Palladium-catalyzed synthesis of 2,1′-disubstituted tetrahydrofurans from γ-hydroxy internal alkenes. Evidence for alkene insertion into a Pd-O bond and stereochemical scrambling via β-hydride elimination

Article abstract of DOI:10.1021/ja054754v

Palladium-catalyzed reactions of γ-hydroxy internal acyclic alkenes with aryl bromides afford 2,1′-disubstituted tetrahydrofurans in good yields with diastereoselectivities of 3-5:1, The analogous transformations of substrates bearing internal cyclic alke

Full text of DOI:10.1021/ja054754v

Published on Web 11/03/2005
Palladium-Catalyzed Synthesis of 2,1′-Disubstituted
Tetrahydrofurans from γ-Hydroxy Internal Alkenes. Evidence
for Alkene Insertion into a Pd-O Bond and Stereochemical
Scrambling via â-Hydride Elimination
Michael B. Hay and John P. Wolfe*
Contribution from the Department of Chemistry, UniVersity of Michigan,
930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received July 15, 2005; E-mail: jpwolfe@umich.edu
Abstract: Palladium-catalyzed reactions of γ-hydroxy internal acyclic alkenes with aryl bromides afford
2,1′-disubstituted tetrahydrofurans in good yields with diastereoselectivities of 3-5:1. The analogous
transformations of substrates bearing internal cyclic alkenes afford fused bicyclic and spirocyclic
tetrahydrofuran derivatives in good yields with excellent diastereoselectivities (>20:1). A series of deuterium
labeling experiments indicate that the origin of the modest diastereoselectivity in reactions of acyclic internal
alkene substrates likely derives from a series of reversible â-hydride elimination and σ-bond rotation
processes that occur following a rare intramolecular alkene syn-insertion into an intermediate Pd(Ar)(OR)
complex. In addition, these studies shed light on the chemoselectivity of insertion, suggesting that the
alkene inserts into the Pd-O bond in preference to the Pd-C bond.
Introduction
preliminary studies indicated that reactions of substrates bearing
internal alkenes afford products that derive from syn-addition
The synthesis of substituted tetrahydrofurans remains a topic
of considerable interest due to the prevalence of these struc-
tures in natural products and other biologically active com-
pounds.1,2 Although a considerable amount of effort has been
devoted to the development of efficient and stereoselective
methods for the construction of these molecules, there are still
few existing methods that allow for intramolecular closure of a
tetrahydrofuran ring with concomitant formation of both a
carbon-carbon bond and a stereocenter at the C1′-carbon
adjacent to the ring.3
We recently reported a new method for the stereoselective
synthesis of tetrahydrofurans from reactions of aryl or vinyl
bromides with γ-hydroxyalkenes.4-9 These reactions lead to the
formation of both a C-O and a C-C bond in a single step,
and transformations of substrates bearing substituents at the 1-
or 3-position afford trans-2,5- or trans-2,3-disubstituted tetra-
hydrofurans with diastereoselectivities of up to g20:1.4,5 Our
of the aryl group and the oxygen atom across the double
bond.4 For example, treatment of internal cyclic alkene 1 with
4-bromoanisole in the presence of NaOtBu and a Pd2(dba)3/
P(o-tol)3 catalyst provided bicyclic product 2 in 69% yield
with >20:1 diastereoselectivity (eq 1). The analogous coupling
of acyclic internal alkene substrate 3 with 4-bromobiphenyl
afforded tetrahydrofuran 4a in 73% yield with modest (5:1)
diastereoselectivity for the product of syn-addition (eq 2).
Curiously, the latter reaction also provided a small amount of
the regioisomeric 3-aryl-2-ethyltetrahydrofuran 4b and a trace
amount of 4c.10
(1) (a) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407-2474. (b) Alali,
F. Q.; Liu, X. -X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. (c)
Hou, X. -L.; Yang, Z.; Wong, H. N. C. Prog. Heterocycl. Chem. 2002, 14,
139-179. (d) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96. (e) Nicotra,
F. Top. Curr. Chem. 1997, 187, 55-83.
(2) (a) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301-2323. (b)
Harmange, J. C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711-
1754.
(3) (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496-
1498. (b) Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner,
M.; Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035-2040.
(c) Semmelhack, M. F.; Epa, W. R. Tetrahedron Lett. 1993, 34, 7205-
7208.
(4) A portion of this work has been previously communicated. See: Wolfe, J.
P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620-1621.
(5) For detailed studies on the scope and limitations of reactions of γ-hydroxy
terminal alkenes, see: Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org.
Chem. 2005, 70, 3099-3107.
On the basis of the observed product stereochemistry, we
proposed that the mechanism of these reactions likely proceeds
either via an unusual intramolecular insertion of an alkene into
the Pd-O bond of a Pd(Ar)(OR) intermediate, 5, followed by
9
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Pd-Catalyzed Synthesis of Disubstituted THFs
A R T I C L E S
Scheme 1
C-C bond-forming reductive elimination of the resulting
complex 6 (Scheme 1, path A) or by alkene insertion into the
Pd-C bond of 5 followed by C-O bond-forming reductive
elimination from intermediate 7 (Scheme 1, path B).4,11,12 We
were unable to differentiate between these two possibilities, as
either pathway could potentially afford the observed major
product. However, we felt this mechanistic scenario was rather
intriguing, as each of these two possible mechanisms involved
one step with very little literature precedent. For example,
documented cases of alkene insertion into late-transition-metal-
oxygen bonds (path A, step 1) are exceptionally rare,13,14 and
only one example of alkene insertion involving a late-transition-
metal complex bearing both a metal-carbon and a metal-
alkoxide bond had been previously reported.14 The formation
of sp3 carbon-oxygen bonds via reductive elimination reactions
from late-transition-metal complexes (path B, step 2) is also
very rare, and known examples involve metals in high oxidation
states such as Ni(III)15 and Pt(IV).16 Reductive eliminations from
Pd(II) complexes that form sp3 C-O bonds have not been
reported.17,18
The mechanistic hypothesis for tetrahydrofuran formation
described above also posed a challenging question. In the
absence of competing pathways or side reactions, the mechanism
shown in Scheme 1 predicts that the tetrahydrofuran forma-
tion should occur with high diastereoselectivity for products
resulting from syn-addition across the double bond. Thus, we
were puzzled by the observation that although cycloalkenes
were converted to tetrahydrofurans with high stereoselectivity
(>20:1), transformations of acyclic internal alkenes proceeded
with modest stereoselectivity (ca. 5:1).19 These results prompted
us to devise new experiments, which ultimately provided both
insights into the origin of the differences in stereoselectivity
and information concerning the chemoselectivity (Pd-O vs
Pd-C) of the alkene insertion into complex 5.
In this paper we present the results of deuterium labeling
studies that are most consistent with a mechanism involving
selective intramolecular insertion of the alkene into the Pd-O
bond of an intermediate Pd(Ar)(OR) complex followed by C-C
bond-forming reductive elimination (Scheme 1, path A). These
experiments also suggest the modest stereoselectivity observed
in reactions of acyclic internal alkene substrates arises from
reversible â-hydride elimination and σ-bond rotation processes
that occur after the alkene insertion step but prior to reductive
elimination. We also describe studies on the scope and limita-
tions of these transformations and their application to the
synthesis of a variety of monocyclic, bicyclic, and spirocyclic
tetrahydrofuran derivatives.
(6) For related transformations of γ-aminoalkenes that afford nitrogen hetero-
cycles, see: (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43,
3605-3608. (b) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127,
8644-8651. (c) Beaudoin Bertrand, M.; Wolfe, J. P. Tetrahedron 2005,
61, 6447-6459. (d) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126,
13906-13907. (e) Yang, Q.; Ney, J. E.; Wolfe, J. P. Org. Lett. 2005, 7,
2575-2578.
(7) (a) For related transformations of γ-alkylidene malonates that afford
carbocycles, see: (a) Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro,
N. Synthesis 2003, 2115-2134. (b) Balme, G.; Bouyssi, D.; Faure, R.;
Gore, J.; Van Hemelryck, B. Tetrahedron 1992, 48, 3891-3902.
(8) For related transformations of γ-hydroxyallenes or -alkynes, see: (a) Kang,
S.-K.; Baik, T. -G.; Kulak, A. N. Synlett 1999, 324-326. (b) Walkup, R.
D.; Guan, L.; Mosher, M. D.; Kim, S. W.; Kim, Y. S. Synlett 1993, 88-
90. (c) Luo, F. T.; Schreuder, I.; Wang, R. T. J. Org. Chem. 1992, 57,
2213-2215.
(9) For related heteroannulations of internal alkynes with o-haloanilines,
o-halophenols, and related compounds, see: Larock, R. C.; Yum, E. K.;
Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270-3271.
(10) The structure of this regioisomer had not been assigned at the time of our
initial communication of these studies (ref 4). We have included the
characterization data for this compound in the Supporting Information of
this paper. In addition, a trace amount (ca. 0.5-1.0%) of regioisomer 4c
was detected upon isolation of 4b by preparative HPLC. This regioisomer
was not present in sufficient amount to detect by 1H NMR analysis of the
mixture of 4a-c.
(11) Trost has noted the formation of a tetrahydrofuran side product in the Heck
arylation of an enyne bearing a secondary OH group and suggested a
mechanism of intermolecular carbopalladation to account for its formation.
See: Trost, B. M.; Pfrengle, W.; Urabe, H.; Dumas, J. J. Am. Chem. Soc.
1992, 114, 1923-1924.
(12) Two other possible mechanisms were ruled out on the basis of product
stereochemistry. Product formation via a Wacker-type mechanism in which
the alkene was activated for nucleophilic attack of the tethered alkene was
discounted as this pathway would afford products resulting from anti-
addition of the oxygen and the arene. Product formation via an intermo-
lecular Heck-type carbopalladation followed by C-O bond-forming
reductive elimination was ruled out on the basis of the high regioselectivity
for five-membered ring formation and also on the basis of the fact that
alcohols substituted at C1 provided trans-2,5-disubstituted tetrahydrofurans
with excellent (>20:1) diastereoselectivity. Intermolecular carbopalladation
reactions of terminal alkenes typically proceed with only 5-7:1 regiose-
lectivity, and it is unlikely that high stereoselectivity for the formation of
trans-2,5-disubstituted products would be obtained if the stereochemistry-
determining event were an intermolecular reaction that occurred two atoms
away from the substrate stereocenter. For further discussion, see refs 4
and 5.
(13) At the time of our preliminary communication no examples of alkene syn-
insertions into Pd-O bonds had been reported. However, in elegant recent
studies, Hayashi has provided evidence for the syn-insertion of an alkene
into a Pd-O bond in the conversion of an o-allylphenol derivative to a
tetrahydrodibenzofuran. See: Hayashi, T.; Yamasaki, K.; Mimura, M.;
Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036-3037.
(14) Bryndza has described the stoichiometric insertion of tetrafluoroethylene
into the Pt-O bond of (dppe)Pt(Me)(OMe). See: (a) Bryndza, H. E.
Organometallics 1985, 4, 406-408. (b) Bryndza, H. E.; Calabrese, J. C.;
Wreford, S. S. Organometallics 1984, 3, 1603-1604.
Results
Stereoselective Synthesis of 1′-Substituted Tetrahydro-
furans from γ-Hydroxy Internal Acyclic Alkenes. As de-
(15) (a) Matsunaga, P. T.; Hillhouse, G. L.; Rheingold, A. L. J. Am. Chem.
Soc. 1993, 115, 2075-2077. (b) Koo, K.; Hillhouse, G. L. Organometallics
1998, 17, 2924-2925.
(16) (a) Dick, A. R.; Kampf, J. W.; Sanford, M. S. Organometallics 2005, 24,
482-485. (b) Williams, B. S.; Goldberg, K. I. J. Am. Chem. Soc. 2001,
123, 2576-2587. (c) Stahl, S. S.; Labinger, J. A.; Bercaw, J. E. Angew.
Chem., Int. Ed. 1998, 37, 2180-2192.
(17) For examples of sp2 C-O bond-forming reductive elimination from
palladium(II) aryl alkoxide complexes, see: (a) Widenhoefer, R. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6504-6411 and references
therein. (b) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109-
13110.
(18) For recent examples of catalytic reactions that may involve sp3 C-O bond-
forming reductive elimination from Pd(IV), see: Desai, L. V.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542-9543.
(19) Both mechanistic pathways (A and B) would be expected to provide high
selectivity for syn-addition products unless other competing mechanistic
pathways are operating simultaneously.
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A R T I C L E S
Hay and Wolfe
Table 1. Reactions of Substrates Bearing Acyclic Internal
of the aryl bromide substrates are also observed in reactions of
both 3 and 9.21
Alkenesa
Transformations of substrates bearing internal alkenes re-
quired higher temperatures (110 °C) than analogous transforma-
tions of substrates bearing terminal alkenes (65 °C),4,5 and gem-
disubstitution of the C1 position was necessary for successful
conversion of internal alkene substrates to tetrahydrofuran
products. For example, the reaction of 4-hexen-1-ol (8) with
4-bromobiphenyl provided only products derived from oxida-
tion/reduction processes (Table 1, entry 1).
The reactions examined in these studies typically afforded
products with ca. 5:1 diastereoselectivity when unhindered aryl
bromides were employed as the coupling partners. However,
in some cases the steric properties of the aryl bromide had an
impact on diastereoselectivity. For example, the reaction of 3
with 2-bromotoluene gave 11a with 3:1 diastereoselectivity as
judged by 1H NMR analysis of the crude reaction mixture; upon
purification 11a was obtained in 79% isolated yield and 6:1 dr
(entry 4).22 The analogous reaction of 9 with 2-bromotoluene
afforded 15a with 2:1 crude dr; the pure product was subse-
quently obtained in 50% yield as a 3:1 mixture of diastereomers
(entry 8).22 In contrast, the reaction of 3 with 1-bromonaph-
thalene afforded 12a with 5:1 crude dr; 12a was isolated in
78% yield as a 10:1 mixture of diastereomers.22 Increased
amounts of regioisomer formation were also observed in reac-
tions of sterically hindered aryl bromides (entries 4, 5, and 8).
Stereoselective Synthesis of Tetrahydrofurans from γ-Hy-
droxy Internal Cyclic Alkenes. In contrast to the transforma-
tions of acyclic internal alkenes described above, reactions of
substrates bearing cyclic alkenes proceeded with generally high
(>20:1) levels of diastereoselectivity and did not afford mixtures
of regioisomers (Table 2). For example, treatment of cyclopen-
tene-derived substrate 1 with N,N-dimethyl-4-bromoaniline in
the presence of NaOtBu and a catalytic amount of Pd2(dba)3/
P(o-tol)3 afforded a 53% yield of 19 as a single diastereomer
(entry 2), and the related coupling of cyclohexene derivative
16 with 1-bromo-4-tert-butylbenzene afforded 21 in 66% yield
and >20:1 dr (entry 4). Reactions of cyclohexene-derived
substrates were typically faster than transformations involving
the analogous cyclopentene derivatives. For example, the
coupling of 1 with 4-bromoanisole (entry 1) required 2 days at
110 °C to reach completion, whereas the related reaction of 16
with 1-bromo-4-tert-butylbenzene (entry 4) was complete after
only 2 h. Moreover, although the stereoselective synthesis of
spirocyclic tetrahydrofuran 24 from cyclohexene derivative 17
was achieved in 61% yield (>20:1 dr, entry 7), efforts to
transform the analogous cyclopentene-containing substrate 18
only afforded products resulting from Heck arylation of the
alkene (entry 10). As was observed in transformations involving
acyclic internal alkene substrates, the major products produced
in reactions of cycloalkene substrates derive from syn-addition
of the aryl group and the oxygen atom across the olefin.
As noted above, the main side products observed in these
reactions are small amounts of dehalogenated arenes resulting
from reduction of the aryl bromide.21 In some cases, transforma-
a Conditions: 1.0 equiv of alcohol, 2.0 equiv of ArBr, 2.0 equiv of
NaOtBu, 1 mol % Pd2(dba)3, 4 mol % P(o-tol)3, toluene (0.125 M), 110
°C. b Diastereomeric ratios are given for the pure, isolated products. The
numbers in parentheses represent the diastereomeric ratios observed in the
crude reaction mixture. In some cases the diastereomeric ratio improved
upon purification as the minor diastereomer was partially separable by
chromatography. c Regioisomer ratios (a:b; see eq 2) are given for the pure,
isolated products. The numbers in parentheses represent the regioisomer
ratios observed in the crude reaction mixture. In some cases the regioisomer
ratio improved upon purification as the minor regioisomer was partially
separable by chromatography. Regioisomer c was not detected by 1H NMR
analysis of crude reaction mixtures or isolated products but may be present
in small amounts (e2%). d Yields represent average isolated yields for two
or more experiments. e Reduction of the aryl bromide was observed.
scribed above, our preliminary experiments indicated that (E)-
alkene 3 was effectively transformed to 2,1′-disubstituted
tetrahydrofuran derivatives upon treatment with an aryl or vinyl
bromide in the presence of NaOtBu and a palladium catalyst.20
To further probe the scope and the stereospecificity of this
methodology, (Z)-alkene substrate 9 was prepared and treated
with three different aryl bromides. As shown in Table 1, the
transformations proved to be stereospecific, and in all reactions
the major product diastereomer resulted from syn-addition of
the aryl group and the heteroatom across the C-C double bond.
As observed in transformations of the (E)-alkene substrate 3,
reactions of (Z)-alkene 9 also afforded 3-aryl-2-ethyltetrahy-
drofuran side products with structures analogous to that of 4b
shown above (eq 2), albeit in greater amounts (ca. 10-25%)
than were formed in similar reactions of 3 (ca. 5-12%). In
addition, small amounts of arenes that derive from reduction
(21) Unarylated tetrahydrofuran or dihydrofuran products were not observed in
these reactions. However, these potential side products would be quite
volatile and may be difficult to detect by GC analysis of crude reaction
mixtures.
(22) In some instances diastereomeric ratios improved upon purification as the
two product diastereomers were partially separable by silica gel chroma-
tography.
(20) The relative stereochemistry of the tetrahydrofuran products was assigned
on the basis of comparison of 1H and 13C NMR chemical shifts to those of
related compounds of known configuration and/or by 1H NMR NOE
experiments. See the Supporting Information for complete details.
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Pd-Catalyzed Synthesis of Disubstituted THFs
A R T I C L E S
Table 2. Reactions of Substrates Bearing Cyclic Internal Alkenes
deuterium labeling experiments could potentially differentiate
between these three scenarios, as formation of the minor
diastereomer via post-insertion â-hydride elimination processes
would lead to positional scrambling of the label, whereas the
other two possibilities would be expected to proceed with
positional retention of the deuterium atom (see the Discussion).
Thus, a series of deuterated substrates were prepared and
converted to tetrahydrofurans under our standard reaction
conditions.
As shown below, tertiary alcohol substrate 27 bearing a
deuterium atom at the 5-position was treated with 4-bromobi-
phenyl in the presence of NaOtBu and catalytic Pd2(dba)3/
P(o-tol)3 to afford a 79:17:4 mixture of the two diastereomers
28 and 29 along with the regioisomeric side product 30 (eq 3).
Interestingly, although the major product diastereomer 28 was
deuterated at the expected 2-position, the minor diastereomer
29 was formed as a mixture of two isotopomers; the major
isotopomer contained a hydrogen atom at C2 and a deuterium
atom at C1′. The regioisomer 30 was deuterated solely at the
1′-position. All products contained a single deuterium atom;
products bearing zero or two deuterium atoms were not
detected.24 Unreacted starting material that was isolated from a
reaction stopped at partial conversion (37%) was deuterated
exclusively at the 5-position; deuterium migration in the starting
material was not observed.
Treatment of the analogous substrate bearing a deuterium
atom at C6 (31) with 4-bromobiphenyl under identical con-
ditions afforded a 75:20:5 ratio of the two diastereomeric
tetrahydrofurans 32 and 33, along with the 3-aryl-2-ethyltet-
rahydrofuran regioisomer 30. The outcome of this transforma-
tion was similar to that described above, with the major
diastereomer bearing the deuterium atom at the expected C1′
position, the minor diastereomer bearing the majority of the
deuterium label at C2, and the regioisomer deuterated exclu-
sively at C1′ (eq 4). As above, unreacted starting material
isolated from a reaction stopped at partial conversion (63%)
was deuterated only at C6.
a Conditions: 1.0 equiv of alcohol, 2.0 equiv of ArBr, 2.0 equiv of
NaOtBu, 2.5 mol % Pd2(dba)3, 10 mol % P(o-tol)3, toluene (0.125 M), 110
°C. b Yields represent average isolated yields for two or more experiments.
c Xantphos (5 mol %) was used in place of P(o-tol)3. d Heck-type products
were observed.
tions of â-bromostyrene (entry 6) or electron-deficient aryl
bromides (entries 5 and 8) proceeded in lower yield than related
reactions of electron-neutral aryl halides due to competing
O-vinylation or O-arylation of the alcohol substrate. The reaction
of the heteroaryl halide 4-bromoisoquinoline was very slow and
proceeded with low conversion when a catalyst comprised of
Pd2(dba)3/P(o-tol)3 was employed. However, use of the chelating
ligand xantphos23 for this transformation afforded 20 in good
yield (78%) with excellent diastereoselectivity (entry 3). Xant-
phos also provided better results than P(o-tol)3 for the reaction
of 16 with 4-bromobenzonitrile (entry 5).
Deuterium Labeling Experiments. As noted above, the
mechanistic hypothesis outlined in Scheme 1 cannot, in itself,
account for the formation of diastereomers formally resulting
from anti-addition of the oxygen atom and the arene across the
double bond of acyclic internal alkenes. However, we felt that
these minor diastereomers could potentially arise via alkene
isomerization, competing Wacker-type anti-alkoxypalladation,3
or competing â-hydride elimination processes that occur post
alkene insertion (see below). It seemed likely that a series of
The reaction between substrate 34 bearing a vinyl CD3 group
in place of the vinyl CH3 group and 4-bromobiphenyl afforded
a mixture of tetrahydrofurans 35 and 36 along with 3-aryl-2-
ethyltetrahydrofuran 37 in a 71:23:6 ratio (eq 5). In contrast to
(24) Monodeuteration was confirmed by MS analysis of the product mixture.
1
2
The percent deuterium incorporation was determined by H and H NMR
spectroscopy and was reproducible within (3% over two runs. Although
the sum of the percent deuterium at C2 and C1′ is <100% for the minor
diastereomers shown in eqs 3-5, this is likely due to small errors associated
with NMR measurement and integration.
(23) Xantphos ) 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
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A R T I C L E S
Hay and Wolfe
the reactions of 27 and 31 described above, no migration of
deuterium was observed in the reaction of 34.
Mechanism and Origin of Moderate Diastereoselectivity
in Reactions of Internal Acyclic Alkene Substrates. In our
preliminary disclosure of the Pd-catalyzed carboetherification
of γ-hydroxyalkenes we suggested that the reactions likely
proceed via an intramolecular alkene insertion into an interme-
diate Pd(Ar)(OR) complex via an organized cyclic transition
state (Scheme 1).4 This mechanism accounts for the observed
syn-addition of the oxygen atom and the arene across the C-C
double bond and is also consistent with the high stereoselectivity
for the formation of trans-2,5- and trans-2,3-disubstituted
tetrahydrofurans from 1- and 3-substituted γ-hydroxy terminal
alkenes (eqs 6 and 7).4,5 Other plausible mechanistic pathways
Discussion
Synthetic Scope and Limitations. Treatment of γ-hydroxy
internal alkenes with aryl bromides in the presence of NaOtBu
and a Pd catalyst affords substituted tetrahydrofuran products
in moderate to good yields with diastereoselectivities ranging
from 3-5:1 (acyclic alkenes) to >20:1 (cyclic alkenes). Two
bonds and two contiguous stereocenters are formed in a single
step, and the major products derive from syn-addition of the
oxygen atom and the arene across the double bond. These
reactions are operationally simple and can be employed for the
synthesis of a range of monocyclic, spirocyclic, and fused
bicyclic products. The starting materials, reagents, and catalysts
are readily available and can be weighed and handled in air.
These reactions are effective with a variety of different aryl/
vinyl halide coupling partners, including aryl halides bearing
electron-donating substituents, electron-withdrawing substitu-
ents, or ortho-substituents, although the best chemical yields
are obtained with electron-neutral or electron-rich aryl bro-
mides. The use of heteroaryl bromides is also feasible, provided
that the chelating phosphine ligand xantphos is used in place
of P(o-tol)3.
In contrast to related reactions of γ-hydroxy terminal alkenes,
which are effective for a broad array of primary, secondary,
and tertiary alcohol substrates, the transformations described
in this paper are currently limited to tertiary alcohols. Reactions
involving internal alkene substrates also require higher reaction
temperatures (110 °C) and/or catalyst loadings (2-5 mol % Pd)
than are employed with substrates bearing terminal alkenes (65
°C, 2 mol % Pd). However, despite these limitations, most
reactions are complete in a few hours.25
The reactions of substrates bearing tethered acyclic internal
alkenes are stereospecific, and reactions of both (E)- and (Z)-
alkene substrates proceed with similar diastereoselectivities.
Mixtures of tetrahydrofuran regioisomers are obtained in these
transformations with regioselectivities from 3:1 to 20:1. The
highest regioselectivities are observed in reactions of unhindered
aryl bromides, and regioselectivities appear to be generally
higher with (E)-alkene substrates. In all cases examined,
excellent selectivity is obtained for 5-exo-cyclization; tetrahy-
dropyran derivatives resulting from 6-endo-cyclization are not
observed.
Transformations of substrates bearing cycloalkenes proceed
with uniformly high diastereoselectivity and regioselectivity
(>20:1). Reactions of cyclohexene derivatives proceed more
rapidly than the analogous reactions of cyclopentene derivatives.
Cyclizations of trisubstituted internal alkenes proceed in good
yield for cyclohexene-containing substrates, but provide only
Heck-type products when cyclopentene derivatives are employed
as starting materials.
were ruled out on the basis of the observed stereoselectivity
and the high regioselectivity (5-exo-addition vs 6-endo-addition)
of these transformations,11 although our preliminary data could
not distinguish between the two possible pathways (Pd-C vs
Pd-O bond insertion) depicted in Scheme 1.
In the absence of competing pathways or other side reactions
the mechanistic hypothesis outlined in Scheme 1 suggests that
very high stereoselectivity for syn-addition should be observed.
This prediction holds true for reactions of cyclic alkene
substrates, which proceed with >20:1 syn-diastereoselectivity,
but transformations of acyclic internal alkenes afford 3-5:1
mixtures of syn- and anti-addition products. The origin of the
modest stereoselectivity for syn-addition observed with acyclic
internal alkene substrates could potentially arise from three
possible scenarios. One possibility would involve rapid (E)-
alkene/(Z)-alkene interconversion under the reaction conditions,
as syn-addition across the different alkene isomers would afford
different product diastereomers. However, three observations
suggest that this scenario is unlikely. First of all, the reactions
are stereospecific, and both the (E)- and the (Z)-alkene isomers
are transformed with ∼5:1 diastereoselectivity for syn-addition
across either the E or the Z double bond (with simple
p-substituted aryl bromide coupling partners). Additionally,
retention of alkene geometry is observed when starting materials
are isolated from reactions that are monitored and stopped at
partial conversion. Finally, the observation that transformations
of 27 and 31 bearing deuterium atoms at the C5 or C6 positions
provide products in which deuterium migration is observed in
the minor diastereomer but not the major diastereomer (eqs 3
and 4) is also not consistent with loss of selectivity via E/Z
isomerization.
It is also possible that the modest diastereoselectivity in these
transformations could arise from two competing mechanisms,
the Wacker-type anti-addition3 and the syn-insertion of the
alkene into the Pd(Ar)(OR) complex, operating simultaneously
at different rates. These competing pathways would provide
opposite diastereomers and should both be stereospecific.
However, this scenario does not account for the observed
(25) Reactions of cyclopentene derivatives require longer reaction times (ca.
48 h).
9
16472 J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005

Pd-Catalyzed Synthesis of Disubstituted THFs
A R T I C L E S
Scheme 2
Scheme 3
migration of deuterium depicted in eqs 3 and 4. As shown in
Scheme 2, the Wacker mechanism should lead to products
resulting from anti-addition with the deuterium label located
on the same carbon that was labeled in the starting material.
For example, the expected diastereomer that would be formed
by Wacker-type reaction of 31 would be 38 (deuterated at C1′)
rather than the observed product 33 (deuterated at C2). Thus, it
does not appear that competing Wacker-type addition is the
predominant pathway for formation of the minor diastereomer.
A third possible mechanism that accounts for formation of
the minor diastereomer with deuterium migration and also for
formation of regioisomer 30 (deuterated at C1′) is shown in
Scheme 3.26 Treatment of 31 with a Pd(0) catalyst, an aryl
bromide, and NaOtBu could afford palladium aryl alkoxide
complex 39.17 syn-Insertion of the alkene into the Pd-O bond
would provide 40,13,14 which could undergo C-C bond-forming
reductive elimination to produce the observed major diastere-
omer with the deuterium label at C1′ (32).27 Alternatively,
rotation about the C2-C1′ σ bond of 40 followed by syn-â-
hydride elimination (via conformer 40′) would provide pal-
ladium aryl hydride alkene complex 41. Reinsertion of the
alkene into the Pd-H bond with opposite regiochemistry would
give 42,28 which could then undergo another C2-C1′ σ bond
rotation and syn-â-deuteride elimination (via conformer 42′) to
give 43. Reinsertion of the alkene into the Pd-D bond with
reversed regiochemistry would provide 44, which could undergo
C-C bond-forming reductive elimination to produce the
observed minor diastereomer with the deuterium label at C2
(33). Alternatively, intermediate 42 could undergo syn-elimina-
tion of the C3 â-hydrogen followed by regiochemically reversed
reinsertion into the Pd-H bond and subsequent C-C bond-
forming reductive elimination from 46 to give regioisomeric
product 30. The observation that deuterium scrambling in the
minor diastereomer is not complete (78% D at C2, 84% H at
C1′)24 could be due to a small amount of diastereomer formation
via the competing Wacker-type pathway described above
(Scheme 2).29
Although, in principle, â-hydride elimination of 40′ could
also occur from the C2′ methyl group, this could be expected
to be considerably slower than the observed elimination from
the C2-H (adjacent to the THF oxygen atom). The transition
state for a â-hydride elimination process leading from an
alkylpalladium complex to a palladium hydride alkene complex
is believed to contain a significant developing positive charge
on the carbon from which the hydride departs.30 The developing
positive charge could be stabilized by the adjacent THF oxygen
in transition state 47 (C2 â-hydride elimination), whereas in
transition state 48 (C2′ methyl â-hydride elimination) the
(26) For an example of stereochemical inversion in an isolated palladium
complex that proceeds through a similar mechanism, see: Burke, B. J.;
Overman, L. E. J. Am. Chem. Soc. 2004, 126, 16820-16833.
(27) Carbon-carbon bond-forming reductive elimination is believed to occur
with retention of configuration. See: Milstein, D.; Stille, J. K. J. Am. Chem.
Soc. 1979, 101, 4981-4991.
(28) For related examples of stereospecific deuterium migration via reversible
â-hydride/deuteride elimination processes, see: (a) Qian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2003, 125, 2056-2057. (b) Reference 13.
positive charge would be relatively unstable due to its location
on a methyl carbon. Thus, transition state 47 should be con-
siderably lower in energy than 48. If isomerization occurs via
9
J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005 16473

A R T I C L E S
Scheme 4
Hay and Wolfe
Scheme 5
reversible â-hydride elimination from the C2′ methyl group,
the minor diastereomer would be expected to contain at least
partial deuterium incorporation at the C2′ methyl group (Scheme
4, 50), which is not observed by 2H NMR analysis of the product
mixture.
Pd-O bond of an intermediate Pd(Ar)(OR) complex. On the
basis of the mechanistic hypothesis outlined in Scheme 3, the
transformation of CD3-labeled substrate 34 would be expected,
as observed, to afford both the major (35) and the minor (36)
diastereomers with no migration of deuterium.
The mechanistic hypothesis described in Scheme 3 can also
be used to explain the large difference in diastereoselectivity
observed in reactions of cyclic alkenes as compared to acyclic
internal alkenes. As shown in Scheme 5, intramolecular insertion
of the cycloalkene into the Pd-O bond of palladium aryl
alkoxide intermediate 53 derived from cyclic olefin substrate 1
would afford 54. Complex 54 contains a single â-hydrogen atom
with a syn-relationship to the metal (H6R). Although H6R
could potentially undergo â-hydride elimination to afford 55,
the Pd(Ar)(H) complex cannot be transferred to the opposite
face of the alkene to afford 56 through a mechanism analogous
to that described in Scheme 3; there is no pathway that would
lead to a σ-alkylpalladium complex similar to 42 that could
undergo a C-C bond rotation as depicted above (Scheme 3,
42 f 42′). In principle, the alkene 57 could be displaced from
the metal and then reassociate on the opposite alkene face to
afford 56. However, the intermediate LnPd(Ar)(H) complex 58
would be likely to undergo unimolecular C-H bond-forming
reductive elimination at a much faster rate than bimolecular
alkene coordination and insertion into the Pd-H bond. Thus,
the mechanism outlined above predicts, as observed, that cyclic
alkenes should be transformed with high levels of diastereose-
lectivity. The origins of the diminished stereo- and regioselec-
tivity observed in reactions of sterically hindered aryl bromides
with acyclic internal alkenes are not entirely clear but may arise
from changes in the relative rates of C-C bond-forming
reductive elimination vs â-hydride elimination or from shifts
in the equilibria shown in Scheme 3.
The results of the additional deuterium labeling experiments
described in eqs 3 and 5 are also consistent with this mechanistic
proposal. As shown in Scheme 3, treatment of 27 with
4-bromobiphenyl in the presence of NaOtBu and a Pd(0)
complex could provide Pd(Ar)(OR) intermediate 51. Intramo-
lecular alkene insertion into the Pd-O bond of 51 followed by
reductive elimination from 52 would afford major diastereomer
28 bearing the deuterium label at C2. From intermediate 52, a
series of σ bond rotations and reversible â-hydride or â-deuteride
elimination reactions analogous to those described above would
afford minor diastereomer 29 or regioisomer 30 bearing the
deuterium at C1′. As noted above, the incomplete scrambling
of the deuterium in 29 may be due, in part, to the formation of
a small amount of the minor diastereomer via competing
Wacker-type cyclization (Scheme 2).29
The transformation described in eq 5 is also consistent with
product formation via intramolecular alkene insertion into the
(29) The reaction of 31 with 4-bromobiphenyl shown in eq 4 afforded the minor
diastereomer 33 with ∼80% deuterium scrambling, whereas the analogous
reaction of 27 (eq 3) provided the minor diastereomer 29 with ∼60%
deuterium scrambling. This small difference was reproducible and is not
believed to be due simply to experimental error. The origin of this difference
is not clear. However, it is possible this difference could be due to a kinetic
isotope effect, which would slow the rate of C2 â-deuteride elimination
from 52 (Scheme 3). This could lead to competing â-hydride elimination
from the CH3 group and partial formation of the minor diastereomer with
no isotopic scrambling through a mechanism similar to that shown in
Scheme 4. The isolation of a trace amount of minor regioisomer 4c (eq 2),
which likely arises from reductive elimination of an intermediate similar
to 49 (Scheme 4), suggests this pathway may be viable, albeit a minor
contributor to the overall product distribution. One might anticipate that
the influence of kinetic isotope effects on other â-hydride elimination/
reinsertion steps could lead to other changes in product distribution.
However, efforts to interpret possible isotope effects in this reaction are
complicated by the fact that primary deuterium kinetic isotope effects for
syn-â-hydride elimination have been reported to range from ∼1.3 to >5
and appear to be dependent on both the catalyst and substrate structure.
Thus, it is not inconceivable that the magnitude of kinetic isotope effects
in this system could depend on the position of the deuterium atom in any
given intermediate. For lead references, see: (a) Mueller, J. A.; Goller, C.
P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724-9734. (b) Steinhoff,
B. A.; Stahl, S. S. Org. Lett. 2002, 4, 4179-4181. (c) Lloyd-Jones, G. C.;
Slatford, P. A. J. Am. Chem. Soc. 2004, 126, 2690-2691.
The outcome of the deuterium labeling experiments described
in eqs 3-5 can also be used to evaluate the potential viability
of a mechanism involving insertion into the Pd-C bond rather
than the Pd-O bond of an intermediate Pd(Ar)(OR) complex
(e.g., 39). As shown in Scheme 6, intramolecular alkene
insertion into the Pd-C bond of 39 (derived from substrate 31
as in Scheme 3) would afford palladium alkyl alkoxide 59. In
principle, this intermediate Pd(II) complex could undergo an
(30) Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005-7013.
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16474 J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005

Pd-Catalyzed Synthesis of Disubstituted THFs
A R T I C L E S
Scheme 6
unprecedented sp3 C-O bond-forming reductive elimination17,18
to afford the observed major diastereomer 32 bearing a
deuterium atom at C1′. However, carbopalladation reactions in
mechanistically related Heck reactions are believed to be
irreversible;31-33 thus, conversion of 59 to observed regioisomer
30 is unlikely. Moreover, there is no plausible pathway that
could lead to the formation of 30 from 39 via either endo- or
exo-carbopalladation of the alkene.
Pd(II) complexes generally favor 6-exo-cyclization over 7-endo-
cyclization,31 with the latter transformations extremely rare for
Pd-C insertion processes31,37 and, to the best of our knowledge,
unknown for Pd-H or Pd-D insertion processes. If this
sequence were to occur, 63 could, in principle, undergo selective
â-hydride elimination of the endocyclic hydrogen atom (via
conformation 63′) in preference to â-elimination of one of the
methyl exo-hydrogen atoms to afford palladium hydrido alkox-
ide 64.38 This type of endo-â-hydride elimination is thermody-
namically favorable relative to competing exo-â-hydride elimi-
nation, but is often kinetically slow.38 From complex 64, alkene
insertion into the Pd-H bond followed by sp3 C-O bond-
forming reductive elimination from 65 would provide observed
minor diastereomer 33.
Although a mechanism could be postulated for the formation
of the observed minor diastereomer 33 bearing a C2 deuterium
atom from 59, several of the required steps appear to be rather
implausible. The pathway for conversion of 59 to 33 would
involve initial rotation about the C2-C1′ bond followed by
â-hydride elimination from conformer 59′ to afford Pd(deuterio)-
(alkoxide) 60. Although related Pd(H)(OMe) complexes have
been described,34 they are known to undergo facile O-H bond-
forming reductive elimination reactions to generate alcohols,
and the formation of Pd(H)(OMe) complexes via O-H bond
oxidative addition is thermodynamically unfavorable.34 Reduc-
tive elimination of potential intermediate 60 would generate
Heck-type product 66, which is not observed in significant
amounts (<2%).
Although we cannot unambiguously rule out the mechanistic
scenario outlined in Scheme 6, this pathway cannot account for
the observed formation of regioisomer 30. In addition, this
scenario requires several steps that would proceed via high-
energy transition states (e.g., 61 or 62) to occur in preference
to alternative pathways that appear to be lower in energy (e.g.,
60 f 66). Thus, product formation via this mechanism seems
unlikely. In contrast, the mechanistic pathway involving in-
tramolecular insertion of the alkene into the Pd-O bond outlined
in Scheme 3 accounts for the formation of all observed products.
Most steps invoked in this pathway are well established (e.g.,
σ bond rotation, â-hydride elimination, and C-C bond-forming
reductive elimination), with the exception of the alkene insertion
Conversion of potential intermediate 60 to the observed minor
diastereomer 33 would require 7-endo-deuteriopalladation either
via twisted transition state 6135 or via eclipsed transition state
62 to afford 63.36 Intramolecular alkene insertion reactions of
(31) (a) Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447-
471. (b) Link, J. T. Org. React. 2002, 60, 157-534. (c) Negishi, E. -i.;
Coperet, C.; Ma, S.; Liou, S. -Y.; Liu, F. Chem. ReV. 1996, 96, 365-
393.
(35) Related carbopalladation reactions of alkenes are believed to proceed via
transition states in which the Pd-C bond is eclipsed with the C-C double
bond; twisted transition states in which the Pd-C and CdC bonds are
perpendicular are believed to be energetically unfavorable. See: Overman,
L. E. Pure. Appl. Chem. 1994, 66, 1423-1431 and references therein.
Insertion of ethylene into Pt-H bonds is also believed to require a coplanar,
eclipsed orientation of the alkene and the platinum hydride. See: Thorn,
D. L.; Hoffmann, R. J. Am. Chem. Soc. 1978, 100, 2079-2090.
(36) Eclipsed transition state 62 would afford the enantiomer of 63 (ent-63).
The mechanistic scheme for conversion of ent-63 to 33 is analogous to
that shown for the conversion of 63 to ent-33 and has been omitted for
clarity.
(37) Gibson, S. E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.; Tozer, M. J. J.
Chem. Soc., Perkin Trans. 1 1997, 447-456 and references therein.
(38) (a) Osakada, K.; Doh, M. -K.; Ozawa, F.; Yamamoto, A. Organometallics
1990, 9, 2197-2198. (b) Zhang, L.; Zetterberg, K. Organometallics 1991,
10, 3806-3813. (c) Newkome, G. R.; Puckett, W. E.; Gupta, V. K.;
Formczek, F. R. Organometallics 1983, 2, 1247-1249.
(32) Perch, N. S.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 6332-
6346.
(33) Previously described examples of â-aryl elimination from (phenethyl)-
palladium(II) complexes typically involve cationic complexes with no syn-
â-hydrogens. Analogous intermediates bearing â-hydrogen atoms appear
to undergo â-hydride elimination more rapidly than â-aryl elimination.
See: (a) Campora, J.; Gutierrez-Puebla, E.; Lopez, J. A.; Monge, A.; Palma,
P.; del Rio, D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40, 3641-
3644. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 119-122. (c) Catellani, M.; Fagnola, M. C. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2421-2422. Most examples of â-alkyl elimination
from Pd(II) intermediates involve strained ring systems. See: (d) Mat-
sumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003,
125, 8862-8869. (e) Wang, X.; Stankovich, S. Z.; Widenhoefer, R. A.
Organometallics 2002, 21, 901-905 and references therein.
(34) Perez, P. J.; Calabrese, J. C.; Bunel, E. E. Organometallics 2001, 20, 337-
345.
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J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005 16475

A R T I C L E S
Hay and Wolfe
0.005 mmol), P(o-tol)3 (6.1 mg, 0.02 mmol), sodium tert-butoxide (96
mg, 1.0 mmol), and the aryl or vinyl bromide (1.0 mmol). The tube
was purged with Ar followed by the addition of toluene (2 mL), the
alcohol substrate (0.5 mmol), and additional toluene (2 mL). The
reaction mixture was heated to 110 °C with stirring until the alcohol
substrate had been completely consumed as judged by GC analysis.
The reaction mixture was cooled to room temperature, and saturated
aqueous NH4Cl (2 mL) and ethyl acetate (10 mL) were added. The
layers were separated, and the aqueous layer was extracted with ethyl
acetate (2 × 10 mL). The combined organic layers were dried over
anhydrous Na2SO4, decanted, and concentrated in vacuo. The crude
material was purified by flash chromatography on silica gel.
into the Pd-O bond, which, although rare, is not entirely
unprecedented.13,14
Conclusions
In conclusion, our studies on the Pd-catalyzed carboetheri-
fication of internal alkenes suggest that the predominant
mechanistic pathway for tetrahydrofuran formation likely
involves a rare syn-insertion of an alkene into the Pd-O bond
of an intermediate palladium aryl alkoxide. These studies also
indicate that the moderate diastereoselectivity observed in
reactions of substrates bearing acyclic internal alkenes is likely
due to stereochemical scrambling via â-hydride elimination/
reinsertion and σ bond rotation processes that occur after the
alkene insertion step. This pathway for stereochemical scram-
bling is not accessible when substrates bearing cyclic internal
alkenes are employed, and high diastereoselectivity for syn-
addition is observed.
(()-(1′S,5R)-5-[1′-(4-Phenyl)phenylethyl]-2,2-dimethyltetrahydro-
furan (4a). Reaction of 64 mg (0.5 mmol) of trans-2-methyl-5-hepten-
2-ol with 4-bromobiphenyl (223 mg, 1.0 mmol) following the general
procedure afforded 100 mg (71%) of the title compound as a colorless
oil. This material was obtained as a 5:1 mixture of diastereomers and
1
contained ∼5% 4b + 4c as judged by H NMR analysis; data are for
1
the major isomer. H NMR (500 MHz, CDCl3): δ 7.60-7.57 (m, 2
The transformations described in this paper represent an
operationally simple and straightforward means for the stereo-
selective construction of 2,1′-disubstituted tetrahydrofurans,
6-substituted octahydrocyclopenta[b]furans, 7-substituted octa-
hydrobenzofurans, and 6-substituted 1-oxaspiro[4.5]decanes.
The reactions are stereospecific and provide good yields with a
variety of different aryl and vinyl bromide coupling partners.
Further studies to improve the scope of these transformations
and the diastereoselectivity in reactions of acyclic internal alkene
substrates are currently under way.
H), 7.53-7.51 (m, 2H), 7.44-7.40 (m, 2 H), 7.34-7.32 (m, 3 H),
4.19-4.15 (m, 1 H), 2.97-2.91 (m, 1 H), 1.92-1.86 (m, 1 H), 1.79-
1.72 (m, 1 H), 1.69-1.62 (m, 1 H), 1.61-1.54 (m, 1 H), 1.30 (d, J )
7.0 Hz, 3 H), 1.213 (s, 3 H), 1.210 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ 143.3, 141.2, 138.9, 128.7, 128.6, 127.0, 126.9, 126.7; 82.6,
80.6, 43.9, 38.5, 28.7, 28.6, 28.0, 16.5. IR (film): 1515, 1059 cm-1
.
Anal. Calcd for C20H24O: C, 85.67; H, 8.63. Found: C, 85.29; H, 8.31.
Acknowledgment. We thank the NIH-NIGMS (Grant GM-
076150) and the University of Michigan for financial support
of this work. J.P.W. acknowledges the Camille and Henry
Dreyfus Foundation for a New Faculty Award and Research
Corp. for an Innovation Award. We also thank Amgen, 3M,
and Eli Lilly for additional unrestricted support.
Experimental Section
General Procedure for Palladium-Catalyzed Reactions of γ-Hy-
droxy Internal Alkenes with Aryl Bromides.39 A flame-dried or oven-
dried Schlenk tube equipped with a magnetic stir bar was cooled under
a stream of argon or nitrogen and charged with Pd2(dba)3 (4.6 mg,
Supporting Information Available: Experimental procedures
for the synthesis of substrates, characterization data for all new
compounds, descriptions of deuterium labeling experiments, and
descriptions of stereochemical assignments (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(39) The yields reported in the Experimental Section and the Supporting
Information describe the result of a single experiment, whereas the yields
reported in eqs 1 and 2 and Tables 2 and 3 are average yields of two or
more experiments. Thus, the yields reported in the Supporting Information
may differ from those shown in eqs 1 and 2 and Tables 2 and 3.
JA054754V
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16476 J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005