Enantioselective synthesis of hydrobenzofuranones using an asymmetric desymmetrizing intramolecular stetter reaction of cyclohexadienones

Article abstract of DOI:10.1021/op600278f

A series of cyclohexadienones were synthesized by dearomatization of phenols followed by Dess - Martin oxidation. Asymmetric intramolecular Stetter reactions of these substrates provide hydrobenzofuranones in good to excellent yields and excellent stereoselectivities. Up to three stereocenters as well as a quaternary stereocenter are formed from polysubstituted substrates. A scale-up experiment demonstrates the utility of this transformation.

Full text of DOI:10.1021/op600278f

Organic Process Research & Development 2007, 11, 598−604
Enantioselective Synthesis of Hydrobenzofuranones Using an Asymmetric
Desymmetrizing Intramolecular Stetter Reaction of Cyclohexadienones
Qin Liu and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523, U.S.A.
Abstract:
economy and simplicity.5 When this reaction is coupled with
a stereoselective process, it has the potential to afford
enantioenriched material from commonly available precur-
sors.6 To contribute to efforts to extend this powerful
transformation, we investigated cyclohexadienones, readily
available from dearomatization of phenols,7 as substrates for
an asymmetric desymmetrizing Stetter reaction (Scheme 1).
In a preliminary communication, we reported the asymmetric
intramolecular Stetter reaction of phenol-derived cyclohexa-
dienones with chiral triazolium salt-based catalysts.8 This
reaction allows for a rapid entry to hydrobenzofurans, which
are core skeletons found in several natural products.9 Herein,
we report our full investigation of this transformation,
including the optimization of reaction conditions, expansion
of the substrate scope, and scale-up of the reaction.
A series of cyclohexadienones were synthesized by dearomati-
zation of phenols followed by Dess-Martin oxidation. Asym-
metric intramolecular Stetter reactions of these substrates
provide hydrobenzofuranones in good to excellent yields and
excellent stereoselectivities. Up to three stereocenters as well
as a quaternary stereocenter are formed from polysubstituted
substrates. A scale-up experiment demonstrates the utility of
this transformation.
Introduction
Introduced by D. Seebach and E. J. Corey, reactivity
umpolung1 is a process in which the normal donor and
acceptor reactivity of a functional group is inverted to provide
non-obvious, complementary reactivity in organic synthesis.
The Stetter reaction2 is an umpolung process in which an
acylanion equivalent, generated from an aldehyde in the
presence of a nucleophilic catalyst, is added to a Michael
acceptor to form a C-C bond. If the Michael acceptor
involves a prochiral alkene, this reaction generates new
stereocenters.3 Recently, our group developed a family of
triazolium catalysts that promotes intramolecular Stetter
reactions in excellent enantioselectivities and diastereose-
lectivities.4
As powerful as it may be, any strategy is inherently
limited if the requisite substrates are esoteric or difficult to
access. In an effort to expand the scope of the asymmetric
intramolecular Stetter reaction in order to access more diverse
product scaffolds amenable to complex molecule total
synthesis, we initiated an effort at using aromatic feedstock
starting materials to provide Stetter substrates. Dearomati-
zation of aromatic compounds is a very useful strategy to
synthesize alicyclic compounds due to the reaction’s high
(5) (a) Woodward, R. B. J. Am. Chem. Soc. 1940, 62, 1208. (b) Waring, A. J.
AdVances in Alicyclic Chemistry; Academic Press: New York, 1966; p 129.
(c) Corey, E. J.; Girotra, N. N.; Mathew, C. T. J. Am. Chem. Soc. 1969, 91,
1557. (d) Wiesner, K.; Tsai, T. Y. R.; Nambiar, K. P. Can. J. Chem. 1978,
56, 1451. (e) Semmelhack, M. F.; Harrison, J. J.; Thebtaranonth, Y. J. Org.
Chem. 1979, 44, 3275. (f) Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc.
1985, 107, 256. (g) Mander, L. N. Synlett 1991, 134. (h) Kopach, M. E.;
Harman, W. D. J. Am. Chem. Soc. 1994, 116, 6581. (i) Maruoka, K.; Ito,
M.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117, 9091. (j) Villar, M.; Kolly-
Kovac, T.; Equey, O.; Renaud, P. Chem.-Eur. J. 2003, 9, 1566. (k) Clive,
D. L. J.; Fletcher, S. P.; Liu, D. Z. J. Org. Chem. 2004, 69, 3282. (l) Canesi,
S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175. (m) Jones, S. B.;
He, L. W.; Castle, S. L. Org. Lett. 2006, 8, 3757. (n) Marsini, M. A.; Gowin,
K. M.; Pettus, T. R. R. Org. Lett. 2006, 8, 3481. (o) Monje, P.; Grana, P.;
Paleo, M. R.; Sardina, F. J. Org. Lett. 2006, 8, 951.
(6) (a) Pearson, A. J.; Zhu, P. Y.; Youngs, W. J.; Bradshaw, J. D.; McConville,
D. B. J. Am. Chem. Soc. 1993, 115, 10376. (b) Pearson, A. J.; Milletti, M.
C.; Zhu, P. Y. Chem. Commun. 1995, 853. (c) Schultz, A. G. Chem.
Commun. 1999, 1263. (d) Imbos, R.; Minnaard, A. J.; Feringa, B. L. J.
Am. Chem. Soc. 2002, 124, 184. (e) Hayashi, Y.; Gotoh, H.; Tamura, T.;
Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028.
(f) Studer, A.; Schleth, F. Synlett 2005, 3033. (g) Hoarau, C.; Pettus, T. R.
R. Org. Lett. 2006, 8, 2843. (h) Zhu, J. L.; Porco, J. A. Org. Lett. 2006, 8,
5169.
(7) (a) Pelter, A.; Elgendy, S. M. A. J. Chem. Soc. Perkin Trans. 1 1993, 1891.
(b) Moriarty, R. M.; Prakash, O. Org. React. 2001, 57, 327. (c) Tran-Huu-
Dau, M. E.; Wartchow, R.; Winterfeldt, E.; Wong, Y. S. Chem.-Eur. J.
2001, 7, 2349. (d) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005,
7, 175.
* Author to whom correspondence may be sent. Fax: (+1)-970-491-1801.
E-mail: rovis@lamar.colostate.edu.
(1) (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. (b) Seebach, D.
Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(2) (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (b) Stetter, H.;
Kuhlmann, H. Org. React. 1991, 40, 407.
(8) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552.
(9) (a) Burke, S. D.; Cobb, J. E.; Takeuchi, K. J. Org. Chem. 1985, 50, 3420.
(b) Chumoyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc.
1994, 116, 11213. (c) Guth, H. HelV. Chim. Acta 1996, 79, 1559. (d) Yao,
S. L.; Johannsen, M.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1998,
63, 118. (e) Jonasson, C.; Ronn, M.; Backvall, J. E. J. Org. Chem. 2000,
65, 2122. (f) Germain, J.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5269.
(g) Takao, K.; Tsujita, T.; Hara, M.; Tadano, K. J. Org. Chem. 2002, 67,
6690. (h) Taber, D. F.; Neubert, T. D.; Rheingold, A. L. J. Am. Chem. Soc.
2002, 124, 12416. (i) Booker-Milburn, K. I.; Hirst, P.; Charmant, J. P. H.;
Taylor, L. H. J. Angew. Chem., Int. Ed. 2003, 42, 1642. (j) Clive, D. L. K.;
Fletcher, S. P. Chem. Commun. 2003, 2464. (k) Yamashita, M.; Ohta, N.;
Shimizu, T.; Matsumoto, K.; Matsuura, Y.; Kawasaki, I.; Tanaka, T.;
Maezaki, N.; Ohta, S. J. Am. Chem. Soc. 2003, 68, 1216.
(3) (a) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim. Acta 1996,
79, 1899. (b) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(c) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. (d) Matsumoto,
Y.; Tomioka, K. Tetrahedron Lett. 2006, 47, 5843.
(4) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
10298. (b) Kerr, M. S.; Rovis, T. Synlett 2003, 1934. (c) Kerr, M. S.; Rovis,
T. J. Am. Chem. Soc. 2004, 126, 8876. (d) Read de Alaniz, J.; Rovis, T. J.
Am. Chem. Soc. 2005, 127, 6284. (e) Reynolds, N. T.; Rovis, T. Tetrahedron
2005, 61, 6368. (f) Moore, J. L.; Kerr, M. S.; Rovis, T. Tetrahedron 2006,
62, 11477.
598
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development
10.1021/op600278f CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/22/2007

Scheme 1. Intramolecular Stetter reaction of
Table 1. Syntheses of monosubstituted substrates
phenol-derived cyclohexadienones
Results and Discussion
Our initial investigations were focused on substrate 1,
which was synthesized in two steps from cresol. (Table 1,
entry 1). First, oxidation of cresol using iodobenzenediacetate
in the presence of excess ethylene glycol as a trapping agent
produces cyclohexadienone 1 in 49% yield. A large excess
(30 equiv) of glycol is required to suppress formation of
undesired byproducts in this reaction, which is rarely a
problem given its cost and water solubility, the latter greatly
facilitating workup. We have spent some effort at using fewer
equivalents of alcohol with some success, but the above
protocol is the most general. Alcohol thus generated is then
converted to aldehyde 1 using Dess-Martin reagent (DMP)
in 87% yield. Using this general procedure, a series of
cyclohexadienones may be synthesized successfully (Table
1).
As can be seen from Table 1, this approach is remarkably
tolerant of arene substitution. Although yields in the arene
oxidation vary, most reactions were conducted only once and
are thus unoptimized. The Dess-Martin oxidation was found
to be the most appropriate for the second step, with fresh
batches of reagent providing the highest and most reproduc-
ible yields.
Subjection of 1 to the standard Stetter reaction conditions
using previously reported triazolium salts4 as catalyst precur-
sors
provides the desired benzohydrofuranone 20 in good yields.
We found the best catalyst to be 26, an aminoindanol-derived
electron-rich triazolium salt, providing the product in 90%
yield and 88% ee in 5 min. The diastereoselectivity of this
pentafluorophenyl catalysts provide lower selectivities. Al-
though at this time we cannot account for these differences,
the tunability of these azolium salts is a hallmark of their
design.10
1
transformation is excellent (>95:5 by H NMR and GC),
favoring formation of the cis-fused hydrobenzofuranone.
Surprisingly, electron-tuning of the arene ring was required
for optimal selectivities as the sterically identical phenyl and
(10) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
599

Table 2. Screen of bases
entrya
base
reaction time
yield (%)
ee (%)b
1
2
3
4
5
KHMDS
KOt-Bu
KH
i-Pr2NEt
Et3N
5 min
30 min
16 h
21 h
32 h
90
83
76
62
68
88
88
76
70
66
Figure 1. Effect of isopropanol as solvent.
a [1] ) 0.04 M. b Determined by GC using a chiral stationary phase.
Table 3. Screen of solvents
yield ee
yield ee
(%) (%)b
entrya solvent (%) (%)b entrya
solvent
CH2Cl2
MeOH
EtOH
CF3CH2OH
i-PrOH
t-BuOH
1
2
3
4
5
6
toluene
xylenes
90
81
88
75
89
7
8
9
16
67
Figure 2. Proposed model for turnover in selectivity in i-PrOH.
29 -11
benzene 88
63 -42
used as the solvent for the reaction. A gradual inversion in
selectivity occurs as the volume fraction of isopropanol
increases to a plateau of ∼60% isopropanol in toluene (Figure
1). We suggest that these effects are most consistent with
the involvement of the alcohol in the transition state likely
via hydrogen bonding to either the nucleophilic enol or the
carbonyl acceptor or both. This hydrogen bonding thus
changes the chiral environment, ultimately affecting the
stereochemical outcome of the reaction.
A stereochemical rationale to account for the turnover in
selectivity is provided in Figure 2. The absolute stereochem-
istry of 20 is consistent with model C wherein minimization
of charge separation is emphasized. We suggest that exten-
sive hydrogen bonding in isopropanol destabilizes this
transition state relative to D since the incipient enolate and
alkoxide are each hydrogen-bonded to solvent. Solvation and
electrostatic effects are likely also playing a role.
Having evaluated the effect of each component on the
reaction, we were faced with a reaction that provided product
in 88% ee. A preliminary screen of different substrates (not
shown) revealed that the enantioselectivities were invariably
<88%. We were particularly intrigued with the effect of
alcoholic solvents on enantioselectivity and speculated
whether hydrogen-bond donors present as intermediates in
the reaction could be interfering. In an effort to minimize
the contribution of bimolecular events to the stereoselectivity
of the process, we evaluated the impact of reaction concen-
tration. When the concentration of 2 decreased from 0.12 to
0.013 M, the ee increased from 79 to 90%. Selectivities were
further improved by a serendipitous discovery that the use
of an argon purge through the reaction leads to improved
Et2O
DMF
THF
67
71
77
87 10
73 11
89 12
0
N/A
64 -63
30 -57
a See Table 2. b See Table 2.
A screen of different bases revealed that KHMDS is the
best base for this reaction (Table 2). KO-t-Bu is equally
effective at inducing asymmetry but requires a longer reaction
time. Amine bases also require longer reactions times,
consistent with their reduced basicity, thereby leading to
lower concentrations of active carbene catalyst. Somewhat
surprising is the reduced selectivity evident when amine bases
are used, a situation not generally encountered in other Stetter
reactions developed in our laboratory.
When screening a variety of solvents (Table 3), we
observed a large effect on both yield and ee. For example,
the reaction results in 16% yield and 67% ee after 3 days
when dichloromethane is used as solvent. Overall, toluene
was found to be the best solvent for this reaction.
By far the most surprising aspect of this study was the
effect of alcoholic solvents on the reaction, which invariably
afford the opposite enantiomer using the same series of
catalyst (Table 3). There is a clear effect of alcohol size on
selectivity with isopropanol providing the highest ee’s.
Trifluoroethanol shuts down the reaction, presumably be-
cause of its increased acidity.
The profound difference between polar aprotic solvents
such as DMF and the alcoholic solvents cannot be accounted
for by polarity alone. In order to study the effect of the
alcohol further, a mixture of toluene and isopropanol was
600
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

Table 4. Effect of concentration
Table 6. Reaction of polysubstituted substrates
entry
concentration 1 (M)
yield (%)
ee (%)a
1
2
3
0.12
0.04
0.013
0.008
0.008
0.005
0.005
85
90
90
90
90
86
91
79
88
90
90
93
90
96
4
5b
6
7b
a See Table 2. b Ar purge.
Table 5. Reaction of monosubstituted substrate
entrya
R
substrate product yield (%) ee (%)b
1
2
3
4
5
6
7
8
9
Me
Et
i-Pr
t-Bu
Ph
4-BrC6H4
CH2OAc
CH2CH2OMe
CH2CH2CO2Me
CH2CH2NHBoc 10
1
2
3
4
5
6
7
8
9
20
27
28
29
30
31
32
33
34
35
90
86
87
86
87
78
86
86
94
28
92
94
94
94
88
85
83
82
87
64
a See Table 5. b See Table 5. c Reaction time ) 5 min. d Reaction time ) 2
h.
the transition state when cyclization occurs trans to the R
group at the 4-position of the dienone. We suggest, therefore,
that this effect may best be rationalized as due to electronics.
Every group in substrates 5-10 is sigma withdrawing, and
this may have a subtle effect in altering the diastereomeric
transition states. Of note is that all the substrates provide
10
a Argon purge, [substrate] ) 0.008 M. b Determined by GC or HPLC using
a chiral stationary phase.
ee’s, entries 5 and 7 in Table 4. We suggest that these effects
are a consequence of the availability of hydrogen-bond
donors under conditions involving higher concentrations or
adventitious oxygen-derived byproducts, and these lead to
competitive transition states similar to D in Figure 2 above.
With the optimized reaction conditions in hand, we
screened a series of monosubstituted dienone substrates. As
the steric size of R group is increased from methyl to tert-
butyl, the enantioselectivity of the transformation remained
largely invariant (Table 5, entries 1-4). Aryl groups result
in slightly lower selectivities (Table 5, entries 5-6). Single-
crystal analysis of 31 (Table 5, entry 6) revealed the absolute
configuration of this product, while the rest were assigned
by analogy. More functionalized substitutions are also
tolerated in the reaction, although with lower ee’s (Table 5,
entries 7-10). In light of the detrimental effect of groups
capable of hydrogen bonding, it is tempting to invoke an
intramolecular hydrogen bond that alters selectivities in the
case of substrates 7-10. However, this scenario clearly
cannot account for depressed selectivities observed with aryl
substituents in substrates 5 and 6. Furthermore, it is difficult
to envision an intramolecular hydrogen bonding affecting
1
products in excellent diastereoselectivities (>95:5 by H
NMR and GC).
Given our previous success in cyclizing onto trisubstituted
Michael acceptors,4d we were intrigued to attempt cycliza-
tions onto dienones derived from trisubstituted phenol starting
materials. A number of 2,4,6-trisubsituted phenols are readily
available. When the derived dienones are subjected to the
optimized reaction conditions, hydrobenzofuranones with
three contiguous stereocenters are formed in good yield and
excellent selectivities (Table 6). No elimination of methoxy
group is observed under the basic reaction conditions (Table
6, entry 2). The tolerance of this reaction to steric bulk is
particularly noteworthy. Dienone 12, derived from the
ubiquitous and inexpensive antioxidant BHT, provides
product 38 in good yield as largely a single enantiomer and
diastereomer (Table 6, entry 3) possessing a neopentyl
stereocenter. Substrate 13, derived from 2,4,6-tri-tert-butyl
phenol, provides product 39 in excellent ee, having three
contiguous stereocenters, two of them being neopentyl.
Significantly, for each reaction in Table 6, a single diaste-
1
reomer is observed (>95:5 by H NMR, GC, and HPLC).
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
601

Attempted epimerization experiments on products 36 and 38
(Et3N in PhMe at 110 °C for 24 h) failed to provide
noticeable evidence of epimeric products. Preliminary semi-
empirical calculations suggest the major diastereomers are
more thermodynamically stable products.11 The relative
configuration of the product was also confirmed by NOE
experiments (see Supporting Information).
Analogously, in order to test whether this chemistry is
able to generate quaternary stereocenters,4c,f cyclohexadi-
enone 15 was synthesized from commercially available 3,4,5-
trimethylphenol. Cyclization of 15 provides the desired
product 40 with a quaternary stereocenter adjacent to a
tertiary ether in good yield and excellent stereoselectivity
(eq 2).
The above examples all involve the synthesis of hy-
drobenzofuranones, largely due to the accessibility of the
substrate by the above route.12 In order to test whether the
oxygen tether was required, we synthesized substrate 41
starting from 4-(3-hydroxypropyl)phenol. However when 41
was subjected to the optimized conditions, the only isolated
product was 6-hydroxy-1-indanone (eq 3a). We suggest this
conducted using the preformed free carbene,4d providing the
desired carbocycle 42 in 60% yield and 90% ee (eq 3b).
The use of several commercially available disubstituted
phenols as starting materials in this chemistry would lead to
chiral racemic dienones. Previous work in our laboratory has
revealed that kinetic resolutions are not practical using this
approach; rather, the catalysts override preexisting stereo-
centers unless they are alpha to the aldehyde.4e However,
we were intrigued by the opportunity to investigate the
relative propensity of our catalysts to induce cyclization onto
disubstituted versus trisubstituted Michael acceptors in an
intramolecular competition. As such, chiral substrates 16-
19 were assembled and subjected to optimized reaction
conditions using catalyst 26 along with an achiral azolium
salt. Substrates 16, 17, and 18 provided the products favoring
cyclization onto the less-substituted olefin, consistent with
expectations. The former provides 43 in 12:1 selectivity over
44 when using an achiral azolium salt. This selectivity is
greatly degraded when the chiral catalyst is used, as it exerts
its influence to provide only 2:1 selectivity, with the minor
product is derived from the elimination of the expected
product under the reaction conditions. Fortunately, we found
that the elimination may be avoided if the reaction of 41 is
(11) For example, 36 is ∼9.9 kJ/mol more stable than the diastereomer having
the methyl group on the endo face of the bicycle, while 38 is ∼36 kJ/mol
more stable than the diastereomer having the bulky tert-butyl in that position.
(12) The use of propylene glycol in the starting material synthesis affords
homologous substrates. These substrates undergo efficient Stetter reactions
using achiral catalysts, but are much more prone to base-induced Michael
cyclization in the presence of our suite of chiral catalysts. Efforts to remedy
this situation are currently underway.
602
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

adduct formed in high ee, (eq 4). Substrates 17 and 18
provide products 45 and 47, respectively, in nearly exclusive
selectivity regardless of catalyst, (eqs 5 and 6). However,
when we subject substrate 19 to both catalysts, we observe
both constitutional isomers formed in identical amounts, eq
7, illustrating no selectivity between cyclization onto a di-
versus trisubstituted Michael acceptor. When this reaction
is conducted using catalyst 26, both isomers are formed in
high ee’s, as the chirality of the catalyst exerts its control.
The different behavior of substrates 17 and 18 versus 19
is not easy to rationalize. We speculated that the dichotomy
lay in product stability. Semi-empirical calculations were
carried out, and the results are consistent with our suggestion
(Scheme 2). Products 45 and 47 are correspondingly more
thermodynamically stable than 46 and 48 by ∼15 kJ/mol.
In contrast, 50 is actually very slightly more stable than 49
(but only ∼1.5 kJ/mol), implying the fused five-membered
ring has a profound effect on the outcome of the reaction.
We suggest this is due to destabilization of 49 having the
fused cyclopentane considerably twisted in the angular
tricycle, a situation that is alleviated in 50. We further suggest
that this difference in ground-state energy is partially
reflected in the transition states leading to each of these
constitutional isomers, thereby negating the typical selectivi-
ties we observe between di- and trisubstituted Michael
acceptors. This situation also allows the chiral catalyst to
exert control over the newly formed, bond providing parallel
kinetic resolution.
hydrobenzofuranones in good yields and excellent selectivi-
ties. Up to three contiguous stereocenters as well as
quaternary stereocenters can be formed using this transfor-
mation. A successful scale-up experiment demonstrates the
utility of this methodology.
Experimental Section
General Procedure for Synthesis of the Substrates. A
flame-dried 100-mL round-bottom flask was charged with
cresol (1.08 g, 10 mmol); the flask was purged under vacuum
for 5 min and then refilled with argon and 2 mL of CH2Cl2.
Ethylene glycol (16.7 mL, 300 mmol) and then PhI(OAc)2
(4.83 g, 15 mmol, dissolved in 40 mL of CH2Cl2) was added
dropwise over 2 h. The solution was then allowed to stir at
ambient temperature for further 30 min. The solution was
concentrated in vacuo, and the residue was subjected to
column chromatography (EtOAc/hexane ) 1:1) to provide
dienone alcohol (823 mg, 49%) as an orange oil.
In a flame-dried 50-mL round-bottom flask, this alcohol
(556 mg, 3.86 mmol) was dissolved in 36 mL CH2Cl2, Dess-
Martin periodinane (1.80 g, 4.25 mmol) was added to the
solution directly, and the solution was then allowed to stir
at ambient temperature for 1 h. The solution was filtered
through Celite 545 and then concentrated in vacuo, and
the residue was subjected to column chromatography
(EtOAc/hexane ) 1:3) to provide 1 (556 mg, 87%) as yellow
oil.
General Procedure for the Synthesis of Hydrobenzo-
furanones. A flame-dried, 25 mL round-bottom flask was
charged with triazolium salt 26 (4.9 mg, 0.012 mmol). The
flask was purged under vacuum for 5 min and then refilled
with argon and 12 mL of toluene. Argon was bubbled
through the solution for 5 min, then KHMDS (0.024 mL,
0.012 mmol) was added, and the solution was allowed to
stir at ambient temperature for 15 min. The substrate (around
20 mg, 0.12 mmol) was dissolved in 3 mL of toluene and
then was added via syringe; the reaction was allowed to stir
at ambient temperature. After the reaction was complete
(checked by TLC), usually in 5 min, the reaction mixture
was directly purified by flash column chromatography.
Finally, in order to test whether this chemistry could be
used on scale, we conducted an experiment using one gram
of 11 as the starting material. Although the catalyst loading
was reduced to 3 mol % and the concentration (0.1 M) is
much higher than that in small-scale experiments (0.008 M),
the reaction proceeds efficiently, providing ent-36 in 82%
yield and 96% ee (eq 8).
In conclusion, a series of cyclohexadienones were syn-
thesized in a rapid and efficient manner. The asymmetric
intramolecular Stetter reactions of these substrates affords
Scheme 2. Calculation of relative energiesa
Acknowledgment
We gratefully acknowledge the National Institute of
General Medical Sciences (GM72586) and Johnson and
a Relative energies calculated using SPARTAN (PM3).
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
603

Johnson (Focused Funding) for partial support of this
research. T.R. thanks Merck Research Laboratories, Eli Lilly,
Amgen, and Boehringer Ingelheim for unrestricted support,
and the Monfort Family Foundation for a Monfort
Professorship. T.R. is a fellow of the Alfred P. Sloan
Foundation.
Supporting Information Available
This information is available free of charge via the Internet
at http://pubs.acs.org.
Received for review December 21, 2006.
OP600278F
604
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development