Construction of contiguous tetrasubstituted carbon stereocenters by intramolecular crossed benzoin reactions catalyzed by N-heterocyclic carbene (NHC) organocatalyst

Article abstract of DOI:10.1002/adsc.201200499

Bicyclic compounds with two contiguous tetrasubstituted carbon stereocenters at bridgehead positions were synthesized by N-heterocyclic carbene (NHC)-catalyzed intramolecular crossed benzoin reactions of symmetrical compounds. This desymmetrization strate

Full text of DOI:10.1002/adsc.201200499

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DOI: 10.1002/adsc.201200499
Construction of Contiguous Tetrasubstituted Carbon
Stereocenters by Intramolecular Crossed Benzoin Reactions
Catalyzed by N-Heterocyclic Carbene (NHC) Organocatalyst
Tadashi Ema,a,* Kumiko Akihara,a Ryoko Obayashi,a and Takashi Sakaia
a
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University,
Tsushima, Okayama 700-8530, Japan
Fax : (+81)-86-251-8092; phone: (+81)-86-251-8091; e-mail: ema@cc.okayama-u.ac.jp
Received: June 7, 2012; Revised: September 3, 2012; Published online: November 13, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200499.
Abstract: Bicyclic compounds with two contiguous rasubstituted carbon stereocenters was synthesized
tetrasubstituted carbon stereocenters at bridgehead by a stepwise strategy. The molecular structure and
positions were synthesized by N-heterocyclic carbene absolute configuration of the (+)-enantiomer of this
(NHC)-catalyzed intramolecular crossed benzoin re- tricyclic compound were determined by X-ray crys-
actions of symmetrical compounds. This desymmetri- tallographic analysis.
zation strategy was applied to asymmetric synthesis
with chiral NHC organocatalysts. Transition-state Keywords: asymmetric catalysis; benzoin reaction;
models were proposed to explain the enantioselectiv- N-heterocyclic carbene; organocatalysis; quaternary
ity. A tricyclic compound with three contiguous tet- stereocenters
Introduction
this synthetic method (Scheme 1, a) is important be-
cause bicyclic skeletons II with the cis-configuration
Asymmetric organocatalysis has attracted much atten- are found in natural products and drugs as represent-
tion in organic synthesis.[1] Chiral organocatalysts are ed by Figure 1. We also decided to develop a synthetic
promising from the viewpoint of reaction diversity, pathway for tricyclic compounds IV bearing three
high enantioselectivity, design flexibility, and green contiguous tetrasubstituted carbon stereocenters
chemistry. Among various organocatalysts, N-hetero- (Scheme 1, b). We envisioned that NHC-catalyzed
cyclic carbenes (NHC) are a unique catalyst class ca- benzoin cyclizations of compounds I and the subse-
[2]
À
pable of achieving various C C bond formations,
quent transformations would give bicyclic compounds
such as the benzoin reaction,[3–5] the Stetter reaction,[6] III with the formyl group at the end of the side chain,
homoenolate reactions,[7] the aza-Morita–Baylis–Hill- which would be converted into tricyclic compounds
man reaction,[8] cycloaddition of ketenes,[9] acylation IV by the second NHC-catalyzed benzoin annulation
of alcohols,[10] and other useful reactions.[11–13] The ef- or transannulation. We considered that either annular
ficient construction of contiguous tetrasubstituted or transannular product IV would be produced selec-
carbon stereocenters, including contiguous quaternary tively by adjusting the length of the alkyl chain to
stereocenters, remains one of the most challenging which the formyl group was attached. Here we report
subjects in organic synthesis,[14] and there are only the formation of two or three contiguous tetrasubsti-
a few examples of NHC-catalyzed formations of con- tuted carbon stereocenters on the basis of the synthet-
tiguous tetrasubstituted carbon stereocenters.[6c,7f]
We have recently reported stereoselective synthesis
of bicyclic compounds II with contiguous tetrasubsti-
ic strategies shown in Scheme 1.
tuted carbon stereocenters at two adjacent bridgehead Results and Discussion
positions via NHC-catalyzed intramolecular crossed
benzoin reactions of symmetrical compounds
I
We conducted the intramolecular crossed benzoin re-
(Scheme 1, a).[5] Although we succeeded in synthesiz- actions of 2a–m using triazolium salt A as an achiral
ing several compounds II, further work was needed to NHC precursor (Scheme 2). The results are shown in
investigate the substrate scope. The establishment of Table 1. In all cases, the reactions took place com-
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Scheme 1. (a) Construction of two contiguous tetrasubstitut-
ed carbon stereocenters by NHC-catalyzed benzoin cycliza-
tion. (b) Stepwise construction of three contiguous tetrasub-
stituted carbon stereocenters.
Figure 1. Natural products and drugs containing tetrasubsti-
tuted carbon stereocenters at the two adjacent bridgehead
positions with the cis-configuration.
pletely diastereoselectively to give 1a–m in good to
high yields. There is a trend that the yields of 1 were
higher in the five-membered ring formation than in
the six-membered ring formation. For example, in the
annulations of 2a, 2g, 2h, and 2j (five-membered ring
formation), catalyst loading could be decreased suc-
cessfully to 5–10 mol% (entries 1, 7, 8, and 10),
whereas 1k–m (six-membered ring formation) were
attained in modest yields even with 20 mol% of cata-
lyst (entries 11–13). We suppose that the five-mem-
bered ring formation is more favorable because of
less steric hindrance around the NHC moiety. On the
other hand, the yields of 1k–m were lower than that
of 1b, which is due to the bulkiness of substituent R
(Scheme 2). Except for 1d,[15] most of the bicyclic
compounds, 1a–c and 1e–m, were newly synthesized
by the present method.
We next carried out the asymmetric desymmetriza-
tion of symmetrical compounds 2a–m by using triazo-
lium salts B–D as chiral NHC precursors (Scheme 3).
The results are summarized in Scheme 3. The enantio-
meric purities of 1a–m were determined by chiral GC
or HPLC. The absolute configuration of (+)-1a was
determined by chemical correlation,[5] while that of
(+)-1j was established by X-ray crystallographic anal-
Scheme 2. Intramolecular crossed benzoin reaction catalyzed
ysis after transformations as described later. The ab- by NHC organocatalyst.
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Construction of Contiguous Tetrasubstituted Carbon Stereocenters by Intramolecular Crossed Benzoin Reactions
Table 1. NHC-catalyzed benzoin cyclization of 2.[a]
solute configurations of 1b–i and 1k–m were tenta-
tively assigned by the analogy of those of (+)-1a and
(+)-1j.
The reaction of 2a with triazolium salt B in the
Entry
2
NHC [mol%]
1
Yield [%][b]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
5
1a
1b
1c
1d
1e
1f
1g
1h
1i
86
59
82
76
73
40
63
83
73
76
47
43
37
20
20
20
20
20
5
10
20
5
presence of Cs2CO3 in CH2Cl2 at 238C (conditions I)
gave (+)-1a in 50% yield with 78% ee. When condi-
tions I was applied to 2b–f, the enantiomeric purities
of 1b (97% ee), 1d (98% ee), and 1f (81% ee) were
high. Interestingly, when the reaction temperature
was increased to 408C (conditions II), the enantio-
meric purities of 1b (>99% ee) and 1f (86% ee) were
improved, although that of 1d (95% ee) decreased
slightly (Scheme 3). The isolated yields were im-
proved at 408C in all cases. In contrast, 1c and 1e
were obtained less enantioselectively under conditions
I. We therefore changed the precatalyst to triazolium
salt C (conditions III). Under conditions III, opti-
mized previously,[5] 1c was obtained in higher yield
but with lower enantiomeric excess, whereas 1e was
obtained in 83% yield with 69% ee. The results in
Scheme 3 indicate that yields were higher in the five-
9
10
11
12
13
2j
2k
2l
1j
1k
1l
20
20
20
2m
1m
[a]
Conditions: 2 (0.300 mmol except for 2h (0.85 mmol) and
2j (2.74 mmol)), NHC precursor A (quantity indicated
above), Et3N (1 equiv. with respect to NHC), THF
(1 mL), 668C, 24 h.
[b]
Isolated yield of 1.
Scheme 3. NHC-catalyzed asymmetric benzoin cyclization of 2. Conditions I: 2 (0.300 mmol), NHC precursor B (30 mol%),
Cs2CO3 (30 mol%), CH2Cl2 (6 mL), 238C, 24 h. Conditions II: the same as conditions I except that the reaction was done at
408C. Conditions III: 2 (0.300 mmol), C (20 mol%), Et3N (20 mol%), THF (1 mL), 238C, 24 h. Conditions IV: the same as
[a]
conditions I except that 2 was added at 238C after NHC had been generated at 408C. Amounts of B and Cs2CO3 were 20
mol%.[b] NHC precursor D was used instead of B.[c] 2.59 mmol scale.
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membered ring formation than in the six-membered formed, whereas the mesityl group of the NHC,
ring formation, whereas enantioselectivities were which is perpendicular to the triazole ring, can act as
higher in the six-membered ring formation than in the a steric barrier. When the major enantiomer, (+)-1a,
À
five-membered ring formation. In the five-membered is produced, the C C bond is formed without severe
ring formation, enantioselectivity was sensitive to the steric repulsion (Figure 2, a). In contrast, when the
size of the adjacent ring.
minor enantiomer, (À)-1a, is produced, the mesityl
We explored the scope of the substituents of 2 group comes into unfavorable contact with the cyclo-
(Scheme 3). When 2g bearing the allyl group as a sub- hexane ring of 2a (Figure 2, b), which is the origin of
stituent was subjected to conditions I, 1g was obtained the enantioselectivity. We observed a trend that enan-
in 31% yield with 70% ee. The same reaction at 408C tioselectivities were higher in the six-membered ring
(conditions II) gave 1g in 65% yield but with 59% ee. formation than in the five-membered ring formation
The use of triazolium salt D under conditions II re- as described above. This trend may be due to the me-
sulted in lower yield and enantiomeric excess (10% sityl group of the NHC moiety hindering the forma-
yield, 53% ee). The use of triazolium salt C (condi- tion of (À)-1b more severely than that of (À)-1a. Be-
tions III) gave 1g with only 13% ee. We considered cause the methyl group of 2a points toward the oppo-
a possibility that the NHC was poorly generated at site side of the NHC moiety with no steric hindrance
238C (conditions I). Thus, a solution of triazolium salt (Figure 2), the replacement of the methyl group by
B and Cs2CO3 in CH2Cl2 was refluxed to generate any other substituent would yield the same absolute
NHC efficiently, and the mixture was then cooled to configuration. In fact, 2j with a bulky substituent was
238C, to which 2g was added to start the reaction converted into (+)-1j with the same absolute configu-
(conditions IV). As a result, 1g was obtained in ration as that of (+)-1a as described below.
higher yield and enantiomeric excess (47% yield,
We extended our strategy to the stepwise construc-
73% ee). Substrates 2h–j were allowed to react under tion of three contiguous tetrasubstituted carbon ste-
conditions IV to give 1h–j in 35–63% yield with 68– reocenters (Scheme 1, b).[17] The synthetic pathway
70% ee. In view of the fact that the six-membered for 5 is shown in Scheme 4. The bicyclic compound 1j,
ring formation was sluggish (Table 1), we performed which was prepared by the benzoin cyclization of 2j
the asymmetric benzoin cyclizations of 2k–m at 408C (Table 1), was subjected to the two-step hydrogena-
(conditions II) to obtain 1k–m in 25–39% yield with tion with Pd/C(en) and then Pd/C to give alcohol 3.
92–94% ee.
Pd/C(en) is a selective catalyst partially deactivated
An aromatic aldehyde is typically advantageous to by complexation of Pd with ethylenediamine.[18] Hy-
the benzoin reaction for the following reasons. (i) The drogenation with Pd/C(en) reduced the olefin func-
Breslow intermediate, which is generated by the addi- tionality selectively, and the second hydrogenation
tion of NHC to aldehyde and the subsequent proton with Pd/C removed the benzyl group. In contrast,
transfer, is stabilized by the aryl group. (ii) An aro-
matic ketone is a stable product. (iii) Side reactions
such as the aldol reaction can be avoided by the pres-
ence of the aryl group.[4d] In the present study, on the
other hand, an aliphatic aldehyde is used, and the
coupling partner is a ketone, which is less reactive
than the aldehyde. Obviously, the aliphatic aldehyde–
ketone crossed benzoin reactions are unfavorable as
compared with aromatic aldehyde–aldehyde benzoin
reactions. Although our attempts to reduce the
amount of NHC were only partially successful, the
catalytic efficiency will be improved by developing
a more active NHC in the future.
To explain the enantioselectivity of the asymmetric
desymmetrization of 2, we propose the transition-
state models for the reaction of chiral NHC B with 2a
(Figure 2). We assume that the intramolecular nucleo-
philic addition of the Breslow intermediate to ketone
is the rate-determining step responsible for enantiose-
lectivity. In the transition-state models, the hydroxy
group of the Breslow intermediate is oriented toward
Figure 2. Transition-state models to explain the enantiose-
lectivity of the asymmetric desymmetrization of 2a with
chiral NHC B. The transition states giving (a) (+)-1a and
the carbonyl oxygen atom, which would facilitate the
subsequent proton transfer.[16] The indane moiety of
À
the NHC is directed away from the C C bond being (b) (À)-1a.
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Construction of Contiguous Tetrasubstituted Carbon Stereocenters by Intramolecular Crossed Benzoin Reactions
dicated the exclusive formation of one diastereomer.
The molecular structure of (+)-5 was determined by
X-ray crystallographic analysis (Figure 3), where the
absolute configuration was determined to be (R,R,R)
by refinement of the Flack parameter.[19] Figure 3
clearly indicates that the first benzoin cyclization
formed the bicyclic skeleton with the cis-configuration
and that the second benzoin cyclization produced the
tricyclic skeleton. Thus, the absolute configuration of
(+)-1j was determined. Even when a racemic mixture
of 5 was recrystallized, a single crystal consisted of
one enantiomer as analyzed by the X-ray method.
Therefore, one enantiomer of 5 can be prepared by
spontaneous crystallization as well as asymmetric syn-
thesis. Although there is a possibility that the transan-
nular reaction could take place, giving 1,2-diol IV
(Scheme 1, b), no transannular product could be
found in the reaction mixture. We hope that a transan-
nular reaction will be achieved by changing the length
Scheme 4. Stepwise construction of three contiguous tetra-
substituted carbon stereocenters.
of the alkyl side chain in the future.
Conclusions
when we conducted the direct hydrogenation of 1j
with Pd/C, a large amount of by-product bearing a n- The asymmetric synthesis of contiguous tetrasubstitut-
butyl group was obtained. The Dess–Martin oxidation ed carbon stereocenters is one of the most challenging
of 3 gave aldehyde 4, which was subjected to the subjects in organic synthesis. Here we have succeeded
second benzoin cyclization using triazolium salt A to in the stereoselective synthesis of bicyclic compounds
give 5. The isolated yields of the racemic compounds 1 with two contiguous tetrasubstituted carbon stereo-
are shown in Scheme 4. When (+)-1j with 68% ee centers via the NHC-catalyzed intramolecular crossed
was used in the same way, optically active (+)-5 with benzoin reactions of symmetrical compounds 2. We
68% ee was obtained in 86% in the final step. Enan- have also demonstrated the stepwise synthesis of tri-
tiomerically pure (+)-5 with>99% ee was obtained in cyclic compound 5 with three contiguous tetrasubsti-
57% by recrystallization. The 13C NMR spectrum in- tuted carbon stereocenters. The present synthetic
methods should be useful because carbon frameworks
of the products can be seen in several natural prod-
ucts and drugs.
Experimental Section
General Remakrs
Syntheses of 1a–f and 2a–f have been reported elsewhere.[5]
1H and 13C NMR spectra were measured on Varian 600 or
400 MHz NMR spectrometers. IR spectra were recorded on
a Shimadzu FTIR-8900 spectrometer. Silica gel column
chromatography was performed using Fuji Silysia BW-127
ZH (100–270 mesh), and thin layer chromatography (TLC)
was performed on Merck silica gel 60 F254
.
1-(4-Hydroxybutyl)-6-hydroxybicyclo
2,7-dione (3)
ACHTUNGTREN[NGNU 4.3.0]nonane-
To a suspension of Pd/C(en) [Wako, 10% (w/w), 72.4 mg] in
dry MeOH (24 mL) was added a solution of 1j (724 mg,
2.21 mmol) in dry MeOH (2 mL). The mixture was stirred
under H2 at room temperature overnight, and Pd/C (Al-
drich, 10% (w/w), 72.4 mg) was added. The mixture was
Figure 3. X-ray crystal structure of (+)-5.
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stirred under H2 at room temperature for 4 h. The mixture
was filtered through Celite, and concentrated. Purification
by silica gel column chromatography (hexane/EtOAc, 1:3)
gave 3 as a colorless oil; yield: 400 mg (75%). 1H NMR
(CDCl3, 600 MHz): d=1.20–1.47 (m, 4H), 1.52–1.60 (m,
2H), 1.72–1.84 (m, 4H), 1.98–2.04 (m, 1H), 2.07–2.11 (m,
1H), 2.12–2.22 (m, 2H), 2.34–2.43 (m, 2H), 2.46–2.51 (m,
1H), 2.56–2.61 (m, 1H), 3.64 (s, 2H); 13C NMR (CDCl3,
150 MHz): d=20.0, 20.1, 24.3, 28.1, 31.0, 32.6, 34.0, 37.5,
61.4, 61.9, 81.4, 212.3, 216.7; IR (neat): n=3400, 2945, 2872,
1747, 1699, 1461, 1402, 1340, 1161, 1063, 1038, 918, 756,
667 cmÀ1; HR-MS (EI): m/z=240.1358, calcd. for C13H20O4:
240.1362.
as colorless crystals; yield: 70.4 mg (86%); 68% ee. Recrys-
tallization from EtOAc/hexane afforded enantiomerically
pure (+)-5 as colorless crystals; yield: 46.4 mg (57%);
>99% ee; [a]27: +152.4 (c 0.79, CHCl3). HPLC [Chiralcel
IA (Daicel ChDemical Industries), hexane/i-PrOH (4:1), flow
rate 0.7 mLminÀ1, detection 290 nm]: (+)-5 11.7 min, (À)-5
20.5 min.
X-Ray Crystallographic Analysis of (+)-5
Single crystals of (+)-5 were obtained by recrystallization
from EtOAc/hexane, and the crystals were mounted on
a glass fiber. The X-ray experiments were carried out on
a Rigaku R-AXIS RAPID II with a VariMax Cu diffractom-
eter including a Rigaku MicroMax-007HF microfocus gener-
ator with a Cu anode operating at 40 kV and 30 mA, Rigaku
VariMax HF optics, and a Rigaku R-AXIS RAPID II image
plate detector. To determine the cell constant and orienta-
tion matrix, three oscillation photographs were taken with
an oscillation angle of 3.08 and exposure time of 10 s per
degree for each frame. Intensity data were collected by
taking 30 oscillation photographs with an oscillation angle
of 308 and exposure time of 15 s per degree for each frame
at 238C. Refraction data were corrected for both Lorentz
and polarization effects. The absolute configuration of (+)-5
was determined to be (R,R,R) by refinement of the Flack
parameter (0.2).[19] Crystal data for (+)-5: C13H18O4, color-
less crystal, crystal dimensions 0.45ꢁ0.42ꢁ0.39 mm3, ortho-
rhombic, space group P212121, a=8.54370(15), b=
8.50084(15), c=15.8759(3) ꢂ, V=1153.04(4) ꢂ3, Z=4,
1calcd =1.373 gcmÀ3, 2q ꢀ 136.28, 12209 total reflections, 2075
unique reflections, 226 parameters, R1 =0.0505 [I> 2.0s(I)],
Rw =0.1197 (all data). The final structure was validated by
the PLATON CIF check. CCDC 868578 contains the sup-
plementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
1-(3-Formylpropyl)-6-hydroxybicyclo
2,7-dione (4)
ACHTUNGTREN[NGNU 4.3.0]nonane-
To
a
mixture of Dess–Martin periodinane (848 mg,
2.00 mmol) in dry CH2Cl2 (9 mL) under Ar was added drop-
wise a solution of 3 (400 mg, 1.66 mmol) in dry CH2Cl2
(1 mL) over 5 min. The mixture was stirred at room temper-
ature overnight. The mixture was filtered through Celite,
and concentrated. Purification by silica gel column chroma-
tography (hexane/EtOAc, 3:1) gave 4 as a colorless oil;
1
yield: 266 mg (67%). H NMR (CDCl3, 400 MHz): d=1.38–
1.69 (m, 4H), 1.71–2.03 (m, 7H), 2.06–2.28 (m, 3H), 2.33–
2.55 (m, 1H), 2.56–2.66 (m, 1H), 3.13 (br s, 1H), 5.69 (s, 1H
(hemiacetal form)), 9.73 (t, J=1.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d=16.8, 20.2, 24.7, 30.7, 33.8, 37.5, 43.9,
60.6, 77.3, 82.1, 92.6, 211.4, 216.4 (hemiacetal form: 17.4,
18.2, 26.6, 29.0, 31.6, 34.1, 34.2, 35.0, 61.2, 105.4, 112.3, 202.0,
215.6); IR (KBr): n=3418, 2967, 2931, 1682, 1466, 1439,
1350, 1231, 1169, 1134, 1057, 1038, 976, 949, 887 cmÀ1; anal.
calcd. for C13H18O4: C 65.53, H 7.61; found: C 65.42, H 7.73;
HR-MS (EI): m/z=238.1208, calcd. for C13H18O4: 238.1205.
5,9-Dihydroxytricyclo[7.4.0.01,5]tridecane-4,10-dione
(5)
To a solution of 4 (139 mg, 0.582 mmol) and triazolium salt
A (42.3 mg, 0.116 mmol, 20 mol%) in dry THF (2 mL)
under Ar was added Et3N (16.2 mL, 0.116 mmol, 20 mol%).
The mixture was stirred at 668C for 24 h. The reaction was
quenched with saturated aqueous NH4Cl. The product was
extracted with EtOAc (ꢁ4). The combined organic layer
was washed with brine, dried over Na2SO4, and concentrat-
ed. Purification by silica gel column chromatography
(hexane/EtOAc, 3:1) gave 5 as white crystals; yield: 104 mg
(75%). 1H NMR (CDCl3, 400 MHz): d=1.26 (br d, J=
13.2 Hz, 1H), 1.53–1.83 (m, 7H), 1.91–1.99 (m, 1H), 2.02–
2.14 (m, 4H), 2.31–2.54 (m, 3H), 2.64 (dt, J=6.4, 14.2 Hz,
1H), 3.86 (s, 1H); 13C NMR (CDCl3, 100 MHz): d=18.1,
21.7, 27.0, 27.2, 27.9, 32.3, 34.5, 37.0, 52.3, 77.4, 80.8, 213.3,
214.7; IR (KBr): n=3445, 2962, 2874, 1738, 1693, 1427,
1373, 1310, 1240, 1147, 1126, 1049, 932, 908, 847 cmÀ1; anal.
calcd. for C13H18O4: C 65.53, H 7.61; found: C 65.18, H 7.64;
HR-MS (EI): m/z=238.1184, calcd. for C13H18O4: 238.1205.
Acknowledgements
We thank Dr. Hiromi Ohta, Dr. Toshimasa Katagiri, Mr. Kei-
suke Kataoka (Okayama University) and the Department of
Instrumental Analysis of the Advanced Science Research
Center of Okayama University for X-ray analysis. We thank
the SC NMR Laboratory of Okayama University for the
measurement of NMR spectra.
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