A New Route for the Total Synthesis of 6,7-Dihydroeponemycin

Article abstract of DOI:10.1002/ejoc.200300401

A new synthesis of dihydroeponemycin (2), a peptide epoxide with potent cytotoxic and antiangiogenesis activity, has been developed. In the initial steps, Fmoc-Leu-Cl was converted into the key amino ketone intermediate 9 by Stille coupling with tributylvinyltin, conjugate addition of PhSA1Me ₂ to the derived enone, S-oxidation, and heat-induced syn elimination. Subsequent reaction of 9 with H₂O₂ and catalytic Triton B produced the corresponding epoxides as a 1:1 diastereomeric mixture in 89 % yield. These epoxides were separated and individually converted into 2 and(2S)-epi-dihydroeponemycin (24) in a four-step "one-pot" protocol (77 % overall yield in both cases). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300401

FULL PAPER
A New Route for the Total Synthesis of 6,7-Dihydroeponemycin
[a]
[a]
[a]
Bibia Bennacer, Christian Rivalle,* and David S. Grierson
Keywords: Asymmetric synthesis / Epoxidation / Michael addition
A new synthesis of dihydroeponemycin (2), a peptide epox- and catalytic Triton B produced the corresponding epoxides
ide with potent cytotoxic and antiangiogenesis activity, has
been developed. In the initial steps, Fmoc-Leu-Cl was con-
verted into the key amino ketone intermediate 9 by Stille
as a 1:1 diastereomeric mixture in 89 % yield. These epoxides
were separated and individually converted into 2 and(2S)-
epi-dihydroeponemycin (24) in a four-step ‘‘one-pot’’ protocol
coupling with tributylvinyltin, conjugate addition of (77 % overall yield in both cases).
PhSAlMe
2
to the derived enone, S-oxidation, and heat-in-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
duced syn elimination. Subsequent reaction of 9 with H
2
O
2
Germany, 2003)
Introduction
Eponemycin (1) has been shown by Crews et al. to be a
potent inhibitor of the proteasome 20S.[
1,2]
The mode of
action may be related to the interesting antiangiogenesis
[3Ϫ6]
properties displayed by this molecule.
In the preceding
[
7]
paper the synthesis of two new furan analogues of epone-
mycin was described, wherein methodology developed by
Myers and co-workers[8Ϫ15] was employed for both the
preparation of the didehydroleucine derivative 3 (R ϭ Boc)
and its subsequent reaction with 2-furyllithium. As an ex-
tension of this approach we envisaged that by reaction of
amide 3 with the organolithium reagent 4 the key amino
ketone intermediate 5 would be obtained (Scheme 1). Epox-
idation of the enone double bond in 5 would complete con-
struction of the reactive αЈ,βЈ-epoxy ketone motif present
in 1, thereby opening the way to the synthesis of this inter-
esting molecule for further investigation of its biological ac-
tivity.
Results and Discussion
The reaction of reagent 4 with the corresponding ami-
noaldehydes 6 and 7 was a pivotal step in several earlier
approaches to eponemycin and its dihydro derivative 2
(
which has the same potency as 1).[
16Ϫ18]
This route pro-
Scheme 1
vides a seemingly direct means to obtain the α-hydroxy-
methyl-substituted enone 5 and the corresponding saturated
compound 9. However, in addition to the preparation of
the sensitive aminoaldehyde starting material, additional
operations involving protection and deprotection of the pri-
mary OH group are required in this strategy in order to
permit selective oxidation of the secondary alcohol function
in 8.
Interestingly, the reactivity of dilithio reagent 4 towards
acids and acid derivatives has received little attention. In
[
a]
UMR
176
CNRS-Institut
Curie,
Laboratoire
de
Pharmacochimie
Bat. 110 Centre Universitaire, 91405 Orsay, France,
Fax: (internat.) ϩ33-1-69075381
E-mail: rivalle@curie.u-psud.fr
[19]
model experiments to explore the conversion of 3 to 5 the
Weinreb-type amide derivative 10 [Boc-Leu-N(OMe)Me]
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2003, 4569Ϫ4574
DOI: 10.1002/ejoc.200300401
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4569

B. Bennacer, C. Rivalle, D. S. Grierson
FULL PAPER
was treated with 4 under a variety of conditions. Despite a
With this positive result in hand, the synthesis of di-
precedent for the reaction of the related Boc-leucine deriva- hydroeponemycin (2) became dependent upon finding suit-
tive with 2-propenyllithium,[20Ϫ22] the desired transform- able conditions to introduce the α-hydroxymethyl side chain
ation was not achieved. Similarly, formation of 5 could not present in 9. The Baylis Hillman reaction[28] using formal-
be detected in the reaction with TeOC-leucine 11 itself. dehyde is the obvious choice for this transformation. How-
Schmidt et al. have previously reported that the reaction of ever, the general conditions, where an amine nucleophile
4
tion.
with acid chlorides leads to competing allyl ester forma- (DABCO, DBU, etc.) is involved in the initial Michael ad-
[
15]
dition step, are incompatible with the presence of the N-
As an alternative goal, the Pd -catalyzed Stille coup- Fmoc group in 15. Yamada et al. have recently described
0
ling[
23,24]
of the corresponding vinyltin reagents 12a,b
[25,26]
alternative conditions using a combination of tributylphos-
[25]
[29]
and their ester precursor 12c with Fmoc-Leu-Cl 14 (ob- phane and (Ϯ)-1,1Ј-bi-2-naphthol combination, but even
tained in 82 % yield from 13 and recrystallized from with this mild Lewis base N-Fmoc deprotection occurred.
CH Cl /hexane) was subsequently evaluated as a means to In contrast, Me AlSPh proved to be a highly effective nucle-
2
2
2
[
30,31]
synthesize dihydroeponemycin 2. These reactions, conduc- ophile and weak base for this process.
In the experi-
ted using 5Ϫ10 mol % [Pd(PPh ) ] or [Pd(PPh ) BnCl ment, 15 was treated with Me AlSPh at Ϫ78 °C in CH Cl .
3
4
3 2
2
2
2
]
(with or without CuI) in a variety of solvents and tempera- THF was then added at the same temperature, followed by
tures up to 65 °C, either did not proceed, or resulted in gaseous HCHO. Compound 17 was isolated as a white crys-
degradation and formation of homocoupling products. In talline solid in 75 % yield. This intermediate was then con-
contrast, the reaction of 14 with n-tributylvinyltin in verted into enone 9 in 62 % overall yield and greater than
HMPA using catalytic [Pd(MeCN) Cl ] (5 mol %) was com- 97 % ee by S-oxidation (mCPBA, Ϫ78 °C, 15 min), and
2
2
plete after 15 min at room temperature, providing enone 15 heating of the resulting sulfoxide in a 9:1 CCl /CHCl mix-
4
3
[
32]
in 60Ϫ80 % isolated yield and with 98 % ee (Scheme 2). ture for 15 h.
Most remarkable was the observation that at 65 °C the In the subsequent epoxidation step, it was again con-
competing decarbonylation reaction occurred, leading to sidered necessary to take precautions to avoid basic con-
formation of 16 predominantly.[
27]
ditions that would result in unwanted Fmoc deprotection.
Scheme 2
4570
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4569Ϫ4574

A New Route for the Total Synthesis of 6,7-Dihydroeponemycin
FULL PAPER
This led us to attempt epoxidation of the deactivated omerically pure form. This involved adding DBU to a co-
double bond in 9 using excess mCPBA. In this reaction oled (Ϫ20 °C) solution of 18a in CH CN, warming the mix-
3
compound 19 was produced in 75 % yield (Scheme 3). A ture to room temperature over five minutes, followed by re-
possible mechanism for the formation of this unexpected cooling and ‘‘neutralizing’’ the liberated amine as its
product involves an initial BaeyerϪVilliger reaction giving hydrochloride salt. PyBOP, HOBT and acid 23 were then
20. This intermediate would be prone to elimination, giving added to the medium at 0 °C, and finally triethylamine was
the acylimine 21, which would react readily with the peracid added dropwise at Ϫ20 °C. In an identical fashion the dia-
to give the oxaziridine 22. The subsequent transformation stereomeric epoxide 18b was coupled with acid 23 to give
of this oxaziridine to the amide 19 on treatment with (2S)-epi-dihydroeponemycin (24) in 77 % overall yield. The
mCPBA is a known process.[
33]
1
H and C NMR spectroscopic data for our sample of syn-
13
thetic dihydroeponemycin were identical in all respects with
[
39,40]
the values reported by Sugawara et al.
Experimental Section
General Remarks: Unless otherwise stated, all reactions were car-
ried out under argon with dry, freshly distilled solvents, flame-dried
glassware, and magnetic stirring. All solvents were reagent grade.
Diethyl ether and tetrahydrofuran (THF) were distilled from so-
dium/benzophenone under argon. Acetonitrile and dichlorometh-
2 2
ane (CH Cl ) were distilled from calcium hydride. Triethylamine
was distilled from calcium hydride and stored over potassium hy-
droxide. N,N-dimethylformamide (DMF) was purchased from Ald-
rich and used without purification unless otherwise noted. All reac-
tions were monitored by thin layer chromatography (TLC) using
E. Merk 60F254 precoated silica gel plates. Flash column chroma-
tography was performed with the indicated solvents and using E.
Merk silica gel 60 (particle size 0.035Ϫ0.070 mm unless otherwise
stated). Yields refer to chromatographically and spectroscopically
pure compounds, except where indicated otherwise. Melting points
were taken on a Kofler melting point apparatus and are uncor-
rected. Optical rotations were measured on a PerkinϪElmer 341
polarimeter at the sodium D line (589 nm) and are reported as
Scheme 3
2
0
Ultimately, it was found that 9 could be converted into a follows: [α]
D
(c in g/100 mL, solvent). Infra-red spectra were re-
1
corded with a PerkinϪElmer 1710FT spectrophotometer. H NMR
spectra were recorded with a Bruker AC-200 (200 MHz) or with a
Bruker AC-300 (300 MHz) spectrometer at ambient temperature
using an internal deuterium lock. Chemical shifts are referenced
to residual chloroform (δ ϭ 7.24 ppm) or residual methanol (δ ϭ
1:1 diastereomeric mixture of epoxides 18a,b in high yield
(89 %) by addition of a catalytic amount of Triton B (2 ϫ
[
34,35]
5
mol %) to a solution of 9 and H O (in THF) at 0 °C.
2
2
These conditions, where the concentration of base present
in the medium is kept very low, did not promote cleavage
of the Fmoc group. Unfortunately, no asymmetric induc-
1
3
4.78 ppm). C NMR spectra were recorded with either a Bruker
AC-200 (50 MHz) spectrometer or a Bruker AC-300 (75 MHz)
spectrometer at ambient temperature using an internal deuterium
was attempted by adding poly--leucine to the lock. Chemical shifts are referenced to chloroform (δ ϭ 77.0 ppm)
tion was observed when
a
JuliaϪColonna-type
[
36Ϫ38]
process
reaction medium. The diastereomeric epoxides 18a and 18b or methanol (δ ϭ 49.0 ppm). High and low resolution mass spectra
were readily separated by silica-gel column chromatography were carried out by the I.C.M.O. Mass Spectrometry Service at
the University of Paris XI. Microanalyses were performed by the
(
EtOAc/cyclohexane, 1:9 to 3:7) and completely charac-
I.C.S.N.-C.N.R.S. Elemental Analysis Center at Gif-sur-Yvette.
High-performance liquid chromatography (HPLC) was performed
with a Waters component Analytical system by the I.C.S.N.-
C.N.R.S. HPLC Center at Gif-sur-Yvette.
terized.
The final step of the synthesis of dihydroeponemycin (2)
[
7]
involved the coupling with N-isooctanoyl--serine (23).
As feared, Fmoc deprotection by treatment of 18a with
Et N, DBU or Hunigs base was followed by instantaneous Fmoc-Leu-Cl (14): DMF (54.5 µL, 0.71 mmol) and freshly distilled
opening of the epoxide ring by the liberated amine. A sub-
sequent (and unsuccessful) attempt was made to intercept
the liberated amine before the intramolecular ring-opening/
ring-forming process could occur, by ensuring that the acti-
vated acid component [PyBOP, HOBT] was present in the
reaction medium at the moment when the amine base was
added. Therefore, to avoid this problem, a practical four-
step ‘‘one-pot’’ coupling protocol was developed, giving ac-
3
thionyl chloride (10.26 mL, 141.5 mmol) were added to a suspen-
sion of Fmoc-Leu-OH (5.00 g, 14.15 mmol) in CH Cl (27 mL).
2 2
The mixture was heated at reflux for 1.5 h, cooled to room tem-
perature and the solvents evaporated to dryness under reduced
pressure to afford the corresponding acid chloride as a colorless
2 2
oil. Crystallization from CH Cl /hexane (1:10, 88 mL) afforded 14
(
4.3 g, 82 %) as white crystals, which can be stored for months over
1
P
4
O
10. M.p. 82Ϫ83 °C. H NMR (300 MHz, CDCl
3
): δ ϭ 7.75 (d,
3
3
J ϭ 7.4 Hz, 2 H, HFmoc), 7.57 (d, J ϭ 7.3 Hz, 2 H, HFmoc), 7.39
3
cess to dihydroeponemycin 2 in 77 % yield, and in enanti- (m, 2 H, HFmoc), 7.29 (m, 2 H, HFmoc), 5.16 (d, JNH,2 ϭ 7.8 Hz,
Eur. J. Org. Chem. 2003, 4569Ϫ4574
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4571

B. Bennacer, C. Rivalle, D. S. Grierson
FULL PAPER
3
1
1
H, NH), 4.50 (m, 3 H, CH2Fmoc and 2-H), 4.21 (t, J ϭ 6.6 Hz, peared by TLC (approx.15 min). The resulting mixture was cau-
H, CHFmoc), 1.72 (m, 2 H, 3-H), 1.57 (m, 1 H, 4-H), 0.96 (m, 6 tiously poured into a mixture of ice cold 1  HCl and extracted
H, CH
C-1) 156.41 (COFmoc), [144.15 ϩ 142.01 ϩ 128.47 ϩ 127.78 ϩ washed with 1  HCl and with brine, dried with Na
120.71, (CFmoc)], 67.92 (CH2Fmoc), 62.14 (2-C), and concentrated under reduced pressure. Gradient flash column
7.80(CHFmoc), 40.58 (C-3), [23.50 ϩ 25.49, (C-5 and C-6)], 22.04 chromatography (SiO , EtOAc/cyclohexane, 15:85, EtOAc/cyclo-
hexane, 1:4) afforded 17 as an oil which gave white crystals on
3
CHCH
3
) ppm. 13C NMR (75 MHz, CDCl
3
): δ ϭ 176.11 with EtOAc (3 ϫ 80 mL). The combined organic phases were
(
,
2
SO , filtered
4
125.61 ϩ
4
2
(C-4) ppm.
2
0
standing (3.16 g, 75 %). M.p. 99 °C. [α]
D
ϭ ϩ73.5 (c ϭ 1.07,
(
(
4S)-4-(9-Fluorenylmethoxycarbonyl)amino-6-methylhept-1-en-3-one
15): Tributylvinyltin (2.60 g, 7.90 mmol) and bis(acetonitrile)palla-
1
3
CHCl
3 3
). H NMR (300 MHz, CDCl ): δ ϭ 7.75 (d, J ϭ 7.5 Hz, 2
H, HFmoc), 7.57 (dd, J ϭ 7.0 Hz, J ϭ 3.9 Hz, 2 H, HFmoc), 7.39
3
4
dium() chloride (98.6 mg, 0.38 mmol) were added to a vigorously
stirred solution of acid chloride 14 (2.80 g, 7.53 mmol) in HMPT
(
m, 4 H, HFmoc), 7.29 (m, 4 H, HSPh), 7.17 (m, 1 H, HSPh), 5.13 (d,
3
3
J ϭ 8.5 Hz, 1 H, NH), 4.43 (m, 1 H, 4-H), 4.39 (d, J ϭ 6.9 Hz,
(22 mL). After 15 min at room temperature, the resulting black
3
2
H, CH2Fmoc), 4.19 (t, J ϭ 6.9 Hz, 1 H, CHFmoc), 3.87 (m, 2 H,
slurry was diluted with saturated aqueous KF (40 mL) and stirred
for 24 h. The mixture was then poured into water (100 mL) and
extracted twice with diethyl ether (50 mL). The combined organic
3
2
1
CH
-H), 3.27 (dd, JSCH a,2 ϭ 4.8 Hz, JSCH a,SCH b ϭ 12.5 Hz, 1 H,
2
2
2
a
b
2
2
ϪS), 3.00 (m, 2 H, CH ϪS and 2-H), 2.27 (s, 1 H, OH), 1.64
m, 1 H, 6-H), 1.48 (ddd, J ϭ 3.2 Hz, J ϭ 4.0 Hz, J ϭ
5a,5b
3
3
2
(
9
phases were washed with brine, dried with Na
a short pad of Celite and concentrated. Gradient flash column
chromatography (SiO , EtOAc/cyclohexane, 7:93, EtOAc/cyclohex-
ane, 8:92) afforded 15 (1.70 g, 63 %) as a soft white solid. [α]
2
SO
4
, filtered through
a
b
.8 Hz, 1 H, 5-H ), 1.23 (m, 1 H, 5-H ), 0.86 (m, 6 H, CH
3
CHCH
): δ ϭ 212.24 (C-3), 156.91
COFmoc), [144.36 ϩ 142.01 ϩ 128.40 ϩ 125.75 ϩ 120.67 ϩ 127.74,
Fmoc)], 135.56 (CPhS), 130.85 (CPhS), 129.89 (CPhS), 127.51 (CPhS),
7.59 (CH2Fmoc), 62.76 (C-1), 58.50 (C-4), 50.49 (C-2),
7.87(CHFmoc), 40.21 (C-5), 32.73 (CH -S), 25.51 (C-6), [23.95 ϩ
1.98, (CH ϪCHϪCH )] ppm. MS (ES, Na): m/z ϭ 526.2 [M ϩ
3
)
13
ppm. C NMR (75 MHz, CDCl
3
2
(
(
2
0
D
ϭ
C
1
3 3
ϩ 29.5 (c ϭ 1.2, CHCl ). H NMR (300 MHz, CDCl ): δ ϭ 7.74
6
4
2
3
3
4
(
d, J ϭ 7.5 Hz, 2 H, HFmoc), 7.58 (dd, J ϭ 7.1 Hz, J ϭ 2.5 Hz,
2
3
3
2
2
2
H, HFmoc), 7.38 (t, J ϭ 7.4 Hz, 2 H, HFmoc), 7.29 (t, J ϭ 7.4 Hz,
H, HFmoc), 6.41 (m, 2 H, 1-H and 2-H), 5.89 (dd,
.2 Hz, 1 H, J1b,2 ϭ 9.2 Hz, 1-H ), 5.38 (d, J ϭ 8.3 Hz, 1 H, NH),
3
3
a
2
J
1b,1a
ϭ
ϩ,
ϩ
Na] 542.2 [M ϩ K] . HRMS (ES, Na): m/z ϭ 526.20280 [M ϩ
3
b
3
ϩ
Na] , calcd. for C30
H
33NSO
4 4
Na: m/z ϭ 526.20280. C30H33NO S
3
4
.72 (m, 1 H, 4-H), 4.38 (d, J ϭ 7.0 Hz, 2 H, CH2Fmoc), 4.20 (t,
(
7
503.66): calcd. C 71.54, H 6.60, N 2.78, O 12.71, S 6.37; found C
1.39, H 6.71, N 2.60, O 12.57, S 6.28.
3
J ϭ 7.0 Hz, 1 H, CHFmoc), 1.60 (m, 3 H, 5-H and 6-H), 0.99 (d,
3
3
13
J ϭ 6.4 Hz, 3 H, CH
3
), 0.91 (d, J ϭ 6.7 Hz, 3 H, CH
): δ ϭ 199.46 (C-3) 156.78 (COFmoc),
144.45 ϩ 142.00 ϩ 128.37 ϩ 127.75 ϩ 125.78 ϩ 120.64, (CFmoc)],
3
) ppm.
C
NMR (75 MHz, CDCl
3
,
(
4S)-4-(9-Fluorenylmethoxycarbonyl)amino-2-hydroxymethyl-6-
methylhept-1-en-3-one (9): A solution of mCPBA (70 %, 1.40 g,
[
133.89 (C-2), 130.89 (C-1), 67.6 (CH2Fmoc), 56.85 (C-4), 47.91
5
1
.66 mmol) in CH
2
Cl
2
(12 mL) was added to a stirred solution of
Cl (90 mL) at Ϫ78 °C. After 15 min,
(CHFmoc), 42.3 (C-5), 25.55 (C-6), [24.02 ϩ 22.49, (C-7 and C-8)]
7 (2.85 g, 5.66 mmol) in CH
2
2
ϩ
ϩ
ppm. MS (ES, Na): m/z ϭ 386.2 [M ϩ Na] , 749.4 [2M ϩ Na] ,
the reaction mixture was warmed to room temperature, quenched
with 10 % aqueous Na SO (100 mL) and extracted twice with di-
ethyl ether (40 mL). The combined organic layers were washed
twice with saturated aqueous NaHCO , with brine, dried with
Na SO , filtered and concentrated in vacuo to provide the corre-
ϩ
7
50.4 [2M ϩ H ϩ Na] . HRMS (ES, Na): m/z ϭ 386.17321 [M
2
3
ϩ
ϩ Na] , calcd. for C23
3 3
H25NO Na: m/z ϭ 386.17321. C23H25NO
(363.46): calcd. C 76.01, H 6.93, N 3.85, O 13.21; found C 76.01,
3
H 6.88, N 3.58, O 13.25. Chiral HPLC (Analytical column, Chiral-
2
4

pak AD; mobile phase: 60:40 hexane/ethanol; flow rate ϭ 1 mL/
sponding unstable sulfoxide (3.00 g, 80 %) as a colorless oil that
was used without any further purification.
min; detection wavelength: 212 nm; room temperature; retention
time ϭ 6.95 min): ee Ն 98 %.
4 3
The above sulfoxide in solution in CCl /CHCl (9:1, 300 mL) was
heated to reflux at 65 °C for 15 h. The resulting solution was cooled
to room temperature and the solvents evaporated. Gradient flash
1
-(9-Fluorenylmethoxycarbonyl)amino-3-methylbut-1-ene (16) (de-
1
carbonylated product): H NMR (300 MHz, CDCl
3
): δ ϭ 7.75 (d,
3
3
J ϭ 7.3 Hz, 2 H, HFmoc), 7.56 (d, J ϭ 7.3 Hz, 2 H, HFmoc), 7.39
3
2
column chromatography (SiO , EtOAc/cyclohexane, 1:4, EtOAc/
(
m, 2 H, HFmoc), 7.32 (m, 2 H, HFmoc), 6.41 (dd, J1,NH ϭ 9.5 Hz,
J
3
3
cyclohexane, 1:3, EtOAc/cyclohexane, 2:3) afforded 9 (1.38 g, 62 %
1,2 ϭ 14.0 Hz, 1 H, 1-H), 6.24 (d, JNH,1 ϭ 9.5 Hz, 1 H, NH),
2
0
.99 (dd, 3
2,3 ϭ 6.9 Hz, 3
J2,1 ϭ 14.0 Hz, 1 H, 2-H), 4.43 (d,
D
over two steps) as a light pink glassy solid. [α] ؍ ؉39.7 (c ϭ 1.05,
4
J
1
3
3
3
CHCl
3 3
). H NMR (300 MHz, CDCl ): δ ϭ 7.74 (d, J ϭ 7.5 Hz, 2
J
2Ј,3Ј ϭ 6.8 Hz, 2 H, CH2Fmoc), 4.20 (t, J ϭ 6.8 Hz, 1 H, CHFmoc),
.28 (m, 1 H, 3-H), 0.98 (m, 6 H, CH
3
4
) ppm. 13C NMR
3 3
CHCH
H, HFmoc), 7.57 (dd, J ϭ 7.2 Hz, J ϭ 2.0 Hz, 2 H, HFmoc), 7.38
t, J ϭ 7.4 Hz, 2 H, HFmoc), 7.29 (td, J ϭ 7.4 Hz, J ϭ 1.1 Hz, 2
H, HFmoc), 6.22 (s, 1 H, 1-H ), 6.13 (s, 1 H, 1-H ), 5.37 (d, J ϭ
.8 Hz, 1 H, NH), 5.10 (m, 1 H, 4-H), 4.36 (m, 4 H, CH2Fmoc
9-H), 4.20 (t, J ϭ 7.0 Hz, 1 H, CHFmoc), 2.11 (s, 1 H, OH), 1.71
2
3
3
4
(
(75 MHz, CDCl
3
): δ ϭ 154.30 (COFmoc), [144.41 ϩ 141.98 ϩ
28.41 ϩ 127.74 ϩ 125.64 ϩ 120.68 (CFmoc)] , 121.96 (C-1), 119.35
a
b
3
1
8
ϩ
(C-2), 67.57 (CH2Fmoc), 47.76 (CHFmoc), 30.84 (C-3), 23.59
3
ϩ
3 3
(CH CHCH ) ppm. MS (ES, Na): m/z ϭ 637.3 [2M ϩ Na] , 330.2
a
b
ϩ
ϩ
(m, 1 H, 6-H), 1.52 (m, 1 H, 5-H ), 1.38 (m, 1 H, 5-H ), 1.00 (d,
7,6 ϭ 6.5 Hz, 3 H, CH
[M ϩ Na] . HRMS (ES, Na): m/z ϭ 330.14700 [M ϩ Na] , calcd.
3
3
J
3
CHCH
3
), 0.90 (d,
J
7,6 ϭ 6.6 Hz, 3 H,
): δ ϭ 201.96 (C-
for C20 Na: m/z ϭ 330.14700.
H21NO
2
1
3
CH
3
CHCH
3
) ppm. C NMR (75 MHz, CDCl
3
(
4S)-4-(9-Fluorenylmethoxycarbonyl)amino-1-hydroxy-6-methyl-2-
phenylthiomethylheptan-3-one (17): AlMe (2 in hexanes,
.03 mL, 10.07 mmol) was slowly added to a vigorously stirred
solution of thiophenol (1.05 mL, 10.07 mmol) in CH Cl (10 mL)
3), 157.76 (COFmoc), 145.53 (C-2), [144.40 ϩ 141.99 ϩ 128.38 ϩ
127.74 ϩ 125.75 ϩ 120.65, (CFmoc)], 127.14 (C-1), 67.63 (CH2Fmoc),
62.99 (C-9), 54.10 (C-4), 47.90 (CHFmoc), 43.51 (C-5), 25.61 (C-6),
[24.03 ϩ 22.31, (C-7 and C-8)] ppm. MS (Electrospray): m/z ϭ
3

5
2
2
ϩ
ϩ
at 0 °C. After 1 h, the resulting mixture was cooled to Ϫ78 °C and 416.1 [M ϩ Na] . HRMS (ES, Na): m/z ϭ 416.18378 [M ϩ Na] ,
treated with a solution of 15 (3.05 g, 8.39 mmol) in CH Cl calcd. for C24 Na: m/z ϭ 416.18378. C24 (393.48):
10 mL). The reaction mixture was then stirred at Ϫ78 °C for 1 h
2
2
H27NO
4
H27NO
4
(
calcd. C 73.26, H 6.92, N 3.56, O 16.26; found C 72.99, H 7.11, N
3.46, O 16.34. Chiral HPLC (Analytical column, Chiralpak AD;
mobile phase: 60:40 hexane/ethanol; flow rate ϭ 1 mL/min; detec-
and diluted with THF (61 mL). Gaseous formaldehyde was
bubbled through this solution until the starting material disap-
4572
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4569Ϫ4574

A New Route for the Total Synthesis of 6,7-Dihydroeponemycin
FULL PAPER
2 H, CH2Fmoc), 4.23 (t, J ϭ 6.8 Hz, 1 H, CHFmoc), 2.61 (d, 3J2,3
ϭ
3
tion wavelength: 212 nm; room temperature; retention time ϭ
3
6.79 min): ee Ն 97 %.
6.9 Hz, 2 H, 2-H), 2.16 (m, 1 H, 3-H), 0.97 (d, J ϭ 6.7 Hz, 6 H,
1
3
CH
3 3 3
CHCH ) ppm. C NMR (75 MHz, CDCl ): δ ϭ 174.86 (C-
(
2RS,4S)-4-(9-Fluorenylmethoxycarbonyl)amino-2-hydroxymethyl- 1), [152.42 ϩ 143.89 ϩ 128.63 ϩ 127.87 ϩ 125.61 ϩ 120.80,
6
1
7
1
-methyl-1,2-oxiranylheptan-3-one (18): H
2
O
2
(35 wt.-% in water,
(CFmoc)], 142.00 (C-4Ј), 68.37 (CH2Fmoc), 47.38 (CHFmoc), 45.41 (C-
2), 25.65 (C-3), 23.13 (C-4.5) ppm. MS (ES, Na): m/z ϭ 346.2 [M
.09 mL, 12.4 mmol) and Triton B (40 wt.-% in MeOH, 35 µL,
ϩ
ϩ
ϩ
7.51 µmol) were added dropwise to a solution of 9 (610 mg,
ϩ Na] , 362.1 [M ϩ K] , 669.5 [2M ϩ Na] . HRMS (ES, Na):
ϩ
.55 mmol) in THF (1.8 mL) at 0 °C. After stirring at 0 °C for 2 h m/z ϭ 346.14191 [M ϩ Na] , calcd. for C H NO Na: m/z ϭ
2
0
21
3

a second portion of Triton B (40 wt.-% in MeOH, 35 µL, 77.51
µmol) was added in order to take the reaction to completion. The
resulting mixture was cautiously quenched with saturated aqueous
346.14191.
(2R,4S)-2-Hydroxymethyl-6-methyl-4-[(S)-N-(6-methylheptanoyl)-
seryl]amino-1,2-oxiranylheptan-3-one (6,7-Dihydroeponemycine) (2):
DBU (37.3 µL, 0.24 mmol) was added dropwise to a solution of
18a (100 mg, 0.24 mmol) in freshly distilled acetonitrile (1 mL) at
Ϫ20 °C. The mixture was immediately warmed to room tempera-
ture for 5 min. The resulting dark purple solution was recooled to
Ϫ20 °C and treated with HCl in 1,4-dioxane (4 , 183 µL,
0.73 mmol). After 5 min at Ϫ20 °C, the vigorously stirred mixture
was warmed to 0 °C and diluted with freshly distilled acetonitrile
NH
4
Cl (10 mL) and extracted with diethyl ether (3 ϫ 5 mL). The
SO , filtered and con-
combined organic layers were dried with Na
centrated in vacuo to afford a 1:1 mixture of epoxides 18a and 18b
which were easily separated by gradient flash column chromatogra-
phy (SiO
EtOAc/cyclohexane, 3:7): (18a: 270 mg, 18b: 218 mg, mixed frac-
tions: 80 mg, total yield 89 %). 18a: light pink oil. [α]
2
4
2
,
EtOAc/cyclohexane,1:9, EtOAc/cyclohexane, 1:4,
2
0
D
ϭ ؉61.5
1
3
3 3
(c ϭ 1.03, CHCl ). H NMR (300 MHz, CDCl ): δ ϭ 7.74 (d, J ϭ
3
7
.4 Hz, 2 H, HFmoc), 7.56 (m, 2 H, HFmoc), 7.38 (t, J ϭ 7.4 Hz, 2 (4 mL) before the successive addition of HOBt (66 mg, 0.49 mmol),
3
3
H, HFmoc), 7.29 (t, J ϭ 7.4 Hz, 2 H, HFmoc), 5.07 (d, J ϭ 8.6 Hz, PyBOP (513.5 mg, 0.98 mmol) and acid 7 (225.9 mg, 0.98 mmol).
3
1
H, NH), 4.39 (m, 1 H, 4-H), 4.34 (d, J ϭ 7.3 Hz, 2 H, CH2Fmoc), The resulting mixture was recooled to Ϫ20 °C and treated with
3
4
.18 (m, 2 H, 9-Ha and CHFmoc), 3.77 (dd,
J9b,OH ϭ 7.2 Hz, triethylamine (103 µL, 0.73 mmol). After stirring for 5 min at Ϫ20
2
b
2
a
J
9b,9a ϭ 12.6 Hz, 1 H, 9-H ), 3.29 (d, J1a,1b ϭ 4.8 Hz, 1 H, 1-H ),
°C, the solution was warmed to 0 °C for 1 h and stirred at room
.08 (d, 2
J1b,1a ϭ 4.8 Hz, 1 H, 1-H ), 1.84 (t, J ϭ 7.2 Hz, 1 H, temperature for 12 h . The mixture was diluted with diethyl ether
b
3
3
a
b
OH), 1.71 (m, 1 H, 6-H), 1.56 (m, 1 H, 5-H ), 1.23 (m, 1 H, 5-H ), (2 mL), cooled to 0 °C, quenched with brine (15 mL) and extracted
0
2
1
6
.95 (m, 6 H, CH
09.33 (C-3), 156.89 (COFmoc), [144.34 ϩ 141.99 ϩ 128.42 ϩ
27.76 ϩ 125.75 ϩ 120.69, (CFmoc)], 67.68 (CH2Fmoc), 62.50 (C-2), KHSO
2.04 (C-9), 52.91 (C-4), 49.82 (C-1), 47.83 (CHFmoc), 40.38 (C-5), with Na
3
CHCH
3
) ppm. 13C NMR (75 MHz, CDCl
3
): δ ϭ with diethyl ether (3 ϫ 5 mL). The combined organic layers were
successively washed with saturated aqueous NH Cl, 2 % aqueous
, saturated aqueous NaHCO and brine, and then dried
SO , filtered and concentrated. Flash column chromatog-
raphy (SiO :15 µm, CH Cl /MeOH 95:5) afforded 2 (75 mg, 77 %)
as a colorless gum. [α] ϭ ؉30.2 (CHCl3, cϭ 1.00). IR (CHCl ):
ν˜ ϭ 3403, 3150, 2960, 1720, 1650, 1510, 1050 cm
H NMR
): δ ϭ 7.13 [d, J ϭ 7.1 Hz, 1 H, NH(C-4)], 6.50
4
4
3
2
4
2
5.74 (C-6), [24.05 ϩ 21.88, (CH
3
CHCH
3
)] ppm. 18b: light yellow
2
2
2
20
1
20
oil. [α]
D
ϭ Ϫ15.5 (c ϭ 1.00, CHCl
3
). H NMR (300 MHz, CDCl ):
3
D
3
3
Ϫ1
1
δ ϭ 7.74 (d, J ϭ 7.4 Hz, 2 H, HFmoc), 7.56 (m, 2 H, HFmoc), 7.38
.
3
3
3
(t, J ϭ 7.3 Hz, 2 H, HFmoc), 7.30 (t, J ϭ 7.3 Hz, 2 H, HFmoc), (300 MHz, CDCl
3
3
3
3
5.07 (d, J ϭ 7.6 Hz, 1 H, NH), 4.60 (m, 1 H, 4-H), 4.41 (d, J ϭ [d, J ϭ 7.0 Hz, 1 H, NH(C-2Ј)], 4.49 (m, 2 H, 2Ј,4-H), 4.19 [d,
3
2
a
2
6
.5 Hz, 2 H, CH2Fmoc), 4.19 (t, J ϭ 6.5 Hz, 1 H, CHFmoc), 4.10
J
C-2CH a,C-2CH b ϭ 12.6 Hz, 1 H, (C-2)CH
2
], 4.00 (dd, J3Јa,3Јb
ϭ
2
2
dd, JCH a,OH ϭ 5.4 Hz, 2JCH a,CH b ϭ 12.6 Hz, 1 H, CH
3
a
2
3
a
2
(
ϪOH), 11.4 Hz, J3Јa,2Ј ϭ 3.4 Hz, 1 H, 3Ј-H ), 3.70 [d, J9b,9a ϭ 12.6 Hz,
2
2
2
J
.76 (dd, 3JCH b,OH ϭ 8.0 Hz,
2
CH b,CH a ϭ 12.6 Hz, 1 H, 1 H, (C-2)CH
b
2
3
3
2
], 3.55 (dd, J3Јb,3Јa ϭ 11.4 Hz, J3Јb,2Ј ϭ 5.8 Hz, 1
2
2
2
b
2
a
2
b
2
a
2
CH
4
2
ϪOH), 3.04 (d, J1a,1b ϭ 4.5 Hz, 1 H, 1-H ), 2.96 (d, J1b,1a
.5 Hz, 1 H, 1-H ), 2.25 (m, 1 H, OH), 1.66 (m, 1 H, 6-H), 1.37 4.9 Hz, 1 H, 1-H ), 2.20 (s and t, 3 H, J2ЈЈ,3ЈЈ ϭ 7.6 Hz, 2ЈЈ-H and
ϭ
H, 3Ј-H ), 3.29 (d, J1a,1b ϭ 4.9 Hz, 1 H, 1-H ), 3.07 (d, J1b,1a ϭ
b
b
3
3
a
a
(
m, 2 H, 5-H), 0.95 (d, J ϭ 6.6 Hz, 3 H, CH
J ϭ 6.6 Hz, 3 H, CH
3
CHCH
) ppm. C NMR (75 MHz, CDCl
δ ϭ 208.07 (C-3), 156.82 (COFmoc), [144.37 ϩ 142.03 ϩ 128.42 ϩ
3
), 0.92 (d,
OH), 1.62 (s, 1 H, OH), 1.57 (m, 4 H, 3ЈЈ-H , 5-H , 6-H and 6ЈЈ-
3
13
b
b
3
CHCH
3
3
): H), 1.27 (m, 4 H, 4ЈЈ-H, 5-H and 3ЈЈ-H ), 1.16 (m, 2 H, 5ЈЈ-H),
3
3
0.92 (d, J7,6 ϭ 6.2 Hz, 3 H, CH CHCH ), 0.91 (d, 3 H, JCH ,6 ϭ
3 3
3
3
127.76 ϩ 125.67 ϩ 120.68, (CFmoc)], 67.67 (CH2Fmoc), 62.87 (C-2 6.1 Hz, CH
3
CHCH
ppm. C NMR (75 MHz, CDCl
3
)] ppm. MS (ES, 1ЈЈ), 172.12 (C-1Ј), 63.43 (C-3Ј), 62.99 (C-2), 62.23 (C-9), 54.13 (C-
3
), 0.83 (d, J ϭ 6.6 Hz, 6 H, CH
3 3
CHCH )
): δ ϭ 208.64 (C-3), 174.65 (C-
1
3
and CH
2
OH), 54.82 (C-4), 50.37 (C-1), 47.88 (CHFmoc), 40.95 (C-
CHCH
3
5), 25.51 (C-6), [23.98 ϩ 22.08, (CH
3
ϩ
ϩ,
ϩ
Na ): m/z ϭ 432.1 [M ϩ Na] 448.1 [M ϩ K] . HRMS (ES, Na): 2Ј), 52.55 (C-4), 50.08 (C-1), 39.25 (C-5 and C-5ЈЈ), 37.19 (C-2ЈЈ),
m/z ϭ 432.17869 ([M ϩ Na] , calcd. for C24
4
1
ϩ
H27NO
5
Na: m/z ϭ
(409.48): calcd. C 70.40, H 6.65, N 3.42, O
9.54; found C 70.69, H 6.35, N 3.18, O 19.44.
28.46 (C-6ЈЈ), 27.68 (C-4ЈЈ), 26.53 (C-3ЈЈ), 25.96 (C-6), 23.97 (C-8),
23.24 (C-7ЈЈ and C-8ЈЈ), 21.74 (C-7) ppm. MS (ES, Na): m/z ϭ
32.17869. C24H27NO
5
ϩ
ϩ
423.2 [M ϩ Na] , 439.2 [M ϩ K] . HRMS (ES, Na): m/z ϭ
4
ϩ
23.24711 [M ϩ Na] , calcd. for C20
36 2 6
H N O Na: m/z ϭ 423.24710.
N-(9-Fluorenylmethoxycarbonyl)3-methylbutyramide (19): mCPBA
C H N O (400.51): calcd. C 59.98, H 9.06, N 6.99; found C
2
0
36
2
6
(
(
70 %, 62.65 mg, 0.25 mmol) was added to a stirred solution of 9
50 mg, 0.13 mmol) in CH Cl (0.25 mL) at room temperature.
60.31, H 9.19, N 6.66.
2
2
After 15 min, the resulting reaction mixture was quenched with a
0 % aqueous Na SO (1.5 mL) and extracted with diethyl ether (3
ϫ 0.5 mL). The combined organic phases were washed twice with
saturated NaHCO and with brine, dried with Na SO
concentrated. Gradient flash column chromatography (SiO
EtOAc/cyclohexane, 1:4, EtOAc/cyclohexane, 2:3) afforded 19
(2S,4S)-2-Hydroxymethyl-6-methyl-4-[(S)-N-(6-methylheptanoyl)-
seryl]amino-1,2-oxiranylheptan-3-one (2-epi-Dihydroeponemycine)
(24): DBU (22.4 µL, 0.15 mmol) was added dropwise to a solution
1
2
3
3
2
4
, filtered and of 14b (60 mg, 0.15 mmol) in freshly distilled acetonitrile (600 µL)
2
,
at Ϫ20 °C. The mixture was immediately warmed to room tempera-
ture for 5 min. The resulting dark purple solution was recooled to
1
(
31 mg, 75 %) as a crystalline solid. M.p. 159 °C. H NMR Ϫ20 °C and treated with a solution of HCl in 1,4-dioxane (4 ,
3
(300 MHz, CDCl ): δ ϭ 7.93 (s, 1 H, NH), 7.75 (d, J ϭ 7.5 Hz, 2 110 µL, 0.44 mmol). After 5 min at Ϫ20 °C, the vigorously stirred
3
3
3
H, HFmoc), 7.58 (d, J ϭ 7.4 Hz, 2 H, HFmoc), 7.40 (t, J ϭ 7.4 Hz, mixture was warmed to 0 °C and diluted with freshly distilled
3
3
2
H, HFmoc), 7.30 (t, J ϭ 7.4 Hz, 2 H, HFmoc), 4.47 (d, J ϭ 6.8 Hz, acetonitrile (2.4 mL) before the successive addition of HOBt
Eur. J. Org. Chem. 2003, 4569Ϫ4574 www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4573

B. Bennacer, C. Rivalle, D. S. Grierson
FULL PAPER
[
[
[
10]
11]
12]
(
(
39.6 mg, 0.29 mmol), PyBOP (308.1 mg, 0.59 mmol) and acid 7
135.6 mg, 0.59 mmol). The resulting mixture was recooled to Ϫ20
C and treated with triethylamine (61.6 µL, 0.44 mmol). After stir-
A. G. Myers, T. Yoon, Tetrahedron Letters 1995, 36, 52,
9429Ϫ9432.
A. G. Myers, J. L. Gleason, T. Yoon, J. Am. Chem. Soc. 1995,
°
1
17, 32, 8488Ϫ8489.
ring for 5 min at Ϫ20 °C, the solution was warmed to 0 °C for 1 h
and stirred for 12 h at room temperature. The mixture was diluted
with diethyl ether (2 mL), cooled to 0 °C, quenched with brine
A. G. Myers, J. L. Gleason, T. Yoon, D. W. Kung, J. Am. Chem.
Soc. 1997, 119, 4, 656Ϫ673.
[13]
A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Ko-
pecky, J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 28,
6496Ϫ6511.
A. G. Myers, P. Scnider, S. Kwon, D. W. Kung, J. Org. Chem.
1999, 64, 9, 3322Ϫ3327.
A. G. Myers, J. L. Gleason, Organic Synthesis, John Wiley &
Sons, New York, 1999, 76, 57Ϫ76.
U. Schmidt, J. Schmidt, Synthesis 1994, 300Ϫ304.
H. Hoshi, T. Ohnuma, S. Aburaki, M. Konishi, T. Oki, Tetra-
hedron Letters 1993, 34, 6, 1047Ϫ1050.
N. Sin, L. Meng, H. Auth, C. M. Crews, Bioorganic & Med-
icinal Chemistry 1998, 6, 1209Ϫ1217.
E. J. Corey, G. N. Widiger, J. Org. Chem. 1975, 40, 2975Ϫ2976.
J. Bach, R. Berenguer, J. Garcia, J. Vilarrasa, Tetrahedron Lett.
1995, 36, 19, 3425Ϫ3428.
Y. Horiguchi, E. Nakamura, I. Kuwajima, J. Am. Chem. Soc.
1989, 111, 16, 6257Ϫ6265.
(
15 mL) and extracted with diethyl ether (3 ϫ 5 mL). The com-
bined organic layers were washed successively with saturated
NH Cl, 2 % KHSO , saturated NaHCO and brine, dried with
Na SO , filtered and concentrated. Flash column chromatography
SiO (15 µm), CH Cl /MeOH, 95:5] afforded 16 (45 mg, 77 %) as
a white solid. [α]
390, 3150, 2950, 1720, 1640, 1520, 1060 cm
[
[
14]
15]
4
4
3
2
4
[
2
2
2
2
0
ϭ Ϫ88.61 (CHCl3, c ϭ 1.00). IR (CHCl
3
): ν˜ ϭ
D
[
[
16]
17]
Ϫ1
1H NMR
3
.
3
(300 MHz, CDCl
3
): δ ϭ 7.31 [d, J ϭ 7.2 Hz, 1 H, NH(C-4)], 6.65
3
[d, J ϭ 6.9 Hz, 1 H, NH(C-2Ј)], 4.65 (m, 1 H, 4-H), 4.42 (m, 1 H,
[18]
2
a
2
Ј-H), 4.22 (d, JC-2CH a,C-2CH b ϭ 12.6 Hz, 1 H, 9-H ), 4.11 (dd,
2 2
2
3
a
[19]
[20]
J
3Јa,3Јb ϭ 11.6 Hz,
J
3Јa,2Ј ϭ 2.7 Hz, 1 H, 3Ј-H ), 3.63 (d,
2JC-2CH b,C-2CH a ϭ 12.6 Hz, 1 H, 9-H ), 3.56 (dd,
1
H, 1-H ), 2.96 (d, J1b,1a ϭ 4.6 Hz, 1 H, 1-H ), 2.22 (t, J2ЈЈ,3ЈЈ
7
2
0
6
ppm. C NMR (75 MHz, CDCl
1
2
b
2
3Јb,3Јa
J ϭ
2
2
3
b
2
1.7 Hz, J3Јb,2Ј ϭ 6.5 Hz, 1 H, 3Ј-H ), 3.03 (d, J1a,1b ϭ 4.6 Hz, 1
[
[
21]
22]
a
2
b
3
ϭ
a
.7 Hz, 2 H, 2ЈЈ-H), 1.51 (m, 3 H, 3ЈЈ-H , 6-H and 6ЈЈ-H), 1.43 (m,
b
N. Sin, K. B. Kim, M. Elofsson, L. Meng, H. Auth, B. H. B.
Kwok, C. M. Crews, Bioorganic & Medicinal Chemistry Letters
1999, 9, 2283Ϫ2288.
H, 5-H), 1.28 (m, 3 H, 4ЈЈ-H and 3ЈЈ-H ), 1.17 (m, 2 H, 5ЈЈ-H),
.91 (d, 3 ), 0.90 (d, 3
7,6 ϭ 6.5 Hz, 3 H, CH CHCH
.5 Hz, 3 H, CH ), 0.84 (d, J ϭ 6.6 Hz, 6 H, CH
): δ ϭ 206.71 (C-3), 174.82 (C-
ЈЈ), 171.77 (C-1Ј), 63.63 (C-2), 63.48 (C-9), 63.32 (C-3Ј), 54.46 (C-
Ј), 53.12 (C-4), 50.22 (C-1), 39.58 (C-5), 39.25 (C-5ЈЈ), 37.17
J
3
3
3
CH ,6
J ϭ
3
3
CHCH
3
3
CHCH
3
)
[23]
D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 11,
13
3
3
636Ϫ3638.
[
[
24]
25]
J. K. Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508Ϫ524.
H. X. Zhang, F. Guib e´ , G. Balavoine, J. Org. Chem. 1990, 55,
6, 1857Ϫ1867.
(
(
C2ЈЈ), 28.47 (C-6ЈЈ), 27.69 (C-4ЈЈ), 26.52 (C-3ЈЈ), 25.55 (C-6), 23.91
C-8), 23.25 (CH CHCH ), 22.19 (C-7) ppm. MS (ES, Na): m/z ϭ
[
[
26]
27]
K. C. Nicolaou, J. J. Liu, Z. Yang, H. Ueno, E. J. Sorensen, C.
F. Claiborne, R. K. Guy, C. K. Hwang, M. Nakada, P. G.
Nantermet, J. Am. Chem. Soc. 1995, 117, 2, 634Ϫ644.
J. Tsuji, Palladium Reagents, Catalysts, Innovations in Organic
Synthesis, John Wiley & Sons, New York, 253Ϫ260.
E. Ciganek, Org. React. 1997, 51, 201Ϫ350.
3
3
ϩ
ϩ
4
4
23.2 [M ϩ Na] , 439.2 [M ϩ K] . HRMS (ES, Na): m/z ϭ
ϩ
23.24711 [M ϩ Na] , calcd. for C20
(400.51): calcd. C 59.98, H 9.06, N 6.99; found C
0.21, H 9.17, N 6.86.
36 2 6
H N O Na: m/z ϭ 423.24710.
20 36 2 6
C H N O
6
[28]
[
[
[
29]
30]
31]
Y. M. A. Yamada, S. Ikegami, Tetrahedron Letters 2000, 41,
2
165Ϫ2169.
A. Itoh, S. Ozawa, K. Oshima, H. Nozaki, Tetrahedron Letters
980, 21, 361Ϫ364.
Acknowledgments
1
We are grateful to Servier Laboratories, Institut Curie (‘‘Pro-
grammme Incitatif Coop e´ ratif Angiogen e` se’’) and the Societ e´ de
Chimie Th e´ rapeutique (scholarship for B. B.) for generous finan-
cial support.
A. Itoh, S. Ozawa, K. Oshima, H. Nozaki, Bull. Chem. Soc.
Jpn. 1981, 54, 1, 274Ϫ278.
I. Paterson, Tetrahedron 1988, 44, 13, 4207Ϫ4219.
E. Schmitz, Advances in Heterocyclic Chemistry, Academic
Press, New York, 1979, 24, 79Ϫ83.
M. T. Barros, C. D. Maycock, M. R. Ventura, Tetrahedron
1999, 55, 3233Ϫ3244.
M. T. Barros, C. D. Maycock, M. R. Ventura, Chem. Eur. J.
2000, 6, 21, 3991Ϫ3996.
S. Juli a´ , J. Masana, J. C. Vega, Angew. Chem. Int. Ed. Engl.
1980, 19, 11, 929Ϫ931.
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1
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1
3
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Received July 1, 2003
4574
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4569Ϫ4574