The Journal of Organic Chemistry
ARTICLE
passing through activated molecular sieves or alumina, tetrahydrofuran
was distilled over sodium and benzophenone, p-TsOH H2O was
3
azeotroped from xylenes, and ZnCl2 was fused under vacuum prior to
use. Other solvents and reagents were used as received from commer-
cially available sources. 1H NMR and 13C NMR spectra were taken in
CDCl3 and recorded at 300 or 500 MHz. 1H NMR chemical shifts were
measured at 300 MHz, referenced relative to trace amounts of chloro-
form (7.26 ppm) or CD3CN (1.96 ppm), and are reported in parts per
million. Coupling constants (J) are reported in Hertz (Hz), with
multiplicity following convention: s, singlet; d, doublet; t, triplet; q,
quartet; dd, doublet of doublets; ddd, doublet of doublet of doublets;
dddd, doublet of doublet of doublet of doublets; dt, doublet of triplets;
dq, doublet of quartets; m, multiplet; bs, broad singlet. 13C NMR spectra
were measured at 75 MHz and referenced relative to residual chloroform
(77.23 ppm) and are reported in parts per million (ppm). Flash column
chromatography was performed with 60 Å silica gel (230À400 mesh) as
a stationary phase using a gradient solvent system (EtOAc/hexanes as
eluant unless indicated otherwise). Thin layer chromatography (TLC)
was performed using glass-backed silica gel F254 (250 μm thickness).
Visualization of developed plates was performed by fluorescence
quenching or by staining with potassium permanganate (KMnO4) or
Hanessian’s (CAM) stain. Infrared spectra were obtained as thin film on
NaCl plates on a FTIR spectrometer.
Figure 7. 1H NMR monitoring of Brønsted acid mediated generation of
diacid 3 from tricyclic-β-lactone 1: (a) 1H NMR expansion (δ 2.5À4.5)
of Brønsted acid mediated conversion of lactone 1 to diacid 3 after 95
min, 12 h, and 120 h. Signal (H1) from dyotropic rearrangement product
2 at δ 2.9 appears after 95 min and 12 h and then is absent after 120 h,
replaced by H2 signal of diacid 3. (b) 1H NMR expansion (δ 2.4À4.5) of
authentic samples of diacid 3 and lactone 2 for comparison.
Representative Procedure for Dyotropic Rearrangement
of (()-14 to (()-16 as Described Using ZnCl2/CH2Cl2. To a
stirred suspension of ZnCl2 (23.0 mg, 0.17 mmol, 1.48 equiv) in CH2Cl2
(1.25 mL) at 0 °C under a N2 atmosphere was added a solution of
β-lactone (()-1425 (22.3 mg, 0.11 mmol, 1.0 equiv) in CH2Cl2 (1 mL)
dropwise by syringe. The heterogeneous reaction was stirred at 0 °C for
10 min then warmed to 23 °C and stirred for 24 h. The reaction mixture
was filtered through a short plug of Celite and SiO2 and eluted with
additional CH2Cl2 (∼1 mL). The combined filtrates were concentrated
under reduced pressure to provide 15.1 mg (68%) of (()-16 as a white
solid containing a trace amount of (()-17. (()-16: Rf = 0.41 (50%
EtOAc/hexanes); IR (thin film) 2956, 1782, 1730, 1516, 1457, 1258,
converted to diacid 3 with p-TsOH H2O in CH3CN, we were
3
interested in following the conversion of β-lactone 1 by 1H NMR
to determine whether dyotropic product 2 is an intermediate in
the conversion of 1to diacid 3(Scheme5, 20 f21 f2f26 f3).
NMR studies clearly show initial formation of dyotropic product
2 at multiple time points (Figure 7, t = 95 min and t = 12 h,
monitoring H1, H2, and H3) with slower conversion to the diacid
3 after several days (t = 120 h).
1
1239, 1144, 1027, and 909 cmÀ1; H NMR (300 MHz, CDCl3) δ
1.55À1.65 (m, 1H), 1.81À2.53 (m, 9H), 2.60 (d, J = 14.4 Hz, 1H),
2.82À2.95 (m, 1H), 3.18 (d, J = 14.4 Hz, 1H), 3.86 (s, 3H), 3.87 (s, 3H),
and 6.75À6.81 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 213.6, 176.1,
148.9, 148.4, 127.8, 122.4, 113.4, 111.2, 94.7, 64.9, 56.18, 56.10, 52.0,
40.1, 36.4, 31.2, 28.4, 21.0, and 19.1; HRMS (ESI+) calcd for C19H23O5
[M + H]+ 331.1545, found 331.1560.
Conversion of (()-14 to (()-16 and (()-17 Using ZnCl2/
CH3CN. Compounds (()-16 and (()-17 were generated following the
representative procedure described above from (()-14 (10 mg, 0.030
mmol, 1.0 equiv) using ZnCl2 (15.5 mg, 0.114 mmol, 3.8 equiv) and
anhydrous CH3CN (1.4 mL). The homogeneous reaction was stirred
for 20 h at 23 °C and then filtered over Celite/SiO2 as described above.
Crude 1H NMR (CDCl3, 300 MHz) showed a 1:3 ratio of 16 to 17. The
mixture was submitted to flash column chromatography (40% EtOAc/
hexanes) yielding 1.8 mg (18%) of (()-16 as a white solid and 5.3 mg
(62%) of (()-17 as a clear oil. (()-17: Rf = 0.59 (40% EtOAc/hexanes);
IR (thin film) 2935, 2850, 1709, 1522, 1456, 1263, 1238, 1142, and
Taken together, our calculations and experiments using Zn-
(II) Lewis acids, a silyl triflate, and Brønsted acids to promote
dyotropic rearrangements of tricyclic-β-lactone 1 indicate that
the rearrangement mechanism depends on the nature of the
activating agent. When Zn(II) Lewis acids are used, a two-step
pathway is predicted, perhaps because interactions with both
oxygens of the carboxylate group and these Lewis acids can occur,
providing some stabilization to the zwitterionic intermediate.
This intermediate is very short-lived, however, and is not easily
trapped, but it can be deprotonated. A TMS group, however,
does not participate in such bridging interactions, and a con-
certed rearrangement is predicted. Brønsted acids also lead to a
facile dyotropic rearrangement that is essentially barrierless and
that occurs on a flat potential energy surface, but which may
continue further to hydration and a Grob-type fragmentation to
provide a diacid. The results described herein provide further
information on the mechanistic features of dyotropic rearrange-
ments, which have been a fascinating subject for theoretical
studies for many years, and which provide useful synthetic routes
to complex polycycles.2,11,25
1028 cmÀ1
;
1H NMR (300 MHz, CDCl3) δ 1.52À1.68 (m, 2H)
1.86À1.92 (m, 2H), 2.04À2.13 (m, 1H), 2.16À2.26 (m, 1H),
2.39À2.61 (m, 3H), 2.63À2.74 (m, 1H), 2.80 (d, J = 13.5 Hz, 1H),
2.92 (d, J = 13.5 Hz, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 5.37À5.39 (m, 1H),
and 6.63À6.76 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 213.9, 148.4,
148.0, 144.7, 129.7, 125.9, 122.3, 113.5, 111.0, 66.6, 56.0 (2); 41.9, 39.3,
29.8, 29.2, 26.1, and 25.9; HRMS (ESI+) calcd for C18H23O3 [M + H]+
287.1647, found 287.1660.
’ EXPERIMENTAL SECTION
Conversion of (()-14 to (()-16 and (()-17 Using ZnCl2/
THF. Compounds (()-16 and (()-17 were generated following the
representative procedure described above from (()-14 (10 mg,
All reactions were performed under a nitrogen atmosphere in oven-
dried glassware. Dichloromethane and acetonitrile were purified by
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dx.doi.org/10.1021/jo2012175 |J. Org. Chem. 2011, 76, 7167–7174