Readily accessible chiral at nitrogen cage structures

Article abstract of DOI:10.1039/c3ob27458f

The reaction of glycine-N-methyl amide with paraformaldehyde in the presence of ytterbium triflate (1 mol%) leads to a novel cage structure 6 which is chiral at nitrogen. Single crystal X-ray analysis and DFT calculations suggest this cage structure is rigid and adopts a single low energy conformation. Use of single enantiomer α-amino amides results in two diastereomeric tertiary amines that differ in their absolute configuration at nitrogen. These diastereoisomers interconvert under acidic conditions but are configurationally stable under basic conditions and can be readily separated by either crystallisation or column chromatography. By reacting racemic chiral α-amino amides a third diastereomeric cage can also be isolated through this reaction protocol. Preparation of mixed cages by reacting two different α-amino amides is also possible allowing for greater structural diversity in the products to be attained. Preliminary mechanistic studies show that all three methylene units in the cage structure are labile and can be replaced under acidic reaction conditions. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27458f

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Readily accessible chiral at nitrogen cage structures†
Julian H. Rowley,a Sze Chak Yau,b Benson M. Kariuki,b Alan R. Kennedya and
Nicholas C. O. Tomkinson*a
Cite this: DOI: 10.1039/c3ob27458f
The reaction of glycine-N-methyl amide with paraformaldehyde in the presence of ytterbium triflate
(1 mol%) leads to a novel cage structure 6 which is chiral at nitrogen. Single crystal X-ray analysis and DFT
calculations suggest this cage structure is rigid and adopts a single low energy conformation. Use of
single enantiomer α-amino amides results in two diastereomeric tertiary amines that differ in their abso-
lute configuration at nitrogen. These diastereoisomers interconvert under acidic conditions but are confi-
gurationally stable under basic conditions and can be readily separated by either crystallisation or column
chromatography. By reacting racemic chiral α-amino amides a third diastereomeric cage can also be iso-
lated through this reaction protocol. Preparation of mixed cages by reacting two different α-amino
amides is also possible allowing for greater structural diversity in the products to be attained. Preliminary
mechanistic studies show that all three methylene units in the cage structure are labile and can be
replaced under acidic reaction conditions.
Received 19th December 2012,
Accepted 29th January 2013
DOI: 10.1039/c3ob27458f
www.rsc.org/obc
The tertiary amines with stereogenic nitrogen that have
found use as chiral control elements are derived from both
Introduction
Tertiary amines are ubiquitous in Nature and have provided synthetic and natural sources, a selection of which are shown
the impetus for invention and discovery in many branches of in Fig. 1. More often than not, both enantiomers of a naturally
chemistry. In the majority of cases tertiary amines, which are occurring compound do not exist within Nature, significantly
pyramidal at nitrogen, are not configurationally stable and detracting from their use in asymmetric synthesis. With some
therefore rapidly interconvert. A number of amines are not tertiary amines (which are chiral at nitrogen) a pseudo
able to undergo this interconversion, predominantly due to enantiomeric amine exists; for example, (+)-quinidine 1 and
conformational restraints, such that the nitrogen is both (−)-quinine. With other amines this is not the case and
stereogenic and configurationally stable.
synthetic routes need to be devised to access the opposite
Compounds that possess chirality at nitrogen have a par- antipode. To circumvent complex multi-step synthesis,
ticular significance in the field of asymmetric synthesis. For
example: as ligands in transition-metal catalysed processes;1
as chiral ions in phase transfer catalysis;2 and as stoichio-
metric additives in asymmetric deprotonation reactions.3 This
significant stereodirecting power is undoubtedly related to the
intimate location of the stereogenic nitrogen to the reaction
centre and provides an incentive for uncovering new configura-
tionally stable tertiary amine scaffolds.
aWestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building,
University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.
E-mail: Nicholas.Tomkinson@strath.ac.uk; Fax: +44 (0) 141 5485743;
Tel: +44 (0) 141 5482276
bSchool of Chemistry, Cardiff University, Main Building, Park Place, Cardiff,
CF10 3AT, UK
†Electronic supplementary information (ESI) available: 1H and 13C spectra for all
compounds reported. CCDC 909951–909956 and 908491–908492. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob27458f
Fig. 1 A selection of naturally occurring and synthetic tertiary amines configu-
rationally stable at nitrogen.
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experimentation has occasionally allowed for identification of
key elements within natural products which impart function
allowing simpler derivatives to be designed. An elegant
example of this tactic is found in the (+)-sparteine surrogate 4
introduced by O’Brien,4 where the accessible scaffold 4 acts as
the complimentary chiral structure to the naturally occurring
(−)-sparteine 2. Despite these strategies, the use of natural pro-
ducts as the source of chirality does have limitations which
can only be circumvented through synthesis.
Fig. 2 Single crystal X-ray structure of 6.
The first synthetic chiral compounds with stereogenic nitro-
gen to be resolved were the Tröger bases 3.5 This early research
inspired numerous avenues of investigation6 and important
advances continue to be made within this area.7 The overall
scaffold is easily prepared by the reaction of aniline and DMSO
in the presence of an acid catalyst. Although methods for the
preparation of Tröger bases are well developed, resolution of
these compounds is non-trivial and remains a significant chal-
lenge. Therefore, preparation of scaffolds that are chiral at
nitrogen, easy to access, but do not require resolution would
represent a significant contribution to the area.
Fig. 3 Low energy conformations and relative energies from DFT calculations.
Given the importance of configurationally stable nitrogen
atoms and the impact they have made upon the field of asym-
metric synthesis we wish to report a structurally novel series of
tertiary amines. Within this paper we describe a simple, scal-
able, and highly effective method to access a novel series of
configurationally stable tertiary amines that are chiral at
nitrogen.
stereogenic and configurationally stable. Examination of 6 by
chiral stationary phase HPLC (Chiralcel OJ) showed two peaks
of equal height and intensity (see ESI†) suggesting that reso-
lution/separation of the enantiomers of 6 would result in novel
amines of potential in synthesis.
DFT calculations on the low energy conformations of 6
showed three accessible and distinct conformations for this
compound (Fig. 3). Along with the structure A which is consist-
ent with that seen in the crystal structure, conformation B lies
5.8 kcal mol−1 higher in energy with the alternative C existing
at 11.6 kcal mol−1 higher in energy. Although alternative con-
formations to that seen in the single crystal X-ray structure are
possible (Fig. 3), these appear to be considerably higher in
energy and it would be expected that A would be the prevalent
conformation adopted in solution. From these calculations
it would be expected that at room temperature the relative
population of conformation A would be >99%. This significant
difference in the relative populations of the low energy con-
formations that 6 could adopt in solution should render the
scaffold rigid and result in consistent functional properties
being observed for these intriguing cage structures.
Preference for conformation A over both B and C resides in
unfavourable gauche interactions between the carbonyl groups
and adjacent methylene units (E) along with the N-methyl
groups and adjacent methylene (D) which exist in both B and
C (Fig. 4). Examination of the crystal structure of 6 shows the
CvO⋯N distances to be greater than the sum of the van der
Waals radii (2.93 Å), suggesting that no explicit stabilisation is
found with adopting conformation A and it is the destabilising
interactions present in B and C that render A preferential.
Although 6 was a chiral compound of interest, preparation/
resolution of this as a single enantiomer presented a sig-
nificant chemical challenge. We therefore elected to examine if
similar structures could be prepared from chiral α-amino acid
derivatives (Scheme 2). Reaction of phenylalanine N-methyl
Results and discussion
The imidazolidinone architecture has provided the platform
for the invention of a series of effective strategies for bond con-
struction including the concepts of LUMO, HOMO and SOMO
catalysis.8 Whilst attempting to prepare the imidazolidinone 7
by condensation of 5 and paraformaldehyde in the presence of
Yb(OTf)3 (CHCl3, Δ, 18 h),9 we were surprised to isolate the
bicyclic amine 6 in 47% yield after purification by crystallisa-
tion (Scheme 1). We were unable to detect any of the target
1
imidazolidinone 7 in the H NMR spectrum of the crude reac-
tion mixture. This simple and effective protocol for the gen-
eration of the complex tertiary amine 6 from commercial
materials suggested that the method had potential and
warranted further investigation.
The molecular structure of 6 as determined by single crystal
X-ray diffraction is shown in Fig. 2. The rigid nature of this
[4.4.1] bicyclic cage renders each of the nitrogen atoms
Scheme 1 Attempted synthesis of imidazolidinone 7.
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Fig. 4 Unfavourable gauche interactions destabilising conformations B and C.
Scheme 3 Synthesis of cage structures derived from alanine and valine.
Scheme 2 Preparation of cage structures 12 and 13 from phenylalanine
N-methyl amide.
amide 11 with paraformaldehyde under the same conditions
as those described above resulted in the formation of two pro-
ducts 12 and 13. Estimation of the relative amounts of these
two compounds from 1H NMR of the crude reaction mixture
suggested a ratio of 8.5 : 1 (12 : 13). These compounds could
easily be separated by chromatography and the products were
isolated in 81% (12) and 5% (13) yield respectively. It is impor-
tant to note that in standard CDCl3 the two diastereoisomers
12 and 13 slowly interconvert at room temperature and it is
necessary to filter the CDCl3 through a short plug of basic
alumina prior to obtaining NMR spectra. Each of the diaster-
eoisomers 12 and 13 are stable to the conditions of silica flash
column chromatography and in solution (base washed CDCl3
for 1 week). Independently heating a chloroform solution of
amine 12 or 13 at reflux in the presence of Yb(OTf)3 (1 mol%)
for 18 h leads to a mixture of the two diastereoisomers (recov-
ery > 90% after purification).
For 12 and 13 the absolute configuration of the stereogenic
carbon atoms are identical (5S,10S). They differ in their abso-
lute configuration at nitrogen where for 12 the configuration
of each nitrogen is (S) and for 13 (R). It is interesting that this
is manifested in the [α]D measurements. For 12 [α]2D0 = −128.9
whereas for 13 [α]2D0 = +78.7 which is of the opposite sign.
Interconversion of 12 and 13 by exposure to Yb(OTf)3 as out-
lined above followed by separation leads to no change in
values for optical rotation.
Fig. 5 Single crystal X-ray structures for phenylalanine, alanine and valine
derived structures.
method by which to access this intriguing class of amine
(Scheme 3). Using 14 as starting material, we were only able to
isolate the major diastereoisomer 15 (47%) and no clear indi-
cation of the alternative diastereoisomer could be seen in the
1H NMR of the crude reaction mixture. With valine N-methyl
amide as starting material the ratio of the two products was
1 : 2 in favour of the isomer 18 (53%) over isomer 17 (27%).
Single crystal X-ray structures for these three compounds are
collected in Fig. 5.
Intrigued by the possibility of preparing alternative struc-
tures we undertook two further sets of experiments. Firstly, we
prepared the mixed structure 19 (33% yield) by the reaction of
11 and 14 (1 equiv. each) under standard conditions (CHCl3,
Yb(OTf)3, Δ) (Scheme 4). The major product from the reaction
of two molecules of phenylalanine N-methyl amide (12) was
also isolated from this reaction mixture in 20% yield.
Of particular note is that both antipodes of the tertiary
amine cage structures are readily accessible from either the
D- or L-amino acids which are commercially available. This
ability to access either enantiomer of the desired amine in just
one step through a simple and robust protocol will be of great
importance in developing this work further.
Application of this methodology to both alanine N-methyl
amide 14 and valine N-methyl amide 16 was also successful,
suggesting this should be a robust, general and practical
A second experiment involved reaction of racemic phenyl-
alanine N-methyl amide ( )-11 (Scheme 5). Along with the
expected isomers from this transformation ( )-12 (37%) and
( )-13 (2%), structure 20 was also isolated as a major
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Scheme 4 Preparation of mixed caged structure from 11 and 14.
Scheme 6 Deuterium incorporation into 12.
Conclusions
We have described a series of novel tertiary amines that are
both stereogenic and configurationally stable at nitrogen. Reac-
tion of chiral α-amino amides with paraformaldehyde in the
presence of a Lewis acid catalyst allows formation of diastereo-
meric cage structures that differ in their absolute configuration
at nitrogen. Interconversion of these structures is possible in
an acidic environment, but under basic conditions the pro-
ducts are stable in solution. The cage structures adopt a single
conformation in the solid state and DFT calculations on 6
reveal that alternative conformations are significantly higher
in energy suggesting this conformation will also be adopted in
solution providing a rigid bicyclic structure. Preparation of
mixed cages through the reaction of two different amino
amides has also been shown to be possible suggesting the
scaffolds can be significantly diversified. Interestingly, reaction
of the cage 12 with deuterated paraformaldehyde shows no
marked preference for exchange of the bridgehead methylene
unit.
Scheme 5 Reaction of paraformaldehyde and racemic phenylalanine N-methyl
amide.
Fig. 6 Single crystal X-ray structures for cage structures 19 and 20.
component of the reaction mixture (34%). Single crystal X-ray
crystallography confirmed the structure of 20 where one of the
benzyl groups extends away from the cage and the second into
the structure (Fig. 6).
Although we had established that under acidic conditions it
was possible to interconvert the two isomers 12 and 13, we
were intrigued if this involved solely the bridge N–C–N
(N1C11N6) bond or if all three of the N–C–N groups present in
the molecule were involved in this process. Reaction of deute-
rated paraformaldehyde with 12 in the presence of Yb(OTf)3 in
CDCl3 (Scheme 6) and monitoring the reaction by 1H NMR
showed the rate of deuterium incorporation into each of the
three centres was roughly equal, showing that isomerisation
was occurring through multiple Lewis acid catalysed mechan-
isms. Recent reports by Lacour showed that configurationally
stable Tröger bases could be prepared by reaction of the
methano-bridged bases with diazo esters to provide configura-
tionally stable ethano-bridged Tröger base derivatives.10 If this
tactic were to be adopted with the current system it would be
necessary to target all three methylene units within the tertiary
amine.
Experimental
Glycine N-methyl amide 511
Glycine methyl ester hydrochloride (10.00 g, 79.7 mmol) was
stirred in an ethanolic solution of methylamine 33 wt%
(50 mL, 402 mmol) for 78 h at ambient temperature. Sodium
hydroxide (3.50 g, 88 mmol, 1.1 equiv.) was added and stirring
continued for 30 minutes. The solvent was removed under
reduced pressure and the residue extracted into ethyl acetate
(3 × 40 mL). The combined extractions were filtered through a
sinter and the solvent removed under reduced pressure to give
the product as a yellow oil (6.57 g, 94%). νmax (ATR)/cm−1 3340,
3078, 2941, 2899, 1643, 1537; 1H NMR (400 MHz, CDCl3)
δ 7.35 (1H, s), 3.10 (2H, s), 2.60 (3H, d, J = 4.9 Hz), 1.37 (2H, s);
13C NMR (101 MHz, CDCl3) δ 173.4, 44.4, 25.3; m/z (ES): 88.9
(M + H+).
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L-Phenylalanine-N-methyl amide 1112
( )-3,8-Dimethyl-1,3,6,8-tetraaza-bicyclo[4.4.1]undecane-4,9-
dione 6
L-Phenylalanine ethyl ester hydrochloride (30.0 g, 131 mmol)
was stirred in an ethanolic solution of methylamine 33 wt% Glycine-N-methyl amide (440 mg, 5 mmol) was dissolved in
(150 mL, 1.2 mol) for 72 hours at ambient temperature. The chloroform (20 mL). Paraformaldehyde (450 mg, 15 mmol, 3
solvent was removed under reduced pressure. The resultant equiv.) and ytterbium(III) trifluoromethanesulfonate hydrate
slurry was taken up in saturated sodium carbonate (50 mL) (31 mg, 0.05 mmol, 1 mol%) were added. The mixture was
and extracted with chloroform (3 × 50 mL). The combined stirred at 60 °C for 18 h. Once cooled to ambient temperature
organic extracts were dried over anhydrous potassium carbo- the mixture was filtered through a 1 cm plug of Celite and the
nate and the solvent removed under reduced pressure to give a filter cake was washed with 100 mL dichloromethane. The
white solid. The residue was recrystallised from ethyl acetate solvent was removed under reduced pressure and the residue
and petroleum ether to give the product as white needles dissolved in hot ethyl acetate (∼20 mL). The solution was
(17.6 g, 75%). Mp: 67–69 °C; [α]2D0 = −89.6 (c = 1, CHCl3); νmax allowed to cool and left at ambient temperature for 24 h. The
(film)/cm−1 3371, 3345, 3290, 2939, 2875, 1644; 1H NMR precipitate was filtered, washed with diethyl ether (10 mL) and
(400 MHz, CDCl3) δ 7.47–7.12 (5H, m), 3.54 (1H, dd, J = 9.5, discarded. The filtrate was concentrated under reduced
3.9 Hz), 3.22 (1H, dd, J = 13.7, 3.9 Hz), 2.83 (3H, d, J = 5.0 Hz), pressure and dissolved in hot ethyl acetate (15 mL), the solu-
2.60 (1H, dd, J = 13.7, 9.5 Hz), 1.38 (2H, s); 13C NMR (101 MHz, tion was cooled to −24 °C and allowed to crystallise for 48 h.
CDCl3) δ 174.8, 138.0, 129.3, 128.7, 126.8, 56.5, 41.0, 25.8; m/z The white crystals were recovered on a sinter, washed with
(ES): 179.1 (M + H+).
diethyl ether (20 mL) and dried under reduced pressure
(247 mg, 47%). Mp: 176–179 °C; νmax (ATR)/cm−1 2967, 2936,
2907, 1618; 1H NMR (500 MHz, CDCl3) δ 4.81 (2H, dd, J = 14.7,
1.3 Hz), 4.19 (2H, d, J = 14.7 Hz), 4.11 (2H, d, J = 7.9 Hz), 3.88
(2H, d, J = 16.2 Hz), 3.63 (2H, d, J = 16.2 Hz), 2.88 (6H, s);
13C NMR (126 MHz, CDCl3) δ 175.1, 78.3, 70.6, 59.0, 36.1; m/z
(ES/APCI): 213.1 (M + H+); HRMS (ES; ion trap) calculated for
C9H16O2N4 213.1346 (M + H+), found 213.1348.
L-Alanine-N-methyl amide 1413
L-Alanine methyl ester hydrochloride (10.00 g, 71.7 mmol) was
stirred in an ethanolic solution of methylamine 33 wt%
(60 mL, 483 mmol) for 72 h at ambient temperature. The
mixture was concentrated under reduced pressure. The result-
ing slurry was taken up into saturated sodium carbonate
(50 mL) and extracted with chloroform (4 × 50 mL). The com-
bined organic extracts were dried over anhydrous potassium
(5S,10S)-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo-
[4.4.1]undecane-4,9-dione 12 and 13
carbonate and the solvent removed under reduced pressure to L-Phenylalanine N-methyl amide (890 mg, 5 mmol) was dis-
give the product as a pale yellow oil (5.11 g, 70%). [α]2D0 = +4.1 solved in chloroform (20 mL). Paraformaldehyde (450 mg,
(c = 2.0, MeOH); νmax (ATR)/cm−1 3298, 2968, 2934, 1651; 15 mmol, 3 equiv.) and ytterbium(III) trifluoromethanesulfo-
1H NMR (400 MHz, CDCl3) δ 7.31 (1H, s), 3.40 (1H, q, J = nate hydrate (31 mg, 0.05 mmol, 1 mol%) were added. The
7.0 Hz), 2.72 (3H, d, J = 5.0 Hz), 1.40 (2H, s), 1.24 (3H, d, J = mixture was stirred at 60 °C for 18 h. Once cooled to ambient
7.0 Hz); 13C NMR (101 MHz, CDCl3) δ 176.4, 50.7, 25.8, 21.7; temperature the mixture was diluted with dichloromethane
m/z (ES): 102.9 (M + H+).
(30 mL), washed with saturated sodium hydrogen carbonate
(3 × 20 mL), brine (30 mL) and then dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the two diastereomers separated by flash chrom-
atography (gradient elution from 80% ethyl acetate in pet-
roleum ether to 100% ethyl acetate) to give first 12 (791 mg,
81%) and second 13 (50 mg, 5%) as white crystalline solids.
L-Valine-N-methyl amide 1614
L-Valine methyl ester hydrochloride (5.00 g, 30 mmol) was
stirred in an ethanolic solution of methylamine 33 wt%
(30 mL, 241 mmol) for 72 h at ambient temperature. The
mixture was concentrated under reduced pressure. The result-
ing slurry was taken up in saturated sodium carbonate (15 mL)
and extracted with chloroform (3 × 30 mL). The combined
(−)-(1S,5S,6S,10S)-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-
bicyclo[4.4.1]undecane-4,9-dione 12
organic extracts were dried over anhydrous potassium carbo- Rf = 0.47 (petroleum ether–ethyl acetate 1 : 4); mp: 128–130 °C;
nate and the solvent removed under reduced pressure to give [α]2D0 = −128.9 (c = 0.85, MeOH); νmax (ATR)/cm−1 2926, 2907,
1
the product as a colourless oil (3.43 g, 88%). [α]2D0 = +17.3 (c = 1626, 1639; H NMR (400 MHz, CDCl3) δ 7.34–7.20 (10H, m),
2.4, MeOH); νmax (ATR)/cm−1 3293, 2959, 2934, 2907, 1645, 4.69 (2H, d, J = 15.3 Hz), 4.40 (2H, d, J = 15.3 Hz), 4.11 (2H, s),
1530; 1H NMR (400 MHz, CDCl3) δ 3.20 (1H, d, J = 3.9 Hz), 2.80 3.83 (2H, dd, J = 9.0, 5.5 Hz), 3.41 (2H. dd, J = 14.7, 5.5 Hz),
(3H, d, J = 5.0 Hz), 2.27 (1H, heptd, J = 6.9, 3.9 Hz), 1.25 (2H, 2.97 (6H, s), 2.95 (2H, dd, J = 14.7, 9.0 Hz); 13C NMR (101 MHz,
s), 0.96 (3H, d, J = 6.9 Hz), 0.80 (3H, d, J = 6.9 Hz); 13C NMR CDCl3) δ 174.6, 139.6, 129.2, 128.3, 126.3, 82.6, 65.2, 64.4, 37.2,
(101 MHz, CDCl3) δ 175.1, 60.3, 30.9, 25.7, 19.8, 16.1; m/z (ES): 34.7; m/z (ES): 415.1 (M + Na+); HRMS (ES; ion trap) calculated
130.9 (M + H+).
for C23H29O2N4 393.2285 (M + H+), found 393.2297.
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(+)-(1R,5S,6R,10S)-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-
bicyclo[4.4.1]undecane-4,9-dione 13
d, J = 15.3 Hz), 4.21 (2H, s), 4.04 (2H, d, J = 15.3 Hz), 3.07 (2H,
d, J = 10.3 Hz), 2.70 (6H, s), 2.30–2.17 (2H, m), 0.95 (6H, d, J =
6.3 Hz), 0.89 (6H, d, J = 6.8 Hz); 13C NMR (101 MHz, CD3CN)
δ 174.8, 83.2, 69.0, 66.0, 37.2, 27.1, 22.4, 20.2; m/z (ES): 319.1
(M + Na+); HRMS (ES; ion trap) calculated for C15H29O2N4
297.2285 (M + H+), found 297.2281.
Rf = 0.16 (petroleum ether–ethyl acetate 1 : 4); mp: 215–218 °C;
[α]D20 = +78.7 (c = 0.75, MeOH); νmax (ATR)/cm−1 2953, 2922,
2804, 1680, 1618; 1H NMR (500 MHz, CDCl3) δ 7.38–7.16 (10H,
m), 4.92 (2H, d, J = 14.9 Hz), 4.24 (2H, s), 4.06 (2H, d, J =
14.9 Hz), 3.93 (2H, dd, J = 10.3, 6.2 Hz), 3.16–3.09 (4H, m), 2.93
(6H, s); 13C NMR (126 MHz, CDCl3) δ 176.5, 137.6, 128.8,
128.7, 126.9, 72.4, 70.8, 62.6, 36.9, 34.6; m/z (ES): 415.2
(M + Na+); HRMS (ES; ion trap) calculated for C23H29O2N4
393.2285 (M + H+), found 393.2282.
(+)-(1R,5S,6R,10S)-5,10-Diisopropyl-3,8-dimethyl-1,3,6,8-
tetraaza-bicyclo[4.4.1]undecane-4,9-dione 18
Rf = 0.1 (petroleum ether–ethyl acetate 1 : 1); mp: 144–155 °C;
[α]D20 = +21.9 (c = 0.75, MeOH); νmax (ATR)/cm−1 2965, 2924,
2868, 1626; 1H NMR (400 MHz, CD3CN) δ 4.90 (2H, d, J =
14.8 Hz), 4.07 (2H, s), 4.03 (2H, d, J = 14.9 Hz), 2.96 (2H, d,
J = 11.4 Hz), 2.75 (6H, s), 2.34–2.23 (2H, m), 0.95 (6H, d, J =
6.4 Hz), 0.91 (6H, d, J = 6.6 Hz); 13C NMR (101 MHz, CD3CN)
δ 176.6, 77.0, 72.3, 63.5, 36.7, 26.2, 20.8, 20.2; m/z (ES) 319.1
(M + Na+); HRMS (ES; ion trap) calculated for C15H29O2N4
297.2285 (M + H+), found 297.2290.
(−)-(1S,5S,6S,10S)-3,5,8,10-Tetramethyl-1,3,6,8-tetraaza-bicyclo-
[4.4.1]undecane-4,9-dione 15
L-Alanine-N-methyl amide (510 mg, 5 mmol) was dissolved in
chloroform (20 mL). Paraformaldehyde (450 mg, 15 mmol, 3
equiv.) and ytterbium(III) trifluoromethanesulfonate hydrate
(31 mg, 0.05 mmol, 1 mol%) were added. The mixture was
stirred at 60 °C for 18 h. Once cooled to ambient temperature
the mixture was diluted with dichloromethane (30 mL),
washed with saturated sodium hydrogen carbonate (3 ×
20 mL), brine (30 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and
the residue crystallised with dichloromethane and 40–60 °C
petroleum ether to give the product as white crystals (280 mg,
47%). Mp: 206–208 °C; [α]2D0 = −(82.8 (c = 1.0, MeOH); νmax
(ATR)/cm–1 2995, 2980, 2931, 2955, 1632; 1H NMR (400 MHz,
CDCl3) δ 4.59 (2H, d, J = 15.2 Hz), 4.27 (2H, d, J = 15.2 Hz),
4.23 (2H, s), 3.67 (2H, q, J = 7.0 Hz), 2.79 (6H, s), 1.32 (6H, d,
J = 7.0 Hz); 13C NMR (101 MHz, CDCl3) δ 174.7, 81.2, 64.2,
57.4, 36.2, 14.9; m/z (ES/APCI): 241.1 (M + H+); HRMS (ES; ion
trap) calculated for C11H21O2N4 241.1659 (M + H+), found
241.1659.
(−)-(1S,5S,6S,10S)-5-Benzyl-3,8,10-trimethyl-1,3,6,8-
tetraazabicyclo[4.4.1]undecane-4,9-dione 19
L-Phenylalanine-N-methyl amide (445 mg, 2.5 mmol) and
L-alanine N-methyl amide (255 mg, 2.5 mmol) were dissolved
in chloroform (20 mL). Paraformaldehyde (450 mg, 15 mmol,
3 equiv.) and ytterbium(III) trifluoromethanesulfonate hydrate
(31 mg, 0.05 mmol, 1 mol%) were added. The mixture was
stirred at 60 °C for 18 h. Once cooled to ambient temperature
the mixture was diluted with dichloromethane (30 mL),
washed with saturated sodium hydrogen carbonate (3 ×
20 mL), brine (30 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and
product isolated by flash chromatography (gradient elution
from 50% ethyl acetate in petroleum ether to 100% ethyl
acetate) to give a white crystalline solid (260 mg, 34%). Rf =
0.14 (petroleum ether–ethyl acetate 1 : 4); mp: 216–218 °C;
[α]D20 = −106.8 (c = 1.0, MeOH); νmax (ATR)/cm−1 2982, 2953,
(5S,10S)-5,10-Diisopropyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo-
[4.4.1]undecane-4,9-dione 17 and 18
1
2922, 2862, 1626; H NMR (400 MHz, CDCl3) δ 7.33–7.16 (5H,
L-Valine-N-methyl amide (650 mg, 5 mmol) was dissolved in
chloroform (20 mL). Paraformaldehyde (450 mg, 15 mmol,
3 equiv.) and ytterbium(III) trifluoromethanesulfonate hydrate
(31 mg, 0.05 mmol, 1 mol%) were added. The mixture was
stirred at 60 °C for 18 h. Once cooled to ambient temperature
the mixture was diluted with dichloromethane (30 mL),
washed with saturated sodium hydrogen carbonate (3 ×
20 mL), brine (30 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and
the two diastereomers separated by flash chromatography
(gradient elution from 50% ethyl acetate in petroleum ether to
100% ethyl acetate) to give first 17 (198 mg, 27%) and second
18 (390 mg, 53%) as white crystalline solids.
m), 4.67 (1H, d, J = 15.2 Hz), 4.66 (1H, d, J = 15.2 Hz), 4.39 (1H,
d, J = 15.3 Hz), 4.32 (1H, d, J = 15.3 Hz), 4.23 (1H, d, J = 14.2
Hz), 4.14 (1H, d, J = 14.2 Hz), 3.83 (1H, dd, J = 9.3, 5.2 Hz), 3.70
(1H, q, J = 7.0 Hz), 3.37 (1H, dd, J = 14.8, 5.2 Hz), 2.94 (1H, dd,
J = 14.8, 9.3 Hz), 2.94 (3H, s), 2.87 (3H, s), 1.39 (3H, d, J =
7.0 Hz); 13C NMR (101 MHz, CDCl3) δ 175.3, 174.7, 139.7,
129.2, 128.3, 126.3, 82.2, 65.1, 64.8, 64.3, 58.2, 37.0, 36.9, 34.6,
15.5; m/z (ES/APCI): 317.3 (M + H+); HRMS (ES; ion trap) calcu-
lated for C17H24O2N4 317.1972 (M + H+), found 317.1978.
Also recovered 197 mg, 20% (−)-(1S,5S,6S,10S)-5,10-
dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo[4.4.1]undecane-
4,9-dione 12.
( )-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo[4.4.1]-
undecane-4,9-dione 12, 13 and 20
(−)-(1S,5S,6S,10S)-5,10-Diisopropyl-3,8-dimethyl-1,3,6,8-
tetraaza-bicyclo[4.4.1]undecane-4,9-dione 17
DL-Phenylalanine N-methyl amide (890 mg, 5 mmol) was dis-
Rf = 0.35 (petroleum ether–ethyl acetate 1 : 1); mp: 125–127 °C; solved in chloroform (20 mL). Paraformaldehyde (450 mg,
[α]2D0 = −12.9 (c = 0.82, MeOH); νmax (ATR)/cm−1 2967, 2955, 15 mmol, 3 equiv.) and ytterbium(III) trifluoromethanesulfo-
2926, 2876, 2862, 1640; 1H NMR (400 MHz, CD3CN) δ 4.73 (2H, nate hydrate (31 mg, 0.05 mmol, 1 mol%) were added. The
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mixture was stirred at 60 °C for 18 h. Once cooled to ambient 34.7; m/z (ES): 421.2 (M + Na+); HRMS (ES) calculated for
temperature the mixture was diluted with dichloromethane C23H23D6O2N4 399.2667 (M + H+), found 399.2666.
(30 mL), washed with saturated sodium hydrogen carbonate
(3 × 20 mL), brine (30 mL) and then dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the three diastereomers separated by flash
chromatography (gradient elution from 80% ethyl acetate in
petroleum ether to 100% ethyl acetate) to give first 12 (366 mg,
37%), second 20 (337 mg, 34%) and third 13 (18 mg, 2%) as
white crystalline solids.
D6-(1R,5S,6R,10S)-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-
bicyclo[4.4.1]undecane-4,9-dione
Mp: 220–222 °C; νmax (ATR)/cm−1 3021, 3922, 2905, 2853, 1697;
1H NMR (400 MHz, CDCl3) δ 7.39–7.20 (10H, m), 3.93 (2H, dd,
J = 10.2, 6.3 Hz), 3.22–3.05 (4H, m), 2.93 (6H, s); 2H NMR
(77 MHz, CHCl3) δ 4.90 (2D, s), 4.23 (2D, s), 4.05 (2D, s);
13C {1H, 2H} NMR (151 MHz, CDCl3) δ 176.5, 137.6, 128.8,
128.7, 126.9, 71.7, 70.7, 61.9, 36.8, 34.5; m/z (ES): 421.2
(M + Na+); HRMS (ES; ion trap) calculated for C23H23D6O2N4
399.2667 (M + H+), found 399.2665.
( )-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo[4.4.1]-
undecane-4,9-dione 12 and 13
Exhibited identical spectroscopic data to the enantiopure
compounds.
Method for monitoring deuterium incorporation
( )-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo[4.4.1]-
undecane-4,9-dione 20
(1S,5S,6S,10S)-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-
bicyclo[4.4.1]undecane-4,9-dione (400 mg, 1.02 mmol) was dis-
solved in deuterated chloroform (4 mL). Deuterated parafor-
maldehyde (98 mg, 3.05 mmol, 3 equiv.) and ytterbium(III)
trifluoromethanesulfonate hydrate (6 mg, 0.01 mmol, 1 mol%)
were added. The mixture was stirred at 60 °C. 200 μL aliquots
were taken, diluted with 700 μL deuterated chloroform and
filtered through a 1 cm plug of basic alumina into an NMR
tube. Deuterium incorporation was determined by 1H NMR
using resonances at 3.83 ppm and 3.41 ppm as integral
references.
Rf = 0.21 (petroleum ether–ethyl acetate 1 : 4); mp: 185–187 °C;
1
νmax (ATR)/cm−1 2924, 1651, 1614; H NMR (400 MHz, CDCl3)
δ 7.35–7.17 (10H, m), 4.83 (1H, d, J = 14.8 Hz), 4.77 (1H, d, J =
15.1 Hz), 4.53 (1H, d, J = 14.9 Hz), 4.38 (1H, d, J = 15.1 Hz),
4.09 (1H, d, J = 14.8 Hz), 3.94 (1H, dd, J = 10.9, 5.5 Hz), 3.86
(1H, dd, J = 5.4, 9.2 Hz), 3.84 (1H, d, J = 14.9 Hz), 3.36 (1H, dd,
J = 14.8, 5.4 Hz), 3.17 (1H, dd, J = 14.5, 5.5 Hz), 3.11 (1H, dd,
J = 14.5, 10.9 Hz), 2.98 (1H, dd, J = 9.2, 14.8 Hz), 2.96 (3H, s),
2.96 (3H, s); 13C NMR (101 MHz, CDCl3) δ 176.7, 174.4, 139.5,
137.7, 129.2, 128.9, 128.6, 128.4, 126.9, 126.4, 72.3, 72.3, 70.5,
65.0, 64.0, 37.1, 36.8, 35.0, 34.6; m/z (ES): 415.2 (M + Na+);
HRMS (ES; ion trap) calculated for C23H29O2N4 393.2285
(M + H+), found 393.2289.
Acknowledgements
The authors thank the EPSRC for financial support and
the mass spectrometry service, Swansea for high-resolution
spectra.
D6-(5S,10S)-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo-
[4.4.1]undecane-4,9-dione 21
L-Phenylalanine N-methyl amide (182 mg, 1.02 mmol) was dis-
solved in chloroform (4 mL). Deuterated paraformaldehyde
(98 mg, 3.05 mmol, 3 equiv.) and ytterbium(III) trifluoromethane-
sulfonate hydrate (6 mg, 0.01 mmol, 1 mol%) were added.
The mixture was stirred at 60 °C for 18 h. Once cooled to
ambient temperature the mixture was diluted with dichloro-
methane (5 mL), washed with saturated sodium hydrogen
carbonate (3 × 5 mL), brine (10 mL) and then dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the two diastereomers separated by flash
chromatography (gradient elution from 80% ethyl acetate in
petroleum ether to 100% ethyl acetate) to give first (148 mg,
73%) and second (22 mg, 11%) as white crystalline solids.
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