Control of regioselectivity and stereoselectivity in (4 + 3) cycloadditions of chiral oxyallyls with unsymmetrically disubstituted furans

Article abstract of DOI:10.1021/jo3011792

The regioselectivities and stereoselectivities of ZnCl₂- catalyzed (4 + 3) cycloadditions between chiral oxazolidinone-substituted oxyallyls and unsymmetrical disubstituted furans have been determined. The substitution pattern on the furan is found to provide a valuable tool for controlling the stereochemistry (endo-I or endo-II) of the 7-membered cycloadduct. While cycloadditions with monosubstituted furans usually favor endo-I products, from addition of the furan to the more crowded face of the oxyallyl, cycloadditions with 2,3- and 2,5-disubstituted furans instead favor the endo-II stereochemistry. Density functional theory calculations are performed to account for the selectivities. For monosubstituted furans, the crowded transition state leading to the endo-I cycloadduct is stabilized by an edge-to-face interaction between the furan and the oxazolidinone 4-Ph group, but this stabilization is overcome by steric clashing if the furan bears a 2-CO₂R group or is 2,3-disubstituted.

Full text of DOI:10.1021/jo3011792

Article
pubs.acs.org/joc
Control of Regioselectivity and Stereoselectivity in (4 + 3)
Cycloadditions of Chiral Oxyallyls with Unsymmetrically
Disubstituted Furans
Yunfei Du,† Elizabeth H. Krenske,*,‡ Jennifer E. Antoline,§ Andrew G. Lohse,§ K. N. Houk,*,∥
and Richard P. Hsung*,§
†School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, P. R. China
‡School of Chemistry, University of Melbourne, Victoria 3010, Australia and Australian Research Council Centre of Excellence for
Free Radical Chemistry and Biotechnology
§Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin at Madison, Madison, Wisconsin 53705,
United States
∥Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: The regioselectivities and stereoselectivities of
ZnCl2-catalyzed (4 + 3) cycloadditions between chiral
oxazolidinone-substituted oxyallyls and unsymmetrical disub-
stituted furans have been determined. The substitution pattern
on the furan is found to provide a valuable tool for controlling
the stereochemistry (endo-I or endo-II) of the 7-membered
cycloadduct. While cycloadditions with monosubstituted
furans usually favor endo-I products, from addition of the
furan to the more crowded face of the oxyallyl, cycloadditions
with 2,3- and 2,5-disubstituted furans instead favor the endo-II stereochemistry. Density functional theory calculations are
performed to account for the selectivities. For monosubstituted furans, the crowded transition state leading to the endo-I
cycloadduct is stabilized by an edge-to-face interaction between the furan and the oxazolidinone 4-Ph group, but this stabilization
is overcome by steric clashing if the furan bears a 2-CO2R group or is 2,3-disubstituted.
substituted furans studied, only those containing a 2-CO2R
group did not follow this behavior.
INTRODUCTION
■
Oxazolidinone-stabilized oxyallyls (3) are a fascinating class of
reactive intermediates, generated by oxidation of allenamides
(1).1,2 Several valuable synthetic routes to 7-membered
carbocycles rely on (4 + 3) cycloadditions between oxyallyl
intermediates and dienes,3,4 and we have found that the
cycloadditions of oxyallyls 3 with monosubstituted furans
(Schemes 1 and 2) display distinctive regioselectivities and
stereoselectivities.5,6 These reactions may be performed either
under thermal conditions or with catalysis by ZnCl2. The
regioselectivities are summarized in Scheme 1, which shows the
achiral oxyallyl 3a; cycloadditions of 3a with 2-substituted
furans (G = Me or CO2Me) favor the “syn” regiochemistry,
while reactions with 3-substituted furans favor “anti”
regiochemistry. The same regioselectivities are obtained with
the chiral oxyallyl 3b (Scheme 2), but in this case the reactions
also feature a novel mode of stereoinduction. Surprisingly,
reactions of 3b with most monosubstituted furans were found
to favor the endo-I stereochemistry, which entails addition of
the furan to the more crowded face of 3b. Density functional
theory calculations6 showed that the crowded transition state is
favored because it contains a stabilizing edge-to-face aromatic
interaction (CH−π) between furan and Ph. Of the mono-
In order to explore the generality of these stereochemical and
regiochemical control elements, we have examined the (4 + 3)
cycloadditions of 3b with more complex, unsymmetrical
disubstituted furans. We report that these reactions often
proceed with high levels of regio- and stereocontrol, even when
the selectivities cannot be easily predicted from individual
substituent effects. Complete control over stereoselectivity can
be obtained through strategic choice of substituents.
RESULTS AND DISCUSSION
■
We investigated the (4 + 3) cycloadditions of oxyallyls 3 with a
range of unsymmetrical disubstituted furans containing Me and
CO2Me substituents at different positions. The cycloadditions
were performed under ZnCl2-catalyzed conditions. Results are
given in Table 1.
Our work commenced with the 2-CO2Me,3-Me-substituted
furan, 4. Based on the selectivities previously observed with
Special Issue: Howard Zimmerman Memorial Issue
Received: June 7, 2012
Published: July 31, 2012
© 2012 American Chemical Society
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Scheme 1. Regioselectivities of (4 + 3) Cycloadditions of Achiral Oxyallyl 3a with Monosubstituted Furans6b
assigned unambiguously by NOESY and COSY (see the
Supporting Information).
Scheme 2. Stereoselectivities of (4 + 3) Cycloadditions of
Chiral Oxyallyl 3b with Monosubstituted Furans6a,c
In 2,3-disubstituted furans, the substituents have opposite
regiodirecting influences (Scheme 1), and the selectivities
obtained with 4−6 indicate that it is the 2-substituent that
dictates the outcome. In order to discern the relative directing
power of Me and CO2Me groups at the 2-position, we
examined the reaction of 3b with 7. The only cycloadduct
detected was 11, where CO2Me is syn to nitrogen. Its structure
was confirmed by NOESY and COSY.
The regioselectivities and stereoselectivities observed here
with disubstituted furans are quite distinct from those reported
previously for monosubstituted furans.6 We performed density
functional theory calculations to explore the selectivities.
Transition states for ZnCl2-catalyzed cycloadditions of the
oxyallyls 3b and 3c with furans 4−7 were computed at the
B3LYP/6-31G(d) level (with LANL2DZ on Zn), as we have
previously done in our studies of related oxyallyl (4 + 3)
cycloadditions. The transition states for the reaction of 3b with
4 are representative and are shown in Figure 2. Regardless of
the regiochemistry, the transition states each show the same
sense of asynchronicity, with more advanced bonding at the
unsubstituted terminus of the oxyallyl. The HOMO coefficient
of the oxyallyl is larger at this terminus.
We previously found that B3LYP activation energies provide
good predictions of regioselectivity and stereoselectivity for
oxyallyl (4 + 3) cycloadditions. In order to provide a better
treatment of dispersion energies in the cycloadditions of 4−7,
which are likely to vary significantly between stereoisomeric
transition states I and II, we calculated the activation barriers
from single-point energies at the M06-2X/6-311+G(d,p) level.
Solvent effects were modeled by means of CPCM calculations.
The M06-2X activation energies in the gas phase and in
dichloromethane are given in Table 2.
monosubstituted furans (Schemes 1 and 2), it is not possible to
predict the major product for 4; a 2-CO2Me substituent favors
syn-II but a 3-Me substituent favors anti-I. The cycloaddition of
3b with 4 was found to give exclusively the syn-II cycloadduct,
8, in 67% yield. The structure of 8 was assigned unambiguously
by X-ray (Figure 1). The cycloaddition of 3b with the 2-Me,3-
CO2Me-substituted furan 5 also gave exclusively a syn-II adduct
(9). Confirmation of the structure of 9 was obtained following
reduction/esterification, which afforded a rearranged derivative
(12) whose X-ray structure was determined (Figure 1).7 The
regioselectivities observed for both 4 and 5 match those
previously obtained6b with the achiral oxyallyl 3a, which
displayed syn selectivities of ≥95:5.
We next examined the 2-Me,3-Me-substituted furan, 6. In
order to deal with competing oxidation of this more electron-
rich furan, we had to switch to the more reactive allenamide,
1c,8 which contains Close’s chiral imidazolidinone auxiliary.9
Previous experiments5 indicated that Close’s imidazolidinone
controls stereoselectivity in the same way as 4-Ph-oxazolidi-
none. Cycloaddition of 3c with 6 afforded mainly the syn-II
product, 10c, but also gave two other cycloadducts: syn-I (10a)
and anti-I (10b). X-ray structures were determined for the two
minor products (Figure 1), while the major product was
The calculated values of ΔG⧧ in the gas phase and in solution
predict a strong preference for the observed product (syn-II) for
both furans 4 and 5. The syn-II TS from 4 is favored by ≥2.9
kcal/mol in dichloromethane, and the syn-II TS from 5 is
favored by ≥4.6 kcal/mol. Lower selectivity is predicted for
furan 6. Indeed, the cycloaddition of 6 with 3b is calculated to
favor the anti-I TS by 0.6 kcal/mol. However, the cycloaddition
of the same furan with 3c, which was studied experimentally, is
correctly predicted to favor syn-II. The syn-II TS is preferred by
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a
Table 1. (4 + 3) Cycloadditions of Oxyallyls with Disubstituted Furans
a
b
Isolated yields are quoted. Isomer ratios are given in parentheses and were determined by 1H and/or 13C NMR. From reaction with allenamide 1b.
From reaction with allenamide 1c.
c
B3LYP alone also correctly predicts the major products for
furans 4−6 (and from 7 in the gas phase), but fails to predict
the presence of minor products in the cycloaddition involving
6.
Our previous calculations showed that a 2-substituent on the
furan favors syn regiochemistry because the shorter forming
bond in the transition state is located at the less-hindered
carbon (C-5) of the furan.6 When the 2-substituent is electron-
withdrawing, this steric effect is reinforced by a strong oxyallyl−
furan interaction energy, related to the large furan LUMO
coefficient at C-5. For 3-substituted furans, by contrast, the anti
regiochemistry is favored because its transition state avoids
steric clashing between the 3-substituent and the oxazolidinone.
The syn selectivities obtained experimentally from furans 4−
7 (Table 1) indicate that the regiodirecting influence of a 2-
substituent outweighs that of a 3-substituent, regardless of
whether the substituent is Me or CO2Me. A 2-CO2Me group
exerts a stronger regiodirecting effect than a 2-Me group (cf. 7)
Figure 1. X-ray structures of cycloadduct 8, ester 12 (derived from 9),
and cycloadducts 10a and 10b.
because the oxyallyl−furan interaction in the TS is stronger
when CO2Me is syn to nitrogen.
The stereoselectivities observed with furans 4−7 cannot be
predicted from those of the corresponding monosubstituted
furans. Most monosubstituted furans favor diastereomer I, due
to the stabilizing edge-to-face aryl−aryl interaction in the
crowded (I) transition state (Scheme 2).6a,c Only for 2-
CO2Me-furan was II favored; in that case, the (syn-)I TS is
destabilized by electrostatic repulsion between the CO2Me
group and the Ph π-cloud.
A similar type of repulsive electrostatic effect influences the
stereoselectivities for 4 and 7, favoring II. More generally,
however, the stereoselectivities for all three 2,3-disubstituted
furans (4−6) are dictated by the furan 3-substituent. This
0.1−0.2 kcal/mol over syn-I and anti-I. Experimentally, a
mixture of products was obtained containing the latter two
isomers as minor products. The agreement between experiment
and theory is not as good for 7, where the calculations predict a
1.1 kcal/mol preference for anti-I in dichloromethane. The
selectivity in the gas phase does correctly predict syn-II,
however. Experimentally, the syn-II cycloadduct was obtained in
40% yield.
Activation energies were also computed with a second
dispersion-inclusive functional, B3LYP-D3 (Supporting Infor-
mation). The predicted selectivities mirror those from M06-2X.
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Figure 2. Transition structures for ZnCl2-catalyzed cycloadditions of oxyallyl 3b with furan 4, optimized with B3LYP. Below each structure are given
the activation energies obtained from M06-2X single-point calculations. Distances in Å, ΔH⧧ and ΔG⧧ in kcal/mol.
a
Table 2. Calculated Activation Energies for ZnCl2-Catalyzed Cycloadditions of 3b with Disubstituted Furans
ΔH⧧ (ΔG⧧) [ΔG⧧
]
soln
reactants
syn-I
anti-I
syn-II
anti-II
4 + 3b·ZnCl2
−13.2
(5.2)
[11.5]
−13.2
(4.3)
[12.5]
−12.8
(3.9)
[8.4]
−12.7
(4.9)
[10.1]
−15.5
(3.6)
[11.9]
−15.0
(2.3)
[7.4]
−16.1
(2.2)
[7.2]
−14.6
(2.6)
[7.3]
−12.1
(3.6)
[8.0]
−6.1
(9.6)
[14.2]
−14.4
(3.8)
[11.0]
−9.9
(6.8)
[11.0]
−13.0
(5.6)
5 + 3b·ZnCl2
6 + 3b·ZnCl2
6 + 3c·ZnCl2
7 + 3b·ZnCl2
[14.1]
−12.4
(3.9)
[8.0]
−7.0
−8.3
−6.0
(9.7)
[14.3]
−9.6
(9.0)
[14.4]
−11.5
(4.8)
[9.9]
(10.4)
[14.9]
−8.3
(8.4)
(7.0)
[16.1]
[11.4]
a
M06-2X/6-311+G(d,p)//B3LYP/6-31G(d)-LANL2DZ. Solution-phase data incorporate CPCM solvation energies in CH2Cl2, computed at the
M06-2X/6-31G(d)-LANL2DZ level. ΔH⧧ and ΔG⧧ in kcal/mol at 298.15 K.
group eliminates the possibility of an edge-to-face CH−π
interaction in the crowded syn-I TS and replaces it with a
repulsive electrostatic interaction (3-CO2Me) or a weaker
CH−π interaction (3-Me). The result is a preference for II.
Only for 6, where no CO2Me group is present, are isomers of I
found as minor products.
unless (a) the 2-substituent is CO2R or (b) there is also a
substituent present at furan C-3. In the latter two cases, syn-II is
preferred instead. These principles enable cycloadditions of
oxyallyls 3 with complex furans to be achieved with high levels
of regioselectivity and stereoselectivity.
EXPERIMENTAL SECTION
■
CONCLUSION
General Procedure for Allenamide (4 + 3) Cycloadditions.
To a solution of a respective allenamide in CH2Cl2 (0.1 M) was added
3−9 equiv of the appropriate furan and 4 Å powdered molecular sieves
(0.5 g). The reaction solution was cooled to −78 °C, and 2.0 equiv of
ZnCl2 (1.0 M in Et2O) was added. Dimethyldioxirane (DMDO) (4.0−
6.0 equiv) in acetone was then added as a chilled solution (at −78 °C)
via a syringe pump over 3−4 h. The syringe pump was cooled using
dry ice during the entire addition time. After the addition, the reaction
mixture was stirred for an additional 14 h before it was quenched with
■
The investigations detailed herein provide a valuable new
approach to controlling the stereoselectivities of (4 + 3)
cycloadditions. The different classes of substituent effects
operating for monosubstituted and disubstituted furans are
outlined in Scheme 3 and can be summarized as follows:
cycloaddition of oxyallyl 3b or 3c with a 2-substituted furan
(including a disubstituted furan) favors the syn-I cycloadduct,
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Scheme 3. Summary of Substituent-Controlled Regioselectivity and Stereoselectivity in (4 + 3) Cycloadditions of Oxyallyl 3b
with Furans
satd aq NaHCO3, filtered through Celite, concentrated in vacuo, and
extracted with CH2Cl2 (4 × 20 mL). The combined organic layers
were dried over Na2SO4 and concentrated in vacuo. The crude residue
was purified via silica gel column chromatography (gradient eluent:
10−75% ethyl acetate in hexane).
CDCl3) δ 0.71 (d, 1H, J = 6.8 Hz), 1.34 (s, 3H), 1.59 (s, 3H), 2.44 (d,
1H, J = 15.6 Hz), 2.57 (d, 1H, J = 15.6 Hz), 2.73 (s, 3H), 3.96 (dq,
1H, J = 6.8, 8.8 Hz), 4.46 (d, 1H, J = 8.8 Hz), 4.49 (d, 1H, 4.2 Hz),
4.66 (s, 1H), 5.10 (d, 1H, J = 4.2 Hz), 7.03 (br, 1H), 7.31−7.33 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 12.1, 15.3, 21.6, 29.3, 50.8, 57.2,
59.7, 64.5, 79.2, 85.9, 125.6, 127.4, 128.4, 129.2, 138.8, 146.3, 162.6,
203.8; IR (thin film) cm−1 2941 m, 1728s, 1686s, 1431 m, 1255 m,
1196s, 1025 m, 855s, 735s, 700s; mass spectrum (APCI) m/e (relative
intensity) 339.2 (45) (M−H)−; HRMS (MALDI-TOF) m/e calcd for
C20H24N2O3Na+ (M + Na+) 363.1679, found 363.1678.
8: reaction scale, 0.50 mmol of allenamide 1b; yield 67%; mass
119.6 mg; Rf = 0.13 (50% EtOAc in hexane); [α]23 −169.6 (c 4.6,
D
CH2Cl2); white solid; mp = 119−120 °C; 1H NMR (400 MHz,
CDCl3) δ 2.04 (s, 3H), 2.54 (d, 1H, J = 16.0 Hz), 2.83 (dd, 1H, J =
5.4, 16.0 Hz), 3.29 (s, 3H), 3.91 (s, 1H), 4.20 (t, 1H, J = 9.0 Hz), 4.62
(t, 1H, J = 9.0 Hz), 4.79 (t, 1H, J = 9.0 Hz), 4.90 (dt, 1H, J = 5.2, 1.6
Hz), 7.00 (d, 1H, J = 1.6 Hz), 7.31−7.45 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 15.3, 44.3, 52.6, 65.9, 68.5, 70.5, 76.8, 88.3, 128.7,
129.3, 129.7, 130.2, 136.6, 142.9, 158.5, 166.9, 200.9; IR (thin film)
cm−1 3280w, 2911w, 1766s, 1437w; mass spectrum (APCI) m/e
(relative intensity) 358.1 (100) (M + H)+; HRMS (MALDI-TOF):
m/e calcd for C19H19NO6Na+ (M + Na+) 380.1105, found 380.1097.
9: reaction scale, 1.00 mmol of allenamide 1b; yield 60%; mass
10c: reaction scale, 0.44 mmol of allenamide 1c; yield 31%; mass
46.4 mg; Rf = 0.23 (50% EtOAc in hexane); [α]23 −105.7 (c 0.83,
D
CH2Cl2); colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.85 (d, 1H, J
= 6.8 Hz), 1.13 (s, 3H), 1. 89 (s, 3H), 2.47 (d, 1H, J = 17.2 Hz), 2.71
(dd, 1H, J = 5.8, 17.2 Hz), 2.79 (s, 3H), 3.43 (s, 1H), 3.92 (dq, 1H, J =
6.8, 9.2 Hz), 4.61 (d, 1H, J = 9.2 Hz), 4.74 (d, 1H, J = 5.8 Hz), 5.86 (s,
1H), 7.27−7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.4, 15.1,
21.4, 29.1, 44.7, 56.3, 68.1, 74.9, 75.9, 87.7, 121.1, 128.5, 128.8, 129.5,
137.0, 146.9, 161.7, 204.2; IR (thin film) cm−1 2933 m, 1703s, 1431,
1400s, 1262 m, 1159 m, 762 m; mass spectrum (APCI) m/e (relative
intensity) 341.2 (60) (M + H)+; HRMS (MALDI-TOF) m/e calcd for
C20H24N2O3Na+ (M + Na+) 363.1679, found 363.1674.
214.2 mg; Rf = 0.25 (50% EtOAc in hexane); [α]23 −74.5 (c 4.0,
D
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 1.30 (s, 3H), 2.60 (d, 1H, J
= 17.5 Hz), 2.88 (dd, 1H, J = 6.0, 17.5 Hz), 3.45 (s, 1H), 3.80 (s, 3H),
4.36 (t, 1H, J = 9.0 Hz), 4.71 (t, 1H, J = 9.0 Hz), 4.83 (t, 1H, J = 9.0
Hz), 4.99 (dd, 1H, J = 6.0, 2.0 Hz), 7.08 (d, 1H, J = 0.25 Hz), 7.48−
7.52 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 15.4, 44.3, 52.6, 66.0,
68.6, 70.6, 76.9, 88.4, 126.4, 128.8, 129.4, 129.8, 130.3, 143.0, 158.6,
167.0, 201.0; IR (thin film) cm−1 2954s, 2930s, 1764s, 1726s; mass
spectrum (APCI) m/e (relative intensity) 358.2 (100) (M + H)+;
HRMS (MALDI-TOF) m/e calcd for C19H19NO6Na+ (M + Na+)
380.1105, found 380.1095.
11: reaction scale, 0.35 mmol of allenamide 1b; yield 40%; mass
50.0 mg; Rf = 0.22 (50% EtOAc in hexane); [α]23 −31.4 (c 6.4,
D
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 1.43 (s, 3H), 2.59 (d, 1H, J
= 16.0 Hz), 2.68 (dd, 1H, J = 5.2, 16.0 Hz), 3.65 (s, 3H), 3.93 (s, 1H),
4.18 (t, 1H, J = 9.0 Hz), 4.65 (t, 1H, J = 9.0 Hz), 4.82 (t, 1H, J = 9.0
Hz), 6.07 (d, 1H, J = 6.0 Hz), 6.66 (d, 1H, J = 6.0 Hz), 7.28−7.41 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 23.2, 51.3, 64.4, 67.2, 70.5, 72.8,
86.1, 89.4, 126.4, 128.4, 129.9, 133.4, 135.6, 136.5, 158.1, 167.5, 199.8;
IR (thin film) cm−1 3520w, 2957w, 2927w, 1759s, 1726s; mass
spectrum (APCI): m/e (relative intensity) 358.2 (35) (M + H)+;
HRMS (MALDI-TOF) m/e calcd for C19H19NO6Na+ (M + Na+)
380.1105, found 380.1090.
10a: reaction scale, 0.44 mmol of allenamide 1c; yield 9%; mass
13.5 mg; Rf = 0.22 (50% EtOAc in hexane); [α]23 +14.9 (c 0.75,
D
CH2Cl2); mp = 162−163 °C; 1H NMR (400 MHz, CDCl3) δ 0.79 (d,
1H, J = 6.8 Hz), 1.46 (s, 3H), 1. 81 (s, 3H), 2.49 (d, 1H, J = 17.8 Hz),
2.60 (dd, 1H, J = 5.8, 17.8 Hz), 2.69 (s, 3H), 3.29 (s, 1H), 3.82 (dq,
1H, J = 6.8, 9.2 Hz), 4.70 (d, 1H, J = 9.2 Hz), 4.75 (d, 1H, J = 5.8 Hz),
5.91 (s, 1H), 7.13 (br, 1H), 7.32 (br, 4H); 13C NMR (100 MHz,
CDCl3) δ 14.0, 15.5, 21.4, 29.3, 43.8, 56.6, 65.2, 69.3, 75.9, 86.8, 128.5,
128.8, 128.9, 129.5, 135.3, 144.8, 159.3, 200.9; IR (thin film) cm−1
2929 m, 1725s, 1687s, 1432 m, 1263 m, 1161 m, 736 m, 694s; mass
spectrum (APCI) m/e (relative intensity) 341.2 (60) (M + H)+;
HRMS (MALDI-TOF) m/e calcd for C20H24N2O3Na+ (M + Na+)
363.1679, found 363.1680.
Synthesis of Ester 12 from Cycloadduct 9. To a solution of
cycloadduct 9 (53.6 mg, 0.150 mmol) in anhyd MeOH (5 mL) was
added NaBH4 (34.2 mg, 0.904 mmol) portionwise within 1 h at 0 °C.
The reaction mixture was further stirred at room temperature for 6 h
until the consumption of the starting material. Saturated aq NaCl (10
mL) was added to quench the reaction. After removal of the volatile
solvent under reduced pressure, the aqueous residue was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layer was dried over
Na2SO4 and concentrated in vacuo, and the crude residue was directly
used for the next step.
10b: reaction scale, 0.44 mmol of allenamide 1c; yield 21%; mass
31.4 mg; Rf = 0.17 (50% EtOAc in hexane); [α]23 −184.3 (c 0.79,
D
CH2Cl2); white solid; mp = 194−195 °C; 1H NMR (400 MHz,
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The above crude residue was taken up in CH2Cl2 (5 mL), and to
this solution were added DMAP (1.1 mg, 0.009 mmol) and Et3N (0.06
mL, 0.431 mmol) with vigorous stirring under ice−water cooling bath.
2,4,6-Trichlorobenzoyl chloride (0.07 mL, 0.450 mmol) was then
added in one portion. The reaction mixture was stirred at rt for 30 h
and was then quenched with cold H2O (10 mL) and extracted with
CH2Cl2 (4 × 20 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo. The crude residue was purified via
silica gel column chromatography (gradient eluent: 10−30% EtOAc in
hexane) to give the pure ester 12 (35.3 mg, 0.062 mmol, 42% over two
steps) as a white solid.
to R.P.H., and DP0985623 to E.H.K.), and the National
Computational Infrastructure National Facility (Australia) and
University of Melbourne for computer resources. E.H.K. also
thanks the ARC Centre of Excellence for Free Radical
Chemistry and Biotechnology for financial support. We thank
Dr. Vic Young and Mr. Gregory T. Rohde of The University of
Minnesota for X-ray crystallography.
REFERENCES
■
12: Rf = 0.21 (30% EtOAc in hexane); [α]23 +29.9 (c 1.05,
(1) For a key review on allenamide chemistry, see: Wei, L.-L.; Xiong,
H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773−782.
D
CH2Cl2); white solid; mp =176−177 °C; 1H NMR (400 MHz,
CDCl3) δ 1.66 (s, 3H), 2.01−2.14 (m, 2H), 2.29 (dt, 1H, J = 8.4, 12.0
Hz), 2.56 (ddd, 1H, J = 2.4, 8.8, 12.0 Hz), 2.79 (dd, 1H, J = 8.8, 11.6
Hz), 3.35 (s, 3H), 3.37 (d, 1H, J = 7.2 Hz), 4.35 (br, 1H), 4.39 (t, 1H,
J = 6.4 Hz), 4.84−4.89 (m, 2H); 4.95 (q, 1H, J = 7.2 Hz), 7.54 (d, 1H,
J = 1.4 Hz), 7.52 (d, 1H, J = 1.4 Hz), 7.35−7.41 (m, 3H), 7.31 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 26.8, 31.2, 33.7, 51.8, 52.3, 60.9, 63.7,
64.4, 72.0, 74.1, 82.2, 128.3, 129.1, 129.2, 131.7, 132.8, 135.2, 136.7,
159.3, 163.6, 169.8 (one carbon peak was missing due to overlapping);
IR (thin film) cm−1 2955 m, 1755s, 1579 m, 1373 m, 1265s, 1209 m,
1117 m, 734 m; mass spectrum (APCI) m/e (relative intensity) 574.0
(7) (M + 6 + H)+, 572.1 (33) (M + 4 + H)+, 569.2 (30) (M + 2)+,
568.1 (96) (M + H)+, 567.1 (90) (M)+, 419.4 (9), 344.2 (22), 329.0
(85), 328.1 (21), 327.0 (100); HRMS (MALDI-TOF) m/e calcd for
C26H24Cl3NO7Na+ (M + Na+) 590.0516, found 590.0511.
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Theoretical Calculations. Density functional theory calculations
were performed using Gaussian 09.10 Geometries were optimized in
the gas phase using the B3LYP11 functional, with a mixed basis set
consisting of LANL2DZ on Zn and 6-31G(d) on all other atoms. The
lowest-energy conformer of each species was identified through
conformational searching. The B3LYP vibrational frequencies were
used to characterize species as minima or transition states, and to
obtain scaled12 zero-point energies and thermal contributions to
enthalpy and entropy. Single-point energies were then computed at
the M06-2X/6-311+G(d,p) level13 and used in conjunction with the
B3LYP thermochemical corrections to obtain gas-phase activation
enthalpies and free energies. Free energies of activation in dichloro-
methane were calculated by incorporating CPCM14 solvation energies
computed at the M06-2X/6-31G(d)-LANL2DZ level (UAKS radii). A
standard state of 1 mol/L was used. Activation energies were also
computed from single-point energy calculations at the B3LYP-D315
level, with zero-damping. The activation energies predicted by B3LYP
and B3LYP-D3 for cycloadditions involving 3b are provided in the
Supporting Information, along with M06-2X activation energies for
cycloadditions of 3c with 4−7.
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ASSOCIATED CONTENT
* Supporting Information
■
(5) For our contributions to the field of (4 + 3) cycloadditions, see:
(a) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C. J. Am.
Chem. Soc. 2001, 123, 7174−7175. (b) Xiong, H.; Hsung, R. P.; Shen,
L.; Hahn, J. M. Tetrahedron Lett. 2002, 43, 4449−4453. (c) Ramesh-
kumar, C.; Xiong, H.; Tracey, M. R.; Berry, C. R.; Yao, L. J.; Hsung, R.
P. J. Org. Chem. 2002, 67, 1339−1345. (d) Xiong, H.; Huang, J.;
Ghosh, S. K.; Hsung, R. P. J. Am. Chem. Soc. 2003, 125, 12694−12695.
(e) Rameshkumar, C.; Hsung, R. P. Angew. Chem., Int. Ed. 2004, 43,
615−618. (f) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50−
51. (g) Antoline, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org.
Lett. 2007, 9, 1275−1278. (h) Antoline, J. E.; Hsung, R. P. Synlett
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S. K. J. Org. Chem. 2011, 76, 3246−3257.
S
NMR spectra and characterizations for all new compounds, X-
ray data (CIF) and thermal ellipsoid plots, optimized
geometries and energies, computed barriers at the B3LYP
and B3LYP-D3 levels for cycloadditions of 3b, and M06-2X
barriers for 3c. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ekrenske@unimelb.edu.au, houk@chem.ucla.edu,
rhsung@wisc.edu.
■
(6) (a) Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Antoline, J. E.;
Hsung, R. P. Chem. Sci. 2010, 1, 387−392. (b) Lohse, A. G.; Krenske,
E. H.; Antoline, J. E.; Houk, K. N.; Hsung, R. P. Org. Lett. 2010, 12,
5506−5509. (c) Antoline, J. E.; Krenske, E. H.; Lohse, A. G.; Houk, K.
N.; Hsung, R. P. J. Am. Chem. Soc. 2011, 133, 14443−14451.
(7) During the synthesis of ester 12 from cycloadduct 9, an acyl
transfer occurred during the esterification step.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NIH and Australian Research Council for
generous financial support (GM-36700 to K.N.H., GM-66055
■
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