Stereoselective Synthesis of (1R,2S,3B)-Camphordiamine

Full text of DOI:10.1021/jo0002137

J . Org. Chem. 2000, 65, 4753-4755
4753
Ster eoselective Syn th esis of
1R,2S,3R)-Ca m p h or d ia m in e
(
Carl A. Busacca,* Scot Campbell, Yong Dong,
Danja Grossbach, Mike Ridges, Lana Smith, and
Earl Spinelli
Departments of Chemical Development and Analytical
Sciences, Boehringer Ingelheim Pharmaceuticals, Inc.,
F igu r e 1.
9
00 Ridgebury Road,
Ridgefield, Connecticut 06877-0368
stereoselective synthesis of exo-camphordiamine with full
characterization is the subject of this paper.
cbusacca@rdg.boehringer-ingelheim.com
Received February 15, 2000
Resu lts a n d Discu ssion
Several investigators have developed diamine synthe-
ses from 1,2-diketones15 via reduction of the intermediate
bisimines. Notable among these was the chirality transfer
methodology of Nantz in which (S,S)-1,2-diphenyleth-
ylenediamine was condensed with diketones and then
In tr od u ction
Chiral diamines1a form the backbone of a large number
of ligands for asymmetric catalysis including those used
15b
for epoxidations, aldol condensations,2 Diels-Alder
1
b
3
reduced with NaBH CN to afford intermediate diamines
3
4
cyclizations, nucleophilic additions to carbonyls, dihy-
with good diastereomeric excess. We reasoned that the
camphor skeleton should enforce reduction from the
5
6
droxylations of alkenes, conjugate additions, protona-
7
8
9
16
tions, cyclopropanations, and aziridinations. Diamines
R-face, however, and that a chiral diamine might not
1
0
are also found in a number of natural products and
be necessary. We thus condensed (R)-camphorquinone 2
with meso-1,2-diphenylethylenediamine 3. Of the two
possible diastereomeric bisimines 4 and 5, only one could
be isolated. This was tentatively assigned as species 4,
yet it also proved to be unstable on storage. Under the
reaction conditions, 5 is not stable, leading to large
amounts of benzaldehyde, 7, and benzaldehyde conden-
sation products 8 and 9. We propose that 5 undergoes a
human pharmaceuticals.11 Several diamine-metal com-
1
2
plexes have important chemotherapeutic roles as well.
A structurally unique chiral diamine for ligand construc-
tion would be exo-camphordiamine 1 (as shown in Figure
1
) due to the large degree of steric crowding enforced by
the bridging 7-gem-dimethyl group.
Several syntheses of isomeric camphordiamines have
been reported,1
3-14
yet in no case was the stereochemistry
17
facile electrocyclic ring opening to 6, which is then
of the various products ever determined. The first true
readily hydrolyzed on workup and chromatography, as
shown in Scheme 1.
(
1) For an outstanding review, see: (a) Le Gall, T.; Mioskowski, C.;
Condensation of (R)-diketone 2 with (S,S)-1,2-diphe-
nylethylenediamine 10, however, led cleanly to bisimine
Lucet, D. Angew. Chem., Int. Ed. Engl. 1998, 37(19), 2580-2627. (b)
Katsuki, T. Coord. Chem. Rev. 1995, 140, 189-214.
1
1 with none of the instabilities associated with the
(2) (a) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, T.; Mu-
kaiyama, T. J . Am. Chem. Soc. 1991, 113, 4247. (b) Denmark, S. E.;
Su, X.; Nishigaichi, Y. J . Am. Chem. Soc. 1998, 120, 12990.
adducts 4 and 5. Formation of diastereomer 13 also
proceeded in fair yield using the (R,R)-diamine 12. With
(
3) (a) Evans, D. A.; Lectka, T.; Miller, S. J . Tetrahedron Lett. 1993,
1
1 and 13 in hand, we next examined reduction of these
3
1
4, 7027. (b) Corey, E. J .; Sarshar, S.; Bordner, J . J . Am. Chem. Soc.
992, 114, 7938.
two species with NaBH /MeOH. The only components in
4
(4) (a) Knochel, P.; Berger, S.; Langer, C.; Lutz, C.; Mobley, T. A.;
addition to unreacted starting bisimines observed after
4 h at ambient temperature were diamines 14 and 15,
respectively (Scheme 2). Initial NMR analyses of 14 and
Reddy, C. K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1496. (b) J iang,
Y.; Gong. L.; Feng, X.; Hu, W.; Li, Z.; Mi, A. Tetrahedron 1997, 53,
1
4327.
5) (a) Sharpless, K. B.; Kolb, H. C.; VanNieuwenhze, M. S. Chem.
(
1
5 quickly established the exo stereochemistry at C3 for
Rev. 1994, 94, 2483. (b) Corey, E. J .; J ardine, P. D.; Vigil, S.; Yuen,
P.-W.; Connel, R. D. J . Am. Chem. Soc. 1989, 111, 9243.
both compounds. This was accomplished by simple ob-
servation of H4: this proton exists in both compounds
as a simple doublet with J ) 7.23 Hz, showing that there
is no coupling to H3 due to orthogonality; only coupling
to H5â is seen. Careful NMR analysis using NOESY
experiments revealed that both 14 and 15 possess the
desired exo stereochemistry at C2 as well. Key NOESY
cross-peaks observed with 14 included H2-H3 and H3-
H12, while for 15 cross-peaks for H2-H3 and H2-H11
were readily seen. These results thus confirmed that
reduction of the camphor bisimines takes place exclu-
(
6) (a) Corey, E. J .; Naef, R.; Hannon, F. J . J . Am. Chem. Soc. 1986,
08, 7114. (b) Rossiter, B. E.; Eguchi, M.; Hernandez, A. E.; Vickers,
D.; Medich, J .; Marr, J .; Heinis, D. Tetrahedron Lett. 1991, 32, 3973.
7) (a) Vedejs, E.; Lee, N. J . Am. Chem. Soc. 1995, 117, 891. (b) Koga,
K.; Yasukata, T. Tetrahedron: Asymmetry 1993, 4, 35.
8) Kobayashi, S.; Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno,
M.; Imai, N. Tetrahedron 1995, 51, 12013.
9) J acobsen, E. J .; Li, Z.; Conser, K. R. J . Am. Chem. Soc. 1993,
15, 5326.
10) (a) Clardy, J .; Kulanthaivel, P.; Hallock, Y. F.; Boros, C.;
1
(
(
(
1
(
Hamilton, S. M.; J anzen, W. P.; Ballas, L. M.; Loomis, C. R.; J iang, J .
B.; Katz, B.; Steiner, J . R. J . Am. Chem. Soc. 1993, 115, 6452. (b)
Rinehart, K. L. J r.; Gardiner, R. A.; Snyder, J . J .; Broquist, H. P. J .
Am. Chem. Soc. 1968, 90, 5639.
(
11) Cheney, B. V.; Szmuszkovicz, J .; Lahti, R. A.; Zichi, D. A. J .
Med. Chem. 1985, 28, 1853.
12) (a) Reedijk, J . Chem. Commun. 1996, 801. (b) Rosenberg, B.;
VanCamp, L.; Trosko, J . E.; Mansour, V. H. Nature 1969, 222, 385.
(15) (a) Corey, E. J .; Pikul, S. White, J . D.; J effrey, S. C. Org. Synth.
1993, 71, 22. (b) Nantz, M. H.; Lee, D. A.; Bender, D. M.; Roohi, A. H.
J . Org. Chem. 1992, 57, 6653.
(
(
13) Duden. Chem. Ber. 1905, II, 176.
(16) Periasamy, M.; Devasagayaraj, A.; Stayanarayana, N.; Naray-
ana, C. Synth. Commun. 1989, 19, 565-573.
(17) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: Essex, 1976; pp 100-106.
(
14) (a) Rupe, H.; Bohny, P. Helv. Chim. Acta 1936, 19, 1305-1323.
(
2
b) Dornow, A.; Fust, K. J .; J ordan, H. D. Chem. Ber. 1957, 90, 2124-
137.
1
0.1021/jo0002137 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/13/2000

4
754 J . Org. Chem., Vol. 65, No. 15, 2000
Notes
Sch em e 1
Sch em e 2
sively from the R-face, as expected, irrespective of the
diamine stereochemistry.
Sch em e 3
The original protocol1 for removal of the auxiliary was
5b
a three-step procedure consisting of (1) biscarbamate
formation, (2) Li(0)/NH double debenzylation, and (3)
3
HBr/HOAc cleavage of the biscarbamate. Rather than
adopting this strategy, we examined transfer hydro-
genolysis. While hydrogenolysis using Pd/C in the pres-
ence of cyclohexene or formic acid donors were sluggish,
use of ammonium formate on the dihydrochlorides of 14
and 15 led to rapid production of (R)-camphordiamine
dihydrochloride (1) and bibenzyl. The compound thus
obtained is a stable, nonhygroscopic salt. It is critical to
isolate the product as the hydrochloride salt using a
nonaqueous workup, as we have shown conclusively that
the free base diamine is not stable to standard extractive
isolation.
been achieved. The sequence is operationally simple, is
readily scaled, and furnishes the optically pure title
compound as a stable, nonhygroscopic, crystalline salt.
The use of (R)-camphordiamine and its derivatives in
asymmetric catalysis is presently under active investiga-
tion.
With this route established, we next carried out the
synthesis of (R)-camphordiamine dihydrochloride 1 using
rac-1, 2-diphenylethylenediamine.1 As shown in Scheme
Exp er im en ta l Section
5a
Dia m in es 14 a n d 15. A 2 L flask was charged with 12.7 g of
rac-1,2-diphenylethylenediamine (60.0 mmol, 1 equiv), 9.94 g of
R)-camphorquinone (60.0 mmol, 1 equiv), and 1.3 L of benzene.
The mixture was heated at reflux using a Dean-Stark trap for
12 h, and then the volatiles were removed in vacuo. The residue
was chromatographed on silica gel eluting with 5:1 Hex/EtOAc
to give 14.8 g (72%) of bisimines 11 and 13. A 14.8 g portion of
bisimines 11 and 13 (43 mmol, 1 equiv) was dissolved in 500
3
, (R)-camphordiamine dihydrochloride 1 was produced
in 38% overall yield for the three-step process. An X-ray
crystal structure obtained for a derivative18 confirmed the
stereochemical findings made via NMR NOESY analysis.
(
Con clu sion
mL of MeOH and cooled to 5 °C under N
then added 8.1 g of NaBH (215 mmol, 5 equiv) at once.
Caution: gas evolution). After the mixture was stirred for 1 h
at ambient temperature, the reaction was quenched by the
addition of 500 mL of 1 N HCl. MeOH was then removed in
vacuo, and the resulting suspension was extracted with EtOAc
2
. To this mixture was
In summary, a convenient stereoselective synthesis of
R)-camphordiamine dihydrochloride from (R)-cam-
phorquinone and rac-1,2-diphenylethylenediamine has
4
(
(
(18) Full details are found in the Supporting Information.

Notes
J . Org. Chem., Vol. 65, No. 15, 2000 4755
and the aqueous phase saved. The EtOAc was dried (MgSO
and the volatiles were removed in vacuo to give 5.0 g of a yellow
oil. This oil was dissolved in 150 mL of MeOH, cooled to 5 °C,
4
),
(1R,2S,3R)-Ca m p h or d ia m in e Dih yd r och lor id e 1. A flask
was charged with 5.00 g of 14 + 15 trihydrate (11.9 mmol, 1
equiv), 3.75 g of NH
MeOH. As N
Pd/C (dry) was cautiously added. The resulting mixture was
heated to reflux under N (warning: gas evolution), and after
4
HCO
2
(59.8 mmol, 5 equiv), and 250 mL of
and reduced with 2.7 g of NaBH
combined aqueous phases from both runs were concentrated
under high vacuum, the resultant solids recrystallized from H
and filtered, and the solids dried at ambient temperature to give
4
as described above. The
2
was bubbled beneath the surface, 2.0 g of 10%
2
O
2
45 min, the mixture was cooled and filtered through a Celite
pad, washing with MeOH. The volatiles were then removed in
vacuo, and the residual solid was washed well with EtOAc and
dried at ambient temperature to give 2.4 g of crude 1 (this
material can be used without further purification). Recrystalli-
1
8.0 g of diamine dihydrochlorides 14 + 15 (88%) as trihydrate
20
salts. Data for 14: colorless solid; mp 282 °C dec; [R]
D
) -70.3
1
(c 0.495, MeOH); H NMR (400 MHz, D
2
O) δ 7.40 (m, 10H), 5.00
(
d, J ) 11.2 Hz, 1H), 4.76 (d, J ) 11.0 Hz, 1H), 3.92 (d, J ) 8.6
Hz, 1H), 3.84 (d, J ) 8.6 Hz, 1H), 2.16 (br s, 1H), 1.92 (m, 1H),
1
3
2
zation from H O provided a colorless solid that was slurried with
MeCN, filtered, and dried to constant weight under high vacuum
.76 (t, J ) 11.7 Hz, 1H), 1.40 (s, 3H), 1.33 (m, 2H), 1.04 (s,
H), 0.95 (s, 3H); 13C NMR (100 MHz, D
O) δ 131.78 (s), 131.70
at ambient temperature to give 1.72 g (60%) of 1 as a colorless
2
solid: mp >300 °C; [R]20
) -30.6 (c 1.03, MeOH); H NMR
1
(
(
s), 130.66 (d), 130.31 (d), 129.60 (d), 129.43 (d), 128.80 (d), 128.35
d), 62.16 (d), 59.70 (d), 59.62 (d), 59.29 (d), 49.62 (s), 47.94 (d),
D
(500.13 MHz, DMSO) δ 6.01 (br s, 6H, 2xNH +), 3.04 (d, J )
3
4
7.73 (s), 34.33 (t), 26.14 (t), 21.02 (q), 20.37 (q), 10.45 (q). Anal.
Calcd for C24 Cl ‚3H O: C, 60.88; H, 8.09; N, 5.92; Cl, 14.98.
Found: C, 61.00; H, 7.70; N, 5.83; Cl, 15.27. Data for 15:
8.3 Hz, 1H, H3), 2.96 (d, J ) 8.3 Hz, 1H, H2), 1.89 (d, J ) 4.4
Hz, 1H, H4), 1.67 (m, 1H, H5â), 1.47 (m, 1H, H6â), 1.13 (m, 1H,
H6R), 1.09 (m, 1H, H5R), 0.97 (s, 3H, H9), 0.89 (s, 3H, H10),
H
32
N
2
2
2
2
0
13
colorless solid; mp 290 °C dec; [R]
D
) +93.4 (c 0.198, MeOH);
O) δ 7.37 (m, 5H), 7.22 (m, 5H), 4.65 (d,
J ) 9.5 Hz, 1H), 4.14 (d, J ) 9.5 Hz, 1H), 3.56 (d, J ) 7.8 Hz,
0.75 (s, 3H, H8); C NMR (125.77 MHz, DMSO) δ 60.05 (C2),
1
H NMR (400 MHz, D
2
55.59 (C3), 49.19 (C4), 48.15 (C1), 46.61 (C7), 34.97 (C6), 25.93
(C5), 21.26 (C8), 21.17 (C9), 11.70 (C10); HRMS calcd for
+
1
H), 3.41 (d, J ) 7.8 Hz, 1H), 1.86 (m, 1H), 1.55 (m, 1H), 1.51
C
10
H
21
N
2
m/z 169.1705, found m/z 169.1705.
1
3
(
(
1
6
(
s, 3H), 1.20-0.90 (m, 3H), 0.87 (s, 3H), 0.86 (s, 3H); C NMR
100 MHz, D O) δ: 139.27 (s), 133.39 (s), 130.13 (d), 129.38 (d),
29.07 (d), 128.92 (d), 128.43 (d), 127.62 (d), 67.54 (d), 63.21 (d),
2.17 (d), 56.46 (d), 48.35 (s), 48.29 (d), 46.91 (s), 34.30 (t), 25.67
Cl
O: C, 74.89; H, 8.17; N, 7.28; Cl, 9.21. Found: C, 74.51; H,
.08; N, 7.12; Cl, 9.23.
2
Su p p or tin g In for m a tion Ava ila ble: Synthesis and full
characterization of two derivatives of the title compound as
well as X-ray crystal structure data. This material is available
free of charge via the Internet at http://pubs.acs.org.
t), 21.21 (q), 20.74 (q), 9.96 (q). Anal. Calcd for C24
H
31
N
2
1
‚
0
8
.5H
2
J O0002137