Mild, fast, and stereoselective epoxide opening by ketone enolate anions. Application to synthesis of the norlignan curculigine

Article abstract of DOI:10.1021/jo020744q

We report here that (1) enolate anions of five- to seven-membered cycloalkanones nucleophilically open cyclopentene and cyclohexene oxides in 57-76% yields and with 4-8:1 diastereoselectivity; (2) enolate anions formed regiospecifically via kinetic deprot

Full text of DOI:10.1021/jo020744q

Mild , F a st, a n d Ster eoselective Ep oxid e Op en in g by Keton e
En ola te An ion s. Ap p lica tion to Syn th esis of th e Nor lign a n
Cu r cu ligin e
Gary H. Posner,* J ohn P. Maxwell,† and Mehmet Kahraman
Department of Chemistry, School of Arts and Sciences, The J ohns Hopkins University,
Baltimore, Maryland 21218
ghp@jhu.edu
Received December 18, 2002
We report here that (1) enolate anions of five- to seven-membered cycloalkanones nucleophilically
open cyclopentene and cyclohexene oxides in 57-76% yields and with 4-8:1 diastereoselectivity;
(2) enolate anions formed regiospecifically via kinetic deprotonation of 2-cyclohexenone and
2-cycloheptenone open cyclohexene oxide in 60-62% yields and with 32-95:1 diastereoselectivity;
and (3) an aryl methyl ketone enolate anion opens a monosubstituted epoxide as the key step in a
short synthesis of the γ-hydroxyketone (GHK) aglycon of the natural product curculigine.
TABLE 1
In tr od u ction
Nucleophilic enolate anions and electrophilic epoxides
are fundamental building blocks in diverse carbon-
carbon bond-forming reactions, including synthesis of
complex target molecules.1,2 Although ester3,4 (pKa 25)
and amide5-7 (pKa 28) enolate anions nucleophilically
open epoxides, ketone (pKa 20) enolate anions generally
do not,3,8 probably as a result of their greater thermody-
namic stability. The electrophilicity of epoxides can be
enhanced, however, by various Lewis acids. Crotti and
colleagues have studied this topic intensively,9 and they
have applied especially Lewis acidic scandium triflate to
facilitate ketone enolate anion opening of epoxides;
typical reaction times are g18 h at room temperature.
We reported recently in preliminary fashion a simple,
mild (-78 °C) and rapid (<1 h) way to activate epoxides
toward nucleophilic opening by ketone enolate anions:
m
n
product
% yield
dr (syn:anti) (H/H)
5
6
6
7
7
6
5
6
5
6
1
2
3
4
5
70
57
76
75
73
6:1
5:1
8:1
4:1
8:1
boron trifluoride-diethyl etherate (BF3‚OEt2) added to
a mixture of enolate and epoxide effectively promotes
carbon-carbon bond formation to produce γ-hydroxy
ketones (GHKs).10 Now we report on the scope of this
process, including (1) enolate anions of five- to seven-
membered cycloalkanones nucleophilically opening cyclo-
pentene and cyclohexene oxides in good yield and with
good diastereoselectivity; (2) enolate anions formed regio-
specifically via kinetic deprotonation of 2-cyclohexenone
and 2-cycloheptenone opening cyclohexene oxide in good
yield and with very good to excellent diastereoselectivity;
and (3) an aryl methyl ketone enolate anion opening a
monosubstituted epoxide as the key step in a short
synthesis of the aglycon GHK of the natural product
curculigine.
Cou p lin g of Cycloa lk a n on e En ola tes w ith Cyclo-
a lk en e Ep oxid es. Deprotonation of five- to seven-
membered cycloalkanones with lithium hexamethyldi-
silazide in tetrahydrofuran at -78 °C followed sequentially
by addition of either cyclopentene epoxide or cyclohexene
epoxide and then dropwise addition of 1 equiv of neat,
precooled BF3‚OEt2 gave GHKs 1-5 in 57-76% yields
and with 4-8:1 diastereoselectivity (Table 1). For all
* To whom correspondence should be addressed. Phone: 410-516-
4670. Fax: 410-516-8420.
† Current address: Vertex Pharmaceuticals, Cambridge, MA.
(1) Smith, J . G. Synthesis 1984, 629-656.
(2) (a) Klunder, J . M.; Posner, G. H. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: New York, 1991; Vol. 3, Chapter 1.5, p 207. (b) Knight, D. W.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
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Chapter 1.6, p 241. (c) Garratt, P. J . In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: New York, 1991; Vol. 3, Chapter 1.7, p 271.
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Lett. 1991, 32, 7583-7586. (b) Crotti, P.; Di Bussolo, V.; Favero, L.;
Macchia, F.; Pineschi, M. Tetrahedron Lett. 1994, 35, 6537-6540. (c)
Crotti, P.; Di Bussolo, V.; Favero, L.; Pineschi, M. J . Org. Chem. 1996,
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2001, 57, 8559-8572.
(10) Posner, G. H.; Wang, Q.; Halford, B. A.; Elias, J . S.; Maxwell,
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10.1021/jo020744q CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/14/2003
J . Org. Chem. 2003, 68, 3049-3054
3049

Posner et al.
SCHEME 1
these GHKs 1-5, the diastereomer with the two adjacent
methine hydrogen atoms syn to each other predominated.
1
Characteristic H NMR absorptions of these GHKs are
as follows. GHK 1: CHOH proton of the major diaste-
reomer δ 3.46-3.33 (m, 1H) and that of the minor
diastereomer δ 3.36-3.24 (m, 1H). GHK 2: CHOH of the
major diastereomer δ 3.95-3.90 (m, 1H) and the minor
diastereomer 3.78 (m, 1H). GHK 3: syn diatereomer δ
CHOH 3.30-3.22 (m, 1H), OH 2.58 (d, J ) 8.0 Hz, 1H),
2.47-2.41 (m, 1H), 2.38-2.29 (m, 2H); anti diastereomer
δ CHOH 3.92-3.24 (m, 1H), 2.80-2.75 (m, 1H). GHK 4:
CHOH of the major diastereomer δ 3.92 (dd, J ) 12.4,
6.8 Hz, 1H) and the minor diastereomer δ 3.77-3.73 (m,
1H). GHK 5: CHOH for the major diastereomer δ 3.33-
3.23 (m, 1H); the minor diastereomer exists a mixture of
the GHK and the corresponding hemiacetal δ 3.57-3.49
(m, 0.72H), 3.33-3.31 (m, 0.28H). Unequivocal assign-
ment of relative stereochemistry to the GHKs 2-5 was
achieved via X-ray crystallography of the corresponding
p-nitrobenzoate esters. Oxidation of the major diastere-
omer of cyclopentanol GHK 2 gave the same diketone as
oxidation of the major diastereomer of cyclohexanol GHK
1, thereby confirming the syn stereochemistry of the
major diastereomer of GHK 1. Lower reaction tempera-
ture (-100 °C) did not raise the diastereoselelectivity of
the coupling reactions. When initial ketone deprotonation
was performed using sodium rather than lithium hexa-
methyldisilazide, the yield of GHK product was increased
by 5-20% but the diastereoselectivity was severely
diminished.
with three contiguous stereogenic centers, in 32-95:1
diastereomeric ratio and in 60-62% overall yields.
To show that the GHK major syn diastereomers 1-5
are the kinetic products of these enolate-epoxide cou-
pling reactions, the pure syn diastereomer of cyclohex-
anone 3 was equilibrated in ethanolic potassium hydrox-
ide at room temperature for 2 days into a 2:3 ratio of
syn:anti diastereomers. The same thermodynamic 2:3
syn:anti ratio was obtained also via basic equilibration
starting with the pure anti diastereomer of GHK 3.
Similar equilibration results were obtained with GHKs
1 and 5.
As before, using sodium rather than lithium hexa-
methyldisilazide gave substantially poorer stereochem-
ical control. 2-Cyclohexenone kinetic lithium enolate
anion did not open cyclopentene epoxide or cis-2-butene
epoxide well. Likewise, 2-cycloheptenone kinetic lithium
enolate did not open cyclopentene epoxide well.
Syn th esis of Na tu r a l P r od u ct Cu r cu ligin e Agly-
con . Some norlignan glucosides have been isolated from
tuberous rhizomes and have been found in vivo to be
potently anti-arrhythmic.11 Structurally related curcu-
ligine was isolated also in very small amounts from the
same plant and was characterized as its peracetylated
glucoside penta-O-methylated ether.12 We report here a
short synthesis of the aglycon (-)-15 of this norlignan
glucoside, starting from allylic alcohol 9,13 in which the
key convergent synthetic step involves BF3‚OEt2-assisted
opening of monosubstituted epoxide (-)-12 by an aryl
methyl ketone enolate anion (Scheme 2). In this key
An additional example of an acyclic ketone enolate
opening of a simple epoxide is shown in eq 1, illustrating
further the usefulness of BF3‚OEt2 in promoting these
coupling reactions to form GHK 6. Using an acyclic
ketone enolate to open cyclohexene epoxide in the pres-
ence of BF3‚OEt2 proceeded well chemically but with poor
diastereocontrol (eq 2). When cyclooctene epoxide was
used, cyclohexanone lithium enolate gave no significant
amount of GHK.
H igh ly Dia st er eoselect ive Cou p lin g of 2-Cyclo-
a lk en on e Kin et ic E n ola t es w it h Cycloh exen e
Ep oxid e. The level of diastereoselectivity in enolate
opening of epoxides was considerably higher (as deter-
mined by NMR spectroscopy of crude product mixtures)
when the kinetic lithium enolate of 2-cyclohexenone and
of 2-cycloheptenone was treated first with cyclohexene
epoxide and then with 1 equiv of neat, precooled BF3‚
OEt2 at -78 °C in THF (Scheme 1). Catalytic hydrogena-
tion of the initial olefinic GHKs 7 and 8 produced the
same major GHK products 3 and 5 shown in Table 1.
Thus, this two-step reaction sequence (Scheme 1) allows
easy transformation of 2-cyclohexenone and 2-cyclohep-
tenone into the corresponding syn GHKs 3 and 5, each
(11) Chang, W.-L.; Chen, C.-H.; Lee, S.-S. J . Nat. Prod. 1999, 62,
734-739.
(12) (a) Chifundera, K.; Palazzino, G.; Messana, I.; Ping, L.; Galeffi,
C.; Cannarsa, G. Phytochemistry 1994, 35, 1343-1348. (b) Galeffi, C.;
Federici, E.; Palazzino, G.; Nicoletti, M. Gazz. Chim. Ital. 1997, 127,
501-504.
(13) Srikrishna, A.; Daneildoss, S. Synth. Commun. 2001, 31, 2357-
2364.
3050 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of the Norlignan Curculigine
XL 400 spectrometer (1H NMR at 400 MHz, 13C at 100 MHz)
with chloroform, tetramethylsilane, or d4-CH3OH as an inter-
nal reference. Chemical shifts are reported in parts per million
(ppm, δ) downfield from tetramethylsilane. Splitting patterns
are described as singlet (s), doublet (d), triplet (t), quartet (q),
and multiplet (m). Electospray ionization (ESI) mass spec-
SCHEME 2
trometry analysis was performed with
a 3-tesla Fourier
Transform mass spectrometer. Electron impact (EI) ionization
was performed using 70 eV ionization conditions. Solvents
were distilled prior to use; methylene chloride (CH2Cl2) was
distilled from CaH2, tetrahydrofuran (THF) and diethyl ether
(ether) were distilled from benzophenone sodium ketyl, chloro-
form (CHCl3) was distilled from 4 Å molecular sieves, and
dimethyl sulfoxide (DMSO) was dried over CaH2 and distilled.
All other starting materials and reagents were purchased from
commercial sources. All ketones used in the study were dried
over MgSO4 and all except for 3,4-dimethoxyacetophenone
were distilled under reduced pressure before use. Cyclohep-
tenone was further purified by flash silica gel column chro-
matography. Flash silica gel refers to particle size 400-230
mesh. Medium-pressure liquid chromatography (MPLC) was
performed with FMI pump and prepacked silica gel column
(Si 60, 40-63µ).
GHK 1. To a solution of LHMDS (1.0 M in THF, 1.10 mL,
1.10 mmol, 1.1 equiv) in THF (2 mL) at -78 °C was added
cyclopentanone (89 µL, 1.0 mmol, 1.0 equiv) over 1 min.
Cyclohexene oxide (0.200 mL, 1.98 mmol, 2.0 equiv) was added
after 20 min, followed by neat BF3‚OEt2 (0.140 mL, 1.10 mmol,
1.1 equiv) over 5 min. After 1 h the reaction was quenched at
-78 °C by the addition of saturated aqueous NH4Cl solution
(2 mL), and the aqueous layer was extracted with Et2O (3 ×
30 mL). The combined organic layers were washed with brine
(10 mL), dried over MgSO4, and concentrated in vacuo. The
crude product was purified by flash silica gel column chroma-
tography with petroleum ether/EtOAc (6:1) to obtain 128 mg
(0.702 mmol, 70%) of a mixture of the two diastereomers in a
step to form GHK (-)-15, the potassium enolate was
found to give better yields than either the sodium or
lithium enolate. Because the aglycon (-)-15 has not
been characterized in the literature, the corresponding
known compounds (-)-16 and (-)-18 were synthesized
in the same manner as (-)-15 (Scheme 2). This provides
confirmation of relative and absolute stereochemistry
of these natural product aglycons. GHK (-)-18 was
obtained from coupling of the TMS ether epoxide (-)-14
with the aryl methyl ketone enolate ion, followed by
desilylation with tetrabutylammonium triphenyldifluoro-
silicate (TBAT),14 an anhydrous, crystalline fluoride
source.
In conclusion, we have demonstrated that diverse
epoxides are easily, rapidly, and diastereoselectively
opened by various cycloalkanone lithium enolates in the
presence of BF3‚OEt2 in THF solvent at -78 °C. Out-
standing diastereoselectivity is evident when the kinetic
lithium enolates of 2-cyclohexenone and 2-cycloheptenone
open cyclohexene oxide. This type of BF3‚OEt2-promoted
opening of a monosubstituted epoxide by a methyl ketone
enolate anion is featured as the key carbon-carbon bond-
forming step in the synthesis of the norlignan natural
product aglycon (-)-15. The fundamental carbon-carbon
bond-forming reactions described here between ketone
enolates and oxiranes using BF3‚OEt2 are expected to be
useful to the international synthetic organic chemistry
community.
1
6:1 ratio as determined by H NMR analysis. The diastereo-
mers were subjected to further flash silica gel chromatographic
analysis in order to obtain separate amounts of each for
individual characterization. Data for GHK 1 (major isomer):
1
Rf ) 0.20 petroleum ether/EtOAc (6:1, 3×). H NMR (CDCl3):
δ 3.46-3.33 (m, 1H), 2.27-2.22 (m, 2H), 2.08-1.79 (m, 6H),
1.77-1.60 (m, 4H), 1.30-1.12 (m, 5H). 13C NMR (CDCl3): δ
222.67, 72.16, 52.60, 45.85, 38.64, 36.57, 30.91, 26.04, 25.35,
24.28, 21.40. FTIR (neat, cm-1): 3434.7, 2927.9, 2855.0, 1731.0,
1449.8, 1159.5, 1063.5, 923.8. HRMS (M + Na): calcd 205.1204,
found 205.1201. Data for GHK 1 (minor isomer): Rf ) 0.14
1
pet ether/EtOAc (6:1, 3×). H NMR (CDCl3): δ 3.36-3.24 (m,
1H), 2.62-2.56 (m, 1H), 2.44-2.24 (m, 2H), 2.17-2.00 (m, 4H),
1.83-1.61 (m, 4H), 1.54-1.48 (m, 1H), 1.31-1.14 (m, 4H),
1.08-0.98 (m, 1H). 13C NMR (CDCl3): δ 223.22, 73.40, 51.50,
44.63, 39.35, 36.60, 27.80, 25.69, 25.41, 25.20, 21.05. FTIR
(neat, cm-1): 3417.4, 2928.8, 2856.2, 1731.3, 1449.3, 1405.3,
1162.1, 1061.8. HRMS (M + Na): calcd 205.1199, found
205.1211.
GHK 2. To a solution of LHMDS (1.0 M in THF, 1.10 mL,
1.10 mmol, 1.1 equiv) in THF (2 mL) at -78 °C was added
cyclohexanone (0.100 mL, 0.96 mmol, 1.0 equiv) over 1 min.
Cyclopentene oxide (0.170 mL, 1.95 mmol, 2.0 equiv) was
added after 15 min, followed by neat BF3‚OEt2 (0.140 mL, 1.10
mmol, 1.1 equiv) over 5 min. After 1 h the reaction was
quenched at -78 °C by the addition of saturated aqueous NH4-
Cl solution (2 mL), and the aqueous layer was extracted with
Et2O (3 × 25 mL). The combined organic layers were washed
with brine (10 mL), dried over MgSO4, and concentrated in
vacuo. The crude product was purified by flash silica gel
column chromatography with petroleum ether/EtOAc (6:1) to
obtain 100 mg (0.549 mmol, 57%) of a mixture of the two
diastereomers in 5:1 ratio as determined by 1H NMR analysis.
The diastereomers were subjected to further flash silica gel
chromatographic analysis in order to obtain sufficient amounts
of each for individual characterization. Data for GHK 2 (major
Exp er im en ta l Section
All reactions were run in flame-dried glassware under an
argon atmosphere. NMR spectra were recorded on a Varian
(14) (a) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J . Am. Chem.
Soc. 1995, 117, 5166-5167. (b) Pilcher, A. S.; DeShong, P. J . Org.
Chem. 1996, 61, 6901-6905.
J . Org. Chem, Vol. 68, No. 8, 2003 3051

Posner et al.
1
isomer): Rf ) 0.30 hexanes/EtOAc (2:1). H NMR (CDCl3): δ
43.16, 34.61, 30.06, 3014, 29.38, 28.40, 24.27, 22.55. FTIR
(neat, cm-1): 3425.1, 2931.5, 2859.8, 163.7, 1453.6, 1342.9,
1168.0, 1092.0, 1072.7, 935.5. HRMS (M + Na): calcd 219.1355,
found 219.1358.
3.95-3.90 (m, 1H), 3.13 (d, J ) 2.4 Hz, 1H), 2.54-2.49 (m,
1H), 2.40-2028 (m, 2H), 2.24-2.17 (m, 1H), 2.14-2.04 (m, 2H),
1.94-1.88 (m, 1H), 1.84-1.76 (m, 2H), 1.75-1.61 (m, 4H),
1.56-1.46 (m, 2H), 1.31-1.22 (m, 1H). 13C NMR (CDCl3): δ
215.53, 74.91, 53.68, 47.22, 42.34, 35.56, 30.05, 28.98, 28.25,
25.07, 23.24. FTIR (neat, cm-1): 3411.0, 2938.3, 2863.4, 1704.1,
1448.2, 1310.5, 1130.5, 981.5. HRMS (M + Na): 205.1204,
found 205.1208. Data for GHK 2 (minor isomer): Rf ) 0.39
hexanes/EtOAc (2:1). 1H NMR (CDCl3): δ 3.95 (s, 1H), 3.78
(m, 1H), 2.48-2.43 (m, 1H), 2.40-2.24 (m, 2H), 2.20-2.07 (m,
2H), 1.98-1.55 (m, 9H), 1.44-1.34 (m, 1H), 1.17-1.06 (m, 1H).
13C NMR (CDCl3): δ 112.3, 77.50, 71.99, 70.37, 68.58, 66.59,
66.26, 65.55, 64.94, 64.18, 63.76. FTIR (neat, cm-1): 3427.9,
2939.2, 2863.3, 1698.5, 1448.3, 1311.2, 1029.7, 984.4. HRMS
(M + Na): calcd 205.1204, found 205.1206.
GHK 3. To a solution of LHMDS (1.0 M in THF, 1.10 mL,
1.10 mmol, 1.1 equiv) in THF (2 mL) at -78 °C was added
cyclohexanone (0.100 mL, 0.96 mmol, 1.0 equiv) over 1 min.
This was stirred for 60 min, and then cyclohexene oxide (0.200
mL, 1.98 mmol, 2.0 equiv) was added, followed after 10 min
by neat BF3‚OEt2 (0.135 mL, 1.05 mmol, 1.1 equiv) over 5 min.
After 1 h the reaction was quenched at -78 °C by the addition
of aqueous pH 7.0 phosphate buffer solution (2 mL), and the
aqueous layer was extracted with Et2O (3 × 25 mL). The
combined organic layers were washed with brine (10 mL),
dried over MgSO4, and concentrated in vacuo. The crude
product was purified by flash silica gel column chromatography
with petroleum ether/EtOAc (6:1) to obtain 129 mg [0.657
mmol, 68%, Rf ) 0.41 hexanes/EtOAc (2:1)] of the major
diastereomer and 17 mg (0.086 mmol, 9%) of the minor
diastereomer as viscous liquids. Data for GHK 3 (major
isomer): 1H NMR (CDCl3): δ 3.30-3.22 (m, 1H), 2.58 (d, J )
8.0 Hz, 1H), 2.47-2.41 (m, 1H), 2.38-2.29 (m, 2H), 2.12-1.95
(m, 5H), 1.82-1.61 (m, 5H), 1.49-1.43 (m, 1H), 1.34-1.17(m,
4H). 13C NMR (CDCl3): δ 216.02, 71.60, 55.14, 42.69, 42.38,
36.86, 30.23, 28.06, 27.54, 26.05, 25.71, 24.96. FTIR (neat,
cm-1): 3431.1, 2931.5, 2856.6, 1703.5, 1448.9, 1132.0, 1062.4,
1051.1. HRMS: (M + Na): calcd 219.1361, found 219.1366.
Data for GHK 3 (minor isomer): 1H NMR (CDCl3): δ 3.30-
3.24 (m, 1H), 2.80-2.75 (m, 1H), 2.47-2.41 (m, 1H), 2.36-
2.27 (m, 1H), 2.11-1.96 (m, 5H), 1.76-1.60 (m, 2H), 1.53-
1.39 (m, 3H), 1.38-1.18 (m, 4H), 0.97-0.88 (m, 2H). 13C NMR
(CDCl3): δ 214.15, 72.10, 50.65, 43.26, 42.44, 36.98, 29.89,
27.99, 27.59, 26.91, 25.82, 25.36, 25.12. FTIR (neat, cm-1):
3393.4, 2930.0, 2857.3, 1704.7, 1448.8, 1131.9, 1069.7, 1056.4.
HRMS: (M + Na): calcd 219.1361, found 219.1364.
GHK 5. To a solution of LHMDS (1.0 M in THF, 1.10 mL,
1.10 mmol, 1.1 equiv) in THF (2 mL) at -78 °C was added
cycloheptanone (0.118 mL, 1.0 mmol, 1.0 equiv) dropwise over
2 min. Cyclohexene oxide (0.200 mL, 1.98 mmol, 2.0 equiv)
was added after 60 min, followed by neat BF3‚OEt2 (0.140 mL,
1.10 mmol, 1.1 equiv) over 5 min. After 1 h the reaction was
quenched at -78 °C by the addition of saturated aqueous NH4-
Cl solution (2 mL), and the aqueous layer was extracted with
Et2O (3 × 30 mL). The combined organic layers were washed
with brine (10 mL), dried over MgSO4, and concentrated in
vacuo. The crude product was purified by flash silica gel
column chromatography with petroleum ether/EtOAc (6:1) to
obtain 133 mg [0.632 mmol, 63%, Rf ) 0.49 hexanes/EtOAc
(2:1)] of the major diastereomer as a white solid (mp ) 66.0-
67.5 °C) and 22 mg (0.105 mmol, 10%) of the minor diastere-
omer. Data for GHK 5 (major isomer): 1H NMR (CDCl3): δ
3.33-3.23 (m, 1H), 2.87 (d, J ) 6.0 Hz, 1H), 2.61 (ddd, J )
13.6, 12.0, 2.8 Hz, 1H), 2.50-2.38 (m, 2H), 2.04-1.83 (m, 4H),
1.80-1.56 (m, 6H), 1.46-1.07 (m, 7H). 13C NMR (CDCl3): δ
219.47, 71.22, 55.55, 48.74, 44.05, 36.09, 30.34, 29.65, 29.52,
26.44, 26.03, 25.22, 24.97. FTIR (neat, cm-1): 3410.5, 2927.0,
2854.2, 1691.6, 1679.4, 1459.9, 1450.8, 1344.0, 1186.1, 1170.0,
1145.8, 1129.7, 1063.2, 1023.0, 942.0. Elemental analysis:
calcd % C: 74.24, H: 10.54; found % C: 74.18, H: 10.54.
HRMS (M + Na): calcd 233.1517, found 233.1518. Data for
GHK 5 (minor isomer): 1H NMR 28:72 keto-alcohol/hemiketal
(CDCl3/D2O): δ 3.57-3.49 (m, 0.72H), 3.33-3.31 (m, 0.28H),
2.68-2.62 (m, 0.3H), 2.58-2.46 (m, 0.7H), 2.03-1.58 (m, 11H),
1.42-0.05 (m, 8H). 13C NMR (CDCl3): (keto alcohol assign-
ments) δ 218.82, 80.19, 55.74, 53.25, 38.96, 31.82, 31.12, 30.32,
27.62, 26.34, 25.90, 24.43, 23.94; (hemiketal assignments) δ
109.43, 72.68, 54.32, 48.40, 43.90, 36.59, 30.45, 28.69, 27.99,
27.14, 25.72, 25.35, 25.14. FTIR (neat, cm-1): 3396.7, 2927.6,
2854.9, 1691.8, 1451.4, 1355.6, 1342.6, 1313.9, 1277.4, 1217.4,
1207.0, 1170.5, 1141.8, 1115.7, 1089.6, 1068.8, 1047.9, 982.7,
941.0. HRMS (M + Na): calcd 233.1517, found 233.1517.
1-(3,4-Dim eth oxyp h en yl)-4-h yd r oxyp en ta n -1-on e (6).
To a solution of NaHMDS (1.0 M in THF, 1.10 mL, 1.1 mmol,
1.2 equiv) in THF (2 mL) at -78 °C was added a solution of
3,4-dimethoxypropiophenone (181 mg, 1.0 mmol, 1.0 equiv) in
THF (1.5 mL) over MS 4 Å. The reaction was stirred for 60
min, and then propylene oxide (0.140 mL, 2.0 mmol, 2.0 equiv)
was added to the reaction, followed after an additional 5 min
by neat BF3‚OEt2 (0.140 mL, 1.1 mmol, 1.1 equiv). After 60
min the reaction was quenched at - 78 °C by the addition of
aqueous pH 7.0 phosphate buffer solution (4 mL) and diluted
with brine (5 mL), and the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with brine (10 mL), dried over MgSO4, filtered, and concen-
trated in vacuo. The crude product was purified by flash silica
gel column chromatography with petroleum ether/EtOAc (1:
1) to obtain 148 mg (0.62 mmol, 62%) of product as a colorless
oil. Data for 6: 1H NMR (CDCl3): δ 7.56 (dd, J ) 8.4, 2.0 Hz,
1H), 7.47 (d, J ) 2.0 Hz, 1H), 6.81 (d, J ) 8.4 Hz, 1H), 3.88 (s,
3H), 3.87 (s, 3H), 3.86-3.79 (m, 1H), 3.11-2.97 (m, 2H), 2.62-
2.39 (s, 1H), 1.92-1.84 (m, 1H), 1.82-1.73 (m, 1H), 1.19 (d, J
) 6.4 Hz, 3H). 13C NMR (CDCl3): δ 199.58, 153.33, 149.01,
130.11, 122.94, 110.21, 110.07, 67.50, 56.11, 56.01, 34.54,
33.50, 23.83. FTIR: (neat, cm-1): 3430.7, 2965.1, 2934.4,
2840.5, 1670.9, 1595.1, 1515.8, 1463.6, 1417.7, 1344.1, 1269.6,
1160.9, 1131.0, 1022.5. HRMS (M + Na): calcd 261.1097,
found 261.1102.
GHK 4. To a solution of LHMDS (1.0 M in THF, 4.4 mL,
4.4 mmol, 1.1 equiv) in THF (8 mL) at -78 °C was added
cycloheptanone (0.47 mL, 4.1 mmol, 1.0 equiv) dropwise.
Cyclopentene oxide (0.98 mL, 8.0 mmol, 2.0 equiv) was added
after 25 min, followed by neat BF3‚OEt2 (0.54 mL, 4.3 mmol,
1.1 equiv) over 5 min. After 1 h the reaction was quenched at
-78 °C by the addition of saturated aqueous NH4Cl solution
(10 mL), and the aqueous layer was extracted with Et2O (3 ×
25 mL). The combined organic layers were washed with brine
(10 mL), dried over MgSO4, and concentrated in vacuo to give
1
a 4:1 ratio of a mixture of isomers as determined by H NMR
analysis. The crude product was purified by MPLC eluted with
25% ethyl acetate in toluene to obtain 0.46 mg of the major
isomer and 0.11 mg of the minor isomer. Data for GHK 4
(major isomer): 1H NMR (CDCl3): δ 3.92 (dd, J ) 12.4, 6.8
Hz, 1H), 3.35 (br, 1H), 2.68-2.63 (m, 1H), 2.46-2.43 (m, 2H),
2.03-1.73 (m, 7H), 1.68-1.47 (m, 4H), 1.40-1.14 (m, 4H). 13
C
NMR (CDCl3): δ 218.16, 74.30, 54.25, 49.20, 43.20, 35.12,
29.40, 29.36, 29.29, 27.96, 24.13, 22.44. FTIR (neat, cm-1):
3425.1, 2931.5, 2859.8, 163.7, 1453.6, 1342.9, 1168.0, 1092.0,
1072.7, 935.5. HRMS (M + Na): calcd 219.1355, found
219.1369. Data for GHK 4 (minor isomer): 1H NMR (CDCl3):
δ 3.77-3.73 (m 1H), 2.67 (br, 1H), 2.52-2.42 (m, 3H), 1.99-
1.77 (m, 7H), 1.73-1.51 (m, 4H), 1.41-1.26 (m, 3H), 1.21-
1.12 (m, 1H). 13C NMR (CDCl3): δ 218.74, 77.65, 57.03, 50.61,
GHK 7. To a solution of LHMDS (1.0 M in THF, 1.10 mL,
1.10 mmol, 1.1 equiv) in THF (3 mL) at -78 °C was added
2-cyclohexen-1-one (0.100 mL, 1.03 mmol, 1.0 equiv). The
enolate solution was stirred for 60 min, and then cyclohexene
oxide (0.200 mL, 1.98 mmol, 1.9 equiv) was added to the
reaction. After 10 min, neat BF3‚OEt2 (0.130 mL, 1.03 mmol,
3052 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of the Norlignan Curculigine
1.0 equiv) was added over 6 min. The reaction was continued
for an additional 60 min at -78 °C and then quenched at
reaction temperature by the addition of pH 7.0 phosphate
buffer solution (4 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with brine (15 mL), dried over MgSO4, and concentrated in
vacuo. The crude product was purified by flash silica gel
column chromatography with petroleum ether/EtOAc (3:1) to
obtain 124 mg (0.638 mmol, 62%) of a single diastereomer as
a clear oil that solidified upon refrigeration (mp 36-37.5 °C).
Data for GHK 7: 1H NMR (CDCl3): δ 6.96-6.91 (m, 1H), 6.02
(ddd, J ) 6.0, 2.8, 0.8 Hz, 1H), 3.38-3.29 (m, 1H), 2.51-2.43
(m, 1H), 2.42-2.32 (m, 1H), 2.30-2.21 (m, 2H), 2.04-1.98 (m,
3H), 1.75-1.67 (m, 2H), 1.55-1.48 (m, 2H), 1.32-1.20 (m, 4H).
13C NMR (CDCl3): δ 202.78, 149.86, 130.15, 72.32, 50.74,
43.38, 36.96, 29.97, 26.79, 26.13, 25.31, 23.50. FTIR (neat,
cm-1): 3441.4, 2929.0, 2854.5, 1667.7, 1449.5, 1426.9, 1387.1,
1218.4, 1131.7, 1062.9, 1046.8. HRMS (M + Na): calcd
217.1199, found 217.1187.
(s, 1H), 6.96 (s, 2H), 4.55 (d, J ) 6.0 Hz, 1H), 3.83 (s, 3H),
3.81 (s, 3H), 3.68-3.64 (m, H), 3.48 (dd, J ) 11.2, 4.0 Hz, 1H),
3.34 (dd, J ) 11.2, 6.0 Hz, 2H). 13C NMR (CDCl3): δ 149.15,
149.03, 131.23, 129.89, 126.72, 119.83, 111.24, 108.96, 63.95,
56.06, 55.96. FTIR (neat, cm-1): 3410.5, 3020.9, 2940.3, 2836.6,
1658.4, 1641.9, 1517.3, 1467.8, 1422.7, 1318.5, 1263.6, 1235.7,
1155.1, 1102.2, 1023.6, 991.2.
Ep oxy Alcoh ol (-)-11. A solution of triol (-)-10 (1.084 g,
4.75 mmol, 1.0 equiv) in pyridine (60 mL) at 0 °C was treated
with tosyl chloride (948 mg, 4.97 mmol, 1.05 equiv). The
reaction was stirred overnight and then filtered through a plug
of flash silica gel to yield 1.61 g crude material. The crude
product was dissolved in MeOH/CH2Cl2 (33 mL, 10:1) at 0 °C
and treated with K2CO3 (585 mg, 4.23 mmol). The reaction
was stirred for 1 h and then filtered through a plug of flash
silica gel with EtOAc/hexanes (1:1) to yield 708 mg of product
(3.37 mmol, 71% for two steps) as an oil that solidified upon
refrigeration (mp 75.5-77.0 °C). [R]25 ) -5.8 (c ) 0.090,
D
1
CHCl3). H NMR (CDCl3): δ 6.99 (d, J ) 2.0 Hz, 1H), 6.96-
6.93 (m, 1H), 6.87 (d, J ) 8.4 Hz, 1H), 4.44 (t, J ) 5.2 Hz,
1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.25-3.22 (m, 1H), 2.86 (dd, J
) 4.8, 4.0 Hz, 1H), 2.83 (dd, J ) 4.8, 2.8 Hz, 1H), 2.29 (d, J )
5.2 Hz, 1H). 13C NMR (CDCl3): δ 174.14, 149.40, 149.17,
133.04, 118.87, 111.29, 109.61, 74.35, 56.14, 56.12, 45.57. FTIR
(neat, cm-1): 3457.3, 2983.0, 2958.5, 2936.0. 2836.2, 1735.9,
1604.1, 1593.4, 1518.0, 1465.9, 1415.3, 1262.6, 1238.0, 1140.3,
1027.1, 916.8, 849.4, 800.8. HRMS (M + Na): calcd 233.0784,
found 233.0790. 98% ee determined by HPLC (tR 21.59 min,
Chiracel AD 10% 2-propanol/hexane, 1.0 mL/min).
Meth yl Eth er Ep oxid e (-)-12. To a slurry of NaH (60%
in mineral oil, 47 mg, 1.18 mmol, 2.9 equiv) in THF/DMSO
(11 mL, 10:1) at room temperature was added a solution of
(-)-11 (86 mg, 0.41 mmol, 1.0 equiv) in THF (2 mL). The
reaction was stirred at room temperature for 40 min, and then
iodomethane (50 µL, 0.82 mmol, 2.0 equiv) was added. After
4 h the reaction was quenched at 0 °C by the addition of ice
and transferred to a separatory funnel containing brine (7 mL).
The product was extracted with CH2Cl2 (3 × 20 mL), the
combined organic layers were washed with brine (10 mL),
dried (MgSO4), and concentrated in vacuo. The crude product
was purified by flash silica gel column chromatography with
hexanes/EtOAc (3:1) to yield 89 mg (0.40 mmol, 97%) of (-)-
12 as a colorless oil. [R]25D ) -20.6 (c ) 0.18, MeOH). 1H NMR
(CDCl3): δ 6.90-6.86 (m, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.84
(d, J ) 6.4 Hz, 1H), 3.36 (s, 3H), 3.18 (m, 1H), 2.74 (t, J ) 4.6,
1H), 2.61 (dd, J ) 4.8, 2.8 Hz, 1H). 13C NMR (CDCl3): δ 149.48,
149.25, 130.69, 119.78, 111.20, 109.82, 85.02, 57.16, 56.15,
56.12, 55.49, 44.52. FTIR (neat, cm-1): 2963.2, 2920.1, 2846.5,
1593.1, 1513.0, 1502.8, 1462.1, 1454.1, 1411.6, 1255.9, 1231.1,
1135.5, 1085.8, 1023.2, 805.0. HRMS (M + Na): calcd 247.0941,
found 247.0938.
Hyd r ogen a tion of 7. A solution of 7 (34 mg, 0.175 mmol)
in EtOAc (2 mL) was stirred with 10% Pd on carbon under an
atmosphere of H2 at room temperature for 20 min. The reaction
was then filtered through a pad of Celite, and the solvent was
removed by evaporation to yield 34 mg of syn-3 (0.173 mmol,
99%) as a clear colorless oil.
GHK 8. To a solution of LHMDS (1.0 M in THF, 4.40 mL,
4.40 mmol, 1.1 equiv) in THF (8 mL) at -78 °C was added
2-cyclohepten-1-one (80% technical grade purified as noted
above, 0.445 mL, 4.0 mmol, 1.0 equiv). The enolate solution
was stirred for 60 min, and then cyclohexene oxide (0.800 mL,
7.91 mmol, 2.0 equiv) was added to the reaction. After 10 min,
neat BF3‚OEt2 (0.560 mL, 4.42 mmol, 1.1 equiv) was added
over 5 min. The reaction was continued for an additional 60
min at -78 °C and then quenched at reaction temperature by
the addition of pH 7.0 phosphate buffer solution (3 mL), and
additional water (10 mL) was added to the solution. The
aqueous layer was extracted with CH2Cl2/ether (2:1, 3 × 30
mL). The combined organic layers were washed with brine (15
mL), dried over MgSO4, and concentrated in vacuo. The crude
product was purified by flash silica gel column chromatography
with petroleum ether/EtOAc (3:1) to obtain 508 mg (2.44 mmol,
60%) as a colorless oil. Data for GHK 8: 1H NMR (CDCl3): δ
6.48 (dt, J ) 12, 5.2 Hz, 1H), 5.96 (dt, J ) 12, 1.6 Hz, 1H),
3.33-3.26 (m, 1H), 3.14 (d, J ) 6.0 Hz, 1H), 2.67-2.63 (m,
1H), 2.39-2.34 (m, 2H), 1.98-1.94 (m, 1H), 1.86-1.74 (m, 5H),
1.67-1.56 (m, 3H), 1.21-1.13 (m, 4H). 13C NMR (CDCl3): δ
208.89, 145.60, 132.48, 71.23, 55.91, 47.08, 36.37, 30.74, 30.11,
26.09, 25.37, 24.97, 23.97. FTIR (neat, cm-1): 3423.8, 3019.1,
2926.0, 2859.1, 2665.8, 1651.2, 1448.2, 1418.2, 1397.7, 1235.7,
1171.0, 1073.8, 908.2. HRMS (M + Na): calcd 231.1355, found
231.1368.
Bu tyl Eth er Ep oxid e (-)-13. To a slurry of NaH (60% in
mineral oil, 71 mg, 1.78 mmol, 2.6 equiv) in THF/DMSO (11
mL, 10:1) at room temperature was added a solution of (-)-
11 (146 mg, 0.695 mmol, 1.0 equiv) in THF (2 mL). The
reaction was stirred at room temperature for 30 min and then
cooled to 0 °C, and 1-iodobutane (0.240 mL, 2.11 mmol, 3.0
equiv) was added. After 3 h the reaction was quenched by the
addition of ice and transferred to a separatory funnel contain-
ing brine (10 mL). The product was extracted with CH2Cl2 (3
× 30 mL), and the combined organic layers were washed with
brine (10 mL), dried (MgSO4), and concentrated in vacuo. The
crude product was purified by preparative plate TLC (2 mm,
silica gel, 2:1 hexanes/EtOAc) to yield 78 mg (0.293 mmol, 42%)
Hyd r ogen a tion of 8. A solution of 8 (10 mg, 0.048 mmol)
in EtOAc (2 mL) was stirred with 10% Pd on carbon under an
atmosphere of H2 at room temperature for 60 min. The reaction
was then filtered through a pad of Celite, and the solvent was
removed by evaporation to yield 10 mg of syn-5 (0.048 mmol,
100%) as a clear colorless oil.
1-(3,4-Dim et h oxyp h en yl)-1(R),2(R),3-t r ih yd r oxyp en -
ta n e (-)-10. Water (75 mL) and tert-butyl alcohol (75 mL)
were stirred with AD-mix-â (18.75 g) and methanesulfonamide
(1.277 g, 13.43 mmol, 1.0 equiv) at room temperature for 30
min and then cooled to 0 °C. 3,4-Dimethoxy-trans-cinnamyl
alcohol 9 (2.6 g, 13.4 mmol, 1.0 equiv) was then added in one
portion. The reaction was stirred in the dark for 48 h, then
Na2SO3 (20 g) was added, and the mixture stirred for 30 min.
The contents of the flask were transferred to a separatory
funnel, and the aqueous layer was extracted with EtOAc (3 ×
150 mL). The combined organic layers were dried over MgSO4,
concentrated in vacuo, and purified by flash silica gel column
chromatography (EtOAc) to yield 2.81 g of (-)-10 (12.3 mmol,
of (-)-13 as a colorless oil. [R]23 ) -31.8 (c ) 0.24, CH3OH).
D
1H NMR (CDCl3): δ 6.89 (br s, 1H), 6.83 (br s, 1H), 6.82 (br s,
1H), 3.91 (d, J ) 6.4 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.47-
3.36 (m, 2H), 3.15 (ddd, J ) 6.4, 4.0, 2.4 Hz, 1H), 2.70 (dd, J
) 4.8, 4.4 Hz, 1H), 2.56 (dd, J ) 4.8, 2.8 Hz, 1H), 1.63-1.51
(m, 2H), 1.43-1.30 (m, 2H), 0.87 (t, J ) 7.6 Hz, 3H). 13C NMR
92%) as a white solid. [R]24 ) -29.0 (MeOH, c ) 0.12), lit.15
D
[R]21 ) -32.1 (MeOH, c ) 0.28). 1H NMR (CD3OD): δ 7.03
(15) Mohamed, K. M. Phytochemistry 2001, 58, 615-618.
J . Org. Chem, Vol. 68, No. 8, 2003 3053
D

Posner et al.
(CDCl3): δ 149.28, 148.99, 131.28, 119.53, 111.06, 109.79,
83.16, 69.08, 56.00, 55.50, 44.50, 32.00, 19.47, 14.03. FTIR
(neat, cm-1): 2942.7, 2932.6, 2870.0, 1601.7, 1592.7, 1514.4,
1463.1, 1417.5, 1262.7, 1231.3, 1137.7, 1091.9, 1027.5, 918.0,
858.6, 804.4, 743.3. HRMS (M + Na): 289.1410, found
289.1402.
The aqueous layer was extracted with CH2Cl2/Et2O (30 mL,
2:1) and CH2Cl2 (2 × 25 mL). The organic layers were
combined, washed with brine (10 mL), dried (MgSO4), and
concentrated. The crude product was purified by preparative
layer silica gel chromatography (500 µm, 70% EtOAc/hexanes)
to yield 22 mg of (-)-16 (0.049 mmol, 26%) as a colorless oil.
TMS Eth er Ep oxid e (-)-14. A solution of (-)-11 (193 mg,
0.918 mmol, 1.0 equiv), triethylamine (0.330 mL, 2.37 mmol,
2.6 equiv), and trimethylsilyl chloride (0.150 mL, 1.18 mmol,
1.3 equiv) in CH2Cl2 (8 mL) was stirred at 0 °C for 2 h. The
solvent was evaporated, and the crude product was dissolved
in ether and filtered through basic Al2O3. After evaporation
of the ether, 122 mg (0.432 mmol, 47%) of (-)-14 was obtained
[R]24 ) -23.8 (c ) 0.26, MeOH). 1H NMR (CDCl3/CD3OD
D
7:3): δ 7.68-7.45 (m, 2H), 7.01-6.82 (m, 4H), 4.05 (d, J ) 7.6
Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H),
3.80-3.72 (m, 1H), 3.47-3.36 (m, 2H), 3.24-3.17 (m, 1H),
3.05-2.92 (m, 1H), 1.76-1.71 (m, 2H), 1.63-1.56 (m, 2H),
1.44-1.36 (m, 2H), 0.92 (t, J ) 7.2 Hz, 3H). 13C NMR (CD3-
OD): δ 201.78, 155.46, 151.00, 150.84, 150.74, 134.14, 131.70,
124.67, 122.18, 113.10, 112.58, 112.11, 112.07, 87.72, 75.81,
70.17, 56.95, 56.88, 56.85, 35.94, 33.51, 29.52, 20.92, 14.73.
HRMS (M + Na): calcd 469.2197, found 469.2186. NMR data
are consistent with the literature values.12b
as a white solid (mp 68-70 °C). [R]24 ) -17.1 (c ) 0.12,
D
1
CHCl3). H NMR (CDCl3): δ 6.94 (d, J ) 1.6 Hz, 1H), 6.86-
6.81 (m, 2H), 4.32 (d, J ) 6.0 Hz, 1H), 3.89 (s, 3H), 3.87 (s,
3H), 3.10 (m, 1H), 2.76 (dd, J ) 4.8, 4.0 Hz, 1H), 2.63 (dd, J )
4.8, 2.8 Hz, 1H), 0.11 (s, 9H). 13C NMR (CDCl3): δ 149.12,
148.78, 133.57, 118.66, 110.96, 109.63, 76.26, 56.82, 56.06,
45.36, 0.30. FTIR (CH2Cl2, cm-1): 3024.2, 3002.6, 2960.2,
2931.6, 2861.1, 1594.0, 1515.3, 1465.3, 1263.6, 1254.1, 1223.9,
1139.7, 1086.9, 1027.8, 937.8, 876.1, 845.5. HRMS (M + Na):
calcd 305.1180, found 305.1179.
Tetr a m eth yl 1-Hyd r oxy Cu r cu ligin e Aglycon (-)-18.
To KHMDS (140 mg, 0.70 mmol, 2.0 equiv) in THF (4 mL) at
-78 °C was added a solution of 3,4-dimethoxyacetophenone
(123 mg, 0.68 mmol, 2.0 equiv) in THF (1 mL). This was stirred
for 1 h at -78 °C, and then a solution of (-)-14 (96 mg, 0.34
mmol, 1.0 equiv) in THF (2 mL) was added to the reaction.
After stirring for 10 min, neat BF3‚EtO2 (86 µL, 0.68 mmol, 2
equiv) was added. The reaction was quenched after 45 min by
the addition of aqueous pH 7.0 phosphate buffer solution and
then transferred to a separatory funnel containing brine (10
mL). The aqueous layer was extracted with CH2Cl2/Et2O (45
mL, 2:1) and CH2Cl2 (2 × 30 mL). The organic layers were
combined, washed with brine (10 mL), dried (MgSO4), and
concentrated to give 214 mg crude material. A portion of the
crude material (18 mg, 8.4%) was dissolved in CH2Cl2 (1.5 mL)
at room temperature and treated with tetrabutylammonium
triphenyldifluorosilicate (TBAT)14 (8 mg, 15 µmol). This was
stirred for 5 min, and then the solvent was evaporated. The
crude material was purified by preparative layer silica gel
chromatography (500 µm, EtOAc eluent) to yield 3.5 mg of (-)-
18 (31%) as a white solid (mp ) 129-130 °C, lit. 125-126 °C).
[R]24 ) -15.7 (c ) 0.135, CHCl3), lit.12a [R]20 ) -15.5 (c )
Tetr a m eth yl 1-O-Meth yl Cu r cu ligin e a glycon (-)-15.
To KHMDS (163 mg, 0.82 mmol, 2.1 equiv) in THF (4 mL) at
-78 °C was added a solution of 3,4-dimethoxyacetophenone
(138 mg, 0.766 mmol, 2.0 equiv) in THF (2 mL). This was
stirred for 1 h, and then a solution of (-)-12 (86 mg, 0.38 mmol,
1.0 equiv) in THF (1.6 mL) was added to the reaction. After
10 min, neat BF3‚OEt2 (0.100 mL, 0.789 mmol, 2.0 equiv) was
added dropwise over 5 min. The reaction was quenched after
1 h by the addition of aqueous pH 7.0 phosphate buffer solution
and then transferred to a separatory funnel containing brine
(10 mL). The aqueous layer was extracted with CH2Cl2/Et2O
(30 mL, 2:1) and CH2Cl2 (2 × 25 mL). The organic layers were
combined and washed with brine (10 mL), dried (MgSO4), and
concentrated. The crude product was purified by flash silica
gel column chromatography to yield 66 mg of (-)-15 (0.163
mmol, 43%) as a colorless oil. [R]25D ) -22.8 (c ) 0.10, MeOH).
1H NMR (CD3OD): δ 7.58 (dd, J ) 8.4, 2.0 Hz, 1H), 7.46 (d, J
) 2.0 Hz, 1H), 6.98 (d, J ) 8.4 Hz, 1H), 6.94-6.91 (m, 2H),
6.87 (dd, J ) 8.0, 2.0 Hz, 1H), 3.94 (d, J ) 7.2 Hz, 1H), 3.89
(s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.73 (ddd, J )
8.4, 7.2, 4.0 Hz, 1H), 3.22 (s, 3H), 3.07 (ddd, J ) 16.8, 8.6, 5.8
Hz, 1H), 2.94 (ddd, J ) 16.8, 8.6, 7.0 Hz, 1H), 1.70-1.55 (m,
2H). 13C NMR (CDCl3): δ 198.92, 153.21, 149.33, 149.15,
149.00, 130.66, 130.27, 122.83, 120.66, 111.04, 110.20, 110.06,
110.02, 88.05, 74.64, 56.70, 56.14, 56.05, 55.98, 34.50, 27.21.
FTIR (neat, cm-1): 3504.6, 2997.3, 2934.6, 2836.8, 1671.1,
1593.3, 1515.2, 1463.8, 1417.5, 1264.4, 1152.2, 1110.6, 1024.2,
876.1, 810.8, 765.3. HRMS (M + Na): calcd 427.1727, found
427.1695.
D
D
1.3, CHCl3). 1H NMR (CDCl3): δ 7.58 (dd, J ) 8.4, 2.0 Hz,
1H), 7.50 (d, J ) 2.0 Hz, 1H), 6.93-6.83 (m, 4H), 4.42 (d, J )
6.4 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.87 (s,
3H), 3.78-3.67 (m, 1H), 3.16 (br d, J ) 3.2 Hz, 1H), 3.10 (dt,
J ) 7.0, 1.6 Hz, 2H), 2.82 (br s, 1H), 1.86-1.77 (m, 2H). HRMS
(M + Na): calcd 413.1571, found 413.1584. NMR data are
consistent with the literature values.12a
Ack n ow led gm en t. We thank the NSF and J ohns
Hopkins University for support of this project. The
authors also thank Prof. Arnold L. Rheingold and Dr.
Lev N. Zakharov of the X-ray Crystallographic Facility
of the Department of Chemistry and Biochemistry,
University of Delaware, Newark, DE, for the X-ray
crystal structure determinations.
Tetr a m eth yl 1-O-Bu tyl Cu r cu ligin e Aglycon (-)-16. To
KHMDS (80 mg, 0.40 mmol, 2.1 equiv) in THF (2 mL) at -78
°C was added a solution of 3,4-dimethoxyacetophenone (68 mg,
0.375 mmol, 2.0 equiv) in THF (1 mL). This was stirred for 1
h at -78 °C, and then a solution of (-)-13 (50 mg, 0.188 mmol,
1.0 equiv) in THF (1.0 mL) was added to the reaction. After
stirring for 10 min, neat BF3‚OEt2 (48 µL, 0.37 mmol, 2 equiv)
was added. The reaction was quenched after 1 h by the
addition of aqueous pH 7.0 phosphate buffer solution and then
transferred to a separatory funnel containing brine (10 mL).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1-8, 9-16, and 18 and X-ray data for
p-nitrobenzoate derivatives of GHKs 2-5. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O020744Q
3054 J . Org. Chem., Vol. 68, No. 8, 2003