158.1 (s), 139.1
(s), 136.7 (s), 126.5 (d), 125.7 (d), 118.0 (s), 70.4 (d), 44.4 (d),
38.2 (t), 35.1 (s), 34.1 (s), 31.5 (q), 30.2 (t), 29.4 (q). MS (FAB)
571 (M + 12)+, 560 (M + H)+, 559 (M)+, 558 (M - H)+, 543 (M
+ 2H - H2O)+, 541 (M - H2O)+, 503 (M - t-Bu)+. Anal. Calcd
for C37H54N2O2: C, 79.52; H, 9.74; N, 5.01. Found: C, 79.48;
H, 9.74; N, 4.92.
allowed to stand at ca. 2 °C for 2 d. The reaction mixture was
filtered, and the filtrate was concentrated in vacuo at rt. The
residue was treated with a mixture of 2 M aq HCl (5 mL) and
extracted with 3 × 5 mL of CH2Cl2. The combined organic
phases were washed with 2 × 5 mL of 2 M aq HCl and 5 mL
of sat. NaHCO3 and dried over MgSO4. After evaporation of
the solvent in vacuo, the residue was recrystallized twice from
MeOH to yield 430 mg (99%) of colorless crystals of the tosylate
(R)-12. Mp 126-129 °C. IR (CsI) 2976, 1598, 1496, 1442, 1355,
1307, 1175, 1098, 1052, 824 cm-1. 1H NMR (300 MHz, CDCl3)
δ 7.72 (d, J ) 8.4 Hz, 4H), 7.31 (d, J ) 8.1 Hz, 4H), 4.27 (dd,
J ) 6.6, 1.8 Hz, 2H), 2.42 (s, 6H), 2.38 (d, J ) 5.7 Hz, 2H),
1.59 (s, 2H), 1.51-1.54 (m, 2H), 1.40-1.48 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 144.7 (s), 134.0 (s), 129.8 (d), 127.6 (d), 82.4
2,2′-[(1S,2S,4S,5S)-Bicyclo[2.2.1]h ep ta n e-2,5-d iylbis(n i-
tr ilom eth ylid in e)]bis-4,6-d i-ter t-bu tylp h en ol [(S)-2]. 2,5-
Di-tert-butylsalicylaldehyde (1.41 g, 6.00 mmol) was dissolved
in hot EtOH (40 mL) and added to a solution of DIANANE
(S)-3 (379 mg, 3.00 mmol) in EtOH (20 mL). After being stirred
at rt for 2 h, the mixture was stored at 4 °C overnight. The
yellow solid was filtered off and recrystallized from EtOH/CH2-
Cl2 to yield 1.36 g (81%) bright yellow needles of the enan-
(d), 41.0 (q), 33.8 (t), 31.6 (t), 21.6 (d). [R]20 +4.0 (CHCl3, c
D
1.00). Anal. Calcd for C21H24O6S2: C, 57.78; H, 5.54. Found:
C, 57.91; H, 5.49.
(1S,4S)-Bicyclo[2.2.1]h ep ta n e-2,5-d ion e [(S)-4]. Diol (S)-
10 (5.13 g, 40.0 mmol) and powdered 3 Å molecular sieves (25.0
g) were suspended in CH2Cl2 (250 mL). PCC (43.1 g, 200 mmol,
5.00 equiv) was added slowly and the resulting mixture was
stirred at rt overnight. Et2O (250 mL) was added with vigorous
stirring, and stirring was continued for 30 min. The mixture
was then allowed to stand for 2 h. The liquid was filtered
through 50 g of Florisil (80-150 µm). The black residue was
extracted with 4 × 50.0 mL of CH2Cl2/Et2O (1/1, v/v) in an
ultrasonic bath. The combined extracts were also filtered
through the Florisil pad. Evaporation of the combined solutions
yielded 3.78 g (76%) of the diketone (S)-4 and the meso
byproduct as a white solid that was used without further
purification (Kugelrohr distillation is possible at 100 °C, 0.12
mbar). The analytical data refer to purified material containing
2.5% of the meso byproduct (by GC). GC (capillary column
WCOT Fused Silica 0.25 mm × 25 m, CP-Chirasil-Dex CB 0.25
µm; He, 1 mL/min; 100 °C, 30 min) τR 18.7 min [(R)-4], 19.5
min [(S)-4], 24.6 min (meso-diketone). Mp 115-133 °C. IR (CsI)
tiopure salen (S)-2. Mp 249-250 °C. [R]20 -343.7 (CHCl3, c
D
1.00). CD (CHCl3) ∆ꢀ242 +1.6, ∆ꢀ254 +7.5, ∆ꢀ271 -31.8, ∆ꢀ303
-2.0, ∆ꢀ341 -15.5. Anal. Calcd for C37H54N2O2: C, 79.52; H,
9.74; N, 5.01. Found: C, 79.34; H, 9.62; N, 5.05. (R)-2: Mp
249-250 °C. [R]20 +343.7 (CHCl3, c 1.00). CD (CHCl3) ∆ꢀ242
D
-1.9, ∆ꢀ255 -7.5, ∆ꢀ271 +31.9, ∆ꢀ303 +1.7, ∆ꢀ341 +15.0. Anal.
Calcd for C37H54N2O2: C, 79.52; H, 9.74; N, 5.01. Found: C,
79.41; H, 9.61; N, 5.06.
(1S,2R,4S,5R)-2,5-Dih yd r oxybicyclo[2.2.1]h ep ta n e [(S)-
10]. A solution of [Pd(C3H5)Cl]2 (14.6 mg, 40.0 µmol) and (S)-
MOP (78.7 mg, 168 µmol) in benzene (2 mL) was placed into
a double-jacketed 50-mL Schlenk flask under Ar. HSiCl3 (19.9
mL, 197 mmol) was added, and the solution was cooled to -3
°C. Norbornadiene (8.34 mL, 82.0 mmol) was added slowly
with magnetic stirring. The reaction mixture was stirred at
-3 °C for ca. 3 d, until it turned into a pale yellowish solid.
The solvent and excess silane were removed in vacuo at rt.
The residue was dissolved in 50.0 mL of dry Et2O under Ar
and cooled to 0 °C. A mixture of dry MeOH (59.9 mL, 1.48
mol), dry NEt3 (80.0 mL, 574 mmol), and dry Et2O (50.0 mL)
was added dropwise. After the solution was stirred at rt
overnight, the precipitated salts were filtered off and washed
with small quantities of Et2O. The combined filtrates were
concentrated in vacuo to yield a yellowish solid. To this solid
was added KHF2 (32.0 g, 410 mmol), THF (80 mL), MeOH (80
mL), and H2O2‚urea (57.8 g, 615 mmol). The resulting white
suspension was stirred overnight at 60 °C. After addition of a
catalytic amount of MnO2, stirring was continued at rt for 4
h. The solids were filtered off with suction, and the filter cake
was washed with MeOH. The combined filtrates were concen-
trated in vacuo. The residue was dissolved in 100 mL of H2O
and extracted with 5 × 100 mL of a CHCl3/i-PrOH mixture
(3/1, v/v). The combined organic phases were dried over MgSO4
and evaporated. The remaining white solid was recrystallized
from CHCl3/n-hexane to give 5.17 g (58% based on norborna-
diene) of the diol (S)-10 (99%ee) as thin white crystals,
containing ca. 4% of the meso-diol (by GC). GC (capillary
column WCOT Fused Silica 0.25 mm × 25 m, CP-Chirasil-
Dex CB 0.25 µm; He, 1 mL/min; 125 °C, 40 min) τR 27.8 min
[(S)-10], 28.5 min [(R)-10], 36.4 min (11). Mp 158 °C. IR (CsI)
2966, 1755, 1737, 1409, 964, 712 cm-1 1H NMR (500 MHz,
.
CHCl3) δ 2.97 (td, J ) 6.5, 1.5 Hz, 2H), 2.34-2.39 (m, 2H),
2.13 (td, J ) 18.0, 2.0 Hz, 2H), 2.08-2.09 (m, 2H). 13C NMR
(125 MHz, CHCl3) δ 212.3 (s), 48.5 (d), 38.9 (t), 36.3 (t). [R]20
D
-4.3 (CHCl3, c 1.00). Anal. Calcd for C7H8O2: C, 67.73; H, 6.50.
Found: C, 67.48; H, 6.42. (R)-4: Mp 118-130 °C. [R]20 +4.2
D
(CHCl3, c 1.00). Anal. Calcd for C7H8O2: C, 67.73; H, 6.50.
Found: C, 67.74; H, 6.50.
(1S,2S,4S,5S)-2,5-Dib en zyla m in obicylo[2.2.1]h ep t a n e
[(S)-14]. Glacial acetic acid (12.0 mL, 208 mmol) was added
dropwise to a suspension of NaBH4 (2.45 g, 65.0 mmol) in dry
CH2Cl2 (200 mL) and the resulting mixture was heated to
reflux for 30 min. A mixture of diketone (S)-4 (3.23 g, 26.0
mmol) in dry CH2Cl2 (50.0 mL) and BnNH2 (7.09 mL, 65.0
mmol) was added dropwise at rt. After being stirred for 6 h
the reaction was quenched by the addition of 5% aq NaOH
(51.8 mL, 65.0 mmol). The mixture was extracted with 3 ×
150 mL of 2 M aq HCl and the combined aqueous phases were
basified by the addition of solid NaOH to pH 9. The resulting
suspension was extracted with 3 × 150 mL of Et2O and the
combined organic phases were dried over MgSO4. After
concentration in vacuo a colorless oil remained, which solidified
slowly. This material was purified by Kugelrohr distillation
at 150 °C, 3 × 10-3 mbar, to yield 7.79 g (98%) of the product
(S)-14 as a colorless solid. Mp 48-49 °C. IR (CsI) 3228, 3029,
2955, 2870, 2797, 1648, 1560, 1496, 1456, 1345, 1143, 1103,
1030, 995, 729, 696 cm-1. 1H NMR (300 MHz, CHCl3) δ 7.14-
7.27 (m, 10H), 3.60 (dd, J ) 12.9, 9.0 Hz, 4H), 3.06 (td, J )
10.2, 3.9 Hz, 2H), 2.21 (br t, J ) 4.2 Hz, 2H), 1.60-1.69 (m,
4H), 1.40 (s, 2H), 1.31 (dd, J ) 12.6, 4.2 Hz, 2H). 13C NMR (75
MHz, CHCl3) δ 140.6 (s), 128.3 (d), 128.2 (d), 126.8 (d), 58.4
1
3301, 2966, 1458, 1448, 1351, 1091, 743 cm-1. H NMR (500
MHz, py-d6) δ 6.00 (s, 2H), 3.92 (dd, J ) 5.0, 3.5 Hz, 2H), 2.41-
2.42 (m, 2H), 2.01 (s, 2H), 1.57-1.59 (m, 4H). 13C NMR (125
MHz, py-d6) δ 73.5 (d), 44.2 (d), 37.7 (t), 31.2 (t). HRMS (EI)
calcd for C7H14N2-H2O 110.073, found 110.073.
CAUTION: In some cases, we experienced an autocatalytic
exothermic process, resulting in uncontrolled reaction and
higher proportions of the meso-isomer. Addition of small
amounts of quinoline to the reaction mixture seemed to
overcome this problem by quenching any free HCl.
(1R,2S,4R,5S)-2,5-Bis[(4-m et h ylp h en yl)su lfon yloxy]-
bicyclo[2.2.1]h ep ta n e [(R)-12]. The diol (R)-10 (128 mg, 1.00
mmol) was dissolved in pyridine (2.0 mL) and cooled to 2 °C.
TosCl (419 mg, 2.20 mmol) was added and the mixture was
(d), 52.5 (t), 39.8 (d), 38.2 (t), 29.2 (t). [R]20 -15.7 (CHCl3, c
D
1.00). Anal. Calcd for C21H26N2: C, 82.31; H, 8.55; N, 9.14.
Found: C, 82.39; H, 8.57; N, 9.13. (R)-14: Mp 43-49 °C. [R]20
D
+14.5 (CHCl3, c 1.00). Anal. Calcd for C21H26N2: C, 82.31; H,
8.55; N, 9.14. Found: C, 81.18; H, 8.52; N, 9.17.
J . Org. Chem, Vol. 69, No. 9, 2004 3055

Berkessel et al.
(1S,2S,4S,5S)-2,5-Dia m in ob icylo[2.2.1]h ep t a n e DIA-
NANE [(S)-3] by Hyd r ogen olysis of (S)-14. A suspension
of the bisbenzylamine (S)-14 (1.53 g, 5.00 mmol) and Pd(OH)2
(15-20% on activated charcoal with 50% H2O, 1.41 g) in EtOH
(50 mL) was stirred under H2 atmospheric pressure (balloon).
After the solution was stirred for 24 h, debenzylation was
found to be complete by GC/MS. The catalyst was filtered off
and the solution was concentrated in vacuo to afford 625 mg
(99%) of DIANANE (S)-3 as a colorless oil that crystallized
upon cooling to 4 °C to yield colorless needles. Mp ca. 20 °C.
GC/MS (capillary column HP-5MS 0.25 mm × 30 m, cross-
linked 5% PH ME Siloxane 0.25 µm; He, 1 mL/min; 100 °C, 5
min, 20 °C/min, 200 °C, 15 min, 20 °C/min, 280 °C, 10 min) τR
5.1 min (3: 126 (M+), 109 (M - NH3)+, 94 (M - 2 NH2)+, 82
(C6H10)+, 68 (C5H8)+), 12.4 min (mono-N-Bn-3: 216 (M+, 172
(C12H14N)+, 132 (C9H10N)+, 125 (M - C7H7)+, 106 (C7H8N)+,
91 (C7H7)+), 28.5 min (14: 306 (M+, 215 (M - C7H7)+, 201 (M
- C7H7N), 91 (C7H7)+). GC (capillary column CP-Chirasil-Dex
CB 0.25 mm × 25 m, WCOT Fused Silica 0.25 µm; He, 1 mL/
min; 150 °C, 40 min) τR 22.7 min (bis-TFA-amide of (S)-3), 23.3
min (bis-TFA-amide of (R)-3), 24.6 min (bis-TFA-amide of meso
compound). IR (film) 3353, 3276, 2944, 2872, 1652, 1594, 1456,
1386, 898 cm-1. 1H NMR (300 MHz, MeOH-d4) δ 3.22 (td, J )
3.3, 1.5 Hz, 2H), 1.99 (br t, J ) 4.5 Hz, 2H), 1.64-1.75 (m,
2H), 1.42 (dd, J ) 1.5, 1.5 Hz, 2H), 1.10-1.17 (m, 2H). 13C
NMR (75 MHz, MeOH-d4) δ 54.1 (d), 44.8 (d), 39.5 (t), 30.1 (t).
P u r ity Deter m in a tion of 2,2′-[(1S,2S,4S,5S)-Bicyclo-
[2.2.1]h ep ta n e-2,5-d iylbis(n itr ilom eth ylid in e)]bis-4,6-d i-
ter t-bu tylp h en ol [(S)-2] Obta in ed fr om th e Above Am in e
[(S)-3]. The enantiopure salen (S)-2 was prepared from
DIANANE (S)-3 obtained by debenzylation of (S)-14 according
to the above procedure. In the recrystallized product, the
corresponding meso-salen could not be detected by NMR.
HPLC analysis revealed that less than 0.2% of the meso-salen
is present in the recrystallized salen (S)-2. HPLC (MN EC
250/4 Nucleodur 100-5 C18 EC; CH3CN, 0.4 mL/min; 60 min;
UV, 220-400 nm) τR 38.2 min (2), 49.5 min (meso-salen). UV
(HPLC) 230, 266, 332 nm (for both peaks). Mp 250 °C. [R]20
D
-343.7 (CHCl3, c 1.00). Anal. Calcd for C37H54N2O2: C, 79.52;
H, 9.74; N, 5.01. Found: C, 79.34; H, 9.91; N, 5.05. (R)-2: Mp
250 °C. [R]20 +344.7 (CHCl3, c 1.00). Anal. Calcd for
D
C
37H54N2O2: C, 79.52; H, 9.74; N, 5.01. Found: C, 79.34; H,
9.55; N, 5.04.
Ack n ow led gm en t. This work was supported by the
European Community (Research Training Network
“Combinatorial Catalysis” HPRN-CT-2000-00014) and
by the Fonds der Chemischen Industrie. M.S. thanks
the Fonds der Chemischen Industrie for a doctoral
fellowship. We furthermore wish to thank Profs. Tamio
Hayashi (Kyoto University), Ian Fleming (Cambridge
University), and J effrey Aube´ (University of Kansas) for
their help and advice concerning the asymmetric hy-
drosilylation of norbornadiene and the Tamao-Fleming-
oxidation protocol.
Su p p or tin g In for m a tion Ava ila ble: X-ray analyses of
compounds (R)-2, rac-2, (S)-3, (S)-6, rac-6, rac-7, (R)-8, and
(R)-12. This material is available free of charge via the Internet
at http://pubs.acs.org. X-ray crystallographic data for com-
pounds (R)-2, rac-2, (S)-3, (S)-6, rac-6, rac-7, (R)-8, and (R)-
12 were collected as summarized in the table. The table also
states the depository numbers at the Cambridge Crystal-
lographic Data Centre. From there, the full set of data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retriev-
ing.html (or from the Cambridge Crystallographic Data Cen-
tre, 12 Union Road, Cambridge CB21EZ, UK; fax (+44) 1223-
336-033; or deposit@ccdc.cam.ac.uk).
J O035841D
3056 J . Org. Chem., Vol. 69, No. 9, 2004