A (-)-sparteine-directed highly enantioselective synthesis of boroproline. Solid- and solution-state structure and properties

Article abstract of DOI:10.1021/jo0708792

(Chemical Equation Presented) A two-step, direct asymmetric synthesis of the trifluoroacetate ammonium salt of boroproline is reported. (-)-Sparteine-mediated lithiation of N-Boc-pyrrolidine afforded N-Boc-aminoboronic acid in good yield and enantioselectivity as determined by HPLC (pinanediol ester). Deprotection using TFA yielded the ammonium salt; full characterization data are presented, and the structure in aqueous solution and the occurrence of a B-N species are discussed.

Full text of DOI:10.1021/jo0708792

A (-)-Sparteine-Directed Highly Enantioselective
Synthesis of Boroproline. Solid- and
toward fibroblast activation protein-R (FAP), DPP VII, or DPP
7
IV. There are also examples of type 1 and 2 enzyme inhibitors
of IgA proteinases from Neisseria gonorrheae and Hemophilus
Solution-State Structure and Properties
8
9
influenzae and bacterial microorganisms as well as activity
1
0
against fibroblast activation protein-R (FAP).
Our interests in aminoboronics are focused on the synthesis
Andrei S. Batsanov, Christophe Grosjean,
Thorben Sch u¨ tz, and Andrew Whiting*
of bifunctional aminoboronic acids of type 1 as potential
1
1
Chemistry Department, Durham UniVersity, Science
Laboratories, South Road, Durham DH1 3LE, U.K.
catalysts. For example, the use of 2 as an efficient catalyst
1
2
for amide bond formation and developments in the use of
1
3
organocatalysts such as proline attracted us to boroproline 3
as a novel bifunctional organic catalyst. In this paper, we report
a novel, simple, enantioselective synthesis of (S)-boroproline
using an asymmetric directed metalation and subsequent study
of structural and chemical properties.
andy.whiting@durham.ac.uk
ReceiVed April 26, 2007
8
The first report of boroproline 3 synthesis was based on
1
4
Matteson’s R-amido-δ-substituted boronates; however, non-
A two-step, direct asymmetric synthesis of the trifluoroac-
etate ammonium salt of boroproline is reported. (-)-
Sparteine-mediated lithiation of N-Boc-pyrrolidine afforded
N-Boc-aminoboronic acid in good yield and enantioselec-
tivity as determined by HPLC (pinanediol ester). Deprotec-
tion using TFA yielded the ammonium salt; full character-
ization data are presented, and the structure in aqueous
solution and the occurrence of a B-N species are discussed.
enantioselective lithiation approaches from either pyrrole or
15
pyrrolidine have been reported. Only pyrrolidine boronic esters
4a and/or 4b have been isolated via the intermediacy of N-Boc-
boronic acid 5; the actual aminoboronic acid 3 has not been
9
isolated or studied, and despite diastereomers 4b being isolated
and separated, no direct enantiomeric synthesis of boroproline
3 has been reported.
(
-)-Sparteine-mediated lithiation of N-Boc-pyrrolidine16,17
results in the formation of (S)-2-lithio-N-Boc-pyrrolidine, and
quenching with a range of electrophiles affords the correspond-
ing 2-substituted N-Boc-pyrrolidines, though not borate elec-
1
Since the report by Matteson on the synthesis of (R)-1-
acetamido-2-phenylethaneboronic acid (the boronic acid ana-
logue of N-acetyl-L-phenylalanine), boronic acid analogues of
amino acids and peptides have been used as enzyme inhibitors.
H-Boroproline, H-boroalanine, H-boroleucine, H-borovaline,
H-boronorleucine, and H-borophenylalanine are known to block
(6) (a) Flentke, G. R.; Munoz, E.; Huber, B. T.; Plaut, A. G.; Kettner,
C. A.; Bachovchin, W. W. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 1556-
1
8
559. (b) Gutheil, W. G.; Bachovchin, W. W. Biochemistry 1993, 32, 8723-
731. (c) 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, 12637-12638.
the enzymatic activity of Cryptosporidium parVum arginine
aminopeptidase (RAP).2 Proteasome inhibitors, based upon
(7) Hu, Y.; Ma, L.; Wu, M.; Wong, M. S.; Li, B.; Corral, S.; Yu, Z.;
Nomanbhoy, T.; Alemayehu, S.; Fuller, S. R.; Rosenblum, J. S.; Rozen-
krants, N.; Minimo, L. C.; Ripka, W. C.; Szardenings, A. K.; Kozarich, J.
W.; Shreder, K. R. Bioorg. Med. Chem. Lett. 2005, 15, 4239-4242.
(8) Bachovchin, W. W.; Plaut, A. G.; Flentke, G. R.; Lynch, M. J. Biol.
Chem. 1993, 265, 3738-3743.
3
boronic dipeptides such as PS-341 (Pyz-Phe-boroLeu), have
also proved to be more potent, selective, and stable than the
4
5
corresponding aldehydes and other natural products. Boropep-
tides based on boroproline, such as valine-boroproline or
(9) Gutheil, W. G. US5574017, 1996.
proline-boroproline, can be used as dipeptidyl peptidase IV
(10) Wallner, B. P.; Miller, G. WO 00/71135 A1, 2000.
(11) (a) Giles, R. L.; Howard, J. A. K.; Patrick, L. G. F.; Probert, M. R.;
Smith, G. E.; Whiting, A. J. Organomet. Chem. 2003, 680, 257-262. (b)
Coghlan, S. W.; Giles, R. L.; Howard, J. A. K.; Patrick, L. G. F.; Probert,
M. R.; Smith, G. E.; Whiting, A. J. Organomet. Chem. 2005, 690, 4784-
4793. (c) H e´ rault, D.; Aelvoet, K.; Blatch, A. J.; Al-Majid, A.; Smethurst,
C. A.; Whiting, A. J. Org. Chem. 2007, 72, 71-75.
6
(
DPP4, a serine protease) inhibitors, while some N-alkylgly-
cine-boroproline derivatives provide improved selectivity
(
1) Matteson, D. S.; Sadhu, K. M. J. Am. Chem. Soc. 1981, 103, 5241-
242.
2) Okkhuysen, P. S.; Chappell, C. L.; Kettner, C.; Sterling, C. R.
Antimicrob. Agents Chemother. 1996, 40, 2781-2784.
3) Palombella, V. J.; Conner, E. M.; Fuseler, J. W.; Destree, A.; Davis,
5
(
(12) Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.;
Whiting, A. AdV. Synth Catal. 2006, 348, 813-820.
(
(13) (a) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724. (b)
List, B. Chem. Commun. 2006, 819-824.
J. M.; Laroux, F. S.; Wolf, R. E.; Huang, J.; Brand, S.; Elliott, P. J.; Lazarus,
D.; McCormack, T.; Parent, L.; Stein, R.; Adams, J.; Grisham, M. B. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 15671-15676.
(14) Matteson, D. S.; Jesthi, P. K.; Sadhu, K. M. Organometallics 1984,
3, 1284-1288.
(
4) (a) Adams, J.; Stein, R. Annu. Rep. Med. Chem. 1996, 31, 279-288.
(15) (a) Kelly, T. A.; Fuchs, V. U.; Perry, C. W.; Snow, R. J. Tetrahedron
1993, 49, 1009-1016. (b) Snow, R.; Kelly, T. A.; Adams, J.; Coutts, S.;
Perry, C. WO93/10127, 1993. (c) 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, 2087-2094.
(
b) Adams, J.; Behnke, M.; Chen, S.; Cruickshank, A. A.; Dick, L. R.;
Grenier, L.; Klunder, J. M.; Ma, Y.-T.; Plamondon, L.; Stein, R. Bioorg.
Med. Chem. Lett. 1998, 8, 333-338.
(5) Dick, L. R.; Cruickshank, A. A.; Greniker, L.; Melandri, F. D.; Nunes,
S. L.; Stein, R. L. J. Biol. Chem. 1996, 271, 7273-7276.
10.1021/jo0708792 CCC: $37.00 © 2007 American Chemical Society
6
276
J. Org. Chem. 2007, 72, 6276-6279
Published on Web 07/12/2007

SCHEME 1. Synthesis of (S)-7 and
Pinanediol-Pyrrolidinylboronates 8
trophiles. However, TMEDA-mediated lithiation followed by
reaction with triisopropyl borate provides racemic boronic acid
FIGURE 1. X-ray structure of (S)-5, showing hydrogen bonds (50%
1
1
thermal ellipsoids). Symmetry transformations: 1 - x, y - /
primed), x - 1, y, z (double-primed). Absolute configuration assigned
by analogy with 9.
2 2
, / - z
1
5c
5.
The synthesis of boroproline was intially approached via
(
the N-Boc-protected pinacol boronate 6, which was thought
would enable isolation and purification. Hence, N-Boc-
pyrrolidine underwent (-)-sparteine-mediated lithiation, fol-
lowed by addition of isopropoxy pinacol borate to provide ester
6
(eq 1), presumably possessing the (S)-stereochemistry based
16
on (-)-sparteine’s usual enantioselection (vide infra). Several
subsequent attempts at simultaneous deprotection of N-Boc and
pinacol ester functions under acidic conditions, followed by
attempted isolation and purification using an ion-exchange resin
1
8
(Dowex) proved unsuccessful, and the free amino-boronic
derivative could not be isolated.
FIGURE 2. X-ray structure of (S)-9 (50% thermal ellipsoids).
(S)-5 was determined by formation of the (1S,2S)-hydrobenzoin
ester 9 (eq 2), which provided crystals which were suitable for
single-crystal X-ray analysis (Figure 2) and confirmed the (S)-
absolute configuration at C2 in 9 and, therefore, in the parent
compound (S)-5.
An alternative approach to boroproline 3 and its derivatives
was therefore examined as in Scheme 1. Racemic boronate 5
was prepared by the TMEDA-mediated lithiation of N-Boc-
pyrrolidine (27%) followed by esterification with (-)-pinanediol
to provide a 1:1 mixture diastereoisomers 8a and 8b (97%), as
confirmed by HPLC.19 The enantioselective synthesis of boronic
acid 5 was achieved using the (-)-sparteine-mediated lithiation
method to yield (S)-5 in good yield and with the presumed
absolute stereochemistry.16 Subsequent formation of the (-)-
pinanediol ester gave diastereosiomer 8b with 90% de according
to HPLC,19 hence confirming the high level of asymmetric
induction in the lithiation-boronation sequence providing
boronic acid (S)-5.
In both (S)-5 and 9 (Figures 1 and 2, respectively), the N1
2
atom is sp -hybridized due to π-conjugation with the carboxylic
group, as indicated by N1-C1 bond distances of 1.331(2) [(S)-
5
] and 1.341(2) Å (9), small (0.06 and 0.04 Å) deviations of
N1 from the C1/C2/C5 plane (A), and the dihedral angles of
.3° and 2.4° between the latter and the COO plane. The
5
pyrrolidine ring conformation is intermediate between a twist
and envelope conformation (C3 and C4 deviating from the A
plane in opposite directions, by 0.15 and -0.50 Å in (S)-5,
-
0.47 and 0.16 Å in 9) with the boronic substituent in a pseudo-
equatorial position. The boronate B is planar-trigonal, its plane
Having isolated the (-)-pinanediol ester 8b with the predicted
absolute stereochemistry (Scheme 1), attempts were made to
confirm the absolute stereochemistry of both boronic acid (S)-5
and pinanediol ester 8b by single-crystal X-ray analysis. These
attempts were unsuccessfull in the case of (S)-5 due to the lack
of a heavy atom to assist absolute stereochemical determination
inclined by 67° [(S)-5] or 75° (9) to the A plane.
(
see Figure 1) and, in the case of 8b, due to the lack of formation
Having obtained the protected pyrrolidineboronic acid (S)-5
in high ee and confirmed its absolute stereochemistry, N-Boc
deprotection was examined using TFA. Smooth deprotection
occurred, and the trifluoroacetate ammonium salt of (S)-7 was
obtained in 73% yield, notably with a B NMR shift at δ 28 in
D2O, clearly diagnostic of a free, uncomplexed boronic acid
of suitable crystals. However, the absolute stereochemistry of
(
16) (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708-
9
1
2
710. (b) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
16, 3231-3239. (c) Bertini Gross, K. M.; Beak, P. J. Am. Chem. Soc.
001, 123, 315-321. (d) Whistler, M. C.; MacNeil, S.; Snieckus, V.; Beak,
11
P. Angew. Chem., Int. Ed. 2004, 43, 2206.
(
17) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006,
607-2609.
18) Mitsumori, S.; Zhang, H.; Ha-Yeon Cheong, P.; Houk, K.; Tanaka,
F.; Barbas, C. J. Am. Chem. Soc. 2006, 128, 1040-1041.
19) HPLC conditions: Chiracel OJ, Hexane:IPA (99:1), 0.5 mL/min, λ
210 nm; tR (S) ) 8.24 min, tR (R) ) 9.46 min.
(vide infra). Studies of intramolecular B-N interactions in
2
0
2
aminoboronic acids have been reported, which show charac-
(
11
21
teristic B NMR shifts in the region ca. 10-12 ppm. The
equilibria involved in the neutralization of the ammonium salts
of aminoboronic acids, and eventual quaternization at B to form
(
)
J. Org. Chem, Vol. 72, No. 16, 2007 6277

FIGURE 4. Variation of H and 11B NMR shifts with pH. 0: B
chemical shifts. ∆: H2 chemical shifts. O: H5 + H5′ chemical shifts.
For full chemical shifts listings, see the Supporting Information.
1
FIGURE 3. Boroproline TFA salt (S)-7 titration with sodium
deuteroxide in D O.
2
boron and amino functions in boroproline systems such as 7
means that an intramolecular complex cannot be the intermediate
species.
SCHEME 2. Effects of Changes in pH upon the Solution
Behavior of Aminoboronic Acid Derivatives
In order to study this further, both H and 11B NMR spectra
1
were also recorded at various pH values as (S)-7 was titrated
with deuteroxide in D2O (Figure 4); the pH profile of the 11
B
NMR shifts shows the transition that must occur between the
2
3
sp boronic acid and sp boronate “ate” complex. Similar to
2
4
literature reports, no evidence was obtained for this transition
occurring after pH 7. This behavior confirms that the first
equilibrium is that of boronate hydroxylation to form a
trihydroxyboronate complex, and a pK value of 5.3 can be
calculated (Figure 4) which agrees with the value of 5.2
determined by titration. Further, it appears that the pKa of the
boronic acids in aminoboronic acids of type (S)-7 are essentially
defined by the stabilization of the trihydroxyboronate complex
by ion pairing with the ammonium ion. Indeed, the pKa value
quoted herein (5.3) compares well to those reported for
the boronate “ate” complex, were initially thought to proceed
20b,22a,24
22,23
arylaminoboronic acids,
despite the lower Lewis acidity
via intermolecular B-N chelation;
however, more recent
26
investigations using 1 B NMR titrations indicate that the first
1
of alkylboronic acids compared to arylboronic acids.
1
The H NMR spectra of (S)-7 in D2O (Figure 4) also show
the changes in the electronic environments at C2 and C5. Both
quaternization at boron and neutralization of the ammonium
salt are clear, causing increased shielding of the vicinal protons.
A significant shift of ca. 0.6 ppm for the C2 proton occurs at
pH > 4, compared to a smaller shift (ca. 0.1 ppm) at C5. This
is in good agreement with the signals recorded in the 11B NMR
spectrum, indicating that quaternization at boron also occurs.
A second change in the same proton’s chemical shift was
observed at higher pH, where deprotonation of the ammonium
equilibrium is that of the quaternization of B leading to a B-N
chelated species 11 in equilibrium in solution with the solvated
zwitterion 12 (Scheme 2).24
A comparison of these observations was made in D2O for
TFA salt (S)-7, involving the addition of hydroxide (1 equiv).
1
11
H and B NMR spectroscopy revealed the occurrence of
1
1
structural changes to amino-boronate (S)-7; in the B NMR
spectrum the boronate shifted from 28 ppm to ca. 2 ppm, which
confirmed the formation of the expected “ate” complex.
2
5
Titration of (S)-7 with hydroxide (Figure 3) confirmed the
presence of an intermediate species en route to the fully
quaternized boron “ate” complex, with pK values of 5.2 and
2
7
ion is expected to occur. However, it is not possible to
unambiguously identify the structure of the transient species
involved, though clearly it cannot be an intramolecular B-N
complex such as 11 (Scheme 2). It is likely that in boroamino
acids such as (S)-7, zwitterionic and bimolecular species are
involved as transition species in the pH titration curves (Figure
1
1.2. This is in good agreement with reported data for o-(N,N-
20b,22a
dimethylaminomethyl)benzene
and for the process shown
in Scheme 2. However, the physical relative position of the
1
11
4
). The most likely explanation for the observed H and
B
(20) (a) Burgemeister, T.; Grobe-Einsler, R.; Grotstollen, R.; Mannschreck,
A.; Wulff, G. Chem. Ber. 1981, 114, 3403-3411. (b) Wulff, G. Pure Appl.
NMR shifts (Figure 4) is explained as in Scheme 3; i.e., the
TFA ammonium salt (S)-7 undergoes neutralization with
hydroxide to form the doubly zwitterionic dimer 14, which is
solvated to give trihydroxyboronate complex 15. Further
increases in pH eventually transform the boroproline system
fully to the neutral amine trihydroxybornate species 16.
Chem. 1982, 54, 2093-2102. (c) Lauer, M.; Wulff, G. J. Organomet. Chem.
1
983, 256, 1-9.
(
21) N o¨ th, H.; Wrackmeyer, B. In Nuclear Magnetic Resonance Spec-
troscopy of Boron Compounds; NMR Basic Principles and Progress Series
4; Springer-Verlag: Berlin, 1978.
22) (a) Norrild, J. C. J. Chem. Soc., Perkin Trans. 2 2001, 719-726.
b) Norrild, J. C.; Søtofte, I. J. Chem. Soc., Perkin Trans. 2 2001, 727-
32.
23) Wiskur, S. L.; Lavigne, J. J.; Ait-Haddou, H.; Lynch, V.; Chiu, Y.
H.; Canary, J. W.; Anslyn, E. V. Org. Lett. 2001, 3, 1311-1314.
24) Zhu, L.; Shabbir, S. H.; Gray, M.; Lynch, V. M.; Sorey, S.; Anslyn,
E. V. J. Am. Chem. Soc. 2006, 128, 1222-1232.
25) Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769-774.
1
(
(
7
(
(26) (a) Yabroff, D. L.; Branch, G. E. K.; Bettman, B. J. Am. Chem.
Soc. 1934, 56, 1850-1857. (b) Babcock, L.; Pizer, R. Inorg. Chem. 1980,
19, 56-61.
(27) pKa of pyrrolidine ) 11.27: Hall, H. K., Jr. J. Am. Chem. Soc.
1957, 79, 5441-5444.
(
(
6
278 J. Org. Chem., Vol. 72, No. 16, 2007

SCHEME 3. Prediction of Effects of Changes in pH upon
the Solution Behavior of Boroproline Aminoboronic Acid
TMEDA (0.97 mL, 6.5 mmol) in Et
Ar. After 10 min, Boc-pyrrolidine (0.88 mL, 5 mmol) in Et
mL) was added dropwise. After 4 h, triisopropyl borate (1.15 mL,
mmol) was added dropwise and the solution allowed to warm to
2
O (48 mL) at -78 °C under
2
O (2
(S)-7
5
rt overnight. The reaction was quenched with aq HCl (20 mL, 5%
solution), the mixture was separated, and the aqueous phase was
extracted with Et
were dried (MgSO
to afford 5 (0.23 g, 27%) as a white solid: IR (KBr) 3360-3155,
2
O (50 mL, 3×). The combined organic extracts
4
), evaporated, washed with hexane, and filtered
-
1 1
1
1
6
2
666, 1356, 1245 cm ; H NMR (400 MHz, D O) δ 1.42 (s, 9H),
.63-1.85 (m, 2H), 1.93-2.09 (m, 2H), 2.92 (dd, 1H, J ) 11.2,
.8 Hz), 3.19-3.29 (m, 1H), 3.38-3.48 (m, 1H); 1 C NMR (101
3
MHz, CDCl
MHz, CDCl
(boroxine, 20).
3
) δ 25.8, 27.6, 28.5, 47.4, 80.2, 157.2; 11B NMR (128
3
) δ 31; m/z (CI) 70.1 (100), 170.2 (80), 591.4
We have reported the direct, highly enantioselective synthesis
of boroproline and isolated it as the trifluoroacetate salt (S)-7
which shows similar properties to other amino boronate systems
when exposed to pH titration.24 It is proposed that a bimolecular
N-(1,1-Dimethylethoxycarbonyl)-(1S,2S,3R,5S)-pinanediol (Pyr-
rolidin-2-yl)boronate (8a + 8b). Compound 5 (0.108 g, 0.5 mmol)
in CHCl (10 mL) was treated with (-)-pinanediol (85 mg, 0.5
3
mmol). After 12 h, the solvent was evaporated to give 8a + 8b
6-membered ring complex 14 is involved as a transition species,
(
0.17 g, 97%) as a clear oil. Analytical and spectroscopic properties
and hydroxylation of the boronate function precedes neutraliza-
tion of the ammonium ion with pK values of 5.2 and 11.2,
respectively. The impact of such equilibria and pH effects on
the ability of the aminoboronic acid to act as a catalyst for
organic reactions is being investigated.
15a
were identical to those reported in the literature.
(S)-(Trifluoroacetate)(pyrrolidin-2-ium)boronic Acid ((S)-7).
(S)-5 (0.50 g, 2.33 mmol) in DCM (15 mL) was treated with TFA
(15 mL). After 3 h, water was added, the DCM layer was separated,
and the aqueous phase was evaporated to give a residue which was
recrystallized from DCM to afford (S)-7 (0.39 g, 73%) as a beige
Experimental Section
solid: mp 103.2 °C; [R]23 +50.1 (c 0.20, DCM); IR (KBr) 3300-
D
-
1 1
3
1
(
2
000, 1755, 1674, 1385, 1200 cm ; H NMR (500 MHz, D O) δ
(S)-N-(1,1-Dimethylethoxycarbonyl)pinacol (Pyrrolidin-2-yl)-
.73-1.81 (m, 1H), 1.85-2.00 (m, 2H,), 2.11-2.17 (m, 1H,), 2.94
boronate (6). s-BuLi (4.80 mL, 5.6 mmol) was added dropwise to
13
m, 1H, J ) 9.4 Hz), 3.20 (t, 2H, J ) 7.4 Hz); C NMR (126
a stirred solution of (-)-sparteine (1.27 mL, 5.6 mmol) in Et
2
O
1
MHz, D O) δ 24.5, 26.6, 46.1, 47.9 (br), 116.4 ( JCF ) 292 Hz),
2
(
24 mL) at -78 °C under Ar. The solution was stirred at -78 °C
2 11 19
1
(
(
62.9 ( JCF ) 36.5 Hz); B NMR (128 MHz, D
188 MHz, D O) δ -76.1; m/z (ES+) 115.9 (100), 114.9 (25); m/z
ES-) 112.9 (100); HRMS (ES+) [M] calcd for C
16.0877, found 116.0879.
S)-N-(1,1-Dimethylethoxycarbonyl)-(1S,2S,3R,5S)-pi-
nanediol (Pyrrolidin-2-yl)boronate ((S)-8). (S)-5 (0.215 g, 1
mmol) in CHCl (25 mL) was treated with (-)-pinanediol (0.17 g,
mmol). After 12 h, the solvent was evaporated to afford (S)-8
0.34 g, 98%) as a clear oil. Analytical and spectroscopic properties
2
O) δ 28; F NMR
2
for 30 min. Boc-pyrrolidine (0.82 mL, 4.66 mmol) in Et O (2 mL)
2
was added dropwise. The mixture was stirred at -78 °C for 4 h.
-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (1.30 g, 7.0
mmol) was added dropwise and the solution allowed to warm to rt
overnight. The reaction was quenched with satd aq NH Cl, the
+
+
4 2
H11NO B
2
1
(
4
mixture was extracted with DCM (2×), the pH was adjusted to 7,
and the mixture was extracted further with DCM (2×). The
3
1
(
4
combined organic extracts were dried (MgSO ) and evaporated.
Purification by SiO
as eluent) gave 6 (1.20 g, 88%) as a white solid: mp 107 °C dec;
2
chromatography (3:1, petroleum ether-EtOAc
1
5a
were identical to those reported in the literature.
2
3
[
R] D +50.6 (c 0.035, DCM); IR (neat) 2976, 1682, 1367, 1144;
(S)-N-(1,1-Dimethylethoxycarbonyl)-(4S,5S)-4,5-diphenyle-
thanediol (Pyrrolidin-2-yl)boronate ((S)-9). (S)-5 (40 mg, 0.19
1
H NMR (400 MHz, CDCl
3
) δ 1.17 (s, 12H), 1.37 (s, 9H), 1.50-
.00 (m, 4H), 2.90-3.40 (m, 3H); 13C NMR (101 MHz, CDCl
) δ
4.4, 24.5, 25.0, 27.2, 27.7, 28.5, 45.9, 78.8, 83.4, 154.9; 11B NMR
) δ 32; m/z (ES+) 298.2 (100).
S)-N-(1,1-Dimethylethoxycarbonyl)(pyrrolidin-2-yl)boron-
ic Acid ((S)-5). s-BuLi (4.66 mL, 6.5 mmol) was added to a stirred
O (48 mL) at
78 °C under Ar. After 10 min, Boc-pyrrolidine (0.88 mL, 5.0
2
2
(
3
mmol) in CHCl (25 mL) was treated with (S,S)-hydrobenzoin (40
3
mg, 0.19 mmol). After 12 h, the solvent was evaporated and
128 MHz, CDCl
3
recrystallized from THF to afford (S)-9 (70.2 mg, 95%) as white
2
3
(
needles: mp 109 °C dec; [R]
-29.3 (c 0.016 in DCM); νmax-
D
-
1
1
(neat)/cm 2980, 2922, 2878, 1658, 1417, 1125; H NMR (400
solution of (-)-sparteine (1.50 mL, 6.5 mmol) in Et
2
MHz, CDCl ) δ 1.52 (s, 9H), 1.81-2.29 (m, 4H), 3.09-3.59, (m,
3
1
3
-
3H), 5.07 (s, 1.5H), 5.20 (s, 0.5H), 7.20-7.42 (m, 10H); C NMR
mmol) in Et
2
O (2 mL) was added dropwise. After 4 h, triisopropyl
(101 MHz, CDCl ) δ 27.6, 27.9, 28.5, 28.7, 29.3, 29.7, 45.3, 46.5,
3
borate (1.15 mL, 5 mmol) was added dropwise and the solution
allowed to warm to rt overnight. The reaction was quenched with
aq HCl (20 mL, 5%), the mixture was separated separated, and the
7
1
3
9.1, 81.1, 86.4, 86.6, 126.3, 126.9, 127.9, 128.1, 128.5, 128.7,
11
39.8, 141.0, 157.3; B NMR (128 MHz, CDCl
94.0 (55), 416.3 (56); HRMS (ES+) [M] calcd for C23 28NO -
BNa 416.2009, found 416.2004.
3
) 33; m/z (ES+)
+
H
4
aqueous phase was extracted with Et
extracts were dried (MgSO ), evaporated, washed with hexane, and
filtered to give (S)-5 (0.77 g, 72%) as a white solid: mp 107 °C
2
O (50 mL, 3×). The combined
4
Acknowledgment. We thank the EPSRC for funding (GR/
S85368/01) and the EPSRC National Mass Spectrometry Service
at Swansea.
23
dec; [R] D +69.5 (c 1.06, DCM); IR (KBr) 3365-3150, 1667,
-
1 1
1
1
3
350, 1243 cm ; H NMR (400 MHz, D
2
O) δ 1.43 (s, 9H), 1.65-
.87 (m, 2H), 1.91-2.10 (m, 2H), 2.93 (dd, 1H, J ) 11.2, 6.8 Hz),
13
.20-3.30 (m, 1H), 3.40-3.50 (m, 1H); C NMR (101 MHz,
Supporting Information Available: General experimental
methods, X-ray crytallographic data for compounds 5 and 9, and
CDCl
CDCl
2
3
) δ 25.8, 27.6, 28.5, 47.4, 80.2, 157.2; 11B NMR (128 MHz,
) δ 31; m/z (CI) 70.1 (100), 170.2 (80), 591.4 (boroxine,
3
1
13
11
19
H, C, B, and F NMR spectra (as appropriate) for compounds
-7 and 9. This material is available free of charge via the Internet
0). Anal. Calcd for C
9 4
H18BNO : C, 50.3; H, 8.4; N, 6.5. Found:
5
C, 49.9; H, 8.55; N, 6.4.
at http://pubs.acs.org.
N-(1,1-Dimethylethoxycarbonyl)(pyrrolidin-2-yl)boronic Acid
5). s-BuLi (4.66 mL, 6.5 mmol) was added to a stirred solution of
(
JO0708792
J. Org. Chem, Vol. 72, No. 16, 2007 6279