Modified chiral triazolium salts for enantioselective benzoin cyclization of enolizable keto-aldehydes: Synthesis of (+)-sappanone B

Article abstract of DOI:10.1021/ol070929p

Equation Presented Asymmetric synthesis of (+)-sappanone B (1), a natural product with a 3-hydroxy chromanone structure, was achieved via enantioselective benzoin cyclization by using a modified Rovis catalyst and triethylamine. This catalyst enabled the

Full text of DOI:10.1021/ol070929p

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2713-2716
Modified Chiral Triazolium Salts for
Enantioselective Benzoin Cyclization of
Enolizable Keto-Aldehydes: Synthesis
of (+)-Sappanone B
Hiroshi Takikawa and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, SORST-JST Agency,
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
ksuzuki@chem.titech.ac.jp
Received April 20, 2007
ABSTRACT
Asymmetric synthesis of (+)-sappanone B (1), a natural product with a 3-hydroxy chromanone structure, was achieved via enantioselective
benzoin cyclization by using a modified Rovis catalyst and triethylamine. This catalyst enabled the successful benzoin cyclization of readily
enolizable keto-aldehydes.
We recently reported the catalytic asymmetric benzoin
cyclization of keto-aldehydes1 by using Rovis triazolium salt,2
opening an enantioselective route to chiral, nonracemic cyclic
ketols. To explore the scope, we became interested in
applying this reaction to the synthesis of various natural
products. (+)-Sappanone B3 (1, Figure 1) is one of the targets
selected along these lines. It is a homoisoflavonoid4 with
significant, recently discoverd xanthine oxidase inhibitory
activity, which was isolated from the heartwood of Caesal-
pinia sappan Leguminosae.5
We initially centered our attention on the absolute ste-
reocontrol.6 However, preliminary model studies immedi-
ately suggested that the real issue was the low cyclization
yield for the enolizable keto-aldehydes.
In this Letter, we report modifications of the Rovis
triazolium salts by introducing electron-withdrawing sub-
stituent(s) to facilitate the generation of the key carbene
spiecies under mild basic conditions, enabling the stereo-
controlled synthesis of 1.7
(1) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew. Chem.,
Int. Ed. 2006, 45, 3492-3494.
(2) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002,
124, 10298-10299.
(3) (a) Saitoh, T.; Sakashita, S.; Nakata, H.; Shimokawa, T.; Kinjo, J.-
E.; Yamahara, J.; Yamasaki, M.; Nohara, T. Chem. Pharm. Bull. 1986, 34,
2506-2511. (b) Namikoshi, M.; Nakata, H.; Yamada, H.; Nagai, M.; Saitoh,
T. Chem. Pharm. Bull. 1987, 35, 2761-2773. (c) Namikoshi, M.; Nakata,
H.; Nuno, M.; Ozawa, T.; Saitoh, T. Chem. Pharm. Bull. 1987, 35, 3568-
3575.
Figure 1. Structure and retrosynthesis of (+)-sappanone B (1).
(4) Tamm, C. Fortschr. Chem. Org. Naturst. 1981, 40, 105-152.
10.1021/ol070929p CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/09/2007

Scheme 1. Two Possible Actions of Carbene Catalyst
Table 1. Asymmetric Benzoin Cyclization of Keto-Aldehyde 4
by Using Triazolium Salt 3aa
Generated from Triazolium Salt
the triazolium salt would become more acidic, making the
generation of the key carbene species possible with a weaker
base, that is, less capable of enolizing 4. Since the generated
carbene would also be less basic, the problematic aldol
reactions would be minimized.
To test this idea, we used a known precatalyst 3b11 with
a C6F5 group (Table 2, entry 1). Indeed, aldol reactions were
byproducts
6-9
yield/%b
R-ketol 5
entry
base
DBU
solvent time/h yield/% ee/%
1
THF
THF
toluene
3.5
26
24
7
10
56
39
31
93
88
92
94
78
31
57
53
2
Et3N
Et3N
3
4c
Table 2. Reactions with Modified Triazolium Saltsa
KHMDS toluene
a All reactions were performed on 1.0 mmol of 4 with a combination of
precatalyst 3a (15 mol %) and base (10 mol %) at room temperature.
Enantiomeric excess was assessed by HPLC analysis on CHIRALPAK AD-
H. b Containing a small amount of unidentified byproduct(s). c Reaction was
performed with prior generated carbene [by mixing 3a (15 mol %) with
KHMDS (10 mol %) for 10 min (toluene, rt)].
Table 1 represents the initial experiments that revealed
the issue. When model keto-aldehyde 4 was treated with
triazolium salt 3a and DBU (THF, room temperature, 3.5
h), the corresponding R-ketol (R)-58 was obtained in only
10% yield (entry 1). The low yield was due to the competing
intramolecular aldol reactions to give byproducts, 5- and
7-membered aldols 6 and 7 (Rf 0.2, silica gel TLC, EtOAc/
hexane ) 1:3) and their dehydration products 8 and 9 (Rf
0.6) in 78% combined yield. Such prevalence of aldol
reactions was not surprising in view of the high acidities of
the protons adjacent to the carbonyl group in 4. We examined
a weaker base, triethylamine, which led to a better yield of
5 (56%) with a slight decrease in the ee (entry 2).9 While
the ee of 5 was recovered by use of toluene as a solvent, the
side reactions again became serious (entry 3). Moreover, prior
generation of the carbene was also ineffective (entry 4),
implying that the carbene also served as a base to promote
the aldol cyclization (Scheme 1).10
byproducts
6-9
yield/%
R-ketol 5
entry
precatalyst
time/h
yield/%
ee/%
1
2
3
4
5
3b
3c
3d
3e
3f
2
2
5
8
5
93
94
67
85
87
68
81
88
92
94
0
0
32
12
11
a All reactions were performed with 1.0 mmol of 4 with a combination
of precatalyst 3b-f (15 mol %) and Et3N (10 mol %) at 0.3 M in toluene
at room temperature. Enantiomeric excess was assessed by HPLC analysis
on CHIRALPAK AD-H.
Faced with this dilemma, we decided to change the catalyst
precursor (Scheme 1). The idea was that if electron-
withdrawing group(s) were installed in the N-phenyl group,
completely suppressed, although the enantioselectivity was
unfortunately diminished.
Encouraged by these data, we prepared several new
triazolium salts 3c-f possessing fluorine or trifluoromethyl
group(s) on the N-phenyl group with hopes of finding a
catalyst that could be capable of suppressing the aldol
(5) Nguyen, M. T. T.; Awale, S.; Tezuka, Y.; Tran, Q. L.; Kadota, S.
Chem. Pharm. Bull. 2005, 53, 984-988.
(6) (a) Davis, F. A.; Chen, B.-C. J. Org. Chem. 1993, 58, 1751-1753.
(b) Arnoldi, A.; Bassoli, A.; Borgonovo, G.; Merlini, L. J. Chem. Soc.,
Perkin Trans. 1 1995, 2447-2453. (c) Jew, S.-S.; Kim, H.-A.; Kim, J.-H.;
Park, H.-G. Heterocycles 1997, 46, 65-70.
(10) For the basicity of imidazol-2-ylidene in THF, see: Kim, Y.-J.;
Streitwieser, A. J. Am. Chem. Soc. 2002, 124, 5757-5761 and references
cited therein.
(7) For a related study, see: Enders, D.; Niemeier, O.; Raabe, G. Synlett
2006, 2431-2434.
(8) The (R) configuration of R-ketol 5 was confirmed by X-ray analysis
of the corresponding (S)-camphanyl derivative. See ref 1.
(9) Use of various bases of different strength (KHMDS, KOt-Bu,
quinuclidine) was unfruitful, invariably producing 6-9 in 50-70% yield.
(11) (a) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876-
8877. (b) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005,
70, 5725-5728. (c) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552-
2553.
2714
Org. Lett., Vol. 9, No. 14, 2007

reaction without sacrificing the enantioselectivity. The
reactivity profiles of 3c-f were compared by the cyclization
of keto-aldehyde 4 (Table 2, entries 2-5).
Table 3. Enantioselective Benzoin Cyclizations of
Keto-Aldehydes 10-14a
Several trends became obvious: (1) Introduction of the
ortho-substituents led to a decreased ee:12 Although o,o′-
difluoro precatalyst 3c could suppress the side reaction
completely, the ee was slightly lower (entry 2). In the case
of the o-fluoro precatalyst 3d, a sizable amount of the aldol
byproducts was produced (entry 3). (2) Meta-disubstituted
precatalysts gave favorable results in suppressing the aldol
reaction without loss of the ee: m,m′-Difluoro precatalyst
3e gave the product in high yield as well as high ee (entry
4). The m,m′-bis(trifluoromethyl) precatalyst 3f gave the best
result, providing optimal yield and ee (entry 5).
Having found a promising triazolium salt 3f, the scope
and limitation were compared with that of 3a with attention
to the reactivity, enantioselectivity, and the extent of compet-
ing aldol reaction (Table 3). In every case listed, the
cyclization yields were higher with modified precatalyst 3f
in comparison to the original Rovis precatalyst 3a. The
enantioselectivities were generally better with 3f, except in
one case. Entry 1 shows the reaction of keto-aldehyde 10
having a methyl group: Cyclization occurred smoothly with
3f in an excellent selectivity, while aldol-type side reactions
were serious when 3a was used. Entry 2 shows the reaction
of highly enolizable keto-aldehyde 11 to give 3-hydroxy-
isoflavanone 16.13 The yield was extremely low in the case
of 3a (13%), whereas 3f gave a much better yield with an
excellent selectivity (61% yield, 90% ee), although side
products were also observed (27%). Biaryl keto-aldehydes1
12 and 13 showed the same trend (entries 3 and 4). The
optimized conditions by using 3f led to the high-yield
formation of (S)-R-ketols with excellent selectivities.14
Furthermore, cyclization of aryl keto-aliphatic aldehyde 14
was possible only with 3f to give R-ketol 19 in high yield,
albeit with moderate selectivity (entry 5).
a Unless otherwise indicated, all reactions were performed with 3f or 3a
(15 mol %) and Et3N (10 mol %) in toluene at room temperature.
Enantiomeric excesses were assessed by HPLC analysis on CHIRALPAK
AD-H or CHIRALCEL OD-H. b The absolute configurations were con-
firmed by X-ray analysis of the corresponding (S)-camphanyl derivatives.
c The corresponding byproducts were also obtained (entry 1: 43%; entry
2: 82%; entry 3: 18%; entry 4: 37%). d The corresponding benzofuran
and aldol were also obtained in 27% combined yield. e Performed with 3a
(10 mol %) and DBU (20 mol %) in THF. f Performed with 3a (20 mol %)
and DBU (20 mol %) in THF. g Performed with 3f (20 mol %) and Et3N
(20 mol %) in toluene.
At this stage, we embarked on the synthesis of (+)-
sappanone B (1). As the cyclization substrate, keto-aldehyde
2 was prepared from the commercially available aldehyde
20 in five steps (Scheme 2). After acetylation of the phenol
in 20, the aldehyde was protected as a 1,3-dioxane acetal,
and deacetylation gave phenol 21 in 95% yield.15 Although
a detour, this temporary acetylation was essential, since the
direct acetalization of 20 failed under a variety of conditions.
Alkylation of phenol 21 with N-methoxy-N-methylchloro-
acetamide16 proceeded in quantitative yield of Weinreb amide
22. Treatment of amide 22 with a benzyl Grignard reagent,17
followed by hydrolysis of the acetal gave keto-aldehyde 2
in 87% yield (2 steps).
Scheme 2. Preparation of Keto-Aldehyde 2
(12) The corresponding reaction by using the triazolium salt with the
ortho-mono-methylated N-phenyl group [15 mol %, Et3N (10 mol %),
toluene, room temperature] provided R-ketol 5 in poorer selectivity (44%,
62% ee).
(13) (a) Minhaj, N.; Tasneem, K.; Khan, Z.; Zaman, A. Tetrahedron
Lett. 1977, 18, 1145-1148. (b) Kim, C.-M.; Ebizuka, Y.; Sankawa, U.
Chem. Pharm. Bull. 1989, 37, 2879-2881. (c) Vila, J.; Balderrama, L.;
Bravo, J. L.; Almanza, G.; Codina, C.; Bastida, J.; Connolly, J. Phytochem-
istry 1998, 49, 2525-2528. (d) Gutierrez-Lugo, M.-T.; Woldemichael, G.
M.; Singh, M. P.; Suarez, P. A.; Maiese, W. M.; Montenegro, G.;
Timmermann, B. N. Nat. Prod. Res. 2005, 19, 173-179.
(14) The origin of the reversal of stereoinduction between biaryl keto-
aldehyde and others is under investigation.
Org. Lett., Vol. 9, No. 14, 2007
2715

chemistry was confirmed by the X-ray analysis of 4-bro-
mobenzoyl derivative 26 [4-bromobenzoyl chloride (3 equiv),
pyridine, room temperature, 5 h].20 Finally, the remaining
two methyl groups were removed by BBr3 (3 equiv, CH2-
Cl2, 0 °C) to give 1 as white amorphous solid in 85% yield
after purification by column chromatography on oxalated
silica gel.21 No loss of the ee was observed during these
demethylation processes, as evidenced by chiral HPLC
analysis of the tri-O-acetyl derivative 25 [Ac2O, pyridine (v/v
1/2), 0 °C]. The specific rotation of synthetic 1 ([R]D +51
for 95% ee, c 1.0, MeOH) agreed with the reported value3
([R]D +51.6, c 1.00, MeOH). Other physical data3 for the
synthetic sample (1H NMR, 13C NMR, IR) were identical
with those of the natural product.22
Scheme 3. Synthesis of (+)-Sappanone B (1) and X-ray
Crystallographic Structure of 4-Bromobenzoyl Derivative 26
Acknowledgment. We are grateful to Banyu Pharma-
ceutical Co., Ltd. for the gift of (1S,2R)-1-amino-2-indanol
and Central Glass Co., Ltd. for the gift of 3,5-bis(trifluo-
romethyl)aniline. We express our gratitude to Prof. Dr.
Hiyoshizo Kotsuki, Kochi University, for helpful suggestion
on the preparation of oxalated silica gel. We also thank Dr.
Hidehiro Uekusa and Ms. Sachiyo Kubo, Tokyo Institute of
Technology, for X-ray analyses. This work was partially
supported by the 21st Century COE program (Tokyo Institute
of Technology) and a Grant-in-Aid for Scientific Research
(JSPS). A JSPS Research Fellowship for Young Scientists
to H.T. is also gratefully acknowledged.
Keto-aldehyde 2 was subjected to the crucial benzoin
cyclization step (Scheme 3). Pleasingly, the above-mentioned
conditions worked well, even with a reduced amount of
catalyst [3f (7.5 mol %), Et3N (7.5 mol %), room temper-
ature, 12 h],18 and tri-O-methyl sappanone B6a (23) was
obtained in excellent yield and enantioselectivity (92%, 95%
ee) with the (R) configuration (vide infra).
Among three methyl protecting groups for the phenols,
the one para to the carbonyl group was cleanly detached by
using an odorless thiolate19 to give phenol 24 in 92% yield
[NaSC12H25 (5 equiv), DMF, 80 °C, 5 h]. The (R) stereo-
Supporting Information Available: Spectroscopic and
analytical data of the compounds in Tables 2 and 3, Schemes
2 and 3, and the synthetic sample of (+)-sappanone B (1),
as well as crystal data for compound 26 and (S)-camphanyl
derivatives of 15, 16, and 19 in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL070929P
(15) Gopinath, R.; Haque, S. J.; Patel, B. K. J. Org. Chem. 2002, 67,
5842-5845.
(16) Dolling, U. H.; Frey L. F.; Tillyer, R. D.; Tschaen, D. M. PCT Int.
Appl. WO 97/10195, 1997.
(20) For the X-ray analysis of 4-bromobenzoyl derivative 26, see the
Supporting Information.
(17) Hashigaki, K.; Kan, K.; Qais, N.; Takeuchi, Y.; Yamato, M. Chem.
Pharm. Bull. 1991, 39, 1126-1131.
(18) It should be noted that the cyclization by using 3a [15 mol %, Et3N
(10 mol %), toluene] gave R-ketol (R)-23 in substantially lower yield (24%,
92% ee).
(21) Application of 1 onto a commercial silica gel caused a serious tailing
of a spot or a band, rendering the assay and purification of 1 extremely
difficult. The situation was cleared by the use of oxalated silica gel. For
oxalated silica gel, see the Supporting information and; Cameron, D. W.;
Riches, A. G. Aust. J. Chem. 1997, 50, 409-424.
(19) Sodium dodecanethiolate was prepared by mixing dodecanethiol with
sodium methoxide (28 wt % in MeOH) followed by evaporation (see the
Supporting Information). For odorless thiols and sulfides, see: Nishide,
K.; Ohsugi, S.; Miyamoto, T.; Kumar, K.; Node, M. Monatsh. Chem. 2004,
135, 189-200.
(22) The spectroscopic analysis of synthetic 1 revealed that all the signals
coincided with those of the natural product, except for the signal of C-9 (δ
38.9, conceiled by d6-DMSO). Although the reported value for C-9 in ref
3a was δ 30.6, no peak was observed at this position. The signal of C-9
appeared at δ 40.7 in d6-acetone. See the Supporting information.
2716
Org. Lett., Vol. 9, No. 14, 2007