A ring closing metathesis based approach for the spiroannulation of cyclopentanes and cyclohexanes. Formal synthesis of (±)-acorones

Article abstract of DOI:10.1055/s-2001-18743

An efficient ring closing metathesis (RCM) reaction based approach was developed for the spiroannulation of cyclopentanes and cyclohexanes and its utility demonstrated in the formal synthesis of the spirosesquiterpenes acorones.

Full text of DOI:10.1055/s-2001-18743

1986
SHORT PAPER
A Ring Closing Metathesis Based Approach for the Spiroannulation of
Cyclopentanes and Cyclohexanes. Formal Synthesis of ( )-Acorones
Formal Synthesis
of
(
)-Acoron
S
es rikrishna,* M. Srinivasa Rao, Santosh J. Gharpure, N. Chandrasekhar Babu
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Fax 91(80)3600683; E-mail: ask@orgchem.iisc.ernet.in
Received 17 September 2001; revised 18 October 2001
Scheme 1. Initially, the cyclic ketones 6a–f were trans-
Abstract: An efficient ring closing metathesis (RCM) reaction
based approach was developed for the spiroannulation of cyclopen-
tanes and cyclohexanes and its utility demonstrated in the formal
synthesis of the spirosesquiterpenes acorones.
formed into the allyl alcohols 7a–f via Horner-Wad-
sworth–Emmons reaction followed by reduction of the
resultant , -unsaturated esters with lithium aluminium
hydride (LAH). One pot Claisen rearrangement of the al-
lyl alcohols 7a–f with ethyl vinyl ether and mercuric ace-
tate furnished the aldehydes 5a–f.4 Reaction of the
aldehydes 5a–f with vinylmagnesium bromide in THF at
room temperature generated the hepta-1,6-dien-3-ols 8a–
f in 85–90% yield. The RCM reaction5 of the dienols 8a–
f in methylene chloride in the presence of 6–8 mol% of
Grubbs' catalyst for 6–8 h at room temperature furnished
the spiro compounds 9a–f in near quantitative yield. Oxi-
dation using pyridinium chlorochromate (PCC) and sodi-
um acetate in methylene chloride transformed the allyl
alcohols 9a–f into the spiroenones 10a–f (Scheme 1).
Key words: spiroannulation, spiro compounds, metathesis reac-
tion, Claisen rearrangement, acorones
The last decade has witnessed a dramatic growth in the ap-
plication of the olefin metathesis reaction in organic syn-
thesis. The substoichiometric nature of the reaction in
combination with the operational simplicity, remarkable
tolerance of Grubbs’ catalyst to various functional groups
and its stability to various conditions are key factors re-
sponsible for the increased utility of this reaction, particu-
larly the intramolecular version, i.e. the ring-closing
metathesis (RCM)1 reaction, using Grubbs’ catalyst
[PhCH=RuCl2(PCy3)2]. Spiro-fused cyclopentanes and
cyclohexanes2 are encountered in a variety of natural
products, but, even though a few examples of RCM reac-
tion generating heteroatom containing spirosystems have
been reported,1c its utility in the construction of carbocy-
clic spiro-systems has received little attention.3 Herein,
we wish to report a general methodology based on an ef-
ficient RCM reaction for the spiroannulation of cyclopen-
tanes and cyclohexanes, and its application in the formal
synthesis of the acorone spirosesquiterpenes.
CH2OH
a,b
c
O
CHO
6a-f
7a-f
5a-f
g
f
O
d
OH
OH
8a-f
9a-f
10a-f
5
e
i
h
OH
OH
O
11a-d
12a-d
13a-d
Scheme 1 Reagents,
conditions
and
yields:
(a)
(EtO)2P(O)CH2COOEt, NaH, reflux, 8 h, 92–98%;4 (b) LiAlH4, Et2O,
–70 °C, 2 h, 90-95%;4 (c) CH2=CHOEt, Hg(OAc)2, sealed tube,
180 °C, 60–65%;4 (d) CH2=CHMgBr, THF, r.t., 1 h, 82–90%; (e) Zn,
CH2=CHCH2Br, THF, sonication, 15 min, 84–88%; (f) 6–8 mol%
Grubbs' catalyst, CH2Cl2, r.t., 6 h; (g) PCC, NaOAc, CH2Cl2, r.t., 1 h.
(h) 6–8 mol% Grubbs' catalyst, C6H6, reflux, 16–18 h; (i) PCC,
CH2Cl2, 1 h.
(CH2)n
(CH2)n
CHO
3 n=0
4 n=1
1 n=0
2 n=1
5
Figure 1
It was considered that RCM reaction of the 1,6-hepta-
dienes 1 and 1,7-octadienes 2 would generate the spiro
compounds 3 and 4, respectively, while the aldehyde 5
could serve as a common precursor for the generation of
the dienes 1 and 2 (Figure 1). Synthesis of , -unsaturated
aldehydes 5, from the corresponding cyclic ketones 6, via
the Claisen rearrangement of the allyl alcohol 7, is well
established.4 The general methodology is depicted in
In a similar manner, sonochemically accelerated reaction
of the aldehydes 5a–d with zinc and allyl bromide in THF
furnished the octa-1,7-diene-4-ols 11a–d in 84–88%
yield. RCM reaction5 of the octadienols 11a–d with 6–8
mol% of Grubbs' catalyst in refluxing benzene for 16-18
h furnished the spiro compounds 12a–d in 84–90% yield.
PCC oxidation in methylene chloride transformed the al-
cohols 12a–d into the spiroenones 13a–d (Table). It is
worth noting that the RCM reaction of the octadienols
11a–d failed to proceed at room temperature. The results
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1986,1988,ftx,en;D21901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

SHORT PAPER
Formal Synthesis of ( )-Acorones
1987
are summarized in the table. The corresponding acetates
14b,c also underwent RCM reaction with Grubbs’catalyst
in refluxing benzene to furnish the spiroacetates 15b,c
(Scheme 2). After successfully demonstrating the meth-
odology, as an application, it has been extended to the for-
mal synthesis of the spiro sesquiterpenes acorones 16.
b
a
OAc
OH
OAc
11b,c
14b,c
15b,c
Scheme 2 Reagent, conditions and yields (a) Ac2O, py, DMAP,
CH2Cl2, r.t., 4 h; 90–92%; (b) 8 mol% Grubbs' catalyst, C6H6, reflux,
18 h, 84–86%.
Table Annulation Reactions
Starting ketone Yield in RCM Oxidation Annulated product
reaction
Sorm and coworkers reported the isolation of the spiroses-
quiterpenes acorone and isoacorone 16 from the oil of
sweet flag, Acorus calamus L, and established the pres-
ence of a novel spiro[4.5]decane carbon framework.6 Fur-
ther phytochemical investigations led to the
characterization of a number of acorane sesquiterpenes.6
The interesting spirocyclic carbon framework made ac-
oranes challenging synthetic targets,7 the most important
aspect in the synthesis of acoranes being the stereocon-
trolled construction of the spiro system. Based on the
methodology described above, a formal synthesis of acor-
ones 16, depicted in Scheme 2, was conceived starting
from cyclohexane-1,4-dione 17. Thus, selective Horner–
Wadsworth–Emmons reaction of the dione 17 generated
the ketoester 18. Two alternate strategies were explored.
In the first strategy, the ketone in 18 was protected as its
ethylene ketal to furnish the ketalester 19, which on regi-
oselective reduction with LAH furnished the allyl alcohol
20. One pot Claisen rearrangement of the allyl alcohol 20
with ethyl vinyl ether and propionic acid generated the al-
dehyde 21, which on reaction with vinylmagnesium bro-
mide furnished the dienol 22. The RCM reaction of the
dienol 22 in methylene chloride with 7 mol% of Grubbs'
catalyst at room temperature furnished the spiro alcohol
23, which on oxidation with PCC and NaOAc in methyl-
ene chloride generated the spiroenone 24. Conversion of
the spiroenone 24 into the spiroenone 25 via hydrolysis of
the ketal and selective Wittig reaction has already been re-
ported.7 In the second strategy it was envisaged that, in-
stead of the protection of the ketone in 18, Wittig
methylenation followed by spiroannulation would direct-
ly generate the spiroenone 25, thereby eliminating the
protection-deprotection protocol. Thus, reaction of the ke-
toester 18 in benzene with methylenetriphenylphospho-
rane at room temperature followed by regioselective
reduction of the resultant compound 26 with LAH fur-
nished the allyl alcohol 27. Claisen rearrangement fol-
lowed by addition of vinylmagnesium bromide to the
resultant aldehyde 28, transformed the allyl alcohol 27
into the dienol# 29. The RCM reaction of the dienol 29 in
methylene chloride with 7 mol% of Grubbs' catalyst at
room temperature furnished the spiro alcohol# 30, which
on oxidation with PCC and NaOAc in methylene chloride
generated directly the spiroenone# 25. Since the
spiroenone 25 has already been transformed into ( )-acor-
ones,7 the present sequence constitutes a formal synthesis
of the spirosesquiterpenes 16 (Scheme 3).
O
96%
98%
92%
92%
O
6a
6b
6c
10a
10b
O
O
O
97%
98%
95%
99%
92%
92%
90%
94%
( )3
( )3
O
O
10c
10d
10e
O
( )7
( )7
6d
6d
6e
O
O
O
( )2
( )2
O
6f
10f
13a
13b
O
87%
89%
89%
90%
85%
88%
86%
86%
O
6a
O
O
6b
O
O
( )3
( )3
O
O
6c
13c
13d
( )7
( )7
6d
Synlett 2001, No. 12, 1986–1988 ISSN 0936-5214 © Thieme Stuttgart · New York

1988
A. Srikrishna et al.
SHORT PAPER
O
COOEt
References
COOEt
a
b (for 19)
c (for 26)
(1) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013.
(c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18.
O
O
X
19 X = O(CH2)2O
26 X = CH2
17
18
(2) (a) Krapcho, A. P. Synthesis 1978, 77. (b) Martin, S. F.
Tetrahedron 1980, 36, 419. (c) Sannigrahi, M. Tetrahedron
1999, 55, 1007.
(3) (a) Kotha, S.; Manivannan, E.; Ganesh, T.; Sreenivasachary,
N.; Deb, A. Synlett 1999, 1618. (b) Bassindale, M. J.;
Hamley, P.; Leitner, A.; Harrity, J. P. A. Tetrahedron Lett.
1999, 40, 3247.
d
OH
CHO
e
CH2OH
f
X
X
X
(4) Srikrishna, A.; Reddy, T. J.; Kumar, P. P.; Vijaykumar, D.
Synlett 1996, 67.
22 X = O(CH2)2O
29 X = CH2
21 X = O(CH2)2O
28 X = CH2
20 X = O(CH2)2O
27 X = CH2
(5) Typical Procedure: The dienol (8 or 11, 0.2-0.3 mmol) was
added to a solution of Grubbs' catalyst (10–12 mg) in
methylene chloride (for 8) or benzene (for 11) and the
solution was stirred at room temperature for 6 h (for 8) or
refluxed for 16–18 h (for 11). Evaporation of the solvent
under reduced pressure and purification of the residue on a
silica gel column furnished the spiro compounds.
(6) (a) Sorm, F.; Herout, V. Collect. Czech. Chem. Commun.
1948, 13, 177. (b) Sorm, F.; Herout, V. Collect. Czech.
Chem. Commun. 1949, 14, 723. (c) Sykora, V.; Herout, V.;
Pliva, J.; Sorm, F. Collect. Czech. Chem. Commun. 1958, 23,
1072. (d) Tomita, B.; Isono, T.; Hirose, H. Tetrahedron Lett.
1970, 1371; and reference cited therein.
g
O
O
OH
h
X
X
O
23 X = O(CH2)2O
30 X = CH2
24 X = O(CH2)2O
16
25 X = CH2
Acorones
Scheme 3 Reagents,
conditions
and
yields:
(a)
(EtO)2P(O)CH2COOEt, NaH, 0 °C, 10 min, 92%; (b) (CH2OH)2, p-
TSA, C6H6, reflux, 10 h, 90%; (c) Ph3P=CH2, C6H6, r.t., 3 h, 75%; (d)
LiAlH4, Et2O, –70 °C, 2 h, 92%, 90%; (e) CH2=CHOEt, EtCOOH
(for 21) or Hg(OAc)2 (for 28), sealed tube, 175 °C, 61%, 60%; (f)
CH2=CHMgBr, THF, r.t., 1 h, 93%, 86%; (g) 7 mol% Grubbs' cata-
lyst, CH2Cl2, r.t., 5 h, 95%, 96%; (h) PCC, NaOAc, CH2Cl2, r.t., 1 h,
94%, 91%.
(7) For the earlier formal and total syntheses of acorones see:
Srikrishna, A.; Kumar, P. P. Tetrahedron 2000, 56, 8189;
and references cited therein.
(8) All the compounds exhibited spectral data consistent with
their structures. Selected spectral data for the alcohol 29:
IR(neat): max/cm–1 3406, 916, 885. 1H NMR (300 MHz,
CDCl3 +CCl4): 5.81 (1 H, dd, J 17.4 and 10.8 Hz), 5.90–
5.75 (1 H, m), 5.30–4.95 (4 H, m), 4.56 (2 H, s), 4.30–4.20
(1 H, m), 2.20–2.05 (4 H, m), 1.90–1.20 (7 H, m). 13C NMR
(75 MHz, CDCl3 +CCl4): 148.9 (C), 146.1 (CH), 142.3
(CH), 114.3 (CH2), 113.6 (CH2), 107.0 (CH2), 70.1 (CH),
48.4 (CH2), 39.5 (C), 38.0 (CH2), 36.6 (CH2), 31.0 (2 C,
CH2). For the spiroalcohol 30: IR(neat): max/cm–1 3346,
887. 1H NMR (300 MHz, CDCl3 +CCl4): 5.87 (1 H, d, J 6
Hz), 5.73 (1 H, dd, J 6 and 1.8 Hz), 4.90–4.80 (1 H, m), 4.60
(2 H, s), 2.26–2.10 (5 H, m), 1.70–1.20 (6 H, m). 13C NMR
(75 MHz, CDCl3 +CCl4): 148.2 (C), 143.3 (CH), 131.9
(CH), 107.5 (CH2), 76.9 (CH), 49.1 (C), 45.7 (CH2), 40.4
(CH2), 39.1 (CH2), 32.4 (CH2), 32.2 (CH2). For the
spiroenone 25: IR(neat): max/cm–1 1715, 890. 1H NMR (300
MHz, CDCl3 +CCl4): 7.48 (1 H, d, J 5.6 Hz), 6.06 (1 H, d,
J 5.6 Hz), 4.68 (2 H, s), 2.28 (2 H, s), 2.50–2.00 (4 H, m),
1.80–1.50 (4 H, m). 13C NMR (75 MHz, CDCl3 +CCl4):
209.2 (C), 171.6 (CH), 146.7 (C), 132.1 (CH), 108.6 (CH2),
46.3 (CH2), 45.8 (C), 37.9 (2 C, CH2), 32.1 (2 C, CH2).
In conclusion, we have developed a convenient and effi-
cient methodology based on the RCM reaction for the
spiroannulation of cyclopentanes and cyclohexanes start-
ing from cyclic ketones, which has the flexibility to be ex-
tended further to spiroannulation of other rings. The
overall efficiency of the methodology points to its high
potential in organic synthesis. As an illustration, the for-
mal synthesis of the spirosesquiterpenes acorones has
been accomplished, demonstrating the utility of the
present methodology in the natural product synthesis.
Acknowledgement
We thank the Council of Scientific and Industrial Research, New
Delhi for the award of research fellowships to SJG and NCB.
Synlett 2001, No. 12, 1986–1988 ISSN 0936-5214 © Thieme Stuttgart · New York