Progress toward the total synthesis of (±)-havellockate

Article abstract of DOI:10.1021/jo101279z

Havellockate (1) was isolated from the soft coral Sinularia granosa located on the Havellock island in the Indian Ocean. This highly compact and polyoxygenated marine diterpene bears a cis-fused hydrindane core that contains eight stereogenic centers as well as a spiro-lactone. To the best of our knowledge, no syntheses of 1 have been reported yet. Herein, we describe the synthesis of the all-carbon framework of havellockate (1) in 18 chemical operations. Our approach highlights the efficiency and utility of the hydroxy-directed Diels-Alder (HDDA) reaction to quickly access the cis-fused hydrindane core and securing the correct stereochemistry at C6 and C7. Moreover, six of the eight stereogenic centers have been installed in the correct stereochemistry.

Full text of DOI:10.1021/jo101279z

pubs.acs.org/joc
Progress toward the Total Synthesis of (()-Havellockate
Rachel L. Beingessner,† Julie A. Farand,‡ and Louis Barriault*
Department of Chemistry, 10 Marie Curie, University of Ottawa, Ottawa, Canada K1N 6N5.
Current address: National Institute for Nanotechnology, National Research Council Canada,
†
Edmonton, Canada. ‡Current address: Merck-Frosst Centre for Therapeutic Research,
16711 Trans Canada Hwy, Kirkland, Canada
lbarriau@uottawa.ca
Received July 5, 2010
Havellockate (1) was isolated from the soft coral Sinularia granosa located on the Havellock island in
the Indian Ocean. This highly compact and polyoxygenated marine diterpene bears a cis-fused
hydrindane core that contains eight stereogenic centers as well as a spiro-lactone. To the best of our
knowledge, no syntheses of 1 have been reported yet. Herein, we describe the synthesis of the all-
carbon framework of havellockate (1) in 18 chemical operations. Our approach highlights the
efficiency and utility of the hydroxy-directed Diels-Alder (HDDA) reaction to quickly access the cis-
fused hydrindane core and securing the correct stereochemistry at C6 and C7. Moreover, six of the
eight stereogenic centers have been installed in the correct stereochemistry.
Introduction
named havellockate (1) was established without ambiguity
by NMR spectroscopy and X-ray analysis (Figure 1). A
cursory inspection of this molecule unveils a cis-fused
hydrindane core bearing eight stereogenic centers and
the presence of a spiro-lactone. As with the other known
diterpenoids isolated from the Sinularia genus, havellockate
(1) is believed to arise from furanocembrane diterpene.4
To the best of our knowledge, the total synthesis of
havellockate (1) has not yet been described.5 In this paper,
recent advances in the synthesis of this natural product are
presented.
Marine organisms provide a seemingly continual supply
of novel compounds often containing complex carbo-
cyclic frameworks.1 Soft corals, for example, produce
large quantities of structurally diverse secondary metabo-
lites that are thought to have roles in defense, competition,
and reproduction of the organism.2 During their quest
for bioactive secondary metabolites, Anjaneyulu and co-
workers discovered a novel diterpenoid from the soft coral
Sinularia granosa located on the Havellock Island in the
Indian Ocean.3 The structure of this compound later
(4) (a) Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298.
(b) Anjaneyulu, A. S. R.; Venugopal, M. J. R. V.; Sarada, P. Indian J. Chem.
2000, 39B, 530.
(1) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7 and references therein.
(2) Faulkner, D. J. Nat. Prod. Rep. 1995, 2, 223.
(3) Anjaneyulu, A. S. R.; Venugopal, M. J. R. V.; Sarada, P.; Clardy, J.;
Lobkovsky, E. Tetrahedron Lett. 1998, 39, 139.
(5) For a previous synthetic study on havellockate, see: Mehta, G.; Senthil
Kumaran, R. Tetrahedron Lett. 2001, 42, 8097.
DOI: 10.1021/jo101279z
r
Published on Web 09/03/2010
J. Org. Chem. 2010, 75, 6337–6346 6337
2010 American Chemical Society

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SCHEME 2
FIGURE 1. Structure of (()-havellockate (1).
SCHEME 1
(1:1) gave the corresponding vinyl iodide 8, which subse-
quently underwent a Stille cross-coupling reaction with
tributyl(vinyl)tin in the presence of AsPh3 (10 mol %), CuI
(10 mol %), and Pd(PhCN)2Cl2 (5 mol %) to generate 9 in
87% yield over two steps.10 Finally, alkylation with methyl-
lithium in THF at -78 °C delivered diene 4 in 55% yield.
We were pleased to observe the HDDA reaction between 4
and acrolein in the presence of MgBr2 OEt2, and 2,6-lutidine in
3
methylene chloride afforded the cycloadduct 10 in 70% yield as
the sole diastereomer (Scheme 3). Treatment of 10 with fluoride
ions afforded a mixture of the desired aldehyde in equilibrium
with the lactol form. Subsequent oxidation using TPAP and
NMO in methylene chloride provided lactone 11 in 73%
yield. At this stage, a stereoselective hydroboration of 11 was
envisioned to install the cis-hydrindane ring junction. Much to
our surprise, the anti-Markovnikov addition of BH3-DMS on
11 did not give the expected product 13 after an oxidative
workup; only starting material was recovered. Other borane
complexes such as BH3-THF, 9-BBN, and catechol borane
were tried in various solvents (THF, DCM, and hexanes)
without success. Keeping in mind that the free hydroxyl group
at C5 may be detrimental to the hydroboration reaction, 11 was
converted to the corresponding silyl ether 12 and submitted to
the above conditions. After 12 was stirred for 24 h, starting
material was recovered along with degradation products. It
became apparent that the synthetic strategy would require a
Results and Discussion
By examining 1, one can imagine that the hydrindane core
2 could arise from a Diels-Alder reaction between diene 4
and dienophile 5 (Scheme 1). However, it is of paramount
importance that the facial selectivity be controlled in such a
way that all the hydrogens at the ring junction are placed syn to
the methyl group at C3. Inspired by the work of Ward,6 we
recently demonstrated the use of temporary metal tethers to
govern the facial selectivity in Diels-Alder reactions of various
2-vinylcycloalken-1-ols.7 Using this approach, we envisioned
that diene 4 and dienophile 5 would undergo a hydroxy-directed
Diels-Alder reaction (HDDA) via transition state A (TS A) to
provide the desired bicyclo[4.3.0]nonane framework 3.
Our first objective was to develop a concise synthesis of
diene 4. This was achieved according to Scheme 2, whereby
commerically available furfuryl alcohol 6 was refluxed in
water in the presence of KH2PO4 (pH of 4.10) for 40 h to
afford the corresponding 4-hydroxy-2-cyclopentanenone
(Scheme 2).8 The crude alcohol was then treated with TBSCl,
Et3N, and DMAP in THF to give 7 in 20% yield over two
steps. Exposure of 7 to iodine9 in a mixture of ether/pyridine
modification. Thus, 10 was exposed to BH3 DMS followed by
3
an oxidative workup to give triol 14 in 81% yield. Next, the
secondary alcohol moiety in 14 was subjected to an oxidation
with TPAP to give the corresponding ketone. In addition, the
primary alcohol was converted to an aldehyde moiety where-
upon cyclization with the tertiary alcohol formed a lactol. This
was further oxidized in situ to provide lactone 15 in 74% yield.
Having 15 in hand, we first investigated the formation of the
β-hydroxy spirolactone subunit (Scheme 4). To this end, addi-
tion of vinylmagnesium bromide followed by a quench with
Ac2O gave ester 16 in 42% yield along with alcohol 16a (26%).
Ozonolysis of the terminal double bond afforded aldehyde 17 in
73% yield. At this point, we envisioned an intramolecular aldol
condensation without elimination to form the desired β-hydroxy
spirolactone 18. Ester17 was therefore first treated with LDA in
THF at -78 °C. To our dismay, no desired spirolactone 18 was
isolated; only degradation products were observed by 1H
NMR. Other bases such as KHMDS, DBU, and freshly sub-
limed potassium tert-butoxide gave either starting material or
alcohol 19 in low yield. Pleasingly, exposure of 17 to NaH in
(6) (a) Ward, D. E.; Abaee, M. S. Org. Lett. 2000, 2, 3937. (b) Ward, D. E.;
Souweha, M. S. Org. Lett. 2005, 7, 3533.
(7) (a) Barriault, L.; Thomas, J. D. O.; Clement, R. J. Org. Chem. 2003,
68, 2317. (b) Barriault, L.; Ang, P. A. J.; Lavigne, R. M. A. Org. Lett. 2004, 6,
ꢀ
ꢀ
1317. (c) Barriault, L.; Grise, C. M.; Clement, R. Chem. Commun. 2008, 3004.
(d) For a review on tethers in cycloaddition, see: (k) Shea, K. J.; Zandi, K. S.;
Gauthier, D. R. Tetrahedron 1998, 54, 2289. (e) For other examples of the use
of temporary tethers in Diels-Alder reactions, see: Souweha, M. S.; Arab,
A.; ApSimon, M.; Fallis, A. G. Org. Lett. 2007, 9, 615. (f) Nicolaou, K. C.;
Harrison, S. T. Angew. Chem., Int. Ed. 2006, 45, 3256. (g) Zografos, A. L.;
Yiotakis, A.; Georgiadis, D. Org. Lett. 2005, 7, 4515. (h) Rath, J.-P.; Kinast,
S.; Maier, M. E. Org. Lett. 2005, 7, 3089. (i) Olsson, R.; Bertozzi, F.; Fredj, T.
Org. Lett. 2000, 2, 1283. (j) Batey, R. A.; Thadani, A. N.; Lough, A. J. J. Am.
Chem. Soc. 1999, 121, 450.
(8) Curran, T. T.; Hay, D. A.; Koegel, C. P.; Evans, J. C. Tetrahedron
1997, 53, 1983.
(9) Johnson, C. R.; Adams, J. P.; Matthew, P. B.; Senanayake, C. B. W.
Tetrahedron Lett. 1992, 33, 917.
(10) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.
Tetrahedron Lett. 1992, 33, 919.
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SCHEME 3
SCHEME 4
THF at 0 °C followed by removal of the TBS group with TBAF
gave lactones 20 and 21 in 24% and 46% yield, respectively,
over two steps. The complete carbocyclic core of havellockate 20
was achieved in 12 steps from commercially available furfuryl
alcohol 6. Two vital pieces of information had been acquired
during the synthesis of 20. First, the facile elimination of the β-
hydroxyl group upon closure of the spirocycle suggested that the
spirolactone should be installed at the very end of the synthesis.
Second, the lactone in havellockate (1) can be established upon a
simple deprotection with TBAF. The free secondary alcohol at
C5 that is generated spontaneously attacks the rigid 6-membered
lactone moiety which after fragmentation of the tetrahedral
intermediate liberates the core of havellockate. Having this
information in mind, we began the exploration of the side-chain
synthesis.
Synthesis of the Side Chain. The retrosynthetic analysis
depicted in Scheme 5 reveals that havellockate (1) could be gene-
rated from enone 26, which could be derived from ketone 25.
Upon closer inspection of 25, one can recognize the presence of a
γ,δ-unsaturated ketone. This type of molecular organization is
characteristic of a Claisen rearrangement of allyl ether 24. One
can propose that intermediate 24 could be synthesized in situ via
the enol ether of 22 and allylic alcohol 23 in the presence of a
catalytic proton source.11 We anticipated that the Claisen re-
arrangement would operate on the less hindered face of the
molecule, thus installing the isopropenyl group with the correct
stereochemistry.
Methyl enol ether 22 was readily obtained by treating ketone
15 with KHMDS in THF at -78 °C followed by addition of
dimethyl sulfate (Scheme 6). A variety of Bronsted acids such as
PTSA, TFA, pivalic acid, CSA, phenol, and 2,6-dimethylphenol
were employed to promote the enol ether exchange between 22
and 23. Various solvents such as DCM, toluene, and benzene as
well as temperature were also scanned. Unfortunately, under
these conditions, neither the desired Claisen product 25 nor enol
ether 24 was isolated from the crude reaction mixture. Only
degradation products and ketone 15 were observed. While ex-
ploring other strategies for preparing intermediate 24, we inves-
tigated Buchwald’s domino copper(I)-catalyzed C-O bond/
Claisen rearrangement.12 The synthesis of the required vinyl
iodide intermediate 29 for this reaction was achieved by first
preparing vinyl triflate 27 in 91% yield using standard con-
ditions. Then, a Pd(PPh3)4-catalyzed stannylation using Me6Sn2
in the presence of LiCl in 1,4-dioxane at 70 °C gave 28 in 75%
yield, which upon exposure to molecular iodine gave the corres-
ponding vinyl iodide 29 in 83% yield. At this point, we were able
to examine the Cu(I)-catalyzed coupling between 29 and 23.
All of the reactions were carried out in the presence of CuI (10
mol %), 1,10-phenanthroline, or tetramethyl-1,10-phenanthro-
line (20 mol %) and 3.0 equiv of cesium carbonate as prescribed
(11) (a) Nakai, T.; Sugiura, M. Tetrahedron Lett. 1996, 37, 7991. (b) Mikami,
K.; Takahashi, K.; Nakai, T. Tetrahedron Lett. 1987, 28, 5879.
(12) Nordmann, F.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978.
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SCHEME 5
SCHEME 6
SCHEME 7
by Buchwald. In addition, highly concentrated mixtures (0.1-
0.5 M of vinyl iodide) were prepared as this was deemed to be
critical for the success of the reaction. Unfortunately, vinyl
iodide 29 failed to react at temperatures ranging from 120 to
150 °C. As the temperature was increased beyond 150 °C, 29
began to decompose and there was no evidence of 24 or 25 by 1H
NMR of the crude reaction mixture.
In the light of the difficulties encountered to generate enol ether
24, we hypothesized that it would be easier to generate havellock-
ate (1) from diene 31 (Scheme 7). Our premise was founded on
the basis that (1) intermediate 30 could be formed via a Claisen
rearrangement or adapted variations using allylic alcohol 31 and
(2) having the internal double bond already in place, prior to the
Claisen rearrangement, would avoid potential problems of late-
stage elimination regioselectivity. In order to validate this ap-
proach, the synthesis of alcohol 31 was investigated.
using IBX14 and related hypervalent iodide reagents15 were also
investigated without giving any tangible success. However, we
found that the treatment of 15 with CuBr2 gave the correspond-
ing R-bromoketone 34 in 87% yield.16 Exposure of the latter to
LiBr (5 equiv) and Li2CO3 (5 equiv) in dry DMF at 150 °C gave
enone 32 in 39% yield along with side product 35 (43%).17 The
structure of 35 was established by X-ray analysis.
We began by first converting ketone 15 to enone 32 (Scheme 8).
Ketone 15 was therefore treated with KHMDS in THF followed
by addition of PhSeCl to give 33 in 48% yield. Selenium oxida-
tion with H2O2 gave the desired enone 32, but in a low yield of
20%. This was further optimized to 80% by changing the oxi-
dant to NaIO4. Despite this improvement, however, the overall
yield of the process remained low (38% over two steps). Other
methods such as Saegusa oxidation13 and dehydrogenation
(15) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed.
2002, 41, 1386.
(16) Berkowitz, W. F.; Wilson, P. J. J. Org. Chem. 1991, 56, 3097.
(17) Jackman, L. M.; Webb, R. L.; Yick, H. C. J. Org. Chem. 1982, 47, 1824.
(13) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(14) Nicolaou, K. C.; Zhang, Y. L.; Baran, P. S. J. Am. Chem. Soc. 2000,
122, 7596.
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SCHEME 8
Closer examination of this intriguing molecule revealed an
acetal at C11 and a bromine at C7. We contemplated whether the
reagents and solvent were contributing to the synthesis of 35. In
particular, it was possible that the excess amount of LiBr used in
the reaction was providing the source of bromine at C7. There-
fore, the E2 elimination was repeated using only Li2CO3 and
NMP as a solvent (eq 1). Although the yield of 32 was greatly
improved over two steps (55%), compound 35 was still present in
a low yield.18 In a subsequent experiment, enone 32 was subjected
to LiBr and Li2CO3 in DMF to give lactol 35 in 28% yield (eq 2).
On the basis of these results, it is likely that LiBr which was being
produced in situ from the E2 elimination reaction of 34 was
further reacting with enone 32 to generate the side product 35.
81% yield, which upon treatment with DDQ in a biphasic
mixture of methylene chloride and water at 0 °C gave 31 in
77% yield. At this point, formation of enol ether 39 proved to
be more challenging than expected. Various Hg(II) salts,
temperatures, and solvents were tried, and only degradation
products were observed. Suspecting that the enone moiety
may be detrimental to the reaction, we envisaged the forma-
tion of the spiro ether prior to the Claisen rearrangement.
Thus, 38 was treated with vinylmagnesium bromide to pro-
vide the alkylated adduct 40 in 74% yield (Scheme 10). Follow-
ing an allylation reaction of the tertiary alcohol, the allyl ether 41
was subjected to a catalytic amount of Grubb’s catalyst to give
42 in 94% yield.19 Removal of the PMB group followed by the
conversion of 43 to the corresponding enol ether afforded 44 in
71% yield.20 Finally, the Claisen rearrangement was effected by
treating 44 in xylene at 155 °C in the presence of Et3N to provide
the desired product 45 in 75% as an equal mixture of diaste-
reomers. Despite this mixture, the Claisen rearrangement was
proven to be an effective strategy for constructing the side chain
portion of the molecule. Most importantly, this approach allows
for the endocyclic double bond within the six-membered ring to
be installed.
Conclusion
During the course of this study, the whole carbocycle
framework was assembled in 18 chemical operations where
six of the eight stereogenic centers of havellockate (1) have
been installed in the proper relative configuration. This
approach clearly highlights the efficiency and utility of the
hydroxy-directed Diels-Alder (HDDA) reaction to quickly
access the cis-fused hydrindane core and securing the correct
stereochemistry at C6 and C7. A description of our studies to
install the isopropenyl group on the chain with the correct
stereochemistry using a modified approach and completion
of havellockate (1) will be reported in due course.
Experimental Section
(()-(R)-4-(tert-Butyldimethylsilanyloxy)-2-vinylcyclopent-2-
enone (9). Triphenylarsine (1.21 g, 10 mol %, 3.96 mmol), Pd-
(PhCN)2Cl2 (760 mg, 5 mol %, 1.98 mmol), and CuI (755 mg, 10
mol %, 3.96 mmol) were weighed in the glovebox and placed into a
Having 32 in hand, halogenation of the enone moiety in
the presence of iodine proceeded smoothly to give iodo 36 in
84% yield (Scheme 9). The latter underwent a Stille-cross
coupling reaction10 with stannane 37 to afford diene 38 in
(19) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
100.
(18) We noticed that the yield of this elimination is highly dependent on the
reaction scale. On a scale larger than 100 mg, the yield varies between 30 and 50%.
(20) Tulshian, D. B.; Tsang, R.; Fraser-Reid, B. J. Org. Chem. 1984, 49,
2347.
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SCHEME 9
SCHEME 10
flame-dried round-bottom flask. A solution of enone 8 (13.4 g, 39.6
mmol) in NMP (80 mL) was then added followed by tributylvi-
nyltin (12.7 mL, 43.6 mmol). The reaction was stirred for 30 min
before the contents of the flask were poured into H2O (50 mL). The
product was extracted with Et2O (3 ꢀ 20 mL), and the combined
organic phases were dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography on
silica gel (10:1 hexanes/EtOAc) provided 9 as a clear colorless oil
(9.4 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J = 2.6 Hz,
1H), 6.34 (dd, J = 17.8, 11.2 Hz, 1H), 6.11 (dd, J = 17.8, 1.5 Hz,
1H), 5.38 (dd, J = 11.2, 1.6 Hz, 1H), 4.91-4.87 (m, 1H), 2.78 (dd,
J = 18.3, 6.1 Hz, 1H), 2.32 (dd, J = 18.3, 2.3 Hz, 1H), 0.88 (s, 9H),
0.09 (d, J = 3.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 204.4 (C),
157.1 (CH), 141.2 (C), 126.0 (CH), 121.1 (CH2), 68.5 (CH), 46.4
in Et2O, 138 mmol) was added dropwise, and the mixture was
stirred for 2 h at -78 °C. The reaction was then quenched with
water (75 mL) at 0 °C, and the aqueous layer was extracted with
Et2O (3 ꢀ 50 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel (4:1 hexanes/Et2O)
1
provided 4 as a clear colorless oil (4.8 g, 55%): H NMR (300
MHz, CDCl3) δ 6.28 (dd, J = 17.9, 11.3 Hz, 1H), 5.73-5.67 (m,
2H), 5.21 (dd, J = 16.3, 1.8 Hz, 1H), 4.64-4.59 (m, 1H), 2.45
(dd, J = 13.2, 6.7 Hz, 1H), 1.99 (s, 1H), 1.84 (dd, J = 13.3, 5.0
Hz, 1H), 1.36 (s, 3H), 0.87 (s, 9H), 0.06 (d, J = 0.8 Hz, 6H); 13
C
NMR (75 MHz, CDCl3) δ 148.3 (C), 131.8 (CH), 129.5 (CH),
117.8 (CH2), 80.8 (C), 72.9 (CH), 53.3 (CH2), 26.1 (CH3), 25.9
(3 ꢀ CH3), 18.2 (C), -4.7 (2 ꢀ CH3); IR (neat, cm-1) 3409 (w),
2962 (s), 2935 (s), 2897 (w), 2859 (m); HRMS (EI) m/z
(Mþ-H2O) calcd for C14H24OSi 236.1597, found 236.1564.
(()-(1S,3R,3aS,4S)-3-(tert-Butyldimethylsilanyloxy)-1-hydroxy-
1-methyl-2,3,3a,4,5,6-hexahydro-1H-indene-4-carbaldehyde (10). A
(CH2), 25.7 (3 ꢀ CH3), 18.1 (C), -4.7 (2 ꢀ CH3); IR (neat, cm-1
)
2957 (m), 2930 (m), 2893 (w), 2859 (m), 1723 (s); HRMS (EI) m/z
(Mþ) calcd for C13H22O2Si 238.1389, found 238.1379.
(()-(1S,4R)-4-(tert-Butyldimethylsilanyloxy)-1-methyl-2-vinyl-
cyclopent-2-enol (4). Ketone 9 (8.2 g, 34 mmol) was placed into a
flame-dried round-bottom flask and diluted with THF (50 mL).
After the mixture was cooled to -78 °C, MeLi (86.0 mL, 1.6 M
mixture of MgBr2 OEt2 (18.0 g, 69.6 mmol) in CH2Cl2 (100 mL)
at room temperature under an atmosphere of argon was treated
with 2,6-lutidine (13.5 mL, 116 mmol). After the mixture was stirred
3
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for 20 min, a solution of diene 4 (5.9 g, 23 mmol) in CH2Cl2 (20 mL)
was added. Following an additional 20 min, acrolein (7.75 mL, 116
mmol) was added and stirring continued for 14 h. The reaction was
then quenched with H2O (50 mL), and the product was extracted
with CH2Cl2 (5 ꢀ 50 mL). The combined organic layers were
washed with a saturated aqueous solution of brine, dried over
anhydrous MgSO4, filtered, and concentrated. Purification by silica
gel flash chromatography on silica gel basified with Et3N (10:1
hexane/Et2O) provided 10 as a colorless crystals (5.1 g, 70%): 1H
NMR (300 MHz, CDCl3) δ 9.78 (d, J = 5.2 Hz, 1H), 5.99 (dd, J =
6.6, 3.3 Hz, 1H), 4.36 (t, J= 3.6 Hz, 1H), 2.95 (s, 1H), 2.71-2.63(m,
2H), 2.22-2.14 (m, 2H), 2.02-1.96 (m, 1H), 1.97 (dd, J = 14.0, 1.3
Hz, 1H), 1.90-1.81(m, 1H), 1.82(dd, J= 14.0, 3.5 Hz, 1H), 1.38 (s,
3H), 0.83 (s, 9H), 0.04 (d, J = 14.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 205.6 (CH), 147.4 (C), 121.0 (CH), 77.0 (C), 74.6 (CH),
49.4 (CH2), 48.9 (CH), 45.8 (CH), 26.4 (CH2), 25.9 (CH3), 25.8 (3 ꢀ
CH3), 21.9 (CH2), 17.9 (C4), -4.9 (CH3), -5.4 (CH3); IR (CHCl3,
cm-1) 3481 (w), 2952 (m), 2931 (s), 2851 (m), 1713 (s); HRMS (EI)
m/z (Mþ - C4H9) calcd for C13H21O3Si 253.1260, found 253.1278;
mp = 68.6-69.0 °C.
Acetic Acid 6-(tert-Butyldimethylsilanyloxy)-4-methyl-2-oxo-
9-vinyl-3-oxatricyclo[5.4.0.04,8]undec-9-yl Ester (16). To a solu-
tion of ketone 15 (32.8 mg, 0.0992 mmol) in THF (4.0 mL) at
-78 °C was added vinylmagnesium bromide (0.25 mmol, 0.31
mL). The reaction mixture was stirred at -78 °C for 30 min.
Acetic anhydride (0.30 mmol, 30 μL) and triethylamine (0.298
mmol, 41.5 μL) were added, and the yellow solution was
warmed to room temperature. The reaction was quenched with
saturated NH4Cl (aq), the aqueous phase was extracted with
CH2Cl2 (3ꢀ), and the combined organic phases were dried over
anhydrous MgSO4. The organic solvent was removed in vacuo,
and the product was purified by flash column chromatography
(20% EtOAc in hexanes) to afford acetate 16 as colorless
crystals (16.6 mg, 42%) and alcohol 16a as colorless crystals
(9.0 mg, 26%). 16: 1H NMR (300 MHz, CDCl3) δ 6.18 (dd, J =
17.6, 10.9 Hz, 1H), 5.33 (d, J = 17.3 Hz, 1H), 5.29 (d, J = 10.7
Hz, 1H), 4.33 (ddd, J = 9.2, 6.6, 2.4 Hz, 1H), 4.01-4.06 (m, 1H),
2.85 (d, J = 2.8 Hz, 1H), 2.54 (d, J = 4.0 Hz, 1H), 2.38-2.33 (m,
1H), 2.30-2.25 (m, 1H), 2.19-2.07 (m, 1H), 2.03 (d, J = 6.4 Hz,
1H), 1.99-1.96 (m, 3H), 1.85 (dd, J = 14.9, 2.2 Hz, 1H),
(()-(1S,3R,3aS,4S,7S,7aS)-3-(tert-Butyldimethylsilanyloxy)-
4-hydroxymethyl-1-methyloctahydroindene-1,7-diol (14). To a
solution of alkene 10 (1.691 mmol, 524.6 mg) in THF (16.9 mL)
1.68-1.58 (m, 1H), 1.47 (s, 3H), 0.84 (s, 9H), -2.6 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 173.6 (C), 169.9 (C), 140.3 (CH),
116.3 (CH2), 88.3 (C), 82.0 (C), 69.3 (CH), 51.0 (CH2), 46.9
(CH), 45.5 (CH), 37.8 (CH), 31.1 (CH2), 26.8 (CH), 25.7 (3 ꢀ
CH3), 22.4 (CH3), 22.2 (CH3), 17.9 (C), -4.8 (CH3), -5.1 (CH3);
IR (CHCl3, cm-1) 2952 (m), 2929 (s), 2891 (m), 2853 (m), 1739
(s); HRMS (EI) m/z (Mþ) calcd for C21H314O5Si 394.2176, found
394.2208; mp = 141.5-142.5 °C. 16a: H NMR (300 MHz,
CDCl3) δ 6.13 (dd, J = 17.3, 10.8 Hz, 1H), 5.33 (d, J = 17.4 Hz,
1H), 5.15 (d, J = 10.8 Hz, 1H), 4.33 (ddd, J = 9.2, 6.5, 2.3 Hz,
1H), 2.89 (d, J = 3.0 Hz, 1H), 2.35 (ddd, J = 7.1, 4.0, 4.0 Hz,
1H), 2.15-2.01 (m, 2H), 1.94 (dd, J = 13.8, 4.8 Hz, 1H), 1.88 (d,
J = 2.2 Hz, 1H), 1.83-1.62 (m, 4H), 1.58 (s, 3H), 0.85 (s, 9H),
0.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 173.9 (C), 143.9
(CH), 113.4 (CH2), 89.0 (C), 73.9 (C), 69.7 (CH), 51.1 (CH2),
50.3 (CH), 45.6 (CH), 37.9 (CH), 32.9 (CH2), 27.5 (CH2), 25.7 (3
ꢀ CH3), 23.9 (CH3), 18.0 (C), -4.8 (CH3), -5.1 (CH3); IR
(CHCl3, cm-1) 3431 (w), 2952 (s), 2932 (s), 2888 (m), 2862 (m),
1737 (s), 1720 (s); HRMS (EI) m/z (Mþ - C4H9) calcd for
C15H23O4Si 295.1366, found 295.1396; mp = 133.2-135.5 °C.
Acetic Acid 6-(tert-Butyldimethylsilanyloxy)-9-formyl-4-methyl-
2-oxo-3-oxatricyclo[5.4.0.04,8]undec-9-yl Ester (17). A solution
of alkene 16 (0.0421 mmol, 16.6 mg) in CH2Cl2 (5.0 mL) was
degassed with O2 for 10 min at room temperature. The solu-
tion was cooled to -78 °C, and ozone was bubbled into the
solution. After 5 min, dimethyl sulfide (0.21 mmol, 15 μL) was
added to the blue solution, and the reaction mixture was
warmed to room temperature. The solution was concentrated,
and the product was purified by flash column chromatography
(30% EtOAc in hexanes) to yield aldehyde 17 as colorless
was added BH3 DMS (4 mmol, 0.4 mL) dropwise during which
3
bubbles were produced in solution. The jelly-like solution was
stirred at room temperature (21 °C) for 4 h after which the borane
was oxidized with 3 N NaOH (1 mL) and 30% H2O2 (1 mL).
Caution: on a large scale, the reaction is very vigorous! The
resulting solution was refluxed overnight and the aqueous layer
was extracted with EtOAc (3ꢀ). The combined organic layers
were dried over anhydrous MgSO4 and concentrated in vacuo,
and the product was purified by flash column chromatography
(60% EtOAc in hexanes) to afford triol 14 as colorless crystals
(455.1 mg, 81%): 1H NMR (300 MHz, CDCl3) δ 4.29 (t, J = 4.1
Hz, 1H), 4.22 (dt, J = 11.1, 4.7 Hz, 1H), 3.67-3.64 (m, 2H), 2.38
(bs, 2H), 2.14-2.09 (m, 1H), 2.01-1.79 (m, 4H), 1.71-1.50 (m,
3H), 1.35 (s, 3H), 1.32-1.21 (m, 2H), 0.87 (s, 9H), 0.05 (d, J =
3.8 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 81.1 (C), 74.5 (CH),
70.2 (CH), 65.3 (CH2), 57.4 (CH), 52.3 (CH), 45.1 (CH), 40.2
(CH), 33.1 (CH2), 32.2 (CH3), 25.9 (3 ꢀ CH3), 25.0 (CH2), 17.7
(C), -3.9 (CH3), -4.8 (CH3); IR (CHCl3, cm-1) 3342 (m), 2961
(m), 2925 (s), 2861 (m); HRMS (EI) m/z (Mþ- [C4H9 þ 2(H2O)])
calcd for C13H21O2Si: 237.1309, found 237.1333. Mp = 163.1-
163.8 °C.
(()-(1S,4S,6R,7R,8S)-6-(tert-Butyl-dimethyl-silanyloxy)-4-
methyl-3-oxatricyclo-[5.4.0.02,6]undecane-2,9-dione (15). Molec-
˚
ular sieves (4 A) (550 mg, 500 mg/mmol of alcohol) were flame-
dried under vacuum in a round-bottom flask. After cooling to
room temperature, the flask was filled with argon and a solution
of triol 14 (456 mg, 1.10 mmol) in CH2Cl2 (25 mL) was added,
followed by NMO (451 mg, 3.85 mmol) and TPAP (19 mg, 0.055
mmol). The dark green solution was stirred for 4 h at room
temperature and was then filtered through a pad of silica gel,
eluting with 5% MeOH in EtOAc. The organic solvent was
removed in vacuo and the crude product was purified by silica gel
flash chromatography (5:1 hexanes/Et2O) to provide 15 as a
white solid (264 mg, 74%): 1H NMR (300 MHz, CDCl3) δ 4.43
(ddd, J = 9.2, 6.6, 2.8 Hz, 1H), 3.17 (s, 1H), 2.77-2.72 (m, 1H),
2.56 (dd, J = 16.3, 5.6 Hz, 1H), 2.43 (d, J = 4.8 Hz, 1H),
2.40-2.22 (m, 2H), 2.12 (dd, J = 14.7, 9.1 Hz, 1H), 2.00 (dd, J =
14.7, 2.7 Hz, 1H), 1.95-1.88 (m, 1H), 1.34 (s, 3H), 0.85 (s, 9H),
0.03 (s, 6H); 13C NMR (75 MHz, C6D6) δ 206.0 (C), 170.7 (C),
87.5 (C), 80.0 (CH), 57.5 (CH), 48.7 (CH2), 47.4 (CH), 37.9
(CH2), 37.5 (CH2), 27.9 (CH2), 25.8 (3 ꢀ CH3), 22.0 (CH3), 18.1
(C4), -4.8 (CH3), -5.1 (CH3); IR (CHCl3, cm-1) 2960 (m), 2935
(m), 2858 (w), 1747 (s), 1708 (m); HRMS (EI) m/z (Mþ - C4H9)
calcd for C13H19O4Si 267.1053, found 267.1048; mp = 104.8-
105.4 °C.
1
crystals (12.2 mg, 73%): H NMR (300 MHz, CDCl3) δ 9.27
(s, 1H), 4.39 (ddd, J = 9.3, 6.6, 2.5 Hz, 1H), 2.92-2.83 (m, 2H),
2.45 (d, J = 4.3 Hz, 1H), 2.15-1.95 (m, 6H), 1.86 (dd, J = 15.1,
2.4 Hz, 1H), 1.67-1.58 (m, 2H), 1.45 (s, 3H), 0.85 (s, 9H), 0.00 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 195.7 (CH), 173.0 (C), 170.8
(C), 88.6 (C), 83.9 (C), 69.5 (CH), 50.2 (CH2), 44.9 (CH),
41.8 (CH), 37.2 (CH), 25.7 (3 ꢀ CH3), 25.6 (CH2), 25.2 (CH2),
22.7 (CH3), 20.8 (CH3), 17.9 (C), -4.9 (CH3), -5.1 (CH3); IR
(CHCl3, cm-1) 2955 (m), 2932 (m), 2888 (w), 2857 (m), 2721
(w), 1740 (s); HRMS (EI) m/z (Mþ - [C6H15Si þ H2O þ OAc])
calcd for C12H12O3 193.0865, found 193.0880; mp = 113.7-
116.1 °C.
Tetracyclic Core (20). To a solution of NaH (0.031 mmol, 1.2
mg) in THF (1.0 mL) at 0 °C was canulated the aldehyde 17
(0.021 mmol, 8.2 mg) in THF (2.0 mL). The solution was
gradually warmed to room temperature and was quenched with
H2O. The aqueous layer was extracted with EtOAc (3ꢀ), the
combined organic layers were dried over anhydrous MgSO4,
J. Org. Chem. Vol. 75, No. 19, 2010 6343

Beingessner et al.
JOCFeatured Article
and the solvent was evaporated in vacuo. The crude product was
diluted in THF (2.0 mL), and TBAF (0.030 mmol, 30 μL) was
added to the solution. After 1 h, the reaction mixture was
concentrated in vacuo, and the product was purified by flash
column chromatography (60% EtOAc in hexanes) using a
Pasteur pipet to afford the tetracyclic core 20 as a colorless oil
(1.3 mg, 24%) and tricyclic core 21 as a colorless oil (2.3 mg,
46%). 20: 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 5.7 Hz,
1H), 6.90 (d, J = 5.7 Hz, 1H), 5.00 (dd, J = 6.6, 4.9 Hz, 1H), 3.25
(dt, J = 10.5, 6.6 Hz, 1H), 2.90-2.84 (m, 1H), 2.68 (dt, J = 14.2,
4.6 Hz, 1H), 2.49-2.43 (m, 1H), 2.32 (d, J = 10.1 Hz, 1H),
1.94-1.76 (m, 3H), 1.68 (s, 1H), 1.50 (s, 3H), 1.44-1.37 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 176.9 (C), 171.1 (C), 159.1 (CH),
119.9 (CH), 89.4 (C), 81.9 (C), 81.6 (C), 49.9 (CH2), 47.7 (CH),
41.6 (CH), 37.2 (CH), 29.6 (CH3), 28.8 (CH2), 21.4 (CH2); IR
(neat, cm-1) 3443 (w), 2964 (w), 2930 (w), 2854 (w), 1750 (s);
HRMS (EI) m/z (Mþ - H2O) calcd for C14H14O4 246.0892,
found 246.0892. 21: 1H NMR (300 MHz, CDCl3) δ 9.51 (s, 1H),
4.95 (t, J = 5.9 Hz, 1H), 3.49 (bs, 1H), 3.22 (dt, J = 10.7, 6.7 Hz,
1H), 2.87-2.80 (m, 1H), 2.30 (d, J = 3.4 Hz, 1H), 2.26 (s, 1H),
2.23-2.15 (m, 1H), 1.96 (dd, J = 15.3, 5.2 Hz, 1H), 1.91-1.84
(m, 1H), 1.81-1.59 (m, 2H), 1.48 (s, 3H), 1.23 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 202.8 (CH), 178.5 (C), 82.7 (C), 82.5 (CH),
78.2 (C), 47.8 (CH2), 47.5 (CH2), 41.3 (CH), 37.8 (CH), 30.0
(CH3), 28.7 (CH2), 18.7 (CH2); IR (neat, cm-1) 3443 (m), 2969
(w), 2932 (m), 2869 (w), 1733 (s); HRMS (EI) m/z (Mþ - [H2O þ
CHO]) calcd for C11H12O3 193.0865, found 193.0857.
HRMS (EI) m/z (Mþ - C4H9) calcd for C13H17O4Si: 265.0897,
found: 265.0895. 35: 1H NMR (500 MHz, C6D6) δ 6.45 (d, J =
10.1 Hz, 1H), 5.77 (dd, J = 10.1, 0.8 Hz, 1H), 5.04 (s, 1H), 4.34
(dd, J = 4.1, 4.1 Hz, 1H), 3.07 (ddd, J = 6.4, 4.8, 1.3 Hz, 1H),
1.84-1.80 (m, 2H), 1.00 (s, 3H), 0.75-0.72 (m, 1H); 13C NMR
(125 MHz, C6D6) δ 193.9 (C), 147.8 (CH), 130.1 (CH), 102.1
(CH), 83.1 (C), 79.3 (CH), 65.7 (C), 60.9 (CH), 55.6 (CH), 45.6
(CH2), 20.4 (CH3); IR (neat, cm-1) 2981 (m), 2935 (m), 1676 (s);
HRMS (EI) m/z (Mþ - CHO) calcd for C10H10O2Br 240.9680,
found 240.9875; mp = 129.8-131.8 °C).
(()-(1S,4S,6R,7R,8S)-6-(tert-Butyldimethylsilanyloxy)-10-
iodo-4-methyl-3-oxatricyclo[5.4.0.02,6]undec-10-ene-2,9-dione (36).
Enone 32 (119 mg, 0.369 mmol) was dissolved in a 1:1 solution
of Et2O/pyridine (5 mL) at room temperature. Iodine (73.0 mg,
0.369 mmol) was then added, and the dark red solution was stirred
for 1 h. The contents of the flask were then poured into a 1 N
solution of HCl (5 mL), and the product was extracted with Et2O
(3 ꢀ 20 mL). The combined organic phases were washed with a
saturated aqueous solution of Na2SO3, dried over anhydrous
MgSO4, filtered, and concentrated. Purification by flash chroma-
tography on silica gel (20:1 hexanes/Et2O) provided 36 as a white
solid (105 mg, 84%): 1H NMR (500 MHz, C6D6) δ 7.25 (d, J = 8.0
Hz, 1H), 3.62 (ddd, J = 9.1, 6.4, 2.3 Hz, 1H), 3.18 (ddd, J = 8.0,
3.4, 1.7 Hz, 1H), 2.17-2.14 (m, 1H), 1.92-1.91 (m, 1H), 1.61 (dd,
J = 15.1, 1.8 Hz, 1H), 1.27 (dd, J = 14.8, 9.6 Hz, 1H), 1.84 (s, 3H),
0.93 (s, 9H), -0.14 (s, 3H), -0.11 (s, 3H); 13C NMR (125 MHz,
C6D6) δ 188.2 (C), 165.8 (C), 155.7 (CH), 106.8 (C), 88.1 (C), 70.0
(CH), 53.1 (CH), 49.3 (CH2), 48.0 (CH), 44.7 (CH), 26.1 (3 ꢀ
CH3), 22.2 (CH3), 18.5 (C), -4.5 (CH3), -4.8 (CH3); IR (neat,
cm-1) 2950 (s), 2929 (s), 2866 (s), 2856 (s), 1732 (s); HRMS (EI) m/
z (Mþ - C4H9I) calcd for C13H16O4Si 264.0818, found 264.0779;
mp = 179.1-179.5 °C.
((E)-3-(4-Methoxybenzyloxy)-2-methylprop-1-enyl)tributyl-
stannane (37). Sodium iodide (1 mg, 0.007 mmol) was flame-
dried under vacuum in a round-bottom flask. After the mixture
was cooled to room temperature, the flask was fitted with a
balloon of argon, and DMF (1 mL) was added followed by NaH
(28 mg, 0.69 mmol). The mixture was cooled to 0 °C, and then
(E)-3-(tributylstannyl)-2-methylpropen-1-ol21 (50 mg, 0.14
mmol) was cannulated into the flask as a solution in DMF
(0.5 mL). After the mixture was stirred for 5 min, PMBCl (87
mg, 0.55 mmol) was added. The contents of the flask were
warmed to room temperature and stirred overnight. The reac-
tion was quenched with a saturated aqueous solution of NH4Cl
and extracted with Et2O (3 ꢀ 30 mL). The combined organic
phases were dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. Purification by flash chromatography on
silica gel (10:1 hexanes/Et2O) provided 37 as a clear colorless oil
(63 mg, 94%): 1H NMR (300 MHz, C6D6) δ 7.30-7.27 (m, 2H),
6.82-6.79 (m, 2H), 6.12 (m, 1H), 4.41 (s, 2H), 3.96 (s, 2H), 3.29
(s, 3H), 1.89-1.85 (m, 3H), 1.68-1.55 (m, 6H), 1.44-1.33 (m,
6H), 1.06-1.01 (m, 5H), 0.96-0.91 (m, 10H); 13C NMR (75
MHz, C6D6) δ 160.5 (C), 152.0 (C), 131.6 (C), 129.8 (CH), 124.3
(CH), 114.4 (CH), 77.0 (CH2), 72.1 (CH2), 55.1 (CH3), 30.1
(CH2), 28.1 (CH2), 22.3 (CH3), 14.3 (CH3), 10.8 (CH2); IR (neat,
cm-1) 2955 (s), 2925 (s), 2851 (s); HRMS (EI) m/z (Mþ - C4H9)
calcd for C20H33O2Sn 425.1503, found 425.1512.
(()-(1S,4S,6R,7R,8S,10S)-10-Bromo-6-(tert-butyldimethyl-
silanyloxy)-4-methyl-3-oxatricyclo[5.4.0.02,6]undecane-2,9-dione
(34). Copper bromide (28 mg, 0.12 mmol) was added to a
solution of ketone 15 (20 mg, 0.062 mmol) in THF (1.0 mL)
and stirred overnight at room temperature. H2O (5 mL) was
added, and the product was extracted with CH2Cl2 (3 ꢀ 10 mL).
The combined organic phases were dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography on silica gel (10:1 hexanes/Et2O) pro-
1
vided 34 as a white solid (19 mg, 87%): H NMR (500 MHz,
C6D6) δ 4.34 (dd, J = 13.0, 7.1 Hz, 1H), 3.63 (ddd, J = 9.5, 6.5,
2.2 Hz, 1H), 2.88-2.87 (m, 1H), 2.63 (ddd, J = 13.2, 7.2, 4.0 Hz,
1H), 2.04-2.03 (m, 1H), 1.81-1.72 (m, 2H), 1.57 (dd, J = 14.9,
2.4 Hz, 1H), 1.20 (dd, J = 14.8, 9.6 Hz, 1H), 0.93 (s, 3H), 0.90 (s,
9H), -0.11 (s, 3H), -0.12 (s, 3H); 13C NMR (125 MHz, C6D6) δ
198.0 (C), 169.7 (C), 87.9 (C), 71.0 (CH), 58.5 (CH), 51.1 (CH),
48.9 (CH2), 47.8 (CH), 40.7 (CH), 40.1 (CH2), 26.1 (3 ꢀ CH3),
22.1 (CH3), 18.5 (C), -4.5 (CH3), -4.8 (CH3); IR (neat, cm-1
)
-
2930 (s), 2857 (s), 1749 (s), 1721 (s); HRMS (EI) m/z (Mþ
C4H9) calcd for C13H18O4BrSi 345.0158, found 345.0203; mp =
151.8-152.9 °C.
(()-(1S,4S,6R,7R,8S)-6-(tert-Butyldimethylsilanyloxy)-4-me-
thyl-3-oxatricyclo[5.4.0.02,6]undec-10-ene-2,9-dione (32). A mix-
ture of lithium carbonate (18 mg, 0.25 mmol) and ketone 34
(20 mg, 0.050 mmol) was refluxed in NMP (2 mL) for 8 h. After
the mixture was cooled to room temperature, a saturated
aqueous solution of NH4Cl (5 mL) was added, and the organic
product was extracted with Et2O (3 ꢀ 20 mL). The combined
organic phases were dried over anhydrous MgSO4, filtered, and
concentrated. Purification by flash chromatography on silica gel
(10:1 hexanes/Et2O) provided 32 as a clear colorless oil (10 mg,
(()-(1S,4S,6R,7R,8S)-6-(tert-Butyldimethylsilanyloxy)-10-
[(1E)-3-(4-methoxybenzyloxy)-2-methylprop-1-en-1-yl]-4-methyl-
3-oxatricyclo[5.4.0.02,6]undec-10-ene-2,9-dione (38). Tripheny-
larsine (9 mg, 10 mol %, 0.03 mmol), Pd(PhCN)2Cl2 (5 mg,
5 mol %, 0.01 mmol), and CuI (5 mg, 10 mol %, 0.03 mmol) were
weighed in the glovebox and placed into a flame-dried round-
bottom flask. After the flask was equipped with a balloon
of argon, a solution of enone 36 (96 mg, 0.28 mmol) in NMP
1
63%) and 35 as a white solid (3 mg, 22%). 32: H NMR (500
MHz, C6D6) δ 6.51 (dd, J = 9.5, 7.7 Hz, 1H), 5.87 (d, J = 9.5
Hz, 1H), 3.71 (ddd, J = 9.1, 6.4, 2.3 Hz, 1H), 3.37 (ddd, J = 7.6,
3.6, 1.4 Hz, 1H), 2.33-2.30 (m, 1H), 1.84 (d, J = 5.0 Hz, 1H),
1.71 (dd, J = 15.1, 2.4 Hz, 1H), 1.36 (dd, J = 15.0, 9.6 Hz, 1H),
1.24 (s, 3H), 0.95 (s, 9H), -0.07 (s, 3H), -0.09 (s, 3H); 13C NMR
(125 MHz, C6D6) δ 194.4 (C), 167.3 (C), 147.8 (CH), 132.4 (CH),
88.0 (C), 70.5 (CH), 54.2 (CH), 49.6 (CH2), 48.1 (CH), 41.0
(CH), 26.2 (3 ꢀ CH3), 22.4 (CH3), 18.5 (C), -4.5 (CH3), -4.8
(CH3); IR (neat, cm-1) 2930 (s), 2857 (s), 1746 (s), 1677 (s);
(21) Scarlato, G. R.; DeMattei, J. A.; Chong, L. S.; Ogawa, A. K.; Lin,
M. R.; Armstrong, R. W. J. Org. Chem. 1996, 61, 6139.
6344 J. Org. Chem. Vol. 75, No. 19, 2010

Beingessner et al.
JOCFeatured Article
(1.5 mL) was added. Vinylstannane 37 (136 mg, 0.140 mmol)
was then cannulated into the mixture using 1 mL of NMP, and
the reaction was stirred for 30 min. The contents of the flask
were then poured into H2O (5 mL), and the product was
extracted with EtOAc (3 ꢀ 10 mL). The combined organic
phases were dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. Purification by flash chromatography on
silica gel (10:1 hexanes/EtOAc) provided 38 as a white solid (117
mg, 81%): 1H NMR (500 MHz, CDCl3) δ 7.30-7.28 (m, 2H),
7.12 (dd, J = 8.0 Hz, 1H), 6.92-6.87 (m, 2H), 6.26 (m, 1H), 4.51
(ddd, J = 8.9, 6.6, 2.5 Hz, 1H), 4.43 (s, 2H), 3.98 (s, 2H), 3.82 (s,
3H), 3.65 (ddd, J = 7.8, 3.3, 1.7 Hz, 1H), 3.18 (ddd, J = 6.0, 5.1,
3.5 Hz, 1H), 2.56 (d, J = 5.1 Hz, 1H), 2.24 (dd, J = 15.0, 9.4 Hz,
1H), 2.12 (dd, J = 15.5, 2.1 Hz, 1H), 1.77 (d, J = 1.3 Hz, 3H),
1.47 (s, 3H), 0.92 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 194.3 (C), 168.8 (C), 159.4 (C), 143.9 (CH),
139.7 (C), 139.0 (C), 130.5 (C), 129.7 (CH), 118.9 (CH), 114.0
(CH), 88.5 (C), 75.6 (CH2), 71.8 (CH2), 70.0 (CH), 55.5 (CH3),
54.2 (CH), 49.8 (CH2), 47.6 (CH), 40.6 (CH), 25.9 (3 ꢀ CH3),
22.1 (CH3), 18.2 (C), 16.2 (CH3), -4.6 (CH3), -4.9 (CH3); IR
(neat, cm-1) 2925 (s), 2854 (s), 1746 (s), 1698 (s); HRMS (EI) m/z
(Mþ) calcd for C29H40O6Si 512.2594, found 512.2568; mp =
60.8-61.9 °C.
(()-(1S,4S,6R,7R,8S,9S)-6-(tert-Butyldimethylsilanyloxy)-9-
hydroxy-10-[(1E)-3-(4-methoxybenzyloxy)-2-methylprop-1-en-1-
yl]-4-methyl-9-vinyl-3-oxatricyclo[5.4.0.02,6]undec-10-en-2-one (40).
Vinylmagnesium bromide (130 μL, 0.86 M, 0.111 mmol) was
added to a solution of 38 (19 mg, 0.037 mmol) in Et2O (0.5 mL)
at -78 °C and stirred for 1 h. The reaction was quenched with an
aqueous solution of NH4Cl, and the product was extracted with
Et2O (3 ꢀ 30 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel (5:2 hexanes/Et2O)
provided 40 as a clear colorless oil (15 mg, 74%): 1H NMR (500
MHz, CDCl3) δ 7.26-7.25 (m, 2H), 6.90-6.88 (m, 2H), 6.04 (d,
J = 7.2 Hz, 1H), 5.95 (dd, JBX = 17.1, JAX = 10.5 Hz, 1H),
5.88-5.87 (m, 1H), 5.26 (dd, JBX = 17.2, JAB = 0.76 Hz, 1H),
5.15 (dd, JAX = 10.5, JAB = 0.92 Hz, 1H), 4.40 (s, 2H), 4.37
(ddd, J = 9.5, 6.1, 2.9 Hz, 1H), 3.92 (s, 2H), 3.82 (s, 3H),
3.42-3.40 (m, 1H), 2.70 (ddd, J = 6.5, 3.9, 3.9 Hz, 1H), 2.19 (dd,
J = 15.1, 9.8, 1H), 1.95-1.92 (m, 2H), 1.77-1.76 (m, 3H), 1.63
(s, 3H), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 171.6 (C), 159.4 (C), 143.9 (CH), 141.4 (C),
140.7 (C), 130.5 (C), 129.6 (CH), 127.2 (CH), 121.7 (CH), 114.0
(CH), 113.2 (CH2), 89.1 (C), 76.3 (C), 75.4 (CH2), 71.9 (CH2),
69.6 (CH), 55.5 (CH3), 51.0 (CH2), 50.2 (CH), 45.2 (CH), 39.7
(CH), 25.9 (3 ꢀ CH3), 24.6 (CH3), 18.2 (C), 16.1 (CH3), -4.6
(CH3), -4.8 (CH3); IR (neat, cm-1) 3441 (brs), 2926 (s), 2853 (s),
1738 (s); LRMS (EI) m/z (Mþ) 540.3.
6.2, 2.5 Hz, 1H), 4.11 (dddd, J = 13.2, 4.9, 1.6, 1.6 Hz, 1H), 4.03
(dddd, J = 13.3, 4.6, 1.8, 1.8 Hz, 1H), 3.91 (m, 2H), 3.81 (s, 3H),
3.41-3.38 (m, 1H), 2.62 (ddd, J = 6.4, 3.8, 3.8 Hz, 1H), 2.19 (dd,
J = 14.8, 9.6 Hz, 1H), 1.98-1.94 (m, 2H), 1.80-1.79 (m, 3H), 1.60
(s, 3H), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H);13C NMR (125 MHz,
CDCl3) δ 171.2 (C), 159.4 (C), 142.1 (CH), 140.1 (C), 137.2 (C),
135.7 (CH), 130.6 (C), 129.5 (CH), 129.1 (CH), 124.9 (CH), 115.6
(CH2),115.5(CH2),114.0(CH),88.6(C4),81.6(C),75.8(CH2) 71.6
(CH2), 69.3 (CH), 66.4 (CH2), 55.5 (CH3), 51.7 (CH2), 49.8 (CH3),
45.6 (CH), 39.7 (CH), 25.9 (3 ꢀ CH3), 24.1 (CH), 18.2 (C), 16.2
(CH3), -4.6 (CH3), -4.8 (CH3);IR(neat, cm-1) 2954(m), 2931(s),
2855 (s), 1739 (s); HRMS (EI) m/z (Mþ - C4H9) calcd for C30H39-
O6Si 523.2516, found 523.2540.
(()-(1S,4S,6R,7R,8S,9S)-6-(tert-Butyldimethylsilanyloxy)-10-
[(1E)-3-(4-methoxybenzyloxy)-2-methylprop-1-en-1-yl]-4-methyl-
9-spiro[3,4-dihydrofuran]-3-oxatricyclo[5.4.0.02,6]undec-10-en-2-
one (42). Alkene 41 (55 mg, 0.095 mmol) was dissolved in CH2Cl2
(1.9 mL, 0.05 M) and degassed under a steady stream of argon for
20 min. Meanwhile, Grubbs’ first-generation catalyst (8 mg, 0.009
mmol) was placed in a Schlenk tube, evacuated, and filled with
argon. Once the degassing was complete, the alkene was cannulated
in the Schlenk tube, and the contents were placed into a 40 °C oil
bath for 30 min. After the mixture was cooled to room temperature,
the solution was concentrated, and the crude product was purified
by flash chromatography on silica gel (10:1 hexanes/Et2O) to
1
provide 42 as a clear colorless oil (47 mg, 94%): H NMR (500
MHz, CDCl3) δ 7.25-7.24 (m, 2H), 6.89-6.87 (m, 2H), 5.97-5.94
(m, 2H), 5.85 (m, 1H), 5.72 (ddd, J = 5.3, 2.3, 2.3 Hz, 1H), 4.70 (m,
2H), 4.39-4.35 (m, 3H), 3.91-3.90 (m, 2H), 3.81 (s, 3H),
3.39-3.37 (m, 1H), 2.73 (ddd, J = 6.1, 4.1, 4.1 Hz, 1H), 2.13 (dd,
J = 14.9, 9.5 Hz, 1H), 1.94 (dd, J = 15.1, 2.5 Hz, 1H), 1.87 (d, J =
4.3 Hz, 1H), 1.76-1.75 (m, 3H), 1.61 (s, 3H), 0.90 (s, 9H), 0.05 (s,
3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.4 (C), 159.3
(C), 141.5 (C), 137.6 (C), 134.0 (CH), 130.8 (C), 129.5 (CH), 126.34
(CH), 126.28 (CH), 123.0 (CH), 114.0 (CH), 91.4 (C), 88.8 (C), 76.2
(CH2), 75.9 (CH2), 71.3 (CH2), 70.0 (CH), 55.5 (CH3), 51.0 (CH),
50.7 (CH2), 46.6 (CH), 39.4 (CH), 25.9 (3 ꢀ CH3), 23.8 (CH3), 18.2
(C), 16.1 (CH3), -4.6 (CH3), -4.8 (CH3); IR (neat, cm-1) 2937 (s),
2857 (s), 1738 (s); HRMS (EI) m/z (Mþ - C4H9) calcd for
C28H35O6Si 495.2203, found 495.2202.
(()-(1S,4S,6R,7R,8S,9S)-6-(tert-Butyldimethylsilanyloxy)-10-
[(1E)-3-hydroxy-2-methylprop-1-en-1-yl]-4-methyl-9-spiro[3,4-di-
hydrofuran]-3-oxatricyclo[5.4.0.02,6]undec-10-en-2-one (43). 2,3-
Dichloro-5,6-dicyano-1,4-benzoquinone (10 mg, 0.045 mmol)
was added to a biphasic solution of 42 (25 mg, 0.045 mmol) in
CH2Cl2 (2 mL) and H2O (200 μL) at 0 °C. The reaction was
stirred for 1 h at 0 °C before being quenched with a saturated
aqueous solution of Na2SO3 (3 mL). The product was extracted
with CH2Cl2 (3 ꢀ 10 mL), dried over anhydrous MgSO4, filtered,
and concentrated. Purification by flash chromatography on
silica gel (5:1 hexanes/Et2O) provided 43 as a clear colorless oil
(()-(1S,4S,6R,7R,8S,9S)-9-(Allyloxy)-6-(tert-butyldimethyl-
silanyloxy)-10-[(1E)-3-(4-methoxybenzyloxy)-2-methylprop-1-
en-1-yl]-4-methyl-9-vinyl-3-oxatricyclo[5.4.0.02,6]undec-10-en-2-
one (41). A flame-dried round-bottom flask was charged with
KH (211 mg, 35% in mineral oil, 1.85 mmol) and washed with
hexanes (3 ꢀ 2 mL). Freshly distilled DME (2 mL) was then
added, and the flask was cooled to 0 °C. Alcohol 40 (40 mg, 0.074
mmol) was cannulated into the flask, and the contents were stirred
for 20 min before freshly distilled allyl bromide (224 μL, 1.85 mmol)
was added. The mixture was stirred at 0 °C for 30 min before being
quenched with an aqueous solution of NH4Cl (5 mL). The product
was extracted with Et2O (3 ꢀ 20 mL), and the combined organic
layers were dried over anhydrous MgSO4, filtered, and concen-
trated. Purification by flash chromatography on silica gel (10:1
hexanes/Et2O) provided 41 as a clear colorless oil (38 mg, 89%): 1H
NMR (500 MHz, CDCl3) δ7.26-7.23 (m, 2H), 6.89-6.86 (m, 2H),
6.10 (d, J = 7.4 Hz, 1H), 6.11-6.10 (m, 1H), 5.95 (dd, J = 17.4,
10.8 Hz, 1H), 5.84 (dddd, J = 17.2, 9.7, 4.8, 4.8, 1H), 5.27-5.20 (m,
3H), 5.09 (dq, J= 10.6, 1.6 Hz, 1H), 4.38 (s, 2H), 4.33 (ddd, J=9.1,
1
(17.5 mg, 91%): H NMR (500 MHz, C6D6) δ 5.95-5.93 (m,
2H), 5.43-5.42 (m, 1H), 5.38-5.36 (m, 1H), 4.52-4.49 (m, 1H),
4.39-4.36 (m, 1H), 3.89 (ddd, J = 12.1, 6.2, 2.7 Hz, 1H),
3.72-3.71 (m, 2H), 3.53-3.51 (m, 1H), 2.39-2.37 (m, 1H),
1.83 (dd, J = 14.8, 2.6 Hz, 1H), 1.61-1.55 (m, 4H), 1.55 (s,
3H), 1.41-1.40 (m, 1H), 1.02 (s, 9H), 0.79-0.77 (m, 1H), 0.03 (s,
3H), 0.00 (s, 3H); 13C NMR (125 MHz, C6D6) δ 170.2 (C), 142.2
(C), 140.7 (C), 134.3 (CH), 126.6 (CH), 126.5 (CH), 120.7 (CH),
92.0 (C), 88.2 (C), 76.4 (CH2), 70.7 (CH), 68.5 (CH2), 51.1 (CH),
51.0 (CH2), 46.9 (CH), 40.4 (CH), 26.3 (3 ꢀ CH3), 24.3 (CH3),
18.6 (C), 15.9 (CH3), -4.3 (CH3), -4.6 (CH3); IR (neat, cm-1
)
3422 (brs), 2929 (s), 2985 (s), 1737 (s), 1716 (m); HRMS (EI) m/z
(Mþ - C4H9) calcd for C20H27O5Si 375.1628, found 375.1607.
(()-(1S,4S,6R,7R,8S,9S)-6-(tert-Butyldimethylsilanyloxy)-10-
[(1E)-2-methyl-3-(vinyloxy)prop-1-en-1-yl]-4-methyl-9-spiro[3,4-di-
hydrofuran]-3-oxatricyclo[5.4.0.02,6]undec-10-en-2-one (44). Mer-
cury trifluoroacetate (2 mg, 0.07 mmol) was added to a solution
J. Org. Chem. Vol. 75, No. 19, 2010 6345

Beingessner et al.
JOCFeatured Article
of 43 (30 mg, 0.069 mmol), Et3N (5 drops), and freshly distilled
ethyl vinyl ether (3 mL) in a Schlenk tube. The contents were placed
in a 40 °C oil bath and stirred for 24 h. The reaction was then
quenched with a saturated aqueous solution of NaHCO3 (5 mL),
and the product was extracted with Et2O (3 ꢀ 10 mL). The
combined organic phases were dried over anhydrous MgSO4,
filtered, and concentrated. Purification by flash chromatography
on silica gel (20:1 hexanes/Et2O) provided 44 as a clear colorless oil
(23 mg, 71%): 1H NMR (500 MHz, C6D6) δ 6.37 (dd, JBX = 14.2,
JAX = 6.7, 1H), 5.96 (m, 1H), 5.91 (d, J = 7.0 Hz, 1H), 5.42-5.41
(m, 1H), 5.33 (dt, J = 4.9, 2.3 Hz, 1H), 4.49 (dt, J = 13.2, 1.8 Hz,
J = 6.9, 1H), 5.41-5.40 and 5.37-5.36 (m, 1H), 5.32-5.31 and
5.22-5.20 (m, 1H), 4.80 and 4.71 (m, 1H), 4.66 and 4.50 (m, 1H),
4.43-4.42 and 4.41-4.40 (m, 1H), 4.31-4.25 (m, 2H), 3.85-3.80
(m, 2H), 3.41-3.36 (m, 2H), 3.13-3.07 (m, 2H), 2.53 (dd, J= 17.4,
3.9 Hz, 1H), 2.34 (ddd, J = 17.3, 10.2, 2.1 Hz, 1H), 2.27-2.24 (m,
2H), 2.18-2.16 (m, 2H), 1.80-1.75 (m, 2H), 1.65 and 1.52 (s, 3H),
1.55-1.49 (m, 2H), 1.48 and 1.46 (s, 3H), 1.29-1.28 (m, 2H), 1.00
(s, 18H), 0.01 and 0.00 (s, 3H), -0.01 and -0.02 (s, 3H); 13C NMR
(125 MHz, C6D6) δ 200.5 and 200.2 (CH), 169.9 and 169.5 (C),
148.2 and 145.8 (C), 145.52 and 145.46 (C), 134.3 and 134.0 (CH),
127.0 and 126.9 (CH), 125.2 and 125.0 (CH), 111.9 and 110.8
(CH2), 92.9 and 92.4 (C), 88.0 (2 ꢀ C), 76.4 and 76.2 (CH2), 70.5
and 70.5 (CH), 51.2 and 51.0 (CH3), 50.86 and 50.87 (CH2), 49.1
and 48.1 (CH2), 46.7 and 46.5 (CH), 41.1 and 40.7 (CH), 40.4 and
40.2 (CH), 26.26 and 26.28 (3 ꢀ CH3), 24.2 and 24.1 (CH), 23.4 and
21.7 (CH3), 18.6 (2 ꢀ C), -4.3 (2 ꢀ CH3), -4.6 (2 ꢀ CH3); IR
(neat, cm-1) 2956 (s), 2929 (s), 2855 (s), 1739 (s); HRMS (EI) m/z
(Mþ - C4H9) calcd for C22H29O5Si 401.1784, found 401.1783.
1H), 4.36 (dt, J = 13.2, 1.9 Hz, 1H), 4.22 (dd, JBX = 14.3, JAB
=
1.8 Hz, 1H), 3.96 (dd, JAX = 6.7, JAB = 1.8 Hz, 1H), 3.89 (s, 3H),
3.50-3.48 (m, 1H), 2.35 (ddd, J = 6.2, 3,9, 3,9 Hz, 1H), 1.82 (dd,
J = 14.8, 2.6 Hz, 1H), 1.62-1.61 (m, 3H), 1.57 (dd, J = 14.7, 9.7
Hz, 1H), 1.54 (s, 3H), 1.39 (d, J = 4.0 Hz, 1H), 1.01 (s, 9H), 0.03 (s,
3H), 0.00 (s, 3H); 13C NMR (125 MHz, C6D6) δ 170.0 (C), 152.3
(CH), 141.8 (C), 136.6 (C), 134.2 (CH), 127.0 (CH), 126.5 (CH),
123.5 (CH), 91.9 (C), 88.1 (C), 87.5 (CH2), 76.3 (CH2), 74.0 (CH2),
70.6 (CH), 51.1 (CH), 51.0 (CH2), 46.9 (CH), 40.4 (CH), 26.3 (3 ꢀ
CH3), 24.3 (CH3), 18.6 (C), 15.9 (CH3), -4.3 (CH3), -4.6 (CH3);
FTIR (neat, cm-1) 2960 (s), 2929 (s), 2854 (s), 1739 (s), 1633 (m);
HRMS (EI) m/z (Mþ - C2H3O) calcd for C24H35O4Si 415.2305,
found 415.2305.
Acknowledgment. We thank the Natural Science and En-
gineering Research Council of Canada (NSERC), Merck-
Frosst Canada, Boehringer Ingelheim, Bristol Myers Squibb,
AstraZeneca, Canada Foundation for Innovation, Ontario
Innovation Trust, Government of Ontario through Premier’s
Research Excellence Award (PREA), and the University of
Ottawa for generous funding. R.L.B. thanks NSERC for a
postgraduate scholarship (PGS-B). J.A.F. thanks the Govern-
ment of Ontario for an Ontario Graduate Scholarship (OGS).
(()-(1S,4S,6R,7R,8S,9S)-6-(tert-Butyldimethylsilanyloxy)-10-
[(2-methyl-1-(2-oxoethyl)prop-2-en-1-yl]-4-methyl-9-spiro[3,4-di-
hydrofuran]-3-oxatricyclo[5.4.0.02,6]undec-10-en-2-one (45). Tri-
ethylamine (1 drop) was added to a solution of 44 (5 mg,
0.01 mmol) in xylene (0.5 mL). The contents of the Schlenk tube
were degassed under a steady flow of argon for 20 min and then
placed in a 155 °C wax bath for 24 h. The crude product was
purified directly by flash chromatography on silica gel (100%
hexanes then 10:1 hexanes/Et2O) provided 45 as a clear colorless
oil (75%, 3.7 mg, dr =1:1, inseparable mixture). Characterized
Supporting Information Available: Experimental proce-
dures for 11, 12, 22, 27-29, and 31. High-field 1H and 13C
NMR spectra for compounds 4, 9-12, 14-17, 20-22, 27-29,
and 31-45. Crystallographic data for 35. ORTEP view of 35.
This material is available free of charge via the Internet at http://
pubs.acs.org.
1
as a mixture of diastereomers: H NMR (500 MHz, C6D6) δ
9.41-9.40 and 9.29-9.28 (m, 1H), 5.87 and 6.57 (d, J = 6.9 and
6346 J. Org. Chem. Vol. 75, No. 19, 2010