Highly enantioselective synthesis of natural phyllodulcin

Article abstract of DOI:10.1021/jo9603385

(S)-[4-Methoxy-3-[(triisopropylsilyl)oxy]phenyl)oxirane (prepared from isovanillin by consecutive silylation, olefination, Sharpless asymmetric cis-dihydroxylation, and dehydration) reacted with [3-(methoxymethoxy)phenyl]lithium (prepared from 3-bromophenol by consecutive methoxymethylation and bromine-lithium exchange) to yield (R)-1-[4-methoxy-3-[(triisopropylsilyl)oxy]phenyl)2-[3-(methoxymethoxy )phenyl]ethanol. The last compound underwent selective hydrogen-metal exchange with excess of butyllithium affording (after carbonation, lactonization, and deprotection of phenolic groups) the title compound [(R)-3,4-dihydro-8-hydroxy-3-(4-methoxy-3-hydroxyphenyl)isocoumarin].

Full text of DOI:10.1021/jo9603385

J . Org. Chem. 1996, 61, 5371-5374
5371
High ly En a n tioselective Syn th esis of Na tu r a l P h yllod u lcin †
Alessio Ramacciotti,‡ Rita Fiaschi,‡ and Elio Napolitano*,‡,§
Universita` di Pisa, Dipartimento di Chimica Bioorganica, Via Bonanno 33, 56126 Pisa, Italy, and
Scuola Normale Superiore, Piazza dei Cavalieri, 56127 Pisa, Italy
Received February 20, 1996X
(S)-[4-Methoxy-3-[(triisopropylsilyl)oxy]phenyl)oxirane (prepared from isovanillin by consecutive
silylation, olefination, Sharpless asymmetric cis-dihydroxylation, and dehydration) reacted with
[3-(methoxymethoxy)phenyl]lithium (prepared from 3-bromophenol by consecutive methoxymethy-
lation and bromine-lithium exchange) to yield (R)-1-[4-methoxy-3-[(triisopropylsilyl)oxy]phenyl)-
2-[3-(methoxymethoxy)phenyl]ethanol. The last compound underwent selective hydrogen-metal
exchange with excess of butyllithium affording (after carbonation, lactonization, and deprotection
of phenolic groups) the title compound [(R)-3,4-dihydro-8-hydroxy-3-(4-methoxy-3-hydroxyphenyl)-
isocoumarin].
In tr od u ction
hydroxy group at C-8);3e however, in spite of the relatively
simple stereochemical problems involved (only one asym-
metric carbon present) no chemical synthesis of natural
3-aryl-3,4-dihydroisocoumarins, featuring an effective
control of the absolute configuration, has been published.
To the best of our knowledge, only one study has dealt
with the asymmetric synthesis of 1, but with only partial
success, owing to the ease of racemization of the benzylic
chiral center; the latter, although introduced in the
appropriate chirality and with high enantioselectivity,
proved to be configurationally unstable under the hydro-
genolytic or strongly acidic conditions required for the
completion of the synthesis.3 On the other hand, the
possibility of obtaining substances related to 1 in optically
pure form might lead to a better understanding of the
relationship between structure and taste of 1 and, more
generally, to the structure-activity relationships of
3-aryl-3,4-dihydroisocoumarins.
In previous publications we have outlined a possibly
wide scope approach to chiral 3-alkyl-3,4-dihydroisocou-
marins, which is shown retrosynthetically in Scheme 1
(structures 2a -5a ).4 According to this approach: (a) the
ortho-metalation promoted by a â-functionalized alkyl
group followed by carbonation was adopted for the
regioselective introduction of C(1) of the targets; (b) the
enantioselective construction of the intermediate 2-phen-
ylethyl alcohol 3a was accomplished by addition of an
organometallic reagent prepared from 4 to the appropri-
ate enantiopure terminal epoxide 5a ; (c) the introduction
of the desired chirality at C(3) of the targets was
ultimately based on the very efficient methods for olefin
oxidation developed by Sharpless. We report here the
extension of the above approach to the first successful
enantioselective synthesis of 1, as the representative of
natural 3-aryl-3,4-dihydroisocoumarins.
Natural 3-aryl-3,4-dihydroisocoumarins constitute a
small class of secondary metabolites particularly abun-
dant in the Hydrangea genus (Saxifragacee).1 Members
of the class differ from each other by the number and
type of oxysubstituents on the aromatic rings; the pres-
ence of an 8-hydroxy group is very frequent. Phyllodulcin
(1) is probably the most interesting representative among
3-aryl-3,4-dihydroisocoumarins. It has long been known
as the sweet component of the plant named amacha in
J apan (Hydrangea macrophylla Seringe var. thumbergii),
whose leaves, fermented and dried, are infused to make
a traditional beverage. Because of its refreshing taste
and strong sweetening power (almost a thousand times
that of sucrose), phyllodulcin (1) has become the lead
compound in studies of structure-activity relationship
aimed at the development of a new class of low-calories
sweeteners, designated as isovanillins because of the
presence of a 3-hydroxy-4-methoxyphenyl group as a
common feature.2 Furthermore, phyllodulcin (1) exhibits
antimicrobial activity, a property shared with other
congeners.1
A number of different methods are available for build-
ing the carbon framework of natural 3-aryl-3,4-dihy-
droisocoumarins and to place regioselectively the oxy
functions on the two aromatic rings (particularly the
For such an extension, at least two specific problems
were foreseen, which were not encountered in our previ-
† Dedicated to Professor A. Marsili on the occasion of his 65th
birthday.
‡ Universita` di Pisa.
(3) (a) Takeuchi, N.; Nakano, T., Goto, K., Tobinaga, S. Heterocycles
1993, 35, 289. (b) Mali, R. S, Shelke, D. W. Indian J . Chem. 1993,
32B, 822. (c) Kessar, S. V.; Gupta, Y. P.; Singh, S. Indian J . Chem.
1993, 32B, 668. (d) Kessar, S. V., Singh, P.; Vohra, R.; Kaur, N. P.;
Venugopal, D. J . Org. Chem. 1992, 57, 6716. (e) Arnoldi. A.; Bossoli,
A.; Merlini, L., Ragg, E. Gazz. Chim. Ital. 1992, 122, 403. (f) Napoli-
tano, E.; Ramacciotti, A.; Fiaschi, R. Gazz. Chim. Ital. 1988, 118, 101.
(g) Watanabe, M.; Sahara, M.; Kubo, M.; Furukawa, S.; Billedeau, R.
J .; Snieckus, V. J . Org. Chem. 1984, 49, 742. See also ref 1a for earlier
synthetic work.
§ Scuola Normale Superiore.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) (a) For the literature prior to 1985, see: Hill, R. A. Progr. Chem.
Nat. Compd., 1986, 49, 1. For recent isolation of 1 from natural sources,
see: (b) Hashimito, T.; Tori, M.; Asakawa, Y. Phytochemistry 1987,
12, 3323. (c) Yoshikawa, M.; Uchida, E.; Chatani, N.; Murukami, N.;
Yamahara, J . Chem. Pharm. Bull. 1992, 40, 3121. (d) Yoshikawa, M.;
Uchida, E.; Chatani, N.; Kobayashi, H.; Naitoh, Y.; Okuno, Y.;
Matsuda, H.; Yamahara, J .; Murakami, N. Chem. Pharm. Bull. 1992,
40, 3352.
(4) (a) Synthesis of (-)-mellein: Napolitano, E. Gazz. Chim. Ital.
1991, 121, 455. (b) Synthesis of isocoumarin portion of AI77-B: Bertelli,
L.; Fiaschi, R.; Napolitano, E. Gazz. Chim. Ital. 1993, 123, 669.
(2) Arnoldi, A.; Bassoli, A.; Merlini, L.; Ragg, E. J . Chem. Soc.,
Perkin Trans. 1 1993, 1359 and references cited therein.
S0022-3263(96)00338-6 CCC: $12.00 © 1996 American Chemical Society

5372 J . Org. Chem., Vol. 61, No. 16, 1996
Ramacciotti et al.
Sch em e 1. Retr osyn th esis of
3,4-Dih yd r oisocou m a r in s Ba sed on th e Lith ia tion
of Ar om a tic Rin gs P r om oted by â-F u n ction a lized
Alk yl Gr ou p s
Sch em e 2. En a n tioselective Syn th esis of
P h yllod u lcin a
ous enantioselective syntheses of isocoumarins, where the
C(3) substituent of the target was an alkyl (such as in
2a ) rather than aryl group such as in 2b. First, whereas
alkyloxiranes 5a are generally and quite selectively
attacked by carbon nucleophiles at the less substituted
carbon atom, with aryloxiranes such as 5b, the attack of
nucleophiles at the benzylic position as well as the
rearrangement of the epoxide to an arylacetaldehyde
prior to the formation of the new carbon-carbon bond
can be serious side reactions, which obviously lead to
unwanted products.5 Secondly, on the basis of our
pervious work with ketalized deoxybenzoins,6 a competi-
tion between positions 2 and 2′ could be expected in the
reaction of 3b with the lithiating agent, which would lead
to a benzyl phthalide rather than to the desired dihy-
droisocoumarin 2b.
We hoped to solve the first problem by an appropriate
choice metal atom to couple 4 and 5b. As to the second
problem, we decided to rely on the use of a hindered silyl
group for the protection of the phenolic OH of the aryl
fragment providing the C(3)-aryl substituent in the final
compound: the use of such a group was expected to
disfavor lithiation at C(2) of 3b;7 furthermore, such a silyl
group, besides offering a good protection of the phenol
throughout the synthesis, was expected to be cleaved
under mild conditions, hopefully avoiding racemization.
a
i
Conditions: (a) Pr3SiCl, imidazole, DMF. (b) Ph3MeP+Br-,
BuLi, THF. (c) AD-mix-R, H2O, tBuOH. (d) p-MeC6H4SO2Cl,
pyridine. (e) NaOH, Bu4N+HSO4-, CH2Cl2/H2O. (f) 4, BuLi, THF.
(g) BuLi, cyclohexane, 16 h, rt; then D2O. (h) PCC, CH2Cl2. (i) BuLi,
cyclohexane, 16 h, rt; then CO2. (j) Ac2O, and then HCl (6 M)/
Et2O. (k) Bu4N+F-, THF.
into its monotosylate 10 (96% yield, 94.8% ee) and finally
into the epoxide11 (100% yield, enantiomeric excess could
not be determined). The reaction of the epoxide 11 with
the lithiated derivative obtained by halogen-metal ex-
change between the protected bromophenol 4 and butyl-
lithium gave the desired alcohol 12 (65% yield, 94% ee),
with no evidence of alternative addition products.5 There
are precedents for such a result of the reaction between
aryllithium reagents and aryloxiranes,9 although its
scope seems to have been overlooked. Also, it is interest-
ing to note that the protected bromophenol 4 underwent
clean halogen-metal exchange, although it could be
considered as a good candidate for hydrogen-metal
exchange, owing to the presence of a hydrogen ortho to a
methoxymethoxy group and to a bromine atom.10 In
agreement with our expectations, the alcohol 12, when
exposed to a 3-fold excess of butyllithium in cyclohexane
Resu lts a n d Discu ssion
Isovanillin (6) was almost quantitatively converted into
the styrene derivative 8 by condensation with triisopro-
pylsilyl chloride followed by Wittig olefination of the
intermediate silylated aldehyde 7 with triphenylmeth-
ylenephosphorane. Asymmetric dihydroxylation accord-
ing to the Sharpless procedure (AD-mix-R)8 converted 8
into the diol 9 (97% yield) with an enantiomeric excess
of 95.1%, as determined by chromatography of its diac-
etate using a chiral stationary phase (see Experimental
Section). Diol 9 (first chiral intermediate) was converted
(5) Gorzinski Smith J . Synthesis 1984, 629.
(6) (a) Napolitano, E.; Ramacciotti, A.; Morsani, M.; Fiaschi, R. Gazz.
Chim. Ital. 1991, 121, 257. (b) Napolitano, E.; Giannone, E., Fiaschi,
R., Marsili, A. J . Org. Chem. 1983, 48, 3653.
(7) For a precedent of such a use of a hindered silyloxy group, see:
Wang, W.; Snieckus, V. J . Org. Chem. 1992, 57, 424.
(8) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(9) Cristol, S. J .; Douglass, J . R.; Meek, J . S. J . Am. Chem. Soc. 1951,
73, 816. For a recent application to the synthesis of the natural
diarylethanol derivative named combretastatin, see: Ramacciotti, A.;
Fiaschi, R.; Napolitano, E. Tetrahedron: Asymmetry 1996, 4, 1101.

Synthesis of Natural Phyllodulcin
J . Org. Chem., Vol. 61, No. 16, 1996 5373
column (0.46 cm i.d., 25 cm) and with a UV detector operating
at 250 nm was used; mixtures of hexane (H) and 2-propanol
(P) were used for the elution. For chromatographies, the flash
technique was applied;11 unless otherwise stated, the eluant
was a mixture of hexane (H) and ethyl acetate (EA). Dry
solvents were obtained by distillation from sodium powder
(Aldrich) under nitrogen. For the thin-layer chromatographies
(TLC), silica gel on aluminum foils was used; for the visualiza-
tion of the spots, the plates were dipped into an ethanolic
solution, containing phosphomolybdic acid (5%) and sulfuric
acid (5%), and heated by means of an heat gun. MgSO4 was
used as the drying agent, unless otherwise stated.
4-Meth oxy-3-[(tr iisop r op ylsilyl)oxy]ben za ld eh yd e (7).
A solution of isovanillin (6) (2.00 g, 13.2 mmol), imidazole (3.20
g, 46 mmol), and triisopropylsilyl chloride (3.2 g, 16.5 mmol)
in DMF (10 mL) was allowed to react at room temperature
for 16 h. The reaction mixture was partitioned between
hexane and water; the organic phase was washed with water,
dried, and evaporated to yield pure 7 (4.1 g, 98% yield) as an
oil. The analytical sample was purified by distillation: bp
180-5 °C/ 0.1 mmHg; 1H NMR δ 1.06-1.32 (m, 21H), 3.86 (s,
3H), 6.94 (d, J ) 8 Hz 1H), 7.35 (d, J ) 2.0 Hz, 1H), 7.44 (dd,
J ) 8 and 2 Hz, 1H), 9.81 (s, 1H); 13C NMR δ 13.47, 18.50,
56.14, 111.71, 119.92, 126.77, 130.74, 146.66, 157.18, 191.55.
Anal. Calcd for C17H28O3Si: C, 72.8; H, 10.1. Found: C, 72.4;
H, 9.9.
4-Meth oxy-3-[(tr iisop r op ylsilyl)oxy]styr en e (8). To a
stirred suspension of methyltriphenylphosphonium bromide
(4,64 g, 13 mmol) in THF (40 mL) was added dropwise
butyllithium (13 mmol, 8.1 mL of a 1.6 M hexane solution)
followed, after 15 min, by the protected isovanillin 6 (3.90 g,
12.6 mmol). The progress of the reaction was monitored by
TLC (H/EA 9:1); after 1 h of stirring at room temperature the
reaction was complete. The reaction mixture was partitioned
between ether and water; the upper organic phase was washed
with brine, dried, and evaporated to afford a residue from
which 8 (3.88 g, 100%yield) was obtained by chromatography
(H/EA 9:1) as an oil: 1H NMR δ 1.08-1.31 (m, 21H), 3.8 (s,
3H), 5.1 (dd, J ) 0.7 and 11.0 Hz, 1H), 5.55 (dd, J ) 0.7 and
17.5 Hz , 1H), 6.60 (dd, J ) 11.0 and 17.5 Hz, 1H), 6.78 (d, J
) 8.2 Hz, 1H), 6.93 (dd, J ) 2.1 and 8.2 Hz, 1H), 6.97 (d, J )
2.1 Hz, 1H); 13C NMR δ 13.56, 18.59, 56.15, 112.10, 112.46,
118.45, 120.52, 131.32, 137.10, 146.13, 151.52. Anal. Calcd
for C18H30O2Si: C, 70.5; H, 9.9. Found: C, 70.6; H, 9.6.
(S)-1-[4-Met h oxy-3-[(t r iisop r op ylsilyl)oxy]p h en yl]-1,
2-eth a n ed iol (9). A mixture containing AD-mix-R8 (Aldrich,
14.0 g) and the styrene 8 (3.00 g, 9.7 mmol) in a 1:1 tert-butyl
alcohol/water (100 mL) was stirred in an ice-water bath for
18 h. Solid sodium sulfite (15 g) was then added and the
mixture, after 30 min of stirring at the room temperature, was
partitioned between ether and brine; the organic phase was
dried and evaporated to leave a residue from which pure 9
(3.22 g, 97%) was obtained by chromatography (H/EA 3:2) as
an oil which solidified on standing: mp 45-46.5 °C; 1H NMR
δ 1.06-1.28 (m, 21H), 3.57-3.63 (m, 2H), 3.78 (s, 3H), 4.67
(dd, J ) 3.9 and 7.9 Hz, 1H), 6.77-6.88 (m, 3H); 13C NMR δ
13.53, 18.54, 56.12, 68.61, 74.78, 112.58, 119.00, 119.56,
133.65, 146.11, 151.20; [R]D +19.75 (c ) 10.37, methanol). Anal.
Calcd for C18H32O4Si: C, 63.5 H, 9.5. Found: C, 63.2; H, 9.8.
For the determination of the enantiomeric eccess, diol 9 (100
mg, 0.29 mmol) was allowed to react for 2 h at room temper-
ature with acetic anhydride (1 mL) in pyridine (2 mL) to yield
quantitatively a diacetate: oil; 1H NMR δ 1.09 (d, J ) 6.2 Hz,
18H), 1.16-1.38 (m, 3H), 2.05 (s, 3H), 2.09 (s, 3H), 3.79 (s,
3H), 4.18-4.32 (m, 2H), 5.91 (dd, J ) 4.5 and 7.5 Hz, 1H),
6.80 (d, J ) 8.9 Hz, 1H), 6.87-6.92 (m, 2H); 13C NMR δ 13.53,
18.53, 21.40, 21.73, 30.34, 56.07, 66.75, 73.52, 112.50, 119.56,
120.54, 129.50, 146.17, 151.73, 170.63, 171.26; ee 95.1%
(eluant: 99:1 H/P).
for 18 h at room temperature, was cleanly metalated at
C(2′), as demostrated by the almost quantitative deute-
rium incorporation upon quenching with deuterium
oxide; the site and the extent of deuterium incorporation
was determined unambiguously by conversion of the
deuterated alcohol 12 to the corresponding ketone 13; in
this compound the aromatic protons give well-separated
1
signals in the H-NMR spectrum. The use of the triiso-
propylsilyl group was essential in order to get a clean
metalation and to minimize the formation of secondary
products, probably arising from desilylation; poorer
results were obtained with the dimethyl tert-butylsilyl
group, whereas the trimethylsilyl group was totally
unsatisfactory. Treatment of metalated 12 with carbon
dioxide led to the intermediate lithium carboxylate 14
which was not characterized but used as a crude product
in the subsequent step. Reaction of 14 in a two-phase
system (ether and aqueous hydrochloric acid) led to the
cyclized and partially deprotected isocoumarin 15; how-
ever, extensive racemization occurred under these condi-
tions, the enantiomeric excess of 15 ranging from 60 to
40%, depending on the pH of the water phase. We
noticed however that the cyclized product itself was
configurationally quite stable to the above conditions,
suggesting that racemization had probably occurred at
the level of an open-chain precursor of 15 and that
cyclization called for milder reaction conditions. Treat-
ment of 14 with acetic anhydride prior to hydrolysis in
the two-phase system described above proved to be
suitable to induce the lactonization and partial depro-
tection of 14; silylated phyllodulcin 15 was in fact
obtained by this sequence in reasonable overall yield from
12 and with 93.5% ee. The final removal of the silyl
group from 14 using tetrabutylammonium fluoride af-
forded the target compound 1 in quantitative yield and
with an optical purity of 94%, which rose to 98% after
one recrystallization, as determined by comparison with
the reported optical rotation of phyllodulcin1b (HPLC
determination of the ee was unsatisfactory with the
column employed.)
In conclusion, the first enantioselective synthesis of the
problematic natural isocoumarin phyllodulcin (1) has
been accomplished by using the Sharpless asymmetric
dihydroxylation for the introduction of the chirality and
the lithiation of an aromatic ring promoted by a â-func-
tionalized alkyl group as a key step, for the regioselective
introduction of the 8-hydroxy group. The approach
should in principle be applicable to the synthesis of other
chiral 8-hydroxy-3,4-dihydroisocoumarins.
Exp er im en ta l Section
1H-NMR (200 MHz) and 13C-NMR (50 MHz) specta were
obtained a samples dissolved in CDCl3 unless otherwise stated;
chemical shifts are in ppm downfield from tetramethylsilane
as internal standard; IR spectra were taken with a FTIR
spectrophotometer (film of pure substance for liquids or Nujol
mulls for solids on KBr disks), and the most intense or
representative bands are reported (in cm-1). Melting points
were obtained with a Kofler hot stage apparatus and are
uncorrected. Boiling points refer to the oven temperature and
were obtained with a bulb-to-bulb distillation apparatus. For
the evaluation of the enantiomeric excess, a Chiracel OD-H
(S)-1-[4-Met h oxy-3-[(t r iisop r op ylsilyl)oxy]p h en yl]-2-
[(p-tolu en esu lfon yl)oxy]eth a n ol (10). p-Toluenesulfonyl
chloride (2.1 g, 11 mmol) was added to an ice-cold solution of
the diol 9 (3 g, 8.8 mol) in pyridine (3 mL). After 2 h, a few
(10) For a case of preference for hydrogen rather than bromine
exchange in a related compound, see: Kles, A.; Kadirof, R.; Bo¨rner,
A.; Holz, J .; Kagan, A. B. Tetrahedron Lett. 1995, 36, 4601. For a recent
study of hydrogen-metal exchange in bromobenzene derivatives, see:
Coe, P. L.; Waring, A. J .; Yarwood, T. D. J . Chem. Soc., Perkin Trans.
1 1995, 2729.
(11) Still, W. C.; Kahn, M.; Mitra, A. P. J . Org. Chem. 1978, 43.
2923.

5374 J . Org. Chem., Vol. 61, No. 16, 1996
Ramacciotti et al.
drops of water were added to dissolve the precipitate, and after
15 min the mixture was partitioned between ether and ice-
water containing 3 mL of concentrated hydrochloric acid. The
organic phase was washed with water and then with brine,
dried, and evaporated to afford a residue from which pure 10
(4.2 g, 96.2%) was obtained by chromatography (H/EA 2:1) as
an oil, which solidified on standing: mp 57-60 °C; 1H NMR δ
1.06 (d, J ) 6.3 Hz, 18H), 1.16-1.19 (m, 3H), 2.44 (s, 3H),
3.77 (s, 3H), 3.97-4.10 (m, 2H), 4.84 (dd, J ) 8.2 and 3.6 Hz,
1H), 6.79-6.86 (m, 3H), 7.33 (d, J ) 8.2 Hz, 2H), 7.77 (d, J )
8.2 Hz, 2H); 13C NMR δ 13.55, 18.56, 22.34, 56.10, 72.07, 75.07,
112.56, 119.05, 119.77, 128.63, 130.57, 131.43, 133.80, 145.90,
146.26, 151.90; [R]D +14.69 (c ) 10.32, methanol); ee 94.8%
(eluant: 9:1 H/P). Anal. Calcd for C25H38O6SSi: C, 60.7; H,
7.7. Found: C, 60.6; H, 7.3.
(S)-[4-Met h oxy-3-[(t r iisop r op ylsilyl)oxy]p h en yl]oxi-
r a n e (11). A solution of the monotosylate 10 (4.00 g, 8 mmol)
in methylene chloride (40 mL) was stirred for 2h with water
(5 mL) containing sodium hydroxide (1.28 g, 32 mmol) and
tetrabutylammonium hydrogen sulfate (100 mg). The mixture
was diluted with ether, and the organic layer was washed with
brine, dried, and evaporated to afford a residue from which
pure 11 (2.58 g, 99.5% yield) was obtained by chromatography
(H/EA 9:1) as an oil; 1H NMR δ 1.052-1.59 (m, 21H), 2.75
(dd, J ) 2.60 and 5.39 Hz, 1H), 3.09 (dd, J ) 4.0 and 5.4 Hz,
1H), 3.79 (s, 3H), 3.75 (dd, J ) 2.6 and 4.0 Hz), 6.75-6.87 (m,
3H); 13C NMR δ 13.57, 18.58, 51.71, 52.87, 56.18, 112.63,
118.10, 119.43, 130.54, 146.39, 151.66; [R]D -3.27 (c ) 10.41,
methanol). Anal. Calcd for C18H30O3Si: C, 67.0; H, 9.4.
Found: C, 67.9; H, 9.7.
(R)-2-[3-(Meth oxym eth oxy)ph en yl]-1-[4-m eth oxy-3-[(tr i-
isop r op ylsily)oxy]p h en yl]et h a n ol (12). To a solution of
3-(methoxymethoxy)bromobenzene (2.20 g, 10.1 mmol) in
tetrahydrofuran (30 mL) stirred under nitrogen at -78 °C was
added butyllithium (10.1 mmol, 5.05 mL of a 2 M hexane
solution). After 1 h epoxide 11 (2.27g, 7 mmol) was added,
and the solution was allowed to warm up to room temperature
over 3 h. After 12 h, the reaction mixture was partitioned
between ether and water; the organic phase was washed with
brine, dried, and evaporated to afford a residue from which
12 (2.25 g, 70% yield) was obtained after chromatography (H/
EA 4:1) as an oil: 1H NMR δ 1.08-1.32 (m, 21H), 2.96 (d, J )
6.7 Hz, 2H), 3.47 (s, 3H), 3.80 (s, 3H), 4.79 (t, J ) 6.7 Hz, 1H),
5.15 (s, 2H), 6.77-6.92 (m, 6H), 7.19 (t, J ) 7.7 Hz, 1H); 13C
NMR δ 13.53, 18.59, 46.54, 56.15, 56.63, 75.50, 95.03, 112.46,
114.86, 117.99, 118.91, 119.41, 123.72, 130.03, 137.04, 140.47,
146.02, 150.97, 157.95; [R]D +42.49 (c ) 6.63, methanol); ee
94% (eluant: 97:3 H/P). Anal. Calcd for C26H40O5Si: C, 67.8;
H, 8.8. Found: C, 67.9; H, 8.7.
2′-Deu ter io-4-m eth oxy-3′-(m eth oxym eth oxy)-3-[(tr iiso-
p r op ylsilyl)oxy]d eoxyben zoin (13). Butyllithium (1 mmol,
0.5 mL of a 2.0 M cyclohexane solution) was added dropwise
to a solution of alcohol 12 (200 mg, 0.43 mmol) in cyclohexane,
and the mixture was allowed to react for 16 h. The reaction
flask was cooled to -78 °C, deuterium oxide (1 mL) was added,
and the mixture was allowed to equilibrate with the room
temperature and then partitioned between ether and water.
The organic phase was dried and evaporated to afford a residue
(deuteriated 12) which was taken up in methylene chloride
(2.5 mL); to the solution was added, pyridinium chlorochro-
mate (215 mg, 1 mmol) and after 3 h of stirring the mixture
was diluted with ether, filtered through a short pad of Florisil,
and evaporated to afford a residue from which 13 (195 mg,
0.42 mmol) was obtained by chromatography (H/EA 4:1) as
an oil: 1H NMR δ 0.96-1.31 (m, 21H), 3.46 (s, 3H), 3.86 (s,
3H), 4.17 (s, 2H), 5.14 (s, 2H), 6.80-6.92 (m, 4H), 7.22 (dd, J )
7.0 and 8.6 Hz, 1H), 7.51 (d, J ) 2.1 Hz, 1H), 7.64 (dd, J ) 2.1
and 8.4 Hz, 1H); 13C-NMR δ 13.44, 18.52, 45.93, 56.16, 56.69,
95.09, 111.49, 115.09, 118.04, 121.02, 123.62, 124.08, 130.25,
137.27, 145.95, 156.04, 158.12, 191.65, 196.73. Anal. Calcd
for C26H38O5Si: C, 68.1; H, 8.4. Found: C, 67.9; H, 8.6.
(R)-3, 4-Dih yd r o-8-h yd r oxy-3-[4-m eth oxy-3-[(tr iisop r o-
p ylsilyl)oxy]p h en yl]isocou m a r in (15). To a solution of
diarylethanol 12 (2.00 g, 4.4 mmol) in cyclohexane (25 mL)
was added butyllithium (10 mmol, 5 mL of a 2 M cyclohexane
solution). After 18 h of stirring at room temperature, the
mixture was poured into ether (100 mL) saturated with dry
ice, and the mixture was allowed to warm up to room
temperature under stirring. The solvent was evaporated, and
the was residue suspended in acetic anhydride (20 mL). After
3 h of stirring, the mixture was partitioned between 6 M
aqueous hydrochloric acid and ether, and the two phases were
further stirred for additional 30 min. The organic phase was
washed with water, with 10% sodium hydrogen carbonate, and
with brine; finally, it was dried and evaporated to afford a
residue from which pure 14 (1.06 g, 53% yield) was obtained
by chromatography (H/EA 7:3) as a solid (needles): mp 168-
172 °C; IR νCO 1680 cm-1; 1H NMR δ 1.05-1.32 (m, 21H), 3.09
(dd, J ) 16.6 and 3.7 Hz, 1H), 3.29 (dd, J ) 11.2 and 16.6 Hz,
1H), 3.81(s, 3H), 5.49 (dd, J ) 3.7 and 11.2 Hz, 1H), 6.71-
7.01 (m, 5H), 7.39 (dd, J ) 8.3 and 7.6 Hz, 1H), 11.00 (s, 1H);
13C NMR δ 13.54, 18.55, 35.53, 56.10, 81.31, 112.50, 116.98,
118.62, 119.19, 120.24, 130.91, 136.93, 140.02, 146.23, 152.01,
162.89, 170.56, 201.21; [R]D +31.98 (c ) 3.83, methanol); ee
93.5% (eluant: 93:7 H/P). Anal. Calcd for C25H33O5Si: C, 68.0;
H, 7.5. Found: C, 68.0; H, 7.5.
(R)-3,4-Dih yd r o-8-h yd r oxy-3-(4-m et h oxy-3-h yd r oxy-
p h en yl)isocou m a r in (1, p h yllod u lcin ). To a solution of the
isocoumarin 14 (0.50 g, 1.08 mmol) in tetrahydrofuran (20 mL)
was added tetrabutylammonium fluoride (1.5 mmol, 1.5 mL
of a 1 M tetrahydrofuran solution). After 1 h the solution was
partitioned between ether and dilute hydrochloric acid; the
organic phase was washed with brine, dried, and evaporated
to afford a residue from which pure 1 (0.3 g, 95% yield) was
obtained by recrystallization from ether/hexane as a white
1
solid: mp 117.5-120 °C (lit.1b 118-120 °C); H NMR δ 3.08
(dd, J ) 3.4 and 16.5 Hz, 1H), 3.31 (dd, J ) 11.9 and 16.5 Hz,
1H), 3.91 (s, 3H), 5.50 (dd, J ) 3.4 and 11.9 Hz, 1H), 5.69 (s,
1H), 6.73 (d, J ) 7.4 Hz), 6.85-7.03 (m, 4H), 7.44 (dd, 7.5 and
8.2 Hz), 11.01 (s, 1H); 13C NMR δ 0.70, 35.71, 56.71, 81.36,
109.14, 111.26, 113.29, 117.08, 118.65, 118.92, 131.76, 137.01,
140.05, 146.51, 147.67, 162.95, 170.51; [R]D +74.4 (c ) 1.16,
methanol); [R]D +67.4 (c ) 1.30, acetone); (lit.1b [R]D +71 (c )
1.31, acetone).
Ack n ow led gm en t. The research was supported by
Ministero della Ricerca Scientifica
(MURST, Roma).
e Tecnologica
J O9603385