Perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol as ligands for the catalytic enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2010.07.016

The catalytic potency of a series of perhydro-1,3-benzoxazines prepared from (-)-8-aminomenthol was examined in the enantioselective addition of diethylzinc to aldehydes. When (2R,3S,3aS,4aR,6R,8aS)-2-isopropyl-6,9,9- trimethyl-3-phenyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7b was used as a chiral ligand, 1-substituted propanols with an (R)-configuration were obtained in high yields and enantiomeric excesses up to >99%. The catalyst can be recovered and used without any loss in its activity.

Full text of DOI:10.1016/j.tetasy.2010.07.016

Tetrahedron: Asymmetry 21 (2010) 2230–2237
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Tetrahedron: Asymmetry
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Perhydro-1,3-benzoxazines derived from (ꢀ)-8-aminomenthol as ligands
for the catalytic enantioselective addition of diethylzinc to aldehydes
*
*
Celia Andrés , Rebeca Infante, Javier Nieto
IU CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic potency of a series of perhydro-1,3-benzoxazines prepared from (ꢀ)-8-aminomenthol was
examined in the enantioselective addition of diethylzinc to aldehydes. When (2R,3S,3aS,4aR,6R,8aS)-2-
isopropyl-6,9,9-trimethyl-3-phenyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7b was used as a
chiral ligand, 1-substituted propanols with an (R)-configuration were obtained in high yields and enan-
tiomeric excesses up to >99%. The catalyst can be recovered and used without any loss in its activity.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 June 2010
Accepted 15 July 2010
Available online 13 August 2010
1. Introduction
2. Results and discussion
Catalytic asymmetric carbon–carbon bond formation is known
as one of the most important organic synthetic processes. In this
field, considerable attention has been devoted to the enantioselec-
tive addition of dialkylzincs to aldehydes in the presence of
catalytic amounts of a chiral ligand.1 The process constitutes a
fundamental and versatile method for obtaining optically active
secondary alcohols, which are versatile and important chiral build-
ing blocks for the synthesis of natural products and biologically ac-
tive compounds. In addition, the reaction of diethylzinc with
aldehydes has also become a classical test in the design of new li-
gands for catalytic enantioselective synthesis.
We began by examining the behavior of zinc amides derived from
perhydro-1,3-benzoxazines 2a–e which essentially differ in the nat-
ure and size of the substituent at the N,O-ketalic carbon of the hetero-
cycle, and the C-2 symmetric chiral bisperhydrobenzoxazine 2f.
Theseperhydro-1,3-benzoxazineswere prepared, assingle diastereo-
mers, in good yields by condensation of (ꢀ)-8-aminomenthol 18 with
the corresponding aldehyde in refluxing toluene (Scheme 1).9
The catalytic potency of 2a–f was examined using the reaction
between Et2Zn and 2-naphthaldehyde with 10 mol % of the catalyst
in a toluene/hexane 2:1 mixture at room temperature for 24 h; the
results are summarized in Table 1.
Since Oguni and Omi reported the first addition of diethylzinc to
aldehydes catalyzed by (S)-leucinol,2 numerous chiral ligands such
as sulfonamide and phosphoramide complexes, chiral amides, dia-
mines, diols and BINOL derivatives, oxazolines, imino alcohols, and
amino alcohols or amino thiols have been developed although b-
amino alcohols hold a prominent position.3 Other five-membered
chiral heterocycles such as oxazolidines have been used less4 de-
spite being promising ligands in the asymmetric addition of alky-
nylzinc to aldehydes.5
Over the last few years, we have reported the utility of chiral
perhydro-1,3-benzoxazines derived from (ꢀ)-8-aminomenthol as
stoichiometric chiral auxiliaries covalently attached to substrate
in diastereoselective synthesis.6,7
Based on the results reported for oxazolidines, we thought that
chiral perhydro-1,3-benzoxazines ligands could also catalyze the
asymmetric addition of dialkylzinc to aldehydes. Herein we report
the discovery of a new chiral perhydro-1,3-benzoxazine-based li-
gand for the asymmetric addition of diethylzinc to aldehydes with
high ee values under mild conditions.
In general, the reactions occurred in good yields but the enanti-
oselectivity induced by chiral perhydro-1,3-benzoxazines 2a–f
was not very high. The best result was obtained with bis-
perhydrobenzoxazine 2f, but the enantioselectivity was just over
50%. In order to improve the observed enantiomeric excesses for this
catalytic process, perhydro-1,3-benzoxazines 2g and 2h bearing a
hydroxyl group were tested. Benzoxazine 2g was prepared as a sin-
gle diastereoisomer in excellent yield by the condensation of (ꢀ)-8-
aminomenthol with phenylglyoxal and a subsequent addition of
phenylmagnesium bromide to the resulting 2-benzoyl perhydro-
1,3-benzoxazine in diethyl ether at 0 °C. As previously described,10
the condensation of (ꢀ)-8-aminomenthol with the glycolaldehyde
dimer in CH2Cl2 at room temperature yielded nearly quantitative
benzoxazine 2h (Scheme 1). Unfortunately both 2g and 2h provided
poor enantioselectivities despite having the structure of a b-amino
alcohol (Table 1, entries 7 and 8). It is interesting to note that
the catalysts 2a–f induced the formation of (S)-1-(naphthalen-
2-yl)propan-1-ol, whereas benzoxazines 2g and 2h provided the
(R)-enantiomer.
Generally, it was expected from the reports in the literature
that the enantioselectivity would increase when the degree of
N-alkyl substitution increased in b-amino alcohols.1b However, the
* Corresponding authors. Tel.: +34 983423564; fax: +34 983423013 (J.N.).
E-mail address: javiernr@qo.uva.es (J. Nieto).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.016

C. Andrés et al. / Tetrahedron: Asymmetry 21 (2010) 2230–2237
2231
Table 1
H
Addition of Et2Zn to 2-naphthaldehyde promoted by chiral perhydro-1,3-benzoxa-
zines 2a–j, 4b, 4d, 4e, 5a–e, 6b, 6e, 7a, 7b and 7e
NH2
OH
N
R1
i
O
*
CHO
1
OH
10 mol% Ligand, Et2Zn
Toluene-hexane, rt
2a, R1 = CH3
2b, R1 = iPr
2c, R1 = Ph
ii
Entrya
Ligand
Yieldb (%)
eec (%)
Config.d
2d, R1 = 1-naphthyl
2e, R1 = 2-naphthyl
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2a
2b
2c
2d
2e
2f
2g
2h
2i
80
50
80
79
83
80
61
52
65
38
12
48
60
95
85
85
80
90
18
68
93
95
44
25
6
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(R)
(R)
H
N
39
17
44
54
30
21
28
25
15
9
38
88
75
76
64
52
15
21
80
97
28
O
N
O
H
2f
2j
4b
4d
4e
5a
5b
5c
5d
5e
6b
6e
7a
7b
7e
H
NH2
OH
N
iii, iv
OH
O
1
2g
v
R2
H
a
b
c
All reactions were carried out for 24 h under argon.
Yield refers to pure compounds after column chromatography.
Enantiomeric excess was determined by HPLC analysis using a chiral column.
The absolute configuration was assigned by comparing the sign of the specific
N
N
OH
vi
OH
d
O
O
rotation and tR of the HPLC analysis with that of the literature data.
2i, R2 = H
2h
2j, R2 = P h
Scheme 1. Reagents and conditions: (i) R1CHO, toluene, reflux, 2a (98%), 2b (88%),
2c (99%), 2d (96%), 2e (98%); (ii) isophthalaldehyde, toluene, reflux, 86%; (iii)
PhCOCHO, CH2Cl2, rt; (iv) PhMgBr, Et2O, 0 °C, 83%; (v) glycolaldehyde dimer, CH2Cl2,
rt, 99%; (vi) R2CH@CHCH2Br, K2CO3, CH3CN, 80–90 °C, 2i (80%), 2j (88%).
R3
R3
OH
N
N
N
H
O
+
R3
OH
O
O
O
H
N-substituted ligands 2i and 2j obtained by alkylation of 2h with
allyl and cinnamyl bromides in the presence of potassium carbon-
ate in refluxing acetonitrile (Scheme 1),10 resulted in only a modest
improvement in the enantioselectivity of the reaction.
We have recently reported the utility of chiral perhydro-1,3-
benzoxazines derived from (ꢀ)-8-aminomenthol in the synthesis
of cis-3,4-disubstituted pyrrolidines by thermally11 or Lewis
acid12-induced intramolecular carbonyl-ene cyclizations. The
cyclization reaction of ketones 3a–e gave a mixture of two cis-3-
hydroxy-3,4-disubstituted pyrrolidines 4a–e and 5a–e fused with
a perhydrobenzoxazine structure and both diastereomers can be
obtained as the major products depending on the reaction condi-
tions (Scheme 2).
3a, R3 = H
5a-e
4a-e
3b, R3 = C6H5
3c, R3 = p-CH3-C6H4
3d, R3 = p-OCH3-C6H4
3e, R3 = iPr
Scheme 2. Diastereoselective keto-ene cyclization of compounds 3a–e.
(entry 14) and 85% yield and 75% ee in the presence of 5b (entry
15). Encouraged by these results, we decided to increase the steric
volume in the vicinity of the hydroxyl group by catalytic hydroge-
nation of the prenyl group to an isopropyl group using hydrogen
and Pd/C catalyst in ethanol (Scheme 3).
We believed that these more rigid structures might discriminate
better between the two enantiotopic faces of the aldehyde within
the transition state complex. Thus, we examined the catalytic
potency of some of these decahydro-4aH-pyrrolo[2,1-b][1,3]benz-
oxazin-3-ols as chiral ligands in the asymmetric ethylation of
naphthaldehyde. The data obtained are also summarized in Table 1.
The results showed that both the chemical yield and the enantiose-
lectivity of the products catalyzed by ligands 4 were low (<38% ee,
entries 11–13). However, when ligands 5 were used, we found a
great improvement not only in the enantioselectivity but also in
the chemical yield (entries 14–18). The (R)-1-(20-naphthyl)-1-pro-
panol was obtained in 95% yield and 88% ee in the presence of 5a
The new ligands 6b, 6e, 7a, and 7e did not improve the ee in the
ethylation of 2-naphthaldehyde (compare entries 11, 13, 14, and
18 vs entries 19, 20, 21, and 23). However, it was surprising that
when ligand 7b was used, both the enantioselectivity and the
chemical yield were excellent (entry 22, 97% ee, 95% yield).
In order to better understand the applications and limitations of
the ligand 7b, different aldehydes were carefully examined. The re-
sults are summarized in Table 2.
Optically active secondary alcohols with >93% ee and excellent
chemical yields were obtained in the enantioselective addition of
diethylzinc to aromatic aldehydes. Aromatic aldehydes bearing
electron-donating and electron-withdrawing groups behaved

2232
C. Andrés et al. / Tetrahedron: Asymmetry 21 (2010) 2230–2237
R3
H
N
Ph
H
N
Ph
OH
N
H
i
i
OH
O
4b, e
OH
O
OH
6b, R3 = C6H5
8b
6b
3
i
6e,
R = Pr
OH
H
OH
OH
N
N
N
ii
i
5a,b,e
Ph
O
Ph
R3
H
OH
O
H
9b
7b
3
7a,
R = H
7b, R3 = C6H5
Scheme 4. Reagents and conditions: (i) LiAlH4, AlCl3, THF, ꢀ10 °C, 92%; (ii)
NaBH3CN, MeOH, HCl 0.1 M (pH ꢁ4), 60 °C, 83%.
3
i
7e,
R = Pr
Scheme 3. Reagents and conditions: (i) 10 wt % Pd/C, H2, EtOH, rt, 6b (93%), 6e
(78%), 7a (92%), 7b (93%), 7e (80%).
Table 3
Addition of Et2Zn to aldehydes promoted by chiral perhydro-1,3-benzoxazines 8b and
9b, and pyrrolidines 11b and 12b
similarly. The best asymmetric induction was found when using
p-trifluoromethylbenzaldehyde as the substrate with a strong elec-
tron-withdrawing –CF3 group which gave up to 99% ee (Table 2, en-
try 12). The enantioselectivity was also excellent for heterocyclic
aldehydes (Table 2, entries 15 and 16). Most gratifyingly, our ligand
was also very effective in the enantioselective addition of diethyl-
Entrya
Ligand
Aldehyde
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
8b
8b
9b
9b
2-Naphthaldehyde
p-Anisaldehyde
2-Naphthaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
2-Naphthaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
84
66
71e
67e
69e
90
93
89
83
95
93
96
91
53 (S)
40 (S)
9 (S)
4 (S)
7 (S)
65 (S)
71 (S)
61 (S)
62 (S)
87 (S)
88 (S)
89 (S)
86 (S)
9b
11b
11b
11b
11b
12b
12b
12b
12b
zinc to the aliphatic hydrocinnamaldehyde (entry 17) and
a,b-
unsaturated aldehydes (entries 13 and 14). Only in the case of
cinnamaldehyde did the ee drop below 90%.13 In addition to the high
enantioselectivity, the reaction time decreased significantly. In all
cases, the reactions were completed in less than 45 min.
For the best catalyst 7b, the relationship between the amount of
the catalyst and the enantioselectivity observed was also exam-
ined. When the quantity of 7b was decreased from 10 mol % to
1 mol %, the enantioselectivity in the ethylation of 2-naphtalde-
hyde remained at 96%, although it was necessary to increase the
reaction time up to 12 h to obtain a 95% chemical yield. A lower
1-Naphthaldehyde
a
b
c
The reactions were processed for 24 h under argon.
Yield refers to pure compounds after column chromatography.
Enantiomeric excess was determined by HPLC analysis using a chiral column.
The absolute configuration was assigned by comparing the sign of the specific
d
rotation and tR of the HPLC analysis with that of literature data.
e
The reactions were processed for 48 h under argon.
Table 2
Addition of Et2Zn to aldehydes promoted by chiral perhydro-1,3-benzoxazine 7b
amount of catalyst (0.2 mol % 7b) led to a slight decrease of both
the enantioselectivity (92% ee) and the yield of the reaction (90%
yield).
O
H
OH
10 mol% 7b, Et2Zn
R
H
R
Toluene-hexane, rt
Entrya
Aldehyde
Yieldb (%)
eec (%)
H
H
i, ii, iii
iv, v
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2-Naphthaldehyde
1-Naphthaldehyde
Benzaldehyde
o-Tolylaldehyde
o-Anisaldehyde
o-Chlorobenzaldehyde
o-Bromobenzaldehyde
m-Chlorobenzaldehyde
p-Tolylaldehyde
95
89
94
96
97
97
99
87
98
99
98
99
93
93
83
94
90
97
96
94
97
95
94
93
96
97
97
97
99
88
94
95
96
93
4b
Ph
OH
HN
Ph
OH
N
11b
10b
vi
H
p-Anisaldehyde
p-Chlorobenzaldehyde
p-Trifluoromethylbenzaldehyde
(E)-Cinnamaldehyde
(E)-a-Methylcinnamaldehyde
2-Furylcarboxaldehyde
Ph
OH
N
12b
2-Thiophenecarboxaldehyde
3-Phenylpropionaldehyde
Scheme 5. Reagents and conditions: (i) LiAlH4, AlCl3, THF, ꢀ10 °C; (ii) PCC, CH2Cl2,
4 Å molecular sieves, rt; (iii) KOH, H2O–MeOH–THF, rt, 48% from 4b; (iv) dimethyl
pyrocarbonate, CH2Cl2, rt; (v) LiAlH4, Et2O, rt, 70%; (vi) 10 wt % Pd/C, H2, EtOH, rt,
80%.
a
b
c
All reactions were processed for 30–45 min under argon.
Yield refers to pure compounds after column chromatography.
Enantiomeric excess was determined by HPLC analysis using a chiral column.

C. Andrés et al. / Tetrahedron: Asymmetry 21 (2010) 2230–2237
4. Experimental
2233
H
R
4.1. Materials and methods
O
Zn
Zn
O
All reactions were carried out in anhydrous solvents under an
argon atmosphere and in oven-dried glasswares. 1H NMR
(300 MHz) and 13C NMR (75 MHz) were registered in CDCl3 as sol-
vent and chemical shifts are given relative to TMS as an internal
reference. Specific rotations were determined on a digital polarim-
eter using a Na lamp and concentration is given in g per 100 mL.
Melting points were determined in open capillary tubes and are
uncorrected. Solvents were dried by standard methods. TLC was
performed on glass-backed plates coated with silica gel 60 with
F254 indicator; the chromatograms were visualized under UV light
and/or by staining with a Ce/Mo reagent. Flash chromatography
was carried out on silica gel 60 (230–240 mesh). Chiral HPLC anal-
ysis was performed using a Daicel Chiralcel OD column (250 ꢂ 4.6
mm), Chiralpak AS-H or Chiralpak AD-H column (250 ꢂ 4.6 mm).
UV detection was monitored at 220 nm or at 254 nm.
N
O
Ph
H
Figure 1. Proposed transition state for the asymmetric addition with 7b.
On the other hand, ligand 7b could be recovered in more than
80% yield after the reaction had been finished by quenching by
the addition of an aqueous ammonium chloride solution, diethyl
ether extraction, and chromatography purification. The recovered
ligand 7b could be reused in two subsequent cycles as the catalyst
in the reaction of ethylation of 2-naphthaldehyde, giving the same
results as freshly prepared catalyst without an obvious decrease in
chemical yield or ee values (cycle 1, 95% yield, 95% ee and cycle 2,
95% yield, 94% ee).
Compounds 2a,16 2c–e,9 2h–j,10 4b,e,11 4d,12 5a,b,e11 and 5c,d12
have been previously described.
4.2. Synthesis of octahydro-1,3-benzoxazines 2a–f
With the aim of evaluating the influence and contribution
exerted by the benzoxazine ring in the asymmetric induction, we
tested the behavior as chiral ligands of the amino menthol deriva-
tives 8b and 9b. Ligands 8b and 9b were obtained by the reductive
ring opening of the 1,3-oxazine ring of 6b and 7b with aluminum
hydride and sodium cyanoborohydride, respectively (Scheme 4).
As shown in Table 3, the ethylation of aromatic aldehydes in the
presence of 8b gave (S)-alcohols in acceptable chemical yields
but with modest enantioselectivity (entries 1 and 2) while negligi-
ble enantioselectivity was induced by 9b (entries 3–5).
A solution of (ꢀ)-8-aminomenthol (2.0 g, 11.7 mmol) and the
appropriate aldehyde (12.9 mmol) in toluene (50 mL) was refluxed
until the reaction was complete (TLC 3–6 h). The solvent was evap-
orated under vacuum, and the residue was purified by recrystalli-
zation and/or by flash chromatography on silica gel using hexane/
EtOAc 8:1 as eluent. For the preparation of bisperhydrobenzox-
azine 2f, only 6.45 mmol of isophthalaldehyde were used.
4.2.1. (2S,4aS,7R,8aR)-2-Isopropyl-4,4,7-trimethyloctahydro-2H-
On the other hand, as previously described,11 the reductive ring
opening of the 1,3-oxazine ring of 4b and elimination of the menthol
appendage by oxidation with PCC followed by treatment with a
2.5 M solution of KOH in THF–MeOH–H2O yielded the correspond-
ing 3-hydroxypyrrolidine derivative 10b which could be easily
methylated by treatment with dimethyl pyrocarbonate, followed
by LAH reduction of the resulting carbamate (Scheme 5). The result-
ing 3-hydroxypyrrolidinol 11b was also tested as a chiral ligand in
the addition of Et2Zn to aldehydes. 1-Substituted propanols with
an (S)-configurationwere obtained in good yields butwith moderate
enantioselectivities (Table 3, entries 6–9). The yields and the enanti-
oselectivities improved considerably when 3-hydroxypyrrolidinol
12b, obtained by catalytic hydrogenation of the prenyl to an isopro-
pyl group, was tested but the enantioselectivity remained below
90%.14 These results suggest that the presence of the oxazine ring
is crucial for getting good enantioselectivities.
1,3-benzoxazine 2b
Yield: 88%. Colorless oil. ½a D25
ꢃ
¼ þ7:8 (c 1.1, CHCl3) .1H NMR (d):
0.85–1.05 (m, 4H); 0.90 (d, 3H, J = 6.5 Hz); 0.93 (d, 6H, J = 6.7 Hz);
1.05 (s, 3H); 1.06 (s, 3H); 1.18 (m, 1H); 1.48–1.75 (m, 4H); 1.91 (m,
1H); 3.34 (td, 1H, J1 = 10.2 Hz, J2 = 4.0 Hz); 4.00 (d, 1H, J = 5.2 Hz).
13C NMR (d): 17.4 (CH3); 18.1 (CH3); 19.6 (CH3); 22.2 (CH3); 25.4
(CH2); 29.6 (CH3); 31.2 (CH); 32.8 (CH); 34.9 (CH2); 41.6 (CH2);
50.8 (C); 51.8 (CH); 74.7 (CH); 86.5 (CH). IR (Film): 3310, 1745,
760 cmꢀ1. HRMS: calcd for C14H28NO [M+H]+ 226.217, found
226.2169.
4.2.2. (2S,4aS,7R,8aR,20S,4a0S,70R,8a0R)-Benzene-1,3-diylbis(4,4,7-
trimethyloctahydro-2H-1,3-benzoxazine) 2f
Yield: 86%. Colorless solid. Mp: 130–131 °C (from ethanol).
½
a 2D5
ꢃ
¼ þ75:8 (c 1.2, CHCl3) 1H NMR (d): 0.86–1.07 (m, 4H); 0.95
(d, 6H, J = 6.5 Hz); 1.10–1.19 (m, 4H); 1.12 (s, 6H); 1.20 (s, 6H);
1.52 (m, 2H); 1.60 (m, 2H); 1.66–1.75 (m, 4H); 2.01 (m, 2H); 3.58
(td, 2H, J1 = 10.3, Hz, J2 = 4.2 Hz); 5.34 (s, 2H); 7.30 (m, 1H); 7.39
(m, 2H); 7.58 (s, 1H). 13C NMR (d): 19.6 (2 CH3); 22.3 (2 CH3);
25.6 (2 CH2); 29.8 (2 CH3); 31.4 (2 CH); 35.0 (2 CH2); 41.6 (2
CH2); 51.5 (2 CH); 51.7 (2 C); 75.2 (2 CH); 83.7 (2 CH); 123.6
(CH); 125.5 (2 CH); 128.3 (2 CH); 141.1 (C). IR (Nujol): 3300,
We propose the transition state shown in Figure 1, in agreement
with the anti-transition state structure proposed by Noyori,15 to ac-
count for the stereoselectivity observed with chiral ligand 7b. In this
transition state, the transfer of the ethyl group occurs to the re-face
of the aldehyde, leading to the (R)-enantiomer of the alcohols.
3050, 1720, 1605, 750, 705, 610 cmꢀ1
28H45N2O2 [M+H]+ 441.3481, found 441.3463.
. HRMS: calcd for
3. Conclusion
C
In conclusion, we have developed a highly effective, new perhy-
dro-1,3-benzoxazine-based chiral ligand 7b for the diethylzinc
addition reaction to aldehydes under mild conditions. A wide vari-
ety of secondary alcohols have been obtained in up to 99% yields
and 99% ee’s. This catalyst is a stable crystalline solid and can be
conveniently prepared on a gram scale from (ꢀ)-8-aminomenthol
in four simple steps and with a good yield.11 The catalytic effect
of this ligand to other asymmetric reactions is currently under
investigation in our laboratory and will be reported in due course.
4.3. Preparation of benzoxazine 2g
A mixture of (ꢀ)-8-aminomenthol (2.5 g, 15 mmol) and phenyl-
glyoxal (2.01 g, 15 mmol) in dichloromethane (75 mL) was stirred
for 24 h at room temperature. The solvent was removed under vac-
uum, quantitatively yielding the 2-benzoyl perhydrobenzoxazine.
This perhydrobenzoxazine was dissolved in anhydrous ethyl ether
(50 mL), cooled to 0 °C, and a commercial (Aldrich) ether 3.0 M

2234
C. Andrés et al. / Tetrahedron: Asymmetry 21 (2010) 2230–2237
solution of phenylmagnesium bromide (7.0 mL) was added drop-
wise, under an argon atmosphere. Stirring was continued until
the disappearance of the starting ketone (TLC, 45 min). The
reaction was quenched with a saturated aqueous solution of NH4Cl
(50 mL). The layers were separated and the aqueous layer was ex-
tracted with ethyl acetate (3 ꢂ 20 mL). The combined organic lay-
ers were washed with brine, dried over MgSO4, concentrated at
reduced pressure, and the residue was purified by flash chromatog-
raphy on silica gel, using hexanes/ethyl acetate 60:1 as eluent.
4.4.3. (2R,3S,3aS,4aR,6R,8aS)-2-Isopropyl-6,9,9-
trimethyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7a
Yield: 92%. Colorless solid. Mp: 73–74 °C (from ethanol).
½
a 2D5
ꢃ
¼ ꢀ45:9 (c 1.1, CHCl3). 1H NMR (d): 0.86 (d, 3H, J = 6.7 Hz),
0.88 (d, 3H, J = 6.7 Hz), 0.88–1.03 (m, 3H), 0.96 (d, 3H, J = 6.5 Hz),
1.10 (s, 3H), 1.13 (s, 3H), 1.35–1.42 (m, 2H), 1.56 (m, 1H), 1.65–
1.75 (m, 2H), 1.83 (m, 1H), 1.84–2.00 (m, 2H), 2.60 (dd, 1H,
J1 = 9.1 Hz, J2 = 7.1 Hz), 3.10 (dd, 1H, J1 = 9.7 Hz, J2 = 9.1 Hz), 3.39
(td, 1H, J1 = 10.4 Hz, J2 = 4.1 Hz), 3.89 (s, 1H), 4.65 (s, 1H). 13C
NMR (d): 21.3 (CH3), 21.7 (2 CH3), 22.2 (CH3), 24.7 (CH2), 26.2
(CH3), 27.8 (CH), 31.2 (CH), 35.0 (CH2), 41.4 (CH2), 43.2 (CH), 47.7
(CH2, CH), 52.7 (C), 74.2 (CH), 74.5 (CH), 91.3 (CH). IR (Nujol):
3500 (br), 1735, 1030, 735, 710 cmꢀ1. HRMS: calcd for C17H32NO2
[M+H]+ 282.2433, found 282.2431.
4.3.1. [(2S,4aS,7R,8aR)-4,4,7-Trimethyloctahydro-2H-1,3-
benzoxazin-2-yl](diphenyl)methanol 2g
Yield: 83%. Colorless solid. Mp: 91–92 °C (from ethanol).
½
a 2D5
ꢃ
¼ þ50:5 (c 1.0, CHCl3). 1H NMR (d): 0.73–1.08 (m, 4H); 0.81
(d, 3H, J = 6.6 Hz); 0.91 (s, 3H); 0.99 (s, 3H); 1.23 (m, 1H); 1.36
(m, 1H); 1.52–1.60 (m, 2H); 1.82 (m, 1H); 3.41 (td, 1H,
J1 = 10.3 Hz, J2 = 4.0 Hz); 3.99 (s, 1H); 4.87 (s, 1H); 7.20–7.23 (m,
6H); 7.36–7.40 (m, 2H); 7.55–7.59 (m, 2H). 13C NMR (d): 19.6
(CH3); 22.2 (CH3); 25.4 (CH2); 29.8 (CH3); 31.3 (CH); 34.9 (CH2);
41.4 (CH2); 51.5 (C); 51.7 (CH); 75.6 (CH); 77.2 (C); 86.4 (CH);
126.8 (CH); 126.9 (CH); 127.0 (2 CH); 127.4 (2 CH); 127.6 (2
CH); 127.7 (2 CH); 144.1 (C); 144.2 (C). HRMS: calcd for
4.4.4. (2R,3S,3aS,4aR,6R,8aS)-2-Isopropyl-6,9,9-trimethyl-3-
phenyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7b
Yield: 93%. Colorless solid. Mp: 91–92 °C (from ethanol).
½
a 2D5
ꢃ
¼ ꢀ92:9 (c 1.1, CHCl3). 1H NMR (d): 0.47 (d, 3H, J = 6.5 Hz),
0.88 (d, 3H, J = 6.5 Hz), 0.89 (d, 3H, J = 6.5 Hz), 0.90–1.10 (m, 3H),
1.13 (s, 3H), 1.14 (s, 3H), 1.37 (m, 1H), 1.43–1.60 (m, 2H), 1.69
(m, 1H), 1.72–1.90 (m, 2H), 2.52 (td, 1H, J1 = 9.9 Hz, J2 = 6.0 Hz),
2.72 (dd, 1H, J1 = 9.1 Hz, J2 = 6.0 Hz), 2.89 (s, 1H), 3.22 (td, 1H,
J1 = 10.4 Hz, J2 = 4.0 Hz), 3.39 (dd, 1H, J1 = 9.9 Hz, J2 = 9.1 Hz), 4.30
(s, 1H), 7.18–7.31 (m, 3H), 7.63–7.63 (m, 2H). 13C NMR (d): 22.3
(CH3), 22.4 (CH3); 22.5 (2 CH3), 24.8 (CH2), 26.2 (CH3), 29.6 (CH),
31.2 (CH), 35.2 (CH2), 41.2 (CH2), 42.7 (CH), 49.0 (CH2), 51.1 (CH),
53.1 (C), 74.4 (CH), 81.4 (C), 93.7 (CH), 126.4 (CH), 126.9 (2 CH),
127.0 (2 CH3), 140.7 (C). IR (Nujol): 3505, 3060, 2935, 1500,
1035, 700 cmꢀ1. HRMS: calcd for C23H36NO2 [M+H]+ 358.2746,
found 358.2741.
C
24H32NO2 [M+H]+ 366.2433, found 366.2413.
4.4. Synthesis of octahydro-1,3-benzoxazines 6b, 6e, 7a, 7b and
7e
A mixture of the corresponding 1,3-benzoxazine 4b, 4e, 5a, 5b
or 5e (4.0 mmol) and 10 wt % palladium on carbon (75 mg) in eth-
anol (30 mL) was stirred at room temperature under H2 at atmo-
spheric pressure until the reaction was completed (TLC, 24–48 h).
The catalyst was separated by filtration over a pad of Celite. The
solvent was eliminated on a rotavapor, and the residue was puri-
fied by flash chromatography on silica gel, using a mixture of hex-
ane–ethyl acetate as eluent.
4.4.5. (2R,3R,3aS,4aR,6R,8aS)-2,3-Diisopropyl-6,9,9-
trimethyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7e
Yield: 80%. Colorless oil. ½a D25
ꢃ
¼ ꢀ51:5 (c 0.7, CHCl3). 1H NMR
(d): 0.83–1.15 (m, 3H), 0.91 (d, 3H, J = 6.6 Hz), 0.94 (d, 3H,
J = 6.6 Hz), 0.97 (d, 3H, J = 6.6 Hz), 1.01 (d, 3H, J = 6.9 Hz), 1.05 (d,
3H, J = 6.9 Hz), 1.09 (s, 3H), 1.13 (s, 3H), 1.39–1.42 (m, 2H); 1.48
(m, 1H); 1.71 (m, 1H), 1.88 (m, 1H), 1.90–210 (m, 3H), 2.13 (m,
1H), 2.68 (dd, 1H, J1 = 8.9 Hz, J2 = 5.3 Hz), 3.14 (dd, 1H, J1 = 9.8 Hz,
J2 = 8.9 Hz), 3.29 (td, 1H, J = 10.4 Hz, J2 = 4.1 Hz), 4.43 (s, 1H). 13C
NMR (d): 17.7 (CH3), 18.8 (CH3), 20.8 (CH3), 22.3 (CH3), 22.4
(CH3), 22.9 (CH3), 24.9 (CH2), 26.3 (CH3), 28.2 (CH), 31.4 (CH),
32.7 (CH), 35.2 (CH2), 41.4 (CH2), 42.7 (CH), 46.2 (CH), 47.0 (CH2),
52.9 (C), 74.4 (CH), 83.9 (C), 93.0 (CH). IR (Film): 3530, 2930,
760, 715 cmꢀ1. HRMS: calcd for C20H38NO2 [M+H]+ 324.2903,
found 324.2894.
4.4.1. (2S,3R,3aS,4aR,6R,8aS)-2-Isopropyl-6,9,9-trimethyl-3-
phenyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 6b
Yield: 93%. Colorless oil. ½a D25
ꢃ
¼ ꢀ52:2 (c 1.0, CHCl3). 1H NMR
(d): 0.73 (d, 3H, J = 6.2 Hz), 0.86 (d, 3H, J = 6.2 Hz), 0.93 (d, 3H,
J = 6.5 Hz), 0.89–1.18 (m, 3H), 1.14 (s, 3H), 1.21 (s, 3H), 1.42–1.52
(m, 2H), 1.66 (m, 1H), 1.72 (m, 1H), 1.87–2.06 (m, 3H), 2.96 (dd,
1H, J1 = 8.7 Hz, J2 = 8.1 Hz), 3.12 (dd, 1H, J1 = 8.1 Hz, J2 = 7.6 Hz),
3.45 (td, 1H, J1 = 10.5 Hz, J2 = 4.2 Hz), 3.75 (s, 1H), 4.55 (s, 1H),
7.19–7.24 (m, 1H), 7.27–7.36 (m, 2H); 7.67–7.68 (m, 2H). 13C
NMR (d): 19.2 (CH3), 21.7 (CH3), 22.0 (CH3), 22.2 (CH3), 24.8
(CH2), 27.0 (CH3), 28.4 (CH), 31.2 (CH), 34.9 (CH2), 41.1 (CH2),
45.1 (CH), 48.7 (CH2), 53.5 (C), 56.9 (CH), 75.0 (CH), 79.8 (C), 92.8
(CH), 124.6 (2 CH), 126.0 (CH), 127.7 (2 CH), 148.8 (C). IR (Film):
3510, 3060, 3025, 1605, 705, 670, 640 cmꢀ1. HRMS: calcd for
4.5. Preparation of amino alcohol 8b
C
23H36NO2 [M+H]+ 358.2746, found 358.2744.
Dry AlCl3 (133 mg, 1.0 mmol) was added, in portions, to a sus-
pension of LiAlH4 (114 mg, 3.0 mmol) in anhydrous THF (15 mL)
cooled to ꢀ10 °C. The mixture was stirred for 10 min and a solution
of 6b (215 mg, 0.6 mmol) in dry THF (10 mL) was added slowly.
The reaction mixture was stirred for 8 min at ꢀ10 °C and the
reaction was quenched by the addition of a 20% NaOH solu-
tion (1.5 mL). The resulting mixture was filtered. The solid was
washed with EtOAc, and the organic layer was dried (MgSO4).
The solvent was eliminated under reduced pressure and the
residue was chromatographed on silica gel with hexane/EtOAc
3:1 as eluent.
4.4.2. (2S,3S,3aS,4aR,6R,8aS)-2,3-Diisopropyl-6,9,9-
trimethyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 6e
Yield: 78%. Colorless oil. ½a D25
ꢃ
¼ ꢀ36:8 (c 0.9, CHCl3). 1H NMR
(d): 0.86 (d, 3H, J = 6.3 Hz), 0.90–1.11 (m, 3H), 0.91 (d, 3H,
J = 6.8 Hz), 0.92 (d, 3H, J = 6.5 Hz), 0.94 (d, 3H, J = 6.8 Hz), 0.98 (d,
3H, J = 6.3 Hz), 1.08 (s, 3H), 1.11 (s, 3H), 1.40–1.53 (m, 2H), 1.60
(m, 1H), 1.68–1.85 (m, 4H), 1.90 (m, 1H), 2.80–288 (m, 2H), 3.21
(s, 1H), 3.46 (td, 1H, J1 = 10.5 Hz, J2 = 4.2 Hz), 4.49 (s, 1H). 13C
NMR (d): 17.5 (CH3), 17.7 (CH3), 20.8 (CH3), 21.0 (CH3), 22.3
(CH3), 23.2 (CH3), 24.9 (CH2), 26.7 (CH3), 28.2 (CH), 31.3 (CH),
35.1 (CH2), 36.8 (CH), 41.3 (CH2), 43.5 (CH), 47.9 (CH2), 48.1 (CH),
53.0 (C), 74.9 (CH), 81.6 (C), 87.2 (CH). IR (Film): 3544, 3200,
2930, 1655, 1265, 710, 680 cmꢀ1. HRMS: calcd for C20H38NO2
[M+H]+ 324.2903, found 324.2891.
4.5.1. (3R,4S)-1-{2-[1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]-
propan-2-yl}-4-isopropyl-3-phenylpyrrolidin-3-ol 8b
Yield: 92%. Colorless solid. Mp: 103–105 °C (from hexane/EtOAc
100:1). ½a 2D5
ꢃ
¼ ꢀ52:9 (c 1.1, CHCl3). 1H NMR (333 K) (d): 0.48 (d,

C. Andrés et al. / Tetrahedron: Asymmetry 21 (2010) 2230–2237
2235
3H, J = 6.6 Hz), 0.81–1.28 (m, 3H), 0.89 (d, 6H, J = 6.6 Hz), 1.02 (s,
3H), 1.17 (s, 3H), 1.39–1.48 (m, 2H), 1.56–1.68 (m, 2H), 1.82 (m,
1H), 1.93 (m, 1H), 2.12–2.23 (m, 2H), 2.92–3.00 (m, 2H), 3.14–
3.20 (m, 2H), 3.65 (td, 1H, J1 = 10.2 Hz, J2 = 4.0 Hz), 7.19 (m, 1H),
7.26–7.33 (m, 2H), 7.46–7.50 (m, 2H), 8.38 (br s, 1H). 13C NMR
(333 K) (d): 16.9 (CH3), 21.4 (CH3), 22.0 (CH3), 22.1 (CH3), 22.2
(CH3), 25.8 (CH2), 27.6 (CH), 31.1 (CH), 35.2 (CH2), 44.4 (CH2),
49.0 (CH), 49.9 (CH2), 55.6 (CH), 59.6 (C), 64.3 (CH2), 73.0 (CH),
80.8 (C), 125.1 (2 CH), 126.6 (CH), 128.1 (2 CH), 145.1 (C). IR (Nu-
jol): 3300, 3060, 760, 700 cmꢀ1. HRMS: calcd for C23H38NO2
[M+H]+ 360.2903, found 360.2903.
perature for 5–6 h. After the elimination of the solvents under re-
duced pressure, the residue was dissolved in 50 mL of CH2Cl2 and
washed with H2O. The organic layer was dried over MgSO4 and fil-
tered, and the solvent was eliminated under vacuum to give an oily
residue that was purified by flash chromatography on silica gel,
using a mixture of MeOH/CHCl3 1:12 as eluent.
4.7.1. (3R,4S)-3-Phenyl-4-(prop-1-en-2-yl)pyrrolidin-3-ol 10b
Yield 48%. Colorless solid. Mp: 163–164 °C (from EtOAc).
½
a 2D5
ꢃ
¼ þ94:9 (c 0.7, MeOH). 1H NMR (d): 1.35 (s, 3H), 2.30 (br s,
2H), 3.12–3.32 (m, 5H), 4.90 (s, 1H), 5.05 (s, 1H), 7.24 (m, 1H),
7.32–7.37 (m, 2H), 7.50–7.52 (m, 2H). 13C NMR (d): 24.9 (CH3),
50.4 (CH2), 58.6 (CH), 63.6 (CH2), 80.9 (C), 113.4 (CH2), 125.1 (2
CH), 126.9 (CH), 128.3 (2 CH), 142.5 (C), 144.0 (C). IR (Nujol):
3300, 3100, 1640, 755, 710, 700, 670 cmꢀ1. HRMS: calcd for
4.6. Preparation of amino alcohol 9b
At first, NaBH3CN (113 mg, 1.8 mmol) was added to a solution
of 7b (215 mg, 0.6 mmol) in methanol (25 mL) cooled to 0 °C and
acidified to pH ꢁ4 by an aqueous solution of HCl 0.1 M. The mix-
ture was heated at 60 °C and the pH was maintained at 4 by a peri-
odic addition of 0.1 M HCl until the reaction was complete (TLC).
The solvents were eliminated under reduced pressure. The residue
was dissolved in CH2Cl2 (40 mL), and an aqueous solution of KOH
2.5 M (20 mL) was added. The mixture was stirred for 30 min, after
which the organic layer was decanted, and the aqueous layer was
extracted with CH2Cl2 (3 ꢂ 20 mL). The combined organic fractions
were washed with brine, dried over anhydrous MgSO4, filtered, and
the solvent was eliminated under reduced pressure. The residue
was purified by flash chromatography on silica gel using a mixture
of hexane/EtOAc 3:1 as eluent.
C
13H18NO [M+H]+ 204.1388, found 204.1382.
4.8. Synthesis of pyrrolidine 11b
Dimethyl pyrocarbonate (198 mg, 1.5 mmol) was added to a
solution of amine 10b (203 mg, 1.0 mmol) in CH2Cl2 (16 mL) and
the mixture was stirred for 20 min at room temperature. The sol-
vent was removed by evaporation, after which the residue was dis-
solved in anhydrous diethyl ether (16 mL) and slowly added to a
suspension of LiAlH4 (213 mg, 5.6 mmol) in anhydrous diethyl
ether (15 mL) at 0 °C. After stirring at 0 °C for 1 h, the reaction
was quenched by addition of a 20% NaOH solution (2.0 mL). The
mixture was then filtered off. The solids were washed with EtOAc
and the solution was dried over anhydrous MgSO4. The solvents
were evaporated and the residue was purified by flash chromatog-
raphy on silica gel with MeOH/CHCl3 1:12 as eluent.
4.6.1. (3S,4R)-1-{2-[1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]-
propan-2-yl}-4-isopropyl-3-phenylpyrrolidin-3-ol 9b
Yield: 83%. Colorless solid. Mp: 175–176 °C (from hexane/EtOAc
100:1). ½a 2D5
ꢃ
¼ ꢀ12:2 (c 0.90, CHCl3). 1H NMR (333 K) (d): 0.57 (d,
4.8.1. (3R,4S)-1-Methyl-3-phenyl-4-(prop-1-en-2-yl)pyrrolidin-
3-ol 11b
3H, J = 5.7 Hz), 0.93–1.20 (m, 3H), 0.93 (d, 6H, J = 6.4 Hz), 1.02 (s,
3H), 1.17 (s, 3H), 1.46 (m, 1H), 1.58–1.75 (m, 3H), 1.83–2.13 (m,
3H), 2.20 (m, 1H), 2.77 (t, 1H, J = 9.3 Hz), 3.03–3.15 (m, 2H), 3.30
(t, 1H, J = 8.3 Hz), 3.68 (m, 1H), 7.21 (m, 1H), 7.28–7.34 (m, 2H),
7.49–7.52 (m, 2H), 8.19 (br s, OH). 13C NMR (333 K) (d): 17.6
(CH3), 21.1 (CH3), 22.0 (CH3), 22.1 (CH3), 22.2 (CH3), 26.1 (CH2),
27.5 (CH), 31.2 (CH), 35.4 (CH2), 44.6 (CH2), 48.8 (CH), 49.7 (CH2),
56.3 (CH), 59.3 (C), 65.0 (CH2), 73.1 (CH), 80.8 (C), 124.8 (2 CH),
126.6 (CH), 128.1 (2 CH), 146.5 (C). IR (Nujol): 3300, 3050, 760,
740, 700 cmꢀ1. HRMS: calcd for C23H38NO2 [M+H]+ 360.2903,
found 360.2897.
Yield: 70%. Colorless solid. Mp: 63–64 °C (from hexane).
½
a 2D5
ꢃ
¼ þ78:5 (c 0.3, CHCl3). 1H NMR (d): 1.41 (s, 3H), 2.43 (s, 3H),
2.82 (d, 1H, J = 10.3 Hz), 2.87–3.05 (m, 3H), 3.13 (d, 1H,
J = 10.3 Hz), 3.18 (t, 1H, J = 8.3 Hz), 4.86 (s, 1H), 4.99 (s, 1H), 7.27
(m, 1H), 7.24–7.39 (m, 2H), 7.54–7.57 (m, 2H). 13C NMR (d): 24.0
(CH3), 42.4 (CH3), 58.4 (CH), 58.8 (CH2), 72.9 (CH2), 80.5 (C),
113.1 (CH2), 124.8 (2 CH), 126.5 (CH), 127.9 (2 CH), 142.3 (C),
145.4 (C). IR (Nujol): 3290, 3100, 1640, 760, 700 cmꢀ1. HRMS: calcd
for C14H20NO [M+H]+ 218.1545, found 218.1532.
4.9. Synthesis of pyrrolidine 12b
4.7. Synthesis of pyrrolidine 10b
A mixture of 11b (130 mg, 0.60 mmol) and 10 wt % palladium
on carbon (13 mg) in ethanol (15 mL) was stirred at room temper-
ature under H2 at atmospheric pressure until the reaction was
complete (TLC, 24–48 h). The catalyst was separated by filtration
over a pad of Celite, after which the solvent was eliminated on a
rotavapor, and the residue was purified by flash chromatography
on silica gel, using a mixture of MeOH/CHCl3 1:12 as eluent.
Dry AlCl3 (334 mg, 2.5 mmol) was added, in portions, to a sus-
pension of LiAlH4 (285 mg, 7.5 mmol) in anhydrous THF (45 mL)
cooled to ꢀ10 °C. The mixture was stirred for 10 min and a solution
of 4b (534 mg, 1.5 mmol) in dry THF (20 mL) was slowly added.
The reaction mixture was stirred for 12 min at ꢀ10 °C and the reac-
tion was quenched by the addition of a 20% NaOH solution (3 mL).
The resulting mixture was filtered, after which the solid was
washed with EtOAc, and the organic layer was dried (MgSO4).
The solvent was eliminated under reduced pressure and the resi-
due was redissolved in CH2Cl2 (40 mL). Next, PCC (1.7 g, 8.0 mmol)
and 4 Å molecular sieves (1.5 g) were added and the mixture was
stirred at room temperature until the oxidation was finished
(TCL, 6–8 h). The solvent was eliminated under reduced pressure,
after which the residue was dissolved in a 15% aqueous solution
of NaOH (25 mL), and the resulting solution was extracted with
CH2Cl2. The organic phase was washed with brine and dried over
MgSO4. The solvents were eliminated under vacuum, after which
the residue was taken up in a 2.5 M solution (16 mL) of KOH in
THF/MeOH/H2O (2:1:1), and the solution was stirred at room tem-
4.9.1. (3R,4S)-1-Methyl-4-isopropyl-3-phenylpyrrolidin-3-ol
12b
Yield: 80%. Colorless oil. ½a D25
ꢃ
¼ ꢀ13:2 (c 1.1,CHCl3). 1H NMR (d):
0.56 (d, 3H, J = 6.5 Hz), 0.87 (d, 3H, J = 6.5 Hz), 1.88 (m, 1H), 2.26
(m, 1H), 2.39 (s, 3H), 2.70–2.79 (m, 3H), 2.88 (dd, 1H, J1 = 9.5 Hz,
J2 = 7.3 Hz), 3.27 (br s, 1H), 7.22 (m, 1H), 7.29–7.34 (m, 2H),
7.53–7.56 (m, 2H). 13C NMR (d): 22.0 (CH3), 22.3 (CH3), 28.9 (CH),
42.2 (CH3), 57.0 (CH), 59.8 (CH2), 73.4 (CH2), 81.3 (C), 124.9
(2CH), 126.3 (CH), 127.0 (2 CH), 144.7 (C). IR (Film): 3400, 3100,
3060, 3030, 1600, 765, 700, 640 cmꢀ1. HRMS: calcd for C14H22NO
[M+H]+ 220.1701, found .220.1689.

2236
C. Andrés et al. / Tetrahedron: Asymmetry 21 (2010) 2230–2237
4.10. General procedure for the addition of diethylzinc to
aldehydes
4.10.10. 1-(m-Chlorophenyl)-1-propanol
Chiralpak AD-H; UV 254 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 21.5 min for enantiomer (R), tR = 24.1 min for enan-
tiomer (S).
To a flame-dried, argon-purged flask containing the ligand
(0.2 mmol) and dry toluene (4 mL) was added a 1 M solution of
diethylzinc in hexane (4 mL, 4 mmol, Aldrich) at room temperature.
After being stirred for 10 min, a solution of the corresponding alde-
hyde (2.0 mmol) in dry toluene (4 mL) was added and allowed to
react at room temperature until the reaction was complete (TLC,
30–45 min). The reaction was quenched with the dropwise addition
of an aqueous ammonium chloride solution. The organic layer was
separated and the aqueous phase was extracted with diethyl ether
(3 ꢂ 20 mL). The combined organic layers were washed with brine,
and dried over anhydrous MgSO4. The solvents were eliminated
under reduced pressure and the residue was purified by column
chromatography on silica gel using mixtures of hexane/EtOAc as
eluent. Theee valueswere determinedby HPLC ona chiral stationary
phase.
4.10.11. 1-(o-Chlorophenyl)-1-propanol
Chiralpak AD-H; UV 254 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 16.7 min for enantiomer (R), tR = 17.4 min for enan-
tiomer (S).
4.10.12. 1-(o-Methoxyphenyl)-1-propanol
Chiralpak AD-H; UV 220 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 26.4 min for enantiomer (S), tR = 34.5 min for enan-
tiomer (R).
4.10.13. 1-(p-Tolyl)-1-propanol
Chiralpak AD-H; UV 220 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 19.5 min for enantiomer (R), tR = 21.3 min for enan-
tiomer (S).
4.10.1. 1-(Naphthalen-2-yl)propan-1-ol
4.10.14. 1-(p-Trifluoromethylphenyl)-1-propanol
Chiralpak AD-H; UV 254 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 17.4 min for enantiomer (R), tR = 18.1 min for enan-
tiomer (S).
Chiracel OD; UV 254 nm; isopropanol/hexane = 10:90; flow
1 mL/min; tR = 11.0 min for enantiomer (S), tR = 12.1 min for enan-
tiomer (R).
4.10.15. 1-(2-Furyl)-1-propanol
4.10.2. 1-(Naphthalen-1-y)propan-1-ol
Chiracel OD; UV 220 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 21.8 min for enantiomer (R), tR = 25.0 min for enan-
tiomer (S).
Chiracel OD; UV 254 nm; isopropanol/hexane = 10:90; flow
1 mL/min; tR = 9.4 min for enantiomer (S), tR = 16.5 min for enan-
tiomer (R).
4.10.16. 1-(Thiophen-2-yl)-1-propanol
Chiracel OD; UV 220 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 25.6 min for enantiomer (R), tR = 28.5 min for enan-
tiomer (S).
4.10.3. 1-Phenylpropan-1-ol
Chiracel OD; UV 254 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 25.0 min for enantiomer (R), tR = 28.8 min for enan-
tiomer (S).
Acknowledgments
4.10.4. 1-(o-Tolyl)-1-propanol
We acknowledge the financial support from the Spanish Minis-
terio de Ciencia e Innovación (project CTQ2008-03960/BQU) and
Junta de Castilla y León (GR168).
Chiralpak AD-H; UV 220 nm; isopropanol/hexane = 1:99; flow
1 mL/min; tR = 14.5 min for enantiomer (R), tR = 17.9 min for enan-
tiomer (S).
References
4.10.5. 1-(p-Methoxyphenyl)propan-1-ol
Chiracel OD; UV 254 nm; isopropanol/hexane = 2:98; flow
1 mL/min; tR = 21.0 min for enantiomer (R), tR = 26.5 min for enan-
tiomer (S).
1. For general discussion and comprehensive reviews, see: (a) Noyori, R.; Suga, S.;
Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda,
Y. J. Organomet. Chem. 1990, 382, 19–37; (b) Noyori, R.; Kitamura, M. Angew.
Chem., Int. Ed. Engl. 1991, 30, 49–69; (c) Soai, K.; Niwa, S. Chem. Rev. 1992, 92,
833–856; (d) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
4.10.6. 1-(p-Chlorophenyl)-1-propanol
2. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823–2824.
Chiracel OD; UV 254 nm; isopropanol/hexane = 2:98; flow
1 mL/min; tR = 14.7 min for enantiomer (S), tR = 16.0 min for enan-
tiomer (R).
3. For some recent examples, see: (a) Viso, A.; Fernández de la Pradilla, R.; Ureña,
M. Tetrahedron 2009, 65, 3757–3766; (b) Forrat, V. J.; Ramón, D. J.; Yus, M.
Tetrahedron: Asymmetry 2009, 20, 65–67; (c) Ananthi, N.; Balakrishnan, U.;
Vinu, A.; Ariga, K.; Velmathi, S. Tetrahedron: Asymmetry 2009, 20, 1731–1735;
(d) Melgar-Fernández, R.; González-Olvera, R.; Olivares-Romero, J. L.;
González-López, V.; Romero-Ponce, L.; Ramírez-Zárate, M. R.; Demare, P.;
Regla, I.; Juriasti, E. Eur. J. Org. Chem. 2008, 655–672; (e) Gou, S.; Judeh, Z. M. A.
Tetrahedron Lett. 2009, 50, 281–283; (f) Coeffard, V.; Mueller-Bunz, H.; Guiry, P.
J. Org. Biomol. Chem. 2009, 7, 1723–1734; (g) Salehi, P.; Dabiri, M.; Kozehgary,
G.; Baghbanzadeh, M. Tetrahedron: Asymmetry 2009, 20, 2609–2611; (h) Binder,
C. M.; Bautista, A.; Zaidlewicz, M.; Krzeminski, M. P.; Oliver, A.; Singaram, B. J.
Org. Chem. 2009, 74, 2337–2343; (i) Wu, Z.-L.; Wu, H.-L.; Wu, P.-Y.; Uang, B.-J.
Tetrahedron: Asymmetry 2009, 20, 1556–1560; (j) Dean, M. A.; Hitchcock, S. R.
Tetrahedron: Asymmetry 2009, 20, 2351–2356; (k) Garabatos-Perera, J. R.;
Butenschön, H. J. Organomet. Chem. 2009, 694, 2047–2052; (l) Scarpi, D.;
Occhiato, E. G.; Guarna, A. Tetrahedron: Asymmetry 2009, 20, 340–350.
4. (a) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1997, 62, 3770–3771; (b) Hof, R. P.;
Poelert, M. A.; Peper, N. C. M. W.; Kellogg, R. M. Tetrahedron: Asymmetry 1994, 5,
31–34; (c) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Rodrigues, O. E. D.;
Silveira, C. C.; Wessjohann, L. A. Tetrahedron 2001, 57, 3291–3295; (d) Parrott,
R. W., II; Hitchcock, S. R. Tetrahedron: Asymmetry 2007, 18, 377–382; (e)
Szakonyi, Z.; Hetényi, A.; Fülöp, F. Tetrahedron 2008, 64, 1034–1039; (f) Dai, W.-
M.; Zhu, H. J.; Hao, X.-J. Tetrahedron: Asymmetry 1996, 7, 1245–1248; (g)
4.10.7. 1-Phenyl-3-pentanol
Chiracel OD; UV 254 nm; isopropanol/hexane = 2:98; flow
1 mL/min; tR = 20.6 min for enantiomer (R), tR = 32.8 min for enan-
tiomer (S).
4.10.8. (E)-1-Phenyl-1-penten-3-ol
Chiralpak AS-H; UV 254 nm; isopropanol/hexane = 2:98; flow
1 mL/min; tR = 11.7 min for enantiomer (R), tR = 13.9 min for enan-
tiomer (S).
4.10.9. 1-(o-Bromophenyl)-1-propanol
Chiralpak AD-H; UV 220 nm;isopropanol/hexane = 1:99; flow
1 mL/min; tR = 18.5 min for enantiomer (R), tR = 19.1 min for enan-
tiomer (S).

C. Andrés et al. / Tetrahedron: Asymmetry 21 (2010) 2230–2237
2237
Falorni, M.; Collu, C.; Conti, S.; Giacomelli, G. Tetrahedron: Asymmetry 1996, 7,
293–299.
9. Rafael Pedrosa, R.; Andrés, C.; Mendiguchía, P.; Nieto, J. J. Org. Chem. 2006, 71,
5388–5391.
5. (a) Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.; Schneider, P. H.
Tetrahedron 2002, 58, 10413–10416; (b) Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006,
128, 10996–10997; (c) Kang, Y.-F.; Wang, R.; Liu, L.; Da, C.-S.; Yan, W.-J.; Xu, Z.-
Q. Tetrahedron Lett. 2005, 46, 863–865; (d) Xu, Z.; Mao, J.; Zhang, Y. Org. Biomol.
Chem. 2008, 6, 1288–1292; (e) Mao, J.; Bao, Z.; Guo, J.; Ji, S. Tetrahedron 2008,
64, 9901–9905; (f) Kang, Y.-F.; Liu, L.; Wang, R.; Zhou, Y.-F.; Yang, W.-J. Adv.
Synth. Catal. 2005, 347, 243–247.
6. (a) Pedrosa, R.; Andrés, C.; Nieto, J. J. Org. Chem. 2002, 67, 782–789; (b) Pedrosa,
R.; Andrés, C.; Nieto, J.; del Pozo, S. J. Org. Chem. 2003, 68, 4923–4931; (c)
Pedrosa, R.; Andrés, C.; Gutiérrez-Loriente, A.; Nieto, J. Eur. J. Org. Chem. 2005,
2449–2458; (d) Pedrosa, R.; Andrés, C.; Martín, L.; Nieto, J.; Roson, C. J. Org.
Chem. 2005, 70, 4332–4337; (e) Pedrosa, R.; Andrés, C.; Arias, R.; Mendiguchıía,
P.; Nieto, J. J. Org. Chem. 2006, 71, 8854–8863.
10. Pedrosa, R.; Andrés, C.; de las Heras, L.; Nieto, J. Org. Lett. 2002, 4, 2513–2516.
11. Pedrosa, R.; Andrés, C.; Rosón, C. D.; Vicente, M. J. Org. Chem. 2003, 68, 1852–1858.
12. Andrés, C.; González, I.; Nieto, J.; Rosón, C. D. Tetrahedron 2009, 65, 9728–9736.
13. It is known that in the diethylzinc addition reaction the chemical yield and
enantioselectivity are usually much lower with aliphatic and
a,b-unsaturated
aldehydes than the identical reaction with aromatic aldehydes. (a) Harada, T.;
Kanda, K. Org. Lett. 2006, 8, 3817–3819; (b) Zhong, J.; Guo, H.; Wang, M.; Yin,
M.; Wang, M. Tetrahedron: Asymmetry 2007, 18, 734–741. See also ref 1c and 1d
and examples therein.
14. For some examples of the use of 3-hydroxypyrrolidines as chiral ligands in the
enantioselective addition of diethylzinc to aldehydes see: (a) Rocha Gonsalves,
A. M. A.; Serra, M. E. S.; Murtinho, D.; Silva, V. F.; Beja, A. M.; Paixão, J. A.; Silva,
M. R.; Veiga, L. A. J. Mol. Catal. A: Chem. 2003, 195, 1–9; (b) Rocha Gonsalves, A.
M. A.; Serra, M. E. S.; Murtinho, D. J. Mol. Catal. A: Chem. 2006, 250, 104–113.
15. (a) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327–6335; (b)
Yamakawa, M.; Noyori, R. Organometallics 1999, 18, 128–133.
7. Pedrosa, R.; Andrés, C.; Nieto, J. In New Methods for the Asymmetric Synthesis of
Nitrogen Heterocycles; Vicario, J. L., Badía, D., Carrillo, L., Eds.; Research
Signpost: Kerala, 2005; pp 65–98.
8. He, X.-C.; Eliel, E. Tetrahedron 1987, 43, 4979–4987.
16. Pedrosa, R.; Andrés, C.; Nieto, J.; del Pozo, S. J. Org. Chem. 2005, 70, 1408–1416.