Carbanion cyclisation of esters. Part 2: Enantiospecific construction of the tricyclic framework of the marine sesquiterpenes, spirodysins

Article abstract of DOI:10.1016/j.tetlet.2003.10.165

Enantiospecific construction of the bicyclo[4.3.0]nonan-8-one 17 employing a lithium and liquid ammonia mediated carbanion cyclisation of the δ-methyl-δ,ε-unsaturated ester 13, and its elaboration to the tricyclic framework of the marine sesquiterpenes sp

Full text of DOI:10.1016/j.tetlet.2003.10.165

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 383–386
Carbanion cyclisation of esters. Part 2: Enantiospecific
construction of the tricyclic framework of the marine
sesquiterpenes, spirodysinsq
A. Srikrishna,* P. Ravi Kumar and S. S. V. Ramasastry
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 10 September 2003; revised 17October 2003; accepted 24 October 2003
Abstract—Enantiospecific construction of the bicyclo[4.3.0]nonan-8-one 17 employing a lithium and liquid ammonia mediated
carbanion cyclisation of the d-methyl-d,e-unsaturated ester 13, and its elaboration to the tricyclic framework of the marine ses-
quiterpenes spirodysins are described.
ꢀ 2003 Elsevier Ltd. All rights reserved.
The marine sponge Dysidea herbacia is a prolific pro-
ducer of structurally diverse secondary metabolites
including sesquiterpene spirolactol/lactones, tricyclic
furans (some based on the furodysin and furodysinin
skeletons and their oxidised derivatives), modified
steroids, polychlorinated alkaloids, brominated diphenyl
ethers and other metabolites.2 The spirodysins are a
small group of sesquiterpenes isolated from D.herbacia ,
contain a furan spirofused to a bicyclo[4.3.0]nonane,
and are probably the biogenetic precursors of furodysins
and furodysinins. The isolation of the first members of
this group spirodysin 1 and herbadysidolide 2 was
reported by the research groups of Wells3a and Charles.3b
A few other derivatives of spirodysins were isolated later
from sponges collected at different geographical regions.
Structures of various spirodysins isolated so far are
depicted in Chart 1. The tricyclic framework in spirody-
sins made them interesting synthetic targets.4 We have
developed a methodology for the enantiospecific con-
struction of the tricyclic framework present in spiro-
dysins based on a carbanion cyclisation of esters, which
is the subject of this communication.
O
H
O
H
H
H
H
H
H
OAc
O
O
O
O
Dysetherin3c
Spirodysin3a 1
Herbadysidolide3b 2
O
H
OMe
OMe
O
H
H
O
O
H
H
H
14-Methoxy-14-deacetoxy-
12,13-Dihydro-14-methoxy-
Dehydro-
spirodysin3d
H
14-deacetoxyspirodysin3d
herbadysidolide3e
H
O
O
H
H
Furodysin
Furodysinin
Chart 1.
Me
Li /
liq. NH3
OH
ð1Þ
COOMe
In the preceding communication1 we have reported a
facile lithium in liquid ammonia mediated 5-exo-trig
reductive cyclisation of d,e-unsaturated esters (Eq. 1)
and demonstrated its utility in the annulation of a
variety of fused, spiro and bridged cyclopentanes. In
order to evaluate its efficacy for the construction of a
quaternary carbon atom, we investigated the reaction
with d,e-unsaturated esters containing a substituent at
See Reference 1.
q Chiral synthons from carvone, Part 61. For Parts 59 and 60, see:
Ref. 10.
* Corresponding author. Tel.: +91-80-2932215; fax: +91-80-3600683;
e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.165

384
A.Srikrishna et al./ Tetrahedron Letters 45 (2004) 383–386
the d-position to generate a,a-disubstituted cyclopenta-
nones. To begin with, the ester 3, which was prepared
from (R)-carvone 4, was chosen for investigating the
cyclisation reaction (Scheme 1). Thus, (R)-carvone 4 was
converted into 3-methallylcarveol 5 employing an alkyl-
ative 1,3-enone transposition followed by regioselective
reduction. JohnsonÕs ortho ester Claisen rearrangement5
of the allyl alcohol 5 with triethyl orthoacetate and
propionic acid transformed the allyl alcohol 5 into the
ester 3. Treatment of a solution of the ester 3 in liquid
ammonia and THF with lithium at )33 ꢁC furnished a
mixture of primary and secondary alcohols, which on
pyridinium chlorochromate (PCC) oxidation furnished
mixture of the cyclised ketone 11 and the aldehyde 12 in
92% yield.7 On the other hand, reaction of the ester 13
in liquid ammonia–THF with lithium resulted in the
H
R
H
CH2OH
Li/liq.NH3
8 R = COOMe
or R = CHO
an easily separable 3:1 mixture of the spiro ketone
6
Li/liq.NH3
and the aldehyde 7 in 88% yield. Similarly, reaction of
the aldehyde 7 with lithium in liquid ammonia followed
by oxidation furnished a 5:2 mixture of the spiroketone
6 and the aldehyde 7 in 68% yield. It is worth noting that
neither the ester 3 nor the aldehyde 7 produced any 6-
endo trig cyclised product (a spiro[5.5]undecane) ruling
out the possibility of a radical pathway in the present
cyclisation (a commonly encountered reaction with
5-alkyl-5-hexenyl radicals).6
R
CH2OH
O
9 R = COOMe
or R = CHO
OMe
O
H
O
1. Li/liq.NH3
+
2. PCC
92%
Reactions of a few other d-substituted-d, e-unsaturated
esters in liquid ammonia with lithium were also inves-
tigated, but the cyclisation was found to be substrate
dependent. For example, the esters 8 and 9 and the
corresponding aldehydes failed to produce any cyclisa-
tion products and resulted in only the primary alcohols,
whereas reaction of the aryl system 10 in liquid ammo-
nia–THF followed by PCC oxidation of the resultant
mixture of alcohols generated an easily separable 2:5
( 2 : 5 )
10
11
12
H
H
Li/liq.NH3
88%
OH
H
COOMe
MeO
OMe
13
14
All the compounds exhibited spectral data consistent with their structures. Yields (unoptimised) refer to isolated and chromatographically pure
22
compounds. Selected spectral data for the spiroketone 6: ½aŠ +50.0 (c 0.84, CHCl3). IR (neat): mmax/cmÀ1 1740, 888. 1H NMR (300 MHz,
D
CDCl3+CCl4): d 5.43 (1H, br s, C@CH), 4.68 (2H, s, C@CH2), 2.76 and 1.99 (2H, 2 · d, J 17.0 Hz), 2.35–2.15 (1H, m), 2.15–1.80 (5H, m), 1.72 (3H,
s) and 1.67(3H, s) (2 · olefinic CH3), 1.45–1.20 (1H, m), 1.16 (3H, s) and 1.10 (3H, s) (2 · tert-CH3). 13C NMR (75 MHz, CDCl3+CCl4): d 220.7(C),
148.6 (C), 137.0 (C), 124.3 (CH), 109.5 (CH2), 48.5 (CH2), 47.8 (CH2), 44.1 (C), 42.4 (CH2), 40.8 (C), 37.7 (CH), 31.1 (CH2), 28.2 (CH3), 27.7
(CH3), 21.0 (CH3), 18.9 (CH3). HRMS: m=z calcd for C16H24ONa (M+Na): 255.1725; found: 255.1725. For the hydrindanone 17: ½aŠ22 +79.2 (c 3.6,
D
CHCl3). IR (neat): mmax/cmÀ1 1740. 1H NMR (300 MHz, CDCl3+CCl4): d 5.56 (1H, s, H-4), 3.63 (1H, d, J 6.9 Hz), 3.35 (3H, s, OCH3), 2.72 (1H,
dd, J 16.8 and 6.0 Hz), 2.20–1.90 (4H, m), 1.75–1.60 (1H, m), 1.71 (3H, s, olefinic CH3), 1.03 (3H, s) and 0.87(3H, s) (2 · tert-CH3). 13C NMR
(75 MHz, CDCl3+CCl4): d 220.2 (C, C@O), 136.3 (C, C-3), 124.6 (CH, C-4), 85.6 (CH, C-2), 56.7(CH 3, OCH3), 48.8 (CH, C-6), 47.3 (C, C-7), 42.7
(CH2), 39.5 (CH, C-1), 25.2 (CH2), 22.8 (CH3), 19.5 (CH3), 18.6 (CH3). HRMS: m=z calcd for C13H20O2Na (M+Na): 231.1361; found: 231.1360.
For the ester 20a: ½aŠ20 )37.5 (c 1.6, CHCl3). IR (neat): mmax/cmÀ1 1736, 910. 1H NMR (300 MHz, CDCl3+CCl4): d 5.79 (1H, dd, J 17.5 and 11.0 Hz,
D
CH@CH2), 5.50 (1H, br s, H-40), 5.05 (1H, d, J 11.0 Hz) and 4.98 (1H, d, J 17.5 Hz) (CH@CH2), 4.04 (2H, q, J 7.0 Hz, OCH2CH3), 3.66 (1H, br d,
J 9.6 Hz, H-20), 3.39 (3H, s, OCH3), 2.40 (1H, d, J 13.5 Hz), 2.28 (1H, d, J 13.5 Hz), 2.30–1.55 (6H, m), 1.69 (3H, s, olefinic CH3), 1.22 (3H, t, J
7.0 Hz, OCH2CH3), 0.87(3H, s) and 0.68 (3H, s) (2 · tert-CH3). 13C NMR (75 MHz, CDCl3+CCl4): d 171.9 (C, OC@O), 141.8 (CH, HC@CH2),
137.0 (C, C-30), 125.2 (CH, C-40), 112.9 (CH2, CH@CH2), 86.5 (CH, C-20), 59.7(CH 2, OCH2CH3), 56.8 (CH3, O–CH3), 52.7(C, C-8 0), 49.1 (CH),
45.2 (C, C-70), 43.1 (CH), 41.7(CH 2), 34.8 (CH2), 26.2 (CH2), 21.6 (CH3), 20.2 (CH3), 19.4 (CH3), 14.4 (CH3, OCH2CH3). HRMS: m=z calcd for
22
C19H30O3Na (M+Na): 329.2093; found: 329.2081. For the lactone 24a: mp 126–127 ꢁC. ½aŠ )47.8 (c 0.9, CHCl3). IR (neat): mmax/cmÀ1 1751. 1H
D
NMR (300 MHz, CDCl3+CCl4): d 4.19 (1H, d of t, J 5.4 and 1.5 Hz) and 4.06 (1H, d of t, J 5.7and 4.2 Hz) (H-5 0), 3.37(3H, s, OCH 3), 3.33 (1H, d,
J 6.0 Hz, H-5), 3.02 (1H, d, J 3.0 Hz, H-2), 2.57(1H, dd, J 8.4 and 6.0 Hz, H-7), 2.48 (1H, ddd, J 8.1, 4.2 and 1.5 Hz, Ha-40), 2.26 (1H, m, Ha-6), 2.04
(1H, t of d, J 13.2 and 9.3 Hz, Hb-40), 1.85–1.70 (1H, m, H-1), 1.65 (1H, dd, J 14.1, 12.3 Hz, Ha-10), 1.48 (1H, dd, J 14.1 and 7.5 Hz, Hb-6), 1.40–
1.20 (1H, m, Hb-10), 1.38 (3H, s, C3–CH3), 1.01 (3H, s) and 0.92 (3H, s) (CH3–C–CH3). 13C NMR (75 MHz, CDCl3+CCl4): d 178.6 (C, OC@O),
84.6 (CH, C-2), 77.0 (C, C-3), 64.7 (CH2, C-50), 60.7(C, C-9), 59.3 (CH, C-5), 54.5 (CH), 51.0 (CH 3, O–CH3), 46.0 (C,C-8), 39.3 (CH2, C-40), 36.0
(CH2), 35.8 (CH), 24.1 (CH2), 23.1 (CH3), 19.9 (CH3), 19.6 (CH3). HRMS: m=z calcd for C16H24O4Na (M+Na): 303.1572; found: 303.1572.
Crystal data for 24a: X-ray data were collected at 293 K on a Smart CCD–Bruker diffractometer with graphite monochromated Mo-Ka radiation
2
ꢀ
(k ¼ 0:7107 A). Structure was solved by direct methods (SIR92). Refinement was by full-matrix least-squares procedures on F using SHELXL-97.
The non-hydrogen atoms were refined anisotropically whereas hydrogen atoms were refined isotropically. C16H24O4, MW ¼ 280.167, colourless
ꢀ
ꢀ
ꢀ
crystal, crystal system: monoclinic, space group: P2(1); cell parameters: a ¼ 8:278(2) A, b ¼ 6:706(2) A, c ¼ 13:449(4) A, b ¼ 90:116(5),
V ¼ 746:69 A ; Z ¼ 2; Dc ¼ 1:247g cm À3; F (0 0 0) ¼ 304.0, l ¼ 0:09 mmÀ1. Total number of l.s. parameters ¼ 277; R1 ¼ 0.043 for 2245 F0 > 4rðF0Þ
3
ꢀ
and 0.0623 for all 2919 data. wR2 ¼ 0.0941; GOF ¼ 1.107; Restrained GOF ¼ 1.106 for all data. Crystallographic data (without structure factor)
have been deposited with the Cambridge Crystallographic Data Centre and the depository number is CCDC 205781.

A.Srikrishna et al./ Tetrahedron Letters 45 (2004) 383–386
385
available monoterpene (R)-carvone 4. The synthetic
sequence is depicted in Scheme 2. Thus, generation of
the kinetic enolate of carvone with lithium diisopropyla-
mide (LDA) followed by alkylation with methyl bro-
moacetate generated the ketoester 15, in 76% yield, in a
highly stereoselective manner. Regiospecific reduction of
the ketone in 15 with sodium borohydride in methanol
furnished the hydroxy ester 16, in 81% yield, in a highly
stereoselective manner, which on Williamson etherifi-
cation furnished the methoxy ester 13, in 70% yield.
Reaction of the ester 13 in liquid ammonia–THF with
lithium followed by oxidation of the resultant alcohol 14
with PCC and sodium acetate furnished exclusively the
hydrindanone 17. A Claisen rearrangement based
spiroannulation of a furan was contemplated for the
conversion of the ketone 17 in to spirodysins. Thus,
Horner–Wadsworth–Emmons reaction of the ketone 17
with triethyl phosphonoacetate and sodium hydride at
120 ꢁC in a sealed tube furnished the conjugated ester 18
in a highly stereoselective manner, which on regioselec-
tive reduction with lithium aluminium hydride (LAH) in
ether at low temperature furnished the allyl alcohol 19.
JohnsonÕs orthoester Claisen rearrangement5 of the allyl
alcohol 19 with triethyl orthoacetate and propionic acid
in a sealed tube at 180 ꢁC furnished a 7:3 mixture of the
c,d-unsaturated esters 20a and 20b, in 71% yield,
which were separated by column chromatography on
silica gel. Reduction of the ester in the major isomer 20a
with LAH in ether furnished the primary alcohol 21. An
ozonolytic cleavage was contemplated for the degrada-
tion of the extra carbon atom present, and to prevent the
regiochemical problems the trisubstituted olefin in 21
was blocked. Regioselective epoxidation of the ring
olefin in 21 in methylene chloride with m-chloroper-
benzoic acid (m-CPBA) furnished, as expected, a 1:1
O
O
HO
a
b
c
4
5
O
CHO
COOEt
d,e
+
( 1 : 3 )
7
6
3
Scheme 1. Reagents, conditions and yields: (a) i. CH2@C(Me)-
CH2MgCl, THF, 0 ꢁC fi rt, 1 h; ii. PCC, silica gel, CH2Cl2, rt, 2 h;
86%; (b) LAH, Et2O, )70 ꢁC, 1 h, 92%; (c) MeC(OEt)3, EtCOOH,
sealed tube, 180 ꢁC, 60 h, 63%; (d) Li, liquid NH3, THF, )33 ꢁC, 1 h; (e)
PCC, silica gel, CH2Cl2, rt, 1 h; 88% (from ester 3).
cyclisation to produce exclusively the trans-bicy-
clo[4.3.0]nonanol 14, in 88% yield in a highly stereo-
selective manner.8;9 The factors, which are responsible
for cyclisation of the d-substituted-d,e-unsaturated es-
ters are not clear at the moment and are currently being
investigated. Ready access to the bicyclo[4.3.0]nonanol
14 prompted us to apply the methodology for the
enantiospecific construction of the tricyclic framework
of spirodysins.
It was contemplated that spiroannulation of a furan to
the hydrindanol 14 would lead to spirodysins. The ester
13 was prepared from the readily and abundantly
H
H
H
H
b
d,e
a
O
H
COOMe
COOMe
MeO
f
O
O
OR
15
17
4
16. R = H
13. R = CH3
c
H
H
H
H
H
h
COOEt
COOEt
+
X
H
MeO
MeO
MeO
18. X = COOEt
19. X = CH2OH
( 7 : 3 )
20a
20b
g
i
X
H
H
H
j
k
O
O
O
OH
OH
Me
Me
H
H
H
MeO
MeO
MeO
23a. α-Me; X = H,OH
24a. α-Me; X = O
23b. β-Me; X = H,OH
24b. β-Me; X = O
21
22a. α-Me
22b. β-Me
l
l
Scheme 2. Reagents, conditions and yields: (a) LDA, THF, )70 ꢁC; BrCH2COOMe, 70 ꢁC fi rt, 6 h; 76%; (b) NaBH4, MeOH, )30 ꢁC, 81%; (c) NaH,
THF, Bu4NI, MeI, reflux, 8 h, 70%; (d) Li, liquid NH3, THF, )33 ꢁC, 1 h, 88%; (e) PCC, NaOAc, CH2Cl2, rt, 2 h, 88%; (f) NaH,
(EtO)2P(O)CH2COOEt, sealed tube, 120 ꢁC, 85%; (g) LAH, Et2O, )40 ꢁC, 86%; (h) MeC(OEt)3, EtCOOH, sealed tube, 180 ꢁC, 72 h; (i) LAH, Et2O,
0 ꢁC, 1 h, 90%; (j) m-CPBA, NaHCO3, CH2Cl2, rt, 81% (22a:22b 1:1); (k) O3/O2, CH2Cl2/MeOH (5:1), )70 ꢁC; Me2S, rt, 8 h, 90–93%; (l) PCC,
NaOAc, CH2Cl2, rt, 1 h, 82–84%.

386
A.Srikrishna et al./ Tetrahedron Letters 45 (2004) 383–386
2. Goetz, G. H.; Harrigan, G. G.; Likos, J. J.Nat.Prod.
2001, 64, 1486–1488.
3. (a) Kazlauskas, R.; Murphy, P. T.; Wells, R. J. Tetrahe-
dron Lett. 1978, 19, 4949–4950; (b) Charles, C.; Braekman,
J. C.; Daloze, D.; Tursch, B.; Declercq, J. P.; Germain,
G.; Van Meerssche, M. Bull.Soc.Chem.Belg.
1978, 87,
481–486; (c) Schram, T. J.; Cardellina, J. H. J.Org.
Chem. 1985, 50, 4155–4157; (d) Reddy, N. S.; Ven-
kateswarlu, Y. Indian J.Chem. 1999, 38B, 1002–1004; (e)
Cameron, G. M.; Stapleton, B. L.; Simonsen, S. M.;
Brecknell, D. J.; Garson, M. J. Tetrahedron 2000, 56,
5247–5252.
4. To the best of our knowledge there is no report in the
literature on the synthesis of spirodysins either in racemic
or optically active forms.
Figure 1. X-ray structure of the lactone 24a.
5. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brock-
som, T. J.; Li, T. t.; Faulkner, D. J.; Petersen, M. R. J.
Am.Chem.Soc. 1970, 92, 741–743.
6. Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, G.; Thoma,
G.; Kulicke, K. J.; Trach, F. Org.React. 1996, 48, 301;
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH, 2001.
7. In contrast, reaction of the ester i, containing an extra
methyl group at the benzylic position, in liquid ammonia
with lithium followed by oxidation of the resulting
mixture of alcohols furnished 1:3 mixture of the aldehyde
ii and the tetralone iii containing a small amount of a-
cuparenone iv, in 86% yield, perhaps due to the steric
crowding of two vicinal quaternary carbon atoms in the
cuparanes.
mixture of the epoxides 22a and 22b, which were sepa-
rated by column chromatography on silica gel. Ozon-
olysis of the vinyl group in 22a followed by reductive
work-up with dimethyl sulfide furnished the hemiacetal
23a, which on oxidation with PCC and sodium acetate
furnished the lactone 24a containing the complete
tricyclic framework of spirodysins. In a similar manner
ozonolysis and oxidation transformed the epoxide 22b
in to the lactone 24b. The stereostructures of the lac-
tones 24a,b were established from their spectral data,
and the stereochemistry at various centres was unam-
biguously established by a single crystal X-ray analysis
of the lactone 24a, which is depicted in Figure 1.
OMe
H
O
O
O
In conclusion, we have discovered a convenient meth-
odology for the enantiospecific construction of the
trans-bicyclo[4.3.0]nonan-8-one 17 employing lithium in
liquid ammonia mediated carbanion cyclisation of the
ester 13. The ketone 17 was further elaborated into the
tricyclic framework of the sesquiterpenes spirodysins.
Currently, we are investigating the extension of this
methodology for the generation of the corresponding cis
isomer and further elaboration to natural spirodysins.
1. Li/liq.NH3
+
+
2. PCC
86%
O
i
ii
iii
iv
8. The structure of the alcohol 14 was established from its
spectral data and was further confirmed by single crystal
X-ray diffraction analysis of the corresponding 4-nitro-
benzoate ester. The crystallographic data has been depos-
ited with the Cambridge Crystallographic Data Center
(CCDC 218889).
9. It is worth mentioning that the radical cyclisation of the
iodide v, obtained from the ester 13 in two steps, produced
a 2:1 (by NMR) mixture of the 5-exo trig and 6-endo-trig
cyclisation products vi and vii.
Acknowledgements
We thank the CCD facility of Indian Institute of Science
for the single crystal X-ray structure determination and
the Council of Scientific and Industrial Research, New
Delhi for the award of a research fellowship to P.R.K.
H
H
H
Bu3SnH
AIBN
+
13
I
H
OMe
OMe
OMe
( 2 : 1 )
v
vi
vii
References and Notes
10. Part 59: Srikrishna, A.; Kumar, P. P.; Reddy, T. J. Arkivoc
2003, iii, 55–66; Part 60: Srikrishna, A.; Dethe, D. H.
Tetrahedron Lett. 2003, 44, 7817–7820.
1. Srikrishna, A.; Ramasastry, S. S. V. Tetrahedron Lett.
2003, 44, see doi:10.1016/j.tetlet.2003.10.164.