A practical synthesis of L-azatyrosine

Full text of DOI:10.1021/jo9515079

J . Org. Chem. 1996, 61, 813-815
813
A P r a ctica l Syn th esis of L-Aza tyr osin e†
organometallic coupling protocol using an organozinc
reagent derived from iodoalanine.9 In addition, several
syntheses of racemic 1 have been published, including a
synthesis by Norton et al. that predated the isolation of
natural 1 by 14 years.4,10 We have recently described a
new method for the synthesis of highly enantiomerically
enriched R-amino acids that is based on the diastereo-
selective alkylation of pseudoephedrine glycinamide (2).11
The method is well suited to the large-scale preparation
of R-amino acids. Both enantiomers of pseudoephedrine
glycinamide (2) are readily prepared on large scale in a
single step from inexpensive reagents.12 Enolates derived
from 2 are powerful nucleophiles and undergo highly
diastereoselective alkylation reactions with a wide range
of electrophiles. Importantly, the pseudoephedrine aux-
iliary is readily removed under mild conditions without
significant epimerization of the R-stereocenter.10 In this
note, we describe a highly practical preparation of
multigram quantities of L-azatyrosine of g99% ee using
this methodology.
The key feature in the planning of our synthetic route
was the selection of an appropriate 2-(halomethyl)-5-
hydroxypyridine derivative as the electrophilic compo-
nent in the alkylation reaction. The benzenesulfonyl
group proved to be ideal for protection of the phenol group
by virtue of its stability to the conditions of free-radical
bromination and the conditions of enolate alkylation. In
addition, the benzenesulfonyl group conferred greatly
enhanced stability to pyridyl benzyl halides such as 5
and 6 (versus, e.g., the corresponding silyl ethers7a) and
was readily cleaved under the conditions of auxiliary
removal (vide infra). The (iodomethyl)pyridine derivative
6 was chosen over the bromide 5 because we have
generally found alkylations with iodides to be more
diastereoselective than the corresponding bromides.
Andrew G. Myers* and J ames L. Gleason
Arnold and Mabel Beckman Laboratories of Chemical
Synthesis, California Institute of Technology,
Pasadena, California 91125
Received August 14, 1995
Oncogenic Ras genes and the G-proteins which they
encode are important targets for anticancer research.1
Ras proteins have been implicated to function as com-
ponents of the cellular signal transduction pathways
related to cell proliferation and differentiation.2 In their
oncogenic form, the natural GTP-ase activity of Ras
proteins is inhibited, leading to overstimulation of the
signaling pathway for cell growth. The potential impor-
tance of oncogenic Ras genes and gene products as targets
for cancer chemotherapy is underscored by the observa-
tion that up to 40% of human colon tumors and 95% of
human pancreatic tumors have been found to contain
oncogenic Ras genes.3
L-Azatyrosine (L-â-(5-hydroxy-2-pyridyl)alanine) (1) is
an antibiotic isolated from Steptomyces chibaensis4 that
has recently been shown to restore normal phenotypic
behavior to transformed cells bearing oncogenic Ras
genes.5 Importantly, L-azatyrosine (1) does not appear
to affect cells possessing normal Ras genes.5a,d In addi-
tion, 1 has been found to inhibit chemical carcinogen-
induced tumor growth in mice harboring normal human
c-Ha Ras genes.6
The limited availability of natural 1 for chemothera-
peutic studies has stimulated the development of two
recent syntheses of optically active 1.7 The first of these7a
employed Williams’ method for the asymmetric synthe-
sis of amino acids,8 while the second7b made use of an
The (iodomethyl)pyridine derivative 6 was prepared in
three steps from commercially available 5-hydroxy-2-
methylpyridine (3). Treatment of 3 (1 equiv) with
benzenesulfonyl chloride (1.1 equiv) and triethylamine
(1.2 equiv) in dichloromethane at 0 °C for 2 h provided
the benzenesulfonate derivative 4 in 95% yield. Bromi-
nation of the methyl group of 4 was achieved using
N-bromosuccinimide (1.4 equiv) with 2,2′-azobis(2-meth-
ylpropiononitrile) as initiator in carbon tetrachloride at
reflux. The principal byproduct of the reaction was the
corresponding dibromide, which was readily removed by
flash-column chromatography. The desired monobro-
† Contribution No. 9122.
(1) (a) Brunton, V. G.; Workman, P. Cancer Chemother. Pharmacol.
1993, 32, 1. (b) Prendergast, G. C.; Gibbs, J . B. Bioessays 1994, 16,
187.
(2) For reviews on Ras genes and proteins see: (a) Barbacid, M.
Annu. Rev. Biochem. 1987, 56, 779. (b) Prendergast, G. C.; Gibbs, J .
B. Adv. Cancer Res. 1993, 62, 19.
(3) (a) Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J .; Arn-
heim, N.; Perucho, M. Cell 1988, 53, 549. (b) Bos, J . L.; Fearon, E. R.
Hamilton, S. R.; Verlaan-de Vries, M.; van Boom, J . H.; van der Eb,
A. J .; Vogelstein B. Nature 1987, 327, 293 (c) Forrester, K.; Almoguera,
C.; Han, K.; Grizzle, W. E.; Perucho, M. Nature 1987, 327, 298
(4) Inouye, S.; Shomura, T.; Tsuruoka, T.; Ogawa, Y.; Watanabe,
H.; Yoshida, J .; Niida, T. Chem. Pharm. Bull. 1975, 23, 2669.
(5) (a) Shindo-Okada, N.; Makabe, O.; Nagahara, H.; Nishimura,
S. Mol. Carcinog. 1989, 2, 159. (b) Chung, D. L.; Brandt-Rauf, P.;
Murphy, R. B.; Nishimura, S.; Yamaizumi, Z.; Weinstein, I. B.; Pincus,
M. R. Anticancer Res. 1991, 11, 1373. (c) Fujita-Yoshigaki, J .; Yokoya-
ma, S.; Shindo-Okada, N.; Nishimura, S. Oncogene 1992, 7, 2019. (d)
Nomura, T.; Ryoyama, K.; Okada, G.; Matano, S.; Nakamura, S.;
Kameyama, T. J pn. J . Cancer Res. 1992, 83, 851. (e) Campa, M. J .;
Glickman, J . F.; Yamamoto, K.; Chang, K.-J . Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 7654. (f) Kyprianou, N.; Taylor-Papadimitriou, J .
Oncogene 1992, 7, 57.
(8) (a) Williams, R. M.; Im, M.-N. Tetrahedron Lett. 1988, 29, 6075.
(b) Williams, R. M.; Im, M.-N. J . Am. Chem. Soc. 1991, 113, 9276.
(9) J ackson, R. F. W.; Wishart, N.; Wood, A.; J ames, K.; Wythes,
M. J . J . Org. Chem. 1992, 57, 3397. (b) Dunn, M. J .; J ackson, R. F.
W.; Pietruszka, J .; Wishart, N.; Ellis, D.; Wythes, M. J . Synlett 1993,
499.
(10) (a) Norton, S. J .; Skinner, C. G.; Shive, W. J . Org. Chem. 1961,
26, 1495. (b) Norton, S. J .; Sullivan, P. T. J . Heterocycl. Chem. 1970,
7, 699. (c) Harris, R. L. N.; Teitei, T. Aust. J . Chem. 1977, 30, 649
(11) Myers, A. G.; Gleason, J . L.; Yoon, T. J . Am. Chem. Soc. 1995,
117, 8488.
(6) Izawa, M.; Takayama, S.; Shindo-Okada, N.; Doi, S.; Kimura,
M.; Katsuki, M.; Nishimura, S. Cancer Res. 1992, 52, 1628.
(7) (a) Schow, S. R.; DeJ oy, S. Q.; Wick, M. M.; Kerwar, S. S. J .
Org. Chem. 1994, 59, 6850. (b) Ye, B.; Burke, T. R. J . Org. Chem. 1995,
60, 2640.
(12) Myers, A. G.; Yoon, T.; Gleason, J . L. Tetrahedron Lett. 1995,
36, 4555.
0022-3263/96/1961-0813$12.00/0 © 1996 American Chemical Society

814 J . Org. Chem., Vol. 61, No. 2, 1996
Notes
mide 5 was isolated as a white solid (mp 103-108 °C) in
52% yield. In marked contrast to silyl ether derivatives,
benzenesulfonate 5 proved to be stable to storage in the
solid state. Finkelstein exchange of the bromide with
sodium iodide in acetone produced the crystalline iodide
6 (mp 111-113 °C) in 93% yield. Like the bromide,
iodide 6 proved to be a storable, stable synthetic inter-
mediate.
found to elute first. In a larger-scale preparation,
conducted using the “optimum” procedure described
above and involving purification by flash column chro-
matography, 7 was obtained in 97% de and 70% yield
(25 g). As expected, use of the bromide 5 in the alkylation
reaction led to reduced diastereoselectivity (85% de at 0
°C) relative to the iodide.
As in our previous studies, the pseudoephedrine aux-
iliary was readily cleaved from the alkylation product 7
by basic hydrolysis (4 equiv of NaOH, H2O, reflux),
conditions which also rapidly hydrolyzed the benzene-
sulfonate protecting group. Extraction of the crude
hydrolysis reaction mixture with dichloromethane led to
90% recovery of the pseudoephedrine auxiliary. The free
amino acid 1 was then isolated by ion exchange chroma-
tography (to remove benzenesulfonic acid), followed by
recrystallization (H2O). When this procedure was con-
ducted on 7 of 97% de, a 73% yield (7.7 g) of optically
pure (g99% ee) L-azatyrosine was obtained. Synthetic
1 provided spectroscopic data and physical constants that
were identical with those reported for the natural prod-
uct.4 Hydrolysis of 7 of lower de (90%) also gave
reasonable yields of enantiomerically enriched product
(47% yield, 99% ee) after a single recrystallization from
water. The chemistry described should be readily adapt-
able to provide enantiomerically pure L-azatyrosine (1)
in whatever quantity might be needed.
The optimum conditions for the alkylation reaction
involved the addition of a solution of iodide 6 (1 equiv)
to a solution of the enolate derived from (R,R)-(-)-
pseudoephedrine glycinamide [1.5 equiv, generated at 0
°C using 2.93 equiv (relative to 6) LDA] in the presence
of lithium chloride (9 equiv) in tetrahydrofuran at -78
°C. After 3 h at -78 °C, the reaction mixture was
warmed to -45 °C and was held at that temperature for
3 h. These conditions typically provided the alkylation
product 7 in 90-95% yield after flash column chroma-
tography. A direct method for the analysis of the
diastereoselectivity of the alkylation reaction was not
found.13 Therefore, an indirect procedure was adopted
involving complete hydrolysis of 7 to the amino acid 1
(vide infra) followed by analysis of the enantiomeric
excess of 1 using a chiral HPLC column.14,15 In this
manner and using the crude alkylation reaction mixture,
it was established that the alkylation reaction had
proceeded with a minimum diastereoselectivity of 90-
91%. When the alkylation reaction was conducted at 0
°C, the diastereoselectivity was slightly diminished (89%
de), as was the product yield (80%). The maximum
reaction diastereoselectivity (94-95% de) was achieved
by conducting the alkylation at -78 °C; however, con-
siderable crystallization of the iodide 6 occurs at this
temperature, particularly on larger scales, resulting in
diminished yields of product (50-75%). For this reason,
the “optimized” protocol, outlined above, entails incuba-
tion at -45 °C for 3 h, to allow the reaction to proceed to
completion. In this context, it is important to note that
if complete consumption of the iodide is not achieved,
significant N-alkylation of both the starting material 2
and the product 7 will occur upon concentration after
workup.16 The diastereomeric ratio of the alkylation
product mixture can be enriched upon flash column
chromatography (4:4:92 methanol:triethylamine:dichlo-
romethane), where the undesired minor diastereomer is
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All reagents were commercial
materials and were used without further purification with the
following exceptions. Tetrahydrofuran was distilled from sodium
benzophenone ketyl. Toluene was distilled from calcium hy-
dride. Lithium chloride was dried in vacuo (150 °C, 0.5 mmHg)
for 12 h and was briefly flame-dried in vacuo after transfer to
reaction flasks. Glycinamide 2 was prepared as described.12 All
reactions were carried out under an argon atmosphere. Chro-
matography was conducted according to the method of Still17
with 230-400 mesh silica gel. NMR spectra were recorded at
300 MHz for 1H and 75 MHz for 13C. High resolution mass
spectra were obtained from the Biomedical Mass Spectrometry
Facility, University of California, Los Angeles. HPLC analysis
was conducted on a Chiralpak WH column (25 cm × 10 mm,
available from J . T. Baker Inc.) using a 0.5 mM CuSO4 mobile
phase (5 mL/min) at 50 °C. Retention times for D- and L-
azatyrosine are 15.8 min and 22.9 min, respectively (255 nm
detection).15
5-(Ben zen esu lfon yloxy)-2-m eth ylp yr id in e (4). Benzene-
sulfonyl chloride (12.9 mL, 101 mmol, 1.10 equiv) was added to
a stirred solution of 5-hydroxy-2-methylpyridine (10.0 g, 91.6
mmol, 1 equiv) and triethylamine (15.3 mL, 110 mmol, 1.20
equiv) in dichloromethane (100 mL) at 0 °C. After stirring for
2 h at 0 °C, water (20 mL) was added and the resulting two-
phase mixture was stirred vigorously for 1 h at 23 °C to quench
any remaining sulfonyl chloride. Saturated aqueous potassium
carbonate solution (100 mL) was added, and the layers were
separated. The aqueous layer was extracted with a second
portion of dichloromethane (150 mL). The combined organic
layers were dried over anhydrous potassium carbonate, filtered,
and concentrated in vacuo. The residue was purified by chro-
matography on silica gel eluting with a gradient of 4:1 to 1:1 of
hexane and ethyl acetate to provide 4 (21.8 g, 95%) as an oil.
Chromatography may be avoided by using exactly 1 equiv of
benzenesulfonyl chloride to afford a product of sufficient purity
for direct submission to benzylic bromination conditions (see
below): IR (neat) 3066, 1594, 1480, 1450, 1384, 1286, 1204, 1177,
(13) 1H NMR analysis is complicated by the presence of amide
rotamers. The involatility of 1 made capillary GC analysis impractical,
and conditions for the separation of the diastereomeric alkylation
products by HPLC have not been found.
(14) Yuki, Y.; Saigo, K.; Tachibana, K.; Hasegawa, M. Chem. Lett.
1986, 1347.
(15) In order to properly identify the minor enantiomer for HPLC
analysis, D-azatyrosine was prepared by alkylation of the enantiomeric
pseudoephedrine glycinamide ((S,S)-(+)-2) with iodide 6 followed by
alkaline hydrolysis. D-Azatyrosine showed equivalent spectroscopic
properties as L-azatyrosine, but opposite optical rotation.
(16) In contrast to other alkyl halides we have studied, small
amounts of N-alkylation products are observed (<5%) during the
1093, 1024, 865, 837, 804, 757, 741, 724, 692 cm-1
;
1H NMR
(CDCl3) δ 8.01 (d, 1H, J ) 2.7 Hz), 7.84 (d, 2H, J ) 7.9 Hz), 7.70
(t, 1H, J ) 7.2 Hz), 7.55 (t, 2H, J ) 7.8 Hz), 7.33 (dd, 1H, J )
8.5, 2.7 Hz), 7.13 (d, 1H, J ) 8.5 Hz), 2.53 (s, 3H). Anal. Calcd
alkylation with the highly reactive electrophile
6 whenever the
reactions are conducted above -78 °C. These N-alkylation products
are readily separated from the desired product by chromatography.
(17) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Notes
J . Org. Chem., Vol. 61, No. 2, 1996 815
for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62. Found: C, 57.66;
H, 4.33; N, 5.47.
purified by chromatography on silica gel eluting with 4:4:92
methanol:triethylamine:dichloromethane. Although the dia-
steromers were largely separable, they were collected together
in order to establish the true overall reaction yield. After
concentration of appropriate fractions, the product residue was
concentrated from toluene (2 × 150 mL) and then chloroform (2
× 150 mL) to remove residual triethylamine. The product 7 was
isolated as a very thick oil (11.6 g, 92%). The diastereoselectivity
of the reaction was determined by removing a small sample of
the crude reaction product (prior to chromatography) and
subjecting it to aqueous alkaline hydrolysis conditions (see
below), followed by acidification of the aqueous hydrolysis
mixture to pH 6 with concd H3PO4 and analysis on a chiral
HPLC column (see General Experimental). TLC Rf major
diasteromer ) 0.52, minor diasteromer ) 0.65 (5:5:90 MeOH:
NEt3:CH2Cl2); IR (neat) 3352, 3062, 2980, 1634, 1480, 1454,
1379, 1205, 1177, 1093, 1024, 868, 755, 738, 702 cm-1; 1H NMR
(approximately 1:1 rotamer ratio, CDCl3) δ 8.10 (d, 0.5H, J )
4.2 Hz), 8.09 (d, 0.5H, J ) 2.7 Hz), 7.83 (d, 2H, J ) 7.2 Hz), 7.69
(t, 1H, J ) 7.4 Hz), 7.55 (t, 2H, J ) 7.9 Hz), 7.16-7.41 (m, 7H),
4.71 (d, 0.5H, J ) 8.4 Hz), 4.60 (d, 0.5H, J ) 9.3 Hz), 4.33 (dd,
0.5H, J ) 6.8, 4.8 Hz), 4.16-4.26 (m, 1H), 4.12 (dd, 0.5H, J )
7.0, 5.7 Hz), 3.44 (dd, 0.5H, J ) 14.5, 4.7 Hz), 3.12 (dd, 0.5H, J
) 14.5, 7.0 Hz), 2.94 (s, 1.5H), 2.90 (s, 1.5H), 2.83-2.99 (m, 1H),
1.5-3.0 (s(br), 3H), 1.01 (d, 1.5H, J ) 6.9 Hz), 0.97 (d, 1.5H, J
) 6.7 Hz); 13C NMR (CDCl3) δ 175.3, 174.6, 157.6, 156.9, 144.9,
143.0, 142.8, 142.1, 141.5, 134.9, 134.5, 130.2, 130.1, 129.8, 128.5,
128.3, 128.2, 128.1, 127.6, 127.1, 126.6, 124.8, 124.7, 75.4, 75.3,
59.0, 58.0, 51.6, 51.2, 42.9, 42.7, 32.5, 26.9, 15.7, 14.1. HRMS
for C24H28N3O5S (MH+) requires 470.1750, found 470.1737.
Anal. Calcd for C24H27N3O5S: C, 61.39; H, 5.80; N, 8.95.
Found: C, 59.96; H, 5.81; N, 8.64.
5-(Ben zen esu lfon yloxy)-2-(br om om eth yl)p yr id in e (5). A
mixture of 4 (33.48 g, 134.3 mmol, 1 equiv) and N-bromosuc-
cinimide (33.47 g, 188.0 mmol, 1.40 equiv) in deoxygenated
carbon tetrachloride (300 mL) was heated to reflux. 2,2′-Azobis-
(2-methylpropiononitrile) (2.00 g, 11.6 mmol, 0.09 equiv) was
added to the refluxing mixture and heating was continued.
Additional 2.00-g portions of 2,2′-Azobis(2-methylpropiononitrile)
were added to the refluxing reaction mixture at 30 min intervals
over a a total reaction period of 2 h. Heating was discontinued
after 2 h, and the reaction mixture was allowed to cool. The
crude reaction mixture was concentrated in vacuo to remove the
bulk of the carbon tetrachloride, and the resulting slurry was
diluted with ethyl acetate (500 mL) and washed with water (400
mL). The organic layer was washed with a mixture of saturated
aqueous sodium bicarbonate solution (250 mL) and saturated
aqueous sodium thiosulfate solution (100 mL). The aqueous
layers were extracted with a second portion of ethyl acetate (250
mL). The combined organic layers were dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified by chromatography on silica gel eluting with a
gradient of 4:1 dichloromethane:hexanes to dichloromethane to
10:1 dichloromethane:ethyl acetate to provide 5 (23.08 g, 52%)
as a white solid: mp 103-108 °C; IR (KBr) 3022, 1584, 1480,
1376, 1368, 1023, 1180, 1087, 1022, 854, 812, 766, 734, 689, 620,
603, 579, 548 cm-1; 1H NMR (CDCl3) δ 8.12 (s, 1H), 7.86 (d, 2H,
J ) 7.4 Hz), 7.72 (t, 1H, J ) 7.5 Hz), 7.57 (t, 2H, J ) 7.9 Hz),
7.45 (d(obs), 2H, J ) 1.5 Hz), 4.51 (s, 2H); 13C NMR (CDCl3) δ
155.6, 145.5, 143.4, 134.8, 134.6, 131.0, 129.4, 128.4, 124.2, 32.5.
Anal. Calcd for C12H10BrNO3S: C, 43.92; H, 3.07; N, 4.27.
Found: C, 43.72; H, 3.01; N, 4.16.
[S]-2-Am in o-3-(5-h yd r oxyp yr id yl)p r op a n oic Acid (L-
Aza tyr osin e, 1). A suspension of 7 (27.22 g, 57.97 mmol, 1
equiv, 97% de) in aqueous sodium hydroxide solution (0.500 M,
464 mL, 232 mmol, 4.00 equiv) was heated at reflux for 6 h.
The resulting homogeneous solution was then cooled to 23 °C
and extracted with two portions of dichloromethane (500 mL,
250 mL). The organic layers were combined and extracted with
water (200 mL) and then dried over anhydrous potassium
carbonate. Concentration of the organic layers provided 8.61 g
(90%) of recovered pseudoephedrine. The combined aqueous
layers were acidified with aqueous hydrochloric acid solution
(1.00 M, 232 mL, 232 mmol, 4.00 equiv) producing a slightly
acidic solution (pH ) 3). The volume of the aqueous solution
was reduced to approximately 100 mL in vacuo, and the
concentrate was applied to an ion exchange resin (100 g, Dowex
50WX4, 50-100 mesh). The resin was flushed with water until
the eluent was neutral (pH ) 6). The product was then eluted
with 0.25 M aqueous ammonium hydroxide solution (Note: on
occasion the product will begin to precipate on the column. In
this case, the column contents are transferred to a large sintered-
glass funnel and the product is eluted with 0.25 M aqueous
ammonium hydroxide solution). The ninhydrin-positive frac-
tions were combined and concentrated to provide 9.73 g of a pale
yellow solid. The solid was recrystallized from water (400 mL)
to afford 4.358 g (41%) of L-azatyrosine as a pale solid. Con-
centration and crystallization of the mother liquors provided two
additional crops of product (3.399 g, 32%). If desired, the mother
liquors may be decolorized by the addition of activated charcol
and filtration through Celite prior to recrystallization. All three
crops of amino acid were g99% ee and all passed CHN
5-(Ben zen esu lfon yloxy)-2-(iod om eth yl)p yr id in e (6). So-
dium iodide (5.48 g, 36.6 mmol, 2.00 eqiuv) was added to a
solution of 5 (6.00 g, 18.3 mmol, 1 equiv) in acetone (75 mL),
and the resulting heterogeneous mixture was stirred for 2.5 h
at 23 °C. Acetone was removed by concentration in vacuo. The
residue was diluted with ethyl acetate (100 mL), and the
resulting mixture was washed with water (100 mL). The organic
layer was extracted with a mixture of saturated aqueous sodium
bicarbonate solution (30 mL) and saturated aqueous sodium
thiosulfate solution (10 mL). The aqueous layers were extracted
with a second portion of ethyl acetate (75 mL). The combined
organic layers were dried over anhydrous sodium sulfate, filtered
and concentrated in vacuo to produce a yellow-brown solid. The
product was recrystallized from a mixture of ethyl acetate (15
mL) and ether (30 mL) to provide 5.18 g of 6 as a stable, light
brown crystalline solid. Concentration of the mother liquors and
recrystallization provided an additional 1.19 g of 6 (total 6.37 g,
93%). Larger scale preparations of this compound (20 g of 6)
provided yields of 75-82%: mp 111-113 °C; IR (KBr) 3032,
1584, 1475, 1450, 1375, 1299, 1203, 1179, 1087, 1020, 946, 853,
808, 763, 733, 689, 611, 583, 568, 545 cm-1; 1H NMR (CDCl3) δ
8.06 (dd, 1H, J ) 1.0, 2.2 Hz), 7.85 (dd, 2H, J ) 1.0, 8.2 Hz),
7.72 (t, 1H, J ) 6.3 Hz) 7.57 (t, 2H, J ) 7.4 Hz), 7.39 (m, 2H),
4.47 (s, 2H); 13C NMR (CDCl3) δ 157.1, 144.9, 143.3, 134.7, 134.4,
130.8, 129.4, 128.3, 123.5, 4.5. Anal. Calcd for C12H10INO3S:
C, 38.42; H, 2.69; N, 3.73. Found: C, 38.51; H, 2.85; N, 3.47.
[[R,R]-2S]-N-(2-Hydr oxy-1-m eth yl-2-ph en yleth yl)-N-m eth -
yl 2-a m in o-3-(2-(5-b en zen esu lfon yloxy)p yr id yl)p r op ion -
a m id e (7). A solution of n-butyllithium in hexanes (2.64 M,
29.5 mL, 78.0 mmol, 2.93 equiv) was added to a solution of
diisopropylamine (11.2 mL, 80.0 mmol, 3.00 equiv) in deoxy-
genated tetrahydrofuran (50 mL) at 0 °C. After 15 min, the
resulting solution of lithium diisopropylamide was transferred
via cannula over 5 min to a stirred slurry of anhydrous 2 (8.89
g, 40.0 mmol, 1.50 equiv) and flame-dried lithium chloride (10.2
g, 240 mmol, 9.00 equiv) in deoxygenated tetrahydrofuran (100
mL) at 0 °C. After 20 min, the bright yellow suspension was
cooled to -78 °C and a solution of 6 (10.0 g, 26.7 mmol, 1 equiv)
in tetrahydrofuran (40 mL with a 10-mL wash) was added slowly
to the reaction mixture. The reaction mixture was stirred for 3
h at -78 °C and was then warmed to -45 °C and stirred for an
additional 3 h. Water (400 mL) was added, and the resulting
two-phase mixture was warmed to 23 °C and extracted with one
400-mL and two 200-mL portions of dichloromethane. The
combined organic layers were dried over anhydrous potassium
carbonate, filtered, and concentrated in vacuo. The residue was
analysis: mp 253-256 °C dec, lit.4 262-263 °C dec; [R]20
)
D
+59.3 (c ) 1.08, 1 N HCl), lit.4 +55 (c ) 1.1, 1 N HCl); IR (KBr)
3084, 2988, 1625, 1597, 1571, 1489, 1410, 1347, 1294, 1255,
1150, 850, 692, 525 cm-1; 1H NMR (D2O) δ 8.05 (d, 1H, J ) 2.5
Hz), 7.28 (dd, 1H, J ) 8.5, 2.8 Hz), 7.21, (d, 1H, J ) 8.4 Hz),
4.03 (dd, 1H, J ) 7.9, 5.1 Hz), 3.29 (dd, 1H, J ) 15.1, 5.1 Hz),
3.15 (dd, 1H, J ) 15.1, 7.9 Hz). Anal. Calcd for C8H10N2O3: C,
52.74; H, 5.53; N, 15.38. Found: C, 52.57; H, 5.65; N, 15.00.
Ack n ow led gm en t. This research was generously
supported by the National Science Foundation and the
National Institutes of Health. J .L.G. acknowledges
postdoctoral fellowship support from the National In-
stitutes of Health.
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