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Novel methodologies for the synthesis of functionalized lipophilic carboranes.

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Full Paper
Received: 2 September 2009
Revised: 29 October 2009
Accepted: 30 October 2009
Published online in Wiley Interscience: 17 December 2009
(www.interscience.com) DOI 10.1002/aoc.1598
Novel methodologies for the synthesis
of functionalized lipophilic carboranes
Subash C. Jonnalagaddaa∗ , Steven R. Vergaa, Parth D. Patela , A. V. Reddyb ,
T. Srinivasb , Patricia M. Scottb and Venkatram R. Mereddyb∗
Novel synthetic protocols for the synthesis of lipophilic carboranes were developed utilizing two C–C bond forming reactions,
namely Baylis–Hillman and enynedioate cycloaddition reactions. Some of these carboranes were converted into further
c 2009 John Wiley & Sons, Ltd.
functionalized carboranes via nucleophilic allylic isomerization. Copyright Keywords: carboranes; low density lipoprotein; lipophilic carboranes; cholesterol; Baylis Hillman reaction
Introduction
Derivatization of carboranes and other polyhedral boranes is an
active area of research in inorganic, organic, organometallic and
materials chemistry.[1] Carboranes are also an excellent source
of multiple boron atoms for potential utility in boron neutron
capture therapy.[2] Several cancer cells overexpress low density
lipoprotein (LDL) receptors through which they consume high
levels of cholesteryl esters for cell membrane biosynthesis.[3]
We envisioned that cholesterol-based functionalized lipophilic
carboranes may serve as native cholesteryl ester mimics for
LDL receptor-mediated targeted delivery.[3] In this regard, we
developed two methodologies for the synthesis of functionalized lipophilic carboranes via C–C bond-forming reactions:
Baylis–Hillman (BH) reaction,[4] and dimerization of terminal
propiolates.[5] BH reaction provides densely functionalized alcohols/amines in one step. It also offers a flexible template that could
be utilized for the preparation of variety of functionalized lipophilic
carboranes. Terminal propiolates undergo self-condensation to
provide enynedioates in the presence of tertiary amines such
as DABCO. We envisaged that the acetylenic esters obtained by
the condensation of cholesteryl propiolates would act as good
precursors for the synthesis of lipophilic carboranes.
Experimental
Preparation of Carboranyl Alcohol, 3
294
To a solution of hexadecyl acrylate 2 (10.0 g, 33.8 mmol) in
tetrahydrofuran (10 ml), was added o-carborane aldehyde 1 (3.9 g,
22.5 mmol) and DABCO (1.9 g, 16.9 mmol) and stirred at 25 ◦ C for
4 days. Upon completion (thin-layer chromatography, TLC), the
reaction mixture was concentrated and purified over silica gel
column chromatography (hexanes : ethyl acetate 4 : 1), to obtain
7.6 g (72%) of carboranyl alcohol 3 as a low melting waxy solid.
1
H NMR (500 MHz, CDCl3 ): δ 6.42 (s, 1H), 5.86 (s, 1H), 5.00 (d,
J = 9.5 Hz, 1H), 4.89 (d, J = 9.5 Hz, 1H), 4.20–4.30 (m, 2H), 4.06
(bs, 1H), 1.74–2.90 (m, 10H), 1.74 (t, J = 7.5 Hz, 2H), 1.27–1.32 (m,
26 H), 0.90 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl3 ): δ 167.1,
136.2, 130.7, 78.5, 75.4, 66.3, 58.0, 32.2, 29.95, 29.94 (2C), 29.91 (2C),
29.87, 29.80, 29.73, 29.61, 29.42, 28.6, 26.1, 22.9, 14.4; ESI-MS: m/z
Appl. Organometal. Chem. 2010, 24, 294–300
468 (M)+ (100%); HRMS-ESI: calcd for C22 H48 O3 B10 Na (M + Na)+ ,
493.4426; observed, 493.4457.
Preparation of Carboranyl Acetate, 4
To a solution of carboranyl alcohol 3 (5.0 g, 10.6 mmol) in
dichloromethane (50 ml), was added Mg(ClO4 )2 (0.35 g, 1.1 mmol)
and acetic anhydride (3.0 ml, 31.8 mmol) and stirred at 50 ◦ C for 6 h.
Upon completion (TLC), the reaction mixture was concentrated
in vacuo and purified by silica gel column chromatography
(hexanes : ethyl acetate 9 : 1), to obtain 4.1 g (76%) of carboranyl
acetate 4. 1 H NMR (500 MHz, CDCl3 ): δ 6.51 (s, 1H), 6.23 (d,
J = 0.5 Hz, 1H), 5.98 (d, J = 0.5 Hz, 1H), 4.18–4.27 (m, 2H), 4.04
(bs, 1H), 1.74–2.90 (m, 10H), 2.16 (s, 3H), 1.72 (qu, J = 7.0 Hz, 2H),
1.20–1.32 (m, 26H), 0.90 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz,
CDCl3 ): δ 168.3, 164.8, 137.9, 129.0, 75.3, 69.5, 66.3, 59.9, 29.95,
29.94 (2C), 29.92, 29.91 (2C), 29.89, 29.81, 29.7, 29.6, 29.4, 28.7, 26.1,
22.9, 20.8, 14.4; ESI-MS: m/z 542 (M + MeOH)+ (100%).
Preparation of β-Carboranyl-α-methylacrylate, 5
To a solution of carboranyl acetate 4 (500 mg, 0.9 mmol) in
methanol (2 ml) was added sodium borohydride (37 mg, 0.9 mmol)
and stirred at 0 ◦ C for 4 h. Upon completion (TLC), the reaction
mixture was concentrated in vacuo. The reaction mixture was
worked up with ether and water and the combined organic layers
were dried (MgSO4 ), concentrated in vacuo and purified by silica
gel column chromatography (hexanes : ethyl acetate 19 : 1), to
obtain 335 mg (82%) of β-carboranyl-α-methylacrylate 5 as a low
∗
Correspondence to: Subash C. Jonnalagadda, Department of Chemistry and
Biochemistry, Rowan University, Glassboro, NJ 08051 USA.
E-mail: jonnalagadda@rowan.edu
∗∗
Venkatram R. Mereddy, Department of Chemistry and Biochemistry, University
of Minnesota Duluth, Duluth, MN 55812, USA. E-mail: vmereddy@d.umn.edu
a Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ
USA
b Department of Chemistry and Biochemistry, University of Minnesota Duluth,
Duluth, MN USA
c 2009 John Wiley & Sons, Ltd.
Copyright Synthesis of functionalized lipophilic carboranes
melting waxy solid. 1 H NMR (500 MHz, CDCl3 ): δ 6.62 (s, 1H), 4.17
(t, J = 6.7 Hz, 2H), 3.80 (bs, 1H), 1.74–2.90 (m, 10H), 2.12 (s, 3H),
1.67–1.71 (m, 2H), 1.27–1.32 (m, 26 H), 0.90 (t, J = 7.0 Hz, 3H); 13 C
NMR (125 MHz, CDCl3 ): δ 167.1, 135.6, 131.9, 72.1, 66.3, 62.6, 32.2,
29.95, 29.94 (2C), 29.93, 29.91, 29.89, 29.81, 29.7, 29.6, 29.4, 28.7,
26.1, 22.9, 14.4, 13.3; ESI-MS: 442 [(M − BH)+ , 100%].
Preparation of β-Carboranyl-α-ethylacrylate, 6
11.51). 1 H NMR (500 MHz, CDCl3 ): δ 6.32 (s, 1H), 5.78 (s, 1H), 4.98
(d, J = 9.5 Hz, 1H), 4.82 (d, J = 9.0 Hz, 1H), 4.28 (dd, J = 6.0,
11.0 Hz, 1H), 4.21 (dd, J = 5.7, 10.7 Hz, 1H), 4.00 (bs, 1H), 3.35–3.43
(m, 4H), 3.32 (t, J = 6.5 Hz, 4H), 1.70–2.90 (m, 10H), 2.21 (qu,
J = 6.0 Hz, 1H), 1.44–1.40 (m, 4H), 1.15–1.26 (m, 52 H), 0.81 (t,
J = 7.0 Hz, 6H); 13 C NMR (125 MHz, CDCl3 ): δ 166.6, 136.8, 130.6,
78.5, 74.7, 71.8 (2C), 69.1, 69.0, 65.0, 58.2, 39.7, 32.2 (2C), 29.98 (4C),
29.96 (4C), 29.94 (2C), 29.92 (2C), 29.89 (2C), 29.85 (2C), 29.82 (2C),
29.76 (2C), 29.64 (2C), 26.4 (2C), 22.9 (2C), 14.41, 14.37; ESI-MS: 770
[(M − BH)+ , 100%]; HRMS-ESI: calcd for C42 H88 O5 B10 Na (M + Na)+ ,
805.7455; observed, 805.7469.
To a solution of carboranyl acetate 4 (500 mg, 0.9 mmol) in diethyl
ether (2 ml) was added methyl magnesium bromide (0.65 ml, 2 M
solution, 1.3 mmol) and stirred at 0 ◦ C for 4 h. Upon completion
(TLC), the reaction mixture was quenched with NH4 Cl, and worked
up with ether and water. The combined organic layers were dried
(MgSO4 ), concentrated in vacuo and purified by silica gel column
chromatography (hexanes : ethyl acetate 19 : 1), to obtain 299 mg
(71%) of β-carboranyl-α-ethylacrylate 6 as a low melting waxy
solid. 1 H NMR (500 MHz, CDCl3 ): δ 6.48 (s, 1H), 4.08 (t, J = 6.7 Hz,
2H), 3.68 (bs, 1H), 1.74–2.90 (m, 10H), 2.49–2.54 (m, 2H), 1.57–1.60
(m, 2H), 1.27–1.32 (m, 26 H), 0.98 (t, J = 7.5 Hz, 3H); 0.80 (t,
J = 6.0 Hz, 3H); 13 C NMR (125 MHz, CDCl3 ): δ 166.8, 141.7, 131.5,
71.9, 66.2, 62.7, 32.2, 29.95, 29.94 (2C), 29.93, 29.91, 29.89, 29.80,
29.7, 29.6, 29.4, 28.7, 26.1, 22.9, 19.8, 14.4, 13.8; ESI-MS: 466 (M)+ ,
297 [100%].
Procedure similar to that of 4 (yield 70%). Low melting waxy
solid. 1 H NMR (500 MHz, CDCl3 ): δ 6.47 (s, 1H), 6.12 (s, 1H), 5.91
(s, 1H), 5.15 (qu, J = 5.0 Hz, 1H), 4.11 (bs, 1H), 3.50–3.56 (m, 4H),
3.30–3.40 (m, 4H), 1.70–2.90 (m, 10H), 2.07 (s, 3H), 1.44–1.50 (m,
4H), 1.15–1.28 (m, 52H), 0.80 (t, J = 7.0 Hz, 6H); 13 C NMR (125 MHz,
CDCl3 ): δ 168.3, 164.1, 137.8, 129.9, 75.3, 73.4, 72.0, 71.9, 69.5, 69.1
(2C), 60.0, 32.2 (2C), 29.96 (2C), 29.95 (2C), 29.92 (2C), 29.90 (2C),
29.89, 29.88, 29.87, 29.86 (2C), 29.80 (2C), 29.72 (2C), 29.71 (2C),
29.62 (2C), 26.31, 26.30, 23.0 (2C), 20.8 (2C), 14.4 (2C); ESI-MS: 832
[M + Na, 100%].
Preparation of β-Carboranyl-α-undecylacrylate, 7
Preparation of Carboranyl Acetate, 10b
To a solution of carboranyl acetate 4 (500 mg, 0.9 mmol) in diethyl
ether (2 ml), was added decyl magnesium bromide (1.3 ml, 1 M
solution, 1.3 mmol) and stirred at 0 ◦ C for 4 h. Upon completion
(TLC), the reaction mixture was quenched with NH4 Cl, and worked
up with ether and water. The combined organic layers were dried
(MgSO4 ), concentrated in vacuo and purified by silica gel column
chromatography (hexanes : ethyl acetate 19 : 1), to obtain 390 mg
(73%) of β-carboranyl-α-undecylacrylate 7 as a low melting waxy
solid. 1 H NMR (500 MHz, CDCl3 ): δ 6.45 (s, 1H), 4.07 (t, J = 6.7 Hz,
2H), 3.66 (bs, 1H), 1.74–2.90 (m, 10H), 2.43–2.46 (m, 2H), 1.57–1.60
(m, 2H), 1.27–1.32 (m, 44 H), 0.81 (t, J = 7.0 Hz, 6H); 13 C NMR
(125 MHz, CDCl3 ): δ 165.7, 139.5, 130.2, 70.6, 64.8, 61.4, 30.92,
30.91, 28.70, 28.69 (2C), 28.67 (2C), 28.64 (2C), 28.62 (2C), 28.57
(2C), 28.51 (2C), 28.34 (2C), 28.29, 28.20 (2C), 28.19, 27.5, 25.4, 24.9,
21.7, 13.1; ESI-MS: 624 [(M + MeOH)+ , 100%], 592 (M)+ , 582
(M − BH)+ ; HRMS-ESI: calcd for C32 H68 O2 B10 Na (M + Na)+ ,
625.6327; observed, 625.6417.
Procedure similar to that of 4 (yield 74%). Low melting waxy solid.
1
H NMR (500 MHz, CDCl3 ): δ 6.40 (s, 1H), 6.14 (s, 1H), 5.90 (s, 1H),
4.27 (dd, J = 5.7, 10.7 Hz, 1H), 4.18 (dd, J = 5.7, 10.7 Hz, 1H), 3.96
(bs, 1H), 3.34–3.42 (m, 4H), 3.32 (t, J = 6.5 Hz, 4H), 1.70–2.90 (m,
10H), 2.21 (qu, J = 6.0 Hz, 1H), 2.07 (s, 3H), 1.44–1.49 (m, 4H),
1.12–1.34 (m, 52H), 0.81 (t, J = 6.7 Hz, 6H); 13 C NMR (125 MHz,
CDCl3 ): δ 168.3, 164.7, 137.9, 129.0, 75.2, 71.7 (2C), 69.4, 68.9, 68.8,
64.8, 59.9, 39.7, 32.2 (2C), 29.96 (4C), 29.94 (4C), 29.92 (4C), 29.90
(4C), 29.88 (2C), 29.74 (2C), 29.62 (2C), 26.4 (2C), 22.9 (2C), 20.7,
14.4 (2C); ESI-MS: 811 [(M − BH)+ , 100%]; HRMS-ESI: calcd for
C44 H90 O6 B10 Na (M + Na)+ , 847.7560; observed, 847.7612.
Preparation of Carboranyl Alcohol, 9a
Procedure similar to that of 3 (yield 69%). Low melting waxy solid.
NMR (500 MHz, CDCl3 ): δ 6.49 (s, 1H), 5.88 (s, 1H), 5.27 (qu,
J = 5.2 Hz, 1H), 4.91 (d, J = 10 Hz, 1H), 4.84 (d, J = 10 Hz, 1H), 4.09
(bs, 1H), 3.62–3.68 (m, 4H), 3.41–3.51 (m, 4H), 1.70–2.90 (m, 10H),
1.54–1.60 (m, 4H), 1.20–1.36 (m, 52 H), 0.91 (t, J = 7.0 Hz, 6H);
13 C NMR (125 MHz, CDCl ): δ 165.9, 136.2, 131.6, 78.6, 75.5, 73.6,
3
72.1, 72.0, 69.2, 69.1, 58.0, 32.2 (2C), 29.96 (2C), 29.94 (2C), 29.92
(2C), 29.89 (2C), 29.87 (2C), 29.81 (2C), 29.79 (2C), 29.71 (2C), 29.70
(2C), 29.62 (2C), 26.31 (2C), 26.29 (2C), 22.9 (2C), 14.4 (2C); ESI-MS:
766 [M+ , 100%]; HRMS-ESI: calcd for C41 H86 O5 B10 Na (M + Na)+ ,
791.7298; observed, 791.7375.
1H
Preparation of Carboranyl Alcohol, 9b
Appl. Organometal. Chem. 2010, 24, 294–300
Preparation of β-Carboranyl-α-methylacrylate, 11a
Procedure similar to that of 5 (yield 82%). Low melting waxy solid.
1 H NMR (500 MHz, CDCl ): δ 6.64 (s, 1H), 5.18 (qu, J = 5.0 Hz, 1H),
3
3.78 (bs, 1H), 3.58–3.62 (m, 4H), 3.40–3.49 (m, 4H), 1.70–2.90 (m,
10H), 2.13 (s, 3H), 1.54–1.59 (m, 4H), 1.10–1.40 (m, 52H), 0.90 (t,
J = 6.7 Hz, 6H); 13 C NMR (125 MHz, CDCl3 ): δ 166.6, 135.7, 132.1,
73.5, 71.9, 71.8 (2C), 69.4 (2C), 62.5, 32.2 (2C), 29.96 (4C), 29.92 (4C),
29.91 (4C), 29.8 (4C), 29.7 (4C), 29.6 (2C), 26.3 (2C), 22.9 (2C), 14.4
(2C), 13.4; ESI-MS: 782 [(M − H + MeOH)+ , 100%]; HRMS-ESI: calcd
for C41 H86 O4 B10 Na (M + Na)+ , 775.7349; observed, 775.7425.
Preparation of β-Carboranyl-α-methylacrylate, 11b
Procedure similar to that of 5 (yield 84%). Low melting waxy solid.
1
H NMR (500 MHz, CDCl3 ): δ 6.64 (d, J = 1.5 Hz, 1H), 4.25 (d,
J = 6.0 Hz, 2H), 3.79 (bs, 1H), 3.43–3.52 (m, 4H), 3.38–3.42 (m,
4H), 1.70–2.90 (m, 10H), 2.27 (qu, J = 6.0 Hz, 1H), 2.12 (s, 3H),
1.53–1.58 (m, 4H), 1.21–1.36 (m, 52H), 0.90 (t, J = 7.0 Hz, 6H); 13 C
NMR (125 MHz, CDCl3 ): δ 166.9, 135.5, 132.1, 72.0, 71.7 (2C), 69.0
(2C), 64.9, 62.6, 39.7, 32.2 (2C), 29.96 (4C), 29.95 (4C), 29.92 (4C),
29.91 (2C), 29.89 (2C), 29.88 (2C), 29.7 (2C), 29.6 (2C), 26.4 (2C),
22.9 (2C), 14.4 (2C), 13.3; ESI-MS: 754 [(M − BH)+ , 100%]; HRMS-ESI:
calcd for C42 H88 O4 B10 Na (M + Na)+ , 789.7506; observed, 789.7558.
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
295
Procedure similar to that of 3 (yield 72%). Low melting waxy
solid (C42 H88 O5 B10 requires C, 64.57; H, 11.35; found C, 64.51; H,
Preparation of Carboranyl Acetate, 10a
S. C. Jonnalagadda et al.
Preparation of β-Carboranyl-α-ethylacrylate 12a
Procedure similar to that of 6 (yield 75%). Low melting waxy solid.
1 H NMR (500 MHz, CDCl ): δ 5.55 (s, 1H), 5.17 (qu, J = 5.0 Hz,
3
1H), 4.58 (bs, 1H), 3.51–3.54 (m, 4H), 3.31–3.40 (m, 4H), 1.70–2.90
(m, 10H), 2.21 (q, J = 7.5 Hz, 2H), 1.46–1.49 (m, 4H), 1.08–1.32
(m, 52H), 0.95 (t, J = 7.5 Hz, 3H), 0.81 (t, J = 6.5 Hz, 6H); 13 C
NMR (125 MHz, CDCl3 ): δ 166.2, 139.7, 122.3, 72.3, 70.7 (2C), 70.0,
68.0 (2C), 60.7, 30.9 (2C), 28.69 (4C), 28.67 (4C), 28.65 (4C), 28.62
(4C), 28.60 (2C), 28.54 (2C), 28.45 (2C), 28.3 (2C), 25.0 (2C), 21.7,
13.1 (2C), 11.0, ESI-MS: 764 (M)+ , 297 [100%]; HRMS-ESI: calcd for
C42 H88 O4 B10 Na (M + Na)+ , 789.7505; observed, 789.7489.
Preparation of β-Carboranyl-α-ethylacrylate, 12b
Procedure similar to that of 6 (yield 77%). Low melting waxy solid
(C43 H90 O4 B10 requires C, 69.47; H, 10.90; found C, 69.67; H, 11.07).
1
H NMR (500 MHz, CDCl3 ): δ 6.65 (s, 1H), 4.22 (d, J = 7.0 Hz, 2H),
3.76 (bs, 1H), 3.40–3.48 (m, 4H), 3.36 (t, J = 8.2 Hz, 4H), 1.70–2.90
(m, 10H), 2.57 (q, J = 9.0 Hz, 2H), 2.22–2.30 (m, 1H), 1.52–1.56 (m,
4H), 1.11–1.40 (m, 52H), 1.04 (t, J = 9.0 Hz, 3H), 0.90 (t, J = 7.0 Hz,
6H); 13 C NMR (125 MHz, CDCl3 ): δ 166.6, 141.4, 131.7, 71.7 (2C), 68.9
(2C), 66.0, 64.7, 62.7, 39.6, 32.1, 31.8 (4C), 31.1 (4C), 29.91 (4C), 29.84
(4C), 29.7 (2C), 29.6 (2C), 26.4 (2C), 22.9 (2C), 22.8 (2C), 15,4 (2C),
14.3 (2C), 13.7; ESI-MS: 768 [(M − BH)+ , 100%]; HRMS-ESI: calcd for
C43 H90 O4 B10 Na (M + Na)+ , 803.7662; observed, 803.7711.
Preparation of β-Carboranyl-α-undecylacrylate, 13a
Procedure similar to that of 7 (yield 74%). White solid, m.p.:
32–34 ◦ C. 1 H NMR (500 MHz, CDCl3 ): δ 6.56 (s, 1H), 5.18 (qu,
J = 5.0 Hz, 1H), 3.75 (bs, 1H), 3.60 (d, J = 5.0 Hz, 4H), 3.39–3.48
(m, 4H), 1.70–2.90 (m, 10H), 2.54–2.58 (m, 2H), 1.53–1.58 (m, 4H),
1.24–1.36 (m, 70H), 0.89–0.93 (m, 9H); 13 C NMR (125 MHz, CDCl3 ):
δ 166.5, 140.8, 131.6, 73.3, 71.9, 71.8 (2C), 69.4 (2C), 62.7, 32.2 (2C),
30.00, 29.97 (5C), 29.92 (2C), 29.91 (3C), 29.87 (3C), 29.85 (3C), 29.80
(3C), 29.63 (2C), 29.62 (3C), 29.60 (3C), 29.3 (3C), 26.7 (2C), 26.4 (3C),
22.9 (2C), 14.4; ESI-MS: 891 [(M + H)+ , 100%].
Preparation of Cholesteryloxypropyl Acrylate, 15
To a solution of cholesteryloxypropanol (9.16 g, 20.6 mmol) in
dichloromethane (50 ml), was added acryloyl chloride (2.5 ml,
31.0 mmol) and triethyl amine (8.6 ml, 62.0 mmol) and stirred
at 0 ◦ C for 6 h. Upon completion, the reaction mixture was
filtered over silica gel with diethyl ether and concentrated in
vacuo. The crude mixture was then purified by silica gel column
chromatography (hexanes : ethyl acetate 9 : 1), to obtain 7.4 g
(72%) of cholesteryloxy acrylate 15. 1 H NMR (500 MHz, CDCl3 ): δ
6.38 (dd, J = 1.5, 17.5 Hz, 1H), 6.11 (dd, J = 9.7, 17.2 Hz, 1H), 5.79
(dd, J = 1.5, 10.0 Hz, 1H), 5.32–5.33 (m, 1H), 4.25 (t, J = 6.2 Hz, 2H),
3.54 (dt, J = 1.7, 6.0 Hz, 2H), 3.08–3.15 (m, 1H), 2.32–2.37 (m, 1H),
2.14–2.20 (m, 1H), 1.78–2.01 (m, 7H), 1.00–1.57 (m, 21H), 0.99 (s,
3H), 0.91 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 2 Hz, 3H), 0.85 (d, J = 2 Hz,
3H), 0.67 (s, 3H); 13 C NMR (125 MHz, CDCl3 ): δ 166.3, 141.1, 130.7,
128.8, 121.8, 79.4, 64.5, 62.1, 57.0, 56.4, 50.4, 42.6, 40.0, 39.8, 39.3,
37.5, 37.1, 36.5, 36.0, 32.2, 32.1, 29.7, 28.6, 28.5, 28.2, 24.5, 24.1,
23.1, 22.8, 21.3, 19.6, 18.9, 12.1; ESI-MS: 498 [(M)+ , 100%].
Preparation of carboranyl alcohol, 16
296
To a solution of cholesteryl acrylate 15 (1.68 g, 3.38 mmol) in
tetrahydrofuran (1 ml), was added o-carborane aldehyde 1 (0.39 g,
www.interscience.wiley.com/journal/aoc
2.25 mmol) and DABCO (0.19 g, 1.69 mmol) and stirred at 25 ◦ C
for 14 days. Upon completion (TLC), the reaction mixture was
concentrated and purified over silica gel column chromatography
(hexanes : ethyl acetate 4 : 1), to obtain 1.8 g (79%) of carboranyl
alcohol 3 as a white solid. M.p.: 126–128 ◦ C (C36 H66 O4 B10 requires
C, 64.43; H, 9.91; found C, 64.47; H, 10.04). 1 H NMR (500 MHz,
CDCl3 ): δ 6.40 (s, 1H), 5.86 (s, 1H), 5.33 (s, 1H), 4.88–4.99 (m, 2H),
4.22–4.42 (m, 2H), 4.07 (bs, 1H), 3.55 (t, J = 6.0 Hz, 2H), 3.08–3.20
(m, 1H), 1.70–2.90 (m, 10H), 2.31–2.34 (m, 1H), 2.12–2.22 (m, 1H),
1.70–2.08 (m, 7H), 1.00–1.56 (m, 21H), 0.98 (s, 3H), 0.84–0.92 (m,
9H), 0.67 (s, 3H); 13 C NMR (125 MHz, CDCl3 ): δ 166.6, 140.8, 136.8,
130.7, 122.0, 79.7, 78.4, 74.5, 64.5, 63.6, 58.2, 56.9, 56.4, 50.4, 42.5,
40.0, 39.7, 39.3, 37.4, 37.1, 36.4, 36.0, 32.2, 32.1, 29.4, 28.6, 28.5,
28.2, 24.5, 24.1, 23.1, 22.8, 21.3, 19.6, 18.9, 12.1; ESI-MS: 670 (M)+ ,
660 [(M − BH)+ , 100%]; HRMS-ESI: calcd for C36 H66 O4 B10 Na (M +
Na)+ : 695.5784; observed: 695.5842.
Preparation of Carboranyl Acetate, 17
Procedure similar to that of 4; yield (80%). Low melting waxy
solid. 1 H NMR (500 MHz, CDCl3 ): δ 6.50 (s, 1H), 6.22 (s, 1H), 5.98
(s, 1H), 5.33–5.35 (m, 1H), 4.29–4.39 (m, 2H), 4.07 (bs, 1H), 3.57 (t,
J = 6.0 Hz, 2H), 3.11–3.19 (m, 1H), 1.70–2.90 (m, 10H), 2.31–2.38
(m, 2H), 2.15 (s, 3H), 1.70–2.08 (m, 7H), 1.03–1.58 (m, 21H), 1.01
(s, 3H), 0.87–0.94 (m, 9H), 0.69 (s, 3H); 13 C NMR (125 MHz, CDCl3 ):
δ 168.3, 168.7, 141.0, 137.9, 129.1, 121.9, 79.5, 75.2, 69.4, 64.3,
63.5, 59.9, 57.0, 56.4, 50.4, 42.6, 40.0, 39.8, 39.3, 37.4, 37.1, 36.4,
36.0, 32.2, 32.1, 29.6, 28.6, 28.5, 28.2, 24.6, 24.1, 23.1, 22.8, 21.3,
20.8, 19.6, 19.0, 12.1; ESI-MS: 744 [(M + MeOH)+ , 100%], 702
(M − BH)+ ; HRMS-ESI: calcd for C38 H68 O5 B10 Na (M + Na)+ ,
737.5890; observed, 737.5925.
Preparation of β-Carboranyl-α-methylacrylate, 18
To a solution of carboranyl acetate 17 (642 mg, 0.9 mmol) in
methanol (2 ml) was added sodium borohydride (37 mg, 0.9 mmol)
and stirred at 0 ◦ C for 4 h. Upon completion (TLC), the reaction
mixture was concentrated in vacuo. The reaction mixture was
worked up with ether and water and the combined organic layers
were dried (MgSO4 ), concentrated invacuo and purified by silica gel
column chromatography (hexanes : ethyl acetate 19 : 1), to obtain
437 mg (74%) of β-carboranyl-α-methylacrylate 18 as a white
solid. White solid, m.p.: 155–157 ◦ C. Anal. calcd for C36 H66 O3 B10 : C,
66.42; H, 10.24; found C, 66.44; H, 10.30. 1 H NMR (500 MHz, CDCl3 ):
δ 6.55 (s, 1H), 5.26–5.27 (m, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.67
(bs, 1H), 3.46 (t, J = 6.0 Hz, 2H), 3.01–3.08 (m, 1H), 1.70–2.90 (m,
10H), 2.23–2.27 (m, 2H), 2.02 (s, 3H), 1.70–2.15 (m, 6H), 0.98–1.55
(m, 20H), 0.92 (s, 3H), 0.78–0.85 (m, 9H), 0.61 (s, 3H); 13 C NMR
(125 MHz, CDCl3 ): δ 167.0, 141.0, 135.6, 132.0, 121.9, 79.5, 72.1,
64.4, 63.6, 62.6, 57.0, 56.4, 50.5, 42.6, 40.0, 39.8, 39.4, 37.5, 37.1,
36.4, 36.0, 32.2, 32.1, 29.5, 28.7, 28.5, 28.3, 24.5, 24.1, 23.1, 22.8,
21.3, 19.6, 18.9, 13.3, 12.1; ESI-MS: 686 [(M + MeOH)+ , 100%], 644
(M − BH)+ ; HRMS-ESI: calcd for C36 H66 O3 B10 Na (M + Na)+ ,
679.5835; observed, 679.5858.
Preparation of β-Carboranyl-α-ethylacrylate, 19
Procedure similar to that of 18; yield (75%). White solid. M.p.:
142–145 ◦ C. 1 H NMR (500 MHz, CDCl3 ): δ 6.48 (s, 1H), 5.26–5.27
(m, 1H), 4.20 (t, J = 6.5 Hz, 2H), 3.67 (bs, 1H), 3.46 (t, J = 6.0 Hz,
2H), 3.02–3.08 (m, 1H), 1.70–2.90 (m, 10H), 2.52 (q, J = 7.5 Hz,
2H), 2.23–2.28 (m, 2H), 1.70–2.15 (m, 7H), 1.01–1.50 (m, 21H), 0.98
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2010, 24, 294–300
Synthesis of functionalized lipophilic carboranes
O
O
2
O
= BH
= CH
1
O
O
X
DABCO, THF, 72%
3, X = OH
Mg(ClO4)2, Ac2O
4, X = OAc, 76%
Conditions
(a) NaBH4, MeOH, 25°C (Nu = H)
(b) MeMgBr, Et2O, 0°C (Nu = Me)
(c) n-DecylMgBr, Et2O, 0°C (Nu = n-Decyl)
Conditions
Nu
O
O
5, Nu = H, 82%
6, Nu = Me, 71%
7, Nu = n-Decyl, 73%
Y
O
O
O
O
= BH
= CH
1
Y
O
O
O
8a, Y = -O8b, Y = -CH2ODABCO, THF
Z
9a, Y = O, Z = OH, 69%
9b, Y = CH2O, Z = OH, 72%
Mg(ClO4)2, Ac2O
10a, Y = O, Z = OAc, 70%
10b, Y = CH2O, Z = OAc, 74%
Conditions
Conditions
(a) NaBH4, MeOH, 25°C (Nu = H)
(b) MeMgBr, Et2O, 0°C (Nu = Me)
(c) n-DecylMgBr, Et2O, 0°C (Nu = n-Decyl)
Nu
Y
O
O
O
11a, Y = O,
11b, Y = CH2O,
12a, Y = O,
12b, Y = CH2O,
13a, Y = O,
13b, Y = CH2O,
Nu = H,
Nu = H,
Nu = Me,
Nu = Me,
Nu = Decyl,
Nu = Decyl,
82%
84%
75%
77%
74%
75%
Scheme 1. Preparation of lipophilic functionalized carboranes.
(t, J = 7.2 Hz, 3H), 0.92 (s, 3H), 0.78–0.85 (m, 9H), 0.61 (s, 3H); 13 C
NMR (125 MHz, CDCl3 ): δ 166.7, 141.6, 141.1, 131.6, 122.0, 79.5,
71.8, 64.4, 63.4, 62.7, 57.0, 56.4, 50.5, 42.6, 40.0, 39.8, 39.4, 37.5,
37.1, 36.4, 36.0, 32.2, 32.1, 29.6, 28.7, 28.5, 28.3, 24.5, 24.1, 23.1, 22.8,
21.3, 19.9, 19.6, 19.0, 13.8, 12.1; ESI-MS: 700 [(M + MeOH)+ , 100%],
668 (M)+ , 658 (M − BH)+ ; HRMS-ESI: calcd for C37 H68 O3 B10 Na
(M + Na)+ , 693.5991; observed, 693.6046.
Preparation of β-Carboranyl-α-undecylacrylate, 20
Procedure similar to that of 18; yield (72%). 1 H NMR (500 MHz,
CDCl3 ): δ 6.46 (s, 1H), 5.26 (s, 1H), 4.19 (t, J = 6.0 Hz, 2H), 3.66
(bs, 1H), 3.46 (t, J = 5.7 Hz, 2H), 3.02–3.08 (m, 1H), 1.70–2.90 (m,
10H), 2.44–2.48 (m, 2H), 2.23–2.28 (m, 2H), 0.78–2.15 (m, 61H),
0.61 (s, 3H); 13 C NMR (125 MHz, CDCl3 ): δ 166.9, 141.0, 140.6, 131.6,
121.9, 79.5, 71.9, 64.3, 63.3, 62.7, 57.0, 56.4, 50.5, 42.6, 40.0, 39.8,
39.4, 37.5, 37.1, 36.4, 36.0, 32.2, 32.1, 30.0, 29.9 (2C), 29.8 (2C),
29.6, 29.55, 29.52, 28.7, 28.5, 28.3, 26.7, 24.5, 24.1, 23.1, 22.9, 22.8,
21.3, 19.6 (2C), 19.0, 14.4, 12.1; 826 [(M + MeOH)+ , 100%], 784
(M − BH)+ ; HRMS-ESI: calcd for C46 H86 O3 B10 Na (M + Na)+ ,
819.7400; observed, 819.7461.
Materials and Methods for Cytotoxicity Experiments
Appl. Organometal. Chem. 2010, 24, 294–300
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
297
A-172 and U87 cell lines were obtained from ATCC. Cells were
grown in 5% CO2 at 37 ◦ C in DMEM supplemented with 10% fetal
bovine serum and 1% primocin. Cells were plated in 96-well plates
at 2000 cells per well and allowed to adhere for 18 h. Cells were then
treated with each compound or with 0.3% DMSO alone for 18 h.
The concentration of compound was 50 µM and the concentration
of DMSO was 0.3% or less. The number of viable cells remaining
after exposure to compounds was determined using an MTS
assay (Cell Titer Aqueous Non-Radioactive Cell Proliferation Assay,
Promega). The tetrazolium salt MTS is converted to a formazan dye
by dehydrogenase enzymes found in metabolically active cells. The
quantity of formazan product measured by absorbance at 490 nm
is directly proportional to the number of living cells in culture. A
20 µl aliquot of MTS was added to 100 µl culture medium in each
well. After incubation at 37 ◦ C for 3 h, absorbance at 490 nm was
measured using an ELISA plate reader. Background of absorbance
of MTS in culture media alone was subtracted from all experimental
and control absorbance values. Cell viability of compound-treated
cells is reported as percent survival. Percentage survival = (OD
490 nm compound-treated cells/OD 490 nm DMSO-treated cells)
×100. Percentage survival represents the ratio of viable cells
remaining in compound treated cells to viable cells remaining in
DMSO treated cells. As mentioned above, all the compounds were
found to be non-toxic in both the cancer cell lines A-172 and U-87,
even at 50 µM concentration, and hence can potentially be utilized
as BNCT agents.
S. C. Jonnalagadda et al.
O
NaH, 76%
H
H
O
(ii) 9-BBN, 75%
(iii) CH2 = CHCOCl,
Et3N, DMAP, 72%
H
HO
14
X
O
Br
(i)
O
H
H
O
DABCO, THF
79%
15
O
O
O
H
H
= BH
= CH
Ac2O
Mg(ClO4)2
1
= BH
= CH
H
H
Conditions
O
Nu
= BH
= CH
H
H
O
Conditions
(a) NaBH4, MeOH, 25°C (Nu = H)
(b) MeMgBr, Et2O, 0°C (Nu = Me)
(c) n-DecylMgBr, Et2O, 0°C (Nu = n-Decyl)
16, X = OH
17, X = OAc, 80%
H
18, Nu = H, 74%
19, Nu = Me, 75%
20, Nu = Decyl, 72%
Scheme 2. Preparation of cholesterol carborane conjugates.
O
(i)
OH
21
O
COOH
DCC, DMAP, 65%
22
(ii) DABCO, THF
65%
O
O
B10H10, CH3CN,
Toluene, 80%
O
O
refluxed overnight and concentrated in vacuo. The crude product
was purified by column chromatography (hexane : ethyl acetate
19 : 1), to obtain pure carboranyl ester 23 (453 mg, 80%). White
solid, m.p. 37–40 ◦ C (C38 H78 O4 B10 requires C, 64.54; H, 11.11;
found, C, 64.45; H, 11.00). 1 H NMR (500 MHz, CDCl3 ): δ 6.97 (d,
J = 15.5 Hz, 1H), 6.22 (d, J = 15.5 Hz, 1H), 4.14 (t, J = 6.5 Hz, 2H),
4.08 (t, J = 6.7 Hz, 2H), 1.60–3.20 (m, 10H), 1.53–1.62 (m, 4H),
1.10–1.24 (m, 52H), 0.81 (t, J = 7.0 Hz, 6H); 13 C NMR (125 MHz,
CDCl3 ): δ 164.6, 159.4, 138.0, 129.7, 75.7, 74.2, 69.2, 65.8, 32.2 (2C),
29.96 (2C), 29.94 (2C), 29.92 (2C), 29.87, 29.84, 29.77, 29.76, 29.65,
29.63, 29.5 (2C), 29.3 (2C), 28.8 (2C), 28.4 (2C), 26.1 (2C), 25.9 (2C),
22.9 (2C), 14.4 (2C); ESI-MS: 696 [(M − BH)+ , 100%]; HRMS-ESI: calcd
for C38 H78 O4 B10 Na (M + Na)+ , 731.6723; observed, 731.6770.
O
O
23
Scheme 3. Preparation of lipophilic carboranes via cycloaddition of
enynedioates.
Preparation of Carboranyl Diester, 23
298
To a solution of hexadecanol 21 (1.0 g, 4.1 mmol) in 10 ml THF was
added propiolic acid (0.5 ml, 8.2 mmol), dicyclohexylcarbodiimide
(10.3 ml, 1 M solution, 10.0 mmol), and dimethylaminopyridine
(49 mg, 0.4 mmol) at 0 ◦ C. The reaction mixture was stirred for 3 h
and worked up with saturated NH4 Cl and ether. The combined
organic layers were dried, concentrated in vacuo and purified
by silica gel column chromatography to obtain 0.8 g (65%) of
hexadecyl propiolate. The propiolate thus obtained was treated
with catalytic DABCO (15 mg, 0.13 mmol) and stirred for 2 h. Upon
completion (TLC), the reaction was worked up with ether and
water. The combined organic layers were dried (MgSO4 ), and used
in the cyloaddition without further purification. A solution of the
crude enyne 22 (0.47 g, 0.8 mmol) in 5 ml toluene was added
to a refluxing solution of decaborane (110 mg, 0.9 mmol), and
acetonitrile (5 ml) in toluene (15 ml). The reaction mixture was
www.interscience.wiley.com/journal/aoc
Preparation of Carboranyl Diester, 26
To a solution of cholesteryloxypropanol 24 (1.8 g, 4.1 mmol)
in 10 ml THF was added propiolic acid (0.5 ml, 8.2 mmol),
dicyclohexylcarbodiimide (10.3 ml, 1 M solution, 10.0 mmol), and
dimethylaminopyridine (49 mg, 0.4 mmol) at 0 ◦ C. The reaction
mixture was stirred for 3 h and worked up with saturated NH4 Cl
and ether. The combined organic layers were dried, concentrated
in vacuo and used in the dimerization without further purification.
The crude propiolate was treated with catalytic DABCO (15 mg,
0.13 mmol) and stirred for 2 h. Upon completion (TLC), the reaction
was worked up with ether and water. The combined organic
layers were dried (MgSO4 ), and purified by silica gel column
chromatography to obtain the pure enyne 25 (0.8 g, 40% yield).
1 H NMR (500 MHz, CDCl ): δ 6.77 (d, J = 15.5 Hz, 1H), 6.47 (d,
3
J = 15.5 Hz, 1H), 5.34 (s, 2H), 4.29–4.33 (m, 4H), 3.52–3.55 (m,
4H), 3.11–3.14 (m, 2H), 2.32–2.34 (m, 2H), 2.16–2.18 (m, 2H),
0.86–2.10 (m, 80H), 0.68 (s, 6H); 13 C NMR (125 MHz, CDCl3 ): δ
164.9, 153.3, 141.1(2C), 141.0, 135.5, 121.8 (2C), 87.3, 81.8, 79.5,
79.4, 64.3, 64.2, 64.1, 63.0, 57.0 (2C), 56.4 (2C), 50.4 (2C), 42.5 (2C),
40.0 (2C), 39.8 (2C), 39.3 (2C), 37.5 (2C), 37.1 (2C), 36.5 (2C), 36.0
(2C), 32.2 (2C), 32.1 (2C), 29.6, 29.4, 28.6 (2C), 28.5 (2C), 28.3 (2C),
24.5 (2C), 24.1 (2C), 23.1 (2C), 22.8 (2C), 21.3 (2C), 19.6 (2C), 19.0
(2C), 12.1 (2C); ESI-MS: 992 [(M)+ , 100%]. A solution of the enyne
25 (0.79 g, 0.8 mmol) in 5 ml toluene was added to a refluxing
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2010, 24, 294–300
Synthesis of functionalized lipophilic carboranes
H
H
O
H
H
HO
O
24
H
(i)
O
H
O
COOH
25
DCC, DMAP
(ii) DABCO, THF
40% combined
H
H
O
O
H
O
76%
B10H10, CH3CN,
Toluene
H
H
O
O
H
O
H
26
O
H
O
H
O
Scheme 4. Preparation of cholesterol carborane conjugates via cycloaddition of enynedioates.
solution of decaborane (110 mg, 0.9 mmol) and acetonitrile (5 ml)
in toluene (15 ml). The reaction mixture was refluxed overnight
and concentrated in vacuo. The crude product was purified by
column chromatography (hexane : ethyl acetate 19 : 1), to obtain
pure carboranyl ester 26 (670 mg, 76%). White solid, m.p. 61–63 ◦ C.
Anal. calcd for C66 H114 O6 B10 : C, 71.30; H, 10.33; found C, 71.04;
H, 10.42. 1 H NMR (500 MHz, CDCl3 ): δ 6.97 (d, J = 15.5 Hz, 1H),
6.22 (d, J = 15.5 Hz, 1H), 5.27 (s, 2H), 4.26 (t, J = 6.2 Hz, 2H), 4.20
(t, J = 6.2 Hz, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.43 (t, J = 5.8 Hz,
2H), 3.02–3.09 (m, 2H), 1.80–3.20 (m, 10H), 2.24–2.30 (m, 2H),
2.08–2.12 (m, 2H), 0.86–2.10 (m, 80H), 0.60 (s, 6H); 13 C NMR
(125 MHz, CDCl3 ): δ 164.6, 159.4, 141.1, 141.0, 138.2, 129.6, 122.0,
121.9, 79.6, 79.5, 75.7, 74.0, 66.5, 64.4, 63.7, 63.2, 57.0 (2C), 56.4
(2C), 50.5, 50.4, 42.6 (2C), 40.0 (2C), 39.8 (2C), 39.4, 39.3, 37.5, 37.4,
37.14, 37.13, 36.5 (2C), 36.1 (2C), 32.2 (2C), 32.1 (2C), 29.6, 29.3, 28.7,
28.6, 28.5 (2C), 28.3 (2C), 24.6 (2C), 24.1 (2C), 23.1 (2C), 22.8 (2C),
21.3 (2C), 19.6 (2C), 19.0 (2C), 12.1 (2C); ESI-MS: 1100 [(M − BH)+ ,
100%]; HRMS-ESI: calcd for C66 H114 O6 B10 Na (M + Na)+ : 1135.9438;
observed: 1135.9508.
Results and Discussion
Appl. Organometal. Chem. 2010, 24, 294–300
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
299
We initiated the synthesis of the lipophilic carborane conjugates
via the Baylis–Hillman reaction of hexadecyl acrylate 2 with
carborane aldehyde[6] 1 in the presence of DABCO. The alcohol 3 thus obtained was treated with Ac2 O in the presence of
Mg(ClO4 )2 to provide the acetate 4.[7] In order to demonstrate the
utility of the current methodology, we prepared few functionalized carboranes via the nucleophilic substitution of the acetate
4. Accordingly, the reaction of 4 with NaBH4 , MeMgBr and nDecylMgBr as nucleophiles led to the formation of isomerized
products 6–8 in good yields (Scheme 1). Under similar conditions, bis(hexadecyloxy)glyceryl acrylates 10a–b were treated
with carboranyl aldehyde 3 to obtain the alcohols 11a–b. Acetate
formation followed by reaction with the above nucleophiles fur-
nished the functionalized bis(hexadecyl) substituted carboranes
in 70–75% yield (Scheme 1).
Similarly, the cholesterol carborane conjugates were synthesized as shown in Scheme 2. Alkylation of cholesterol with allyl
bromide, hydroboration and esterification of the resulting alcohol with acryloyl chloride provided the acrylate ester 15. The
reaction of acrylate with carborane aldehyde 1 in the presence of
DABCO provided the alcohol 16. The acrylate derived directly from
cholesterol was too sluggish to react with aldehyde 1 under these
conditions. Formation of the acetate and subsequent nucleophilic
substitution yielded the cholesterol carborane conjugates 18–20.
After synthesizing several functionalized carboranes via BH reaction, we synthesized lipophilic and cholesterol-based carboranes
via enynedioate cycloaddition protocol. The requisite enyne dioate
22 was synthesized via esterification of hexadecanol with propiolic
acid followed by the self-condensation of the resulting propiolate
with DABCO. Cyclization of the alkyne 22 with decaborane was
achieved by refluxing in acetonitrile and toluene mixture leading
to the formation of the carborane dicarboxylate ester 23 in 80%
yield (Scheme 3).
Similarly, the cholesteryl carborane dicarboxylate ester 26 was
synthesized starting from the alcohol 24 in three steps involving
DCC coupling, self-condensation of the resulting propiolate and
cycloaddition (Scheme 4).
To determine the usefulness of these compounds for possible
applications in BNCT, they were tested for effect on the viability
of human glioblastoma multiforme cell lines A-172 and U87. The
cell line A-172 is known to have an elevated level of LDL receptors
on the cell surface (∼million receptors/cell).[8] U87 cells, which
express undetectable LDL receptor levels, were used as negative
controls. The cholesterol-carborane conjugates (16–20,26) and
bishexadecyloxyglyceryl carborane conjugates (3–13,23) were
evaluated for cytotoxicity. Cells were treated with compound at a
concentration of 50 µM, dissolved in 0.3% or less DMSO for 18 h.
Cell viability was determined using a colorimetric MTS assay. All
the compounds were found to be non-toxic to both the cancer
cell lines at 50 µM concentration.
S. C. Jonnalagadda et al.
Conclusions
In conclusion, we have developed novel synthetic protocols
for the preparation of lipophilic functionalized carboranes via
Baylis–Hillman and enynedioate cycloaddition protocols. Owing
to the ease and flexibility of present protocols in preparing a wide
array of carborane molecules, we believe this work could prove
useful to inorganic and organic chemists.
[2]
Acknowledgments
We thank the Departments of Chemistry and Biochemistry, Rowan
University, and University of Minnesota, Duluth for the funding.
Partial support for this work was provided by research grants from
the National Institutes of Health (CA129993) (V.R.M.) and Whiteside
Institute for Clinical Research (V.R.M.).
[3]
[4]
[5]
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