Pinane-Type Tridentate Reagents for Enantioselective Reactions: Reduction of Ketones and Addition of Diethylzinc to Aldehydes

Article abstract of DOI:10.1021/jo982403b

The reduction of aryl and alkenyl methyl ketones using lithium aluminum hydride modified with (1R,2S,3S,5A)-(+)-10-anilino-3-ethoxy-2-hydroxypinane (10b) afforded chiral secondary alcohols in 83-96% chemical yields and 50-91% ee with dominance of R enantiomers. The reduction of acetophenone in the presence of lithium iodide gave the alcohol product with higher ee. On the other hand, the addition reaction of diethylzinc to benzaldehyde using the pinane-based diols 5-9 as promoters gave 1-phenylpropanol in favor of the S enantiomer up to 88% ee. Using the pinane-based alcohols 10a-e as promoters, the R enantiomer was obtained as the major product. The addition reactions of diethylzinc to various substituted benzaldehydes, employing the diol ligands 5c and 8e, afforded predominantly the corresponding (S)-alcohols. The chiral modifiers 5-10 were prepared from (1R)-(-)-myrtenol and were readily recovered (>90%) after the asymmetric reactions. In this study, LAH reduction and Et₂Zn addition are complementary methods for the preparation of optically active secondary alcohols. The ligand 10-butylanilino-2,3-dihydroxypinane 5c promoted the Et₂Zn additions effectively, whereas the modifier 10-anilino-3-ethoxy-2-hydroxypinane 10b induced the LAH reductions in a highly enantioselective manner.

Full text of DOI:10.1021/jo982403b

J . Org. Chem. 1999, 64, 3207-3212
3207
P in a n e-Typ e Tr id en ta te Rea gen ts for En a n tioselective Rea ction s:
Red u ction of Keton es a n d Ad d ition of Dieth ylzin c to Ald eh yd es
Yie-J ia Cherng,† J im-Min Fang,*,† and Ta-J ung Lu*,‡
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, Republic of China, and
Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan, Republic of China
Received December 8, 1998
The reduction of aryl and alkenyl methyl ketones using lithium aluminum hydride modified with
(1R,2S,3S,5R)-(+)-10-anilino-3-ethoxy-2-hydroxypinane (10b) afforded chiral secondary alcohols in
83-96% chemical yields and 50-91% ee with dominance of R enantiomers. The reduction of
acetophenone in the presence of lithium iodide gave the alcohol product with higher ee. On the
other hand, the addition reaction of diethylzinc to benzaldehyde using the pinane-based diols 5-9
as promoters gave 1-phenylpropanol in favor of the S enantiomer up to 88% ee. Using the pinane-
based alcohols 10a -e as promoters, the R enantiomer was obtained as the major product. The
addition reactions of diethylzinc to various substituted benzaldehydes, employing the diol ligands
5c and 8e, afforded predominantly the corresponding (S)-alcohols. The chiral modifiers 5-10 were
prepared from (1R)-(-)-myrtenol and were readily recovered (>90%) after the asymmetric reactions.
In this study, LAH reduction and Et2Zn addition are complementary methods for the preparation
of optically active secondary alcohols. The ligand 10-butylanilino-2,3-dihydroxypinane 5c promoted
the Et2Zn additions effectively, whereas the modifier 10-anilino-3-ethoxy-2-hydroxypinane 10b
induced the LAH reductions in a highly enantioselective manner.
In tr od u ction
and (Ipc)2BCl, have been successfully utilized in asym-
metric reduction of ketones. Unlike bidentate chiral
ligands, the tridentate chiral ligands are not extensively
studied. We envisaged that LAH and Et2Zn can be
modified by the tridentate ligands 5-12 to form chiral
reagents with rigid structure, which may exert distinct
stereochemical bias to convey asymmetric induction. We
report herein the study in this aspect.5
Enantiomerically pure chiral secondary alcohols are
important starting materials for the total synthesis of
natural products.1 Asymmetric reduction of ketones2 and
nucleophilic addition to aldehydes3 are two general
methods for the preparation of optically active secondary
alcohols. In this paper, we report the use of pinane-type
tridentates 5-12 (Figure 1) as the chiral modifiers of
lithium aluminumhydride (LAH) reductions and dieth-
ylzinc additions. Asymmetric LAH reduction2 and Et2Zn
addition3 have been advanced to achieve high efficiency
and remarkable enantioselectivity. Pinanes and their
derivatives are economic and readily available com-
pounds; pinane-derived boranes,4 such as Alpine-Borane
Resu lts a n d Discu ssion
Preparation of pinane-type tridentates 5-12 was
straightforward (Scheme 1). (1R)-(-)-Myrtenol (1) was
reacted with PBr3 to give (1R)-(-)-myrtenyl bromide (2)
in 85% yield. The substitution reaction of 2 was easily
carried out by treatment with a series of amines and
alcohols, giving 3 and 4, which were subsequently
converted to diols 5-9 by the known procedure using
OsO4-Me3NO as the oxidizing agents. Alternatively,
compounds 4 could be prepared by alkylation of (1R)-
(-)-myrtenol with alkyl bromides. Selective alkylation of
the secondary hydroxyl group of the diols 5-9 furnished
the desired modifiers 10-12 in respectable yields.
To determine the optical purity of the prepared ligands,
a 3,5-dinitrobenzoate derivative 13 was synthesized from
10b for HPLC analysis (Scheme 2). A racemic mixture
of â-pinene underwent photooxidation, followed by NaBH4
reduction of the resulting hydroperoxide, to afford (()-
myrtenol. By a procedure similar to that described in
Scheme 1, (()-myrtenol was transformed into (()-10b via
dihydroxylation and selective ethylation of the resulting
diol. Treatment of (()-10b with 3,5-dinitrobenzoyl chlo-
ride in the presence of Et3N yielded a racemic ester (()-
13, of which two enantiomers were separable on a
† National Taiwan University. Current address of YJ C: Chung-Tai
Institute of Health Science and Technology, Taichung, Taiwan.
‡ National Chung-Hsing University.
(1) Application of chiral alcohols to the synthesis of leukotrienes and
alkaloids: (a) Sato, F.; Kobayashi, Y. Synlett 1992, 849. (b) Grigg, R.;
Santhakumar, V.; Sridharan, V.; Thornton-Pett, M.; Bridge, A. W.
Tetrahedron 1993, 49, 5177. (c) Iwata, C.; Takemoto, Y. Chem.
Commun. 1996, 2497.
(2) Reviews of asymmetric reduction of ketones: (a) Nishizawa, M.;
Noyori, R. in Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, pp 159-182. (b) Singh,
V. K. Synthesis 1992, 605. (c) Parratt, J . S.; Cripps, M. C.; Faulcon-
bridge, S. J .; Holt, K. E.; Rippe, C. L.; Savage, S. P.; Taylor, S. J . C.
Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 1997, 93, 291. (d) Pereira,
R. D. Crit. Rev. Biotechnol. 1998, 18, 25. Examples of asymmetric LAH
reductions: (e) Landor, S. R.; Miller, B. J .; Tatchell, A. R. J . Chem.
Soc. C 1966, 2280. (f) Baggett, N.; Stribblehill, P. J . Chem. Soc., Perkin
Trans. 1 1977, 1123. (g) Noyori, R.; Tomino, I.; Nishizawa, M. J . Am.
Chem. Soc. 1979, 101, 5843.
(3) Reviews of asymmetric Et2Zn additions: (a) Noyori, R.; Kita-
mura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49. (b) Soai, K.; Niwa,
S. Chem. Rev. 1992, 92, 833. (c) J iang, Y.; Qin, Y.; Huang, Z. Hecheng
Huaxue 1993, 1, 1. (d) Berrisford, D. J .; Bolm, C. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1717. (e) Mikami, K.; Terada, M. Kagaku to Kogyo
(Osaka) 1997, 71, 249.
(4) (a) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano,
A. J . Am. Chem. Soc. 1980, 102, 867. (b) Brown, H. C.; Ramachandran,
P. V. Acc. Chem. Res. 1992, 25, 16. (c) Deloux, L.; Srebnik, M. Chem.
Rev. 1993, 93, 763.
(5) Our earlier reports on asymmetric LAH reductions: (a) Lu, T.-
J .; Liu, S.-W. J . Chin. Chem. Soc. 1994, 41, 205. (b) Lu, T.-J .; Liu,
S.-W. J . Chin. Chem. Soc. 1994, 41, 467. (c) Cherng, Y.-J .; Fang, J .-
M.; Lu, T.-J . Tetrahedron: Asymmetry 1995, 6, 89.
10.1021/jo982403b CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/15/1999

3208 J . Org. Chem., Vol. 64, No. 9, 1999
Cherng et al.
Sch em e 1a
a
Reagents and conditions: (i) PBr3, pyridine, PhH, rt, 1 h, 85%;
(ii) KH, R1R2NH, THF, rt, 3 h, 74-85%; (iii) R3OH, KH, THF, rt,
6 h, 65-81%; (iv) NaH or KH, R3Br, rt, 6 h, 80-98%; (v) OsO4,
Me3NO, THF/Me2CO/H2O, reflux, 4 days, 50-81%; (vi) NaH, R4Br,
rt, 24 h, 76-92%.
Sch em e 2a
a
Reagents and conditions: (i) O2, TPP, hν, CHCl3; (ii) NaBH4,
MeOH; (iii) PBr3, pyridine, PhH, rt, 85%; (iv) KH, R1R2NH, THF,
rt, 85%; (v) OsO4, Me3NO, THF/Me2CO/H2O, reflux, 50%; (vi) NaH,
EtBr, 83%; (vii) 3,5-(NO2)2C6H3COCl, Et3N.
ferentiate the two reaction faces of the reactant. Thus,
rationally designed pinane-based modifiers 10-12, pos-
sessing a rigid bicyclic pinane skeleton and an ethoxy
substituent at C-3, were prepared.5c The LAH reduction
of acetophenone using modifiers 11 or 12, having ben-
zyloxy or N-methylanilino groups at C-10, still resulted
in low enantioselectivity (up to 26% ee). However,
remarkable enantioselectivity was procured by using the
modifier 10 containing an anilino group at C-10. Table 1
lists the results of asymmetric LAH reductions of ac-
etophenone and 1-acetylnaphthalene using modifiers
10a -e with different alkoxy groups at C-3. The reactions
were carried out in Et2O/THF (1:10) solution with a ratio
of LAH/modifier/ketone ) 2.0:2.2:1.0. The best ee values,
62% and 80% for the reactions of acetophenone and
1-acetylnaphthalene, were obtained by using the modifier
10b having an ethoxy group at C-3. Use of 10e having a
benzyloxy group at C-3 resulted in an opposite enan-
tiotopic selection, though the ee values were low (15%
and 3%).
F igu r e 1. Pinane-type tridentates used in this study.
Chiralcel OD column. An optically enriched sample 10b,
[R]25D +11.5 (CHCl3, c 1.04) was similarly prepared from
(1R)-(-)-myrtenol and converted to the ester 13, which
consisted of two enantiomers in a ratio of 96.9:3.1 as
determined by the HPLC analysis. The original sample
of (1R)-(-)-myrtenol and the ligand (+)-10b therefrom
were thus deduced to have 93.8% enantiomeric excess
(ee).
LAH Red u ction s. Our preliminary study5a,b indicated
that secondary alcohols can be obtained in moderate
optical yields (up to 52%) in the reduction of prochiral
ketones by LAH using pinane-based diol modifiers 5-9.
After examination of the Dreiding molecular models of
putative transition structures (see Figure 3)6 in an
attempt to develop more effective modifiers, we envisaged
that a C-3 alkoxy group is sterically more demanding
than a hydroxyl group and therefore can better dif-
(6) Analogous transition states in asymmetric LAH reductions using
aminodiol or diamino alcohol tridentate modifiers have been proposed.
(a) Morrison, J . D.; Grandbois, E. R.; Howard, S. I.; Weisman, G. R.
Tetrahedron Lett. 1981, 22, 2619. (b) Sato, T.; Goto, Y.; Fujisawa, T.
Tetrahedron Lett. 1982, 23, 4111. Similar transition states in the
reactions of organolithiums: (c) Mukaiyama, T.; Soai, K.; Sato, T.;
Shimizu, H.; Suzuki, K. J . Am. Chem. Soc. 1979, 101, 1455. (d) Corey,
E. J .; Hannon, F. J . Tetrahedron Lett. 1987, 28, 5233. (e) Seebach, D.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.

Pinane-Type Tridentate Reagents
J . Org. Chem., Vol. 64, No. 9, 1999 3209
Ta ble 1. LAH Red u ction of Acetop h en on e a n d
1-Acetyln a p h th a len e Usin g Mod ifier s 10a -ea
modifier,
R )
product eec/
(yield/%)b
entry
ketone
%
configd
1
2
3
4
5
6
7
8
9
acetophenone
acetophenone
acetophenone
acetophenone
acetophenone
2-acetylnaphthalene 10a , Me
2-acetylnaphthalene 10b, Et
2-acetylnaphthalene 10c, Pr
2-acetylnaphthalene 10d , Bu
10a , Me
10b, Et
10c, Pr
10d , Bu
14a (83) 48
14a (85) 62
14a (85) 47
14a (86) 46
R
R
R
R
S
R
R
R
R
S
10e, PhCH2 14a (84) 14
14i (84)
14i (93)
14i (87)
14i (86)
55
80
62
66
3
10 2-acetylnaphthalene 10e, PhCH2 14i (90)
a
The reaction was conducted in Et2O/THF (1:10) solution at
-78 °C for 1 h with a molar ratio of LAH/modifier/ketone ) 2.0:
b
2.2:1.0. Isolated yields. c The ee value was determined by HPLC
d
analysis. The configuration of the major enantiomer was as-
signed by comparison of the optical rotation with the reported
value.
Ta ble 2. Red u ction of Meth yl Keton es RCOCH3 w ith
LiAlH4 a n d Ch ir a l Mod ifier 10ba
additive
(equiv)b
product
(yield/%) (%) config
ee
entry
RCOCH3, R )
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph
Ph
o-tolyl
2-bromophenyl
2-chlorophenyl
2-methoxyphenyl
2-nitrophenyl
2,4-dimethylphenyl
2,5-dimethoxyphenyl
1-naphthyl
1-naphthyl
1-naphthyl
2-naphthyl
2-phenanthyl
2-fluorenyl
14a (85) 62
14a (91) 83
14b (86) 79c
14c (86) 78
14d (86) 78
14e (86) 91
14f (85) 72d
14g (87) 74
14h (91) 91
14i (93) 80
14i (92) 84
R
R
R
R
R
R
R
R
R
R
R
R
R
LiI (1)
F igu r e 2. In this study, the asymmetric LAH reduction gave
predominantly (R)-alcohols 14-18, whereas the asymmetric
Et2Zn addition gave predominantly (S)-alcohols 19.
LiI (1)
(Table 2, entries 6 and 9) gave the highest optical yield
(97%) by calculation based on the maximum optical
purity (93.8%) of the modifier 10b.
HMPA (6) 14i (85) 66
14j (96) 50
14k (94) 87
14l (95) 81
A wide range of aromatic and alkenyl methyl ketones
can be reduced by LAH in the presence of modifier 10b
to give chiral secondary alcohols in synthetically useful
yields and enantioselectivities. 1-Acetylnaphthalene,
2-acetylnaphthalene, 2-acetylphenanthrene, and 2-acet-
ylfluorene were reduced to give 80, 50, 87, and 81% ee,
respectively. Heterocyclic compounds, such as 2-acetyl-
furan and 2-acetylthiophenes (Table 2, entries 16-20),
were similarly reduced to achieve 52-83% ee. The
reductions of 4-phenyl-3-buten-2-one and cyclohexenyl
methyl ketone also produced the corresponding allylic
alcohols with predominance of R enantiomers. No 1,4-
reduction products were observed in such instances.
A 1:10 mixture of Et2O/THF appeared to be the solvent
of choice for the asymmetric LAH reduction. When the
reduction of 1-acetylnaphthalene was conducted in Et2O
or Et2O/THF (1:1) solution, the enantioselectivity dropped
dramatically, giving 14i with 31-35% ee. As the addition
of HMPA or lithium iodide is known to affect the
enantioselectivities in certain reactions (such as alkyla-
tion reactions of enolates or allylmetals),7 we also exam-
ined their effects in the LAH reductions. Our results
indicated that the enantioselectivity of the alcohol prod-
ucts was increased in some instances by addition of LiI
(Table 2, entries 2, 11, and 22). On the other hand, the
enantioselectivity decreased in the reduction of 1-acetyl-
naphthalene in the presence of the cosolvent HMPA
(Table 2, entry 12).
2-furyl
2-thienyl
2-(3-methylthienyl)
2-(5-chlorothienyl)
2-(5-bromothienyl)
PhCHdCH
15 (88)
52
R
R
16a (90) 83
16b (92) 54
16c (92) 61
16d (94) 63
17 (93)
17 (91)
18 (89)
50
R
R
R
PhCHdCH
1-cyclohexenyl
LiI(1)
52
74d
a
Refer to the footnote of Table 1 for reaction conditions, isolated
yields, ee values, optical yields, and absolute configuration of major
enantiomers. Based on the amount of respective ketone. c The
alcohol product was treated with phenyl isocyanide to give the
corresponding carbamate, of which the ee value was determined
by HPLC analysis. The alcohol product was treated with 3,5-
dinitrobenzoyl chloride to give the corresponding ester, of which
the ee value was determined by HPLC analysis.
b
d
Several mono- and disubstituted acetophenones were
reduced by LAH/10b (Table 2) to afford the corresponding
phenylethanols 14a -h (Figure 2) in favor of the R
configuration alcohols (62-91% ee). The chiral reducing
agent was prepared in situ by mixing a standardized
Et2O stock solution of LAH with modifier 10b at room
temperature for 1 h. THF solutions of prochiral ketones
were then added at -78 °C and stirred for another 1 h
to furnish the corresponding secondary alcohols in 83-
96% chemical yields. The nitro group did not interfere
with the reduction of methyl 2-nitrophenyl ketone (Table
2, entry 7), giving 85% of the desired alcohol. The chiral
modifier 10b was recovered nearly quantitatively (>96%)
from the reaction mixture by silica gel chromatography.
Among the examined examples, the reduction of 2′-
methoxyacetophenone and 2′,5′-dimethoxyacetophenone
(7) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. (b)
Chang, C.-J .; Fang, J .-M.; Liao, L.-F. J . Org. Chem. 1993, 58, 1754
and the references therein.

3210 J . Org. Chem., Vol. 64, No. 9, 1999
Cherng et al.
Ta ble 3. Ch ir a l Liga n d P r om oted Rea ction of
Ben za ld eh yd e w ith Dieth ylzin c, Givin g Alcoh ol 19a a
entry
ligand
yieldb/%
eeb/%
configb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
10a
10b
10c
10d
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
7b
7c
7d
7e
8a
8b
8c
8d
8e
8f
(60)c
(9)c
R
R
R
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
(73)c
(47)c
(68)c
(50)c
(66)c
(46)c
85 (81)c
84 (83)c
83 (81)c
84 (82)c
87 (77)c
81 (80)c
77 (77)c
83 (79)c
84 (84)c
79 (75)c
86 (88)c
87 (83)c
86 (84)c
84 (87)c
88 (88)c,d
84 (85)c
81 (88)c
84 (85)c
91 (92)c,d
(68)e
82 (62)c
82 (79)c
88 (79)c
82 (79)c
37 (16)c
77 (69)c
69 (62)c
86 (78)c
84 (85)c
23 (11)c
77 (57)c
81 (72)c
86 (80)c
81 (73)c
76 (74)c,d
77 (71)c
70 (79)c
79 (78)c
86 (82)c,d
(70)e
F igu r e 3. Favorable transition states proposed for the asym-
metric LAH reduction (A) and Et2Zn addition (B).
The facial selectivities realized in the LAH reduction
of aromatic methyl ketones using modifier 10b are
superior to those utilizing simple terpenic diol modifiers
(<30% ee).8 Our results demonstrated the importance of
the anilino substituent at C-10 in the modifier 10b,
compared with the N-methylanilino substituent of 11 or
the benzyloxy substituent of 12, for the control of chirality
in the enantioselective LAH reduction of ketones. The
asymmetric induction was further improved by the
ethoxy group at C-3 of modifier 10b, compared with the
hydroxyl group of modifiers 5-9. A possible transition
state for the stereochemical outcome, as exemplified by
the reaction of acetophenone, is illustrated in Figure 3
(A).6 The chiral LAH/10b reagent is presumably formed
by O-Al-N bondings and O-Li-O chelation. The ethoxy
group at C-3 thus plays a role to differentiate two reaction
faces of this chiral reducing agent. The incoming carbonyl
group would coordinate with the Li+ ion to form a
chairlike transition state, in which the aryl group is
equatorially oriented. Attack of hydride thus occurs at
the si-face of acetophenone to furnish the observed R
alcohol. The alternative transition state by placing the
bulkier aryl group on the axial position is disfavored as
it would exert repulsions against the anilino and ethoxy
groups. Diols 5-9 are poor modifiers because their
hydroxyl groups at C-2 and C-3 would compete in bonding
with aluminum hydride and thus reduce the face selec-
tion.
Et2Zn Ad d ition . Unlike LAH reduction, modifiers
5-10 operated differently in the addition of diethylzinc
onto benzaldehyde. The diol ligands 5-9 turned out to
be better promoters than the alcohol ligand 10 for the
asymmetric Et2Zn addition reactions. The addition reac-
tion with benzaldehyde was generally carried out at room
temperature by using 2.2 equiv of Et2Zn and 2 mol % of
a pinane-type promoter (Table 3). The reaction using
alcohol ligands 10a -d gave the product 1-phenylpropanol
(19a ) in favor of the R enantiomer (9-50% ee), whereas
that using diol ligands 5-9 gave predominantly the S
enantiomer (up to 88% ee).
9a
9b
9c
9d
80 (85)c
85 (90)c
82 (85)c
85 (89)c
70 (80)c
84 (84)c
61 (75)c
83 (79)c
a
The reaction was conducted in hexane solution at room
temperature for 16 h with a molar ratio of PhCHO/Et2Zn/ligand
b
) 1.0:2.2:0.02. Refer to the footnote of Table 1 for isolated yields,
ee values, and absolute configuration of major enantiomers. c The
number in parentheses indicates the result of a similar reaction
d
conducted in toluene solution. The yield and ee value of the
alcohol product 19a decreased when the reaction was performed
with 1.2 equiv of Et2Zn in toluene solution. Using 8a : 68% yield,
66% ee. Using 8e: 72% yield, 75% ee. e The reaction was performed
with 1.2 equiv of Et2Zn in toluene solution.
Ta ble 4. Non lin ea r Effect of Op tica lly En r ich ed Liga n d
8e in th e Rea ction of Ben za ld eh yd e w ith Dieth ylzin c,
Givin g Alcoh ol 19a a
entry
ee/% of 8e
yield/%
ee/% of 19a
config
1
2
3
4
5
6
14.1
23.5
37.6
47.0
70.5
93.8
88
87
89
88
88
91
33
41
54
67
77
82
S
S
S
S
S
S
a
Molar ratio PhCHO/Et2Zn/8e ) 1.0:2.2:0.02. The reaction was
conducted in hexane solution, refer to Table
conditions.
3 for detailed
occurred with the same enantiotopic face selection (com-
pared entries 23 and 24 of Table 3). The enantioselec-
tivity slightly decreased when the reaction was conducted
with 1.2 equiv of Et2Zn (entries 19 and 23, Table 3). A
nonlinear asymmetric effect was observed by using the
chiral ligand 8e of different optical purities to promote
the addition of Et2Zn with PhCHO. The product (S)-19a
was obtained in a higher optical yield by comparison with
the optical purity of the starting ligand 8e, when 8e had
70.5% or less enantiomeric excesses (entries 1-5, Table
4).
The chemical yields of S enriched alcohol 19a were in
the range of 75-92%, and the chiral ligands were
recovered in good yields (ca. 94%) from the reaction
mixture by silica gel chromatography. The ee value of
19a was determined by HPLC on a Chiralcel OD column.
In most cases, the reactions performed in hexane solution
tended to show higher asymmetric induction than those
performed in toluene. The Et2Zn addition reactions using
either the ligand 8e or the diastereomer 8f, prepared
from (1R)-myrtenol with (S)- or (R)-1-phenylbutanol,
Using diol ligands 5c or 8e as the chiral promoters,
the addition reactions of Et2Zn to various substituted
benzaldehydes also afforded the products 19b-h in
dominance of S enantiomers (Table 5). The ee values of
19b-h were determined by HPLC analyses of their
(8) (a) Haller, R.; Schneider, H. J . Chem. Ber. 1973, 106, 1312. (b)
Lund, E. D.; Shaw, P. E. J . Org. Chem. 1977, 42, 2073.

Pinane-Type Tridentate Reagents
J . Org. Chem., Vol. 64, No. 9, 1999 3211
Ta ble 5. Ch ir a l Liga n d P r om oted Rea ction of
Su bstitu ted Ben za ld eh yd es w ith Dieth ylzin ca
tion of optically active secondary alcohols. Formation of
(R)-alcohols is favored in the LAH reduction, whereas
formation of (S)-alcohols is favored in the Et2Zn addition.
The diol ligands 5-9 are efficient promoters for asym-
metric Et2Zn additions, whereas the alcohol 10b is the
best modifier for LAH reductions according to our current
results. We have also found that asymmetric Et2Zn
addition promoted by alcohols 10 showed an enantiotopic
preference opposite to those reactions using diol promot-
ers 5-9. The designed compounds 5-10 may not be ideal
modifiers by comparison with those reagents showing
extremely high enantioselectivity in the similar reac-
tions.2,3 However, the present methods are still practical
as the pinane-type reagents are easily prepared, and
these chiral modifiers are recovered from the reaction
mixture in nearly quantitative yields.
entry
aldehyde
ligand productb yield/% ee/% configc
1
2
3
5
6
7
8
9
10
11
12
13
14
o-FC6H4CHO
o-FC6H4CHO
p-FC6H4CHO
m-ClC6H4CHO
m-ClC6H4CHO
p-ClC6H4CHO
p-ClC6H4CHO
m-BrC6H4CHO
m-BrC6H4CHO
p-BrC6H4CHO
p-BrC6H4CHO
p-MeC6H4CHO
p-MeC6H4CHO
5c
8e
5c
5c
8e
5c
8e
5c
5c
5c
8e
5c
8e
19b
19b
19c
19d
19d
19e
19e
19f
19f
19g
19g
19h
19h
80
80
81
89
84
84
81
80
86
80
78
87
86
75
78
80
79
71
84
82
79
72
65
55
67
54
S
S
S
S
S
S
S
S
S
S
S
a
The reaction was conducted in hexane solution with a molar
ratio of aldehyde/Et2Zn/ligand ) 1.0:2.2:0.02. Refer to Table 3 for
b
detailed conditions. The alcohol products or their 3,5-dinitroben-
zoate derivatives were analyzed by HPLC on a Chiralcel OD
column to determine the ee values. c Configuration of the major
enantiomer was assigned according to the measurement of optical
rotation.
Exp er im en ta l Section
All reactions were carried out under nitrogen atmosphere
except as otherwise noted. Melting points are uncorrected. 1H
NMR spectra were recorded at 200, 300, or 400 MHz; 13C NMR
spectra were recorded at 50, 75, or 100 MHz. Chloroform (δ )
7.24 ppm) was used as internal standard in 1H NMR spectra.
Mass spectra were recorded at an ionizing voltage of 70 or 20
eV. Merck silica gel 60F sheets were used for analytical thin-
layer chromatography. Column chromatography was per-
formed on SiO2 (70-230 mesh); gradients of EtOAc and
n-hexane were used as eluents. Enantiomeric excess was
determined by HPLC using a Chiralcel OD column (0.46 cm
i.d. × 25 cm). The optical rotations were measured in CHCl3
solution on a digital polarimeter with a cuvette of 1 cm length.
Gen er a l P r oced u r e for th e P r ep a r a tion of C-10 Su b-
stitu ted r-P in a n ed iols 5-9. To a stirred suspension of KH
(24 mmol) in dry THF (20 mL) was added dropwise the
nucleophile (12 mmol, aniline or alcohol) via a syringe, and
the reaction was stirred at room temperature for 30 min after
the completion of the addition. A solution of myrtenyl bromide
(12 mmol) dissolved in THF (10 mL) was then added slowly.
The reaction was stirred at room temperature for 3-6 h. The
reaction was quenched by addition of H2O (2 mL). THF was
removed under reduced pressure, and the residue was ex-
tracted with EtOAc. The organic layer was washed with brine,
dried (MgSO4), filtered, and concentrated. The crude product
was purified by flash column chromatography (EtOAc/hexane
) 1:20) to give the C-10 substituted R-pinenes 3 and 4 (65-
85% chemical yields).
corresponding 3,5-dinitrobenzoate derivatives on a Chiral-
cel OD column.
As the addition reaction showed a nonlinear asym-
metric effect, it may involve a quite complicated mech-
anism.3,9 To explain why the diol ligands 5-9 are better
promoters than the alcohol ligands 10 for the formation
of 19a with higher chemical yields and ee values, one
can assume that a diol ligand favors to react with Et2Zn
to form a cyclic dialkoxyzinc intermediate.9 The zinc ion
in this intermediate is also chelated with the anilino or
alkoxy group at C-10 (Figure 3, B). By analogy to
previously proposed intermediates3,9 for diol ligand-
promoted Et2Zn addition reactions, a transition state
illustrated in B is a reasonable working hypothesis. It
involves a chairlike form with the participation of two
Et2Zn molecules. The bulkier phenyl group would take
the energetically favorable equatorial position and trans-
fer of an ethyl group occurs at the si-face of PhCHO to
furnish the observed (S)-alcohol. Several other possible
intermediates were excluded for steric reasons according
to examination of their molecular models.
Con clu sion
To a stirred solution of the R-pinene derivative (3 or 4, 10
mmol) in THF (28 mL)/water (3 mL)/acetone (10 mL) was
added trimethylamine N-oxide (12 mmol) at room temperature.
A 1% w/w OsO4-THF solution (8 mL, 3 mol %) was added,
and the mixture was refluxed. The reaction was monitored by
TLC until no starting material could be detected (ca. 4 days).
The reaction mixture was quenched by addition of saturated
NaHSO3 solution (20 mL). The solvent was removed by rotary
evaporation. The aqueous layer was extracted with EtOAc. The
combined organic layer was washed with brine, dried (MgSO4),
filtered, and concentrated. The crude product was purified by
flash column chromatography (silica gel, EtOAc/hexane ) 1:10)
to furnish the desired C-10-substituted R-pinanediols 5-9 (50-
81% chemical yields).
Gen er a l P r oced u r e for th e P r ep a r a tion of C-3 Alk oxy-
Su bstitu ted r-P in a n ols 10-12. To a stirred suspension of
NaH (3 mmol) in dry THF (20 mL) was added a THF solution
(5 mL) of the diol 5-9 (1 mmol). After 30 min, a solution of
alkyl bromide (1.1 mmol) in THF (3 mL) was added via a
syringe, and the mixture was stirred at room temperature for
24 h. The reaction was quenched by addition of H2O (1 mL).
THF was removed under reduced pressure, and the residue
was extracted with EtOAc. The organic layer was washed with
brine, dried (MgSO4), filtered, and concentrated. The crude
product was purified by flash column chromatography (silica
We have demonstrated that asymmetric LAH reduc-
tion of ketones and Et2Zn addition to aldehydes are
effectively promoted by pinane-type tridentate ligands.
These two methods are complementary in the prepara-
(9) Discussion of reaction mechanism: (a) Kitamura, M.; Suga, S.;
Oka, H.; Noyori, R. J . Am. Chem. Soc. 1998, 120, 9800. (b) Goldfuss,
B.; Houk, K. N. J . Org. Chem. 1998, 63, 8998. (c) Seebach, D.; Plattner,
D. A.; Beck, A. K.; Wang, Y. M.; Hunziker, D. Helv. Chim. Acta 1992,
75, 2171. (d) Nowotny, S.; Vettel, S.; Knochel, P. Tetrahedron Lett.
1994, 35, 4539. (e) Bolm, C.; Mueller, J . Tetrahedron 1994, 50, 4355.
(f) Rijnberg, E.; Hovestad, N. J .; Kleij, A. W.; J astrzebski, J . T. B. H.;
Boersma, J .; J assen, M. D.; Spek, A. L.; van Koten, G. Organometallics
1997, 16, 2847. (g) Kotsulei, H.; Wakao, M.; Hayakawa, H.; Shiman-
ouchi, T.; Shiro, M. J . Org. Chem. 1996, 61, 8915. Examples of
asymmetric Et2Zn additions using diol promoters: (h) Bolm, C.;
Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 205. (i)
Rosini, C.; Franzini, L.; Pini, D.; Salvadori, P. Tetrahedron: Asymmetry
1990, 1, 587. (j) Prasad, K. R. K.; J oshi, N. N. Tetrahedron: Asymmetry
1996, 7, 1957. (k) Kitajima, H.; Ito, K., Katsuki, T. Chem. Lett. 1996,
343. Examples of asymmetric Et2Zn additions using terpenic amino
alcohol promoters: (l) Masui, M.; Shioiri, T. Synlett 1997, 273. (m)
Goralski, C. T.; Chrisman, W.; Hasha, D. L.; Nicholson, L. W.; Rudolf,
P. R.; Zakett, D.; Singaram, B. Tetrahedron: Asymmetry 1997, 8, 3863.
(n) Genov, M.; Dimitrov, V.; Ivanova, V. Tetrahedron: Asymmetry 1997,
8, 3703.

3212 J . Org. Chem., Vol. 64, No. 9, 1999
Cherng et al.
gel) with elution of hexane/EtOAc to give the corresponding
C-3 alkoxy-substituted R-pinanol products 10-12 (76-92%
chemical yields).
H), 1.19 (s, 3 H), 0.89 (t, J ) 7.2 Hz, 3 H), 0.71 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 142.24, 128.43 (2 C), 127.65, 126.66
(2 C), 82.79, 78.25, 75.14, 66.09, 48.95, 40.56, 40.28, 38.65,
37.10, 27.77, 27.74, 23.83, 17.10, 13.90; MS m/z (rel intensity)
318 (1, M+), 155 (72); HRMS calcd for C20H30O3 318.2195, found
318.2198.
Gen er a l P r oced u r e for th e LAH Red u ction of Meth yl
Keton es (Ta bles 1 a n d 2). A stock solution of lithium
aluminum hydride (0.6 mL of 1 M solution in Et2O) was placed
in a 10 mL round-bottomed flask. An appropriate chiral
modifier (10a -e, 0.66 mmol, 1.1 equiv) in THF solution (3 mL)
was added dropwise at room temperature, and evolution of
hydrogen was apparent. The mixture was stirred at room
temperature for 1 h and cooled to -78 °C, and a solution of
methyl ketone (0.3 mmol, 0.5 equiv) in THF (3 mL) was added
dropwise. The reaction was complete in 1 h as shown by TLC
analysis. A solution of dilute aqueous HCl (5%) solution (3 mL)
was added slowly, and the mixture was warmed to room
temperature and stirred for 4 h. After removal of THF by
rotary evaporation, the mixture was extracted with EtOAc.
The organic phase was washed with brine, dried (MgSO4),
filtered, and concentrated. The residue was chromatographed
on a silica gel column by elution with gradients of EtOAc/
hexane to give the desired alcohol products 14a -18 (83-96%
chemical yields) and the modifier 10a -e (90-96% recovery).
The ee values of the alcohol products were determined by
HPLC on a Chiralcel OD column (2-propanol/hexane elution).
The absolute configuration of major enantiomers was assigned
by comparison of the optical rotations with the reported values.
Gen er a l P r oced u r e for th e Ad d ition of Dieth ylzin ic
to Ald eh yd es (Ta bles 3-5). The chiral catalyst (5-10, 0.038
mmol, 0.02 equiv) was dissolved in hexane (10 mL) and Et2Zn
(4.2 mmol, 2.2 equiv, 1 M standard solution in hexane) was
injected. An appropriate aldehyde (1.9 mmol, 1 equiv) was
added dropwise via a syringe, and the mixture was stirred for
16 h. The mixture was quenched by addition of 5% HCl (3 mL).
The hexane layer was separated and subsequently washed
with brine. After drying over MgSO4 and filtration, the hexane
was removed under reduced pressure, and the crude alcohol
products 19-22 (60-92% chemical yields) were purified by
flash column chromatography (hexane/EtOAc). The chiral
catalyst was recovered in 92-96% yields. The ee values of the
alcohol products were determined by HPLC on a Chiralcel OD
column (2-propanol/hexane elution). The absolute configura-
tion of the major enantiomer was assigned by comparison of
the optical rotation with the reported value.
(1R ,2S ,3S ,5R )-(-)-2-An ilin om e t h yl-6,6-d im e t h yl-3-
eth oxybicyclo[3.1.1]h ep ta n -2-ol (10b): oil; [R]25 ) +11.5
D
1
(c ) 1.0, CHCl3); IR (CHCl3) 3520, 1610 cm-1; H NMR (300
MHz, CDCl3) δ 7.16 (t, J ) 8.0 Hz, 2 H), 6.67 (t, J ) 8.0 Hz,
1 H), 6.59 (d, J ) 8.0 Hz, 2 H), 4.24 (br s, 1 H, NH), 4.15 (s, 1
H, OH), 3.74-3.66 (m, 2 H), 3.52-3.46 (m, 1 H), 3.17 (d, J )
11.7 Hz, 1 H), 3.08 (d, J ) 11.7 Hz, 1 H), 2.43-2.38 (m, 1 H),
2.26-2.17 (m, 2 H), 1.97-1.78 (m, 1 H), 1.75 (ddd, J ) 13.8,
5.1, 2.7 Hz, 1 H), 1.47 (d, J ) 9.9 Hz, 1 H), 1.26 (s, 3 H), 1.22
(t, J ) 3.6 Hz, 3 H), 0.98 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 149.11, 129.26 (2 C), 117.06, 112.93 (2 C), 75.23, 73.92, 65.31,
53.49, 49.43, 40.42, 38.29, 35.40, 27.64, 27.56, 24.16, 15.54;
MS m/z (rel intensity) 289 (15, M+), 106 (100); HRMS calcd
for C18H27NO2 289.2042, found 289.2036.
N-[6,6-Dim eth yl-3-eth oxy-2-h yd r oxybicyclo[3.1.1]h ep t-
10-yl]-N-p h en yl-3,5-d in itr oben za m id e (13): HPLC (Chiral-
cel OD, 2-propanol/hexane (2:1), 1 mL/min) tR 31.5 min
[(1R,2S,3S,5R)-isomer], 42.3 min [(1S,2R,3R,5S)-isomer].
1-(1-Cycloh exen yl)eth a n ol (18):19 [R]25 ) +7.4 (c ) 2.6,
D
CHCl3) (74% ee favoring the R enantiomer) (lit.19 [R]25D +3.29
(c ) 2.49, CHCl3)); HPLC for the 3,5-nitrobenzoate derivative
(Chiralcel OD, 2-propanol/hexane (1:40), 0.41 mL/min) tR 42.2
min (S-enantiomer), 46.6 min (R-enantiomer).
1-(2-F lu or op h en yl)p r op a n ol (19b):21 [R]25D ) -22.4 (c )
2.0, CHCl3) (75% ee favoring the S-enantiomer) (lit.21 [R]25
D
-20.06 (c ) 1.77, CHCl3, 62% ee favoring the S enantiomer);
HPLC for the 3,5-nitrobenzoate derivative (Chiralcel OD,
2-propanol/hexane (1:5), 0.48 mL/min) tR 36.4 min (R enanti-
omer), 43.4 min (S enantiomer).
Ack n ow led gm en t. We thank the National Science
Council of the Republic of China for financial support.
Su p p or tin g In for m a tion Ava ila ble: Additional physical
and spectral data of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O982403B
(1R ,2S ,3S ,5R )-(+)-6,6-Dim e t h yl-2-(N -b u t yla n ilin o)-
m eth ylbicyclo[3.1.1]h ep ta n e-2,3-d iol (5c): solid; mp 80-
81 °C; [R]25D ) +11.1 (c ) 0.94, CHCl3); IR (CHCl3) 3520 (OH),
(10) (a) Davies, S. G.; Goodfellow, C. L. J . Chem. Soc., Perkin Trans.
1 1990, 393. (b) Takemura, T,; Saito, K.; Nakazawa, S.; Mori, N.
Tetrahedron Lett. 1992, 33, 6335.
(11) Nakamura, K.; Kawasaki, M.; Ohno, A. Bull. Chem. Soc. J pn.
1996, 69, 1079.
(12) Resnick, S. M.; Torok, D. S.; Gibson, D. T. J . Org. Chem. 1995,
60. 3546.
(13) Kaufman, T. S. Tetrahedron Lett. 1996, 37, 5329.
(14) Corrie, J . E. T.; Reid, G. P.; Trenthan, D. R.; Hursthouse, M.
B.; Mazid, M. A. J . Chem. Soc., Perkin Trans. 1 1992, 1015.
(15) Ziffer, H.; Kawai, K.; Kasai, M.; Imuta, M.; Forussios, C. J . Org.
Chem. 1983, 48, 3017.
1
1605, 1054 cm-1; H NMR (300 MHz, CDCl3) δ 7.24 (dd, J )
8.0, 7.8 Hz, 2 H), 6.92 (d, J ) 8.0 Hz, 2 H), 6.79 (t, J ) 7.8 Hz,
1 H), 4.09 (dd, J ) 9.3, 5.7 Hz, 1 H), 3.48 (d, J ) 15.0 Hz, 1
H), 3.33 (t, J ) 7.8 Hz, 2 H), 3.30 (d, J ) 15.0 Hz, 1 H), 2.53-
2.43 (m, 1 H), 2.24-2.16 (m, 1 H), 2.15 (t, J ) 6.0 Hz, 1 H),
1.97-1.91 (m, 1 H), 1.70 (ddd, J ) 13.8, 5.4, 2.4 Hz, 1 H), 1.58-
1.26 (m, 4 H) 1.47 (d, J ) 9.6 Hz, 1 H), 1.28 (s, 3 H), 1.04 (s,
3 H), 0.93 (t, J ) 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
149.89, 129.18 (2 C), 118.41, 115.46 (2 C), 76.00, 67.64, 61.33,
53.43, 51.43, 40.55, 38.82, 38.00, 28.03, 27.74, 27.67, 24.28,
20.21, 13.86; MS m/z (rel intensity) 317 (13, M+), 162 (100),
149 (9); HRMS calcd for C20H31NO2 317.2355, found 317.2353.
(1R,1′R,2S,3S,5R)-(+)-6,6-Dim eth yl-2-(1-p h en ylbu toxy)-
m eth ylbicyclo[3.1.1]h ep ta n e-2,3-d iol (8e): solid; mp 62-
(16) (a) Naemura, K.; Murata, M.; Tanaka, R.; Yano, M.; Hirose,
K.; Tobe, Y. Tetrahedron: Asymmetry 1996, 7, 3285. (b) Collyen, K. J .
Chem. Soc, 1940, 7, 676.
(17) Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.; Poli, S.;
Gardini, F. Tetrahedron: Asymmetry 1993, 4, 1607. (b) Bradshaw, C.
W.; Hummel, W.: Wong, C.-H. J . Org. Chem. 1992, 57, 1532.
(18) Srary, I.; Zajicek, J .; Kocovsky, P. Tetrahedron 1992, 48, 7229.
(19) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(20) Kang, J .; Lee, J . W.; Kim, J . I. J . Chem. Soc., Chem. Commun.
1994, 2009.
(21) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M. Tetrahedron
1994, 50, 4363.
(22) Chaloner, P. A.; Langadianou, E.; Perera, S. A. R. J . Chem.
Soc., Perkin Trans. 1 1991, 2731.
63 °C; [R]25 ) +61.6 (c ) 0.7, CHCl3); IR (CHCl3) 3570, 1180
D
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.40-7.23 (m, 5 H), 4.24
(dd, J ) 7.8, 5.7 Hz, 1 H), 4.04 (dt, J ) 9.3, 5.7 Hz, 1 H), 3.39
(s, 1 H, OH), 3.29 (d, J ) 9.3 Hz, 1 H), 3.25 (d, J ) 9.3 Hz, 1
H), 3.02 (d, J ) 3.8 Hz, 1 H, OH), 2.44-2.36 (m, 1 H), 2.21-
2.16 (m, 1 H), 2.10 (t, J ) 6.0 Hz, 1 H), 1.91-1.76 (m, 2 H),
1.71-1.56 (m, 2 H), 1.48 (d, J ) 9.9 Hz, 1 H), 1.43-1.27 (m, 2