Ring transformation of glycidic amides with ortho-metalated phenols to enantiopure 3-hydroxychromanones

Article abstract of DOI:10.1021/jo982242b

A novel access to hitherto unknown enantiopure 2-alkylchroman-4-ones 10 was found by a reaction of ortho-metalated O-MOM-protected phenols with Weinreb amides 8 of enantiopure cis- or trans-glycidic acids. Upon acidic hydrolysis, the resulting o-MOMO-benz

Full text of DOI:10.1021/jo982242b

J . Org. Chem. 1999, 64, 3489-3491
3489
Rin g Tr a n sfor m a tion of Glycid ic Am id es w ith Or th o-Meta la ted
P h en ols to En a n tiop u r e 3-Hyd r oxych r om a n on es
Karsten Woydowski, Burkhard Ziemer, and J u¨rgen Liebscher*
Institut fu¨r Chemie, Humboldt-Universita¨t Berlin, Hessische Strasse 1-2, D-10115 Berlin, Germany
Received November 10, 1998
A novel access to hitherto unknown enantiopure 2-alkylchroman-4-ones 10 was found by a reaction
of ortho-metalated O-MOM-protected phenols with Weinreb amides 8 of enantiopure cis- or trans-
glycidic acids. Upon acidic hydrolysis, the resulting o-MOMO-benzoyloxiranes 9 undergo ring
transformation to 2-alkylchroman-4-ones 10. 2-Alkylidenecoumaran-3-ones 11 were formed as
alternative products, depending on the configuration of the starting oxirane ring and on the type
of phenol used as starting material.
Sch em e 1
In tr od u ction
3-Hydroxyflavanones (trans-2,3-dihydro-2-aryl-3-hy-
droxy-4H-benzopyran-4-ones) and other 3-substituted
chromanones are widely found in plants.1,2 They are
biologically important as intermediates in the biogenesis
of naturally occurring flavanoid-type products. There are
also pharmaceutically and other biologically active com-
pounds found in this series.3,4 Different routes have been
developed to this class of products5,6 such as stereoselec-
tive oxidation of flavanone derivatives by dimethyldiox-
irane, cyclization of 2′-hydroxychalcone dibromides or
bromohydrins in the presence of a base, and oxidative
ring closure of 2′-hydroxychalcones with alkaline hydro-
gen peroxide. In the last three cases, 2′-hydroxychalcone
epoxides 2 have been postulated as intermediates that
are ring-transformed by intramolecular nucleophilic at-
tack of the phenolic OH-group at the â-position of the
chalcone epoxide.5 Such epoxides 2 can also be prepared
by epoxidation of protected or unprotected 2′-hydroxy-
chalcones 1 and transformed to 3-hydroxyflavones 3 in
a separate step (Scheme 1).5,6 As a side reaction, forma-
tion of 2-(R-hydroxybenzyl)-3-coumaranones 45,8 by al-
ternative attack of the phenolic OH-group at the R-po-
sition of the chalcone epoxide 2 and eventually their
dehydration to products 58 was observed.
of chroman-4-ones,7 respectively. 2-Alkyl-3-hydroxychro-
man-4-ones are scarce and not reported in optically active
form. We report here a new access to 3-hydroxychroman-
4-ones enabling the synthesis of enantiopure cis- or trans-
products substituted by alkyl groups at position 2. This
route is based on our general strategy to synthesize het-
erocycles by ring transformation of glycidic acid deriva-
tives with binucleophiles that react at the carbonyl group
and at one of the oxirane carbon atoms.9 To achieve 3-hy-
droxychroman-4-ones we applied phenols 6 as binucleo-
philes and enantiopure Weinreb amides 8 of glycidic
acids.
Recently, optically active compounds were synthesized
in the 3-hydroxychroman-4-one series with either 2-aryl
substituents or 3-alkyl groups starting from optically ac-
tive chalcone epoxides6 or by asymmetric hydroxylation
* Corresponding author. Fax: +49 (0)30 20938907, e-mail: liebscher@
chemie.hu-berlin.de.
(1) B. A. Bohm, The Flavonoids-Advances in Research since 1986;
Harborne, J . B., Ed.; Champan & Hall, London, 1994; p 419.
(2) Geissman, T. A. The Chemistry of Flavonoid Compounds; Per-
gamon: Oxford, 1962.
(3) Bohm, B. A. The Flavonoids; Harborne, J . B., Mabry T. J ., Mabry,
H., Eds.; Champan & Hall: London, 1975; p 560.
(4) Bo¨hm, K. Die Flavonoide: Eine U¨ bersicht u¨ber ihre Physiologie,
Pharmakodynamik und therapeutische Anwendung; Cantor: Aulen-
dorf, 1967.
(5) (a) Patonay, T.; Le´vai, A.; Nemes, C.; Timar, T.; To´th, G.; Adam,
W. J . Org. Chem. 1996, 61, 5375 and references therein. (b) Patonay,
T.; To´th, G.; Adam, W. Tetrahedron Lett. 1993, 34, 5055.
(6) (a) van Rensburg, H.; van Heerden, Pieter S.; Bezuidenhout, B.
C. B.; Ferreira, D. Tetrahedron 1997, 53, 14141. (b) van Rensburg, H.;
van Heerden, Pieter S.; Bezuidenhout, B. C. B.; Ferreira, D. J . Chem
Soc., Chem. Commun. 1996, 2747.
Resu lts a n d Discu ssion
Although phenols 6 themselves are known as O-C-C
binucleophilic building blocks, in our study both protec-
tion and activation were necessary. This could be con-
veniently attained by introducing a MOM-group to the
oxygen atom. The O-MOM-moiety as an efficient ortho-
(7) Davis, F. A.; Weismiller, M. C. J . Org. Chem. 1990, 55, 3715.
(8) (a) Adams, J . C.; Main, L. Tetrahedron 1992, 48, 9929. (b) Adams,
J . C.; Main, L. Tetrahedron 1991, 47, 4979.
(9) (a) Woydowski, K.; Ziemer, B.; Liebscher, J . Tetrahedron Asym-
metry 1998, 9, 1231. (b) Woydowski, K.; Liebscher, J . Synthesis 1998,
1110.
10.1021/jo982242b CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/24/1999

3490 J . Org. Chem., Vol. 64, No. 10, 1999
Woydowski and Ziemer
Sch em e 2
satisfactory yields in the trans as well as in the cis series
depending on the configuration (trans or cis, respectively)
of the starting glycidic amide 8. Remarkably, the first
members of cis-3-hydroxy-chroman-4-ones could just re-
cently be synthesized but with 2-aryl substituents, i.e.,
of flavones.6 As byproducts of 10, 2-alkylidenecoumarones
11 (aurone analogues) were observed in some cases ob-
viously formed from 9 by R-attack of the appearing phe-
nolic OH group at the oxirane and subsequent dehydra-
tion. In a comparable ring transformation of a racemic
2-hydroxybenzoyloxirane reported in the literature5 using
HCl/water/EtOH at room temperature, R-attack predomi-
nated, too, leading to 2-(R-hydroxyalkyl)coumaranone 4.
The extent of R-attack at the benzoyloxiranes 9 (forma-
tion of 11) seems to depend on the type of phenol 6 and
on the configuration of 9 (see Table 1). Thus cases of ex-
clusive formation of hydroxychromanones 10 were ob-
served in the trans series (see Table 1, entries 1-3), while
mixtures of 10 and 2-alkylidenecoumaranones 11 were
formed in most cases of the cis series (see entries 5-7).
It could be seen from a molecular model that the attack
of the phenolic OH-group at the â-position by formation
of 10 is somewhat sterically hindered in the cis series as
compared with the trans series. 1-Naphthol derivatives
9d and 9h gave exclusive R-attack regardless of the rela-
tive configuration at the oxirane ring (entries 4 and 8).
Since the OH-group of 1-naphthol is shielded by the peri
H-atom, the cyclization obviously occurred at the steri-
cally less hindered R-position of the oxirane ring affording
11.12
Structure elucidation of products 10 and 11 was based
on X-ray crystal analysis of the chromanone 10i13 and of
benzofuranones 1114 and 11h 15 and spectroscopic data
3
(see Experimental Section). The J (2-H, 3-H) coupling
Ta ble 1. Syn th esis of Ben zoyloxir a n es 9,
3-Hyd r oxych r om a n -4-on es 10, a n d
2-Alk ylid en ecou m a r a n on es 11
constants of 10 are in accordance with the relative
configuration (∼6 Hz for cis and ∼12 Hz for trans, see
Experimental Section) revealing bisaxial conformation of
the protons at position 2 and 3 of the trans chromanones
10a -c. No diastereomers of 8-10 could be observed in
the crude products. Thus epimerization did not occur, and
diastereomerically pure products 10 were formed. 3-Pro-
pyl-1-hydroxymethyloxirane16 and methyl 3-methylox-
irane-2-carboxylate17 were used as starting materials for
Weinreb amides 8 with ee ) 94% and ee > 98%,
respectively (check by chiral HPLC). Since racemization,
i.e., inversion of configuration at both chiral ring atoms
of the oxirane ring of 8, was not possible in the reactions
performed, products 8-10 have the same ee like the
starting materials, i.e., 94 or 98%, respectively. The
yield (%)
entry
R1
R2
R3
R4
R5
9
10 11
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
n-Pr
n-Pr
n-Pr
n-Pr
H
H
H
H
H
H
H
H
H
H
H
H
95 89
61 76
68 74
Me
OMe
H
CHdCHCHdCH 73
60
Me
Me Me
Me OMe
H
H
H
H
H
H
H
83 62 13
63 64 10
66 55
H
H
9
93
H
H
Me
H
CHdCHCHdCH 67
47 44
Me CHdCHCHdCH
H
directing group10 allowed ortho-metalation with t-BuLi
(formation of 7) (Scheme 2). Subsequent reaction with
enantiopure N-methoxy-N-methyloxirane carboxamides
8 formed the corresponding epoxides 9 in satisfactory to
high yields (see Table 1). From several procedures re-
ported for the ring transformation of o-hydroxybenzoyl-
oxiranes to benzochromanones, acidic conditions5,6 seemed
advantageous over basic.5,8 In our study, diluted HCl in
water/EtOH5 was not successful since either the MOM
group survived or the oxirane moiety was cleaved to a
corresponding chlorohydrin.11 Refluxing of 9 in HClO4/
EtOH/water was appropriate, while TFA/EtOH/water
gave lower yields. The trans-epoxides 9 required some-
what harsher reaction conditions (longer reaction times
and higher concentration of acid), i.e., the tendency to
the anticipated ring transformation turned out to be
higher for the cis-epoxides 9. In most cases the envisaged
2-alkyl-3-hydroxychroman-4-ones 10 were obtained in
(10) Sniekus, V. Chem. Rev. 1990, 90, 879.
(11) For an analogous side reaction in the hydroflavanone-series,
see Takahashi, H.; Kubota, Y.; Fang, L.; Li, S.; Onda, M. Chem. Pharm.
Bull. 1986, 34, 4597.
(12) Petit, Y.; Bendrider, M.; Blain, M.; Leclercq, J .-M THEOCHEM
1998, 428, 27.
(13) Full details have been deposited at the Fachinformationzentrum
Karlsruhe, 76344 Eggenstein-Leopoldshaven, Germany; this material
can be obtained on quoting a full literature citation and the deposition
number CSD-410343.
(14) Full details have been deposited at the Fachinformationzentrum
Karlsruhe, 76344 Eggenstein-Leopoldshaven, Germany; this material
can be obtained on quoting a full literature citation and the deposition
number CSD-410341.
(15) Full details have been deposited at the Fachinformationzentrum
Karlsruhe, 76344 Eggenstein-Leopoldshaven, Germany; this material
can be obtained on quoting a full literature citation and the deposition
number CSD-410342.
(16) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 6,3936.
(17) Petit, Y.; Sanner, C.; Larcheveque, M. Synthesis 1988, 538.

Ring Transformation of Glycidic Amides
J . Org. Chem., Vol. 64, No. 10, 1999 3491
9e: 1H NMR δ 1.34 (d, J ) 5.4, 3 H), 3.53 (m, 1 H), 3.56 (s,
3 H), 4.34 (d, J ) 4.9, 1 H), 5.35 (dd, J ) 7.8, 10.6, 2H), 7.12-
7.86 (m, 4 H); 13C NMR δ 13.5 (CH3), 56.9 (CH3), 55.4 (CH),
61.2 (CH), 94.9 (CH2), 115.0 (CH), 122.4 (CH), 130.9 (CH),
135.0 (CH), 127.4 (C), 157.2 (C), 195.9 (C).
2-alkylidenecoumaranones 11 were found to be Z14,15
regardless if they are derived from cis or trans oxiranes
9. Thus their formation can be interpreted by an E1-like
â-elimination of water from intermediate 2-(R-hydroxy-
alkyl)coumaranone 12 affording the thermodynamically
more stable (Z)-products.
In summary, a new route to 3-hydroxychroman-4-ones
was developed, allowing the synthesis of enantiopure
compounds in the cis or in the trans series with alkyl
substituents in 2-position. Since all these compounds are
new, an important gap in the flavanoid chemistry could
be filled.
9h : 1H NMR δ 1.30 (d, J ) 5.3, 3 H), 3.45 (m, 1 H), 3.48 (s,
3 H), 4.42 (d, J ) 4.7, 1 H), 5.12 (dd, J ) 5.8, 8.6, 2 H), 7.19-
8.22 (m, 6 H); 13C NMR δ 13.1 (CH3), 58.7 (CH3), 56.0 (CH),
59.9 (CH), 102.4 (CH2), 124.0 (CH), 125.1 (CH), 125.3 (CH),
127.4 (CH), 128.5 (CH), 129.1 (CH), 128.0 (C), 128.6 (C), 137.4
(C), 154.9 (C), 196.9 (C).
9i: 1H NMR δ 1.26 (d, J ) 5.4, 3 H), 3.43 (m, 1 H), 3.47 (s,
3 H), 4.27 (d, J ) 4.9, 1 H), 5.30 (dd, J ) 7.8, 8.0, 2 H), 7.29-
8.19 (m, 6 H); 13C NMR δ 13.5 (CH3), 56.9 (CH3), 55.6 (CH),
61.0 (CH), 95.2 (CH), 110.3 (CH), 125.5 (CH), 128.9 (CH), 129.7
(CH), 130.5 (CH), 132.4 (CH), 127.4 (C), 129.2 (C), 136.9 (C),
153.3 (C), 196.4 (C).
Exp er im en ta l Section
Gen er a l. Melting points were determined with a hot-stage
apparatus and are uncorrected. 1H NMR and 13C NMR spectra
were recorded in CDCl3 at 300 and 75.5 MHz, respectively,
with TMS as internal standard. 13C signal assignment is based
on DEPT experiments, Optical rotation was determined with
c ) 1 in CHCl3. Silica gel (0.04-0.063 mm, Merck) was used
for preparative column chromatography. If not otherwise
mentioned, chemicals were purchased from Merck. Starting
materials 8 were prepared from known glycidic acids16,17and
the resulting oxiranecarboxylic acids were reacted to the
Weinreb amides 8.18
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Hyd r oxy-
ch r om a n -4-on es 10 a n d 2-Alk ylid en ecou m a r a n on es 11.
Aqueous HClO4 (70%, 0.3 mmol for cis-epoxides, 0.4 mmol for
trans-epoxides) was added to a solution of the benzoyloxirane
9 (1 mmol) in water/EtOH (2:3, 3 mL). The mixture was re-
fluxed for 1 h (cis-epoxides 9) or 1.5 h (trans-epoxides 9) and
was diluted with water (7 mL) after being cooled to room tem-
perature. The mixture was extracted with CH2Cl2 (2 × 7 mL),
and the combined organic phases were dried, evaporated, and
purified by column chromatography with pentane/ether (1:1).
10a : colorless crystals, mp ) 42-44 °C (after chromatog-
Wein r eb Am id es 8. DCC (8.22 g, 40 mmol) was added to
a solution of the oxirane carboxylic acid (R1 ) n-Pr, R2 ) H;
40 mmol) and Et3N (5.53 mL, 40 mmol) or to a suspension of
the K-salt (R1 ) H, R2 ) Me, 40 mmol) without Et3N in 50 mL
of dry THF (8b) or CH2Cl2 (8a ) at 0 °C under argon atmo-
sphere. N,O-Dimethylhydroxylamine hydrochloride (3.90 g, 40
mmol) was added, and the mixture was stirred at rt for 20 h.
After filtration, the solution was evaporated and purified by
column chromatography with CH2Cl2/acetone (95:5) to yield
8a (R1 ) n-Pr, R2 ) H) in 82% or 8b (R1 ) H, R2 ) Me) in 57%
raphy), Rf ) 0.64, [R]20 ) +79.4°; 1H NMR δ 0.94 (t, J ) 7.4,
D
3 H), 1.43-1.97 (m, 4 H), 3.65 (s, 1 H), 4.07 (m, 1 H), 4.20 (d,
J ) 12.4, 1 H), 6.89-7.79 (m, 4 H); 13C NMR δ 14.3 (CH3),
18.2 (CH2), 34.14 (CH2), 73.2 (CH), 82.1 (CH), 118.2 (CH), 121.0
(CH), 127.6 (CH), 137.0 (CH), 118.9 (C), 162.3 (C), 195.3 (C).
Anal. Calcd for C12H14O3 (206.26): C, 69.87; H, 6.86. Found:
C, 69.77; H, 6.91.
10e: colorless crystals, mp ) 98 °C (hexane), Rf ) 0.44, [R]20
D
1
) -158.5°; H NMR δ 1.21 (d, J ) 6.7, 3 H), 3.63 (d, J ) 2.2,
1 H), 4.69 (dd, J ) 1.7, 6.1, 1 H), 4.84 (m, 1 H), 6.86-7.77 (m,
4 H); 13C NMR δ 12.1 (CH3), 72.7 (CH), 77.0 (CH), 118.9 (CH),
121.7 (CH), 127.0 (CH), 137.3 (CH), 119.2 (C), 180.0 (C), 194.3
(C). Anal. Calcd for C10H10O3 (178.20): C, 67.40; H, 5.67.
Found: C, 67.10; H, 5.68.
as a colorless oil.
1
8a : [R]20 ) +2.1°; H NMR δ 0.92 (t, J ) 7.2, 3 H), 1.43-
D
1.59 (m, 4 H), 3.08 (m, 1 H), 3.17 (s, 3 H), 3.59 (d, J ) 1.8, 1
H), 3.71 (s, 3 H); 13C NMR δ 15.0 (CH3), 20.6 (CH2), 34.8 (CH2),
33.7 (CH3), 53.5 (CH3), 59.2 (CH), 63.1 (CH), 169.8 (C). Anal.
Calcd for C8H15NO3 (173.24): C 55.46, H 8.75, N 8.09. Found:
10i: light yellow crystals, mp ) 153-155 °C (hexane), Rf )
0.49, [R]20 ) -2.3°; 1H NMR δ 1.23 (d, J ) 6.6, 3 H), 3.65 (d,
D
C 55.73, H 8.73, N 8.01.
1
8b: [R]20 ) +82.5°; H NMR δ 1.24 (d, J ) 5.4, 3 H), 3.14
J ) 2.5, 1 H), 4.82 (dd, J ) 2.4, 6.0, 1 H), 4.88 (m, 1 H), 7.25
(s, 1 H), 7.27-7.82 (m, 4 H), 8.38 (s, 1 H); 13C NMR δ 12.3
(CH), 73.3 (CH), 76.5 (CH), 113.4 (CH), 124.9 (CH), 126.7 (CH),
128.8 (CH), 129.5 (CH), 129.7 (CH), 119.9 (C), 128.2 (C), 138.4
(C), 154.4 (C), 194.8 (C). Anal. Calcd for C14H12O3 (228.26):
C, 73.66; H, 5.31. Found: C, 73.35; H, 5.35.
D
(s, 3 H), 3.24 (m, 1 H), 3.64 (s, 3 C), 3.78 (d, J ) 4.7, 1 H); 13
C
NMR δ 13.6 (CH3), 32.9 (CH3), 53.8 (CH3), 53.5 (CH), 62.1 (CH),
168.5 (C); HR-MS calcd: 145.0739, found: 145.0693.
Gen er a l P r oced u r e for th e P r ep a r a tion of (2-MOMO-
ben zoyl)oxir a n es 9. O-MOM-derivatives of phenols 6 were
prepared in 70-90% yield, adopting a known procedure for
MOM-protection of thiophenols.19
t-BuLi (0.99 mL, 1.58 mmol, 1.6 M in pentane) was added
to a solution of the corresponding O-MOM-phenol (1.5 mmol)
at 0 °C under argon atmosphere. The mixture was stirred at
room temperature for 3 h. After being cooled to 0 °C, the
Weinreb amide 8 (1.5 mmol) dissolved in dry diethyl ether (1
mL) was added, and the mixture was stirred at room temper-
ature for 2 h. The mixture was quenched with diluted NH4-
Cl-solution (7 mL) and extracted with diethyl ether (2 × 7 mL).
The combined organic phases were dried, evaporated, and
purified by column chromatography with pentane/ether (1:1).
The resulting colorless oils 9 were characterized just by 1H
and 13C NMR spectra and were further converted to 10
and 11.
1
11e: light yellow oil, Rf ) 0.69, H NMR δ 1.94 (d, J ) 7.5,
3 H), 6.13 (q, J ) 7.5, 1 H), 7.05-7.68 (m, 4 H); 13C NMR δ
11.6 (CH3), 112.7 (CH), 113.2 (CH), 123.3 (CH), 125.0 (CH),
137.3 (CH), 122.1 (C), 150.3 (C), 166.5 (C), 184.0 (C); MS m/z
(%): 160 (M+, 6), 121 (28), 92 (100), 65 (10).
11h : light yellow crystals, mp ) 150-152 °C (hexane), Rf
) 0.79; 1H NMR δ 2.05 (d, J ) 7.5, 3 H), 6.24 (q, J ) 7.5, 1 H),
7.18-8.21 (m, 6 H); 13C NMR δ 11.8 (CH3), 113.4 (CH), 119.5
(CH), 122.3 (CH), 123.6 (CH), 127.3 (CH), 129.0 (CH), 130.7
(CH), 117.8 (C), 121.3 (C), 138.6 (C), 151.0 (C), 166.4 (C), 183.4
(C); MS m/z (%): 210 (M+, 100), 170 (31), 114 (38), 126 (16) IR
(KBr): 808 (C)C-H), 1629 (CdC), 1707 (CdO) Anal. Calcd
for C14H10O2 (210.24): C, 79.98; 4.80. Found: C, 80.05; H, 4.83.
Ack n ow led gm en t. The financial support of Deut-
sche Forschungsgemeinschaft and Fonds der Chemis-
chen Industrie is gratefully acknowledged.
9a : 1H NMR δ 1.08 (t, J ) 7.7, 3 H), 1.63-1.95 (m, 4 H),
3.22 (m, 1 H), 3.58 (s, 3 H), 4.15 (d, J ) 2.0, 1 H), 5.37 (s, 2 H),
7.14-7.81 (m, 4 H); 13C NMR δ 14.3 (CH3), 19.6 (CH2), 34.5
(CH2), 56.9 (CH3), 60.3 (CH), 60.8 (CH), 95.1 (CH2), 115.1 (CH),
122.5 (CH), 130.8 (CH), 134.7 (CH), 127.5 (C), 157.2 (C), 197.4
(C).
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal analy-
ses of compounds 10i, 11d , and 11h ; 1H and 13C NMR spectra,
mp, Rf, optical rotation, and elemental analyses of compounds
9b, 9c, 9d , 9f, 9g, 10b, 10c, 10f, 10g, 11d , 11f, and 11g. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Nahm, S.; Weinreb, S. M. Tetrahedron Lett., 1981, 22, 3815.
(19) Fukuyama, M.; Nakatsuka, M.; Kishi, Y. Tetrahedron Lett.,
1976, 17, 3393.
J O982242B