A synthetic approach to the fusicoccane A-B ring fragment based on a Pauson-Khand cycloaddition/Norrish type 1 fragmentation

Article abstract of DOI:10.1021/jo800933f

(Chemical Equation Presented) A synthetic approach to the A-B ring system within the fusicoccane family of diterpenes is presented. Key steps in this approach are a diastereoselective Pauson-Khand reaction, a Norrish 1 photofragmentation, a Charette cyclopropanation, and a ring-closing metathesis process.

Full text of DOI:10.1021/jo800933f

A Synthetic Approach to the Fusicoccane A-B Ring Fragment
Based on a Pauson-Khand Cycloaddition/Norrish Type 1
Fragmentation
Gregory R. Dake,* Erik E. Fenster, and Brian O. Patrick†
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia, VancouVer,
B.C., Canada, V6T 1Z1
gdake@chem.ubc.ca
ReceiVed May 13, 2008
A synthetic approach to the A-B ring system within the fusicoccane family of diterpenes is presented.
Key steps in this approach are a diastereoselective Pauson-Khand reaction, a Norrish 1 photofragmentation,
a Charette cyclopropanation, and a ring-closing metathesis process.
Introduction
The fusicoccane family of diterpenes are characterized by a
fused 5-8-5 carbocyclic skeleton (Figure 1). Members of this
family class have been isolated and characterized from a number
of natural sources, including fungi, liverworts, and higher
plants.1 The fusicoccane diterpenoids, with the structurally
related classes typified by the cotylenins, fusicoplagins, ophiobo-
lines, and plagiospirolides, exhibit interesting phytohormonal
activities.2 In the case of the fusicoccanes, this activity results
from the interaction with 14-3-3 proteins in the plant’s
† Manager, University of British Columbia X-Ray Analysis Facility.
(1) Fusicoccins:(a) Ballio, A.; Chain, E. B.; De Leo, P.; Erlanger, B. F.;
Mauri, M.; Tonolo, A. Nature 1964, 203, 297–298. (b) Barrow, K. D.; Barton,
D. H. R.; Chain, E.; Conlay, C.; Samle, T. C.; Thomas, R.; Waight, E. S. J. Chem.
Soc., Chem. Commun. 1968, 1195–1197. (c) Hough, E.; Hursthouse, M. B.;
Neidle, S.; Rogers, D. J. Chem. Soc., Chem. Commun. 1968, 1197. (d) Barrow,
K. D.; Barton, D. H. R.; Chain, E.; Conlay, C.; Samle, T. C.; Thomas, R.; Waight,
E. S. J. Chem. Soc., Chem. Commun. 1968, 1198–1200. (e) Barrow, K. D.;
Barton, D. H. R.; Chain, E.; Conlay, C.; Samle, T. C.; Thomas, R.; Waight,
E. S. J. Chem. Soc. C 1971, 1259–1264. (f) Barrow, K. D.; Barton, D. H. R.;
Chain, E.; Ohnsorge, U. F. W.; Thomas, R. J. Chem. Soc. C 1971, 1265–1274.
(g) Barrow, K. D.; Barton, D. H. R.; Chain, E.; Bageenda-Kasujja, D. J. Chem.
Soc., Perkin Trans. 1 1975, 87, 7–883. Cotylenins: (h) Sassa, T.; Tojyo, T.;
Munakata, K. Nature 1970, 227, 379. (i) Sassa, T. Agric. Biol. Chem. 1971, 35,
1415–1418. (j) Sassa, T.; Togashi, M. Agric. Biol. Chem. 1973, 37, 1505–1506.
(k) Sassa, T.; Ooi, T.; Nukina, M.; Ikeda, M.; Kato, N. Biosci. Biotechnol.
Biochem. 1998, 62, 1815–1818. Liverwort fusicoccanes: (l) Baxter, G.; Cameron,
A. F.; Connolly, J. D.; Rycroft, D. S. Tetrahedron Lett. 1983, 35, 3787–3788.
(m) Asakawa, Y.; Lin, X.; Tori, M.; Kondo, K. Phytochemistry 1990, 29,
25972603. Fusicoplagins: (n) Hashimoto, Y.; Tori, M.; Taira, Z.; Asakawa, Y.
Tetrahedron Lett. 1985, 26, 6473–6476Periconicins: (o) Kim, S.; Shin, D.-S.;
Lee, T.; Oh, K.-B. J. Nat. Prod. 2004, 67, 448–450.
FIGURE 1. Prototypical fusicoccane diterpenes.
membranes, causing membrane hyperpolarization and activation
of plasma membrane H+-ATP-ase.3
We became intrigued with the liverwort fusicoccane family
of natural products after we recognized structural similarities
between members of this family and that of nitiol, a sesterterpene
natural product. Specifically, the cis-relationship between the
methyl group and the isopropyl group appended on a five-
(2) For a review on the biology of ophiobolanes and fusicoccanes, see: Au,
T. K.; Chick, W. S. H.; Leung, P. C. Life Sci. 2000, 67, 733–742.
(3) (a) Marre´, E. Annu. ReV. Plant Physiol. 1979, 30, 273–288. (b) De Boer,
B. Trends Plant Sci. 1997, 2, 60–66. (c) Wu¨rtele, M.; Jelich-Ottmann, C.;
Wittinghofer, A.; Oecking, C. EMBO J. 2003, 22, 987–994.
10.1021/jo800933f CCC: $40.75
Published on Web 07/25/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6711–6715 6711

Dake et al.
precedent within Fu¨rstner’s dactylol synthesis.10,11 We thus
intended to use a synthetic approach formatted on our previous
work on the nitianes to produce the requisite metathesis substrate
(eq 1). The key sequences in this route would involve a
Pauson-Khand reaction to establish the stereogenic center at
C10 (fusicoccane numbering), followed by a photochemical ring
cleavage reaction.12 A key question in this approach was one
of diastereoselectivity: Would there be enough steric differentia-
tion at C11 in enyne 4 to produce 5 with reasonable diastereo-
selectivity at C10? With this problem in mind, a synthetic route
to a surrogate of 4 was developed.
SCHEME 1. An Analysis of the Fusicoccane Skeleton
SCHEME 2. Stereoselective Preparation of Pauson-Khand
Substratesa
Known lactone (S)-(+)-6 was readily constructed from
L-glutamic acid in three steps by using a literature procedure
(4) (a) Wilson, M. S.; Woo, J. C. S.; Dake, G. R. J. Org. Chem. 2006, 71,
4237–4245. (b) Wilson, M. S.; Dake, G. R. Org. Lett. 2001, 3, 2041–2044.
(5) For liverwort fusicoccanes: (a) Kato, N.; Wu, X.; Nishikawa, H.;
Takeshita, H. Synlett 1993, 29, 3–295. (b) Kato, N.; Wu, X.; Nishikawa, H.;
Nakanishi, K.; Takeshita, H. J. Chem. Soc., Perkin Trans. 1 1994, 1047–1053.
(c) Kato, N.; Nakanishi, K.; Wu, X.; Nishikawa, H.; Takeshita, H. Tetrahedron
Lett. 1994, 35, 8205–8208. (d) Williams, D. R.; Robinson, L. A.; Nevill, C. R.;
Reddy, J. P. Angew. Chem., Int. Ed. 2007, 46, 915–918. For other fusicoccanes
and ophiobolanes, and generalized methods for the synthesis of the tricyclic
ring system typified by the fusicoccane diterpenes: (e) Dauben, W. G.; Hart,
D. J. J. Org. Chem. 1977, 42, 922–923. (f) Randall, M. L.; Lo, P. C.-K.;
Bonitatebus, P. J., Jr.; Snapper, M. L. J. Am. Chem. Soc. 1999, 121, 4534–
4535. (g) Lo, P. C.-K.; Snapper, M. L. Org. Lett. 2001, 3, 2819–2821. (h) Bader,
S. J.; Snapper, M. L. J. Am. Chem. Soc. 2005, 127, 15453–15456. (i) Sieburth,
S. McN.; McGee, K. F., Jr.; Al-Tel, T. H. J. Am. Chem. Soc. 1998, 120, 587–
588. (j) Sieburth, S. McN.; McGee, K. F., Jr.; Al-Tel, T. H Tetrahedron Lett.
1999, 40, 4007–4010. (k) Sieburth, S. McN.; McGee, K. F., Jr.; Al-Tel, T. H.
Synthesis 2001, 118, 5–1197. (l) Wender, P. A.; Nuss, J. M.; Smith, D. B.; Sua´rez-
Sobrino, A.; Vågberg, J.; Decotas, D.; Brodner, J. J. Org. Chem. 1997, 62, 4908–
4909. (m) Paquette, L. A.; Colapret, J. A.; Andrews, D. R. J. Org. Chem. 1985,
50, 201–205. (n) Paquette, L. A.; Wang, T.-Z.; Vo, N. H. J. Am. Chem. Soc.
1993, 115, 1676–1683. (o) Rowley, M.; Kishi, Y. Tetrahedron Lett. 1988, 29,
4909–4912. (p) Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989,
111, 2735–2737. (q) Dauben, W. G.; Warshawsky, A. M. J. Org. Chem. 1990,
55, 3075–3087. (r) Snider, B. B.; Yang, K. J. Org. Chem. 1992, 57, 3615–3626.
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113, 5765–5775. (b) Mehta, G. Pure Appl. Chem. 1990, 62, 1263–1268. (c)
Mehta, G.; Krishnamurthy, N.; Karra, S. R. J. Chem. Soc., Chem. Commun.
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(7) For recent reviews on the Nazarov cyclization, see: (a) Tius, M. A. Eur.
J. Org. Chem. 2005, 2193–2206. (b) Pellissier, H. Tetrahedron 2005, 61, 6479–
6517. (c) Frontier, A. J.; Collision, C. Tetrahedron 2005, 61, 7577–7606.
(8) For recent syntheses that use a Nazarov reaction as a key step, see: (a)
Waters, S. P.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2005,
127, 13514–13515. (b) Liang, G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem.
Soc. 2006, 8, 11022–11023. (c) He, W.; Huang, J.; Sun, X.; Frontier, A. J. J. Am.
Chem. Soc. 2007, 129, 498–499. (d) Wan, L.; Tius, M. A. Org. Lett. 2007, 9,
647–650. (e) Reference 5d.
(9) (a) Yet, L. Chem. ReV. 2000, 100, 2963–3007. (b) Mehta, G.; Singh, V.
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1992, 48, 5757–5821.
(10) (a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746–8749.
For other metathesis-based approaches to eight-membered rings, see: (b)
Bourgeois, D.; Pancrazi, A.; Ricard, L.; Prunet, J. Angew. Chem., Int. Ed. 2000,
39, 726–728. (c) Mori, M.; Kitamura, T.; Sakikabara, N.; Sato, Y. Org. Lett.
2000, 2, 543–545.
a Reagents and conditions: (a) LDA, THF, -78 °C, 30 min, then CH3I,
-78 °C (93%); (b) LDA, HMPA, THF, -78 °C, 1 h, then 5-iodopent-2-
yne, -78 °C to rt (54%, 80% based on conversion); (c) DIBAL-H, CH2Cl2,
-78 °C (92%); (d) KHMDS, CH3PPh3Br, THF, 0 °C to rt, (99%); (e)
TBSCl, imidazole, DMF, 50 °C (95%); (f) TIPSCl, imidazole, DMF, 70
°C (56%); (g) TBAF, THF (99%); (h) for 12: 2,2-dimethoxypropane,
p-TsOH, CH2Cl2 (87%); for 13: 3,3-dimethoxypentane, p-TsOH, CH2Cl2
(91%); for 14: cyclohexanone (neat), CuSO4, p-TsOH (96%).
membered ring in each of these natural products suggested that
a related synthetic approach that we had applied to the
construction of the nitiane A-ring system could be utilized within
an approach to the fusicoccane ring system.4
As expected, a significant amount of attention by synthetic
chemists has been brought to bear on the tricyclic ring system
typified by the fusicoccane diterpenes and its structural relatives.
A number of total syntheses and synthetic approaches to these
and structurally related natural products have been disclosed.5
The specific problem in establishing the cis-relationship of the
methyl and isopropyl groups on the five-membered ring has
been dealt with by using a number of creative solutions,
including a doubly diastereoselective addition of an allylstannane
or allylchromium reagent to an aldehyde.6 Our analysis of the
fusicoccane ring system is presented in Scheme 1. In a linear
fashion, the target tricyclic ring would be envisioned to arise
from three successive ring-forming events. We planned to
annulate the final five-membered carbocycle onto the central
eight-membered ring in 2 using Nazarov methodology.7,8
(11) Reviews of enyne metathesis: (a) Chattopadhyay, S. K.; Karmakar, S.;
Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63,
3919–3952. (b) Mori, M. AdV. Synth. Catal. 2007, 349, 121–135. (c) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317–1382. (d) Poulson, C. S.;
Madsen, R. Synthesis 2003, 1–18. (e) Mori, M.; Kitamura, T.; Sato, Y. Synthesis
2001, 654–664.
(12) For a review outlining the use of photochemical processes as key
reactions within total synthesis endeavours, see: Hoffmann, N. Chem. ReV. 2008,
108, 1052–1103.
The construction of eight-membered rings is recognized to
be challenging, often requiring the development of new synthetic
methodology.9 In this instance, the central eight-membered ring
in 3 was envisioned to arise from an enyne or diene ring-closing
metathesis reaction of a substrate related to 1, based on the
6712 J. Org. Chem. Vol. 73, No. 17, 2008

Fusicoccane Synthetic Approach
that was modified somewhat to improve both material through-
put and reaction yields on multigram scales.13 A two-step
alkylation sequence was used to establish the stereogenic
quaternary carbon center of the enyne substrate (Scheme 2).
Treatment of lactone 6 with LDA and methyl iodide generated
a monomethylated lactone 7 as a ∼9:1 mixture of diastereomers.
This mixture was inconsequential as its deprotonation using
LDA (1.1 equiv) in THF with HPMA (2.2 equiv) followed by
the addition of 5-iodopent-2-yne produced the desired compound
8 in 40-50% yield (depending on reaction scale) with ∼5% of
the undesired diastereomer and ∼30% of unalkylated lactone
as the major byproducts. The use of LDA with HMPA was
uniquely effectivesin the absence of the HMPA additive the
major reaction was an E2 process on the electrophile. This
sequence, while not optimal, could be performed on 35-80 g
scales and the unalkylated lactone starting material was easily
separable for recycling of material. The lactone was subse-
quently processed in a straightforward manner to the enyne 9
by using a DIBAL-H reduction followed by a Wittig reaction.
Reasonable diastereoselection in the Pauson-Khand reaction
FIGURE 2. NOE experiments on 15a and 15b.
experiments were used to establish the relative stereochemistry
of 15a and 15b (Figure 2). Deprotection of each of the product
mixtures (15-19a/b) generated diols whose spectral data could
be directly compared.
Compounds 17a/b were not easily separable, and so this
mixture was typically taken directly into the next reaction
sequence (eq 3). Conjugate reduction of the enone function in
17a/b with L-Selectride followed by a methyl iodide quench
produced readily separable ketones in 96% combined yield. At
this point a straightforward separation provided the desired
diastereomer 20.
was needed for a useful synthesis of the A-ring fragment.14
A
number of protecting group patterns were evaluated to determine
the best choice. It was reasoned that the protecting group on
the secondary alcohol of enyne 9 should be as large as possible.
To that end a number of enynes 10-14 were synthesized by
using standard procedures (silylation and ketalization).
These enyne substrates were then individually subjected to
Pauson-Khand conditions (Co2(CO)8, 4Å molecular sieves,
CH2Cl2; NMO, rt).15 The results are summarized in eq 2 and
Table 1.
Ketone 20 was subjected to photolytic Norrish 1 fragmenta-
tion conditions (UV light, λ > 190 nm, methanol).16 Gratify-
ingly, the functionalized cyclopentane derivative 21 could be
produced in 41-70% yield, depending on the reaction condi-
tions. Running the reactions at higher dilutions (0.015 M) for
∼5 h consistently resulted in useful yields of 70%. Prolonged
reaction times resulted in lowered yields.
At this stage, ester 21 was processed to allylic alcohol 25 by
using standard synthetic procedures (Scheme 3). An important
intermediate along this route was the nitrile 23, as its crystals
TABLE 1. Evaluation of Protecting Group Modifications on the
Pauson-Khand Reaction
yielda
drb
pdts
entry substrate
P1
P2
(%) (major/minor) (major/minor)
(13) Frieman, B. A.; Bock, C. W.; Bhat, K. L. Heterocycles 2001, 55, 2099–
2108.
1
2
3
4
5
10
11
12
13
14
TBS TBS
TBS TIPS
-C(Me)2-
-C(Et)2-
83
86
89
84
79
2.4:1
2.8:1
6.1:1
1.3:1
2.2:1
15a/15b
16a/16b
17a/17b
18a/18b
19a/19b
(14) For reviews containing pertinent references, see: (a) Ojima, I.; Tzama-
rioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635–662. (b) Geis,
O.; Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1998, 37, 911–914. (c)
Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263–3447. (d) Fletcher,
A. J.; Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000, 1657. (e) Rivero,
M. R.; Adrio, J.; Carretero, J. C. Eur. J. Org. Chem. 2002, 288, 1–2889. (f)
Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. Engl. 2003, 42, 1800–
1810. (g) Bon˜aga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795–9833.
(h) Blanco-Urgoiti, J.; An˜orbe, L.; Pe´rez-Serrano, L.; Dom´ınguez, G.; Pe´rez-
Castells, J. Chem. Soc. ReV. 2004, 33, 32–42.
-C(C5H10)-
a Combined isolated yield. b dr ) diastereomeric ratio; determined by
GC analysis.
The results within Table 1 show that one protecting group
strategy for the diol, the isopropyl acetonide, was obviously
superior to other alternatives (entry 3). This empirical result is
somewhat unexpected, especially in light of the results in entries
4 and 5. The result in entry 3 was welcome and useful for our
purposes, but no mechanistic underpinning can be presented to
rationalize it at the present time. The Pauson-Khand reaction
of 12 was highly reproducible on several scales.
(15) (a) Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez, G.; Pe´rez-Castells,
J. Org. Lett. 1999, 1, 1187–1188. (b) Shambayati, S.; Crowe, W. E.; Schreiber,
S. Tetrahedron Lett. 1990, 31, 5289–5292.
(16) (a) Norrish, R. G. W.; Bamford, C. H. Nature 1936, 138, 1016. (b)
Norrish, R. W.; Bamford, C. H. Nature 1937, 140, 195. Reviews: (c) Turro,
N. J.; Dalton, J. C.; Dawes, K.; Farrington, G.; Hautala, R.; Morton, D.;
Niemczyk, M.; Schore, N. Acc. Chem. Res. 1972, 5, 92. (d) Coyle, J. D.; Carless,
H. A. J. Chem. Soc. ReV. 1972, 1, 465–480. (e) Chapman, O. L.; Weiss, D. S.
Org. Photochem. 1973, 3, 197. (f) WeissD. S. Organic Photochemistry; Marcel
Dekker: New York, 1981; Vol. 5, pp 347-420. (g) HorspoolW. M. Specialist
Periodical Report, Photochemistry; Royal Society of Chemistry: London, UK,
1988; Vol. 19, pp 151-157. (h) Horspool, W. M. Photochemistry 1994, 25, 67.
The structural constitution and relative stereochemistry of the
products was established by NMR methods. Specifically, NOE
J. Org. Chem. Vol. 73, No. 17, 2008 6713

Dake et al.
SCHEME 4. Elaboration to the A-B Ring Systema
SCHEME 3. Installation of the C7 Stereocentera
a Reagents and conditions: (a) H5IO6, EtOAc (85%); (b) Ohira-Bestmann
phosphonate, K2CO3, MeOH (70%); (c) n-BuLi, THF, -78 °C, then CH3I,
-78 °C to rt; (d) (IMes)Cl2RudCHPh (30 mol %), CH2Cl2, 40 °C (53 %).
desired eight-membered ring, but only when catalyzed by a
Grubbs “Type 2” N-heterocyclic carbene containing ruthenium
catalyst20 at high loadings (30 mol %) in dichloromethane (40
°C). Major side products (as analyzed by GC-MS) in this
reaction mixture included compounds resulting from cross-
metathesis of (a) 2 equiv of 1 and (b) 1 and styrene (originating
from the catalyst).21 Alkene ring-closing metathesis did not
proceed on a related substrate to 1 with use of either a Grubbs
“Type 2” catalyst or a Schrock catalyst.
The successful construction of 3 has provided significant
information regarding this strategy for a fusicoccane synthesis.
The relative stereochemistry of the A-ring fragment of the
fusicoccane ring system was established by application of our
diastereoselective Pauson-Khand-Norrish 1 ring-opening pro-
cess. Reagent-controlled cyclopropanation followed by ring
opening was used to install the methyl group at C(7) of the
fusicoccanes with the appropriate stereochemical configuration.
The eight-membered ring of the fusicoccane skeleton was
constructed by using a metathesis strategy. Our aim is to utilize
3 as a common intermediate for the installation of differently
functionalized five-membered C ring equivalents to access a
number of fusicoccane natural products.22 A second generation
approach may utilize a more convergent strategy for the natural
product skeleton while maintaining the specific tactics described
in this paper to establish crucial relative stereochemical
configurations. Our laboratory is continuing work toward the
solution of these problems.
a Reagents and conditions: (a) LAH, Et2O, 0 to 25 °C (95%); (b) Et3N,
MsCl, CH2Cl2, 0 °C; (c) NaCN, DMSO, 60 °C (96%); (d) DIBAL-H,
CH2Cl2, -78 °C (95%); (e) (MeO)2P(O)CH2CO2Me, DBU, CH3CN, -15
°C (85%); (f) DIBAL-H, CH2Cl2, -78 °C (95%); (g) dioxaborolane 26 (1
equiv) then Zn(CH2I)2, CH2Cl2, 0 to 25 °C (97%); (h) Et3N, MsCl, CH2Cl2,
0 °C to rt; (i) NaI, acetone, 25 °C (90%); (j) n-BuLi, TMEDA, 4 Å MS,
Et2O, -78 °C (88%).
were amenable to X-ray analysis, allowing for verification of
its constitution and relative stereochemistry. Using this sequence,
alcohol 25 could be produced in an efficient manner.
The elegant and useful protocols of Charette and his group
were then used to establish the necessary pendant methyl group
substitution on C-7 of the eight-membered B-ring.17,18 Treat-
ment of 25 with di(iodomethylene)zinc in the presence of 1.1
equiv of the chiral organoboron promoter (S,S)-26 led to
formation of cyclopropane 27 in >90% yield with >95:5
diastereoselectivity. We encountered reduced diastereoselectivity
in this cyclopropanation reaction when the reaction was scaled
up, perhaps because of its exothermicity. For consistent results,
synthetic material was processed in parallel batches on ∼250
mg scales. Conversion of 27 to alkene 28 was performed by
(a) conversion of the hydroxyl function to an iodide followed
by (b) lithium-halogen exchange followed by cyclopropane ring
opening.
Experimental Section
[3.3.0]-(5R,6R)-6-((2S)-2,3-O-Isopropylidene-2,3-dihydroxypro-
pyl)-2,6-dimethylbicyclonon-1-en-3-one (17a) and [3.3.0]-(5S,6R)-
6-((2S)-2,3-O-Isopropylidene-2,3-dihydroxypropyl)-2,6-dimethyl-
bicyclonon-1-en-3-one (17b).
A solution of (2S,4R)-1,2-O-
isopropylidene-4-methyl-4-vinyl-7-nonyne-1,2-diol (12) (5.10 g,
21.6 mmol, 1 equiv) in methylene chloride (430 mL) was added to
4 Å molecular sieves (51.0 g) followed by dicobalt octacarbonyl
(8.12 g, 23.7 mmol, 1.10 equiv) in 1 portion and the reaction
mixture was stirred at rt for 1 h. 4-Methylmorpholine N-oxide (22.8
g, 0.194 mol, 9.0 equiv) was added in 3 portions to the reaction
Alkene 28 was subjected to periodate cleavage (Scheme 4).
This process was followed by reaction between the resulting
aldehyde and the Ohira-Bestmann phosphonate (a modified
Gilbert-Seyferth process) to produce terminal alkyne 29.19 In
our hands, the enyne metathesis of compound 1 did furnish the
(17) Charette, A. B.; Naud, J. Tetrahedron Lett. 1998, 39, 7259–7262.
(18) (a) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651–
2652. (b) Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60, 1081–
1083. (c) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc.
1998, 120, 11943–11952. (d) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am.
Chem. Soc. 2001, 123, 12168–12175.
(20) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(21) Attempting the enyne metathesis ring closure under an ethylene
atmosphere led to formation of a 1,3-diene from the alkyne function in the starting
material. See: Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082–6083.
(19) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Mueller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 6, 521–522.
(22) Preliminary model studies investigating the installation of the fusiccocane
“C-ring” have been conducted. Please refer to the Supporting Information.
6714 J. Org. Chem. Vol. 73, No. 17, 2008

Fusicoccane Synthetic Approach
mixture at 0 °C and the reaction mixture was stirred at rt overnight.
The reaction mixture was filtered through a plug of silica gel, the
silica gel was washed with ether (500 mL), and the filtrate was
concentrated to yield a clear brown liquid. The crude liquid was
purified by column chromatography (1/9 ethyl acetate-hexanes)
to yield 5.09 g (89%) of a 86:14 mixture of the two diastereomers
17a and 17b (gas chromatography analysis) as a clear colorless
liquid. Further purification of an analytical sample by column
chromatography (1/19 ethyl acetate-hexanes) was performed to
yield an analytically pure sample of 17a as a clear colorless liquid.
73.7, 70.7, 52.8, 49.7, 46.9, 45.5, 43.3, 37.6, 37.4, 26.9, 25.9, 25.5,
23.2, 19.7. Anal. Calcd for C17H28O3: C, 72.82; H, 10.06. Found:
C, 72.42; H, 10.19.
(1R,2S,3R)-3-Isopropyl-1-((2S)-2,3-O-isopropylidene-2,3-dihy-
droxypropyl)-1-methyl-2-methylethanoatecyclopentane (21). A
solution of [3.3.0]-(1R,5S,6R)-6-((2S)-2,3-O-isopropylidene-2,3-
dihydroxypropyl)-2,2,6-trimethylbicyclononan-3-one (20) (1.48 g,
5.28 mmol, 1 equiv) in methanol (350 mL) in a quartz reaction
vessel was irradiated with light from a 450-W Hanovia medium
pressure mercury lamp for 5.5 h, after which the reaction mixture
was concentrated in vacuo to yield a clear colorless liquid. The
crude liquid was purified by column chromatography (1/19 ethyl
acetate-hexanes) to yield 1.15 g (70%) of 21 as a clear colorless
liquid, and 0.133 g (9%) of 20 as a clear colorless liquid.
1
IR (neat): 2985, 2933, 1706, 1668 cm-1. H NMR (300 MHz,
CDCl3): δ 4.18-3.93 (m, 2H), 3.42 (t, J ) 7.6 Hz, 0.84H), 3.35
(t, J ) 7.7 Hz, 0.16H), 2.75-2.25 (4H), 2.10-1.55 (m, 8H), 1.35
(s, 5.03H), 1.29 (s, 2.52H), 1.10 (s, 0.48H), 0.65 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 210.7, 210.5, 183.0 182.6, 132.5, 132.0, 108.8,
108.6, 73.6, 73.1, 70.5, 70.3, 56.3, 53.5, 45.1, 41.1, 40.7, 39.9, 37.4,
36.7, 35.5, 35.0, 26.9, 26.8, 25.8, 25.4, 24.4, 24.0, 18.1, 8.2. LRMS
(EI) m/z (rel intensity): 264 (M+, 27).
25.1
[R]D +22.20 ( 0.02 (0.645, CHCl3). IR (neat): 2953, 2872,
1
1740 cm-1. H NMR (300 MHz, CDCl3): δ 4.17-4.06 (m, 2H),
3.65 (s, 3H), 3.42 (t, J ) 7.16 Hz, 1H), 2.27-2.04 (m, 3H),
1.81-1.69 (m, 3H), 1.65-1.54 (m, 2H), 1.47-1.29 (m, 2H), 1.37
(s, 3H), 1.33 (s, 3H), 1.25-1.12 (m, 1H), 0.89 (s, 3H), 0.86 (d, J
) 5.82 Hz, 3H), 0.84 (d, J ) 5.82 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 174.8, 108.0, 73.9, 70.8, 51.6, 49.7, 45.8, 45.2, 44.2,
36.9, 30.5, 29.7, 27.5, 26.9, 25.9, 22.7, 22.0, 21.7. Anal. Calcd for
C18H32O4: C, 69.19; H, 10.32. Found: C, 69.09; H, 10.34.
[6.3.0]-(1R,5S,8S,9R)-1,5-Dimethyl-9-isopropyl-3-(prop-1-en-
2-yl)bicycloundec-2-ene (3). Ruthenium [1,3-bis-(2,4,6-trimethyl-
phenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexyl-
phosphine) (68 mg, 0.08 mmol, 30 mol %) was added in 1 portion
to a solution of (1R,2S,3R)-1-(2-but-2-ynyl)-3-isopropyl-1-methyl-
2-((3S)-3-methylpent-4-enyl)cyclopentane (1) (70 mg, 0.27 mmol,
1 equiv) in methylene chloride (5 mL) and the reaction mixture
was heated to reflux for 18 h. Triethylamine (0.5 mL) was added,
and the reaction mixture was concentrated in vacuo to yield a dark
red liquid. Purification by column chromatography (hexanes)
yielded 37 mg (53%) of the title compound as a clear, colorless
liquid.
[3.3.0]-(5R,6R)-6-((2S)-2,3-O-Isopropylidene-2,3-dihydroxypro-
20.7
pyl)-2,6-dimethylbicyclonon-1-en-3-one (17a): [R]D -48.47 (
0.08 (c 0.303, CHCl3). IR (neat): 2985, 2933, 1706, 1668 cm-1
.
1H NMR (400 MHz, CDCl3): δ 4.18-4.10 (m, 1H), 4.01 (dd, J )
7.8, 5.9 Hz, 1H), 3.42 (t, J ) 7.6 Hz, 1H), 2.70 (m, 1H), 2.59-2.29
(m, 3H), 2.04 (dd, J ) 18.1, 2.9 Hz, 1H), 1.97-1.78 (m, 2H),
1.74-1.57 (m, 2H), 1.64 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H), 0.64
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 210.6, 182.4, 132.6, 108.8,
73.6, 70.3, 53.5, 45.1, 41.1, 40.0, 36.8, 27.0, 25.8, 24.0, 18.1, 8.2.
LRMS (EI) m/z (rel intensity): 264 (M+, 5). Anal. Calcd for
C16H24O3: C, 72.69; H, 9.15. Found: C, 72.52; H, 9.28.
[3.3.0]-(1R,5S,6R)-6-((2S)-2,3-O-Isopropylidene-2,3-dihydroxy-
propyl)-2,2,6-trimethylbicyclononan-3-one (20). L-Selectride (16.0
mL of a 1.0 M solution in THF, 16.0 mmol, 1.05 equiv) was added
dropwise to a solution of a 5.2:1 mixture of [3.3.0]-(5R,6R)-6-(2′,3′-
O-isopropylidene-2′,3′-dihydroxypropyl)-2,6-dimethylbicyclonon-
1-en-3-one (17a) and [3.3.0]-(5S,6R)-6-(2′,3′-O-isopropylidene-2′,3′-
dihydroxypropyl)-2,6-dimethylbicyclonon-1-en-3-one (17b) (4.03
g, 15.2 mmol, 1 equiv) in THF (150 mL) at -78 °C and the reaction
mixture was stirred at -78 °C for 30 min. Iodomethane (0.996
mL, 16.0 mmol, 1.05 equiv) was added dropwise and the reaction
mixture was warmed to rt over 30 min, followed by stirring at rt
overnight. Water (100 mL) was added and the mixture was extracted
with ether (3 × 50 mL). The ether extracts were combined, washed
with a 2 N aqueous solution of sodium hydroxide (50 mL) and a
saturated aqueous solution of sodium chloride (50 mL), dried over
magnesium sulfate, and concentrated in vacuo to yield a clear
colorless liquid. The crude liquid was purified by column chroma-
tography (1/19 ethyl acetate-hexanes) to yield 3.45 g (81%) of 20
as a clear colorless liquid and 0.639 g (15%) of [3.3.0]-(1S,5R,6R)-
6-((2S)-2,3-O-isopropylidene-2,3-dihydroxypropyl)-2,2,6-trimeth-
[R]D20.0 +8.87 ( 0.15 (c 0.100, CHCl3). IR (neat): 3089, 2926,
2854, 1637 cm-1. 1H NMR (300 MHz, CDCl3): δ 5.40 (d, J ) 9.4
Hz, 1H), 5.01 (s, 1H), 4.87 (s, 1H), 2.57 (d, J ) 13 Hz, 1H), 2.12
(d, J ) 13 Hz, 1H), 1.90 (s, 3H), 1.85-1.00 (m, 12H), 1.01 (d, J
) 6.2 Hz, 3H), 0.85 (d, J ) 6.9 Hz, 3H), 0.70 (d, J ) 6.9 Hz, 3H),
0.63 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 145.0, 144.4, 113.8,
112.4, 50.4, 50.3, 48.0, 45.7, 38.8, 38.1, 38.0, 32.1, 29.7, 27.3, 25.3,
22.4, 22.0, 14.2, 14.1. LRMS (EI) m/z (rel intensity): 260 (M+, 1).
Acknowledgement. The authors thank the University of
British Columbia, the Natural Sciences and Engineering Re-
search Council (NSERC) of Canada, GlaxoSmithKline, and
Merck-Frosst for the financial support of our programs.
ylbicyclononan-3-one as a white solid.
22.4
20: [R]D
+58.15 ( 0.09 (c 0.367, CHCl3). IR (neat): 2932,
Supporting Information Available: Experimental proce-
dures and characterization data for compounds 1-31. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
1737 cm-1. H NMR (400 MHz, CDCl3): δ 4.19-4.11 (m, 1H),
4.04 (dd, J ) 7.92 5.79 Hz, 1H), 3.44 (t, J ) 7.92 Hz, 1H),
2.47-2.24 (m, 3H), 2.06-1.98 (m, 1H), 1.82-1.64 (m, 3H),
1.52-1.33 (m, 3H), 1.37 (s, 3H), 1.33 (s, 3H), 1.02 (s, 3H), 1.00
(s, 3H), 0.95 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 222.9, 108.4,
JO800933F
J. Org. Chem. Vol. 73, No. 17, 2008 6715