New indane derived aminoalcohols as chiral ligands for the catalytic enantioselective addition of diethylzine to aldehydes

Article abstract of DOI:10.1016/S0957-4166(97)00163-8

Secondary amines react with (1R,2S)-indene oxide 1 in a completely regioselective manner leading to trans-2-dialkylamino-1-indanols 4a-d in high yield. A Mitsunobu inversion via the corresponding p-nitrobenzoates, followed by reduction with DIBALH leads t

Full text of DOI:10.1016/S0957-4166(97)00163-8

Tetrahednm Asymmetry. Vol. 8. No. 10. pp. 1559-1568, 1997
@ 1997 Elsevier Science Ltd. All rights reserved.
Printed in Great Britain
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New indane derived aminoalcohols as chiral ligands for the catalytic
enantioselective addition of diethylzinc to aldehydes
Liufs Solgl,~'b't A n t o n Vidal-Ferran, a Albert M o y a n o ,a M i q u e i A. Pericb.s ab,. and
Antoni Riera a
aUnitat de Recerca en Sfntesi Asimetrica (URSA), Departament de Qufmica Org~,nica, Universitat de
Barcelona, c/Mart/i Franqubs, 1-11. 08028- Barcelona, Spain
b Servei de Calorimetria de Reacci6 i An/ilisi T~rmica, Universitat de Barcelona, c/Martf i Franqu~s, 1-11,
08028 Barcelona, Spain
Abstract:
Secondary amines react with (IR,2S)-indene oxide 1 in a completely
regioselective manner leading to trans-2-dialkylamino-l-indanols 4a-d in high yield. A
Mitsunobu inversion via the corresponding p-nitrobenzoates, followed by reduction with
DIBALH leads to the cis-2-dialkylamino-l-indanols 5a-d also in high yield. These two
new classes of aminoindanols have been tested as chiral ligands for the enantioselective
addition of diethylzinc to both aliphatic and aromatic aldehydes, leading to l-substituted
l-propanols with up to 80% e.e. A very simple procedure t-or the enantiomeric enrichment
of 1 from 88% to >_99% e.e. is also reported. @ 1997 Elsevier Science Ltd
Indene oxide 1, nowadays readily available in enantioenriched form through a manganese-salen
catalysed Jacobsen epoxidation, I has gained considerable importance as a chiral starting material.
Being a potential precursor to the cis-aminoindanol moiety present in Merck's HIV protease inhibitor
Indinavir 2,2 it has also been studied by chemists at Merck and by others as a source of cis-
aminoalcohols and related species with activity as chiral ligands for enantioselective catalysis.3
~
N
"
~
OH f~PhH OH
.
N .... =-"
1
2
Up to now, the functionalization of I has relied on regioselective Ritter reactions leading exclusively
to 1-amino-2-indanol derivatives 3.4 We report in the present paper efficient methodology allowing the
preparation of both the cis and trans stereoisomers of the regioisomeric 2-amino- 1-indanols 4 (trans)
and 5 (cis). Initial results on the catalytic activity of these substances in the enantioselective addition
of diethylzinc to aldehydes are also reported.
~ ~ O H
[ ~ ~ N R2
[ ~ ~ N R2
NR2
3
OH
4
OH
5
*
Corresponding author. Email: mpb@ursa.qo.ub.es
1" Email: lsc@ursaqo.ub.es
1559

1560
L. SOLA et al.
The starting material for the present study has been readily available 88% e.e. (1R,2S)-indene oxide
1, prepared by sodium hypochlorite oxidation of indene in dichloromethane at 0°C mediated by the
( R , R ) enantiomer of the standard Jacobsen catalyst.5
In order to test the operation of non-linear effects in the reactions catalysed by our target ligands,
we have investigated ways for the improvement of the enantiomeric purity of 1. As a result of these
efforts, we have now developed a very simple procedure for the enantiomeric enrichment of this
compound up to 99.0% e.e. Our method is based on the fact that 1, a liquid at room temperature,
solidifies near 0°C. Moreover, being appreciably soluble in hexane at room temperature, it crystallises
with enantiomeric enrichment at - 2 0 ° C affording samples of 1 with an e.e. higher than 99%.
When
1 was treated at room temperature with 2 eq. of a secondary amine and 2 eq. of
lithium perchlorate in acetonitrile solution, under the conditions developed by Crotti,6 a completely
regioselective and stereospecific ring opening took place leading in high yield to trans-2-amino-1-
indanols 4a--d (Scheme 1 and Table 1).
2.0 eq. R2NH
CH3CN, r.t., 24h
~)H
1
4a-d
5.0 eq. Ph3P
Toluene-THF (1:1)
4.4 eq. P-O2NC6H4COOH | -20°C; then r.t. 72h.
5.0 eq. DEAD
[
~
8.0 eq. DIBALH
NR2 q 0H2Cl2' -20°C
NR2
@
OH
OCOC6H4NO 2
5a.-d
6a-d
Scheme 1.
Table 1. Yieldsa in the synthesis of ligands 4a-d and 5a~l
Entry
R2NH
4[%]
6{%]
5[%]
100
70
a
ipr2NH
~ N H
75
75
:b
70
86
c
(n-C4H9)2NH
/
72
93
87
85
80
d
t / ~ t ' l H
85b
\<
aReaction conditions as indicated in scheme 1. bRing-opening was performed
at 65°C for 48h.

New indane derived aminoalcohols
1561
H H
quartet
doublet
~
~
On the inverted p-nitrobenzoates
fiq is decreased by ca. 0.4-1.0 ppm
Y
t
>
On the inverted p-nitrobenzoates
8d is increased by ca. 2.1-2.6 ppm
X = O H " Y = N R 2
Figure 1. Confirmation of the regiochemistry of 4, 5, and 6 from NMR data.
The observed regioselectivity of this ring opening is highly remarkable. Thus, when performing the
same reaction on styrene oxide, Crotti observed that only very bulky amines such as diisopropylamine
or dicyclohexylamine are able to induce a completely regioselective attack to the 13-carbon. 6a
Piperidine, in turn, reacts with styrene oxide with complete lack of regioselectivity while in the present
case (entry b in Table 1) the ring-opening is totally regioselective.
With 4a-d in hand, we planned to gain access to the more interesting cis stereoisomers 5a-d.
According to previous experience in our laboratories, a Mitsunobu inversion7 at C-I followed
by reduction appeared as the safest alternative in terms of stereocontrol. Bearing in mind the
rather congested nature of 4a-d, the Mitsunobu inversion was performed with p-nitrobenzoic
acid,
a more efficient nucleophile for the inversion of congested secondary alcohols.7c In this
way, the cis p-nitrobenzoates 6a-d were obtained in 75-93% yield. Reduction of 6a~l with
DIBALH in dichloromethane led in high yield (70-100%) to the desired cis aminoalcohols 5a--d in
diastereomerically pure form.
The regiochemistry of the final compounds was established by comparison with its unambiguously
prepared regioisomer cis-l-di-n-butylamino-2-indanol. 8 Moreover, the NMR data of 4a--d fully
supports the 2-amino-l-indanol regiochemistry as summarised in Figure 1.
In order to determine the optimal ligand structure, all eight species (4a~l, 5a~l), obtained from
88% e.e. 1, were initially tested in the enantioselective addition of diethylzinc9 to benzaldehyde (Ta)
leading to l-phenyl- 1-propanol (Sa) under the experimental conditions shown in Scheme 2. The results
of these reactions are summarised in Table 2.
0
OH
2.2 eq. Et2Zn
0.06 eq. Ligand
H
it_
toluene, r.t., 20h
7a
8a
Scheme 2.
Not unexpectedly, the cis ligands 5a-d are superior to the corresponding trans ones 4a-d both in
terms of turnover (conversion) and enantioselectivity. This can be clearly related to the greater ease of
the cis ligands for the fulfilment of the geometrical restrictions associated to the formation of a zinc
chelate, as it is assumed to occur when aminoalcohols interact with Et2Zn.
On the other hand, in agreement with previous studies by our group, 1° it is seen that the branched
and acyclic diisopropyl group is rather inefficient as a building block for these ligands. Conversely, the

1562
L. SOLA et al.
Table 2. Enantioselective addition of diethylzinc to benzaldehyde mediated by ligands 4 or 5
Liganda Conversionb
[%]
Selectivity c
[%]
Absolute config.
of 8ad
Enantiomeric
excesse of 8a [%]
4a
4b
4c
4d
5a
5b
5c
5d
51
100
88
91
79
99
95
99
89
98
90
88
90
97
92
95
R
R
R
R
S
1
29
31
56
35
40
44
73
S
S
S
aAIl ligands reported in this table are derived from 88% e.e. 1, and are thus assumed to
be of 88% e.e. bDetermined by integration of residual 7a in front of all new products
in the gas chromatogram of the reaction crude. CDetermined by integration of 8a (both
enantiomers in front of other reaction products in the gas chromatogram of the reaction
crude, dEstablished by comparison of retention times in GC ([~-DEXTM 120 column;
isothermal at 112°C;tR(R): 48.5 rain, tR(S): 51. l rain) with those of authentic samples.
eBy GC as in c (see above).
presence of a piperidino substituent is optimal in terms of turnover, and the cis-2,6-dimethylpiperidino
fragment I1 induces the highest enantioselectivities both in the cis and in the trans series.
The influence of the enantiomeric purity of the ligands on the enantioselectivity of the addition
reaction was tested with ligands 4d and 5d. Thus, working with 99.0% e.e. ligands (derived from
99.0% e.e. 1) under the conditions shown in Scheme 2, the enantiomeric excess of (R)-8a obtained
with 4d did not show any appreciable variation with respect to the value reported in Table 2. On the
other hand, in the case of 5d the enantiomeric excess of (S)-8a increased from 73 to 78%.
For 5d, the influence of the reaction temperature on enantioselectivity was also studied. Rather
unexpectedly, lowering the reaction temperature to 0°C provoked a significant decrease (from 78 to
73%) in the e.e. of the resulting (S)-8.
In view of these results, 5d of 99.0% e.e. was used as a catalytic ligand in the addition at room
temperature of Et2Zn to a family of aldehydes comprising both aromatic and aliphatic specimens as
shown in Scheme 3 and Table 3.
O
2.2 eq. Et2Zn
0.06 eq. 5d
H,,./,~~, "
3.
R
H
toluene, r.t., 20h
R
"
s
7a-h
8a-h
Scheme 3.
In all cases, the S enantiomer of the resulting alcohol was preferentially obtained, as it could be
established in every case by comparison of the retention times of the enantiomers on cx- or I~-DEXQ

New indane derived aminoalcohols
1563
Table 3. Enantioselective addition of diethylzinc to aldehydesa 7a-h mediated by ligand 5db
Starting
Resulting
Alcohol
Conversionc
[%]
Selectivityd
[%]
Enantiomeric
Excesse [%]
Aldehyde
(Ta)
8a
99
97
94
92
78
69
ff•CHO
. . ~ C HO(7b)
8b
H3C" ".#"
' ~ C HO (7c)
8e
88
96
71
H3CO-
v
HO
A
~
C
(7d)
8d
8e
81"
8g
98
92
81
74
95
72
83
92
80
66
65
69
F"
v
HO
~ C
(7e)
CI
~ C H O (7t")
H
O
~
C
(Tg)r
...,~CHO
(Th)f
$h
93
94
56
aUnless otherwise stated, the reactions were performed at room temperature, b99.0% e.e. 5d was
used throughout the study. CDetermined by integration of residual 7 in front of all new products in
the gas chromatogram of the reaction crude, dDetermined by integration of 8 (both enantiomers) in
front of other reaction products, eBy GC using either a [3-DEXTM 120 column (for 8a-$f) or a
0~-DEXTM 120 column (for 8g and 8h). fReaction performed at 0°C
columns (see Table 3) with those of samples of known configuration. This is in agreement with the
empirical predictive model developed by Noyori. 9b
A m o n g the aromatic aldehydes, the best results are obtained with the parent benzaldehyde 7a and
with the p-substituted ones 7b--d, specially in terms of chemical selectivity. Thus, reduction becomes
a serious problem with o-substituted substrates 7e--f. Finally, for the normally more problematic non-
conjugated substrates 7 g - h , the reaction temperature was lowered to 0°C. In this way, the enantiomeric
excess of the resulting alcohols 8g-h was kept in a level similar to that of the benzyi alcohols 8 b - f .

1564
L. SOLA et al.
Conclusions
In summary, we have developed a very simple method for the enantiomeric enrichment of the very
important intermediate indene oxide 1 up to 99.0% e.e. We have subsequently developed short and
efficient routes for the preparation of the hitherto unknown homochiral trans- and cis-2-dialkylamino- 1-
indanols 4 and 5, regioisomers of the much employed as chiral ligands and auxiliaries l-dialkylamino-
2-indanols 3. The aminoalcohols 4 and 5 have been tested as ligands in the enantioselective addition of
diethylzinc to aldehydes. Although the enantioselectivities achieved in these reactions are only modest,
in the only example where a direct comparison with the regioisomeric aminoindanol 3 is possible 5c,
the presently developed ligand has similar or even slightly better characteristics. According to that, it
can be anticipated that other ligands and auxiliaries based on the cis 2-amino-l-indanol structure will
probably depict interesting properties. Work in this area is being actively pursued in our laboratories
and will be reported in due course.
Experimental section
General
Optical rotations were measured at room temperature on a Perkin-Elmer MC 241 polarimeter
(concentration in g/100 mL). IH-NMR spectra were recorded on Varian Gemini 200, Varian-Unity-
300 and Varian-Unity-Plus-300 spectrometers in CDCI3 operating at 200 or 300 MHz respectively.
13C-NMR spectra were obtained on the same instruments operating at 50 or 75 MHz respectively.
Chemical shifts are quoted relative to TMS for 1H-NMR and relative to the solvent for 13C-NMR
(77.0 ppm for 13C of CDCI3). Coupling constants (J) are given in Hz. Signal multiplicities in 13C-
NMR were established by DEPT experiments. IR spectra were recorded on a Nicolet 510 VI'-IR
instrument in Fourier transform mode. Mass spectra were recorded on a Hewlen Packard HP-5988A
instrument at 70 eV ionizing voltage and ammonia was used for chemical ionization (CI). THF was
distilled under N2 from sodium benzophenone ketyl; CH2C12 was distilled under N2 from Call2; the
required secondary amines were distilled from Call2 prior to use, the aldehydes were distilled just
before being used and all the other commercial chemicals were used as received. All reactions were
performed in oven-dried glassware under a N2 atmosphere. Reaction progress was followed by TLC
(Merck DC-Alufolien KIESELGEL 60 F254). Chromatographic separations were carried out using
Et3N pre-treated (2.5% v/v) SiO2 (70-230 mesh). (IR, 2S)-indene oxide 1 was prepared following
the procedure described by Jacobsen et al. 5a
lndene oxide 1 enantiomeric enrichment
Indene oxide 1 (17.8 g, 88~: e.e.) was dissolved in dry hexane at room temperature and the
resulting solution was cooled to - 18°C overnight. 4.7 g of yellow crystals (99% e.e., by HPLC using
a Chiralcel® OB column) were separated at -20°C. let]D23=-40.3 (c=1.7 in CHCI3).
( I R, 2R)- 2-Diisopropylamino- 1-indanol 4a
Diisopropylamine (1.45 mL, 10 retool) was added via syringe into a mixture of 88% e.e. indene
oxide 1 (0.66 g, 5 mmol) and LiC104 (1.06 g, 10 mmol) in acetonitrile (2 mL) at room temperature
under N2. After stirring for 24 h at room temperature, H20 (40 mL) was added and the aqueous layer
was extracted with CH2CI2 (3 ×40 mL). The combined organic extracts were dried and concentrated
in vacuo. The residual oil was purified by chromatography using hexane:EtOAc (100:0-70:30)as
eluent to give 0.87 g (75%) of 4a as an oil: [et]D23=+18.3 (c=1.41 in CHCI3); 1H-NMR (300 MHz,
CDCI3) ~ 7.25-7.15 (m, 4H), 4.34 (q, IH, J=7.8 Hz), 4.22 (d, IH, J=7.2 Hz), 3.25-3.0 (m, 3H), 2.74
(d×d, IH, J=15.9 Hz, J=8.1 Hz), 1.12 (d, 12H, J=6.6 Hz); 13C-NMR (75 MHz, CDCIj) ~ 143.6 (C),
139.3 (C), 127.0 (CH), 126.5 (CH), 125.6 (CH), 77.0 (CH), 67.8 (CH), 44.7 (CH), 37.6 (CH2), 24.2
(CHj), 23.3 (CHj); IR (KBr)3396, 2962, 1460, 1393, 1362, 1231, 1198, 1071, 741; MS (CI, NHj)
m/z 234 (CI5H23NO.H +, 100%).

New indane derived aminoalcohols
(1R, 2R)-2-Piperidino- 1-indanol 4b
1565
Piperidine (2 mL, 20 mmol), 88% e.e. indene oxide 1 ( 1.32 g, 10 mmol) LiCIO4 (2.13 g, 20 mmol)
in acetonitrile (4 mL) were treated as described for 4a. The work-up was identical to the one described
for 4a to give 1.52 g (70%) of 4b as an oil: [~x]D23=+3.0 (c=l.00 in CHCI3); IH-NMR (200 MHz,
CDCI3) 8 7.3-7.1 (m, 4H), 4 . 7 4 . 6 (m, IH), 4.05 (d, 1H, J--5.2 Hz), 3.45 (bs, IH), 3.25 (dxd, 1H,
J=16.2 Hz, J=7 Hz), 2.80 (dxd, IH, J=16 Hz, J=5.6 Hz), 2.65-2.55 (m, 4H), 1.60-1.40 (m, 6H); 13C-
NMR (75 MHz, CDCI3); 6 140.9 (C), 140.0 (C), 127.7 (CH), 126.3 (CH), 125.9 (CH), 124.9 (CH),
78.5 (CH), 73.6 (CH), 50.7 (CH2), 40.1 (CH2), 26.3 (CH2), 24.5 (CH2); IR (KBr) 3265, 2937, 2860,
2800, 1455, 1341, 1162, 1106, 1038, 999 i 745 c m - I ; MS (CI, NH3) m/z 218 (CI4HIgNO.H+, 100%).
(1R,2R)-2-Di-n-butylamino- l-indanol 4c
Di-n-butylamine (6.8 mL, 40 mmol), 88% e.c. indene oxide 1 (2.64 g, 20 mmol) LiCIO4 (4.26 g,
40 mmol) in acetonitrile (8 mL) were treated as described for 4a. The work-up was identical to the
one described for 4a to give 3.7 g (71%) of 4c as an oil: [c~]D23=+20.4 (c=1.05 in CHCI3); IH-NMR
(200 MHz, CDC13) 6 7.25-7.15 (m, 4H), 4.44 (q, IH. J=7.4 Hz), 4.22 (d, IH, J=6.6 Hz), 3.2 (dxd,
1H, J=15.6 Hz, J=7.4 Hz), 2.78 (dxd, IH, J=15.6 Hz. J=7.4 Hz), 2.59 (t, 4H, J=7.2 Hz), 2.4 (br s,
1H), 1.6-1.2 (m, 8H), 0.88 (t, 6H); 13C-NMR (50 MHz, CDCI3) ~ 141.6, (C), 139.7 (C), 127.3 (CH),
126.4 (CH), 124.9 (CH), 75.0 (CH), 73.8 (CH), 52.4 (CH2), 38.6 (CH2), 31.7 (CH2), 20.4 (CH2),
14.1 (CH3); IR (KBr) 3355, 2958, 1607, 1461, 1378, 1181, 1077, 868,745 c m - l ; MS (CI, NH3) re~z:
262 (CITH27NO.H+100%).
(1R, 2R)-2-(cis-2, 6-Dimethylpiperidino)- 1-indanol 4d
cis-2,6-Dimethylpiperidine (2.1 mL, 15.1 mmol) was added via syringe into a mixture of 99% e.e.
indene oxide 1 (1.0 g, 7.6 mmol) and LiCIO4 (1.6 g, 15.1 mmol) in acetonitrile (6 mL) at room
temperature under N2. After stirring for 48 h at 65°C, H20 (50 mL) was added and the aqueous layer
was extracted with CH2C12 (3x50 mL). The work-up was identical to thc one described for 4a to
give 1.57 g (85%) of 4d as an oil: [otlD23=+l.0 (c=2.18 in CHCI3); IH-NMR (200 MHz, CDCI3)
~i 7.35 (m, 1H), 7.15 (m, 3H), 4.84 (q, IH, J=7.6 Hz), 4.7 (d, IH, J=7.0 Hz), 3.31 (dxd, 1H, J=16
Hz, J=8.0 Hz), 3.1-2.9 (m, 2H), 2.8 (d×d, IH, J=16 Hz, J=7.5 Hz), 1.8-1.5 (m, 4H), 1.4-1.3 (m,
4H), 1.05 (d, 3H, J=4.2 Hz), 1.0 (d, 3H, J=4.0 Hz); 13C-NMR (50 MHz, CDC13) 6 143 (C), 138.5
(C), 126.6 (CH), 126.0 (CH), 124.7 (CH), 124.4 (CH), 76.7 (CH), 71.4 (CH), 55.6 (CH), 54.5 (CH),
38.5 (CH2), 35.9 (CH2), 35.4 (CH2), 23.6 (CH2), 23.5 (CH3), 23.1 (CH3); MS (CI, NH3) m/z: 246
(CI6H23NO.H+ 100%).
4-Nitrobenzoic acid (1S,2R)-2-diisopropylamino-l-indanyl ester 6a
A solution of 88% e.e. 4a (364 mg, 1.63 mmol), PPh3 (2.09 g, 8 mmol) and 4-nitrobenzoic acid
(1.2 g, 7.2 mmol) in toluene (16 mL) and THF (16 mL) under N2 was cooled at -20°C. Diethyl
azodicarboxylate (DEAD) (1.26 mL, 8.0 mmol) was added via syringe into the solution. The mixture
was stirred at - 2 0 ° C for 3 h, allowed to reach room temperature and stirred for another 72 h.
The solvents were removed in vacuo and the residual oil was purified by chromatography using
hexane:EtOAc (95:5) as eluent to give 490 mg (75%) of 6a as a yellow oil: [oth)23= - 122.4 (c=l.l in
CHC13); IH-NMR (200 MHz, CDC13) 6 8.30 (m, 4H), 7.30-7.15 (m, 4H), 6.52 (d, 1H, J=8.2 Hz),
3.9 (q, IH, J=8.4 Hz), 3.3-3.1 (m, 2H), 3.05-2.95 (m, 2H), 1.08 (d, 6H, J=6.2 Hz), 0.99 (d, 6H, J=6.6
Hz); 13C-NMR (50 MHz, CDC13) 6 166 (C), 151 (C), 141.5 (C), 139.5(C), 136.5 (C), 130.8 (CH),
128.5 (CH), 126.8 (CH), 125.0 (CH), 124.1 (CH), 123.5 (CH), 79.7 (CH), 63.6 (CH), 45.0 (CH), 34.2
(CH2), 23.4 (CH3) 22.0 (CH3); IR (KBr) 3110, 3070, 3050, 2966, 1761, 1528, 1341, 1273, 1123,
749, 720 cm-1; MS (CI, NH3) re~z: 383 (C22H26N204.H+100%).
4-Nitrobenzoic acid (1S,2R)-2-piperidino- l-indanyl ester 6b
Compound 4b of 88% e.e. (500 mg, 2.03 mmol), PPh3 (2.62 g, 10 mmol), 4-nitrobenzoic acid
(1.49 g, 8.9 mmol) in toluene (22 mL), THF (22 mL) and DEAD (1.58 mL, 10 mmol) were treated

1566
L. SOLA et al.
as described for 6a to give 0.49 g (69%) of 6b as a yellow oil: [CX]D23= - 149 (C=1.125 in CHC13);
IH-NMR (300 MHz, CDCI3) ~ 8.4-8.3 (m, 4H), 7.4-7.2 (m, 4H), 6.71 (d, 1H, ,/=5.6 Hz), 3.65-3.55
(m, 1H), 3.30 (d×d, IH, J=16 Hz, J=8 Hz), 3.0 (dxd, IH, J=16 Hz, J=7.5 Hz), 2.7-2.5 (m, 4H),
1.8-1.4 (m, 6H); 13C-NMR (75 MHz, CDCI3) 6 165 (C), 151 (C), 141.8 (C), 140.0 (C), 136.1 (C),
131.4 (CH), 129.7 (CH), 127.6 (CH), 125.5 (CH), 125.2 (CH), 124.0 (CH), 81.0 (CH), 72.5 (CH),
52.4 (CH2), 34.9 (CH2), 26.5 (CH2), 24.8 (CH2); IR (KBr) 2937, 2860, 2795, 1723, 1528, 1343,
1271, 1117, 1015, 751,720 cm-l; MS (CI, NH3) m/z: 267 (C21H22N204.H÷ 100%).
4-Nitrobenzoic acid (1S,2R)-2-di-n-butylarnino-l-indanyl ester 6c
Compound 4e of 88% e.e. (600 mg, 2.3 mmol), PPh3 (2.96 g, 11.3 mmol), 4-nitrobenzoic acid (1.67
g, 10.1 mmol) in toluene (22 mL) and THF (22 mL) and DEAD (1.96 mL, 11.3 mmol) were treated as
described for 6a to give 0.87 g (93%) of 6c as a yellow oil: [Or]D23= - 109.5 (C=0.97 in CHCI3); IH-
NMR (300 MHz, CDC13) 8 8.30-8.25 (m, 4H), 7.35-7.25 (m, 4H), 6.65 (d, IH, J=6.2 Hz), 4.1-3.9
(m, 1H), 3.22 (dxd, IH, J=16 Hz, J=6.9 Hz), 2.95 (dxd, IH, J=16 Hz, J=8 Hz), 2.7-2.5 (m, 4H),
1.6-1.5 (m, 4H), !.4-1.25 (m, 4H), 0.88 (t, 6H, J=7.3 Hz); 13C-NMR (75 MHz, CDCI3) 8 164.6
(C), 150.5 (C), 141.3 (C), 139.5 (C), 135.6 (C), 130.7 (CH), 128.9 (CH), 127.0 (CH), 124.9 (CH),
123.5 (CH), 80.4 (CH), 67.9 (CH), 50.9 (CH2), 32.2 (CH2), 30.2 (CH2), 20.4 (CH2), 14.0 (CH3); IR
(KBr) 2958, 2880, 1725, 1609, 1530, 1463, 1272, 1104, 1015, 874, 720 cm-1; MS (CI, NH3) m/z:
411 (C24H30N204.H+100%).
4-Nitrobenzoic acid (1S,2R)- 2-(cis-2, 6-dimethylpiperidino )- l-indanyl ester 6d
Compound 4d of 99% e.e. (500 mg, 2.03 mmol), PPh3 (2.62 g, 10 mmol), 4-nitrobenzoic acid (1.49
g, 8.9 mmol) in toluene (22 mL) and THF (22 mL) and DEAD (1.58 mL, 10 mmol) were treated as
described for 6a to give 0.49 g (69%) of 6d as a yellow oil: [C~]D23= - 105.3 (C=1.05 in CHCI3); IH-
NMR (300 MHz, CDCI3) 8 8.30-8.25 (m, 4H), 7.30-7.20 (m, 4H), 6.82 (d, IH, J=7.2 Hz), 4.35 (q,
IH, J=7.5 Hz), 3.25-3.0 (m, 2H), 2.9-2.75 (m, 2H), 1.7-1.6 (m, 4H), 1.45-1.35 (m, 2H), 1.14 (d, 3H,
J=6.3 Hz), 1.13 (d, 3H, J=6.3 Hz); 13C-NMR (75 MHz, CDCI3) 5 164.6 (C), 140.6 (C), 139.2 (C),
135.6 (C), 130.7 (CH), 128.8 (CH), 127.0 (CH), 125.0(CH), 124.9 (CH), 123.5 (CH), 82.2 (CH), 65.1
(CH), 53.8 (CH), 53.5 (CH), 34.2 (CH2), 33.4 (CH2), 20.7 (CH2), 20.8 (CH3), 20.5 (CH3); IR (KBr)
2939, 1717, 1530, 1273, 1123,874, 745,720 cm-l; MS (CI, NH3) re~z: 395 (C23H26N204.H+I00%).
(1S, 2R)-2-Diisopropylamino- 1-indanol 5a
To a solution 4-nitrobenzoic acid (IS,2R)-2-diisopropylamino-1-indanyl ester 6a of 88% e.e. (380
mg, 0.95 mmol) in CH2CI2 (8 mL) at -20°C under N2, DIBALH (1 M in hexanes, 7.8 mL, 7.6 mmol)
was added dropwise. The mixture was stirred at -20°C for 19 h. Brine (60 mL) and CH2C12 (90
mL) were added carefully and the mixture stirred vigorously. The organic phase was separated and
the aqueous layer extracted with CH2C12 (2x 30 mL). The combined organic extracts were dried and
concentrated in vacuo. The residual oil was purified by chromatography using hexane:EtOAc (95:5)
as eluent to give 215 mg (100%) of 5a as an oil: [0C]D23=--79.9 (C=1.2 in CHCI3); IH-NMR (300
MHz, CDCI3) 8 7.4-7.2 (m, 4H), 4.92 (d, IH, J=7 Hz), 3.30-3.20 (m, 3H), 2.9-2.8 (m, 2H), 1.11 (d,
6H, J=5.2 Hz), 1.06 (d, 6H, J=4.8 Hz); 13C-NMR (75 MHz, CDCI3) ~i 142.0 (C), 139.6 (C), 127.4
(CH), 126.5 (CH), 124.5 (CH), 123.6 (CH), 75.9 (CH), 67.2 (CH), 45.0 (CH), 34.5 (CH2), 24.9 i 21.6
(CH3); IR (KBr) 3400 (t, OH), 2975, 1475, 1400, 1360, 1225, 1050, 750 cm-I; MS (CI, NH3) m/z:
334 (CIsH23NO.H+100%).
( 1S, 2R)-2-Piperidino- l-indanol 5b
Compound 6b of 88% e.e. (445 mg, 1.24 mmol) in CH2C12 (11 mL) and DIBALH 1 M in
hexanes (9.9 mL, 9.9 mmol) were treated as described for 5a to give 185 mg (70%) of 5b as an oil:
let]D23=--27.1 (C=0.9 in CHCI3); 1H-NMR (300 MHz, CDCI3) ~ 7.6-7.0 (m, 4H), 5.18 (d, 1H, J=6.2
Hz), 3.0-2.8 (m, 3H), 2.7-2.5 (m, 4H), 1.8-1.4 (m, 6H); 13C-NMR (75 MHz, CDC13) ~ 143.4 (C),
139.3 (C), 127.9 (CH), 126.7 (CH), 124.4 (CH), 124.0 (CH), 77.3 (CH), 76.4 (CH), 52.3 (CH2), 32.3

New indane derived aminoalcohols
1567
(CH2), 25.6 (CH2), 24.2 (CH2); IR (KBr) 3395, 2941, 1459, 1212, 1127, 1063, 890, 754,652 c m - ] ;
MS (CI, NH3) re~z: 218 (CI4HI9NO.H+ 100%).
( lR,2R)-2-Di-n-but3,lamino- l-indanol 5c
Compound 6c of 88% e.e. (650 mg, 1.46 retool) in CH2C12 (13 mL) and DIBALH (1 M in
hexanes, 11.7 mL, 11.7 retool) were treated as described for 5a to give 323 mg (85%) of 5c as an oil:
[~x]D23=-46.2 (c=0.385 in CHCI3); IH-NMR (300 MHz, CDCI3) 6 7.45-7.25 (m, 4H), 5.18 (d, IH,
J=7.4 Hz), 3.50 (q, IH, J=7.6 Hz), 3.0 (d×d, IH, J=15.6 Hz, J=7.6 Hz), 2.85 (d×d, IH, J=15.6 Hz,
J=6.6 Hz), 2.8-2.4 (m, 4H), 1.65-1.45 (m, 4H), 1.5-1.3 (m, 4H), 0.95 (t, 6H, J--7.3 Hz); 13C-NMR
(75 MHz, CDCI3) 6 143.7 (C), 139.7 (C), 127.9 (CH), 126.8 (CH), 124.8 (CH), 124.0 (CH), 77.3
(CH), 72.8 (CH), 51.3 (CH2), 30.7 (CH2), 30.0 (CH2), 20.7 (CH2), 14.1 (CH3); IR (KBr) 3375, 2958,
2871, 1617, 1462, 1378, 1169, 1057, 747 cm -1' MS (CI, NH3) re~z: 262 (CI7H27NO.H + 100%).
( IS,2R)-2-(cis-2,6-Dimethyl-l-piperidino)- l-indanol 5d
Compound 6d of 99% e.e. (313 mg, 0.79 retool) in CH2C12 (5 mL) and DIBALH (1 M in hexanes,
6.4 mL, 6.4 mmol) were treated as described for 5a to give 185 mg (70%) of 5b as an oil; [c~] D23= - 15.6
(c=1.70 in CHCI3); IH-NMR (200 MHz, CDCI3) 6 7.35-7.2 (m, 4H), 5.30 (d, IH, J=7.6 Hz), 3.85
(q, IH, J=9.2 Hz). 3.0-2.8 (m, 3H), 2.7 (br s, 1H), 1.8-1.2 (m, 6H), 1.20 (d, 3H, J=6.3 Hz), 1.12
(d, 3H, J=6.3 Hz); 13C-NMR (50 MHz, CDCI3) 6 143.0 (C), 139.7 (C), 127.8 (CH), 126.7 (CH),
124.8 (CH), 124.5 (CH), 78.9 (CH), 69.7 (CH), 54.8 (CH), 54.5 (CH), 34.5 (CH2), 34.4 (CH2), 29.9
(CH2),21.7(CHz),21.6(CH3),21.1 (CH3) IR(KBr) 3400, 2931, 1611. 1463, 1378, 1318, 1216,
1154, 1055, 942, 747 cm -]" MS (CI, NH3) m/z: 246 (CI6H23NO.H+ 100%).
General procedure fiw the enantioselective aminoalcohol-catalyzed addition of diethylzinc to aldehydes
The aldehyde (1 mmol) was added at room temperature to a solution of the chiral ligand (0.06
mmol, 6 mol%) in toluene (2 mL), the mixture was stirred for 20 min and then cooled (if necessary)
to the desired temperature and diethylzinc (2.2 mL of a 1 M hexanes solution, 2.2 mmol) was added
dropwise. The reaction mixture was stirred for the corresponding reaction time under N2, quenched by
the addition of a saturated NH4CI solution (10 mL), and the mixture was then extracted with CH2C12
(3× 10 mL). The combined organic extracts were dried and concentrated in vacuo and the enantiomeric
excesses were determined from the crude mixture by GC analyses. Conditions of GC analyses: [3-
DEX@ or o~-DEX@ 120 column, 30 m length, 0.25 mm intern diameter, isotherm temperature program,
He as carrier gas (2.4 mL/min). For 1-phenylpropanol: I3-DEX 120@ column, 112°C, tR R isomer
49.3 min, tR S isomer 52.0 min. For l-(p-tolyl)propanol: [3-DEX 120@ column, 120°C, tR R isomer
48.1 min, tR S isomer 51.9 min. For l-(4-methoxyphenyl)propanol: [3-DEX 120@ column, 135°C,
tR R isomer 65.3 min, tR S isomer 68. l min. For l-(4-fluorophenyl)propanol: I3-DEX 120@ column,
112°C, te R isomer 53.1 min, tR S isomer 58.8 min. For l-(2-chlorophenyl)propanol: 13-DEX 120@
column, 135°C, tR R isomer 45.8 rain, tR S isomer 50.2 min. For 1-(1-naphthyl)propanol: [3-DEX
120@ column, 160°C, tR S isomer 96.5 min, tR R isomer 101.1 rain. For 1-phenyl-3-pentanol: cx-DEX
120@ column, 115°C, tR R isomer 74.4 rain, tR S isomer 75.6 min. For 5-methyl-3-hexanol: 01-DEX
120@ column, 65°C, tR R isomer 14.7 min, tR S isomer 15.2 min.
Acknowledgements
Financial support from CIRIT-CICYT (QFN93-4407), from DGICYT (PB95-0265) and from CIRIT
(GRQ93-1083) is gratefully acknowledged. Anton Vidal-Ferran thanks MEC for a contract under the
program Acciones para la Incorporacidn a Espa~a de Doctores y Tecn6logos.
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1568
L. SOLA et al.
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11. Theoretical and experimental results on the rational design of cis-2,6-dimethylpiperidino containing
ligands will be reported separately.
(Received in UK 27 February 1997; accepted 8 April 1997)