Cedranediolborane as a borylating agent for the preparation of boronic acids: Synthesis of a boronated nucleoside analogue

Article abstract of DOI:10.1055/s-2001-10762

Cedranediolborane can be cross-coupled with aryl iodides under Pd(0) catalysis to yield aryl boronates which can easily be deprotected to form the corresponding free boronic acids. The application of this methodology has led to the preparation of a boronated nucleoside indole analogue.

Full text of DOI:10.1055/s-2001-10762

266
LETTER
Cedranediolborane as a Borylating Agent for the Preparation of Boronic
Acids: Synthesis of a Boronated Nucleoside Analogue
Yi-Lin Song, Christophe Morin*
Laboratoire d'Etudes Dynamiques et Structurales de la Sélectivité (UMR CNRS 5616),
Université Joseph Fourier, BP 53X, 38041 Grenoble Cedex 9, France
Fax +476 514 382; E-mail: christophe.morin@ujf-grenoble.fr
Received 20 November 2000
To prepare 1, cedrane-8,9-diol,11 readily obtained by di-
Abstract: Cedranediolborane can be cross-coupled with aryl io-
hydroxylation of (-)- -cedrene,12 was treated with the bo-
dides under Pd(0) catalysis to yield aryl boronates which can easily
rane-dimethyl sulfide (BMS) complex.13 The product
be deprotected to form the corresponding free boronic acids. The
decomposed upon attempted distillation under high vacu-
um, but crude 1, left on evaporation of the volatiles from
the reaction mixture, was of sufficient quality for the
cross-coupling reactions. These reactions were carried out
with aryl iodides (see Table) using catalytic amounts of
tetrakis(triphenylphosphine)palladium(0) and copper(I)
iodide.14 The boronates 2 thus readily formed were found
to be air- and chromatography stable compounds that
could be converted to the free boronic acids 3 by transes-
terification with diethanolamine,15 followed by acid treat-
ment.16 This procedure is compatible with functionalized
aryl iodides (see Table), for example the iodopyrimidine
in entry 7 which is of particular interest as the product is
similar to that used in the preparation of boronated pyri-
midines and nucleosides.17
application of this methodology has led to the preparation of a bo-
ronated nucleoside indole analogue.
Key words: cedrane, borylation, boronic acids, boronates, nucleo-
side
Boronic acids and their esters (boronates) are valuable in-
termediates, useful in synthetic applications such as Suzu-
ki-Miyaura couplings and Matteson asymmetric
homologations. In addition, boronated analogues of
biomolecules1 are of interest for their possible use in bo-
ron neutron capture therapy (BNCT),2 as inhibitors of
serine proteases,3 and as chemosensors during recognition
events.4,5
Aryl boronates can be obtained from aryl halides by a
metalation/borylation sequence. A newer method though,
involves Pd-mediated borylations with either bis(pinaco-
lato)-diboron6 or pinacolborane,7 and such cross-cou-
plings have resulted in straightforward syntheses of
clinically useful 4-borono-L-phenylalanine.8 However,
deprotection of boronate esters has not always been trou-
ble-free,9 and some biological evaluations had to be per-
formed with boronates rather than the free boronic acids.10
We now introduce cedranediolborane 1 as a new borylat-
ing agent which, after coupling with aryl iodides, easily
yields the corresponding free boronic acids.
To exploit the synthetic potential of borylating agent 1, we
undertook the preparation of the boronated nucleoside 4,
which could not be obtained previously by coupling of 5-
indolyl-boronates with halide 9 due to the lack of a suit-
able boronic acid protecting group.18,19 The preparation of
the required 5-iodoindole started with the commercially
available 5-bromo derivative 5, whose sodium salt was
silylated to give 6. After halogen exchange in 6 by
quenching the corresponding lithio derivative with iodine
(to give 7) desilylation was effected by aqueous base
treatement to afford 8 in 69% overall yield from 5. This
new preparation of 5-iodoindole 8 was found to be the
most practical of several examined.20
Nucleoside formation21 was effected by treating the sodi-
um salt of 8 with the deoxyribosyl derivative 922, which
gave a single anomer 1023 (79%). Given the coupling con-
stants observed for H-1’(5.6 and 8.4 Hz), the configura-
tion was assigned.24 The borylation step was next carried
out with cedranediolborane 1 by using the general proce-
dure described above14 which proceeded efficiently
OH
OH
O
O
BMS
BH
H
H
CH2Cl2 , 0-25 °C, 10h
1
1. NH(CH2CH2OH)2
H
O
O
,
Pd(PPh3)4/CuI
Et3N, dioxane
1
ArB(OH)2
Ar
B
Ar
I
2. H+/H2O
3
2
Synlett 2001, No. 2, 266–268 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Cedranediolborane as a Borylating Agent for the Preparation of Boronic Acids
267
Table Reaction of 1 with representative aryl iodides and deprotec-
tion of the resulting boronates.
5: X = Br , R = H
X
a
6: X = Br , R = TBDMS
b
c
N
R
7: X = I , R = TBDMS
8: X = I , R = H
I
TolO
+
e
d
O
8
N
TolO
Cl
O
OTol
9
OTol
10
H
H
O
N
O
B
B
g
O
O
N
N
HO
RO
O
O
aoverall yields from aryl iodides. bpreviously obtained by
esterification12 of phenylboronic acid. cconverted to the free boronic
OH
OR
d
acid without isolation. phenylboronic acid (3, Ar = C6H5) is com-
13
11: R = Tol
12: R = H
mercially available.eauthentic sample prepared according to ref.30.
fcharacterized as known6 pinacol boronate after reaction with pina-
col. gauthentic sample prepared according to ref. 31. hstarting iodide
prepared according to ref. 32 and product described in ref. 17.
f
h
(HO)2B
HO
TBDMS =
Si
N
O
O
Tol =
(81%) to give 11. Cleavage of the toluoates to provide
1225 was followed by formation of "ate" complex 13 by
treatment with diethanolamine. Deprotection of 13 to the
free boronic acid 426, could then be effected (Amberlite
IRC 50 (H+) without cleavage of the nucleoside linkage.
OH
4
Reagents and conditions: (a) NaH, 1.2 equiv., MeCN, 1h, then TB-
DMSiCl, 1.25 equiv., overnight, 96%; (b) nBuLi, 1.1 equiv.,
THF, - 85 °C, 1 h, then I2 in THF,1.15 equiv., 83%; (c) 0.5 M NaOH
in 1:1 THF/H2O, overnight, 87%; (d) 9 added to preformed 8-Na salt
(8 in 0.1 M MeCN, NaH, 1.1 equiv., 30 min.), 4 h, 79%; (e) 1,
Pd(PPh3)4/CuI, 81%; (f) NaOMe (3 equiv.), CH3OH, overnight;
78%; (g) NH(CH2CH2OH)2 (1.2 equiv.), Et2O, 2 h, 93%; (h) MeOH,
Amberlite IRC-50 (H+) to pH 7, 2 h, 68%.
Nucleoside 4 is the first boronated indole nucleoside to be
prepared.27 This structurally simple nucleoside analogue,
whose nucleobase is expected to display hydrophobic/
stacking interactions,28 may be useful as well for the intro-
duction of substituents at C-5 on the indole ring through
subsequent Suzuki-Miyaura couplings,29 in addition to
possible applications in BNCT.
(5) de Silva, A.P.; Gunarane, H.Q.N.; Gunnlaugsson, T.; Huxley,
A.J.M.; McCoy, C.P.; Rademacher, J.T.; Rice, T.E. Chem.
Rev. 1997, 97, 1515.
(6) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
60, 7508.
(7) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org.
Chem. 2000, 65, 164. Song, Y. L. Synlett 2000, 1210.
(8) Nakamura, H.; Fujiwara, M.; Yamamoto, Y. J. Org. Chem.
1998, 63, 7529. Malan, C.; Morin, C. J. Org. Chem. 1998, 63,
8019. Nakamura, H.; Fujiwara, M.; Yamamoto, Y. Bull.
Chem. Soc. Jpn. 2000, 73, 231.
Acknowledgement
A stipend to Y.-L.S. under a collaboration agreement between the
Région Rhône-Alpes and the city of Shanghai (P.R. of China) is
gratefully acknowledged. Prof. F.-G. Tao is thanked for a gift of
8,9-cedranediol,12 Dr. M. Kotera for practical advices on the prepa-
ration of 922 and Ms. G. Rescourio for exploratory work18 with bo-
ronated indoles.
References and Notes
(9) This is particularly true of pinacol- and pinanediol-derived
boronates. For a vivid description of deprotection efforts, see:
Brown, H.C.; Rangaishenvi, M.V. J. Organomet. Chem. 1988,
358, 15.
(10) Boronates have thus been considered as "pro-substrates". For
a discussion, see inter alia: Snow, R.J.; Bachovchin, W.W.;
Barton, R.W.; Cambell, S.J.; Coutts, S.J.; Freema, D.M.;
Gutheil, W.G.; Kelly, T.A.; Kennedy, C.A.; Krolikowski,
(1) Morin, C. Tetrahedron 1994, 50, 12521.
(2) Soloway, A.H.; Tjarks, W.; Barnum, B.A.; Rong, F. G.; Barth,
R.F.; Codogni, I.M.; Wilson, J.G. Chem. Rev. 1998, 98, 1515.
(3) Babine, R.E.; Bender, S.L. Chem. Rev. 1997, 97, 1359.
(4) Wülff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812.
Synlett 2001, No. 2, 266–268 ISSN 0936-5214 © Thieme Stuttgart · New York

268
Y.-L. Song, C. Morin
LETTER
(19) No boronic acid protecting groups were found to be
compatible with the sensitive nucleoside bond; the use of
reducible ones (see Malan, C.; Morin, C.; Preckher, G.
Tetrahedron Lett. 1996, 37, 6705) was precluded by the
presence of the 2-3 unsaturation of the indole ring.
(20) For previous preparations of 5-iodo indole, see: Thesing, J.;
Semler, G.; Mohr, G. Chem. Ber. 1962, 95, 2205. Hydorn,
A.E. J. Org. Chem. 1967, 32, 4100.
(21) Kazimierczuk, Z.; Cogttan, H.B.; Revankar, G.R.; Robins,
R.K. J. Am. Chem. Soc. 1984, 106, 6379. Vorbrüggen, H.;
Ruh-Pohlenz, C. Org. React. 1999, 55, 3.
(22) Roland, V.; Kotera, M.; Lhomme, J. Synth. Commun. 1997,
27, 4039.
D.A.; Leonard, S.F.; Pargellis, C.A.; Tong, L.; Adams, J. J.
Am. Chem. Soc. 1994, 116, 10860. For a recent example of a
boronate replacing the carboxylic acid function in a
biomolecule, see: Feng, S.; Hellberg, M. Tetrahedron Lett.
2000, 41, 5813.
(11) Narula, A.S.; Trifilieff, E.; Luu, B.; Ourisson, G. Tetrahedron
Lett. 1977, 3959.
(12) Song, Y.; Ding, Z.; Wang, Q.; Tao, F. Synth. Commun. 1998,
28, 3757.
(13) To a stirred suspension of cedranediol (2.38g, 10 mmol) in dry
CH2Cl2 (4 mL) under argon at 4 °C was added dropwise fresh
borane-dimethyl sulfide (1.1 mL of a 10 M solution in Me2S)
and the resulting mixture was allowed to warm to room
temperature. After about 10 h, a clear solution was obtained,
which was stirred for an additional 4 h. Evaporation of the
volatiles under reduced pressure (p < 50 mmHg and t < 80 °C)
afforded air-sensitive cedranediolborane 1: 1H NMR
(300MHz, CDCl3) 0.81 (d, J = 7.0Hz, 3H, CH3), 1.04(s, 3H,
CH3), 1.14(s, 3H, CH3), 1.41(s, 3H, CH3), 1.10-2.25(m, 11H,
(23) 10: mp 136-7 °C; 1H NMR (300MHz, CDCl3) 2.43(s, 3H),
2.45(s, 3H), 2.65(m, 1H), 2.84(m, 1H), 4.57(m, 1H), 4.64(m,
2H), 5.71(m, 1H), 6.41(dd, J1 = 5.6Hz, J2 = 8.4Hz, 1H),
6.45(d, J = 3.3Hz, 1H), 7.23-7.30(m, 6H), 7.38(dd, J1 = 1.7Hz,
J2 = 8.7Hz, 1H), 7.91(d, J = 8.2Hz, 2H), 7.93(s, 1H), 7.97(d,
J = 8.2Hz, 2H); 13C NMR (75MHz, CDCl3) 21.86, 21.90,
38.05, 64.31, 75.08, 81.93, 84.01, 85.75, 103.00, 112.08,
124.87, 126.69, 126.98, 129.41, 129.45, 129.85, 129.94,
130.09, 130.59, 131.87, 135.19, 144.26, 144.64, 166.16,
166.38. Anal. calcd. for C29H26INO5: C, 58.50; H, 4.40, N,
2.35. Found : C, 58.75; H, 4.43, N, 2.35.
CH, CH2), 4.13(dd, J1 = 7.0Hz, J2 = 8.4Hz, 1H, OCH); 13
NMR (75MHz, CDCl3) 15.50, 25.63, 28.50, 28.82, 31.07,
36.14, 39.15, 42.04, 42.61, 44.27, 51.67, 57.73, 58.23, 78.21,
85.86.
C
(14) Representative procedure: To a stirred mixture of 4-
iodotoluene (65 mg, 0.3 mmol), CuI (4 mg) and 1 (248 mg, 1.0
mmol) in dry 1,4-dioxane (2 mL) under argon, was added
Et3N (0.5 mL, 3.6 mmol). Ar was bubbled through the reaction
mixture for 20 min before addition of Pd(PPh3)4 (4 mg). The
mixture was then heated to 80 °C and stirred for 20 h. After
being allowed to cool to room temperature, the reaction
mixture was quenched with water and extracted with
cyclohexane. The organic layer was washed with brine and
dried over NaSO4 and, after filtration, the volatiles were
removed under reduced pressure. The residue was purified by
flash chromatography (9/1 hexane/ethyl acetate) on silica gel
to yield cedranediol p-tolylboronate (87 mg, 86% yield): 1H
NMR (300MHz, CDCl3) 0.82(d, J = 7.0Hz, 3H, CH3),
1.08(s, 3H, CH3), 1.20(s, 3H, CH3), 1.52(s, 3H, CH3), 1.28-
2.35(m, 11H, CH, CH2), 2.40(s, 3H, Ar-CH3), 4.28(dd,
J1 = 7.2Hz, J2 = 8.4Hz, 1H, OCH), 7.23(d, J = 7.8Hz, 2H, Ar-
H), 7.77(d, J = 7.8Hz, 2H, Ar-H); 13C NMR (75MHz, CDCl3)
15.50, 21.90, 25.64, 28.47, 28.54, 31.03, 36.20, 39.29,
42.03, 42.52, 44.06, 51.74, 58.06, 58.18, 78.80, 85.88, 128.75,
135.09, 141.72.
(24) Robbins, M.J.; Robbins, R.K. J. Am. Chem. Soc. 1965, 89,
4734.
(25) 12: mp 123-5 °C. 1H NMR (300MHz, CDCl3) 0.79(d,
J = 7.0Hz, 3H), 1.07(s, 3H), 1.18(s, 3H), 1.51(s, 3H), 0.88-
2.34(m, 11H), 2.30(m, 1H), 2.52(m, 1H), 3.64(m, 2H),
3.90(m, 1H), 4.27(t, J = 7.6Hz, 1H), 4.45(m, 1H), 6.35(t,
J = 6.4Hz, 1H), 6.57(d, J = 3.2Hz, 1H), 7.19(d, J = 3.2Hz,
1H), 7.48(d, J = 8.3Hz, 1H), 7.71(d, J = 8.3Hz, 1H), 8.17(s,
1H); 13C NMR (75MHz, CDCl3) 15.51, 25.63, 28.49, 28.54,
31.02, 36.17, 39.31, 40.09, 41.99, 42.55, 44.03, 51.79,
58.09(2), 62.61, 71.66, 78.78, 84.62, 85.83, 86.06, 104.31,
109.54, 124.28, 128.54, 128.97, 129.20, 138.35. FAB-HRMS,
m/z (M+H)+: 480.2926 (calcd. for C28H3911BNO5: 480.2922).
(26) 4: [ ]D23 = -27° (c = 0.01, CH3OH). 1H NMR (300MHz,
CD3OD) 2.27(m, 1H), 2.54(m, 1H), 3.65(m, 2H), 3.91(m,
1H), 4.43(m, 1H), 6.40(t, J = 7.0Hz, 1H), 6.48(d, J = 3.2Hz,
1H), 7.40-7.49(m, 2H), 7.55(d, J = 8.4Hz, 1H), 7.83(s, 1H);
13C NMR (75MHz, CD3OD) 40.91, 63.56, 72.72, 86.05,
88.08, 104.38, 110.23, 125.61, 128.17, 130.16, 138.65. 4 was
esterified with cedranediol to yield boronate 12, identical to
the sample prepared above.
(15) Matteson, D.S.; Ray, R.; Rocks, R.R.; Tsai, D.J.
Organometallics 1983, 2, 1536.
(27) For reviews about boronated nucleosides, see refs 1,2 and
also: Gouadgon, N.M.; Fulcrand El-Kattan, G.; Schinazi, R.F.
Nucleosides Nucleotides 1994, 13, 849. Soloway, A.H.; Zhuo,
J.-C.; Rong, F.-G.; Lunato, A.J.; Ives, D.H.; Barth, R.F.;
Anisuzzaman, A.K.M.; Barth, C.D.; Barnum, B.A. J.
Organomet. Chem. 1999, 581, 150. Lesnikowski, Z.J.; Shi, J.;
Schinazi, R.F. J. Organomet. Chem. 1999, 581, 156.
(28) For a review, see: Kool, E.T.; Morales.J.C.; Guckian, K.M.
Angew. Chem., Int. Ed. 2000, 39, 991.
(29) For an example of a nucleoside indole designed for
crosslinking see : Coleman, R.S.; Dong, Y.; Arthur, J.C.
Tetrahedron Lett. 1993, 34, 6867. For use of a 4-substituted
indole nucleoside in DNA recognition see: Chepanoske, C.L.;
Langelier, C.R.; Chmiel, N.H.; David, S.S, Org. Lett. 2000,
1341.
(16) General procedure: A THF solution of 2 and diethanolamine
(2 equiv.) was stirred overnight. After being acidified with 1
M HCl the reaction mixture was stirred for 30 min and then
diluted with water and extracted with ethyl acetate. The
combined organic layers were then extracted with 1M NaOH.
After being acidified to pH 1 with 1 M HCl, the aqueous
extracts were extracted with ethyl acetate to yield pure 3, free
from cedranediol. For acid sensitive compounds, after the
addition of diethanolamine, purification was effected by
column chromatography to remove the cedranediol. Then, to
a solution of the ate complex, Amberlite IRC-50 (H+) was
added portionwise until pH 7 was reached whereupon the
mixture was stirred for an additional 2 h, before final
purification (cc on silica gel).
(17) Wojtowicz-Rajchel, A.; Golankiewicz K. Org. Prep. Proced.
Int. 1998, 30, 433. See also: Schinazi, R.F.; Prusoff, W.H. J.
Org. Chem. 1985, 50, 841. Gronowitz, S.; Hörnfeldt, A.B.;
Kristjansson, V.; Musil, T. Chem. Scripta 1986, 26, 305.
(18) Morin, C.; Rescourio, G. unpublished results (Rescourio, G.
Diplôme d'Etudes Approfondies, Grenoble 1999).
(30) Bean, F.R.; Johnson, J.R. J. Am. Chem. Soc. 1932, 54, 4415.
(31) Nielsen, D.R.; McEwen, W.E. J. Am. Chem. Soc. 1957, 79,
3081.
(32) Das, R.; Kundu, N.G. Synth. Commun. 1988, 18, 855.
Article Identifier:
1437-2096,E;2001,0,02,0266,0268,ftx,en;G24100ST.pdf
Synlett 2001, No. 2, 266–268 ISSN 0936-5214 © Thieme Stuttgart · New York