Synthetic studies on the CDEF ring system of lactonamycin

Article abstract of DOI:10.1016/j.tet.2006.10.004

Both (1) furan-maleimide Diels-Alder cycloaddition reaction and (2) furan-benzyne cycloaddition, Suzuki cross-coupling, boron-mediated aldol, and electrophilic aromatic substitution reactions were examined for the construction of the CDEF ring system of l

Full text of DOI:10.1016/j.tet.2006.10.004

Tetrahedron 62 (2006) 12252–12263
Synthetic studies on the CDEF ring system of lactonamycin
a
Ronan Le Vezouet, Andrew J. P. White, Jeremy N. Burrows and Anthony G. M. Barrett
a
b
a,
*
ꢀ
€
aDepartment of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
bAstraZeneca, Sodertalje S-151 85, Sweden
Received 4 August 2006; revised 26 September 2006; accepted 5 October 2006
Available online 30 October 2006
Abstract—Both (1) furan–maleimide Diels–Alder cycloaddition reaction and (2) furan–benzyne cycloaddition, Suzuki cross-coupling,
boron-mediated aldol, and electrophilic aromatic substitution reactions were examined for the construction of the CDEF ring system of
lactonamycin (1).
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Kelly’s group more recently reported an asymmetric synthe-
sis of the AB ring system.3 Of particular relevance to the
work presented here, two syntheses of model systems related
to the aromatic CDEF core of lactonamycin have also been
reported. Behar’s approach was based on the construction of
ring E by an elegant tandem conjugate cyanide addition–
Dieckmann condensation.4 Shortly thereafter, Kelly pub-
lished a second approach toward the same lactonamycin
segment by the assemblage of the D and E rings using
Diels–Alder cycloaddition reactions.5 Danishefsky and
co-workers recently completed a diastereoselective synthe-
sis of the entire lactonamycin aglycon, with the CDEF frag-
ment assembled using successive Diels–Alder reactions.6
Finally, we have reported the synthesis of the ABCD tetracy-
clic ring system of lactonamycin using an iterative sequence
of Michael addition and oxidation reactions.7 Herein, we
report our own studies on the approaches to the CDEF ring
system using notably benzyne–furan and maleimide–furan
cycloaddition reactions, Suzuki coupling reaction, and elec-
trophilic aromatic substitutions.
Lactonamycin (1) and lactonamycin-Z (2) have intriguing
structural features, which include a naphtho[e]isoindole
ring system (DEF-rings) and a densely oxygenated fused
perhydrofuran-furanone ring system (AB-rings) (Fig. 1).1
Lactonamycin (1) shows significant levels of antimicrobial
activity against Gram-positive bacteria being especially
active against methicillin-resistant Staphylococcus aureus
(MRSA) and vancomycin-resistant Enterococcus (VRE)
with minimum inhibitory concentration levels of 0.39 and
0.20 mg/mL, respectively. In addition, it shows significant
levels of cytotoxicity against various tumor cell lines with
IC50 ranging from 0.06 to 3.30 mg/mL. Whilst there has
been no total synthesis of 1 yet published, synthetic studies
toward lactonamycin 1 have been reported by four groups.
Cox and Danishefsky have described two routes to model
systems of the densely oxygenated ABCD portion,2 while
O
Me
N
O
C
O
OH
D
A
B
O
F
O
MeO
O
E
2. Results and discussion
OH
RO
2.1. The benzyne cycloaddition strategy
O
Me
OH
1: R =
2: R =
Initially, we sought to synthesize the lactonamycin CDEF
ring system 3 by formation of the hydroquinone ring C using
a double Friedel–Crafts acylation of naphthol 5 using suc-
cinic anhydride 4 (Scheme 1). In turn, naphthalene 5 should
be available using a [4+2] cycloaddition reaction of the
aryne derived from iodo-triflate 7 and the diene 6,8 and sub-
sequent aromatization.9 Whilst the regioselectivity of the
cycloaddition reaction could be problematical, the use of
symmetrical dienes to replace 6 and ring D manipulation
was considered as a fall back option. Finally, iodo-triflate
OH
O
Me
HO
Figure 1. Structures of lactonamycin (1) and lactonamycin-Z (2).
Keywords: Lactonamycin; Diels–Alder reaction; Benzyne; Suzuki cou-
pling; Butenolide; Friedel–Crafts reaction.
* Corresponding author. Tel.: +44 207 594 5766; fax: +44 207 594 5805;
e-mail: agmb@imperial.ac.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.004

R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
12253
7 should be available from imide 9 via reduction, iodination,
and triflation.
imide 9 from the hydrolysis of commercial 3,6-dihydroxy-
phthalonitrile13 and subsequent coupling with MeNH2 was
less efficient (25%) due to the poor solubility of the
intermediate phthalic acid and partial decarboxylation.14
Subsequent conversion to the benzyne precursor 7 proved
troublesome. Clemmensen reduction15 of imide 9 to lactam
8 proceeded in poor yield and the product was difficult to
purify. Attempted selective mono-tert-butyldimethylsilyl-
ation of hydroquinone 8 using excess lithium carbonate16
gave an intractable mixture, whereas silylation using
n-butyllithium or lithium hydride (1 equiv) gave the desired
mono-protected hydroquinone 13 (18%), diether 12 (28%),
and recovered hydroquinone 8 (30%). Finally, both iodin-
ation17 and bromination of phenol 13 were unsuccessful
giving mixtures of products. In the light of these difficulties
the approach was modified with a two-step imide reduc-
tion12b,18 and substrate benzylation to overcome the poor
reactivity and low solubility of hydroquinone 9. Sequential
sodium borohydride and triethylsilane–TFA18b,c reduction
of diether 14 gave lactam 16 (81%). We next sought to con-
vert the diether 16 into the corresponding phenol 19 for
regioselective ring halogenation. Selective mono-debenzyl-
ation using magnesium bromide19 gave phenol 17 (73%)
as the only isomer, the structure of which was established
by NOE analysis and X-ray crystal structure determination.
Methylationofphenol17anddebenzylation byhydrogenoly-
sis gave the methyl ether 19 (91% overall). Attempted
iodination or bromination of phenol 19 largely proved
unsatisfactory under diverse reaction conditions. However,
reaction with bromine in the presence of sodium acetate in
acetic acid20 gave the bromide 20 (52%), the structure of
which was established by X-ray crystal structure determi-
nation. Attempted conversion of the derived bromo-triflate
21 into the corresponding benzyne and trapping with
2-methoxyfuran9b,21 via bromine–lithium exchange using
Friedel-Crafts Acylations
OH OR
Me
N
F
O
C
D
E
Diels-Alder
OR
3
OH
[4 + 2] benzyne cycloaddition
Me
N
O
OH
+
+
O
O
O
OTBS
4
5
7
8
Me
N
OMe
OTMS
TfO
O
I
OTBS
6
Me
Me
O
N
N
HO
HO
O
O
OH
Scheme 1. Initial retrosynthetic analysis.
OH
9
Diels–Alder reaction of diene 1010 with N-methylmaleimide
11 and in situ aromatization gave imide 911 in excellent over-
all yield (92%) (Scheme 2).12 In contrast, the synthesis of
Me
N
OSiMe3
O
O
O
11
Et3N, ZnCl2
Me3SiCl
Zn(Hg)
4
9
8
100 %
30%
92%
OSiMe3
10
Cs2CO3,
BnBr (92%)
n-BuLi or LiH,
t-BuMe2SiCl
OBn
OBn
t-BuMe2SiO
O
O
O
NaBH4
100%
NMe
NMe
NMe
O
X
OBn
OBn
RO
15 (X = OH)
16 (X = H)
14
12 R = t-BuMe2Si (28%)
13 R = H (18%)
Et3SiH, TFA
81%
OR
O
OMe
OR
O
.
MgBr2 Et2O
H2, Pd/C
100%
NMe
NMe
73%
X
OBn
17 (R = H)
18 (R = Me)
19 (R = X = H)
20 (R = H, X = Br)
21 (R = Tf, X = Br)
MeI, K2CO3
91%
Br2, NaOAc 52%
Tf2O, Et3N 55%
Scheme 2. Synthesis of imide 9 and derivatization to benzyne precursor 21.

12254
R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
n- or tert-butyllithium in THF, diethyl ether, or hexane at
ꢀ78 or ꢀ100 ꢁC gave only intractable mixtures of products.
Consequently, the benzyne strategy in Scheme 1 is aban-
doned.
conveniently carried out using only 1 equiv of lithium di-
iso-propylamide and with inverse addition to suppress the
formation of the diselenide 30. Selenide oxidation with hy-
drogen peroxide in the presence of pyridine gave the unsat-
urated g-lactam 32 in good overall yield. Bromobutenolide
34 was readily prepared from tetronic acid 33 using oxalyl
bromide (81%).29
2.2. The palladium coupling and Friedel–Crafts
cyclization strategies
O
O
Our attention was next directed toward an approach whereby
the carbon framework of the lactonamycin tetracyclic CDEF
ring system would be assembled using either a sequential
Michael addition or a palladium coupling reaction and
subsequent Friedel–Crafts hydroxyalkylation (Fig. 2). The
naphthalene partners 27 and 28 were prepared by the
methods in Scheme 3 using a benzyne–furan cycloaddition
reaction to provide naphthalene 2522 and regioselective
ortho-bromination.23,24 The substitution pattern of bromide
26 was defined by NMR experiments, and confirmed by
X-ray crystal structure determination. Boronic acid 28 was
readily prepared from bromide 27 by sequential bromine–
lithium exchange at ꢀ78 ꢁC to furnish the corresponding
insoluble lithio-derivative, condensation with B(OiPr)3,
and subsequent hydrolysis.
PhSe
PhSe
LDA;
N
Boc
N Boc
PhSeBr
30 (42%)
29
LDA; addition
to PhSeBr
O
O
PhSe
H2O2, C5H5N
N
Boc
N Boc
31 (68%)
32 (69%)
O
O
O
(COBr)2, DMF
O
HO
Br
33
34 (81%)
Me
Scheme 4. Synthesis of the pyrrolinone and furanone coupling partners.
N
F
MeO
OMe
D
O
Unfortunately, attempted conversion of the bromide 27, via
the corresponding Grignard reagent or aryllithium, to a
cuprate, and addition to the simple Michael acceptor
2-cyclohexenone or to lactam 32 proved to be unsuccessful,
probably on account of proton transfer to the naphthyl
carbanion.30 In contrast, the Suzuki coupling reaction31 of
the boronic acid 28 and the bromide 34 smoothly provided
the adduct 35 (Scheme 5). Reaction of the butenolide 35
with methylamine followed by reaction with hydrogen
chloride in dioxane readily provided lactam 36, which was
presumably formed via reversible ring opening and an
imine–enamine tautomerization.32 In order to introduce the
last carbon fragment a to the carbonyl of lactam 36, an
enol boration and aldol reaction sequence were examined.
Thus, lactam 36 was converted into the aldol adduct 37
(65%) by sequential reaction with dibutylboron triflate, tri-
ethylamine, and dimethoxyacetaldehyde. Such a process,
which presumably proceeds via the 2-(dibutylboryloxy)-
pyrrole, has indirect precedent in aldol reactions of esters
and enoates,33 or with amides using dicyclohexylboron
iodide,34 although has not been applied to functionalize
the unsaturated amides before.
1,4-conjugate addition or
E
C
palladium catalyzed coupling
OR
22
MeO
Benzyne Cycloaddition Friedel-Crafts hydroxyalkylation
Figure 2. Summary of the conjugate addition and Friedel–Crafts reaction
approach.
OMe
OMe
OMe OR
OMe
Br
X
furan,
NaNH2
HCl
O
OMe
OMe
23
24
25 R = H, X = H (93%)
Br2
K2CO3, MeI
26 R = H, X = Br (84%)
27 R = Me, X = Br (94%)
28 R = Me, X = B(OH)2 (92%)
n-BuLi; B(Oi-Pr)3; HCl, H2O
Scheme 3. Synthesis of naphthalene 28.
We planned to introduce the pyrrolinone unit 1) by Michael
addition of organometallic reagents derived from bromide
27 to a 2-pyrrolinone derivative 2) or by palladium-catalyzed
coupling of 28 with a related 4-bromo-2-pyrrolinone or a
synthetic equivalent. Although such Michael addition reac-
tions have indirect literature precedent, attempted additions
to N-alkyl-2-pyrrolinones have been reported to be fruit-
less.25 Not surprisingly, the presence of an electron-with-
drawing group on the nitrogen appears to substantially
increase the potency of the Michael acceptor.25,26 Thus, car-
bamate 32 (Scheme 4) was selected as the Michael acceptor
to be prepared by a selenoxide elimination reaction27 and
furanone 34 to explore the complimentary palladium cou-
pling reaction. In contrast to the Zoretic and Soja results,28
the conversion of lactam 29 into the selenide 31 was most
Attempted cyclizations of the acetal 37 to produce the corre-
sponding anthracene 43 or an equivalent system using
diverse Brønsted and Lewis acid catalysts at ꢀ78 to 120 ꢁC
gave only intractable mixtures of products. We reasoned
that these failures resulted from deactivation of the
nucleophilicity of the naphthalene unit by the electron-
withdrawing pyrrolinone carbonyl. The conversion of pyr-
rolinone 37 to a silyloxypyrrole was expected to not only
alleviate this deactivation, but also incorporates an additional
electron-donating substituent onto the naphthalene ring,
ortho to the site of cyclization. Thus, the pyrrolinone 37
was converted into the pyrrole 38 by reaction with tert-
€
butyldimethylsilyl triflate and Hunig’s base. Subsequent
35

R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
12255
Me
N
O
OMe OMe
OMe
OMe OMe
O
Pd2(dba)3, KF,
P(t-Bu)3 or
PdCl2(PPh3)2
2 M KF, H2O
O
NH2Me;
HCl
28 + 34
OMe
35 (91%)
36 (76%)
Me
N
Me
N
OMe OMe
OMe OMe
O
OTBS
Mg,
MeOH
Et3N, Bu2BOTf;
(MeO)2CHCHO;
H2O2
t-BuMe2SiOTf
i-Pr2NEt;
OH
OMe
OTBS
OMe
38
MeO
OMe
MeO
OMe
37 (65%)
Me
N
Me
N
OMe OMe
OMe OMe
O
O
ZnBr2
iso-Pr2NLi,
(MeO)2CHCO2Me
OMe
OMe
OMe
39 (32%)
40 (93%)
Me
Me
N
N
OMe OMe
OMe OMe
O
O
iso-Pr2NLi, AcCl
H
O
OAc
MeO
OMe
MeO
OMe
OMe
OMe
41 (69%)
42 (40%)
Me
N
OMe OMe
O
OH
OMe
43
Scheme 5. Synthesis and cyclization of lactam 36.
reaction with zinc bromide gave an unstable adduct tenta-
tively assigned as the anthracene 39,36 which presumably
arose via the desired Friedel–Crafts methoxy alkylation and
loss of water or silanol by an E1 process via the pyrrole-
stabilized carbenium ion. As an alternative possible route
to the desired anthracene, pyrrolinone 36 was reduced using
magnesium in methanol (93%)37 and the resulting g-lactam
40 was converted into the keto-lactam 41 (69%) by a crossed
Claisencondensationreaction.38 Acetal41wasconvertedinto
the Z-enol acetate 42 (40%) by deprotonation with lithium
di-iso-propylamide and O-acylation with acetyl chloride.39
The geometry of the enol acetate 42 was confirmed as Z by
an NOESY experiment. Frustratingly, attempted cyclization
of either keto-ester 41 or the enol acetate 42 under acidic or
Lewis acid condition gave complex mixtures of products.
gave the naphthyl lactam 36. Attempted conversion into
the CDEF unit of the antibacterial natural product lactona-
mycin using an aldol reaction with dimethoxyacetaldehyde
and Friedel–Crafts hydroxy alkylation gave the isomeric
anthracene lactam 39 rather than the required tetracycle 43.
4. Experimentaly
4.1. 4,7-Dihydroxy-2-methyl-2,3-dihydro-1,3-isoindole-
dione (9)
(a) 3,6-Dihydroxyphthalonitrile (3.00 g, 18.7 mmol) and
KOH (19.0 g, 339 mmol) in H2O (19 mL) were heated at
reflux for 3 h (Ar). After cooling to 0 ꢁC, the mixture was
acidified with 30% H2SO4 and extracted with EtOAc
(15ꢂ75 mL). The combined organic extracts were dried
(MgSO4), filtered, and rotary evaporated. The residue was
3. Conclusion
y
The Suzuki coupling of boronic acid 28 with the bromo-
butenolide 34 and subsequent reaction with methylamine
General experimental conditions and additional experiments are available
in Supplementary data.

12256
R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
dried over large quantities of P4O10 under vacuum to yield
3,6-dihydroxyphthalic acid (3.59 g) as an off-white solid,
4.3. 7-tert-(Butyldimethylsilyloxy)-4-hydroxy-2-methyl-
2,3-dihydro-1-isoindolone (13)
1
which was used directly without further purification: H
NMR (270 MHz, DMSO-d6) d 7.01 (s, 1H), 14.43 (s, 1H);
(a) A suspension of hydroquinone 8 (303 mg, 1.69 mmol) in
THF (12 mL) was heated at reflux for 10 min. After cooling
to ꢀ78 ꢁC, n-BuLi (2.5 M in hexanes; 744 mL, 1.86 mmol)
was added dropwise and the solution was allowed to warm
to room temperature over 1 h. t-BuMe2SiCl (280 mg,
1.86 mmol) was added at ꢀ78 ꢁC and the solution was al-
lowed to warm to room temperature overnight. After rotary
evaporation, the residue was partitioned between H2O
(15 mL) and EtOAc (15 mL), the layers were separated,
and the aqueous phase was further extracted with EtOAc
(4ꢂ15 mL). The combined organic extracts were washed
with brine, dried (MgSO4), filtered, and rotary evaporated.
Chromatography (EtOAc/hexanes, 3:7) gave the disilylated
hydroquinone 12 (193 mg, 28%) and the desired mono-
silylated hydroquinone 13 (89 mg, 18%) as white solids.
13C NMR (75 MHz, DMSO-d6) d 173.7, 156.5, 124.7,
ꢃ
113.9; m/z (EI) 198 (M+ ); m/z (HRMS) (EI) calcd for
ꢃ
C8H6O6 (M+ ): 198.0164; found: 198.0159. The crude di-
hydroxyphthalic acid (3.59 g) and MeNH2 (2.0 M in THF;
18.7 mL, 37.5 mmol) in THF (45 mL) were stirred at room
temperature for 1.5 h, heated at reflux for 1.5 h, after which
time DCC (3.87 g, 18.7 mmol) was added at room tempera-
ture. The mixture was stirred overnight, heated at reflux for
10 h, and cooled. Dicyclohexylurea was filtered off and the
filtrate was dried (MgSO4), filtered, and rotary evaporated.
The yellow solid was recrystallized from MeOH to give
imide 9 as yellow needles (905 mg, 25%).
(b) Diene 1010 (85.0 g, 350 mmol) and N-methylmaleimide
11 (43.0 g, 385 mmol) were stirred at 40 ꢁC for 72 h (Ar),
with small aliquots of CH2Cl2 added to enable stirring. After
cooling to 0 ꢁC, TFA (10 mL) was added dropwise and the
mixture was stirred for 45 min. The resultant solid was fil-
tered off and washed with cold EtOAc and Et2O to yield
imide 9 (61.7 g, 92%) as a yellow solid. Recrystallization
from MeOH gave imide 9 as yellow needles: Rf¼0.36
(EtOAc/hexanes, 1:1); mp >230 ꢁC (MeOH); IR (KBr
disc) 3440, 3334, 1741, 1680, 1643, 1450, 1383, 1302,
(b) LiH (18 mg, 2.23 mmol) was added portionwise to a sus-
pension of hydroquinone 8 (400 mg, 2.23 mmol) in DMF
(8 mL) at ꢀ78 ꢁC and the solution was allowed to warm to
room temperature over 1 h. t-BuMe2SiCl (336 mg,
2.23 mmol) was added at ꢀ78 ꢁC and the solution was al-
lowed to warm to room temperature overnight. After rotary
evaporation, the residue was partitioned between H2O
(15 mL) and EtOAc (20 mL), the layers were separated
and the aqueous phase was further extracted with EtOAc
(4ꢂ20 mL). The combined organic extracts were washed
with brine, dried (MgSO4), filtered, rotary evaporated, and
chromatographed (EtOAc/hexanes, 3:7) to give the disilyl-
ated hydroquinone 12 (245 mg, 27%) and the desired
mono-silylated hydroquinone 13 (98 mg, 15%) as white
solids. Ether 13: Rf¼0.21 (EtOAc/hexanes, 4:1); mp
>230 ꢁC (MeOH/hexanes); IR (KBr disc) 3139, 1660,
1
1002, 928 cmꢀ1; H NMR (270 MHz, DMSO-d6) d 2.91
(s, 3H), 7.04 (s, 2H), 10.15 (s, 2H); 13C NMR (75 MHz,
DMSO-d6) d 167.0, 148.3, 126.1, 114.7, 23.6; m/z (CI,
NH3) 211 (M+NH4)+, 194 (M+H)+; m/z (HRMS) (CI,
NH3) calcd for C9H8NO4 (M+H)+: 194.0453; found:
194.0450. Anal. Calcd for C9H7NO4: C, 55.96; H, 3.65; N,
7.25. Found: C, 56.10; H, 3.48; N, 7.26%.
4.2. 4,7-Dihydroxy-2-methyl-2,3-dihydro-1-isoindolone (8)
1600, 1500, 1459, 1271 cmꢀ1 1H NMR (270 MHz,
;
DMSO-d6) d 0.14 (s, 6H), 0.97 (s, 9H), 2.98 (s, 3H), 4.21
(s, 2H), 6.67 (d, 1H, J¼8.5 Hz), 6.83 (d, 1H, J¼8.5 Hz),
9.51 (br s, 1H); 13C NMR (75 MHz, DMSO-d6) d 166.7,
146.7, 145.1, 129.2, 123.3, 121.0, 119.1, 49.0, 29.3, 26.2,
18.6, ꢀ4.2; m/z (CI, NH3) 294 (M+H)+; m/z (HRMS) (CI,
NH3) calcd for C15H24NO3Si (M+H)+: 294.1525; found:
294.1518. Anal. Calcd for C15H23NO3Si: C, 61.40; H,
7.90; N, 4.77. Found: C, 61.40; H, 7.88; N, 4.68%. Diether
12: Rf¼0.29 (EtOAc/hexanes, 1:9); mp 106–108 ꢁC (Et2O/
hexanes); IR (film) 1700, 1493, 1274, 1251, 1004,
Concd HCl (4.8 mL) was added to Zn powder (33.8 g,
518 mmol) and HgCl2 (2.81 g, 10.4 mmol) at 0 ꢁC. The mix-
ture was stirred for 5 min at room temperature before being
allowed to stand for 15 min. Concd HCl (52 mL), glacial
AcOH (35 mL), and phthalimide 9 (5.00 g, 25.9 mmol)
were successively added to the amalgam at 0 ꢁC. The mix-
ture was heated at reflux overnight, cooled to room tem-
perature, and filtered. After the addition of H2O (60 mL),
the mixture was extracted with EtOAc (6ꢂ100 mL) and
the combined organic extracts were rotary evaporated. The
residue was dissolved in saturated aqueous sodium EDTA
(50 mL) and the mixture was extracted with EtOAc
(8ꢂ80 mL). The combined organic extracts were dried
(MgSO4), filtered, rotary evaporated, and chromatographed
(EtOAc/hexanes, 5:1) to give lactam 8 (1.4 g, 30%) as
a white solid: Rf¼0.35 (EtOAc/hexanes, 7:3); mp 220 ꢁC
(dec) (MeOH); IR (KBr disc) 3458, 3409, 3141, 1658,
1
836 cmꢀ1; H NMR (270 MHz, CDCl3) d 0.19 (s, 6H),
0.21 (s, 6H), 0.99 (s, 9H), 1.03 (s, 9H), 3.11 (s, 3H), 4.16
(s, 2H), 6.67 (d, 1H, J¼9.0 Hz), 6.76 (d, 1H, J¼9.0 Hz);
13C NMR (67.5 MHz, CDCl3) d 167.4, 147.4, 144.3, 132.9,
123.6, 122.1, 120.9, 49.4, 29.3, 25.9, 25.7, 18.5, 18.1,
ꢀ4.2, ꢀ4.5; m/z (CI, NH3) 408 (M+H)+; m/z (HRMS) (CI,
NH3) calcd for C21H38NO3Si2 (M+H)+: 408.2390; found:
408.2383. Anal. Calcd for C21H37NO3Si2: C, 61.88; H,
9.16; N, 3.44. Found: C, 62.08; H, 9.26; N, 3.51%.
1614, 1477, 1456, 1296 cmꢀ1
;
1H NMR (270 MHz,
DMSO-d6) d 3.00 (s, 3H), 4.26 (s, 2H), 6.63 (d, 1H, J¼
8.5 Hz), 6.79 (d, 1H, J¼8.5 Hz), 8.68 (br s, 1H), 9.25 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d 168.4, 147.9,
145.1, 127.9, 119.9, 118.5, 115.9, 49.9, 29.1; m/z (CI, NH3)
197 (M+NH4)+, 180 (M+H)+; m/z (HRMS) (CI, NH3) calcd
for C9H10NO3 (M+H)+: 180.0661; found: 180.0651. Anal.
Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.19; H, 4.83; N, 7.68%.
4.4. 4,7-Di-(benzyloxy)-2-methyl-2,3-dihydro-1,3-iso-
indoledione (14)
Cs2CO3 (20.2 g, 62.1 mmol) was added to hydroquinone 9
(3.00 g, 15.5 mmol), PhCH2Br (9.3 mL, 77.7 mmol), and
KI (258 mg, 1.55 mmol) in DMF (25 mL). The mixture
was stirred at room temperature for 8 h, quenched with

R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
12257
iced H2O (50 mL), and extracted with EtOAc (5ꢂ50 mL).
The combined organic extracts were washed with brine,
dried (MgSO4), filtered, rotary evaporated, and chro-
matographed (CH2Cl2/hexanes, 3:1 to CH2Cl2) to give iso-
indolinedione 14 (5.35 g, 92%) as a pale yellow solid.
Recrystallization from MeOH yielded imide 14 as pale yel-
low needles: Rf¼0.15 (CH2Cl2); mp 155 ꢁC (MeOH); IR
13C NMR (75 MHz, CDCl3) d 167.2, 150.3, 147.7, 137.4,
136.7, 131.9, 128.7, 128.5, 128.2, 127.6, 127.4, 127.0,
122.7, 115.2, 114.8, 71.7, 70.5, 49.5, 29.4; m/z (CI, NH3)
736 (2M+NH4)+, 719 (2M+H)+, 360 (M+H)+; m/z (HRMS)
(CI, NH3) calcd for C23H22NO3 (M+H)+: 360.1600; found:
360.1596. Anal. Calcd for C23H21NO3: C, 76.86; H, 5.89;
N, 3.90. Found: C, 76.96; H, 5.97; N, 3.80%.
(film) 1689, 1500, 1453, 1265, 1058 cmꢀ1 1H NMR
;
(270 MHz, CDCl3) d 3.09 (s, 3H), 5.20 (s, 4H), 7.03 (s,
2H), 7.24–7.46 (m, 10H); 13C NMR (67.5 MHz, CDCl3)
d 166.5, 149.8, 136.3, 128.8, 128.1, 126.9, 122.3, 119.6,
4.7. 4-Benzyloxy-7-hydroxy-2-methyl-2,3-dihydro-1-
isoindolone (17)
ꢃ
71.4, 23.8; m/z (EI) 373 (M+ ); m/z (HRMS) (EI) calcd for
MgBr2$OEt2 (10.4 g, 40.1 mmol) was added portionwise to
diether 16 (13.1 g, 36.4 mmol) in PhMe (650 mL) and Et2O
(100 mL) at 75 ꢁC (Ar). The mixture was heated to reflux
overnight, cooled to 0 ꢁC, quenched with ice-cold HCl
(2 M, 250 mL), and diluted with EtOAc (400 mL). The
layers were separated and the aqueous phase was further
extracted with EtOAc (3ꢂ350 mL). The combined organic
extracts were washed with brine, dried (MgSO4), filtered,
and rotary evaporated to yield a white solid, which was
washed with hot hexanes and recrystallized from MeOH to
give phenol 17 (7.16 g, 73%) as white needles: Rf¼0.29
(Et2O/hexanes, 1:1); mp 127–129 ꢁC (MeOH); IR (film)
ꢃ
C23H19NO4 (M+ ): 373.1314; found: 373.1313. Anal. Calcd
for C23H19NO4: C, 73.98; H, 5.13; N, 3.75. Found: C, 74.01;
H, 4.99; N, 3.63%.
4.5. 4,7-Di-(benzyloxy)-3-hydroxy-2-methyl-2,3-
dihydro-1-isoindolone (15)
NaBH4 (172 mg, 4.54 mmol) was added portionwise to
imide 14 (113 mg, 0.30 mmol) in MeOH (2 mL) and
CHCl3 (3 mL) at 0 ꢁC. After 1 h and rotary evaporation, the
residue was partitioned between H2O (15 mL) and CH2Cl2
(15 mL). The layers were separated and the aqueous phase
was further extracted with CH2Cl2 (2ꢂ10 mL) and EtOAc
(10 mL). The combined organic extracts were washed with
brine, dried (MgSO4), filtered, rotary evaporated, and
chromatographed (EtOAc/CH2Cl2, 1:9 to 1:4) to give hy-
droxylactam 15 (114 mg, 100%) as a white solid. Recrystal-
lization from EtOAc gave lactam 15 as colorless prisms:
Rf¼0.26 (EtOAc/CH2Cl2, 1:4); mp 136–137 ꢁC (EtOAc);
3400, 1678, 1503, 1453, 1283, 1265 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 3.15 (s, 3H), 4.32 (s, 2H), 5.09 (s,
2H), 6.80 (d, 1H, J¼8.5 Hz), 6.97 (d, 1H, J¼8.5 Hz), 7.35–
7.41 (m, 5H), 8.14 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 169.9, 149.5, 146.6, 136.8, 128.8, 128.6, 128.2, 127.5,
118.1, 117.5, 115.0, 71.0, 50.6, 28.9; m/z (CI, NH3) 270
(M+H)+; m/z (HRMS) (CI, NH3) calcd for C16H16NO3
(M+H)+: 270.1130; found: 270.1130. Anal. Calcd for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.46;
H, 5.66; N, 5.13%. Crystal data for phenol 19:
C16H15NO3, M¼269.3, monoclinic, P21 (no. 14), a¼
1
IR (film) 3344, 1687, 1501, 1453, 1274, 1027 cmꢀ1; H
NMR (270 MHz, CDCl3) d 3.00 (s, 3H), 3.41 (d, 1H, J¼
9.0 Hz), 5.03 (s, 2H), 5.10 (s, 2H), 5.71 (d, 1H, J¼9.0 Hz),
6.74 (d, 1H, J¼9.0 Hz), 6.87 (d, 1H, J¼9.0 Hz), 7.21–7.48
(m, 10H); 13C NMR (67.5 MHz, CDCl3) d 165.8, 149.8,
148.5, 136.9, 136.6, 133.3, 128.7, 128.6, 128.1, 127.8,
127.3, 127.0, 120.1, 117.6, 116.8, 81.3, 71.5, 70.9, 26.2;
m/z (CI, NH3) 393 (M+NH4)+, 376 (M+H)+; m/z (HRMS)
(CI, NH3) calcd for C23H22NO4 (M+H)+: 376.1549; found:
376.1552. Anal. Calcd for C23H21NO4: C, 73.58; H, 5.64;
N, 3.73. Found: C, 73.67; H, 5.70; N, 3.70%.
ꢁ
˚
13.727(11), b¼6.873(4), c¼15.329(8) A, b¼108.97(5) ,
V¼1367.8(15) A , Z¼4, Dc¼1.308 g cmꢀ3, m(Cu Ka)¼
3
˚
0.74 mmꢀ1, T¼293 K, colorless platy needles; 2121 inde-
pendent measured reflections, F2 refinement, R1¼0.051,
wR2¼0.141, 1530 independent observed reflections ½jFoj >
4sðjFojÞ; 2q ꢄ 120ꢁꢅ, 175 parameters; for additional crys-
tal data and structure refinement, see Supplementary data.
4.8. 4-Benzyloxy-7-methoxy-2-methyl-2,3-dihydro-1-
isoindolone (18)
4.6. 4,7-Di-(benzyloxy)-2-methyl-2,3-dihydro-1-iso-
indolone (16)
Phenol 17 (11.3 g, 42.0 mmol), MeI (3.9 mL, 62.9 mmol),
and K2CO3 (8.70 g, 62.9 mmol) in Me2CO (210 mL) were
heated at reflux for 8 h. The mixture was rotary evaporated
and the residue was partitioned between H2O (250 mL)
and CH2Cl2 (250 mL). The layers were separated and the
aqueous phase was further extracted with CH2Cl2
(3ꢂ250 mL). The combined organic extracts were washed
with brine, dried (MgSO4), filtered, rotary evaporated, and
chromatographed (EtOAc/hexanes, 4:1) to give methyl ether
18 (10.8 g, 91%) as a white solid: Rf¼0.24 (EtOAc/hexanes,
4:1); mp 142–145 ꢁC (CH2Cl2); IR (film) 1688, 1502, 1263,
1062 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 3.15 (s, 3H), 3.93
(s, 3H), 4.29 (s, 2H), 5.11 (s, 2H), 6.82 (d, 1H, J¼9.0 Hz),
6.99 (d, 1H, J¼9.0 Hz), 7.33–7.43 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 167.3, 151.4, 147.2, 136.8, 132.0,
128.6, 128.1, 127.3, 121.5, 115.3, 111.2, 70.6, 56.3, 49.4,
29.4; m/z (CI, NH3) 284 (M+H)+; m/z (HRMS) (CI, NH3)
calcd for C17H18NO3 (M+H)+: 284.1287; found: 284.1288.
TFA (70 mL) and Et3SiH (17.2 mL, 108 mmol) were added
with stirring sequentially to hydroxylactam 15 (27.0 g,
71.9 mmol) in CH2Cl2 (70 mL) at 0 ꢁC. After stirring for
15 min, the resulting colorless solution was rotary evapo-
rated and the residue was partitioned between EtOAc
(250 mL) and saturated aqueous NaHCO3 (200 mL), and
the aqueous layer was further extracted with EtOAc
(3ꢂ200 mL). The combined organic extracts were washed
with brine, dried (MgSO4), filtered, rotary evaporated, and
chromatographed (CH2Cl2 to Et2O/CH2Cl2, 7:3) to give lac-
tam 16 (20.9 g, 81%) as a white solid. Recrystallization from
MeOH and Et2O gave lactam 16 as colorless crystals:
Rf¼0.32 (Et2O/CH2Cl2, 1:9); mp 116 ꢁC (MeOH/Et2O); IR
(film) 1690, 1500, 1453, 1265, 1058 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 3.18 (s, 3H), 4.31 (s, 2H), 5.09 (s,
2H), 5.23 (s, 2H), 6.83 (d, 1H, J¼9.0 Hz), 6.92 (d, 1H,
J¼9.0 Hz), 7.28–7.41 (m, 8H), 7.54 (d, 2H, J¼7.5 Hz);

12258
R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94.
Found: C, 71.97; H, 5.91; N, 4.82%.
(105 mL, 0.76 mmol) in CH2Cl2 (1 mL) at ꢀ78 ꢁC. The mix-
ture was allowed to warm to room temperature overnight and
rotary evaporated. The residue was partitioned between
saturated aqueous NaHCO3 (5 mL) and EtOAc (8 mL), the
layers were separated and the aqueous phase was further
extracted with EtOAc (2ꢂ8 mL). The combined organic
extracts were washed with brine, dried (MgSO4), filtered,
rotary evaporated, and chromatographed (EtOAc/hexanes,
4:1) to give triflate 21 (84 mg, 55%) as a white solid:
Rf¼0.41 (EtOAc); mp 156–159 ꢁC (MeOH); IR (film)
4.9. 4-Hydroxy-7-methoxy-2-methyl-2,3-dihydro-1-iso-
indolone (19)
Benzyl ether 18 (9.70 g, 34.2 mmol) and 10% Pd/C (0.97 g,
10% w/w) in MeOH (50 mL) and EtOAc (50 mL) were
stirred overnight under H2 (atmospheric pressure), filtered
through a pad of CeliteÒ, and rotary evaporated. The residue
was chromatographed (CH2Cl2 to MeOH/CH2Cl2, 1:19) to
give phenol 19 (6.59 g, 100%) as a white solid. Recrystalli-
zation from MeOH yielded phenol 19 as white crystals:
Rf¼0.14 (EtOAc); mp >230 ꢁC (MeOH); IR (KBr disc)
3172, 1662, 1612, 1502, 1427, 1267, 1061 cmꢀ1; 1H NMR
(300 MHz, DMSO-d6) d 2.98 (s, 3H), 3.75 (s, 3H), 4.23 (s,
2H), 6.83 (d, 1H, J¼8.5 Hz), 6.89 (d, 1H, J¼8.5 Hz), 9.47
(br s, 1H); 13C NMR (75 MHz, DMSO-d6) d 166.7, 150.1,
146.2, 130.0, 121.1, 118.9, 113.0, 56.6, 49.1, 29.3; m/z
(CI, NH3) 194 (M+H)+; m/z (HRMS) (CI, NH3) calcd for
C10H12NO3 (M+H)+: 194.0817; found: 194.0817. Anal.
Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found:
C, 62.28; H, 5.64; N, 7.14%.
1
1700, 1476, 1424, 1214, 1136 cmꢀ1; H NMR (300 MHz,
CDCl3) d 3.15 (s, 3H), 3.99 (s, 3H), 4.45 (s, 2H), 7.18 (s,
1H); 13C NMR (75 MHz, CDCl3) d 165.1, 156.4, 137.4,
134.2, 121.8, 120.6, 118.5 (q, JC–F¼321 Hz), 116.8, 56.8,
49.4, 29.4; m/z (CI, NH3) 406, 404 (M+H)+; m/z (HRMS)
(CI, NH3) calcd for C11H1081BrF3NO5S (M+H)+:
405.9395; found: 405.9392; calcd for C11H1079BrF3NO5S
(M+H)+: 403.9415; found: 403.9419.
4.12. 2-Bromo-5,8-dimethoxy-1-naphthol (26)24
(a) A freshly prepared solution of Br2 in CH2Cl2 (1.0 M,
18.4 mL, 18.4 mmol) was added dropwise to naphthol
2522,41 (3.60 g, 17.5 mmol) in CH2Cl2 (170 mL) at ꢀ78 ꢁC.
After stirring for 30 min, the mixture was allowed to warm
to room temperature, stirred for a further 30 min, and poured
into ice-cold saturated aqueous NaHCO3 (250 mL). The
phases were separated, the aqueous portion was further
extracted with CH2Cl2, the combined organic extracts were
washed with brine, dried (MgSO4), filtered, rotary evapo-
rated, and chromatographed (Et2O/hexanes, 1:9 to 3:7) to
give bromonaphthol 26 (4.21 g, 84%) as a white solid.
4.10. 5-Bromo-4-hydroxy-7-methoxy-2-methyl-2,3-
dihydro-1-isoindolone (20)
Br2 (117 mL, 2.28 mmol) in glacial AcOH (0.5 mL) was
added dropwise to phenol 19 (400 mg, 2.07 mmol) and
NaOAc$3H2O (620 mg, 4.55 mmol) in glacial AcOH
(2.4 mL). After stirring at room temperature for 30 min, satu-
rated aqueous Na2S2O5 (15 mL) was added and the mixture
was extracted successively with CH2Cl2 (15 mL) and EtOAc
(4ꢂ15 mL). The combined organic extracts were dried
(MgSO4), filtered, rotary evaporated, and chromatographed
(MeOH/CH2Cl2, 3:97) to give bromide 20 (295 mg, 52%) as
a white solid. Recrystallization from MeOH yielded bromide
20 as white needles: Rf¼0.18 (EtOAc); mp >230 ꢁC
(MeOH); IR (KBr disc) 3467, 1662, 1591, 1500, 1456,
(b) NBS (6.72 g, 37.7 mmol) in MeCN (75 mL) was added
dropwise to naphthol 2522,40 (7.00 g, 34.3 mmol) in MeCN
(100 mL) at ꢀ20 ꢁC. After stirring at ꢀ20 ꢁC for 1 h, the
mixture was rotary evaporated and the residual solid was dis-
solved in CH2Cl2. The solution was washed with brine, dried
(MgSO4), filtered, rotary evaporated, and chromatographed
(Et2O/hexanes, 1:9 to 3:7) to give bromonaphthol 26
(6.33 g, 65%) as a white solid. Recrystallization from Et2O
and hexanes yielded bromide 26 as transparent plates:
Rf¼0.28 (EtOAc/hexanes, 1:4); mp 135 ꢁC (Et2O/hexanes);
1404, 1365, 1298, 1219, 1101, 1068 cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6) d 2.98 (s, 3H), 3.78 (s, 3H), 4.30 (s,
2H), 7.15 (s, 1H), 9.63 (br s, 1H); 13C NMR (75 MHz,
DMSO-d6) d 165.9, 150.4, 142.9, 131.9, 120.7, 116.3, 114.6,
56.8, 49.7, 29.3; m/z (CI, NH3) 274, 272 (M+H)+; m/z
(HRMS) (CI, NH3) calcd for C10H1181BrNO3 (M+H)+:
273.9902; found: 273.9903; calcd for C10H1179BrNO3
(M+H)+: 271.9922; found: 271.9921. Anal. Calcd for
C10H10BrNO3: C, 44.14; H, 3.70; N, 5.15. Found: C, 44.26;
H,3.78;N, 5.06%.Crystaldataforbromide27:C10H10BrNO3,
IR (film) 3332, 1610, 1390, 1253, 1126, 1088, 1051 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 3.93 (s, 3H), 4.02 (s, 3H),
6.66 (d, 1H, J¼8.5 Hz), 6.72 (d, 1H, J¼8.5 Hz), 7.55 (d,
1H, J¼9.0 Hz), 7.60 (d, 1H, J¼9.0 Hz), 10.18 (s, 1H); 13C
NMR (100 MHz, CDCl3) d 150.5, 150.3, 149.1, 130.8,
127.2, 116.1, 114.2, 105.5, 104.7, 103.4, 56.6, 55.7; m/z
(CI, NH3) 302, 300 (M+NH4)+, 285, 283 (M+H)+; m/z
(HRMS) (CI, NH3) calcd for C12H1281BrO3 (M+H)+:
284.9949; found: 284.9939; calcd for C12H1279BrO3
(M+H)+: 282.9970; found: 282.9963. Anal. Calcd for
C12H11BrO3: C, 50.91; H, 3.92. Found: C, 51.19; H,
4.03%. Crystal data for bromide 26: C12H11BrO3,
M¼272.1, monoclinic, P21 (no. 15), a¼12.273(16), b¼
3
ꢁ
˚
˚
10.084(17), c¼17.528(4) A, b¼102.95(13) , V¼2114.1(7) A ,
Z¼8, Dc¼1.710 g cmꢀ3, m(Cu Ka)¼5.22 mmꢀ1, T¼293 K,
colorless platy needles; 1514 independent measured reflec-
tions, F2 refinement, R1¼0.064, wR2¼0.167, 1034 indepen-
dent observed absorption corrected reflections ½jFoj >
4sðjFojÞ; 2q ꢄ 120ꢁꢅ, 147 parameters; for additional crystal
data and structure refinement, see Supplementary data.
M¼283.1, orthorhombic, P21 (no. 61), a¼6.032(13),
3
˚
˚
b¼15.959(4), c¼23.569(3) A, V¼2268.8(8) A , Z¼8,
Dc¼1.658 g cmꢀ3, m(Cu Ka)¼4.86 mmꢀ1, T¼293 K, color-
less plates; 1673 independent measured reflections, F2
refinement, R1¼0.075, wR2¼0.200, 1214 independent ob-
served absorption corrected reflections ½jFoj > 4sðjFojÞ;
2q ꢄ 126ꢁꢅ, 150 parameters; for additional crystal data and
structure refinement, see Supplementary data.
4.11. 5-Bromo-7-methoxy-2-methyl-1-oxo-2,3-dihydro-
1H-4-isoindolyl trifluoromethanesulfonate (21)
(CF3SO2)2O (96 mL, 0.57 mmol) was added dropwise to
phenol 20 (103 mg, 0.38 mmol) and freshly distilled Et3N

R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
12259
4.13. 2-Bromo-1,5,8-trimethoxynaphthalene (27)
for 1.5 h before being transferred dropwise to PhSeBr
(402 mg, 1.70 mmol) in THF (4 mL) at ꢀ78 ꢁC (Ar). After stir-
ring at ꢀ78 ꢁC for 15 min, saturated aqueous NH4Cl (10 mL)
was added, the layers were separated and the aqueous phase
was further extracted with CH2Cl2 (2ꢂ15 mL). The combined
organic extracts were washed with brine, dried (MgSO4), fil-
tered, rotary evaporated, and chromatographed (Et2O/hexanes,
1:9) to give the selenide 31 (375 mg, 68%) as a white solid: 1H
NMR (300 MHz, CDCl3) d 1.47 (s, 9H), 1.98–2.08 (m, 1H),
2.37–2.50 (m, 1H), 3.32–3.41 (m, 1H), 3.55–3.62 (m, 1H),
3.89–3.93 (m, 1H), 7.24–7.33 (m, 3H), 7.64 (d, 2H,
J¼7.0 Hz); m/z (CI, NH3) 700 (2M[80Se78Se]+NH4)+, 359,
357 (M+NH4)+, 342, 340 (M+H)+; m/z (HRMS) (CI, NH3)
calcd for C15H23N2O380Se (M+NH4)+: 359.0874; found:
359.0877; calcd for C15H23N2O378Se (M+NH4)+: 357.0882;
found: 357.0890. Direct addition of PhSeBr to the lactam eno-
late gave an adduct that was tentatively assigned as the corre-
sponding diselenide 30. n-BuLi (2.5 M in hexanes; 7.3 mL,
18.3 mmol) was added dropwise with stirring to freshly dis-
tilled i-Pr2NH (2.6 mL, 18.3 mmol) in THF (40 mL) at 0 ꢁC
(Ar). After 30 min, the solution was cooled to ꢀ78 ꢁC and
transferred dropwise with stirring via cannula to pyrrolidinone
29 (3.22 g, 17.4 mmol) in THF (40 mL) at ꢀ78 ꢁC (Ar). After
1.5 h, PhSeBr (4.31 g, 18.3 mmol) in THF (40 mL) was added
dropwise with stirring via cannula at ꢀ78 ꢁC. After 3 h, satu-
rated aqueous NH4Cl (120 mL) was added, the layers were
separated, and the aqueous phase was further extracted with
CH2Cl2 (2ꢂ100 mL). The combined organic extracts were
washed with brine, dried (MgSO4), filtered, rotary evaporated,
and chromatographed (hexanes) to give an adduct that was ten-
tatively assigned as the pyrrolidinone 30(3.6 g, 42%) as a white
solid: 1H NMR (300 MHz, CDCl3) d 1.51 (s, 9H), 2.24 (t, 2H,
J¼7.0 Hz), 3.29 (t, 2H, J¼7.0 Hz), 7.31–7.43 (m, 6H), 7.73 (d,
4H, J¼7.5 Hz).
Naphthol 26 (5.50 g, 19.4 mmol), Cs2CO3 (12.7 g,
38.9 mmol), and MeI (3.6 mL, 58.3 mmol) in Me2CO
(25 mL) were heated at reflux overnight. The mixture was
rotary evaporated, the residual solid was partitioned between
EtOAc (100 mL) and H2O (100 mL), the layers were sepa-
rated, and the aqueous phase was further extracted with
EtOAc (2ꢂ100 mL). The combined organic extracts were
washed with brine, dried (MgSO4), filtered, rotary evapo-
rated, and chromatographed (CH2Cl2/hexanes, 3:7) to give
trimethoxynaphthalene 27 (5.43 g, 94%) as a white solid:
Rf¼0.44 (EtOAc/hexanes, 1:4); mp 67–69 ꢁC (CH2Cl2/
hexanes); IR (film) 1617, 1578, 1456, 1406, 1343, 1259,
1
1094, 1056 cmꢀ1; H NMR (300 MHz, CDCl3) d 3.91 (s,
3H), 3.96 (s, 6H), 6.75 (d, 1H, J¼8.5 Hz), 6.84 (d, 1H, J¼
8.5 Hz), 7.62 (d, 1H, J¼9.0 Hz), 7.93 (d, 1H, J¼9.0 Hz);
13C NMR (75 MHz, CDCl3) d 152.8, 149.8, 149.3, 130.0,
128.0, 122.3, 119.6, 116.3, 107.6, 104.3, 61.8, 57.2, 55.8;
m/z (CI, NH3) 316, 314 (M+NH4)+, 299, 297 (M+H)+; m/z
(HRMS) (CI, NH3) calcd for C13H1781BrNO3 (M+NH4)+:
316.0371; found: 316.0372; calcd for C13H1779BrNO3
(M+NH4)+: 314.0392; found: 314.0397. Anal. Calcd for
C13H13BrO3: C, 52.55; H, 4.41. Found: C, 52.62; H, 4.35%.
4.14. 1,5,8-Trimethoxy-2-naphthaleneboronic acid (28)
n-BuLi (2.5 M in hexanes; 1.75 mL, 4.38 mmol) was added
dropwise to bromonaphthalene 27 (1.00 g, 3.37 mmol) in
THF (25 mL) at ꢀ78 ꢁC. After 5 min, triisopropyl borate
(1.01 mL, 4.38 mmol) was added dropwise with stirring.
After 30 min at ꢀ78 ꢁC, the solution was allowed to warm
to room temperature and after 1 h, 10% aqueous HCl
(20 mL) was added and the mixture was vigorously stirred
for 45 min. The layers were separated and the aqueous phase
was further extracted with EtOAc (4ꢂ20 mL). The combined
organic extracts were washed with brine, dried (MgSO4),
filtered, rotary evaporated, and chromatographed (EtOAc/
hexanes, 1:4 to 2:3) to give boronic acid 28 (811 mg, 92%)
as a white solid: Rf¼0.41 (EtOAc/hexanes, 1:1); mp 128–
132 ꢁC (EtOAc/hexanes); IR (film) 3430, 1620, 1575,
4.16. tert-Butyl 2-oxo-2,5-dihydro-1H-1-pyrrolecarb-
oxylate (32)
Pyridine (108 mL, 1.33 mmol) and aqueous H2O2 (35% w/w,
329 mL, 3.99 mmol) were successively added to selenide 31
(227 mg, 0.67 mmol) in CH2Cl2 (7.4 mL) at ꢀ78 ꢁC and the
mixture was allowed to warm to room temperature over 2 h.
Saturated aqueous NH4Cl (5 mL) was added, the layers were
separated, and the organic phase was washed with aqueous
HCl (1 M, 5 mL) and brine, dried (MgSO4), filtered, rotary
evaporated, and chromatographed (Et2O/hexanes, 1:3) to
give lactam 32 (84 mg, 69%) as a white solid: Rf ¼0.29
(EtOAc/hexanes, 1:1); IR (film) 1774, 1739, 1718, 1359,
1503, 1462, 1380, 1358, 1259, 1100, 1060, 729 cmꢀ1; H
1
NMR (300 MHz, CDCl3) d 3.92 (s, 3H), 3.98 (s, 3H), 4.01
(s, 3H), 6.68 (br s, 2H), 6.82 (s, 2H), 7.91 (d, 1H, J¼
8.5 Hz), 8.10 (d, 1H, J¼8.5 Hz); 13C NMR (75 MHz,
CDCl3) d 163.4, 149.8, 149.6, 131.5, 131.1, 119.7, 118.4,
106.0, 105.3, 64.0, 56.6, 55.9; m/z (CI, NH3) 280
(M+NH4)+, 263 (M+H)+. Anal. Calcd for C13H15BO5: C,
59.58; H, 5.77. Found: C, 59.60; H, 5.79%. It was found to
be essential to add the triisopropyl borate only 5 min after
the addition of n-BuLi. Failure to do so gave the reduced
1,4,8-trimethoxynaphthalene30a,41 as by-product, the amount
of which increased on extending the metalation period.
1321, 1296, 1161 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d 1.58 (s, 9H), 4.37 (d, 2H, J¼2.0 Hz), 6.17–6.20 (m, 1H),
7.19–7.21 (m, 1H); 13C NMR (75 MHz, CDCl3) d 169.1,
149.6, 145.1, 128.0, 83.0, 51.6, 28.1; m/z (CI, NH3) 201
(M+NH4)+, 184 (M+H)+; m/z (HRMS) (CI, NH3) calcd for
C9H14NO3 (M+H)+: 184.0974; found: 184.0974.
4.15. tert-Butyl 2-oxo-3-phenylselenenyl-1-pyrrolidine-
carboxylate (31)
4.17. 4-Bromo-5H-2-furanone (34)29
n-BuLi (2.5 M in hexanes; 648 mL, 1.62 mmol) was added
dropwise to freshly distilled i-Pr2NH (250 mL, 1.78 mmol) in
THF (5 mL) at 0 ꢁC (Ar). After stirring for 45 min at 0 ꢁC,
the solution was cooled to ꢀ78 ꢁC and transferred dropwise
to pyrrolidinone 2942 (300 mg, 1.62 mmol) in THF (5 mL) at
ꢀ78 ꢁC (Ar). The resulting solution was stirred at ꢀ78 ꢁC
Oxalyl bromide (10.0 mL, 108 mmol) was added dropwise
over 1 h to a suspension of tetronic acid (33) (9.00 g,
89.9 mmol) in CH2Cl2 (200 mL) and DMF (9 mL), while
carefully maintaining the reaction temperature at 0 ꢁC. The
yellow solution turned green and was stirred successively
at 0 ꢁC for 1 h and at room temperature for 2 h. H2O

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R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
(250 mL) was added, the layers were separated, and the aque-
ous phase was further extracted with Et2O (4ꢂ100 mL).
The combined organic extracts were washed successively
with H2O, saturated aqueous NaHCO3, and brine, dried
(MgSO4), filtered, and rotary evaporated. Recrystallization
of the residual solid from Et2O gave bromofuranone 34
(11.9 g, 81%) as white needles: Rf¼0.41 (EtOAc/hexanes,
7:3); mp 76–77 ꢁC (Et2O); IR (film) 1776, 1748, 1600,
atrefluxfor6 h. Aftercoolingtoroomtemperature, themixture
was diluted with EtOAc (100 mL), carefully washed with
saturated aqueous NaHCO3 (2ꢂ150 mL) and brine, dried
(MgSO4), filtered, rotary evaporated, and chromatographed
(EtOAc to MeOH/EtOAc, 1:19) to give pyrrolinone 36
(2.47 g, 76%) as a yellow solid. Recrystallization from EtOAc
yielded pyrrolinone 36 as yellow crystals: Rf¼0.16 (EtOAc);
mp 165–167 ꢁC (EtOAc); IR (film) 1678, 1452, 1414, 1367,
1
1264, 1154, 1014, 867 cmꢀ1; H NMR (300 MHz, CDCl3)
1350, 1260, 1111, 1074, 1035, 820, 800, 728 cmꢀ1 1H
;
d 4.84 (d, 2H, J¼1.5 Hz), 6.32 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 170.8, 146.3, 121.7, 74.9; m/z (CI, NH3) 182, 180
(M+NH4)+; m/z (HRMS) (CI, NH3) calcd for C4H781BrNO2
(M+NH4)+: 181.9640; found: 181.9635; calcd for
C4H779BrNO2 (M+NH4)+: 179.9660; found: 179.9665.
NMR (300 MHz, CDCl3) d 3.13 (s, 3H), 3.79 (s, 3H), 3.96
(s, 3H), 3.99 (s, 3H), 4.54 (s, 2H), 6.71 (s, 1H), 6.79 (d, 1H,
J¼8.5 Hz), 6.83 (d, 1H, J¼8.5 Hz), 7.46 (d, 1H, J¼9.0 Hz),
8.04 (d, 1H, J¼9.0 Hz); 13C NMR (75 MHz, CDCl3)
d 171.9, 155.4, 151.8, 150.2, 149.6, 129.3, 124.9, 124.2,
122.9, 120.9, 118.9, 106.7, 105.4, 62.3, 56.6 (2C), 55.9, 29.0;
m/z (CI, NH3) 627 (2M+H)+, 331 (M+NH4)+, 314 (M+H)+;
m/z (HRMS) (CI, NH3) calcd for C18H20NO4 (M+H)+:
314.1392; found: 314.1396. Anal. Calcd for C18H19NO4: C,
68.99; H, 6.11; N, 4.47. Found: C, 69.06; H, 6.13; N, 4.45%.
4.18. 4-(1,5,8-Trimethoxy-2-naphthyl)-5H-2-furanone (35)
(a) P(t-Bu)3 (3.6 mg, 0.018 mmol) was added to boronic acid
28 (135 mg, 0.52 mmol), bromofuranone 34 (80 mg,
0.49 mmol), Pd2(dba)3 (6.7 mg, 0.0074 mmol), and KF
(86 mg, 1.47 mmol) in Ar sparged THF (2 mL) (Ar). The
mixture was heated at 60 ꢁC for 6 h, after which time a fur-
ther amount of bromolactone 34 (80 mg, 0.49 mmol) was
added (80 mg, 0.49 mmol). The mixture was heated at
60 ꢁC for an additional 12 h, cooled to room temperature,
diluted with EtOAc (5 mL), and filtered through a pad of
CeliteÒ. The filtered residue was washed repeatedly with
EtOAc and the filtrate was rotary evaporated and chromato-
graphed (Et2O/hexanes, 1:1) to give furanone 35 (99 mg,
64%) as a yellow solid. Recrystallized from EtOAc and
hexanes yielded furanone 35 as bright yellow needles.
4.20. 3-(1-Hydroxy-2,2-dimethoxyethyl)-1-methyl-4-
(1,5,8-trimethoxy-2-naphthyl)-1,5-dihydro-2-pyrrolone
(37)
Bu2BOSO2CF3 (1.0 M in CH2Cl2; 1.76 mL, 1.76 mmol)
was added dropwise to pyrrolinone 36 (500 mg,
1.60 mmol) in anhydrous CH2Cl2 (8.5 mL) at ꢀ78 ꢁC. The
mixture was stirred for 5 min and freshly distilled Et3N
(267 mL, 1.91 mmol) was added dropwise. After stirring
for 1.5 h at ꢀ78 ꢁC, the solution was treated with freshly dis-
tilled anhydrous dimethoxyacetaldehyde43,44 (664 mg,
6.38 mmol) in one portion. The mixture was stirred for 2 h
at ꢀ78 ꢁC, diluted with EtOAc (25 mL), and washed with
saturated aqueous NH4Cl (10 mL). The aqueous phase was
further extracted with EtOAc (4ꢂ20 mL) and the combined
organic extracts were dried (MgSO4), filtered, rotary evapo-
rated, and chromatographed (CH2Cl2 then EtOAc) to give
acetal 37 as an oil. Et2O was added to the oil and evaporated
in vacuo at 40 ꢁC. The procedure was repeated three times to
give acetal 37 (434 mg, 65%) as an off-white foam: Rf¼0.11
(EtOAc); mp 105–108 ꢁC (EtOAc); IR (film) 3404, 2935,
(b) Boronic acid 28 (1.45 g, 5.53 mmol), bromofuranone 34
(1.17 g, 7.19 mmol), and PdCl2(PPh3)2 (78 mg, 0.11 mmol)
in aqueous KF (2 M, 15 mL) and THF (15 mL) were heated
at reflux for 5 h. After cooling to room temperature, the layers
were separated and the aqueous phase was further extracted
with EtOAc (4ꢂ25 mL). The combined organic extracts
werewashed with brine, dried (MgSO4), filtered, rotary evap-
orated, and chromatographed (Et2O/hexanes, 1:1) to givefur-
anone 35 (1.52 g, 91%) as a yellow solid. Recrystallization
from EtOAc and hexanes yielded furanone 35 as bright yel-
low needles: Rf¼0.18 (Et2O/hexanes, 1:1); mp 139–141 ꢁC
(EtOAc/hexanes); IR (film) 1746, 1603, 1572, 1455, 1417,
1671, 1452, 1414, 1261, 1072, 729 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 3.12 (s, 3H), 3.34 (s, 3H), 3.42 (s,
3H), 3.77 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 4.34 (d, 1H,
J¼20.0 Hz), 4.47–4.54 (m, 2H), 4.91 (d, 1H, J¼7.0 Hz),
6.79 (d, 1H, J¼8.5 Hz), 6.83 (d, 1H, J¼8.5 Hz), 7.53 (d,
1H, J¼8.5 Hz), 8.09 (d, 1H, J¼8.5 Hz); 13C NMR
(75 MHz, CDCl3) d 171.3, 154.2, 150.4, 150.0, 149.6,
132.0, 129.2, 127.6, 124.3, 120.9, 118.7, 106.2, 105.1,
104.8, 67.9, 62.6, 56.6, 55.9, 55.7 (2C), 54.1, 28.9; m/z
(CI, NH3) 418 (M+H)+; m/z (HRMS) (CI, NH3) calcd for
C22H28NO7 (M+H)+: 418.1866; found: 418.1847. Anal.
Calcd for C22H27NO7: C, 63.30; H, 6.52; N, 3.36. Found:
C, 63.12; H, 6.32; N, 3.23%.
1
1369, 1347, 1260, 1159, 1077, 1050, 730 cmꢀ1; H NMR
(300 MHz, CDCl3) d 3.83 (s, 3H), 3.98 (s, 3H), 4.00 (s,
3H), 5.42 (d, 2H, J¼1.5 Hz), 6.60 (s, 1H), 6.87 (s, 2H),
7.46 (d, 1H, J¼9.0 Hz), 8.07 (d, 1H, J¼9.0 Hz); 13C NMR
(75 MHz, CDCl3) d 174.4, 162.1, 156.6, 150.2, 149.5,
130.0, 124.4, 120.7, 120.6, 119.3, 115.6, 107.0, 106.4,
73.4, 62.9, 56.6, 56.0; m/z (CI, NH3) 318 (M+NH4)+, 301
(M+H)+; m/z (HRMS) (CI, NH3) calcd for C17H20NO5
(M+NH4)+: 318.1341; found: 318.1352. Anal. Calcd for
C17H16O5: C, 67.99; H, 5.37. Found: C, 67.98; H, 5.22%.
4.19. 1-Methyl-4-(1,5,8-trimethoxy-2-naphthyl)-1,5-di-
hydro-2-pyrrolone (36)
4.21. 5,7,10,11-Tetramethoxy-2-methyl-1,2-dihydro-
naphtho[2,3-e]isoindol-3-one (39)
Furanone35 (3.1 g, 10.3 mmol) and MeNH2 (2.0 M in MeOH;
31 mL, 61.9 mmol) were heated at 65 ꢁC for 3 h, and the
mixture was rotary evaporated and the residue was dissolved
in anhydrous dioxane (100 mL). HCl (4.0 M in dioxane;
7.7 mL, 31.0 mmol) was added and the mixture was heated
i-Pr2NEt (55 mL, 0.32 mmol) and TMSOTf (82 mL,
0.36 mmol) were successively added dropwise to acetal 37
(60 mg, 0.14 mmol) in anhydrous CH2Cl2 (6 mL) at
ꢀ78 ꢁC (Ar). The mixture was allowed to warm to room
temperature over 1 h, after which i-Pr2NEt (28 mL,

R. Le Veꢀzoue€t et al. / Tetrahedron 62 (2006) 12252–12263
12261
0.22 mmol) and t-BuMe2OSO2CF3 (49 mL, 0.22 mmol)
were successively added dropwise at 0 ꢁC. After stirring
for further 2 h at room temperature, anhydrous ZnBr2
(32 mg, 0.14 mmol) was added in one portion. The mixture
was stirred overnight at room temperature, diluted with
CH2Cl2 (6 mL) and H2O (8 mL), the layers were separated,
and the aqueous phase was further extracted with EtOAc
(3ꢂ8 mL). The combined organic extracts were dried
(MgSO4), filtered, and rotary evaporated. Preparative thin
layer chromatography (EtOAc) gave an unstable yellow
solid, tentatively assigned as the tetramethoxyanthracene
39 (17 mg, 32%), which decomposed within 36 h: 1H
NMR (300 MHz, CDCl3) d 3.33 (s, 3H), 3.99 (s, 3H), 4.07
(s, 6H), 4.15 (s, 3H), 4.95 (s, 2H), 6.72 (d, 1H, J¼8.0 Hz),
6.79 (d, 1H, J¼8.0 Hz), 7.28 (s, 1H), 9.13 (s, 1H); m/z
(ES+) 368 (M+H)+; m/z (ESꢀ) 366 (MꢀH).
with EtOAc (3ꢂ10 mL). The combined organic extracts
were washed with brine, dried (MgSO4), filtered, rotary
evaporated, and chromatographed (CH2Cl2 then EtOAc/
hexanes, 1:1 to 7:3) to give ketoacetal 41 (151 mg, 69%)
as an orange solid containing both diastereoisomers (1:9):
Rf¼0.30 (EtOAc/hexanes, 4:1); mp 125–127 ꢁC (EtOAc/
hexanes); IR (film) 2935, 1737, 1691, 1601, 1581, 1450,
1
1413, 1350, 1259, 1105, 1066, 1001, 800, 729 cmꢀ1; H
NMR (400 MHz, CDCl3) selected peaks for major isomer
d 2.88 (s, 3H), 3.26–3.30 (m, 1H), 3.27 (s, 3H), 3.34 (s,
3H), 3.79–3.84 (m, 1H), 3.81 (s, 3H), 3.92 (s, 3H), 3.93 (s,
3H), 4.45 (d, 1H, J¼8.5 Hz), 4.69–4.75 (m, 1H), 5.11 (s,
1H), 6.70 (d, 1H, J¼8.5 Hz), 6.77 (d, 1H, J¼8.5 Hz), 7.30
(d, 1H, J¼9.0 Hz), 8.03 (d, 1H, J¼9.0 Hz); 13C NMR
(100 MHz, CDCl3) selected peaks for major isomer
d 200.7, 169.0, 153.8, 149.4, 149.3, 130.5, 127.9, 123.9,
120.5, 119.0, 106.2, 103.9, 102.3, 63.0, 57.1, 56.4, 55.6,
55.0, 54.25, 54.20, 32.3, 29.7; m/z (CI, NH3) 418 (M+H)+;
m/z (HRMS) (CI, NH3) calcd for C22H28NO7 (M+H)+:
418.1866; found: 418.1855. Anal. Calcd for C22H27NO7:
C, 63.30; H, 6.52; N, 3.36. Found: C, 63.38; H, 6.67; N,
3.35%.
4.22. 1-Methyl-4-(1,5,8-trimethoxy-2-naphthyl)-2-
pyrrolidinone (40)
Mg turnings (419 mg, 17.2 mmol) were added to pyrroli-
none 36 (270 mg, 0.86 mmol) in MeOH (24 mL) at 0 ꢁC.
After stirring for 30 min at 0 ꢁC, a vigorous exothermic re-
action occurred. The mixture was successively stirred at
room temperature for 20 min and diluted with CH2Cl2
(25 mL) and saturated aqueous NH4Cl (20 mL). The layers
were separated and the aqueous phase was further extracted
with EtOAc (3ꢂ25 mL). The combined organic extracts
were washed with brine, dried (MgSO4), filtered, rotary
evaporated, and chromatographed (CH2Cl2/EtOAc gradient)
to give pyrrolidinone 40 (253 mg, 93%) as a yellow oil,
which crystallized upon standing: Rf¼0.17 (EtOAc); mp
87–89 ꢁC (EtOAc); IR (film) 1691, 1601, 1581, 1504,
4.24. (3-(Z)-1-Acetoxy-2,2-dimethoxyethylidene)-1-
methyl-4-(1,5,8-trimethoxy-2-naphthyl)-2-pyrrolidi-
none (42)
LDA (1.8 M in heptane, THF, and PhEt; 114 mL, 0.21 mmol)
was added dropwise to ketone 41 (78 mg, 0.19 mmol) in an-
hydrous THF (2 mL) at ꢀ78 ꢁC. After stirring at this temper-
ature for 1.5 h, freshly distilled AcCl (53 mL, 0.75 mmol)
was added dropwise and the mixture was allowed to warm
to room temperature overnight. EtOAc (8 mL) and H2O
(8 mL) were added, the layers were separated, and the aque-
ous phase was further extracted with EtOAc (3ꢂ8 mL). The
combined organic extracts were washed with brine, dried
(MgSO4), filtered, rotary evaporated, and chromatographed
(EtOAc) to give enol acetate 42 (34 mg, 40%) as a light am-
ber oil: Rf¼0.18 (EtOAc/hexanes, 4:1); 1H NMR (400 MHz,
CDCl3) d 2.35 (s, 3H), 2.89 (s, 3H), 2.94 (s, 3H), 3.20–3.23
(m, 1H), 3.21 (s, 3H), 3.90 (s, 3H), 3.94–3.99 (m, 1H), 3.95
(s, 3H), 3.99 (s, 3H), 4.62 (d, 1H, J¼0.5 Hz), 4.98 (dd, 1H,
J¼2.5, 8.5 Hz), 6.70 (d, 1H, J¼8.5 Hz), 6.77 (d, 1H, J¼
8.5 Hz), 7.30 (d, 1H, J¼9.0 Hz), 8.03 (d, 1H, J¼9.0 Hz);
13C NMR (100 MHz, CDCl3) d 168.9, 165.7, 152.7, 149.7,
149.3, 146.5, 134.2, 128.1, 125.3, 125.1, 120.6, 119.1,
106.1, 103.6, 100.2, 62.6, 56.6, 55.79, 55.76, 54.6, 54.2,
1452, 1414, 1349, 1261, 1105, 1065, 1003, 802, 730 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 2.60 (dd, 1H, J¼8.0,
17.0 Hz), 2.85 (dd, 1H, J¼9.5, 17.0 Hz), 2.92 (s, 3H), 3.42
(dd, 1H, J¼7.0, 10.0 Hz), 3.79 (dd, 1H, J¼8.5, 10.0 Hz),
3.80 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 4.24–4.33 (m, 1H),
6.72 (d, 1H, J¼8.5 Hz), 6.80 (d, 1H, J¼8.5 Hz), 7.36 (d,
1H, J¼9.0 Hz), 8.05 (d, 1H, J¼9.0 Hz); 13C NMR
(100 MHz, CDCl3) d 174.0, 153.4, 149.6, 149.5, 132.7,
127.8, 123.9, 120.6, 119.1, 106.3, 103.8, 63.0, 56.7, 56.6,
55.8, 38.7, 29.6, 29.4; m/z (CI, NH3) 631 (2M+H)+, 333
(M+NH4)+, 316 (M+H)+; m/z (HRMS) (CI, NH3) calcd for
C18H22NO4 (M+H)+: 316.1549; found: 316.1550. Anal.
Calcd for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found:
C, 68.73; H, 6.84; N, 4.52%.
ꢃ
33.2, 29.9, 20.9; m/z (EI) 459 (M+ ); m/z (HRMS) (EI) calcd
ꢃ
4.23. 3-(2,2-Dimethoxyacetyl)-1-methyl-4-(1,5,8-tri-
methoxy-2-naphthyl)-2-pyrrolidinone (41)
for C24H29NO8 (M+ ): 459.1893; found: 459.1888.
n-BuLi (2.5 M in hexanes; 232 mL, 0.58 mmol) was added
dropwise to freshly distilled i-Pr2NH (76 mL, 0.58 mmol)
in anhydrous THF (2 mL) at 0 ꢁC. After stirring for 45 min
at 0 ꢁC and cooling to ꢀ78 ꢁC, pyrrolidinone 40 (166 mg,
0.53 mmol) in anhydrous THF (3 mL) was added dropwise
and the solution was stirred for further 1.5 h. The mixture
was added dropwise to methyl dimethoxyacetate (258 mL,
2.11 mmol) in anhydrous THF (1.5 mL) at ꢀ78 ꢁC. Stirring
was continued for 5 min at ꢀ78 ꢁC and 5 min at room tem-
perature, after which saturated aqueous NH4Cl (10 mL) and
EtOAc (10 mL) were successively added. The layers were
separated and the aqueous phase was further extracted
Acknowledgements
We thank GlaxoSmithKline for the generous endowment (to
A.G.M.B.), the Royal Society and the Wolfson Foundation
for a Royal Society Wolfson Research Merit Award (to
A.G.M.B.), the Wolfson Foundation for establishing the
Wolfson Centre for Organic Chemistry in Medical Sciences
at Imperial College, the Engineering and Physical Sciences
Research Council and AstraZeneca for generous support of
our studies. We additionally thank Peter R. Haycock and
Richard N. Sheppard for high-resolution NMR spectros-
copy.

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16. Wymann, W. E.; Davis, R.; Patterson, J. W.; Pfister, J. R. Synth.
Commun. 1988, 18, 1379.
Supplementary data
17. Merkushev, E. B. Synthesis 1988, 923.
Additional experimental procedures and structural data for
all new compounds and crystallographic data (including
ORTEPs and CIFs) for compounds 17, 20, and 26 (CCDC
613463, 613464 and 613465, respectively). Supplementary
data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2006.10.004.
18. (a) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
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