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A. A. Birkbeck et al. / Tetrahedron Letters 45 (2004) 6147–6150
MeO
MeO
OEt
O
OEt
O
(i)
5
+
RO
O
HO
OH
5
R = Ti (OiPr)3
9
10
6
7
8
R = H
(ii)
R = Ac
R = MgBr
MeO
MeO
O
O
O
ref. 8
(v)
O
2
4
5
RO
RO
OH
O
OH
O
11 R = H
12 R = Ac
13 R = Ts
14 R = Ts
15 R = H
16
(iii)
(iv)
(vi)
Scheme 2. Reagents and conditions: (i) 6, toluene, Ti(OiPr)4, rt, 30 min;added to 9, 0 °C, 20 min;ultrasound, 20–40 °C, 5 h;satd aq NaF, 5 h;(ii)
CH3CH(OEt)2, CSA, rt, 30 min;(iii) Ac 2O, py, 18 h, 15% overall, (52%*);(iv) KOH, MeOH, rt, 3 h; p-TsCl, K2CO3, acetone, rt, 7 h, 85%;(v) TiCl 4,
CH2Cl2, )78 °C, 2 h, 44% (95%*);(vi) KOH, H 2O, MeOH, 70 °C, 4 h, 81% (*yields based on consumed starting material).
We have previously shown6;7 that 2,5-dimethyl-4-phen-
yldioxolanes are isomerized in high yield to the corre-
sponding 2-benzopyrans using titanium(IV) chloride,
except where an electron releasing methoxy oxygen
atom on the aromatic ring ortho to the dioxolanyl group
led to an alternative unwanted reaction.7 As anticipated
the ortho-acetoxy group led to decomposition of 12
when treated with the titanium reagent. However, con-
version of the acetate 12 into the enantiopure tosylate
135 (in an overall yield for the two steps of 85%) pro-
vided more stable protection for, and reduced electron
availability from, the ortho-tosyloxy oxygen atom,
which effectively prevented the subsequent unwanted
dioxolane ring-opening. Treatment of tosylate 13 with
titanium(IV) chloride led to its clean conversion into the
enantiopure 2-benzopyran 145 as the sole product, al-
though starting dioxolane 13 was recovered together
with the corresponding erythro-diol, which was readily
reconverted into the dioxolane 13 through acetalation
with 1,1-dimethoxyethane and camphorsulfonic acid.
The product 14 was obtained in a yield of 44%, or 95%
based on the recovery of starting material 13 and diol.
Hydrolysis of the tosylate 14 afforded the known8
enantiopure 2-benzopyran-4,5-diol 15 in 81% yield and
this has previously been converted through oxidative
dealkylation with silver(II) oxide into the enantiopure
2-benzopyran-5,8-quinone 16 in a yield of 91%.8 The
diol 15 and the quinone 16 derived by this method
were identical to those obtained previously.8
the previous adduct 10 and considerable quantities of
starting material 6. Adduct 17 was converted, without
purification as above, into the C-2 epimeric mixture of
acetoxyphenyldioxolanes 19 via the phenols 18. Careful
chromatographic separation of the mixture of enantio-
pure dioxolanes 19 from the acetate 7 and the small
quantities of the minor diastereoisomeric dioxolane 12
gave 195 in an overall yield of 36% for the three steps, or
70% based on consumed phenol 5. This represented an
average yield per step of about 89%. Conversion of the
C-2 epimeric mixture of acetoxydioxolanes 19 into the
corresponding mixture of C-2 epimeric tosyloxydioxo-
lanes 20,5 through hydrolysis and reprotection, was
achieved in an overall yield of 84% for the two steps.
Treatment of the C-2-epimeric dioxolanes 20 with tita-
nium(IV) chloride led to their clean conversion into the
mixture of C-1 epimeric 2-benzopyrans 215 and 235 al-
though, once again, starting dioxolanes 20 and threo-
diol were also recovered. The threo-diol was recycled to
the mixture of dioxolanes 20. Chromatographic sepa-
ration readily afforded the individual 2-benzopyrans 21
and 23 in yields of 44% and 14%, respectively, or 66%
and 21%, respectively, based on consumed dioxolanes
20. Hydrolysis of each of these gave the corresponding
4,5-diols 22 and 24, each in a yield of 84%. The diol 22
was subjected to oxidative dealkylation with silver(II)
oxide to yield the enantiopure quinone 25 and similarly
the diol 24 gave the enantiopure quinone 26 in unop-
timized yields of 72% and 67%, respectively.
The alternative ultrasound-promoted reaction3 of the
bromomagnesium phenolate 8 with the same lactalde-
hyde 9 afforded the benzyl-epimeric adduct 17 (Scheme
3) in a diastereoisomeric ratio of 93:7 accompanied by
In conclusion, a concise, convergent synthesis of the
enantiopure 2-benzopyranquinones 16, 25 and 26 is
achieved from the inexpensive, commercially available