Stereoselective synthesis of phthalans
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 9, September, 2016 2231
Scheme 3
Note. The scheme is given for one of the possible enantiomers, namely, SS.
amino alcohol methiodides, which furnished phthalan 9b
with (R)ꢀconfiguration of the chiral center.
Experimental
We have got more evidence for stereoselectivity of cyclꢀ
1
NMR Н spectra were recorded on a Varianꢀ400 instrument
with operating frequency 400 MHz, chemical shifts are reported
using δ values. Me Si was used as an internal standard for CDCl
ization of δꢀdiols in our study involving diol 8 with two
chiral centers. For starting material, we used pure racemic
diastereomer 8а, which was synthesized by the reaction of
orthoꢀlithiated racemic alcohol 6 with 2,4ꢀdimethylbenzoꢀ
phenone and isolated from the mixture of diastereomers
by crystallization; the identical configuration of chiral cenꢀ
4
3
solutions. Specific optical rotation values were measured using
a VNIEKIPPRODMASh EPOꢀ1A polarimeter in 0.1 and
.25 dm cuvettes.
Starting diols were prepared by lithiation of 1ꢀphenylethanol
followed by the reaction with corresponding benzophenones
using the known procedure.9
Cyclization of diols (general procedure). A solution of diol 7
or 8 (0.01 mol) in toluene (20 mL) was heated under reflux with
conc. H PO (1 mL) and P O (100 mg) for 24 h, and the reaction
0
9
ters (SS/RR) was determined using Xꢀray study. Unforꢀ
tunately, it was not possible to isolate the other racemic
diastereomer of diol 8 with different configuration of chiral
centers (SR/RS) as a pure substance and to study cyclizaꢀ
tion of this compound.
3
4
2
5
was monitored by chromatography. The organic layer was sepaꢀ
Cyclization of diol 8а furnished phthalan 10, whose
Н NMR spectrum contained two different sets of signals
from two diastereomers in 6 : 1 ratio. The ratio of diaꢀ
stereomers was assessed using the ratio of the intensities of
signals of protons at the chiral carbon of the starting alcoꢀ
rated, washed with water, satd. aq. Na CO (2×20 mL) and, finally,
2
3
1
with water. The solution was dried over MgSO . Toluene was reꢀ
4
moved, the residue was crystallized from the appropriate solvent.
3
ꢀMethylꢀ1,1ꢀdiphenylꢀ1,3ꢀdihydroisobenzofuran (9) was
prepared by cyclization of racemic diol 7 as yellow oil (yield
5%). An aliquot of the reaction mixture was subjected to chroꢀ
matography on silica gel (40ꢀ100 mesh) using petroleum ether
b.p. 40—70 °C) as an eluent to obtain pure phthalan, m. p. 93 °С.
9
hol (СН —СН). This result confirmed the correctness of
3
the proposed by us reaction mechanism involving two difꢀ
ferent paths (Scheme 3).
(
1
NMR H, δ: 1.66 (d, 3 H, CH —CH, J
= 6.8 Hz); 5.34 (q, 1 H,
3
H,H
The main path (А) leads to phthalan 10а with retained
configuration of chiral centers of the starting diol. The
path B proceeding nucleophilic attack of triaryl carbinol
hydroxyl group on the benzylic position and resulting in
the inversion of configuration of the chiral center of the
starting 1ꢀphenylethanol, delivered phthalan 10b. The posiꢀ
tion of the signal of the proton at С(3) also confirms the
described above relative configuration; for diastereomer
СН—СН , J
= 6.8 Hz); 7.10—7.40 (m, 14 Н, НAr).
H,H
3
(S)ꢀ3ꢀMethylꢀ1,1ꢀdiphenylꢀ1,3ꢀdihydroisobenzofuran ((S)ꢀ9)
was prepared by two methods. These are cyclization of diol (S)ꢀ7
(
(
method A) and cyclization of amino alcohol methiodide (R)ꢀ11
method B).
Method A. Yield 93%, m.p. 95 °С (from petroleum ether),
α]D20 –107.5° (с 1, ethanol), ee 81.7%. NMR Н, δ: 1.62 (d, 3 H,
1
[
CH —CH, J
= 6.8 Hz); 5.31 (q, 1 H, СН—СН , J
= 6.8 Hz);
3
H,H
3
H,H
7
.10—7.40 (m, 14 Н, Нarom).
Method B. [α]D –131° (с 1, ethanol).
1
0а, it is located in an upper field (δ 5.16), than for diasteꢀ
1
1
reomer 10b with different configurations (δ 5.51). Earlier,
we observed correlation of this type for two diastereomeric
phthalans12 bearing a methoxy substituent. The main diaꢀ
stereomer 10а with the same configuration of chiral cenꢀ
ters was isolated by crystallization from petroleum ether.
In conclusion, cyclization of δꢀdiols prepared from
enantiomerically pure 1ꢀphenylethanol, allows the synꢀ
thesis of 1,3ꢀdisubstituted phthalans with predetermined
configuration of chiral centers depending on the configuꢀ
ration of the starting alcohol.
Literature data for (R)ꢀ9: m.p. 92 °C. [α]D 131.5° (с 1,
ethanol).
1ꢀ(2,4ꢀDimethylphenyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1,3ꢀdihydroisoꢀ
benzofuran (10) was obtained from (SS/RR)ꢀ8а as a diastereoꢀ
mer mixture (6 : 1) in quantitative yield. NMR Н, δ: 1.47 and
1
1
2
.71 (both d, 3 H, CH —CH, J
.13, 2.32 (all s, 3 Н, оꢀ, pꢀСН ); 5.16 and 5.51 (both q, 1 H,
= 6.8 Hz); 2.06, 2.21 and
3
H,H
3
СН—СН , J
= 6.8 Hz); 6.8—7.4 (m, 12 Н, Нarom).
3
H,H
(1S, 3S)ꢀ1ꢀ(2,4ꢀDimethylphenyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1,3ꢀdiꢀ
hydroisobenzofuran (10а) was isolated from the reaction mixture
by crystallization from the petroleum ether, m.p. 73 °С. Literaꢀ