Synthesis of a tetradehydro-disorazole C1

Article abstract of DOI:10.1002/ejoc.200500675

The synthesis of a protected 9,9′,10,10′-tetradehydro- disorazole C₁ is described. A C1-C8 oxazole fragment with an E-vinylic iodide terminus is coupled to a suitable C9-C19 enyne. The resulting ω-hydroxycarboxylic acid is cyclodimerized stepwi

Full text of DOI:10.1002/ejoc.200500675

FULL PAPER
DOI: 10.1002/ejoc.200500675
Synthesis of a Tetradehydro-Disorazole C1
Barbara Niess,[a] Ingo V. Hartung,[b] Lars O. Haustedt,[c] and H. Martin R. Hoffmann*[a]
Dedicated to Professor Gerhard Höfle
Keywords: Disorazoles / Macrodiolides / 1,3-Oxazoles / Natural product synthesis
The synthesis of a protected 9,9Ј,10,10Ј-tetradehydro-disor-
azole C1 is described. A C1–C8 oxazole fragment with an E-
vinylic iodide terminus is coupled to a suitable C9–C19 en-
lactonization. In addition, simplified masked analogues of
disorazole C1 with truncated side chains are prepared.
yne. The resulting ω-hydroxycarboxylic acid is cyclodimer- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ized stepwise via intermolecular esterification, followed by
Germany, 2006)
human cancer cell lines such as A-549 (human lung carci-
noma) or A-498 (human kidney carcinoma).[2,3] Recently,
the biosynthetic gene cluster for the disorazoles was iden-
tified and sequenced.[4]
1. Introduction
The disorazoles comprise a class of 29 macrodiolides
which have been isolated from the fermentation broth of
the myxobacterium Sorangium cellulosum in 1994 by Höfle
The disorazoles are each built up from two hydroxy ac-
and his coworkers.[1] The main compound disorazole A1 as ids. Their complex structure is based on a polyolefinic poly-
well as several of the other isolated disorazoles show excep- ketide chain which is terminated by a masked amino acid
tionally promising biological activity inhibiting the prolifer- forming a 2,4-disubstituted oxazole. Disorazoles can also
ation of human cancer cell lines in subnanomolar concen- be regarded as a class of naturally occurring cyclophanes in
tration. Disorazoles A1 and E1 bind to tubulin, induce de- which the benzenoid moieties are replaced by oxazoles.[5]
polymerization of microtubules and thus arrest the cell cy- The main compound disorazole A1 is a non-symmetric
cle in G2/M phase. Disorazole A1 is up to 100 times more macrodiolide being built up from two distinct ω-hydroxy-
efficacious than epothilon B in its antiproliferative effect in carboxylic acids (Scheme 1). In contrast, the rare disorazole
Scheme 1. Cyclization strategy of disorazoles C1 and A1.
C1 is C2-symmetric corresponding to the dimerized
southern half of disorazole A1. To date no bioactivity data
are available for disorazole C1 due to its low natural abun-
dance.
In this final account on our synthetic efforts towards the
disorazoles[6] we report the synthesis of a disorazole C1 ana-
logue and the preparation of a simplified analogue without
the C17–C19, C17Ј–C19Ј side chains.[7]
[a] Department of Organic Chemistry, University of Hannover,
Schneiderberg 1b, 30167 Hannover
Fax: +49-511-7623011
E-mail: hoffmann@mbox.oci.uni-hannover.de
[b] Corporate Research, Research Center Europe, Medicinal
Chemistry IV, Schering AG,
13342 Berlin, Germany
[c] Analyticon Discovery GmbH,
Hermannswerder Haus 17, 14473 Potsdam, Germany
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Synthesis of a Tetradehydro-Disorazole C1
FULL PAPER
Our calculations suggested that the unwanted lactoni-
zation to the 15-membered ring should be efficiently sup-
pressed if the central C9–C10 Z-configured double bond
rather than the adjacent Z-double bond was masked as an
acetylene. The retrosynthesis of the masked segments of dis-
orazole C1 is depicted in Scheme 2.
In contrast to our first generation approach – disconnec-
tion between C10–C11 – we turned to a disconnection strat-
egy of this half between C8 and C9 affording Z-enyne 2
and E-configured vinyl iodide 3. This was due to problems
arising from construction of the C7–C8 double bond by a
Wittig reaction using triphenyl[1-(trimethylsilyl)propargyl]-
phosphonium bromide.[6c] During this reaction the double
bond could be built up at best in 49% yield and with only
low E/Z-selectivity.
2. Results and Discussion
The retrosynthetic analysis is similar to that previously
described for disorazole A1.[6c] Disconnection at the ester
linkages leads to a northern and a southern half which in
the case of disorazole C1 are identical. For the latter a direct
cyclodimerization was envisaged for constructing the
macrocycle.[8] Our strategy included protection of the labile
conjugated triene by masking one of the Z-double bonds
as an alkyne. The choice of the double bond to be protected
was thought to be critical. A competing lactonization reac-
tion which would lead to a 15-membered macrolactone was
undesirable and had to be suppressed. Additionally, the tri-
ple bond likely blocks a facile electrocyclization of the tri-
ene to a cyclohexadiene. Therefore, a molecular mechanics
calculation was performed providing the relative minimized
E-configured vinyl iodide 3 was prepared starting
energies of the two possible 15-membered macrolactones I from the previously reported alcohol 4[6c] which is
and II along with the two possible 30-membered macrodiol- accessible in eight steps from 2-(benzyloxy)acetaldehyde
ides III and IV (Figure 1).[6c]
(Scheme 3).
Figure 1. Minimized energies of 15-membered lactones I and II and 30-membered macrodiolides III and IV.
Scheme 2. Retrosynthesis of the southern segment of disorazoles C1 and A1.
Eur. J. Org. Chem. 2006, 1132–1143
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B. Niess, I. V. Hartung, L. O. Haustedt, H. M. R. Hoffmann,
FULL PAPER
Scheme 3. C1–C8 precursor. Reaction conditions: a) (ClCO)2,
Et3N, DMSO/CH2Cl2, –78 °C to –40 °C; then: A, K2CO3, MeOH,
0 °C to room temp., 75% starting from 4; b) nBu3SnH, Pd(PPh3)4,
THF, then I2, 88%, E-selective.
Oxidation of the alcohol 4 gave the corresponding alde-
hyde which was then transformed into the terminal alkyne
5 applying the Ohira–Bestmann reagent.[9] This two-step
transformation was best accomplished without intermediate
isolation of the unstable aldehyde.[10] Hence, the reaction
mixture of the Swern oxidation was directly added at
–40 °C to the Ohira–Bestmann reagent and K2CO3. The
latter had to be used in large excess to avoid deleterious
side reactions. This procedure made the oxazolyl-alkyne 5
accessible in reproducible 75% yield over two steps. Sub-
sequently, the alkyne was converted into the E-configured
vinyl iodide 3 by hydrostannylation/metal–iodine exchange
in very good E-selectivity and yield.[11] This procedure
proved to be superior compared to e. g. hydrozirconation.
The respective Z-enyne 2 was derived from the known Z-
configured vinyl iodide 6[6c] by 2C-elongation via Sonoga-
shira cross coupling reaction with (trimethylsilyl)acetylene
(Scheme 4).
Scheme 5. Fully resolved southern segment. Reaction conditions:
a) PdCl2(PPh3)2, CuI, Et3N, DMF, room temp., 77% 1, 89% 8; b)
1.1  LiOH, THF, room temp., quant.
In order to examine the direct cyclodimerization ap-
proach the methyl ester was saponified with aqueous lith-
ium hydroxide yielding the corresponding hydroxy acid 9
quantitatively. Various applied conditions to dimerize 9,
among them dipyridyl-thionocarbonat/DMAP,[12] trichlo-
robenzoyl chloride/DMAP[13] and 2-chloro-1-methylpyridi-
nium iodide/DMAP,[14] met with no success. It is worthy of
note that not in a single case was a 15-membered macrolac-
tone isolated. In one instance the corresponding monomer
ethyl ester was isolated, resulting from reaction with trace
amounts of ethanol in the reaction mixture. Although this
failure in inducing a direct dimerization called for a pro-
longed stepwise endgame, the absence of any 15-membered
macrolactone underscored our assumption that the central
triple bond blocks the undesired intramolecular cyclization.
Remarkably, under comparable reaction conditions using a
didehydro disorazole C1 hydroxy acid with the alkyne in the
C11–C12 position, Meyers et al. reported exclusive forma-
tion of the corresponding 15-membered macrolactone.[7a]
In an additional attempt to induce a direct dimerization
Scheme 4. C9–C19 fragment. Reaction conditions: a) 1. (trimethyl- we turned our attention briefly to a double Sonogashira
silyl)acetylene, PdCl2(PPh3)2, CuI, Et3N, CH3CN, room temp.,
endgame (Scheme 6). Firstly, the ester linkage between ox-
99%; 2. TBAF (1.1 equiv.), THF, 0 °C to room temp., 81%; b)
azole fragment 10 and a simplified C9–C16 fragment 11
TBAF (10.0 equiv.), THF, room temp., 95%.
was constructed, circumventing the macrolactonization
step. Unfortunately, cyclodimerization of this ester requir-
Deprotection of the terminal triple bond set the stage for ing a macrocyclization by means of two sp-sp2 couplings
the crucial coupling which was achieved under Sonogashira was not successful under the conditions applied.[15]
conditions giving a fully resolved southern fragment 1 in
In context with the cyclization studies we prepared an-
77% yield (Scheme 5). It turned out that the removal of the other simplified southern half without the C17–C19 side
C14-TBS group in the dieneyne segment 1 proved to be chains. The required enyne fragment was obtained starting
difficult (see below). For this reason deprotection of the from homoallyl alcohol 14 (Scheme 7).
TBS ether had to be achieved before cross coupling so that
TES protection and subsequent oxidative cleavage of the
the simple C14-unprotected C9–C19 hydroxy fragment 7 double bond by ozonolysis afforded aldehyde 15. This was
was entered into the Sonogashira reaction. The yield of the transformed to the corresponding Z-configured vinyl iodide
dienyne segment 8 was thus even improved to 89%.
with IPh3PCH2I applying the Stork–Zhao olefination.[16]
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Synthesis of a Tetradehydro-Disorazole C1
FULL PAPER
Scheme 7. Simplified C9–C16 fragment. Reaction conditions: a)
(+)–Ipc2BOMe, allylmagnesium bromide, Et2O, –98 °C, 79%, 89%
ee; b) 1. TESOTf, 2,6-lutidine, DCM, 0 °C to room temp., 84%; 2.
O3, PPh3, CH2Cl2, –78 °C to room temp., 85%; c) 1. IPh3PCH2I,
NaHMDS, HMPA, THF, –78 °C to room temp., 72%, Z/E Ͼ10:1;
2. CHϵCMgBr, Pd(PPh3)4, THF, room temp., 95%; d) TBAF,
THF, 0 °C to room temp., 79%; e) PdCl2(PPh3)2, CuI, 3, Et3N,
DMF, room temp., 67% 18, 81% 19; f) 1  LiOH, THF, room
temp., quant. Ipc = Isopinocampheyl.
Scheme 6. Alternative cyclodimerization attempt. Reaction condi-
tions: a) LiOH, THF, H2O, room temp., quant.; b) 2-chloro-1-
methylpyridinium iodide, Et3N, DMAP, toluene, 80 °C, 58 %.
Negishi coupling with ethynylmagnesium bromide pro- these fragments 19 and 20 were submitted to a variety of
ceeded with retention of the double bond geometry yielding esterification conditions giving the open dimer 21 in at best
the free terminal alkyne 16 directly.[17] Finally, Sonogashira 34% yield applying Yamaguchi’s conditions (Scheme 8).
coupling with 3 under our standard conditions afforded the
Removal of the triethylsilyl group in 21 with buffered
simplified southern segment 18. Once again, Sonogashira TBAF and chemoselective saponification of the methyl es-
coupling of the C14-unprotected enyne 17 was slightly ter with barium hydroxide in the presence of the internal
higher yielding to give hydroxy ester 19.
ester linkage[18] led to the dimeric hydroxy acid which under
Treatment of 18 with aqueous lithium hydroxide in THF Yamaguchi conditions was macrocyclized to 22 in 35%
provided free oxazolecarboxylic acid 20. In model studies, yield. The macrocycle thus synthesized serves not only as a
Scheme 8. Cyclisation to the simplified analogue. Reaction conditions: a) Cl3C6H2COCl, Et3N, DMAP, toluene, room temp., 8 h, 34%;
b) 1. TBAF, AcOH/ H2O (1:1), THF, room temp., 86%; 2. Ba(OH)2, H2O, MeOH, THF, room temp., quant.; 3. Cl3C6H2COCl, Et3N,
DMAP, toluene, room temp., 35%.
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B. Niess, I. V. Hartung, L. O. Haustedt, H. M. R. Hoffmann,
FULL PAPER
Scheme 9. Synthesis of a disorazole C1 analogue. Reaction conditions: a) 1  LiOH, THF, room temp., quant.; b) For 24: DPTC, DMAP,
toluene, reflux, 45%; for 25: 25, Cl3C6H2COCl, Et3N, toluene, room temp.; 8, DMAP, toluene, 40 °C, 69 %; c) 1. 27, TBAF, AcOH, H2O,
THF, room temp., 87%; no reaction for 26; 2. Ba(OH)2, H2O, MeOH, THF, room temp., quant.; 3. Cl3C6H2COCl, Et3N, DMAP, toluene,
40 °C, 31 %.
Scheme 10. Protecting group manipulation. Reaction conditions: a) TESOTf, 2,6-lutidine, DMAP, CH2Cl2, –40 °C to –20 °C, 85 %; b)
1  LiOH, THF, room temp., quant.
model for our cyclization studies but also provides an entry
into SAR studies.
The TES-protected derivative 25 and alcohol 8 were es-
terified with greatly improved efficiency by portionwise ac-
We next turned our attention to effecting the stepwise tivation of the acid yielding 27 in 69% isolated yield
dimerization of the full C1–C19 system. A TBS-protected (Scheme 9). The triethylsilyl ether in 27 could then be
dimer 26 was prepared starting from alcohol 8 and carbox- cleaved with buffered TBAF delivering the corresponding
ylic acid 24 in 45% yield applying DPTC/DMAP[7a] alcohol in respectable 87% yield.
(Scheme 9).
Selective saponification of the terminal methyl ester in
In the subsequent deprotection step we encountered diffi- the presence of the internal ester linkage was again quanti-
culties removing the TBS group. Either the substrate de- tatively achieved with aqueous barium hydroxide in THF/
composed or it did not react at all what brought us to MeOH. Finally, the dimeric seco acid was submitted to Ya-
change the TBS ether to the more labile TES ether maguchi lactonization giving the macrodiolide 28 in 31%
(Scheme 10).
yield. As shown by Wipf and Graham the tetradehydro ana-
From this methyl ester 23 the oxazole carboxylic acid logue can be efficiently transformed to disorazole C1 under
25 was liberated with a lithium hydroxide solution in THF Lindlar conditions.[7c]
(Scheme 10). The crude acid was then submitted to esterifi-
cation conditions. Simple activation of the acid with trichlo-
robenzoyl chloride/Et3N followed by slow addition to the
C14 alcohol 8 furnished the ester 27 in only 35% yield.
3. Conclusion
Generally, under various conditions some of the starting
Our flexible and modular strategy allows the synthesis of
alcohol 8 could be reisolated but no acid, implying that the six different disorazole hydroxy acid precursors[6] and the
activated acid decomposes significantly before being able to completion of the synthesis of the disorazole C1 macrocycle.
react.
The threefold role of the C9–C10 triple bond is noteworthy:
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Synthesis of a Tetradehydro-Disorazole C1
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H, H-6), 3.91 (s, 3 H, CO2CH3), 3.41 (s, 3 H, OCH3), 3.28 (dd, J
= 15.2, 7.8 Hz, 1 H, Ha-5), 3.21 (dd, J = 15.2, 6.2 Hz, 1 H, Hb-5),
2.49 (d, J = 2.1 Hz, 1 H, H-8). 13C NMR: (100 MHz, CDCl3): δ =
160.87, 160.86 (Cq, C-4, C-1), 143.39 (CH, C-3), 132.74 (Cq, C-2),
79.72 (CH, C-6), 74.45 (Cq, C-7), 67.58 (CH, C-8), 55.90 (CH3,
OCH3), 51.38 (CH3, CO2CH3), 34.09 (CH2, C-5). MS (room
temp.): m/z (%) = 209 (3, [M+]), 208 (6, [M+ – 1]), 194 (46), 178
(38), 166 (37), 146 (10), 69 (100). HR-MS: m/z calcd. for
C10H10NO4: 208.0610, found: 208.0613.
Firstly, a rigid structural element is introduced thus sup-
pressing any unproductive intramolecular cyclizations. The
appropriate positioning (C9–C10 vs. C11–C12) was guided
by molecular mechanics. Secondly, its presence provides us
with a retrosynthetic handle allowing for a convergent Son-
ogashira cross coupling. Finally, it causes an obvious stabi-
lizing effect on the monomeric ω-hydroxy acids by blocking
electrocyclizations. Late stage diversification is feasible and
our modular retrosynthetic design offers the opportunity
for an entry into SAR studies.
The disorazoles – especially the non-C2-symmetric mem-
bers – remain a prime target for synthetic organic chemists.
Besides posing a significant synthetic challenge, the non-
symmetric macrodiolide skeleton of disorazole A1 reminds
us of the rather unexplored biosynthetic origin of such
(E)-Oxazolyl-vinyl Iodide 3: The (1,3-oxazolyl)alkyne 5 (120 mg,
0.574 mmol, 1.0 equiv.) and Pd(PPh3)4 (3 mg, 0.002 mmol,
0.004 equiv.) were dissolved in THF (5.7 mL) and treated with
Bu3SnH (0.19 mL, 0.69 mmol, 1.2 equiv.) at room temp. After 2 h
the reaction mixture was cooled to –20 °C and I2 (204 mg,
0.804 mmol, 1.4 equiv.) in THF (5 mL) was added dropwise to the
reaction mixture keeping the temperature between –20 °C and
structural features, which add an additional level of com- –15 °C. The resulting mixture was warmed to room temperature.
After 1 h the mixture was treated with satd. KF solution. The aque-
ous phase was extracted with MTBE and the combined organic
layers were washed with satd. Na2S2O3 solution. This was re-ex-
tracted with MTBE and the combined organic layers were dried
(Na2SO4). The solvent was evaporated and the residue was purified
by chromatography furnishing 3 (170 mg, 88%) as colorless wax.
plexity to the structural space present in polyketide natural
products.
Experimental Section
[α]2D0 = –9.1 (c = 1.59, CHCl ). IR (neat): ν = 2931, 2825, 1734,
Infrared spectra were recorded on a Perkin–Elmer 1710 infrared
spectrometer. 1H NMR and 13C NMR spectra were recorded on
Bruker AVS 400 and Bruker AVM 500 spectrometer in deuterated
chloroform or acetone with tetramethylsilane as internal standard
˜
3
1583, 1436, 1343, 1314, 1206, 1136, 1096, 1004, 1004, 936, 806,
769 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1 H, H-3),
6.48–6.40 (m, 2 H, H-7, H-8), 4.09 (dtd, J = 7.7, 6.0, 0.7 Hz, 1 H,
H-6), 3.89 (s, 3 H, CO2CH3), 3.26 (s, 3 H, OCH3), 3.07 (dd, J =
15.1, 7.7 Hz, 1 H, Ha-5), 2.98 (dd, J = 15.1, 5.8 Hz, 1 H, Hb-5).
13C NMR (100 MHz, CDCl3): 162.01, 161.53 (Cq, C-4, C-1),
144.34, 143.97 (CH, C-7, C-3), 133.36 (Cq, C-2), 81.09 (CH, C-8),
80.07 (CH, C-6), 56.84 (CH3, OCH3), 52.08 (CH3, CO2CH3), 33.89
(CH2, C-5). MS (70 °C): m/z (%) = 337 (5, [M+]), 306 (37), 210
(46), 197 (100), 178 (36), 159 (3), 141 (41), 109 (5), 71 (35). HR-
MS: m/z calcd. for C10H12NO4I: 336.9811, found: 336.9810.
1
when indicated. H NMR chemical shifts are reported in parts per
million (ppm) downfield from tetramethylsilane (δ = 0 ppm) as in-
ternal standard or in relation to CDCl3 (δ = 7.26 ppm). The follow-
ing abbreviations are used to describe spin multiplicity: s = singlet,
br. s = broad singlet, d = doublet, t = triplet, q = quadruplet, m =
multiplet, dd = doublet of doublets, etc. Coupling constants (J) are
reported in Hertz (Hz). 13C NMR spectra were fully decoupled
with chemical shifts reported relative to the solvent signal (CDCl3,
77.0 ppm). Signal assignments are based on DEPT and – if neces-
1
sary – on additional H-1H-COSY and HMQC experiments. The
TBS-Protected Enyne 2: PdCl2(PPh3)2 (137 mg, 0.195 mmol,
0.1 equiv.) and CuI (74 mg, 0.39 mmol, 0.2 equiv.) were dissolved
in CH3CN (15 mL) and stirred for 20 min at room temp. To this
vinyl iodide 6 (1.083 g, 1.95 mmol, 1.0 equiv.) in CH3CN (5 mL),
TMS-acetylene (0.55 mL, 3.90 mmol, 2.0 equiv.) and, after 20 min,
Et3N (5.44 mL, 39.0 mmol, 20.0 equiv.) were added successively.
After 5 h at room temp. the reaction mixture was hydrolyzed with
satd. NH4Cl solution. The aqueous phase was extracted with
MTBE, the organic phases were dried (Na2SO4) and the solvent
was evaporated. Flash chromatography afforded TMS-protected al-
kyne (1011.7 mg, 99%).
numbering of carbon and hydrogen signals refers to the numbering
of the natural product. Mass spectra were performed on a Finnigan
MAT 312 (70 eV), a VG Autospec (HR-MS) spectrometer or with
a Micromass LCT with lock-spray unit (ESI-MS).
Oxazolyl-alkyne 5: Oxalyl chloride (0.30 mL, 3.49 mmol,
1.5 equiv.) and DMSO (0.50 mL, 6.98 mmol, 3.0 equiv.) in CH2Cl2
(6 mL) were cooled to –78 °C, stirred for 10 min and afterwards
oxazole alcohol 4 (500 mg, 2.33 mmol, 1.0 equiv.) in CH2Cl2
(3.0 mL) was added. After 30 min Et3N (1.29 mL, 9.30 mmol,
4.0 equiv.) was added. The reaction mixture was stirred for 3 h at
–78 °C while its progress was monitored by GC. After complete oxi-
dation, Ohira–Bestmann reagent (893 mg, 4.65 mmol, 2.0 equiv.)
was dissolved in MeOH (5 mL) in a separate flask and treated at
0 °C with K2CO3 (1.93 g, 13.95 mmol, 6.0 equiv.). This suspension
was stirred for 10 min and then the chilled reaction mixture
(–40 °C) of the Swern oxidation was transferred to this flask using
MeOH (3 mL) for rinse. The mixture was allowed to reach room
temperature and after 18 h satd. NH4Cl solution was added and
the aqueous layer was extracted with MTBE. The combined or-
ganic layers were dried (Na2SO4) and the solvent was evaporated.
Purification of the crude product by flash chromatography afforded
alkyne 5 (364 mg, 75% over two steps) as colorless, viscous oil.
[α]2D0 = +21.4 (c = 0.87, CHCl ). IR (neat): ν = ν = 3248, 3117,
This TMS-protected enyne (1.0 g, 1.9 mmol, 1.0 equiv.) in THF
(20 mL) was treated with TBAF (2.1 mL, 1  solution in THF,
2.1 mmol, 1.1 equiv.) at 0 °C and was afterwards allowed to reach
room temp. After 4 h at room temp. the reaction mixture was hy-
drolyzed with H2O and the aqueous phase was extracted with
MTBE. The combined organic layers were dried (Na2SO4) and the
crude product was purified by flash chromatography to give 2
(14.0 mg, 81%) as colorless oil together with 89 mg of 7 (14%). [α]
20
= +35.0 (c = 1.16, CHCl ). IR (neat): ν = 3313, 2953, 2928,
˜
D
3
2884, 2856, 2099, 1668, 1614, 1471, 1379, 1361, 1249, 1189, 1146,
1080, 1029, 973, 936, 858, 831, 772, 693, 668, 636, 604 cm–1. 1H
NMR (400 MHz, CDCl3, TMS): δ = 6.17 (dtd, J = 11.0, 7.0,
0.7 Hz, 1 H, H-12), 5.67 (dq, J = 15.3, 6.5 Hz, 1 H, H-18), 5.47
(dq [= ddd], J = 10.9, 1.76 Hz, 1 H, H-11), 5.35 (ddq, J = 15.3,
9.1, 1.7 Hz, 1 H, H-17), 4.56–4.70 (m, 2 H, OCH2OSEM), 3.87 (d,
˜
˜
3
2995, 2935, 2112, 1719, 1583, 1453, 1435, 1323, 1272, 1200, 1163,
1097, 1060, 995, 928, 850, 811, 775 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.17 (s, 1 H, H-3), 4.49 (ddd, J = 7.8, 6.2, 2.1 Hz, 1
J
=
9.2 Hz,
1
H, H-16), 3.65–3.76 (m,
2
H, H-14, Ha-
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B. Niess, I. V. Hartung, L. O. Haustedt, H. M. R. Hoffmann,
OCH2CH2TMS), 3.48–3.56 (m, 1 H, Hb-OCH2CH2TMS), 3.12 satd. NH4Cl solution. The aqueous layer was extracted with
FULL PAPER
(dd, J = 1.7, 0.7 Hz, 1 H, H-9), 2.56–2.60 (m, 2 H, H-13), 1.75 (dd,
J = 6.5, 1.6 Hz, 3 H, H-19), 0.90–0.94 (m, 2 H, OCH2CH2TMS),
0.94 (s, 3 H, Me), 0.93 [s, 9 H, SiC(CH3)3] 0.87 (s, 3 H, MeЈ), 0.07
MTBE, the combined organic layers were dried (Na2SO4) and the
solvent was evaporated. Purification by chromatography yielded
the Z-configured vinyl iodide (544 mg, 72%) as colorless oil. This
(s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3Ј), 0.03 [s, 9 H, Si(CH3)3,SEM]. vinyl iodide (507 mg, 1.01 mmol, 1.0 equiv.) in THF (5 mL) was
13C NMR (100 MHz, CDCl3, TMS): 144.44 (CH, C-12), 130.85
added to Pd(PPh3)4 (58 mg, 0.05 mol, 0.05 equiv.). Ethynylmagne-
(CH, C-18), 127.89 (CH, C-17), 108.28 (CH, C-11), 91.75 (CH2, sium bromide (3 mL, 0.5  solution in THF, 1.51 mmol, 1.5 equiv.)
OCH2OSEM), 81.69 (Cq, C-10), 81.43 (CH, C-16), 80.79 (CH, C- was dropped slowly into this mixture. After 2 h at room temp. the
9), 75.79 (CH, C-14), 65.05 (CH2, OCH2CH2TMS), 43.26 (Cq, C-
reaction mixture was diluted with MTBE and hydrolyzed with satd.
15), 34.34 (CH2, C-13), 26.11 [CH3, SiC(CH3)3], 20.17 (CH3, Me), NH4Cl solution. The aqueous layer was extracted with MTBE and
19.50 (CH3, MeЈ), 18.35 [Cq, SiC(CH3)3], 18.12 (CH2, the combined organic phases were dried (Na2SO4). After removal
OCH2CH2TMS), 17.86 (CH3, C-19), –1.44 [CH3, Si(CH3)3], –3.43 of the solvents the residue was purified by flash chromatography
(CH3, SiCH3,TBS), –4.26 (CH3, SiCH3,TBS). MS (110 °C): m/z (%) and enyne 16 (393 mg, 95%) was obtained as colorless oil. [α]2D0
=
= 452 (1, [M+]), 395 (2), 394 (1), 388 (2), 387 (3), 367 (3), 365 (2),
357 (3), 337 (4), 319 (18), 318 (29), 317 (42), 289 (11), 271 (28), 270
(20), 269 (33), 251 (29), 242 (19), 241 (33), 233 (28), 209 (99), 201
–6.1 (c = 0.79, CHCl ). IR (neat): ν = 3292, 2954, 2875, 2097, 1612,
˜
3
1512, 1463, 1434, 1415, 1359, 1301, 1245, 1172, 1085, 1036, 1007,
1
821, 739 cm–1. H NMR (400 MHz, CDCl3, TMS): δ = 7.24 (d, J
(41), 147 (56), 143 (99), 73 (100). HR-MS: m/z calcd. for = 8.7 Hz, 2 H, PMB), 6.86 (d, J = 8.7 Hz, 2 H, PMB), 6.15 (dt, J
C21H39O3Si2: 395.2438 (M+ – tBu), found: 395.2438.
= 10.9, 7.2 Hz, 1 H, H-12), 5.46 (dd, J = 10.9, 1.8 Hz, 1 H, H-11),
4.43 (d, J = 11.8 Hz, 1 H, Ha-PMPCH2), 4.37 (d, J = 11.8 Hz, 1
H, Hb-PMPCH2), 3.80 (s, 3 H, CH3OPh), 3.79 (dd, J = 6.4, 4.6 Hz,
1 H, H-14), 3.24 (d, J = 8.6 Hz, 1 H, Ha-16), 3.12 (d, J = 8.6 Hz,
1 H, Hb-16), 3.07 (d, J = 1.8 Hz, 1 H, H-9), 2.58 (dddd, J = 15.3,
6.7, 4.7, 1.9 Hz, 1 H, Ha-13), 2.47 (dddd, J = 15.3, 7.6, 6.5, 1.2, 1
H, Hb-13), 0.94 [t, J = 7.9 Hz, 9 H, Si(CH2CH3)3], 0.90 (s, 3 H,
Me), 0.88 (s, 3 H, MeЈ), 0.58 [q, J = 7.9 Hz, 6 H, Si(CH2CH3)3].
13C NMR (100 MHz, CDCl3, TMS): δ = 158.97 (Cq, COCH3,PMB),
144.53 (CH, C-12), 131.06 (Cq, CCH2,PMB), 128.95 (CH, PMB),
113.63 (CH, PMB), 108.45 (CH, C-11), 81.63 (CH, C-9), 80.67 (Cq,
C-10), 77.03 (CH2, C-16), 75.82 (CH, C-14), 72.80 (CH2,
PMPCH2), 55.24 (CH3, CH3OPh), 40.21 (Cq, C-15), 34.32 (CH2,
C-13), 21.46 (CH3, Me), 20.99 (CH3, MeЈ), 7.06 [CH3, Si-
(CH2CH3)3], 5.39 [CH2, Si(CH2CH3)3].
PMB-Protected Aldehyde 15: Homoallyl alcohol 14 (690 mg,
2.61 mmol, 1.0 equiv.) in CH2Cl2 (5.3 mL) was cooled to 0 °C, 2,6-
lutidine (0.61 mL, 5.23 mmol, 2.0 equiv.) was added, followed by
the dropwise addition of TESOTf (0.71 mL, 3.14 mmol, 1.2 equiv.).
After 30 min at 0 °C and 4 h at room temp. the reaction mixture
was hydrolyzed with satd. NaHCO3 solution. The aqueous layer
was extracted with MTBE, the combined organic layers were dried
(Na2SO4) and the solvents were removed. The crude product was
purified by flash chromatography furnishing the TES-protected
alcohol (825 mg, 84%) as a colorless oil. This alcohol (800 mg,
2.12 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (15 mL), cooled
to –78 °C and a drop of Sudan red was added. O3 was bubbled
through this solution until the indicator turned colorless. For ad-
ditional few minutes oxygen was passed through the mixture. Fi-
nally, PPh3 (998 mg, 3.81 mmol, 1.8 equiv.) was added and the reac-
tion mixture was warmed to room temp. After 2 h the solvent was
removed and the residue was purified by flash chromatography af-
fording aldehyde 15 (649 mg, 85%) as colorless oil. [α]2D0 = –3.7 (c
PMB-Protected Hydroxy Enyne 17: TES-protected enyne 16
(195 mg, 0.49 mmol, 1.0 equiv.) was dissolved in THF (2 mL) and
treated with concd. AcOH (0.1 mL), H2O (0.1 mL) and
TBAF·H2O (723 mg, 2.45 mmol, 5.0 equiv.). After 2 d at room
temp. the reaction mixture was diluted with MTBE and H2O. The
aqueous layer was extracted with MTBE and the combined organic
layers were dried (Na2SO4). The solvent was evaporated and the
crude residue was purified by flash chromatography furnishing
alcohol 17 (111 mg, 79%) as colorless oil. [α]2D0 = –42.5 (c = 1.10,
= 1.14, CHCl ). IR (neat): ν = 2955, 2875, 1725, 1612, 1513, 1462,
˜
3
1414, 1361, 1301, 1245, 1172, 1085, 1005, 820, 725 cm–1. H NMR
1
(400 MHz, CDCl3, TMS): δ = 9.52 (dd, J = 2.8, 1.9 Hz, 1 H, H-
12), 7.98 (d, J = 8.6 Hz, 2 H, PMB), 6.63 (d, J = 8.6 Hz, 2 H,
PMB), 4.16 (d, J = 11.7 Hz, 1 H, Ha-PMPCH2), 4.08 (d, J =
11.7 Hz, 1 H, Hb-PMPCH2), 3.99 (dd, J = 6.2, 4.9 Hz, 1 H, H-14)
CHCl ). IR (neat): ν = 3469, 3288, 2958, 2860, 2095, 1612, 1512,
˜
3
3.56 (s, 3 H, CH3OPh), 2.95 (d, J = 8.8 Hz, 1 H, Ha-16), 2.87 (d, 1465, 1418, 1360, 1301, 1245, 1173, 1076, 1033, 819, 736 cm–1. H
1
J = 8.8 Hz, 1 H, Hb-16), 2.38 (ddd, J = 16.6, 4.9, 1.8 Hz, 1 H, Ha-
13), 2.23 (ddd, J = 16.5, 6.1, 2.8, 1 H, Hb-13), 0.69 [t, J = 7.8 Hz, PMB), 6.87 (d, J = 8.7 Hz, 2 H, PMB), 6.23 (dtd, J = 10.9, 7.5,
9 H, Si(CH2CH3)3], 0.66 (s, 3 H, Me), 0.61 (s, 3 H, MeЈ), 0.34 [q, 0.5 Hz, 1 H, H-12), 5.54 (ddd, J = 10.9, 3.7, 1.6 Hz, 1 H, H-11),
J = 7.8 Hz, 6 H, Si(CH2CH3)3]. 13C NMR (100 MHz, CDCl3, 4.44 (s, 2 H, PMPCH2), 3.80 (s, 3 H, CH3OPh), 3.53 (dt, J = 10.0,
TMS): δ = 202.22 (CH, C-12), 159.04 (Cq, COCH3,PMB), 130.62 3.1 Hz, 1 H, H-14), 3.38 (d, J = 8.9 Hz, 1 H, Ha-16), 3.36–3.33 (m,
(Cq, CCH2,PMB), 129.05 (CH, PMB), 113.65 (CH, PMB), 76.26 1 H, OH), 3.28 (d, J = 8.6 Hz, 1 H, Hb-16), 3.08 (d, J = 1.9 Hz, 1
(CH2, C-16), 72.71 (CH2, PMPCH2), 71.69 (CH, C-14), 55.23 H, H-9), 2.58 (dddd, J = 14.5, 7.5, 2.5, 1.7 Hz, 1 H, Ha-13), 2.33
(CH3, CH3OPh), 48.04 (CH2, C-13), 39.76 (Cq, C-15), 21.35 (CH3, (dddd, J = 14.5, 10.1, 7.0, 1.4, 1 H, Hb-13), 0.94 (s, 6 H, Me, MeЈ).
Me), 21.02 (CH3, MeЈ), 6.95 [CH3, Si(CH2CH3)3], 5.18 [CH2,
13C NMR (100 MHz, CDCl3, TMS): δ = 159.31 (Cq, COCH3,PMB),
Si(CH2CH3)3]. ESI-MS: m/z calcd. for C21H36NaO4Si: 403.2281, 144.05 (CH, C-12), 129.90 (Cq, CCH2,PMB), 129.21 (CH, PMB),
NMR (400 MHz, CDCl3, TMS): δ = 7.23 (d, J = 8.5 Hz, 2 H,
found: 403.2279.
113.82 (CH, PMB), 109.15 (CH, C-11), 81.53 (Cq, C-10), 80.58
(CH, C-9), 79.50 (CH2, C-16), 78.29 (CH, C-14), 73.32 (CH2,
PMPCH2), 55.27 (CH3, CH3OPh), 38.44 (Cq, C-15), 33.14 (CH2,
C-13), 22.85 (CH3, Me), 19.73 (CH3, MeЈ). ESI-MS: m/z calcd. for
C18H24NaO3: 311.1623, found: 311.1616.
PMB-Protected Enyne 16: Freshly prepared IPPh3CH2I[16] (1.27 g,
2.4 mmol, 1.6 equiv.) was suspended in THF (5 mL) and NaHMDS
(1.2 mL, 2  solution in THF, 2.4 mmol, 1.6 equiv.) was added
dropwise at room temp. until a clear, orange-red solution was
formed. After 10 min at room temp. HMPA (45 µL) was added and
the reaction mixture was cooled to –78 °C. Afterwards, aldehyde
15 (570 mg, 1.5 mmol, 1.0 equiv.) in THF (4 mL) was added slowly
and the mixture was stirred for additional 30 min at –78 °C. After
warming to room temp. the reaction mixture was hydrolyzed with
General Procedure for the Sonogashira Coupling: PdCl2(PPh3)2 and
CuI were dissolved in degassed DMF in an atmosphere of Ar and
stirred for 10 min. The vinyl iodide in degassed DMF and Et3N
were added and the mixture is stirred for additional 10 min at room
temp. Finally, the enyne compound in DMF was added and the
1138
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1132–1143

Synthesis of a Tetradehydro-Disorazole C1
FULL PAPER
reaction mixture was stirred at room temp. until completion was
indicated by TLC. The mixture was hydrolyzed with satd. NH4Cl
solution. The aqueous phase was extracted with MTBE and the
combined organic layers were dried (Na2SO4). After evaporation
of the solvent the residue was purified by flash chromatography.
128.94 (CH, PMB), 113.80 (CH, C-8), 113.65 (CH, PMB), 109.25
(CH, C-11), 91.17, 88.30 (Cq, C-9, C-10), 79.25 (CH, C-6), 77.04
(CH2, C-16), 75.94 (CH, C-14), 72.82 (CH2, PMPCH2), 56.80
(CH3, CHOCH3), 55.26 (CH3, CH3OPh), 52.10 (CH3, CO2CH3),
40.27 (Cq, C-15), 34.58, 34.53 (CH2, C-5, C-13), 21.62 (CH3, CH3),
20.90 (CH3, CH3Ј), 7.10 [CH3, Si(CH2CH3)3], 5.40 [CH2,
Si(CH2CH3)3]. ESI-MS: m/z calcd. for C34H49NNaO7Si: 634.3176,
found: 634.3184.
PMB-Protected (7E,11Z)-Hydroxydienyne 19: Following the gene-
ral procedure for the Sonogashira coupling vinyl iodide 3 (130 mg,
0.385 mmol, 1.0 equiv.) and enyne 17 (111 mg, 0.385 mmol,
1.0 equiv.) in DMF (1.2 mL each) were allowed to react in the pres-
ence of PdCl2(PPh)2 (14 mg, 0.019 mmol, 0.05 equiv.) and CuI
(7 mg, 0.039 mmol, 0.1 equiv.) in DMF (1.2 mL) and Et3N
(1.0 mL). The reaction was complete after 5 h at room temp. After
general workup hydroxy-dienyne 19 (156 mg, 81%) was obtained
General Procedure for Saponification of the Methyl Ester: The
methyl ester was dissolved in THF and slowly treated with a LiOH
solution (1  in H2O) at room temp. The mixture was stirred until
completion of the reaction and afterwards adjusted to a pH value
of 2–3 with 1  HCl. After addition of MTBE and separation of
phases the aqueous phase was extracted with MTBE (6×). The
combined organic layers were dried (Na2SO4) and the solvent was
as colorless oil. [α]2D0 = –43.3 (c = 1.14, CHCl ). IR (neat): ν =
˜
3
3469, 2931, 2851, 1743, 1612, 1584, 1513, 1463, 1438, 1344, 1322,
1302, 1246, 1199, 1171, 1139, 1097, 1033, 1004, 956, 807, 762 cm–1. evaporated. The crude acid was generally used directly in the next
1H NMR (400 MHz, CDCl3, TMS): δ = 8.16 (s, 1 H, H-3), 7.23 step without further purification.
(d, J = 8.5 Hz, 2 H, PMB), 6.87 (d, J = 8.7 Hz, 2 H, PMB), 6.18
TES-Protected Dimer 21: Following the general saponification pro-
(dt, J = 10.8, 7.3 Hz, 1 H, H-12), 5.96 (dd, J = 15.8, 7.3 Hz, 1 H,
cedure methyl ester 18 (81 mg, 0.133 mmol, 1.0 equiv.) in THF
H-7), 5.86 (dd, J = 15.8, 2.1 Hz, 1 H, H-8), 5.66 (dd, J = 10.8,
(1.3 mL) was treated with LiOH (0.27 mL, 1  solution in H2O,
1.8 Hz, 1 H, H-11), 4.44 (s, 2 H, PMPCH2), 4.19–4.14 (m, 1 H, H-
0.265 mmol, 2.0 equiv.). The mixture was stirred for 4 h at room
temp. The crude acid was dissolved in toluene (1 mL) and to this
solution was added 2,4,6-trichlorobenzoyl chloride (72 mg,
0.296 mmol) and Et3N (33 mg, 0.327 mmol) in toluene (1.5 mL).
6), 3.90 (s, 3 H, CO2CH3), 3.80 (s, 3 H, CH3OPh), 3.54 (dd, J =
10.0, 2.5 Hz, 1 H, H-14), 3.38 (d, J = 8.9 Hz, 1 H, Ha-16), 3.36–
3.33 (m, 1 H, OH), 3.31 (d, J = 8.9 Hz,1 H, Hb-16), 3.26 (s, 3 H,
CHOCH3), 3.10 (dd, J = 15.1, 7.8 Hz, 1 H, Ha-5), 2.99 (dd, J =
After 45 min at room temp. the activated acid was added at room
15.1, 5.6, 1 H, Hb-5), 2.56 (dddd, J = 14.5, 7.5, 2.6, 1.6 Hz, 1 H,
temp. to a solution of 17 (68 mg, 0.137 mmol, 1.03 equiv.) and
Ha-13), 2.31 (dddd, J = 14.4, 10.1, 7.0, 1.3, 1 H, Hb-13), 0.95 (s, 3
DMAP (49 mg, 0.398 mmol, 3.0 equiv.) in toluene (1 mL) over a
period of 70 min. After the addition was complete the reaction mix-
ture was stirred for another 5 hours. The mixture was hydrolyzed
with satd. NaHCO3 solution and diluted with MTBE. The aqueous
H, Me), 0.94 (s, 3 H, MeЈ). 13C NMR (100 MHz, CDCl3, TMS): δ
= 162.36, 161.57 (Cq, C-1, C-4), 159.24 (Cq, COCH3,PMB), 143.92
(CH, C-3), 142.61 (CH, C-12), 140.15 (CH, C-7), 133.31 (Cq, C-2),
129.81 (Cq, CCH2,PMB), 129.11 (CH, PMB), 113.80 (CH, PMB),
phase was extracted with MTBE and the organic phases were dried
113.70 (CH, C-8), 109.15 (CH, C-11), 90.99, 88.06 (Cq, C-9, C-10),
(Na2SO4). The solvent was removed and the crude product was
79.45 (CH2, C-16), 79.15 (CH, C-6), 78.29 (CH, C-14), 73.24 (CH2,
purified by flash chromatography yielding dimer 21 (50 mg, 34%)
PMPCH2), 56.74 (CH3, CHOCH3), 55.20 (CH3, CH3OPh), 52.03
(CH3, CO2CH3), 38.43 (Cq, C-15), 34.49 (CH2, C-5), 33.18 (CH2,
C-13), 22.77 (CH3, Me), 19.60 (CH3, MeЈ). ESI-MS: m/z calcd. for
C28H35NNaO7: 520.2311, found: 520.2306.
as colorless oil, together with 25 mg of a mixture consisting of
alcohol and dimer. [α]2D0 = +13.8 (c = 1.49, CHCl ). IR (neat): ν =
˜
3
2954, 2875, 1740, 1612, 1584, 1513, 1463, 1440, 1357, 1318, 1246,
1200, 1170, 1137, 1095, 1034, 1005, 956, 821, 760, 736 cm–1. 1H
NMR (400 MHz, CDCl3, TMS): δ = 8.17, 7.99 (s, 2 H, H-3, H-
3Ј), 7.25–7.22 (m, 4 H, PMB), 6.88–6.83 (m, 4 H, PMB), 6.09 (dt,
J = 10.6, 7.2 Hz, 1 H, H-12OTES), 5.98 (dd, J = 15.9, 7.2 Hz, 1 H,
H-7/H-7Ј), 5.97 (dd, J = 15.9, 7.3 Hz, 1 H, H-7/H-7Ј), 5.99–5.96
PMB,TES-Protected (7E,11Z)-Dienyne 18: Following the general
procedure for the Sonogashira coupling, the oxazolyl-vinyl iodide
3 (152 mg, 0.452 mmol, 1.05 equiv.) and the enyne 16 (173 mg,
0.430 mmol, 1.0 equiv.) in DMF (1.5 mL each) were allowed to re-
act in the presence of PdCl2(PPh)2 (15 mg, 0.022 mmol, 0.05 equiv.) (m, 1 H, H-12ester), 5.88 (dd, J = 15.8, 2.1 Hz, 1 H, H-8/H-8Ј), 5.86
and CuI (8 mg, 0.043 mmol, 0.1 equiv.) in DMF (1.5 mL) and Et3N
(1.2 mL). The reaction was complete after 3 h at room temp. Gene-
ral workup afforded TES-protected dienyne 18 (176 mg, 67%) as
(dd, J = 15.9, 1.7 Hz, 1 H, H-8/H-8Ј), 5.60 (dq, J = 10.8, 1.8 Hz,
2 H, H-11, H-11Ј), 5.31 (dd, J = 9.6, 3.6 Hz, 1 H, H-14ester), 4.44–
4.35 (m, 2 H, PMPCH2), 4.37 (s, 2 H, PMPCH2Ј), 4.19–4.14 (m, 2
H, H-6, H-6Ј), 3.91 (s, 3 H, CO2CH3), 3.80, 3.79 (s, 6 H, CH3OPh,
CH3OPhЈ), 3.80–3.77 (m, 1 H, H-14OTES), 3.27, 3.26 (s, 6 H,
CHOCH3, CHOCH3Ј), 3.28–3.24 (m, 1 H, Ha-16), 3.22–3.20 (m, 2
H, H-16Ј), 3.13–3.05 (m, 3 H, Hb-16, Ha-5, Ha-5Ј), 3.00 (dd, J =
15.1, 5.8 Hz, 1 H, Hb-5/Hb-5Ј), 2.96 (dd, J = 15.2, 5.3, 1 H, Hb-5/
Hb-5Ј), 2.75–2.63 (m, 2 H, H-13ester), 2.61–2.54 (m, 1 H, Ha-
colorless oil. [α]2D0 = –31.4 (c = 0.70, CHCl ). IR (neat): ν = 2952,
˜
3
2875, 1748, 1612, 1584, 1513, 1437, 1322, 1246, 1199, 1170, 1138,
1091, 1034, 1004, 956, 806, 725 cm–1. 1H NMR (400 MHz, CDCl3,
TMS): δ = 8.15 (s, 1 H, H-3), 7.24 (d, J = 8.5 Hz, 2 H, PMB), 6.86
(d, J = 8.7 Hz, 2 H, PMB), 6.10 (dt, J = 10.8, 7.3 Hz, 1 H, H-12),
5.96 (dd, J = 15.9, 7.3 Hz, 1 H, H-7), 5.86 (dd, J = 15.9, 2.1 Hz, 1
H, H-8), 5.58 (dq, J = 10.8, 1.7 Hz, 1 H, H-11), 4.42 (d, J = 13OTES), 2.49–2.41 (m, 1 H, Hb-13OTES), 0.94 [t, J = 8.0 Hz, 9 H,
11.7 Hz, 1 H, Ha-PMPCH2), 4.37 (d, J = 11.7 Hz, 1 H, Hb-
Si(CH2CH3)3], 1.02, 1.00, 0.90, 0.89 (s, 12 H, 4 Me), 0.58 [q, J =
PMPCH2), 4.19–4.14 (m, 1 H, H-6), 3.90 (s, 3 H, CO2CH3), 3.80 8.1 Hz, 6 H, Si(CH2CH3)3. 13C NMR (100 MHz, CDCl3, TMS):
(s, 3 H, CH3OPh), 3.78 (dd, J = 6.3, 4.6 Hz, 1 H, H-14), 3.27 (s, 3 162.41, 162.39, 161.63, 160.70 (Cq, C-1, C-1Ј, C-4, C-4Ј), 159.07,
H, CHOCH3), 3.11 (d, J = 8.5 Hz, 2 H, H-16), 3.09 (dd, J = 15.1,
7.8 Hz, 1 H, Ha-5), 2.98 (dd, J = 15.1, 5.6, 1 H, Hb-5), 2.57 (dddd,
J = 15.3, 6.8, 4.7, 1.9 Hz, 1 H, Ha-13), 2.44 (dddd, J = 15.3, 7.3,
6.7, 1.0, 1 H, Hb-13), 0.94 [t, J = 7.9 Hz, 9 H, Si(CH2CH3)3], 0.90
(s, 3 H, Me), 0.89 (s, 3 H, MeЈ), 0.58 [q, J = 7.9 Hz, 6 H,
Si(CH2CH3)3]. 13C NMR (100 MHz, CDCl3, TMS): δ = 162.46,
158.99 (Cq, COCH3,PMB, COCH3,PMBЈ), 144.02, 143.54 (CH, C-3,
C-3Ј), 143.13 (CH, C-12OTES), 140.51, 140.23 (CH, C-7, C-7Ј),
133.41 (Cq, C-2, C-2Ј), 131.04, 130.57 (Cq, CCH2,PMB, CCH2,PMBЈ),
129.17, 128.94 (CH, PMB, PMBЈ), 113.58, 113.87 (CH, C-8, C-8Ј),
113.88, 113.66 (CH, PMB, PMBЈ), 111.06, 109.24 (CH, C-11, C-
11Ј), 91.37, 91.24, 88.26, 87.92 (Cq, C-9, C-9, C-10Ј, C-10Ј), 79.23,
161.66 (Cq, C-1, C-4), 158.99 (Cq, PMB), 143.98 (CH, C-3), 143.17 79.14 (CH, C-6, C-6Ј), 76.34 (CH2, C-16, C-16Ј), 77.24, 75.93 (CH,
(CH, C-12), 140.16 (CH, C-7), 133.40 (Cq, C-2), 131.04 (Cq, PMB), C-14, C-14Ј), 72.99, 72.82 (CH2, PMPCH2, PMPCH2Ј), 56.88,
Eur. J. Org. Chem. 2006, 1132–1143
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1139

B. Niess, I. V. Hartung, L. O. Haustedt, H. M. R. Hoffmann,
56.76 (CH3, CHOCH3, CHOCH3Ј), 55.28, 55.24 (CH3, CH3OPh, hydrolyzed with satd. NaHCO3 solution. The aqueous phase was
FULL PAPER
CH3OPhЈ), 52.11 (CH3, CO2CH3), 40.27, 39.08 (Cq, C-15, C-15Ј),
34.61, 34.58, 34.55, 34.53 (CH2, C-5, C-5Ј, C-13, C-13Ј),], 21.62,
extracted with MTBE and the combined organic layers were dried
(Na2SO4). After evaporation of the solvents the residue was puri-
21.40, 21.21, 20.91 (CH3, 4 Me), 7.10 [CH3, Si(CH2CH3)3], 5.40 fied by flash chromatography yielding dimer 22 (13 mg, 35%) as
[CH2, Si(CH2CH3)3]. ESI-MS: m/z calcd. for C61H81N2O13Si: colorless foam. [α]2D0 = –107.5 (c = 0.40, CHCl ). IR (neat): ν =
˜
3
1077.5508, found: 1077.5525.
2927, 2854, 1737, 1612, 1584, 1513, 1464, 1358, 1303, 1246, 1171,
1138, 1097, 1035, 989, 956, 820, 753 cm–1. 1H NMR (400 MHz,
CDCl3, TMS): δ = 8.00 (s, 2 H, H-3, H-3Ј), 7.24 (d, J = 8.7 Hz, 4
H, PMB), 6.85 (d, J = 8.7 Hz, 4 H, PMB), 5.97 (dd, J = 15.9,
7.7 Hz, 2 H, H-12, H-12Ј), 5.96 (dt, J = 10.5, 5.2 Hz, 2 H, H-7, H-
7Ј), 5.65 (ddd, J = 16.0, 2.3, 0.8 Hz, 2 H, H-8/H-8Ј), 5.52 (dm, J =
10.5 Hz, 2 H, H-11, H-11Ј), 5.35 (dd, J = 11.04, 2.3 Hz, 2 H, H-
14, H-14Ј), 4.40–4.36 (m, 4 H, PMBCH2), 4.12 (dddd, J = 9.8, 7.7,
3.9, 0.9 Hz, 2 H, H-6, H-6Ј), 3.79 (s, 6 H, CH3OPh, CH3OPhЈ),
3.35 (s, 6 H, CHOCH3, CHOCH3Ј), 3.30–3.29 (m, 2 H, Ha-5, Ha-
5Ј), 3.20 (s, 4 H, H-16, H-16Ј), 3.00 (dd, J = 14.2, 9.8 Hz, 2 H, Hb-
5, Hb-5Ј), 2.93 (dt, J = 13.4, 10.8 Hz, 2 H, Ha-13), 2.38–2.33 (m, 2
H, Hb-13), 1.03, 1.01 (s, 12 H, 4 Me). 13C NMR (100 MHz, CDCl3,
TMS): δ = 161.62 (Cq, C-4, C-4Ј), 161.60 (Cq, C-1, C-1Ј), 159.07
(Cq, COCH3,PMB, COCH3,PMBЈ), 143.34 (CH, C-3, C-3Ј), 141.10,
140.23 (CH, C-12, C-12Ј, C-7, C-7Ј), 133.56 (Cq, C-2, C-2Ј), 130.50
(Cq, CCH2,PMB, CCH2,PMBЈ), 129.13 (CH, PMB), 113.67 (CH,
PMB), 113.55 (CH, C-8, C-8Ј), 111.99 (CH, C-11, C-11Ј), 90.82,
87.80 (Cq, C-9, C-9Ј, C-10, C-10Ј), 79.58 (CH, C-6, C-6Ј), 77.20
(CH, C-14, C-14Ј), 76.31 (CH2, C-16, C-16Ј), 73.00 (CH2,
PMPCH2, PMPCH2Ј), 56.86 (CH3, CHOCH3, CHOCH3Ј), 55.23
(CH3, CH3OPh, CH3OPhЈ), 38.86 (Cq, C-15, C-15Ј), 34.37 (CH2,
C-5, C-5Ј), 31.14 (CH2, C-13, C-13Ј), 21.26, 21.20 (CH3, 4 Me).
ESI-MS: m/z calcd. for C54H62N2NaO12: 953.4200, found:
953.4221.
PMB-Protected Tetradehydro-Dimer 22: TES-Dimer 21 (50 mg
0.046 mmol, 1.0 equiv.) was dissolved in THF (0.5 mL) and treated
with concd. AcOH (13 µL, 0.232 mmol, 5.0 equiv.), 1 drop of H2O
and TBAF (0.46 mL, 1  solution in THF, 0.464 mmol,
10.0 equiv.). After stirring for 3 d at room temp. the reaction mix-
ture was diluted with H2O and MTBE. The phases were separated
and the aqueous phase was extracted with MTBE. The combined
organic layers were dried (Na2SO4) and the solvent was evaporated.
Purification of the crude residue by flash chromatography gave the
hydroxy dimer (38.4 mg, 86%) as slightly yellow oil. [α]2D0 = –2.9 [c
= 0.55, (CH ) CO]. IR (neat): ν = 3480, 2932, 1738, 1612, 1584,
˜
3 2
1513, 1464, 1440, 1362, 1316, 1302, 1246, 1200, 1170, 1138, 1098,
1034, 1005, 956, 820, 760, 735 cm–1. H NMR (400 MHz, CDCl3,
1
TMS): δ = 8.46, 8.40 (s, 2 H, H-3, H-3Ј), 7.29–7.25 (m, 4 H, PMB),
6.91–6.87 (m, 4 H, PMB), 6.20 (ddd, J = 10.5, 7.9, 6.7 Hz, 1 H, H-
12OH), 6.08 (dd, J = 15.9, 7.0 Hz, 1 H, H-7/H-7Ј), 6.06 (dd, J =
15.9, 6.8 Hz, 1 H, H-7/H-7Ј), 6.00–5.96 (m, 3 H, H-12ester, H-8,
H8Ј), 5.66–5.64 (m, 2 H, H-11, H-11Ј), 5.26 (dd, J = 7.2, 6.0 Hz, 1
H, H-14ester), 4.43 (s, 2 H, PMBCH2), 4.40–4.36 (m, 2 H,
PMPCH2Ј), 4.24–4.19 (m, 2 H, H-6, H-6Ј), 3.82 (s, 3 H, CO2CH3),
3.79, 3.78 (s, 6 H, CH3OPh, CH3OPhЈ), 3.63 (d, J = 4.6 Hz, 1 H,
OH), 3.57–3.52 (m, 1 H, H-14OH), 3.39 (d, J = 8.9 Hz, 1 H, Ha-
16), 3.30–3.29 (m, 2 H, H-16Ј), 3.29 (d, J = 8.9 Hz, 1 H, Hb-16),
3.25, 3.24 (s, 6 H, CHOCH3, CHOCH3Ј), 3.10–2.97 (m, 4 H, H-5,
H-5Ј), 2.72–2.69 (m, 2 H, H-13ester), 2.63 (dddd, J = 14.4, 7.9, 2.5,
1.6 Hz, 1 H, Ha-13OH), 2.28 (dddd, J = 14.4, 10.0, 6.5, 1.4 Hz, 1
H, Hb-13OH), 1.02, 1.01, 0.94, 0.93 (s, 12 H, 4 Me). 13C NMR
(100 MHz, CDCl3, TMS): δ = 162.94, 162.89 (Cq, C-4, C-4Ј),
(11Z,18E)-Hydroxyenyne 7: TBS ether 2 (200 mg, 0.44 mmol,
1.0 equiv.) in THF (4.5 mL) was cooled to 0 °C and TBAF (4.5 mL,
1  solution in THF, 10.0 equiv.) was added dropwise. The reaction
mixture was warmed to room temp. and stirred for 24 h. MTBE
161.85, 160.98 (Cq, C-1, C-1Ј), 159.94, 159.93 (Cq, COCH3,PMB), and H2O were added and after separation of the phases the aque-
145.22, 145.10 (CH, C-3, C-3Ј), 143.97 (CH, C-12OH), 142.07, ous layer was extracted with MTBE. After drying (Na2SO4) the
141.70 (CH, C-7, C-7Ј), 141.06 (CH, C-12ester), 134.00, 133.88 (Cq, solvent was evaporated and the residue was purified by flash
C-2, C-2Ј), 131.49, 131.34 (Cq, CCH2,PMB), 129.77, 129.61 (CH, chromatography. The alcohol 7 was obtained as a colorless oil
PMB), 114.26, 114.21 (CH, PMB), 113.64, 113.48 (CH, C-8, C-8Ј),
111.45, 109.89 (CH, C-11, C-11Ј), 92.40, 91.89, 88.34, 87.88 (Cq,
(143 mg, 95%). [α]2D0 = +18.9 (c = 0.85, CHCl ). IR (neat): ν =
˜
3
3486, 3312, 2953, 2882, 2097, 1668, 1468, 1380, 1249, 1191, 1145,
C-9, C-9Ј, C-10, C-10Ј), 79.38 (CH, C-6, C-6Ј), 78.42 (CH2, C- 1095, 1022, 973, 921, 858, 833, 759, 738, 693 cm–1. 1H NMR
16/C-16Ј), 77.34 (CH, C-14/C-14Ј), 76.87 (CH2, C-16/C-16Ј), 76.64
(CH, C-14/C-14Ј), 73.40, 73.34 (CH2, PMPCH2, PMPCH2Ј), 56.66,
(400 MHz, CDCl3): δ = 6.26 (dddd, J = 10.8, 8.0, 6.3, 0.9 Hz, 1 H,
H-12), 5.66 (dqd, J = 15.3, 6.5, 0.7 Hz, 1 H, H-18), 5.53 (ddt, J =
56.62 (CH3, CHOCH3, CHOCH3Ј), 55.28, 55.27 (CH3, CH3OPh, 10.9, 2.3, 1.5 Hz, 1 H, H-11), 5.39 (ddq, J = 15.3, 8.6, 1.6 Hz, 1 H,
CH3OPhЈ), 51.69 (CH3, CO2CH3), 39.61, 39.56 (Cq, C-15, C-15Ј), H-17), 4.64 (d, J = 6.8 Hz, 1 H, Ha-OCH2OSEM), 4.57 (d, J =
34.58, 34.52 (CH2, C-5, C-5Ј), 33.77, 31.65 (CH2, C-13, C-13Ј), 6.8 Hz, 1 H, Hb-OCH2OSEM), 3.90 (d, J = 8.5 Hz, 1 H, H-16),
21.93, 21.55, 21.25, 20.55 (CH3, 4 Me). ESI-MS: m/z calcd. for
C55H66N2NaO13: 985.4463, found: 985.4487.
3.78–3.71 (m, 1 H, Ha-TMSCH2CH2OSEM), 3.69–3.64 (m, 2 H, H-
14, OH), 3.51–3.44 (m, 1 H, Hb-TMSCH2CH2OSEM), 3.09 (dd, J
= 2.3, 0.8 Hz, 1 H, H-9), 2.61–2.54 (m, 1 H, Ha-13), 2.35–2.27 (m,
1 H, Hb-13), 1.74 (dd, J = 6.4, 1.6 Hz, 3 H, H-19), 0.96–0.91 (m,
2 H, TMSCH2CH2OSEM), 0.89 (s, 3 H, Me), 0.86 (s, 3 H, MeЈ),
0.01 [s, 9 H, Si(CH3)3,SEM]. 13C NMR (100 MHz, CDCl3): δ =
144.57 (CH, C-12), 131.45 (CH, C-18), 126.93 (CH, C-17), 108.75
(CH, C-11), 92.02 (CH2, OCH2O), 84.42 (CH, C-16), 81.45 (Cq, C-
10), 80.58 (CH, C-9), 75.67 (CH, C-14), 65.91 (CH2,
TMSCH2CH2OSEM), 40.85 (Cq, C-15), 32.43 (CH2, C-13), 20.67
(CH3, Me), 19.30 (CH3, MeЈ), 18.10 (CH2, TMSCH2CH2OSEM),
17.87 (CH3, C-19), –1.49 [CH3, Si(CH3)3,SEM]. ESI-MS: m/z calcd.
for C19H34NaO3Si: 361.2175, found: 361.2187.
The hydroxy dimer (prepared as above) was dissolved in THF
(1 mL) and cooled to 0 °C. To this a Ba(OH)2 solution [0.6 mL of
a satd. solution of Ba(OH)2 in MeOH/H2O, 3:2, v/v] was added.
The reaction mixture was allowed to reach room temp. and stirred
for 3 h. For workup the mixture was acidified with 1  HCl and
diluted with MTBE. The aqueous phase was extracted with MTBE.
The combined organic layers were dried (Na2SO4) and the solvent
was evaporated. The crude residue was used directly in the next
step. A stock solution of 2,4,6-trichlorobenzoyl chloride (48 mg,
0.197 mmol) and Et3N (22 mg, 0.218 mmol) in toluene (1 mL) was
prepared. From this 0.6 mL were added to the crude acid in toluene
(1.2 mL) at room temp. After 1 h the mixture was diluted with tolu-
(7E,11Z,18E)-Hydroxydienyne 8: Following the general procedure
ene (1.6 mL) and added at room temp. to DMAP (19 mg, for the Sonogashira coupling PdCl2(PPh3)2 (19 mg, 0.027 mmol,
0.158 mmol, 4.0 equiv.) in toluene (8 mL) over a period of 5 h. Stir-
ring was continued for additional 24 h. Afterwards, the mixture was
0.05 equiv.) and CuI (10 mg, 0.054 mmol, 0.10 equiv.) were dis-
solved in DMF (2.0 mL). Oxazol vinyl iodide (183 mg,
3
1140
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1132–1143

Synthesis of a Tetradehydro-Disorazole C1
FULL PAPER
0.544 mmol, 1.00 equiv.) in DMF (2.0 mL) and Et3N (1.2 mL) were
added followed by addition of enyne 7 (184 mg, 0.544 mmol,
1.00 equiv.) in DMF (2.0 mL). The reaction was complete after 6 h
19.71, 19.31 (CH3, Me, MeЈ), 18.09 (CH2, CH2CH2TMS), 17.81
(CH3, C-19), 7.07 [CH3, Si(CH2CH3)3], 5.59 [CH2, Si(CH2CH3)3],
–1.21
[CH3,
Si(CH3)3,SEM].
ESI-MS:
m/z calcd.
for
at room temp. General workup gave 8 (267 mg, 89%) as a colorless C35H59NNaO7Si2: 684.3728, found: 684.3734.
oil. [α]2D0 = –26.7 (c = 1.21, CHCl ). IR (neat): ν = 3497, 2951,
˜
3
TBS-Protected Dimer 26: Following the general procedure for
methyl ester saponification ester 1 (31 mg, 0.046 mmol, 1.0 equiv.)
was saponified during 4 h. After workup the crude acid was used
directly in the next step. Alcohol 8 (25 mg, 0.046 mmol, 1.0 equiv.)
and acid 24 were dissolved in toluene (0.6 mL) and treated with
DPTC (17 mg, 0.074 mmol, 1.6 equiv.) and a crystal of DMAP. The
reaction mixture was refluxed for 36 h. After cooling to room temp.
MTBE was added, followed by silica gel and evaporation to dry-
ness. Flash chromatography furnished 26 (19 mg, 45%) as a color-
1748, 1585, 1437, 1323, 1196, 1167, 1139, 1104, 1008, 859, 835,
763 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1 H, H-3), 6.20
(ddd, J = 10.8, 8.2, 6.4 Hz, 1 H, H-12), 5.95 (dd, J = 15.9, 7.3 Hz,
1 H, H-7), 5.86 (dd, J = 15.9, 2.1 Hz, 1 H, H-8), 5.68–5.61 (m, 2
H, H-11, H-18), 5.39 (ddt, J = 15.3, 8.6, 1.6, 1 H, H-17), 4.62 (d,
J = 6.8 Hz, 1 H, Ha-OCH2O), 4.56 (d, J = 6.8 Hz, 1 H, Hb-
OCH2O), 4.18–4.13 (m, 1 H, H-6), 3.89 (d, J = 8.4 Hz, 1 H, H-
16), 3.89 (s,
3 H, CO2CH3), 3.77–3.70 (m, 1 H, Ha-
OCH2CH2TMS), 3.67–3.64 (m, 1 H, H-14), 3.50–3.44 (m, 1 H, Hb-
OCH2CH2TMS), 3.26 (s, 3 H, OCH3), 3.09 (dd, J = 14.9, 7.9 Hz,
1 H, Ha-5), 2.98 (dd, J = 14.9, 5.6 Hz, 1 H, Hb-5), 2.57–2.52 (m, 1
H, Ha-13), 2.31–2.23 (m, 1 H, Hb-13), 1.73 (dd, J = 6.3, 1.5 Hz, 3
H, H-19), 0.95–0.84 (m, 2 H, CH2TMS), 0.88 (s, 3 H, CH3), 0.84
(s, 3 H, CH3Ј), –0.004 [s, 9 H, Si(CH3)3]. 13C NMR (100 MHz,
CDCl3): 162.41, 161.59 (Cq, C-4, CO2CH3), 143.92 (CH, C-3),
143.23 (CH, C-12), 140.09 (CH, C-7), 133.38 (Cq, C-2), 131.34
(CH, C-11/C-18), 127.03 (CH, C17), 113.79 (CH, C-8), 109.50 (CH,
C-11/C-18), 92.11 (CH2, OCH2O), 90.99, 88.17 (Cq, C-9, C-10),
84.38 (CH, C-16), 79.21 (CH, C-6), 75.77 (CH, C-14), 65.90 (CH2,
OCH2CH2TMS), 56.75 (CH3, OCH3), 52.02 (CH3, CO2CH3),
40.96 (Cq, C-15), 34.56 (CH2, C-5), 32.56 (CH2, C-13), 20.62, 19.25
(CH3, Me, MeЈ), 18.11 (CH2, CH2CH2TMS), 17.80 (CH3, C-19),
less oil. [α]2D0 = +35.6 (c = 0.94, CHCl ). IR (neat): ν = 2929, 2884,
˜
3
1742, 1583, 1464, 1437, 1360, 1320, 1249, 1196, 1168, 1137, 1101,
1026, 972, 955, 858, 833, 760, 693 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.17, 8.06 (s, 2 H, H-3, H-3Ј), 6.08 (dt, J = 10.8,
7.2 Hz, 1 H, H-12OTBS), 6.01 (dd, J = 15.9, 6.7 Hz, 1 H, H-7/H-
7Ј), 5.95 (dd, J = 16.0, 6.8 Hz, 1 H, H-7/H-7Ј), 5.91 (dd, J = 15.7,
2.4 Hz, 1 H, H-8/H-8Ј), 5.94–5.89 (m, 1 H, H-12ester), 5.87 (dd, J
= 15.8, 2.2 Hz, 1 H, H-8/H-8Ј), 5.64 (dq, J = 15.3, 6.2 Hz, 2 H, H-
18, H-18Ј), 5.59–5.54 (m, 2 H, H-11, H-11Ј), 5.38 (ddq, J = 15.3,
9.1, 1.5, 1 H, H-17/H-17Ј), 5.33 (ddq, J = 15.3, 9.1, 1.5 Hz, 1 H,
H-17/H-17Ј), 5.22 (dd, J = 7.3, 5.6 Hz, 1 H, H-14ester), 4.64 (d, J
= 6.7 Hz, 2 H, H-OCH2O), 4.54 (d, J = 6.9 Hz, 1 H, Ha-OCH2OЈ),
4.50 (d, J = 6.9 Hz, 1 H, Hb-OCH2OЈ), 4.21–4.16 (m, 2 H, H-6, H-
6Ј), 3.90 (s, 3 H, CO2CH3), 3.85 (d, J = 9.0 Hz, 1 H, H-16OTBS),
3.75 (d, J = 8.9 Hz, 1 H, H-16ester), 3.73–3.63 (m, 3 H, Ha-
OCH2CH2TMS, Ha-OCH2CH2TMSЈ, H-14OTBS), 3.53–3.46 (m, 2
H, Hb-OCH2CH2TMS, Hb-OCH2CH2TMSЈ), 3.28, 3.27 (s, 6 H,
OCH3, OCH3Ј), 3.11 (dd, J = 15.1, 7.7 Hz, 1 H, Ha-5), 3.07 (dd, J
= 15.3, 8.0 Hz, 1 H, Hb-5), 3.00 (dd, J = 15.0, 5.7 Hz, 1 H, Ha-5Ј),
2.97 (dd, J = 15.2, 5.2 Hz, 1 H, Hb-5Ј): 2.69–2.65 (m, 2 H, H-
13ester), 2.55–2.51 (m, 2 H, H-13OTBS), 1.73–1.69 (m, 6 H, H-19, H-
19Ј), 1.02, 0.97, 0.91, 0.84, (s, 12 H, 4 Me), 0.94–0.83 (m, 4 H,
OCH2CH2TMS, OCH2CH2TMSЈ), 0.90 [s, 9 H, SiC(CH3)3,TBS],
0.05 (s, 3 H, SiCH3,TBS), 0.04 (s, 3 H, SiCH3Ј,TBS), –0.003 [s, 18 H,
2×Si(CH3)3,SEM]. 13C NMR (100 MHz, CDCl3): δ = 162.46, 162.38
(Cq, C-4, C-4Ј), 161.59 (Cq, C-1OTBS), 160.65 (Cq, C-1ester), 143.97,
143.46 (CH, C-3, C-3Ј), 142.99 (CH, C-12OTBS), 140.56, 140.38
(CH, C-7, C-7Ј), 140.18 (CH, C-12ester), 133.57, 133.44 (Cq, C-2,
C-2Ј), 131.39 (CH, C-18ester), 130.57 (CH, C-18OTBS), 128.09,
127.36 (CH, C-17, C-17Ј), 113.63, 113.53 (CH, C-8, C-8Ј), 110.98
(CH, C-11ester), 109.05 (CH, C-11OTBS), 91.96, 91.85 (CH2,
OCH2O, OCH2OЈ), 91.31, 91.22 (Cq, C-9, C-9Ј), 88.32, 87.92 (Cq,
C-10, C-10Ј), 81.66 (CH, C-16ester), 81.52 (CH, C-16OTBS), 79.18
(CH, C-6, C-6Ј), 77.20 (CH, C-14ester), 75.91 (CH, C-14OTBS),
65.33, 65.05 (CH2, OCH2CH2TMS, OCH2CH2TMSЈ), 56.83, 56.77
(CH3, OCH3, OCH3Ј), 52.05 (CH3, CO2CH3), 43.28 (Cq, C-
15OTBS), 41.81 (Cq, C-15ester), 34.66, 34.56 (CH2, C-5, C-5Ј), 34.56
(CH2, C-13OTBS), 31.30 (CH2, C-13ester), 26.11 [CH3, SiC(CH3)3],
20.16, 19.91, 19.56, 19.37 (CH3, 4 Me), 18.33 [Cq, SiC(CH3)3],
18.10, 18.06 (CH2, CH2CH2TMS, CH2CH2TMSЈ), 17.85 (CH3, C-
19, C-19Ј), –1.43, –1.44 [CH3, Si(CH3)3,SEM, Si(CH3)3,SEMЈ], –3.42
(CH3, SiCH3,TBS), –4.29 (CH3, SiCH3,TBSЈ). ESI-MS: m/z calcd. for
C63H100N2NaO13Si3: 1199.6431, found: 1199.6454.
–1.29
[CH3,
Si(CH3)3,SEM].
ESI-MS:
m/z calcd.
for
C29H45NNaO7Si: 570.2863, found: 570.2883.
TES-Protected (7E,11Z,18E)-Dienyne 23: Alcohol
8 (145 mg
0.265 mmol, 1.0 equiv.) in CH2Cl2 (1.8 mL) was cooled to –40 °C.
2,6-Lutidine (71 µL, 0.609 mmol, 2.3 equiv.) was added followed by
the dropwise addition of TESOTf (96 µL, 0.424 mmol, 1.6 equiv.).
The reaction mixture was stirred for 1.5 h keeping it between –40
and –15 °C. Finally, the mixture was hydrolyzed at –20 °C with
satd. NaHCO3 solution. After warming to room temp. the aqueous
phase was extracted with MTBE and the combined organic layers
were dried (Na2SO4). The solvents were evaporated. Flash
chromatography afforded 23 (149 mg, 85%) as slightly yellow oil.
[α]2D0 = –8.8 (c = 1.03, CHCl ). IR (neat): ν = 2952, 2877, 1752,
˜
3
1585, 1437, 1323, 1248, 1196, 1166, 1138, 1099, 1029, 1005, 859,
1
835, 737 cm–1. H NMR (400 MHz, CDCl3): δ = 8.18 (s, 1 H, H-
3), 6.05 (dt, J = 10.8, 7.4 Hz, 1 H, H-12), 5.98 (dd, J = 15.8, 7.3 Hz,
1 H, H-7), 5.88 (dd, J = 15.8, 2.1 Hz, 1 H, H-8), 5.61 (dq, J = 15.4,
6.5 Hz, 1 H, H-18), 5.58 (dm, J = 10.8 Hz, 1 H, H-11), 5.32 (ddq,
J = 15.4, 9.0, 1.8, 1 H, H-17), 4.65 (d, J = 6.7 Hz, 1 H, Ha-
OCH2O), 4.54 (d, J = 6.7 Hz, 1 H, Hb-OCH2O), 4.19–4.14 (m, 1
H, H-6), 3.89 (s, 3 H, CO2CH3), 3.82 (d, J = 9.0 Hz, 1 H, H-16),
3.74–3.66 (m, 1 H, Ha-OCH2CH2TMS), 3.66 (dd, J = 7.0, 3.8 Hz,
1 H, H-14), 3.55–3.48 (m, 1 H, Hb-OCH2CH2TMS), 3.25 (s, 3 H,
OCH3), 3.12 (dd, J = 15.1, 7.9 Hz, 1 H, Ha-5), 3.01 (dd, J = 15.1,
5.6 Hz, 1 H, Hb-5), 2.54 (dddd, J = 15.1, 7.3, 3.8, 1.8 Hz, 1 H, Ha-
13), 2.41 (dtd, J = 15.1, 7.4, 1.3 Hz, 1 H, Hb-13), 1.72 (dd, J = 6.4,
1.4 Hz, 3 H, H-19), 0.96 [t, J = 8.0 Hz, 9 H, Si(CH2CH3)3], 0.94–
0.90 (m, 2 H, CH2CH2TMS), 0.92 (s, 3 H, Me), 0.86 (s, 3 H, MeЈ),
0.61 [q, J = 8.0 Hz, 6 H, Si(CH2CH3)3], 0.02 [s, 9 H, Si(CH3)3]. 13
C
NMR (100 MHz, CDCl3): δ = 162.45, 161.61 (Cq, C-4, C-1), 143.95 TES-Protected Dimer 27: Following the general procedure for
(CH, C-12), 143.03 (CH, C-3), 140.22 (CH, C-7), 133.38 (Cq, C-2), methyl ester saponification, the TES-protected ester 23 (50 mg, 75.6
130.52 (CH, C-11/C-18), 128.08 (CH, C-17), 113.76 (CH, C-8),
µmol, 1.0 equiv.) in THF (1 mL) was saponified during 3 h using
109.29 (CH, C-11/C-18), 91.82 (CH2, OCH2O), 91.04, 88.30 (Cq, aqueous LiOH solution (0.23 mL, 1  in H2O, 226.9 µmol,
C-9, C-10), 81.45 (CH, C-16), 79.25 (CH, C-6), 76.10 (CH, C-14), 3.0 equiv.). After general workup the crude acid was used directly
65.06 (CH2, OCH2CH2TMS), 56.76 (CH3, OCH3), 52.02 (CH3,
CO2CH3), 43.08 (Cq, C-15), 34.58 (CH2, C-5), 34.39 (CH2, C-13),
in the next step. For the next step a stock solution of 2,4,6-trichlo-
robenzoyl chloride (64 mg, 262.5 µmol, 3.5 equiv.) and Et3N
Eur. J. Org. Chem. 2006, 1132–1143
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1141

B. Niess, I. V. Hartung, L. O. Haustedt, H. M. R. Hoffmann,
FULL PAPER
(30 mg, 288.8 µmol, 3.8 equiv.) in toluene (1.5 mL) was prepared.
The crude acid was dissolved in toluene (1 mL). From this solution
one portion (0.2 mL) was transferred to a separate flask and
treated dropwise with the above prepared stock solution (0.3 mL).
H2O and MTBE. After separation of the phases the aqueous layer
was extracted with MTBE. The combined organic layers were dried
(Na2SO4) and after removal of the solvent purification by flash
chromatography gave the hydroxy dimer (34 mg, 87%) as a slightly
After 45 min at room temp. the activated acid was added to a 40 °C yellow oil. [α]2D0 = +14.8 [c = 0.63, (CH ) CO]. IR (neat): ν = 3505,
˜
3 2
warm solution of alcohol 8 (37 mg, 67.5 µmol, 0.9 equiv.) and
DMAP (27 mg, 225 µmol, 3.0 equiv.) in toluene (1 mL) over 45 min
using a perfusor. This procedure was repeated four times using the
carboxylic acid solution (0.2 mL each). After complete addition of
the last portion of activated acid the reaction mixture was stirred
for an additional 2 h at 40 °C before being diluted with MTBE
and hydrolyzed with satd. NH4Cl solution. The aqueous phase was
extracted with MTBE, the combined organic layers were dried
(Na2SO4) and the solvents were evaporated. Purification by flash
2951, 1741, 1584, 1437, 1317, 1248, 1196, 1168, 1137, 1102, 1023,
859, 834, 760 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.17, 8.05 (s,
2 H, H-3, H-3Ј), 6.20 (ddd, J = 10.8, 8.0. 6.2 Hz, 1 H, H-12OH),
5.98 (dd, J = 15.9, 7.3 Hz, 1 H, H-7/H-7Ј), 5.97 (dd, J = 15.9,
7.3 Hz, 1 H, H-7/H-7Ј), 5.88 (dd, J = 15.9, 2.0 Hz, 1 H, H-8/H-8Ј),
5.87 (dd, J = 15.9, 2.1 Hz, 1 H, H-8/H-8Ј), 5.95–5.92 (m, 1 H, H-
12ester), 5.69–5.49 (m, 4 H, H-11, H-11Ј, H-18, H-18Ј), 5.39 (ddq,
J = 15.2, 7.1, 1.5, 1 H, H-17/H-17Ј), 5.37 (ddq, J = 15.3, 7.9, 1.4,
1 H, H-17/H-17Ј), 5.21 (dd, J = 8.2, 4.8 Hz, 1 H, H-14ester), 4.64
(d, J = 6.8 Hz, 1 H, Ha-OCH2O), 4.63 (d, J = 6.7 Hz, 1 H, Ha-
OCH2OЈ), 4.56 (d, J = 6.7 Hz, 1 H, Hb-OCH2OЈ), 4.48 (d, J =
6.8 Hz, 1 H, Hb-OCH2O), 4.20–4.15 (m, 2 H, H-6, H-6Ј), 3.91–3.88
(m, 1 H, H-16/H-16Ј), 3.90 (s, 3 H, CO2CH3), 3.77–3.64 (m, 5 H,
chromatography yielded 27 (55 mg, 69%) as a colorless oil. [α]2D0
=
+35.5 (c = 1.45, CHCl ). IR (neat): ν = 2952, 2878, 1745, 1584,
˜
3
1438, 1322, 1197, 1167, 1137, 1103, 1028, 973, 859, 835, 761,
1
738 cm–1. H NMR (400 MHz, CDCl3): δ = 8.17, 8.14 (s, 2 H, H-
3, H-3Ј), 6.05 (dt, J = 10.8, 7.4 Hz, 1 H, H-12OTES), 6.00 (dd, J =
16.0, 7.0 Hz, 1 H, H-7Ј), 5.98 (dd, J = 15.9, 7.1 Hz, 1 H, H-7),
5.95–5.89 (m, 1 H, H-12ester), 5.90 (dd, J = 15.8, 2.3 Hz, 1 H, H-
8), 5.87 (dd, J = 15.9, 2.3 Hz, 1 H, H-8Ј), 5.63 (dq, J = 15.2, 6.4 Hz,
H-16/H-16Ј,
H-14OH
,
OH,
Ha-OCH2CH2TMS,
Ha-
OCH2CH2TMSЈ), 3.52–3.43 (m, 2 H, Hb-OCH2CH2TMS, Hb-
OCH2CH2TMSЈ), 3.27, 3.26 (s, 6 H, OCH3, OCH3Ј), 3.11 (dd, J =
15.1, 7.8 Hz, 1 H, Ha-5/ Ha-5Ј), 3.07 (dd, J = 15.1, 8.2 Hz, 1 H,
1 H, H-18), 5.60–5.53 (m, 3 H, H-11, H-11Ј, H-18Ј), 5.38 (ddq, J Ha-5/ Ha-5Ј), 3.00 (dd, J = 15.1, 5.7 Hz, 1 H, Hb-5/Hb-5Ј), 2.97
= 15.3, 9.0, 1.6, 1 H, H-17), 5.33 (ddq, J = 15.3, 8.8, 1.7 Hz, 1 H, (dd, J = 15.1, 5.3 Hz, 1 H, Hb-5/Hb-5Ј), 2.68–2.64 (m, 2 H, H-
H-17Ј), 5.22 (dd, J = 7.3, 5.6 Hz, 1 H, H-14ester), 4.65 (d, J = 13ester), 2.57–2.52 (m, 1 H, Ha-13OH), 2.28 (dddd, J = 14.57, 9.99,
6.7 Hz, 1 H, Ha-OCH2O), 4.55 (d, J = 6.7 Hz, 1 H, Hb-OCH2O),
4.64 (d, J = 6.9 Hz, 1 H, Ha-OCH2OЈ), 4.56 (d, J = 6.9 Hz, 1 H,
Hb-OCH2OЈ), 4.21–4.15 (m, 2 H, H-6, H-6Ј), 3.90 (s, 3 H,
6.38, 1.52 Hz, 1 H, Hb-13OH), 1.73 (dd, J = 6.5, 1.6 Hz, 3 H, H-
19/H-19Ј), 1.70 (dd, J = 6.4, 1.6 Hz, 3 H, H-19/H-19Ј), 0.94–0.84
(m, 4 H, OCH2CH2TMS, OCH2CH2TMSЈ), 1.02, 0.95, 0.88, 0.85
CO2CH3), 3.83 (d, J = 9.0 Hz, 1 H, H-16OTES), 3.75 (d, J = 8.9 Hz, (s, 12 H, 4 Me), 0.002 [s, 18 H, Si(CH3)3,SEM, Si(CH3)3,SEMЈ]. 13C
1 H, H-16ester), 3.73–3.63 (m, 3 H, Ha-OCH2CH2TMS, Ha- NMR (100 MHz, CDCl3): δ = 162.41, 162.36 (Cq, C-4, C-4Ј),
OCH2CH2TMSЈ, H-14OTES), 3.53–3.46 (m,
OCH2CH2TMS, Hb-OCH2CH2TMSЈ), 3.27, 3.26 (s, 6 H, OCH3,
OCH3Ј), 3.11 (dd, J = 15.1, 7.7 Hz, 1 H, Ha-5), 3.07 (dd, J = 15.8,
2
H, Hb-
161.59 (Cq, C-1OH), 160.63 (Cq, C-1ester), 143.99, 143.48 (CH, C-3,
C-3Ј), 143.22 (CH, C-12OH), 140.51, 140.24 (CH, C-7, C-7Ј), 140.17
(CH, C-12ester), 133.50, 133.38 (Cq, C-2, C-2Ј), 131.45, 131.41 (CH,
7.8 Hz, 1 H, Hb-5), 3.00 (dd, J = 15.0, 5.7 Hz, 1 H, Ha-5Ј), 2.97 C-18, C-18Ј), 127.26 (CH, C17ester), 126.98 (CH, C-17OH), 113.72,
(dd, J = 15.2, 5.1 Hz, 1 H, Hb-5Ј): 2.58–2.64 (m, 2 H, H-13ester), 113.55 (CH, C-8, C-8Ј), 111.00 (CH, C-11ester), 109.50 (CH, C-
2.59–2.52 (m, 1 H, Ha-13OTES), 2.46–2.38 (m, 1 H, Hb-13OTES), 11OH), 92.07, 91.88 (CH2, OCH2O, OCH2OЈ), 91.27, 91.04 (Cq, C-
1.71–1.69 (m, 6 H, H-19, H-19Ј), 1.02, 0.96, 0.91, 0.84, (s, 12 H,
9, C-9Ј), 88.13, 87.90 (Cq, C-10, C-10Ј), 84.41 (CH, C-16OH), 81.59
4 Me), 0.96–0.84 (m, 4 H, OCH2CH2TMS, OCH2CH2TMSЈ), 0.94 (CH, C-16ester), 79.17 (CH, C-6, C-6Ј), 77.20 (CH, C-14ester), 75.76
[t, J = 7.7 Hz, 9 H, Si(CH2CH3)3], 0.59 [q, J = 7.8 Hz, 6 H,
Si(CH2CH3)3], –0.002 [s, 18 H, Si(CH3)3,SEM, Si(CH3)3,SEMЈ]. 13C
(CH, C-14OH), 65.90, 65.30 (CH2, OCH2CH2TMS), 56.84, 56.78
(CH3, OCH3, OCH3Ј), 52.08 (CH3, CO2CH3), 401.77 (Cq,
NMR (100 MHz, CDCl3): δ = 162.46, 162.37 (Cq, C-4, C-4Ј), C-15ester), 40.95 (Cq, C-15OH), 34.61, 34.54 (CH2, C-5, C-5Ј), 32.55
161.59 (Cq, C-1OTES), 160.64 (Cq, C-1ester), 143.98, 143.47 (CH, C- (CH2, C-13OH), 31.25 (CH2, C-13ester), 20.68, 19.90, 19.33, 19.27
3, C-3Ј), 142.99 (CH, C-12OTES), 140.52, 140.37 (CH, C-7, C-7Ј),
140.18 (CH, C-12ester), 133.53, 133.41 (Cq, C-2, C-2Ј), 131.41 (CH, OCH2CH2TMSЈ), 17.89, 17.85 (CH3, C-19, C-19Ј), –1.44, –1.48
C-18ester), 130.50 (CH, C-18OTES), 128.13, 127.31 (CH, C-17, C- [CH3, Si(CH3)3,SEM Si(CH3)3,SEM]. ESI-MS: m/z calcd. for
(CH3,
4 Me),
18.11,
18.04
(CH2,
OCH2CH2TMS,
,
17Ј), 113.63, 113.54 (CH, C-8, C-8Ј), 110.98 (CH, C-11ester), 109.31
(CH, C-11OTES), 92.05, 92.01 (CH2, OCH2O, OCH2OЈ), 91.29,
91.13 (Cq, C-9, C-9Ј), 88.27, 87.90 (Cq, C-10, C-10Ј), 81.63, 81.49
(CH, C-16, C-16Ј), 79.17 (CH, C-6, C-6Ј), 77.20 (CH, C-14ester),
76.12 (CH, C-14OTES), 65.32, 65.02 (CH2, OCH2CH2TMS,
OCH2CH2TMSЈ), 56.83, 56.77 (CH3, OCH3, OCH3Ј), 52.08 (CH3,
CO2CH3), 43.10 (Cq, C-15OTES), 41.79 (Cq, C-15ester), 34.63, 34.55
(CH2, C-5, C-5Ј), 34.42 (CH2, C-13OTES), 31.28 (CH2, C-13ester),
19.89, 19.73, 19.35, 19.32 (CH3, 4 Me), 18.09, 18.05 (CH2,
CH2CH2TMS, CH2CH2TMSЈ), 17.86, 17.82 (CH3, C-19, C-19Ј),
7.07 [CH3, Si(CH2CH3)3], 5.55 [CH2, Si(CH2CH3)3], –1.44, –1.45
C57H86N2NaO13Si2: 1085.5566, found: 1085.5585.
The hydroxy dimer (23 mg, 22 µmol, 1.0 equiv.) in THF (0.5 mL)
was cooled to 0 °C and treated with Ba(OH)2 solution [0.3 mL of
a satd. solution of Ba(OH)2 in MeOH/H2O, 3:2, v/v]. The reaction
mixture was warmed to room temp. and was stirred for 3 h. After
completion of the reaction, the mixture was acidified with 1  HCl
solution and diluted with MTBE. The phases were separated and
the aqueous layer was extracted with MTBE (6×). The combined
organic layers were dried (Na2SO4) and the solvents evaporated to
dryness. The crude hydroxy acid was used in the next step without
further purification.
[CH3, Si(CH3)3,SEM
, Si(CH3)3,SEMЈ]. ESI-MS: m/z calcd. for
The crude acid was dissolved in toluene (1.2 mL) and a solution
(0.3 mL) of 2,4,6-trichlorobenzoyl chloride (48 mg, 0.197 mmol)
and Et3N (22 mg, 0.218 mmol) in toluene (1 mL) was added. After
1 h at room temp. the activated acid was diluted with toluene to
3.0 mL and was dropped during 5 h to DMAP (10 mg, 88 µmol,
4.0 equiv.) in toluene (4 mL) at a temperature of 40 °C. Completion
of addition was followed by stirring for 24 h. The reaction mixture
C63H100N2NaO13Si3: 1199.6431, found: 1199.6429.
Tetradehydro-Dimer 28: The TES-dimer 27 (43 mg, 36.6 µmol,
1.0 equiv.) was dissolved in THF (1 mL) and treated with H2O and
concd. AcOH, two drops each. TBAF (0.55 mL, 1  in THF, 549
µmol, 15.0 equiv.) was added at room temp. The reaction mixture
was stirred 3 d at this temperature being afterwards diluted with
1142
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1132–1143

Synthesis of a Tetradehydro-Disorazole C1
FULL PAPER
Sasse, S. Baasner, P. Schmidt, E. Günther, WO 2004/024149
A1.
B. Julien, R. C. Reid, WO 2004/053065 A2.
was hydrolyzed with satd. NaHCO3 solution and the aqueous
phase was extracted with MTBE. The combined organic layers
were dried (Na2SO4), the solvents were removed and the crude resi-
due was purified by flash chromatography affording 28 (7 mg,
31%) as a colorless oil. [α]2D0 = +120.9 (c = 0.42, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.05 (s, 2 H, H-3, H-3Ј), 6.07–5.81 (m, 6
H, H-12, H-12Ј, H-18, H-18Ј, H-7, H-7Ј), 5.68–5.61 (m, 2 H, H-8,
H-8Ј), 5.52–5.50 (m, 2 H, H-11, H-11Ј), 5.44–5.38 (m, 2 H, H-17,
H-17Ј), 5.31–5.27 (m, 2 H, H-14, H-14Ј), 4.69–4.65 (m, 2 H, Ha-
OCH2O, Ha-OCH2OЈ), 4.53–4.50 (m, 2 H, Hb-OCH2O, Hb-
OCH2OЈ), 4.18–4.10 (m, 2 H, H-6, H-6Ј), 3.76–3.65 (m, 4 H,
OCH2CH2TMS, OCH2CH2TMSЈ), 3.55–3.48 (m, 2 H, H-16, H-
16Ј), 3.36 (s, 6 H, OCH3, OCH3Ј), 3.34–3.27 (m, 2 H, Ha-5, Ha-
5Ј), 3.05–3.00 (m, 2 H, Hb-5, Hb-5Ј), 2.98–2.91 (m, 2 H, Ha-13, Ha-
13Ј), 2.40–2.36 (m, 2 H, Hb-13, Hb-13Ј), 1.74–1.70 (m, 6 H, H-19,
H-19Ј), 1.05 (s, 6 H, Me, MeЈ), 0.99 (s, 6 H, Me, MeЈ), 0.94–0.84
(m, 4 H, OCH2CH2TMS, OCH2CH2TMSЈ), 0.01 [s, 18 H, Si(CH3)
3,SEM, Si(CH3)3,SEMЈ]. 13C NMR (100 MHz, CDCl3): 161.74 (Cq,
C-4, C-4Ј), 160.47 (Cq, C-1, C-1Ј), 143.31 (CH, C-3, C-3Ј), 141.14,
140.14 (CH, C-12, C-12Ј, C-7, C-7Ј), 133.63 (Cq, C-2, C-2Ј), 131.48
(CH, C-18, C-18Ј), 127.35 (CH, C17, C-17Ј), 113.52, 112.10 (CH,
C-8, C-8Ј, C-11, C-11Ј), 91.95 (CH2, OCH2O, OCH2OЈ), 90.83,
87.75 (Cq, C-9, C-9Ј, C-10, C-10Ј), 81.64, 79.58, 77.20 (CH, C-
16, C-16Ј, C-14, C-14Ј, C-6, C-6Ј), 65.40 (CH2, OCH2CH2TMS,
OCH2CH2TMSЈ), 56.81 (CH3, OCH3, OCH3Ј), 41.58 (Cq, C-15,
C-15Ј), 34.35 (CH2, C-5, C-5Ј), 31.30 (CH2, C-13, C-13Ј), 19.80,
[4]
[5]
a) F. Diederich, Cyclophanes, Royal Society of Chemisty, Cam-
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Schäfer, H. M. R. Hoffmann, Synthesis 2003, 1844; b) L. O.
Haustedt, S. B. Panicker, M. Kleinert, I. V. Hartung, U. Eggert,
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I. V. Hartung, B. Niess, L. O. Haustedt, H. M. R. Hoffmann,
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For other approaches to disorazole C1 see: a) M. C. Hillier,
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a) S. Ohira, Synth. Commun. 1989, 19, 561; b) S. Müller, B.
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19.40,
OCH2CH2TMSЈ), 17.95 (CH3, C-19, C-19Ј), –1.43 [CH3,
Si(CH3)3,SEM Si(CH3)3,SEMЈ]. ESI-MS: m/z calcd. for
(CH3,
4 Me),
18.03
(CH2,
OCH2CH2TMS,
[10]
[11]
,
C56H83N2O13Si2: 1031.5485, found: 1031.5499.
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Acknowledgments
We thank the Deutsche Forschungsgemeinschaft for support of our
work and the GBF Braunschweig for cooperation. We thank Dr. E.
Hofer and the spectroscopy facility at the Department of Organic
Chemistry for their excellent analytical service and Ulrike Eggert
for experimental assistance.
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[15] The conditions applied included our standard Sonogashira
conditions [PdCl2(PPh3)2, CuI, Et3N, DMF, r.t] and the slow
addition (perfusor) of 12 to PdCl2(PPh3)2, CuI, Et3N in THF
at room temp.
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Received: September 3, 2005
Published Online: December 20, 2005
Eur. J. Org. Chem. 2006, 1132–1143
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1143