Connective synthesis of spirovetivanes: Total synthesis of (±)-agarospirol, (±)-hinesol and (±)-α-vetispirene

Article abstract of DOI:10.1002/ejoc.200400236

A concise, connective synthesis of naturally occurring spirovetivanes 1 and 3, in racemic form, is presented. This novel approach involves the efficient assembly of the advanced intermediate 12 through a unique spiroannulation protocol. Wiley-VCH Verlag GmbH & Co. KGaA1 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400236

SHORT COMMUNICATION
Connective Synthesis of Spirovetivanes: Total Synthesis of (؎)-Agarospirol,
(؎)-Hinesol and (؎)-α-Vetispirene
[a]
[a]
[a]
´
´
Nuno Maulide, Jean-Christophe Vanherck, and Istvan E. Marko*
Dedicated with respect and admiration to Professor W. B. Motherwell
Keywords: Spiro compounds / Total synthesis / Spiroannulation / Orthoesters / Diastereocontrol
A concise, connective synthesis of naturally occurring spiro-
vetivanes 1 and 3, in racemic form, is presented. This novel
approach involves the efficient assembly of the advanced in-
termediate 12 through a unique spiroannulation protocol.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Recently we have reported an efficient and connective
spiroannulation methodology that allows the expeditious
construction of a variety of spirocyclic derivatives of differ-
ent ring sizes.[2] This two-step approach involves the initial
condensation between a silyl enol ether 4 and a func-
tionalised orthoester 5, followed by base-catalysed intra-
molecular cyclisation of the resulting β-keto ketals 6, to af-
ford, in good to excellent yields, monoprotected spiro dike-
tones 7 (Scheme 1).
Furthermore, when 3-substituted silyl enol ethers such as
8 are employed, complete diastereocontrol is exercised both
in the condensation and in the spiroannulation steps
(Scheme 2).
Molecules possessing a spirocyclic framework are ubiqui-
tous in nature, many among them displaying interesting
biological and odoriferous properties. For example, α-vetis-
pirene (1), chamigrene (2), agarospirol (3a) and hinesol (3b)
contain a spiro[4.5]decane or a spiro[5.5]undecane core em-
bedded in their structures. It is therefore hardly surprising
that a range of elegant strategies have been developed for
the rapid assembly of such subunits.[1]
The generation of diastereomerically pure, monopro-
tected spiro diketones such as 11a provides an efficient ac-
cess to the spiro[4.5] core present in several naturally occur-
ring sesquiterpenes (Scheme 2).
In this communication, we wish to report our results in
the successful attainment of this strategy, culminating in the
total synthesis of (Ϯ)-agarospirol (3a), (Ϯ)-hinesol (3b)[3]
and (Ϯ)-α-vetispirene (1).[4] Our proposed antithetic analy-
sis is presented in Scheme 3. Ketone 12 was envisaged as
being a key precursor that could, after appropriate func-
tionalisation of the five-membered ring, lead to the desired
products 1 and 3. The spiro derivative 12 could conceivably
derive from the masked diketone 11a, itself readily access-
ible by our condensation/spiroannulation methodology. In
this approach, the two crucial stereogenic centres, present
in the cores of 1 and 3, have been readily implemented at
an early stage of the synthesis.
Our route towards the spirovetivanes 1 and 3 began with
the zinc chloride catalysed condensation between the silyl
enol ether 8a (readily available by the addition of dimethyl
cuprate to cyclohex-2-enone in the presence of Me3SiCl)[5]
and orthoester 9, affording the desired β-keto ketal 10a as
[a]
´
´
Universite catholique de Louvain, Departement de Chimie,
ˆ
Batiment Lavoisier,
Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
E-mail: marko@chim.ucl.ac.be
3962
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400236
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Total Synthesis of ( )-Agarospirol, ( )-Hinesol and ( )-α-Vetispirene
SHORT COMMUNICATION
Scheme 1
Scheme 2
Scheme 3
a single diastereoisomer in 71% yield (Scheme 4). Spiro-
It was anticipated that the introduction of the trisubsti-
cyclisation of 10a proceeded smoothly in the presence of tuted endocyclic double bond could be accomplished by
potassium tert-butoxide in wet THF, to give the mono-pro- acid-catalysed dehydration of the tertiary alcohol derived
tected diketone 11a in 85% yield.[6]
from ketone 11a.[7] Unfortunately, despite considerable ef-
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´
N. Maulide, J.-C. Vanherck, I. E. Marko
SHORT COMMUNICATION
Scheme 4. Reagents and conditions: (i) ZnCl2, 9, CH2Cl2, room temperature; (ii) tBuOK, THF/H2O, room temperature; (iii) potassium
hexamethyl disilazane (KHMDS), PhNTf2, THF, Ϫ78 °C to room temperature; (iv) ceric ammonium nitrate (CAN), CH3CN/H2O, 60
°C; (v) 20 mol % Fe(acac)3, THF/N-methyl-2-pyrrolidinone (NMP), Ϫ15 °C to 0 °C.
forts only mixtures of exo- and endocyclic alkenes were ob- actions bodes well for future synthetic applications of this
tained. Attention was therefore turned to the use of a coup- methodology.[11]
ling protocol between vinyl triflate 13 and a suitable or-
It is interesting to note that this entire sequence (enol
ganometallic reagent. Initial attempts at installing the tri- triflate synthesis, ketal removal and FeIII-catalysed coup-
substituted alkene by uniting triflate 13 with MeLi or ling) can be realised sequentially without chromatographic
MeMgBr, in the presence of Ni or Pd catalyst, resulted purification of the intermediates 13 and 14. Moreover, it
either in recovered starting material or in erratic reactions.[8] can easily be performed on multigram scale, and the overall
Iron()-catalysed coupling processes, which have re- yields average 87%.
ceived a considerable amount of attention recently, were
Having successfully secured large quantities of ketone 12,
also assessed, alas to no avail.[9] An unexpected solution to we then focused our attention upon the elaboration of the
this problem was discovered when the FeIII-catalysed reac- five-membered ring and the introduction of the requisite
tion was performed on a sample of 13 contaminated by appendages. Initial attempts at directly installing the isopro-
small amounts of ketone 14. Whilst 13 was recovered quan- pylol side-chain present in 3 by aldol reaction between the
titatively, 14 reacted smoothly and chemoselectively under anion derived from ketone 12 and acetone met with failure.
these conditions, affording in excellent yield the long- Subsequent efforts employing Lewis acid mediated conden-
sought-after adduct 12. It appears, therefore, that the steric sations of the silyl enol ether derivative 15 with 2,2-dimeth-
hindrance provided by the dioxolane substituent precludes oxypropane also resulted in recovered starting material 12
any access to the vinyl triflate by the iron reagent.
(Scheme 5).
At this stage, overcoming the last obstacle before the suc-
Molecular modelling studies revealed that the presence
cessful implementation of our strategy heavily depended of the two α-methyl substituents provides sufficient steric
upon delineating a suitable protocol that would selectively hindrance around C2 so as to preclude a proper approach
unmask the ketone function in 13 without hydrolysing the of the incoming electrophile. Only the smallest reagents
sensitive enol triflate functionality. In the event (Scheme 4), might be able to reach that centre. The elegant work of
treatment of ketal 13 under our CAN-catalysed deprotec- Junjappa et al. on the preparation and subsequent trans-
tion conditions (3% CAN in buffered acetonitrile, 1 hour, formation of α-oxo ketene dithioketals inspired us and pro-
60 °C), smoothly and quantitatively unveiled the carbonyl vided the ultimate solution to our predicament.[12]
function, to afford 14 in Ͼ99% yields.[10] It is noteworthy
Thus, we were delighted to observe that successive treat-
that the acid-labile triflate moiety is untouched under ment of ketone 12 with KHMDS, carbon disulfide,
these conditions. KHMDS and finally methyl iodide led to the desired ad-
Triflate 14 was then subjected to Fe(acac)3-catalysed duct 16 in 86% yield (Scheme 5). The ketone function was
coupling in the presence of three equivalents of methylmag- then chemoselectively reduced, with NaBH4 in refluxing
nesium iodide in THF/NMP, leading exclusively to the en- ethanol, and the crude mixture of diastereoisomeric allylic
docyclic alkene 12 in excellent yield.[9] As already demon- alcohols 17 was directly subjected to the action of boron
strated in the seminal contributions of Cahiez et al. the re- trifluorideϪdiethyl ether in refluxing methanol for 15
markable chemoselectivity of iron()-mediated coupling re- hours.[12] Gratifyingly, the α,β-unsaturated ester 18 could
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Eur. J. Org. Chem. 2004, 3962Ϫ3967

Total Synthesis of ( )-Agarospirol, ( )-Hinesol and ( )-α-Vetispirene
SHORT COMMUNICATION
Scheme 5. Reagents and conditions: (i) lithium diisopropyl amide (LDA), TMSCl, Ϫ78 °C to room temperature; (ii) KHMDS, Ϫ78 °C,
then CS2, then KHMDS, CH3 I; (iii) NaBH4, EtOH, reflux; (iv) BF3·OEt2, MeOH, reflux.
be isolated in 60% overall yield. This three-step sequence agent in THF for 2 hours, followed directly by dehydration
successfully accomplishes an impressive formal 1,2-transpo- in the presence of catalytic amounts of p-toluenesulfonic
sition of functionality within the five-membered ring, whilst acid (PTSA) in dry benzene, smoothly provided (Ϯ)-α-vetis-
providing access to an intermediate bearing close resem- pirene (1) in an overall yield of 60% (Scheme 6).
blance to a broad variety of spirovetivanes.
Thus, smooth and selective reduction of substrate 18,
The key intermediate 18 has already been transformed using magnesium in methanol, afforded the saturated ester
by Yamada et al. into (Ϯ)-α-vetispirene (1).[3b] Accordingly, 19 as an inseparable 2:3 mixture of C2-epimers in quantitat-
treatment of unsaturated ester 18 with excess Grignard re- ive yield (Scheme 6).[13] Finally, addition of methylmag-
Scheme 6. Reagents and conditions: (i) MeMgBr, 0 °C to room temperature; (ii) PTSA, benzene, 5 °C to room temperature; (iii) Mg,
MeOH, 0 °C to room temperature.
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N. Maulide, J.-C. Vanherck, I. E. Marko
SHORT COMMUNICATION
3
6.6 Hz, 3 H, CH3), 1.73Ϫ2.40 (m, 11 H, CH2), 5.93 (td, JH,H
ϭ
nesium bromide to this mixture of stereoisomers provided
(Ϯ)-agarospirol (3a) and (Ϯ)-hinesol (3b) in 98% yield (2:3
ratio).
In summary, we have shown that our condensation/spi-
roannulation methodology allows a ready and stereocon-
trolled access to three naturally occurring spirovetivanes.
4.2, JH,H ϭ 1.2 Hz, 1 H, vinylic CH) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 16.2, 19.6, 22.4, 25.6, 33.0, 37.8, 39.3, 55.5, 116.0,
120.2, 149.0, 216.9 ppm. MS (CI): m/z (%) ϭ 313 (5) [M ϩ 1]ϩ,
163 (30), 145 (10), 130 (10). HRMS (CI): calcd. for C12H15 F3O4S:
313.072141; found 313.071255 [M ϩ 1]ϩ.
4
With our approach, the highly functionalised key inter- 6,10-Dimethylspiro[4.5]dec-6-en-1-one (12): Fe(acac)3 (22 mg, 6.4
µmol) was added to a solution of triflate 14 (100 mg, 0.32 mmol)
in a mixture of THF (5 mL) and NMP (3 mL). The resulting red
solution was then cooled to Ϫ15 °C, and methylmagnesium iodide
(0.3 mL, 3 in ether) was added dropwise. The resulting greenish
suspension was stirred for 20 minutes, then water was added to
quench the reaction. The organic layer was extracted with diethyl
ether, dried (MgSO4), and the solvents were evaporated under re-
duced pressure. The crude ketone 12 was then purified by flash
chromatography (silica, petroleum ether/Et2O, 10:1) to yield pure
mediate 12 could be efficiently assembled in only five steps
and in 54% overall yield. This precursor was subsequently
transformed into (Ϯ)-agarospirol (3a), (Ϯ)-hinesol (3b) and
(Ϯ)-α-vetispirene (1) in good overall yields.
Further efforts are now directed to the establishment of
an enantioselective version of these syntheses, and towards
broadening the scope and application of this connective
methodology.
1
12 (55 mg, 96%) as a colourless oil. H NMR (200 MHz, CDCl3):
δ ϭ 1.08 (d, 3JH,H ϭ 6.8 Hz, 3 H, CH3), 1.74Ϫ2.58 (m, 14 H, CH2),
5.78 (broad s, 1 H, vinylic CH) ppm. 13C NMR (50 MHz, CDCl3):
δ ϭ 16.1, 19.4, 20.2, 22.7, 26.2, 34.7, 35.0, 39.5, 56.6, 125.5, 133.2,
221.6 ppm. MS (CI): m/z (%) ϭ 179 (100) [M ϩ 1]ϩ, 178 (55) [M]ϩ,
161 (70), 135 (25). HRMS (CI): calcd. for C12H18O: 178.135765;
found 178.135772 [M]ϩ.
Experimental Section
General Remarks: Unless otherwise stated, all the reactions were
carried out using anhydrous conditions and under argon. H and
1
13C NMR spectra were recorded with a Varian Gemini 200 and
300 instruments. Chemical shifts are expressed as parts per million
(ppm) down-field from tetramethylsilane or calibrated from CDCl3.
Mass spectra were obtained using Varian MAT-44 and Finnigan
MAT-TSQ 70 spectrometers with electron impact (70 eV) and
chemical ionisation (100 eV, ionisation gas: isobutane). Elemental
analyses were performed in Prof. S. Laschat’s analytical laboratory
(Institut für Organische Chemie, Universität Stuttgart, Germany).
High-resolution mass spectra were recorded in Prof. R. Flamant’s
Acknowledgments
´
Financial support of this work by the Universite catholique de
Louvain, the Fonds pour la Recherche dans l’Industrie et l’Agricul-
ture (F.R.I.A., studentships to J.-C.V. and N.M.) and the Actions
´
de Recherche Concertees (convention 96/01Ϫ197) is gratefully
acknowledged. I.E.M. is grateful to Merck for receiving the Merck
Academic Development Program Award, to Merck Frosst for the
Merck Frosst Lectureship and to Astra-Zeneca for the Astra-
Zeneca European Lectureship.
´
laboratory (Universite de Mons, Belgium).
11-Methyl-1,4-dioxaspiro[4.0.5.3]tetradecan-7-one (11a): To a solu-
tion of β-keto ketal 10a (3.4 g, 13 mmol) in THF (75 mL) were
added water (0.2 mL, 13 mmol) and potassium tert-butoxide
(2.05 g, 18 mmol). The orange reaction mixture was stirred for 60
minutes at room temperature. Following quenching with saturated
sodium hydrogen carbonate solution, the organic phase was ex-
tracted with diethyl ether, dried (MgSO4), and the solvents were
evaporated under reduced pressure to yield the crude spiro ketone
11a, which was further purified by flash chromatography (silica,
petroleum ether/EtOAc, 7:3) to afford pure 11a (2.4 g, 85%) as a
colourless solid. 1H NMR (200 MHz, CDCl3): δ ϭ 1.17 (d, 3JH,H ϭ
6.8 Hz, 3 H, CH3), 1.43Ϫ2.09 (m, 10 H, CH2), 2.39Ϫ2.46 (m, 2 H,
CH), 2.62Ϫ2.68 (m, 1 H, CH), 3.80Ϫ4.06 (m, 4 H, OCH2) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 17.5, 20.2, 26.1, 30.4, 31.0, 36.8,
40.7, 42.4, 62.7, 63.0, 64.2, 119.2, 211.0 ppm. MS (CI): m/z (%) ϭ
225 (100) [M ϩ 1]ϩ, 224 (10) [M]ϩ, 112 (20), 99 (20). C13H20O3:
calcd. C 69.61, H 8.99; found C 69.69, H 9.21.
[1]
For reviews on the preparation of spirocyclic compounds, see:
[1a]
[1b]
M. Sannigrahi, Tetrahedron 1999, 55, 9007Ϫ9071.
J. A.
Marshall, S. F. Brady, N. H. Andersen, Fortsch. Chem. Org.
Naturst. 1974, 31, 283Ϫ376.
[2] [2a]
´
I. E. Marko, J.-C. Vanherck, A. Ates, B. Tinant, J.-P. Le-
clercq, Tetrahedron Lett. 2003, 44, 3333Ϫ3336. For a previous
[2b]
´
I. E. Marko, A. Ates,
utilisation of such orthoesters, see:
Synlett 1999, 1033Ϫ1036. For elegant uses of other orthoesters,
[2c]
see:
P. Ding, L. Ghosez, Tetrahedron 2002, 58, 1565Ϫ1571.
C. Huart, L. Ghosez, Angew. Chem. Int. Ed. Engl. 1997,
[2d]
36, 634Ϫ636.
[3]
For previous total syntheses of agarospirol and/or hinesol, see:
[3a]
J. A. Marshall, S. F. Brady, J. Org. Chem. 1970, 35,
[3b]
4068Ϫ4077.
K. Yamada, K. Aoki, H. Nagase, Y. Hayak-
[3c]
awa, Y. Hirata, Tetrahedron Lett. 1973, 4967Ϫ4970.
W. G.
Dauben, D. J. Hart, J. Am. Chem. Soc. 1975, 97, 1622Ϫ1623.
10-Methyl-1-oxospiro[4.5]dec-6-en-6-yl Trifluoromethanesulfonate
(14): To a solution of protected triflate 13 (110 mg, 0.31 mmol) in
a mixture of acetonitrile (3 mL) and borate buffer (pH ϭ 8.00,
3 mL), was added ceric ammonium nitrate (6 mg, 9 µmol). The
yellow solution was then heated at 60 °C for 60 minutes. After
cooling to room temperature, water was added, and the organic
phase was extracted with dichloromethane, dried (MgSO4), and the
solvents were evaporated under reduced pressure. The crude triflate
14, (95 mg, 99%) thus obtained as a colourless oil, was pure enough
to be directly used in the next step. For analytical purposes, a
sample was purified by flash chromatography (silica, petroleum
ether/Et2O, 10:1), affording pure triflate 14 (90 mg, 94%) as a
[3d]
D. A. Chass, D. Buddhasukh, P. D. Magnus, J. Org. Chem.
1978, 43, 1750Ϫ1756. [3e] J. Lafontaine, M. Mongrain, M. Serg-
ent-Guay, L. Ruest, P. Deslongchamps, Can. J. Chem. 1980, 58,
2460Ϫ2476.
[3f]
L. A. Paquette, T. H. Yan, G. J. Wells, J. Org.
[3g]
Chem. 1984, 49, 3610Ϫ3617.
T. Hatsui, J.-J. Wang, S.-y.
Ikeda, H. Takeshita, Synlett 1995, 35Ϫ37. [3h] Y. Du, X. Lu, J.
Org. Chem. 2003, 68, 6463Ϫ6465.
For previous total syntheses of α-vetispirene, see: [4a] D. Caine,
[4]
[5]
A. A. Boucugnani, S. T. Chao, J. B. Dawson, P. F. Ingwalson,
J. Org. Chem. 1976, 41, 1539Ϫ1544.
quette, Tetrahedron Lett. 1982, 23, 3227Ϫ3230.
Tetrahedron Lett. 1985, 26, 2309Ϫ2310; and ref. [3b].
C. R. Johnson, T. J. Marren, Tetrahedron Lett. 1987, 28,
27Ϫ30.
[4b]
T. H. Yan, L. A. Pa-
[4c]
G. Balme,
1
3
colourless oil. H NMR (300 MHz, CDCl3): δ ϭ 0.93 (d, JH,H
ϭ
3966
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Total Synthesis of ( )-Agarospirol, ( )-Hinesol and ( )-α-Vetispirene
SHORT COMMUNICATION
´
I. E. Marko, A. Ates, A. Gautier, B. Leroy, J.-M. Plancher,
[6]
[10] [10a]
The structure and relative stereochemistry of 11a had been pre-
viously established unambiguously by single-crystal X-ray dif-
Y. Quesnel, J.-C. Vanherck, Angew. Chem. Int. Ed. 1999, 38,
fraction analysis, see ref.[2a]
.
3207Ϫ3209. [10b] A. Ates, A. Gautier, B. Leroy, J.-M. Plancher,
[7]
[8]
´
This transformation is well precedented in the previous total
Y. Quesnel, J.-C. Vanherck, I. E. Marko, Tetrahedron 2003,
syntheses of, e.g., 3a and 3b, see ref.[3]
.
59, 8989Ϫ8999.
[8a]
Ni catalysis:
C. A. Busacca, M. C. Erikson, R. Fiaschi,
[11] [11a] G. Cahiez, H. Avedissian, Synthesis 1998, 1199Ϫ1205. [11b]
W. Dohle, F. Kopp, G. Cahiez, P. Knochel, Synlett 2001,
1901Ϫ1904.
[8b]
Tetrahedron Lett. 1999, 40, 3101Ϫ3104. Pd-catalysis:
T.
Mandai, T. Matsumoto, J. Tsuji, S. Saito, Tetrahedron Lett.
1993, 34, 2513Ϫ2516.
[12] [12a]
B. Myrboh, H. Ila, H. Junjappa, J. Org. Chem. 1983, 48,
[9]
[12b]
For recent examples of FeIII-catalysed coupling reactions, see:
5327Ϫ5332.
B. Myrboh, C. V. Asokan, H. Ila, H. Jun-
[9a]
[12c]
A. Fürstner, M. Mendez, Angew. Chem. Int. Ed. 2003, 42,
jappa, Synthesis 1984, 50Ϫ51.
Junjappa, Synthesis 1985, 163Ϫ165.
T. Hudlicky, G. Sinai-Singde, M. G. Natchus, Tetrahedron
Lett. 1987, 28, 5287Ϫ5290.
C. V. Asokan, H. Ila, H.
[9b]
5355Ϫ5357.
N. Ostergaard, B. T. Pedersen, N. Skjaerbaek,
[9c]
[13] [13a]
P. Vedso, M. Bergtrup, Synlett 2002, 1889Ϫ1891.
Fürstner, A. Leitner, M. Mendez, H. Krause, J. Am. Chem.
A.
[13b]
S. Gabriels, D. Van Haver, M.
[9d]
Soc. 2002, 124, 13856Ϫ13863.
J. Quintin, X. Franck, R.
Vandewalle, P. De Clercq, D. Viterbo, Eur. J. Org. Chem.
1999, 1803Ϫ1809.
Hocquemiller, B. Figadere, Tetrahedron Lett. 2002, 43,
3547Ϫ3549. [9e] A. Fürstner, A. Leitner, Angew. Chem. Int. Ed.
2002, 41, 609Ϫ612.
Received April 7, 2004
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