Relative and absolute configuration of allohedycaryol. Enantiospecific total synthesis of its enantiomer

Article abstract of DOI:10.1021/jo9602534

The enantiomer of (+)-allohedycaryol, a germacrane alcohol isolated from giant fennel (Ferula communis L.), has been synthesized, thereby elucidating the relative and absolute stereochemistry of the natural product. The synthesis of (-)-allohedycaryol started from (+)-α-cyperone (5) which was available in relatively large quantities via alkylation of imine 7 derived from (+)-dihydrocarvone and (R)-(+)-1-phenylethylamine. In a number of steps 5 was converted into the mesylate 4 with a regio- and stereoselective epoxidation as the key step. A Marshall fragmentation of 4 was used to prepare the trans,trans-cyclodeca-1,6-diene ring present in allohedycaryol. The conformation of synthetic (-)-allohedycaryol was elucidated via photochemical conversion into a bourbonane system. The synthesis of (-)-allohedycaryol also showed that natural (+)-allohedycaryol has the opposite absolute stereochemistry to that normally found in higher plants.

Full text of DOI:10.1021/jo9602534

4022
J . Org. Chem. 1996, 61, 4022-4027
Rela tive a n d Absolu te Con figu r a tion of Alloh ed yca r yol.
En a n tiosp ecific Tota l Syn th esis of Its En a n tiom er
Vladimir N. Zhabinskii,† Adriaan J . Minnaard, J oannes B. P. A. Wijnberg,* and
Aede de Groot*
Laboratory of Organic Chemistry, Agricultural University, Dreijenplein 8,
6703 HB Wageningen, The Netherlands
Received February 7, 1996X
The enantiomer of (+)-allohedycaryol, a germacrane alcohol isolated from giant fennel (Ferula
communis L.), has been synthesized, thereby elucidating the relative and absolute stereochemistry
of the natural product. The synthesis of (-)-allohedycaryol started from (+)-R-cyperone (5) which
was available in relatively large quantities via alkylation of imine 7 derived from (+)-dihydrocarvone
and (R)-(+)-1-phenylethylamine. In a number of steps 5 was converted into the mesylate 4 with
a regio- and stereoselective epoxidation as the key step. A Marshall fragmentation of 4 was used
to prepare the trans,trans-cyclodeca-1,6-diene ring present in allohedycaryol. The conformation of
synthetic (-)-allohedycaryol was elucidated via photochemical conversion into a bourbonane system.
The synthesis of (-)-allohedycaryol also showed that natural (+)-allohedycaryol has the opposite
absolute stereochemistry to that normally found in higher plants.
Ch a r t 1
In tr od u ction
Through the ages, plant species belonging to the genus
Ferula (Umbelliferae) have been used in folk medicine1
and are now known as rich sources of secondary metabo-
lites. A long list of sesquiterpene alcohols and lactones
as well as coumarins has been reported.2 Recently, a new
main component has been isolated from the essential oil
obtained from the roots of F. communis L. (giant fennel),
a plant toxic to livestock and widespread in the Mediter-
ranean area.3 The compound was originally thought to
be a bisabolane sesquiterpene alcohol but through syn-
thesis of this alcohol, it turned out that the proposed
bisabolane structure was incorrect.4 Then the germa-
cradiene structure 1 with unknown relative and absolute
stereochemistry was assigned to this new natural product
(Chart 1). Being a double bond regioisomer of the
germacrane alcohol (+)-hedycaryol (2),5 the name allo-
hedycaryol was proposed for 1.3
cycloaddition,7 allogermacranes are the most likely pre-
cursors of bourbonanes, a small class of sesquiterpenes
possessing the cyclobuta[1,2:3,4]dicyclopentene skeleton
3.8 In contrast to the synthesis of trans,trans-germacrane
sesquiterpenes and their double bond stereoisomers,9
little attention has been paid to the synthesis of the
regioisomeric allogermacranes.10
Because of our interest in biogeneticlike cyclization
reactions of germacranes,11 and because the relative and
absolute stereochemistry of allohedycaryol was unsettled,
we decided to investigate its enantiospecific synthesis
following the strategy outlined in Scheme 1. The key step
in this approach is the conversion of mesylate 4 into
allohedycaryol by means of a Marshall fragmentation
reaction in which both double bonds are regio- and
stereospecifically formed.12 The synthesis of 4 in turn
was planned starting from (+)-R-cyperone (5) via a
Germacrane sesquiterpenes, structurally characterized
by a trans,trans-cyclodeca-1,5-diene ring system, are
widespread in nature and probably act as intermediates
in the biosynthetic pathways towards eudesmanes, gua-
ianes, and other types of sesquiterpenes.6 Allogermac-
ranes, in which a trans,trans-cyclodeca-1,6-diene ring
system is present, are not very abundant in nature and
may play a different role in the biosynthesis of sesquit-
erpenes. Since the trans,trans-cyclodeca-1,6-diene unit
is known to undergo a smooth photochemical [2 + 2]
(7) Heathcock, C. H.; Badger, R. A.; Starkey, R. A. J . Org. Chem.
1972, 37, 231.
(8) (a) Yoshihara, K.; Ohta, Y.; Sakai, T.; Hirose, Y. Tetrahedron
Lett. 1969, 2263. (b) Raldugin, V. A.; Salenko, V. L.; Gamov, N. S.;
Titova, T. F.; Khan, V. A.; Pentegova, V. A. Chem. Nat. Compd. (Engl.
Transl.) 1980, 154.
(9) For example, all stereoisomers of (()-2 have been synthesized,
see: (a) Kodama, M.; Matsuki, Y.; Itoˆ, S. Tetrahedron Lett. 1976, 1121.
(b) Kodama, M.; Yokoo, S.; Yamada, H.; Itoˆ, S. Tetrahedron Lett. 1978,
3121. It is of interest to note that during the synthesis of (()-2 a by-
product was formed to which structure 1 was assigned.9a
(10) (a) Kodama, M.; Shimada, K.; Takahashi, T.; Kabuto, C.; Itoˆ,
S. Tetrahedron Lett. 1981, 22, 4271. (b) Schreiber, S. L.; Hawley, R.
C. Tetrahedron Lett. 1985, 26, 5971.
(11) (a) Piet, D. P.; Minnaard, A. J .; van der Heijden, K. A.;
Franssen, M. C. R.; Wijnberg, J . B. P. A.; de Groot, A. Tetrahedron
1995, 51, 243. (b) Piet, D. P.; Schrijvers, R.; Franssen, M. C. R.; de
Groot, A. Tetrahedron 1995, 51, 6303.
(12) (a) Marshall J . A. Synthesis 1971, 229. The fragmentation has
also been used for the synthesis of (()- and (+)-hedycaryol, see: (b)
Wharton, P. S.; Sundin, C. E.; J ohnson, D. W.; Kluender, H. C. J . Org.
Chem. 1972, 37, 34 and (c) Minnaard, A. J .; Wijnberg, J . B. P. A.; de
Groot, A. Tetrahedron 1994, 50, 4755, respectively.
† Present address: Institute of Bioorganic Chemistry, 220141 Minsk,
Zhodinskaya 5/2, Belarus.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Gunther, R. T. In The Greek Herbal of Dioscorides; University
Press: Oxford, 1934; p 323.
(2) For an extensive review, see: Gonzalez, A. G.; Barrera, J . B.
Prog. Chem. Org. Nat. Prod. 1995, 64, 1.
(3) Valle, M. G.; Appendino, G.; Nano, G. M.; Picci, V. Phytochemistry
1987, 26, 253.
(4) Kreiser, W. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1991; Vol. 8, pp 39-61.
(5) J ones, R. V. H.; Sutherland, M. D. J . Chem. Soc., Chem.
Commun. 1968, 1229.
(6) Banthorpe, D. V. In Natural Products: Their Chemistry and
Biological Significance; Longman Scientific & Technical: Harlow, 1994;
Chapter 5.
S0022-3263(96)00253-8 CCC: $12.00 © 1996 American Chemical Society

Relative and Absolute Configuration of Allohedycaryol
J . Org. Chem., Vol. 61, No. 12, 1996 4023
Sch em e 1
Sch em e 2
Sch em e 3
number of conversions with the introduction of an
equatorial hydroxyl group at C(1)13 as the most challeng-
ing step. An easy access to (+)-R-cyperone was therefore
needed, and a simple procedure for the synthesis of 5
starting from (+)-dihydrocarvone (6) was developed.
Since the absolute and relative stereochemistry of
natural allohedycaryol was unknown, we realized that
the synthetic route depicted in Scheme 1 might lead to
the formation of the enantiomer or, at worst, to the
formation of a diastereomer of allohedycaryol. We have
opted for an equatorial Me group at C(4) and the absolute
stereochemistry around C(7) as present in (+)-hedycaryol
(2). This absolute stereochemistry is normally found in
higher plants (vide infra).
azeotropic imination of 6 and (R)-(+)-1-phenylethylamine
(8), both commercially available, to afford the imine 7
(Scheme 2). The alkylation of 7 was performed in THF
at 40 °C with a slight excess EVK. After hydrolysis of
the imine, the product was dissolved in MeOH and
treated with NaOMe at room temperature to give an
easily separable mixture of 5 and the ketol 9 in a ratio
of ca. 5:1, respectively. Flash chromatography afforded
pure 5 in 47% overall yield from (+)-dihydrocarvone.21
With easy access to 5, we could start with our synthetic
route toward allohedycaryol (Scheme 3). Dehydrogena-
tion of 5 with DDQ in dry dioxane afforded (-)-1,2-
dehydro-R-cyperone (10) in good yield.15c Selective ep-
oxidation of the isopropenyl side chain in 10 produced
11 as a 1:1 mixture of diastereomers. Treatment of 11
with t-BuOK in dry DMSO and quenching of the result-
ing enolate with aqueous NH4Cl gave an unstable de-
conjugated ketone which was directly reduced with
Resu lts a n d Discu ssion
(+)-R-Cyperone (5)14 has been widely used as a starting
material for the synthesis of various other fused-ring
sesquiterpenes.15 Whereas (-)-10-epi-R-cyperone can be
easily synthesized from (+)-dihydrocarvone,16 the syn-
thetic methods leading to 5 are either rather laborious
or give low yields.17 Because relatively large quantities
of 5 were needed for our study, we were looking for a
more efficient method for the preparation of this com-
pound.
Recently, an improved synthesis of homochiral naph-
thalenones was reported.18 The key step in this synthesis
was based on the deracemizing alkylation of chiral imines
derived from racemic cyclanones.19 It was shown that
in the alkylation of imine 7 derived from 6 with methyl
vinyl ketone (MVK) the inherent preference for axial
alkylation15a was largely overruled by the chiral induction
of the imine substituent. We realized that this method
could also be used for a short and efficient synthesis of
(+)-R-cyperone, simply by replacing MVK by ethyl vinyl
ketone (EVK). The synthesis of 520 started with the
22
NaBH4 in the presence of CaCl2 to afford the stable
1
allylic alcohol 12. In the H NMR spectrum of 12, also a
1:1 diastereomeric mixture, the coupling constant be-
tween R H-3 and â H-4 (J 3,4) was found to be 8.8 Hz,
which indicates that the Me group at C(4) and the
hydroxyl group at C(3) possess an equatorial R and â
orientation, respectively.23 Together with the other NMR
data, this observation unequivocally establishes the
identity of 12.
In order to achieve an oxygen function at C(1), some
allylic rearrangement experiments23,24 were performed
with 12, but the results were poor. We therefore focused
our attention on the stereoselective Sharpless epoxidation
of the C(1)-C(2) double bond in 12. It was found in the
literature25 that treatment of a â-allylic alcohol structur-
(13) The numbering system as given in structure 4 will be followed
throughout the text of this paper.
(14) Connolly, J . D.; Hill, R. A. Dictionary of Terpenoids; Chapman
& Hall: London, 1991; Vol. 1, Mono- and Sesquiterpenoids, p 326.
(15) For some representative examples, see: (a) Ho, T.-L. Enanti-
oselective Synthesis, Natural Products from Chiral Terpenes; Wiley
Interscience: New York, 1992; pp 132-135. (b) Li, Y.; Chen, X.; Shao,
S.; Li, T. Synth. Commun. 1993, 23, 2457. (c) Liu, L.; Xiong, Z.; Nan,
F.; Li, T.; Li, Y. Bull. Soc. Chim. Belg. 1995, 104, 73.
(16) Howe, R.; McQuillin, F. J . J . Chem. Soc. 1955, 2423.
(17) (a) Reference 15a, pp 198-200 and 272-273. (b) Haaksma, A.
A.; J ansen, B. J . M.; de Groot, A. Tetrahedron 1992, 48, 3121. (c)
Agami, C.; Kadouri-Puchot, C.; Le Guen, V. Tetrahedron: Asymm.
1993, 4, 641.
(21) The use of (S)-(-)-1-phenylethylamine resulted in a selective
formation of (-)-10-epi-R-cyperone in 67% overall yield from (+)-
dihydrocarvone.
(18) Tenius, B. S. M.; de Oliveira, E. R.; Ferraz, H. M. C. Tetrahe-
dron: Asymm. 1993, 4, 633.
(19) (a) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J . J . Am. Chem.
Soc. 1985, 107, 273. Review: (b) d’Angelo, J .; Desmae¨le, D.; Dumas,
F.; Guingant, A. Tetrahedron: Asymm. 1992, 3, 459.
(20) The well-described procedure was followed: Revial, G.; Pfau,
M. Org. Synth. 1992, 70, 35.
(22) Krieg, R.; Scho¨necker, B. Liebigs Ann. Chem. 1994, 1025.
(23) Ando, M.; Akahane, A.; Takase, K. Bull. Chem. Soc. J pn. 1978,
51, 283.
(24) (a) Narasaka, K. In Stereocontrolled Organic Synthesis; Trost,
B. M., Ed.; Blackwell Science: London, 1994; pp 17-36.

4024 J . Org. Chem., Vol. 61, No. 12, 1996
Zhabinskii et al.
Sch em e 4
Sch em e 5
ally related to 12 with t-BuOOH catalyzed by vanadyl
acetylacetonate (VO(acac)2) resulted in the formation of
the corresponding â cis-epoxy alcohol in reasonable yield.
With 12, however, the t-BuOOH/VO(acac)2 reaction only
showed oxidation to the corresponding enone.26 Appar-
ently, the equatorial â hydroxyl group in 12 is not
properly positioned for assistance in the epoxidation
reaction, and oxidation of the alcohol function will be
preferred.27
Because reduction of the mesylate ester of 12 only gave
elimination products, the removal of the C(3) hydroxyl
group of 12 was performed via reduction of its phospho-
rdiamidate with Li in EtNH2.32 This reaction proceeded
smoothly and was attended with reductive opening of the
epoxide ring in the side chain to provide the diene 16 in
about 60% overall yield from 12 (Scheme 5).
At this stage, we had to introduce an epoxide ring at
the sterically less favored â side of the C(1)-C(2) double
bond. For this purpose, we chose a strategy based on
the trans-diaxial bromohydrin formation.33 Treatment
of 16 with N-bromosuccinimide (NBS) in aqueous dioxane
followed by ring closure with methanolic KOH afforded
the â epoxide 17 as the sole product in 61% yield. As
expected (vide supra), epoxidation of the C(5)-C(6)
double bond did not take place.
Another possibility for introducing a hydroxyl function
at C(1) involves the stereospecific [2,3] sigmatropic
rearrangement of secondary allylic selenoxides.28 To
determine the applicability of the above [2,3] sigmatropic
rearrangement to the 3â-allylic alcohol system in 12, the
epoxide ring in the side chain had to be reduced first29
1
(Scheme 4). In the H NMR spectrum of the resulting
diol 13, J 3,4 was found to be 8.5 Hz which confirmed the
equatorial R orientation of the Me group at C(4).23
Treatment of diol 13 with o-nitrophenyl selenocyanate
in the presence of tri-n-butylphosphine afforded the R
selenide 14 in 91% yield. Oxidation of 14 with H2O2 in
the presence of pyridine at -30 °C proceeded smoothly,
but gave, in addition to the expected rearrangement, also
R epoxidation of the C(5)-C(6) double bond30 to give 15
as the sole product in 86% yield.31
The regioselective opening of the epoxide ring in 17
was the next step. Normally, nucleophilic attack on an
epoxide ring gives rise to diaxial ring opening,34 but in
case of the â epoxide 17 it was found that the diequatorial
ring opening prevailed when sodium phenylselenide was
used as the nucleophile.35 After reductive cleavage of the
Se-C(2) bond with Raney nickel, the resulting â C(1)-
alcohol 18 was treated with MsCl in pyridine to afford
the desired mesylate 4 in 92% overall yield from 17. In
Because none of the above approaches yielded a work-
able result, we were forced to develop an alternative route
for the conversion of 12 into the mesylate 4.
From examination of molecular models, it appeared
that the C(5)-C(6) double bond in 12 is sterically more
shielded than the C(1)-C(2) double bond. It was there-
fore expected that the selective epoxidation of the C(1)-
C(2) double bond without participation of the hydroxyl
group at C(3) would be possible. Based on these consid-
erations, a synthetic pathway was devised in which the
hydroxyl group at C(3) of 12 was removed prior to the
epoxidation of the C(1)-C(2) double bond.
1
the H NMR spectrum of 4 a one-proton double doublet
(J ) 11.0, 5.3 Hz) appears at δ 4.29, which is consistent
with the presence of an equatorial mesylate group at C(1).
Completion of the synthesis of allohedycaryol was
accomplished by successive treatment of 4 with excess
fresh BH3‚THF and NaOMe in MeOH. After purification
by aqueous AgNO3 extraction,36 allohedycaryol was ob-
tained as a colorless oil in 68% yield. The synthetic
material was spectroscopically identical to the natural
product isolated from F. communis.37 However, the
specific rotation obtained for our synthetic product ([R]D
-192°) was opposite to that ([R]D +181°) reported for
(25) Yamakawa, K.; Nishitani, K.; Tominaga, T. Tetrahedron Lett.
1975, 2829.
(26) Recently, a similar result has been found during the t-BuOOH/
VO(acac)2 epoxidation of a steroidal allylic alcohol: Kocovsky, P. J .
Chem. Soc., Perkin Trans. 1 1994, 1759.
(27) In contrast to 12, treatment of its C(3) epimer46 with t-BuOOH/
VO(acac)2 gave selectively the corresponding R epoxide.
(28) Zoretic, P. A.; Chambers, R. J .; Marbury, G. D.; Riebiro, A. A.
J . Org. Chem. 1985, 50, 2981.
(29) It was expected that ring opening of the side-chain epoxide in
12 would occur during the formation of the allylic selenide. For
example, see: Clive, D. L. J . Tetrahedron 1978, 34, 1049.
(30) The epoxidation of olefinic bonds, probably due to the formation
of arylperoxyseleninic acid, is a known problem in the selenoxide
chemistry, see: (a) Grieco, P. A.; Yokoyama, Y.; Gilman, S.; Nishizawa,
M. J . Org. Chem. 1977, 42, 2034. (b) Hori, T.; Sharpless, K. B. J . Org.
Chem. 1978, 43, 1689.
(32) (a) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J . Am.
Chem. Soc. 1972, 94, 5098. (b) Trost, B. M.; Renaut, P. J . Am. Chem.
Soc. 1982, 104, 6668.
(33) Henbest, H. B.; Wilson, R. A. L. J . Chem. Soc. 1959, 4136.
(34) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, 1983; p 165.
(35) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. J . Org. Chem.
1993, 58, 7204.
(36) Southwell, I. A. Phytochemistry 1970, 9, 2243.
(37) We thank Prof. Dr. G. Appendino for supplying copies of the
NMR spectra of natural allohedycaryol.
(31) The observation that the use of pyridine did not prevent the
epoxidation of the C(5)-C(6) double bond suggests an intramolecularly
directed process.28

Relative and Absolute Configuration of Allohedycaryol
J . Org. Chem., Vol. 61, No. 12, 1996 4025
Ch a r t 2
Me group shifted markedly to lower field (∆δ ) 0.56 ppm)
which proves a syn relationship between the 2-propanol
group and the angular Me group. The doublet of the R
C(4) Me group was hardly shifted by varying the con-
centration of the shift reagent. It is of interest to note
that most of the naturally occurring bourbonane sesqui-
terpenes possess the same relative stereochemistry as
found for 19.43
Sch em e 6
Exp er im en ta l Section 44
Ma ter ia ls. All reagents were purchased from Aldrich or
J anssen except for N,N,N′,N′-tetramethylphosphorodiamidic
chloride which was purchased from Fluka. The compounds
5,17b 9,16 and 1017b have been characterized before.
(+)-r-Cyp er on e (5). To a solution of 10.0 g (65.8 mmol) of
(+)-dihydrocarvone (6) in 70 mL of dry toluene was added 9.3
mL (72.2 mmol) of (R)-(+)-1-phenylethylamine (8). The reac-
tion mixture was refluxed under Dean-Stark conditions until
completion (14 h) and concentrated under reduced pressure.
The remaining crude imine 7 was dissolved in 75 mL of dry
THF, and 7.9 mL (79 mmol) of EVK was added. After stirring
in the dark at 40 °C for 3 d, 25 mL of 10% aqueous AcOH was
added. The reaction mixture was vigorously stirred for 1 h
and then poured into 50 mL of brine. After extraction with
five portions of petroleum ether (bp 40-60 °C), the combined
organic layers were washed successively with 0.2 M aqueous
HCl, saturated aqueous NaHCO3, and brine. The solution was
dried and evaporated. The remaining residue was dissolved
in 100 mL of MeOH, and 4 mL of 1 M NaOMe in MeOH was
added dropwise. The reaction mixture was stirred at rt for
30 h, diluted with water, and extracted with EtOAc. The
combined organic layers were washed with brine, dried, and
evaporated. Flash chromatography (50:1 petroleum ether (bp
40-60 °C)/EtOAc) gave, in order of elution, 1.10 g (11%) of 6
and 6.74 g (47%) of 5: [R]D +92.2° (c 2.04) (lit.17b +91.1°). The
spectroscopic data for 5 were identical with those reported in
the literature.17b Further elution (2:1 petroleum ether (bp 40-
60 °C)/EtOAc) gave 1.4 g (9%) of the known ketol 9.16
(-)-1,2-Deh yd r o-r-cyp er on e (10). A mixture of 1.33 g
(6.10 mmol) of 5 and 1.93 g (8.50 mmol) of DDQ in 50 mL of
dry dioxane was refluxed for 24 h. The reaction mixture was
allowed to come to rt and filtered. The filtrate was evaporated
under reduced pressure, and the remaining residue was
purified by column chromatography (5:1 petroleum ether (bp
40-60 °C)/EtOAc) to give 1.01 g (76%) of 10: [R]D -161.5° (c
1.37) (lit.17b -149.0°); mp 50-51 °C (from pentane).45 Anal.
Calcd for C15H20O: C, 83.28; H, 9.32. Found: C, 83.31; H, 9.47.
The spectroscopic data for 10 were identical with those
reported in the literature.17b
(4a S-cis)-5,6,7,8-Tetr a h yd r o-1,4a -d im eth yl-7-(2-m eth y-
loxir a n yl)-2(4a H)-n a p h th a len on e (11). To a stirred solu-
tion of 1.95 g (9.03 mmol) of 10 in 120 mL of a 1:1 mixture of
CH2Cl2 and acetone was added 0.240 g (0.91 mmol) of 18-
crown-6 followed by a solution of 3.6 g (43 mmol) of NaHCO3
in 48 mL of water. The mixture was cooled to 0 °C, and a
solution of 6.6 g (10.7 mmol) of Oxone in 30 mL of water was
added dropwise. The reaction mixture was vigorously stirred
at 0 °C for 3.5 h and then treated with an excess of saturated
aqueous Na2S2O3 and saturated aqueous NaHCO3 for 20 min.
The mixture was extracted with CH2Cl2, and the combined
organic layers were washed with water, dried, and evaporated
to afford 1.98 g (94%) of 11 as a 1:1 diastereomeric mixture:
13C NMR δ 10.52 (q), 18.08 (q), 18.51 (q), 22.75 (t), 23.25 (t),
natural allohedycaryol,3 which meant that we had syn-
thesized the antipode of the natural product as structure
(-)-1 illustrates (Chart 2). Consequently, structure (+)-1
represents the relative and absolute configuration of
natural allohedycaryol. This also means that natural
(+)-1 possesses the ent-configuration,38 which is remark-
able because ent-sesquiterpenes are rarely found in
higher plants.39 In addition, the possibility that (+)-
hedycaryol (2) acts as a direct precursor of (+)-1 can be
ruled out because the ent-form of 2 has not been found
in nature.40
The conformation of allohedycaryol was also investi-
gated. It has been demonstrated41 that a trans,trans-
cyclodeca-1,6-diene ring preferably adopts an “elongated
chair” conformation. This is not surprising because such
a conformation is essentially Pitzer-strain free, and all
the Van der Waals radii are respected.42 Cyclodeca-1,6-
diene ring systems in which one of the double bonds bears
a Me group show the same preference.41b It is most likely
that allohedycaryol also will exist in the elongated chair
conformation all the more so because in this conformation
both the C(4) methyl group and the C(7) 2-propanol group
adopt the pseudoequatorial orientation as the three-
dimensional structure (-)-1 in Scheme 6 indicates. The
preference for one distinct conformation was supported
by the NMR spectra of our synthetic (-)-1. Further
information about the conformation of allohedycaryol was
obtained from the UV spectrum of (-)-1, in which the
absorption maximum at <190 nm shows strong tailing
toward the red (260 nm). This tailing indicates that both
double bonds are lying parallel and close to each other.41b
The rather close proximity of the double bonds in (-)-1
was further proved by irradiation of (-)-1 in MeCN
solution with a low-pressure Hg lamp. This resulted in
a smooth convertion of 1 into 19 in almost quantitative
1
yield. The structure of 19 was established with H NMR
spectroscopy using Eu(fod)3 as a shift reagent. With
increasing concentration of the shift reagent, the angular
(38) The conventions proposed for describing germacrane sesquit-
erpenes are followed: Rogers, D.; Moss, G. P.; Neidle, S. J . Chem. Soc.,
Chem. Commun. 1972, 142.
(39) Prof. Dr. G. Appendino attended us to an article in which the
isolation of R-ferulene, another ent-sesquiterpene from F. communis,
has been reported: Carboni, S.; Da Settimo, A.; Malaguzzi, V.; Marsili,
A; Pacini, P. L. Tetrahedron Lett. 1965, 3017.
(43) Reference 14, p 636.
(40) In the Chemical Abstracts, the S-configuration is erroneously
assigned to (+)-hedycaryol (2) probably because a corrigendum of
reference 5 has been overlooked: J . Chem. Soc., Chem. Commun. 1970,
892. Recently, the R-configuration of natural (+)-2 has been ascer-
tained through its synthesis starting from (-)-guaiol of known absolute
configuration.12c
(41) (a) White, D. N. J .; Bovill, M. J . Tetrahedron Lett. 1975, 27,
2239. (b) Neykov, G. D.; Ivanov, P. M.; Orahovats, A. S. J . Mol. Struct.
1987, 153, 147.
(44) For a general description of the experimental procedures
employed in this research, see: Kesselmans, R. P. W.; Wijnberg, J . B.
P. A.; Minnaard, A. J .; Walinga, R. E.; de Groot, A. J . Org. Chem. 1991,
56, 7237. NMR spectra were recorded at 200 MHz (1H) and at 50 MHz
(
13C) in CDCl3. The 1H NMR experiments using Eu(fod)3 as a shift
reagent were performed at 400 MHz. Optical rotations were measured
in CHCl3 solutions. Column chromatography was performed using
Merck silica gel 60 (70-230 mesh). Product solutions were dried over
MgSO4, unless otherwise reported.
(42) Dale, J .; Moussebois, C. J . Chem. Soc. (C) 1966, 264.
(45) Previously, compound 10 was reported as an oil.15c,17b

4026 J . Org. Chem., Vol. 61, No. 12, 1996
Zhabinskii et al.
23.45 (d), 29.36 (t), 29.78 (t), 37.30 (d), 40.15 (s), 45.07 (d), 45.37
(d), 53.11 (t), 53.44 (t), 58.74 (s), 126.16 (d), 129.48 (s), 156.32
(d), 156.37 (d), 158.56 (s), 186.26 (s). The H NMR and mass
(q), 26.36 (q), 28.08 (q), 35.20 (d), 35.90 (q), 36.90 (s), 47.25
(d), 49.20 (d), 72.93 (s), 120.02 (d), 124.75 (d), 125.50 (d), 126.01
(d), 130.81 (d), 133.07 (d), 133.42 (s), 139.15 (d), 143.49 (s),
147.94 (s); MS m/ z (relative intensity) 421 (M+, 1), 219 (7),
201 (9), 161 (100), 159 (10), 145 (21), 119 (17), 105 (16), 69
(19), 59 (45); HRMS calcd for C21H27NO3Se (M+) 421.1156,
found 421.1157. To a solution of 390 mg (0.926 mmol) of 14
and 0.3 mL of pyridine in 25 mL of THF was added dropwise
2.4 mL (25 mmol) of 35% H2O2 at -30 °C. The reaction
mixture was stirred at -30 °C for 1 h and then allowed to
come to rt. After addition of water, the reaction mixture was
extracted with EtOAc. The combined organic layers were
washed with saturated aqueous NaHCO3 and water, dried over
Na2SO4, and evaporated. The remaining residue was purified
by column chromatography (2:1 to 1:2 petroleum ether (bp 40-
60 °C)/EtOAc) to afford 202 mg (86%) of 15: [R]D ) +9.4° (c
2.06); 1H NMR δ 0.83 (d, J ) 7.2 Hz, 3 H), 1.02 (m, 1 H), 1.08
(s, 3 H), 1.19 (s, 3 H), 1.24 (m, 1 H), 1.26 (s, 3 H), 1.81-2.23
(m, 4 H), 2.68 (br q, J ) 7.2 Hz, 1 H), 3.18 (s, 1 H), 3.54 (br s,
1 H), 5.53 (dd, J ) 10.0, 2.0 Hz, 1 H), 5.90 (ddd, J ) 10.0, 5.1,
2.8 Hz, 1 H); 13C NMR δ 12.83 (q), 18.86 (t), 20.97 (q), 25.28
(q), 27.46 (t), 28.81 (q), 30.75 (d), 36.76 (s), 45.49 (d), 53.66
(d), 63.92 (s), 72.26 (s), 73.33 (d), 127.55 (d), 133.18 (d); MS
m/ z (relative intensity) 252 (M+, 10), 219 (45), 193 (64), 123
(67), 122 (43), 110 (46), 107 (45), 95 (49), 59 (100), 43 (54);
HRMS calcd for C15H24O3 (M+) 252.1725, found 252.1725.
[2R -(2r,4a r,8â)]-2,3,4,4a ,7,8-H e x a h y d r o -r,r,4a ,8-
tetr a m eth yl-2-n a p h th a len em eth a n ol (16). To a stirred
solution of 8.77 g (37.5 mmol) of 12 in a mixture of 40 mL of
dry THF and 10 mL of N,N,N′,N′-tetramethylethylenediamine
(TMEDA) was added dropwise 20 mL of BuLi (2.5 M in
hexane) at -78 °C. The reaction mixture was stirred at -78
°C for 15 min, and then 7.5 mL (52 mmol) of N,N,N′,N′-
tetramethylphosphorodiamidic chloride was added. After stir-
ring at -78 °C for 5 min, the cooling bath was removed and
the reaction mixture was allowed to come to rt and stirred for
an additional 1 h. The reaction mixture was then added, via
syringe, to a solution of 3.0 g (428 mmol) of Li in 200 mL of
EtNH2 at 0 °C. After stirring at 0 °C for 1 h, 100 mL of
saturated aqueous NH4Cl was added and EtNH2 was allowed
to evaporate by standing at rt overnight. Addition of water
to the remaining layer was followed by extraction with EtOAc.
After drying and evaporation of the combined organic layers,
column chromatography (4:1 petroleum ether (bp 40-60 °C)/
EtOAc) afforded 5.60 g (68%) of 16 (GC purity >85%):47 1H
NMR δ 1.06 (d, J ) 6.6 Hz, 3H), 1.10 (s, 3H), 1.16 (s, 3H),
1.22 (s, 3H), 1.38-1.74 (m, 6 H), 2.10-2.24 (m, 2 H), 2.42 (m,
1 H), 5.31 (dd, J ) 10.0, 2.3 Hz, 1 H), 5.37 (br s, 1 H), 5.50
(ddd, J ) 10.0, 5.2, 2.3 Hz, 1 H); 13C NMR δ 17.70 (q), 20.29
(t), 25.85 (q), 27.27 (q), 27.98 (q), 30.88 (d), 36.43 (s), 36.74 (t),
37.14 (t), 47.71 (d), 73.07 (s), 116.11 (d), 123.33 (d), 137.72 (d),
148.47 (s); MS m/ z (relative intensity) 205 (M+ - 15, 2), 162
(66), 161 (9), 147 (100), 133 (14), 119 (11), 105 (17), 91 (12), 81
(12), 59 (51); HRMS calcd for C14H21O (M+ - 15) 205.1592,
found 205.1593.
1
spectral data for 11 corresponded with those reported in the
literature.15c
[1R-(1r,2â,4aâ,7â)-1,2,4a,5,6,7-Hexah ydr o-1,4a-dim eth yl-
7-(2-m eth yloxir a n yl)-2-n a p h th a len ol (12). To a stirred
solution of 1.98 g (8.53 mmol) of 11 in 50 mL of dry DMSO
was added 3.0 g (24.6 mmol) of t-BuOK. The reaction mixture
was stirred at rt for 45 min and then poured into ice-water
containing 5.0 g of NH4Cl. The mixture was extracted with
CH2Cl2, and the combined organic layers were washed with
water, dried over Na2SO4, and evaporated. The so-obtained
crude deconjugated ketone was used directly for next step
reaction. A solution of 1.94 g (17.5 mmol) of anhydrous CaCl2
in 40 mL of dry EtOH was added dropwise to a stirred solution
of 1.1 g (29.1 mmol) of NaBH4 in 40 mL of dry EtOH at -25
°C. The solution was stirred at this temperature for 30 min,
and then a solution of the crude deconjugated ketone in a
mixture of 20 mL of dry EtOH and 10 mL of dry THF was
added. After stirring at -25 °C for an additional 1.5 h, the
reaction mixture was treated with 10 mL of acetone and
allowed to come to rt. The solution was concentrated under
reduced pressure, diluted with water, and then treated with
AcOH until a clear solution was formed. After extraction with
CH2Cl2, the combined organic layers were washed with water,
dried, and evaporated. The residue was purified by flash
chromatography (5:1 petroleum ether (bp 40-60 °C)/EtOAc)
to afford 1.35 g (67%) of 12 as a 1:1 diastereomeric mixture:46
1H NMR (major peaks) δ 2.54-2.61 (m, 2 H), 3.60 (d, J ) 8.8
Hz, 1 H), 5.25, 5.46 (br s, br s, 1:1 ratio, 1 H), 5.43 (br d, J )
10.0 Hz, 1 H), 5.50 (br d, J ) 10.0 Hz, 1 H); 13C NMR δ 13.78
(q), 17.32 (q), 18.53 (q), 20.85 (t), 20.96 (t), 26.61 (q), 35.81 (t),
35.88 (t), 36.31 (s), 39.82 (d), 42.21 (d), 43.91 (d), 52.47 (t), 53.26
(t), 59.50 (s), 59.55 (s), 60.35 (t), 75.60 (d), 118.14 (d), 119.05
(d), 127.97 (d), 128.06 (d), 138.01 (d), 144.85 (s), 145.01 (s);
MS m/ z (relative intensity) 234 (M+, 36), 201 (90), 177 (62),
159 (98), 143 (100), 131 (70), 119 (86), 105 (83), 91 (73), 43
(69); HRMS calcd for C15H22O2 (M+) 234.1620, found 234.1619.
[1S-(2r,4a r,7r,8â)]-2,3,4,4a ,7,8-Hexa h yd r o-7-h yd r oxy-
r,r,4a,8-tetr am eth yl-2-n aph th alen em eth an ol (13). A mix-
ture of 1.30 g (5.56 mmol) of 12 and 0.60 g (15.8 mmol) of LAH
in 25 mL of dry THF was stirred at rt for 1 h. The excess
LAH was destroyed by careful addition of 2 mL of water at 0
°C. After addition of 5.0 g of MgSO4, the mixture was stirred
at rt for 5 min and then filtered. The filtrate was evaporated
1
to give 1.20 g (91%) of 13: [R]D ) -43.1° (c 0.07); H NMR δ
1.07 (s, 3 H), 1.10 (s, 3 H), 1.13 (d, J ) 6.5 Hz, 3 H), 1.16 (s, 3
H), 1.29-1.72 (m, 6 H), 2.08 (m, 1 H), 2.24 (m, 1 H), 3.64 (dd,
J ) 8.5, 4.8 Hz, 1 H), 5.35-5.47 (m, 3 H); 13C NMR δ 13.87
(q), 20.16 (t), 25.75 (q), 26.52 (q), 28.02 (q), 36.30 (t), 36.30 (s),
40.13 (d), 47.58 (d), 73.05 (s), 75.95 (d), 119.15 (d), 127.67 (d),
138.74 (d), 144.93 (s); MS m/ z (relative intensity) 178 (M+
-
58, 41), 163 (18), 160 (39), 149 (13), 145 (100), 135 (12), 121
(10), 105 (10), 91 (8), 59 (41); HRMS calcd for C14H21O2 (M+
15) 221.1542, found 221.1545.
-
[1aR-(1ar,3â,5r,7ar)]-1a,2,3,5,6,7,7a,7b-Octah ydr o-r,r,3,-
7a -tetr a m eth yl-5-n a p h th [1,2-b]oxir en em eth a n ol (17). To
a stirred solution of 5.43 g (24.7 mmol) of 16 in a mixture of
200 mL of dioxane and 40 mL of water was added dropwise a
solution of 5.21 g (29.3 mmol) of NBS in 50 mL of dioxane at
0 °C. The reaction mixture was stirred at 5-10 °C for 30 min,
and then 8.0 g (143 mmol) of KOH in 50 mL of MeOH was
added. After stirring at rt for another 1 h, the reaction mixture
was diluted with EtOAc, washed with water, dried, and
evaporated. Flash chromatography of the remaining residue
(9:1 to 3:1 petroleum ether (bp 40-60 °C)/EtOAc) gave 3.55 g
(61%) of 17 as white crystals: mp 148-149 °C (from EtOH);
[1a S-(1a r,2â,4a â,5r,8a rR*)]-1a ,2,4,4a ,5,8-Hexa h yd r o-5-
h yd r oxy-r,r,4a ,8-tetr a m eth yl-3H-n a p h th [1,8a -b]oxir en e-
2-m eth a n ol (15). To a solution of 236 mg (1.0 mmol) of 13
and 342 mg (1.5 mmol) of o-nitrophenyl selenocyanate in 10
mL of dry THF was added 0.40 mL (1.61 mmol) of tri-n-
butylphosphine. The mixture was allowed to stand at rt for
20 h and then concentrated at reduced pressure. The concen-
trate was purified by column chromatography (20:1 to 5:1
petroleum ether (bp 40-60 °C)/EtOAc) to give 397 mg (91%)
1
of R selenide 14: [R]D ) -409° (c 0.30); H NMR δ 1.10 (s, 3
H), 1.14 (s, 3 H), 1.18 (d, J ) 6.8 Hz, 3 H), 1.21 (s, 3 H), 1.25-
1.75 (m, 5 H), 2.24 (m, 1 H), 2.92 (m, 1 H), 4.03 (dd, J ) 5.3,
4.3 Hz, 1 H), 5.43 (d, J ) 9.5 Hz, 1 H), 5.49 (br s, 1 H), 5.87
(dd, J ) 9.5, 5.5 Hz, 1 H), 7.24 (dt J ) 8.1, 1.3 Hz, 1 H), 7.45
(dt, J ) 8.2, 1.5 Hz, 1 H), 7.67 (dd, J ) 8.1, 1.1 Hz, 1 H), 8.12
(dd, J ) 8.2, 1.5 Hz, 1 H); 13C NMR δ 16.71 (q), 20.01 (t), 25.63
1
[R]D ) -99.8° (c 0.46); H NMR δ 0.96 (d, J ) 6.6 Hz, 3 H),
1.10 (s, 3 H), 1.15 (s, 3 H), 1.19 (s, 3 H), 1.24-1.39 (m, 2 H),
1.49-1.77 (m, 4 H), 2.08-2.36 (m, 3 H), 2.75 (d, J ) 3.8 Hz, 1
H), 3.22 (br d, J ) 3.8 Hz, 1 H), 5.27 (br s, 1 H); 13C NMR δ
17.23 (q), 20.20 (t), 22.63 (q), 25.71 (q), 26.77 (d), 27.87 (q),
33.64 (s), 35.33 (t), 36.43 (t), 47.25 (d), 54.20 (d), 61.34 (d), 72.90
(46) This reaction also gave a small amount (ca. 5%) of the C(3)
epimer of 12 [1H NMR (main peaks) δ 2.49-2.61 (m, 2 H), 3.82 (dd, J
) 5.1, 3.6 Hz, 1 H), 5.22-5.52 (m, 2 H), 5.72 (m, 1 H)].
(47) In a smaller scale experiment using freshly distilled TMEDA,
the yield of 16 was 82%. The same reduction procedure applied on the
C(3) epimer of 1246 yielded 16 in 95%.

Relative and Absolute Configuration of Allohedycaryol
J . Org. Chem., Vol. 61, No. 12, 1996 4027
(s), 116.30 (d), 146.96 (s); MS m/ z (relative intensity) 218 (M+
- 18, 25), 178 (100), 163 (70), 145 (54), 134 (49), 121 (81), 119
16 mL of NaOMe (2 M in MeOH). The reaction mixture was
allowed to come to rt and stirred overnight. After addition of
20 mL of saturated aqueous NH4Cl and 10 mL of 25%
ammonia to the cooled reaction mixture, petroleum ether (bp
40-60 °C), was added. Stirring was continued for an ad-
ditional 30 min after which the two-phase mixture was
separated. The aqueous layer was extracted with petroleum
ether (bp 40-60 °C) and the combined organic layers were
(45), 105 (48), 93 (30), 59 (88); HRMS calcd for C15H22O (M+
18) 218.1671, found 218.1669.
-
[2R-(2r,4ar,5r,8â)]-2,3,4,4a,5,6,7,8-Octah ydr o-5-h ydr oxy-
r,r,4a ,8-tetr a m eth yl-2-n a p h th a len em eth a n ol (18). To an
ethanolic solution of NaOEt, prepared from 75 mg (3.26 mmol)
of Na and 20 mL of dry EtOH, were successively added 500
mg (3.18 mmol) of benzeneselenol and 318 mg (1.35 mmol) of
17. The reaction mixture was refluxed for 7 h, allowed to come
to rt, and then treated with 5.0 g of Raney nickel for 1 h. After
filtration of the solid material, the filtrate was concentrated
under reduced pressure, dissolved in CHCl3, and washed with
water. The organic layer was dried over Na2SO4 and evapo-
rated. Flash chromatography (5:1 to 2:1 petroleum ether (bp
40-60 °C)/EtOAc) afforded 300 mg (93%) of 18: [R]D ) -71.7°
(c 0.06); 1H NMR δ 0.97 (d, J ) 6.8 Hz, 3 H), 0.99 (s, 3 H),
1.11 (s, 3 H), 1.18 (s, 3 H), 1.22-1.40 (m, 2 H), 1.50-2.20 (m,
10 H), 3.21 (dd, J ) 11.0, 4.6 Hz, 1 H), 5.41 (br s, 1 H); 13C
NMR δ 17.80 (q), 18.43 (q), 20.33 (t), 25.66 (q), 27.87 (q), 30.45
(t), 32.30 (d), 33.27 (t), 36.64 (t), 40.27 (s), 47.74 (d), 72.96 (s),
80.14 (d), 119.57 (d), 147.16 (s); MS m/ z (relative intensity)
223 (M+ - 15, 1), 180 (31) 162 (100), 147 (48), 133 (14), 123
(35), 105 (23), 91 (15), 81 (13), 59 (51); HRMS calcd for
C14H23O2 (M+ - 15) 223.1698, found 223.1697.
[2R-(2r,4a r,5r,8â)]-2,3,4,4a ,5,6,7,8-Octa h yd r o-5-[(m eth -
ylsu lfon yl)oxy]-r,r,4a,8-tetr am eth yl-2-n aph th alen em eth -
a n ol (4). To a stirred solution of 298 mg (1.25 mmol) of 18 in
6 mL of pyridine was added a solution of 300 mg (2.63 mmol)
of MsCl in 3 mL of pyridine at 0 °C. After stirring at 0 °C for
1 h, saturated aqueous NaHCO3 was added dropwise. The
reaction mixture was stirred for an additional 5 min and then
extracted with CH2Cl2. The combined organic layers were
washed with water, dried over Na2SO4, and evaporated. After
removal of the residual pyridine by azeotropic distillation with
toluene, 392 mg (99%) of 4 was obtained: [R]D -25.2° (c 0.47);
1H NMR δ 0.99 (d, J ) 6.4 Hz, 3 H), 1.08 (s, 3 H), 1.10 (s, 3
H), 1.18 (s, 3 H), 1.25-2.30 (m, 11 H), 2.98 (s, 3 H), 4.29 (dd,
J ) 11.0, 5.3 Hz, 1 H), 5.51 (br s, 1 H); 13C NMR δ 18.15 (q),
18.86 (q), 20.08 (t), 25.54 (q), 27.97 (q), 28.75 (t), 32.01 (d),
32.75 (t), 36.64 (t), 38.82 (q), 39.83 (s), 47.64 (d), 72.74 (s), 90.88
(d), 121.53 (d), 145.06 (s); MS m/ z (relative intensity) 258 (M+
- 58, 2), 204 (7), 162 (100), 147 (40), 133 (11), 120 (11), 119
(11), 105 (18), 91 (12), 59 (28); HRMS calcd for C15H25O4S (M+
- 15) 301.1474, found 301.1472.
dried over Na
2SO4 and evaporated. The remaining residue
was dissolved in a mixture of 15 mL of hexane and 5 mL of
tert-butyl methyl ether and extracted with 20% aqueous
AgNO3. The combined aqueous layers were washed with tert-
butyl methyl ether and then cooled to 0 °C. After addition of
25% ammonia, the aqueous layer was extracted with tert-butyl
methyl ether. The combined organic layers were washed with
brine and dried over Na2SO4. Evaporation gave 185 mg (68%)
of pure 1: [R]D ) -192° (c 0.92) (lit.3 +181°); UV (CH3CN)
λmax <190 nm, tail to 260 nm. The NMR and mass spectral
data for (-)-1 corresponded with those reported for natural
(+)-1.3
[1R -(1r,3a r,3b â,6â,6a â,6b r)]-Deca h yd r o-r,r,3a ,6-t et -
r a m et h yl-1-cyclob u t a [1,2:3,4]d icyclop en t en em et h a n ol
(19). A solution of 26 mg (0.12 mmol) of (-)-1 in 4 mL of
MeCN placed in a sealed quartz cuvet was irradiated for 14 h
using a CAMAG Universal UV-lamp 29230. The reaction
progress was monitored by GC. After completion, the solvent
was evaporated under reduced pressure to give 25 mg (96%)
of 19 (GC purity >98%): [R]D ) -1.3° (c 0.95); 1H NMR δ 0.75
(d, J ) 7.2 Hz, 3 H), 0.86 (s, 3 H), 1.13 (s, 6 H), 1.24 (br s,
OH), 1.39-1.66 (m, 7 H), 1.73-1.96 (m, 5 H), 2.28 (ddd, J )
6.3, 6.3, 2.8 Hz, 1 H); 13C NMR δ 20.28 (q), 20.57 (q), 24.55 (t),
28.27 (q), 28.48 (q), 28.84 (t), 33.31 (t), 38.57 (d), 43.19 (s,t),
44.84 (d), 50.39 (d), 51.70 (d), 61.93 (d), 71.81 (s); MS m/ z
(relative intensity) 222 (M+, 1), 161 (8), 149 (13), 140 (8), 122
(11), 107 (14), 95 (8), 82 (100), 67 (18), 59 (40); HRMS calcd
for C15H26O (M+) 222.1984, found 222.1983.
Ack n ow led gm en t. We thank A. van Veldhuizen for
recording 1H and 13C NMR spectra and H. J ongejan for
mass spectral data and elemental analyses.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 4 and 12-19 (9 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(-)-Alloh ed yca r yol (1). To a stirred solution of 385 mg
(1.22 mmol) of 4 in 5 mL of dry THF was added 8 mL of 1 M
BH3‚THF at 0 °C. The reaction mixture was stirred at 0 °C
for 2 h and additionally at rt for 2 h. After cooling to 0 °C, 1.5
mL of MeOH was added dropwise, immediately followed by
J O9602534