Synthesis, enantiomer separation, and absolute configuration of 2,6-oxygenated 9-azabicyclo[3.3.1]nonanes

Article abstract of DOI:10.1021/jo400506h

The synthesis of the enantiomerically pure N-Boc 9-azabicyclo[3.3.1]nonane- 2,6-dione (4b), a potentially useful chiral building block, from N-Bn and N-Boc 9-azabicyclo[3.3.1]nonane-2,6-diols 2a and 2b was accomplished. The enantiomer resolution of diols

Full text of DOI:10.1021/jo400506h

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Article
Synthesis, Enantiomer Separation and Absolute
Configuration of 2,6-Oxygenated 9-Azabicyclo[3.3.1]nonanes
Vidmantas Bieliunas, Dovile Rackauskaite, Edvinas Orentas, and Sigitas Stoncius
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400506h • Publication Date (Web): 01 May 2013
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Synthesis, Enantiomer Separation and Absolute Configuration of 2,6-
Oxygenated 9-Azabicyclo[3.3.1]nonanes
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Vidmantas Bieliūnas, Dovil÷ Račkauskait÷, Edvinas Orentas, and Sigitas Stončius*
Department of Organic Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
sigitas.stoncius@chf.vu.lt
OH
OH
O
OH
OH
R= Bn, Boc
N
N
N
Boc
Boc
R
O
Abstract: The synthesis of the enantiomerically pure NꢀBoc 9ꢀazabicyclo [3.3.1]nonaneꢀ2,6ꢀ
dione (4b), a potentially useful chiral building block, from NꢀBn and NꢀBoc 9ꢀ
azabicyclo[3.3.1]nonaneꢀ2,6ꢀdiols 2a and 2b was accomplished. The enantiomer resolution of
diols 2a and 2b was achieved by crystallization of their diastereomeric esters or by kinetic
resolution of the racemic diol 2a using lipase from Candida rugosa (CRL). Both enantiomers of
NꢀBoc protected diol 2b were converted into the corresponding enantiomerically pure diones 4b,
the absolute configuration of which was determined by comparison of the experimental and
simulated circular dichroism (CD) spectra, obtained by ab initio timeꢀdependent density
functional theory (TDDFT) calculations. The (−)ꢀ(1R,5R)/(+)ꢀ(1S,5S) absolute configuration of
4b inferred from the TDDFT calculations was confirmed via analysis of the CD spectrum of
endo,endoꢀdibenzoate (+)ꢀ7 derived from diol (+)ꢀ2b and application of the benzoate exciton
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chirality method. The assigned absolute configuration was further supported by the results of
kinetic resolution of diol 2a using Candida rugosa lipase, which exhibited kinetic preference
towards the (1R,2R,5R,6R)ꢀenantiomer in agreement with the Kazlauskas’ rule.
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Introduction
The bicyclic skeleton of 9ꢀazabicyclo[3.3.1]nonane (granatane) is common to numerous
macroline, sarpagine and ajmalineꢀrelated indole alkaloids, an important class of natural
products with diverse biological activity.1 These three structurally similar classes of alkaloids
possess an indoleꢀannulated azabicyclo [3.3.1]nonane (cycloocta[b]indole) scaffold, which has
recently been a subject of biologyꢀoriented synthesis (BIOS).2 Macrolineꢀlike compounds,
obtained using the BIOS approach, have been identified as promising targets for developing a
novel class of potent and selective antibiotic agents with activity against Mycobacterium
tuberculosis.3
To date, the PictetꢀSpengler reaction of tryptophan derivatives remains a key strategic
transformation for the stereospecific synthesis of macroline, sarpagine and ajmalineꢀrelated
indole alkaloids.1,4 As a consequence, the synthesis of congeners possessing oxygenated indole
ring requires the optimisation of enantioselective routes to the relevant oxygenated tryptophan
analogues.1,5 By contrast, the potential of the 9ꢀazabicyclo [3.3.1]nonane synthons for de novo
construction of the indole moiety of cycloocta[b]indole core is considerably less explored.
Moreover, while 2,6ꢀoxygenated 9ꢀazabicyclo[3.3.1]nonanes attracted attention as a suitable
precursors for the synthesis of ajmaline and sarpagine alkaloids,6 their synthesis in an
enantiomerically pure form has never been reported and, in general, literature examples of
simple enantiopure 9ꢀazabicyclo[3.3.1]nonane derivatives remain scarce.7
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We have demonstrated the utility of the enantiomerically pure bicyclo[3.3.1]nonaneꢀ2,6ꢀ
dione8 for the synthesis of chiral C2ꢀsymmetric cleft molecules, incorporating selfꢀ
complementary hydrogen bonding heteroaromatic moieties. Such monomeric units with inherent
geometric features responsible for controlled spatial aggregation provide access to various
supramolecular structures, such as cages,9 helical tubular oligomers10 and belts.11 The threeꢀ
dimensional structure of the supramolecular assemblies was profoundly governed by the
enantiomeric purity of the building blocks, whereas long alkyl chains were prerequisite to attain
the sufficient solubility in nonꢀpolar solvents.10,11
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In connection with our ongoing research on the synthesis of novel supramolecular
synthons, we focused on the derivatives of 9ꢀazabicyclo[3.3.1]nonane, which offer an unique
advantage to introduce solubilizing groups at the position not accessible in case of carbocyclic
congeners, i.e. on the apical nitrogen atom. As the synthetic methodologies to access the
enantiomerically pure compounds of this framework are unavailable, we focused on the
synthesis and enantiomer separation of 2,6ꢀoxygenated 9ꢀazabicyclo[3.3.1]nonane derivatives,
and determination of their absolute configuration. CD spectroscopy today is a wellꢀestablished
technique for determination of the absolute configuration of chiral compounds.12 A variety of
methodologies, ranging from empirical rules to ab initio quantum mechanical methods, have
been devised for the correlation of the observed sign and magnitude of Cotton effects (CEs) in
the CD spectra with the absolute configuration. In recent years, highꢀlevel quantum mechanical
calculations have emerged as a general and convenient method for the determination of absolute
stereochemistry. In particular, the timeꢀdependent density functional theory (TDDFT)13 has
become a practicable tool in theoretical CD spectroscopy due to a reasonable balance between
accuracy and computational efficiency. As the chiroptical properties depend on the contribution
of all populated conformers, theoretical calculations provide an efficient method for the
determination of the absolute configuration of the conformationally flexible molecules.14
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In this work, the enantiomer resolution of 2,6ꢀoxygenated 9ꢀazabicyclo[3.3.1]nonane
derivatives by crystallization of diastereomeric salts and camphanate esters, as well as enzymatic
kinetic resolution was investigated and synthesis of the potentially useful chiral building blocks
was accomplished. The chiroptical properties of the obtained enantiomerically pure compounds
were studied and the absolute configuration was inferred from the TDDFT calculations and
application of the benzoate exciton chirality method.
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Results and Discussion
Synthesis
of
racemic
9-azabicyclononanes.
Racemic
Nꢀbenzyl
9ꢀ
azabicyclo[3.3.1]nonaneꢀ2,6ꢀdiol (2a) was obtained from synꢀdiepoxide 1 following the reported
procedure.15 The reaction of diepoxide 1 with benzylamine in water under reflux produced a 1:1
mixture of isomeric 9ꢀazabicyclo[3.3.1]ꢀ and [4.2.1]nonanediols 2a and 3a in a quantitative yield
(Scheme 1).
Scheme 1a
OH
OH
OH
a
O
O
OH
N
N
R
R
1
(±)-2a R=Bn
2c R= (R)-PhMe(CH)-
3a
3c
OH
O
d, e
b
OH
N
N
R
R
O
(±)-2a R=Bn
(±)-2b R=Boc
2c R= (R)-PhMe(CH)-
(±)-4a
(±)-4b
R=Bn
R=Boc
c
a Conditions: (a) BnNH2 or (R)ꢀ1ꢀphenylethylamine, H2O, reflux. (b) i) TFAA, DCM, ꢀ60 °C; ii)
TEA, DCM, reflux; iii) 2.5N NaOH, THF, rt, 95ꢀ98%. (c) i) H2, Pd/C, AcOH, MeOH, rt; ii)
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Boc2O, TEA, MeOH, reflux, 70ꢀ71%. (d) R=Bn: tꢀBuOK, PhH, Ph2CO, rt, 68%. (e) R=Boc: cat.
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RuO2, NaIO4, CCl4ꢀMeCNꢀH2O, rt, 80%.
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The interconversion of 3a to the desired thermodynamically more stable diol 2a was
accomplished via trifluoroacetylation of the obtained mixture, followed by isomerization in
refluxing dichloromethane. Subsequent saponification of the resulting bistrifluoroacetate
afforded diol 2a in 95ꢀ98% overall yield solely as endo,endo diastereomer.15
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For a large scale synthesis of 2a, the use of rather expensive commercial diepoxide 1 was
not practical and the convenient method for preparation of 1 from cheap 1,5ꢀcyclooctadiene was
required. According to literature, the former compound could be synthesized by epoxidation of
1,5ꢀcyclooctadiene using either peroxyacetic acid (57% yield)16 or MeReO3/H2O2 (80ꢀ97% yield
on a small scale).17 We employed an alternative procedure for oxidation of 1,5ꢀcyclooctadiene
using inexpensive and safe oxidant OXONE®. The twoꢀphase procedure using an aqueous
solution of OXONE® and ethyl acetate in combination with acetone18 as a mediator afforded
diepoxide 1 in 60ꢀ77% yield. The crude product showed only minute amount of impurities in the
NMR spectra and could be used for the synthesis of 2a without further purification.
Initial attempts to obtain dione 4a by oxidation of diol 2a using a number of standard
oxidising reagents met little success. The benzyl protecting group was therefore replaced with
more convenient tertꢀbutyloxycarbonyl (Boc) group to give 2b,15 which could be oxidised to the
corresponding dione 4b in high yields by using Swern or RuO2 catalyzed oxidation with sodium
periodate (Scheme 1). Room temperature ruthenium catalyzed oxidation gave higher yields, was
operationally simpler than Swern oxidation and could be easily adapted to a largeꢀscale
synthesis. On the other hand, by using Oppenauer oxidation19 of 2a, Nꢀbenzyl dione 4a could be
obtained in 68% yield, but proved to be rather unstable. This is consistent with the similar
disappointing results of the oxidation of the Nꢀmethyl congener of 2a, reported earlier.6b All
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attempts to synthesize Nꢀunsubstituted dione by deprotection of 4b under standard conditions
(TFA/DCM) were equally unproductive.
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In order to attain the enantiomerically enriched azabicyclic derivatives, a few catalytic
asymmetric methodologies for enantioselective opening of mesoꢀepoxides were briefly
investigated. From this point of view, diepoxide 1 represents a particularly challenging substrate,
as the reaction with benzylamine (or any other achiral nucleophile) has to be both enantioꢀ and
regioselective to avoid the formation of the achiral diol 3. In addition, skeletal isomerization of
mesoꢀ3 to the desired diol 2 is in principle reversible and proceeds via formation of the transient
aziridinium intermediate, thus providing a pathway for racemization at the same time.20 A very
efficient titanium isopropoxide/BINOL catalyzed enantioselective desymmetrization of a few
mesoꢀepoxides with benzylamines as nucleophiles has been reported;21 coordination of the
substrate to the catalyst in a bidentate fashion was found to be prerequisite for high
stereoselectivity. We reasoned that diepoxide 1 could provide such coordination to Ti/BINOL
complex via oxygen atoms of both epoxide moieties. Nevertheless, Ti(iꢀPrO)4/(R)ꢀBINOL (1
mol%) catalyzed reaction of diepoxide 1 with benzylamine or (R)ꢀ1ꢀphenylethylamine in the
presence of water21a afforded only a trace amounts of both diols 2 and 3. On the other hand, ringꢀ
opening reaction of 1 with (R)ꢀ1ꢀphenylethylamine in water under standard conditions (Scheme
1) produced corresponding azabicyclo[3.3.1]ꢀ and [4.2.1]nonanediols 2c and 3c approximately in
a 1:1 ratio as an inseparable mixture, which could be isomerized to the required
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1
azabicyclo[3.3.1]nonane diol 2c via the corresponding bistrifluoroacetate. The H NMR of the
crude reaction product (ca 50% yield), however, indicated the formation of the two
diasteromeric endo,endoꢀdiols 2c in roughly 1:1 ratio. The results of ytterbium (III) triflate/(R)ꢀ
BINOL catalyzed22 ringꢀopening reaction of 1 with pꢀanisidine, derivatives of which can be
oxidatively deprotected,23 were equally disappointing.
Enantiomer resolution. With racemic compounds 2a-b and 4b in hand, we focused on
their resolution into enantiomers. Because of the basic nature amino alcohol 2a seemed to be
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perfectly suited for enantiomer resolution via fractional crystallization of diastereomeric salts
with chiral acids. Nevertheless, attempts to resolve racemic diol 2a with a number of
enantiomerically pure acids afforded only partially enantiomerically enriched alcohols (ca 20%
ee), as determined by chiral HPLC of the corresponding benzoate 7 (Scheme 2, vide infra).
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Scheme 2a
OR*
OR1
O
b
c
a
(±)-2a
(±)-2b
R=Bn
R=Boc
OR*
OR1
N
N
N
R
R
Boc
O
(-)-5a R=Bn
(-)-5b
(-)-2a R=Bn, R1=H
(-)-4b
d
1
R=Boc
(-)-2b
(-)-7
R=Boc, R =H
a
e
1
, R=Boc, R =Bz
R1O
R*O
O
O
c
b
R*=
O
R*O
(+)-6a
R1O
(+)-2a
N
N
R
1
N
R
Boc
O
O
(+)-4b
R=Bn
R=Boc
R=Bn, R =H
d
1
6b
(+)-2b
R=Boc, R =H
e
(+)-7 R=Boc, R1=Bz
a
Conditions: (a) i) Camphanic chloride, DMAP, TEA, DCM, rt, 93ꢀ96%; ii) Fractional
crystallization, 18ꢀ37%. (b) K2CO3, MeOH, rt, quant. (c) cat. RuO2, NaIO4, CCl4ꢀMeCNꢀH2O,
rt, 72ꢀ86%. (d) i) H2, Pd/C, AcOH, MeOH, rt; ii) Boc2O, TEA, MeOH, reflux, 70ꢀ71%. (e)
PhCOCl, DMAP, TEA, DCM, rt, 69ꢀ94%.
Encouraged by a successful enantiomer resolution of numerous spirocyclic,24 bicyclic25
and polycyclic alcohols26 via camphanate esters, we investigated the resolution of esters 5-6,
obtained in 93ꢀ96% yields from racemic diols 2a-b and enantiomerically pure (−)ꢀ(1S)ꢀ
camphanic chloride (Scheme 2). Fractional crystallization of the diastereomeric mixture of Nꢀ
Boc diesters 5b and 6b from methanol afforded diastereomerically pure 6b in 31% yield.
Interestingly, solutions of 6b in chloroform exhibited no measurable specific rotation angle. The
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second diastereomer (−)ꢀ5b (20% yield) was obtained by concentration of the mother liquor and
fractional crystallization of the residue from dichloromethaneꢀdiethyl ether mixtures. The
diastereomeric purity of the resolved diastereomers was determined from their 1H NMR spectra,
where the diagnostic resonance signals corresponding to the methyl groups of the camphanate
moieties were sufficiently resolved. Subsequent hydrolysis of the individual diastereomers (−)ꢀ
5b and 6b afforded practically enantiomerically pure diols (−)ꢀ2b (99% ee) and (+)ꢀ2b (98% ee),
respectively, as determined by chiral HPLC of the corresponding benzoates 7 (Scheme 2). The
resolution was reproducible on both small and relatively large (7 mmol) scale and the resolving
reagent could be recovered as camphanic acid after hydrolysis of the camphanate esters in 82%
average yield.
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Analogously, diastereomerically pure camphanates (−)ꢀ5a (18%) and (+)ꢀ6a (37%) were
obtained via fractional crystallization of the diasteromeric mixture of NꢀBn diesters 5a and 6a.
Subsequent saponification of the individual diesters (−)ꢀ5a and (+)ꢀ6a afforded enantiomerically
pure diols (−)ꢀ2a and (+)ꢀ2a, respectively. The obtained (−)ꢀ2a and (+)ꢀ2a were converted to
diols (−)ꢀ and (+)ꢀ2b, respectively, via an exchange of the Nꢀprotecting group by hydrogenolysis
and subsequent Boc protection.15 The latter chemical correlation relates the absolute
configurations of the NꢀBn and NꢀBoc series, i.e. camphanates (−)ꢀ5a, (−)ꢀ5b, diols (−)ꢀ2a, (−)ꢀ
2b and dibenzoate (−)ꢀ7 possess the same absolute configuration of the azabicyclic framework at
the C1, C2, C5 and C6 stereogenic centers (Scheme 2). While the separation and subsequent
saponification of NꢀBoc and NꢀBn diastereomeric camphanates afforded the corresponding
enantiomerically pure diols in a comparable overall yields, the resolution of NꢀBn protected
camphanates 5a and 6a was found to be more difficult to reproduce, especially in the case of (−)ꢀ
5a. Subsequent RuO2 catalyzed oxidation of diols (−)ꢀ2b and (+)ꢀ2b (Scheme 2) proceeded
uneventfully to give enantiomerically pure diones (−)ꢀ4a and (+)ꢀ4b, respectively.
Enzymatic kinetic resolution. Although the enantiomers of 2a-b could be obtained via
resolution of the corresponding camphanates, the separation procedure required several
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fractional crystallizations and involved additional esterification/ saponification synthetic steps.
Therefore alternative methodologies based on the enzymatic kinetic resolution of enantiomers
were explored, including the Baker’s yeast mediated reduction of racemic dione 4b. The latter
method was found to be a very efficient way for resolution of the racemic bicyclo[3.3.1]nonaneꢀ
2,6ꢀdione, a carbocyclic analogue of 4b, providing enantiomerically pure (+)ꢀ2,6ꢀdione8 after
two consecutive fermentations. Despite the bulky Boc protecting group at 9th position of
bicyclic framework, a rather fast reduction of dione 4b with Baker’s yeast occurred, but the
enantiomeric purity of the recovered dione (+)ꢀ4b was below 30% even after the repeated
fermentation or fermentation under high dilution conditions.27
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An alternative pathway is the differentiation of the enantiomers of alcohols by hydrolytic
enzymes, either by stereoselective esterification of the racemic alcohols or by hydrolysis of the
corresponding esters.28 Lipases are particularly useful in organic synthesis, because they are
efficient, simple to use and can function in organic solvents,29 thus substantially simplifying the
purification procedures. Resolution of bicyclic diols both by lipaseꢀcatalyzed hydrolysis of the
corresponding diacetates30 and transesterification31 has been reported, including the enantiomer
resolution of 9ꢀoxabicyclo[3.3.1]nonaneꢀ2,6ꢀdiol using lipases from Candida antarctica (CAL)
or Candida rugosa (CRL).32
We investigated the kinetic resolution of racemic diols 2a and 2b, using Candida rugosa
lipase (CRL) and vinyl acetate as an irreversible acyl donor. Initial experiments revealed that the
acetylation of NꢀBoc diol 2b was extremely sluggish, giving negligible conversion after one
week. By contrast, NꢀBn protected diol 2a underwent a very fast acetylation in pure vinyl acetate
at 20 °C producing mixture of unreacted diol (+)ꢀ2a and corresponding monoꢀ and diacetates 8
and 9 (Scheme 3).
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Scheme 3
5
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8
HO
CRL
OAc
(±)-2a
HO
N
9
Bn
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(+)-2a
OAc
OAc
OH
OAc
N
N
Bn
Bn
8
(-)-9
To elucidate the efficiency of the lipase catalyzed resolution, a detailed kinetic study
(Figure 1) was performed by taking aliquots from the reaction mixture and monitoring the
reaction progress by GCꢀMS. For ee determination, the unreacted diol 2a, monoacetate 8 and
diacetate 9 were separated by column chromatography; 2a and 8 were converted to the
corresponding diacetates 9 by a standard acetylation with acetic anhydride in the presence of
DMAP and analyzed by chiral HPLC.
100
90
16%
80
36%
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20
10
0
54%
81%
78%
84%
70%
72%
81%
76%
88%
98%
90%
84%
85%
90%
78%
0
30
60
90 120 150 180 210 240 270
t, min
Figure 1. Conversion (2a (■); 8 (•); 9 (
▲)) and enantiomeric excesses of the CRL catalyzed
acetylation of (±)ꢀ2a at 20 °C.
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Thus, in pure vinyl acetate approx. 53% conversion of 2a was reached in 2.5 h (Figure
1). At this point, the remaining diol (+)ꢀ2a had the enantiomeric purity of 84%, whereas the
corresponding monoacetate 8 exhibited a rather modest enantiomeric excess (78% ee). The latter
steadily decreased as the reaction proceeded further (Figure 1) due to the subsequent acetylation
of 8 to give diacetate 9. After 4.5 hours, 64% of the diol was consumed to produce a 36:51:13
mixture of 2a (98% ee), 8 (70% ee) and 9 (90% ee), respectively. Attempts to improve the
efficiency of the kinetic resolution by performing the acetylation in organic solvents met little
success, probably due to a very limited solubility of 2a. For example, negligible conversions
were attained in methyl tertꢀbutyl ether in the presence of two, three or four equivalents of vinyl
acetate after one week. Fortunately, the enantiomeric purity of the enantioenriched 2a (78ꢀ84%
ee) could be readily improved by a single recrystallization to give enantiopure material.
Preparative scale resolution of racemic 2a was conducted in pure vinyl acetate and the
reaction was quenched after 2.5 hours by filtering off the enzyme and evaporation. Separation of
the unreacted diol from acetates 8 and 9 and subsequent recrystallization afforded
enantiomerically pure (+)ꢀ2a (27%). The other enantiomer, (−)ꢀ2a, was obtained in 23% yield by
single crystallization of the enantioenriched diol, obtained after saponification of the combined
fractions, containing acetates 8 and 9. Although CRL mediated kinetic resolution proceeded with
moderate enantioselectivity, the described procedure provides convenient and fast method to
attain both enantiomers of 2a in 50% combined yield. The remaining practically racemic diol 2a
(47%) could be recovered from the combined mother liquors and reused in the subsequent
resolutions.
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Chiroptical properties and absolute configuration. For determination of the absolute
configuration, the chiroptical properties of the obtained enantiomerically pure diones 4b were
studied. The absolute configuration of chiral ketones can be assigned from the analysis of CD
spectra using the octant rule for the n→π* transition of the carbonyl chromophore. While
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numerous successful applications have proved the octant rule as a practicable tool for
determination of the absolute configuration of many saturated ketones,33 the prediction of the CE
sign should be made with caution when molecular conformation is ambiguous. Moreover, the
validity of the octant rule may become even more disputable when two nonꢀequivalent carbonyl
chromophores are present in the molecule.34 Although compounds of both NꢀBn and NꢀBoc
series lack molecular symmetry, NꢀBn derivatives behave as pseudo C2ꢀsymmetric due to a rapid
inversion of trigonal pyramidal nitrogen atom. By contrast, the presence of coꢀplanar carbamate
moiety and hindered rotation around (O=)C−N(sp2) bond renders the two halves of the bicyclic
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1
framework nonꢀequivalent in the NꢀBoc series. This is evident from the H and 13C NMR
spectral data of 2b, 4-6b and 7, where the two separate resonance signals corresponding to
H−C1/H−C5 (and H−C2/H−C6) are observed.
In the experimental CD spectrum of (+)ꢀ4b, a bisignate CE centered at 306 nm (negative
at 319 nm and positive at 292 nm), attributable to the n→π* transitions of the C=O groups, is
observed and the positive CE at 232 nm is assigned to the n→π* transition of the carbamate
chromophore. As expected, (−)ꢀ4b exhibited the mirrorꢀimage CD spectrum (Figure 2).
2
1
0
-1
-2
-3
-4
-5
-6
200
225
250
275
300
, nm
325
350
375
400
λ
Figure 2. CD spectra of diones (+)ꢀ4b (− −) and (−)ꢀ4b (−·−·) in ethanol; wavelength corrected,
Boltzmannꢀaveraged CD of (1R,5R)ꢀ4b (─), calculated at B3LYP/6ꢀ311++G(2d,2p) level.
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As the octant rule is clearly inapplicable in this case, the absolute configuration of 4b
was inferred from the comparison of experimental and TDDFT calculated CD spectra.
Conformational analysis of arbitrarily chosen (1R,5R)ꢀenantiomer of 4b using MMFF94 force
field, followed by optimization using DFT at B3LYP/6ꢀ31G(d) level identified chairꢀchair (cꢀc),
two chairꢀboat (cꢀb and cꢀb1) and double twistboat (tbꢀtb) conformations within a 1 kcal/mol
window (Figure 3).
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Figure 3. Structures of the low energy conformers of 4b optimized at B3LYP/6ꢀ311++G(d,p)
level of theory.
The obtained structures were further optimized at B3LYP/6ꢀ311G++(d,p) level and
harmonic vibrational frequencies were then calculated to confirm the stability of all
conformations and to permit the calculation of their relative free energies (Table 1). At the
B3LYP/6ꢀ311G++(d,p) level, cꢀc conformation is predicted to be lower in energy than the cꢀb
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conformer only by 0.15 kcal/mol. The two chairꢀboat conformers (cꢀb and cꢀb1) are comparably
populated and together with the cꢀc conformer they constitute ~88% of the equilibrium mixture.
7
8
9
Table 1. (1R,5R)-4b: Conformational energies and Circular Dichroism
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c
ꢀGa
P(ꢀG)b
λ, nm
Conformer
Rvel
cꢀc
0
37.0
28.6
22.0
12.4
324, 312
318, 307
319, 307
7.30, ꢀ13.57
18.26, ꢀ18.69
12.71, ꢀ16.84
0.30, 0.29
cꢀb
0.15
0.31
0.65
cꢀb1
tbꢀtb
332, 298
a
b
B3LYP/6ꢀ311G++(d,p) relative free energies in kcal/mol. Populations obtained from ꢀG
c
values, using Boltzmann statistics and T = 298 K. B3LYP/6ꢀ311++G(2d,2p) calculated n→π*
C=O transitions; R values in 10ꢀ40 esu2 cm2.
Excitation energies, oscillator strengths and rotational strengths were predicted for the
conformations of (1R,5R)ꢀ4b, at their B3LYP/6ꢀ311++G(d,p) equilibrium geometries, using
B3LYP and the 6ꢀ311++G(2d,2p) basis set. The calculated rotatory strengths (Rvel) were
simulated into the CD curves assuming a Gaussian band shape35 with a halfꢀwidth at 1/e of the
peak maximum (σ) value of 0.26 eV, approximately matching the broadening of the CD bands
in the experimental spectra (see Supporting Information, Fig. S1). For the determination of the
absolute configuration of 4b, the signs of the Cotton effects for the n→π* transition of the
carbonyl chromophores were diagnostic. For each conformer two lowꢀenergy transitions are
predicted within the range 332−298 nm, attributable to n→π* excitations of the C=O groups,
wellꢀseparated from the nextꢀhighest excitations. For the three most populated cꢀc, cꢀb and cꢀb1
conformers calculations uniformly predict a bisignate n→π* CD, positive at the longer
wavelengths and negative at shorter wavelengths, whereas for the tbꢀtb conformer a very weak
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positive CD is predicted (Table 1). The Boltzmannꢀaveraged CD spectrum of the equilibrium
mixture of conformers, blueꢀshifted by 13 nm to match experimental λmax of the CE at 319 nm,
is plotted in Figure 2. Qualitatively, the calculated CD spectrum well reproduces the shape and
relative intensity of the CEs in the experimental CD spectra of 4b. The predicted CD spectrum
of (1R,5R)ꢀ4b exhibits a bisignate CE (positive at 320 nm and negative at 290 nm) followed by
negative CE below 250 nm, in agreement with the experimental spectrum of (−)ꢀ4b. The DFT
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calculations thus lead to the conclusion that the absolute configuration of dione 4b is (−)ꢀ
(1R,5R)/(+)ꢀ(1S,5S). As a result, (−)ꢀ(1R,2R,5R,6R)/(+)ꢀ(1S,2S,5S,6S) absolute configuration can
be assigned to diols 2a and 2b on the basis of the chemical correlation described above (Scheme
2).
The absolute configuration of dione 4b inferred from the TDDFT calculations was
confirmed via analysis of the CD spectrum of dibenzoate (+)ꢀ7 derived from diol (+)ꢀ2b, and
application of the benzoate exciton chirality method.36 The benzoate chromophores with intense
π→π* absorptions are wellꢀstudied excitons that give rise to a characteristic pair of CD bands
1
with opposite signs originating from the La transitions. In the experimental CD spectrum of the
(+)ꢀ7, the negative exciton couplet located at the benzoate chromophore 1La transition
wavelength at 231 nm was observed (Figure 4). In concordance with the excitonꢀtype coupling,
the strong absorption maximum at the same wavelength was observed in the UV spectrum of
(+)ꢀ7.
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-2
-4
-6
-8
-10
200
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250
, nm
275
300
λ
Figure 4. CD spectrum of dibenzoate (+)ꢀ7 in ethanol.
Conformational analysis of arbitrarily chosen (1R,2R,5R,6R)ꢀenantiomer of 7 using
MMFF94 force field, followed by further optimization of the obtained structures using DFT at
B3LYP/6ꢀ31G(d) level, predicts four stable chairꢀchair conformations. The corresponding chairꢀ
boat conformers were found much higher in energy and thus insignificantly populated. At the
B3LYP/6ꢀ31G(d) level, low energy chairꢀchair conformers of (1R,2R,5R,6R)ꢀ7 differ principally
with regard to the conformation around HC2,6−O bonds (see Supporting Information, Fig. S2).
The benzoate moieties adopt conformation typical for alkyl benzoates,14 i.e. sꢀtrans
conformation around the benzoate (O)C−O bond with the ester carbonyl group syn with the
respect to bicyclic methine H−C2,6 hydrogens. All four conformers of (1R,2R,5R,6R)ꢀ7 are
characterized by a positive helicity of the interacting transition electric dipole moments, which
are polarized along the long axis of the benzoate chromophore. As a result, a positive exciton
couplet is predicted for the (1R,2R,5R,6R) enantiomer of dibenzoate 7 and, consequently, an
opposite (1S,2S,5S,6S) configuration can be assigned to the (+)ꢀ enantiomer of 7, which
exhibited a negative exciton couplet in the experimental CD spectrum (Figure 4). This
conclusion is consistent with the experimental and TDDFT analysis of endo,endoꢀdibenzoate of
bicyclo[3.3.1]nonaneꢀ2,6ꢀdiol,37 i.e. in the experimental CD spectra of (+)ꢀ(1S,2R,5S,6R)ꢀ
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enantiomer a positive exciton couplet is observed (note the opposite (1S,5S) notation of the
absolute configuration here due to the change of CahnꢀIngoldꢀPrelog priority in comparison with
the 9ꢀaza congener 7). The CD analysis of the benzoate 7 thus yields the same (−)ꢀ
(1R,2R,5R,6R)/(+)ꢀ(1S,2S,5S,6S) absolute configuration of 2b, as concluded above from the
TDDFT calculations of the CD spectrum of 4b and chemical correlation (Scheme 2), and
permits an unequivocal assignment of the absolute configuration.
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The correctness of the assigned absolute configuration is further supported by the results
of kinetic resolution of diol 2a using Candida rugosa lipase (Scheme 3). According to
Kazlauskas’ rule,38 CRL exhibits kinetic preference towards the (R)ꢀconfigured secondary
alcohols or their acylated derivatives, provided that the larger substituent at the diol stereogenic
center has also the higher priority according to the Cahn–Ingold–Prelog (CIP) nomenclature.
Hence, the (1S,2S,5S,6S) absolute configuration of the slowꢀreacting enantiomer (+)ꢀ2a (Scheme
3) predicted using the Kazlauskas’ rule is consistent with, and adds support to, the previous
assignment using TDDFT calculations and the exciton chirality method.
Conclusions
The synthesis of enantiomerically pure 9ꢀazabicyclic 2,6ꢀdiols 2a, 2b and 2,6ꢀdione 4b
was accomplished. The enantiomer resolution of diols was achieved by crystallization of their
diastereomeric camphanates or by kinetic resolution using lipase from Candida rugosa (CRL).
Although CRL mediated kinetic resolution proceeded with moderate enantioselectivity, the
procedure described provides convenient and fast method to attain both enantiomers of 2a. The
(−)ꢀ(1R,5R)/(+)ꢀ(1S,5S) absolute configuration of enantiomerically pure diones 4b, obtained
from enantiomers of NꢀBoc diol 2b, was determined by TDDFT calculations and unequivocally
confirmed via analysis of the CD spectrum of endo,endoꢀdibenzoate (+)ꢀ7 and application of the
benzoate exciton chirality method. The assigned absolute configuration was further supported by
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the results of kinetic resolution of diol 2a using CRL, which exhibited kinetic preference
towards the (1R,2R,5R,6R)ꢀenantiomer in agreement with the Kazlauskas’ rule. This is the first
example of 2,6ꢀoxygenated 9ꢀazabicyclo[3.3.1]nonanes, a potentially useful chiral building
blocks, obtained in an enantiomerically pure form. Application of these scaffolds for the
synthesis of novel chiral supramolecular synthons is in progress and will be reported in due
course.
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Experimental
1
General Methods. H and 13C NMR spectra were recorded in CDCl3 at 300 MHz for
protons and 75 MHz for carbon and chemical shifts are reported in ppm relative to solvent
resonance signal as an internal standard (1H NMR δ = 7.26 ppm, 13C NMR δ = 77.0 ppm). IR
spectra were recorded in KBr pellets. Optical rotations were measured at 589 nm; [α]20 values
are given in 10–1 deg cm2 g–1, and concentrations are given in units of g/100 cm3. The CD and
UV spectra were recorded at 20 °C in a 0.1 cm cell. The stock solutions were prepared by
weighting compound into volumetric flask and diluting with UVꢀgrade ethanol. The CD spectra
were measured in millidegrees and normalized into ꢁε (dm3 mol–1cm–1) units. Melting points
were recorded with a Koefler melting apparatus and are not corrected. High resolution mass
spectra (HRMS) were recorded on a timeꢀofꢀflight (TOF) spectrometer with electrospray
ionization (ESI).
The enantiomeric excesses were determined using HPLC system, equipped with diode
array detector and CHIRALPAK IAꢀ3, IBꢀ3 and ICꢀ3 analytical (250×4.6 mm) columns. The
chiral HPLC methods were calibrated with the corresponding racemic mixtures. The conversion
of substrates in the lipaseꢀcatalyzed acetylation was followed by GCꢀMS using 30 m × 0.25 mm
RESTEK Rtxꢀ1701 column, temperature programꢀ 200 °C (3 min), 200 °C → 260 °C (25
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°C/min), 260 °C (6 min); the ratio of compounds was determined by integration of the peak area
and was not corrected.
7
8
9
All solvents and reagents for the reactions were of reagent grade and were dried and
distilled under argon immediately before use as follows: dichloromethane and triethylamine
from calcium hydride, benzene from sodium. Thinꢀlayer chromatography was carried out on
Kieselgel 60 F254 (Merck) sheets coated with silica gel, and Kieselgel 60 silica gel (0.040–
0.063 mm, Merck) was used for column chromatography. Petroleum ether refers to the fraction
boiling in the range 40−60 °C. Lipase from Candida rugosa (Type VII, ≥700 unit/mg solid;
L1754) was purchased from SigmaꢀAldrich®.
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5,10-dioxatricyclo[7.1.0.04,6]decane (1).17 To a 2.0 L threeꢀnecked flask equipped with
mechanical stirrer, dropping funnel and thermometer, were added NaHCO3 (30 g, 0.357 mol),
water (400 mL), acetone (120 mL), ethyl acetate (400 mL) and cyclooctadiene (10 g, 0.093 mol).
A solution of Oxone (114 g, 0.186 mol) in water (440 mL) was added dropwise over 1 h to the
vigorously stirred reaction mixture at the rate to keep mixture temperature below 30 °C. After
addition, the mixture was stirred for an additional 1h, then the organic layer was separated and
washed with brine and dried (Na2SO4). The solvent was evaporated to afford 1 (9.97 g, 77%) as
colorless oil, which solidified on standing; the product was TLC and NMR pure and was used
1
for the next step without further purification: mp 28ꢀ30 °C; H NMR
δ 1.78−1.91 (m, 4H),
1.92−2.03 (m, 4H), 2.92−2.99 (m, 4H), in agreement with the literature data.17
(±)-endo,endo-9-benzyl-9-azabicyclo[3.3.1]nonane-2,6-diol (2a) and (±)-endo,endo-
tert-butyl 2,6-dihydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (2b).15 Obtained from
diepoxide 1 following the reported procedures.15
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(±)-9-benzyl-9-azabicyclo[3.3.1]nonane-2,6-dione (4a). tꢀBuOK (135 mg, 1.2 mmol),
benzophenone (547 mg, 3 mmol) and diol (±)ꢀ2a (74 mg, 0.3 mmol) were sequentially added to
dry benzene (5 mL) under an argon atmosphere. The resulting mixture was stirred at room
temperature for 24 h. The orange mixture was transferred to a separatory funnel and extracted
with an aqueous 10% HCl (1×10 ml and 2×5 mL). Combined aqueous layer was treated with a
solution of KOH (3.4 g) in water (10 mL) and extracted with dichloromethane (3×10 ml),
combined organic layer was dried with Na2SO4 and evaporated under reduced pressure. Yellow
residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate
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mixture (7:3, Rf = 0.37) to afford 4a (52 mg, 68%) as a colorless oil which solidified on
1
standing: mp 89−91 °C (DCM/hexane); H NMR
δ 1.93−2.04 (m, 2H), 2.38−2.56 (m, 4H),
2.69−2.80 (m, 2H), 3.38−3.40 (m, 2H), 3.83 (ABq, ꢀδAB = 0.04, JAB = 13.4 Hz, 2H), 7.24−7.38
(m, 5H); 13C NMR
δ
24.1 (CH2), 35.3 (CH2), 56.4 (CH2), 62.9 (CH), 127.7 (CH), 128.6 (2×CH),
137.0 (C), 212.1 (C=O); IR ν 3028, 2951, 1960, 1718, 1706, 1494, 1451, 1125, 1114, 992 cmꢀ1;
HRMS (ESI) calcd for C15H18NO2 [M+H]+ 244.1338, found 244.1344.
tert-butyl 2,6-dioxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (4b). Diol 2b (669 mg,
2.6 mmol) was dissolved in MeCN:CCl4:H2O (8:8:12 ml) mixture and then NaIO4 (2.22 g, 10.4
mmol) and RuO2ꢂH2O (3.9 mg, 1 mol%) were added under constant stirring. The reaction
mixture was vigorously stirred for 36 h at room temperature and then diluted with
dichloromethane (52 mL) and water (26 mL). Phases were separated and aqueous phase was
extracted with dichloromethane (2×40 mL). Combined organic phase was dried with Na2SO4
and evaporated under reduced pressure. Brown oily residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate mixture (7:3, Rf = 0.33) to give
4b as colorless oil, which solidified on standing; yields and spectral data are given below.
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(±)-4b: Obtained from (±)ꢀ2a in 80% yield: mp 94−96 °C; H NMR
δ
1.47 (s, 9H), 2.10 (br s,
25.5
5
6
2H), 2.33−2.46 (m, 4H), 2.51−2.64 (m, 2H), 4.69 (br s, 1H), 4.82 (br s, 1H); 13C NMR
δ
7
8
9
(CH2), 28.4 (CH3), 35.0 (CH2), 57.8 (CH), 59.0 (CH), 81.6 (C), 153.8 (C=O), 208.8 (C=O); IR ν
2978, 1721, 1691, 1408, 1318, 1171 cmꢀ1; Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N,
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5.53. Found: C, 61.82; H, 7.59; N, 5.81; Chiral HPLC (Chiralcel ICꢀ3 column, hexane/2-
propanol 75:25, 1 mL/min): t1 = 11.59 min, t2 = 13.13 min.
(+)-(1S,5S)-4b: Obtained from (+)ꢀ2a in 76% yield: mp 78−80 °C; [α]D +35 (c 1.0, CHCl3); CD
λmax (ꢁε) 319 (−0.56), 306 (0), 292 (+0.57), 232 (+1.65) nm; UV λmax (logε) 303 (1.89) nm.
Chiral HPLC (Chiralcel ICꢀ3 column, hexane/2-propanol 75:25, 1 mL/min) showed >99%
ee (tmajor = 13.12 min).
(−)-(1R,5R)-4b: Obtained from (−)ꢀ2a in 83% yield: mp 78−80 °C; [α]D −35 (c 1.0, CHCl3);
Chiral HPLC (Chiralcel ICꢀ3 column, hexane/2-propanol 75:25, 1 mL/min) showed >99%
ee (tmajor = 11.50 min).
General procedure for the synthesis of camphanates 5a-6a and 5b-6b. Triethylamine
(4.2 mL, 30 mmol) was slowly added to a suspension of a corresponding racemic diol 2a or 2b
(7 mmol), (S)ꢀcamphanic chloride (3.25 g, 15 mmol) and DMAP (43 mg, 5 mol%) in dry
dichloromethane (50 mL), resulting in complete dissolution of starting materials and subsequent
precipitation of triethylammonium chloride. The reaction mixture was stirred under an argon
atmosphere at room temperature until no more diol or monoester could be detected by TLC (ca 6
h). The resulting mixture was then diluted with dichloromethane (50 mL) and washed with water
(25 mL), 0.5% aqueous HCl (25 mL) and saturated NaHCO3 (25 mL). The organic phase was
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dried with Na2SO4, filtered and evaporated under reduced pressure to afford crude camphanates
5a-6a (96%) and 5b-6b (93%) as yellowish solids, which were used without further purification.
Fractional crystallization of 5a-6a. Diastereomeric mixture of NꢀBn camphanates 5a-6a
(1 g) was dissolved in minimal amount of dichloromethane and diluted with warm diethyl ether
(40 mL). Crystallization began a few minutes after the dilution; the precipitate was collected and
the procedure was repeated two more times using 25 and 20 mL of Et2O, respectively, to give
diastereomerically pure (+)ꢀ6a (369 mg, 37%) as a colorless crystalline powder. Mother liquors
from first two crystallizations of (+)ꢀ6a were combined and evaporated under reduced pressure.
The obtained solid residue was recrystallized from methanol to afford diasteromerically pure
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(−)ꢀ5a (178 mg, 18%) as colorless crystalline solid.
1
(−)-5a: mp 165−169 °C (MeOH); [α]D − 22 (c 1.0, CHCl3); H NMR
δ 0.92 (s, 6H), 1.04 (s,
6H), 1.11 (s, 6H), 1.68 (ddd, J = 13.4, 9.3, 4.3 Hz, 2H), 1.86−2.16 (m, 12H), 2.38 (ddd, J = 13.3,
10.6, 4.2 Hz, 2H), 2.88−2.93 (m, 2H), 3.95 (d, J = 14.0 Hz, 1H), 4.06 (d, J = 14.0 Hz, 1H),
5.36−5.43 (m, 2H), 7.22−7.38 (m, 5H); 13C NMR
δ 9.7 (CH3), 16.7 (CH3), 16.9 (CH3), 21.0
(CH2), 26.4 (CH2), 28.9 (CH2), 30.6 (CH2), 51.7 (CH), 54.2 (C), 54.8 (C), 56.3 (CH2), 71.6
(CH), 90.9 (C), 127.2 (CH), 128.0 (CH), 128.4 (CH), 138.7 (C), 166.7 (C=O), 178.1 (C=O); IR ν
2968, 1792, 1749, 1457, 1320, 1265, 1171, 1109, 1062, 740, 701 cmꢀ1; HRMS (ESI) calcd for
C35H46NO8 [M+H]+ 608.3223, found 608.3206.
(+)-6a: mp 217−220 °C (Et2O/DCM); [α]D +4 (c 1.0, CHCl3); 1H NMR
δ 0.95 (s, 6H), 1.03 (s,
6H), 1.11 (s, 6H), 1.62−1.71 (m, 2H), 1.85−2.15 (m, 12H), 2.40 (ddd, J = 12.7, 10.3, 4.3 Hz,
1H), 2.88−2.95 (m, 2H), 3.96 (d, J = 13.9 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 5.33−5.41 (m, 2H),
7.22−7.37 (m, 5H); 13C NMR
δ 9.7 (CH3), 16.7 (CH3), 16.8 (CH3), 21.0 (CH2), 26.4 (CH2), 28.8
(CH2), 30.5 (CH2), 51.7 (CH), 54.2 (C), 54.8 (C), 56.4 (CH2), 71.8 (CH), 91.0 (C), 127.2 (CH),
128.1 (CH), 128.4 (CH), 138.8 (C), 166.9 (C=O), 178.3 (C=O); IR ν 2972, 1786, 1744, 1455,
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1311, 1263, 1172, 1110, 1063, 740, 700 cmꢀ1; HRMS (ESI) calcd for C35H46NO8 [M+H]+
608.3223, found 608.3221.
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Fractional crystallization of 5b-6b. Diastereomeric mixture of NꢀBoc camphanates 5b-
6b (4 g) was recrystallized twice from methanol to afford diastereomerically pure 6b (1.26 g,
31%) as a colorless crystalline solid. The combined mother liquors were evaporated under
reduced pressure and the residue was filtered through a pad of silica gel (5 g), using ethyl
acetate/petroleum ether (1:1) as eluent. The resulting solution was evaporated under reduced
pressure. Solid residue (2.70 g) was dissolved in minimal amount of dichloromethane and
diluted with warm diethyl ether (100 mL). Crystallization began a few minutes after the dilution;
the collected crystalline material (1.17 g) was reꢀprecipitated from DCM with Et2O (25 mL) to
give diastereomerically pure (−)ꢀ5b (870 mg, 20%) as a colorless crystalline solid.
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(−)-5b: mp 203−206 °C (Et2O/DCM); [α]D −16 (c 1.5, CHCl3); 1H NMR
δ 0.94 (s, 3H), 0.95 (s,
3H), 1.04 (s, 3H), 1.06 (s, 3H), 1.11 (s, 3H), 1.12 (s, 3H), 1.47 (s, 9H), 1.63−1.73 (m, 2H),
1.79−2.14 (m, 12H), 2.41 (ddd, J = 13.3, 10.6, 4.3 Hz, 2H), 4.18 (t, J = 4.4 Hz, 1H), 4.29 (t, J =
4.8 Hz, 1H), 5.04−5.16 (m, 2H); 13C NMR
δ 9.7 (CH3), 16.7 (CH3), 16.9 (CH3), 22.1 (CH2), 22.4
(CH2), 25.8 (CH2), 25.9 (CH2), 28.2 (CH3), 28.9 (CH2), 30.6 (CH2), 46.1 (CH), 47.7 (CH), 54.2
(C), 54.3 (C), 54.76 (C), 54.81 (C), 71.7 (CH), 71.9 (CH), 80.8 (C), 90.8 (C), 90.9 (C), 153.7
(C=O), 166.4 (C=O), 166.5 (C=O), 177.9 (C=O), 178.2 (C=O); IR ν 2971, 1795, 1746, 1701,
1313, 1264, 1168, 1107, 1060 cmꢀ1; HRMS (ESI) calcd for C33H47NNaO10 [M+Na]+ 640.3098,
found 640.3099.
6b: mp 211−213 °C (MeOH); [α]D 0 (c 1.5, CHCl3); 1H NMR
δ 0.94 (s, 3H), 0.95 (s, 3H), 1.04
(s, 6H), 1.10 (s, 3H), 1.11 (s, 3H), 1.46 (s, 9H), 1.67 (ddd, J = 13.0, 8.3, 4.0 Hz, 2H), 1.76−2.18
(m, 12H), 2.35−2.48 (m, 2H), 4.20 (t, J = 4.3 Hz, 1H), 4.31 (t, J = 4.1 Hz, 1H), 5.02−5.12 (m,
2H); 13C NMR
δ 9.8 (CH3), 16.7 (CH3), 16.8 (CH3), 22.1 (CH2), 22.5 (CH2), 25.96 (CH2), 25.99
(CH2), 28.3 (CH3), 28.80 (CH2), 28.84 (CH2), 30.5 (CH2), 30.6 (CH2), 46.0 (CH), 47.6 (CH),
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54.2 (C), 54.3 (C), 54.8 (C), 71.7 (CH), 72.1 (CH), 80.6 (C), 90.8 (C), 153.7 (C=O), 166.4
(C=O), 166.6 (C=O), 178.16 (C=O), 178.21 (C=O); IR ν 2971, 1790, 1748, 1702, 1315, 1262,
1170, 1106, 1063 cmꢀ1; HRMS (ESI) calcd for C33H47NNaO10 [M+Na]+ 640.3098, found
640.3108.
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General procedure for hydrolysis of camphanates 5a-b and 6a-b. A mixture of
camphanate ester (2 mmol) and K2CO3 (2.76 g, 20 mmol) in methanol (40 mL) was stirred at
room temperature for 3 h, then diluted with water (50 mL) and CHCl3 (50 mL). Layers were
separated and the aqueous layer was extracted with CHCl3 (3×40 mL). Combined organic phase
was dried with Na2SO4 and evaporated under reduced pressure. The obtained residues were
purified by recrystallization or column chromatography to give the corresponding diols (−)ꢀ, (+)ꢀ
2a and (−)ꢀ, (+)ꢀ2b; yields and spectral data are given below.
The remaining aqueous layer was acidified with conc. HCl (4 mL) and extracted with ethyl
acetate (4×30 mL). Combined organic phase was dried with Na2SO4 and evaporated under
reduced pressure to afford pure (according to 1H NMR) (S)ꢀcamphanic acid as an offꢀwhite solid
1
in 82% average yield, mp 198−200 °C (EtOAc), reported39 mp 198−199 °C; H NMR
δ 1.02 (s,
3H), 1.10 (s, 3H), 1.13 (s, 3H), 1.73 (ddd, J = 13.4, 9.3, 4.3 Hz, 1H), 1.97 (ddd, J = 13.2, 10.7,
4.6 Hz, 1H), 2.09 (ddd, J = 13.6, 9.3, 4.5 Hz, 1H), 2.47 (ddd, J = 13.4, 10.7, 4.3 Hz, 1H), 8.12
(br s, 1H).
(−)-(1R,2R,5R,6R)-2a: Obtained from (−)ꢀ5a; purification by recrystallization from CHCl3
1
afforded colorless crystals in 89% yield: mp 142−144 °C; [α]D −30 (c 1.0, CHCl3); H NMR
δ
1.46 (br s, 2H), 1.64–2.04 (m, 8H), 2.73 (t, J = 4.8 Hz, 2H), 3.95 (s, 2H), 4.10–4.20 (m, 2H),
7.20–7.38 (m, 5H); 13C NMR
δ
20.0 (CH2), 30.0 (CH2), 54.7 (CH), 56.3 (CH2), 67.9 (CH), 126.9
1
(CH), 128.1 (CH), 128.2 (CH), 139.8 (C). The H and 13C NMR spectra of racemate in CD3OD
were reported previously;15 (−)ꢀ2a was converted to (−)ꢀ2b via an exchange of the Nꢀprotecting
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group by hydrogenolysis and subsequent Boc protection, following the procedures reported
earlier.15
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(+)-(1S,2S,5S,6S)-2a: Obtained from (−)-6a; purification by recrystallization from CHCl3
afforded colorless crystals in 88% yield: mp 142−144 °C; [α]D +30 (c 1.0, CHCl3). (+)-2a was
converted to (+)ꢀ2b via an exchange of the Nꢀprotecting group by hydrogenolysis and
subsequent Boc protection, following the procedures reported earlier.15
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(−)-(1R,2R,5R,6R)-2b: Obtained from (−)ꢀ5b; purification by column chromatography on silica
gel with a petroleum ether – ethyl acetate mixture (2:8, Rf = 0.28) afforded a colorless glassꢀlike
1
solid in 98% yield: [α]D −10 (c 2.0, CHCl3); H NMR
δ 1.43 (s, 9H), 1.58−1.97 (m, 6H),
2.04−2.20 (m, 2H), 3.24 (br s, 1H), 3.81−3.92 (m, 2H), 4.01 (t, J = 4.9 Hz, 1H), 4.10 (t, J = 5.0
Hz, 1H); 13C NMR
δ
21.4 (CH2), 21.9 (CH2), 28.6 (CH3), 29.1 (CH2), 29.7 (CH2), 49.4 (CH),
50.7 (CH), 68.7 (CH), 69.5 (CH), 80.2 (C), 155.0 (C=O), in agreement with the literature data.15
Chiral HPLC of the corresponding benzoate (−)ꢀ7 (vide infra) showed 99% ee.
(+)-(1S,2S,5S,6S)-2b: Obtained from 6b; purification by column chromatography on silica gel
with a petroleum ether – ethyl acetate mixture (2:8, Rf = 0.28) afforded a colorless glassꢀlike
solid in 97% yield: [α]D +10 (c 2.0, CHCl3). Chiral HPLC of the corresponding benzoate
(+)ꢀ7 (vide infra) showed 98% ee.
General
Procedure
for
the
Synthesis
of
9-(tert-butoxycarbonyl)-9-
azabicyclo[3.3.1]nonane-2,6-diyl dibenzoates (7). For ee determination, diols 2b obtained via
fractional crystallization of camphanate esters were converted to the corresponding benzoates 7.
A mixture of diol 2b (52 mg, 0.2 mmol), DMAP (2.4 mg, 10 mol%), TEA (141 ꢁL, 1 mmol) and
benzoyl chloride (93 ꢁL, 0.8 mmol) in dry dichloromethane (3 mL) was refluxed for 48 h under
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argon atmosphere. Cooled reaction mixture was washed with water (2×5 mL), dried with
Na2SO4 and the solvent was evaporated under reduced pressure. Oily residue was purified by
column chromatography on silica gel with petroleum ether/ethyl acetate mixture (95:5, Rf =
0.24) to give the corresponding benzoate 7.
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(±)-7: Obtained from (±)ꢀ2b in 94% yield as a colorless oil, which solidified on standing: mp
1
128−130 °C; H NMR
δ 1.50 (s, 9H), 1.88−2.33 (m, 8H), 4.36 (t, J = 5.0 Hz, 1H), 4.47 (t, J =
5.0 Hz, 1H), 5.23 (dt, J = 11.7, 6.0 Hz, 2H), 7.43−7.49 (m, 4H), 7.55−7.61 (m, 2H), 8.03−8.07
(m, 4H); 13C NMR
δ
22.5 (CH2), 22.8 (CH2), 26.2 (CH2), 28.3 (CH3), 46.4 (CH), 48.0 (CH),
71.1 (CH), 71.3 (CH), 80.5 (C), 128.4 (CH), 129.6 (CH), 130.1 (C), 130.2 (C), 133.0 (C), 133.1
(C), 153.9 (C=O), 165.4 (C=O), 165.5 (C=O); IR ν 2972, 1721, 1690, 1315, 1271, 1110, 711 cmꢀ
1; HRMS (ESI) calcd for C27H31NNaO6 [M+Na]+ 488.2049, found 488.2075. Chiral HPLC
(Chiralcel IBꢀ3 column, hexane/2ꢀpropanol 99:1, 1 mL/min): t1 = 9.12 min, t2 = 10.31 min.
(−)-7: Obtained from (−)ꢀ2b as a colorless oil in 69% yield: [α]D −13 (c 1.0, CHCl3). Chiral
HPLC (Chiralcel IBꢀ3 column, hexane/2ꢀpropanol 99:1, 1 mL/min) showed 99% ee (tmajor = 9.99
min, tminor = 9.2 min).
(+)-7: Obtained from (+)ꢀ2b as a colorless oil in 71% yield: [α]D +13 (c 1.0, CHCl3); CD λmax
(ꢁε) 238 (−9.82), 231 (0), 224 (+10.23) nm; UV λmax (logε) 281 (3.08, sh), 273 (3.19), 231
(4.38) nm. Chiral HPLC (Chiralcel IBꢀ3 column, hexane/2ꢀpropanol 99:1, 1 mL/min) showed
98% ee (tmajor = 9.04 min, tminor = 10.44 min).
Lipase-Catalyzed Acetylation of (±)-2a. Candida Rugosa lipase (600 mg) was added to
the solution of diol (±)ꢀ2a (3 g, 12.1 mmol) in freshly distilled vinyl acetate (150 mL) and the
mixture was stirred for 2.5 h at 20 °C. The reaction was quenched by filtering off the enzyme
through a pad of Celite®. After evaporation of vinyl acetate the unreacted diol 2a was easily
separated from the monoacetate 8 (Rf = 0.32) and diacetate 9 (Rf = 0.71) by column
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chromatography on silica gel with petroleum ether/ethyl acetate mixture (2:1). Subsequent
elution with ethyl acetate afforded unreacted diol (1.448 g, 84% ee), which was recrystallized
from hexane/CHCl3 (1:1) mixture to afford (+)ꢀ2a (820 mg, 27%), [α]D +31 (c 1.17, CHCl3),
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99% ee, as determined by chiral HPLC of the corresponding diacetate 9 (vide infra).
Fractions containing monoacetate 8 and diacetate 9 were combined and first hydrolyzed (vide
infra) to give diol 2a (1.268 g), which was then recrystallized as described above to give (−)ꢀ2a
(700 mg, 23%), 99% ee. Almost racemic diol 2a (1.4 g) was recovered from the combined
mother liquors left after crystallizations.
In a separate experiment, a kinetic study was performed by taking aliquots from the reaction
mixture every 30 minutes: the enzyme was filtered off, the filtrate evaporated to dryness and the
obtained residue was analysed by GCꢀMS. For ee determination, the unreacted diol 2a,
monoacetate 8 and diacetate 9 were separated by column chromatography; 2a and 8 were
converted to the corresponding diacetates 9 and analysed by chiral HPLC (vide infra).
9-benzyl-6-hydroxy-9-azabicyclo[3.3.1]non-2-yl acetate (8): Yellowish oil: 1H NMR
1.64−2.05 (m, 9H), 1.98 (s, 3H), 2.67 (br s, 1H), 2.82 (br s, 1H), 3.93 (ABq, ꢀδAB = 0.07, JAB
δ
=
13.9 Hz, 2H), 4.0−4.11 (m, 1H), 5.21 (dt, J = 11.4, 5.8 Hz, 1H), 7.16−7.33 (m, 5H); 13C NMR δ
19.1 (CH2), 21.3 (CH3), 21.8 (CH2), 26.5 (CH2), 29.8 (CH2), 52.1 (CH), 54.3 (CH), 56.3 (CH2),
68.5 (CH), 70.0 (CH), 126.9 (CH), 128.1 (CH), 128.2 (CH), 139.5 (C), 170.6 (C=O); IR ν 3412,
2941, 1732, 1243, 1031, 892, 741, 699 cmꢀ1; HRMS (ESI) calcd for C17H24NO3 [M+H]+
290.1756, found 290.1765.
General Procedure for Hydrolysis of Acetates 8 and 9. Solid K2CO3 (2 eq.) was added
to a solution of diacetate 9 (or the monoacetate 8; 1 eq.) in a minimal amount of methanol. The
reaction mixture was stirred for 3 h at room temperature, then diluted with water and the product
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extracted with DCM. The organic phase was dried with Na2SO4 and evaporated under reduced
pressure. Column chromatography of the residue on silica gel with ethyl acetate gave the diol 2a
in quantitative yields.
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General Procedure for the Synthesis of 9-benzyl-9-azabicyclo[3.3.1]nonane-2,6-diyl
diacetates (9). For ee determination, diol 2a and monoacetate 8 obtained via kinetic resolution
using CRL were converted to the corresponding diacetates 9. Acetic anhydride (5 eq.) and
DMAP (2 mol%) were added to the solution of diol 2a (or monoacetate 8; 1 eq.) in a minimal
amount of dichloromethane. The reaction mixture was stirred at room temperature overnight,
and then neutralized with saturated aqueous NaHCO3 solution. The product was extracted with
dichloromethane, the organic phase was dried with Na2SO4 and evaporated under reduced
pressure. Column chromatography of the residue on silica gel with petroleum ether/ethyl acetate
mixture (85:15, Rf = 0.44) gave 9 as a colorless oil in quantitative yields.
1
(±)-9: Obtained from (±)ꢀ2a: H NMR
δ 1.76−2.11 (m, 8H), 2.02 (s, 6H), 2.83−2.88 (m, 2H),
3.93 (d, J = 14.0 Hz, 1H), 4.03 (d, J = 14.0 Hz, 1H), 5.18−5.25 (m, 2H), 7.20−7.37 (m, 5H); 13C
NMR δ 20.8 (CH2), 21.1 (CH3), 26.2 (CH2), 51.5 (CH), 56.2 (CH2), 70.2 (CH), 126.9 (CH),
128.0 (CH), 128.1 (CH), 139.0 (C), 170.3 (C=O); IR ν 2959, 1733, 1369, 1230, 1029 cmꢀ1;
HRMS (ESI) calcd for C19H26NO4 [M+H]+ 332.1862, found 332.1864. Chiral HPLC (Chiralcel
IAꢀ3 column, hexane/2ꢀpropanol 99:1, 1 mL/min): t1 = 7.14 min, t2 = 8.35 min.
(−)-9: Obtained from (−)ꢀ2a: [α]D −7 (c 1.0, CHCl3). Chiral HPLC (Chiralcel IAꢀ3 column,
hexane/2ꢀpropanol 99:1, 1 mL/min) showed 99% ee (tmajor = 7.34 min, tminor = 8.43 min).
(+)-9: Obtained from (+)ꢀ2a. Chiral HPLC (Chiralcel IAꢀ3 column, hexane/2ꢀpropanol 99:1, 1
mL/min) showed 99% ee (tmajor = 8.41 min, tminor = 7.37 min).
Computational details. Conformational search of 4a and 7 was performed with
SPARTAN’1040 using MonteꢀCarlo method and MMFF94 force field. The minimum energy
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Page 29 of 34
The Journal of Organic Chemistry
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conformers found by molecular mechanics were further optimized using DFT at B3LYP/6ꢀ
31G(d) level. In the case of 4a, the obtained conformers were additionally optimized at
B3LYP/6ꢀ311G++(d,p) level using Gaussian software41 followed by calculations of their
harmonic vibrational frequencies to verify their stability and to calculate conformational free
energies; population percentages were calculated using ꢁG and applying Boltzmann statistics at
T= 298.15 K.
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The electronic circular dichroism calculations of the conformers were carried out by means of
the Gaussian software employing the TDDFT approach, the B3LYP functional and the 6ꢀ
311G++(2d,2p) basis set. The rotational strength calculations were carried out both in velocity
(Rvel) and length formalism (Rlen); the results in the two formalisms were almost identical. The
CD spectra of the individual conformers were simulated by overlapping Gaussian functions for
each transition35 using SpecDis.42 The halfꢀwidth at 1/e of the peak maximum (σ) value of 0.26
eV and Rvel were used in this work. The calculated CD spectrum of 4b was Boltzmann averaged
according to the population percentages of individual conformers and was blueꢀshifted by 13 nm
in relation to the experimental ones to match the experimental λmax value of the long wavelength
CE.
Acknowledgments
This research was funded by the European Social Fund under the Global Grant measure
(VP1ꢀ3.1ꢀŠMMꢀ07ꢀKꢀ01ꢀ030). V. B. acknowledges Lithuanian Science Council for Student
Research Fellowship Award. We are grateful to prof. V. Šikšnys, Institute of Biotechnology,
Vilnius University, for providing access to the CD spectrometer and Dr. G. Bagdžiūnas for the
recording of the CD data. Dr. A. Stončius, Center for Physical Sciences and Technology, is
acknowledged for the GCꢀMS analysis.
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