[1,2]-Wittig rearrangement of acetals iii [1]. New 1,2-alkoxyalcohols, 1,2-alkoxyamines and 1,2-dialkoxy compounds as chiral ligands for organomagnesium and organolithium compounds and for lithium aluminum hydride

Article abstract of DOI:10.1007/s007060070064

Eight O-substituted 1,2-diols and one O,N-substituted 1,2-aminoalcohol derived from 2-alkoxyoctahydro-7,8,8-trimethyl-4,7-methanobenzofurans via a [1,2]-Witting rearrangement and subsequent substitution were synthesized and tested as additives for the ena

Full text of DOI:10.1007/s007060070064

Monatshefte f uÈ r Chemie 131, 867±877 (2000)
[1,2]-Wittig Rearrangement of Acetals III [1].
New 1,2-Alkoxyalcohols, 1,2-Alkoxyamines
and 1,2-Dialkoxy Compounds as Chiral
Ligands for Organomagnesium and
Organolithium Compounds and for
Lithium Aluminum Hydride
Ã
Peter G aÈ rtner , Martin Letschnig, and Max Knollm uÈ ller
Institut f uÈ r Organische Chemie, Technische Universit aÈ t Wien, A-1060 Wien, Austria
Summary. Eight O-substituted 1,2-diols and one O,N-substituted 1,2-aminoalcohol derived from 2-
alkoxyoctahydro-7,8,8-trimethyl-4,7-methanobenzofurans via a [1,2]-Witting rearrangement and
subsequent substitution were synthesized and tested as additives for the enantioselective addition of
butyllithium and butylmagnesium chloride to benzaldehyde and for the reduction of acetophenone
with lithium aluminum hydride. The selectivity of the reactions was determined by GC of the
obtained 1-phenyl-1-pentanol and 1-phenylethanol on a chiral phase. Best results with regard to
selectivity (52% ee and 94% ee, resp.) were achieved in the formation of 1-phenyl-1-pentanol by
addition of the substituted 1,2-aminoalcohol to the organometallic reagent and in the reduction of
acetophenone using an ꢀ-alkoxyalcohol (62% ee).
Keywords. Acetals; [1,2]-Wittig rearrangement; Ligands, chiral; Carbonyl addition, stereoselective.
Introduction
The enantioselective addition of organometallic reagents to aldehydes and the
reduction of asymmetric ketones are two fundamental synthetic procedures to obtain
stereoselectively chiral secondary alcohols [2±4]. This structural feature is part of
many natural products or can serve as an important synthetic intermediate for various
other functionalities, e.g. halide, amine, ester, and ether and is therefore a valuable
target. A frequently used method to achieve this enantioselective addition and
reduction is to perform the reaction in the presence of a chiral ligand. This is often a
bifunctional compound capable of forming a chelate such as an alkoxy or amino
alcohol [5]. Many chiral ligands have already been synthesized and tested in this type
of reaction, some of them being highly selective [3, 4]. However, effort in the
development of new ligands is still ongoing [6±10]. Recently, we have described the
à Corresponding author

868
P. G aÈ rtner et al.
Fig. 1. ꢀ-Alkoxyalcohols 1±6 and derivatives 7±9 of these
Scheme 1. Selective alkylation experiments with chiral additives
Scheme 2. Selective reduction experiments with alcohols 1±6 as chiral additives
facile synthesis of six new ꢀ-alkoxyalcohols (1±6) from acetals by a simple [1,2]-
Wittig rearrangement [1, 11]. The fact that many ligands used so far have 1,2-
functionalities [12] prompted us ± in continuation of our efforts searching for new
chiral ligands [13, 14] ± to test 1±6 and their derivatives 7±9 as additives.
In the present communication, results of the application of 1±9 in the reaction
of butylmagnesium chloride and butyllithium with benzaldehyde (Scheme 1) and
in the reduction of acetophenone with lithium aluminum hydride (Scheme 2) are
reported.
Results and Discussion
Synthesis of derivatives 7±9
ꢀ
-Alkoxyamine 7 was prepared from a mixture of 1 and 2 by Swern oxidation [15]
and subsequent reductive amination [16]. Starting with a diastereomeric mixture was
obviously without consequence, the center of chirality being destroyed in the
oxidation step. The reduction of the intermediate imine was highly selective,

Chiral Ligands for Kryptobase Reactions
869
Scheme 3. Synthesis of ꢀ-alkoxyamine 7
furnishing 7 as the single stereoisomer. Unexpectedly, aminonitrile 12 was formed as
a by-product in this reaction, but it was also afforded in a highly selective way. The
absolute con®guration of the amine carbon atom was assigned based on the coupling
constant between the vicinal hydrogens bound to the ether carbon and the amine
center. For ꢀ-alkoxyalcohols it is well known that this value is bigger for products
with syn-con®guration like 1 (J ˆ 9.4 Hz) than for anti-isomers like 2 (J ˆ 3.8 Hz)
[17]. Compound 7 exhibited a coupling constant of 9.0 Hz which is similar to the
value observed for 1. Thus, it is likely that ꢀ-alkoxyamine 7 has also syn-
con®guration which should be formed under non-chelating conditions according to
the Felkin-Anh model [18]. For aminonitrile 12 no such coupling exists, because the
carbon under question is quaternary, but considering that the nitrile just replaces the
hydride in attacking the imine carbon the newly formed chiral center should be of S-
con®guration. It is worth mentioning that an approach via chloride 10 which was
obtained as a diastereomeric mixture after treatment of 1 and 2 with thionyl chloride
and subsequent Hofmann alkylation with diethylamine was not successful. Whereas
10 was obtained quantitatively, no reaction occurred with the amine which is
probably due to the high steric hindrance at this carbon. A further indication for this
assumption was given by the reaction of 1 and 2 with 4-methylbenzenesulfonyl
chloride. This did not afford the expected tosylates but instead also yielded 10. The
formation of chloro derivatives via tosylates is not unprecedented and usually
assisted by a neighboring group [19] which in our system could be the ꢀ-alkoxy
substituent. However, the driving force for this transformation should be the steric
requirement of the large tosyl group compared with the small chloride atom.
Ethers 8 and 9 were synthesized from alcohols 2 and 5 by deprotonation with n-
butyllithium and O-alkylation with methyl iodide. Whereas 8 was obtained in
excellent yield, the conversion of 5 was poor. This seems also to be a result of
pronounced steric hindrance in 5 compared with 2.

870
P. G aÈ rtner et al.
Scheme 4. Synthesis of ethers 8 and 9
Selectivity experiments with benzaldehyde
The reactions with butylmagnesium chloride and butyllithium were carried out in
diethyl ether as well as in tetrahydrofuran, because it is known that these solvents
form complexes with the organometallic reagent; in addition, we have observed a
strong in¯uence of the solvent on enantioselectivity in earlier investigations [13]. For
reasons of comparability and to exclude any reaction of an organometallic species
without a chiral ligand we chose the same reaction conditions as described earlier
[
13]. Thus, since one equivalent of the organometallic reagent is consumed by each
ꢀ
acidic proton of the additive, the reaction was carried out at � 78 C using the
following ratios: benzaldehyde:organometallic reagent: 8,9ˆ 1:4.7:5.2, benzaldehyde:
organometallic reagent: 1±5,7 ˆ 1:9.2:5.2, and benzaldehyde:organometallic reagent:
6
ˆ 1:14.4:5.2. Due to the low temperature the reaction mixtures were heterogeneous
Table 1. Yield and enantiomeric excesses of 1-phenyl-1-pentanol in the alkylation of benzaldehyde by
n-BuMgCl and n-BuLi in the presence of additives 1±9 and 1±7
Organometallic
Compound
Additive
Solvent
Yield %
% ee (abs. conf.)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuLi
2
2
3
3
4
5
5
6
6
7
8
8
9
1
2
2
6
7
Et O
2
97
71
62
73
50
89
80
24
3
48 (R)
13 (R)
8 (R)
43 (S)
18 (S)
9 (R)
10 (S)
49 (S)
±
THF
Et O
2
THF
Et O
2
Et O
2
THF
Et O
2
THF
1
1
1
1
1
1
1
1
1
Et O
2
38
68
41
< 1
< 1
93
99
1.1
< 1
52 (R)
8 (R)
1 (S)
Et O
2
THF
THF
THF
4 (R)
1 (R)
1 (R)
1 (R)
33 (R)
94 (R)
n-BuLi
Et O
2
n-BuLi
THF
THF
n-BuLi
n-BuLi
Et O
2

Chiral Ligands for Kryptobase Reactions
871
with some ligands. However, this fact obviously is of no fundamental in¯uence
on the results, since even in heterogeneous systems high selectivities can be achieved
[8].
In Table 1 the results of those experiments are summarized which yielded at
least some 1-phenyl-1-pentanol under the reaction conditions de®ned above. All
other experiments have been omitted from the table, but they are included in the
discussion as well. Ligand 1 was not tested in Et O, and 7 was not used in THF.
2
Reactions with n-BuLi have not been carried out with 8 and 9, because results with
n-BuMgCl were not promising at all.
As can be seen from Table 1, experiments in which additives 1, 5, 8, and 9 were
used did not show any signi®cant selectivity. Enantiomeric excess in these cases
was lower than 10% ee. For ligands 2, 3, 6, and 7 at least the Grignard addition in
one of the solvents (Et O for 2, 6, and 7, THF for 3) showed a moderate selectivity
2
(> 43% ee). The con®guration of the alcohol formed in excess not only switched
depending on the ligand (R: 2, 7; S: 3, 6), but also for the same ligand (3, 5, 8)
in different solvents as was observed already in earlier investigations [13].
Surprisingly, reactions with n-BuLi gave only low conversions in most cases. Only
if 2 was used as an additive the yield was good, but the reaction was nearly non-
selective. On the other hand, if ꢀ-alkoxyamine 7 was added as chiral ligand the
selectivity was 94% ee, but the yield was very small. To see whether a change of
the reaction temperature would effect the conversion in the experiments with n-
ꢀ
BuLi positively, the reaction with ligand 4 was also performed at 0 C. However, no
product was obtained under these conditions, too.
Selectivity experiments with acetophenone
For the same reasons as already mentioned above the reactions with lithium
aluminum hydride were also carried out in both solvents. In detail, a solution of
ꢀ
two equivalents of the additive 1±6 in THF and diethyl ether was cooled to 0 C
before one molar equivalent of lithium aluminum hydride was added. For 6 with its
two acidic protons a second equivalent of LiA1H was used. The mixture was
4
ꢀ
stirred for 30 min to complete the complex formation, cooled to � 78 C, and a
solution of 0.8 equivalents of acetophenone in the corresponding solvent was added
dropwise. After stirring for exactly 1 h keeping the temperature between � 83 and
ꢀ
�
73 C, the reaction was quenched with 2 N hydrochloric acid and worked up by
extraction to give a crude product which was analyzed by gas chromatography to
determine yield and enantioselectivity.
Again, selectivities were heavily in¯uenced by the solvent used, resulting in the
predominant formation of the other enantiomer of 1-phenylethanol in the case of 1,
2, and 6. However, enantiomeric excesses for the products were only low (1, 2) to
moderate (3, 5, 6). Only using additive 4 in Et O resulted in a product with 62% ee
which dropped to 27% ee if the reaction was performed in THF.
2
With the best ligand in this series (4) we carried out two additional experiments
with the intention of further improving the selectivity. In the ®rst one we added one
equivalent of N-methylaniline to the lithium aluminum hydride complex prior to
the reduction. Although this addition of an achiral amine has been described to
improve the selectivity for other auxiliaries signi®cantly [20], we obtained 1-

872
P. G aÈ rtner et al.
Table 2. Yield and enantiomeric excesses of 1-phenylethanol in the reduction of acetophenone by
LiAlH in the presence of additives 1±6
4
Additive
Solvent
Yield (%)
% ee (abs. conf.)
1
2
3
4
5
6
7
8
9
0
1
2
1
1
2
2
3
3
4
4
5
5
6
6
Et O
2
84
54
13 (R)
5 (S)
THF
Et O
2
15
17 (S)
8 (R)
THF
40
Et O
2
42
15 (S)
37 (S)
62 (S)
27 (S)
43 (S)
9 (S)
THF
71
Et O
2
> 99
60
THF
Et O
2
39
1
1
1
THF
20
Et O
2
96
14 (S)
42 (R)
THF
92
phenylethanol with only 20% ee. In the second one, LiAlH was replaced by
4
NaBH which resulted in a non-selective reaction (1.5% ee).
4
Conclusions
Some of the alcohols obtained via [1,2]-Wittig rearrangement of acetals of
octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-ol and derivative 7 exhibit
moderate enantioselectivities as ligands for the addition of butylmagnesium chloride
to benzaldehyde and the reduction of acetophenone with lithium aluminum hydride.
Ethers 8 and 9 showed no selectivity at all. The addition of butyllithium to
benzaldehyde in diethyl ether was highly selective in the presence of 7. However, in
this case the question of the low conversion has still to be addressed and will be the
issue of further investigations. In none of the reaction systems a general preference
was found with regard to absolute con®guration of the enantiomer formed in excess
or to a solvent in which higher selectivities could be achieved. A so-called magic
effect of the diarylhydroxymethyl-group [21] which is present in 5 and 6 was not
observed in our investigation. These two ligands exhibited no signi®cant better
selectivity compared to the other additives.
Experimental
General techniques
All reactions were carried out under a nitrogen atmosphere in dry, freshly distilled solvents under
anhydrous conditions unless otherwise stated. Tetrahydrofuran (THF) and diethyl ether (Et O) were
2
distilled from sodium/benzophenone. n-Butyllithium and n-butylmagnesium chloride were purchased
from Aldrich as 2.5 M solution in n-hexane and 2 M solution in Et O and THF and used immediately.
2
The content of n-butyllithium in n-hexane was determined by titration with t-butanol using 1,10-
phenanthroline as indicator. All other reagents were purchased in standard commerical quality unless
otherwise stated. Reactions were monitored by TLC carried out on 0.25 mm Merck silica gel plates

Chiral Ligands for Kryptobase Reactions
873
(
60F-254) using UV light for visualizing and molybdato phosphoric acid (5% in ethanol) and heat
as developing agents. For vacuum ¯ash chromatography (VFC) and column chromatography (CC),
the amount of silica gel 60 (Merck, 0.2±0.5 mm mesh size) and the eluent are given. Melting points
were recorded according to Ko¯er and are uncorrected. Microanalyses were performed at the
Institute of Physical Chemistry, University of Vienna, under the supervision of Mag. J. Theiner; their
results agreed with the calculated values within experimental error. NMR spectra were recorded on a
Bruker AC 200 instrument and calibrated using the solvent resonance as internal standard. Optical
rotations were recorded on a Perkin Elmer 241 polarimeter. GC analyses were performed on a Carlo
Erba HR-GC 5300 Mega Series using a 50 m Macherey-Nagel fused silica capillary column (FS-
3
Lipodex/E) with an ID of 0.25 Helium 5.0 was used as carrier gas with a ¯ow rate of 4.3 cm /min
ꢀ
(
column pre-pressure: 210 kPa). The injector was heated to 220 C, and injected samples were
ꢀ
splitted in a ratio of 1:73. For 1-phenyl-1-pentanol the column temperature was held at 100 C for
ꢀ ꢀ
5
0 min and then raised to 140 C at a rate of 1 C/min. 1-Phenylethanol was analyzed isothermal with
ꢀ
ꢀ
a column temperature of 100 C. Compounds were detected in both cases with a FID (260 C), and
chromatograms were recorded on a Carlo Erba SP4270 integrator and processed with LABNET2
software from Spectra Physics. Rt benzaldehyde 7.3 min, (R)-1-phenyl-1-pentanol 63.7 min, (S)-1-
phenyl-1-pentanol 64.3 min, acetophenone 12.5 min, (S)-1-phenyl-1-ethanol 16.5 min, (R)-1-phenyl-
1
-ethanol 17 min. The absolute con®guration of the major isomer was based on retention times
0
of reference samples prepared via acetal formation between racemic alcohol and (2S,2 S-
0
0
0
0
0
0
(2ꢀ2 ꢀ,3aꢀ,3a ꢀ,4ꢁ,4 ꢁ,7ꢁ,7 ꢁ,7aꢀ,7a ꢀ))-2,2 -oxybis-(octahydro-7,8,8-trimethyl-4,7-methanoben-
zofuran) ((MBE) O), separation of the diastereomers, and acid catalyzed cleavage with methanol
2
[
13, 22]. Compounds 1±6 were prepared as described in Refs. [1, 11]. Abbreviations used: PE ˆ
petroleum ether.
Ã
methanobenzofuran-2-methanamine (7; C H NO)
(
2R-(2ꢀ(R ),3aꢀ,4ꢁ,7ꢁ,7aꢀ))-N-Butyl-octahydro-7,8,8-trimethyl-ꢀ-phenyl-4,7-
23 35
3
A mixture of 0.419 g (1.48 mmol) of 11, 0.70 cm (6.91 mmol) of n-butanamine, 0.085 g (1.40 mmol)
3
of sodium cyanoborohydride, 0.35 cm (6.21 mmol) of glacial acetic acid, and 0.66 g of MgSO in
4
3
3 cm of ethanol was stirred for 48 h at room temperature. 14 cm of a 1 N aqueous NaOH solution
3
1
3
and 140 cm of brine were added, the aqueous phase was extracted thoroughly with ethyl acetate, the
combined organic layers were dried over Na SO , and the solvent was evaporated. Column
2
4
chromatography (50 g, PE:Et O:NEt ˆ 300:30:1 to 400:100:1 to 0:20:1) afforded 0.149 g (30%) of
2
3
7
and 0.099 g (20%) of 12.
2
3
1
7
m, 5H, Ph-H), 4.18-4.03 (m, 1H, 2-H), 3.80 (d, 1H, 7a-H), 3.41 (d, 1H, CHNHR), 2.46-0.74 (m,
1
7H, aliphatic H and NH, therein: 1.00, 0.98 and 0.79 (3s, 9H, 3 CH ))ppm; C NMR (50 MHz, ꢂ,
: Colorless oil; ‰ꢀŠ ˆ � 47:1 (c ˆ 1.42, CH Cl ); H NMR (200 MHz, ꢂ, CDCl ): 7.36-7.18
D
2
2
3
(
3
2
3
CDCl ): 141.7 (s, C(ph)-1), 128.6, 128.2 (2d, C(ph)-2, C(ph)-6, C(ph)-3, C(ph)-5), 127.3 (d, C(ph)-
3
4), 91.1 (d, C-7a), 84.1 (d, C-2), 66.3 (d, CHNHR), 48.9, 47.6 (2d, C-3a, C-4), 48.2, 46.7 (2s, C-7,
C-8), 47.3 (t, N-CH ), 33.1, 32.4, 32.2 (3t, C-3, C-6, NCH CH ), 28.9 (t, C-5), 22.8, 20.4 (2q, 2 CH ),
3
2
2
2
20.4 (t, NCH CH CH ), 14.0 (q, butyl-CH ), 11.7 (q, CH ) ppm.
2 2 2 3 3
Ã
methanobenzofuran-2-acetonitrile (12; C H N O)
(
2R-(2ꢀ(S ),3aꢀ,4ꢁ,7ꢁ,7aꢀ))-ꢀ-Butylamino-octahydro-7,8,8-trimethyl-ꢀ-phenyl-4,7-
2
4 34 2
2
D
3
1
Yellow oil; ‰ꢀŠ ˆ � 23:8 (c ˆ 2.19, CH Cl ); H NMR (200 MHz, ꢂ, CDCl ): 7.65-7.22 (m, 5H, Ph-
2
2
3
H), 4.32 (d, 1H, 7a-H), 4.18 (dd, 1H, 2-H), 2.78-0.74 (m, 27H, aliphatic H and NH, therein: 1.00,
13
0
.88 and 0.79 (3s, 9H, 3 CH ))ppm; C NMR (50 MHz, ꢂ, CDCl ): 136.2 (s, C(ph)-1), 128.7, (d,
C(ph)-3, C(ph)-4, C(ph)-5), 127.1 (d, C(ph)-2, C(ph)-6), 120.4 (s, CN), 94.1 (d, C-7a), 88.7 (d, C-2),
9.7, (s, CNHR), 49.4, 47.6 (2d, C-3a, C-4), 48.7, 46.7 (2s, C-7, C-8), 44.2 (t, N-CH ), 33.1, 32.2,
3
3
6
2

874
P. G aÈ rtner et al.
3
2.0 (3t, C-3, C-6, NCH CH ), 28.5 (t, C-5), 22.6, 19.8 (2q, 2 CH ), 20.3 (t, NCH CH CH ), 13.9
2
2
3
2
2
2
(
q, butyl-CH ), 11.6 (q, CH ) ppm.
3 3
Ã
methanobenzofuran (8; C H O )
(
2R-(2ꢀ(S ),3aꢀ,4ꢁ,7ꢁ,7aꢀ))-Octahydro-2-(methoxyphenylmethyl)-7,8,8-trimethyl-4,7-
20 28 2
3
.46 cm (1.2 mmol) of a solution of butyllithium in THF were added to a solution of 0.267 g
0
3
0.93 mmol) of 2 in 16 cm of THF. The solution was stirred for 90 min at room temperature, and
(
subsequently 1.72 g (12 mmol) of methyl iodide were added. The solution was stirred for 15 h at
room temperature, concentrated under vacuum, and the, residue was distributed between H O and
2
Et O. The aqueous phase was extracted twice with Et O, the combined organic layers were dried
2 2
over Na SO , and the solvent was evaporated. VFC (10 g, PE:Et O ˆ 10:1) gave 0.247 g (88%) of 8
2
4
2
as colorless crystals.
ꢀ
20
D
1
M.p.: 67±69 C; ‰ꢀŠ ˆ ‡42:6 (c ˆ 1, CHCl ); H NMR (200 MHz, ꢂ, CDCl ): 7.42-7.18 (m, 5H,
3
3
Ph-H), 4.30-4.13 (m, 2H, 2-H, therein: 4.26 (d, 1H, CHOCH )), 3.92 (d, 1H, 7a-H), 3.32 (s, 3H,
3
1
3
OCH ) 2.38-0.72 (m, 17H, aliphatic H, therein: 0.96, 0.92 and 0.78 (3s, 9H, 3 CH )) ppm; C NMR
3
3
(
50 MHz, ꢂ, CDCl ): 139.2 (s, C(ph)-1), 128.2 (d, C(ph)-3, C(ph)-5), 127.3 (d C(ph)-4), 126.8 (d,
3
C(ph)-2, C(ph)-6), 93.5 (d, C-7a), 87.1 (d, CHOCH ) 84.1 (d, C-2), 57.3 (q, OCH ), 49.1, 48.4 (2d,
3
3
C-3a, C-4), 48.2, 46.6 (2s, C-7, C-8), 32.3 (t, C-3), 31.5 (t, C-6), 28.7 (t, C-5), 22.8, 20.2, 11.7 (3q,
CH ) ppm.
3
3
(
2R-(2ꢀ,3aꢀ,4ꢁ,7ꢁ,7aꢀ))-Octahydro-2-(methoxydiphenylmethyl)-7,8,8-trimethyl-4,7-
methanobenzofuran (9; C H O )
26 32 2
3
Prepared analogously to 8 from 1.969 g (5.43 mmol) of 5, 2.76 cm (7.2 mmol) of butyllithium
solution, and 9.97 g (71 mmol) of methyl iodide; yield after VFC (40 g silica gel, PE:Et O ˆ 1:0 to
2
3
0:1): 0.353 g (17%) of 9 as a colorless oil.
2
0
1
‰
ꢀŠ ˆ � 66:7 (c ˆ 0.86, CHCl ); H NMR (200 MHz, ꢂ, CDCl ): 7.53 (dd, 2H, 2 4(ph)-H), 7.43-
D
3
3
7
3
.18 (m, 8H, Ph-H), 5.15 (m, 1H, 2-H), 3.09 (d, 1H, 7a-H), 3.07 (s, 3H, OCH ), 2.50-2.28 (m, 1H,
3
a-H), 2.11-1.92 (m, 1H, 4-H), 1.63-0.47 (m, 15H, aliphatic H, therein: 1.04, 0.91 and 0.75 (3s, 9H, 3
13
CH ) ppm; C NMR (50 MHz, ꢂ, CDCl ): 143.1, 142.3 (2s, 2 C(ph)-1), 129.4, 129.4 (2d, 2 C(ph)-3,
3
3
2
C(ph)-5), 127.6, 127.2 (2d, 2 C(ph)-2, 2 C(ph)-6), 127.0, 126.9 (2d, 2 C(ph)-4), 94.0 (d, C-7a), 84.6
(
(
d, COCH ), 83.6 (d, C-2), 51.5 (q, OCH ), 49.4, 48.2 (2d, C-3a, C-4), 48.5, 45.9 (2s, C-7, C-8), 32.9
3
3
t, C-3), 32.0 (t, C-6), 28.5 (t, C-5), 22.7, 20.0, 11.6 (3q, 3 CH ) ppm.
3
(
2R-(2ꢀ,3aꢀ,4ꢁ, 7ꢁ,7aꢀ))-2-Chlorphenylmethyl-octahydro-7,8,8-trimethyl-4,7-
methanobenzofuran (10; C H ClO)
19 25
3
A solution of 0.1 g (0.35 mmol) of a diastereomeric mixture of 1 and 2 and 0.09 cm (1.24 mmol) of
3
SOCl in 10 cm of Et O was stirred for 4 h at room temperature, quenched with water, and extracted
2
2
exhaustively with Et O. The combined organic layers were dried over Na SO , and the solvent was
2
2
4
evaporated to furnish 0.11 g (100%) of 10 as a diastereomeric mixture.
1
Colorless oil; H NMR (200 MHz, ꢂ, CDCl ): 7.49-7.22 (m, 10H, Ph-H), 5.02 (d, 1H, CHCl, A),
3
4
.81 (d, 1H, CHCl, B), 4.60-4.47 (m, 2H, 2-H), 4.08 (d, 1H, 7a-H, A), 3.82 (d, 1H, 7a-H, B), 2.50-0.77
1
3
(
m, 34H, aliphatic H, therein: 0.96, 0.95 and 0.81 (3s, 18H, 6 CH )) ppm; C NMR (50 MHz, ꢂ,
3
CDCl ): 139.1, (s, C(ph)-1), B), 138.6 (s, C(ph)-1), A), 128.4, 128.4, 128.2, 128.0, 127.5 (5d, C(ph)-
3
3
, C(ph)-5), C(ph)-2, C(ph)-6, C(ph)-4), 93.5 (d, C-7a, A), 92.8 (d, C-7a, B) 84.5 (d, C-2, A), 83.9 (d,
C-2, B), 67.2 (d, CHCl, A), 65.5 (d, CHCl, B), 49.1, 48.2 (2d, C-4, C-3a, A), 48.9, 47.6 (2d, C-4, C-
a, B), 48.4, 46.5 (2s, C-7, C-8, A), 48.3, 46.5 (2s, C-7, C-8, B), 34.2 (t, C-3, B), 33.3 (t, C-3, A), 32.2
t, C-6), 28.7 (t, C-5), 22.7, 20.3, 20.2 and 11.5 (4q, 6 CH ) ppm.
3
(
3

Chiral Ligands for Kryptobase Reactions
875
(
2R-(2ꢀ,3aꢀ,4ꢁ,7ꢁ,7aꢀ))-(Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-
phenylmethanon (11; C H O )
19 24 2
3
A solution of 0.68 cm (4.85 mmol) of tri¯uoroacetic acid anhydride in 1.62 cm of CH Cl was
3
2
2
3
3
ꢀ
added to a mixture of 0.46 cm (6.46 mmol of DMSO and 3.2 cm of CH Cl at � 50 C, and the
2
2
mixture was stirred for 20 min. A solution of 0.923 g (3.22 mmol) of a diastereomeric mixture of 1
3
3
and 2 in 3.2 cm of CH Cl was added, and Stirring was continued for further 30 min. 1.29 cm
2
2
anhydrous triethylamine was added dropwise, and the mixture was allowed to warm to room
temperature. It was quenched with H O, and the aqueous phase was extracted twice with CH Cl .
2
2
2
The combined organic layers were dried over Na SO , and the solvent was evaporated. VFC (40 g,
2
4
PE:Et O ˆ 30:1) afforded 0.524 g (57%) of 11 as a colorless oil.
2
2
3
1
‰
ꢀŠ ˆ � 19:9 (c ˆ 3.17, CH Cl ); H NMR (200 MHz, ꢂ, CDCl ): 7.95 (d, 2H, 2(ph)-H), 6(ph)-
D
2
2
3
H, 6(ph)-H), 7.62-7.38 (m, 3H, 3(ph)-H, 4(ph)-H, 5(ph)-H), 5.44 (dd, 1H, 2-H), 4.08 (d, 1H, 7a-H),
1
.41-0.72 (m, 17H, aliphatic H, therein: 1.10, 1.03 and 0.82 (3s, 9H, 3 CH )) ppm; C NMR
3
2
3
(
50 MHz, ꢂ, CDCl ): 199.8 (s, C=O), 134.7 (s, C(ph)-1), 133.1 d, C(ph)-4), 128.6, 128.5 (2d, C(ph)-
3
2, C(ph)-6, C(ph)-3, C(ph)-5, 93.2 (d, C-7a), 80.4 (d, C-2), 48.7, 47.3 (2d, C-3a, C-4), 48.3, 46.9 (2s,
C-7, C-8), 34.7, 32.0 (2t, C-3, C-6), 28.7 (t, C-5), 22.7, 20.6, 11.5 (3q, 3 CH ))ppm.
3
Reaction of benzaldehyde with n-butyllithium and n-butylmagnesium chloride
using protic additives 1±7
A solution of 0.35 mmol of n-BuMgCl or n-BuLi was added to a solution of 0.2 mmol of 1±5 or 7 in
0
3
.88 cm of THF or Et O at 0 C. In the case of 6, 0.55 mmol of the organometallic compound were
ꢀ
2
ꢀ
used. The mixture was stirred for 30 min at this temperature and then cooled to � 78 C. A solution of
3
.38 mmol of benzaldehyde in 0.77 cm of the corresponding solvent was added, and the mixture was
0
ꢀ
stirred at � 78Æ5 C After 1 h the reaction mixture was quenched with H O, allowed to reach room
2
3
3
temperature, and 0.1 cm of the organic layer were diluted with 0.9 cm n-hexane and dried over
Na SO . If n-BuMgCl was used, the mixture was treated with solid NH Cl prior to the dilution
2
4
4
sequence. The solution was ®ltered through an Anotop 10 membrane ®lter and analyzed without any
further treatment by gas chromatography. Enantiomeric excess and yield were determined from
signal areas after recalculation considering response factors determined by calibration solutions.
Reaction of benzaldehyde with n-butylmagnesium chloride using aprotic additive 8±9
The reaction was carried out as described for protic additives, only the amount of n-BuMgCl was
reduced to 0.18 mmol for 0.2 mmol of additive.
Reduction of acetophenone with lithium aluminum hydride using protic additives 1±6
3
A solution of 0.1 mmol of LiAlH was added to a solution of 0.2 mmol of 1±5 in 0.88 cm of THF or
4
ꢀ
3
Et O at 0 C. In case of additive 6, 0.2 cm of LiAlH were used. The mixture was stirred for 30 min
2
4
ꢀ
ꢀ
3
at 0 C, cooled to � 78 C, and a solution of 0.08 mmol of acetophenone in 0.1 cm of the
ꢀ
corresponding solvent was added. The mixture was stirred for 1 h at � 78Æ5 C, quenched with H O
2
3
and allowed to reach room temperature. After treatment with 2 N hydrochloric acid, 0.1 cm of the
3
organic layer were diluted with 0.9 cm of n-hexane and dried over Na SO This solution was ®ltered
2
4
through an Anotop 10 membrane ®lter and analyzed directly by gas chromatography. Enantiomeric
excess and yield were determined from signal areas after recalculation considering response factors
determined by calibration solutions. When additive 1 was used in a tenfold larger scale, the whole
amount of product was isolated by column chromatography, and the enantiomeric excess was
determined as usual by gas chromatography.

876
P. G aÈ rtner et al.
Reduction of acetophenone with lithium aluminum hydride/N-methylaniline using additive 4
3
Following the above procedure for the reduction of acetophenone, 0.2 mmol 4 in 0.88 cm Et O were
2
3
treated with 0.1 mmol of LiAlH . A solution of 0.1 mmol of N-methylaniline in 0.33 cm of Et O
4
2
ꢀ
was added to this mixture. After cooling to � 78 C, 0.08 mmol of acetophenone were added. All
other steps were performed as described above.
Reduction of acetophenone with sodium borohydride using additive 4
3
Following the above procedure for the reduction of acetophenone, 0.2 mmol of 4 in 0.88 cm of Et O
2
ꢀ
were treated with 0.1 mmol of NaBH . After cooling to � 78 C, 0.08 mmol of acetophenone were
4
added. All other steps were performed as described above.
References
[
[
[
1] G aÈ rtner P, Letsching MF, Knollm uÈ ller M, Mereiter K (2000) Tetrahedron Asymm 11: 1003
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033; Wilken J, Groger H, Kossenjans M, Martens J (1997) Tetrahedron Asymm 8: 2761;
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1
[
7] Recent papers about the enantioselective addition of organotitan compounds: Duthaler RO,
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239
1
[
[
8] Recent papers about the enantioselective addition of organomagnesium compounds: Weber B,
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(
1994) Tetrahedron 50: 6117
9] Recent papers about the enantioselective addition of organolithium compounds: Ye M, Logaraj
S, Jackman LM, Hillegass K, Hirsch KA, Bollinger AM, Grosz AL, Mani V (1994) Tetrahedron

Chiral Ligands for Kryptobase Reactions
877
50: 6109; Huffman MA, Yasuda N, DeCamp AE, Grabowski EJJ (1995) J Org Chem 60: 1590;
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[
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2
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[
[
[
[
[
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[
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[
1231
Received March 10, 2000. Accepted March 23, 2000