New bicyclic γ- and δ-aminoalcohols as catalysts for the asymmetric diethylzinc addition to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2008.06.002

A new class of chiral non-racemic γ- and δ-amino alcohols based on bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane have been synthesized and used as catalysts in the asymmetric diethylzinc addition to benzaldehyde.

Full text of DOI:10.1016/j.tetasy.2008.06.002

Tetrahedron: Asymmetry 19 (2008) 1484–1493
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New bicyclic
c- and d-aminoalcohols as catalysts for the asymmetric
diethylzinc addition to benzaldehyde
*
Cecilia Olsson, Sara Helgesson, Torbjörn Frejd
Division of Organic Chemistry, Kemicentrum, Lund University, PO Box 124, SE-221 00 Lund, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2008
Accepted 2 June 2008
A new class of chiral non-racemic
clo[2.2.2]octane have been synthesized and used as catalysts in the asymmetric diethylzinc addition to
benzaldehyde.
c- and d-amino alcohols based on bicyclo[2.2.1]heptane and bicy-
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(BHEPTAMOLs) and bicyclo[2.2.2]octane-2,6-aminoalcohols (BOC-
TAMOLs).à The catalytic ability of these amino alcohols toward
Since 1984, when Oguni et al. used (S)-leucinol in a catalytic
amount to obtain moderate enantiomeric excess in the addition
of diethyl zinc to benzaldehyde,1 there has been a remarkable
number of chiral ligands developed for this reaction.2–4 The dieth-
ylzinc addition has become one of the most used ‘test reactions’ for
the asymmetric induction of new metal coordinated ligands and
catalysts. To reduce the number of possible close energy diastereo-
meric transition states many of the ligands make use of a rigid
backbone. Bicyclic frameworks could be very useful for this pur-
pose and many ligands of this type have been tested. The most
well-known is DAIB [(ꢀ)-3-exo-(dimethylamino)isoborneol],
which was the first ligand to give high enantioselectivity in the
diethylzinc addition to benzaldehydes.5 Many of the bicyclic
ligands are developed from the chiral pool6–9 (i.e., camphor
or fenchone) but there are also examples of de novo synthetic
ligands.10–12 The advantage of the non-natural ligands is that both
enantiomers are often available. A variety of chiral diols, amino
alcohols, diamines, and amino thiols have been tested as catalysts
the enantioselective addition of diethylzinc to benzaldehyde was
evaluated. Due to a less than convenient synthesis, the bicyclo-
[2.2.2]octane-2,5-aminoalcohols and bicyclo[2.2.1]heptane-2,6-
aminoalcohols have not been included in this study.
2. Results and discussion
2.1. Synthesis of 2,5-BHEPTAMOLs
A four-step synthesis to the BHEPTAMOLs was used, as is de-
scribed below. Aryl-substituted hydroxy ketones (ꢀ)-6–(ꢀ)-9 were
synthesized by the addition of organolithium or Grignard reagents
to optically active hydroxy ketone (ꢀ)-1, followed by TPAP/NMO
oxidation as previously described by our group.13 Reaction of the
ketones with benzylamine, followed by azeotropic removal of
water, gave the corresponding benzylimines, which were reduced
with NaBH4 to give endo-amines (ꢀ)-10–(ꢀ)-13, selectively, while
one-pot reductive amination of (ꢀ)-6 in the presence of NaBH3CN
or NaBH(OAc)3 gave the endo- and exo-aminoalcohol isomers in
90:10 and 70:30 ratios, respectively. The lower selectivities in
these cases were probably caused by the anchoring effect of the
hydride reagent to the alcohol, since NaBH4 only gave reduction
from the less sterically hindered exo-face.15,16 We also wanted to
test some tertiary amines corresponding to secondary amines
(ꢀ)-10–(ꢀ)-13. A method for the alkylation of secondary amines
without the formation of quaternary ammonium salts, using
1.1 equiv of an alkylbromide and 1.5 equiv of Hünig’s base in
CH3CN, was found in the literature.17 In our cases, however, for
in the reaction, but the majority are b-amino alcohols. The c- and
d-aminoalcohols are less frequent but there has been increased
interest in them recently.9
We recently reported the influence of various bicyclic diols on
the enantioselectivity in the diethylzinc addition to benzalde-
hyde.13,14 We found that the key features of an efficient catalyst
were the presence of a third coordinating group and the distance
between the coordinating groups. Starting from the same optically
active material as used for the diol-synthesis, a new series of
bicyclic aminoalcohols were synthesized. Herein, we present
the
synthesis
of
bicyclo[2.2.1]heptane-2,5-aminoalcohols
We suggest that the aminoalcohols based upon the bicyclo[2.2.1]heptane
framework should be named BHEPTAMOLs (bicyclo[2.2.1]heptaneaminoalcohols).
à
* Corresponding author.
We suggest that the aminoalcohols based upon the bicyclo[2.2.2]octane frame-
E-mail address: Torbjorn.Frejd@organic.lu.se (T. Frejd).
work should be named BOCTAMOLs (bicyclo[2.2.2]octaneaminoalcohols).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.002

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
1485
the ethylation of aminoalcohols (ꢀ)-10–(ꢀ)-13, the amount of EtBr
was increased to 10 equiv to obtain complete conversion without
significant amounts of quarternization. Thus, tertiary aminoalco-
hols (ꢀ)-14–(ꢀ)-17 were isolated in 70–93% yield (Scheme 1).
Ph
Ph
19
OH OH
ii
OH
Ph
O
HO
(-)-6: R=Ph
HO
i
ii
(-)-7: R=1-Naphth
(-)-8: R=o-An
(-)-9: R=Bn
R
R
iii
i
Ph
OH
OH
OH
O
O
OH
23
OH
(-)-1
(-)-2: R=Ph
NHBn
31
(-)-3: R=1-Naphth
(-)-4: R=o-An
(-)-5: R=Bn
iii
33
iv
O
iv
Ph
R
R
NEt
NH
OH
OH
Bn
Bn
32
O
(-)-14: R=Ph
(-)-10: R=Ph
(-)-15: R=1-Naphth
(+)-16: R=o-An
(-)-17: R=Bn
(-)-11: R=1-Naphth
(-)-12: R=o-An
(-)-13: R=Bn
Scheme 3. Reagents and conditions: (i) (a) BnNH2, toluene, reflux; (b) NaBH4,
MeOH, 0 °C; (ii) NaBH4, MeOH, 0 °C; (iii) BnNH2, NaBH(OAc)3, THF, rt; (iv) (a)
BnNH2, toluene, reflux; (b) H2O.
Scheme 1. Reagents and conditions: (i) RMgX/RLi, THF, 0 °C (63–82%); (ii) TPAP,
NMO, CH2Cl2, MS 4 Å, rt (85–95%); (iii) (a) BnNH2, toluene, reflux, 5 h; (b) NaBH4,
MeOH, 0 °C, then rt, 15 min (64–97%); (iv) EtBr, Hünig’s base, CH3CN, overnight,
80 °C (70–93%).
the hydroxyl group.16,15 TLC analysis of the reaction mixture from
reductive amination using NaBH3CN in THF showed a very unselec-
tive reaction.
2.2. Synthesis of 2,6-BOCTAMOLs
We concluded that the only way to prevent the retro-aldol reac-
tion was to protect the alcohol before the imine synthesis. Stan-
dard methods for MEM- and TBDMS-protection failed.19,20 We
then turned to protection by acylation. Reaction of hydroxy ke-
tones (+)-23–(+)-26 with acetic anhydride in pyridine with cata-
lytic amounts of DMAP, according to a literature procedure,21
gave the keto esters (ꢀ)-27–(+)-30 in 47–72% yield (Scheme 2).
We were puzzled by the relatively low yields, since TLC-analysis
of the reaction mixture showed rather clean reactions. We specu-
lated that the low yields were mainly caused by polymerization
of the reactant and/or the product.
In the reaction of phenyl-, 1-naphthyl-, and benzyl-substituted
hydroxy ketones (+)-23, (+)-24, and (+)-26, small amounts (>10%)
of the corresponding unsaturated ketones from elimination of the
alcohol or ester were observed by NMR-analysis of the crude prod-
ucts. However, for the o-anisyl-substituted hydroxy ketone (ꢀ)-25,
the corresponding unsaturated ketone was isolated in 30% yield.
Acylation involving either Sc(OTf)322 or TMSOTf23 gave the unsatu-
rated ketone as the main product.
Naphthyl-substituted acetate (ꢀ)-28 appeared as rotamers in
solution (in benzene and in CHCl3) and therefore gave considerably
broadened NMR-signals. The chemical shifts of some protons and
the coupling pattern changed when the NMR-sample was heated
to 343 K, but the signals remained broad. Additional structural evi-
dence of this compound was established from the mass-spectral
fragmentation pattern (EI).
Imine formation was now successful; reaction of ketoacetate
(ꢀ)-27 with 5 equiv of benzylamine, 2 equiv of acetic acid, and
MS 4 Å in toluene at 80 °C gave high conversion to imine 34
(Scheme 4). The addition of acetic acid was crucial for the reaction
to proceed and it was important to have an excess of benzylamine
in relation to acetic acid to avoid side reactions caused by elimina-
tion. Reduction of the imine with NaBH4 in methanol gave com-
pound 35. Despite repeated column chromatography, compound
35 could not be separated from N-benzyl-acetamide formed in
the reaction. Therefore, the crude product of 35 was reacted di-
rectly with LiAlH4 to cleave off the acetate, which gave aminoalco-
hol (+)-36 in 91% yield. Finally, compound (+)-37 was obtained by
reaction of (+)-36 with ethylbromide and Hünig’s base, as
We attempted to synthesize 2,6-BOCTAMOLs by the same pro-
cedure that was used for the synthesis of 2,5-BHEPTAMOLs. Aryl-
substituted diols (+)-19–(+)-22 were synthesized by the addition
of organolithium or Grignard reagents to optically active hydroxy
ketone (ꢀ)-18, as previously described.18 The diols were oxidized
with TPAP/NMO to give hydroxy ketones (+)-23–(+)-26 (Scheme
2).
i
ii
iii
R
R
R
O
OH
OH OH
O
O
OH
OAc
(-)-18
(+)-19: R=Ph
(+)-23: R=Ph
(-)-27: R=Ph
(+)-20: R=1-Naphth (+)-24: R=1-Naphth (-)-28: R=1-Naphth
(+)-21: R=o-An
(+)-22: R=Bn
(+)-25: R=o-An
(-)-26: R=Bn
(+)-29: R=o-An
(+)-30: R=Bn
Scheme 2. Reagents and conditions: (i) RMgX or RLi, Et2O/THF (65–94%); (ii) TPAP,
NMO, MS 4 Å, CH2Cl2, rt, 1 h (87–90%); (iii) Ac2O, DMAP, pyridine, 60 °C, 1.5–7 days
(47–72%).
We attempted to synthesize 36 (Scheme 4) from 23 by using the
same two-step procedure as we had used for the [2.2.1]-system
described above. Disappointingly, this resulted in an isomeric
mixture of 33, caused by a retro-aldol reaction, which opened
the bicyclic ring (Scheme 3). Reaction of hydroxy ketone 23 with
NaBH4 resulted only in diol 19, but no ring-opening products were
observed. Thus, we suspected that the imine, and not the reducing
agent, caused the ring-opening. Indeed, the formation of the imine
followed by hydrolysis resulted in ring-opened diketone 32. Lower
reaction temperature (using MS 4 Å, Na2SO4 or KOH as drying
agents) did not prevent ring-opening. It only led to incomplete
consumption of the reagent or formation of several by-products.
Even if reductive amination with NaBH3CN or NaBH(OAc)3 were
expected to give less selective reduction, we hoped that these
reagents would prevent ring-opening. However, the reaction of
hydroxy ketone 23 with benzylamine and NaBH(OAc)3 in THF at
rt gave diol 31, formed by endo-face reduction of the hydroxy
ketone. This clearly shows the anchoring effect of NaBH(OAc)3 to

1486
C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
6). Unfortunately, the o-anisyl-substituted aminoalcohol could
not be obtained due to the complete elimination of acetic acid dur-
ing the imine synthesis. The only isolated product was 46. For the
reaction of 1-naphthyl-substituted ketoacetate (ꢀ)-28, tertiary
aminoalcohol 43 was isolated in 21% yield, along with the expected
product (+)-41 in 57% yield. Evidently, the acyl group had migrated
from the hydroxyl group to the aminogroup, giving the corre-
sponding acetamide derivative, which was reduced with LiAlH4
to the N-ethyl amine. The same reactions occurred during the syn-
thesis of benzyl-substituted aminoalcohol (+)-42. Compound (+)-
42 was isolated in 23% yield, along with tertiary aminoalcohol
(+)-44 in 18% yield and tricyclic structure (+)-45 in 19% yield.
According to TLC-analysis, compound (+)-45 was formed during
the NaBH4 reduction. The migration of the acyl group occurred
via a six-membered transition state and clearly depended on the
size of the side group, since no migration was observed with the
phenyl substituent. Large substituents should decrease the dis-
tance between the nitrogen and oxygen and thus promote the
migration. If the migration occurred after the reduction by NaBH4
an increased reaction time would promote the formation of the
amide and hence the reaction could be controlled to give the
tertiary aminoalcohol after reduction by LiAlH4. However, these
aspects have not been investigated.
i
ii
Ph
Ph
Ph
O
OAc
NBn
OAc NHBn
OAc
(-)-27
35
34
iii
iv
Ph
Ph
OH NHBn
OH NEtBn
(+)-36
(+)-37
Scheme 4. Reagents and conditions: (i) BnNH2, AcOH, toluene, 4 Å MS, 80 °C, 1–2
days; (ii) NaBH4, MeOH, 0 °C; (iii) LiAlH4, THF, 0 °C (91% over three steps); (iv) EtBr,
Hünig’s base, CH3CN, 3 days (70%).
described above. Other methods to remove the ester function in 35
(NaOH in aq ethanol, MeNH2 in ethanol, KCN in ethanol) resulted
in the formation of one unknown compound; possibly the amide,
formed by migration of the acyl group from the oxygen to the
nitrogen. However, due to considerable broadening of the NMR-
signals the compound was not identified.
Direct reduction of the imine and ester functions of 34 with
LiAlH4 resulted in exo-amine 40 (Scheme 5) instead of the desired
aminoalcohol 36. TLC analysis of the reaction over time showed
initially that another product was formed, which was identified
as diketone 32 upon hydrolysis. When the reaction was allowed
to run for 2 h at rt, the only isolated product was 40. This shed
some light on the reaction mechanism. Apparently, the ester was
cleaved off before the reduction of the imine. The initially formed
aluminumhydride-alkoxide 38 may undergo ring-opening analo-
gous to the retro-aldol reaction. This would generate Al-coordi-
nated enaminoketone 39. However, due to coordination by
aluminum to nitrogen and the carbonyl, reduction of the carbonyl
was slow and 39 could equilibrate back to bicyclic structure 38.
This coordination also explains why no inversion at C2 was
observed, which would be expected if there had been a free rota-
tion of the carbonyl unit. Ring-opened structure 39 was the kinetic
product and hydrolysis at an early stage resulted in compound 32.
When the reaction was allowed to run for a longer time, the imine
was eventually reduced from the endo-face by the coordinated
hydridoaluminate, giving the aminoalcohol 40.
R=Ph: (-)-27
R
R=1-Naphth: (-)-
28
O
OAc
R=o-An: 29
R=Bn: (+)-30
i
R
+
R
R
+
+
R
O
N
NHBn
OH HN
OH
N
Bn
Bn
Bn
Et
(+)-36 (91%)
(+)-41 (57%)
-
-
-
-
43 (21%)
-
-
4 6
-
-
-
(+)-44 (18%)
(+)-45 (19%)
(+)-42 (23%)
Scheme 6. Reagents and conditions: (i) (1) BnNH2, AcOH, toluene, MS 4 Å, 80 °C, 2
days; (2) NaBH4, MeOH, 0 °C, then rt, 15 min; (3) LiAlH4, THF, 0 °C, 40 min.
2.3. Catalysis
The diethylzinc additions to benzaldehyde were performed at rt
in THF for 48 h in the presence of 10 mol % of the aminoalcohols.
The results from the reactions are summarized in Table 1. When
the reaction temperature was decreased to 0 °C, it resulted in only
a slight increase in ee [from 64% to 67% for catalyst (+)-10] but gave
a slower conversion. Numerous reports in the literature show that
the best results for the reactions catalyzed with amino alcohols are
achieved in diethyl ether or hydrocarbon solvents, because of the
high background reaction in coordinating solvents such as THF.5
However, with catalyst (+)-10, the reactions performed in hexane,
diethyl ether/hexane, and toluene/hexane at 0 °C gave inferior re-
sults (40–44% ee) compared to the reaction in THF (entry 1, 64%).
The results were surprising, since the background reaction in
THF, without the addition of a catalyst, gave 34% yield, which
showed a considerable competing reaction catalyzed by THF. With
aminoalcohol (+)-37, however, the choice of solvents did not affect
either the yield or the enantioselectivity (entry 12). The amount of
catalyst (+)-37 was reduced to 5 mol % without any influence on
either the conversion or the enantioselectivity, whereas 2 mol %
of the catalyst gave 74% ee and 42% yield, and 0.5 mol % of the cat-
alyst gave only 29% yield and 10% ee.
LiAlH4
THF
Ph
Ph
Ph
NBn
OAc
NBn
O
NBn
O
Al
Al
H2
H2
34
38
39
1) rt, 2h
2) H2O
1) <0.5 h, 0 °C
2) H2O
O
Ph
O
Ph
NHBn
OH
40
Scheme 5. Reduction of 34 with LiAlH4.
32
The route developed for the synthesis of aminoalcohol (+)-36,
starting from ketoacetate (ꢀ)-27, was applied to 1-naphthyl-, benz-
yl-, and o-anisyl-substituted ketoacetates (ꢀ)-28–(+)-30 (Scheme

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
Table 1 (continued)
1487
Table 1
Application of bicyclic amino alcohols as catalysts in the addition of diethylzinc to
benzaldehyde
Entry
Catalyst
eea of 1-
phenylpropanol
(%)
Yielda of 1-
phenylpropanol
(%)
Config.b of 1-
phenylpropanol
Entry Catalyst
eea of 1-
Yielda of 1-
Config.b of 1-
phenylpropanol phenylpropanol phenylpropanol
(%)
64
(%)
Ph
Ph
OH
13
74
89
44
(R)
OH
Et
N
N
1
82
(R)
Bn
Bn
(+)-44
HN
Bn
(+)-10
Ph
14
rac
—
1Naph
O
2
3
4
5
6
42
66
82
58
56
88
65
87
62
42
(S)
(S)
(S)
(R)
(R)
NH
OH
Bn
Bn
(+)-45
(−)-11
a
Determined by GC analysis using a chiral Supelco betaDEX column. The yields
were calculated from the peak area given by simple integration using 1-decanol as
the internal standard.
o-An
NH
b
OH
Determined by the order of elution on the Supelco betaDEX column.
(−)-12
Generally, as expected from reports in the literature,2 the
enantioselectivity increased when the degree of N-alkyl substitu-
tion increased. This was especially noticeable for the phenyl-
substituted BOCTAMOLs (+)-36 and (+)-37 when the ee was im-
proved from 58% with the secondary aminoalcohol (+)-36 (entry
5) to 89% with the tertiary aminoalcohol (+)-37 (entry 12), which
also represents the highest selectivity in this study. The only
exception to this observation was the o-anisyl-substituted BHEP-
TAMOLs. The secondary amino alcohol (ꢀ)-12 gave 66% ee while
the tertiary amino alcohol (+)-16 gave only 40% ee (entries 3 and
10). In the series of BHEPTAMOLs the highest ee (86%) was ob-
tained with the benzyl-substituted derivative (ꢀ)-17 (entry 11).
The comparable selectivities for the phenyl- and the o-anisyl-
substituted catalysts (+)-10 and (ꢀ)-12 (entries 1 and 3) were in
contrast to the results obtained with the bicyclic diols (BODOLs)
previously reported by our group.14,13 The presence of the methoxy
group of the o-anisyl substituent had a considerable positive im-
pact on the selectivity. As expected, the tricyclic structure (+)-45
was inefficient as a catalyst since it lacked the hydroxyl group,
which is supposed to react with diethylzinc providing the ethylzinc
alkoxide, generally being considered the active catalyst.2,24
Bn
OH
NH
Bn
Ph
(−)-13
OH HN
Bn
(+)-36
1Naph
OH HN
Bn
(+)-41
Ph
7
8
48
74
76
84
(R)
(R)
OH HN
Bn
(+)-42
Ph
OH
For the two series, different side groups gave the best results. In
the [2.2.1]-series (ꢀ)-17 (entry 11), carrying the benzyl side group,
was the best catalyst, while in the [2.2.2]-series (+)-37 (entry 12),
carrying the phenyl side group, was the best catalyst. There was
otherwise no general trend that one of the backbones was better
than the other for achieving efficient catalysis, despite different
distances between the coordinating groups.
N
Et
Bn
(+)-14
1Naph
9
10
11
56
40
86
92
50
92
(S)
(S)
(S)
N
Et
OH
Martinez et al. presented a qualitative empirical explanation to
the observed enantioselectivity imposed by norbornane-derived
Bn
Bn
(−)-15
b-,
Noyori model suggesting that the b-aminoalcohol 47 gave a 5/4/4
transition state, the -amino alcohol 48 a tricyclic 6/4/4 transition
c
-, and d-aminoalcohols (Fig. 1).9 The study was based on the
o-An
OH
c
N
Et
state, and the d-amino alcohol 49 a 7/4/4 transition state. Thus, the
BOCTAMOLs were expected to form a six-membered zinc-chelate
and the BHEPTAMOLs a seven-membered ring zinc-chelate (Fig. 2).
(+)-16
Bn
OH
N
Et
Bn
Ph
(−)-17
NR2
47
HO
HO
OH
NR2
12
89
90
(R)
49
48
R2N
OH
Et
N
Bn
Figure 1. b-, c
-, and d-aminoalcohols developed by Martinez et al.9
(+)-37

1488
C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
in H2O (940 mL) or with a solution of p-methoxybenzaldehyde
(10 mL), concd H2SO4 (50 mL), and ethanol (95%, 940 mL). Flash
chromatography was performed on Matrex (25–70 m) silica gel.
GC analyses were performed on a betaDEX column (Supelco,
m film thickness). NMR spectra were
Ar
Ar
l
R2HN
Zn
O
NR2
Et
O
Et
Et
Zn
Zn
Zn
30 m ꢁ 0.25 mm id, 25
l
Et
O
O
recorded on a Bruker DRX 400 MHz spectrometer, using the resid-
ual solvent as internal standard. Optical rotations were recorded on
Ph
Ph
H
H
a
Perkin–Elmer 241 polarimeter at 20 °C and are given in
10ꢀ1 deg cm2 gꢀ1. IR spectra were recorded on a Shimadzu 8300
FTIR spectrometer. Melting points were taken on a Sanyo Gallenk-
amp melting point apparatus (MPD.350.BM3.5) and are uncor-
rected. Elemental analyses were performed by H. Kolbe
Mikroanalytisches Laboratorium, Höhenweg 17, D-45470 Mülheim
an der Ruhr.
I
II
Figure 2. The suggested 6/4/4 TS of BOCTAMOLs (I) and 7/4/4 TS of BHEPTAMOLs
(II).
The positioning of the amine and the hydroxyl groups directly
at the bicyclic backbone in our catalysts would decrease the con-
formational flexibility of the six- and seven-membered rings, plau-
sibly giving rise to fewer possible diastereomeric transition states.
We made simple models of the suggested 6/4/4 and 7/4/4 arrange-
ments to try to gain some insight in the enantioselection given by
our systems. We set the O–Zn bond to be 2 Å and took into consid-
eration the sterical interactions and the orientation of the electron-
pairs involved in the bond-formation to identify the most energet-
ically favored transition structures. However, we found several
possible structures resulting in the opposing configuration of the
1-phenylpropanol. Since this was contradicted by the experimental
results, which clearly show moderate to high enantioselectivity for
all catalysts, this simple study was not enough to explain the
experimental results. Thorough computational calculations on
the proposed transition states and other possible structures, such
as the 6/6 and 7/6 bicyclic transition states as suggested by Norrby
et al.,25 would hopefully give results consistent with the experi-
mental results.
4.2. General procedure: addition of Et2Zn to benzaldehyde
The catalyst (10 mol %) was dissolved in dry THF (0.7 mL), and
diethylzinc (1.0 M in hexane, 1 mL, 1.0 mmol) was added at rt.
The mixture was stirred for 30 min, and then freshly distilled benz-
aldehyde (51 lL, 0.5 mmol) was added. The reaction was stirred
under a flow of N2 at rt for 48 h then satd aqueous NH4Cl was
added. Dichloromethane (10 mL) was used to extract the aqueous
phase on an IsoluteÒ Phase Separator column. Yields and ee were
analyzed by GC on a Supelco betaDEX column (isothermal at
130 °C). 1-Octanol was used as internal standard. The retention
times were benzaldehyde 4.6 min, benzylalcohol 9.3 min, 1-deca-
nol 13.7 min, (R)-1-phenylpropanol 14.1 min, and (S)-1-phenylpro-
panol 14.8 min.
4.3. (1S,2R,4S,5R)-2-Benzyl-bicyclo[2.2.1]heptan-2,5-diol (ꢀ)-5
A solution of (ꢀ)-1 (0.30 g, 2.3 mmol) in dry THF (8 mL) was
added to BnMgCl (1.0 M in ether, 7.3 mL, 7.3 mmol) at 0 °C under
a nitrogen atmosphere. The resulting slurry was stirred at rt for
16 h then water was added. The mixture was worked up as fol-
lows: extraction with EtOAc, washing of the collected organic
phases with satd aqueous NaHCO3 and brine followed by drying
over Na2SO4 and removal of the solvent under reduced pressure.
The residue was recrystallized from toluene to give (ꢀ)-5 (0.32 g,
63%, 96% ee) as white crystals; TLC Rf 0.5 (CH2Cl2–iPrOH, 90:10);
3. Conclusion
In conclusion, the presented results demonstrate that 2,5-BHEP-
TAMOLs and 2,6-BOCTAMOLs are efficient catalysts in the diethyl-
zinc addition to benzaldehyde, which indicates that the formation
of aminoalcohol–zinc chelates was not particularly sensitive to the
distance between the coordinating groups. These results stand in
contrast to results given by similar bicyclic diols, previously stud-
ied by our group, where a longer distance between the coordinat-
ing groups was detrimental for the catalytic efficiency.13 Generally
the tertiary aminoalcohols gave higher ee than the corresponding
secondary aminoalcohols. Otherwise, no clear structural features
could be discerned. In the series of BHEPTAMOLs the benzyl-
substituted catalyst (ꢀ)-17 gave the highest ee and in the series
of BOCTAMOLs the phenyl-substituted catalyst (+)-37 gave the
highest ee. The synthesis of the 2,5-BHEPTAMOLs was rather
straightforward, while the synthesis of the 2,5-BOCTAMOLs was
complicated by competing retro-aldol reaction, elimination reac-
tions, and migration of functional groups.
mp 131–133 °C; ½a D20
ꢂ
¼ ꢀ18 (c 1.0, CHCl3); IR (KBr) 3298 cmꢀ1
;
1H NMR (400 MHz, pyridine-d5) d 1.30 (1H, dd, J = 13.0, 2.8 Hz),
1.57 (1H, dt, J = 12.5, 3.4 Hz), 1.74 (1H, dm, J = 10.1 Hz), 1.86 (1H,
dd, J = 13.0, 5.1 Hz), 2.10–2.12 (1H, dm, J = 10.0 Hz), 2.33 (1H, d,
J = 3.8 Hz), 2.44 (1H, d, J = 4.8 Hz), 2.95–3.00 (1H, m), 3.01 (1H,
dAB, JAB = 13.6 Hz), 3.09 (1H, dAB, JAB = 13.6 Hz), 4.31 (1H, d,
J = 6.1 Hz), 5.55 (1H, br s), 6.00 (1H, br s), 7.25–7.29 (1H, m),
7.34–7.39 (2H, m), 7.54–7.59 (2H, m); 13C NMR (100 MHz, pyri-
dine-d5) d 35.4, 36.2, 42.4, 46.7, 46.9, 49.0, 74.2, 78.6, 126.8,
128.7, 131.9, 140.0; HRMS (FAB+) [MꢀOH]: calcd for C14H17O:
201.1274, found: 201.1292. Anal. Calcd for C14H18O2: C, 77.03; H,
8.31. Found: C, 76.93; H, 8.35.
4. Experimental
4.1. General
4.4. (1R,2S,4S,6S)-2-Benzyl-bicyclo[2.2.2]octane-2,6-diol (+)-22
A solution of 2.0 M BnMgCl in THF (17.5 mL, 35 mmol) was
added to a solution of (ꢀ)-18 (2.0 g, 14 mmol) in diethyl ether
(150 mL) at 0 °C. The mixture was stirred at rt for 45 min then satd
aqueous NH4Cl (100 mL) was added. The reaction was worked up
as follows: extraction with diethyl ether, washing of the collected
organic phases with brine followed by drying over Na2SO4, and
removal of the solvent under reduced pressure. The residue was
recrystallized from heptane–EtOAc, and the mother liquor was
purified by column chromatography (SiO2, heptane–EtOAc,
75:25) to give (+)-22 (1.43 g, 89%) in 99% ee as white crystals;
All reactions were carried out in oven-dried glassware under a
nitrogen atmosphere. THF and diethyl ether was distilled from so-
dium and benzophenone and benzaldehyde and benzylamine were
distilled prior to use. Bicyclic compounds 1, 2, 3, 4, 6, 7, 813 and 19,
20, and 2118 were synthesized according to previous procedures.
All reagents were purchased from Aldrich and used as received.
TLC was carried out on Silica Gel (60 F254, Merck) and spots were
visualized with UV light or by staining with
a solution of
H3[P(Mo3O10)4] (25 g), Ce(SO4)2 (10 g), and concd H2SO4 (60 mL)

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
1489
TLC Rf 0.5 (heptane–EtOAc, 1:1); mp 86–87 °C; ½a D20
ꢂ
¼ þ61 (c 1.05,
4.8. (1S,4R,6R)-6-Hydroxy-6-(1-naphthyl)-bicyclo[2.2.2]octan-
2-one (+)-24
CHCl3); IR (KBr) 3208 (br) cmꢀ1
;
1H NMR (400 MHz, C6D6) d 1.00–
1.07 (3H, m), 1.41–1.53 (6H, m), 1.84–1.90 (1H, m), 2.50–2.53 (2H,
m), 2.74 (1H, dAB, JAB = 13.6 Hz), 3.18 (1H, s), 3.58–3.62 (1H, m),
7.10–7.15 (1H, m), 7.17–7.21 (2H, m), 7.26–7.28 (2H, m); 13C
NMR (100 MHz, C6D6) d 21.3, 23.7, 26.5, 38.0, 39.4, 45.1, 48.5,
71.3, 74.9, 126.9, 128.7, 131.4, 138.3; HRMS (FAB+) [M+Na]: calcd
The title compound was synthesized following the same proce-
dure as for (ꢀ)-9, from (+)-20 (0.50 g, 1.9 mmol). The crude product
was purified by column chromatography (SiO2, heptane–EtOAc,
75:25) to give (+)-24 as white crystals (0.41 g, 81%, 99% ee); TLC
for
C15H20O2Na: 255.1361, found: 255.1368. Anal. Calcd for
Rf 0.59 (heptane–EtOAc, 1:1); mp 177–180 °C; ½a D20
¼ þ14 (c
ꢂ
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.51; H, 8.62.
0.65, CHCl3); IR (KBr) 3457, 1713 cmꢀ1 1H NMR (400 MHz, C6D6)
;
d 0.95–1.04 (2H, m), 1.43–1.52 (1H, m), 1.56–1.64 (1H, m), 1.73–
1.74 (1H, m), 1.76 (1H, s), 1.83 (1H, dm, J = 12.0 Hz), 1.99 (1H,
dm, J = 18.0 Hz), 2.35 (1H, dm, J = 14.0 Hz), 2.52 (1H, dt, J = 18.4,
2.4 Hz), 3.05–3.06 (1H, m), 7.00–7.02 (1H, m), 7.09–7.13 (1H, m),
7.25–7.34 (2H, m), 7.55–7.57 (1H, m), 7.65–7.67 (1H, m), 8.82–
8.84 (1H, m); 13C NMR (100 MHz, C6D6) d 20.7, 25.0, 29.1, 43.5,
43.7, 54.0, 76.4, 123.4, 124.7, 126.1, 126.1, 128.7, 129.5, 129.6,
132.6, 136.2, 140.8, 211.4; HRMS (FAB+) [M+Na]: calcd for
4.5. (1S,4S,5R)-5-Benzyl-5-hydroxy-bicyclo[2.2.1]heptan-2-one
(ꢀ)-9
Compound (ꢀ)-5 (0.35 g, 1.6 mmol), NMO (0.37 g, 3.2 mmol),
4 Å MS, and TPAP (0.03 g, 0.08 mmol) were mixed in CH2Cl2
(20 mL). The resulting mixture was stirred at rt for 45 min, then di-
luted with EtOAc and filtered through Celite/silica (rinsed with
EtOAc). The solvent was removed under reduced pressure and
the crude product was purified by column chromatography (SiO2,
heptane–EtOAc, 7:3) to give (ꢀ)-9 (0.33 g, 95%) in 96% ee as a white
C18H18O2Na: 289.1204, found: 289.1206. Anal. Calcd for
C18H18O2: C, 81.17; H, 6.81. Found: C, 81.11; H, 6.76.
solid; TLC Rf 0.5 (heptane–EtOAc, 1:1); ½a D20
ꢂ
¼ ꢀ45 (c 1.1, CHCl3);
mp 90–93 °C; IR (KBr) 3430, 1726 cmꢀ1
;
1H NMR (400 MHz, pyri-
4.9. (1S,4R,6R)-6-Hydroxy-6-(2-methoxy-phenyl)-
bicyclo[2.2.2]octan-2-one (ꢀ)-25
dine-d5) d 1.69 (1H, m), 1.72 (1H, m), 1.91–2.00 (2H, m), 2.06–
2.10 (1H, m), 2.57 (1H, m), 2.60 (1H, m), 2.93–2.98 (1H, dd,
J = 17.4, 4.4 Hz), 3.06 (1H, dAB, JAB = 13.7 Hz), 3.14 (1H, dAB,
The title compound was synthesized following the same proce-
dure as for (ꢀ)-9, from (+)-21 (1.0 g, 4.0 mmol). The crude product
was purified by column chromatography (SiO2, heptane–EtOAc,
1:1) to give (ꢀ)-25 (0.86 g, 87%, 99% ee) as white crystals; TLC Rf
JAB = 13.7 Hz), 6.26 (1H, s), 7.26–7.30 (1H, m), 7.35–7.39 (2H, m),
7.54–7.55 (2H, m); 13C NMR (100 MHz, pyridine-d5) d 37.7, 40.3,
42.1, 46.0, 49.0, 52.2, 78.2, 127.0, 128.8, 131.8, 139.4, 217.4; HRMS
(FAB+) [M+H]: calcd for C14H17O2: 217.1229, found: 217.1230.
Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.86; H, 7.42.
0.38 (heptane–EtOAc, 1:1); mp 91–94 °C;
½
a 2D0
ꢂ
¼ ꢀ33 (c 1.3,
CHCl3); IR (KBr) 3507, 1720 cmꢀ1
;
1H NMR (400 MHz, C6D6) d
1.08–1.28 (3H, m), 1.34–1.40 (1H, m), 1.89–1.91 (1H, m), 2.03–
2.09 (2H, m), 2.24 (1H, dm, J = 14.8 Hz), 2.60 (1H, dt, J = 18.4,
2.4 Hz), 2.94 (3H, s), 3.01–3.02 (1H, m), 4.79 (1H, s), 6.38–6.41
(1H, m), 6.77–6.81 (1H, m), 6.98–7.03 (1H, m), 7.08–7.10 (1H,
m); 13C NMR (100 MHz, C6D6) d 19.5, 24.1, 28.3, 38.7, 43.5, 53.5,
54.4, 76.2, 111.9, 120.5, 126.8, 128.6, 131.7, 157.8, 211.4; HRMS
4.6. (1S,4R,6S)-6-Benzyl-6-hydroxy-bicyclo[2.2.2]octane-2-one
(+)-26
The title compound was synthesized following the same proce-
dure as for (ꢀ)-9, from (+)-22 (2.8 g, 12 mmol) to give (+)-26
(2.47 g, 89%, 99% ee) as white crystals; TLC Rf 0.47 (heptane–EtOAc,
(FAB+) [M+Na]: calcd for
C15H18O3Na: 269.1154, found:
1:1); ½a 2D0
ꢂ
¼ þ46 (c 0.95, CHCl3); mp 115–117 °C; IR (KBr) 3428,
269.1153. Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C,
73.05; H, 7.27.
1717 cmꢀ1
;
1H NMR (400 MHz, C6D6) d 1.07–1.10 (2H, m), 1.27–
1.32 (1H, m), 1.36 (1H, s), 1.39–1.48 (3H, m), 1.67–1.71 (1H, m),
1.93 (1H, dt, J = 18.4, 2.8 Hz), 2.16 (1H, t, J = 2.8 Hz), 2.28 (1H,
4.10. (1R,2R,4R,5R)-5-Benzylamino-2-phenyl-
bicyclo[2.2.1]heptane-2-ol (+)-10
dm, J = 18.4 Hz), 2.46 (1H, dAB, JAB = 13.6 Hz), 2.53 (1H, dAB,
JAB = 13.6 Hz), 6.95–6.98 (2H, m), 7.04–7.11 (3H, m); 13C NMR
(100 MHz, C6D6) d 20.0, 24.8, 28.7, 42.0, 43.6, 46.2, 53.1, 73.6,
127.4, 129.0, 131.0, 136.6, 212.0; HRMS (FAB+) [M+Na]: calcd for
Benzylamine (1.0 mL, 9.1 mmol) was added to a solution of (+)-
6 (0.82 g, 4.1 mmol) in toluene (50 mL). The resulting solution was
refluxed in a Dean–Stark equipment for 5 h. The mixture was
cooled to rt followed by removal of the solvent under reduced
pressure. The residue was dissolved in methanol (35 mL), and
NaBH4 (0.31 g, 8.2 mmol) was added at 0 °C. The ice-bath was re-
moved and after 15 min, water (15 mL) was added. The methanol
was removed under reduced pressure, and the aqueous phase
was extracted with EtOAc (3 ꢁ 15 mL). The combined organic
phases were washed with brine, dried (Na2SO4), and the solvent
was removed under reduced pressure. The residue was column
chromatographed (SiO2, EtOAc–NH4OH, 99:1) to give (+)-10
(1.12 g, 96%) of >99% ee as a white solid; TLC Rf concentration
C
C
15H18O2Na: 253.1204, found: 253.1202. Anal. Calcd for
15H18O2: C, 78.32; H, 7.88. Found: C, 78.24; H, 7.85.
4.7. (1S,4R,6R)-6-Hydroxy-6-phenyl-bicyclo[2.2.2]octan-2-one
(+)-23
The title compound was synthesized following the same proce-
dure as for (ꢀ)-9, from (+)-19 (1.7 g, 7.8 mmol). The crude product
was purified by recrystallization from diethyl ether and column
chromatography of the mother liquor (SiO2, heptane–EtOAc,
75:25) to give (+)-23 as white crystals (1.5 g, 90%, 99% ee); Rf
0.46 (heptane–EtOAc, 1:1); mp 102–106 °C; ½a D20
¼ þ13 (c 1.0,
ꢂ
dependent; mp 76–79 °C; ½a D20
¼ þ40 (c 0.7, CHCl3); IR (KBr)
ꢂ
CHCl3); IR (KBr) 3337, 1713, 1697 cmꢀ1
;
1H NMR (400 MHz,
3370, 3283 cmꢀ1 1H NMR (400 MHz, pyridine-d5) d 7.81–7.83
;
C6D6) d 1.02–1.09 (2H, m), 1.27–1.34 (2H, m), 1.64–1.71 (2H, m),
1.77–1.81 (1H, m), 1.92–1.95 (1H, m), 1.97–2.00 (1H, m), 2.41
(1H, dm, J = 18.4 Hz), 2.56 (1H, t, J = 2.8 Hz), 7.04–7.14 (3H, m),
7.18–7.22 (2H, m); 13C NMR (100 MHz, C6D6) d 19.5, 24.7, 29.0,
41.6, 43.4, 55.0, 75.3, 126.4, 127.8, 128.8, 146.2, 211.4; HRMS
(2H, m), 7.53–7.54 (2H, m), 7.36–7.45 (4H, m), 7.27–7.32 (2H,
m), 6.39 (1H, br s), 3.84 (1H, dAB, JAB = 13.2 Hz), 3.78 (1H, dAB
,
JAB = 13.2 Hz), 3.23–3.27 (1H, m), 2.57 (1H, d, J = 3.9 Hz), 2.40–
2.44 (3H, m), 2.31 (1H, dt, J = 12.6 Hz, 3.4 Hz), 2.17–2.21 (1H, m),
1.85–1.89 (1H, m), 1.74–1.77 (1H, m), 1.41–1.44 (1H, m); 13C
NMR (100 MHz, pyridine-d5): d 32.3, 39.4, 40.2, 41.5, 49.2, 53.0,
58.4, 79.6, 126.9, 127.0, 127.5, 128.8, 129.1, 142.2, 151.5 (one peak
(FAB+) [M+Na]: calcd for
C14H16O2Na: 239.1048, found:
239.1033. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C,
77.71; H, 7.44.

1490
C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
hidden by solvent); HRMS (FAB+) [M+H]: calcd for C20H24NO:
294.1858, found: 294.1852. Anal. Calcd for C20H23NO: C, 81.87;
H, 7.90. Found: C, 81.79; H, 7.97.
4.14. (1R,2R,4R,5R)-5-(N-Benzyl-N-ethyl-amino)-2-phenyl-
bicyclo[2.2.1]heptan-2-ol (+)-14
EtBr (0.25 mL, 3.4 mmol) and Hünig’s base (89 lL, 0.51 mmol)
were added to a solution of (+)-10 (0.10 g, 0.34 mmol) in CH3CN
(5 mL). The mixture was heated to 80 °C in a capped vial (Pyrex)
overnight. The solvent was removed under reduced pressure, and
the crude product was purified by column chromatography (SiO2,
heptane–EtOAc, 3:7) to give (+)-14 as a clear oil (0.10 g, 93%) of
4.11. (1S,2S,4S,5S)-5-Benzylamino-2-(2-methoxy-phenyl)-
bicyclo[2.2.1]heptane-2-ol (ꢀ)-12
The title compound was synthesized following the same proce-
dure as for (+)-10, from (ꢀ)-8 (0.15 g, 0.6 mmol) to give (ꢀ)-12
(0.17 g, 89%, 99% ee) as a clear oil; TLC Rf concentration dependent;
>99% ee; TLC Rf was concentration dependent; ½a D20
¼ þ20 (c 3.0,
ꢂ
CHCl3); IR (NaCl) 3413 (br) cmꢀ1 1H NMR (400 MHz, C6D6) d
;
½
a 2D0
ꢂ
¼ ꢀ5 (c 0.5, CHCl3); IR (NaCl) 3541 cmꢀ1;1H NMR (400 MHz,
0.74 (3H, t, J = 7.2 Hz), 1.31–1.34 (1H, m), 1.36–1.43 (1H, m),
1.64–1.68 (1H, m), 2.00 (1H, ddAB, J = 13.2, 3.6 Hz), 2.12–2.14
(1H, m), 2.17–2.23 (2H, m), 2.41–2.46 (2H, m), 2.51–2.58 (1H,
m), 2.70–2.74 (1H, m), 3.47 (2H, s), 3.56 (1H, s), 7.09–7.18 (1H,
m), 7.18–7.22 (2H, m) 7.25–7.30 (2H, m), 7.36–7.38 (2H, m),
7.68–7.71 (2H, m); 13C NMR (100 MHz, C6D6) d 8.9, 30.8, 40.1,
41.8, 43.1, 44.7, 49.9, 55.9, 61.4, 79.4, 126.4, 127.0, 127.6, 129.0,
129.5, 140.3, 149.9 (one peak hidden by solvent); HRMS (FAB+)
[M+H]: calcd for C22H28NO: 322.2171, found: 322.2180. Anal. Calcd
for C22H27NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 82.19; H, 8.52; N,
4.39.
pyridine-d5) d 1.41 (1H, dtAB, JAB = 10.1, 1.5 Hz), 1.62 (1H, dtAB
,
JAB = 10.1, 1.3 Hz), 1.87–1.94 (1H, m), 2.32 (1H, dt, J = 12.7,
4.7 Hz), 2.37 (1H, m), 2.53 (1H, ddAB, JAB = 13.9, 3.3 Hz), 2.81 (1H,
d, J = 4.4 Hz), 3.22–3.27 (1H, m), 3.71 (3H, s), 3.80 (1H, dAB
,
JAB = 13.3 Hz), 3.87 (1H, dAB, JAB = 13.2 Hz), 5.12 (1H, br s), 6.98–
7.05 (2H, m), 7.27–7.32 (2H, m), 7.39–7.43 (2H, m), 7.44–7.46
(1H, m), 7.53–7.58 (2H, m); 13C NMR (100 MHz, pyridine-d5) d
31.0, 38.7, 39.2, 41.2, 46.5, 53.1, 55.7, 59.3, 79.6, 112.6, 120.9,
126.0, 127.4, 128.6, 129.0 (4C), 137.6, 142.4, 158.3; HRMS (ES+)
[MꢀOH] calcd for C21H24NO: 306.1858, found: 306.1866. Anal.
Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C, 78.11;
H, 7.70; N, 4.26.
4.15. (1S,2R,4S,5S)-2-Benzyl-5-(N-benzyl-N-ethyl-amino)-
bicyclo[2.2.1]heptan-2-ol (ꢀ)-17
4.12. (1S,2R,4S,5S)-2-Benzyl-5-benzylamino-bicyclo-
[2.2.1]heptan-2-ol (ꢀ)-13
The title compound was synthesized following the same pro-
cedure as for (+)-14, from (ꢀ)-13 (0.11 g, 0.35 mmol) to give
(ꢀ)-17 (82%, 0.096 g, 98% ee) as a yellow oil; TLC Rf was concen-
The title compound was synthesized following the same proce-
dure as for (+)-10, from (ꢀ)-9 (0.22 g, 1.0 mmol) to give (ꢀ)-13
(0.27 g, 87%, 98% ee) as a clear oil; TLC Rf was concentration depen-
tration dependent;
3433 cmꢀ1
½
a 2D0
ꢂ
¼ ꢀ21 (c 1.3, CHCl3); IR (NaCl)
1H NMR (400 MHz, C6D6) d 0.68 (3H, t, J = 7.2 Hz),
dent; ½a 2D0
ꢂ
¼ ꢀ41 (c 1.2, CHCl3); IR (NaCl) 3396, 3300 cmꢀ1
;
1H
;
1.25–1.33 (2H, m), 1.40–1.43 (1H, m), 1.48–1.53 (1H, m), 1.67–
1.71 (1H, m), 1.90 (1H, dt, J = 12.8, 3.2 Hz), 2.04–2.05 (2H, m),
2.29–2.34 (1H, m), 2.43–2.48 (1H, m), 2.64–2.67 (1H, m), 2.75
NMR (400 MHz, pyridine-d5) d 1.41 (1H, dt, J = 10.2, 1.5 Hz),
1.65–1.72 (3H, m), 1.86 (1H, ddAB, J = 13.1, 3.3 Hz), 1.99 (1H, dt,
J = 12.5, 3.3 Hz), 2.18 (1H, d, J = 3.8 Hz), 2.35 (1H, m), 2.35 (1H,
m), 2.94 (1H, dAB, JAB = 13.5 Hz), 3.06 (1H, dAB, JAB = 13.5 Hz),
(1H, dAB, JAB = 13.6 Hz), 2.78 (1H, br s), 2.93 (1H, dAB, JAB
=
13.2 Hz), 3.38 (1H, dAB, JAB = 14.4 Hz), 3.42 (1H, dAB, JAB = 14.0 Hz),
7.05–7.09 (1H, m), 7.11–7.14 (3H, m) 7.21–7.25 (2H, m), 7.27–
7.29 (2H, m), 7.43–7.45 (2H, m); 13C NMR (100 MHz, C6D6) d
8.8, 30.2, 39.2, 40.2, 41.7, 44.7, 47.9, 48.0, 55.9, 61.5, 78.8.
126.8, 127.4, 128.5, 128.9, 129.3, 131.6, 139.2, 140.5; HRMS
(FAB+) [M+H]: calcd for C23H30NO: 336.2327, found: 336.2330.
Anal. Calcd for C23H29NO: C, 82.34; H, 8.71; N, 4.18. Found: C,
83.30; H, 8.67; N, 4.14.
3.14–3.19 (1H, m), 3.67 (1H, dAB, JAB = 13.1 Hz), 3.73 (1H, dAB
,
JAB = 13.1 Hz), 5.34 (1H, br s), 7.22–7.39 (6H, m), 7.42–7.44 (2H,
m), 7.56–7.58 (2H, m); 13C NMR (100 MHz, pyridine-d5) d 32.1,
38.5, 39.2, 41.4, 48.0, 49.0, 52.9, 58.1, 78.8, 126.7, 127.4, 128.5,
129.0, 129.0, 131.8, 139.8, 142.0; HRMS (FAB+) [M+Na]: calcd for
C
C
21H25NONa: 330.1828, found: 330.1834. Anal. Calcd for
21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 81.96; H, 8.24; N,
4.60.
4.16. (1S,2S,4S,5S)-5-(N-Benzyl-N-ethyl-amino)-2-(2-methoxy-
phenyl)-bicyclo[2.2.1]heptan-2-ol ((+)-16)
4.13. (1S,2S,4S,5S)-5-Benzylamino-2-(1-naphthyl)-bicyclo-
[2.2.1]heptan-2-ol (ꢀ)-11
The title compound was synthesized following the same pro-
cedure as for (+)-14, from (ꢀ)-12 (0.10 g, 0.31 mmol) to give
(+)-16 (0.094 g, 86%, 99% ee) as a clear oil; TLC Rf was concentra-
The title compound was synthesized following the same proce-
dure as for (+)-10, from (ꢀ)-7 (0.50 g, 2.0 mmol) to give (ꢀ)-11
(0.67 g, 97%, >99% ee) as a white solid; TLC Rf was concentration
tion dependent; ½a D20
ꢂ
¼ þ21 (c 2.5, CHCl3); IR (NaCl) 3554 cmꢀ1
;
dependent; ½a 2D0
ꢂ
¼ ꢀ45 (c 0.55, CHCl3); mp 115–117 °C; IR (KBr)
1H NMR (400 MHz, C6D6) d 0.87 (3H, t, J = 7.2 Hz), 1.35–1.39
3296, 3273, 3049 cmꢀ1
;
1H NMR (400 MHz, pyridine-d5) d 1.52
(1H, m), 1.61–1.64 (1H, m), 1.66–1.70 (1H, m), 2.06 (1H, ddAB
,
(1H, dm, J = 10.1 Hz), 1.76 (1H, dm, J = 10.1 Hz), 1.97–2.04 (1H,
m), 2.22 (1H, ddAB, JAB = 13.2, 4.6 Hz), 2.38 (1H, m), 2.46 (1H, dt,
J = 12.7, 3.6 Hz), 2.88 (1H, ddAB, JAB = 13.2, 3.1 Hz), 3.03 (1H, d,
J = 4.3 Hz), 3.28–3.33 (1H, m), 3.85 (1H, dAB, JAB = 13.3 Hz), 3.96
(1H, dAB, JAB = 13.3 Hz), 6.65 (1H, br s), 7.30–7.33 (1H, m), 7.38–
7.47 (3H, m), 7.49–7.61 (5H, m), 7.84 (1H, d, J = 8.1 Hz), 7.95–
7.97 (1H, m), 7.95–7.97 (1H, m), 9.21 (1H, d, J = 8.6 Hz); 13C NMR
(100 MHz, pyridine-d5) d 31.4, 39.1, 40.8, 41.3, 47.7, 53.1, 59.2,
80.3, 122.4, 125.5, 125.6, 126.0, 127.5, 128.4, 129.1, 129.5, 129.8,
132.8, 136.3, 142.4, 146.2; HRMS (FAB+) [M+H]: calcd for
J = 13.2, 4.4 Hz), 2.19–2.21 (1H, m), 2.59–2.79 (5H, m), 2.86–
2.91 (1H, m), 3.09 (3H, s), 3.56 (1H, dAB, JAB = 14.0 Hz), 3.78 (1H,
dAB, JAB = 14.0 Hz), 4.10 (1H, s), 6.50 (1H, dd, J = 8.0, 0.8 Hz),
6.85–6.89 (1H, m) 7.03–7.08 (1H, m), 7.11–7.18 (1H, m), 7.22–
7.29 (3H, m), 7.59–7.61 (2H, m); 13C NMR (100 MHz, C6D6) d
8.9, 28.6, 38.1, 38.4, 41.3, 45.0, 46.7, 54.9, 56.2, 64.2, 80.6,
112.0, 121.0, 126.3, 127.2, 128.8, 129.6, 137.4, 141.6, 157.9,
(one peak hidden by solvent); HRMS (FAB+) [M+H]: calcd for
C
C
23H30NO2: 352.2277, found: 352.2272. Anal. Calcd for
23H29O2N: C, 78.59; H, 8.32; N, 3.99. Found: C, 78.45; H, 8.27;
C24H26ON: 344.2014, found: 344.2013. Anal. Calcd for C24H25NO:
N, 4.06.
C, 83.93; H, 7.34. Found: C, 84.06; H, 7.39.

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
1491
4.17. (1S,2S,4S,5S)-5-(N-Benzyl-N-ethyl-amino)-2-(1-naphthyl)-
bicyclo[2.2.1]heptan-2-ol (ꢀ)-15
found: 281.1141. Anal. Calcd for C16H18O3: C, 74.39; H, 7.02.
Found: C, 74.30; H, 6.96.
The title compound was synthesized following the same proce-
dure as for (+)-14, from (ꢀ)-11 (0.10 g, 0.29 mmol) to give (ꢀ)-15
(0.076 g, 70%, >99% ee) as a yellow oil; TLC Rf was concentration
4.20. (1S,2R,4R)-2-Acetoxy-6-oxo-2-(1-naphthyl)-bicyclo-
[2.2.2]octane (ꢀ)-28
dependent; ½a 2D0
ꢂ
¼ ꢀ1:5 (c 1.4, CHCl3); IR (NaCl) 3355 (br) cmꢀ1
;
The title compound was synthesized following the same proce-
dure as for (ꢀ)-27, from (+)-24 (0.42 g, 1.6 mmol), except that the
reaction time was 1.5 days. The crude product was purified by col-
umn chromatography (SiO2, pentane–diethyl ether, 1:1) to give
(ꢀ)-28 (0.32 g, 65%, 99% ee) as white crystals; TLC Rf 0.33 (pen-
1H NMR (400 MHz, C6D6) d 0.80 (3H, t, J = 7.2 Hz), 1.34–1.38 (1H,
m), 1.51–1.60 (2H, m), 2.09–2.10 (1H, m), 2.12–2.16 (1H, m),
2.25 (1H, br s), 2.30 (1H, dt, J = 12.4, 3.6 Hz), 2.46–2.55 (1H, m),
2.59–2.68 (1H, m), 2.72–2.76 (2H, m), 2.78–2.82 (1H, m), 3.51
(1H, dAB, JAB = 14.0 Hz), 3.64 (1H, dAB, JAB = 14.0 Hz), 7.10–7.14
(1H, m) 7.20–7.26 (3H, m), 7.28–7.32 (1H, m), 7.35–7.41 (2H, m),
7.49–7.64 (2H, m), 7.62–7.64 (1H, m), 7.71–7.73 (1H, m), 8.97–
8.99 (1H, m); 13C NMR (100 MHz, C6D6) d 8.9, 29.3, 38.8, 40.9,
41.5, 44.8, 47.8, 56.0, 62.9, 81.1, 122.5, 125.0, 125.8, 126.0, 127.4,
128.7, 128.8, 128.9, 129.3, 129.5, 132.7, 136.3, 141.0, 144.3; HRMS
(FAB+) [M+H]: calcd for C26H30NO: 372.2327, found: 372.2333.
Anal. Calcd for C26H29NO: C, 84.06; H, 7.87, N, 3.77. Found: C,
84.15; H, 7.83; N, 3.73.
tane–diethyl ether, 1:1); mp 188–190 °C;
½
a 2D0
ꢂ
¼ ꢀ28 (c 0.6,
CHCl3); IR (KBr) 1734 cmꢀ1
;
1H NMR (400MHz, C6D6, mixture of
two rotamers); d 0.82–1.08 (br m), 1.09–1.23 (br m), 1.41–1.61
(br m), 1.62–1.70 (br m), 1.99 (dt, J = 18.4, 2.8 Hz), 2.01–2.09 (br
d), 2.22–2.39 (1H, br m), 2.24 (br d, J = 13.6 Hz), 3.00 (br d,
J = 15.2 Hz), 3.40 (br s), 4.33 (br s), the reported peaks integrates
to 13H in total, 7.19–7.36 (4H, m), 7.39–7.51 (1H, m), 7.54 (1H,
d, J = 8.4 Hz), 7.59–7.70 (1H, m), 8.36 (br d, J = 7.6 Hz), 8.76–8.83
(br m), the last two peaks integrate 1H together; 13C NMR is not gi-
ven since the two rotamers give peaks that are too broad; HRMS
(FAB+) [M+Na]: calcd for C20H20O3Na: 331.1310, found: 331.1320.
Anal. Calcd for C20H20O3: C, 77.90; H, 6.54. Found: C, 77.84; H, 6.60.
4.18. (1R,2R,4S,6S)-6-(N-Benzyl-N-ethyl-amino)-2-phenyl-
bicyclo[2.2.2]octan-2-ol (+)-37
4.21. (1S,2R,4R)-2-Acetoxy-6-oxo-2-(2-methoxy-phenyl)-
bicyclo[2.2.2]octane (+)-29
The title compound was synthesized following the same pro-
cedure as for (+)-14, from (+)-36 (0.28 g, 0.91 mmol), except that
the reaction time was 3 days. The crude product was purified by
column chromatography (SiO2, heptane–EtOAc, 8:2) to give (+)-37
(0.22 g, 70%, 99% ee) as a yellow oil; TLC Rf was concentration
The title compound was synthesized following the same proce-
dure as for (ꢀ)-27, from (ꢀ)-25 (0.42 g, 1.6 mmol), except that the
reaction time was 4.5 days (another portion of 3 equiv Ac2O and
DMAP (cat.) was added after 3.5 days). The crude product was puri-
fied by column chromatography (SiO2, heptane–EtOAc, 8:2) to give
(+)-29 (0.15 g, 52%, 99% ee) as white crystals; TLC Rf 0.43 (heptane–
dependent. IR (KBr) 3179 (br) cmꢀ1; ½a D20
¼ þ165 (c 0.6, CHCl3);
ꢂ
1H NMR (C6D6, 400 MHz) d 0.64 (3H, t, J = 7.2 Hz), 0.93–1.02
(1H, m), 1.14–1.24 (1H, m), 1.26–1.35 (1H, m), 1.48–1.58 (1H,
m), 1.60–1.64 (1H, m), 1.76–1.84 (2H, m), 1.99–2.03 (1H, m),
2.18 (1H, dt, J = 14.4, 3.2 Hz), 2.34 (1H, dt, J = 14.4, 2.0 Hz),
2.53–2.64 (2H, m), 2.71–2.80 (1H, m), 3.40–3.57 (2H, m), 7.07–
7.12 (1H, m), 7.15–7.19 (3H, m), 7.29–7.35 (4H, m), 7.78–7.81
(2H, m), 8.12 (1H, br s); 13C NMR (C6D6, 100 MHz) d 7.8, 21.8,
23.9, 27.1, 33.6, 37.6, 42.0, 43.9, 53.8, 59.4, 76.1, 126.9, 127.5,
127.7, 128.7, 129.2, 129.4, 139.9, 149.5. HRMS (FAB+) [M]: calcd
EtOAc, 1:1); mp 152–155 °C; ½a D20
¼ þ24 (c 0.25, CHCl3); IR (KBr)
ꢂ
1725 cmꢀ1 1H NMR (400 MHz, C6D6) d 1.00–1.12 (2H, m), 1.36–
;
1.47 (1H, m), 1.47–1.54 (1H, m), 1.62 (3H, s), 1.77–1.80 (1H, m),
2.00 (1H, dt, J = 18.4, 3.2 Hz), 2.34 (1H, dt, J = 15.2, 2.4 Hz), 2.34
(1H, dt, J = 18.4, 2.8 Hz), 2.53 (1H, dt, J = 15.6, 3.2 Hz), 3.26 (3H,
s), 3.84–3.85 (1H, m), 6.54 (1H, dd, J = 8.4, 1.2 Hz), 6.83 (1H, td,
J = 7.6, 1.2 Hz), 7.04–7.08 (1H, m), 7.32 (1H, dd, J = 8.0, 1.6 Hz);
13C NMR (100 MHz, C6D6) d 19.4, 21.8, 24.8, 28.6, 40.9, 43.9, 49.9,
55.3, 83.6, 112.8, 120.5, 129.3, 129.3, 129.4, 158.4, 168.6, 210.9;
HRMS (FAB+) [M+Na]: calcd for C17H20O4Na: 311.1259, found:
311.1244. Anal. Calcd for C17H20O4: C, 70.81; H, 6.99. Found: C,
70.76; H, 6.94. 6-(2-Methoxy-phenyl)-bicyclo[2.2.2]oct-5-en-2-one
was isolated as a by-product (29%); TLC Rf 0.71 (heptane–EtOAc,
1:1); 1H NMR (400 MHz, C6D6) d 1.27–1.32 (2H, m), 1.59–1.69
(2H, m), 1.81 (1H, dd, J = 18.0, 2.4 Hz), 1.98 (1H, dm, J = 18.0 Hz),
2.50 (1H, h, J = 2.8 Hz), 3.27 (3H, s), 3.68–3.70 (1H, m), 6.26 (1H,
dd, J = 6.4, 1.6 Hz), 6.47–6.49 (1H, dd, J = 8.4, 1.2 Hz), 6.82 (1H, td,
J = 7.2, 1.2 Hz), 7.04–7.08 (1H, m), 7.11–7.13 (1H, m); 13C NMR
(100 MHz, C6D6) d 23.0, 25.4, 33.2, 41.1, 53.6, 55.1, 111.4, 121.2,
129.0, 129.3, 129.8, 133.0, 141.3, 157.7, 210.4; HRMS (FAB+)
[M+H]: calcd for C15H16O2: 228.1150, found: 228.1150.
for
C23H29NO: 335.2249, found: 335.2248. Anal. Calcd for
C23H29NO: C, 82.34; H, 8.71, N, 4.18. Found: C, 82.29; H, 8.77;
N, 4.14.
4.19. (1S,2R,4R)-2-Acetoxy-6-oxo-2-phenyl-bicyclo- [2.2.2]-
octane (ꢀ)-27
Ac2O (0.63 mL, 6.7 mmol) and DMAP (cat.) were added to a
solution of (+)-23 (0.50 g, 2.3 mmol) in pyridine (10 mL). The reac-
tion mixture was stirred at 60 °C for 2 d then satd aqueous NaHCO3
was added and the aqueous phase was extracted with diethyl ether
(3 ꢁ 30 mL). The combined organic phases were washed repeat-
edly with CuSO4 solution until there was no color change of the
aqueous phase, then washed with brine and dried over Na2SO4.
The solvent was removed under reduced pressure and the remain-
ing crude product was purified by column chromatography to give
(ꢀ)-27 (0.43 g, 72%, 99% ee) as white crystals; TLC Rf 0.53 (hep-
4.22. (1S,2S,4R)-2-Acetoxy-6-oxo-2-benzyl-bicyclo[2.2.2]octane
(+)-30
tane–EtOAc, 1:1); mp 118–120 °C, ½a D20
¼ ꢀ48 (c 0.4, CHCl3); IR
ꢂ
(KBr) 1738, 1725 cmꢀ1 1H NMR (400 MHz, C6D6) d 0.93–1.00
;
The title compound was synthesized following the same proce-
dure as for (ꢀ)-27, from (+)-26 (2.05 g, 8.9 mmol), except that the
reaction was heated at 60 °C for 4 days (another portion of 3 equiv
Ac2O and DMAP (cat.) was added after 3 days), then at 80 °C for an-
other 3 days. The crude product was purified by column chroma-
tography (SiO2, heptane–EtOAc, 75:25) to give (+)-30 (1.13 g,
47%, 99% ee) as white crystals; TLC Rf 0.57 (heptane–EtOAc, 1:1);
(1H, m), 1.02–1.07 (1H, m), 1.15–1.20 (2H, m), 1.53 (3H, s), 1.70–
1.73 (1H, m), 1.94 (1H, dt, J = 18.4, 2.8 Hz), 2.08 (1H, dt, J = 16.0,
2.8 Hz), 2.15 (1H, dt, J = 18.8, 2.8 Hz), 2.43 (1H, dt, J = 16.0,
2.8 Hz), 2.89 (1H, t, J = 2.8 Hz), 7.02–7.06 (1H, m), 7.10–7.15 (2H,
m), 7.24–7.27 (2H, m); 13C NMR (100 MHz, C6D6) d 18.5, 21.8,
23.9, 28.8, 38.6, 43.8, 54.1, 83.9, 126.2, 127.9, 128.8, 142.6, 168.4,
210.2; HRMS (FAB+) [M+Na]: calcd for C16H18O3Na: 281.1154,
mp 132–133 °C; ½a D20
ꢂ
¼ þ51 (c 0.8, CHCl3); IR (KBr) 1727 cmꢀ1
;

1492
C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
1H NMR (400 MHz, C6D6) d 1.00–1.05 (2H, m), 1.28–1.36 (1H, m),
1.41–1.51 (1H, m), 1.52–1.57 (1H, m), 1.55 (3H, s), 1.58–1.62
(1H, m), 1.88 (1H, dt, J = 18.4, 3.2 Hz), 1.98 (1H, m), 2.02 (1H, m),
(FAB+) [M+H]: calcd for C25H28ON: 358.2171, found: 358.2173.
Anal. Calcd for C25H27ON: C, 83.99; H, 7.61; N, 3.92. Found: C,
83.90; H, 7.56; N, 3.90. (1R,2R,4S,6S)-6-(N-Benzyl-N-ethyl-ami-
no)-2-(1-naphthyl)-bicyclo[2.2.2]octan-2-ol (43) was isolated as a
by-product in 21% yield; TLC Rf concentration dependent;1H NMR
(400 MHz, C6D6) d 0.68 (3H, t, J = 7.0 Hz), 1.13–1.38 (4H, m),
1.68–1.70 (1H, m), 1.70–1.78 (1H, m), 1.80–1.89 (1H, m), 1.90–
2.02 (2H, m), 2.60–2.75 (3H, m), 2.81–2.90 (2H, m), 3.55 (2H, br,
s) 7.03–7.11 (3H, m), 7.27–7.40 (5H, m), 7.41–7.47 (1H, m), 7.64
(1H, d, J = 8.0 Hz), 7.74 (1H, dd, J = 8.0, 1.6 Hz), 9.40 (1H, d,
J = 8.8 Hz); 13C NMR (100 MHz, C6D6) d 8.0, 23.1, 24.2, 27.3, 33.1,
33.8, 42.0, 47.0, 53.8, 59.4, 77.2, 122.1, 124.9, 125.4, 125.8, 127.7,
128.9, 129.0, 129.1, 129.3, 130.2, 133.3, 136.4, 139.7, 145.1; HRMS
(FAB+) [M+H]: calcd for C27H32ON: 386.2484, found: 386.2479.
2.93 (1H, t, J = 3.2 Hz), 3.06 (1H, dAB, JAB = 14.4 Hz), 3.47 (1H, dAB
,
JAB = 14.4 Hz), 7.05–7.15 (5H, m); 13C NMR (100 MHz, C6D6) d
19.1, 22.3, 24.5, 28.6, 40.5, 40,7, 43.5, 49.9, 84.8, 127.4, 128.9,
130.7, 136.8, 170.3, 210.1; HRMS (FAB+) [M+Na]: calcd for
C
C
17H20O3Na: 295.1310, found: 295.1318. Anal. Calcd for
17H20O3: C, 74.97; H, 7.40. Found: C, 75.08; H, 7.33.
4.23. (1R,2R,4S,6S)-6-Benzylamino-2-phenyl-bicyclo-
[2.2.2]octan-2-ol (+)-36
Benzylamine (0.70 mL, 6.8 mmol), acetic acid (0.15 mL,
2.6 mmol) and MS 4 Å were added to a solution of (ꢀ)-27 (0.33 g,
1.3 mmol) in toluene (15 mL), and the mixture was heated to
80 °C for 2 days. The MS were filtered off and the toluene was re-
moved under reduced pressure. The remaining mixture was dis-
solved in methanol (20 mL) and cooled to 0 °C, then NaBH4
(0.49 g, 13 mmol) was added. The mixture was stirred for 15 min
then water was added and the aqueous phase was extracted with
diethyl ether (3 ꢁ 40 mL). The combined organic phases were
washed with satd aqueous NaHCO3 and brine, then dried over
Na2SO4. The solvent was removed under reduced pressure and
the remaining mixture was dissolved in dry THF. The mixture
was cooled to 0 °C then a 1 M solution of LiAlH4 in THF (5.2 mL,
5.2 mmol) was added. The cooling bath was removed and the mix-
ture was stirred at rt for 40 min. The reaction was quenched by the
addition of water (0.2 mL), 15% NaOH-solution (0.2 mL) and water
(0.6 mL), and after 20 min of stirring at rt the precipitate was fil-
tered off and rinsed with diethyl ether. The solvents were removed
under reduced pressure, and the crude product was purified by col-
umn chromatography (SiO2, heptane–EtOAc, 60:40 + 0.3% NEt3)
giving (+)-36 as yellow crystals (0.36 g, 91%, 99% ee) that were pure
according to NMR analysis. The product was recrystallized from
heptane–EtOAc to give white crystals; TLC Rf concentration depen-
4.25. (1R,2S,4S,6S)-6-Benzylamino-2-benzyl-
bicyclo[2.2.2]octan-2-ol (+)-42
The title compound was synthesized following the same proce-
dure as for (ꢀ)-27, from (+)-30 (0.75 g, 2.8 mmol). The crude prod-
uct was purified by column chromatography (SiO2, heptane–EtOAc,
9:1?7:3) to give (+)-42 (0.21 g, 23%, 99% ee) as a yellow solid; TLC
Rf concentration dependent; mp 78–83 °C; ½a D20
¼ þ88 (c 0.65,
ꢂ
CHCl3); IR (KBr) 3267 cmꢀ1 1H NMR (400 MHz, C6D6) d 0.98–
;
1.27 (5H, m), 1.41–1.43 (1H, m), 1.49–1.65 (4H, m), 1.94–2.01
(1H, m), 2.48–2.52 (1H, m), 2.66 (1H, dAB, JAB = 13.6 Hz), 3.07 (1H,
dAB, JAB = 12.8 Hz), 3.18 (1H, dAB, JAB = 12.8 Hz), 3.31 (1H, dAB,
JAB = 12.8 Hz), 6.97–7.00 (2H, m), 7.03–7.15 (4H, m), 7.24–7.29
(2H, m), 7.61–7.64 (2H, m); 13C NMR (100 MHz, C6D6) d 22.0,
24.4, 26.7, 34.6, 34.8, 46.5, 48.7, 51.2, 56.4, 74.3, 126.6, 127.6,
128.2, 128.8, 129.0, 131.7, 139.9, 140.2; HRMS (FAB+) [M+H]: calcd
for
C22H28ON: 322.2171, found: 322.2166. Anal. Calcd for
C22H27ON: C, 82.20; H, 8.47; N, 4.36. Found: C, 82.15; H, 8.43; N,
4.51.
4.26. (1R,2S,4S,6S)-6-(N-Benzyl-N-ethyl-amino)-2-benzyl-
bicyclo[2.2.2]octan-2-ol (+)-44
dent; mp 118–119 °C; ½a D20
ꢂ
¼ þ129 (c 1.2, CHCl3); IR (KBr) 3263,
3146; 1H NMR(400 MHz, C6D6) d 0.87–0.95 (1H, m), 1.07–1.16
(1H, m), 1.24–1.32 (2H, m), 1.39–1.47 (1H, m), 1.58–1.66 (2H,
m), 1.73–1.76 (1H, m), 2.17 (1H, dt, J = 14.4, 3.2 Hz), 2.42 (1H, dt,
J = 14.4, 2.4 Hz), 2.61–2.66 (1H, m), 3.37 (1H, dAB, JAB = 13.2 Hz),
3.57 (1H, dAB, JAB = 13.2 Hz), 7.07–7.13 (1H, m), 7.13–7.21 (7H,
m), 7.31–7.36 (2H, m), 8.25 (1H, br s); 13C NMR (100 MHz, C6D6)
d 21.7, 24.0, 26.8, 34.9, 39.2, 44.1, 51.6, 57.0, 76.0, 126.9, 127.6,
127.8, 128.3, 128.9, 129.1, 140.2, 149.6; HRMS (FAB+) [M+Na]:
calcd for C21H25NONa: 330.1834, found: 330.1836. Anal. Calcd for
Compound 44 was isolated as byproduct (0.18 g, 18%) (clear
oil); TLC Rf concentration dependent; ½a D20
¼ þ170 (c 0.5, CHCl3);
ꢂ
IR (KBr) 3224 cmꢀ1 1H NMR (400 MHz, C6D6) d 0.50 (3H, t,
;
J = 6.8 Hz), 1.12–1.30 (4H, m), 1.48–1.53 (1H, m), 1.53–1.73 (4H,
m), 1.85 (1H, br s), 1.99 (1H, dm, J = 13.2 Hz), 2.35–2.47 (3H, m),
2.66 (1H, dAB, JAB = 13.2 Hz), 3.06 (1H, dAB, JAB = 13.6 Hz), 3.10–
3.40 (2H, m), 7.03–7.26 (8H, m), 7.56–7.60 (2H, m); 13C NMR
(100 MHz, C6D6) d 7.9, 22.3, 24.3, 27.0, 32.5, 33.4, 41.8, 45.9,
48.1, 53.6, 59.0, 74.5, 126.6, 127.6, 128.2, 129.0, 129.5, 131.7,
139.7, 139.8; HRMS (FAB+) [M+H]: calcd for C24H32ON: 350.2484,
found: 350.2477. Anal. Calcd for C24H31ON: C, 82.47; H, 8.94; N,
4.01. Found: C, 82.40; H, 8.97; N, 3.96.
C21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 81.97; H, 8.22, N,
4.53.
4.24. (1R,2R,4S,6S)-6-Benzylamino-2-(1-naphthyl)-bicyclo-
[2.2.2]octan-2-ol (+)-41
4.27. (1S,2R,3S)-3,6-Dibenzyl-5-methyl-4-oxa-6-aza-tricyclo-
The title compound was synthesized following the same proce-
dure as for (+)-36, from (ꢀ)-28 (0.25 g, 0.81 mmol). The crude
product was purified by column chromatography (SiO2, heptane–
EtOAc, 7:3 + 0.3% NEt3) to give (+)-41 (0.16 g, 57%, 99% ee) as a yel-
low solid; TLC Rf concentration dependent; mp 119–125 °C;
[5.3.1.03,8]undecane (+)-45
Compound 45 was also isolated as a byproduct (0.19 g, 19%)
(clear oil); TLC Rf 0.78 (heptane–EtOAc, 1:1); ½a D20
¼ þ4 (c 0.5,
ꢂ
CHCl3); 1H NMR (400 MHz, C6D6) d 0.76–0.87 (1H, m), 1.05–1.10
(2H, m), 1.27 (3H, d, J = 5.6 Hz), 1.28–1.35 (2H, m), 1.49–1.63
(3H, m), 1.68–1.70 (1H, m), 1.77 (1H, dm, J = 14.8 Hz), 2.67 (1H,
½
a 2D0
ꢂ
¼ þ13 (c 0.45, CHCl3); IR(KBr) 3288, 3191 (br) cmꢀ1
;
1H
NMR (400 MHz, C6D6) d 1.07–1.24 (3H, m), 1.44–1.48 (1H, m),
1.61–1.75 (3H, m), 2.18–2.22 (1H, m), 2.42 (1H, m), 2.69–2.76
(2H, m), 3.42 (1H, dAB, JAB = 13.2 Hz), 3.62 (1H, dAB, JAB = 12.8 Hz),
7.05–7.11 (2H, m), 7.13–7.16 (4H, m), 7.29–7.35 (2H, m), 7.38–
7.40 (1H, m), 7.44–7.48 (1H, m), 7.65–7.67 (1H, m), 7.74–7.76
(1H, m); 13C NMR (100 MHz, C6D6) d 22.8, 24.3, 26.9, 34.4, 35.9,
46.7, 51.5, 56.9, 77.5, 122.8, 124.8, 125.3, 125.7, 127.8, 128.5,
128.9, 129.1, 129.5, 130.1, 133.4, 136.5, 140.2, 144.8; HRMS
dAB, JAB = 13.6 Hz), 2.68–2.73 (1H, m), 2.83 (1H, dAB, JAB = 14.0 Hz),
3.47 (1H, dAB, JAB = 14.4 Hz), 3.71 (1H, dAB, JAB = 14.4 Hz), 4.69
(1H, q, J = 5.6 Hz), 7.07–7.10 (1H, m), 7.14–7.21 (3H, m), 7.23–
7.30 (4H, m), 7.46–7.48 (2H, m); 13C NMR (100 MHz, C6D6) d
20.6, 20.7, 26.1, 26.7, 29.4, 29.9, 38.4, 47.6, 50.2, 52.9, 75.3, 77.0,
126.7, 127.2, 128.3, 128.8, 129.0, 131.7, 138.9, 141.4; HRMS
(FAB+) [M+Na]: calcd for C24H29ONNa: 370.2143, found:

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1484–1493
1493
12. Martins, J. E. D.; Mehlecke, C. M.; Gamba, M.; Costa, V. E. U. Tetrahedron:
Asymmetry 2006, 17, 1817–1823.
13. Olsson, C.; Friberg, A.; Frejd, T. Tetrahedron: Asymmetry 2008, 19, doi:10.1016/
j.tetasy.2008.05.024.
370.2143. Anal. Calcd for C24H29ON: C, 82.95; H, 8.41; N, 4.03.
Found: C, 83.06; H, 8.37; N, 4.04.
14. Sarvary, I.; Wan, Y.; Frejd, T. J. Chem. Soc., Perkin Trans.
645–651.
1 2002,
References
15. Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24, 273–276.
16. Nutaitis, C. F.; Gribble, G. W. Tetrahedron Lett. 1983, 24, 4287–4290.
17. Moore, J. L.; Taylor, S. M.; Soloshonok, V. A. ARKIVOC (Gainesville, FL, US) 2005,
287–292.
18. Friberg, A.; Sarvary, I.; Wendt, O.; Frejd, T. Tetrahedron: Asymmetry 2008, 19,
submitted for publication.
19. Corey, E. J.; Gras, J. L.; Ulrich, P. Tetrahedron Lett. 1976, 809–812.
20. Corey, E. J.; Cho, H.; Ruecker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, 3455–
3458.
21. Hoefle, G.; Steglich, W.; Vorbrueggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17,
569.
22. Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117,
4413–4414.
23. Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J. Org. Chem. 1998, 63,
2342–2347.
24. Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327–6335.
25. Rasmussen, T.; Norrby, P. O. J. Am. Chem. Soc. 2001, 123, 2464–2465.
1. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823–2824.
2. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 34–48.
3. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856.
4. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
5. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071–
6072.
6. Knollmuller, M.; Ferencic, M.; Gartner, P. Tetrahedron: Asymmetry 1999, 10,
3969–3975.
7. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S.;
Martinez-Ruiz, P. Tetrahedron: Asymmetry 2002, 13, 1457–1460.
8. Chelucci, G. Chem. Soc. Rev. 2006, 35, 1230–1243.
9. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; de la Moya Cerero, S.; Martinez Ruiz, P.;
Diaz Morillo, C. Tetrahedron: Asymmetry 2007, 18, 742–749. and references
cited therein.
10. de Oliveira, L. F.; Costa, V. E. U. Tetrahedron: Asymmetry 2004, 15, 2583–
2590.
11. Tanyeli, C.; Suenbuel, M. Tetrahedron: Asymmetry 2005, 16, 2039–2043.