Convergent syntheses of N-Boc-protected (2S,4R)-4-(Z)-propenylproline and 5-chloro-1-(methoxymethoxy)pyrrol-2-carboxylic acid - Two essential building blocks for the signal metabolite hormaomycin

Article abstract of DOI:10.1002/ejoc.200400480

An efficient and scalable synthesis of enantiomerically pure N-Boc-protected 4-(Z)-propenylproline (15) using the conventional Wittig reaction to construct the double bond has been developed [11% yield over 8 steps from N-Boc-protected (2S,4R)-4-hydroxyproline, 7]. The O-MOM-protected 5-chloro-1-hydroxypyrrole-2-carboxylic acid [Chpca(MOM)-OH (29)] was prepared along a reasonably efficient synthetic route applying the thermal rearrangement of 2-azido-6-chloropyridine N-oxide (22) as a key step in fairly good overall yield [9% over 7 steps from easily accessible 2,6-dichloro-pyridine N-oxide (21)]. The suitability of the MOM-protected N-hydroxy group during the preparation of the N-hydroxypyrroles functionalized at C-2, was confirmed by the successful synthesis of Chpca-(3-Ncp)Ala-OFM 33 obtained from the acylated amino ester Chpca(MOM)-(3-Ncp)Ala-OFM 32, which was selectively deprotected leaving the sensitive N-hydroxypyrrole unit intact. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400480

FULL PAPER
Convergent Syntheses of N-Boc-Protected (2S,4R)-4-(Z)-Propenylproline and
5-Chloro-1-(methoxymethoxy)pyrrol-2-carboxylic Acid ؊ Two Essential
Building Blocks for the Signal Metabolite Hormaomycin
Boris D. Zlatopolskiy,[a] Hans-Peter Kroll,[a] Elisa Melotto,[a] and Armin de Meijere*[a]
Keywords: Amino acids / Nitrogen heterocycles / Synthetic methods / Chiral pool / Total synthesis
An efficient and scalable synthesis of enantiomerically pure
N-Boc-protected 4-(Z)-propenylproline (15) using the con-
ventional Wittig reaction to construct the double bond has
been developed [11% yield over 8 steps from N-Boc-pro-
tected (2S,4R)-4-hydroxyproline, 7]. The O-MOM-protected
5-chloro-1-hydroxypyrrole-2-carboxylic acid [Chpca(MOM)-
OH (29)] was prepared along a reasonably efficient synthetic
route applying the thermal rearrangement of 2-azido-6-chlo-
ropyridine N-oxide (22) as a key step in fairly good overall
yield [9% over 7 steps from easily accessible 2,6-dichloro-
pyridine N-oxide (21)]. The suitability of the MOM-protected
N-hydroxy group during the preparation of the N-hydroxy-
pyrroles functionalized at C-2, was confirmed by the success-
ful synthesis of Chpca-(3-Ncp)Ala-OFM 33 obtained from the
acylated amino ester Chpca(MOM)-(3-Ncp)Ala-OFM 32,
which was selectively deprotected leaving the sensitive N-
hydroxypyrrole unit intact.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
The cyclic depsipeptide hormaomycin 1 has a unique
structure and quite an interesting spectrum of biological
activities.[1] Besides one residue of the proteinogenic amino
acid isoleucine [(S)-Ile], it contains two units of 3-methyl-
phenylalanine [(βMe)Phe], one of (2R)-allo-threonine [a-
Thr] as well as two moieties of 3-(trans-2Ј-nitrocyclo-
propyl)alanine [(3-Ncp)Ala] and one of 4-(Z)-propenyl-
proline [(4-PE)Pro]. The side chain of 1 is terminated with
a residue of 5-chloro-1-hydroxypyrrole-2-carboxylic acid
[Chpca] (Figure 1). The latter three have never been found
in any natural product before. The importance of the
(3-Ncp)Ala and (βMe)Phe residues of hormaomycin for its
biological activity is unclear.[2] However, very early
during the investigations concerning hormaomycin it was
recognized that the residues of [(4-PE)Pro and Chpca are
crucially important for the two main biological activities
of hormaomycin: its essentially selective antibiotic activity
against Coryneform bacteria and the morphogenous
action on the producing strain and other Streptomyces
species.[2a,2c,3] For our ongoing development of a synthetic
access to hormaomycin and a representative series of its
biologically significant analogues[2c,4] we were in need of
suitably protected (2S,4R)-4-(Z)-propenylproline as well as
Figure 1. Structure and absolute configuration of hormaomycin
1. I (S)-Ile; II (2S,3R)-(βMe)Phe; III (2R)-a-Thr; IV (1ЈR,2ЈR)-(3-
Ncp)Ala; V (2S,4R)-4-(Z)-(4-PE)Pro; VI Chpca
thesis of either of these compounds had ever been reported,
we developed suitable convergent accesses to N-Boc-pro-
tected (2S,4R)-4-(Z)-propenylproline (15) and O-meth-
oxymethyl-(MOM-)protected 5-chloro-1-hydroxypyrrol-2-
carboxylic acid (29).
Results and Discussion
Initially, the N-protected tert-butyl (S)-(E)-propylidene-
5-chloro-1-hydroxypyrrole-2-carboxylic acid. Since no syn- pyroglutamate 4 was chosen as a starting material for the
synthesis of the target compound 15 (Scheme 1). A decon-
[a]
jugating isomerization of compound 4 was expected to give
the corresponding 4-propenylpyroglutamate, which might
be transformed to the appropriate 4-propenylproline. At
least for simple models studied before, this transformation
Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-(0)551-399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
4492
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DOI: 10.1002/ejoc.200400480
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Two Essential Building Blocks for the Signal Metabolite Hormaomycin
FULL PAPER
often proceeded in such a way that the (E)-α,β-unsaturated that only the (E)-isomer had been formed. Thus, this decon-
esters or amides gave the (Z)-deconjugated products, and jugating isomerization provides access to yet unknown 4-
in contrast a (Z)-configured conjugated double bond was alkenyl-substituted pyroglutamic acids (and consequently
converted into an (E)-configured double bond with good alkenyl-substituted glutamic acids, prolines and leucines).
selectivity.[5] The N-Boc-protected tert-butyl (S)-4-(E)-pro- However, the ‘‘wrong’’ configuration of the double bond in
pylidenepyroglutamate 4[6] was prepared as described by 5 and the configurational instability precluded to use this
Ezquerra et al.[7] for the corresponding ethyl ester. Towards procedure for the synthesis of N-Boc-protected 4-(Z)-pro-
this, the enolate of the tert-butyl ester 2,[8] generated by penylproline 15.
treatment with LiHMDS in THF, in the presence of 1.15
equivalent of BF3·Et2O at Ϫ78 °C was added to propanal
to give the known (hydroxypropyl)pyroglutamate derivative
3[9] as a partially separable mixture of three out of four
possible diastereomers (the configuration at C-2 was re-
tained) in much better yield (78 rather than 28%) than re-
ported before.[7]
In an alternative approach, the conventional Wittig reac-
tion was used to construct the double bond (Scheme 2). The
N-Boc-protected 4-hydroxyproline 7 was treated with ethyl
chloroformate and triethylamine in CH2Cl2 at Ϫ30 °C, and
the mixed anhydride was reduced with aqueous NaBH4 in
the presence of tetra-n-butylammonium bromide as a
phase-transfer catalyst to give the N-Boc-protected 4-
hydroxyprolinol 8 in 82% yield. The primary hydroxy group
of 8 was selectively protected as a tert-butyldimethylsilyl
ether 9 (82% yield) as described by Williams et al.[11] Treat-
ment of 9 with mesyl chloride and triethylamine in CH2Cl2
gave the mesylate 10 in almost quantitative yield. This in
turn was transformed into the nitrile 11 by treatment with
tetrabutylammonium cyanide in MeCN at 65 °C for 6 h in
reproducible (yield around 60%) on a 30Ϫ50 g scale.[12]
The latter was reduced to the configurationally unstable
crude aldehyde 12 with DIBAH in 97% yield. By slow ad-
dition of 12 to 3Ϫ4 equivalents of the ylide generated from
ethyltriphenylphosphonium bromide with potassium tert-
butoxide[13] in THF at Ϫ78 °C, the epimerization at C-4
was significantly decreased. The fully protected 4-(Z)-pro-
penylprolinol 13, which contained only traces of the
(2S,4S)-epimer was obtained with excellent E/Z-selectivity
(E/Z ratio 1:14Ϫ1:30). The tert-butyldimethylsilyl group
was smoothly removed with tetrabutylammonium fluoride
in THF to furnish the alcohol 14 in 42% yield over 3 steps
(from 11). This primary alcohol was oxidized with 10 equiv-
alents of Jones reagent in acetone at 4 °C to give the desired
N-Boc-protected 4-(Z)-propenylproline 15 in 65% yield
(11% overall yield from 7 over 8 steps).[14] The high dia-
stereo- and enantiomeric purity of this product was con-
firmed by HPLC (d.r. Ͼ 98:1, e.e. 97%).[15] This same syn-
thetic sequence was also successfully applied for the dia-
stereo- and enantioselective preparation of the deuterium
labeled H-(4-PE)Pro-OH.[16]
Scheme 1
Compound 3 was treated with an excess of mesyl chloride
and triethylamine in CH2Cl2, and the resulting mixture of
(E)- and (Z)-diastereomeric 4-propylidenepyroglutamate
derivatives was separated by column chromatography to
give the required (E)-isomer 4 (60%) along with a small
amount of the (Z)-isomer (4%). The configuration of the
double bond in the main product was proved by a NOESY
experiment. The N-protected 4-(E)-propylidenepyrogluta-
mate (S)-4 was treated with a slight excess of LiHMDS in
THF/HMPT mixture at Ϫ78 °C, and the resulting enolate
was quenched with 2,6-di-tert-butylphenol as a sterically
encumbered proton source. This method of enolate quench-
ing is known to give preferentially cis-isomers because of
the protonation from the least hindered side.[10] The dia-
stereomeric mixture obtained in this case was separated by
column chromatography to give the cis- 5 (37%) and the
trans-isomer 6 (19%). An attempt to remove the last 10% of
the trans-isomer from 5 failed because of its configurational
instability, which led to tailing on the column due to
30Ϫ40% epimerization to the thermodynamically more
stable trans-isomer upon each usual flash chromatography.
Surprisingly, the NMR spectra of these products disclosed
N-Hydroxy- and N-alkoxypyrroles apparently have not
attracted much attention of chemists. Only the preparation
of several 2-cyano-1-hydroxypyrroles by thermal decompo-
sition of the corresponding 3-unsubstituted 2-azidopyridine
N-oxides in benzene, has been described by Abramovitch et
al.[17] and this was used as a lead motif for the preparation
of the suitably protected 5-chloro-1-hydroxypyrrole-2-carb-
oxylic acid.
Since an attempted direct oxidation of 2-amino-6-chloro-
pyridine[18] with m-chloroperbenzoic acid (m-CPBA) ac-
cording to the protocol of Pentimalli[19] unexpectedly did not
give the desired N-oxide 20, it was prepared from 2-acet-
amido-6-chloropyridine (16)[20] or alternatively from 2,6-di-
chloropyridine N-oxide[21] (21) (Scheme 3).
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B. D. Zlatopolskiy, H.-P. Kroll, E. Melotto, A. de Meijere
FULL PAPER
Scheme 2
a sealed tube at 100 °C for 24 h gave 20 as the free base in
a single step in 55% yield. Subsequent diazotization of 20
followed by treatment with sodium azide provided 2-azido-
6-chloropyridine N-oxide 22 in 76% yield.
Thermal decomposition of the latter in degassed benzene
furnished 5-chloro-2-cyano-1-hydroxypyrrole 23 in 49%
yield along with the deoxygenated pyrrole 24 (13%)
(Scheme 4). All attempts to hydrolyze 23 under different
conditions led only to its decomposition. Therefore the N-
hydroxy compound 23 was transformed into a meth-
Scheme 3
2-Acetamido-6-chloropyridine (16) could be oxidized
with m-CPBA in dichloromethane to give the N-oxide 17
(93%) which was N-acylated with Boc2O to furnish the di-
acylated amine 18 in 65% yield. Deacetylation to the N-
Boc-protected amine 19 in 60% yield was achieved with
N,N,NЈ,NЈ-tetramethylguanidine (TMG) in methanol. Re-
moval of the Boc group from the latter with 3.9  HCl in
2-propanol led to the desired amine as the hydrochloride
20·HCl in 97% yield. More efficiently, the treatment of 2,6-
dichloropyridine N-oxide 21 with 25% NH3 in methanol in Scheme 4
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Two Essential Building Blocks for the Signal Metabolite Hormaomycin
FULL PAPER
oxymethyl ether 25. Hydrolysis of the nitrile group in 25 carboxylic acid (29) can easily be extended and used for the
with sodium hydroperoxide under PTC conditions accord- synthesis of related potentially pharmacologically relevant
ing to a protocol of Cacchi et al.[22] gave the amide 26 (all compounds as for example new analogues of kainic acid,[26]
attempts to hydrolyze 25 and 26 to the respective acids were compounds related to the new inhibitor of influenza, or
also unsucessful). This intermediate was acylated with neuraminidase A-315675[27] besides new modified ana-
Boc2O in acetonitrile in the presence of 4-pyrrolidinopyrid- logues of hormaomycin 1.
ine (4-PP) to give the bis(tert-butoxycarbonyl)amide 27
(84%) along with the N-Boc-bis(pyrrolecarbonyl)amine 28
as a side product (10%). Further hydrolysis of 27 under al-
Experimental Section
kaline conditions[23] then gave O-MOM-protected Chpca-
General Aspects: 1H NMR spectra: Bruker AM 250 (250 MHz),
Varian Inova 300 (300 MHz). 1H chemical shifts are reported in
ppm relative to residual peaks of deuterated solvents or tetrameth-
ylsilane. Higher order NMR spectra were approximately inter-
preted as first-order spectra, if possible. The observed signal multi-
plicities are characterized as follows: s singlet, d doublet, t triplet,
q quadruplet, quin quintet, m multiplet, br broad, Ar-H aryl-H.
13C NMR spectra [additional DEPT (Distortionless Enhancement
by Polarization Transfer) or APT (Attached Proton Test)]: Bruker
AM 250 (62.9 MHz), Varian Inova 300 (75.5 MHz) instruments.
13C chemical shifts are reported relative to peaks of the respective
solvent or tetramethylsilane. The following abbreviations are used:
DEPT: ϩ primary or tertiary (positive signal in DEPT), Ϫ second-
ary (negative signal in DEPT), Cquat quaternary (no signal in
DEPT); APT: ϩ primary or tertiary (positive signal in APT), Ϫ
secondary or quaternary (negative signal in APT). IR spectra:
Bruker IFS 66 (FT-IR) spectrometer, samples measured as KBr
pellets or oils between KBr plates. MS: EI-MS: Finnigan MAT
95, 70 eV, high resolution EI-MS spectra with perfluorokerosene as
reference substance. ESI-MS: Finnigan LCQ. MS (HR-EI): pre-
selected ion peak matching at R ϾϾ 10000 to be within Ϯ2 ppm
of the exact masses. HPLC: pump: Kontron 322 system, detector:
Kontron DAD 440, mixer: Kontron HPLC 360, data system: Kon-
tron Kromasystem 200, columns: Knauer Nucleosil-100 C18 (5 µm,
3 mm ϫ 250 mm). Optical rotations: PerkinϪElmer 241 digital
polarimeter, 1-dm cell; optical rotation values are given in 10Ϫ1 deg
cm2 gϪ1; concentrations (c) are given in g/100 mL. M.p.: Büchi 510
capillary melting point apparatus, uncorrected values. TLC:
MachereyϪNagel precoated sheets, 0.25 mm Sil G/UV254. The
chromatograms were viewed under UV light and/or by treatment
with phosphomolybdic acid (10% in ethanol), or ninhydrin (0.2%
in ethanol). Column chromatography: Merck silica gel, grade 60,
230Ϫ400 mesh and Baker silica gel, 40Ϫ140 mesh. Preparative
TLC: MachereyϪNagel, silica gel SIL G/UV254, layer thickness
0.25 mm (100 ϫ 200 mm or 200 ϫ 200 mm). Elemental analyses:
Mikroanalytisches Laboratorium des Instituts für Organische und
Biomolekulare Chemie der Universität Göttingen. Starting materi-
als: Anhydrous solvents were prepared according to standard meth-
ods by distillation over drying agents and were stored under argon.
All other solvents were distilled before use. All reactions were car-
ried out with magnetic stirring and, if air or moisture sensitive, in
flame-dried glassware under argon or nitrogen. Organic extracts
were dried with anhydrous MgSO4. tert-Butyl (S)-N-(tert-butyloxy-
carbonyl)pyroglutamate (2),[28] (2S,4R)-(N-tert-butyloxycarbonyl)-
4-hydroxyproline (7),[29] (2S,4R)-(N-tert-butyloxycarbonyl)-4-
hydroxyprolinol tert-butyldimethylsilyl ether (9),[11] tetrabutyl-
ammonium cyanide,[30] 2-acetamino-6-chloropyridine (16),[20] 2,6-
dichloropyridine N-oxide (21)[21] were prepared as described else-
where. (2S,1ЈR,2ЈR)-3-(2Ј-Nitrocyclopropyl)alanine was kindly pro-
vided by O. V. Larionov (Göttingen).[24]
OH 29 (43% overall yield over 4 steps from 23).
To test the applicability of 29 towards the synthesis of
hormaomycin 1, the fully protected dipeptide-like side
chain of 1 was synthesized and deprotected (Scheme 5).
(2S,1ЈR,2ЈR)-H-(3-Ncp)Ala-OH 30[24] was first protected
with Boc2O and then esterified with 9-fluorenylmethanol
(FmOH) using EDC in the presence of 4-pyrrolidinopyrid-
ine to yield 31 (62% over 2 steps) (Scheme 5). The latter,
after removal of the Boc group, was coupled with O-MOM-
protected Chpca-OH 29 to give the N-pyrrolcarbonylamino
ester 32 in 76% yield. Removal of the MOM group suc-
ceeded by treatment with MgBr2·Et2O in CH2Cl2 (78%).[25]
The resulting 33 was further transformed into the free acid
34, by treatment with tris-(2Ј-aminoethyl)amine, however, it
was too unstable (complete polymerization in THF or
CDCl3 solution within 30 min) to be used in any further
peptide condensation step. Eventually, the side chain of
hormaomycin 1 was attached to the preformed ring part
in a stepwise manner, before finally cleaving off the MOM
protective group under conditions mentioned above.[4]
Scheme 5
Conclusion
The newly developed efficient diastereo- and enantiose-
lective routes to N-Boc-protected 4-(Z)-propenylproline 15
tert-Butyl (2S)-N-Boc-4-(1Ј-hydroxypropyl)pyroglutamate (3):
A
as well as O-MOM-protected 5-chloro-1-hydroxypyrrol-2- solution of LiHMDS in THF, prepared by addition of a 2.47 
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FULL PAPER
BuLi solution in hexane (2.33 mL, 5.75 mmol) to a solution of
(62.9 MHz, CDCl3): δ ϭ 12.6 (ϩ, C-3Ј), 22.6 (Ϫ, C-2Ј), 25.5 (Ϫ,
HMDS (1.30 mL, 6.16 mmol) in THF (18 mL) at Ϫ78 °C followed C-3), 27.7 [ϩ, C(CH3)3], 27.8 [ϩ, C(CH3)3], 56.4 (ϩ, C-2), 82.0
by stirring of the resulting mixture at 4 °C for 1 h, was added to a
solution of 2 (1.43 g, 5.01 mmol) in THF (40 mL) at Ϫ78 °C, and
[Cquat, C(CH3)3], 83.0 [Cquat, C(CH3)3], 127.9 (Cquat, C-4), 140.2
(ϩ, C-1Ј), 149.8 (Cquat, NCO2), 166.2 (Cquat, C-1), 170.2 (Cquat
,
the resulting mixture was stirred at the same temperature for an C-5).
additional 1 h. solution of propionaldehyde (0.42 mL,
A
(Z)-isomer: Rf ϭ 0.75 (EtOAc/hexane, 3:7). 1H NMR (250 MHz,
CDCl3): δ ϭ 1.01 (t, J ϭ 7.5 Hz, 3 H, 3Ј-H), 1.45 [s, 9 H, C(CH3)3],
1.51 [s, 9 H, C(CH3)3], 2.43Ϫ2.58 (m, 1 H, 3-Ha), 2.75 (dddd, J ϭ
7.5, 7.5, 7.5, 7.5 Hz, 2 H, 2Ј-H), 2.89Ϫ3.09 (m, 1 H, 3-Hb), 4.42
(dd, J ϭ 7.8, 3.5 Hz, 1 H, 2-H), 5.92Ϫ6.06 (m, 1 H, 1Ј-H). 13C
5.79 mmol) and BF3·Et2O (0.73 mL, 5.76 mmol) in THF (18 mL)
was then added, and stirring continued at the same temperature
for 75 min. The reaction was then quenched with saturated NH4Cl
(30 mL), and the mixture was diluted with Et2O (250 mL). The
organic layer was separated, washed with water (3 ϫ 40 mL), 0.5 NMR (62.9 MHz, CDCl3): δ ϭ 13.7 (ϩ, C-3Ј), 20.6 (Ϫ, C-2Ј), 27.8
 H2SO4 (3 ϫ 40 mL), water (3 ϫ 40 mL), brine (2 ϫ 30 mL), [ϩ, C(CH3)3], 27.9 [ϩ, C(CH3)3], 29.1 (Ϫ, C-3), 56.5 (ϩ, C-2), 82.0
dried, filtered and concentrated under reduced pressure. The resi-
[Cquat, C(CH3)3], 83.0 [Cquat, C(CH3)3], 126.0 (Cquat, C-4), 144.8
due was separated by column chromatography (EtOAc/hexane, 1:3) (ϩ, C-1Ј), 150.1 (Cquat, NCO2), 165.9 (Cquat, C-1), 170.2 (Cquat
,
to give one pure diastereomer (785 mg, 46%) as a colorless oil, and
an inseparable mixture of two other diastereomers in a ratio of
1:3 [550 mg, 78% overall yield of 3]. No attempts to elucidate the
configuration of these products were made. The pure diastereomer:
C-5).
tert-Butyl (2S,4S)-N-Boc-4-(E)-(1Ј-propenyl)pyroglutamate (5) and
tert-Butyl (2S,4R)-N-Boc-4-(E)-(1Ј-propenyl)pyroglutamate (6): A
solution of LiHMDS in THF/HMPT, prepared by addition of a
2.47  BuLi solution in hexane (0.54 mL, 1.33 mmol) to a solution
of HMDS (0.33 mL, 1.56 mmol) and HMPT (0.356 g, 1.99 mmol)
in THF (5 mL) at Ϫ78 °C followed by stirring of the resulting mix-
ture at 4 °C for 15 min, was added dropwise to a solution of 4
(0.375 g, 1.15 mmol) in THF (5 mL) at Ϫ78 °C within 20 min, and
the mixture was stirred at the same temperature for an additional
1 h. Then a solution of 2,6-di-tert-butylphenol (0.713 g, 3.46 mmol)
in THF (1 mL) was added within 10 min, and then a saturated
aqueous NH4Cl solution (ca. 8 mL). The mixture was allowed to
warm to 20 °C and diluted with Et2O (50 mL). The organic layer
was separated, washed with water (3 ϫ 40 mL), 0.5  H2SO4 (3 ϫ
40 mL), water (3 ϫ 40 mL), brine (2 ϫ 30 mL), dried, filtered and
concentrated under reduced pressure. The residue containing the
mixture of diastereomers and 2,6-di-tert-butylphenol was separated
by column chromatography (twice, EtOAc/hexane, 1:3) to give 5
(140 mg, 37%) as a slightly yellow oil and 6 (70 mg, 19%) as a
colorless solid. Compound 5 contained a little of another dia-
stereomer (according to TLC; it was not visible in the 1H NMR
spectrum), and an attempt to remove this impurity by additional
column chromatography was made. As the (2S,4S)-isomer 5 appar-
ently isomerized to the other diastereomer, only material of essen-
tially the same quality (70 mg) together with the (2S,4R)-isomer 6
(40 mg) and a mixed fraction (25 mg) were obtained.
1
Rf ϭ 0.23 (EtOAc/hexane, 1:3). H NMR (250 MHz, CDCl3): δ ϭ
0.98 (t, J ϭ 7.3 Hz, 3 H, 3Ј-H), 1.48 [s, 9 H, C(CH3)3], 1.50 [s, 9 H,
C(CH3)3], 1.84Ϫ2.12 (m, 2 H, 3-H), 2.63 (dt, J ϭ 12.2, 8.7 Hz, 1 H,
4-H), 3.59Ϫ3.70 (m, 1 H, 1Ј-H), 4.24 (s, 1 H, OH), 4.44 (d, J ϭ
8.0 Hz, 1 H, 2-H). The signal of 2Ј-H overlapped with that of the
tert-butyl group. 13C NMR (62.9 MHz, CDCl3): δ ϭ 8.8 (ϩ, C-3Ј),
24.9 (Ϫ, C-2Ј), 26.7 (Ϫ, C-3), 27.4 [ϩ, C(CH3)3], 27.5 [ϩ, C(CH3)3],
45.5 (ϩ, C-4), 57.4 (ϩ, C-2), 72.7 (ϩ, C-1Ј), 82.1 [Cquat, C(CH3)3],
83.2 [Cquat, C(CH3)3], 148.5 (Cquat, NCO2), 169.6 (Cquat, C-1), 176.1
(Cquat, C-5). The mixture of diastereomers: Rf ϭ 0.15 (EtOAc/hex-
ane, 1:3). 1H NMR (250 MHz, CDCl3): δ ϭ 0.99 (t, J ϭ 7.3 Hz,
3 H, 3Ј-H), 1.15Ϫ1.30 (m, 0.4 H, 2Ј-Ha), 1.48 [s, 9 H, C(CH3)3],
1.50 [s, 9 H, C(CH3)3], 1.85Ϫ2.10 (m, 0.6 H, 3-H), 2.31Ϫ2.80 (m,
2 H, 3-H, 4-H), 3.49Ϫ3.70 (m, 1 H, 1Ј-H), 4.12 (s, 1 H, OH), 4.35
(dd, J ϭ 8.0, 8.0 Hz, 0.7 H, 2-H), 4.43 (dd, J ϭ 1.2, 10.4 Hz, 0.3 H,
2-H). The signal of 2Ј-H overlapped with that of the tert-butyl
group. 13C NMR (62.9 MHz, CDCl3): δ ϭ 8.5, 9.0 (ϩ, C-3Ј), 18.5,
21.6 (Ϫ, C-2Ј), 24.6 (Ϫ, C-3), 27.0, 27.1 [ϩ, C(CH3)3], 27.7, 27.8
[ϩ, C(CH3)3], 46.7, 47.2 (ϩ, C-4), 57.8, 57.9 (ϩ, C-2), 70.0, 72.9
(ϩ, C-1Ј), 82.1, 82.3 [Cquat, C(CH3)3], 83.2, 83.8 [Cquat, C(CH3)3],
148.9, 149.0 (Cquat, NCO2), 169.8, 170.5 (Cquat, C-1), 174.6, 175.9
(Cquat, C-5).
tert-Butyl 2-(S)-N-Boc-4-(E)-propylidenepyroglutamate (4): Et3N
(4.00 mL, 28.56 mmol) followed by mesyl chloride (0.23 mL,
2.97 mmol) was added dropwise to a stirred ice-cold solution of the
mixture of diastereomers of 3 (0.55 g, 1.60 mmol) in CH2Cl2
(20 mL), and the mixture was then allowed to warm to 20 °C. Stir-
ring was continued for an additional 48 h, and the reaction was
then quenched with water (3 mL). EtOAc (80 mL) was added, and
the organic layer was washed with water (4 ϫ 20 mL) and brine (2
ϫ 20 mL), dried, filtered and concentrated under reduced pressure.
The resulting oily residue was identical with the one obtained by
reaction of the pure diastereomer of 3 (0.785 g, 2.29 mmol) with
Et3N (5.8 mL, 41.44 mmol) and mesyl chloride (0.32 mL,
4.13 mmol) in CH2Cl2 (20 mL). Both portions were combined and
purified by column chromatography (twice: first EtOAc/hexane,
3:7, then EtOAc/hexane, 1:3) to give 4 (760 mg, 60%) as a faintly
tan solid and the (Z)-isomer (55 mg, 4%). The configuration of the
main product was confirmed by NOESY NMR measurement.
5: Rf ϭ 0.38 (EtOAc/hexane, 1:3). 1H NMR (250 MHz, CDCl3):
δ ϭ 1.47 [s, 9 H, C(CH3)3], 1.50 [s, 9 H, C(CH3)3], 1.66 (dd, J ϭ
5.0, 1.3 Hz, 3 H, 3Ј-H), 1.86 (dd, J ϭ 12.5, 6.5 Hz, 1 H, 3-Ha), 2.53
(ddd, J ϭ 13.3, 6.5, 6.5 Hz, 1 H, 3-Hb), 3.09Ϫ3.23 (m, 1 H, 4-H),
4.38 (dd, J ϭ 9.0, 5.8 Hz, 1 H, 2-H), 5.30Ϫ5.52 (m, 1 H, 1Ј-H),
5.52Ϫ5.72 (m, 1 H, 2Ј-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 17.8
(ϩ, C-3Ј), 27.7 [ϩ, 2 ϫ C(CH3)3], 28.6 (Ϫ, C-3), 45.7 (ϩ, C-4),
58.0 (ϩ, C-2), 82.0 [Cquat, C(CH3)3], 83.1 [Cquat, C(CH3)3], 126.3
(ϩ, C-2Ј), 129.3 (ϩ, C-1Ј), 149.4 (Cquat, NCO2), 170.1 (Cquat, C-1),
173.6 (Cquat, C-5).
6: Rf ϭ 0.42 (EtOAc/hexane, 1:3), m.p. 70Ϫ71 °C, [α]2D0 ϭ 7.1 (c ϭ
0.31, CHCl3). IR (KBr): ν˜ ϭ 2979 cmϪ1, 2934, 1781, 1743, 1708,
1457, 1367, 1296, 1221, 1155. 1H NMR (250 MHz, CDCl3): δ ϭ
1.48 [s, 9 H, C(CH3)3], 1.50 [s, 9 H, C(CH3)3], 1.71 (dd, J ϭ 6.3,
1.3 Hz, 3 H, 3Ј-H), 2.04Ϫ2.31 (m, 2 H, 3-H), 3.19Ϫ3.24 (m, 1 H,
4-H), 4.44 (dd, J ϭ 9.0, 1.8 Hz, 1 H, 2-H), 5.47 (dd, J ϭ 9.0, 1.3 Hz,
1 H, 1Ј-H), 5.63 (dq, J ϭ 1.3, 6.3 Hz, 1 H, 2Ј-H). 13C NMR
4: Rf ϭ 0.55 (EtOAc/hexane, 3:7). 1H NMR (250 MHz, CDCl3):
δ ϭ 1.01 (t, J ϭ 7.5 Hz, 3 H, 3Ј-H), 1.42 [s, 9 H, C(CH3)3], 1.45 [s, (62.9 MHz, CDCl3): δ ϭ 17.9 (ϩ, C-3Ј), 27.77 [ϩ, C(CH3)3], 27.79
9 H, C(CH3)3], 2.11 (dddd, J ϭ 7.5, 7.5, 7.5, 7.5 Hz, 2 H, 2Ј-H), [ϩ, C(CH3)3], 28.7 (Ϫ, C-3), 44.7 (ϩ, C-4), 57.5 (ϩ, C-2), 82.2
2.42Ϫ2.54 (m, 1 H, 3-Ha), 2.89Ϫ3.09 (m, 1 H, 3-Hb), 4.45 (dd, J ϭ
[Cquat, C(CH3)3], 83.1 [Cquat, C(CH3)3], 126.0 (ϩ, C-2Ј), 129.7 (ϩ,
7.8, 3.5 Hz, 1 H, 2-H), 6.57Ϫ6.70 (m, 1 H, 1Ј-H). 13C NMR C-1Ј), 149.4 (Cquat, NCO2), 170.1 (Cquat, C-1), 173.6 (Cquat, C-5).
4496
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4492Ϫ4502

Two Essential Building Blocks for the Signal Metabolite Hormaomycin
MS (ESI), positive m/z (%) ϭ 348 (75) [M ϩ Naϩ]. Elemental upon seeding. M.p. 55Ϫ58 °C, [α]2D0 ϭ Ϫ25.9 (c ϭ 0.9, CHCl3). IR
FULL PAPER
analysis calcd. (%) for C17H27NO5 (325.4): calcd. C 62.75, H 8.36,
N 4.30; found C 62.59, H 8.60, N 4.04.
(film): ν˜ ϭ 2952 cmϪ1, 2895, 2855, 2240, 1696, 1471, 1400, 1259,
1172, 1099. 1H NMR (300 MHz, C2D2Cl4, 358 K): δ ϭ 0.10 [s,
6 H, Si(CH3)2], 0.94 [s, 9 H, SiC(CH3)3], 1.48 [s, 9 H, C(CH3)3],
2.29Ϫ2.46 (m, 2 H, 3-H), 2.96 (dddd, J ϭ 8.2, 8.2, 8.2, 8.2 Hz, 1 H,
4-H), 3.42 (dd, J ϭ 8.2, 10.6 Hz, 1 H, 5-Ha), 3.74 (dd, J ϭ 3.0,
9.8 Hz, 1 H, 1-Ha), 3.79Ϫ3.95 (m, 2 H, 1-Hb, 2-H), 3.96 (dd, J ϭ
8.2, 10.6 Hz, 1 H, 5-Hb). 13C NMR (75.5 MHz, C2D2Cl4, 358 K):
δ ϭ Ϫ5.6 [ϩ, Si(CH3)2], 17.9 (Cquat, SiC), 25.7 [ϩ, SiC(CH3)3], 26.3
(ϩ, C-4), 28.2 [ϩ, C(CH3)3], 31.9 (Ϫ, C-3), 49.8 (Ϫ, C-5), 57.8 (ϩ,
C-2), 62.9 (Ϫ, C-1), 80.0 [Cquat, C(CH3)3], 119.8 (Cquat, CN), 153.2
(Cquat, NCO2). MS (CI), m/z (%) ϭ 358 (8) [M ϩ NH4ϩ], 341 (100)
[M ϩ Hϩ]. Elemental analysis calcd. (%) for C17H32N2O3Si (340.5):
calcd. C 59.96, H 9.47, N 8.23; found C 60.29, H 9.55, N 8.04.
(2S,4R)-N-Boc-4-Hydroxyprolinol (8): To a solution of 7 (57.5 g,
248 mmol) and triethylamine (38.4 mL, 273 mmol) in CH2Cl2
(1000 mL) was added at Ϫ30 °C ethyl chloroformate (25 mL,
261 mmol), and the mixture was stirred for 40 min. To this mixture
were added tetra-n-butylammonium bromide (8.5 g, 26.4 mmol)
and then carefully, by small portions a suspension of NaBH4 (40 g,
1057 mmol) in ice-cold water (50 mL). The reaction mixture was
allowed to warm to Ϫ10 °C and stirred for 1 h. The temperature
of the mixture was further increased to 0 °C, and stirring was con-
tinued at this temperature for 1 h. The pH value of the aqueous
layer was then carefully adjusted to 5Ϫ6 with 50% acetic acid, and
the mixture was filtered through Celite. The organic layer was (2S,4S)-N-Boc-O-TBDMS-4-Formylprolinol (12): A 1  solution of
separated, and the aqueous layer was extracted with CH2Cl2 (3 ϫ
100 mL). The aqueous layer was discarded, and the combined or-
ganic fractions were dried, concentrated under reduced pressure,
and the residue was purified by column chromatography (EtOAc/
DIBAH in hexane (36.1 mL, 36.10 mmol) was added dropwise at
Ϫ30 °C over 10 min to a stirred solution of the cyanide 11 (9.10 g,
26.72 mmol) in CH2Cl2 (90 mL). The reaction mixture was stirred
at Ϫ30 to Ϫ20 °C for 2 h, then methanol (2.1 mL) was added drop-
hexane, 7:3, Rf ϭ 0.24) to give 8 (44.23 g, 82%) as a colorless solid. wise at 0 °C within 3 min, and stirring was continued at the same
M.p. 53Ϫ55 °C (ref.[31] m.p. 55Ϫ58 °C), [α]2D0 ϭ Ϫ58.8 (c ϭ 1.05,
temperature for 15 min. A saturated aqueous NH4Cl solution
EtOH) (ref.[31] [α]2D0ϭ Ϫ58.87, c ϭ 1.009, EtOH). IR (KBr): ν˜ ϭ (8.4 mL) was then added, and the mixture was allowed to warm to
3381 cmϪ1, 2981, 2942, 2899, 1653, 1412, 1160, 1041. 1H NMR
20 °C. After 45 min, the reaction mixture was diluted with Et2O
(250 MHz, CDCl3): δ ϭ 1.47 [s, 9 H, C(CH3)3], 1.57Ϫ1.80 (m, 1 H, (80 mL), saturated aqueous potassium sodium tartrate (14 mL) was
3-Ha), 1.89Ϫ1.98 (br, 1 H, OH), 1.98Ϫ2.11 (m, 1 H, 3-Hb), added and vigorous stirring was continued for an additional 1 h.
3.35Ϫ3.63 (m, 3 H, 2-H, 5-H), 3.70 (dd, J ϭ 9.4, 9.4 Hz, 1 H, 1- The phases were separated, and the organic fraction was washed
Ha), 4.04Ϫ4.25 (m, 1 H, 1-Hb), 4.29Ϫ4.45 (m, 1 H, 4-H),
twice with a solution of citric acid (5.14 g, 26.72 mmol) in water
4.95Ϫ5.09 (br, 1 H, OH). 13C NMR (62.9 MHz, CDCl3): δ ϭ 28.3 (120 mL), with water (5 ϫ 50 mL), brine (2 ϫ 20 mL), dried, fil-
[ϩ, C(CH3)3], 37.3 (Ϫ, C-3), 54.9, 55.6 (Ϫ, C-5), 57.7, 58.6 (ϩ, C- tered and concentrated under reduced pressure. The residue was
2), 63.8, 66.4 (Ϫ, C-1), 68.8 (ϩ, C-4), 80.4 [Cquat, C(CH3)3], 155.0, taken up with hexane (30 mL), filtered through a pad of Celite
156.9 (Cquat, NCO2).
and concentrated under reduced pressure to give the aldehyde 12
(9.0 g, 98% crude) as a colorless oil, which was used for the next
step without further purification. Rf ϭ 0.37 (EtOAc/hexane, 1:4).
1H NMR (250 MHz, CDCl3): δ ϭ 0.03 [s, 6 H, Si(CH3)2], 0.86 [s,
9 H, SiC(CH3)3], 1.43 [s, 9 H, C(CH3)3], 1.78Ϫ2.20 (m, 1 H, 3-Ha),
2.22Ϫ2.41 (m, 1 H, 3-Hb), 2.78Ϫ3.12 (m, 1 H, 4-H), 3.45Ϫ4.02 (m,
5 H, 1-H, 2-H, 5-H), 9.63 (s, 1 H, CHO).
(2S,4R)-N-Boc-O-TBDMS-4-Mesyloxyprolinol (10): To a solution
of 9 (48.14 g, 145 mmol) and triethylamine (30.4 mL, 218 mmol) in
CH2Cl2 (120 mL) at Ϫ40 °C was added mesyl chloride (15.2 mL,
196 mmol) within 10 min. The mixture was allowed to warm to
0 °C and stirred for an additional 3 h, before saturated NaHCO3
(100 mL) was added. The reaction mixture was taken up with Et2O
(500 mL), the organic layer was washed with H2O (3 ϫ 100 mL), (2S,4R)-N-Boc-4-(Z)-Propenylprolinol (14): A freshly prepared 0.85
1  NaHSO4 (3 ϫ 100 mL), H2O (2 ϫ 100 mL), brine (2 ϫ
100 mL) and dried. Concentration under reduced pressure gave 10
(58.2 g, 98%) as a light yellow oil. Rf ϭ 0.53 (EtOAc/hexane, 1:2.3),
 solution of tBuOK in THF (108 mL, 91.8 mmol) was added to
suspension of ethyltriphenylphosponium bromide (44.00 g,
118.52 mmol) in THF (50 mL) at 0 °C. The cooling bath was re-
a
[α]2D0 ϭ Ϫ38.5 (c ϭ 0.55, CHCl3). IR (film): ν˜ ϭ 2930 cmϪ1, 2858, moved, and stirring continued for an additional 2 h. The mixture
1698, 1473, 1404, 1366, 1257, 1174, 1120. 1H NMR (250 MHz,
was then cooled to Ϫ78 °C, and a solution of 12 (9.00 g,
CDCl3): δ ϭ 0.01 [s, 6 H, Si(CH3)2], 0.85 [s, 9 H, SiC(CH3)3], 1.44
26.20 mmol) in THF (30 mL) was added dropwise within 2 h. Stir-
[s, 9 H, C(CH3)3], 2.30Ϫ2.49 (m, 2 H, 3-H), 3.02 (s, 3 H, CH3), ring was continued at the same temperature for an additional 24 h,
3.44Ϫ3.63 (m, 2 H, 5-H), 3.63Ϫ4.15 (m, 3 H, 1-H, 2-H), 5.25Ϫ5.33 and then the mixture was allowed to warm to 20 °C for 24 h. After
(m, 1 H, 4-H). 13C NMR (75.5 MHz, C2D2Cl4, 353 K): δ ϭ Ϫ5.7 48 h, the reaction flask was immersed in an ice-water bath, and
[ϩ, Si(CH3)2], 17.8 (Cquat, SiC), 25.6 [ϩ, SiC(CH3)3], 28.3 [ϩ,
C(CH3)3], 34.8 (Ϫ, CϪ3), 38.4 (ϩ, SO2Me), 52.4 (Ϫ, C-5), 57.0 (ϩ,
a saturated aqueous solution of Na2SO4 (50 mL) was added. The
reaction mixture was concentrated under reduced pressure, the resi-
C-2), 63.4 (Ϫ, C-1), 78.9 (ϩ, C-4), 79.6 [Cquat, C(CH3)3], 153.6 due was taken up with CH2Cl2/Et2O, 1:4 (200 mL), filtered through
(Cquat, NCO2). MS (ESI), positive: m/z (%) ϭ 432 (91) [M ϩ Naϩ]. a pad of silica gel (10 cm), concentrated, the residue was dissolved
in Et2O (20 mL), the solution was filtered, concentrated, the resi-
(2S,4S)-N-Boc-O-TBDMS-4-Cyanoprolinol (11): A sealed round-
bottomed flask containing a solution of the mesyl ester 10 (52.8 g,
129 mmol) and tetra-n-butylammonium cyanide (72.0 g, 268 mmol)
due was dissolved in Et2O/hexane, 1:1 (20 mL), the solution was
filtered, concentrated, the residue was dissolved in hexane (20 mL),
the solution was filtered, concentrated, the residue was dissolved in
in anhydrous MeCN (50 mL) was placed in an oil-bath which was
pentane (20 mL), the solution was filtered, concentrated, and the
preheated to 65Ϫ68 °C. After stirring the contents of the flask for
residue was finally purified by column chromatography (EtOAc/
hexane, 1:8, Rf ϭ 0.51) to give impure (2S,4R)-N-Boc-O-TBDMS-
6 h, the mixture was taken up with EtOAc/hexane, 1:4 (500 mL),
washed with water (8 ϫ 100 mL) and brine (2 ϫ 50 mL), dried and
4-(Z)-propenylprolinol 13 (5.3 g) which was used for the next step
filtered through a pad of silica gel (5 cm). The solvents were re-
without further purification.
moved under reduced pressure, and the residue was purified by
column chromatography (EtOAc/hexane, 1:3, Rf ϭ 0.50) to give 11 TBAF·3H2O (8.86 g, 28.1 mmol) was added with stirring to a solu-
(26.5 g, 60%) as a yellowish oil which solidified to a colorless solid
tion of the crude alkene 13 (5.0 g, max. 14 mmol) in THF (15 mL)
Eur. J. Org. Chem. 2004, 4492Ϫ4502
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4497

B. D. Zlatopolskiy, H.-P. Kroll, E. Melotto, A. de Meijere
FULL PAPER
at 20 °C. After 1.5 h, the mixture was taken up with Et2O (100 mL),
washed with water (5 ϫ 20 mL), brine (2 ϫ 20 mL), dried, concen-
trated under reduced pressure, and the residue was purified by col-
1.93Ϫ2.12 (m, 1 H, 3-Ha), 2.27Ϫ2.54 (m, 1 H, 3-Hb), 3.06 (ddddd,
J ϭ 9.6, 9.6, 9.6, 9.6, 9.6 Hz, 1 H, 4-H), 2.98Ϫ3.20 (m, 1 H, 5-Ha),
3.64Ϫ3.86 (m, 1 H, 5-Hb), 4.25, 4.35 (2 dd, J ϭ 8.3, 8.3 Hz, 1 H,
umn chromatography (EtOAc/hexane, 1:2.5, Rf ϭ 0.32) to give 14 2-H), 5.26 (ddq, J ϭ 9.6, 8.5, 1.8 Hz, 1 H, 1Ј-H), 5.52 (dq, J ϭ
(2.69 g, 42% over 3 steps from 11) as a colorless oil which solidified
into a colorless solid upon seeding, and the (2S,4S)-epimer epi-14
(0.12 g, 2%) as a colorless oil.
8.5, 6.8 Hz, 1 H, 2Ј-H), 10.30Ϫ11.40 (br, 1 H, CO2H). 13C NMR
(62.9 MHz, CDCl3): δ ϭ 13.1 (ϩ, CH3), 28.1, 28.3 [ϩ, C(CH3)3],
35.7, 36.1 (ϩ, C-4), 36.1, 37.3 (Ϫ, C-3), 51.4, 51.9 (Ϫ, C-5), 58.9,
59.1 (ϩ, C-2), 80.6 [Cquat, C(CH3)3], 126.6, 126.9 (ϩ, C-2Ј), 129.0,
129.2 (ϩ, C-1Ј), 153.6, 154.8 (Cquat, NCO2), 177.3, 178.4 (Cquat, C-
1). MS (ESI), positive m/z (%) ϭ 300 (35) [M Ϫ Hϩ ϩ2Naϩ], 278
(16) [M ϩ Naϩ]; negative m/z ϭ 254 (100) [M Ϫ Hϩ]. HRMS (EI):
calcd. for C13H21NO4: 255.1471; correct mass. Elemental analysis
calcd. (%) for C13H21NO4 (255.3): calcd. C 61.16, H 8.29, N 5.49;
found C 61.16, H 8.23, N 5.31.
14: M.p. 41Ϫ43 °C, [α]2D0 ϭ Ϫ47.9 (c ϭ 0.97, CHCl3). IR (film):
ν˜ ϭ 3398 cmϪ1, 2976, 2932, 2871, 1696, 1402, 1164. 1H NMR
(250 MHz, CDCl3): δ ϭ 1.23 (ddd, J ϭ 10.8, 10.8, 10.8 Hz, 1 H, 3-
Ha), 1.46 [s, 9 H, C(CH3)3], 1.65 (dd, J ϭ 6.9, 0.8 Hz, 3 H, 3Ј-H),
2.13 (ddd, J ϭ 10.8, 6.5, 6.5 Hz, 1 H, 3-Hb), 2.90 (ddd, J ϭ 10.8,
10.8, 10.8 Hz, 1 H, 5-Ha), 2.85Ϫ3.10 (m, 1 H, 4-H), 3.52Ϫ3.77 (m,
3 H, 5-Hb, 2-H, 1-Ha), 3.96 (dd, J ϭ 7.6, 14.9 Hz, 1 H, 1-Hb), 5.18
(m, 1 H, 1Ј-H), 5.30 (dd, J ϭ 8.9, 1.8 Hz, 1 H, OH), 5.52 (dq, J ϭ 2-Acetamido-6-chloropyridine N-Oxide (17): m-Chloroperbenzoic
9.8, 6.9 Hz, 1 H, 2Ј-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 13.2 acid (11.97 g, 90% purity, 62.44 mmol) was added to a solution of
(ϩ, CH3), 28.4 [ϩ, C(CH3)3], 35.2 (ϩ, C-4), 35.8 (Ϫ, C-3), 52.7 (Ϫ, 2-acetamido-6-chloropyridine (16)[20] (8.24 g, 48.30 mmol) in
C-5), 61.1 (ϩ, C-2), 67.6 (Ϫ, C-1), 80.4 [Cquat, C(CH3)3], 126.3 (ϩ, CH2Cl2 (100 mL), and stirring was continued for an additional
C-2Ј), 129.8 (ϩ, C-1Ј), 156.8 (Cquat, NCO2). MS (EI): m/z (%) ϭ
60 h. K2CO3 (6.5 g) was then added to the mixture, and after stir-
ring for 1 h the mixture was filtered, the solution was concentrated
241 (1) [Mϩ], 210 (35) [Mϩ Ϫ CH3O], 168 (9), 154 (100) [Mϩ
Ϫ
C5H11O], 110 (96) [C7H12Nϩ], 67 (5), 57 (89) [C4H9ϩ], 41 (15) under reduced pressure, and the residue was recrystallized from
[C3H5ϩ]. HRMS (EI): calcd. for C13H23NO3: 241.1678; correct
CH2Cl2/hexane to give 17 (8.35 g, 93%) as a colorless solid. 1H
mass. Elemental analysis calcd. (%) for C13H23NO3 (241.3): calcd. NMR (250 MHz, CDCl3): δ ϭ 2.29 (s, 3 H, CH3), 7.15Ϫ7.31 (m,
C 64.70, H 9.61, N 5.80; found C 64.83, H 9.74, N 5.64.
2 H, 4-H, 5-H), 8.35 (dd, J ϭ 2.5, 10.0 Hz, 1 H, 3-H), 9.80Ϫ10.20
(br, 1 H, NH). 13C NMR (62.9 MHz, CDCl3): δ ϭ 25.0 (ϩ, CH3),
112.1 (ϩ, C-3), 119.4 (ϩ, C-5), 127.2 (ϩ, C-4), 140.0 (Cquat, C-6),
145.4 (Cquat, C-2), 169.0 (Cquat, CH3CO). MS (EI, 70 eV): m/z
(%) ϭ 188/186 (30/100) [Mϩ], 146/144 (30:100) [Mϩ Ϫ C2H2O],
130/128 (3:8), 43 (78) [C2H3Oϩ]. HRMS (EI): calcd. for
C7H7ClN2O2: 186.0196; correct mass.
epi-14: Rf ϭ 0.28, EtOAc/hexane, 1:2.5. 1H NMR (250 MHz,
CDCl3): δ ϭ 1.44 [s, 9 H, C(CH3)3], 1.60 (dd, J ϭ 6.8, 1.8 Hz, 3 H,
3Ј-H), 1.68Ϫ1.85 (m, 2 H, 3-H), 3.01 (ddd, J ϭ 9.7, 9.7, 9.7 Hz,
1 H, 5-Ha), 3.13 (m, 1 H, 4-H), 3.48 (dd, J ϭ 9.7, 6.9 Hz, 1 H, 5-
Hb), 3.54Ϫ3.59 (m, 2 H, 1-Ha, 2-H), 3.77Ϫ4.12 (m, 1 H, 1-Hb),
4.40 (br, 1 H, OH), 5.21 (dd, J ϭ 10.9, 10.9 Hz, 1 H, 1Ј-H), 5.48
(dq, J ϭ 10.9, 6.8 Hz, 1 H, 2Ј-H). 13C NMR (62.9 MHz, CDCl3): tert-Butyl Acetyl(6-chloropyridin-2-yl)carbamate N-Oxide (18):
δ ϭ 13.2 (ϩ, CH3), 28.4 [ϩ, C(CH3)3], 34.8 (ϩ, C-4), 35.1 (Ϫ, C-
DMAP (0.54 g, 4.42 mmol) was added to a solution of 17 (8.35 g,
44.75 mmol) and Boc2O (11.09 g, 50.81 mmol) in acetonitrile
(60 mL), and stirring was continued for an additional 12 h. The
reaction mixture was diluted with EtOAc (250 mL), washed with 1
 NaHSO4 (3 ϫ 40 mL), saturated aqueous NaHCO3 (3 ϫ 40 mL),
H2O (3 ϫ 40 mL), brine (2 ϫ 20 mL), dried, filtered and concen-
trated under reduced pressure. The crude product was recrystallized
from EtOAc/hexane to give 18 (8.31 g, 65%) as a colorless solid
which slowly decomposed at ambient temperature. Rf ϭ 0.59
(EtOAc/hexane, 1:1). 1H NMR (250 MHz, CDCl3): δ ϭ 1.35 [s,
9 H, C(CH3)3], 2.58 (s, 3 H, CH3), 7.08Ϫ7.22 (m, 2 H, 3-H, 5-H),
7.41Ϫ7.49 (m, 1 H, 4-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 25.5
(ϩ, CH3), 27.5 [ϩ, C(CH3)3], 84.5 [Cquat, C(CH3)3], 124.0 (ϩ, C-
3), 52.7 (Ϫ, C-5), 59.6 (ϩ, C-2), 67.7 (Ϫ, C-1), 80.2 [Cquat
,
C(CH3)3], 125.9 (ϩ, C-2Ј), 130.4 (ϩ, C-1Ј), 158.3 (Cquat, NCO2).
(2S,4R)-N-Boc-4-(Z)-Propenylproline (15): A 2.67  solution of
Jones reagent (36.5 mL, 97.46 mmol) was added to a solution of
alcohol 14 (2.35 g, 9.74 mmol) in acetone (800 mL) at 4 °C within
1 h, and the mixture was stirred at the same temperature for an
additional 2 h. Isopropanol (5 mL) was then added dropwise within
10 min, and the mixture was allowed to warm to 20 °C. The reac-
tion mixture was concentrated to 200 mL under reduced pressure
at a bath temperature not higher than 30 °C, the residue was taken
up with Et2O (500 mL) and the mixture was washed with water (3
ϫ 100 mL). The aqueous fraction was back-extracted with diethyl
ether (3 ϫ 50 mL), and the organic layers were combined, washed
with brine (2 ϫ 50 mL), dried, filtered, concentrated to 100 mL
under reduced pressure, and the residue was extracted with satu-
rated aqueous solution of NaHCO3 (5 ϫ 40 mL). The combined
aqueous fractions were washed with Et2O (2 ϫ 50 mL), the pH of
the aqueous fractions was carefully adjusted to 2.5Ϫ3 with solid
NaHSO4, the formed emulsion was extracted with Et2O (2 ϫ
100 mL) and the organic fraction was washed with 1  NaHSO4
3), 124.5 (ϩ, C-5), 125.8 (ϩ, C-4), 141.9 (Cquat, C-6), 145.8 (Cquat
,
C-2), 150.0 (Cquat, NCO2), 171.8 (Cquat, CH3CO). MS (EI, 70 eV):
m/z (%) ϭ 288/286 (5:14) [Mϩ], 172/170 (30:100) [Mϩ Ϫ C6H12O2],
146/144 (30:90) [Mϩ Ϫ C6H12O3], 57 (93) [C4H9ϩ], 43 (32)
[C2H3Oϩ]. HRMS (EI): calcd. for C12H15ClN2O4: 286.0720; cor-
rect mass.
2-(tert-Butyloxycarbonylamino)-6-chloropyridine N-Oxide (19): To a
solution of 18 (8.31 g, 28.98 mmol) in methanol (70 mL) was added
(3 ϫ 50 mL), water (3 ϫ 50 mL), brine (2 ϫ 20 mL), dried, filtered 1,1,3,3-tetramethylguanidine (4.53 mL, 36.10 mmol), and stirring
and concentrated under reduced pressure. The residue was recrys-
tallized twice from hexane and finally purified by column chroma-
tography [EtOAc/hexane, 1:3 (2% AcOH), Rf ϭ 0.27] to give 15
was continued for an additional 40 min. The mixture was concen-
trated under reduced pressure to ca. 30 mL, the residue was diluted
with Et2O (100 mL), the mixture was washed with 1  NaHCO3
(2 ϫ 20 mL), brine (2 ϫ 20 mL), dried, filtered and concentrated
(1.63 g, 65%) as a colorless solid. HPLC: detection: 200 nm, tR
ϭ
18.58 min, gradient: 20 Ǟ 50% MeCN in H2O (0.1% TFA) for under reduced pressure to leave a solid residue which was recrys-
30 min, purity Ͼ 99%. M.p. 84Ϫ85 °C. [α]2D0 ϭ Ϫ84.4 (c ϭ 0.86,
tallized from octane to give 19 (4.25 g, 60%) as a colorless solid.
CHCl3). IR (KBr): ν˜ ϭ 3020, 2975, 2943, 2880, 2625, 1736, 1633, M.p. 103Ϫ105 °C. IR (KBr): ν˜ ϭ 3297 cmϪ1, 3122, 2980, 1728,
1441, 1369, 1252, 1168. 1H NMR (250 MHz, CDCl3): δ ϭ 1.42, 1608, 1560, 1500, 1377, 1275, 1257, 1182, 1159. 1H NMR
1.48 [2 s, 9 H, C(CH3)3], 1.66 (d, J ϭ 6.8 Hz, 3 H, 3Ј-H), 1.72Ϫ1.84, (250 MHz, CDCl3): δ ϭ 1.50 [s, 9 H, C(CH3)3], 7.09 (dd, J ϭ 2.0,
4498
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4492Ϫ4502

Two Essential Building Blocks for the Signal Metabolite Hormaomycin
FULL PAPER
8.3 Hz, 1 H, 3-H), 7.19 (dd, J ϭ 8.3, 8.3 Hz, 1 H, 4-H), 8.06 (dd, 5-Chloro-1-hydroxypyrrole-2-carbonitrile (23) and 5-Chloro-2-car-
J ϭ 2.0, 8.3 Hz, 1 H, 5-H), 9.13Ϫ9.31 (br, 1 H, NH). 13C NMR bonitrile (24): A solution of 2-azido-6-chloropyridine N-oxide 22
(62.9 MHz, CDCl3): δ ϭ 28.0 [ϩ, C(CH3)3], 82.5 [Cquat, C(CH3)3], (1.27 g, 7.45 mmol) in anhydrous benzene (32 mL) under argon was
110.6 (ϩ, C-3), 118.2 (ϩ, C-5), 126.9 (ϩ, C-4), 140.0 (Cquat, C-6), sealed in a thick-walled tube. The tube was heated first at 90 °C,
146.0 (Cquat, C-2), 151.2 (Cquat, NCO2). MS (EI, 70 eV): m/z (%) ϭ then the temperature was allowed to increase to 105 °C, and the
246/244 (6:20) [Mϩ], 190/188 (3:8) [Mϩ Ϫ C4H8], 173/171 (5:17)
[Mϩ Ϫ C4H9O], 146/144 (11:36) [C5H5ClN2Oϩ], 57 (100) [C4H9ϩ],
41 (8). HRMS (EI): calcd. for C10H13ClN2O3: 244.0615; correct
mass.
reaction mixture was left at this temperature for 15 min. Then the
temperature was decreased to 85 °C, and stirring continued for an
additional 4 h. After this, the reaction mixture was allowed to cool
to 20 °C, and was concentrated under reduced pressure at a tem-
perature not higher than 35 °C to give a red solid, which was puri-
fied by column chromatography (silica gel, EtOAc/hexane, 1:4) to
give 23 (0.517 g, 49%, Rf ϭ 0.37) as a light tan solid and 24 (0.12 g,
13%, Rf ϭ 0.49) as a colorless solid.
2-Amino-6-chloropyridine N-Oxide Hydrochloride (20·HCl): The N-
Boc-protected amide 19 (4.22 g, 17.25 mmol) was deprotected by
treatment with 3.9  HCl in dioxane (100 mL) for 24 h. All volatiles
were then removed and the residue was triturated with Et2O to give
20·HCl (3.03 g, 97%) as a colorless solid.
23: Rf ϭ 0.52 (EtOAc/hexane, 1:3); m.p. 101Ϫ102 °C. IR (KBr):
ν˜ ϭ 3139 cmϪ1, 3127, 3007, 2900, 2241, 1516, 1425, 1403, 1378.
1H NMR (250 MHz, CDCl3): δ ϭ 6.03 (d, J ϭ 5.0 Hz, 1 H, 4-
H), 6.67 (d, J ϭ 5.0 Hz, 1 H, 3-H), 8.96 (br, 1 H, OH). 13C NMR
(62.9 MHz, CDCl3): δ ϭ 100.5 (Cquat, C-2), 104.9 (ϩ, C-4), 111.0
(Cquat, CN), 116.0 (ϩ, C-3), 131.9 (Cquat, C-5). MS (EI, 70 eV): m/z
(%) ϭ 144/142 (30:100) [Mϩ], 127/125 (17:57) [Mϩ Ϫ OH], 107
(2) [Mϩ Ϫ Cl], 89 (3), 80 (49), 73 (9), 64 (26), 52 (9). HRMS (EI):
calcd. for C5H3ClN2O: 141.9934; correct mass. Elemental analysis
calcd. (%) for C5H3ClN2O (142.5): calcd. C 42.13, H 2.12, N 19.65;
found C 42.03, H 2.35, N 19.44.
2-Amino-6-chloropyridine N-Oxide (20): 2,6-Dichloropyridine N-
oxide (21)[21] (6.30 g, 38.4 mmol) was heated with 25% NH3 in
MeOH (100 mL) in a sealed tube at 105 °C for 26 h (TLC control).
The tube was cooled in an ice-water bath, then opened, and the
reaction mixture was filtered and concentrated under reduced
pressure. The residue was dissolved in MeOH/CHCl3, 1:4, the solu-
tion was filtered again and concentrated to give a dark-red oil,
which was purified by column chromatography (MeOH/CHCl3,
1:4, Rf ϭ 0.50) and then by recrystallization (CHCl3/hexane) to
give 20 (3.04 g, 55%) as a colorless solid. Rf ϭ 0.23 (EtOAc/hexane,
1:1); m.p. 133Ϫ135 °C. IR (KBr): ν˜ ϭ 3400Ϫ2500 cmϪ1, 3192,
3147, 1653, 1628, 1550, 1502, 1412, 1216, 1188. 1H NMR
(250 MHz, CDCl3): δ ϭ 5.03 (br, 2 H, NH2), 6.31 (dd, J ϭ 0.5,
7.9 Hz, 1 H, 3-H), 6.57 (dd, J ϭ 0.5, 7.9 Hz, 1 H, 5-H), 7.29 (dd,
J ϭ 7.9, 7.9 Hz, 1 H, 4-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ
106.4 (ϩ, C-3), 112.5 (ϩ, C-5), 139.9 (ϩ, C-4), 149.1 (Cquat, C-6),
158.7 (Cquat, C-2). MS (EI, 70 eV): m/z (%) ϭ 146/144 (30:100)
[Mϩ], 128/126 (10:30) [Mϩ Ϫ H2O], 119/117 (5:16) [Mϩ Ϫ HCN],
109 (2) [Mϩ Ϫ Cl], 100 (7), 99 (10), 92 (17), 93/91 (5:16), 81 (7).
HRMS (EI): calcd. for C5H5ClN2O: 144.0090; correct mass. Ele-
mental analysis calcd. (%) for C5H5ClN2O (144.6): calcd. C 41.54,
H 3.49, N 19.38; found C 41.41, H 3.54, N 19.46.
24: Rf ϭ 0.49 (EtOAc/hexane, 1:4), m.p. 104Ϫ105 °C. IR (KBr):
ν˜ ϭ 3144 cmϪ1, 3122, 3078, 2978, 22331, 1731, 1543, 1449, 1421,
1383, 1261, 1145, 1035. 1H NMR (250 MHz, CDCl3): δ ϭ 6.03 (d,
J ϭ 7.5 Hz, 1 H, 4-H), 6.67 (d, J ϭ 7.5 Hz, 1 H, 3-H), 8.96 (bs,
1 H, NH). 13C NMR (62.9 MHz, CDCl3): δ ϭ 100.0 (Cquat, C-2),
108.6 (ϩ, C-4), 113.6 (Cquat, CN), 120.8 (Cquat, C-5), 121.5 (ϩ, C-
3). MS (EI, 70 eV): m/z (%) ϭ 128/126 (30:100) [Mϩ], 101/99 (1:3)
[Mϩ Ϫ HCN], 91 (4) [Mϩ Ϫ Cl], 77/75 (1:4), 64 (16). HRMS (EI):
calcd. for C5H3ClN2: 125.9985; correct mass.
2-Azido-6-chloropyridine N-Oxide (22): A 2.5  aqueous NaNO2
(11.3 mL) was added dropwise to an ice-cold solution of 2-amino-
5-Chloro-1-(methoxymethoxy)pyrrole-2-carbonitrile (25): To a vig-
6-chloropyridine N-oxide (20) (3.80 g, 26.3 mmol) in 85 mL of 10% orously stirred emulsion of a 24% aqueous NaOH solution
HCl at such a rate that the internal temperature did not exceed 5
(1.40 mL) in a solution of 5-chloro-1-hydroxypyrrole-2-carbonitrile
°C. The reaction mixture was stirred for an additional 10 min, then
(23) (0.65 g, 4.56 mmol) and TEBAC (0.07 g, 0.31 mmol) in
a 2.5  NaN3 solution (11.3 mL) was added dropwise at such a CH2Cl2 (10 mL) was added MOMCl (0.74 g, 9.19 mmol), and vig-
rate that the internal temperature did not exceed 5 °C, and stirring
was continued at the same temperature for an additional 1 h. The
reaction mixture was extracted with CH2Cl2 (8 ϫ 50 mL), dried
and filtered through a short column with silica gel eluting first with
orous stirring was continued for an additional 30 min. The organic
layer was then separated, and the aqueous fraction was extracted
with CH2Cl2 (3 ϫ 10 mL). The combined organic layers were then
concentrated under reduced pressure, and the crude product was
CH2Cl2 (1 L) and then with CH2Cl2/Et2O, 1:1 (1 L). The combined purified first by column chromatography (EtOAc/hexane, 1:7) and
fractions were concentrated to ca. 15 mL under reduced pressure
and hexane (150 mL) was added. The precipitate was separated by
finally by bulb-to-bulb distillation at a bath temperature 60Ϫ100
°C and a pressure of 0.02 Torr to give 25 (0.84 g, 98%) as a colorless
filtration and washed with CH2Cl2/hexane, 1:10 to give after drying liquid which solidified in a refrigerator to a colorless solid. Rf ϭ
22 (3.4 g, 76%) as a faint yellow solid. M.p. 83Ϫ88 °C (decomp.). 0.55 (EtOAc/hexane, 1:4). IR (film): ν˜ ϭ 3136 cmϪ1, 2945, 2839,
1
IR (KBr): ν˜ ϭ 3126 cmϪ1, 3077, 2130, 1597, 1470, 1390, 1212. H
2227, 1430, 1218, 1167, 1091. 1H NMR (250 MHz, CDCl3): δ ϭ
NMR (250 MHz, CDCl3): 6.84 (dd, J ϭ 2.0, 8.3 Hz, 1 H, 3-H), 3.73 (s, 3 H, CH3), 5.18 (s, 2 H, CH2), 6.05 (d, J ϭ 4.8 Hz, 1 H, 4-
7.11 (dd, J ϭ 8.3, 8.3 Hz, 1 H, 4-H), 7.24 (dd, J ϭ 2.0, 8.6 Hz, 1 H, H), 6.65 (d, J ϭ 4.8 Hz, 1 H, 3-H). 13C NMR (62.9 MHz, CDCl3):
5-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 114.5 (ϩ, C-3), 121.5 (ϩ,
δ ϭ 58.9 (ϩ, CH3), 102.1 (Cquat, C-2), 104.2 (Ϫ, CH2), 105.1 (ϩ,
C-5), 126.2 (ϩ, C-4), 145.4 (Cquat, C-6), 156.8 (Cquat, C-2). MS (EI, C-4), 111.6 (Cquat, CN), 115.5 (ϩ, C-3), 118.6 (Cquat, C-5). MS (EI,
70 eV): m/z (%) ϭ 172/170 (14:44) [Mϩ], 144/142 (5:16) [Mϩ 70 eV): m/z (%) ϭ 188/186 (3:8) [Mϩ], 127/125 (2:5) [Mϩ
N2], 114/112 (18:56), 87/85 (6:18), 76 (100). HRMS (EI): calcd. for
C2H5O2], 64 (3), 45 (100) [C2H5Oϩ]. HRMS (EI): calcd. for
Ϫ
Ϫ
C5H3ClN4O: 169.9995; correct mass. Elemental analysis calcd. (%) C7H7ClN2O2: 186.0196; correct mass. Elemental analysis calcd. (%)
for C5H3ClN4O (170.6): calcd. C 35.21, H 1.77, N 32.85; found C for C7H7ClN2O2 (186.6): calcd. C 45.06, H 3.78, N 15.01; found C
35.35, H 2.01, N 32.66.
44.87, H 3.79, N 14.81.
Eur. J. Org. Chem. 2004, 4492Ϫ4502
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4499

B. D. Zlatopolskiy, H.-P. Kroll, E. Melotto, A. de Meijere
FULL PAPER
5-Chloro-1-(methoxymethoxy)pyrrole-2-carboxamide (26): To a vig-
orously stirred solution of 5-chloro-1-(methoxymethoxy)pyrrole-2-
5-Chloro-1-(methoxymethoxy)pyrrole-2-carboxylic Acid (29): To a
solution of the twofold N-Boc-substituted derivative 27 (1.320 g,
carbonitrile (25) (0.84 g, 4.50 mmol) and tetra-n-butylammonium 3.26 mmol) in dioxane (16 mL) was added 1  NaOH solution
hydrogen sulfate (0.32 g, 0.94 mmol) in CH2Cl2 (9 mL) were added (4.3 mL), and the mixture was stirred at 55 °C for 2 h. Then, all
a 20% aqueous NaOH (2.00 mL) and 30% H2O2 (3.28 mL,
32.10 mmol), and vigorous stirring was continued for an additional
90 min. The layers were separated and the water layer after satu-
ration with sodium chloride was additionally extracted with
volatiles were removed under reduced pressure, the residue was
taken up with H2O (40 mL), and the resulting solution washed with
CH2Cl2 (5 ϫ 10 mL). The pH of the water layer was adjusted with
1  KHSO4 to 3, the aqueous phase saturated with sodium chlo-
CH2Cl2 (4 ϫ 5 mL). The combined organic layers were concen- ride, and the product was extracted with CH2Cl2 (4 ϫ 20 mL). The
trated under reduced pressure and the residue was purified by col-
umn chromatography (EtOAc/hexanes, 1:1, Rf ϭ 0.29) to give 26
(0.80 g, 87%) as a colorless solid. M.p. 43Ϫ45 °C. IR (film): ν˜ ϭ
organic phase was dried and concentrated to give after recrystalli-
zation from CH2Cl2/hexane the acid 29 (0.399 mg, 60%) as a color-
less solid. Rf ϭ 0.36 [EtOAc/hexane, 1:2.5 (5% AcOH)],
3466 cmϪ1, 3339, 3192, 2943, 2838, 1658, 1606, 1440, 1166, 1085. m.p. 120Ϫ122 °C (decomp.). IR (KBr): ν˜ ϭ 3451 cmϪ1, 3135, 3006,
1H NMR (250 MHz, CDCl3): δ ϭ 3.55 (s, 3 H, CH3), 5.25 (s, 2 H, 2964, 2944, 2618, 2562, 1671, 1543, 1533, 1447, 1437, 1323, 1263,
CH2), 5.50Ϫ6.50 (br, 2 H, NH2), 6.05 (d, J ϭ 4.8 Hz, 1 H, 4-H),
1
1159, 1119. H NMR (250 MHz, CDCl3): δ ϭ 3.71 (s, 3 H, CH3),
6.73 (d, J ϭ 4.8 Hz, 1 H, 3-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 5.25 (s, 2 H, CH2), 6.06 (d, J ϭ 4.9 Hz, 1 H, 4-H), 6.95 (d, J ϭ
59.5 (ϩ, CH3), 104.2 (ϩ, C-4), 104.8 (Ϫ, CH2), 111.4 (ϩ, C-3),
4.9 Hz, 1 H, 3-H), 9.8Ϫ12.2 (br, 1 H, CO2H). 13C NMR
118.6 (Cquat, C-2), 122.1 (Cquat, C-5), 160.4 (Cquat, CONH2). MS (62.9 MHz, CDCl3): δ ϭ 58.9 (ϩ, CH3), 104.6 (Ϫ, CH2), 104.7 (ϩ,
(EI, 70 eV): m/z (%) ϭ 206/204 (11:32) [Mϩ], 174/172 (23:70) [Mϩ
C-4), 116.0 (ϩ, C-3), 117.7 (Cquat, C-2), 122.8 (Cquat, C-5), 163.6
Ϫ CH4O], 145:143 (4:13) [Mϩ Ϫ C2H5O2], 90:88 (2:6), 45 (100) (Cquat, CO). MS (EI, 70 eV): m/z (%) ϭ 207:205 (13:43) [Mϩ],
[C2H5Oϩ]. HRMS (EI): calcd. for C7H9ClN2O3: 204.0302; correct
mass. Elemental analysis calcd. (%) for C7H9ClN2O3 (204.6): calcd.
C 41.09, H 4.43, N 13.69; found C 41.32, H 4.21, N 13.47.
177:175 (2:5) [Mϩ Ϫ CH2O], 145:143 (2:7) [Mϩ Ϫ C2H6O2], 129
(7), 91:89 (2:6), 75:73 (1:3), 45 (100) [C2H5Oϩ]. HRMS (EI): calcd.
for C7H8ClNO4: 205.0142; correct mass. Elemental analysis calcd.
(%) for C7H8ClNO4 (205.6): calcd. C 40.89, H 3.92, N 6.81; found
C 40.93, H 3.94, N 6.68.
Di-tert-butyl [5-Chloro-1-(methoxymethoxy)pyrrol-2-yl]carbonyl-
imidodicarbamate (27) and tert-Butyl Bis[(5-chloro-1-(methoxymeth-
oxy)pyrrol-2-yl)carbonyl]imidocarbamate (28): To a solution of 5-
chloro-1-(methoxymethoxy)pyrrole-2-carboxamide (26) (0.80 g,
3.91 mmol) and Boc2O (5.12 g, 23.46 mmol) in anhydrous MeCN
(20 mL) was added 4-pyrrolidinopyridine (50 mg, 0.34 mmol), and
stirring was continued for an additional 2.5 h. The mixture was
concentrated under reduced pressure, and the crude product was
purified by column chromatography (EtOAc/hexane, 1:8) to give
the desired twofold N-Boc-substituted product 27 (1.324 g, 84%,
Rf ϭ 0.13) as a colorless solid and the by-product 28 (95 mg, 10%,
Rf ϭ 0.07) as a viscous opaque oil.
N-Boc-3-(2S,1ЈS,2ЈR)-(trans-2Ј-Nitrocyclopropyl)alanine:
A solu-
tion of Boc2O (0.500 g, 2.29 mmol) in acetone (2 mL) was added
to a vigorously stirred solution of 3-(2S,1ЈR,2ЈR)-(trans-2Ј-nitro-
cyclopropyl)alanine (30) (0.266 g, 1.53 mmol) in 1  NaOH
(1.53 mL) with some NaHCO3 (ca. 50 mg) (when a precipitate was
formed, acetone and/or water were added to obtain a homogeneous
solution), and stirring was continued for another 15 h. N,N-Di-
methylaminopropylamine (0.11 mL, 0.88 mmol) was then added.
After an additional 10 min, acetone was removed under reduced
pressure, and the pH of the residual aqueous solution was adjusted
to 2Ϫ3 with 1  NaHSO4 solution. The resulting emulsion was
extracted with Et2O (50 mL), and the ethereal layer was washed
with 1  NaHSO4 solution (2 ϫ 10 mL), water (3 ϫ 10 mL), brine
(2 ϫ 5 mL), dried, filtered and concentrated under reduced press-
ure. The residue was taken up with hexane, filtered through a pad
of Celite, and concentrated under reduced pressure to give the
title compound (0.353 g, 84%) as an extremely viscous colorless oil.
Rf ϭ 0.06 [EtOAc/hexane, 1:3 (2% AcOH)], [α]2D0ϭ 20.6 (c ϭ 0.81,
CHCl3). IR (film): ν˜ ϭ 3700Ϫ2250 cmϪ1, 3101, 2979, 2935, 1715,
27: M.p. 67Ϫ68 °C. IR (KBr): ν˜ ϭ 3123 cmϪ1, 3012, 2971, 2946,
1793, 1696, 1431, 1391, 1371, 1275, 1255, 1156, 1102. 1H NMR
(250 MHz, CDCl3): δ ϭ 1.42 [s, 18 H, 2 ϫ C(CH3)3], 3.68 (s, 3 H,
CH3), 5.22 (s, 2 H, CH2), 6.07 (d, J ϭ 4.9 Hz, 1 H, 4-H), 6.75 (d,
J ϭ 4.9 Hz, 1 H, 3-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 27.7
[ϩ, 2 ϫ C(CH3)3], 58.8 (ϩ, CH3), 84.0 [Cquat, 2 ϫ C(CH3)3], 104.5
(Ϫ, CH2), 104.9 (ϩ, C-4), 116.0 (ϩ, C-3), 122.3 (Cquat, C-2), 124.2
(Cquat, C-5), 149.3 (Cquat, NCO2), 157.0 (Cquat, CON). MS (EI,
70 eV): m/z (%) ϭ 406:404 (2:6) [Mϩ], 350:348 (2:5) [Mϩ Ϫ C4H8],
294:292 (2:6) [Mϩ Ϫ C8H16], 250:248 (11:35) [Mϩ Ϫ C9H16O2],
190:188 (11:35), 174:172 (30:100) [C7H7NO2Clϩ] 143 (31), 57 (100)
[C4H9ϩ], 45 (58) [C2H5Oϩ]. HRMS (EI): calcd. for C17H25ClN2O7:
404.1350; correct mass. Elemental analysis calcd. (%) for
C17H25ClN2O7 (404.9): calcd. C 50.44, H 6.22, N 6.92; found C
50.26, H 5.99, N 6.85.
1
1545, 1437, 1394, 1369, 1253, 1163. H NMR (250 MHz, CDCl3):
δ ϭ 1.14 (ddd, J ϭ 6.5, 6.5, 6.5 Hz, 1 H, 3Ј-Ha), 1.45 [s, 9 H,
C(CH3)3], 1.59Ϫ1.82 (m, 1 H, 3Ј-Hb), 1.82Ϫ1.94 (m, 1 H, 1Ј-H),
1.94Ϫ2.21 (m, 2 H, 3-H), 4.10Ϫ4.23 (m, 1 H, 2Ј-H), 4.25Ϫ4.38,
4.42Ϫ4.53 (2 m, 1 H, 2-H), 5.22Ϫ5.40, 6.10Ϫ7.30 (br, 2 H, NH,
CO2H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 17.5 (Ϫ, C-3Ј), 22.0
(ϩ, C-1Ј), 28.1 [ϩ, C(CH3)3], 33.4, 33.6 (Ϫ, C-3), 52.5, 53.7 (ϩ, C-
2), 59.2 (ϩ, C-2Ј), 80.6, 82.5 [Cquat, C(CH3)3], 155.4, 156.9 (Cquat
,
28: IR (film): ν˜ ϭ 3131 cmϪ1, 2979, 2940, 2946, 2840, 1751, 1700,
1429, 1395, 1370, 1256, 1149, 1087. H NMR (250 MHz, CDCl3):
δ ϭ 1.39 [s, 9 H, C(CH3)3], 3.64 (s, 6 H, 2 ϫ CH3), 5.24 (s,
4 H, 2 ϫ CH2), 6.03 (d, J ϭ 4.8 Hz, 2 H, 2 ϫ 4-H), 6.74 (d, J ϭ
NCO2), 175.1, 175.4 (Cquat, C-1). MS (ESI): positive mode, m/z
(%) ϭ 319 (32) [M Ϫ Hϩ ϩ2Naϩ], 297 (86) [M ϩ Naϩ]; negative
mode, m/z (%) ϭ 273 (30) [M Ϫ Hϩ].
1
4.8 Hz, 2 H, 2 ϫ 3-H). 13C NMR (62.9 MHz, CDCl3): δ ϭ 27.5 Boc-(S)-(3-Ncp)Ala-OFm (31): EDC (0.223 g, 1.16 mmol) was ad-
[ϩ, C(CH3)3], 58.9 (ϩ, 2 ϫ CH3), 84.5 [Cquat, C(CH3)3], 104.8
(Ϫ, 2 ϫ CH2), 104.8 (ϩ, 2 ϫ C-4), 115.2 (ϩ, 2 ϫ C-3), 122.5
ded to a cooled (4 °C) solution of Boc-(S)-(3-Ncp)Ala-OH
(0.213 g, 0.78 mmol), 4-pyrrolidinopyridine (36 mg, 0.24 mmol)
(Cquat, 2 ϫ C-2), 123.6 (Cquat, 2 ϫ C-5), 151.1 (Cquat, NCO2), 158.9 and 9-fluorenylmethanol (0.152 g, 0.78 mmol) in CH2Cl2 (6 mL).
(Cquat, 2 ϫ CON). MS (CI), m/z (%) ϭ 513:512:511:510:509 The temperature was allowed to reach 20 °C and stirring was con-
(13:15:68:22:100)
[M
ϩ
NH4ϩ],
496:495:494:493:492
tinued for 5 h. The mixture was then diluted with Et2O (50 mL)
and subjected to the usual aqueous workup. The organic layer was
(13:15:68:22:100) [M ϩ Hϩ].
4500
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4492Ϫ4502

Two Essential Building Blocks for the Signal Metabolite Hormaomycin
dried, filtered and concentrated under reduced pressure. The resi-
FULL PAPER
510:508 (1:3) [Mϩ Ϫ CH3O], 191 (10), 178 (100) [C14H10ϩ], 165
due was crystallized from hexane, taken up with Et2O (4 mL), and (12), 130:128 (3:10) [C5H3ClNOϩ], 45 (36) [C2H5Oϩ]. HRMS (EI):
the solution was filtered through a silica gel pad (1.5 cm) to give,
after concentration of the filtrate under reduced pressure, 31
calcd. for C27H26ClN3O7: 539.1459; correct mass. Elemental analy-
sis calcd. (%) for C27H26ClN3O7 (540.0): calcd. C 60.06, H 4.85, N
(0.26 g, 74%) as a colorless solid. Rf ϭ 0.30 (EtOAc/hexane, 1:4), 7.78; found C 60.10, H 5.00, N 7.71.
m.p. 79Ϫ81 °C, [α]2D0 ϭ Ϫ27.0 (c ϭ 0.3, CHCl3). IR (KBr): ν˜ ϭ
3420 cmϪ1, 3067, 2980, 2934, 1738, 1715, 1684, 1545, 1521, 1451,
1369, 1208, 1163. 1H NMR (250 MHz, CDCl3): δ ϭ 1.14 (ddd, J ϭ
6.8, 6.8, 5.3 Hz, 1 H, 3Ј-Ha), 1.43 [s, 9 H, C(CH3)3], 1.43Ϫ1.60 (m,
1 H, 3Ј-Hb), 1.58Ϫ1.71 (m, 1 H, 1Ј-H), 1.72Ϫ1.92 (m, 2 H, 3-H),
3.90 (ddd, J ϭ 6.9, 3.5, 3.5 Hz, 1 H, 2-H), 4.23 (t, J ϭ 6.0 Hz, 1 H,
9ЈЈЈ-H), 4.35 (ddd, J ϭ 6.8, 6.8, 6.8 Hz, 1 H, 1Ј-H), 4.55 (dd, J ϭ
10.8, 6.0 Hz, 1 H, 1ЈЈ-Ha), 4.66 (dd, J ϭ 10.8, 6.0 Hz, 1 H, 1ЈЈ-Hb),
5.13 (d, J ϭ 8 Hz, 1 H, NH), 7.26Ϫ7.48 (m, 4 H, Ar-H), 7.57 (d,
J ϭ 7.4 Hz, 2 H, Ar-H), 7.77 (d, J ϭ 7.5 Hz, 2 H, Ar-H). 13C NMR
(62.9 MHz, CDCl3): δ ϭ 17.5 (Ϫ, C-3Ј), 21.8 (ϩ, C-1Ј), 28.1 [ϩ,
C(CH3)3], 33.6 (Ϫ, C-3), 46.6 (ϩ, C-1ЈЈ), 52.6 (ϩ, C-2), 59.0 (ϩ,
C-2Ј), 66.9 (Ϫ,C-2ЈЈ), 80.2 [Cquat, C(CH3)3], 119.9, 120.0 (ϩ, Ar-
C), 124.6, 124.7 (ϩ, Ar-C), 127.1 (ϩ, Ar-C), 127.9 (ϩ, Ar-C),
Chpca-(2S)-(3-Ncp)Ala-OFm
(33):
MgBr2·Et2O
(0.239 g,
0.93 mmol) and EtSH (0.07 mL, 0.95 mmol) were added to a vigor-
ously stirred solution of the acylamino ester 32 (50 mg, 92.6 µmol)
in CH2Cl2 (15 mL), and stirring was continued for another 3 h.
The reaction mixture was then taken up with EtOAc (40 mL), and
washed with 1  NaHSO4 solution (3 ϫ 10 mL), water (3 ϫ 5 mL),
brine (2 ϫ 5 mL), dried, filtered and concentrated under reduced
pressure. The residue was purified by preparative TLC (200 ϫ
200 mm, EtOAc/hexane, 1:4, 2 runs) and gave 33 (36 mg, 78%) as
an extremely viscous oil which was unlimitedly stable upon storage
under argon at Ϫ28 °C. Rf ϭ 0.20 (EtOAc/hexane, 1:3). IR (KBr):
ν˜ ϭ 3750Ϫ1800 cmϪ1, 3067, 1740, 1542, 1451, 1426, 1368, 1198.
1H NMR (250 MHz, CDCl3): δ ϭ 0.83Ϫ0.96 [m, 1 H, 3Ј-Ha, (3-
Ncp)Ala], 1.42Ϫ1.56 [m, 1 H, 3Ј-Hb, (3-Ncp)Ala], 1.67Ϫ1.82 [m,
3 H, 1Ј-H, 3-H, (3-Ncp)Ala], 3.89 [ddd, J ϭ 7.0, 3.1, 3.1 Hz, 1 H,
2-H, (3-Ncp)Ala], 4.25 (t, J ϭ 5.1 Hz, 1 H, 9ЈЈ-H, Fm), 4.67 (dd,
J ϭ 10.7, 5.1 Hz, 1 H, 1Ј-Ha, Fm), 4.82 (dd, J ϭ 10.7, 5.1 Hz, 1 H,
1Ј-Hb, Fm), 5.96 (d, J ϭ 5.0 Hz, 1 H, 4-H, Chpca), 6.37 (d, J ϭ
7.0 Hz, 1 H, NH), 6.40 (d, J ϭ 5.0 Hz, 1 H, 3-H, Chpca), 7.26Ϫ7.37
(m, 2 H, Ar-H, Fm), 7.42 (dd, J ϭ 7.3, 7.3 Hz, 2 H, Ar-H, Fm),
7.56 (d, J ϭ 7.3 Hz, 2 H, Ar-H, Fm), 7.76 (dd, J ϭ 7.1, 5.3 Hz,
2 H, Ar-H, Fm), 13.0Ϫ13.3 (br, 1 H, OH); the signal of 1Ј-Ha of
the Fm group overlapped with the signal of 1Ј-H of the (3-Ncp)Ala
moiety. 13C NMR (62.9 MHz, CDCl3): δ ϭ 17.4 [Ϫ, C-3Ј, (3-
Ncp)Ala], 21.6 [ϩ, C-1Ј, (3-Ncp)Ala], 33.4 [Ϫ, C-3, (3-Ncp)Ala],
46.7 (ϩ, C-9ЈЈ, Fm), 51.2 [ϩ, C-2, (3-Ncp)Ala], 58.9 [ϩ, C-2Ј, (3-
Ncp)Ala], 66.9 (Ϫ, C-1Ј, Fm), 102.8 (ϩ, C-4, Chpca), 106.1 (ϩ, C-
3, Chpca), 114.4 (Cquat, C-2, Chpca), 116.0 (Cquat, C-5, Chpca),
120.0, 120.1 (ϩ, Ar-C, Fm), 124.4, 124.5 (ϩ, Ar-C, Fm), 127.2,
127.3 (ϩ, Ar-C, Fm), 128.0 (ϩ, Ar-C, Fm), 141.3, 141.4 (Cquat, Ar-
C, Fm), 142.9, 143.0 (Cquat, Ar-C, Fm), 162.2 (Cquat, C-1, Chpca),
170.9 [Cquat, C-1, (3-Ncp)Ala]. MS (EI, 70 eV), m/z (%) ϭ 497:495
(2:7) [Mϩ], 319:317 (1:4) [Mϩ Ϫ C14H10], 178 (100) [C14H10ϩ],
146:144 (3:10) [C5H2ClNO2ϩ]. HRMS (EI): calcd. for
C25H22ClN3O7: 495.1197; correct mass.
141.2, 141.3 (Cquat, Ar-C), 143.0, 143.2 (Cquat, Ar-C), 155.0 (Cquat
,
NCO2), 175.4 (Cquat, C-1). MS (EI, 70 eV), m/z (%) ϭ 452 (3) [Mϩ],
178 (100) [C14H10ϩ], 129 (2) [C5H9N2O2ϩ], 91 (3) [C7H7ϩ], 57 (16)
[C4H9ϩ], 41 (5) [C3H5ϩ]. HRMS (EI): calcd. for C25H28N2O6:
452.1947; correct mass. Elemental analysis calcd. (%) for
C25H28N2O6 (452.5): calcd. C 66.36, H 6.24, N 6.19; found C 66.11,
H 5.99, N 6.02.
Chpca(MOM)-(2S)-(3-Ncp)Ala-OFm (32): The ester 31 (0.223 g,
0.49 mmol) was deprotected by treatment with 4  HCl in EtOAc
(5 mL) for 90 min to give HCl·H-(3-Ncp)Ala-OFm (0.182 g, 95%)
as a colorless solid. EDC (93 mg, 0.49 mmol) and HOAt (64 mg,
0.47 mmol) were added to a cooled (4 °C) solution of 29 (96 mg,
0.47 mmol) in anhydrous CH2Cl2 (5 mL). After 5 min, to the solu-
tion of the amino ester were added DIEA (61 mg, 0.47 mmol) and
TMP (0.114 g, 0.94 mmol) in anhydrous CH2Cl2 (1 mL). After 3 h,
the reaction mixture was diluted with Et2O (50 mL) and subjected
to the usual aqueous workup. The organic layer was dried, filtered
and concentrated under reduced pressure. The residue was crys-
tallized from Et2O/pentane to give 32 (0.202 g, 76% on two steps)
as a colorless solid. Rf ϭ 0.20 (EtOAc/hexane, 1:3), m.p. 94Ϫ95
°C, [α]2D0 ϭ Ϫ33.3 (c ϭ 0.3, CHCl3). IR (KBr): ν˜ ϭ 3370 cmϪ1
,
3038, 2962, 2935, 2836, 1729, 1638, 1538, 1428, 1374, 1339, 1239,
1164. 1H NMR (250 MHz, CDCl3): δ ϭ 1.14 [ddd, J ϭ 6.8, 6.8,
5.5 Hz, 1 H, 3Ј-Ha, (3-Ncp)Ala], 1.47Ϫ1.60 [m, 1 H, 3Ј-Hb, (3-
Ncp)Ala], 1.69Ϫ1.90 [m, 3 H, 1Ј-H, 3-H, (3-Ncp)Ala], 3.57 (s, 3 H, Chpca-(2S)-(3-Ncp)Ala-OH (34): The ester 33 (35 mg, 70.6 µmol)
OMe), 3.89 [ddd, J ϭ 7.0, 3.3, 3.3 Hz, 1 H, 2-H, (3-Ncp)Ala], 4.25 was deprotected by treatment with 10% tris(2-aminoethyl)amine
(t, J ϭ 5.8 Hz, 1 H, 9ЈЈ-H, Fm), 4.63 (dd, J ϭ 10.6, 5.8 Hz, 1 H, (TAEA) in CH2Cl2 (1 mL) for 20 min and the mixture was then
1Ј-Ha, Fm), 4.73 (dd, J ϭ 10.6, 5.8 Hz, 1 H, 1Ј-Hb, Fm), 5.17 (d, taken up with EtOAc (30 mL). The organic layer was briefly
J ϭ 6.8 Hz, 1 H, OCH2O), 5.25 (d, J ϭ 6.8 Hz, 1 H, OCH2O), 6.04 washed with 1  NaHSO4 solution (3 ϫ 10 mL), water (3 ϫ 5 mL),
(d, J ϭ 4.7 Hz, 1 H, 4-H, Chpca), 6.68 (d, J ϭ 4.7 Hz, 1 H, 3-H,
brine (2 ϫ 5 mL), dried, filtered and concentrated to give 34 as a
Chpca), 7.17 (d, J ϭ 7.0 Hz, 1 H, NH), 7.26Ϫ7.37 (m, 2 H, Ar-H, turbid oil which completely polymerized into a colorless insoluble
Fm), 7.42 (dd, J ϭ 7.0, 7.0 Hz, 2 H, Ar-H, Fm), 7.57 (d, J ϭ 7.3 Hz, solid at 20 °C within ca. 2 h. In solution 34 was even less stable.
2 H, Ar-H, Fm), 7.77 (dd, J ϭ 7.5, 3.6 Hz, 2 H, Ar-H, Fm); the 1H NMR (250 MHz, [D6]acetone): δ ϭ 1.30 [ddd, J ϭ 7.0, 7.0,
signal of 1Ј-Hb of the Fm group overlapped with the signal of 1Ј-
7.0 Hz, 1 H, 3Ј-Ha, (3-Ncp)Ala], 1.71Ϫ1.87 [m, 1 H, 3Ј-Hb, (3-
H of the (3-Ncp)Ala moiety. 13C NMR (62.9 MHz, CDCl3): δ ϭ Ncp)Ala], 1.90Ϫ2.21 [m, 3 H, 1Ј-H, 3-H, (3-Ncp)Ala], 4.42 [ddd,
17.5 [Ϫ, C-3Ј, (3-Ncp)Ala], 21.7 [ϩ, C-1Ј, (3-Ncp)Ala], 33.3 [Ϫ, J ϭ 6.3, 3.5, 3.5 Hz, 1 H, 2-H, (3-Ncp)Ala], 4.71Ϫ4.84 [m, 1 H,
C-3, (3-Ncp)Ala], 46.6 (ϩ, C-9ЈЈ, Fm), 51.3 [ϩ, C-2, (3-Ncp)Ala], 2Ј-H, (3-Ncp)Ala], 6.03 (d, J ϭ 5.0 Hz, 1 H, 4-H, Chpca), 6.82 (d,
58.9 [ϩ, C-2Ј, (3-Ncp)Ala], 59.4 (ϩ, OMe), 66.9 (Ϫ, C-1Ј, Fm), J ϭ 5.0 Hz, 1 H, 3-H, Chpca), 7.0Ϫ8.0 (br, 2 H, OH, CO2H), 8.17
104.2 (ϩ, C-4, Chpca), 104.8 (Ϫ, OCH2O), 111.1 (ϩ, C-3, Chpca),
118.7 (Cquat, C-2, Chpca), 119.9, 120.0 (ϩ, Ar-C, Fm), 121.7 (Cquat
C-5, Chpca), 124.5, 124.6 (ϩ, Ar-C, Fm), 127.1, 127.2 (ϩ, Ar-C,
(d, J ϭ 7.5 Hz, 1 H, NH). It was impossible to obtain a 13C NMR
spectrum because 34 underwent complete decomposition during
the measurement. MS (EI, 70 eV), m/z (%) ϭ 319:317 (12:40) [Mϩ],
,
Fm), 127.9 (ϩ, Ar-C, Fm), 141.2, 141.3 (Cquat, Ar-C, Fm), 143.0, 283 (6), 144 (100), 130:128 (15:46) [C5H3ClNOϩ], 112 (6), 91:89
143.1 (Cquat, Ar-C, Fm), 158.0 (Cquat, C-1, Chpca), 171.1 [Cquat, C-
(4:12), 80 (18) [C5H6Nϩ], 64 (12), 45 (10) [CO2Hϩ]. HRMS (EI):
1, (3-Ncp)Ala]. MS (EI, 70 eV), m/z (%) ϭ 541:539 (1:2) [Mϩ], calcd. for C11H12ClN3O6: 317.0414; correct mass.
Eur. J. Org. Chem. 2004, 4492Ϫ4502
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4501

B. D. Zlatopolskiy, H.-P. Kroll, E. Melotto, A. de Meijere
FULL PAPER
buffer gave the acid 15 in lower yield and of lower purity than
Acknowledgments
[14b]
oxidation with Jones reagent.
Cf.: A. Barco, S. Benetti, G.
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB-416, Project A3) and the Fonds der Chemischen Industrie.
The authors are indebted to Dr. B. Knieriem (Göttingen) for his
careful proofreading of the final manuscript.
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[15] [15a]
The peak of the (2S,4S)-epimer of 15 was unobservable.
[15b]
The enantiomeric excess was determined according to the
Merfey method in the modification of Brückner (cf.: H.
Brückner, C. Keller-Hoehl, Chromatographia 1990, 30,
621Ϫ629; P. Marfey, Carlsberg Res. Communications 1984, 49,
591Ϫ596) for the corresponding (S)-FDVA derivative, obtained
after removal of the Boc group from 15).
B. Zlatopolskiy, K. Loscha, P. Alvermann, S. I. Kozhushkov,
S. V. Nikolaev, A. Zeeck, A. de Meijere, Chem. Eur. J. 2004,
10, 4708Ϫ4717. By mistakes, the formula of hormaomycin in
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trimethylpropyl)silyl]oxy}methyl]pyrrolidine-1-carboxylate was
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[13]
Use of potassium tert-butoxide leads to an increase of the Z-
selectivity of the Wittig olefination. Cf.: B.-Z. Zheng, H.
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[14] [14a]
Several other methods to oxidize the alcohol 14 can be
applied: PDC in DMF or in two steps: first Swern or
DessϪMartin oxidation and then oxidation of the intermediate
aldehyde with sodium chlorite in tert-butyl alcohol/phosphate
Received July 7, 2004
4502
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4492Ϫ4502