Stereoselectivities and regioselectivities of (4 + 3) cycloadditions between allenamide-derived chiral oxazolidinone-stabilized oxyallyls and furans: Experiment and theory

Article abstract of DOI:10.1021/ja205700p

A systematic investigation of the regioselectivities and stereoselectivities of (4 + 3) cycloadditions between unsymmetrical furans and a chiral oxazolidinone-substituted oxyallyl is presented. Cycloadditions were performed using an oxyallyl containing a

Full text of DOI:10.1021/ja205700p

ARTICLE
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Stereoselectivities and Regioselectivities of (4 + 3) Cycloadditions
Between Allenamide-Derived Chiral Oxazolidinone-Stabilized
Oxyallyls and Furans: Experiment and Theory
Jennifer E. Antoline,† Elizabeth H. Krenske,*,‡,§ Andrew G. Lohse,† K. N. Houk,*,‡ and Richard P. Hsung*,†
†Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53705, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
§School of Chemistry, University of Melbourne, Victoria 3010, Australia, and Australian Research Council Centre of Excellence for Free
Radical Chemistry and Biotechnology
S Supporting Information
b
ABSTRACT: A systematic investigation of the regioselectivities and stereoselectiv-
ities of (4 + 3) cycloadditions between unsymmetrical furans and a chiral
oxazolidinone-substituted oxyallyl is presented. Cycloadditions were performed
using an oxyallyl containing a (R)-4-phenyl-2-oxazolidinone auxiliary (2Ph), under
either thermal or ZnCl2-catalyzed conditions. Reactions of 2Ph with 2-substituted
furans gave syn cycloadducts selectively, while cycloadditions with 3-substituted
furans gave selectively anti cycloadducts. The stereoselectivities were in favor of a
single diastereoisomer (I) in all but one case (2-CO2R). Density functional theory
calculations were performed to explain the selectivities. The results support a mechanism in which all cycloadducts are formed from
the E isomer of the oxyallyl (in which the oxazolidinone CdO and oxyallyl oxygen are anti to each other) or the corresponding (E)-
ZnCl2 complex. The major diastereomer is derived from addition of the furan to the more crowded face of the oxyallyl. Crowded
transition states are favored because they possess a stabilizing CHꢀπ interaction between the furan and the Ph group.
’ INTRODUCTION
Scheme 1. (4 + 3) Cycloadditions of Oxazolidinone-
Substituted Oxyallyls
The (4 + 3) cycloadditions of oxyallyl (1) with dienes
represent a valuable synthetic route to 7-membered carbocycles.1
We recently reported the cycloadditions shown in Scheme 1,
where a chiral oxazolidinone-stabilized oxyallyl (2) is generated
by oxidation of an allenamide and reacts with a cyclopentadiene,
pyrrole, or furan.2 This sequence provides access to a diverse
range of cycloadducts having endo stereochemistry.3 Regioselec-
tive reactions with unsymmetrical furans have also been achieved.
During our initial studies, we were surprised to find that the use of
a 4-phenyl-2-oxazolidinone auxiliary (2, R = Ph) (“2Ph”) led to
unusual selectivities in reactions involving several furans. We have
therefore carried out a detailed survey of the regio- and stereo-
chemical features of the oxyallyl protocol using this auxiliary.
Experimental and computational results, presented here, support
a novel mode of stereoinduction for these reactions, in which the
furan adds preferentially to the more crowded face of the oxyallyl.
The crowded transition state is stabilized by an attractive CHꢀπ
interaction between the furan and the Ph group.
of ZnCl2, the dr increased to g96:4. Originally, it was thought2
that the stereoselectivities of cycloadditions involving 2 arose
through steric control, as depicted in Scheme 2. The presence of
the bulky R group was thought to block one face of the oxyallyl
from the approaching furan. Addition of the furan to the less
Cycloaddition of 2Ph with furan led selectively to the cycload-
duct I with a diastereomer ratio (I:II) of 82:18.2a In the presence
Received: June 20, 2011
Published: August 18, 2011
r
2011 American Chemical Society
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hindered face of 2-Z (or its ZnCl2 chelate) would lead to the
major diastereomer of the cycloadduct (I), while addition to the
more hindered face would lead to the minor diastereomer (II).
Computational studies, however, revealed an altogether dif-
ferent mechanism.4 Computations showed that only cycloaddi-
tions involving the E isomer of 2Ph are energetically feasible
(Scheme 3). The OꢀO repulsion is very destabilizing in con-
formations previously proposed (Scheme 2). This is true even in
the presence of ZnCl2. Furan actually adds to the more crowded
face of 2Ph-E, where a favorable CHꢀπ interaction between the
furan and the Ph group stabilizes the transition state by approxi-
mately 0.2 kcal/mol over the uncrowded TS.
and position of substitution. The data support the anti disposi-
tion of oxygens and attractive CHꢀπ model and also indicate
situations where the CHꢀπ interaction can be overcome by
substituents on the furan, resulting in altered selectivities.
’ BACKGROUND
Previous Reports on Regioselectivities. Numerous regiose-
lective cycloadditions between furans and N- or O-substituted
oxyallyls have previously been reported.1 Some representative
examples are shown in Scheme 4. In principle, the reactions of
achiral heteroatom-substituted oxyallyls with unsymmetrical
furans can yield two regioisomeric endo adducts; we denote
these by the terms syn and anti, in reference to the position
ultimately adopted by the substituents on the furan relative to the
heteroatom.
We present here experimental and computational studies of
the cycloadditions of 2Ph with a range of monosubstituted furans,
chosen to represent all available variations of electronic character
Walters5 generated nitrogen-substituted oxyallyl intermedi-
ates from the R,R0-dihalide 3, by treatment with either Et3N in
trifluoroethanol or Et3N/LiClO4 in acetonitrile. Both reacted
with 2-methylfuran or 2-methoxyfuran to give predominantly
anti adducts (4b). F€ohlisch6 generated an oxygen-stabilized
oxyallyl cation by treatment of the R-haloketone 5 with Et3N/
LiClO4, and its cycloaddition with 2-methylfuran gave predomi-
nantly the anti cycloadduct 6b.7 By contrast, when Albizati8
treated the dimethylacetal 7 with a Lewis acid (TMSOTf, SnCl4,
TiCl4, or BCl3), only the syn cycloadduct (6a) was obtained. In
the reactions of both 3 and 5, detectable amounts of a third type
of adduct resulting from the “sickle” form of the oxyallyl
intermediate (rather than the “W” form) were also produced.9
We recently reported the regioselectivities of cycloadditions
involving the parent achiral oxazolidinone-substituted oxyallyl
(Scheme 5).10 Reactions with 2-methyl- or 2-CO2Me-furan led
predominantly to syn cycloadducts, while anti adducts were
obtained from 3-methyl- and 3-CO2Et-furan. Inclusion of ZnCl2
increased the yields but had little effect on the regioselectivity.
Previous Reports on Stereoselectivities. Incorporation of a
chiral auxiliary on the oxyallyl increases the number of possible
Scheme 2. Steric Model Originally Proposed for (4 + 3)
Cycloadditions of 2
Scheme 3. CHꢀπ-Directed Stereoinduction
Scheme 4. (4 + 3) Cycloadditions of Achiral Oxygen- and Nitrogen-Stabilized Oxyallyl Intermediates5ꢀ8
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endo cycloadducts to four. For each of the syn and anti regioi-
somers, there are two diastereomers, I and II, which differ
according to the face of the oxyallyl intermediate to which the
furan binds. Selected literature examples involving chiral nitrogen-
and oxygen-substituted oxyallyls are shown in Scheme 6.
Walters generated a chiral nitrogen-stabilized oxyallyl inter-
mediate by treatment of the R-haloketone 8 with Et3N/
trifluoroethanol, and it reacted with 3-bromofuran to give selectively
the anti-II adduct 9.11 Hoffmann studied the asymmetric (4 + 3)
cycloadditions of oxygen-stabilized oxyallyl cations generated from
10 by treatment with TMSOTf; their cycloadditions with 3-sub-
stituted furans led predominantly to anti-I adducts.12 These results
have recently been shown to conform to a CHꢀπ mode of
stereoinduction similar to that proposed for our oxyallyls 2.13
Scheme 5. (4 + 3) Cycloadditions of an Achiral Oxazolidi-
none-Stabilized Oxyallyl10
’ RESULTS AND DISCUSSION
We have now investigated the asymmetric cycloadditions of
2Ph with a range of 2- and 3-substituted furans. Methyl and
acyloxymethyl-substituted furans were used as electron-rich
substrates,14 while ester and cyano-substituted furans were used
as electron-poor substrates. The experimentally measured regio-
and stereoselectivities are given in Tables 1ꢀ3.15
1. Cycloadditions of 2Ph with 2-Substituted Furans. 1.1.
Cycloadditions in the Absence of ZnCl2. The cycloaddition of 2Ph
with 2-methylfuran (Table 1) gave a 54% total yield of the endo
cycloadducts 12aꢀd, in which the diastereomer ratio (dr) of I:II
Scheme 6. (4 + 3) Cycloadditions of Chiral Oxygen- and Nitrogen-Stabilized Oxyallyl Intermediates11,12
a
Table 1. Cycloadditions of 2Ph with 2-Substituted Furans in the Absence of ZnCl2
a Isolated yields. Isomer distributions are given in parentheses and were determined by 1H and/or 13C NMR.
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a
Table 2. Cycloadditions of 2Ph with 2-Substituted Furans in the Presence of ZnCl2
a Isolated yields. Isomer distributions are given in parentheses and were determined by 1H and/or 13C NMR.
a
Table 3. Cycloadditions of 2Ph with 3-Substituted Furans in the Presence of ZnCl2
a Isolated yields. Isomer distributions are given in parentheses and were determined by 1H and/or 13C NMR. b The regiochemistry of all minor isomers
were assigned as syn by COSY and NMR coupling patterns, but the stereochemistry (I or II) was not determined; they are listed as II here by comparison
with the computational data.
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Scheme 7. Previous Calculations4 on the Oxyallyl 2Ph, its
ZnCl2 Complexes, and its Cycloadditions with Furan.
Energies are in kcal/mol
Figure 1. X-ray crystal structures of cycloadducts.
(Scheme 5),10 although for 2-methylfuran the syn:anti ratio is
lower with 2Ph than with the parent oxyallyl.
was 90:10. The regioisomer ratios were equivalent for the two
diastereomers: I was obtained with a syn:anti ratio of 67:23
(12a:12b), while II was obtained with a syn:anti ratio of 70:30
(12c:12d). Stereochemical assignments were made on the basis of
NMR coupling patterns and COSY spectra. The olefinic protons
in both of the I isomers (12a and 12b) are shifted unusually
upfield, due to anisotropic shielding by the nearby Ph ring on the
oxazolidinone. Similar shielding effects were also observed with
the other I isomers described below. The II isomers 12c and 12d
showed nosuch upfield shifting. For the syn-I isomer (12a), the 1H
NMR spectrum had to be collected at high temperature to discern
the coupling patterns (Supporting Information).
In contrast, the cycloadditions of 2Ph with 2-EWG-substituted
furans produced diastereomer II but no observable I. Methyl 2-furoate
and allyl 2-furoate gave the syn-II isomers 13c and 130c as the sole
cycloadducts in 40ꢀ60% yield. The stereochemistry of 13c was
unambiguously assigned by X-ray crystallography (Figure 1).
1.2. Cycloadditions in the Presence of ZnCl2. Inclusion of
ZnCl2 in the reaction mixture for cycloaddition with 2-methyl-
furan raised the diastereomer ratio from 90:10 to 100:0
(Table 2). The syn:anti ratio increased to 80:20.
With methyl 2-furoate, the major product was still the syn-II
isomer 13c, but it was now accompanied by a small amount of
syn-I (13a). The structure of 13a was assigned spectroscopically;
anisotropic shielding was again evident.2d Somewhat surpris-
ingly, on going from the furoate ester to its nitrile analogue, a
return in stereoselectivity back to I was observed! The syn-I
isomer 14a was obtained from 2-cyanofuran with a dr of 83:17.
The regioselectivity for both the ester and the nitrile was
completely in favor of syn.
2. Cycloadditions of 2Ph with 3-Substituted Furans. The
cycloadditions of 2Ph with 3-substituted furans were studied
under ZnCl2-catalyzed conditions. Our results are listed in
Table 3. The stereochemistry of the major cycloadducts was
unambiguously assigned by means of COSY and NOESY
analysis and, in the cases of ethyl 3-furoate and 3-bromofuran,
by X-ray single crystal structures (Figure 1). In all of the major
products, the olefinic proton showed the typical anisotropic
shielding by the Ph ring on the oxazolidinone. For the minor
isomers, the regiochemistry could be firmly assigned as syn by
COSY and NMR coupling patterns, but the stereochemistry was
not determined. The syn regiochemistry ruled out the use of Ph
shielding as a stereochemical diagnostic. We have tentatively
assigned the II stereochemistry to the minor isomers, on the basis
of our computational results reported below.
The regio- and stereoselectivities of the cycloadditions invol-
ving 3-substituted furans differ markedly from those of 2-sub-
stituted furans. All of the 3-substituted furans gave selectively the
anti-I cycloadduct. For 3-methylfuran and methyl 3-furoate, the
anti:syn ratio was approximately 90:10. 3-phenylfuran and 3-acet-
oxymethylfuran gave more modest anti:syn ratios (60:40 and
70:30, respectively), but replacement of the acetyl group in the
latter by a pivaloyl group increased the anti selectivity to 100:0.
3-bromofuran also gave 100:0 anti selectivity.
The regioselectivities of these reactions mirror those of the
parent oxazolidinone-substituted oxyallyl with 3-substituted furans
(Scheme 5),10 both in direction and magnitude. Similar anti-I
selectivity was reported by Hoffmann for the cycloadditions of
3-substituted furans with related oxygen-substituted oxyallyl
cations (Scheme 6).12
The regioselectivities observed here parallel those observed
previously for the parent oxazolidinone-substituted oxyallyl
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Figure 2. Transition structures for the (4 + 3) cycloadditions of 2Ph with 2-methylfuran, calculated at the B3LYP/6-31G(d) level. Bond lengths in Å,
energies in kcal/mol. ΔHq and ΔGq (in parentheses) are given below the TSs.
Table 4. Calculated Activation Energies and Experimental
Cycloadduct Ratios for the (4 + 3) Cycloadditions of 2Ph with
2-Substituted Furansa
syn-I
anti-I
syn-II
anti-II
Reactions in the absence of ZnCl2
2-Methylfuran
ΔHq
6.2
7.5
6.7
7.8
ΔGq
20.4
67%
22.0
23%
20.9
7%
22.2
3%
Experimental
Methyl 2-furoate
ΔHq
5.3
8.7
3.4
9.3
ΔGq
20.5
23.2
19.3
100%
23.3
Experimental
Reactions in the presence of ZnCl2
2-Methylfuran
ΔHq
ΔGq
Figure 3. Total dispersion energies of the syn-I and syn-II transition
states for cycloadditions of 2Ph with 2-substituted furans, calculated at
the B3LYP-D/6-31G(d) level (kcal/mol).
ꢀ2.9
11.7
80%
ꢀ1.7
13.6
20%
ꢀ1.9
ꢀ0.6
11.7
13.4
Experimental
Methyl 2-furoate
ΔHq
ꢀ1.1
14.1
30%
4.1
ꢀ1.7
13.9
70%
5.4
ΔGq
18.5
18.4
Experimental
2-Cyanofuran
ΔHq
2.3
6.1
3.4
7.6
ΔGq
17.0
20.9
17.7
21.4
Experimental
83%
17%
a B3LYP/6-31G(d), 298.15 K, kcal/mol; Experimental isomer ratios
given as percentages.
3. Computational Studies. Numerous theoretical studies of
oxyallyl cations and their cycloadditions have been reported
previously.5,16ꢀ18 Cramer17b,c showed that the cycloadditions
can take place by various mechanisms; the highly electrophilic
hydroxyallyl cation was calculated to react with furan by a two-
step process commencing with electrophilic attack at C-2 of the
furan. We have found4 that the less electrophilic, neutral oxyallyls
2 undergo concerted, asynchronous cycloadditions with furans.
Figure 4. Syn-I transition structures for the ZnCl2-catalyzed (4 + 3)
cycloadditions of 2Ph with 2-CO2Me- and 2-CN-furan, calculated at the
B3LYP/6-31G(d) level. Distances in Å.
Our earlier findings4 are summarized in Scheme 7. At the
B3LYP/6-31G(d) level, only the E conformer of 2Ph was an
energy minimum. Attempts to locate the Z conformer led to the
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Table 5. Calculated Activation Energies and Experimental
Cycloadduct Ratios for the ZnCl2-Catalyzed (4 + 3)
Cycloadditions of 2Ph with 3-Substituted Furansa
5-position of the furan more electrophilic than the 2-position.
The regioselectivity for the donor-substituted furan (2-Me-
furan) is unexpected. Here electronic effects are small, and the
regioselectivity instead arises from a preference for the transi-
tion state that allows the more advanced bonding interaction
to be made to the less-substituted carbon (C-5) of the furan
(Figure 2).
The stereoselectivities observed with 2-methylfuran and 2-cy-
anofuran conform to the CHꢀπ model (Scheme 3) and have a
magnitude somewhat smaller than that observed with furan itself
(82:18 uncatalyzed, g96:4 with ZnCl2). The proton involved in
the CHꢀπ interaction is H-3 or H-4 of the furan (for the syn and
anti isomers, respectively), which points roughly toward the
center of the Ph ring in the I transition states. The stabilizing
role of the CHꢀπ interaction has both electrostatic and
dispersive components. To estimate the role of the latter,
the dispersion energies in the transition states were calculated
by means of Grimme’s 2006 empirical B3LYP-D formula,
which sums the dispersion energies between each pair of
atoms in the structure.20 A comparison between the disper-
sion energies of the syn-I and syn-II transition states for each
2-substituted furan is shown in Figure 3. Dispersive stabiliza-
tion is 0.02ꢀ2.9 kcal/mol stronger in the I transition states
than the II transition states.
syn-I
anti-I
syn-II
anti-II
3-Methylfuran
ΔHq
ΔGq
ꢀ1.4
ꢀ2.8
11.6
88%
ꢀ2.0
11.8
12%
ꢀ1.9
12.7
10.9
Experimental
Methyl 3-furoate
ΔHq
ΔGq
Experimentalb
0.9
ꢀ4.9
11.7
90%
ꢀ1.9
13.2
10%
ꢀ3.2
12.8
16.7
a B3LYP/6-31G(d), 298.15 K, kcal/mol; experimental isomer ratios
given as percentages. b Experimental data for ethyl 3-furoate.
isomeric cyclopropanone. ZnCl2 complexes were located for
both the E and the Z conformers, but the Z complex was 6.2 kcal/
mol less stable. Transition states were located for cycloadditions
involving both the E and the Z conformers, but those involving
the Z isomer were disfavored by g15.4 kcal/mol (g5.2 kcal/mol
for the ZnCl2 complexes). Electrostatic repulsion between the
oxygen atoms destabilizes all of the Z structures.
The concerted transition state geometries are asynchronous
such that the more advanced bonding interaction involves the
more nucleophilic (CH2) carbon of the oxyallyl. This is the case
also for reactions with substituted furans, shown in Scheme 5.10
On the other hand, the calculated Mulliken charges in the
transition states indicate net charge transfer of 0.05ꢀ0.17e from
the furan to the oxyallyl. Overall, the oxyallyls 2 are best
characterized as ambiphilic toward furans. The activation barriers
for reactions with either Me- or CO2Me-substituted furans
(Scheme 5) are lower than those for furan itself. Methyl 2-furoate
has the lowest barrier (ΔHq 3.2 kcal/mol lower than for furan).
To model the reactions of 2Ph with substituted furans, we
calculated transition states involving addition to the E oxyallyl
only. Calculations were performed at the B3LYP/6-31G(d) level
(including LANL2DZ+ECP for Zn) in Gaussian 03.19 In Figure 2
are shown the four isomeric transition structures calculated for
the reaction of 2Ph with 2-methylfuran. These are representative
of the transition states calculated for the other furans also.
Concerted, asynchronous transition states were found for all of
the cycloadditions.
3.1. Cycloadditions of 2Ph with 2-Substituted Furans. The
calculated activation energies for reactions of 2Ph-E with 2-sub-
stituted furans are listed in Table 4. The experimental selectivities
are also included in the table for comparison.
The calculations correctly predict the major product for each
2-substituted furan. Some differences in the minor isomers are
found, which for the ZnCl2-catalyzed cycloadditions may be due
to the use of excess furan and ZnCl2 in the experiment. For
example, a furan molecule may coordinate to the Zn center of
The reversal in stereoselectivity for 2-CO2Me-furan was at first
suprising, but it is indeed predicted by theory. The syn-II
transition state is favored over the other three TSs by 1.9 kcal/
mol in the uncatalyzed reaction and by 0.6 kcal/mol in the ZnCl2-
catalyzed reaction (ΔΔHq). A top-down view of the syn-I
transition state for 2-CO2Me-furan under ZnCl2-catalyzed con-
ditions is shown in Figure 4a. A destabilizing electrostatic
interaction takes place between the ester carbonyl group and
the Ph π-cloud. The distance between the carbonyl oxygen and
the nearby C-2 of the Ph ring (red line: 3.22 Å) is equal to the
sum of the van der Waals radii for C and O. This interaction
outweighs the stabilizing effect of the CHꢀπ interaction, and the
uncrowded (II) transition state is instead favored.
The calculations also correctly predict that the seemingly small
change from a 2-CO2Me to a 2-CN group should induce a return
to syn-I selectivity. The syn-I transition state for 2-CN-furan is
shown in Figure 4b. The CN group is positioned further from the
Ph ring (NꢀC 3.56 Å), and therefore does not present such
severe electrostatic repulsion as the CO2Me group.
3.2. Cycloadditions of 2Ph with 3-Substituted Furans. The
calculated activation energies for ZnCl2-catalyzed reactions of
2Ph with 3-substituted furans are listed in Table 5, together with
the experimental selectivities.
The calculations correctly predict the regio- and stereochem-
istry of the major product for methyl 3-furoate. For 3-methylfur-
an, the free energies of activation do not capture the correct
stereoselectivity, but the enthalpies do predict both the regio-
and stereoselectivity. As with the 2-EWG-substituted furans, the
regioselectivity for 3-CO2Me-furan is under electronic control,
since C-2 of the furan is more electrophilic than C-5. For 3-Me-
furan, the regioselectivity is instead steric in origin, arising
through avoidance of clashing between the Me group and the
Ph group.
2Ph-E ZnCl2, or ZnCl2 may coordinate to the furan that under-
3
goes cycloaddition. These factors would lead to small differences
in the proportions of the minor isomers but are unlikely to affect
the overall selectivity.
The oxyallyl 2Ph is more nucleophilic at the CH2 terminus and
more electrophilic at the CHN terminus. Yet, cycloadditions of
2Ph with both 2-EWG and 2-EDG-substituted furans favor the
syn cycloadducts. This regioselectivity is predictable for the
EWG-substituted furans, since the substituent renders the
Both 3-substituted furans favor the I stereoisomer, as do the
four other 3-substituted furans in Table 3. The anti arrangement
enables the CHꢀπ interaction in the crowded TS to take place
without interference from the substituent. The calculations
predict that for both 3-substituted furans, the minor (syn) isomer
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Scheme 8. Summary of Factors Responsible for Regio- and
Stereocontrol in the (4 + 3) Cycloadditions of 2Ph with Furans
Chiral oxazolidinone auxiliaries have been used to achieve a wide
range of other asymmetric transformations, including DielsꢀAlder
reactions,24 aldol condensations,25 enolate alkylation,26 hydroxyla-
tion,27 and amination,28 Michael additions,29 epoxide synthesis,30 and
resolutions of R-halo carbonyl compounds.31 The results described
herein for the (4 + 3) cycloadditions of 2Ph likely hold relevance to
stereocontrol in these other oxazolidinone-directed reactions.
’ EXPERIMENTAL METHODS
Typical Procedure for (4 + 3) Cycloadditions. To a solution of
the allenamide in CH2Cl2 (0.1 M) were added the appropriate furan
(3ꢀ9 equiv) and 4 Å powder molecular sieves (0.5 g). The solution was
cooled to ꢀ78 °C, and ZnCl2 (1.0 M in ether, 2.0 equiv) was added.
DMDO (4.0ꢀ6.0 equiv, in acetone) was then added as a chilled solution
via syringe pump (at ꢀ78 °C) over 3ꢀ4 h. The reaction mixture was
stirred for a further 14 h, then quenched with saturated aqueous
NaHCO3, filtered through Celite, concentrated in vacuo, extracted with
CH2Cl2, dried over Na2SO4, and concentrated in vacuo. The crude
residue was purified via column chromatography on silica gel (gradient
eluent: 10 to 75% ethyl acetate in hexane).
’ THEORETICAL CALCULATIONS
should have the II stereochemistry, as the syn-I transition state is
subject to unfavorable interaction between the Ph group and the
furan 3-substituent.
Density functional theory calculations were performed at the B3LYP/
6-31G(d) level32 in Gaussian 03.19 The LANL2DZ basis set and effective
core potential were used for Zn.33 Species were characterized as minima
or transition states on the basis of vibrational frequency analysis and,
where appropriate, IRC calculations.34 Zero-point energy and thermal
corrections were derived (unscaled) from the B3LYP/6-31G(d) fre-
quencies. Conformational searching was performed for each species in
order to identify the lowest-energy conformer. Enthalpies and free
energies are reported at 298.15 K, with a standard state of 1 atm.
’ CONCLUSIONS
A summary of the origins of the regio- and stereoselectivities
of the (4 + 3) cycloadditions is given in Scheme 8. The oxyallyls 2
undergo (4 + 3) cycloadditions with furans through concerted
transition states in most cases. Generally, bond development at
the TS is most advanced at the nucleophilic (CH2) terminus of 2.
The regioselectivities of (4 + 3) cycloadditions between 2 and
furans arise through steric effects, but these are complemented by
electronic effects when the substituent is an electron-withdraw-
ing group. For 2-substituted furans, syn cycloadducts are formed
selectively, because this arrangement enables the stronger bond-
ing interaction in the TS to involve the less-hindered (C-5)
carbon. For 2-EWG-substituted furans, C-5 is also more electro-
philic than C-2, enhancing regiocontrol. 3-Substituted furans
undergo cycloaddition preferentially in the anti geometry, in
order to avoid steric clashing between the 3-substituent and the
Ph ring. Similar anti selectivity has even been observed when the
Ph group is absent,10 indicating that the pseudoaxial group at the
4-position of the oxazolidinone has a steric influence even when it
is only an H atom. For 3-EWG-substituted furans, the anti
selectivity is complemented by the electronic effect of the
substituent, which renders C-2 more electrophilic than C-5.
All but two of the furans studied (Tables 1ꢀ3) lead selectively
to the cycloadduct I. Only for 2-CO2R-furans (R = Me, allyl) does
the unexpected II isomer predominate. The CHꢀπ model
(Scheme 3) therefore appears to have broad applicability for
monosubstituted furans. When the oxazolidinone Ph group is
replaced by a nonaromatic group, the stabilizing CHꢀπ interac-
tion is lost, and the stereoselectivity reverts to favor II, as shown by
our earlier studies with a 4-Bn-oxazolidinone and with Seebach
etal.’s21 4-iPr-5,5-Ph2-oxazolidinoneauxiliary.4 Reversals of stereo-
selectivity have also previously been observed to occur in hetero-
DielsꢀAlder reactions22 and conjugate radical additions23 cata-
lyzed by chiral Lewis acid/bis(oxazoline) complexes, when the Ph
groups on the ligand were replaced by tBu groups.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental procedures,
b
NMR spectra and characterizations for all new compounds, X-ray
data, computed geometries and energies, and a complete citation
for ref 19. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
ekrenske@unimelb.edu.au; houk@chem.ucla.edu; rhsung@wisc.edu
’ ACKNOWLEDGMENT
We thank the NIH (GM36700 to KNH and GM-66055 to R.
P.H.) and Australian Research Council (DP0985623 to E.H.K.)
for generous financial support, and the NCSA, UCLA ATS,
UCLA IDRE, and NCF NI (Australia) for computer resources.
EHK also thanks the AustralianꢀAmerican Fulbright Commis-
sion for a postdoctoral scholarship and the ARC Centre of
Excellence for Free Radical Chemistry and Biotechnology for
financial support. We thank Dr Vic Young and Dr Ben Kucera of
the University of Minnesota for X-ray crystallography.
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