Pd(II)-Catalyzed cyclogeneration of carbocations: Subsequent rearrangement and trapping under oxidative conditions

Article abstract of DOI:10.1016/j.tet.2004.06.023

A catalytic oxidative polycyclization reaction initiated by the carbocyclization of 1,5-dienes with Pd(II) is reported. Trapping of a putative carbocation with suitable functional groups (phenols, alkenes, alcohols, sulfonamide), or rearrangement protocol

Full text of DOI:10.1016/j.tet.2004.06.023

Tetrahedron 60 (2004) 7405–7410
Pd(II)-Catalyzed cyclogeneration of carbocations: subsequent
rearrangement and trapping under oxidative conditions
*
´
Jeong Hwan Koh, Cheryl Mascarenhas and Michel R. Gagne
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
Received 1 April 2004; revised 2 June 2004; accepted 4 June 2004
Dedicated to Professor Robert H. Grubbs in recognition of his receipt of the 2003 Tetrahedron Prize
Abstract—A catalytic oxidative polycyclization reaction initiated by the carbocyclization of 1,5-dienes with Pd(II) is reported. Trapping of a
putative carbocation with suitable functional groups (phenols, alkenes, alcohols, sulfonamide), or rearrangement protocols (Pinacol) yields
poly-cyclic products in good yields and in excellent diastereoselectivities. Turnover of the intermediate Pd–C bond is via b-H elimination.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
cation-olefin cascades of polyprenoids, for example, Eq. 2.4
The resulting C–Hg bond is stable and amenable to
numerous derivitization protocols.5,6
Carbocations are key intermediates in the biosynthesis of
the terpenoid natural products. These reactive intermediates
are normally generated by alkene or epoxide protonation, or
pyrophosphate elimination followed by trapping or
rearrangement under careful enzymatic guidance.1 Because
enantioselective proton delivery is considerably more
difficult to control in non-enzymatic situations, their
application to synthesis is significantly less developed.2
Notable exceptions, however, are Yamamoto’s chiral
Brønsted Lewis Acid (BLA) catalysts,3 which can deliver
Hþ with a preference for one enantioface of a polyene
reactant and, thereby, initiate enantioselective cation-olefin
polycyclization reactions, in analogy to steroid biosynthesis
(e.g., Eq. 1).
ð2Þ
Another electrophilic species that has shown significant
utility in the activation of alkenes towards hetero-nucleo-
philes is Pd(II).7 However, few applications of Pd(II) utilize
carbon-based nucleophiles,8 though several recent publi-
cations are demonstrating that this limitation is being
solved, especially for enolic nucleophiles.9–11 Like the
Hg(II)-initiated cascade in Eq. 2, the addition of alkene
nucleophiles to Pd(II)-alkene intermediates would be a
valuable reaction as the carbocyclic products would contain
Pd–C bonds that could be derivitized in situ so that the
metal could be used in catalytic quantities (Hg(II) is a
stoichiometric reagent).6 The first evidence that Pd(II) could
catalytically12 generate cations by the action of an alkene
nucleophile on an activated alkene was realized by Over-
man in the Pd(II)-catalyzed Cope-rearrangement reactions
(Eq. 3),13 wherein a cyclic cation was proposed as an
intermediate in the rearrangement.13b Grob-type fragmenta-
tion consumed the cation and led to the diene product; one
ð1Þ
The analogy between proton reactivity and electrophiles
like Hg(II) and Brþ has stimulated the development of
methods for activating alkenes towards the addition of
carbon and hetero-nucleophiles alike.2 Similar to Hþ,
electrophiles like Hg(II) prefer to coordinate and activate
electron rich alkenes and are thus able to initiate steroid-like
Keywords: Polycyclization; Carbocations; Carbocycles; Palladium.
*
Corresponding author. Tel.: þ1-91-99626341; fax: þ1-91-99626342;
e-mail address: mgagne@unc.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.023

7406
J. H. Koh et al. / Tetrahedron 60 (2004) 7405–7410
type of diene did provide a cyclic product.14 More recent
studies have shown that carbocycles can be routinely
maintained if the carbon nucleophile is an enol,9,10 or an
indole.11 Two recent intermolecular C–C bond forming
reactions that reasonably propose cationic intermediates
have been reported by Vitagliano using pincer-ligated Pt-
dications15 and by Wiedenhoefer with PtCl2.16
Attempts to utilize CuCl2 (Table 1, entry 2) or O2 (entry 3)
as the stoichiometric oxidant were less successful and
products incorporating Cl (presumably Cl2 trapping of the
cation) or low conversions were obtained, respectively. The
optimum procedure utilized CH3CN at elevated tempera-
tures and provided the bicycle in 85% yield, free of the
Wacker product (entry 5). In contrast to PdCl2, catalytic
Pd(OAc)2 provided none of 2, and only the Wacker product
3 in 95% yield (entry 6).20
The optimized protocol was applied to a variety of poly-enyl
compounds with traps for the putative cation; the resulting
alkene containing products were hydrogenated (H2, Pd/C)
and analyzed. As shown in Table 2 (entry 2), cascade
cyclizations were possible from trienylphenol (5) to provide
tricyclic products in excellent yields (89%), again as a
mixture of three alkene isomers (70:17:13). Hydrogenation
and NMR analysis showed the product (6) to have a trans–
trans ring junction with diaxial methyl groups.17 When
primary alcohols were utilized as the terminal trapping
agent both dienyl (7, entry 3) and trienyl (9, entry 4)
alcohols provided the desired bi-21 and tricyclic hydrofur-
ans.22 The bicyclic product (8) was obtained as a single
isomer after hydrogenation, while the tricycle was a mixture
of two (91:9). The major diastereomer (10a) was unam-
biguously assigned to be dinor-ambrox, a compound whose
scent has been described as having ‘a strong earthy odor
reminiscent of a freshly plowed field’.22 The minor
diastereomer (10b) was not conclusively identified, but
literature data (1H NMR) was consistent with the C-9
epimer. A sulfonamide (11) is also an efficient trap of the
cation and annulated pyrrolidine products (12a, 12b) were
obtained, again with good stereocontrol of the ring junction
(94:6, entry 5).23 Stimulated by the ring-expanding/
contracting pinacol rearrangement reactions reported by
Overman,24 we also examined the 1,5-dienyl carbinol (13)
in entry 6. As expected, the putative tertiary carbocation
undergoes a rearrangement to provide a bicyclic ketone as a
mixture of two diastereomers, each a 1:1 mixture of alkene
isomers. Hydrogenation provided the saturated products as
an 85:15 mixture of cis (14a) and trans (14b) ring
junctions.25 The preference for cis-selective migration has
been noted in several bicyclic Pinacol rearrangement
reactions.24,26
ð3Þ
2. Results and discussion
We recently initiated a program to investigate methods for
trapping the putative cation generated by the Pd(II)-
mediated cycloisomerization of 1,5-dienes.17 To this end,
we examined catalysts for the bicyclization of dienylphenol
1, which was designed to trap the cation with the
heteroatom, followed by proton loss. Since Pd(II) has a
strong preference for the less substituted alkenes, the
terminal alkene was expected to be the point of initiation.
In the case of weakly ligated Pd(II) sources, rapid b-hydride
elimination of the Pd–C bond was expected, and several
reoxidation (Pd(0) to Pd(II)) procedures were investiga-
ted.7a
As shown in Eq. 4, mono- and bicyclic products were
obtained when PdCl2(PhCN)2 (10 mol%) was reacted with 1
at RT in the presence of 4 equiv. of benzoquinone (BQ). The
monocyclic product (3) is presumably the result of a
Wacker-type cyclization and is well precedented.18 The
desired product (2) was formed as a mixture of alkene
isomers, and exclusively with a trans ring junction. Proof of
the ring stereochemistry was obtained by comparison to the
known hydrogenation product (4).17,19
In contrast to the smooth high yielding reactions of 1,5-
dienyl compounds, the 1,6-dienyl substrate (15) in entry 7
was more capricious. Multiple alkene products were
obtained and hydrogenation provided a 68:32 mixture of
two identifiable diastereomers (16a, 16b), both of which
ð4Þ
Table 1. Optimization of PdCl2-catalyzd oxidative cyclization reactions
Entry
Catalyst (10 mol%)
Oxidant (equiv.)
Solvent
Temp, time
Conversiona (%, 2þ3)
Ratioa 2:3
1
2
3
4
5
6
(PhCN)2PdCl2
(PhCN)2PdCl2
(PhCN)2PdCl2
(PhCN)2PdCl2
(PhCN)2PdCl2
Pd(OAc)2
BQ (4.0)
CuCl2 (2.5)
O2 (1 atm)
BQ (4.0)
BQ (4.0)
BQ (4.0)
CH2Cl2
DCE
THF
THF
CH3CN
THF
RT, 40 h
RT, 20 h
60 8C, 40 h
60 8C, 40 h
80 8C, 15 h
60 8C, 24 h
39
59b
16
75
85
95
74:26
72:28
75:25
90:10
.99:1
.1:99
a
Determined by GC.
20% of a Cl containing compound (GC-MS) was observed as a byproduct.
b

J. H. Koh et al. / Tetrahedron 60 (2004) 7405–7410
Table 2. PdCl2-catalyzed oxidative cyclization reactionsa
7407
Entry
Substrate
Reaction time (h)
Alkene product (yield,b alkene ratioc)
Hydrogenated product (yield,b drd)
1
15
4
6
8
1
(83%, 68:19:13)
(98%, .99:1)
2
48
5
7
(89%, 70:17:13)
(98%, .99:1)
3
4
15
20
(80%, .99:1)
(98%,e .99:1)
9
(80%, 84:8:5:3)
10a
(98%, 91:9)
10b
5
40
11
(75%, 80:12:8)
12a
(98%, 94:6)f
12b
6
17
13
(85%, 43:43:7:7)
14a
(98%, 85:15)
14b
7
60
15
(75%, 14:27:17:15)
16a
(98%,g 68:32)
16b
a
Reaction conditions are as described in Table 1 entry 5.
Yield after chromatographic purification.
Determined by GC.
b
c
d
e
f
Determined by GC and 1H NMR.
Hydrogenation was carried out in Et2O.
The major is assigned the trans configuration by analogy.
Includes 20% of unknown isomers
g
contained trans ring junctions but were epimeric at C-1.27
The major C-1 diastereomer was equatorial, but the natural
selectivity of the C–C bond-forming step is not clear since
b-H elimination compromises this stereocenter. This
compound was contaminated with 20% of several uni-
dentified structural isomers (GC-MS).
3. Conclusions
Based on the precedence established by Overman in the
PdCl2-catalyzed Cope-rearrangement we report herein a
PdCl2-catalyzed cyclization reaction that is consistent with
a mechanism involving the cyclo-generation of cyclic

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J. H. Koh et al. / Tetrahedron 60 (2004) 7405–7410
Scheme 1. Synthetic procedure for substrates 7, 9, and 11.
38-cations from 1,5- and 1,6-dienes.†28 When provided with
suitable traps for the cation, various poly-cyclization
products are formed that are each consistent with an
intermediate carbocation. Turnover is achieved by b-
hydride elimination to yield cycloalkene products, usually
as a mixture of alkene isomers. The resulting Pd(0) is
reoxidized under standard benzoquinone oxidation con-
ditions to the reactive Pd(II)-form. Future directions for this
work will include developing traps (e.g., CO/MeOH) for the
intermediate alkyl, more efficient reoxidation procedures,
and asymmetric variants.
4.2. Substrate synthesis
4.2.1. 1,5-Dienyl alcohol (7).30 A solution of methylmag-
nesium bomide in ether (21 mL, 60 mmol) was added to a
stirred suspension of bis(triphenylphosphine)nickel dichlor-
ide (650 mg, 1.0 mmol) in dry toluene (45 mL) under dry
nitrogen. The resulting red solution was stirred at room
temperature for 20 min, and a solution of 5-(3-butenyl)-2,3-
dihyrofuran (17) (2.5 g, 20 mmol) in toluene (30 mL) was
then added. The mixture was heated to 80 8C for 1.5 h,
cooled to room temperature, and poured into a saturated
ammonium chloride solution (60 mL) with vigorous
stirring. The mixture was stirred until decolorized and the
organic material was extracted with ether. The combined
extracts were dried (MgSO4) and evaporated to leave a
yellow oil. The crude mixture was purified by column
chromatography on silica gel (Hexene–EtOAc¼2:1) to give
4. Experimental
4.1. General
1
the product (7) as a colorless oil (2.2 g, 79%). H NMR
Pd(II)-catalyzed cyclization reactions were performed
under a dinitrogen atmosphere using standard Schlenk
techniques. NMR spectra were recorded on a Bruker
Avance400 spectrometer; chemical shifts are given in ppm
and are referenced to residual solvent peaks. Gas chroma-
tography was performed on an HP 6890 gas chromatog-
raphy equipped with an HP-5 column. GC-MS analysis was
performed on an Agilent 5973. High resolution mass
spectrum was performed by the Mass Spectrometry Service
Laboratory at the University of Minnesota. Synthesis of 1, 5,
and 15 were performed as previously described,17 as was
13.29 Synthesis of 7, 9, and 11 were performed by
modification of existing literature procedures30,31
(Scheme 1). The cyclization products 4, 6, and 16 were
previously reported,17 as were 8,21 10,22 and 14.25 All new
compounds were determined to be .95% pure by GC and
1H NMR spectroscopy.
(400 MHz, CDCl3) d 5.76 (m, 1H), 5.11 (t, J¼6.0 Hz, 1H),
4.96 (dd, J¼17.2, 1.6 Hz, 1H), 4.92 (dd, J¼10.0, 1.2 Hz,
1H), 3.59 (q, J¼6.4 Hz, 2H), 2.27 (q, J¼6.8 Hz, 2H), 2.09–
2.16 (m, 4H), 1.57 (s, 3H); 13C NMR (100 MHz, CDCl3) d
138.9, 138.6, 120.7, 114.9, 62.7, 39.5, 32.5, 31.8, 16.5;
HRMS (CI) [MþH]/z Calcd 141.1279, found 141.1279.
4.2.2. 1,5,9-Trienyl alcohol (9).30 1,5,9-Trienyl alcohol (9)
1
was prepared in 80% yield from 19 as described for 7. H
NMR (400 MHz, CDCl3) d 5.77 (m, 1H), 5.09 (dd, J¼8.0,
7.6 Hz, 2H), 4.98 (dd, J¼16.8, 2.0 Hz, 1H), 4.91 (dd,
J¼10.0, 1.2 Hz, 1H), 3.59 (t, J¼6.4 Hz, 2H), 2.26 (q,
J¼6.4 Hz, 2H), 2.02–2.16 (m, 8H), 1.65 (s, 3H), 1.58 (s,
3H); 13C NMR (100 MHz, CDCl3) d 139.2, 139.1, 135.1,
124.6, 120.3, 114.6, 62.8, 40.1, 39.4, 32.7, 31.8, 26.8, 16.5,
16.3; HRMS (CI) [MþNH4]/z Calcd 226.2171, found
226.2178.
†
4.2.3. 1,5-Dienyl sulfonamide (11). A mixture of 8-iodo-5-
methyl-1,5-octadiene (18) (0.38 g, 1.54 mmol) and tosyla-
mide monosodium salt31 (0.3 g, 1.54 mmol) in DMF
(5.0 mL) were stirred at 80 8C for 5 h. The reaction mixture
was cooled to room temperature and ether was added. The
resulting solution was washed with brine, dried over
MgSO4, and evaporated under vacuum. The crude mixture
The bicyclization reactions in entries 1, 3, 5 and 7 can also be explained
by an initiating oxypalladation of the alkene proximal to the
heteroatom,28 followed by a 6-endo coordination insertion/b-hydride
elimination. The all trans ring junctions in the tricyclic products are not
consistent with a propagating 6-endo cyclization, since this leads to a cis
A-ring junction. The terminally trisubstituted compound ortho-
geranylphenol does not react under the standard reaction conditions. A
more thorough mechanistic analysis will be published in due course.

J. H. Koh et al. / Tetrahedron 60 (2004) 7405–7410
7409
was purified by column chromatography on silica gel
(Hexene–EtOAc¼4:1) to give the product (11) as a
References and notes
1
colorless oil (0.32 g, 72%). H NMR (400 MHz, CDCl3) d
1. Richards, J. H.; Hendrickson, J. B. The Biosynthesis of
Steroids, Terpenes, and Acetogenins. W.A. Benjamin Inc:
New York, 1964; pp 240–288.
7.71 (d, J¼8.0 Hz, 2H), 7.27 (d, J¼8.0 Hz, 2H), 5.71 (m,
1H), 4.89–4.99 (m, 3H), 4.61 (t, J¼6.0 Hz, 1H), 2.91 (q,
J¼6.4 Hz, 2H), 2.39 (s, 3H), 1.98–2.15 (m, 6H), 1.51 (s,
3H); 13C NMR (100 MHz, CDCl3) d 143.2, 138.5, 138.4,
137.1, 129.6, 127.0, 120.0, 114.6, 42.8, 38.9, 32.0, 27.9,
21.4, 16.0; HRMS (CI) [MþH]/z Calcd 294.1528, found
294.1532.
2. Bartlett, P. A. Asymmetric Synthesis, Morrison, J. D., Ed.;
Academic: New York, 1984; Vol. 3, pp 341–409.
3. (a) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem.
Soc. 2002, 124, 3647–3655. (b) Nakamura, S.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131–8140.
4. Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Org. Chem.
1986, 51, 806–813.
4.3. General procedure for catalytic cyclization
5. Larock, R. C. Organomercury Compounds in Organic
Synthesis. Springer: Berlin, 1985; pp 155–229.
To a solution of (PhCN)2PdCl2 (7.1 mg, 18.5 mmol), and
benzoquinone (80 mg, 0.74 mmol) in CH3CN (3.0 mL) was
added trienylphenol (5) (50 mg, 0.185 mmol). The resulting
solution was stirred at 80 8C for 48 h. The reaction mixture
was cooled to room temperature, filtered through a plug of
silica gel, and eluted with ether. The filtrate was
concentrated under vacuum and chromatographed (hex-
ane–EtOAc¼9:1) to give a mixture of alkene products
(44 mg, 89%, 70:17:13). The colorless oil was taken up in
MeOH (2.0 mL), and Pd/C (5 mol%) was added. The
resulting slurry was stirred under hydrogen atmosphere
(1 atm) at room temperature for 5 h. The reaction mixture
was filtered through a plug of Celite, and washed with ether.
The filtrate was concentrated under vacuum to give tricyclic
product (6) as a colorless oil (44 mg, 98%).17
6. Several recent developments in Hg(II) chemistry include (a)
enantioselective L*Hg(II) reagents and (b) an enyne carbo-
cyclization that is catalytic in Hg(OTf)2; (a) Kang, S. H.; Kim,
M. J. Am. Chem. Soc. 2003, 125, 4684–4685. (b) Nishizawa,
M.; Yadav, V. K.; Skwarczynski, M.; Imagawa, T. H.;
Sugihara, T. Org. Lett. 2003, 5, 1609–1611.
7. (a) Hegedus, L. S. Transition Metals in the Synthesis of
Complex Organic Molecules. University Science Books: Mill
Valley, CA, 1994; pp 199–236. (b) Hegedus, L. S. Compre-
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Vol. 4, pp 551–569.
8. Hegedus, L. S. Comprehensive Organic Synthesis, Trost,
B. M., Ed.; Pergamon, 1991; Vol. 4, pp 571–583.
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2056–2057. (b) Wang, X.; Pei, T.; Han, X.; Widenhoefer,
R. A. Org. Lett. 2003, 5, 2699–2701. (c) Widenhoefer, R. A.
Acc. Chem. Res. 2002, 35, 905–913. (d) Pei, T.; Widenhoefer,
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4.3.1. Trans-fused bicyclic furan (8). 1H NMR (400 MHz,
CDCl3) d 3.80 (m, 2H), 1.58–1.86 (m, 7H), 1.35–1.41 (m,
4H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3) d 80.9,
64.7, 47.9, 38.7, 28.9, 26.7, 26.5, 23.7, 17.1; HRMS (CI)
[MþH]/z Calcd 141.1279, found 141.1280.
10. Toyota, M.; Rudyanto, M.; Ihara, M. J. Org. Chem. 2002, 76,
3374–3386.
1
4.3.2. Trans-fused bicyclic pyrrolidine (12a). H NMR
(400 MHz, CDCl3) d 7.71 (d, J¼8.0 Hz, 2H), 7.24 (d,
J¼8.0 Hz, 2H), 3.43 (td, J¼9.2, 1.2 Hz, 1H), 3.27 (t,
J¼9.2 Hz, 1H), 2.39 (s, 3H), 1.78 (m, 1H), 1.49–1.71 (m,
4H), 1.47 (dd, J¼12.8, 4.4 Hz, 1H), 1.15–1.38 (m, 5H),
1.04 (s, 3H); 13C NMR (100 MHz, CDCl3) d 142.5, 139.1,
129.7, 127.5, 66.5, 49.8, 46.5, 38.4, 30.1, 26.9, 25.8, 22.6,
21.8, 17.3; HRMS (CI) [MþH]/z Calcd 294.1528, found
294.1533.
11. Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125,
9578–9579.
12. For early examples of stoichiometric Pd(II) reactivity see: (a)
Trebellas, J. C.; Olechowski, J. R.; Jonassen, H. B.
J. Organomet. Chem. 1966, 6, 412–420. (b) Heimbach, P.;
Molin, M. J. Organomet. Chem. 1973, 49, 477–482. (c)
Heimbach, P.; Molin, M. J. Organomet. Chem. 1973, 49,
483–494. (d) Brown, E. D.; Sam, T. W.; Sutherland, J. K.;
Torre, A. J. Chem. Soc., Perkin Trans. 1 1975, 2326–2332. (e)
Hegedus, L. S.; Williams, R. E.; McGuire, M. A.; Hayashi, T.
J. Am. Chem. Soc. 1980, 102, 4973–4979.
4.3.3. Wacker product (3). 1H NMR (400 MHz, CDCl3) d
7.07 (t, J¼7.6 Hz, 1H), 6.94 (d, J¼7.2 Hz, 1H), 6.80 (t,
J¼7.2 Hz, 1H), 6.73 (d, J¼8.0 Hz, 1H), 6.34 (d, J¼10.0 Hz,
1H), 5.80 (m, 1H), 5.53 (d, J¼10.0 Hz, 1H), 4.99 (d,
J¼17.2 Hz, 1H), 4.91 (d, J¼8.8 Hz, 1H), 2.11–2.70 (m,
2H), 1.69–1.84 (m, 2H), 1.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 153.1, 138.5, 129.3, 129.0, 126.3, 122.9, 120.9,
120.5, 116.0, 114.3, 40.5, 28.3, 26.6, 25.2; HRMS (ESI)
[MþNa]/z Calcd 223.1094, found 223.1091.
13. (a) Overman, L. E.; Knoll, F. M. J. Am. Chem. Soc. 1980, 102,
865–867. (b) Overman, L. E.; Jacobsen, E. J. J. Am. Chem.
Soc. 1982, 104, 7225–7231. (c) Overman, L. E.; Renaldo, A. F.
J. Am. Chem. Soc. 1990, 112, 3945–3949.
14. Overman, L. E.; Renaldo, A. F. Tetrahedron Lett. 1983, 24,
235–238.
15. Hahn, C.; Cucciolito, M. E.; Vitagliano, A. J. Am. Chem. Soc.
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16. Wiang, W.; Widenhoefer, R. A. Chem. Commun. 2004,
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Acknowledgements
17. For examples of non-oxidative Pd(II)- and Pt(II)-mediated
cation-olefin reactions with pincer-ligated metal complexes,
This work was supported by the NIH (GM-60578), we also
thank Ms. Claire Catteral (University of Bristol exchange
student) for experimental assistance with compound 13.
MRG is a Camille Dreyfus Teacher Scholar.
´
see: Koh, J. H.; Gagne, M. R. Angew. Chem., Int. Ed. 2004, in
press.
18. For a recent example of an asymmetric variant using BQ see:

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Uozumi, Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T.
J. Org. Chem. 1999, 64, 1620–1625.
26. For examples of cis selective pinacol rearrangements, see (a)
Trost, B. M.; Neilsen, J. B.; Hoogsteen, K. J. Am. Chem. Soc.
1992, 114, 5432–5434. (b) Hirst, G. C.; Howard, P. N.;
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Herrinton, P. M.; Hopkins, M. H.; Mishra, P.; Brown, M. J.;
Overman, L. E. J. Org. Chem. 1987, 52, 3711–3712.
27. The stereochemistry of the major diastereomer was unam-
biguously determined by X-ray methods, see Ref. 17 for
additional characterization on both stereoisomers.
19. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 10333–10334.
20. Chloride-containing Pd(II)-catalyzed Wacker cyclizations are
known to proceed by exo addition of nucleophile, while non-
chloride containing catalyst can proceed by endo addition
mechanisms, see Hayashi, T.; Yamasaki, K.; Mimura, M.;
Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036–3037.
21. The cis-fused bicyclic furan is known, see: Nishizawa, M.;
Iwamoto, Y.; Takao, H.; Imagawa, H.; Sugihara, T. Org. Lett.
2002, 2, 1685–1687.
28. For references related to the alternative oxypalladation-
initiated mechanism, see: (a) Hayashi, T.; Yamasaki, K.;
Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126,
3036–3037. (b) Hosokawa, T.; Murahashi, S.-I. Acc. Chem.
Res. 1990, 23, 49–54. (c) Balsells, D.; Maseras, F.; Keay,
B. A.; Ziegler, T. Organometallics 2004, 23, 2784–2796. (d)
Weider, P. R.; Hegedus, L. S.; Asada, H.; D’Andreq, S. V.
J. Org. Chem. 1985, 50, 4276–4281.
22. Dinorambrox and 9-epi-dinorambrox, see: Ohloff, G.; Giersch,
W.; Pickenhagen, W.; Furrer, A.; Frei, B. Helv. Chim. Acta
1985, 68, 2002–2029.
23. We assign the trans configuration for entry 5 by analogy.
24. (a) Overman, L. E.; Wolfe, J. P. J. Org. Chem. 2002, 67,
6421–6429. (b) Overman, L. E. Acc. Chem. Res. 1992, 25,
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29. Holt, D. A. Tetrahedron Lett. 1981, 22, 2243–2246.
30. Kocienski, P.; Wadman, S.; Cooper, K. J. Org. Chem. 1989,
54, 1215–1217.
25. (a) House, H. O.; Gaa, C. P.; VanDerveer, D. J. Org. Chem.
1983, 48, 1661–1670. (b) House, H. O.; Nomura, S. G.;
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31. Bottino, F.; Grazia, M. D.; Finocchiaro, P.; Fronczek, R. R.;
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