Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides

Article abstract of DOI:10.1039/b701179b

Attack of cellular thiols on the antitumor natural product leinamycin is believed to generate a sulfenate intermediate that undergoes subsequent rearrangement to a DNA-alkylating episulfonium ion. Here, 2-(trimethylsilyl) ethyl sulfoxides were employed in

Full text of DOI:10.1039/b701179b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides
Kripa Keerthi and Kent S. Gates*
Received 25th January 2007, Accepted 7th March 2007
First published as an Advance Article on the web 13th April 2007
DOI: 10.1039/b701179b
Attack of cellular thiols on the antitumor natural product leinamycin is believed to generate a sulfenate
intermediate that undergoes subsequent rearrangement to a DNA-alkylating episulfonium ion. Here,
2-(trimethylsilyl)ethyl sulfoxides were employed in a fluoride-triggered generation of sulfenate anions
related to the putative leinamycin-sulfenate. The resulting sulfenates enter smoothly into a
leinamycin-type rearrangement reaction to afford an episulfonium ion alkylating agent. The results
provide evidence that the sulfenate ion is, indeed, a competent intermediate in the leinamycin
rearrangement. Further, the molecules examined here may provide a foundation for the design of
functional leinamycin analogues that bypass the unstable and synthetically challenging
1,2-dithiolan-3-one 1-oxide moiety found in the natural product.
Introduction
Historically, natural products have represented a rich source
of structurally novel organic molecules that generate DNA-
damaging reactive intermediates via interesting and unexpected
chemical reactions.1,2 The characterization of new chemical re-
actions by which small molecules can modify cellular DNA is
relevant to diverse fields including medicinal chemistry, toxicology,
and biotechnology.
Leinamycin (1) provides an interesting example of a structurally
unique natural product that damages DNA via novel chemical
mechanisms.3–6 Initial attack of cellular thiols on leinamycin’s
1,2-dithiolan-3-one 1-oxide “triggering unit” is believed to yield
a key sulfenate intermediate (2) that undergoes intramolecular
cyclization with the neighboring carbonyl group.7,8 The persulfide
(3, RSS−) ejected in this reaction causes oxidative stress,9–13 while
the resulting 1-oxa-2-thiolan-5-one derivative of leinamycin (4)
undergoes further rearrangement to yield an episulfonium ion (5)
that alkylates guanine residues in duplex DNA (Scheme 1).8–14
The sulfenate ion (2) is proposed7,8 to be a key intermediate in
the thiol-triggered conversion of leinamycin to a DNA-alkylating
episulfonium ion, however, to date, there is no experimental
support for the existence of this entity. In an effort to fill this gap in
Scheme 1 DNA alkylation by leinamycin (1).
our knowledge, we set out to generate discrete sulfenate ions
related to 2 and determine whether these intermediates are, in
fact, competent to enter the leinamycin rearrangement reaction
manifold. For this task, we employed small synthetic molecules
containing just the “core” functional groups involved in the
leinamycin rearrangement. This approach builds upon our recent
finding15 that stripped-down leinamycin analogues such as 6
smoothly undergo a thiol-triggered, leinamycin-type rearrange-
ment to generate the episulfonium alkylating agent 9 (Scheme 2).
Sulfenate ions (RSO−) and sulfenic acids (RSOH) are typically
not stable, isolable species,16–18 however, methods exist for their
in situ generation.16,19–28 In the present study, we employed the
2-(trimethylsilyl)ethyl sulfoxide group as a sulfenate precursor.
Departments of Chemistry and Biochemistry, University of Missouri–
Columbia, Columbia, MO 65211, USA. E-mail: gatesk@missouri.edu;
Fax: +1 573 882-2754; Tel: +1 573 882-6763
Scheme 2 A small model compound that mimics leinamycin (ref. 15).
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2-(Trimethylsilyl)ethyl sulfoxides can undergo both fluoride-
triggered and spontaneous elimination of sulfenate species.29 For
ease of synthesis, we targeted sulfenates containing a neighboring
phenyl thioester group in place of the acyl persulfide moiety
found in the putative intermediates 2 and 7 (Schemes 1 and 2).
Importantly, the leaving group ability of the PhS− group is similar
to that expected for RSS−, as judged by the pKa values of the
conjugate acids.30,31
ester derivatives obtained following treatment of the products with
diazomethane.
Consistent with the expectation that this process proceeds via
the desired sulfenate ion 14a, when the reaction is conducted in
the presence of excess methyl iodide, the characteristic16,33 sulfenate
trapping product 16is obtained in 35% yield along with 15a (25%,
Scheme 5). In the context of this reaction, it is useful to note that
sulfenate ions are ambident nucleophiles that can react at either
sulfur or oxygen.33 In the leinamycin rearrangement, the oxygen
atom of the sulfenate is the nucleophile, whereas the sulfur atom
serves as a nucleophile in typical reactions of this functional group
with methyl iodide and other alkyl halides.16,33,34
Results and discussion
The sulfenate precursors were prepared as shown in Scheme 3.
The known15 carboxylic acid 11was activated with DCC–DMAP
and converted to the thioester 12aby reaction with thiophenol.
In addition, we prepared ester derivatives 12b and cby analogous
reactions. The methyl ester 12dwas synthesized by treatment of 11
with diazomethane. The desired sulfenate precursors 13were then
obtained via oxidation of the sulfide group in 12 with dimethyl
dioxirane (DMD).32
Scheme 5 Trapping the sulfenate intermediate.
The ester derivatives (13b–d) also undergo fluoride-triggered
rearrangement in THF to provide 15a in yields comparable to
those obtained from 13a. Evidently, a good leaving group (e.g.
PhS− or p-NO2PhO−) on the carbonyl is not required for the
rearrangement to proceed. The cyclization of 14 to 8 may be
favored by the potent nucleophilicity of the sulfenate anion.35
Extended incubation of 13a for 20 h in THF–MeOH in the
absence of TBAF does not afford any rearranged product 15b,
yielding instead only the product 13d resulting from methanolysis
of the thioester group in the starting material. However, in a
different solvent mixture consisting of 1 : 1 CH3CN and sodium
phosphate buffer (50 mM, pH 7), compounds 13a and 13b undergo
a slow (48 h), fluoride-independent conversion to the episulfonium-
derived product 10, albeit in somewhat lower yields (30%) than
those obtained in the fluoride-triggered process.36
Initially, we suspected that this fluoride-independent reac-
tion might proceed via the same sulfenate intermediate (14,
Scheme 4) generated in the fluoride-triggered reactions, because
it is known that 2-(trimethylsilyl)ethyl sulfoxides can undergo
fluoride-independent release of sulfenate species.29 However, the
intermediacy of a free sulfenate anion or sulfenic acid in these
reactions was called into question by our inability to trap this
intermediate with methyl iodide under our standard trapping
conditions used previously.34 Further evidence arguing against
a straightforward elimination of sulfenate from 13a and 13b in
this fluoride-independent process was provided by the observation
that the reaction occurs only with these activated esters. The less
reactive esters 13c and 13dreturn starting material under these
reaction conditions. Thus, the 2-(trimethylsilyl)ethyl sulfoxide
group is inherently stable in the context of 13c and 13d; however,
interaction of this functional group with the adjacent activated
ester groups in 13a and 13b stimulates rearrangement to 10. This
transformation may proceed via initial attack of the sulfoxide
oxygen on the adjacent activated carbonyl group to yield 17,
followed by loss of the 2-(trimethylsilyl)ethyl group to generate the
oxathiolanone intermediate 8 that, in turn, yields the episulfonium
ion 9 (Scheme 6).37
Scheme 3 Preparation of sulfenate precursors 13. Reagents and condi-
tions: a. DCC, DMAP, PhSH or p-NO2PhOH, or PhOH (for 12a–c); b.
CH2N2 (for 12d); c. DMD, acetone.
Treatment of the thioester 13a with tetrabutylammonium
fluoride (TBAF) in THF rapidly (3 h) affords the rearrangement
product 15a (65%, Scheme 4). This product is envisioned to arise
from reaction of the episulfonium ion 9with excess fluoride ion.
When the TBAF-triggered reaction is carried out in a 4 : 1 mixture
of THF and methanol, the product (15b) resulting from trapping
of the episulfonium ion (9) with methanol is obtained in 22% yield
alongside 15a (45%). The acids were characterized as the methyl
Scheme 4 Fluoride-triggered rearrangement of sulfenate precursors 13.
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was evaporated under reduced pressure to yield a yellow oil. The
crude product was purified by flash column chromatography on
silica gel eluted with 19 : 1 hexane : ethylacetate to yield 12a as a
colorless oil (211 mg, 82%, Rf = 0.5 in 10 : 1 hexane : ethylacetate).
1H-NMR (250 MHz, CDCl3) d 7.60–7.28 (m, 8H, aromatic), 5.28
(m, 1H), 3.72 (d, J = 7.1 Hz, 2H), 2.85 (m, 2H), 1.77 (s, 6H),
0.87 (m, 2H), 0.0 (s, 9H) ppm. 13C-NMR (62.9 MHz, CDCl3)
d 193.05, 147.58, 145.64, 134.47, 133.12, 131.49, 130.80, 129.43,
129.24, 128.39, 125.02, 122.78, 33.9, 32.78, 25.77, 18.03, 17.56,
−1.80 ppm. HRMS (ESI) calcd for C23H30OS2SiNa [M + Na]+
437.1399, found 437.1419.
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethylsulfanyl]-
benzoic acid p-nitrophenyl ester 12b
Scheme 6 Proposed mechanism for fluoride-independent conversion of
13a and 13b to 10.
To a stirred solution of 1115 (200 mg, 0.62 mmol) in dry, distilled
THF (2 mL) under nitrogen, dicyclohexyl carbodiimide (153 mg,
0.74 mmol) and a catalytic amount of 4-dimethylaminopyridine
(7.6 mg, 0.06 mmol) were added. After about 30 min of stirring,
p-nitrophenol (103 mg, 0.74 mmol) in THF (1 mL) was added and
stirring was continued for 48 h. The dicyclohexylurea precipitate
was removed by filtration and the filtrate was evaporated under
reduced pressure to give a dark yellow oil. Flash column chro-
matography on silica gel eluted with 19 : 1 hexane : ethylacetate
gave 12b as a pale yellow oil (247 mg, 90% yield, Rf = 0.55 in 10 : 1
hexane : ethylacetate). 1H-NMR (250 MHz, CDCl3) d 8.38 (d, J =
7.0 Hz, 2H), 7.57–7.44 (m, 5H), 5.35 (m, 1H), 3.78 (d, J = 7.1 Hz,
2H), 2.89 (m, 2H), 1.82 (s, 6H), 0.87 (m, 2H), 0.0 (s, 9H) ppm.
13C-NMR (62.9 MHz, CDCl3) d 166.39, 155.75, 147.78, 145.43,
138.38, 133.36, 132.27, 128.68, 126.04, 125.28, 122.61, 122.47,
33.51, 32.78, 25.76, 18.03, 17.52, −1.91 ppm. HRMS (ESI) calcd
for C23H29NO4SSiNa [M + Na]+ 466.1478, found 466.1490.
Conclusions
In summary, we utilized 2-(trimethylsilyl)ethyl sulfoxides as pre-
cursors in the fluoride-triggered generation of sulfenate ions
related to a key intermediate (2) proposed previously in the
thiol-triggered alkylation of DNA by leinamycin (Scheme 1).
Our results provide evidence that the sulfenate ion is, indeed, a
competent intermediate in the leinamycin rearrangement reaction.
In addition, for two of the 2-(trimethylsilyl)ethyl sulfoxides (13a
and b), we observed an unexpected fluoride-independent reaction
in which attack of the sulfoxide group on a neighboring activated
ester, followed by loss of the 2-(trimethylsilyl)ethyl group, affords
entry into the leinamycin rearrangement via the oxathiolanone
intermediate 8. Overall, these studies provide a better grasp of
the intermediates involved in the thiol-triggered conversion of
leinamycin to a DNA-alkylating agent. In addition, the molecules
examined here may provide a foundation for the design of
functional leinamycin analogues that bypass the unstable38 and
synthetically challenging39,40 1,2-dithiolan-3-one 1-oxide moiety
found in the natural product.
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethylsulfanyl]-
benzoic acid phenyl ester 12c
To a stirred solution of 1115 (200 mg, 0.62 mmol) in dry, distilled
THF (2 mL) under nitrogen, dicyclohexyl carbodiimide (153 mg,
0.74 mmol) and a catalytic amount of 4-dimethylaminopyridine
(7.6 mg, 0.06 mmol) were added. After about 30 min of stirring,
phenol (69.64 mg, 0.74 mmol) in dry THF (1 mL) was added
and stirring was continued for 48 h. At the end of the reaction,
the dicyclohexylurea precipitate was removed by filtration and the
filtrate was evaporated under reduced pressure to give a pale yellow
oil. Flash column chromatography on silica gel eluted with 19 : 1
hexane : ethylacetate gave 12c as a colorless oil (187 mg, 76% yield,
Experimental
Materials were purchased from the following suppliers: HPLC
grade solvents, Fisher; silica gel 60 (0.04–0.063 mm pore size) for
column chromatography, Merck; TLC plates coated with general
purpose silica containing UV254 fluorophore, Aldrich Chemical
Company; all chemicals were purchased from Aldrich Chemical
Company and were of the highest purity available unless otherwise
noted. Water was distilled, deionized and glass redistilled. All
reactions were carried out under an atmosphere of nitrogen, unless
otherwise noted.
1
Rf = 0.51 in 10 : 1 hexane : ethylacetate). H-NMR (250 MHz,
CDCl3) d 7.50–7.31 (m, 8H, aromatic), 5.34 (m, 1H), 3.80 (d, J =
7.1 Hz, 2H), 2.91 (m, 2H), 1.82 (s, 6H), 0.90 (m, 2H), 0.0 (s,
9H) ppm. 13C-NMR (62.9 MHz, CDCl3) d 167.47, 151.02, 147.49,
139.44, 133.09, 132.09, 131.65, 129.47, 128.51, 125.96, 122.85,
121.58, 33.42, 32.86, 25.76, 18.03, 17.49, −1.90 ppm. HRMS (ESI)
calcd for C23H30O2SSiNa [M + Na]+ 421.1627, found 421.1637.
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethylsulfanyl]-
benzoic acid S-phenyl ester 12a
To a solution of 1115 (200 mg, 0.62 mmol) in dry THF (2 mL) main-
tained under an atmosphere of nitrogen, dicyclohexyl carbodi-
imide (153 mg, 0.74 mmol) and a catalytic amount of 4-dimethyl-
aminopyridine (7.6 mg, 0.06 mmol) were added. The solution was
allowed to stir for 30 min and thiophenol (76 lL, ◦0.74 mmol)
was added. The resulting mixture was stirred at 24 C for 48 h.
The dicyclohexylurea precipitate was filtered off and the solvent
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethylsulfanyl]-
benzoic acid methyl ester 12d
To a solution of 1115 (50 mg, 0.15 mmol) in ether (1 mL)
freshly prepared diazomethane (1 mL of a 0.66 M solution in
ether, warning: EXPLOSION HAZARD) was added.41 When the
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reaction was complete as judged by thin layer chromatography the
solvent was evaporated under reduced pressure to give 12d as a
colorless oil (44 mg, 85%, Rf = 0.68 in 9 : 1 hexane : ethylacetate)
as a pure compound. 1H-NMR (250 MHz, CDCl3) d 7.32 (m, 3H),
5.27 (m, 1H), 3.93 (s, 3H), 3.70 (d, J = 7.1 Hz, 2H), 3.81 (m, 2H),
1.76 (s, 1H), 0.83 (m, 2H), 0.0 (s, 9H) ppm. 13C-NMR (62.9 MHz,
CDCl3) d 169.58, 147.14, 139.97, 132.95, 131.85, 131.20, 128.28,
125.71, 122.91, 52.29, 33.23, 32.94, 25.75, 18.01, 17.48, −1.86 ppm.
HRMS (ESI) calcd for C18H28O2SSiNa [M + Na]+ 359.1471, found
359.1460.
3.84 (s, 3H), 3.60 (d, J = 6.7 Hz, 2H), 3.39 (m, 1H), 2.90 (m,
1H), 1.67 (s, 6H), 1.22 (m, 1H), 0.79 (m, 1H), 0.0 (s, 9H) ppm.
13C-NMR (62.9 MHz, CDCl3) d 168.45, 141.83, 141.16, 133.73,
132.82, 132.25, 130.33, 127.58, 122.25, 52.63, 50.20, 30.67, 25.70,
18.12, 11.22, −1.91 ppm. HRMS (ESI) calcd for C18H28O3SSiNa
[M + Na]+ 375.1420, found 375.1428.
Fluoride-triggered production of 2-(1-fluoro-1-methylethyl)-2,3-
dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester (15a) by
treatment of (13a–d) with tetrabutylammonium fluoride in THF,
followed by diazomethane workup
General procedure for the conversion of sulfides 12a–d to sulfoxides
13a–d
A solution of 13a (20 mg, 0.046 mmol) in THF (1 mL) was placed
in a flame-dried flask flushed with nitrogen. To this solution,
tetrabutylammonium fluoride (0.37 mL of a 1 M solution in THF,
0.37 mmol, 0.27 M) from a freshly opened bottle was added. The
reaction mixture turned deep yellow and was stirred for 3 h. Dilute
HCl (1 mL of a 1 M solution, pH ≈ 3) was added, followed
by addition of diazomethane (2 mL of a 0.66 M solution in
ether, warning: EXPLOSION HAZARD) with vigorous stirring.
Stirring was continued for 30 min and the mixture was extracted
with diethyl ether (3 × 5 mL). The ether extracts were combined
and washed with water (1 × 5 mL) followed by brine (1 × 5 mL).
The organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to yield a pale yellow oil.
Flash column chromatography on silica gel eluted with 9 : 1
hexane : ethylacetate gave 15a as a colorless oil (7.7 mg, 65%,
To a rapidly stirred dilute solution of the sulfide 12a–d (50 mg,
0.12 mmol) in HPLC grade acetone (10 mL) freshly prepared
dimethyl dioxirane32 (1.5 mL of a ∼ 0.09 M solution in acetone)
was added slowly. The reaction was fast and careful monitoring
by TLC was essential to limit overoxidation. The solvent mixture
was evaporated under reduced pressure to give the sulfoxide 13a–d
as a colorless oil and as a pure compound. These compounds are
unstable and were used without further purification.
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethanesulfinyl]-
benzoic acid S-phenyl ester 13a
Obtained in 72% yield (Rf = 0.56 in 4 : 1 hexane : ethylacetate). 1H-
NMR (250 MHz, CDCl3) d 7.59–7.55 (m, 3H), 7.48–7.41 (m, 5H),
5.22 (m, 1H), 3.79 (m, 2H), 3.34 (m, 1H), 2.98 (m, 1H), 1.73 (s, 6H),
1.22 (m, 1H), 0.78 (m, 1H), 0.03 (s, 9H) ppm. 13C-NMR (62.9 MHz,
CDCl3) d 192.09, 143.16, 140.14, 138.78, 134.61, 133.79, 130.29,
129.59, 129.27, 127.79, 126.38, 122.25, 50.86, 30.37, 25.69, 18.13,
10.89, −1.90 ppm. LRMS (ESI) calcd for C23H31O2S2Si [M + H]+
431.15, found 431.12.
1
Rf = 0.42 in 6 : 1 hexane : ethylacetate). H-NMR (500 MHz,
d6-acetone) d 7.78 (dd, J = 8, 1 Hz, 1 H), 7.41 (qd, J = 8, 1 Hz,
1 H), 7.12 (t, J = 7.5 Hz, 1 H), 4.06 (ddd, J = 12, 9.5, 6.5 Hz, 1 H),
3.86 (s, 3 H), 3.46 (dd, J = 16.5, 9.5 Hz, 1 H), 3.36 (dd, J = 16.5,
6.5 Hz, 1 H), 1.42 (d, J = 21.5, 3 H), 1.37 (d, J = 21.5 Hz, 3 H)
ppm. 19F-NMR (235.35 MHz, CDCl3) d −139.35 (complex m)
ppm. (19F NMR chemical shift was determined relative to internal
CFCl3 at d 0.0). 13C-NMR (125.75 MHz, CDCl3) d 166.67, 145.14,
141.32, 128.90, 127.79, 124.19, 123.63, 96.95 (d, J = 169.8 Hz),
55.88 (d, J = 25.2 Hz), 52.16, 36.29 (d, J = 3.8 Hz), 25.48 (d,
J = 23.9 Hz), 22.74 (d, J = 23.9 Hz) ppm. HRMS (EI) calcd for
C13H15FO2S [M+] 254.0776, found 254.0781. Similarly, compounds
13b–d generate 15a in comparable yields (13b, 50%; 13c, 56%; 13d,
54%).
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethanesulfinyl]-
benzoic acid p-nitrophenyl ester 13b
Obtained in 85% yield (Rf = 0.27 in 5 : 1 hexane : ethylacetate).
1H-NMR (300 MHz, CDCl3) d 8.34 (d, J = 2.2 Hz, 2H), 7.63–
7.29 (m, 5H), 5.22 (m, 1H), 3.55 (d, J = 6.8 Hz, 2H), 3.48 (m,
1H), 2.95 (m, 1H), 1.78 (s, 6H), 1.24 (m, 1H), 0.87 (m, 1H), 0.0 (s,
9H) ppm. LRMS (ESI) calcd for C23H30NO5SSi [M + H]+ 460.16,
found 460.19.
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethanesulfinyl]-
benzoic acid phenyl ester 13c
Generation of 2-(1-methoxy-1-methylethyl)-2,3-dihydrobenzo-
[b]thiophene-7-carboxylic acid methyl ester 15b by treatment of
13a with tetrabutylammonium fluoride in THF–MeOH, followed
by diazomethane workup
Obtained in 96% yield (Rf = 0.32 in 5 : 1 hexane : ethylacetate).
1H-NMR (250 MHz, CDCl3) d 7.64–7.29 (m, 8H, aromatic),
5.23 (m, 1H), 3.66 (d, J = 6.7 Hz, 2H), 3.49 (m, 1H), 2.99 (m,
1H), 1.76 (s, 6H), 1.27 (m, 1H), 0.84 (m, 1H), 0.02 (s, 9H) ppm.
13C-NMR (62.9 MHz, CDCl3) d 166.61, 150.74, 141.52, 133.95,
133.04, 131.78, 130.48, 129.46, 127.99, 126.01, 122.05, 121.71,
50.11, 33.87, 32.13, 31.55, 18.14, 11.14, −1.99 ppm. HRMS (ESI)
calcd for C23H30O3SSiNa [M + Na]+ 437.1577, found 437.1564.
To a solution of 13a (20 mg, 0.046 mmol) in THF (0.8 mL) under
nitrogen, dry distilled methanol (200 lL) was added followed by
tetrabutylammonium fluoride (0.37 mL of a 1 M solution in THF,
0.37 mmol, 0.27 M). The reaction mixture turned dark yellow and
was stirred for 3 h. Dilute HCl (1 mL of a 1 M solution, pH ≈
3) was added and the resulting biphasic mixture was treated with
diazomethane (2 mL of a ∼ 0.66 M solution in ether, warning:
EXPLOSION HAZARD) with vigorous stirring. After 30 min,
the mixture was extracted with diethyl ether (3 × 5 mL). The
ether extracts were combined, washed with water (1 × 5 mL)
followed by brine (1 × 5 mL), dried over anhydrous sodium sulfate,
3-(3-Methylbut-2-enyl)-2-[2-(trimethylsilanyl)-ethanesulfinyl]-
phenyl]benzoic acid methyl ester 13d
Obtained in 53% yield (Rf = 0.38 in 5 : 1 hexane : ethylacetate).
1H-NMR (250 MHz, CDCl3) d 7.40–7.28 (m, 3H), 5.14 (m, 1H),
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and concentrated under reduced pressure to yield a pale yellow
oil. Flash column chromatography on silica gel eluted with 6 : 1
hexane : ethylacetate gave 15a (5.3 mg, 45%) as a colorless oil and
15b (2.7 mg, 22%, Rf = 0.33 in 6 : 1 hexane : ethylacetate) as a
colorless oil. All spectral data for this compound matched those
reported previously.15
Acknowledgements
We thank the National Institutes of Health (CA 83925 and CA
119131) for support of this research.
Notes and references
1 K. S. Gates, in Comprehensive Natural Products Chemistry, ed.
E. T. Kool, Pergamon, New York, 1999, vol. 7, pp. 491–552.
2 W. C. Tse and D. L. Boger, Chem. Biol., 2004, 11, 1607–1617.
3 K. S. Gates, Chem. Res. Toxicol., 2000, 13, 953–956.
4 M. Hara, K. Asano, I. Kawamoto, T. Takiguchi, S. Katsumata, K.-I.
Takahashi and H. Nakano, J. Antibiot., 1989, 42, 1768–1774.
5 M. Hara, Y. Saitoh and H. Nakano, Biochemistry, 1990, 29, 5676–
5681.
6 M. Hara, I. Takahashi, M. Yoshida, I. Kawamoto, M. Morimoto and
H. Nakano, J. Antibiot., 1989, 42, 333–335.
7 S. B. Behroozi, W. Kim and K. S. Gates, J. Org. Chem., 1995, 60,
3964–3966.
Trapping by methyl iodide of the sulfenate intermediate 14a
generated from 13a
To a stirred solution of 13a (20 mg, 0.046 mmol) in THF (1 mL)
under nitrogen, tetrabutylammonium fluoride (0.37 mL of a 1 M
solution in THF, 0.37 mmol, 0.27 M), and excess methyl iodide
(0.14 mL, 2.3 mmol, for a final concentration of 1.7 M) were added.
The reaction was stirred for 3 h and quenched by dilute HCl (1 mL
of a 1 M solution, pH ≈ 3). To this biphasic reaction mixture,
diazomethane (2 mL of a ∼0.66 M solution in ether, warning:
EXPLOSION HAZARD) was added with vigorous stirring. After
30 min, the mixture was extracted with diethyl ether (3 × 5 mL).
The combined ether extracts were washed with water (1 × 5 mL)
followed by brine (1 × 5 mL), dried over anhydrous sodium
sulfate and evaporated under reduced pressure. Flash column
chromatography on silica gel eluted with 4 : 1 hexane : ethylacetate
yielded 15a (3 mg, 25%) and 16 (4.3 mg, 35%, Rf = 0.09 in 4 : 1
hexane : ethylacetate). 1H-NMR (500 MHz, CDCl3) d 7.46 (d, J =
3.75 Hz, 1 H), 7.42 (t, J = 3.75 Hz, 1 H), 7.37 (d, J = 3.75 Hz),
5.20 (m, 1 H), 3.93 (s, 3 H), 3.68 (d, J = 3.5 Hz, 2 H), 3.05 (s, 3 H),
1.74 (d, J = 5.5 Hz, 6 H) ppm. 13C-NMR (125.75 MHz, CDCl3)
d 168.34, 141.87, 141.40, 133.93, 132.92, 131.87, 130.45, 127.58,
121.93, 52.65, 40.17, 30.37, 25.62, 18.05 ppm. HRMS (EI) calcd
for C14H18O3S [M +] 266.0976, found 266.0973.
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of acetonitrile (2.5 mL), sodium phosphate buffer (0.5 mL of
a 500 mM, pH 7), and water (2 mL). Final concentrations in
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50 mM, pH 7, acetonitrile 50% by volume. Dilute HCl (1 mL
of a 1 M solution, pH ≈ 3) was added to the reaction, followed
by diazomethane (2 mL of a ∼0.66 M solution in ether, warning:
EXPLOSION HAZARD). The mixture was stirred for 30 min
and then extracted with diethyl ether (3 × 5 mL). The combined
ether extracts were washed with water (1 × 5 mL) and brine (1 ×
5 mL), dried over anhydrous sodium sulfate, and concentrated
under reduced pressure to yield a pale yellow oil. Flash column
chromatography on silica gel eluted with 6 : 1 hexane : ethylacetate
yielded 10 as a colorless oil (3.9 mg, 33%, Rf = 0.15 in 6 : 1 hexane :
ethylacetate). All spectral data for this compound matched those
reported previously. Similarly, 13b affords 10 (32% yield) under
these reaction conditions. It is noteworthy that addition of KF
(50 mM) does not alter the rate or yield of this reaction. Finally,
compounds 13c and 13d remained unchanged when subjected to
the conditions described above (either with or without KF).
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35 For
a related example involving intramolecular attack of an
a-effect nucleophile, hydroxylamine (RNHOH), on a methyl ester,
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36 Added KF has no effect on either the rates or yields of these reactions,
presumably because hydration of the fluoride ion in aqueous solution
diminishes the rate of its reaction with the 2-(trimethylsilyl)ethyl group.
For example, see: R. I. Hogrefe, A. P. McCaffrey, L. U. Borozdina,
E. S. McCampbell and M. M. Vaghefi, Nucleic Acids Res., 1993, 21(20),
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37 In a related reaction, removal of a 2-(trimethylsilyl)ethyl protecting
group from sulfur can be stimulated by acylating agents, see: Y. Wang,
41 Aldrich Technical Bulletin AL-180 (http://www.sigmaaldrich.com/
aldrich/bulletin/al_techbull_al180.pdf).
1600 | Org. Biomol. Chem., 2007, 5, 1595–1600
This journal is
The Royal Society of Chemistry 2007
©