Angewandte
Chemie
Table 1: Two-stephydroxylation of isoxazoles 3b–e.[a]
Table 2: Angular hydroxylation of isoxazolium 7a (see Scheme 3).[a]
Entry
Solvent
pH value of NaOCl
Yield [%]
8a
9
1
2
3
4
5
6
MeCN
MeOH
Me2CO
Me2CO
MeCN/H2O (1:3)
MeCN/H2O (1:3)
ca. 12
ca. 12
ca. 12
8.6[c]
48
37
40
36
45
16
13
39
11[b]
41
Isoxazole
R1
R2
R3
t [h]
Yield [%]
(step1)
(step2)
ca. 12
64
71
8.7[c]
3b
3c
3d
3e
Ph
Ph
tBu
Ph
Me
CO2Et
H
Ph
18
18
97 (4b)
– (4c)
76 (4d)
95 (4e)
73 (5b)
Me
tBu
Ph
80 (5c)[b,c]
84 (5d)
[a] Aq NaOCl (ca. 8 equiv) in the indicated solvent (0.05m) at 08C for
10 min. Acidic workupwith 0.5 m HCl. [b] Acid 10 (see Scheme 3) was
obtained (ca. 10% yield). [c] The pH value of the NaOCl solution (ca. 12)
was adjusted with concentrated HCl (see the Supporting Information).
24
H
25[d]
84 (5e)[b,e]
[a] Step1: Meerwein reagent (1.05–1.1 equiv) in CH 2Cl2 (0.5m) at room
temperature. Step 2: Unless otherwise noted, aq NaOCl (ca. 4 equiv) in
MeCN (0.3m) at 08C for 10 min. [b] Acidic workupwith 0.5 m HCl.
[c] Overall yield after two steps. [d] At 0.25m in CH2Cl2. [e] In the
presence of pyridine (4.0 equiv).
with the Meerwein reagent led to a substantial decrease in the
enantiomeric purity (65% ee),[15] presumably due to acidic
impurities in the Meerwein reagent that caused the SN1
ionization of the ketol next to the isoxazole unit.[16] 4
Molecular sieves proved to be effective for suppressing this
racemization: Isoxazolium salt 7a, prepared by the N-
methylation of (R)-6 in the presence of 4 molecular
sieves, was treated with aqueous NaOCl, and acidic workup
gave diol 8a with full stereochemical integrity (98% ee;
Table 2, entry 1). Also, importantly, diol 8a had cis config-
uration (as determined by X-ray crystallography; see
Scheme 3), which could be related to the attack of the
oxidant from the convex face of the tetracyclic system in 7a,
as will be discussed below.
A remaining problem was the low yield of diol 8a, and
phthalimide 9 was identified as the major side product.[17]
After considerable experimentation, the issue was improved
by carefully choosing the solvent and pH value. The yield of
8a decreased slightly with methanol (Table 2, entry 2), and
substantially with acetone (Table 2, entry 3)as the solvent.
The latter case, however, gave an interesting hint, in the
formation of carboxylic acid 10 (ca. 10%; see Scheme 3),
which could be ascribed to the base-induced retro-Claisen
degradation of 8a (the pH value of commercial NaOCl is ca.
12).[18] This recognition prompted us to adjust the pH value of
the NaOCl solution.[19] Indeed, at pH 8–9, the yield of 8a was
even improved in acetone (Table 2, entry 4), although for-
mation of phthalimide 9 remained serious. However, this
issue was nicely solved by employing acetonitrile with an
increased water content (Table 2, entry 5), and the optimal
yield of 8a was achieved with the pH adjustment (to 8.7;
Table 2, entry 6).
diketoester 5c in 80% yield (over two steps from 3c). Less-
substituted isoxazolium salts 4d and 4e (where R2 = H)also
underwent smooth hydroxylation to give the secondary
alcohols 5d and 5e. However, the latter case required that
the reaction be performed in the presence of pyridine;
otherwise, the yield of 5e was substantially lower (ca. 42%)
due to further oxidation to 1,3-diphenylpropan-1,2,3-trione
(ca. 43%).[14]
After these promising results, the protocol was applied to
more elaborate substrates, with attention to the stereochem-
ical aspects. An enantiomerically enriched isoxazole (R)-6
(98% ee)was used for the model study (Scheme 3). Table 2
shows several notable points. Firstly, the N-methylation
should be carried out in the presence of an acid scavenger
in order to preserve the enantiomeric purity. A preliminary
attempt at the N-methylation by simple treatment of (R)-6
With regard to the mechanistic insight, the intermediacy
of epoxides was revealed by an interesting observation. Upon
careful basic workup (aqueous NaOH), an unexpected
product was obtained, which was proven by X-ray crystallog-
raphy to be epoxide 11 with an unusual iminoxy moiety
(Scheme 4).[20] Thus, the initial step is the epoxidation of 7a to
give epoxide B, which undergoes hydrolytic ring opening to
give amino ether C. N-Chlorination gives chloride D, which
undergoes elimination of HCl to afford epoxide 11. While
addition of aqueous NaOH facilitates this elimination, the
acidic workup of the synthetic protocol allows ready hydrol-
ysis of D and/or 11 en route to diol 8a.[21]
Scheme 3. Model system for the study of stereochemical aspects and
ORTEP diagram of 8a with the thermal ellipsoids at 50% probability.
Bn=benzyl, MS=molecular sieves.
Angew. Chem. Int. Ed. 2008, 47, 7446 –7449ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim