A new approach to the synthesis of piperazinomycin and bouvardin: Facile access to cycloisodityrosine via an intramolecular SNAr reaction

Full text of DOI:10.1021/jo951375j

J . Org. Chem. 1996, 61, 771-774
771
Notes
A New Ap p r oa ch to th e Syn th esis of
P ip er a zin om ycin a n d Bou va r d in : F a cile
Access to Cycloisod ityr osin e via a n
In tr a m olecu la r SNAr Rea ction
Rene´ Beugelmans, Antony Bigot,
Miche`le Bois-Choussy, and J ieping Zhu*
Institut de Chimie des Substances Naturelles,
91198 Gif-sur-Yvette, France
Received J uly 27, 1995
Cycloisodityrosine (1) is a key subunit in a number of
bioactive natural products, such as piperazinomycin (3),1
bouvardin (4), deoxybouvardin (5), and structurally
related bicyclic hexapeptides RA I-XIV (Figure 1).2
Recently, in a series of elegant papers, Boger et al.3 have
demonstrated that cycloisodityrosine derivatives consti-
tute the pharmacophore of natural products in contrast
to earlier considerations2 and, thus, have stimulated
interest in this class of compounds.
Until recently, efforts to critically examine the biologi-
cal role of cycloisodityrosine derivatives have been limited
by their synthetic inaccessibility. Cyclization via mac-
rolactamization4 under different activating conditions
including polymer-supported agents, ring closure via C3-
O2 bond formation based on Ullmann ether synthesis,5
and intramolecular oxidative phenol coupling6 have all
failed to give the elusive 14-membered ring. An indirect
thallium trinitrate (TTN)-promoted intramolecular phe-
nol coupling has been developed by Yamamura et al. and
used in the total synthesis of piperazinomycin7 and
deoxybouvardin,8 but the key cyclization step proceeded
in only 5% yield (Scheme 1). Alternatively, ring closure
via C1-O2 bond formation based on intramolecular
Ullmann ether synthesis has been developed by Boger’s
group9 and successfully applied in the total synthsis of
bouvardin,10 deoxybouvardin,5 and piperazinomycin.11
However, the yield was still low to moderate. As shown
in Scheme 1, cyclization of dipeptide 8 under optimal
conditions gave the desired macrocycle 9 in only 5-10%
yield;11 intramolecular N-acylation resulting in the for-
mation of 10 (5-15%) and 11 (4-25%) was inevitable
under all attempted conditions.11
F igu r e 1.
Sch em e 1
Our interest in the synthesis of vancomycin-type
antibiotics has unveiled an efficient synthesis of 16-
(1) Tamai, S.; Kaneda, M.; Nakamura, S. J . Antibiot. 1982, 35,
1130-1136.
(2) Itokwa, H.; Takeya, K. Heterocycles 1993, 35, 1467-1501.
(3) Boger, D. L.; Patane, M. A.; J in, Q.; Kitos, P. A. Bioorg. Med.
Chem. 1994, 2, 85-100.
(4) Boger, D. L.; Yohannes, D. J . Org. Chem. 1991, 56, 1763-1767.
(5) Boger, D. L.; Yohannes, D.; Zhou, J .; Patane, M. A. J . Am. Chem.
Soc. 1993, 115, 3420-3430.
(6) Bates, R. B.; Gin, S. L.; Hassen, M. A.; Hruby, V. J .; J anda, K.
D.; Kriek, G. R.; Michaud, J . P.; Vine, D. B. Heterocycles 1984, 22,
785-790.
(7) Nishiyama, S.; Nakamura, K.; Suzuki, Y.; Yamamura, S. Tet-
rahedron Lett. 1986, 27, 4481-4484.
membered polypeptidic macrocycles12 via biaryl ether
formation based on intramolecular aromatic nucleophilic
(SNAr) substitution. This useful methodology was then-
expanded to the synthesis of 17-membered natural
(8) Inaba, T.; Umezawa, I.; Yuasa, M.; Inoue, T.; Mihashi, S.;
Itokawa, H.; Ogura, K. J . Org. Chem. 1987, 52, 2957-2958.
(9) Boger, D. L.; Yohannes, D. J . Org. Chem. 1991, 56, 1763-1767.
(10) Boger, D. L.; Patane, M. A.; Zhou, J . J . Am. Chem. Soc. 1994,
116, 8544-8556.
product K-1313 and 14-membered m,m-cyclophane,14
subunit found in teicoplanin. The very recent com-
a
(11) Boger, D. L.; Zhou, J . J . Am. Chem. Soc. 1993, 115, 11426-
11433.
0022-3263/96/1961-0771$12.00/0 © 1996 American Chemical Society

772 J . Org. Chem., Vol. 61, No. 2, 1996
Notes
Sch em e 2
Sch em e 3
from the known alkylation mechanism.16 The optical
munication from Boger’s group15 dealing with the syn-
thesis of simplified cycloisodityrosine (2a ) based on our
method prompts us to detail our own results concerning
the synthesis of the fully functionalized cycloisodityrosine
derivative (2b), a m,p-cyclophane, which is a key inter-
mediate in our projected total syntheses of piperazino-
mycin and deoxybouvardin.
purity of 15 was probed by conversion to the correspond-
1
ing (S)-lactate 16. The H NMR and GC/MS spectra of
16 showed that the optical purity of 15 was higher than
95%.
A significant amount of disubstituted compound 17 was
formed when the coupling of 12 and HO organocuprate
of bislactim ether 13 was run at -20 °C. The structure
of 17 was determined based on spectroscopic data (1H
and 13C NMR, HRMS). While no detailed mechanistic
study has yet been carried out, the formation of 17 may
be tentatively explained by 1,2-addition of organocuprate
onto the nitro group leading to intermediate A, followed
by complete reduction to secondary amine 17 via hy-
droxyamino intermediate B (Scheme 3). Cu+ may have
a rate-accelerating effect on the last reduction step (B to
17).21 A closely related reaction of a nitroarene with an
arylmagnesium halide was reported by Gilman et al. to
afford a complex mixture including nitroso, azoxy, azo,
and secondary amine.22 However, to the best of our
knowledge, the corresponding reaction with a HO orga-
nocuprate has not yet been described. The high reactivity
of the nitro group toward organometallic reagents may
explain the low to moderate yields obtained in the
alkylation of p-nitrobenzyl halides.18
Completion of the synthesis of 2b was as follows.
Reaction of 15 with N-Boc-L-Tyr using EDC as coupling
reagent in the presence of HOBt gave the dipeptide 18
in 97% yield. Without optimization, treatment of 18 with
K2CO3 in DMF (0.01 M) at room temperature for 3 h
cleanly afforded equal amounts of atropisomers12b 19 and
20 in 62% total yield. Apparently, the SNAr reaction
proceeded much faster than the intramolecular N-acyl-
ation11 as no products resulting from this latter process
were observed (vide supra).
The synthesis of the nonproteinogenic amino acid
methyl L-(S)-3-fluoro-4-nitrophenylalanate (15) is shown
in Scheme 2.13 A diastereoselective alkylation of Scho¨llko-
pf’s bislactim ether16 was a key step. The reaction of
3-fluoro-4-nitrobenzyl bromide 12 with the lithium aza-
enolate of 13 gave only a poor yield (<10%) of alkylated
product, presumably due to the high acidity of benzylic
protons17 and, more importantly, the presence of multi-
electrophilic centers in 12. Blank and Seebach18 also
obtained a moderate yield (30%) in the alkylation of
p-nitrobenzyl halides with their glycine template under
SN2 conditions. An attempt to switch the reaction course
from SN2 to a radical anion mechanism19 failed to give
the coupled product 14. However, when the lithium salt
of 13 was transmetalated into a higher order (HO)
organocuprate,20 14 could be reproducibly isolated in 75%
yield, provided that the reaction was run at -78 °C. That
SN2 (displacement of bromide) prevails over SNAr (dis-
placement of fluoride) under these conditions may be
explained by the HSAB principle if one considers the
organocuprate as a soft nucleophile. Hydrolysis of 14
under acidic conditions afforded the desired amino ester
15 in 92% yield. The S configuration of 15 was assumed
(12) (a) Beugelmans, R.; Zhu, J .; Husson, N.; Bois-Choussy, M.;
Singh, G. P. J . Chem. Soc., Chem. Commun. 1994, 439-440. (b)
Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J .; Zhu,
J . J . Org. Chem. 1994, 59, 5535-5542. (c) Bois-Choussy, M.; Beugel-
mans, R.; Bouillon, J . P.; Zhu, J . Tetrahedron Lett. 1995, 36, 4781-
4784.
The mass spectra and the elemental analysis of 19 and
20 reveal that they are constitutional isomers calculated
for C24H27N3O8. Both compounds exibited a character-
istic, strongly shielded H-19 at 5.37 and 5.34 ppm due
to the anisotropic effect of the tyrosine aromatic ring,
indicative of a cyclized structure. Attempted thermo-
atropoisomerization in DMSO-d6 at 110 °C failed to give
any equilibrium, probably due to the high energy re-
(13) Beugelmans, R.; Bigot, A.; Zhu, J . Tetrahedron Lett. 1994, 35,
7391-7394.
(14) Beugelmans, R.; Bourdet, S.; Zhu, J . Tetrahedron Lett. 1995,
36, 1279-1282.
(15) Boger, D. L.; Borzilleri, R. M. Bioorg. Med. Chem. Lett. 1995,
5, 1187-1190.
(16) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 798-799.
(17) Friedman, L.; Shechter, H. J . Org. Chem. 1960, 25, 877-879.
(18) Blank, S.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1993, 32,
1765-1766.
(19) Kornblum, N. Angew. Chem., Int. Ed. Engl. 1975, 14, 734-
745. (b) Kornblum, N.; Swiger, R. T.; Earl, G. W.; Pinnick, H. W.;
Stuchal, F. W. J . Am. Chem. Soc. 1970, 92, 5513-5514.
(20) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-
631. (b) Baldwin, J . E.; Adlington, R. M.; Mitchell, M. B. J . Chem. Soc.,
Chem. Commun. 1993, 1332-1335.
(21) Bartoli, G.; Medici, A.; Rosini, G.; Tavernari, D. Synthesis 1978,
436-437.
(22) (a) Gilman H.; McCracken, R. J . Am. Chem. Soc. 1927, 49, 1052.
(b) Curtin, D. Y.; Kauer, J . C. J . Am. Chem. Soc. 1953, 75, 6041-
6042. (c) Yost, Y.; Gutmann, H. R.; Muscoplat, C. C. J . Chem. Soc. C
1971, 2119-2122. (d) Bartoli, G. Acc. Chem. Res. 1984, 17, 109-115.

Notes
J . Org. Chem., Vol. 61, No. 2, 1996 773
Sch em e 4
synthesis of natural products based on these results will
be reported in due course.
F igu r e 2.
Exp er im en ta l Section
quired for this process. A control experiment showed that
no interchange of these two cyclic compounds occurred
under the above SNAr reaction and that both 16 and
N-Boc-L-Tyr-Tyr OMe were configurationally stable un-
der the cyclization conditions. These results gave indirect
evidence that the two cyclization products did not result
from the epimerization of two stereogenic centers and
hence are atropisomers.12b,23
Considering the difficulty encountered in the previous
syntheses of cycloisodityrosine, the facile cyclization
reported here is remarkable. High dilution technique
was not needed, so the solution conformation of the
cyclization precursor 18 may be such that the two
reactive sites are close.24 To gain information regarding
the solution conformation, we carried out a computational
simulation (Macromodel, Batchmin Version 3.5 a, Oplsa
force field, water set).25 As shown in Figure 2, the lowest
energy conformer has a bent orientation in which an
edge-to-face geometry between two aromatic rings is
evident. The two reactive sites (OH and CF) are within
5.129 Å, resulting in a low activation energy and favor-
able entropy for cyclization. The atomic charge model
or charge transfer (CT) model26 may be responsible for
such conformational preference.
General procedures and methods for characterization have
been described previously.12b Melting points are uncorrected.
(2S ,5R )-2-(3′-F lu or o-4′-n it r ob e n zyl)-5-isop r op yl-3,6-
d im eth oxy-2,5-d ih yd r op yr a zin e (14). Copper cyanide (208
mg, 2.32 mmol) was placed in a flame-dried, two-necked round-
bottomed flask (50 mL), evacuated with a vacuum pump, and
purged with argon. The procedure was repeated three times,
and dry THF (25 mL) was injected. In another flame-dried, two-
necked flask (25 mL) were introduced (2R)-(-)-2,5-dihydro-3,6-
dimethoxy-2-isopropylpyrazine (13) (831 µL, 4.64 mmol) and dry
THF (6 mL). The solution was cooled to -78 °C, and n-
butyllithium (1.6 M, 2.9 mL, 4.64 mmol) was added dropwise.
After being stirred for 10 min, it was transferred via cannula to
the flask containing the copper cyanide slurry, precooled to 0
°C. The reaction mixture was further stirred for 5 min after
addition, the resulting tan solution was recooled to -78 °C, and
the THF solution (3 mL) of 3-fluoro-4-nitrobenzyl bromide (12,
543 mg, 2.32 mmol) was introduced dropwise via syringe. The
reaction mixture was stirred at this temperature for 1 h and
quenched by addition of 10 mL of aqueous NH4Cl:NH4OH (9:1).
The aqueous solution was extracted with EtOAc. The combined
organic phase was washed with water, dried (Na2SO4), and
evaporated in vacuo. Purification by flash chromatography
(SiO2, heptane:ether ) 10:1) afforded starting material 12 (109
mg, 20%) and product 14 as a colorless oil (586 mg, 75%): [R]D
) +23.2° (CHCl3, c ) 0.97); IR (CHCl3) 2987, 1700, 1606, 1525,
1
1437, 1350, 1025 cm-1; H NMR (200 MHz, CDCl3) δ 0.64 (d, J
) 6.9 Hz, 3H), 0.98 (d, J ) 6.9 Hz, 3H), 2.19 (d of septet, J )
3.4, 6.9 Hz, 1H), 3.13 (dd, J ) 6.0, 13.2 Hz, 1H), 3.21 (dd, J )
4.5, 13.2 Hz, 1H), 3.63 (t, J ) 3.4 Hz, 1H), 3.67 (s, 3H), 3.73 (s,
3H), 4.30 (dt, J ) 4.1, 6.0 Hz, 1H), 7.09 (m, 2H), 7.95 (t, J ) 8.2
Hz, 1H); 13C NMR (CDCl3) δ 16.7, 19.0, 31.9, 39.8, 52.5, 55.9,
60.9, 119.7 (d, J ) 21.0 Hz), 125.5 (d, J ) 27.1 Hz), 125.7, 126.0
(d, J ) 3.9 Hz), 148.1, 155.0 (d, J ) 260.0 Hz), 161.8, 164.5; MS
m/z 338 (M + 1), 294, 183. Anal. Calcd for C16H20FN3O4: C,
56.97; H, 5.98; N, 12.45. Found: C, 57.50; H, 6.23; N, 12.18. A
variable amount of 17 was also isolated: [R]D ) +40.5° (CHCl3,
c ) 0.5); IR (CHCl3) 2975, 1700, 1675 cm-1; 1H NMR (200 MHz,
CDCl3) δ 0.60 (d, J ) 6.6 Hz, 3H), 0.68 (d, J ) 6.6 Hz, 3H), 0.98
(d, J ) 6.9 Hz, 3H), 1.05 (d, J ) 6.9 Hz, 3H), 2.12 (m, 1H), 2.25
(m, 1H), 2.98 (dd, J ) 4.4, 13.5 Hz, 1H), 3.08 (dd, J ) 4.7, 13.5
Hz, 1H), 3.25 (t, J ) 3.3 Hz, 1H), 3.60 (s, 3H), 3.66 (s, 3H), 3.71
(s, 3H), 3.78 (s, 3H), 4.00 (t, J ) 3.0 Hz, 1H), 4.31 (q, J ) 4.4
Hz, 1H), 5.29 (d, J ) 3.0 Hz, 1H), 5.75 (s, 1H), 6.8-7.2 (m, 2H),
7.29 (t, J ) 8.4 Hz, 1H); MS m/z 489, 474; HRMS m/z 489.2742
(C25H36FN5O4 requires 489.2751).
In summary, we describe a new and efficient method
for the synthesis of cycloisodityrosine derivatives using
an intramolecular SNAr reaction. The conditions are
much milder and the yield is much higher than those
previously reported. The NO2 function in 2b provides
an opportunity to introduce not only the hydroxyl group
found in the natural products13 but also others such as
amino and amide for bioactivity evaluation. Further
studies in this direction as well as toward the total
(23) Inoue et al. have recently detailed their total synthesis of
deoxybouvardin: Inoue, T.; Inaba, T.; Umezawa, I.; Yuasa, M.; Itokawa,
H.; Ogura, K.; Komatsu, K.; Hara, H.; Hoshino, O. Chem. Pharm. Bull.
1995, 43, 1325-1335. They noted that the 14-membered cycloisodity-
rosine, obtained via Yamamura's method, is an equilibrium mixture
of two compounds. We think that these two separable compounds could
be the two atropisomers instead of the two conformers as mentioned
in ref 8.
(24) (a) Winnik, M. A. Acc. Chem. Res. 1985, 18, 73-79. (b) Menger,
F. M. Acc. Chem. Res. 1985, 18, 128-134. (c) Mandolini, L. Bull. Soc.
Chim. Fr. 1988, 173-176.
Meth yl (S)-3-F lu or o-4-n itr op h en yla la n a te (15). To a
solution of 14 (230 mg, 0.68 mmol) in THF-acetonitrile (3/1)
was added 0.25 N HCl. After the solution was stirred for 30
min at room temperature, the volatiles were removed under
reduced pressure, the residue was extracted with CH2Cl2 to
remove the neutral species, and the aqueous phase was then
(25) J orgensen, W. L.; Tirado-Rivers, J . J . Am. Chem. Soc. 1988,
110, 1657-1666.
(26) Hunter, C. A.; Sanders, J . K. M. J . Am. Chem. Soc. 1990, 112,
5525-5534.

774 J . Org. Chem., Vol. 61, No. 2, 1996
Notes
basified with aqueous NaHCO3 and extracted with CH2Cl2. The
combined organic phase was washed with brine, dried (Na2SO4),
and evaporated to afford 15 (150 mg, 92%): [R]D ) +15° (c ) 1,
CHCl3); IR (CHCl3) 3450, 2988, 1738, 1613, 1531, 1269, 1063
cm-1; 1H NMR (250 MHz, CDCl3) δ 1.62 (brs, 2H), 2.93 (dd, J )
7.9, 13.7 Hz, 1H), 3.15 (dd, J ) 5.3, 13.7 Hz, 1H), 3.73 (m, 1H),
3.74 (s, 3H), 7.17 (m, 2H), 8.02 (t, J ) 8.2 Hz, 1H); 13C NMR
(CDCl3) δ 40.6, 55.3, 68.1, 119.2 (d, J ) 17.0 Hz), 125.5 (d, J )
30.5 Hz), 126.1, 147.3, 155.5 (d, J ) 211.0 Hz), 174.8; MS m/z
243 (M+ + 1), 242 (M+), 189. 15 contained a small amount of
methyl L-valinate, so no microanalysis was done.
Hz), 125.6 (d, J ) 27.5 Hz), 126.1 (d, J ) 2.6 Hz), 127.3, 130.3,
145.8, 155.4 (d, J ) 264.0 Hz), 155.8, 170.7, 171.9; MS m/z 506,
505. Anal. Calcd for C24H28FN3O8: C, 57.02; H, 5.58. Found:
C, 57.04; H, 5.71.
Ma cr ocycliza tion of 18. To a solution of 18 (20 mg, 0.04
mmol) in DMF (4 mL) was added K2CO3 (16 mg, 0.12 mmol).
After being stirred at room temperature for 3 h, the reaction
mixture was diluted with aqueous NaHCO3 and extracted with
EtOAc (10 × 20 mL). The combined organic phase was washed
with brine, dried (Na2SO4), and evaporated. Purification by flash
chromatography (SiO2, heptane:EtOAc ) 1:1) afforded two
products, 19 (6 mg, 31%) and 20 (6 mg, 31%). Compound 19:
mp 249-250 °C; [R]D ) -9.0° (CHCl3, c ) 0.1); IR (CHCl3) 3625,
3427, 3025, 1744, 1683, 1506 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.40 (s, 9H), 2.7-3.0 (m, 3H), 3.32 (dd, J ) 5.3, 12.1 Hz, 1H),
3.65 (s, 3H), 4.1-4.2 (m, 2H), 5.23 (d, J ) 9.3 Hz, 1H), 5.37 (br
s, 1H), 6.45 (d, J ) 7.4 Hz, 1H), 6.73 (dd, J ) 1.6, 8.4 Hz, 1H),
7.04 (dd, J ) 2.5, 8.3 Hz, 1H), 7.10 (dd, J ) 2.5, 8.3 Hz, 1H),
7.27 (dd, J ) 2.1, 8.3 Hz, 1H), 7.46 (dd, J ) 2.1, 8.3 Hz, 1H),
7.88 (t, J ) 8.4 Hz, 1H); 13C NMR (CDCl3) δ 28.4, 34.9, 39.0,
52.7, 53.2, 58.5, 80.7, 115.8, 117.0, 121.5, 124.2, 124.6, 125.7,
130.6, 131.2, 133.1, 135.7, 137.0, 144.8, 156.3, 156.6, 171.4; MS
m/z 485 (M+), 426, 384. Anal. Calcd for C24H27N3O8: C, 59.37;
H, 5.61. Found: C, 59.11; H, 5.65. Compound 20: mp 130-
131 °C; [R]D ) +35.4° (CHCl3, c ) 0.28); IR (CHCl3) 3425, 3031,
1744, 1718, 1681, 1500 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.50
(s, 9H), 2.9-3.0 (m, 3H), 3.51 (dd, J ) 5.3, 13.5 Hz, 1H), 3.68 (s,
3H), 4.25 (m, 1H), 4.57 (dt, J ) 4.9, 9.0 Hz, 1H), 5.09 (d, J ) 9.0
Hz, 1H), 5.34 (br s, 1H), 5.99 (brs, 1H), 6.74 (dd, J ) 1.6, 8.4
Hz, 1H), 7.08 (dd, J ) 2.5, 8.3 Hz, 1H), 7.17 (dd, J ) 2.5, 8.3 Hz,
1H), 7.4-7.5 (m, 2H), 7.87 (t, J ) 8.4 Hz, 1H); 13C NMR (CDCl3)
δ 28.4, 35.3, 38.8, 52.7, 53.0, 57.1, 81.6, 117.4, 121.8, 123.8, 124.9,
125.8, 130.3, 133.2, 135.0, 144.5, 156.5, 156.9, 171.2; MS m/z
485 (M+), 426, 384; HRMS m/z 485.1816 (C24H27N3O8 requires
485.1798).
16. To a solution of 15 (50 mg, 0.21 mmol) in CH2Cl2 was
added (S)-Me(MeCOO)CHCOCl (29 mL, 0.25 mmol), Et3N (35
mL, 0.25 mmol), and DMAP (3 mg, 0.025 mmol). After being
stirred at room temperature for 1 h, the reaction was quenched
by addition of aqueous NH4Cl and extracted with CH2Cl2. The
combined organic phase was washed with brine, dried (Na2SO4),
and evaporated. Purification by flash chromatography (SiO2,
heptane:EtOAc ) 1:2) afforded product 16 as a yellow solid (72
mg, 96%): mp 80-81°C; [R]D ) +41.7° (CHCl3, c ) 0.23); IR
(CHCl3) 3419, 2985, 1744, 1688, 1606, 1531, 1375 cm-1; 1H NMR
(200 MHz, CDCl3) δ 1.45 (d, J ) 6.8 Hz, 3H), 2.14 (s, 3H), 3.17
(dd, J ) 5.6, 13.8 Hz, 1H), 3.36 (dd, J ) 5.8, 13.8 Hz, 1H), 3.80
(s, 3H), 4.88 (m, 1H), 5.13 (q, J ) 6.8 Hz, 1H), 6.64 (d, J ) 6.9
Hz, 1H), 7.0-7.1 (m, 2H), 8.02 (t, J ) 8.0 Hz, 1H); MS m/z 356
(M+), 241; HRMS m/z 356.1124 (C15H17FN2O7 requires 356.1020).
Dip ep tid e 18. To a solution of compound 16 (162 mg, 0.67
mmol) in 20 mL of CH2Cl2 were added N-Boc-L-(S)-tyrosine (188
mg, 0.67 mmol), HOBt (135 mg, 0.67 mmol), and EDC (141 mg,
0.74 mmol). After being stirred at room temperature for 12 h,
the reaction mixture was diluted with aqueous HCl (0.1 N), and
the aqueous phase was extracted with CH2Cl2. The combined
organic phase was washed with brine, dried (Na2SO4), and
evaporated. Recrystallization from CH2Cl2 and heptane afforded
product 18 as a yellow solid (320 mg, 97%): mp 96-97 °C; [R]D
) +12.3° (CHCl3, c ) 0.13); IR (CHCl3) 3429, 3329, 2977, 1749,
1696, 1683, 1616 cm-1 1H NMR (250 MHz, CDCl3) δ 1.43 (s,
;
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
15-19, and 20 and GC analysis of 16 (6 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
9H), 2.92 (dd, J ) 7.1, 13.8 Hz, 1H), 3.02 (dd, J ) 6.5, 13.8 Hz,
1H), 3.09 (dd, J ) 5.8, 13.9 Hz, 1H), 3.21 (dd, J ) 5.8, 13.9 Hz,
1H), 3.72 (s, 3H), 4.26 (q, J ) 7.1 Hz, 1H), 4.80 (q, J ) 6.0 Hz,
1H), 4.92 (brs, 1H), 5.09 (brs, 1H), 6.42 (d, J ) 7.1 Hz, 1H), 6.75
(d, J ) 8.5 Hz, 2H), 6.9-7.0 (m, 2H), 7.05 (d, J ) 8.5 Hz, 2H),
7.96 (t, J ) 8.1 Hz, 1H); 13C NMR (CDCl3, a drop of CD3OD) δ
28.2, 37.5, 37.6, 52.6, 52.7, 56.1, 80.6, 115.5, 119.2 (d, J ) 20.3
J O951375J