Stereoselective dioxirane hydroxylations and the synthesis of tripod boronic acid esters

Article abstract of DOI:10.1016/j.tetlet.2007.03.101

Methyl(trifluoromethyl)dioxirane (TFDO, 1b), a powerful yet selective oxidant, was employed to achieve in high yield the direct stereoselective hydroxylation at tert-CH of cis,cis-1,3,5-trimethylcyclohexane (4), yielding triol 7 bearing all-axial disposit

Full text of DOI:10.1016/j.tetlet.2007.03.101

Tetrahedron Letters 48 (2007) 3575–3578
Stereoselective dioxirane hydroxylations and the synthesis of
tripod boronic acid esters
Lucia D’Accolti,a Michele Fiorentino,a Caterina Fusco,a Francesco Capitellia,b and
Ruggero Curcia,*
a
`
Dipartimento Chimica, Universita di Bari, and C.N.R.— ICCOM, (Istituto Chimica Composti Organometallici), Bari Section,
v. Amendola 173, I-70126 Bari, Italy
bIstituto Cristallografia CNR, v. Amendola 123/o, 70123 Bari, Italy
Received 15 February 2007; revised 12 March 2007; accepted 16 March 2007
Available online 21 March 2007
Abstract—Methyl(trifluoromethyl)dioxirane (TFDO, 1b), a powerful yet selective oxidant, was employed to achieve in high yield the
direct stereoselective hydroxylation at tert-CH of cis,cis-1,3,5-trimethylcyclohexane (4), yielding triol 7 bearing all-axial disposition
of the three OH groups. Similarly, TFDO oxidation of 1,3- and of 1,4-dimethylcyclohexane gave the corresponding Z-diols 5 and 6,
respectively. Triol 7 was a convenient starting material to synthesize a novel borate—that is, 1-bora-2,8,9-trioxa-3,5,7-trimethyl-
adamantane (8)—having a peculiar cage-shaped ‘tripod’ structure. From triol 7, novel tripod arylboronic Bro¨nsted-assisted Lewis
acids (BLA) could be obtained, as exemplified by 10a and 10b.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
binding constants of reactions between compounds con-
taining OH functionalities and arylboronic acids, such
as phenylboronic acid PhB(OH)2.1,5b
In the past decades, a great deal of interest was devoted
to the chemistry of borate esters and boronic acid deriv-
atives because of their applications in chemistry and
biology.1,2 These remarkable organic intermediates have
been widely employed to carry out a number of syn-
thetic transformations, including Diels–Alder reactions,
enantioselective syntheses, and Suzuki cross-coupling
reactions.3,4 Actually, the chemical stability of boronic
acids R1B(OH)2 and their esters, coupled with favorable
steric properties, make them excellent reagents for geo-
metrically controlled syntheses. Also, it was found that
boronic acid analogues of natural substrates could func-
tion as effective enzyme inhibitors.1
It is well recognized that in aqueous solution the derived
boronic esters—as well as the parent boronic acids—can
exist in a trigonal planar form in equilibrium with the
corresponding tetrahedral anionic form [ArB(OR)2-
OH]ꢀ, the position of the equilibria depending upon
the pKa values. A thorough understanding of these equi-
libria is desirable in order to design effective boronic
ester-based sensors.
In borates B(OR2)3 and boronic acid esters R1B(OR2)2,
reversible exchange between them and water (or in gen-
eral a given protic species ROH) is usually fairly rapid,
so that acyclic esters must be protected from moisture.
However, sterically hindered cyclic borates or boronic
esters (which represent the most useful synthetic inter-
mediates) are not easily hydrolyzed and can be handled
similarly to stable organic compounds. The general
properties of boronic esters and borates have been
reviewed in detail.2
Recently, much interest has attracted research focusing
on employing boronic acid compounds for the develop-
ment of sensors, based on the renowned ability of boro-
nic acids to bind tightly with saccharides and other
polyols.1,5 In fact, several comprehensive studies were
devoted to establishing the various features and the
Keywords: Boronic acids; Borates; BLA; Dioxiranes; Methyl(trifluo-
O
O
romethyl)dioxirane; Stereoselective oxidations.
H3C
R
(1a: R = CH3;
1b: R = CF3)
C
*
Corresponding author. Tel.: +39 080 5442070; fax: +39 080
5442924; e-mail: curci@ba.iccom.cnr.it
1
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.101

3576
L. D’Accolti et al. / Tetrahedron Letters 48 (2007) 3575–3578
Based on the above background, during our work on
stereoselective oxidations6 employing isolated di-
methyldioxirane (DDO) (1a)7a,b and methyl(trifluoro-
methyl)dioxirane (TFDO) (1b),6,8 we set out to obtain
stable borates having a sterically strained framework
and novel Bro¨nsted acid-assisted Lewis acids (BLA)3
that display a unique ‘tripod’ architecture. Our initial
results are described herein.
as already reported in detail.8 On a 2–5 mmol scale, the
simple oxidation procedure merely involved the addition
of an aliquot of standardized8 dioxirane solution in one
portion to the substrate dissolved in CH2Cl2 (5–10 mL)
and kept at 0 ꢁC. A moderate excess of dioxirane 1b was
applied in order to achieve complete substrate conver-
sions, as monitored by GC and GC/MS. Removal of
the solvent in vacuo and column chromatography (sili-
cagel) gave products 5, 6, or 7, respectively, in practi-
cally quantitative yield.
2. Results and discussion
The novel triol 7 (a solid, mp 134–135 ꢁC) was fully
1
characterized by H and 13C NMR, yielding spectra in
It was documented that a novel approach to the efficient
oxygenation of hydrocarbons under mild conditions
consists in the selective O-insertion into C–H bonds
using dioxiranes.6 Actually, it is recognized that oxida-
tions of ‘unactivated’ hydrocarbon C–H bonds generally
require reaction times of hours and excess oxidant
employing DDO (1a).7,8 Instead, the powerful TFDO
(1b) allows one to carry out these transformations often
in a matter of minutes and with a high selectivity.6
complete agreement with the given structure.13 The all-
axial disposition of the three hydroxy functionalities
was further unambiguously determined by X-ray crys-
tallography (Fig. 1).14
The feat of obtaining 7 directly as a single diastereomer
is in itself remarkable; actually, other approaches to its
synthesis that could be envisaged would necessarily be
more elaborate, requiring multiple steps. Because of
the precise stereochemistry of 7, it is perhaps no surprise
that, from this, ‘tripod’ borate 8 could be easily obtained
in high yield upon reaction with BCl3/Py under the con-
ditions given in Eq. 4, Chart 2.
For instance, illustrating the high stereoselectivity of the
dioxirane O-insertion, a specific case is the exclusive
bridgehead hydroxylation of cis-decalin, which gives
only the tertiary cis-decalinol; a similar stereoselective
configuration retention was also observed for trans-
decalin.8 Previously it had been shown that the C–H
hydroxylation of cis- and trans-1,2-dimethylcyclohex-
anes by dioxiranes is also highly stereocontrolled.7,8
It should be noted that the analogue of tripod borate 8
lacking the three methyl substituents, that is, 3,5,7-tri-
methyl-2,8,9-trioxa-1-boraadamantane appears to have
been synthesized (method, yields, and characteristics
undisclosed); it was patented and claimed to be an effi-
cient catalyst in homogeneous olefin polimerization.15
We now report that a similar high stereoselectivity can
be achieved in the TFDO hydroxylation of commercial9
cis-1,3- and of cis-1,4-dimethyl substituted cyclohexanes
(2 and 3), as well as in the hydroxylation of 1,3,5-tri-
methyl cyclohexane 4 (Chart 1).10 Starting with these,
the corresponding all-cis-diols 511 and 6,12 and all-cis
triol 713 could be obtained in high yield and with no epi-
merization at the tert-C–H reaction centers, as illus-
trated by Eqs. 1–3, in Chart 1. The transformations
reported therein are representative of the typical reac-
tion conditions adopted.
The novel tripod borate ester 8 displays a geometry
around tricovalent boron, that is, somewhat distorted
(O–B–O 113.9ꢁ, MM2 output) with respect to the planar
structure typical of open-shaped borates, for instance
B(OPh)3.3a In fact, the caged borate (11B NMR, d
18.3) has the structure of fourfold heterosubstituted
adamantane, that is, 1-bora-2,8,9-trioxa-3,5,7-trimethyl-
adamantane. Remarkably stable, it could be isolated as
a white solid (mp 62–64 ꢁC) and fully characterized by
11
1H, 13C, and B NMR.16 We find that 8 is resistant to
To carry out oxidations in Eqs. 1–3, isolated TFDO (1b)
solutions that were 0.7–0.8 M in its parent ketone 1,1,1-
trifluoropropanone (TFP) were prepared and employed
TFDO (1b),
3 equiv.
OH
CH3
OH
CH3
(1)
30 min,
H3C
CH3
H3C
conv. >99%
2
5
(98% isol. yield)
OH
CH3
TFDO (1b),
3.5 equiv.
CH3
(2)
(3)
HO
30 min,
conv. >99%
CH3
3
6
(98% isol. yield)
O H
TFDO (1b),
OH
OH
5 equiv.
CH3
H3C
H3C
H3C
CH3
120 min,
conv. >99%
H3C
Figure 1. Partial view of unit cell assembling four molecules (two are
shown) of triol 7, computer-generated (ball-and-stick models) from X-
4
7
(92% isol. yield)
˚
ray crystallographic data. a = 9.939(2), b = 9.986(4), c = 11.696(5) A.
˚
Chart 1.
Selected H-bond lengths within Hꢁ ꢁ ꢁO 1.8 A are shown.

L. D’Accolti et al. / Tetrahedron Letters 48 (2007) 3575–3578
3577
O
O
B
sity of the emission is depressed, being I = 247 au (kmax
294 nm) for 9b and I = 95.8 au (kmax 305 nm) for the
corresponding BLA acid 10b.
BCl3 (1.1
equiv) / Py
O
H3C
CH3
(4)
(5)
7
7
CHCl3
-10 to 25 ˚C, 10 h
H3C
8
(92% isol. yield)
In summary, we provide herein one more example show-
ing that the high reactivity and selectivity achievable
using dioxiranes, chiefly TFDO 1b, in electrophilic O-
insertions into unactivated C–H bonds can be exploited
to obtain synthons that are useful in building com-
pounds presenting peculiar architecture and properties.
Obviously, organic compounds displaying several OH
or OR moieties that are favorably arranged sterically
can be effective ligand systems for various metal com-
plexes. These might show enhanced or peculiar proper-
ties as catalysts. For instance, cage-shaped borates
display enhanced catalytic activity in hetero Diels–Alder
reactions with respect to open-shaped borates. This was
rationalized in terms of reduced p-electron overlap
between boron and its ligand oxygens.3a
Ar
H
O
B
ArB(OH)2 (9a,b)
(1.1 equiv)
O
O
H3C
CH3
dry CH2Cl2
9 h, 25˚C
H3C
10a,b (90% isol. yield)
a: Ar = C6H5-
b: Ar = [3,5-(CF3)2C6H3-]
Chart 2.
hydrolysis upon moderate exposure to atmospheric
moisture at 25 ꢁC; however, it can be perhydrolyzed
using alkaline H2O2,17 regenerating triol
unchanged stereochemistry.
7 with
Besides its value in designing effective metal catalysts,
all-cis triol 7 might also find useful applications in test-
ing the capability of simple and complex boronic acids
to act as selective sensors toward certain natural target
molecules.1,5
In order to test triol 7 as a probe for boronic acid sen-
sors, we made it react with two widely employed boronic
acids, that is, benzeneboronic acid (9a) or 3,5-bis(triflu-
oromethyl)benzeneboronic acid (9b)1,3c under the condi-
tions given in Eq. 5, Chart 2. These reactions were run
on a 0.2 mmol scale in 5–10 mL of methylene chloride
solvent, affording the corresponding BLA acids 10a or
10b in practically quantitative yields (Chart 2, Eq. 5).
Both 10a (11B NMR, d ꢀ17.1) and 10b (11B NMR, d
ꢀ17.2) could be successfully isolated as white solids
and were fully characterized.18,19 The recorded 1H-
and 13C NMR spectra were in excellent agreement with
their highly symmetrical structure; for instance, in line
with their C3 symmetry, in their proton spectra both
presented a singlet CH3 resonance (10a, 1.29; 10b,
1.31 ppm), and again just one CH3 signal (10a, 30.9;
10b, 29.7 ppm) in the proton-decoupled 13C NMR spec-
tra for the three methyl groups.
Acknowledgments
Partial support of this work by the Ministry of Univer-
sity and Scientific and Research of Italy (MIUR) and by
the National Research Council of Italy (CNR) is grate-
fully acknowledged. We are also grateful to Professor A.
Basu (Brown University, Providence, RI, USA) for
helpful suggestions and to Professor C. Giacovazzo
(University of Bari, Italy) for encouragement and in car-
rying out this work.
References and notes
Soluble in organic solvents such as CH2Cl2, CHCl3,
THF, MeCN, the BLA acids above have a limited solu-
bility in water. By dissolving solid 10a in warm water
(50–60 ꢁC), solutions that were ca. 5 · 10ꢀ3 M in BLA
could be prepared; an apparent pH of 2.5 was measured
for such solutions at 25 ꢁC.
1. (a) Yang, W.; Gao, X.; Wang, B. In Organoboronic Acid;
Hall, D. G., Ed.; Wiley-VCH: NY, 2005; Chapter 13, p
481; (b) Wang, W.; Gao, X.; Wang, B. Curr. Org. Chem.
2002, 6, 1285, see references cited therein.
2. Matteson, D. S. Tetrahedron 1989, 45, 1859.
3. (a) Yasuda, M.; Yoshioka, S.; Yamasaki, S.; Somyo, T.;
Chiba, K.; Baba, A. Org. Lett. 2006, 8, 761; (b)
Nakashima, D.; Yamamoto, H. Org. Lett. 2005, 7, 1251;
(c) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am.
Chem. Soc. 1996, 118, 3049.
4. (a) Wong, K. T.; Chin, Y. Y.; Liao, Y. L.; Lin, C. C.;
Chou, M. Y.; Leung, M. K. J. Org. Chem 2002, 67, 1041;
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633; (c) Suzuki, A. J. Organomet. Chem. 1999, 576,
147; (d) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457.
5. (a) Luvino, D.; Smietana, M.; Vasseur, J. J. Tetrahedron
Lett. 2006, 47, 9253; (b) Kaur, G.; Fang, H.; Gao, X.; Li,
H.; Wang, B. Tetrahedron 2006, 62, 2583; (c) Ricardo, A.;
Frye, F.; Carrigan, M. A.; Tipton, J. D.; Powell, D. H.;
Benner, S. A. J. Org. Chem. 2006, 71, 9503; (d) Mulla, H.
R.; Agard, N. J.; Basu, A. Bioorg. Med. Chem. Lett. 2004,
14, 25.
Significant changes were monitored in the fluorescence
spectra of both boronic acids 9a and 9b upon binding
to triol 7. For instance, benzene boronic acid 9a (UV
kmax1 242 and kmax2 263 nm), upon irradiation at
263 nm (c 0.015 M, CH2Cl2), yields an emission spec-
trum with kmax 299 nm and intensity (I) of 15.1 au. Its
BLA derivative 10a (UV kmax1 234 and kmax2 267 nm),
when irradiated at the 267 nm at a similar concentration
in the same solvent, gives an emission spectrum with
kmax 288 nm, with a more than 25-fold increase in emis-
sion intensity (I = 388 au).
By contrast, proceeding in a similar manner we find
that—on going from 3,5-bis(trifluoromethyl)benzene-
boronic acid (9b) (UV kmax1 236 and kmax2 263 nm) to
BLA 10b (UV kmax1 231 and kmax2 263 nm)—the inten-
6. Curci, R.; D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2006,
39, 1, see references cited therein.

3578
L. D’Accolti et al. / Tetrahedron Letters 48 (2007) 3575–3578
7. (a) Murray, R. W.; Singh, M. Org. Synth. 1997, 74, 91; (b)
174.23 g molꢀ1, triclinic, space group: P-1, a = 114.01(3);
b = 100.43(4); c = 91.14(3) deg.; cell volume = 1037.2(6)
Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J.
Org. Chem 1988, 53, 3890; (c) Marples, B. A.; Muxworthy,
J. P.; Baggaley, K. H. Tetrahedron Lett. 1991, 32, 533, see
also references cited therein.
3
A , Z = 2, T = 293(2) K, qc = 1.116 g cmꢀ3
,
l =
˚
0.082 mmꢀ1, # range = 5.07–27.50ꢁ. The SHELXL-97 pro-
gram was employed for refinement. The complete supple-
mentary files can be obtained upon request to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK; email:
deposit@ccdc.cam.ac.uk.
8. Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am.
Chem. Soc. 1989, 111, 6749.
9. cis-1,3-and cis-1,4-Dimethylcyclohexanes (2) and (3) as
well as cis,cis-1,3,5-trimethylcyclohexanes (4) (Chem-
SampCo, Trenton NJ, USA) gave spectral data in
agreement with the literature.
10. (a) Dalling, D. K.; Grant, D. M. J. Am. Chem. Soc. 1967,
89, 6612; (b) Segre, A.; Musher, J. I. J. Am. Chem. Soc.
1967, 89, 706.
15. Lapointe, R. E.; Stevens, J. C.; Nickias, P. N.; McAdon,
M. H. U.S. Patent 5,721,185, 1998.
16. (a) 3,5,7-Trimethyl-2,8,9-trioxa-1-boratricyclo [3.3.1.-
13,7]decane (8): white solid, mp 62–64 ꢁC (cryst n-pen-
tane); 1H NMR (CDCl3, 500 MHz): d 1.87 (d, 3H,
J = 13.0 Hz), 1.45 (d, 3H, J = 13.0 Hz), 1.25 (s, 9H); 13C
NMR (CDCl3, 125 MHz): d 71.8, 47.2, 30.5; 11B NMR
(128.4 MHz, CDCl3, ext. ref. Et2OÆBF3): d 18.265; FT-IR
(CH2Cl2) 2960, 2922, 2850, 2358, 1734, 1450, 1396, 1373,
1259, 1093, 1022, 798 cmꢀ1; Anal. Calcd for C9H15BO3: C,
59.4; H, 8.3. Found: C, 59.9; H, 8.2; (b) Lappert, M. F. J.
Chem. Soc. 1953, 667.
11. (a) White solid (mp 92–94 ꢁC, lit.11b 92–93 ꢁC); column
chromatography (silicagel, n-hexane/Et2O 3:1) yields 5
(purity >98%, GC); 1H NMR (CDCl3, 500 MHz): d
3.85 (s, 2H), 1.92 (m, 2H), 1.68 (m, 2H), 1.47 (m, 1H), 1.29
(m, 1H), 1.26 (m, 1H), 1.19 (m, 1H), 1.14 (s, 6H); 13C
NMR (CDCl3, 125 MHz): d 71.3, 47.8, 37.9, 30.8,
17.3; GC/MS (70 eV) m/z (rel intensity): 126 (3), 101 (5),
83 (7), 71 (8), 58 (12), 43 (100); (b) Meinwald, J.;
Yankeelov, J. A., Jr. J. Am. Chem. Soc. 1958, 80, 5266;
(c) Eastman, R. H.; Quinn, R. A. J. Am. Chem. Soc. 1960,
82, 4249.
17. For instance, see: Pelter, A.; Maddocks, U.; Smith, K.
Chem Commun. 1978, 805.
18. BLA (10a): white solid, mp 103–104 ꢁC; 1H NMR (CDCl3,
500 MHz): d 7.79–7.78 (m, 2H), 7.37–7.29 (m, 3H), 1.94
(d, 3H, J = 14.0 Hz), 1.54 (d, 3H, J = 14.0 Hz), 1.29 (s,
9H); 13C NMR (CDCl3, 125 MHz): d 133.5 (C-B), 129.8,
127.3, 70.9, 47.7, 30.9; 11B NMR (128.4 MHz, CDCl3, ext.
ref. NaBF4): d ꢀ17.15; FT-IR (CH2Cl2) 3153, 2926, 2873,
1791, 1600, 1473, 1436, 1375, 1365, 1350, 1317, 1207,
1099 cmꢀ1; Anal. Calcd for C15H21BO3: C, 69.3; H, 8.1.
Found: C, 66.9; H 8.0.
12. (a) White solid (mp 163–165 ꢁC, lit.12b 164–165 ꢁC); 6
(purity >98%, GC); spectral data were in agreement with
the literature.12b,c (b) Causa, A. G.; Chen, H. Y.; Tark, S.
Y.; Harwood, H. J. J. Org. Chem. 1973, 38, 1385; (c)
Courtot, P.; Kinastowski, S.; Lumbroso, H. Bull. Soc.
Chim. Fr. 1964, 489.
13. White solid, mp 134–135 ꢁC; column chromatography11a
gives 7 (purity 98%, GC); 1H NMR (CDCl3, 500 MHz): d
3.99 (s, 3H), 1.89 (d, 3H, J = 14.3 Hz), 1.37 (d, 3H,
J = 14.3 Hz), 1.18 (s, 9H); 13C NMR (CDCl3, 125 MHz):
d 72.1, 48.1, 31.6; FT-IR (CH2Cl2): 3367, 2969, 1455,
1390, 1186, 901 cmꢀ1; GC/MS (70 eV) m/z (rel intensity):
174 (0.1), 159 (1.1), 123 (5), 101 (33), 83 (7), 59 (19), 43
(100); Anal. Calcd for C9H18O3: C, 62.0; H, 10.4. Found:
C, 62.0; H, 10.2.
19. BLA (10b): white solid, mp 174–176 ꢁC; 1H NMR (CDCl3,
500 MHz): d 8.19 (s, 2H), 7.83 (s, 1H), 1.96 (d, 3H,
J = 14.0 Hz), 1.57 (d, 3H, J = 14.0 Hz), 1.31 (s, 9H); 13C
NMR (CDCl3, 125 MHz): d 132.7, 129.7 (q, C–CF3,
J = 32 Hz), 123.6 (q, CF3, J = 272 Hz), 122.5, 71.0, 49.3,
29.7; 11B NMR (128.4 MHz, CDCl3, ext. ref. NaBF4): d
ꢀ17.22; FT-IR (CH2Cl2) 3150, 2925, 1600, 1375, 1350,
1320, 1202, 1099 cmꢀ1; Anal. Calcd for C17H19BF6O3: C,
51.5; H, 4.8. Found: C, 50.9; H, 5.1. HRMS (MALDI,
TOF) Calcd for C17H18BF6O3ꢀNaþ: 418.115. Found:
418.560 [(MꢀH)+Na+].
14. Cambridge Crystallographic Data Centre, CCDC no.
633318. Salient data for 7: C18H36O6, MT =