New and Efficient Synthesis of an Amino Acid for Preparing Phosphine-Functionalized Peptidomimetics

Full text of DOI:10.1021/jo9803075

5262
J . Org. Chem. 1998, 63, 5262-5264
Sch em e 1. Syn th esis of Ch ir on 1
New a n d Efficien t Syn th esis of a n Am in o
Acid for P r ep a r in g
P h osp h in e-F u n ction a lized P ep tid om im etics
Alexander M. Porte, Wilfred A. van der Donk,† and
Kevin Burgess*
Department of Chemistry, Texas A & M University,
College Station, Texas 77843
Received February 18, 1998
Gilbertson and co-workers have used the N-protected
amino acid 1 as the key building block in syntheses of
peptidomimetics having one or more phosphine-contain-
ing side chains.1,2 These products have conformational
properties that may be conveniently modulated by adding
metals to coordinate with the phosphine moieties. More-
over, libraries of peptidomimetics derived from 1 can be
produced via combinatorial methods;3,4 hence, they are
obvious targets for high-throughput catalyst screening,
an interest shared by our group5-7 and by Gilbertson et
al.8,9
phide. The resulting phosphine needed to be protected
immediately to shelter it from oxidation in the subse-
quent steps in this synthesis and in solid-phase syntheses
of peptidomimetics. Phosphine boranes have been used
extensively to protect phosphorus(III) centers,14-16 but in
our studies the derivative 4 was insufficiently robust to
tolerate the unavoidable oxidation steps that follow later
in the synthesis. Consequently, the intermediate phos-
phine was oxidized to the corresponding phosphine
sulfide 5. Treatment with aqueous acid had the desired
effect of cleaving the oxazolidine ring, but removal of the
tert-butyloxycarbonyl N-protection was an undesired
consequence. The latter group was therefore reinstated
to give the alcohol 6, which was purified via flash
chromatography.
Oxidation of alcohol 6 to the corresponding acid
without racemization of the adjacent chiral center was a
nontrivial challenge. The Moffatt oxidation17,18 has been
used in similar situations where stereochemical integrity
is an issue;19 this step, followed by further oxidation of
the aldehyde produced using buffered permanganate,20
gave the corresponding BOC-protected amino acid 1 in
94% ee. The best method identified for oxidation of the
alcohol, however, was a pyridinium dichromate oxida-
tion21 in the presence of molecular sieves, giving the
product 1 in >99% ee as assessed via chiral-phase
The published route to the phosphine sulfide 1 involves
diastereoselective transfer of an azido group10 to an
oxazolidinone enolate.1 This paper describes an alterna-
tive procedure that does not involve expensive chiral
auxiliaries, or diastereoselective reactions which are
critically dependent upon reaction conditions and workup
procedures. It does, however, give optically pure product
via a protocol amenable to scale-up.
Serine was converted into the BOC-protected ester 2
(Scheme 1) via a practical improvement11 of earlier
procedures.12,13 Reduction of the ester and tosylation
gave the intermediate 3, which was conveniently purified
via recrystallization. A phosphine functionality was then
introduced via a nucleophilic displacement using phos-
† Present address: University of Illinois at Urbana-Champaign,
Department of Chemistry, 600 South Mathews Ave., Urbana, IL 61801.
(1) Gilbertson, S. R.; Chen, G.; McLoughlin, M. J . Am. Chem. Soc.
1994, 116, 4481-2.
(2) Gilbertson, S. R.; Chen, G. H.; Kao, J .; Beatty, A.; Campana, C.
F. J . Org. Chem. 1997, 62, 5557-5566.
(3) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gordon, E. M. J . Med. Chem. 1994, 37, 1233-51.
(4) Gordon, E. M.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gallop, M. A. J . Med. Chem. 1994, 37, 1385-401.
(5) Burgess, K.; Lim, H.-J .; Porte, A. M.; Sulikowski, G. A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 220-2.
(6) Burgess, K.; Moye-Sherman, D.; Porte, A. M. In Molecular
Diversity and Combinatorial Chemistry; Chaiken, I. M., J anda, K. D.,
Eds.; American Chemical Society: Washington, DC, 1996; pp 128-36.
(7) Burgess, K.; Porte, A. M. In Advances in Catalytic Processes;
Doyle, M. P., Ed.; J AI Press: Greenwich, CT, 1997; Vol. 2, pp 69-82.
(8) Gilbertson, S. R.; Wang, X. Tetrahedron Lett. 1996, 36, 6475-8.
(9) Gilbertson, S. R.; Chang, C.-W. T. Chem. Commun. 1997, 975-
6.
(14) Pellon, P. Tetrahedron Lett. 1992, 33, 4451-2.
(15) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K.
J . Am. Chem. Soc. 1990, 112, 5244.
(16) Corey, E. J .; Chen, Z.; Tanoury, G. J . J . Am. Chem. Soc. 1993,
115, 11000-1.
(17) Pfitzner, K. E.; Moffatt, J . G. J . Am. Chem. Soc. 1965, 87, 5661-
5669.
(18) Pfitzner, K. E.; Moffatt, J . G. J . Am. Chem. Soc. 1965, 87, 5670-
5678.
(10) Evans, D. A.; Britton, T. C. J . Am. Chem. Soc. 1987, 109, 6881-
3.
(19) Fearon, K.; Spaltenstein, A.; Hopkins, P. B.; Gelb, M. H. J . Med.
Chem. 1987, 30, 1617-1622.
(11) McKillop, A.; Taylor, R. J . K.; Watson, R. J .; Lewis, N. Synthesis
1994, 31-3.
(12) Garner, P.; Park, J . M. Org. Synth. 1991, 70, 18-28.
(13) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-4.
(20) Abiko, A.; Roberts, J . C.; Takemasa, T.; Masamune, S. Tetra-
hedron Lett. 1986, 27, 4537-4540.
(21) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399-402.
S0022-3263(98)00307-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/25/1998

Notes
J . Org. Chem., Vol. 63, No. 15, 1998 5263
mL of a 10 M solution of n-butyllithium in hexanes was added,
providing a bright orange solution of the phosphine anion. After
being stirred for 0.5 h, the solution was warmed to 0 °C and
added via cannula dropwise to a solution of 3 (5.0 g, 13 mmol)
in 150 mL of THF. The addition was continued until the orange
color persisted and TLC showed complete consumption of the
sulfonyl starting material. The reaction mixture was then
treated with a stoichiometric amount of elemental sulfur (416
mg, 13 mmol) at 0 °C. The reaction was followed by TLC and
stopped when the phosphine starting material had disappeared
(approximately 1 h). The solvent was removed, giving a crude
oil that was then recrystallized from ethyl acetate/hexanes,
providing 3.42 g of colorless crystals. Recovery of material from
the mother liquor and recrystallization of this gave 1.02 g
slightly yellow crystals (pure enough for use in the next stage
in this sequence). The combined yield of these materials was
4.44 g (87%): mp 133-134.5 °C; Rf 0.24 (9:1 hexanes/EtOAc);
1H NMR (300 MHz, C6D5CD3, 90 °C) δ 8.05-8.25 (b, 2H), 7.72-
7.90 (m, 2H), 6.94-7.25 (m, 6H), 4.20-4.80 (b, 2H), 3.65-3.80
(b, 1H), 3.25-3.70 (b, 1H), 2.40-2.70 (b, 1H), 1.60 (s, 3H), 1.45
(s, 12H); 13C NMR (75.4 MHz, C6D5CD3, 90 °C) δ 152.1, 132.1-
128.6, 80.1, 67.6, 54.8, 35.6 (d, J CP ) 51.6 Hz), 28.7, 27.8; 31P
NMR (121 MHz, C6D5CD3, 90 °C) δ 37.4; IR 3054, 2975, 1688,
1396, 1166, 1099 cm-1; HRMS (FAB/acc. mass) m/z calcd
454.1582 for C23H30NO3PS + Na, found 454.1605; [R]D -13.2
(c ) 1.12, CHCl3, 25 °C).
analytical HPLC of the corresponding methyl ester
(formed via treatment of 1 with diazomethane).
Only one chromatographic separation was used in the
synthesis of 1 from serine. The intermediate preceding
this separation, i.e., compound 5, could be prepared on a
very large scale, and purification of 6 is the only major
restriction on the amounts of 6 and 1 that can be
produced. The synthesis begins with serine, which is
fortunate because both enantiomers of this amino acid
are relatively cheap. In this synthesis, L-serine was used
as a starting material, giving the phosphine sulfide in
the D-series. The overall yield of the product 1 from
serine was 22%.
Chiron 1 can be used in the typical reactions involved
in peptide syntheses, and the phosphine sulfide side
chains can be reduced to the corresponding phosphines
using Raney nickel1 or via an alkylation of the sulfur and
reaction with a phosphorus(III) compound.22
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were uncorrected.
Proton NMR spectra were recorded at 200 or 300 MHz; 13C
spectra at 50 or 75.4 MHz; 31P spectra were recorded at 121 MHz
referenced to H3PO4 external standard. Where necessary, the
carbon multiplicities were determined via APT experiments.
Thin-layer chromatography was performed using silica gel 60
F254 plates. Flash chromatography was performed using silica
gel (230-600 mesh). DMF was stored over 4 Å molecular sieves
for 1 week before use; CH2Cl2, THF, and methanol were distilled
from appropriate drying agents. 4-Methyl-(S)-N-(tert-butyloxy-
carbonyl)-2,2-dimethyl-4-oxazolidinecarboxylate 2 was synthe-
sized via a literature procedure,11 and it is also available from
Aldrich Chemical Co. Other chemicals were purchased from
commercial suppliers and used as received.
(S)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-3-[(d ip h en ylp h os-
p h in o)su lfid e]p r op a n -1-ol (6). The protected intermediate 5
(812 mg, 1.9 mmol) was placed in 10 mL of MeOH and cooled to
0 °C. Gaseous HCl was bubbled through the reaction for 5 min,
whereupon the starting material was consumed (TLC). The
solvent was then removed and the residue was redissolved in
10 mL of THF and cooled to 0 °C. Triethylamine (1.05 mL, 7.5
mmol) was added, followed by di-tert-butyl dicarbonate (615 mg,
2.8 mmol), and the solution was stirred for 2 h. The reaction
was diluted with EtOAc (40 mL) and washed with 0.5 M HCl
and brine. The organic layer was dried over Na2SO4, and
filtered, and the solvent was removed. Purification was per-
formed via flash chromatography on silica gel (3:2 hexanes/
EtOAc), providing 621 mg (84%) of 6 as a white solid: mp 106-
107.5 °C; Rf 0.21 (3:2 hexanes/EtOAc); 1H NMR (300 MHz,
CDCl3) δ 7.90-8.00 (m, 2H), 7.75-7.85 (m, 2H), 7.38-7.55 (m,
6H), 5.22 (d, J ) 9.4 Hz, 1H), 3.92 (m, 2H), 3.62 (m, 1H), 3.45
(m, 1H), 3.15 (m, 1H), 2.70 (m, 1H), 1.35 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 155.5, 133.8, 132.7, 131.7 (d, J CP ) 14.5 Hz),
131.6 (d, J CP ) 14.6 Hz), 131.3 (d, J CP ) 10.5 Hz), 130.7 (d, J CP
) 10.5 Hz), 128.8 (d, J CP)9.1 Hz), 128.7 (d, J CP ) 9.0 Hz), 79.7,
64.3 (d, J CP ) 6.5 Hz), 49.4, 33.8 (d, J CP ) 54.6 Hz), 28.3; 31P
NMR (121 MHz, CDCl3) δ 38.3; IR 3392, 2968, 1685, 1509, 1165,
(S )-N -t er t -Bu t oxyca r b on yl-4-[[(4′-m e t h ylb e n ze n e su l-
fon yl)oxy]m eth yl]-2,2-d im eth yloxa zolid in e (3). A solution
of 2 (2.59 g, 10.0 mmol) in 10 mL of THF was added dropwise to
a stirred suspension of lithium borohydride (650 mg, 30 mmol)
at 0 °C in 15 mL of THF. The reaction was allowed to warm to
room temperature and stirred until all starting material was
consumed as determined by TLC (ca. 4 h). The solution was
diluted with 200 mL of ethyl acetate. Dropwise addition of 1 M
HCl gave an emulsion. This dropwise addition was continued
until the emulsion disappeared and layers separated. The
aqueous layer was removed, and the organic layer was washed
with brine, dried over Na2SO4, and filtered. Removal of solvent
gave an oil that was used for the next step without further
purification. Thus, this oil was dissolved in 20 mL of dry
pyridine and cooled to 0 °C. 4-Methylbenzenesulfonyl chloride
(2.09 g, 11 mmol) was added, and the resulting yellow solution
was stored at 0 °C for 24 h. The solvent was then removed,
and remaining material was redissolved in ethyl acetate (100
mL) and washed three times with 1 M HCl (20 mL), one time
with brine (20 mL), dried over Na2SO4, and filtered. After
removal of solvent, the remaining solid was recrystallized from
ethyl acetate/hexanes to provide 2.58 g of colorless crystals
(67%): mp 108-109 °C; Rf 0.2 (9:1 hexanes/ethyl acetate); 1H
NMR (200 MHz, C6D6, 60 °C) δ 7.74 (d, J ) 8.0 Hz, 2H), 6.80 (d,
J ) 8.0 Hz, 2H), 4.22-4.27 (m, 1H), 3.88-4.08 (m, 2H), 3.73-
3.78 (m, 1H), 3.52-3.59 (m, 1H), 1.91 (s, 3H), 1.52 (s, 3H), 1.37
(s, 12H); 13C NMR (50 MHz, C6D6, 60 °C) δ 151.8, 144.6, 134.3,
130.0, 128.5, 128.0, 127.6, 94.3, 80.2, 68.3, 65.0, 56.2, 28.4, 27.1,
750 cm-1; HRMS (FAB/acc. mass) m/z calcd 414.1269 for C20H26
-
NO3PS + Na, found 414.1277; [R]D 0.11 (c ) 2.85, CHCl3, 25
°C).
(S)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-3-[(d ip h en ylp h os-
p h in o)su lfid e]-1-p r op a n oic Acid (1). Alcohol 6 (293 mg, 0.75
mmol) in 1.5 mL of DMF was added to a slurry of PDC (1.41 g,
3.75 mmol) and 3 Å powdered molecular sieves (1 g) in 2 mL of
DMF. Dichloroacetic acid (30 µL, 0.37 mmol) was then added
to the mixture. The solution was stirred for 12 h, after which
time all the alcohol starting material was consumed but some
intermediate aldehyde remained (TLC). Attempts to completely
oxidize this aldehyde intermediate under more forcing conditions
were unsuccessful. The solution was diluted in ether (30 mL)
and filtered through Celite. The filtrate was washed two times
with 0.5 M HCl (10 mL). The acid was extracted into aqueous
base by washing the organic solution three times with 1 N NaOH
(15 mL). This aqueous base layer was then carefully acidified
with 1 M HCl until the solution became turbid and an acidic
pH was observed. The organic material was extracted three
times with ether (15 mL), and the combined organic layers were
then washed with brine and dried over Na2SO4. Removal of the
solvent gave 139 mg (46%) of 1 as a fluffy white crystalline solid.
The optical purity of this material was determined by formation
of the methyl ester (diazomethane) and separation via HPLC
((S,S)-Whelk-O1 analytical column; eluting with 95:5-90:10 for
15 min then isocratic 90:10 hexanes/2-propanol, flow rate 0.8
mL/min, 254 nm, t1 ) 16.5 min, t2 ) 18.2 min). The HPLC
separation was calibrated using racemic material. None of the
23.6, 21.2; IR 3021, 1692, 1389, 1377, 1366, 1175, 653 cm-1
;
HRMS (FAB/acc. mass) m/z calcd 385.4790 for C18H27NO6S,
found 385.4773; [R]D -79.2 (c ) 2.01, CHCl3, 25 °C).
(S)-N-(ter t-Bu toxycar bon yl)-4-[(m eth ylen ediph en ylph os-
p h in o)su lfid e]-2,2-d im eth yloxa zolid in e (5). A flask was
charged with diphenylphosphine (7.25 g, 20 mmol), and 150 mL
of THF was added. The solution was cooled to -78 °C, and 2
(22) Gilbertson, S. R.; Wang, X. F.; Hoge, G. S.; Klug, C. A.; Schaefer,
J . Organometallics 1996, 15, 4678-4680.

5264 J . Org. Chem., Vol. 63, No. 15, 1998
Notes
other enantiomer was observed in the analysis of the optically
active material: mp 70-73 °C; Rf 0.22 (9:1 CHCl3/ MeOH); H
Chemical Society, The National Institutes of Health
(GM 50772 and DA 06554), and The Robert A. Welch
Foundation for support for this research, and K.B.
thanks the NIH for a Research Career Development
Award and the Alfred P. Sloan Foundation for a fellow-
ship. NMR facilities were provided by the NSF via the
chemical instrumentation program.
1
NMR (300 MHz, CDCl3) δ 7.75-7.85 (m, 4H), 7.20-7.35 (m, 6H),
5.56 (d, J ) 9.6 Hz, 1H), 4.42 (m, 1H), 3.15 (m, 1H), 1.35 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 175.5 (d, J CP ) 16.1 Hz), 155.2,
133.1 (d, J CP ) 31.1 Hz), 131.9 (d, J CP ) 30.5 Hz), 131.6, 131.1,
131.0, 130.9, 130.8, 130.7, 128.8, 128.7, 128.7, 128.6, 80.3, 50.2,
32.7 (d, J CP ) 57.6 Hz), 28.1; 31P NMR (121 MHz,CDCl3) δ 39.4;
IR 3318, 2979, 1718, 1501, 1170, 790 cm-1; HRMS (FAB/acc.
mass) m/z calcd 428.1061 for C20H26NO3PS + Na, found 428.1067;
[R]D 0.01 (c ) 3.16, CHCl3, 25 °C).
Ack n ow led gm en t. We thank The Petroleum Re-
search Foundation, administered by The American
J O9803075