A formal total synthesis of virantmycin: A modular approach towards tetrahydroquinoline natural products

Article abstract of DOI:10.1002/ejoc.200600635

A synthesis of an advanced intermediate towards the racemic form of the antiviral agent virantmycin has been developed featuring an intramolecular aza-xylylene Diels-Alder reaction. The required arylthiocarbamate has been constructed using an efficient ox

Full text of DOI:10.1002/ejoc.200600635

FULL PAPER
DOI: 10.1002/ejoc.200600635
A Formal Total Synthesis of Virantmycin: A Modular Approach towards
Tetrahydroquinoline Natural Products
Daniel Keck,[a] Sylvia Vanderheiden,[a] and Stefan Bräse*[a]
Keywords: Natural products / Antiviral agents / Cycloaddition / Heterocycles
A synthesis of an advanced intermediate towards the racemic
form of the antiviral agent virantmycin has been developed
featuring an intramolecular aza-xylylene Diels–Alder reac-
tion. The required arylthiocarbamate has been constructed
using an efficient oxidative cyclization strategy. A novel syn-
thetic approach to chlorine-substituted allylic alcohols using
an unprecedented palladium-catalyzed cross-coupling reac-
tion of α,β-unsaturated ketones and protected propargylic
alcohols is reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Nishiyama[7] and Corey.[8] A modified approach developed
by our group was applied to the synthesis of several other
tetrahydroquinoline natural products.[9]
Introduction
(–)-Virantmycin (1) (Figure 1) is an unusual chlorinated
member of the large class of tetrahydroquinoline alkaloids.
It was isolated from a strain of Streptomyces nitrosporeus
[1]
¯
by Omura et al. and was found to be a potent DNA and
Results and Discussion
RNA virus inhibitor as well as an antifungal agent.[2] Se-
veral total syntheses of racemic ( )-virantmycin (2),[3] natu-
ral (–)-virantmycin[4] and the unnatural (+)-antipode[5] have
been completed to date, stressing the importance and the
promising pharmacological profile of the substance.
Retrosynthetic Analysis
Our synthetic strategy is based on a published total syn-
thesis of ( )-virantmycin by Corey and Steinhagen whose
key steps are summarized in Scheme 1.[3e] The authors used
a late stage palladium-catalyzed carboxyesterification/sa-
ponification strategy after reductive carbamate opening and
establishment of the methyl ether on iodoquinoline 3 which
can be obtained from the crucial intramolecular Diels–Al-
der step. Cyclization precursor 4 is readily available by ad-
dition of the simple substrates 5 and 6, TBS deprotection
and subsequent benzylic chlorination. Isocyanate 5 can be
synthesized from commercially available 2-aminobenzyl
alcohol by iodination with iodine monochloride, TBS pro-
tection and isocyanate formation by treatment with phos-
gene. Allylic alcohol 6 can be obtained in a 6-step reaction
sequence starting from methyl vinyl ketone and ethyl pro-
piolate.
With these results in mind, we envisioned a shorter syn-
thesis towards common precursor 3 using our method of
carbamate formation[9] which is summarized in Scheme 2.
We decided to introduce the iodine atom at a very late stage
in our synthetic approach, after cyclization of precursor 8.
This carbamate is formed by a modified reaction type origi-
nally developed by Appel.[10] The reaction of an arylthio-
carbamate with triphenylphosphane/tetrachloromethane
leads to the cleavage of the thiocarbamate upon formation
Figure 1. (–)-Virantmycin (1).
Various synthetic approaches towards the construction
of tetrahydroquinoline ring systems are available, including
insertion, ring expansion and ring contraction reactions.[6]
However, one of the most versatile and convergent strate-
gies for the construction of tetrahydroquinoline alkaloids is
the Diels–Alder reaction of o-azaxylylenes which are
formed by a 1,4-elimination from a suitable benzylic halide
precursor and suitable dienophiles as reported by
[a] Institute of Organic Chemistry, University of Karlsruhe (TH),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-6088581
E-mail: braese@ioc.uka.de
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Formal Total Synthesis of Virantmycin
FULL PAPER
ture to yield the cyclized product in a yield of 53%.[12]
A
more effective possibility for the formation of 9 has been
proposed by Hirai[13] who used a commercially unavailable
thiazolium catalyst along with thiocarbonyl diimidazole
which provided the desired product in 74% yield. Thus,
while the first two methods clearly suffer from low yields
and the consequential problematic purification of the reac-
tion product, the third literature precedent for the synthesis
of 9 suffers from the fact that the catalyst is not commer-
cially available and the application of the more expensive
thiocarbonyl diimidazole.
We were sure that the low yields of the simplest synthesis,
the reaction of 2-aminobenzyl alcohol with carbon disul-
fide, could be explained by an insufficient tendency for de-
hydrosulfurization from the occurring intermediate and the
reversible character of this reaction step. Thus, our task was
to find reagents that are able to remove the sulfur species
irreversibly from the reaction. When checking the literature
for nonaromatic cyclic thiocarbamates, we found that this
could be achieved by the addition of reagents like ethyl
chloroformate,[14] lead nitrate,[15] or hydrogen peroxide.[16]
Especially the method using hydrogen peroxide seemed ap-
pealing to us as it utilises cheap reagents, can be performed
without using anhydrous or inert conditions and is very
quick. When trying this reaction type on our aromatic sub-
strate 10 we were pleased to find that the cyclized product
could be obtained in a yield of 78% in less than 2 hours by
stirring 2-aminobenzyl alcohol, carbon disulfide and base
in methanol with subsequent addition of hydrogen peroxide
which leads to colorization and warming of the reaction
mixture and the formation of a sulfur precipitate. Optimiza-
tion studies revealed that the yield was significantly lower
when using less than three equivalents of carbon disulfide
which seemed to be the optimal amount. Utilisation of
imidazole as base or of other solvents like CH2Cl2 does not
provide any product; see Scheme 3.
Scheme 1. Corey’s retrosynthetic analysis of ( )-virantmycin.
of a benzylic chloride and an isocyanate that can be trapped
in situ by a suitable nucleophile, in our case allylic
alcohol 6.
Scheme 2. Modified retrosynthetic analysis towards common pre-
cursor 3.
Optimized Synthesis of 1,4-Dihydrobenzo[d][1,3]oxazine-2-
thione (9)
One key fragment for our synthetic route towards vir-
antmycin is arylthiocarbamate 9. This substance has been
known for more than 110 years, but synthetic methodolo-
gies for its reliable and high-yield formation are scarce. The
classical method developed by Paal and Laudenheimer,[11]
heating 2-aminobenzyl alcohol (10) in carbon disulfide at
reflux for several hours without additional solvent leads to
formation of the desired product 9 in a maximum yield of
Scheme 3. Optimized synthesis of 1,4-dihydrobenzo[d][1,3]oxazine-
2-thione (9).
In summary, we were able to transfer the oxidative thio-
30% which can be raised to about 40%, if the reaction is carbamate formation strategy to the synthesis of an aro-
performed in a sealed vial. A second possibility includes the matic 2-thioxo-1,3-O,N-heterocycle which provides us with
reaction of 2-azidobenzyl alcohol in the presence of tri- a cheap and versatile synthesis of these compounds with a
phenylphosphane in a Staudinger type reaction leading to minimum amount of the toxic reagent carbon disulfide. In
an iminophosphorane. This intermediate can be reacted addition, this synthesis can easily be scaled up to multigram
with carbon disulfide in a sealed vial at elevated tempera- amounts.
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D. Keck, S. Vanderheiden, S. Bräse
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A Novel Synthetic Approach Towards 2-Chloromethylene-
5,6-dimethylhept-5-en-1-ol (6) and Similar Allylic Alcohols
Table 1. Optimization of the palladium-catalyzed coupling of 13
with methyl vinyl ketone (12).[a]
Reaction time
For the synthesis of allylic alcohol 6, we relied upon a Entry
Equiv. of Pd(OAc)2
Yield [%]
[h]
palladium-catalyzed reaction that is well known for propi-
1
2
3
0.02
0.02
0.02
0.03
0.03
0.05
4
6
15
5
15
15
25
32
34
33
48
61
olic acid esters.[17] In this reaction type, alkyl propiolates
are reacted with α,β-unsaturated aldehydes or ketones, e.g.
acrolein or methyl vinyl ketone, under palladium acetate
catalysis in the presence of chloride or bromide nucleophiles
yielding the desired bromo- or chloro-substituted α,β-unsat-
urated esters directly. Unfortunately, this creates the neces-
sity to carry out a cumbersome complete reduction – selec-
tive protection – oxidation sequence to receive a properly
protected derivative. We wanted to develop a reaction se-
quence that omits these steps and leads directly to the de-
sired protected keto alcohol. This strategy and our results
are summarized in Scheme 4.
4
5
6[b]
[a] All reactions were carried out with 4 equiv. of methyl vinyl
ketone and 4 equiv. of lithium chloride. [b] Reaction carried out
with 3.5 equiv. of lithium chloride.
The reaction conditions for the cross-coupling reaction
were optimized using the PMB derivative 13. The results
are summarized in Table 1. Entry 1 shows the conditions
that were optimal when reacting ethyl propiolate with
methyl vinyl ketone, which in the case of 13 resulted in for-
mation of the desired product 16 in 25% yield along with
a small amount of the E-chloro isomer. The major side re-
action was the 1,4-addition of acetic acid (the solvent) to
methyl vinyl ketone. This shows that the reaction is rela-
tively slow in comparison to this 1,4-addition. Longer reac-
tion times (entry 2 and 3) did not lead to a significantly
increased yield. A higher catalyst loading with short reac-
tion time also did not improve the yield (entry 4). The in-
crease of catalyst loading was still important for good
yields, but the reaction of propargylic alcohols proved to be
slow. We obtained the best result using 5 mol-% catalyst,
3.5 equiv. lithium chloride and 4 equiv. of methyl vinyl
ketone which lead to 61% of the desired product in 15 h
(entry 6). When subjecting alcohols 14 and 15 to these opti-
mized reaction conditions we received 17 and 18 unevent-
fully in 61% and 47% yield, respectively, which has not
been optimized. These results show the versatility and ro-
bustness of this new reaction type which cuts the former
four-step synthesis[3e] to two steps.
Products 16–18 were reacted in a Wittig-type reaction[21]
using isopropyltriphenylphosphonium iodide. This reaction
does not occur when using lithium bases like n-butyllithium
Scheme 4. Novel synthesis of allylic alcohol 6.
Thus, we surveyed the direct reaction of a protected pro- or lithium bis(trimethylsilyl)amide (LiHMDS) in various
pargylic alcohol with methyl vinyl ketone in the presence of solvents, in some cases the reactant even decomposes. When
palladium acetate. The reaction of propargylic alcohol itself using potassium bis(trimethylsilyl)amide (KHMDS) in tol-
under standard conditions does not lead to the formation uene solution, the reaction proceeds in all three cases, but
of any product but to quick decomposition of the catalyst with distinct differences in yield. The best yield was ob-
upon formation of palladium black. To the best of our tained for ketone 17 which was transformed to 20 in a yield
knowledge, this reaction type has not been investigated up of 90%. For the PMB derivative 16 and TBS derivative 18,
to now, the only resembling example being the reaction of the desired products 19 and 21 were obtained in yields of
2-propynyl tosylcarbamate with acrolein in the presence of 53% and 58%, respectively, along with substantial amounts
lithium bromide leading to the bromo-allylic carbamate in of unreacted starting material. This ratio could not be al-
a yield of 58%.[18] We chose three propargylic alcohols, a tered by using larger excesses of Wittig reagent. We attri-
PMB derivate 13 (synthesized by reaction of propargylic bute this finding to the fact that the protecting groups PMB
bromide with 4-methoxybenzylic alcohol in the presence of and TBS are more acidic than TIPS leading to deproton-
sodium hydride in a yield of 92%[19]), a TIPS derivative 14 ation by the Wittig reagent. Additionally, the bulkier TIPS
(reaction of propargylic alcohol with TIPS chloride in the group might prevent deprotonation of the carbonyl group’s
presence of imidazole in a yield of 93%[20]) and a TBS de- α-proton which is also quite acidic. The synthesis of unpro-
rivative 15 which is commercially available; see Table 1.
tected allylic alcohol 6 could be achieved by application of
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Formal Total Synthesis of Virantmycin
FULL PAPER
standard deprotection conditions. The PMB group was re- bonate (several hours at Ͻ0.1 Torr and 100 °C) was added
moved using DDQ in CH2Cl2/H2O[22] in an excellent yield to a solution of 8 in dichloromethane and stirring for 4 d
of 98%, while the TIPS group was easily removed using at room temperature smoothly provided tricyclus 7 in a
TBAF in THF in a yield of 90%.[23] The deprotection of yield of 85%. The completion of our synthesis of advanced
TBS was not carried out as it did not provide notably better intermediate 3 could be achieved by aromatic iodination
results than PMB while being much more expensive.
using iodine monochloride in CH2Cl2 which provided the
In summary, we succeeded in synthesizing key allylic desired compound as a single regioisomer in a yield of 90%;
alcohol 6 using a novel palladium-catalyzed cross-coupling see Scheme 6.
reaction. The now three-step synthesis starting from readily
available protected propargylic alcohols provides the de-
sired product in a combined yield of 28% (PMB) or 49%
(TIPS). The synthesis of derivatives of virantmycin could
easily be achieved by using other α,β-unsaturated com-
pounds or nucleophiles, thus providing an entrance into a
large class of possible analogues.
Synthesis of Carbamate 8 and Development of an Advanced
Purification Strategy
Using allylic alcohol 6, we started to investigate the reac-
tion of this alcohol in the Appel-type reaction with cyclic
thiocarbamate 9. Using our standard conditions, the reac-
tion proceeded smoothly, but purification of the product
proved to be cumbersome as the reaction byproduct tri-
phenylphosphane sulfide cannot be easily removed by col-
Scheme 6. Cyclization and final iodination.
umn chromatography. Experiments to remove the sulfide by
Thus, we have completed the synthesis of the advanced
different filtration techniques were unsuccessful, other precursor 3 in four consecutive steps starting from 9 in an
methods like alkylation with methyl trifluoromethanesul- overall yield of 49%. The remaining steps of the total syn-
fonate[24] could not be utilized because of possible alky- thesis towards ( )-virantmycin have already been per-
lation of product 8. So we examined the transformation of formed. The corresponding substances have been synthe-
triphenylphosphane sulfide to the corresponding oxide by sized, charaterized and published by Corey and Steinhagen.
trifluoroacetic anhydride as described by Michalski.[25] As Thus, we have completed a novel modified formal total syn-
summarized in Scheme 5, we exposed the dissolved crude thesis of ( )-virantmycin.
reaction product in CH2Cl2 and treated it with trifluoro-
acetic anhydride which lead to complete consumption of
the sulfide byproduct by formation of the oxide which could
Conclusion
be separated much more easily by chromatographic purifi-
In conclusion, we have devised a novel synthesis of the
cation. Thus, we were able to synthesize the desired carba-
advanced intermediate 3 thus completing a formal total
synthesis of ( )-virantmycin as the ongoing steps are al-
mate in 83% isolated yield due to our optimized purifica-
tion conditions.
ready known from literature precedence.[3e] The key inter-
mediate for the [4+2]-Diels–Alder-type cycloaddition, car-
bamate 8, can be obtained in 2 steps in a convenient synthe-
sis starting from 2-aminobenzyl alcohol in a combined yield
of 61% due to the novel synthetic approach towards aro-
matic thiocarbamates using oxidative removal of the reac-
tion byproducts and our improved purification protocol
using trifluoroacetic anhydride. Following Corey’s route,
the synthesis of this compound would require five consecu-
tive steps with an overall yield of 55% (calculated from the
synthesis of 4 without the first iodination step[3e]). This Ap-
pel-type reaction can easily be adapted to other allylic
alcohols which makes it suitable for analogue construction.
In addition, a novel synthesis of the required allylic alcohol
Scheme 5. Synthesis of carbamate intermediate 8.
Completion of the Formal Total Synthesis: Intramolecular
Cyclization of Carbamate 8 and Iodination
Having completed the synthesis of advanced carbamate 6 including a new palladium-catalyzed coupling has been
intermediate 8, the stage was set for the key [4+2] cycload- developed and optimized shortening the former 6-step se-
dition which was performed using the standard conditions quence (40% overall yield) to four convenient steps (49%
from our earlier work in this field.[9] Thus, dry caesium car- for TIPS protection).
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D. Keck, S. Vanderheiden, S. Bräse
FULL PAPER
(20 mL). After extraction with Et2O (3×50 mL), drying with
Na2SO4 and concentration in vacuo, the residue was purified by
column chromatography (n-pentane–Et2O, 9:1) yielding the prod-
uct as a yellow oil (4.88 g, 27.7 mmol, 92%). 1H NMR (CDCl3,
400 MHz): δ = 2.47 (t, J = 2.4 Hz, 1 H, CϵCH), 3.80 (s, 3 H,
OCH3), 4.14 (d, J = 2.4 Hz, 2 H, OCH2), 4.54 (s, 2 H, OCH2 ben-
zylic), 6.88 (br. d, J = 8.3 Hz, 2 H, Ar-H), 7.29 (br. d, J = 8.3 Hz,
2 H, Ar-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 55.3 (p), 56.7
(s), 71.2 (s), 74.6 (t), 79.8 (q), 113.9 (t), 129.3 (q), 129.9 (t), 159.5
Experimental Section
All reactions were carried out in dried glassware in an atmosphere
of argon. Solvents were distilled or dried using standard methods
prior to use where appropriate. All chemicals were purchased from
commercial suppliers and used without further purification. Flash
chromatography was performed using silica gel 60 (230–400 mesh
provided by Macherey–Nagel). TLC was performed using pre-
coated aluminium foil sheets silica gel 60 F254 provided by Merck.
1H and 13C NMR spectra were recorded on Bruker AM 400 or
DRX 500, using the residual signals of the solvent as standard.
Multiplicities are described as: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad. Coupling constants J are
reported in Hz. Numbers of attached protons in the 13C spectra
were elucidated using DEPT90 and 135 and are given in the form:
p = primary (RCH3), s = secondary (R2CH2), t = tertiary (R3CH),
q = quaternary (R4C). Mass spectrometry (MS) as well as high
resultion MS (HRMS) was performed on a Finnigan MAT 90
using electron impact (EI) at 70 eV. Ion mass/charge ratios (m/z)
are reported as values in atomic mass units followed by the inten-
sities relative to the base peak in parathenses. Infrared spectra (IR)
were obtained on a Bruker IFS 88 as film on KBr and are reported
as values in cm–1 using the following abbreviations for absorption
strength: s = strong, m = medium, w = weak. Elemental analyses
were carried out on a Heraeus CHN-O-Rapid and are given as
percentage values with the abbreviation calcd. = calculated. Melt-
ing points were measured on a MelTemp II apparatus by Labara-
tory devices. The values are reported in °C and are uncorrected.
(q) ppm. IR (film on KBr): ν = 3288 (m), 3001 (w), 2937 (m), 2907
˜
(m), 2837 (m), 1612 (s), 1585 (m), 1513 (s), 1464 (m), 1442 (m),
1386 (w), 1352 (m), 1302 (m), 1250 (s), 1175 (m), 1079 (s), 1034 (s),
820 (m), 637 (m) cm–1. MS (EI, 70 eV): m/z (%): 176 ([M+], 53),
136 (48), 121 (100), 78 (12). HRMS (C11H12O2): calcd. 176.0837,
found 176.0834. C11H12O2 (176.21): calcd. C 74.98, H 6.86, found
C 74.35, H 6.65.
Triisopropyl(prop-2-ynyloxy)silane (14):[20] To a solution of propar-
gylic alcohol (1.52 g, 27.1 mmol) in CH2Cl2 (60 mL) was added
imidazole (3.69 mg, 54.2 mmol, 2.0 equiv.) followed by triisopro-
pylsilyl chloride (5.75 g, 29.8 mmol, 1.1 equiv.). The mixture was
stirred for 18 h, quenched by the addition of H2O (50 mL) and
extracted with Et2O (3×40 mL). The combined extracts were dried
with Na2SO4, concentrated in vacuo and the remaining residue was
purified by column chromatography (n-pentane–Et2O, 9:1) yielding
the product as a yellow oil (5.35 g, 25.1 mmol, 93%). 1H NMR
(CDCl3, 400 MHz): δ = 1.03–1.19 (m, 21 H, TIPS), 2.39 (t, 1 H, J
= 2.4 Hz, CϵCH), 4.38 (d, 1 H, J = 2.4 Hz, OCH2) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 12.0 (t), 17.9 (p), 51.8 (s), 77.6 (t),
1,4-Dihydro-benzo[d][1,3]oxazine-2-thione (9):[12] In a two-necked
flask with a reflux condenser, 2-aminobenzyl alcohol (3.80 g,
30.3 mmol) was dissolved in MeOH (40 mL) and triethylamine
(4.25 mL, 3.06 g, 30.3 mmol) and carbon disulfide (5.48 mL,
6.91 g, 90.8 mmol, 3.0 equiv.) were added with stirring. After 1 h
at room temp., hydrogen peroxide (6.30 mL, 60.6 mmol, 2.0 equiv.)
was added dropwise in order to keep the solution boiling slightly.
The color of the solution changed from orange to black and a
yellow precipitate of sulfur was formed. After the addition was
completed, the mixture was filtered and the volatiles removed un-
der reduced pressure. The crude product was dissolved in the mini-
mum amount of MeOH and column chromatography (n-pentane–
Et2O, 1:1) of this solution provided the product as a beige solid
(3.89 g, 23.5 mmol, 78%). Additional purification could be
achieved by recrystallization from CH2Cl2/hexanes. Compare
ref.[12] for spectroscopic data. M.p. 137 °C (CH2Cl2/hexanes). 1H
NMR (CDCl3, 400 MHz): δ = 5.36 (s, 2 H, CH2O), 6.95 (br. d, J
= 7.9 Hz, 1 H, Ar-H), 7.11–7.18 (m, 2 H, Ar-H), 7.31 (dd, J =
7.9 Hz, J = 7.6 Hz, 1 H, Ar–H), 10.18 (s, 1 H, NH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 69.7 (s), 114.0 (t), 118.1 (q), 124.1 (t), 125.4
82.5 (q) ppm. IR (film on KBr): ν = 3312 (m), 2944 (s), 2892 (m),
˜
2867 (s), 1465 (m), 1384 (w), 1370 (m), 1262 (w), 1102 (s), 1070
(m), 1014 (w), 1000 (m), 920 (w), 882 (m), 773 (m), 683 (m), 660
(m) cm–1. MS (EI, 70 eV): m/z (%): 212 ([M+], 53), 169 (92), 127
(100), 99 (36), 77 (57), 69 (77). HRMS (M – C3H7): calcd. 169.1049,
found 169.1045. C12H24OSi (212.40): calcd. C 67.86, H 11.39,
found C 67.92, H 11.34.
6-Chloro-5-[(4-methoxybenzyloxy)methyl]hex-5-en-2-one (16): To a
solution of palladium(II) acetate (162 mg, 0.72 mmol, 0.05 equiv.)
in acetic acid (50 mL), lithium chloride (2.15 g, 50.6 mmol,
3.5 equiv.), methyl vinyl ketone (4.06 g, 57.9 mmol, 4.0 equiv.)
and 1-methoxy-4-[(prop-2-ynyloxy)methyl]benzene (13) (2.55 g,
14.5 mmol) were added at room temp. and turned the solution’s
color to orange. The mixture was stirred for 18 h and the reaction
was then quenched by addition of H2O (90 mL). The aqueous
phase was extracted with Et2O (150 mL), the organic phase dried
with Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography (n-pentane–Et2O, 1:1) yielding the de-
1
sired product as a yellow oil (2.50 g, 8.84 mmol, 61%). H NMR
(CDCl3, 400 MHz): δ = 2.10 (s, 3 H, CH3), 2.44–2.48 (m, 2 H,
CH2), 2.57–2.61 (m, 2 H, CH2), 3.80 (s, 3 H, OCH3), 4.18 (d, 2 H,
J = 0.9 Hz, CH2 allylic), 4.41 (s, 2 H, CH2 benzylic), 6.01 (t, 1 H,
J = 0.9 Hz, C=CHCl), 6.86–6.90 (br. d, 2 H, J = 8.8 Hz, Ar-H),
7.24–7.28 (br. d, 2 H, J = 8.8 Hz, Ar-H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 27.3 (s), 30.1 (p), 41.7 (s), 55.4 (p), 66.6 (s), 72.2
(s), 113.9 (t), 116.0 (t), 129.6 (t), 130.2 (q), 138.2 (q), 159.4 (q),
(t), 129.8 (t), 133.0 (q), 185.8 (q) ppm. IR (film on KBr): ν = 3190
˜
(m), 3137 (m), 3018 (m), 1624 (m), 1604 (m), 1536 (s), 1498 (m),
1452 (m), 1418 (m), 1321 (m), 1225 (m), 1162 (m), 1108 (m), 971
(m), 892 (m), 859 (m), 758 (s) cm–1. MS (EI, 70 eV): m/z (%): 165
([M+], 100), 132 (30), 104 (60), 78 (40). HRMS (C8H7NOS): calcd.
165.0248, found 165.0247. C8H7NOS (165.21): calcd. C 58.16, H
4.27, N 8.48, found C 57.81, H 4.45, N 8.19.
207.6 (q) ppm. IR (film on KBr): ν = 3071 (w), 3000 (w), 2933 (m),
˜
1-Methoxy-4-[(prop-2-ynyloxy)methyl]benzene (13):[19] To a cooled
(0 °C) suspension of sodium hydride (60% in mineral oil, 1.32 g,
33.0 mmol, 1.1 equiv.) in DMF (25 mL), 4-methoxybenzyl alcohol
(4.15 g, 30.0 mmol) was added and the mixture was stirred for
25 min. Then propargylic bromide (4.91 g, 33.0 mmol, 1.1 equiv.)
was added and the reaction was stirred for 2.5 h at 0 °C and for
1 h at room temp. After cooling to 0 °C, the reaction was quenched
by the addition of 0.65  aqueous potassium carbonate solution
2858 (w), 2838 (w), 1715 (s), 1612 (m), 1586 (w), 1513 (s), 1464
(m), 1441 (m), 1359 (m), 1302 (m), 1248 (s), 1173 (m), 1081 (m),
1034 (m), 923 (w), 820 (m) cm–1. MS (EI, 70 eV): m/z (%): 282
([M+], 0.2), 137 (83), 121 (100), 77 (5). HRMS (C15H19ClO3): calcd.
282.1023, found 282.1025. C15H19ClO3 (282.76): calcd. C 63.71,
H 6.77, found C 63.78, H 6.95.
6-Chloro-5-[(triisopropylsilanyloxy)methyl]hex-5-en-2-one (17): To a
solution of palladium(II) acetate (147 mg, 0.66 mmol, 0.05 equiv.)
4920
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4916–4923

Formal Total Synthesis of Virantmycin
FULL PAPER
in acetic acid (45 mL), lithium chloride (649 mg, 15.3 mmol,
(p), 66.6 (s), 72.1 (s), 113.9 (t), 114.8 (t), 125.1 (q), 126.8 (q), 129.6
3.5 equiv.), methyl vinyl ketone (1.22 g, 17.5 mmol, 4.0 equiv.) and (t), 130.4 (q), 139.9 (q), 159.4 (q) ppm. IR (film on KBr): ν = 2995
˜
triisopropyl(prop-2-ynyloxy)silane (14) (1.00 g, 4.37 mmol) were
added at room temp. and turned the solution’s color to orange. The
mixture was stirred for 15 h and the reaction was then quenched
by addition of H2O (90 mL). The aqueous phase was extracted with
(w), 2918 (m), 2858 (w), 1612 (w), 1586 (w), 1514 (m), 1463 (w),
1357 (w), 1302 (w), 1249 (m), 1173 (w), 1084 (m), 1037 (m), 820
(w) cm–1. MS (EI, 70 eV): m/z (%): 308 ([M+], 0.5), 203 (5), 136
(4), 121 (100), 83 (11), 55 (7). HRMS (C18H25ClO2): calcd.
Et2O (150 mL), the organic phase dried with Na2SO4 and concen- 308.1543, found 308.1540. C18H25ClO2 (308.84): calcd. C 70.00,
trated in vacuo. The residue was purified by column chromatog-
raphy (n-pentane–Et2O, 9:1) yielding the desired product as a yel-
low oil (856 mg, 2.68 mmol, 61%). 1H NMR (CDCl3, 400 MHz):
δ = 1.03–1.16 (m, 21 H, TIPS), 2.10 (s, 3 H, CH3), 2.44–2.48 (m, 2
H, CH2), 2.57–2.65 (m, 2 H, CH2), 4.18 (s, 2 H, CH2 allylic), 6.01
(br. s, 1 H, C=CHCl) ppm. 13C NMR (CDCl3, 100 MHz): δ =
11.0 (t), 17.9 (p), 26.6 (s), 29.8 (p), 42.2 (s), 60.9 (s), 112.4 (t), 140.8
H 8.16, found C 70.12, H 7.92.
{[2-(Chloromethylene)-5,6-dimethylhept-5-enyl]oxy}triisopropyl-
silane (20): A suspension of isopropyltriphenylphosphonium iodide
(2.74 g, 6.34 mmol, 1.5 equiv.) in toluene (70 mL) was cooled to
0 °C and potassium bis(trimethylsilyl)amide (0.5  in toluene,
12.7 mL, 6.34 mmol, 1.5 equiv.) was added. The orange suspension
was stirred for 30 min, then 17 (1.35 g, 4.23 mmol) was added and
the now turbid solution was stirred for 14 h at room temp. The
reaction was quenched by the addition of H2O (50 mL) and ex-
tracted with Et2O (3×70 mL). The combined extracts were dried
with Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography (n-pentane–Et2O, 9:1) yielding the de-
sired product as a yellow oil along with inseparable impurities
(1.97 g, 5.71 mmol, 90%). The product was used as such in the
(q), 207.6 (q) ppm. IR (film on KBr): ν = 2943 (w), 2893 (w), 2867
˜
(m), 1720 (m), 1463 (w), 1134 (w), 1100 (w), 1013 (w), 918 (w), 882
(m), 789 (w), 682 (m) cm–1. MS (EI, 70 eV): m/z (%): no [M+], 275
(100), 109 (45), 43 (59). HRMS (M – C3H7): calcd. 275.1234, found
275.1232. C16H31ClO2Si (318.95): calcd. C 60.25, H 9.80, found
C 60.37, H 9.82.
5-[(tert-Butyldimethylsilanyloxy)methyl]-6-chlorohex-5-en-2-one
(18): To a solution of palladium(II) acetate (33 mg, 0.15 mmol,
0.05 equiv.) in acetic acid (15 mL), lithium chloride (436 mg,
10.3 mmol, 3.5 equiv.), methyl vinyl ketone (823 mg, 11.7 mmol,
4.0 equiv.) and commercially available tert-butyldimethyl(prop-2-
ynyloxy)silane (15) (500 mg, 2.94 mmol) were added at room temp.
and turned the solution’s color to orange. The mixture was stirred
for 15 h and the reaction was then quenched by addition of H2O
(25 mL). The aqueous phase was extracted with Et2O (50 mL), the
organic phase dried with Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (n-pentane–Et2O,
1
subsequent reaction. H NMR (CDCl3, 400 MHz): δ = 1.03–1.16
(m, 21 H, TIPS), 1.60 (s, 9 H, 3× CH3), 2.07–2.17 (m, 2 H, CH2),
2.22–2.29 (m, 2 H, CH2), 4.37 (d, 2 H, J = 1.2 Hz, CH2 allylic),
5.71 (br. s, 1 H, C=CHCl) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 12.3 (p), 18.0 (p), 18.3 (p), 20.1 (p), 20.5 (p), 30.9 (s), 33.2 (s),
60.5 (s), 112.4 (t), 124.9 (q), 126.9 (q), 142.5 (q) ppm.
tert-Butyl-{[2-(chloromethylene)-5,6-dimethylhept-5-enyl]oxy}-
dimethylsilane (21): A suspension of isopropyltriphenylphospho-
nium iodide (770 mg, 1.78 mmol, 1.5 equiv.) in toluene (10 mL) was
cooled to 0 °C and potassium bis(trimethylsilyl)amide (0.5  in tol-
uene, 3.56 mL, 1.78 mmol, 1.5 equiv.) was added. The orange sus-
9:1) yielding the desired product as a yellow oil (380 mg,
1
1.37 mmol, 47%). H NMR (CDCl3, 400 MHz): δ = 0.07 (s, 6 H, pension was stirred for 30 min, then 18 (310 mg, 1.18 mmol) was
2× SiCH3), 0.89 (br. s, 9 H, 3× CH2), 2.13 (s, 3 H, CH3), 2.40–2.48
added and the now turbid solution was stirred for 15 h at room
(m, 2 H, CH2), 2.51–2.65 (m, 2 H, CH2), 4.15 (s, 2 H, CH2 allylic), temp. The reaction was quenched by the addition of H2O (15 mL)
5.90 (br. s, 1 H, C=CHCl) ppm. 13C NMR (CDCl3, 100 MHz): δ
= –5.0 (p), 18.4 (q), 26.6 (p), 26.7 (s), 29.8 (p), 42.0 (s), 66.4 (s),
and extracted with Et2O (3×25 mL). The combined extracts were
dried with Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (n-pentane–Et2O, 9:1) yielding
the desired product as yellow oil (174 mg, 0.57 mmol, 48%). 1H
123.2 (t), 133.8 (q), 207.7 (q) ppm. IR (film on KBr): ν = 2955 (m),
˜
2930 (m), 2894 (w), 2857 (m), 1719 (m), 1471 (w), 1361 (w), 1254
(m), 1129 (m), 1098 (w), 1072 (m), 837 (m), 777 (m) cm–1. MS (EI, NMR (CDCl3, 400 MHz): δ = 0.09 (s, 6 H, 2× SiCH3), 0.91 (br. s,
70 eV): m/z (%): 276 ([M+], 0.1), 221 (55), 219 (100), 109 (83), 93
(38), 43 (93). C13H25ClO2Si (276.87): calcd. C 56.39, H 9.10, found
C 56.61, H 9.24.
9 H, 3× CH3), 1.63 (s, 9 H, 3× CH3), 2.07–2.15 (m, 2 H, CH2),
2.24–2.30 (m, 2 H, CH2), 4.37 (d, 2 H, J = 1.2 Hz, CH2 allylic),
5.81 (br. s, 1 H, C=CHCl) ppm. 13C NMR (CDCl3, 100 MHz): δ
= –5.4 (p), 18.1 (q), 18.4 (p), 20.1 (p), 20.6 (p), 25.9 (p), 30.8 (s),
33.2 (s), 66.5 (s), 111.8 (t), 126.7 (q), 132.6 (q), 142 (q) ppm.
1-{[2-(Chloromethylene)-5,6-dimethylhept-5-enyloxy]methyl}-4-
methoxybenzene (19): A suspension of isopropyltriphenylphospho-
nium iodide (6.98 g, 16.6 mmol, 1.5 equiv.) in toluene (50 mL) was
cooled to 0 °C and potassium bis(trimethylsilyl)amide (0.5  in tol-
uene, 32.3 mL, 16.6 mmol, 1.5 equiv.) was added. The orange sus-
pension was stirred for 30 min, then 16 (3.05 g, 10.7 mmol) was
added and the now turbid solution was stirred for 16 h at room
temp. The reaction was quenched by the addition of H2O (400 mL)
and extracted with Et2O (4×50 mL). The combined extracts were
dried with Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (n-pentane–Et2O, 7:3) yielding
unreacted 16 (515 mg, 1.82 mmol) along with the desired product
as yellow oil (1.83 g, 6.13 mmol, 56%, 69% based on recovered
IR (film on KBr): ν = 2955 (m), 2929 (m), 2857 (m), 1471 (w), 1374
˜
(w), 1255 (w), 1120 (w), 1076 (w), 838 (m), 777 (m). MS (EI, 70 eV):
m/z (%): 302 ([M+], 0.9), 245 (25), 189 (18), 135 (69), 83 (100), 55
(26) cm–1. HRMS (C16H31ClOSi): calcd. 302.1833, found 302.1839.
C16H31ClOSi (302.96): calcd. C 63.43, H 10.31, found C 63.24, H
10.12.
2-(Chloromethylene)-5,6-dimethylhept-5-en-1-ol (6). From PMB-
Protected Precursor 19: To a solution of 19 (100 mg, 0.32 mmol) in
CH2Cl2/pH 7 buffer, 19:1 (4 mL) was added DDQ (111 mg,
0.49 mmol, 1.5 equiv.) at room temp. The green solution was stirred
for 60 min whereupon a yellow precipitate was formed. The reac-
tion mixture was diluted with CH2Cl2 (5 mL) and H2O (5 mL). The
phases were separated and the organic phase was dried with
Na2SO4 and concentrated in vacuo. The residue was subjected to
column chromatography (n-pentane–Et2O, 6:1) yielding the desired
product as a pale yellow oil (60 mg, 0.32 mmol, 98%).
1
starting material). H NMR (CDCl3, 400 MHz): δ = 1.62 (s, 3 H,
CH3), 1.63 (s, 3 H, CH3), 1.64 (s, 3 H, CH3), 2.14–2.18 (m, 2 H,
CH2), 2.21–2.25 (m, 2 H, CH2), 3.81 (s, 3 H, OCH3), 4.22 (d, 2 H,
J = 0.9 Hz, CH2 allylic), 4.43 (s, 2 H, CH2 benzylic), 5.96 (t, 1 H,
J = 0.9 Hz, C=CHCl), 6.86–6.90 (br. d, 2 H, J = 8.8 Hz, Ar-H),
7.26–7.30 (br. d, 1 H, J = 8.8 Hz, Ar-H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 18.5 (p), 20.2 (p), 20.7 (p), 31.5 (s), 33.2 (s), 55.4
From TIPS-Protected Precursor 20: To a solution of 20 (1.46 g,
4.23 mmol) in THF (40 mL) was added tetrabutylammonium fluo-
Eur. J. Org. Chem. 2006, 4916–4923
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4921

D. Keck, S. Vanderheiden, S. Bräse
FULL PAPER
ride trihydrate (1.22 g, 4.65 mmol, 1.1 equiv.) in THF (10 mL) at
room temp. and the mixture was stirred for 15 min. The reaction
was then quenched with H2O (20 mL) and extracted with Et2O
(3×50 mL). The combined organic extracts were washed with brine
(30 mL), dried with Na2SO4 and concentrated in vacuo. The resi-
due was purified by column chromatography (n-pentane–Et2O, 6:1)
yielding the product as a pale yellow oil (719 mg, 3.81 mmol, 90%).
AHB), 6.98–7.14 (m, 2 H, Ar-H), 7.22–7.28 (m, 1 H, Ar-H), 7.98
(br. d, 1 H, J = 8.4 Hz, Ar-H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 18.3 (p), 19.9 (p), 20.6 (p), 27.8 (s), 33.5 (s), 33.6 (s), 57.8 (t),
63.3 (s), 68.9 (q), 120.7 (t), 120.8 (q), 124.4 (t), 124.8 (q), 125.9 (q),
127.8 (t), 129.4 (t), 132.9 (q), 154.9 (q) ppm. IR (film on KBr): ν
˜
= 3491 (w), 3068 (m), 2924 (m), 2863 (m), 2727 (w), 1753 (s), 1605
(w), 1582 (m), 1493 (m) 1458 (m), 1400 (m), 1369 (m), 1351 (m),
1H NMR (CDCl3, 400 MHz): δ = 1.63 (s, 9 H, 3× CH3), 1.86 (br. 1309 (m), 1268 (m), 1220 (m), 1188 (m), 1157 (m), 1108 (m), 1057
s, 1 H, OH), 2.14–2.18 (m, 2 H, CH2), 2.21–2.25 (m, 2 H, CH2), (m), 1027 (m), 986 (m), 960 (m), 821 (s), 708 (m), 685 (m), 661 (m)
4.31 (s, 2 H, CH2OH), 5.88 (s, 1 H, C=CHCl) ppm. 13C NMR cm–1. MS (EI, 70 eV): m/z (%): 319 ([M+], 45), 284 (10), 222 (100),
(CDCl3, 100 MHz): δ = 18.4 (p), 20.2 (p), 20.7 (p), 31.6 (s), 33.2 (s), 186 (18), 142 (37), 55 (9). HRMS (C18H22ClNO2): calcd. 319.1339,
60.4 (s), 114.2 (t), 125.4 (q), 126.6 (q), 141.9 (q). IR (film on KBr):
ν = 3337 (m), 3068 (w), 2987 (m), 2921 (m), 1632 (w), 1600 (w),
˜
found 319.1334. C18H22ClNO2 (319.83): calcd. C 67.60, H 6.93, N
4.38, found C 67.55, H 7.12, N 4.18.
1446 (m), 1373 (w), 1315 (w), 1263 (w), 1234 (w), 1159 (w), 1019
(m), 864 (w), 807 (m). MS (EI, 70 eV): m/z (%): 188 ([M+], 3), 153
(12), 83 (100), 55 (39), 41 (35). HRMS (C10H17ClO): calcd.
188.0968, found 188.0965. C10H17ClO (188.69): calcd. C 63.65,
H 9.08, found C 63.82, H 9.31.
4-Chloro-3a-(3,4-dimethylpent-3-enyl)-7-iodo-3,3a,4,5-tetrahydro-
oxazolo[3,4-a]quinolin-1-one (3): To a solution of 7 (150 mg,
0.47 mmol) in CH2Cl2 (6 mL), iodine monochloride (84 mg,
0.52 mmol, 1.1 equiv.) and the mixture was stirred for 24 h at room
temp. The reaction was quenched by addition of saturated aqueous
Na2S2O3 solution (10 mL). After speration of the phases, the aque-
ous phase was extracted with CH2Cl2 (3×10 mL), the combined
extracts were dried with Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (n-pentane–Et2O,
1:1) yielding the product as a brown solid (188 mg, 0.42 mmol,
2-(Chloromethylene)-5,6-dimethylhept-5-enyl [2-(Chloromethyl)-
phenyl]carbamate (8): To a solution of 9 (345 mg, 2.09 mmol) and
triphenylphosphane (657 mg, 2.50 mmol, 1.20 equiv.) in acetoni-
trile (20 mL) was added tetrachloromethane (440 mg, 2.86 mmol,
1.37 equiv.) and the mixture was stirred at 50 °C for 3 h, changing
the color from pale yellow to orange. It was then cooled to 0 °C, 6
(660 mg, 3.50 mmol, 1.67 equiv.) was added and the mixture was
stirred at 50 °C for 40 h. After cooling, the volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2
(5 mL), trifluoroacetic anhydride (658 mg, 3.14 mmol, 1.5 equiv.)
was added, stirred for 4 h at room temp. The reaction was again
concentrated to dryness. The residue was subjected to column
chromatography (n-pentane–Et2O, 1:1) providing the product as a
beige solid (624 mg, 1.80 mmol, 83 %). 1H NMR (CDCl3,
400 MHz): δ = 1.57 (9 H, 3× s, 3× CH3), 2.11–2.14 (m, 2 H, CH2),
2.15–2.18 (m, 2 H, CH2), 4.55 (s, 2 H, CH2Cl), 4.88 (d, 2 H, J =
0.9 Hz, OCH2 allylic), 5.96 (t, 1 H, J = 0.9 Hz, C=CHCl), 6.91 (br.
s, 1 H, NH), 7.05 (ddd, 1 H, J = 7.5 Hz, J = 7.5 Hz, J = 1.0 Hz,
Ar-H), 7.22 (dd, 1 H, J = 7.5 Hz, J = 1.4 Hz, Ar-H), 7.32 (ddd, 1
H, J = 7.5 Hz, J = 7.5 Hz, J = 1.4 Hz, Ar-H), 7.79 (d, 1 H, J =
7.5 Hz, Ar-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 18.3 (p),
20.1 (p), 20.6 (p), 31.3 (s), 33.1 (s), 43.9 (s), 62.4 (s), 116.3 (t), 122.9
(t), 124.6 (t), 125.5 (q), 126.2 (q), 127.3 (q), 130.1 (t), 130.2 (t),
1
90%). H NMR (CDCl3, 400 MHz): δ = 1.51 (s, 3 H, CH3), 1.74
(s, 6 H, 2× CH3), 1.98–1.87 (m, 2 H, CH2), 2.10–1.99 (m, 2 H,
CH2), 3.21 (dd, 1 H, J = 18.6 Hz, J = 1.5 Hz, CHClCHAHB), 3.51
(dd, 1 H, J = 18.6 Hz, J = 4.7 Hz, CHClCHAHB), 4.28 (d, 1 H, J
= 9.0 Hz, OCHAHB), 4.42 (dd, 1 H, J = 4.7 Hz, J = 1.5 Hz, CHCl),
4.60 (d, 1 H, J = 9.0 Hz, OCHAHB), 7.52 (br. s, 1 H, Ar-H), 7.62
(dd, 1 H, J = 8.7 Hz, J = 1.9 Hz, Ar-H), 7.84 (br. d, 1 H, J =
8.7 Hz, Ar-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 24.0 (p),
28.6 (p), 28.9 (p), 31.0 (s), 31.6 (s), 33.0 (s), 56.7 (t), 63.0 (s), 68.8
(q), 75.5 (q), 78.3 (q), 88.2 (q), 122.5 (t), 123.0 (q), 132.6 (q), 136.9
(t), 138.2 (t), 154.4 (q) ppm. IR (film on KBr): ν = 2964 (m), 2926
˜
(m), 1855 (w), 1758 (m), 1487 (m), 1398 (m), 1361 (w), 1322 (w),
1295 (w), 1261 (m), 1221 (w), 1098 (m), 1026 (m), 966 (w), 872 (w),
802 (m), 750 (w) ppm. MS (EI, 70 eV): m/z (%): no [M+], 319 (15),
222 (10), 97 (13), 84 (86), 49 (100). C18H21ClINO2 (445.72): calcd.
C 48.50, H 4.75, N 3.14, found C 48.76, H 4.61, N 3.32.
Acknowledgments
136.6 (q), 137.4 (q), 153.5 (q) ppm. IR (film on KBr): ν = 3288 (s),
˜
3124 (m), 3072 (m), 2981 (m), 2924 (s), 2867 (m), 2726 (w), 2318
(w), 2063 (w), 1947 (w), 1918 (w), 1887 (w), 1696 (s), 1593 (s), 1545
(s), 1457 (s), 1372 (m), 1252 (s), 1071 (s), 908 (w), 806 (m), 677 (s)
cm–1. MS (EI, 70 eV): m/z (%): 355 ([M+], 1.5), 170 (6), 135 (5), 83
(10), 58 (58), 43 (100). HRMS (C18H23Cl2NO2): calcd. 355.1108,
found 355.1106. C18H23Cl2NO2 (356.29): calcd. C 60.68, H 6.50, N
3.93, found C 60.76, H 6.65, N 4.20.
Financial support from the Landesgraduiertenförderung Baden-
Württemberg (fellowship for D. K.) is gratefully acknowledged. We
thank Jens Meyer for the preparation of some of the compounds
and Henning Steinhagen and Frank Avemaria for helpful dis-
cussions.
¯
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4916–4923

Formal Total Synthesis of Virantmycin
FULL PAPER
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Received: July 21, 2006
Published Online: August 31, 2006
Eur. J. Org. Chem. 2006, 4916–4923
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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