Proline sulphonamide-catalysed Yamada-Otani condensation: Reaction development, substrate scope and scaffold reactivity

Article abstract of DOI:10.1039/c2ob25400j

The development of a proline sulphonamide-catalysed method for enantioselective and diastereoselective construction of functionalized cyclohexenones is described. Impact of catalyst structure as well as solvent effects and additives are explored. A significant substrate scope is demonstrated by variation of both the aldehyde and the enone components. Diastereoselective derivatization of the cyclohexenone scaffold illustrates its utility as a building block for chemical synthesis.

Full text of DOI:10.1039/c2ob25400j

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Volume 10 | Number 25 | 7 July 2012 | Pages 4809–4988
ISSN 1477-0520
PAPER
Rich G. Carter et al.
Proline sulphonamide-catalysed Yamada–Otani condensation: reaction
development, substrate scope and scaffold reactivity
1477-0520(2012)10:25;1-C

Dynamic ArtVicielweALritnicklesOnline
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4851
www.rsc.org/obc
PAPER
Proline sulphonamide-catalysed Yamada–Otani condensation: reaction
development, substrate scope and scaffold reactivity†‡
Hua Yang,a Somdev Banerjeeb and Rich G. Carter*b
Received 24th February 2012, Accepted 27th March 2012
DOI: 10.1039/c2ob25400j
The development of a proline sulphonamide-catalysed method for enantioselective and diastereoselective
construction of functionalized cyclohexenones is described. Impact of catalyst structure as well as solvent
effects and additives are explored. A significant substrate scope is demonstrated by variation of both the
aldehyde and the enone components. Diastereoselective derivatization of the cyclohexenone scaffold
illustrates its utility as a building block for chemical synthesis.
using α,α-disubstituted aldehydes prompted us to reinvestigate
the Yamada–Otani reaction.
Introduction and background
Stereogenic quaternary centres are widely present in natural pro-
ducts and new methods for their construction continue to be
needed to address this challenge.1 The efficient construction of
all-carbon quaternary centres is a central focus of organic che-
mistry.1a,2 More specifically, stereogenic, γ,γ-disubstituted
cycloalkenones embody a potentially powerful building block in
natural product synthesis. An important method for accessing
this structural motif is the Hajos–Parrish reaction,3 which typi-
cally generates bicyclic enone systems and employs a cyclic
β-di-ketone starting material (Scheme 1, eqn (1)). Recent
examples from several laboratories have utilized the Michael
addition itself as the enantiodetermining step via transition
metal,4 Brønsted acid5 or phase-transfer catalysis.6 In order to
access stereogenic, γ,γ-disubstituted cycloalkenones, aldehyde-
based nucleophiles are needed; however, this functional group
has not been widely used to date. Yamada and Otani reported a
traceless auxiliary-based approach in this area in the late 1960s
and early 1970s (Scheme 1, eqn (2)).7 This concept has essen-
tially laid dormant over the next four decades8 – likely due to
the difficulty related to catalytic turnover and the disappointing
levels of enantioselectivity. Recent advances by our laboratory9
as well as others8,10 in methods for controlling stereochemistry
In a preliminary communication, we disclosed our develop-
ment of an organocatalysed method facilitating Yamada–Otani-
type reactivity on systems containing β-substitution on the enone
moiety.11 Concurrently to our discoveries, the Kotsuki laboratory
reported a dual catalysis method using enone moiety not contain-
ing β-subsitution.8 We view this work as a perfect complement
to our protocols for systems containing β-substitution. Herein,
we disclose a full account of our development of proline sulpho-
namide-catalysed method for facilitating the annulation of
α-aryl, α-alkyl-disubstituted aldehydes with acyclic enones to
generate highly functionalized cyclohexenones in excellent
levels of diastereoselectivity and enantioselectivity.
aCollege of Chemistry & Chemical Engineering, Central South
University, Changsha, Hunan 410083, China
bDepartment of Chemistry, Oregon State University, Corvallis,
OR 97331, US. E-mail: rich.carter@oregonstate.edu;
Fax: +1 541-737-2062; Tel: +1 541-737-9486
†Electronic supplementary information (ESI) available: Remaining
experimental procedures and copies of NMR spectra and CIF data are
provided. CCDC reference numbers 753483, 753484, 869713 and
869714. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25400j
‡This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Scheme 1 Pioneering work in synthesis of γ,γ-disubstituted
cycloalkenones.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4851–4863 | 4851

View Article Online
Scheme 3 Likely equilibria between imine and enamines depending
on substitution patterns.
enamine in solution.14 Interestingly, we have found 1H NMR
analysis of a premixed solution of benzyl amine and 2-phenyl-
propanal in CDCl3 does yield the imine 20 (R = Bn, Ar = Ph) as
the major product [1H NMR spectra: δ 7.82 (d, J = 4.4 Hz, 1H),
7.1–7.5 (m, 10H), 4.59 (s, 2H), 3.70 (dq, J = 4.4, 6.8 Hz, 1H),
1.49 (d, J = 6.8 Hz, 3H) ppm] and shows essentially complete
consumption of the aldehyde signal at 9.7 ppm. It should be
noted, however, that the spectra is complex (containing
additional signals between 4.5–5.0 ppm as well as at 2.6 ppm)
which we attribute to the dynamic enamine–imine equilibria.
Using the knowledge gained from these cyclic enone systems,
we next sought out to apply our work to acyclic enones. We
were well-aware of the added complexity that acyclic enones
introduced into the system – primarily due to the added
rotational flexibility surrounding the C–C σ-bond separating the
carbonyl and alkene moieties of the enone. We were encouraged
by the pioneering work by other groups in this area;15 however,
we recognized that acyclic enone substrates were noticeable
more challenging than acyclic enal systems. We chose to study
the reactivity of 2-phenyl propanal with 3-pentenone as the
initial model system. It should be noted that 2-pentenone is sold
as only an approximately 70% pure solution with the remaining
mass balance being 4-methyl-3-pentenone (also known as
mesityl oxide). We did not ever observe reactivity with the
mesityl oxide under the reaction conditions and made no attempt
to purify the 3-pentenone prior to use.
The initial exploration of this transformation on acyclic
enones is shown in Table 1. We were pleased to see that our orig-
inal conditions9b did provide the desired product – albeit in
modest chemical yield and dr (entry 1). The relative stereo-
chemistry of the cyclohexenone product was conclusively estab-
lished by X-ray crystallographic analysis (Fig. 1). For
optimization, we first focused on the impact of the amine and
other additives to the reaction process. Interestingly, addition of
molecular sieves to the reaction mixture led to a dramatic accel-
eration in the reaction rate and enantioselectivity of the process
(entry 2). This additive effect would appear at first glance to be
counter-intuitive as the removal of water from the reaction
system greatly complicates any feasible mechanism for catalyst
turnover. We also probed if alternate amines would prove ben-
eficial in the transformation. Consequently, we screened a series
of amines – all of which proved inferior to the parent benzyl
amine. Addition of ortho-substitution on the benzyl ring led to
Scheme 2 Prior work from our laboratory using α,α-disubstituted
aldehydes/imines.
Results and discussion
We based our initial forays into this area on prior work with
cyclic enones (primarily cyclohexenone) as shown in
Scheme 2.9 In these reactions, we were able to develop con-
ditions for facilitating the enantioselectivity construction of
[2.2.2] bicyclic systems using a proline sulphonamide12 organo-
catalyst (nicknamed Hua Cat-®) developed in our laboratory.13
Both enantiomers of this catalyst have now been commercialized
through Sigma and Synthetech, Inc. In eqn (1), we first studied
the utility of symmetrical aldehydes where R = alkyl using a pre-
formed imine (e.g. 11). These transformations were performed
neat using excess (5 equiv.) of the enone to provide the bicyclic
ketone products in excellent endo/exo selectivity but in modest
chemical yield (eqn (1)).9a The reactivity of this system could be
greatly improved by substitution of one of the two alkyl substi-
tutions on the aldehyde or imine for an aryl moiety (eqn (2)).9b
This modification also allowed us to change to a multi-com-
ponent coupling process in which the pre-formed enamine was
not isolated prior to addition of the enone and proline sulphon-
amide organocatalyst.
The rational behind the replacement of one of the two alkyl
substituents for an aryl moiety can be found in imine–enamine
equilibria (Scheme 3). We hypothesize that replacement of the
alkyl moiety for an aryl group likely improves the concentration
of enamine relative to imine in solution by a lowering of the pKa
of the α-hydrogen through added conjugation in resultant
enamine 19/21. d’Angelo and co-workers hypothesized decades
earlier that the rate of conjugate addition of enamines to suitable
electrophiles was directly correlated to the concentration of the
4852 | Org. Biomol. Chem., 2012, 10, 4851–4863
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 1 Additive effects on annulation reactiona
Entry Amine
Additive Yield (%) er (dr)
1b
2
BnNH2
BnNH2
None
Mol.
sieves
Mol.
sieves
Mol.
sieves
Mol.
30
66
77 : 23 (>20 : 1)
91 : 9 (>20 : 1)
3
4
5
6
7
8
9
2-Cl-C6H4-
CH2NH2
2-Me-C6H4-
CH2NH2
2,6-Cl-C6H3-
CH2NH2
2,4,6-Me-C6H2-
CH2NH2
(R)-PhCH(Me)NH2 Mol.
sieves
(R)-PhCH(Me)NH2 Mol.
sieves
20
39
0
79.5 : 21.5
(>20 : 1)
78 : 22 (>20 : 1)
n/a
n/a
n/a
n/a
sieves
Mol.
sieves
0
0
0
Allylamine
Mol.
sieves
36
90.5 : 9.5
(>20 : 1)
a Enantiomeric ratios (er) determined by chiral HPLC analysis and
diastereomeric ratios (dr) determined by 1H NMR analysis. b This
reaction was performed for 24 h.
Fig. 1 ORTEP representation of enone 23.
Scheme 4 Possible mechanism for catalytic cycle.
reduction of chemical efficiency as shown by both 2-methyl- and
2-chlorobenzyl amine (entries 3 and 4). Not surprisingly, ortho,
ortho-disubstitution on the benzyl amine was also deleterious to
the reaction – leading to no product formation (entries 5 and 6).
Use of a chiral amine (α-methyl benzylamine) could potentially
provide an added stereocontrolling element; however, the
increased steric bulk using either (R)- or (S)-α-methyl benzyl-
amine led to no product formation (entries 7 and 8). Less hin-
dered amines such as allyl amine did produce the desired
product, but in reduced chemical yield (entry 9).
A likely mechanism for this transformation is illustrated in
Scheme 4. An in-depth computational analysis of this process
can be found elsewhere.16 The experimental procedure premixes
the aldehyde and benzylamine prior to addition of the enone or
catalyst. Consequently, we hypothesize that the imine–enamine
mixture 24–25 is preformed and the presumed enamine (E)-25 is
the reactive nucleophile in the enamine–iminium ion, dual-cata-
lysed10h,17 Michael addition to form the key quaternary stereo-
genic centre and the vicinal stereocenter. Additional support for
this hypothesis can be found in the products derived from the
cyclohexenone series 15 described in Scheme 2 in which the
benzyl amine moiety is incorporated in the product 15 where
subsequent elimination is not viable. The important role of the
molecular sieves in the reaction is likely to remove the water
from the reaction media, which would possibly disrupt the key
hydrogen bonding network present in transition state 28. After
enamine tautomerization, an intramolecular Mannich cyclization
followed by elimination of benzyl amine would yield zwitterion
32. The presence of molecular sieves in the reaction complicates
any mechanistic explanation for the proline sulphonamide
hydrolysis step. If water is not the nucleophile for catalyst clea-
vage, it is possible that the by-product benzylamine could
undergo iminium ion–imine exchange with 32 after its elimin-
ation from intermediate 31. If this iminium ion–imine exchange
is operative, it would require that a subsequent imine hydrolysis
step occur to reveal the enone product 23.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4851–4863 | 4853

View Article Online
Table 2 Variation of catalyst structurea
Scheme 5 Synthesis of second generation catalyst.
Entry
Catalyst
Time (h)
Yield
er (dr)
1
2
3
4
5
12
3
32
33
34
36
60
60
60
60
66%
32%
11%
Trace
Trace
90.7 : 9.3 (>20 : 1)
84.4 : 15.6 (>20 : 1)
62 : 38 (20 : 1)
n/a
n/a
a Enantiomeric ratios (er) determined by chiral HPLC analysis and
diastereomeric ratios (dr) determined by 1H NMR analysis.
Fig. 2 ORTEP representation of catalyst 39.
but the level of enantioselectivities was lower than the parent
toluene conditions (entry 1). Cyclohexane also performed with
reduced levels of stereoselectivity (entry 6). Fortunately,
trifluorotoluene and 1,2-dichloroethane both proved to be useful
solvents – with the later providing superior levels of diastereos-
electivity (entry 8).
Table 3 Solvent effects on annulation reactiona
We also became intrigued by the possibility that we could
augment the enantioselectivity in this process by tuning the sul-
phonamide pKa (Scheme 5). In support of this hypothesis, we
synthesized the p-dodecyl ester version of our parent catalyst.
This catalyst was readily available from commercial sulphon-
amide carboxylic acid 35 which was esterified and coupled with
Cbz-proline followed by hydrogenation to afford proline sulpho-
namide 39 in high yield. The product 39 was crystalline and its
structure was unambiguously determined by X-ray analysis
(Fig. 2).
Entry
Solvent
Time (h)
Yield (%)
er (dr)
1
2
3
4
5
6
7
8
Toluene
MTBE
2-Me-THF
CH2Cl2
CHCl3
Cyclohexane
CF3-C6H5
1,2-DCE
36
36
36
36
36
60
60
60
66
52
52
67
63
62
71
67
90.7 : 9.3 (>20 : 1)
73.5 : 26.5 (18 : 1)
78 : 22 (>20 : 1)
87 : 13 (>20 : 1)
85.5 : 14.5 (>20 : 1)
83.5 : 15.5 (19 : 1)
92 : 8 (20 : 1)
92.1 : 7.9 (>20 : 1)
We were pleased to find that this catalyst did appear to provide
slightly higher enantioselectivities under otherwise identical con-
ditions (Table 4, entries 1–2). In addition, the requirement of
molecular sieves for this reaction continued to be prevalent
(entry 3). We also explored if less than one equivalent of the
amine could be used with comparable efficiency. If 0.8 equival-
ent of benzyl amine was added, a reduced chemical yield was
observed (entry 4). Interestingly, reduction of the equivalency of
benzyl amine could be tolerated (0.5 equiv. BnNH2) if an acid
additive was used (1 mol% 4-fluorobenzoic acid) (entry 5).
With the optimization complete, we turned our focus to briefly
screening the scope of the aldehyde component (Table 5). We
were pleased to find that p-methyl, p-bromo and p-chloro moi-
eties were all tolerated on the aromatic ring (entries a–c). X-ray
crystallographic analysis of enone 22b allowed for the assign-
ment of absolute configuration (Fig. 3). Interestingly, replace-
ment of the aromatic ring for a methyl ester (entry d) led to a
dramatic drop in diastereoselectivity under the reaction
conditions.
a Enantiomeric ratios (er) determined by chiral HPLC analysis and
diastereomeric ratios (dr) determined by 1H NMR analysis.
Given the early success of this transformation, we wanted to
explore if the sulphonamide scaffold was unique in providing
this reactivity (Table 2). Consequently, we screened proline as
well as other proline derivatives to gain a fair comparison with
the proline sulphonamide 12. Both proline (3) and the proline
tetrazole 33 proved inferior – providing noticeably lower levels
of chemical yield and stereoselectivity versus the proline
sulphonamide 12 (entries 2 and 3). Use of prolinol derivatives
34a and 34b led to only trace amounts of product formation –
even after extended reaction times (entries 4 and 5).
We next explored the impact of solvent on the transformation
(Table 3). Use of MTBE or 2-methyl-THF led to notable
decreases in enantioselectivity (entries 2–3). The poor perform-
ance of 2-methyl-THF was surprising as we had previously used
this solvent in proline sulphonamide-catalysed aldol reactions
with considerable success.18 Dichloromethane and chloroform
proved more effective than oxygenated solvents (entries 4–5),
An in-depth analysis of scope on the enone component is
described in Table 6. We were pleased to see that both the repla-
cement of the β-methyl moiety with a longer alkyl chain (butyl)
4854 | Org. Biomol. Chem., 2012, 10, 4851–4863
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 4 Utilization of an improved proline sulphonamide catalysta
Catalyst
Entry (20 mol %)
Yield
(%)
Additives
er (dr)
1
2
3
4
5
Hua Cat
BnNH2 (1 equiv.),
mol. sieves, 60 h
BnNH2 (1 equiv.),
mol. sieves, 60 h
BnNH2 (1 equiv.),
48 h
BnNH2 (0.8 equiv.),
mol. sieves, 60 h
BnNH2 (0.5 equiv.),
(p-C6H4F)CO2H
(1 mol%), mol.
sieves, 60 h
67
74
66
56
70
92 : 8
(>20 : 1)
94.5 : 5.5
(>20 : 1)
85.5 : 14.5
(20 : 1)
91.5 : 8.5
(>20 : 1)
90.5 : 9.5
(>20 : 1)
Hua Cat II
Hua Cat II
Hua Cat II
Hua Cat II
Fig. 3 ORTEP representation of cyclohexenone 41b.
Table 6 Scope of enone componenta
a Enantiomeric ratios (er) determined by chiral HPLC analysis and
diastereomeric ratios (dr) determined by 1H NMR analysis.
Entry
R
R′ R′′ Yield (%) er (dr)
Table 5 Scope of aldehyde componenta
a
b
c
d
e
f
Bu
Bu
Bu
Me
i-Pr
Ph
H
Me
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
84
76
68
95.7 : 4.3 (>20 : 1)
91.5 : 8.5 (>20 : 1)
95.9 : 4.1 (>20 : 1)
89 : 11 (>20 : 1)
Me 33
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0
n/a
48
43
55
65
32
79
68
68
54
62
55
39
61
97.5 : 2.5 (>20 : 1)
87.8 : 12.2 (>20 : 1)
63.8 : 36.2 (>20 : 1)
56.6 : 43.4 (>20 : 1)
88.3 : 11.7 (16 : 1)
92.6 : 7.4 (>20 : 1)
92.7 : 7.3 (>20 : 1)
89.7 : 10.3 (>20 : 1)
91.4 : 8.6 (>20 : 1)
81.6 : 18.4 (>20 : 1)
92.8 : 7.2 (15 : 1)
98.8 : 1.2 (>20 : 1)
96.9 : 3.1 (8 : 1)
g
h
i
p-Cl-C6H4–
Br(CH2)3–
I(CH2)3–
TsO(CH2)3–
CH2vCH(CH2)3–
BnO(CH2)4–
TBSO(CH2)4–
N3(CH2)4–
I(CH2)4–
I(CH2)5–
PhSO2(CH2)4–
PhthN(CH2)5–
Entry
R
Yield (%)
er (dr)
jb
k
l
A
B
C
D
p-Me-C6H4–
p-Br-C6H4–
p-Cl-C6H4–
MeO2C–
56
54
52
72
94.4 : 5.6 (>20 : 1)
93.6 : 6.4 (>20 : 1)
93.6 : 6.4 (20 : 1)
n/d (1.5 : 1)
m
n
o
p
q
r
a Enantiomeric ratios (er) determined by chiral HPLC analysis and
diastereomeric ratios (dr) determined by 1H NMR analysis.
a Enantiomeric ratios (er) determined by chiral HPLC analysis and
diastereomeric ratios (dr) determined by 1H NMR analysis. b This
reaction was run using catalyst 12. Use of catalyst 39 gave lower levels
of enantioselectivity (80 : 20 er).
was tolerated with a variety of aldehyde nucleophiles (entries
a–c) as well as additional substitution on the alkene (entry d);
however, α-branching at this position appeared to be too steri-
cally demanding (entry e). Aromatic substitution in the β-pos-
ition does lead to enantioenriched products 43f and 43g in
modest chemical yield (entries f–g). Product 43g produced crys-
tals that were suitable for X-ray crystallographic analysis
(Fig. 4).19 We also studied the placement of functional groups on
the β-position of the enone. Using of propyl halides (e.g. 42h
and 42i) led to modest chemical yield and greatly reduced enan-
tioselectivity (entries h and i). Interestingly, this effect appears to
be limited to the propyl halides (entries h and i) as propyl tosy-
late (entry j) as well as butyl and pentyl iodides (entries o–p)
give more reasonable enantioselectivities. Alkenes, benzyl
ethers, silyloxy moieties and azides are all tolerated on the alkyl
chain (entries k–n). We were also pleased to see that phenyl
sulfone and phthalamide moieties could also be incorporated
with good levels of enantioselectivity (entries q–r).
The stereochemically rich cyclohexenone scaffold can be
further derivatized with high levels of diastereoselectivity
(Scheme 6). Enolization using LDA and DMPU followed by the
addition of a suitable electrophile produced the α-functionalized
products 44 and 45. Nucleophilic addition to the enone scaffolds
was possible in both a 1,2- and a 1,4-pathway. Addition of
methyl or phenyllithium provided the 3° alcohol products 46 and
47 in high selectivity and chemical yield. We were unable to
determine the relative stereochemistry of the newly formed 3°
alcohol moiety. The conjugate addition20 proceeded equally well
– with again high levels of diastereoselectivity being observed in
products 48 and 49.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4851–4863 | 4855

View Article Online
and aq. HCl (50 mL, 1 N). The organic layer was washed with
brine (3 × 100 mL). The dried (Na2SO4) extract was concen-
trated in vacuo and purified by chromatography over silica gel,
eluting with 5–25% EtOAc–CH2Cl2, to give sulphonamide 36
(7.26 g, 19.7 mmol, 79%) as a white solid. Mp: 105–106 °C; IR
(neat) 3330, 2916, 2845, 1713, 1282, 1157, 1124, 765, 738,
1
694 cm−1; H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz,
2H), 8.02 (d, J = 8.4 Hz, 2H), 4.99 (br s, 2H), 4.38 (t, J = 6.8
Hz, 2H), 1.79–1.83 (m, 2H), 1.29–1.46 (m, 18H), 0.90 (t, J =
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.2, 145.6,
134.4, 130.4, 126.5, 66.0, 31.9, 29.64, 29.58, 29.53, 29.4, 29.3,
28.6, 26.0, 22.7, 14.1; HRMS (EI+) calcd for C19H31NO4S
(M+), 369.1974 found 369.1971.
Fig. 4 ORTEP representation of cyclohexenone 43g.
Z-L-Sulphonamide 38
To a solution of Z-L-proline 37 (2.88 g, 11.6 mmol) in CH2Cl2
(58 mL) was added sulphonamide 36 (4.27 g, 11.6 mmol),
DMAP (1.41 g, 11.6 mmol) and EDCI (2.22 g, 11.6 mmol)
respectively. The reaction mixture was stirred at room tempera-
ture for 4 d before being partitioned between DCM (50 mL) and
aq. HCl (50 mL, 1 N). The organic layer was washed with half-
saturated brine (3 × 80 mL). The dried (Na2SO4) extract was
concentrated in vacuo and purified by chromatography over
silica gel, eluting with 10–60% EtOAc–CH2Cl2, to give Z-L-sul-
phonamide 38 (5.06 g, 8.42 mmol, 73%) as a colorless oil. [α]D23
= −94.0° (c = 3.1, CHCl3); IR (neat) 3477, 2922, 2851, 1718,
Scheme 6 Derivatization of cyclohexenone scaffold.
Conclusion
In conclusion, the extension of the Hajos–Parrish reaction3 to
include aldehyde components with acyclic enones represents one
of first major advances to since its discovery nearly forty years
ago. This proline sulphonamide-catalysed protocol generates
useful cyclohexenone building blocks in a highly stereoselective
process. The scope of this transformation has been extensively
explored and subsequent derivatization of the product enone
scaffold has been demonstrated. A plausible mechanism is out-
lined for this transformation. Further application of this chem-
istry in natural product synthesis will be disclosed in due course.
1
1691, 1615, 1435, 1266, 1092, 863, 770, 700, 618 cm−1; H
NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.94 (d, J
= 7.6 Hz, 2H), 7.19–7.29 (m, 5H), 5.06 (d, J = 12.4 Hz, 1H),
4.91 (d, J = 12.4 Hz, 1H), 4.23–4.31 (m, 3H), 3.35–3.39 (m,
2H), 1.69–2.01 (m, 6H), 1.29–1.43 (m, 19H), 0.90 (t, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 156.2, 146.1,
136.3, 133.2, 129.6, 128.4, 127.9, 127.7, 127.0, 67.3, 65.5,
62.8, 46.9, 31.9, 29.7, 29.6, 29.4, 28.7, 26.0, 24.3, 22.7, 14.1;
HRMS (CI+) calcd for C32H45N2O7S (M + 1), 601.2947 found
601.2921.
Experimental section
Sulphonamide 36
Sulphonamide 39
To a solution of 1-dodecanol (9.30 g, 50 mmol) in DMF
(100 mL) was added sulphonamide 35 (5.03 g, 25 mmol),
DMAP (1.53 g, 12.5 mmol) and EDCI (4.80 g, 25 mmol)
respectively. The reaction mixture was stirred at room tempera-
ture for 48 h before being partitioned between EtOAc (150 mL)
To a solution of Z-L-sulphonamide 38 (3.72 g, 6.20 mmol) in
MeOH (100 mL) was added Pd/C (0.37 g, 10%). The mixture
was stirred at rt for under an atmosphere of hydrogen. After
20 h, the reaction was filtered through Celite and silica gel pad,
and the filtrate was concentrated in vacuo to give white solid.
4856 | Org. Biomol. Chem., 2012, 10, 4851–4863
This journal is © The Royal Society of Chemistry 2012

View Article Online
4,5-Dimethyl-4-(4-methylphenyl)-2-cyclohexen-1-one 41a
The crude product was purified by chromatography over silica
gel, eluting with 1–20% MeOH–CH2Cl2, to give sulphonamide
39 (2.37 g, 5.08 mmol, 82%) as a white solid. Mp: 166–168 °C;
[α]2D3 = −88.1° (c = 0.7, CHCl3); IR (neat) 3129, 3074, 2922,
Reaction time 60 h. Purified by chromatography over silica gel,
eluting with 1–4% EtOAc–hexanes, to give enone 41a (30.1 mg,
56%, 94.4 : 5.6 er, >20 : 1 dr, colorless crystal). Enantiomeric
excess was determined by chiral HPLC [4.6 × 250 mm Daicel
OJ column, 95 : 5 hexanes–i-PrOH, 1.0 mL min−1, retention
times 9.89 min (major) and 18.5 min (minor)] to be 94.4 : 5.6 er:
Mp: 64–66 °C; [α]2D3 = −90.4° (c = 1.2, CHCl3); IR (neat) 2961,
1
1729, 1620, 1560, 1391, 1266, 857, 732, 618 cm−1; H NMR
(400 MHz, CDCl3) δ 8.69 (br s, 1H), 8.12 (d, J = 8.4 Hz, 2H),
8.00 (d, J = 8.4 Hz, 2H), 4.33–4.38 (m, 3H), 3.37–3.51 (m, 2H),
2.35–2.38 (m, 1H), 1.75–2.05 (m, 5H), 1.29–1.45 (m, 19H),
0.90 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.2,
165.6, 146.9, 133.3, 129.8, 126.5, 65.7, 63.0, 46.8, 31.9, 29.9,
29.63, 29.55, 29.4, 29.3, 28.7, 26.0, 24.6, 22.7, 14.1; HRMS
(CI+) calcd for C24H39N2O5S (M + 1), 467.2580 found
467.2566.
1680, 1455, 1385, 1276, 1116, 816, 778 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 7.18–7.22 (m, 4H), 6.83 (d, J = 10.0 Hz,
1H), 6.09 (d, J = 10.0 Hz, 1H), 2.36–2.46 (m, 6H), 1.45 (s, 3H),
0.86–0.87 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0,
159.4, 143.3, 136.4, 129.1, 127.3, 126.7, 43.9, 42.6, 40.6, 20.9,
16.9, 15.8; HRMS (CI+) calcd for C15H19O (M + 1), 215.1436
found 215.1435.
General procedure for three-component reaction with acyclic
enone (20 mol% catalyst)
The aldehyde (0.25 mmol), benzyl amine (0.25 mmol) and 4 Å
MS (0.1 g) were added to dichloroethane solution (0.25 mL) in a
vial. After stirring at room temperature for 30 min, the corre-
sponding enone (0.75 mmol, 3 equiv.) and sulphonamide 39
(23.3 mg, 0.05 mmol) were added to it at room temperature.
After stirring at same temperature, reaction was loaded directly
onto silica gel and was purified by chromatography, eluting with
1–5% EtOAc–hexanes, to give the corresponding product.
4-(4-Bromophenyl)-4,5-dimethyl-2-cyclohexen-1-one 41b21
Reaction time 60 h. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 41b (37.4 mg,
54%, 93.6 : 6.4 er, >20 : 1 dr, colorless crystal). Enantiomeric
excess was determined by chiral HPLC [4.6 × 250 mm Daicel
OJ column, 98 : 2 hexanes–i-PrOH, 1.0 mL min−1, retention
times 16.6 min (major) and 20.3 min (minor)] to be 93.6 : 6.4 er:
Mp: 144–146 °C; [α]2D3 = −101.6° (c = 1.3, CHCl3); IR (neat)
2976, 1685, 1457, 1081, 808, 792, 716 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 7.47–7.51 (m, 1H), 7.17–7.20 (m, 1H),
6.78 (d, J = 10.0 Hz, 1H), 6.10 (d, J = 10.4 Hz, 1H), 2.34–2.44
(m, 3H), 1.44 (s, 3H), 0.84 (d, J = 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 199.5, 158.1, 145.4, 131.5, 128.7, 127.8,
120.8, 44.0, 42.4, 40.6, 16.9, 15.7; HRMS (CI+) calcd for
C14H16OBr (M + 1), 279.0385 found 279.0382.
4,5-Dimethyl-4-phenyl-2-cyclohexen-1-one (23)
Reaction time 60 h. Purified by chromatography over silica gel,
eluting with 1–4% EtOAc–hexanes, to give enone 23 (37.3 mg,
75%, 94.6 : 5.4 er, >20 : 1 dr, colorless crystal). Enantiomeric
excess was determined by chiral HPLC [4.6 × 250 mm Daicel
OD column, 99 : 1 hexanes–i-PrOH, 1.0 mL min−1, retention
times 13.3 min (major) and 16.1 min (minor)] to be 94.6 : 5.4 er:
Mp: 48–50 °C; [α]D23 = −63.4° (c = 1.2, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.27–7.40 (m, 5H), 6.84 (d, J = 10.0 Hz,
1H), 6.10 (d, J = 10.0 Hz, 1H), 2.36–2.45 (m, 3H), 1.47 (s, 3H),
0.84–0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9,
159.1, 146.2, 128.4, 127.4, 126.8, 126.7, 44.2, 42.6, 40.6, 16.9,
15.8; HRMS (CI+) calcd for C14H17O (M + 1), 201.1279 found
201.1269.
4-(4-Chlorophenyl)-4,5-dimethyl-2-cyclohexen-1-one 41c
Reaction time 60 h. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 41c (30.6 mg,
52%, 93.6 : 6.4 er, >20 : 1 dr, light yellow crystal). Enantiomeric
excess was determined by chiral HPLC [4.6 × 250 mm Daicel
OJ column, 95 : 5 hexanes–i-PrOH, 1.0 mL min−1, retention
times 11.6 min (major) and 14.2 min (minor)] to be 93.6 : 6.4 er:
Mp: 133–135 °C; [α]2D3 = −97.6° (c = 1.3, CHCl3); IR (neat)
2965, 2927, 1685, 1484, 1457, 1271, 1005, 814, 732, 700 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.34–7.36 (m, 2H), 7.23–7.28
(m, 2H), 6.79 (d, J = 10.4 Hz, 1H), 6.10 (d, J = 10.0 Hz, 1H),
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4851–4863 | 4857

View Article Online
2.33–2.47 (m, 3H), 1.44 (s, 3H), 0.84 (d, J = 6.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 199.5, 158.3, 144.8, 132.7, 128.5,
128.3, 127.7, 44.0, 42.5, 40.6, 16.9, 15.7; HRMS (CI+) calcd
for C14H16OCl (M + 1), 235.0890 found 235.0883.
4-(4-Bromophenyl)-5-butyl-4-methyl-2-cyclohexen-1-one (43c)
Reaction time 3 d. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 43c (54.5 mg,
68%, 95.9 : 4.1 er, >20 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel AS-H
column, 90 : 10 hexanes–i-PrOH, 1.0 mL min−1, retention times
36.8 min (major) and 28.2 min (minor)] to be 95.9 : 4.1 er: [α]D23
= −125° (c = 1.5, CHCl3); IR (neat) 2953, 2930, 1680, 1490,
1077, 1003, 816, 723 cm−1 1H NMR (400 MHz, CDCl3) δ
;
7.49–7.52 (m, 2H), 7.18–7.21 (m, 2H), 6.74 (d, J = 10.0 Hz,
1H), 6.08 (d, J = 10.0 Hz, 1H), 2.62 (dd, J = 16.8, 4.0 Hz, 1H),
2.14–2.33 (m, 2H), 1.45 (s, 3H), 0.89–1.31 (m, 6H), 0.77 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.6, 158.6,
145.4, 131.5, 128.8, 127.5, 120.8, 45.4, 44.3, 39.5, 29.3, 29.1,
22.4, 16.9, 13.8; HRMS (CI+) calcd for C17H22OBr (M + 1),
321.0854 found 321.0860.
5-Butyl-4-methyl-4-phenyl-2-cyclohexen-1-one (43a)
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–3% EtOAc–hexanes, to give enone 43a (50.9 mg,
84%, 95.7 : 4.3 er, >20 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel OD
column, 99.5 : 0.5 hexanes–i-PrOH, 0.8 mL min−1, retention times
17.0 min (major) and 12.6 min (minor)] to be 95.7 : 4.3 er. [α]D23
=
−100.9° (c = 2.0, CHCl3); IR (neat) 2253, 2930, 1680, 1498,
1373, 1272, 1023, 762, 704 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.26–7.39 (m, 4H), 6.80 (d, J = 10.0 Hz, 1H), 6.07 (d, J = 10.0
Hz, 1H), 2.61 (dd, J = 16.0, 3.2 Hz, 1H), 2.18–2.34 (m, 2H), 1.46
(s, 3H), 0.92–1.30 (m, 7H), 0.73 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 200.0, 159.5, 146.3, 128.4, 127.2, 127.0,
126.7, 45.4, 44.4, 39.6, 29.2, 29.1, 22.4, 16.9, 13.8; HRMS (CI+)
calcd for C17H23O (M + 1), 243.1749 found 243.1748.
4,5,6-Trimethyl-4-phenyl-2-cyclohexen-1-one (43d)
Reaction time 7 d. Purified by chromatography over silica gel,
eluting with 1–4% EtOAc–hexanes, to give enone 43d (17.6 mg,
33%, 89 : 11 er, >20 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel AS-H
column, 99 : 1 hexanes–i-PrOH, 0.9 mL min−1, 254 nm, reten-
tion times 13.5 min (major) and 11.1 min (minor)] to be 89 : 11
er: [α]2D3 = −32.1° (c = 1.4, CHCl3); IR (neat) 2969, 2922, 1673,
1
1459, 1365, 1116, 1019, 735, 700 cm−1; H NMR (400 MHz,
CDCl3) δ 7.26–7.39 (m, 6H), 6.60 (q, J = 1.2 Hz, 1H),
2.36–2.46 (m, 2H), 1.87 (d, J = 1.6 Hz, 3H), 1.44 (s, 3H),
0.82–0.84 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0,
154.4, 147.0, 133.4, 128.3, 126.9, 126.6, 44.5, 42.6, 40.8, 17.2,
15.8, 15.7; HRMS (CI+) calcd for C15H19O (M + 1), 215.1436
found 215.1442.
5-Butyl-4-methyl-4-(4-methylphenyl)-2-cyclohexen-1-one (43b)
Reaction time 3 d. Purified by chromatography over silica gel,
eluting with 1–4% EtOAc–hexanes, to give enone 35e (48.9 mg,
76%, 91.5 : 8.5 er, >20 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel AS-H
column, 98 : 2 hexanes–i-PrOH, 1.0 mL min−1, retention times
33.9 min (major) and 38.1 min (minor)] to be 91.5 : 8.5 er: [α]D23
= −97.4° (c = 2.0, CHCl3); IR (neat) 2954, 2927, 1685, 1457,
1
1266, 1124, 1021, 814, 776, 721 cm−1; H NMR (400 MHz,
CDCl3) δ 7.17–7.22 (m, 4H), 6.78 (d, J = 10.0 Hz, 1H), 6.06 (d,
J = 10.0 Hz, 1H), 2.61 (dd, J = 16.4, 3.6 Hz, 1H), 2.38 (s, 3H),
2.17–2.34 (m, 2H), 1.45 (s, 3H), 0.94–1.29 (m, 6H), 0.77 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.1, 159.8,
143.3, 136.3, 129.1, 127.0, 126.8, 45.3, 44.1, 39.6, 29.3, 29.1,
22.5, 20.9, 17.0, 13.8; HRMS (CI+) calcd for C18H25O (M + 1),
257.1905 found 257.1910.
4,5-Diphenyl-4-methyl-2-cyclohexen-1-one (43f)
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–4% EtOAc–hexanes, to give enone 43f (31.1 mg,
47%, 97.5 : 2.5 er, >20 : 1 dr, white solid). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel OD
column, 99 : 1 hexanes–i-PrOH, 1.0 mL min−1, retention times
29.1 min (major) and 23.8 min (minor)] to be 97.5 : 2.5 er: Mp:
104–106 °C; [α]2D3 = −102.9° (c = 1.4, CHCl3); IR (neat) 3020,
2971, 1669, 1495, 1446, 1266, 798, 770, 700 cm−1; H NMR
1
4858 | Org. Biomol. Chem., 2012, 10, 4851–4863
This journal is © The Royal Society of Chemistry 2012

View Article Online
(400 MHz, CDCl3) δ 7.28–7.32 (m, 4H), 7.12–7.21 (m, 3H),
7.05 (dd, J = 8.0, 2.4 Hz, 1H), 6.97 (d, J = 10.0 Hz, 1H), 6.64
(d, J = 7.2 Hz, 2H), 6.22 (d, J = 10.0 Hz, 1H), 3.57 (dd, J =
14.0, 3.6 Hz, 1H), 3.11 (dd, J = 16.8, 14.2 Hz, 1H), 2.63 (dd, J
= 16.8, 4.0 Hz, 1H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 199.9, 158.8, 145.5, 138.9, 129.0, 128.2, 127.6, 127.19,
127.17, 127.0, 126.9, 52.2, 45.4, 40.1, 17.3; HRMS (CI+) calcd
for C19H19O (M + 1), 263.1436 found 263.1437.
HRMS (EI+) calcd for C16H19OBr (M+), 306.0619 found
306.0618.
5-(3-Iodopropyl)-4-methyl-4-phenyl-2-cyclohexen-1-one (43i)
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–3% EtOAc–hexanes, to give enone 43i (57.6 mg,
65%, 56.6 : 43.4 er, >20 : 1 dr, colorless oil). Enantiomeric
excess was determined by chiral HPLC [4.6 × 250 mm Daicel
OD column, 99 : 1 hexanes–i-PrOH, 1.0 mL min−1, retention
times 23.9 min (major) and 19.8 min (minor)] to be 56.6 : 43.4
er; IR (neat) 2957, 2918, 2848, 1680, 1455, 1369, 1276, 1023,
5-(4-Chlorophenyl)-4-phenyl-4-methyl-2-cyclohexen-1-one (43g)
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 43g (32.2 mg,
43%, 87.8 : 12.2 er, >20 : 1 dr, light yellow crystal). Enantio-
meric excess was determined by chiral HPLC [4.6 × 250 mm
1
781, 766, 704 cm−1; H NMR (400 MHz, CDCl3) δ 7.28–7.41
(m, 5H), 6.81 (d, J = 10.0 Hz, 1H), 6.09 (d, J = 10.0 Hz, 1H),
2.91–3.07 (m, 2H), 2.57 (dd, J = 16.4, 3.6 Hz, 1H), 2.24–2.38
(m, 2H), 1.71–1.89 (m, 1H), 1.24–1.57 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 199.3, 159.2, 145.8, 128.6, 127.2, 127.0,
126.9, 44.8, 44.3, 39.7, 31.0, 30.8, 16.9, 6.0; HRMS (CI+) calcd
for C16H19OI (M+), 354.0481 found 354.0478.
Daicel AS-H column, 90 : 10 hexanes–i-PrOH, 1.0 mL min−1
,
retention times 44.5 min (major) and 37.6 min (minor)] to be
87.8 : 12.2 er: Mp: 106–108 °C; [α]2D3 = −150.2° (c = 1.1,
CHCl3); IR (neat) 3031, 2976, 1685, 1495, 1255, 1097, 1015,
1
830, 759, 700 cm−1; H NMR (400 MHz, CDCl3) δ 7.28–7.34
(m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 7.04 (dd, J = 8.0, 2.0 Hz,
2H), 6.96 (d, J = 10.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 6.22
(d, J = 10.4 Hz, 1H), 3.54 (dd, J = 14.4, 3.6 Hz, 1H), 3.06 (dd, J
= 16.8, 14.8 Hz, 1H), 2.60 (dd, J = 16.4, 3.6 Hz, 1H), 1.38 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 199.4, 158.6, 145.1, 137.4,
132.9, 130.2, 128.3, 127.8, 127.2, 127.1, 51.6, 45.2, 39.9, 17.1;
HRMS (CI+) calcd for C19H18OCl (M + 1), 297.1046 found
297.1044.
4-Methyl-4-phenyl-5-(3-tosyloxylbutyl)-2-cyclohexen-1-one (43j)
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 2–20% EtOAc–hexanes, to give enone 43j
(31.8 mg, 32%, 88.3 : 11.7 er, 16 : 1 dr, colorless oil). Enantio-
meric excess was determined by chiral HPLC [4.6 × 250 mm
Daicel AD column, 90 : 10 hexanes–i-PrOH, 1.0 mL min−1
,
retention times 36.7 min (major) and 30.2 min (minor)] to be
88.3 : 11.7 er: [α]2D3 = −24.6° (c = 1.1, CHCl3); IR (neat) 2957,
2926, 1677, 1357, 1178, 953, 918, 816, 762, 704, 661 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.26–7.40
(m, 7H), 6.78 (d, J = 10.0 Hz, 1H), 6.07 (d, J = 10.0 Hz, 1H),
3.82–3.88 (m, 2H), 2.47–2.52 (m, 4H), 2.14–2.31 (m, 2H),
1.61–1.62 (m, 1H), 1.44(s, 3H), 1.23–1.29 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 199.1, 159.1, 145.8, 144.8, 133.1, 129.8,
128.6, 127.9, 127.1, 127.0, 126.8, 70.1, 45.2, 44.3, 39.4, 26.5,
25.9, 21.7, 17.0; HRMS (CI+) calcd for C23H26O4S (M+),
398.1552 found 398.1543.
5-(3-Bromopropyl)-4-methyl-4-phenyl-2-cyclohexen-1-one (43h)
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 43h (42.2 mg,
55%, 63.8 : 36.2 er, >20 : 1 dr, colorless oil). Enantiomeric
excess was determined by chiral HPLC [4.6 × 250 mm Daicel
OD column, 98 : 2 hexanes–i-PrOH, 1.0 mL min−1, retention
times 20.0 min (major) and 24.0 min (minor)] to be
63.8 : 36.2 er: [α]2D3 = −26.7° (c = 1.1, CHCl3); IR (neat) 2926,
1
1684, 1660, 1501, 770, 700 cm−1; H NMR (400 MHz, CDCl3)
δ 7.28–7.41 (m, 5H), 6.81 (d, J = 10.4 Hz, 1H), 6.09 (d, J =
10.0 Hz, 1H), 3.13–3.29 (m, 2H), 2.58 (dd, J = 16.4, 3.6 Hz,
1H), 2.21–2.39 (m, 2H), 1.77–1.89 (m, 1H), 1.24–1.57 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 199.3, 159.2, 145.8, 128.6,
127.2, 127.0, 126.9, 45.1, 44.4, 39.7, 33.2, 30.3, 28.5, 16.9;
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4851–4863 | 4859

View Article Online
Daicel OJ column, 85 : 15 hexanes–i-PrOH, 1.0 mL min−1
,
4-Methyl-5-(4-pentenyl)-4-phenyl-2-cyclohexen-1-one (43k)
retention times 11.8 min (major) and 14.7 min (minor)] to be
89.7 : 10.3 er: [α]2D3 = −59.0° (c = 2.0, CHCl3); IR (neat) 2949,
2930, 2852, 1684, 1470, 1385,1252, 1101, 1027, 836, 774, 704,
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–3% EtOAc–hexanes, to give enone 43k (50.2 mg,
79%, 92.6 : 7.4 er, >20 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel OD
column, 99.5 : 0.5 hexanes–i-PrOH, 1.0 mL min−1, retention
times 13.5 min (major) and 17.6 min (minor)] to be 92.6 : 7.4 er;
[α]2D3 = −78.5° (c = 1.2, CHCl3); IR (neat) 3058, 3023, 2926,
2852, 1684, 1498, 1459, 1264, 1023, 992, 914, 789, 762,
1
665 cm−1; H NMR (400 MHz, CDCl3) δ 7.26–7.39 (m, 5H),
6.80 (d, J = 10.4 Hz, 1H), 6.07 (d, J = 10.0 Hz, 1H), 3.44 (t, J =
6.4 Hz, 2H), 2.61 (dd, J = 16.0, 3.2 Hz, 1H), 2.23–2.34 (m, 2H),
1.46 (s, 3H), 1.37 (m, 7H), 0.86 (s, 9H), −0.005 (s, 3H), −0.008
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.8, 159.5, 146.2,
128.4, 127.2, 126.9, 126.8, 62.7, 45.5, 44.4, 39.6, 32.5, 29.4,
26.0, 23.2, 18.3, 16.9, −5.32; HRMS (CI+) calcd for
C23H37O2Si (M + 1), 373.2563 found 373.2549.
1
704 cm−1; H NMR (400 MHz, CDCl3) δ 7.27–7.40 (m, 5H),
6.80 (d, J = 10.0 Hz, 1H), 6.08 (d, J = 10.0 Hz, 1H), 5.58–5.66
(m, 1H), 4.81–4.86 (m, 2H), 2.61 (dd, J = 16.4, 2.8 Hz, 1H),
2.19–2.35 (m, 2H), 1.76–1.95 (m, 2H), 1.46 (s, 3H), 1.05–1.46
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 199.8, 159.4, 146.2,
138.2, 128.4, 127.2, 127.0, 126.8, 114.6, 45.3, 44.4, 39.6, 33.3,
29.0, 26.1, 16.9; HRMS (CI+) calcd for C18H22O (M+),
254.1671 found 254.1663.
5-(4-Azidobutyl)-4-methyl-4-phenyl-2-cyclohexen-1-one (43n)
Reaction time 4 d (no light). Purified by chromatography over
silica gel, eluting with 1–5% EtOAc–hexanes, to give enone 43n
(38.2 mg, 54%, 91.4 : 8.6 er, >20 : 1 dr, colorless oil). Enantio-
meric excess was determined by chiral HPLC [4.6 × 250 mm
Daicel OD column, 98 : 2 hexanes–i-PrOH, 1.0 mL min−1, reten-
tion times 20.0 min (major) and 25.8 min (minor)] to be
91.4 : 8.6 er: [α]2D3 = −67.9° (c = 1.2, CHCl3); IR (neat) 2934,
4-Methyl-4-phenyl-5-(4-phenylmethoxybutyl)-2-cyclohexen-1-
one (43i)
1
2860, 2093, 1684, 1260, 766, 700 cm−1; H NMR (400 MHz,
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 43i (59.2 mg,
68%, 92.7 : 7.3 er, >20 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel OJ
column, 85 : 15 hexanes–i-PrOH, 1.0 mL min−1, retention times
20.9 min (major) and 29.2 min (minor)] to be 92.7 : 7.3 er; [α]D23
= −51.3° (c = 1.6, CHCl3); IR (neat) 2926, 2852, 1680, 1451,
CDCl3) δ 7.28–7.41 (m, 5H), 6.81 (d, J = 10.0 Hz, 1H), 6.08 (d,
J = 10.0 Hz, 1H), 3.07 (t, J = 6.4 Hz, 2H), 2.60 (dd, J = 16.4,
3.2 Hz, 1H), 2.18–2.36 (m, 2H), 1.46 (s, 3H), 1.05–1.45 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 199.5, 159.3, 146.0, 128.5,
127.2, 126.9, 51.0, 45.3, 44.4, 39.6, 29.0, 28.5, 24.0, 16.8;
HRMS (EI+) calcd for C17H21N3O (M+), 283.1685 found
283.1677.
1097, 758, 735, 700 cm−1 1H NMR (400 MHz, CDCl3) δ
;
7.26–7.39 (m, 10H), 6.80 (d, J = 10.0 Hz, 1H), 6.08 (d, J = 10.0
Hz, 1H), 4.41 (s, 2H), 3.28–3.31 (m, 2H), 2.62 (dd, J = 16.0, 2.8
Hz, 1H), 2.19–2.34 (m, 2H), 1.02–1.46 (m, 9H); 13C NMR
(100 MHz, CDCl3) δ 199.8, 159.4, 146.2, 138.5, 128.43,
128.35, 127.6, 127.5, 127.2, 127.0, 126.8, 72.9, 69.9, 45.4,
44.4, 39.6, 29.5, 29.4, 23.6, 16.9; HRMS (EI+) calcd for
C24H28O2 (M+), 348.2089 found 348.2085.
5-(4-Iodobutyl)-4-methyl-4-phenyl-2-cyclohexen-1-one (43o)
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 43o (57.1 mg,
62%, 81.6 : 18.4 er, >20 : 1 dr, colorless oil). Enantiomeric
excess was determined by chiral HPLC [4.6 × 250 mm Daicel
OD column, 99 : 1 hexanes–i-PrOH, 1.0 mL min−1, retention
times 18.1 min (major) and 23.5 min (minor)] to be 81.6 : 18.4
er: [α]2D3 = −27.3° (c = 1.6, CHCl3); IR (neat) 2926, 2856, 1680,
5-[4-[(1,1-Dimethylethyl)dimethylsilyl]oxybutyl]-4-methyl-4-
phenyl-2-cyclohexen-1-one (43m)
1498, 1459, 1369, 1101, 1027, 766, 707 cm−1 1H NMR
;
Reaction time 5 d. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 43m
(62.9 mg, 68%, 89.7 : 10.3 er, >20 : 1 dr, colorless oil). Enantio-
meric excess was determined by chiral HPLC [4.6 × 250 mm
(400 MHz, CDCl3) δ 7.29–7.42 (m, 5H), 6.82 (d, J = 10.4 Hz,
1H), 6.09 (d, J = 10.0 Hz, 1H), 2.96–3.02 (m, 2H), 2.63 (dd, J =
16.4, 3.6 Hz, 1H), 2.23–2.37 (m, 2H), 1.09–1.65 (m, 9H);
13C NMR (100 MHz, CDCl3) δ 199.6, 159.3, 146.0, 128.5,
4860 | Org. Biomol. Chem., 2012, 10, 4851–4863
This journal is © The Royal Society of Chemistry 2012

View Article Online
127.2, 126.9, 45.2, 44.4, 39.6, 32.9, 28.4, 27.8, 16.8, 6.23;
HRMS (EI+) calcd for C17H21OI (M+), 368.0638 found
368.0625.
382.1603 found 382.1584.
4-Methyl-4-phenyl-5-(6-phthalimidohexyl)-2-cyclohexen-1-one
(43r)
Reaction time 5 d. Purified by chromatography over silica gel,
eluting with 1–6% EtOAc–hexanes, to give enone 43r (61.3 mg,
61%, 96.9 : 3.1 er, 8 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel OD
column, 90 : 10 hexanes–i-PrOH, 1.0 mL min−1, retention times
26.4 min (major) and 24.5 min (minor)] to be 96.9 : 3.1 er: [α]D23
= −38.3° (c = 1.0, CHCl3); IR (neat) 2933, 2851, 1767, 1718,
5-(5-Iodopentyl)-4-methyl-4-phenyl-2-cyclohexen-1-one (43p)
Reaction time 5 d. Purified by chromatography over silica gel,
eluting with 1–5% EtOAc–hexanes, to give enone 43p (52.6 mg,
55%, 92.8 : 7.2 er, 16 : 1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Daicel OD
column, 99 : 1 hexanes–i-PrOH, 1.0 mL min−1, retention times
16.9 min (major) and 21.9 min (minor)] to be 92.8 : 7.2 er: [α]D23
= −64.2° (c = 2.1, CHCl3); IR (neat) 2922, 2851, 1685, 1451,
1
1680, 1467, 1391, 1369, 1064, 765, 721, 705 cm−1; H NMR
(400 MHz, CDCl3) δ 7.70–7.86 (m, 4H), 7.22–7.37 (m, 5H),
6.78 (d, J = 10.0 Hz, 1H), 6.06 (d, J = 10.0 Hz, 1H), 3.58 (t, J =
7.2 Hz, 2H), 2.59 (dd, J = 16.4, 3.2 Hz, 1H), 2.00–2.33 (m, 3H),
1.10–1.64 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 199.8,
168.4, 159.4, 146.2, 133.9, 132.2, 128.4, 128.3, 127.9, 127.1,
126.9, 126.8, 123.2, 45.4, 44.4, 39.6, 37.8, 29.5, 28.3, 26.63,
26.56, 16.9; HRMS (EI+) calcd for C26H27NO3 (M+), 401.1991
found 401.183.
1364, 1260, 1168, 1026, 787, 765, 700 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 7.28–7.40 (m, 5H), 6.80 (d, J = 10.0 Hz,
1H), 6.08 (dd, J = 10.4, 0.8 Hz, 1H), 3.06 (t, J = 7.2 Hz, 2H),
2.59 (dd, J = 16.8, 2.8 Hz, 1H), 1.59–1.66 (m, 2H), 1.46 (s, 3H),
1.12–1.33 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 199.7,
159.4, 146.1, 128.5, 127.2, 126.94, 126.86, 45.3, 44.4, 39.6,
33.0, 30.1, 20.3, 25.8, 16.9, 6.84; HRMS (EI+) calcd for
C18H23OI (M+), 382.0794 found 382.0809.
4,5,6-Trimethyl-4-phenyl-2-cyclohexen-1-one (44)
To a solution of 23 (20 mg, 0.1 mmol) in THF (0.2 mL) at
−78 °C was added sequentially LDA§ (0.15 mL, 0.15 mmol, 1.0
M in THF–hexanes) and freshly distilled DMPU (0.05 mL,
0.4 mmol). The reaction was gradually warmed to 0 °C over a
period of 20 min. After recooling the system to −78 °C, MeI
(182.4 mg, 80 μl, 1.0 mmol) was added. After 2 h, the reaction
was quenched with sat. aq. NH4Cl (0.2 mL), warmed to rt and
partitioned between Et2O (5 mL) and water (5 mL). The aqueous
layer was extracted with Et2O (3 × 5 mL) and the combined
organic layer was dried with anhydrous MgSO4, concentrated in
vacuo and purified by chromatography over silica gel eluting
with 1–4% of EtOAc–hexanes to give 44 (17 mg, 0.08 mmol,
86%, >20 : 1 dr) as a thick oil: [α]2D3 = −38.0°; IR (neat) 2971,
4-Methyl-4-phenyl-5-(4-phenylsulfonyl)-2-cyclohexen-1-one
(43q)
Reaction time 5 d. Purified by chromatography over silica gel,
eluting with 5–20% EtOAc–hexanes, to give enone 43q
(37.2 mg, 39%, 98.8 : 1.2 er, 15 : 1 dr, colorless oil). Enantio-
meric excess was determined by chiral HPLC [4.6 × 250 mm
Daicel OD column, 90 : 10 hexanes–i-PrOH, 1.0 mL min−1
,
retention times 37.2 min (major) and 28.2 min (minor)] to be
98.8 : 1.2 er: [α]2D3 = −55.9° (c = 1.8, CHCl3); IR (neat) 2922,
2927, 2878, 1712, 1680 cm−1 1H NMR (400 MHz, CDCl3)
;
2867, 1677, 1447, 1307, 1143, 1085, 766, 707, 684, 598 cm−1
;
δ 7.26–7.39 (m, 5H), 6.77 (d, J = 10.0 Hz, 1H), 6.08 (d, J =
10.0 Hz, 1H), 2.35–2.43 (m, 1H), 2.03–2.10 (m, 1H), 1.48
1H NMR (400 MHz, CDCl3) δ 7.83–7.85 (m, 2H), 7.54–7.68
(m, 4H), 7.26–7.39 (m, 4H), 6.77 (d, J = 10.0 Hz, 1H), 6.06 (d,
J = 10.4 Hz, 1H), 2.85 (t, J = 8.0 Hz, 2H), 2.51 (dd, J = 16.4,
3.6 Hz, 1H), 2.14–2.30 (m, 2H), 1.02–1.60 (m, 9H); 13C NMR
(100 MHz, CDCl3) δ 199.3, 159.2, 145.9, 139.1, 133.7, 129.3,
128.6, 128.0, 127.2, 127.0, 126.9, 55.8, 45.1, 44.3, 39.5, 29.0,
25.6, 22.3, 16.8; HRMS (EI+) calcd for C23H26O3S (M+),
§Preparation of LDA Solution (1 M in THF–hexanes): To a solution of
diisopropylamine (0.607 g, 0.85 mL, 6.0 mmol) in THF (2.63 mL) at
−78 °C, was added n-BuLi (2.52 mL, 6.3 mmol, 2.5 M in hexanes).
After 5 min, the white slurry was warmed to −10 °C and stirred for
15 min prior to use.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4851–4863 | 4861

View Article Online
(s, 3H), 1.19 (d, J = 6.8 Hz, 3H), 0.96–1.00 (m, 1H), 0.828 (d, J
= 6.8 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 201.6, 158.2,
146.8, 128.4, 127.0, 126.7, 126.6, 46.5, 44.9, 44.1, 30.9, 16.1,
13.7, 12.1; HRMS (CI+) calcd for C15H18O (M+) 215.1436,
found 215.1442.
7.2 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 148.2, 147.0,
140.1, 130.0, 128.3, 128.1, 127.5, 127.0, 126.3, 126.1, 44.4,
43.6, 37.1, 18.0, 15.8; HRMS (CI+) calcd for C20H22O (M+)
278.1671, found 278.1664.
1,4,5-Trimethyl-4-phenyl-2-cyclohexen-1-ol (47)
6-Allyl-4,5-dimethyl-4-phenyl-2-cyclohexen-1-one (45)
To a solution of 23 (0.02 g, 0.1 mmol) in THF (0.2 mL) at
−78 °C was added MeLi (0.25 mL, 0.4 mmol, 1.6 M in Et2O).
After 2 h, the reaction was quenched with sat. aq. NH4Cl
(0.2 mL), warmed to rt and partitioned between Et2O (5 mL)
and water (5 mL). The aqueous layer was extracted with Et2O (3
× 3.5 mL) and the combined organic layer was dried with anhy-
drous MgSO4, concentrated in vacuo and purified by chromato-
graphy over silica gel eluting with 1–4% of EtOAc–hexanes to
give 47 (17 mg, 0.08 mmol, 81%, >20 : 1 dr) as a thick oil: [α]D23
To a solution of 23 (20 mg, 0.1 mmol) in THF (0.2 mL) at
−78 °C was added sequentially LDA§ (0.15 mL, 0.15 mmol, 1.0
M in THF–hexanes) and freshly distilled DMPU (0.05 mL,
0.4 mmol). The reaction was gradually warmed to 0 °C over a
period of 20 min. After recooling the system to −78 °C, allyl
bromide (125.1 mg, 90 μL, 1.0 mmol) and TBAI (0.37 g,
1.0 mmol) were added. After 2 h, the reaction was then with sat.
aq. NH4Cl (0.2 mL), warmed to rt and partitioned between Et2O
(5 mL) and water (5 mL). The aqueous layer was extracted with
Et2O (3 × 5 mL) and the combined organic layer was dried with
anhydrous MgSO4, concentrated in vacuo and purified by
chromatography over silica gel eluting with 1–4% of EtOAc–
hexanes to give 45 (0.019 g, 0.08 mmol, 94%, >20 : 1 dr) as a
1
= −16.8°; IR (neat) 3281, 3058, 3009, 2971, 2867 cm−1; H
NMR (400 MHz, CDCl3) δ 7.21–7.35 (m, 5H), 5.68 (d, J = 10.0
Hz, 1H), 5.54 (d, J = 10.0 Hz, 1H), 1.93–1.97 (m, 1H), 1.75 (d,
J = 8.0 Hz, 2H), 1.58 (s, 2H), 1.44 (s, 3H), 1.32 (s, 3H), 0.79 (d,
J = 6.8 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 137.5, 132.4,
128.0, 127.0, 125.9, 70.7, 43.9, 43.6, 39.2, 28.8, 17.9, 16.0;
HRMS (CI+) calcd for C15H20O (M+) 216.1514, found
216.1511.
thick oil: [α]2D3 = −109.1°; IR (neat) 2973, 1675, 761, 702 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.26–7.39 (m, 5H), 6.78 (d, J =
10.0 Hz, 1H), 6.09 (d, J = 10.0 Hz, 1H), 5.68–5.80 (m, 1H),
5.00–5.09 (m, 2H), 2.91–2.95 (m, 1H), 2.43–2.47 (m, 1H),
2.22–2.35 (m, 2H), 1.48 (s, 3H), 0.83 (d, J = 6.8 Hz, 3H); 13C
NMR (400 MHz, CDCl3) δ 200.2, 158.48, 146.7, 135.0, 128.4,
127.1, 127.1, 126.7, 117.1 48.43, 44.71, 42.6, 30.1, 16.5, 13.2;
HRMS (CI+) calcd for C17H20O (M+) 241.1592, found
241.1584.
3-Vinyl-4,5-dimethyl-4-phenyl-1-cyclohexanone (48)
To a suspension of CuCN (18 mg, 0.2 mmol) in THF (0.2 mL)
at −78 °C was added vinyl magnesium bromide (0.6 mL,
0.4 mmol, 0.7 M in THF). The reaction mixture was gradually
warmed to 0 °C over a period of 30 min. After recooling the
system to −78 °C, a solution of 23 (20 mg, 0.1 mmol) in THF
(0.3 mL) was added. After 12 h, the reaction was quenched with
sat. aq. NH4Cl (0.2 mL), warmed to rt and partitioned between
Et2O (5 mL) and water (5 mL). The aqueous layer was extracted
with Et2O (3 × 5 mL) and the combined organic layer was dried
with anhydrous MgSO4, concentrated in vacuo and purified by
chromatography over silica gel eluting with 1–4% of EtOAc–
hexanes to give 48 (16 mg, 0.07 mmol, 73%, 12 : 1 dr) as a thick
4,5-Dimethyl-1,4-diphenyl-2-cyclohexen-1-ol (46)
To a solution of 23 (20 mg, 0.1 mmol) in THF (0.2 mL) at
−78 °C was added PhLi (0.25 mL, 0.4 mmol, 1.7 M in Bu2O).
After 2 h, the reaction was quenched with sat. aq. NH4Cl
(0.2 mL), warmed to rt and partitioned between Et2O (5 mL)
and water (5 mL). The aqueous layer was extracted with Et2O (3
× 5 mL) and the combined organic layer was dried with anhy-
drous MgSO4, concentrated in vacuo and purified by chromato-
graphy over silica gel eluting with 1–4% of EtOAc–hexanes to
give 46 (23 mg, 0.08 mmol, 82%, >20 : 1 dr) as a thick oil: [α]D23
1
oil: [α]2D3 = −29.5°; IR (neat) 3080, 2971, 1707 cm−1; H NMR
(400 MHz, CDCl3) δ 7.22–7.35 (m, 5H), 5.39–5.43 (m, 1H),
4.87 (d, J = 10.8 Hz, 1H), 4.72 (d, J = 14.8 Hz, 1H), 2.80–2.86
(m, 2H), 2.65–2.66 (m, 1H), 2.35–2.56 (m, 3H), 1.61 (s, 3H),
0.95 (d, J = 6.4 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 211.0,
145.6, 137.9, 128.0, 127.1, 126.0, 116.7, 52.4, 45.8, 43.3, 42.3,
32.9, 20.4, 17.0; HRMS (CI+) calcd for C16H20O (M+)
= −13.8°; IR (neat) 3374, 3085, 3020, 2965, 2867 cm−1; H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 1.2 Hz, 2H), 7.22–7.46
(m, 8H), 5.93 (d, J = 10.0 Hz, 1H), 5.87 (d, J = 11.2 Hz, 1H),
2.06–2.16 (m, 3H), 1.80–1.86 (m, 1H), 1.42 (s, 3H), 0.70 (d, J =
1
4862 | Org. Biomol. Chem., 2012, 10, 4851–4863
This journal is © The Royal Society of Chemistry 2012

View Article Online
3 (a) Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615–1621;
(b) Z. G. Hajos and D. R. Parrish, Org. Synth., 1990, Coll. vol. 7, 363–
367; (c) P. Buchschacher, A. Fürst and J. Gutzwiller, Org. Synth., 1990,
Coll. vol. 7, 368–372; (d) C. F. Barbas III, Angew. Chem., Int. Ed., 2007,
47, 42–47.
229.1592, found 229.1599.
4 (a) M. Shibasaki and N. Yoshikawa, Chem. Rev., 2002, 102, 2187–2210;
(b) J. Leonard, E. Diez-Barra and S. Merino, Eur. J. Org. Chem., 1998,
2051–2061.
5 (a) T. Akiyama, T. Katoh and K. Mori, Angew. Chem., Int. Ed., 2009, 48,
4226–4228; (b) R. Yazaki, N. Kumagai and M. Shibasaki, J. Am. Chem.
Soc., 2010, 132, 10275–10277.
6 (a) T. Ooi, T. Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi and
K. Maruoka, Angew. Chem., Int. Ed., 2003, 42, 3796–3798; (b) R. He,
C. Ding and K. Maruoka, Angew. Chem., Int. Ed., 2009, 48, 4559–4561;
(c) F. Wu, H. Li, R. Hong and L. Deng, Angew. Chem., Int. Ed., 2006,
45, 947–950; (d) B. Wang, F. Wu, Y. Wang, X. Liu and L. Deng, J. Am.
Chem. Soc., 2007, 129, 768–769; (e) B. Tan, P. J. Chua, Y. Li and
G. Zhong, Org. Lett., 2008, 10, 2437–2440.
7 (a) S.-I. Yamada and G. Otani, Tetrahedron Lett., 1969, 4237–4240;
(b) G. Otani and S.-I. Yamada, Chem. Pharm. Bull., 1973, 21, 2112–
2118.
3-Butyl-4,5-dimethyl-4-phenyl-1-cyclohexanone (49)
To a suspension of CuCN (30 mg, 0.33 mmol) in THF (0.2 mL),
cooled at −78 °C, was added n-BuLi (0.42 mL, 0.67 mmol, 1.6
M in hexanes) and the reaction mixture was gradually warmed to
0 °C. After recooling the system to −78 °C, a solution of 23
(50 mg, 0.25 mmol) in THF (0.3 mL) was added. After 2 h, the
reaction was quenched with sat. aq. NH4Cl (0.2 mL), warmed to
rt and partitioned between Et2O (5 mL) and water (5 mL). The
aqueous layer was extracted with Et2O (3 × 5 mL) and the com-
bined organic layer was dried with anhydrous MgSO4, concen-
trated in vacuo and purified by chromatography over silica gel
eluting with 1–4% of EtOAc–hexanes to give 49 (0.060 g,
0.23 mmol, 90%, >20 : 1 dr) as a thick oil: [α]2D3 = −57.8°; IR
(neat) 3085, 3052, 2954, 2873, 1718 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.34–7.35 (m, 5H), 2.82–2.85 (m, 1H), 2.72–2.77 (m,
1H), 2.33–2.43 (m, 3H), 1.84–1.86 (m, 1H), 1.56 (s, 3H),
1.02–1.18 (m, 1H), 1.00–1.02 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H),
0.86–0.94 (m, 2H), 0.78–0.86 (m, 1H), 0.66 (t, J = 7.2 Hz, 3H);
13C NMR (400 MHz, CDCl3) δ 211.8, 146.3, 128.0, 127.1
126.8, 125.8, 49.4, 45.8, 43.5, 41.5, 32.9, 29.7, 28.6, 22.2, 21.0,
17.3, 13.7; HRMS (CI+) calcd for C18H26O (M+) 259.2062,
found 259.2070.
8 Y. Inokoishi, N. Sasakura, K. Nakano, Y. Ichikawa and H. Kotsuki, Org.
Lett., 2010, 12, 1616–1619.
9 (a) H. Yang and R. G. Carter, J. Org. Chem., 2009, 74, 5151–5156;
(b) H. Yang and R. G. Carter, Tetrahedron, 2010, 61, 4854–4859.
10 (a) D. Enders, A. Zamponi, T. Schaefer, C. Nuebling, H. Eichanauer,
A. Sitki Demir and G. Raabe, Chem. Ber., 1994, 127, 1707–1721; (b) N.
S. Chowdari, J. T. Suri and C. F. Barbas, III, Org. Lett., 2004, 6, 2507–
2510; (c) M. P. Lalonde, Y. Chen and E. N. Jacobsen, Angew. Chem., Int.
Ed., 2006, 45, 6366–6370; (d) S. H. McCooey and S. J. Conon, Org.
Lett., 2007, 9, 599–602; (e) S. Mukherjee and B. List, J. Am. Chem. Soc.,
2007, 129, 11336–11337; (f) O. Penon, A. Carlone, A. Mazzanti,
M. Locatelli, L. Bambri, G. Bartolli and P. Melchiorre, Chem.–Eur. J.,
2008, 14, 4788–4791; (g) S. Belot, A. Massaro, A. Tenti, A. Mordini and
A. Alexakis, Org. Lett., 2008, 10, 4557–4560; (h) M. Bella,
D. M. S. Schietroma, P. P. Cusella, T. Gasperi and V. Visca, Chem.
Commun., 2009, 597–599; (i) J. Mareda, G. Bollot, G. Bernardinello and
Y. Filinchuk, Chem.–Eur. J., 2009, 15, 3204–3220; ( j) A. Quintard,
S. Belot, E. Marchal and A. Alexakis, Eur. J. Org. Chem., 2010, 927–
936; (k) Q. Zhu and Y. Lu, Chem. Commun., 2010, 46, 2235–2237; (l) A.
R. Brown, W.-H. Kuo and E. N. Jacobsen, J. Am. Chem. Soc., 2010, 132,
9286–9288; (m) G. Jiang and B. List, Angew. Chem., Int. Ed., 2011, 50,
9471–9474.
Acknowledgements
11 H. Yang and R. G. Carter, Org. Lett., 2010, 12, 3108–3111.
12 For a detailed review of proline sulphonamides, see: H. Yang and R.
G. Carter, Synlett, 2010, 2827–2838.
13 (a) H. Yang and R. G. Carter, Org. Lett., 2008, 10, 4649–4652;
(b) H. Yang and R. G. Carter, J. Org. Chem., 2010, 75, 4929–4938.
14 J. d’Angelo, D. Desmaële, F. Dumas and A. Guingant, Tetrahedron:
Asymmetry, 1992, 3, 459–505.
15 (a) A. B. Northrup and D. W. C. MacMillan, J. Am. Chem. Soc., 2002,
124, 2458–2460; (b) R. Thayumanavan, B. Dhevalapally, K. Sakthivel,
F. Tanaka and C. F. Barbas III, Tetrahedron Lett., 2002, 43, 3817–3820;
(c) D. B. Ramachary, N. S. Chowdari and C. F. Barbas III, Angew.
Chem., Int. Ed., 2003, 42, 4233–4237; (d) N. Halland, P. S. Aburel and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2004, 43, 1272–1277; (e) P. Li,
J. N. Payette and H. Yamamoto, J. Am. Chem. Soc., 2007, 129, 9534–
9435; (f) L.-Y. Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti,
G. Bartoli and P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48, 7196–
7199; (g) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi,
F. Pesciaioli, M.-P. Song, G. Bartoli and P. Melchiorre, Angew. Chem.,
Int. Ed., 2009, 48, 7200–7203; (h) H.-F. Wang, H.-F. Cui, C. Zhuo, P. Li,
C. W. Zheng, Y. Q. Yang and G. Zhao, Chem.–Eur. J., 2009, 15, 13295–
13298.
Financial support was provided by the Oregon State University
(OSU) Venture Fund and the National Science Foundation
(CHE-0848704).
The
National
Science
Foundation
(CHE-0722319) and the Murdock Charitable Trust (2005265)
are acknowledged for their support of the NMR facility. We
thank Dr Lev N. Zakharov (OSU and University of Oregon) for
X-ray crystallographic analysis of compounds 23, 39, 41b and
43g and Professor Max Deinzer and Dr Jeff (OSU) for mass
spectra data. We thank Dr Kenichi Harada (OSU) for the spectra
data for the imine 24. Finally, we are grateful to Dr Paul Ha-
Yeon Cheong (OSU) his assistance with the reaction mechanism
and Dr Roger Hanselmann (Rib-X Pharmaceuticals) and for his
helpful discussions.
16 M. Pierce, S. Mahapatra, H. Yang, R. G. Carter and P. H.-Y. Cheong,
Submitted.
Notes and references
17 B.-C. Hong, M.-F. Wu, H.-C. Tseng and J.-H. Liao, Org. Lett., 2006, 8,
2217–2220.
18 H. Yang, S. Mahapatra, P. H.-Y. Cheong and R. G. Carter, J. Org. Chem.,
2010, 75, 7279–7290.
19 The X-ray data collected for 43g was of the racemate.
20 B. H. Lipshutz, R. S. Wilhelm and J. A. Kozlowski, J. Org. Chem., 1984,
49, 3938–3942.
1 (a) M. Bella and T. Gasperi, Synthesis, 2009, 1583–1614;
(b) A. C. B. Burtoloso, Synlett, 2009, 320–327; (c) S. Kotha, A. C. Deb,
K. Lahiri and E. Manivannan, Synthesis, 2009, 165–193; (d) P. G. Cozzi,
R. Hilgraf and N. Zimmermann, Eur. J. Org. Chem., 2007, 5969–5994;
(e) I. Denissova and L. Barriault, Tetrahedron, 2003, 59, 10105–10146;
(f) J. Christoffers and A. Mann, Angew. Chem., Int. Ed., 2001, 40, 4591–
4597; (g) E. J. Corey and A. Guzman-Perez, Angew. Chem., Int. Ed.,
1998, 37, 388–401.
21 R. L. N. Harris, F. Komitsky, Jr and C. Djerassi, J. Am. Chem. Soc.,
1967, 89, 4765–4775.
2 A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945–2963.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4851–4863 | 4863