Asymmetric synthesis of γ-hydroxy α-enones by 1,8-diazabicyclo[5.4.0]undec-7-ene-catalyzed stereoselective rearrangement of chiral α-sulfinyl enones

Article abstract of DOI:10.1021/ol1015724

The asymmetric rearrangement of optically active α-sulfinyl enone 1 induced by catalytic DBU and triphenylphosphine gave optically active γ-hydroxy α-enone derivatives (up to 99% ee) in good yield following treatment with aqueous hydrogen peroxide.

Full text of DOI:10.1021/ol1015724

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3882-3885
Asymmetric Synthesis of γ-Hydroxy
r-Enones by 1,8-Diazabicyclo[5.4.0]undec-
7-ene-Catalyzed Stereoselective
Rearrangement of Chiral r-Sulfinyl
Enones
Motofumi Miura,*,† Masaharu Toriyama,† Takashi Kawakubo,§ Ken Yasukawa,†
Toshio Takido,‡ and Shigeyasu Motohashi†
School of Pharmacy, Nihon UniVersity, 7-7-1, Narashinodai, Funabashi-shi,
Chiba 274-8555, Japan, College of Science and Technology, Nihon UniVersity,
1-8-14, Kanda-surugadai, Chiyodaku 101-8308, Japan, and Department of Pharmacy,
Jikei UniVersity, School of Medicine Hospital, 3-19-18, Nishi-shinbashi, Minatoku,
Tokyo 105-8471, Japan
miura.motofumi@nihon-u.ac.jp
Received July 8, 2010
ABSTRACT
The asymmetric rearrangement of optically active r-sulfinyl enone 1 induced by catalytic DBU and triphenylphosphine gave optically active
γ-hydroxy r-enone derivatives (up to 99% ee) in good yield following treatment with aqueous hydrogen peroxide.
The stereoselective synthesis of γ-hydroxy R-enones is an
important topic in organic synthesis because these com-
pounds are found in many natural products, most of which
possess important bioactivity. For example, Piper nigrum
components and their synthetic derivatives have been shown
to have anticancer activity.1 A fatty acid with strong cytotoxic
activity has been isolated from corn extract.2 Vancoresmycin
has been isolated from Amycolatopis ST101170,3 and
recently, we have reported the isolation of alpinoids B and
C from Alpinia officinarum. These compounds possess a
chiral γ-hydroxy R-enone moiety and they are anticipated
to possess anticancer and antiviral activity.4 Nicolaou and
co-workers reported a total synthesis of BE-43472B where
have also a chiral γ-hydroxy R-enone was used in a key
step.5 Posner and Peterson reported an enantiocontrolled
synthesis of γ-hydroxy-(E)-R,ꢀ-unsaturated sulfones and
(2) (a) Hayashi, Y.; Ishihara, N.; Takahashi, M.; Fujii, E.; Uenakai, K.;
Masada, S.; Ichimoto, I. Biosci. Biotech. Biochem. 1996, 60, 1115–1117.
(b) Kuga, H.; Ejima, A.; Mitsui, I.; Sato, K.; Ishihara, N.; Fukuda, K.;
Uenakai, K. Biosci. Biotech. Biochem. 1993, 57, 1020–1021. (c) Matsushita,
Y.; Sugamoto, K.; Nakama, T.; Matsui, T.; Hayashi, Y.; Uenakai, K.
Tetrahedron Lett. 1997, 38, 6055–6058.
† School of Pharmacy, Nihon University.
‡ College of Science and Technology, Nihon University.
§ Depertment of Pharmacy, Jikei University School of Medicine Hospital.
(1) (a) Wei, K.; Li, W.; Koike, K.; Pei, Y.-P.; Chen, Y.-J.; Nikaido, T.
J. Nat. Prod. 2004, 67, 1005–1009. (b) Srinivas, Ch.; Sai Pavan Kumar,
Ch. N. S.; China Raju, B.; Jayathirtha R, V.; Naidu, V. G. M.; Ramakrishna,
S.; Diwan, P. V. Bioorg. Med. Chem. Lett. 2009, 19, 5915–5918.
(3) Hopmann, C.; Kurz, M.; Bronstrup, M.; Wink, J.; LaBeller, D.
Tetrahedron Lett. 2002, 43, 435–438.
(4) Sun, Y.; Matsubara, H.; Kitanaka, S.; Yasukawa, K. HelV. Chim.
Acta 2008, 91, 118–123.
10.1021/ol1015724  2010 American Chemical Society
Published on Web 08/12/2010

esters using enantioenriched R-selenyl aldehydes with EWG-
stabilized carbanions.6
Table 1. Optimization of the Stereoselective Rearrangement of
R-Sulfinyl Enone 1a Using Various Amines
In the mid-1980s, we discovered a new 2,3-sigmatropic
rearrangement involving cyclic enones and R-chloroalkyl
sulfoxides under strongly basic conditions, which gave
optically active cyclic γ-hydroxy R-enones (67-82% ee) in
moderate yields.7
Nokami and co-workers reported that racemic ꢀ-keto-
sulfoxides and aldehydes condensed in the presence of a
secondary amine, in a Knoevenagel-type carbon chain
elongation,andthatthiswasaccompaniedbyaMislow-Evans-
type rearrangement to give a racemic γ-hydroxy R-enone.8
However, this report did not mention the chirality of the
γ-hydroxyl group. Recently, we reported that the stereo-
selective Luche reduction of R-sulfinyl enones treated with
ytterbium chloride hexahydrate and sodium borohydride
in methanol proceeded in excellent yield and with high
stereoselectivity (Scheme 1).9 Subsequently, when an
Scheme 1. Asymmetric Reduction and Sigmatropic
Rearrangement of R-Sulfinyl Enones
a Reaction conditions: 1a (0.2 mmol), amine or PPh3 (0.24 mmol),
CH3CN (2 mL), and the reactions were carried out at rt. b Isolated yield.
c The ee was determined by HPLC equipped with a DAICEL IC-3 column.
d DBU (10 mol %), PPh3 (0.3 mmol), and CH3CN (2 mL) was used at 0 °C.
acetonitrile solution of chiral R-sulfinyl enone (1.0 equiv)
in the presence of diethylamine was stirred for 2 h (procedure
A, Supporting Information), γ-hydroxy R-enone was obtained
in good yield, but the stereoselectivity was very low (Scheme
1 and Table S1, Supporting Information). As a consequence,
we became interested in exploring the potential of this reaction
to have its stereoselectivity improved using various amines and
R-sulfinyl enones as chiral auxiliaries. Herein, we report on the
use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed
sigmatropic rearrangement of R-sulfinyl enones with triph-
enylphosphine (PPh3) leading to chiral γ-hydroxy R-enones in
high ee.
Initial studies using (Ss,E)-1,7-diphenyl-4-(4-tolylsulfinyl)-
hept-4-en-3-one 1a as the substrate were aimed at determin-
ing the optimal stereoselective reaction conditions for the
asymmetric rearrangement reaction using various amines.
These results are summarized in Table 1. For the detailed
preparation of substrates 1a-l, see the Supporting Infor-
mation. Et2NH and Et3N provided 2a in good yield but
with almost no enantioselectivity when used for inducing
the rearrangement of 1a (Table 1, entries 1 and 2). The
cyclic amines piperidine and morphorine gave excellent
yields and somewhat better selectivity (Table 1, entries 5
and 6). The chiral amines L-prolinamide and D-prolinamide
produced the same results as the cyclic amines (Table 1,
entries 7 and 8). The bulky cyclic amine 1,4-diazabi-
cyclo[2.2.2]octane (DABCO) displayed good stereoselec-
tivity and moderate yield (Table 1, entry 9). We also found
that DBU gave rise to excellent stereoselectivity; however, the
yield was very low (Table 1, entry 10). On the other hand, when
PPh3 was used, 2a was obtained in moderate yield and low
stereoselectivity within 10 h (Table 1, entry 11).
Finally, use of a catalytic amount of DBU together with
PPh3 produced a somewhat better chemical yield of 2a from
1a, and the stereoselectivity was high (Table 1, entry 12).
However, the product 2a decomposed during the usual
workup, thus decreasing the amount of the target compound.
Accordingly, we next attempted to find a more suitable
system that incorporated appropriate quenching conditions
for the DBU-catalyzed sigmatropic rearrangement. The
asymmetric rearrangement yields following treatment with
various quenching reagents are summarized in Table 2. We
(5) (a) Nicolaou, K. C.; Lim, Y. H.; Becker, J. Angew. Chem., Int. Ed.
2009, 48, 3444–3448. (b) Nicolaou, K. C.; Becker, J.; Lim, Y. H.; Lemire,
A.; Neubauer, T.; Montero, A. J. Am. Chem. Soc. 2009, 131, 14812–14826.
(6) Peterson, K. S.; Posner, G. H. Org. Lett. 2008, 10, 4685–4687.
(7) (a) Satoh, T.; Motohashi, S.; Yamakawa, K. Tetrahedron lett. 1986,
27, 2889–2892. (b) Satoh, T.; Motohashi, S.; Tokutake, T.; Yamakawa, K.
Bull. Chem. Soc. Jpn. 1992, 65, 2966–2973.
(8) (a) Nokami, J.; Nishimura, A.; Sunami, M.; Wakabayashi, S.
Tetrahedron Lett. 1987, 28, 649–650. (b) Nokami, J.; Taniguchi, T.; Ogawa,
Y. Chem. Lett. 1994, 43–44. (c) Nokami, J.; Osafune, M.; Shiraishi, K.;
Sumida, S.; Imai, N. J. Chem. Soc., Perkin Trans. 1 1997, 2947–2948. (d)
Nokami, J.; Kataoka, K.; Shiraishi, K.; Osafune, M.; Hussain, I.; Sumida,
S. J. Org. Chem. 2001, 66, 1228–1232. (e) Giardina`, A.; Marcantoni, E.;
Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 4, 713–718.
(9) Miura, M.; Toriyama, M.; Motohashi, S. Tetrahedron: Asymmetry
2007, 18, 1269–1271.
Org. Lett., Vol. 12, No. 17, 2010
3883

by entries 1-12, almost all of the reactions gave good en-
antioselectivity.
Table 2. Optimization Studies of Efficiently Quenching Reagent
in the Asymmetric Rearrangement of R-Sulfinyl Enone 1a
The absolute configuration at C(6) was assigned by
application of the modified Mosher method.10 Mosher
acylation of 2g and 2j with both (RS)- and (RR)-R-methoxy-
R-(trifluoromethyl)benzeneacetyl (MTPA) chloride yielded
the C(6) (RR)- and (RS)-MTPA esters. The determination
of ∆δ value (δS - δR) for the protons neighboring C(6) led
to the assignment of the (6R) configuration for 2g and 2j
(Table 4).
2a
entrya
quenching reagent
yieldb (%)
eec (%)
1
2
3
4
5% aq HCl solution
water
satd aq NH4Cl solution
3% aq H2O2 solution
dec
47
46
77
99
99
>99
1
Table 4. Characteristic H NMR Data (600 MHz, CDCl3) of the
Mosher Esters Derived from 2g and 2j
a Reaction conditions: 1a (0.2 mmol), DBU (0.02 mmol), PPh3 (0.3
mmol), CH3CN (4 mL); the reactions were carried out at 0 °C. b Isolated
yield. c The ee was determined by HPLC equipped with a DAICEL IC-3
column.
from 2g
from 2j
a
b
a
b
δS
δR ∆δ(δS - δR) δS
δR
∆δ(δS - δR)
H-C (4) 6.04 6.21
H-C (5) 6.68 6.61
H-C (6) 5.40 5.41
H3-C(10) 0.88 0.83
i-Pr (8)
-0.17
-0.07
(R)
6.04 6.17 -0.13
6.60 6.67 -0.07
5.59 5.59 (R)
first chose 5% aqueous HCl solution, but this did not have
any quenching activity. Moreover, the product 2a was
completely decomposed (Table 2, entry 1). Water and
saturated aqueous NH4Cl solution gave the same low yields
(Table 2, entries 2 and 3). Most notably, 3% aqueous H2O2
solution efficiently quenched this asymmetric reaction (Table
2, entry 4).
+0.05
0.91, 0.85, +0.06, +0.06
0.93 0.87
a δ of (RS)-MTPA ester. b δof (RR)-MTPA ester.
However, the diphenyl-substituted compound (entry 8)
gave excellent yield but only moderate enantioselectivity.
R1 ) phenyl group compounds tended to give lower yields
than the others (entries 2 and 6), and these compounds
2b and 2f were very unstable at room temperature. Thus,
we believe that product 2b and 2f were decomposed in
this system, and therefore the isolated yield was reduced.
On the basis of Nokami’s report8 and our own findings, a
proposed mechanism for the DBU-catalyzed asymmetric
sigmatropic rearrangement is illustrated in Figure 1. DBU
deprotonates at the γ-position, and the enolate is generated
in stage I. The protonated DBU may form a sterically
hindered complex to intermediate 1. Enolate attack on the
lone-pair coordinated protonated DBU may then occur
followed by asymmetric rearrangement (II).
After optimization of the reaction conditions, the generality
of the sigmatropic rearrangement was explored. A series of
R-sulfinyl enones were examined (procedure B in the Support-
ing Information). The yields of the asymmetric sigmatropic
rearrangement products ranged from good to excellent, and the
results of our findings are summarized in Table 3. As shown
Table 3. Enantioselective Sigmatropic Rearrangement of
Various R-Sulfinyl Enones
This generates a chiral γ-oxysulfanyl R-enone (III) that
undergoes oxidation and hydolysis. This generates the chiral
γ-hydroxy R-enone and sulfinic acid in the final stage (IV).
In conclusion, we have developed an efficient method of
carrying out a highly enantioselective sigmatropic rearrange-
ment of R-sulfinyl enones utilizing catalytic quantities of
DBU, with PPh3, and aqueous H2O2 workup. This leads to
good yields of chiral γ-hydroxy R-enone.
entrya
R1
R2
2
yieldb (%) eec (%)
1
2
3
4
5
6
7
8
PhCH2CH2
Ph
i-PrCH2
PhCH2
PhCH2
PhCH2
2a
2b
2c
2d
2e
2f
2g
2h
2i
77
56
76
70
68
55
72
97
75
85
92
84
>99
78
97
87
90
89
90
58
71
77
74
86
CH3CH2CH2 PhCH2
i-Pr
Ph
PhCH2
nBu
nBu
nBu
i-Pr
PhCH2CH2
Ph2CH
Ph
PhCH2CH2
Ph
The reaction proceeds via a sigmatropic rearrange-
ment.11 The mild reaction conditions and short reaction
times make this an attractive methodology for accessing
9
10
11
12
i-Pr
2j
cyclopentyl 2k
cyclopentyl 2l
(10) (a) Kusumi, T.; Ooi, T.; Ohkubo, Y.; Yabuuchi, T. Bull. Chem.
Soc. Jpn. 2006, 79, 965–980. (b) Li, G.; Xu, M. L.; Chio, H. G.; Lee, S. H.;
Jahng, Y. D.; Lee, C. S.; Moon, D. C.; Woo, M. H.; Son, J. K. Chem.
Phram, Bull. 2003, 51, 262–264.
PhCH2CH2
a Reaction conditions: 1 (0.5 mmol), DBU (0.05 mmol), PPh3 (1.5
mmol), CH3CN (6 mL); the reactions were carried out at 0 °C for 30 min
followed by quenching with 3% H2O2 at 0 °C. b Isolated yield. c The ee
was determined by HPLC equipped with a DAICEL IC-3 column.
(11) (a) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100–2104.
(b) Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93,
4956–4957.
3884
Org. Lett., Vol. 12, No. 17, 2010

Figure 1. Possible mechanism for the rearrangement of 1.
chiral γ-hydroxy R-enones. Synthetic applications of the
present reaction are currently being investigated in this
laboratory.
mass spectroscopy measurements. We also thank Mr. Atsu-
hito Suzuki (College of Science and Technology, Nihon
University) for technical research.
Supporting Information Available: Detailed descriptions
of the experimental procedure and full characterization of
the new compounds shown in Table 3 This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was partially supported
by the MEXT “Academic Frontier” project (2007) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. We thank Dr. Kouichi Metori (Analytical Center,
School of Pharmacy, Nihon University) for performing the
OL1015724
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3885