'One-pot' reactions: Total synthesis of the spirocyclic marine sesquiterpene, (+)-axenol

Article abstract of DOI:10.1055/s-2002-34211

The marine sesquiterpene alcohol (+) axenol was prepared in a very short way from (+)-menthone using a one-pot olefination-ring closing metathesis.

Full text of DOI:10.1055/s-2002-34211

1712
LETTER
‘One-pot’ Reactions: Total Synthesis of the Spirocyclic Marine Sesquiterpene,
(+)-Axenol
Total
S
ynthesis of
a
the Spirocy
i
clic
M
arine
S
O
esquiterpene, (+)-
e
A
xenol sterreich, Iris Klein, Dietrich Spitzner*
Institut für Chemie, Abt. Bioorganische Chemie, Universität Hohenheim, Garbenstr. 30 70599 Stuttgart, Germany
Fax +49(711)4593703; E-mail: spitzner@uni-hohenheim.de
Received 19 June 2002
Dedicated to Professor Dr. Dr. h. c. Ekkehard Winterfeldt on the occasion of his 70th birthday.
(+)-menthone and methyl vinyl ketone by Michael ad-
Abstract: The marine sesquiterpene alcohol (+) axenol was pre-
pared in a very short way from (+)-menthone using a one-pot olefi-
nation-ring closing metathesis.
dition.9,10 Adduct 2a was subjected to a methylenation
reaction followed by a ring closing metathesis. The
successful formation of the olefins from the corres-
ponding carbonyl compounds using the Kauffmann
Key words: domino reaction, methylenation, metathesis, organo-
metallic, natural products
methylenation
reaction
with
Mo
complex
(THF)2Cl(O)Mo(CH2)2Mo(O)Cl(THF)2 (5)11 and the
efficiency of the new generation of Grubbs-catalyst
{[MesIm][(Cy)3P]RuCl2CHPh} (6).12
‘One-pot’ synthesis or domino reactions have been used
to increase the synthetic efficiency of complex natural
products,1,2 while the olefin metathesis is regarded as a
very important carbon-carbon forming reaction in organic
synthesis. Presently the commercially available catalysts
for the metathesis are poisoned by phosphines or phos-
phine oxides generated in the reactions.3 Hence, for the
above stated facts olefins made by the Wittig reaction
have to be carefully cleaned up prior to the metathesis re-
action.4 Therefore olefination and metathesis are not eas-
ily combined in a ‘one-pot’ domino reaction. Only the
Tebbe reaction may be used in this context.5 In the present
study we report on a new organometallic domino reaction
involving a methylenation reaction followed by a ring
closing olefin metathesis. This sequence was used for the
synthesis of the marine natural product (+)-axenol [(+)-1]
possessing a spiro[5.4]decane skeleton (spiroaxane).6
This and similar compounds (with the opposite absolute
stereochemistry) have been isolated from different marine
organisms.7 These compounds are of biological signifi-
cance for example they are important in defense or com-
munication of some marine organisms.8
The Kauffmann complex was conveniently generated in
situ from the thermally stable MoOCl3(THF)2 with two
molar equivalents of methyl lithium in THF at –80 °C un-
der argon.
We applied 1.5 equivalents of the methylenation com-
plex per carbonyl group and observed that (Scheme 2):
(1) Only two of the carbonyls of the keto-aldehyde 2a
were selectively methylenated to give the intermediate di-
olefin 2b. (2) The di-olefin 2b was then directly cyclized
using catalyst 6 to produce the isomeric spirocyclic ke-
tones 3 and 4 at room temperature.13
Separation of ketones 3 and 4 was performed on silica gel
impregnated with AgNO3 (10%) and dichloromethane as
eluent.14 Finally, reduction of ketone 3 with LiBH(s-Bu)3
in THF gave the natural product (+)-axenol [(+)-1], whose
NMR spectra were identical with those reported for the
natural product.15
Acknowledgement
The retro-synthesis (Scheme 1) of the spiroaxane 1 leads
to compound 2a which was previously prepared from
We thank Dr. F. Wolf, Haarmann & Reimer GmbH, Holzminden,
Germany, for a generous gift of chemicals.
X
X
2a
Y
Y
OH
A
B
(+)-1
Scheme 1
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1712,1714,ftx,en;G16902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Total Synthesis of the Spirocyclic Marine Sesquiterpene, (+)-Axenol
1713
(10) (a) We considered the McMurry coupling (17 equiv TiCl3/35
equiv C8K, DME, 85 °C) for the spiro ring closure which
would have led directly to the spiro ketone 3 (and 4) but we
could not detect the formation of these products by GC-MS
analysis. (b) Clive, D. L. J.; Zhang, C.; Keshava Murthy, K.
S.; Hayward, W. D.; Daigneault, S. J. Org. Chem. 1991, 56,
6447.
O
R
2
+
R
O
(11) (a) Kauffmann, T.; Baune, J.; Fiegenbaum, P.;
Hansmersmann, U.; Neiteler, C.; Papenberg, M.;
2a; R = O
2b; R = CH2
HO
O
Wieschollek, R. Chem. Ber. 1993, 126, 89. (b) Kauffmann,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1258; Angew.
Chem. 1997, 109, 1312.
(a),(b)
(12) (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 3783. (b) Fürstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3012; Angew. Chem. 2000,
112, 3140.
1
(13) Domino reaction: To a stirring solution of 5.01 g (13.8
mmol) MoOCl3(THF)2(5) in THF (30 mL) under Ar at
–80 °C was added 15.8 mL of a solution of 1.6 M MeLi in
diethyl ether. Stirring was continued at –80 °C for 10 min
after which a solution of 1.07 g (4.2 mmol) of the ketone 2a
(2:1) in THF (5 mL) was added slowly using a syringe. The
reaction mixture was slowly warmed to r.t. over night. To the
brown reaction mixture was added 179 mg (0.2 mmol) of the
catalyst {[MesIm][(Cy)3P]RuCl2CHPh}(6) and stirring was
continued at r.t. for additional 24 h (monitoring by GC). The
reaction mixture was diluted with petrol ether/diethyl ether,
(10 + 1) and the suspension filtered through silica gel. The
concentrated filtrate was distilled. Kugelrohr (110–120 °C/
0.06 Torr); yield (3 + 4, as 2:1-mixture): 0.510 g (60%),
colorless oil. The mixture was chromatographed on silica
gel/10% AgNO3, eluent CH2Cl2. IR (Film): = 2956, 2930,
2955, 2870 (CH), 1704 (C=O), 1652 (C=C), 1460, 1376,
1130 cm–1. C15H24O: HRMS: Calcd 220.1827. Found:
220.1821.
6
O
OH
(+)-1
3
O
4
Scheme 2 Reagents: (a) (THF)2Cl(O)Mo(CH2)2Mo(O)Cl(THF)2
(5), THF, –80 °C to 23 °C; (b) {[MesIm][(Cy)3P]RuCl2CHPh} (6), 5
mol%, 24 h, 23 °C, 60%; (c) L-Selectride, THF, 23 °C, 6 h, pyridine-
1-oxide, 84%.
3: 1H NMR (CDCl3): = 0.89 (d, J = 8.4 Hz, 3 H, CH3), 0.92
(d, J = 6.6 Hz, 6 H, CH3), 1.37 (ddd, J = 12.8 Hz, J = 12.8
Hz, J = 3.8 Hz, 1 H, 8-H), 1.50–1.75 (m, 4 H, 10-H, 9-H,
4-H), 1.75 (br s, 3 H, allylic-CH3), 2.05–2.40 [m, 5 H, 3-H,
8-H, 7-H, CH(CH3)2], 2.84 (ddd, J = 13.4 Hz, J = 9.4 Hz,
J = 5.2 Hz, 1 H, 4-H), 5.35 (s, 1 H, 1-H). 13C NMR (CDCl3):
= 16.9 (q, CH3), 17.2 (q, CH3), 19.0 (q, CH3), 21.7 (q,
CH3), 26.5 [d, CH(CH3)2], 28.4 (t, C-4), 28.8 (t, C-8), 32.0
(t, C-9), 36.3 (t, C-3), 43.8 (d, C-10), 53.6 (d, C-7), 69.9 (s,
C-5), 123.3 (d, C-1), 145.1 (s, C-2), 212.8 (s, CO). GC-EI-
MS: m/z (%) = 220 (25) [M+], 192 (14) 149 (12), 121 (100),
108 (62). CD (methanol): max( / ) = 296 nm
References
(1) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(2) Nicolaou, K. C. Aktuelle Entwicklungen in der
Naturstofforschung; 14. Irseer Naturstofftage der
DECHEMA e.V.: Irsee, 2002.
(3) (a) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202.
(b) Improved catalysts see also: Aeilts, S. L.; Cefalo, D. R.;
Bonitatebus, P. J. Jr.; Houser, J. H.; Hoveyda, A. H.;
Schrock, R. R. Angew. Chem. 2001, 113, 1500.
(4) Oesterreich, K.; Spitzner, D. Tetrahedron 2002, 58, 4331.
(5) (a) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J.
Am. Chem. Soc. 1996, 118, 1565. (b) Nicolaou, K. C.;
Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc.
1996, 118, 10335.
(6) For alternative syntheses of this class of compounds:
(a) Caine, D.; Deutsch, H. J. Am. Chem. Soc. 1978, 100,
8030. (b) Ohira, S.; Yoshihara, N.; Hasegawa, T. Chem.
Lett. 1998, 739.
(+4.56 103/+1.38).
4: 1H NMR (CDCl3): = 0.86–0.91 (3 d, 9 H, 3 Me), 1.54–
1.6 (m, 1 H), 1.61–1.68 (m, 1 H), 1.76 (d, J = 1.1 Hz, 3 H,
allyl. CH3), 1.84–1.91 (m, 1 H), 1.96–2.07 (m, 3 H), 2.08–
2.15 (m, 2 H), 2.16–2.24 (m, 2 H), 2.25–2.34 (1 H), 5.50 (s,
1 H, 1-H). 13C NMR (CDCl3): = 15.9 (q), 16.8 (q), 19.1 (q),
21.3 (q), 24.6 (t, C-8), 26.1 (d, C-10), 29.2 (t, C-4), 34.5 (t,
C-9), 35.5 (t, C-3), 41.4 [d, CH(CH3)2] 53.9 (d, C-7), 68.0 (s,
C-5), 126.4 (d, C-1), 141.3 (s, C-2), 215.7 (s, CO). GC-EI-
MS: m/z (%) = 220 (20) [M+], 192 (10) 149 (10), 121 (100),
108 (60). CD (methanol): max( / ) = 296 nm (–
3.48 103/–1.05).
(7) Chang, C. W. J. Prog. Chem. Org. Nat. Prod. 2000, 80, 1.
(8) Wright, A. D.; Wang, H.; Gurrath, M.; König, G. M.; Kocak,
G.; Neumann, G.; Loria, P.; Foley, M.; Tilley, L. J. Med.
Chem. 2001, 44, 873.
(+)-1: A solution of 88 mg (0.4 mmol) of ketone 3 in THF
(10 mL) at r.t. was added 2 mL (2 mmol) of L-Selectride
[1.0 M LiBH(s-Bu)3 in THF] with stirring. Stirring was
continued over night. After this time 0.5 g of solid pyridine-
1-oxide was added and stirring was continued for another
1 h. The solution was concentrated and the remaining oil
dissolved in diethyl ether (50 mL), the etheral solution
washed with 2 N HCl (15 mL), water (3 10 mL), dried
(9) (a) Corey, E. J.; Nozoe, S. J. Am. Chem. Soc. 1965, 87,
5728. (b) Triketon 2a was used as a 2:1 mixture of
diastereomers, which could not be separated. The desired
(2R)-diastereomer is the major isomer in the mixture.
Synlett 2002, No. 10, 1712–1714 ISSN 0936-5214 © Thieme Stuttgart · New York

1714
K. Oesterreich et al.
LETTER
(MgSO4), concentrated, and the residue purified on silica gel
(petroleum ether/diethyl ether, 10 +1). Yield 75 mg (84%).
IR(film): = 3470 (OH), 2950 (CH) cm–1. 1H NMR
(CDCl3): = 16.2 (q, CH3), 16.9 (q, allylic-CH3), 20.7 and
21.2 [q, CH(CH3)2], 24.4 (t, C-8), 29.3 [d, CH(CH3)2], 31.7
(t, C-4), 33.9 (t, C-9), 34.0 (d, C-10), 36.3 (t, C-3), 45.3 (d,
C-7), 58.9 (s, C-5), 76.4 (d, C-6), 125.5 (d, C-1), 142.8 (s,
C-2). GC-MS (70 eV): m/z (%) = 222 (70), 204 (20), 121
(100). [ ]D25 +23 (c 0.6, CHCl3). [Lit.15: +1.3 (c 0.6, CHCl3,
589 nm); lit.5b: [ ]D32 –17 (c 0.5, CHCl3) for (–)-1].
(CDCl3): = 0.73 (d, J = 6.7 Hz, 3 H, CH3), 0.92 [d, J = 6.6
Hz, 3 H, CH(CH)3], 0.93 [d, J = 6.6 Hz, 3 H, CH(CH)3], 1.05
(dddd, J = 3.7 Hz, J = 12.8 Hz, J = 12.8 Hz, J = 12.8 Hz, 1
H, 9-H), 1.15 (m, 1 H, 7-H), 1.26 (dddd, J = 3.7 Hz, J = 12.8
Hz, J = 12.8 Hz, J = 12.8 Hz, 1 H, 8-H), 1.45 (m, 1 H, 9-H),
1.55 [m, 1 H, CH(CH3)2], 1.65 (m, 1 H, 8-H), 1.70 (m, 1 H,
10-H), 1.75 (q, J = 1.5 Hz, 3 H, allylic-CH3), 1.78 (ddd,
J = 12.5 Hz, J = 8.0, J = 8.0 Hz, 1 H, 4-H), 1.88 (ddd,
J = 12.5 Hz, J = 8.0, J = 8.0 Hz, 1 H, 4-H), 2.21 (m, 2 H,
3-H), 3.52 (br s, 1 H, 6-H), 5.18 (m, 1 H, 1-H). 13C NMR
(14) Williams, C. M.; Mander, L. N. Tetrahedron 2001, 57, 425.
(15) (a) Barrow, C. J.; Blunt, J. W.; Munro, M. H. G. Aust. J.
Chem. 1988, 41, 1755. (b) We are indebted to Professor J.
W. Blunt, Univ. of Canterbury, New Zealand, for providing
the 1H and 13C NMR spectra of (+)-1.
Synlett 2002, No. 10, 1712–1714 ISSN 0936-5214 © Thieme Stuttgart · New York