Unmasking the 6,7,5-Tricarbocyclic Frame of [5 + 2]/[4 + 2] Pyrone-Alkene Cycloadducts

Article abstract of DOI:10.1021/jo9917893

Opening of the bridging ether of 8-oxabicyclo[3.2.1]oct-6-ene systems 1,7-fused to a five-membered carbocycle that bears a double bond conjugated to that of the oxabicycle can be induced at low temperaure by the addition of an organolithium reagent. If this double bond is unsubstituted, the opening occurs via an anti-1,6-addition pathway, and if substituted it takes place by means of a more classical syn S_N2′ addition.

Full text of DOI:10.1021/jo9917893

2528
J . Org. Chem. 2000, 65, 2528-2531
Un m a sk in g th e 6,7,5-Tr ica r bocyclic F r a m e of [5 + 2]/[4 + 2]
P yr on e-Alk en e Cycloa d d u cts
J . Ramo´n Rodr´ıguez, Luis Castedo, and J ose´ L. Mascaren˜as*
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Universidad de Santiago de
Compostela, 15706 Santiago de Compostela, Spain
Received November 17, 1999
Opening of the bridging ether of 8-oxabicyclo[3.2.1]oct-6-ene systems 1,7-fused to a five-membered
carbocycle that bears a double bond conjugated to that of the oxabicycle can be induced at low
temperaure by the addition of an organolithium reagent. If this double bond is unsubstituted, the
opening occurs via an anti-1,6-addition pathway, and if substituted it takes place by means of a
more classical syn SN2′ addition.
Sch em e 1
In tr od u ction
The enormous synthetic accomplishments of recent
decades could certainly generate the impression that
organic synthesis has reached such a degree of maturity
that any compound, even the most complex, can be
synthesized using the currently available methods. This
is probably not far from the truth; however, much
remains to be learned before such compounds can be
assembled in a truly practical and efficient way.1 One of
the best ways to address this objective is to develop
processes that afford a maximum increase in target-
relevant molecular complexity at a minimal economical
and ecological cost.2 Among the transformations that best
fit with this profile are cycloaddition reactions,3 which
create new rings by simple addition of two or more
molecules, and tandem processes,4 which integrate mul-
tistep processes in a single operation. We have recently
reported the successful coupling of [5 + 2] and [4 + 2]
cycloadditions in a one-pot process to obtain relatively
complex, fused 6,7,5-tricarbocyclic systems from simple
starting materials (Scheme 1).5 The transformation oc-
curs with complete atom economy6 and creates four new
carbon-carbon bonds and five new stereocenters.
Since the tricarbocyclic core of the resulting adducts
bears a marked similarity to the basic polycyclic skeleton
of dolastane and spheroane diterpenes,7 this tandem
cycloaddition methodology might afford an immediate
entry to these natural products provided the oxa-bridge
on the seven-membered ring could be removed efficiently.
Unfortunately, initial attempts to break this bridge in
compounds 2 and 4 failed.5 The precedents on reductive
or nucleophilic opening of the bridging ether in simple
8-oxabicyclo[3.2.1]oct-6-ene systems8 prompted us to
investigate whether the introduction of a double bond in
the tetrahydrofuran moiety of the central oxabicycle of
our adducts might be a convenient solution to the
problem. Herein we report the results of these studies,
which led to the discovery of unprecedented bridge-
opening pathways.
* To whom correspondence should be addressed. FAX number:
34-981-595012; e-mail: qojoselm@usc.es.
(1) (a) Hudlicky, T.; Natchus, M. G. In Organic Synthesis: Theory
and Applications; Hudlicky, T., Ed.; J AI Press: Greenwich, CT, 1993;
Vol. 2, p 1. (b) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory
and Applications; Hudlicky, T., Ed.; J AI Press: Greenwich, CT, 1993;
Vol. 2, p 27. (c) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind.
1997, 766. (d) Hendrickson, J . B. ChemTech 1998, September, p 35.
(e) Sheldon, R. A. ChemTech 1994, March, p 38. (f) Hall, N. Science
1994, 266, 32.
(2) Bertz, S. H.; Sommer, T. J . In Organic Synthesis: Theory and
Applications; Hudlicky, T., Ed.; J AI Press: Greenwich, CT, 1993; Vol.
2, p 67.
(3) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990. (b) Ghosez, L. In Stereocontrolled
Organic Synthesis; Trost, B. M., Ed.; Blackwell Science: Boston, 1994;
p 193.
Resu lts a n d Discu ssion
The required double-bond equipped adducts (5)
should be easily obtainable using our thermal tandem
(4) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Grigg, R.
Tetrahedron Symposia-In-Print Number 62, 1996, 52, 11385. (e)
Ziegler, F. E. In Comprehensive Organic Synthesis; Paquette, L. A.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 7.3. (f) Bunce, R.
A. Tetrahedron 1995, 51, 13103. (g) Parsons, P. J .; Penkett, C. S.; Shell,
A. J . Chem. Rev. 1996, 96, 195. (h) Neuschutz, K.; Velker, J .; Neier,
R. Synthesis 1998, 227.
(6) For a discussion on atom economy, see: (a) Trost, B. M. Science
1991, 254, 1471. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995,
34, 259.
(7) For a detailed account of these natural products, see: Connolly,
J . D.; Hill, R. A. Dictionary of Terpenoids; Chapman & Hall: New York,
1991; Vol. 2.
(8) An ample review of techniques for opening the oxa-bridge of
oxabicyclic systems has recently appeared: (a) Chiu, P.; Lautens, M.
In Topics in Current Chemistry; Springer-Verlag: Berlin, 1997; Vol.
190, p 1. See also: (b) Lautens, M. Synlett 1993, 177. (c) Woo, S.; Keay,
B. Synthesis 1996, 669.
(5) Rodr´ıguez, J . R.; Rumbo, A.; Castedo, L.; Mascaren˜as, J . L. J .
Org. Chem. 1999, 64, 966.
10.1021/jo9917893 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

[5 + 2]/[4 + 2] Pyrone-Alkene Cycloadducts
J . Org. Chem., Vol. 65, No. 8, 2000 2529
Sch em e 2
Sch em e 4
Sch em e 3
Me2CuLi (toluene, rt) or n-Bu2CuCNLi2 (THF/Et2O, 0 °C),
the major product isolated was the vinyl sulfone 10 (38%
and 51%, respectively, Scheme 4), doubtless the result
of a seemingly very easy phenyl sulfone elimination
reaction.11 On the other hand, treatment of 9 with 2.1
equiv of MeLi in THF at -78 °C, for 15 min, gave as
major product the methylated derivative 11a . We ob-
served that this reaction proceeds via the intermediate
10, suggesting the occurrence of a barely precedented
geminal carbon-carbon coupling between the organo-
lithium and this sulfone.12 The same type of reaction
occurred upon treatment of 9 with n-BuLi (Et2O, -78 °C),
the major product in this case being the n-butyl deriva-
tive 11b.
The oxa bridge also resisted the action of oxophilic
reagents used with a view to weakening the carbon-
oxygen bond and so facilitating the operation of alterna-
tive carbocationic opening mechanisms. Hence, treatment
of 9 with TMSI in CH3CN or with BF3‚Et2O in the
presence of ethanedithiol or NaI led to complete recovery
of the starting material, and reaction with BBr3 gave a
relatively complex mixture of secondary products. Since
the presence of the gem-disulfone group seemed to
introduce an unwanted side reactivity in the system
which does not allow us to really evaluate the feasibility
of inducing the desired nucleophilic type of oxa-bridge
opening, we attempted to remove the sulfonyl groups by
treatment of 9 with Na(Hg) (6% in MeOH/THF, rt,
Scheme 5).13 The major products of this reaction were
the desulfonated derivatives 12 and 13 that could not be
separated by silica gel flash chromatography (12/13 1.7:1
[5 + 2]/[4 + 2] cycloaddition methodology with an alkyne
instead of an alkene as two-carbon partner in the first
intramolecular cycloaddition (Scheme 2). Although it
seemed reasonable to think that the hydro- or carbo-
metalation methods that successfully open the bridging
ether of oxabicyclic[3.2.1]oct-6-enes would also open
compounds such as 5, at the outset of this research it
was not clear how the fused five-membered ring might
influence the process.9
The tetracyclic adduct 9, which bears a gem-disulfonyl
group on the five-membered carbocycle, was readily
assembled in just two steps from the known bromopyrone
6 (Scheme 3).10 Reaction of 6 with the bis-sulfonyl butyne
7 under basic phase-transfer conditions gave the required
cycloaddition precursor 8 in moderate yield (57%). When
a solution of 8 in toluene was heated at 160 °C for 12 h
in a sealed tube, in the presence of 5 equiv of 2,3-
dimethylbutadiene, the expected tetracyclic compound 9
was obtained in 93% yield. Initial efforts to break the
oxa-bridge of 9 were carried out using DIBAL-H for
attempted reductive SN2′ ring opening.8 Unfortunately,
heating compound 9 with an excess of DIBAL-H in
refluxing hexanes gave a relatively complex mixture of
products, and NMR analysis of the reaction crude showed
that in none of them was the ether bridge broken.
Curiously, when 9 was treated with cuprates such as
1
by H NMR, 41% overall yield). Remarkably, treatment
of this mixture with t-BuLi in Et2O at -78 °C led to the
instantaneous formation of the unbridged product 14
(87% yield from 12), a compound that arises from an anti
1,6-addition of the organolithium reagent to the diene
12, with compound 13 being almost completely recov-
ered.14 The stereochemistry of the tricycle 14 was inferred
1
from the H NMR coupling pattern for H-2, and particu-
(11) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993; Chapter 7, p 262.
(12) There are precedents of the geminal alkylative desulfonation
of vinyl sulfones using Grignard reagents and nickel or iron catalysts.
See: Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993; Chapter 7, p 351.
(13) For a recent review on desulfonation reactions, see: Na´jera,
C.; Yus, M. Tetrahedron 1999, 55, 10547.
(9) The presence of a third substituent at the double bond in
7-oxabicyclic [2.2.1] systems seems to impair the SN2′-reactivity; see:
Lautens, M.; Fillion, E. J . Org. Chem. 1998, 63, 647.
(10) Rumbo, A.; Castedo, L.; Mourin˜o, A.; Mascaren˜as, J . L. J . Org.
Chem. 1993, 58, 5585.
(14) It has been shown that generating an anion in an alkyl group
attached to the double bond of 7-oxanorbornenes brings about ether
bridge cleavage: (a) Arjona, O.; Conde, S.; Plumet, J . Viso, A.
Tetrahedron Lett. 1995, 36, 6157. (b) Arjona, O.; Leon, M. L.; Plumet,
J . J . Org. Chem. 1999, 64, 272.

2530 J . Org. Chem., Vol. 65, No. 8, 2000
Ramo´n Rodr´ıguez et al.
Sch em e 6
F igu r e 1. MM-optimized conformation of 14.15
Sch em e 5
been discovered. In both cases the success of the reaction
depends on the five-membered ring possesing a double
bond conjugated to that of the oxabicycle. This double
bond either mediates a 1,6-addition reaction or stabilizes
the carbanion resulting from carbometalation of the oxa-
bicyclic alkene. As a result of these discoveries we can
state that the way for applying the tandem [5 + 2]/
[4 + 2] cycloaddition methodology to the synthesis of
tricarbocyclic diterpenes is unblocked.
Exp er im en ta l Section
Gen er a l P r oced u r es. See ref 2.
4,4-Bis(p h en ylsu lfon yl)-1-bu tyn e (7). To a solution of bis-
(phenylsulfonyl)methane (3.5 g, 11.8 mmol) in DMF (20 mL)
was slowly added a suspension of NaH (520 mg, 13 mmol, 60%
mineral oil,). After stirring for 5 min at room temperature and
10 min at 70 °C, propargyl bromide (1.4 mL, 12.5 mmol, 80wt
% in toluene) was slowly added, and the resulting mixture was
stirred at 70 °C for 5 min. The DMF was removed under
vacuum and the residue partitioned between Et2O and H2O.
The organic layer was washed with aqueous HCl (5%), dried,
filtered, and concentrated. The residue was purified by silica
gel flash chromatography (15-40% EtOAc/hexane) to give
3.615 g of 7 as a white solid [91%, Rf 0.68 (50% EtOAc/hexane),
larly from the observation of NOE between the tert-butyl
at C-2 and the methyl and tert-butyl groups of the TBS
(Figure 1).15
Having discovered that the presence of a conjugated
double bond in the ring adjacent to the central oxabicyclic-
[3.2.1]octene unit of our tetracyclic adducts provides an
excellent site for triggering the bridge-opening, we were
curious about the reactivity of the methyl-substituted
analogue 11, for which the 1,6-pathway might be im-
paired. Quite surprisingly, diene 11a reacted very rapidly
with t-BuLi (Et2O, -78 °C) to give the SN2′ ring-opened
product arising from a syn attack of the organolithium
to the less substituted position of the double bond (79%
yield), with the resulting keto-alcohol existing almost
completely in a closed hemiketal form (15, Scheme 6).
Therefore it seems that the presence of a carbanion-
stabilizing feature such as a conjugated double bond in
the five-membered ring fused to the oxabicyclic alkene
allows a standard SN2′ ring-opening process to occur,
provided the alternative 1,6-addition mechanism is im-
peded. The stereochemistry of the tricycle 15 was easily
1
mp 96 °C]. H NMR δ 7.99-7.54 (10H, m), 4.61 (1H, t, J ) 6
Hz), 3.11 (2H, dd, J ) 6 and 2.5 Hz), 1.92 (1H, br s).13C NMR
δ 138.0 (C), 135.3 (CH), 130.2 (CH), 129.6 (CH), 82.3 (CH),
77.2 (CH), 72.7 (C), 17.0 (CH2).
3-(ter t-Bu tyld im eth ylsilyloxy)-2-[2,2-bis(p h en ylsu lfo-
n yl)-4-p en tyn yl]-4H-4-p yr a n on e (8). Bromopyrone 610 (1 g,
3.13 mmol) and disulfone 7 (1.05 g, 3.14 mmol) were added to
a suspension of NaOH (626 mg, 15.6 mmol) and n-Bu4NHSO4
(212 mg, 0.626 mmol) in CH2Cl2/H2O (30 mL, 2:1). The mixture
was vigorously stirred at room temperature for 12 h, poured
into a saturated aqueous solution of NH4Cl, and extracted with
CH2Cl2. The organic extracts were dried, filtered, and concen-
trated to give a residue that was purified by silica gel flash
chromatography (25-40% EtOAc/hexane), affording 1.02 g of
compound 8 as a white solid [57%, Rf 0.44 (50% EtOAc/
1
deduced from the observation in the H NMR spectrum
of a almost negligible coupling (approx 1 Hz) between H-7
and H-8.
1
hexane), mp 175-177 °C]. H NMR δ 8.01 (4H, brd, J ) 7.3
Hz), 7.70-7.41 (m, 7H), 6.26 (1H, d, J ) 5.5 Hz), 3.85 (2H, s),
3.48 (2H, d, J ) 2.6 Hz), 2.06 (1H, t, J ) 2.6 Hz), 0.90 (9H, s),
0.27 (6H, s); 13C NMR δ 174.1 (C), 153.2 (CH), 150.2 (C), 144.5
(C), 136.8 (C), 135.4 (CH), 131.9 (CH), 129.6 (CH), 129.3 (CH),
116.0 (CH), 88.8 (C), 76.6 (CH), 75.0 (C), 27.3 (CH2), 26.4 (CH3),
22.8 (CH2), 19.2 (C), -2.9 (CH3).
Con clu sion
In summary, two unprecedented ways of opening the
bridging ether of 8-oxabicyclo[3.2.1]oct-6-ene systems
that are 1,7-fused to a five-membered carbocycle have
(1R*,3R*,8S*,9S*)-3-(ter t-Bu t yld im et h ylsilyloxy)-5,6-
d im e t h yl-13,13-b is(p h e n ylsu lfon yl)-15-oxa t e t r a cyclo-
[7.5.1.01,11.03,8]p en ta d eca -5,10-d ien -2-on e (9). A solution of
(15) MM minimization was carried out using MM2 as implemented
in CS Chem 3D Pro (Cambridge Soft Corporation).

[5 + 2]/[4 + 2] Pyrone-Alkene Cycloadducts
J . Org. Chem., Vol. 65, No. 8, 2000 2531
compound 8 (425 mg, 0.743 mmol) and 2,3-dimethylbutadiene
(0.41 mL, 3.7 mmol) in toluene (25 mL) was heated at 160 °C
in a sealed tube for 12 h. The solvent was evaporated, and
the crude was purified by flash chromatography on silica gel
(5-10% EtOAc/hexanes) to afford 452 mg of compound 9 as a
white solid [93%, Rf 0.45 (25% EtOAc/hexanes), mp 206 °C].
1H NMR δ 8.11-7.97 (4H, m), 7.73-7.53 (6H, m), 5.80 (1H, d,
J ) 1.7 Hz), 4.47 (1H, d, J ) 2.2 Hz), 3.42 (1H, d, J ) 15.7
Hz), 3.11 (2H, s), 2.66 (1H, d, J ) 15.7 Hz), 2.37 (1H, d, J )
16 Hz), 2.01 (1H, m), 1.95 (3H, m), 1.67 (3H, s), 1.63 (3H, s),
0.73 (9H, s), 0.06 (3H, s), -0.15 (3H, s). 13C NMR δ 200.7 (C),
144.9 (C), 136.5 (C), 136.1 (C), 134.8 (CH), 134.6 (CH), 131.6
(CH), 131.4 (CH), 129.0 (CH), 128.9 (C), 128.6 (CH), 125.7 (C),
123.7 (C), 96.8 (C), 94.8 (C), 92.1 (CH), 81.7 (C), 48.0 (CH),
42.1 (CH2), 35.4 (CH2), 31.9 (CH2), 30.6 (CH2), 25.6 (CH3), 19.0
(C), 18.8 (CH3), 18.1 (C), -2.8 (CH3), -3.4 (CH3).
(1R*,3R*,8S*,9S*)-3-(ter t-Bu t yld im et h ylsilyloxy)-5,6-
d i m e t h y l -1 3 -(p h e n y l s u l fo n y l )-1 5 -o x a t e t r a c y c l o -
[7.5.1.01,11.03,8]p en ta d eca -5,10,12-tr ien -2-on e (10). n-BuLi
(0.383 mL, 0.91 mmol, 2.4 M in hexanes) was added to a cooled
(-78 °C) solution of CuCN (45 mg, 0.50 mmol) in THF/Et2O
(10 mL, 1:1). The reaction mixture was allowed to reach room
temperature and recooled at 0 °C. To the resulting suspension
was added a solution of 9 (100 mg, 0.153 mmol) in THF/Et2O
(3 mL, 1:1). The mixture was stirred at room temperature for
1 h, poured into brine, and extracted with Et2O. Drying,
filtering, and concentration gave a residue that was purified
by silica gel flash chromatography (5-10% EtOAc/hexane) to
afford 40 mg of 10 as a white solid [51%, Rf 0.6 (25% EtOAc/
hexanes), mp 110 °C]. 1H NMR δ 7.88 (2H, m), 7.75-7.56 (3H,
m), 6.92 (1H, s), 6.36 (1H, s), 4.92 (1H, s), 2.98 (1H, d, J ) 15
Hz), 2.61 (1H, d, J ) 15 Hz), 2.29 (2H, m), 2.02 (3H, m), 1.69
(3H, s), 1.61 (3H, s), 0.73 (9H, s), 0.08 (3H, s), -0.20 (3H, s).
13C NMR δ 200.5 (C), 153.7 (C), 149.4 (C), 139.0 (C), 134.3
(CH), 130.2 (CH), 129.7 (CH), 129.6 (CH), 128.4 (CH), 126.8
(C), 124.1 (C), 97.0 (C), 94.3 (CH), 81.8 (C), 47.9 (CH), 42.5
(CH2), 36.1 (CH2), 32.6 (CH2), 26.0 (CH3), 19.3 (CH3), 19.2
(CH3), 18.6 (C), -2.3 (CH3), -3.2 (CH3).
(1R*,3R*,8S*,9S*)-3-(ter t-Bu t yld im et h ylsilyloxy)-5,6,-
13-tr im eth yl-15-oxa tetr a cyclo[7.5.1.01,11.03,8]p en ta d eca -5,-
10,12-tr ien -2-on e (11a ). MeLi (0.62 mL, 0.93 mmol, 1.5 M
in Et2O) was added to a solution of 9 (300 mg, 0.458 mmol) in
THF (10 mL) cooled at -78 °C. The reaction mixture was
stirred at that temperature for 15 min, poured in brine, and
extracted with Et2O. Drying, filtering, and concentration of
the organic extracts led to a residue that was purified by silica
gel flash chromatography to afford 69 mg of compound 11a as
a viscous colorless oil [38%, Rf 0.66 (10% EtOAc/hexanes)]. 1H
NMR δ 5.75 (1H, s), 5.70 (1H, br s), 4.82 (1H, d, J ) 2.1 Hz),
2.69 (1H, d, J ) 16.6 Hz), 2.38-2.23 (3H, m), 2.13-1.98 (3H,
m), 1.93 (3H, s), 1.73 (3H, s), 1.66 (3H, s), 0.78 (9H, s), 0.12
(3H, s), -0.12 (3H, s). 13C NMR δ 203.6 (C), 156.9 (C), 153.3
(C), 125.4 (C), 123.9 (C), 117.7 (CH), 117.5 (CH), 97.7 (C), 93.1
(CH), 81.8 (C), 48.2 (CH), 43.1 (CH2), 38.2 (CH2), 35.5 (CH2),
25.7 (CH3), 19.1 (C), 18.9 (CH3), 18.3 (CH3), 18.2 (CH3), -2.9
(CH3), -3.2 (CH3).
(1R*,3R*,8S*,9S*)-3-(ter t-Bu t yld im et h ylsilyloxy)-5,6-
d im e t h y l-15-o xa t e t r a c y c lo [7.5.1.01,11.03,8]p e n t a d e c a -
5,10,12-tr ien -2-on e (12) a n d (1R*,3R*,8S*,9S*)-3-(ter t-
Bu t yld im et h ylsilyloxy)-5,6-d im et h yl-15-oxa t et r a cyclo-
[7.5.1.01,11.03,8]p en ta d eca -5,10-d ien -2-on e (13). Freshly pre-
pared Na(Hg) (1.8 g, 6% in Na) was added to a solution of 9
(400 mg, 0.611 mmol) in THF/MeOH (30 mL, 1:1). The
resulting suspension was stirred for 30 min at room temper-
ature and filtered through a short path of Celite with MeOH
washings. The filtrate was concentrated, poured into brine,
and extracted with Et2O. Drying, filtering, and concentration
of the organic extracts led to a residue that was purified by
silica gel flash chromatography to afford 88 mg of a mixture
of compounds 12 and 13 (approximately 1.7:1). [41%, Rf 0.69
1
(12% EtOAc/hexanes)]. H NMR of the mixture: δ 6.32 (br s),
6.03 (br s), 5.90 (s), 5.83 (s), 4.84 (br s), 4.68 (br s), 2.83 (d,
J ) 16.2 Hz), 2.44-2.19 (m), 2.10-1.90 (m), 1.73 (s), 1.62 (s),
1.58 (s), 0.73 (br s), 0.10 (br s), -0.10 (s), -0.18 (s).
(2R*,3a R*,4a R*,8a S*)-2-ter t-Bu tyl-4a -(ter t-bu tyld im e-
th ylsilyloxy)-3a -h yd r oxy-6,7-d im eth yl-2,3,3a ,4,4a ,5,8,8a -
octah ydr oben zo[f]azu len -4-on e (14). t-BuLi (0.32 mL, 0.512
mmol, 1.6 M in pentanes) was added to a solution of the
previously obtained 1.7:1 mixture of 12 and 13 (37 mg, approx
0.1 mmol) in Et2O (6 mL) cooled at -78 °C. After 2 min, the
reaction mixture was poured into brine and extracted with
Et2O. Drying and concentration of the organic extracts led to
a residue that was purified by silica gel flash chromatography
to afford 24 mg of 14 as a white solid [87%, Rf 0.65 (12% EtOAc/
1
hexanes), mp 85 °C] and 11 mg of 13. H NMR δ 6.24 (1H, d,
J ) 11.7 Hz), 5.97 (1H, s), 5.51 (1H, dd, J ) 6.7 and 11.7 Hz),
2.82 (2H, m), 2.55 (1H, d, J ) 16.2 Hz), 2.13 (2H, m), 2.01
(1H, dd, J ) 12.6 and 5.9 Hz), 1.99 (1H, m), 1.83 (1H, dd, J )
12.7 and 9.3 Hz), 1.66 (3H, s), 1.54 (3H, s), 0.88 (9H, s), 0.80
(9H, s), 0.12 (3H, s), 0.05 (3H, s); 13C NMR δ 207.2 (C), 141.8
(C), 139.0 (CH), 128.8 (CH), 124.8 (C), 124.7 (CH), 123.8 (C),
87.7 (C), 83.3 (C), 52.8 (CH), 44.9 (CH), 43.6 (CH2), 42.4 (CH2),
37.4 (CH2), 31.7 (C), 27.8 (CH3), 26.0 (CH3) 18.7 (CH3), 18.4
(C), 18.1 (CH3), -2.1 (CH3), -2.6 (CH3). 1H NMR of 13: δ 5.90
(1H, s), 4.68 (1H, br s), 2.45-1.81 (8H, m), 1.73 (3H, s), 1.62
(3H, s), 1.52 (m, 2H), 0.73 (9H, s), 0.10 (3H, s), -0.10 (3H, s).
(1R*,7S*,8S*,9S*, 14R*)-7-ter t-Bu t yl-14-(ter t-b u t yld i-
m e t h ylsilylo xy)-4,11,12-t r im e t h yl-15-oxa t e t r a c y c lo -
[6.6.1.02,6.09,14]p en ta d eca -2(6),4,11-tr ien -1-ol (15). t-BuLi
(0.30 mL, 0.48 mmol, 1.6 M in pentanes) was added to a
solution of diene 11a (40 mg, 0.103 mmol) in Et2O (5 mL)
cooled at -78 °C. After 5 min the reaction mixture was poured
into brine and extracted with Et2O. Drying, filtering, and
concentration of the organic extracts led to a residue that was
purified by silica gel flash chromatography to afford 36 mg of
15 as a viscous colorless oil [79%, Rf 0.44 (10% EtOAc/
hexanes)]. 1H NMR δ 6.07 (1H, s), 3.88 (1H, br s), 3.10 (2H,
m), 2.75 (1H, br s), 2.45 (2H, m), 2.04 (4H, m), 1.93 (2H, m),
1.87 (3H, s), 1.78 (3H, s), 0.99 (9H, s), 0.79 (9H, s), -0.08 (3H,
s), -0.3 (3H, s). 13C NMR δ 143.3 (C), 142.6 (C), 140.2 (C),
130.4 (CH), 125.9 (C), 123.9 (C), 103.7 (C), 88.8 (C), 82.0 (CH),
60.3 (C), 53.8 (CH), 49.3 (CH), 43.6 (CH2), 39.0 (CH2), 35.6
(CH2), 34.0 (C), 29.4 (CH3), 26.1 (CH3), 19.5 (CH3), 18.2 (CH3),
16.1 (C), 14.1 (CH3), -2.5 (CH3), -2.8 (CH3).
(1R*,3R*,8S*,9S*)-13-Bu tyl-3-(ter t-Bu tyld im eth ylsilyl-
oxy)-5,6-d im et h yl-15-oxa t et r a cyclo[7.5.1.01,11.03,8]p en t a -
d eca -5,10,12-tr ien -2-on e (11b). n-BuLi (0.2 mL, 0.5 mmol,
2.5 M in hexane) was added to a solution of 9 (105 mg, 0.16
mmol) in Et2O (8 mL) cooled at -78 °C. The mixture was
allowed to reach room temperature, poured into brine, and
extracted with Et2O. Drying and concentration of the organic
extracts led to a residue that was purified by silica gel flash
chromatography to afford 41 mg of compound 11b as a viscous
Ack n ow led gm en t. We are grateful to the Xunta de
Galicia (XUGA 20906B96) and the Spanish Ministry of
Education and Culture (PB97 0524) for financial sup-
port and for a research grant to J .R.R. We also thank
R. Gesto for running the NMR experiments.
1
colorless oil [59%, Rf 0.87 (25% EtOAc/hexanes)]. H NMR δ
5.81 (1H, s), 5.75 (1H, br s), 4.79 (1H, br s), 2.65 (1H, d, J )
16.3 Hz), 2.36-1.95 (8H, m), 2.13-1.98 (3H, m), 1.69 (3H, s),
1.62 (3H, s), 1.51-1.20 (4H, m), 0.86 (3H, t, J ) 6.6 Hz), 0.76
(9H, s), 0.11 (3H, s), -0.16 (3H, s). 13C NMR δ 203.7 (C), 162.0
(C), 153.5 (C), 126.1 (C), 124.4 (C), 117.9 (CH), 116.8 (CH),
97.8 (C), 93.7 (CH), 82.1 (C), 48.7 (CH), 43.5 (CH2), 37.0 (CH2),
36.0 (CH2), 32.5 (CH2), 29.6 (CH2), 26.1 (CH3), 22.7 (CH2), 19.6
(CH3), 19.3 (CH3), 18.7 (C), 14.2 (CH3), -2.5 (CH3), -3.3 (CH3).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H, 13C
NMR, and HMBC, HMQC, and NOE spectra of selected
products, and full lists of mass spectral data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O9917893