Mycothiazole: Synthesis of the C8-C18 subunit and further evidence of the (Z)-Δ14 double bond configuration

Article abstract of DOI:10.1002/ejoc.200600671

The synthesis of mycothiazole derivatives was undertaken in order to have further evidence of the C14-C15 double bond configuration. The recently revised (Z) configuration in the natural compound is consistent with the data found for our synthetic analogs

Full text of DOI:10.1002/ejoc.200600671

FULL PAPER
DOI: 10.1002/ejoc.200600671
Mycothiazole: Synthesis of the C8–C18 Subunit and Further Evidence of the
(Z)-∆14 Double Bond Configuration
Miriam Rega,[a] Paloma Candal,[a] Carlos Jiménez,[a] and Jaime Rodríguez*[a]
Keywords: Sulfur heterocycles / Cross metathesis / Configuration determination
The synthesis of mycothiazole derivatives was undertaken in
order to have further evidence of the C14–C15 double bond
configuration. The recently revised (Z) configuration in the
natural compound is consistent with the data found for our
synthetic analogs.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Mycothiazole (1) is a marine natural compound isolated
by Crews et al. from the Vanuatuan sponge Spongia mycofi-
jiensis[1] and is also found in the extracts of another marine
sponge of the genus Dactylospongia.[2] Compound 1 shows
antihelminthic activity in vitro, and it is being studied by
the National Cancer Institute (NCI) in the Unites States
because it exhibits selective toxicity against small cell lung
cancer lines.[3] Its stereostructure was solved in 2000 by an
asymmetric total synthesis,[4] even though some discrepanc-
ies Ϫattributed to possible contamination of the isolated
productϪ were found in the [α]2D3 values between the syn-
thetic and natural products. Another total synthesis of rac-
mycothiazole was recently published by Cossy and cowork-
ers and no mention was made of problems concerning the
overall structure of mycothiazole.[5] An additional synthesis
of simplified analogs was published in 2006 and discrepan-
cies in the configuration of the C14–C15 double bond were
not discussed.[6] Very recently Crews et al. revised the ini-
tially proposed (E) configuration to (Z) on the basis of
NOE measurements and comparison with a new natural
analog, mycothiazole-4,19-diol.[7]
Scheme 1. Retrosynthetic analysis of mycothiazole.
The development of this synthetic strategy prompted us
to investigate different 1,4 diene systems with (E)- or (Z)
geometry which can further confirm the proposed (Z) con-
figuration of the C14 double bond of 1.
During our attempt directed towards the total synthesis
of 1 and analogs, we have synthesized two (Z)-∆14-config-
ured intermediates which have provided additional corrobo-
ration of the new proposed structure of naturally derived
mycothiazole.
Results and Discussion
As shown in Scheme 1, our retrosynthetic strategy for 1
is based in a convergent approach. We envisioned that a
coupling reaction of a 1,4-dienethiazole, C8–C18 segment 2
and 1,3-diene system 3,[8] would be furnished by a regio-
and stereoselective metal mediated allylation.
In order to obtain the 1,4-diene with the (Z) configura-
tion we considered two different approximations: a metal
cross-coupling methodology and a Wittig-like approach.
Firstly, silyl-protected amide 4a was prepared with the use
of standard procedures from methyl 3-hydroxy-2,2-dimeth-
ylpropanoate. Treatment of this compound with Lawesson’s
reagent[9] followed by Hantzsch’s methodology[10] gave the
thiazole in moderate yield (50%). By using an aprotic sol-
vent such as THF, an intermediary 2-thiazoline was ob-
[a] Departamento de Química Fundamental, Facultad de Ciencias,
Universidad de A Coruña,
15071 A Coruña, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 934–942

Mycothiazole: the C8–C18 Subunit and the (Z)-∆14 Double Bond
FULL PAPER
1
served by H NMR spectroscopic analysis, which was then
dehydrated with trifluoroacetic acid to afford thiazolic com-
pound 5a in almost quantitative yield (see Scheme 2). The
resulting ester was fully reduced and later brominated to
give thiazole 6a. The bromide was then converted into ter-
minal alkyne 7 through an indium/palladium assisted cross-
coupling reaction developed by Sarandeses et al.[11] This al-
kyne was transformed into 8 by copper catalysis, and then
hydrogenated under LindlarЈs conditions to diene 9 in a
very moderate yield (26%, see Scheme 3).
Scheme 2. Synthesis of the thiazole core. Reagents and conditions:
(i): 1. TBDPSCl, imidazole, DMF, 95%; 2. KOH, EtOH, 80%; 3.
PCl5, hexanes, then aq. NH3, 85%. (ii): 1. BnBr, NaH, 70%; 2.
KOH, EtOH, 95%; 3. PCl5, hexanes, then aq. NH3, 90%. (iii): 1.
Lawesson, DCM, 90%; 2. BrCH2COCO2Et, Py, TFAA, THF,
95%. (iv): 1. Lawesson, DCM, 95%; 2. BrCH2COCO2Et, EtOH,
∆, 95%. (v): 1. DIBAL-H, Et2O, –78 °C, 90%; 2. CBr4, Ph3P, THF,
95%. (vi): 1. DIBAL-H, DCM, –40 °C, 80%; 2. CBr4, Ph3P, THF,
80%.
Scheme 3. Synthesis of C8–C18 fragments of mycothiazole with a
(Z)-∆14 configuration. Reagents and conditions: (i): InCl3, ϵMgBr,
Pd(dppf)Cl2, THF, 70%. (ii): CH2=CHCH2Br EtMgBr, CuBr,
THF, 80%. (iii): H2; Lindlar, quinoline,THF/EtOH, 26%. (iv): 1.
Lawesson, DCM, 95%; 2. ClCH2COCH2CO2Et, EtOH, ∆, 95%;
3. DIBAL-H, PhMe, 95%. (v): CH2=CHCH2CH2PPh3Br, nBuLi,
THF, 41%.
A more direct route to obtain a similar diene involved a
The second strategy to obtain (Z)-analog 11 involved the cross metathesis process of 12b and 1,4-pentadiene, a CM
synthesis of the thiazole core from the thioamide of 4b (pre- type I alkene (rapid homodimerization). Attempted metath-
viously synthesized in Scheme 2) and ethyl 4-chloro-3- esis reaction between these two alkenes in the presence of
oxobutyrate. The resulting ester was reduced with the use the Grubbs second generation catalyst at room temperature
of DIBAL-H in toluene to afford aldehyde 10, which was was unsuccessful (Scheme 4). However, the reaction heated
used for the key Wittig reaction with 3-butenyltri- at 40 °C with 7.8 equiv. of diene and in the presence of 8%
phenylphosphonium bromide. This reaction to (Z)-∆14 al- loading of catalyst in dichloromethane proceeded with very
kene 11 resulted in low conversion (41%), which was likely poor conversion. After chromatographic removal of the ru-
a result of enolization of the aldehyde during formation of thenium residues, we isolated unreacted alkene 12b, homo-
the double bond.
In additional effort to confirm the (Z) configuration of from the diene, and desired product 14b in only 20% yield.
the C14 double bond, and to have more spectroscopic data With both (Z) and (E) models in hand, edited gHSQC
dimerization, and polymerization side products derived
for this type of system, we decided to obtain the same diene experiments were run to verify assignments for carbons and
but with an (E) geometry. We envisioned an ene cross me- protons from C13 to C16 (see Figure 1). The highfield val-
tathesis (CM) approach, where 6a was converted into CM ues observed for (Z) models 9 and 11 at C13 (δC
=
type III alkene 12a[12] (no homodimerization) by using in- 29.8 ppm) and C16 (δC = 31.7 ppm) matched those reported
dium trichloride cross coupling chemistry.[11] This terminal for the natural product, whereas the same carbons reso-
alkene was metathesized with tosylated 5-pentenol, a CM nated downfield in (E) compound 14a. Clearly, the carbon
type II alkene,[13] by using the second generation ruthenium chemical shifts for C13 and C16 in 9 and 11 showed a note-
alkylidine complex as a catalyst,[14] to give 13 in a 68% worthy steric compression effect, as one would expect.[16]
yield. The E/Z selectivity of the reaction was strongly domi-
In conclusion, NMR studies confirmed the (Z) configu-
nated by the (E) isomer, with small amounts of the sterically ration of the ∆14 double bond of mycothiazole, as reported
less favored (Z) isomeric double bond.[15] β-elimination of very recently by Crews and coworkers. Investigations di-
the tosyl group in 13 gave desired product 14a by using NaI rected at the total synthesis of 1 are underway in our re-
and DBU in DME.
search group.
Eur. J. Org. Chem. 2007, 934–942
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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935

M. Rega, P. Candal, C. Jiménez, J. Rodríguez
FULL PAPER
Scheme 4. Synthesis of analogs of mycothiazole with a (E)-∆14 configuration. Reagents and conditions: (i): InCl3,CH2=CHMgBr,
Pd(dppf)Cl2, THF, 80%; (ii): CH2=CHCH2CH2CH2OTs, Grubbs 2nd generation, catalyst, PhMe, 80 °C, 50%. (iii):
CH2=CHCH2CH=CH2, Grubbs 2nd generation, CH2Cl2, room temp., 20%. (iv): NaI, DBU, DME, 20%.
ing: hexanes and ethyl acetate used in chromatography were dis-
tilled prior to use. Reactions were monitored by thin layer
chromatography (TLC) carried out on Merck silica gel plates (60
F254) by using UV light as the visualizing agent and an ethanolic
solution of phosphomolybdic acid or p-anisaldehyde/sulfuric acid/
acetic acid and heat as developing agents. Flash chromatography
was performed on silica gel Merck 60 (230–400 mesh) following
Still conditions. 1H NMR spectra were recorded with a Bruker AC
200F (200 MHz) and Bruker Avance 300 (300 MHz) and 500
(500 MHz). Chemical shifts are reported with the solvent as the
internal standard (CHCl3 δ = 7.26 ppm, C6H6 δ = 7.16 ppm). Data
are reported as follows: chemical shift, multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, br. = broad, m = multiplet
or overlap of non-equivalent resonances), coupling constants (Hz),
integration and assignment. 13C NMR spectra were recorded with
a Bruker AC 200F (50 MHz) and Bruker Avance 300 (75 MHz)
and 500 (125 MHz) with complete proton decoupling. Chemical
shifts are reported in ppm with the solvent as an internal reference
(CDCl3 δ = 77.16 ppm, C6H6 δ = 128.26 ppm). Data are reported
as follows: chemical shift, multiplicity with respect to proton (de-
duced from DEPT experiments, s = quaternary C, d = CH, t =
CH2, q = CH3), and assignment. LRESIMS or ApCIMS spectra
were run with a Thermoquest Navigator spectrometer using MeOH
as a solvent. HRESIMS were measured with a Bruker FTMS Apex
or a Waters Q-TOF Premier spectrometer.
3-(tert-Butyldiphenylsilyloxy)-2,2-dimethylpropanamide (4a): To a
stirred solution of methyl 2,2-dimethyl-3-hydroxypropionate (2 mL,
15.4 mmol) in anhydrous N,N-dimethylformamide (10 mL), cooled
in a ice bath, imidazole (4.10 g, 59.6 mmol) and tert-butyldiphenyl-
silane chloride (5 mL, 18.8 mmol) were slowly added. The reaction
mixture was stirred at 0 °C for 15 min and then warmed to room
temperature. After 12 h, a 5% solution of hydrochloric acid
(15 mL) was added, and the aqueous phase was extracted with di-
ethyl ether (3ϫ20 mL). The combined organic extracts were
washed with water (50 mL) and a saturated aqueous solution of
NaCl (50 mL), dried with Na2SO4, filtered, and concentrated under
reduced pressure. The yellow oil obtained was flash chromato-
graphed (silica gel, 10% ethyl acetate in hexanes) to give methyl 3-
(tert-butyldiphenylsilyloxy)-2,2-dimethylpropanoate as a colorless
oil (5.4 g, 95%).1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.66 (m,
4 H, SiPh), 7.41 (m, 6 H, SiPh), 3.68 (s, 3 H, OCH3), 3.66 (s, 2 H,
8-H), 1.21 (s, 6 H, 20-H and 21-H), 1.04 [s, 9 H, SiC(CH3)3] ppm.
13C NMR (75 MHz, CDCl3): δ = 177.0 (s, C-10), 135.7 (d, SiPh),
133.6 (s, SiPh), 129.7 (d, SiPh), 127.7 (d, SiPh), 70.9 (t, C-8), 51.7
Figure 1. Edited gHSQC experiment of models 11 (in CDCl3) and
14a (in C6D6).
Experimental Section
General Methods: All reactions were conducted in oven (135 °C) or
flame-dried glassware under an inert atmosphere of dry argon (Ar-
gon C50) with dry solvents under anhydrous conditions, unless
otherwise noted. Solvents were dried by distillation from a suitable
desiccating agent. Tetrahydrofuran, diethyl ether, toluene, and di-
methylethyleneglycol were distilled from sodium/benzophenone.
Dichloromethane, hexane, and acetonitrile were distilled from cal-
cium hydride. Pyridine was distilled from potassium hydroxide.
Starting materials and reagents were purchased from commercial
suppliers and used without further purification except the follow-
936
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Eur. J. Org. Chem. 2007, 934–942

Mycothiazole: the C8–C18 Subunit and the (Z)-∆14 Double Bond
FULL PAPER
(q, OCH3), 45.1 (s, C-9), 26.8 [q, SiC(CH3)3], 22.2 (q, C-20 and C-
m/z (%) = 223 (4) [M + H]+, 245 (34) [M + Na]+, 261 (8)
21), 19.4 [s, SiC(CH3)3] ppm. (+)-LRESIMS: m/z (%) = 371 (3) [M + K]+, 277 (100) [M + Na + MeOH]+.
[M + H]+, 393 (100) [M + Na]+, 409 (5) [M + K]+.
To a stirred solution of methyl 3-(benzyloxy)-2,2-dimethylpropano-
ate (4.6 g, 20.8 mmol) in ethanol (50 mL), a 10% KOH ethanol
solution (20 mL) was added. The reaction mixture was heated at
reflux for 24 h and then poured into ice (100 mL). By the addition
of a 10% solution of hydrochloric acid, the formation of a white
solid was observed, until pH 3–4. The mixture was extracted with
dichloromethane (3ϫ100 mL), and the organic phase was dried
with MgSO4, filtered, and concentrated in vacuo. The crude mate-
rial, 3-(benzyloxy)-2,2-dimethylpropanoic acid, was obtained as a
To a stirred solution of methyl 3-(tert-butyldiphenylsilyloxy)-2,2-
dimethylpropanoate (5.6 g, 15 mmol) in ethanol (50 mL), a 10%
KOH ethanol solution (25 mL) was added. The reaction mixture
was heated at reflux for 24 h and then poured into ice (200 mL).
By the addition of a 10% solution of hydrochloric acid, the forma-
tion of a white solid was observed, until pH 3–4. The mixture was
extracted with dichloromethane (3ϫ300 mL), and the organic
phase was dried with MgSO4, filtered, and concentrated in vacuo.
The residue was flash chromatographed (silica gel, 10% ethyl ace-
tate in hexanes) to give 3-(tert-butyldiphenylsilyloxy)-2,2-dimeth-
ylpropanoic acid as a white solid (4.3 g, 80%). 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.67 (m, 4 H, SiPh), 7.41 (m, 6 H, SiPh), 3.67
(s, 2 H, 8-H), 1.24 (s, 6 H, 20-H and 21-H), 1.06 [s, 9 H, SiC-
(CH3)3] ppm. 13C NMR (50 MHz, CDCl3): δ = 183.0 (s, C-10),
135.7 (d, SiPh), 133.4 (s, SiPh), 129.8 (d, SiPh), 127.9 (d, SiPh),
70.6 (t, C-8), 44.9 (s, C-9), 26.9 [q, SiC(CH3)3], 22.0 (q, C-20 and
C-21), 19.5 [s, SiC(CH3)3] ppm. (+)-LRESIMS: m/z (%) = 357 (4)
[M + H]+, 379 (100) [M + Na]+, 395 (3) [M + K]+. (+)-HRESIMS:
calcd. for C21H29O3Si [M + H]+ 357.1886; found 357.1896.
1
white solid (4.1 g, 95%). H NMR (200 MHz, CDCl3, 25 °C): δ =
11.49 (br. s, 1 H, OH), 7.35 (m, 5 H, Ph), 4.59 (s, 2 H, CH2Ph),
3.51 (s, 2 H, 8-H), 1.28 (s, 6 H, 20-H and 21-H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 182.9 (s, C-10), 138.1 (s, Ph), 127.5 (d,
Ph),127.4 (d, Ph), 76.5 (t, C-8), 73.3 (t, CH2Ph), 43.5 (s, C-9), 22.3
(q, C-20 and C-21) ppm. (+)-LRESIMS: m/z (%) = 209 (12) [M +
H]+, 231 (100) [M + Na]+, 263 (10) [M + Na + MeOH]+. (+)-
HRESIMS: calcd. for C12H17O3 [M + H]+ 209.1178; found:
209.1178.
To a stirred suspension of 3-(benzyloxy)-2,2-dimethylpropanoic
acid (4.1 g, 19.7 mmol) in anhydrous hexane (60 mL), cooled in an
ice bath, was added phosphorus pentachloride (4.8 g, 21.7 mmol).
The resultant suspension was stirred for 10 min at 0 °C and 1 h at
room temperature. A 30% solution of ammonia (12 mL) was slowly
added at 0 °C, and the reaction was stirred at this temperature for
3 h. Water (200 mL) was added, and the mixture was extracted with
dichloromethane (3ϫ100 mL). The organic phase was dried with
MgSO4, filtered, and concentrated in vacuo. The crude material, 3-
(benzyloxy)-2,2-dimethylpropanamide (4b), was obtained as a
To a stirred suspension of 3-(tert-butyldiphenylsilyloxy)-2,2-di-
methylpropanoic acid (2.5 g, 7.10 mmol) in anhydrous hexane
(10 mL), cooled in an ice bath, was added phosphorus pentachlo-
ride (2.18 g, 9.94 mmol). The resultant suspension was stirred for
10 min at 0 °C and 1 h at room temperature. A 30% solution of
ammonia (5 mL) was slowly added at 0 °C, and the reaction was
stirred at this temperature for 3 h. Water (50 mL) was added, and
the mixture was extracted with dichloromethane (3ϫ50 mL). The
organic phase was dried with MgSO4, filtered, and concentrated in
vacuo. The residue was flash chromatographed (silica gel, 30%
ethyl acetate in hexanes) to give 3-(tert-butyldiphenylsilyloxy)-2,2-
1
white solid (3.7 g, 90%). H NMR (200 MHz, CDCl3, 25 °C): δ =
7.33 (m, 5 H, Ph), 6.65 (br. s, 1 H, NH2), 5.95 (br. s, 1 H, NH2),
4.56 (s, 2 H, CH2Ph), 3.43 (s, 2 H, 8-H), 1.19 (s, 6 H, 20-H and 21-
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 179.7 (s, C-10), 137.6
(s, Ph), 128.5 (d, Ph), 128.4 (d, Ph), 127.8 (d, Ph), 127.5 (d, Ph),
127.3 (d, Ph), 76.6 (t, C-8), 73.5 (t, CH2Ph), 42.6 (s, C-9), 23.0 (q,
1
dimethylpropanamide (4a) as a white solid (2.1 g, 85%). H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.68 (m, 4 H, SiPh), 7.43 (m, 6 H,
SiPh), 6.71 (br. s, 1 H, NH2), 5.42 (br. s, 1 H, NH2), 3.62 (s, 2 H,
8-H), 1.16 (s, 6 H, 20-H and 21-H), 1.09 [s, 9 H, SiC(CH3)3] ppm.
13C NMR (50 MHz, CDCl3): δ = 179.6 (s, C-10), 135.6 (d, SiPh),
132.6 (s, SiPh), 129.9 (d, SiPh), 127.8 (d, SiPh), 70.2 (t, C-8), 43.6
(s, C-9), 26.9 [q, SiC(CH3)3], 22.6 (q, C-20and C-21), 19.2 [s,
SiC(CH3)3] ppm. (+)-LRESIMS: m/z (%) = 356 (25) [M + H]+, 378
(100) [M + Na]+, 394 (33) [M + K]+. (+)-HRESIMS: calcd. for
C21H30NO2Si [M + H]+ 356.2046; found 356.2045.
C-20 and C-21) ppm. (+)-LRESIMS: m/z (%)
= 208 (44)
[M + H]+, 230 (100) [M + Na]+, 246 (21) [M + K]+. (+)-HRESIMS:
calcd. for C12H18NO2 [M + H]+ 208.1338; found 208.1341.
Ethyl 2-[2-(tert-Butyldiphenylsilyloxy)-1,1-dimethylethyl]thiazol-4-
carboxylate (5a): To a stirred suspension of LawessonЈs reagent
(0.36 g, 0.86 mmol) in anhydrous dichloromethane (6 mL) was
added a solution of 3-(tert-butyldiphenylsilyloxy)-2,2-dimethylpro-
panamide (4a) (0.5 g, 1.42 mmol) in anhydrous dichloromethane
(6 mL). The reaction mixture was stirred for 24 h. The solvent was
evaporated under reduced pressure, and water/diethyl ether (1:1,
20 mL) was added to the residue. The aqueous phase was extracted
with diethyl ether (3ϫ10 mL), and the combined organic extracts
were washed with a saturated aqueous solution of NaHCO3
(50 mL) and a saturated aqueous solution of NaCl (50 mL), dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The yellow solid obtained was flash chromatographed (silica gel,
30% ethyl acetate in hexanes) to give 3-(tert-butyldiphenylsilyloxy)-
2,2-dimethylpropanethioamide as a white solid (0.48 g, 90%). 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 8.5 (br. s, 1 H, NH2), 7.65
(m, 4 H, SiPh), 7.43 (m, 6 H, SiPh), 3.62 (s, 2 H, 8-H), 1.3 (s, 6 H,
20-H and 21-H), 1.09 [s, 9 H, SiC(CH3)3] ppm. 13C NMR (50 MHz,
CDCl3): δ = 217.2 (s, C-10), 135.7 (d, SiPh), 132.4 (s, SiPh), 130.2
3-(Benzyloxy)-2,2-dimethylpropanamide (4b): To a stirred suspen-
sion of 60% sodium hydride (NaH) in mineral oil (4.5 g,
111.2 mmol) in anhydrous tetrahydrofuran (40 mL), cooled in an
ice bath, was added methyl 2,2-dimethyl-3-hydroxypropionate
(4.8 mL, 37.0 mmol). The resultant suspension was stirred for
20 min at room temperature. Benzyl bromide (4.5 mL, 37 mmol)
was slowly added at 0 °C, and the reaction was stirred at room
temperature for 24 h. The reaction suspension was chilled in an ice
bath, and the excess NaH was quenched with water (50 mL). The
reaction mixture was extracted with ethyl acetate (3ϫ50 mL). The
combined organics were dried with MgSO4, filtered, and concen-
trated. The residue was flash chromatographed (silica gel, 10%
ethyl acetate in hexanes) to give methyl 3-(benzyloxy)-2,2-dimethyl-
propanoate as a colorless oil (5.6 g, 70%). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 7.32 (m, 5 H, Ph), 4.54 (s, 2 H, CH2Ph), 3.69 (d, SiPh), 128.0 (d, SiPh), 71.6 (t, C-8), 48.3 (s, C-9), 27.1 [q,
(s, 3 H, OCH3), 3.47 (s, 2 H, 8-H), 1.23 (s, 6 H, 20-H and 21-H)
SiC(CH3)3], 25.9 (q, C-20 and C-21), 19.4 [s, SiC(CH3)3] ppm. (+)-
ppm. 13C NMR (75 MHz, CDCl3): δ = 177 (s, C-10), 138.3 (s, Ph), LRESIMS: m/z (%) = 372(39) [M + H]+, 394 (8) [M + Na]+. (+)-
128.2 (d, Ph), 127.3 (d, Ph), 76.8 (t, C-8), 73.1 (t, CH2Ph), 52.8 (q, HRESIMS: calcd. for C21H30NOSSi [M + H]+ 372.1817; found
OCH3), 43.8 (s, C-9), 26.2 (q, C-20 and C-21) ppm. (+)-LRESIMS:
372.1820.
Eur. J. Org. Chem. 2007, 934–942
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937

M. Rega, P. Candal, C. Jiménez, J. Rodríguez
FULL PAPER
To a stirred solution of 3-(tert-butyldiphenylsilyloxy)-2,2-dimethyl-
propanethioamide (0.05 g, 0.136 mmol) in anhydrous dimethyl-
formamide (2.5 mL) was added ethyl bromopyruvate (0.05 mL,
0.358 mmol). The reaction mixture was stirred at room temperature
for 2 h, and ethyl acetate (40 mL) was added to dilute. The organic
phase was washed with water (3ϫ40 mL), dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
flash chromatographed (silica gel, 10% ethyl acetate in hexanes)
to give ethyl 2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4-
47.3 (s, C-9), 26.2 (q, C-20 and C-21) ppm. (+)-LRESIMS: m/z (%)
= 224 (100) [M + H]+, 246 (50) [M + Na]+. (+)-HRESIMS: calcd.
for C12H18NOS [M + H]+ 224.1109; found 224.1104.
To a stirred solution of 3-(benzyloxy)-2,2-dimethylpropanethio-
amide (1.0 g, 4.6 mmol) in ethanol (40 mL) was added ethyl bromo-
pyruvate (1.0 mL, 7.2 mmol). The reaction mixture was heated at
reflux for 24 h. The solvent was evaporated under reduced pressure,
and a mixture of saturated aqueous solution of NaHCO3/diethyl
ether (1:1, 40 mL) was added to the residue. The aqueous phase
was extracted with diethyl ether (3ϫ20 mL), and the combined
organic extracts were dried with Na2SO4, filtered, and concentrated
under reduced pressure. The residue was flash chromatographed
(silica gel, 30% ethyl acetate in hexanes) to give ethyl 2-(2-ben-
zyloxy-1,1-dimethylethyl)thiazol-4-carboxylate (5b) as a yellow oil
(1.3 g, 95%). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 8.05 (s, 1 H,
11-H), 7.31 (m, 5 H, Ph), 4.52 (s, 2 H, CH2Ph), 4.39 (q, 3J = 7.1 Hz,
2 H, OCH2CH3), 3.62 (s, 2 H, 8-H), 1.53 (s, 6 H, 20-H and 21-H),
1.39 (t, 3J = 7.1 Hz, 3 H, OCH2CH3) ppm. (+)-LRESIMS: m/z (%)
= 320 (100) [M + H]+, 342 (77) [M + Na]+.
hydroxy-4,5-dihydrothiazol-4-carboxylate as
a
colorless oil
1
(0.066 g, 90%). H NMR (200 MHz, CDCl3, 25 °C): δ = 7.65 (m,
4 H, SiPh), 7.39 (m, 6 H, SiPh), 4.25 (dq, 3J = 2.5, 7.1 Hz, 2 H,
OCH2CH3), 3.82 (d, 3J = 12.0 Hz, 1 H, 11-H), 3.34 (d, 3J =
12.0 Hz, 1 H, 11Ј-H), 3.66 (s, 2 H, 8-H), 1.26 (m, 9 H, 20-H and
21-H and OCH2CH3), 1.05 [s, 9 H, SiC(CH3)3] ppm. 13C NMR
(50 MHz, CDCl3): δ = 184.5 (s. C-10), 171.3 (s, C-13), 135.8 (d,
SiPh), 133.6 (s, SiPh), 129.7 (d, SiPh), 127.7 (d, SiPh), 105.5 (s, C-
12), 71.5 (t, C-12), 62.8 (t, CH3CH2O), 44.1 (s, C-9), 40.3 (t, C-11),
26.9 [q, SiC(CH3)3], 24.4 (t, C-20 and C-21), 19.5 [s, SiC(CH3)3],
14.1 (q, CH3CH2O) ppm. (+)-LRESIMS: m/z (%) = 486 (100) [M
+ H]+, 508 (37) [M + Na]+.
4-Bromomethyl-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-
thiazole (6a): To a stirred solution of ethyl 2-[2-(tert-butyldiphenyl-
silyloxy)-1,1-dimethylethyl]thiazol-4-carboxylate (5a) (0.34 g,
0.72 mmol) in anhydrous diethyl ether (5 mL) at –78 °C, was slowly
added DIBAL-H (1.6 mL, 1.6 mmol). After 1 h, the reaction was
quenched with a 1  aqueous solution of KHSO4 (2 mL) and
stirred for 1 h. The mixture was extracted with diethyl ether
(3ϫ5 mL), and the combined organic extracts were washed with a
1  aqueous solution of KHSO4 (3ϫ5 mL), water (5 mL) and a
saturated aqueous solution of NaCl (5 mL), dried with MgSO4,
filtered, and concentrated in vacuo. The residue was flash chro-
matographed (silica gel, 20% ethyl acetate in hexanes) to give 4-
hydroxymethyl-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-
thiazole as a white solid (0.28 g, 90 %). 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.61 (m, 4 H, SiPh), 7.38 (m, 6 H, SiPh), 7.05
(t, J = 0.9 Hz, 1 H, 11-H), 4.74 (d, J = 4.6 Hz, 2 H, 13-H), 3.76
(s, 2 H, 8-H), 3.12 (t, 3J = 4.6 Hz, 1 H, OH), 1.47 (s, 6 H, 20-H
and 21-H), 1.03 [s, 9 H, SiC(CH3)3] ppm. 13C NMR (50 MHz,
CDCl3): δ = 178.6 (s, C-10), 155.5 (s, C-12), 135.6 (d, SiPh), 133.1
(s, SiPh), 129.7 (d, SiPh), 127.6 (d, SiPh), 113.7 (d, C-11), 72.4 (t,
C-8), 61.0 (t, C-13), 43.2 (s, C-9), 27.3 [q, SiC(CH3)3], 25.4 (q, C-
20 and C-21), 19.5 [s, SiC(CH3)3] ppm. (+)-LRESIMS: m/z (%) =
426 (61) [M + H]+, 448 (100) [M + Na]+, 464 (24) [M + K]+. (+)-
HRESIMS: calcd. for C24H32NO2SiS [M + H]+ 426.1923; found
426.1938.
To a stirred solution of 3-(tert-butyldiphenylsilyloxy)-2,2-dimethyl-
propanethioamide (0.42 g, 1.12 mmol) in anhydrous tetra-
hydrofuran (25 mL) was added ethyl bromopyruvate (0.5 mL,
3.58 mmol). The reaction mixture was stirred at room temperature
for 2 h and anhydrous pyridine (2 mL) and trifluoroacetic anhy-
dride (0.25 mL, 1.75 mmol) were added. Dichloromethane
(100 mL) was added to dilute. The organic phase was washed with
saturated aqueous solution of NaHCO3 (3ϫ100 mL) and water
(3ϫ100 mL), dried with Na2SO4, filtered, and concentrated under
reduced pressure. The residue was flash chromatographed (silica
gel, 10% ethyl acetate in hexanes) to give ethyl 2-[2-(tert-butyldi-
phenylsilyloxy)-1,1-dimethylethyl]thiazol-4-carboxylate (5a) as a
1
colorless oil (0.495 g, 95%). H NMR (200 MHz, CDCl3, 25 °C):
δ = 8.09 (s, 1 H, 11-H), 7.62 (m, 4 H, SiPh), 7.38 (m, 6 H, SiPh),
3
3
3
4.43 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.82 (s, 2 H, 8-H), 1.52 (s,
3
6 H, 20-H and 21-H), 1.41 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.05
[s, 9 H, SiC(CH3)3] ppm. 13C NMR (50 MHz, CDCl3): δ = 178.4
(s, C-10), 161.5 (s, C-13), 146.5 (s, C-12), 135.6 (d, SiPh), 133.1 (s,
SiPh), 129.7 (d, SiPh), 127.6 (d, SiPh), 126.8 (d, 11-C), 72.4 (t, 8-
C), 61.0 (t, CH3CH2O), 43.4 (s, 9-C), 26.8 [q, SiC(CH3)3], 25.4 (t,
20-C and 21-C), 19.5 [s, SiC(CH3)3], 14.4 (q, CH3CH2O) ppm. (+)-
LRESIMS: m/z (%) = 468 (48) [M + H]+, 490 (100) [M + Na]+,
506 (5) [M + K]+.
Ethyl 2-(2-Benzyloxy-1,1-dimethylethyl)thiazol-4-carboxylate (5b):
To a stirred suspension of LawessonЈs reagent (5.5 g, 13.3 mmol)
in anhydrous dichloromethane (20 mL) was added a solution of
3-(benzyloxy)-2,2-dimethylpropanamide (4b) (2.5 g, 12.0 mmol) in
anhydrous dichloromethane (20 mL). The reaction mixture was
stirred for 24 h. The solvent was evaporated under reduced pres-
sure, and water/diethyl ether (1:1, 60 mL) was added to the residue.
The aqueous phase was extracted with diethyl ether (3ϫ30 mL),
and the combined organic extracts were washed with a saturated
aqueous solution of NaHCO3 (100 mL) and a saturated aqueous
solution of NaCl (100 mL), dried with Na2SO4, filtered, and con-
centrated under reduced pressure. The yellow solid obtained was
flash chromatographed (silica gel, 30% ethyl acetate in hexanes)
to give 3-benzyloxy-2,2-dimethylpropanethioamide as a white solid
To a stirred solution of 4-hydroxymethyl-2-[2-(tert-butyldiphenyl-
silyloxy)-1,1-dimethylethyl]thiazole (0.34 g, 0.80 mmol) and carbon
tetrabromide (0.58 g, 1.73 mmol) in anhydrous tetrahydrofuran
(5 mL), cooled in an ice bath, was added a solution of tri-
phenylphosphane (0.50 g, 1.88 mmol) in tetrahydrofuran (5 mL).
The reaction was then warmed to room temperature. After 30 min,
the reaction was quenched with a saturated aqueous solution of
NaHCO3 (15 mL). The mixture was extracted with diethyl ether
(3ϫ10 mL), and the combined organic extracts were washed with
water (30 mL) and a saturated aqueous solution of NaCl (30 mL),
dried with MgSO4, filtered, and concentrated in vacuo. The residue
was flash chromatographed (silica gel, 5% ethyl acetate in hexanes)
to give 4-bromomethyl-2-[2-(tert-butyldiphenylsilyloxy)-1,1-di-
methylethyl]thiazole (6a) as a colorless oil (0.37 g, 95%). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.62 (m, 4 H, SiPh), 7.42 (m, 6 H,
SiPh), 7.22 (s, 1 H, 11-H), 4.63 (d, 2 H, 13-H), 3.28 (s, 2 H, 8-H),
1
(2.5 g, 95%). H NMR (200 MHz, CDCl3, 25 °C): δ = 8.38 (br. s,
1 H, NH2), 7.83 (br. s, 1 H, NH2), 7.33 (m, 5 H, Ph), 4.57 (s, 2 H,
CH2Ph), 3.54 (s, 2 H, 8-H), 1.34 (s, 6 H, 20-H and 21-H) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 216.5 (s, C-10), 137.3 (s, Ph), 128.5 1.49 (s, 6 H, 20-H and 21-H), 1.03 [s, 9 H, SiC(CH3)3] ppm. 13C
(d, Ph), 128.0 (d, Ph), 127.6 (d, Ph), 77.6 (t, C-8), 73.7 (t, CH2Ph), NMR (50 MHz, CDCl3): δ = 178.6 (s, C-10), 151.3 (s, C-12), 135.6
938
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 934–942

Mycothiazole: the C8–C18 Subunit and the (Z)-∆14 Double Bond
FULL PAPER
(d, SiPh), 133.1 (s, SiPh), 129.7 (d, SiPh), 127.6 (d, SiPh), 117 (d,
and Et2O (5 mL) was added. The organic phase was washed with
C-11), 72.4 (t, C-8), 43.2 (s, C-9), 27.8 (t, C-13), 27 [q, SiC(CH3)], aqueous HCl (10%, 5 mL), saturated aqueous NaHCO3 (10 mL),
25.4 (q, C-20 and C-21), 19.5 [s, SiC(CH3)3] ppm. (+)-LRESIMS;
m/z (%) = 488 (72) [M + H, 79Br]+, 490 (74) [M + H, 81Br]+, 510
(81) [M + Na, 79Br]+, 512 (100) [M + Na, 81Br]+.
and saturated aqueous NaCl (10 mL), dried, filtered, and concen-
trated in vacuo. The residue was flash chromatographed (silica gel,
10% ethyl acetate in hexanes) to give 2-[2-(tert-butyldiphenylsilyl-
oxy)-1,1-dimethylethyl]-4-prop-2-ynylthiazole (7) as a yellow oil
4-Bromomethyl-2-(2-benzyloxy-1,1-dimethylethyl)thiazole (6b): To a
stirred solution of ethyl 2-(2-benzyloxy-1,1-dimethylethyl)thiazol-
4-carboxylate (5b) (1.4 g, 4.4 mmol) in anhydrous dichloromethane
(20 mL) at –40 °C, was slowly added DIBAL-H (15 mL, 15 mmol).
After 20 min, the addition of DIBAL-H (5 mL, 5 mmol) was re-
peated. The reaction was followed by TLC repeating additions of
DIBAL-H until the end of the reaction. When the starting material
had disappeared, the reaction was quenched with methanol and
then poured into ice with a 10% solution of hydrochloric acid.
After 15 min the mixture was extracted with diethyl ether
(3ϫ100 mL), and the organic phase was dried with MgSO4, fil-
tered, and concentrated in vacuo. The residue was flash chromato-
graphed (silica gel, 20 % ethyl acetate in hexanes) to give 4-hy-
droxymethyl-2-(2-benzyloxy-1,1-dimethylethyl)thiazole as a yellow
1
(0.063 g, 70%). H NMR (200 MHz, CDCl3, 25 °C): δ = 7.60 (m,
3
4 H, SiPh), 7.38 (m, 6 H, SiPh), 7.16 (t, J = 1.2 Hz, 1 H, 11-H),
3
3.76 (br. s, 4 H, 13-H and 8-H), 2.23 (t, J = 2.7 Hz, 1 H, 15-H),
1.47 (s, 6 H, 20-H and 21-H), 1.04 [s, 9 H, SiC(CH3)3] ppm. 13C
NMR (50 MHz, CDCl3): δ = 178.2 (s, C-10), 150.5 (s, C-12), 135.6
(d, SiPh), 133.1 (s, SiPh), 129.7 (d, SiPh), 127.6 (d, SiPh), 113.5 (d,
C-11), 80.8 (s, C-14), 72.4 (t, C-8), 70.5 (d, C-15), 43.2 (s, C-9),
27.3 [q, SiC(CH3)3], 25.4 (q, C-20 and C-21), 22.2 (t, C-13), 19.5
[s, SiC(CH3)3] ppm. (+)-LRESIMS: m/z (%) = 434(62) [M + H]+,
456 (100) [M + Na]+.
2-[2-(tert-Butyldiphenylsilyloxy)-1,1-dimethylethyl]-4-hex-5-en-2-
ynylthiazole (8): To a stirred solution of 2-[2-(tert-butyldiphenyl-
silyloxy)-1,1-dimethylethyl]-4-prop-2-ynylthiazole (7) (0.179 g,
0.413 mmol) in anhydrous tetrahydrofuran (1.5 mL), ethylmagne-
sium bromide (0.2 mL, 0.60 mmol) was slowly added. The reaction
mixture was then heated for 1 h at reflux and cooled to 20 °C. A
tiny amount of copper(I) bromide was then added in one portion,
and the mixture was stirred for 15 min. Allyl bromide
(0.12 mL,1.37 mmol) were added dropwise, and the temperature
was raised again to reflux. After 1 h, the reaction mixture was co-
oled and hydrolyzed with a saturated aqueous solution of NH4Cl
(3 mL). The water layer was extracted with diethyl ether (3ϫ2 mL),
and the extracts were dried with Na2SO4, filtered, and concentrated
in vacuo. The residue was flash chromatographed (silica gel, 2%
diethyl ether in hexanes) to give 2-[2-(tert-butyldiphenylsilyloxy)-
1,1-dimethylethyl]-4-hex-5-en-2-ynylthiazole (8) as a colorless oil
1
oil (1.0 g, 80%). H NMR (200 MHz, CDCl3, 25 °C): δ = 7.32 (m,
5 H, Ph), 7.05 (s, 1 H, 11-H), 4.63 (d, 3J = 5.6 Hz, 2 H, 13-H), 4.51
(s, 2 H, CH2Ph), 3.63 (s, 2 H, 8-H), 3.15 (t, 3J = 5.6 Hz, 1 H, OH),
1.47 (s, 6 H, 20-H and 21-H) ppm. LRESIMS; m/z (%) = 278 (26)
[M + H]+, 300 (100) [M + Na]+, 316 (5) [M + K]+.
To a stirred solution of 4-hydroxymethyl-2-(2-benzyloxy-1,1-di-
methylethyl)thiazole (0.7 g, 2.5 mmol) and carbon tetrabromide
(1.6 g, 4.7 mmol) in anhydrous tetrahydrofuran (10 mL), cooled in
an ice bath, was added a solution of triphenylphosphane (1.4 g,
5.1 mmol) in tetrahydrofuran (10 mL). The reaction was then
warmed to room temperature. After 24 h, the solvent was evapo-
rated under reduced pressure, and the residue was flash chromato-
graphed (silica gel, 20% ethyl acetate in hexanes) to give 4-bro-
momethyl-2-(2-benzyloxy-1,1-dimethylethyl)thiazole (6b) as a col-
orless oil (0.7 g, 80%). 1H NMR (200 MHz, CDCl3, 25 °C): δ =
7.31 (m, 5 H, Ph), 7.22 (s, 1 H, 11-H), 4.63 (s, 2 H, CH2Ph), 4.53
(s, 2 H, 13-H), 3.62 (s, 2 H, 8-H), 1.42 (s, 6 H, 20-H and 21-H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 178.5 (s, C-10), 151.3 (s, C-
12), 138.4 (s, Ph), 128.3 (d, Ph), 127.3 (d, Ph), 117.3 (d, C-11), 78.8
(t, C-8), 73.3 (t, CH2Ph), 42.2 (s, C-9), 27.6 (t, C-13), 25.9 (q, C-
20 and C-21) ppm. (+)-LRESIMS: m/z (%) = 340 (69) [M + H,
79Br]+, 342 (52) [M + H, 81Br]+, 362 (100) [M + Na, 79Br]+, 364
(89) [M + Na, 81Br]+.
1
(0.157 g, 80%). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.58 (m,
3
4 H, SiPh), 7.40 (m, 6 H, SiPh), 7.13 (t, J = 1.2 Hz, 1 H, 11-H),
3
3
5.88 (tdd, J = 5.2, 10.3, 16.8 Hz, 1 H, 17-H), 5.39 (ddd, J = 1.8,
3.5, 16.9 Hz, 1 H, 18-H), 5.14 (ddd, 3J = 1.7, 3.4, 10.0 Hz, 1 H,
18Ј-H), 3.77–3.75 (m, 4 H, 13-H and 8-H), 3.04 (tt, 3J = 2.1, 4.2 Hz,
2 H, 16-H), 1.46 (s, 6 H, 20-H and 21-H), 1.02 [s, 9 H, SiC(CH3)3]
ppm. 13C NMR (75 MHz, CDCl3): δ = 178.2 (s, C-10), 152.1 (s, C-
12), 135.8 (d, SiPh), 133.6 (s, SiPh), 133.1 (d, C-17), 129.7 (d, SiPh),
127.7 (d, SiPh), 116.1 (t, C-18), 113.4 (d, C-11),79.2 (s, C-15), 79.1
(s, C-14), 72.8 (t, C-8), 43.2 (s, C-9), 26.9 [q, SiC(CH3)], 25.5 (q,
C-20 and C-21), 23.3 (t, C-16), 22.3 (t, C-13), 19.5 [s, SiC(CH3)3]
ppm. (+)-HRESIMS: calcd. for C29H36NOSSi [M + H]+ 474.2287;
found 474.2260.
General Procedure for the Preparation of Indium Organometallics:
A 25 mL round-bottomed flask furnished with a stirrer bar was
charged with InCl3 (0.37 mmol) and dried under vacuum with a
heat gun. The mixture was cooled, a positive argon pressure was
established, and dry THF (4 mL) was added. The resulting solution
was cooled to –78 °C, and a solution of RLi or RMgBr (1.1 mmol,
1.0–1.8  in hexanes, THF, or Et2O) was slowly added (15–30 min).
The mixture was stirred for 30 min, the cooling bath was removed,
and the reaction mixture was warmed to room temperature.
(Z)-2-[2-(tert-Butyldiphenylsilyloxy)-1,1-dimethylethyl]-4-(hexa-2,5-
dienyl)thiazole (9): To a stirred solution of 2-[2-(tert-butyldiphenyl-
silyloxy)-1,1-dimethylethyl]-4-hex-5-en-2-ynylthiazole (8) (0.035 g,
0.074 mmol) in ethanol/tetrahydrofuran (1:1, 0.75 mL) was added
LindlarЈs catalyst (0.004 g). Quinoline (0.01 mL, 0.081 mmol) was
also added. The reaction flask was evacuated, purged with hydro-
gen three times, and then stirred under a hydrogen atmosphere for
14 h. The reaction was filtered through celite with ethyl acetate and
the solvent evaporated under reduced pressure. The residue was
flash chromatographed (silica gel, 1% diethyl ether in hexanes) to
give (Z)-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4-
(hexa-2,5-dienyl)thiazole (9) as colorless oil (0.009 g, 26%). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.58 (m, 4 H, SiPh), 7.38 (m,
6 H, SiPh), 6.76 (t, 3J = 1.1 Hz, 1 H, 11-H), 5.92–5.57 (m, 3 H, 14-
2-[2-(tert-Butyldiphenylsilyloxy)-1,1-dimethylethyl]-4-prop-2-ynyl-
thiazole (7): A solution of ethynylindium (0.27 mmol, ≈ 0.1 ) (pre-
pared following the general procedure) was added to a mixture of
4-bromomethyl-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethyl-
ethyl]thiazole (6a) (0.10 g, 0.21 mmol) and palladium catalyst
{[1,1Ј-bis(diphenylphosphanyl)ferrocenedichloropalladium(II)],
complex with dichloromethane 1:1} (0.005 g, 0.006 mmol) in anhy-
drous tetrahydrofuran (3 mL). The resulting mixture was heated at
reflux under an argon atmosphere until the starting material was
consumed, and the reaction was then quenched by the addition of
a few drops of methanol. The mixture was concentrated in vacuo
3
H, 15-H and 17-H), 5.06 (qd, J = 1.8, 17.2 Hz, 1 H, 18-H), 4.99
3
(ddd, J = 1.6, 3.3, 10.2 Hz, 1 H, 18Ј-H), 3.74 (s, 2 H, 8-H), 3.56
3
3
(d, J = 7.2 Hz, 2 H, 13-H), 2.89 (ddd, J = 1.5, 6.3, 7.2 Hz, 2 H,
16-H), 1.45 (s, 6 H, 20-H and 21-H), 1.00 [s, 9 H, SiC(CH3)3] ppm.
Eur. J. Org. Chem. 2007, 934–942
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
939

M. Rega, P. Candal, C. Jiménez, J. Rodríguez
FULL PAPER
1H NMR (300 MHz, C6D6, 25 °C): δ = 7.71 (m, 4 H, SiPh), 7.22
Ph), 7.02 (s, 1 H, 11-H), 4.52 (s, 2 H, CH2Ph), 3.82 (d, 2 H, 13-H),
3.62 (s, 2 H, 8-H), 1.45 (s, 6 H, 20-H and 21-H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 199.2 (s, C-14), 178.2 (s, C-10), 147.4 (s, C-
3
(m, 6 H, SiPh), 6.45 (t, J = 0.9 Hz, 1 H, 11-H), 5.84–5.48 (m, 3
H, 14-H, 15-H, and 17-H), 5.03 (qd, 3J = 1.8, 17.2 Hz, 1 H, 18-H),
3
4.96 (ddd, J = 1.6, 3.4, 10.0 Hz, 1 H, 18Ј-H), 3.88 (s, 2 H, 8-H), 12), 138.3 (s, Ph), 128.5 (d, Ph), 127.6 (d, Ph), 115.4 (d, C-11), 79.3
3
3
3.55 (d, J = 7.3 Hz, 2 H, 13-H), 2.74 (ddd, J = 1.4, 6.2, 7.4 Hz,
(t, C-8), 73.2 (t, CH2Ph), 46.2 (t, C-13), 42.3 (s, C-9), 26 (q, C-20
2 H, 16-H), 1.43 (s, 6 H, 20-H and 21-H), 1.13 [s, 9 H, SiC(CH3)3] and C-21) ppm.
1
ppm. H NMR (500 MHz, C6D6, 25 °C): δ = 7.70 (m, 4 H, SiPh),
2-(2-Benzyloxy-1,1-dimethylethyl)-4-(2Z)-hexa-2,5-dienylthiazole
7.22 (m, 6 H, SiPh), 6.45 (t, 3J = 1.2 Hz, 1 H, 11-H), 5.82–5.50 (m,
(11): To a stirred suspension of 3-butenyltriphenylphosphonium
bromide (0.058 g, 0.15 mmol), in anhydrous tetrahydrofuran, a
solution of butyllithium in hexanes (0.1 mL, 0.15 mmol) was slowly
added. After 10 min, a solution of 2-(2-benzyloxy-1,1-dimethyl-
ethyl)thiazol-4-ethanal (10) (0.041 g, 0.15 mmol) in tetrahydrofuran
(1 mL) was added. The reaction was followed by TLC. When the
starting material was no longer observed, water (10 mL) was added
to the reaction. The mixture was extracted with diethyl ether
(3ϫ5 mL), and the combined organic extracts were washed with
saturated aqueous solution of NaCl (3 ϫ 20 mL), dried with
MgSO4, filtered, and concentrated in vacuo. The residue was flash
chromatographed (silica gel, 5% ethyl acetate in hexanes) to give
2-(2-benzyloxy-1,1-dimethylethyl)-4-(2Z)-hexa-2,5-dienylthiazole
(11) as a yellow oil (0.020 g, 41%). 1H NMR (200 MHz, CDCl3,
25 °C): δ = 7.33 (m, 5 H, Ph), 6.75 (t, 1 H, 11-H), 5.72 (m, 1 H,
17-H), 5.75 (m, 1 H, 14-H), 5.62 (m, 1 H, 15-H), 5.05 (m, 1 H, 18-
H), 4.54 (s, 2 H, CH2Ph), 3.63 (s, 2 H, 8-H), 3.56 (d, 1 H, 13-H),
2.89 (t, 1 H, 16-H), 1.35 (s, 6 H, 20-H and 21-H) ppm.
3 H, 14-H, 15-H, and 17-H), 5.03 (ddd, 3J = 1.7, 3.5, 17.2 Hz, 1
3
H, 18-H), 4.95 (ddd, J = 1.7, 3.2, 10.3 Hz, 1 H, 18Ј-H), 3.88 (s, 2
3
3
H, 8-H), 3.55 (d, J = 7.3 Hz, 2 H, 13-H), 2.75 (t, J = 6.7 Hz, 2
H, 16-H), 1.43 (s, 6 H, 20-H and 21-H), 1.13 [s, 9 H, SiC(CH3)3]
ppm. 13C NMR (75 MHz, CDCl3): δ = 177.7 (s, C-10), 155.1 (s, C-
12), 136.8 (d, C-17), 135.8 (d, SiPh), 133.7 (s, SiPh), 129.7 (d, SiPh),
128.8 (d, C-15), 127.7 (d, SiPh), 127.3 (d, C-14), 115.1 (t, C-18),
112.1 (d, C-11), 72.9 (t, C-8), 43.1 (s, C-9), 31.7 (t, C-16), 29.8 (t,
C-13), 26.9 [q, SiC(CH3)3], 25.5 (q, C-20 and C-21), 19.5 [s,
SiC(CH3)3] ppm. 13C NMR (75 MHz, C6D6): δ = 177.6 (s, 10-C),
155.7 (s, C-12), 137.1 (d, C-17), 136.3 (d, SiPh), 134.2 (s, SiPh),
130.2 (d, SiPh), 128.8 (d, C-15), 128.3 (d, SiPh), 128.1 (d, C-14),
115.2 (t, C-18), 112.5 (d, C-11), 73.4 (t, C-8), 43.5 (s, C-9), 32.0 (t,
C-16), 30.3 (t, C-13), 27.3 [q, SiC(CH3)3], 25.7 (q, C-20 and C-21),
19.8 [s, SiC(CH3)3] ppm. 13C NMR (125 MHz, C6D6): δ = 177.6
(s, C-10), 155.7 (s, C-12), 137.1 (d, C-17), 136.3 (d, SiPh), 134.2 (s,
SiPh), 130.2 (d, SiPh), 128.8 (d, C-15), 128.3 (d, SiPh), 128.1 (d,
C-14), 115.2 (t, C-18), 112.5 (d, C-11), 73.4 (t, C-8), 43.5 (s, C-9),
32.0 (t, C-16), 30.3 (t, C-13), 27.3 [q, SiC(CH3)3], 25.8 (q, C-20 and
C-21), 19.8 [s, SiC(CH3)3] ppm. (+)-HRESIMS: calcd. for
C29H38NOSSi [M + H]+ 476.2443; found 476.2441.
4-Allyl-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]thiazole
(12a): A solution of trivinylindium (1.2 mmol, ≈ 0.1 ) (prepared
following the general procedure) was added to a mixture of 4-bro-
momethyl-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]thi-
azole (6a) (0.5 g, 1.02 mmol) and palladium catalyst {[1,1Ј-bis(di-
phenylphosphanyl)ferrocenedichloropalladium(II)], complex with
dichloromethane 1:1} (0.029 g, 0.036 mmol) in anhydrous tetra-
hydrofuran (5 mL) heated at reflux. The resulting mixture was
heated at reflux under an argon atmosphere until the starting mate-
rial was consumed, and the reaction was then quenched by the
addition of a few drops of methanol. The mixture was concentrated
in vacuo and Et2O (10 mL) was added. The organic phase was
washed with aqueous HCl (10 %, 10 mL), saturated aqueous
NaHCO3 (30 mL), and saturated aqueous NaCl (30 mL), dried,
filtered, and concentrated in vacuo. The residue was flash chro-
matographed (silica gel, 10% ethyl acetate in hexanes) to give 4-
allyl-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]thiazole
(12a) as a yellowish oil (0.36 g, 80%). 1H NMR (200 MHz, CDCl3,
2-(2-Benzyloxy-1,1-dimethylethyl)thiazol-4-ethanal (10): To a stirred
solution of 3-(benzyloxy)-2,2-dimethylpropanethioamide (2.8 g,
12.4 mmol) in ethanol (35 mL) was added ethyl 4-chloro-3-oxo-bu-
tyrate (2.4 mL, 17.4 mmol). The reaction mixture was heated at
reflux for 24 h. The solvent was evaporated under reduced pressure
and a saturated aqueous solution of NaHCO3/diethyl ether (1:1,
50 mL) was added to the residue. The aqueous phase was extracted
with diethyl ether (3ϫ25 mL), and the combined organic extracts
were dried with Na2SO4, filtered, and concentrated under reduced
pressure. The residue was flash chromatographed (silica gel, 30%
ethyl acetate in hexanes) to give ethyl 2-(2-benzyloxy-1,1-dimethyl-
ethyl)thiazol-4-acetate as a brown oil (3.7 g, 95 %). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.32 (m, 5 H, Ph), 7.05 (s, 1 H, 11-
H), 4.52 (s, 2 H, CH2Ph), 4.23 (q, 2 H, OCH2CH3), 3.82 (s, 2 H,
13-H), 3.62 (s, 2 H, 8-H), 1.43 (s, 6 H, 20-H and 21-H), 1.22 (t, 3
H, OCH2CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 177.1 (s, C-
10), 170.2 (s, C-14), 148.3 (s, C-12), 139.2 (s, Ph), 128.5 (d, Ph),
127.6 (d, Ph), 115.3 (d, C-11), 79.4 (t, C-8), 73.4 (t, CH2Ph), 61.2
(t, OCH2CH3), 42.2 (s, C-9), 38.1 (t, C-13), 26 (q, C-20 and C-21),
14.0 (q, OCH2CH3) ppm.
3
25 °C): δ = 7.60 (m, 4 H, SiPh), 7.38 (m, 6 H, SiPh), 6.80 (t, J =
3
0.9 Hz, 1 H, 11-H), 6.09 (tdd, J = 6.7, 10.1, 16.9 Hz, 1 H, 14-H),
5.16 (m, 2 H, 15-H), 3.77 (s, 2 H, 8-H), 3.57 (ddd, 3J = 1.3, 2.4,
6.7 Hz, 2 H, 13-H), 1.47 (s, 6 H, 20-H and 21-H), 1.02 [s, 9 H,
SiC(CH3)3] ppm. 13C NMR (50 MHz, CDCl3): δ = 177.7 (s, C-10),
154.8 (s, C-12), 135.8 (d, SiPh), 135.7 (d, C-14), 133.7 (s, SiPh),
129.7 (d, SiPh), 127.7 (d, SiPh), 116.7 (t, C-15), 112.5 (d, C-11),
72.9 (t, C-8), 43.1 (s, C-9), 36.3 (t, C-13), 26.9 [q, SiC(CH3)3], 25.6
(q, C-20and C-21), 19.5 [s, SiC(CH3)3] ppm. (+)-LRESIMS: m/z
(%) = 436 (61) [M + H]+, 458 (100) [M + Na]+, 474 (8) [M + K]+.
To a stirred solution of ethyl 2-(2-benzyloxy-1,1-dimethylethyl)-
thiazol-4-acetate (1 g, 3.0 mmol) in anhydrous toluene (20 mL) at
–80 °C was slowly added DIBAL-H (3.6 mL, 3.6 mmol). The in-
ternal temperature was maintained at –78 °C. After 20 min, the ad-
dition of DIBAL-H (1.2 mL, 0.9 mmol) was repeated. The reaction
was followed by TLC. When the starting material was not ob-
served, the reaction was quenched with methanol and then poured
into ice with a 10% solution of hydrochloric acid. After 15 min,
the mixture was extracted with ethyl acetate (3ϫ100 mL), and the
organic phase was dried with MgSO4, filtered, and concentrated in
vacuo. The residue was flash chromatographed (silica gel, 20 %
ethyl acetate in hexanes) to give 2-(2-benzyloxy-1,1-dimethylethyl)-
4-Allyl-2-(2-benzyloxy-1,1-dimethylethyl)thiazole (12b): A solution
of trivinylindium (2 mmol, ≈ 0.1 ) (prepared following the general
procedure) was added to a mixture of 4-bromomethyl-2-(2-ben-
zyloxy-1,1-dimethylethyl)thiazole (6b) (0.7 g, 2 mmol) and palla-
dium catalyst {[1,1Ј-bis(diphenylphosphanyl)ferrocenedichloropal-
ladium(II)], complex with dichloromethane 1:1} (0.032 g,
0.04 mmol) in anhydrous tetrahydrofuran (7 mL) heated at reflux.
thiazol-4-ethanal (10) as a yellow oil (0.8 g, 95 %). 1H NMR The resulting mixture was heated at reflux under an argon atmo-
(200 MHz, CDCl3, 25 °C): δ = 9.83 (t, 1 H, 14-H), 7.32 (m, 5 H, sphere until the starting material was consumed, and the reaction
940
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Eur. J. Org. Chem. 2007, 934–942

Mycothiazole: the C8–C18 Subunit and the (Z)-∆14 Double Bond
FULL PAPER
was then quenched by the addition of a few drops of methanol.
The mixture was concentrated in vacuo and Et2O (10 mL) was
added. The organic phase was washed with aqueous HCl (10%,
15 mL), saturated aqueous NaHCO3 (15 mL), and saturated aque-
ous NaCl (15 mL), dried, filtered, and concentrated in vacuo. The
residue was flash chromatographed (silica gel, 10% ethyl acetate in
hexanes) to give 4-allyl-2-(2-benzyloxy-1,1-dimethylethyl)thiazole
(12b) as a colorless oil (0.45 g, 80%). 1H NMR (200 MHz, CDCl3,
(m, 2 H, SiPh), 7.34 (m, 4 H, SiPh), 6.77 (s, 1 H, 11-H), 5.84 (ttd,
3J = 6.4, 10.1, 16.6 Hz, 1 H, 17-H), 5.70 (ttd, 3J = 1.2, 6.6, 14.6 Hz,
3
1 H, 14-H), 5.59 (m, 1 H, 15-H), 5.05 (ddd, J = 1.7, 3.4, 17.2 Hz,
3
1 H, 18-H), 5.00 (ddd, J = 1.3, 3.0, 10.0 Hz, 1 H, 18Ј-H), 3.75 (s,
2 H, 8-H), 3.53 (d, 3J = 6.6 Hz, 2 H, 13-H), 2.80 (ddt, 3J = 1.0,
2.5, 6.4 Hz, 2 H, 16-H), 1.46 (s, 6 H, 20-H and 21-H), 1.00 [s, 9 H,
1
SiC(CH3)3] ppm. H NMR (500 MHz, C6D6, 25 °C): δ = 7.70 (m,
3
SiPh), 7.22 (m, SiPh), 6.44 (d, J = 0.9 Hz, 1 H, 11-H), 5.80–5.45
25 °C): δ = 7.31 (m, 5 H, Ph), 6.79 (t, 3J = 0.9 Hz, 1 H, 11-H), 6.08
(m, 3 H, 14-H, 15-H and 17-H), 5.02 (m, 1 H, 18-H), 4.97 (m, 1
3
(m, 1 H, 14-H), 5.18 (qd, JH,H = 1.7, 4.3 Hz, 1 H, 15-H), 5.11 (t, H, 18Ј-H), 3.88 (s, 2 H, 8-H), 3.51 (d, 3J = 6.6 Hz, 2 H, 13-H), 2.66
3J = 1.3 Hz, 1 H, 15Ј-H), 4.52 (s, 2 H, CH2Ph), 3.62 (s, 2 H, 8-H),
3.56 (ddd, 3J = 1.3, 2.4, 6.8 Hz, 2 H, 13-H), 1.47 (s, 6 H, 20-H and
(t, J = 6.3 Hz, 2 H, 13-H), 1.13 (s, 6 H, 20-H and 21-H), 0.42 [s,
3
9 H, SiC(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 137.1 (d,
21-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 177.5 (s, C-10), 154.5 C-17), 135.8 (d, SiPh), 133.6 (s, SiPh), 129.7 (d, SiPh), 127.7 (d,
(s, C-12), 138.5 (s, Ph), 135.4 (d, C-14), 128.2 (d, Ph), 127.3 (d, Ph),
116.5 (t, C-15), 112.5 (d, C-11), 79.0 (t, C-8), 73.2 (t, CH2Ph), 41.9
SiPh), 115.3 (t, C-18), 112.5 (d, C-11), 72.8 (t, C-8), 43.2 (s, C-9),
36.8 (t, C-16), 34.8 (t, C-13), 26.9 [q, SiC(CH3)3], 25.6 (q, C-20 and
(s, C-9), 36.0 (t, C-13), 25.9 (q, C-20 and C-21) ppm. (+)-LRES- C-21), 19.5 [s, SiC(CH3)3] ppm. 13C NMR (125 MHz, C6D6): δ =
IMS: m/z (%) = 288 (65) [M + H]+, 310 (100) [M + Na]+.
177.5 (s, C-10), 156.1 (s, C-12), 137.4, 136.3, 134.2, 130.2, 129.0,
115.5 (t, C-18), 112.7 (d, C-11), 73.4 (t, C-8), 43.6 (s, C-9), 35.7 (t,
C-13), 32.6 (t, C-16), 27.3 [q, SiC(CH3)3], 25.8 (q, C-20 and C-21),
19.8 [s, SiC(CH3)3] ppm. (+)-HRESIMS: calcd. for C29H38NOSSi
[M + H]+ 476.2443; found 476.2455.
6{2-[2-(tert-Butyldiphenylsilyloxy)-1,1-dimethylethyl]thiazol-4-
yl}hex-4-enyl-4-methylbenzenesulfonate (13): To a stirred solution
of tricyclohexylphosphane[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihy-
droimidazol-2-ylidene][benzylidene]ruthenium(IV) dichloride
(GrubbsЈ ruthenium catalyst) (4.7 mg, 0.0055 mmol) in anhydrous
toluene (0.250 mL), was slowly added a solution of 4-allyl-2-[2-
(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]thiazole (12a)
(0.033 g, 0.076 mmol) and 4-octene-1,8-ditosylate (0.063 g,
0.139 mmol) in toluene (0.5 mL). The reaction mixture was heated
at 80 °C for 18 h, and the reaction was then quenched by the ad-
dition of a few drops of methanol. The reaction mixture was sus-
pended into silica gel and flash chromatographed (silica gel, 8%
diethyl ether in hexanes) to give 6{2-[2-(tert-butyldiphenylsilyloxy)-
1,1-dimethylethyl]thiazol-4-yl}hex-4-enyl-4-methylbenzenesulfo-
nate (13) as a mixture Z/E isomers (1:7) as a colorless oil (0.024 g,
2-(2-Benzyloxy-1,1-dimethylethyl)-4-(2E)-hexa-2,5-dienylthiazole
(14b): In a sealed tube was placed tricyclohexylphosphane[1,3-
bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzyl-
idene]ruthenium(IV) dichloride (GrubbsЈ ruthenium catalyst)
(6.5 mg, 0.0076 mmol) and was added a mixture of a 0.7  solution
of 1,4-pentadiene in anhydrous dichloromethane (1 mL,
0.70 mmol) and 4-allyl-2-(2-benzyloxy-1,1-dimethylethyl)thiazole
(12b) (0.026 g, 0.09 mmol). The tube was sealed under an argon
atmosphere and heated to 40 °C. After 24 h, the solvent was evapo-
rated under reduced pressure and the catalyst was separated by
flash chromatography (silica gel, 50% diethyl ether in hexanes) to
give a mixture of starting material and 2-(2-benzyloxy-1,1-di-
methylethyl)-4-(2E)-hexa-2,5-dienylthiazole (14b). The yield of the
reaction was calculated using the integration of the 11-H and 16-
1
50%). H NMR (500 MHz, CDCl3, 25 °C): δ = 7.79 (m, 2 H, Ts),
7.57 (m, 4 H, SiPh), 7.41 (m, 2 H, Ts), 7.34 (m, 6 H, SiPh), 6.71
3
(s, 1 H, 11-H), 5.63 (ttd, J = 1.1, 6.7, 14.9 Hz, 1 H, 14-H), 5.45
1
1
3
H H NMR signals. H NMR (200 MHz, CDCl3, 25 °C): δ = 7.30
(m, Ph), 6.76 (t, 3J = 0.9 Hz, 11-H), 5.93–5.43 (m, 14-H, 15-H, and
17-H), 5.06–4.96 (m, 18-H and 18Ј-H), 4.52 (s, CH2Ph), 3.61 (s, 8-
H), 3.51 (d, 3J = 6.6 Hz, 13-H), 2.81 (t, 3J = 6.3 Hz, 16-H), 1.47
(s, 20-H and 21-H) ppm. (+)-HRESIMS: calcd. for C20H26NOS [M
+ H]+ 328.1735; found 328.1735.
(m, 1 H, 15-H), 4.04 (t, J = 6.3 Hz, 2 H, 18-H), 3.74 (s, 2 H, 8-
3
3
H), 3.43 (d, J = 6.7 Hz, 2 H, 13-H), 2.43 (s, 3 H, Ts), 2.08 (q, J
3
= 6.9 Hz, 2 H, 17-H), 1.73 (td, J = 6.5, 13.4 Hz, 2 H, 16-H), 1.45
(s, 6 H, 20-H and 21-H), 1.00 [s, 9 H, SiC(CH3)3] ppm. 13C NMR
(125 MHz, CDCl3): δ = 177.7 (s, C-10), 155.2 (s, C-12), 144.8 (s,
Ts), 135.8 (d, SiPh), 133.6 (s, Ts), 133.4 (s, SiPh), 130.4 (t, C-15),
129.9 (d, Ts), 129.7 (d, SiPh), 128.6 (d, C-14), 128.0 (d, Ts), 127.7
(d, SiPh), 112.3 (d, C-11), 72.9 (t, C-8), 69.9 (t, C-18), 43.1 (s, C-
9), 34.9 (t, C-13), 28.6 (q, C-16), 28.3 (q, C-17), 26.9 [q, SiC-
(CH3)3], 25.6 (q, C-20 and C-21), 21.7 (q, Ts), 19.5 [s, SiC(CH3)3]
ppm. (+)-HRESIMS: calcd. for C36H46NO4S2Si [M + H]+
648.2638; found 648.2699.
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR, 13C NMR, and mass spectra for all synthetic com-
pounds.
Acknowledgments
(E)-2-[2-(tert-Butyldiphenylsilyloxy)-1,1-dimethylethyl]-4-(hexa-2,5-
dienyl)thiazole (14a): To a stirred solution of 6{2-[2-(tert-butyldi-
phenylsilyloxy)-1,1-dimethylethyl]thiazol-4-yl}hex-4-enyl-4-methyl-
benzenesulfonate (13) (0.023 g, 0.035 mmol) and sodium iodide
(0.016 g, 0.107 mmol) in anhydrous dimethylethylenglycol
(0.35 mL), 1,8-diazabicylo[5.4.0]-undec-7-ene (0.01 mL,
0.065 mmol) was added. The reaction mixture was heated at reflux.
After 2 h, the reaction was diluted with diethyl ether (2 mL) and
water (2 mL) was also added. The aqueous phase was extracted
with diethyl ether (3ϫ2 mL), and the combined organic extracts
were washed with a saturated aqueous solution of NaCl (5 mL),
dried with Na2SO4, filtered, and concentrated in vacuo. The residue
was flash chromatographed (silica gel, 2% diethyl ether in hexanes)
to give (E)-2-[2-(tert-butyldiphenylsilyloxy)-1,1-dimethylethyl]-4-
(hexa-2,5-dienyl)thiazole (14a) as a colorless oil (0.0034 g, 20%).
1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.57 (m, 4 H, SiPh), 7.41
This work was financially supported by grants from Xunta de Gal-
icia (PGIDIT05RMA10302PR) and the Spanish Ministerio de Ed-
ucación y Ciencia, Grant CQT2005-00793. M. R. also thanks the
FPU program for a fellowship. We also thank Dr. Denis Calnan
(Waters Co.) for HRESIMS data.
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Eur. J. Org. Chem. 2007, 934–942
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941

M. Rega, P. Candal, C. Jiménez, J. Rodríguez
FULL PAPER
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Received: August 1, 2006
Published Online: December 15, 2006
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942
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