Studies toward the total synthesis of vinigrol. Synthesis of the octalin ring

Article abstract of DOI:10.1021/jo051318i

Herein, we disclose our results regarding various strategies toward the assembly of the octanyl ring of vinigrol. Attempts to generate the problematic eight-membered ring through a ring expansion or via unification of the terminal olefins using the ring-c

Full text of DOI:10.1021/jo051318i

Studies toward the Total Synthesis of Vinigrol. Synthesis of the
Octalin Ring
Louis Morency and Louis Barriault*
Department of Chemistry, 10 Marie Curie, University of Ottawa, Ottawa, Canada, K1N 6N5
lbarriau@science.uottawa.ca
Received June 27, 2005
Herein, we disclose our results regarding various strategies toward the assembly of the octanyl
ring of vinigrol. Attempts to generate the problematic eight-membered ring through a ring expansion
or via unification of the terminal olefins using the ring-closing metathesis were not successful.
The cyclooctane ring was created via a sequential hydroxy Diels-Alder/Claisen rearrangement
reaction of diene 55 and N-benzylmaleimide.
Introduction
Vinigrol (1) was isolated in 1987 from a culture of the
fungal strain identified as Virgaria nigra.1 This diterpene
bears a cis-decalin subunit surmounted by an eight-
membered ring that constitutes an unprecedented tri-
cyclo[4.4.4.0.4a,8a]tetradecane skeleton. The biological ac-
tivities of 1 reside in the antihypertensive, platelet
aggregation-inhibiting, and tumor necrosis factor (TNF)
antagonist properties.2 Its unusual and complex archi-
tecture combined with the promising biological activities
have stimulated the creation of several synthetic ap-
proaches.3
Claisen/ene reaction (Scheme 1).4 Microwave-assisted
heating of 2 produces the 10-membered ring 3, which
immediately undergoes a Claisen rearrangement to give
enone 4. The latter is poised to cyclize via a transannular
ene reaction to give decalin 5. However, we observed that
large substituents at the terminal allylic position (R *
H) are detrimental to the cascade process, thus impeding
the installation of the iso-propyl group at C9.
Recently, we reported the synthesis of the cis-decalin
subunit of vinigrol (1) using the tandem oxy-Cope/
In light of these results, we decided to explore new
avenues aimed at constructing the tricyclic core of
vinigrol (1). A cursory inspection of vinigrol (1) reveals a
compact structure where the formation of the cyclooctane
ring overhanging the decalin core represents a major
synthetic challenge. We investigated three different
synthetic pathways for the formation of this eight-
membered ring. The first one involves a ring expansion
triggered by a Claisen rearrangement5 of the correspond-
ing vinyl ether 6 to give the tricycle 7 (eq 1). The second
route, illustrated in eq 2, exploits the ring-closing me-
tathesis (RCM) of diene 8 to generate the vinigrol
skeleton 9. Finally, the third approach took advantage
of a sequential hydroxy-Diels-Alder/Claisen reaction of
diene 10 and N-benzylmaleimide to create the corre-
(1) Uchida, I.; Ando, T.; Fukami, N.; Yoshida, K.; Hashimoto, M. J.
Org. Chem. 1987, 52, 5292.
(2) (a) Ando, T.; Tsurumi, Y.; Ohata, N.; Uchida, I.; Yoshida, K.;
Okuhara, M. J. Antibiot. 1988, 41, 25. (b) Ando, T.; Yoshida, K.;
Okuhara, M. J. Antibiot. 1988, 41, 31. (c) Norris, D. B.; Depledge, P.;
Jackson, A. P. PCT Int. Appl. W0 91 07 953, 1991; Chem Abstr. 1991,
115, 64776h.
(3) (a) Paquette, L. A.; Efremov, I.; Liu, Z. J. Org. Chem. 2005, 70,
505. (b) Paquette, L. A.; Efremov, I. J. Org. Chem. 2005, 70, 510. (c)
Paquette, L. A.; Liu, Z.; Efremov, I. J. Org. Chem. 2005, 70, 514. (d)
Gentric, L.; Hanna, I.; Ricard, L. Org. Lett. 2003, 5, 1139. (e) Gentric,
L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631. (f)
Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim, I. H.; Crawford, J. J.
Org. Chem. 2003, 68, 6096. (g) Miyashita, M.; Shirahama, H.; Matsuda,
F.; Kito, M.; Sakai, T.; Okada, N. Tetrahedron 1999, 55, 14369. (h)
Devaux, J.-F.; Hanna, I.; Lallemand, J.-Y. J. Org. Chem. 1997, 62,
5062. (i) Kito, M.; Sakai, T.; Shirahama, H.; Miyashita, M.; Matsuda,
F. Synlett 1997, 219. (j) Kito, M.; Sakai, T.; Haruta, N.; Shirahama,
H.; Matsuda, F. Synlett 1996, 1057. (k) Mehta, G.; Reddy, K. S. Synlett
1996, 625. (l) Devaux, J.-F.; Hanna, I.; Fraisse, P.; Lallemand, J.-Y.
Tetrahedron Lett. 1995, 36, 9471. (m) Devaux, J.-F.; Hanna, I.;
Lallemand, J.-Y. J. Org. Chem. 1993, 58, 2349.
(4) Barriault, L.; Morency, L. Tetrahedron Lett. 2004, 45, 6105.
(5) Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
10.1021/jo051318i CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/24/2005
J. Org. Chem. 2005, 70, 8841-8853
8841

Morency and Barriault
SCHEME 1
SCHEME 2
MeOH to give alcohol 16 in 90% yield. The treatment of
16 with MgBr2‚OEt2/Et3N8 in dichloromethane generated
in situ the corresponding magnesium alkoxide which was
poised to undergo an HDDA reaction with methyl acry-
late to provide the cycloadduct 176a in 78% yield as a
single diastereomer.9 Reduction of the ester group in 17
with lithium aluminum hydride followed by the protec-
tion of the primary alcohol with DPSCl gave silyloxy
ether 18 in 78% yield over two steps. The installation of
the tertiary alcohol at C8a required the introduction of
a benzoate group at C1 (97% yield) followed by a
dihydroxylation reaction using OsO4 and NMO to produce
diol 19 in 82% yield.
sponding bicyclo[5.3.1]undecenone 11 (eq 3). Herein, we
report our progress directed toward the synthesis of the
cyclooctane belt embedded in vinigrol (1).
Treatment of diol 19 with 2-methoxypropene and PTSA
in dichloromethane provided the corresponding acetonide
20 in quantitative yield. Removal of the benzoate group
with K2CO3 in methanol (75% yield) followed by a Dess-
Martin periodinane oxidation10 produced ketone 22 in
100% yield. The addition of vinylmagnesium bromide to
ketone 22 was realized in the presence of anhydrous
cerium chloride in THF at -78 °C to produce alcohol 23
in 96% yield. Cleavage of the silyl ether group employing
TBAF followed by a ruthenium-mediated oxidation11 of
the resulting diol 24 led to the formation in situ of
aldehyde 25, which can exist in equilibrium with lactol
26. The latter mixture was further oxidized to give
lactone 27 in 51% yield. The installation of the enol ether
moiety, required for the subsequent Claisen rearrange-
ment, was accomplished by treatment of 27 with the
Petasis’ reagent12 in toluene at 65 °C. The desired enol
ether 28 was obtained in 85% yield.
Results and Discussion
Formation of the Cyclooctane Belt through the
Claisen Rearrangement. We proposed that the Claisen
rearrangement of the vinyl ether 6 could provide the
tricyclic core of vinigrol 7 (Scheme 2). The required vinyl
ether 6 could be prepared from the cycloadduct 12.
Recently, we reported a highly stereoselective synthesis
of bicyclo [4.4.0] decene 12 using the hydroxy-directed
Diels-Alder reaction (HDDA) between semicyclic dienes
such as 13 and various activated dienophiles (Scheme
3).6,7 The regio- and stereoselectivity of the reaction was
rationalized by the formation of a temporary metal tether
intermediate 14, which underwent an intramolecular
Diels-Alder reaction to afford the corresponding cycload-
duct 12, which represents the cis-decalin portion of
vinigrol.
At this stage, all the requisite carbons embedded in
the vinigrol skeleton were installed. The next objective
was the creation of the eight-membered ring. Initial
(7) (a) For a review on tethers in cycloadditions, see: Shea, K. J.;
Zandi, K. S.; Gauthier, D. R. Tetrahedron 1998, 54, 2289 and references
therein. (b) Olsson, R.; Bertozzi, F.; Fredj, T. Org. Lett. 2000, 2, 1283.
(c) Batey, R. A.; Thadani, A. N.; Lough, A. J. J. Am. Chem. Soc. 1999,
121, 450. (d) Stork, G.; Chan, T. Y. J. Am. Chem. Soc. 1995, 117, 6595.
(e) Nicolaou, K. C.; Ueno, H.; Liu, J.-J.; Nantermet, Z.; Yang, Z.;
Renaud, J.; Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995, 117,
653. (f) Shimada, S.; Osoda, K.; Narasaka, K. Bull. Chem. Soc. Jpn.
1993, 66, 1254-1257. (g) Stork, G.; Chan, T. Y.; Breault, G. A. J. Am.
Chem. Soc. 1992, 114, 7578. (h) Sieburth, S.; Fensterbamk, L. J. Org.
Chem. 1992, 57, 5279. (i) Narasaka, K.; Shimada, K.; Osoda, N.;
Iwasawa, N. Synthesis 1991, 1171. (j) Tamao, K.; Kobayashi, K.; Ito,
Y. J. Am. Chem. Soc. 1989, 111, 6478.
To probe the feasibility of this approach, a model study
was engaged using 2-vinylcyclohexenol 16 as a semicyclic
diene (Scheme 4). The synthesis commenced with a 1,2-
reduction of enone 156a with NaBH4 and CeCl3‚7H2O in
(8) Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702.
(9) The diastereomeric excess was determined by 1H NMR 300 and
500 MHz of the crude reaction mixture.
(10) Dess, D. B.; Martin J. C. J. Am. Chem. Soc. 1991, 113, 2350.
(11) Ley, S. V.; Griffith, W. P. Aldrichimica Acta 1990, 23, 1.
(12) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392. (b) Petasis, N. A.; Lu, S.-P.; Bzowej, E. I.; Fu, D.-K., Staszewski,
J. P.; Akritopoulou-Zanze, I.; Patane, M. A.; Hu, Y.-H. Pure Appl. Chem.
1996, 68, 667.
(6) (a) Barriault, L.; Thomas, J. D. O.; Cle´ment, R. J. Org. Chem.
2003, 68, 2317. (b) For the first example of Diels-Alder reaction by
self-assembly of the components on a Lewis acid, see: Ward, D. E.;
Abaee, M. S. Org. Lett. 2000, 2, 3937. (c) Ward, D. E.; Souweha, M. S.
Org. Lett. 2005, 7, 3533.
8842 J. Org. Chem., Vol. 70, No. 22, 2005

Studies Toward the Total Synthesis of Vinigrol
SCHEME 3
SCHEME 4
SCHEME 5
attempts to rearrange vinyl enol ether 28 to ketone 29
under thermal conditions were fruitless. Conventional
heating of a solution of 28 (ca. 0.05 M) in toluene at
temperatures ranging from 160 to 210 °C in a sealed tube
or using microwave irradiation led to recovery of the
starting material or the formation of a complex mixture
from which no Claisen rearrangement product 29 was
isolated. We then turned our attention toward the use
of hard and soft Lewis acids to catalyze this rearrange-
ment.13 Despite considerable experimental efforts, all
runs using Pd(0)L4, Pd(II)L2,14 AgBF4, AlMe3, AlMe2Cl,
Dibal-H, i-Bu3Al,15 bis(4-bromo-di-tert-butylphenoxyde
(MABr),16 and Mg(OTf)2 in various solvents and condi-
tions resulted in the degradation of 28 or its partial
recovery. Interestingly, enol ether 28 was completely
converted into ketone 30 in the presence of MgBr2-OEt2
in dichloromethane (Scheme 5). It became clear that the
formation of the eight-membered ring should be realized
by other means.
SCHEME 6
Formation of the Eight-Membered Ring via Ring-
Closing Metathesis. In the second approach, we rec-
ognized that the octanyl ring in 9 could be generated from
an RCM of diene 8 (Scheme 6).17 A cursory inspection
reveals that conformer 31 should be the favored ground
state conformation. The latter compound could be pre-
pared from ketone 32. Semiempirical calculations (AM1)
of conformers 33 and 34 reveal that the heat of formation
of 33 is 3.8 kcal/mol higher in energy than that of
conformer 34 (Figure 1). On the basis of this and the ease
of formation of lactone 27, we anticipated that the
reactive conformer 8 could be trapped in the RCM
conditions to give tricycle 9.
The synthesis began by treatment of ketone 22 with
ClMg(CH2)3OMgCl18 and CeCl3 in THF to give alcohol
35 in 82% yield (Scheme 7). Protection of the primary
alcohol as a TBS ether group (100%) and a subsequent
(13) Lutz, R. P. Chem. Rev. 1984, 84, 205 and references therein.
(14) (a) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579.
(b) Baan, J. L.; Bickelhaupt, F. Tetrahedron Lett. 1986, 27, 6267.
(15) Paquette, L. A.; Friedrich, D.; Rogers, R. D. J. Org. Chem. 1991,
56, 3841.
(16) Marouka, K.; Nonoshita, K.; Banno, H.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 7922.
(17) During the course of this research, Paquette and co-workers
also explored the formation of the cyclcooctane ring of vinigrol via RCM;
see ref 3c
(18) Normant, J. F.; Alexakis, A.; Cahiez, G. Tetrahedron Lett. 1978,
33, 3013.
J. Org. Chem, Vol. 70, No. 22, 2005 8843

Morency and Barriault
TABLE 1. Hydrogenation of 37
a N.D. ) not determined. b The TBS group was partially removed during the reduction process.
SCHEME 8
FIGURE 1. Relative heats of formation of 33 and 34.
SCHEME 7
SCHEME 9
elimination of the tertiary alcohol using POCl3 and DBU
in pyridine produced decalin 37 in 77% yield. At this
point, a stereoselective reduction of the trisubstituted
genation of 37 at 1300 psi and in the presence of the
ruthenium-based catalyst 43 gave decalin 38 in quantita-
tive yield as the sole detectable isomer.20,21
exocyclic double bond at C1-C2 was investigated. A large
number of metal-catalyzed hydrogenation protocols were
scanned, though only hydrogenation methods using Pd/
C, Raney Ni, and Ru were capable of reducing this olefin
to yield decalins 38 and 39 in variable ratios (Table 1).
Hydrogenation of 37 with Raney Ni gave a mixture of
38 and 39 in a ratio of 4:1 in 99% yield (entry 1).
Surprisingly, the reduction on Pd/C in ethanol afforded
39 as the major product (entry 2). A similar result was
recently reported by Trost.19 They found that high-
pressure hydrogenation of 40 with Pd/C afforded exclu-
sively 41 (Scheme 8). They attributed the formation of
41 to “an equilibration in the semihydrogenation step due
to a slow final reductive elimination step”. They circum-
vent this problem by hydrogenation of 40 over iridium
black, yielding the desired product 42. In our case,
hydrogenation of 37 in the presence of iridium black did
not give 38; rather, starting material was recovered along
with several degradation products. Fortunately, hydro-
Removal of both silicon protective groups on 38 was
realized with TBAF to afford the desired diol 44 in 100%
yield (Scheme 9). This diol was subjected to TPAP
oxidation,11 thereby leading to the corresponding dialde-
hyde 45. The latter was immediately treated with a slight
excess of Ph3PdCH2 to provide diene 46 in 72% yield.
We were now in a position to explore the RCM approach
aimed at forming the octalin belt. As previously men-
tioned, our hopes to close the eight-membered ring were
based on the ease of the cis-decalin framework to adopt
the reactive conformation 8 in the RCM reaction condi-
tions.22 Unfortunately, all attempts to cyclize 46 via RCM
(20) This catalyst was generated in situ from H2Imes(Cl)2Py2Rud
CHPh (6 mol %) in methanol with Et3N. For procedure, see: (a)
Dharmasena, U. L.; Foucault, H. M.; dos Santos, E. N.; Fogg, F. E.;
Nolan, S. P. Organometallics 2005, 24, 1056. (b) Grubbs R. H.; Love,
J. A.; Sanford, M. S. Organometallics 2001, 20, 5314.
(21) The relative stereochemistry of 38 was established by X-ray
diffraction. For an ORTEP view of 38 (benzoate derivative), see the
Supporting Information.
(19) Trost, B. M.; Pissot-Soldermanne, C.; Chen, I.; Schroeder, G.
M. J. Am. Chem. Soc. 2004, 126, 4480.
8844 J. Org. Chem., Vol. 70, No. 22, 2005

Studies Toward the Total Synthesis of Vinigrol
TABLE 2. Claisen Rearrangement of Cycloadduct 58
SCHEME 10
starting
entry material
product
(yield)
R
R1
1
2
3
4
5
6
58c
58d
58e
58f
58g
58g
PMB MOM 59c (25%)a
PMB TMS
PMB Bz
59d (35%)a
degradationa
DPS
DPS
DPS
TES
TMS
TMS
60f (40%)a and 61f (15%)a
60g (42%)a and 61g (30%)a
60g (65%)b and 59g (14%)b
using Grubbs’ first- and second-generation catalysts were
not productive. We also tried to obtain the tricycle 47 by
TiCl3-mediated coupling reaction of the dialdehyde groups
in 45. However, the exposure of dialdehyde 45 to reaction
conditions prescribed by McMurry23 gave only degrada-
tion products. In accordance with our results, Paquette
and co-workers recently reported unsuccessful approaches
to generate the cyclooctane ring by assembling two side
chains attached on a cis-decalin framework using various
ring-closing methods.3a-c,f
Sequential HDDA/Claisen Rearrangement. Since
our attempts to generate the eight-membered ring in 1
by unifying alkyl chains present on the cis-decalin system
via a [3,3]-rearrangement or through RCM were not
successful, we envisaged the creation vinigrol core 48 via
an intramolecular alkylation of 49 (Scheme 10). The
bicyclo[5.3.1]undecanone subunit 49 could be prepared
from a sequential hydroxy-directed Diels-Alder/Claisen
rearrangement24 between diene 51 and dienophile 50.
Diene 51 could be synthesized from lactone 52 derived
from the readily available aldehyde 53.
a Heating in a sealed tube at 170 °C in toluene and 10 equiv of
triethylamine. b Irradiation with microwaves at 600 W in aceto-
nitrile at 170 °C for 30 min.
DMAP, and triethylamine gave 56a and 56b in good
yields. The completion of dienes 57a and 57b required
addition of vinylmagnesium bromide in THF at -78 °C
to produce the corresponding lactols that upon treatment
with SOCl2 and DMAP in methylene chloride and a
subsequent exposure to fluorine ion provided semicyclic
dienes 57a and 57b in 69 and 37% yields, respectively,
over three steps.
Hydroxy-directed Diels-Alder reaction of 57a,b and
N-benzylmaleimide provided the desired bicyclo[4.4.0]-
decenes 58a and 58b in 67 and 64% yield, respectively,
as the sole diastereomers. The latter were poised to
undergo a thermal Claisen [3,3]-shift. Surprisingly, the
thermal rearrangement of 58a and 58b in the presence
of triethylamine gave only the 1,3-hydrogen shift byprod-
ucts 59a and 59b in 64 and 28% yields, respectively. The
hydroxy moiety in 58a and 58b was then protected with
various groups, and the resulting cycloadducts 58c-g
were heated at 170 °C in toluene (sealed tube) in the
presence of triethylamine. The results are summarized
in Table 2. Heating of 1,5-dienes 58c-e led to the double
bond isomerized products 59c and 59d (entries 1 and 2)
or a complex mixture from which no desired Claisen
product 60 was isolated (entry 3). We were gratified to
find that diene 58f rearranged under the above reaction
conditions to produce the expected Claisen product 60f
in 40% yield along with 61f (15% yield) (entry 4).29 The
latter is the result of a [3,3]-sigmatropic shift of 59f
generated during the course of the reaction. The instal-
lation of a TMS protecting group at C1 did not have a
significant effect on the chemical yield for the transfor-
mation of 58g to the desired Claisen product 60g (entry
5). The latter was isolated in 42% yield along with the
spiro compound 61g (30% yield). Fortunately, the expo-
sure of 58g to microwave radiation30,31 (170 °C, 600 W)
Condensation of Weiler’s dianion25 upon aldehydes
53a26 and 53b27 afforded the corresponding â-ketoesters
54a and 54b in 67 and 64% yields, respectively (Scheme
11). The latter was diastereoselectively reduced to the
corresponding 1,3-anti diols using Me4NBH4 in a mixture
of acetic acid/acetonitrile at -25 °C.28 The resulting diols
were treated with trifluoroacetic acid in dichloromethane
to give lactones 55a and 55b in 40% yield (84% yield
based on consumed starting material) and 36% yield (70%
yield based on recovered starting material) over two steps
as single diastereomers. Protection of the secondary
alcohol as triethylsiloxy ether in the presence of TESCl,
(22) (a) Scholl, S.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 6543.
(23) (a) McMurry, J. E. Chem. Rev. 1989, 89, 1513. (b) McMurry, J.
E. Acc. Chem. Res. 1983, 16, 405.
(24) Barriault, L.; Ang, P. A. J.; Lavigne, R. M. A. Org. Lett. 2004,
6, 1317.
(25) Weiler, L.; Huckin, S. N. J. Am. Chem. Soc. 1974, 96, 1082.
(26) Hayashi, N.; Fujiwara, K.; Murai, A. Tetrahedron 1997, 53,
12425.
(27) The aldehyde 53b was made from the corresponding alcohol
via a Swern oxidation. See: Brenn, A. P.; Murphy, J. A.; Patterson, C.
W.; Wooster, N. F. Tetrahedron 1993, 49, 10643.
(28) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 10, 3560.
(29) The structure of 61f was established by NMR spectroscopy and
confirmed by X-ray analysis. For ORTEP view of 61f, see the Sup-
porting Information.
J. Org. Chem, Vol. 70, No. 22, 2005 8845

Morency and Barriault
SCHEME 11
SCHEME 12
problematic eight-membered ring earlier in the synthesis
employing a sequential HDDA/[3,3] reaction. This ap-
proach was rewarded with success, affording the bicyclo-
[5.3.1]undecenone subunit embedded in the vinigrol
framework. Completion of the tricyclic ring of vinigrol
via an intramolecular alkylation upon the bridgehead
ketone is currently in progress and will be reported in
due course.
for 30 min in acetonitrile furnished 60g in 65% yield. In
this case, we isolated 59g as a side product in 14% yield.
Interestingly, heating of 58g in acetonitrile in a sealed
tube at 170 °C led to a complex mixture from which no
desired Claisen products 60g or 61g were isolated. It is
clear now that the choice of the protecting groups R and
R1 and the heating source are crucial for the Claisen
reaction to occur; however, their role in the reaction
process remains elusive. Finally, the silicon groups on
60g were removed with HCl in THF to afford the
corresponding monoprotected alcohol 62 in 99% yield
(Scheme 12). At this stage, the stereochemistry of the
bicyclo[5.3.1]undecenone 62 was established without
ambiguity by X-ray diffraction.32
In summary, we described three different approaches
toward the elaboration of the vinigrol framework. The
key feature of the first two synthetic routes was the
successful exploitation of the HDDA reaction to construct
the vinigrol cis-decalin unit 22. However, this approach
was plagued by the inability to form the eight-membered
ring of vinigrol via a Claisen rearrangement or by a ring
closure metathesis. We thus decided to generate this
General Experimental Section
All reactions were performed under argon in flame-dried
glassware equipped with a magnetic stir bar and a rubber
septum unless otherwise indicated. Solvents used were freshly
distilled prior to use: ether, THF, and 1,2-dimethoxyethane
(DME) over sodium and benzophenone; dichloromethane,
toluene, and DMF over calcium hydride. All other commercial
reagents were used without purification. Microwave reactions
were performed using a microwave oven equipped with a
pressure-monitoring device and a fiber optic temperature
probe. The reaction vessel was a quartz tube, and in each case
a carboflon was added to aid in the absorption of microwave
radiation. Reactions were monitored by TLC analysis using
glass plates precoated (250-µm thickness) with silica gel 60
F254. TLC plates were viewed using UV light, p-anisaldehyde
staining solution, phosphomolybdic acid staining solution, or
potassium permanganate staining solution. Flash chromatog-
raphy was carried out on 230-400 mesh silica gel 60. 1H and
13C NMR spectra were recorded on 300 and 500 MHz spec-
trometer in the specified deuterated solvent. IR spectra were
recorded on a FTIR spectrometer. HRMS spectra were ob-
tained using a spectrometer, and melting points were recorded
using a melting point apparatus.
5-(tert-Butyldiphenylsilanyloxymethyl)-1,2,3,4,4a,5,6,7-
octahydronaphthalen-1-ol (18). LiAlH4 (0.075 g, 1.97 mmol)
was added to a solution of ester 176a (0.41 g, 1.97 mmol) in
THF (20 mL) at -78 °C. The reaction was stirred for 30 min.
A solution of sodium tartrate 1 M (3 mL) was added and stirred
for 15 h. The aqueous layer was extracted 3 times with ethyl
acetate (3 × 40 mL). The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evapo-
rated. The crude product was purified by flash silica column
chromatography (EtOAc) to afford 360 mg of the primary
alcohol (99% yield) as a white solid. The alcohol was dissolved
in DMF (10 mL). Imidazole (0.293 g, 4.3 mmol) was added,
followed by DPSCl (0.563 mL, 2.2 mmol). The reaction was
stirred at room temperature for 1.5 h. The reaction was
(30) For a review on microwaves in organic synthesis, see: (a)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (b) Loupy, A.;
Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe´, D.
Synthesis 1998, 1213. (c) Majetich, G.; Hichs, R. J. Journal of
Microwave Power and Electromagnetic Energy 1995, 30, 27. (d) Loupy,
A.; Perreux, L. Tetrahedron 2001, 57, 9199. (e) Lidstro¨m, P.; Tierny,
J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
(31) Nonpolar solvents such as toluene do not absorb microwaves,
and therefore, a glass-coated Carboflon was placed inside the reaction
cell. Carboflon readily absorbs microwave energy and transmits heat
to the reaction mixture through conduction. This microwave oven is
equipped with a fiber optic probe placed inside the reaction cell to
monitor the temperature and pressure of the reaction.
(32) For ORTEP view of 62, see Supporting Information.
8846 J. Org. Chem., Vol. 70, No. 22, 2005

Studies Toward the Total Synthesis of Vinigrol
quenched using saturated NH4Cl(aq). The aqueous layer was
extracted 3 times with a mixture of 1:1 hexane/diethyl ether
(3 × 30 mL). The organic layer was dried over anhydrous
MgSO4 and filtered, and the solvent was evaporated. The crude
product was purified by flash silica column chromatography
(10-80% EtOAc/hexanes, gradient elution) to afford 69 mg of
starting material and 650 mg of 18 (78% yield) as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.70-7.62 (m, 4H), 7.43-
7.33 (m, 6H), 5.59 (s, 1H), 4.01-3.98 (m, 1H), 3.62-3.50 (m,
2H), 2.12-2.07 (m, 3H), 1.99-1.88 (m, 1H), 1.85-1.72 (m, 1H),
1.65-1.61 (m, 1H), 1.53 (d, J ) 1.1 Hz, 1H), 1.52-1.48 (m,
3H), 1.26-1.14 (m, 3H), 1.03 (s, 9H); 13C NMR (CDCl3, 75
MHz) δ 144.4, 135.5 (×4), 134.0 (×2), 129.5 (×2), 127.6 (×4),
114.4, 73.2, 65.9, 39.5, 38.4, 38.2, 27.5, 26.8 (×3), 25.1, 24.4,
21.6, 19.3; IR (neat) 3346, 2929, 2857, 1110 cm-1; EI HRMS
calcd for C23H27O2Si (M+ - tBu) 363.1870, obsd 363.1874.
anhydrous MgSO4 and filtered, and the solvent was evaporated
by rotary evaporation under vacuum. The crude product was
purified by flash silica column chromatography (20% EtOAc/
hexanes) to afford 751 mg of 20 (100% yield) as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 8.09 (d, J ) 7.1 Hz, 2H), 7.69-
7.66 (m, 4H), 7.58-7.53 (m, 1H), 7.47-7.34 (m, 8H), 5.32 (dd,
J ) 4.2, 12.0 Hz, 1H), 4.76 (s, 1H), 3.63-3.52 (m, 2H), 2.62-
2.57 (m, 1H), 2.17-1.97 (m, 3H), 1.87-1.74 (m, 3H), 1.69-
1.55 (m, 1H), 1.50 (s, 3H), 1.47-1.25 (m, 2H), 1.23 (s, 3H),
1.19-1.09 (m, 2H), 1.06 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
165.4, 135.5 (×4), 133.9, 133.9, 132.9, 130.5, 129.6 (×2), 129.5,
129.5, 128.3 (×2), 127.6 (×4), 107.3, 83.8, 76.8, 72.6, 66.2, 40.8,
32.4, 29.6, 27.5, 26.9, 26.8 (×3), 22.6, 22.5, 19.2, 17.3; IR (neat)
2945, 2856, 1716, 1266, 1101 cm-1; EI HRMS calcd for
C37H46O5Si (M+) 598.31145, obsd 598.31267.
6-(tert-Butyldiphenylsilanyloxymethyl)-2,2-dimethyl-
octahydronaphtho[1,8a-d][1,3]dioxol-10-ol (21). Benzoate
20 (0.818 g, 1.37 mmol) was dissolved in benzene (5 mL) and
MeOH (5 mL). K2CO3 was added until it did not dissolve and
heated to reflux for 6 h, then cooled to room temperature for
72 h, and filtered through a Celite pad with diethyl ether. The
solvent was evaporated. The crude product was purified by
flash silica column chromatography (20% EtOAc/hexanes) to
afford 510 mg of 21 (75% yield) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 7.65-7.62 (m, 4H), 7.42-7.32 (m, 6H),
4.50 (s, 1H), 3.71-3.68 (m, 1H), 3.56-3.45 (m, 2H), 2.53-2.47
(m, 1H), 2.05-1.94 (m, 2H), 1.86-1.62 (m, 5H), 1.53 (s, 3H),
1.48 (s, 3H), 1.36-1.22 (m, 3H), 1.19-1.07 (m, 2H), 1.02 (s,
9H); 13C NMR (CDCl3, 75 MHz) δ 135.5 (×4), 134.1 (×2), 129.5
(×2), 127.6 (×4), 106.7, 85.9, 75.0, 71.6, 66.3, 40.1, 32.7, 31.1,
27.7, 27.2, 26.8 (×3), 23.6, 23.0, 22.6, 19.3, 17.6; IR (neat) 3456,
2935, 2858, 1103, 1039 cm-1; EI HRMS calcd for C30H42O4Si
(M+) 494.28524, obsd 494.28459.
Benzoic Acid 5-(tert-Butyldiphenylsilanyloxymethyl)-
8,8a-dihydroxydecahydronaphthalen-1-yl Ester (19). Al-
cohol 18 (0.729 g, 1.73 mmol) was dissolved in dichloromethane
(9 mL). Pyridine (0.42 mL, 5.2 mmol), DMAP (1 crystal), and
benzoyl chloride (0.3 mL, 2.6 mmol) were added and stirred
for 15 h. HCl 2 N (4 mL) was added, and the aqueous layer
was extracted 3 times with dichloromethane (3 × 50 mL). The
organic layer was dried over anhydrous MgSO4 and filtered,
and the solvent was evaporated. The crude product was
purified by flash silica column chromatography (10% EtOAc/
hexanes) to afford 84 mg of benzoate (97% yield) as a colorless
oil: 1H NMR (500 MHz, CDCl3) δ 8.18-8.15 (m, 2H), 7.76-
7.71 (m, 4H), 7.59-7.53 (m, 1H), 7.49-7.39 (m, 8H), 5.64 (s,
1H), 5.46 (d, J ) 11.0 Hz, 1H), 3.71-3.64 (m, 2H), 2.38-2.35
(m, 1H), 2.27-2.24 (m, 1H), 2.14-2.07 (m, 2H), 1.97-1.93 (m,
1H), 1.86-1.75 (m, 2H), 1.68-1.62 (m, 1H), 1.61-1.59 (m, 1H),
1.57-1.54 (m, 1H), 1.35-1.29 (m, 1H), 1.21-1.15 (m, 1H), 1.13
(s, 9H); 13C NMR (CDCl3, 125 MHz) δ 165.5, 139.8, 135.5 (×4),
134.0 (×2), 132.7 (×2), 130.7, 129.6 (×2), 129.5 (×2), 128.3
(×2), 127.6 (×2), 127.54, 115.6, 75.2, 65.8, 39.6, 38.4, 34.9, 27.4,
26.9 (×3), 25.0, 24.5, 21.5, 19.2; IR (neat) 3063, 2937, 2854,
6-(tert-Butyldiphenylsilanyloxymethyl)-2,2-dimethyl-
octahydronaphtho[1,8a-d][1,3]dioxol-10-one (22). Alcohol
21 (0.004 g, 0.008 mmol) was dissolved in CH2Cl2 (10 mL).
Dess-Martin periodinane (4 mg, 0.009 mmol) was added, and
the reaction was stirred for 3 h at room temperature. A
solution of NaHCO3sat was added, followed by Na2S2O3sat, and
stirred for 20 min. The aqueous layer was extracted 3 times
with dichloromethane (3 × 20 mL). The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was
evaporated. The crude product was purified by flash silica
column chromatography (20% EtOAc/hexanes) to afford 4 mg
of 22 (100% yield) as white crystals. mp 76.7-77.5 °C: 1H
NMR (300 MHz, CDCl3) δ 7.64-7.59 (m, 4H), 7.43-7.32 (m,
6H), 4.12 (t, J ) 2.7 Hz, 1H), 3.58-3.45 (m, 2H), 2.58-2.53
(m, 1H), 2.41-2.36 (m, 1H), 2.25-2.15 (m, 2H), 2.10-1.90 (m,
2H), 1.89-1.80 (m, 1H), 1.77-1.60 (m, 2H), 1.54 (s, 3H), 1.52-
1722, 1267, 1102 cm-1; EI HRMS calcd for C30H31O3Si (M+
-
tBu) 467.2042, obsd 467.1834. The resulting benzoate (84 mg,
0.16 mmol) was dissolved in THF (1.6 mL) and water (0.32
mL). NMO (0.037 g, 0.32 mmol) was added, followed by
osmium tetroxide 4% in water (0.050 mL, 0.008 mmol). The
reaction was stirred for 6 h at reflux and 18 h at room
temperature. The reaction was not finished. NMO (0.02 g, 0.17
mmol) and osmium tetraoxide 4% in water (0.02 mL, 0.003)
were added and stirred for 24 h at reflux. After completion,
the reaction was quenched with a saturated aqueous solution
of Na2S2O3. The aqueous layer was extracted 3 times with ethyl
acetate (3 × 10 mL). The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evapo-
rated. The crude product was purified by flash silica column
chromatography (20% EtOAc/hexanes) to afford 73 mg of 19
(82% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.96-7.92 (m, 2H), 7.67-7.63 (m, 4H), 7.56 (tt, 1.3, 7.4 Hz,
1H), 7.44-7.34 (m, 8H), 5.12 (dd, J ) 4.4, 12.1 Hz, 1H), 4.40-
4.35 (m, 1H), 3.55-3.41 (m, 2H), 2.94 (s, 1H), 2.91 (d, J ) 2.1
Hz, 1H), 2.46-2.35 (m, 1H), 2.13-2.01 (m, 2H), 1.91-1.80 (m,
2H), 1.75-1.61 (m, 2H), 1.56-1.40 (m, 3H), 1.28-1.13 (m, 2H),
1.04 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 165.9, 135.6 (×4),
133.7 (×2), 133.3, 129.9, 129.6, 129.5, 129.3 (×2), 128.6 (×2),
127.6 (×4), 83.9, 73.6, 68.4, 65.8, 43.6, 35.8, 29.3, 28.8, 26.8
(×3), 23.6, 21.6, 21.3, 19.2; IR (neat) 3470, 2921, 2854, 1722,
1272, 1106 cm-1; EI HRMS calcd for C30H33O5Si (M+ - tBu)
501.2097, obsd 501.1991.
1.39 (m, 1H), 1.38 (s, 3H), 1.23-1.10 (m, 2H), 1.01 (s, 9H); 13
C
NMR (CDCl3, 75 MHz) δ 209.8, 135.5 (×4), 133.9, 133.8, 129.6
(×2), 127.6 (×4), 109.1, 87.2, 74.3, 65.7, 42.9, 41.1, 32.7, 26.8
(×3), 26.7, 25.3, 25.2, 23,3, 21.3, 19.3, 16.9; IR (neat) 2939,
2861, 1724, 1110 cm-1; EI HRMS calcd for C30H40O4Si (M+)
492.26959, obsd 492.27021.
6-(tert-Butyldiphenylsilanyloxymethyl)-2,2-dimethyl-
10-vinyloctahydronaphtho[1,8a-d][1,3]dioxol-10-ol (23).
A suspension of CeCl3 (0.044 g, 0.18 mmol) in dry THF (0.6
mL) was stirred at 0 °C for 2 h. Ketone 22 (0.03 g, 0.06 mmol)
was dissolved in THF (0.2 mL), cannulated into the CeCl3
suspension, and stirred for 15 h at room temperature. The
solution was cooled to -78 °C, and vinylmagnesium bromide
0.9 M (0.2 mL, 0.18 mmol) was added dropwise. The reaction
was stirred for 30 min at -78 °C. Saturated NH4Cl(aq) was
added. The aqueous layer was extracted 3 times with dichlo-
romethane (3 × 20 mL). The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evapo-
rated. The crude product was purified by flash silica column
chromatography (20% EtOAc/hexanes) to afford 30 mg of 23
(96% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.66-7.64 (m, 4H), 7.42-7.33 (m, 6H), 6.44 (dd, J ) 10.8, 17.3
Hz, 1H), 5.35 (d, J ) 17.4 Hz, 1H), 5.21 (d, 10.9 Hz, 1H), 4.56
Benzoic Acid 6-(tert-Butyldiphenylsilanyloxymethyl)-
2,2-dimethyloctahydronaphtho[1,8a-d][1,3]dioxol-10-yl
Ester (20). Diol 19 (0.693 g, 1.24 mmol) was dissolved in CH2-
Cl2 (12 mL). 2-Methoxypropene (0.356 mL, 3.72 mmol) and
TsOH (1 crystal) were added, and then the solution turned
dark red. The reaction was done after 10 min. NaHCO3sat was
added. The aqueous layer was extracted 3 times with dichlo-
romethane (3 × 60 mL). The organic layer was dried over
J. Org. Chem, Vol. 70, No. 22, 2005 8847

Morency and Barriault
(s, 1H), 3.79-3.55 (m, 2H), 2.37 (s, 1H), 2.08-2.03 (m, 1H),
1.96-1.89 (m, 1H), 1.81-1.56 (m, 5H), 1.49 (s, 3H), 1.38 (s,
3H), 1.33-1.1 (m, 4H), 1.03 (s, 9H), 0.94-0.84 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 143.7, 135.6 (×4), 134.1 (×2), 129.5
(×2), 127.6 (×4), 113.1, 107.1, 75.5, 73.6, 65.8, 38.8, 37.4, 27.9,
27.3, 26.9 (×3), 23.3, 23.2, 20.5, 19.3, 18.1; IR (neat) 3464,
2928, 2852, 1109, 1041 cm-1; EI HRMS calcd for C32H44O4Si
(M+) 520.30089, obsd 520.30007.
6-Hydroxymethyl-2,2-dimethyl-10-vinyloctahydronaph-
tho[1,8a-d][1,3]dioxol-10-ol (24). Compound 23 (0.033 g,
0.063 mmol) was dissolved in THF (0.5 mL). TBAF (0.089 mL
of a 1 M solution in THF, 0.089 mmol) was added. The reaction
was stirred for 15 h, then concentrated in vacuo. The crude
product was purified by flash silica column chromatography
(80% EtOAc/hexanes) to afford 16 mg of 24 (90% yield) as a
white solid. mp 119.9-123.9 °C: 1H NMR (300 MHz, CDCl3)
δ 6.40 (dd, J ) 11.0, 17.3 Hz, 1H), 5.33 (d, J ) 17.2 Hz, 1H),
5.20 (d, J ) 10.9 Hz, 1H), 4.52 (s, 1H), 3.78-3.54 (m, 2H),
2.18-2.16 (m, 1H), 2.07-1.67 (m, 8H), 1.60-1.53 (m, 1H), 1.46
(s, 3H), 1.36 (s, 3H), 1.32-1.14 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ 143.5, 113.2, 107.2, 75.4, 73.7, 64.9, 38.7, 37.3, 29.7,
28.1, 27.2, 23.6 (×2), 20.0, 18.9; IR (neat) 3427, 2930, 2869,
1250, 1207, 1044, 1011 cm-1; EI HRMS calcd for C15H23O4
(M+ - Me) 267.15964, obsd 267.1389.
Lactone (27). Molecular sieves 4 Å (0.05 g) were flame-
dried under vacuum. Diol 24 (0.01 g, 0.035 mmol) was
dissolved in dichloromethane (0.5 mL) and cannulated into the
flask containing the sieves. NMO (0.017 g, 0.142 mmol) was
added, followed by TPAP (1 grain). The reaction was stirred
for 20 min, and the crude product was purified by flash silica
column chromatography (20% EtOAc/hexanes) to afford 5 mg
of 27 (51% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 5.97 (dd, J ) 11.2, 17.5 Hz, 1H), 5.47 (dd, J ) 1.4, 7.5 Hz,
1H), 5.21 (dd, J ) 1.4, 11.2 Hz, 1H), 4.21 (d, J ) 5.1 Hz, 1H),
2.76 (s, 1H), 2.14-2.09 (m, 2H), 2.06-1.87 (m, 4H), 1.83-1.77
(m, 1H), 1.75-1.60 (m, 1H), 1.59-1.50 (m, 3H), 1.46 (s, 3H),
1.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.1, 135.8, 114.9,
107.9, 83.3, 77.2, 74.7, 44.6, 37.4, 34.0, 28.6, 28.3, 26.3, 24.7,
23.4, 16.7; IR (neat) 2935, 1741, 1092 cm-1; EI HRMS calcd
for C16H22O4 (M+) 278.15181, obsd 278.15268.
Enol Ether (28). A solution of ester 27 (519 mg, 1.8 mmol)
in a 0.11 M solution of Petasis’ reagent (Cp2TiMe2) in toluene
(50 mL,5.4 mmol) was heated at 80 °C for 15 h. The solution
was concentrated and purified by flash chromatography twice
(5% EtOAc/94% hexanes/1% Et3N) to afford 420 mg of 28 (85%
yield) as a yellow oil: 1H NMR (500 MHz, C6D6) δ 6.12 (dd,
J ) 17.4, 11.1 Hz, 1H), 5.63 (dd, J ) 17.4, 2.1 Hz, 1H), 5.14 (s,
1H), 4.61 (s, 1H), 4.29-4.28 (m, 1H), 3.95 (s, 1H), 2.45-2.44
(m, 1H), 2.28 (qt, 13.8, 4.7 Hz, 1H), 2.14-1.99 (m, 4H), 1.97
(s, 1H), 1.87-1.79 (m, 2H), 1.55-1.49 (m, 1H), 1.46 (d, J )
0.6 Hz, 3H), 1.45-1.32 (m, 2H), 1.30 (d, J ) 0.4 Hz, 3H); 13C
NMR (125 MHz, C6D6) δ 163.4, 139.0, 113.5, 107.2, 87.2, 78.4,
78.0, 75.4, 42.7, 37.5, 35.4, 32.6, 28.8, 26.3, 25.5, 23.6, 17.7;
IR (neat) 2930, 1245, 1090 cm-1; EI HRMS calcd for C17H24O3
(M+) 276.17255, obsd 276.17433.
26.6, 25.6, 22.3, 13.7, 24.6; IR (neat) 2988, 2934, 1707, 1207,
1056 cm-1; EI HRMS calcd for C17H24O3 (M+ - HBr) 276.17255,
obsd 276.17233.
6-(tert-Butyldiphenylsilanyloxymethyl)-10-(3-hydroxy-
propyl)-2,2-dimethyloctahydronaphtho[1,8a-d][1,3]-
dioxol-10-ol (35). A suspension of CeCl3 (0.328 g, 1.33 mmol)
in dry THF (0.6 mL) was stirred at 0 °C for 2 h. Ketone 22
(0.225 g, 0.44 mmol) was dissolved in THF (8 mL), cannulated
into the CeCl3 suspension, and stirred for 15 h at room
temperature. The solution was cooled to -78 °C, and ClMgO-
(CH2)3MgCl 0.34 M (8 mL, 2.66 mmol) was added dropwise.
Saturated NH4Cl(aq) and a few drops of glacial acetic acid were
added. The aqueous layer was extracted 3 times with diethyl
ether (3 × 50 mL). The organic layer was dried over anhydrous
MgSO4 and filtered, and the solvent was evaporated. The crude
product was purified by flash silica column chromatography
(80% EtOAc/hexanes) to afford 41 mg of starting material 22
(18%) and 200 mg of 35 (82% yield) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 7.64-7.59 (m, 4H), 7.43-7.31 (m, 6H),
4.69-4.67 (m, 1H), 3.76-3.63 (m, 2H), 3.57-3.46 (m, 2H),
2.49-2.44 (m, 1H), 2.03-1.56 (m, 11H), 1.51 (s, 3H), 1.47 (s,
3H), 1.25-1.10 (m, 6H), 1.02 (s, 9H); 13C NMR (CDCl3, 125
MHz) δ 135.5 (×4), 134.1, 134.0, 129.5 (×2), 127.6 (×4), 107.0,
87.6, 75.0, 73.3, 66.8, 63.5, 38.5, 33.0, 32.9, 30.9, 27.7, 27.4,
26.9, 25.4, 23.4, 22.8, 20.8, 19.3, 17.5; IR (neat) 3399, 2943,
2862, 1099, 1050 cm-1; EI HRMS calcd for C33H48O5Si (M+)
552.32710, obsd 552.3249.
10-[3-(tert-Butyldimethylsilanyloxy)-propyl]-6-(tert-
butyldiphenylsilanyloxymethyl)2,2-dimethyloctahydro-
naphtho[1,8a-d][1,3]dioxol-10-ol (36). A solution of alcohol
35 (1.03 g, 1.9 mmol), tert-butyldimethylsilyl chloride (1.5 g,
10 mmol), and imidazole (1.5 g, 22 mmol) in DMF (25 mL)
was stirred at room temperature overnight. The reaction was
quenched by adding saturated NH4Cl(aq). The aqueous layer
was extracted 3 times with a mixture of 1:1 diethyl ether/
hexanes (3 × 100 mL). The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evapo-
rated. The crude product was purified by flash silica column
chromatography (20% EtOAc/hexanes) to afford 1.3 g of 36
(100% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.63 (d, J ) 7.1 Hz, 4H), 7.41-7.32 (m, 6H), 4.73 (s, 1H), 3.74-
3.59 (m, 2H), 3.56-3.46 (m, 2H), 2.74-2.68 (m, 1H), 2.49-
2.42 (m, 1H), 1.97-1.85 (m, 3H), 1.82-1.80 (m, 1H), 1.76-
1.65 (m, 4H), 1.62-1.56 (m, 3H), 1.50-1.43 (m, 2H), 1.50 (s,
3H), 1.47 (s, 3H), 1.38-1.17 (m, 6H), 1.01 (s, 9H), 0.88 (s, 9H),
0.05 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 135.6 (×4), 134.1
(×2), 129.5 (×2), 127.6 (×4), 106.8, 87.5, 74.4, 73.2, 66.8, 63.8,
38.6, 33.3, 30.9, 27.7, 27.4, 26.9 (×3), 26.0 (×3), 25.4, 23.3, 22.8,
20.8, 19.3, 18.3, 17.5, -5.3 (×2); IR (neat) 3417, 2930, 2864,
1257, 1099 cm-1; EI HRMS calcd for C39H62O5Si2 (M+)
666.41358, obsd 666.4597.
10-[3-(tert-Butyldimethylsilanyloxy)-propylidene]-6-
(tert-butyldiphenylsilanyloxymethyl)-2,2-dimethylocta-
hydronaphtho[1,8a-d][1,3]dioxole (37). A solution of the
alcohol 36 (20 mg, 0.03 mmol) in DBU (0.1 mL) and pyridine
(0.5 mL) was stirred at room temperature. POCl3 (0.1 mL) was
added and stirred for 45 min. The reaction was quenched by
adding saturated NH4Cl(aq). The aqueous layer was extracted
3 times with dichloromethane (3 × 15 mL). The organic layer
was dried over anhydrous MgSO4 and filtered, and the solvent
was evaporated. The crude product was purified by flash silica
column chromatography (20% EtOAc/hexanes) to afford 15 mg
of 37 (77% yield) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 7.65-7.62 (m, 4H), 7.41-7.32 (m, 6H), 5.67 (t, J ) 7.4 Hz,
1H), 4.06 (t, J ) 2.6 Hz, 1H), 3.58 (t, J ) 7.3 Hz, 2H), 3.51 (d,
J ) 7.4 Hz, 2H), 2.61-2.59 (m, 1H), 2.52-2.45 (m, 1H), 2.25
(q, J ) 7.3 Hz, 2H), 2.01-1.98 (m, 1H), 1.89-1.80 (m, 1H),
1.78-1.72 (m, 3H), 1.66-1.57 (m, 1H), 1.54 (s, 3H), 1.36 (s,
3H), 1.33-1.06 (m, 4H), 1.01 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H);
13C NMR (CDCl3, 125 MHz) δ 144.1, 135.6 (×4), 134.2 (×2),
129.4 (×3), 127.5 (×4), 116.6, 107.1, 84.6, 78.1, 66.7, 63.2, 42.5,
33.4, 31.0, 27.0 (×3), 26.9 (×4), 26.4, 26.0, 24.3, 22.9, 19.3, 18.3,
1-[10-(3-Bromopropylidene)-2,2-dimethyloctahydro-
naphtho[1,8a-d][1,3]dioxol-6-yl]-ethanone (30). To a solu-
tion of 28 (9 mg, 0.03 mmol) in toluene (1 mL) was added
MgBr2, and the mixture was stirred at room temperature for
15 h. The reaction was quenched by adding water. The aqueous
layer was extracted 3 times with diethyl ether (3 × 10 mL).
The organic layer was dried over anhydrous MgSO4 and
filtered, and the solvent was evaporated. The crude product
was purified by flash silica column chromatography (10%
EtOAc/hexanes) to afford 11 mg of 30 (99% yield) as a colorless
oil: 1H NMR (500 MHz, C6D6) δ 6.21 (t, J ) 8.7 Hz, 1H), 3.77
(t, J ) 2.7 Hz, 1H), 3.75-3.67 (m, 2H), 3.18-3.14 (m, 1H),
2.31-2.27 (m, 1H), 2.18 (dt, J ) 14.3, 9.9 Hz, 1H), 2.01-1.97
(m, 1H), 1.93-1.88 (m, 1H), 1.74 (s, 3H), 1.73-1.66 (m, 1H),
1.47 (s, 3H), 1.46-1.41 (m, 2H), 1.29 (s, 3H), 1.28-1.23 (m,
1H), 1.16-1.06 (m, 3H); 13C NMR (125 MHz, C6D6) δ 208.8,
148.9, 117.4, 107.4, 84.2, 77.0, 45.0, 43.6, 27.4, 27.4, 26.9, 26.3,
8848 J. Org. Chem., Vol. 70, No. 22, 2005

Studies Toward the Total Synthesis of Vinigrol
17.4, -5.2, -5.3; IR (neat) 2931, 2857, 1106 cm-1; EI HRMS
calcd for C35H51O4Si2 (M+ - tBu) 591.33259, obsd 591.35122.
25.0, 23.2, 19.3; IR (neat) 2930, 2859, 1247, 1036 cm-1; EI
HRMS calcd for C19H30O2 (M+) 290.22458, obsd 290.22256.
6-(4-Methoxybenzyloxy)-hex-2-enal (53a). A solution of
oxalyl chloride (0.63 mL, 7.2 mmol) in dichloromethane (50
mL) was cooled to -78 °C. Methylsulfoxide (1.02 mL, 14.4
mmol) was added dropwise, resulting in the formation of a lot
of gas. The solution was stirred for 20 min. 6-(4-Methoxyben-
zyloxy)-trans-hex-2-en-1-ol (1.33 g, 5.99 mmol) was dissolved
in dichloromethane (10 mL), cannulated into the Swern
reagent solution, and stirred for 90 min at -78 °C. Triethyl-
amine (4.2 mL, 30 mmol) was added, and the reaction was
warmed to room temperature while being stirred for 20 min.
Saturated NH4Cl(aq) was added. The aqueous layer was ex-
tracted 3 times with dichloromethane (3 × 100 mL). The
organic layer was dried over anhydrous MgSO4 and filtered,
and the solvent was evaporated. The crude product was
purified by flash silica column chromatography (20% EtOAc/
hexanes) to afford 968 mg of 53a (93% yield) as a light yellow
oil: 1H NMR (300 MHz, CDCl3) δ 9.46 (d, J ) 8 Hz, 1H), 7.23
(d, J ) 8 Hz, 2H), 6.86 (d, J ) 9 Hz, 2H), 6.80 (t, J ) 7 Hz,
1H), 6.08 (ddd, J ) 16, 8, 1 Hz, 1H), 4.41 (s, 2H), 3.78 (s, 3H),
3.46 (t, J ) 6 Hz, 2H), 2.42 (q, J ) 8 Hz, 2H), 1.78 (quint, J )
6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 194.1, 159.2, 158.3,
133.1, 130.3, 129.3 (×2), 113.8 (×2), 72.7, 68.7, 55.2, 29.6, 27.9;
IR (neat) 2937, 2857, 2838, 2736, 1688, 1612, 1513, 1248, 1100
cm-1; EI HRMS calcd for C14H18O3 (M+) 234.12560, obsd
234.12515.
5-Hydroxy-10-(4-methoxybenzyloxy)-3-oxo-dec-6-eno-
ic Acid Methyl Ester (54a). Methyl acetoacetate (1.01 mL,
9.36 mmol) was dissolved in THF (40 mL) and cooled to 0 °C.
Sodium hydride 60% in mineral oil (0.56 g, 14.04 mmol) was
added and stirred for 20 min. n-Butyllithium (2.31 M in
hexane, 4.5 mL, 10.3 mmol) was added and stirred for 20 min
and then cooled to -78 °C. Alcohol 53a (1.03 g, 4.68 mmol)
was dissolved in THF (7 mL) and cannulated into the anion
solution, and the resultant mixture was stirred at -78 °C for
20 min. Saturated NH4Cl(aq) was added. The aqueous layer was
extracted 3 times with diethyl ether (3 × 100 mL). The organic
layer was dried over anhydrous MgSO4 and filtered, and the
solvent was evaporated. The crude product was purified by
flash silica column chromatography (30% EtOAc/hexanes) to
afford 1.09 g of 54a (67% yield) as a light yellow oil: 1H NMR
(300 MHz, CDCl3) δ 7.22 (d, J ) 8 Hz, 2H), 6.85 (d, J ) 8 Hz,
2H), 5.67 (dt, J ) 15, 7 Hz, 1H), 5.43 (dd, J ) 15, 6 Hz, 1H),
4.54-4.47 (m, 1H), 4.39 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.47
(s, 2H), 3.40 (t, J ) 2 Hz, 2H), 2.70-2.66 (m, 3H), 2.08 (q, J )
7 Hz, 2H), 1.64 (quint, J ) 2 Hz 2H); 13C NMR (75 MHz,
CDCl3) δ 202.7, 167.3, 159.0, 131.9 (×2), 130.8 (×2), 130.5,
129.2, 113.7, 72.5, 69.1, 68.3, 55.2, 52.4, 51.2, 49.6, 29.0, 28.7;
IR (neat) 3408, 2940, 2853, 1745, 1710, 1513, 1247 cm-1; EI
HRMS calcd for C19H24O5 (M+ - H2O) 332.16238, obsd
332.1583.
10-[3-(tert-Butyldimethylsilanyloxy)-propyl]-6-(tert-
butyldiphenylsilanyloxymethyl)-2,2-dimethyloctahydro-
naphtho[1,8a-d][1,3]dioxole (38). In a glovebox, a solution
of RuCl2(H2IMes)(py)2(CHPh) (0.001 g, 0.0014 mmol) in metha-
nol (1 mL) and benzene (1 mL) was added to the olefin 37
(0.014 g, 0.022 mmol). Triethylamine (0.0091 mL) was added,
and the solution was pressurized to 1350 psi with H2. The
reaction mixture in the autoclave was stirred and heated for
5 days at 80 °C. The reaction was concentrated. The crude
product was purified by flash silica column chromatography
(10% EtOAc/hexanes) to afford 0.013 g of 38 (93% yield) as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.66-7.62 (m, 4H),
7.42-7.31 (m, 6H), 4.20-4.19 (m, 1H), 3.61 (d, J ) 7 Hz, 2H),
3.50 (d, J ) 7 Hz, 2H), 2.69-2.60 (m, 1H), 2.03-1.92 (m, 2H),
1.81-1.58 (m, 8H), 1.56 (s, 3H), 1.50-1.45 (m, 2H), 1.43 (s,
3H), 1.23 (s, 2H), 1.18-1.06 (m, 2H), 1.01 (s, 9H), 0.87 (s, 9H),
0.02 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 135.6 (×2), 134.1
(×2), 129.5 (×2), 127.6 (×4), 106.6, 85.8, 73.5, 66.4, 63.7, 46.4,
41.9, 33.2, 31.7, 28.4, 28.2, 28.0, 26.8 (×3), 26.0 (×3), 25.6, 25.3,
24.4, 22.9, 19.3, 18.3, 17.6, -5.3 (×2); IR (neat) 2929, 2857,
1110 cm-1; EI HRMS calcd for C35H51O4Si2 (M+) 650.41866,
obsd 650.41375.
10-[3-(tert-Butyldimethylsilanyloxy)-propyl]-6-(tert-
butyldiphenylsilanyloxymethyl)-2,2-dimethyloctahydro-
naphtho[1,8a-d][1,3]dioxole (39). 1H NMR (500 MHz, CDCl3)
δ 7.64-7.62 (m, 4H), 7.44-7.32 (m, 6H), 4.08-4.05 (m, 1H),
3.70-3.55 (m, 2H), 3.55-3.50 (m, 2H), 2.30-2.20 (m, 1H),
2.05-1.90 (m, 2H), 1.88-1.60 (m, 10H), 1.55-1.20 (m, 11H),
1.02 (s, 9H).
3-(6-Hydroxymethyl-2,2-dimethyloctahydronaphtho-
[1,8a-d][1,3]dioxol-10-yl)-propan-1-ol (44). To a solution of
protected alcohols 38 (130 mg, 0.2 mmol) in THF (2 mL) was
added TBAF (1 mL of a 1 M solution in THF, 0.8 mmol). The
reaction was stirred at room temperature for 72 h. The solution
was concentrated and purified by flash silica column chroma-
tography (5% MeOH/EtOAc) to afford 60 mg of 44 (100% yield)
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 4.21-4.08 (m,
1H), 3.69-3.61 (m, 2H), 3.50 (d, J ) 7.5 Hz, 2H), 2.54-2.47
(m, 1H), 2.34-2.21 (m, 1H), 2.05-1.95 (m, 2H), 1.89-1.62 (m,
7H), 1.53 (s, 3H), 1.52-1.43 (m, 3H), 1.43 (s, 3H), 1.30-1.07
(m, 5H); 13C NMR (125 MHz, CDCl3) δ 106.7, 85.8, 73.4, 65.9,
63.1, 46.1, 41.9, 33.5, 31.3, 28.4 (×2), 28.1, 25.4, 25.2, 24.5,
22.9, 17.8; IR (neat) 3377, 2933, 2866, 1033 cm-1; EI HRMS
calcd for C17H30O4 (M+) 298.21441, obsd 298.21567.
10-But-3-enyl-2,2-dimethyl-6-vinyloctahydronaphtho-
[1,8a-d][1,3]dioxole (46). A catalytic amount of TPAP (1
crystal) and NMO (14 mg, 0.12 mmol) was added to a solution
of diol 44 in acetonitrile (1 mL) over 4 Å molecular sieves (50
mg). The reaction was stirred for 20 min. The mixture was
filtered through a silica gel pad (5% methanol/95% ethyl
acetate). The solvent was evaporated, and the crude dialdehyde
45 was used immediately to avoid decomposition. Methyl-
triphenylphosphonium iodide (0.057 g, 0.14 mmol) was dis-
solved in THF (1 mL) and cooled to 0 °C. KHMDS (10.43 M in
toluene, 0.325 mL, 0.14 mmol) was added, and the solution
turned yellow. Dialdehyde 45 (0.010 g, 0.03 mmol) in THF (1
mL) was cannulated into the ylide solution. The reaction was
stirred at 0 °C for 30 min. The reaction was quenched by
adding saturated NH4Cl(aq). The aqueous layer was extracted
3 times with diethyl ether (3 × 10 mL). The organic layer was
dried over anhydrous MgSO4 and filtered, and the solvent was
evaporated. The crude product was purified by flash silica
column chromatography (10% EtOAc/hexanes) to afford 7 mg
of 46 (72% yield) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 5.88-5.75 (m, 2H), 5.03-4.92 (m, 4H), 4.19 (s, 1H), 3.01-
2.99 (m, 1H), 2.25-2.10 (m, 1H), 2.04-1.89 (m, 3H), 1.88-
10-(tert-Butyldiphenylsilanyloxy)-5-hydroxy-3-oxo-dec-
6-enoic Acid Methyl Ester (54b). Methyl acetoacetate (14.5
mL, 136.5 mmol) was dissolved in THF (200 mL) and cooled
to 0 °C. Sodium hydride 60% in mineral oil (8.2 g, 204.6 mmol)
was added and stirred for 20 min. n-Butyllithium (2.5 M, 60
mL, 150 mmol) was added and stirred for 20 min and then
cooled to -78 °C. 6-(tert-Butyldiphenylsilanyloxy)-hex-2-enal
(24 g, 68.2 mmol) was dissolved in THF (30 mL) and cannu-
lated into the anion solution. The resulting mixture was stirred
at -78 °C for 20 min. Saturated NH4Cl(aq) was added. The
aqueous layer was extracted 3 times with diethyl ether (3 ×
200 mL). The organic layer was dried over anhydrous MgSO4
and filtered, and the solvent was evaporated. The crude
product was purified by flash silica column chromatography
(20% EtOAc/hexanes) to afford 20.7 g of 54b (64% yield) as a
light yellow oil: 1H NMR (500 MHz, acetone-d6) δ 7.70 (dd,
J ) 8, 2 Hz, 4H), 7.48-7.42 (m, 6H), 5.70 (dt, J ) 15, 7 Hz,
1H), 5.53 (dd, J ) 15, 6 Hz, 1H), 4.52-4.50 (m, 1H), 3.95 (d,
J ) 4 Hz, 1H), 3.72 (t, J ) 6 Hz, 2H), 3.66 (s, 3H), 3.58 (s,
2H), 2.84-2.65 (m, 2H), 2.15 (q, J ) 7 Hz, 2H), 1.67 (quint,
1.65 (m, 6H), 1.53 (s, 3H), 1.42 (s, 3H), 1.37-1.23 (m, 6H); 13
C
NMR (125 MHz, CDCl3) δ 143.1, 138.8, 114.4, 113.3, 106.6,
85.9, 73.6, 46.6, 45.5, 35.0, 32.3, 29.7, 28.5, 28.4, 28.2, 28.0,
J. Org. Chem, Vol. 70, No. 22, 2005 8849

Morency and Barriault
J ) 7 Hz, 2H), 1.06 (s, 9H); 13C NMR (125 MHz, acetone-d6) δ
202.5, 168.4, 136.3 (×4), 134.8 (×2), 133.9, 130.8, 130.6 (×2),
128.7 (×4), 69.1, 63.9, 52.2, 51.2, 50.3, 32.9, 29.1, 27.3 (×3),
EI HRMS calcd for C23H27O5Si (M+ - tBu) 411.16278, obsd
411.16135.
(1.1 mL, 7.63 mmol) and (dimethylamino)pyridine (0.014 g,
0.11 mmol) were added, followed by triethylsilyl chloride (0.064
mL, 3.81 mmol). The reaction was stirred for 30 min. Saturated
NH4Cl(aq) was added. The aqueous layer was extracted 3 times
with diethyl ether (3 × 50 mL). The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was
evaporated. The crude product was purified by flash silica
column chromatography (15% EtOAc/hexanes) to afford 442
mg of 56a (80% yield) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.26-7.21 (m, 2H), 6.88-6.83 (m, 2H), 5.75 (dt, J )
15, 6 Hz, 1H), 5.52-5.44 (m, 1H), 4.60-4.53 (m, 1H), 4.40 (s,
2H), 4.16-4.07 (m, 1H), 3.78 (s, 3H), 3.42 (t, J ) 6 Hz, 2H),
2.80 (ddd, J ) 17, 6, 2 Hz, 1H), 2.40 (dd, J ) 17, 8 Hz, 1H),
2.16-2.07 (m, 3H), 1.71-1.62 (m, 3H), 0.93 (t, J ) 8 Hz, 9H),
0.50 (q, J ) 8 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 170.3,
159.1, 134.4, 130.5, 129.2 (×2), 127.8, 113.7 (×2), 77.7, 72.5,
69.1, 64.3, 55.3, 40.3, 39.1, 28.8, 28.7, 6.7 (×3), 4.7 (×3); IR
(neat) 2954, 2876, 1741, 1513, 1247, 1096 cm-1; EI HRMS calcd
for C22H33O5Si (M+ - Et) 405.20973, obsd 405.20812.
2-[5-(4-Methoxybenzyloxy)-pent-1-enyl]-6-vinyl-3,4-di-
hydro-2H-pyran-4-ol (57a). The lactone 56a (0.745 g, 1.72
mmol) was dissolved in THF (17 mL) and cooled to -78 °C.
Vinylmagnesium bromide, 0.9 M in THF, (5.72 mL, 5.15 mmol)
was added, and the reaction was stirred for 30 min. The
reaction was quenched by adding saturated NH4Cl(aq). The
aqueous layer was extracted 3 times with diethyl ether (3 ×
50 mL). The organic layer was dried over anhydrous MgSO4
and filtered, and the solvent was evaporated. The crude
product was used directly to avoid decomposition. The lactol
intermediate was dissolved in dichloromethane (17 mL) and
cooled to 0 °C. 2,6-(Dimethylamino)pyridine (0.63 g, 5.16 mmol)
was added, followed by thionyl chloride (0.125 mL, 1.72 mmol),
and the reaction was stirred for 30 min. The reaction was
quenched by adding NaHCO3sat. The aqueous layer was
extracted 3 times with dichloromethane (3 × 50 mL). The
organic layer was dried over anhydrous MgSO4 and filtered,
and the solvent was evaporated. The crude product was used
directly to avoid decomposition. The diene was dissolved in
THF (17 mL), and tetrabutylammonium fluoride 1 M in THF
(1.9 mL, 1.89 mmol) was added. The reaction turned dark
brown, and the solvent was evaporated after 30 min. The crude
product was purified by flash silica column chromatography
(50% EtOAc/hexanes) to afford 392 mg of 57a (69% yield) as a
colorless oil: 1H NMR (500 MHz, acetone-d6) δ 7.26 (d, J ) 9
Hz, 2H), 6.89 (d, J ) 9 Hz, 2H), 6.08 (dd, J ) 17, 11 Hz, 1H),
5.84-5.78 (m, 1H), 5.61 (ddt, J ) 15, 6, 1 Hz, 1H), 5.46 (dd,
J ) 17, 2 Hz, 1H), 5.03 (dd, J ) 11, 2 Hz, 1H), 4.84 (s, 1H),
4.48 (m, 1H), 4.41-4.38 (m, 1H), 4.41 (s, 2H), 3.78 (s, 3H), 3.45
(t, J ) 6 Hz, 2H), 2.12-2.10 (m, 2H), 2.11 (quint, J ) 4 Hz,
2H), 1.67 (quint, J ) 6 Hz, 2H), 1.61-1.53 (m, 1H); 13C NMR
(125 MHz, acetone-d6) δ 160.6, 152.0, 134.0, 133.2 (×2), 132.5,
131.5, 130.4 (×2), 114.9, 114.3, 109.4, 76.7, 73.4, 70.2, 64.2,
56.0, 39.6, 30.5, 30.1; IR (neat) 3420, 2941, 2857, 1614, 1599,
1515 cm-1; EI HRMS indeterminable.
19.8; IR (neat) 3448, 2932, 2857, 1748, 1716, 1428, 1111 cm-1
;
5-Hydroxy-10-(4-methoxybenzyloxy)-3-oxo-dec-6-eno-
ic Acid Methyl Ester (55a). Acetonitrile (13 mL) and acetic
acid (13 mL) were mixed at 0 °C. Tetramethylammonium
borohydride (1.1 g, 12.5 mmol) was added and stirred for 20
min. The mixture was frozen in a bath at -78 °C, and a
solution of ketone 54a (1.09 g, 3.1 mmol) in acetonitrile (5 mL)
was cannulated into the flask. The reaction was kept in the
freezer for 15 h at -25 °C. The reaction was quenched by
adding sodium potassium tartrate 0.5 M (40 mL) and warming
to room temperature. The organic layer was washed with
NaHCO3sat. The aqueous layer was extracted 3 times with
dichloromethane (3 × 60 mL). The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evapo-
rated. The crude product was dissolved in dichloromethane
(26 mL) and treated directly with trifluoroacitic acid (0.047
mL, 0.63 mmol). The reaction was stirred for 15 h at room
temperature. The reaction was stopped by adding Na2CO3 until
a neutral pH was obtained. The reaction was filtered and
concentrated. The crude product was purified by flash silica
column chromatography (70% EtOAc) to afford 442 mg (40%)
of starting material and 407 mg of 55a (40% yield) as a light
yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.25-7.22 (m, 2H),
6.85 (d, J ) 9 Hz, 2H), 5.75 (dt, J ) 15, 7 Hz, 1H), 5.46 (dd,
J ) 15, 7 Hz, 1H), 4.61-4.54 (m, 1H), 4.40 (s, 2H), 4.25-4.20
(m, 1H), 3.78 (s, 3H), 3.41 (t, J ) 6 Hz, 2H), 2.87 (ddd, J ) 17,
6, 1 Hz, 1H), 2.42 (dd, J ) 17, 8 Hz, 1H), 2.27-2.09 (m, 4H),
1.71-1.55 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 170.2, 159.1,
134.5, 130.5, 129.3 (×2), 127.6, 113.8 (×2), 77.6, 72.5, 69.0,
63.8, 55.3, 39.4, 38.3, 28.7 (×2); IR (neat) 3427, 2933, 2860,
1732, 1512, 1245 cm-1; EI HRMS calcd for C14H24O5 (M+)
320.16238, obsd 320.16072.
6-[5-(tert-Butyldiphenylsilanyloxy)-pent-1-enyl]-4-hy-
droxytetrahydropyran-2-one (55b). Acetonitrile (17 mL)
and acetic acid (17 mL) were mixed at 0 °C. Tetramethylam-
monium borohydride (1.7 g, 19.3 mmol) was added and stirred
for 20 min. The mixture was frozen in a bath at -78 °C, and
a solution of ketone 54b (2.26 g, 4.82 mmol) in acetonitrile (5
mL) was cannulated into the flask. The reaction was kept in
the freezer for 15 h at -25 °C. The reaction was quenched by
adding sodium potassium tartrate 0.5 M (60 mL) and warmed
to room temperature. The organic layer was washed with
NaHCO3sat. The aqueous layer was extracted 3 times with
dichloromethane (3 × 100 mL). The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was
evaporated. The crude product was dissolved in dichlo-
romethane (26 mL) and treated directly with trifluoroacetic
acid (0.065 mL, 0.84 mmol). The reaction was stirred for 15 h
at room temperature. The reaction was stopped by adding Na2-
CO3 until a neutral pH was obtained. The reaction was filtered
and concentrated. The crude product was purified by flash
silica column chromatography (25% EtOAc/hexanes to 35%
EtOAc/hexanes) to afford 767 mg (34%) of starting material
2-[5-(tert-Butyldiphenylsilanyloxy)-pent-1-enyl]-6-vinyl-
3,4-dihydro-2H-pyran-4-ol (57b). The lactone 55b (2.04 g,
4.65 mmol) was dissolved in dichloromethane (47 mL). Tri-
ethylamine (3.9 mL, 27.9 mmol) and (dimethylamino)pyridine
(0.051 g, 0.42 mmol) were added, followed by triethylsilyl
chloride (2.3 mL, 14 mmol). The reaction was stirred for 30
min. Saturated NH4Cl(aq) was added. The aqueous layer was
extracted 3 times with dichloromethane (3 × 50 mL). The
organic layer was dried over anhydrous MgSO4 and filtered,
and the solvent was evaporated. The crude product was
purified by flash silica column chromatography (10% EtOAc/
hexanes) to afford a colorless oil that dissolved in THF (41
mL) and cooled to -78 °C. Vinylmagnesium bromide, 0.9 M
in THF (13.6 mL, 12.2 mmol), was added, and the reaction
was stirred for 30 min. The reaction was quenched by adding
saturated NH4Cl(aq). The aqueous layer was extracted 3 times
with diethyl ether (3 × 50 mL). The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was
1
and 759 mg of 55b (36% yield) as a yellow oil: H NMR (500
MHz, CDCl3) δ 7.66-7.64 (m, 4H), 7.40-7.34 (m, 6H), 5.75
(dt, J ) 15, 6 Hz, 1H), 5.47 (dd, J ) 15, 7 Hz, 1H), 4.58-4.54
(m, 1H), 4.19 (br s, 1H), 3.84 (s, 1H), 3.65 (t, J ) 6 Hz, 2H),
2.84 (dd, J ) 17, 5 Hz, 1H), 2.43 (dd, J ) 17, 8 Hz, 1H), 2.22-
2.13 (m, 3H), 1.63-1.59 (m, 3H), 1.04 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 171.2, 135.4 (×4), 134.6, 133.7 (×2), 129.5,
127.6 (×4), 127.4, 77.9, 63.3, 62.9, 39.3, 38.0, 31.5, 28.3, 26.8
(×3), 19.1; IR (neat) 3420, 3071, 2931, 2858, 1733, 1428, 1242,
969 cm-1; EI HRMS calcd for C10H14O3 (M+ - tBDPSOH)
182.0943, obsd 182.0506.
6-[5-(4-Methoxybenzyloxy)-pent-1-enyl]-4-triethylsi-
lanyloxytetrahydropyran-2-one (56a). Alcohol 55a (0.407
g, 1.27 mmol) was dissolved in THF (13 mL). Triethylamine
8850 J. Org. Chem., Vol. 70, No. 22, 2005

Studies Toward the Total Synthesis of Vinigrol
evaporated. The crude product was used directly to avoid
decomposition. The lactol intermediate was dissolved in dichlo-
romethane (41 mL) and cooled to 0 °C. (Dimethylamino)-
pyridine (1.5 g, 12.3 mmol) was added, followed by thionyl
chloride (0.3 mL, 4.1 mmol), and the reaction was stirred for
30 min. The reaction was quenched by adding NaHCO3sat. The
aqueous layer was extracted 3 times with dichloromethane
(3 × 50 mL). The organic layer was dried over anhydrous
MgSO4 and filtered, and the solvent was evaporated. The crude
product was used directly to avoid decomposition. The diene
was dissolved in THF (40 mL) and cooled to -78 °C, and
tetrabutylammonium fluoride, 1 M in THF (4 mL, 4 mmol),
was added. The reaction turned dark brown, and the solvent
was evaporated after 30 min. The crude product was purified
by flash silica column chromatography (30% EtOAc/hexanes)
to afford 777 mg of 57b (37% yield) as a colorless oil: 1H NMR
(300 MHz, acetone-d6) δ 7.80-7.69 (m, 4H), 7.49-7.34 (m, 6H),
6.09 (dd, J ) 17, 11 Hz, 1H), 5.85-5.76 (m, 1H), 5.63 (ddd,
J ) 15, 6, 1 Hz, 1H), 5.47 (dd, J ) 17, 2 Hz, 1H), 5.03 (dd,
J ) 11, 2 Hz, 1H), 4.84 (s, 1H), 4.52-4.42 (m, 1H), 4.38 (dd,
J ) 6, 5 Hz, 1H), 3.87 (d, J ) 6 Hz, 1H), 3.74 (t, J ) 6 Hz,
2H), 2.22 (q, J ) 7 Hz, 1H), 2.11 (ddt, J ) 13, 6, 2 Hz, 1H),
2.06-2.04 (m, 1H), 1.70 (quint, J ) 6 Hz, 2H), 1.63-1.52 (m,
1H), 1.05 (s, 9H); 13C NMR (75 MHz, acetone-d6) δ 152.0, 136.8
(×4), 135.1 (×2), 133.9, 133.1, 131.4, 131.1 (×2), 129.1 (×4),
114.3, 109.4, 76.6, 64.3, 64.2, 39.6, 33.1, 29.6, 27.7 (×3), 20.2;
IR (neat) 3345, 2955, 2930, 2857, 1111 cm-1; EI HRMS calcd
for C28H34O2 (M+ - H2O) 430.23281, obsd 430.23637.
2-Benzyl-9-hydroxy-7-[5-(4-methoxybenzyloxy)-pent-1-
enyl]-3a,7,8,9,9a,9b-hexahydro-4H-pyrano[3,2-e]isoindole-
1,3-dione (58a). To a suspension of MgBr2‚Et2O (0.568 g, 1.1
mmol) in dichloromethane (4 mL) was added triethylamine
(0.46 mL, 3.3 mmol), and the mixture was stirred for 20 min
at room temperature. The alcohol 57a (0.361 g, 1.1 mmol) and
benzylmaleimide (2.1 g, 11 mmol) in dichloromethane (4 mL)
were cannulated into the magnesium solution and stirred for
30 min. The reaction was quenched by adding saturated NH4-
Cl(aq). The aqueous layer was extracted 3 times with dichlo-
romethane (3 × 30 mL). The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evapo-
rated. The crude product was purified by flash silica column
chromatography (40% EtOAc/hexanes) to afford 383 mg of 58a
(67% yield) as a yellow oil: 1H NMR (500 MHz, acetone-d6) δ
7.36-7.23 (m, 7H), 6.90 (d, J ) 6 Hz, 2H), 5.70 (dt, J ) 15, 7
Hz, 1H), 5.37 (dd, J ) 15, 6 Hz, 1H), 4.88-4.85 (m, 1H), 4.67
(d, JAB ) 15 Hz, 1H), 4.63 (d, JAB ) 15 Hz, 1H), 4.42 (s, 2H),
4.36-4.29 (m, 1H), 4.25-4.20 (m, 1H), 3.79 (s, 3H), 3.75 (dd,
J ) 9, 6 Hz, 1H), 3.45 (t, J ) 6 Hz, 2H), 3.31-3.27 (m, 1H),
3.12-3.09 (m, 1H), 2.61 (ddd, J ) 15, 8, 2 Hz, 1H), 2.21-2.16
(m, 2H), 2.12 (q, J ) 7 Hz, 2H), 1.94-1.88 (m, 1H), 1.66 (quint,
J ) 7 Hz, 2H), 1.63-1.57 (m, 1H); 13C NMR (125 MHz, acetone-
d6) δ 181.7, 180.1, 160.0, 154.2, 136.7, 132.4, 131.9, 131.0 (×2),
129.8 (×2), 129.2 (×2), 128.0 (×3), 114.3, 97.0, 76.4, 72.7, 69.6,
66.1, 66.0, 55.4, 42.7, 42.5, 42.3, 39.2, 38.6, 29.4, 23.9; IR (neat)
3665, 2924, 2853, 1688 cm-1; EI HRMS calcd for C31H33NO5
(M+ - H2O) 499.23587, obsd 499.23767.
7.42 (m, 6H), 7.29-7.22 (m, 5H), 5.68 (dtd, 15, 7, 1 Hz, 1H),
5.36 (ddq, 16, 7, 1 Hz, 1H), 4.88-4.85 (m, 1H), 4.66 (d, JAB
)
15 Hz, 1H), 4.62 (d, JAB ) 15 Hz, 1H), 4.35-4.28 (m, 1H), 4.21
(dd, J ) 11, 7 Hz, 1H), 4.19 (d, J ) 11 Hz, 1H), 3.76-3.73 (m,
1H), 3.73 (t, J ) 6 Hz, 2H), 3.30-3.27 (m, 1H), 3.10 (tq, 7, 2
Hz, 1H), 2.61 (ddd, J ) 15, 8, 2 Hz, 1H), 2.17 (q, J ) 7 Hz,
2H), 1.86 (ddd, J ) 13, 5, 2 Hz, 1H), 1.68 (quint, J ) 7 Hz,
2H), 1.61 (q, J ) 12 Hz, 2H), 1.06 (s, 9H); 13C NMR (125 MHz,
acetone-d6) δ 181.2, 179.5, 153.7, 136.2, 135.6 (×4), 134.0 (×2),
131.9, 130.4, 129.9 (×2), 128.6 (×2), 128.0 (×4), 127.5, 127.4
(×2), 96.4, 75.9, 65.6, 63.2, 42.2, 42.0, 41.8, 38.7, 38.1, 32.0,
28.4, 26.6 (×3), 23.3, 19.1; IR (neat) 3426, 2936, 2859, 1689,
1436, 1347, 1103 cm-1; EI HRMS calcd for C39H43NO4Si
(M+ - H2O) 617.29614, obsd 617.29546.
2-Benzyl-7-[5-(4-methoxybenzyloxy)-pent-1-enyl]-9-meth-
oxymethoxy-3a,7,8,9,9a,9b-hexahydro-4H-pyrano[3,2-e]-
isoindole-1,3-dione (58c). Alcohol 58a (0.02 g, 0.03 mmol)
was dissolved in dichloromethane (2 mL). Diisopropylethyl-
amine (0.052 mL, 0.3 mmol) was added, followed by MOMCl
(0.005 mL, 0.06 mmol). The reaction was heated to reflux for
5 h. The reaction was cooled to room temperature and
quenched by adding NaHCO3sat. The aqueous layer was
extracted 3 times with dichloromethane (3 × 15 mL). The
organic layer was dried over anhydrous MgSO4 and filtered,
and the solvent was evaporated. The crude product was
purified by flash column chromatography (30% EtOAc/hex-
anes) to afford 12 mg of 58c (71% yield) as a colorless oil: 1H
NMR (500 MHz, acetone-d6) δ 7.30-7.22 (m, 7H), 6.90 (d, J )
9 Hz, 2H), 5.71 (td, 15, 7 Hz, 1H), 5.46 (dd, J ) 15, 7 Hz, 1H),
4.84-4.82 (m, 1H), 4.66 (d, J ) 7 Hz, 1H), 4.60-4.59 (m, 3H),
4.41 (s, 2H), 4.33-4.28 (m, 2H), 3.78 (s, 3H), 3.68 (dd, J ) 9,
6 Hz, 1H), 3.44 (t, J ) 6 Hz, 2H), 3.33 (s, 3H), 3.18 (dt, J ) 8,
2 Hz, 1H), 3.04-3.01 (m, 1H), 2.52 (ddd, J ) 9, 7, 2 Hz, 1H),
2.31-2.23 (m, 2H), 2.12 (q, J ) 7 Hz, 2H), 2.04-2.00 (m, 1H),
1.65 (quint, J ) 6 Hz, 2H); 13C NMR (125 MHz, acetone-d6) δ
179.2, 177.4, 159.3, 153.2, 136.7, 131.7, 131.4, 130.5 (×2), 129.1
(×2), 128.4 (×2), 127.5 (×2), 127.2, 113.6, 96.2, 95.8, 75.7, 72.1,
71.8, 68.0, 54.9, 54.7, 41.7, 41.2, 41.1. 36.2, 35.1, 29.1, 28.7,
23.4; IR (neat) 2938, 2852, 1699, 1506 cm-1
.
2-Benzyl-7-[5-(4-methoxybenzyloxy)-pent-1-enyl]-9-tri-
methylsilanyloxy-3a,7,8,9,9a,9b-hexahydro-4H-pyrano-
[3,2-e]isoindole-1,3-dione (58d). Alcohol 58a (0.02 g, 0.04
mmol) was dissolved in dichloromethane (1 mL) and then
cooled to 0 °C. Lutidine (0.045 mL, 0.39 mmol) was added,
followed by trimethylsilyltriflate (0.014 mL, 0.77 mmol), and
the reaction was stirred for 30 min. The reaction was quenched
by adding NHCO3sat. The aqueous layer was extracted 3 times
with dichloromethane (3 × 10 mL). The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was
evaporated. The crude product was purified by flash column
chromatography (50% EtOAc/hexanes) to afford 24 mg of 58d
(quant yield) as a colorless oil: 1H NMR (500 MHz, acetone-
d6) δ 7.29-7.21 (m, 7H), 6.89 (d, J ) 9 Hz, 2H), 5.71 (dt, J )
15, 8 Hz, 1H), 5.43 (dd, J ) 15, 7 Hz, 1H), 4.78-4.76 (m, 1H),
4.61-4.55 (m, 3H), 4.40 (s, 2H), 4.32-4.29 (m, 1H), 3.78 (s,
3H), 3.69 (dd, J ) 9, 5 Hz, 1H), 3.44 (t, J ) 6 Hz, 2H), 3.16
(td, 9, 2 Hz, 1H), 2.90-2.87 (m, 1H), 2.48 (ddd, J ) 15, 7, 2
Hz, 1H), 2.36 (q, J ) 13 Hz, 1H), 2.26-2.22 (m, 1H), 2.11 (q,
J ) 8 Hz, 2H), 1.85-1.81 (m, 1H), 1.65 (quint, J ) 7 Hz, 2H),
0.16 (s, 9H); 13C NMR (125 MHz, acetone-d6) δ 180.1, 178.1,
160.2, 155.0, 137.5, 132.5, 132.0, 131.3, 130.0 (×2), 129.2 (×2),
128.3 (×2), 128.1, 114.5(×2), 96.3, 76.9, 72.9, 69.9, 67.5, 55.6,
42.5, 42.4, 42.2, 39.1, 38.5, 30.0, 25.1, 0.4 (×3); IR (neat) 2946,
2855, 1704, 1250, 1097 cm-1; EI HRMS calcd for C34H43NO6Si
(M+) 589.28597, obsd 589.28510.
2-Benzyl-7-[5-(tert-butyldiphenylsilanyloxy)-pent-1-
enyl]-9-hydroxy-3a,7,8,9,9a,9b-hexahydro-4H-pyrano[3,2-
e]isoindole-1,3-dione (58b). To a suspension of MgBr2‚Et2O
(0.041 g, 0.16 mmol) in dichloromethane (1 mL) was added
triethylamine (0.033 mL, 0.23 mmol), and the mixture was
stirred for 20 min at room temperature. The alcohol 57b (0.035
g, 0.08 mmol) and benzylmaleimide (0.150 g, 0.8 mmol) in
dichloromethane (1 mL) were cannulated into the magnesium
solution and stirred for 30 min. The reaction was done, so
quenched by adding saturated NH4Cl(aq). The aqueous layer
was extracted 3 times with dichloromethane (3 × 10 mL). The
organic layer was dried over anhydrous MgSO4 and filtered,
and the solvent was evaporated. The crude product was
purified by flash silica column chromatography (40% EtOAc/
hexanes) to afford 33 mg of 58b (64% yield) as a yellow oil: 1H
NMR (500 MHz, acetone-d6) δ 7.70 (dd, J ) 8, 2 Hz, 4H), 7.47-
2-Benzyl-7-[5-(tert-butyldiphenylsilanyloxy)-pent-1-
enyl]-9-triethylsilanyloxy-3a,7,8,9,9a,9b-hexahydro-4H-
pyrano[3,2-e]isoindole-1,3-dione (58f). Alcohol 58b (0.033
g, 0.05 mmol) was dissolved in THF (1 mL). Triethylamine
(0.042 mL, 0.3 mmol) and (dimethylamino)pyridine (0.001 g,
0.0045 mmol) were added, followed by triethylsilyl chloride
(0.026 mL, 0.155 mmol). The reaction was stirred for 30 min.
J. Org. Chem, Vol. 70, No. 22, 2005 8851

Morency and Barriault
Saturated NH4Cl(aq) was added. The aqueous layer was ex-
tracted 3 times with diethyl ether (3 × 10 mL). The organic
layer was dried over anhydrous MgSO4 and filtered, and the
solvent was evaporated. The crude product was purified by
flash column chromatography (10% EtOAc/hexanes) to afford
24 mg of 58f (64% yield) as a colorless oil: 1H NMR (500 MHz,
acetone-d6) δ 7.71 (dd, J ) 7, 2 Hz, 4H), 7.48-7.42 (m, 6H),
7.27-7.18 (m, 5H), 5.71 (dt, J ) 14, 6 Hz, 1H), 5.42 (dd, J )
15, 6 Hz, 1H), 4.76-4.73 (m, 1H), 4.61-4.53 (m, 3H), 4.28 (dd,
J ) 11, 6 Hz, 1H), 3.76-3.75 (m, 1H), 3.72 (t, J ) 6 Hz, 2H),
3.20-3.16 (m, 1H), 2.91-2.80 (m, 1H), 2.51 (ddd, J ) 15, 8, 1
Hz, 1H), 2.44 (q, J ) 12 Hz, 1H), 1.81-1.77 (m, 1H), 1.68
(quint, J ) 6 Hz, 2H), 1.05-1.00 (m, 3H), 1.05 (s, 9H), 1.00 (t,
J ) 8 Hz, 9H), 0.68 (q, J ) 8 Hz, 6H); 13C NMR (125 MHz,
acetone-d6) δ 180.6, 178.4, 155.7, 138.0, 136.8 (×4), 135.2 (×2),
133.0, 131.8, 131.1, 129.7 (×2), 129.2 (×2), 128.7 (×4), 128.5
(×2), 96.2, 77.4, 68.0, 64.4, 43.2, 43.0, 42.9, 39.8, 38.9, 33.2,
29.6, 27.8 (×3), 25.8, 20.3, 7.8 (×3), 6.1 (×3); IR (neat) 2954,
to afford 7 mg of starting material (21%) and 9 g of 59b (28%
yield) as a colorless oil: 1H NMR (500 MHz, C6D6) δ 7.88-
7.86 (m, 4H), 7.48 (d, J ) 7 Hz, 2H), 7.34 (s, 6H), 7.17 (t, J )
7 Hz, 2H), 7.10 (t, J ) 7 Hz, 1H), 6.01 (dd, J ) 15, 7 Hz, 1H),
5.61 (dt, J ) 15, 8 Hz, 1H), 5.42 (d, J ) 4 Hz, 1H), 4.50 (d,
JAB ) 14 Hz, 1H), 4.45 (d, JAB ) 14 Hz, 1H), 4.30 (d, J ) 4 Hz,
1H), 3.70 (t, J ) 6 Hz, 2H), 2.85 (d, J ) 8 Hz, 1H), 2.30-2.27
(m, 1H), 2.17-2.13 (m, 4H), 1.84-1.63 (m, 5H), 1.39-1.35 (m,
2H), 1.27 (s, 9H); 13C NMR (125 MHz, C6D6) δ 180.2, 177.8,
151.9, 136.0, 135.7 (×4), 134.0 (×2), 132.0, 129.6 (×2), 129.5,
128.8 (×2), 128.6 (×4), 127.9, 127.7, 98.9, 75.5, 64.2, 63.1, 43.3,
42.3, 39.7, 37.1, 32.0, 28.4, 26.8 (×3), 25.2, 23.7, 19.1; IR (neat)
3420, 2931, 2857, 1691, 1428, 1399, 1110 cm-1; EI HRMS calcd
for C39H43NO4Si (M+ - H2O) 617.29614, obsd 617.29653.
Procedure for the [3 + 3] Rearrangement of 58g with
Microwave Irradiation. A solution of alcohol 58g (0.033 g,
0.05 mmol) and triethylamine (0.05 mL) in toluene (14 mL)
was degassed with argon. The mixture was heated gradually
to 170 °C for 5 min and maintained at 170 °C for 30 min. The
reaction was cooled and concentrated. The crude product was
purified by flash silica column chromatography (20% EtOAc/
hexanes) to afford 21 mg of 60g (65%) as a light yellow oil
and 5 g of 59g (14% yield) as a colorless oil.
2-Benzyl-7-[5-(tert-butyldiphenylsilanyloxy)-pent-1-
enyl]-9-trimethylsilanyloxy-3a,5,7,8,9,9b-hexahydro-4H-
pyrano[3,2-e]isoindole-1,3-dione (59g). 1H NMR (500 MHz,
C6D6) δ 7.83-7.79 (m, 4H), 7.44 (d, J ) 7 Hz, 2H), 7.28-7.26
(m, 6H), 7.13 (t, J ) 7 Hz, 2H), 7.03 (t, J ) 7 Hz, 1H), 6.14
(dd, J ) 15,9 Hz, 1H), 5.47 (dt, J ) 14,6 Hz, 1H), 4.55 (d,
JAB ) 14 Hz, 1H), 4.49 (d, JAB ) 14 Hz, 1H), 4.48-4.47 (m,
1H), 4.14 (t, J ) 3 Hz, 1H), 3.65 (t, J ) 6 Hz, 2H), 2.81 (d,
J ) 8 Hz, 1H), 2.31-2.27 (m, 1H), 2.09 (q, J ) 7 Hz, 2H), 2.02-
1.95 (m, 1H), 1.82-1.75 (m, 4H), 1.68-1.61 (m, 3H), 1.20 (s,
9H), 0.35 (s, 9H); 13C NMR (125 MHz, C6D6) δ 177.2, 175.5,
151.5, 136.7, 135.6 (×4), 134.0 (×2), 131.3, 130.1, 129.6 (×2),
128.4 (×2), 128.3 (×2), 128.2, 127.9 (×4), 101.3, 75.0, 64.5, 64.1,
44.6, 41.7, 40.4, 36.9, 32.1, 28.5, 26.7 (×3), 24.9, 21.3, 19.1,
0.4 (×3); IR (neat) 2931, 2857, 1709, 1110 cm-1; EI HRMS calcd
for C38H44NO5Si (M+ - tBu) 650.27580, obsd 650.27368.
2874, 1705, 1112 cm-1
.
2-Benzyl-7-[5-(tert-butyldiphenylsilanyloxy)-pent-1-
enyl]-9-trimethylsilanyloxy-3a,7,8,9,9a,9b-hexahydro-4H-
pyrano[3,2-e]isoindole-1,3-dione (58g). Alcohol 58b (0.015
g, 0.03 mmol) was dissolved in dichloromethane (1 mL) and
then cooled at 0 °C. Lutidine (0.036 mL, 0.3 mmol) was added,
followed by trimethylsilyltriflate (0.011 mL, 0.06 mmol), and
the reaction was stirred for 30 min. The reaction was quenched
by adding NaHCO3sat. The aqueous layer was extracted 3 times
with dichloromethane (3 × 10 mL). The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was
evaporated. The crude product was purified by flash column
chromatography (15% EtOAc/hexanes) to afford 15 mg of 58g
(71% yield) as a colorless oil: 1H NMR (300 MHz, acetone-d6)
δ 7.72-7.69 (m, 4H), 7.46-7.41 (m, 6H), 7.29-7.20 (m, 5H),
5.70 (dt, J ) 15, 7 Hz, 1H), 5.44 (dd, J ) 15, 7 Hz, 1H), 4.79-
4.76 (m, 1H), 4.63-4.52 (m, 3H), 4.30 (dd, J ) 9, 7 Hz, 1H),
3.72 (t, J ) 6 Hz, 2H), 3.69-3.67 (m, 1H), 3.24-3.13 (m, 1H),
2.91-2.90 (m, 1H), 2.49 (ddd, J ) 15, 7, 2 Hz, 1H), 2.37 (q,
J ) 11 Hz, 1H), 2.28-2.14 (m, 4H), 1.81 (ddd, J ) 13, 5, 2 Hz,
1H), 1.68 (quint, J ) 7 Hz, 1H), 1.05 (s, 9H), 0.16 (s, 9H); 13C
NMR (75 MHz, acetone-d6) δ 180.1, 178.5, 155.4, 137.9, 136.8
(×4), 135.1 (×2), 132.9, 131.8, 131.0 (×2), 129.6 (×2), 129.1
(×4), 128.7 (×2), 128.4, 96.7, 77.3, 67.9, 64.3, 42.9, 42.8, 42.6,
39.5, 38.9, 33.1, 29.6, 27.7 (×3), 25.5, 20.2, 0.8 (×3); IR (neat)
4-Benzyl-9-[3-(tert-butyldiphenylsilanyloxy)-propyl]-
13-trimethylsilanyloxy-4-aza-tricyclo[6.5.1.02,6]tetradec-
10-ene-3,5,14-trione (60g). 1H NMR (500 MHz, C6D6) δ 7.88-
7.86 (m, 4H), 7.58 (d, J ) 7 Hz, 2H), 7.37-7.36 (m, 6H), 7.23
(t, J ) 8 Hz, 2H), 7.15 (t, J ) 7 Hz, 1H), 5.37-5.33 (m, 1H),
5.30-5.26 (m, 1H), 4.72 (d, J ) 4 Hz, 1H), 4.68 (d, J ) 4 Hz,
1H), 4.51-4.49 (m, 1H), 3.73-3.69 (m, 2H), 2.87-2.84 (m, 2H),
2.61-2.54 (m, 2H), 2.30-2.16 (m, 3H), 2.07 (dd, 18, 5 Hz, 1H),
1.69-1.53 (m, 3H), 1.41-1.31 (m, 1H), 1.26 (s, 9H), 1.01 (dt,
J ) 33, 7 Hz, 1H), 0.12 (s, 9H); 13C NMR (125 MHz, C6D6) δ
212.3, 178.2, 176.4, 137.1, 136.3 (×4), 134.7 (×2), 134.6, 130.3
(×2), 129.9 (×2), 129.2 (×2), 128.7, 128.4 (×4), 126.5, 67.0, 64.5,
54.1, 51.4, 43.0, 42.5, 42.1, 37.0, 35.1, 31.9, 31.8, 31.1, 27.5
(×3), 19.8, 0.5 (×3); IR (neat) 3070, 2933, 2858, 1706, 1395,
2936, 2857, 1704, 1397, 1111 cm-1
.
2-Benzyl-9-hydroxy-7-[5-(4-methoxybenzyloxy)-pent-1-
enyl]-3a,5,7,8,9,9b-hexahydro-4H-pyrano[3,2-e]isoindole-
1,3-dione (59a). A solution of alcohol 58a (0.014 g, 0.03 mmol)
and triethylamine (0.01 mL) in toluene (3 mL) was degassed
with argon. The mixture was heated to 160 °C for 15 h in a
wax bath. The reaction was cooled and concentrated. The crude
product was purified by flash silica column chromatography
(60% EtOAc/hexanes) to afford 9 g of 59a (64% yield) as a
colorless oil: 1H NMR (500 MHz, C6D6) δ 7.46 (d, J ) 7 Hz,
2H), 7.32 (d, J ) 9 Hz, 2H), 7.16 (t, J ) 7 Hz, 2H), 7.09 (d,
J ) 7 Hz, 1H), 6.90 (d, J ) 9 Hz, 2H), 6.01 (dd, J ) 15, 7 Hz,
1H), 5.62 (dd, J ) 15, 7 Hz, 1H), 5.39 (d, J ) 4 Hz, 1H), 4.50-
4.43 (m, 3H), 4.41 (s, 2H), 4.28-4.27 (m, 1H), 3.40 (s, 3H), 3.38
(t, J ) 6 Hz, 2H), 2.82 (d, J ) 9 Hz, 1H), 2.29-2.26 (m, 1H),
1110 cm-1
.
Procedure for the [3 + 3] Rearrangement of 58f in a
Sealed Tube. A solution of alcohol 58f (0.06 g, 0.08 mmol)
and triethylamine (0.03 mL) in toluene (14 mL) was degassed
with argon. The mixture was heated at 170 °C for 15 h in a
wax bath. The reaction was cooled and concentrated. The crude
product was purified by flash silica column chromatography
(15% EtOAc/hexanes) to afford 24 mg of 60f (40%) as a
colorless oil and 9 mg of 61f (15%) as white crystals. mp 158.5-
158.9 °C.
4-Benzyl-9-[3-(tert-butyldiphenylsilanyloxy)-propyl]-
13-triethylsilanyloxy-4-aza-tricyclo[6.5.1.02,6]tetradec-
10-ene-3,5,14-trione (60f). 1H NMR (500 MHz, C6D6) δ 7.82-
7.79 (m, 4H), 7.52 (d, J ) 7 Hz, 2H), 7.32-7.23 (m, 6H), 7.10
(t, J ) 8 Hz, 2H), 7.02 (t, J ) 7 Hz, 1H), 5.30-5.25 (m, 1H),
5.23-5.19 (m, 1H), 4.60 (s, 2H), 4.38-4.36 (m, 1H), 3.64 (t,
J ) 6 Hz, 2H), 2.88 (dd, J ) 11, 5 Hz, 1H), 2.67-2.61 (m, 1H),
2.58-2.52 (m, 1H), 2.51 (t, J ) 10 Hz, 1H), 2.33 (dt, J ) 17, 7
Hz, 1H), 2.10 (q, J ) 7 Hz, 1H), 2.02 (q, J ) 160-150 Hz, 3H),
2.17-2.11 (m, 3H), 1.83-1.66 (m, 6H), 1.36-1.31 (m, 1H); 13
C
NMR (125 MHz, C6D6) δ 180.5, 178.1, 159.6, 152.2, 136.3,
132.12, 131.5, 129.9 (×2), 129.3 (×2), 129.1 (×2), 128.9 (×2),
114.0, 101.1, 75.7, 72.7, 69.3, 64.4, 29.1, 25.5, 23.9; IR (neat)
3418, 2932, 2854, 1690 cm-1; EI HRMS calcd for C31H33NO5
(M+ - H2O) 499.23587, obsd 499.2335.
2-Benzyl-7-[5-(tert-butyldiphenylsilanyloxy)-pent-1-
enyl]-9-hydroxy-3a,5,7,8,9,9b-hexahydro-4H-pyrano[3,2-
e]isoindole-1,3-dione (59b). A solution of alcohol 58b (0.033
g, 0.05 mmol) and triethylamine (0.01 mL) in toluene (3 mL)
was degassed with argon. The mixture was heated to 160 °C
for 15 h in a wax bath. The reaction was cooled and concen-
trated. The crude product was purified by flash silica column
chromatography (20% EtOAc/hexanes to 30% EtOAc/hexanes)
8852 J. Org. Chem., Vol. 70, No. 22, 2005

Studies Toward the Total Synthesis of Vinigrol
1.60-1.50 (m, 1H), 1.40-1.35 (m, 1H), 1.23-1.15 (m, 2H), 1.21
(s, 9H), 1.02 (t, J ) 8 Hz, 9H), 0.65-0.62 (m, 6H); 13C NMR
(125 MHz, C6D6) δ 211.1, 178.2, 175.8, 136.9, 136.4 (×4), 135.6,
134.8 (×2), 130.3 (×2), 130.2, 129.2 (×2), 128.7 (×2), 128.5
(×4), 127.1, 69.1, 64.7, 54.6, 53.0, 43.1, 41.6, 40.0, 36.0, 35.6,
31.4, 31.1, 29.1, 27.5 (×3), 19.9, 7.7 (×3), 5.6 (×3); IR (neat)
14-trione (62). Compound 60g (0.039 g, 0.06 mmol) was
dissolved in THF (1 mL). HCl (2 N, 0.1 mL) was added and
stirred for 30 min at room temperature. The reaction was
quenched by adding NaHCO3sat. The aqueous layer was
extracted 3 times with diethyl ether (3 × 15 mL). The organic
layer was dried over anhydrous MgSO4 and filtered, and the
solvent was evaporated. The crude product was purified by
flash silica column chromatography (40% EtOAc/hexanes) to
afford 15 mg of (99% yield) as white crystals. mp 133.3-134.4
°C. 1H NMR (500 MHz, CDCl3) δ 7.66-7.62 (m, 4H), 7.42-
7.35 (m, 8H), 7.26-7.22 (m, 3H), 5.49 (q, J ) 9 Hz, 1H), 5.44
(t, J ) 13 Hz, 1H), 5.16 (t, J ) 9 Hz, 1H), 4.69 (d, J ) 14 Hz,
1H), 4.60 (d, J ) 14 Hz, 1H), 3.87-3.81 (m, 1H), 3.74 (dd, J )
12, 11 Hz, 1H), 3.56-3.51 (m, 3H), 3.05 (t, J ) 10 Hz, 1H),
2.80 (d, J ) 14 Hz, 1H), 2.20-2.18 (m, 1H), 2.15-1.95 (m, 3H),
1.52-1.48 (m, 1H), 1.27-1.16 (m, 2H), 1.12-1.08 (m, 1H), 1.04
(s, 9H), 0.94-0.85 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 209.4,
181.0, 178.5, 136.6, 135.4 (×4), 134.2, 133.8 (×2), 129.5 (×2),
129.4 (×2), 128.7 (×2), 128.4, 127.5 (×4), 126.7, 73.7, 63.5, 54.6,
54.0, 43.4, 39.5, 35.7, 34.3, 33.4, 29.4, 27.6, 26.7 (×3), 23.9,
2953, 2876, 1706, 1110, 1089 cm-1
.
1
Spiro 61f H NMR (500 MHz, C6D6): δ 7.80 (t, J ) 8 Hz,
4H), 7.54 (d, J ) 7 Hz, 2H), 7.34 (t, J ) 7 Hz, 2H), 7.32-7.27
(m, 4H), 7.11 (t, J ) 7 Hz, 2H), 7.04 (t, J ) 8 Hz, 1H), 5.36-
5.34 (m, 1H), 4.92-4.90 (m, 1H), 4.87 (dd, J ) 10, 8 Hz, 1H),
4.58 (d, JAB ) 13 Hz, 1H), 4.50 (d, JAB ) 13 Hz, 1H), 3.56-
3.49 (m, 2H), 3.44 (d, J ) 9 Hz, 1H), 2.93 (dd, J ) 16, 10 Hz,
1H), 2.33-2.24 (m, 3H), 2.15 (dt, J ) 17, 4 Hz, 1H), 1.96-
1.85 (m, 2H), 1.9 (s, 9H), 1.82-1.75 (m, 1H), 1.53-1.45 (m,
1H), 1.44-1.37 (m, 1H), 1.26-1.13 (m, 2H), 1.08 (t, J ) 8 Hz,
9H), 0.71 (sept, J ) 8 Hz, 6H); 13C NMR (125 MHz, C6D6) δ
208.1, 178.4, 176.6, 137.3, 136.4 (×4), 134.6 (×2), 130.3 (×2),
130.2 (×2), 129.1 (×2), 128.7 (×4), 128.4, 126.7, 126.6, 67.5,
63.9, 58.2, 42.9, 41.9, 40.6, 39.3, 38.4, 33.2, 30.9, 30.7,27.5 (×3),
19.9, 19.8, 7.7 (×3), 5.8 (×3); IR (neat) 2954, 1707, 1095 cm-1
;
19.0; IR (neat) 3430, 2920, 2857, 1685, 1428, 1402, 1110 cm-1
;
MS ESI calcd for C45H59NNaO5Si2 (M+ Na) 772.4, found 772.1.
Procedure for the [3 + 3] Rearrangement of 58g in a
Sealed Tube. A solution of alcohol 58g (0.03 g, 0.04 mmol)
and triethylamine (0.03 mL) in toluene (20 mL) was degassed
with argon. The mixture was heated to 170 °C for 15 h in a
wax bath. The reaction was cooled and concentrated. The crude
product was purified by flash silica column chromatography
(25% EtOAc/hexanes) to afford 50 mg of 60g (42% yield) as a
light yellow oil and 13 mg of 61g (30%) as a yellow oil.
Spiro (61g). 1H NMR (300 MHz, C6D6) δ 7.82-7.74 (m, 4H),
7.53 (d, J ) 7 Hz, 2H), 7.36-7.26 (m, 6H), 7.13-7.01 (m, 3H),
5.36-5.32 (m, 1H), 4.98-4.93 (m, 1H), 4.82 (dd, J ) 10, 7 Hz,
1H), 4.58 (d, J ) 14 Hz, 1H), 4.50 (d, J ) 14 Hz, 1H), 3.57-
3.47 (m, 2H), 3.38 (d, J ) 9 Hz, 1H), 2.87-2.78 (m, 1H), 2.42-
2.21 (m, 3H), 2.16-2.03 (m, 2H), 2.02-1.84 (m, 2H), 1.81-
EI HRMS calcd for C35H36NO5Si (M+ - tBu) 578.23628, obsd
578.23824.
Acknowledgment. We thank the Natural Science
and Engineering Research Council of Canada (NSERC),
Merck-Frosst Canada, Boehringer Ingelheim, Bristol
Myers Squibb, AstraZeneca, Canada Foundation for
Innovation, Ontario Innovation Trust, and the Univer-
sity of Ottawa for generous funding. L.M. thanks
NSERC for post-graduate scholarships (PGS-A and B).
We thank Mr. Tushar Tangri for the preparation of
some intermediates. We are grateful to Prof. Deryn Fogg
and Ureshini Dhamasena for their assistance in the
hydrogenation of 37.
1.67 (m, 1H), 1.62-1.34 (m, 3H), 1.19 (s, 9H), 0.21 (s, 9H); 13
C
NMR (75 MHz,C6D6) δ 208.3, 178.5, 176.7, 137.3, 136.4 (×4),
134.6 (×2), 130.3 (×4), 130.1 (×2), 129.2, 129.1 (×4), 126.9,
126.4, 67.9, 64.0, 58.0, 42.9, 42.0, 40.6, 40.6, 39.2, 38.4, 33.2,
30.8, 30.7, 27.5 (×3), 20.3, 19.8, 0.9 (×3); IR (neat) 2959, 2858,
1703, 1110 cm-1; MS EI calcd for C38H44NO5Si2 (M+ - tBu)
650.27580, found 650.27348.
1
Supporting Information Available: High-field H and
13C NMR spectra for compounds 18-24, 27, 28, 30, 35-38,
44-46, 53-62, and ORTEP views of 38 (benzoate derivative)
and 62. This material is available free of charge via the
Internet at http://pubs.acs.org.
4-Benzyl-9-[3-(tert-butyldiphenylsilanyloxy)-propyl]-
13-hydroxy-4-aza-tricyclo[6.5.1.02,6]tetradec-10-ene-3,5,-
JO051318I
J. Org. Chem, Vol. 70, No. 22, 2005 8853