Enantioselective cyclization of enamide-ynes and application to the synthesis of the kopsifoline core

Article abstract of DOI:10.1016/j.tet.2013.02.091

We report the palladium-catalyzed enantioselective cyclization of 1,6-enamidynes to form spirocyclic ring systems. We applied this methodology to the concise synthesis of the skeletal core of the kopsifoline alkaloids.

Full text of DOI:10.1016/j.tet.2013.02.091

Tetrahedron xxx (2013) 1e7
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective cyclization of enamide-ynes and application to the
synthesis of the kopsifoline core
*
Britton K. Corkey, Stephen T. Heller, Yi-Ming Wang, F. Dean Toste
Department of Chemistry, University of California, Berkeley, Latimer Hall, Berkeley, CA 94720, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the palladium-catalyzed enantioselective cyclization of 1,6-enamidynes to form spirocyclic
ring systems. We applied this methodology to the concise synthesis of the skeletal core of the kopsifoline
alkaloids.
Received 20 January 2013
Received in revised form 22 February 2013
Accepted 26 February 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
Enantioselective synthesis
Electrophilic activation
Spirocyclization
Natural product synthesis
1. Introduction
Pd(II) developed by our group have utilized enols or silyl enol
ethers as the nucleophilic alkene, with charge neutralization and
The cyclization of 1,6-enynes stands out as a robust and atom-
economical method among the myriad strategies for the synthe-
sis of cyclopentanes. While the thermal Alder ene reaction of 1,6-
enynes has been known for some time,1 transition metal-
catalyzed processes are substantially younger. Beginning with the
seminal work of Trost,2 a wide variety of catalyst systems have been
employed across a truly impressive range of substrates.3 As proof of
its utility in the construction of complex molecules, dozens of
natural product total syntheses that rely on a 1,6-enyne cyclization
have been reported. Further extension of the metal-catalyzed cy-
clization paradigm has yielded a variety of 1,7- and 1,8-enyne cy-
clizations, as well as numerous methods that exploit metalated
cyclization intermediates to further functionalize the cyclopentane
skeleton.
product formation occurring upon loss of proton or silyl group. We
reasoned that alternatively, product formation can occur by trap-
ping of the oxocarbenium or iminium intermediate by an external
alcohol nucleophile to give an acetal or aminal product (Scheme 1).
Our group first reported a highly efficient Au(I)-catalyzed Conia-
ene reaction in 2004,4 which, along with work by Echavarren on
the addition of enol ethers into alkynes, demonstrated that
were highly competent catalysts for the addition of electron-rich
alkenes into unactivated
-systems.5 Further work in our group
has led to the development of Pd(II)- and Au(I)-catalyzed enan-
tioselective variants of these transformations.6 The transformations
that have previously been amenable to the chiral cationic Au(I) and
p-acids
p
Scheme 1. Previously reported enantioselective 1,6-enyne cyclizations and enantio-
selective cyclization of 1,6-enamide-ynes.
Encouragingly, PtCl2-catalyzed transformations involving simi-
lar substrates have recently been reported.7 Herein we report the
application of this strategy to 1,6-enamide-ynes in the preparation
of enantioenriched spirocyclic nitrogen heterocycles. The method
* Corresponding author. Tel.: þ1 5106422850; e-mail address: fdtoste@
berkeley.edu (F.D. Toste).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.091
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2
B.K. Corkey et al. / Tetrahedron xxx (2013) 1e7
reported here enables the enantioselective generation of an all-
carbon stereocenter to nitrogen functionality. Given the preva-
lence of these motifs in alkaloid natural products, we embarked on
a concise synthesis of the core of the kopsifoline family of alkaloids
as a demonstration of the expedient access to molecular complexity
that this methodology affords.
extensive screening (Scheme 3). We hypothesized that the moderate
level of enantioinduction stemmed from the lack of a sterically de-
manding group near the enol ether that would allow for efficient
discrimination of the faces of the substrate. Thus we turned our at-
tention to the analogous 1,6-enamide-yne system.
b
The kopsifolines are a family of monoterpenoid indole alkaloids
isolated in 2004 from Kopsia fruticosa.8 This novel class of com-
pounds exhibits an unprecedented hexacyclic carbon skeleton.
While similar to the aspidospermine natural products,9 the kop-
sifolines introduce additional challenges to synthesis with an ad-
Scheme 3. Cyclization of dihydropyran substrate 2.
ditional ring, and
a total of three all-carbon quaternary
stereocenters (Fig. 1). The congested, multiply bridging ring system
presents a serious challenge to synthesis, and the lack of biological
data further encourages synthetic investigation.
We prepared N-nosyl enamide-yne 4a as a model substrate and
embarked on a survey of ligand choice and other reaction param-
eters (Table 1). We found that while chelating bisphosphinopalla-
dium(II) triflates and tosylates furnished desired hemiaminal 5a0 in
moderate to good yield (entries 1e3), catalysts bearing more co-
ordinating benzoate or chloride ligands were inactive (entries 4 and
5). Although the product was obtained as a mixture of di-
astereomers, reduction of 5a0 to piperidine 5a was conveniently
carried out using triethylsilane, whose optical purity could be
determined by chiral HPLC.
Table 1
Catalysts optimization
Fig. 1. Kopsifoline AeF.
Previously, Padwa and co-workers reported the racemic syn-
thesis of the kopsifoline core in 13 steps through a dipolar cyclo-
addition approach.10 The kopsifolines attracted our attention with
the observation that the FD spiro ring system (ring labels shown on
Kopsifoline A in Fig. 1) could potentially be forged through a Pd(II)-
catalyzed enantioselective enyne cyclization. In our retrosynthesis,
we envisioned that ring C could be constructed by an intra-
Entry
L
M
X
Solvent
Time
(h)
5a0
Yield
5a
%eea
1
2
3
4
5
6
7
8
Dppp
Pd OTf
Pd OTs
Pd OTf
Pd Cl
DCM
DCM
DCM
DCM
0.75 66
2
3
48
48
7
d
d
25
d
d
52
76
84
84
90
90
d
5
rac-BINAP
(R)-BINAP
rac-BINAP
rac-BINAP
(R)-DTBMSegphos Pd OTf
(R)-DTBMSegphos Pd OTf
(R)-DTBMSegphos Pd OTf
(R)-DTBMSegphos Pd OTf
(R)-Binaphane
(R)-Binaphane
(R)-Binaphane
(R)-DTBMSegphos Pt
(R)-Binaphane Pt
71
42
NR
NR
69
76
76
77
71
molecular Mannich cyclization of a b-ketoester onto in situ gener-
ated indole imine A (Scheme 2).11 Imine A could in turn be formed
from the reaction of the appropriately 3-substituted indole C with
the imine generated from aminal B. Finally, we believed that spi-
rocyclic aminal B could be formed enantioselectively using a cat-
ionic Pd(II)-catalyzed cyclization of enyne D.
Pd OBz DCM
DCM
Toluene
MTBE
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
8
14
20
2
9
10
11b
12
13
14
Pd OTf
Pd OTf
Pd OTs
2
78
Decomp
68
48
16
16
c
c
75
9
a
ee measured after reduction of 5a0 to the corresponding piperidine 5a.
Catalyst (1 mol %) used, 2.93 mmol scale.
Mixed complex PtLCl(OTf) generated by in situ mixture of MLCl2 and AgOTf
b
c
(3 mol % each). AgOTf (5 mol %) alone at 50 ꢀC gave 10% conversion. Use of in situ
generated PtL(OTf)2 resulted in extensive olefin isomerization.
Scheme 2. Retrosynthetic analysis of kopsifoline core 1.
((R)-BINAP)Pd(OTf)2 was found to give cyclization product with
poor enantioselectivity (entry 3). By switching to a more sterically
demanding chiral bisphosphine, improvement in both yield and
enantioselectivity was observed (entry 6 vs 3). Out of a range of
solvents screened, ethereal solvents MTBE and diethyl ether gave
the best yield and enantioselectivity. Finally, change of ligand to
((R)-binaphane)Pd(OTf)2 furnished the desired product in 90% ee,
with no decrease in enantioselectivity observed when the reaction
was performed on nearly 3 mmol scale, and catalyst loading was
reduced to 1 mol %. Interestingly, while the corresponding plati-
num complexes were also competent catalysts, the levels of
enantioinduction achieved by these catalysts were uniformly low
(entries 13 and 14).12
2. Results and discussion
2.1. Optimization and scope
Initially, we investigated dihydropyran derived 1,6-alkoxyenynes,
2
under conditions developed for the cyclization of 1,6-
silyloxyenynes, with the inclusion of excess methanol to trap the
generated oxocarbenium ion. It was found that, indeed, exposure of 2
to (DTBM-Segphos)Pd(OTf)2 resulted in the formation of the ex-
pected acetal product 3 as a mixture of diastereomers with modest
yields and moderate enantioselectivities. Though encouraging, the
enantioselectivity could not be improved beyond 66% ee despite
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B.K. Corkey et al. / Tetrahedron xxx (2013) 1e7
3
With these conditions in hand, we explored the substrate scope
of the transformation. Exploration of enamide ring size revealed
that five- and seven-membered rings were tolerated, with the
seven-membered ring system giving desired product with excep-
tional enantioselectivity. The five-membered ring enamide affor-
ded desired product 5b with moderate enantioselectivity (78% ee)
under standard conditions, which could be improved to 84% ee by
switching the solvent to MTBE. A benzo-tethered alkyne afforded
product 5e13 in good enantioselectivity, as did switching the pro-
tecting group to 1-naphthalenesulfonyl in 5f (Scheme 4).
Scheme 5. Cyclization of indole and acyclic enamide substrates.
Ozonolysis of 5c0 afforded the corresponding ketone 10 in 95%
yield. Initially, our investigation focused on reaction of 10 under
Lewis acidic conditions with 3-methylindole. Unfortunately, under
a variety of conditions, the desired aza-Mannich/intramolecular
Mannich cascade could not be effected, and only pentacycle 11
could be obtained (Fig. 2). It appears that 11 formed from diversion
of the desired aza-Mannich intermediate by facile Wag-
nereMeerwein shift of the newly introduced alkyl group from the
indole 3-position to the 2-position.
Scheme 4. Substrate scope of 1,6-enamide-yne cyclization.
Fig. 2. Formation of undesired pentacycle 11.
We speculated that the latent enamine found in the indole nu-
cleus could be a competent substrate when appropriately tethered
to an alkyne. Thus we prepared 3-substituted indole 6. Although
initial studies of 6 under standard reaction conditions resulted in
the formation of many side products, we found that addition of
substrate to a preformed solution of catalyst, AcOH, and MeOH in
DCM resulted in much cleaner reaction. While ((R)-binaphane)
Pd(OTf)2 afforded spirocycle 7 in 50% ee, switching to ((R)-DTBM-
Segphos)Pd(OTf)2 afforded desired product with an improved
enantioselectivity of 71% ee.14
Similarly, acyclic tosylenamide 8 cyclized to give imine 9 under
standard conditions, although enantioselectivity was low (26% ee).
Switching to ((R)-DTBM-Segphos)Pd(OTf)2 improved enantiose-
lectivity to 46% ee. Additional optimization revealed that methanol
was unnecessary, and that more coordinating ligands on palladium
(e.g., benzoate, 60% ee) gave further improvements in enantiose-
lectivity. Accordingly, the 3,5-dinitrobenzoate complex gave prod-
uct with good yield and in the highest enantioselectivity (64% ee)
among the catalysts surveyed. While the selectivity achieved is still
moderate, this result is remarkable nonetheless, given the signifi-
cantly greater conformational freedom available to an acyclic sub-
strate (Scheme 5).
Thus, we turned our attention to 3-unsubstituted indoles, with
the hope of introducing the C-5, C-6 ethylene bridge at a later stage,
a strategy utilized by Natsume and co-workers in their synthesis of
the Aspidosperma alkaloids.15 Switching to the more easily removed
nosyl protecting group, cyclization of 1,6-enamide-yne 4a occurred
under the conditions described earlier to give hemiaminal 5a0 in
78% yield, 90% ee. Ozonolytic cleavage of 5a afforded ketone 12 in
excellent yield.16 Reaction of 12 with indole in the presence of
BF3$Et2O at ꢁ78 ꢀC furnished a 3-alkylated indole as a single di-
astereomer; however, X-ray crystallography revealed that the un-
desired anti-isomer 13-anti was formed.17 Fortunately, subsequent
experiments revealed that the desired isomer 13-syn was preferred
at higher temperatures (Scheme 6).
2.2. Synthesis of the kopsifoline core
Scheme 6. Indolization of hemiaminal ketone 12.
As a demonstration of the power of this newly developed
method, we synthesized the core of kopsifoline alkaloids in 90% ee
starting from commercially available d-valerolactone in 12 steps.
Similar reactivity was observed when 6-methoxyindole was
employed as a nucleophile. Thus, while isomer 14-anti was formed
exclusively at ꢁ78 ꢀC, the desired syn-isomer was favored (2:1) at
warmer temperature. Moreover, resubjecting 14-anti to the
As described in the previous section, tosyl protected cyclization
product 5c0 could be obtained from 1,6-enamide-yne 4c in 93% ee.
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4
B.K. Corkey et al. / Tetrahedron xxx (2013) 1e7
ꢀ
ꢀ
reaction conditions furnished an additional 9% of the desired di-
astereomer 14-syn for a total yield of 31% (Scheme 6).
solvents were obtained by storage over 3 A or 4 A molecular sieves
overnight. Palladium complexes were prepared as reported by
Sodeoka and co-worker.20 TLC analysis of reaction mixtures was
performed on Merck silica gel 60 F254 TLC plates and visualized by
UV, I2/silica, and/or ceric ammonium molybdate stain. Flash chro-
Introduction of the C-16 ester was accomplished by treating
ketone 14-syn with 2 equiv of LHMDS followed by trapping with
Mander’s reagent to afford ester 15. The nosyl group of 15 could be
effectively cleaved with either K2CO3/PhSH or LiOH/mercaptoacetic
acid;18 however, the use of LiOH/mercaptoacetic acid was preferred
as the deprotected amine could be isolated after extraction with
aqueous sodium bicarbonate. The crude piperidine thus obtained
was treated with ethylene oxide in methanol to give ethanolamine
16 in 56% yield over these two steps (Scheme 7).
ꢀ
matography was carried out with ICN SiliTech 32-63 D 60 A silica gel.
Standard aqueous workup refers to extraction with the indicated
solvent, followed by drying of the combined organic layers with
sodium sulfate (magnesium sulfate when extracting with diethyl
ether), gravity filtration, and removal of solvent by rotary evapora-
tion. 1H and 13C NMR spectra were recorded with Bruker AV-300,
AVQ-400, AVB-400, AV-500, DRX-500, and AV-600 spectrometers
andwere referenced to 1H (residual) and13C signalsof thedeuterated
solvents, respectively.21 Mass spectral and microanalytical data were
obtained via the Micro-Mass/Analytical Facility operated by the
College of Chemistry, University of California, Berkeley.
4.2. General procedure for the Pd catalyzed cyclization of 1,
6-enamide-yne 4
A solution of substrate (0.02 mmol), acetic acid (0.1 mL),
Scheme 7. Synthesis of cyclization precursor 16.
methanol (30 mL), and ((R)-binaphane)Pd(OH2)2(OTf)2 (1 mol %) in
Activation of the primary hydroxyl group using meth-
anesulfonyl chloride and potassium carbonate furnished primary
chloride 17 that was directly treated under basic conditions in order
to induce alkylation at the indole C-3. Initial results with various
bases in mixtures of THF/HMPA resulted in formation of 1 in poor
yields (<15%). Subsequently, we found that treatment of 17 with
potassium tert-butoxide in a 5:1 mixture of THF/DMSO at ꢁ78 ꢀC
induced the cyclization cascade to afford kopsifoline core 1 as one
diastereomer in 40% yield from alcohol 16.
diethyl ether (1 mL) was stirred until the reaction was complete as
determined by TLC.6b The reaction was neutralized with saturated
sodium bicarbonate (1 mL). The organic phase was separated and
concentrated before being redissolved in dichloromethane (1 mL)
and filtered through a plug of silica to remove catalyst. To this so-
lution were then added triethylsilane (2.2 equiv) and boron tri-
fluoride etherate (1.1 equiv) and the reaction mixture was stirred
for 20 min at room temperature. Purification on silica gel gave the
desired products 5 (Scheme 9).
The formation of a single diastereomer presumably results from
the fact that the intramolecular Mannich reaction can only take place
when the imine is formed on the same face of the piperidine ring as
the ketoester. Thus, while the SN2 reaction between the indole and
the alkyl chloride may occur on either face of the indole, productive
Mannich closure can only occur in one diastereomer (Scheme 8).
4.3. Synthesis of substrates
Substrates were prepared as illustrated below:
Scheme 8. Presumed mechanism of cyclization cascade to kopsifoline core 1.
3. Conclusions
To summarize, we have developed
methodology for the enantioselective synthesis of
a
palladium-catalyzed
-amino spiro-
b
cycles.19 This method enabled a facile, enantioselective synthesis of
the kopsifoline core in 12 steps from valerolactam in 90% ee. The
rapid assembly of this natural product core demonstrates the effi-
ciency of our approach in the synthesis of stereochemically com-
plex natural product system.
4. Experimental
Scheme 9. Synthesis of substrates.
4.1. General information
4.4. Characterization of substrates and products
Unless otherwise noted, reagents were obtained from commer-
cial sources and used without further purification. All reactions were
carried out under N2 using Schlenk line techniques, unless otherwise
stated. Dry and degassed THF, dichloromethane, diethyl ether, tolu-
ene, triethylamine, and dimethylformamide were obtained by pas-
sage through activated alumina columns under argon. All other dried
4.4.1. 6-Methoxy-1-methylene-7-oxaspiro[4.5]decane (3). A solu-
tion of vinyl ether 1 (18.0 mg, 0.12 mmol), acetic acid (80
mL),
methanol (20 L), and (R)-DTBMSegphosPd(OTf)2 (1.1 mg, 1 mol %)
m
in 2 mL diethyl ether was stirred for 2 h at room temperature. The
reaction was neutralized with saturated aqueous sodium
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B.K. Corkey et al. / Tetrahedron xxx (2013) 1e7
5
bicarbonate (5 mL) and extracted with diethyl ether. Flash chro-
matography (hexanes/ethyl acetate 50:1) gave acetal 3 as a volatile
oil (9 mg, 46%). Chiraldex G-TA; 90 ꢀC hold 0 min, then 5 ꢀC/min to
150 ꢀC; 2.0 mL/min He carrier gas, tM¼9.5 min, tm¼8.9 min, 66% ee.
J¼7, 2.1 Hz, 1H), 7.26 (m, 2H), 4.82 (t, J¼2.3 Hz, 1H), 4.35 (t, J¼2.3 Hz,
1H), 2.71 (m, 2H), 2.00e2.20 (m, 4H). 13C NMR (126 MHz, CDCl3)
d
176.2, 155.3,149.2, 144.2, 127.7, 126.4, 122.0, 120.8, 107.9, 68.1, 34.7,
33.8, 25.1. HRMS (EI): calcd for [C13H13N]þ: 183.1048, found
183.1047. HPLC Chiralcel AD column (98:2 hexanes/isopropanol,
1.0 mL/min): tM¼10.5 min, tm¼9.8 min: 71% ee.
1H NMR (500 MHz, CDCl3)
d 4.97 (s, 1H), 4.94 (s, 1H), 4.15 (s, 1H),
3.92 (m, 1H), 3.54 (m, 1H), 3.38 (s, 3H), 2.47 (m, 2H), 1.97 (m, 1H),
1.68 (m, 1H), 1.66e1.48 (m, 6H). 13C NMR (75.5 MHz, CDCl3)
d 157.7,
107.5, 105.5, 64.5, 56.5, 49.0, 34.7, 33.7, 33.6, 23.2, 22.6.
4.4.10. 4-Methyl-N-((1-methyl-2-methylenecyclopentyl)methylene)
benzenesulfonamide (9). Yield 75%. 1H NMR (300 MHz, CDCl3)
4.4.2. 6-Methylene-2-tosyl-2-azaspiro[4.4]nonane (5b). The racemic
product has been characterized previously.7a Yield 59%. HPLC Chir-
alcel AD column (95:5 hexanes/ethanol, 1.0 mL/min): tM¼16.1 min,
tm¼20.9 min: 84% ee.
d
8.32 (s, 1H), 7.78 (d, J¼8.1 Hz, 2H), 7.32 (d, J¼8.1 Hz, 2H), 5.05 (br s,
1H), 4.69 (br s, 1H), 2.30e2.55 (m, 2H), 2.43 (s, 3H), 2.09 (m, 1H),
1.80e1.60 (m, 3H), 1.24 (s, 3H). 13C NMR (126 MHz, CDCl3)
180.4,
d
154.8, 144.2, 135.0, 129.7, 127.9, 109.8, 51.8, 37.6, 33.4, 23.6, 22.9,
21.6. HRMS (EI): calcd for [C15H19NO2S]þ: 277.1137, found 277.1143.
HPLC Chiralcel AD column (95:5 hexanes/ethanol, 1.0 mL/min):
tM¼10.2 min, tm¼9.5 min: 64% ee.
4.4.3. 1-Methylene-7-tosyl-7-azaspiro[4.5]decane (5c). The racemic
product has been characterized previously.7a Yield 71%. HPLC Chir-
alcel AD column (95:5 hexanes/ethanol, 1.0 mL/min): tM¼9.2 min,
tm¼10.9 min: 93% ee.
4.5. Procedures and characterization of intermediates for the
synthesis of the kopsifoline core
4.4.4. 1-Methylene-7-tosyl-7-azaspiro[4.6]undecane (5d). The race-
mic product has been characterized previously.7a Yield 70%. Chir-
alcel AD column (98:2 hexanes/ethanol, 1.0 mL/min): tM¼12.2 min,
tm¼14.7 min: >99% ee.
4.5.1. 1-((2-Nitrophenyl)sulfonyl)-5-(pent-4-yn-1-yl)-1,2,3,4-
tetrahydropyridine (4a). The title compound was synthesized in
four steps from valerolactam (33% overall yield) in analogy to
procedures previously reported.7a
4.4.5. 5-(2-Ethynylbenzyl)-1-(2-nitrophenylsulfonyl)-1,2,3,4-
1H NMR (500 MHz, CDCl3)
d
7.95 (dd, J¼7.0, 1.5 Hz, 1H), 7.70 (m,
tetrahydropyridine (4e). 1H NMR (400 MHz, CDCl3)
d
7.94 (d, 1H,
2H), 7.61 (dd, J¼7.0, 1.5 Hz, 1H), 3.50 (m, 2H), 2.15 (m, 4H), 1.98 (t,
J¼2.5 Hz, 1H), 1.94 (t, J¼6.0 Hz, 2H), 1.78 (quint, J¼6.0 Hz, 2H). 1.65
J¼7.6 Hz), 7.58e7.74 (m, 3H), 7.48 (d, 1H, J¼8.0 Hz), 7.25e7.31 (m,
1H), 7.23e7.17 (m,1H), 6.58 (s,1H), 3.52 (s, 2H), 3.47 (m, 2H), 3.01 (s,
1H), 1.94 (t, 2H, J¼6.4 Hz), 1.74 (quint, 2H, J¼6.0 Hz). 13C NMR
(quint, J¼7.5 Hz, 2H). 13C NMR (126 MHz, CDCl3)
d 148.2, 133.7,
131.6, 130.4,124.0, 120.7, 119.4, 84.0, 68.8, 43.9, 34.0, 26.2, 24.4, 21.2,
17.7. HRMS (FAB): calcd for [C16H19N2O4S]þ: 334.09873, found
334.09824.
(100 MHz, CDCl3)
d 141.6, 133.6, 132.9, 131.7, 130.4, 129.0, 126.3,
124.0, 122.0, 120.7, 82.3, 81.2, 43.8, 39.5, 24.3, 21.1. HRMS (FAB):
calcd for [C20H19N2O4S]þ: 383.1060, found: 383.1070.
4.5.2. 6-Methoxy-1-methylene-7-((2-nitrophenyl)sulfonyl)-7-
azaspiro[4.5]decane (5a0, major diastereomer). To a solution of 3a
(980 mg, 2.93 mmol) in diethyl ether (200 mL), acetic acid (19 mL)
and methanol (3.2 mL) was added ((R)-binaphane)Pd(OTf)2(OH2)2
(35 mg, 1 mol %). After 21 h the reaction was carefully quenched
with slow addition of saturated sodium bicarbonate solution
(250 mL). Concentration afforded the crude product as a 10:1
mixture of diastereomers, which were separated by flash chroma-
tography (5:1 hexanes/ethyl acetate) to give the title product
(840 mg, 78%) as a light yellow oil.
4.4.6. 1-Methylene-10-((2-nitrophenyl)sulfonyl)-1,3-dihydrospiro[in-
dene-2,30-piperidine] (5e). Yield 73%: 1H NMR (300 MHz, CDCl3)
d
7.93e7.88 (m,1H), 7.60e7.75 (m, 3H), 7.48e7.42 (m,1H), 7.10e7.30
(m, 3H), 5.60 (s, 1H), 4.97 (s, 1H), 3.91e4.05 (m, 1H), 3.57 (d,
J¼12.0 Hz, 1H), 2.60e2.90 (m, 3H), 1.55e2.00 (m, 4H). 13C NMR
(75 MHz, CDCl3) d 155.4, 143.1, 139.6, 133.6, 131.9, 131.6, 131.1, 129.2,
126.9, 125.8, 124.1, 121.0, 103.7, 55.9, 46.5, 46.4, 41.0, 35.0, 22.6.
4.4.7. 1-(Naphthalen-1-ylsulfonyl)-5-(pent-4-yn-1-yl)-1,2,3,4-
tetrahydropyridine (4f). 1H NMR (500 MHz, CDCl3): 1H NMR
[
a
]
þ32.3 (CHCl3, c 1.0 g/100 mL). HPLC Chiralcel AD column
D
(500 MHz, CDCl3)
d
8.36 (s, 1H), 7.87e8.03 (m, 3H), 7.76 (dd, J¼8.7,
(99:01 hexanes/isopropanol, 1.0 mL/min): tM¼21.5 min,
1.7 Hz, 1H), 7.57e7.68 (m, 2H), 6.60 (s, 1H), 3.32e3.40 (m, 2H),
2.04e2.15 (m, 4H), 1.96e2.02 (m, 1H), 1.79 (t, J¼6.1 Hz, 2H),
1.52e1.64 (m, 4H). 13C NMR (126 MHz): 135.0, 134.9, 132.3, 129.4
(two peaks), 128.9, 128.5, 128.1, 127.7, 122.6, 120.6, 120.2, 84.1, 69.0,
43.8, 34.0, 26.3, 24.4, 21.0, 17.6. HRMS (ESIþ): calcd for
[C20H21O2NSþH]þ: 340.1366, found: 340.1368.
tm¼24.1 min: 90% ee. 1H NMR (300 MHz, CDCl3)
d 8.00 (m, 1H),
7.58e7.71 (m, 3H), 4.98 (m, 2H), 4.56 (s, 1H), 3.70 (dd, J¼12.0,
3.9 Hz, 1H), 3.19 (dt, J¼12.6, 3.6 Hz, 1H), 3.15 (s, 3H), 2.38 (m, 2H),
2.02 (dt, J¼12.6, 4.8 Hz, 1H), 1.18e1.82 (m, 7H). 13C NMR (126 MHz,
CDCl3)
d 154.7, 148.2, 134.5, 133.6, 132.0, 130.3, 124.4, 109.5, 89.1,
57.9, 50.3, 41.2, 35.5, 33.8, 29.7, 22.8, 22.2. HRMS (FAB): calcd for
[C16H19N2O4S]þ (loss of methoxide): 335.10655, found: 335.10643.
4.4.8. 1-Methylene-7-(naphthalen-1-ylsulfonyl)-7-azaspiro[4.5]dec-
ane (5f). Yield 62%. 1H NMR (500 MHz, CDCl3)
d
8.31e8.32 (m, 1H),
4.5.3. 6-Methoxy-7-((2-nitrophenyl)sulfonyl)-7-azaspiro[4.5]decan-
1-one (12, major diastereomer). A solution of 5a0 (750 mg,
2.05 mmol) in methanol (50 mL) was subjected to a stream of ozone
at ꢁ78 ꢀC for 5 min. Dimethyl sulfide was added, and the solution
was allowed to come to room temperature. Concentration yielded
a colorless oil, which was taken into dichloromethane (100 mL),
washed with water (3ꢂ200 mL), and dried over MgSO4. Concen-
tration gave the title product (740 mg, 98%) as a white foam.
7.97 (t, J¼7.5 Hz, 2H), 7.92 (d, J¼7.8 Hz, 1H), 7.73 (dd, J¼8.6, 1.8 Hz,
1H), 7.59e7.68 (m, 2H), 4.91 (t, J¼2.0 Hz, 1H), 4.66 (t, J¼2.2 Hz, 1H),
3.77e3.84 (m, 1H), 3.44 (d, J¼11.4 Hz, 1H), 2.26e2.50 (m, 3H),
2.10e2.16 (m, 1H), 2.06 (d, J¼11.5 Hz, 1H), 1.62e1.83 (m, 4H),
1.39e1.52 (m, 2H), 1.21e1.35 (m, 1H). 13C NMR (126 MHz, CDCl3)
d
158.0, 134.9, 133.9, 132.4, 129.4, 129.3, 128.8, 128.0, 127.6, 123.1,
105.8, 55.0, 46.7, 45.6, 35.8, 35.3, 33.9, 22.9, 22.6. HRMS (ESIþ):
calcd for [C20H23O2NSþH]þ: 342.1522, found: 342.1531. HPLC
Chiralcel AD column (99:1 hexanes/isopropanol, 1.0 mL/min):
tM¼28.6 min, tm¼35.7 min: 93% ee.
[a
]
þ41.7 (CHCl3, c 0.75 g/100 mL). 1H NMR (500 MHz, CDCl3)
D
d
8.02 (d, J¼7.0 Hz, 1H), 7.71 (m, 2H), 7.63 (d, J¼7.0, 1H), 4.88 (s, 1H),
3.77 (br d, J¼12.0 Hz, 1H), 3.19 (dt, J¼13.0, 3.5 Hz, 1H), 3.06 (s, 3H),
2.45 (m, 1H), 2.24 (m, 3H), 1.91 (m, 2H), 1.50e1.52 (m, 3H), 1.17 (d,
4.4.9. 2-Methylenespiro[cyclopentane-1,10-indene] (7). Yield 41%. 1H
J¼13.5 Hz, 1H). 13C NMR (126 MHz, CDCl3)
d 216.6, 147.8, 133.9,
NMR (400 MHz, CDCl3)
d
7.98 (s, 1H), 7.60 (d, J¼8 Hz, 1H), 7.34 (dt,
131.8, 130.2, 124.2, 85.1, 56.6, 53.4, 40.9, 37.1, 32.3, 25.4, 21.8, 17.6.
Please cite this article in press as: Corkey, B. K.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.02.091

6
B.K. Corkey et al. / Tetrahedron xxx (2013) 1e7
HRMS (FAB): calcd for [C15H17N2O5S]þ (loss of methoxide):
337.08582, found: 337.08601.
NMR (126 MHz, CD3CN) d 216.6, 156.4, 135.3, 133.2, 132.6, 131.0,
129.2, 123.6, 122.3, 122.0, 117.9, 109.7, 109.5, 94.2, 55.1, 53.2, 50.7,
41.9, 36.5, 33.7, 28.7, 26.1, 21.7, 17.5. HRMS (FAB): calcd for
[C24H25N3O3S]þ: 483.1464, found: 483.1465.
4.5.4. (5R,6S)-6-(1H-Indol-3-yl)-7-((2-nitrophenyl)sulfonyl)-7-
azaspiro[4.5]decan-1-one (13-anti). To a solution of 12 (236 mg,
0.64 mmol) and indole (112 mg, 0.96 mmol) in dichloromethane
(7 mL) at ꢁ78 ꢀC was added boron trifluoride etherate (0.09 mL,
0.70 mmol). The reaction was warmed to ꢁ30 ꢀC and stirred for
30 min. The reaction was quenched with saturated sodium bi-
carbonate solution, extracted with dichloromethane, and dried
over MgSO4. Flash chromatography (1:1 hexanes/ethyl acetate)
gave the title product (115 mg, 40%).
4.5.6. Methyl 6-methoxy-3-((5R,6R)-2-(methoxycarbonyl)-7-((2-
nitrophenyl)sulfonyl)-1-oxo-7-azaspiro[4.5]decan-6-yl)-1H-indole-
1-carboxylate (15). To a solution of LHMDS (124 mg, 0.74 mmol) in
THF (8 mL) at ꢁ78 ꢀC was added a solution of 14-syn (90 mg,
0.186 mmol) and HMPA (68
mL, 0.39 mmol) in THF (8 mL). After
stirring for 1 h, methyl cyanoformate (74
m
L, 0.93 mmol) was added
and the reaction was warmed to room temperature. The reaction
was quenched with 10% sodium bicarbonate solution, extracted
with dichloromethane, washed with brine, and dried over MgSO4.
Flash chromatography (3:2 hexanes/ethyl acetate) gave the title
product (79 mg, 71%) as a 2:1:1 keto, epi-keto and enol isomers.
1H NMR (300 MHz, CD2Cl2)
1H), 7.40e6.90 (br m, 8H), 5.56 (br s, 1H), 3.87 (br m, 1H), 3.40 (br s,
1H), 1.40e2.50 (br m, 10H). 13C NMR (75.5 MHz, CD2Cl2)
218.6,
d
8.52 (br, 1H), 7.60 (br d, J¼6.9 Hz,
d
134.9, 134.0, 132.7, 131.0, 129.7, 127.9, 123.6,122.6,120.3,118.8,111.8,
111.3, 52.0, 42.4, 37.7, 36.0, 26.6, 21.1, 18.0. HRMS (ESIþ): calcd for
[C23H23N3O5SþH]þ: 454.1437, found: 454.1428.
1H NMR (400 MHz, CDCl3)
d 9.70 (br, 0.25H, enol), 7.12e7.70 (m),
6.84e7.00 (m), 6.70e7.80 (m), 5.53 (s, 0.5H), 5.42 (s, 0.25H), 5.21 (s,
0.25H), 4.04 (m), 3.99 (s), 3.94 (d, J¼12.4 Hz), 3.70 (s), 3.65 (s), 3.45
(m), 3.30 (m), 3.28 (s), 3.21 (t, J¼10 Hz), 2.91 (dd, J¼13.2, 6.4 Hz),
Relative stereochemistry of the title product as determined via
X-ray crystallography (Fig. 3).
2.28e2.80 (m), 1.45e1.95 (m). 13C NMR (126 MHz, CDCl3)
d 210.0,
209.6,175.4,171.2,169.9,169.6,168.6,158.4,158.2,151.2,151.1,148.0,
147.5, 134.9 (br), 133.4, 133.1, 133.0, 132.9, 132.8, 131.1, 131.0, 130.7,
130.3, 129.4, 129.2, 124.7, 124.0, 123.8, 123.7, 123.5, 122.7, 122.5,
121.3, 119.5, 118.4, 118.2, 117.5, 114.7, 114.6, 112.6, 112.1, 101.7, 99.3,
98.8, 77.4, 77.3, 77.1, 76.7, 64.4, 60.4, 55.7, 55.0, 54.0, 53.9, 53.7, 53.4,
52.6, 52.4, 51.7, 51.6, 51.3, 50.8, 49.8, 42.8, 42.1, 41.8, 33.6, 33.0, 32.7,
30.7, 28.0, 27.0, 26.9, 23.4, 23.0, 22.5, 21.8, 21.6, 21.3, 21.1, 19.1, 14.2,
13.7. HRMS (FAB): calcd for [C28H29N3O10S]þ: 599.1574, found:
599.1558.
4.5.7. Methyl 3-((5R,6R)-7-(2-hydroxyethyl)-2-(methoxycarbonyl)-1-
oxo-7-azaspiro[4.5]decan-6-yl)-6-methoxy-1H-indole-1-carboxylate
(16). A solution of 15 (176 mg, 0.294 mmol), mercaptoacetic acid
(0.1 mL, 1.5 mmol), lithium hydroxide (71 mg, 3.0 mmol), and DMF
(1 mL) was stirred for 1 h. The reaction mixture was poured into 30%
saturated sodium bicarbonate solution (50 mL) and extracted with
dichloromethane (5ꢂ20 mL). The organic layer was washed with
30% saturated sodium bicarbonate solution and the aqueous layer
was further extracted with dichloromethane (2ꢂ20 mL). The com-
bined organics were dried over MgSO4 before being concentrated to
afford the crude piperidine.
This crude material was dissolved in methanol (8 mL) and added
to a solution of ethylene oxide (5 mL) in methanol (10 mL)
at ꢁ78 ꢀC. The reaction was warmed to room temperature and
Fig. 3. X-ray structure of 13-anti.
4.5.5. (5R,6R)-6-(6-Methoxy-1H-indol-3-yl)-7-((2-nitrophenyl)sul-
fonyl)-7-azaspiro[4.5]decan-1-one (14-syn). To a solution of 12
(750 mg, 2.04 mmol) and 6-methoxyindole (540 mg, 3.67 mmol) in
dichloromethane (45 mL) at 0 ꢀC was added boron trifluoride
etherate (0.51 mL, 4.06 mmol). The ice bath was removed and the
reaction was allowed to stir for 15 min. The reaction was quenched
with saturated sodium bicarbonate solution, extracted with
dichloromethane, and dried over MgSO4. Flash chromatography
(8:5 hexanes/ethyl acetate) gave the desired syn-isomer (220 mg,
22%), as well as a mixture of syn- and anti-isomers (320 mg, 33%). A
solution of anti-isomer was treated with 1.0 equiv boron trifluoride
etherate at room temperature for 15 min and worked up as de-
scribed above to yield additional desired product (90 mg, 9%) for
a total yield of 31%. The relative stereochemistry was assigned by
analogy to the corresponding indole adduct (vide supra).
stirred for
3 h. Concentration and flash chromatography
(270:10:0.6:0.6 DCM/MeOH/H2O/NH4OH with further elution with
90:10:0.6:0.6) gave the desired ethanolamine (75 mg, 56% yield) as
a predominantly 2:1 mixture of diastereomers.
[
a
]
D þ41.3 (CH2Cl2, c 2.2 g/100 mL). 1H NMR (400 MHz, CD2Cl2)
d
7.77 (br, 1H), 7.43 (m, 1H), 7.26 (m, 1H), 6.89 (m, 1H), 4.00 (s, 3H
major), 3.99 (s, 3H minor), 3.86 (s, 3H major), 3.85 (s, 3H minor),
3.68 (s, 3H major), 3.45 (s, 3H, minor), 3.50e3.75 (m), 3.08e3.35
(m), 2.80e2.90 (m), 2.63 (m, 1H), 1.54e2.30 (m), 1.44 (m, 1H). 13
C
NMR (126 MHz, CD2Cl2)
d 212.2, 211.9, 169.9, 168.2, 158.3, 158.1,
151.3, 135.7 (br), 123.4 (br), 119.6 (br), 119.1, 117.8 (br), 111.8 (br),
111.7 (br), 99.2 (br), 62.4 (br), 57.8, 57.7, 56.8, 55.7, 55.5, 54.6 (br),
53.8, 52.1, 51.9, 50.6 (br), 35.0, 34.6, 33.4 (br), 32.3 (br), 24.3, 22.9,
22.8, 22.3, 21.3, 20.9. HRMS (FAB): calcd for [C24H31N2O7]þ (pro-
tonated): 459.2131, found 459.2142.
[a
]
D ꢁ13.0 (CHCl3, c 0.15 g/100 mL). 1H NMR (400 MHz, CD3CN)
4.5.8. (3aR,3a1R,6S,11bS)-methyl 9-methoxy-15-oxo-2,3,3a1,4,5,6,6a,7,
12,13-decahydro-1H-3a,6-methanoindolizino[10,80:2,3,4]cyclohepta[1,2-
b]indole-6-carboxylate (1). To a suspension of ethanolamine 16
(31 mg, 0.0676 mmol) and potassium carbonate (93 mg, 0.68 mmol)
d
9.13 (br, 1H), 7.46 (d, J¼7.6 Hz, 1H), 7.36 (d, J¼8.0 Hz, 1H), 7.32 (d,
J¼2.4 Hz, 1H), 7.23 (d, J¼8 Hz, 1H), 7.12 (d, J¼8.0 Hz, 1H), 6.96 (t,
J¼8.0 Hz, 1H), 6.80 (d, J¼2.0 Hz), 6.61 (dd, J¼8.4, 2.0 Hz, 1H), 5.45 (s,
1H), 3.78 (m, 1H), 3.76 (s, 3H), 3.36 (m, 1H), 2.57 (m, 1H), 2.28 (td,
J¼14, 4.4 Hz, 1H), 1.65e2.20 (m, 7H), 1.34 (br d, J¼14 Hz, 1H). 13C
was added methanesulfonyl chloride (13
mL, 0.169 mmol). The
Please cite this article in press as: Corkey, B. K.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.02.091

B.K. Corkey et al. / Tetrahedron xxx (2013) 1e7
7
Chem., Int. Ed. 2008, 47, 4268 For specific metals, see: Au and Pt: (f) Pradal, A.;
Chao, C.-M.; Toullec, P. Y.; Michelet, V. Beilstein. J. Org. Chem. 2011, 7, 1021; (g)
Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410; (h) Shapiro, N. D.;
Toste, F. D. Synlett 2010, 675 Ru: (i) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2002,
124, 5025 Rh: (j) Tong, X.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 6370;
(k) Ota, K.; Chatani, N. Chem. Commun. 2008, 2906; (l) Ota, K.; Lee, S. I.; Tang, J.-
M.; Takachi, M.; Nakai, H.; Morimoto, T.; Sakurai, H.; Kataoka, K.; Chatani, N. J. Am.
Chem. Soc. 2009,131,15203; (m) Kim, S. Y.; Chung, Y. K. J. Org. Chem. 2010, 75,1281
Ir: (n) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S. J. Org. Chem. 2001,
66, 4433.
reaction vessel was covered with aluminum foil and the reaction
mixture was stirred at room temperature for 16 h before being poured
into water and extracted three times with dichloromethane. The
combined organics were washed with 10% sodium bicarbonate in
brine, and this aqueous phase was back extracted twice with
dichloromethane. The combined organics were dried over MgSO4 and
concentrated to give the crude chloride, which was used in the next
step without further purification.
To a solution of potassium tert-butoxide (10 mg, 0.089 mmol)
and DMSO (0.5 mL) in THF (7 mL) was added crude chloride 17
(13.5 mg, 0.0283 mmol) in THF (3 mL) at ꢁ78 ꢀC. The resulting
slurry was stirred for 20 min before being allowed to warm to room
temperature. The reaction mixture was quenched with 10% sodium
bicarbonate solution and extracted with dichloromethane. The
combined organics were washed once with brine and dried over
MgSO4. Concentration followed by column chromatography (100:1
DCM/MeOH) gave the title product as a film (4.3 mg, 40% over two
steps).
€
4. (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
4526; (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed.
2004, 43, 5350; (c) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991; (d) Minnihan,
E.; Colletti, S. L.; Toste, F. D.; Shen, H. C. J. Org. Chem. 2007, 72, 6287.
ꢁ
5. Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Chem.dEur. J. 2003, 9, 2627.
6. (a) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168; (b) Corkey, B. K.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764; (c) Brazeau, J. F.; Zhang, S.;
Colomer, I.; Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 2742 For
general reviews, see: (d) Marinetti, A.; Brissy, D. In Phosphorus Compounds,
Catalysis by Metal Complexes; Peruzzini, M., Eds.Gonsalvi, L., Eds.; Springer:
Heidelberg, 2011; Vol. 37, pp 305e341; (e) Watson, I. D. G.; Toste, F. D. Chem. Sci.
2012, 3, 2899.
7. (a) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367 See also; (b)
Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10,1791; (c) Kozak, J. A.;
Dodd, J. M.; Harrison, T. J.; Jardine, K. J.; Patrick, B. O.; Dake, G. R. J. Org. Chem.
2009, 74, 6929.
[
a
]
þ14.3 (CH2Cl2, c 0.3 g/100 mL). 1H NMR (400 MHz, C6D6)
D
d
6.78 (d, J¼8.4 Hz, 1H), 6.34 (dd, J¼8.4, 2.2 Hz, 1H), 5.90 (d,
J¼2.2 Hz, 1H), 4.67 (s, 1H), 3.90 (br s, 1H), 3.41 (s, 3H), 3.40 (s, 3H),
2.84 (m, 1H), 2.74 (t, J¼8.4 Hz, 1H), 2.56 (m, 1H), 2.40 (s, 1H),
2.06e2.22 (m, 2H), 1.96 (m, 2H), 1.72 (m, 2H), 1.56 (dd, J¼12.4,
7.6 Hz, 1H), 1.46 (td, J¼14.8, 6.8 Hz, 1H), 1.29 (m, 1H), 1.18 (td, J¼14.8,
6.8 Hz, 1H), 0.91 (td, J¼14.8, 6.8 Hz, 1H). 13C NMR (100 MHz, C6D6)
8. (a) Kam, T.-S.; Choo, Y.-M. Tetrahedron Lett. 2003, 44, 1317; (b) Kan, T.-S.; Choo,
Y.-M. Helv. Chim. Acta 2004, 87, 991.
9. Cordell, G. A. The Alkaloids; Academic: New York, NY, 1998; Vol. 51.
10. Hong, X.; France, S.; Padwa, A. Tetrahedron 2007, 63, 5962.
11. (a) For a related approach to Aspidophytine see: He, F.; Bo, Y.; Altom, J. D. J. Am.
Chem. Soc. 1999, 122, 6771; (b) For a general review of cascade processes in total
synthesis see: Nicolaou, K. C.; Edmonds, D. J.; Bulgar, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134.
d
208.7, 171.7, 160.9, 151.3, 127.7, 122.0, 103.2, 94.1, 80.5, 76.0, 64.8,
54.6, 53.9, 52.8, 51.7, 51.3, 48.3, 44.3, 28.8, 28.1, 21.7, 20.3. HRMS
12. For examples of enantioselective Pt-catalyzed cycloisomerization reactions see:
ˇ
(FAB): calcd for [C22H26N2O4þLi]þ: 389.2053, found: 389.2049.
(a) Charruault, L.; Michelet, V.; Taras, R.; Gladiali, S.; Genet, J.-P. Chem. Commun.
2004, 850; (b) Toullec, P. Y.; Chao, C.-M.; Chen, Q.; Gladiali, S.; Genet, J. P.;
Michelet, V. Adv. Synth. Catal. 2008, 350, 2401.
Acknowledgements
13. For examples of related spirocyclic amines in medicinal chemistry see: (a)
Bondensgaard, K.; Ankersen, M.; Thogersen, H. L.; Hansen, B. S.; Wulff, B. S.;
Bywater, R. P. J. Med. Chem. 2004, 47, 888; (b) Patchett, A. A. J. Med. Chem. 2002,
45, 5609.
14. For a review of methods for the enantioselective synthesis of spirocyclic
oxindoles see: Ball-Jones, R. N.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012,
10, 5165.
We gratefully acknowledge NIHGMS (R01 GM073932), financial
support. Solvias and Takasago are acknowledged for the generous
donation of phosphine ligands.
References and notes
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16. Lewis acid promoted reaction of hemiaminal
9 with indole resulted its
1. (a) Huntsman, W. D.; Hall, R. P. J. Org. Chem. 1962, 27, 1988; (b) Bortolussi, M.;
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decomposition.
17. Other Lewis acids examined greatly favored the formation of the anti-isomer.
For example MgBr2$Et2O at 0 ꢀC gave 77% yield of >30:1 anti/syn adducts.
18. Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
19. For a review enantioselective methods for the synthesis of spiro compounds
see: Rios, R. Chem. Soc. Rev. 2012, 41, 1060.
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G. C. Org. Biomol. Chem. 2003,1, 215; (e) Michelet, V.; Toullec, P.; Genet, J.-P. Angew
Please cite this article in press as: Corkey, B. K.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.02.091