Organocatalytic, enantioselective intramolecular [6 + 2] cycloaddition reaction for the formation of tricyclopentanoids and insight on its mechanism from a computational study

Article abstract of DOI:10.1021/ja108516b

Diphenylprolinol silyl ether was found to be an effective organocatalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2] cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with a δ-formylalkyl group to afford synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. The cis-fused triquinane derivatives were obtained exclusively; the trans-fused isomers were not detected among the reaction products. The intramolecular [6 + 2] cycloaddition occurs between the fulvene functionality (6π) and the enamine double bond (2π) generated from the formyl group in the substrates and the diphenylprolinol silyl ether. The absolute configuration of the reaction products was determined by vibrational circular dichroism. The reaction mechanism was investigated using molecular orbital calculations, B3LYP and MP2 geometry optimizations, and subsequent single-point energy evaluations on model reaction sequences. These calculations revealed the following: (i) The intermolecular [6 + 2] cycloaddition of a fulvene and an enamine double bond proceeds in a stepwise mechanism via a zwitterionic intermediate. (ii) On the other hand, the intramolecular [6 + 2] cycloaddition leading to the cis-fused triquinane skeleton proceeds in a concerted mechanism via a highly asynchronous transition state. (iii) The fulvene functionality and the enamine double bond adopt the gauche-syn conformation during the C-C bond formation processes in the [6 + 2] cycloaddition. (iv) The energy profiles calculated for the intramolecular reaction explain the observed exclusive formation of the cis-fused triquinane derivatives in the [6 + 2] cycloaddition reactions. The reasons for the enantioselectivity seen in these [6 + 2] cycloaddition reactions are also discussed.

Full text of DOI:10.1021/ja108516b

ARTICLE
pubs.acs.org/JACS
Organocatalytic, Enantioselective Intramolecular [6 + 2] Cycloaddition
Reaction for the Formation of Tricyclopentanoids and Insight on Its
Mechanism from a Computational Study
Yujiro Hayashi,*,†,§ Hiroaki Gotoh,† Masakazu Honma,† Kuppusamy Sankar,† Indresh Kumar,†
Hayato Ishikawa,† Kohzo Konno,‡ Hiroharu Yui,‡,§ Seiji Tsuzuki,|| and Tadafumi Uchimaru*,||
†Department of Industrial Chemistry, Faculty of Engineering, ‡Department of Chemistry, Faculty of Science, and §Research Institute for
Science and Technology, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Nanosystem Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan
S Supporting Information
b
ABSTRACT: Diphenylprolinol silyl ether was found to be an effective organo-
catalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2]
cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with
a δ-formylalkyl group to afford synthetically useful linear triquinane derivatives
in good yields and excellent enantioselectivities. The cis-fused triquinane
derivatives were obtained exclusively; the trans-fused isomers were not detected
among the reaction products. The intramolecular [6 + 2] cycloaddition occurs
between the fulvene functionality (6π) and the enamine double bond (2π) generated from the formyl group in the substrates and
the diphenylprolinol silyl ether. The absolute configuration of the reaction products was determined by vibrational circular
dichroism. The reaction mechanism was investigated using molecular orbital calculations, B3LYP and MP2 geometry optimizations,
and subsequent single-point energy evaluations on model reaction sequences. These calculations revealed the following: (i) The
intermolecular [6 + 2] cycloaddition of a fulvene and an enamine double bond proceeds in a stepwise mechanism via a zwitterionic
intermediate. (ii) On the other hand, the intramolecular [6 + 2] cycloaddition leading to the cis-fused triquinane skeleton proceeds
in a concerted mechanism via a highly asynchronous transition state. (iii) The fulvene functionality and the enamine double bond
adopt the gauche-syn conformation during the CꢀC bond formation processes in the [6 + 2] cycloaddition. (iv) The energy profiles
calculated for the intramolecular reaction explain the observed exclusive formation of the cis-fused triquinane derivatives in the [6 +
2] cycloaddition reactions. The reasons for the enantioselectivity seen in these [6 + 2] cycloaddition reactions are also discussed.
’ INTRODUCTION
One theme in the rapidly developing field of organocatalysts9 has
been their successful application to cycloaddition reactions such as
the [4 + 2] cycloaddition reaction,10 [3 + 2] cycloaddition reaction,11
[2 + 2] cycloaddition reaction,12 [4 + 3] cycloaddition reaction,13 and
[2 + 1] cycloaddition reaction.14 Diarylprolinol silyl ether,15 which
has been developed independently by our group16 and Jørgensen’s
group,17 is an effective organocatalyst, which has been employed in
several asymmetric reactions. We have also developed diarylprolinol
silyl ether-mediated cycloadditions such as the DielsꢀAlder
reaction,16e,h formal aza [3 + 3] cycloaddition reaction,16f and formal
carbo [3 + 3] cycloaddition reaction.16j Our interest in the application
of diphenylprolinol silyl ether to cycloaddition reactions promoted us
to investigate its use in the intramolecular formal [6 + 2] cycloaddi-
tion reaction of fulvenes, which will be described in this Article.
Cycloaddition reactions are one of the most powerful methods
for the construction of cyclic skeletons.1 However, as compared
to the well-established [4 + 2] cycloaddition (DielsꢀAlder) re-
action,2 only a few [6 + 2] cycloaddition reactions are known. In
fact, concerted [6 + 2] cycloaddition reactions are forbidden by
the WoodwardꢀHoffmann rules when the reaction is thermally
activated and the two reacting π systems add in a suprafacial
fashion.3 On the other hand, transition metals can promote the
[6 + 2] cycloaddition reactions of 1,3,5-cycloheptatriene,4 and
the intramolecular [6 + 2] cycloaddition of vinylcyclobutanones.5
Fulvene moieties are known to act as the 6π-component in some
[6 + 2] cycloaddition reactions, and Hong has reported an
intermolecular [6 + 2] cycloaddition reaction of aminofulvenes
with electron-deficient alkenes,6 while Houk disclosed an intra-
molecular [6 + 2] cycloaddition reaction of fulvene with enamines7
to afford linearly fused tricyclopentanoids. As far as we are aware,
there is only one report of an enantioselective [6 + 2] cycloaddition
reaction, that between cycloheptatriene and alkynes catalyzed by
a chiral cobalt reagent.4e,8
’ RESULTS AND DISCUSSION
Houk has already reported that fulvenes substituted at the
exocyclic 6-position by a 6-(ω-formylalkyl)group react with an
Received: January 10, 2010
Published: November 03, 2011
r
2011 American Chemical Society
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equimolar amount of Et2NH and K2CO3 in the presence of
molecular sieves in benzene to afford tricyclopentanoids by the
successive reactions of enamine generation, [6 + 2] cycloaddi-
tion, and deamination.7 As there is no asymmetric version of this
reaction, and the cyclopentanoids obtained are useful chiral
intermediates that form the key framework of several natural
products, we started to investigate this reaction using chiral organo-
catalysts (see Figure 1). We selected 4,4-bis(methoxycarbo-
nyl)-6-(2,4-cyclopentadien-1-ylidene)hexanal 3a as a model sub-
strate, which was easily synthesized from dimethyl malonate as
shown in Scheme 1. Dimethyl malonate was successively alky-
lated with (p-methoxyphenyl)methoxypropyl iodide and allyl
bromide. Oxidative cleavage of the allyl double bond with a
catalytic amount of OsO4 and NaIO4 gave an aldehyde, which
was treated with cyclopentadiene to provide a fulvene derivative.
After removal of the PMB protecting group with DDQ, oxidation
of the resulting alcohol proceeded smoothly to afford 3a in good
yield.
As excellent results had been obtained for the model com-
pound 3a, the generality of the reaction was examined (Table 2).
The reaction proceeds efficiently without any substituent on the
tether as in 6-(2,4-cyclopentadien-1-ylidene)hexanal 3b, which
gives the triquinane 4b of excellent enantiomeric purity (entry 2).
It should be noted that the reaction catalyzed by 10 mol % of
diphenylprolinol silyl ether 1 in the presence of PhCO2H is fast
and is complete within 3 h for the formation of 4b, while it is
reported that it takes 24 h to go to completion in the presence of
an equimolar amount of Et2NH, K2CO3, and molecular sieves in
benzene.7 Nearly optically pure 4c, a useful synthetic intermedi-
ate, was formed in good yield from the substrate 3c possessing a
dithiane moiety (entry 3). Linear tetracycles 4d, 4e, 4f, and 4g
were also synthesized in excellent enantiomeric purity (entries
4ꢀ7). It is worth noting that indoline derivative 4e, which is also
a useful chiral intermediate, was prepared from the acyclic aniline
precursor 3e via this [6 + 2] cycloaddition reaction (entry 5).
The intramolecular [6 + 2] cycloaddition reaction of 3a was
examined in detail (see eq 1) with the results summarized in
Table 1. When proline was used as catalyst in toluene, the desired
triquinane 4a was obtained in 15% yield with low ee (39% ee,
entry 1). The enantioselectivity dramatically increased to 98%
when a catalytic amount of diphenylprolinol silyl ether 1 was
employed (10 mol %), albeit the product yield was low (entry 2).
To increase the yield, additives were investigated. Whereas
NaOAc was not suitable (entry 3), benzoic acid was found to
be effective, affording the product 4a in good yield (89%) and
excellent enantiomeric purity (98% ee, entry 4). Screening of sol-
vents indicated that toluene was the optimal choice (entries 4ꢀ9). It
should be noted that trifluoromethyl-substituted diarylprolinol
silyl ether 2 was not effective in the present reaction (entry 10).
Table 1. Effect of the Catalyst and Solvent on the [6 + 2]
Cycloaddition Reaction of 3aa
entry
cat.
additive
NaOAc
solvent time (h) yield (%)b ee (%)c
1
2
proline
toluene
toluene
toluene
6
15
21
39
89
65
60
68
63
39
<5
39
98
96
98
99
96
97
92
98
1
1
1
1
1
1
1
1
2
3
3
3
4
PhCO2H toluene
PhCO2H benzene
PhCO2H CH2Cl2
PhCO2H MeCN
PhCO2H DMF
PhCO2H MeOH
PhCO2H toluene
3
5
1.5
0.5
0.5
3
6
7
8
9
3
10
25
a Reaction conditions: aldehyde 3a (0.3 mmol), catalyst (0.03 mmol),
and additive (0.06 mmol) in solvent (3.0 mL) at room temperature for
the indicated time. b Isolated yield. c The ee’s are determined on chiral
stationary phase HPLC.
Figure 1. Organocatalysts examined in this study.
Scheme 1. Synthesis of 3a
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Table 2. Catalytic Asymmetric [6 + 2] Cycloaddition Reac-
tion with Various Substratesa
p-Bromo-substituted phenol derivative 3g is a suitable precursor
for the [6 + 2] cycloaddition reaction, affording the product 4g in
90% ee (entry 7). Further transformations of this compound,
including cross-coupling reactions, would be possible because of
the arylbromo functional group. Oxa-analogue 4h was also syn-
thesized from the α-alkoxyaldehyde 3h in excellent enantiomeric
purity (entry 8). Thus, NCbz and ether functional groups do not
interfere with the reaction, and both chiral aza- and oxa-analo-
gues can be obtained in excellent enantiomeric purity. Not only
6-monosubstituted fulvene derivatives, but also 6,6-disubstituted
fulvenes such as 3i are suitable substrates, affording the triqui-
nane derivative 4i possessing a quaternary chiral center in
excellent enantiomeric purity (entry 9). Up to this point, only
the synthesis of the triquinane ring system by the formation of
two new five-membered rings had been examined. Next, con-
comitant formation of a five- with a six-membered ring was
investigated using 3j having a naphthalene moiety in the tether
chain. This reaction proceeds smoothly and with high enantio-
selectivity to afford the cyclized product 4j in good yield (entry 10).
Contrary to the successful result of entry 10, the reaction of
3k that contains bismethoxycarbonyl substituents on the tether
chain was very slow, and starting material was recovered even
though the catalyst 1 was employed in 20 mol % (entry 11). Thus,
the triquinane ring system can be easily prepared by this asymmetric
double five-membered ring closure, while 5 + 6-membered ring
formation can proceed when the reacting formyl group and fulvene
unit are held in close proximity.
Determination of the Absolute Configuration. The abso-
lute configuration of 4d was determined by vibrational circular
dichroism (VCD). Calculations of IR and VCD spectra for 4d
were carried out using Gaussian 03.18 The geometry of 4d was
optimized by using density functional theory (DFT), which was
performed with B3LYP functional and the 6-311G+(2d,p) basis
set. The pattern and sign of the calculated VCD spectrum agreed
well with those of the experimental VCD spectrum in the region
of 1700ꢀ1200 cmꢀ1 (Figure 2). For example, experimental
VCD bands at 1481, 1473, and 1458 cmꢀ1 showed a (+, ꢀ, +)
pattern. This pattern was reproduced by the calculated VCD
bands at 1480, 1471, and 1455 cmꢀ1
.
Theoretical Study. Postulated Reaction Mechanism and Cal-
culation Model. According to the reaction mechanism proposed
by Houk for the racemic intramolecular [6 + 2] cycloaddition
reaction,7 the following sequence would be postulated for the
conversion of the substrate 3 to the triquinane derivative 4
(Figure 3): (i) the formyl group in 3 reacts with the amine catalyst 1
to generate the corresponding enamine 5, (ii) the enamine
double bond and the fulvene functionality undergo intramole-
cular [6 + 2] cycloaddition via zwitterion 50 (vide infra), and then
(iii) the amine catalyst 1 is expelled from the addition product to
afford the triquinane derivative 4. There are two possible reaction
paths from 50 to product. One is the attack of cyclopentadienyl
anion on iminium ion, followed by the elimination of amine
catalyst 1 generating the addition product (path A). The other is
the hydrolysis of iminium ion 50 by water with the release of
catalyst, followed by an intramolecular addition reaction and
dehydration to provide the addition product (path B). If the
reaction proceeds via pathway B, it will fail under anhydrous
conditions as hydrolysis of the iminium ion cannot occur. When
performed under anhydrous conditions in the presence of
molecular sieves using compound 3h, which is not a reactive
substrate, requiring 36 h for completion of the reaction under
standard conditions, the reaction proceeded equally as well,
a Reaction conditions: Aldehyde 3 (0.3 mmol), catalyst 1 (0.03 mmol),
and PhCO2H (0.06 mmol) in toluene (3.0 mL) at room temperature for
b
c
the indicated time. Isolated yield. The ee’s are determined by chiral
stationary phase HPLC or GC. dReaction temperature is ꢀ40 °C.
eCatalyst (20 mol %) was employed. fnd = not determined.
Dihydrobenzofuran derivatives 4f and 4g were also prepared
efficiently from the acyclic phenol precursors 3f, 3g (entries 6, 7).
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Figure 2. Top: Comparison of calculated (A) and experimental VCD spectra (C) of 4d. Bottom: Comparison of calculated (B) and experimental
IR spectra (D) of 4d.
Figure 3. Mechanism postulated for the intramolecular [6 + 2] cycloaddition reaction. The cis-fused triquinane derivatives 4 are formed exclusively.
The trans-fused isomers 6 were not detected among the reaction products.
and there was no effect of molecular sieves on either reactivity
or enantioselectivity. Therefore, the reaction proceeds via
direct attack of the cyclopentadienyl anion on the iminium
ion (path A).
To model the [6 + 2] cycloaddition reaction of 5, we in-
vestigated the intermolecular reaction of fulvene 7 and enamine
(N,N-dimethylvinylamine) 8 (eq 3). Two CꢀC bonds are
formed in this reaction. One is that between the double bond
terminal (the 20-position) of enamine 8 and the exocyclic
6-position of fulvene 7. The other is that between the nitrogen
neighboring position (the 10-position) of enamine 8 and the
1-position (or the 4-position) of fulvene 7. Elimination of
dimethylamine 10 from the cycloaddition product 12 yields
bicyclic compound 9. The reaction sequence given in eq 3
corresponds to the conversion of the enamine intermediate 5
to the triquinane derivative 4 with the regeneration of the
catalyst 1. We also carried out calculations on the intramole-
cular [6 + 2] cycloaddition reaction of 5a (R = R0 = H, NR00
=
2
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NMe2, Figure 3; see also Figure 8). To the best of our
knowledge, this is the first systematic theoretical study on
the mechanism of a [6 + 2] cycloaddition reaction.
Computational Methodology. The Gaussian 03 program18
was used for the molecular orbital calculations. Geometry
optimizations were performed at the hybrid density functional
theory (B3LYP)19 and the MP220 levels using the 6-311G(d,p)
basis set.21 Frequency calculations were carried out for the opti-
mized structures to verify the stationary points as energy minima or
saddle points. In addition, by using the intrinsic reaction coordinate
(IRC) procedure, we followed minimum energy paths from the
transition states to verify the nature of the reactants and products.22
Single-point energies of the optimized stationary points for the
model reaction eq 3 were computed with the MP2 method and
coupled cluster calculations with single and double substitutions
with noninteractive triple excitations [CCSD(T)].23 We cal-
culated CCSD(T) level relative energy at the basis set limit
[ECCSD(T)(limit)] of each stationary point (the energy difference
between each stationary point and the reactants 7 and 8).24
Solvation corrections for the experimentally used solvent, toluene,
were calculated by using the CPCM method26 and the UAKS
radii with single-point HF/6-31+G(d) level of theory27 at the
MP2-optimized geometries.
[6 + 2] Cycloaddition Reaction of 7 and 8. For the [6 + 2]
cycloaddition reaction of fulvene 7 and enamine 8 (eq 3), the
B3LYP and MP2 levels of calculations both suggested a stepwise
CꢀC bond formation mechanism via an intermediate. First, a CꢀC
bond is formed between the 20-position of enamine 8 and the
exocyclic 6-position of fulvene 7 to yield the intermediate 11.
Next, ring-closure of the intermediate 11 forming the second CꢀC
bond results in the cycloaddition product 12 (eq 4). Population
analysis indicates that the intermediate 11 has zwitterionic
character. The dimethylamino group and the fulvene moiety in
11 are positively and negatively charged, respectively.28 There-
fore, formation of the intermediate 11 can be considered as
arising from nucleophilic attack of the enamine moiety at the
exocyclic 6-position of fulvene, resulting in an anionic cyclopen-
tadiene ring and formation of an iminium ion. Transition states
TS-1 and TS-2 were located for the first and the second CꢀC
bond formation steps, respectively.29 Neither B3LYP level
calculations nor MP2 level calculations located a pathway for a
concerted mechanism; that is, simultaneous formation of the two
CꢀC bonds is unlikely for 7 and 8.
Figure 4. Top and side views of the structures of the zwitterionic
intermediate 11, the transition states TS-1 and TS-2, and the cycloaddi-
tion product 12.
Figure 5. Possible approaches of the enamine double bond toward the
fulvene functionality: (A) gauche-syn, (B) gauche-anti, and (C) antiperi-
planar.
enamine 8 approach each other in the gauche-syn configuration
(Figure 5 A). The dihedral angle of C5ꢀC6ꢀC20ꢀC10 (see eqs
3 and 4 for atom numbering) is around ꢀ60° in TS-1, and the
value of this dihedral angle remains almost unchanged in the
zwitterionic intermediate 11 and TS-2 (Table 3). We tried to
locate energy minima for the gauche-anti (B) and antiperiplanar
(C) conformers (Figure 5) of the intermediate through rotation
of the C6ꢀC20 single bond in the zwitterionic intermediate 11,
but such potential energy minima were not found.30 The gauche-
syn conformation in TS-2 would result in a trans relationship
between the dimethylamino group and the bridgehead hydrogen
atom in the cycloaddition product 12.31
The gas-phase and solution-phase relative enthalpy values of
the stationary points in eq 4, as well as their CCSD(T) level
relative electronic energies at the basis set limit (ECCSD(T)(limit)),
are given in Table 4. Relative enthalpy values are schematically
plotted in Figure 6. The gas-phase enthalpy values at 298 K
indicate that the zwitterionic intermediate 11 and the two
transition states for the [6 + 2] cycloaddition process TS-1 and
TS-2 are higher in energy than the reactants fulvene 7 and
enamine 8 by 7.03, 9.48, and 9.90 kcal/mol, respectively. The
gas-phase enthalpy values of the cycloaddition product 12 and
the final products (9 + 10) are lower than that of the reactants by
22.38 and 12.67 kcal/mol, respectively.32
Optimized structures of the zwitterionic intermediate 11, the
transition states TS-1 and TS-2, and the cycloaddition product
12 are shown in Figure 4. Three models can be postulated for
how the enamine double bond approaches the fulvene function-
ality in the [6 + 2] cycloaddition reaction, gauche-syn (A), gauche-
anti (B), and antiperiplanar (C) (Figure 5). The B3LYP and MP2
transition states differ somewhat in the forming bond lengths
(Table 3), but both calculations suggest that fulvene 7 and
Intramolecular [6 + 2] Cycloaddition Reaction of Enamine 5.
Seebach et al. have systematically investigated the X-ray crystal
structures and NMRs of enamines derived from diarylprolinol
ethers and aldehydes. Preferences for the CꢀN single bond to
adopt the s-trans conformation and for the enamine double bond
to adopt the E configuration have been pointed out (Figure 7).33
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Table 3. Calculated Values for the Energies and Geometric Parameters of the Zwitterionic Intermediate 11 and the Transition
States TS-1 and TS-2
11
TS-1
TS-2
B3LYPa
MP2b
B3LYPa
MP2b
B3LYPa
MP2b
energy (au)
ꢀ444.857229
ꢀ443.472935
ꢀ444.854871
348.5
ꢀ443.466225
256.4
ꢀ444.849224
263.7
ꢀ443.467170
152.0
imaginary freq
geometric parameter (in Å and deg)c
C5ꢀC6
1.4611
1.4701
1.6298
1.4526
1.3076
3.2171
112.26
105.34
124.21
89.82
1.4131
1.9493
1.4012
1.3327
3.5173
112.37
105.89
126.80
90.81
1.3899
2.1667
1.3832
1.3456
3.3607
108.78
98.25
1.4918
1.5741
1.4809
1.3080
2.8962
109.25
109.78
128.10
74.23
1.4951
1.5705
1.4793
1.2923
2.8612
108.82
104.62
128.12
84.24
C6ꢀC20
1.6714
1.4452
1.3154
3.4229
C10ꢀC20
C20ꢀN
C1ꢀC10
C5ꢀC6ꢀC20
C6ꢀC20ꢀC10
C20ꢀC10ꢀN
C1ꢀC5ꢀC6ꢀC20
C4ꢀC5ꢀC6ꢀC20
C5ꢀC6ꢀC20ꢀC10
113.59
108.94
125.63
91.59
125.95
89.19
ꢀ77.92
ꢀ62.80
ꢀ80.25
ꢀ59.76
ꢀ80.85
ꢀ61.11
ꢀ87.60
ꢀ55.43
ꢀ87.66
ꢀ53.59
ꢀ76.38
ꢀ48.31
a Optimized at the B3LYP/6-311G(d,p) level. b Optimized at the MP2/6-311G(d,p) level. c See eq 3 for atom numbering.
Table 4. CCSD(T) Relative Energies at the Basis Set Limit
and Gas-Phase and Solution-Phase Enthalpy Values of the
Stationary Pointsa
H (0 K)c H (298 K)d H (298 K) + Esol
b
e
ECCSD(T)(limit)
7 + 8
TS-1
11
0.00
8.43
0.00
10.00
0.00
9.48
0.00
9.05
Figure 7. Preferable conformation and reaction pattern of the enamines
derived from diarylprolinol ethers.
4.54
7.77
7.03
2.40
TS-2
12
7.72
10.70
9.90
5.21
ꢀ26.25
ꢀ14.51
ꢀ21.20
ꢀ12.41
ꢀ22.38
ꢀ12.67
ꢀ22.68
ꢀ13.29
tures D and E will yield the cis- and trans-zwitterionic intermediates
13 and 14, respectively. We have been unable to detect either
of these by NMR. For the cis intermediate 13, intramolecular
[6 + 2] cycloaddition affords the cis-fused tricyclic adduct 15. As
seen in the stereochemistry of cycloaddition product 12, the
gauche-syn approach will produce the trans relationship between
the pyrrolidine ring and the bridgehead hydrogen atom in 15.
The experimental conditions are weakly acidic, and prolinol silyl
9 + 10
a Energy values are given in kcal/mol. b CCSD(T) relative energies at the
basis set limit. See the Supporting Information. c Gas-phase relative
enthalpy value at 0 K. d Gas-phase relative enthalpy value at 298 K.
e Relative enthalpy value at 298 K including solvation energy.
ether catalyst (HNR00 ) will thus be rapidly eliminated in an
2
antiperiplanar manner from 15 to give the cis-fused triquinane
skeleton 4. Were the same reaction sequence to occur, the trans-
zwitterionic intermediate 14 would be converted to the trans-
fused triquinane skeleton 6 via the trans-fused tricyclic adduct 16
(Figure 8). Protonation of 13 and 14 might occur to afford
cyclopentadiene intermediates 130 and 140, which could revert
again to 13 and 14 by deprotonation because cyclopentadiene is
acidic. The direct transformation of 130 and 140 to starting material 5
by base-mediated elimination as shown in Figure 9 might also be
possible.
The experiments indicate, however, that the trans-fused tri-
quinane derivatives 6 are not produced. The cis-fused derivatives
4 were obtained exclusively. Houk et al. pointed out the pos-
sibility of reversible formation of the cis- and trans-zwitterionic
intermediates, and that only cis intermediates will cyclize, giving
the cis-fused triquinane skeleton, because the trans-fused isomer
is considerably more ring strained than the cis (Figure 8).7 There
are two seemingly plausible reaction paths for the isomerization
between 13 and 14. One is retro reaction via starting material 5
Figure 6. Schematically plotted gas-phase (ꢀ) and solution-phase (---)
relative enthalpy values (at 298 K) for the stationary points. Numerical
values are given in Table 4.
Considering these conformational preferences in the enamine
moiety, two gauche-syn transition structures can be postulated for
the first CꢀC bond formation step in 5 (Figure 8). The struc-
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Figure 10. Pathways suggested for intramolecular [6 + 2] cycloaddition
of 5a in the present work.
Figure 8. Postulated reaction paths for the conversion of enamine 5
into the triquinane skeleton.
Figure 11. Top and side views of the structures of TS-3, TS-4, and
TS-5.
B3LYP and MP2 calculations of the cis- and trans-zwitterionic
intermediates 13a and 14a indicate that both isomers take the
gauche-syn conformation, and that the trans-isomer 14a is slightly
lower in energy than the cis isomer 13a.35
In addition, we located the transition states TS-4 and TS-5
leading to the cis- and trans-fused adducts 15a and 16a, respec-
tively. Surprisingly, the IRC calculation indicates that TS-4
connects directly 5a and the cis-fused tricyclic isomer 15a. We
were not able to locate a transition state connecting the putative
cis-zwitterionic intermediate 13a and cis-fused product 15a.
Meanwhile, TS-5 connects the trans-zwitterionic intermediate
14a and the trans-fused tricyclic product 16a. TS-3 was located
separately for the formation of the trans-zwitterionic intermedi-
ate 14a (Figure 10). These results indicate a concerted pathway
via TS-4 for the conversion of 5a to the cis-fused tricyclic skeleton
15a. The zwitterionic intermediate 13a does not exist along the
reaction coordinate for the [6 + 2] cyclization. On the other
hand, a stepwise mechanism via TS-3, the zwitterionic inter-
mediate 14a, and TS-5 is suggested for the conversion of 5a to
the trans-fused tricyclic isomer 16a (Figure 10). The structures of
TS-3ꢀTS-5 are given in Figure 11. The fulvene and enamine
functionalities adopt the gauche-syn configuration in these transi-
tion states as well.
Figure 9. Postulated mechanism for conversion of protonated inter-
mediates 130 and 140 to starting material 5.
(13 a 5 a 14). The other is the direct isomerization of 13 and
14 (13 a 14) via enamineꢀiminium tautomerization. However,
in the latter path, overall enantioselectivity would erode because
inversion of the labile stereocenter of 14 would lead to ent-13. As
high enantioselectivity is realized, the former must be the actual
path taken. We carried out calculations on the simplest models of
the cis- and trans-fused adducts, 15a and 16a (R = R0 = H, NR00
=
2
NMe2, Figure 8). B3LYP and MP2 calculations using the 6-311G
(d,p) basis set make the trans-fused isomer 16a, respectively, 9.65
and 11.70 kcal/mol higher in energy than the cis-fused adduct 15a
(see Figure 12, including the zero-point energies34). Meanwhile,
The B3LYP and MP2-optimized forming bond (C6ꢀC20)
lengths in TS-3 are 1.7984 and 2.1236 Å, respectively. The
corresponding forming bond (C1ꢀC10) lengths in TS-5 are
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Table 5. Calculated Values for the Energies and the Bond Distances of the Zwitterionic Intermediates 13a and 14a, the Tricyclic
Intermediates 15a and 16a, and Transition States TS-3ꢀTS-5a
13a
14a
15a
16a
B3LYPb
MP2c
B3LYP
MP2
B3LYP
MP2
B3LYP
MP2
energy
ꢀ561.614061
1.7468
ꢀ559.874746
1.6755
ꢀ561.617602
1.7578
ꢀ559.876667
1.6701
ꢀ561.655573
1.5822
ꢀ559.926433
1.5731
ꢀ561.640005
1.5487
ꢀ559.907372
1.5431
d
e
C6ꢀC20
C1ꢀC10
3.3688
3.1873
3.5339
3.3123
1.5751
1.5404
1.5880
1.5749
TS-3
TS-4
TS-5
B3LYP
MP2
B3LYP
MP2
B3LYP
MP2
energy
ꢀ561.617599
130.4
ꢀ559.874138
192.3
ꢀ561.608444
177.3
ꢀ559.870072
275.3
ꢀ561.604882
185.9
ꢀ559.865051
89.4
imaginary freq
d
C6ꢀC20
1.7984
2.1236
1.7200
1.8180
1.5664
1.5274
e
C1ꢀC10
3.5472
3.4697
3.0939
3.1557
2.8310
2.4960
a Energies, imaginary frequencies, and bond distances are given in au, cmꢀ1, and Å, respectively. b B3LYP/6-311G(d,p) optimized results. c MP2/6-
311G(d,p) optimized results. d Bond distance between the 6-position of the fulvene moiety and the CꢀC double bond terminus of the enamine moiety.
e Bond distance between the 1-position of the fulvene moiety and the carbon atom adjacent to the nitrogen of the enamine moiety.
Figure 12. B3LYP/6-311G(d,p) calculated energies (including the
zero-point energies34) relative to the IRC end point of 5a are plotted.37
2.8310 and 2.4960 Å (Table 5). These two CꢀC bonds will be
formed simultaneously in the concerted transition state TS-4.
However, TS-4 shows highly asynchronous character: CꢀC bond
formation at the 1-position of the fulvene moiety (C1ꢀC10) pro-
Figure 13. (a) Chemical structure of the model enamine prepared from
propanal and diphenylprolinol silyl ether 1; (b) side view of the model
ceeds significantly behind CꢀC bond formation at the 6-position
of the fulvene moiety (C6ꢀC20) (see Table 5).36 Although the
enamine; (c) top view of the model enamine, and (d) bottom view of the
model enamine. The Re face of the CꢀC bond terminal of the enamine
two bonds are being formed concertedly in TS-4, the forming
moiety is effectively blocked by the diphenyltrimethylsiloxymethyl group.
bond lengths indicate that TS-4 can be characterized as an almost
pure transition state for nucleophilic attack by the enamine
moiety at the 6-position of the fulvene functionality.
concerted formation of the cis-fused tricyclic product 15a via TS4
will be energetically favored over stepwise formation of the trans-
fused counterpart 16a.
Energy profiles for the reaction paths from 5a to the cis- and
trans-fused adduct 15a and 16a are given in Figure 12. For
stepwise formation of the trans-fused isomer 16a (Figure 10), the
second cyclization step via TS-5 is rate-limiting. TS-5 for the
second cyclization step is higher in energy by 8.35 and 6.80 kcal/
mol (including the zero-point energies34) than TS-3 for the first
cyclization step in B3LYP and MP2 calculations, respectively.
Meanwhile, B3LYP and MP2 calculations, respectively, suggest
that the highly asynchronous TS-4, leading concertedly to the
cis-fused tricyclic isomer (Figure 10), is lower in energy by 2.58 and
3.85 kcal/mol than the rate-limiting TS-5 for stepwise formation
of the trans-fused counterpart.38 These results indicate that the
Exclusive formation of the cis-fused triquinane skeleton can be
rationalized as the result of reversible formation of the trans-
zwitterionic intermediate 14a. The barrier height for isomeriza-
tion of 14a through the reverse reaction via TS-3 to 5a is very
low. The highly asynchronous concerted transition state TS-4
connecting 5a and the cis-fused tricyclic product 15a is energe-
tically more favorable than the rate-limiting second cyclization
process of 14a (TS-5) for stepwise formation of the trans-fused
tricyclic product 16a (see Figure 12). Thus, the trans intermedi-
ate 14a will not undergo the second cyclization process, but will
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Journal of the American Chemical Society
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revert to 5a, eventually funneling all of the material into the
pathway leading to the cis-fused tricyclic product 15a (Figures 10
and 12). Protonation of the anionic cyclopentadiene ring of 14a
may occur, but any protonation and deprotonation processes will
be reversible regenerating 14a, after which the reverse reaction
can proceed to regenerate 5a. Alternatively, base-mediated
elimination may occur to convert the protonated intermediate
directly to the starting material 5a by the same mechanism as
shown in Figure 9. Therefore, material taking nonproductive
pathways will be recycled to 5a leading to eventual exclusive
conversion to the cis-fused tricyclic intermediates 15a via the concerted
transition state TS-4. This mechanism rationalizes the experi-
mental observation that the cis-fused triquinane derivatives 4 are
obtained exclusively.
Concerning the enamine, Seebach’s group have shown that
the synclinal-exo conformation (the dihedral angle of NꢀCꢀ
CꢀO) is the most stable in the solid state.33 Although Shinisha
and Sunoj calculated results for the Michael reaction of propanal
and nitrostyrene catalyzed by diphenylprolinol silyl ether 1,39
they seem not to pay attention to this dihedral angle. Therefore,
we performed a calculation of this enamine structure based on a
synclinal-exo conformation. We optimized the structure of the
model enamine prepared from propanal and diphenylprolinol
silyl ether 1 shown in Figure 13 (see Figure 7, R = Me). We
considered the s-trans conformation and E configuration for the
enamine moiety (Figure 7).16i,33,39 For the CꢀC single bond at
the 2-position, the synclinal-exo conformation (the dihedral angle
of NꢀCꢀCꢀO) was assumed.33 The B3LYP/6-311G(d,p)-
optimized structure (Figure 13) indicates that the gauche-syn
approach of the fulvene moiety to the Re face of the CꢀC double
bond terminal of the enamine is effectively blocked by the
diphenyltrimethylsiloxymethyl group, and hence that gauche-
syn attack of the fulvene moiety by the enamine double bond
will exclusively take place from the less sterically hindered Si face
of the enamine. We conclude that high enantioselectivities in
the [6 + 2] cycloaddition reactions stem from the following
two factors: (i) The enamine has a strong preference for the s-trans
conformation and E configuration.16i,33,39 (ii) The bulky diphe-
nyltrimethylsiloxymethyl group at the 2-position of the pyrroli-
dine ring effectively differentiates the Re- and Si-faces of the
enamine moiety for the gauche-syn mode approach of the enamine
and fulvene moieties.
while the second CꢀC bond is formed between the 1- or
4-position of the fulvene functionality and the nitrogen-neigh-
boring carbon of the enamine moiety. The calculated structures
indicate that the fulvene functionality approaches the enamine
double bond in the gauche-syn conformation (Figure 5A). The
energy profiles for the intramolecular reaction suggest that for-
mation of the trans-zwitterionic intermediate is reversible. The
experimental observation of exclusive formation of the cis-fused
triquinane derivatives is rationalized as a consequence of rever-
sible formation of the trans-zwitterionic intermediate and en-
ergetically favorable concerted formation of the cis-fused tricyclic
product. The s-trans conformation and E configuration will be
highly preferred in the enamine moiety, and quite effective en-
antiomeric differentiation of its π-faces in the gauche-syn mode of
the CꢀC bond formation processes is achieved due to the
bulkiness of the diphenyltrimethylsiloxymethyl group on the pyr-
rolidine ring. These two factors are essential for high enantios-
electivities in these [6 + 2] cycloaddition reactions.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, spectroscopic data of all new compounds. (i) Estimation
procedure for the CCSD(T) level relation energy [ECCSD(T)(limit)
]
of each stationary point at the basis set limit, (ii) isomerization of
the cycloaddition product 12, (iii) Cartesian coordinates and ab-
solute energies for all reported structures, (iv) energies of single-
point calculations for the stationary points, (v) relative energies
of the stationary points for the intramolecular [6 + 2] cycloaddi-
tion 5a, (vi) MP2/6-311G(d,p) calculated energy profiles for the
intramolecular cycloaddition 5a, and (vii) the complete ref 18.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
hayashi@ci.kagu.tus.ac.jp; t-uchimaru@aist.go.jp
’ ACKNOWLEDGMENT
I.K. is thankful to the Inoue Foundation for Science for a
postdoctoral fellowship. This work was partially supported by a
Grant-in-Aid for Scientific Research on Innovative Areas "Ad-
vanced Molecular Transformations by Organocatalysts" from
The Ministry of Education, Culture, Sports, Science And Tech-
nology, Japan. Computations were performed on the AIST Super
Cluster. We thank the Tsukuba Advanced Computing Center
(TACC) in AIST for the provision of the computational facilities.
We also thank the referees for their valuable comments and
suggestions.
’ CONCLUSION
We have found that the diphenylprolinol silyl ether-mediated
reaction of fulvenes having a δ-formylalkyl group at the exocyclic
6-position proceeds with excellent enantioselectivity to afford
linear cis-fused triquinane derivatives. This is the first example of
an organocatalyst-mediated, asymmetric, catalytic, intramolecu-
lar [6 + 2] cycloaddition. The formyl group in the substrates is
initially converted into the corresponding enamine, after which
an intramolecular cycloaddition occurs between the fulvene (6π)
and the enamine (2π) functionalities. Computational investiga-
tions on model reaction sequences have shown that the model
reaction of the intermolecular [6 + 2] cycloaddition proceeds in a
stepwise mechanism via a zwitterionic intermediate. On the other
hand, intramolecular [6 + 2] cycloaddition leading to the cis-
fused linear triquinane skeleton proceeds in a concerted mechan-
ism via a highly asynchronous transition state. CꢀC bond formation
occurs through nucleophilic attack of the enamine double bond
terminus at the exocyclic 6-position of the fulvene functionality,
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(24) The details of the procedure for estimating the ECCSD(T)(limit)
are given in the Supporting Information. The relative energies calculated
for the B3LYP- and MP2-optimized stationary-point structures did not
differ significantly: the differences were less than 1.5 kcal/mol. We
calculated relative enthalpy values for the MP2-optimized stationary
points by using the ECCSD(T)(limit) relative energies and the enthalpy
correction terms derived from the MP2 calculations. For zero-point
energy corrections, the MP2/6-311G(d,p) frequencies were scaled by a
factor of 0.9663.25a For enthalpy and entropy (at 298.15 K) calculations,
the recommended scaling factors for the MP2/6-311G(d,p) frequencies
are 1.0061 and 1.0175, respectively.25b These factors are close to 1.0, and
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Journal of the American Chemical Society
ARTICLE
thus the MP2 enthalpy and entropy correction terms derived from the
harmonic approximation were used without scaling.
(25) (a) Irikura, K. K.; Johnson, R. D., III; Kacker, R. N.; Kessel, R.
J. Chem. Phys. 2009, 130, 114102. (b) Scott, A. P.; Radom, L. J. Phys.
Chem. 1996, 100, 16502.
(26) (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995. (b)
Cossi, M.; Rega, N; Scalmani, G.; Barone, V. J. Comput. Chem. 2003,
24, 669.
(27) Takano, Y.; Houk, K. N. J. Chem. Theory Comput. 2005, 1, 70.
(28) The atomic polar tensor-based charges (Cioslowski, J. J. Am.
Chem. Soc. 1989, 111, 8333) indicate that the total charges of NMe2 and
cyclopentadiene moieties of MP2/6-311G(d,p)-optimized 11 are
+0.7072 and ꢀ0.8773, respectively.
levels, respectively. The optimized structures of the cis and the trans isomers
13a and 14a take the gauche-syn conformation. The B3LYP-optimized
dihedral angles (corresponding to the C5ꢀC6ꢀC20ꢀC10 dihedral angle
in the model) were ꢀ51.2° and ꢀ69.2° for 13a and 14a, respectively, while
the MP2-optimized dihedral angles were ꢀ52.0° and ꢀ66.1°.
(36) The CꢀC bond distance between the 6-position of the fulvene
moiety and the CꢀC double bond terminal of the enamine moietry
(C6ꢀC20) in TS-4 is, respectively, 1.7200 and 1.8180 Å in B3LYP- and
MP2-optimized structures (Table 5). These bond distances are slightly
longer than the corresponding bond lengths in the cis-fused tricyclic
product 15a (Table 5, 1.5822 and 1.5731 Å). Meanwhile, the other
forming bond in TS-4 (C1ꢀC10), the CꢀC bond between the 1-posi-
tion of the fulvene moiety and the carbon atom adjacent to the nitrogen
of the enamine moiety, is quite long, more than 3 Å, 3.0939 and 3.1557 Å
in B3LYP and MP2 structures (Table 5). These bond lengths are much
longer than the corresponding B3LYP and MP2 CꢀC bond distances of
1.5751 and 1.5404 Å in 15a, and are also considerably longer than the
B3LYP and MP2 bond distances, 2.8310 and 2.4960 Å in TS-5 (Table 5).
(37) The numerical values and the MP2 energy profiles are given in
the Supporting Information.
(29) The intermediate 11, as well as the transition states TS-1 and
TS-2, was a pure singlet closed-shell species with S2 = 0. We also
considered the possibility of a radical-pair-like intermediate for the
stepwise CꢀC bond formation process. We tried to locate such an open-
shell intermediate by using the unrestricted method, but this did not
locate any diradical species along the [6 + 2] reaction coordinate.
(30) The dihedral angle of C5ꢀC6ꢀC20ꢀC10 is ꢀ62.80° in the
B3LYP energy minimum of the zwitterionic intermediate 11 (see
Table 3). In the B3LYP calculation, separation of the intermediate 11
into the reactants fulvene 7 and enamine 8 occurred in the C5ꢀC6ꢀ
C20ꢀC10 dihedral angle region from ꢀ100° to ꢀ105°. Meanwhile, the
spontaneous conversion of 11 into the cycloaddition product 12 was
observed in the C5ꢀC6ꢀC20ꢀC10 dihedral angle region of ꢀ5° to
ꢀ10°. The zwitterionic state will therefore be maintained within the
C5ꢀC6ꢀC20ꢀC10 dihedral angle region from ꢀ10° to ꢀ100°. Except
for within this dihedral angle region, the zwitterionic structure will collapse.
Geometry optimization starting from the gauche-anti (B) conformation
resulted in separation into fulvene 7 and enamine 8. These results imply
that the gauche-syn conformation is electrostatically stabilized. If the
positively charged NMe2 moiety and the negatively charged cyclopen-
tadiene ring are forced to be located distantly, the charge separated elec-
tronic structure will be energetically disfavorable, and the zwitterionic
structure collapses.
(38) After considering solvation energy, TS-4 is still energetically
favorable over TS-5. CPCM calculations suggested solvation energies of
5.78 and 6.66 kcal/mol for the B3LYP geometries of TS-4 and TS-5. The
corresponding values for the MP2 geometries were 4.53 and 4.51 kcal/mol.
As a consequence, the B3LYP and MP2 geometries suggest that TS-4 will
be lower by 1.70 and 3.87 kcal/mol than TS-5 in toluene solution.
(39) Shinisha, C. B.; Sunoj, R. B. Org. Biomol. Chem. 2008, 6, 3921.
(31) The dimethylamino group in the trans isomer of the cycloaddi-
tion product 12 is positioned on the inner face of the two five-membered
rings (Figure 4). This trans isomer was found to be less stable by
1.80 kcal/mol than the cis isomer having the dimethylamino group on
the outer side of the two rings. In pursuit of a pathway leading to the cis
isomer of the product, the potential energy surface was explored. Neither
a reaction pathway connecting the zwitterionic intermediate 11 and the
cis product nor a [6 + 2] cycloaddition pathway directly leading to the
cis product was found. Instead, a pathway for isomerization between the
trans cycloaddition product 12 and its cis isomer was located. (See the
Supporting Information.)
(32) The CPCM calculations suggested a pronounced solvation
effect for the zwitterionic intermediate 11 and TS-2 (Table 4). For these
stationary points, the solution-phase relative enthalpy values are calcu-
lated to be lower than the corresponding gas-phase values by about
5 kcal/mol. For the final products 9 and 10, the solution-phase relative
enthalpy is about 0.6 kcal/mol lower than the gas-phase value. Mean-
while, the solvation effects are found to be relatively small for TS-1 and
the cycloaddition product 12. The differences between the gas-phase
and solution-phase relative enthalpy values for TS-1 and 12 are less than
0.5 kcal/mol.
(33) (a) Seebach, D.; Groselj, U.; Badine, D. M.; Schweizer, W. B.;
Beck, A. K. Helv. Chim. Acta 2008, 91, 1999. (b) Groselj, U.; Seebach, D.;
Badine, D. M.; Schweizer, W. B.; Beck, A. K.; Krossing, I.; Klose, P.;
Hayashi, Y.; Uchimaru, T. Helv. Chim. Acta 2009, 92, 1225.
(34) A scaling factor of 0.9877 was used for the B3LYP/6-311G(d,p)
frequencies. Andersson, M. P.; Uvdal, P. J. Phys. Chem. A 2005,
109, 2937. See ref 25a for the scaling factor of the MP2/6-311G(d,p)
frequencies.
(35) The calculated energy differences between the cis and trans
isomers 13a and 14a were 2.52 and 1.24 kcal/mol (including the zero-
point energies34) at the B3LYP/6-311G(d,p) and MP2/6-311G(d,p)
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