Enantioselective annulation reactions of bisenolates prepared through dearomatization reactions of aromatic and heteroaromatic diesters

Article abstract of DOI:10.1002/ejoc.201101427

A one-pot, enantioselective strategy for the dearomatization-annulation of aromatic diesters to give a range of highly functionalized polycyclic molecules with excellent enantioselectivity is presented. This methodology is based on the reaction of bisenolates, prepared by treating aromatic diesters with trialkyltin lithium reagents, which involves a stanna-Brook rearrangement, with 1,ω-dihaloalkanes and other biselectrophiles. We have also developed experimental conditions for performing these reactions with substoichiometric amounts of the required tin reagent by in situ recycling of Me ₆Sn₂ into Me₃SnLi with excess lithium metal, and provide a study of the scope and limitations of this synthetic methodology. The alkylation of chiral bisenolates opens a straightforward one-pot access to highly functionalized bicyclic compounds from aromatic diesters. A stanna-Brook rearrangement originates the key bisenolate intermediate. Copyright

Full text of DOI:10.1002/ejoc.201101427

FULL PAPER
DOI: 10.1002/ejoc.201101427
Enantioselective Annulation Reactions of Bisenolates Prepared Through
Dearomatization Reactions of Aromatic and Heteroaromatic Diesters
Jaime Pérez-Vázquez,[a] Alberte X. Veiga,[a] Gustavo Prado,[a] F. Javier Sardina,*[a] and
M. Rita Paleo*[a]
Keywords: Synthetic methods / Rearrangement / Annulation / Alkylation / Enantioselectivity / Tin
A one-pot, enantioselective strategy for the dearomatization–
annulation of aromatic diesters to give a range of highly
other biselectrophiles. We have also developed experimental
conditions for performing these reactions with substoichio-
functionalized polycyclic molecules with excellent enantio- metric amounts of the required tin reagent by in situ recycl-
selectivity is presented. This methodology is based on the
reaction of bisenolates, prepared by treating aromatic di-
esters with trialkyltin lithium reagents, which involves a
stanna-Brook rearrangement, with 1,ω-dihaloalkanes and
ing of Me6Sn2 into Me3SnLi with excess lithium metal, and
provide a study of the scope and limitations of this synthetic
methodology.
of complex cyclic frameworks present in natural and bioac-
tive compounds. Notwithstanding these attractive possibil-
ities, there are only a handful of publications that describe
useful results in this area.[9]
Introduction
Synthetic methodologies based on the use of tandem de-
aromatization[1]–alkylation reactions hold great potential
for the preparation of complex organic structures.[2] Several
of the general methods available to dearomatize arene com-
pounds, such as nucleophilic addition to aromatic rings,[1a,3]
oxidation,[4] reduction,[5] and transition-metal-mediated
processes[6] (along with some other reactions of narrower
scope)[7] have been developed into highly useful tandem de-
aromatization–alkylation protocols. To further increase the
synthetic value of this type of approach, several enantio-
selective variants of some of these transformations have
been developed.[2,4] Worthy of note in this particular respect
are the alkylation–dearomatization reactions of phen-
ols[2d–2e] and anilines.[2f]
Despite their great potential, there is a certain scarcity of
synthetic tandem procedures based on reductive dearomati-
zation reactions coupled to alkylative processes. This is sur-
prising because these reductive dearomatizations provide an
efficient route to highly nucleophilic anionic, or even dian-
ionic, intermediates that could be advantageously used for
C–C bond formation (e.g. for the stereocontrolled construc-
tion of quaternary stereocentres).[8] One could even envision
the coupling of a reductive dearomatization process and an
annulation reaction to open short routes for the preparation
In the past few years we have undertaken a program to
broaden the synthetic utility of dearomatization reactions
by coupling them to annulation protocols. We have reported
the successful pairing of a new dearomatization reaction of
phthalates and related diesters, brought about by anionic
tin nucleophiles, with a bisalkylation reaction. This tandem
sequence allows the stereoselective preparation of 6,5-, 6,6-
and 6,7-fused carbobicyclic and heterobicyclic systems with
the concomitant formation of one or two quaternary stereo-
centres in the process.[10] Our procedure involves the
treatment of benzene and pyridine diesters with R3SnLi,
to provide highly nucleophilic bisenolates (a process that
involves a stanna-Brook rearrangement)[11] followed by
trapping the intermediates with 1,ω-dihaloalkanes and re-
lated biselectrophiles. This dearomatization–alkylation pro-
cedure (Scheme 1) does not result from the nucleophilic ad-
dition of trialkylstannyllithium to the electron-deficient
aromatic ring (as in many nucleophilic addition-initiated
dearomatization reactions),[1a,3] but instead from 1,2-ad-
dition to a carboxylate group followed by 1,2 Li–Sn re-
arrangement of the initial stannyl alkoxide adduct
(Scheme 1). Reaction of 4 with a second equivalent of
R3SnLi gave rise to the bisenolate 5, which was finally
trapped with different biselectrophiles to yield the bicyclic
products.
[a] Departamento de Química Orgánica and Centro Singular de
Investigación en Química Biológica y Materiales Moleculares,
Universidad de Santiago de Compostela
15782 Santiago de Compostela, Spain
Herein we report the results of our work, which are
aimed at increasing the usefulness and applicability of this
methodology. Firstly, we explored the scope of the reaction
with regards to the type of aromatic diesters that could be
used (e.g. five-membered ring heteroaromatics, such as
Fax: +34-981595012
E-mail: javier.sardina@usc.es
rita.paleo@usc.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101427.
Eur. J. Org. Chem. 2012, 975–987
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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ture to 40 °C. All bicyclic compounds were obtained with
complete stereoselectivity, as only one stereoisomer was de-
1
tected in the H NMR spectra of the crude reaction mix-
tures (Scheme 2).
Scheme 2. Dearomatizing anionic cyclization of furan and thio-
phene diesters.
Scheme 1. Mechanism for the dearomatization–alkylation pro-
cedure mediated by Me3SnLi.
Diethylthiophene-2,3-dicarboxylate (8, X = S) was ob-
tained by the Fischer esterification of the corresponding di-
furan, thiophene, benzofuran and naphthalene derivatives). acid, which was prepared by the dilithiation of thiophene
Secondly, we undertook the task to find reaction conditions 2-carboxylic acid with BuLi followed by quenching with
that would require only substoichiometric (catalytic) carbon dioxide.[19] In a manner analogous to that of 7,
amounts of tin reagents (due to their toxicity and cost). when the dearomatization–bisalkylation procedure was ap-
Finally, we engaged in the development of an enantioselec- plied to 8, fused 5,5- and 5,6-ring systems were obtained
tive variant of this transformation.
after sequential treatment with Me3SnLi and 1,3-diiodo-
propane (10a, 55%) or 1,4-diiodobutane (10b, 60%). Again
some starting material and a ring-opened product were ob-
served in the reaction mixture. When a functionalized bis-
electrophile, such as cis-1,4-dichloro-2-butene, was used the
expected tetrahydrobenzothiophene 10c was isolated in
52% yield.
We then investigated the behaviour of benzofuran diester
11. Benzofurans have been used recently in dearomatizing
[4+2] cycloadditions[7a] and radical reactions.[20] Under
stanna-Brook conditions, benzofuran 11 was transformed
into the corresponding bisenolate, which was alkylated with
different 1,ω-dihaloalkanes to give the corresponding tricy-
clic compound 12 (n = 1–3) in good yields (Scheme 3).
Results and Discussion
We first studied the behaviour of five-membered-ring
aromatic heterocycles such as furan and thiophene. Dearo-
matized furans[12] have been previously obtained by a de-
carboxylative Claisen rearrangement,[7b] [2,3]-Still–Wittig
rearrangement,[13] aryl radical addition[14] and nucleophilic
addition to carbene complexes of chromium,[15] among
other methods.[16]
Furan diester 7 (X = O) was prepared in iPrOH by the
Fischer esterification of the corresponding diacid, which
was obtained by regioselective deprotonation of 3-furoic
acid at C-2 with BuLi followed by quenching with carbon
dioxide.[17] Treatment of a tetrahydrofuran (THF) solution
of 7 with Me3SnLi (215 mol-%) at low temperature followed
by the trapping of the intermediate bisenolate with 1,3-di-
iodopropane (120 mol-%) afforded 5,5-fused bicyclic 9a.
The 1H NMR spectrum of the crude reaction mixture
showed dearomatized 9a as the main product with minor
proportions of starting material, a ring-opened product and
the monoacid derived from the partial hydrolysis of 7.[18]
After chromatographic purification, 9a was isolated in 63%
yield. When 1,4-diiodobutane was used as the electrophile
under the same reaction conditions, 9b was obtained in
59% yield. The ring-forming bisalkylation of the furan-de-
rived bisenolate proved to be more difficult with 1,5-diiodo-
pentane but, as observed previously with phthalate and pyr-
idine diesters,[10] the 5,7-fused bicycle 9c was prepared, al-
Scheme 3. Dearomatizing anionic cyclizations of benzofuran dies-
beit in a lower yield (48%), by warming the reaction mix- ters.
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Enantioselective Annulation Reactions of Bisenolates
Naphthalene diester derivatives, with different substitu- fusion of the new ring was confirmed by the X-ray crystal-
tion patterns, were also investigated as substrates for our lographic analysis of diol 16c, which was obtained by
dearomatization–annulation methodology (Scheme 4). We LiAlH4 reduction of 16b in THF at 0 °C.[21]
first explored the behaviour of naphthalene systems that
We next decided to explore whether the presence of two
possess the two required carboxylate moieties in the same carboxylate groups in the aromatic system was an absolute
ring. Unfortunately, under the reaction conditions em- requirement for the dearomatization reaction to take place.
ployed, 1,2- and 2,3-disubstituted naphthalenes afforded In principle, the stanna-Brook reaction could also take
complex reaction mixtures. The results obtained with 1,2- place if one of the carboxylate groups was replaced by a
disubstituted naphthalene may be due to the instability of different electron-withdrawing group. To explore this hy-
the intermediate bisenolate to form, which could be due to pothesis we studied the behaviour of several benzoates fur-
the steric crowding around the substituent at the 1-position. ther substituted in their p- and o-positions with different
The total loss of the aromaticity of both rings in the inter- electron-withdrawing groups. Complex reaction mixtures
mediate bisenolate derived from the 2,3-disubstituted were obtained when keto, formyl, nitro and cyano benzo-
naphthalene diester can account for the observed results in ates[22] were used as substrates, but p-imino substituted
this particular case. In stark contrast to these negative re- benzoates, which bear a p-methoxyphenyl (PMP) moiety as
sults, the reaction of diisopropyl naphthalene-1,4-dicarb- the N-protecting group, were found to provide clean reac-
oxylate (13) with Me3SnLi followed by addition of 1,3-di- tions when submitted to the stanna-Brook–bisalkylation
bromopropane provided tricyclic 15a in an 87% isolated protocol. Interestingly, we did not detect dearomatized
yield.Theanalogousreactionwith1,4-diiodobutaneasthebis- products after treatment of p-imino-benzoate 17 with
electrophile did not provide the desired tricyclic diester but Me3SnLi followed by the addition of an electrophile; in-
instead a mixture of mono- and dialkylated compounds. stead we observed that the bisalkylation took place on the
The use of a more rigid biselectrophile, such as 1,2-bis- N and C atoms that originally formed the imine group and
(chloromethyl)benzene, proved more successful and allowed that the regioselectivity of the process could be easily con-
the preparation of tetracyclic 15b in 60% yield. However, trolled (Scheme 5). Thus, treatment of 17 with Me3SnLi in
with 1,4-dichloro-2-butene no alkylation was observed and THF at low temperature followed by the addition of 1-iodo-
starting ester 13 was recovered. This unexpected result was propane afforded the C-alkylated, secondary benzylamine
probably due to the fact that the electrophile acts as a 18a in 78% yield. The alkylation reaction was shown to be
chlorinating agent with concomitant liberation of butadi- regioselective as it proceeded exclusively on the imine
ene, and not as a C-electrophile.
carbon. However, the use of a harder electrophile, such as
Me2SO4, gave mainly the N-methylated, C-unsubstituted
product 18b. Additionally, the use of biselectrophiles such
as 1,3-dibromopropane or 1,4-diiodobutane led to the cor-
responding pyrrolidine 18c or piperidine 18d in good yields.
δ-Lactam 18e was also easily prepared in good yield when
methyl γ-iodobutyrate was used as the biselectrophile.
Scheme 4. Dearomatizing anionic cyclizations of naphthalene de-
rivatives.
We then proceeded to study the behaviour of naphth-
alene systems where the required carboxylate groups were
attached to different rings. Complex mixtures were obtained
for the reaction of 1,5-naphthalene dicarboxylate with
Me3SnLi and 1,ω-dihaloalkanes, but when diisopropyl
naphthalene-2,6-dicarboxylate (14) was treated with
Me3SnLi followed by the addition of 1,3-dibromopropane
Scheme 5. Me3SnLi addition to 17.
In all the annulations described so far, the Me3SnLi re-
or 1,4-diiodobutane, the desired cyclized products 16a and quired was prepared by treatment of a THF solution of
16b were isolated in 79 and 66% yield, respectively. The syn hexamethyldistannane with MeLi[23] because of the sim-
Eur. J. Org. Chem. 2012, 975–987
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F. J. Sardina, M. R. Paleo et al.
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plicity of the procedure and the homogeneity of the reac- diiodobutane was used as the electrophile. This substoichio-
tion mixture obtained, although in this process one equiva- metric procedure can also be successfully applied to hetero-
lent of tin is wasted as Me4Sn. An alternative procedure for aromatic diesters, as thiophene 8 (X = S) provided the ex-
the preparation of Me3SnLi involves the reaction of Me6Sn2 pected bicycle 10b in 56% yield. Despite the fact that the
or Me3SnCl with excess lithium in THF.[24] Because, ac- yields obtained by using this catalytic procedure are slightly
cording to our proposed mechanism for the stanna-Brook lower than when stoichiometric Me3SnLi is used,[10] we
rearrangement, a molecule of Me6Sn2 is obtained per bisen- consider that the economic savings and the lower toxicity
olate molecule formed, we decide to explore if this ditin of the process make it a valuable alternative. Nevertheless,
compound could be recycled into Me3SnLi in situ, thus some limitations to the general applicability of this catalytic
turning the procedure catalytic in the tin reagent. To test procedure were found as no reaction was observed when
this hypothesis, we prepared a solution of a substoichi- terephthalate and naphthalene diesters were subjected to
ometric amount of Me3SnLi from Me3SnCl (10 mol-%) and these conditions.
excess lithium in THF at room temperature. After cooling
The next step in our exploration of this chemistry was
to –78 °C, a solution of diisopropylphthalate (100 mol-%) the development of an asymmetric version of this method-
in THF was added and the resulting mixture was stirred ology. Our entry to the asymmetric construction of quater-
while a dark red colour developed. Addition of 1,3-di- nary centres relies on the use of esters derived from chiral
bromopropane to this dark red solution provided the hyd- alcohol auxiliaries. Thus we explored the behaviour of chi-
rindane 21a, which proved that Me6Sn2 could be success- ral bisenolates in which all the stereochemical information
fully recycled into Me3SnLi under the reaction conditions resides in the alcoholic component of the ester function-
used. After some experimentation we discovered that the ality. In particular, we chose for these preliminary assays
bisenolate was prepared after 16 h at –78 °C by using hindered esters derived from picolinic acid 23 and the fol-
2000 mol-% of lithium and 10 mol-% of Me3SnCl. Under lowing alcohols: (–)-menthol, (–)-borneol, (1R,2S)-trans-2-
these conditions, we prepared the hydrindanes 21a and 22a phenyl-1-cyclohexanol, (S)-1-phenylethanol and (–)-8-
in 77 and 60% yield, respectively (Scheme 6). The hexa- phenylmenthol. All esters were prepared using 1-ethyl-3-(3-
hydronaphthalene 21b was isolated in 68% yield when 1,4- dimethylaminopropyl)carbodiimide (EDC) as the coupling
agent and 4-(dimethylamino)pyridine (DMAP) as the nu-
cleophilic catalyst in CH2Cl2. Sequential treatment of esters
24 with Me3SnLi to generate the chiral bisenolate followed
by addition of 1,3-dibromopropane for the alkylation–cycli-
zation process afforded tetrahydroindolizines 25 in good,
unoptimized yields. As shown in Scheme 7, the best dia-
stereomeric ratio (99:1) was obtained by using (–)-8-phen-
ylmenthol as the chiral auxiliary (25e). A favourable face-
to-face π–π interaction can explain the high degree of
stereocontrol obtained in the alkylation of the bisenolate
(with the pendent 8-phenylmenthyl moiety)[25] with 1,3-di-
bromopropane. Furthermore, when 1,4-dibromobutane and
Scheme 6. Results using substoichiometric Sn reagent.
Scheme 7. Asymmetric dearomatization–cyclization of pyridine diesters.
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Enantioselective Annulation Reactions of Bisenolates
1,5-diiodopentane were used as electrophiles, the corre- showed that the reaction took place with very high dia-
sponding quinolizine 26e and azepine 27e were also ob- stereoselectivity as only one diastereoisomer was identified.
tained with good diastereoselectivities (94:6 and 93:7, To confirm the level of diastereoselectivity, the tricyclic
respectively). Single crystals of 25e suitable for X-ray analy- compound was reduced to the diol 34 with LiAlH4 in 75%
sis were obtained by recrystallization from Et2O/CH2Cl2. yield and the esters derived from 34 and both enantiomers
X-ray analysis revealed that the absolute configuration of of α-methoxyphenylacetic acid (MPA)[28] were prepared. 1H
indolizine 25e was R.[21]
NMR spectroscopy of the crude mixtures at 500 MHz
Once we had shown the successful enantioselective de- showed an enantiomeric ratio of 98:2, which proved again
aromatization–annulation process in pyridine diesters, we that (–)-8-phenylmenthol is an excellent chiral inductor for
chose a different heteroaromatic system to prove the enan- the bisalkylation of lithium bisenolates obtained from the
tioselective dearomatization–alkylation with more elaborate stanna-Brook rearrangement of heteroaromatic diesters.
nucleophiles and electrophiles. Thus when quinoline diester
28 was treated with Me3SnLi followed by the addition of
primary halides (Scheme 8) the expected products were ob-
tained with excellent enantioselectivity and fair to excellent
yields.
Scheme 8. Asymmetric dearomatization–alkylation of quinoline di-
ester.
Scheme 9. Asymmetric dearomatization–cyclization of 30.
A limitation of this enantioselective dearomatization–an-
nulation was found when our attempts to carry out the re-
actions by using substoichiometric amounts of tin com-
pounds failed. Complex reaction mixtures were obtained
from these experiments. We believe that the slow formation
of the required bisenolates under the substoichiometric con-
ditions allows ample opportunity for decomposition reac-
tions to take place, which are probably caused by the bulki-
ness of the chiral auxiliary.
As a synthetic application of this methodology, we devel-
oped an enantioselective approach to the tricyclic benzo-
furan derivative 33, which is a projected intermediate for
the synthesis of analogs of galantamine,[26] an alkaloid that
acts as a selective, reversible, competitive acetylcholinester-
Conclusions
We have developed a one-pot, enantioselective strategy
for the dearomatization–annulation of aromatic diesters to
give a range of highly functionalized polycyclic molecules
with excellent enantioselectivities. For some compounds, we
have found experimental conditions for performing the re-
action with substoichiometric amounts of the required tin
reagent. Currently, we are investigating the application of
this process to the synthesis of natural products.
Experimental Section
ase inhibitor. 7-Methoxybenzofuran 30 was prepared from Diisopropyl Furan-2,3-dicarboxylate (7): A solution of furan-2,3-
dicarboxylic acid[17] (625 mg, 4.0 mmol) in toluene (40 mL) and
iPrOH (20 mL) was treated with H2SO4 (130 μL) and heated to
reflux in an apparatus with a Dean–Stark trap. During the first
6 h, 6 mL of distillate was withdrawn every hour and replenished
by an equal volume of 2:1 toluene/iPrOH. After 24 h, the solution
was cooled to room temperature and concentrated in vacuo to
5 mL, diluted with CH2Cl2, and washed with cold, saturated
NaHCO3. The organic extract was washed with water and brine,
dried and concentrated to an oily residue, which was purified by
commercially available 2-methoxyphenol in three steps[27] in
41% overall yield (Scheme 9). Selective hydrolysis of the es-
ter in the 2-position was quantitatively achieved by using
LiOH in a 1:1 dioxane/H2O mixture. Esterification of 31
with (–)-8-phenylmenthol in the presence of EDC and
DMAP in CH2Cl2 afforded chiral diester 32 in 84% yield.
Treatment of 32 with Me3SnLi to give a chiral bisenolate
followed by alkylation with cis-2-butene-1,4-dioldimesylate
led to the tricycle 33 in 50% yield. Careful examination of
bulb-to-bulb distillation under reduced pressure, and stored as a
the 1H NMR spectrum of the crude reaction mixture colourless oil over 4 Å molecular sieves (675 mg, 70%). H NMR
1
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F. J. Sardina, M. R. Paleo et al.
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(250 MHz, CDCl3): δ = 7.46 (d, J = 1.8 Hz, 1 H), 6.70 (d, J =
NMR (62.9 MHz, CDCl3): δ = 173.7, 171.4, 144.6, 105.5, 92.7,
1.8 Hz, 1 H), 5.25 (hept, J = 6.3 Hz, 1 H), 5.20 (hept, J = 6.3 Hz,
68.6, 68.4, 64.0, 35.3, 34.1, 30.7, 24.6, 22.8, 21.42, 21.38 ppm. IR
1 H), 1.35 (d, J = 6.3 Hz, 6 H), 1.34 (d, J = 6.3 Hz, 6 H) ppm. 13C
(KBr): ν = 1737 cm–1. C H O (310.39): calcd. C 65.78, H 8.44;
˜
17 26
5
NMR (62.9 MHz, CDCl3): δ = 161.8, 157.2, 144.1, 143.8, 124.1, found C 65.95, H 8.27.
112.6, 69.3, 69.0, 21.57, 21.55 ppm. IR (KBr): ν = 1728 cm–1.
˜
Diethyl 4,5,6,6a-Tetrahydro-3aH-cyclopenta[b]thiophene-3a,6a-di-
carboxylate (10a): A solution of Me3SnLi in THF at –78 °C was
treated with a solution of 8[19] (105 mg, 0.46 mmol) in THF and
stirred for 1 h. 1,3-Diiodopropane (60 μL, 0.52 mmol) was added,
and the mixture stirred for 1 h at –78 °C and for 14 h while slowly
warming to room temperature. Work up as for 9a afforded 10a
HRMS (ESI): calcd. for C12H17O5 [M + H]+ 241.1071; found
241.1079. C12H16O5 (240.26): calcd. C 59.99, H 6.71; found C
59.89, H 6.83.
Preparation of Me3SnLi: MeLi (215 mol-%, 1.6 m in Et2O) was
added to a solution of Me6Sn2 (220 mol-%) in THF (0.5 m) at 0 °C.
After 15 min, the solution was cooled to –78 °C and treated with
a solution of the corresponding aromatic diester (100 mol-%) in
THF (0.2 m).
1
(68 mg, 55%) as a colourless oil. H NMR (250 MHz, CDCl3): δ
= 6.10 (dd, J = 6.1, 0.7 Hz, 1 H), 5.56 (dd, J = 6.1, 0.5 Hz, 1 H),
4.12 (m, 4 H), 2.50 (m, 1 H), 2.22 (m, 2 H), 1.97 (m, 3 H), 1.22 (t,
J = 7.1 Hz, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 173.6,
172.3, 125.6, 124.9, 71.7, 71.6, 61.4, 61.0, 41.0, 39.2, 24.7, 13.9, 13.8
Diisopropyl 4,5,6,6a-Tetrahydro-3aH-cyclopenta[b]furan-3a,6a-di-
carboxylate (9a): A solution of Me3SnLi in THF at –78 °C was
treated with a solution of 7 (120 mg, 0.50 mmol) in THF, stirred
for 20 min, warmed to –50 °C and stirred for 40 min. 1,3-Diiodo-
propane (70 μL, 0.61 mmol) was added, and the mixture stirred for
3 h at –50 °C and for 18 h while slowly warming to room tempera-
ture. The reaction was quenched by adding pH 5.6 acetate buffer
(5 mL) and then partitioned between CH2Cl2 (10 mL) and acetate
buffer (5 mL). The aqueous layer was extracted with CH2Cl2 and
the combined organic extracts were washed with brine, dried with
Na2SO4 and concentrated. The crude product was an inseparable
mixture of starting furan and 9a so it was dissolved in a 1:1 diox-
ane/water mixture (4 mL) and treated with LiOH.H2O (63 mg,
1.5 mmol). After stirring for 3 h at room temperature, pH 5.6 acet-
ate buffer (15 mL) was added. The aqueous layer was extracted
with CH2Cl2 and the combined organic phase was washed with
brine, dried (Na2SO4), filtered and concentrated. The residue was
purified by column chromatography (neutral Al2O3, CH2Cl2/hex-
ppm. IR (KBr): ν = 1727 cm–1. C H O S (270.34): calcd. C 57.76,
˜
13 18
4
H 6.71, S 11.86; found C 57.43, H 7.10, S 11.56.
Diethyl 3a,4,5,6,7,7a-Hexahydrobenzo[b]thiophene-3a,7a-dicarb-
oxylate (10b): A solution of Me3SnLi in THF at –78 °C was treated
with 8[19] (100 mg, 0.44 mmol) in THF and stirred for 1 h. 1,4-
Diiodobutane (70 μL, 0.53 mmol) was added and the mixture
stirred for 1 h at –78 °C and for 14 h while slowly warming up to
room temperature. Work up as for 9a afforded 10b (75 mg, 60%)
1
as a colourless oil. H NMR (250 MHz, CDCl3): δ = 5.99 (d, J =
6.3 Hz, 1 H), 5.95 (d, J = 6.3 Hz, 1 H), 4.13 (quint, J = 7.1 Hz, 4
H), 2.18 (m, 2 H), 2.00 (m, 1 H), 1.69 (m, 3 H), 1.48 (m, 1 H), 1.33
(m, 1 H), 1.22 (q, J = 7.2 Hz, 6 H) ppm. 13C NMR (62.9 MHz,
CDCl3): δ = 173.1, 172.9, 130.9, 121.7, 63.0, 61.2, 60.8, 59.8, 33.7,
28.9, 21.1, 19.4, 14.1, 13.9 ppm. IR (KBr): ν = 1729 cm–1. HRMS
˜
(ESI): calcd. for C14H20O4SNa [M + Na]+ 307.0975; found
307.0981. C14H20O4S (284.37): calcd. C 59.13, H 7.09, S 11.28;
ane, 1:1) to give 9a (89 mg, 63%) as a colourless oil. 1H NMR found C 58.78, H 7.07, S 11.04.
(250 MHz, CDCl3): δ = 6.43 (d, J = 2.7 Hz, 1 H), 4.98 (hept, J =
Diethyl 3a,4,7,7a-Tetrahydrobenzo[b]thiophene-3a,7a-dicarboxylate
6.3 Hz, 1 H), 4.90 (hept, J = 6.3 Hz, 1 H), 4.76 (d, J = 2.7 Hz, 1
H), 2.29–2.03 (m, 3 H), 1.89–1.61 (m, 3 H), 1.18 (m, 12 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 172.3, 170.3, 147.0, 103.9, 97.3,
68.9, 68.5, 68.2, 39.9, 37.4, 23.5, 21.58, 21.56, 21.50, 21.46 ppm. IR
(10c): A solution of Me3SnLi in THF at –78 °C was treated with
8[19] (92 mg, 0.40 mmol) in THF and stirred for 1 h. cis-1,4-
Dichloro-2-butene (50 μL, 0.48 mmol) was added, and the mixture
stirred for 1 h at –78 °C, slowly allowed to reach room temp. for
14 h, and heated at 30 °C for 3 h. Work up as for 9a afforded 10c
(KBr): ν = 1729 cm–1. C H O (282.34): calcd. C 63.81, H 7.85;
˜
15 22
5
found C 63.41, H 8.25.
1
as a colourless oil (59 mg, 52%). H NMR (500 MHz, CDCl3): δ
Diisopropyl 3a,4,5,6,7,7a-Hexahydrobenzofuran-3a,7a-dicarboxyl-
ate (9b): Following the procedure described above for 9a and using
1,4-diiodobutane (80 μL, 0.61 mmol) provided 9b as a colourless
= 6.05 (d, J = 6.3 Hz, 1 H), 6.03 (d, J = 6.3 Hz, 1 H), 5.86 (m, 1
H), 5.77 (m, 1 H), 4.14 (m, 4 H), 2.84 (dquint, J = 19.0, 2.6 Hz, 1
H), 2.74 (m, 1 H), 2.49 (m, 2 H), 1.22 (q, J = 7.3 Hz, 6 H) ppm.
oil (87 mg, 59%). 1H NMR (250 MHz, CDCl3): δ = 6.35 (d, J = 13C NMR (62.9 MHz, CDCl3): δ = 172.9, 172.5, 131.6, 124.7,
2.7 Hz, 1 H), 5.07 (hept, J = 6.3 Hz, 1 H), 4.92 (m, 2 H), 2.03 (m,
2 H), 1.88 (m, 2 H), 1.46 (m, 4 H), 1.28 (d, J = 6.3 Hz, 3 H), 1.23
(d, J = 6.3 Hz, 3 H), 1.17 (d, J = 6.3 Hz, 6 H) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 172.8, 170.8, 146.0, 106.4, 87.9, 68.4, 68.0,
57.2, 32.4, 29.1, 21.6, 21.41, 21.36, 21.3, 20.1, 19.2 ppm. IR (KBr):
124.4, 122.8, 61.7, 61.4, 60.9, 58.0, 34.0, 30.5, 13.9, 13.8 ppm. IR
(KBr): ν = 1730 cm–1. C H O S (282.35): calcd. C 59.55, H 6.43,
˜
14 18
4
S 11.36; found C 59.78, H 6.63, S 11.32.
Diisopropyl Benzofuran-2,3-dicarboxylate (11): Toluene (25 mL)
was added to a solution of benzofuran-2,3-dicarboxylic acid (1 g,
4.85 mmol) in iPrOH (25 mL) in the presence of H2SO4 (150 μL),
and the mixture was heated to reflux in apparatus with a Dean–
Stark trap. During the first 6 hours, 6 mL of distillate was with-
drawn every hour and replenished by an equal volume of iPrOH/
toluene. After 36 hours, the solution was evaporated under reduced
pressure to 5 mL, diluted with CH2Cl2 (20 mL) and neutralized
with cold, saturated NaHCO3 solution. The organic layer was
washed with brine, dried and concentrated. The residue was puri-
fied by bulb-to-bulb distillation to yield 11 as a colourless oil
(1.21 g, 86%). 1H NMR (250 MHz, CDCl3): δ = 7.85 (d, J =
7.8 Hz, 1 H), 7.56 (d, J = 8.3 Hz, 1 H), 7.45 (m, 1 H), 7.35 (m, 1
ν = 1729 cm–1. HRMS (ESI): calcd. for C H O [M + H]+
˜
16 25
5
297.1697; found 297.1697. C16H24O5 (296.36): calcd. C 64.84, H
8.16; found C 64.51, H 8.18.
Diisopropyl 4,5,6,7,8,8a-Hexahydro-3aH-cyclohepta[b]furan-3a,8a-
dicarboxylate (9c): A solution of Me3SnLi in THF at –78 °C was
treated with a solution of 7 (120 mg, 0.50 mmol) in THF and
stirred for 1 h. 1,5-Diiodopentane (90 μL, 0.60 mmol) in N,N-di-
methylformamide (DMF, 2 mL) was added, and the reaction mix-
ture was stirred for 14 h while warming from –78 °C to room tem-
perature, and then at 40 °C for 6 h. Work up as for 9a afforded
9c (74 mg, 48%) as a colourless oil after bulb-to-bulb distillation
1
(0.01 Torr, 80 °C). H NMR (250 MHz, CDCl3): δ = 6.41 (d, J = H), 5.33 (m, 2 H), 1.42 (d, J = 6.3 Hz, 6 H), 1.40 (d, J = 6.3 Hz, 6
2.7 Hz, 1 H), 4.92 (m, 2 H), 4.83 (d, J = 2.7 Hz, 1 H), 2.18 (m, 1
H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 162.0, 158.3, 153.9,
H), 1.94 (m, 3 H), 1.73–1.24 (m, 6 H), 1.18 (m, 12 H) ppm. 13C 145.7, 127.7, 125.4, 124.4, 122.5, 118.3, 112.1, 70.1, 69.3, 21.8, 21.7
980
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 975–987

Enantioselective Annulation Reactions of Bisenolates
ppm. IR (CHCl ): ν = 1728 cm–1. HRMS (ESI): calcd. for
6.82 (m, 2 H), 5.79 (m, 2 H), 5.04 (hept, J = 6.3 Hz, 1 H), 4.91
(hept, J = 6.3 Hz, 1 H), 2.73 (m, 4 H), 1.23 (d, J = 6.3 Hz, 3 H),
1.21 (d, J = 6.3 Hz, 3 H), 1.13 (d, J = 6.3 Hz, 3 H), 1.07 (d, J =
6.3 Hz, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 171.5, 170.5,
159.1, 129.8, 129.1, 126.7, 125.4, 123.3, 121.0, 109.9, 91.7, 69.1,
˜
3
C16H19O5 [M + H]+ 291.1227; found 291.1232. C16H18O5 (290.32):
calcd. C 66.19, H 6.25; found C 66.22, H 6.52.
Diisopropyl
2,3,3a,8b-Tetrahydro-1H-benzo[b]cyclopenta[d]furan-
3a,8b-dicarboxylate (12a): A solution of Me3SnLi in THF at –78 °C
was treated with a solution of 11 (110 mg, 0.38 mmol) in THF
(2 mL), warmed to –55 °C and stirred for 1 h. 1,3-Diiodopropane
(50 μL, 0.44 mmol) was added, the mixture stirred for 15 h while
slowly warming to room temperature, and heated at 30 °C for 3 h.
The reaction was quenched by adding pH 5.6 acetate buffer and
then partitioned between CH2Cl2 and acetate buffer. The aqueous
layer was extracted with CH2Cl2, and the combined organic ex-
tracts were washed with brine, dried (Na2SO4) and concentrated.
The residue was purified by column chromatography (Al2O3,
CH2Cl2/hexane, 3:1) to give 12a (88 mg, 70%) as a white solid; m.p.
82–85 °C (EtOH). 1H NMR (250 MHz, CDCl3): δ = 7.12 (m, 2 H),
69.0, 59.4, 33.9, 31.7, 21.5, 21.4, 21.2 ppm. IR (KBr): ν = 1762,
˜
1725 cm–1. C20H24O5 (344.41): calcd. C 69.75, H 7.02; found C
69.45, H 7.02.
Diisopropyl Naphthalene-1,4-dicarboxylate (13): A suspension of
naphthalene-1,4-dicarboxylic acid (1.0 g, 4.62 mmol) and benzyltri-
ethylamonium chloride (25 mg, 0.11 mmol) in 1,2-dichloroethane
(8 mL) was heated to reflux and treated with SOCl2 (870 μL,
12 mmol). The reaction mixture was heated to reflux for 12 h, fil-
tered hot, and the filtrate was concentrated. The residue was dried
under vacuum in the presence of NaOH pellets. The crude acid
chloride was dissolved in CH2Cl2 (24 mL), DMAP (56 mg,
6.86 (m, 2 H), 5.03 (hept, J = 6.3 Hz, 1 H), 4.91 (hept, J = 6.3 Hz, 0.46 mmol) and iPrOH (1.5 mL, 19 mmol) were added, and the re-
1 H), 2.48 (td, J = 12.8, 6.4 Hz, 1 H), 2.26 (m, 3 H), 1.83 (m, 1 H),
1.49 (m, 1 H), 1.24 (d, J = 6.1 Hz, 3 H), 1.22 (d, J = 6.1 Hz, 3 H),
sulting solution was cooled to 0 °C and treated with Et3N (2.7 mL,
19 mmol). The reaction mixture was stirred for 15 min at 0 °C and
1.13 (d, J = 6.3 Hz, 3 H), 1.07 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR at room temperature for 4 h. The mixture was washed with HCl
(62.9 MHz, CDCl3): δ = 171.0, 170.4, 159.4, 129.2, 128.9, 123.3,
(2 m) and water, and the organic layer was dried and concentrated.
Column chromatography (EtOAc/hexane, 1:20) afforded 13 (1.18 g,
85%) as a white solid; m.p. 69–70 °C (CH2Cl2/hexane). H NMR
(250 MHz, CDCl3): δ = 8.78 (dd, J = 6.7, 3.4 Hz, 2 H), 8.02 (s, 2
H), 7,61 (dd, J = 6.7, 3.4 Hz, 2 H), 5.37 (hept, J = 6.3 Hz, 2 H),
1.43 (d, J = 6.3 Hz, 12 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
121.2, 109.8, 98.5, 69.1, 68.8, 67.8, 40.4, 38.3, 23.8, 21.6, 21.5,
21.32, 21.31 ppm. IR (CHCl ): ν = 1734 cm–1. HRMS (ESI): calcd.
1
˜
3
for C19H25O5 [M + H]+ 333.1693; found 333.1699. C19H24O5
(332.40): calcd. C 68.66, H 7.28; found C 68.38, H 7.68.
Diisopropyl 1,2,3,4,4a,9b-Hexahydrodibenzo[b,d]furan-4a,9b-dicarb-
oxylate (12b): Using the same procedure as for 12a with 1,4-diiodo-
butane (60 μL, 0.45 mmol) as the electrophile, 12b was obtained
as a white solid (89 mg, 68%); m.p. 84–86 °C (EtOH). 1H NMR
166.9, 132.3, 131.3, 127.6, 127.5, 125.9, 69.1, 21.9 ppm. IR (KBr): ν
˜
= 1713 cm–1. C18H20O4 (300.35): calcd. C 71.98, H 6.71; found C
71.78, H 7.01.
(250 MHz, CD2Cl2): δ = 7.20 (m, 2 H), 6.92 (td, J = 7.6, 0.9 Hz, 1 Diisopropyl Naphthalene-2,6-dicarboxylate (14): Using the same
H), 6.86 (d, J = 8.0 Hz, 1 H), 5.06 (hept, J = 6.3 Hz, 1 H), 4.83
(hept, J = 6.2 Hz, 1 H), 2.42 (dt, J = 14.2, 4.1 Hz, 1 H), 2.14 (m,
2 H), 1.70 (m, 2 H), 1.51 (m, 3 H), 1.27 (d, J = 6.3 Hz, 3 H), 1.23
(d, J = 6.3 Hz, 3 H), 1.09 (d, J = 6.2 Hz, 3 H), 1.08 (d, J = 6.2 Hz,
procedure as for 13, naphthalene-2,6-dicarboxylic acid (500 mg,
2.3 mmol) afforded 14 (615 mg, 89%); m.p. 118–120 °C (CH2Cl2/
hexane). H NMR (250 MHz, CDCl3): δ = 8.59 (s, 2 H), 8.10 (dd,
1
J = 8.5, 1.0 Hz, 2 H), 7.98 (d, J = 8.5 Hz, 2 H), 5.31 (hept, J =
3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 171.7, 170.5, 157.6, 6.2 Hz, 2 H), 1.41 (d, J = 6.2 Hz, 12 H) ppm. 13C NMR (62.9 MHz,
129.3, 129.0, 123.4, 121.1, 111.3, 89.7, 68.8, 68.5, 57.1, 33.2, 29.2,
21.7, 21.5, 21.3, 21.2, 20.7, 20.3 ppm. HRMS (ESI): calcd. for
C20H26O5Na [M + Na]+ 369.1672; found 369.1678.
CDCl3): δ = 165.9, 134.5, 130.4, 130.1, 129.4, 126.0, 68.8, 22.0 ppm.
IR (KBr): ν = 1708 cm–1. C H O (300.35): calcd. C 71.98, H
˜
18 20
4
6.71; found C 71.70, H 7.00.
Diisopropyl 6,7,8,9,10,10a-Hexahydro-5aH-benzo[b]cyclohepta[d]-
furan-5a,10a-dicarboxylate (12c): A solution of Me3SnLi in THF
at –78 °C was treated with a solution of 11 (102 mg, 0.35 mmol) in
THF, warmed to –55 °C and stirred for 1.5 h. 1,5-Diiodopentane
(60 μL, 0.40 mmol) in DMF (1.2 mL) was added, the mixture was
stirred for 8 h while slowly warming to room temperature, and
heated at 45 °C for 14 h. Work up as for 12a and purification by
column chromatography (neutral Al2O3, CH2Cl2/hexane, 1:2) af-
forded 12c (75 mg, 59%) as a white solid; m.p. 81–84 °C (EtOH).
Diisopropyl 2,3,3a,9b-Tetrahydro-1H-cyclopenta[a]naphthalene-
5,9b-dicarboxylate (15a): A solution of Me3SnLi (0.77 mmol) in
THF at –78 °C was treated with a solution of 13 (109 mg,
0.36 mmol) in THF (2 mL). After stirring for 4 h, 1,3-dibromopro-
pane (40 μL, 0.40 mmol) was added, and the resulting mixture was
stirred for 2 h at –78 °C and for 18 h while slowly warming to room
temperature. The reaction was quenched with pH 7.0 phosphate
buffer (0.2 mL) and partitioned between CH2Cl2 and phosphate
buffer. The aqueous phase was extracted with CH2Cl2, and the
1H NMR (250 MHz, CD2Cl2): δ = 7.16 (m, 2 H), 6.89 (td, J = 7.5, combined organic phase was washed with brine, dried and concen-
1.0 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 4.90 (m, 2 H), 2.41–2.03
trated. The residue was purified by column chromatography (70–
(m, 4 H), 1.73–1.12 (m, 15 H), 1.04 (d, J = 6.2 Hz, 3 H) ppm. 13C 230 SiO2, EtOAc/hexane, 1:20) to give 15a as a colourless oil
1
NMR (62.9 MHz, CD2Cl2): δ = 173.0, 171.4, 158.9, 130.6, 129.5,
(108 mg, 87%). H NMR (250 MHz, CD2Cl2): δ = 7.83 (m, 1 H),
7.24 (m, 3 H), 6.82 (d, J = 4.7 Hz, 1 H), 5.17 (hept, J = 6.3 Hz, 1
124.9, 121.1, 109.7, 95.4, 69.4, 69.3, 63.7, 36.4, 35.4, 31.2, 25.0,
23.2, 21.8, 21.7, 21.6, 21.5 ppm. IR (KBr): ν = 1734 cm–1. HRMS H), 4.95 (hept, J = 6.3 Hz, 1 H), 3.31 (m, 1 H), 2.57 (m, 1 H), 2.04
˜
(ESI): calcd. for C21H29O5 [M + H]+ 361.2010; found 361.2010. (m, 2 H), 1.63 (m, 3 H), 1.33 (d, J = 6.3 Hz, 6 H), 1.16 (d, J =
C21H28O5 (360.45): calcd. C 69.98, H 7.83; found C 69.58, H 7.82.
6.2 Hz, 3 H), 1.14 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (62.9 MHz,
CD2Cl2): δ = 175.1, 166.8, 140.4, 136.8, 129.1, 129.0, 128.5, 127.5,
127.3, 126.7, 69.0, 68.6, 56.7, 43.8, 38.6, 33.0, 23.3, 22.2, 21.8, 21.7
Diisopropyl 1,4,4a,9b-Tetrahydrodibenzo[b,d]furan-4a,9b-dicarb-
oxylate (12d): Compound 12d was prepared following the same
procedure as for 12a. Thus, 11 (120 mg, 0.41 mmol) and cis-1,4-
dichloro-2-butene (50 μL, 0.48 mmol) afforded 12d (85 mg, 60%)
as a white solid, after work up and purification by column
chromatography (neutral Al2O3, CH2Cl2/hexane, 1:1); m.p. 79–
81 °C (EtOH). 1H NMR (250 MHz, CDCl3): δ = 7.11 (m, 2 H),
ppm. IR (KBr): ν = 1717 cm–1. C H O (342.43): calcd. C 73.66,
˜
21 26
4
H 7.65; found C 73.91, H 7.82.
Diisopropyl 6a,7,12,12a-Tetrahydrotetraphene-5,12a-dicarboxylate
(15b): Using the same procedure as for 15a with 1,2-ortho-di-
chloroxylene (65 mg, 0.37 mmol) as the electrophile, 13 (101 mg,
Eur. J. Org. Chem. 2012, 975–987
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
981

F. J. Sardina, M. R. Paleo et al.
FULL PAPER
0.34 mmol) afforded 15b (82 mg, 60%) as a colourless oil. 1H NMR resulting mixture was stirred for 2 h at –78 °C. The reaction mix-
(250 MHz, CD2Cl2): δ = 7.86 (m, 1 H), 7.29 (m, 2 H), 7.12 (m, 5 ture was quenched with deoxygenated pH 7.0 phosphate buffer and
H), 6.92 (d, J = 3.4 Hz, 1 H), 5.11 (hept, J = 6.3 Hz, 2 H), 3.56
(m, 1 H), 3.26 (d, J = 16.9 Hz, 1 H), 3.07 (m, 2 H), 2.85 (dd, J =
partitioned between CH2Cl2 and phosphate buffer. The aqueous
phase was extracted with CH2Cl2, and the combined organic phase
17.4, 3.8 Hz, 1 H), 1.31 (d, J = 6.2 Hz, 6 H), 1.22 (d, J = 6.3 Hz, was washed with brine, dried, and concentrated. The residue was
3 H), 1.14 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (62.9 MHz, purified by column chromatography (neutral Al2O3, CH2Cl2/hex-
CD2Cl2): δ = 174.6, 165.9, 143.3, 138.9, 136.7, 133.9, 131.6, 130.2,
129.6, 129.0, 128.8, 127.7, 127.5, 126.4, 126.3, 125.7, 69.4, 68.9,
ane, 2:1 to 3:1) to give 18a as a colourless oil (93 mg, 78%). 1H
NMR (250 MHz, CD2Cl2): δ = 7.95 (d, J = 8.2 Hz, 2 H), 7.42 (d,
J = 8.2 Hz, 2 H), 6.64 (m, 2 H), 6.43 (m, 2 H), 4.31 (t, J = 6.8 Hz,
1 H), 3.93 (m, 1 H), 3.86 (s, 3 H), 3.64 (s, 3 H), 1.74 (m, 2 H), 1.37
(m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (62.9 MHz,
CD2Cl2): δ = 167.3, 152.5, 151.0, 142.0, 130.2, 129.5, 127.1, 115.1,
50.8, 36.6, 34.2, 31.7, 22.2, 22.1, 22.0, 21.7 ppm. IR (KBr): ν =
˜
1756 cm–1. HRMS (ESI): calcd. for C26H29O4 [M + H]+ 405.2066;
found 405.2102.
Diisopropyl
2,3,3a,9b-Tetrahydro-1H-cyclopenta[a]naphthalene-
114.8, 59.0, 56.1, 52.4, 41.4, 20.0, 14.3 ppm. IR (KBr): ν = 1706
˜
3a,7-dicarboxylate (16a): Following the same procedure as for 15a,
starting from 14 (103 mg, 0.34 mmol) and using 1,3-dibromoprop-
ane (40 μL, 0.39 mmol) as the electrophile, 16a was obtained as a
colourless oil (93 mg, 79%). 1H NMR (250 MHz, CD2Cl2): δ =
7.80 (dd, J = 7.8, 1.6 Hz, 1 H), 7.73 (s, 1 H), 7.23 (d, J = 7.8 Hz,
1 H), 6.49 (d, J = 9.6 Hz, 1 H), 5.81 (d, J = 9.6 Hz, 1 H), 5.19
(hept, J = 6.3 Hz, 1 H), 4.88 (hept, J = 6.3 Hz, 1 H), 3.61 (t, J =
9.1 Hz, 1 H), 2.41–2.10 (m, 2 H), 2.01 (m, 1 H), 1.62 (m, 3 H), 1.34
(d, J = 6.2 Hz, 6 H), 1.13 (t, J = 6.7 Hz, 6 H) ppm. 13C NMR
(62.9 MHz, CD2Cl2): δ = 174.8, 166.3, 143.5, 131.3, 131.1, 129.8,
129.0, 128.4, 128.1, 126.4, 68.7, 68.5, 53.5, 45.9, 40.2, 37.0, 23.9,
cm–1. C19H23NO3 (313.40): calcd. C 72.82, H 7.40, N 4.47; found
C 72.56, H 7.60, N 4.61.
Methyl 4-[{(4-Methoxyphenyl)methylamino}methyl]benzoate (18b):
A solution of Me3SnLi (0.80 mmol) in THF was treated with a
solution of 17[29] (98 mg, 0.36 mmol) in THF (4 mL) at –78 °C.
After stirring for 2 h, Me2SO4 (45 μL, 0.47 mmol) was added, and
the resulting mixture was stirred for 2 h at –78 °C, slowly warmed
to room temperature for 4 h and stirred for 4 h. Work up and puri-
fication as for 18a afforded 18b as a yellowish oil, which was recrys-
tallized from CH2Cl2/hexane to give a white solid (63 mg, 60%);
1
22.2, 21.88, 21.85 ppm. IR (KBr): ν = 1717 cm–1. C H O
m.p. 57–58 °C (CH2Cl2/hexane). H NMR (250 MHz, CD2Cl2): δ
˜
21 26
4
= 7.96 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 6.79 (d, J =
9.0 Hz, 2 H), 6.70 (d, J = 9.0 Hz, 2 H), 4.48 (s, 2 H), 3.86 (s, 3 H),
3.72 (s, 3 H), 2.94 (s, 3 H) ppm. 13C NMR (62.9 MHz, CD2Cl2): δ
= 167.3, 152.5, 145.7, 144.9, 130.2, 129.5, 127.6, 115.1, 114.9, 58.3,
(342.43): calcd. C 73.66, H 7.65; found C 73.56, H 8.00.
Diisopropyl 4b,5,6,7,8,8a-Hexahydrophenanthrene-2,8a-dicarboxyl-
ate (16b): Following the same procedure as for 15a, starting from
14 (92 mg, 0.31 mmol) and using 1.4-diiodobutane (46 μL,
0.35 mmol) as the electrophile, 16b as a colourless oil (72 mg, 66%).
1H NMR (250 MHz, CD2Cl2): δ = 7.80 (dd, J = 7.8, 1.7 Hz, 1 H),
7.69 (d, J = 1.7 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 6.60 (d, J =
9.5 Hz, 1 H), 5.78 (dd, J = 9.5, 1.0 Hz, 1 H), 5.19 (hept, J = 6.3 Hz,
1 H), 4.77 (hept, J = 6.3 Hz, 1 H), 3.22 (m, 1 H), 2.00 (m, 1 H),
1.63 (m, 3 H), 1.39 (m, 4 H), 1.33 (d, J = 6.3 Hz, 6 H), 1.04 (d, J =
6.3 Hz, 3 H), 1.03 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (62.9 MHz,
CD2Cl2): δ = 175.0, 166.3, 146.2, 132.3, 132.1, 129.8, 129.3, 128.5,
127.8, 127.7, 68.6, 68.2, 47.9, 42.4, 34.5, 30.3, 24.6, 22.5, 22.2,
56.1, 52.4, 39.8 ppm. IR (KBr): ν = 1720 cm–1. C H NO
˜
17 19
3
(285.34): calcd. C 71.56, H 6.71, N 4.91; found C 71.30, H 6.48, N
5.00.
Methyl 4-[1-(4-Methoxyphenyl)pyrrolidin-2-yl]benzoate (18c):
A
solution of Me3SnLi (0.77 mmol) in THF was treated with a solu-
tion of 17[29] (95 mg, 0.35 mmol) in THF (4 mL) at –78 °C. After
stirring for 2 h, 1,3-dibromopropane (40 μL, 0.39 mmol) was
added, and the resulting mixture was stirred for 1 h at –78 °C and
4 h while warming to room temperature. Work up as for 18a fol-
lowed by column chromatography (neutral Al2O3, EtOAc/hexane,
1:6) afforded 18c as a white solid (96 mg, 87%); m.p. 79–80 °C
(CH2Cl2/hexane). 1H NMR (250 MHz, CDCl3): δ = 7.96 (d, J =
8.3 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 6.74 (d, J = 9.0 Hz, 2 H),
6.39 (d, J = 9.0 Hz, 2 H), 4.64 (dd, J = 8.5, 1.9 Hz, 1 H), 3.88 (s,
3 H), 3.70 (m, 1 H), 3.69 (s, 3 H), 3.35 (dd, J = 16.1, 8.3 Hz, 1 H),
2.39 (m, 1 H), 1.93 (m, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3):
δ = 167.0, 151.0, 150.7, 141.8, 129.9, 128.6, 126.0, 114.8, 113.0,
21.75, 21.74 ppm. IR (KBr): ν = 1716 cm–1. C H O (356.46):
˜
22 28
4
calcd. C 74.13, H 7.92; found C 73.87, H 7.56.
[(4bS,8aS)-4b,5,6,7,8,8a-Hexahydrophenanthrene-2,8a-diyl]di-
methanol (16c): A suspension of LiAlH4 (20 mg, 0.53 mmol) in
THF (1 mL) at 0 °C was treated with a solution of 16b (90 mg,
0.25 mmol) in THF (1 mL). The reaction mixture was stirred for
12 h while slowly warming to room temperature. After cooling to
0 °C, EtOAc (1 mL) was carefully added, followed by CHCl3, satu-
rated aqueous Na2CO3, solid KH2PO4 and Na2SO4. The resulting
suspension was stirred at room temperature for 1 h, filtered through
celite and the solvents evaporated. The product was obtained as
white crystals after crystallization from CH2Cl2/hexane (47 mg,
77%); m.p. 100–101 °C. 1H NMR (250 MHz, CDCl3): δ = 7.11 (dd,
J = 7.6, 1.5 Hz, 1 H), 7.04 (m, 2 H), 6.52 (d, J = 9.6 Hz, 1 H), 5.58
(dd, J = 9.6, 1.3 Hz, 1 H), 4.59 (s, 2 H), 3.28 (d, J = 10.7 Hz, 1 H),
3.14 (d, J = 10.7 Hz, 1 H), 2.60 (dd, J = 11.8, 3.8 Hz, 1 H), 1.86 (br.
s, 1 H), 1.71–1.18 (m, 9 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ
= 139.7, 138.9, 134.0, 132.1, 128.9, 127.9, 126.4, 125.2, 69.1, 65.2,
41.4, 32.8, 31.1, 24.8, 22.6 ppm. C16H20O2 (244.33): calcd. C 78.65,
H 8.25; found C 78.58, H 8.25.
63.3, 55.8, 52.0, 49.7, 36.1, 23.3 ppm. IR (KBr): ν = 1720, 1713
˜
cm–1. C19H21NO3 (311.38): calcd. C 73.29, H 6.80, N 4.50; found
C 72.99, H 7.09, N 4.46.
Methyl 4-[1-(4-Methoxyphenyl)piperidin-2-yl]benzoate (18d): Fol-
lowing the same procedure as for 18c, starting from 17[29] (105 mg,
0.39 mmol) and using 1.4-diiodobutane (62 μL, 0.47 mmol) as the
electrophile. The reaction mixture was stirred for 2 h at –78 °C and
4 h while warming to room temperature. Work up and purification
as for 18a, gave 18d as a white solid (95 mg, 75%); m.p. 83–84 °C
1
(CH2Cl2/hexane). H NMR (250 MHz, CD2Cl2): δ = 7.81 (d, J =
8.3 Hz, 2 H), 7.35 (d, J = 8.3 Hz, 2 H), 6.90 (m, 2 H), 6.64 (m, 2
H) 4.06 (dd, J = 9.7, 2.9 Hz, 1 H), 3.81 (s, 3 H), 3.64 (s, 3 H), 3.34
(m, 1 H), 2.80 (m, 1 H), 1.94–1.42 (m, 6 H) ppm. 13C NMR
(62.9 MHz, CD2Cl2): δ = 167.3, 155.7, 151.3, 146.7, 129.8, 128.8,
128.1, 125.0, 114.2, 65.0, 57.9, 55.7, 52.3, 37.1, 27.1, 24.9 ppm. IR
Methyl 4-[1-(4-Methoxyphenylamino)butyl]benzoate (18a): A solu-
tion of Me3SnLi (0.83 mmol) in THF was treated with a solution
of 17[29] (102 mg, 0.38 mmol) in THF (4 mL) at –78 °C. After stir-
ring for 2 h, 1-iodopropane (46 μL, 0.47 mmol) was added, and the
(KBr): ν = 1721 cm–1. C H NO (325.41): calcd. C 73.82, H 7.12,
˜
20 23
3
N 4.30; found C 73.42, H 7.46, N 4.27.
982
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 975–987

Enantioselective Annulation Reactions of Bisenolates
Methyl 4-[1-(4-Methoxyphenyl)-6-oxopiperidin-2-yl]benzoate (18e): = 9.5 Hz, 1 H), 4.66 (td, J = 10.6, 4.4 Hz, 1 H), 3.65 (m, 1 H), 3.62
Following the same procedure as for 18c, starting from 17[29]
(s, 3 H), 3.49 (dt, J = 10.4, 7.6 Hz, 1 H), 2.32 (m, 1 H), 1.97 (m, 1
(100 mg, 0.37 mmol), using methyl 4-iodobutyrate (102 mg, H), 1.84 (ddd, J = 12.3, 10.6, 3.5 Hz, 1 H), 1.74 (m, 3 H), 1.44 (m,
0.45 mmol) as the electrophile and stirring for 2 h at –78 °C, 4 h
while warming to room temperature and 14 h at 45 °C. Work up
and purification as for 18a, gave 18d as a white solid (84 mg, 67%);
1 H), 1.31 (m, 2 H), 1.22 (s, 3 H), 1.17 (s, 3 H), 0.88 (m, 2 H), 0.77
(d, J = 6.5 Hz, 3 H), 0.68 (ddd, J = 25.0, 13.0, 3.5 Hz, 1 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 171.9, 166.8, 150.1, 143.3,
127.9, 125.8, 125.3, 123.3, 109.3, 98.8, 76.3, 68.7, 51.1, 50.7, 50.2,
1
m.p. 82 °C (dec., CH2Cl2/hexane). H NMR (250 MHz, CD2Cl2):
δ = 7.94 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.01 (d, J 41.2, 40.2, 37.6, 34.4, 31.2, 30.1, 27.2, 24.4, 21.7, 20.9 ppm. IR
= 8.7 Hz, 2 H), 6.74 (d, J = 8.7 Hz, 2 H), 5.01 (t, J = 5.1 Hz, 1 H),
3.86 (s, 3 H), 3.70 (s, 3 H), 2.63 (m, 2 H), 2.34 (m, 1 H), 1.90 (m.
3 H) ppm. 13C NMR (62.9 MHz, CD2Cl2): δ = 171.1, 167.0, 158.5,
147.5, 135.5, 130.1, 130.0, 129.1, 127.7, 114.4, 65.6, 55.8, 52.5, 33.2,
(KBr): ν = 1728, 1692 cm–1. C H NO (437.57): calcd. C 74.11,
˜
27 35 4
H 8.06, N 3.20; found C 74.16, H 8.19, N 3.17.
7-Methyl
9a-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] (9aR)-2,3,4,9a-Tetrahydro-1H-quinolizine-7,9a-dicarboxylate
(26e): Compound 26e was prepared from 24e (56 mg, 0.14 mmol)
following the above procedure using 1,4-dibromobutane (44 μL,
0.36 mmol) as the electrophile at –78 °C for 1 h before DMF
(1 mL) was added and, after 20 min, the cooling bath was removed
and the reaction mixture was allowed to reach room temperature
and heated at 60 °C for 12 h. Work up as for 15a followed by col-
umn chromatography purification (SiO2, EtOAc/hexane, 1:6), af-
forded 26e as a pale yellow oil (37 mg, 58%): 1H NMR (750 MHz,
CDCl3): δ = 7.26 (m, 5 H), 7.14 (m, 1 H), 6.28 (dd, J = 9.8, 1.3 Hz,
1 H), 4.81 (td, J = 10.6, 4.3 Hz, 1 H), 4.50 (d, J = 9.8 Hz, 1 H),
3.64 (s, 3 H), 3.57 (td, J = 13.1, 3.3 Hz, 1 H), 3.18 (m, 1 H), 2.08
(m, 1 H), 1.97 (m, 2 H), 1.72 (m, 2 H), 1.62 (m, 1 H), 1.54 (m, 2
H), 1.41 (m, 2 H), 1.30 (m, 1 H), 1.29 (s, 3 H), 1.20 (s, 3 H), 0.97
(m, 2 H), 0.84 (d, J = 6.6 Hz, 3 H), 0.77 (ddd, J = 25.0, 13.0,
3.5 Hz, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 170.1, 166.6,
150.5, 148.3, 128.0, 125.6, 125.3, 122.5, 113.5, 95.7, 76.8, 65.6, 52.4,
50.6, 49.8, 41.6, 40.1, 35.6, 34.4, 31.3, 29.0, 27.2, 25.5, 25.1, 21.8,
32.8, 18.4 ppm. IR (KBr): ν = 1718, 1707 cm–1. HRMS (ESI):
˜
calcd. for C20H22NO4 [M + H]+ 340.1549; found 340.1543.
Procedure Using Substoichiometric Sn Reagent: To small pieces of
lithium wire (56 mg, 8 mmol) suspended in dry THF (1 mL) at
room temperature was added Me3SnCl (40 μL, 0.04 mmol). After
stirring for 30 min, the suspension was cooled to –78 °C and treated
with a solution of the corresponding diester (0.4 mmol) in THF
(1 mL). After 16 h at –78 °C, the solution was transferred[30]
through a cannula to a flask cooled to –78 °C and treated with the
corresponding electrophile. The reaction mixture was stirred for 6 h
while slowly warming to room temperature. Work up as for 18a
and column chromatography (SiO2, EtOAc/hexane, 1:20) afforded
the corresponding bicycles 21a[10] (90 mg, 77%), 21b[10] (83 mg,
68%), 22a[10] (SiO2, EtOAc/hexane, 1:10, 73 mg, 60%) and 10b
(neutral Al2O3, CH2Cl2/hexane, 1:1, 64 mg, 56%).
5-Methyl
2-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] Pyridine-2,5-dicarboxylate (24e): A suspension of 5-(meth-
oxycarbonyl)pyridine-2-carboxylic acid[31] (23, 200 mg, 1.10 mmol)
in CH2Cl2 (6 mL) was treated with (–)-8-phenylmenthol (256 mg,
1.10 mol), DMAP (22 mg, 0.18 mmol) and EDC (238 mg,
1.24 mmol) at room temperature. The reaction mixture was heated
to reflux in a sealed tube and every 48 h more EDC (238 mg,
1.24 mmol) and DMAP (22 mg, 0.18 mmol) were added. After
heating to reflux for 7 days, the resulting solution was cooled to
room temperature and washed with water and saturated aqueous
NaCl solution. The organic phase was dried (Na2SO4) and the sol-
vents evaporated. Column chromatography of the residue (SiO2,
EtOAc/hexane, 1:6) afforded 24e (354 mg, 81%) as a white solid
after recrystallization from MeOH; m.p. 131–133 °C. 1H NMR
(250 MHz, CDCl3): δ = 9.15 (dd, J = 2.1, 0.7 Hz, 1 H), 8.14 (dd,
21.3 ppm. IR (KBr): ν = 1726, 1689 cm–1. C H NO (451.60):
˜
28 37
4
calcd. C 74.47, H 8.26, N 3.10; found C 74.62, H 8.46, N 3.15.
3-Methyl 10a-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] (10aR)-6,7,8,9,10,10a-Hexahydropyrido[1,2-a]azepine-3,10a-
dicarboxylate (27e): Compound 27e was prepared from 24e (50 mg,
0.13 mmol) following the above procedure using 1,5-diiodopentane
(25 μL, 0.17 mmol) as the electrophile at –78 °C for 1 h before
DMF (1 mL) was added, and, after 20 min, the cooling bath was
removed and the reaction mixture was allowed to reach room tem-
perature and heated at 60 °C for 12 h. Work up as for 15a followed
by column chromatography (SiO2, EtOAc/hexane, 1:6) afforded 27e
1
as a pale yellow oil (37 mg, 62%). H NMR (250 MHz, CDCl3): δ
= 7.38 (s, 1 H), 7.26 (m, 4 H), 7.14 (m, 1 H), 6.47 (dd, J = 9.6,
J = 8.1, 2.1 Hz, 1 H), 7.22 (m, 3 H), 6.99 (t, J = 7.7 Hz, 2 H), 6.80 1.2 Hz, 1 H), 4.76 (td, J = 10.6, 4.4 Hz, 1 H), 4.59 (d, J = 9.6 Hz,
(t, J = 7.3 Hz, 1 H), 5.14 (td, J = 10.8, 4.5 Hz, 1 H), 3.93 (s, 3 H), 1 H), 3.66 (s, 3 H), 3.29 (m, 2 H), 2.12–1.14 (m, 19 H), 0.96 (m, 2
2.24 (td, J = 12.1, 3.6 Hz, 1 H), 1.95 (m, 1 H), 1.83 (m, 1 H), 1.68 H), 0.82 (d, J = 6.4 Hz, 3 H), 0.75 (m, 1 H) ppm. 13C NMR
(m, 1 H), 1.51 (m, 1 H), 1.29 (s, 3 H), 1.17 (s, 3 H), 1.15 (m, 2 H), (62.9 MHz, CDCl3, main isomer): δ = 172.7, 166.6, 150.4, 147.3,
0.91 (m, 1 H), 0.85 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (62.9 MHz, 128.0, 125.7, 125.3, 124.5, 113.5, 97.4, 76.4, 67.7, 53.3, 50.6, 50.1,
CDCl3): δ = 164.9, 162.9, 151.5, 150.7, 150.3, 137.6, 127.8, 127.7,
125.1, 124.7, 124.3, 75.9, 52.6, 50.2, 41.4, 39.4, 34.4, 31.2, 29.2,
26.3, 23.5, 21.7 ppm. C24H29NO4 (395.49): calcd. C 72.89, H 7.39,
N 3.54; found C 72.76, H 7.47, N 3.64.
41.6, 40.4, 40.2, 34.4, 31.3, 31.2, 29.5, 29.0, 27.2, 25.0, 22.4, 21.7
ppm. IR (KBr): ν = 1729, 1690 cm–1. C H NO (465.62): calcd.
˜
29 39
4
C 74.81, H 8.44, N 3.01; found C 75.15, H 8.34, N 3.12.
6-(Methoxycarbonyl)quinoline-2-carboxylic Acid: To a stirring solu-
6-Methyl
8a-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
tion of dimethyl quinoline-2,6-dicarboxylate[32] (1.75 g, 7.1 mmol)
hexyl] (8aR)-1,2,3,8a-Tetrahydroindolizine-6,8a-dicarboxylate (25e): in dioxane (45 mL) at room temperature was added a solution of
A solution of Me3SnLi (0.40 mmol) in THF was treated with a
solution of 24e (70 mg, 0.18 mmol) in THF at –78 °C. After stirring
for 45 min, 1,3-dibromopropane (25 μL, 0.25 mmol) was added.
The reaction mixture was stirred for 12 h while slowly warming to
room temperature. Work up as for 15a followed by column
chromatography (SiO2, EtOAc/hexane, 1:6), afforded 25e as a white
solid (61 mg, 79%) after crystallization from Et2O/CH2Cl2; m.p.
LiOH·H2O (300 mg, 7.1 mmol) in H2O (5.6 mL). After stirring for
16 h, the reaction mixture was filtered, and the filtrate was washed
with dioxane. The solid was dissolved in water, and the aqueous
solution was cooled to 0 °C and acidified with HCl. The precipitate
was isolated by filtration and washed with water to give the product
as a white powder after drying (1.40 g, 85%). 1H NMR (250 MHz,
CD3OD): δ = 8.74 (s, 1 H), 8.65 (d, J = 8.5 Hz, 1 H), 8.41–8.22
(m, 3 H), 4.00 (s, 3 H) ppm. 13C NMR (62.9 MHz, [D6]DMSO): δ
= 166.0, 165.7, 150.7, 148.3, 139.5, 130.8, 130.2, 129.3, 129.0, 128.1,
1
130–133 °C. H NMR (750 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.19
(m, 4 H), 7.08 (m, 1 H), 6.42 (dd, J = 9.5, 1.0 Hz, 1 H), 4.88 (d, J
Eur. J. Org. Chem. 2012, 975–987
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
983

F. J. Sardina, M. R. Paleo et al.
FULL PAPER
121.6, 52.7 ppm. IR (KBr): ν = 1724 cm–1. C H NO (231.21):
calcd. C 62.34, H 3.92, N 6.06; found C 62.62, H 3.98, N 6.31.
9.8 Hz, 1 H), 5.38 (dd, J = 9.9, 2.0 Hz, 1 H), 4.79 (td, J = 10.7,
4.3 Hz, 1 H), 3.97 (s, 1 H), 3.79 (s, 3 H), 2.12 (ddd, J = 12.4, 10.7,
3.5 Hz, 1 H), 2.05 (td, J = 12.6, 4.8 Hz, 1 H), 1.97 (td, J = 12.7,
4.8 Hz, 1 H), 1.83–1.69 (m, 3 H), 1.63 (m, 10 H), 1.48 (m, 2 H),
1.28 (s, 3 H), 1.18 (s, 3 H), 1.13 (m, 1 H), 0.90–0.81 (m, 5 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 172.7, 167.1, 152.2, 147.0,
131.2, 128.7, 128.3, 126.3, 125.6, 125.2, 124.8, 123.1, 118.3, 117.5,
111.8, 63.2, 51.5, 49.7, 41.2, 39.6, 39.1, 34.4, 31.3, 29.0, 28.6, 26.6,
˜
12
9
4
6-Methyl 2-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] Quinoline-2,6-dicarboxylate (28): A suspension of 6-(meth-
oxycarbonyl)quinoline-2-carboxylic acid (700 mg, 3.0 mmol) in
CH2Cl2 (20 mL) was treated with (–)-8-phenylmenthol (705 mg,
3.0 mol), DMAP (135 mg, 1.1 mmol) and bis(2-pyridyl)carbonate
(DPC, 820 mg, 3.8 mmol) at room temperature. The reaction mix-
ture was heated to reflux in a sealed tube and, after 24 h, more
DPC (650 mg, 3.0 mmol) and DMAP (135 mg, 1.1 mmol) were
added. After heating to reflux for 4 days, the resulting solution was
cooled to room temperature, pH 7.0 phosphate buffer was added
and the mixture was extracted twice with CH2Cl2. The organic
phase was dried (Na2SO4) and the solvents evaporated. Flash col-
umn chromatography of the residue (SiO2, EtOAc/hexane, 1:10)
afforded 28 (1.16 g, 85%) as a white foam. 1H NMR (250 MHz,
CD2Cl2): δ = 8.61 (d, J = 2.0 Hz, 1 H), 8.25 (m, 3 H), 7.43 (d, J =
8.5 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 2 H), 7.02 (t, J = 7.5 Hz, 2 H),
6.79 (t, J = 7.3 Hz, 1 H), 5.15 (td, J = 10.7, 4.4 Hz, 1 H), 3.98 (s,
3 H), 2.29 (ddd, J = 12.1, 10.4, 3.6 Hz, 1 H), 2.05 (m, 1 H), 1.90–
1.49 (m, 3 H), 1.38 (s, 3 H), 1.26 (s, 3 H), 1.23 (m, 2 H), 0.98 (m,
1 H), 0.92 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3):
δ = 166.1, 163.3, 151.5, 149.7, 149.0, 137.9, 131.0, 130.3, 129.4,
129.1, 128.0, 127.8, 125.1, 124.7, 121.6, 76.1, 52.4, 50.3, 41.4, 39.5,
24.6, 21.7, 20.6, 20.1, 18.5 ppm. IR (KBr): ν = 1713 cm–1. HRMS
˜
(ESI): calcd. for C35H46NO4 [M + H]+ 544.3421; found 544.3404.
C35H45NO4 (543.74): calcd. C 77.31, H 8.34, N 2.58; found C
77.06, H 8.62, N 2.44.
6-Methyl
hexyl]
2-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
(2R)-2-Phenethyl-1,2-dihydroquinoline-2,6-dicarboxylate
(29c): A solution of Me3SnLi (0.88 mmol) in THF (1 mL) at –78 °C
was treated with a solution of 28 (180 mg, 0.4 mmol) in THF
(3 mL). After 1 h, 2-(bromoethyl)benzene (60 μL, 0.44 mmol) was
added. The reaction mixture was stirred for 3 h while slowly warm-
ing to room temperature and stirred at 25 °C for 12 h. Work up as
for 15a followed by column chromatography (SiO2, EtOAc/hexane,
1:10) afforded 29c as a white foam (154 mg, 70%). 1H NMR
(750 MHz, CD2Cl2): δ = 7.68 (dd, J = 8.4, 2.0 Hz, 1 H), 7.53 (d, J
= 1.9 Hz, 1 H), 7.38–7.15 (m, 10 H), 6.43 (d, J = 9.9 Hz, 1 H), 6.40
(d, J = 8.4 Hz, 1 H), 5.44 (dd, J = 9.9, 2.0 Hz, 1 H), 4.81 (dt, J =
10.7, 4.3 Hz, 1 H), 3.95 (s, 1 H), 3.81 (s, 3 H), 2.62 (m, 2 H), 2.16
(ddd, J = 12.2, 10.5, 3.6 Hz, 1 H), 2.02 (ddd, J = 13.6, 12.1, 5.1 Hz,
1 H), 1.83–1.72 (m, 3 H), 1.66 (m, 1 H), 1.46 (m, 1 H), 1.28 (s, 3
H), 1.18 (s, 3 H), 1.15 (m, 1 H), 0.89 (m, 2 H), 0.85 (d, J = 6.6 Hz,
3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 172.6, 167.1, 152.3,
146.8, 141.4, 131.2, 128.7, 128.42, 128.36, 128.32, 126.6, 125.9,
125.5, 125.2, 122.7, 118.4, 117.3, 111.8, 76.5, 63.1, 51.5, 49.6, 42.6,
34.4, 31.2, 28.7, 26.4, 24.1, 21.7 ppm. IR (KBr): ν = 1726 cm–1.
˜
HRMS (ESI): calcd. for C28H31NO4Na [M + Na]+ 468.2145; found
468.2149. C28H31NO4 (445.56): calcd. C 75.48, H 7.01, N 3.14;
found C 75.08, H 6.90, N 3.03.
6-Methyl
2-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] (2R)-2-Propyl-1,2-dihydroquinoline-2,6-dicarboxylate (29a):
A solution of Me3SnLi (0.62 mmol) in THF (0.7 mL) at –78 °C
was treated with a solution of 28 (127 mg, 0.28 mmol) in THF
(2.1 mL). After 1 h, 1-iodopropane (50 μL, 0.44 mmol) was added.
The reaction mixture was stirred for 8 h while slowly warming to
room temperature. Work up as for 15a followed by column
chromatography (SiO2, EtOAc/hexane, 1:10) afforded 29a (125 mg,
41.1, 39.5, 34.4, 31.2, 30.2, 29.3, 26.5, 24.2, 21.7 ppm. IR (KBr): ν
˜
= 1712 cm–1. HRMS (ESI): calcd. for C36H41NO4Na [M + Na]+
574.2928; found 574.2930. C36H41NO4·H2O (569.73): calcd. C
75.89, H 7.61, N 2.46; found C 75.78, H 7.21, N 2.37.
6-Methyl
2-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
1
90%) as a white foam. H NMR (500 MHz, CDCl3): δ = 7.66 (dd,
hexyl] (2R)-2-[2-(2-Methyl-1,3-dioxolan-2-yl)ethyl]-1,2-dihydroquin-
oline-2,6-dicarboxylate (29d). A solution of Me3SnLi (0.42 mmol)
in THF (0.5 mL) at –78 °C was treated with a solution of 28
J = 8.4, 2.0 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 4.2 Hz,
4 H), 7.23 (m, 1 H), 6.32 (d, J = 9.8 Hz, 1 H), 6.31 (d, J = 8.3 Hz,
1 H), 5.36 (dd, J = 9.8, 2.1 Hz, 1 H), 4.79 (td, J = 10.7, 4.3 Hz, 1 (85 mg, 0.19 mmol) in THF (1.2 mL). After 1 h, 2-(2-bromoethyl)-
H), 3.82 (s, 3 H), 3.77 (s, 1 H), 2.12 (ddd, J = 12.1, 10.5, 3.6 Hz, 1
H), 1.77 (m, 2 H), 1.66 (m, 2 H), 1.41 (m, 2 H), 1.29 (m, 5 H), 1.17
2-methyl-1,3-dioxolane[34] (71 mg, 0.36 mmol) was added, immedi-
ately followed by hexamethylphosphoramide (0.2 mL). The reac-
(s, 3 H), 1.14 (m, 1 H), 0.91 (t, J = 7.2 Hz, 3 H), 0.87 (m, 2 H), tion mixture was stirred for 24 h at –78 °C. Work up as for 15a
0.84 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = followed by column chromatography (SiO2, EtOAc/hexane, 1:3) af-
172.9, 167.1, 152.1, 146.9, 131.1, 128.6, 128.3, 126.0, 125.6, 125.2,
123.1, 118.2, 117.4, 111.7, 76.4, 63.1, 51.5, 49.6, 43.2, 41.1, 39.6,
forded 29d as a white foam (51 mg, 48%). 1H NMR (750 MHz,
CDCl3): δ = 7.65 (dd, J = 8.5, 2.0 Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1
H), 7.39–7.31 (m, 4 H), 7.24 (m, 1 H), 6.33 (d, J = 9.9 Hz, 1 H),
6.28 (d, J = 8.4 Hz, 1 H), 5.34 (dd, J = 9.9, 2.0 Hz, 1 H), 4.79 (td,
J = 10.7, 4.3 Hz, 1 H), 3.99–3.89 (m, 4 H), 3.82 (s, 3 H), 3.64 (s, 1
H), 2.11 (ddd, J = 12.3, 10.5, 3.5 Hz, 1 H), 1.85–1.73 (m, 3 H),
1.65 (m, 3 H), 1.59 (m, 1 H), 1.45 (m, 1 H), 1.31 (s, 3 H), 1.27 (s,
3 H), 1.17 (s, 3 H), 1.12 (m, 1 H), 0.84 (m, 2 H), 0,83 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 172.8, 167.1,
152.3, 146.9, 131.2, 128.7, 128.4, 126.6, 125.6, 125.2, 122.8, 118.3,
117.2, 111.8, 109.7, 64.7, 62.7, 51.5, 49.8, 41.1, 39.6, 35.0, 34.4,
34.4, 31.2, 28.9, 26.6, 24.7, 21.7, 16.9, 14.1 ppm. IR (KBr): ν = 1712
˜
cm–1. HRMS (ESI): calcd. for C31H39NO4Na [M + Na]+ 512.2771;
found 512.2775. C31H39NO4 (489.65): calcd. C 76.04, H 8.03, N
2.86; found C 76.30, H 8.27, N 2.74.
6-Methyl
2-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] (2R)-2-(3,4-Dimethylpent-3-en-1-yl)-1,2-dihydroquinoline-2,6-
dicarboxylate (29b): A solution of Me3SnLi (0.42 mmol) in THF
(0.5 mL) at –78 °C was treated with a solution of 28 (85 mg,
0.19 mmol) in THF (1.4 mL). After 1 h, 5-bromo-2,3-dimeth-
ylpent-2-ene[33] (65 mg, 0.37 mmol) was added. The reaction mix-
ture was stirred for 3 h while slowly warming to room temperature
and then stirred at 25 °C for 12 h. Work up as for 15a, followed by
column chromatography (SiO2, EtOAc/hexane, 1:10) afforded 29b
33.3, 31.2, 29.1, 26.6, 24.4, 24.1, 21.7 ppm. IR (KBr): ν = 1712
˜
cm–1. HRMS (ESI): calcd. for C34H43NO6Na [M + Na]+ 584.2983;
found 584.2981.
3-(Methoxycarbonyl)-7-methoxybenzofuran-2-carboxylic Acid (31):
A solution of dimethyl 7-methoxybenzofuran-2,3-dicarboxylate[27]
(30, 6.07 g, 23 mmol) in a 1:1 dioxane/H2O solution (230 mL) at
0 °C was treated with LiOH·H2O (1 g, 24 mmol), and the mixture
1
as a pale yellow oil (80 mg, 77%). H NMR (500 MHz, CD2Cl2):
δ = 7.64 (dd, J = 8.4, 2.0 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.34
(m, 4 H), 7.23 (m, 1 H), 6.38 (d, J = 8.3 Hz, 1 H), 6.37 (d, J =
984
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 975–987

Enantioselective Annulation Reactions of Bisenolates
was stirred for 2 h. The solution was acidified with HCl (6 n), and
saturated aqueous Na2CO3 solution, solid KH2PO4 and Na2SO4.
The resulting suspension was stirred at room temp. for 1 h and
the white solid was collected, dried and used without further purifi-
cation (5.64 g, 98%); m.p. 212–214 °C (MeOH). 1H NMR filtered through celite before the solvents were evaporated. The resi-
(250 MHz, CDCl3): δ = 14.18 (br. s, 1 H), 7.57 (d, J = 8.1 Hz, 1
due was chromatographed through a short column of SiO2 (4%
H), 7.34 (t, J = 8.0 Hz, 1 H), 6.98 (d, J = 7.9 Hz, 1 H), 4.17 (s, 3 iPrOH/CH2Cl2) to give 34 (126 mg, 75%) as a colourless oil. 1H
H), 4.00 (s, 3 H) ppm. 13C NMR (62.9 MHz, DMSO): δ = 162.8, NMR (250 MHz, CDCl3): δ = 6.81 (m, 1 H), 6.68 (m, 1 H), 6.60
159.2, 146.4, 145.3, 142.9, 126.3, 125.8, 117.1, 113.6, 109.7, 56.0,
(dd, J = 7.4, 1.0 Hz, 1 H), 5.78 (m, 2 H), 4.05–3.57 (m, 9 H), 2.61–
52.7 ppm. IR (KBr): ν = 1760 cm–1. HRMS (ESI): calcd. for 2.24 (m, 4 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 146.9,
˜
C12H11O6 [M + H]+ 251.0550; found 251.0551. C12H10O6 (250.21):
calcd. C 57.60, H 4.03; found C 57.25, H 3.99.
143.9, 133.4, 127.2, 126.0, 121.3, 115.1, 111.1, 94.0, 66.5, 65.6, 55.6,
54.2, 32.9, 32.2 ppm. HRMS (ESI): calcd. for C15H18O4Na [M +
Na]+ 285.1097; found 285.1100.
3-Methyl
2-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] 7-Methoxybenzofuran-2,3-dicarboxylate (32): A solution of
31 (0,94 g, 3.76 mmol), (–)-8-phenylmenthol (872 mg, 3.76 mmol),
DPC (850 mg, 3.94 mmol) and DMAP (83 mg, 0.68 mmol) in dry
dichloroethane (18 mL) was sealed in a vessel and heated to reflux
for 1 day. The reaction mixture was cooled to room temperature,
H2O was added and the layers were separated. The organic layer
was washed with water and brine, dried and evaporated under re-
duced pressure. The crude product was purified by flash column
chromatography (EtOAc/toluene, 1:50) to give 32 (1.47 g, 84%) as
a white foam. [α]2D4 = –21.6 (c = 0.5, MeOH). 1H NMR (250 MHz,
CD2Cl2): δ = 7.43 (dd, J = 8.0, 0.9 Hz, 1 H), 7.30 (t, J = 8.0 Hz, 1
H), 7.23 (m, 2 H), 6.99 (m, 3 H), 6.66 (m, 1 H), 5.12 (td, J = 10.8,
4.5 Hz, 1 H), 4.03 (s, 3 H), 3.95 (s, 3 H), 2.10 (m, 2 H), 1.82–1.43
(m, 3 H), 1.34 (s, 3 H), 1.26 (s, 3 H), 1.20 (m, 2 H), 0.94 (m, 1 H),
0.93 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (250 MHz, CD2Cl2): δ =
163.2, 158.0, 151.4, 146.6, 146.2, 144.0, 128.1, 127.7, 125.7, 125.1,
118.0, 114.6, 109.4, 76.6, 56.6, 52.6, 51.3, 42.0, 40.2, 35.0, 32.0,
(2R,2ЈR)-[(4aR,9bR)-6-Methoxy-1,4,4a,9b-tetrahydrodibenzo-
[b,d]furan-4a,9b-diyl]bis(methylene)bis(2-methoxy-2-phenylacetate)
(35): A solution of 34 (61 mg, 0.23 mmol) in 1,2-dichloroethane
(0.6 mL) was added to a solution of (R)-methoxyphenylacetic acid
[(R)-MPA, 85 mg, 0.51 mmol], DPC (105 mg, 0.49 mmol) and
DMAP (8.5 mg, 0.07 mmol) in 1,2-dichloroethane (0.65 mL). The
reaction mixture was stirred for 1 day at 40 °C. H2O was added,
the layers were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic layer was washed with H2O
and brine, dried and concentrated. The crude product was purified
by column chromatography (SiO2, CH2Cl2) to give 35 (113 mg,
87%) as a colourless foam. [α]2D4 = –57.2 (0.5, MeOH). H NMR
1
(500 MHz, CD2Cl2): δ = 7.32 (m, 10 H), 6.72 (m, 2 H), 6.50 (dd,
J = 7.2, 1.5 Hz, 1 H), 5.63 (m, 2 H), 4.76 (s, 1 H), 4.68 (s, 1 H),
4.36 (d, J = 11.8 Hz, 1 H), 4.28 (d, J = 11.8 Hz, 1 H), 4.24 (d, J =
11.6 Hz, 1 H), 4.19 (d, J = 11.6 Hz, 1 H), 3.77 (s, 3 H), 3.36 (s, 3
H), 3.33 (s, 3 H), 2.33 (dd, J = 15.9, 5.6 Hz, 1 H), 2.20 (dd, J =
15.7, 5.8 Hz, 1 H), 1.98 (m, 1 H), 1.89 (m, 1 H) ppm. 13C NMR
(250 MHz, CD2Cl2): δ = 170.6, 170.5, 147.5, 144.6, 136.85, 136.83,
132.6, 129.3, 129.2, 129.1, 127.74, 127.67, 126.2, 121.8, 115.7,
112.5, 91.8, 83.0, 82.9, 67.4, 67.2, 57.84, 57.80, 56.2, 52.7, 32.9, 32.0
28.1, 27.1, 25.4, 22.1 ppm. IR (CHCl ): ν = 1722 cm–1. HRMS
˜
3
(ESI): calcd. for C28H32O6Na [M + Na]+ 487.2091; found 487.2091.
C28H32O6 (464.56): calcd. C 72.39, H 6.94; found C 72.18, H 7.10.
9b-Methyl 4a-[(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclo-
hexyl] (4aR,9bS)-6-Methoxy-1,4,4a,9b-tetrahydrodibenzo[b,d]furan-
4a,9b-dicarboxylate (33): A solution of Me3SnLi (0.29 mmol) in
THF (1.4 mL) was treated with a solution of 32 (65 mg, 0.14 mmol)
in THF (1.4 mL) at –78 °C. After stirring for 1 h, a solution of cis-
1,4-bis(methylsulfonyloxy)-2-butene[35] (42 mg, 0.17 mmol) in
DMF (0.75 mL) was added dropwise, and the reaction mixture was
stirred for 1 day at –55 °C. The reaction mixture was quenched
with deoxygenated pH 5.6 acetate buffer and partitioned between
CH2Cl2 and acetate buffer. The aqueous phase was extracted with
CH2Cl2, and the combined organic phase was washed with water
and brine, dried and concentrated. The crude product was purified
by flash column chromatography (EtOAc/toluene, 1:50) to give 33
(36 mg, 50%) as a pale yellow foam. 1H NMR (500 MHz, CD2Cl2):
δ = 7.30 (m, 4 H), 7.15 (m, 1 H), 6.83 (t, J = 7.8 Hz, 1 H), 6.74
(m, 2 H), 5.83 (m, 2 H), 4.87 (td, J = 10.6, 4.2 Hz, 1 H), 3.82 (s, 3
H), 3.62 (s, 3 H), 2.78 (m, 2 H), 2.65 (dd, J = 16.2, 5.8 Hz, 1 H),
2.49 (d, J = 16.6 Hz, 1 H), 2.05 (m, 2 H), 1.47 (m, 2 H), 1.36 (s, 3
H), 1.26 (s, 3 H), 1.24 (m, 1 H), 1.07 (dd, J = 23.2, 11.7 Hz, 1 H),
0.95 (m, 1 H), 0.88 (d, J = 6.3 Hz, 3 H), 0.78 (ddd, J = 14.9, 12.5,
2.9 Hz, 1 H) ppm. 13C NMR (62.9 MHz, CD2Cl2): δ = 173.3, 171.4,
151.3, 148.3, 144.8, 131.7, 128.6, 127.8, 126.3, 125.9, 125.8, 122.2,
115.8, 112.8, 94.2, 77.7, 60.8, 56.4, 52.9, 50.9, 41.6, 40.9, 34.9, 34.7,
ppm. IR (KBr): ν = 1753 cm–1. C H O (558.63): calcd. C 70.95,
˜
33 34
8
H 6.13; found C 70.58, H 6.42.
(2S,2ЈS)-[(4aR,9bR)-6-Methoxy-1,4,4a,9b-tetrahydrodibenzo[b,d]-
furan-4a,9b-diyl]bis(methylene)bis(2-methoxy-2-phenylacetate) (36):
Following the same procedure as above with (S)-MPA (91 mg,
0.55 mmol), 34 (65 mg, 0.25 mmol) gave 35 (100 mg, 72%) as a
colourless foam. [α]2D0 = +28 (c = 0.5, MeOH). 1H NMR (500 MHz,
CD2Cl2): δ = 7.28 (m, 10 H), 6.78 (dd, J = 8.0, 7.6 Hz, 1 H), 6.72
(dd, J = 8.1, 1.2 Hz, 1 H), 6.56 (dd, J = 7.5, 1.2 Hz, 1 H), 5.72 (m,
2 H), 4.70 (s, 1 H), 4.60 (s, 1 H), 4.27 (d, J = 11.8 Hz, 1 H), 4.18
(d, J = 11.6 Hz, 1 H), 4.16 (d, J = 11.6 Hz, 1 H), 4.01 (d, J =
11.8 Hz, 1 H), 3.77 (s, 3 H), 3.34 (s, 3 H), 3.33 (s, 3 H), 2.41 (dd,
J = 15.9, 5.9 Hz, 1 H), 2.18 (m, 2 H), 2.00 (m, 1 H) ppm. 13C NMR
(250 MHz, CD2Cl2): δ = 170.5, 170.3, 147.7, 144.4, 136.73, 136.69,
133.0. 129.2, 129.14, 129.10, 129.07, 127.7, 127.63, 127.58, 126.3,
121.7, 115.7, 112.5, 91.9, 82.9, 67.7, 67.1, 57.8, 56.3, 52.4, 33.5, 32.2
ppm. IR (KBr): ν = 1754 cm–1. C H O (558.63): calcd. C 70.95,
˜
33 34
8
H 6.13; found C 71.22, H 6.28.
Supporting Information (see footnote on the first page of this arti-
1
cle): General experimental methods and copies of the H and 13C
NMR spectra for all new compounds.
32.5, 31.9, 31.0, 28.0, 23.1, 22.1 ppm. IR (KBr): ν = 1741, 1727
˜
cm–1. C32H38O6 (518.65): calcd. C 74.11, H 7.39; found C 74.22, H
7.67.
Acknowledgments
[(4aR,9bR)-6-Methoxy-1,4,4a,9b-tetrahydrodibenzo[b,d]furan-
4a,9b-diyl]dimethanol (34): A suspension of LiAlH4 (60 mg,
1.6 mmol) in THF (1 mL) was treated with a solution of 33
(330 mg, 0.64 mmol) in THF (1.1 mL) at 0 °C. After stirring for
3 h at 0 °C, EtOAc (1 mL) was carefully added followed by CHCl3,
Financial support from the Spanish Ministerio de Ciencia y Tecno-
logía (MCYT) (fellowship to A. V.) and the Xunta de Galicia
(grant numbers 10PXIB209113PR and 10PXIB209155PR) is grate-
fully acknowledged.
Eur. J. Org. Chem. 2012, 975–987
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
985

F. J. Sardina, M. R. Paleo et al.
FULL PAPER
[7]
[8]
a) N. Chopin, H. Gérard, I. Chataigner, S. R. Piettre, J. Org.
Chem. 2009, 74, 1237–1246; b) J. E. Camp, D. Craig, Tetrahe-
dron Lett. 2009, 50, 3503–3508.
a) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.
2007, 5969–5994; b) B. M. Trost, C. Jiang, Synthesis 2006, 369–
396; c) J. Christoffers, A. Baro, Quaternary Stereocenters: Chal-
lenges and Solutions for Organic Synthesis, Wiley-VCH,
Weinheim, Germany, 2005.
a) T. J. Donohoe, A. J. McRiner, M. Helliwell, P. Sheldrake, J.
Chem. Soc. Perkin Trans. 1 2001, 1435–1445; b) T. J. Donohoe,
A. J. McRiner, P. Sheldrake, Org. Lett. 2000, 2, 3861–3863.
P. Monje, P. Graña, M. R. Paleo, F. J. Sardina, Org. Lett. 2006,
8, 951–954.
M. R. Paleo, M. I. Calaza, P. Graña, F. J. Sardina, Org. Lett.
2004, 6, 1061–1063.
[1]
a) F. López-Ortiz, M. J. Iglesias, I. Fernández, C. M. Andújar-
Sánchez, G. Ruiz-Gómez, Chem. Rev. 2007, 107, 1580–1691,
and references cited therein; b) S. P. Roche, J. A. Porco Jr., An-
gew. Chem. Int. Ed. 2011, 50, 4068–4093.
a) F. Ding, M. T. Valahovic, J. M. Keane, M. R. Anstey, M.
Sabat, C. O. Trindle, W. D. Harman, J. Org. Chem. 2004, 69,
2257–2267; b) S. Dong, J. Zhu, J. A. Porco Jr., J. Am. Chem.
Soc. 2008, 130, 2738–2739; c) J. Liang, J. Chen, J. Liu, L. Li,
H. Zhang, Chem. Commun. 2010, 46, 3666–3668; d) J. Qi, A. B.
Beeler, Q. Zhang, J. A. Porco Jr., J. Am. Chem. Soc. 2010, 132,
13642–13644, and references cited therein; e) M. A. Lovchik,
A. Goeke, G. Fráter, Tetrahedron: Asymmetry 2006, 17, 1693–
1699; f) J. García-Fortanet, F. Kessler, S. L. Buchwald, J. Am.
Chem. Soc. 2009, 131, 6676–6677.
a) H. Brice, J. Clayden, Chem. Commun. 2009, 1964–1966; b)
J. Clayden, S. Parris, N. Cabedo, A. H. Payne, Angew. Chem.
2008, 120, 5138; Angew. Chem. Int. Ed. 2008, 47, 5060–5062;
c) S. Lu, Z. Xu, M. Bao, Y. Yamamoto, Angew. Chem. 2008,
120, 4438; Angew. Chem. Int. Ed. 2008, 47, 4366–4369; d) G.
Ruiz-Gómez, A. Francesch, M. J. Iglesias, F. López-Ortiz, C.
Cuevas, M. Serrano-Ruiz, Org. Lett. 2008, 10, 3981–3984; e)
G. Ruiz-Gómez, M. J. Iglesias, M. Serrano-Ruiz, F. López-Or-
tiz, J. Org. Chem. 2007, 72, 9704–9712; f) G. Barbe, G. Pelletier,
A. B. Charette, Org. Lett. 2009, 11, 3398–3401; g) J. Clayden,
M. N. Kenworthy, M. Helliwell, Org. Lett. 2003, 5, 831–834;
h) T. Bach, Angew. Chem. 1996, 108, 795; Angew. Chem. Int.
Ed. Engl. 1996, 35, 729–730; i) I. Fernández, A. Forcén-Acebal,
S. García-Granda, F. López-Ortiz, J. Org. Chem. 2003, 68,
4472–4485.
a) T. Dohi, A. Maruyama, N. Takenaga, K. Senami, Y. Mina-
mitsuji, H. Fujioka, S. B. Caemmerer, Y. Kita, Angew. Chem.
2008, 120, 3847; Angew. Chem. Int. Ed. 2008, 47, 3787–3790;
b) N. T. Vo, R. D. M. Pace, F. O’Hara, M. J. Gaunt, J. Am.
Chem. Soc. 2008, 130, 404–405; c) S. Quideau, G. Lyvinec, M.
Marguerit, K. Bathany, A. Ozanne-Beaudenon, T. Buffeteau,
D. Cavagnat, A. Chénedé, Angew. Chem. 2009, 121, 4675; An-
gew. Chem. Int. Ed. 2009, 48, 4605–4609; d) L. Pouységu, S.
Chassaing, D. Dejugnac, A.-M. Lamidey, K. Miqueu, J.-M.
Sotiropoulos, S. Quideau, Angew. Chem. 2008, 120, 3608; An-
gew. Chem. Int. Ed. 2008, 47, 3552–3555; e) J. Liang, J. Chen,
F. Du, X. Zeng, L. Li, H. Zhang, Org. Lett. 2009, 11, 2820–
2823; f) J. Zhu, N. P. Grigoriadis, J. P. Lee, J. A. Porco Jr., J.
Am. Chem. Soc. 2005, 127, 9342–9343; g) Q. Liu, T. Rovis,
Org. Process Res. Dev. 2007, 11, 598–604; h) L. H. Mejorado,
T. R. R. Pettus, J. Am. Chem. Soc. 2006, 128, 15625–15631; i)
S. P. Cook, A. Polara, S. J. Danishefsky, J. Am. Chem. Soc.
2006, 128, 16440–16441.
a) A. G. Schultz, Chem. Commun. 1999, 1263–1271; b) T. J.
Donohoe, G. C. Freestone, C. E. Headley, C. L. Rigby, R. P. C.
Cousins, G. Bhalay, Org. Lett. 2004, 6, 3055–3058; c) T. J.
Donohoe, D. J. Johnson, L. H. Mace, R. E. Thomas, J. Y. K.
Chiu, J. S. Rodrigues, R. G. Compton, C. E. Banks, P. Tomcik,
M. J. Bamford, O. Ichihara, Org. Biomol. Chem. 2006, 4, 1071–
1084; d) H. Pérez, C. Melero, A. Guijarro, M. Yus, Tetrahedron
2009, 65, 10769–10783; e) T. Kumamoto, K. Hosoya, S. Kan-
zaki, K. Masuko, M. Watanabe, K. Shirai, Bull. Chem. Soc.
Jpn. 1986, 59, 3097–3101; f) A. G. Schultz, A. Wang, J. Org.
Chem. 1996, 61, 4857–4859; g) R. Lebeuf, F. Robert, Y. Land-
ais, Org. Lett. 2005, 7, 4557–4560.
a) A. R. Pape, K. P. Kaliappan, E. P. Kündig, Chem. Rev. 2000,
100, 2917–2940; b) F. C. Pigge, J. J. Coniglio, R. Dalvi, J. Am.
Chem. Soc. 2006, 128, 3498–3499; c) P. L. Smith, M. D. Chor-
dia, W. D. Harman, Tetrahedron 2001, 57, 8203–8225; d) E. P.
Kündig, A. Bellido, K. P. Kaliappan, A. R. Pape, S. Radix,
Org. Biomol. Chem. 2006, 4, 342–351; e) A. Quattropani, G.
Anderson, G. Bernardinelli, E. P. Kündig, J. Am. Chem. Soc.
1997, 119, 4773–4774; f) J. Barluenga, A. A. Trabanco, J.
Flórez, S. García-Granda, E. Martín, J. Am. Chem. Soc. 1996,
118, 13099–13100.
[2]
[9]
[10]
[11]
[12]
[13]
J. A. Joule, K. Mills, Heterocyclic Chemistry, 4th ed., Blackwell
Science, Oxford, UK, 2004, chapter 15.
P. A. Caruana, A. J. Frontier, Tetrahedron 2004, 60, 10921–
10926.
[3]
[14]
[15]
D. Crich, M. Patel, Org. Lett. 2005, 7, 3625–3628.
J. Barluenga, S. K. Nandy, Y. R. S. Laxmi, J. R. Suárez, I. Me-
rino, J. Flórez, S. García-Granda, J. Montejo-Bernardo, Chem.
Eur. J. 2003, 9, 5725–5736, and references therein.
a) H. Chen, R. Liu, W. H. Myers, W. D. Harman, J. Am. Chem.
Soc. 1998, 120, 509–520; b) Y. Ohta, M. Doe, Y. Morimoto, T.
Kinoshita, J. Heterocycl. Chem. 2000, 37, 751–755.
J. P. Dumas, S. J. Boyer, J. A. Dixon, T. K. Joe, H. C. E.
Kluender, W. Lee, D. Nagarathnam, R. N. Sibley, N. Su, U. S.
Patent 6689883, 2004.
Isopropyl and ethyl esters were found to give better results in
the stanna-Brook rearrangement–bisalkylation procedure than
methyl or tert-butyl esters. We attribute this behaviour to a
balance between hindrance towards nucleophilic addition of
the R3SnLi and leaving group ability of the OR group. Bu3SnLi
can also be used for these transformations with only a slight
decrease in yield due to the fact that the n-butyltin byproducts
are harder to remove from the final products; see ref.[10]
a) Diethyl thiophene-2,3-dicarboxylate: K.-Y. Tserng, L. Bauer,
J. Org. Chem. 1975, 40, 172–175; b) Thiophene-2,3-dicarboxyl-
ic acid: K. Hammer, T. Benneche, H. Hope, K. Undheim, Acta
Chem. Scand. 1997, 51, 392–402.
[16]
[17]
[18]
[4]
[19]
[20]
[21]
A. S. Kyei, K. Tchabanenko, J. E. Baldwin, R. M. Adlington,
Tetrahedron Lett. 2004, 45, 8931–8934.
CCDC-845741 (for 16c) and -845740 (for 25e) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.uk/data_request/cif.
a) E. V. Panteleeva, T. A. Vaganova, E. A. Lukyanets, V. D.
Shteingarts, Russ. J. Org. Chem. 2006, 42, 1280–1288; b) E. V.
Panteleeva, M. Y. Lukyanova, L. M. Pokrovsky, V. D. Shtein-
garts, Russ. Chem. Bull. Int. Ed. 2007, 56, 1110–1118.
W. C. Still, J. Am. Chem. Soc. 1977, 99, 4836–4838.
C. Tamborski, F. E. Ford, E. J. Soloski, J. Org. Chem. 1963,
28, 237–239.
[22]
[5]
[23]
[24]
[25]
[26]
[27]
D. B. Berkowitz, J. M. McFadden, M. K. Sloss, J. Org. Chem.
2000, 65, 2907–2918.
J. Marco-Contelles, M. C. Carreiras, C. Rodríguez, M. Villar-
roya, A. G. García, Chem. Rev. 2006, 106, 116–133.
Compound 30 was prepared following the procedure for the
synthesis of diethyl 7-methoxybenzofuran-2,3-dicarboxylate
using methyl bromoacetate and dimethyl oxalate instead of the
ethyl analogs, see: E. Ohshima, T. Kawakita, K. Yanagawa, K.
Iida, R. Koike, Y. Nakasato, T. Matsuzaki, K. Ohmori, S. Sato,
H. Ishii, H. Manabe, M. Ichimura, F. Suzuki, U. S. Pat. Appl.
20020128290, 2002.
B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal, J. M.
Balkovec, J. J. Baldwin, M. E. Christy, G. S. Ponticello, S. L.
Varga, J. P. Springer, J. Org. Chem. 1986, 51, 2370–2374.
R. E. Grote, E. R. Jarvo, Org. Lett. 2009, 11, 485–488.
[6]
[28]
[29]
986
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Eur. J. Org. Chem. 2012, 975–987

Enantioselective Annulation Reactions of Bisenolates
[30] The solution was kept cold during cannulation by using a CO2
jacket to surround the cannula.
[33]
[34]
A. N. De Silva, C. L. Francis, A. D. Ward, Aust. J. Chem. 1993,
46, 1657–1671.
M. C. Pumar, A. Mouriño, L. Castedo, An. Quim., Ser. C 1988,
84, 105–111.
[31] a) X.-B. Wang, J. E. Dacres, X. Yang, K. M. Broadus, L. Lis,
L.-S. Wang, S. R. Kass, J. Am. Chem. Soc. 2003, 125, 296–304;
b) M. M. Faul, A. M. Ratz, K. A. Sullivan, W. G. Trankle,
L. L. Winneroski, J. Org. Chem. 2001, 66, 5772–5782.
[32] F. A. Bottino, G. Di Pasquale, A. Pollicino, A. Recca, P. A.
Staniland, J. Heterocycl. Chem. 1989, 26, 929–931.
[35] Z. Ding, J. J. Tufariello, Synth. Commun. 1990, 20, 227–230.
Received: September 29, 2011
Published Online: December 19, 2011
Eur. J. Org. Chem. 2012, 975–987
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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987