Diels-Alder cycloaddition and ring-closing metathesis: A versatile, stereoselective, and general route to embellished bridged bicyclic systems, carbocyclic framework of secoatisanes, and homologues

Article abstract of DOI:10.1021/jo901279g

(Chemical Equation Presented) A general and stereoselective methodology for the synthesis of bridged bicyclic octenones having various types of alkenyl chains and a tricyclic framework of secoatisanes and higher analogues is reported. In situ generation and cycloaddition of 2-allyl-6,6- spiroepoxycyclohexadienones with ethyl acrylate gave bicyclo[2.2.2]octanes having an allyl group at the bridgehead and other chemically distinguishable functionality in a regio- and stereoselective fashion. Selective manipulation of adducts led to the introduction of other olefinic chain of variable lengths at the carbon adjacent to the bridge head. Ring-closing metathesis in bicyclooctanes having olefin tethers provided an efficient route to tricyclic systems having bicyclo[2.2.2]octane framework having spiro-fused six-, seven-, and eight-membered rings.

Full text of DOI:10.1021/jo901279g

pubs.acs.org/joc
Diels-Alder Cycloaddition and Ring-Closing Metathesis: A Versatile,
Stereoselective, and General Route to Embellished Bridged Bicyclic
Systems, Carbocyclic Framework of Secoatisanes, and Homologues
Vishwakarma Singh,*,† Pramod K. Sahu,† Bharat C. Sahu,† and Shaikh M. Mobin‡
†Department of Chemistry and ‡National Single X-ray Diffraction Facility, Indian Institute of Technology,
Bombay, Mumbai 400 076, India
vks@chem.iitb.ac.in
Received June 15, 2009
A general and stereoselective methodology for the synthesis of bridged bicyclic octenones having
various types of alkenyl chains and a tricyclic framework of secoatisanes and higher analogues is
reported. In situ generation and cycloaddition of 2-allyl-6,6-spiroepoxycyclohexadienones with ethyl
acrylate gave bicyclo[2.2.2]octanes having an allyl group at the bridgehead and other chemically
distinguishable functionality in a regio- and stereoselective fashion. Selective manipulation of
adducts led to the introduction of other olefinic chain of variable lengths at the carbon adjacent to
the bridge head. Ring-closing metathesis in bicyclooctanes having olefin tethers provided an efficient
route to tricyclic systems having bicyclo[2.2.2]octane framework having spiro-fused six-, seven-, and
eight-membered rings.
Introduction
(Figure 1) having tricyclo[6.2.2.01,6]dodecane framework of
type 3 were isolated recently from Chinese mangrove Exoe-
caria.3 The tricyclo[6.2.2.01,6]dodecane core is also present in
the molecular structure of platencin 2d, which was recently
isolated from Stereptomyces plantecis.4 Platencin, a potent
inhibitor of FabH and FabF,2 has also stimulated intense
interest on account of its biological activity and unusual
structure.5 While there are no synthetic studies toward
recently isolated secoatisanes, only a few routes to atisanes
Atisanes and secoatisanes constitute an important class of
diterpenoids that have generated significant interest by
virtue of their complex molecular architecture containing a
spiro-fused bicyclo[2.2.2]octane framework and diverse bio-
logical properties.1-3 Serofendic acid A 1, a member of a
unique class of atisane diterpenoids, recently isolated from
lipophilic extracts of fetal calf serum has been found to
possess neuroprotective activity.2 While atisanes type diter-
penoids are known for long time, seco-atisanes 2a-c
(4) Jayasuriya, H.; Herath, K. B.; Zhang, C.; Zink, D. L.; Basilio, A.;
Genilloud, O.; Diez, M. T.; Vicente, F.; Gonzalez, I.; Salazar, O.; Pelaez, F.;
Cummings, R.; Ha, S.; Wang, J.; Singh, S. B. Angew. Chem., Int. Ed. 2007, 46,
4684–4688.
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Zheng, J.-C.; Lee, D. Angew. Chem., Int. Ed. 2008, 47, 6201–6203. (d)
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Int. Ed. 2008, 47, 1780–1783.
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Blunt, J. W.; Cardellina, J. H.; McMahon, J. B.; Gulakowski, R. J.; Cragg, G. M.;
Cox, P. A.; Brinen, L. S.; Clardy, J.; Boyd, M. R. Tetrahedron 1991, 47, 4547–
4554. (c) Lal, A. R.; Cambie, R. C.; Rutledge, P. S.; Woodgate, P. D. Tetrahedron
Lett. 1989, 30, 3205–3208. (d) Perry, N. B.; Burgess, E. J.; Baek, S-H; Weavers,
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R.; Shirakawa, H.; Osakada, F.; Mori, H.; Asakawa, N.; Yonaga, M.;
Nishizawa, Y.; Sugimoto, H.; Shimohama, S.; Katsuki, H.; Kaneko, S.;
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6092 J. Org. Chem. 2009, 74, 6092–6104
Published on Web 07/17/2009
DOI: 10.1021/jo901279g
r
2009 American Chemical Society

Singh et al.
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SCHEME 1
FIGURE 1. Serofendic acid A 1, secoatisanes 2a-c, platencin 2d,
and potential intermediates 3 and 4.
diterpenoids have been developed.6-9 Some of these em-
ployed a double Michael addition to create spiro-annulated
bicyclo[2.2.2]octane system,8a-c whereas others used indirect
methods.6,9
Recently, there has been an upsurge of interest in the
development of new methods involving reactive intermedi-
ates arising as a result of oxidative dearomatization such as
o-quinols, cyclohexadienone ketals, and spiroepoxycyclo-
hexa-2,4-dienones, and the chemistry of these species has
provided efficient methodology for the synthesis of a variety
of molecular architectures.10-12
In view of the limited routes available for the construction
of tricyclo[6.2.2.01,6]dodecane framework and our continu-
ing interest11 in the development of new methods employing
6,6-spiroepoxycyclohexadienones, we considered develop-
ing a new and general route to functionalized tricyclo-
[6.2.2.01,6]dodecanes of type 3a as well as the higher
homologues of type 3b,c having medium rings fused to the
bridged bicyclooctane framework. It was envisaged that a
ring-closing metathesis reaction in appropriately designed
bridged bicyclic compounds of type 4 would provide a
general and flexible entry to annulated bicyclooctenones of
type 3. The crucial precursor of type 4 was thought to be
derived from the functionalized bicyclo[2.2.2]octenones of
type 5. The precursor 5 was thought to be prepared from the
aromatic precursor 8 via its transformation to spiroepoxy-
cyclohexadienone 7, cycloaddition, and subsequent manip-
ulation of the adduct 6 (Scheme 1).
There are several interesting features of our strategy. For
example, the allylic chain at the bridgehead in crucial precursor
4 is derived from the starting aromatic precursor 8. The other
olefinic tether will be introduced by manipulation of the endo
ester group in 5, thus keeping both the tethers in appropriate
stereochemical disposition required for the ring-closing me-
tathesis. Furthermore, the bridged bicyclic precursor 4 is
generated via manipulation of the adduct 6 which is endowed
with easily distinguishable functionalities and rapidly as-
sembled from a simple aromatic precursors of type 8.
We wish to report herein a general and stereoselec-
tive methodology for the synthesis of embellished bi-
cyclo[2.2.2]octanes of type 4 having various types olefinic
tethers from simple aromatic precursors, and their ring-
closing metathesis leading to functionalized tricyclo-
[6.2.2.01,6]dodecanes 3a and their homologues 3b,c having
medium rings.
FIGURE 2. Cyclohexa-2,4-dienones and potential dienophile.
Results and Discussion
Synthesis of the Bicyclic Systems of Type 4 Endowed with
Olefinic Tethers. Conceptually, the bicyclic systems of type 4
may be accessible via a direct cycloaddition of cyclohexa-2,4-
dienones such as 9 with ethyl acrylate followed by further
manipulation. However, cyclohexadienones of type 9 are not
accessible as these are keto tautomers of the corresponding
phenols. We therefore employed the 6,6-spiroepoxycyclo-
hexa-2,4-dienone 7, which may be generated by the oxidative
dearomatization of o-hydroxymethyl phenols and its cy-
cloaddition with acrylate and manipulation of the resulting
adduct for the synthesis of bridged bicyclic systems of type 4.
Thus, the o-hydroxymethyl phenols 12a,b were easily
prepared from p-cresol 10a and salicyldehyde 10b, respec-
tively. Allylation of p-cresol followed by Claisen rearrange-
ment gave 11a which upon hydroxymethylation readily gave
the known11b compound 12a in good yield (Scheme 2).
Similarly, the aldehyde 11b was prepared from salicylde-
hyde13 and reduced with sodium borohydride to give the
hydroxymethyl phenol 12b.
(7) (a) Toyota, M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65, 4565–
4570. (b) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc.
1998, 120, 4916–4925. (c) Berettoni, M.; Chiara, G. D.; Iacoangeli, T.; Surdo,
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(8) (a) Ihara, M.; Makita, K.; Tokunaga, Y.; Fukumoto, K J. Org. Chem.
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T. J. Chem. Soc., Perkin Trans. 1 1986, 2151–2161. (c) Hagiwara, H.;
Okamoto, T.; Harada, N.; Uda, H. Tetrahedron 1995, 51, 9891–9898.
(9) (a) Abad, A.; Agullo, C.; Cunat, A. C.; Marzal, I. A.; Navarro, I.;
Gris, A. Tetrahedron 2006, 62, 3266–3283. (b) Abad, a.; Agullo, C.; Cunat, A.
C.; Navarro, I. Tetrahedron Lett. 2001, 42, 8965–8968.
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Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383–1429.
(c) Liao, C. -C.; Peddiniti, R. K. Acc. Chem. Res. 2002, 35, 856–866. (d)
Quideau, S.; Pouysegu, L. Org. Prep. Proc. Int. 1999, 31, 617–680.
(11) (a) Singh, V. Acc. Chem. Res. 1999, 32, 324–333. (b) Singh, V.;
Praveena, J. D.; Karki, K.; Mobin, S. M. J. Org. Chem. 2007, 72, 2058–2067.
(c) Singh, V.; Chandra, G.; Mobin, S. M. Synlett. 2008, 3111–3114. (d) Singh,
V.; Chandra, G.; Mobin, S. M. Synthesis 2008, 2719–2728. (e) Singh, V.;
Singh, R. B.; Mobin, S. M. Synth. Commun. 2009, 39, 111–119.
(12) (a) Wood, J. L.; Graeber, J. K.; Njardarson, J. T. Tetrahedron 2003,
59, 8855–8858. (b) Quideau, S.; Lebon, M.; Lamidey, A.-M. Org. Lett. 2002,
4, 3975–3978. (c) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4,
493–496. (d) Bonnarme, V.; Mondon, M.; Gesson, J.-P.; Cousson, A. J.
Chem. Soc., Chem. Commun. 1999, 1143–1144. (e) Carlini, R.; Higgs, K.;
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SCHEME 2
SCHEME 3
A solution of 6-allyl-2-hydroxymethyl-4-methylphenol
12a in acetonitrile containing ethyl acrylate was oxidized
with aqueous sodium m-periodate,14 following a procedure
developed in our laboratory,15 to give the endo adduct 14 in
reasonably good yield as a result of regio- and stereoselective
cycloaddition of in situ generated cyclohexa-2,4-dienone 13
and ethyl acrylate (Scheme 2).
However, oxidation of the precursor 12b under similar
conditions gave the desired adduct 17 in very poor yield
(9%), and the dimer 16 was obtained as a major product. The
structure of dimer 16 was deduced from its spectral features
and further confirmed through single-crystal X-ray diffrac-
tion (Supporting Information). It appears that the formation
of the dimer 16 is presumably due to the relatively faster rate
of intermolecular cycloaddition as compared to 13 which has
a methyl group at C-4. In view of the above, it was thought
that in situ generation of the cyclohexadienone 15 via retro
Diels-Alder reaction of the dimer 16 and subsequent inter-
ception with ethyl acrylate under thermal activation might
lead to the formation of the desired adduct 17. Therefore, the
dimer 16 was prepared by the oxidation of 12b and heated in
the presence of ethyl acrylate. Indeed, chromatography of
the reaction mixture furnished the desired adduct 17 in
excellent yield (91%) (Scheme 3).
The structure of both adducts was deduced from their
spectral data and comparison. Thus, the IR spectrum of
adduct 14 showed a broad absorption band at 1736 cm-1 for
the carbonyl groups of R-epoxy ketone and the ester group.
The 1H NMR (300 MHz) spectrum displayed characteristic
signals at δ 5.92-5.78 (m, 1H), 5.13-5.04 (m, 2H), and 5.64
(s with structure, 1H) for olefinic protons of the allyl moiety
and the β-proton of β,γ-enone group, respectively. The
methylene protons of ester were observed at δ 4.12 (q, J=
6 Hz, 2H). The protons of the oxirane ring showed a
characteristic signals at δ 3.15 as part of an AB system
(JAB=6 Hz) and 2.92 (part of an AB system, JAB=6 Hz).
It further exhibited a signal at δ 2.85 (dd with structure, J1=
12 Hz, J2=6 Hz, 1H). The methine proton attached to the R-
carbon of ester showed signals at δ 2.65 (dd with structure,
J1 =10 Hz, J2 =6 Hz, 1H), 2.50-2.33 (m, 3H). It further
showed signals at δ 1.94 (s with structure, 3H), 1.82 (ddd, J1=
12 Hz, J2=6 Hz, J3=3 Hz, 1H), 1.26 (t, J=6 Hz, 3H, CH3).
The 13C NMR (75 MHz) spectrum exhibited characteristic
signals at δ 203.9 and 172.9 for the carbonyl groups present
in the ethano bridge and ester groups, respectively. In
addition, signals were observed at δ 143.4, 134.0, 122.7,
118.2 for four olefinic carbons. Other carbons showed their
signals at δ 60.7, 57.6, 54.2 52.5, 44.0, 43.3 34.1, 28.7, 20.6,
and 14.1. The aforementioned spectral features clearly sug-
gested the structure of adduct 14. The orientation of the
oxirane ring was suggested on the basis of the general
tendencies of spiroepoxycyclohexadienones during their cy-
cloaddition and comparison of the spectral features of
related compounds.11,14 This stereogenic center is inconse-
quential as it will be lost during further transformations. The
adduct 17 also displayed similar spectral characteristics.
The presence and disposition of carbonyl, oxirane, and
ester functionalities in the aforementioned adducts provided
a unique opportunity for their selective manipulation and
elaboration to the desired bicyclic systems. Thus, treatment
of the epoxyketone 14 with activated zinc in aqueous metha-
nol containing ammonium chloride furnished the β-keto
alcohol 18 in excellent yield (92%) as a syn/anti mixture
(1H NMR spectrum) (Scheme 4). The β-keto alcohol 18 thus
obtained was oxidized with Jones’ reagent to the correspond-
ing acid, which upon decarboxylation gave the desired
compound 19. Similarly, the adduct 17 was also converted
into the ketoester 21. The structures of all the compounds
were fully consistent with their data. In order to introduce
the other olefinic tether in the bicyclic compound 19 and 21,
conversion of ester groups into aldehydes was required.
Hence, the carbonyl group in 19 was protected, and the
resulting ketal ester 22 was reduced with lithium aluminum
hydride to give the alcohols 23 in excellent yield (Scheme 4).
Various reagents were explored for the oxidation of 23 into
the aldehyde 24. The alcohol 23 was readily oxidized with
PCC;16 however, deprotection of the ketal group was found
to occur. After considerable experimentation, TPAP-
NMO17 was found to be the best reagent for the oxidation
of 23 as it furnished the aldehyde 24 quantitatively without
any problem. Similarly, the ketal ester 25 was also trans-
formed into aldehyde 27 (Scheme 4).
In order to introduce the alkenyl chains, the aldehydes 24
and 27 were treated with various Grignard reagents. Thus,
reaction of aldehyde 24 with vinylmagnesium bromide gave
the alcohols 28a and 28b, the former being a major product,
(14) (a) Adler, E.; Brasen, S.; Miyake, H. Acta Chem. Scand. 1971, 25B,
2055–2069. (b) Adler, E.; Holmberg, K. Acta Chem. Scand. 1974, 28B, 465–
472.
(15) Singh, V.; Porinchu, M.; Vedantham, P.; Sahu, P. K. Org. Synth.
2005, 81, 171–177.
(16) (a) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647–2650.
(b) Patel, S.; Mishra, B. K. Tetrahedron 2007, 63, 4367–4406.
(17) (a) Lenz, R.; Ley, S. V. J. Chem. Soc., Perkin Trans 1 1997, 3291–
3292. (b) Marko, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle-Regnaut, I.; Urch,
C. J.; Brown, S. M. J. Am. Chem. Soc. 1997, 119, 12661–12662.
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SCHEME 4
SCHEME 5
SCHEME 6
in addition to a small amount of the reduced product 23.
Similar reaction of 27 with vinylmagnesium bromide also
furnished the alcohols 29a,b containing 29a as major pro-
duct. The addition of allylmagnesium bromide to 24 also
gave diastereomeric alcohols 30a and 30b in excellent yield.
Similarly, the reaction of aldehyde 27 with allyl- and bute-
nylmagnesium bromides furnished the alcohols 31a,b and
32a,b, respectively (Scheme 5). The structure of these alco-
hols was deduced by comparison of their spectral features
and further transformations (vide infra). Further, the alco-
hol 28b was oxidized with MnO2 to the ketone 33. Removal
of the ketal group in compound 30b gave the keto alcohol 34,
which was oxidized to furnish the dione 35. Similarly,
hydrolysis of the compound 32a gave 36 which upon oxida-
tion with PCC gave the dione 37 (Scheme 6).
It may be mentioned that bridged bicyclic systems en-
dowed with olefinic tethers are not readily accessible and the
aforementioned methodology provides a general and stereo-
selective synthesis of such systems. The methodology is
general, flexible, and readily adaptable. After the bridged
bicyclo[2.2.2]octenones 28-37 appropriately disposed with
olefinic tethers were synthesized, their ring-closing metath-
esis reaction was examined as described below.
Studies on Ring-Closing Metathesis: Synthesis of Functiona-
lized Tricyclo[6.2.2.01,6]dodecanes, Tricyclo[7.2.2.01,7]tridecanes,
and Tricyclo[8.2.2.01,8]tetradecanes. Ring-closing metathesis has
proved to be a general and versatile method for the formation
of various types of rings.18,19 A large number of examples
dealing with ring-closing metathesis on a variety of precursors
are known, and enumerable applications in synthesis are
continuously being reported.20-22 Studies on ring-closing me-
tathesis and related reactions on bridged bicyclo[2.2.2]octanes
are, however, limited. This is presumably due to lack of methods
leading to bridged polycyclic systems endowed with appropri-
ately disposed alkenyl chains. Recently, Phillips and co-workers
have developed ROM-RCM in bridged bicyclo[2.2.2]octanes
and employed in the synthesis of the natural product.22
The ring-closing metathesis, though very general, the steric,
conformational, and geometric factors, and the functionality
in the substrates govern the cyclization in a subtle fashion,
and they often produce oligomers resulting from olefin polym-
erization (intermolecular RCM). The bicyclic compounds
28-37 which contain two olefinic tethers and a CdC bond in
the bicyclo[2.2.2]octane framework may also undergo reac-
tions such as ring-opening-ring-closing metathesis, especially
(18) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003. (b) Alkene Metathesis in Organic Synthesis;
Furstner, A., Ed.; Springer-Verlag: Germany 1998. (c) Nicolaou, K. C. In Classics
in Total Synthesis; Nicolaou, K. C., Snyder, S. A., Ed.; Wiley-VCH: Weinheim,
2003; Vol. II, p 161. (d) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592–4633. (e) Kotha, S.; Sreenivasachary, N. Indian J. Chem. 2001,
40B, 763–780.
(19) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198.
(b) Sieck, S. R.; Hanson, P. R. Chemtracts 2006, 19, 280–294. (c) Villar, H.;
Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55–66. (d) Sledz, P.; Mauduit,
M.; Grela, K. Chem. Soc. Rev. 2008, 37, 2433–2442.
(20) (a) Crimmins, M. T.; Jacobs, D. L. Org. Lett. 2009, 11, 2695–2698.
(b) Jeon, K. O; Rayabarapu, D.; Rolfe, A.; Volp, K.; Omar, I.; Hanson, P. R.
Tetrahedron 2009, 65, 4992–5000. (c) Schnabel, C.; Hiersemann, M. Org.
Lett. 2009, 11, 2555–2558. (d) Malik, C. K.; Hossain, Md. F.; Ghosh, S.
Tetrahedron Lett. 2009, 50, 3063–3066. (e) Klare; Hendrik, F. T.; Oestreich,
M. Angew. Chem., Int. Ed. 2009, 48, 2085–2089. (f) Srikrishna, A.; Beeraiah,
B.; Gowri, V. Tetrahedron 2009, 65, 2649–2654.
(21) (a) Crimmins, M. T.; Mc Dougall, P. J.; Ellis, J. M. Org. Lett. 2006, 8,
4079–4082. (b) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int.
Ed. 2006, 45, 2664–2670. (c) Clark, J. S. J. Chem. Soc., Chem. Commun. 2006,
34, 3571–3581. (d) Ermalenko, M. S.; Roulland, E. Org. Lett. 2005, 7, 2225–
2228. (e) Schmidt, B. Angew. Chem., Int. Ed. 2003, 42, 4996–4999.
(22) (a) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127,
5334–5335. (b) Chandler, C. L.; Phillips, A. J. Org. Lett. 2005, 7, 3493–3495.
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SCHEME 7
SCHEME 8
SCHEME 9
between the tether at the methine carbon and the CdC double
bond in the ethano bridge, and oligomerization, in addition to
the desired cyclization. Keeping this in mind, we explored the
ring-closing metathesis in 28-37.
Thus, a solution of compound 28a in CH2Cl2 was treated
with first-generation Grubbs’ catalyst (38) at ambient tem-
perature, which led to a smooth reaction and furnished the
tricyclic keto alcohol 39a in excellent yield. Similarly, treat-
ment of 28b and 29a,b furnished the corresponding cyclized
products 39b and 41a,b, respectively, in very good yields
(Scheme 7). The product 39b was hydrolyzed with aq HCl to
give the hydroxy ketone 40 in excellent yield. Further, the
ketal alcohol 41b was transformed into the keto ketal 42
which upon removal of the protecting group furnished the
dione 43 (Scheme 7).
SCHEME 10
The structures of all the products were suggested by their
1H NMR and 13C NMR spectra and comparison of their
spectral features. The stereostructure of the keto alcohol 40
was further confirmed through single-crystal X-ray diffrac-
tion studies (see the Supporting Information) which also
proved the structures of its precursors, especially the stereo-
chemical orientation of the hydroxyl group in 28b and 39b.
The structure and stereochemistry of other products were
deduced by comparison of their spectral features with those
of 28b and 39b.
Ring-closing metathesis of the trienone 33 was also ex-
amined. Thus, a solution of 33 in dichloromethane was
treated with the catalyst 38. The reaction was sluggish as
compared to the aforementioned substrates. After the reac-
tion mixture was stirred for 5 h followed by chromatography,
the product 44 was isolated in moderate yield (65%)
(Scheme 8). The compound 44 was also prepared by oxida-
tion of the ketal alcohol 39a with MnO2. The sluggishness of
the keto ketal 33 toward ring-closing metathesis could be due
to geometrical constraints imposed by the presence of a
conjugated carbonyl group in one of the tethers.
first-generation catalyst 38, which furnished the cyclized
product 45a having a seven-membered ring annulated to
bicyclo[2.2.2]octane framework, in excellent yield. The ketal
alcohol 45a was converted into the dione 46 via PCC oxida-
tion and hydrolysis of the ketal group (Scheme 9). Ring-
closing metathesis of the compound 31b also gave the
tricyclic compound 45b which upon hydrolysis furnished
the keto alcohol 47. Similarly, the ketal alcohol 30a and keto
alcohol 34 underwent smooth ring-closing metathesis to give
the corresponding tricyclic compounds 48 and 49, respec-
tively, in excellent yield. Further, the keto alcohol 49 was
oxidized with PCC to give the dione 50 (Scheme 9).
The structures of all the products were deduced from their
spectral features and comparison. The stereochemical dis-
position of hydroxyl groups in 45a and 49 was further
confirmed through a single-crystal X-ray structure (see the
The bicyclic compounds 30a, 31a,b, and 34 were also
subjected to ring-closing metathesis. First, a solution of the
compound 31a in dichloromethane was stirred with Grubbs’
6096 J. Org. Chem. Vol. 74, No. 16, 2009

Singh et al.
JOCArticle
Supporting Information). This also confirmed the structure
of the preceding intermediates including the Grignard addi-
tion products 31a, 30b, and their congeners.
1H). 13C NMR (100 MHz, CDCl3): δ 154.0, 136.8, 130.1, 127.1,
126.2, 124.7, 120.0, 115.9, 64.5, 34.3. HRMS (ESI) (m/z): found
187.0747 [M þ Na]þ, calcd for C10H12O2Na 187.0735.
(1S*,2S*,4S*,5R*)-Ethyl 1-Allyl-5-spirooxirane-6-oxo-8-methyl-
bicyclo[2.2.2]oct-7-ene-2-carboxylate (14). To a solution of 2-allyl-
4-methyl-6-hydroxymethylphenol 12a (10 g, 56 mmol) in acetoni-
trile (200 mL) cooled at ∼0 °C was added ethyl acrylate (30 mL,
excess) followed by the addition of a saturated solution of
sodium metaperiodate (40 g, 187 mmol in 70 mL water) dropwise
over a period of 2 h. After the reaction mixture was stirred in an ice
bath for 3 h, it was further stirred overnight at ambient tempera-
ture (∼28 °C). The reaction mixture was saturated with sodium
chloride and filtered through a Celite pad. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate
(3 ꢀ 50 mL). The combined extract was washed with brine and
dried. The solvent was evaporated under reduced pressure, and
the residue was chromatographed on silica gel. Elution with
petroleum ether-ethyl acetate (90:10) gave the compound 14
The construction of eight-membered rings is generally
considered to be difficult due to conformational, steric,
and entropic factors.23 Though a number of rings of various
sizes have been prepared by ring-closing metathesis, the
formation of medium and larger rings depend on various
factors including the functional groups, in a subtle fashion.
In view of this, it was interesting to examine the ring-closing
metathesis of compounds 32a,b which would lead to forma-
tion of eight-membered rings. Thus, compounds 32a and 32b
were treated with Grubbs’ first-generation catalyst 38. How-
ever, in both cases, a complex mixture of products was
obtained from which we could not isolate the desired com-
pound. Hence, ring-closing metathesis was attempted on the
dione 37. It was indeed gratifying to note that the treatment
of 37 with Grubbs’ second-generation catalyst 52 ensued a
smooth reaction and furnished the tricyclic dienedione 51
having an eight-membered ring annulated to the bridged
bicyclic octane framework, in excellent yield (Scheme 10).
(7.13 g, 46%) as a colorless liquid. IR (neat) νmax: 1736 cm-1
.
1H NMR (300 MHz, CDCl3): δ 5.92-5.78 (m, 1H), 5.64 (s with
structure, 1H), 5.13-5.04 (m, 2H), 4.12 (q, J=6 Hz, 2H), 3.15
(part of an AB system, JAB = 6 Hz, 1H), 2.92 (part of an AB
system, JAB=6 Hz, 1H), 2.85 (dd with structure, J1=12 Hz, J2=6
Hz, 1H), 2.65 (dd with structure, J1=10 Hz, J2=6 Hz, 1H), 2.50-
2.33 (merged m, 3H), 1.94 (s with structure, 3H), 1.82 (ddd, J1=12
Hz, J2=6 Hz, J3=3 Hz, 1H), 1.26 (t, 3H, J=6 Hz). 13C NMR (75
MHz, CDCl3): δ 203.9, 172.9, 143.4, 134.0, 122.7, 118.2, 60.7, 57.6,
54.2, 52.5, 44.0, 43.3, 34.1, 28.7, 20.6, 14.1. HRMS (ESI) (m/z):
found 299.1250 [M þ Na]þ, calcd for C16H20O4Na 299.1259.
(1S*,2S*,6R*,7R*,8R*,9R*)-6,9-Bis-spiroepoxy-1,4-diallyl-
tricyclo[6.2.2.02,7]dodec-3,11-diene-5,10-dione (16). To a solu-
tion of the o-hydroxymethylphenol 12b (13 g, 79.26 mmol)
in acetonitrile (200 mL) was added a solution of NaIO4 (56 g,
261 mmol) in water (200 mL) dropwise at ∼10 °C in 2 h. The
reaction mixture was then stirred for 3 h at ambient tempera-
ture. The reaction mixture was filtered on a Celite bed to
remove inorganic salts. The organic layer was separated from
the filtrate, and the aqueous layer was extracted with ethyl
acetate (3 ꢀ 50 mL). The organic extracts were combined and
washed with brine (50 mL) and dried over sodium sulfate.
Removal of solvent gave a solid which was recrystallized from
petroleum ether-ethyl acetate (85:15) to give the compound 16
(9.75 g, 76%) as a solid. Mp: 147-149 °C. IR (film) νmax: 3442,
Conclusion
In summary, a new, general, and stereoselective metho-
dology for the synthesis of bicyclo[2.2.2]octenones annulated
with functionalized six-, seven-, and eight-membered rings
has been developed. The key features of the methodology are
the cycloaddition of 2-allyl-6,6-spiroepoxycyclohexa-2,4-
dienones with ethyl acrylate and ring-closing metathesis.
The cycloaddition of 2-allyl-6,6-spiroepoxycyclohexa-2,4-
dienones with ethyl acrylate gives bicyclo[2.2.2]octanes dis-
posed with chemically distinguishable functional groups.
Regioselective manipulation of functional groups permitted
introduction of various types of olefinic tethers in the desired
stereochemical orientation. Interestingly, the present meth-
odology creates structural, functional, and stereochemical
complexity in the very first step of the synthesis from readily
available aromatic precursors, which is one of the important
aspects of design and development of methodology.24,25
1
3348, 1731, 1684, 1645 cm-1. H NMR (300 MHz, CDCl3):
δ 6.63-6.57 (dd, J1=8 Hz, J2=7 Hz, 1H), 6.53 (d, J=5 Hz, 1H),
6.08-5.92 (m, 1H), 5.84-5.7 (merged m, 2H), 5.26-5.04
(merged m, 4H), 3.34 (dd, J1 = 5 Hz, J2 = 9 Hz, 1H), 3.16
(part of an AB system, JAB=6 Hz, 1H), 3.09-2.92 (complex m,
2H), 2.92 (part of an AB system, JAB=6 Hz, 1H), 2.92-2.88
(m, 1H), 2.86-2.81 (AB system, JAB=6 Hz, 2H), 2.78-2.70 (m,
2H), 2.55-2.46 (dd, J1=15 Hz, J2 =7.5 Hz, 1H), 13C NMR
(75 MHz, CDCl3): δ 204.5, 192.5, 141.6, 140.0, 134.3, 133.6,
133.55, 118.9, 117.5, 58.9, 58.5, 57.8, 57.7, 53.8, 40.8, 39.9, 39.5,
34.0, 33.7. HRMS (ESI) (m/z): found 325.1453 [M þ H]þ, calcd
for C20H21O4 325.1440.
Experimental Section
2-Allyl-6-hydroxymethylphenol (12b). To a solution of the
aldehyde 11b (10 g, 61.7 mmol) in methanol-H2O (4:1,
125 mL) was added sodium borohydride (2.34 g, 61.5 mmol)
at ∼5 °C, and the reaction mixture was stirred for 1 h. The
reaction mixture was diluted with water (5 mL), and then dilute
HCl (2 mL, 50%) was added slowly. Methanol was removed
under reduced pressure, water (10 mL) was added to the residue
and extracted with ethyl acetate (3 ꢀ 60 mL), and the combined
extract was washed with brine and dried on sodium sulfate.
Removal of solvent followed by chromatography on silica gel
[petroleum ether-ethyl acetate (90:10)] gave the compound 12b
as a thick liquid (9.11 g, 90%). IR (film) ν max: 3367 cm-1. 1H
NMR (400 MHz, CDCl3): δ 7.32 (s, 1H); 7.09 (d, J=7.3 Hz, 1H);
6.93 (d, J=7.3 Hz, 1H); 6.79 (m, 1H); 6.07-5.97 (m, 1H); 5.14-
5.08 (m, 2H); 4.85 (br s, 2H); 3.42 (d, J=6.2 Hz, 2H); 2.2 (br s,
Crystal data of 16: C20H20O4, M 324.36, space group, triclinic,
˚
˚
˚
˚
P-1, a=8.663(2) A, b=9.548(3) A, c=10.915(3) A, λ=0.7107 A,
3
ꢀ
˚
R=90.92(2)°, β=94.53(2)°, γ=116.86(3)°, U 801.5(4) A , Z=2,
Dc=1.344 mg/m3, T=293(2) K, F(000)=344, size=0.33 ꢀ 0.28 ꢀ
0.23 mm. Reflections collected/unique 2818/2305 [R(int) =
0.0202], final R indices [I > 2σ(I)] R1=0.0319, wR2=0.0823.
R indices (all data) R1=0.0397, wR2=0.0846.
(1S*,2S*,4S*,5R*)-Ethyl 1-Allyl-5-spirooxirane-6-oxobicyclo-
[2.2.2]oct-7-ene-2-carboxylate (17). A mixture of the dimer 16
(10 g, 30.8 mmol) in o-dichlorobenzene (50 mL) and ethyl acrylate
(20 mL, excess) was heated at 110 °C for 7 h. It was charged on
a column of silica gel. Elution with petroleum ether ethyl
acetate (96:4) removed the o-dichlorobenzene and unreacted ethyl
(23) (a) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881–930. (b) Petasis, N.
A.; Patane, M. A. Tetrahedron 1992, 48, 5757–5821.
(24) (a) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259–281. (b) Corey,
E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John Wiley & Sons: New
York 1989.
(25) Chanon, M.; Barone, R.; Baralotto, C.; Julliard, M.; Hendrickson,
J. B. Synthesis 1998, 1559–1583.
J. Org. Chem. Vol. 74, No. 16, 2009 6097

Singh et al.
JOCArticle
acrylate. Further elution with petroleum ether/ethyl acetate
(90:10) gave the epoxy ketone 17 (14.8 g, 91%) as a colorless
liquid. IR (neat) νmax: 1735 cm-1. 1H NMR (300 MHz, CDCl3): δ
6.60-6.56 (dd, J1=8.2 Hz, J2=6.6 Hz, 1H), 6.10 (d, J=8.2 Hz,
1H), 5.94-5.81 (m, 1H), 5.14-5.06 (m, 2H), 4.13 (q, J=7 Hz, 2H),
3.17 (part of an AB system, JAB =6.2 Hz, 1H), 2.91-2.85 (m,
merged with AB system, JAB=6.2 Hz, 2H), 2.74-2.66 (dd, J1=14
Hz, J2 = 6.6 Hz, 1H), 2.65-2.60 (m, 1H), 2.55-2.40 (m, 2H),
1.84-1.80 (ddd, J1=14 Hz, J2=6 Hz, J3=5 Hz, 1H), 1.27 (t, J=7
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 203.9, 172.8, 133.9,
133.6, 131.0, 118.5, 60.9, 57.7, 54.4, 53.3, 43.5, 38.0, 34.1, 29.4,
14.2. HRMS (ESI) (m/z): found 263.1294 [M þ H]þ, calcd for
C15H19O4 263. 1283.
Ethyl 1-Allyl-5-hydroxymethyl-8-methyl-6-oxobicyclo[2.2.2]oct-
7-ene-2-carboxylate (18). To a solution of the adduct 14 (7.8 g, 28.2
mmol) in MeOH-H2O (5:1, 120 mL) were added zinc (activated
56 g, excess) and NH4Cl (9 g, 168 mmol). The reaction mixture was
stirred at ambient temperature (∼30 °C). After completion of the
reaction (TLC, 8 h), the reaction mixture was filtered on a Celite
bed and washed with ethyl acetate (3 ꢀ 20 mL). The filtrate was
concentrated under vacuum; the residue was diluted with water
(50 mL) and extracted with ethyl acetate (4 ꢀ 40 mL). The
combined extract was washed with brine and dried over anhydrous
Na2SO4. The solvent was removed in vacuo, and the residue was
chromatographed on silica gel. Elution with petroleum ether-
ethyl acetate (80:20) gave the β-keto alcohol 18 as a liquid (syn/anti
mixture, 7.22 g, 92%). IR (neat) νmax: 3490, 1719 cm-1. 1H NMR
(300 MHz, CDCl3): δ 5.91-5.76 (m, 1H), 5.55 (s with structure,
1H), 5.11-5.0 (m, 2H), 4.10 (q, J=6 Hz, 2H), 3.85-3.76 (m, 1H),
3.64 (br s, 1H), 2.77-2.69 (m, 1H), 2.67-2.49 (m, 3H), 2.37-2.15
(m, 3H), 1.92 (two s with structure, total 3H), 1.66-1.55 (m, 1H),
1.24 (t, J=6 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 212.8, 173.0,
146.7, 134.5, 121.3, 118.0, 62.7, 60.7, 54.4, 49.1, 44.3, 39.6, 34.0,
27.6, 20.1, 14.1 (signals due to major isomer). HRMS (ESI) (m/z):
found 279.1600 [M þ H] þ, calcd for C16H23O4 279.1596.
reaction mixture was stirred at ambient temperature (∼30 °C).
After completion of the reaction (TLC, 8 h), it was filtered
through a Celite bed and washed with ethyl acetate (30 mL). The
filtrate was concentrated under vacuum; the residue was diluted
with water (50 mL) and extracted with ethyl acetate (4 ꢀ 50 mL).
The combined extract was washed with brine and dried over
anhydrous Na2SO4. The solvent was removed under vacuum,
and the residue was purified by column chromatography. Elu-
tion with petroleum ether-ethyl acetate (75:25) gave the β-keto
alcohol 20 as a liquid (syn/anti mixture, 9 g, 91%). IR (neat)
1
ν
max: 3418, 1716, 1639 cm-1. H NMR (400 MHz, CDCl3): δ
6.66 and 6.50 (each of these dd, J1=8.4 Hz, J2=6.9 Hz, total
1H), 6.00-5.80 (merged m, total 2H), 5.12-5.05 (m, 2H), 4.12
(two merged q, J=7 Hz, 2H), 3.85-3.54 (m, 2H), 3.05-2.90 (m,
total 1H), 2.84-2.50 (m, total 2H), 2.48-2.20 (cluster of m,
4H), 1.80-1.60 (m merged with signal due to H2O present in
CDCl3, 1H), 1.25 (two merged t, J=7 Hz, total 3H). 13C NMR
(100 MHz, CDCl3): δ 212.4, 173.1, 137.2, 134.4, 129.4, 118.1,
62.6, 60.8, 54.3, 49.5, 43.7, 34.2, 34.0, 28.2, 14.2 (signals due to
major isomer). HRMS ESI (m/z): found 265.1448 [M þ H]þ,
calcd for C15H21O4 265.1440.
The β-keto alcohol 20 thus obtained was oxidized and sub-
jected to decarboxylation as follows. Thus, a solution of the β-
keto alcohol 20 (4 g, 15.15 mmol) in acetone (120 mL) was
oxidized with a freshly prepared Jones’ reagent at ∼5 °C. After
completion of the reaction (TLC), acetone was removed under
vacuum. The residue was diluted with water (25 mL) and
extracted with ethyl acetate (5 ꢀ 20 mL). The combined extract
was dried over anhydrous sodium sulfate. Solvent was removed
under vacuum, and the resulting β-keto acid was dissolved in a
THF-H2O mixture (1:1, 100 mL) and refluxed for 12 h. The
reaction mixture was then saturated with sodium chloride, and
the organic layer was separated. The aqueous layer was ex-
tracted with ether (3 ꢀ 30 mL), and the organic layers were
combined and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure, and the product was
purified by column chromatography on silica gel. Elution with
petroleum ether-ethyl acetate (97:3) gave the title compound 21
as a colorless liquid (2.0 g, 57%). IR (neat) νmax: 1726 cm-1. 1H
NMR (400 MHz, CDCl3): δ 6.56 (dd, J1=8.2 Hz, J2=6.4 Hz,
1H), 6.00 (d, J=8.2 Hz, 1H), 5.94-5.82 (m, 1H), 5.10-5.00 (m,
2H), 4.13 (q, J=7 Hz, 2H), 3.05-3.00 (m, 1H), 2.75 (dd, J1=10
Hz, J2=7 Hz, 1H), 2.62 (d of part of an AB system, JAB=14 Hz,
J2=7.6 Hz, 1H), 2.48 (d of part of an AB system, JAB=14 Hz, J2
=7.6 Hz, 1H), 2.20-2.10 (m, 3H), 1.80-1.70 (m, 1H), 1.27 (t, J
= 7 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 203.9, 173.3,
136.2, 134.7, 129.7, 118.0, 60.7, 54.0, 42.6, 39.8, 34.1, 33.0, 31.9,
14.2. HRMS ESI (m/z): found 235.1329 [MþH]þ, calcd for
C14H19O3 235.1334.
(1S*,2S*,4R*)-Ethyl 1-Allyl-7-spiro(1,3-dioxalane)-5-methylbicyclo-
[2.2.2]oct-5-ene-2-carboxylate (22). To a mixture of ethylene
glycol (1 mL, excess), p-toluenesulfonic acid (0.05 g), and benzene
(15 mL) dried in a Dean-Stark apparatus was added a solution of
the keto ester 19 (1.0 g, 4.03 mmol) in dry benzene. The reaction
mixture was refluxed for 4 h. It was cooled, and a saturated solution
of sodium bicarbonate (20 mL) was slowly added. The benzene layer
was separated, and the aqueous layer was extracted with ether (3 ꢀ
20 mL). The combined organic layer was washed with brine and
dried on anhydrous sodium sulfate. The solvent was removed under
vacuum, and the resulting product was chromatographed on silica
gel [petroleum ether-ethyl acetate (98:2)] to give the ketal ester
22 asaliquid(1.1g, 94%).IR(neat) νmax:1734cm-1.1HNMR(300
MHz, CDCl3): δ 6.06-5.91 (m, 1H), 5.63 (s with structure, 1H),
5.01-4.90 (m, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.92-3.80 (br s, 4H),
3.25-3.05 (m, 1H), 2.51-2.40 (m, 3H), 2.02-1.90 (m, 1H), 1.84 (s
with structure, 3H), 1.70-1.65 (m, 2H), 1.56-1.45 (m, 1H), 1.21(t,
J=7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3):δ175.2, 142.8, 136.5,
124.6, 115.1, 114.1, 64.3, 64.2, 59.9, 47.1, 42.6, 42.0, 36.3, 34.6, 32.3,
(1S*,2S*,4R*) Ethyl 1-Allyl-8-methyl-6-oxobicyclo[2.2.2]oct-
7-ene-2-carboxylate (19). To a solution of the β-keto alcohol 18
(2 g, 7.2 mmol) in acetone (50 mL) at ∼5 °C was added freshly
prepared Jones’ reagent dropwise. After completion of the
reaction (TLC), acetone was removed under vacuum. The
residue was diluted with water (20 mL) and extracted with ethyl
acetate (4 ꢀ 30 mL). The extract was combined and dried on
anhydrous Na2SO4, and the solvent was removed under vacuum
to give the carboxylic acid, which was subjected to decarboxyla-
tion without further purification. The carboxylic acid thus
obtained was dissolved in THF-H2O mixture (1:1, 40 mL)
and refluxed for 12 h. The reaction mixture was saturated with
sodium chloride, and the organic layer was separated. The
aqueous layer was extracted with ether (3 ꢀ 30 mL), and the
organic layers were combined and dried on anhydrous sodium
sulfate. The solvent was removed under reduced pressure, and
the product was chromatographed on silica gel. Elution with
petroleum ether-ethyl acetate (97:3) gave the title compound 19
as a colorless liquid (1.12 g, 63%). IR (neat) νmax: 1737, 1727
cm-1. 1H NMR (300 MHz, CDCl3): δ 5.95-5.80 (m, 1H), 5.52
(s, 1H), 5.11-5.00 (m, 2H), 4.10 (q, J=6 Hz, 2H), 2.77-2.68 (m,
2H), 2.58 (d of part of an AB system, JAB=14 Hz, J2=7 Hz, 1H),
2.41 (d of part of an AB system, JAB=14 Hz, J2=7 Hz, 1H),
2.19-2.02 (m, 3H), 1.89 (s, 3H), 1.77-1.64 (m, 1H, merged with
signal due to H2O present in CDCl3), 1.24 (t, J=6 Hz, 3H). 13
C
NMR (75 MHz, CDCl3): δ 209.9, 173.4, 145.7, 134.8, 121.4,
117.6, 60.5, 53.8, 43.1, 39.3, 37.2, 34.1, 32.2, 20.1, 14.1. HRMS
(ESI) (m/z): found 249.1501 [MþH]þ, calcd for C15H21O3
249.1491.
(1S*,2S*,4R*) Ethyl 1-Allyl-6-oxobicyclo[2.2.2]oct-7-ene-2-
carboxylate (21). To a solution of the adduct 17 (9.8 g,
37.40 mmol) in MeOH-H2O (5:1, 180 mL) were added zinc
(activated 70 g, excess) and NH4Cl (11 g, 205 mmol, excess). The
6098 J. Org. Chem. Vol. 74, No. 16, 2009

Singh et al.
JOCArticle
19.9, 14.0. HRMS (ESI) (m/z): found 293.1765 [M þ H]þ, calcd for
C17H25O4 293.1753.
4.67 mmol) in dry ether (20 mL) was slowly added to a stirred
suspension of lithium aluminum hydride (0.260 g, 6.84 mmol) in
ether (30 mL) at ∼5 °C. After completion of the reaction (TLC), the
reaction mixture was worked up as described previously and the
product was chromatographed on silica gel. Elution with petroleum
ether-ethyl acetate (80:20) furnished the ketal alcohol 26 as a liquid
(0.97g,88%).IR(neat) νmax: 3421, 2942 cm-1.1H NMR (400 MHz,
CDCl3):δ6.35 (dd, J1=8.3 Hz, J2=6.4 Hz, 1H), 6.17-6.05 (m, 1H),
5.94 (d, J=8.3 Hz, 1H), 5.12-4.95 (merged m, 2H), 3.85-3.82 (m,
4H), 3.72 (dd J1=12.5 Hz, J2=7.5 Hz, 1H), 1.96-1.88 (m, 1H),
1.74-1.62 (m, 2H), 1.36-1.22 (m, 2H). 13C NMR (100 MHz,
(1S*,4R*,6S*)-1-Allyl-7-spiro(1,3-dioxalane)-6-hydroxymethyl-
3-methylbicyclo[2.2.2]oct-2-ene (23). To a stirred suspension of
lithium aluminum hydride (0.100 g, 2.63 mmol) in ether (25 mL)
was added dropwise a solution of ketal ester 22 (0.8g, ∼2.73 mmol)
in dry ether (15 mL) at ∼5 °C, and the reaction mixture was stirred
at ambient temperature. After completion of the reaction (TLC),
the reaction mixture was cooled, and excess lithium aluminum
hydride was destroyed by addition of ethyl acetate (2 mL) followed
by aqueous sodium hydroxide solution (20 mL). It was further
stirred for 2 h, and then the organic layer was separated. The
aqueous layer was extracted with ether (3 ꢀ 20 mL). The combined
organic layer was washed with brine and dried on anhydrous
sodium sulfate. Removal of solvent followed by chromatography
of the product on silica gel [(petroleum ether-ethyl acetate (80:20)]
furnished the ketal alcohol 23 as a colorless liquid (0.657 g, 96%).
IR (neat) νmax: 3424, 1635 cm-1. 1H NMR (300 MHz, CDCl3): δ
6.20-6.00 (m, 1H), 5.50 (s, 1H), 5.10-4.95 (m, 2H), 3.86 (br s,
4H), 3.71 (dd, J1=10.2 Hz, J2=3.5 Hz, 1H), 3.34 (dd, J1=10.2 Hz,
J2=7.5 Hz, 1H), 2.70-2.50 (m, 1H), 2.50-2.30 (m, 3H), 1.98-1.6
(singlet merged with m and signal due to H2O in CDCl3, 6H),
1.42-1.20 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 144.6, 137.0,
125.0, 115.2, 114.8, 64.9, 64.1, 46.5, 42.4, 38.6, 36.2 34.3, 30.6,
20.0. HRMS (ESI) (m/z): found 273.1476 [MþNa]þ, calcd for
C15H22O3Na 273.1467.
ꢁ
CDCl3): δ 137.1, 135.6, 133.4, 115.6, 114.6, 65.1, 64.3, 64.2, 46.5,
43.0, 38.2, 34.4, 31.5, 30.8. HRMS (ESI) (m/z): found 237.1484 [M þ
H]þ, calcd for C14H21O3 237.1491.
(1S*,2S*,4R*)-1-Allyl-7-spiro(1,3-dioxalane)bicyclo[2.2.2]oct-
5-ene-2-carbaldehyde (27). To a stirred mixture of ketal alcohol
26 (1.5 g, 6.35 mmol), NMO (1.28 g, 10.98 mmol), and powdered
˚
4 A molecular sieves (3 g) in dichloromethane (100 mL) was
added TPAP (0.080 g, 0.22 mmol) at room temperature under
nitrogen atmosphere. After completion of reaction (TLC, 12 h),
it was filtered through a small pad of silica gel. The filtrate was
concentrated, and the productwaschromatographedonsilica gel
(petroleum ether-ethyl acetate, 90:10) to give the aldehyde 27 as
1
a colorless liquid (1.40 g, 94%). IR (neat) νmax: 1718 cm-1. H
NMR (400 MHz, CDCl3): δ 9.4 (d, J=6 Hz, 1H), 6.48 (dd, J1=
8.4 Hz, J2=6.6 Hz, 1H), 6.09 (d, J=8.4 Hz, 1H), 6.05-5.95 (m,
1H), 5.09-5.03 (m, 2H), 3.90-3.85 (m, 4H), 3.06-3.00 (m, 2H),
2.78-2.76 (m, 1H), 2.60-2.55 (m, 2H), 1.94-1.88 (m, 1H),
1.78-1.55 (m, merged with signal due to H2O present in CDCl3,
3H). 13C NMR (100 MHz, CDCl3): δ 203.5, 136.2, 135.6, 132.2,
117.4, 113.4, 64.6, 50.0, 46.4, 43.1, 34.7, 30.8, 28.1. HRMS (ESI)
(m/z): found 235.1337 [M þ H]þ, calcd for C14H19O3 235.1334.
(1S*,4R*,6S*)-1-Allyl-7-spiro(1,3-dioxalane)-3-methyl-6-[(S*)-
1-hydroxyprop-2-enyl]bicyclo[2.2.2]oct-2-ene (28a) and (1S*,4R*,
6S*)-1-Allyl-7-spiro(1,3-dioxalane)-3-methyl-6-[(R*)-1-hydroxyprop-
2-enyl]bicyclo[2.2.2]oct-2-ene (28b). To a stirred solution of aldehyde
24 (0.2 g, 0.8 mmol) in dry THF (15 mL) at ∼0 °C was added
dropwise a solution of vinylmagnesium bromide (3.2 mL, 3.2
mmol) and the mixture stirred at ambient temperature (2 h). The
reaction mixture was cooled, and saturated ammonium chloride
solution (5 mL) was added dropwise and further stirred for 1 h.
The reaction mixture was extracted with ether (3 ꢀ 20 mL) and
dried over anhydrous sodium sulfate. The solvent was removed,
and the resulting product was chromatographed on silica gel.
Elution with petroleum ether-ethyl acetate (88:12) first gave the
less polar alcohol 28a (0.135 g, 61%) as a colorless liquid. IR(neat)
(1S*,2S*,4R*)-1-Allyl-7-spiro(1,3-dioxalane)-5-methylbicyclo-
[2.2.2]oct-5-ene-2-carbaldehyde (24). To a stirred solution of ketal
alcohol 23 (2.0 g, 8 mmol) in dichloromethane (100 mL), NMO
˚
(1 g, 8.5 mmol), and powdered 4 A molecular sieves (3.5 g) was
added TPAP (100 mg, 0.28 mmol) at room temperature under
nitrogenatmosphere. Aftercompletionofreaction(TLC, 12h), it
was filtered through a small pad of silica gel, and the filtrate was
concentrated under vacuum. Chromatography of the residue
(petroleum ether-ethyl acetate, 98:2) furnished the aldehyde
24 as a colorless liquid (1.95 g, 98%). IR (neat) νmax: 1717,
1637 cm-1. 1H NMR (400MHz, CDCl3): δ 9.40 (d, J=4 Hz, 1H),
6.06- 5.94 (m, 1H), 5.67 (s, 1H), 5.09-5.00 (m, 2H), 3.97-3.80
(m, 4H), 3.05-2.96 (m, 1H), 2.54-2.50 (m, 3H), 1.91-1.55 (s
merged with m, 7H). 13C NMR (100 MHz, CDCl3): δ 203.8,
145.3, 135.8, 124.3, 117.1, 113.8, 64.5, 50.7, 46.8, 42.8, 36.4, 34.8,
27.5, 20.1. HRMS (ESI) (m/z): found 271.1304 [M þ Na]þ, calcd
for C15H20O3Na 271.1310.
(1S*,2S*,4R*)-Ethyl 1-Allyl-7-spiro(1,3-dioxalane)bicyclo-
[2.2.2]oct-5-ene-2-carboxylate (25). To a mixture of ethylene
glycol (2 mL, excess), p-toluenesulfonic acid (0.03 g), and benzene
(30 mL) dried in a Dean-Stark apparatus was added a solution of
the keto ester 21 (1.3 g, 5.55 mmol) in dry benzene. The reaction
mixture was refluxed for 4 h, after which time it was cooled,
poured into a saturated solution of sodium bicarbonate (30 mL)
and crushed ice, and stirred vigorously. The benzene layer was
separated, and the aqueous layer was extracted with ether (2 ꢀ 20
mL). The combined organic layer was washed with saturated
sodium bicarbonate (2ꢀ20 mL) and dried over anhydrous
sodium sulfate. Removal of solvent followed by chromatography
on silica gel [petroleum ether-ethyl acetate (94:6)] gave the ketal
ν
max: 3437, 1636 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.18-6.03
(m, 1H), 5.78-5.64 (mergedm, 2H), 5.20 (dt, J1=18 Hz, J2=2 Hz,
1H), 5.13-4.19 (merged m, 3H), 4.60 (br m, 1H), 3.93-3.83(m,
4H), 2.65 (m of a d of part of an ABsystem, JAB=15 Hz, J2=7 Hz,
1H), 2.51 (m of a d of part of an ABsystem, JAB=15 Hz, J2=8 Hz,
1H), 2.46-2.39 (m, 2H), 1.84 (d, J=2 Hz, 3H), 1.71-1.58 (m
merged with signal due to water present in CDCl3, 4H), 1.45-1.43
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 146.5, 140.1, 136.9,
125.1, 115.7, 115.1, 114.0, 71.2, 64.3, 64.2, 47.1, 42.3, 40.5, 36.7,
34.2, 27.0, 20.2. HRMS (ESI) (m/z): found 299.1624 [M þ Na]þ,
calcd for C17H24O3Na 299.1623.
ester 25 as a colorless liquid (1.5 g, 97%). IR (neat) νmax:1735cm-1
.
1H NMR (400 MHz, CDCl3): δ 6.40 (dd, J1=8.1 Hz, J2=6.6 Hz,
1H), 6.07 (d, J=8.1 Hz, 1H), 6.5-5.95 (m, 1H), 5.01-4.93 (m, 2H),
4.04 (q, J=7.3 Hz, 2H), 3.90-3.86 (m, 4H), 3.10 (dd, J1=9.6 Hz,
J2 = 5.3 Hz, 1H), 2.70 (m, 1H), 2.57-2.50 (m, 2H), 2,07-2.00
(m, 1H), 1.68 (m, 2H), 1.56-1.50 (m, 1H), 1.27 (t, J=7.3 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 175.3, 136.5, 134.1, 132.9, 115.6,
113.9, 76.5, 64.6, 64.3, 60.2, 46.8, 42.5, 42.0, 34.7, 33.3, 30.9,
14.2. HRMS (ESI) (m/z): found 279.1596 [M þ H]þ, calcd for
C16H23O4 279.1596.
Further elution with petroleum ether-ethyl acetate (85:15)
furnished the more polar product 28b (0.040 g, 18%) as a
colorless liquid. IR (neat) νmax: 3421, 1622 cm-1 1H NMR
.
(400 MHz, CDCl3): δ 6.20-6.10 (m, 1H), 5.76-5.68 (m, 1H),
5.39 (br s, 1H), 5.17-4.9 (m, 4H), 4.43-4.40 (m, 1H), 3.89-3.83
(m, 4H), 2.7-2.58 (m, 2H), 2.48-2.30 (m, 2H), 1.84-1.58 (s
merged with m, 7H), 1.36-1.22 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 142.7, 139.1, 137.7, 126.1, 115.3, 115.1, 114.8, 73.4,
64.3, 64.1, 46.7, 42.5, 41.7, 36.3, 34.7, 27.6, 20.0. HRMS (ESI)
(m/z): found 299.1620 [M þ Na]þ, calcd for C17H24O3Na
299.1623.
(1S*,4R*,6S*)-1-Allyl-7-spiro(1,3-dioxalane)-6-hydroxymethylbi-
cyclo[2.2.2]oct-2-ene (26). A solution of ketal ester 25 (1.3 g,
J. Org. Chem. Vol. 74, No. 16, 2009 6099

Singh et al.
JOCArticle
1
Continued elution with petroleum ether-ethyl acetate (80:20)
gave the reduced alcohol 23 (0.015 g, 7%).
liquid. IR (film) νmax: 3410, 1622 cm-1. H NMR (300 MHz,
CDCl3): δ 6.2-6.01 (m, 1H), 5.88-5.68 (m, 1H), 5.48 (s, 1H),
5.20-4.86 (m, 4H), 3.83 (br s, 5H), 2.70-2.34 (m, 4H), 2.16-
1.91 (m, 1H), 1.90-1.42 (s merged with m, total 8H), 1.38-1.20
(m, 1H). 13C NMR (75 MHz, CDCl3 þ CCl4): δ 142.7, 137.6,
135.7, 125.5, 118.0, 115.3, 114.8, 71.0, 64.1, 63.9, 46.7, 42.2, 40.9,
37.7, 36.3, 34.6, 28.5, 20.1. HRMS (ESI) (m/z): found 313.1779
[M þ Na]þ, calcd for C18H26O3Na 313.1780. Continued elution
with petroleum ether-ethyl acetate (80:20) gave the alcohol 23
(0.036 g, 9%).
(1S*,4R*,6S*)-1-Allyl-7-spiro(1,3-dioxalane)-6-[(S*)-1-hydro-
xyprop-2-enyl]bicyclo[2.2.2]oct-2-ene (29a) and (1S*,4R*,6S*)-1-
Allyl-7-spiro(1,3-dioxalane)-6-[(R*)-1-hydroxyprop-2-enyl]bicyclo-
[2.2.2]oct-2-ene (29b). To a stirred solution of aldehyde 27 (0.7 g,
3 mmol) in dry THF (20 mL) at ∼0 °C was added dropwise a
solution of vinylmagnesium bromide (12 mL, 12 mmol) and the
mixture stirred at ambient temperature (2.5 h). The reaction
mixture was worked up as described above, and the product was
chromatographed on silica gel. Elution with petroleum ether-
ethyl acetate (90:10) first gave the less polar alcohol 29a (0.420 g,
(1S*,4R*,6S*)-1-Allyl-7-spiro(1,3-dioxalane)-6-[(S*)-1-hydro-
xybut-2-enyl]bicyclo[2.2.2]oct-2-ene (31a) and (1S*,4R*,6S*)-1-
Allyl-7-spiro(1,3-dioxalane)-6-[(R*)-1-hydroxybut-3-enyl]bicyclo-
[2.2.2]oct-2-ene (31b). To magnesium (freshly activated, 0.4 g,
16.6 mmol) in dry ether (10 mL) and a crystal of iodine was added
a dilute solution of allyl bromide (0.6 mL, 6.8 mmol) in ether
(25 mL) very slowly over 1 h under vigorous stirring at ∼5 °C.
It was further stirred for 2 h. A solution of the ketal aldehyde 27
(0.4 g, 1.7 mmol) in dry ether (10 mL) was added to the reaction
mixture at 0 °C. The reaction mixture was further stirred for 1 h at
ambienttemperature. Themixture was quenched with a saturated
solution of ammonium chloride (10 mL) and further stirred for
0.5 h. The reaction mixture was worked up as described before
and the product was chromatographed on silica gel. Elution
with petroleum ether-ethyl acetate (87:13) gave the alcohol 31a
(0.245 g, 52%) as a colorless liquid. IR (neat) νmax: 3547 cm-1. 1H
NMR (300 MHz, CDCl3): δ 6.42 (dd, J1=8.1 Hz, J2=6.3 Hz,
1H), 6.14-6.00 (merged m, 2H), 5.86-5.72 (m, 1H), 5.12-4.98
(m, 4H), 4.06 (t, J=6.6 Hz, 1H), 3.90-3.85 (m, 4H), 2.74-2.58 (m
merged with m of an AB system, 2H), 2.50 (d of part of AB
system, JAB=15.5 Hz, J2=7.7 Hz, 1H), 2.38-2.30 (m, 1H), 2.26-
2.00 (m, 2H), 1.82-1.62 (m, 3H), 1.54-1.46 (m, 1H), 1.40 (br s,
1H). 13C NMR (100 MHz, CDCl3): δ 136.8, 136.4, 135.2, 133.3,
117.3, 115.7, 114.8, 70.1, 64.3, 64.1, 46.8, 42.4, 40.4, 39.1, 34.0,
30.8, 27.4. HRMS (ESI) (m/z): found 277.1815 [M þ H]þ, calcd
for C17H25O3 277.1804.
54%) as a colorless liquid. IR (neat) νmax: 3487, 1635 cm-1. H
1
NMR (400 MHz, CDCl3): δ 6.42 (dd, J1=8 Hz, J2=7 Hz, 1H),
6.18-6.06 (m, 2H), 5.74 (ddd, J1=16.4 Hz, J2=11.7 Hz, J3=3 Hz,
1H), 5.20 (m of d, J=16.4 Hz, 1H), 5.14-5.00 (cluster of m, 3H),
4.60-4.55(m, 1H), 3.91-3.85(m, 4H), 2.74-2.64(m, 2H), 2.54(m
of part of an AB system, JAB=14.8 Hz, 1H), 2.43-2.37(m, 1H),
1.74-1.64(m, 3H), 1.44 (d, J=4.5 Hz, 1H), 1.42-1.34 (m, 1H). 13
C
NMR (100 MHz, CDCl3): δ 140.1, 136.7, 136.2, 133.5, 115.8,
114.8, 114.1, 71.2, 64.3, 64.1, 46.8, 42.5, 39.8, 34.0, 30.8,
27.8. HRMS (ESI) (m/z): found 285.1465 [M þNa]þ, calcd for
C16H22O3Na 285.1467.
Further elution with petroleum ether-ethyl acetate (85:15)
gave the alcohol 29b as a colorless liquid (0.115 g, 15%). IR
(neat) νmax: 3446, 1635 cm-1. 1H NMR(300 MHz, CDCl3): δ 6.28
(dd, J1=8.3 Hz, J2=6.4 Hz, 1H), 6.24-6.12 (m, 1H), 5.84 (d, J=
8.8 Hz, 1H), 5.82-5.72 (m, 1H), 5.22-4.98 (merged m, 4H),
4.46-4.40 (m, 1H), 3.91-3.86 (m, 4H), 2.74-2.62 (m, 3H), 2.46
(dd, J1=15 Hz, J2=7 Hz, 1H), 1.84-1.76 (m, 1H), 1.74-1.62
(merged m, 3H), 1.48 (br s, 1H), 1.40-1.32 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 139.2, 137.5, 134.1, 133.7, 115.6, 114.9, 73.6,
64.3, 64.0, 46.4, 42.7, 40.6, 34.6, 30.6, 28.5. HRMS (ESI) (m/z):
found 285.1465 [M þ Na]þ, calcd for C16H22O3Na 285.1467.
Continued elution with petroleum ether-ethyl acetate (80:20)
gave the reduced alcohol 26 (0.090 g, 13%).
(1S*,4R*,6S*)-1-Allyl-7-spiro(1,3-dioxalane)-3-methyl-6-[(S*)-
1-hydroxybut-3-enyl]bicyclo[2.2.2]oct-2-ene (30a) and (1S*,4R*,
6S*)-1-Allyl-7-spiro(1,3-dioxalane)-3-methyl-6-[(R*)-1-hydroxy-
but-3-enyl]bicyclo[2.2.2]oct-2-ene (30b). To a suspension of mag-
nesium (freshly activated, 0.40 g, 16.6 mmol) in dry ether (10 mL)
was added a crystal of iodine. A dilute solution of allyl bromide
(0.6 mL, 6.8 mmol) in ether (25 mL) was added very slowly over
∼1 h under vigorous stirring. The solution was further stirred for
1 h and then added to a solution of the ketal aldehyde 24 (0.4 g,
1.61 mmol) in dry ether (10 mL) at 0 °C. After addition of the
Grignard reagent, the reaction mixture was further stirred for 2 h
at ambient temperature. The reaction mixture was cooled in ice
bath, and a saturated solution of ammonium chloride (10 mL)
was added dropwise and stirred for 0.5 h. The organic layer
was separated, and the aqueous layer was extracted with ether
(3 ꢀ 20 mL). The combined extract was washed with brine (30
mL) and dried over anhydrous sodium sulfate. Removal of
solvent gave the crude product which was chromatographed
on silica gel. Elution with petroleum ether-ethyl acetate (90:10)
Further elution with petroleum ether-ethyl acetate (85:15)
furnished the lower alcohol 31b (0.190 g, 40%) as a colorless
1
liquid. IR (film) νmax: 3435, 1637 cm-1. H NMR (400 MHz,
CDCl3): δ 6.33 (dd, J1=8 Hz, J2=6.6 Hz, 1H), 6.19-6.08 (m,
1H), 5.96 (d, J = 8 Hz, 1H), 5.86-5.75 (m, 1H), 5.13-4.95
(merged m, 4H), 3.93-3.84 (m, 5H), 2.70-2.56 (m, 3H), 2.53-
2.44 (m, 1H), 2.10-2.02 (m, 1H), 1.96-1.78 (m, 2H), 1.72-1.53
(m overlapped with signal due to H2O present in CDCl3, 3H),
1.38-1.28 (complex m, 1H). 13C NMR (100 MHz, CDCl3): δ
137.5, 135.7, 134.6, 133.1, 118.1, 71.2, 64.3, 64.0, 46.6, 42.5, 40.4,
38.1, 34.5, 30.7, 29.2. HRMS (ESI) (m/z): found 299.1632
[M þ Na]þ, calcd for C17H24O3Na 299.1634. Continued elution
with petroleum ether-ethyl acetate (80:20) gave the alcohol 26
(0.01 g, 2%).
(1S*,4R*,6S*)-1-Allyl-7-spiro(1,3-dioxalane)-6-[(S*)-1-hydro-
xypent-4-enyl]bicyclo[2.2.2]oct-2-ene (32a) and (1S*,4R*,6S*)-1-
Allyl-7-spiro(1,3-dioxalane)-6-[(R*)-1-hydroxypent-4-enyl]bicyclo-
[2.2.2]oct-2-ene (32b). To magnesium (freshly activated, 0.360 g,
15 mmol) in dry THF (10 mL) and a crystal of iodine, a dilute
solution of 4-bromobutene (0.8 mL, 8 mmol) in THF (25 mL) was
added very slowly over∼1 h under vigorous stirring, at 5 °C. It was
further stirred for 1 h. To this was added a solution of the ketal
aldehyde 27 (0.350 g, 1.49 mmol) in dry THF (10 mL) at ∼0 °C.
The reaction mixture was further stirred for 2 h at ambient
temperature. Usual workup as described earlier followed by
chromatography on silica gel [petroleum ether-ethyl acetate
85:15] gave the alcohol 32a (0.28 g, 64%) as a colorless liquid.
IR (neat) νmax: 3564 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.43
(dd, J1=8 Hz, J2=6.6 Hz, 1H), 6.13- 6.02 (merged m, 2H), 5.87-
5.76 (m, 1H), 5.10-4.93 (m, 4H), 4.04-3.82 (m, 5H), 2.74-2.68
(m, 1H), 2.63 (d of part of AB system, JAB=15.6 Hz, J2=7.0 Hz,
1H), 2.50 (d of part of AB system, JAB=15.6 Hz, J2=7.0 Hz, 1H),
gavethe alcohol30a (0.280 g, 60%) as a colorless liquid. IR (film)
1
ν
max: 3547, 1638 cm-1. H NMR (400 MHz, CDCl3): δ 6.10-
5.98 (m, 1H), 5.86-5.74 (m, 1H), 5.62 (br s, 1H), 5.12-4.96 (m,
4H), 4.10-4.05 (m, 1H), 3.90-3.80 (m, 4H), 2.60 (d of part of an
AB system, JAB=17.1 Hz, J2=7.6 Hz, 1H), 2.50-2.42 (m, 2H),
2.36-2.28 (m, 1H), 2.22-2.12 (m, 1H), 2.06-1.98 (m, 1H), 1.82
(d, J=1.5 Hz, 3H), 1.76-1.63 (m, 3H), 1.58-1.50 (m, 2H). 13
C
NMR (100 MHz, CDCl3): δ 146.9, 136.8, 135.4, 124.8, 117.0,
115.7, 115.1, 70.2, 64.3, 64.2, 47.0, 42.2, 40.3, 39.6, 36.6, 34.2,
26.5, 20.3. HRMS (ESI) (m/z): found 313.1782 [M þ Na]þ, calcd
for C18H26O3Na 313.1780.
Further elution with petroleum ether-ethyl acetate (82:18)
furnished the lower alcohol 30b (0.136 g, 29%) as a colorless
6100 J. Org. Chem. Vol. 74, No. 16, 2009

Singh et al.
JOCArticle
2.34-2.28 (m, 1H), 2.20-2.00 (m, 2H), 1.80-1.63 (merged m,
3H), 1.55-1.45 (m, 2H), 1.38-1.30 (m, 1H), 1.27 (d, J=3.6 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 138.5, 136.6, 136.4, 133.1,
115.6, 114.6, 114.5, 69.8, 64.1, 63.9, 46.7, 42.3, 39.5, 34.8, 33.8, 30.7,
30.1, 27.3. HRMS (ESI) (m/z): found 291.1959 [M þ H]þ, calcd
for C18H27O3 291.1960.
J2=7 Hz, 1H), 2.37 (d of part of an AB system, JAB=13 Hz, J2=7
Hz, 1H), 2.13-1.95 (m, 4H), 1.85-1.76 (m merged with s, 5H),
1.60-1.40 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 210.6, 198.9,
144.8, 143.3, 135.1, 131.9, 122.4, 117.9, 54.5, 46.9, 39.6, 37.4, 34.0,
32.1, 20.2, 18.5. HRMS (ESI) (m/z): found 245.1547 [M þ H]þ,
calcd for C16H21O2 245.1542.
Continued elution with petroleum ether-ethyl acetate (80:20)
gave the lower alcohol 32b (0.030 g, 7%) as a colorless liquid. IR
(neat) νmax: 3432 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.31 (dd,
J1=8.2 Hz, J2=7.05 Hz, 1H), 6.18- 6.07 (merged m, 1H), 5.93 (d,
J=8.2 Hz, 1H), 5.88-5.77 (m, 1H), 5.08-4.4 (m, 4H), 3.86 (br
m, 5H), 2.69-2.54 (m, 3H), 2.46-2.38 (m, 1H), 2.30-2.18 (m,
1H), 2.12-2.00 (m, 1H), 1.84-1.76 (m, 1H), 1.73-1.60 (m
merged with signal due to H2O, 2H), 1.40-1.20 (m, 4H). 13C
NMR (100 MHz, CDCl3): δ 139.0, 137.5, 134.5, 133.4, 115.2,
115.1, 115.0, 72.2, 64.3, 64.0, 46.6, 42.6, 41.3, 34.6, 32.3, 30.8,
30.6, 29.2. HRMS ESI (m/z): found 313.1775 [M þ Na]þ, calcd
for C18H26O3Na 313.1780.
(1S*,4R*,7S*)-1-Allyl-7-[(S*)-1-hydroxypent-4-enyl]bicyclo-
[2.2.2]oct-5-en-2-one (36). To a solution of 32a (0.14 g,
0.48 mmol) in acetone-water (20 mL, 4:1) was added aq HCl
(0.2 mL) at ∼10 °C. The reaction mixture was stirred at ambient
temperature for 6 h. Acetone was removed, and the aqueous
residue was extracted with ethyl acetate (3ꢀ15 mL). The
combined extract was washed with aq sodium bicarbonate
followed by brine and dried on anhydrous sodium sulfate.
The solvent was removed, and the product was chromato-
graphed on silica gel. Elution with petroleum ether-ethyl
acetate (88:12) gave the keto alcohol 36 (0.115 g, 97%) as a
colorless liquid. IR (neat) νmax: 3468, 1714 cm-1. 1H NMR (400
MHz, CDCl3): δ 6.53 (dd, J1=8.1 Hz, J2=6.6 Hz, 1H), 6.02-
5.90 (merged m, 2H), 5.85-5.74 (m, 1H), 5.20-4.94 (m, 4H),
4.00-3.99 (m, 1H), 2.98-2.97 (m, 1H), 2.64-2.48 (m, 2H),
2.20-1.82 (m, 4H), 1.96-1.82 (m, 2H), 1.72-1.48 (m, merged
with signal due to H2O present in CDCl3, 2H), 1.40-1.30 (m,
1H), 1.22(d, J=4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
211.4, 138.2, 137.3, 135.2, 129.7, 117.9, 115.0, 69.7, 54.3, 41.1,
39.4, 34.9, 33.6, 31.3, 30.1, 27.1. HRMS (ESI) (m/z): found
247.1700 [M þ H]þ, calcd for C16H23O2 247.1698.
(1S*,2S*,4R*)-1-Allyl-5-methyl-7-spiro(1,3-dioxalane)-2-[prop-
2-en-1-one]bicyclo[2.2.2]oct-5-ene (33). A suspension of the ketal
alcohol 28b (0.1 g, 0.36 mmol) and freshly prepared MnO2 (1 g,
excess) in dichloromethane (30 mL) was stirred at ambient con-
ditions for 24 h. The suspension was filtered on a Celite bed, and
the solvent was removed. The crude product was chromato-
graphed on silica gel [(petroleum ether-ethyl acetate (80:20)] to
give the product 33 (0.09 g, 91%) as a colorless liquid. IR (neat)
ν
max: 1701 cm-1. 1H NMR (400 MHz, CDCl3): δ 6.24 (dd, J1=
17.5 Hz, J2=10 Hz, 1H), 6.10 (dd, J1=17.5 Hz, J2=1.5 Hz, 1H),
5.90-5.79 (m, 1H), 5.70-5.56 (m, 2H), 4.81 (m of d, J=12.1 Hz,
2H), 3.84-3.80 (br m, 4H), 3.41 (dd, J1=10.1 Hz, J2=6.2 Hz,
1H), 2.46-2.38 (m, 3H), 2.0-1.9 (m, 1H), 1.76 (d, J = 2 Hz,
3H), 1.68-1.60 (m, 2H), 1.31-1.23 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 201.2, 141.7, 136.8, 136.6, 127.4, 126.3,
115.9, 114.5, 64.4, 64.2, 47.3, 46.8, 42.2, 36.5, 34.5, 31.9,
19.9. HRMS (ESI) (m/z): found 297.1468 [MþNa]þ, calcd for
C17H22O3Na 297.1467.
(1S*,4R*,7S*)-1-Allyl-7-(1-oxopent-4-enyl)bicyclo[2.2.2]oct-5-
en-2-one (37). To a solution of compound 36 (0.100 g, 0.40 mmol)
in CH2Cl2 (15 mL) was added PCC (0.22 g, 1 mmol), and the
reaction mixture was stirred at ambient temperature for 5 h, after
which time it was filtered through a column of silica gel which
gave the dione 37 (0.085 g, 86%) as a colorless liquid. IR (neat)
ν
max: 1716 cm-1. 1H NMR (400 MHz, CDCl3): δ 6.43 (dd, J1=8
Hz, J2=6.6 Hz, 1H), 6.02 (d, J=8 Hz, 1H), 5.91-5.72 (m, 2H),
5.05-4.95 (m, 4H), 3.04-2.98 (m, 1H), 2.91 (dd, J1=10 Hz, J2=
6.6 Hz, 1H), 2.65-2.44 (m, 4H), 2.32-2.14 (m, 5H), 1.54-1.46
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 210.1, 208.2, 137.1,
135.2, 135.0, 131.2, 117.9, 115.5, 54.4, 48.0, 42.9, 39.8, 33.8, 32.5,
31.9, 27.4. HRMS (ESI) (m/z) found 245.1537 [M þ H]þ, calcd
for C16H21O2 245.1542.
(1S*,4R*,7S*)-1-Allyl-5-methyl-7-[(R*)-1-hydroxybut-3-enyl]-
bicyclo[2.2.2]oct-5-en-2-one (34). To an ice-cold solution of ketal
alcohol 30b (1.0 g, 3.4 mmol) in acetone-water (4:1, 50 mL) was
added concentrated hydrochloric acid (2 mL), and the reaction
mixture was stirred at ambient temperature. After completion of
reaction (3 h, TLC), the reaction mixture was neutralized with
solid NaHCO3 and acetone was removed. To the residue were
added water (20mL) and ether (50mL), andthe organiclayer was
separated. The aqueous layer was extracted with ether (2 ꢀ 20
mL), and the combined organic layer was dried over anhydrous
sodium sulfate. Removal of solvent followed by chromatography
on silica gel (petroleum ether-ethyl acetate, 80:20) furnished the
(1S*,6S*,8R*)-11-Spiro(1,3-dioxalane)-9-methyl-5(S*)-hydroxy-
tricyclo[6.2.2.01,6]dodeca-3,9-diene (39a). To a degassed solution of
diene 28a (0.030 g, 0.10 mmol) in dichloromethane (15 mL) was
added Grubbs’ catalyst 38 (5 mg, 0.006 mmol), and the reaction
mixture was stirred at ambient temperature under nitrogen for 1 h.
Removal of solvent followed by chromatography of the residue on
silica gel [petroleum ether-ethyl acetate (70:30)] gave the title
keto alcohol 34 (0.82 g, 97%) as a colorless liquid. IR (neat) νmax
:
compound 39a as a colorless liquid (0.025 g, 96%). IR (neat)
3455, 1722 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.01-5.70 (m,
2H), 5.39 (s, 1H), 5.24-4.88 (m, 4H), 3.83 (br s, 1H), 2.66 (s with
structure, 1H), 2.46 (d, J=6.9 Hz, 2H), 2.30-2.02 (m, 4H), 2.0-
1.8 (m, 5H), 1.64 (br s, 1H), 1.58-1.42 (m, 1H). 13C NMR (75
MHz, CDCl3 þ CCl4): δ 210.6, 145.7, 135.9, 135.0, 121.9, 118.7,
117.4, 70.5, 54.7, 42.2, 39.0, 37.7, 36.7, 34.5, 28.5, 20.2. HRMS
(ESI) (m/z): found 269.1526 [MþNa]þ, calcd for C16H22O2Na
269.1517.
ν
max: 3429, 1657 cm-1. H NMR (300 MHz, CDCl3): δ 5.77 (m
1
of d, J=10.5 Hz, 1H), 5.63 (m of d, J=10.5 Hz, 1H), 5.51 (br m,
1H), 3.95-3.80 (m, 4H), 3.60-3.53 (m, 1H), 2.47 (m, 1H), 2.30 (m
of part of an AB system, JAB=18 Hz, 1H), 2.13 (m of part of an AB
system, JAB=18 Hz, 1H), 1.98-1.84 (m, 2H), 1.80(d, J=1.4 Hz,
3H), 1.73 (d of part of an AB system, JAB=12 Hz, J2=3 Hz, 1H),
1.61 (t of part of an AB system, JAB=12 Hz, J2=3 Hz, 1H), 1.48-
1.38 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 143.8, 130.9, 127.3,
127.1, 114.1, 74.2, 64.9, 64.6, 45.7, 43.2, 41.3, 36.7, 30.0, 28.2,
20.0. HRMS (ESI) (m/z): found 271.1307 [M þ Na]þ, calcd for
C15H20O3Na 271.1310.
(1S*,4R*,7S*)-1-Allyl-5-methyl-7-(1-oxobut-3-enyl)bicyclo[2.2.2]-
oct-5-en-2-one (35). A suspension of the keto alcohol 34 (0.5 g,
2.03 mmol) and PCC (0.650 g, 3 mmol) in CH2Cl2 (30 mL) was
stirred under ambient conditions for 24 h. The reaction mixture was
filtered through a Celite bed, solvent was removed in vacuo, and the
resulting product was chromatographed. Elution with petroleum
ether-ethyl acetate (90:10) furnished the diketone 35 (0.49 g, 98%)
as a colorless liquid. IR (neat) νmax: 1722 cm-1. 1H NMR (400 MHz,
CDCl3): δ 6.79-6.70 (m, 1H), 5.99 (dd, J1=15 Hz, J2=2 Hz, 1H),
5.83-5.69 (m, 1H), 5.49 (s, 1H), 4.95- 4.87 (m, 3H), 3.08-2.94 (m,
1H), 2.66 (br s, 1H), 2.42 (d of part of an AB system, JAB=13 Hz,
(1S*,6S*,8R*)-11-Spiro(1,3-dioxalane)-9-methyl-5(R*)-hydroxy-
tricyclo[6.2.2.01,6]dodeca-3,9-diene (39b). To a degassed solution of
diene 28b (0.110 g, 0.4 mmol) in dichloromethane (40 mL) was
added Grubbs’ catalyst 38 (17 mg, 0.02 mmol) and the mixture
stirred at ambient temperature for 1 h under nitrogen. Removal of
solvent followed by chromatography of the residue on silica gel
[petroleum ether-ethyl acetate (90:10)] gave the title compound
39b as a colorless liquid (0.084 g, 85%). IR (neat) νmax: 3430 cm-1
.
J. Org. Chem. Vol. 74, No. 16, 2009 6101

Singh et al.
JOCArticle
1H NMR (300 MHz, CDCl3): δ 5.96-5.80 (m, 2H), 5.6 (br s, 1H),
3.99-3.80 (m 4H), 3.78-3.70 (m, 1H), 2.54-2.48 (br m, 1H), 2.46-
2.35 (m, 1H), 2.35-2.21 (m, 2H), 2.06-1.97 (m, 1H), 1.82-1.72
(singlet merged with m, 4H), 1.66-1.58 (m, 2H), 1.34 (d, J=11.4 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 147.6, 129.9, 127.7, 125.9,
113.8, 66.8, 64.9, 64.5, 43.5, 42.9, 36.9, 36.5, 27.8, 26.6, 20.2. HRMS
(ESI) (m/z): found 271.1315 [M þ Na]þ, calcd for C15H20O3Na:
271.1310.
CDCl3): δ 138.6, 134.2, 129.9, 127.7, 113.4, 66.9, 64.9, 64.6, 44.0,
42.6, 35.9, 31.2, 27.6, 27.2. HRMS (ESI) (m/z): found 235.1342
[M þ H]þ, calcd for C14H19O3 235.1334.
(1S*,6S*,8R*)-11-Spiro(1,3-dioxalane)tricyclo[6.2.2.01,6]dodeca-
3,9-dien-5-one (42). To a solution of compound 41b (0.030 g,
0.128 mmol) in CH2Cl2 (20 mL) was added MnO2 (0.5 g, excess),
and the reaction mixture was stirred at ambient temperature for 10 h
(TLC). The suspension was filtered through a Celite bed and
washed with CH2Cl2 (10 mL), and the solvent was removed. The
resulting product was chromatographed on silica gel (petroleum
ether-EtOAc, 85:15) to give 42 (0.024 g, 82%) as a colorless solid.
Mp: 50-52 °C. IR (film) νmax: 1679 cm-1. 1H NMR (400 MHz,
CDCl3): δ 6.92 (ddd, J1=9.9 Hz, J2=5.9 Hz, J3=2.2 Hz, 1H), 6.40
(superimposed dd, J=8 Hz, 1H), 6.0 (dd, J1=9.9 Hz, J2=2 Hz,
1H), 5.88 (d, J=8 Hz, 1H), 3.98-3.88 (m, 4H), 2.92 (dd, J1=10 Hz,
J2=6.4 Hz, 1H), 2.78-2.68 (merged m, 2H), 2.60 (d of part of an
AB system, JAB=18 Hz, J2=5.5 Hz, 1H), 2.17 (m of d, J=13 Hz,
1H), 1.80-1.72 (m, 2H), 1.62 (m of d, J=13 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 199.8, 147.1, 137.7, 132.7, 129.9, 113.0, 65.1,
65.0, 47.1, 45.6, 43.0, 30.4, 28.6. 26.1. HRMS (ESI) (m/z): found
233.1180 [M þ H]þ, calcd for C14H17O3 233.1178.
(1S*,6S*,8R*)-12-Methyl-5(R*)-hydroxytricyclo[6.2.2.01,6]-
dodeca-3,11-dien-10-one (40). To a stirred solution of 39b
(0.110 g, 0.44 mmol) in acetone-water (4:1, 5 mL) was added
concd HCl (0.1 mL). After completion of the reaction (3 h,
TLC), the reaction mixture was neutralized by addition of solid
NaHCO3. Acetone was removed, and the residue was diluted
with water and extracted with ether (2 ꢀ 15 mL). The combined
organic extract was washed with saturated sodium bicarbonate
(1 ꢀ 10 mL) and brine (1 ꢀ 10 mL) and dried over anhydrous
sodium sulfate. Solvent was removed under vacuum, and the
product was chromatographed on silica gel. Elution with
petroleum ether-ethyl acetate (90:10) gave the title compound
40 (0.083 g, 92%) as a colorless solid. Mp: 122-124 °C. IR
(film) νmax: 3386, 1724 cm-1. 1H NMR (300 MHz, CDCl3): δ
5.99-5.86 (m, 2H), 5.44 (s, 1H), 3.87-3.79 (m, 1H), 2.84-2.69
(m, 2H), 2.37-2.31 (m, 1H), 2.20-2.16 (m, 4H), 1.94-1.80
(singlet merged with m, 4H), 1.23 (d, J = 11.3 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 211.7, 149.5, 128.9, 127.3, 122.4,
66.3, 49.6, 41.1, 38.2, 37.2, 27.5, 27.4, 20.4. HRMS (ESI) (m/z):
found 227.1042 [M þ Na]þ, calcd for C13H16O2Na 227.1048.
Crystal data of 40: C13H16O2, M 204.25, space group,
(1S*,6S*,8R*)-Tricyclo[6.2.2.01,6]dodeca-3,11-diene-5,10-dione
(43). To a solution of 42 (0.015 g, 0.06 mmol) in acetone-water
(10 mL, 4:1) was added aq HCl (10%, 0.03 mL) at ∼10 °C. The
reaction mixture was stirred at ambient temperature for 10 h.
Acetone was removed, and the aqueous residue was extracted
with ethyl acetate (3 ꢀ 10 mL). The combined extract was washed
with aq sodium bicarbonate followed by brine and dried on
anhydrous sodium sulfate. Removal of solvent followed by
chromatography on silica gel [petroleum ether-ethyl acetate
85:15] gave 43 (0.011 g, 92%) as a colorless solid.Mp: 113-
˚
˚
triclinic, P-1, a=8.1475(9) A, b=8.2598(17) A, c=8.4400(10)
˚
˚
A, λ = 0.71073 A, R = 79.263(13)°, β = 70.219(10)°, γ =
3
3
1
80.475(12)°, U 519.41(14) A , Z = 2, Dc = 1.300 mg/m , T =
293(2) K, F(000)=218, size=0.40 ꢀ 0.35 ꢀ 0.30 mm. Reflections
collected/unique 1946/1811 [R(int) = 0.0339], final R indices
[I > 2σ(I)] R1=0.0629, wR2=0.1698, R indices (all data) R1=
0.0939, wR2=0.1912
115 °C. IR (neat) νmax: 1715, 1682 cm-1. H NMR (400 MHz,
˚
CDCl3): δ 6.95 (dd, J1=10 Hz, J2=6 Hz, 1H), 6.56 (superimposed
dd, J=7 Hz, 1H), 6.07 (d with structure, J=10 Hz, 1H), 5.81(d, J=
7 Hz, 1H), 3.11-3.00 (m, 2H), 2.70 (dd, J1=10 Hz, J2=5 Hz, 1H),
2.56 (dd, J1=19.4 Hz, J2=10 Hz, 1H). 2.42 (d with structure, J=
14.3 Hz, 1H), 2.16-2.12 (m, 2H), 1.88 (superimposed ddd, J1=
14.3 Hz, J2=10 Hz, J3=3 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 210.9, 197.2, 146.6, 139.7, 130.1, 129.9, 54.5, 46.3, 40.6, 31.0,
28.7, 27.2. HRMS (ESI) (m/z): found 189.0912 [M þ H]þ, calcd
for C12H13O2 189.0916.
(1S*,6S*,8R*)-11-Spiro(1,3-dioxalane)-5(S*)-hydroxytricyclo-
[6.2.2.01,6]dodeca-3,9-diene (41a). To a degassed solution of diene
29a (0.220 g, 0.83 mmol) in dichloromethane (50 mL) was added
Grubbs’ first-generation catalyst 38 (34 mg, 0.04 mmol), and the
reaction mixture was stirred at ambient temperature under nitro-
gen for 2 h. Removal of solvent followed by chromatography on
silica gel (petroleum ether-ethyl acetate, 85:15) gave 41a (0.160 g,
81%) as a colorless liquid. IR (neat) νmax: 3413, 1657 cm-1. 1H
NMR (400 MHz, CDCl3): δ 6.35 (dd, J1=8.4 Hz, J2=7 Hz, 1H),
5.92 (d, J=8.4 Hz, 1H), 5.82-5.76 (m, 1H), 5.64 (m of d, J=10
Hz, 1H), 3.94-3.80 (m, 4H), 3.60 (br m, 1H), 2.70 (br s, 1H), 2.34
(m of part of an AB system, JAB=17.5 Hz, 1H), 2.18 (m of part of
an AB system, JAB=17.5 Hz, 1H), 2.00-1.89 (m, 2H), 1.74 (d of
part of an AB system, JAB=12 Hz, J2=2.4 Hz,1H), 1.65-1.58 (m
merged with signal due to H2O present in CDCl3, 1H), 1.47-1.41
(m, 1H), 1.28-1.24 (m, 1H). 13C NMR (100 MHz, CDCl3): δ
135.0, 134.7, 130.8, 126.8, 113.4, 73.5, 64.7, 64.4, 45.1, 43.5, 39.9,
30.8, 30.2, 27.7. HRMS (ESI) (m/z): found 235.1331 [M þ H]þ,
calcd for C14H19O3 235.1334.
(1S*,6S*,8R*)-11-Spiro(1,3-dioxalane)-9-methyltricyclo[6.2.2.01,6]-
dodeca-3,9-dien-5-one (44). To a degassed solution of 33 (0.050 g,
0.18 mmol) in dichloromethane (40 mL) was added Grubbs’
catalyst 38 (8 mg, 0.01 mmol) and the mixture stirred at ambient
temperature for 5 h under nitrogen. Removal of solvent fol-
lowed by chromatography of the residue on silica gel (petroleum
ether-ethyl acetate, 98:2) gave the title compound 44 as a
1
colorless liquid (28 mg, 64%). IR (film) νmax: 1701 cm-1. H
NMR (400 MHz, CDCl3): δ 6.84 (ddd, J1=8.2 Hz, J2=5.9 Hz, J3
=2.4 Hz, 1H), 5.94 (m of d, J=8.2 Hz, 1H), 5.40 (s with str, 1H),
3.95-3.8 (m, 4H), 2.81 (dd, J1=9.5 Hz, J2=3.7 Hz, 1H), 2.63
(superimposed dd of part of an AB system, JAB=19 Hz, J2=J3=
3 Hz, 1H), 2.50 (m of dd of part of an AB system, JAB=19 Hz,
J2=5.8 Hz, 1H), 2.42-2.36 (m, 1H), 2.09 (ddd, J1=10.6 Hz, J2=
5 Hz, J3=3.5 Hz, 1H), 1.73-1.60 (m merged with d, J=1.5 Hz,
total 5H), 1.55 (superimposed dd of d, J1=13.3 Hz, J2=J3=3.1
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 199.8, 146.9, 146.6,
129.8, 124.6, 113.3, 64.9, 64.8, 47.2, 46.1, 42.4, 35.9, 28.6, 25.5,
20.1. HRMS (ESI) (m/z): found 247.1344 [M þ H]þ, calcd for
C15H19O3 247.1334.
Preparation of Compound 44 by Oxidation of 39a. To a
solution of compound 39a (0.020 g, 0.072 mmol) in CH2Cl2
(20 mL) was added freshly prepared MnO2 (0.200 g), and the
reaction mixture was stirred for 4 h at ambient temperature. It
was filtered on a Celite bed and washed with CH2Cl2 (15 mL).
The filtrate was concentrated in vacuo, and the residue was
chromatographed. Elution with petroleum ether-ethyl acetate
(1S*,6S*,8R*)-11-Spiro(1,3-dioxalane)-5(R*)-hydroxytricyclo-
[6.2.2.01,6]dodeca-3,9-diene (41b). To a degassed solution of diene
29b (0.066 g, 0.25 mmol) in dichloromethane (25 mL) was added
Grubbs’ first-generation catalyst 38 (15 mg, 0.02 mmol) and the
mixture stirred at ambient temperature under nitrogen for 3 h
(TLC). Removal of solvent followed by chromatography on silica
gel (petroleum ether-ethyl acetate, 85:15) gave 41b (0.050 g, 86%)
1
as a colorless liquid. IR (film) νmax: 3465 cm-1. H NMR (400
MHz, CDCl3): δ6.45 (superimposeddd, J=8 Hz, 1H), 6.04 (d, J=
8.4 Hz, 1H), 5.95-5.82 (merged m, 2H), 3.98-3.84 (m, 4H),
3.83-3.76 (m, 1H), 2.80-2.74 (br m, 1H), 2.46-2.40 (m, 1H),
2.37-2.22 (m, 2H), 2.06-2.00 (m, 1H), 1.86-1.78 (m, 2H), 1.68-
1.60 (m, 1H), 1.36 (d, J=11.4 Hz, 1H). 13C NMR (100 MHz,
6102 J. Org. Chem. Vol. 74, No. 16, 2009

Singh et al.
JOCArticle
(70.30) gave the compound 44 as a colorless liquid (0.019 g,
96%) which was found to be identical with the compound
prepared above.
(1S*,7S*,9R*)-(6R*)-Hydroxytricyclo[7.2.2.01,7]trideca-3,12-
dien-11-one (47). To a solution of compound 45b (0.050 g,
0.2 mmol) in acetone-H2O (15 mL, 4:1) was added concd HCl
(0.8 mL) at 0-5 °C, and the reaction mixture was stirred for 8 h.
The reaction mixture was neutralized with NaHCO3, and acet-
one was removed under vacuum. The mixture was was diluted
with water and extracted with ether (3 ꢀ 20 mL). The combined
extract was washed with brine (10 mL) and dried. Solvent was
removed in vacuo, and the product was chromatographed on
silica gel [petroleum ether-ethyl acetate (82: 18)] to give the keto
(1S*,7S*,9R*)-12-Spiro(1,3-dioxalane)-(6S*)-hydroxytricyclo-
[7.2.2.01,7]trideca-3,10-diene (45a). To a degassed solution of
triene 31a (0.190 g, 0.68 mmol) in dichloromethane (50 mL)
was added Grubbs’ first-generation catalyst 38 (28 mg,
0.03 mmol), and the reaction mixture was stirred at ambient
temperature for 7 h under nitrogen. Removal of solvent followed
by chromatography on silica gel (petroleum ether-ethyl acetate,
80:20) gave 45a (0.140 g, 82%) as a colorless solid. Mp: 116-118
°C. IR (film) νmax: 3413, cm-1. 1H NMR (300 MHz, CDCl3): δ
6.32 (dd, J1=8.2 Hz, J2=6.4 Hz, 1H), 6.01-5.90 (merged m, 2H),
5.84-5.75 (m, 1H), 3.92-3.85 (m, 4H), 3.06-2.96 (m, 1H), 2.64-
2.24 (merged m, 6H), 2.06-1.94 (m, 1H), 1.74-1.58 (m, merged
with broad s, 3H), 1.26-1.18 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 134.5, 132.3, 131.6, 128.4, 114.5, 73.4, 64.9, 64.6, 47.7,
47.3, 43.0, 35.7, 33.4, 30.3, 26.4. HRMS (ESI) (m/z): found
249.1502 [M þ H]þ, calcd for C15H21O3 249.1491.
alcohol 47 (0.038 g, 92%) as a colorless liquid. IR (film) νmax
:
3420, 1714 cm-1 1H NMR (400 MHz, CDCl3): δ 6.54
.
(superimposed dd, J1 = J2 = 8 Hz, 1H), 6.05-5.96 (m, 1H),
5.87-5.77(m, 2H), 3.89 (br m, 1H), 2.99-2.93 (m, 1H), 2.66-
2.48 (m, 2H), 2.44-2.34 (m, 1H), 2.32-1.94 (merged m, 5H),
1.88-1.80 (m, 1H), 1.41-1.38 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 211.9, 138.4, 130.4, 129.2, 128.6, 70.5, 52.1, 44.6, 39.9,
33.4, 30.8, 28.3. HRMS (ESI) (m/z): found 205.1237 [M þ H]þ,
calcd for C13H17O2 205.1229.
Crystal data of 45a: C30H40O6, M 496.2 (two molecules),
(1S*,7S*,9R*)-12-Spiro(1,3-dioxalane)-10-methyl-(6S*)-hydroxy-
tricyclo[7.2.2.01,7]trideca-3,10-diene (48). To a degassed solution of
compound 30a (0.048 g, 0.16 mmol) in CH2Cl2 (30 mL) was
added first-generation Grubbs’ catalyst 38 (14 mg, 0.02 mmol),
and the reaction mixture was stirred for 5 h at ambient tem-
perature. Removal of solvent followed by chromatography on
silica gel [petroleum ether-ethyl acetate (70:30)] gave the com-
˚
space group, orthorhombic, Pbca, a=8.424(3) A, b=23.69(5) A,
˚
˚
˚
c=25.47(9) A, λ=0.7107 A, R=90.00°, β=90.00°, γ=90.00°, U
3
ꢀ
˚
3
5083(10) A , Z=8, Dc=1.298 mg/m , T=293(2) K, F(000)=
2144, size=0.28 ꢀ 0.24 ꢀ 0.21 mm. Reflections collected/unique
4458/2142 [R(int) = 0.0882], final R indices [I > 2σ(I)] R1 =
0.0346, wR2=0.0465 R indices (all data) R1=0.0992, wR2=
0.0526.
pound 48 (0.035 g, 81%) as a colorless liquid. IR (film) νmax
:
(1S*,7S*,9R*)-12-Spiro(1,3-dioxalane)-(6R*)-hydroxytricyclo-
[7.2.2.01,7]trideca-3,10-diene(45b). Toa degassedsolutionofdiene
31b (0.100 g, 0.36 mmol) in dichloromethane (40 mL) was added
Grubbs’ first-generation catalyst 38 (15 mg, 0.02 mmol) and the
mixture stirred at ambient temperature for 5 h under nitrogen.
Removal of solvent followed by chromatography on silica gel
[petroleum ether-ethyl acetate (70:30)] gave 45b (0.084 g, 94%) as
a colorless liquid. IR (film) νmax: 3430 cm-1. 1H NMR (400 MHz,
CDCl3):δ6.40 (dd, J1=8 Hz, J2=6.6Hz, 1H), 6.04-5.95 (m, 2H),
5.83-5.74 (m, 1H), 4.0-3.80 (merged m, 5H), 2.68-2.62 (m, 1H),
2.58-2.42 (m, 3H), 2.34-2.24 (m, 2H), 1.92-1.84 (m, 1H), 1.76-
1.66 (m, 2H), 1.62-1.54 (m, 1H), 1.44-1.38 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 136.5, 132.1, 130.9, 129.4, 114.6, 71.4, 64.9,
64.6, 45.8, 43.2, 43.0, 33.5, 31.4, 30.4, 27.0. HRMS (ESI) (m/z):
found 249.1497 [M þ H]þ, calcd for C15H21O3 249.1490.
(1S*,7S*,9R*)-Tricyclo[7.2.2.01,7]trideca-3,12-dien-11-one (46).
To a solution of compound 45a (0.110 g, 0.443 mmol) in CH2Cl2
(15 mL) were added PCC (0.382 g, 1.77 mmol) and sodium acetate
(0.084 g, 1.02 mmol), and the reaction mixture was stirred at
ambient temperature for 8 h (TLC) and then filtered through a
column of silica gel to give a keto ketal (0.076 g, 69%) as a colorless
liquid which was subjected to hydrolysis as described below.
To a solution of the keto ketal thus obtained (0.020 g, 0.081
mmol) in acetone-water (10 mL, 4:1) was added aq HCl (0.4
mL) at ∼10 °C. The reaction mixture was stirred at ambient
temperature for 10 h. Acetone was removed, and the aqueous
residue was extracted with ethyl acetate (3ꢀ10 mL). The
combined extract was washed with aq sodium bicarbonate
followed by brine and dried on anhydrous sodium sulfate.
Removal of solvent followed by chromatography on silica gel
[petroleum ether-ethyl acetate 90:10] gave 46 (0.015 g, 93%) as
3430 cm-1. 1H NMR (400 MHz, CDCl3): δ 6.00-5.584 (m, 1H),
5.81-5.74 (m, 1H), 5.50 (br s, 1H), 4.00-3.8 (m, 5H), 3.01-2.95
(m, 1H), 2.55-2.20 (m, 6H), 2.00-1.90 (m, 1H), 1.78 (d, J=1.5
Hz, 3H), 1.74-1.64 (m, 2H), 1.26-1.18 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 143.3, 131.7, 128.2, 124.3, 114.9, 73.5, 64.9,
64.6, 48.2, 47.9, 42.6, 35.9, 35.8, 32.8, 26.5, 20.2. HRMS
(ESI) (m/z): found 285.1459 [MþNa]þ, calcd for C16H22O3Na
285.1467.
(1S*,7S*,9R*)-13-Methyl-(6R*)-hydroxy-tricyclo[7.2.2.01,7]-
trideca-3,12-dien-11-one (49). To a degassed solution of diene 34
(0.120 g, 0.48 mmol) in CH2Cl2 (50 mL) was added Grubbs’
catalyst 38 (20 mg, 0.024 mmol) and stirred at ambient tem-
perature for 8 h, under nitrogen. Removal of solvent followed
by chromatography of the residue on silica gel [petroleum ether-
ethyl acetate (90:10)] gave the title compound 49, as a colorless
solid (0.088 g, 83%), mp. 127-128 °C. IR (film) νmax: 3433, 1719
cm-1. 1H NMR (300 MHz, CDCl3): δ 6.01-5.94 (m, 1H), 5.83-
5.74 (m, 1H), 5.39 (s, 1H), 3.90-3.81 (m, 1H), 2.70-2.65 (m,
1H), 2.60-2.48 (m, 2H), 2.35 (m of d, J=16 Hz, 1H), 2.23 (dd, J1
=16 Hz, J2=5 Hz, 1H), 2.19-2.08 (m, 3H), 1.98-1.70 (m, 1H),
1.88-1.76 (singlet merged with m, 4H), 1.44 (d, J=9.6 Hz, 1H).
13C NMR (75 MHz, CDCl3): δ 212.0, 148.0, 130.4, 129.1, 120.5,
70.5, 51.8, 45.1, 39.6, 36.3, 33.4, 30.3, 28.4, 20.3. HRMS (ESI)
(m/z): Found 219.1389 [M þ H]þ, calcd for C14H19O2 219.1385.
Crystal data of 49: C14H18O2, M 218.28, space group, triclinic,
˚
˚
˚
P-1, a = 8.1740(16) A, b = 8.4240(6) A, c = 8.5710(7) A,
˚
λ=0.70930 A, R=98.169(7)°, β=100.674(10)°, γ=90.637(10)°,
3
3
˚
U = 573.66(13) A , Z = 2, Dc = 1.264 mg/m , T = 293(2) K,
F(000)=236, size=0.35 ꢀ 0.20 ꢀ 0.15 mm. Reflections collected/
unique 1820/1820 [R(int)=0.0000], final R indices [I > 2σ(I)]
R1=0.0347, wR2=0.0803. R indices (all data) R1=0.0420,
wR2=0.0853.
a colorless solid. Mp: 118-120 °C. IR (film) νmax: 1702 (br) cm-1
.
1H NMR (400 MHz, CDCl3): δ 6.62 (dd, J1=8 Hz, J2=6.6 Hz,
1H), 6.11-6.02 (m, 1H), 5.88-5.81(m, 1H), 5.69(d, J=8 Hz, 1H),
3.28 (dd, J1 = 10 Hz, J2 = 6.2 Hz, 1H), 3.20 (br d, J = 17.5
Hz), 3.06-2.96(merged m, 2H), 2.78 (dd, J1 = 15 Hz, J2 =
6.2 Hz, 1H), 2.34 (dd, J1=15 Hz, J2=6.2 Hz, 1H), 2.19-2.00
(merged m, 3H), 1.84-1.76 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 209.1, 207.3, 139.0, 129.7, 128.4, 125.3, 56.7, 47.1,
43.3, 38.8, 31.7, 28.5, 28.1. HRMS (ESI) (m/z): found 203.1082
[M þ H]þ, calcd for C13H15O2 203.1072.
(1S*,7S*,9R*)-13-Methyltricyclo[7.2.2.01,7]trideca-3,12-dien-11-
one (50). To a stirred solution of the keto alcohol 49 (0.060 g,
0.27 mmol) in dichloromethane (15 mL) were added PCC (0.148
˚
g, 0.68 mmol) and molecular sieves (4 A, previously dried) and
the mixture stirred at ambient temperature until completion of
the reaction (TLC, 1 h). The reaction mixture was filtered on a
Celite bed and washed with ether (3 ꢀ 15 mL). The filtrate was
concentrated under vacuum, and the product was chromato-
graphed on silica gel [petroleum ether-ethyl acetate (90:10)] to
J. Org. Chem. Vol. 74, No. 16, 2009 6103

Singh et al.
JOCArticle
furnish the diketone 50 as a colorless solid (0.056 g, 94%). Mp:
J1=9.6 Hz, J2=6.3 Hz, 1H), 3.06-3.00 (m, 1H), 2.72-2.64 (dd,
J1=13.2 Hz, J2=6.3 Hz, 1H), 2.58-2.26 (cluster of m, 5H), 2.17
(dd, J1=13.2 Hz, J2=8.9 Hz, 1H), 2.10-2.02 (br m, 1H), 2.00-
1.92 (m, 1H), 1.82-1.72 (m, 1H). 13C NMR (75 MHz, CDCl3): δ
214.4, 209.2, 138.3, 130.0, 128.8, 128.7, 53.2, 47.0, 45.4, 39.4,
33.3, 32.5, 28.9, 23.2. HRMS (ESI) (m/z): found 217.1221[M þ
H]þ, calcd for C14H17O2 217.1229.
1
100-102 °C. IR (film) νmax: 1731 cm-1. H NMR (300 MHz,
CDCl3): δ 6.12-6.01 (m, 1H), 5.88-5.76 (m, 1H), 5.26 (br s,
1H), 3.30-3.22 (m, 2H), 2.98 (dd, J1=18 Hz, J2=7.2 Hz, 1H),
2.80-2.69 (merged m, 2H), 2.28 (dd, J1=15 Hz, J2=6.6 Hz, 1H),
2.15-2.05 (m, 2H), 2.05-1.95 (m, 1H), 1.88 (d, J=1.5 Hz, 3H),
1.80-1.62 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 209.1, 207.1,
148.5, 129.7, 125.0, 120.4, 56.60, 47.6, 43.1, 38.21, 36.9, 28.0,
27.7, 20.1. HRMS (ESI) (m/z): found 217.1237 [M þ H]þ, calcd
for C14H17O2 217.1229.
Acknowledgment. We are grateful to the Department of
Science and Technology for continuing financial support. P.
K.S. thanks CSIR and B.C.S. thanks DST and CSIR New
Delhi for fellowships. Thanks are due to DST for creating a
national single-crystal X-ray facility.
(1S*,8S*,10R*)-Tricyclo[8.2.2.01,8]tetradeca-3,13-diene-7,12-
dione (51). To a degassed solution of diene 37 (0.048 g,
0.196 mmol) in dichloromethane (20 mL) was added second-
generation Grubbs’ catalyst 52 (8 mg, 0.01 mmol) and the
mixture stirred at ambient temperature under nitrogen. Re-
moval of solvent followed by chromatography on silica gel
[petroleum ether-ethyl acetate (90:10)] gave 51 (0.038 g, 89%)
as a colorless solid. Mp: 95-97 °C. IR (film) νmax: 1722, 1701
cm-1. 1H NMR (300 MHz, CDCl3): δ 6.62 (dd, J1=8.0 Hz, J2=
6.6 Hz, 1H), 6.02-5.80 (m, 2H), 5.68 (d, J=8.0 z, 1H), 3.17 (dd,
Supporting Information Available: 1H NMR and 13C NMR
spectra of compounds 12b, 14, 16-37, and 39-51, ORTEP
diagrams of 16, 40, 45a, and 49, and CIF data of 16, 40, 45a, and
49. This material is available free of charge via the Internet at
http://pubs.acs.org.
6104 J. Org. Chem. Vol. 74, No. 16, 2009