A short enantioselective synthetic route to (+)-cassiol

Article abstract of DOI:10.1055/s-1998-1605

A formal total synthesis of (+)-cassiol (2) from ethyl α-methylpropionylacetate (3) was achieved through the application of asymmetric Michael reaction.

Full text of DOI:10.1055/s-1998-1605

February 1998
SYNLETT
129
A Short Enantioselective Synthetic Route to (+)-Cassiol
*
Soumen Maiti, Basudeb Achari and Asish K Banerjee
Department of Medicinal Chemistry, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Calcutta- 700 032, India
Fax 91-33-4730284/4735197; Email : IICHBIO@GIASCIL01.VSNL.NET.IN
Received 17 October 1997
2
Abstract : A formal total synthesis of (+)-cassiol ( ) from ethyl α-
(Scheme). This was subjected to Michael reaction with acrolein and the
product hydrolyzed to obtain the Michael product as an oil. The crude
product was directly cyclized using pyrrolidine-acetic acid, affording
3
methylpropionylacetate ( ) was achieved through the application of
asymmetric Michael reaction.
25
7,8
5
(+)- , [α]
+ 76.75° (c 2.085, CHCl ), in 49% yield. Repeating the
3
D
same reaction with (R)-(+)-α-methylbenzylamine under identical
Chinese cinnamon has long been used in the traditional Chinese
medicine as a diaphoretic, an antipyretic, and an analgesic. An aqueous
extract from Cinnamomi cortex (the dried stem bark of Cinnamomi
25
5
conditions yielded (-)- , [α]
- 76.18° ( c 2.494, CHCl ). Lithium
3
D
5
aluminium hydride reduction of the carbonyl groups of (+)- and
subsequent oxidation of the unsaturated alcohol with MnO afforded the
1
2
cassia Blumme) was reported to have potent antiulcerogenic activity.
25
6
keto-alcohol (-)- , [α]
- 21.86° (c 1.07, MeOH), in 92% overall
yield. Silylation of the primary hydroxyl group of gave , [α]
D
1
The active principle proved to be cassioside ( ), the aglycone [(+)-
25
6
7
2
D
2
cassiol, ] of which inhibited ulceration more strongly.
3a
24
-22.75° ( c 1.65, MeOH ) [ Lit. [α]
-23.6° (c 1.80, MeOH)],
D
3
2
To date, a number of syntheses of (+)- have been recorded. We were
previously obtained in twelve steps from (S)-(-)-methyl 3-(1’-methyl-
2
attracted by the possibility of synthesising (+)- through the chiral
3a
2
2’-oxocyclohexyl)propionate and converted to (+)- in three steps.
5
cyclohexenone intermediate (+)- derivable in turn by the condensation
The present work therefore constitutes a formal total synthesis of (+)-
cassiol.
4
of acrolein with the chiral enamine of an acyclic β-ketoester; similar
reaction of electron deficient olefins with chiral imines and enamines
The scope of this simple and efficient enantioselective synthetic route
based upon acyclic ketone derivatives is being explored further.
derived from cyclic ketones and commercially available S- or R-α-
4,5
methyl benzylamine has been reported to proceed with remarkable π-
facial stereoselectivity and extensively utilized in the synthesis of
4
ACKNOWLEDGEMENT
various natural polycyclic systems incorporating quaternary centres.
: We are grateful to DST, New Delhi for
We report herein a successful implementation of this strategy, leading to
financial support ( Grant No. SP/Sl/G-41/93 to AKB ) and Prof. U. R.
Ghatak (IICB, Calcutta) for his valuable suggestions and criticism.
7
the synthesis of the key intermediate (-)- , representing a formal total
2
synthesis of (+)- .
3
Thus, ethyl α-methylpropionylacetate ( ) was condensed with (S)-(-)-α-
References and Notes
6
4
methylbenzylamine to give the chiral enamine
in 92% yield
1984
1.
2.
3.
Tanaka, S.; Akira, T.; Tabata, M. Yakugaku Zasshi
601-606; Tanaka, S.; Akira, T.; Tabata, M. Planta Medica
440-443.
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Shiraga, Y.; Okano, K.; Akira, T.; Fukaya, C.; Yokoyama, K.;
Tanaka, S.; Fukui, H.; Tabata, M. Tetrahedron
4711.
1988
, 44, 4703-
a) Takemoto, Y.; Fukaya, C.; Yokoyama, K. Tetrahedron Lett.
1989
, 30, 723-724. b) Uno, T.; Watanabe, H.; Mori, K.
1990
, 46, 5563-5566. c) Corey, E. J.; Guzman-
Tetrahedron,
1994
Perez, A.; Loh, T.-P. J. Am. Chem. Soc., , 116, 3611-3612. d)
Irie, O.; Fujiwara. Y.; Nemeto, H.; Shishido, K. Tetrahedron Lett.,
1996
, 37, 9229-9232. e) Taber, D. F.; Meagley, R. P.; Doren, D. J.
1996
, 61, 5723-5728. f) Trost, B. M.; Li, Y. J. Am.
J. Org. Chem.
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4.
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Cave, C.; Desmaele, D.; d’ Angelo, J. J. Org. Chem.
4361-4368 and references cited therein.
1997
, 119, 826-827
Lucero, M. J.; Houk, K. N. J. Am. Chem. Soc.
and references cited therein.
4
Preparation of the chiral enamine : To a solution of ethyl α-
3
methylpropionylacetate ( ) (15.8 g, 0.1 mole ) in dry benzene (50
ml) was added (S)-(-)-α-methylbenzylamine (12.12 g, 0.1 mole)
and a catalytic amount of p-toluenesulphonic acid. The reaction
mixture was stirred at room temp. for 8 hr under N and then
2
refluxed 14 hr using Dean-Stark apparatus. The solvent was
removed and the product distilled under reduced pressure to yield
4
as pale yellow oil (24g, 92%; b.p. 145-150°C/0.3mm). I.R.(neat)
-1
1
: 3244, 1644, 1598, 1247, 1118, 775 and 697 cm ; H NMR (100
MHz, CDCl ) : δ 0.94 (3H, t, J 8 Hz), 1.30 (3H, t, J 7.5 Hz), 1.50
3
(3H, d, J 8 Hz), 1.80 (3H, s, vinyl methyl), 2.04-2.42 (2H, m),
4.17 (2H, q, J 7.5 Hz), 4.54 (2H, quintet, J 7 Hz), 7.30 (5H, br s),

130
LETTERS
SYNLETT
and 9.64 (1H, br d, J 7 Hz, chelated NH) [ cf Felk, A.; Revial, G.;
Viossat, B.; Lemoini, P.; Pfau, M. Tetrahedron:Asymmetry 1994,
5, 1459-1462].
afford a red liquid. Chromatography over silica gel and elution
with 5-10% ethyl actate-petrol yielded (+)-5 (8.5g, 49%; b.p. 85-
88°C/0.3mm) as a colourless oil. I.R.(neat) : 1727, 1679, 1249 and
-1
1
1177 cm ; H NMR (100 MHz, CDCl ) : δ 1.24 (3H, t, J 6 Hz),
7.
Preparation of (+)-5 from 4 : To a stirred solution of 4 (23g, 88
mmol) in benzene (100 ml) at 10°C was added freshly distilled
acrolein (5.56g, 99 mmol) and a catalytic amount of hydroquinone
3
1.36 (3H, s), 1.72-2.04 (1H, m), 1.82 (3H, d, J 2 Hz), 2.24-2.68
13
(3H, m), 4.16 (2H, q, J 7 Hz) and 6.64 (1H, m). C NMR (25
MHz, CDCl ) : δ 197.2 (s), 172.7 (s), 143.6 (t), 134.6 (s), 60.9 (t),
53.1 (s), 33.5 (t), 23.2 (t), 20.1 (q), 16.2 (q), and 13.8 (q).
under N . The mixture was stirred at 10°C for 10 hr and at room
3
2
temp for further a 72 hr. It was cooled, treated with a mixture of
acetic acid (8 ml) and water (5 ml), and stirred 3 hr at room temp.
The organic layer was separated, the aqueous layer extracted with
ether (3× 50 ml), the combined organic extract washed, dried, and
the solvent evaporated. The crude Michael product, a red oil, was
taken in ethanol (100 ml) and treated with pyrrolidine (5 ml) and
33% acetic acid (9 ml). The mixture was refluxed with stirring for
8.
9.
The optical purities of (+)-5 and (-)-5 were determined by their
chemical transformation to the respective enol acetates, (-)-8
25
25
([α]
- 52.34°, c 4.51, CHCl , > 96% o.p.) and (+)-8 ([α]
3 D
D
+ 52.2°, c 2.30, CHCl , > 96% o.p.), through hydrogenation
3
followed by treatment with acetic anhydride-perchloric acid. The
o.p.’s were determined by comparing the [α] value with that
D
9
27
8 hr under N . Ethanol was removed and the residue partitioned
reported for (+)-8 ([α]
+ 54.2°, c 3.38, CHCl , > 99% ee).
3
2
D
between ether (200 ml) and water (100 ml). The aqueous layer
was separated and further extracted with ether (2× 50 ml). The
combined organic layer was washed, dried, and concentrated to
Sugai, T.; Kakeya, H.; Ohta, H.; Morooka, M.; Ohba, S.
Tetrahedron 1989, 45, 6135-6144.