Application of arene-ruthenium chemistry to a formal total synthesis of OF 4949 III

Article abstract of DOI:10.1021/jo960956l

A convergent formal total synthesis of OF 4949 III is described. Arene-ruthenium chemistry was used in the construction of the diaryl ether linkage in high yield, and cycloamidation under high dilution conditions (0.005 M) was achieved using DPPA as coupling reagent. SmI₂ was used to reductively remove the 2-iodoethyl ester protecting group in the presence of DMPU or HMPA.

Full text of DOI:10.1021/jo960956l

J . Org. Chem. 1996, 61, 6581-6586
6581
Ap p lica tion of Ar en e-Ru th en iu m Ch em istr y to a F or m a l Tota l
Syn th esis of OF 4949 III
Anthony J . Pearson,* Penglie Zhang, and Kieseung Lee
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106
Received May 24, 1996X
A convergent formal total synthesis of OF 4949 III is described. Arene-ruthenium chemistry was
used in the construction of the diaryl ether linkage in high yield, and cycloamidation under high
dilution conditions (0.005 M) was achieved using DPPA as coupling reagent. SmI2 was used to
reductively remove the 2-iodoethyl ester protecting group in the presence of DMPU or HMPA.
In tr od u ction
the phenoxide of tyrosine to give related aryl ether
derivatives without racemization.9 J ung and Starkey
reported a two-step preparation of O-(aryloxy)phenols via
cyclohexenone oxides,10 and a new route was introduced
by Rao’s group featuring a bromoquinone substitution
reaction.11 Very recently, a Diels-Alder reaction was
employed by Olsen for the synthesis of (S,S)-isodityrosi-
nol.12
OF 4949 I-IV were isolated from Ehrlich ascites
carcinoma cells of Penicilliun rugulosum.1 These agents
have exhibited potential aminopeptidase B inhibitory
activity, immunopotentiating activity and confirmed
antitumor activity without appreciable cytotoxicity. They
may constitute a new class of potentially useful antitu-
mor agents that can act as toxicity-free immunopoten-
tiators. Their structures were elucidated based on
spectroscopic and chemical degradative studies, the
characteristic feature being the isodityrosine subunit
connected by a diaryl ether linkage. The first total
synthesis of OF 4949 III was reported by Yamamura’s
group,2 based on a biomimetic, oxidative thallium trini-
trate (TTN)-promoted two-step phenolic coupling meth-
odology. In Schmidt’s and Evans’ approaches,3,4 CuO was
used as the mediator of the modified Ullmann reaction,
while CuBr‚SMe2 was used in Boger’s approach.5
A novel approach has been developed in our laboratory
to synthesize diaryl ether or triaryl diethers by using
transition metals.13 Chloroarenes are activated toward
nucleophilic substitution via complexation with MCp (M
) Fe, Ru) or Mn(CO)3, allowing the construction of the
diaryl ethers from amino acid derivatives with little or
no racemization. Ru is superior to Mn and Fe because
the attachment of chloroarene derivatives to cyclopen-
tadienyl ruthenium can be effected under very mild
conditions that are compatible with the racemization
prone amino acid functionalities. Ruthenium chemistry
has been successfully used in the synthesis of K-13 and
a model of Teicoplanin A.13e,f,h We report herein a formal
total synthesis of OF 4949 III (1) which again demon-
strates the application of this chemistry.
Resu lts a n d Discu ssion
Our strategy to synthesize OF 4949 III is illustrated
in Scheme 1. To suppress competitive succinimide or
iminosuccinic anhydride formation, macrocyclization was
chosen to be effected at the C11-N10 amide bond.5
According to this retrosynthetic analysis, two intermedi-
ates 4 and 5 were required.
The synthesis of intermediate 4 (Scheme 2) started
from 6 (prepared from commercially available 3-hydroxy-
4-methoxybenzaldehyde). The carboxylic acid was se-
lectively protected as its benzyl ester in the presence of
the phenolic group with BnBr/DBU. Subsequent protec-
tion of the phenolic group with TBDMSCl was ac-
Other methods to set in place a diaryl ether linkage
have also been developed. The SNAr reaction was
employed by Zhu6 and Hamilton7 in the synthesis of
several structurally related compounds, while Still has
used a similar method to prepare aryl thioether analogs.8
Brown used the reactivity of aryliodonium salts toward
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) (a) Sano, S.; Ikai, K.; Kuroda, H.; Nakamura, T.; Obayashi, A.;
Ezure, Y.; Enomoto, H. J . Antibiot. 1986, 39, 1674. (b) Sano, S.; Ikai,
K.; Katayama, K.; Takesako, K.; Nakamura, T.; Obayashi, A.; Ezure,
Y.; Enomoto, H. J . Antibiot. 1986, 39, 1685. (c) Sano, S.; Ueno, M.;
Katayama, K.; Nakamura, T.; Obayashi, A. J . Antibiot. 1986, 39, 1697.
(d) Sano, S.; Ikai, K.; Yoshikawa, Y.; Nakamura, T.; Obayashi, A. J .
Antibiot. 1987, 40, 512.
(2) Nishiyama, S.; Suzuki, Y.; Yamamura, S. Tetrahedron Lett. 1988,
29 , 559.
(3) Schmidt, U.; Weller, D.; Holder, A.; Lieberknecht, A. Tetrahedron
Lett. 1988, 29 , 3227.
(4) Evans, D. A.; Ellman, J . A. J . Am. Chem. Soc. 1989, 111, 1063.
(5) Boger, D. L.; Yohannes, D. J . Org. Chem. 1990, 55, 6000.
(6) For recent examples of Zhu’s work, see: (a) Zhu, J .; Bouillon,
J .-P.; Singh, G. P.; Chastanet, J .; Beugelmans, R. Tetrahedron Lett.
1995, 36, 7081. (b) Neuville, L.; Bois-Choussy, M.; Zhu, J . Tetrahedron
Lett. 1995, 36, 8787.
(7) Mann, M. J .; Pant, N.; Hamilton, A. D. J . Chem. Soc., Chem.
Commun. 1986, 158.
(8) Hobbs, D. W.; Still, W. C. Tetrahedron Lett. 1987, 28, 2805.
(9) Crimmin, M. J .; Brown, A. G. Tetrahedron Lett. 1990, 31, 2017.
(10) J ung, M. E.; Starkey, L. S. Tetrahedron Lett. 1995, 36, 7363.
(11) (a) Rao, A. V. R.; Gurjar, M. K.; Reddy, A. B.; Khare, V. B.
Tetrahedron Lett. 1993, 34, 1657. (b)Rao, A. V. R.; Gurjar, M. K.;
Kaiwar, V.; Khare, V. B. Tetrahedron Lett. 1993, 34, 1661.
(12) (a) Feng, X.; Olsen, R. K. J . Org. Chem. 1992, 57, 5811. (b)
Olsen, R. K.; Feng, X.; Campbell, M.; Shao, R.-L.; Math, S. K. J . Org.
Chem. 1995, 50, 6025.
(13) (a) Pearson, A. J .; Bruhn, P. R. J . Org. Chem. 1991, 56, 7092.
(b) Pearson, A. J .; Shin, H. J . Org. Chem. 1994, 59, 2314. (c) Pearson,
A. J .; Shin, H. Tetrahedron Lett. 1992, 48, 7527. (d) Pearson, A. J .;
Park, J . G.; Zhu, P. Y. J . Org. Chem. 1992, 57, 3583. (e) Pearson, A.
J .; Lee, K. J . Org. Chem. 1994, 59, 2304. (f) Pearson, A. J .; Lee, K. J .
Org. Chem. 1995, 60, 7153 . (g) Pearson, A. J .; Bignan, G. Tetrahedron
Lett. 1996, 37, 735. (h) Pearson, A. J .; Bignan, G.; Zhang, P.; Chelliah,
M. J . Org. Chem. 1996, 61, 3941.
S0022-3263(96)00956-5 CCC: $12.00 © 1996 American Chemical Society

6582 J . Org. Chem., Vol. 61, No. 19, 1996
Pearson et al.
Sch em e 1
Sch em e 3a
a
Reaction conditions, reagents and yields: (a) PTSA (2.0 equiv),
MeOH, reflux, 12 h, 95%; (b) H2, Pd-C (10%), 5 N HCl (3.0 equiv),
THF, rt, 4 h, then Boc-Asn, HOBt‚H2O (1.5 equiv), EDC (1.2 equiv),
iPr2NEt (1.0 equiv), THF/DMF (1:1), 0 °C to rt , 24 h, 81%; (c)
(CH3CN)3RuCpPF6 (1.2 equiv), 1,2-dichloroethane, reflux, 5 h,
100%.
ylmethyl)-2-oxazolidinone] was effected by standard meth-
ods, and the product 10 was treated with trisyl azide
under Evans’s azidation conditions to afford the R-azido
compound 11. The diastereomer ratio was determined
to be 97:3 by HPLC. Deprotection of 11 with TBAF (1.0
M in THF) gave disappointingly low yield (30-40%). We
also tried deprotection with HF/Py, but the product was
obtained in only 23% yield. Acceptable yield (>60%) was
achieved by using anhydrous TBAF (azeotropically dried
with benzene).15 Removal of the chiral auxiliary with
LiOH/H2O2, followed by ester formation with DCC/2-
bromoethanol gave 13 in high yield, which was then
subjected to hydrogenolysis conditions to give the amine
hydrochloride, and this was reacted with CbzCl/NaHCO3
to afford the Cbz protected compound 4 in 83% yield.
The chloroarene ruthenium complex 5 was synthesized
from 14 (Scheme 3), which was also prepared by Evans’s
azidation methodology.4 Acid-catalyzed esterification
under reflux conditions gave 15 in 95% yield. Hydro-
genolysis of 15 with Pd-C (10%)/H2 (1 atm) in THF/
MeOH (1:1) suffered from serious problems with dechlo-
rination. The same problem was encountered when THF
alone was used as the solvent. It was presumed that the
newly formed amino group coordinates with Pd and
enhances the catalytic activity of the metal which can
now cleave the C-Cl bond easily. The dechlorination
problem was solved by adding 3 equiv of HCl to the
reaction mixture, in anticipation that the HCl would
remove NH2 from the catalytic center immediately after
its formation. The resulting amine hydrochloride was
used in subsequent peptide formation under standard
reaction conditions with N-Boc-Asn, HOBt‚H2O, EDC and
N-methylmorpholine as base to give the dipeptide, but
with complete epimerization at one center (identity is
unknown). iPr2NEt was then used as the base to give
the desired dipeptide 16 with less than 5% epimerization.
The minor epimer was removed by recrystallization in
THF/hexane, and the pure dipeptide was obtained in 81%
yield. Complexation of 16 with [(CH3CN)3RuCp]PF6
under the usual conditions13f gave the intermediate 5 in
essentially quantitative yield.
Sch em e 2a
a
Reaction conditions, reagents and yields: (a) BnBr (1.0 equiv),
DBU, benzene, reflux, 7 h, 65%; (b) TBDMSCl (1.2 equiv), DMAP
(0.08 equiv), Et3N (1.3 equiv), CH2Cl2, rt, 20 h, 86%; (c) H2, Pd-C
(10%), THF, rt, 3.5 h, 99%; (d) Et3N (1.3 equiv), pivaloyl chloride
(1.1 equiv) then (4S)-4-(phenylmethyl)-2-oxazolidinone/n-BuLi
(0.95 equiv), THF, -78 °C to rt, 12 h, 87%; (e) KHMDS (1.3 equiv),
trisyl azide (1.1 equiv), THF, -78 °C, 2 min, 75%; (f) TBAF (1.0
equiv), THF, 0 °C, 1 h, 62%; (g) LiOH (2 equiv), H2O2 (6 equiv),
THF, 0 °C, 1.5 h, then 2-bromoethanol (1.2 equiv), DCC (1.1 equiv),
CH2Cl2, 0 °C, 12 h, 87%; (h) H2, Pd-C (10%), 5 N HCl (3 equiv),
THF, rt, 1.5 h, then CbzCl (1.1 equiv), NaHCO3 (2.5 equiv), CH2Cl2/
H2O, 0 °C to rt, 5 h, 84%.
The coupling reaction was first conducted according to
the standard protocol developed in our laboratory (Scheme
4). Compound 4 was treated with sodium 2,6-di-tert-
butyl phenoxide and then allowed to react with the
dipeptide complex 5 in THF. The mixture was stirred
at -78 °C for 1 h and then at rt for 3 h. After filtering
complished by employing the standard procedure to give
8,14 which was selectively deprotected to give acid 9 under
hydrogenolysis conditions employing Pd-C (10%)/H2 (1
atm). Attachment of the chiral auxiliary [(4S)-4-(phen-
(15) A new Pd-catalyzed desilylation of phenolic TBDMS ethers has
been reported recently. Wilson, N. S.; Keay, B. A. Tetrahedron Lett.
1996, 37, 153.
(14) Ono, N.; Yamada, T.; Saito, T. Bull. Chem. Soc. J pn. 1978, 51,
2401

Total Synthesis of OF 4949 III
Sch em e 4a
J . Org. Chem., Vol. 61, No. 19, 1996 6583
(59%). After the Boc protecting group was removed with
30% TFA/CH2Cl2 in the presence of thioanisole, DPPA-
promoted cycloamidation was accomplished by slow ad-
dition of 19 into a DPPA/NaHCO3/DMF mixture over 3
h via a syringe pump (final concentration: 0.005 M), and
stirring for a further period of 3 days at 0 °C furnished
2 as a white solid in 53% yield, mp 181-183 °C (lit. 179-
182 °C), [R]23D -73° (c 0.35, CH3OH) (lit. -74°, c 0.1, CH3-
OH).5 1H NMR spectroscopy of compound 2 provided
evidence for the cycloamidation: the aromatic proton Ha
(see structure) stood out clearly in the higher field region
(∼6.0 ppm), compared with between 7.7-6.7 ppm for all
other aromatic Hs. This is a known feature for this series
of compounds.17 Intermediate 2 was used by Boger to
synthesize OF 4949 III,5 so our results constitute a formal
total synthesis of this target.
Con clu sion s
Chloroarene-ruthenium chemistry was used for con-
struction of the aryl ether linkage in the development of
a convergent total synthesis of OF 4949 III. The dipep-
tide 16 with polar substituents can be metalated selec-
tively under the usual complexation conditions in quan-
titative yield. Deprotection of a 2-iodoethyl ester was
effected by using SmI2 in the presence of DMPU or
HMPA in satisfactory yield, and both Boc and Cbz were
stable under these mild conditions.
a
Reaction conditions, reagents and yields: (a) Sodium 2,6-di-
tert-butylphenoxide (1.1 equiv), acetone, -30 °C then to rt; (b)
sunlamp (300 W), CH3CN rt, 24 h, two times, 77% two steps; (c)
NaI (7 equiv), acetone, reflux, 5 h, 98%; (d) SmI2 (7 equiv), DMPU
(42 equiv), THF, 0 °C, 10 min, rt, 3 h, 61%; (e) 30% TFA/CH2Cl2,
thioanisole (20 equiv), 0 °C, 1.5 h then DPPA (1.5 equiv), NaHCO3
(5 equiv), DMF, 0 °C, 3 d, 52%.
Exp er im en ta l Section
through a Celite pad and removal of the solvent, complex
17 was obtained in 87% yield. Demetalation (two cycles)
was achieved in CH3CN with a sun lamp (300W, GE) in
a quartz tube to give compound 3 in 34% yield. The
metal was recovered in the form of (CH3CN)3RuCpPF6
in more than 80% yield. To optimize this reaction,
acetone was employed as the solvent in the coupling step,
which was performed at -30 °C and allowed to warm to
rt.13g Demetalation gave 3 in 77% yield (two steps). It
should be noted that in the NMR spectrum the CO2Me
group gave two peaks in about 1:1 ratio, which we
attributed to restricted rotation about a C-N bond
(amide resonance). NMR at 90 °C in CD3NO2 led to
partial coalescence to a singlet, and the peak doubling
reappeared when cooling to rt. Similar phenomena have
been observed previously in our laboratory.13f
Gen er a l. Genral procedures are as described elsewhere.16
3-(3-Hyd r oxy-4-m eth oxyp h en yl)p r op ion ic Acid Ben zyl
Ester (7). To a stirred solution of 3-(3-hydroxy-4-methoxy-
phenyl)propionic acid (6) (4.90 g, 25.0 mmol) in 50 mL of dry
benzene were added DBU (3.73 mL, 1.0 equiv), and benzyl
bromide (3.56 mL, 1.0 equiv), and the resulting mixture was
heated to reflux for 7 h under Ar. The reaction mixture was
cooled to rt, washed with water, saturated NaHCO3, and brine,
and dried with MgSO4. Removal of solvent under reduced
pressure gave a pale yellow residue, which was purified by
flash chromatography to afford 4.44 g (65%) of 7 as a pale
yellow solid: mp 52.5-54.0 °C; Rf 0.47 (6:4 hex/EtOAc); IR
(KBr) 1723 cm-1; 1H NMR (CDCl3) δ 7.36-7.25 (m, 5H), 6.77-
6.64 (m, 3H), 5.58 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H), 2.88 (t,
2H, J ) 7.8 Hz), 2.64 (t, 2H, J ) 7.8 Hz); 13C NMR (CDCl3) δ
172.7, 145.5, 145.0, 135.0, 133.7, 128.5, 128.2, 119.6, 114.5,
110.6, 66.2, 55.9, 36.0, 30.3; HRMS calcd for C17H18O4 286.1205,
found 286.1210.
3-[4-Met h oxy-3-(ter t-b u t yld im et h ylsilyloxy)p h en yl]-
p r op ion ic Acid Ben zyl Ester (8). To a stirred solution of
the benzyl ester 7 (4.36 g, 15.3 mmol) and TBDMSCl (2.75 g,
1.2 equiv) in 50 mL of CH2Cl2 were added DMAP (0.149 g,
0.08 equiv) and Et3N (2.76 mL, 1.30 equiv), and the resulting
mixture was stirred for 17 h under Ar. The reaction mixture
was washed with water, saturated NH4Cl, and brine and dried
with MgSO4. The solvent was removed to give crude product,
which was purified by flash chromatography to provide 5.22
g (86%) of 8 as a colorless oil: Rf 0.49 (7:3 hex/EtOAc); 1H NMR
(CDCl3) δ 7.36-7.32 (m, 5H), 6.78 (d, 1H, J ) 8.2 Hz), 6.75 (d,
1H, J ) 2.0 Hz), 6.71 (dd, 1h, J ) 8.2, 2.0 Hz), 5.09 (s, 2H),
3.77 (s, 3H), 2.85 (t, 2H, J ) 7.7 Hz), 2.63 (t, 2H, J ) 7.7 Hz),
1.00 (s, 9H), 0.14 (s, 6H); 13C NMR (CDCl3) δ 172.8, 149.4,
144.9, 135.9, 133.0, 128.5, 128.2, 121.2, 121.0, 112.2, 66.2, 55.5,
36.1, 30.2, 25.7, 18.4, -4.6; HRMS calcd for C23H32O4 Si
400.2070, found 400.2074.
To complete the synthesis, we needed to remove the
carboxylic acid protecting group. The 2-bromoethyl ester
was chosen as the carboxylic acid protecting group
because it has been found to give better yield in both
coupling and demetalation reactions.13e Finkelstein reac-
tion (7 equiv of NaI, acetone, reflux) gave the 2-iodoethyl
ester in 98% yield. Halogen exchange was confirmed by
upfield shift of methylene group next to the halogen atom
1
from ∼3.6 ppm to ∼3.2 ppm in the H NMR spectrum.
The 2-iodoethyl ester was reductively deprotected with
SmI2 using DMPU as an additive (7 equiv of SmI2, SmI2:
DMPU 1:6). The reaction proceeded very well at 0 °C to
rt, and the stability of Boc and Cbz group under these
very mild neutral conditions was remarkable.16 The acid
19 was obtained in 61% yield, with ∼15% starting
material recovered. The polarity of the deprotected acid
was comparable to that of DMPU, so in order to overcome
difficulties in separating the product, HMPA was used
as an alternate additive that could readily be removed
by washing with 0.1 N HCl, giving comparable yield
3-[4-Met h oxy-3-(ter t-b u t yld im et h ylsilyloxy)p h en yl]-
p r op ion ic Acid (9). TBDMS-protected phenylpropionic acid
(17) (a) Williams, D. H.; Kalman J . R. J . Am. Chem. Soc. 1980, 102,
897. (b) Williams, D. H.; Williamson, M. P. J . Chem. Soc., Perkin Trans.
1 1985, 949.
(16) Pearson, A. J .; Lee, K. J . Org. Chem. 1994, 59, 225.
(18) Kofron, W. G.; Baclawski, L. M. J . Org. Chem. 1976, 41, 1879.

6584 J . Org. Chem., Vol. 61, No. 19, 1996
Pearson et al.
benzyl ester (8) (5.19 g 13.0 mmol) was added into a slurry of
Pd-C (10%) (∼530 mg) in 60 mL of THF. The mixture was
stirred for 3.5 h at rt under hydrogen atmosphere (1 atm). The
solid catalyst was filtered off, and the filter cake was washed
with 20 mL of THF. The solvent was removed in vacuo to
give a white solid, which was dried further under high vacuum
to provide pure product 9 (3.95 g, 99%): mp 75.5-77.5 °C; Rf
0.47 (6:4 hex/EtOAc); IR 3400-2500 (br), 1702 cm-1; 1H NMR
(CD2Cl2) δ 6.79 (d, 1H, J ) 8.2 Hz), 6.76 (d, 1H, J ) 2.0 Hz),
6.71 (dd, 1H, J ) 8.2, 2.0 Hz), 3.76 (s, 3H), 2.83 (t, 2H, J ) 7.7
Hz), 2.62 (t, 2H, J ) 7.7 Hz), 0.98 (s, 9H), 0.14 (s, 6H); 13C
NMR (CD2Cl2) δ 179.3, 149.9, 145.2, 133.3, 121.5, 121.3, 112.5,
55.8, 36.1, 30.1, 15.8, 18.7, -4.6; HRMS calcd for C16H26O4 Si
310.1600, found 310.1600.
The solution was washed with brine and the aqueous layer
was again extracted with CH2Cl2. The combined organic
extracts were dried over Na2SO4 and concentrated. Flash
chromatography gave 12 (377 mg, 62%) as a pale yellow
solid: mp 153-155 °C; Rf 0.34 (1:1, hex/EtOAc); [R]23 +79.3°
D
(c 0.60, CHCl3); IR (CHCl3) 3546 1787, 1713 cm-1 1H NMR
;
(CDCl3) δ 7.36-7.20 (m, 5H), 6.88-6.80 (m, 3H), 5.63 (s, 1H),
5.22 (dd, 1H, J ) 9.0, 5.4 Hz), 4.65-4.60 (m, 1H), 4.21-4.10
(m, 2H), 3.85 (s, 3H), 3.32 (dd, 1H, J ) 13.4, 3.1 Hz), 3.13 (dd,
1H, J )13.7, 5.4 Hz), 2.95 (dd, 1H, J ) 13.7, 9.0 Hz), 2.82, dd,
1H, J ) 13.4, 9.5 Hz); 13C NMR (CDCl3) δ 170.5, 152.7, 145.8,
145.6, 134.7, 129.4, 129.0, 128.7, 127.5, 120.9, 115.3, 110.7,
66.5, 61.4, 55.9, 55.4, 37.5, 37.0; HRMS calcd for C20H20N4O5
396.1434, found 396.1424.
(4S)-3-[3-[4-Met h oxy-3-(ter t-b u t yld im et h ylsilyloxy)-
p h en yl]-1-oxop r op ion yl]-4-(p h en ylm et h yl)-2-oxa zolid i-
n on e (10). To a stirred, precooled solution (-78 °C) of the
TBDMS protected phenylpropionic acid 9 (1.99 g, 6.49 mmol)
in 60 mL of THF under N2 were added by syringe 1.18 mL
(1.3 equiv) of freshly distilled Et3N followed by 0.88 mL (1.1
equiv) of distilled pivaloyl chloride. The resulting slurry was
stirred at -78 °C for 25 min and 0 °C for 50 min and then
cooled again to -78 °C under N2. In a separate flask, 1.07 g
(1.0 equiv) of (4S)-4-(phenylmethyl)-2-oxazolidinone was dis-
solved in 40 mL of THF and cooled to -78 °C, to this solution
was added by syringe 4.06 mL of n-BuLi (1.6 M in hexane),
and the resulting solution was stirred at -78 °C for 25 min
under N2. This metalated oxazolidinone solution was trans-
ferred to the above slurry via cannula, and the resulting
mixture was stirred for 30 min at -78 °C and then overnight
at rt. The reaction was quenched with 40 mL of 1.0 N
NaHSO4, and the volatile was removed in vacuo. The product
was extracted with CH2Cl2, and the organic layer was washed
with brine, dried over Na2SO4, and concentrated to give a pale
yellow oily residue. Flash chromatography provided 10 (2.50
g, 87%) as a colorless oil: Rf 0.32 (7:3 hex/EtOAc); [R]23D +36.8°
(2S )-2-Azid o-3-(3-h yd r oxy-4-m e t h oxyp h e n yl)p r op i-
on ic Acid 2-Br om oeth yl Ester (13). Into a solution of 12
(655 mg, 1.68 mmol, 1 equiv) in 15 mL of THF and 5 mL of
H2O, cooled to 0 °C, were added H2O2 (30%, 1.04 mL, 6 equiv)
and LiOH (0.5 M, 6.8 mL, 2 equiv). The mixture was stirred
for 1.5 h and quenched by addition of Na2SO3 (1.5 M, 9.0 mL).
After removal of THF, the aqueous residue was acidified with
6 N HCl and extracted with EtOAc. The extracts were dried
over Na2SO4 and evaporated to give 374 mg acid, which was
then subjected to the next reaction directly. To a precooled
solution (0 °C) of the acid (374 mg, 1.58 mmol) in 25 mL CH2-
Cl2 were added DMAP (9 mg, 0.08 equiv), 2-bromoethanol (236
µL, 2 equiv), and then DCC (359 mg, 1.1 equiv). The resulting
mixture was stirred overnight (0 °C to rt) and filtered. The
solvent was evaporated, and the slightly brown residue was
separated on a flash column to give 472 mg (87%) product as
a pale yellow oil: Rf 0.41 (3:2 hex/EtOAc); [R]24D -24.1° (c 1.95,
CHCl3); IR (CHCl3) 3549, 1753 cm-1; 1H NMR (CDCl3) δ 6.80-
6.60 (m, 3H), 5.65 (s, 1H), 4.42 (t, 2H, J ) 6.1 Hz), 4.00 (dd,
1H, J ) 8.5, 5.6 Hz), 3.83 (s, 3H), 3.46 (t, 2H, J ) 6.1 Hz),
3.07 (dd, 1H, J ) 14.0, 5.6 Hz), 2.90 (dd, 1H, J ) 14.0, 8.5
Hz); 13C NMR (CDCl3) δ 169.5, 145.8, 145.6, 128.7, 120.8,
115.2, 110.7, 64.8, 63.1, 55.9, 37.0, 28.0; HRMS calcd for
C12H14N3O4Br 343.0168, found 343.0170.
(c 0.49, CHCl3); IR (CHCl3) 3695, 3610, 1786, 1706, 1611 cm-1
;
1H NMR (CD2Cl2) δ 7.35-7.16 (m, 5H), 6.83-6.78 (m, 3H),
4.69-4,62 (m, 1H), 4.21-4.11(m, 2H), 3.76 (s, 3H), 3.29-3.09
(m, 3H), 2.92-2.77 (m, 3H), 1.00 (s, 9H), 0.15 (s, 6H); 13C NMR
(CD2Cl2) δ 172.6, 153.8, 149.8, 145.2, 135.9, 133.7, 129.8, 129.2,
127.2, 121.8. 121.6, 112.5, 66.6, 55.8, 55.3, 38.3, 37.7, 29.8,
25.9, 18.7, -4.6; HRMS calcd for C26H33NO5 Si 469.2284, found
469.2296.
(2S)-2-[N-[(P h en ylm et h oxy)ca r b on yl]a m in o]-3-(3-h y-
d r oxy-4-m eth oxyp h en yl)p r op ion ic Acid 2-Br om oeth yl
Ester (4). To a preactivated (with H2, 30 min) slurry of Pd-C
(10%, 5.5 mg) in 5 mL of THF/MeOH (1:1) were added 55.4
mg (0.16 mmol) of azido compound 13 and 5 N HCl (100 µL, 3
equiv). After stirring under 1 atm H2 for 1.5 h, the mixture
was filtered through Celite and solvent was removed under
reduced pressure. The residue was dried in vacuo and then
redissolved in 10 mL of CH2Cl2 and 5 mL of H2O. The solution
was cooled to 0 °C, NaHCO3 (27.1 mg, 2 equiv) and 27 µL of
CbzCl (1.1 equiv) were added, and the mixture was stirred at
for 1.5 h at 0 °C and 2 h at rt. Extraction with CH2Cl2 and
evaporation of solvent provided 80 mg of crude product. Flash
chromatography (4:1 hex/EtOAc) gave 61.5 mg (84%) of
(4S,2S)-3-[2-Azid o-3-[4-m eth oxy-3-(ter t-bu tyld im eth yl-
silyloxy)p h en yl]-1-oxop r op ion yl]-4-(p h en ylm eth yl)-2-ox-
a zolid in on e (11). To a stirred solution of the chiral auxiliary
adduct 10 (476 mg, 1.04 equiv) in 20 mL of THF at -78 °C
was added rapidly, by syringe, 2.71 mL (0.5 M in toluene, 1.3
equiv) of KHMDS, and the resulting solution was stirred for
20 min at -78 °C under Ar. To this solution was transferred,
via cannula over 30 s, a precooled (-78 °C) solution of 354.5
mg (1.1 equiv) of trisyl azide in 10 mL of THF. The resulting
solution was stirred for 5 min at -78 °C and quenched by rapid
addition of 149.0 µL (2.5 equiv) of glacial acetic acid followed
by immediate warming to 35 °C with a water bath. The white
slurry was stirred for 3 h at rt, diluted with 50 mL of CH2Cl2,
and separated. The organic layer was washed with a mixture
of brine and aqueous NaHCO3, dried over Na2SO4, and
concentrated. Flash chromatography of the crude product gave
product 4 as a colorless oil. Rf 0.27 (6:4 hex/EtOAc); [R]24
D
-22.7° (c 0.51, CHCl3); IR (CHCl3) 3695, 3550, 3445 1733, 1604
cm-1; 1H NMR (CDCl3) δ 7.33 (b, 5H), 6.80-6.50 (m, 3H), 5.64
(s, 1H), 5.21 (d, 1H, J ) 7.7Hz), 5.10 (s, 2H), 4.62 (dd, 1H, J
) 7.7, 5.5 Hz), 4.40 (t, 2H, J ) 5.8 Hz), 3.85 (s, 3H), 3.46(t,
2H, J ) 5.8 Hz), 3.03 (d, 2H, J ) 5.5 Hz); 13C NMR (CDCl3) δ
171.2, 155.6, 145.8, 145.7, 136.1, 128.5, 128.2, 128,1, 120.8,
115.4, 110.8, 67.0, 64.5, 55.9, 54.8, 37.4, 28.1; HRMS calcd for
C20H22NO6Br 451.0630, found 451.0635.
399 mg (75%) of 11 as a colorless oil: Rf 0.36 (CH2Cl2); [R]23
D
+70.4° (c 0.50, CHCl3); IR (CHCl3) 1785, 1711 cm-1; 1H NMR
(CD2Cl2) δ 7.39-7.22 (m, 5H), 6.89-6.81 (m, 3H), 5.17 (dd,
1H, J ) 9.2, 5.2 Hz) 4.67-4.61 (m, 1H), 4.23-4.14 (m, 2H),
3.78 (s, 3H), 3.28 (dd, 1H, J ) 13.5, 3.2 Hz), 3.12, dd, 1H, J )
13.8, 5.2 Hz), 2.96-2.85 (m, 2H), 1.00 (s, 9H), 0.166 (s, 3H),
0.161 (s, 3H); 13C NMR (CD2Cl2) δ 170.8, 153.2, 150.7, 145.3,
135.4, 129.8, 128.7, 127.7, 122.7, 122.2, 112.5, 67.1, 62.1, 55.8,
37.1, 25.8, 18.7, -4.59, -4.63; HRMS calcd for C25H34N2O5Si
(M - N2)+ 482.2237, found 482.2256.
(2S)-2-Azid o-3-(4-ch lor op h en yl)p r op ion ic Acid Meth yl
Ester (15). A solution of the acid 14 (970 mg, 4.3 mmol) and
p-toluenesulfonic acid (818 mg, 1 equiv) in 30 mL of anhydrous
CH3OH was refluxed for 8 h. After cooling to rt, the mixture
was adjusted to basic with saturated NaHCO3 and extracted
with EtOAc. The organic layer was washed with brine, dried
over MgSO4, and flash chromatographed to give 994 mg (95%)
of the methyl ester 15 as a colorless oil: Rf 0.41 (4:1 hex/
EtOAc); [R]24 -50.7° (c 0.76, CHCl3); IR (CHCl3) 1740 cm-1
;
(4S,2S)-3-[2-Azid o-3-(3-h yd r oxy-4-m et h oxyp h en yl)-1-
oxopr opion yl]-4-(ph en ylm eth yl)-2-oxazolidin on e (12). The
R-azido adduct 11 (815.6 mg, 1.60 mmol) in 20 mL of THF
was cooled to 0 °C with an ice bath. To this was added
anhydrous TBAF solution, and the resulting mixture was
stirred for 1 h at 0 °C and then diluted with 50 mL of CH2Cl2.
D
1H NMR (CDCl3) δ 7.29 (d, 2H), 7.16 (d, 2H), 4.06 (dd, 1H, J
) 8.6, 5.3 Hz), 3.78 (s, 3H), 3.14 (dd, 1H, J ) 14.0, 5.3 Hz),
2.97 (dd, 1H, J ) 14.0, 8.6 Hz); 13C NMR (CDCl3) δ 170.1,
134.3, 133.2, 130.5, 128.8, 63.0, 59.1, 52.7, 36.9; HRMS calcd
for C10H10N3O2Cl 239.0461, found 239.0461.

Total Synthesis of OF 4949 III
J . Org. Chem., Vol. 61, No. 19, 1996 6585
N-[N-[(1,1-Dim eth yleth oxy)ca r bon yl-L-a sp a r a gin yl]-L-
(p-ch lor op h en yl)a la n in e Meth yl Ester (16). A slurry of
Pd/C (10%, 80 mg) in 20 mL of THF was purged with H2 for
30 min. To the slurry was added (2S)-2-azido-3-(4-chlorophen-
yl)propionic acid methyl ester (15) (800 mg, 3.33 mmol) and 5
N HCl (2 mL, 3 equiv). The mixture was stirred at rt under
1 atm of H2 for 4 h and then filtered through Celite. After
removing solvent the solid was redissolved in a mixture of 25
mL of THF and 15 mL of DMF and was cooled to 0 °C. Into
the solution were added N-Boc-asparagine (930 mg, 1.2 equiv),
allowed to warm to rt over a period of 4-5 h. Similar workup
as in method A gave 17 as a brown solid which gave identical
analytical data.
(S)-O-[5-[2-[[(P h en ylm et h oxy)ca r b on yl]a m in o]-2-[(2-
b r om oet h oxy)ca r b on yl]et h yl]-2-m et h oxyp h en yl]-N-[N-
[(1,1-d im et h ylet h oxy)ca r b on yl]-L-a sp a r a gin yl]-L-t yr o-
sin e Meth yl Ester (3). A solution of complex 17 in ∼15 mL
of freshly distilled CH3CN in a quartz tube was purged with
N2 for 20 min and then irradiated with a sunlamp for 24 h.
The solvent was removed, and ∼1.5 mL of CH3CN was added.
The unreacted complex was precipitated by the addition of 100
mL of Et2O. The ether solution was decanted and set aside,
and the residue was subjected to the photoreaction conditions
again. The combined ether solution was dried and flash
chromatographed to give (34%, method A), 65 mg (77% overall
yield, method B) of the tripeptide 3 as a white solid: Rf 0.31
(EtOAc), 0.51 (THF/CHCl3, 1/1); [R]24D +24.6° (c 0.93, CHCl3);
IR (CHCl3) 3513, 1737, 1717, 1693 cm-1; 1H NMR (CD3NO2) δ
7.80-7.40 (bs, 5H), 7.10-6.60 (m, 8H), 6.10-5.30 (bs, 4H), 5.04
(s, 2H), 4.80-4.20 (m, 5H), 3.78 (s, 3H), 3.66 (s, 3H), 3.37 (dd,
2H, J ) 5.7, 5.7 Hz), 3.40-3.20 (m, 6H), 1.42 (s, 9H); 13C NMR
(CD3NO2) δ 173.2, 171.5, 171.2, 170.8, 156.7, 155.6, 150.4,
145.9, 136.2, 130.7, 130.6, 130.5, 130.3, 130.1, 128.7, 128.6,
128.2, 128.1, 125.4, 121.6, 117.6, 112.9, 80.4, 68.0, 67.0, 64.7,
56.0, 54.9, 53.6, 53.4, 52.3, 51.0, 50.9, 37.2, 28.3, 25.6; HRMS
(FAB) calculated for C39H48N4O12Br (M + H)+ 843.2452, found
843.2435.
i
HOBt‚H2O (678 mg, 1.5 equiv), Pr2NEt (580 µL, 430 mg, 1
equiv), and EDC (770 mg, 1.2 equiv). The mixture was stirred
for 24 h (0 °C to rt). THF was then removed, the residue was
diluted with 150 mL CH2Cl2 and washed with 1 N NaHSO4, 1
N NaHCO3, and saturated brine, and the organic layer was
separated and dried over Na2SO4. After removing the solvent,
recrystallization with THF/hexane gave 1.14 g (81%) desired
dipeptide (two crops) as a white solid: mp 209-211 °C. [R]23
D
-5.1° (c 0.04, CH3OH); IR (CHCl3) 3387, 3345, 1745, 1676,
1626 cm-1; 1H NMR (acetone-d6) δ 7.60 (bs, 1 H), 7.38 (d, 2H,
J ) 8.6 Hz), 7.32 (d, 2H, J ) 8.6 Hz), 7.05 (bs, 1H), 6.46 (bs,
2H), 4.74 (dd, 1H, J ) 12.9, 6.7 Hz), 4.46 (br, 1H), 3.72 (s,
3H), 3.20 (dd, 1H, J ) 13.9, 6.7 Hz), 3.10 (dd, 1H, J ) 13.9,
6.7 Hz), 2.80 (dd, 1H, J ) 15.9, 5.5 Hz), 2.65 (dd, 1H, J ) 15.9,
6.1 Hz), 1.41 (s, 9H). 13C NMR (CDCl3) δ 173.3, 171.5, 170.9,
135.9, 130.7, 129.3, 128.6, 127.1, 80.1, 53.6, 52.1, 51.1, 38.0,
36.9, 28.2; HRMS calcd for C19H26N3O6Cl 427.1510, found
427.1526.
(S)-O-[5-[2-[[(P h en ylm et h oxy)ca r b on yl]a m in o]-2-[(2-
iodoeth oxy)car bon yl]eth yl]-2-m eth oxyph en yl]-N-[N-[(1,1-
dim eth yleth oxy)car bon yl]-L-aspar agin yl]-L-tyr osin e Meth -
yl Ester (18). To a solution of 3 (65.0 mg, 0.077 mmol) in 3
mL of anhydrous acetone was added NaI (64.0 mg, 7 equiv).
The mixture was refluxed under Ar for 6 h. The solvent was
removed, and the residue was purified by flash chromatogra-
phy (EtOAc) to give 67.0 mg (98%) of iodoethyl ester 18 as a
[η6-[(2S)-[4-Ch lor o-1-[2-[[N-[(1,1-d im et h ylet h oxy)ca r -
bon yl]-L-a sp a r a gin yl]a m in o]-2-(m eth oxyca r bon yl)eth yl]-
ben zen e]]](η5-cyclop en ta d ien yl)r u th en iu m Hexa flu or o-
p h osp h a te (5). A mixture of the dipeptide 16 (85.6 mg, 0.2
mmol, 1 equiv) and [(CH3CN)3RuCp]PF6 (104 mg, 1.2 equiv)
in 12 mL of 1,2-dichloroethane was purged with Ar for 20 min
and then refluxed for 5 h. After filtration through Celite, the
solvent was removed to give 189 mg (100%) of the dipeptide
complex as a brown solid: 1H NMR (CD3CN) δ 7.34 (d, J )
6.7 Hz), 6.46 (dd, 2H, J ) 8.0, 6.5 Hz), 6.25 (d, 1H, J ) 6.5
Hz), 6.22 (bs, 1H), 6.09 (d, 1H, J ) 8.0 Hz), 6.00 (bs, 1H), 5.74
(bs, 1H), 4.62 (dd, 1H, J ) 8.7, 4.7 Hz), 4.28 (dd, 1H, J ) 5.7,
5.5 Hz), 3.70 (s, 3H), 3.01 (dd, 1H, J ) 14.1, 4.7 Hz), 2.79 (dd,
1H, J ) 14.1, 8.7 Hz), 2.62 (dd, 1H, J )16.2, 5.7 Hz), 2.50 (dd,
1H, J ) 16.2, 5.5 Hz), 1.41 (s, 9H); 13C NMR (CD3CN) δ 173.6,
172.6, 171.4, 155.3, 105.8, 101.8, 88.3, 88.2, 88.0, 83.8, 80.4,
54.0, 53.4, 52.2, 45.6, 36.8, 36.3, 28.6.
[η6-[4-[(S)-5-[2-[[(P h en ylm et h oxy)ca r b on yl]a m in o]-2-
[(2-br om oeth oxy)ca r bon yl]eth yl]-2-m eth oxyp h en oxy]-1-
[2-(m eth oxyca r bon yl)-2-[N-[N-[(1,1-d im eth yleth oxy)ca r -
b on yl]-L-a sp a r a gin yl]a m in o]et h yl]b en zen e]] (η5-cyclo-
p en t a d ien yl)r u t h en iu m H exa flu or op h osp h a t e (17).
Meth od A: To a pre-cooled (0 °C) solution of phenol 4 (90.5
mg, 0.2 mmol, 1 equiv) in 8 mL of THF was added a stock
solution of sodium 2,6-di-tert-butylphenoxide (as prepared in
method B) (3.3 mL, 1.1 equiv). The mixture was stirred for
25 min at 0 °C and for 5 min at rt under Ar and then
transferred via cannula into a precooled solution (-78 °C) of
the complex 5 (148 mg, 1 equiv) in 5 mL of THF. After stirring
at -78 °C for 1 h and rt for 3 h, the solvent was removed and
the residue was redissolved in ∼2 mL of CH3CN and precipi-
tated with 100 mL of Et2O. The precipitate was dissolved in
15 mL of CH3CN and filtered through neutral alumina (1 × 5
cm) to give complex 17 as a brown solid. No further purifica-
tion was performed, and the product was used in the next
reaction directly: 1H NMR (CDCl3) δ 7.50-7.10 (m, 8H), 6.5-
5.7 (m, 9H), 5.25 (s, 5H), 5.02 (s, 2H), 4.70-4.20 (m, 5H), 3.81
(s, 3H), 3.70 (s, 3H), 3.58 (dd, 2H, J ) 5.5, 5.5 Hz), 3.30-2.40
(m, 6H, 1.41 (s, 9H). Meth od B: A basic stock solution was
first prepared from 53.5 mg of NaH and 276 mg of 2,6-di-tert-
butylphenol in 20 mL of THF at rt for 30 min. THF was then
removed, and the yellow residue was dissolved in 20 mL of
freshly distilled acetone. A 1.65 mL (1.1 equiv) amount of this
new stock solution was quickly added to a precooled solution
(-30 °C) of the phenol 4 (50 mg, 1.1 equiv) in 3 mL of dry
acetone. After stirring for 20 min, the solution was transferred
via cannula to a precooled solution of 5 (73.5 mg, 1 equiv) in
3 mL of acetone. The mixture was stirred at -30 °C and
white solid: Rf 0.31 (EtOAc); [R]24 +20.0° (c 0.40, CHCl3); IR
D
(CHCl3) 1745, 1719, 1685 cm-1
;
1H NMR (CD3NO2) δ 7.45-
7.30 (m, 5H), 7.29-7.10 (m, 4H), 7.07 (s, 1H), 6.95-6.79 (m,
3H) 6.19 (bs, 1H), 6.00 (bt, 1H, J ) 10 Hz), 5.81 (bt, 1H, J )
10 Hz), 5.72 (b, 1H), 5.07 (b, 2H), 4.70 (m, 1H), 4.52 (m, 1H),
4.45-4.25 (m, 3H), 3.80 (s, 3H), 3.72 and 3.70 (two singlets,
3H), 3.34 (t, 2H, J ) 6.0 Hz), 3.25-2.90 (m, 4H), 2.85-2.50
(m, 2H),1.41 (s, 9H); 13C NMR (CD3NO2) parentheses denote
shifts for amide resonance conformer: δ 174.54 (174.48), 173.3,
172.7, 172.6, 158.61 (158.53), 157.33 (157.06), 152.13 (152.06),
145.33 (145.66), 138.0, 132.48 (132.42), 132.0, 131.0, 129.9,
129.4, 129.1, 127.53 (127.46), 123.87 (123.80), 117.77 (117.92),
114.5, 81.2, 67.8, 66.8, 56.63 (56.76), 55.0, 53.1, 52.5, 37.90
(38.01), 28.7, 1.5; HRMS (FAB) calcd for C39H48N4O12I (M +
H)+ 891.2314, found 891.2289.
(S)-O-[5-[2-[[(P h en ylm eth oxy)ca r bon yl]a m in o]-2-ca r -
boxyeth yl]-2-m eth oxyph en yl]-N-[N-[(1,1-dim eth yleth oxy)-
ca r bon yl]-L-a sp a r a gin yl]-L-tyr osin e Meth yl Ester (19). To
a stirred 0 °C solution of iodoethyl ester 18 (33 mg, 0.037
mmol) in 4 mL of THF was added DMPU (190 µL, 42 equiv)
by syringe. To the resulting solution was added SmI2 (2.6 mL,
0.1 M in THF, 7 equiv). After stirring at 0 °C for 10 min and
then at rt for 3 h, the reaction mixture was diluted with 15
mL of CH2Cl2 and treated with 15 mL of 0.1 N HCl. The
organic layer was separated, and the aqueous layer was
extracted three times with CH2Cl2. The combined organic
layer was washed with 0.2 M Na2S2O3 and brine and dried
over Na2SO4. The solvent was evaporated in vacuo, and the
pale yellow oil was purified on a small silica gel column (EtOAc
and then 5% HOAc in EtOAc). The fractions containing the
product were diluted with benzene and evaporated under
reduced pressure with the bath temperature below 10 °C. The
product 19 (16 mg, 61%) was obtained as a white powder. This
compound was not further purified, but was carried forward
to the cycloamidation: Rf 0.42 (5% HOAc/EtOAc); 1H NMR
(CD3OD) δ 7.25 (bs, 5H), 7.20-6.70 (m, 7H), 5.02 (d, 1H, J )
14.0 Hz), 4.96 (d, 1H, J ) 14.0 Hz), 4.60 (m, 1H), 4.52 (m, 1H),
4.20 (m, 3H), 3.71 (s, 3H), 3.68 and 3.66 (two singlets, 3H),
3.25-2.80 (m, 4H), 2.65-2.35 (m, 2H),1.40 (s, 9H); 13C NMR
(CD3OD) parentheses denote shifts for amide resonance con-
former δ 175.5, 173.5, 172.8 (172.9), 158.8, 157.9 (158.0), 157.2,

6586 J . Org. Chem., Vol. 61, No. 19, 1996
Pearson et al.
151.7 (151.9), 145.2 (145.4), 138.4, 132.2, 132.0, 131.3, 189.3,
128.8, 128.6, 127.4 (127.3), 124.0 (123.6), 117.5, 114.2, 80.7,
67.2, 62.3, 56.5, 55.1, 52.8, 28.7.
1H), 5.24 (d, 1H, J ) 12.4 Hz), 5.12 (d, 1H, J ) 12.4 Hz), 4.90
(m, 1H), 4.81 (m, 1H), 4.56 (m, 1H), 3.88 (s, 3H), 3,80 (s, 1H),
3.36 (dd, 1H, J ) 13.5, 2.5 Hz), 2.97 (dd, 1H, J ) 13.5, 3.1
Hz), 2.76 (dd, 1H, J ) 14.0, 3.3 Hz), 2.97 (m, 2H), 2.45 (dd,
1H, J ) 14.0, 4.7 Hz); 13C NMR (CD3OD) δ 174.4, 173.0, 171.9,
171.3, 157.3, 155.3, 150.6, 149.3, 138.1, 135.2, 133.2, 131.6,
130.4, 130.2, 129.7, 129.5, 129.3, 129.1, 127.9, 124.9, 123.4,
122.9, 117.3, 113.1, 67.6, 56.6, 55.1, 54.9, 42.1, 40.1, 39.4, 38.2,
35.9; HRMS calcd for C32H34N4O9 618.2326, found 618.2331.
Meth yl (9S,12S,15S)-12-(2-Am in o-2-oxoeth yl)-9-[[(ph en -
ylm et h oxy)ca r b on yl]a m in o]-4-m et h oxy-10,13-d ioxo-2-
oxa -11,14-d ia za tr icyclo[5.2.2.1]d ocosa -3,5,7(22),17,19,20-
h exa en e-15-ca r boxyla te (2). To a precooled solution (0 °C)
of the acid 19 (11.0 mg, 0.022 mmol) in 4 mL of CH2Cl2 was
added by syringe 37.5 µL of thioanisole (20 equiv) and 2 mL
of TFA. The resulting mixture was stirred at 0 °C for 1.5 h.
The solvent was evaporated, and the residue was dried in
vacuo to give a pale yellow oil. The oil was redissolved in 2
mL of DMF and was added by syringe pump over a period of
3 h to a precooled (0 °C) solution of NaHCO3 (6.5 mg, 5 equiv)
and DPPA (5 µL, 1.5 equiv) in ∼1.5 mL of DMF. After stirring
at 0 °C for 3 days, DMF was removed under reduced pressure.
TLC separation (silica gel, EtOAc) gave 4.8 mg (52%) of
cyclized product 2 as a white solid: mp 181-183 °C (lit.5 179-
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (GM 36925) is gratefully
acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of all compounds reported (33 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.
182 °C); [R]23 -73° (c 0.35, CH3OH) (lit.5 -74°, c 0.1, CH3-
D
OH); Rf 0.13 (EtOAc); IR (CHCl3) 3438, 1736, 1718, 1693, 1685,
1
1600 cm-1; H NMR (CD3OD) δ 7.70-7.54 (m, 7H), 7.36 (dd,
1H, J ) 8.0, 1.9 Hz), 7.23 (dd, 1H, J ) 8.0, 1.9 Hz), 7.10 (dd,
1H, J ) 8.0, 1.9 Hz), 6.75 (dd, 1H, J ) 8.0, 1.9 Hz), 6.05 (s,
J O960956L