Novel heterocyclic systems. Synthesis of 2,7-dimethyl-10-oxa-1,8-diaza- anthracen-9-one and derivatives

Article abstract of DOI:10.1016/j.tet.2004.09.111

Synthesis of novel heterocycles, which contain the unique 10-oxa-1,8-diazaanthracen-9-one tricyclic core, is reported. The core structure was assembled via a dehydrative-cyclization strategy. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.09.111

Tetrahedron 60 (2004) 11751–11758
Novel heterocyclic systems. Synthesis of
2,7-dimethyl-10-oxa-1,8-diaza-anthracen-9-one and derivatives
*
Dimitar B. Gotchev and Daniel L. Comins
Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA
Received 17 August 2004; revised 30 September 2004; accepted 30 September 2004
Abstract—Synthesis of novel heterocycles, which contain the unique 10-oxa-1,8-diazaanthracen-9-one tricyclic core, is reported. The core
structure was assembled via a dehydrative-cyclization strategy.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Nucleophilic addition to 7 by the organolithium species
derived from iodide 6 via lithium–halogen exchange
afforded alcohol 8. Benzylic oxidation,6 followed by methyl
ether cleavage using aqueous hydrobromic acid yielded
ketone 10.7
During a recent effort in our laboratories directed at the
development of chiral ketones for use as asymmetric
epoxidation catalysts,1 we synthesized a series of hetero-
cycles containing the novel 10-oxa-1,8-diazaanthracen-9-
one backbone, i.e. compounds 1 and 2 (Fig. 1).
Exposure of diol 10 to a solution of hydrobromic acid in
refluxing acetic acid provided the desired ketone 1.
Alternatively, ketone 9 could be converted to tricycle 1 by
direct exposure to refluxing hydrobromic acid in acetic acid,
presumably via compound 10. Mechanistically, diol 10
undergoes a dehydrative-cyclization to provide ketone 1 via
intermediate 12 (Scheme 2).8
Compounds with related frameworks include 1,8-diaza-10-
oxa-9-thia-9,10-dihydroanthracene (3)2, 2,7-bis[2-(N,N-
diethylamino)ethoxy]-1,8-diazafluorenone dihydrochloride
(4) and tilorone (5) (Fig. 2).3 Compounds such as 3 are of
interest for their potential biological activity as central
nervous system agents and can be synthetically obtained by
the condensation of the disodium salt of 2-mercapto-
3-hydroxypyridine and 2-chloro-3-nitropyridine.2 The 1,8-
diazafluorenone 4 is a weakly active interferon inducer in
mice and shows interaction with calf thymus DNA similar
to that of tilorone (5), which in turn exhibits antitumor,
anti-inflamatory, immunostimulating, interferogenic and
virucidal biological activities.3 The first synthesis of
dimethyl-10-oxa-1,8-diaza-anthracen-9-one (1) and the
novel derivative 2 are reported herein.
We also developed a mild, two-step protocol for the
preparation of ketone 1 from 10 that avoided the use of
the harsh HBr/acetic acid medium needed for the
dehydrative-cyclization (Scheme 1). Triflation of both
hydroxyls in 10 afforded the cyclization precursor 11. The
use of Pd(0) or Ni(0) catalysts did not result in carbon–
carbon bond formation at the C-3 positions of the pyridine
rings. Instead, the oxo-bridged compound 1 was formed as
the sole product. This conversion is presumed to be the
result of oxidative addition of the transition metal complex
to one of the carbon-trifluoromethanesulfonate bonds.
Aqueous hydrolysis of the other trifluoromethanesulfonate
moiety promoted by the transition metal complex present,
followed by a dehydrating cyclization similar to that
operating in Scheme 2, gave the unanticipated product 1.
2. Results and discussion
Our approach to ketone 1 involves the preparation and
coupling of pyridines 6 and 7. Formylation of the known
iodide 64 provided aldehyde 7 in 75% yield (Scheme 1).5
Recrystallization from CHCl3/hexanes (1:1) yielded X-ray
quality crystals of ketone 1, which on X-ray analysis
unambiguously confirmed the novel 10-oxa-1,8-diaza-
anthracen-9-one atom connectivity present in ketone 1
(Fig. 3).9
Keywords: Heterocycle; 10-Oxa-1,8-diaza-anthracen-9-one; Dehydrative
cyclization.
* Corresponding author. Tel.: C1 919 515 2911; fax: C1 919 515 9371;
e-mail: daniel_comins@ncsu.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.111

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D. B. Gotchev, D. L. Comins / Tetrahedron 60 (2004) 11751–11758
Figure 1. Novel heterocyclic compounds containing the 10-oxa-1,8-diazaanthracen-9-one backbone.
Figure 2. Biologically active heterocycles with related frameworks to that of 10-oxa-1,8-diaza-anthracene-9-one.
Scheme 1. (a) n-BuLi, DMF (75%); (b) n-BuLi/6, then 7 (59%); (c) MnO2, CH2Cl2 (100%); (d) HBr (48% solution in H2O) (92%); (e) Tf2O, pyridine, CH2Cl2
(96%); (f) (Ni(COD)2), DMF, 60 8C (83%); (g) PdCl2, bis(pinacolato)diboron, 80 8C; then PdCl2, Na2CO3 (2 M solution in H2O) (55%); (h) HBr (30% solution
in AcOH), reflux (99%).
Scheme 2.
Efforts to produce 2 directly from ketone 1 via lateral
metalation/alkylation were unsuccessful. Attempts to depro-
tonate and subsequently alkylate the lateral methyl groups
in anthracenone 1 with styrene oxide failed. The use of
LiHMDS or KHMDS in THF or a 1:1 mixture of THF
and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone
(DMPU) at various reaction temperatures did not result in
the formation of the desired dianion. This result prompted us

D. B. Gotchev, D. L. Comins / Tetrahedron 60 (2004) 11751–11758
11753
cyclization yielded the targeted polyheterocyclic ketone 2 as
a mixture of diastereomers.
The cylcization of tethered benzylic triflates to provide
highly substituted indolizidinium compounds has been
extended to the formation of compound 19. Using similar
methodology for the synthesis of ketone 2, acylation of the
methoxymethyl-protected pyridinol 15 using n-BuLi and
benzoyl chloride, followed by TBS-deprotection, triflation
and in situ cyclization yielded the novel racemic zwitterion
19. Interestingly, the methoxy methyl group proved to be
labile upon formation of the indolizidinium ring, and
compound 19 was isolated rather than its MOM-protected
analog (Scheme 4).
Figure 3. Crystal structure of tricyclic ketone 1.
to explore alkylation conditions with the 1,3-dioxolane
protected ketone. Attempted deprotonation of the lateral
methyl groups of the cyclic ketal under a variety of basic
conditions quantitatively returned the starting material or
resulted in competitive deprotonation of the pyridine rings.
We next turned our attention to installing the phenylethyl
side chain first. Generation of the dianion from commer-
cially available pyridinol 13 using sec-BuLi, and subsequent
nucleophilic addition to styrene oxide followed by regio-
specific iodination at C-2, generated diol 14 (Scheme 3).10
Disilylation with TBSCl, followed by selective hydrolysis
of the aromatic TBS ether11 and protection of the resulting
pyridinol as the methoxymethyl ether, yielded iodide 15 in
good yield.12 Formylation of the lithiated species resulting
from lithium-halogen exchange on 15 was achieved by
trapping with ethyl formate rather than dimethylformamide,
as the latter gave lower yields of the desired aldehyde 16.
Nucleophilic addition to compound 16 by the aryllithium
generated from iodide 15 and n-BuLi afforded alcohol 17.
Benzylic oxidation with MnO2 was followed by selective
deprotection of the MOM group with dimethylboron
bromide in the presence of the TBS ether.13 Subsequent
triflation of the resulting diol yielded bis-trifluoromethane
sulfonate 18. Similar to the synthesis of 1, exposure of 18 to
bis(1,5-cyclooctadiene)nickel(0) (Ni(COD)2) resulted in the
formation of the 10-oxa-1,8,-diaza-anthracene-9-one
backbone. Removal of the TBS ether, triflation and in situ
Scheme 4. (a) n-BuLi, PhCOCl (69%); (b) TBAF, THF (80%); (c) Tf2O,
DIEA, CH2Cl2 (67%).
3. Conclusions
In summary, the synthesis of the novel heterocycles 1 and 2
was accomplished from commercially available materials in
6 and 13 steps, respectively. A novel transition metal-
catalyzed dehydrating cyclization was discovered which
circumvented the use of a strongly acidic reaction medium
to afford the tricyclic core. The unprecedented 10-oxa-1,8-
diazaanthracen-9-one backbone of 1 and 2 was unambigu-
ously determined by X-ray crystallographic analysis.
Similar to the synthesis of compound 2, the cyclization of
tethered benzylic triflates can be expected to generate other
highly substituted indolizidinium compounds. Although this
study used racemic styrene oxide, the methodology could
Scheme 3. (a) sec-BuLi, then styrene oxide (64%); (b) Na2CO3, I2, THF/H2O 1:1 (63%); (c) TBSCl, imidazole, DMF (91%); (d) AcOH/THF/H2O 4:2:1 (77%);
(e) MOMCl, DIEA, THF (92%); (f) n-BuLi, ethyl formate (75%); (g) n-BuLi/15, then 16 (68%); (h) MnO2, CH2Cl2 (100%); (i) Me2BBr, CH2Cl2 (88%);
(j) Tf2O, pyridine (97%); (k) Ni(COD)2, DMF (66%); (l) TBAF, THF (83%); (m) Tf2O, DIEA, CH2Cl2 (99%).

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D. B. Gotchev, D. L. Comins / Tetrahedron 60 (2004) 11751–11758
lead to enantiopure ketones by alkylating the dianion of
5-hydroxy-2-methylpyridine with the corresponding opti-
cally active epoxide, either antipode of which being
commercially available.
CH2Cl2 (100 mL) was added activated MnO2 (13.96 g,
160.7 mmol), and the resulting mixture was stirred at rt for
48 h under an argon atmosphere. The manganese residues
were removed by filtration through Celite, and then washed
with CH2Cl2 (500 mL). The filtrate was evaporated in
vacuo. Purification by silica gel chromatography (80 to
100% EtOAc in hexanes) gave 2.92 g (100%) of the desired
product 9 as a white solid: mp 147–148 8C; IR (neat) 2928,
4. Experimental
1
1676, 1464, 1263 cmK1; H NMR (CDCl3, 300 MHz) d
4.1. General procedures
7.21 (d, JZ8.6 Hz, 2H), 7.17 (d, JZ8.6 Hz, 2H), 3.68
(s, 6H), 2.45 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 193.2,
153.2, 149.5, 145.2, 126.0, 120.3, 56.1, 23.4. Anal. Calcd
for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C,
66.02; H, 6.02; N, 10.22.
All reactions were performed in oven or flame dried
glassware under argon atmosphere and stirred magnetically.
Tetrahydrofuran (THF) and toluene were distilled from
sodium/benzophenone ketyl prior to use. Trifluorometha-
nesulfonic anhydride (triflic anhydride) was distilled and
stored under argon. Other reagents and solvents from
commercial sources were stored under argon and used
directly. Melting points were obtained from a Thomas-
Hoover capillary melting point apparatus and are
uncorrected. Radial preparative layer chromatography
(radial PLC) was performed on a Chromatotron (Harrison
Associates, Palo Alto, CA) using glass plates coated with 1,
2 or 4 mm layers of Kieselgel 60 PF254 containing gypsum.
High-resolution mass spectral analysis (HRMS) was
performed at North Carolina State University. Elemental
analyses were performed by Atlantic Microlab Inc. NMR
spectra were obtained using a Varian Gemini GN-300
(300 MHz), Varian Mercury 300 (300 MHz), or Varian
Mercury 400 (400 MHz) spectrometer. Chemical shifts are
in d units (ppm) with TMS (0.0 ppm) used as the internal
4.1.3. Bis-(3-hydroxy-6-methylpyridin-2-yl)methanone
(10). Compound 9 (530 mg, 1.95 mmol) was dissolved in
aqueous HBr (48% in H2O, 30 mL, 0.265 mol). The reaction
mixture was refluxed for 24 h, cooled to rt, and the mixture
was concentrated in vacuo. To the residue was added
aqueous saturated NaHCO3 (50 mL), and the mixture was
extracted with EtOAc (3!50 mL). The combined organic
extracts were dried over MgSO4, filtered through Celite, and
concentrated in vacuo. Purification by silica gel chromato-
graphy (30 to 50% EtOAc in hexanes) gave 438 mg (92%)
of the desired product 10 as a yellow solid: mp 157–158 8C;
1
IR (neat) 3000, 1618, 1582, 1468, 1311 cmK1; H NMR
(CDCl3, 300 MHz) d 14.15 (s, 2H), 7.47 (d, JZ8.6 Hz, 2H),
7.38 (d, JZ8.6 Hz, 2H), 2.61 (s, 6H); 13C NMR (CDCl3,
75 MHz) d 195.1, 157.0, 149.0, 136.3, 130.7, 130.4, 23.2.
Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47.
Found: C, 63.90; H, 5.02; N, 11.50.
1
standard for H NMR spectra and the CDCl3 absorption
(77.2 ppm) or C6D6 absorption (128.4 ppm) for 13C NMR
spectra. IR spectra were recorded on a Perkin–Elmer 1430
spectrometer. HPLC was performed using Waters and
Associates (Milifrod, MA) 600 E multi solvent delivery
system with a 486 tunable detector equipped with an
YMC-pack sil (150!4.6 mm I.D.) analytical column or an
YMC-pack sil (150!10 mm I.D.) preparative column.
4.1.4. Trifluoromethanesulfonic acid 6-methyl-2-
(6-methyl-3-trifluoromethanesulfonyloxy-pyridine-2-
carbonyl)pyridin-3-yl ester (11). A solution of 10
(121 mg, 0.495 mmol) and pyridine (400 ml, 4.96 mmol)
in anhydrous CH2Cl2 (5 mL) was cooled to 0 8C under
argon. A solution of freshly distilled triflic anhydride
(330 ml, 1.98 mmol) in CH2Cl2 (1.0 mL) was added
dropwise over a period of 5 min. The contents of the flask
were allowed to warm to rt over 30 min and then stirred for
3 h. The reaction mixture was filtered through Celite with
CH2Cl2, and the solvent was removed in vacuo. Purification
by silica gel chromatography (10 to 20% EtOAc in hexanes)
gave 243 mg (96%) of the desired product 11 as a white
solid: mp 82.5–83.5 8C; IR (neat) 2921, 1702, 1584, 1430,
4.1.1. Bis-(3-methoxy-6-methylpyridin-2-yl)methanol
(8). To a stirred solution of compound 6 (138 mg,
0.550 mmol) in THF (3 mL) at K78 8C was added n-BuLi
(2.40 M in hexanes, 250 ml, 0.605 mmol) dropwise over
5 min. The resulting solution was stirred for additional
15 min and then compound 7 (91.0 mg, 0.605 mmol) in
THF (2.0 mL) was added over 10 min. The mixture was
strirred at K78 8C for 2 h and then warmed gradually to
0 8C over 1 h. The reaction was quenched with a saturated
aqueous solution of NaHCO3 (30 mL), and the aqueous
layer was extracted with ethyl acetate (3!30 mL). The
combined organic extracts were dried over MgSO4, filtered
through Celite, and the solvent was removed in vacuo.
Purification by silica gel chromatography (20 to 30% EtOAc
in hexanes) gave 89.0 mg (59%) of the desired product 8 as
a white solid: mp 116.0–117.5 8C; IR (neat) 3425, 1639,
1
1307, 1215 cmK1; H NMR (CDCl3, 300 MHz) d 7.63 (d,
JZ8.6 Hz, 2H), 7.42 (d, JZ8.6 Hz, 2H), 2.54 (s, 6H); 13C
NMR (CDCl3, 75 MHz) d 188.8, 158.8, 145.9, 143.8, 130.4,
127.8, 118.6 (1C, q, JZ317.5 Hz), 23.9; 19F NMR (CDCl3,
300 MHz) d 74.0. Anal. Calcd for C15H10F6N2O7S2: C,
35.44; H, 1.98; N, 5.51. Found: C, 35.43; H, 1.98; N, 5.50.
4.1.5. 2,7-Dimethyl-10-oxa-1,8-diazaanthracen-9-one
(1). Method A. To a solution of 11 (1.038 g, 2.040 mmol)
in anhydrous DMF (30 mL) at rt was added Ni(COD)2
(618 mg, 2.25 mmol). The resulting mixture was heated at
60 8C for 72 h. Saturated aqueous NaHCO3 (150 mL) was
added, and the reaction mixture was extracted with CH2Cl2
(3!150 mL). The combined organic extracts were dried
over MgSO4, filtered through Celite, and concentrated in
vacuo. Purification by silica gel chromatography (20 to 30%
1
1464, 1253 cmK1; H NMR (CDCl3, 300 MHz) d 7.03 (m,
4H), 6.23 (bs, 1H), 6.00 (bs, 1H), 3.65 (s, 6H), 2.45 (s, 6H);
13C NMR (CDCl3, 75 MHz) d 151.4, 149.3, 148.5, 122.5,
118.9, 67.4, 56.0, 23.5. Anal. Calcd for C15H18N2O3: C,
65.68; H, 6.61; N, 10.21. Found: C, 65.79; H, 6.60; N, 10.29.
4.1.2. Bis-(3-methoxy-6-methylpyridin-2-yl)methanone
(9). To a solution of 8 (2.94 g, 10.7 mmol) in anhydrous

D. B. Gotchev, D. L. Comins / Tetrahedron 60 (2004) 11751–11758
11755
EtOAc in hexanes) gave 357 mg (83%) of the desired
product 1 as a yellow solid: mp 255–257 8C; IR (neat) 3037,
with 10% HCl dropwise until the solution pH was 3. The
mixture was filtered through Celite, and the solvent
removed in vacuo. Purification by silica gel chromatography
(50 to 100% EtOAc in hexanes) gave 1.63 g (63%) of the
desired product 14 as a white foam; IR (neat) 3060, 2342,
1
1672, 1467, 1274 cmK1; H NMR (CDCl3, 300 MHz) d
7.79 (d, JZ8.4 Hz, 2H), 7.53 (d, JZ8.4 Hz, 2H), 2.76
(s, 6H); 13C NMR (CDCl3, 75 MHz) d 175.3, 157.0, 151.8,
137.8, 129.5, 127.3, 24.6; HRMS (MCH)C calcd for
C13H10N2O2 227.0821, found 227.0817.
1557, 1454, 1288, 1064, 910 cmK1 1H NMR (CDCl3,
;
300 MHz) d 7.30 (m, 5H), 7.09 (d, JZ8.1 Hz, 1H), 6.96 (d,
JZ8.1 Hz, 1H), 6.10 (bs, 1H), 4.78 (t, JZ6.3 Hz, 1H), 3.75
(bs, 1H), 2.84 (m, 2H), 2.13 (q, JZ6.8 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) d 155.6, 151.0, 144.7, 128.6, 127.6,
126.1, 123.8, 122.5, 110.0, 74.1, 38.5, 33.3; HRMS
(MCH)C calcd for C14H14INO2 356.0148, found 356.0140.
Method B. A flask charged with 11 (400 mg, 0.787 mmol),
bis(pinacolato)diboron (100 mg, 0.393 mmol) and PdCl2
(58 mg, 0.079 mmol) was flushed with argon. DMF (12 mL)
was added, the reaction mixture degassed, and the contents
of the flask heated at 80 8C for 2 h. The solution was cooled
to rt and PdCl2 (58 mg, 0.079 mmol) and Na2CO3 (2.0 M in
H2O, 1.0 mL, 2.0 mmol) were added. The reaction mixture
was heated at 80 8C for 24 h. The mixture was cooled to rt
and filtered through Celite with MeOH (30 mL). The filtrate
was washed with H2O (30 mL) and brine (30 mL), dried
over MgSO4, and concentrated in vacuo. Purification by
silica gel chromatography (20 to 30% EtOAc in hexanes)
gave 91.0 mg (55%) of the desired product 1 as a yellow
solid.
4.1.7. 6-[3-(tert-Butyldimethylsilanyloxy)-3-phenyl-
propyl]-2-iodo-3-methoxymethoxypyridine (15). To a
solution of 14 (1.07 g, 3.01 mmol) in DMF (30 mL) at
20 8C was added imidazole (1.64 g, 24.1 mmol) and tert-
butyldimethylsilyl chloride (1.81 g, 12.0 mmol). The
resulting mixture was stirred at rt for 12 h. The reaction
mixture was quenched with saturated aqueous NaHCO3
(100 mL) and extracted with CH2Cl2 (3!100 mL). The
combined organic layers were washed with brine (100 mL),
dried over Na2SO4, filtered through Celite, and concentrated
in vacuo. Purification by silica gel chromatography (0 to
10% EtOAc in hexanes) gave 1.60 g (91%) of the desired
bissilyl ether product as a colorless oil; IR (neat) 2953,
2855, 1541, 1441, 1361, 1295, 1255, 1091, 1059, 896, 836,
Method C. Compound 10 (421 mg, 1.55 mmol) was
dissolved in HBr (30% in AcOH, 20 mL, 0.10 mol). The
reaction mixture was refluxed for 48 h, cooled to rt, and
concentrated in vacuo. To the residue was added aqueous
saturated NaHCO3 (50 mL), and the mixture was extracted
with EtOAc (3!50 mL). The combined organic extracts
were dried over MgSO4, filtered through Celite, and
concentrated in vacuo. Purification by silica gel chroma-
tography (20 to 30% EtOAc in hexanes) gave 346 mg (99%)
of the desired product 1 as a yellow solid.
1
776 cmK1; H NMR (CDCl3, 300 MHz) d 7.63 (m, 7H),
5.10 (t, JZ5.6 Hz, 1H), 3.12 (m, 2H), 2.41 (m, 2H), 1.43 (s,
9H), 1.26 (s, 9H), 0.64 (s, 6H), 0.39 (s, 3H), 0.22 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 156.4, 150.6, 145.5, 128.3, 127.2,
126.3, 126.2, 124.8, 122.3, 115.3, 74.8, 40.9, 33.4, 26.1,
26.0, 18.5, K3.8, K3.8, K4.4, K4.7; HRMS (MCH)C
calcd for C26H42INO2Si2 584.1877, found 584.1879.
4.1.6. 6-(3-Hydroxy-3-phenylpropyl)-2-iodopyridin-3-ol
(14). A solution of 5-hydroxy-2-methylpyridine (13)
(1.25 g, 11.5 mmol) in THF (80 mL) was cooled to
K20 8C. A solution of sec-BuLi (0.97 M in cyclohexane,
24.1 mL, 24.1 mmol) was added dropwise over a period of
5 min. The resulting dark red mixture was stirred at K20 8C
for an additional 45 min. The mixture was cooled to K78 8C
and neat styrene oxide (6.5 mL, 57 mmol) was added over a
period of 10 min. After 2 h, the reaction mixture was
quenched with saturated aqueous NH4Cl (100 mL) and
warmed up to rt, during which time it became colorless. The
mixture was extracted with CH2Cl2 (3!100 mL). The
combined organic extracts were dried over MgSO4, filtered
through Celite, and concentrated in vacuo. Purification by
silica gel chromatography (50 to 100% EtOAc in hexanes)
gave 1.68 g (64%) of the desired diol product as a colorless
oil; IR (neat) 3027, 2360, 1574, 1494, 1452, 1275, 1124,
The above bissilyl ether (1.60 g, 2.74 mmol) was dissolved
in a 4:2:1 mixture of CH3COOH/H2O/THF (250 mL) at
20 8C and stirred for 4 h. The reaction mixture was carefully
quenched with saturated aqueous NaHCO3 (300 mL) and
extracted with CH2Cl2 (3!300 mL). The combined organic
layers were dried over MgSO4, filtered through Celite, and
concentrated in vacuo. Purification by silica gel chromato-
graphy (10 to 30% EtOAc in hexanes) gave 995 mg (77%)
of the desired product as a white foam; IR (neat) 3418, 2956,
1
2856, 1545, 1488, 1359, 1286, 1248, 1085, 981 cmK1; H
NMR (CDCl3, 300 MHz) d 7.29 (m, 5H), 7.09 (d, JZ
8.0 Hz, 1H), 6.94 (d, JZ8.1 Hz, 1H), 5.30 (bs, 1H), 4.72
(t, JZ5.4 Hz, 1H), 2.74 (m, 2H), 2.04 (m, 2H), 0.89 (s, 9H),
0.02 (s, 3H), K0.16 (s, 3H); 13C NMR (CDCl3, 75 MHz) d
156.1, 151.1, 145.3, 128.3, 127.2, 126.0, 126.4, 122.4,
110.2, 74.7, 41.1, 33.1, 26.1, 18.4, K4.4, K4.7; HRMS
(MCH)C calcd for C20H28INO2Si 470.1012, found
470.1027.
1060, 911 cmK1 1H NMR (CDCl3, 300 MHz) d 8.14
;
(s, 1H), 7.93 (bs, 1H), 7.33 (bs, 1H), 7.22 (m, 5H), 7.11 (d,
JZ2.3 Hz, 1H), 7.00 (d, JZ8.5 Hz, 1H), 4.80 (t, JZ5.8 Hz,
1H), 2.87 (t, JZ6.7 Hz, 2H), 2.12 (q, JZ6.3 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 153.0, 151.5, 144.6, 135.6, 128.5,
127.4, 126.0, 125.8, 124.6, 74.1, 38.4, 33.1; HRMS (MC
H)C calcd for C14H15NO2 230.1181, found 230.1193.
A solution of the above phenol (1.29 g, 2.75 mmol) in THF
(65 mL) was cooled to 0 8C and N,N-diisopropylethylamine
(1.0 mL, 5.43 mmol) was added dropwise over a period of
5 min. After stirring at 0 8C for 15 min, chloromethyl
methyl ether (1.50 mL, 19.0 mmol) was added dropwise
over 5 min. The mixture was stirred for 30 min, then
gradually warmed to rt. After stirring at 20 8C for 40 h, the
reaction mixture was quenched with a buffered solution
(pH 8) of NH4OH and NH4Cl (275 mL) and then extracted
To a solution of the above diol (1.68 g, 7.33 mmol) and
Na2CO3 (1.63 g, 15.4 mmol) in 1:1 H2O/THF (220 mL) was
added I2 (1.86 g, 7.33 mmol). After stirring at rt for 1 h, the
iodine color disappeared and the reaction was quenched

11756
D. B. Gotchev, D. L. Comins / Tetrahedron 60 (2004) 11751–11758
with ethyl acetate (3!250 mL). The combined organic
layers were dried over MgSO4, filtered through Celite with
ethyl acetate, and concentrated in vacuo. Purification by
silica gel chromatography (0 to 10% EtOAc in hexanes)
gave 1.30 g (92%) of 15 as a colorless oil; IR (neat) 2958,
1551, 1488, 1291, 1246 cmK1; 1H NMR (CDCl3, 300 MHz)
d 7.29 (m, 5H), 7.15 (d, JZ8.4 Hz, 1H), 6.96 (d, JZ8.4 Hz,
1H), 5.21 (s, 2H), 4.74 (t, JZ5.4 Hz, 1H), 3.50 (s, 3H), 2.77
(m, 2H), 2.06 (m, 2H), 0.89 (s, 9H), K0.03 (s, 3 H), K0.15
(s, 3H); 13C NMR (CDCl3, 75 MHz) d 157.5, 151.4, 145.4,
128.3, 127.2, 126.2, 122.5, 122.0, 112.0, 95.4, 74.8, 56.8,
40.9, 33.3, 26.1, 18.5, K4.4, K4.7; HRMS (MCH)C calcd
for C22H32INO3Si 514.1274, found 514.1301.
(MCH)C calcd for C45H66N2O7Si2 803.4487, found
803.4510.
4.1.10. Trifluoromethanesulfonic acid-6-[3-(tert-butyl-
dimethylsilanyloxy)-3-phenylpropyl]-3-[6-[3-tert-butyl-
dimethylsilanyloxy)-3-phenylpropyl]-3-trifluorometha-
nesulfonyloxypyridine-2-carbonyl]-pyridin-3-yl ester
(18). To a solution of 17 (348 mg, 0.434 mmol) in
anhydrous CH2Cl2 (20 mL) was added activated MnO2
(566 mg, 6.50 mmol), and the resulting mixture was stirred
at rt for 30 h under an argon atmosphere. The residual
manganese was removed by filtration (Celite). The filtrate
was concentrated in vacuo. Purification by silica gel
chromatography (10 to 20% EtOAc in hexanes) gave
347 mg (100%) of the desired ketone as a white foam; IR
(neat) 2956, 2952, 2856, 1698, 1568, 1463, 1404, 1361,
1306, 1255, 1203, 1158, 1083, 981, 836, 777, 701 cmK1; 1H
NMR (CDCl3, 300 MHz) d 7.42 (d, JZ8.6 Hz, 2H), 7.24
(m, 10H), 7.12 (d, JZ7.7 Hz, 2H), 5.05 (s, 4H), 4.68 (t, JZ
5.8 Hz, 2H), 3.34 (s, 6H), 2.74 (m, 4H), 1.97 (m, 4H), 0.88
(s, 18H), K0.03 (s, 6H), K0.18 (s, 6H); 13C NMR (CDCl3,
75 MHz) d 193.4, 154.7, 150.8, 146.4, 145.5, 128.1, 127.0,
126.0, 125.2, 124.3, 95.3, 74.6, 56.3, 40.6, 33.3, 26.0, 18.4,
K4.5, K4.8; HRMS (MCH)C calcd for C45H64N2O7Si2
801.4330, found 801.4311.
4.1.8. 6-[3-(tert-Butyldimethylsilanyloxy)-3-phenyl-
propyl]-3-methoxymethoxypyridine- 2-carbaldehyde
(16). To a solution of 15 (727 mg, 1.42 mmol) in THF
(15 mL) at K78 8C was added n-BuLi (2.17 M in hexanes,
720 ml, 1.56 mmol) dropwise over 5 min. The resulting
solution was stirred for additional 30 min and then ethyl
formate (1.1 mL, 14 mmol) was added over 10 min. The
reaction mixture was gradually warmed to 0 8C over 3 h and
quenched with saturated aqueous NaHCO3 (100 mL). The
aqueous layer was extracted with ethyl acetate (3!
100 mL). The combined organic extracts were dried over
MgSO4, filtered through Celite, and concentrated in vacuo.
Purification by silica gel chromatography (0 to 10% EtOAc
in hexanes) gave 441 mg (75%) of 16 as a colorless oil; IR
(neat) 2954, 2927, 2855, 1713, 1561, 1469, 1389, 1250,
The above ketone (184 mg, 0.229 mmol) was dissolved in
anhydrous CH2Cl2 (5 mL) and cooled to K78 8C. Me2BBr
(2.01 M in CH2Cl2, 680 ml, 1.37 mmol) was added dropo-
wise and the mixture was stirred at K78 8C for 4 h.
Additional Me2BBr (2.01 M in CH2Cl2, 680 ml, 1.37 mmol)
was then added. After stirring for 4 h, the mixture was
cannulated into a vigorously stirred mixture of THF
(10 mL) and saturated aqueous NaHCO3 (15 mL) at 20 8C.
After 5 min, the mixture was diluted with ethyl acetate
(50 mL). The organic layer was separated and washed
successively with H2O (50 mL), 10% aqueous sodium
bisulfate (50 mL), and brine (50 mL). The combined
aqueous layers were extracted with ethyl acetate (2!
50 mL). The organic layers were combined, dried over
MgSO4, filtered through Celite, and concentrated in vacuo.
Purification by flash chromatography (10 to 20% EtOAc in
hexanes) gave 144 mg (88%) of the desired bisphenol as a
colorless oil; IR (neat) 3362, 2968, 2857, 1623, 1594, 1464,
1257, 1173, 1084, 972 cmK1; 1H NMR (CDCl3, 300 MHz)
d 7.42 (d, JZ8.6 Hz, 2H), 7.29 (m, 14H), 4.78 (t, JZ5.8 Hz,
2H), 2.88 (m, 4H), 2.13 (m, 4H), 0.90 (s, 18H), 0.03 (s, 6H),
K0.14 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 195.4, 156.8,
152.9, 145.1, 136.5, 130.1, 129.9, 128.3, 127.2, 126.1, 74.6,
40.7, 33.3, 26.1, 18.4, K4.4, K4.8; HRMS (MCH)C calcd
for C41H56N2O5Si2 713.3806, found 713.3800.
1155, 1082, 973, 775, 700 cmK1 1H NMR (CDCl3,
;
300 MHz) d 10.30 (s, 1 H), 7.54 (d, JZ8.8 Hz, 1H), 7.31
(m, 5H), 7.26 (d, JZ8.6 Hz, 1H), 5.29 (s, 2H), 4.76 (t, JZ
5.4 Hz, 1H), 3.51 (s, 3H), 2.87 (m, 2H), 2.11 (m, 2H), 0.89
(s, 9H), 0.03 (s, 3H), K0.15 (s, 3H); 13C NMR (CDCl3,
75 MHz) d 191.1, 156.1, 154.0, 145.4, 140.9, 128.3, 128.2,
127.2, 126.1, 124.9, 95.1, 74.8, 56.8, 40.8, 33.6, 26.1, 18.5,
K4.4, K4.7; HRMS (MCH)C calcd for C23H33NO4Si
416.2257, found 416.2253.
4.1.9. Bis-[6-[3-(tert-butyldimethylsilanyloxy)-3-phenyl-
propyl]-3-methoxymethoxypyridin-2-yl]-methanol (17).
To a solution of 15 (349 mg, 0.680 mmol) in THF (7 mL) at
K78 8C was added n-BuLi (2.17 M in hexanes, 310 ml,
0.680 mmol) dropwise over 5 min. The resulting solution
was stirred for 15 min, then compound 16 (311 mg,
0.748 mmol) in THF (5 mL) was added dropwise over
10 min. After the addition was complete, the reaction
mixture was stirred at K78 8C for 2 h and then warmed
gradually to 0 8C over 1 h. The reaction was quenched with
a saturated aqueous NaHCO3 (50 mL) and extracted with
ethyl acetate (3!50 mL). The combined organic extracts
were dried over MgSO4, filtered through Celite, and
concentrated in vacuo. Purification by silica gel chroma-
tography (0 to 10% EtOAc in hexanes) gave 371 mg (68%)
of 17 as a colorless oil; IR (neat) 3375, 2954, 2928, 2856,
1580, 1469, 1403, 1361, 1255, 1155, 1081, 1056, 993, 836,
A solution of the above bisphenol (107 mg, 0.150 mmol)
and pyridine (120 ml, 1.50 mmol) in anhydrous CH2Cl2
(5 mL) was cooled to 0 8C under argon. A solution of freshly
distilled triflic anhydride (130 ml, 0.750 mmol) in CH2Cl2
(1.0 mL) was added dropwise over a period of 5 min. The
mixture was warmed to rt over 30 min and stirred for 16 h.
The reaction mixture was filtered through Celite with
CH2Cl2 and the solvent was removed in vacuo. Purification
by silica gel chromatography (0 to 10% EtOAc in hexanes)
gave 142 mg (97%) of 18 as a white foam; IR (neat) 2956,
2858, 1710, 1587, 1462, 1434, 1362, 1253, 1217, 1140,
1
776 cmK1; H NMR (CDCl3, 300 MHz) d 7.25 (m, 12H),
6.94 (d, JZ6.2 Hz, 2H), 6.24 (d, JZ4.3 Hz, 1H), 6.05 (bs,
1H), 4.98 (m, 4H), 4.74 (m, 2H), 3.19 (s, 3H), 3.18 (s, 3H),
2.75 (m, 4H), 2.03 (m, 4H), 0.91 (s, 18H), K0.02 (s, 6H),
K0.14 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 153.3, 149.7,
148.9, 145.6, 128.1, 127.0, 126.0, 122.3, 121.9, 94.5, 74.7,
68.6, 58.8, 40.9, 33.2, 26.1, 18.4, K4.4, K4.7; HRMS

D. B. Gotchev, D. L. Comins / Tetrahedron 60 (2004) 11751–11758
11757
1
1086 cmK1; H NMR (CDCl3, 300 MHz) d 7.60 (d, JZ
NMR (CD3CN, 300 MHz) d 8.99 (t, JZ7.1 Hz, 1H), 8.50
(t, JZ6.7 Hz, 1H), 8.23 (m, 1H), 7.25 (m, 2H), 7.15
(m, 1H), 6.98 (m, 1H), 6.69 (bs, 1H), 4.80 (t, JZ5.1 Hz,
1H), 3.54 (t, JZ5.2 Hz, 1H).14
8.6 Hz, 2H), 7.33 (d, JZ8.6 Hz, 2H), 7.25 (m, 10H), 4.68
(t, JZ5.6 Hz, 2H), 2.81 (m, 4 H), 1.99 (m, 4H), 0.86
(s, 18H), K0.05 (s, 6H), K0.18 (s, 6H); 13C NMR (CDCl3,
75 MHz) d 188.4, 162.0, 146.1, 145.0, 143.7, 130.3, 127.9,
127.2, 126.9, 126.0, 118.7 (q, JZ1275 Hz), 74.2, 39.8, 33.2,
26.0, 18.4, K4.5, K4.9; 19F NMR (CDCl3, 300 MHz) d
K73.9; HRMS (MCH)C calcd for C43H54F6N2O9S2Si2
977.2792, found 977.2810.
4.1.12. 5-Benzoyl-6-oxy-3-phenyl-2,3-dihydro-1H-indo-
lizinylium Zwitter ion (19). To a solution of 15 (64 mg,
0.13 mmol) in THF (2.0 mL) at K78 8C was added n-BuLi
(2.28 M in hexanes, 60 ml, 0.14 mmol) dropwise over 5 min.
The resulting solution was stirred for 15 min, and benzoyl
chloride (150 ml, 1.25 mmol) was added over 10 min. The
reaction was stirred at K78 8C for 2 h and then warmed to
0 8C over 1 h. The reaction was quenched with a saturated
aqueous NaHCO3 (20 mL), and the aqueous layer was
extracted with ethyl acetate (3!20 mL). The combined
organic extracts were dried over MgSO4, filtered through
Celite, and concentrated in vacuo. Purification by silica gel
chromatography (0 to 10% EtOAc in hexanes) gave 42.0 mg
(69%) of the desired ketone as a colorless oil; IR (neat)
2954, 2928, 2855, 1681, 1459, 1255, 1155, 1082, 979,
4.1.11. 2,7-Bis-3-phenyl-10-oxa-1,8-diazoniacyclopent-
aneanthracene-9-one bistrifluromethanesulfonate salt
(2). To a solution of 18 (416 mg, 0.426 mmol) in anhydrous
DMF (10 mL) at rt was added Ni(COD)2 (123 mg,
0.447 mmol). The resulting mixture was heated to 60 8C
for 48 h, and then saturated aqueous NaHCO3 (50 mL) was
added. The reaction mixture was extracted with CH2Cl2
(3!50 mL). The combined organic extracts were dried over
MgSO4, filtered through Celite, and concentrated in vacuo.
Purification by silica gel chromatography (0 to 10% EtOAc
in hexanes) gave 196 mg (66%) of the desired cyclic ketone
product as a yellow solid: mp 170–173 8C; IR (neat) 2928,
836 cmK1 1H NMR (CDCl3, 300 MHz) d 7.86 (d, JZ
;
7.9 Hz, 2H), 7.46 (m, 5H), 7.27 (m, 3H), 7.17 (d, JZ8.4 Hz,
2H), 5.10 (s, 2H), 4.75 (t, JZ5.9 Hz, 1H), 3.36 (s, 3H), 2.82
(m, 2H), 2.08 (m, 2H), 0.88 (m, 9H), 0.00 (s, 3H), K0.17 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 194.2, 155.1, 149.7,
146.9, 145.5, 136.6, 133.6, 130.5, 128.5, 128.2, 127.1,
126.1, 124.5, 124.0, 95.2, 74.8, 56.5, 40.8, 35.5, 26.1, 18.5,
K4.4, K4.7; HRMS (MCH)C calcd for C29H37NO4Si
492.2570, found 492.2563.
2856, 1685, 1466, 1258, 1092, 836, 776, 700 cmK1; H
1
NMR (CDCl3, 300 MHz) d 7.75 (d, JZ8.7 Hz, 2H), 7.59 (d,
JZ8.6 Hz, 2H), 7.28 (m, 10H), 4.81 (t, JZ5.8 Hz, 2H), 3.08
(m, 4H), 2.14 (m, 4H), 0.89 (s, 18H), K0.03 (s, 6H), K0.15
(s, 6H); 13C NMR (CDCl3, 75 MHz) d 175.3, 160.7, 151.9,
145.3, 137.9, 128.7, 128.3, 127.2, 126.1, 74.9, 41.0, 34.7,
26.1, 18.4, K4.4, K4.7; HRMS (MCH)C calcd for
C41H54N2O4Si2 695.3700, found 695.3736.
A solution of the above ketone (308 mg, 0.626 mmol) in
THF (10 mL) was cooled to 0 8C. Tetrabutylammonium
fluoride (1.0 M in THF, 3.8 mL, 3.8 mmol) was added
dropwise over a period of 10 min. After the addition was
complete, the reaction mixture was warmed to rt over a
period of 30 min and stirred for an additional 1 h. The
reaction mixture was poured into saturated aqueous NH4Cl
(50 mL) and extracted with EtOAc (3!50 mL). The
combined organic extracts were dried over MgSO4, filtered
through Celite, and concentrated in vacuo. Purification by
silica gel chromatography (50 to 100% EtOAc in hexanes)
gave 186 mg (80%) of the desired alcohol product as a
colorless oil; IR (neat) 3406, 2923, 1675, 1596, 1461, 1255,
1154, 1081, 976 cmK1; 1H NMR (CDCl3, 300 MHz) d 7.84
(d, JZ7.7 Hz, 2H), 7.50 (m, 5H), 7.26 (m, 3H), 7.19 (d, JZ
7.7 Hz, 2H), 5.08 (s, 2H), 4.65 (t, JZ5.9 Hz, 1H), 3.80 (bs,
1H), 3.33 (s, 3H), 2.87 (m, 2H), 2.11 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 193.8, 154.4, 149.7, 146.5, 144.9,
136.3, 133.6, 130.2, 128.5, 128.3, 128.3, 127.2, 124.9,
124.2, 95.0, 73.4, 56.4, 38.6, 33.3; HRMS (MCH)C calcd
for C23H23NO4 378.1705, found 378.1702.
A solution of the above ketone (45 mg, 0.064 mmol) in THF
(1.0 mL) was cooled to 0 8C. Tetrabutylammonium fluoride
(1.0 M in THF, 380 ml, 0.384 mmol) was added dropwise
over a period of 10 min. The reaction was warmed to rt over
a period of 30 min and stirred for an additional 1 h. The
mixture was poured into saturated aqueous NH4Cl (20 mL)
and extracted with EtOAc (3!20 mL). The combined
organic extracts were dried over MgSO4, filtered through
Celite, and concentrated in vacuo. Purification by silica gel
chromatography (30 to 50% EtOAc in hexanes) gave
25.0 mg (83%) of the desired diol as a colorless oil; IR
(neat) 3384, 3067, 2926, 1676, 1604, 1469, 1266, 1124,
1
1061 cmK1; H NMR (CDCl3, 300 MHz) d 7.82 (d, JZ
8.7 Hz, 2H), 7.58 (d, JZ8.6 Hz, 2H), 7.30 (m, 10H), 4.85 (t,
JZ5.8 Hz, 2H), 3.41 (bs, 2H), 3.15 (m, 4H), 2.27 (m, 4H);
13C NMR (CDCl3, 75 MHz) d 175.0, 160.3, 151.9, 145.0,
137.6, 129.2, 128.5, 127.6, 127.4, 126.1, 73.7, 38.7, 34.5;
HRMS (MCH)C calcd for C29H26N2O4 467.1971, found
467.1989.
A solution of the above diol (25.0 mg, 0.0536 mmol) in
anhydrous CH2Cl2 (2.0 mL) was cooled to 0 8C under
argon. N,N-Diisopropylethylamine (20 ml, 0.12 mmol) was
added and the reaction mixture was stirred for 15 min at
0 8C. A solution of freshly distilled triflic anhydride (15 ml,
0.085 mmol) in CH2Cl2 (1.0 mL) was added dropwise over
a period of 5 min. The reaction mixture was warmed to rt
over 30 min and stirred for 16 h. The mixture was filtered
through Celite with CH2Cl2 and the solvent was removed in
vacuo. Purification by HPLC (Whatman Partisil 10 C-8
column, 50% H2O/CH3CN, 2.0 mL/min) gave 50.0 mg
(128%) of the desired crude product 2 as a purple solid; 1H
A solution of the above alcohol (78.0 mg, 0.207 mmol) in
anhydrous CH2Cl2 (4 mL) was cooled to 0 8C under argon.
N,N-Diisopropylethylamine (40 ml, 0.23 mmol) was added
and the reaction mixture was stirred for 15 min at 0 8C.
A solution of freshly distilled triflic anhydride (40 ml,
0.227 mmol) in CH2Cl2 (1.0 mL) was added dropwise over
a period of 5 min. The reaction mixture warmed to rt over
30 min and stirred for 1 h. The reaction mixture was filtered
through Celite with CH2Cl2 and the solvent removed in
vacuo. Purification by flash chromatography (silica gel)
with 0–30% MeOH/EtOAc gave 43.3 mg (67%) of 19 as a

11758
D. B. Gotchev, D. L. Comins / Tetrahedron 60 (2004) 11751–11758
J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120, 5943.
(h) Adam, W.; Saha-Moller, C. R.; Zhao, C.-G. Tetrahedron:
Asymmetry 1999, 10, 2749. (i) Shu, L.; Shi, Y. J. Org. Chem.
2000, 65, 8807. (j) Wang, Z.-X.; Miller, S. M.; Anderson,
O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521. (k) Denmark, S. E.;
Matsuhashi, H. J. Org. Chem. 2002, 67, 3479. (l) Shu, L.;
Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293.
colorless oil; IR (neat) 3383, 1646, 1595, 1542, 1480, 1412,
1369, 1221, 1143, 1005 cmK1 1H NMR (CD3OD,
;
300 MHz) d 7.65 (d, JZ9.1 Hz, 1H), 7.53 (d, JZ9.1 Hz,
1H), 7.44 (d, JZ7.5 Hz, 2H), 7.37 (d, JZ7.3 Hz, 1H), 7.20
(t, JZ7.7 Hz, 2H), 7.03 (t, JZ7.9 Hz, 2H), 6.95 (m, 3H),
6.24 (dd, JZ4.4, 4.9 Hz, 1H), 3.55 (m, 1H), 3.38 (m, 1H),
2.91 (m, 1H), 2.30 (m, 1H); 13C NMR (CD3OD, 75 MHz) d
193.0, 168.0, 142.9, 140.7, 139.6, 137.1, 136.4, 134.6,
130.5, 130.0, 129.9, 129.1, 128.5, 125.5, 74.1, 32.0, 31.2;
HRMS (MCH)C calcd for C21H17NO2 316.1338, found
316.1346.
2. Davies, J. S.; Smith, K.; Turner, J. R.; Gymer, G. Tetrahedron
Lett. 1979, 52, 5035.
3. Szulc, Z.; Mlochowski, J. Heterocycles 1984, 22, 73.
4. Massa, M. A.; Patt, W. C.; Ahn, K.; Sisneros, A. M.; Herman,
S. B.; Doherty, A. Bioorg. Med. Chem. Lett. 1988, 16, 2117.
5. Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257.
6. Fatiadi, A. J. Synthesis 1976, 133.
Acknowledgements
7. May, E. L.; Jacobsen, A. E.; Mattson, M. V.; Coop, A.; Aceto,
M. D.; Bowman, E. R.; Traynor, J. R.; Wood, J. H.; Harris,
L. S. Med. Chem. Res. 1988, 8, 311.
We express appreciation to the National Institutes of Health
(Grant GM 34442) for financial support of this research.
D.G. also thanks the Burroughs-Wellcome Fellowship Fund
for a second year Graduate Assistantship. The authors thank
Dr. Paul Boyle for X-ray crystallographic analysis of 1.
NMR and mass spectra and X-ray data were obtained at
NCSU instrumentation laboratories, which were established
by grants from the North Carolina Biotechnology
Center and the National Science Foundation (Grants
CHE-9509532, CHE-0078253).
8. (a) Trecourt, F.; Queguiner, G. J. Chem. Res. (S) 1982, 76.
(b) Trecourt, F.; Marsais, F.; Gungor, T.; Queguiner, G.
J. Chem. Soc., Perkin Trans. 1 1990, 2409.
9. Crystallographic data (excluding structure factors) for the
structure 1 in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 247660. Copy of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: C44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
10. Saksena, A. K.; Lovey, R. G.; Girijavallabhan, V. M.; Guzik,
H.; Ganguly, A. K. Tetrahedron Lett. 1993, 34, 3267.
11. Klebe, J. Advances in Organic Chemistry, Methods and
Advances; Wiley-Interscience: New York, 1992; pp 97–178.
12. Interchange of the TBS ether for the labile MOM protecting
group in 15 was necessary to obtain aldehyde 16, as the bulky
silyl ether prevented lithium–halogen exchange.
References and notes
1. For leading references on asymmetric epoxidation mediated in
situ by chiral ketones see: (a) Curci, R.; Fiorentino, M.; Serio,
M. R. J. Chem. Soc., Chem. Commun. 1984, 155. (b) Denmark,
S. E.; Forbes, D. C.; Hays, D. S.; DePue, J. S.; Wilde, R. G.
J. Org. Chem. 1995, 60, 1391. (c) Yang, D.; Yip, Y. C.; Tang,
M. W.; Wong, M. K.; Zheng, J. H.; Cheung, K. K. J. Am.
Chem. Soc. 1996, 118, 491. (d) Yang, D.; Wang, X.-C.; Wong,
M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem. Soc. 1996, 118,
11311. (e) Denmark, S. E.; Wu, Z.; Crudden, C. M.;
Matsuhashi, H. J. Org. Chem. 1997, 62, 8288. (f) Wang,
Z.-X.; Shi, Y. J. Org. Chem. 1997, 62, 8622. (g) Yang, D.;
Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng,
13. Guindon, Y.; Yoahim, C.; Morton, H. E. J. Org. Chem. 1984,
49, 3912.
14. Purification of crude 2 by HPLC yielded compound 2
contaminated with about 20% N,N-diisopropylethylamine
trifluoromethanesulfonate salt. Hence, the compound was not
analyzed by 13C NMR. Note: the validity of the cyclization
was confirmed by obtaining the zwitterionic compound 19
from 15, which undergoes the same type cyclization.