Conversion of optically active hydrindanone to (+)-bakkenolide-A

Article abstract of DOI:10.1248/cpb.56.1436

A total synthesis of (+)-bakkenolide-A was carried out via the key intermediate 4, which was prepared based on an asymmetric cyclization- carbonylation reaction established in our laboratory. Diastereoselective construction of the spirolactone moiety was achieved using Mitsuhashi's protocol as a key step.

Full text of DOI:10.1248/cpb.56.1436

1436
Chem. Pharm. Bull. 56(10) 1436—1437 (2008)
Vol. 56, No. 10
Conversion of Optically Active Hydrindanone to (ꢀ)-Bakkenolide-A
Taichi KUSAKABE, Keisuke KATO,* Satoshi MOTODATE, Satoshi TAKAISHI, and Hiroyuki AKITA*
Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan.
Received May 28, 2008; accepted July 22, 2008; published online July 29, 2008
A total synthesis of (ꢀ)-bakkenolide-A was carried out via the key intermediate 4, which was prepared
based on an asymmetric cyclization-carbonylation reaction established in our laboratory. Diastereoselective con-
struction of the spirolactone moiety was achieved using Mitsuhashi’s protocol as a key step.
Key words (ꢀ)-bakkenolide-A; hydrindanone; asymmetric cyclization-carbonylation
The bakkanes are an interesting class of sesquiterpenes
containing a cis-hydrindane skeleton decorated with two qua-
ternary centers and a spiro-b-methylene-g-lactone moiety.1)
Bakkenolide-A, which was first reported from the buds of the
Petasites japonicus,2—4) shows cytotoxicity toward several
carcinoma cell lines, and is an effective insect antifeedant.1)
Since the first synthesis of bakkenolide-A by Evans,5,6)
a
number of alternative syntheses have been described.1,7—10)
We previously reported the first examples of an asymmetric
cyclization-carbonylation of meso-2-alkyl-2-propargylcyclo-
hexane-1,3-diols11,12) and 2-alkyl-2-propargylcyclohexane-
1,3-diones13,14) catalyzed by palladium(II) with chiral bisoxa-
zoline (box) ligands. In addition, we recently reported a par-
allel kinetic resolution of racemic propargyl ketols 1 for a
formal synthesis of (ꢀ)-bakkenolide-A (Chart 1).15) These
three reactions are possible routes to the synthesis of the
same optically active hydrindanes. As an application of the
parallel kinetic resolution of racemic propargyl ketols 1,15)
we report the total synthesis of (ꢀ)-bakkenolide-A using
Mitsuhashi’s protocol16) for construction of the spirolactone
moiety.
Chart 1
Chart 2
We envisaged the chiral hydrindanone 4, which was ob-
tained by asymmetric cyclization-carbonylation reactions es-
tablished in our laboratory,15) as a potential precursor to (ꢀ)-
bakkenolide-A.17,18) Mitsuhashi and co-workers have synthe-
sized spirolactones from steroids.16) We applied the Mit-
suhashi’s method for the synthesis of (ꢀ)-bakkenolide-A.
(ꢀ)-Bakkenolide-A may be obtained from cyano diester 5
(Chart 2). In this case, the cyano group was to be introduced
from the convex face of diester 6,5,6) which may be prepared
by Knoevenagel reaction of the chiral hydrindanone 4.
Optically active hydrindanone 4 was obtained by the our
previously reported procedure based on asymmetric cycliza-
tion-carbonylation reaction (37% yield; 6 steps from 2), and
Chart 3
Knoevenagel reaction of 4 with diisopropyl malonate gave butylphosphine afforded the selenide,19) which was oxidized
diester 6 (Charts 2, 3). For construction of the spirolactone with hydrogen peroxide gave (ꢀ)-bakkenolide-A in 58%
moiety of (ꢀ)-bakkenolide-A, a quaternary cyano group was yield over four steps. The spectral data were found to be
introduced stereoselectively on the five-membered ring. The identical to those reported by Reddy9) and Naya.4)
shape of the molecule allowed control of the cyanide ap-
In conclusion, we carried out a total synthesis of (ꢀ)-
proach from the convex face, giving cyano diester 5 in 84% bakkenolide-A as an application of the asymmetric cycliza-
yield (two steps). The use of diethyl malonate resulted in a tion-carbonylation reactions established in our laboratory,
decreased yield of 7 due to partial decarboxylation.16) The using Mitsuhashi’s protocol for construction of spirolactone
stereochemistry of 5 was determined by conversion to (ꢀ)- moiety.
bakkenolide-A in a four-step sequence. Reduction of the
ester groups of 5 followed by lactonization furnished hydrox-
Experimental
General Experimental Methods All melting points were measured on
a Yanaco MP-3S micro melting point apparatus and are uncorrected. 1H- and
ymethyllactone 8 as a ca. 1 : 1 mixture of diastereomers.
Treatment of 8 with o-nitrophenyl selenocyanate and tri-n- 13C-NMR spectra were recorded on JEOL AL 400 and JEOL Lambda 500
∗ To whom correspondence should be addressed. e-mail: kkk@phar.toho-u.ac.jp
© 2008 Pharmaceutical Society of Japan

October 2008
1437
spectrometer in CDCl3 with Me4Si as an internal reference. High-resolution
mass spectra (HR-MS) and the fast atom bombardment mass spectra (FAB-
for C15H24O3 252.1726; Found 252.1720.
Synthesis of (ꢀ)-Bakkenolide-A To
a
solution of
8
(21.6 mg,
MS) were obtained with a JEOL GC mate II, a JMS-SX102 and a JEOL 0.086 mmol) in THF (4 ml) were added 2-nitrophenyl seleno cyanate (97 mg,
JMS 600 H spectrometers. IR spectra were recorded with a JASCO FT/IR- 0.43 mmol) and tributyl phosphine (86.6 mg, 0.43 mmol), and the mixture
300 spectrometer. All reagents were purchased from commercial sources was stirred at room temperature for 2 h. H2O2 (1.0 ml) was then added to the
and used without purification. All evaporations were performed under re- reaction mixture and stirring was continued at room temperature for 18 h.
duced pressure. For column chromatography, silica gel (Kieselgel 60) was The reaction mixture was quenched with sat. Na2SO3 aq. (10 ml) at 0 °C and
employed.
extracted with CHCl3 (15 ml). The organic layer was separated, the aqueous
layer was extracted with CHCl3 (15 ml), and the combined organic layers
were dried with MgSO4 and concentrated in vacuo. The residue was purified
by preparative TLC (hexane/EtOAcꢁ4/1) to afford (ꢀ)-bakkenolide-A
(13.4 mg, 67% yield).
Preparation of Cyano Diester 5 To a solution of 4 (70.8 mg,
0.43 mmol) in CH2Cl2 (3 ml) were added TiCl4 (242 mg, 1.28 mmol) in
CH2Cl2 (0.5 ml) and pyridine (202 mg, 2.56 mmol) in CH2Cl2 (0.5 ml) at
0 °C, and the mixture stirred for 12 h at room temperature. The reaction mix-
ture was then diluted with water (15 ml) and CH2Cl2 (15 ml). The organic
layer was separated, the aqueous layer was extracted with CH2Cl2 (30 ml),
(ꢀ)-Bakkenolide-A: [a]D20 ꢀ16.3 (cꢁ0.54, MeOH); 1H-NMR (CDCl3) d:
0.85 (3H, d, Jꢁ6.8 Hz), 0.99 (3H, s), 1.13—1.26 (1H, m), 1.45—1.61 (6H,
and the combined organic layers were dried with MgSO4 and concentrated in m), 1.94—1.99 (3H, m), 2.09 (1H, t, Jꢁ13.0 Hz), 2.25—2.29 (1H, m),
vacuo. To a solution of the crude product in DMF (3 ml) were added water 4.70—4.82 (2H, m), 5.03 (1H, m), 5.10 (1H, m); 13C-NMR (CDCl3) d: 16.3,
(1 ml), NH4Cl (46 mg, 0.86 mmol) and NaCN (63 mg, 1.29 mmol), and the
mixture stirred at 100 °C for 8 h. The reaction mixture was diluted with
19.1, 21.0, 23.3, 30.9, 33.9, 42.3, 44.0, 46.2, 48.5, 49.8, 70.3, 105.8, 150.4,
182.5; IR (KBr) 1772, 1669 cmꢂ1; HR-MS-EI m/z: [Mꢀ] Calcd for
water (15 ml) and AcOEt (15 ml). The organic layer was separated, the aque- C15H22O2 234.1620; Found 234.1615.
ous layer was extracted with AcOEt (15 ml), and the combined organic lay-
ers were dried with MgSO4 and concentrated in vacuo. The crude product
was chromatographed on silica gel (14 g, n-hexane/AcOEtꢁ30 : 1 to 20 : 1)
afforded (ꢀ)-5 (130 mg, 84% yield) as a white solid.
References
1) Silva L. F., Jr., Synthesis, 2001, 671—689 (2001).
2) Abe N., Onoda R., Shirahata K., Kato T., Woods M. C., Kitahara Y.,
Tetrahedron Lett., 9, 369—373 (1968).
3) Naya K., Takagi I., Hayashi M., Nakamura S., Kobayashi M., Kat-
sumura S., Chem. Ind., 1968, 318—320 (1968).
4) Naya K., Hayashi M., Takagi I., Nakamura S., Kobayashi M., Bull.
Chem. Soc. Jpn., 45, 3673—3685 (1972).
5) Evans D. A., Sims C. L., Tetrahedron Lett., 14, 4691—4694 (1973).
6) Evans D. A., Sims C. L., Andrews G. C., J. Am. Chem. Soc., 99,
5453—5461 (1977).
(ꢀ)-5: White solid, mp 90—92 °C (hexane), [a]D22 ꢀ15.7 (cꢁ0.37,
1
CHCl3); H-NMR (CDCl3) d: 0.77 (3H, d, Jꢁ6.7 Hz), 1.00 (3H, s), 1.05—
1.16 (1H, m), 1.29 (12H, d, Jꢁ6.3 Hz), 1.28—1.64 (6H, m), 2.01—2.18
(5H, m), 3.35 (1H, s), 5.10—5.14 (2H, m); 13C-NMR (CDCl3) d: 16.2, 20.2,
21.3, 21.5, 21.5, 21.6, 21.6, 23.5, 30.7, 36.2, 40.3, 40.6, 42.9, 45.6, 50.5,
60.5, 69.9, 69.9, 124.1, 165.8, 165.9; IR (KBr) 2236, 1722 cmꢂ1; HR-MS-EI
m/z: [Mꢀ] Calcd for C21H33NO4 363.2410; Found 363.2406.
(ꢃ)-7 was obtained from preliminary experiments using racemic sub-
strate.
7) Srikrishna A., Reddy T. J., Nagaraju S., Sattigeri J. A., Tetrahedron
Lett., 35, 7841—7844 (1994).
1
(ꢃ)-7: Colorless oil, H-NMR (CDCl3) d: 0.78 (3H, d, Jꢁ6.7 Hz), 1.01
(3H, s), 1.26—1.33 ( 3H, m), 1.31 (3H, t, Jꢁ7.2 Hz), 1.31 (3H, t, Jꢁ7.2 Hz),
1.39—1.52 (2H, m), 1.61—1.62 (2H, m), 2.02—2.19 (5H, m), 3.43 (1H, s),
4.25—4.29 (4H, m) ; 13C-NMR (CDCl3) d: 14.0, 16.2, 20.2, 21.3, 23.5,
30.7, 36.3, 40.4, 40.6, 43.0, 45.7, 50.4, 60.1, 62.1, 124.1, 166.3, 166.4; IR
(neat) 2929, 2239, 1731 cmꢂ1; HR-MS-EI m/z: [Mꢀ] Calcd for C19H29NO4
335.2097; Found 335.2097.
8) Brocksom T. J., Coelho F., Depres J.-P., Green A. G., Freire de Lima
M. E., Hamelin O., Hartmann B., Kanazawa A. M., Wang Y., J. Am.
Chem. Soc., 124, 15313—15325 (2002).
9) Reddy D. S., Org. Lett., 6, 3345—3347 (2004).
10) Jiang C.-H., Bhattacharyya A., Sha C.-K., Org. Lett., 9, 3241—3243
(2007).
Synthesis of Hydroxymethyllactone 8 To a solution of (ꢀ)-5 (20.9 mg,
0.06 mmol) in THF (2 ml) was added LiBH4 (13.1 mg, 0.60 mmol), and the
mixture was stirred at 50 °C for 5 h. The mixture was cooled to room tem-
perature, quenched with 10% HCl (1.5 ml) and then stirred at 60 °C for 4 h.
The reaction mixture was then diluted with water (10 ml) and extracted with
11) Kato K., Tanaka M., Yamamoto Y., Akita H., Tetrahedron Lett., 43,
1511—1513 (2002).
12) Kato K., Matsuba C., Kusakabe T., Takayama H., Yamamura S.,
Mochida T., Akita H., Peganova T. A., Vologdin N. V., Gusev O. V.,
Tetrahedron, 62, 9988—9999 (2006).
CHCl3 (15 ml). The organic layer was separated, the aqueous layer was ex- 13) Kato K., Tanaka M., Yamamura S., Yamamoto Y., Akita H., Tetrahe-
tracted with CHCl3 (15 ml), and the combined organic layers were dried with dron Lett., 44, 3089—3092 (2003).
MgSO4 and concentrated in vacuo. The residue was purified by column 14) Kusakabe T., Kato K., Takaishi S., Yamamura S., Mochida T., Akita
chromatography on silica gel (3.5 g). The fraction eluted with hexane/ace-
tone (8/1) afforded 8 (12.6 mg, 87% yield) as a 1 : 1 mixture of diastere-
omers.
H., Peganova T. A., Vologdin N. V., Gusev O. V., Tetrahedron, 64,
319—327 (2008).
15) Kato K., Motodate S., Takaishi S., Kusakabe T., Akita H., Tetrahedron,
64, 4627—4636 (2008).
8: White solid; mp 102—104 °C (Et2O), 1H-NMR (CDCl3) (mixture of di-
astereomers, ratioꢁ1 : 1) d: 0.82 (1.5H, d, Jꢁ6.7 Hz), 0.83 (1.5H, d, 16) Kano K., Hayashi K., Mitsuhashi H., Chem. Pharm. Bull., 30, 1198—
Jꢁ6.7 Hz), 0.94 (1.5H, s), 0.97 (1.5H, s), 1.13—2.37 (13H, m), 2.33—2.37
(1H, m), 3.57—3.65 (1H, m), 3.80—3.85 (1H, m), 4.29—4.34 (2H, m); 13C-
NMR (CDCl3) (mixture of diastereomers, ratioꢁ1 : 1) d: 16.3, 16.6, 19.0,
19.2, 20.9, 20.9, 23.2, 23.5, 30.7, 30.7, 32.1, 33.7, 34.1, 40.7, 41.4, 43.6,
1203 (1982).
17) Srikrishna A., Reddy T. J., Tetrahedron, 54, 11517—11524 (1998).
18) Greene A. E., Coelho F., Depres J. P., Brocksom T. J., Tetrahedron
Lett., 29, 5661—5662 (1988).
43.9, 44.9, 45.7, 47.9, 48.1, 48.6, 49.3, 49.8, 61.1, 62.0, 68.4, 68.7, 183.2, 19) Grieco P. A., Gilman S., Nishizawa M., J. Org. Chem., 41, 1485—
183.6 (15Cꢄ2); IR (KBr) 3432, 1732 cmꢂ1; HR-MS-EI m/z: [Mꢀ] Calcd
1486 (1976).