Enantioselective total syntheses of novel PKC activator (+)-decursin and its derivatives using catalytic asymmetric epoxidation of an enone

Article abstract of DOI:10.1016/S0040-4039(00)01702-0

The catalytic asymmetric total syntheses of (+)-decursin and three related natural products, (+)-decursinol, (-)-prantschimgin and (+)-marmesin, were achieved for the first time using catalytic asymmetric epoxidation of an enone as the key step. The catalytic asymmetric epoxidation of enone was found to be promoted effectively by novel multifunctional asymmetric catalyst generated from La(O-i-Pr)₃, BINOL and O=AsPh₃ in a 1:1:1 ratio to afford epoxide in 94% yield and 96% ee, which was recrystallized to give the optically pure epoxide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01702-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9569–9574
Enantioselective total syntheses of novel PKC activator
(+)-decursin and its derivatives using catalytic asymmetric
epoxidation of an enone†
Tetsuhiro Nemoto, Takashi Ohshima and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 13 September 2000; accepted 21 September 2000
Abstract
The catalytic asymmetric total syntheses of (+)-decursin and three related natural products, (+)-decursi-
nol, (−)-prantschimgin and (+)-marmesin, were achieved for the first time using catalytic asymmetric
epoxidation of an enone as the key step. The catalytic asymmetric epoxidation of enone was found to be
promoted effectively by novel multifunctional asymmetric catalyst generated from La(O-i-Pr)3, BINOL
and OꢀAsPh3 in a 1:1:1 ratio to afford epoxide in 94% yield and 96% ee, which was recrystallized to give
the optically pure epoxide. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: catalytic asymmetric synthesis; (+)-decursin; asymmetric catalyst; epoxidation of enone.
Protein kinase C (PKC) is thought to play principal roles in cellular signal transductions and
has been focused on as a target of anticancer drug screening.1 Recently, it was shown that
(+)-decursin (1)2,3 (a dihydropyranocoumarin originally isolated from Angelica decursiva Fr. et
Sav.2a) exhibits cytotoxicity against several human cancer cell lines and relatively low cytotoxic-
ity against normal fibroblasts.2c,d The cytotoxic activity of 1 was found to be related to the
mechanism of PKC activation.2c,d However, this has not yet been clarified. Moreover, 1 has a
simple structure among the exogenous PKC activators reported so far. These profiles have made
1 quite attractive as a lead compound for drug discovery and a biological tool for clarification
of the mechanism of PKC activation. Herein we report the first catalytic asymmetric total
syntheses of (+)-decursin (1) and three related natural products 2, 3 and 4 using catalytic
asymmetric epoxidation of an enone as the key step (Fig. 1).
* Corresponding author.
†
This paper is dedicated to Professor Harry Wasserman on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01702-0

9570
H3C
O
HO
CH3
O
H3C
H3C
O
O
O
O
O
O
H3C
CH3
1: (+)-decursin
2: (+)-decursinol
CH3
O
H3C
O
H3C
HO
CH3
CH3
H3C
O
O
O
O
O
O
3: (–)-prantschimgin
4: (+)-marmesin
Figure 1. Structures of (+)-decursin (1), (+)-decursinol (2), (−)-prantschimgin (3) and (+)-marmesin (4)
From a synthetic point of view, we chose the strategy based on the palladium-catalyzed
intramolecular CꢁO coupling reaction4 to construct the dihydropyran ring for (+)-decursin (1)
and the dihydrofuran ring for (−)-prantschimgin (3), respectively (Scheme 1). This strategy
allowed us to synthesize all natural compounds from the same intermediate (−)-peucedanol (5).
Although there are many different ways of constructing the chiral center at the C-2% position,
catalytic asymmetric epoxidation of enone 7 followed by methylation should be the most
effective method. It is well known that Sharpless asymmetric epoxidation of tert-allylic alcohol5
and asymmetric hydrogenation of a-substituted enone6 do not proceed so well.
OH
O
O
2'
H3C
H3C
1, 2, 3, 4
H3C
OH
HO
O
O
MOMO
O
O
O
O
Pd-Catalyzed
Intramolecular
5: (–)-peucedanol
6
Catalytic Asymmetric
C-O Coupling Reaction
Epoxidation
O
HO
H3C
HO
O
O
MOMO
7
8: esculetin
Scheme 1. Retrosynthetic analysis of 1, 2, 3 and 4
Scheme 2 summarizes the construction of the required epoxidation precursor 7. Our synthesis
started with commercially available esculetin (8). Selective protection of the C-7 hydroxyl group
as MOM ether7 followed by conversion of the other hydroxyl group to the triflate afforded 9.
To introduce the enone moiety,8 we carried out palladium-catalyzed formylation of triflate 9 in
the presence of triethylsilane9 under a CO atmosphere (82%) followed by Wittig reaction to
afford a 11:1 isomeric mixture of (E)- and (Z)-enone 7 (94%). These isomers were separated by
silica gel column chromatography and (Z)-7 was successfully isomerized to the desired (E)-7
isomer by treatment with DBU (81%).
Having pure (E)-7 in large quantities, we then focused on the catalytic asymmetric epoxida-
tion of (E)-7. Preliminary experiments using several general conditions, such as TBHP–Triton B,
,
H2O2–NaOH and even TBHP–La(O-i-Pr)3 with or without MS 4 A, provided undesired results.
Semiempirical molecular orbital calculation (AM1) of (E)-7 suggested that the LUMO at the
b-position of (E)-7 would be much smaller than that of the 3,4-dihydro version of (E)-7.10

9571
O
c. CO
HO
HO
TfO
H
a. MOMCl
cat. Pd(OAc)2
b. Tf2O, i-Pr2NEt
O
O
MOMO
7
O
O
MOMO
O
O
8: esculetin
9
10
O
d.
O
PPh3
H3C
H3C
H3C
+
O
O
O
MOMO
O
O
MOMO
(Z)-7
(11 : 1)
(E)-7
e. DBU
Scheme 2. Reagents and conditions: (a) MOMCl, K2CO3, DMF, −20°C, 85%. (b) Tf2O, i-Pr2NEt, CH2Cl2, −30 to
0°C, 90%. (c) Pd(OAc)2, DPPP, HSiEt3, i-Pr2NEt, CO (15 atm), DMF, 60°C, 82%. (d) Wittig reagent, THF, 60°C,
94% (E/Z=11:1). (e) DBU, CH2Cl2, 40°C, 81%
Despite the above-mentioned negative factors in epoxidation, we expected that by using the
multifunctional asymmetric catalyst developed in our group11,12 we could overcome these
problems. The unique feature of the catalyst is believed to be a result of a synergistic
cooperation of metals and ligands. As we expected, Yb–BINOL (1:1) complex12 catalyzed the
asymmetric epoxidation of (E)-7 to afford epoxyketone 613 (88%, 83% ee) (Table 1, entry 1).
After optimization of the reaction conditions, we finally found that a La–BINOL complex with
Table 1
Catalytic asymmetric epoxidation of enone (E)-7 to epoxyketone 6 using Ln–BINOL complexes
catalyst, additive
7
+
TBHP in decane ꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢂ
6
a
,
(2 equiv.)
MS 4 A, THF, rt
Entry
Catalyst (mol %)
Additives (mol %)
Time (h)
Yield (%)
Ee (%)
1b
2
3
4
5
Yb–(R)-BINOL (1:1) (25)
La–(R)-BINOL (1:1) (25)
La–(R)-BINOL (1:1) (25)
La–(R)-BINOL (1:1) (25)
La–(R)-BINOL (1:1) (25)
La–(R)-BINOL (1:1) (25)
La–(R)-BINOL (1:1) (25)
–
–
15
25
2.5
4
25
12
6
88
28
98
89
55
56
88
83
20
97
91
75
91
95
OꢀPPh3 (100)
OꢀPPh3 (25)
OꢀAsPh3 (100)
OꢀAsPh3 (75)
OꢀAsPh3 (50)
6
7
8
9
La–(R)-BINOL (1:1) (25)
La–(R)-BINOL (1:1) (10)
OꢀAsPh3 (25)
OꢀAsPh3 (10)
2
5
94
90
96
93
10
11
La(O-i-Pr)3 (10)
La(O-i-Pr)3 (10)
OꢀAsPh3 (10)
–
18
24
Trace
Trace
–
–
a
,
MS 4 A was not dried (1000 mg/mmol).
b
,
MS 4 A was dried for 3 h at 180°C under reduced pressure before use (200 mg/mmol) and TBHP in toluene was
used.

9572
triphenylphosphine oxide12d or triphenylarsine oxide was highly effective for the catalytic
asymmetric epoxidation. In terms of atom economy, the best result was obtained using 1 equiv.
of triphenylarsine oxide to La(O-i-Pr)314–BINOL (94%, 96% ee, entry 8).15 A single recrystalliza-
tion of 96% ee epoxide 6 from hexane–acetone affords >99% ee epoxide 6 in 76% purified yield.
Although several methodologies for catalytic asymmetric epoxidation of enones have been
developed,16 only a few applications to total syntheses have been reported.17 No examples using
an enolizable enone as a substrate could be found. To the best of our knowledge, this is the first
application of this chemistry.
With the nearly optically pure advanced intermediate 6 in hand, the stage was set for
completion of the total synthesis (Scheme 3). Methylation of epoxyketone 6 afforded epoxyalco-
hol 10 (76%, conv. 91%), and subsequent regioselective reduction18 (74%) followed by removal
of the MOM group (92%) provided common intermediate (−)-peucedanol (5). Selective transfor-
mation of the phenolic hydroxyl group to the triflate provided substrate 11. With the use of 10
mol% Pd(OAc)2, 20 mol% DPPF, and NaO-t-Bu, the five-membered ring product (+)-marmesin
(4) was obtained exclusively. We next examined the Pd-catalyzed direct six-membered ring
formation using diol 11 under a variety of reaction conditions. However, in all cases we
obtained only the five-membered ring product. Thus, the secondary hydroxyl group was first
protected with a TES group. Cyclization of the mono-protected substrate 12 proceeded in 91%
yield using 10 mol% Pd(OAc)2, 12 mol% (S)-tol-BINAP, and K2CO3. After removal of the TES
group (+)-decursinol (2) was obtained. Finally, esterification of (+)-marmesin (4) and (+)-
decursinol (2) resulted in the first asymmetric total syntheses of (−)-prantschimgin (3) and
(+)-decursin (1), respectively.19
OH
O
O
HO
b. NaBH4,
BH3•THF
O
H3C
H3C
H3C
a. MeMgBr
O
H3C
H3C
MOMO
OH
HO
5: (–)-peucedanol
c. HCl
O
O
O
MOMO
O
O
6
10
[α]D25 –38.8 (c 0.57, EtOH)19
OH
e. Pd(OAc)2,
DPPF
d. Tf2O,
i-Pr2NEt
CH3
O
H3C
O
CH3
H3C
H3C
f
4
H3C
OH
TfO
O
O
O
O
O
[α]D23 +21.7 (c 0.90, CHCl3)19
3: (–)-prantschimgin
[α]D25 –34.6 (c 0.72, CHCl3)19
11
g. TESCl,
imidazole
OH
h. Pd(OAc)2,
(S)-tol-BINAP
H3C
O
H3C
H3C
TESO
TfO
j
2
CH3 O
O
O
O
i. TBAF
O
H3C
O
CH3
1: (+)-decursin
[α]D24 +135.2 (c 0.66, CHCl3)19
12
[α]D22 +6.8 (c 0.65, CHCl3)19
Scheme 3. Reagents and conditions: (a) MeMgBr, THF, −78°C, conv. 91%. (b) NaBH4, BH3·THF, THF, 0°C, 74%.
(c) Conc. HCl–H2O–THF (1:3:4), 40°C, 92%. (d) Tf2O, i-Pr2NEt, CH2Cl2, 0°C, 92%. (e) Pd(OAc)2 (10 mol %), DPPF
(20 mol %), NaO-t-Bu, toluene, 90°C, 80%. (f) Senecioyl chloride, DMAP, LHMDS, THF, −40 to 0°C, 72%. (g)
TESCl, imidazole, CH2Cl2, rt, 92%. (h) Pd(OAc)2 (10 mol %), (S)-tol-BINAP (12 mol %), K2CO3, toluene, 90°C,
91%. (i) TBAF, THF, rt, 95%. (j) Senecioyl chloride, DMAP, LHMDS, THF, −40 to 0°C, 83%

9573
In summary, we have succeeded in catalytic asymmetric total syntheses of natural coumarins
(+)-decursin (1), (+)-decursinol (2), (−)-prantschimgin (3), and (+)-marmesin (4) from the same
intermediate (−)-peucedanol (5). 5 was synthesized in an optically pure form by catalytic
asymmetric epoxidation of enone 7 using La(O-i-Pr)3, BINOL, and OꢀAsPh3 in the best ratio
(1:1:1). Further studies on the mechanism of the catalytic asymmetric epoxidation and the
structural determination of the asymmetric catalyst will be described in due course.
Acknowledgements
This work was supported by CREST and JSPS.
References
1. Fargo, A.; Nishizuka, Y. FEBS Lett. 1990, 268, 350 and references cited therein.
2. (a) Hata, K.; Sano, K. Yakugaku Zasshi 1969, 89, 549. (b) Sano, K.; Yosioka, I.; Kitagawa, I. Chem. Pharm.
Bull. 1973, 21, 2095. (c) Ahn, K.-S.; Sim, W.-S.; Kim, I.-H. Planta Med. 1996, 62, 7. (d) Ahn, K.-S.; Sim, W.-S.;
Lee, I.-K.; Seu, Y.-B.; Kim, I.-H. Planta Med. 1997, 63, 360.
3. For racemic syntheses of 1 and related natural coumarins, see: (a) Steck, W. Can. J. Chem. 1971, 49, 2297. (b)
Murray, R. D. H.; Sutcliffe, M.; McCabe, P. H. Tetrahedron 1971, 27, 4901.
4. (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333. (b) Mann, G.; Incarvito, C.;
Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224.
5. Johnson, R. A. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: New York, 1991;
Vol. 7, p. 389.
6. Keinan, E.; Greenspoon, N. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon:
New York, 1991; Vol. 8, p. 523.
7. Catalytic asymmetric epoxidations using enones protected with other protecting group, such as Bn and PMB,
provided worse result due to their low solubility in THF.
8. We at first examined Heck reaction and Stille coupling reaction extensively. However, we could not obtain a
satisfactory result.
9. Standard formylation condition using Bu3SnH as a reductant gave no desired aldehyde 10.
10. LUMOs of 7 and 14.
11. For a review, see: Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236.
12. For catalytic asymmetric epoxidations of enones catalyzed by multifunctional asymmetric catalysts, see: (a)
Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329. (b)
Watanabe, S.; Kobayashi, Y.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7353.
(c) Watanabe, S.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. J. Org. Chem. 1998, 63, 8090. (d) Daikai, K.;
Kamura, M.; Inanaga, J. Tetrahedron Lett. 1998, 39, 7321.
13. The absolute configuration of epoxide 6 was determined by transformation to the authentic natural compounds
(+)-2 and (+)-4. See: (a) Lemmich, J.; Nielsen, E. Tetrahedron Lett. 1969, 3. (b) Harada, I.; Hirose, Y.; Nakazaki,
M. Tetrahedron Lett. 1968, 5463. The enantiomeric excess was determined by chiral stationary phase HPLC
analysis (DAICEL CHIRALPAK AD, hexane/2-propanol (9:1, v/v), flow rate: 1.0 mL/min, retention time: 28
min (1%S,2%R)-isomer and 36 min (1%R,2%S)-isomer, detected at 254 nm).

9574
14. La(O-i-Pr)3 can be purchased from Kojundo Chemical Laboratory Co., Ltd., 5-1-28, Chiyoda, Sakado-shi,
Saitama 350-0214, Japan (fax: +(81)-492-84-1351).
15. The catalytic asymmetric epoxidation of 7 is as follows. To a mixture of (R)-BINOL (7.2 mg, 0.025 mmol),
,
triphenylarsine oxide (8.1 mg, 0.025 mmol) and MS 4 A (250 mg) in dry THF (3.4 mL) was added a solution of
La(O-i-Pr)3 (0.125 mL, 0.025 mmol, 0.2 M solution in THF) at room temperature. After being stirred for 1 h at
the same temperature, TBHP (0.1 mL, 0.5 mmol, 5 M solution in decane) was added. After being stirred for 30
min, enone 7 (68.5 mg, 0.25 mmol) was added and the mixture was stirred at room temperature. After 5 h, the
reaction was quenched by addition of 2.5% aqueous critic acid (5 mL) at 0°C and extracted with ethyl acetate (3
10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. After
concentration in vacuo, the residue was purified by flash column chromatography (SiO2, hexane/ethyl acetate 4/1)
to give epoxyketone 6 (65.0 mg, 90%, 93% ee) as a white solid.
16. For representative examples of the catalytic asymmetric epoxidation of enones, see: (a) Corey, E. J.; Zhang, F.-Y.
Org. Lett. 1999, 1, 1287. (b) Yu, H. B.; Zheng, X. F.; Lin, Z. M.; Hu, Q. S.; Huang, W. S.; Pu, L. J. Org. Chem.
1999, 64, 8149. (c) Elston, C. L.; Jackson, R. F. W.; MacDonald, S. J. F.; Murray, P. J. Angew. Chem., Int. Ed.
Engl. 1997, 36, 410. (d) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 1725. (e) Julia´, S.;
Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl. 1980, 19, 929. For a review, see: Porter, M. J.; Skidmore,
J. Chem. Commun. 2000, 1215 and references cited therein.
17. Cappi, M. W.; Chen, W.-P.; Flood, R. W.; Liao, Y.-W.; Roberts, S. M.; Skidmore, J.; Smith, J. A.; Williamson,
N. M. Chem. Commun. 1998, 1159 and references cited therein.
18. Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1968, 90, 2686.
19. The enantiomeric excesses of 2 and 12 were confirmed by chiral stationary phase HPLC analysis.
.