NMR elucidation of a novel (S)-pentacyclo-undecane bis-(4-phenyloxazoline) ligand and related derivatives

Article abstract of DOI:10.1002/mrc.2279

The NMR elucidation of a novel ligand (S)-pentacyclo-undecane bis-(4-phenyloxazoline) and related pentacyclo-undecane (PCU) derivatives is reported. Two-dimensional NMR proved to be a powerful technique in overcoming the difficulties associated with the elucidation of these compounds when only one-dimensional NMR data is utilized. A chiral substituent was introduced to both 'arms' of the PCU skeleton to produce derivatives 1-3. These derivatives display C₁ symmetry with all thecage atoms being nonequivalent. Owing to overlapping of peaks in the ¹H spectra, identification of these diastereomeric protons was very difficult. The ¹³C spectra gave rise to clear splitting of the nonequivalent carbons. This is unusual compared to similar PCU derivatives with chiral substituents as splitting of all the diastereomeric cage carbons has not yet been reported. Nuclear Overhauser enhancement spectroscopy (NOESY) correlations of derivatives 1-3 confirm the different conformations of the molecule in which the side 'arms' occupy different orientations with respect to cage moiety. Copyright

Full text of DOI:10.1002/mrc.2279

Research Article
Received: 18 April 2008
Revised: 2 June 2008
Accepted: 7 June 2008
Published online in Wiley Interscience: 15 October 2008
(www.interscience.com) DOI 10.1002/mrc.2279
NMR elucidation of a novel
(S)-pentacyclo-undecane
bis-(4-phenyloxazoline) ligand and related
derivatives
Grant A. Boyle,a Thavendran Govender,b Hendrik G. Kruger,a∗
Glenn E. M. Maguirea and Tricia Naickera
TheNMRelucidationofanovelligand(S)-pentacyclo-undecanebis-(4-phenyloxazoline)andrelatedpentacyclo-undecane(PCU)
derivatives is reported. Two-dimensional NMR proved to be a powerful technique in overcoming the difficulties associated
with the elucidation of these compounds when only one-dimensional NMR data is utilized. A chiral substituent was introduced
to both ‘arms’ of the PCU skeleton to produce derivatives 1–3. These derivatives display C1 symmetry with all thecage atoms
1
being nonequivalent. Owing to overlapping of peaks in the H spectra, identification of these diastereomeric protons was
very difficult. The 13C spectra gave rise to clear splitting of the nonequivalent carbons. This is unusual compared to similar
PCU derivatives with chiral substituents as splitting of all the diastereomeric cage carbons has not yet been reported. Nuclear
Overhauser enhancement spectroscopy (NOESY) correlations of derivatives 1–3 confirm the different conformations of the
c
molecule in which the side ‘arms’ occupy different orientations with respect to cage moiety. Copyright ꢀ 2008 John Wiley &
Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: NMR; 1H NMR; 13C NMR; 2D NMR; PCU; chiral ligands
Introduction
allthederivatives1–5beinginvestigated.Ozonolysisof7followed
by an oxidative workup using formic acid and hydrogen peroxide
afforded the PCU diacid 8.[15] To avoid competing reactions due to
thefreehydroxylgroupontheaminoalcohol,itwasdecidedtopro-
tect the alcohol by using tert-butyldimethylsilyl (TBDMSi) chloride
to give (S) tert-butyldimethylsilyl 2-amino-3-phenylpronoate 9.[17]
This protecting group is known to be hydroxyl group selective in
thepresenceofaprimaryamine.AnN,N-dicyclohexylcarbodiimide
(DDC) promoted condensation of the PCU diacid 8 with 9 af-
forded the protected PCU bis-amide 1 which was purified using
column chromatography.[18] The PCU bis-amino alcohol 2 was
obtained by deprotection of 1 with tetra-N-butylammonium flu-
oride (TBAF) and purification was again achieved using column
chromatography.[17] Cyclization was achieved by the chlorination
of2usingthionylchloridetogivethePCUbis-chloride10,followed
by treatment with aqueous sodium hydroxide[14,19] to yield the
novel ligand PCU bis-(4-phenyloxazoline) 3, which was isolated
by column chromatography in 80% yield from the PCU bis-amino
alcohol 2 (Scheme 1).
Organic chemists have explored the chemistry of pentacyclo-
undecane(PCU)cagecompoundsformanyyears.[1–3] Theeffectof
the unique cage geometry on chemical reactivity and the behavior
of the rest of the molecules has been extensively studied.[1,3]
The difficulties associated with the NMR elucidation of these
compounds have been highlighted by many authors.[4–7] Broad
unresolved overlapping resonances as a result of through-space
effects, geminal and vicinal proton–proton coupling and long-
range proton–proton interactions make the assignments of cage
1Hspectraquitechallenging.The2DNMRtechniquehasbeenused
as an invaluable tool to overcome these difficulties. Our group has
been actively involved in the elucidation of the PCU-derived cage
compounds.[7–11] A branch of our research interests involves the
chemistry of the PCU cage and the attachment of chiral ligands to
the cage for applications in asymmetric catalysis.[12,13] As a result,
the NMR elucidation of four PCU derivatives 1–4 was recently
investigated. Ligand 3 is currently being tested as a catalyst in
the asymmetric Diels–Alder reaction of cyclopentadiene and 3-
acryloyl-2-oxazolidinone.[14] The novel compounds 1 and 2 are
precursors of ligand 3. Derivative 4 is the precursor of ligand 5 and
the full NMR elucidation of 4 is reported below. The elucidation of
ligand 5 was not achieved because of its instability and only the
1H and 13C NMR spectra were recorded (Fig. 1).
∗
Correspondence to: Hendrik G. Kruger, School of Chemistry, University of
KwaZulu-Natal, Durban 4001, South Africa. E-mail: kruger@ukzn.ac.za
a
School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa
The PCU dione
oxahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane 7 as described
previously.[15,16] This diene 7 is an intermediate in the synthesis of
6 was converted to the 3,5-diallyl-4-
b
School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban
4001, South Africa
c
Magn. Reson. Chem. 2008, 46, 1089–1095
Copyright ꢀ 2008 John Wiley & Sons, Ltd.

G. A. Boyle et al.
EDC (2.02 eq), Hobt (2.02 eq),
(S)-Phen-O-TBDMSi (2.2 eq)
9
1) O3, Dry MeOH
2) H2O2, HCOOH
Dry CH2Cl2
12 hrs
O
O
8
O
O
O
O
O
O
O
Ph
Ph
OH
HO
NH
HN
6
7
OTBDMS TBDMSO
1
TBAF (5 eq)
Dry THF
48 hrs
5 % aq NaOH
SOCl2 (10 eq)
Dry CH2Cl2
3 hrs
CH2Cl2 / MeOH
12 hrs
O
O
O
O
2
O
3
O
O
O
O
Ph
NH
Cl
HN
Cl
Ph
Ph
Ph
NH
OH
HN
HO
N
N
Ph
Ph
10
Scheme 1. Synthesis of novel compounds 1–3.
(S)-Phen-O-TBDMSi (2 eq)
9
1) O3, Dry MeOH
2) (CH3)2S
Molecular sieves, CHCl3
1.5 hrs
O
O
O
O
O
Ph
Ph
N
N
H
H
OTBDMS TBDMSO
5
7
4
Scheme 2. Synthesis of novel compounds 4 and 5.
Ozonolysis of 7 followed by a reductive workup using dimethyl
sulfide, affordedthenovelPCUdialdehyde 4. ASchiffbasereaction
of 4 with 9 in the presence of molecular sieves afforded the PCU
diimine 5 (Scheme 2).
a coupling constant of 10.5 Hz.[7–11] Owing to major overlapping
of protons, only the coupling constant of H-4 could be calculated.
Also, from the 1H spectrum protons H-3ꢁ and H-4ꢁ at 5.21
and 4.05 ppm were assigned, respectively, from their literature
values.[17,20] In addition, the silyl protons were assigned based
on integration, 0.0 (H-10ꢁ = 12 Hꢁs) and 0.9 ppm (H-11ꢁ = 18 Hꢁs).
Recording the 13C spectra in attach proton test (APT) mode
assisted in distinguishing the quaternary and methylene car-
bons from the methine and methyl carbons. On the basis of
heteronuclear single quantum coherence (HSQC) spectrum of 1,
the carbons corresponding to H-4ꢁ and H-4 were identified. By
elimination, the methylene signal at 3.0 ppm was assigned to C-1ꢁ
and its correlation to the doublet at 2.56 ppm was assigned to H-1ꢁ.
H-1ꢁ also displays a COSY and Nuclear Overhauser Enhancement
Spectroscopy (NOESY) interaction with the overlapping cage me-
thine signals at 2.87 ppm. The position of H-1ꢁ was also confirmed
with HMBC correlations with the cage skeleton (see below).
The quaternary carbons were assigned as follows: C-9ꢁ at
18.2 ppm was assigned because of its HMBC correlation to the
methyl protons attached to the silyl atom; C-5ꢁ at 140 ppm
was assigned based on its correlations to H-3ꢁ and H-4ꢁ and
Results and Discussion
Note that the left half of the PCU skeleton in 1–3 is the mirror
image of the right half, with the result that the chiral side arms
induce a diastereomeric character to the cage skeleton. Owing to
overlapping in the 1H spectra, identification of the nonequivalent
protons was very difficult. However, the 13C spectra gave rise to
clear splitting of the carbon atoms (C-1–C-11) and (C1ꢁ –C-8ꢁ) on
the cage and ‘side arms’ of 1, respectively. This is unprecedented
compared to analogous PCU derivatives reported before, as
splitting of only the diastereomeric carbons closest to the new
chiral center is usually observed.[7–11] The nature of this effect was
investigated and is discussed below.
1
In the H spectrum of 1, the characteristic methylene protons
(H-4) register as doublets at 1.65 (H-4a) and 1.98 ppm (H-4b) with
c
Copyright ꢀ 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc
Magn. Reson. Chem. 2008, 46, 1089–1095

NMR elucidation of chiral PCU ligands
Ha
Hs
Ha
3
Hs
4
4
5
3
5
2 6
1 7
2 6
1 7
9
10
9
10
11
8
11
1'
1'
2'
8
1'
2'
1'
2'
7'
7'
6'
7'
7'
6'
6'
6'
2'
O
O
O
O
5'
O
O
5'
8'
8'
8'
8'
5'
NH
HN
5'
NH
HN
3'
3'
3'
3'
7'
7'
7'
7'
6'
6'
6'
6'
4'
4'
4'
4'
O
O
OH
HO
10'
10'
Si
Si
10'
10'
9'
11'
11'
11'
9'
11'
11'
11'
1
2
Ha
Hs
4
Ha
3
Hs
Ha
3
Hs
5
4
4
3
5
5
2 6
1 7
2 6
2 6
1 7
9
10
9
10
10
11
9
8
8
11
1'
1'
1 7
8
11
1'
2'
1'
2'
1'
1'
2'
2'
O
O
6'
O
2'
3'
2'
O
O
4'
3'
4'
3'
O
O
N
N
Ph
Ph
H
H
N
N
3'
5'
6'
5'
6'
8'
4'
4'
OTBDMS TBDMSO
5
7'
6'
7'
8'
7'
7'
4
3
Figure 1. PCU derivatives 1–5.
C-2ꢁ at 169 ppm, which is characteristic of an amide carbonyl
carbon; it also has HMBC correlations with H-3ꢁ, H-1ꢁ and some
of the aromatic protons (7.36–7.52 ppm). Through elimination,
the set of quaternary carbons at 94.2 ppm was assigned to the
diastereomeric C-8 and C-11 carbons.
In view of the above stated assignments, the overlapping of
cage methine protons at 2.87 ppm may be assumed to result
from H1/7, H2/6 and H9/10. Interestingly, the aromatic protons
(7.36–7.52 ppm) show NOESY interactions with H-1ꢁ, H1/7, H2/6,
H9/10 and H-3/5. The silyl methyl protons H-10ꢁ and H-11ꢁ display
NOESY interactions with H-1ꢁ, H1/7, H2/6 and H9/10.
All the cage carbon signals display splitting as a result of the
diastereomeric effect (induced by the chiral side arms). The nature
of this effect is confirmed due to the absence of any splitting
of the nonchiral (nondiastereomeric) methylene signal of H-4. In
addition, high-temperature NMR experiments of 1 at 60, 120 and
150 ◦CrevealedthecagecarbonsignalsofC-1/7,C-9/10andC-8/11
remained split throughout the temperature ramp. This confirmed
the diastereomeric effect experienced by these carbon atoms.
The proton signal appearing at 2.56 ppm displays a HMBC
correlation to a cage carbon signal at 44.1 ppm, and a COSY
and NOESY correlation to the H-4. Therefore, it could either be
assigned to H-2/6 or H-3/5. However, this HMBC correlation also
corresponds to a carbon sharing a correlation with H-1ꢁ, thus
eliminating H-2/6. Therefore, the signal at 44.1 ppm was assigned
to H-3/5. Signals at 58.0 ppm share HMBC correlations to H-4, H-1ꢁ,
H-3/5 and the overlapping cage protons. The possibility of this
signal being C-1/7 was ruled out as C-1/7 cannot correlate to H-4
and these carbon signals were subsequently assigned to C-9/10.
The remaining cage carbon signals at 47.0 and 41.4 ppm were
assigned to C-1/7 and C-2/6 respectively based on the HMBC and
NOESY spectra.
This observation suggests a conformation of 1 in which one
of the ‘arms’ is perhaps positioned in front and the other at the
back of the cage moiety. From the high-temperature experiments,
the split carbon signals on the side arm (C-1ꢁ –C-8ꢁ) at room tem-
perature gradually became a single peak as the temperature was
increased (60, 120 and 150 ◦C) indicating that these carbon atoms
experienced splitting due to a conformational effect. When the
heteroatoms on the side arms are positioned in close proximity to
the cage, it induces a through-space deshielding effect resulting in
nonequivalenceofatomsonthecageandthatofthe‘arm’similarto
observations in previous reports of related chiral PCU ligands.[9,11]
The infrared (IR) spectrum of 1 displays a sharp N–H absorption
at 3312 cm−1, and methyl absorptions at 2949 and 2929 cm−1
;
the absorption at 1646 cm−1 confirms the presence of the amide
bond. The mass spectrum of 1 exhibits the correct molecular ion
peak at m/z 741.4118 ([M + H]+). The assignments of all signals for
1 are reported in Table 1.
Thesamemethodologywasusedtoelucidate2.C-8/11,C-2ꢁ and
C-4ꢁ carbon signals in 2 do not display splitting as in the case of the
derivative 1. A possible explanation could be the absence of the
bulkyTBDMSigroupin2;hence,theconformationaleffectinwhich
c
Magn. Reson. Chem. 2008, 46, 1089–1095
Copyright ꢀ 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

G. A. Boyle et al.
Table 1. NMR data of PCU derivatives 1 and 2a,b
Ha
Hs
Ha
3
H
s
4
4
5
3
5
2
1
6
2
1
6
9
10
9
10
7
7
8
11
1'
2'
1'
2'
8
11
1'
2'
1'
2'
7'
7'
7'
7'
6'
6'
6'
6'
O
O
O
O
5'
O
O
5'
8'
8'
8'
7'
8'
5'
NH
HN
5'
NH
HN
3'
3'
3'
3'
7'
7'
7'
6'
6'
6'
6'
4'
4'
4'
4'
O
O
OH
HO
10'
10'
Si
Si
10'
10'
9'
11'
11'
11'
9'
11'
11'
11'
2
1
Derivative 1
Derivative 2
Atom no.
1H (ppm)
13C (ppm)
1H (ppm)
13C ppm
1/7
2/6
3/5
4a
4s
2.87 m
2.87 m
2.56 m
1.65c d
1.98c d
–
48.83/47.82
41.50/41.44
44.28/44.19
43.35
2.73 m
2.73 m
2.45 s
1.55c d
1.90c d
–
48.63/48.01
41.54/41.39
44.12/44.00
43.48
43.35
43.48
8/11
9/10
1ꢁ
94.21/94.16
59.11/58.06
39.91/39.89
169.2/169.1
54.64/54.60
66.60/66.11
140.36/140.30
126.92/126.91
128.52/128.32
127.24/127.27
18.26
94.14
2.87 m
3.06 m
–
2.73 m
2.82 m
–
59.05/58.40
39.49/39.47
170.1
2ꢁ
3ꢁ
5.21 s
4.05 m
–
5.02 s
3.73 m
–
55.23/55.17
65.90
4ꢁ
5ꢁ
139.33/139.32
126.6
6ꢁ
7.52 m
7.43 m
7.36 m
–
7.43 m
7.29 m
7.23 m
7ꢁ
128.6
8ꢁ
127.6
9ꢁ
10ꢁ
11ꢁ
0.98 s
0.00 s
−5.600
25.83
a Solvent CDCl3.
b 400 MHz for 1H and 100 MHz for 13C.
c Coupling constant = 10.5 Hz.
one of the ‘arms’ is closer to a different part of the cage moiety is
lesspronounced.FromtheIRspectrum,thepresenceofthealcohol
group was confirmed by the broad band at 3288 cm−1 and as was
the case with 1, the presence of the amide bond absorption was
still present at 1641 cm−1. Presence of the expected molecular ion
peak of m/z 513.2396 ([M + H]+) in the mass spectrum confirmed
the structure of compound 2. The detailed NMR assignments are
presented in Table 1.
The elucidation of the PCU bis-(4-phenyloxazoline) 3 followed
a similar approach as mentioned above. The 1H spectrum of 3
differs from its precursors in that all the cage protons appear as
clear signals and H-4ꢁ is split into two separate doublet of doublets.
From the 13C spectrum, the absence of the carbonyl carbon signal
at 170 ppm and presence of the characteristic imine carbon signal
at 165 ppm were indicative that cyclization was achieved. Also,
C-3ꢁ displays a distinct downfield shift as a result of the adjacent
imine bond. HMBC correlations of C-2ꢁ with protons H-3ꢁ and H-4ꢁ
confirm the formation of the oxazoline ring. The aromatic protons
(7.21–7.38 ppm) show a NOESY interaction with H-2/6. Similar
to 1, this observation indicates the different conformations of 3
in which the ‘arms’ exist as different conformations with respect
to the cage moiety. A weak, but observable COSY correlation
between H-3ꢁ and H-1ꢁ is observed which is unusual as these
protons are more than three bonds apart (in fact, they are four
bonds apart).
TheIRspectrumof3displaysthecharacteristicimineabsorption
band at 1663 cm−1 and aromatic ether absorption band at
1217 cm−1. Also, as expected, disappearance of the amide bond
absorptions was observed. The mass spectrum of 3 displays the
correctmolecularionpeakatm/z477.2147([M+H]+). Thedetailed
assignments are presented in Table 2.
c
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Copyright ꢀ 2008 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2008, 46, 1089–1095

NMR elucidation of chiral PCU ligands
Table 2. NMR data for PCU derivative 3 and 4a,b
Ha
Hs
4
Ha
Hs
4
3
5
3
5
2
1
6
7
2
1
6
7
9
10
9
8
10
11
8
11
1'
1'
1'
1'
2'
2'
O
O
O
O
4'
4'
2'
2'
O
O
N
N
H
H
3'
7'
3'
6'
5'
5'
6'
8'
7'
6'
7'
6'
8'
7'
3
Derivative 3
4
Derivative 4
Atom no.
1H ppm
13C ppm
1H ppm
13C ppm
1/7
2/6
3/5
4a
4s
2.82 s
2.64 s
2.41 s
1.51c d
1.90c d
–
48.67/48.58
41.86/41.84
44.64/44.61
43.55
2.68 m
2.71 m
2.50 s
1.59c d
1.93c d
–
48.57
41.62
44.16
43.45
43.45
92.77
59.21
45.99
200.5
–
43.55
8/11
9/10
1ꢁ
93.71/93.69
59.26/59.16
32.11/32.96
165.9/165.8
69.66/69.61
74.76/74.69
142.3
2.75 s
2.98 s
–
2.64 m
2.85 s
9.77 s
–
2ꢁ
3ꢁ
5.18 t
4.61/4.08d dd
4ꢁ
–
–
5ꢁ
–
–
–
6ꢁ
7.34 m
7.28 m
7.24 m
126.5
–
–
7ꢁ
128.8
8ꢁ
126.5
a Solvent CDCl3.
b 400 MHz for 1H and 100 MHz for 13C.
c Coupling constant = 10.5 Hz.
d Coupling constant = 9.5 Hz.
Derivative 4 is a meso compound making all the atoms except Conclusion
the methylene group hydrogens at C-4 equivalent. Once again,
the elucidation followed a similar approach as presented above.
From the H spectrum, the signal at 9.7 ppm was characteristic
The NMR elucidation of the novel ligand (S)-pentacyclo-undecane
bis-(4-phenyloxazoline) 3, two of its precursors 1–2 and the PCU
dialdehyde 4 was successfully achieved. 2D NMR techniques were
required to identify the NMR signals for the PCU derivatives
1–3 that display C1 symmetry with all the cage atoms being
nonequivalent. The 13C spectra of these derivatives gave rise to
clear splitting of the nonequivalent carbons, with the exception
of C-9ꢁ, C-10ꢁ, C-11ꢁ in 1; C-8/11, C-2ꢁ, C-4ꢁ, C-6ꢁ, C-7ꢁ, C-8ꢁ in 2 and
C-6ꢁ, C-7ꢁ, C-8ꢁ in 3. NOESY correlations of derivatives 1–3 indicate
conformational differences with respect to the side arms. The
heteroatoms on the side arm induce a through-space deshielding
effect resulting in nonequivalence of atoms on the cage skeleton
and that of the side ‘arm’. Even though the cage carbons become
diastereomeric with respect to the chiral side arms, the same level
of nonequivalence by related chiral cage ligands has not yet been
reported. As expected, the meso PCU dialdehyde 4 gave rise to six
1
of an aldehyde proton. In addition, only the proton signals H-4,
H-3/5 and H-1ꢁ appear as separate signals while the remaining
cage protons display overlapping (2.5–2.8 ppm). On the basis of
the meso nature of the molecule, the 13C spectrum was somewhat
simplified and overlapping of the equivalent carbons occur. Six
distinct carbon signals were observed for derivative 4 as against 11
carbon signals which were observed for the chiral derivatives 1–3.
From the HSQC, HMBC, NOESY and COSY spectra, the overlapping
proton signals were distinguished and all the assignments were
verified.
The IR spectrum displays the characteristic aldehyde absorption
band at 1719 cm−1 and the mass spectrum displays the correct
molecular ion peak at m/z 242.1248 ([M + H]+). The detailed
assignments are presented in Table 2.
c
Magn. Reson. Chem. 2008, 46, 1089–1095
Copyright ꢀ 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

G. A. Boyle et al.
distinct carbon signals as compared to the chiral derivatives 1–3
(S)-tert-Butyldimethylsilyl 2-amino-3-phenylpronoate 9
which gave rise to 11 carbon signals.
(S)-Phenylglycine methyl ester (1.0 g, 4.9 mmol) was added to a
stirred solution of lithium aluminum hydride (0.4 g, 9.8 mmol)
in dry tetrahydrofuran (THF) (150 ml) at ambient temperature.
Thereafter, the solution was refluxed for 1.5 h. The reaction
mixture was then allowed to cool after which an equal volume of
diethyl ether was added. The reaction mixture was quenched with
saturated aqueous Na2SO4 solution. It was filtered and the solvent
wasremovedinvacuotoyieldpureaminoalcoholasyellowcrystals
(0.6 g, 88%). To a solution of the amino alcohol (3.0 g, 21.7 mmol)
in dry CH2Cl2 (150 ml) were added at room temperature Et3N
(6.3 ml, 44.5 mmol) and 4-Dimethylaminopyridine (DMAP) (0.5 g,
4.09 mmol). The solution was cooled to 0 ◦C and TBDMSiCl (3.4 g,
27.7 mmol) in CH2Cl2 (20 ml) was added. The solution was stirred
for further 48 h at room temperature and then H2O (30 ml) was
added. The layers were separated and the aqueous layer was
extracted with CH2Cl2. The combined organic phases were dried
over anhydrous Na2SO4 and the solvent was removed in vacuo.
The resulting residue was purified by column chromatography
(CH2Cl2/MeOH, 95 : 5) to afford product 9 (4.5 g, 83%) as a yellow
oil. 1H NMR (CDCl3, δ): 0.04 (6H, s), 0.91 (9H, s), 1.85 (NH, br s), 3.50
(1H, dd CH2O), 3.72 (1H, dd, CH2O), 4.07 (1H, dd, CHPh), 7.40–7.23
(5H, m); 13C NMR (CDCl3, δ): −5.41 (CH3), 18.3 (CH3), 25.9(C(CH3)3),
Experimental
Allsyntheticexperimentswereconductedunderanatmosphereof
nitrogen, unless otherwise indicated. All the solvents were distilled
over the appropriate desiccant. NMR spectra were recorded on a
Bruker AVANCE III 400 MHz instrument using ∼50 mg of sample
per 0.5 ml of CDCl3. IR spectra were obtained on a Perkin Elmer
Spectrum 100 instrument with an attenuated total reflectance
(ATR) attachment. Optical rotations were carried out on a Perkin
Elmer 341 polarimeter. All melting points are uncorrected. Column
chromatography was carried out using silica gel 60. Electron spray
mass spectra were carried out on a Waters LCT Premier time-of-
flight (TOF) mass spectrometer.
The chemical shifts were referenced to the solvent peak
7.24 ppmforCDCl3 atambienttemperature. The1HNMRspectrum
was recorded at 400.222 MHz (spectral width, 8223.685 Hz;
acquisition time, 1.992 s; pulse width, 9 µs; scans, 16; relaxation
delay, 1.0 s). The 13C NMR spectrum was recorded at 100.635 MHz
(spectral width, 24038.461 Hz; acquisition time, 1.363 s; pulse
width, 13.801 µs; scans, 2400; relaxation delay, 2.00 s). The 2D
experimental data parameters were as follows: 90◦ pulse width,
9 µs for all the spectra; spectral width for 1H, 822.68 for 1–4;
spectral width for 13C, 24038.46 for 1–4; number of data points
per spectrum, 2048, (COSY) for 1–4, 2048, (NOESY) for 1–4,
4096, (HMBC) for 1–4, 1024 (HSQC) for 1–4; number of time-
incremented spectra, 128 (COSY) for 1–4, 256, (NOESY) for 1–4,
128, (HMBC) for 1–4, 256 (HSQC) for 1–4; relaxation delay, 1.38 s
(COSY) for 2 and 3, 1.39 s (COSY) for 1, 1.44 s (COSY) for 4, 1.98 s
(NOESY) for 2 and 3, 1.96 s (NOESY) for 1, 2.01 s (NOESY) for 4, 1.31,
1.25, 1.30, 1.41 s(HMBC)for1–4respectively, 1.45, 1.43, 1.45, 1.47 s
(HSQC) for 1–4 respectively; spectra acquired in phase-sensitive
mode, 1–4 (NOESY and HSQC); spectra acquired in absolute value
mode, 1–4 (COSY and HMBC); gradients used for 1–4 (COSY,
HSQC and HMBC). All NMR spectra are available as Supporting
Information.
57.6 (CHPh), 69.5 (CH2O), 126.9, 127.2, 128.2, 142.6 (aromatic)[17,20]
.
PCU bis-amide 1
To a stirred solution of 8 (2.0 g, 7.25 mmol) in dry CH2Cl2
(150 ml), N-Hydroxybenzotriazole (2.0 g, 14.6 mmol) and then
N,N-Dicyclohexylcarbodiimide (3.0 g, 14.6 mmol) were added. This
mixture was allowed to stir for 15 min until a clear homogenous
solutionwasobtained. Thereafter, amixtureof 9(4.5 g, 18.0 mmol)
andEt3N(4.0 ml,28.9 mmol)in50 mldryCH2Cl2 wasaddedandthe
resulting mixture was stirred at ambient temperature for a further
12 h. The reaction mixture was then filtered and H2O added to
the filtrate. The layers were separated and the aqueous layer was
extracted with CH2Cl2. The combined organic phases were dried
over anhydrous Na2SO4 and the solvent was removed in vacuo.
The resulting residue was purified by column chromatography
(Hexane/EtOAc, 50 : 50) to afford compound 1 (4.8 g, 90%) as a
yellow solid. [α]20D − 11.35 (c1, CH2Cl2). IR νmax: 3312 (s), 1646 (vs),
1112 (vs) and 776 cm−1 (vs). mp 126–130 ◦C. High resolution mass
spectrum (HRMS) calcd for C43H60N2O5Si2 ([M + H]+), 741.4119;
found, 741.4118.
5,5-Dicarboxymethyl-4-oxahexacyclo[5.4.1.02,6.05,10.05,9
08,11]dodecane 8
.
A solution of the diene 7 (5.0 g, 20.3 mmol) in dry methanol
(150 ml) was cooled to −78 ◦C via application of an external
dry-ice–acetone bath and then was purged with nitrogen for
20 min. Ozone was bubbled into the mixture until a blue-purple
color persisted, thereby indicating the presence of excess ozone
and completion of the reaction. Excess ozone was flushed from
the reaction vessel with a stream of nitrogen, and the reaction
mixture was concentrated invacuo to yield the ozonide. Hydrogen
peroxide (50 ml, 30%) was added dropwise to a stirred, ice-bath-
cooled mixture of the ozonide and formic acid (50 ml, 80%). The
resulting mixture was stirred at ambient temperature for 1 h and
then gently refluxed for 12 h. The reaction mixture was allowed
to cool gradually to ambient temperature during which time the
product precipitated out of solution. Pure 8 (4.7 g, 82%) was
thereby obtained as a colorless microcrystalline solid: 1H NMR
(DMSO, δ) : 1.45 (AB, JAB = 10 Hz, 1H),1.83 (AB, JAB = 10 Hz, 1H),
2.36–2.80 (m, 12H), 12.15 (br s, 2H); (DMSO)13C NMR δ: 37.94 (t),
41.27 (d), 42.81 (t), 44.04 (d), 47.91 (d), 58.55 (d), 92.56 (s) and
171.40 (s).
PCU bis-amino alcohol 2
The PCU bis-amide 1 (5.5 g, 7.41 mmol) was dissolved in dry THF
(200 ml) and TBAF (29.6 ml, 1 M in THF) was added. The mixture
was stirred for 48 h at ambient temperature. Brine was added and
the layers were separated. The aqueous layer was extracted with
EtOAc. The combined organic layers were dried over anhydrous
Na2SO4 and the solvents were removed in vacuo. The resulting
residue was purified by column chromatography (EtOAc/MeOH,
95 : 5) to afford the deprotected alcohol 2 (3.0 g, 76%) as a pale
yellow solid. [α]20 + 32.45 (c1, CH2Cl2). IR νmax: 3288 (br), 1641
D
(vs), 1039 (s) and 706 cm−1(vs). mp 50–60 ◦C. HRMS: calculated for
C31H32N2O5 ([M + H]+), 513.2389; found, 513.2396.
PCU bis-(4-phenyloxazoline) 3
To a stirred solution of 2 (1.0 g, 1.88 mmol) in dry CH2Cl2 (100 ml),
SOCl2 (2.7 ml, 37.5 mmol) was added. The solution was stirred at
c
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Copyright ꢀ 2008 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2008, 46, 1089–1095

NMR elucidation of chiral PCU ligands
ambient temperature for 3 h. The resulting mixture was poured
into H2O and extracted with CH2Cl2. The combined organic
extracts were dried over Na2SO4 and the solvent removed in
vacuo to yield a brown residue of the PCU bis-chloride 10
which was used without further purification. The residue was
treated with NaOH (1 g in 20 ml H2O) in a MeOH (50 ml)/CH2Cl2
(30 ml) solution at ambient temperature for 12 h. The organic
solvents were evaporated in vacuo and the residue was extracted
with CH2Cl2. The combined organic extracts were dried over
anhydrous Na2SO4 and the solvents removed in vacuo. The
resulting residue was purified by column chromatography (100%
EtOAc) to afford the PCU bis-(4-phenyloxazoline) 3 (0.72 g, 80%)
as a yellow oil. [α]20D − 57.24 (c 0.85, (CH3)2CHOH). IR νmax: 2964
(w), 1663 (s), 984 (s) and 700 cm−1 (vs). HRMS: calculated for
C31H28N2O3 ([M + H]+), 477.2178; found, 477.2174.
(C-2/6), 44.1 (C-3/5), 43.5 (C-4), 94.1 (C-8/11), 59.1 (C9/10), 38.4
(C-1ꢁ), 162.5 (C-2ꢁ), 58.5 (C-3ꢁ), 68.0 (C-4ꢁ), 140.1 (C-5ꢁ), 126–130
(C-6ꢁ, C-7ꢁ, C-8ꢁ), 18.1 (C-9ꢁ), −4.2 (C-10ꢁ) and 26.0 (C-11ꢁ).
Supporting information
Supporting information may be found in the online version of this
article.
Acknowledgements
The authors thank Mr Dilip Jagjivan for his help in carrying out
the NMR spectroscopy experiments. This work was supported
by grants from the National Research Foundation, Gun 2046819
(South Africa), Aspen Pharmacare and the University of KwaZulu-
Natal.
PCU dialdehyde 4
References
A solution of the diene 7 (5.0 g, 20.3 mmol) in dry methanol
(150 ml) was cooled to −78 ◦C via application of an external dry-
ice–acetone bath and then was purged with nitrogen for 20 min.
Ozone was bubbled into the mixture until a blue-purple color
persisted, thereby indicating the presence of excess ozone and
completion of reaction. The excess ozone was flushed from the
reaction vessel with a stream of nitrogen. The reaction mixture
was then transferred to a round bottom flask and (CH3)2S (6.4 ml,
83.2 mmol)wasaddedandstirredfor12 hatambienttemperature.
The solvents were evaporated in vacuo and the residue was
extracted with CH2Cl2. The combined organic extracts were dried
over anhydrous Na2SO4 and the solvents were removed in vacuo.
The resulting residue was purified by column chromatography
(Hexane/EtOAc, 70 : 30) to afford the PCU dialdehyde 4 (0.49 g,
49%) as a yellow oil. IR νmax: 2958 (s) 1719 (vs), 1075 (s) and
527 cm−1 (w). HRMS: calculated for C43H60N2O5Si2 ([M + H]+),
242.1247; found, 242.1248.
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PCU diimine 5
PCU dialdehyde 4 (0.05 g, 0.20 mmol) was dissolved in 5 ml
dry CHCl3 and 9 (0.10 g, 0.40 mmol) was added along with 4 Å
molecular sieves. The reaction mixture was left to stand without
stirring for 1.5 h. The reaction mixture was filtered and the solvent
removed in vacuo to afford the PCU diimine 5 (0.14 g, 100%) as
1
a brown oil. H NMR (CDCl3, δ) : 1.01 (AB, JAB = 10 Hz, 1H), 1.52
(AB, JAB = 10 Hz, 1H), 2.13–2.62 (m), 3.3–3.8(m); 4.15 (H-3ꢁ), 4.05
(H-4ꢁ) and 7.2–7.4 (aromatic). (CDCl3)13C NMR δ: 48.1 (C-1/7), 41.5
c
Magn. Reson. Chem. 2008, 46, 1089–1095
Copyright ꢀ 2008 John Wiley & Sons, Ltd.
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