Samarium Diiodide Catalyzed Radical Cascade Cyclizations that Construct Quaternary Stereocenters

Article abstract of DOI:10.1055/s-0039-1690196

SmI ₂ -catalyzed radical cascade cyclizations were used to generate complex carbocyclic products bearing quaternary stereocenters with high selectivity. Bicyclic scaffolds containing four contiguous stereocenters and one quaternary stereocenter

Full text of DOI:10.1055/s-0039-1690196

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
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H.-M. Huang et al.
Cluster
Synlett
Samarium Diiodide Catalyzed Radical Cascade Cyclizations that
Construct Quaternary Stereocenters
Huan-Ming Huang
0
0
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0-
0
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1-9
4
6
1-6
5
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O
H
O
SmII
Ph
quaternary stereocenters
four contiguous stereocenters
high diastereocontrol
room temperature
catalytic SmI2
radical relay
Qiong He
0
0
0
0-0
0
0
2-
6
3
5
5-3
9
5
1
Ph
Me
Me
Ph
H
Ph
David J. Procter*
0
0
0
0-0
0
0
3-3
1
7
9-2
5
0
9
5 mol% SmI2
THF, rt
96%, >95:5 dr
H
School of Chemistry, University of Manchester,
Oxford Road, Manchester, M13 9PL, UK
david.j.procter@manchester.ac.uk
EtO2C CO2Et
EtO2C
CO2Et
Published as part of the Cluster 9th Pacific Symposium on Radical
Chemistry
Received: 25.07.2019
Accepted after revision: 15.08.2019
Published online: 28.08.2019
used in natural product synthesis.9 For example, SmI2 has
recently been used to mediate key steps, that also construct
quaternary stereocenters, in approaches to the important
natural product targets (+)-pleuromutilin,8k (–)-maoecrys-
tal Z,8p (+)-crotogoudin,8l and strychnine8s (Scheme 1A). Al-
most all reactions involving SmI2 require the use of super-
stoichiometric amounts of the reagent. Therefore, the de-
velopment of radical reactions that require only catalytic
amounts of SmI2 is an important goal.
DOI: 10.1055/s-0039-1690196; Art ID: st-2019-v0387-c
Abstract SmI2-catalyzed radical cascade cyclizations were used to
generate complex carbocyclic products bearing quaternary stereocen-
ters with high selectivity. Bicyclic scaffolds containing four contiguous
stereocenters and one quaternary stereocenter were obtained in excel-
lent yields (up to 99%) and with high diastereocontrol by using 5 mol%
of SmI2 at ambient temperature in the absence of co-reductants or ad-
ditives. Mechanistic studies support a radical relay mechanism.
A. SmI2-mediated cascades that set quaternary all-carbon stereocenters
– Application in natural product synthesis
Key words radical relay, catalysis, samarium diiodide, cascade reac-
tion, cyclization
OH
H
• 2.5 equiv SmI2
(+)-pleuromutilin
H
HO
OAc
O
O
O
Cascade cyclizations are powerful tools for the con-
struction of complex architectures, including those found in
natural products.1 Cascades in which the mediator can be
used in catalytic rather than stoichiometric amounts are
particularly desirable.2 Radical intermediates are well suit-
ed to exploitation in selective cascade processes, and the
development of radical cyclization cascades, particularly
catalytic radical cascades, has seen great progress in recent
years.3 The selective construction of quaternary stereocen-
ters remains a significant challenge because of the inherent
steric congestion encountered during the construction of
fully substituted stereogenic centers, a problem that is ex-
acerbated in complex molecular settings.4 Although there
are elegant approaches to the stereocontrolled construction
of quaternary stereocenters,5 the construction of such cen-
ters during catalytic radical cascade reactions is less devel-
oped.6
H
O
O
• 3.0 equiv SmI2
O
O
(–)-maoecrystal Z
N
H
OH
Me
O
Me
N
H
H
O
• 2.4 equiv SmI2
O
strychnine
O
• 2.5 equiv SmI2
(+)-crotogoudin
B. SmI2-catalyzed cascades that set quaternary all-carbon stereocenters
O
H
Ar/
O
HetAr
R1
R2
R1
H
Ar/
HetAr
SmII
R2
H
Ar/
HetAr
– via
EtO2C CO2Et
EtO2C CO2Et
IIISm
O
• 4 contiguous stereocenters
• quaternary, all-carbon
stereocenters
• catalytic SmI2
• no stoichiometric
co-reductant
R1
R2
H
H
• high stereocontrol
• mild conditions
EtO2C CO2Et
The single-electron reductant samarium diiodide (SmI2)
is well-known for its ability to build complex molecular ar-
chitectures.7 In particular, SmI2-mediated cyclization cas-
cades have been developed8 and some of these have been
Scheme 1 (A) SmI2-mediated radical cascade reactions that generate
quaternary stereocenters: selected applications in natural product syn-
thesis. (B) This work: SmI2-catalyzed radical cascade cyclizations that
generate quaternary stereocenters.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H.-M. Huang et al.
Cluster
Synlett
The few examples of reactions that are catalytic in SmI2
employ superstoichiometric amounts of terminal reduc-
tants and additives, for example TMSOTf and TMSCl, to
achieve turnover.7h Zinc amalgam,10 magnesium,11 mis-
chmetal,12 and electrochemistry with samarium elec-
trodes13 have been used to regenerate Sm(II) from Sm(III) in
catalytic SmI2 systems. Unfortunately, these approaches to
catalysis with SmI2 currently lack generality and are inher-
ently limited by the fact that superstoichiometric amounts
of terminal reductants and additives are required.
We recently reported a SmI2-catalyzed radical cascade
cyclization that operates by radical relay14 and that does not
require superstoichiometric amounts of terminal reductant
and additives.15 Here, we describe the SmI2-catalyzed cy-
clization of substrates bearing trisubstituted alkene moi-
eties that delivers complex products bearing quaternary
stereocenters with high diastereocontrol (Scheme 1B). Our
approach constitutes a rare example of the catalytic con-
struction of complex scaffolds containing quaternary ste-
reocenters without recourse to the use of co-reductants,
co-oxidants, or additives.16
Table 1 Optimization of the SmI2-Catalyzed Radical Cyclization Cas-
cade to Construct Quaternary Stereocentersa
O
Ph
H
H
O
Me
Ph
H
Ph
Ph
SmII
Me
EtO2C CO2Et
EtO2C CO2Et
1a
2a
Entry
SmI2
Lewis acid
(5 mol%)
Temperature Yieldb (%)
2a
1a
1
5 mol%
–
–
–
–
–
–
65 °C
86
–
–
2
5 mol%
r.t.
99 (96)c
3
3 mol%
r.t.
78
–
21
4
–
–
–
–
–
r.t.
97
93
92
97
98
5d
6d
7
r.t.
–
65 °C
r.t.
–
e
SmI2/O2
–
8
SmI3
r.t.
–
a General conditions: Substrate 1a (0.1 mmol) in THF (4 mL, 0.025 M) un-
der N2 was stirred at the indicated temperature. A catalytic amount of a 0.1
M solution of SmI2 in THF was then added. The reaction was quenched after
20 min.
We used the trisubstituted alkene 1a to assess the via-
bility of forming quaternary stereocenters by using SmI2 ca-
talysis. Under our previously optimized conditions (5 mol%
SmI2, 65 °C),15 the corresponding product 2a was obtained
in 86% yield with essentially complete diastereocontrol (Ta-
ble 1, entry 1). Interestingly, the product 2a could be ob-
tained in an improved 96% isolated yield when the reaction
was run at room temperature (entry 2). Lowering the cata-
lyst loading to 3 mol% gave a 78% NMR yield of 2a, with 21%
of 1a remaining (entry 3). Crucially, in the absence of SmI2,
only starting material was recovered, even after prolonging
the reaction time and heating (entries 4–6). To underline
the radical nature of the process and to help rule out an al-
ternative Lewis acid-mediated cyclization,17 1a was ex-
posed to SmI3, either generated in situ or prepared inde-
pendently; in both cases, only starting material was recov-
ered (entries 7 and 8). Furthermore, a range of additional
Lewis acids [Sm(OTf)3, Al(OTf)3, Er(OTf)3, La(OTf)3, Fe(OTf)3,
Sc(OTf)3, Yb(OTf)3, and Gd(OTf)3] were screened, but only
the starting material was returned in all cases (95–99% re-
covery).
Next, we examined the scope of the SmI2-catalyzed rad-
ical cascade (Scheme 2).18 In addition to variation of the es-
ter groups (the formation of 2b), the catalytic process was
found to tolerate the presence of fluoro (2c, 2d, 2o, and 2q),
methoxy (2e, 2i, 2n, and 2p), trifluoromethyl (2f and 2r),
bromo (2g), or trifluoromethoxy (2h) substituents on ei-
ther the aryl group of the aryl ketone or the aryl group on
the alkene. In all cases, cascade products bearing quaterna-
ry stereocenters were obtained in high yields and with high
diastereocontrol. Furthermore, naphthyl (2j and 2k), thie-
nyl (2l), benzofuryl (2m), and imidazolyl (2s) substituents
were compatible with the cascade process. Given that the
methyl group is one of the most common and most import-
b Determined by 1H NMR spectroscopy with 1,3,5-trimethoxybenzene as
the internal standard.
c Isolated yield: >95:5 dr as determined by 1H NMR analysis of the crude
product mixture.
d The reaction mixture was stirred for 18 h.
e SmI2 was exposed to O2 before addition to the reaction mixture.
ant structural elements in drugs,19 it is noteworthy that the
catalytic radical cascade cyclization permits the convenient
assembly of complex scaffolds bearing a methyl substituent
at the quaternary stereocenter (2a–s). This methyl substitu-
ent would be difficult to introduce by alternative approach-
es. Finally, more-hindered alkyl substituents (ethyl, propyl,
or isopropyl) on the trisubstituted alkene were also tolerat-
ed, and the cascade products 2t–v were obtained with high
diastereocontrol. The relative stereochemistry of the prod-
ucts was assigned on the basis of NOE experiments (see
Supporting Information).
The SmI2-catalyzed cascade reaction can operate on
larger-scale; for example, 2a was prepared on a 2 mmol
scale in 94% yield and with high diastereoselectivity by us-
ing 5 mol% of SmI2 (Scheme 3A). Furthermore, the alterna-
tive trisubstituted alkene substrate 1w underwent a SmI2-
catalyzed cascade cyclization to give tetrahydrofuran 2w,
an alternative scaffold bearing a quaternary stereocenter, in
good yield, albeit as a mixture of diastereoisomers (Scheme
3B). The structure of one of the diastereoisomers of 2w was
confirmed by X-ray crystallographic analysis.20
In addition to gaining evidence against the operation of
a Lewis acid-mediated process, we found that the presence
of a substoichiometric or stoichiometric amount of the
radical inhibitor TEMPO in reactions of 1a prevented the
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

C
H.-M. Huang et al.
Cluster
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O
Ar/
H
O
HetAr
R2
R1
R1
SmI2 (5 mol%)
THF, rt
Ar/
HetAr
R2
H
H
SmII
1
2
R3O2C CO2R3
R3O2C CO2R3
O
O
O
H
O
H
O
H
Ph
H
H
Ph
Ph
H
Ph
H
Ph
H
OMe
Me
H
Me
Me
Me
H
Me
H
Br
H
H
CF3
H
H
F
EtO2C
CO2Et
EtO2C
CO2Et
RO2C
CO2R
EtO2C CO2Et
EtO2C CO2Et
2f
2g
2a R = Et, 96%, >95:5 dr
2b R = Me, 97%, >95:5 dr
2c 2–F, 90%, 93:7 dr
2d 4–F, 95%, >95:5 dr
2e
93%, >95:5 dr
97%, >95:5 dr
95%, >95:5 dr
O
H
O
H
O
H
O
H
O
H
Ph
H
Ph
Ph
Ph
Ph
H
Me
H
Me
H
Me
H
Me
H
Me
S
OCF3
OMe
H
H
H
H
EtO2C CO2Et
EtO2C CO2Et
EtO2C CO2Et
EtO2C
CO2Et
EtO2C CO2Et
2kb
2l
2h
2i
2ja
92%, 92:8 dr
92%, >95:5 dr
93%, 93:7 dr
87%, >95:5 dr
91%, >95:5 dr
O
H
O
H
O
H
O
H
O
H
MeO
F
Ph
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
H
O
MeO
F
H
H
H
H
H
EtO2C CO2Et
EtO2C
CO2Et
EtO2C CO2Et
EtO2C
CO2Et
EtO2C
CO2Et
2mc
88%, >95:5 dr
2n
2o
2p
2q
91%, >95:5 dr
94%, >95:5 dr
91%, >95:5 dr
99%, >95:5 dr
O
H
O
H
N
N
Me
O
H
O
H
O
H
F3C
Me
Ph
H
Ph
H
Ph
Me
Ph
H
Me
Ph
H
Et
Ph
H
Me
Ph
H
Ph
H
H
H
H
EtO2C CO2Et
EtO2C CO2Et
EtO2C CO2Et
EtO2C CO2Et
EtO2C CO2Et
2r
2s
2t
2ub
2v
98%, >95:5 dr
55%, >95:5 dr
95%, 95:5 dr
73%, 83:17 dr
93%, >95:5 dr
Scheme 2 Reaction conditions: 1 (0.1 mmol), SmI2 (5 mol%) 20 min, THF (4 mL, 0.025 M), r.t., under N2, then exposure to air. All yields are isolated
yields. The dr was determined by 1H NMR analysis of the crude product mixtures. a 20 mol% SmI2. b 10 mol% SmI2. c 25 mol% SmI2.
formation of the cascade product 2a. Further support for a
radical mechanism was obtained by an EPR experiment in-
volving the spin trap 5,5-dimethyl-1-pyrroline N-oxide
(DMPO); the product of trapping of 3 was detected by EPR
and also by HRMS (Scheme 4A). We also monitored the col-
or of SmI2-catalyzed cascade reactions; for example, in a re-
action of 1a, the reaction mixture retained the characteris-
tic blue color of SmI2 long after the starting material 1a had
been consumed (see the Supporting Information). This re-
sult suggests that SmI2 is regenerated and that the reagent
is not acting as an initiator of an electron-transfer chain
process.21 These mechanistic observations are consistent
with a catalytic cycle that we previously proposed (Scheme
4B).15 Ketyl radical intermediate I is generated by reductive
single-electron transfer (SET) from SmI2. After fragmenta-
tion, the resultant radical enolate intermediate II22 under-
goes a 5-exo-trig cyclization to give the tertiary benzylic
radical III. Facile cyclization constructs the second five-
membered ring and sets two further stereocenters, includ-
ing the quaternary stereocenter, with high diastereoselec-
tivity. Finally, the ketyl radical intermediate IV collapses to
give product 2a and Sm(II) after reverse SET to Sm(III). We
believe that the high diastereoselectivity observed in the
formation of the quaternary stereocenter arises from a
preference for transition structure V in which the unfavor-
able 1,3-steric interactions present in VI are relieved. For
the cyclization of alternative trisubstituted alkene substrate
1w, which results in a 1:1 mixture of two diastereoisomeric
products, we believe that the preference is less clear cut;
transition structures VII and VIII both suffer from unfavor-
able steric interactions and consequently a mixture of two
diastereoisomeric products results (Scheme 4C).
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

D
H.-M. Huang et al.
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A. EPR study
A. SmI2-catalyzed radical cascade: larger-scale experiment
Me
Me
O
H
O
O
O
O
N
Ph
Ph
Me
15% SmI2
50% DMPO
Ph
Me
Ph
Ph
Ph
Ph
1a
SmI2 (5 mol%)
Ph
Me
H
H
THF, rt
THF, rt
94%, >95:5 dr
2a
Me
EtO2C
CO2Et
EtO2C CO2Et
1a
3
EtO2C CO2Et
2.0 mmol, 0.90 g
EtO2C CO2Et
1.9 mmol, 0.84 g
3
Confirmed by EPR &
HRMS: 562.3156
B. SmI2-catalyzed radical cascade using an alternative trisubstituted alkene
~9.8 GHz
2 G
2 mW
Ph
H
O
O
Ph
Me
H
SmI2 (20 mol%)
Ph
1w
Ph
Me
Room temperature
*
H
THF, rt
56%
O
O
B. Proposed catalytic cycle
2w 50:50 dr*
X-ray
2a
1a
SmII
X-ray crystal
structure of 2w
SmIII
Me
Ph
H
O
H
SmIII
O
Ph
H
Ph
Me
Ph
IV
I
SmI2-catalysis
by radical relay
Scheme 3 Additional examples of SmI2-catalyzed cyclizations that
generate quaternary stereocenters
EtO2C CO2Et
IIISm
EtO2C CO2Et
SmII
Ph
O
IIISm
In summary, we have developed a SmI2-catalyzed radi-
cal cascade cyclization that constructs complex scaffolds
bearing four contiguous stereocenters, including a quater-
nary stereocenter, in high yield and with high diastereocon-
trol. The cascade cyclizations take place at room tempera-
ture, use 5 mol% of SmI2, and do not require superstoichio-
metric co-reductants or additives. Mechanistic studies
support a radical relay mechanism in which Sm(II) is regen-
erated.
Ph
Ph
O
Ph
Me
Me
H
H
II
III
EtO2C
CO2Et
EtO2C CO2Et
C. Proposed origin of diastereoselectivity
– cyclization of 1a
CO2Et
H
CO2Et
H
H
H
H
H
Ph
Ph
EtO2C
EtO2C
Me
Ph
H
H
OSmIII
OSmIII
H
H
Ph
Me
Funding Information
VI
V
Support for this work was provided by the UK Engineering and Physi-
cal Sciences Research Council [EPSRC; EP/M005062/01 (Postdoctoral
Fellowship to H.-M.H. and EPSRC Established Career Fellowship to
D.J.P.)] and the EPSRC UK National EPR Facility and Service at the Uni-
– cyclization of 1w
H
H
H
H
Me
Me
Ph
Ph
O
H
H
O
H
H
Ph
OSmIII
OSmIII
H
Ph
versity of Manchester (NS/A000055/1).
E
n
g
i
n
e
eri
n
g
a
n
d
P
h
ysi
c
a
lS
c
i
e
n
c
es
R
esearc
h
C
o
u
n
c
i
l(EP/M
0
0
5
0
6
2/01)
H
VIII
VII
Scheme 4 EPR study, proposed catalytic cycle, and possible origin of
diastereocontrol in the construction of quaternary stereocenters
Acknowledgment
We thank Mr. Bin Wang, Mr. Adam Brookfield, and Professor David
Collison for their assistance with the EPR studies.
References and Notes
Supporting Information
(1) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int.
Ed. 2006, 45, 7134. (b) Ardkhean, R.; Caputo, D. F. J.; Morrow, S.
M.; Shi, H.; Xiong, Y.; Anderson, E. A. Chem. Soc. Rev. 2016, 45,
1557. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690196.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(2) Delidovich, I.; Palkovits, R. Green Chem. 2016, 18, 590.
(3) (a) Hung, K.; Hu, X.; Maimone, T. J. Nat. Prod. Rep. 2018, 35, 174.
(b) Plesniak, M. P.; Huang, H.-M.; Procter, D. J. Nat. Rev. Chem.
2017, 1, 0077. (c) Kärkäs, M. D.; Porco, J. A. Jr.; Stephenson, C. R.
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H.-M. Huang et al.
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Synlett
J. Chem. Rev. 2016, 116, 9683. (d) Sebren, L. J.; Devery, J. J. III.;
Stephenson, C. R. J. ACS Catal. 2014, 4, 703. (e) Zhang, B.; Studer,
A. Chem. Soc. Rev. 2015, 44, 3505.
(11) (a) Nomura, R.; Matsuno, T.; Endo, T. J. Am. Chem. Soc. 1996, 118,
11666. (b) Aspinall, H. C.; Greeves, N.; Valla, C. Org. Lett. 2005, 7,
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(6) (a) Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre, P.
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(b) Zhang, Y. F.; Mellah, M. ACS Catal. 2017, 7, 8480.
(14) For a recent review of catalytic radical relays, see: (a) Huang H.-
M., Garduño-Castro M. H., Morrill C., Procter D. J.; Chem. Soc.
Rev.; DOI: 10.1039/c8cs00947c. For selected examples involving
ketyl radicals, see: (b) Lu, Z.; Shen, M.; Yoon, T. P. J. Am. Chem.
Soc. 2011, 133, 1162. (c) Amador, A. G.; Sherbrook, E. M.; Yoon,
T. P. J. Am. Chem. Soc. 2016, 138, 4722. (d) Amador, A. G.;
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(18) SmI2-Catalyzed Cyclization Cascade; General Procedure
An oven-dried vial containing a stirrer bar was charged with the
appropriate substrate 1 (0.1 mmol, 1 equiv) then placed under a
positive pressure of N2. THF (0.025 M, 4.0 mL) was added, and
the solution was stirred at r.t. Fresh SmI2 solution (typically, 5%,
0.1 M, 0.05 mL) was added and, after the specified time (typi-
cally, 20 min), the mixture was filtered through a pad of silica
gel, which was washed with CH2Cl2 (3 × 5 mL). The solution was
concentrated in vacuo to give product 2 typically without the
need for further purification. In some cases, products required
purification by chromatography (silica gel).
(7) For reviews on the use of samarium diiodide, see: (a) Just-Bar-
ingo, X.; Procter, D. J. Acc. Chem. Res. 2015, 48, 1263. (b) Szostak,
M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem. Rev. 2014,
114, 5959. (c) Szostak, M.; Spain, M.; Procter, D. J. Chem. Soc.
Rev. 2013, 42, 9155. (d) Szostak, M.; Spain, M.; Parmar, D.;
Procter, D. J. Chem. Commun. 2012, 48, 330. (e) Szostak, M.;
Procter, D. J. Angew. Chem. Int. Ed. 2012, 51, 9238.
(f) Beemelmanns, C.; Reissig, H.-U. Chem. Soc. Rev. 2011, 40,
2199. (g) Beemelmanns, C.; Reissig, H.-U. Pure Appl. Chem. 2011,
83, 507. (h) Procter, D. J.; Flowers, R. A. II.; Skrydstrup, T.
Organic Synthesis using Samarium Diiodide: A Practical Guide;
Royal Society of Chemistry: Cambridge, 2009. (i) Flowers, R. A.
II. Synlett 2008, 1427. (j) Kagan, H. B. Tetrahedron 2003, 59,
10351. (k) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745.
(l) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
(8) For recent examples, see: (a) Huang, H.-M.; McDouall, J. J. W.;
Procter, D. J. Angew. Chem. Int. Ed. 2018, 57, 4995. (b) Plesniak,
M. P.; Garduño-Castro, M. H.; Lenz, P.; Just-Baringo, X.; Procter,
D. J. Nat. Commun. 2018, 9, 4802. (c) Kern, N.; Plesniak, M. P.;
McDouall, J. J. W.; Procter, D. J. Nat. Chem. 2017, 9, 1198.
(d) Huang, H.-M.; Procter, D. J. Angew. Chem. Int. Ed. 2017, 56,
14262. (e) Huang, H.-M.; Procter, D. J. J. Am. Chem. Soc. 2017,
139, 1661. (f) Huang, H.-M.; Bonilla, P.; Procter, D. J. Org. Biomol.
Chem. 2017, 15, 4159. (g) Ruscoe, R. E.; Huang, H.; Flitsch, S.;
Procter, D. J. Chem. Eur. J. 2016, 22, 116. (h) Huang, H.-M.;
Procter, D. J. J. Am. Chem. Soc. 2016, 138, 7770. (i) Rao, C. N.;
Lentz, D.; Reissig, H.-U. Angew. Chem. Int. Ed. 2015, 54, 2750.
(j) Rao, C. N.; Bentz, C.; Reissig, H.-U. Chem. Eur. J. 2015, 21,
15951. (k) Fazakerley, N. J.; Helm, M. D.; Procter, D. J. Chem. Eur.
J. 2013, 19, 6718. (l) Breitler, S.; Carreira, E. M. Angew. Chem. Int.
Ed. 2013, 52, 11168. (m) Parmar, D.; Matsubara, H.; Price, K.;
Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2012, 134, 12751.
(n) Sautier, B.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Org. Lett.
2012, 14, 146. (o) Li, Z.; Nakashige, M.; Chain, W. J. J. Am. Chem.
Soc. 2011, 133, 6553. (p) Cha, J. Y.; Yeoman, J. T. S.; Reisman, S. E.
J. Am. Chem. Soc. 2011, 133, 14964. (q) Coote, S. C.; Quenum, S.;
Procter, D. J. Org. Biomol. Chem. 2011, 9, 5104. (r) Parmar, D.;
Price, K.; Spain, M.; Matsubara, H.; Bradley, P. A.; Procter, D. J.
J. Am. Chem. Soc. 2011, 133, 2418. (s) Beemelmanns, C.; Reissig,
H.-U. Angew. Chem. Int. Ed. 2010, 49, 8021. (t) Helm, M. D.; Da
Silva, M.; Sucunza, D.; Findley, T. J. K.; Procter, D. J. Angew. Chem.
Int. Ed. 2009, 48, 9315. (u) Reisman, S. E.; Ready, J. M.; Weiss, M.
M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska, T. V.; Smith, C.
J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087.
Diethyl rac-(3aS,4S,5S,6aR)-5-Benzoyl-4-methyl-4-phenyl-
hexahydropentalene-2,2(1H)-dicarboxylate (2a)
Colorless oil; yield: 43.2 mg (96%). IR (neat): 2981, 1724, 1446,
1252, 1182, 907, 710 cm−1. 1H NMR (400 MHz, CDCl3):  = 7.50–
7.40 (m, 2 H, ArH), 7.39–7.32 (m, 1 H, ArH), 7.28–7.10 (m, 7 H,
ArH), 4.23–4.13 [m, 5 H, 2 × CH2CH3 and C(O)CH], 3.09 [dt,
J = 10.9, 9.3 Hz, 1 H, CCH2CHC(Me)Ph], 2.97–2.86 (m, 1 H,
CCH2CH), 2.66 (dd, J = 13.4, 7.9 Hz, 1 H, 1 H from CCH2CHCH2),
2.27 [d, J = 9.3 Hz, 2 H, CCH2CHC(Me)Ph], 2.24–2.11 (m, 2 H,
CCH2CHCH2), 2.01 (dd, J = 13.3, 8.1 Hz,
1 H, 1 H from
CCH2CHCH2), 1.29–1.19 (m, 9 H, 2 × CH2CH3 and CH3). 13C NMR
(101 MHz, CDCl3):  = 201.2 (C=O), 172.3 [OC(O)], 171.6
[OC(O)], 149.6 (ArCq), 137.9 (ArCq), 132.5 (ArCH), 128.4
(2 × ArCH), 128.4 (2 × ArCH), 128.1 (2 × ArCH), 126.2 (2 × ArCH),
126.1 (ArCH), 64.0 (Cq), 62.0 [C(O)CH], 61.51 (CH2CH3), 61.5
(CH2CH3), 57.4 [CCH2CHC(Me)Ph], 50.2 (Cq), 42.3 (CCH2CH),
40.1 (CCH2CHCH2), 35.5 [CCH2CHC(Me)Ph], 34.5 (CCH2CH), 19.6
(CH3), 14.2 (CH2CH3), 14.1 (CH2CH3). MS (ESI+): m/z (%): 471.2
[M + Na]+. HRMS (ESI+): m/z [M + Na]+ calcd for C28H32NaO5:
471.2142; Found: 471.2136.
(9) (a) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem. Int. Ed.
2009, 48, 7140. (b) Edmonds, D. J.; Johnston, D.; Procter, D. J.
Chem. Rev. 2004, 104, 3371.
(10) Corey, E. J.; Zheng, G. Z. Tetrahedron Lett. 1997, 38, 2045.
Diethyl
rac-(3aR,4S,5S,6aS)-5-Benzoyl-4-ethyl-4-phenyl-
hexahydropentalene- 2,2(1H)-dicarboxylate (2t)
Colorless oil; yield: 44.1 mg (95%). IR (neat): 2970, 1726, 1674,
1455, 1365, 1217, 908, 762 cm−1 1H NMR (400 MHz, CDCl3):
.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

F
H.-M. Huang et al.
Cluster
Synlett
 = 7.96–7.88 (m, 2 H, ArH), 7.60–7.52 (m, 1 H, ArH), 7.47 (dd,
J = 8.3, 6.9 Hz, 2 H, ArH), 7.38–7.29 (m, 4 H, ArH), 7.23–7.17 (m,
1 H, ArH), 4.32–4.12 [m, 5 H, 2 × CH2CH3 and C(O)CH], 3.11 [dt,
J = 12.1, 7.7 Hz, 1 H, CCH2CHC(Et)Ph], 3.03–2.87 (m, 1 H,
CCH2CH), 2.74–2.56 [m, 2 H, 1 H from CCH2CHC(Et)Ph and 1 H
from CCH2CHCH2], 2.48 (dd, J = 13.6, 5.1 Hz, 1 H, 1 H from
CCH2CHCH2), 2.35 [ddd, J = 12.7, 7.1, 1.3 Hz, 1 H, 1 H from
CCH2CHC(Et)Ph], 2.06–1.89 (m, 2 H, CCH2CHCH2), 1.71 (qd,
J = 6.8, 4.2 Hz, 2 H, PhCCH2CH3), 1.29 (dt, J = 15.5, 7.1 Hz, 6 H,
2 × CH2CH3), 0.47 (t, J = 7.2 Hz, 3 H, PhCCH2CH3). 13C NMR (101
MHz, CDCl3):  = 203.9 (C=O), 172.9 [OC(O)], 172.0 [OC(O)],
149.1 (ArCq), 139.4 (ArCq), 132.9 (ArCH), 128.7 (2 × ArCH),
128.6 (2 × ArCH), 128.5 (2 × ArCH), 126.5 (2 × ArCH), 126.0
(ArCH), 61.7 (Cq), 61.5 (CH2CH3), 61.4 (CH2CH3), 59.0 [C(O)CH],
57.9 (Cq), 51.2 [CCH2CHC(Et)Ph], 43.0 (CCH2CH), 39.3
(CCH2CHCH2), 36.1 (CCH2CH), 35.1 [CCH2CHC(Et)Ph], 28.5
(PhCCH2CH3), 14.3 (CH2CH3), 14.2 (CH2CH3), 10.6 (PhCCH2CH3).
MS (ESI+): m/z (%): 485.3 [M + Na]+. HRMS (ESI+): m/z [M + H]+
Calcd for C29H35O5: 463.2479; Found: 463.2474.
(19) Schönherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256.
(20) CCDC 1915447 contains the supplementary crystallographic
data for compound 2w. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(21) (a) Studer, A.; Curran, D. P. Nat. Chem. 2014, 6, 765. (b) Studer,
A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58.
(22) For a review of the chemistry of samarium enolates, see:
Rudkin, I. M.; Miller, L. C.; Procter, D. J. Spec. Period. Rep.:
Organomet. Chem. 2008, 34, 19.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F