Strategies for expanding structural diversity available from olefin isomerization-Claisen rearrangement reactions

Article abstract of DOI:10.1021/jo0605851

Boron-substituted di(allyl) ethers provide an efficient conduit for expanding the structural diversity available from olefin isomerization-Claisen rearrangement (ICR) reactions. Easily prepared allyl propargyl ethers undergo chemoselective Zr(IV)-catalyze

Full text of DOI:10.1021/jo0605851

Strategies for Expanding Structural Diversity Available from Olefin
Isomerization-Claisen Rearrangement Reactions
Benjamin D. Stevens, Christopher J. Bungard, and Scott G. Nelson*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
sgnelson@pitt.edu
ReceiVed March 16, 2006
Boron-substituted di(allyl) ethers provide an efficient conduit for expanding the structural diversity available
from olefin isomerization-Claisen rearrangement (ICR) reactions. Easily prepared allyl propargyl ethers
undergo chemoselective Zr(IV)-catalyzed hydroboration to afford the boron-substituted ICR substrates.
The boron-substituted allyl residue undergoes chemoselective Ir(I)-catalyzed olefin isomerization and in
situ Claisen rearrangement to afford stereodefined â-boryl aldehyde products. Functionalization of the
C-B linkage by oxidation or Suzuki cross-coupling provides a route to Claisen adducts previously
inaccessible from the ICR methodology.
Introduction
easily prepared di(allyl) ethers as direct progenitors of aliphatic
Claisen rearrangements and relies on chemoselective Ir(I)-
catalyzed olefin isomerization to arrive at the characteristic allyl
vinyl ether Claisen rearrangement precursors (eq 1).4 However,
[3,3] Sigmatropic rearrangements are characterized by their
ability to rapidly introduce molecular complexity from simple
precursors and to dramatically alter substrate morphology in a
single operation.1 Ireland enolate Claisen and anionic oxy-Cope
rearrangements constitute the most extensively utilized [3,3]
rearrangements in synthesis activities due, in large part, to the
facile substrate preparation and mild reaction conditions offered
by these activated reaction variants.2 With the goal of imparting
similar operational features to aliphatic Claisen rearrangements,
we developed olefin isomerization-Claisen rearrangement
(ICR) reactions as a strategy for affecting highly stereoselective
[3,3] sigmatropic rearrangements.3 The olefin isomerization-
Claisen rearrangement methodology is predicated on exploiting
(1) (a) Ziegler, F. E. Chem. ReV. 1988, 88, 1423. (b) Ito, H.; Taguchi,
T. Chem. Soc. ReV. 1999, 28, 43. (c) Hiersemann, M.; Abraham, L. Eur. J.
Org. Chem. 2002, 1461. (d) Nubbemeyer, U. Synthesis 2003, 961.
(2) (a) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 827. (b) Wilson, S.
R. Org. React. (New York) 1993, 43 93. (c) Paquette, L. A. Tetrahedron
1997, 53, 13971.
di(allyl) ethers bearing substituents that, due to conjugative
stabilization, retard olefin isomerization were not effective ICR
substrates. Unfortunately, this family of substrates included aryl-,
10.1021/jo0605851 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/20/2006
J. Org. Chem. 2006, 71, 6397-6402
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Stevens et al.
a γ substituent (X) that would not impede isomerization and,
following the olefin isomerization-rearrangement sequence,
could be used to introduce the desired substituents (eq 2). The
synthetic versatility of C-B linkages as precursors to new C-O
or C-C bonds inspired us to investigate boron-containing
di(allyl) ethers as the requisite ICR substrates. The reaction
design emerging from these considerations would involve
chemoselective hydroboration of allyl propargyl ether 2 to
provide the boron-substituted di(allyl) ether 1 (Figure 3).
Iridium-catalyzed olefin isomerization would proceed to deliver
allyl vinyl ether 3 that, under the optimized ICR reaction
conditions, would directly undergo ensuing Claisen rearrange-
ment to afford the boron-substituted Claisen adduct 4. The
emerging Claisen adducts would offer opportunities for direct
aldehyde functionalization or manipulation of the boronic ester
functionality to access a diverse array of Claisen adducts from
the common synthesis precursor 4.
FIGURE 1. Structural diversity available from modified ICR reactions.
FIGURE 2. Reactivity profile for ICR reactions.
alkenyl-, or oxygen-substituted substrates, each of which would
afford valuable synthesis templates provided they could be
engaged in the ICR reactions. To circumvent this limitation,
we envisioned a strategy for accessing a broader family of
Claisen adducts with the boron-substituted di(allyl) ether 1
serving as the common synthesis template (Figure 1). Herein,
we describe the ICR reactions of boron-substituted di(allyl)
ethers, the properties of the derived â-boryl aldehydes, and the
utility of these species as conduits to Claisen adducts previously
inaccessible from the ICR methodology.
FIGURE 3. ICR reactions of boron-substituted di(allyl) ethers.
Results and Discussion
Implementing this ICR reaction design required efficient
hydroboration of the allyl propargyl ethers that would serve as
precursors to the di(allyl) ether ICR substrates. In addressing
the issue of chemoselectivity, we were inspired by Srebnik’s
report of chemoselective Zr(IV)-catalyzed hydroboration of
alkynes in the presence of alkene functionalities.6 On the basis
of this precedent, we examined the hydroboration of allyl
propargyl ether 5 with pinacolborane using Cp2Zr(H)Cl as the
catalyst (eq 3). Under the reported conditions, we discovered
Chemoselective olefin isomerization of di(allyl) ethers is an
essential component of the ICR reaction design.3 Iridium
insertion into the sterically more accessible C-H bond ensures
that the R-substituted allyl residue is protected from isomer-
ization (Figure 2).5 However, γ substituents on the unsubstituted
allyl residue that retard olefin isomerization through conjugative
stabilization lead to either no isomerization or competitive
isomerization of the substituted allyl unit. We required, therefore,
(3) (a) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am. Chem. Soc. 2003,
125, 13000-13001. (b) Stevens, B. D.; Nelson, S. G. J. Org. Chem. 2005,
70, 4375-4379. (c) Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128,
4232-4233.
(4) Other examples of olefin isomerization-Claisen rearrangements: (a)
Reuter, J. M.; Salomon, R. G. J. Org. Chem. 1977, 42, 3360. (b) Wille, A.;
Tomm, S.; Frauenrath, H. Synthesis 1998, 305. (c) Higashino, T.; Sakaguchi,
S.; Ishii, Y. Org. Lett. 2000, 2, 4193. (d) Ben Ammar, H.; Le Noˆtre, J.;
Salem, M.; Kaddachi, M. T.; Dixneuf, P. H. J. Organomet. Chem. 2002,
662, 63. (e) Le Noˆtre, J.; Brissieux, L.; Se´meril, D.; Bruneau, C.; Dixneuf,
P. H. Chem Commun. 2002, 1772. (f) Schmidt, B. Synlett 2004, 1541.
(5) For a detailed investigation of Ir(I)-catalyzed allylic ether isomer-
ization, see: Ohmura, T.; Yamamoto, Y.; Miyaura, N. Organometallics
1999, 18, 413 and references therein.
that alkyne hydroboration was very sluggish and did not afford
useable yields of the desired pinacolate boronic ester 6.
(6) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127-3128.
6398 J. Org. Chem., Vol. 71, No. 17, 2006

Strategies for Expanding Structural DiVersity
However, conducting the Zr(IV)-catalyzed hydroboration of 5
under microwave irradiation resulted in highly efficient alkyne
hydroboration without competing alkene hydroboration.7
Thus, the boron-substituted ICR substrates were obtained by
Williamson etherification of the allylic alcohols 7 with propargyl
bromide (NaH, THF, 65 °C) to afford the allyl propargyl ethers
5a-c (73-84%). Microwave-accelerated hydroboration of the
resulting propargyl ethers under Zr(IV) catalysis (5 mol % of
Cp2Zr(H)Cl, CH2Cl2, 100 °C microwave IR probe temperature)
then afforded the desired ICR substrates in the form of the
boron-containing di(allyl) ethers 6a-c (75-83%). A similar
reaction sequence provided the enantioenriched trienyl allyl ether
6d from the corresponding 3S-trienyl alcohol 7d indicative of
the zirconium-catalyzed hydroboration’s faithful chemoselec-
tivity even in the presence of multiple alkene functionalities.
Having secured access to the boron-containing di(allyl) ethers,
we were prepared to evaluate these materials as substrates for
the ICR bond reorganization. Successfully engaging these
substrates in the ICR sequence was predicated on achieving
selective vinyl boronate-allyl boronic ester isomerization
without competing isomerization of the R-substituted allyl
residue.8 Subjecting 6 to the standard ICR reaction conditions
(2 mol % of Ir(PCy3)3+, 25:1 CH2Cl2/acetone) elicited chemo-
selective vinyl boronate isomerization to afford the desired
E-allyl boronate (eq 4). Despite the presence of the boron
FIGURE 4. X-ray structure of Claisen adduct 8c.
The structure of the ICR-derived aldehydes 8 offered intrigu-
ing possibilities for eliciting unique reactivity patterns during
nucleophilic addition to the aldehyde function. We entertained
the notion that chelate organization of the R-chiral aldehyde
might be achieved by boron coordination of the aldehyde
oxygen. Similar chelate organization of alkyl boronic esters has
been exploited by Molander to achieve highly diastereoselective
carbonyl reductions.9 However, X-ray structure analysis of the
â-boryl aldehyde 8c revealed no evidence for this type of
chelation (Figure 4). Indeed, the boron atom in 8c exhibits none
of the pyramidalization that would accompany even weak Lewis
acid-base association (B-O distance of ∼2.9 Å). Poor overlap
between the oxygen lone pair residing in an sp2 hybrid orbital
and the vacant boron p orbital is believed to provide the barrier
for B-O chelation. These geometric constraints precluding
B-O coordination, however, would be largely relieved upon
oxygen rehybridization to an sp3 geometry. Consistent with this
n
supposition, reacting 8a with PrOLi affords an adduct that is
substituent, steric crowding continues to protect the alternative
allyl residue from alkene isomerization. Moreover, olefin
isomerization remains highly E selective, a significant observa-
tion considering that olefin stereochemistry is directly reflected
in Claisen diastereoselection. In accord with the optimized ICR
reaction conditions, the allyl vinyl ethers emerging from olefin
isomerization were directly engaged in thermal [3,3] sigmatropic
rearrangement to generate the 2,3-syn-â-boryl aldehydes 8a-c
(61-67%, syn/anti ) 91:9-92:8). The enantioenriched di(allyl)
ether 6d undergoes analogous ICR reorganization to afford the
diene-substituted Claisen adduct 8d; ICR reactions of enantio-
enriched di(allyl) ethers proceed with near perfect translation
of chirality (eq 5).3a,c
immune to further nucleophilic addition and, following workup,
affords the starting aldehyde with no stereochemical erosion
(eq 6).10 These observations in conjunction with corroborating
1H NMR data support the alkoxide-mediated formation of the
chelated borate acetal 9 indicative of the effect oxygen rehy-
bridization has on internal Lewis acid-base coordination.11
(9) (a) Molander, G. A.; Bobbitt, K. L.; Murray, C. K. J. Am. Chem.
Soc. 1992, 114, 2759-2760. (b) Molander, G. A.; Bobbitt, K. L. J. Am.
Chem. Soc. 1993, 115, 7517-7518. For other examples of stereoselective
nucleophilic additions due to internal boron chelation, see: (c) Curtius, A.
D.; Mears, R. J.; Whiting, A. Tetrahedron 1993, 49, 187-198. (d) Mears,
R. J.; Whiting, A. Tetrahedron Lett. 1993, 34, 8155-8156. (e) Mears, R.
J.; Sailes, H. E.; Watts, J. P.; Whiting, A. J. Chem. Soc., Perkin Trans. 1
2000, 3250-3263. (f) Sailes, H. E.; Watts, J. P.; Whiting, A. J. Chem.
Soc., Perkin Trans. 1 2000, 3362-3374.
(10) Examples of nucleophile-mediated in situ aldehyde protection: (a)
Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1981, 22, 4213-4216. (b)
Reetz, M. T.; Wenderoth, B.; Peter, R. J. Chem. Soc., Chem. Commun.
1983, 406-408.
(7) For an example of Rh(I)-catalyzed hydroborations accelerated by
microwave irradiation, see: Hadebe, S. W.; Robinson, R. S. Tetrahedron
Lett. 2006, 47, 1299-1302.
(8) (a) Moriya, T.; Suzuki, A.; Miyaura, N. Tetrahedron Lett. 1995, 36,
1887-1888. (b) Yamamoto, Y.; Miyairi, T.; Ohmura, T.; Miyaura, N. J.
Org. Chem. 1999, 64, 296-298.
J. Org. Chem, Vol. 71, No. 17, 2006 6399

Stevens et al.
The solid-state conformation of aldehyde 8c orients the boron-
containing alkyl group to eclipse the carbonyl π system (dihedral
angle ) 4°), an orientation that is reminiscent of the low-energy
conformation about the Csp2-Csp3 bonds identified by Kara-
batsos (eq 7).12 A minimal perturbation to this solid-state
conformation would yield a Felkin-type orientation of the R
stereogenic center, wherein the boronate ester-containing alkyl
group functions as the “medium” group.13 Consistent with this
expectation, the â-boronic aldehyde 8a undergoes Lewis acid-
mediated Mukaiyama aldol addition (1.5 equiv of Me2AlCl,
CH2Cl2, -78 °C) with silyl ketene acetal 10 to afford, after
C-B bond oxidation, the Felkin-derived syn (C3-C4) aldol
adduct 11 (60%, g97:3 syn/anti) (eq 8).14 Alternatively,
δ-lactone 12 can be isolated directly from the addition-
oxidation sequence by acidifying the reaction mixture prior to
workup (71%, g97:3 cis/trans). The aldehyde 13 lacking the
â-boronic ester undergoes similar Felkin-selective Mukaiyama
aldol addition, reaffirming that the boron substituent in 8 plays
no special organizational role in defining stereoselectivity during
carbonyl addition (eq 9).15
circumventing epimerization and activating the boron moiety
toward cross coupling. However, attempted Suzuki cross-
coupling of 9 resulted in extensive â-hydride elimination
(eq 10). Despite the failure of the boronate acetals as Suzuki
reaction partners, nucleophilic addition to the aldehyde function
was expected to deliver similar internally activated boronate
species as potential cross-coupling partners. For example,
hydride-mediated reduction of aldehyde 8a afforded a stable
intermediate assigned as cyclic borinic acid 14 (50-60%),
although the free boronic acid or an oligomeric equivalent cannot
be conclusively excluded.17 In contrast to the pinacolate boronic
esters 8 and borate acetal 9, the borinic acid 14 proved to be an
efficient alkyl group donor in the targeted B-Calkyl Suzuki cross-
coupling reactions.18 Considerable optimization of the ensuing
cross-coupling reactions revealed a reaction system composed
of 5 mol % of Pd(OAc)2/25 mol % of PPh3 in aqueous Na2CO3/
t-amyl alcohol afforded efficient coupling of borinic acid 14
with both aryl and heteroaryl bromides (Table 1).19 Aryl
bromides, including 3-bromopyridine and 3-bromoquinoline,
participate in efficient coupling with 14 to afford the â-aryl
alcohols 15a-f (36-89%). Only 2-bromopyridine provided
notable difficulties as an aryl bromide reaction partner in the
cross-coupling reaction.
To probe the additional structural diversity that could be
accessed from the ICR-Suzuki cross-coupling sequence, we
explored the Claisen-derived aldehydes 8 as possible templates
for diversity-oriented synthesis. The ICR-derived aldehyde 8a
was subjected to nucleophilic addition with allylmagnesium
(12) Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367-1371.
(13) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2201. See also: (b) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61.
(14) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,
1011-1014. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem.
Soc. 1974, 96, 7503-7509. (c) Saigo, K.; Osaki, M.; Mukaiyama, T. Chem.
Lett. 1975, 989-990.
(15) Heathcock, C. H.; Flippin, L. A. J. Am. Chem. Soc. 1983, 105,
1667-1668.
(16) For reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457-2483. (b) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-coupling
Reactions; Wiley-VCH: Weinheim, 1998; p 517. (c) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147-168. (d) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633-9695 and references
therein. (e) Leadbeater, N. E. Chem. Commun. 2005, 23, 2881-2902. (f)
Apukkuttan, P.; Van der Eycken, E.; Dehaen, W. Synlett 2005, 127-133.
(g) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419-2440.
(17) 1H and 13C NMR spectral data for 14 were fully consistent with
the indicated structure. However, our inability to obtain satisfactory mass
spectral data for 14 precludes us from conclusively eliminating the free
boronic acid alcohol or an oligomeric form of 14 as alternative structures
for the species derived from the hydride addition.
(18) (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369-6372. (b) Sato, M.; Miyaura, N.; Suzuki, A. Chem.
Lett. 1989, 1405-1408. (c) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem.
1993, 58, 2201-2208. (d) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa,
M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321.
(19) Reaction conditions for Suzuki couplings were derived from the
following procedures: (a) Huff, B. E.; Koenig, T. M.; Mitchell, D.;
Staszak, M. A. Org. Synth., Coll. Vol. X 1995, 102. (b) Kirchoff, J. H.;
Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
13662-13663.
Verifying the ICR-derived boronic esters 8 as conduits to
structurally diverse Claisen adducts required these materials to
function as effective substrates for Suzuki cross-coupling
reactions.16 Initial efforts to directly engage the ICR-derived
aldehydes in basic Suzuki reaction conditions elicited consider-
able epimerization of the R-chiral aldehydes. Protecting the
aldehyde as the borate acetal 9 was considered a strategy for
(11) Borate complex 9 was not rigorously characterized; however, 1H
NMR analysis of crude reaction mixtures was completely consistent with
the proposed structure. These data coupled with the indicated reactivity
patterns exhibited by 9 (see eq 6) provided the basis for the structure
assignment. See Supporting Information for details of the 1H NMR
experiment.
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Strategies for Expanding Structural DiVersity
TABLE 1. Suzuki Cross-Coupling of Borinic Acid 15
Claisen rearrangements from easily prepared starting materials.
The boron-modified ICR reactions serve to expand the structural
diversity available directly from the ICR reactions and from
ensuing derivatization of the Claisen adducts. We anticipate that
merging the ICR methodology with ensuing Suzuki cross-
coupling reactions will further expand the utility of the ICR
technology in various synthesis activities.
Experimental Section
Representative Procedure for Synthesis of Di(allyl) Ethers
6. 2-{(1E)-3-[(E)-1-Phenylhept-1-en-3-yloxy]prop-1-enyl}-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (6a). A microwave-compatible
reaction vessel was charged with 56 mg of Cp2Zr(H)Cl21 (0.05
equiv, 0.22 mmol) and 0.33 mL of CH2Cl2 (3.0 M in alkyne). The
resulting suspension was cooled to 0 °C, and 1.00 g of propargylic
ether 5a (4.38 mmol) and 617 mg of pinacolborane (1.1 equiv,
4.82 mmol) were added. The reaction was allowed to warm to
ï
ambient temperature and was then heated at 100 C (internal IR
probe) in a microwave reactor for 45 min. The solvent was removed
in vacuo, and the residue was purified by flash chromatography
(5% EtOAc in hexanes) on Iatrobeads 6RS-8060 silica gel to afford
1
1.18 g (75%) of the title compound as a colorless oil. H NMR
(300 MHz, CDCl3): δ 7.42-7.20 (m, 5H), 6.66 (dt, J ) 18, 4.6
Hz, 1H), 6.49 (d, J ) 16 Hz, 1H), 6.05 (dd, J ) 16, 8.0 Hz, 1H),
5.73 (dt, J ) 18, 1.8 Hz, 1H), 4.15 (ddd, J ) 15, 4.4, 1.9 Hz, 1H),
3.96 (ddd, J ) 15, 4.8, 1.8 Hz, 1H), 3.85 (dt, J ) 6.5, 7.3 Hz, 1H),
1.78-1.50 (m, 2H), 1.27 (s, 12H), 1.40-1.24 (m, 4H), 0.89 (m,
3H). 13C NMR (75 MHz, CDCl3): δ 149.8, 136.5, 132.0, 130.5,
128.4, 127.5, 126.3, 118.6 (br), 83.0, 80.4, 69.5, 35.5, 27.4, 24.6,
22.6, 14.0. MS (EI) m/z 356 (M+), 341, 326, 299, 270, 257, 199,
173, 167, 155, 143, 131, 117, 105, 91, 85, 77, 67, 57. HRMS m/z
calcd for C22H3311BO3, 356.2523; found, 356.2523.
a Reaction conditions: Pd(OAc)2 (5 mol %), PPh3 (25 mol %), aryl
bromide (2 equiv), aq Na2CO3/tAmOH, 80 °C. b Values reported for purified
materials.
SCHEME 1
Representative Procedure for ICR Reactions of Di(allyl)
Ethers 6: R*-(E,2R,3S)-3-Methyl-2-[(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)methyl]-5-phenylpent-4-enal (8a). A solution
of 14 mg of [(cC8H14)2IrCl]2 (1.0 mol %, 0.02 equiv of Ir) and 27
mg of PCy3 (6.0 mol %, 0.06 equiv) in 1.2 mL of CH2Cl2 was
added to a solution of 11 mg of NaBPh4 (2.0 mol %, 0.02 equiv)
in 1.2 mL of 25:1 CH2Cl2/acetone (0.67 M final concentration in
6a), and the resulting yellow solution was stirred for 5 min at
ambient temperature. Di(allyl) ether 6a (0.500 g, 1.59 mmol) was
added. The reaction was stirred for 90 min at ambient temperature
whereupon 25 mg of PPh3 (6.0 mol %, 0.06 equiv) was added, and
the resulting solution was heated at 40 °C for 4 h. The solvent was
removed in vacuo, and the residue was purified by flash chroma-
tography (8% EtOAc in hexanes) on Iatrobeads 6RS-8060 silica
gel to afford 0.326 g (65%) of the title compound as a colorless
oil. The diastereomer ratio was determined by integration of the
vinyl CH resonance from 300 MHz 1H NMR of the crude product
bromide that, in accord with the corresponding hydride addi-
tions, afforded the borinic acid 16 as a mixture of homoallylic
alcohol diastereomers (78%, dr ∼ 2:1). Cross-coupling of 16
with 2-bromoquinoline under the optimized Suzuki conditions
then provided the diaryl alcohol 17 (58%). Engaging 17 in ring-
closing metathesis under Grubbs’ conditions (5 mol % of 18)
and alcohol oxidation (Dess-Martin) afforded the â,γ-unsat-
urated ketone 19 as a 92:8 mixture of diastereomers, reflecting
the diastereoselection of the initial Claisen rearrangement (48%
for two steps) (Scheme 1).20
1
mixture (syn:anti ) 92:8). H NMR (300 MHz, CDCl3): δ 9.76
(d, J ) 0.8 Hz, 1H), 7.36-7.20 (m, 5H), 6.42 (d, J ) 16 Hz, 1H),
6.19 (dd, J ) 16, 7.5 Hz, 1H), 2.85 (m, 1H), 2.70 (m, 1H), 1.24 (s,
6H), 1.21 (s, 6H), 1.12 (d, J ) 6.9 Hz, 1H), 1.00 (dd, J ) 16, 10
Hz, 1H), 0.82 (dd, J ) 16, 5.0 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 204.8, 137.1, 132.7, 130.1, 128.4, 127.1, 126.0, 83.1,
53.2, 37.8, 24.7, 24.5, 16.4, 6.7 (br). Satisfactory MS data could
not be obtained for this compound; copies of the 1H and 13C spectra
are provided.
Representative Procedure for the Suzuki Cross-Coupling
Reaction of 14: R*-(E,2S,3R)-2-Benzyl-3-phenylnon-4-en-1-ol
(15a). A mixture of 3.1 mg of palladium(II) acetate (5 mol %, 0.014
mmol), 11 mg of triphenylphosphine (0.042 mmol), and 75 mg of
borinic acid 14 (0.27 mmol) were placed in a CEM microwave
tube.19a The tube was sealed and evacuated under vacuum for 30
min and then backfilled with N2; the evacuate-backfill cycle was
Conclusion
Olefin isomerization-Claisen rearrangement reactions pro-
vide convenient access to highly diastereoselective aliphatic
(20) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18-29 and references therein.
(21) Buchwald, S.; LaMaire, S.; Nielsen, R.; Watson, B.; King, S. Org.
Synth., Coll. Vol. IX 1994, 162.
J. Org. Chem, Vol. 71, No. 17, 2006 6401

Stevens et al.
1
repeated two additional times.22 tert-Amyl alcohol (0.5 mL), 0.060
mL of bromobenzene (0.090 g, 0.57 mmol), and 0.25 mL of
aqueous 1.3 M sodium carbonate were added, and the reaction
mixture was stirred for 60 min at ambient temperature.23 The
reaction mixture was then heated at 80 °C for 5.5 h (yellow solution
f white suspension). The reaction was diluted with water, and the
biphasic mixture was extracted with EtOAc (3×). The combined
organic extracts were dried (Na2SO4), filtered, and concentrated.
The crude product mixture was purified by flash chromatography
(SiO2, 6:1 hexanes/EtOAc) to afford 54 mg (67%) of the title
compound as a colorless oil. Separation of the diastereomers by
GC-MS [HP-1 (12 m × 0.20 mm), pressure 21 kPa, method: 70
°C for 2.00 min, ramp at 10 °C/min to 300 °C, hold for 60 min]
provided the diastereomer ratio: 4.5% (Tr ) 18.80), 95.5% (Tr
)18.97). IR (thin film) 3389, 3026, 2926, 1601, 1494, 1453, 1030,
970, 700 cm-1. H NMR (300 MHz, CDCl3): δ 7.37-7.09 (m,
10H), 5.69 (dd, J ) 15.2, 8.8 Hz, 1H), 5.58 (dt, J ) 15.1, 6.1 Hz,
1H), 3.70 (dd, J ) 11.2, 4.0 Hz, 1H), 3.55 (dd, J ) 11.3, 4.2 Hz,
1H), 3.34 (t, J ) 9.1 Hz, 1H), 2.55 (dd, J ) 13.8, 4.8 Hz, 1H),
2.46 (dd, J ) 13.7. 9.7 Hz, 1H), 2.14 (m, 1H), 2.03 (q, J ) 6.8 Hz,
2H), 1.33 (m, 4H), 0.88 (t, J ) 7.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 144.0, 140.9, 132.0, 131.9, 129.0, 128.6, 128.3, 127.9,
126.2, 125.8, 62.1, 51.2, 47.7, 35.2, 32.2, 31.5, 22.2, 13.9. MS (EI)
m/z 308 (M+), 290, 233, 199, 173, 117, 91. HRMS (EI) m/z calcd
for C22H28O, 308.2140; found, 308.2147.
Acknowledgment. Support from the National Science
Foundation (CHE 0316000), the Bristol-Myers Squibb Founda-
tion, the Merck Research Laboratories, and Eli Lilly & Company
is gratefully acknowledged.
Supporting Information Available: Experimental procedures,
characterization data, 1H and 13C NMR spectra, and X-ray diffrac-
tion data are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
(22) For reproducible results, it is essential to remove all oxygen from
the 14/precatalyst mixture using high vacuum prior to introducing the
solvent.
(23) For the development of this solvent system for Suzuki cross-coupling
reactions, see ref 19b.
JO0605851
6402 J. Org. Chem., Vol. 71, No. 17, 2006