Modified coumarins. 16. Cyclohexane-annelated analogs of pyranocoumarins

Article abstract of DOI:10.1007/s10600-005-0159-y

Modified derivatives of angular and linear pyranocoumarins containing a condensed cyclohexane moiety were prepared by fusing a 2,2- dimethyltetrahydropyran ring to the coumarin system and annelating a pyrone ring to derivatives of 2,2-dimethylchromane. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-005-0159-y

Chemistry of Natural Compounds, Vol. 41, No. 4, 2005
MODIFIED COUMARINS. 16. CYCLOHEXANE-ANNELATED
ANALOGS OF PYRANOCOUMARINS
Ya. L. Garazd,1 M. M. Garazd,2 and V. P. Khilya1
UDC 547.814.5
Modified derivatives of angular and linear pyranocoumarins containing a condensed cyclohexane moiety
were prepared by fusing a 2,2-dimethyltetrahydropyran ring to the coumarin system and annelating a pyrone
ring to derivatives of 2,2-dimethylchromane.
Key words: coumarins, pyranocoumarins, furocoumarins, chromanones, glycosides, glycosylation, 7,8,9,10-
tetrahydrobenzo[ ]chromen-6-one.
c
Pyranocoumarins are a widely distributed group of coumarins that contain a 2,2-dimethylpyran ring annelated to a
benzopyran-2-one system [1]. Most natural pyranocoumarins are deivatives of the linear pyran xanthyletin (1) or its angular
isomer seselin (2).
Me
Me
Me
Me
O
O
O
O
O
O
1
2
Our goal was to synthesize modified analogs of pyranocoumarins that contain an annelated cyclohexane ring.
Pyranocoumarins were synthesized by two methods: 1) fusing a 2,2-dimethylpyran ring to the coumarin system and
2) annelating a pyrone ring to a 2,2-dimethylchromane core.
3-Hydroxy-4-methyl-(3), 1-hydroxy-3-methyl-(5),and3,4-dihydroxy-7,8,9,10-tetrahydrobenzo[ ]chromen-6-one(10)
c
that were necessary for further transformations were prepared by Pechmann condensation of 2-carbethoxycyclohexanone with
2-methylresorcinol, orcinol, and pyrogallol, respectively, in the presence of conc. H SO at 0°C [2]. 3-Hydroxy-4-
2
4
methylbenzo[ ]chromen-6-one (4) was synthesized by the Hartley method by condensation of 2-bromobenzoic acid and
c
2-methylresorcinol in NaOH solution using copper sulfate solution (10%) as a catalyst [3].
Hydroxycoumarins 3, 4, and 5 were condensed with 3,3-dimethylallylbromide in the presence of -toluenesulfonic acid
p
[4] to give the linear dihydropuranocoumarins 7,9,9-trimethyl-1,2,3,4,10,11-hexahydrobenzo[ ]pyrano[3,2- ]chromen-5-one
c
g
(6), 7,9,9-trimethyl-10,11-dihydrobenzo[ ]pyrano[3,2- ]chromen-5-one (7), and 2,2,5-trimethyl-3,4,9,11,12-
c
g
hexahydrobenzo[ ]pyrano[2,3- ]chromen-8-one (9).
c
f
The results were the same if the alkylating agent 3-methyl-2-buten-1-ol was used instead of 3,3-dimethylallylbromide.
The PMR spectra of 6, 7, and 9 exhibit a broadened splitting pattern for the aromatic protons compared with the starting
coumarins because of decoupling of H-6 of the benzopyran ring. Furthermore, PMR spectra of the resulting compounds have
signals characteristic of the 2,2-dimethyltetrahydropyran ring [5].
1)TarasShevchenkoKievNational University, 01033, Ukraine, Kiev, ul. Vladimirskaya, 64; 2) InstituteofBioorganic
and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Ukraine, Kiev, ul. Murmanskaya, 1, e-mail:
gmm@i.com.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 313-318, July-August, 2005. Original article
submitted February 15, 2005.
0009-3130/05/4104-0388 ©2005 Springer Science+Business Media, Inc.
388

Me
Me
Me
O
O
O
Me
Me
3DDQ
Br
HO
O
O
Me
Me
O
O
O
8
p-TSA
DDQ
Me
3
2DDQ
6
Me
Br
Me
Me
O
O
O
HO
O
O
p-TSA
4
7
Me
O
O
Br
Me
O
O
p-TSA
OH
O
Me
5
Me
9
Treatment of 6 with two equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane causes
dehydrogenation primarily of the cyclohexane ring annelated to the coumarin system to give 7. Reaction of 6 with three
equivalents of DDQ in toluene leads to complete aromatization of the system to form 7,9,9-trimethylbenzo[ ]pyrano[3,2-
c
]chromen-5-one (8). The PMR spectrum of 8 has two doublets at 5.71 and 6.43 ppm with SSCC J = 9.6 Hz that are typical
g
of an annelated pyran ring [5]. It should be noted that 8 is also formed by aromatization of 7 using DDQ in toluene.
Condensation of 10 and 3,3-dimethylallylbromide in the presence of -toluenesulfonic acid formed the linear
p
dihydropyranocoumarin 7-hydroxy-9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[ ]pyrano[3,2- ]chromen-5-one (11).
c
g
Hydroxydihydropyranocoumarin 11 was glycosylated by a modified Michael method [6]. Acetobromoglucose (Ac Glu Br) or
p
4
acetobromogalactose (Ac Gal Br) and the potassium salt of 11 were condensed in aqueous acetone with cooling (0°C).
p
4
OH
OR
OR
OH
Me
Me
O
O
O
Me
Me
O
O
O
HO
O
O
Me
Me
O
O
O
a
b
c
10
11
12, 13
14, 15
12:
13:
14:
R = Glup
R = Ac Glup
4
15:
=
Galp
R
R = Ac Galp
4
a. (CH ) CH=CHCH Br, p-TSA; b. KOH, CH COCH -H O, Ac GalpBr (or Ac GlupBr); c. MeONa, MeOH
3 2
2
3
3
2
4
4
Signals for protons of the coumarin aglycons and carbohydrates were found unambiguously in PMR spectra of the
synthesized tetra-O-acetylglycopyranosides 12 and 13. The configuration of the anomeric center was determined using PMR
spectroscopy. The presence in the spectra of a doublet for anomeric H-1′ at 5.14 ppm with SSCC J = 7.5 Hz (for glucoside 12)
and 5.05 ppm with SSCC J = 8.1 Hz (for galactoside 13) is consistent with formation of a 1,2-
(β-configuration of the anomeric center) [7]. IR spectra of 12 and 13 have two bands at 1760-1730 and 1710-1715 cm that
are typical of C O stretching vibrations of acetyls and coumarins, respectively.
-glycoside bond
trans
-1
Deacetylation of 12 and 13 bya modified Zemplen method (NaOMe in MeOH) produced β-D-glycopyranosides 14 and
15 in high yields. PMR spectra of the synthesized glycosides contain signals for the carbohydrate and aglycon. In contrast with
the starting peracetates, theylack signals for the acetyls. Retention of the β-configuration was confirmed bythe presence in the
PMR spectra of a doublet for anomeric H-1′ at 4.97 ppm with SSCC J = 7.2 Hz (for glucopyranoside 14) and 4.96 ppm with
-1
SSCC J = 7.8 Hz (for galactopyranoside 15). IR spectra of 14 and 15 have two bands at 3300-3400 and 1700-1710 cm that
are typical for stretching vibrations of alcohols and coumarin C=O bonds, respectively.
389

Pechmann condensation of 2,2-dimethylchroman-7-ol (16) and ethyl-2-oxocyclohexanecarboxylate in the presence of
conc. H SO produced 9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one (17), a modified analog of
2
4
the natural pyranocoumarin dihydroxanthyletin that contains an annelated cyclohexane moiety.
O
Me
Me
O
Me
Me
O
O
O
OH
COOEt
EtOH, H SO
2
4
+
17
16
Pechmann condensation of 2,2-dimethyl-5-hydroxy-7-methoxy-4-chromanone (18) and ethyl-2-
oxocyclohexanecarboxylate in the presence of conc. H SO formed 11-methoxy-2,2-dimethyl-2,3,7,8,9,10-
2
4
hexahydrobenzo[c]pyrano[2,3-h]chromen-4,6-dione (19). The PMR spectrum of 19 exhibits signals for the chromanone ring
(6H singlet for two methyls and a singlet for the CH protons), the cyclohexane moiety, and a 1H singlet for the aromatic
2
protons. Reduction of19usingNaBH in CH OHproducedchromanol 20, dehydration ofwhich under acid-catalysis conditions
4
3
(HCl in dioxane) [8] produced 11-methoxy-2,2-dimethyl-7,8,9,10-tetrahydrobenzo[c]pyrano[2,3-h]chromen-6-one (21), a
modified analog of the natural pyranocoumarin 5-methoxyseselin that contains an annelated cyclohexane moiety. The PMR
spectrum of 21 contains two doublets at 5.70 and 6.61 ppm with SSCC J = 9.6 Hz that are typical of an annelated pyran ring
[5].
Me
Me
Me
Me
OH
Me
Me
O
Me
Me
O
COOEt
O
O
O
O
O
O
O
O
OH
O
O
O
NaBH
HCl
4
MeOH
EtOH, H SO
2
4
OMe
OMe
OMe
OMe
18
19
20
21
Pechmann condensation of7-methoxy-5-hydroxy-2,2-dimethylchromane(22)andethyl-2-oxocyclohexanecarboxylate
in the presence of conc. H SO led to partial demethoxylation of the reaction product to form a mixture of 11-methoxy-2,2-
2
4
dimethyl-3,4,7,8,9,10-hexahydrobenzo[c]pyrano[2,3-h]chromen-6-one (23) and its 11-hydroxy derivative (24).
Me
Me
Me
Me
Me
Me
O
CO OEt
O
OH
O
O
O
O
O
O
EtOH, H SO
2
4
+
+
OMe
OMe
OH
22
23
24
11-Hydroxy-2,2-dimethyl-3,4,7,8,9,10-hexahydrobenzo[c]pyrano[2,3-h]chromen-6-one (24) was used as starting
material to annelate a furan ring to the dihdyropyranocoumarin system. The MacLeod approach [9] was used to fuse the furan
ring. Alkylation of 24 under Williamson reaction conditions using chloroacetone formed oxoester 25, which cyclized smoothly
on heatingwith NaOHsolution (1 N) and subsequent acidolysis to3,5,5-trimethyl-6,7,10,11,12,13-hexahydrobenzo[c]furo[2,3-
f]pyrano[2,3-h]chromen-9-one (26).
Me
Me
Me
Me
O
O
O
O
O
O
O
MeCOCH Cl
2
1. 1N NaOH
2. 1N H SO
4
24
Me
K CO
2
3
2
O
O
Me
25
26
390

EXPERIMENTAL
The course of reactions and purity of products were monitored using TLC on Merck 60 F254 plates with elution by
CHCl :CH OH (9:1). Melting points were determined on a Kofler block. IR and UV spectra were measured on a Nicolet FTIR
3
3
Nexus 475 spectrometer and Specord M40 spectrophotometer, respectively. PMR spectra were recorded on a Varian VXR-300
spectrometer at 300 MHz relative to TMS (internal standard). Elemental analyses of all compounds agreed with those
calculated.
Syntheses of 3-5, 16, 18, and 22 have been reported [2, 10, 11]. Acetobromoglycopyranosides were prepared as before
[12].
7,9,9-Trimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one (6). A mixture of 3 (2.30 g,
10 mmol), 3,3-dimethylallylbromide (1.75 mL, 15 mmol) or 3-methyl-2-buten-1-ol (1.52 mL, 15 mmol), and p-toluenesulfonic
acid monohydrate (1.90 g, 10 mmol) in toluene (50 mL) was held at 100-110°C for 24 h (completion ofreaction was determined
using TLC). After the reaction was complete, solvent was removed in vacuo in a rotary evaporator. The solid was dissolved
in CHCl (50 mL). The resulting solution was treated with NaOH solution (1 N, 2×50 mL) and saturated NaCl solution.
3
Acidification of the combined alkaline solutions regenerated unreacted hydroxycoumarin. The organic layer was dried over
anhydrous MgSO . Solvent was removed in vacuo in a rotaryevaporator. The oily residue was crystallized from hexane, yield
4
-1
68%, mp 135-136°C, C H O . IR spectrum (KBr, cm ): 2940, 1706, 1614, 1582, 1392, 1262, 1164, 1126.
19 22
3
UV spectrum (CH CN, λ , nm, log ε): 210 (4.69), 224 (4.26), 328 (4.24).
3
max
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.36 (6H, s, two CH -9), 1.78 (4H, m, CH -2, CH -3), 1.83 (2H, t,
3
3
2
2
J = 7.2, CH -10), 2.26 (3H, s, CH -7), 2.55 (2H, m, CH -4), 2.73 (2H, m, CH -1), 2.84 (2H, t, J = 7.2, CH -11), 7.11 (1H, s,
2
3
2
2
2
H-12).
7,9,9-Trimethyl-10,11-dihydrobenzo[c]pyrano[3,2-g]chromen-5-one (7)waspreparedanalogouslyto6startingwith
-1
4 (2.26 g, 10 mmol), yield 74%, mp 142-143°C, C H O . IR spectrum (KBr, cm ): 1720, 1610, 1572, 1486, 1454, 1380,
19 18
3
1368, 1356, 1316, 1276, 1240, 1228, 1184, 1160, 1122, 1088.
UV spectrum (CH CN, λ , nm, log ε): 212 (4.50), 226 (4.60), 286 (4.13), 311 (4.05).
3
max
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.38 (6H, s, two CH -9), 1.86 (2H, t, J = 7.2, CH -10), 2.29 (3H,
3
3
2
s, CH -7), 2.89 (2H, t, J = 7.2, CH -11), 7.44 (1H, t, J = 8.1, H-3), 7.59 (1H, s, H-12), 7.73 (1H, t, J = 8.1, H-2), 7.97 (1H, d,
3
2
J = 8.1, H-4), 8.33 (1H, d, J = 8.1, H-1).
7,9,9-Trimethyl-10,11-dihydrobenzo[c]pyrano[3,2-g]chromen-5-one (7). A solution of 6 (0.60 g, 2 mmol) in
dioxane (5 mL) was treated with a solution of DDQ (0.91 g, 4 mmol) in dioxane (5 mL) and heated for 6 h (completion of
reaction was determined using TLC). After the reaction was complete, the solid hydroquinone was filtered off. Solvent was
removed in vacuo in a rotary evaporator. The oily residue was crystallized from hexane:propan-2-ol (2:1), yield 54%.
7,9,9-Trimethylbenzo[c]pyrano[3,2-g]chromen-5-one (8). A solution of 7 (0.59 g, 2 mmol) in toluene (10 mL) was
treated with a solution of DDQ (0.68 g, 3 mmol) in toluene (10 mL) and held at 100 C for 8 h (completion of reaction was
determined using TLC). After the reaction was complete, the solid hydroquinone was filtered off. Solvent was removed in
vacuo in a rotary evaporator. The solid was dissolved in CHCl (50 mL) and treated with NaOH solution (1 N, 2×50 mL) and
3
saturated NaCl solution. The organic phase was dried over anhydrous MgSO . Solvent was removed in vacuo in a rotary
4
evaporator. The oily residue was crystallized from propan-2-ol, yield 72%, mp 150-151°C, C H O . IR spectrum
19 16
3
-1
(KBr, cm ): 1728, 1616, 1444, 1378, 1320, 1280, 1186, 1158, 1124.
UV spectrum (CH CN, λ , nm, log ε): 210 (4.37), 257 (4.57), 265 (4.55), 288 (3.93), 344 (4.00).
3
max
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.44 (6H, s, two CH -9), 2.32 (3H, s, CH -7), 5.71 (1H, d, J = 9.6,
3
3
3
H-10), 6.43 (1H, d, J = 9.6, H-11), 7.48 (1H, t, J = 8.1, H-3), 7.50 (1H, s, H-12), 7.76 (1H, t, J = 8.1, H-2), 7.98 (1H, d, J = 8.1,
H-4), 8.35 (1H, d, J = 8.1, H-1).
7,9,9-Trimethylbenzo[c]pyrano[3,2-g]chromen-5-one (8) was also produced in 65% yield starting with 6 (0.60 g,
2 mmol) and DDQ (1.82 g, 8 mmol).
2,2,5-Trimethyl-3,4,9,10,11,12-hexahydrobenzo[c]pyrano[2,3-f]chromen-8-one (9) was prepared analogously to
-1
6 starting with 5 (2.30 g, 10 mmol), yield 75%, mp 141-142°C, C H O . IR spectrum (KBr, cm ): 2928, 1698, 1606, 1452,
19 22
3
1416, 1404, 1388, 1168, 1148, 1114, 1088.
UV spectrum (CH CN, λ , nm, log ε): 208 (4.54), 304 (4.16).
3
max
391

PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.34 (6H, s, two CH -2), 1.69 (4H, m, CH -10, CH -11), 1.82
6
3
2
2
(2H, t, J = 7.2, CH -3), 2.23 (3H, s, CH -5), 2.40 (2H, m, CH -9), 2.62 (2H, t, J = 7.2, CH -4), 3.06 (2H, m, CH -12), 6.64 (1H,
2
3
2
2
2
s, H-6).
3,4-Dihydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one (10). A cooled (0°C) solution of pyrogallol (12.6 g,
0.1 mol) and ethyl-2-oxocyclohexanecarboxylate (16.0 mL, 0.1 mol) in EtOH (20 mL) was vigorously stirred and cooled and
treated dropwise with conc. H SO (10 mL). The reaction mixture was stirred until it thickened, after which it was left
2
4
overnight at room temperature. The mixture was poured into icewater (250 mL). The resulting precipitate was filtered off and
-1
crystallized from CH CN, yield 86%, mp 259-260°C (lit. 269-276°C [13], 276°C [14]), C H O . IR spectrum (KBr, cm ):
3
13 12 4
3468, 2940, 1704, 1680, 1612, 1584, 1512, 1384, 1330, 1204, 1098.
UV spectrum (EtOH, λ , nm, log ε): 203 (4.76), 264 (4.25), 324 (4.39).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.70-1.80 (4H, m, CH -8, CH -9), 2.38 (2H, m, CH -10), 2.70
6
2
2
2
(2H, m, CH -7), 6.77 (1H, d, J = 8.7, H-2), 7.00 (1H, d, J = 8.7, H-1), 9.35 and 9.94 (2H, two br.s, OH-3, OH-4).
2
7-Hydroxy-9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one (11). A mixture of 10
(2.32 g, 10 mmol), 3,3-dimethylallylbromide (1.75 mL, 15 mmol), and p-toluenesulfonic acid monohdyrate (1.90 g, 10 mmol)
in toluene (50 mL) was held at 100-110°C for 24 h (completion of reaction was determined using TLC). After the reaction was
complete, solvent was removed in vacuo in a rotary evaporator. The oily residue was crystallized from propan-2-ol, yield 43%,
-1
mp 204-205°C, C H O . IR spectrum (KBr, cm ): 3432, 2932, 1710, 1690, 1628, 1582, 1468, 1398, 1368, 1274, 1124.
18 20
4
UV spectrum (EtOH, λ , nm, log ε): 211 (4.86), 266 (4.31), 331 (4.43).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.31 (6H, s, two CH -9), 1.71 (4H, m, CH -2, CH -3), 1.78 (2H,
6
3
2
2
t, J = 7.2, CH -10), 2.37 (2H, m, CH -4), 2.70 (2H, m, CH -1), 2.77 (2H, t, J = 7.2, CH -11), 6.90 (1H, s, H-12), 8.94 (1H, s,
2
2
2
2
OH-7).
7-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-
g]chromen-5-one (12). A solution of 11 (1.50 g, 5 mmol) in acetone (5 mL) and KOH solution (2.8 mL, 10%, 5 mmol) was
stirred vigorously and cooled (0°C) for 30 min. Acetobromoglucose (2.06 g, 5 mmol) was added in portions with stirring over
1 h. The resulting solution was stirred for 4 h with cooling (0°C) and left overnight at room temperature. The reaction mixture
was diluted with CHCl (25 mL) and treated successively in a separatory funnel with KOH solution (1 N, 2×25 mL) and water
3
(25 mL). The organic phase was dried over anhydrous MgSO . Solvent was removed in vacuo in a rotary evaporator. The oily
4
-1
residue was crystallized from propan-2-ol, yield 49%, mp 116-117°C, C H O . IR spectrum (KBr, cm ): 1760, 1732, 1712,
32 38 13
1680, 1618, 1460, 1388, 1224, 1124, 1048.
UV spectrum (EtOH, λ , nm, log ε): 210 (4.74), 328 (4.25).
max
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.33, 1.40 (6H, two s, two CH -9), 1.75-1.90 (6H, m, CH -2, CH -3,
3
3
2
2
CH -10), 2.02, 2.04, 2.16 (12H, three s, four CH COO), 2.54 (2H, m, CH -4), 2.70 (2H, m, CH -1), 2.83 (2H, t, J = 7.2,
2
3
2
2
CH -11), 3.64 (1H, m, H-5′), 4.10 (1H, dd, J = 12.0, J = 2.4, H-6′α), 4.21 (1H, dd, J = 12.0, J = 5.7, H-6′β), 5.14 (1H, d,
2
J = 7.5, H-1′), 5.23-5.32 (2H, m, H-2′, H-3′), 5.41 (1H, dd, J = 9.9, J = 9.6, H-4′), 7.05 (1H, s, H-12).
7-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-
g]chromen-5-one (13) was prepared analogously to 12 starting with 11 (1.50 g, 5 mmol) and acetobromogalactose (2.06 g,
-1
5 mmol), yield 54%, mp 143-144°C, C H O . IR spectrum (KBr, cm ): 1752, 1728, 1710, 1614, 1574, 1484, 1460, 1372,
32 38 13
1228, 1158, 1124, 1078.
UV spectrum (EtOH, λ , nm, log ε): 210 (4.73), 328 (4.30).
max
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.35, 1.42 (6H, two s, two CH -9), 1.70-1.90 (6H, m, CH -2, CH -3,
3
3
2
2
CH -10), 1.97, 2.01, 2.18, 2.22 (12H, four s, four CH COO), 2.54 (2H, m, CH -4), 2.71 (2H, m, CH -1), 2.84 (2H, t, J = 7.2,
2
3
2
2
CH -11), 3.82 (1H, t, J = 6.9, H-5′), 4.11 (2H, d, J = 7.2, CH -6′), 5.05 (1H, d, J = 8.1, H-1′), 5.08 (1H, dd, J = 8.1, J = 3.3,
2
2
H-3′), 5.41 (1H, d, J = 3.3, H-4′), 5.59 (1H, dd, J = 8.1, J = 8.1, H-2′), 7.06 (1H, s, H-12).
7-(β-D-Glucopyranosyloxy)-9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one (14). A
solution of 12 peracetate (1.26 g, 2 mmol) in absolute MeOH (10 mL) was treated with NaOMe (50 mg). The reaction mixture
was boiled for 30 min (completion of reaction was determined using TLC). The precipitate that formed on cooling (0°C) was
-1
filtered off and washed with cold MeOH, yield 91%, mp 235-236°C, C H O . IR spectrum (KBr, cm ): 3364, 2928, 1704,
24 30
9
1680, 1612, 1576, 1460, 1392, 1124, 1064.
UV spectrum (EtOH, λ , nm, log ε): 211 (4.65), 328 (4.21).
max
392

PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.31, 1.36 (6H, two s, two CH -9), 1.65-1.84 (6H, m, CH -2,
6
3
2
CH -3, CH -10), 2.39 (2H, m, CH -4), 2.73 (2H, m, CH -1), 2.82 (2H, t, J = 7.2, CH -11), 3.06 (1H, m, H-4′), 3.19 (2H, m,
2
2
2
2
2
H-2′, H-3′), 3.27-3.42 (2H, m, H-5′, H-6′α), 3.55 (1H, dd, J = 11.7, J = 5.4, H-6′β), 4.27 (1H, t, J = 5.6, OH-6), 4.97 (1H, d,
J = 7.2, H-1′), 5.06 (1H, d, J = 4.5, OH), 5.17 (1H, d, J = 4.2, OH), 5.20 (1H, d, J = 4.5, OH), 7.19 (1H, s, H-12).
7-(β-D-Galactopyranosyloxy)-9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one (15)
was prepared analogously to 14 starting with 13 (1.26 g, 2 mmol), yield 87%, mp 184-185°C, C H O . IR spectrum
24 30
9
-1
(KBr, cm ): 3408, 2932, 1708, 1690, 1612, 1574, 1484, 1462, 1392, 1158, 1122, 1072.
UV spectrum (EtOH, λ , nm, log ε): 210 (4.61), 328 (4.16).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.34, 1.41 (6H, two s, two CH -9), 1.70-1.90 (6H, m, CH -2,
6
3
2
CH -3, CH -10), 2.41 (2H, m, CH -4), 2.73 (2H, m, CH -1), 2.83 (2H, t, J = 7.2, CH -11), 3.15-3.70 (6H, m, H-2′, H-3′, H-4′,
2
2
2
2
2
H-5′, CH -6′), 4.25 (1H, t, J = 5.6, OH-6), 4.37 (1H, d, J = 4.5, OH), 4.67 (1H, d, J = 4.2, OH), 4.76 (1H, d, J = 4.5, OH), 4.96
2
(1H, d, J = 7.8, H-1′), 7.13 (1H, s, H-12).
9,9-Dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one (17). Asolution of16(0.89g, 5mmol)
and ethyl-2-oxocyclohexanecarboxylate (0.8 mL, 5 mmol) in EtOH (5 mL) was vigorously stirred and treated dropwise with
conc. H SO (5 mL). The reaction mixture was left overnight at room temperature and poured into icewater (50 mL). The
2
4
resulting precipitate was filtered off and crystallized from propan-2-ol, yield 78%, mp 145-146°C, C H O . IR spectrum
18 20
3
-1
(KBr, cm ): 1712, 1620, 1570, 1498, 1392, 1306, 1156, 1112.
UV spectrum (EtOH, λ , nm, log ε): 207 (4.67), 222 (4.22), 329 (4.25).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.29 (6H, s, two CH -9), 1.98 (4H, m, CH -2, CH -3), 1.79 (2H,
6
3
2
2
t, J = 7.2, CH -10), 2.34 (2H, m, CH -4), 2.68 (2H, m, CH -1), 2.78 (2H, t, J = 7.2, CH -11), 6.62 (1H, s, H-7), 7.38 (1H, s,
2
2
2
2
H-12).
11-Methoxy-2,2-dimethyl-2,3,7,8,9,10-hexahydrobenzo[c]pyrano[2,3-h]chromen-4,6-dione (19). Asolution of18
(2.22 g, 10 mmol) and ethyl-2-oxocyclohexanecarboxylate (1.60 mL, 10 mmol) in EtOH(5 mL) was treated dropwise with conc.
H SO (10 mL). The reaction mixture was held at 50°C for 8 h, left overnight at room temperature, and poured into icewater
2
4
(100 mL). The resulting precipitate was filtered off and crystallized from propan-2-ol, yield 56%, mp 213-214°C, C H O .
19 20
5
-1
IR spectrum (KBr, cm ): 1710, 1690, 1612, 1574, 1468, 1382, 1262, 1236, 1204, 1110.
UV spectrum (CH CN, λ , nm, log ε): 218 (4.53), 284 (4.44), 311 (4.32).
3
max
PMR spectrum (300 MHz, CDCl , δ, ppm): 1.47 (6H, s, two CH -2), 1.72 (4H, m, CH -8, CH -9), 2.54 (2H, m,
3
3
2
2
CH -10), 2.72 (2H, s, CH -3), 3.00 (2H, m, CH -7), 3.91 (3H, s, CH O-11), 6.26 (1H, s, H-12).
2
2
2
3
4-Hydroxy-11-methoxy-2,2-dimethyl-2,3,7,8,9,10-hexahydrobenzo[c]pyrano[2,3-h]chromen-4-one (20). Asolution
of 19 (1.31 g, 4 mmol) in MeOH (10 mL) was treated in portions with NaBH (0.46 g, 12 mmol). The reaction mixture was
4
held at room temperature and stirred vigorously for 2 h (completion of reaction was determined using TLC), poured into
saturated NaCl solution (100 mL), and extracted with ethylacetate (3×20 mL). The organic phase was dried over anhydrous
MgSO . Solvent was removed in vacuo in a rotary evaporator. The solid was crystallized from MeOH, yield 82%, mp 231-
4
-1
232°C, C H O . IR spectrum (KBr, cm ): 3393, 1712, 1620, 1588, 1480, 1432, 1388, 1196, 1116.
19 22
5
UV spectrum (EtOH, λ , nm, log ε): 212 (4.77), 252 (4.06), 262 (4.08), 326 (4.29).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.36, 1.41 (6H, two s, two CH -2), 1.63 (4H, m, CH -8, CH -9),
6
3
2
2
1.87 (1H, dd, J = 12.0, J = 5.7, H-3α), 1.99 (1H, dd, J = 12.0, J = 2.4, H-3β), 2.37 (2H, m, CH -10), 2.95 (2H, m, CH -7), 3.79
2
2
(1H, s, CH O-11), 4.92 (1H, m, H-4), 5.05 (1H, d, J = 5.4, OH-4), 6.31 (1H, s, H-12).
3
11-Methoxy-2,2-dimethyl-7,8,9,10-tetrahydrobenzo[c]pyrano[2,3-h]chromen-6-one (21). A solution of 20
(1.00 g, 3 mmol) in dioxane (10 mL) was treated with HCl solution (4 M, 10 mL). The reaction mixture was held at room
temperature and vigorouslystirred for 4 h (completion ofreaction was determined using TLC). After the reaction was complete,
solvent was removed in vacuo in a rotary evaporator. The solid was crystallized from MeOH, yield 79%, mp 236-237°C,
-1
C H O . IR spectrum (KBr, cm ): 1708, 1620, 1580, 1484, 1366, 1140, 1118, 1106.
19 20
4
UV spectrum (EtOH, λ , nm, log ε): 230 (4.63), 292 (4.33), 326 (4.24).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.40 (6H, s, two CH -2), 1.62 (4H, m, CH -8, CH -9), 2.34 (2H,
6
3
2
2
m, CH -10), 2.90 (2H, m, CH -7), 3.79 (3H, s, CH O-11), 5.70 (1H, d, J = 9.6, H-3), 6.37 (1H, s, H-12), 6.61 (1H, d, J = 9.6,
2
2
3
H-4).
Hexahydrobenzo[c]pyrano[2,3-h]chromen-6-ones 23 and 24. A solution of 20 (3.12 g, 15 mmol) and ethyl-2-
oxocyclohexanecarboxylate (2.40 mL, 15 mmol) in EtOH(10mL)wasstirredvigorouslyand treated dropwise with conc. H SO
2
4
393

(20 mL). The resulting mixture was held at 50 C for 4 h, left overnight at room temperature, and poured into icewater
(100 mL). The resulting precipitate was dissolved in CHCl (50 mL) and treated with NaOH solution (1 N, 2×50 mL) and
3
saturated NaCl solution. The organic phase was dried over anhydrous MgSO . Solvent was removed in vacuo in a rotary
4
evaporator. The oily residue was crystallized from MeOH to afford 23. The combined alkaline solutions were acidified to
pH 4. The resulting precipitate of 24 was filtered off and crystallized from propan-2-ol.
11-Methoxy-2,2-dimethyl-3,4,7,8,9,10-hexahydrobenzo[c]pyrano[2,3-h]chromen-6-one (23), yield 39%, mp 175-
-1
176°C, C H O . IR spectrum (KBr, cm ): 1714, 1622, 1602, 1486, 1470, 1436, 1378, 1326, 1208, 1152, 1122, 1082.
19 22
4
UV spectrum (CH CN, λ , nm, log ε): 209 (4.51), 253 (3.94), 262 (3.92), 333 (4.12).
3
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.31 (6H, s, two CH -2), 1.66 (4H, m, CH -8, CH -9), 1.80 (2H,
6
3
2
2
t, J = 7.2, CH -3), 2.36 (2H, m, CH -10), 2.68 (2H, t, J = 7.2, CH -4), 2.96 (2H, m, CH -7), 3.78 (3H, s, CH O-11), 6.24 (1H,
2
2
2
2
3
s, H-12).
11-Hydroxy-2,2-dimethyl-3,4,7,8,9,10-hexahydrobenzo[c]pyrano[2,3-h]chromen-6-one (24), yield 45%, mp188-
-1
189°C, C H O . IR spectrum (KBr, cm ): 3296, 2972, 1690, 1666, 1612, 1566, 1428, 1396, 1368, 1284, 1260, 1156, 1076.
18 20
4
UV spectrum (EtOH, λ , nm, log ε): 213 (4.65), 251 (3.93), 260 (3.94), 329 (4.31).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.33 (6H, s, two CH -2), 1.67 (4H, m, CH -8, CH -9), 1.74 (2H,
6
3
2
2
t, J = 7.2, CH -3), 2.35 (2H, m, CH -10), 2.64 (2H, t, J = 7.2, CH -4), 3.02 (2H, m, CH -7), 6.25 (1H, s, H-12), 10.13 (1H, s,
2
2
2
2
OH-11).
2,2-Dimethyl-11-(2-oxopropoxy)-3,4,7,8,9,10-hexahydrobenzo[c]pyrano[2,3-h]chromen-6-one (25). Ahotsolution
of 24 (1.20 g, 4 mmol) in absolute acetone (20 mL) was treated with freshly calcined potash (1.66 g, 10 mmol), stirred
vigorously, heated (50-56°C), and treated with chloroacetone (0.35 mL, 4.4 mmol). The resulting mixture was heated for 3 h
and stirred vigorously (course of reaction was monitored using TLC). After the reaction was complete, the mixture was cooled
to room temperature, poured into icewater (100 mL), and acidified to pH 4. The solid was filtered off and crystallized from
-1
propan-2-ol (75%), yield 85%, mp 174-175°C, C H O . IR spectrum (KBr, cm ): 1728, 1710, 1610, 1432, 1392, 1292, 1160,
21 24
5
1132.
UV spectrum (EtOH, λ , nm, log ε): 214 (4.74), 321 (4.42).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.35 (6H, s, two CH -2), 1.68 (2H, m, CH -8, CH -9), 1.78 (2H,
6
3
2
2
t, J = 7.2, CH -3), 2.19 (3H, s, CH -3′), 2.37 (2H, m, CH -10), 2.66 (2H, t, J = 7.2, CH -4), 3.04 (2H, m, CH -7), 4.84 (2H, s,
2
3
2
2
2
CH -1′), 6.39 (1H, s, H-12).
2
3,5,5-Trimethyl-6,7,10,11,12,13-hexahydrobenzo[c]furo[2,3-f]pyrano[2,3-h]chromen-9-one (26). A solution of
25 (1.07 g, 3 mmol) in propan-2-ol (10 mL) was treated with NaOH solution (1 N, 10 mL). The reaction mixture was heated
for 3 h (completion of reaction was determined using TLC). After the reaction was complete, the mixture was cooled to room
temperature, poured into icewater (100 mL), and acidified to pH 4. The solid was filtered off and crystallized from propan-2-ol
-1
(75%), yield 91%, mp232-233°C, C H O . IR spectrum (KBr, cm ): 1702, 1680, 1616, 1582, 1468, 1420, 1370, 1312, 1280,
21 22
4
1266, 1156, 1126.
UV spectrum (EtOH, λ , nm, log ε): 210 (4.48), 230 (4.39), 259 (4.33), 274 (4.30), 313 (4.17).
max
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.38 (6H, s, two CH -5), 1.71 (4H, m, CH -11, CH -12), 1.84
6
3
2
2
(2H, t, J = 6.6, CH -6), 2.38 (3H, s, CH -3), 2.43 (2H, m, CH -13), 2.86 (2H, t, J = 6.6, CH -7), 3.08 (2H, m, CH -10), 7.52
2
3
2
2
2
(1H, s, H-2).
ACKNOWLEDGMENT
We thank OAO Eksimed (Kiev, Ukraine) for help in performing the work.
REFERENCES
1.
2.
3.
R. D. H. Murray, The Naturally Occurring Coumarins, Springer, Vienna-New York (2002).
Ya. L. Garazd, T. N. Panteleimonova, M. M. Garazd, and V. P. Khilya, Khim. Prir. Soedin., 422 (2002).
W. Hurtley, J. Chem. Soc., 1870 (1929).
394

4.
5.
M. M. Jetter, N. D. Heindel, and J. D. Laskin, J. Heterocycl. Chem., 27, 995 (1990).
M. E. Perel′son, Yu. N. Sheinker, and A. A. Savina, Spectra and Structure of Coumarins, Chromones, and
Xanthones [in Russian], Meditsina, Moscow (1975).
6.
7.
8.
Ya. L. Garazd, M. M. Garazd, and V. P. Khilya, Khim. Prir. Soedin., 7 (2004).
J. F. Stoddart, Stereochemistry of Carbohydrates, Interscience, New York (1971).
A. Levai, T. Timar, P. Sebok, and T. Eszenyi, Heterocycles, 53, 1193 (2000).
J. K. MacLeod and B. R. Worth, Tetrahedron Lett., 237 (1972).
9.
10.
11.
12.
13.
14.
Ya. L. Garazd, A. S. Ogorodniichuk, M. M. Garazd, and V. P. Khilya, Khim. Prir. Soedin., 345 (2002).
Ya. L. Garazd, M. M. Garazd, and V. P. Khilya, Khim. Prir. Soedin., 352 (2004).
C. E. Redemann and C. Niemann, in: Organic Synthesis, Vol. 22, John Wiley & Sons, New York (1942), p. 1.
V. Boekelheide and F. C. Pennington, J. Am. Chem. Soc., 74, 1558 (1952).
S. S. Soman and K. N. Trivedi, Indian J. Chem., Sect. B, 31, 30 (1992).
395