Observations on the deprotection of pinanediol and pinacol boronate esters via fluorinated intermediates

Article abstract of DOI:10.1021/jo901930v

(Chemical Equation Presented) Methods for the deprotection of pinanediol and pinacol esters of various boronic acids via fluoroborane intermediates were evaluated. Treatment of the boronate esters with potassium hydrogen difluoride normally gives trifluor

Full text of DOI:10.1021/jo901930v

pubs.acs.org/joc
methods for the synthesis of chiral alkyl boronic acids of
Observations on the Deprotection of Pinanediol
and Pinacol Boronate Esters via Fluorinated
Intermediates
general structure 1, normally involving protection of the
boronic acid group as esters of chiral diols (e.g., pinanediol,
as illustrated for 2) (reviewed in Matteson9). Deprotection of
these esters can be achieved by methods including cleavage
with boron trichloride,10,11 transesterification with other
boronic acids,12 or acidic hydrolysis.3,13,14 The success of
these approaches varies for reasons including functional
group incompatibilities, impure product mixtures, and
difficulties in separation of the free diol from the boronic
acid without reformation of the ester (a solid phase techni-
que has been developed to assist with this15). Although
the N-methyliminodiacetic acid boronate, an alternative
readily removable boronic acid protecting group, has been
reported,16 there remains a need for improved methods
for deprotection of pinanediol boronate esters,11 because of
the useful chiral induction properties of the pinanediol
group.
Steven R. Inglis, Esther C. Y. Woon, Amber L. Thompson,
and Christopher J. Schofield*
The Department of Chemistry, Chemistry Research
Laboratory, University of Oxford, 12 Mansfield Road,
Oxford, OX1 3TA, United Kingdom
christopher.schofield@chem.ox.ac.uk
Received September 7, 2009
In the course of work on the development of phenylboro-
nic acids as inhibitors of penicillin binding proteins, we
evaluated various methods for the deprotection of pinacol
phenylboronate esters.5 A series of substituted phenylboro-
nic acid pinacol esters 3 and 4 were deprotected in good yields
by treatment with potassium hydrogen difluoride (KHF2) to
generate the trifluorinated intermediates 5 and 6 which were
hydrolyzed in the presence of trimethylsilyl chloride
(TMSCl) to give the boronic acids 7 and 8 (Scheme 1),
according to the method of Yuen and Hutton,17 which was
based on the pioneering work of Vedejs et al.18 Here we
report the application of this methodology to the deprotec-
tion of other boronate esters including R-amido pinanediol
boronate esters. We found that in cases where a neighboring
amide carbonyl group can coordinate with the boron, di-
fluoroboranes, instead of trifluoroborates, could be isolated,
depending on the workup procedure used. We also report
Methods for the deprotection of pinanediol and pinacol
esters of various boronic acids via fluoroborane inter-
mediates were evaluated. Treatment of the boronate
esters with potassium hydrogen difluoride normally gives
trifluoroborate salts; in the case of R-amido alkyl or
o-amido phenyl boronate esters, aqueous workup gives
difluoroboranes. Procedures for transformation of both
trifluoroborates and difluoroboranes to free boronic
acids are described.
Boronic acids are used as inhibitors of enzymes bearing
nucleophilic residues at their active sites. Numerous studies
on the synthesis and biological evaluation of boronic acid
derivatives as inhibitors of enzymes including serine pro-
teases (for reviews see Walker and Lynas1 and Yang et al.2),
β-lactamases,3,4 penicillin binding proteins,5-7 and the hu-
man proteasome8 have been reported. There are established
(9) Matteson, D. S. Tetrahedron 1998, 54, 10555–10606.
(10) Kinder, D. H.; Katzenellenbogen, J. A. J. Med. Chem. 1985, 28,
1917–1925.
(1) Walker, B.; Lynas, J. F. Cell. Mol. Life Sci. 2001, 58, 596–624.
(2) Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23, 346–368.
(3) Morandi, F.; Caselli, E.; Morandi, S.; Focia, P. J.; Blazquez, J.;
Shoichet, B. K.; Prati, F. J. Am. Chem. Soc. 2003, 125, 685–695.
(4) Venturelli, A.; Tondi, D.; Cancian, L.; Morandi, F.; Cannazza, G.;
Segatore, B.; Prati, F.; Amicosante, G.; Shoichet Brian, K.; Costi, M. P.
J. Med. Chem. 2007, 50, 5644–5654.
(5) Inglis, S. R.; Zervosen, A.; Woon, E. C. Y.; Gerards, T.; Teller, N.;
Fischer, D. S.; Luxen, A.; Schofield, C. J. J. Med. Chem. 2009, 52, 6097–6106.
(6) Nicola, G.; Peddi, S.; Stefanova, M.; Nicholas, R. A.; Gutheil, W. G.;
Davies, C. Biochemistry 2005, 44, 8207–8217.
(7) Pechenov, A.; Stefanova, M. E.; Nicholas, R. A.; Peddi, S.; Gutheil,
W. G. Biochemistry 2003, 42, 579–588.
(8) Dorsey, B. D.; Iqbal, M.; Chatterjee, S.; Menta, E.; Bernardini, R.;
Bernareggi, A.; Cassara, P. G.; D’Arasmo, G.; Ferretti, E.; De Munari, S.;
Oliva, A.; Pezzoni, G.; Allievi, C.; Strepponi, I.; Ruggeri, B.; Ator, M. A.;
Williams, M.; MallamoT, J. P. J. Med. Chem. 2008, 51, 1068–1072.
(11) Matteson, D. S.; Jesthi, P. K.; Sadhu, K. M. Organometallics 1984, 3,
1284–1288.
(12) Snow, R. J.; Bachovchin, W. W.; Barton, R. W.; Campbell, S. J.;
Coutts, S. J.; Freeman, D. M.; Gutheil, W. G.; Kelly, T. A.; Kennedy, C. A.;
Krolikowski, D. A.; Leonard, S. F.; Pargellis, C. A.; Tong, L.; Adams, J.
J. Am. Chem. Soc. 1994, 116, 10860–10869.
(13) Morandi, S.; Morandi, F.; Caselli, E.; Shoichet, B. K.; Prati, F.
Bioorg. Med. Chem. 2008, 16, 1195–1205.
(14) Thomson, J. M.; Distler, A. M.; Prati, F.; Bonomo, R. A. J. Biol.
Chem. 2006, 281, 26734–26744.
(15) Pennington, T. E.; Cynantya, K. B.; Hutton, C. A. Tetrahedron Lett.
2004, 45, 6657–6660.
(16) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–
14085.
(17) Yuen, A. K. L.; Hutton, C. A. Tetrahedron Lett. 2005, 46, 7899–7903.
(18) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.
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468 J. Org. Chem. 2010, 75, 468–471
Published on Web 12/16/2009
DOI: 10.1021/jo901930v
r
2009 American Chemical Society

Inglis et al.
JOCNote
SCHEME 1. Deprotection of Pinacol Phenyl Boronates5
SCHEME 3. Deprotection of o-Amido Pinacol Phenylboro-
nates via Difluoroboranes
difluoroborane 12 (Scheme 2). Difluoroborane analogues of
R-amido alkyl boronic acids have been previously reported,
but were prepared from their corresponding boronic acids by
treatment with aqueous hydrofluoric acid.10 Trifluoroborate
11 was converted to the difluoroborane 12 by suspension
in water with stirring; almost complete conversion was
observed after 1 h (overnight stirring gave complete
conversion).
SCHEME 2. Fluoroboranes from R-Amido Boronates
A comparison of the different workup procedures was
made with the use of R-amido pinanediol boronate 13 and
pinacol ester 14 (Scheme 2). For both 13 and 14, use of
aqueous or nonaqueous workup procedures gave the di-
fluoroboranes (15 and 16) and the trifluoroborate products
(17 and 18), respectively. Yields were lower in the cases of
reaction of 13. In the case of the nonaqueous procedure, this
is probably due to the poor solubility of product 17 in hot
acetone during workup in the presence of pinanediol. In the
case of the aqueous procedure, this is probably due to loss of
material because of partial solubility in water (some 17 later
crystallized from the aqueous phase).
We have prepared the trifluoro o-amido phenylborate
salt 5 from its parent pinacol ester 3 via the nonaqueous
workup procedure5 (Scheme 1); however, the product 5 was
difficult to isolate. In contrast, a series of m-amido pinacol
phenylboronates of general structure 4 were converted into
the corresponding trifluoroborates 6 in good yields and
purities with use of the aqueous workup procedure5
(Scheme 1). We were then interested in whether applica-
tion of the aqueous workup could serve as an improvement
to the procedure for formation of trifluoroborates of
o-amido phenylboronic acids. Following treatment of 3,
19, and 20 with KHF2, exposure of the isolated intermediates
to water led to formation of the difluoroboranes 21, 22, and
23 in good yields (Scheme 3) in a manner similar to that
used for the R-amido alkyl compounds (Scheme 2). Genera-
tion of the difluoroborane 21 as described here gives an
improvement in the yield, purity, and ease of application
compared to the preparation of the corresponding trifluor-
oborate salt 5.5
on the evaluation of procedures for the conversion of
the different fluorinated intermediates into free boronic
acids.
When preparing trifluoroborate salts from their parent
diol esters, both separation of the trifluoroborate salt from
the diol and isolation of the trifluoroborate salt from the
excess KHF2 are necessary. The first process can be achieved
by washing the crude salt with a nonpolar solvent, while the
second can involve either aqueous (washing) or nonaqueous
(extraction with hot solvent) procedures (Scheme 1). While
the initially reported method17 used nonaqueous conditions,
in application of this method to the preparation of substi-
tuted phenyl boronic acids,5 we found it easier to use an
aqueous procedure in most cases.
Because of the biomedicinal importance of peptide boro-
nic acids, we investigated the extension of the fluoroborate
methodology for the deprotection of R-amido pinanediol
boronates (Scheme 2). In initial work on 9 and 10, we tested
both aqueous and nonaqueous workup procedures, and
found it was possible to obtain salt 11 from 9 by aqueous
workup in good yield, provided that the amount of water
used was minimized. When an excess of water was used, it
was noted that significant quantities of product were being
carried to the filtrate. Instead of the anticipated trifluorobo-
rate salt, this material was identified as the corresponding
The conversion of simple pinanediol and pinacol alkyl-
boronates into potassium trifluoroborates was also investi-
gated (Scheme 4). When applying this methodology to 24
and 25, it was found that the nonaqueous workup proce-
dure was preferable because of the relatively high solu-
bility of the products in water, leading to lower yields for
the aqueous procedure; this highlights a limitation of the
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Inglis et al.
JOCNote
SCHEME 4. Deprotection of Simple Alkyl Boronates
reported; however, this was mediated by lithium aluminum
hydride.23 Treatment of the difluoroborane 16 with TMSCl
in aqueous acetonitrile only resulted in 50% conversion to
the boronic acid after 1 h (Scheme 5). When 12 was treated
with either aqueous lithium hydroxide (5 equiv) or potassium
carbonate (1.5 equiv) at room temperature overnight, no
reaction was observed. It has been reported that difluoro-
boranes are readily hydrolyzed to free boronic acids in
tris(hydroxymethyl)aminomethane (tris) buffer.10 Studies
on difluoroborane 15 in D2O/CD3CN involving 1H and
19F NMR spectroscopy (Figure S-41, Supporting Infor-
mation) revealed this difluoroborane was not hydrolyzed
rapidly in water alone. Addition of dilute aqueous ammonia
led to efficient hydrolysis of the difluoroborane to give 34.
This reaction may proceed via initial reaction of ammonia on
the boron atom; an analogous mechanism is plausible in tris
buffer.10
SCHEME 5. Conversion of R-Amido Fluoroboranes into Boro-
nic Acids
Treatment of difluoroboranes 12, 15, 16, and 35 with
aqueous ammonia on a preparative scale led to their con-
version to the boronic acids 31, 34, 33, and 36, respectively,
in good yields (Scheme 5). 19F NMR confirmed the pro-
ducts were free of fluorine. To verify that the deprotection
procedures did not affect optical purity, the boronic acid 31
was reconverted to its pinanediol boronate ester 9; the
optical rotation was consistent with that of an original
enantiopure sample of
9 (Scheme S-1, Supporting
Information). Treatment of the o-amido aryl difluorobor-
anes 21-23 with aqueous ammonia solution also mediated
hydrolysis to give the benzoxazaborinines 7, 37, and 38,
respectively, in good yields (Scheme 3). We had previously
prepared 7 from its trifluoroborate precursor by treatment
with TMSCl (Scheme 1);5 however, the overall yield was low.
The two-step procedure presented here is an improved meth-
od for the preparation of this class of boronic acids from their
pinacol protected precursors. For comparison with the di-
fluoroboranes, we investigated the hydrolysis of a m-amido
phenyl trifluoroborate 6 (Scheme 1) with aqueous ammonia
by 1H and 19F NMR spectroscopy, as described above for 15.
These studies revealed the trifluoroborate was hydrolyzed
under these conditions (data not shown), but at a slower rate
than the TMSCl procedure. Similarly, the R-amido alkyl
trifluoroborate, 18, was converted to boronic acid 33 by
aqueous ammonia treatment, but at a comparatively much
slower rate than with the difluoroboranes (Scheme 5).
The different behavior of the R-amido alkyl and o-amido
phenylboronic acids, with respect to trifluoroborate or di-
fluoroborane isolation, compared with the unfunctionalized
alkyl and m-amido phenylboronic acids, on exposure of their
trifluoroborate salts to water, suggests that neighboring
group participation is important for conversion to the
difluoroborane. This is likely to involve the amido carbonyl
oxygen atom reacting with the boron intramolecularly.
Where this interaction cannot occur, the trifluoroborate is
obtained independent of the workup procedure employed.
Where neighboring group participation occurs, we propose
that the partially water-soluble trifluoroborate salt loses a
fluoride ion, leading to precipitation of the relatively water
insoluble difluoroborane (Figure 1).
aPrior to optimization. bOvernight reaction. cReaction 50% complete.
aqueous workup method. Notably, the trifluoroborates 26
and 27 were isolated in these cases, even after exposure of the
products to water.
Although transformation of pinanediol alkylboronates to
potassium19,20 and cesium21 trifluoroborate salts has been
reported (reviewed in Darses and Genet22), conversion of
these compounds into free boronic acids was not included as
part of these investigations. As reported,17 an effective
method for the conversion of phenyltrifluoroborates into
boronic acids is by treatment with TMSCl in aqueous acetoni-
trile (as illustrated for 7 and 8 in Scheme 1). Application of this
method to the simple trifluoroborates 26 and 27 gave the
boronic acids 28 and 29 (Scheme 4). When applied to
R-amido trifluoroborates 11 and 30, the respective boronic
acids 31 and 32 were obtained in modest yields and variable
purity, as judged by 1H NMR spectroscopy (Scheme 5);
however, the analytically pure trifluoroborate 18 was con-
verted to the boronic acid 33 in high yield and purity by this
method (Scheme 5).
We then investigated the hydrolysis of the difluoroborane
intermediates. One example of conversion of a simple (non
R-amido) difluoroborane into a boronic acid has been
(19) Kim, B. J.; Matteson, D. S. Angew. Chem., Int. Ed. 2004, 43, 3056–
3058.
(20) Matteson, D. S.; Kim, G. Y. Org. Lett. 2002, 4, 2153–2155.
(21) Matteson, D. S.; Maliakal, D.; Pharazyn, P. S.; Kim, B. J. Synlett
2006, 3501–3503.
(23) Al-Juaid, S. S.; Eaborn, C.; El-Kheli, M. N. A.; Hitchcock, P. B.;
Lickiss, P. D.; Molla, M. E.; Smith, J. D.; Zora, J. A. J. Chem. Soc., Dalton
Trans. 1989, 447–452.
(22) Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2003, 4313–4327.
470 J. Org. Chem. Vol. 75, No. 2, 2010

Inglis et al.
JOCNote
with the intramolecular reactions observed for crystals
of 9, suggesting an intramolecular stabilization of the di-
fluoroboranes.
In summary, both R-amido alkyl pinanediolboronates,
and o-amido pinacol phenylboronates can be deprotected
to their free boronic acids via trifluoroborate or difluoro-
borane intermediates, by using different workup procedures.
The choice of either the nonaqueous or aqueous procedure
depends on the solubility properties of the fluorinated inter-
mediates (in organic solvents or water) and the ease with
which the different products will crystallize or precipitate. In
our experience, the success of the nonaqueous method to
prepare trifluoroborate salts may also be influenced by the
purity of the starting material; in contrast, it is possible for
crude starting materials, carried through several steps with-
out purification, to be converted into analytically pure
difluoroboranes by the aqueous procedure. The difluorobor-
anes are best converted into boronic acids by treatment with
aqueous ammonia, while trifluoroborates are best converted
to the same by treatment with TMSCl. These observations
should assist in the sometimes problematic deprotection of
pinanediol and pinacol boronate esters, providing a new tool
in the synthesis of biologically important boronic acids.
FIGURE 1. Possible mechanism for the formation of difluorobor-
anes from trifluoroborates.
FIGURE 2. Thermal ellipsoid plot of 9 showing the tetrahedral
˚
coordination at boron; B5 lies 0.376 A out of the plane defined by
˚
O1, O4, and C9. Selected bond lengths: B5-O1 1.418(3) A, B5-O4
Experimental Section
˚
˚
˚
1.438(3) A, B5-O6 1.638(3) A, B5-C9 1.629(3) A, compared with
˚
˚
B-O = 1.37(3) A; B-C = 1.56(3) A for three-coordinate boron in
CBO2 motifs reported in the Cambridge Structural Database.28,29
Ellipsoids are drawn at the 50% probability and the minor compo-
nent of the disorder is omitted for clarity.
Example procedures are given below (full experimental de-
tails are provided in Supporting Information).
N-[(1R)-1-(Difluoroboryl)-3-methylbutyl]-2-(2-thienyl)aceta-
mide, 15. To a stirred solution of boronate 13 (0.336 g, 0.863
mmol) in methanol (9 mL) was added 4.5 M KHF2(aq) (1.8 mL,
8.10 mmol). {Note: KHF2 is corrosive and discolors glassware
after prolonged exposure.} The resulting mixture was stirred
for 1 h at rt, then concentrated to dryness. The resulting solid
was collected by filtration and washed with hot ether (5 Â 15
mL). The remaining solid was suspended in water (25 mL) and
stirred overnight. The solid was collected, washed with a little
water, and dried to give 15 (0.126 g, 56%) as a white powder,
mp 125-135 °C. Anal. Calcd for C11H16BF2NOS: C, 50.99; H,
6.22; N, 5.41. Found: C, 50.91; H, 6.15; N, 5.39.
{(1R)-3-Methyl-1-[(phenylacetyl)amino]butyl}boronic Acid,
31. Difluoroborane 12 (100 mg, 0.39 mmol) was stirred in
CH3CN (7.5 mL) and water (5 mL) before addition of an 8%
NH3(aq) solution (1.5 mL). The mixture was stirred at rt for 2 h
before being concentrated carefully under vacuum to a volume
of ∼3 mL, at which point precipitation was observed. The
mixture was extracted with ethyl acetate; the combined extracts
were washed with brine and dried (Na2SO4), and the solvent was
removed to give 31 (80 mg, 81%) as a white solid, mp 85-100 °C.
Anal. Calcd for C13H20BNO3: C, 62.68; H, 8.09; N, 5.62. Found:
C, 62.72; H, 8.03; N, 5.49.
Evidence for neighboring group participation came
from a crystal structure of the pinanediol boronate 9
(Figure 2),24 which reveals reaction of the R-amido oxygen
atom with boron, causing the boron atom to have tetrahedral
character. Related structures have been reported.12,25-27 The
IR spectrum of 9 in the solid state contained a band at 1599
cm-1, which is low for an amide CO stretch. This band was
shifted to 1651 cm-1 in the solution IR spectrum of 9, sug-
gesting that the intramolecular reaction is less important in
solution. IR spectra of the difluoroboranes (e.g., 12 and 15)
typically displayed amide bands in the region 1635 and 1610
cm-1 for the solid and liquid states, respectively, consistent
(24) The structure was determined from single-crystal X-ray diffraction
data collected at low temperature with an Oxford Cryosystems Cryostream
N2 open-flow cooling device.30 Data were collected with an Enraf-Nonius
˚
KappaCCD diffractometer (Mo KR radiation; λ= 0.71073 A) and processed
with the DENZO-SMN package,31 including interframe scaling (which was
carried out with Scalepack within DENZO-SMN). The structure was solved
with SIR92.32 Refinement was carried out with full-matrix least squares
within the CRYSTALS suite33 on F2. For further details see the crystal-
lographic information file (CIF).34
(25) Besong, G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T.
Org. Biomol. Chem. 2006, 4, 2193–2207.
(26) Lange, H.; Beirgander, K.; Frohlich, R.; Kehr, S.; Nakamura, S.;
Shibata, N.; Toru, T.; Hoppe, M. Chem.;Asian J. 2008, 3, 88–101.
(27) Matteson, D. S.; Michnick, T. J.; Willett, R. D.; Patterson, C. D.
Organometallics. 1989, 8, 726–729.
Acknowledgment. We thank the European Union
(European Community Sixth Framework Programme) via
EUR-INTAFAR for funding, and Dr. Barbara Odell for
assistance with NMR spectroscopy.
(28) Allen, F. H. Acta Crystallogr. B 2002, 58, 380–388.
Supporting Information Available: Full experimental de-
tails, NMR spectra, and NMR studies on the hydrolysis of
difluoroboranes. This material is available free of charge via the
Internet at http://pubs.acs.org.
(29) Bruno, I. J.; Cole, J. C.; Edgington, P. R.; Kessler, M.; Macrae, C. F.;
McCabe, P.; Pearson, J.; Taylor, R. Acta Crystallogr. B 2002, 58, 389–397.
(30) Cosier, J.; Glazer, A. M. J. Appl. Crystallogr. 1986, 19, 105–107.
(31) Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data
Collected in Oscillation Mode. In Methods Enzymology; Carter, C. W.,
Sweet, R. M., Eds.; Academic Press: New York, 1997; Vol. 276.
(32) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla,
M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
(33) Betteridge, P. W.; Carruthers, J. R.; Cooper, G. I.; Prout, C. K.;
Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487–1487.
(34) Crystallographic data for compound 9 have been deposited with
the Cambridge Crystallographic Data Centre, CCDC 749874, which can
be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/
data_request/cif.
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