Synthesis of new chiral auxiliaries for 6π-azaelectrocyclization: 4- and 7-alkyl substituted cis-1-amino-2-indanols

Article abstract of DOI:10.1016/j.tetasy.2003.10.029

The synthesis of new chiral auxiliaries, 7-alkyl substituted cis-1-amino-2-indanol derivatives, was established by the Diels-Alder reaction of 1-substituted dienes with cyclopentenone followed by the asymmetric epoxidation of the resulting indene derivatives and then the Ritter reaction. These bulky cis-aminoindanol derivatives are very effective as chiral auxiliaries and nitrogen sources in the asymmetric 6π-azaelectrocyclization. The corresponding 4-alkyl derivative was also prepared using a similar method.

Full text of DOI:10.1016/j.tetasy.2003.10.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 185–188
Synthesis of new chiral auxiliaries for 6p-azaelectrocyclization:
- and 7-alkyl substituted cis-1-amino-2-indanols
4
Toyoharu Kobayashi, Katsunori Tanaka, Junichi Miwa and Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda, Hyogo 669-1337, Japan
Received 1 September 2003; accepted 18 October 2003
Abstract—The synthesis of new chiral auxiliaries, 7-alkyl substituted cis-1-amino-2-indanol derivatives, was established by the
Diels–Alder reaction of 1-substituted dienes with cyclopentenone followed by the asymmetric epoxidation of the resulting indene
derivatives and then the Ritter reaction. These bulky cis-aminoindanol derivatives are very effective as chiral auxiliaries and nitrogen
sources in the asymmetric 6p-azaelectrocyclization. The corresponding 4-alkyl derivative was also prepared using a similar method.
Ó 2003 Elsevier Ltd. All rights reserved.
Chiral cis-1-amino-2-indanol has been recognized as a
satisfactory chiral auxiliary and ligand for advanced
asymmetric reactions. Both its sterically bulky indane
structure and the conformationally restricted cis-
aminoalcohol moiety, compared with a simple amino
alcohol such as 2-phenylglycinol, create an effective
chiral discriminative environment, in which a highly
diastereo- or enantioselective reaction could be achieved.
After many trials using the commercially available chiral
amines, we finally found that cis-1-amino-2-indanol A
provided excellent stereoselectivity in the reaction with
the sterically hindered trienal 1 (Fig. 2). However, from
the reaction with a more general aldehyde 2, A had the
moderate selectivity of 3:1, and therefore, as shown in
Figure 1, the more bulky 4- and 7-alkyl substituted cis-
aminoindanol derivatives such as B–D were investi-
gated. 4-Methyl substituted cis-aminoindanol B afforded
a 3:1 diastereoselectivity by the reaction with the alde-
hyde 2, the selectivity of which is similar to that ob-
tained by employing the simple aminoindanol A. In
contrast, a remarkably high diastereoselectivity was also
observed using the 7-alkyl substituted aminoindanols;
the methyl derivative C produced the corresponding
piperidine derivative with a 12:1 diastereoselectivity, and
the isopropyl substituted aminoindanol D with a 24:1
diastereoselectivity at room temperature. Moreover, the
1
Recently, we have been evaluating the promising chiral
amines, which achieve highly stereoselective asymmetric
6
carbonyl-2,4,6-trienal compounds under quite mild
p-azaelectrocyclization via the reaction with (E)-3-
2
conditions. This facile 6p-azaelectrocyclization was
based on the remarkable orbital interaction between the
HOMO and LUMO of 1-azatrienes resulting from the
combination of substituent effects, that is the C4-ester
3
and C6-alkenyl or phenyl substituents (Fig. 1).
Figure 1.
*
0
Corresponding author. Tel.: +81-0798-54-6381; fax: +81-0798-51-0914; e-mail: katsumura@ksc.kwansei.ac.jp
957-4166/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.029

186
T. Kobayashi et al. / Tetrahedron: Asymmetry 15 (2004) 185–188
Figure 2.
isopropyl derivative D provided an almost single isomer
at a lower temperature of 13 °C. Thus, we achieved a
highly stereoselective azaelectrocyclization by utilizing
the more bulky 7-alkyl substituted aminoindanols C and
substituted indene derivatives 3–5 were needed
(Scheme 1). Thus, 4-methylindene 3 was prepared on a
50 g scale starting from the Diels–Alder reaction between
1,3-pentadiene and cyclopentenone according to the
method of House and Rasmusson. Aromatization of the
D–A adduct via treatment with Pd/C at 200 °C produced
7-methylindanone 6 in 50% yield, which was reduced by
4
6
D. Herein, we report the synthesis of these chiral cis-
1
-amino-2-indanol derivatives B–D, which would also
be useful as chiral auxiliaries and ligands for metal
catalyzed asymmetric reactions (Fig. 2).
4
LiAlH and then dehydrated via treatment with a cata-
lytic amount of p-toluenesulfonic acid at 80 °C to give the
desired product 3 in 96% yield in two steps. The
7-substituted indene 5 was prepared from commercially
available 4-methylindanone 7 in 72% yield by a sequence
of LAH reduction and acid treatment. The synthesis of
4-isopropyl substituted indene 4 then occurred. Unfor-
tunately, various attempts in preparing a large quantity
The synthesis of chiral 4- and 7-substituted cis-1-amino-
2
commercially available A developed by MerckÕs group.
This procedure involved the asymmetric epoxidation of
the indene derivatives and the modified Ritter reaction of
the resulting indene oxides. Therefore, the 4- and 7-
-indanols B–D was followed by the procedure of the
5
Scheme 1. Reagents and conditions: (a) LAH, ether; (b) p-TsOH (0.1 equiv), benzene, gradually to 80 °C; (c) 2.5 M NaOH aq acetone, 0 °C, 2.5 h
2 mol scale); (d) p-TsOH (0.005 equiv), Na SO , toluene:THF (2:1), )78 °C; (f) 2-cyclopentenone, 2,5-di-
, benzene, 80 °C; (e) TMSCl, LiN(TMS)
tert-butylhydroquinone, benzene, 200 °C, 72 h; (g) p-TsOH, acetone; (h) 10% Pd/C, p-cymene, 200 °C, 48 h; (i) TsCl, NaH, THF; (j) NiCl (1.0 equiv),
NaBH
(30 equiv), MeOH, 0 °C.
(
2
4
2
2
4

T. Kobayashi et al. / Tetrahedron: Asymmetry 15 (2004) 185–188
187
of the corresponding isopropyl substituted 1,3-dienes
proved unsuccessful using the same method, which gave
a mixture of regio- and stereoisomers. Therefore, we
selected the corresponding 2-siloxy-4-isopropyl-1,3-
pentadiene as a partner for the D–A reaction with
cyclopentenone, as shown in Scheme 1. Thus, more than
reaction were examined as the key steps towards the
substituted aminoindanols B–D. Thus, according to the
5
procedure developed by MerckÕs group, indene 3 was
treated with 3.9 equiv of sodium hypochlorite solution in
0
the presence of 1.2 mol % of (S,S)-(+)-N,N -bis(3,5-
di-tert-butylsalicylidene)-1,2-cyclohexanediaminoman-
ganese(III) chloride and 6.0 mol % of 4-phenylpyridine
N-oxide at 0 °C for 7 h to provide the desired indene
2
00 g of isobutylaldehyde was treated with a 2.5 M
solution of sodium hydroxide in acetone to give the
corresponding aldol product in 69% yield, which was
then dehydrated by treatment with p-toluenesulfonic
acid to provide the (E)-a,b-unsaturated ketone 8 with
8
oxide 13 in 67% yield and 85% ee after rapid chroma-
tography on alumina. Quite fortunately, the compound
13 thus obtained was recrystallized from a mixture
of ether and hexane to give the enantiomerically pure
7
5% yield on 200 g scale. The treatment of 8 with
24
chlorotrimethylsilane and solid lithium bis(trimethyl-
silyl)amide in a mixed solvent system of THF and tolu-
ene (1:2) at )78 °C provided the desired siloxydiene 9 in
(+)-indene oxide 13, ½aꢀ +2.6 (c 0.9, CHCl ). Epoxide
D
3
13 was then reacted with fuming sulfuric acid (30% of
SO ) in acetonitrile to give the intermediary oxazoline
derivative, which was hydrolyzed without purification in
3
7
9% yield. The purification of all the products so far was
successfully done by distillation that enabled us to easily
prepare the siloxydiene 9 on a >100 g scale. The sil-
oxydiene 9 was then reacted with cyclopentenone in the
presence of 2,5-di-tert-butylhydroquinone in benzene at
H
2
O at 100 °C to provide the desired ())-7-methyl-cis-1-
22
amino-2-indanol C [99% ee, ½aꢀ )110.8 (c 0.6, CHCl
3
)]
D
in 52% yield in two steps.
2
00 °C for 72 h to give the desired cycloadduct, which
Meanwhile, the application of the same reaction con-
ditions as JacobsenÕs epoxidation (mentioned previ-
ously) towards the 4-isopropyl substituted indene 4
disappointedly gave the indene oxide 14 in both a lower
chemical yield (ꢁ50%) and enantioselectivity (ꢁ50% ee).
Therefore, we attempted the improved JacobsenÕs
epoxidation protocol under anhydrous and lower tem-
was hydrolyzed immediately without further purifica-
tion, by treatment with p-toluenesulfonic acid in acetone
to provide the diketone 10 with 69% yield in two steps.
This diketone consisted of two stereoisomers based on
1
H NMR analysis. The oxidative aromatization was
successfully achieved by treatment of the diketones 10
with 10% Pd/C in p-cymene at 200 °C for 2 days to pro-
duce the phenol 11 in 72% yield. In order to remove the
phenolic hydroxy group of 11, the nickel catalyzed
reductive deoxygenation by sodium borohydride was
successfully employed. Thus the tosylate, prepared by
treatment of the phenol 11 with p-toluenesulfonyl chlor-
ide and sodium hydride, was reacted with 30 equiv of
sodium borohydride in the presence of 1 equiv of nickel-
(II) chloride hexahydrate in methanol to give the desired
alcohol 12 in 84% yield in two steps, accompanied by the
simultaneous reduction of the ketone group. As previ-
ously described, the alcohol 12 was quantitatively
dehydrated by a reaction with p-toluenesulfonic acid to
provide the 4-isopropyl indene 4.
9
perature conditions. Indene 4 was treated with 2 equiv
of m-chloroperbenzoic acid and 5 equiv of N-meth-
ylmorpholine N-oxide in the presence of 5 mol %
0
of (S,S)-(+)-N,N -bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediaminomanganese(III) chloride at )78 °C
to provide the indene oxide 14 in 86% yield and 56% ee.
Unfortunately, recrystallization did not effectively iso-
late the enantiomerically pure epoxide 14. The indene
oxide 14 was then directly subjected to the Ritter reac-
tion followed by hydrolysis of the oxazoline intermedi-
ate using the same procedure as that utilized for 13 to
provide the isopropyl substituted compound D in 77%
yield in two steps (39% yield after recrystallization). The
7
2
0
enantiomerically homogeneous ())-D [99% ee, ½aꢀ
D
)
recrystallization from toluene. The obtained enantio-
114.2 (c 0.5, CHCl )] was successfully obtained by
3
With a sufficient amount of indenes 3–5 in hand, the
JacobsenÕs asymmetric epoxidation and the Ritter
10
meric excess of ())-D was analyzed by chiral HPLC.
Scheme 2. Reagents and conditions: (a) 1.8 M NaClO aq (4.0 equiv), (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-diaminoman-
ganese(III) chloride (1.2 mol %), 4-phenylpyridine N-oxide (6 mol %), CH Cl , rt; (b) m-CPBA (2 equiv), NMO (5 equiv), S,S-(+)-N,N-bis(3,5-di-tert-
butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (5 mol %), CH Cl SO , CH CN, rt, 30 min, then H O,
, )78 °C; (c) fuming H
00 °C, 2 h.
2
2
2
2
2
4
3
2
1

188
T. Kobayashi et al. / Tetrahedron: Asymmetry 15 (2004) 185–188
Similarly, JacobsenÕs improved epoxidation of indene 5
provided the indene oxide 15 in 73% yield and 88% ee.
The obtained 15 was then converted into B with 56%
yield in two steps, from which the enantiomerically
their diastereoselectivity for stereoselective azaelectro-
cyclization has been investigated (see Ref. 2).
5
. (a) Senanayake, C. H.; Roberts, F. E.; DiMichele, L. M.;
Liu, J.; Fredenburg, L. E.; Foster, B. S.; Douglas, A. W.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron
Lett. 1995, 36, 3993; (b) Larrow, J. F.; Roberts, E.;
Verhoeven, T. R.; Ryan, K. M.; Senanayake, C. H.;
Reider, P. J.; Jacobsen, E. N. Org. Synth. 1999, 76, 46.
. House, H. O.; Rasmusson, C. H. J. Org. Chem. 1963, 28,
27.
24
homogeneous ())-B [99% ee, ½aꢀ )30.7 (c 0.9, CHCl
3
)],
D
was successfully obtained by recrystallization from tol-
uene. Thus, a sufficient amount of chiral 7-methyl and 7-
isopropyl substituted cis-aminoindanol C and D along
with 4-methyl substituted compound B were pro-
6
11
duced (Scheme 2).
7. Wang, F.; Chiba, K.; Tada, M. J. Chem. Soc., Perkin
Trans. 1 1992, 1897.
8
. The enantiomeric excess of 13 was analyzed by chiral
HPLC [OD column, 5% isopropanol in hexane, 6.9 min
for the first eluted isomer (major product) and 7.4 min for
the second eluted isomer].
. Palucki, M.; Pospisil, P. J.; Zhang, W.; Jacobsen, E. N.
J. Am. Chem. Soc. 1994, 116, 9333.
In summary, we established the synthesis of new chiral
auxiliaries, 7-methyl and 7-isopropyl substituted cis-1-
amino-2-indanol derivatives C and D, which proved to
be very effective as chiral auxiliaries and nitrogen sour-
ces. We also prepared the corresponding 4-alkyl deriv-
ative B. These bulky cis-aminoindanol derivatives are
considered to be new, effective chiral auxiliaries and/or
ligands for a variety of asymmetric reactions.
9
1
0. The enantiomeric excess of C was determined by reacting
C with 2,4-dinitrofluorobenzene in CH Cl . The yellow
2
2
solution was diluted with ethanol (1:10), and then
analyzed by HPLC on an OD column, 10% isopropanal
in hexane, with 27 min for the first eluted isomer (major
product) and 41 min for the second eluted isomer.
1
1. Spectral data of aminoindanol derivatives: 4-Methyl-cis-1-
2
4
Acknowledgements
amino-2-indanol B: ½aꢀ )30.7 (c 0.9, CHCl ); IR (KBr
D
3
ꢂ1
1
disk, cm ) 3349 (br), 1601, 1476, 1335, 1026; H NMR
(400 MHz, CDCl
) d 2.26 (s, 3H), 2.88 (dd, 1H, J ¼ 16:6,
.7 Hz), 3.01 (dd, 1H, J ¼ 16:6, 5.6 Hz), 4.33 (d, 1H,
J ¼ 5:4 Hz), 4.39 (ddd, 1H, J ¼ 5:6, 5.4, 2.7 Hz), 7.06 (d,
This study was supported by a Grant-in-Aid for Scien-
tific Research 09480145 from the Ministry of Education,
Science, Sports and Culture of Japan. K.T. is grateful to
the JSPS for a Research Fellowship for Young Scientist.
3
2
1
3
1
H, J ¼ 7:0 Hz), 7.11–7.19 (m, 2H); C NMR (100 MHz,
3
CDCl
) d 18.8, 38.0, 58.6, 72.1, 121.1, 127.1, 128.8, 134.8,
þ
1
1
7
39.7, 143.5; EI HRMS m=e calcd for C10
63.0997, found 163.0989.
H13NO (M )
2
D
2
-Methyl-cis-1-amino-2-indanol C: ½aꢀ )110.8 (c 0.6,
ꢂ1
References and notes
CHCl ); IR (KBr disk, cm ) 3314–2571 (br), 1593, 1474,
3
1
1
3
346, 1098; H NMR (400 MHz, CDCl ) d 2.19 (br s, 3H),
1
. (a) Senanayake, C. H. Aldrichim. Acta 1998, 31, 3; (b)
Ghosh, A. K.; Fidanze, S.; Senanyake, C. H. Synthesis
2.39 (s, 3H), 2.81 (dd, 1H, J ¼ 15:9, 7.6 Hz), 3.13 (dd, 1H,
J ¼ 15:9, 7.3 Hz), 4.22 (d, 1H, J ¼ 6:6 Hz), 4.35 (ddd, 1H,
J ¼ 7:1, 7.1, 7.1 Hz), 7.00–7.03 (m, 2H), 7.14 (dd, 1H,
1998, 937; (c) Watson, D. J.; Lawrence, C. M.; Meyers, A.
1
3
I. Tetrahedron Lett. 2000, 41, 815; (d) Groaning, M. D.;
Meyers, A. I. Tetrahedron 2000, 56, 9843; (e) Thompson,
C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc.
J ¼ 7:6, 7.3 Hz); C NMR (100 MHz, CDCl
3
) d 18.4,
39.3, 55.6, 71.2, 122.7, 128.26, 128.32, 134.5, 140.7, 142.6;
H13NO (M ) 163.0996, found
þ
EI HRMS m=e calcd for C10
163.1001.
2000, 122, 10482; (f) Palmer, M. J.; Kenny, J. A.;
2
0
Walsgrove, T.; Kawamoto, A. M.; Wills, M. J. Chem.
Soc., Perkin Trans. 1 2002, 416; (g) Gademann, K.;
Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed.
7-Isopropyl-cis-1-amino-2-indanol D: ½aꢀ )114.2 (c 0.5,
D
); IR (KBr disk, cm ) 3194 (br), 1586, 1480, 1451,
1383, 1333, 1094; H NMR (400 MHz, CDCl ) d 1.25 (d,
3
ꢂ1
CHCl
3
1
2
002, 41, 3059.
. Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124,
660.
3H, J ¼ 6:8 Hz), 1.31 (d, 3H, J ¼ 6:8 Hz), 2.31 (br s, 3H),
2.80 (dd, 1H, J ¼ 15:6, 8.3 Hz), 3.14 (dd, 1H, J ¼ 15:6,
7.6 Hz), 3.13–3.21 (m, 1H), 4.29 (br d, 1H, J ¼ 6:6 Hz),
4.34–4.38 (m, 1H), 7.03 (d, 1H, J ¼ 7:3 Hz), 7.14 (d, 1H,
2
3
4
9
. Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S.
J. Org. Chem. 2001, 66, 3099.
. We have also synthesized 7-ethyl, 7-tert-butyl, and 4-
isopropyl substituted cis-1-amino-2-indanol derivatives as
their racemates by a similar method described herein, and
1
3
J ¼ 7:8 Hz), 7.23 (dd, 1H, J ¼ 7:6, 7.6 Hz); C NMR
3
(100 MHz, CDCl ) d 23.9, 24.2, 30.0 39.3, 55.0, 71.4,
122.7, 123.6, 128.8, 140.6, 141.3, 145.8; CI HRMS m=z
þ
calcd for C12
H
18 (M+H) 192.1387, found 192.1383.