Enantioselective synthesis of a fluorinated analogue of the orsellinic acid-type twelve-membered lactone lasiodiplodin

Article abstract of DOI:10.1021/jo0012445

The chemoenzymatic synthesis of the racemate and the one enantiomer of the fluorinated analogue 8 of the natural cyclooxygenase inhibitor lasiodiplodin is decribed. A lipase-mediated deracemization of the fluorohydrin 18 provided the chiral, nonracemic building block for the enantioselective synthesis of the title compound. The key step was the formation of the 12-membered lactene by a ring-closing metathesis.

Full text of DOI:10.1021/jo0012445

J . Org. Chem. 2000, 65, 8737-8742
8737
En a n tioselective Syn th esis of a F lu or in a ted An a logu e of th e
Or sellin ic Acid -Typ e Tw elve-Mem ber ed La cton e La siod ip lod in
Martina Runge and Gu¨nter Haufe*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t Mu¨nster, Corrensstr. 40,
D-48149 Mu¨nster, Germany
haufe@uni-muenster.de
Received August 15, 2000
The chemoenzymatic synthesis of the racemate and the one enantiomer of the fluorinated analogue
8 of the natural cyclooxygenase inhibitor lasiodiplodin is decribed. A lipase-mediated deracemization
of the fluorohydrin 18 provided the chiral, nonracemic building block for the enantioselective
synthesis of the title compound. The key step was the formation of the 12-membered lactone by a
ring-closing metathesis.
In tr od u ction
anhydrides and high dilution resulted in the fluoro-
methyl-substituted macrolides.
The development of methods1 to synthesize particularly
optically active new fluorinated organic compounds2 has
advanced progress in biochemistry and medicine during
the past decades.3a By exchanging hydrogen for fluorine,
the chemical and biological behavior of modified natural
compounds can be changed dramatically. The sterically
nondemanding fluorine atom does not significantly change
the geometry of a molecule, but has a strong influence
on the electron density of neighboring groups and results
in a lower polarizability.3
Monofluorinated lactones with medium to large ring-
size can easily be synthesized by two general synthetic
pathways. In a convenient two-step procedure by bro-
mofluorination of terminal unsaturated fatty acids 1a
with NBS/Et3N‚3HF bromofluorides bearing a secondary
fluoride have been formed which were subsequently
cyclized under basic conditions.4 Fluoromethyl substi-
tuted macrolides on the other hand have been synthe-
sized in a five-step sequence starting with the unsatur-
ated fatty acids 1a .4b,5 The key step was the regioselective
opening6 of the epoxides derived from unsaturated fatty
acid esters 1b, resulting in the formation of fluorohydrins
5 bearing a primary fluorine substituent. After hydroly-
sis, final cyclization using Yamaguchi’s method7 of mixed
This methodology has already been applied success-
fully to the synthesis of both enantiomers of fluoro-
phoracantholide I, namely (9S)-10-fluorodecan-9-olide
and its (9R)-enantiomer, which are fluorinated analogues
of the metasternal gland secretion of the eucalypt lon-
gicorn (Phoracantha synonyma).8 This synthesis was
based on a lipase-catalyzed resolution by way of the
acetylation of 10-fluoro-9-hydroxydecanoate.5,9
This paper reports the synthesis of a monofluorinated
analogue of the 12-membered orsellinic acid type lactone
lasiodiplodin 7a , a constituent of the fungus Lasiodiplo-
dia theobromae10a and of the wood of Euphorbia splen-
dens10b and Euphorbia fidjiana.10c Its de-O-methyl de-
rivative 7b is also a secondary metabolite of Arnebia
euchroma, a plant used in traditional Chinese medicine.10d
* To whom correspondence should be addressed. Phone: 49-251-
83-33281. Fax: 49-251-83-39772.
(1) (a) Synthetic Fluorine Chemistry; Olah, G. A.; Chambers, R. D.;
Prakash, G. S., Eds., J ohn Wiley & Sons: New York, 1992. (b)
Chemistry of Organofluorine Compounds II; Hudlicky, M.; Pavlat, Eds.,
American Chemical Society: Washington, 1995.
(2) (a) Enantiocontrolled Synthesis of Fluoro-organic Compounds.
Stereochemical Challenges and Biomedical Targets; Soloshonok, V. A.,
Ed., J ohn Wiley & Sons: Chichester, 1999. (b) Asymmetric Fluoroor-
ganic Chemistry. Synthesis, Applications, and Future Directions;
Ramachandran, P. V., Ed., ACS Symposium Series 746, American
Chemical Society: Washington, 2000.
(3) (a) Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Studies in Organic Chemistry, Vol. 48, Filler,
R.; Kobayashi, Y.; Yagupolskii, L. M., Eds., Elsevier: Amsterdam 1993.
(b) Welch, J . T.; Ewarakrishnan, S. Fluorine in Bioorganic Chemistry;
Wiley & Sons: New York, 1991.
(4) (a) Sattler, A.; Haufe, G. Tetrahedron 1996, 52, 5469-5474. (b)
Runge, M.; O’Hagan, D.; Haufe, G. J . Polym. Sci. A, Polym. Chem.
2000, 38, 2004-2012.
(5) Sattler, A.; Haufe, G. Liebigs Ann. Chem. 1994, 921-925.
(6) Sattler, A.; Haufe, G. J . Fluorine Chem. 1994, 69, 185-190.
(7) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(8) (a) Moore, B. P.; Brown, W. V. Austr. J . Chem. 1976, 29, 1365-
1374. (b) Kitahara, T.; Koseki, K.; Mori, K. Agric. Biol. Chem. 1987,
51, 3417-3421.
(9) (a) Sattler, A.; Haufe, G. Tetrahedron: Asymmetry 1995, 6,
2841-2848. (b) Sattler, A.; Haufe, G. In Preparative Biotransforma-
tions; Roberts, S. M.; Wiggins, K.; Casy, G. Eds.; J ohn Wiley & Sons:
Chichester, 1997; pp 1:10.70-1:10.76.
10.1021/jo0012445 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/14/2000

8738 J . Org. Chem., Vol. 65, No. 25, 2000
Runge and Haufe
Sch em e 1a
a
Reagents and conditions: (a) 1. Mg, Et2O, 2. Extraction with
Et2O [58%]; (b) 1,5-dibromopentane, Li2CuCl4 (cat.), THF, -20 °C,
2.5 h, [50 %]; (c) m-CPBA, CH2Cl2, 0 °C f rt, 19 h, [85 %].
Both naturally occurring lactones were found to be
efficient inhibitors of prostaglandin biosynthesis and both
exhibit significant antileukemic activity.10b,10d Thus, sev-
eral total syntheses of these compounds have been
published.11
Resu lts a n d Discu ssion
According to our experience in the synthesis of mono-
fluorinated macrolides, we intended to construct the title
compound 8 analogously to the fluoro-phoracantholides.5,9
Retrosynthetic analysis of 8 led to the benzoic ester 9
bearing a 9-fluoro-8-hydroxynonane as a side-chain in the
ortho-position. This compound should be available by
regioselective hydrofluorination of the oxirane formed by
alkylation of the methyl group of benzoic acid 11 with
the bromide 12.
The starting material 11 (R ) H) was obtained from
orcinol in a three-step reaction pathway according to
reference11e while 8-bromoct-1-ene oxide (12) was syn-
thesized analogously to known procedures12 in three steps
from allyl chloride and 1,5-dibromopentane via 13 (Scheme
1).
Alkylation of benzoic acid 11 with the bromide 12 gave
10a which had to be protected as the methyl ester prior
to the hydrofluorination of the oxirane ring. There are
many different methods for the synthesis of fluorohydrins
from epoxides.13 To obtain selectively the regioisomer 9
in a high yield, we employed potassium hydrogen difluo-
ride (KHF2) and 18-crown-6 in DMF under refluxing
conditions according to the method applied for other
epoxides.6,14 A 90:10 mixture of regioisomers was formed
from which 9 was isolated by column chromatography
(Scheme 2).
For the final cyclization, the methyl ester 9 had to be
first hydrolyzed. However, all attempts to hydrolyze o,o′-
disubstituted benzoic esters 9 (R ) Me, t-Bu, CHPh2)
under various conditions, including enzymatic hydrolysis
by Candida rugosa lipase or porcine pancreatic lipase,
failed. Using mildly basic conditions, only the methyl
ester 9 (R ) Me) was reisolated, while under forcing
conditions (60 °C), the fluorohydrin moiety was not stable
and gave partially the epoxide, besides other products.
The hydrolysis with sulfuric acid of the methyl ester or
with trifluorocetic acid of the tert-butyl ester (9, R ) t-Bu)
resulted in partial defluorination without hydrolysis of
the ester function. Under the conditions of benzhydryl
ester synthesis the side chain was cleaved partially, and
a mixture of compounds was formed.
Consequently, we planned an alternative synthetic
strategy for “fluoro-lasiodiplodin” 8 which was based on
ring-closing metathesis as the key step to form the
macrocyclic ring. Since this methodology is evolving into
a mature preparative method, it was applied to several
(10) (a) Aldridge, D. C.; Galt, S.; Giles, D.; Turner, W. B. J . Chem.
Soc. C 1971, 1623-1627. (b) Lee, K. H.; Hayashi, N.; Okano, M.; Hall,
I.; Wu, R. Y. Phytochemistry 1982, 21, 1119-1121. (c) Cambie, R.; Lat,
A.; Rutledge, P.; Woodgate, P. Phytochemistry 1991, 30, 287-292. (d)
Xin-Sheng, Y.; Ebizuka, Y.; Noguchi, H.; Kiuchi, F.; Itaka, Y.; Sankawa,
U.; Seto, H. Tetrahedron Lett. 1983, 24, 2407-2410.
(11) (a) Gerlach, H.; Thalmann, A. Helv. Chim. Acta 1977, 60, 2866-
2871. (b) Takahashi, T.; Kasuga, K.; Tsuji, J . Tetrahedron Lett. 1978,
4917-4920. (c) Danishefsky, S. J .; Etheredge, S. J . J . Org. Chem. 1979,
44, 4716-4717. (d) Fink, M.; Gaier, H.; Gerlach, H. Helv. Chim. Acta
1982, 65, 2563-2569. (e) Braun, M.; Mahler, U.; Houben, S. Liebigs
Ann. Chem. 1990, 513-517. (f) Solladie´, G.; Rubio, A.; Carreno, M. C.;
Garcia Ruano, J . L. Tetrahedron: Asymmetry 1990, 1, 187-198. (g)
J ones, G. B.; Huber, R. S. Synlett 1993, 367-368. (h) Bracher, F.;
Schulte, B. J . Chem. Soc., Perkin Trans. 1 1996, 2619-2622. (i)
Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005-7008. (j)
J ones, G. B.; Huber, R. S.; Capman, B. J . Tetrahedron: Asymmetry
1997, 8, 1797-1809. (k) Fu¨rstner, A.; Seidel, G.; Kindler. Tetrahedron
1999, 52, 8215-8230.
(13) (a) Yoneda, N. Tetrahedron 1991, 47, 5329-5365. (b) Olah, G.
A.; Li, X.-Y. In Synthetic Fluorine Chemistry; Olah, G. A.; Chambers,
R. D.; Prakash, G. K. S., Eds., Wiley: New York, 1992; pp 163-204.
(c) References until 1990 were reviewed: Bo¨hm, S., in Houben-Weyl,
Methods of Organic Chemistry, 4th ed., Vol E10b1, Baasner, B.;
Hagemann, H.; Tatlow, J . C., Eds., Thieme-Verlag: Stuttgart, 1999;
pp 137-158. (d) Miethchen, R.; Peters, D., in Houben-Weyl, Methods
of Organic Chemistry, 4th ed., Vol E10a, Baasner, B.; Hagemann, H.;
Tatlow, J . C., Eds., Thieme-Verlag: Stuttgart, 1999; pp 95-158.
(14) ) (a) Landini, D.; Molinari, H.; Penso, M.; Rampoldi, A. Synthesis
1988, 953-955. (b) Landini, D.; Albanese, D.; Penso, M. Tetrahedron
1992, 48, 4163-4170. (c) Tamura, M.; Shibakami, M.; Sekiya, A. J .
Fluorine Chem. 1997, 85, 147-149. (d) Barbier, P.; Mohr, P.; Muller,
M.; Masciadri, R. J . Org. Chem. 1998, 63, 6984-6989.
(12) (a) Van Campen, M. G.; Meisner, D. F.; Parmerter, S. M. J .
Am. Chem. Soc. 1948, 70, 2296-2297. (b) J ohnson, D. K.; Donohoe,
J .; Kang, J . Synth. Commun. 1994, 24, 1557-1564.

Synthesis of Lasiodiplodin Analogue
J . Org. Chem., Vol. 65, No. 25, 2000 8739
Sch em e 2a
Sch em e 3a
a
Reagents and conditions: (a) m-CPBA, CH2Cl2, 12 h to give
20 [58%]; (b) KHF2, 18-crown-6, DMF, reflux, 36 h, chromatogra-
phy [83%].
Sch em e 4a
a
Reagents and conditions: (a) 1. LDA, THF, -78 °C f -15
°C, 3 h 2. 8-bromooct-1-ene oxide 12, THF, -30 °C, 12 h f rt [55%];
(b) DCC, DMAP, CH3OH, CH2Cl2 [67%]; (c) KHF2, 18-crown-6,
DMF, reflux, 36 h, chromatography [50%].
natural product total syntheses and was also the crucial
step in the synthesis of (R)-(+)-lasiodiplodin.11i The target
compound 8 should be formed from diene 15 by ring-
closing metathesis and subsequent hydrogenation. Com-
pound 15 should be available from the phenol 16 which
could be formed from the known salicylic acid derivative
17 by esterification with 1-fluoro-oct-7-en-2-ol (18). The
fluorohydrin 18 should be available from 1,7-octadiene
(19).
a
Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride,
Et3N, THF, 12 h, rt; (b) 1-fluoro-oct-7-en-2-ol (18), toluene, DMAP,
100 °C, 2.5 h [64%]; (c) (CF3SO2)2O, pyridine, 0 °C f rt, 24 h [80%];
(d) allyltributylstannane, Pd2(dba)3, TFP, LiCl, NMP, 40 °C, 41 h
[65%]; (e) (PCy3)2Cl2RudCHPh, CH2Cl2, 45 °C, 36 h [65%]; (f) H2,
Pd/C, MeOH, rt, 12 h [83 %].
1-fluoro-oct-7-en-2-ol (18) as the main regioisomer (83%),
which was purified by flash chromatography (Scheme 3).
Esterification of 17 with the fluorinated alcohol 18
under Yamaguchi’s conditions7 resulted in the formation
of 16a . After activation of 16a with (CF3SO2)2O in
pyridine,20 the corresponding aryltriflate 16b was sub-
jected to a Stille reaction with allyltributylstannane and
Pd2(dba)3/tris(2-furyl)phosphane (TFP) as catalyst in the
presence of LiCl in N-methylpyrrolidone (NMP) analo-
gously to ref 21. In this way the cross-coupling product
15 was obtained as a precursor for cyclization. The
macrocyclization was achieved by ring-closing metathesis
in high dilution in dichloromethane catalyzed with ben-
zylidenebis(tricyclohexylphosphine)dichlororuthenium
(Cl2(PCy3)2RudCHPh),22 a catalyst introduced to metath-
esis reactions by Grubbs et al.23 The resulting unsatur-
ated macrolide 14, formed as an 81:19 mixture of (E)-
and (Z)-isomers, was hydrogenated in the presence of
palladium on carbon to give the racemic “fluoro-lasio-
diplodin” 8 in 18% overall yield (Scheme 4).
The starting material, 2,4-dimethoxysalicylic acid (17),
was prepared from 3,5-dimethoxyphenol by a four-step
procedure15-18 in 38% overall yield. The synthesis of 18
started from 1,7-octadiene (19), which was transformed
into the mono-epoxide 20. Refluxing of 20 with KHF2/
18-crown-6 in DMF according to the literature6,19 led to
The synthesis of the (S)-enantiomer of compound 8 was
accomplished by enzymatic resolution of 1-fluoro-oct-7-
en-2-ol (18), as the key step. Compound 18 was derace-
(15) Bell, K. H.; McCaffery, L. F. Austr. J . Chem. 1992, 45, 1213-
1224.
(16) MacMillan, J . J . Chem. Soc. 1954, 2585-2587.
(17) Kiehlmann, E.; Lauener, R. W. Can. J . Chem. 1989, 67, 335-
344.
(18) Maillard, J .; Vincent, M.; Delaunay, P. Bull. Soc. Chim. Fr.
1966, 2520-2524.
(19) Yang, S. S.; Min, J . M.; Beattie, T. R. Synth. Commun. 1988,
18, 899-905.
(20) Ritter, K. Synthesis 1993, 735-762.
(21) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585-
9595.
(22) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803.
(23) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem. 1995, 107, 2179-2181; Angew. Chem., Int. Ed. Engl. 1995, 34,
2039-2041.

8740 J . Org. Chem., Vol. 65, No. 25, 2000
Runge and Haufe
ethanol, 9:1 containing 0.1% H2O and 0.01% TFA). Elemental
analyses: Mikroanalytisches Laboratorium, Universita¨t Mu¨n-
ster.
mized by a lipase-catalyzed acetylation with Candida
antarctica lipase (CAL, Novozym435) and vinyl acetate
in cyclohexane according to a procedure which we have
successfully used for other fluorinated alcohols,9,24 to
obtain the chiral nonracemic (R)-(+)-18 and (S)-(-)-18
with very high ee’s after separation of (R)-(+)-18 and (S)-
(+)-21 by chromatography and hydrolysis of acetate 21
(eq 1).
2,4-Dimethoxy-6-methyl benzoic acid (11) was prepared
from orcinol as described in ref 11g. Allyl chloride, 1,5-
dibromopentane, 3,5-dimethoxyphenol, and 1,7-octadiene were
purchased from Acros chemicals. Benzylidenebis(tricyclohexyl-
phosphine)dichlororuthenium was obtained from Fluka chemi-
cals while all other applied reagents were obtained from Acros
and Aldrich chemicals. All solvents were purified by distillation
and stored over molecular sieves. CH2Cl2 was dried by distil-
lation from P2O5 and stored over molecular sieves (0.4 nm).
THF was dried by distillation from Na/K alloy. Lipase No-
vozym435 was kindly donated by Novo Nordisk A/S.
8-Br om o-oct-1-en e (13). According to procedures given in
ref 12 (allylmagnesium chloride12a was used instead of allyl-
magnesium bromide12b), treatment of magnesium (25.0 g, 1.03
mol) in Et2O (250 mL) with allyl chloride (23.6 g, 0.31 mol) at
-15 °C gave an ethereal solution of allylmagnesium chloride
(180 mmol, 58%). After filtration under an argon atmosphere
the ethereal solution of this Grignard reagent (77 mmol) was
added dropwise to a suspension of dibromopentane (19.48 g,
84.7 mmol), CuCl2 (1.65 g, 12.3 mmol) and LiCl (1.04 g, 24.5
mmol) in THF (100 mL) at -20 °C and stirred for 2 h at this
temperature. After warming to room temperature and the
usual workup, 13 was isolated as a colorless liquid by distil-
lation using a spinning band column. Yield: 7.47 g (50%), bp
84 °C/20 mmHg (lit.:12b Yield: 33%, bp 98-99 °C/24 mmHg).
The spectroscopic data agree with published ones.12b
Ep oxid a tion w ith m -CP BA. A solution of the olefins (13
or 19) in CH2Cl2 was dropped into a solution of m-CPBA in
CH2Cl2 at 0 °C. The reaction mixture was stirred for another
20 h at room temperature (reaction monitored by TLC). After
separating the formed m-CBA by filtration, the filtrate was
treated with aqueous solutions of 10% Na2SO3, 10% NaHCO3,
and saturated aqueous NaCl. After drying with Na2SO4,
evaporating the solvent, and purifying by column chromatog-
raphy (silica gel, cyclohexane/ethyl acetate, 3:1), the oxiranes
were obtained.
The enantiomer (S)-(-)-18 was used as a functional
building block for the synthesis of (S)-(+)-8 as described
above for the racemate without loss of optical activity.
Unfortunately the enantiomeric excess of the final prod-
uct could neither be determined by chiral GC, nor using
chiral HPLC, nor with the chiral shift reagent Eu(hfc)3
1
in 19F or H NMR spectroscopy.25
Con clu sion
The monofluorinated analogue 8 of lasiodiplodin has
been synthesized using a ring-closing metathesis as the
key step. After preparation of the acid 17 in an overall
yield of 38% in four steps and synthesis of the fluorohy-
drin 18 in 48% yield in two steps, the racemic target
molecule 8 was prepared in five steps in 18% overall
yield. The enantioselective synthesis was achieved by
lipase-mediated acetylation of fluorohydrin 18 with No-
vozym435 and vinyl acetate resulting in obtaining both
enantiomers of the desired building block. After hydroly-
sis of the acetate (S)-(+)-21, the enantiomer (S)-(+)-8 was
obtained analogously to the preparation of the racemate.
8-Br om o-1,2-ep oxyocta n e (12). From 13 (11.01 g, 62
mmol) in CH2Cl2 (60 mL) and m-CPBA (17.36 g, 74 mmol) in
CH2Cl2 (150 mL) was formed 12 and isolated as described
1
above. Yield: 10.98 g (85%). H NMR: δ 1.27-1.60 (m, 8H),
1.80 (tt, J ) 6.7 Hz, 2H), 2.41 (dd, J ) 5.1 Hz, J ) 2.7 Hz,
1H), 2.69 (dd, J ) 5.1 Hz, J ) 4.1 Hz, 1H), 2.81-2.89 (m, 1H),
3.37 (t, J ) 6.7 Hz, 2H); 13C NMR: δ 25.7 (t), 28.0 (t), 28.5 (t),
31.8 (t), 32.2 (t), 33.7 (t), 46.9 (t), 52.1 (d); MS m/z: 205/207
(0.2), 176/178 (1), 162/164 (1), 148/150 (8), 127 (4), 95 (100),
71 (83), 67 (24). Anal. Calcd for C8H15OBr (207.1): C, 46.39;
H, 7.31. Found: C, 46.39; H, 7.42.
Exp er im en ta l Section
7,8-Ep oxyoct-1-en e (20). From 19 (5.50 g, 50 mmol) in
CH2Cl2 (50 mL) and m-CPBA (9.38 g, 40 mmol) in CH2Cl2 (100
mL) was formed 20 and purified by column chromatography
(silica gel, CH2Cl2). Yield: 3.65 g (58%). 1H NMR: δ 1.40-
1.60 (m, 6H), 2.03-2.13 (m, 2H), 2.45 (dd, J ) 5.0 Hz, J ) 2.6
Hz, 1H), 2.73 (dd, J ) 5.0 Hz, J ) 4.06 Hz, 1H), 2.87-2.92
(m, 1H), 4.92-5.05 (m, 2H), 5.80 (ddt, J ) 17.2 Hz, J ) 10.3
Hz, J ) 6.7 Hz, 1H); 13C NMR: δ 25.4-33.6 (4t), 47.0 (d), 52.2
(t), 114.5 (t), 138.6 (d); MS m/z: 127 (2), 125 (2), 97 (6), 83
Gen er a l. Melting/boiling points: uncorrected values. 1H
NMR (300 MHz), 13C NMR (75.5 MHz) and 19F NMR (282.4
MHz), about 20% solutions in CDCl3, TMS for 1H, CDCl3 for
13C, and CFCl3 for 19F as internal standards. The multiplicity
of 13C signals was determined by DEPT technique. Mass
spectra (70 eV): GLC/MS coupling. Gas liquid chromatogra-
phy: Quartz capillary column, Hewlett-Packard, HP-1 (0.52
µm), dimensions: 25 m, L 0.33 mm. The ee’s were determined
by GLC analysis on a â-cyclodextrin phase, Sulpelco, Beta-
Dex 120 (0.25 µm), dimensions: 30 m, L 0.25 mm. Thin-layer
chromatography: Merck silica gel DC 60 F254. Flash chroma-
tography: Merck silica gel 60. Chiral HPLC: Chira OJ (Grom
Co., 250 × 2 mm, cellulose-tris-4-methylbenzoate, heptane/
1
(25), 71 (16), 67 (75). H NMR spectroscopic data agree with
published data.26
6-(8′,9′-Epoxyn on -1′-yl)-2,4-dim eth oxyben zoic Acid (10a).
Under an argon atmosphere, a THF-solution of LDA was
prepared by adding 1.6 M n-butyllithium (9.3 mL, 15 mmol)
in diisopropylamine (2.1 mL, 15 mmol) dissolved in THF (18
mL) at -78 °C. Under an argon atmosphere this solution was
injected slowly into a stirred solution of 2,4-dimethoxy-6-
methylbenzoic acid (11) (1.30 g, 7.1 mmol) in THF (18 mL) at
-78 °C and allowed to warm to -15 °C. After stirring at -15
°C to -10 °C for 3 h, the reaction mixture was cooled to -30
°C, and 8-bromo-1,2-epoxyoctane (12) (1.46 g, 7.1 mmol)
(24) (a) Goj, O.; Burchardt, A.; Haufe, G. Tetrahedron: Asymmetry
1997, 8, 399-408. (b) Skupin, R.; Cooper, T. G.; Fro¨hlich, R.; Prigge,
J .; Haufe, G. Tetrahedron: Asymmetry 1997, 8, 2453-2464. (c)
Takahashi, T.; Fukushima, A.; Tanaka, Y.; Segawa, M.; Hori, H.;
Takeuchi, Y.; Burchardt, A.; Haufe, G. Chirality 2000, 12, 458-463.
(25) To proof the stereoconservation of the esterification step, we
hydrolyzed (2′S)-16a with KOH/MeOH. No loss of optical purity was
found in the formed fluorohydrin (S)-18 by chiral GLC. With 20-50
mol % of the shift reagent, the ortho methoxy groups of 14, 15, and 8
were broadened showing a shoulder. No exact determination of the ee
was possible.
(26) Byrom, N. T.; Grigg, R.; Kongkathip, B.; Reimer, G.; Wade, A.
R. J . Chem. Soc., Perkin Trans. 1 1984, 8, 1643-1653.

Synthesis of Lasiodiplodin Analogue
J . Org. Chem., Vol. 65, No. 25, 2000 8741
dissolved in THF (3.5 mL) was added. The resulting solution
was allowed to warm to room temperature over a period of 12
h. The reaction mixture was hydrolyzed with saturated aque-
ous NH4Cl (80 mL), and the pH was adjusted to pH 3 with 2
N HCl. The volume of the mixture was reduced to 100 mL by
evaporation and extracted with CH2Cl2. The organic layer was
dried with Na2SO4 and evaporated. Purification of the crude
product by column chromatography (silica gel, ethyl acetate)
gave 10a (1.25 g, 55%). 1H NMR: δ 1.20-1.60 (br m, 12H),
2.45 (dd, J ) 4.8 Hz, J ) 2.9 Hz, 1H), 2.73 (dd, J ) 4.8 Hz, J
) 4.5 Hz, 1H), 2.79 (t, 2H), 2.87-2.93 (m, 1H), 3.81, 3.87 (2s,
6H), 6.34, 6.39 (2d, J ) 2.4 Hz, 2H); 13C NMR: δ 25.8 (t), 29.0
(t), 29.2 (t), 31.1 (t), 32.2 (t), 34.5 (t), 47.0 (t), 52.4 (d), 55.3 (q),
56.1 (q), 96.2 (d), 107.2 (d), 113.8 (s), 146.0 (s), 161.8 (s), 169.6
(s) 171.1 (s); MS (silylated 10a ) m/z: 396 (5), 395 (17), 394
(58), 379 (16), 377 (16), 349 (4), 305 (17), 304 (41), 279 (35);
268 (56), 267 (33), 224 (39); 191 (100), 178 (39), 177 (31), 152
(74), 151 (27), 135 (17), 91 (3), 89 (22), 77 (11), 73 (99).
Meth yl 6-(8′,9′-Ep oxyn on -1′-yl)-2,4-d im eth oxy-6-m eth -
ylben zoa te (10b). Under argon, 10a (2.04 g, 6.3 mmol), DCC
(2.69 g, 10 mmol), methanol (1.5 mL, 50 mmol), and DMAP
(0.16 g, 1.3 mmol) were dissolved in CH2Cl2 (30 mL) and stirred
at room temperature for 12 h until esterification was complete
(monitored by TLC). N,N-Dicyclohexylurea was filtered off, the
filtrate was washed with water, 5% acetic acid solution, and
again with water and dried (MgSO4), and the solvent was
evaporated in vacuo to give the ester 10b (1.42 g, 67%) after
column chromatography (silica gel, pentane/Et2O, 1:1). 1H
NMR: δ 1.22-1.59 (br m, 12H,), 2.42 (dd, J ) 4.9 Hz, J ) 2.6
Hz, 1H), 2.52 (t, 2H), 2.71 (dd, J ) 4.9 Hz, J ) 4.1 Hz, 1H),
2.82-2.88 (m, 1H), 3.75, 3.79 (2s, 6H), 3.84 (s, 3H), 6.25-6.30
(m, 2H), 13C NMR: δ 25.8 (t), 29.3 (t), 29.4 (t), 31.0 (t), 32.3
(t), 33.8 (t), 46.9 (t), 51.9 (q), 52.2 (d), 55.2 (q), 55.8 (q), 96.0
(d), 105.8 (d) 157.9 (s), 161.2 (s), 168.7 (s); MS m/z: 337 (6),
336 (25), 306 (3), 305 (14), 304 (10); 289 (10), 277 (4), 210 (100),
191 (39), 179 (8), 152 (9), 151 (24), 121 (4), 91 (5), 77 (4).
Hz), 114.5 (t), 138.6 (d); 19F NMR: δ -228.9 (dt, J ) 47.7 Hz,
J ) 19.1 Hz); MS m/z: 146 (<0.1), 128 (8), 113 (22), 95 (76),
67 (61).
En zym a tic Resolu tion of 1-F lu or o-oct-7-en -2-ol (18).
Racemic 18 (146 mg, 1 mmol) and vinylic acetate (129 mg, 1.5
mmol) were dissolved in cyclohexane (5 mL). After addition of
Novozym435 (73.6 mg), the resulting suspension was stirred
at room temperature until 50% conversion was reached. For
reaction monitoring, a 0.2 mL aliquot of the suspension was
filtered through silica gel (addition of 2 mL of ethyl acetate as
eluent) and submitted to GLC analysis. After completion of
the reaction (about 12 h), the whole suspension was treated
in the same manner. Column chromatography (silica gel,
cyclohexane/ethyl acetate, 3:1) provided the acetate (S)-(+)-
21 and the fluorohydrin (R)-(+)-18.
(2R)-(+)-1-F lu or o-oct-7-en -2-ol ((2R)-(+)-18). Yield: 49.6
mg (34%); [R]20 ) +6.9 (c 1.04, CH2Cl2), 92% ee (GLC).
D
(7S)-(+)-7-Acetoxy-8-flu or o-oct-1-en e ((7S)-(+)-21). Yield:
99.6 mg (45%); [R]20 ) +7.7 (c 1.31, CH2Cl2), 98% ee (GLC).
D
1H NMR: δ 1.20-1.50 (m, 4H), 1.55-1.57 (m), 1.95-2.10 (m,
2H), 2.07 (s, 3H), 4.39 (ddd, J H,F ) 47.2 Hz, J ) 10.0 Hz, J )
4.8 Hz, 1H), 4.47 (ddd, J H,F ) 47.5 Hz, J ) 10.3 Hz, J ) 3.3
Hz, 1H), 4.96 (m, 2H), 4.97-5.11 (m, 1H), 5.78 (ddt, J ) 16.9
Hz, J ) 10.2 Hz, J ) 6.7 Hz, 1H); 13C NMR: δ 20.9 (q), 24.5
(t), 28.5 (t), 29.3 (dt, J C,F ) 5.9 Hz), 33.4 (t), 72.2 (dd, J C,F
)
17.8 Hz), 83.5 (dt, J C,F ) 172.9 Hz), 114.6 (t), 138.4 (d), 170.4
(s); 19F NMR: δ -231.1 (dt, J ) 47.7 Hz, J ) 21.0 Hz); MS
m/z: 188 (<1), 173 (1), 146 (1), 128 (30), 113 (15), 95 (100), 86
(30), 81 (34), 68 (91), 67 (70). Anal. Calcd for C10H17O2F
(188.3): C, 63.80; H, 9.11. Found: C, 64.09; H, 9.22.
(2S)-(-)-1-F lu or o-oct-7-en -2-ol ((2S)-(-)-18). (S)-(+)-21
(188 mg, 1 mmol) dissolved in methanol (10 mL) was treated
with KOH (80 mg, 2 mmol) and stirred for 2 h at room
temperature. The solvent was removed in vacuo, and the
residue was diluted with water and extracted with ethyl
acetate. Drying the combined organic layers (MgSO4) and
evaporating the solvent gave (2S)-(-)-18 (139 mg, 95%): [R]20
) -7.1 (c 1.03, CH2Cl2), >98% ee (GLC).
Oxir a n e Rin g Op en in g w ith KHF 2/18-Cr ow n -6.5 To an
argon-covered solution of 18-crown-6 (10.6 g, 40 mmol) and
KHF2 (7.8 g, 100 mmol) in refluxing dry DMF (120 mL) was
added the relevant epoxide (25 mmol). The solution was
refluxed for additional 36 h. After cooling, the solution was
poured into ice-water, and the mixture was extracted with
CH2Cl2. The combined organic layer was repeatedly washed
with water and dried with Na2SO4. Evaporation of the solvent
gave the respective secondary â-fluorohydrins together with
about 10% of their regioisomers. The isomers were separated
by flash chromatography (silica gel, cyclohexane/ethyl acetate,
3:1).
D
1′-F lu or oct -7′-en -2′-yl 2-H yd r oxy-4,6-d im et h oxyb en -
zoa te (16a ). Under an argon atmosphere, 2,4,6-trichloroben-
zoyl chloride (0.91 mL, 5.7 mmol) was added to a stirred
mixture of 17 (1.13 g, 5.7 mmol) and Et3N (0.85 mL, 6.3 mmol)
in THF (57 mL). After stirring at room temperature for 12 h
and removing the triethylamine hydrochloride under argon,
the resulting anhydride was diluted with toluene (60 mL) and
treated with 18 (0.88 g, 6.3 mmol) and DMAP (1.51 g, 12.4
mmol) and refluxed for 2.5 h. Subsequently, the reaction
mixture was washed successively with water, 3% aqueous HCl,
water, 10% aqueous NaHCO3 solution, and water again and
dried. The solvent was removed, and the residue was purified
by column chromatography (silica gel, CH2Cl2) to give 16a .
Yield: 1.19 g (64%). 1H NMR: δ 1.40-1.53 (m, 4H), 1.70-
1.90 (m, 2H), 2.03 (m, 2H), 3.80, 3.79 (2s, 6H), 4.43-4.66 (dm,
J H,F ) 47.2 Hz, 2H), 4.91-5.04 (m, 2H), 5.20-5.36 (m, 1H),
5.80 (ddt, J ) 16.9 Hz, J ) 10.2 Hz, J ) 6.7 Hz, 1H), 5.96,
6.10 (2d, J ) 2.4 Hz); 13C NMR: δ 24.4 (t), 28.6 (t), 29.6 (t),
33.5 (t), 55.4 (q),. 55.9 (q) 72.9 (dd, J C,F ) 20.4 Hz), 83.5 (dt,
J C,F ) 172.9 Hz), 91.7 (d), 93.4 (d), 114.6 (t), 138.5 (d), 162.5
(s), 165.5 (s), 165.8 (s), 170.6 (s); 19F NMR: δ -230.3 (dt, J )
47.7 Hz, J ) 19.1 Hz); MS m/z: 326 (0), 325 (0.2), 199 (4), 180
(100), 152 (20), 137 (10), 109 (2), 95 (5), 79 (2), 67 (4), 55 (6),
41 (11), 39 (12). Anal. Calcd for C17H23O5F (326.4): C, 62.55;
H, 7.11. Found: C, 62.07; H, 7.16.
Meth yl 6-(9′-Flu or o-8′-h ydr oxyn on -1′-yl)-2,4-dim eth oxy-
ben zoa te (9). Synthesized from the oxirane 10b (0.87 g, 2.6
1
mmol). Yield: 0.46 g (50%). H NMR: δ 1.20-1.60 (m, 10H),
1.90-2.10 (m, 2H), 2.52 (m, 3H, 1′-H2), 3.77, 3.79, 3.85 (3s),
3.78-3.80 (m, 1H), 4.26 (ddd, J H,F ) 48.2 Hz, J ) 9.3 Hz, J )
6.7 Hz, 1H), 4.40 (ddd, J H,F ) 47.0 Hz, J ) 9.5 Hz, J ) 3.1 Hz,
1H), 6.28-6.32 (m, 2H); 13C NMR: δ 25.3 (t), 29.2 (t), 29.4 (t),
31.1 (t), 31.8 (dt), 33.9 (t), 52.0 (q), 55.4 (q), 55.9 (q), 70.7 (dd,
J CF ) 17.4 Hz), 87.1 (dt, J CF ) 165.3 Hz), 96.2 (d), 105.9 (d),
116.3 (s,), 143.0 (s,), 158.1 (s), 175.9 (s), 192 (s); 19F NMR: δ
-228.6 (dt, J ) 47.7 Hz, J ) 19.1 Hz); MS m/z: 356 (0.5), 355
(1), 325 (10), 324 (7), 307 (4), 305 (1), 291 (24), 210 (100), 191
(51), 179 (22), 151 (35); 121 (10); 91 (14), 77 (14), 63 (19). Anal.
Calcd for C19H29O5F (356.5): C, 64.02; H, 8.21. Found: C,
64.34; H, 8.19.
(2′S)-(-)-16a : Yield 1.24 g (67%); [R]20 ) -27.4 (c 1.06,
D
1-F lu or ooct-7-en -2-ol (18).27 Synthesized from the oxirane
CH2Cl2).
1
20 (3.15 g, 25 mmol). Yield: 3.03 g (83%). H NMR: δ 1.30-
1′-Fluorooct-7′-en-2′-yl2,4-Dimethoxy-6-trifluoromethane-
su lfon a teben zoa te (16b). To a solution of 16a (0.74 g, 2.3
mmol) in pyridine (1.2 mL) was slowly added trifluoromethane-
sulfonic anhydride (0.71 g, 0.42 mL, 2.5 mmol) at 0 °C. The
resulting mixture was stirred for 24 h while allowing it to
warm to room temperature. The resulting mixture was poured
into water and extracted with Et2O. The ethereal extract was
washed sequentially with water, 10% aqueous HCl, and
concentrated aqueous NaCl solution and dried (MgSO4).
Evaporation of the solvent gave the trifluoromethanesulfonate
1.55 (m, 6H), 1.80-1.95 (br s, 1H), 2.02-2.12 (m, 2H), 3.82-
3.91 (m, 1H), 4.27 (ddd, J H,F ) 48.2 Hz, J ) 9.3 Hz, J ) 6.7
Hz, 1H), 4.42 (ddd, J H,F ) 47.0 Hz, J ) 9.3 Hz, J ) 3.1 Hz,
1H), 4.91-5.05 (m, 2H), 5.80 (ddt, J ) 16.9 Hz, J ) 10.3 Hz,
J ) 6.7 Hz, 1H); 13C NMR: δ 24.7 (t), 28.8 (t), 31.7 (dt, J C,F
)
7.6 Hz), 33.5 (t); 70.4 (dd, J C,F ) 17.8 Hz), 87.0 (dt, J C,F ) 167.9
(27) First synthesized by Ishihara, J .; Hanafusa, T. J . Chem. Soc.,
Chem. Commun. 1989, 1848-1850, no spectroscopic data given.

8742 J . Org. Chem., Vol. 65, No. 25, 2000
Runge and Haufe
16b. Yield: 0.84 g (80%). 1H NMR: δ 1.40-1.58 (m, 4H), 1.70-
1.85 (m, 2H), 2.02-2.13 (m, 2H), 3.84 (s, 6H), 4.51 (ddd, J H,F
J ) 4.1 Hz, 1H), 4.59 (ddd, J H,F ) 47.7 Hz, J ) 10.3 Hz, J )
4.0 Hz, 1H), 5.14-5.46 (m, 3H), 6.33, 6.34 (2d, J ) 2.1 Hz,
2H); 13C NMR: δ 19.7 (t), 24.8 (t), 32.5 (dt, J C,F ) 2.5 Hz),
38.3 (t), 55.3 (q), 56.1 (q), 70.0 (dd, J C,F ) 20.4 Hz), 84.1 (dt,
J C,F ) 172.9 Hz), 97.1 (d), 107.3 (d), 116.8 (t), 128.7 (d), 132.9
(d), 141.1 (s), 158.8 (s), 161.4 (s), 167.9 (s); 19F NMR: δ -230.8
(dt, J ) 47.7 Hz, J ) 19.1 Hz); MS m/z: 323 (12), 322 (63),
289 (10), 217 (39), 207 (100), 204 (66), 178 (24), 158 (8), 115
(10), 91 (8), 77 (8); HMRS calcd for C18H23O4F 322.1580, found
322.1569.
3
) 47.4 Hz, J ) 10.3 Hz, J H,H ) 3.6 Hz, 1H, 1′-H); 4.59 (ddd,
2
3
2J H,F ) 47.4 Hz, J H,H ) 10.3 Hz, J H,H ) 3.3 Hz, 1H), 4.90-
5.05 (m, 2H), 5.20-5.33 (m, 1H), 5.80 (ddt, J ) 17.2 Hz, J )
10.3 Hz, J ) 6.7 Hz, 1H), 6.44-6.48 (m, 2H); 13C NMR: δ 24.5
(t), 29.1 (t), 29.4 (dt, J CF ) 4.9 Hz), 33.5 (t), 55.9 (q), 56.4 (q),
74.1 (dd, J C,F ) 22.6 Hz), 83.2 (dt, J C,F ) 175.1 Hz), 98.5 (d),
99.0 (d), 110.2 (t), 120.7 (t, J C,F ) 361.5 Hz), 138.6 (d), 148.0
(s), 159.5 (s), 162.5 (s), 162.8 (s), 176.3 (s); 19F NMR: δ -231.3
(dt, J ) 22.7 Hz, J ) 47.7 Hz, 1F), -73.8 (s, CF3).
(7S)-(+)-14: Yield 98 mg (66%); [R]20D ) +59.7 (c 0.49, CH2-
Cl2).
(2′S)-(-)-16b: Yield 0.79 g (75%); [R]20 ) -10.8 (c 0.97,
D
CH2Cl2).
7-F lu or om eth yl-2,4-d im eth oxy-7,8,9,10,11,12,13,14-oc-
ta h yd r o-6-oxa ben zocyclod o-d eca n -5-on e (8). Compound
14 (70 mg, 0.22 mmol) was dissolved in methanol (5 mL) and
hydrogenated over Pd/C. Stirring the suspension for 12 h
under a hydrogen atmosphere gave 8. Yield: 58 mg (83%). 1H
NMR: δ 1.22-1.49 (m, 8H) 1.57-1.72 (m, 2H), 1.75-1.86 (m,
1H), 1.92-2.02 (m, 1H), 2.52-2.75 (m, 2H), 3.79, 3.80 (2s, 6H),
4.49 (ddd, J H,F ) 47.2 Hz, J ) 9.8 Hz, J ) 4.8 Hz, 1H), 4.57
(ddd, J H,F ) 47.2 Hz, J ) 9.8 Hz, J ) 5.5 Hz, 1H), 527-5.40
(m, 1H), 6.30-6.34 (m, 2H); 13C NMR: δ 21.7 (t), 24.1 (t), 25.5
(t), 26.4 (t), 27.1 (dt, J C,F ) 5.1 Hz), 30.0 (t), 30.6 (t); 55.3 (q),
56.0 (q), 73.2 (dd, J C,F ) 20.4 Hz), 83.4 (dt, J C,F ) 172.9 Hz),
96.4 (d), 106.1 (d), 117.3 (s), 143.0 (s), 158.1 (s), 161.5 (s), 168.2
(s); 19F NMR: δ -229.5 (dt, J ) 47.7 Hz, J ) 19.1 Hz); MS
m/z: 324 (2), 323 (14), 322 (66), 289 (12), 277 (5), 260 (14),
233 (5), 217 (36), 207 (100), 204 (68), 189 (34), 178 (27), 161
(8), 145 (5), 128 (5), 115 (10), 91 (8), 77 (8), 67 (5); HMRS calcd
for C18H25O4F 324.1737, found 324.1773.
1′-F lu or ooct-7′-en -2′-yl 2-Ally-4,6-d im eth oxyben zoa te
(15). The triflate 16b (0.38 g, 0.83 mmol) was dissolved in
N-methylpyrrolidone (5 mL) and treated with anhydrous LiCl
106 mg, 2.5 mmol), trifurylphosphine (23.1 mg, 12 mol %), and
Pd2(dba)3 (11.4 mg, 3 mol %). After 10 min at room tempera-
ture, the solution was treated with allyltributyltin (0.14 mL,
0.97 mmol), and the mixture was stirred at 40 °C for 40 h.
Dilution with saturated KF solution was followed by extraction
with ethyl acetate, drying (MgSO4), and evaporation. Column
chromatography (silica gel, cyclohexane/ethyl acetate, 3:1) gave
15. Yield: 190 mg (65%). 1H NMR: δ 1.40-1.54 (m, 4H), 1.65-
1.80 (m, 2H), 2.03-2.11 (m, 2H), 3.37 (d, J ) 6.4 Hz, 2H), 3.79,
3.80 (2s, 6H), 4.48 (ddd, J H,F ) 47.2 Hz, J ) 10.0 Hz, J ) 5.0
Hz, 1H), 4.56 (ddd, J H,F ) 47.7 Hz, J ) 7.4 Hz, J ) 3.3 Hz,
1H); 4.90-5.10 (m, 4H), 5.20-5.34 (m, 1H), 5.72-5.99 (m, 2H),
6.34 (m 2H); 13C NMR: δ 24.6 (t), 26.9 (t), 29.5 (dt, J C,F ) 5.1
Hz), 33.6 (t), 37.7 (t), 55.4 (q), 55.8 (q), 72.9 (dd, J C,F ) 20.3
Hz), 83.6 (dt, J C,F ) 175.5 Hz), 96.8 (d), 106.1 (d), 114.5 (t),
116.3 (t), 136.3 (d), 138.6 (d), 140.2 (s), 158.3 (s), 161.6 (s), 162.6
(7S)-(+)-8. Yield 60 mg (85%); [R]20 ) +11.6 (c 0.57, CH2-
D
Cl2).
3
(s), 167.6 (s); 19F NMR: δ -230.3 (dt, J ) 49.6 Hz, J ) 19.1
Hz); MS m/z: 351 (4), 350 (15), 222 (19), 207 (100), 205 (90),
177 (34), 146 (13), 115 (12), 91 (12), 41 (22); HRMS calcd for
Ack n ow led gm en t. The authors are grateful to the
“Deutsche Forschungsgemeinschaft” and the “Fonds der
Chemischen Industrie” for generous support. M.R.
would like to thank the Graduiertenkolleg “Hochreak-
tive Mehrfachbindungssysteme” for a stipend. The kind
donation of chemicals and enzymes by Bayer AG,
Leverkusen, Hu¨ls AG, Marl and Novo Nordisk A/S,
Denmark, are gratefully acknowledged.
C
20H27O4F 350.1893, found 350.1861.
(2′S)-(-)-15: Yield 0.18 g (62%); [R]20D ) -20.7 (c 0.65, CH2-
Cl2).
7-Flu or om eth yl-2,4-dim eth oxy-7,8,9,10,11,14-h exah ydr o-
6-oxa ben zocyclod od ecen -5-on (14). Solutions of the diene
15 (0.16 g, 0.46 mmol) and of benzylidenebis(tricyclohexyl-
phosphine)dichlororuthenium (16 mg, 0.02 mmol, 4.3 mol %)
in CH2Cl2 each (27 mL) were simultaneously added dropwise
to CH2Cl2 (27 mL) over a period of 12 h at reflux. After stirring
for another 24 h at that temperature, the solvent was removed
in vacuo, and the residue was purified by flash chromatogra-
phy (silica gel, cyclohexane/ethyl acetate 3:1) to give 14.
Yield: 90 mg (65%) as a mixture of E/Z-isomers (81:19): 1H
NMR: δ 1.23-1.85 (m, 6H), 2.11-2.25 (m, 2H), 3.04-3.12 (m,
2H), 3.78, 3.80 (2s, 6H), 4.43 (ddd, J H,F ) 47.7 Hz, J ) 9.5 Hz,
Su p p or tin g In for m a tion Ava ila ble: Synthesis of 17 from
3,5-dimethoxyphenol, spectroscopic data of compounds 17 and
1
its precursors, and copies of H, 13C, and 19F NMR spectra of
compounds 8, 14, 15, 16a , 16b, and 18. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0012445