Use of a heck reaction for the synthesis of a new α-azido phosphotyrosyl mimetic suitably protected for peptide synthesis

Full text of DOI:10.1021/jo000643x

6288
J . Org. Chem. 2000, 65, 6288-6292
nate-based pTyr mimetics makes the preparation of novel
Pmp derivatives an important area of investigation.
There is also a growing interest in R-azido acids which
may serve as latent amino acid surrogates that can be
introduced into peptides and subsequently reduced to the
free amino compounds. Such agents may also be utilized
as nonnatural amino acid replacements in their own
right.8-10 Accordingly, herein is reported protected R-azi-
do 3-((4-phosphonomethyl)phenyl)propanoic acid ana-
logue 4, which is the first example of a pTyr mimetic
containing an azido group at the biologically important
R-center. As such, it may be considered both as a new
pTyr mimetic in its own right and as a “masked” variant
of L-Pmp(tBu2)-OH, in which the amino group is in latent
form.
Use of a Heck Rea ction for th e Syn th esis of
a New r-Azid o P h osp h otyr osyl Mim etic
Su ita bly P r otected for P ep tid e Syn th esis
Terrence R. Burke, J r,* Ding-Guo Liu, and Yang Gao
Laboratory of Medicinal Chemistry, Division of Basic
Sciences, National Cancer Institute, National Institutes of
Health, Building 37, Rm 5C06, Bethesda, Maryland
20892-4255
tburke@helix.nih.gov
Received April 26, 2000
Fundamental to both solution- and solid-phase syn-
thesis is the use of urethane-based R-amino protection,
such as acid-labile Boc or base-labile Fmoc species. A
little explored alternative to such carbonyl-based amino
protection strategies is represented by R-azido acids, in
which the azide functions as a latent amine equivalent
that is both stable to a range of carboxylic acid coupling
protocols and can be converted easily in situ to the free
R-amino group under mild conditions.1 Such an approach
obviates the need for formal amino protection and
potentially allows chain elongation in sterically limiting
situations which would otherwise be difficult using bulky
Boc or Fmoc groups. Recent papers describing the enzy-
matic and chiral HPLC resolution of R-azido acids,2 as
well as the utilization of chiral R-azido-masked acyl
cyanides as synthetic equivalents of N-protected, C-
activated R-amino acids,3 have highlighted a growing
interest in chiral R-azido acids as novel building blocks.
Furthermore, besides having utility as masked R-amino
acids for peptide synthesis, R-azido acids have also found
wide use as versatile synthetic intermediates.4-7
In the field of cellular signal transduction, novel amino
acid analogues of phosphotyrosyl residues (pTyr, 1) have
emerged as important molecular probes. Among these
pTyr mimetics, phosphonomethyl phenylalanine1 (Pmp
2) has proven to be a particularly useful agent, due to
its ability to faithfully replicate several biological interac-
tions of native pTyr residues,2-4 while at the same time
being stable toward cellular phosphatases.5 Since its
original preparation as the racemic, free phosphonic
acid,1 enantioselective synthesis of Pmp in its NR-Fmoc
4-(bis(tert-butyl)phosphonomethyl)-L-phenylalanine form6,7
((NR-Fmoc-L-Pmp(tBu2)-OH, 3) has allowed facile intro-
duction of Pmp into a variety of peptides using standard
Fmoc protocols. The biological importance of phospho-
Key to the synthesis of 4, is the palladium-catalyzed
Heck coupling11 of bis(tert-butyl)((4-bromophenyl)meth-
yl)phosphonate (10) with chiral acrylamide 9 (formed by
pivaloyl mixed anhydride amidation of acrylic acid and
commercially available Evans reagent, (S)-(-)-4-benzyl-
2-oxazolidinone (8):12 The 4-benzyl oxazolidinone was
utilized rather than the 4-phenyl species, due to the
former’s hydrogenolytic stability under the Pd-C/H2
conditions required later in the synthesis (Scheme 1).
This coupling represents an example of a Heck reaction
carried out on chiral reactants.13,14 It provides a facile
entry into the functionalized ((4-phosphonomethyl)phe-
nyl)propenoic acid skeleton (11), which by analogy to
work reported on tyrosine and phenylalanine analogues,15
may serve as a versatile starting point for the preparation
(8) Meldal, M.; J uliano, M. A.; J ansson, A. M. Tetrahedron Lett.
1997, 38, 2531-2534.
* To whom correspondence should be addressed. Tel: 301-402-1717;
FAX: 301-402-2275.
(1) Marseigne, I.; Roques, B. P. J . Org. Chem. 1988, 53, 3621-3624.
(2) Burke, T. R., J r.; Yao, Z.-J .; Smyth, M. S.; Ye, B. Curr. Pharm.
Des. 1997, 3, 291-304.
(3) Burke, T. R.; Zhang, Z. Y. Biopolymers 1998, 47, 225-241.
(4) Burke, T. R., J r.; Gao, Y.; Yao, Z.-J . In Biomedical Chemistry:
Applying Chemical Principles to the Understanding and Treatment of
Disease; 1st ed.; Torrence, P. R., Ed.; J oh Wiley & Sons: New York,
2000; pp 189-210.
(5) Domchek, S. M.; Auger, K. R.; Chatterjee, S.; Burke, T. R.;
Shoelson, S. E. Biochemistry 1992, 31, 9865-9870.
(6) Liu, W. Q.; Roques, B. P.; Garbay-J aureguiberry, C. Tetrahedron
Asymmetry 1995, 6, 647-650.
(7) Yao, Z. J .; Gao, Y.; Burke, T. R., J r. Tetrahedron Asymmetry
1999, 10, 3727-3734.
(9) Tornoe, C. W.; Sonke, T.; Maes, I.; Schoemaker, H. E.; Meldal,
M. Tetrahedron Asymm. 2000, 11, 1239-1248.
(10) Nemoto, H.; Ma, R.; Ibaragi, T.; Suzuki, I.; Shibuya, M.
Tetrahedron 2000, 56, 1463-1468.
(11) Heck, R. F. In Additions to and Substitutions at C-C pi-Bonds;
1st ed.; Semmelhack, M. F., Ed.; Pergamon Press: New York, 1991;
Vol. 4, pp 833-911.
(12) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
1988, 110, 1238-1256.
(13) Vallgarda, J .; Appelberg, U.; Csoregh, I.; Hacksell, U. J . Chem.
Soc., Perkin Trans. 1 1994, 461-469.
(14) Voigt, K.; Lansky, A.; Noltemeyer, M.; Meijere, A. D. Liebigs
Ann. 1996, 899-911.
(15) Hruby, V. J .; Li, G.; Haskell-Luevano, C.; Shenderovich, M.
Biopolymers 1997, 43, 219-266.
10.1021/jo000643x This article not subject to U.S. Copyright. Published 2000 by the American Chemical Society
Published on Web 08/22/2000

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6289
Sch em e 1a
Sch em e 2
phosphono)methyl)phenyl)propanoic acid (4), in high
yield without noticeable hydrolysis of tert-butyl phospho-
nate protection.
To determine the enantiomeric purity of final product
4, leucine amide dipeptides were prepared by solid-phase
techniques, with HPLC separation performed on result-
ing azido diastereomers.24 Racemic D,L-leucine-containing
dipeptides (14) first served as standards which showed
good separation of diastereomers (diastereomeric reten-
tion time difference of 1.0 min). Next, dipeptide 15 was
prepared using enantiomerically pure L-leucine and
shown to have less than 3% diastereomeric contamina-
tion resulting from the D-isomer (Scheme 2).
a
(a) (1) Pivaloyl chloride, N-methylmorpholine, -78 °C; (2)
lithim salt of 8, -78 °C to rt (49%); (b) Pd(OAc)2, P(o-tolyl)3, NEt3,
85 °C (79%); (c) H2/Pd0 (82%); (d) LiOH, H2O2, THF/H2O, 0 °C
(81%); (e) KHMDS, trisyl azide (77%); (f) LiOH, H2O2, THF/H2O,
0 °C (88%).
of a variety of novel â-substituted, conformationally
restricted pTyr mimetics.16
Con clu sion
Hydrogenation of 11 cleanly provided saturated con-
gener 12, which is a key branch point in the synthesis.
In the first instance, 12 could be hydrolyzed directly to
((4-(bis(tert-butyl)phosphono)methyl)phenyl)propanoic acid
(5) using aqueous lithium hydroxide and hydrogen per-
oxide.17 Although, previously ((4-phosphonomethyl)phe-
nyl)propanoic acid had been reported in its bis-ethyl
protected phosphonate form 6,18 analogue 5 bears more
synthetically useful tert-butyl phosphonate protection,
and as such it represents a novel desamino pTyr mimetic
suitably protected for N-terminal incorporation into
signal transduction-related inhibitors using TFA cleavage
protocols. Alternatively, intermediate 12 could be func-
tionalized at the R-position, leading to desired final azido
product 4. Therefore subjecting 12 to trisyl azide-medi-
ated electrophilic azide addition under (S)-chiral induc-
tion of the appended Evan’s auxiliary,19-23 R-azido com-
pound 13 could be obtained enantioselectively, in greater
than 94% ee (see below). To complete the synthesis,
cleavage of the chiral auxiliary using aqueous lithium
hydroxide in the presence of hydrogen peroxide, provided
the desired final product, l-R-azido-((4-(bis(tert-butyl)-
Reported herein is an application of a Heck reaction
for the preparation of novel pTyr mimetics. Of particular
note, analogue 4 is the first R-azido-based pTyr mimetic
yet reported, and as such, it represents a new member
of a growing family of R-azido acids. Finally as a unique
azido variant of the widely used pTyr mimetic Pmp (3),
compound 4 may find use as a new pTyr mimetic in the
construction of novel signal transduction inhibitors.
Exp er im en ta l Section
Gen er a l P r oced u r es. Elemental analyses were obtained
from Atlantic Microlab Inc., Norcross. Solvent was removed by
rotary evaporation under reduced pressure, and silica gel
chromatography was performed using high performance silica
gel (60 Å pore, 10 µm particle size). Anhydrous solvents were
obtained commercially and used without further drying. Ana-
lytical HPLC were conducted using a Vydac C18 column (10 mm
diam × 250 mm long; solvent A ) 0.1% aqueous TFA; solvent B
) 0.1% TFA in acetonitrile; flow rate ) 2 mL/min.).
(S)-4-Ben zyl-3-(p r op -2-en oyl)-1,3-oxa zolid in -2-on e (9). To
a
solution of acrylic acid (7) (8.2 mL; 120 mmol) and N-
methylmorpholine (NMM) (13.2 mL; 120 mmol) in anhydrous
THF (100 mL) at -78 °C under argon was added pivaloyl
chloride (14.8 mL; 120 mmol), and the mixture was stirred at
-78 °C (1 h). To a separate round-bottom flask containing Evan’s
reagent, (S)-(-)-4-Benzyl-2-oxazolidineone25 (8) (17.7 g; 100
mmol) in anhydrous THF (200 mL) at -78 °C under argon,
was added n-BuLi, 1.6 M in hexanes (62 mL; 100 mmol), and
the solution was stirred at -78 °C (30 min). To this was then
added via cannula at -78 °C the suspension of acryloyl mixed
(16) Gao, Y.; Burke, T. R., J r., manuscript in preparation.
(17) Pais, G. C. G.; Maier, M. E. J . Org. Chem. 1999, 64, 4551-
4554.
(18) Parkanyi, C.; Huang, L.; Chu, S. G.; J effries, A. T. Collect.
Czech. Chem. Commun. 1996, 61, 342-354.
(19) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011-4030.
(20) Pearson, A. J .; Park, J . G.J . Org. Chem. 1992, 57, 1744-1752.
(21) Pearson, A. J .; Lee, K. S.J . Org. Chem. 1994, 59, 2304-2313.
(22) de Laszlo, S. E.; Bush, B. L.; Doyle, J . J .; Greenlee, W. J .;
Hangauer, D. G.; Halgren, T. A.; Lynch, R. J .; Schorn, T. W.; Siegl, P.
K. S. J . Med. Chem. 1992, 35, 833-846.
(23) Nicolas, E.; Russell, K. C.; Knollenberg, J .; Hruby, V. J . J . Org.
Chem. 1993, 58, 7565-7571.
(24) Yao, Z. J .; Gao, Y.; Voigt, J . H.; Ford, H.; Burke, T. R.
Tetrahedron 1999, 55, 2865-2874.
(25) Both (S)-(-)- and (R)-(+) 4-benzyl-2-oxazolidinone can be
purchase from Aldrich Chemical Corp., St. Louis, MO.

6290 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
anhydride, and the resulting mixture was stirred first at -78
°C (1.5 h) and then at room temperature (2 h). The mixture was
partitioned between saturated NH4Cl/EtOAc, and the combined
organics were washed with brine, dried (MgSO4), and taken to
dryness to yield a syrup (27.6 g). Purification by silica gel
chromatography (EtOAc in hexanes, from 0% to 50%) provided
unreacted Evan’s reagent (6.44 g) as well as product (9) as a
white foam, which crystallized (7.16 g; 49% based on recovered
starting material), mp 70-72 °C. 1H NMR (CDCl3) δ 7.61 (dd,
1H, J ) 10.7, 17.1 Hz), 7.49-7.26 (m, 5H), 6.70 (dd, 1H, J )
1.7, 17.1 Hz), 6.03 (dd, 1H, J ) 1.7, 10.2 Hz), 4.99-4.79 (m, 1H),
3.37-4.25 (m, 2 H), 3.44 (dd, 1H, J ) 3.0, 13.2 Hz), 2.92 (dd,
1H, J ) 9.8, 13.2 Hz). FABMS (+VE, NBA) m/z 232 (MH+). Anal.
Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.57;
H, 5.82; N, 6.08.
addition of an ice-cold solution of LiOH‚H2O (164 mg; 3.89 mmol)
in H2O (10 mL), and the mixture was then stirred at 0 °C (4 h).
The mixture was diluted with H2O (100 mL) and washed with
CH2Cl2, the aqueous was cooled to ∼0 °C, ice-cold 0.1 N HCl
was added (∼80 mL), and the mixture was then extracted with
EtOAc. Combined organics were dried (MgSO4) and taken to a
syrup, which quickly crystallized to provide 5 as a white solid
(563 mg; 81% yield), mp 101 (soften); 106-110 °C. 1H NMR
(CDCl3) δ 7.28 (dd, 2H, J ) 2.1, 8.1 Hz), 7.21 (d, 2H, J ) 8.1
Hz), 3.09 (d, 2H, J ) 21.4 Hz), 3.02 (t, 2H, J ) 7.7 Hz), 2.72 (t,
2H, J ) 7.7 Hz), 1.49 (s, 18H). FABMS (-VE, NBA) m/z 355
(M - H). Anal. Calcd for C18H29O5P: C, 60.66; H, 8.20. Found:
C, 60.90; H, 8.10.
3-(2-(S)-Azid o-3-(4-((bis(ter t-bu tyl)p h osp h on o)m eth yl)-
p h en yl)p r op a n oyl)-4(S)-ben zyl-1,3-oxa zolid in -2-on e (13).
To anhydrous THF (50 mL) at -78 °C under argon was added
potassium bis(trimethylsilyl)amide, 0.5 M in toluene (29.0 mL;
14.5 mmol), followed by, via cannula, a precooled (-78 °C)
solution of 12 (6.20 g; 12.1 mmol) in anhydrous THF (50 mL),
and the resulting violet solution was stirred at -78 °C (30 min).
To this was added rapidly, via cannula, a precooled (-78 °C)
solution of (2,4,5-triisopropyl)phenylsulfonyl azide (4.50 g; 14.5
mmol). The resulting yellow solution was stirred at -78 °C (2
min) and quenched by addition of HOAc (3.8 mL; 66.6 mmol)
followed by solid KOAc (4.87 g; 49. 7 mmol). The mixture was
stirred at room temperature (3.5 h), partitioned between satu-
rated NaHCO3 in brine/EtOAc, washed with saturated NaHCO3
in brine, dried (MgSO4), and taken to dryness to yield a yellow
resin (8.66 g). Purification by silica gel chromatography (50%
EtOAc in hexanes) provided 13 as a white foam (5.13 g, 77%).
Crystallization from ether provided an analytical sample, mp
80 °C (soften); 115-117 °C. 1H NMR (CDCl3) δ 7.46-7.27 (m,
9H), 5.37 (dd, 1H, J ) 6.0, 9.0 Hz), 4.70-4.58 (m, 1H), 4.30-
4.14 (m, 2H), 3.40 (dd, 1H, J ) 3.0, 13.2 Hz), 3.28 (dd, 1H, J )
6.0, 13.2 Hz), 3.10 (d, 2H, J ) 21.4 Hz), 2.90 (dd, 1H, J ) 9.4,
13.2 Hz), 1.50 (s, 9H), 1.49 (s, 9H). FABMS (+VE) m/z 557 (MH+),
501 (MH+ - C4H8), 445 (MH+ - 2C4H8). Anal. Calcd for
Bis(ter t-b u t yl) ((4-Br om op h en yl)m et h yl)p h osp h on a t e
(10). To a solution of di-tert-butyl phosphite (9.70 g; 50 mmol)
in anhydrous THF (100 mL) at -78 °C under argon was added
n-BuLi, 1.6 M in hexanes (33.2 mL; 50 mmol), over 5 min, and
the solution was stirred first at -78 °C (30 min) and then at 0
°C (30 min). To this was added a solution of 4-bromobenzyl
bromide (12.5 g; 50 mmol) in anhydrous THF (20 mL), and the
mixture was stirred at 0 °C and then allowed to come to room
temperature and stirred overnight. The mixture was partitioned
between saturated aqueous NH4Cl and EtOAc; the combined
organic extracts were washed with brine, dried (MgSO4), and
taken to dryness, yielding a light yellow crystalline solid (18.27
g). Purification by silica gel chromatography (EtOAc in hexanes;
from 0% to 100%) provided 10 as a cream-colored crystalline
solid (15.21 g; 82% yield), mp 45 °C (soften), 48-56 °C. 1H NMR
(CDCl3) δ 7.42 (d, 2H J ) 8.3 Hz), 7.16 (dd, 2H J ) 2.4, 8.3 Hz),
2.99 (d, 2H J ) 21.5 Hz), 1.43 (s, 18 H). HR-FABMS (+VE) m/z
calcd for C15H25N3O3PBr (M+): 3363.0725. Found: 3363.0735
(∆m ) 2.8 ppm). Anal. Calcd for C15H24BrO3P: C, 49.60; H, 6.66.
Found: C, 50.20; H, 6.60.
3-(3-(4-((Bis(ter t-bu tyl)p h osp h on o)m eth yl)p h en yl)p r op -
2-en oyl)-4(S)-ben zyl-1,3-oxa zolid in -2-on e (11). A mixture of
acrylamide 9 (1.48 g; 6.40 mmol), di-tert-butyl (4-bromobenzyl)-
phosphonate (10) (2.36 g; 6.40 mmol), Pd(OAc)2 (72 mg; 0.032
mmol), and tri-O-tolyl phosphine (390 mg; 1.28 mmol) in a
round-bottom flask sealed with a rubber septum was alternately
evacuated and flushed with argon (3×) and then to this was
added NEt3 (12 mL), and the mixture was heated with stirring
at 85 °C (overnight). The resulting suspension was partitioned
between ice-cold saturated NH4Cl/EtOAc, and the combined
organics were washed with brine, dried (MgSO4), and taken to
dryness to yield a foam (3.73 g). Purification by silica gel
chromatography (EtOAc in hexanes, from 20% to 100%) provided
11 as a crystalline solid (2.58 g, 79%). Recrystallization from
ether:hexanes provided an analytical sample, mp 128-129 °C.
1H NMR (CDCl3) δ 7.98 (s, 2H), 7.66 (d, 2H, J ) 8.1 Hz), 7.48-
7.31 (m, 1H), 4.95-4.84 (m, 1H), 4.38-4.27 (m, 2H), 3.46 (dd,
1H, J ) 3.0, 13.2 Hz), 3.15 (d, 2H, J ) 22.2 Hz), 2.94 (dd, 1H, J
) 9.4, 13.2 Hz), 1.52 (s, 18 Hz). FABMS (+VE) m/z 514 (MH+).
Anal. Calcd for C28H36NO6P: C, 65.48; H, 7.07; N, 2.73. Found:
C, 65.74; H, 7.06; N, 2.81.
C
28H37N4O6P: C, 60.42; H, 6.70; N, 10.07. Found: C, 60.53; H,
6.79; N,10.09.
3-(2(S)-Azid o-3-(4-((b is(ter t-b u t yl)p h osp h on o)m et h yl)-
p h en yl)p r op a n oic Acid (4). To a solution of 13 (4.77 g; 8.60
mmol) in THF (40 mL) with H2O (10 mL) at 0 °C was added
aqueous H2O2, 30% w/w (4.88 mL; 43.0 mmol) dropwise, followed
by dropwise addition of an ice-cold solution of LiOH‚H2O (722
mg; 17.2 mmol) in H2O (40 mL), and the mixture was then
stirred at 0 °C (2 h). To the solution was added Na2SO3 (5.42 g;
43.0 mmol) in H2O (20 mL), the mixture was diluted with brine
(300 mL) and washed with CH2Cl2, the aqueous was cooled to
∼0 °C, ice-cold 1.0 N HCl was added until the pH e 3, and the
mixture was extracted with EtOAc. Combined organics were
dried (MgSO4), and solvent was removed to provide 6 as a highly
crystalline white solid (3.00 g; 88% yield), mp 68-72 °C. 1H NMR
(CDCl3) δ 7.29 (brs, 4H), 4.24-4.14 (m, 1H), 3.25-3.00 (m, 4H),
1.49 (s, 9H), 1.44 (s, 9H). FABMS (-VE) m/z 396 (M-H). HR-
FABMS (-VE, MCA, Gly) m/z calcd. for C18H27N3O3P (M-H):
396.1688. Found: 396.1667 (∆m ) 2.1 mmu; 5.3 ppm). [R]D
)
+14.1° (c 0.95, CHCl3). Anal. Calcd for C18H28N3O5P•3/4H2O: C,
52.61; H, 7.24; N, 10.23. Found: C, 52.63; H, 6.77; N, 10.36.
Deter m in a tion of En a n tiom er ic P u r ity of An a logu e 4.
Dipeptides 14 and 15 were prepared from protected azido acid
4 using Rink amide resin26 (0.4 mequiv/g, purchased from
Bachem Corp., Torrance, CA) with Fmoc-protocols similar to
those previously described.27 Fmoc-D,L-Leu and Fmoc-L-Leu-Rink
amide resins were prepared by coupling the appropriate Fmoc-
protected amino acides to Rink resin, with the resulting Fmoc-
protected resins (12.5 mg) then being washed well with several
1 mL portions of N-methyl-2-pyrolidoinone (NMP). Fmoc amino
protection was removed by treatment with 20% piperidine in
NMP (0.5 mL, 2 min followed by 0.5 mL, 20 min). Resins were
washed well with NMP (10 × 1 mL) and then coupled overnight
with a solution of active ester formed by reacting 12.5 µmol each
of protected azido acid 4, 1-hydroxybenzotriazole (HOBt), and
1,3-diisopropylcarbodiimide (DIPCDI) in NMP (1.0 mL, 10 min).
3-(3-(4-((Bis(ter t-b u t yl)p h osp h on o)m et h yl)p h en yl)p r o-
p a n oyl)-4(S)-ben zyl-1,3-oxa zolid in -2-on e (12). A solution of
11 (6.48 g; 12.7 mmol) in absolute EtOH (50 mL) was hydroge-
nated over Pd black (200 mg) at 40 psi H2 in a Parr apparatus
(overnight). Additional Pd black was added (200 mg) and
hydrogenation cotinued (overnight). Catalyst was removed by
filtration, and the filtrate was taken to dryness to yield a white
crystalline solid, which was triturated with ether to provide a
white solid. This was combined with additional product obtained
by cooling the filtrate to -78 °C, providing 12 as a combined
1
total of 5.37 g (82% yield), mp 114-115 °C. H NMR (CDCl3) δ
7.43-7.34 (m, 4H), 7.27 (s, 5H), 4.80-4.66 (m, 1H), 4.28-4.23
(m, 2H), 3.40-3.30 (m, 3H), 3.15-3.05 (m, 4H), 2.84 (dd, 1H, J
) 9.4, 13.2 Hz), 1.53 (s, 18 Hz). FABMS (+VE, NBA) m/z 516
(MH+), 404 (MH+ - 2C4H8). Anal. Calcd for C28H38NO6P: C,
65.23; H, 7.43; N, 2.72. Found: C, 64.94; H, 7.34; N, 2.79.
(3-(4-((Bis(t er t-b u t yl)p h osp h on o)m e t h yl)p h e n yl)p r o-
p a n oic Acid (5). To a solution of 12 (1.0 g; 1.95 mml) in THF
(15 mL) with H2O (5 mL) at 0 °C was added aqueous H2O2, 30%
w/w (1.10 mL; 9.74 mmol) dropwise, followed by dropwise
(26) Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790.
(27) Burke, T. R.; Yao, Z. J .; Zhao, H.; Milne, G. W. A.; Wu, L.;
Zhang, Z. Y.; Voigt, J . H. Tetrahedron 1998, 54, 9981-9994.

Additions and Corrections
J . Org. Chem., Vol. 65, No. 19, 2000 6291
Resins were first washed with NMP (10 × 1 mL) and dichlo-
romethane (10 × 1 mL), and then dipeptides were cleaved from
the resin using a mixture of trifluoroacetic acid (TFA, 1.80 mL)
and H2O (200 µl) (1h), taken to dryness, and analyzed by HPLC
(linear gradient from 10% B to 90% B over 20 min). Retention
times of diastereomeric peaks as determined using dipeptide 14
prepared from racemic D,L-leucine indicated diastereomers elut-
ing at 18.6 min and 19.1 min. Enantiomeric contamination of
azido acid 4 was then determined by similar analysis of dipeptide
15, where diastereomeric contamination accounted for an area
less than 3% of that observed for the major diastereomer. These
results indicated greater than 94% enantiomeric purity.
Ack n ow led gm en t. Appreciation is expressed to Dr.
J ames Kelley and Ms. Lynne Anderson of the LMCH
for mass spectral analysis.
J O000643X
Additions and Corrections
Vol. 65, 2000
P . An d r ew Eva n s* a n d Th a r a Ma n a n ga n . Stereoselective
Synthesis of Cyclic Ethers Using Vinylogous Sulfonates as
Radical Acceptors: Effect of E/Z Geometry and Temperature on
Diastereoselectivity.
Page 4524. The values for ( )n in the original Scheme 1
are incorrect (for 6 and 1). The corrected Scheme 1 is
presented below.
Sch em e 1
J O004007A
10.1021/jo004007a
Published on Web 08/30/2000

6292
J . Org. Chem. 2000, 65, 6292
Vol. 65, 2000
Mich a el Du bber a n d Th isbe K. Lin d h or st*. Synthesis of
Carbohydrate-Centered Oligosaccharide Mimetics Equipped with
a Functionalized Tether.
Page 5277. Corrected Schemes 2 and 3 are depicted
below.
Sch em e 2. Tr eh a lose P a th w a ya
a
Key: (a) allyl bromide, NaH, DMF; (b) 9-BBN-H, THF; (c) 7, TMS-OTf, acetonitrile; (d) aqueous TFA, THF, or acetonitrile; (e)
6-bromohexanol, BF3‚Et2O, CH2Cl2.
Sch em e 3. Ap p lica tion s of 11
J O004005Q
10.1021/jo004005q
Published on Web 08/30/2000