Diastereo- and enantioselective aldol reaction of granatanone (pseudopelletierine)

Article abstract of DOI:10.1016/j.tet.2011.09.096

Granatanone (granatan-3-one, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one, pseudopelletierine or pseudopelletrierin) undergoes deprotonation with lithium amides giving a lithium enolate, which reacts with aldehydes diastereoselectively giving exclusively exo i

Full text of DOI:10.1016/j.tet.2011.09.096

Tetrahedron 67 (2011) 9433e9439
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereo- and enantioselective aldol reaction of granatanone
(pseudopelletierine)
,
a
a
b
Ryszard Laznya , Karol Wolosewicz , Paulina Zielinska , Zofia Urbanczyk-Lipkowska ,
*
Przemyslaw Kalicki b
a Institute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-339 Bialystok, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw 48, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2011
Received in revised form 4 September 2011
Accepted 20 September 2011
Available online 25 September 2011
Granatanone (granatan-3-one, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one, pseudopelletierine or pseu-
dopelletrierin) undergoes deprotonation with lithium amides giving a lithium enolate, which reacts with
aldehydes diastereoselectively giving exclusively exo isomers and anti/syn selectivity up to 98:2. Gran-
atanone can be enantioselectively lithiated by chiral lithium amides and the resulting non-racemic
enolate can be reacted with aldehydes giving aldols with enantiomeric excess up to 93% (99% ee after
recrystallization). The absolute and relative configuration of the aldol products was determined by NMR
spectroscopy and X-ray analysis.
Keywords:
Chiral lithium amide
Aldol reaction
Granatanone
Stereoselective synthesis
Enantioselective synthesis
Granatanone; aldol reaction; asymmetric synthesis; enantioselective deprotonation; chiral lithium
amide.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
and enantioselective directed aldol reactions of granatanone via
a lithium enolate.
Granatan-3-one or simply granatanone (1, 9-methyl-9-
azabicyclo[3.3.1]nonan-3-one) known also as pseudopelletierine
(or pseudopelletrierin) is an alkaloid from the bark of the pome-
2. Results and discussion
€
granate tree obtained synthetically via a RobinsoneSchopf type
procedure.1,2 The bicyclic skeleton of 9-azabicyclo[3.3.1]nonane is
an important substructure of a variety of compounds, which pos-
sess anti-Parkinson’s,3 neuroleptic,4,5 and hypotensive activity.6
Granatanone and its derivatives were used for synthesis of poten-
tial cocaine-binding site ligands.7 Aldol reaction of tropinone 2,
a homologue of granatanone 1 has been used successfully as a key
step in the asymmetric syntheses8 of several bioactive derivatives
including cocaine9 and some potentially biologically active alka-
loids.10,11 Related to granatanone tropane derivatives make nu-
merous extensively studied ligands for biological receptors.12,13
Interestingly the aldol reaction of granatanone which can allow
for the stereocontrolled construction on the 9-azabicyclo[3.3.1]
nonane scaffold was, to the best of our knowledge, not studied or
reported. Herein we wish to describe the first diastereoselective
Granatanone is a Cs symmetrical molecule with distinctly dif-
ferentiated exo and endo sides. Thus subjection of granatanone to
a deprotonation (lithiation) reaction with lithium amide bases
would give a chiral lithium enolate (Scheme 1). Chiral lithium
amides, which are capable of enantioselective deprotonation of
ketones14 should in theory give a non-racemic mixture of the
lithium enolate. Enantioselective deprotonation of nor-
granatanone Cbz derivative with a chiral lithium amide was used
for the preparation of chiral silyl enol ethers by Momose.15 Re-
action of preformed chiral enolates with electrophiles should re-
tain the asymmetry of the enolate and give non-racemic products.
Such a strategy based on desymmetrization of ketones was suc-
cessfully used previously for the synthesis of tropane de-
rivatives.10,16 By analogy to the known reactivity of the tropane
analogue10 electrophiles are expected to approach the gran-
atanone enolate from a pseudo axial direction and give the exo
products, despite that the endo isomers are usually more ther-
modynamically stable. Approach of electrophiles to cyclic enolates
from the axial direction is usually favored stereoelectronically.17,18
* Corresponding author. Tel.: þ48 85 745 7834; fax: þ48 85 745 7589; e-mail
address: lazny@uwb.edu.pl (R. Lazny).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.096

9434
R. Lazny et al. / Tetrahedron 67 (2011) 9433e9439
We have tested achievability of such stereocontrolled aldol re-
actions of granatanone lithium enolate generated with LDA and
selected chiral lithium amides.
H3C
H3C
H3C
N
N
E
N
electrophile
lithiation
H
H
OLi
n
n
n
O
O
exo-Product
1
Li enolate
n = 1, Granatanone
2
n = 0, Tropinone
Scheme 1. Formation and reaction of tropinone and granatanone lithium enolates.
2.1. Diastereoselective aldol reaction of granatanone
Reaction of granatanone under standard conditions with LDA
gave the lithium enolate which was reacted without isolation with
selected aldehydes (Table 1). Such reactions of bicyclic ketones of
type 1 or 2 can in principle give four diastereomers. Analysis of the
crude product mixtures obtained by reacting aldehydes with the
preformed lithium enolate showed high conversion to aldols. To our
satisfaction the NMR spectra of the crude products indicated also
high diastereomeric purity. The analysis of the spectra suggested the
exo isomers to be the only detectable products. The assignment of
signals was helped by comparison with the known tropane ana-
logues and correlation spectroscopy (1He1H and 1He13C).
Fig. 1. X-ray structure of the major isomer of aldol synthesized via deprotonation with
ꢀ
LDA (3a, exo,anti) showing intramolecular H-bond: N1/O2 2.753(2), N1/H 1.88(3) A,
N1/HeO2 angle 151(2)ꢀ. Displacement ellipsoids are drawn at 30% probability level,
atoms numbering arbitrary.
Table 1
Directed aldol reaction of granatanone via addition of lithium enolate to aldehyde
H3C
H3C
H3C
HO
HO
H
R
N
N
H
R
N
1) LDA
2) RCHO
H
H
Fig. 2. X-ray structure of the minor isomer of aldol synthesized via deprotonation with
O
O
exo,anti 3
O
exo,syn 3
ꢀ
LDA (3b, exo,syn) showing intramolecular H-bond: N1/O2 2.775(2), N1/H 1.93(2) A,
1
N1/HeO2 angle 152(2)ꢀ. Displacement ellipsoids are drawn at 30% probability level,
atoms numbering arbitrary.
Entry
R
Yield of
aldol 3 (%) anti:
exo,syn
Ratio exo, exo, anti ppma
exo, syn ppma,b
(J, Hz)
(J, Hz)
minor 3b (Fig. 2) evidenced the presence of relatively strong intra-
molecular hydrogen bonds between the amine nitrogen and the aldol
hydroxyl group (for geometry see Figs. 1 and 2). The other studied
reactions also showed high exo,anti selectivity (Table 1). The high exo
selectivity was expected by analogy to the known reactions of tropi-
none.19,10 Accordingly effects such as the stereoelectronic preference
of the electrophile for the axial approach to cyclic enolates17,18,20
and steric hindrance of the endo approach may be responsible for
the observed pseudo axial attack of the aldehyde on the preformed
lithium enolate. To rationalize the observed anti selectivity one could
consider stability of lithium aldolates directly formed in the reaction
with aldehydes (Scheme 2). Owing to stabilizing OeLieO bonding in
aldolates and steric interactions the transition state for formation of
the exo,anti isomers should be lower in energy compared to the
exo,syn counterpart (Scheme 2). Close inspection of models of
products 3 reveals possible steric congestion in the exo,syn isomer of
the aldolate and resulting destabilizing steric interactions of the
phenyl group with the axial hydrogen on C-4 and the rest of the pi-
peridine ring of the granatanone scaffold (B vs A). Even though under
the applied experimental conditions, the reactions are most likely
kinetically controlled the same interactions may influence the
stabilities of competing transition states. The transition state leading
to exo,anti lithium aldolate most likely benefits from diminished
steric interactions of the R group of the aldehyde with the nitrogen
bridge and C-4 hydrogen as shown in favored exo,anti approach A
(Scheme 2). This type of interaction in approaching reactants could
account for the somewhat lowered diastereoselectivity in case of less
sterically demanding aldehydes: acetaldehyde and hexanal.
1
2
3
4
Ph
3a, 97
98:2
92:8
97:3
85:15
5.35 (d, 3.9)
5.33 (d, 3.1)
6.05 (d, 2.8)
5.09 (d, 1.76)
5.15 (d, 1.8)
5.43 (d, 3.7)
4-NO2C6H4 3b, 98
1-Naphthyl 3c, 50
Me
3d, 93
3e, 60
3f, 98
3g, 94
4.19 (dq, J1¼6.3, 4.06 (dq, J1¼6.3,
J2¼2.6)
J2¼1.9)
5
6
n-Pentyl
i-Pr
89:11
96:4
4.02e3.97
multiplet
3.82e3.73
multiplet
3.51 (dd, J1¼9.5, 4.4 (d, J¼3.6)
J2¼2.6)
7
p-BrPh
>99:1
5.20 (d, J¼3.3)
No data
a
Characteristic signals found in 1H NMR spectra of the crude product.
Pure exo,syn aldols were not isolated.
b
Ratios of isomers exo,syn to exo,anti was inferred from integration
of doublets corresponding to the carbinol hydrogens CH(OH)-R. The
diastereoselectivity of the reaction was excellent in most cases.
Slightly lower diastereomeric ratio of crude products was measured
for reaction with acetaldehyde and hexanal (Table 1, entries 4 and 5).
The aldols were fairly unstable to typical chromatography (de-
composition and equilibration of diastereomers was observed).
However, purification by precipitation followed by crystallization
gave pure crystalline aldols derived from benzaldehyde 3a and p-nitro
benzaldehyde 3b. Overall, the aldols were obtained in excellent yields
(>90%) except for aldols derived from hexanal and naphthaldehyde
which gave fair yields (50 and 60%, Table 1, entries 3 and 5). The rel-
ative configurations assigned based on NMR spectroscopic data were
confirmed by X-ray structure determination of the products 3a and
3b. The crystal structures of the major aldol product 3a (Fig.1) and the

R. Lazny et al. / Tetrahedron 67 (2011) 9433e9439
9435
Ph
H
Ph
O
H
Ph
O
H
O
H
H
Ph
H
O
quench
H2O
H
H
H
H
N
Li
H
N
N
N
Li
H
H
Me
Me
Me
Me
O
O
O
H
OLi
H
H
H
favored exo,anti approach A
exo,anti
interamolecular H-bond in
exo,anti isomer
Li aldolate
approach of aldehyde
to Li enloate from pseudoaxial
direction
(see X-ray)
H
Ph
N
O
H
H
Li
Me
O
H
disfavored exo,syn approach B
Scheme 2. Rationalization of observed anti diastereoselectivity of the aldol reaction.
2.2. Diastereoselective and enantioselective aldol reaction of
granatanone
NLi
NLi
N
N
N
Ph
Ph
Ph
Ph
The reaction with benzaldehyde was studied as a representative
example. The enantiomeric excess of aldol product 3a was mea-
sured by NMR spectroscopy in the presence of (R)-(-)-2,2,2-
trifluoro-1-(9-anthryl)ethanol and was confirmed by HPLC analy-
sis on chiral stationary phase (urethane derivatives of 3a and 3f).
The enantioselective deprotonation of granatanone (Scheme 3) was
probed with four selected, well known chiral lithium amides14,21e23
(Fig. 3, 4e7). For optimum selectivity lithium chloride, which is
known to interact with aggregated lithium amides improving
enantioselectivity, was used as an additive.24 The amount of LiCl
used was based on previous optimization studies except for lithium
amide 7, which was not studied before in this capacity. A short
optimization of the amount of additive for lithium amide 7 (Table 2,
entries 4e7) showed very good results for 0.25e1.0 equiv of LiCl.
Using chemical shifts of enantiomers in the presence of chiral
solvating agent it was possible to correlate absolute configuration
of the major aldol product formed with studied lithium amides. It
turned out that lithium amide 7 gave the aldol with opposite ab-
solute configuration to that with lithium amides 4e6.
4
5
CH3
Ph
N
Li
Ph
N
Ph
Li
6
7
Fig. 3. Chiral lithium amides used for deprotonation of granatanone.
Table 2
Enantioselectivity of aldol reaction resulting from enantioselective deprotonation of
granatanone with chiral lithium amides
Entry
Chiral
lithium
amide
Equiv of
LiCl
additive
Yield of
Major
Product % ee
precipitated
product (%)
enantiomer
1
2
3
4
5
6
7
8
4
5
6
7
7
7
7
7
1.0
0.5
1.0
1.0
67
72
81
60
78
96
86
84
ent-3a
ent-3a
ent-3a
3a
ꢁ93 (98.7a)
ꢁ87
H3C
HO
ꢁ77
82
N
H
0.5
3a
83 (93a,b
80
)
O
N
Ph
0.25
None
0.5
3ab
pro-S
pro-R
H
3a
3g
65
H
O
H
89 (99a,b
)
*
a
1) R1 R2NLi, LiCl
2) PhCHO
The enantiomeric excess after a single recrystallization.
The absolute structure of this product was determined by X-ray crystallographic
3
b
analysis.
CH3
OH
H3C
N
H
aldehyde acceptor and remained very high (81e95% ee for crude
product, Table 3). The observed lower enantioselectivity of the aldol
reaction with acetaldehyde (Table 3, entry 2) is most likely a result
of high reactivity of the aldehyde and technical problems (volatil-
ity) with controlling the reaction temperature during reagent
addition.
1
Ph
H
O
ent-3
Scheme 3. Enantioselective aldol reaction of granatanone lithium enolate.
2.3. Absolute configuration of deprotonation of granatanone
with lithium amides
The diastereoselectivity of the aldol reaction remained very high
(>95%) with strong preference for exo,anti isomers with all lithium
amides studied. The highest enantioselectivity (93% ee) was ob-
tained with Koga-type bidentate lithium amide 4. The enantio-
meric and diastereomeric excess of products could be boosted by
careful crystallization to excellent levels (typically 93e98%). The
enantiomeric excess of aldols was unaffected by variation of
The absolute configuration and enantiomeric purity of formed
aldols of granatanone depended primarily on enantiotopic group
selective proton removal from either left or right side of the Cs
symmetrical molecules of granatanone (Scheme 3). For gran-
atanone one should expect the same absolute sense of proton ab-
straction as observed for tropinone and other cyclic ketones

9436
R. Lazny et al. / Tetrahedron 67 (2011) 9433e9439
Table 3
Enantioselective and diastereoselective aldol reaction of granatanone with chiral
lithium amide 4
H3C
CH3
OH
N
N
H
R
1) 4, THF
0.5 equiv LiCl
H
O
2) RCHO
O
Entry
R
Yield of
precipitated
product (%)
ee of crude
product (%)
ee after single
recrystallization (%)
1
2
3
4
Ph
CH3
1-Naphthyl
i-Pr
67
72
75
67
93
81
90
93
98.7
81
99
Fig. 5. X-ray structure of aldol (þ)-3g synthesized via deprotonation of granatanone
with lithium amide (R)-7 showing C(1)-S and C(10)-R configuration. Thermal ellipsoids
drawn at 30% probability level, atoms numbering arbitrary.
99
before.14 The formed chiral enolate reacts with aldehyde in the
presence of a chiral amine originally used for preparation of lithium
amide. Because of the presence of the chiral amine, in principle, the
enantioselection could also operate at the stage of the reaction with
electrophile (different rates of reaction of two enantiomeric eno-
lates with aldehydes in the presence of chiral amine). However,
under the reaction conditions (excess of aldehyde, high reactivity of
aldehydes toward enolates) the preferential reaction of one of the
enantiomers of the non-racemic enolate mixtures (kinetic resolu-
tion) in the presence of the chiral amine (complexed or not with
enolate25e27) is not significant and should not affect the overall
enantioselectivity.
The absolute sense of deprotonation was inferred from X-ray
analysis of the enantiomerically pure product (þ)-3a (Fig. 4),
obtained with chiral amide (R)-7. Absolute structure of (þ)-3a
was determined via anomalous scattering on the basis of 2263
Friedel pairs measured at 150 K, with refined Flack parameter
ꢁ0.01(14). Additional proof came from determination of the ab-
solute stereochemistry of a more suitable for crystallography,
deprotonation product, the bromine containing aldol (þ)-3g,
which was synthesized in enantiomerically enriched form with
help of amide (R)-7 (Table 2, entry 8 and Fig. 5). Flack parameter
for (þ)-3g was 0.074(14), for 2340 Friedel pairs measured at
150 K. It turned out indeed that the preference of deprotonation
of granatanone with lithium amides was the same as observed
previously for tropinone.10 In order to rationalize the preference
of amide 6 for deprotonation of cyclic ketones a model has been
proposed by Majewski and Gleave,28 later on criticized by Simp-
kins.29 As a rationalization of the preference of amide (R)-7 for
removal of the pro-R hydrogen of granatanone we propose to
consider interactions in the complex of lithium amide with
granatanone molecule. Complexation of carbonyl compound with
lithium amides prior deprotonation has been observed
experimentaly.25e27 Dissociation of chiral lithium amide dimmer
or aggregate with LiCl prior complexation with ketone is implic-
itly supposed. For simplicity our rational does not take into ac-
count interactions with LiCl. These, however, should not make
a qualitative difference because in the studied cases addition of
LiCl did not change overall absolute sense of proton abstraction.
The destabilizing interactions between methyl group at the ster-
eogenic carbon atom of the lithium amide in the R-7/pro-S
complex which are absent in the competing R-7/pro-R complex
could be responsible for preference of the latter (Fig. 6). Conse-
quently formation of the favored complex of the chiral amide R-7
could explain the experimentally observed preferred absolute
sense of proton abstraction.
Ph
Ph
Ph
Ph
Ph
O
Li
Li
Ph
N
H
N
H
O
C
H
Me
C
H
H
H
N
Me
N
Me
(R)-7/pro-R
Me
7
(R)- /pro-S
Fig. 6. Favored (left) and disfavored (right) approach of lithium amide reagent (R)-7 to
granatanone. Sterically interacting groups marked in red.
3. Conclusion
Granatanone (pseudopelletierine) is an interesting scaffold
which can be used for stereoselective functionalization and build-
up of carbon skeleton through deprotonation with lithium am-
ides. Aldol reaction of granatanone lithium enolates obtained by
enantioselective lithiation by chiral lithium amides can provide
aldols in high diastereomeric and enantiomeric purity. The pre-
ferred diastereomer (exo,anti) is obtained with great selectivity
regardless of lithium amide used. The highest enantioselection is
observed with Koga-type bidentate lithium amide 4 (93% ee),
however the benzhydryl derivative of commercial phenylethyl-
amine 7 may serve as an economical alternative when work-up is
combined with product crystallization. Such economical protocol
provided enantiomeric purity of 93e99% ee.
Fig. 4. X-ray structure of aldol (þ)-3a synthesized via deprotonation of granatanone
with lithium amide (R)-7 showing C(4)-S and C(5)-R configuration. Thermal ellipsoids
drawn at 30% probability level, atoms numbering arbitrary.

R. Lazny et al. / Tetrahedron 67 (2011) 9433e9439
9437
4. Experimental section
4.1. General methods
mixture was warmed up to rt and extracted with dichloromethane
(4ꢂ10 mL). The combined organic extracts were dried over anhy-
drous Na2SO4 and concentrated under vacuum. The resulting crude
product was dissolved in small portion of dichloromethane (ca.
1 mL) and treated with hexane until precipitation. The precipitated
solid product was washed with hexane from remaining chiral
amine and dried under vacuum. Yields of precipitated products are
given in Tables 2 and 3.
Thin-layer chromatography (TLC) was performed on pre-coated
plates (Merck, silica gel 60, F254). The spots were detected using UV
light (254 nm), and phosphomolybdic acid followed by charring.
Infrared (IR) spectra of compounds were recorded on a Nicolet
Magna-IR 550 FTIR Series II Spectrometer (CHCl3). Only diagnostic
peaks are reported (cmꢁ1). Magnetic resonance spectra (1H NMR
and 13C NMR) were recorded on a Bruker AVANCE II 400 spec-
trometer in CDCl3 at ambient temperature. Chemical shifts are re-
ported in parts per million downfield of tetramethylsilane. Specific
rotation was measured with Optical Activity AA-10R Automatic
Polarimeter. Reagents were purchased from Aldrich. Granatanone
was synthesized as described2 and sublimed before use.
4-Nitrobenzaldehyde was used without purification. Aldehydes
were purified by standard techniques.30 Crystallographic data were
4.3.1. 2-(Hydroxy(phenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]
nonan-3-one (exo,anti-3a). Yield (0.252 g; 97%) after precipitation;
analytical sample was recrystallized from diethyl ether; mp:
103e106 ꢀC; Rf 0.38 (10% CH3OH/CH2Cl2); 1H NMR (400 MHz,
CDCl3)
d
: 7.72 (br s, 1H), 7.36e7.30 (m, 5H), 5.35 (d, J¼3.9 Hz, 1H),
3.45 (d, J¼3.9 Hz, 1H), 3.42e3.38 (m, 1H), 3.09 (dd, J1¼6.9 Hz,
J2¼16.3 Hz, 1H), 2.82 (s, 3H), 2.61 (d, J¼3.8 Hz, 1H), 2.47(d,
J¼16.3 Hz, 1H), 2.16e2.10 (m, 2H), 1.61e1.57 (m, 2H), 1.42e1.37 (m,
2H); 13C NMR (100 MHz, CDCl3)
d: 208.8, 141.5, 128.0, 127.3, 125.4,
collected with a BrukereNonius Apex-X8 CCD-diffractometer with
77.7, 61.1, 60.5, 54.2, 48.5, 39.8, 22.5, 22.4, 16.5; IR (CHCl3) n: 3066,
2945, 1703, 1129 cmꢁ1; HRMS (ESI): m/z calcd for (C16H21NO2$Na):
282.1470, found: 282.1465.
ꢀ
Cu K
a
radiation (
l
¼01.54178 A) at 150 K. The structures were solved
by direct methods and refined using SHELXS9731 and SHELXL9731
programs. All non-H atoms were refined anisotropically; all
H-atoms bonded to carbon atoms were placed on geometrically
calculated positions and refined using a riding model. The hydroxyl
H-atoms in three structures were located from Dr maps and refined
isotropically. Anomalous scattering method was used for absolute
structure determination.32
Crystal data for C16H21NO2 (rac-3a): MW 259.34, monoclinic,
ꢀ
space group P21/c, a¼12.2438(3), b¼11.2004(3), c¼11.1808(3) A,
3
b
¼115.9850(10)ꢀ, V¼1378.28(6) A , Z¼4, Dc¼1.250 mg mꢁ3
,
ꢀ
F(000)¼560, crystal dimension 0.36ꢂ0.30ꢂ0.09 mm, radiation Cu
ꢀ
K
a
(l
¼01.54178 A). 12502 reflections were collected in the range of
ꢁ14ꢃhꢃ13, ꢁ12ꢃkꢃ12, ꢁ12ꢃlꢃ13; of these 2329 were in-
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 815108, 815107, 815109, and 842429, respectively for com-
pounds 3a, exo,syn-3b, (þ)-3a and (þ)-3g. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
dependent, R(int)¼0.042. The structure was solved and refined
using 2096 reflections with I>2s. Final R and Rw were 0.0369 and
0.0934, respectively.
Enantiomerically enriched (ꢁ)-3a prepared with lithium amide 4:
ee¼93% [1H NMR in the presence of (R)-(ꢁ)-2,2,2-trifluoro-1-(9-
anthryl)ethanol] measured on the crude product.
½
a 2D0
from hexane.
ꢄ
ꢁ40.5 (c 1.0, CHCl3), Mp 115e117 ꢀC after recrystallization
Crystal data for C16H21NO2 (þ)-3a (prepared with lithium amide
4.2. General procedure for diastereoselective aldol reaction
(with LDA)
7): MW 259.34, orthorhombic, space group P212121, a¼10.2382(2),
3
ꢀ
ꢀ
b¼12.1544(2), c¼21.9542(4) A, V¼2731.96(9) A , Z¼8,
Dc¼1.261
mg
mꢁ3
,
F(000)¼1120,
crystal
dimensions
¼1.54178 A).
To a cooled to 0 ꢀC, stirred solution of DIPA (0.17 mL,1.2 mmol) in
THF (3 mL) was added n-BuLi (0.50 mL, 1.2 mmol, 2.40 M) in hex-
anes. After 30 min the mixture was cooled to ꢁ78 ꢀC and solution of
granatanone (0.153 g, 1.0 mmol) in THF (3 mL) was added dropwise.
After 1 h aldehyde (1.2 mmol), was added and the reaction mixture
was stirred for 15 min. Then the reaction was quenched with aq
satd NH4Cl solution (6 mL). The mixture was warmed up to rt and
extracted with dichloromethane (4ꢂ10 mL). The combined organic
extracts were dried over anhydrous Na2SO4 and concentrated un-
der vacuum. The resulting crude product was dissolved in small
portion of dichloromethane (ca. 1 mL) and treated with hexane
until precipitation. The precipitated solid product was dried under
vacuum. The crude product 3e, which was an oil, was vacuum dried
only.
0.57ꢂ0.38ꢂ0.34 mm, T¼150 K, radiation Cu K
a
(l
ꢀ
21,253 reflections were collected in the range of ꢁ12ꢃhꢃ9,
ꢁ14ꢃkꢃ14, ꢁ226ꢃlꢃ26; of these 5096 were independent, R(int)¼
0.047. The structure was solved and refined using 4997 reflections
with I>2s(I). Final R and Rw were 0.0330 and 0.0871, respectively.
Absolute structure (Flack) parameter was ꢁ0.01(14) for 2163 Frie-
del pairs.
4.3.2. 2-(Hydroxy(4-nitrophenyl)methyl)-9-methyl-9-azabicyclo
[3.3.1]nonan-3-one (exo,anti-3b). Yield (0.298 g; 98%) after pre-
cipitation; analytical sample was recrystallized from mixed solvent
(dichloromethane/hexane); mp: 149e152 ꢀC; Rf 0.30 (AcOEt, de-
composition); 1H NMR (400 MHz, CDCl3)
d
: 8.16 (d, J¼8.8 Hz, 2H),
7.99 (br s, 1H), 7.44 (d, J¼8.8 Hz, 2H), 5.33 (d, J¼3.1 Hz, 1H), 3.43 (d,
J¼4.21 Hz, 1H), 3.35e3.28 (m, 1H), 2.87 (dd, J1¼16.4 Hz, J2¼7.0 Hz,
1H), 2.74 (s, 3H), 2.60e2.56 (m, 1H), 2.42 (d, J¼16.4 Hz, 1H),
2.22e2.06 (m, 2H), 1.62e1.45 (m, 2H), 2.40e2.27 (m, 2H); 13C NMR
4.3. General procedure for diastereoselective and
enantioselective aldol reaction (with chiral Li amides 4e7)
(100 MHz, CDCl3) d: 207.9, 149.1, 147.0, 126.3, 123.3, 77.0, 60.8, 60.1,
To a cooled to 0 ꢀC, stirred solution of chiral amine corre-
sponding to lithium amide 4e7 (1.2 mmol) in THF (3 mL) was added
n-BuLi (0.50 mL, 1.2 mmol, 2.40 M) in hexanes. After 30 min an-
hydrous LiCl (0.25e1.0 mmol) was added in THF (2 mL) and the
mixture was stirred for 10 min. Then the mixture was cooled to
ꢁ78 ꢀC and solution of granatanone (0.153 g, 1.0 mmol) in THF
(3 mL) was added dropwise. After 1 h aldehyde (1.2 mmol), was
added and the reaction mixture was stirred for 15 min. Then the
reaction was quenched with aq satd NH4Cl solution (6 mL). The
54.0, 48.6, 39.8, 22.5, 22.4, 16.4; IR (CHCl3) n: 2946, 2902, 1705,
1522, 1349, 1127 cmꢁ1; HRMS (ESI): m/z calcd for (C16H20N2O4Na):
327.1321, found: 327.1309.
4.3.3. exo,syn-2-[Hydroxy(4-nitrophenyl)methyl]-9-methyl-9-
azabicyclo[3.3.1]nonan-3-one (exo,syn-3b). Tedious crystallizations
from remaining mother liquor gave a fraction of minor isomer of
3b. Recrystallized from mixed solvent (dichloromethaneehexane),
mp 172e174 ꢀC (decomp.); Rf: 0.52 (5% MeOH/DCM); 1H NMR

9438
R. Lazny et al. / Tetrahedron 67 (2011) 9433e9439
(CDCl3, 400 MHz): 8.26e8.23 (m, 2H), 7.94 (br s, 1H), 7.64e7.62 (m,
2H), 5.13 (d, J¼1.7 Hz, 1H), 3.37e3.29 (m, 1H), 3.16 (dd, J¼17.2 Hz,
7.2 Hz, 1H), 2.92 (d, J¼4.4 Hz, 1H), 2.65 (s, 3H), 2.58 (d, J¼17.2 Hz,
1H), 2.48 (s,1H), 2.12e2.02 (app tt, J¼13.7 Hz, 4.3 Hz,1H), 2.00e1.89
(app tt, J¼14.0 Hz, 4.9 Hz, 1H), 1.65e1.42 (m, 1H) 1.39e1.31 (m, 1H),
1.01e0.96 (m, 1H); 13C NMR (CDCl3, 100 MHz): 210.6, 151.4, 147.2,
126.5, 123.7, 75.9, 59.4, 54.1, 53.7, 46.9, 39.8, 22.7, 22.5, 16.3; IR
54.2, 48.6, 39.8, 35.0, 31.7, 25.5, 22.6, 22.5, 22.4,16.8,14.0; IR (CHCl3)
: 2935, 2860, 1698, 1153, 1127 cmꢁ1; MS (EI) m/z: 253 (1), 182 (48),
110 (67), 96 (100), 57 (35), 43 (43), 42 (75), 41 (65); HRMS (ESI): m/z
n
calcd for (C15H27NO2Na): 276.1939, found: 276.1925.
4.3.7. 2-(1-Hydroxy-2-methylpropyl)-9-methyl-9-azabicyclo[3.3.1]
nonan-3-one (exo,anti-3f). Yield (0.220 g; 98%) after precipitation;
analytical sample was recrystallized from mixed solvent
(dichloromethane/hexane); Mp: 77e79 ꢀC; Rf 0.47 (10% CH3OH/
(CHCl3) n ;
: 2944, 2871, 1705, 1601, 1522, 1470, 1346, 1079, 856 cmꢁ1
HRMS (ESI): calculated for (C16H20N2O4Na): 327.1321, found:
327.1314.
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d: 7.33 (br s, 1H), 3.51 (dd,
Crystal data for C16H20N2O4 (minor isomer rac-3b): MW 304.34,
J1¼9.5 Hz, J2¼2.6 Hz, 1H), 3.25e3.19 (m, 1H), 3.14 (d, J¼4.0 Hz, 1H),
2.85 (dd, J1¼7.0, J2¼16.2 Hz, 1H), 2.66 (s, 3H), 2.54 (s, 1H), 2.42 (d,
J¼16.2 Hz, 1H), 2.12e2.00 (m, 2H), 1.60e1.50 (m, 2H), 1.59e1.41 (m,
1H),1.31e1.25 (m, 2H), 0.97 (d, J¼6.6 Hz, 3H), 0.94 (d, J¼6.6 Hz, 3H);
triclinic, space group P(ꢁ)1, a¼6.2540(1), b¼7.2689(2),
c¼17.5157(4) A,
a¼80.350(1),
b
¼89.170(1),
g
¼70.369(1)ꢀ,
ꢀ
3
V¼738.61(3) A , Z¼2, Dc¼1.368 mg mꢁ3, F(000)¼324, crystal di-
ꢀ
mensions 0.45ꢂ0.23ꢂ0.07 mm, radiation Cu K
a
(
l¼1.54178 A).
13C NMR (100 MHz, CDCl3)
d
: 210.9, 82.3, 61.3, 55.5, 54.1, 48.7, 39.7,
ꢀ
12667 reflections were collected in the range of ꢁ7ꢃhꢃ7, ꢁ8ꢃkꢃ8,
32.0, 22.8, 22.6, 19.4, 18.9, 16.7; IR (CHCl3) n: 2944, 2870, 1701, 1155,
ꢁ20ꢃlꢃ20; of these 2483 were independent, R(int)¼0.031. The
1125 cmꢁ1; MS (EI) m/z: 225 (1), 182 (30), 153 (22), 110 (65), 96
(100), 94 (29), 43 (67), 42 (63); HRMS (ESI): m/z calcd for
(C13H23NO2Na): 248.1626, found: 248.1638.
structure was solved and refined using 2290 reflections with I>2
s.
Final R and Rw were 0.0402 and 0.1079, respectively.
Enantiomerically enriched prepared with lithium amide 4:
ee¼93% [1H NMR in the presence of (R)-(ꢁ)-2,2,2-trifluoro-1-(9-
anthryl)ethanol] measured on the crude product.
4.3.4. 2-(Hydroxy(naphthalen-1-yl)methyl)-9-methyl-9-azabicyclo
[3.3.1]nonan-3-one (3c). Yield (0.155 g; 50%) after precipitation;
analytical sample was recrystallized from mixed solvent
(dichloromethane/hexane); mp: 125e128 ꢀC; Rf 0.46 (10% CH3OH/
½
a 2D0
ꢄ
þ118.3 (c 1.0, CHCl3), Mp 111e113 ꢀC, after recrystallization
from heptane.
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d: 7.90e7.86 (m, 2H), 7.78 (d,
J¼8.2 Hz, 1H), 7.62 (d, J¼7.2 Hz, 1H), 7.50e7.47 (m, 3H), 6.05 (d,
J¼2.8 Hz, 1H), 3.53e3.50 (m, 1H), 3.40e3.30 (m, 1H), 3.05 (dd,
J1¼7.0 Hz, J2¼16.2 Hz), 2.84e2.80 (m, 1H), 2.77 (s, 1H), 2.44 (dd,
J1¼1.2 Hz, J2¼16.2 Hz), 2.20e2.10 (m, 2H), 1.60e1.50 (m, 2H),
4.3.8. 2-((4-Bromophenyl)(hydroxy)methyl)-9-methyl-9-azabicyclo
[3.3.1]nonan-3-one (3g). Yield (0.320 g; 94%) after precipitation;
analytical sample was recrystallized from mixed solvent (dichloro-
methane/hexane); Mp: 132e134 ꢀC; Rf 0.63 (10% CH3OH/CH2Cl2); 1H
1.40e1.30 (m, 2H); 13C NMR (100 MHz, CDCl3)
d: 208.5, 136.9, 133.6,
NMR (400 MHz, CDCl3)
d
: 7.63 (br s,1H), 7.43 (d, J¼8.4 Hz,1H), 7.15 (d,
129.9, 129.2, 127.9, 125.9, 125.3, 125.1, 123.1, 121.9, 74.2, 60.7, 59.6,
J¼8.4 Hz,1H), 5.20 (d, J¼3.3 Hz,1H), 3.36 (d, J¼4.1 Hz,1H), 3.30e3.28
(m, 1H), 2.88 (dd, J1¼16.3 Hz, J2¼7.0 Hz, 1H), 2.73 (s, 3H), 2.52 (d,
J¼3.3 Hz, 1H), 2.42 (d, J¼16.3 Hz, 1H), 2.18e2.05 (m, 2H), 1.60e1.45
54.2, 48.5, 39.9, 22.7, 22.6, 16.6; IR (CHCl3) n: 3063, 2945, 2820,
1704, 1512, 1128 cmꢁ1; HRMS (ESI): m/z calcd for (C20H23NO2Na):
332,1626, found: 332.1640.
(m, 2H),1.35e1.25 (m, 2H); 13C NMR (100 MHz, CDCl3)
d: 208.6,140.7,
Enantiomerically enriched prepared with lithium amide 4:
ee¼90% [1H NMR in the presence of (R)-(ꢁ)-2,2,2-trifluoro-1-(9-
anthryl)ethanol] measured on the crude product.
131.2, 127.3, 121.1, 77.3, 60.8, 60.7, 54.2, 48.6, 39.9, 22.6, 22.5, 16.6; IR
(CHCl3)
n
: 2945, 1704, 1228, 1127, 1072 cmꢁ1; HRMS (ESI): m/z calcd
for (C16H20NO2BrNa): 360.0575, found: 360.0565.
½
a 2D0
ꢄ
ꢁ64.1 (c 1.0, CHCl3), Mp 141e144 ꢀC after recrystallization
Enantiomericallyenriched(þ)-3g prepared with lithium amide 7:
ee¼89% [1H NMR in the presence of (R)-(ꢁ)-2,2,2-trifluoro-1-(9-
anthryl)ethanol] measured on the crude product.
from hexane.
4.3.5. 2-(1-Hydroxyethyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one
(exo,anti-3d). Yield (0.183 g; 93%) after precipitation; analytical
sample was recrystallized from mixed solvent (dichloromethane/
hexane); Mp: 109e111 ꢀC; Rf 0.47 (10% CH3OH/CH2Cl2); 1H NMR
½
a 2D0
ꢄ
þ7.1 (c 1.0, CHCl3), Mp 135e137 ꢀC, after recrystallization
from ethyl acetate.
Crystal data for C16H20BrNO2 (þ)-3g: MW 338.24, orthorhombic,
ꢀ
space group P212121, a¼12.2345(2), b¼12.8613(2), c¼18.9881(4) A,
3
V¼2987.81(9) A , Z¼8, Dc¼1.504 mg mꢁ3, F(000)¼1392, crystal
ꢀ
(400 MHz, CDCl3)
d
: 6.80 (br s, 1H), 4.22e4.16 (dq, J1¼6.3 Hz,
J2¼2.6 Hz, 1H), 3.25e3.20 (m, 1H), 3.18 (d, J¼4.2 Hz, 1H), 2.83 (dd,
J1¼16.4 Hz, J2¼7 Hz, 1H), 2.66 (s, 3H), 2.41 (d, J¼16.4 Hz, 1H), 2.19 (s,
1H), 2.16e2.00 (m, 2H), 1.60e1.52 (m, 2H), 1.30e1.25 (m, 2H), 1.09
dimension 0.57ꢂ0.56ꢂ0.49 mm, T¼150(2) K; radiation Cu K
a
ꢀ
(l
¼01.54178 A). 26326 reflections were collected in the range of
ꢁ14ꢃhꢃ15, ꢁ14ꢃkꢃ15, ꢁ21ꢃlꢃ22; of these 5524 were in-
dependent, R(int)¼0.062. The structure was solved and refined
(d, J¼6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
: 210.5, 71.8, 61.2,
: 2980, 2943,
59.5, 54.0, 48.5, 39.8, 22.6, 22.5, 20.8, 16.7; IR (CHCl3)
n
using 5488 reflections with I>2s. Final R and Rw were 0.0349 and
1698, 1156, 1127 cmꢁ1; MS (EI) m/z: 197 (2), 110 (87), 96 (100), 94
(30), 57 (21), 43 (23), 42 (87), 41 (27); HRMS (ESI): m/z calcd for
(C11H19NO2Na): 220.1313, found: 220.1320.
0.0875, respectively. Absolute structure (Flack) parameter was
0.074(14) for 2340 measured Friedel pairs.
Enantiomerically enriched prepared with lithium amide 4:
ee¼81% [1H NMR in the presence of (R)-(ꢁ)-2,2,2-trifluoro-1-(9-
anthryl)ethanol] measured on the crude product.
Acknowledgements
The work was supported by the University of Bialystok (BST-
125) and Ministry of Science and Higher Education (grant No. N
N204 546939). We also thank Dr. L. Siergiejczyk for assistance in
recording NMR spectra.
½
a 2D0
ꢄ
þ49.4 (c 1.0, CHCl3), Mp 112e114 ꢀC after recrystallization
from heptane.
4.3.6. 2-(1-Hydroxyhexyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one
(exo,anti-3e). Yield (0.152 g; 60%); Rf 0.50 (10% CH3OH/CH2Cl2); 1H
NMR (400 MHz, CDCl3)
d: 7.04 (br s, 1H), 4.02e3.97 (m, 1H),
References and notes
3.25e3.21 (m, 1H), 3.19 (d, J¼4.0 Hz, 1H), 2.85 (dd, J1¼7.0 Hz,
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2.10e2.02 (m, 2H),1.60e1.52 (m, 2H),1.45e1.22 (m,10H), 0.92e0.83
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