Polycations. 19. The synthesis of symmetrical dicationic lipids with internal dimethylazonia functionalities separated by a spacer unit and pendant chains

Article abstract of DOI:10.1016/j.chemphyslip.2009.04.004

Herein is reported the preparation of several series of symmetrical polyammonium salts that serve as cationic lipids or precursors thereof, and are structurally based on several series of parent diamines where dimethylazonia functionalities are present, separated by a central structural unit, and pendant terminal chains. The resultant materials are of significant interest for a variety of purposes, such as serving as antihydrophobic species and as transfectins, the details of which are provided in separate reports. Attempts to effect selective alkylation to provide the corresponding unsymmetrical cationic lipids were without success, always leading to relatively useless mixtures of products.

Full text of DOI:10.1016/j.chemphyslip.2009.04.004

Chemistry and Physics of Lipids 160 (2009) 105–108
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Chemistry and Physics of Lipids
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Polycations. 19. The synthesis of symmetrical dicationic lipids with internal
dimethylazonia functionalities separated by a spacer unit and pendant chains
Robert Engela,∗, JaimeLee Iolani Rizzob, Diego Montenegroa, Jay Leba, Delroy Colemana, Carolyn Honga,
Herby Jeantyb, Marie Thomasa,c
a Department of Chemistry and Biochemistry, Queens College of CUNY, 65-30 Kissena Boulevard, Flushing, NY 11367, USA
b Department of Chemistry and Physical Sciences, Pace University, 1 Pace Plaza, New York, NY 10038, USA
c Doctoral Program in Chemistry, The Graduate Center of CUNY, 365 5th Avenue, New York, NY 10016, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein is reported the preparation of several series of symmetrical polyammonium salts that serve as
cationic lipids or precursors thereof, and are structurally based on several series of parent diamines
where dimethylazonia functionalities are present, separated by a central structural unit, and pendant
terminal chains. The resultant materials are of significant interest for a variety of purposes, such as serving
as antihydrophobic species and as transfectins, the details of which are provided in separate reports.
Attempts to effect selective alkylation to provide the corresponding unsymmetrical cationic lipids were
without success, always leading to relatively useless mixtures of products.
Received 10 February 2009
Received in revised form 23 April 2009
Accepted 27 April 2009
Available online 3 May 2009
Keywords:
Cationic lipid
Polycation
© 2009 Elsevier Ireland Ltd. All rights reserved.
Quaternary ammonium salt
Antihydrophobic effect
Diol
Tetraol
1. Introduction
the construction of such species have been used, for example,
those syntheses wherein “end-components” bearing a tertiary
In the course of our investigations of polyammonium salts for
their application to a variety of purposes, we had cause to prepare
several series of cationic lipids wherein the bulk of the molecule
was arranged structurally in a flexible linear manner. Such polyca-
tionic species have been referred to as polycationic “strings.” In a
recent report (Engel et al., in press) we have discussed the syntheses
of several series of such polycationic strings in which the cationic
sites were located at the nitrogens of 1,4-diazabicyclo[2.2.2]octane
(dabco) components incorporated along the string. In the current
work we are reporting the syntheses of several series of simi-
lar polycationic lipids that are structurally based on: (a) several
␣,␻-bis(dimethylamino)alkanes (as shown below) with the nitro-
gen atoms again providing the cationic sites, and (b) ␣,␻-dihalo
species which can be used in alkylation of two substituted dimethy-
laminoalkane units.
amine have been used in displacement reaction upon a “central-
component” bearing two reactive halogen sites. An example of
this type of system is provided by using a dihalo reagent such as
␣,␣ꢀ-dibromo-p-xylene (shown below as A) in reaction with two
equivalent amounts of a terminal dimethylaminoalkane (shown
below as B).
Dicationic lipids of this type (regardless of their route of synthe-
sis) can provide salts bearing structural features of varying types
rendering them useful for numerous applications. Included among
these types are gemini lipids for which application has been found
in the construction of artificial membranes (Iwamoto et al., 2000,
2004; Bhattacharya and Bajaj, 2007; Bajaj et al., 2008) and as trans-
fectins (Camilleri et al., 2000; Martin et al., 2005). The polycationic
lipids reported herein are based on relatively simpler structures
(polycationic strings) and can be anticipated to exhibit properties
varying as a function of terminal chain length, charge separation,
and appended functional groups (hydroxyl groups) as noted.
Although most of the new compounds synthesized and reported
herein are prepared by alkylation of simple di-tertiary amines of
the type ␣,␻-bis(dimethylamino) alkanes, this is not the situa-
tion in all instances. In certain instances other approaches toward
∗
Corresponding author. Fax: +1 728 997 5531.
E-mail address: robert.engel@qc.cuny.edu (R. Engel).
0009-3084/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.chemphyslip.2009.04.004

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R. Engel et al. / Chemistry and Physics of Lipids 160 (2009) 105–108
Table 1
Analytical and yield data for newly synthesized dicationic strings.
.
Cpd. no.
1
RX
n
Yield
1H NMR (solvent) (ı)
13 C NMR (ı)
Analyses
2
82.5%
(D2O) 1.88–1.91 (4H) br, 3.12 (12H)
s, 3.30–3.50 (8H) br, 3.65 (4H) t
26.1, 53.3, 60.4, 62.6, 64.8
Calcd: C12 H30N2O2Br2(H2O); C:
34.96%; H: 7.82%; found: C: 34.71%;
H: 7.87%
2
3
3
3
61.5%
64.0%
(D2O) 0.88 (6H) t, 1.70 (4H) br, 2.20
(2H) br, 3.03 (12H) s, 3.21–3.32
(8H) br
9.7, 15.7, 16.7, 50.6, 60.1, 66.2
19.1, 27.4, 53.2, 60.4, 62.6, 64.8
Calcd: C13 H32N2Br2; C: 41.50%; H:
8.57%; found: C: 41.31%; H: 8.66%
(D2O) 1.90–2.01 (4H) br, 2.22–3.20
(2H) br, 3.10 (12H) s, 3.33–3.55
(8H) br, 3.69 (4H) t
Calcd: C13 H32N2O2Cl2; C: 48.90%;
H: 10.10%; found: C: 48.99%; H:
10.39%
4
5
3
3
88.0%
74.2%
(D2O) 2.33 (2H) br, 3.17 (6H) s, 3.19
(6H) s, 3.44–3.54 (12H) br, 4.23
(2H) m
16.9, 51.9, 52.1, 61.2, 61.4, 63.6, 66.0,
66.2
Calcd: C13 H32N2O2Cl2(H2O); C:
48.59%; H: 10.66%; found: C:
48.31%; H: 10.84%
Cl(CH2)6OH
(D2O) 1.30–1.37 (8H) br, 1.45–1.62
(4H) br, 1.68–1.78 (4H) br,
14.8, 20.0, 22.8, 23.3, 29.1, 48.8,
58.1, 59.7, 62.9,
Calcd: C19 H44N2O2Cl2; C: 56.56%;
H: 10.99%; found: C: 56.81%; H:
10.70%
2.20–2.28 (2H) br, 3.07 (12H) s,
3.25–3.34 (8H) m, 3.51 (4H) t
(CDCl3) 0.82 (6H) t, 1.12–1.35 (34H)
br, 1.66 (4H) br, 1.87 (4H) br, 3.30
(12H) s, 3.46–3.52 (8H) br
6
CH3(CH2)11 Br
3
74.3%
14.1, 20.9, 22.6, 22.8, 26.2, 29.2,
29.26, 29.34, 29.4, 29.5, 31.8, 45.2,
51.4, 55.6, 64.1
Calcd: C31 H68N2Br2; C: 59.22%; H:
10.90%; found: C: 59.13%; H: 10.98%
7
4
4
4
4
54.3%
73.0%
68.5%
88.5%
(D2O) 1.23–1.38 (4H) m, 1.40–1.55
(4H) br, 2.98 (12H) s, 3.17–3.32
(8H) br, 3.50 (4H) t
20.0, 22.6, 51.3, 62.3, 63.7, 65.0
Calcd: C14 H34N2O2Cl2; C: 50.44%;
H: 10.28%; found: C: 50.80%; H:
10.21%
8
Cl(CH2)6OH
Cl(CH2)10 OH
CH3(CH2)16 Br
(D2O) 1.33–1.47 (8H) br, 1.48–1.49
(4H) br, 1.61–1.64 (8H) br, 3.16
(12H) s, 3.33 (8H) m, 3.69 (4H) t
18.8, 21.5, 24.2, 24.9, 30.6, 50.2,
61.2, 62.5, 63.9
Calcd: C20H46N2O2Cl2; C: 57.54%;
H: 11.11%; found: C: 57.27%; H:
11.40%
9
(D2O) 1.35–1.49 (20H) br, 1.51–1.52
(8H) br, 1.63–1.66 (8H) br, 3.19
(12H) s, 3.35 (8H) m, 3.71 (4H) t
18.2, 18.5, 18.8, 19.2, 19.7, 21.5, 24.3,
24.9, 30.7, 50.2, 61.2, 62.6, 63.9
Calcd: C28H62N2O2Cl2; C: 63.49%;
H: 11.80%; found: C: 63.41%; H:
11.91%
10
(CDCl3) 0.81 (6H) t, 1.11–1.31 (52H)
br, 1.68 (4H) br, 2.09 (4H) br, 3.21
(12H) s, 3.35 (4H) br, 3.86 (4H) br
14.2, 19.9, 22.7, 22.9, 26.3, 27.3,
29.2, 29.3, 29.4, 29.49, 29.51, 29.63,
29.66, 29.68, 29.72, 31.9, 42.7, 50.9,
63.7
Calcd: C40H86N2Br2; C: 63.64%; H:
11.48%; found: C: 63.62%; H: 11.57%
11
12
CH3I
6
6
91.5%
87.0%
(D2O) 1.34 (4H) br, 1.71 (4H) br,
3.01 (18H) s, 3.23 (4H) br
22.2, 25.0, 52.8, 66.4
Calcd: C12 H30N2I2; C: 31.59%; H:
6.63%; found: C: 31.48%; H: 6.72%
(D2O) 0.86 (6H) t, 1.29 (4H) br, 1.78
(8H) br, 2.94 (12H) s, 3.16 (8H) br
14.7, 18.2, 20.9, 24.2, 49.6, 62.9,
64.5
Calcd: C16 H38N2I2; C: 37.51%; H:
7.48%; found: C: 37.44%; H: 7.62%
13
14
6
6
77.6%
47.0%
(D2O) 1.23–1.38 (8H) m, 1.38–1.51
(4H) m, 2.90 (12H) s, 3.12–3.25 (8H)
m, 3.45–3.58 (4H) t
24.1, 26.8, 27.5, 52.8, 63.4, 66.0, 66.2
Calcd: C16 H38N2O2Cl2(H2O); C:
50.65%; H: 10.63%; found: C:
50.88%; H: 10.59%
(D2O) 1.32 (4H) br, 1.69 (4H) br,
3.05 (6H) s, 3.06 (6H) s, 3.28–3.34
(8H) m, 3.46–3.48 (4H) m, 4.15 (2H)
m
21.8, 25.0, 51.5, 51.7, 63.6, 65.3,
65.6, 66.1
Calcd: C16 H38N2O4Cl2; C: 48.85%;
H: 9.74%; found: C: 48.48%; H:
9.54%
15
16
CH3(CH2)3Br
Cl(CH2)6OH
6
6
72.0%
60.1%
(D2O) 0.83 (6H) t, 1.29 (8H) br, 1.61
(8H) br, 2.92 (12H) s, 3.17 (8H) br
12.8, 19.0, 21.8, 23.8, 25.1, 42.5,
50.4, 63.6
Calcd: C18 H42N2Br2; C: 48.44%; H:
9.48%; found: C: 48.21%; H: 9.59%
(D2O) 1.28–1.32 (12H) br, 1.43–1.49
(4H) br, 1.66–1.67 (8H) br, 2.94
(12H) s, 3.16–3.20 (8H) m, 3.49 (4H)
t
22.2, 24.7, 24.9, 25.5, 25.6, 31.3,
46.1, 62.1, 64.1, 64.3
Calcd: C22H50N2O2Cl2; C: 59.31%;
H: 11.31%; found: C: 59.38%; H:
11.41%
17
C6H5CH2Cl
6
37.0%
(D2O) 1.33 (4H) br, 1.80 (4H) br,
2.91 (12H) s, 3.19 (4H) br, 4.28 (4H)
br, 7.57 (10H) br
22.0, 25.2, 42.9, 49.6, 67.8, 127.2,
129.1, 130.8, 132.8
Calcd: C24H38N2Cl2; C: 71.47%; H:
7.89%; found: C: 71.48%; H: 8.13%

R. Engel et al. / Chemistry and Physics of Lipids 160 (2009) 105–108
107
Table 1 (Continued )
Cpd. no.
18
RX
n
Yield
1H NMR (solvent) (ı)
13 C NMR (ı)
Analyses
CH3(CH2)7Cl
6
46.0%
(CDCl3) 0.87 (6H) t, 1.26–1.35 (24H)
br, 1.72 (4H) br, 2.00 (4H) br, 3.39
(12H) s, 3.50 (4H) br, 3.73 (4H) br
14.0, 21.7, 22.6, 22.9, 24.4, 26.3,
29.0, 29.2, 31.6, 51.0, 64.2, 64.8
Calcd: C26H58N2Cl2; C: 66.49%; H:
12.45%; found: C: 66.24%; H:
12.61%
19
20
CH3(CH2)9Cl
CH3(CH2)11 Cl
6
6
38.0%
51.0%
(CDCl3) 0.81 (4H) t, 1.19–1.26 (22H)
br, 1.36–1.41 (8H) br, 1.67–1.71 (4H)
br, 2.13 (12H) s, 2.15–2.19 (12H) br,
3.45 (4H) t
(CDCl3) 0.74 (6H) t, 1.10–1.30 (40H)
br, 1.59 (4H) br, 1.83 (4H) br, 3.25
(12H) s, 3.39 (4H) br, 3.54 (4H) br
14.0, 22.6, 26.8, 27.4, 27.7, 28.8,
29.2, 29.4, 29.5, 31.8, 32.6, 45.0,
45.4, 59.8
Calcd: C30H66N2Cl2; C: 68.53%; H:
12.65%; found: C: 68.39%; H:
12.81%
14.0, 21.7, 22.5, 22.8, 24.7, 25.7,
26.2, 27.1, 29.2, 29.3, 29.4, 31.8,
44.8, 50.9, 64.0, 64.5
Calcd: C34H74 N2Cl2; C: 70.18%; H:
12.82%; found: C: 70.04%; H:
12.93%
21
22
CH3(CH2)13 Br
CH3(CH2)15 Br
6
6
51.8%
52.2%
(CDCl3) 0.81 (6H) t, 1.16–1.38 (48H)
br, 1.55 (4H) br, 1.69 (4H) br, 3.36
(12H) s, 3.41 (4H) br, 3.69 (4H) br
(CDCl3) 0.83 (6H) t, 1.21–1.38 (56H)
br, 1.59 (4H) br, 1.71 (4H) br, 3.37
(12H) s, 3.45 (4H) br, 3.49 (4H) br
14.1, 21.5, 22.7, 22.9, 24.0, 26.3,
29.3, 29.4, 29.47, 29.51, 29.59,
29.65, 29.68, 31.9, 51.1, 64.2, 64.9
14.1, 21.6, 22.7, 22.9, 24.4, 26.3,
26.8, 27.2, 29.28, 29.35, 29.41,
29.49, 29.60, 29.65, 29.69, 31.9,
45.4, 51.1, 59.3, 64.2
Calcd: C38H82N2Br2; C: 62.79%; H:
11.37%; found: C: 62.58%; H: 11.41%
Calcd: C42H90N2Br2; C: 64.43%; H:
11.59%; found: C: 64.19%; H: 11.82%
23
24
CH3(CH2)17 Br
Cl(CH2)3OH
6
8
83.0%
61.4%
(CDCl3) 0.88 (6H) t, 1.26–1.48
(68H) br, 1.71 (4H) br, 3.37 (12H) s,
3.42–3.50 (8H) br
14.1, 22.7, 22.8, 26.1, 26.3, 26.9,
27.3, 29.23, 29.29, 29.35, 29.38,
29.46, 29.59, 29.62, 29.65, 29.70,
31.9, 45.4, 51.2, 59.3, 63.8
20.9, 24.5, 25.0, 27.1, 49.8, 58.1,
60.6, 63.4
Calcd: C46H98N2Br2; C: 65.84%; H:
11.77%; found: C: 65.79%; H: 11.83%
(D2O) 1.30 (8H) br, 1.65–1.75 (4H)
br, 1.85–1.95 (4H) br, 2.99 (12H) s,
3.15–3.35 (8H) br, 3.61 (4H) t
Calcd: C18 H42N2O2Cl2(H2O); C:
53.05%; H: 10.88%; found: C:
52.75%; H: 10.91%
Prior efforts of these laboratories have been reported in which
a variety of polycationic salts have been constructed and used for a
variety of purposes including the investigation of the antihydropho-
bic effect (Cohen et al., 1998) and for the preparation of ionic liquids
(Lall et al., 2002). Additional summaries of these efforts have also
been published (Cohen and Engel, 1998, 2002).
vents increases. In some instances (i.e. compounds 4, 13, and 24) the
hydrophilic character was sufficient that even after drying under
high vacuum, upon exposure to ordinary air the materials rapidly
picked up water such that their analyses were of the hydrated forms
rather than anhydrous. In each of these instances each of the termini
of the chains involved a primary hydroxyl group.
It should also be noted in the instance of the material 4 that,
since a racemic mixture of the 3-chloro-1,2-propanediol was used
as the reagent, it consists of a mixture of diastereoisomers, as shown
below.
2. Results and discussion
The series of dicationic lipids and related salts have for the most
part been synthesized by the reaction of a central unit consist-
ing of an ␣,␻-bis(dimethylamino)alkane, acting as a nucleophile,
with a primary haloalkane or substituted haloalkane acting as the
electrophile. In all instances the isolated pure products are com-
posed of the skeletal portions of a “central unit” and two terminal
units.
Numerous attempts were made to accomplish in reasonable
yield the addition of only one terminal unit to a central unit.
Attainment of this goal was attempted through variation of solvent
systems as well as ratios of reactants. In all instances, these attempts
were unsuccessful toward the preparation of monocationic species
in readily isolable reasonable yield. Earlier attempts at the prepara-
tion of unsymmetrical polycationic lipids based on the di-tertiary
amine 1,4-diazabicyclo[2.2.2]octane (dabco) were quite successful
through the use of a proper reactant ratio and choice of solvent
(Engel et al., in press). Apparently the proximity of the nitrogen
sites and the stereoelectronic effect within the dabco ring system
allows such a differentiation of the reactivity of the sites while in
the more distant and spatially variant nitrogens of the species of the
class␣,␻-bis(dimethylamino)alkanepermitsindependentactionof
these sites which precludes their facile chemical differentiation.
The organization of the compounds newly synthesized by reac-
tion of the ␣,␻-bis(dimethylamino)alkanes and shown within
Table 1, as well as in Section 3, is based on the structural factors; the
initial factor is the distance between the cationic sites (n in Table 1),
followed by the length of the terminal chains, the second modified
by pendant functional groups on the terminal units.
The mixture consists of a meso-species and a racemate, evidence
for which may be found in the 13C NMR spectrum. While not all car-
bon atoms are differentiable for the racemate and meso-species,
two resonances may be observed for diastereotopic methyl car-
bon atoms on nitrogen and for the diastereotopic carbon atoms
of the terminal chains attached to nitrogen and adjacent to the
stereogenic sites. These types of observations have been discussed
in work concerned with ionic liquid materials of related struc-
While all of these newyl prepared cationic lipid materials exhibit
some water solubility, with some it is significantly greater than with
others. As anticipated, with increasing chain length (lipophilicity)
water solubility decreases and solubility in ordinary organic sol-

108
R. Engel et al. / Chemistry and Physics of Lipids 160 (2009) 105–108
Table 2
was further washed with anhydrous ether until no impurities could
be detected beyond the limits of the analytical method (NMR). The
resultant materials were isolated in the yields with analytical data
as noted in Table 1.
Yield data for newly synthesized dicationic strings prepared by the reaction.
3.3. Preparation of dicationic lipid salts by the reaction of
˛,␻-dihaloalkanes with 3-dimethylamino-1-propanol General
procedure (1–5, 13, 24)
.
Cpd. no.
n
Yield
1
5
13
24
2
3
6
8
82.5%
64.0%
77.6%
61.4%
The appropriate ␣,␻-dihaloalkane (5 mmol) was dissolved in
absoluteethanol(75 mL)andthe3-dimethylamino-1-propanolwas
added to it dropwise with stirring. The reaction mixture was then
heated to reflux and stirred for 3 days. After cooling, volatile materi-
als were evaporated under reduced pressure and the residual solid
was dried under high vacuum. Preliminary NMR analysis was per-
formed to determine any impurities present, and, if so, the solid
was washed with anhydrous ether until the NMR spectrum exhib-
ited no further impurities. The NMR analyses were in accord with
those obtained for the materials obtained by the alternative proce-
dure for their preparation (see Table 1). Yield data for the materials
prepared in this manner are shown in Table 2.
ture (Thomas et al., in press) and are dependent on the associated
anion.
An alternative approach to the preparation of several of these
compounds (1, 5, 13, and 24) has been investigated. This involves
the use of the appropriate ␣,␻-dihaloalkane (for the central
portion of the target material) in reaction with 3-dimethylamino1-
propanol. The analytical data for materials prepared in this manner
correspond with those listed in Table 1, but yields are different. The
yieldsofproductspreparedinthismannerareshowninTable2. This
alternative approach toward construction of the dicationic species
has also been used for the preparation of N,N,Nꢀ,Nꢀ-tetramethyl-
N,Nꢀ-bis(3-hydroxypropyl-1,4-diazoniamethyl)benzene dibromide
(25). Full details on this preparation are provided in Section 3.
The variability of isolated yields for the series of compounds
prepared would appear to be a function of both their residual
solubility in the solvent systems used, as well as their ability to
absorb water from atmospheric sources. Best isolated yields for
each are reported.
3.4. Preparation of N,N,Nꢀ,Nꢀ-tetramethyl-N,Nꢀ-bis(3-
hydroxypropyl-1,4-diazoniamethyl)benzene dibromide (25)
␣,␣ꢀ-Dibromo-p-xylene (A, 1.00 g; 3.79 mmol) was dissolved in
absolute ethanol (75 mL) and to it was added dropwise with stirring
3-dimethylamino-1-propanol (0.78 g; 7.58 mmol). The reaction
mixture was stirred at room temperature for 2 days after which
time volatile materials were evaporated under reduced pressure
and the residual solid was dried under high vacuum. In this way
was isolated the desired product (1.25 g; 70.2% yield) which exhib-
ited the following NMR spectra: 1H: (ı, D2O) 2.00 (4H) m; 2.95 (12H)
s; 3.33 (4H) m; 3.57 (4H) m; 4.52 (4H) s; 7.61 (4H) s. 13C: 25.7, 50.5,
58.8, 67.7, 67.8, 130.3, 134.3. Calcd. for C18 H34N2O2Br2: C: 45.97%;
H: 7.28%. Found: C: 45.73%; H: 7.20%.
Acknowledgements
We are grateful to the Magnet Program at the CUNY Gradu-
ate Center and the NYC LSAMP for financial support to one of us
(MT), as well as the Howard Hughes Medical Institute for financial
support of the pre-college research experience, as well as Pace Uni-
versity Scholarly Research and Kenan Awards (JR), and finally the
PSC-CUNY Research Award program for general financial support
of this effort.
3. Experimental
3.1. General
All chemicals and solvents used in these syntheses and purifi-
cations were of commercial reagent quality and used without
further purification. All 1H and 13C NMR spectra were measured
with samples in commercial deuterated solvents using a Brüker
400 MHz DPX400 instrument. Elemental analyses were performed
by Schwarzkopf Microanalytical Services of Woodside, NY.
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3.2. Preparation of dicationic lipid salts by the reaction of
˛,␻-bis(dimethylamino)alkanes with haloalkanes General
procedure (1–24)
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The appropriate ␣,␻-bis(dimethylamino)alkane (1.5 mmol) was
dissolved in acetonitrile (75 mL) and to it at ambient temperature
was added dropwise with stirring the appropriate 1-haloalkane
reagent (3.0 mmol). The resulting mixture was heated to reflux and
stirred for 4 days. After cooling, the resultant white powder pre-
cipitate was collected by suction filtration through sintered glass,
washed with anhydrous ether (3× 30 mL) and dried under high vac-
uum. If residual impurities were detected by NMR analysis, the solid
Thomas, M., Rothman, L., Hatcher, J., Agarkar, P., Ramkirath, R., Lall-Ramnarine, S.,
Engel, R., Synthesis, in press.