Fluorescence screening of tartaric acid-derived azamacrocycles synthesized via sequential hydroformylation/reductive amination as potential ligands for asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2005.03.035

Azamacrocycles containing a tartaric acid-derived unit and aryl units were synthesized via rhodium-catalyzed hydroformylation while the subsequent reductive amination was carried out in a tandem or stepwise fashion. Upon fluorescence emission experiments,

Full text of DOI:10.1016/j.tetasy.2005.03.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1919–1926
Fluorescence screening of tartaric acid-derived azamacrocycles
synthesized via sequential hydroformylation/reductive amination
as potential ligands for asymmetric catalysis
Goran Angelovski,a, Mark D. Keranenb,* and Peter Eilbrachta,*
¨
aFachbereich Chemie, Organische Chemie I, Universita¨t Dortmund, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
bDepartment of Math, Science & Technology, University of Minnesota, Crookston, 2900 University Ave., Crookston MN 56716, USA
Received 26 January 2005; accepted 30 March 2005
Abstract—Azamacrocycles containing a tartaric acid-derived unit and aryl units were synthesized via rhodium-catalyzed hydro-
formylation while the subsequent reductive amination was carried out in a tandem or stepwise fashion. Upon fluorescence emission
experiments, some of the macrocycles showed chelating affinities toward transition metals such as zinc or rhodium.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Macrocycles potentially have improved characteristics
as chiral auxiliaries over their acyclic analogues, as the
decrease in the number of diastereomeric transition
states in many metal-catalyzed enantioselective pro-
cesses can be even higher,14 due to the presence of other
groups on the macrocycle which can both contribute to
the rigidity of the system and act as complexing/direct-
ing moieties able to influence the enantioselectivity of
a process.
Chiral macrocycles serve a wide variety of functions in
asymmetric reactions, from acting as reagents for the
optical resolution of amino acids and their derivatives,
substrates for ion complexation, ligands in asymmetric
synthesis to act as carbohydrate mimics in building en-
zyme models.1 One of the more widely-used chiral units
in catalysis is derived from L-tartaric acid, a very inex-
pensive and easily available compound. Acyclic tartaric
acid derivatives are used as phosphorus or nitrogen
ligands in asymmetric hydrogenation,2 allylboration,3
epoxidation,4 or in the stereoselective addition of
organometallics to a carbonyl group as seen with TAD-
DOL type ligands.5 Furthermore, amides derived from
tartaric acid are used as the resolving agent when ab-
sorbed on silica6 in the resolution of both a-amino acid
derivatives or complexes of platinum(II) with tartaric
acid amine derivatives, some of which exhibit antitumor
activity.7 There are numerous reports of syntheses8 and
applications of L-tartaric acid-based crowns or aza-
crowns. They can be used in selective ion complexation,9
ion transport,10 chiral recognition,11 molecular cataly-
sis,12 or as photoionophores.13
In previous reports,15,16 we have demonstrated efficient
syntheses of azamacrocycles containing aryl and piper-
azine units via tandem (hydroaminomethylation) or
stepwise (regioselective hydroformylation followed by
reductive amination) processes. This work applies these
methods toward the synthesis of azamacrocycles con-
taining tartaric acid-derived units and investigates their
use as ligands in asymmetric synthesis by employing a
rapid fluorescence spectroscopic assay. Fluorescence
screening was chosen as the method of evaluation due
to its high sensitivity toward detecting the interactions
of fluorophores with metals.17
2. Results and discussion
*
Corresponding authors. Tel.: +49 231 755 3858; fax: +49 231 755
5363 (P.E.); tel.: +1 218 281 8188; fax: +1 218 281 8250 (M.D.K.);
e-mail addresses: keran004@umn.edu; peter.eilbracht@udo.edu
Current address: Max Planck Institute for Biological Cybernetics,
The synthesis of azamacrocycles via sequential hydro-
formylation/reductive amination requires both a diolefin
and diamine. Depending on the desired structure and
recognition abilities, which we want to be present in
Tubingen, Germany.
¨
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.035

1920
G. Angelovski et al. / Tetrahedron: Asymmetry 16 (2005) 1919–1926
HO
O
OH
O
O
O
O
O
a)
b)
O
O
O
O
L
-tartaric acid
1
2
O
Bn
N
O
O
O
3a,
O
O
0.4 % [Rh(acac)(CO)2]
O
O
0.4 % [Rh(acac)(CO)2]
O
O
2
40 bar H2
50 oC, toluene
38 %
O
N
Bn
30 bar CO/H2 (1:1)
70 oC, CH2Cl2
86 %
O
5
4, 1:1 dr
O
O
BnHN
NHBn
( )n
3a, n=6; 3b, n=3
3a, 0.4 % [Rh(acac)(CO)2], 80 bar CO/H2 (1:1), 80 oC, toluene, 32 %
Scheme 1. Reagents and conditions: (a) methylallyl chloride, Et3N, DMF, 63%; (b) 2,2-dimethoxypropane, p-TsOH(cat.), C6H6, 59%.
the final compound, various groups can be included in
one or both precursors. Our plan was to synthesize
chiral olefins containing ester or amine derivatives of
tartaric acid. Furthermore, to prevent the formation of
regioisomers, olefins bearing methylallyl groups were
synthesized. Acetonide-protected tartaric acid methyl-
allyl ester 2 was made starting from L-tartaric acid in
two steps (Scheme 1). Subsequent esterification of the
acid with methallyl chloride was performed according
to a modified procedure,18 giving ester 1 in 63% isolated
yield. The second step was the protection of the diol as
an acetonide with 2,2-dimethoxypropane.
of azamacrocycle 10a was 44%, while when using amine
3b,19b the yield of azamacrocycle 10b was 57% (Scheme
2).
O
O
O
O
O
O
O
O
b)
a)
BnHN
NHBn
EtO
OEt
7
6
O
O
O
O
Bn
N
Bn
N
c)
The synthesis of azamacrocycle 5 using diamine 3a19a
was performed using two methods, first via the hydro-
aminomethylation and second via the stepwise hydro-
formylation/reductive amination sequence (Scheme 1).
The isolated yield of 5 in the first case (tandem reaction)
was 32%, while in the stepwise method, aldehyde 4 was
isolated in 86% after the hydroformylation step. The
purity of aldehyde 4 was sufficient enough for it to be
used in the next step without further purification. The
subsequent rhodium-catalyzed reductive amination/
cyclization step was performed by adding amine 3a to
aldehyde 4, stirring the mixture until imine/enamine
formation was complete, and finally pressurizing the
mixture with H2.
BnHN
NHBn
8
9
3a or 3b
0.4 % [Rh(acac)(CO)2]
N
O
N
N
9
( )n
O
N
80 bar CO/H2 (1:1)
80 oC, toluene
44-57%
10a-b, 1:1 dr
10a: n=5, 44%
10b: n=2, 57%
Scheme 2. Reagents and conditions: (a) BnNH2, K2CO3, MeOH, 94%;
(b) LiAlH4, 1,4-dioxane, 78%; (c) methallylchloride, NaOH, i-PrOH,
37%.
After this encouraging result, attempts at the generation
of a tetraazamacrocycle were made. For this purpose,
an aminodiolefin derived from tartaric acid was
synthesized. Protected diester 6 was prepared from
commercially available (+)-diethyl L-tartrate and 2,2-
dimethoxypropane according to a literature proce-
dure.20 Diamide 7 was synthesized in 94% yield after
the amidation of 6 with benzylamine, using K2CO3 in
methanol. This represents an improvement upon a pre-
viously reported synthesis21 of 7 which gave the amide
after four synthetic steps when starting from dimethyl
L-tartrate. Amide 7 was sufficiently pure to be taken
on to reduction with LiAlH4 to give diamine 8 in 78%
yield. Finally, methallylation of 8 proceeded to give
bis-methallyl amine 9 in 37% yield. Ultimately, two
hydroaminomethylation reactions were performed with
diolefin 9. When paired with amine 3a, the final yield
NMR spectra of 10a and 10b showed that these were
very rigid structures. There was signal splitting present
in almost every resonance in the 13C NMR spectrum
of both compounds. This rigidity could in some way
be expected, as both of the tetraazamacrocycles not only
have benzyl groups on their nitrogens but also a 1,3-
dioxolane ring within the macrocycle making the entire
system prone to rigid conformations. A similar result
was also observed in cases where only the two benzyl
groups were present in the macrocycle.15
After the synthesis of chiral macrocycles containing a
tartaric acid unit, our subsequent goal was the synthesis
and incorporation of a second chiral unit into the
macrocycle. Our previous experience in the synthesis

G. Angelovski et al. / Tetrahedron: Asymmetry 16 (2005) 1919–1926
1921
of macrocycles containing an (S)-BINOL unit15 via
hydroaminomethylation prompted us to carry out an
analogous synthesis in this case. Amine 8, a secondary
amine, is appropriate for use in this methodology, while
hydroaminomethylation was performed with olefin 1122
to give BINOL-macrocycle 12 in 30% isolated yield as a
1:1 mixture of diastereoisomers as determined by NMR
(Scheme 3).
O
O
N
N
O
O
O
O
15
O
O
O
O
13
N
0.4 mol % [Rh(acac)(CO)2]
O
O
O
O
8 + 11
N
N
O
80 bar CO/H2 (1:1)
80 oC, toluene
30 %
O
O
N
O
12, 1:1 dr
16
Scheme 3.
Figure 1.
This result was better than expected for the coupling of
two rigid units, and thus the stepwise method was also
performed to see if further gains in product yields could
be obtained. Starting from dialdehydes 1315 and 1416
and amine 8, two macrocycles having aryl and chiral
units were synthesized (Fig. 1). The isolated yield of aza-
macrocycle 15 containing a resorcinol unit was low after
several attempts (15%), which indicates that the rigidity
of the compound is quite high and that cyclization
cannot be easily accomplished. The isolated yield of
compound 16 was comparable to the tandem reaction
ꢀ39%. Even though full rotation of the C1–C10 bond
of the BINOL unit is not possible, a small degree of
naphthol movement is possible, making the whole sys-
tem more flexible and allowing for the cyclization to
proceed at a higher yield than in the case of the resor-
cinol derivative 15.
has two chiral units, one of which (BINOL) is com-
monly employed in ligands used in catalytic asymmetric
transformations.24 As BINOL is also a suitable fluoro-
phore, we used it to investigate the complexation of
aryl-containing azamacrocycles with some transition
metals commonly used in catalysis, such as rhodium,
zinc, or titanium.
For this investigation, we dissolved macrocycles 15, 16,
and 18 in acetonitrile and performed fluorescent spec-
troscopy measurements upon the addition of various
amounts of metals. The first experiment was the titra-
tion of 15 with Zn2+ (Fig. 2). Enhancement of the emis-
sion signal was observed until addition of one equivalent
of metal, where it remained constant upon the addition
of more metal to the system. This likely indicates the
formation of a 1:1 complex between the macrocycle
and zinc.
One final synthetic transformation was performed by
removing the acetonide from the diol in 15 (Scheme
4). Following mild acidic cleavage, macrocyclic diol 18
was obtained in 65% isolated yield. Alternatively 18
was synthesized via the stepwise reductive amination/
cyclization reaction starting from aldehyde 14 and di-
amine 17.23 Although, this route should be easier as it
required fewer synthetic steps, the compound obtained
this way was more difficult to purify sufficiently since
the macrocyclic amino alcohol is very polar and makes
for difficult silica gel chromatography.
Experiments using 15 with rhodium and titanium failed
to show any noticeable interaction with the host. One
can rapidly conclude, however, that chelation of 15 with
zinc is effective, and that this ligand:metal pair would be
worth further investigation in asymmetric reactions
where zinc is used as the catalyst.
Fluorescence experiments with 16 showed somewhat
different results. While effective complexation with zinc
and titanium was not observed, quenching of the fluo-
rescence was seen this time upon the addition of rho-
dium. Since this effect can be due either to complex
The macrocycles obtained via the previously described
syntheses have very interesting structures, possessing
both chiral and aryl units. Furthermore, macrocycle 16
Bn
H2/[Rh]
HO
OH
O
O
O
O
2M HCl
N
N
O
O
50 oC, 1d
70 oC, 3h
O
O
O
O
OH
OH
+
15
Bn NH
HN Bn
toluene
64 %
MeOH
65 %
Bn
17
14
18
Scheme 4.

1922
G. Angelovski et al. / Tetrahedron: Asymmetry 16 (2005) 1919–1926
1.11
1.10
1.09
1.08
1.07
1.06
1.05
1.04
1.4
25oC
40oC
1.3
1.2
1.1
1.0
2
4
6
8
10
12
5
10
15
20
25
Concentration of Zn2+ (µM)
Concentration of Rh3+ (µM)
Figure 2. Enhancement of the fluorescence intensity of 15 (10 lM,
Figure 4. Quenching of the fluorescence intensity of 17 (20 lM,
kex = 308 nm, CH3CN, 25 ꢁC) upon addition of ZnCl2.
k
ex = 308 nm, CH3CN, 25 and 40 ꢁC) upon addition of RhCl3.
Calculated values for 25 ꢁC: Ks = 15.13 · 10ꢀ2 molꢀ1 (r = 0.9988), for
40 ꢁC: Ks = 8.29 · 10ꢀ3 molꢀ1 (r = 0.9991).
formation between the fluorophore and the quencher
(static quenching) or due to collisions between the fluo-
rophore and the quencher (dynamic quenching),25
experiments were performed at two different tempera-
tures (25 ꢁC and 40 ꢁC). With an increase of the tempera-
ture, static quenching was expected to be lower (complex
formation is disfavored at higher temperatures), while
the physical collisions involved in the dynamic quench-
ing should be higher at higher temperatures. As shown
in Figure 3, the quenching of the fluorescence emission
was lower when increasing the temperature, clearly indi-
cating that rhodium does indeed form a complex with
macrocycle 16.
F0/F = 1 + Ks[Q].25 The calculated values were approxi-
mately halved in both cases when the temperature was
increased from 25 to 40 ꢁC.
An interesting relationship was noticed between the
structure of the azamacrocycle and its affinity for chelat-
ing different metals. Although macrocyles 15 and 18
have similar structures and sizes of the macrocyclic cav-
ity, they chelate drastically different metals (15 chelates
Zn, 18 chelates Rh). This property is potentially impor-
tant since this difference in affinity results from a simple
synthetic transformation, such as deprotection of the
acetonide. Furthermore, the difference in affinities of
15 and 16 toward rhodium might be due to the distance
of two ether oxygens from one another. In macrocycle
16 they are closer and can participate more in chelation,
while in 15 they are further apart from one another.
25oC
1.16
40oC
1.14
1.12
1.10
1.08
1.06
1.04
1.02
1.00
3. Conclusion
In conclusion, we have reported a procedure for the
efficient synthesis of azamacrocycles containing chiral
(tartaric acid derivatives) and aryl units via hydro-
aminomethylation strategies. Depending on the choice
of reactants, the chiral unit can be easily introduced
either as part of the aldehyde or the amine required
for the reductive amination/cyclization step. This is an
additional example of tandem and stepwise hydroformyl-
ation/reductive amination reactions offering various
options for the rapid synthesis of azamacrocycles
bearing various functional groups.
0
5
10
15
20
25
30
35
Concentration of Rh3+ (µM)
Figure 3. Quenching of the fluorescence intensity of 16 (20 lM,
k
ex = 337 nm, CH3CN, 25 and 40 ꢁC) upon addition of RhCl3.
Calculated values for 25 ꢁC: Ks = 4.89 · 10ꢀ2 molꢀ1 (r = 0.9974), for
40 ꢁC: Ks = 2.28 · 10ꢀ2 molꢀ1 (r = 0.9956).
The same results were observed with compound 18.
Upon addition of rhodium to its solution in acetonitrile,
an analogous quenching of the fluorescence intensity is
observed (Fig. 4). Temperature dependent experiments
were performed again, confirming the formation of a
ligand:metal complex which is more stable at lower
temperatures.
In addition, the complexation of some macrocycles with
zinc and rhodium was investigated. The selectivity of
complexation for these metals differs, and complex sta-
bility seems to be greatly dependent on the structure
of the macrocycle. Nonetheless, these results are both
promising and encouraging, showing that these easily-
synthesized compounds can be used as asymmetric
ligands for zinc and rhodium.
Static quenching constants were calculated upon fitting
of the curves according to the Stern–Volmer equation:

G. Angelovski et al. / Tetrahedron: Asymmetry 16 (2005) 1919–1926
1923
4. Experimental
4.1. General remarks
ride (13 mL, 132.8 mmol) in 10 mL of dry DMF added
over a period of 3 h. The reaction mixture was stirred
overnight at room temperature. The solvent was
removed in vacuo at <35 ꢁC. The residue was taken up
in 40 mL of EtOAc and washed with 2 · 20 mL ice
water, 2 · 20 mL ice cold saturated NaHCO3 solution,
and 2 · 10 mL of saturated NaCl solution. The organic
layer was dried to give 5.43 g (63%) of crude 1 as a
yellow oil. Compound 1 was used for the next reaction
without further purification. An analytical sample was
prepared after purification by column chromatography
(silica gel, n-hexane:Et2O 9:1). 1H NMR (400 MHz,
CDCl3): d = 4.98 (s, 2H), 4.92 (s, 2H), 4.66–4.58 (m,
6H), 3.46 (br s, 2H), 1.72 (s, 6H). 13C NMR
(100 MHz, CDCl3): d = 171.16, 138.94, 113.87, 72.09,
69.27, 19.22. IR (film, NaCl), m [cmꢀ1] = 3489, 2945,
1747, 1660, 1452, 1379, 1269, 1128, 1091, 908. EA for
C12H18O6 (258.27 g/mol) calcd: C, 55.8; H, 7.0. Found:
All chemicals were purchased from commercial sources
and used without further purification. 1H and 13C
NMR spectra were recorded at room temperature with
a Bruker DRX 400 and DRX 500 spectrometers. Unless
otherwise specified, CDCl3 was used as solvent with
TMS (0.00 ppm) as the internal standard. The 13C
NMR spectra were referenced to CDCl3 (77.00 ppm).
FTIR spectra were performed on a Nicolet Impact 400
D spectrometer using neat compounds as films between
NaCl plates or as KBr pellets. Mass spectra were
recorded with a JEOL JMS-SX 102A spectrometer
(FAB), on Finnigan MAT TSQ spectrometer (ESI)
and Finnigan MS 8200 spectrometer (EI, 70 eV). GC–
MS coupling was recorded on Finnigan ION-TRAP
spectrometer (model 800, EI, 70 eV) with Aerograph
8521-a (CP-Sil-5CB 25 m) from Dani. Elemental analy-
ses were performed with a Leco CHNS-932 analyzer.
Optical rotations were performed on a Perkin Elmer
341 polarimeter. Fluorescence measurements were per-
formed with a Perkin Elmer LS 50B spectrofluorometer
at 25 and 40 ꢁC. Column chromatography was carried
out on silica gel 60 (70–230 mesh ASTM) from Mache-
C, 55.6; H, 7.0. MS (FAB): 281 [M+Na]+, 259
20
D
[M+H]+. ½aꢁ =+21.9 (c 0.5, CH2Cl2).
4.1.2. Preparation of (4R,5R)-2,2-dimethyl-[1,3]dioxolane-
4,5-dicarboxylic acid bis-(2-methylallyl) ester 2. To a
stirred solution of 1 (1.02 g, 3.95 mmol) and p-TsOH
(13 mg, 68 lmol) in benzene (7 mL) at room temperature
was
added
2,2-dimethoxy
propane
(495
rey-Nagel GmbH & Co. KG, Duren, or Alumina N
¨
mg, 4.75 mmol). The reaction mixture was heated at
80 ꢁC for 3 h while benzene–MeOH azeotrope was
distilled. After cooling, the reaction mixture was
neutralized with 20 mg of anhydrous Na2CO3. The
resulting suspension was subjected to a short-path
column chromatography (silica gel, n-hexane/EtOAc
10:1) and the combined fractions concentrated under
reduced pressure to give an oil. The crude product was
purified by column chromatography (silica gel, n-hex-
ane/EtOAc 95:5) to give 692 mg (59%) of 2 as a yellow
(Activity III) from ICN Biomedicals, Eschwege. Pres-
sure reactions were carried out in autoclaves of type A
(250 mL, PTFE insert) from Berghof, Eningen or similar
housemade autoclaves (100 mL, stainless steel) with spe-
cially designed heating and stirring mantles.
General procedure for reactions in the autoclave: After
charging the autoclave with the starting material, the
catalyst precursor, and the solvent, the reactor was
flushed with argon, pressurized with H2 and CO, and
heated to the required reaction temperature. Following
the reaction, the solvent was removed by rotary evapo-
ration and the products were purified by column
chromatography.
1
oil. H NMR (400 MHz, CDCl3): d = 4.96 (s, 2H), 4.91
(s, 2H), 4.78 (s, 2H), 4.58 (s, 4H), 1.71 (s, 6H), 1.46 (s,
6H). 13C NMR (100 MHz, CDCl3): d = 169.20, 138.88,
113.80, 77.07, 68.84, 26.27, 19.33. IR (film, NaCl), m
[cmꢀ1] = 2989, 1766, 1660, 1454, 1383, 1375, 1205,
1113, 999, 908. EA for C15H22O6 (298.34 g/mol) calcd:
General method A: hydroaminomethylation reaction:
Diolefin, diamine, and catalyst were dissolved in toluene
and placed in the autoclave. The autoclave was pressur-
ized with CO and H2 and heated. After cooling, the sol-
vent was removed in a rotary evaporator and the crude
mixture purified by column chromatography.
C, 60.4; H, 7.4. Found: C, 60.5, H, 7.5. MS (FAB): 321
20
[M+Na]+, 299 [M+H]+. ½aꢁ =ꢀ37.6 (c 1.1, CH2Cl2).
D
4.1.3. Preparation of (4R,5R)-2,2-dimethyl-[1,3]dioxolane-
4,5-dicarboxylic acid bis-(2-methyl-4-oxo-butyl) ester
4. Compound
2 (195 mg, 0.65 mmol), [Rh(acac)-
(CO)2] (4 mg, 16 lmol) was dissolved in CH2Cl2
(10 mL) and placed in the autoclave. The autoclave
was pressurized with 80 bar CO:H2 (1:1) and heated at
80 ꢁC for 18 h. After cooling the solvent was removed
in a rotary evaporator and the crude mixture purified
by column chromatography (silica gel, CH2Cl2) to give
200 mg (86%) of 4 as a colorless oil. 1H NMR
(500 MHz, CDCl3): d = 9.70 (s, 2H), 4.68 (s, 2H),
4.11–4.08 (m, 2H), 4.02–3.98 (m, 2H), 2.51–2.42 (m,
4H), 2.33–2.28 (m, 2H), 1.43 (s, 6H), 0.97 (d,
J = 6.5 Hz, 6H). 13C NMR (125 MHz, CDCl3):
d = 200.76, 169.40, 113.92, 7.05, 69.57, 47.51, 27.62,
26.31. IR (film, NaCl), m [cmꢀ1] = 2964, 2939, 1755,
1724, 1464, 1377, 1259, 1207, 1165, 1109, 1016. GC–
MS: 358.5 [M]+, 252.1, 207.2, 178.2.
General method B: reductive amination reaction: Dialde-
hyde, diamine, and catalyst were dissolved in toluene,
placed in the autoclave and stirred at room temperature
for 1 h. The autoclave was pressurized with H2 and
heated. After cooling, the solvent was removed in a
rotary evaporator and the crude mixture purified by
column chromatography.
4.1.1. Preparation of (2R,3R)-2,3-dihydroxy-succinic acid
bis-(2-methylallyl) ester 1. To a solution of (2R,3R)-
tartaric acid (5.01 g, 33.4 mmol) in 15 mL of sieve-dried
DMF at 0 ꢁC under nitrogen, was added Et3N (18.5 mL,
133.5 mmol). The reaction mixture was allowed to warm
to room temperature and a solution of methylallyl chlo-

1924
G. Angelovski et al. / Tetrahedron: Asymmetry 16 (2005) 1919–1926
4.1.4. Preparation of 10,17-dibenzyl-2,2,7,20-tetramethyl-
octadecahydro-1,3,5,22-tetraoxa-10,17-diaza-cyclopenta-
cyclodocosene-4,23-dione 5. General method A: Com-
pound 2 (181 mg, 0.61 mmol), 3a (180 mg, 0.61 mmol)
and [Rh(acac)(CO)2] (7 mg, 27 lmol) were dissolved in
toluene (40 mL), pressurized with 80 bar CO:H2 (1:1),
heated at 80 ꢁC for 2 d and purified by column chroma-
tography (silica gel, CH2Cl2:MeOH 97:3) to give 123 mg
(32%) 5 as a colorless viscous oil.
EA for C21H28N2O2 (340.47 g/mol) calcd: C, 74.1; H,
8.3; N, 8.2. Found: C, 73.9; H, 8.4; N, 8.0. HRMS
(FAB): calcd: 341.2229 [M+H]+, found: 341.2241.
20
D
½aꢁ =ꢀ14.6 (c 0.7, CH2Cl2).
4.1.7. Preparation of (4S,5S)-benzyl-(5-{[benzyl-(2-meth-
ylallyl)-amino]-methyl}-2,2-dimethyl-[1,3]dioxolan-4-yl-
methyl)-(2-methylallyl)-amine 9. To a mixture of 8
(1.75 g, 5.14 mmol) in i-PrOH (15 mL), methylallyl chlo-
ride (1.40 g, 15.46 mmol) was added dropwise and kept
for 2 h at 50–60 ꢁC, after which the reaction mixture
was neutralized with 40% NaOH (1 mL) and stirred
for 30 min. Then, another 1.40 g of methylallyl chloride
was added, and the mixture stirred for 2 h at 80 ꢁC. The
reaction was cooled and treated with 40% NaOH
(1 mL). Isopropanol was removed in a rotary evapora-
tor and water (20 mL) added to the mixture. The aque-
ous layer was extracted with Et2O (3 · 30 mL), the
organic phase washed with brine, dried over MgSO4
and the solvent removed in vacuo. The crude product
was purified by column chromatography (silica gel,
CH2Cl2:EtOAc 9:1) to give 847 mg (37%) of 9 as a yel-
low viscous oil. 1H NMR (400 MHz, CDCl3):
d = 7.25–7.12 (m, 10H), 4.81 (br s, 2H), 4.73 (br s,
2H), 3.76–3.74 (m, 2H), 3.52 (dd, J = 78.8, 13.8 Hz,
4H), 2.90 (dd, J = 56.2, 13.5 Hz, 4H), 2.47 (ddd,
J = 52.2, 13.2, 2.0 Hz, 4H), 1.63 (s, 6H), 1.25 (s, 6H).
13C NMR (100 MHz, CDCl3): d = 143.73, 139.57,
128.86, 128.07, 126.70, 112.88, 108.75, 48.76, 61.52,
General method B: Compound 4 (170 mg, 0.47 mmol),
3a (141 mg, 0.48 mmol) and [Rh(acac)(CO)2] (6 mg,
23 lmol) were dissolved in toluene (40 mL), pressurized
with 40 bar H2, heated at 50 ꢁC for 1 d and purified by
column chromatography (silica gel, CH2Cl2:MeOH
97:3) to give 110 mg (38%) 5 as a colorless viscous oil.
1H NMR (500 MHz, CDCl3): signals for a 1:1 mixture
of diastereoisomers: d = 7.25–7.20 (m, 8H), 7.17–7.13
(m, 2H), 4.72–4.69 (m, 2H), 4.03–3.91 (m, 4H), 3.52–
3.46 (m, 2H), 3.41–3.34 (m, 2H), 2.38–2.26 (m, 8H),
1.94–1.88 (m, 2H), 1.57–1.48 (m, 2H), 1.45 (s, 6H),
1.43–1.35 (m, 4H), 1.28–1.18 (m, 6H), 0.77 (dd,
J = 6.0, 3.2 Hz, 6H). 13C NMR (125 MHz, CDCl3): sig-
nals for a 1:1 mixture of diastereoisomers: d = 169.65
and 169.62, 139.99 and 139.96, 128.82, 128.06, 126.71,
113.83, 77.27, 70.59 and 70.54, 59.14, 53.37 and 53.31,
50.79 and 50.70, 30.66 and 30.63, 30.45 and 30.37,
27.14 and 27.00 and 26.95 and 26.91, 26.46, 16.74 and
16.68. IR (film, NaCl), m [cmꢀ1] = 2931, 2856, 2796,
1761, 1454, 1373, 1254, 1205, 1111, 1078, 735, 698.
HRMS (FAB) for C37H54N2O6 calcd: 622.3982 [M]+,
found: 622.3994.
58.73, 55.66, 27.23, 20.83. IR (film, NaCl),
m
[cmꢀ1] = 2983, 2933, 2798, 1452, 1379, 1369, 1065, 897,
739, 698. EA for C29H40N2O2 (448.65 g/mol) calcd: C,
77.6; H, 9.0; N, 6.2. Found: C, 77.7; H, 9.2; N, 6.0.
HRMS (FAB): calcd: 447.3012 [M+H]+, found:
20
D
4.1.5. Preparation of (4R,5R)-2,2-dimethyl-[1,3]dioxol-
ane-4,5-dicarboxylic acid bis-benzylamide (7). A mix-
ture of 6 (5.01 g, 20.34 mmol), benzylamine (5.24 g,
48.90 mmol), K2CO3 (0.67 g, 4.85 mmol) and MeOH
(50 mL) was refluxed for 18 h and then cooled. Excess
benzylamine was removed by distillation under reduced
pressure (0.2 mbar) to give 7.08 g (94%) of 7 as a reddish
viscous oil, which was used for the next step without
further purification. Spectroscopic data for 7 were the
same as reported in the literature.21
447.3015. ½aꢁ =+5.0 (c 1.0, CH2Cl2).
4.1.8. Preparation of (4S,5S)-5,10,17,22-tetrabenzyl-2,2,7,20-
tetramethyl-docosahydro-1,3-dioxa-5,10,17,22-tetraaza-cyclo-
pentacyclodocosene (10a). General method A: Compound
9 (115 mg, 0.26 mmol), 3a (79 mg, 0.27 mmol) and
[Rh(acac)(CO)2] (4 mg, 16 lmol) were dissolved in
toluene (40 mL), pressurized with 80 bar CO:H2 (1:1),
heated at 80 ꢁC for 3 d and purified by column chroma-
tography (silica gel, CH2Cl2:MeOH 97:3) to give 89 mg
1
(44%) 10a as a yellow viscous oil. H NMR (500 MHz,
4.1.6. Preparation of (4S,5S)-benzyl-[5-(benzylamino-methyl)-
2,2-dimethyl-[1,3]dioxolan-4-ylmethyl]-amine 8. LiAlH4
(1.90 g, 50.07 mmol) was suspended into 100 mL abs.
dioxane. A solution of 7 (7.05 g, 19.1 mmol) in 50 mL
of abs. dioxane was added dropwise and mixture re-
fluxed for 18 h. After cooling, 3 mL of water were added
slowly to the solution, followed by 3 mL of 10% NaOH
and 5 mL water. The solution was filtered and solvent
evaporated to give 5.07 g (78%) of crude 8 as a yellow
viscous oil. An analytical sample was prepared by
column chromatography purification (Al2O3N, Act III,
CDCl3): signals for a mixture of diastereoisomers:
d = 7.26–7.12 (m, 20H), 3.86–3.70 (m, 3H), 3.63–3.56
(m, 1H), 3.54–3.47 (m, 3H), 3.42–3.34 (m, 3H), 2.61–
2.44 (m, 4H), 2.38–2.24 (m, 8H), 2.20–2.08 (m, 4H),
1.69–1.50 (m, 4H), 1.44–1.38 (m, 4H), 1.28–1.25 (m,
6H), 1.22–1.17 (m, 4H), 1.09–0.98 (m, 2H), 0.79–0.65
(m, 6H). 13C NMR (125 MHz, CDCl3): signals for a
mixture of diastereoisomers: d = 140.20 and 139.82 and
139.76 and 139.49, 129.20 and 129.09 and 128.97
and 128.83 and 128.71, 128.24 and 128.13 and 127.99
and 126.86, 126.79 and 126.67 and 126.64 and 126.57,
108.88 and 108.79 and 108.59, 79.43 and 79.29, 78.30
and 78.25, 62.73 and 62.33 and 61.79, 61.40 and 61.29,
60.09 and 59.98 and 59.84, 59.66 and 59.55, 59.22 and
59.13, 57.54 and 56.81 and 56.59 and 56.06, 54.79, 53.42
and 53.36 and 53.31, 51.19 and 51.11 and 50.93,
32.11 and 31.93, 29.46 and 29.33 and 29.13 and 28.83,
27.33 and 27.30, 27.26 and 27.15 and 27.06 and 26.98
1
CH2Cl2). H NMR (500 MHz, CDCl3): d = 7.23–7.21
(m, 8H), 7.18–7.15 (m, 2H), 3.90–3.85 (m, 2H), 3.73 (s,
4H), 2.73–2.67 (m, 4H), 1.62 (br s, 2H), 1.31 (s, 6H).
13C NMR (125 MHz, CDCl3): d = 140.10, 128.33,
128.02, 126.90, 108.70, 78.74, 53.98, 51.16, 27.17. IR
(film, NaCl), m [cmꢀ1] = 2983, 2931, 2825, 1495, 1454,
1379, 1369, 1254, 1215, 1167, 1072, 1028, 737, 698.

G. Angelovski et al. / Tetrahedron: Asymmetry 16 (2005) 1919–1926
1925
and 26.86, 18.42 and 18.37 and 18.33 and 18.27. IR (film,
NaCl), m [cmꢀ1] = 3026, 2929, 2856, 2796, 1495, 1452,
1377, 1369, 1259, 1240, 1066, 1028, 804, 735, 698. HRMS
(FAB) for C51H72N4O2 calcd: 772.5655 [M]+; found:
772.5631.
123.38 and 123.29 and 123.26, 121.39 and 120.79 and
120.73 and 120.29, 116.70 and 116.12 and 115.49 and
115.45, 108.76 and 108.73, 78.98 and 78.92 and 78.71
and 78.62, 75.02 and 74.89 and 74.27 and 73.67, 59.60
and 59.45 and 59.07, 57.39 and 56.99 and 56.81 and
56.62, 51.68 and 51.63 and 51.50 and 51.25, 31.36 and
31.29 and 30.86, 30.97 and 30.62 and 29.96 and 29.75,
27.29 and 27.26 and 27.18, 16.70 and 16.65 and 16.54
and 16.47. IR (film, NaCl), m [cmꢀ1] = 2954, 2929,
2871, 2808, 1622, 1591, 1508, 1495, 1456, 1379, 1369,
1354, 1265, 1244, 1147, 1066, 1018, 908, 806, 735.
HRMS (FAB) for C51H58N2O4 calcd: 763.4475
[M+H]+, 785.4294 [M+Na]+; found: 763.4510, 785.4258.
4.1.9. Preparation of (4S,5S)-5,10,14,19-tetrabenzyl-
2,2,7,17-tetramethyl-octadecahydro-1,3-dioxa-5, 10,14,19-
tetraaza-cyclopentacyclononadecene 10b. General method
A: Compound 9 (116 mg, 0.26 mmol), 3b (74 mg,
0.29 mmol) and [Rh(acac)(CO)2] (5 mg, 19 lmol) were
dissolved in toluene (40 mL), pressurized with 80 bar
CO:H2 (1:1), heated at 80 ꢁC for 3 d and purified by col-
umn chromatography (silica gel, CH2Cl2:MeOH 97:3) to
1
give 109 mg (57%) 10b as a yellow viscous oil. H NMR
4.1.11. Preparation of (9S,13S)-7,15-dibenzyl-11,11-dimet-
hyl-2,10,12,20-tetraoxa-7,15-diaza-tricyclo[19.3.1.09,13]-
pentacosa-1(24),21(25),22-triene-23-carboxylic acid methyl
ester 15. General method B: Compound 13 (191 mg,
0.62 mmol), 8 (229 mg, 0.67 mmol) and [Rh(acac)(CO)2]
(17 mg, 66 lmol) were dissolved in toluene (40 mL),
pressurized with 40 bar H2, heated at 50 ꢁC for 1 d
and purified twice by column chromatography (silica
gel, CH2Cl2, then n-hexane:EtOAc 4:1) to give 57 mg
(400 MHz, CDCl3): signals for a 1:1 mixture of diastereo-
isomers: d = 7.27–7.12 (m, 20H), 3.94–3.78 (m, 2H), 3.75–
3.72 (m, 1H), 3.56 (s, 1H), 3.53–3.32 (m, 6H), 2.78–2.65
(m, 2H), 2.54–2.44 (m, 2H), 2.42–2.26 (m, 8H), 2.22–
2.00 (m, 4H), 1.72–1.50 (m, 6H), 1.32–1.23 (m, 6H),
1.11–0.98 (m, 2H), 0.81–0.73 (m, 2H), 0.69–0.64 (m,
4H). 13C NMR (100 MHz, CDCl3): signals for a 1:1 mix-
ture of diastereoisomers: d = 139.92 and 139.82 and
139.75 and 139.68, 129.12 and 129.03, 128.93 and
128.83, 128.05 and 128.02, 127.97, 126.64, 108.72 and
108.55, 79.48 and 79.10 and 78.36, 62.62 and 61.89 and
61.49 and 60.82, 60.49 and 60.24 and 59.95 and 59.84,
59.24 and 59.13 and 59.06 and 58.89, 57.55 and 56.71
and 56.62 and 55.91, 51.81 and 51.70 and 51.58 and
51.53 and 51.46, 51.28 and 51.19, 32.12, 31.66, 29.55
and 29.38 and 29.01 and 28.93, 27.41 and 27.28, 18.44
and 18.42 and 18.40 and 18.33. IR (film, NaCl), m
[cmꢀ1] = 3060, 3026, 2951, 2931, 2868, 2798, 1495, 1452,
1379, 1369, 1252, 1061, 1028, 910, 735, 698. HRMS
(FAB) for C48H66N4O2 calcd: 731.5264 [M+H]+,
753.5083 [M+Na]+; found: 731.5290, 753.5081.
(15%) 15 as
a
colorless viscous oil. 1H NMR
(400 MHz, CDCl3): d = 7.18–7.12 (m, 10H), 7.11 (s,
1H), 7.10 (s, 1H), 6.75 (s, 1H), 4.13–4.09 (m, 2H),
4.07–4.02 (m, 2H), 3.81 (s, 3H), 3.68 (br s, 2H), 3.51
(dd, J = 112.5, 13.7 Hz, 4H), 2.57–2.42 (m, 6H), 2.37–
2.32 (m, 2H), 1.72–1.66 (m, 4H), 1.58–1.45 (m, 4H),
1.21 (s, 6H). 13C NMR (100 MHz, CDCl3): d = 159.82,
139.50, 132.18, 128.99, 128.12, 126.74, 109.02, 106.95,
78.88, 67.99, 58.88, 56.58, 53.59, 52.15, 27.23, 26.05,
23.09. IR (film, NaCl), m [cmꢀ1] = 2933, 2871, 2806,
1724, 1593, 1452, 1348, 1300, 1236, 1163, 1061, 769,
737. HRMS (FAB): for C37H48N2O6 calcd: 616.3512
21
[M]+; found: 616.3542. ½aꢁ =+13.0 (c 0.2, CH2Cl2).
D
4.1.10. Preparation of (9S,13S)-7,15-dibenzyl-4,11,11,18-
tetramethyl-2,10,12,20-tetraoxa-7,15-diaza-dinaphtho[a,c]-
bicyclo[18.3.0.09,13]-cyclotriacosane 12. General method
A: Compound 11 (147 mg, 0.37 mmol), 8 (126 mg,
0.37 mmol) and [Rh(acac)(CO)2] (4 mg, 16 lmol) were
dissolved in toluene (40 mL), pressurized with 80 bar
CO:H2 (1:1), heated at 80 ꢁC for 3 d, and purified by col-
umn chromatography (silica gel, CH2Cl2:EtOAc 9:1) to
give 86 mg (30%) 12 as a yellow viscous oil.
4.1.12. Preparation of (9S,13S)-7,15-dibenzyl-11,11-
dimethyl-2,10,12,20-tetraoxa-7,15-diaza-dinaphtho[a,c]-bi-
cyclo[18.3.0.09,13]-cyclotriacosane 16. General method
B: Compound 14 (221 mg, 0.45 mmol), 8 (176 mg,
0.52 mmol) and [Rh(acac)(CO)2] (11 mg, 43 lmol) were
dissolved in toluene (40 mL), pressurized with 40 bar
H2, heated at 50 ꢁC for 1 d, purified twice by column
chromatography (silica gel, CH2Cl2, then n-hex-
ane:EtOAc 4:1) to give 130 mg (39%) 16 as a colorless
1
viscous oil. H NMR (400 MHz, CDCl3): d = 7.81 (d,
1H NMR (500 MHz, CDCl3): signals for a 1:1 mixture
of diastereoisomers: d = 7.93–7.86 (m, 4H), 7.42–7.37
(m, 2H), 7.34–7.14 (m, 16H), 4.06–4.04 (m, 0.5H),
3.99–3.98 (m, 0.5H), 3.92–3.90 (m, 1H), 3.84–3.70 (m,
4H), 3.68–3.58 (m, 2H), 3.52–3.41 (m, 2H), 2.76–2.71
(m, 1H), 2.67–2.65 (m, 0.5H), 2.54–2.49 (m, 3.5H),
2.41–2.37 (m, 0.5H), 2.28–2.10 (m, 2.5H), 1.60–1.52
(m, 2H), 1.41–1.39 (m, 3H), 1.37–1.35 (m, 3H), 1.34–
1.29 (m, 4H), 0.59–0.57 (m, 3H), 0.34–0.32 (m, 3H).
13C NMR (125 MHz, CDCl3): signals for a 1:1 mixture
of diastereoisomers: d = 154.67 and 154.64 and 154.58
and 154.52, 139.46 and 139.41, 134.24, 129.43 and
129.23 and 129.14 and 129.11, 129.03 and 129.00 and
128.96 and 128.88, 128.06 and 128.02 and 127.99,
127.77 and 127.70, 126.71 and 126.68 and 126.64,
126.01 and 125.95, 125.45 and 125.41, 123.48 and
J = 9.0 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.32 (d,
J = 9.0 Hz, 2H), 7.24–7.10 (m, 14H), 7.05–7.03 (m,
2H), 3.94–3.89 (m, 2H), 3.80–3.76 (m, 2H), 3.73 (br
s, 2H), 3.47 (dd, J = 108.7, 13.8 Hz, 4H), 2.48 (dd,
J = 74.0, 12.3 Hz, 4H), 2.31–2.28 (m, 2H), 2.12–2.09
(m, 2H), 1.44–1.41 (m, 2H), 1.36–1.19 (m, 12H). 13C
NMR (100 MHz, CDCl3): d = 154.68, 139.46, 134.21,
129.26, 129.06, 128.93, 128.05, 127.79, 126.70, 126.11,
125.40, 123.42, 120.67, 116.08, 108.71, 78.79, 69.49,
59.39, 56.96, 53.27, 27.23, 27.03, 23.43. IR (film,
NaCl),
m
[cmꢀ1] = 3059, 2981, 2935, 2871, 2806,
1722, 1680, 1622, 1593, 1506, 1495, 1456, 1431, 1379,
1369, 1354, 1331, 1263, 1169, 1147, 1132, 1084, 1020,
808, 737. HRMS (FAB) for C49H54N2O4 calcd:
21
735.4162 [M+H]+; found: 735.4136. ½aꢁ =ꢀ78.7 (c
D
0.8, CH2Cl2).

1926
G. Angelovski et al. / Tetrahedron: Asymmetry 16 (2005) 1919–1926
4. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5976–5978; (b) Lu, L. D.-L.; Johnson, R. A.; Finn,
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5. Ito, Y. N.; Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.;
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Seebach, D. Helv. Chim. Acta 1994, 77, 2071–2110.
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4.1.13. Preparation of (9S,10S)-7,12-dibenzyl-9,10-dihy-
droxy-2,17-dioxa-7,12-diaza-bicyclo[16.3.1]docosa-1(21),
18(22),19-triene-20-carboxylic acid methyl ester 18
4.1.13.1. Procedure A. Compound 15 (33 mg,
0.054 mmol) was dissolved in CH3OH (3 mL) and 2 M
HCl (3 mL) added. The solution was heated at 70 ꢁC
for 5 h. After cooling, methanol was removed in a rotary
evaporator, and the solution subjected to pH 12 with so-
lid NaOH and extracted with CH2Cl2 (3 · 30 mL). The
organic phase was washed with brine, dried over MgSO4
and the solvent removed in vacuo. The yield of crude 18
was 20 mg (65%) as a colorless viscous oil.
`
8. (a) Arnaud, N.; Picard, C.; Cazaux, L.; Tisnes, P.
4.1.13.2. Procedure B. General method B: Com-
pound 13 (200 mg, 0.65 mmol), 16 (195 mg, 0.65 mmol)
and [Rh(acac)(CO)2] (19 mg, 74 lmol) were dissolved in
toluene (40 mL), pressurized with 40 bar H2, heated at
50 ꢁC for 1 d and purified twice by column chroma-
tography (silica gel, CH2Cl2, then n-hexane:EtOAc
4:1) to give 240 mg (64%) 18 as a colorless viscous
oil. 1H NMR (400 MHz, CDCl3): d = 7.22–7.15 (m,
10H), 7.10 (d, J = 2.3 Hz, 2H), 6.78 (s, J = 2.3 Hz,
1H), 4.02 (t, J = 5.3 Hz, 4H), 3.82 (s, 3H), 3.53 (dd,
J = 117.7, 13.3 Hz, 4H), 3.49 (br s, 2H), 2.67–2.53 (m,
4H), 2.44–2.39 (m, 4H), 1.76–1.57 (m, 8H). 13C NMR
(100 MHz, CDCl3): d = 166.83, 159.77, 132.01,
129.15, 128.34, 127.23, 108.77, 107.55, 68.80, 67.93,
59.38, 56.36, 53.33, 52.18, 25.85, 22.71. IR (film,
NaCl), m [cmꢀ1] = 3427, 3311, 3028, 2949, 2871, 2852,
1732, 1606, 1495, 1454, 1300, 1238, 1157, 1053,
Tetrahedron 1997, 53, 13757–13768; (b) Bogatsky, A. V.;
Lukyanenko, N. G.; Lobach, A. V.; Nazarova, N. Yu.;
Karpenko, L. P. Synthesis 1984, 139–140.
9. (a) Behr, J.-P.; Lehn, J.-M.; Moras, D.; Thierry, J. C. J.
Am. Chem. Soc. 1981, 103, 701–703; (b) Choi, H.-J.;
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11. Kuhn, R.; Erni, F.; Bereuter, T.; Hausler, J. Anal. Chem.
1992, 64, 2815–2820.
12. (a) Behr, J.-P.; Lehn, J.-M. J. Chem. Soc., Chem. Commun.
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¨
910, 768. HRMS (FAB): for C34H44N2O6 calcd:
21
577.3278 [M+H]+; found: 577.3260 ½aꢁ =ꢀ24.0 (c
D
0.06, CH2Cl2).
´
16. Angelovski, G.; Costisella, B.; Kolaric, B.; Engelhard, M.;
Eilbracht, P. J. Org. Chem. 2004, 69, 5290–5294.
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Acknowledgements
The authors would like to thank DAAD and DFG for
financial support. We also thank Degussa A. G, Dussel-
¨
dorf for the donation of chemicals.
´
19. (a) Kafka, S.; Klasek, A.; Sedmera, P. Collect. Czech.
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