Asymmetric synthesis of a selective endothelin a receptor antagonist

Article abstract of DOI:10.1248/cpb.50.1066

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conjugate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96% ee via purification as (S)-(-)-1-phe

Full text of DOI:10.1248/cpb.50.1066

1066
Chem. Pharm. Bull. 50(8) 1066—1072 (2002)
Vol. 50, No. 8
Asymmetric Synthesis of a Selective Endothelin A Receptor Antagonist
Yoshiaki KATO, ,a Kenji NIIYAMA,b Hideki JONA,b Shigemitsu OKADA,a Atsushi AKAO,a
*
a
Shouichi HIRAGA,a Yoshimi TSUCHIYA,b Koji TOMIMOTO,a and Toshiaki MASE
a Process Research, Process R&D, Laboratories for Technology Development, Banyu Pharmaceutical Co., Ltd.; 3–9–1
Kamimutsuna, Okazaki, Aichi 444–0858, Japan: and b Banyu Tsukuba Research Institute; Okubo-3, Tsukuba 300–2611,
Ibaraki, Japan. Received March 29, 2002; accepted May 15, 2002
An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conju-
gate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96%
ee via purification as (S)-(؊)-1-phenylethylamine salt. Pd(OAc)2/dppf (1,1؅-bis(diphenylphosphino)ferrocene)
catalyzed carbonylation followed by chemoselective addition of aryllithium derived from 23 which gave ketone
24. Diastereoselective reduction of the ketone with catecholborane followed by concomitant activation of the re-
sulting alcohol and cyclization gave the late intermediate 26. Introduction of amino moiety on the pyridine ring
by imidoyl rearrangement followed by deprotection and purification by crystallization furnished the enantiomer-
ically pure target molecule 1b in 8% overall yield from 16.
Key words endothelin antagonist; asymmetric conjugate addition; oxazoline; thiomicamine; phosphate mediated cyclization
Endothelin receptor antagonists are currently being evalu- include an asymmetric conjugate addition of the top aryl
ated as potential therapeutic agents for the treatment of hy- metal to the Michael acceptor 5 or its equivalents, construc-
pertension, congestive heart failure and renal diseases.1) tion of the chiral alcohol 7 followed by the stereospecific cy-
Medicinal chemistry efforts led to the discovery of the earlier clization to form the fused five-membered ring with three
drug candidate 1a, which is a relatively non-selective antago- consecutive stereocenters.
nist for the receptor subtypes.2—4) Recently, a more selective
A number of methods have been reported for the stereose-
endothelin A receptor antagonist 1b was identified and is lective conjugate additions of chiral a,b-unsaturated esters
being developed as a potentially more effective drug.5) or their equivalents10) including Meyers’ oxazoline,11) Evans’
Synthetically, these are quite challenging target molecules. oxazolidone,12,13) and Oppolzer’s sultam.14) First, several oxa-
The main common structural feature is the fused five-mem- zolidinones were evaluated. a,b-Unsaturated carboxylic acid
bered ring with three contiguous stereocenters. Two general 11 was synthesized from commercially available 2-chloro-3-
approaches can be envisioned as outlined in Chart 1. Both of cyanopyridine 9 via DIBAL-H (diisobutylaluminum hydride)
them require chiral conjugate addition utilizing chiral auxil- reduction of the nitrile group to the aldehyde 10, Horner–
iary and stereospecific cyclization as the key steps. Earlier Emmons reaction with (EtO)2P(O)CH2COOEt followed by
work on the synthesis of 1a showed that both are viable ap- hydrolysis of the ester. Acid chloride of the acid 11 was
proaches.6,7) We have recently disclosed a practical asymmet- treated with various oxazolidinone lithium salts to give a,b-
ric synthesis of 1b utilizing the “bottom to top” approach
A.8) We have also disclosed an alternative asymmetric syn-
thesis of 1b starting from amino substituted pyridine utilizing
the “top to bottom” approach B.9) In this paper, we wish to
report another “top to bottom” approach B starting from non-
amino substituted pyridine, which can be utilized to further
derivatization study of the alkyl amino moiety on the pyri-
dine ring. In this approach, the major challenge is to carry
out a series of asymmetric reactions to build the fused cy-
clopentane ring with three stereocenters. The key steps will
Chart 1
To whom correspondence should be addressed. e-mail: katoys@banyu.co.jp
© 2002 Pharmaceutical Society of Japan

August 2002
1067
Chart 2
unsaturated oxazolidinones 12a—e with E-stereochemistry.
The Michael addition product 19 was then hydrolyzed by
The conjugate addition was carried out with a Grignard treatment with sulfuric acid in dioxane–H2O followed by
reagent 13 prepared from 6-bromo-2,3-dihydrobenzofuran crystallization from 2-propanol/isopropyl ether to give the
188) in the presence of a catalytic amount of CuBr–Me2S at optically pure carboxylic acid 15 in Ͻ50% yield. A large
Ϫ78 °C. The stereoselectivity was determined by chiral amount of mother liquor loss was the cause of the lower iso-
HPLC after hydrolysis to the acid 15. For our substrate, 4- lation yield, and no appropriate solvent system had been
phenyl-2-oxazolidinone 14a gave good stereoselectivity found to give good isolation yield with satisfactory optical
(80% de) with moderate yield, and 5,5-dimethyl-4-phenyl-2- purity. Several amine salt were then evaluated for the isola-
oxazolidinone 14d showed moderate stereoselectivity (66% tion, and we found both (S) and (R)-1-phenylethylamine salt
de) with good yield (Chart 2).
gave good results. Unfortunately, commercially inexpensive
However, the result of oxazolidinones was not satisfactory, racemic 1-phenylethylamine showed no purification effect.
and an oxazoline derived from inexpensive (1S,2S)-(ϩ)- Once fairly pure amine salt was isolated in good yield with-
thiomicamine was much more economical and thus pre- out chromatography, it was treated under acidic conditions
ferred. Therefore, aldehyde 10 was coupled with the Horner– and extracted to the organic solvent to give free acid in quan-
Emmons reagent generated in situ from the oxazoline 16 and titative recovery yield from the amine salt. Finally, conjugate
(EtO)2P(O)Cl in the presence of 2 eq of LDA (lithium diiso- addition, hydrolysis, amine salt formation and salt break was
propylamide) to give the conjugate addition precursor 17 carried out successively to give pure acid 15 (96% ee) in 60%
with E-stereochemistry. The efficient synthesis of the top aryl yield from 17. The absolute configuration of 15 was deter-
bromide 18 (6-bromo-2,3-dihydrobenzofuran) has been re- mined after converting to 1b, and the stereochemistry of 1b
ported.8) The conjugate addition was carried out by 1.5 eq of was determined by X-ray as the HCl salt. The carboxyl group
aryllithium from 18 and the Michael acceptor 17 at Ϫ78 °C was then protected by esterification with tert-BuOH to give
in THF (tetrahydrofuran) to give the Michael product 19 in 21 in 91% yield. With the intermediate 21 in hand, methoxy-
85% de with 63% assay yield. The stereoselectivity was de- carbonylation of 2115) was accomplished with CO (1 kg/cm2)
termined by chiral HPLC after hydrolysis to the acid 15. A in methanol in the presence of NaHCO3 and a catalytic
significant amount (13%) of double Michael product 20 gen- amount of Pd(OAc)2 and 1,1Ј-bis(diphenylphosphino)fer-
erated in the reaction was the cause of the lower yield. After rocene (DPPF) in 97% yield. From the readily accessible 4-
many attempts, we found that addition of 1.5—3.0 eq of bromo-3-hydroxymethylanisole,6,7) the bottom aryl bromide
TMEDA (N,N,NЈ,NЈ-tetramethylethylenediamine) reduced 23 was prepared by introduction of the PMB ( p-methoxy-
the double Michael product (ca. 6%) to give 19 in better benzyl) protecting group to the hydroxymethyl group under
assay yield (76%) with 85% de (Chart 3).
standard conditions. Chemoselective addition of aryllithium

1068
Vol. 50, No. 8
Chart 3
Chart 4
1.6/1). L-Selectride® offered no selectivity at all (1/1) and
NaBH4 gave a slightly opposite selectivity (1/1.4). We chose
catecholborane for this reaction and the 9/1 mixture of di-
astereoisomer was subjected to the next reaction without fur-
ther purification.
With the crude alcohol 25 in hand, the key cyclization step
was then investigated. Based on the experience with earlier
drug candidate 1a, we opted to use a phosphate for activation
of the alcohol. Mesylate and tosylate are probably too active
and will likely decompose or scramble the stereochemistry of
the carbinol. Indeed, the activation of the alcohol and the cy-
from 23 to the methyl ester of 22 at low temperature afforded
ketone 24 in 88% yield (Chart 4).
In order to set up the alkylative cyclization, the ketone
needs to be stereoselectively reduced and the resulting alco-
hol activated. A variety of reducing agents were screened and
the results are summarized in Table 1. Catechol borane and
9-BBN gave good selectivity (9/1) in 78—79% yields. BH3–
THF complex, DIBAL-H and Red-Al® gave the same selec-
tivity (4—5/1) in good to moderate yield (47—82%).
Zn(BH4)2, Li-9-BBN-H and LAH (lithium aluminum hy-
dride) also offered essentially the same selectivity (1.2—

August 2002
1069
clization was accomplished in one step by sequential treat-
In conclusion, a new asymmetric synthesis of 1b was ac-
ment of 25 with (EtO)2POCl and LiHMDS [lithium bis- complished in 8% overall yield from chiral oxazoline 16 in a
(trimethylsilyl)amide] to give the late intermediate 26. The highly stereo- and regio-controlled manner.
reaction presumably involves deprotonation of the alcohol,
formation of the phosphate intermediate, enolization of the
Experimental
Melting points were determined with a Yanaco MP micromelting point
1
ester and alkylation of the enolate by the phosphate. The
stereospecificity (SN2 inversion) of this type of cyclization
was demonstrated in the synthesis of the 1a.6) This also was
the basis for the stereochemical assignment for the alcohol
stereogenic center in 25. The isopropyl amino moiety was
then introduced on the pyridine ring of the crude intermedi-
ate 26 by imidoyl rearrangement16) via pyridine N-oxide to
give the pure compound 27 after chromatography in 38%
yield from alcohol 25. With the intermediate 27 in hand, all
that remained to be done was to remove the three protecting
groups. Hydrogenolysis of the PMB ether followed by
DIBAL-H reduction gave compound 28 in 87% yield. Then,
28 was treated with TFA (trifluoroacetic acid) and purified by
crystallization from MeOH (methanol) to afford the target
molecule 1b in 71% yield with Ͼ99% purity as a single
enantiomer. (Chart 5).
apparatus and were not corrected. The H-NMR spectra were recorded on a
Varian VXR-300 (300 MHz) spectrometer and a JEOL JNM-EX270 (270
MHz) spectrometer with tetramethylsilane (TMS) as an internal standard.
13C-NMR spectra were recorded on a BRUKER AVANCE500 (125 MHz).
IR absorption spectra were recorded on a Horiba FT-200 spectrometer. Spe-
cific rotations were measured on a Jasco DIP-370 polarimeter, and mass
spectra (MS) were measured on a JEOL JMS-SX102A spectrometer. The
silica gel used for column chromatography was WAKO gel C-300. All reac-
tions involving air-sensitive reagents were performed under a nitrogen at-
mosphere.
2-Chloro-3-formylpyridine (10) To a suspension of 2-chloro-3-cyano-
pyridine 9 (173 g, 1.25 mol) in toluene (600 ml) was added 1.0 M DIBAL-H
in toluene (1.5 l, 1.5 mol) at Ϫ40 °C, and the mixture was warmed to 0 °C.
The reaction mixture was poured into a mixed solution of conc. H2SO4
(400 ml, 14.4 mol) and ice-cold water (3.6 l), and was stirred vigorously at
room temperature until the imine intermediate was consumed completely.
The product was extracted with toluene (2ϫ400 ml), and the combined or-
ganic layers were washed with water (1 l), sat. NaHCO3 (1 l), then water
again (1 l). The organic layer was subjected to the azeotropic distillation
with toluene and concentrated to give the crude product (145 g assay) in
82% yield which could be used for the next reaction without further purifica-
tion. Pure product 10 (117 g) was obtained by crystallization with heptane
(200 ml) in 66% yield from 9. HPLC: column, YMC ODS A-303: eluent,
CH3CN/H2O (40/60): flow rate, 1.0 ml/min; tR for 9, 5.7 min; tR for 10,
6.4 min. mp 80 °C. IR (KBr) cmϪ1: 3043, 2883, 1695, 1572, 1414, 1373,
1261, 1184, 1124, 1065, 824, 808, 725, 621. 1H-NMR (300 MHz, CDCl3) d:
7.43 (dd, Jϭ7.6, 4.7 Hz, 1H), 8.24 (dd, Jϭ7.6, 2.0 Hz, 1H), 8.62 (dd, Jϭ4.7,
2.0 Hz, 1H), 10.46 (s, 1H). High resolution (HR)-MS electron impact ((EI))
calcd for C6H4ClNO (M)ϩ 140.9981, found 140.9958.
Table 1. Reduction of Ketone 24
Selectivity
(desired/undesired)
Reducing agent
Yield (%)
Catecholborane
9-BBN
BH3–THF
DIBAL-H
Red-Al®
9/1
9/1
5/1
4/1
4/1
1.6/1
1.2/1
1.2/1
1/1
79
78
47
82
58
65
94
85
52
86
3-(-2-Chloro-3-pyridinyl)-(E)-2-propenoic Acid (11) To a suspension
of 60% sodium hydride (18.0 g, 0.45 mol) in THF (1400 ml) was added
(EtO)2P(O)CH2CO2Et (89.3 ml, 0.45 mol) under nitrogen at 5 °C for 30 min.
The mixture was stirred at 1 °C for 30 min and a solution of 2-chloro-3-
formylpyridine 10 (42.5 g, 0.30 mol) in THF (100 ml) was added to the mix-
ture at 5—7 °C. The mixture was stirred at 1—3 °C for 1 h and the reaction
was quenched with sat. NH4Cl (300 ml). The product was extracted with
tert-butyl methyl ether (2ϫ300 ml) and the combined organic solution was
Zn(BH4)2
Li-9-BBN-H
LAH
L-Selectride®
NaBH4
1/1.4
The ratio of diastereoisomer was determined by 1H-NMR.
Chart 5

1070
Vol. 50, No. 8
washed with brine (300 ml). After concentration, the product was crystal- cooling to 0 °C, 30% H2O2 (0.54 ml, 4.76 mol) and LiOH (99.9 mg, 2.38
lized from methanol–water to give crystalline ethyl ester of compound 11 mmol) was added to the solution, and the mixture was stirred at room tem-
(56.2 g) in 89% yield. HPLC: column, YMC ODS A-303: eluent, perature for 40 min. After cooling to 0 °C, the reaction was quenched with
CH3CN/H2O (50/50): flow rate, 1.0 ml/min; tR for 11, 8.30 min. 1H-NMR
1 M sodium sulfate (6 ml) and sat NaHCO4 (10 ml). Heptane (10 ml) was
(270 MHz, CDCl3) d: 1.28 (t, 3H), 4.22 (q, 2H), 6.38 (d, 1H), 7.22 (dd, 1H), added to the mixture and the aqueous layer was separated and washed with
7.85 (dd, 1H), 7.90 (d, 1H), 8.32 (dd, 1H). tert-butyl methyl ether (20 ml). The aqueous layer was acidified (pH 1) with
To a solution of the above ester (56.2 g, 0.266 mol) in methanol (600 ml) 6 M HCl, and the product was extracted with tert-butyl methyl ether
was added 1 M NaOH (400 ml, 0.40 mol), and the mixture was stirred at (3ϫ30 ml). The combined organic layer was washed with brine (20 ml) and
50 °C for 1 h. After cooling to room temperature, the mixture was washed concentrated to dryness to give enantiomeric mixture of compound 15. The
with tert-butyl methyl ether (1700 ml). The product in the organic layer was stereoselectivity was determined by chiral HPLC at this stage. HPLC:
extracted with 1 M NaOH (2ϫ400 ml) and the combined aqueous layer was
column, DAICEL CHIRALCEL OJ: eluent, 2-propanol/ethanol/TFA
adjusted to pH 2 with 6 M HCl. The product was extracted with ethyl acetate (600/400/1): flow rate, 0.5 ml/min; tR for 15, 16.0 min; tR for enantiomer,
(4ϫ1000 ml) and the combined organic layer was washed with brine 14.5 min.
(700 ml) and concentrated to dryness to give compound 11 (45.6 g) in 93%
yield (83% yield from 10). HPLC: column, YMC ODS A-303: eluent, 4,5-dihydro-1,3-oxazol-2-yl]vinyl}pyridine (17) To a solution of diiso-
CH3CN/H2O (50/50): flow rate, 1.0 ml/min; tR for 11, 1.88 min. 1H-NMR
propylamine (149 ml, 1.06 mol) in THF (600 ml) was added n-BuLi (1.66 M
(270 MHz, CDCl3) d: 6.48 (d, 1H), 7.33 (dd, 1H), 7.42 (dd, 1H), 8.06 (d, in hexane, 583 ml, 968 mmol) at Ϫ78 °C. A solution of (4S,5S)-4-
1H), 8.43 (dd, 1H). methoxymethyl-2-methyl-5-(4-methylthiophenyl)-4,5-dihydro-1,3-oxazole
2-Chloro-3-{(E)-[2-(4S,5S)-4-methoxymethyl-5-(4-methylthiophenyl)-
Oxazolidinone Derivatives (12a—e) To a solution of compound 11 16 (106 g, 422 mmol) in THF (200 ml) was added dropwise to the LDA solu-
(29.9 g, 0.163 mol) in CHCl3 (300 ml) was added SOCl2 (33.5 ml, 0.459 mol) tion at the same temperature and stirred at Ϫ78 °C for 30 min. ClPO(OEt)2
and the mixture was refluxed for 2 h. After cooling to room temperature, the (66.9 ml, 463 mmol) was added at Ϫ78 °C, then the reaction mixture was
mixture was concentrated and residual SOCl2 was eliminated by azeotropic warmed to 0 °C and stirred for 30 min. A solution of 10 (65.5 g, 463 mmol)
distillation with toluene. The residue was dissolved in THF (50 ml) and the
solution was used as 1.5 M solution of acid chloride of compound 11.
in THF (200 ml) was added dropwise to the reaction mixture and the mixture
was stirred for 30 min at 0 °C. The reaction was quenched with 10% NH4Cl
(S)-(ϩ)-4-Phenyl-2-oxazolidinone (3.56 g, 21.8 mmol) was dissolved in and extracted with ethyl acetate. The organic layer was separated, washed
THF (70 ml) under nitrogen and cooled to Ϫ72 °C. To the solution was with water and brine, dried over MgSO4, and concentrated to dryness. The
added n-BuLi (n-butyl lithium, 1.40 M in hexane, 15.6 ml, 21.8 mmol) keep- residue was purified by silica gel column chromatography (C-300,
ing the temperature below Ϫ66 °C, and then the acid chloride solution hexane/ethyl acetateϭ1/1) to give pure compound 17 (146 g) in 92% yield
(1.5 M, 21.8 ml, 32.7 mmol) keeping the temperature below Ϫ72 °C. After
as a solid. HPLC: column, YMC ODS A-303: eluent, CH3CN/H2O (80/20):
stirring at Ϫ72 °C for 30 min, water (500 ml) was added and the mixture was flow rate, 1.0 ml/min; tR for 17, 5.34 min. mp 63—69 °C. [a]D20ϭϩ157°
stirred vigorously at room temperature. The product was extracted with ethyl (cϭ1.0, CHCl3). IR (KBr) cmϪ1: 2918, 2887, 1655, 1605, 1560, 1406, 1325,
acetate (4ϫ70 ml) and the combined organic layer was washed with sat. 1126, 1084, 1063, 974, 808. H-NMR (300 MHz, CDCl3) d: 2.49 (3H, s),
1
NaHCO3 (20 ml) and brine (20 ml). The organic layer was dried over 3.44 (3H, s), 3.60 (dd, Jϭ9.7, 6.0 Hz, 1H), 3.67 (dd, Jϭ9.7, 4.5 Hz, 1H),
MgSO4, and concentrated to dryness to give the crude product. The yellow 4.21—4.30 (m, 1H), 5.40 (d, Jϭ7.2 Hz, 1H), 6.72 (d, Jϭ16.4 Hz, 1H),
solid was crystallized from toluene–heptane to give the crystalline com- 7.22—7.32 (m, 4H), 7.30 (dd, Jϭ7.8, 4.7 Hz, 1H), 7.75 (d, Jϭ16.4 Hz, 1H),
1
pound 12a (6.07 g) in 85% yield. H-NMR (270 MHz, CDCl3) d: 4.29 (dd, 7.93 (dd, Jϭ7.8, 1.9 Hz, 1H), 8.37 (dd, Jϭ4.7, 1.9 Hz, 1H). HR-MS (FAB)
1H), 4.36 (dd, 1H), 5.57 (dd, 1H), 7.44—7.26 (m, 6H), 7.93 (d, 1H), 8.04 calcd for C19H20ClN2O2S (Mϩ1)ϩ 375.0934, found 375.0927.
(dd, 1H), 8.06 (d, 1H), 8.40 (m, 1H).
In a similar manner, compounds 12b—e were prepared.
(3S)-3-(-2-Chloro-3-pyridinyl)-3-(2,3-dihydro-1-benzofuran-6-yl)-
propanoic Acid (15) To a solution of 6-bromo-2,3-dihydro-1-benzofuran
12b was prepared from 11 and (4S,5R)-(Ϫ)-4-methyl-5-phenyl-2-oxazo- 18 (47.9 g, 0.241 mol) in THF (1.2 l), was added dropwise N,N,NЈ,NЈ-tetra-
lidinone in 65% yield. 1H-NMR (270 MHz, CDCl3) d: 0.94 (d, 3H), 0.97 (d,
methylethylenediamine (72.7 ml, 0.482 mol) and n-BuLi (1.53 M in hexane,
3H), 2.29 (m, 1H), 4.25 (dd, 1H), 4.29 (dd, 1H), 4.60 (ddd, 1H), 7.24 (dd, 158 ml, 0.242 mol) at Ϫ78 °C, and the mixture was stirred for 30 min. A so-
1H), 7.95 (d, 1H), 8.06 (dd, 1H), 8.14 (d, 1H), 8.40 (m, 1H). lution of oxazoline 17 (60.2 g, 0.161 mol) in THF (200 ml) was added drop-
12c was prepared from 11 and (4S)-(Ϫ)-4-isopropyl-2-oxazolidinone in wise for 15 min. The reaction was quenched by addition of acetic acid
32% yield. 1H-NMR (270 MHz, CDCl3) d: 1.00 (d, 3H), 4.88 (dq, 1H), 5.74 (41 ml) and water (1.2 l), and the product was extracted with tert-butyl
(d, 1H), 7.46—7.28 (m, 6H), 7.94 (d, 1H), 8.08 (dd, 1H), 8.17 (d, 1H), 8.42
(dd, 1H).
methyl ether (720 ml). HPLC assay showed 76% assay yield of compound
19 in the solution. After concentration of the organic layer, the residue was
12d was prepared from 11 and (4R)-5,5-dimethyl-4-phenyl-2-oxazolidi- dissolved in a mixed solution of 1,4-dioxane (276 ml) and water (276 ml).
1
none in 83% yield. H-NMR (270 MHz, CDCl3) d: 1.06 (s, 3H), 1.65 (s,
3H), 5.20 (s, 1H), 7.43—7.20 (m, 6H), 8.03 (d, 1H), 8.07 (dd, 1H), 8.10 (d, at 110 °C for 1.5 h. The reaction mixture was cooled to room temperature
1H), 8.40 (m, 1H). and the solution was adjusted to pH 2 with 6 N NaOH (642 ml). Once the
12e was prepared from 11 and (4R,5S)-4,5-diphenyl-2-oxazolidinone in product was extracted with ethyl acetate (513 ml) and extracted again with
90% yield. 1H-NMR (270 MHz, CDCl3) d: 5.80 (d, 1H), 6.00 (d, 1H),
0.2 N NaOH (2ϫ321 ml) from the organic layer, the combined aqueous layer
7.13—6.89 (m, 10H), 7.33 (dd, 1H), 8.05 (d, 1H), 8.08 (dd, 1H), 8.14 (d, was acidified (pH 3) with 2 N HCl and the product was extracted with ethyl
1H), 8.40 (m, 1H). acetate (321 ml). The organic layer was washed with water, dried over
conc. H2SO4 (128 ml) was added to the mixture and the mixture was stirred
Michael Addition to Oxazolidinone Derivatives (12a—e) Followed by MgSO4, and concentrated to 149 g. Chiral HPLC showed 85% ee of the
Hydrolysis A suspension of magnesium granules (2.08 g, 85.6 mol) in stereoselectivity in this stage. The solution was diluted with ethyl acetate
THF (20 ml) was refluxed under the nitrogen atmosphere. To the mixture (74.9 g) and (S)-(Ϫ)-1-phenylethylamine (19.0 ml, 147 mmol) was added.
was added a solution of 6-bromo-2,3-dihydro-1-benzofuran 18 (14.2 g, The mixture was stirred at room temperature overnight and the resulting
71.3 mmol) in THF (55 ml) for 40 min, and the mixture was stirred at 70 °C crystal was filtered, washed with tert-butyl methyl ether, and dried to give
for 2 h. After cooling, titration of the mixture showed 0.76 M of the Grignard
reagent 13.
(S)-(Ϫ)-1-phenylethylamine salt of compound 15 (41.1 g, 96% ee) in 60%
yield from 17. IR (KBr) cmϪ1: 2935, 1620, 1541, 1385, 1244, 1184, 1074,
To a solution of CuBr·Me2S (93.7 mg, 0.46 mmol) in THF (2.8 ml) was 987, 752, 700. The amine salt (15.7 g, 36.9 mmol) was suspended in ethyl
added the above Grignard reagent (0.76 M, 3 ml, 2.28 mmol) at 5 °C under acetate (100 ml) and water (100 ml), and the pH was adjusted to 3.0 with 2 N
the nitrogen atmosphere, and the mixture was stirred for 20 min. The mix- HCl (19 ml). The organic layer was separated, washed with water and brine,
ture was cooled to Ϫ78 °C and a solution of oxazolidinone derivatives dried over MgSO4, and concentrated to dryness to give crystalline com-
(12a—e) (1.52 mmol) in THF was added at Ϫ78 °C for 10 min. After stir- pound 15 (11.2 g) in quantitative yield from amine salt. HPLC: column,
ring at Ϫ78 °C for 1 h, the reaction was quenched with sat. NH4Cl (30 ml) YMC ODS A-303: eluent, CH3CN/0.1 M H3PO4 (40/60): flow rate,
and the mixture was stirred vigorously at room temperature for 1 h. The 1.0 ml/min; tR for 15, 8.25 min. mp 156—158 °C. [a]D20ϭϩ20.6° (cϭ1.000,
product was extracted with tert-butyl methyl ether (3ϫ40 ml), and the com- DMSO). IR (KBr) cmϪ1: 2908, 2517, 1709, 1578, 1495, 1408, 1331, 1238,
bined organic layer was washed with water (20 ml) and brine (20 ml). The 1186, 1095, 984, 955, 802. 1H-NMR (300 MHz, CDCl3) d: 3.01 (dd,
organic layer was dried over MgSO4, and concentrated to dryness. The prod- Jϭ16.3, 8.1 Hz, 1H), 3.07 (dd, Jϭ16.3, 7.8 Hz, 1H), 3.16 (t, Jϭ8.6 Hz, 2H),
uct was subjected to the next reaction without further purification.
4.55 (t, Jϭ8.6 Hz, 2H), 4.92 (dd, Jϭ8.1, 7.8 Hz, 1H), 6.64 (d, Jϭ1.3 Hz,
The above residue was dissolved in THF (6 ml) and water (6 ml). After 1H), 6.73 (dd, Jϭ7.6, 1.3 Hz, 1H), 7.11 (d, Jϭ7.6 Hz, 1H), 7.21 (dd, Jϭ7.7,

August 2002
1071
4.6 Hz, 1H), 7.59 (dd, Jϭ7.7, 1.7 Hz, 1H), 8.26 (dd, Jϭ4.6, 1.7 Hz, 1H). HR- 6.7 Hz, 1H), 2.58 (dd, Jϭ15.8, 9.2 Hz, 1H), 3.13 (t, Jϭ8.6 Hz, 2H), 3.78 (s,
MS (FAB) calcd for C16H15ClNO3 (Mϩ1)ϩ 304.0740, found 304.0757.
3H), 3.81 (s, 3H), 3.95—4.10 (m, 1H), 4.29 (dd, Jϭ9.2, 6.7 Hz, 1H), 4.40—
tert-Butyl (3S)-3-(2-Chloro-3-pyridinyl)-3-(2,3-dihydro-1-benzofuran- 4.63 (m, 4H), 4.67 (d, Jϭ12.5 Hz, 1H), 4,82 (d, Jϭ12.5 Hz, 1H), 6.11 (s,
6-yl)propanoate (21) To a solution of compound 15 (9.29 g, 30.6 mmol) 1H), 6.46 (d, Jϭ1.5 Hz, 1H), 6.52 (dd, Jϭ7.6, 1.5 Hz, 1H), 6.59—6.71 (m,
in THF (69 ml) was added tert-butyl alcohol (19.8 ml), 4-dimethylaminopy-
2H), 6.88 (d, Jϭ8.8 Hz, 2H), 6.99 (d, Jϭ7.6 Hz, 1H), 7.08 (d, Jϭ2.3 Hz,
ridine (5.59 g, 45.8 mmol) and EDCl (8.79 g, 45.9 mmol), and the mixture 1H), 7.33 (d, Jϭ8.8 Hz, 2H), 7.38 (dd, Jϭ7.9, 4.9 Hz, 1H), 7.76 (dd, Jϭ7.9,
was stirred at room temperature for 5 h. tert-Butyl methyl ether (70 ml) was 1.2 Hz, 1H), 8.58 (dd, Jϭ4.9, 1.2 Hz, 1H). HR-MS (FAB) calcd for
added to the reaction mixture, and the organic solution was washed with C37H42NO7 (Mϩ1)ϩ 612.2961, found 612.2966.
10% citric acid (80ϩ50 ml), sat. NaHCO4 (50 ml), water (50 ml) and brine
Diastereomer (Less Polar): IR (KBr) cmϪ1: 3417, 1720, 1614, 1504, 1433,
1
(50 ml) successively. The organic layer was dried over MgSO4 and concen- 1209, 1149, 1032, 814, 764, 636, 505. H-NMR (300 MHz, CDCl3) d: 1.24
trated to dryness to give crystalline compound 21 (10.0 g) in 91% yield. (s, 9H), 2.68 (dd, Jϭ15.5, 7.6 Hz, 1H), 2.75 (dd, Jϭ15.5, 9.2 Hz, 1H), 3.03
HPLC: column, YMC ODS A-303: eluent, CH3CN/H2O (70/30): flow rate, (t, Jϭ8.6 Hz, 2H), 3.76 (s, 3H), 3.80 (s, 3H), 4.19 (br s, 1H), 4.44 (t,
1.0 ml/min; tR for 21, 9.21 min. Chiral HPLC: column, DAICEL CHIRAL- Jϭ8.6 Hz, 2H), 4.37—4.72 (m, 4H), 5.00 (d, Jϭ12.1 Hz, 1H), 5.95—6.04
PAK AD: eluent, hexane/2-propanol (85/15): flow rate, 1.0 ml/min; tR for (m, 2H), 6.39—6.50 (m, 3H), 6.79 (d, Jϭ7.3 Hz, 1H), 6.86 (d, Jϭ8.7 Hz,
ester 21, 6.8 min; tR for enantiomer, 8.2 min. mp 49 °C. [a]D20ϭϪ16.6°
2H), 7.00 (d, Jϭ2.3 Hz, 1H), 7.29—7.40 (m, 3H), 7.69 (dd, Jϭ7.7, 1.1 Hz,
(cϭ1.000, CHCl3). IR (KBr) cmϪ1: 2974, 1724, 1566, 1493, 1404, 1365, 1H), 8.54 (dd, Jϭ4.8, 1.1 Hz, 1H). HR-MS (FAB) calcd for C37H42NO7
1
1211, 1147, 1068, 987, 951, 770. H-NMR (300 MHz, CDCl3) d: 1.31 (s,
9H), 2.90 (dd, Jϭ15.4, 8.0 Hz, 1H), 2.97 (dd, Jϭ15.4, 8.4 Hz, 1H), 3.17 (t,
(Mϩ1)ϩ 612.2961, found 612.2966.
tert-Butyl (5S,6R,7R)-2-(N-Benzoyl-N-isopropylamino)-5-(2,3-dihy-
Jϭ8.6 Hz, 2H), 4.55 (t, Jϭ8.6 Hz, 2H), 4.90 (dd, Jϭ8.4, 8.0 Hz, 1H), 6.65 dro-1-benzo-furan-6-yl)-7-[4-methoxy-2-(4-methoxybenzyloxymethyl)-
(d, Jϭ1.5 Hz, 1H), 6.74 (dd, Jϭ7.6, 1.5 Hz, 1H), 7.11 (d, Jϭ7.6 Hz, 1H), phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate (27) To a
7.21 (dd, Jϭ7.8, 4.7 Hz, 1H), 7.64 (dd, Jϭ7.8, 1.9 Hz, 1H), 8.26 (dd, Jϭ4.7, solution of compound 25 (9 : 1 mixture of diastereomer, 5.53 g, 9.04 mmol)
1.9 Hz, 1H). HR-MS (FAB) calcd for C20H23ClNO3 (Mϩ1)ϩ 360.1366,
in THF (70 ml) was added (EtO)2POCl (2.0 ml, 13.8 mmol) and LiHMDS
found 360.1362.
(1.0 M in THF, 45 ml, 45 mmol) at Ϫ10 °C under nitrogen. The reaction mix-
tert-Butyl (3S)-3-(2-Methoxycarbony-3-pyridinyl)-3-(2,3-dihydro-1- ture was stirred for 30 min at room temperature then quenched with sat.
benzofuran-6-yl)propanoate (22) A mixture of compound 21 (3.00 g, NH4Cl. The product was extracted with EtOAc, and the organic layer was
8.34 mmol), NaHCO3 (840 mg, 10.0 mmol), Pd(OAc)2 (187 mg, 0.833 washed with water and brine, dried over MgSO4, and concentrated to dry-
mmol) and 1,1Ј-bis(diphenylphosphino)ferrocene (462 mg, 0.833 mmol) in ness. HPLC assay indicated 84% assay yield of 26 in the residue. Analytical
methanol (30 ml) was treated under CO (1 kg/cm2) at 70 °C for 18 h. The re- data of pure 26: IR (KBr) cmϪ1: 1718, 1610, 1583, 1504, 1427, 1205, 1147,
1
action mixture was filtered through celite®, and the filtrate was diluted with 1038, 989, 816, 766. H-NMR (300 MHz, CDCl3) d: 1.31 (s, 9H), 3.22 (t,
ethyl acetate. The organic solution was washed with water and brine, dried Jϭ8.6 Hz, 2H), 3.32 (t, Jϭ10.0 Hz, 1H), 3.79 (s, 3H), 3.81 (s, 3H), 4.40—
over MgSO4, and concentrated to dryness. The residue was purified by silica 4.65 (m, 6H), 4.72 (br, 1H), 4.94 (d, Jϭ10.2 Hz, 1H), 6.67 (s, 1H), 6.76 (d,
gel column chromatography (C-300, hexane/ethyl acetateϭ7/3) to give pure Jϭ7.6 Hz, 1H), 6.82 (d, Jϭ9.0 Hz, 1H), 6.83 (d, Jϭ8.2 Hz, 2H), 6.96—7.08
compound 22 (3.09 g) in 97% yield as an oil. HPLC: column, YMC ODS A- (m, 2H), 7.09 (d, Jϭ4.8 Hz, 1H), 7.15 (d, Jϭ7.6 Hz, 1H), 7.27 (s, 1H), 7.28
303: eluent, CH3CN/H2O (70/30): flow rate, 1.0 ml/min; tR for 22, 6.63 min.
(d, Jϭ8.2 Hz, 2H), 8.42 (d, Jϭ4.8 Hz, 1H). HR-MS (FAB) calcd for
[a]D20ϭϪ82.5° (cϭ1.0, MeOH). IR (KBr) cmϪ1: 1720, 1614, 1427, 1296, C37H40NO6 (Mϩ1)ϩ 594.2856, found 594.2831.
1
1198, 1140, 1093, 987, 955, 770, 627, 500. H-NMR (300 MHz, CDCl3) d:
1.29 (s, 9H), 2.95 (d, Jϭ8.2 Hz, 2H), 3.16 (t, Jϭ8.6 Hz, 2H), 3.99 (s, 3H),
4.55 (t, Jϭ8.6 Hz, 2H), 5.35 (t, Jϭ8.2 Hz, 1H), 6.70 (d, Jϭ0.9 Hz, 1H), 6.77
(dd, Jϭ7.6, 0.9 Hz, 1H), 7.10 (d, Jϭ7.6 Hz, 1H), 7.38 (dd, Jϭ8.0, 4.6 Hz,
The crude 26 was dissolved in CHCl3 (60 ml), and 3-chloroperoxybenzoic
acid (5.46 g, 31.6 mmol) was added to the solution at 0 °C under nitrogen.
The mixture was stirred at 0 °C for 12 h, and the reaction was quenched with
sodium thiosulfate solution. The product was extracted with ethyl acetate,
1H), 7.73 (dd, Jϭ8.0, 1.4 Hz, 1H), 8.54 (dd, Jϭ4.6, 1.4 Hz, 1H). HR-MS and the organic layer was washed with water and brine, dried over MgSO4
(FAB) calcd for C22H26NO5 (Mϩ1)ϩ 384.1811, found 384.1826.
and concentrated to dryness. The residue was dissolved in CHCl3 (60 ml)
tert-Butyl (3S)-3-{2-[4-Methoxy-2-(4-methoxy-benzyloxymethyl)ben- again, and triethylamine (7.6 ml, 54.5 mmol) and Isopropylbenzimidoyl
zoyl]-3-pyridinyl}-3-(2,3-dihydro-1-benzofuran-6yl)propanoate (24) To chloride (4.90 g, 27.0 mmol) were added to the solution. The mixture was
a solution of 4-Bromo-3-(4-methoxybenzyloxymethyl)anisole 23 (1.55 g, stirred at 70 °C for 7 h, and the reaction was quenched with water. The prod-
4.60 mmol) in THF (16 ml) was added dropwise n-BuLi (1.63 M in hexane, uct was extracted with ethyl acetate, and the organic layer was washed with
2.82 ml, 4.60 mmol) at Ϫ78 °C, and the mixture was stirred for 30 min. The water and brine. The organic layer was dried over MgSO4, concentrated to
mixture was added dropwise to a cold solution of compound 22 (1.59 g, dryness, and purified by silica gel column chromatography (C-300,
4.15 mmol) in THF (28 ml) at Ϫ78 °C for 2 min and the whole was stirred hexane/ethyl acetateϭ8/2) to give compound 27 (2.60 g) in 38% yield from
for 10 min. The reaction was quenched with sat. NH4Cl and the product was 25. IR (KBr) cmϪ1: 3369, 1714, 1641, 1581, 1502, 1439, 1942, 1200, 1142,
extracted with EtOAc. The organic layer was washed with brine, dried over 708, 631, 498. 1H-NMR (300 MHz, CDCl3) d: 1.09 (d, Jϭ6.9 Hz, 3H), 1.17
MgSO4, and concentrated to dryness. The residue was purified by silica gel (d, Jϭ6.9 Hz, 3H), 1.31 (s, 9H), 3.19 (t, Jϭ8.6 Hz, 2H), 3.26 (dd, Jϭ9.9,
column chromatography (C-300, hexane/ethyl acetateϭ7/3) to give pure 8.6 Hz, 1H), 3.76 (s, 3H), 3.83 (s, 3H), 4.46 (d, Jϭ8.6 Hz, 1H), 4.51 (s, 2H),
compound 24 (2.23 g) in 88% yield as an oil. [a]D20ϭϪ77.4° (cϭ1.0,
4.57 (t, Jϭ8.6 Hz, 2H), 4.41—4.63 (m, 1H), 4.81 (d, Jϭ15.5 Hz, 1H),
MeOH). IR (KBr) cmϪ1: 1722, 1655, 1601, 1566, 1502, 1433, 1290, 1198, 4.88—5.05 (m, 1H), 5.02 (d, Jϭ9.9 Hz, 1H), 6.50—6.55 (m, 2H), 6.63 (d,
1
1140, 1034, 949, 812, 758, 623, 498. H-NMR (300 MHz, CDCl3) d: 1.29
(s, 9H), 2.88 (dd, Jϭ15.5, 8.8 Hz, 1H), 2.98 (dd, Jϭ15.5, 7.3 Hz, 1H), 3.04
Jϭ7.6 Hz, 1H), 6.71—6.87 (m, 4H), 6.96—7.04 (m, 2H), 7.06—7.33 (m,
8H). HR-MS (FAB) calcd for C47H51N2O7 (Mϩ1)ϩ 755.3696, found
(t, Jϭ8.6 Hz, 2H), 3.82 (s, 3H), 3.85 (s, 3H), 4.46 (t, Jϭ8.6 Hz, 2H), 4.62 (s, 755.3673.
2H), 4.74 (dd, Jϭ8.8, 7.3 Hz, 1H), 5.06 (s, 2H), 6.54 (d, Jϭ1.4 Hz, 1H),
6.55—6.65 (m, 2H), 6.87—6.97 (m, 3H), 7.08 (d, Jϭ8.7 Hz, 1H), 7.12—
tert-Butyl (5S,6R,7R)-5-(2,3-Dihydro-1-benzofuran-6-yl)-7-[2-(hydroxy-
methyl)-4-methoxy-phenyl]-2-(isopropylamino)-6,7-dihydro-5H-cy-
7.44 (m, 4H), 7.73 (dd, Jϭ8.1, 1.5 Hz, 1H), 8.44 (dd, Jϭ4.7, 1.5 Hz, 1H). clopenta[b]pyridine-6-carboxylate (28) To a solution of compound 27
HR-MS (FAB) calcd for C37H40NO7 (Mϩ1)ϩ 610.2805, found 610.2806.
(2.60 g, 3.44 mmol) in ethyl acetate (30 ml) and methanol (30 ml) was added
tert-Butyl (3S)-3-{2-{(S)-Hydroxy[4-methoxy-2-(4-methoxybenzyl- 20% Pd(OH)2 (4.00 g), and the mixture was hydrogenated at ambient tem-
oxymethyl)phenyl]methyl-3-pyridinyl}-3-(2,3-dihydro-1-benzofuran-6-
perature under H2 (1 kg/cm2) for 2 d. The reaction mixture was filtered
yl)propanoate (25) To a solution of compound 24 (7.78 g, 12.8 mmol) in through Celite® and the filtrate was concentrated to dryness. The residue was
THF (60 ml) was added catecholborane (1.0 M in THF, 40 ml, 40 mmol) at dissolved in THF (34 ml), and DIBAL (1.01 M in toluene, 17 ml, 17.2 mmol)
Ϫ10 °C and the mixture was stirred at room temperature for 1 h. The reac- was added to the solution under nitrogen at Ϫ78 °C for 10 min. After stirring
tion was quenched with 30% H2O2 and 1 N NaOH by stirring at room tem-
perature for 1 h, and the product was extracted with ethyl acetate. The or-
at Ϫ78 °C for 1 h, the reaction was quenched with sat. NH4Cl, and the prod-
uct was extracted with ethyl acetate. The organic layer was washed with 1 N
ganic layer was washed with water and brine, dried over MgSO4, and con- KHSO4 and brine, dried over MgSO4, and concentrated to dryness to give
centrated to dryness to give compound 25 (9 : 1 mixture of diastereomer, compound 28 (1.59 g) in 87% yield as a solid. mp 72 °C. [a]D20ϭϩ37.8°
6.19 g) in 79% yield as an oil. A pure sample of 25 was obtained through sil- (cϭ1.0, MeOH). IR (KBr) cmϪ1: 3250, 2964, 2359, 1713, 1603, 1495, 1435,
1
ica gel column chromatography (C-300, hexane/ethyl acetateϭ7/3). IR 1367, 1201, 1142, 764, 631, 500. H-NMR (300 MHz, CDCl3) d: 1.09 (d,
(KBr) cmϪ1: 1722, 1608, 1502, 1431, 1363, 1292, 1209, 1151, 1032, 814,
629, 503. H-NMR (300 MHz, CDCl3) d: 1.22 (s, 9H), 2.29 (dd, Jϭ15.8,
Jϭ6.3 Hz, 3H), 1.14 (d, Jϭ6.3 Hz, 3H), 1.36 (s, 9H), 3.23 (t, Jϭ8.6 Hz, 2H),
3.46 (dd, Jϭ8.5, 7.7 Hz, 1H), 3.60—3.75 (m, 1H), 3.81 (s, 3H), 4.29 (d,
1

1072
Vol. 50, No. 8
910 (2000), and references cited therein.
2) Ishikawa K., Nagase T., Mase T., Hayama T., Ihara M., Nishikibe M.,
Yano M., PCT Int. Appl. WO 9505374, 1995.
Jϭ7.9 Hz, 1H), 4.46 (d, Jϭ11.5 Hz, 1H), 4.52 (d, Jϭ7.7 Hz, 1H), 4.60 (t,
Jϭ8.6 Hz, 2H), 4.98 (d, Jϭ8.5 Hz, 1H), 5.03 (d, Jϭ11.5 Hz, 1H), 6.15 (d,
Jϭ8.5 Hz, 1H), 6.73—6.85 (m, 3H), 6.98 (d, Jϭ2.0 Hz, 1H), 7.04—7.14 (m,
2H), 7.18 (d, Jϭ7.6 Hz, 1H). HR-MS (FAB) calcd for C32H39N2O5 (Mϩ1)ϩ
531.2859, found 531.2866.
3) Niiyama K., Hayama T., Mase T., Nagase T., Fukami T., Hisaka A.,
Nishikibe M., Ihara M., Yano M., Ishikawa K., The 216th National
Meeting of the American Chemical Society, Boston, MA, August
1998, Abstract #56.
4) Niiyama K., Hayama T., Mase T., Nagase T., Fukami T., Takahashi H.,
Hisaka A., Nishikibe M., Ihara M., Yano M., Ishikawa K., The 15th
EFMC International Synposium on Medicinal Chemistry, Edinburgh,
Scotland, September 1998, p. 297.
(5S,6R,7R)-5-(2,3-Dihydro-1-benzofuran-6-yl)-7-[2-(hydroxymethyl)-
4-methoxy-phenyl]-2-(isopropylamino)-6,7-dihydro-5H-cyclopenta[b]-
pyridine-6-carboxylic Acid (1b) Compound 27 (21.0 g, 39.6 mmol) was
treated with TFA (63 ml) at the ambient temperature for 1 h, and the mixture
was concentrated to dryness. Water (100 ml) and ethyl acetate (200 ml) were
added to the residue and the mixture was neutralized with NaHCO3. After
separation, the product was extracted with ethyl acetate (2ϫ100 ml). The
combined organic layer was dried over MgSO4, and concentrated to dryness.
The solid residue was crystallized from ethanol to give the title compound
1b (13.3 g, 99.9% ee) as a white crystalline solid in 71% yield. HPLC: col-
umn, DAICEL CHIRALPAK AD: eluent, hexane/2-propanol/CF3COOH
(700/300/1): flow rate, 1.0 ml/min; tR for 1b, 8.5 min; tR for enantiomer,
5) Manuscript in preparation.
6) Song Z. J., Zhao M., Desmond R., Devine P., Tschaen D. M., Tillyer
R., Frey L., Heid R., Xu F., Foster B., Li J., Reamer R., Volante R.,
Grabowski E. J., Dolling U.-H., Reider P. J., Okada S., Kato Y., Mano
E., J. Org. Chem., 64, 9658—9667 (1999).
7) Devine P. N., Desmond R., Frey L. F., Heid R. M., Song Z., Tillyer R.
D., Tschaen D. M., Zhao M., Kato Y., Mano E., Okada S., Kato S.,
Mase T., J. Synth. Org. Chem. Jpn., 57, 1016—1025 (1999).
8) Song Z. J., Zhao M., Frey L., Li J., Tan L., Chen C. Y., Tschaen D. M.,
Tillyer R., Grabowski E. J. J., Volante R. P., Reider P. J., Kato Y.,
Okada S., Nemoto T., Sato H., Akao A., Mase T., Org. Lett., 3, 3357—
3360 (2001).
13.5 min. mp 203 °C (dec.). [a]D20ϭϩ63° (cϭ1.002, DMF). IR (KBr) cmϪ1
:
1
2966, 1670, 1618, 1500, 1394, 1250, 1171, 1034, 999, 814, 721. H-NMR
(300 MHz, DMSO) d: 0.98 (d, Jϭ6.4 Hz, 3H), 1.04 (d, Jϭ6.4 Hz, 3H), 3.01
(dd, Jϭ8.8, 8.6 Hz, 1H), 3.15 (t, Jϭ8.8 Hz, 2H), 3.58—3.75 (m, 1H), 3.73
(s, 3H), 4.33 (d, Jϭ8.6 Hz, 1H), 4.40—4.56 (m, 3H), 4.57—4.73 (m, 2H),
6.25 (d, Jϭ8.3 Hz, 1H), 6.60 (d, Jϭ1.4 Hz, 1H), 6.71 (dd, Jϭ7.6, 1.4 Hz,
1H), 6.75 (dd, Jϭ8.5, 2.9 Hz, 1H), 6.87—6.97 (m, 2H), 7.02 (d, Jϭ2.8 Hz,
1H), 7.18 (d, Jϭ7.6 Hz, 1H). 13C-NMR (125 MHz, DMSO) d: 22.6, 22.8,
29.2, 42.2, 50.0, 51.5, 55.3, 61.1, 62.0, 71.3, 108.7, 112.5, 120.4, 124.1,
125.3, 126.2, 129.6, 132.0, 134.0, 142.6, 144.2, 158.1, 160.5, 161.9, 175.6.
HR-MS (FAB) calcd for C28H31N2O5 (Mϩ1)ϩ 475.2233, found 475.2247;
Anal. Calcd for C28H30N2O5: C, 70.87; H, 6.37; N, 5.90. Found: C, 70.39; H,
6.43; N, 5.83.
9) Manuscript in press.
10) Rossiter B. E., Swingle N. M., Chem. Rev., 92, 771—806 (1992).
11) Meyers A. I., Smith R. K., Whitten C. E., J. Org. Chem., 44, 2250—
2256 (1979).
12) Liao S., Han Y., Qiu W., Bruck M., Hruby V. J., Tetrahedron Lett., 37,
7917—7920 (1996).
13) Lin J., Liao S., Hruby V. J., Tetrahedron Lett., 39, 3117—3120 (1998).
14) Oppolzer W., Tetrahedron, 43, 1969—2004 (1987).
15) Koch K., Biggers M. S., J. Org. Chem., 59, 1216—1218 (1994).
16) Abramovitch R. A., Pilski J., Konitz A., Tomasik P., J. Org. Chem., 48,
4391—4393 (1983).
References and Notes
1) Astles P. C., Brown T. J., Halley F., Handscombe C. M., Harris N. V.,
Majid T. N., McCarthy C., McLay I. M., Morley A., Porter B., Roach
A. G., Sargent C., Smith C., Walsh R. J. A., J. Med. Chem., 43, 900—