Electrostatic effects on the reactions of cyclohexanone oxocarbenium ions

Article abstract of DOI:10.1021/jo060968z

Nucleophilic substitution reactions of 4-substituted cyclohexanone acetals display different selectivities depending upon the electronic nature of the substituent. Alkyl groups favor equatorial positions in the oxocarbenium ions, but alkoxy groups prefer

Full text of DOI:10.1021/jo060968z

Electrostatic Effects on the Reactions of Cyclohexanone
Oxocarbenium Ions
Glen Baghdasarian and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
kwoerpel@uci.edu
ReceiVed May 10, 2006
Nucleophilic substitution reactions of 4-substituted cyclohexanone acetals display different selectivities
depending upon the electronic nature of the substituent. Alkyl groups favor equatorial positions in the
oxocarbenium ions, but alkoxy groups prefer axial conformers. The reactions of acetals with alkoxy
groups constrained to either equatorial or axial positions suggest that the presence of an axial alkoxy
group distorts the oxocarbenium ion, changing its inherent preferences for facial attack.
Introduction
structures, which exhibit different stereoselectivities than ad-
ditions to their alkyl analogues.11-19
Electrostatic effects exert powerful influences on conforma-
tional equilibria. For example, 4-methoxycyclohexanone prefers
the pseudoaxial conformation 2 in a number of solvents despite
the fact that this conformer is sterically disfavored (eq 1).1,2
Similar conformational preferences are exhibited by 4-halocy-
clohexanones, with the fluoro derivative having the highest axial
preference.3,4 This trend indicates that electrostatic forces
between the partially negatively charged substituent and the
partially positively charged carbonyl carbon atom are most likely
the origin of the contrasteric conformational preference.5 In
addition to ketones, other cyclic carbonyl compounds bearing
heteroatom substituents also favor axial conformers.6-10 The
counterintuitive preference for the axial conformer influences
nucleophilic additions to 4-alkoxycyclohexanones and related
Our studies of oxocarbenium ion reactivity have shown that
electrostatic effects dramatically influence the conformational
preferences of these cations. Structural evidence20 confirms that
electronegative heteroatoms such as oxygen atoms favor con-
formers that bring the negatively charged substituent close to
the positively charged oxocarbenium ion carbon,21 in accord
with theoretical studies.22,23 Once the conformer is defined,
(1) Stolow, R. D.; Giants, T. W. J. Chem. Soc., Chem. Commun. 1971,
528-529.
(11) Cianetti, C.; Di Maio, G.; Pignatelli, V.; Tagliatesta, P.; Vecchi,
E.; Zeuli, E. Tetrahedron 1983, 39, 657-666.
(12) Di Maio, G.; Li, W.; Vecchi, E. Tetrahedron 1985, 41, 4891-4896.
(13) Nagao, Y.; Goto, M.; Ochiai, M. Chem. Lett. 1990, 1507-1510.
(14) Wu, Y.-D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991,
113, 5018-5027.
(2) Baldry, K. W.; Gordon, M. H.; Hafter, R.; Robinson, M. J. T.
Tetrahedron 1976, 32, 2589-2594.
(3) Dosˇen-Mic´ovic´, L.; Jeremic´, D.; Allinger, N. L. J. Am. Chem. Soc.
1983, 105, 1723-1733.
(4) Freitas, M. P.; Tormena, C. F.; Oliveira, P. R.; Rittner, R. THEOCHEM
2002, 589-590, 147-151.
(15) Shi, Z.; Boyd, R. J. J. Am. Chem. Soc. 1993, 115, 9614-9619.
(16) Yadav, V. K.; Jeyaraj, D. A. J. Org. Chem. 1998, 63, 3474-3477.
(17) Tomoda, S.; Senju, T. Tetrahedron 1999, 55, 3871-3882.
(18) Di Maio, G.; Mascia, M. G.; Vecchi, E. Tetrahedron 2002, 58,
3313-3318.
(5) For an explanation invoking orbital effects, see: Nagao, Y.; Goto,
M. Heterocycles 1995, 41, 883-888.
(6) Bowen, J. P.; Allinger, N. L. J. Org. Chem. 1987, 52, 1830-1834.
(7) Nagao, Y.; Goto, M.; Ochiai, M.; Shiro, M. Chem. Lett. 1990, 1503-
1506.
(19) Catanoso, G.; Vecchi, E. Tetrahedron 2003, 59, 5555-5561.
(20) Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem. Soc.
2005, 127, 5322-5323.
(8) Boudreault, N.; Ball, R. G.; Bayly, C.; Bernstein, M. A.; Leblanc,
Y. Tetrahedron 1994, 50, 7947-7956.
(9) Morimoto, Y.; Shirahama, H. Tetrahedron 1997, 53, 2013-2024.
(10) Branda¨nge, S.; Fa¨rnba¨ck, M.; Leijonmarck, H.; Sundin, A. J. Am.
Chem. Soc. 2003, 125, 11942-11955.
(21) Dudley, T. J.; Smoliakova, I. P.; Hoffmann, M. R. J. Org. Chem.
1999, 64, 1247-1253 and references therein.
(22) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc.
1992, 114, 859-864.
10.1021/jo060968z CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006
J. Org. Chem. 2006, 71, 6851-6858
6851

Baghdasarian and Woerpel
stereoelectronic effects of the ring system determine which face
is attacked by nucleophiles.24-28 In this paper, we provide
evidence that electrostatic effects dictate the conformational
preferences of alkoxy-substituted cyclohexanone-derived oxo-
carbenium ions. Because the stereoelectronic bias for nucleo-
philic addition in these systems is not high, the electrostatic
effects appear to be strong enough to alter the inherent facial
preference for nucleophilic attack by deforming the shape of
the electrophile.
intermediates. The reaction with the alkyl-substituted acetal 3a
is consistent with equatorial attack of the large nucleophile on
the equatorially substituted cation (as shown in structure 9).29
Equatorial attack is anticipated because the large nucleophile
develops destabilizing steric interactions if it approaches from
the axial face (with smaller nucleophiles, axial approach is
generally favored).33,34 The opposite selectivity exhibited by the
4-alkoxy-substituted oxocarbenium ion most likely results from
a change in conformational preference. Because a considerable
amount of positive charge resides on the carbon atom of an
oxocarbenium ion,21 electrostatic forces bring the alkoxy group
close to the carbocationic carbon in the axial isomer (cation
10). This electrostatic effect, observed for 4-alkoxycyclohex-
anones (eq 1)1,2 and related substrates,4,6-10 should be higher
for the oxocarbenium ion.35 An axial preference for the alkoxy-
substituted oxocarbenium ion is consistent with our studies of
endocyclic oxocarbenium ions20,24-26,28,36 and is supported by
ab initio calculations that show the axial conformer (10) to be
favored by 4.6 kcal/mol over the equatorial conformer.37
Subsequent equatorial attack on the axial conformer 10 would
give rise to the observed product. Studies with conformationally
constrained substrates provide additional evidence to support
this analysis (vide infra).
Results and Discussion
The conformational preferences of cyclohexanone oxocar-
benium ions were evaluated by analysis of the stereoselectivities
of reactions of substituted acetals. Only substrates with sub-
stituents at C-4 were analyzed because steric effects that emerge
in the transition state for nucleophilic attack complicate the
analysis of C-3 and C-2-substituted electrophiles. The syntheses
of the acetals are provided as Supporting Information. Stereo-
selectivities were typically determined by a combination of gas
chromatography (GC) or gas chromatography/mass spectrometry
(GCMS) and were confirmed by 1H NMR spectroscopy. In the
case of enol ether nucleophiles, control experiments verified
that the selectivities were the result of kinetic control. Because
the stereocenter formed in each reaction was a quaternary carbon
atom, spectroscopic methods were not generally useful for
determining stereochemistry, so X-ray crystallography was
typically employed. In some cases, chemical correlation and
spectroscopic methods could be used to define stereochemical
configurations. Details of the stereochemical proofs are provided
as Supporting Information.
When a smaller nucleophile was employed, alkyl- and alkoxy-
substituted acetals again displayed opposite selectivities, but the
magnitudes of the selectivities were higher for the alkyl acetal
than for the alkoxy acetal. The reactions of alkyl-substituted
cyclohexanone acetals 3a and 3c provided the trans products
11a and 11c,38 respectively, with selectivities that compared to
The major products observed for nucleophilic substitution
reactions of 4-substituted cyclohexanone acetals with sterically
large nucleophiles depend dramatically upon the electronic
nature of the substituent. With 4-alkylcyclohexanone acetal 3a,
the nucleophile was incorporated trans to the substituent (eq
2).29,30 The reaction of 4-alkoxy-substituted acetal 3b, however,
provided cis products preferentially. This cis selectivity with
the alkoxy-substituted acetal 3b was also observed when the
analogous allylic silane31 7 was employed as the nucleophile
(eq 3).32
(24) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208-12209.
(25) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168-169.
(26) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521-15528.
(27) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003,
125, 14149-14152.
(28) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel,
K. A. J. Am. Chem. Soc. 2005, 127, 10879-10884.
(29) Nakamura, E.; Horiguchi, Y.; Shimada, J.-i.; Kuwajima, I. J. Chem.
Soc., Chem. Commun. 1983, 796-797.
(30) The products are drawn to indicate relative stereochemistry, not
necessarily the conformational preference of the product. This convention
was chosen because in many cases it evokes the conformation of the
oxocarbenium ion from which the product was formed.
(31) Baker, W. R.; Pratt, J. K. Tetrahedron 1993, 49, 8739-8756.
(32) Using different solvents and Lewis acids showed only small effects
on selectivities, but the yields of the reactions were sometimes markedly
influenced. In all examples, the selectivities were reported for reaction
conditions that gave the cleanest products
(33) Ashby, E. C.; Laemmle, J. T. Chem. ReV. 1975, 75, 521-546.
(34) Gung, B. W. Chem. ReV. 1999, 99, 1377-1386.
(35) Ab initio calculations (HF/6-31G*) show that the axial conformer
of 4-methoxycyclohexanone (2) is favored by 0.9 kcal/mol, and the
4-methoxy oxocarbenium ion (the analogue of 10) preferred the axial
conformer by 4.6 kcal/mol.
(36) Chamberland, S.; Woerpel, K. A. Org. Lett. 2004, 6, 4739-4741.
(37) The geometry optimizations were performed at the HF/6-31G* level
using MacSpartan (Wavefunction, Irvine, CA). The structure of the low-
energy axial conformer is provided as Supporting Information.
(38) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899-
3910.
The contrasting selectivities shown in eq 2 provide insight
into the conformational preferences of the oxocarbenium ion
(23) Miljkovic´, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L. J. Org.
Chem. 1997, 62, 7597-7604.
6852 J. Org. Chem., Vol. 71, No. 18, 2006

Cyclohexanone Oxocarbenium Ions
those exhibited by larger nucleophiles (eq 2). The substitution
with the alkoxy-substituted acetal 3b provided the cis product
as observed for the larger nucleophiles (eqs 2 and 3), but the
reaction was not as selective. Similar modest cis-selectivities
were observed with other π-nucleophiles (eq 5).32
Analyses of the reactions of conformationally flexible sub-
strates 3a and 3b are complicated by the fact that the reactive
conformers cannot be determined with ease. The alkyl-
substituted oxocarbenium ions should favor the equatorial
isomer, and an alkoxy group in an oxocarbenium can have a
strong preference for the axial orientation.22,25,26 The reactions
of alkoxy-substituted oxocarbenium ions, however, might be
complicated by electronic differences on facial selectivity caused
by the remote alkoxy group.17 Consequently, it would be
valuable to know the influence on selectivity exerted by an
alkoxy group in the equatorial and axial orientations.
The variation in selectivity depending upon nucleophile size
for the alkoxy-substituted acetal 3b was not anticipated. Because
the conformational preference for the oxocarbenium ion inter-
mediates should be independent of the nucleophile, similar
selectivities should be observed. It is unlikely that the types of
nucleophiles employed have inherently different preferences for
axial versus equatorial selectivity in additions. This proposal
can be discounted as the primary cause of the unusual behavior
of acetal 3b, since selectivities for the alkyl-substituted acetal
3a are independent of the nucleophile. An alternative explanation
for the lower selectivity with smaller nucleophiles would invoke
the Curtin-Hammett principle39 to propose that equatorial attack
on the axial conformer 10 would be slower than equatorial attack
on the corresponding equatorial conformer. To be correct, this
dependence must operate only with small nucleophiles and not
large nucleophiles, and it would not occur with alkyl-substituted
cations. These conditions are severely limiting, making this
argument unsatisfying.
Reactions of the conformationally constrained acetal 20 reveal
that the presence of an equatorially disposed alkoxy group at
C-4 provides products with selectivities similar to those
exhibited by 4-alkyl-substituted acetals. Allyltrimethylsilane
attacked the electrophile from the equatorial face to provide
the 1,4-trans product (eq 8). This facial preference contrasts with
the 1,4-cis selectivity observed for the unconstrained 4-alkoxy-
substituted acetal (eq 4). Axial attack was favored for additions
of Et2Zn (eq 9). The results shown in eqs 8 and 9 both show an
increase in the amount of products formed by axial attack as
compared to the 4-alkyl counterparts (eqs 4 and 6, respectively).
This perturbation in selectivity is likely the result of flattening
of the six-membered ring by the fused five-membered ring,
which has been shown to increase the amount of axial attack to
ketones.34,41
Other nucleophiles also showed different selectivities with
the different acetals. Additions of Et2Zn40 provided only low
selectivity with the alkyl-substituted acetals 3a and 3c but
favored the trans product 14b with the alkoxy-substituted system
(eq 6). This result is likely due to axial attack of the alkylzinc
reagent,17 as would be expected from application of torsional
and stereoelectronic considerations.33,34 Using Me3SiCN as the
nucleophile, the cis product was favored for the alkyl substrate,38
but the trans product was again preferred with the alkoxy
substrate. The reactions with Me3SiCN demonstrate a contrasting
trend to the behavior of the silyl enol ethers in eq 2: this
nucleophile attacks oxocarbenium ions with a significant
preference for the axial face38 (structures 18 and 19), as would
be expected with a small nucleophile.33,34
(39) Seeman, J. I. Chem. ReV. 1983, 83, 83-134.
(40) Powell, N. A.; Rychnovsky, S. D. J. Org. Chem. 1999, 64, 2026-
2037.
(41) Casadevall, E.; Pouet, Y. Tetrahedron Lett. 1976, 2841-2844.
J. Org. Chem, Vol. 71, No. 18, 2006 6853

Baghdasarian and Woerpel
Nucleophilic substitutions of substrates with the C-4-alkoxy
group constrained to an axial position exhibit selectivities that
are almost identical to those of the unconstrained acetal 3b.
Substitution reactions of acetal 23 with allyltributylstannane
occurred with modest selectivity for equatorial attack (eq 10);
the relative stereochemistry and its magnitude compare closely
to unconstrained example shown in eq 4.42 Substitution with
Et2Zn proceeded with high selectivity, favoring axial addition
to the oxocarbenium ion 26. The unconstrained system (eq 6)
provided the analogous product with 87:13 selectivity.
attraction that biases the cation to the axial conformer (27) by
4.6 kcal/mol37 should draw the cationic carbon toward the
benzyloxy group in this conformer. Computational studies37
reveal significant flattening of the dihedral angle at the sp2-
hybridized carbon atom of the oxocarbenium ion 27 (39°)
compared to cyclohexanone (54°).14 This distortion of the cation
from a more idealized chair conformer (27) to a flattened
conformer (as depicted in 28)37 should alter the inherent facial
selectivity34,41 of the cyclohexanone oxocarbenium ion by
exposing the axial face to nucleophilic attack. Such flattening
of the ring of a cyclohexanone is known to increase the
proportion of axial attack,14,34,41 and electrostatic distortion has
also been invoked to explain the enhanced axial reductions of
ketones bearing electronegative substituents at C-4.14-16,34 The
electrostatic attraction and the resulting distortion should be
more pronounced for oxocarbenium ions, since one component
now bears a full positive charge.44
Conclusion
Studies of 4-alkoxy-substituted cyclohexanone acetals reveal
that the alkoxy group exerts a powerful influence on the
conformational preference and reactivity of exocyclic oxocar-
benium ions. The preference for axial conformers is consistent
with observations of the corresponding cyclohexanones1,2 and
our studies of tetrahydropyran and tetrahydrofuran oxocarbe-
nium ions.24-26,28 This study also revealed a new influence of
an alkoxy substituent. The electrostatic forces that favor axial
conformers appear to distort the oxocarbenium ion, therefore
changing its inherent preference for facial attack.
The control experiments with alkyl-substituted acetals 3a,c
and constrained 4-alkoxy acetals 20 and 23 reveal the confor-
mational preference and the facial selectivity for nucleophilic
attack of the unconstrained 4-alkoxy oxocarbenium ion 10. The
strong correlation between the selectivities for the axially
constrained alkoxy acetal 23 and the unconstrained alkoxy acetal
3b indicate that the constrained oxocarbenium ion 26 resembles
the reactive conformer of the unconstrained oxocarbenium ion
(namely 10). Larger nucleophiles favored equatorial attack with
all substrates examined (see, for example, eq 2). On the other
hand, oxocarbenium ions bearing an axial alkoxy group at C-4
showed more axial attack than a substrate with an alkyl group
at C-4 (compare, for example, eqs 4 and 10 to eq 2).
Experimental Section
Details of the syntheses of substrates and stereochemical proofs
are provided as Supporting Information.
The enhanced axial selectivity exhibited by the axially
disposed 4-alkoxy oxocarbenium ions could be the result of
interactions between the nucleophile and the remote substituent.
The axial alkoxy group, bearing partial negative charge on
oxygen, could repel the nucleophile electrostatically. This
phenomenon has been invoked to explain the selective reduc-
tions of alkoxycyclohexanone derivatives with metal hydride
ions,15,43 although the importance of this effect has been
questioned.16 Electrostatic repulsion, however, should be smaller
with π-nucleophiles, because they are neutral, so this effect is
unlikely in the cases reported here.
Ketones 5a and 6a. To a cooled (-78 °C) solution of 3a (0.100
g, 0.402 mmol) in toluene (1 mL) was added enol ether 445 (0.08
g, 0.5 mmol), the mixture was allowed to stir for 2 min, then a
solution of SnBr4 (1 M in CH2Cl2, 0.48 mL, 0.48 mmol) was added.
The solution was allowed to warm (0 °C), and NaHCO3 (1 mL
saturated, aqueous) was added. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (5 × 1 mL). The organic
layers were combined, filtered through Na2SO4, and concentrated
in vacuo. A selectivity of 4:96 (6a/5a) was determined by subjecting
the unpurified oil to GCMS: tR (major) 19.9 min, tR (minor) 19.8
min. The resulting oil was purified by flash chromatography (95:5
to 91:9 hexanes/EtOAc) to afford the product as a colorless oil
(0.087 g, 71%): 1H NMR (500 MHz, CDCl3) δ 7.31-7.25 (m,
2H), 7.21-7.14 (m, 3H), 3.21 (s, 3H), 2.67 (sep, J ) 6.9, 1H),
2.62-2.61 (m, 2H), 2.57 (s, 2H), 1.83-1.81 (m, 2H), 1.57-1.51-
(m, 4H), 1.44 (ddd, J ) 13.6, 13.4, 3.1, 2H), 1.26-1.23 (m, 3H),
1.06 (d, J ) 6.9, 6H); 13C NMR (125 MHz, CDCl3), δ 213.4, 143.0,
The enhanced axial attack on alkoxy-substituted oxocarbe-
nium ions could result from a powerful electrostatic effect
influencing the structure of the electrophile. The electrostatic
(42) The substitution with allyltrimethylsilane provided mostly decom-
position products arising from elimination of the benzyloxy group. The
reaction with allylstannane proceeded with few side products, so this result
makes a better comparison.
(43) For a discussion comparing the models for nucleophilic attack to
cyclohexanones and examination of the reactions of conformationally
constrained 2-substituted cyclohexanones, see: Rosenberg, R. E.; Abel, R.
L.; Drake, M. D.; Fox, D. J.; Ignatz, A. K.; Kwiat, D. M.; Schaal, K. M.;
Virkler, P. R. J. Org. Chem. 2001, 66, 1694-1700.
(44) Comparing the charges of acetaldehyde and its methyl oxocarbenium
ion using Mulliken population analysis shows the oxocarbenium ion to have
larger charge on the carbon, although an AIM analysis shows acetaldehyde
has a larger charge at carbon. See ref 21 and: Wiberg, K. B.; Rablen, P. R.
J. Comput. Chem. 1993, 14, 1504-1518.
(45) Beutelman, H. P.; Xie, L.; Saunders, W. H., Jr. J. Org. Chem. 1989,
54, 1703-1709.
6854 J. Org. Chem., Vol. 71, No. 18, 2006

Cyclohexanone Oxocarbenium Ions
128.3, 128.2, 125.5, 75.0, 48.6, 47.5, 42.2, 38.8, 36.2, 33.6, 33.2,
27.8, 18.0; HRMS (EI) m/z calcd for C20H30O2Na (M + Na)+
325.2144, found 325.2140. Anal. Calcd for C20H30O2: C, 79.42;
H, 10.00. Found: C, 79.58; H, 10.03.
Alkenes 11b and 12b. To a cooled (-78 °C) solution of 3b
(0.150 g, 0.600 mmol) in CH2Cl2 (3 mL) was added allyltrimeth-
ylsilane (0.39 mL, 2.4 mmol), the mixture was stirred for 2 min,
and then TMSOTf (0.13 mL, 0.72 mmol) was added. The solution
was warmed (0 °C), and NaHCO3 (3 mL saturated, aqueous) was
added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (5 × 3 mL). The organic layers were
combined, filtered through Na2SO4, and concentrated in vacuo. A
selectivity of 80:20 (12b/11b) was determined by subjecting the
unpurified oil to GC: tR (major) 15.4 min, tR (minor) 16.0 min.
The resulting oil was purified by flash chromatography (97:3 to
96:4 hexanes/EtOAc) to afford the products separately as colorless
oils. 12b (0.104 g, 67%): 1H NMR (500 MHz, CDCl3) δ 7.38-
7.31 (m, 4H), 7.28-7.24 (m, 1H), 5.82 (ddt, J ) 17.4, 10.2, 7.2,
1H), 5.10-5.03 (m, 2H), 4.50 (s, 2H), 3.61-3.57 (m, 1H), 3.18
(s, 3H) 2.26 (d, J ) 7.2, 2H), 1.77-1.64 (m, 6H), 1.56 (dt, J )
13.2, 4.0, 2H); 13C NMR (125 MHz, CDCl3) δ 139.2, 133.7, 128.3,
127.30, 127.25, 117.3, 74.7, 73.4, 69.7, 48.4, 40.3, 28.8, 25.8; IR
(thin film) 2931, 1454, 1369, 1075 cm-1; HRMS (EI) m/z calcd
for C14H19O2 (M - C3H5)+ 219.1385, found 219.1383. Anal. Calcd
for C17H24O2: C, 78.42; H, 9.29. Found: C, 78.67; H, 9.56. 11b
(0.028 g, 18%): 1H NMR (500 MHz, CDCl3) δ 7.36-7.32 (m,
4H), 7.28-7.25 (m, 1H), 5.80 (ddt, J ) 17.5, 10.3, 7.3, 1H), 5.08-
5.02 (m, 2H), 4.56 (s, 2H), 3.32 (tt, J ) 10.4, 4.0, 1H), 3.17 (s,
3H) 2.20-2.18 (m, 2H), 1.88-1.81 (m, 4H), 1.65-1.58 (m, 2H),
1.25-1.19 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 139.1, 133.8,
128.3, 127.5, 127.3, 117.5, 73.9, 69.8, 48.2, 40.9, 34.3, 31.6, 27.2;
IR (thin film) 2941, 1449, 1364, 1070 cm-1. Anal. Calcd for
C17H24O2: C, 78.42; H, 9.29. Found: C, 78.31; H, 9.44.
Ketone 13 (X ) O). To a cooled (-78 °C) solution of 3b (0.050
g, 0.20 mmol) in CH2Cl2 (1 mL) was added 2-(trimethylsiloxypro-
pene) (0.08 g, 0.24 mmol), the mixture was stirred for 2 min, and
then BF3‚OEt2 (0.21 mL, 0.24 mmol) was added. The solution was
allowed to warm to (0 °C), and NaHCO3 (3 mL saturated, aqueous)
was added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (5 × 3 mL). The organic layers were
combined, filtered through Na2SO4, and concentrated in vacuo. A
selectivity of 61:39 was determined by subjecting the unpurified
oil to 1H NMR spectroscopy. The resulting oil was purified by flash
chromatography (91:9 to 83:17 hexanes/EtOAc) to afford the ketone
13 (X ) O) and a mixture of ketone 13 (X ) O) and its minor
diastereomer (as an 8:92 mixture as determined by NMR) as
colorless oils. Ketone 13 (X ) O) (0.023 g, 42%): 1H NMR (500
MHz, CDCl3) δ 7.35-7.34 (m, 4H), 7.29-7.25 (m, 1H), 4.50 (s,
2H), 3.62-3.59 (m, 1H), 3.26 (s, 3H), 2.59 (s, 2H), 2.20 (s, 3H),
1.81-1.69 (m, 6H), 1.65-1.62 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 207.6, 139.1, 128.3, 127.33, 127.32, 75.0, 72.8, 69.8,
49.6, 49.0, 32.2, 29.2, 25.7; IR (thin film) 3067, 3023, 1705, 1433,
1422, 1068 cm-1; HRMS (EI) m/z calcd for C16H20O2 (M -
MeOH)+ 244.1463, found 244.1475. Anal. Calcd for C17H24O3: C,
73.88; H, 8.75. Found: C, 74.12; H, 8.97. Minor diasteroeomer
of 13 (X ) O) (0.021 g, 38%): 1H NMR (500 MHz, CDCl3) δ
7.35-7.30 (m, 4.29H), 7.28-7.23 (m, 1.7H), 4.55 (s, 2H), 3.62-
3.59 (m, 0.1H), 3.35 (ddt, J ) 10.2, 8.3, 4.0, 1H), 3.25 (s, 0.24H),
3.24 (s, 3H) 2.58 (s, 0.17H), 2.54 (s, 2H), 2.20 (s, 0.23H), 2.19 (s,
3H), 1.90-1.68 (m, 4.87H), 1.75-1.66 (m, 0.63H) 1.67-1.59 (m,
2.61H), 1.41 (ddd, J ) 13.5, 13.4, 3.8, 2H); 13C NMR (125 MHz,
CDCl3) δ 207.7, 139.0, 128.31, 127.5, 127.4, 76.1, 74.2, 69.9, 49.5,
48.6, 32.2, 31.8, 27.1; IR (thin film) 2933, 2844, 1706, 1450, 1228
cm-1; HRMS (EI) m/z calcd for C13H21O2 (M - MeOH)+ 244.1463,
found 244.1461. Anal. Calcd for C17H24O3: C, 73.88; H, 8.75.
Found: C, 73.74; H, 8.83.
Ketones 5b and 6b. To a cooled (-78 °C) solution of 3b (0.050
g, 0.200 mmol) in toluene (1 mL) was added enol ether 445 (0.076
g, 0.24 mmol), the mixture was stirred for 2 min, and then SnBr4
(1 M in CH2Cl2, 0.24 mL, 0.24 mmol) was added. The solution
was allowed to warm (0 °C), and NaHCO3 (3 mL saturated,
aqueous) was added. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (5 × 3 mL). The organic layers
were combined, filtered through Na2SO4, and concentrated in vacuo.
A selectivity of 94:6 (6b/5b) was determined by subjecting the
unpurified oil to GCMS: tR (major) 19.9 min, tR (minor) 20.4 min.
The resulting oil was purified by flash chromatography (97:3 to
96:4 hexanes/EtOAc) to afford the product as a colorless oil (0.05
g, 86%): 1H NMR (500 MHz, CDCl3) δ 7.34-7.32 (m, 4H), 7.28-
7.25 (m, 1H), 4.50 (s, 2H), 3.61-3.58 (m, 1H), 3.23 (s, 3H), 2.70
(sep, J ) 6.9, 1H), 2.62 (s, 2H), 1.85-1.69 (m, 6H), 1.64-1.61
(m, 2H), 1.07 (d, J ) 6.9, 6H); 13C NMR (125 MHz, CDCl3) δ
213.1, 139.1, 127.3, 127.3, 75.2, 72.7, 69.7, 49.0, 46.5, 42.1, 29.1,
25.6, 18.0; IR (thin film) 2925, 1705, 1456, 1368, 1062 cm-1
;
HRMS (ES) m/z calcd for C19H29O3 (M + H)+ 305.2117, found
305.2102. Anal. Calcd for C19H28O3: C, 74.96; H, 9.27. Found:
C, 74.80; H, 9.15.
Alkene 8. To a cooled (-78 °C) solution of 3b (0.15 g, 0.60
mmol) in CH2Cl2 (3 mL) was added silane 731 (0.19 g, 1.2 mmol),
the mixture was stirred for 2 min, and then SnBr4 (1 M in CH2Cl2,
0.72 mL, 0.72 mmol) was added. The solution was allowed to warm
(0 °C) and NaHCO3 (3 mL saturated, aqueous) was added. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (5 × 3 mL). The organic layers were combined, filtered
through Na2SO4, and concentrated in vacuo. A selectivity of 94:6
was determined by subjecting the unpurified oil to GCMS: tR
(major) 18.7 min, tR (minor) 19.4 min. The resulting oil was purified
by flash chromatography (98:2 to 97:3 hexanes/EtOAc) to afford
the product as a colorless oil (0.15 g, 80%): 1H NMR (500 MHz,
CDCl3) δ 7.35-7.32 (m, 4H), 7.28-7.23 (m, 1H), 4.90-4.89 (m,
1H), 4.81-4.80 (m, 1H), 4.50 (s, 2H), 3.62-3.56 (m, 1H), 3.20
(s, 3H), 2.28 (sep, J ) 6.8, 1H), 2.21 (s, 2H), 1.73-1.64 (m, 6H),
1.58-1.54 (m, 2H), 1.03 (d, J ) 6.8, 6H); 13C NMR (125 MHz,
CDCl3), δ 152.1, 139.3, 128.3, 127.34, 127.28, 110.0, 75.6, 73.3,
69.7, 48.5, 40.1, 34.1, 29.0, 25.9, 22.0; IR (thin film) 3085, 3030,
2958, 2870, 1637, 1455 cm-1; HRMS (EI) m/z calcd for C20H30O2
Na (M + Na)+ 325.2144, found 325.2139. Anal. Calcd for
C20H30O2: C, 79.42; H, 10.00. Found: C, 79.01; H, 10.22.
Alkenes 11a and 12a. To a cooled (-78 °C) solution of 3a
(0.100 g, 0.402 mmol) in CH2Cl2 (2 mL) was added allyltrimeth-
ylsilane (0.26 mL, 1.6 mmol), the mixture was allowed to stir for
2 min, and then TMSOTf (0.09 mL, 0.50 mmol) was added. The
solution was allowed to warm (0 °C), and NaHCO3 (3 mL saturated,
aqueous) was added. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (5 × 2 mL). The organic layers
were combined, filtered through Na2SO4, and concentrated in vacuo.
A selectivity of 5:95 (12a/11a) was determined by subjecting the
unpurified oil to GCMS: tR (major) 17.2 min, tR (minor) 17.4 min.
The resulting oil was purified by flash chromatography (99:1 to
98:2 hexanes/EtOAc) to afford the product (as a 95:5 mixture as
determined by GCMS) as a colorless oil (0.057 g, 55%): 1H NMR
(500 MHz, CDCl3) δ 7.28-7.24 (m, 2.66H), 7.17-7.14 (m, 3.71H),
5.81 (ddt, J ) 17.5, 10.3, 7.3, 1.01H), 5.07-5.01 (m, 2.11H), 3.21
(s, 0.13H), 3.16 (s, 3H), 2.63-2.60 (m, 2.49H), 2.33-2.30 (m,
0.08H), 2.18 (dt, J ) 7.4, 1.2, 2.11H), 1.84-1.81 (m, 2.32H), 1.56-
1.51 (m, 4.61H), 1.28-1.15 (m, 5.77H); 13C NMR (125 MHz,
CDCl3), δ 143.1, 134.0, 128.3, 128.2, 125.5, 117.2, 74.4, 48.1, 41.9,
38.9, 36.6, 33.4, 33.3, 27.8; IR (thin film) 2853, 1455, 1079, 699
cm-1; HRMS (EI) m/z calcd for C17H23 (M - CH3O)+ 227.1800,
found 227.1809.
Alkene 13 (X ) CH2). To a cooled (-78 °C) solution of 3b
(0.150 g, 0.600 mmol) in CH2Cl2 (3 mL) was added 2-methallyl-
trimethylsilane (0.31 mL, 2.4 mmol), the mixture was allowed to
stir for 2 min, and then SnBr4 (1 M in CH2Cl2, 0.72 mL, 0.72 mmol)
was added. The solution was allowed to warm (0 °C), and NaHCO3
(3 mL saturated, aqueous) was added. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (5 × 3 mL). The
J. Org. Chem, Vol. 71, No. 18, 2006 6855

Baghdasarian and Woerpel
organic layers were combined, filtered through Na2SO4, and
concentrated in vacuo. A selectivity of 88:12 was determined by
subjecting the unpurified oil to GC: tR (major) 16.3 min, tR (minor)
17.0 min. The resulting oil was purified by flash chromatography
(98:2 to 96:4 hexanes/EtOAc) to afford the products (13, X ) CH2,
and its diastereomer) separately as colorless oils. Alkene 13 (X )
CH2) (0.099 g, 60%): 1H NMR (500 MHz, CDCl3) δ 7.34-7.33
(m, 4H), 7.27-7.23 (m, 1H), 4.86-4.85 (m, 1H), 4.70 (s, 1H),
4.50 (s, 2H), 3.61-3.56 (m, 1H), 3.18 (s, 3H), 2.20 (s, 2H), 1.81
(s, 3H), 1.76-1.64 (m, 6H), 1.58-1.55 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 142.2, 139.2, 128.3, 127.3, 127.2, 114.1, 75.3, 73.4,
69.7, 48.5, 42.7, 29.2, 26.0, 24.2; IR (thin film) 3063, 2930, 1643,
1491,1367 cm-1; HRMS (EI) m/z calcd for C17H22O (M - MeOH)+
242.1671, found 242.1668. Anal. Calcd for C18H26O2: C, 78.79;
H, 9.55. Found: C, 78.52; H, 9.68. Minor diastereomer of 13 (X
) CH2) (0.017 g, 10%): 1H NMR (500 MHz, CDCl3), δ 7.36-
7.31 (m, 4H) 7.27-7.24 (m, 1H), 4.84 (dt, J ) 3.9, 1.5, 1H), 4.66
(m, 1H), 4.56 (s, 2H), 3.31 (tt, J ) 10.4, 4.0, 1H), 3.19 (s, 3H),
2.14 (s, 2H), 1.89-1.79 (m, 7H) 1.65-1.58 (m, 2H), 1.22 (ddd,
J ) 13.7, 13.4, 3.7, 2H); 13C NMR (125 MHz, CDCl3) δ 142.4,
139.2, 128.3, 127.5, 127.3, 114.2, 76.8, 74.4, 69.8, 48.1, 43.4, 32.1,
271.1682. Anal. Calcd for C16H24O2: C, 77.38; H, 9.74. Found:
C, 77.57; H, 9.79.
Methyl Ethers 14c and 15c. To a cooled (-78 °C) solution of
3c (0.126 g, 0.600 mmol) in CH2Cl2 (3 mL) was added diethylzinc
(1 M in hexanes, 1.2 mL, 1.2 mmol), the mixture was stirred for
10 s, and then TMSOTf (0.13 mL, 0.72 mmol) was added. The
solution was allowed to warm (0 °C), and NaHCO3 (3 mL saturated,
aqueous) was added. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (5 × 3 mL). The organic layers
were combined, filtered through Na2SO4, and concentrated in vacuo.
A selectivity of 50:50 (14c/15c) was determined by subjecting the
unpurified oil to GC: tR (major) 8.5 min, tR (minor) 8.9 min. The
resulting oil was purified by flash chromatography (98:2 hexanes/
EtOAc) to afford the product (as a 50:50 mixture as determinded
by NMR) as a colorless oil (0.09 g, 75%): 1H NMR (500 MHz,
CDCl3) δ 3.16 (s, 3H), 3.10 (s, 3H), 1.89-1.79, (m, 4H), 1.69-
1.66 (m, 2H), 1.56 (q, J ) 7.4, 2H), 1.51-1.49 (m, 2H), 1.40 (q,
J ) 7.5, 2H), 1.35-1.20 (m, 4H), 1.10 (ddd, J ) 13.9, 13.6, 3.6,
2H), 1.05-1.00 (m, 3H), 0.96-0.90 (m, 1.5H), 0.85-0.80 (m,
26H); 13C NMR (125 MHz, CDCl3) δ 75.9, 74.1, 48.05, 47.98,
47.82, 47.80, 34.3, 33.8, 32.4, 32.2, 29.6, 27.61, 27.59, 24.0, 23.0,
22.2, 7.1, 6.7; IR (thin film) 2933, 1456, 1367 cm-1; HRMS (ES)
m/z calcd for C13H26O (M)+ 198.1984, found 198.1981.
Nitriles 16a and 17a. To a cooled (-78 °C) solution of 3a (0.150
g, 0.600 mmol) in CH2Cl2 (3 mL) was added cyanotrimethylsilane
(0.09 mL, 0.7 mmol), the mixture was stirred for 2 min, and then
TMSOTf (0.13 mL, 0.72 mmol) was added. The solution was
allowed to warm (0 °C), and NaHCO3 (3 mL saturated, aqueous)
was added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (5 × 3 mL). The organic layers were
combined, filtered through Na2SO4, and concentrated in vacuo. A
selectivity of 81:19 (16a/17a) was determined by subjecting the
unpurified oil to GC: tR (major) 15.1 min, tR (minor) 15.2 min.
The resulting oil was purified by flash chromatography (83:17 to
75:25 hexanes/ CH2Cl2) to afford the product (as a 75:25 mixture
as determined by NMR) as a colorless oil (0.14 g, 94%): 1H NMR
(500 MHz, CDCl3) δ 7.28-7.25 (m, 2.50H), 7.18-7.14 (m, 3.75H),
3.43 (s, 3H), 3.38 (s, 0.74H), 2.63-2.58 (m, 2.51H), 2.26-2.23
(m, 2H), 2.18-2.15 (m, 0.66H), 1.94-1.85 (m, 2H), 1.70 (td, J )
13.6, 3.9, 0.51H), 1.64-1.51 (m, 3.14H), 1.47-1.41 (m, 2H), 1.35-
1.43 (m, 3.97H); 13C NMR (125 MHz, CDCl3) δ 142.3, 142.2,
128.3, 128.2 125.7, 125.6, 120.4, 119.4, 76.6, 73.0, 52.5, 52.3, 37.8,
37.7, 35.7, 35.0, 34.8, 33.2, 33.0, 33.0, 26.2; IR (thin film) 3022,
2928, 2859, 1495, 1106 cm-1; HRMS (EI) m/z calcd for C15H21O
(M - CN)+ 217.1592, found 217.1585. Anal. Calcd for C16H21-
ON: C, 78.97; H, 8.70; N, 5.76. Found: C, 79.05; H, 8.84; N,
5.84.
Nitriles 16b and 17b. To a cooled (-78 °C) solution of 3b
(0.150 g, 0.600 mmol) in CH2Cl2 (3 mL) was added cyanotri-
methylsilane (0.31 mL, 2.4 mmol), the mixture was stirred for 2
min, and then TMSOTf (0.13 mL, 0.72 mmol) was added. The
solution was allowed to warm (0 °C), and NaHCO3 (3 mL saturated,
aqueous) was added. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (5 × 3 mL). The organic layers
were combined, filtered through Na2SO4, and concentrated in vacuo.
A selectivity of 24:76 (16b/17b) was determined by subjecting the
unpurified oil to GC: tR (major) 15.1 min, tR (minor) 15.2 min.
The resulting oil was purified by flash chromatography (97:3 to
96:4 hexanes/EtOAc) to afford the products 17b and a mixture of
17b and 16b (as a 2:1 mixture as determined by NMR) separately
as colorless oils. 17b (0.04 g, 24%): 1H NMR (500 MHz, CDCl3)
δ 7.36-7.31 (m, 4H), 7.29-7.26 (m, 1H), 4.50 (s, 2H), 3.60-
3.54 (m, 1H), 3.44 (s, 3H), 2.06-2.01 (m, 2H), 1.94-1.88 (m,
4H), 1.81-1.74 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 138.6,
128.4, 127.5, 127.3, 119.6, 74.7, 72.2, 69.9, 52.5, 30.5, 25.6; IR
(thin film) 2924, 2833, 1495, 1368 cm-1; HRMS (EI) m/z calcd
for C15H20O2N (M + H)+ 246.1494, found 246.1483. Anal. Calcd
for C15H19O2N: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.01; H,
7.92; N, 5.68. Mixture of 17b and 16b (0.1 g, 65%): 1H NMR
27.3, 24.3; IR (thin film) 2934, 1637, 1457, 1367, 1076 cm-1
;
HRMS (EI) m/z calcd for C14H19O2 (M - C4H7)+ 201.1279, found
201.1276. Anal. Calcd for C18H26O2: C, 78.79; H, 9.55. Found:
C, 78.57; H, 9.72.
Methyl Ethers 14a and 15a. To a cooled (-78 °C) solution of
3a (0.15 g, 0.60 mmol) in CH2Cl2 (3 mL) was added a solution of
Et2Zn (1 M in hexanes, 0.7 mL, 0.7 mmol), the mixture was stirred
for 10 s, and then TMSOTf (0.13 mL, 0.72 mmol) was added. The
solution was allowed to warm (0 °C), and NaHCO3 (3 mL saturated,
aqueous) was added. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (5 × 3 mL). The organic layers
were combined, filtered through Na2SO4, and concentrated in vacuo.
A selectivity of 35:65 (15a/14a) was determined by subjecting the
unpurified oil to GCMS: tR (major) 16.3 min, tR (minor) 17.0 min.
The resulting oil was purified by flash chromatography (97:3
hexanes/EtOAc) to afford the products (as a 2:1 mixture as
determined by NMR) as a colorless oil (0.12 g, 80%): 1H NMR
(500 MHz, CDCl3) δ 7.27-7.22 (m, 3.21H), 7.20-7.11 (m, 4.44H),
3.14 (s, 3H), 3.09 (s, 1.37H), 2.63-2.58 (2.96H), 1.83-1.79 (m,
0.97H), 1.76-1.66 (m, 4.19H), 1.56-1.52 (m, 6.07H), 1.42-1.31
(4.12H), 1.29-1.18 (m, 1.57H), 1.14-1.01 (m, 3.01H), 0.84-0.80
(m, 4.51H); 13C NMR (125 MHz, CDCl3) δ 143.1, 142.9, 128.29,
128.25, 128.24, 128.18, 125.6, 125.5, 75.8, 74.4, 47.9, 47.8, 38.9,
37.6, 36.9, 36.1, 33.6, 33.3, 33.1, 32.8, 29.5, 28.9, 27.9, 24.3, 7.1,
6.7; IR (thin film) 2928, 1495, 1128 cm-1. Anal. Calcd for
C17H26O: C, 82.87; H, 10.64. Found: C, 82.96; H, 10.66.
Methyl Ethers 14b and 15b. To a cooled (-78 °C) solution of
3b (0.15 g, 0.60 mmol) in CH2Cl2 (3 mL) was added a solution of
Et2Zn 1 M in hexanes (0.7 mL, 0.7 mmol), the mixture was stirred
for 10 s, and then TMSOTf (0.13 mL, 0.72 mmol) was added. The
solution was allowed to warm (0 °C), and NaHCO3 (3 mL saturated,
aqueous) was added. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (5 × 3 mL). The organic layers
were combined, filtered through Na2SO4, and concentrated in vacuo.
A selectivity of 87:13 (14b/15b) was determined by subjecting the
unpurified oil to GC: tR (major) 15.2 min, tR (minor) 14.6 min.
The resulting oil was purified by flash chromatography (97:3
hexanes/EtOAc) to afford the product (as a 8:1 mixture as
determined by NMR) as a colorless oil (0.11 g, 70%): 1H NMR
(400 MHz, CDCl3) δ 7.37-7.30 (m, 4.10H), 7.28-7.23 (m, 1.20H),
4.56 (s, 2H), 4.50 (s, 0.14H), 3.62-3.58 (m, 0.06H), 3.32 (tt, J )
10.0, 3.8, 1H), 3.12 (s, 0.18H), 3.11 (s, 3H), 1.88-1.79 (m, 3.96H),
1.67-1.57 (m, 2.40H), 1.49 (q, J ) 7.5, 0.21H), 1.41 (q, J ) 7.5,
2H), 1.18-1.10 (m, 1.96H), 0.85-0.81 (m, 3.15H); 13C NMR (125
MHz, CDCl3) δ 139.3, 139.2, 128.2, 127.4, 127.27, 127.25, 127.2,
77.2, 77.0, 74.7, 73.8, 73.7, 69.7, 48.2, 47.8, 31.3, 28.6, 28.5, 27.2,
25.9, 7.2, 6.9; IR (thin film) 2937, 1457, 1367, 1072 cm-1; HRMS
(ES) m/z calcd for C16H24NaO2 (M + Na)+ 271.1674, found
6856 J. Org. Chem., Vol. 71, No. 18, 2006

Cyclohexanone Oxocarbenium Ions
1
(500 MHz, CDCl3) δ 7.38-7.25 (m, 7.39H), 4.52 (s, 1.15H), 4.50
(s, 1.74H), 3.60-3.54 (m, 1H), 3.54-3.48 (m, 0.48H), 3.44
(s, 3.12H), 3.43 (s, 1.17H), 2.25-2.17 (m, 0.92H), 2.09-1.98
(m, 2.10H), 1.98-1.85 (m, 5.01H), 1.83-1.71 (m, 3.9H); 13C NMR
(125 MHz, CDCl3) δ 138.57, 138.55, 128.4, 128.4, 127.5, 127.5,
127.4, 127.3, 119.7, 119.6, 74.7, 74.2, 73.0, 72.2, 70.1, 69.9, 52.8,
and its minor diastereomer (0.03 g, 33%) H NMR (500 MHz,
CDCl3) δ 3.98-3.91 (m, 2H), 3.18 (s, 3H), 3.13 (s, 0.58H), 3.09
(ddd, J ) 10.4, 10.3, 3.9, 1H), 3.04-3.98 (m, 0.23H), 2.13-1.86
(m, 4.83H), 1.84-1.74 (m, 0.44H), 1.66 (q, J ) 7.4, 2H), 1.61-
1.34 (m, 5.01H), 1.25 (t, J ) 12.5, 1H), 1.21-1.14 (m, 0.41H),
1.03-0.98 (m, 0.23H), 0.87-0.84 (m, 3.54H); 13C NMR (125 MHz,
CDCl3) δ 83.38, 83.36, 77.2, 75.7, 67.7, 67.2, 48.5, 47.9, 41.7,
39.8, 36.2, 36.1, 32.3, 31.6, 30.8, 30.5, 29.1, 27.2, 26.5, 7.3, 6.8;
IR (thin film) 2937, 1461, 1357, 1128 cm-1; HRMS (EI) m/z calcd
for C10H17O (M - MeO)+ 153.1279, found 153.1279. Anal. Calcd
for C11H20O2: C, 71.70; H, 10.94. Found: C, 71.75; H, 10.73.
Benzyl Ether 24. To a cooled (-78 °C) solution of 23 (0.076
g, 0.248 mmol) in CH2Cl2 (2 mL) was added allyltributyltin (0.3
mL, 0.8 mmol), and the mixture was allowed to stir for 2 min,
then TMSOTf (0.05 mL, 0.4 mmol) was added. The solution was
warmed (0 °C), and NaHCO3 (2 mL saturated, aqueous) was added.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (5 × 2 mL). The organic layers were combined,
filtered through Na2SO4, and concentrated in vacuo. A selectivity
of 82:18 was determined by subjecting the unpurified oil to GC:
tR (major) 18.1 min, tR (minor) 17.7 min. The resulting oil was
purified by flash chromatography (99:1 to 98:2 hexanes/EtOAc)
to afford the products 24 and a mixture of 24 and its minor
diastereomer (as a 3.7:1 mixture as determined by NMR) separately
as colorless oils. 24 (0.051 g, 65%): 1H NMR (500 MHz, CDCl3)
δ 7.36-7.30 (m, 4H), 7.25-7.22 (m, 1H), 5.74 (ddt, J ) 16.9,
10.4, 7.3, 1H), 5.03-4.99 (m, 2H), 4.61 (s, 2H), 3.17 (s, 3H), 2.16-
2.14 (m, 2H), 1.79-1.60 (m, 6H), 1.53 (ddd, J ) 13.8, 13.6, 4.6,
2H), 1.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 140.4, 133.9,
128.2, 126.8, 126.7, 117.2, 79.7, 73.9, 65.7, 48.4, 41.7, 38.7, 29.3,
52.4, 30.5, 26.6, 26.0; IR (thin film) 2941, 2866, 1495, 1028 cm-1
;
HRMS (EI) m/z calcd for C15H20O2N (M + H)+ 246.1494, found
246.1503. Anal. Calcd for C15H19O2N: C, 73.44; H, 7.81; N, 5.71.
Found: C, 73.58; H, 7.88; N, 5.76.
Methyl Ether 21. To a cooled (-78 °C) solution of 20 (0.10 g,
0.50 mmol) in CH2Cl2 (2 mL) was added allyltrimethylsilane (0.35
mL, 2.1 mmol), the mixture was allowed to stir for 2 min, and
then TMSOTf (0.12 mL, 0.64 mmol) was added. The solution was
allowed to warm (0 °C), and NaHCO3 (2 mL saturated, aqueous)
was added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (5 × 2 mL). The organic layers were
combined, filtered through Na2SO4, and concentrated in vacuo. A
selectivity of 90:10 was determined by 1H NMR spectroscopy. The
resulting oil was purified by flash chromatography (99:1 hexanes/
EtOAc) to afford the products 21 and a mixture of 21 and its minor
diastereomer (as a 5:1 mixture as determined by 1H NMR
spectroscopy) separately as colorless oils. 21 (0.03 g, 26%): 1H
NMR (500 MHz, CDCl3) δ 5.81 (ddt, J ) 17.4, 10.3, 7.3, 1H),
5.10-5.04 (m, 2H), 3.94-3.89 (m, 2H), 3.19 (s, 3H), 2.99 (ddd, J
) 11.2, 10.2, 3.9, 1H), 2.28 (ddt, J ) 14.4, 7.2, 1.3, 1H), 2.20
(ddt, J ) 14.4, 7.2, 1.3, 1H), 2.10 (dt, J ) 13.6, 3.1, 1H), 1.99-
1.88 (m, 3H), 1.83-1.74 (m, 1H), 1.63-1.48 (m, 2H), 1.24 (ddd,
J ) 14.4, 13.3, 4.0, 1H), 1.08 (dd, J ) 13.5, 12.6, 1H); 13C NMR
(125 MHz, CDCl3) δ 133.6, 117.6, 83.1, 75.5, 67.3, 48.1, 41.3,
39.8, 36.5, 31.7, 30.5, 26.4; IR (thin film) 3074, 2936, 1639, 1456,
1358, 1076 cm-1; HRMS (EI) m/z calcd for C12H21O2 (M + H)+
197.1542, found 197.1549. Anal. Calcd for C12H20O2: C, 73.43;
H, 10.27. Found: C, 73.72; H, 10.28. 21 and its minor diastere-
omer (0.06 g, 54%): 1H NMR (500 MHz, CDCl3) δ 5.87-5.76
(m, 1.18H), 5.14-5.04 (m, 2.43H), 3.98-3.81 (m, 2.44H), 3.24
(s, 0.54H), 3.19 (s, 3H), 3.09 (ddd, J ) 10.7, 9.9, 3.9, 0.20H), 2.99
(ddd, J ) 11.1, 10.3, 3.9, 1H), 2.43-2.42 (m, 0.34H), 2.28 (ddt, J
) 14.6, 7.2, 1.2, 1H), 2.20 (ddt, J ) 14.2, 7.3, 1.2, 1H), 2.12-
2.00 (m, 1.49H), 1.99-1.88 (m, 3.67H), 1.79 (tddd, J ) 12.4, 10.0,
6.6, 3.3, 1H), 1.63-1.36 (m, 2.96H), 1.32-1.21 (m, 1.63H), 1.08
(t, J ) 13.4, 12.6, 1H); 13C NMR (125 MHz, CDCl3) δ 133.6,
133.4, 117.6, 117.5, 83.1, 83.1, 75.5, 67.7, 67.2, 48.8, 48.1, 41.6,
41.3, 39.7, 37.1, 36.4, 36.4, 32.4, 31.7, 30.7, 30.4, 27.0, 26.4; IR
(thin film) 3074, 2938, 1640, 1358, 1075 cm-1; HRMS (EI) m/z
calcd for C12H21O2 (M + H)+ 197.1542, found 197.1549. Anal.
Calcd for C12H20O2: C, 73.43; H, 10.27. Found: C, 73.68; H, 10.55.
Methyl Ether 22. To a cooled (-78 °C) solution of 20 (0.10 g,
0.50 mmol) in CH2Cl2 (2 mL) was added a solution of Et2Zn (1 M
in hexanes, 0.64 mL, 0.64 mmol), the mixture was allowed to stir
for 10 s, and then TMSOTf (0.12 mL, 0.64 mmol) was added. The
solution was allowed to warm (0 °C), and NaHCO3 (2 mL saturated,
aqueous) was added. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (5 × 2 mL). The organic layers
were combined, filtered through Na2SO4, and concentrated in vacuo.
A selectivity of 88:12 was determined by subjecting the unpurified
oil to GC: tR (major) 9.3 min, tR (minor) 9.1 min. The resulting
oil was purified by flash chromatography (99:1 hexanes/EtOAc)
to afford the products 22 and a mixture of 22 and its minor
diastereomer (as a 5:1 mixture as determined by NMR) separately
as colorless oils. 22 (0.05 g, 45%): 1H NMR (500 MHz, CDCl3),
δ 3.98-3.91 (m, 2H), 3.18 (s, 3H), 3.09 (ddd, J ) 10.5, 10.0, 3.9,
1H), 2.06 (dt, J ) 12.4, 2.8, 1H), 2.04-1.93 (m, 2H), 1.89 (dtd, J
) 12.2, 2.8, 2.5, 1H), 1.66 (q, J ) 7.4, 2H), 1.61-1.34 (m, 4H),
1.25 (t, J ) 12.5, 1H), 0.85 (t, J ) 7.4, 3H); 13C NMR (125 MHz,
CDCl3) δ 83.4, 77.2, 67.7, 48.5, 41.7, 36.2, 32.3, 30.8, 27.2, 24.6,
6.8; IR (thin film) 2937, 1460, 1357, 1257 cm-1; HRMS (EI) m/z
calcd for C9H15O2 (M - C2H5)+ 155.1072, found 155.1078. 22
27.1, 24.0; IR (thin film) 3071, 2957, 1639, 1496, 1368, 1082 cm-1
Anal. Calcd for C21H32O2: C, 79.70; H, 10.19. Found: C, 79.54;
H, 10.33. Mixture of 24 and its minor diastereomer (0.020 g,
15%): H NMR (500 MHz, CDCl3) δ 7.40-7.31 (m, 5.25H), 7.27-
.
1
7.22 (m, 3.53H), 5.87 (ddt, J ) 17.2, 10.2, 7.1, 1H), 5.74 (ddt, J
) 17.6, 10.4, 7.3, 0.27H), 5.12-5.06 (m, 2H), 5.04-4.98 (m,
0.57H), 4.65 (s, 2H), 4.62 (s, 0.54H), 3.18-3.17 (m, 3.91H), 2.34-
2.33 (m, 2H), 2.16-2.15 (m, 0.55H), 1.99-1.94 (m, 2H), 1.80-
1.66 (m, 3.5H), 1.66-1.48 (m, 6.29H) 1.03-1.02 (m, 11.88H); 13
C
NMR (125 MHz, CDCl3) δ 140.2, 140.1, 134.2, 133.9, 128.3, 128.2,
126.94, 126.91, 126.86, 126.7, 117.2, 117.0, 79.7, 79.1, 76.8, 75.4,
65.7, 65.7, 48.4, 48.3, 41.8, 41.7, 38.7, 36.1, 29.7, 29.4, 27.1, 26.0,
24.0; IR (thin film) 3070, 3029, 2957, 1638, 1496, 1454 cm-1. Anal.
Calcd for C21H32O2: C, 79.70; H, 10.19. Found: C, 79.47; H, 10.40.
Benzyl Ether 25. To a cooled (-78 °C) solution of 23 (0.100
g, 0.33 mmol) in CH2Cl2 (2 mL) was added a solution of Et2Zn (1
M in hexanes, 0.39 mL, 0.39 mmol), the mixture was allowed to
stir for 10 s, and then TMSOTf (0.09 mL, 0.39 mmol) was added.
The solution was allowed to warm (0 °C), and NaHCO3 (2 mL,
saturated, aqueous) was added. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (5 × 2 mL). The organic
layers were combined, filtered through Na2SO4, and concentrated
in vacuo. A selectivity of 97:3 was determined by subjecting the
unpurified oil to GCMS: tR (major) 19.4 min, tR (minor) 19.0 min.
The resulting oil was purified by flash chromatography (98:2 to
97:3 hexanes/EtOAc) to afford the product as a colorless oil (0.078
g, 79%): 1H NMR (500 MHz, CDCl3) δ 7.41-7.39 (m, 2H), 7.34-
7.31 (m, 2H), 7.26-7.22 (m, 1H), 4.66 (s, 2H), 3.13 (s, 3H), 1.98-
1.92 (m, 2H), 1.72 (ddd, J ) 13.6, 13.5, 3.9, 2H), 1.62-1.55 (m,
4H), 1.48 (td, J ) 14.3, 4.0, 2H), 1.01 (s, 9H), 0.85 (t, J ) 7.4,
3H); 13C NMR (125 MHz, CDCl3) δ 140.1, 128.2, 126.9, 79.3,
75.4, 65.6, 48.0, 38.7, 29.6, 27.2, 26.1, 23.2, 6.9; IR (thin film)
2963, 2875, 1120, 1070 cm-1. Anal. Calcd for C20H32O2: C, 78.90;
H, 10.59. Found: C, 79.00; H, 10.56.
Acknowledgment. This research was supported by the
National Institutes of Health, National Institute of General
Medical Sciences (GM-61066). K.A.W. thanks Amgen, Johnson
J. Org. Chem, Vol. 71, No. 18, 2006 6857

Baghdasarian and Woerpel
Supporting Information Available: Complete experimental
procedures, product characterization, stereochemical proofs, and GC
and spectral data for selected compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
& Johnson, Lilly, and Merck Research Laboratories for generous
support for research. We also thank Professor H. W. Moore
(UCI) for helpful discussions. We thank Dr. Joe Ziller, Dr.
Robert Doedens, and Mr. D. Joshua Dibble for X-ray crystal-
lographic studies, Dr. John Greaves for mass spectrometric data,
and Dr. Phil Dennison for assistance with NMR studies.
JO060968Z
6858 J. Org. Chem., Vol. 71, No. 18, 2006