Synthesis and structural investigation of internally coordinated α-amidoboronic acids

Article abstract of DOI:10.1021/jo051757h

Six new N-acyl-boroGly derivatives, along with their N-acyl-boroSar analogues, have been synthesized by modification of conventional procedures. Structural characterization of these α-amidoboronic acids was accomplished by extensive use of ¹¹B

Full text of DOI:10.1021/jo051757h

Synthesis and Structural Investigation of Internally Coordinated
r-Amidoboronic Acids
§
§
§
§
§
Jack H. Lai, Yuxin Liu, Wengen Wu, Yuhong Zhou, Hlaing H. Maw,
§
‡
,‡
William W. Bachovchin, Krishna L. Bhat, and Charles W. Bock*
Department of Biochemistry, Tufts UniVersity School of Medicine, 136 Harrison AVenue,
Boston, Massachusetts 02111, and Department of Chemistry and Biochemistry, School of Science and
Health, Philadelphia UniVersity, School House Lane and Henry AVenue, Philadelphia, PennsylVania 19144
bockc@philau.edu
ReceiVed August 19, 2005
Six new N-acyl-boroGly derivatives, along with their N-acyl-boroSar analogues, have been synthesized
by modification of conventional procedures. Structural characterization of these R-amidoboronic acids
1
1
1
was accomplished by extensive use of B and H NMR spectroscopy. These compounds were prepared
to determine the extent of intramolecular B-O dative bond formation within the context of a five-
membered (:OdC-N-C-B) ring motif. It is shown that the formation of such dative bonds depends on
the nature of the substituents at both the acyl carbon and the nitrogen atoms. Computational evidence
from second-order Møller-Plesset perturbation theory is provided in support of these findings.
Introduction
proteases that are pharmacological targets include the follow-
5
ing: elastase, involved in inflammation and emphysema;
Serine proteases constitute a large and functionally diverse
class of proteolytic enzymes that have a common catalytic
mechanism.1 They play an important role in the mediation of
a number of pathological conditions and, as a consequence, they
are targets for inhibition by therapeutic agents.5 Serine
6
thrombin, a blood coagulation enzyme; and hepatitis C pro-
7
8
tease, which is required for viral replication.
-4
Peptide boronic acids, in which the -B(OH)2 functional group
is connected to a peptide or peptidomimetic sequence, form a
-8
2
,3,9
class of potent and specific inhibitors of serine proteases.
For example, Bachovchin and co-workers
10,11
§
‡
have reported that
Tufts University School of Medicine.
Philadelphia University.
aminoboronic acid dipeptides of the form L-Xaa-Proline-(2R)-
boronic acid (L-Xaa-R-boroPro) are exceptionally potent inhibi-
tors of serine protease dipeptidyl peptidase IV (DPP IV, CD26),
an extracellular membrane-bound enzyme; L-Valyl-Proline-(2R)-
boronic acid, in particular, has shown both hematopoietic
(
1) Craik, C. S.; Debouk, C. PerspectiVe in Drug DiscoVery and Design;
Anderson, P. S., Kenyon, G. L., Marshall, G. R., Eds.; ESCOM Science
Publishers BV; Leiden, The Netherlands, 1995; Vol. 2, No. 3.
(
2) Powers, J. C.; Harper, J. Inhibitors of Serine Proteases; Elsevier
Scientific Publishing Co.; New York, 1986; Vol. 12.
3) Ivanov, D.; Bachovchin, W. W.; Redfield, A. G. Biochemistry 2002,
1, 1587.
(
1
2
13
stimulation and antitumor activity. Interestingly, the dipep-
tidyl boronic acid derivative Bortezomib (Velcade) has been
4
6
(4) Jagannathan, S.; Forsyth, T. P.; Kettnee, C. A. J Org. Chem. 2001,
6, 6375.
(
(
(
5) Edwards, P. D.; Bernstein, P. R. Med. Res. ReV. 1994, 14, 127.
(9) Dembitski, V. M.; Quntar, A. A. A.; Srebnik, M. Med. Chem. 2004,
4, 1001.
(10) Coutts, S. J.; Kelly, T. A.; Snow, R. J.; Kennedy, C. A.; Barton, R.
W.; Adams, J.; Krolikowski, D. A.; Freeman, D. M.; Campbell, S. J.;
Ksiazek, J. F.; Bachovchin, W. W. J. Med. Chem. 1996, 39, 2087.
(11) Snow, R. J.; Bachovchin, W. W. AdV. Med. Chem. 1995, 3, 149.
6) Lorand, L.; Mann, K. C. Methods Enzymol. 1993, 222, 1.
7) Love, R. A.; Parge, H. E.; Wickersham, J. A.; Hostomsky, Z.; Habuka,
N.; Moomaw, E. W.; Adachi, T.; Hostomska, Z. Cell 1996, 87, 331.
8) Grakoui, A.; Mccourt, D. W.; Wychowski, C.; Feinstone, S. M.; Rice,
C. M. J. ViVol. 1993, 67, 2832.
(
10.1021/jo051757h CCC: $33.50 © 2006 American Chemical Society
5
12
J. Org. Chem. 2006, 71, 512-519
Published on Web 12/16/2005

Internally Coordinated R-Amidoboronic Acids
approved recently by the FDA as a proteasome inhibitor and it
represents the only new treatment option for multiple myeloma
1
4
that has become available in more than a decade. The
inhibitory mechanism of boronic acid dipeptides utilizes the
empty 2p orbital centered on the boron atom. This orbital is
believed to interact with the catalytic serine to form a stable
1
5,16
“
ate” complex,
which mimics the transition state for amide
However, dipeptides derived from proline
1
7-21
hydrolysis.
boronic acid such as AlaboroPro and ProboroPro are known to
lose their inhibitory activity in aqueous solution at neutral pH.
This loss of activity has been shown to be due to the reversible
formation of an intramolecular six-membered cyclic species
FIGURE 1. Compounds synthesized in this investigation.
bonds has been correlated to some unexpected physiological
(
:N-C-C-N-C-B), analogous to a diketopiperazine, in
3
1-34
behavior.
2
2,23
which an amine nitrogen atom coordinates to the boron.
In this article we study intramolecular B-O dative bond
formation in some simple R-amidoboronic acids; such acids are
Recently, we found that L-Xaa-boroSar dipeptides represent a
new class of DPP IV inhibitors with IC50 values in the
submicromolar range.24 Although the biological activity of these
dipeptides is typically an order of magnitude lower than that
for the analogous boroPro compounds, their tendency for
intramolecular, pH-dependent cyclization is also lower, by 1 to
4
also known to be inhibitors of serine proteases. In particular,
we describe the synthesis of six new N-acyl-boroGly derivatives
and their N-acyl-boroSar analogues, see Figure 1.
In basic aqueous media, the boron atom in these R-amido-
boronic acids is expected to be tetracoordinated, as a result of
24
3
orders of magnitude (except for Xaa ) Gly, Pro). A plausible
3
5-38
borate ion formation,
and this is indeed observed (vide
explanation for the reduced cyclization rate of these boroSar
inhibitors is the formation of an intramolecular five-membered
infra). In acidic media, the boron atom in each of these
compounds has the potential to be tetracoordinated via the
formation of an intramolecular B-O dative bond in the context
of a five-membered (:OdC-N-C-B) ring motif. 11B and H
NMR spectroscopy, in conjunction with computational meth-
odology, are used to investigate the extent to which the carbonyl
oxygen atom in these R-amidoboronic acids coordinates to the
boron. We specifically chose substituents at the acyl carbon atom
that do not contain any nitrogen atoms to avoid the competitive
formation of intramolecular ring structures involving a B-N
dative bond.
(:OdC-N-C-B) ring structure in which the carbonyl oxygen
atom coordinates to the boron, effectively stabilizing the active
trans conformer of the dipeptide. Such intramolecular five-
1
membered-ring motifs with a B-O dative bond have been
observed in esters derived from boronic acids,2
5-27
and postu-
lated as intermediates in the stereoselective reduction of
neighboring carbonyl groups.2
8-30
However, relatively little is
known about the factors associated with the formation of these
intramolecular (:OdC-N-C-B) rings, or their influence on
the therapeutic efficacy of potential drugs. It should be
mentioned that the presence of intramolecular B-N dative
Results and Discussion
(
12) Jones, B.; Adams, S.; Miller, G. T.; Jesson, M. I.; Watanabe, T.;
Wallner, B. P. Blood 2003, 102, 1641.
13) Jones, B.; Miller, G. T.; Jesson, M. I.; Watanabe, T.; Wallner, B.
P.; Adams, S. Proc. Am. Soc. Clin. Oncol. 2003, 22, 215 (abstract 860).
14) Kane R. C.; Bross P. F.; Farrel, A. T.; Pazdur, R. Oncologist 2003,
, 508.
15) Mathews, D. A.; Alden, R. A.; Birktoft, J. J.; Freer, S. T.; Krout, J.
J. Biol. Chem. 1975, 250, 7120.
16) Bachovchin, W. W.; Wong, W. Y. L.; Farr-Jones, S.; Shenvi, A.
B.; Kettner, C. A. Biochemistry 1988, 27, 7689.
17) Matteson, D. S.; Sadhu, K. M.; Lienhard, G. E. J. Am. Chem. Soc.
981, 103, 5241.
18) Kinder, D. H.; Katzenellenbogen, J. A. J. Med. Chem. 1985, 28,
917.
Synthesis. The syntheses of the N-acyl-boroGly derivatives
a-f and their corresponding N-acyl-boroSar analogues 2a-f
1
(
were accomplished by adaptation of the methods described in
Scheme 1; detailed procedures are given in the Supporting
Information. The pinanediol ester of glycine or sarcosine boronic
(
8
(
3
9
40
acid was formylated with formic acid and then deprotected
4
1
(
using boron trichloride in methylene chloride at -78 °C to
afford the desired compounds 1a and 2a as outlined in Scheme
(
1
(
(31) Fisher, L.; Holme, T. J. Comput. Chem. 2001, 22, 913.
(32) Sood, A.; Sood, C. K.; Spielvogel, B. F.; Hall, I. H.; Wong, O. T.
J. Pharm. Sci. 1992, 49, 131.
(33) Rajendran, K. G.; Chen, S. Y.; Sood, A.; Spielvogel, B. F.; Hall, I.
H. Biomed. Pharmacother. 1995, 49, 131.
1
(
(
(
19) Shenvi, A. B. Biochemistry 1986, 25, 1286.
20) Kettner, C. A.; Shenvi, A. B. J. Biol. Chem. 1994, 259, 15106.
21) Flentke, G. R.; Munoz, E.; Hubner, B. T.; Plaut, A. G.; Kettner, C.
A.; Bachovchin, W. W. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 1556.
22) Kelly, T. A.; Adams, J.; Bachovchin, W. W.; Barton, R. W.;
Campbell, S. J.; Coutts, S. J.; Kennedy, C. A.; Snow, R. J. J. Am. Chem.
Soc. 1993, 115, 12637.
(34) Hall, I. H.; Chen, S. Y.; Rajendran, K. G.; Sood, B. F.; Spielvogel,
B. F.; Shih, J. EnViron. Health Perspect. 1994, 102, 21.
(35) Van Duin, M.; Peters, J. A.; Kieboom, A. P. G.; Van Bekkum, H.;
Tetrahedron 1984, 40, 2901.
(
(
23) Snow, R. J.; Bachovchin, W. W.; Barton, R. W.; Campbell, S. J.;
(36) Van Duin, M.; Peters, J. A.; Kieboom, A. P. G.; Van Bekkum, H.
Tetrahedron 1985, 41, 3411.
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.
(37) Pizer, R. D.; Ricatto, P. J.; Tihal, C. A. Polyhedron 1993, 12, 2137.
(38) Pizer, R. D.; Ricatto, P. J. Inorg. Chem. 1994, 33, 2402.
(39) (a) The pinanediol ester of glycine boronic acid was prepared from
(+)-pinanediol chloromethylboronate by using the method reported to
prepare boroAla-pn: Pechenov, A.; Stefanova, M. E.; Nicholas, R. A.; Peddi,
S.; Gutheil, W. G. Biochemistry 2003, 42, 579. (b) The pinanediol ester of
sarcosine boronic acid was prepared from dimethylamine by using the
method reported to prepare boroPro-pn: Gigson, F. S.; Singh, A. K.;
Soumeillant, M. C.; Manchand, P. S.; Humora, M.; Kronenthal, D. R. Org.
Proc. Res. DeV. 2002, 6, 814.
(
24) Unpublished results (J.H.L.); see Supporting Information.
(25) Biedryzycki, M.; Scouten, W. H.; Biedrzycka, Z. J. Organomet.
Chem. 1992, 431, 255.
26) Liu, X.; Hubbard, J. L.; Scouten, W. H. J. Organomet. Chem. 1995,
93, 91.
27) Matteson, D. S.; Michnick, J.; Willett, R. D.; Patterson, C. D.
Organometallics 1989, 8, 726.
28) Molander, G. A.; Bobbitt, K. L.; Murray, C. K. J. Am. Chem. Soc.
992, 114, 2759.
(
4
(
(
1
(40) Duckek, W.; Deutsch, J.; Vieth, S.; Niclas, H.-J. Synthesis 1996,
37.
(41) Martichonok, V.; Jones, J. B. J. Am. Chem. Soc. 1996, 118, 950.
(
(
29) Molander, G. A.; Bobbitt, K. L. J. Am. Chem. Soc. 1993, 115, 7517.
30) James, J. J.; Whiting, A. J. Chem. Soc., Perkin 2 1996, 1861.
J. Org. Chem, Vol. 71, No. 2, 2006 513

Lai et al.
SCHEME 1a
high values of pH (9.7-12.5) for all the boronic acids we
synthesized are quite similar, δAVE ) -16.9 ( 0.4 ppm, a
reflection of their common tetracoordinated borate ion structure
3
5-38
in basic media.
In contrast, at low values of pH (1.0-1.9),
1
1
the B chemical shifts range from -11.4 to +10.6 ppm,
suggesting a variety of different boron environments in this
series of related acids.
To understand the structural origin of the different 11B shifts
for these related compounds in acidic media, we examined their
potential energy surfaces (PESs) using computational methods.
49-53
Our experience with a variety of boronic acid derivatives,
54-57
in conjunction with AM1 and PM3
potential energy surface
scans of 1a-f and 2a-f, indicate that the most important
conformations of the simple R-amidoboronic acids discussed
in this article are those illustrated in Figure 2 for N-acetyl-
borosarcosine 2b; the trans and cis designations refer to rotation
a
Reagents and conditions: (i) DIPEA, HATU, DMF; (ii) BCl3, CH2Cl2,
(ω) about the N3-C4 bond.
-
-
78 °C, 30% yield for two steps; (iii) DIPEA, CH2Cl2; (iv) BCl3, CH2Cl2,
78 °C, 30-50% yield for two steps.
A trans conformation for these compounds is expected to be
58
favored at low pH, because the potential exists for the carbonyl
oxygen atom to interact with the boronic acid group. For
example, in the trans-OB conformation the boron and carbonyl
oxygen atoms are in relatively close proximity. If a B-O dative
bond forms, the increased coordination of the boron atom in
the resulting five-membered ring structure will be observed in
TABLE 1. 11B NMR Chemical Shifts, δ (in ppm), Relative to
Boric Acid for Compounds 1a-f and 2a-f at High and Low Values
of the pH, Recorded in 90% D2O/H2O at 25 °C
compd
δ (pH)
δ (pH)
compd
δ (pH)
δ (pH)
1
1
1
1
a
b
c
+7.6 (1.1) -17.1 (12.0)
-5.8 (1.0) -16.9 (10.0)
-5.8 (1.5) -16.7 (10.2)
2a
2b
2c
2d
-3.4 (1.2) -17.0 (12.0)
-10.8 (1.3) -16.9 (12.0)
-10.8 (1.7) -16.9 (12.0)
-11.4 (1.2) -16.6 (12.0)
11
46,47,59
the B spectrum.
For some of the R-amidoboronic acids
in this study, however, computations show that a trans-OB form
can be a local minimum on the PES, even though the B-O
distance is quite long (>∼2.4 Å) (vide infra); experimental B-O
dative bond lengths in boronate esters are much shorter, 1.56-
d
-8. (1.2)
-16.9 (12.0)
-
11.3 (12.0)
1
1
e
f
+10.6 (1.4) -17.2 (9.7)
-3.7 (1.6) -16.8 (12.5)
2e
2f
+8.9 (1.9) -17.8 (12.0)
-10.1 (1.3) -16.6 (12.4)
25-27
1.64 Å.
In a trans-OB conformer with a long B-O distance,
it seems more appropriate to describe the boron-oxygen
interaction as an electrostatic attraction between the positively
charged boron and the negatively charged oxygen atoms, rather
than as a B-O dative bond. In the trans-OH conformation an
H‚‚‚O hydrogen bond is part of a seven-membered ring and
the boron atom is tricoordinated. This type of motif for a boronic
1
. Acylation of the pinanediol ester of boroGly or boroSar with
acetyl chloride, propanoyl chloride, pivaloyl chloride, or benzoyl
chloride, followed by deprotection gave 1b-d, 1f, 2b-d, and
2f respectively as shown in Scheme 1. Reaction of the pinanediol
ester of boroGly or boroSar and trifluoroacetic anhydride with
subsequent treatment with boron trichloride gave 1e and 2e as
depicted in Scheme 1. It should be pointed out that the
compounds containing a trifluroacyl amide moiety are unstable
at high pH,
facilitates basic hydrolysis.
Spectroscopic and Computational Results. The 11B and H
NMR chemical shifts for the boronic acid derivatives synthe-
sized in this study are listed in Tables 1 and 2, respectively, at
both high and low values of the pH.
6
0
acid has been observed recently by Zhao et al. in the solid
5
1
phase and has been predicted by Bhat et al. in computational
studies performed in the gas phase; its role on the inhibitory
potency of boronic acid dipeptides is not well understood.
We consider first the parent compound, N-formylglycine
4
2-44
because the electron-withdrawing CF3 group
1
11
boronic acid 1a (R1 ) R2 ) H), for which the B chemical
shift relative to boric acid is +7.6 ppm at pH 1.1 compared to
1
11
-
17.1 ppm at pH 12.0, see Table 1; H 300 MHz and B 300
It is well established that the 11B chemical shifts for
tetracoordinated boron species appear at several tens of ppm
upfield compared to the corresponding tricoordinated
(
49) Bhat, K. L.; Hayik, S.; Bock, C. W. J. Mol. Struct. (THEOCHEM)
2003, 638, 107.
50) Bhat, K. L.; Hayik, S.; Corvo, J. N.; Maryck, D. M.; Bock, C. W.
J. Mol. Struct. (THEOCHEM) 2004, 673, 145.
51) Bhat, K. L.; Braz, V.; Laverty, E.; Bock, C. W. J. Mol. Struct.
(
2
5,45-48
species,
e.g., for n-butylboronic acid at pH values from
(
1
.0 to 7.3, where the boron atom is expected to be entirely
(THEOCHEM) 2004, 712, 9.
(52) Bhat, K. L.; Howard, N. J.; Rostami, H.; Lai, J. H.; Bock, C. W. J.
Mol. Struct. (THEOCHEM) 2005, 723, 147.
1
1
tricoordinated, the B chemical shift is +13.8 ppm relative to
boric acid, whereas at pH 13.4, where the boron is expected to
be tetracoordinated as a result of borate ion formation, the shift
(
53) Lai, J. H.; Zhou, Y.; Sudmeier, J. L.; Wu, W.; Sanford, D. G.;
Hliang, M.; Poplawski, S.; Bachovchin, W. W. AdV. Exp. Med. Biol. 2003,
524, 333.
2
4
11
is -14.7 ppm. As can be seen from Table 1, the B shifts at
(54) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J.
Am. Chem. Soc. 1985, 107, 3902.
(55) Dewar, M. J. S.; Jie, C.; Zoebish, E. G. Organometalics 1988, 7,
513.
(
(
42) Imazawa, M.; Eckstein, F. J. Org. Chem. 1979, 44 (12), 2039.
43) Albanese, D.; Corcella, F.; Landini, D.; Maia, A.; Penso, M. J. Chem.
(56) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209.
(57) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 221.
(58) Williams, K. B.; Adhyarle, B.; German, I.; Alverez, E. J. Chem.
Edu. 2002, 79 (3), 37.
therein.
(59) Draffin, S. P.; Duggan, P. J.; Duggan, S. A. Org. Lett. 2001, 3,
917.
(
47) Singhai, R. P.; Ramamurthy, B.; Govindraj, N.; Sarwar, Y. J.
(60) Zhao, J.; Davidson, M. G.; Mahon, M. F.; Kociok-K o¨ hn, G.; James,
T. D. J. Am. Chem. Soc. 2004, 126, 16179.
514 J. Org. Chem., Vol. 71, No. 2, 2006

Internally Coordinated R-Amidoboronic Acids
TABLE 2. 1H NMR Chemical Shifts, δ (in ppm), for Compounds 1a-f and 2a-f at High and Low Values of the pH Recorded in 90%
D2O/10% H2O at 25 °C
R-H
R-H
N-Me
compd
δ (pH)
δ (pH)
compd
δ (pH)
δ (pH)
δ (pH)
δ (pH)
1
1
a
2.66(s) (1.1)
2.20(s) (12.1)
2a
2.41(s) (1.2)
2.41(s) (12.1)
3.11(s) (1.2)
3.01(s) (12.1)
2.87(s) (12.1)
2.91(s) (11.8)
2.38(s) (12.1)
b
2.36(s) (1.0)
2.14(s) (10.7)
2b
2.39(s) (1.3)
2.80(s) (12.0)
3.14(s) (1.3)
3.07(s) (11.8)
1
1
1
c
d
e
2.34(s) (1.5)
2.31(s) (1.2)
2.60(s) (1.4)
2.14(s) (10.2)
2.13(s) (12.0)
2.31(s) (9.7)
2c
2d
2e
2.41(s) (1.6)
2.49(s) (1.2)
2.70(s) (1.9)
2.39(s) (10.2)
2.45(s) (12.0)
1.97(s) (12.0)
2.28(s) (12.0)
3.13(s) (1.6)
3.31(s) (1.2)
3.23(s) (1.9)
3.04(s) (1.9)
3.16(s) (10.2)
3.30(s) (12.0)
3.20(s) (12.2)
2.68(s) (12.2)
2.60(s) (12.2)
3.00(s) (12.4)
3.14(s) (12.4)
2.63(s) (1.9)
2.90(s) (1.9)
1
f
2.60(s) (1.6)
2.38(s) (12.5)
2f
2.65(s) (1.3)
2.48(s) (12.4)
3.27(s) (1.3)
2.70(s) (12.4)
were initiated with B-O distances consistent with the presence
2
5-27
of a dative bond,
2
the resulting B-O distances, 2.56 and
.71 Å in the gas and aqueous phase, respectively, are quite
long, and the boronic acid moiety is essentially planar (sp ).
Thus, we find no evidence for a dative-bonded conformer of
2
1
a.
Since no data are available concerning the relative stabilities
of various conformers of 1a we also optimized cis, trans, and
trans-OH forms, see Figure 2, at the same computational level.
The relative energies of the resulting structures, both in vacuo
and in aqueous media, along with a few selected geometrical
parameters, are listed in Table 3.
Interestingly, the hydrogen-bonded seven-membered-ring
trans-OH conformer of 1a has the lowest energy, both in vacuo
5
1,60
and in aqueous media.
The calculated O‚‚‚H(O) bond
lengths, 1.84 and 1.75 Å, respectively, and the corresponding
O‚‚‚H-O bond angles, 154.1° and 158.6°, in this conformer
are consistent with a relatively strong hydrogen bond.67 Both
the trans and trans-OB conformers are ∼3.4 kcal/mol higher
in energy than the trans-OH conformer in the gas phase, and
FIGURE 2. Conformations of the :OdC-N-C-B backbone of
N-acetylborosarcosine, 2b.
∼
1.5 kcal/mol higher in solution. Thus, not only is there no
B-O dative bond in the trans-OB conformer, it is not even the
MHz spectra of 1a are shown in Figures 1S-3S of the
Supporting Information. The fact that this 11B shift is positive
at low pH clearly suggests that the boron atom in 1a is
predominantly tricoordinated in acidic media. To further cor-
roborate this conclusion, we optimized the geometry of a trans-
OB conformer of 1a in vacuo and in aqueous media using
global minimum on the PES.
Turning to the other boronic acids synthesized in this study,
we note that incorporating a methyl group in 1a at either the
acyl carbon, to give N-acetylglycine boronic acid 1b, or the
nitrogen, to give N-formylborosarcosine 2a, results in an upfield
shift relative to 1a in the B signal at low pHsthe resulting
values of δ are negative, -5.8 and -3.4 ppm, respectively, see
Table 1. Indeed, incorporating a methyl group at both the acyl
carbon atom and the nitrogen atom to give N-acetylborosarcosine
61
second-order Møller-Plesset (MP2) perturbation theory at the
1
1
MP2/6-311++G** computational level. The GAUSSIAN 03
suite of programs62 was employed for the calculations in this
study, and self-consistent reaction field (SCRF) methods with
63-66
an IEF polarizable continuum model (PCM)
were used for
2
b leads to a further upfield shiftcsthe value of δ is -10.8
the optimizations in aqueous media. Although the optimizations
1
1
ppm; B 300 MHz NMR spectra of 2b are shown in Figures
S and 5S of the Supporting Information. Lengthening the chain
4
(
61) Møller, C.; Plesset, M. S. Phys. ReV. 1934, 46, 618.
(62) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
at the carbon in 1b and 2b from methyl to ethyl groups, giving
1c and 2c, respectively, has virtually no effect on the chemical
shift, although increasing the bulky nature of the group at the
carbon in 1b and 2b from Me to t-Bu, giving 1d and 2d,
respectively, does lead to a small additional upfield shift.
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez C.; Pople, J. A. GAUSSIAN 03;
Gaussian, Inc.: Pittsburgh, PA, 2003.
(63) Cances, M. T.; Mennucci, B.; Tomasi, J. Chem. Phys. 1997, 107,
3032.
(64) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem. Phys. Lett.
1998, 286, 253.
(65) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151.
(66) Cossi, M.; Scalmoni, G.; Rega, N.; Barone, V. J. Chem. Phys. 2002,
117, 43.
(67) Kyte, J. Structure in Protein Chemistry; Garland: New York, 1995;
p 165.
J. Org. Chem, Vol. 71, No. 2, 2006 515

Lai et al.
TABLE 3. MP2(FULL)/6-311++G**//MP2(FULL)/6-311++G** Relative Energies, Erel (kcal/mol), and Selected Structural Parametersa
vacuo aqueous media (SCRF)
compd
compd/conf
Erel
B-O
τCNCX
τCNCB
Erel
B-O
τCNCX
τCNCB
1
a
cis
trans
trans-OB
trans-OH
cis
trans-OB
trans-OH
cis
trans-OB
trans-OH
cis
trans-OB
trans-OH
cis
trans-OB
trans-OH
cis
+6.52
+3.34
+3.50
+0.00
+9.24
+3.26
+0.00
+6.19
+2.81
+0.00
+6.03
+1.29
+0.00
+8.19
+2.50
+0.00
+3.77
+1.99
+0.00
4.804
4.360
2.561
3.164
4.267
2.417
3.133
4.696
2.410
3.150
4.265
1.733
3.099
4.343
2.656
3.182
4.320
2.473
3.139
0.0
180.0
180.0
41.4
64.5
-66.5
37.4
66.6
120.9
36.3
70.9
-75.7
14.8
75.0
-74.1
45.9
67.1
-76.6
44.7
+3.82
+1.60
+1.45
+0.00
+6.32
+0.00
+1.10
+3.87
+0.00
+1.18
+6.66
+0.00
+4.07
+5.41
+0.31
+0.00
+1.05
+0.00
+0.11
4.800
4.384
2.707
3.162
4.368
1.661
3.132
4.598
1.675
3.148
4.288
1.640
3.097
4.455
2.820
3.193
4.389
2.600
3.146
0.0
176.2b
179.8
47.6
180.0
178.3
172.4
-19.6
179.5
172.1
-3.6
177.5
175.2
-19.4
177.5
171.9
-16.6
-179.1
174.7
-16.6
178.9
174.1
179.9
-176.9
173.2
-10.9
179.3
172.8
1.6
179.2
175.2
-16.6
178.6
172.4
-8.2
63.6
c
1
2
2
1
2
b
a
b
e
-73.1
4.0
65.7
110.1
3.4
c
69.7
c
-78.5
4.5
73.7
-81.4
53.0
67.3
-85.7
50.0
c
179.6
175.1
-12.9
178.5
173.5
c
e
trans-OB
trans-OH
76.2
75.5
a
b
The B-O distance is in Å, and the τCNCX (X ) H, C) and τCNCB torsional angles are in deg.) Frequency analyses at several computational levels using
density functional theory suggest that this conformer is a first-order transition state. c No trans acyclic form could be found on the PES.
Substitution of a phenyl group at the acyl carbon to give 1f
these calculated results provide additional support for our
experimental findings.
11
and 2f also results in a negative B chemical shift. These
negative 11B shifts at low pH certainly suggest greater tetra-
coordination of the boron atoms in compounds 1b-d, 1f, 2a-
d, and 2f compared to that found in 1a.
To determine whether calculations also support the presence
of a B-O dative bond in the amidoboronic acids discussed
above, we optimized the geometry of several conformers of 1b,
To assess the effect of introducing an electron-withdrawing
group on the formyl carbon atom, we synthesized trifluoroacyl
glycine boronic acid, 1e, and its sarcosine analogue, 2e, in which
the appropriate hydrogen atom in 1a and 2a was replaced by a
1
trifluoromethyl group; the H 300 MHz spectrum of 2e is shown
in Figure 6S of the Supporting Information. At low values of
2
a, and 2b at the MP2/6-311++G** computational level; the
11
the pH, the observed B shifts are positive, +10.6 and +8.9
relative energies are listed in Table 3. When the optimization
of 2b is initiated from a trans-OB geometry, the resulting B-O
distances, 1.73 and 1.64 Å in vacuo and in aqueous media,
respectively, are much shorter than the corresponding distances
in 1a, and the local environment about the boron atom has
significant tetrahedral character as measured by the H o¨ pft
ppm, respectively, see Table 1. This suggests that there is no
intramolecular B-O dative bond present in either of these
compounds. We also optimized the geometries of several
conformers of 1e and 2e at the MP2/6-311++G** computa-
tional level. The trans-OB forms have very long B-O distances,
2
2
.66 Å in vacuo and 2.82 Å in aqueous solution for 1e, and
.47 and 2.60 Å for 2e. Furthermore, in aqueous media the trans-
6
8
index; the values of THCDA are 52.1% and 65.7% in vacuo
and in aquous media, respectively. Furthermore, the calculated
NPA charge distribution in this conformer of 2b shows a transfer
of electron density from the carbonyl oxygen atom to the boron
atom, and NBO analyses (HF level) clearly identify a B-O
dative bonding orbital. Although in vacuo the trans-OB form
of 2b is 2.8 kcal/mol higher in energy than the trans-OH form,
in aqueous media the trans-OB form is 4.1 kcal/mol lower in
energy than the trans-OH form. Thus, in aqueous media the
lowest energy form of 2b has an intramolecular B-O dative
OB conformer of 1e not the global minimum on the MP2 PES
and for 2e the trans-OB and trans-OH conformers are very close
in energy. Thus, these computational results are in accord with
our experimental observations.
Finally, to illustrate the complex acid-base equilibria in-
volved with an R-amidoboronic acid containing an intramlecular
1
B-O dative bond, a set of 1D 300 MHz H NMR spectra of
2
b in 90% H2O/10% D2O at 25 °C and at different values of
bond, consistent with the observed upfield 11B chemical shifts
of 2b relative to that of 1a.
the pH were recorded, see Figure 3A; the corresponding 2D
1
1
H/ H NOESY spectrum is shown in Figure 3B. At low values
1
1
1
1
of the pH, 2D H/ H COSY and H/ H NOESY spectra indicate
that the species labeled A in Figure 3A has a trans C2-N3-C4-C5
linkage. Although it is not possible to unambiguously identify
the specific trans conformer(s) involved from these experiments,
In vacuo the calculated B-O distance for the trans-OB forms
of 1b and 2a are quite long (>2.4 Å) and the trans-OH form is
lower in energy, see Table 3. In contrast, when the optimizations
are performed in aqueous media the resulting B-O distances
are much shorter (<1.7 Å), consistent with the presence of a
B-O dative bond.2 Furthermore, the trans-OB form is lower
in energy than the trans-OH form. It is interesting that in
aqueous solution the length of the B-O dative bond in both 1b
and 2a is slightly longer than it is in 2b, which correlates well
with the lower upfield 11B chemical shifts of 1b and 2a
compared to that of 2b, see Table 1. Thus, in aqueous media
1
1
the large upfield B chemical shift observed for 2b at low pH,
in conjunction with the results of our MP2 optimizations,
strongly suggests that the trans-OB conformer is present. Of
course, as the pH increases above ∼9, boronate ion formation
becomes a competitive process. There is an upfield shift in the
signal from the N-CH3 protons of A, a result of the rapid
exchange between A and a trans form, B, of the associated
boronate ion, see Scheme 2. Furthermore, a cis form of this
borate ion, C, is also evident in Figure 3A; C is in slow
5,27
(68) H o¨ pft, H. J. Organomet. Chem. 1999, 581, 129.
516 J. Org. Chem., Vol. 71, No. 2, 2006

Internally Coordinated R-Amidoboronic Acids
T C
SCHEME 2. Summary of the Microscopic (pk and pk )
and Macroscopic (pK2b) Acid-Base Equilibrium Constants
and pH-Dependent Structural Changes Involved with 2b
SCHEME 3. Proposed Mechanism for Alkali Hydrolysis of
2b
Interestingly, 2b was readily hydrolyzed and deboronated into
1
acetic acid and dimethylamine at high pH, as confirmed by H
NMR (data not shown). On the basis of the rate of the
disappearance of the N-methyl peaks and the appearance of acyl
1
methyl peaks in the H NMR spectra, the half-life of decom-
position is ∼48 h at room temperature. The instability of 2b at
high pH suggests that the dative-bonded trans-OB conformer
plays a catalytic role in enhancing the rate of amide hydrolysis
via the mechanism shown in Scheme 3.
Conclusions
A collection of simple N-acyl-boroGly derivatives and their
1
1
boroSar analogues have been synthesized, characterized by
B
1
and H NMR spectroscopy, and studied computationally with
second-order Møller-Plesset perturbation theory. Each of these
R-amidoboronic acids is amenable to the formation of an
intramolecular B-O dative bond in the context of a five-
1
1
membered (:O-C-N-C-B) ring motif. The B chemical
shifts observed for the compounds in this study at high values
of pH, δAVE ) -16.9 ( 0.4 ppm, reflect their common
1
FIGURE 3. (A) Stack plot of 1D H 300 MHz NMR spectra of 2b in
35-38
9
0% H
2
O/10% D
2
O at 25 °C and various values of the pH. Forms A,
tetracoordinated borate ion structure in basic media,
whereas
B, and C are described in the text; decomposition products are indicated
at low values of pH, the corresponding chemical shifts range
from -11.4 to +10.6 ppm, suggesting a variety of possible
boron environments in acidic media. For the parent compound,
N-formylglycine boronic acid 1a, and the trifluoro derivatives
1
1
with an asterisk. (B) 2D H/ H NOESY spectrum of 2b at pH ∼2. The
NOE peaks between H-b and H-c indicate a trans conformer.
exchange with A, and the ratio of the species A to C decreases
as the pH increases; the ratio of B:C is 4:3 at pH 11.3.
The microscopic equilibrium constant, pkT, was obtained by
measuring the N-methyl chemical shifts in the interval between
B and A. At pH 11.3 the N-methyl shifts were at their titration
midpoint, which leads to a value of 11.3 for pkT. Knowing that
forms B and C are in the ratio of 4:3 at that pH leads to a
microscopic equilibrium constant, pkC, of 11.4, which is larger
than pkT by log 0.1. The sum of microscopic equilibrium
constants kT and kC leads to a macroscopic constant, K2b, for
which pK2b is 11.0.
1
1
1e and 2e, positive B chemical shifts indicate that there are
no B-O dative-bonded conformers present in acidic media.
Calculations at the MP2(FULL)/6-311++G** computational
level in vacuo and in aqueous media also find no evidence for
a dative-bonded conformer on the PES. However, substitution
of electron donating groups on the acyl carbon and/or nitrogen
1
1
atoms leads to compounds with upfield B shifts in acidic
media, indicating tetracoodination of the boron atom as a result
of intramolecular B-O dative bond formation. Calculations in
aqueous media find similar results.
J. Org. Chem, Vol. 71, No. 2, 2006 517

Lai et al.
+
In vacuo, our MP2(FULL)/6-311++G** calculations con-
sistently find that the seven-membered hydrogen-bonded ring
structure, trans-OH, is the lowest energy conformer of the
R-amidoboronic acids in this study. In aqueous media, however,
when a B-O dative bond forms, it is the five-membered trans-
OB conformer that is often lowest in energy, although the SCRF
energy differences between the trans-OB and trans-OH con-
formers in these cases is usually quite small. The competition
between trans-OH and trans-OB forms and its influence on the
inhibitory potency of boronic acid dipeptides need to be further
addressed.
50), 227.1 ([2 × (M - H
2
O) + H] , 82), 114.3 ([M - H
2
O +
+
+
H] , 100); tr ) 4.8 min; HRMS calcd for C
4
H
9
BNO
2
[MH
-
H
2
O] 114.0726, found 114.0730.
N-(2,2-Dimethyl-propionyl)-boroGly 1d. H NMR (D
.21 (9H, s, -CMe ), 2.31(2H, s, -NCH
B-); 13C NMR (D
u) 28.3, 37.5, 38.0, 188.0; 11B NMR (D
1
2
O) δ
2
O) δ
1
3
2
(
2
O, pH 1.76) δ -7.9; LC-
MS (ESI+) for C
6
H14BNO
3
m/z (rel intensity) 424.3 ([3 × (M -
+
+
H
2
O) + H] , 2), 283.2 ([2 × (M - H
2
O) + H] , 31), 142.2 ([M
+
-
H
2
6 2
O + H] , 100); tr ) 9.6 min; HRMS calcd for C H13BNO
+
[MH - H
2
O] 142.1039, found 142.1044.
1
N-Benzoyl-boroGly 1f. H NMR (D O) δ 2.60 (2H, s,
2
-NCH
J ) 7.3 Hz, Ar-H), 7.88 (2H, d, J ) 7.6 Hz, Ar-H); C NMR
O) δ (u) 36.7, 130.0, 130.5, 131.4, 136.4, 174.6; 11B NMR (D
O,
pH 1.58) δ -3.7; LC-MS (ESI+) for C m/z (rel intensity)
2
B-), 7.64 (2H, dd, J ) 7.3, 7.6 Hz, Ar-H), 7.71 (1H, d,
13
(D
2
2
Experimental Section
8 3
H10BNO
+
+
N-Formyl-boroGly 1a. To a stirred solution of (+)-pinanediol-
-(N-methylamino)-1-methyl boronate hydrochloride (H-boroGly-
323.1 ([2 × (M - H
2
O) + H] , 16), 162.1 ([M - H O + H] ,
100); tr ) 12.9 min; HRMS calcd for C
2
+
1
H
8 9
BNO
2
2
[MH - H O]
pn‚HCl) (245 mg, 1 mmol) and formic acid (60 mg, 96%, 1.2 mmol)
in anhydrous DMF (3 mL) was added HATU (400 mg, 1.05 mmol)
at 0 °C under argon atmosphere. To this solution was added N,N-
diisopropylethylamine (DIPEA, 0.4 mL, 99.5%, 2.3 mmol) and the
mixture was stirred overnight. DMF was removed under reduced
pressure and the residue was dissolved in ethyl acetate (100 mL),
162.0726, found 162.0726.
N-2,2,2-Trifluoroacetyl-boroGly 1e. To an ice cold solution
of H-boroGly-pn‚HCl (245 mg, 1 mmol) and trifluoroacetic
anhydride (210 mg, 99+%, 1 mmol) in anhydrous dichloromethane
(10 mL) was added DIPEA (0.4 mL, 99.5%, 2.3 mmol) under argon
and then the solution was stirred for 3 h. The reaction mixture was
concentrated to a small volume (2-3 mL) and the product TFAc-
boroGly-pn was isolated by column chromatography on silica gel
with ethyl acetate-methanol (5:1) as eluant.
The above product was dissolved in anhydrous dichloromethane
3
(5 mL) then cooled to -78 °C, and BCl in dichloromethane (2
mL, 1.0 M) was added; the reaction mixture was stirred for 1 h. It
was then evaporated to dryness under reduced pressure and
coevaporated with anhydrous methanol (2 × 5 mL), and the residue
was partitioned between water (20 mL) and ether (30 mL). The
washed sequentially with KHSO
4
(0.1 m, 3 × 15 mL), NaHCO
3
(
5%, 3 × 10 mL), and brine (3 × 10 mL), and dried (MgSO4).
Removal of solvent afforded the crude HCO-boroGly-pn, which
was used without further purification. To the crude HCO-boroGly-
pn dissolved in anhydrous dichloromethane (5 mL), cooled to -78
°
C, was added a solution of boron trichloride (2 mL, 1.0 M) in
dichloromethane (2 mL) and the mixture was then stirred for 1 h.
The reaction mixture was evaporated to dryness under reduced
pressure and coevaporated with anhydrous methanol (2 × 5 mL).
The residue was then partitioned between water (20 mL) and ether
product TFAc-boroGly-OH was isolated as a white powder from
the aqueous layer with HPLC (yield: 32%). H NMR (D
1
(
2
30 mL) and the product was isolated as a white powder (yield:
5%), using HPLC from the aqueous layer after lyophilization. H
2
O) δ
1
11
2.60(2H, s, -NCH
2
2
B-); B NMR (D O, pH 1.44) δ 10.6; LC-
NMR (D O, pH 1.02) δ 2.66 (2H, s, -NCH B-), 8.05 (1H, s,
2
2
MS (ESI+) for C
3
H
5
F
3
BNO
3
m/z (rel intensity) 307.0 ([2 × (M -
13
11
+
+
HCO-); C NMR (D
2
O) δ (u) 29.9, 167.7; B NMR (D
2
O, pH
H
2
O) + H] , 18), 154.0 ([M - H
2
O + H] , 100); tr ) 7.0 min.
1
2
.06) δ 10.4; LC-MS (ESI+) for C
2
H
6
BNO m/z (rel intensity)
3
N-Formyl-boroSar 2a. This compound was prepared following
+
56.0 ([3 × (M - H
2
O) + H] , 100), 171.1 ([2 × (M - H
2
O) +
the same procedure as described for 1a but with H-boroSar-pn‚
+
+
HCl as the starting material. 1H NMR (D O) δ 2.41 (2H, s,
H] , 99), 86.3 ([M - H
2
O + H] , 84); tr ) 3.4 min.
2
13
General Procedure for the Preparation of 1b-1d and 1f. To
an ice-cold solution of H-boroGly-pn‚HCl (245 mg, 1 mmol) and
-NCH
(D
O) δ (u) 38.8, 42.9, 167.8; 1 B NMR (D
LC-MS (ESI+) for C
2
B-), 3.11 (3H, s, -NCH1
3
), 7.92 (1H, s, HCO-); C NMR
2
2
O, pH 1.17) δ -3.4;
RCOCl (R ) CH
3
, C
2 5
H , CMe
3
or C
H
6 5
) in anhydrous dichloro-
3 8
H BNO
3
m/z (rel intensity) 298.1 ([3 × (M
+
+
methane (10 mL) was added N,N-diisopropylethylamine (0.4 mL,
9.5%, 2.3 mmol) under argon and the solution was stirred for 3
h. The reaction mixture was then diluted with ethyl acetate (100
mL) and washed with KHSO (5%,
(0.1 m, 3 × 15 mL), NaHCO
), and
- H
2
O) + H] , 53), 199.1 ([2 × (M - H
2
O) + H] , 100), 100.3
+
9
([M - H
2
O + H] , 32); tr ) 4.4 min; HRMS calcd for C
3 9 3
H BON
+
[MH ] 118.0675, found 118.0672.
4
3
General Procedures for the Preparation of 2b-d and 2f.
These compounds were prepared following the same procedure that
was used for 1b-d and 1f but with H-boroSar-pn‚HCl as the
starting material.
3
× 10 mL), and brine (3 × 10 mL), dried (MgSO
4
concentrated to dryness to afford the crude RCO-boro-Gly-pn. The
crude product was dissolved in anhydrous dichloromethane (5 mL),
the solution was cooled to -78 °C, and boron trichloride in
dichloromethane (5 mL, 5 mmol) was added. The reaction mixture
was stirred for 1 h. It was then evaporated to dryness and
coevaporated by adding anhydrous methanol (2 × 5 mL). The
residue was partitioned between water (20 mL) and ether (30 mL).
The product RCO-boroGly-OH was isolated from the aqueous layer
1
N-Acetyl-boroSar 2b. H NMR (D O) δ 2.18 (3H, s,
2
1
3
CH CO-), 2.39 (2H, s, -NCH B-), 3.14 (3H, s, -NCH );
3
2
3
C
11
NMR (D O) δ (u) 17.1, 38.7, 47.7, 177.6; B NMR (D O, pH
2
2
1.30) δ -10.80; LC-MS (ESI+) for C H BNO m/z (rel intensity)
4
10
3
+
340.1 ([3 × (M - H O) + H] , 100), 227.1 ([2 × (M - H O) +
2
2
+
+
H] , 98), 114.3 ([M - H O + H] , 98); tr ) 4.8 min; HRMS
2
+
as a white powder after lypophilization with HPLC.
calcd for C H BNO [MH - H O] 114.0726, found 114.0731.
4
9
2
2
1
1
N-Acetyl-boroGly 1b. H NMR (D
2
O) δ 2.10 (3H, s,
B-); 13C NMR (D
O) δ (u) 19.1,
O, pH 0.99) δ -5.6; LC-MS (ESI+) for
N-Propionyl-boroSar 2c. H NMR (D
2
O) δ 1.14 (3H, t, J )
CH
3
CO-), 2.36 (2H, s, -NCH
2
2
7.6 Hz, CH
7.6 Hz, CH
10.8, 24.0, 38.2, 48.0, 180.8; B NMR (D
3
CH
2
-), 2.41 (2H, s, -NCH
2
B-), 2.51 (2H, q, J )
7.5, 179.7; 11B NMR (D
13
3
C
1
5
1
2
3
CH
2
-), 3.13 (3H, s, -NCH
3
); C NMR (D
2
O) δ (u)
+
11
3
H
8
BNO
3
m/z (rel intensity) 298.1 ([3 × (M - H
2
O) + H] , 100),
2
O, pH 1.26) δ -10.8;
+
+
99.2 ([2 × (M - H
2
O) + H] , 79), 100.4 ([M - H
2
O + H] ,
LC-MS (ESI+) for C
5
H12BNO
3
m/z (rel intensity) 382.2 ([3 × (M
+
+
+
1); tr ) 4.2 min; HRMS calcd for C
3
H
7
BNO
2
[MH - H
2
O]
- H
2
O) + H] , 48), 255.1 ([2 × (M - H
2
O) + H] , 74), 128.2
+
00.0570, found 100.0571.
([M - H
2
O + H] , 100); tr ) 5.9 min; HRMS calcd for
1
+
N-Propionyl-boroGly 1c. H NMR (D
2
O, pH 1.49) δ 1.14 (3H,
B-), 2.41 (2H, q, J
O) δ (u) 11.1, 26.8, 36.7,
C
5
H
11BNO
2
[MH - H
N-(2,2-Dimethylpropionyl)-boroSar 2d. H NMR (D
(9H, s, (CH C-), 2.49 (2H, s, -NCH B-), 3.31 (3H, s, -NCH
O) δ (u) 28.9, 37.9, 40.3, 52.6, 184.6; B NMR (D
pH 1.22) δ -11.4; LC-MS (ESI+) for C m/z (rel
2
O] 128.0883, found 128.0884.
1
t, J ) 7.6 Hz, CH
3
CH
2
-), 2.34(2H, s, -NCH
2
2
O) δ 1.31
);
O,
)
1
C
7.6 Hz, CH CH
3
2
-); 13C NMR (D
2
3
)
3
2
3
82.9; 11B NMR (D
O, pH 1.49) δ -5.8; LC-MS (ESI+) for
13
C NMR (D
11
2
2
2
+
4
H10BNO
3
m/z (rel intensity) 340.2 ([3 × (M - H
2
O) + H] ,
7 3
H16BNO
518 J. Org. Chem., Vol. 71, No. 2, 2006

Internally Coordinated R-Amidoboronic Acids
+
intensity) 466.3 ([3 × (M - H
2
O) + H] , 5), 311.2 ([2 × (M -
(ESI+) for C
4
H
7
F
3
BNO
3
m/z (rel intensity) 502.1 ([3 × (M - H
2
O)
+
+
+
+
H
2
O) + H] , 24), 156.1 ([M - H
2
O + H] , 100); tr ) 12.3 min;
[MH - H
+ H] , 4), 335.1 ([2 × (M - H
2
O) + H] , 100), 168.4 ([M -
+
+
HRMS calcd for C
7
H
15BNO
2
2
O] 156.1196, found
H
2
O + H] , 55); tr ) 12.1 min; HRMS calcd for C
H
4 6
3
F BNO
2
+
1
56.1201.
N-Benzoyl-boroSar 2f. H NMR (D
NCH B-), 3.27 (3H, s, -NCH
), 7.64-7.70 (5H, m, Ar-H); 13
O) δ (u) 40.5, 49.2, 129.1, 131.0, 131.5, 135.4, 175.3;
2
[MH - H O] 168.0444, found 168.0451.
1
2
O) δ 2.65 (2H, s,
-
2
3
C
Acknowledgment. One of the authors (K.L.B) would like
to thank the National Textile Center (CO3-PH01) for financial
support of this work.
NMR (D
2
11
B NMR (D
2
9 3
O, pH 1.34) δ -10.0; LC-MS (ESI+) for C H12BNO
+
m/z (rel intensity) 351.1 ([2 × (M - H
2
O) + H] , 7), 216.0 ([ M
+
+
+
Na] , 4), 176.0 ([M - H
2
+
O + H] , 100); tr ) 12.8 min; HRMS
Supporting Information Available: General analytical chemi-
cal procedures, characterization data of all target compounds 1a-
calcd for C
9
H
11BNO
2
2
[MH - H O] 176.0883, found 176.0889.
N-2,2,2-Trifluoroacetyl-boroSar 2e. This compound was pre-
1
13
11
f, 2a-f ( H NMR, C NMR, B NMR, LC-MS), selected stack-
plot NMR spectra, and pdb files. This material is available free of
charge via the Internet at http://pubs.acs.org.
pared by using the same procedure that was used for 1e but with
1
H-boroSar-pn‚HCl. H NMR (D
2
O) δ two isomers, 2.63 (2H, s,
); and 2.70 (2H, s, -NCH B-),
); B NMR (D O, pH 1.87, δ) 8.9; LC-MS
-
NCH
.23 (3H, s, NCH
2
B-), 2.90 (3H, s, -NCH
3
2
11
3
3
2
JO051757H
J. Org. Chem, Vol. 71, No. 2, 2006 519