Approaches to the enantioselective synthesis of ferrugine and its analogues

Article abstract of DOI:10.1016/j.tet.2012.07.061

A four-step synthetic route, to ferrugine (2α-benzoyltropane), its methyl analogue (2-acetyltropane) and their N-benzyl analogues is reported. The reaction sequence uses tropinone or N-benzylnortropinone aldols as key intermediates. Reduction of aldol der

Full text of DOI:10.1016/j.tet.2012.07.061

Tetrahedron 68 (2012) 8236e8244
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journal homepage: www.elsevier.com/locate/tet
Approaches to the enantioselective synthesis of ferrugine and its analogues
,
a
a
b
Ryszard Laznya , Michal Sienkiewicz , Tomasz Olenski , 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, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A four-step synthetic route, to ferrugine (2a-benzoyltropane), its methyl analogue (2-acetyltropane) and
Received 30 April 2012
Received in revised form 22 June 2012
Accepted 17 July 2012
their N-benzyl analogues is reported. The reaction sequence uses tropinone or N-benzylnortropinone
aldols as key intermediates. Reduction of aldol derived N-tosylhydrazones and oxidation of the side chain
hydroxyl group followed by spontaneous diastereomer equilibration provides the final products. Relative
configuration of the exo,anti N-methyl and N-benzyl aldols was retained during N-tosylhydrazone for-
mation. The relative stereochemistry of N-tosylhydrazones was assigned by single crystal diffraction. The
final products, ferrugine and its methyl analogue, were synthesized in enantiomerically pure form via
asymmetric deprotonation of tropinone using chiral lithium amide/lithium chloride aggregate prepared
in situ from (S,S)-N,N-bis(1-phenylethyl)amine hydrochloride.
Available online 22 July 2012
Keywords:
Aldol reaction
Aldol carbonyl deoxygenation
Enantioselective deprotonation
Tropinone
Ó 2012 Elsevier Ltd. All rights reserved.
N-Benzylnortropinone
Ferrugine
1. Introduction
Unlike ferruginine, which has been synthesized by several
approaches4e9 ferrugine has been accessed synthetically only in
Ferrugine is a tropane alkaloid isolated from the extracts of the
Australian arboreal species Darlingiana ferruginea.1 Other tropane
alkaloids, many of which are known for their potent biological
activity2 include cocaine, atropine and baogonteng A. Tropanes like
ferrugine (1, Fig. 1) and closely related, ferruginine (2) are nicotinic
receptor antagonists, potentially useful in the treatment of
Alzheimer’s disease.3
two ways: (i) by Bick et al.10 via anhydroecgonine obtained from
cocaine, (ii) by Grainger et al. via thermal elimination of dieth-
yldithiocarbamate as the key reaction.11 Bick’s synthesis relied on
the chiral pool approach, employing (ꢀ)-cocaine (6) as starting
material to get the enantiomerically pure key intermediate anhy-
droecgonine (5),12,13 and its ester hydrogenation of which followed
by reaction with diphenylcadmium gave (ꢀ)-ent-ferrugine. The
synthesis being not very effective nonetheless provided confirma-
tion of structure and absolute configuration of natural (þ)-ferru-
gine. The chiral pool approach using cocaine can give the unnatural
enantiomer, (ꢀ)-ent-ferrugine only (Scheme 1). The more recent
route by Grainger et al., leads to racemic ferrugine, via a sequence of
nine synthetic transformations,11 which cannot be easily carried
out in an asymmetric fashion. In principle, combination of the Bick
route with the known preparation of enantiomerically enriched
anhydroecgonine methyl ester (4, R¼Me) obtained via enantiose-
lective deprotonation of tropinone14e17 may constitute an enan-
tioselective approach giving either enantiomeric form of ferrugine
(Scheme 1).
O
O
Me
Ph
N
N
Me
Me
2
(+)-ferrugine (1)
(+)-ferruginine ( )
Fig. 1. Structures of natural ferrugine and ferruginine.
N-Benzyl analogue of ferrugine 10 or 2-acetyl N-benzylnor-
tropane could be formally synthesized enantioselectively using
a combination of Node’s18,19 enzymatic (PLE catalyzed) deal-
koxycarbonylation of dicarboxylates 7 combined with the Bick
route (Scheme 2). Any method used for synthesis of ferruginine (2)4
* Corresponding author. Tel.: þ48 85 745 7834; fax: þ48 85 747 0113; e-mail
address: lazny@uwb.edu.pl (R. Lazny).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.061

R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
8237
t-Bu
NLi
O
OLi
O
N
OLi
N
3
Ph
2
lithium amide
4
8
N
3
3
ent
-
lithium amide
N
N
1
or
5
ref. 14
ref. 14
Me6
Me
Me
7
Me
tropinone
tropinone
2 steps
ref. 14
OCOPh
N
O
Bick's
MeOOC
HCl aq
ref. 13
route
HOOC
ROOC
dry HCl
Ph
5 steps
ROH
N
N
N
ref. 12
ref. 10
Me
HCl salt of
Me
Me
Me
natural cocaine (6)
(-)-ent-ferrugine
4
anhydroecgonine (5)
1
(
ent- )
or its enatiomer using
enatiomeric reagent ent-3
Scheme 1. Formal enantiselective synthesis of ferrugine based on Bick’s approach and asymmetric deprotonation of tropinone.
(e.g., synthesis by Aggarwal,5 Husson,6 Rapaport,7 or Rigby8) could
in principle also be adopted by adding alkene hydrogenation for
synthesis of acetyl analogous of ferrugine. However, all such ap-
proaches would be excessively lengthy and would give minimal
yield of the target molecule. In a preliminary communication we
have demonstrated viability of a short route to either enantiomer of
ferrugine via enantioselective aldol reaction.20 Herein we wish to
report our full study on possible approaches to the synthesis of
ferrugine and its N-benzyl and acetyl analogues via a short syn-
thetic sequence.
of tropinone at the C-2 position. The reaction turned out to be most
effective with benzoyl cyanide as acyl donor (Scheme 3). Using
benzoyl chloride gave besides 12, several other products with
predominance of an enone formed by a ring opening reaction
known with chloroformates.26
1. LDA
N
N
Me
2. PhCOCN
Me
COPh
X
X
as its enol form
O
N
O
N
Tropinone, X = O
ROOC
ROOC
COOR
11
, X = NNMe2
PLE
12
(67%), X = O
13 (63%), X = NNMe2
ref. 18,19
Bn
8
Bn
7
diester
R = Bn or Et
N
Me
COPh
O
Bick's
route
ROOC
Ph
( )-ferrugine
5 steps
N
N
Scheme 3. Approaches to ferrugine via direct C-acylation of tropane scaffold.
Bn
Bn
9
analogue of ferrugine
10
The actual challenge was however, the selective removal of
the C-3 carbonyl in the resulting 1,3-diketone 12. Disappointingly
no method for regioselective conversion of the cyclic ketone
carbonyl into a leaving group could be found. Efforts to use
synthetic ketone equivalents: e.g., use of tropinone N,N-dime-
thylhydrazone (11) differentiated the two carbonyls effectively.
Masking one of the carbonyls gave opportunity for functional
group manipulation leading to the desired removal of the C-3
carbonyl. Nonetheless the attempts to reduce and eliminate the
masked carbonyl in 13 (side chain protection, reduction to amine
or hydrazine, N-acylation, followed by elimination of formed
amide or hydrazide) were fruitless. Therefore we turned our at-
tention to deoxygenation of tropinone aldols in hope of using the
Scheme 2. Formal enantiselective synthesis of ferrugine based on Bick’s approach and
enzymatic (PLE) dealkoxycarbonylation.
2. Results and discussion
The asymmetric deprotonation of Cs symmetrical molecules,21,22
e.g., tropinone is a powerful, proven, methodology for the synthesis
of enantiomerically pure compounds including tropane de-
rivatives.14,23 Because deprotonation followed by acylation is the
simplest method for stereoselective introducing of acyl group on
tropane scaffold24,25 we have turned our attention to benzoylation

8238
R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
known enantioselective aldol reactions as the method for in-
troduction of the C-2 side chain in ferrugine and in its analogues.
Tropinone and N-benzylnortropinone aldols could be prepared
by known and adopted procedures in both racemic and optically
pure forms. The racemic tropinone aldol 14a and the unknown
analogue 14b as well as their N-benzyl counterparts 14c and 14d
were prepared in nearly diastereomerically pure forms (ꢁ95% of
the exo,anti diastereoisomer; Scheme 4). The relative stereo-
chemistry of the N-benzyl aldols 14c,d was inferred from the
NMR data to be exo,anti in analogy to the known aldol 14a. The
exo,anti configuration in 14c was later also confirmed by X-ray
structure analysis.27 Based on our experience, reduction of
tosylhydrazones was judged to be the most suitable method for
removal of the carbonyl group in the aldols. In our plan the final
(ethanol) gave hydrazones ready for the next step. Hydrazones
15a,b were obtained in good yields 82% and 65% (Scheme 4).
Although the relative stereochemistry of the tosylhydrazones
formed should not affect the overall outcome of the planned
synthetic sequence (Scheme 4), because of removal of one ster-
eocenter and configurational lability of the C-2 stereocenter of
the final products under basic conditions (presence of amine in
the molecule itself), the question whether the relative configu-
ration remained unchanged in the tosylhydrazones formed was
intriguing. As no NMR data for this type of compound was
available the only reliable method at hand was single crystal X-
ray diffraction. Crystal structures of two representative tosylhy-
drazones of tropinone (15a) and N-benzylnortropinone (15c) al-
dols are shown in Figs. 2 and 3. As can be seen, the hydrazones
H
H
HO
R2
H
HO
R2
H
TsNHNH2
DIBAL
1. LDA, THF
2. R2CHO
N
N
R1
R1
Ti(OiPr)4
CH2Cl2
N
R1
EtOH
O
2
NNHTs
2
O
1
tropinone: R1 = Me
N-benzyl
14a
15a
1
-
-
R = Me, R = Ph (91%)
R = Me, R = Ph (82%)
1
2
15b R1 = Me, R2 = Me (65%)
15c R1 = Bn, R2 = Ph (93%)
15d R1 = Bn, R2 = Me (91 %)
14b
R = Me, R = Me (87%)
nortropinone: R1 = Bn
-14c R1 = Bn, R2 = Ph (75%)
-14d R1 = Bn, R2 = Me (50 %)
H
R2
H
O
R2
H
HO
DMP, py
CH2Cl2
H
N
N
R1
N
R1
R1
O
R2
-16a R1 = Me, R2 = Ph (83%)
-16b R1 = Me, R2 = Me (80%)
-16c R1 = Bn, R2 = Ph (21%)
-1 R1 = Me, R2 = Ph (56%), endo only
-17b R1 = Me, R2 = Me (53%), endo/exo 6:1
-17d R1 = Bn, R2 = Me (8 %), endo/exo 3:1
1
2
16d
-
R = Bn, R = Me (30 %)
Scheme 4. Synthesis of racemic ferrugine and its N-benzyl and C-2 acetyl analogues.
transformationdside chain hydroxyl oxidationdwas to remove
the side chain stereocenter making the strategy insensitive to
aldol isomerization. Consequently we could proceed with the
deoxygenation of the carbonyl group even if the tosylhydrazone
intermediates were obtained as diastereomeric mixtures. This
must have been taken into account because of the known pro-
pensity of tropinone aldols to isomerization and, the recently
observed, higher stability of the exo,syn over the exo,anti iso-
mers.28 Effective transformation of such aldols to hydrazones
was somewhat challenging. Unfortunately reactivity of the car-
bonyl in the aldols was apparently sterically hindered by the exo
side chain and the bicyclic tropane skeleton. In addition reactions
of such aldols containing amine functionality are often compli-
cated by easy retroaldolization, dehydration or isomerization.
Formation of tosylhydrazones was found satisfactory only if
promoted by titanium(IV) isopropoxide, a reagent successfully
used for the preparation of imines from hindered ketones.29
Despite good conversion (>80% by NMR) the tosylhydrazone
products were hard to isolate in good yields (<25%). Optimiza-
tion of the reaction medium (abs EtOH) and workup (removal of
copious amounts of titanium hydroxides) allowed for isolation of
the hydrazones 15 in satisfactory purities as single di-
astereomers. Chromatographic purification or crystallization
Fig. 2. X-ray structure of N-tosylhydrazone of exo-2-(10-hydroxybenzyl)tropane (15a).
Geometry of intramolecular H-bonds: O1eH1O 0.93(2), O1/N1 2.760(2), H1O/N1
1.90(2) A, O1eH1O/N1 154(2)ꢂ and C(14)eH(14) 0ꢂ.88(3), C(14)/N(2) 3.169(3),
ꢀ
ꢀ
H(14)/N(2) 2.52(3) A, angle C(14)eH(14)/N(2) 131(2) . Displacement ellipsoids are
drawn at 30% probability level, atoms numbering arbitrary.

R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
8239
same procedure in 53% yield but as a mixture of two isomers. In
this case the acetyl group preference of the endo over the exo
configuration was much less definite and was inferred from NMR
spectra to be ca. 6:1. This agreed with observations by Grainger.11
Disappointingly oxidation of the N-benzyl analogues 16c,d fol-
lowed by chromatographic isolation gave the desired product
17d in 8% yield (Scheme 4). The ratio of endo/exo isomers found
by NMR was ca. 3:1 (64:36 by GCeMS). The product of oxidation
of 16c was identified by GCeMS in chromatographically purified
fraction but could not be isolated in pure form. Explanation of
encountered problems with the N-benzyl analogues and possible
solutions calls for further studies.
Because yields of the two last steps in the syntheses of the N-
benzyl derivatives remained below our expectations we con-
strained applications of the enantioselective variant to the N-
methyl derivatives (Scheme 5). Following the literature pro-
cedure,14 the aldol product (þ)-14a was prepared in very good yield
and ee using (S,S)-N,N-bis(1-phenylethyl)amine ((S,S)-10) hydro-
chloride and 2 equiv of n-butyllithium. Adopting the procedure for
reaction with acetaldehyde gave the aldol (þ)-14b admixed with its
diastereomer. Crystallization of crude aldols gave diastereomeri-
cally pure products (þ)-14a and (þ)-14b with 99% ee, and in 80%
and 65% yields. The optically pure (ee ꢁ99%) tosylhydrazones
(þ)-15a and (þ)-15b were prepared in 55% and 60% yields, re-
spectively. Following step gave the chiral alcohols (þ)-16a in 74%
yield (ee ꢁ99%) and (þ)-16b in 70% yield (ee ꢁ90%). Finally, oxi-
dation concomitant with spontaneous exo/endo isomerization
provided (þ)-ferrugine ((þ)-1) in 56% yield as well as its acetyl
Fig. 3. X-ray structure of N-tosylhydrazone of exo-2-(10-hydroxybenzyl)-N-benzyl-
nortropinone (15c). Geometry of intramolecular H-bond: O1eH1O 1.07(3), O1/N1
2.628(2), H1O/N1 1.62(3) A, angle O1eH1O/N1 154(3) . Displacement ellipsoids are
ꢂ
ꢀ
drawn at 30% probability level, atoms numbering arbitrary.
retained the relative configuration of the exo,anti aldols. Their
molecular structure is dominated by intramolecular hydrogen
bonds between side chain hydroxyl and the ring nitrogen atom,
which exist even if other strong acceptors are present (tosyl
oxygens, hydrazone moiety). In compound 15a another relatively
strong intramolecular H-bond is observed between C14 proton
and N2 nitrogen of the hydrazone group of geometry shown in
Fig. 2. Hydrazone proton in compound 15c is involved in in-
termolecular hydrogen bond of geometry N3eH3N 0.95(2),
N3/O1 [0.5ꢀx, yꢀ0.5, 0.5ꢀz] 2.764(2), H3N/O1 1.83(2),
N3eH3N/O1 167(2).
The optimal tosylhydrazone removal method, found for 15a,
was reduction with DIBAL-H in dichloromethane.30 Other re-
agents, e.g.,: NaBH4 in a mixture of acetic acid with MeOH, NaBH4
in abs ethanol,31 NaBH4 in DMF, and LAH,32 gave inferior results
(0e55% yield). It appeared that success of the DIBAL-H reduction
depended on purity of the tosylhydrazone substrates. When
crystallized or carefully chromatographed and dry substrates
were used the reduction gave good yields (80e83%) of the N-
methyl derivatives 16a,b. However, the N-benzyl products 16c,d
were obtained in markedly worse yields (21e30%). At this stage
of the synthesis the N-benzyl analogues began to cause prob-
lems, which could not be overcome entirely. In our hands, the
yields for the N-benzyl products in the reduction step and the
following oxidation step (vide infra) remained evidently lower
than for the N-methyl derivatives (Scheme 4). Oxidation of the
side chain hydroxyl was the last step. The presence of the tertiary
amine in the target molecule narrows the choice of potential
oxidants. Use of the classic Swern oxidation, or its modifications
(SO3$Py), gave disappointing results. Treatment of 16a with
DesseMartin periodinane33,34 under typical conditions (dry
DCM, pyridine, rt) unfailingly provided the product of oxidation
in 56% yield (after meticulous purification by PTLC). Gratifyingly
NMR data of the product fully agreed with literature data
reported for ferrugine 1 isolated from a plant material.1,10,11 We
envisaged that the presence of the carbonyl in the side chain
analogue 17b as a mixture of exo/endo isomers (2a-acetyltropane/
2b
-acetyltropane, ca. 85:15). Enantiomeric excess measured by 1H
O
N
O
overall
four steps
R1
N
( )-17a, 34%
( )-17b, 25%
Me
Tropinone
Me
( )-1, R1 = Ph (ee 99%)
1
17b
( )-
, R = Me (ee 90%)
Me Me
1.
Ph
N
Li
Ph
10
DMP
Li-(S,S)-
2. R1CHO
OH
H
R1
N
OH
H
O
N
Me
R1
1
16a
-
-
, R = Ph (ee 99%)
, R = Me (ee 90%)
1
16b
Me
DIBAL
-14a, R1 = Ph (ee 99%)
-14b, R1 = Me (ee 99%)
OH
TsNHN
N
H
R1
would render the hydrogen at the C-2 (
a to ketone carbonyl)
TsNHNH2,
Ti(OiPr)4
sufficiently acidic to enolize in the presence of amine and
spontaneously equilibrate the mixture of possible exo and endo
isomers of the oxidation product 1 (Scheme 4). Inspection of
NMR spectra of the oxidation product indicated the presence of
virtually one isomer (endo) as described for ferrugine. Clearly for
2-benzoyl tropane (1) the thermodynamic equilibrium, as was
expected, is strongly shifted toward the endo form. The acetyl
analogue of ferrugine (2-acetyltropane, 17b) was obtained by the
Me
1
15a
-
-
, R = Ph (ee 99%)
, R = Me (ee 99%)
1
15b
Scheme 5. Enantioselective synthesis of ferrugine and its acetyl analogue (absolute
configurations as shown).

8240
R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
NMR was ꢁ99% for (þ)-ferrugine and ꢁ90% for the major di-
astereomer of the acetyltropane 17b. The absolute configuration of
synthesized ferrugine was a result of propensity for selective re-
moval of one the enantiotopic protons in tropinone molecule by
enantiomeric form of the chiral amide used in the aldol reaction
step. The absolute configuration of ferrugine 1 agreed with known
sense of enantioselection for chiral amide Li-(S,S)-10 in reaction
with tropinone14 and with correlation of absolute configuration of
(ꢀ)-cocaine with ferrugine by Bick’s synthesis.10
4.2. General procedure for the preparation of benzoyl tro-
panes 12 and 13
A solution of n-buthyllithium in hexane (2.33 M, 1.2 equiv) was
added dropwise to a cooled (0 ꢂC) solution of diisopropylamine
(1.2 equiv) in THF (10 mL for 3.0 mmol of ketone or hydrazone). The
mixture was stirred for 30 min, then tropinone (at ꢀ78 ꢂC) or N,N-
dimethylhydrazone of tropinone (at 0 ꢂC) was added (1 equiv) in
THF (3 mL for 3.0 mmol of ketone or hydrazone). After stirring for
1e4 h at the same temperature, benzoyl cyanide (1.15 equiv) was
added at ꢀ78 ꢂC. After stirring for 15 min the reaction was
quenched with aq solution of K2CO3 (40%, 5 mL), warmed up to rt,
and extracted with DCM (3ꢃ15 mL). The crude extracts of 12 were
additionally washed with aq AgNO3 (5%, 2ꢃ10 mL) followed by aq
ammonia solution (10%, 5 mL). The combined extracts were dried
over MgSO4 and concentrated to give the crude product. Purifica-
tion by dry-column flash chromatography on silica gel (0e15%
MeOH/DCM) gave products as oils.
3. Conclusions
We showed that enantioselective deprotonation combined
with deoxygenation of the aldol carbonyl group can be an ex-
pedient strategy for synthesizing C-2 acyl tropanes. The same
simple, four-step, route depending on lithium amide bases used,
allows to prepare racemic form, or either enantiomer of the
acyltropane at will. The practicability of the approach was
demonstrated by the synthesis of natural ferrugine and its
methyl analogue (2-acetyltropane) with high enantiomeric pu-
rity (ꢁ90e99%) using convenient chiral amine hydrochloride as
the chiral reagent. However, limitations of this approach are
problems with reduction of tosylhydrazones and oxidation of
the side chain alcohols in case of the N-benzylnortropane de-
rivatives. Nonetheless, these problems may be overcome by fur-
ther study.
4.2.1. 2-Benzoyl-8-methyl-8-azabicyclo[3.2.1]octan-3-on (12) as
predominating enol form 2-benzoyl-8-methyl-8-azabicyclo[3.2.1]oct-
2-en-3-ol.24 Yield: 0.489 g, 67%; Rf¼0.65 (10% MeOH/DCM). 1H
NMR (CDCl3): enol form (ꢁ90%): 16.42 (br s, 1H), 7.62e7.41 (m, 5H),
3.85 (d, J¼5.7 Hz, 1H), 3.45 (t, J¼6.0 Hz, 1H), 2.93 (ddd, J1¼19.2 Hz,
J2¼5.5 Hz, J3¼1.9 Hz, 1H), 2.38e2.00 (m, 2H), 2.34 (s, 3H), 2.23 (d,
J¼19.2 Hz, 1H), 2.07e1.98 (m, 1H), 1.76e1.67 (m, 1H); 13C NMR
(CDCl3): 195.1, 181.2, 134.9, 130.4, 128.5, 128.1, 112.4, 59.4, 57.8, 40.1,
36.7, 33.7, 29.0.
4. Experimental section
4.1. General methods
4.2.2. 2-Benzoyl-3-(20,20-Dimethylhydrazono)-8-methyl-8-azabicyclo
[3.2.1]octane (13) as enol form. Yield: 0.539 g, 63%; Rf¼0.61 (20%
MeOH/DCM). 1H NMR (CDCl3): enol form (ꢁ98%) 12.06 (br s, 1H),
7.35e7.27 (m, 5H), 3.78 (d, J¼5.1 Hz, 1H), 3.45 (t, J¼5.6 Hz, 1H), 3.06
(dd, J1¼18.9 Hz, J2¼5.1 Hz, 1H), 2.55 (s, 6H), 2.50 (s, 1H), 2.35 (s, 3H),
2.15e2.25 (m, 2H), 1.99e1.90 (m, 1H), 1.62e1.55 (m, 1H); 13C NMR
(CDCl3): 191.7, 160.7, 141.3, 128.7, 128.0 (2C), 126.5 (2C), 102.6, 60.5,
57.9, 48.3 (2C), 36.6, 34.1, 32.1, 28.3; nmax (CHCl3): 2961, 2461, 1574,
1534, 1306 cmꢀ1. HRMS (EI): Mþ, found 285.1837, C17H23N3O re-
quires 285.1841.
Thin-layer chromatography (TLC) was performed on pre-coated
plates (Merck, silica gel 60, F254) unless indicted otherwise. The
spots were detected using UV light (254 nm), and phosphomolyb-
dic acid followed by charring. Infrared (IR) spectra of compounds
were recorded on a Nicolet Magna-IR 550 FTIR Series II Spec-
trometer (CHCl3). Only diagnostic peaks are reported (cmꢀ1).
Magnetic resonance spectra (1H NMR and 13C NMR) were recorded
on a Bruker AVANCE II 400 spectrometer in CDCl3 at ambient
temperature. Chemical shifts are reported in parts per million
downfield of tetramethylsilane. Specific rotation was measured
with Optical Activity AA-10R or Perkin Elmer 141 Automatic Po-
larimeter. Reagents were purchased from Aldrich. The chiral amine
10 is available commercially in both enantiomeric forms (e.g.,
Aldrich, (ꢀ)-bis[(S)-1-phenylethyl]amine). Tropinone and alde-
hydes were purified by standard techniques.35 N-benzylnor-
tropinone was prepared as described.36 All enantiomeric excesses
were measured by 1H NMR in the presence of (þ)-2,2,2-trifluoro-1-
(9-anthryl)ethanol (TFAE).
4.3. General procedure for the preparation of aldols
( )-14aed (LDA deprotonation of ketone)
A solution of n-buthyllithium in hexane (2.33 M, 1.2 equiv) was
added dropwise to a cooled (0 ꢂC) solution of diisopropylamine
(1.2 equiv) in THF (10e25 mL). The mixture was stirred for 30 min,
then cooled to ꢀ78 ꢂC and a solution of ketone (1 equiv) in THF
(5e10 mL) was added dropwise. After stirring for 2 h, aldehyde
(1.15 equiv) was added and the mixture was stirred for another
10e40 min. The reaction was quenched with NH4Claq (20 mL),
allowed to warm up to rt and extracted with DCM (3ꢃ30 mL). The
combined extracts were dried over MgSO4 and concentrated to give
the crude product. Precipitation or crystallization from mixed sol-
vent system hexane/dichloromethane gave the major aldol isomer
exo,anti as white solid.
Crystallographic data were collected with a Bruker-Nonius
Apex-X8 CCD-diffractometer with CuK
ꢀ
a
radiation (
l
¼01.54178 A).
The structures were solved by direct methods and refined using
SHELXS9737 and SHELXL9737 programs. All non-H atoms were re-
fined 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 both structures were lo-
cated from Dr maps and refined isotropically.
4.4. General procedure for preparation of enantiomerically
enriched aldols (D)-14a,b
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 873342 and 873341, respectively, for compounds 15a, and
15c. 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).
A solution of n-buthyllithium in hexane (2.33 M, 2.4 equiv) was
added dropwise to
a
cooled (0 ꢂC) solution of (R,R)-bis(1-
phenylethyl)amine hydrochloride (1.2 equiv) in THF (10 mL). The
mixture was stirred for 45 min, then cooled to ꢀ78 ꢂC and a solu-
tion of ketone (1 equiv) in THF (6 mL) was added dropwise. After
stirring for 2 h, aldehyde (1.15 equiv) was added and the mixture
was stirred for another 10e40 min. The reaction was quenched

R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
8241
with NH4Claq (20 mL), allowed to warm up to rt, and extracted with
DCM (3ꢃ30 mL). The combined extracts were dried over MgSO4
and concentrated to give the crude product and chiral amine
mixture. The product was taken up in small portion of warm
dichloromethane and the resulting solution was diluted slowly
with hexane to precipitate the solid product. The chiral amine
remained in supernatant and was saved for recovery.
benzylnortropinone (2.153 g, 10 mmol, 1 equiv) in THF (10 mL).
After 2 h, freshly distilled acetaldehyde (0.60 mL, 11.5 mmol,
1.15 equiv) in THF (1 mL) was added, and the mixture was stirred
for another 40 min. Then the reaction was worked up as described
in general procedure. Crystallization gave aldol 14d (1.290 g, 50%)
as a white crystals, mp ¼ 107e112 ꢂC. Rf¼0.8 (10% MeOH/DCM). 1H
NMR (200 MHz, CDCl3): 7.36e7.34 (m, 5H), 6.94 (br s, 1H), 4.05 (dq,
J1¼2.0 Hz, J2¼6.5 Hz, 1H), 3.64 (d, J¼3.2 Hz, 2H), 3.58e3.51 (m, 2H),
2.66 (ddd, J1¼3.8 Hz, J2¼5.0 Hz, J3¼16.0 Hz, 1H), 2.36e2.34 (m, 1H),
2.28e2.26 (m, 2H), 2.11 (d, J¼1.9 Hz, 1H), 1.70e1.60 (m, 2H), 1.09 (d,
J¼6.4 Hz, 3H). 13C NMR (50 MHz, CDCl3): 209.8, 137.5, 128.9, 128.7,
127.7, 70.4, 65.5, 62.9, 58.5, 56.9, 51.5, 26.8, 26.4, 20.8. IR (CHCl3):
3193 (eOH), 1708 (C]O) cmꢀ1; HRMS (EI): Mþ, found 259.1568,
C16H21NO2 requires 259.1572.
4.4.1. (þ)-(1S,2R,10S,5R)-2-(10-Hydroxybenzyl)-tropinone ((þ)-14a).24
To solution of chiral lithium amide (12 mmol) was added a solution
of tropinone (0.696 g, 5 mmol, 1 equiv) in THF (6 mL). After 2 h,
benzaldehyde (0.59 mL, 5.75 mmol, 1.15 equiv) was added, and the
mixture was stirred for another 10 min. Then the experiment was
performed as described in general procedure. Crystallization from
hexane/dichloromethane gave aldol 14a (0.981 g, 80%) as white
crystals, mp ¼ 129e131 ꢂC. 1H NMR (CDCl3): 7.70 (br s, 1H),
7.37e7.22 (m, 5H), 5.23 (d, J¼3.0 Hz, 1H), 3.65e3.56 (m, 1H),
3.54e3.44 (m, 1H), 2.86 (ddd, J¼2.0, 5.0, 15.5 Hz, 1H), 2.47 (s, 3H),
2.45e2.39 (m, 1H), 2.36 (t, J¼2.0 Hz, 1H), 2.33e2.12 (m, 2H),
4.5. General procedure for the preparation of tosylhy-
drazones 15aed
To a solution of titanium(IV) isopropoxide (1 equiv) in abs EtOH
(5e18 mL) was added p-toluenesulfonyl hydrazide (1 equiv) and
corresponding aldol 14aed (1 equiv). After stirring at rt for 120 h
was added NaClaq (5e10 mL). The mixture was filtrated through
pad of Celite and washed with DCM (4ꢃ10 mL). The aqueous layer
was extracted with DCM (3ꢃ25 mL). The combine extracts were
dried over MgSO4 and concentrated. Purification through dry-
column flash chromatography (0e20% MeOH/DCMþNH3) gave
the product.
1.73e1.46 (m, 2H); ee ꢁ99%; ½a D20
ꢄ
þ21 (c 1.2, MeOH), Ref.24 ½a D20
ꢄ
þ23 (c 0.0173, CHCl3), Ref.14 ½a D20
þ19.7 (c 1.2, MeOH).
ꢄ
4.4.2. (ꢅ)-exo,anti-2-(10-Hydroxyethyl)tropinone (14b). To solution
of LDA (36 mmol) was added a solution of tropinone (4.176 g,
30 mmol, 1 equiv) in THF (10 mL). After 2 h, freshly distilled acet-
aldehyde (2 mL, 35 mmol, 1.15 equiv) in THF (2 mL) was added, and
the mixture was stirred for another 40 min. Then the reaction was
worked up as described in general procedure. Crystallization gave
aldol 14b (4.765 g, 87%) as a white crystals, mp ¼ 99e104 ꢂC.
Rf¼0.78 (10% MeOH/DCM). 1H NMR (CDCl3): 7.13 (br s, 1H), 4.16 (dq,
J¼2.0, 6.5 Hz, 1H), 3.46e3.35 (m, 2H), 2.70 (ddd, J¼1.5, 5.0, 16.0 Hz,
1H), 2.39 (s, 3H), 2.35e2.03 (m, 4H), 1.68e1.43 (m, 2H), 1.08 (d,
J¼6.5 Hz, 3H); 13C NMR (CDCl3): 209.6, 70.7, 67.8, 62.9, 61.5, 51.5,
4.5.1. (ꢅ)-N0-Tosylhydrazone
exo-2-(10-hydroxybenzyl)tropane
a solution of titanium(IV) isopropoxide (2.94 mL,
(15a). To
10 mmol, 1 equiv) in EtOH (18 mL) was added p-toluenesulfonyl
hydrazide (1.563 g, 10 mmol, 1 equiv) and exo,anti-2-(10-hydrox-
ybenzyl)tropinone aldol 14a (2.454 g, 10 mmol, 1 equiv). Then the
reaction was carried out as described in general procedure to give
the product (3.412 g, 82%), mp 156e160 ꢂC. Rf¼0.6 (10% MeOH/
DCM). 1H NMR (CDCl3): 7.54e7.50 (m, 2H), 7.21e7.16 (m, 2H),
7.11e7.07 (m, 2H), 7.07e6.97 (m, 3H), 5.05 (d, J¼4.0 Hz, 1H),
3.39e3.34 (m, 1H), 3.33e3.28 (m, 1H), 2.59e2.52 (m, 1H), 2.45 (s,
3H), 2.44e2.39 (m, 2H), 2.30 (s, 3H), 2.14e1.97 (m, 2H), 1.62e1.53
(m, 1H), 1.45e1.36 (m, 1H); 13C NMR (CDCl3): 156.8, 143.5, 141.8,
135.2, 129.6, 127.7, 127.6, 126.7, 126.0, 77.3, 67.0, 60.8, 56.7, 40.8,
36.0, 26.3, 25.7, 21.6. nmax (KBr) 3500 (eOH),1599 (C]N),1165,1335
(SO2) cmꢀ1; m/z 152 (100), 106 (37), 105 (38), 95 (37), 94 (32), 91
(53), 82 (64), 77 (46%); HRMS (EI): MþþH, found 414.1857,
C22H28N3O3S requires 414.1852.
40.7, 26.4, 26.3, 21.0; nmax (CHCl3): 3150 (eOH), 1705 (C]O) cmꢀ1
.
m/z 183 (Mþ, 3), 110 (72), 96 (78), 83 (79), 82 (100), 81 (85), 55 (72),
42 (71), 40 (94); HRMS (EI): Mþ, found 183.2480, C10H17NO2 re-
quires 183.2475.
4.4.3. (þ)-(1S,2R,10R,5R)-2-(10-Hydroxyethyl)-tropinone ((þ)-14b).
To solution of chiral lithium amide (7.2 mmol) was added a solution
of tropinone (0.418 g, 3.0 mmol, 1 equiv) in THF (6 mL). After 2 h,
freshly distilled acetaldehyde (0.2 mL, 3.5 mmol, 1.15 equiv) in THF
(0.2 mL) was added, and the mixture was stirred for another
40 min. Then the experiment was performed as described in gen-
eral procedure. The crude product was obtained as a mixture of
diastereoisomers (0.544 g, 99%). Crystallization gave the major
isomer (0.365 g, 65%) as white crystals, mp 102e105 ꢂC. ee ꢁ99%;
Crystal data for (rac)-15a: monoclinic, space group P21/n;
a¼9.8531(2), b¼10.3665(2), c¼21.3902(4) A,
b
¼102.183(1)ꢂ,
ꢀ
a 2D0
ꢄ
þ47 (c 1, MeOH).
V¼2135.64(7) A , Z¼4, Dcalcd¼1.286 mg mꢀ3, F(000)¼880, crystal
3
ꢀ
½
ꢀ
dimensions 0.29ꢃ0.27ꢃ0.07 mm, radiation CuK
a
(
l
¼1.54178 A).
4.4.4. (ꢅ)-exo,anti-2-(10-Hydroxybenzyl)-N-benzylnortropinone
(14c). To solution of LDA (7.2 mmol) was added a solution of N-
benzylnortropinone (1.292 g, 6 mmol, 1 equiv) in THF (7 mL). After
2 h, benzaldehyde (0.70 mL, 6.9 mmol, 1.15 equiv) was added, and
the mixture was stirred for another 10 min. Then the reaction was
worked up as described in general procedure. Crystallization gave
aldol 14c (1.454 g, 75%) as white crystals, mp ¼ 99e104 ꢂC. Rf¼0.77
(10% MeOH/DCM). 1H NMR (CDCl3): 7.43e7.21 (m, 10H), 5.11 (d,
J¼3 Hz, 1H), 3.73e3.65 (m, 3H), 3.58e3.57 (m, 1H), 2.82 (ddd,
J1¼1.5 Hz, J2¼4.5 Hz, J3¼6 Hz,1H), 2.45e2.44 (m,1H), 2.36e2.32 (m,
3H), 1.70e1.66 (m, 2H); 13C NMR (CDCl3): 208.3, 141.6, 137.6, 129.0,
128.7, 128.0, 127.7, 127.2, 125.5, 76.4, 65.1, 64.5, 58.9, 57.0, 51.5, 26.8,
26.3; nmax (CHCl3): 3173 (eOH), 1712 (C]O) cmꢀ1, HRMS (EI): Mþ,
found 321,1722, C21H23NO2 requires 321.1729.
16,168 reflections were collected in the range of ꢀ11ꢆhꢆ11, ꢀ11
ꢆkꢆ12, ꢀ24ꢆlꢆ25; of these 3734 were independent, R(int)¼
0.0398. The structure was solved and refined using 2999 reflections
with I>2s. Final R and Rw were 0.0421and 0.1160, respectively.
4.5.2. (þ)-N0-Tosylhydrazone of (þ)-(1S,2R,10S,5R)-2-(10-hydrox-
ybenzyl)tropinone ((þ)-15a). To a solution of titanium(IV) iso-
propoxide (0.77 mL, 2.6 mmol, 1 equiv) in EtOH (11 mL) was added
p-toluenesulfonyl hydrazide (0.406 g, 2.6 mmol, 1 equiv) and
(þ)-14a (0.648 g, 2.6 mmol, 1 equiv). Then the reaction was carried
out as described in general procedure to give the product (0.591 g,
55%) as an oil ee ꢁ99%; ½a D20
þ78 (c 1, MeOH).
ꢄ
4.5.3. (ꢅ)-N0-Tosylhydrazone of exo-2-(10-hydroxyethyl)tropinone
(15b). To a solution of titanium(IV) (0.47 mL, 1.6 mmol, 1 equiv) in
EtOH (5 mL) was added p-toluenesulfonyl hydrazide (0.250 g,
1.6 mmol, 1 equiv) and 14b (0.290 g, 1.6 mmol, 1 equiv). Then the
4.4.5. (ꢅ)-exo,anti-2-(10-Hydroxyethyl)-N-benzylnortropinone
(14d). To solution of LDA (12 mmol) was added a solution of N-

8242
R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
reaction was carried out as described in general procedure to give
the product (6.934 g, 62%), mp 158e161 ꢂC. Rf¼0.5 (10% MeOH/
DCM). 1H NMR (CDCl3): 7.90e7.23 (m, 2H), 7.39e7.20 (m, 2H),
4.10e3.93 (m, 1H), 3.40e3.18 (m, 2H), 2.62e2.47 (m, 1H), 2.39 (s,
3H), 2.27 (s, 3H), 2.25e2.19 (m, 1H), 2.13e1.98 (m, 3H), 1.67e1.30
(m, 3H), 0.56 (d, J¼6.5 Hz, 2H); 13C NMR (CDCl3): 154.5, 143.8, 135.1,
129.3, 128.2, 71.7, 68.0, 60.5, 54.4, 40.6, 36.3, 26.1, 25.5, 20.2, 19.1;
nmax (KBr) 3215 (eOH), 1600 (C]N), 1338, 1167 (SO2) cmꢀ1; m/z 351
(Mþ,1) 196 (59), 152 (63), 122 (42), 94 (45), 92 (52), 91 (87), 82
(100), 42 (50%); HRMS (EI): MþþH, found 352.1704, C17H26N3O3S
requires 352.1695.
for 24 h, another portion of DIBAL was added (1 M, 2e3 equiv).
After 72 h, the reaction was quenched with water (20 mL), allowed
to warm to rt and extracted with DCM (3ꢃ15 mL). The combined
extracts were dried over MgSO4 and concentrated.
4.6.1. (ꢅ)-exo-2-(10-Hydroxybenzyl)tropane (16a). To a solution of
15a (0.414 g, 1.00 mmol, 1 equiv) in DCM (20 mL), was added a so-
lution of DIBAL in hexane (1 M, 5.0 mL, 5.0 mmol, 5 equiv). Then the
reaction was carried out as described in general procedure to give
the crude product. Purification by dry-column flash chromatogra-
phy on silica gel (0e10% MeOH/DCMþNH3) gave colorless oil
(0.192 g, 83%). Rf¼0.4 (10% MeOH/DCM); 1H NMR (CDCl3):
7.42e7.16 (m, 5H), 5.23 (d, J¼2.5 Hz, 1H), 3.54e3.45 (m, 1H),
3.32e3.21 (m, 1H), 2.33 (s, 3H), 2.28e1.95 (m, 3H), 1.70e1.53 (m,
3H), 1.44e1.18 (m, 3H); 13C NMR (CDCl3): 144.2, 127.8, 126.4, 125.7,
78.2, 68.2, 62.2, 44.9, 41.1, 31.2, 26.4, 24.6, 14.3. nmax (KBr) 3670
(eOH) cmꢀ1; m/z 231 (Mþ, 12), 125 (21), 96 (64), 84 (51), 83 (33), 82
(100), 57 (46), 42 (38%); HRMS (EI): Mþ, found 231.1618, C15H21NO
requires 231.1623.
4.5.4. (þ)-N0-Tosylhydrazone of (þ)-(1S,2R,10R,5R)-2-(10-hydrox-
yethyl)tropinone ((þ)-15b). To a solution of titanium(IV) isoprop-
oxide (0.47 mL, 1.6 mmol, 1 equiv) in EtOH (5 mL) was added p-
toluenesulfonyl hydrazide (0.250 g, 1.6 mmol, 1 equiv) and (þ)-14b
(0.290 g, 1.6 mmol, 1 equiv). Then the reaction was carried out as
described in general procedure to give the product as an oil (7.512 g,
65%), ee ꢁ99%; ½a D20
þ61 (c 1, MeOH).
ꢄ
4.5.5. (ꢅ)-N0-Tosylhydrazone of exo-2-(10-hydroxybenzyl)-N-benzyl-
nortropinone (15c). To a solution of titanium(IV) isopropoxide
(0.79 mL, 2.65 mmol, 1 equiv) in EtOH (24 mL) was added p-tolue-
nesulfonyl hydrazide (0.494 g, 2.65 mmol, 1 equiv) and 14c (0.853 g,
2.65 mmol, 1 equiv). Then the reaction was carried out as described
in general procedure to give the product (1.131 g, 93%), mp
156e160 ꢂC. Rf¼0.86 (10% MeOH/DCM). 1H NMR (CDCl3): 7.37e7.34
(m, 4H), 7.33e7.27 (m, 5H), 7.19e7.00 (m, 5H), 4.92 (d, J¼4.0 Hz, 1H),
3.92e3.45 (m, 2H), 3.42e3.34 (m, 2H), 2.57e2.54 (m, 1H), 2.43e2.39
(m, 6H), 2.12e1.93 (m, 3H), 1.64e1.58 (m, 1H), 1.44e1.39 (m, 1H); 13C
NMR (CDCl3): 157.1, 143.4, 141.6, 137.9, 135.2, 129.5, 129.4, 128.9,
128.6, 128.5, 128.4, 127.9, 127.8, 127.6, 127.5, 127.2, 126.7, 126.0, 76.8,
64.7, 58.0, 57.1, 56.9, 36.1, 26.3, 26.2, 21.5; nmax (CHCl3) 3304 (eOH),
1600 (C]N), 1165, 1333 (SO2) cmꢀ1; HRMS (ESI): MþþNa, found
512.1973, C28H31N3O3SNa requires 512.1984.
4.6.2. (þ)-(1S,2R,10S,5S)-2-(10-Hydroxybenzyl)-tropane ((þ)-16a).
To a solution of (þ)-15a (0.530 g, 1.28 mmol, 1 equiv) in DCM
(24 mL), was added a solution of DIBAL in hexane (1 M, 6.5 mL,
6.5 mmol, 5 equiv). Then the experiment was performed as de-
scribed in general procedure. Purification by dry-column flash
chromatography (0e10% MeOH/DCMþNH3) gave a colorless oil
(0.220 g, 74%). ee ꢁ99%; ½a D20
þ35 (c 1, MeOH).
ꢄ
4.6.3. (ꢅ)-exo-2-(10-Hydroxyethyl)tropane (16b). To a solution of
15b (0.699 g, 2 mmol, 1 equiv) in DCM (15 mL), was added a solu-
tion of DIBAL in hexane (1 M, 12 mL, 12 mmol, 6 equiv). Then the
reaction was carried out as described in general procedure to give
the crude product. Purification by column chromatography on
neutral aluminum oxide (0e5% MeOH/DCM) gave colorless oil
(0.271 g, 80%). Rf¼0.24 (5% MeOH/DCMþNH3); 1H NMR (CDCl3):
4.16 (dd, J¼1.5, 6.5 Hz, 1H), 3.26e3.11 (m, 2H), 2.40e2.27 (m, 1H),
2.22 (s, 3H), 2.16e1.81 (m, 3H), 1.74e1.15 (m, 4H), 1.14 (d, J¼6.5 Hz,
3H); 13C NMR (CDCl3): 72.3, 68.5, 61.8, 44.0, 41.2, 31.6, 26.0, 24.6,
20.8, 14.0; nmax (KBr) 3670 (eOH) cmꢀ1; m/z 169 (Mþ, 25) 97 (17),
96 (88), 94 (16), 84 (23), 83 (28), 57 (49), 42 (40%); HRMS (EI): Mþ,
found 169.2643. C15H21NO requires 169.2640.
Crystal data for (rac)-15c: monoclinic, space group P21/c,
a¼24.6542(5), b¼5.8232(1), c¼17.1721(4) A,
b
¼91.3090(1)ꢂ,
ꢀ
V¼2464.69(9) A , Z¼4, Dcalcd¼1.319 mg mꢀ3, F(000)¼1040, crystal
3
ꢀ
ꢀ
dimensions 0.80ꢃ0.47ꢃ0.45 mm, radiation CuK
a
(l
¼1.54178 A).
26,658 reflections were collected in the range of ꢀ29ꢆhꢆ29, ꢀ5
ꢆkꢆ6, ꢀ19ꢆlꢆ20; of these 4363 were independent, R(int)¼0.0393.
The structure was solved and refined using 4035 reflections with
I>2
s
. Final R and Rw were 0.0361 and 0.0938, respectively.
4.6.4. (þ)-(1S,2R,10R,5S)-2-(10-Hydroxyethyl)-tropane ((þ)-16b). To
a solution of (þ)-15b (0.699 g, 2 mmol, 1 equiv) in DCM (15 mL),
was added a solution of DIBAL in hexane (1 M, 12 mL, 12 mmol,
6 equiv). Then the experiment was performed as described in
general procedure. Purification by column chromatography on
neutral aluminum oxide (0e5% MeOH/DCM) gave a colorless oil
4.5.6. (ꢅ)-N0-Tosylhydrazone of exo,anti-2-(10-hydroxyethyl)-N-ben-
zylnortropinone (15d). To a solution of titanium(IV) isopropoxide
(1.45 mL, 4.9 mmol) in EtOH (18 mL) was added p-toluenesulfonyl
hydrazide (0.912 g, 4.9 mmol) and 14d (1.271 g, 4.9 mmol). Then
the reaction was carried out as described in general procedure to
give the product (1.906 g, 91%), mp 149e155 ꢂC. Rf¼0.76 (10%
MeOH/DCM); 1H NMR (200 MHz, CDCl3): 7.79e7.77 (m, 2H),
7.29e7.22 (m, 7H), 3.89 (dq, J1¼6.0 Hz, J2¼12.5 Hz, 1H), 3.51 (s, 2H),
3.43e3.37 (m, 1H), 3.35e3.32 (m, 1H), 2.49e2.39 (m, 3H), 2.37 (s,
3H), 2.31e2.26 (m, 1H), 2.10e2.06 (m, 3H), 1.65e1.60 (m, 1H),
1.48e1.42 (m, 1H), 0.53 (d, J¼6.3 Hz, 3H); 13C NMR (50 MHz, CDCl3):
155.3, 143.8, 137.1, 135.0, 129.8, 129.4, 128.9, 128.6, 128.1, 128.0,
127.6, 71.6, 65.6, 57.7, 57.0, 54.6, 36.3, 26.4, 26.0, 21.5, 21.4, 19.9. IR
(CHCl3): 3216 (eOH), 1599 (C]N) 1336, 1166 (eSO2) cmꢀ1. HRMS
(ESI): MþþNa, found 450.1836, C23H29N3O3SNa requires 450.1830.
(0.240 g, 71%). ee ꢁ90%; ½a D20
þ48 (c 1, MeOH).
ꢄ
4.6.5. (ꢅ)-exo-2-(10-Hydroxybenzyl)-N-benzylnortropane (16c). To
a solution of 15c (1.903 g, 4.16 mmol, 1 equiv) in DCM (10 mL), was
added a solution of DIBAL in hexane (1 M, 25 mL, 25 mmol,
6 equiv). Then the experiment was performed as described in
general procedure. Purification by dry-column flash chromatogra-
phy on neutral aluminum oxide (0e50% AcOEt/hexane) gave yellow
oil (0.267 g, 21%). Rf¼0.77 (10% MeOH/DCM); 1H NMR (CDCl3):
7.43e7.39 (m, 10H), 5.14 (d, 1H), 3.60e3.49 (m, 4H), 2.30e2.09 (m,
2H), 1.69e1.62 (m, 2H), 1.38e1.33 (m, 2H), 0.99e0.97 (m, 3H); 13C
NMR (CDCl3): 144.0, 138.1, 128.9, 128.4, 127.7, 127.2, 126.2, 125.6,
72.0, 66.4, 59.2, 57.7, 45.1, 31.6, 27.0, 24.8, 14.8. nmax (CHCl3) 3387
(eOH) cmꢀ1; HRMS (EI): Mþ, found 307.1947, C21H25NO requires
307.1936.
4.6. General procedure for the reductive removal of tosylhy-
drazone group
To a cooled solution (0 ꢂC) of corresponding tosylhydrazone
15aed (1 equiv) in dry DCM (10e24 mL), was added a solution of
diisobutylaluminum hydride in hexane (1 M, 3 equiv). After stirring
4.6.6. (ꢅ)-exo-2-(10-Hydroxyethyl)-N-benzylnortropane (16d). To
a solution of 15d (1.864 g, 4.36 mmol, 1 equiv) in DCM (18 mL), was

R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
8243
added a solution of DIBAL in hexane (1 M, 26.16 mL, 26.16 mmol,
(0.059 g, 59%) mixture of two diastereoisomers endo/exo (
a/
b) in ca.
6 equiv). Then the reaction was carried out as described in general
procedure to give the crude product. Purification by dry-column
flash chromatography on neutral aluminum oxide (0e10% MeOH/
DCM) gave yellow oil (0.321 g, 30%). Rf¼0.47 (10% MeOH/DCM); 1H
NMR (CDCl3): 7.33e7.32 (m, 5H), 4.10 (dq, J1¼1.1 Hz, J2¼6.3 Hz, 1H),
3.52 (d, J¼12.8 Hz, 1H), 3.42 (d, J¼12.8 Hz, 1H), 3.36e3.31 (m, 1H),
3.25e3.21 (m, 1H), 2.22e2.02 (m, 2H), 2.00e1.90 (m, 1H), 1.74e1.65
(m, 3H), 1.54e1.49 (m, 1H), 1.38e1.32 (m, 1H), 1.25e1.24 (m, 1H),
1.13 (d, J¼6.4 Hz, 3H); 13C NMR (CDCl3): 138.2, 128.9, 128.5, 127.2,
72.4, 67.1, 59.2, 57.8, 44.2, 31.7, 26.9, 24.9, 20.9, 14.8; IR (CHCl3):
3179 (eOH) cmꢀ1; MS (EI): 245 (Mþ,19), 200 (11),172 (25),158 (49),
104 (8), 91 (100), 65 (13), 41 (10); HRMS (EI): Mþ, found 245.1771,
C16H23NO requires 245.1780.
6:1 ratio (ee of the major isomer ꢁ90%).
4.7.5. (ꢅ)-2-Acetyl-N-benzylnortropane (17d).38 To a solution of
16d (0.294 g, 1.20 mmol) in DCM (4 mL), was added pyridine
(0.30 mL, 3.60 mmol) and DMP (1.022 g, 2.40 mmol). Then the ex-
periment was performed as described in general procedure. Puri-
fication by column chromatography on neutral aluminum oxide
(0e2% MeOH/DCM) gave a yellowish oil (0.023 g, 8%) mixture of
two diastereoisomers endo/exo (
a
/
b
) ca. 3:1 ratio. Rf¼0.6 (10%
MeOH/DCM); GCeMS: tR¼46.03 min, m/z 243 (Mþ, 55), 200 (35),
172 (52), 159 (31), 158 (88), 104 (23), 91 (100), 43 (28);
tR¼46.37 min, m/z 243 (Mþ, 38), 200 (23), 172 (33), 159 (18), 158
(53), 104 (15), 91 (100), 43 (22); 1H NMR (CDCl3): (mixture of di-
astereoisomers) 7.45e7.37 (m, 2H), 7.35e7.21 (m, 3H), 3.63 (s, 2H,
CH2Ph endo isomer), 3.52e3.46 (m, 1H), 3.43 (12.5%, d, J¼13.0 Hz,
CHPh exo isomer), 3.33 (12.5%, d, J¼13.0 Hz, CHPh exo isomer),
3.24e3.17 (m, 1H), 2.98e2.86 (m, 1H), 2.07 (75% s, 3H, endo-CH3),
2.30e1.20 (m, 8H), 1.88 (25% s, 3H, exo-CH3); 13C NMR (CDCl3):
(mixture of diastereoisomers) 210.0, 209.0, 139.8, 129.1, 128.6,
128.3, 128.1, 126.99, 126.97, 126.94, 61.28, 60.5, 58.9, 58.4, 56.5, 54.7,
53.3, 30.4, 29.84, 28.4, 27.4, 26.4, 26.2, 25.8, 23.8, 18.6, 16.7.
4.7. General procedure for oxidation of alcohols 16
To a solution of corresponding alcohol 16aed (1 equiv) in dry
DCM (2e4 mL) was added pyridine (3 equiv) and DesseMartin
periodinane (2 equiv). After stirring for 22 h at rt KOH (2 M, 5 mL)
was added and the reaction mixture extracted DCM (3ꢃ15 mL). The
combined organic layers were washed with a mixture of KOH (2 M,
15 mL) and Na2S2O3 (20%, 15 mL), dried over MgSO4 and
concentrated.
Acknowledgements
4.7.1. (ꢅ)-endo-2-Benzoyltropane [(ꢅ)-ferrugine] (1).10,11 To a solu-
tion of 16a (0.347 g, 1.5 mmol, 1 equiv) in DCM (2 mL) was added
pyridine (0.37 mL, 4.5 mmol, 3 equiv) and DMP (1.273 g, 3 mmol,
2 equiv). Then the reaction was carried out as described in general
procedure to give the crude product. Purification by dry-column
flash chromatography (0e0.5% MeOH/DCMþNH3) followed by
PTLC (silica gel, 5% MeOH/DCMþNH3) gave yellow oil (0.192 g, 56%).
Rf¼0.5 (10% MeOH/DCM); Rf¼0.5 (10% MeOH/DCM); 1H NMR
(CDCl3): 7.98e7.92 (m, 2H), 7.57e7.51 (m, 1H), 7.49e7.43 (m, 2H),
3.82e3.76 (m, 1H), 3.35 (d, J¼6.0 Hz, 1H), 3.20e3.15 (m, 1H), 2.35 (s,
3H), 2.05e1.69 (m, 5H), 1.62e1.45 (m, 3H); 13C NMR (CDCl3): 201.5,
136.3, 132.8, 128.6, 128.4, 63.6, 61.1, 47.7, 40.3, 29.8, 26.0, 22.7, 18.5.
The work was supported by the University of Bialystok (BST-
125) and Ministry of Science and Higher Education (grant N N204
546939) We also thank Dr. L. Siergiejczyk for assistance in re-
cording NMR spectra.
References and notes
1. Bick, I. R. C.; Gillard, J. W.; Woodruff, M. Chem. Ind. (London) 1975, 794.
2. Lounasmaa, M.; Tamminen, T. In The Alkaloids, Chemistry and Pharmacology;
Cordell, G. A., Ed.; Academic: New York, NY, 1993; pp 1e114.
3. Swanson, K. L.; Albuquerque, E. X. Handb. Exp. Pharmacol. 1992, 102, 620e621.
€
€
€
4. Jonsson, S. Y.; Lofstrom, C. M. G.; Backvall, J.-E. J. Org. Chem. 2000, 65, 8454e8457.
5. Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett. 2004, 6, 1469e1471.
6. Gauthier, I.; Royer, J.; Husson, H.-P. J. Org. Chem. 1997, 62, 6704e6705.
ꢁ
7. Hernandez, A. S.; Thaler, A.; Castells, J.; Rapoport, H. J. Org. Chem. 1996, 61,
4.7.2. (þ)-endo-2-Benzoyltropane, (þ)-ferrugine ((þ)-1). To a solu-
tion of (þ)-16a (0.200 g, 0.86 mmol, 1 equiv) in DCM (2 mL), was
added pyridine (0.21 mL, 2.58 mmol, 3 equiv) and DMP (0.745 g,
1.76 mmol, 2 equiv). Then the experiment was performed as de-
scribed in general procedure. Purification using PTLC (silica gel, 5%
314e323.
8. Rigby, J. H.; Pigge, F. C. J. Org. Chem. 2002, 60, 7392e7393.
9. Piccardi, R.; Renaud, P. Eur. J. Org. Chem. 2007, 2007, 4752e4757.
10. Bick, I. R. C.; Gillard, J. W.; Leow, H.-M. Aust. J. Chem. 1979, 32, 2537e2543.
11. Ahmed, S.; Baker, L. A.; Grainger, R. S.; Innocenti, P.; Quevedo, C. E. J. Org. Chem.
2008, 73, 8116e8119.
12. Campbell, H. F.; Edwards, O. E.; Kolt, R. Can. J. Chem. 1977, 55, 1372e1379.
13. Zhang, C.; Lomenzo, S. A.; Ballay, C. J.; Trudell, M. L. J. Org. Chem. 1997, 62,
7888e7889.
MeOH/DCMþNH3) gave a yellow oil (0.110 g, 56%); ee ꢁ99%; ½a D20
ꢄ
þ100 (c 1, CHCl3), þ29 (c 0.3, CHCl3); Ref.10 ½a D19
þ55 (CHCl3).
ꢄ
14. Majewski, M.; Lazny, R. J. Org. Chem. 1995, 60, 5825e5830.
15. Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 2002, 58, 533e534.
16. Bunn, B. J.; Simpkins, N. S.; Spavold, Z.; Crimrnin, J. J. Chem. Soc., Perkin Trans. 1
1993, 3113e3116.
17. Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773e4775.
18. Katoh, T.; Kakiya, K.; Nakai, T.; Nakamura, S.; Nishide, K.; Node, M. Tetrahedron:
Asymmetry 2002, 13, 2351e2358.
4.7.3. (ꢅ)-2-Acetyltropane (17b).11 To a solution of 16b (0.188 g,
1.11 mmol, 1 equiv) in DCM (4 mL), was added pyridine (0.27 mL,
3.33 mmol, 3 equiv) and DMP (0.945 g, 2.22 mmol, 2 equiv). Then
the experiment was performed as described in general procedure.
Purification using PTLC (silica gel, 5% MeOH/DCMþNH3) gave yel-
19. Node, M.; Nakamura, S.; Nakamura, D.; Katoh, T.; Nishide, K. Tetrahedron Lett.
low oil (0.098 g, 53%). Rf¼0.5 (10% MeOH/DCM); endo/exo (
a/b) ca.
1999, 40, 5357e5360.
6:1 ratio, 1H NMR (CDCl3): (endo isomer) 3.42 (dd, J¼2.0, 6.5 Hz,
1H), 3.18e3.10 (m, 1H), 2.84 (ddd, J¼2.5, 6.0, 11.5 Hz, 1H), 2.32 (s,
3H), 2.11 (s, 3H), 2.05e1.84 (m, 2H), 1.83e1.73 (m, 1H), 1.71e1.58 (m,
2H), 1.55e1.40 (m, 3H); 13C NMR (CDCl3): 209.7, 65.4, 61.0, 53.1,
50.6, 29.7, 28.4, 25.7, 23.2, 18.0; m/z 167 (44), 123 (49), 122 (88), 108
(45), 94 (100), 91 (45), 57 (58), 44 (42), 42 (77%); nmax (CHCl3) 1705
20. Sienkiewicz, M.; Wilkaniec, U.; Lazny, R. Tetrahedron Lett. 2009, 50, 7196e7198.
21. O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439e1458.
22. Simpkins, N. S.; Weller, M. D. In Stereochemical Aspects of Organolithium Com-
pounds: Topics in Stereochemistry; Gawley, R. E., Ed.; Helvetica Chimica Acta:
2010; pp 1e52.
23. Pollini, G. P.; Benetti, S.; De Risi, C.; Zanirato, V. Chem. Rev. 2006, 106,
2434e2454.
24. Majewski, M.; Zheng, G.-Z. Can. J. Chem. 1992, 70, 2618e2626.
25. Majewski, M.; Lazny, R. Tetrahedron Lett. 1994, 35, 3653e3656.
26. Majewski, M.; Lazny, R.; Ulaczyk, A. Can. J. Chem. 1997, 75, 754e761.
27. Brzezinski, K.; Lazny, R.; Sienkiewicz, M.; Wojtulewski, S.; Dauter, Z. Acta
Crystallogr. 2012, E68, o149eo150.
28. Lazny, R.; Nodzewska, A.; Tomczuk, I. Tetrahedron Lett. 2011, 52, 5680e5683.
29. Alexakis, A.; Gille, S.; Prian, F.; Rosset, S.; Ditrich, K. Tetrahedron Lett. 2004, 45,
1449e1451.
(C]O) cmꢀ1
.
4.7.4. (þ)-2-Acetyltropane ((þ)-17b). To
a
solution of (þ)-16b
(0.101 g, 0.60 mmol, 1 equiv) in DCM (4 mL), was added pyridine
(0.15 mL, 1.80 mmol, 3 equiv) and DMP (0.511 g, 1.20 mmol,
2 equiv). Then the experiment was performed as described in
general procedure. Purification by column chromatography on
neutral aluminum oxide (0e2% MeOH/DCM) gave a yellowish oil
30. Lightner, D. A.; Paquette, L. A.; Chayangkoon, P.; Lin, H. S.; Peterson, J. R. J. Org.
Chem. 2002, 53, 1969e1973.
31. Tavernier, D.; Hosten, N.; Anteunis, M. Synthesis 1979, 613e614.

8244
R. Lazny et al. / Tetrahedron 68 (2012) 8236e8244
32. Kutney, J. P.; Singh, A. K. Can. J. Chem. 1983, 61, 1111e1114.
36. Momose, T.; Toshima, M.; Toyooka, N.; Hirai, Y.; Eugster, C. H. J. Chem. Soc.,
Perkin Trans. 1 1997, 1307e1314.
37. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
38. Petersen, J. S.; Toeteberg-Kaulen, S.; Rapoport, H. J. Org. Chem. 1984, 49,
2948e2953.
33. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 2002, 59, 7549e7552.
34. Dess, D. B.; Martin, J. C. J. Org. Chem. 2002, 48, 4155e4156.
35. Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 6th ed.;
Elsevier Burlington: 2009.