The total synthesis of (±)-fumimycin

Article abstract of DOI:10.1002/chem.201001036

The antibiotic agent fumimycin has been synthesized for the first time. This natural product was found to inhibit the bacterial peptide deformylase and may represent a lead structure to a class of novel antibacterials. Our synthetic strategy towards fumimycin involved the following steps: Dakin oxidation of an aldehyde functionality, conversion of an oxime through radical fragmentation to form an N-diphenylphosphoryl group, construction of an α-trisubstituted amine by 1,2-addition to a ketimine, a Claisen rearrangement with subsequent transition-metal-catalyzed olefin isomerization to install a propenyl chain and final amidation. Peptide deformylase (PDF)-inhibitor synthesis: A strategy involving amine formation through addition to a ketimine has been successfully employed for the first total synthesis of the antibiotic agent fumimycin (see scheme).

Full text of DOI:10.1002/chem.201001036

DOI: 10.1002/chem.201001036
The Total Synthesis of (ꢀ)-Fumimycin
Patrick J. Gross and Stefan Brꢀse*[a]
Abstract: The antibiotic agent fumimy-
cin has been synthesized for the first
time. This natural product was found to
inhibit the bacterial peptide deformy-
lase and may represent a lead structure
to a class of novel antibacterials. Our
synthetic strategy towards fumimycin
involved the following steps: Dakin ox-
idation of an aldehyde functionality,
conversion of an oxime through radical
fragmentation to form an N-diphenyl-
phosphoryl group, construction of an
a-trisubstituted amine by 1,2-addition
to a ketimine, a Claisen rearrangement
with subsequent transition-metal-cata-
lyzed olefin isomerization to install a
propenyl chain and final amidation.
Keywords: amines · fumimycin · in-
hibitors · natural products · total
synthesis
Introduction
was proposed to be an alanine unit linked to a phenyl group
at the a-carbon, possessing both lactone and amide moiety
(Scheme 1). Structurally, fumimycin is related to sorbicillac-
tone A (2),[6] a sponge-derived natural product possessing
antileukemic activity. They both possess a six-membered
ring fused to a five-membered lactone as skeleton and have
an a-trisubstituted amine linked to a fumaric acid moiety.
Fumimycin shows optical activity, but its absolute configura-
tion is as yet unknown.
In 2007, Kim and co-workers reported the structural deter-
mination and the biological activity of fumimycin (1).[1] It
was isolated from the fermentation broth of Aspergillus fu-
misynnematus F746, a fungus that was collected from a
Korean soil sample. The mycotoxin[2] fumimycin displayed
high activity in a screening of peptide deformylase (PDF)
inhibition. Peptide deformylase,[3] a member of a unique
subclass of metalloenzymes, catalyzes the removal of the
formyl group at the N-terminus of bacterial proteins. This
mechanism is essential for prokaryotic growth, but not for
mammalian cells. The screening for PDF inhibitors thus
allows identification of selective mechanism-based antibac-
terial agents, which are potentially non-toxic. Several studies
have shown that PDF inhibitors act as broad-spectrum anti-
bacterial agents.[4] Fumimycin showed inhibition of Staphy-
lococcus aureus PDF, specifically two methicillin-resistant S.
aureus (MRSA) strains and two quinolone-resistant S.
aureus (QRSA) strains, with an IC50 value of 4.1 mm. There-
fore, fumimycin may represent a lead structure to a class of
novel antibacterials.[5]
Scheme 1. Fumimycin (1) and structurally related sorbicillactone A (2).
Based on HRMS and NMR spectroscopy studies (1H, 13C,
COSY, DEPT, HMQC spectra), the structure of fumimycin
Despite the interest in new antibacterials,[7] no synthesis
of fumimycin has been achieved so far. The significant bio-
logical properties and the distinctive structural features of
this natural compound prompted us to approach the synthe-
sis of fumimycin. We have previously reported methods for
the asymmetric construction of a-trisubstituted amines[8] and
our preliminary results towards a derivative of fumimycin.[9]
Since we were not able to convert this material into fumimy-
cin itself, we explored systematically alternatives to synthe-
size the natural product. Herein, we describe our various
[a] Dipl.-Chem. P. J. Gross, Prof. Dr. S. Brꢀse
Institut fꢁr Organische Chemie
Karlsruher Institut fꢁr Technologie (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax : (+49)721-608-8581
E-mail: braese@kit.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001036.
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FULL PAPER
strategies towards (ꢀ)-fumimycin and the 18step sequence,
quence involving a Claisen rearrangement and subsequent
olefin isomerization, by using allyl ether 5 (right pathway).
Key steps in both pathways are the construction of the a-tri-
substituted amine through the 1,2-addition of a methyl
Grignard reagent to ketimines 6 and 7, respectively.[12] To
improve the reactivity of the ketimines, we postulated that
an electron withdrawing group at the nitrogen atom had to
be installed. In the left pathway, selective bromination of
the aromatic core is necessary. Both pathways include Frie-
del–Crafts acylation with an oxalyl derivative and lactoniza-
tion. Starting materials for these synthetic routes are the
bis-protected phenol 8 and para-hydroxy benzaldehyde (9),
which would be allylated and oxidized prior to acylation.
accomplishing the first total synthesis.
Results and Discussion
Synthetic plan: Fumimycin (1) is a highly polar compound
with a carboxylic acid group and two phenol groups. To sim-
plify synthetic handling, we decided to deprotect these func-
tionalities at the very end of the synthesis. We intended to
introduce the fumaric acid side chain by amidation of an a-
trisubstituted amine, which derives from 3 through N-depro-
tection (Scheme 2).
The 1-propenyl side chain at C1 could be installed by a
palladium-catalyzed cross-coupling of aryl bromide 4 with 1-
propene boronic acid[10] or (trialkyl)-1-propenyl stannane[11]
(left pathway). Alternatively, we planned a two-step se-
Approach by bromination: We first pursued the synthetic
pathway through the bromination/cross-coupling sequence
(Scheme 3), starting from sesamol (10). We hoped to ach-
ieve selective bromination at C5 of one of the intermediate
compounds of the sequence. To that end, we tried to block
the C2- and C6-position of 10 by silylation of the hydroxyl
group, installing the very bulky tert-butyldiphenylsilyl group
(TBDPS), to form 15. Subsequent reaction of 15 with N-bro-
mosuccinimide (NBS) gave exclusively the undesired 6-
bromo compound. Unfortunately, the same regioselectivity
was observed when a lithiation/bromination process was em-
ployed.[13] To overcome this obstacle we decided to use the
reactivity at the C6 position of 10 in a Friedel–Crafts acyla-
tion with ethyl oxalyl chloride to produce 11. The phenol
group of 11 was again protected with bulky groups (12a:
tert-butyldimethylsilyl (TBS), 12b: TBDPS, 12c: pivaloyl)
and bromination was performed. In all cases, only bromina-
tion at C2 was observed, indicating that the electronic ef-
fects for the aromatic substitution dominated over steric fac-
tors.
All attempts to achieve direct condensation of ketone 12a
with phosphonamide[14] to form 17 gave only unsatisfying
yields; therefore we used a more reliable two-step proce-
dure. Ketone 12a was converted with hydroxylamine to the
oxime 13 in 96% yield (E/Z 1:1), followed by transforma-
tion to the ketimine 17. This reaction proceeds via the un-
stable intermediate 14a.[15] At elevated temperature, homo-
ꢁ
lytic cleavage of the N O bond forms the radical 14b and
the phosphorous-centered radical, the recombination of
which forms the diphenylphosphoryl group in 17. Neither 13
nor 17 could be brominated. Attempted palladium-catalyzed
[16]
ꢁ
C H activation approaches were also unsuccessful.
Due to the presence of the phosphoryl group, the keti-
mine functionality in 17 is eletrophilic enough to react readi-
ly with methylmagnesium chloride to form the a-trisubstitut-
ed amine 18 in 65% yield. Deprotection of the two dioxo-
lane oxygen atoms required a two-step sequence: oxidation
[17]
of 18 by using Pb
G
to form the ortho-ester 19
through a radical mechanism (as 1:1 mixture of diastereo-
mers), followed by an acidic cleavage under mild conditions
to give catechol 20 in only moderate yields. To our disap-
pointment, all attempts at the halogenation of 20 failed. We
also considered allylation of the 4-hydroxyl group to install
Scheme 2. Planned synthetic pathways towards 1.
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S. Brꢀse and P. J. Gross
Scheme 3. Attempts at selective bromination: a) ClCOCO2Et, AlCl3, CH2Cl2, 08C, 90%; b) for 12a: TBSCl, iPr2NEt, CH2Cl2, RT, 95%; for 12b:
TBDPSCl, iPr2NEt, CH2Cl2, RT, quant, for 12c: PivCl, Et3N, CH2Cl2, RT, 89%; c) H2NOH·HCl, pyridine, EtOH, reflux, 96%; d) ClPPh2, Et3N, n-
hexane/CH2Cl2 1:1, ꢁ508C, 70%; e) TBDPSCl, iPr2NEt, CH2Cl2, RT, 99%; f) NBS, CH3CN, 608C; or sBuLi THF/n-hexane 2:1, ꢁ788C, Br2; g) MeMgCl,
toluene, 08C, 65%; h) PbACTHNUTRGNEUNG(OAc)4, benzene, 808C; i) AcOH, MeOH, 608C, 61% over two steps.
the desired olefinic side chain through a Claisen rearrange-
ment, but selective allylation could not be accomplished.
Due to the problems with reactivity and selectivity we de-
cided to turn our attention to the synthetic pathway through
the Claisen rearrangement.
We reasoned that the Claisen rearrangement product with
the free hydroxyl groups might be unstable under the high
temperature conditions. Hence, we tested protecting groups
again, but neither pivaloyl ester 30a nor para-methoxy
benzyl (PMB) ether 30b could be converted into the desired
product. We tested solvents with different polarities, the use
of Lewis acid catalysts, microwave conditions and high pres-
sure in a sealed tube for the Claisen rearrangement, all with-
out success. Considering the lack of reactivity, we reasoned
that this system is especially sensitive to steric hindrance.
Adjacent to the allyl ether, even groups with moderate bulk-
iness prevent the formation of the favorable chair-like tran-
sition state for the [3,3] rearrangement. Consequently, we
decided to use the small methyl group as protecting group.
Approach by Claisen rearrangement starting from catechol
21: For this route we started with the regioselective allyla-
tion of the para-hydroxyl group in 21 (Scheme 4). Oxidation
of the aldehyde took place without epoxidation of the allylic
group and was best accomplished with oxone to yield the
unstable formate ester 22, which was hydrolyzed with a
methanolic NaHCO3 solution.[18] The highest yield for the
following Friedel–Crafts acylation was achieved by using
TiCl4 at ꢁ158C to give 23. Protection of both hydroxyl
groups and oxime formation gave 24 in high yields. Installa-
tion of a diphenylphosphoryl group and subsequent methyl
Grignard addition was carried out as described above and
gave rise to a-trisubstituted amine 25. Heating of 25 led to
decomposition instead of the Claisen rearrangement, most
likely due to the thermal instability of the TBS groups.
Therefore we cleaved the TBS group using tetrabutylammo-
nium fluoride (TBAF) to form the diol 27. Heating of 27
gave complex mixtures through partial lactonization. To
avoid this side reaction, both phenol groups were protected.
Unfortunately, neither the bis-acetate 28a nor the bis-triiso-
propylsilyl (TIPS) ether 28b underwent the [3,3] rearrange-
ment. Conversion of 27 through acid catalysis with para-tol-
uenesulfonic acid (PTSA) gave lactone 29, which again de-
composed when heated.
Approach by Claisen rearrangement starting from vanillin
(31): For this synthetic pathway (Scheme 5, for intermediate
structures, see Scheme 6 in the Experimental Section), vanil-
lin (31) could be employed as an inexpensive starting mate-
rial. At the beginning of this route, the same steps as dis-
cussed in Scheme 4 were utilized. Vanillin (31) was allylated,
then subjected to a Dakin oxidation by using H2O2/B(OH)3/
H2SO4,[19] under which conditions the initially formed for-
mate ester was directly hydrolysed. Friedel–Crafts acylation
and silylation gave ketone 32 in good yield. As described
above, the procedure for oxime formation, diphenylphos-
phoryl formation and 1,2-addition gave amine 33, which we
hoped would undergo Claisen rearrangement. Heating of 33
in DMF to 1208C lead to lactonization, enabled through the
thermal instability of the TBS ether under these conditions.
Further heating to reflux finally gave rise to the desired
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Total Synthesis of (ꢀ)-Fumimycin
FULL PAPER
Scheme 4. Synthetic route starting with selective allylation of catechol 21,
attempts for Claisen rearrangement: a) allyl bromide, Na2CO3, DMF,
358C, 65%; b) oxone, DMF, RT; c) NaHCO3, MeOH, H2O, RT, 75 %
over two steps; d) ClCOCO2Et, TiCl4, CH2Cl2, ꢁ158C, 73%; e) TBSCl,
iPr2NEt, CH2Cl2, RT, 81%; f) H2NOH·HCl, pyridine, EtOH, reflux,
98%; g) ClPPh2, Et3N, THF, ꢁ508C, 61%; h) MeMgBr, toluene, ꢁ788C,
73%; i) TBAF, AcOH, THF, 08C!RT, 73%; j) for 28a: AcCl, Et3N,
CH2Cl2, RT, 73%; for 28b: TIPSCl, iPr2NEt, DMAP, CH2Cl2, RT, 83%;
k) PTSA, toluene, reflux, 49%; l) for 30a: PivCl, Et3N, DMAP, CH2Cl2,
RT, 80%; for 30b: PMBCl, K2CO3, DMF, 658C, 48%. DMAP=4-dime-
thylaminopyridine.
[3,3] rearrangement. Subsequent isomerization of the termi-
nal double bond to provide olefin 34 was accomplished
under rhodium catalysis[20] in excellent yield (trans/cis 10:1).
Undesired cis-34 could be separated from trans-34 through
column chromatography with 10% AgNO3.[21]
Our initial plan was to protect the newly generated
phenol group with subsequent cleavage of the methyl ether,
avoiding the generation of the free catechol group. But de-
methylation of the silylether 37a was unsuccessful due to
the hindrance of the adjacent TIPS group. We synthesized
acetate 37b and subjected it to demethylation conditions
employing MgI2,[22] hoping that the acetate might coordinate
to the metal and facilitate the reaction. Disappointingly,
again only decomposition could be observed. We did not
succeed in the demethylation of 34 before screening a multi-
Scheme 5. Total synthesis of fumimycin (1): a) allyl bromide, K2CO3, ace-
tone, reflux, 85%; b) H2O2, B(OH)3, H2SO4, THF, 308C, 81%; c) ClCO-
CO2Et, TiCl4, CH2Cl2, ꢁ158C, 82%; d) TBSCl, iPr2NEt, CH2Cl2, RT;
e) H2NOH·HCl, pyridine, EtOH, reflux, 91% over two steps; f) ClPPh2,
Et3N, THF, ꢁ508C, 74%; g) MeMgBr, toluene, ꢁ788C, 65%; h) DMF,
1208C; i) DMF, reflux, 55% over two steps; j) RhCl3·H2O, EtOH, 458C,
96% (trans/cis 10:1); k) BI3, CH2Cl2, ꢁ208C, 90%; l) for 37a: TIPSCl,
iPr2NEt, DMAP, CH2Cl2, RT, 64%; for 37b: AcCl, Et3N, DMAP,
CH2Cl2, RT, 89%; m) TIPSOTf, 2,6-lutidine, CH2Cl2, ꢁ158C!RT, 83 %;
n) HCl, MeOH, 558C; o) 41, pyridine, CH2Cl2, 08C!RT, 24% over two
steps; p) CHOCO2H·H2O, THF, RT, 60%; q) oxalyl chloride, DMF,
CH2Cl2, 08C!RT, quant; r) TBAF, AcOH, THF, RT, 93%; s) TFA,
CH2Cl2, 08C!RT, quant.
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S. Brꢀse and P. J. Gross
tude of deprotection conditions. One problem was the cycli-
zation of the 4-hydroxyl function with the sp2 carbon at 2’.[23]
With boron triiodide[24] this side reaction could be sup-
pressed, giving the desired diol 35 in 90% yield, which was
then selectively monosilylated to form 36, employing triiso-
propylsilyl triflate and 2,6-lutidine. Deprotection of the ni-
trogen in the presence of the silyl group required carefully
chosen acidic conditions. The crude product was directly
used in the next step, avoiding the isolation of the free
amine. For the amidation of 39, acid chloride 41 was em-
ployed, derived from phosphoranylidene 40.[25] The reaction
sequence gave amide 42 only in low yield, which was then
subjected to desilylation with TBAF/AcOH. As the last step
of the sequence, the cleavage of the tert-butyl ester was ach-
ieved with trifluoroacetic acid, yielding (ꢀ)-fumimycin (1)
in quantitative yield.
The NMR spectral data, as well as the HRMS and IR
data are consistent with those for the natural (ꢁ)-fumimy-
cin.
Conclusion
In summary, three synthetic pathways towards the synthesis
of fumimycin have been pursued. Ultimately, a pathway
starting from vanillin (31) and employing a Claisen rear-
rangement culminated in the synthesis of (ꢀ)-fumimycin (1)
in 18 steps (16-step longest linear sequence, 2.2% overall
yield). We have reported the first total synthesis of this nat-
ural product possessing highly interesting biological proper-
ties.
Scheme 6. Overview of further structures in the synthesis towards Fumi-
mycin.
Experimental Section
1
81%). H NMR (500 MHz, CDCl3): d=3.80 (s, 3H), 4.52 (dm, J=5.6 Hz,
2H), 5.12 (brs, 1H), 5.25 (dq, J=10.4, 1.3 Hz, 1H), 5.36 (dq, J=17.3,
1.5 Hz, 1H), 6.08 (ddt, J=17.3, 10.5, 5.6 Hz, 1H), 6.31 (dd, J=8.6,
2.8 Hz, 1H), 6.46 (d, J=2.8 Hz, 1H), 6.75 ppm (dd, J=8.6 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=55.8, 71.1, 100.7, 105.9, 115.5, 117.8,
133.7, 141.9, 150.5, 150.6 ppm; IR (KBr): n˜ =3360, 2940, 2603, 1607, 1455,
4-Allyloxy-3-methoxybenzaldehyde (43): Allylbromide (0.69 mL, 0.95 g,
7.9 mmol, 1.2 equiv) was added to a suspension of vanillin (31) (1.00 g,
6.57 mmol, 1.00 equiv) and K2CO3 (1.82 g, 13.1 mmol, 2.00 equiv) in ace-
tone (10 mL). The mixture was heated to reflux for 6 h. After filtration,
the filtrate was concentrated under reduced pressure. Flash chromatogra-
phy (cyclohexane/EtOAc 5:1!3:1) afforded the allylether 43 as a color-
less oil (1.07 g, 85%). 1H NMR (400 MHz, CDCl3): d=3.93 (s, 3H), 4.70
(dm, J=5.4 Hz, 2H), 5.34 (dq, J=10.5, 1.2 Hz, 1H), 5.44 (dq, J=17.3,
1.4 Hz, 1H), 6.08 (ddt, J=17.3, 10.5, 5.3 Hz, 1H), 6.97 (d, J=7.5 Hz,
1H), 7.42 (brs, 1H), 7.43 (dd, J=7.5, 1.9 Hz, 1H), 9.85 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=55.9, 69.6, 109.2, 111.8, 118.6, 126.4,
130.0, 132.1, 149.7, 153.3, 190.7 ppm; IR (KBr): n˜ =3080, 2938, 2728,
1586, 1268, 1136, 935, 810, 732 cmꢁ1; MS (EI): m/z (%): 192 (100) [M+],
152 (69) [C8H7O3+]. HRMS (EI): m/z: calcd for C11H12O3: 192.0786;
found 192.0790.
1217, 952, 722 cmꢁ1 MS (EI): m/z (%): 180 (44) [M+], 139 (100)
;
[C7H7O3+]; HRMS (EI): m/z: calcd for C10H12O3: 180.0786; found
180.0786.
Ethyl (5-allyloxy-2-hydroxy-4-methoxyphenyl)oxoacetate (45): A solution
of 44 (100 mg, 0.550 mmol, 1.00 equiv) and ethyl oxalyl chloride
(0.074 mL, 91 mg, 0.67 mmol, 1.2 equiv) in CH2Cl2 (1.0 mL) was cooled
to ꢁ158C. TiCl4 (1.0m in CH2Cl2, 0.67 mL, 0.67 mmol, 1.2 equiv) was
added over 20 min. After additional stirring for 40 min, the mixture was
poured into ice-cooled 1m HCl (15 mL). The aqueous layer was extracted
with CH2Cl2 (4ꢃ15 mL). The combined organic extracts were washed
with H2O (20 mL) and brine (20 mL), dried over Na2SO4, and concentrat-
ed under reduced pressure. Flash chromatography (cyclohexane/EtOAc
5:1) afforded the phenol 45 as a yellow solid (126 mg, 82%). M.p. 56–
578C; 1H NMR (400 MHz, CDCl3): d=1.43 (t, J=7.1 Hz, 3H), 3.94 (s,
3H), 4.44 (q, J=7.1 Hz, 2H), 4.54 (dt, J=5.6, 1.4 Hz, 2H), 5.32 (dq, J=
10.5, 1.3 Hz, 1H), 5.41 (dq, J=17.2, 1.5 Hz, 1H), 6.05 (ddt, J=17.2, 10.5,
5.5 Hz, 1H), 6.49 (s, 1H), 7.25 (s, 1H), 11.80 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d=14.1, 56.4, 62.5, 70.6, 100.5, 108.4, 114.4, 118.6,
132.8, 141.4, 159.2, 162.6, 162.7, 187.2 ppm; IR (KBr): n˜ =3089, 2912,
1725, 1511, 1201, 1007, 953, 757 cmꢁ1; MS (FAB): m/z (%): 281 (83)
4-Allyloxy-3-methoxyphenol (44): Boric acid (3.22 g, 52.0 mmol,
5.00 equiv) was suspended in THF (30 mL), H2O2 (30% in H2O, 3.4 mL),
and H2SO4 (1.5 mL). After stirring for 30 min, 43 (2.00 g, 10.4 mmol,
1.00 equiv) was added as a solution in THF (10 mL) within 15 min. After
additional stirring for 5 h, the mixture was filtered. The filtrate was neu-
tralized by addition of sat. aqueous NaHCO3 solution (100 mL); the
aqueous layer was extracted with EtOAc (3ꢃ50 mL). The combined or-
ganic extracts were washed with brine (50 mL), dried over Na2SO4, and
concentrated under reduced pressure. Flash chromatography (cyclohex-
ane/EtOAc 4:1!3:1) afforded the phenol 44 as a brown oil (1.48 g,
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Total Synthesis of (ꢀ)-Fumimycin
FULL PAPER
[M+], 239 (46) [C11H11O6+], 207 (88), [C11H11O4+], 165 (36), [C8H5O4+];
HRMS (FAB+) m/z: calcd for C14H17O6: 281.1025; found 281.1023.
9.3 Hz), 133.3, 134.0 (d, JP =133.9 Hz), 142.8, 152.9, 155.2, 165.0 (d, JP =
15.5 Hz), 169.0 ppm (d, JP =7.6 Hz); IR (KBr): n˜ =3438, 3059, 2929, 2645,
1591, 1370, 1216, 983, 841 cmꢁ1; MS (EI): m/z (%): 552 (6) [M+], 552
(22) [C29H35NO6PSi+], 536 (72) [C28H31NO6SiP+], 201 (100); HRMS
(EI): m/z: calcd for C32H40NO6SiP: 593.2363; found 593.2365.
Ethyl (5-allyloxy-2 tert-butyldimethylsilanyloxy-4-methoxyphenyl)oxo-
ACHTUNGTRENNUNGacetate (32): A solution of 45 (11.57 g, 41.29 mmol, 1.00 equiv) and tert-
butyldimethylchlorosilane (8.08 g, 53.7 mmol, 1.30 equiv) in CH2Cl2
(20 mL) was cooled to 08C. iPr2NEt (11 mL, 8.0 g, 62 mmol, 1.5 equiv)
was added within 5 min. The mixture was stirred at 08C for 4 h, followed
by stirring at RT for 1 d. The reaction was quenched by addition of H2O
(300 mL), the aqueous layer was extracted with EtOAc (4ꢃ250 mL). The
combined organic extracts were washed with H2O (300 mL) and brine
(300 mL), dried over Na2SO4, and concentrated under reduced pressure.
Flash chromatography (cyclohexane/EtOAc 7:1!4:1) afforded the sily-
Ethyl 2-[5-allyloxy-2-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-2-
diphenylphosphinoylamino-propionate (33): A solution of 47 (10.67 g,
17.97 mmol, 1.00 equiv) in toluene (240 mL) was cooled to ꢁ788C.
MeMgBr (3m in Et2O, 12 mL, 36 mmol, 2.0 equiv) was added dropwise.
After stirring for 3 h sat. aqueous KHSO4 solution (600 mL) was added.
The phases were separated; the aqueous layer was extracted with EtOAc
(3ꢃ150 mL). The combined organic extracts were washed with brine
(130 mL), dried over Na2SO4, and concentrated under reduced pressure.
Flash chromatography (cyclohexane/EtOAc 2:1!2:3) afforded the amine
33 as a highly viscous brown oil (7.11 g, 65%). 1H NMR (400 MHz,
[D6]acetone): d=0.24 (s, 3H), 0.33 (s, 3H), 0.94 (s, 9H), 1.14 (t, J=
7.1 Hz, 3H), 1.83 (s, 3H), 3.79 (s, 3H), 4.06 (dq, J=10.8, 7.1 Hz, 1H),
4.24 (dq, J=10.8, 7.1 Hz, 1H), 4.38 (mc, 2H), 5.20 (dq, J=10.5, 1.5 Hz,
1H), 5.39 (dq, J=17.3, 1.5 Hz, 1H), 6.04 (ddt, J=17.3, 10.5, 5.3 Hz, 1H),
6.45 (s, 1H), 6.88 (s, 1H), 7.28–7.34 (m, 2H), 7.40–7.56 (m, 4H), 7.62–
7.70 (m, 2H), 7.90–7.96 ppm (m, 2H); 13C NMR (100 MHz, [D6]acetone):
d=ꢁ2.6, 15.3, 20.3, 25.8 (d, JP =4.1 Hz), 27.6, 57.3, 62.4, 63.1, 72.4, 105.5,
116.5, 118.0, 126.4, 129.9 (d, JP =12.7 Hz), 130.2 (d, JP =12.5 Hz), 133.0
(d, JP =2.6 Hz), 133.4 (d, JP =2.8 Hz), 133.5 (JP =9.5 Hz), 133.7 (JP =
9.5 Hz), 136.1 (d, JP =129.4 Hz), 136.5, 137.1 (d, JP =131.9 Hz), 143.5,
159.1, 151.5, 176.4 (d, JP =8.7 Hz) ppm; IR (KBr): n˜ =3335, 2932, 1735,
1611, 1510, 1391, 1245, 1123, 913, 839 cmꢁ1; MS (EI): m/z (%): 609 (16)
[M+], 568 (52) [C30H39NO6PSi+], 552 (100) [C29H35NO6SiP+], 536 (78);
HRMS (EI): m/z: calcd for C33H44NO6SiP: 609.2676; found 609.2673.
1
lether 32 as a yellow oil (15.42 g, 95%). H NMR (400 MHz, CDCl3): d=
0.28 (s, 6H), 0.96 (s, 9H), 1.35 (t, J=7.2 Hz, 3H), 3.87 (s, 3H), 4.33 (q,
J=7.2 Hz, 2H), 4.57 (dt, J=4.6, 1.4 Hz, 2H), 5.29 (dq, J=10.5, 1.4 Hz,
1H), 5.43 (dq, J=17.2, 1.4 Hz, 1H), 6.06 (ddt, J=17.2, 10.5, 5.5 Hz, 1H),
6.39 (s, 1H), 7.27 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=ꢁ3.8,
13.9, 19.0, 26.1, 56.0, 61.7, 70.1, 103.3, 113.4, 116.4, 118.5, 132.7, 142.8,
153.5, 155.8, 165.0, 185.6 ppm; IR (KBr): n˜ =3083, 2932, 1744, 1605, 1511,
1366, 1221, 1019, 886, 788 cmꢁ1; MS (EI): m/z (%): 394 (3) [M+], 337
(100) [C16H21O6Si+], 321 (18) [C17H25O4Si+]. HRMS (EI): m/z: calcd for
C20H30O6Si: 394.1812; found 394.1809.
Ethyl [5-allyloxy-2-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-(hy-
droxy imino) acetate (46):
A mixture of 32 (20.82 g, 52.77 mmol,
1.00 equiv), hydroxylamine hydrochloride (7.33 g, 106 mmol, 2.00 equiv),
EtOH (175 mL), and pyridine (41 mL, 40 g, 510 mmol, 9.7 equiv) was
heated to reflux for 70 min. The reaction was diluted with H2O (300 mL)
and extracted with EtOAc (4ꢃ250 mL). The combined organic extracts
were washed with H2O (200 mL) and brine (200 mL), dried over Na2SO4,
and concentrated under reduced pressure. Flash chromatography (cyclo-
hexane/EtOAc 6:1!3:1) afforded the oxime 46 as 1:1 mixture of separa-
ble E/Z isomers as a yellow oil (20.67 g, 96%). Isomer 13a: 1H NMR
(400 MHz, CDCl3): d=0.19 (s, 6H), 0.93 (s, 9H), 1.29 (t, J=7.1 Hz, 3H),
3.83 (s, 3H), 4.31 (q, J=7.1 Hz, 2H), 4.54 (dt, J=5.5, 1.4 Hz, 2H), 5.26
(dq, J=10.4, 1.4 Hz, 1H), 5.38 (dq, J=17.3, 1.4 Hz, 1H), 6.05 (ddt, J=
17.3, 10.4, 5.5 Hz, 1H), 6.39 (s, 1H), 6.95 (s, 1H), 10.51 ppm (brs, 1H);
13C NMR (100 MHz, CDCl3): d=ꢁ4.1, 14.0, 18.4, 25.8, 55.8, 61.7, 70.4,
104.2, 114.2, 114.7, 118.1, 133.2, 142.5, 148.3, 148.6, 151.4, 162.8 ppm; IR
5-Allyloxy-3-diphenylphosphinoylamino-6-methoxy-3-methyl-3H-benzo-
furan-2-one (48):
A solution of 33 (505 mg, 0.828 mmol) in DMF
(5.0 mL) was heated to 1208C for 19 h. The solvent was removed under
reduced pressure. The lactone 48 was obtained as a brown solid and used
in the next step without further purification. 1H NMR (400 MHz,
CDCl3): d=1.69 (s, 3H), 3.77 (s, 3H), 4.43 (mc, 2H), 5.28 (dq, J=10.6,
1.4 Hz, 1H), 5.41 (dq, J=17.3, 1.4 Hz, 1H), 6.06 (ddt, J=17.3, 10.6,
5.5 Hz, 1H), 6.35 (s, 1H), 7.06 (s, 1H), 7.28–7.58 (m, 8H), 7.82–7.90 ppm
(m, 2H); 13C NMR (100 MHz, [D6]acetone): d=27.7 (d, JP =5.2 Hz),
56.2, 59.0, 70.5, 95.8, 111.2, 118.0 (d, JP =2.0 Hz), 118.2, 128.3 (d, JP =
12.9 Hz), 128.5 (d, JP =12.7 Hz), 131.4 (JP =10.1 Hz), 131.6 (d, JP =
128.7 Hz), 131.6 (d, JP =2.5 Hz), 131.9 (JP =9.7 Hz), 132.1 (d, JP =2.7 Hz),
132.7 (d, JP =130.2 Hz), 133.0, 144.9, 146.7, 151.1, 179.0 ppm (d, JP =
4.2 Hz); IR (KBr): n˜ =3079, 2843, 1628, 1439, 1190, 1034, 856 cmꢁ1; MS
(EI): m/z (%): 449 (36) [M+], 408 (3) [C22H19NO5P+], 380 (100); HRMS
(EI): m/z: calcd for C25H24NO5P: 449.1392; found 449.1394.
(KBr): n˜ =3436, 2931, 1737, 1512, 1414, 1260, 1154, 1050, 944, 784 cmꢁ1
;
Isomer 13b: 1H NMR (400 MHz, CDCl3): d=0.15 (s, 6H), 0.92 (s, 9H),
1.29 (t, J=7.1 Hz, 3H), 3.84 (s, 3H), 4.28 (q, J=7.1 Hz, 2H), 4.53 (dt, J=
5.6, 1.4 Hz, 2H), 5.25 (dq, J=10.5, 1.4 Hz, 1H), 5.38 (dq, J=17.2, 1.4 Hz,
1H), 6.07 (ddt, J=17.2, 10.5, 5.6 Hz, 1H), 6.43 (s, 1H), 6.84 (s, 1H),
9.64 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3): d=ꢁ4.5, 14.0, 18.0,
25.6, 55.8, 61.8, 70.6, 104.0, 112.0, 115.2, 118.0, 133.3, 142.1, 147.8, 148.7,
151.3, 163.3 ppm; IR (KBr): n˜ =3406, 2931, 1728, 1510, 1411, 1261, 1147,
993, 838 cmꢁ1; mixture of isomers: MS (EI): m/z (%): 409 (54) [M+], 368
(46) [C17H26NO6Si+], 352 (100) [C16H22NO6Si+]; HRMS (EI): m/z: calcd
for C20H31NO6Si: 409.1921; found 409.1921.
4-Allyl-3-diphenylphosphinoylamino-5-hydroxy-6-methoxy-3-methyl-3H-
benzo-furan-2-one (49): A solution of crude 48 (1.70 g, 2.79 mmol) in
DMF (75 mL) was heated to reflux for 39 h. The solvent was removed
under reduced pressure; the residue was dissolved in EtOAc (200 mL).
The mixture was washed with half-saturated aqueous NaCl solution (3ꢃ
175 mL) and with brine (175 mL), dried over Na2SO4, and concentrated
under reduced pressure. Flash chromatography (cyclohexane/EtOAc
2:1+5% MeOH) afforded the lactone 49 as a brown solid (920 mg, 55%
over two steps). M.p. 200–2028C; 1H NMR (500 MHz, [D6]acetone): d=
1.70 (s, 3H), 3.18 (dm, J=15.3 Hz, 1H), 3.55 (ddm, J=15.3, 7.1 Hz, 1H),
3.86 (s, 3H), 4.89 (dddd, J=10.3, 3ꢃ1.5 Hz, 1H), 4.89 (dddd, J=17.2, 3ꢃ
1.6 Hz, 1H), 5.55 (d, 9.3 Hz), 5.95 (dddd, J=17.2, 10.3, 7.1, 5.0 Hz, 1H),
6.58 (s, 1H), 7.21 (s, 1H), 7.36–7.44 (m, 4H), 7.46–7.54 (m, 2H), 7.72–
7.80 ppm (m, 4H); 13C NMR (100 MHz, [D6]acetone): d=27.5 (d, JP =
8.0 Hz), 30.7, 57.7, 61.1 (d, JP =6.4 Hz), 95.7, 116.2, 120.6, 125.8, 129.8 (d,
JP =12.9 Hz), 130.0 (d, JP =12.8 Hz), 133.4, 133.5 (JP =10.3 Hz), 133.6,
133.8 (JP =9.9 Hz), 134.8 (d, JP =129.3 Hz), 135.0 (d, JP =125.7 Hz), 138.5,
143.0, 147.4, 149.9, 180.8 ppm; IR (KBr): n˜ =3441, 2932, 2468, 1636, 1358,
1188, 1027, 943, 822 cmꢁ1; MS (EI): m/z (%): 449 (18) [M+], 232 (22),
218 (100), 201 (84); HRMS (EI): m/z: calcd for C25H24NO5P: 449.1392;
found 449.1395.
Ethyl [5-allyloxy-2-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-(di-
phenyl phosphorylimino) acetate (47): A solution of 46 (1:1 mixture of
E/Z isomers, 7.55 g, 18.4 mmol, 1.00 equiv) in THF (40 mL) and Et3N
(2.6 mL, 1.9 g, 18 mmol, 1.0 equiv) was cooled to ꢁ508C (acetonitrile/dry
ice bath). Chlorodiphenylphosphine (3.4 mL, 4.1 g, 18 mmol, 1.0 equiv)
was added as a solution in THF (8.0 mL) within 15 min. The dry ice was
removed from the cool bath and the reaction was allowed to warm
slowly. After 4 h H2O (150 mL) was added, the mixture was extracted
with EtOAc (4ꢃ100 mL). The combined organic extracts were washed
with H2O (100 mL) and brine (100 mL), dried over Na2SO4, and concen-
trated under reduced pressure. Flash chromatography (cyclohexane/
EtOAc 2:1!1:1) afforded the ketimine 47 as an orange oil (8.10 g,
1
74%). H NMR (400 MHz, CDCl3): d=0.26 (s, 6H), 0.91 (s, 9H), 1.28 (t,
J=7.2 Hz, 3H), 3.86 (s, 3H), 4.38 (q, J=7.2 Hz, 2H), 4.60 (dt, J=5.5,
1.4 Hz, 2H), 5.29 (dq, J=10.5, 1.4 Hz, 1H), 5.38 (dq, J=17.3, 1.4 Hz,
1H), 6.06 (ddt, J=17.3, 10.5, 5.5 Hz, 1H), 6.39 (s, 1H), 7.40–7.50 (m,
6H), 7.52 (s, 1H), 7.80–8.00 ppm (m, 4H); 13C NMR (125 MHz, CDCl3):
d=ꢁ3.6, 13.7, 19.2, 26.3, 56.0, 62.4, 70.4, 103.4, 114.4, 117.8 (d, JP =
10.5 Hz), 118.3, 128.3 (d, JP =12.8 Hz), 131.4 (d, JP =2.5 Hz), 131.7 (JP =
3-Diphenylphosphinoylamino-5-hydroxy-6-methoxy-3-methyl-4-[(E)-pro-
penyl]-3H-benzofuran-2-one (34): A mixture of 49 (299 mg, 0.666 mmol,
Chem. Eur. J. 2010, 16, 12660 – 12667
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12665

S. Brꢀse and P. J. Gross
1.00 equiv) and rhodium
(III)chloride hydrate (12.8 mg, 33.3 mmol,
0.12 g, 1.5 mmol, 10 equiv) and
a
solution of the acid chloride 41
(0.32 mmol, 1.3 equiv) in CH2Cl2 (0.70 mL) were added dropwise. After
1 h, the mixture was allowed to warm to RT, followed by stirring for an-
other 2 h. The reaction was quenched with water (20 mL), and the result-
ing mixture was extracted with EtOAc (4ꢃ15 mL). The combined organ-
ic layers were washed with water (4ꢃ20 mL) and brine (20 mL), followed
by drying over Na2SO4. Removal of the solvent and column chromatogra-
phy (cyclohexane/EtOAc 5:1!2:1) afforded 42 as a light brown oil
(19.4 mg, 24%). 1H NMR (400 MHz, CDCl3): d=1.11 (d, J=7.4 Hz,
9H), 1.12 (d, J=7.4 Hz, 9H), 1.34 (sept, J=7.4 Hz, 3H), 1.48 (s, 9H),
1.73 (s, 3H), 1.91 (dd, J=6.7, 1.7 Hz, 3H), 5.93 (s, 1H), 6.33 (dq, J=15.8,
1.7 Hz, 1H), 6.58 (s, 1H), 6.67 (d, J=15.4 Hz, 1H), 6.70 (dq, J=15.8,
6.7 Hz, 1H), 6.85 (d, J=15.4 Hz, 1H), 7.03 ppm (brs, 1H); 13C NMR
(100 MHz, CDCl3): d=12.6, 17.9, 19.8, 23.4, 28.0, 58.3, 82.0, 99.4, 117.1,
120.4, 121.4, 133.1, 134.0, 134.1, 142.3, 143.2, 145.7, 162.8, 164.7,
176.1 ppm; IR (KBr): n˜ =1811, 1719, 1510, 1369, 1279, 1062, 975, 923,
883 cmꢁ1; MS (FAB): m/z (%): 545 (6) [(M+H)+], 375 (26) [C21H31O4Si+
], 331 (100), 303 (10), 133 (14); HRMS (FAB): m/z: calcd for
C29H43NO7Si (M+H): 545.2809; found 545.2812.
0.050 equiv) in EtOH (9.0 mL) was heated to 458C. After 4 h, the reac-
tion was allowed to cool to RT and filtered through a 3 cm pad of celite.
The filtrate was concentrated under reduced pressure. Flash chromatog-
raphy (cyclohexane/EtOAc 3:2+5% MeOH!3:2+10% MeOH) afford-
ed the lactone 34 as a light brown solid (E/Z 10:1, 288 mg, 96%; an ana-
lytical portion was separated by flash chromatography on silica gel with
10% AgNO3 to give pure
E
product). M.p. 199–2008C; 1H NMR
(500 MHz, CD3OD): d=1.70 (d, J=1.4 Hz, 3H), 1.82 (dd, J=6.6, 1.5 Hz,
3H), 3.85 (s, 3H), 6.47 (dq, J=15.8, 1.5 Hz, 1H), 6.52 (s, 1H), 6.62 (dq,
J=15.8, 6.6 Hz, 1H), 7.31–7.37 (m, 2H), 7.41–7.48 (m, 3H), 7.52–7.60 (m,
3H), 7.68–7.74 ppm (m, 2H); 13C NMR (125 MHz, CD3OD): d=20.0,
26.4 (d, JP =9.3 Hz), 57.0, 60.4, 94.8, 118.7, 122.8, 124.2, 129.0 (d, JP =
13.1 Hz), 129.4 (d, JP =13.1 Hz), 132.9 (d, JP =130.6 Hz), 133.0 (d, JP =
2.5 Hz), 133.0 (JP =10.5 Hz), 133.1 (JP =10.4 Hz), 133.4, 133.6, 133.8 (d,
JP =126.1 Hz), 142.9, 146.5, 150.0, 181.0 ppm; IR (KBr): n˜ =3487, 3242,
2975, 2848, 1631, 1469, 1314, 1174, 1038, 924 cmꢁ1; MS (EI): m/z (%): 449
(24) [M+], 406 (14), 218 (68), 201 (100); HRMS (EI): m/z: calcd for
C25H24NO5P: 449.1392; found 449.1400.
5,6-Dihydroxy-(E)-3-(4-tert-butoxy-4-oxobut-2-enamido)-3-methyl-6-tri-
AHCTUNGTERGiNNUN sopropylsilanyloxy-3H-benzofuran-2-one (50): AcOH (0.016 mL, 0.017 g,
5,6-Dihydroxy-3-diphenylphosphinoylamino-3-methyl-4-((E)-propenyl)-
3H-benzofuran-2-one (35):
A solution of BI3 (1.10 g, 2.81 mmol,
0.28 mmol, 5.0 equiv) and TBAF (1m in THF, 0.072 mL, 0.072 mmol,
1.3 equiv) were added to a solution of 42 (30.3 mg, 0.0555 mmol) in THF
(0.70 mL). After stirring for 2 h, water (20 mL) was added. The resulting
mixture was extracted with Et2O (4ꢃ10 mL). The combined organic
layers were washed with brine (15 mL) and dried over Na2SO4. Removal
of the solvent and column chromatography (cyclohexane/EtOAc 3:1
+10% MeOH!2:1 +10% MeOH) afforded 50 (20.2 mg, 93%) as a
brown oil. 1H NMR (400 MHz, CD3OD): d=1.49 (s, 9H), 1.65 (s, 3H),
1.91 (dd, J=6.6, J=1.6 Hz, 3H), 6.49 (dq, J=15.8, 1.6 Hz, 1H), 6.49 (s,
1H), 6.52 (d, J=15.5 Hz, 1H), 6.68 (dq, J=15.8, 6.6 Hz, 1H), 6.93 ppm
(d, J=15.5 Hz, 1H); 13C NMR (100 MHz, CD3OD): d=19.8, 23.5, 28.2,
59.5, 83.0, 97.7, 117.0, 122.7, 123.3, 133.9, 134.4, 134.9, 141.9, 147.3, 147.4,
165.0, 165.8, 178.2 ppm; IR (KBr): n˜ =2934, 1741, 1619, 1474, 1252, 1167,
1106, 1021, 878 cmꢁ1; MS (FAB): m/z (%): 390 (38) [(M+H)+], 333 (22)
[C16H15NO7+], 219 (100) [C12H11O4+], 133 (36); HRMS (FAB): m/z:
calcd for C20H24NO7 (M+H): 390.1553; found 390.1550.
2.50 equiv) in CH2Cl2 (8.0 mL) was slowly added at ꢁ208C to a suspen-
sion of 34 (506 mg, 1.13 mmol) in CH2Cl2 (10 mL). After 50 min, the re-
action was poured into ice-cooled Na2S2O3 solution (60 mL). The result-
ing mixture was extracted with EtOAc (4ꢃ60 mL). The combined organ-
ic layers were washed with water (100 mL) and brine (100 mL), followed
by drying over Na2SO4. Removal of the solvent and column chromatogra-
phy (cyclohexane/EtOAc 3:2+5% MeOH) afforded 35 as a light brown
solid (440 mg, 90%). M.p. 1368C; 1H NMR (400 MHz, [D6]acetone): d=
1.77 (s, 3H,), 1.80 (d, J=3.9 Hz, 3H), 6.68 (d, J=11.0 Hz, 1H), 6.64–6.60
(m, 2H), 6.64 (s, 1H), 6.97 (s, 1H), 7.32–7.38 (m, 2H), 7.44–7.54 (m, 3H),
7.56–7.68 (m, 3H), 7.80–7.88 (m, 2H), 9.87 ppm (s, 1H);13C NMR
(100 MHz, [D6]acetone): d=20.8, 27.2 (d, JP =9.1 Hz), 61.1 (d, JP =
2.0 Hz), 99.1, 117.8, 123.3, 125.1, 129.7 (d, JP =13.2 Hz), 130.2 (d, JP =
12.6 Hz), 133.5 (d, JP =10.6 Hz), 133.5 (d, JP =2.9 Hz), 133.7 (d, JP =
10.4 Hz), 133.8 (d, JP =129.3 Hz), 134.0 (d, JP =2.5 Hz), 134.5, 135.1 (d,
JP =124.7 Hz), 142.4, 147.4, 147.9, 181.9 ppm. IR (ATR): n˜ =2980, 1790,
1628, 1437, 1174, 1145, 1026, 918 cmꢁ1. MS (FAB): m/z (%): 436 (52)
[(M+H)+], 218 (96), 201 (58), 154 (100), 133 (90); HRMS (FAB): m/z:
calcd for C24H23NO5P [M+H]: 436.1314; found 436.1312.
(E)-3-[5,6-Dihydroxy-3-methyl-2-oxo-4-((E)-propenyl)-2,3-dihydro-ben-
zofuran-3-ylcarbamoyl]-acrylic acid (Fumimycin (1)): Compound 50
(8.7 mg, 0.022 mmol) was dissolved in CH2Cl2 (0.60 mL), cooled to 08C
and treated with trifluoroacetic acid (0.30 mL). After 4 h, the solvent was
removed at RT under reduced pressure to yield 1 as a brown solid
(7.4 mg, quant). 1H NMR (500 MHz, CDCl3/CD3OD 1.00:1.00): d=1.38
(s, 3H), 1.62 (dd, J=6.4, 1.5 Hz, 3H), 6.08 (dq, J=15.8, 1.5 Hz, 1H), 6.23
(s, 1H), 6.34 (d, J=15.5 Hz, 1H), 6.36 (dq, J=15.8, 6.4 Hz, 1H),
6.69 ppm (d, J=15.5 Hz, 1H); 13C NMR (125 MHz, CDCl3/CD3OD
1.00:1.00): d=19.2, 22.6, 58.4, 96.8, 115.9, 121.4, 122.0, 131.7, 133.5, 134.7,
140.6, 145.9, 146.1, 163.8, 167.3, 177.4 ppm; IR (ATR): n˜ =3300, 2922,
1800, 1708, 1645, 1436, 1319, 1261, 1149, 1080, 970, 920 cmꢁ1; MS (EI):
m/z (%): 333 (2) [M+], 281 (2), 218 [C12H10O4+] (10), 142 (12), 99 (16),
44 (100); HRMS (EI): m/z calcd for C16H15NO7: 333.0849; found
333.0847.
3-Diphenylphosphinoylamino-5-hydroxy-3-methyl-4-((E)-propenyl)-6-tri-
ACHTUNGTRENNUNGisopropylsilanyloxy-3H-benzofuran-2-one (36): 2,6-Lutidine (0.11 mL,
99 mg, 0.93 mmol, 5.0 equiv) and TIPSOTf (0.11 mL, 0.13 g, 0.43 mmol,
2.3 equiv) were added to a suspension of 35 (80.6 mg, 0.185 mmol) in
CH2Cl2 (3.0 mL) at ꢁ158C. The mixture was slowly allowed to warm to
RT and stirred for 9 h. The reaction was quenched with water (30 mL),
and the resulting mixture was extracted with EtOAc (4ꢃ10 mL). The
combined organic layers were washed with water (2ꢃ30 mL) and brine
(30 mL), followed by drying over Na2SO4. Removal of the solvent and
column chromatography (cyclohexane/EtOAc 3:2!1:1) afforded 36
(91.0 mg, 83%) as a light brown oil. 1H NMR (400 MHz, CDCl3): d=
1.12 (d, J=7.4 Hz, 9H), 1.13 (d, J=7.4 Hz, 9H), 1.33 (sept, J=7.4 Hz,
3H), 1.73 (s, 3H), 1.91 (d, J=5.4 Hz, 3H), 3.62 (d, J=6.0 Hz, 1H), 5.84
(s, 1H), 6.35 (s, 1H), 6.58–6.63 (m, 2H), 7.30–7.46 (m, 6H), 7.68–
7.82 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=12.6, 17.9, 17.9, 19.8,
25.8 (d, JP =8.3 Hz), 59.2 (d, J=2.3 Hz), 98.9, 116.8, 121.8, 127.8, 127.9
(d, JP =13.0 Hz), 128.4 (d, JP =12.6 Hz), 131.4 (d, JP =10.1 Hz), 131.7 (d,
JP =2.8 Hz), 131.7 (d, JP =131.7 Hz), 132.0 (d, JP =2.8 Hz), 132.3 (d, JP =
125.0 Hz), 132.4 (d, JP =10.0 Hz), 133.2, 142.0, 143.5, 145.2, 178.8 ppm;
IR (KBr): n˜ =2932, 1740, 1559, 1388, 1252, 1168, 1123, 1021 cmꢁ1; MS
(FAB): m/z (%): 592 (18) [(M+H)+], 375 (20) [C21H31O4Si+], 331 (66),
218 (100), 201 (92); HRMS (FAB): m/z calcd for C33H43NO5SiP [M+H]:
592.2648; found 592.2646.
Acknowledgements
We are grateful to Miriam Gçdtler for her valuable experimental assis-
tance. We thank the Foundation of German Business for financial sup-
port (fellowship for P.G.).
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propylsilanyloxy-3H-benzofuran-2-one (42): Compound 36 (65.0 mg,
0.149 mmol) was dissolved in HCl (0.5m in MeOH, 2.0 mL) and heated
to 558C. After 3.5 h the solvent was removed in vacuo. The residue was
suspended in CH2Cl2 (1.0 mL) and cooled to 08C. Pyridine (0.12 mL,
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Received: April 20, 2010
Published online: September 21, 2010
Chem. Eur. J. 2010, 16, 12660 – 12667
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