Systematic synthesis of multifluorinated α,α-difluoro-γ-lactones through intramolecular radical cyclization

Article abstract of DOI:10.1021/jo982035b

Carbon radicals from allyl O-(trimethylsilyl)-α-bromo-α,α- difluoroacetal can cyclize onto the olefinic part regiospecifically to give γ-lactols in good yield. The lactols are then converted to the corresponding α,α-difluoro-γ-lactones. Systematic synthesis of multifluorinated-α,α- difluoro-γ-lactones has thus been accomplished through intramolecular radical cyclization as a key reaction. Semiempirical MO calculation study suggested a unique nature of α,α-difluoroacetate in that complete delocalization of the electrons in the SOMO orbital of α,α-difluoroacetyl radical occurred; this caused unsuccessful cyclization. To apply the present radical reaction, the first synthesis of both enantiomers of difluoroeldanolide, analogues of the sex pheromone of the male African sugarcane borer, has been demonstrated. Electrophysiological tests revealed that the difluorinated analogues were as active as the natural eldanolide on the olfactory receptors.

Full text of DOI:10.1021/jo982035b

252
J . Org. Chem. 1999, 64, 252-265
System a tic Syn th esis of Mu ltiflu or in a ted r,r-Diflu or o-γ-la cton es
th r ou gh In tr a m olecu la r Ra d ica l Cycliza tion
Toshiyuki Itoh,*,† Kohei Sakabe,† Kazutoshi Kudo,† Hiroyuki Ohara,† Yumiko Takagi,‡
Hiroshi Kihara,‡ Pierre Zagatti,§ and Michel Renou§
Department of Chemistry, Faculty of Education, Okayama University, Okayama 700-8530, J apan,
Department of Natural Science, Hyogo University of Teacher Education, Yashiro, Hyogo 673-14, J apan,
and INRA, Unite de Phytopharmacie et Mediateurs Chimiques, Route de Saint Cyr,
78026 Versailles, France
Received October 8, 1998
Carbon radicals from allyl O-(trimethylsilyl)-R-bromo-R,R-difluoroacetal can cyclize onto the olefinic
part regiospecifically to give γ-lactols in good yield. The lactols are then converted to the
corresponding R,R-difluoro-γ-lactones. Systematic synthesis of multifluorinated-R,R-difluoro-γ-
lactones has thus been accomplished through intramolecular radical cyclization as a key reaction.
Semiempirical MO calculation study suggested a unique nature of R,R-difluoroacetate in that
complete delocalization of the electrons in the SOMO orbital of R,R-difluoroacetyl radical occurred;
this caused unsuccessful cyclization. To apply the present radical reaction, the first synthesis of
both enantiomers of difluoroeldanolide, analogues of the sex pheromone of the male African
sugarcane borer, has been demonstrated. Electrophysiological tests revealed that the difluorinated
analogues were as active as the natural eldanolide on the olfactory receptors.
In tr od u ction
logues of biomolecules have thus been synthesized such
as amino acids,4 vitamin D3,5 nucleotides,6 prostaglan-
dins,7 fatty acids,7 and insect pheromones.8 We focused
on the synthesis of R,R-difluoro-γ-lactones because a
significant class of γ-lactone compounds has been found
among biologically active molecules.1,9
Partially fluorinated analogues of biologically impor-
tant compounds demonstrated dramatic changes and
distinctive modifications in their biological activities;1 this
makes efficient methods for the synthesis of selectively
fluorinated compounds ever more necessary.2,3 Most
work, however, has focused on monofluorination of
molecules, and only limited examples have been reported
on introduction of the gem-difluoromethylene moiety.1
Because it is believed that difluoromethylene moiety acts
similarly to ether-oxygen in vivo, interesting biological
activity is anticipated for analogues of R,R-difluorinated
biomolecules; many types of partially difluorinated ana-
Free-radical intramolecular cyclization of olefins is of
paramount importance in organic synthesis for the
construction of five- or six-membered rings.10 However,
limited examples were reported to provide R-halo- or R,R-
dihalo-γ-lactone derivatives by radical reaction,11 and
there was no successful example of synthesizing R,R-
difluoro-γ-lactone using the radical cyclization method
when we began this project; Barth and O-Yang reported
that only the starting material was recovered when allyl
R,R-difluoro-R-iodeacetate was reacted with hexabu-
† Okayama University.
‡ Hyogo University of Teacher Education.
§ INRA, Unite de Phytopharmacie et Mediateurs Chimiques.
(1) A review see: Welch, J . T. Tetrahedron 1987, 43, 3123.
(2) A recent review of the synthetic of geminaldifluoromethylene
compounds, see: Tozer, M. J .; Herpin, T. F. Tetrahedron 1996, 52,
8619.
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Chem. 1988, 53, 2406.
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Med. Chem. 1980, 23, 234. (b) Bannai, K.; Toru, T.; Oba, T.; Tanaka,
T.; Okamura, N.; Watanabe, K.; Hazato, A.; Kurozumi, S. Tetrahedron,
1983, 39, 3807. (c) Premchandran, R. H.; Ogletree, M. L.; Fried. J . J .
Org. Chem. 1993, 58, 5724.
(3) Synthetic methods for difluoromethyl compounds has progressed
extensively recently. For examples, see. (a) Percy, J . M.; Wilkes, R. D.
Tetrahedron 1997, 53, 14749. (b) Taguchi, T.; Kurishita, M.; Shibuya,
A.; Aso, K. Tetrahedron 1997, 53, 9497. (c) Okano, T.; Ishihara, H.;
Takakura, N.; Tsuge, H.; Eguchi, S.; Kimoto, H. J . Org. Chem. 1997,
62, 7192. (d) Weigel, J . A. J . Org. Chem. 1997, 62, 6108. (e) Crowley,
P. J .; Percy, J . M.; Stansfield, K. Chem. Commun. 1997, 2033. (f)
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Xu, Y.; Dolbier, W. R. J r.; Rong, X. X. J . Org. Chem. 1997, 62, 1576.
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10.1021/jo982035b CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

Synthesis of R,R-Difluoro-γ-lactones
J . Org. Chem., Vol. 64, No. 1, 1999 253
Sch em e 1. Syn th esis of r,r-Diflu or o-γ-la cton e
th r ou gh In tr a m olecu la r Ra d ica l Cycliza tion
P r otocol
Sch em e 2. Syn th esis of r,r-Diflu or o-γ-la cton es
th r ou gh In tr a m olecu la r Ra d ica l Cycliza tion
tylditin under irradiation conditions of a sunlamp.12 We
also tried to synthesize γ-lactone 1 directly from allyl
R-bromo- or R-iodo-R,R-difluoroacetate via radical cycliza-
tion, but all efforts failed (path B in Scheme 1). Desired
compound 1 was obtained only when carbon radicals from
allyl O-(trimethylsilyl)-R-bromo-R,R-difluoroacetals 3 were
subjected to the reaction (path A in Scheme 1).13 In this
paper, we describe full details of the results of investiga-
tion on the systematic synthesis of multifluorinated R,R-
difluoro-γ-lactones using a free-radical intramolecular
cyclization strategy.
out with zinc-zinc electrode.17 Transition metal sup-
ported radical cyclization of 2a was also investigated
using RuCl2(PPh3)2,18a Cu(bpy)Cl,18b and CuBr/Fe;18c how-
ever, none of the desired cyclized product was obtained.
Radical cyclization of the R-bromoacetal method was
developed as an indirect but efficient route to γ-lactones
by Ueno et al.20a and Stork et al.20b These results strongly
suggested to us that increasing flexibility of the inter-
mediate radical species would probably solve the problem
in this project, and therefore R-bromoacetal was next
subjected to the radical reaction. As anticipated, the
desired cyclic acetal was obtained for the first time
through this route, though the original Ueno-Stork-type
acetals, O-ethyl- or O-butylacetal radicals, gave the
corresponding cyclized compounds in very low yield of
less than 10%. We finally found that the use of O-
(trimethylsilyl) (TMS) acetal was essential for efficient
cyclization, and the intramolecular radical addition of
R,R-difluoro-O-TMS-acetals 3a onto olefin was accom-
plished regiospecifically to give the corresponding five-
membered lactols 4a in good yield.13a The lactols 4a were
then converted to the desired R,R-difluoro-γ-lactones 1a
by PDC oxidation (Scheme 2).
Various types of new difluoroanalogues of γ-lactones
1 were synthesized through the present radical cycliza-
tion methodology (Table 1). To a benzene solution of
O-TMS-acetal 3a (R ) PhCH2CH2; X, X1 ) H; X2 ) Br)
and 6 mol % of AIBN was slowly added a benzene
solution of 1.5 equiv of tributyltinhydride (Bu3SnH) over
5 h under reflux conditions. The reaction mixture was
heated to reflux for an additional 4 h and then cooled to
room temperature. After evaporation, silica gel flash
column chromatography using hexanes-ethyl acetate
(200:1 to 50:1) as eluent afforded cyclized product 4a in
62% yield. This step finished regiospecifically to provide
Resu lts a n d Discu ssion
1. Syn th esis of Mu ltiflu or in a ted r,r-Diflu or o-γ-
la cton es. Esters of R-radical species have reportedly
been considered unsuitable for C-C bond formation
because of their stable nature.11 Cyclization of allyl
R-bromo-R,R-difluoroacetate 2a (R ) PhCH2CH2; X, X1
) H) has been attempted using tributylstannylhydride
(Bu3SnH) as reductant in the presence of radical initia-
tors such as azobisisobutyronitrile (AIBN) or triethylbo-
rane14 in benzene, in toluene, or in xylene under various
temperature conditions, but the only product identified
was the reduction compound 5a (R ) PhCH2CH2; X, X1
) H). Significant amounts of an unidentified complex
mixture were obtained if the reaction was performed at
elevated temperature, such as under xylene reflux condi-
tions. Radical reaction using atom transfer method also
gave no cyclized compound but afforded complex mix-
tures.15 We then tried electro-reductive intramolecular
cyclization of esters 2a ,16 but no desired lactone 1a was
obtained, though we found an interesting reaction that
reductive cleavage of the acyl group occurred to provide
corresponding alcohol 6a when the reaction was carried
(12) Barth, F.; O-Yang, C. Tetrahedron Lett. 1990, 31, 1121.
(13) (a) Itoh, T.; Ohara, H.; Emoto, S. Tetrahedron Lett. 1995, 36,
3531. (b) Itoh, T.; Sakabe, K.; Kudo, K.; Zagatti, P.; Renou, M.
Tetrahedron Lett. 1998, 39, 4071.
(14) For examples, see: (a) Matsumoto, K.; Miura, K.; Oshima, K.;
Utimoto, K. Tetrahedron Lett. 1992, 33, 7031. (b) Czernecki, S.; Ayadi,
E.; Xie, J . Tetrahedron Lett. 1996, 37, 9193.
(15) Reviews, see: (a) Curran, D. P. Synthesis 1988, 417. (b) Giese,
B. Radicals in Organic Synthesis; Formation of Carbon-Carbon Bonds;
Pergamon Press: Oxford, 1986. A recent example, see: (c) Kim, S.; Lee,
I. Y.; Yoon, J .-Y.; Oh, D. H. J . Am. Chem. Soc. 1996, 118, 5138.
(16) Ozaki, S.; Matsushita, H.; Ohmori, H. J . Chem. Soc., Chem.
Commun. 1992, 1120.
(17) Itoh, T.; Ohara, H.; Emoto, S. Novel Trends in Electroorganic
Synthesis; Torii, S., Ed.; Kodansha: Tokyo, 1995; p 289.
(18) Yamamoto, T.; Ishibuchi, S.; Ishizuka, T.; Haratake, M.;
Kunieda, T. J . Org. Chem. 1993, 58, 1997.
(19) (a) Udding, J . H.; Tuijp, K(C.) J . M.; van Zanden, M. N. A.;
Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1994, 59, 1993. (b)
Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh,
K. J . Org. Chem. 1993, 58, 464. (c) Benincasa, M.; Forti, L.; Ghelfi, F.;
Pagnoni, U. M. Tetrahedron Lett. 1995, 36, 1103.
(20) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara,
M. J . Am. Chem. Soc. 1982, 104, 5564. (b) Stork, G.; Mook, R., J r.;
Biller, S.; Rychnovsky, S. D. J . Am. Chem. Soc. 1983, 105, 3741.

254 J . Org. Chem., Vol. 64, No. 1, 1999
Itoh et al.
Ta ble 1. Syn th esis of r,r-Diflu or o-γ-la cton es 1 th r ou gh In tr a m olecu la r Ra d ica l Cycliza tion P r otocola
a
b
n-Bu3SnH, AIBN (10 mol %), C6H6, reflux. Determined by capillary GC analysis (MS φ0.25 × 25 m). c Yield of corresponding R-chloro-
R,R-difluoroacetate 3a a . Results of PDC oxidation. e Results of Dess-Martin oxidation. f In accordance with the nomenclature, it should
be cited as cis-1:trans-1.
d
only five-membered lactol; and no six-membered lactol
was obtained. TMS ) lactol 4a was then treated with
tetrabutylammonium fluoride (TBAF) at room temper-
ature for 12 h to provide the deprotected lactol which was
used immediately for oxidation without further purifica-
tion. PDC oxidation of the lactol in CH2Cl2 in the presence
of molecular sieves 4A powder at room temperature for
6 h21 and subsequent purification using silica gel flash
column gave the desired R,R-difluoro-γ-lactone 1a in 72%
yield (Table 1, entry 1). Lactone 1a was also obtained
from R-chloro-R,R-difluoroacetal 3a a (R ) PhCH2CH2; X,
X1 ) H; X2 ) Cl) in 40% overall yield. Six types of new
R,R-difluoro-γ-lactones 1a -f were obtained by the same
(21) Chidambaram, N.; Bhat. S.; Chandrasekaran, S. J . Org. Chem.
1992, 57, 5013.

Synthesis of R,R-Difluoro-γ-lactones
J . Org. Chem., Vol. 64, No. 1, 1999 255
sequence (Table 1, entries 1-6). The most important
point of the present reaction is that radical cyclization
occurred regiospecifically. Neither six-membered lactol
nor intermolecular coupling products formed.
the hydrogen atom. In fact, MM2 calculation of 4i
suggested that (4,5-cis)-isomers are sterically more stable
than corresponding (4,5-trans)-isomers.25 This well agrees
with the rule hypothesized by Yadav et al.:26 they
discussed a guiding factor for the trans disposition of
C-methyl group and the adjacent side chain during
intramolecular radical cyclization.
This strategy was applicable for the synthesis of five
more highly fluorinated types of γ-lactones 1g-k . The
starting fluoroallyl alcohol 6 was prepared by the method
of Percy et al.22 Trifluoroethanol was initially converted
to the corresponding methoxyethoxymethyl ether (MEM)
which was then treated with n-BuLi at -78 °C in THF
to form corresponding vinyllithium species;24 this then
reacted with propionaldehyde to release 6g22b and 6h in
83% and 88% yield, respectively. Alcohol 6g was con-
verted to R-bromo-R,R-difluoroacetate 2g, which was
prepared in situ from the corresponding sodium salts and
oxalic chloride in the presence of triethylamine in ether
at 0 °C in 75% yield. Using 1,1,1,2-tetrafluoroethane as
starting material, another types of fluoro allyl alcohols,
6i-k , were similarly prepared.22,23 Starting esters 2i-k
were thus prepared through the same reaction sequences
in 72-75% yield and then were converted to O-TMS-
acetal by DIBAL reduction and subsequent treatment
with TMSOTf in the presence of pyridine as base in more
than 70% yield. Synthesis of highly fluorinated R,R-
difluoro-γ-lactones 1g-k was accomplished through the
present radical cyclization protocol, though it was es-
sential to use Dess-Martin oxidation24 instead of PDC
oxidation in the last step for these compounds. Synthesis
of five new types of R,R-difluoro-γ-lactones, 1g-k , has
thus been accomplished through the radical cyclization
methodology (Table 1, entries 7-11). Direct radical
cyclization of ester 2g or 2i was again attempted using
AIBN as radical initiator in the presence of Bu3SnH or
Et3SiH under benzene or toluene reflux conditions. None
of the desired γ-lactone 1g or 1i was obtained, and only
complex mixtures were produced. Therefore, the present
methodology was confirmed as the best way to synthesize
these types of highly fluorinated R,R-difluoro-γ-lactones
through intramolecular radical reaction.
It was interesting that radical cyclization products
were obtained when both O-(trimethylsilyl)-R-bromo-R,R-
difluoroacetal 3a and O-(trimethylsilyl)-R-chloro-R,R-
difluoro 3a a were subjected, while no desired cyclized
acetal was produced when chloroacetal, 3ia , was sub-
jected to the reaction; neither cyclized products nor
unreacted starting acetal 3ia was recovered, and only the
complex mixtures were obtained. These results might be
explained by the differences in reactivity between â-
methyl radical and â-difluoromethyl radical. The â-meth-
yl radical, which was generated from radical cyclization
of acetal 3a , was converted to the methyl group quickly
by reduction with Bu3SnH, while reduction of the stable
difluoromethyl radical, which was derived from acetal 3i,
proceeded slowly; further reaction caused by highly
reactive chlorine radical, appeared to form a complex
mixture, though we have no direct evidence to confirm
this.
Various types of R,R-difluoro-γ-lactones were thus
synthesized through the present radical cyclization using
stoichiometric quantities of Bu3SnH as reducing agent.
However, the growing concern about tin toxicity is
providing a powerful incentive to discover processes
utilizing tin compounds as catalyst, and several methods
employing Bu3SnH in this capacity have been devel-
oped.27,28 Among methods which use tin as catalysis, the
system of (Bu3Sn)2O-PMHS (TMSO-(SiHMeO)n-TMS)-
BuOH developed by G. Fu and colleagues28d,e was con-
sidered to the best one from the standpoints of cost,
reagent stability, and broad applicability. The technique
was found applicable to our radical cyclization after
optimization of the reaction conditions. We encountered
a serious problem of the reaction quitting at low conver-
sion using that system, though the desired cyclized
compound 4a was indeed obtained. Fortunately, this was
solved by the addition of radical initiator (5 mol % of
AIBN) eight times at 4 h intervals during the reaction,
and 7.5 mol % of (Bu3Sn)2O was added to the reaction
mixture 24 h after the reaction had begun. We thus
succeeded in reducing the amount of tin reagent signifi-
cantly and accomplished the synthesis of R,R-difluoro-γ-
lactone 1a as follows: treatment of trimethylsilylacetal
3a with 15 mol % of (Bu3Sn)2O (7.5 mol %, two times), 5
equiv of PMHS, 5.5 equiv of n-BuOH, and 40 mol % AIBN
(5 mol % added every 4 h) in toluene at 80 °C for 32 h
provided the desired cyclized compound 4a , then subse-
Trimethylsilyl group of 4g was deprotected by treat-
ment with tetrabutylammonium fluoride (TBAF) and the
subsequent PDC oxidation provided corresponding γ-lac-
tone 1g as a separable mixture (cis-1g:trans-1g ) 72:
28) (Table 1, entry 7). Each isomer was isolated by silica
gel flash column chromatography, and the stereochem-
istry was assigned by the NOE experiment of 1g in 1H
NMR analysis; strong NOE (15%) was observed between
CF2H group at 4-position with 5-H in cis-1g, while none
was observed in trans-1g. The stereochemistry of 1i
obtained was tentatively assigned as cis-form by NOE
1
experiment in H NMR analysis; strong NOE (12%) was
observed between CF2H group at 3-position with 4-H in
1i, while the opposite isomer has not yet been isolated.
As mentioned, R,R-difluoro-γ-lactone, trans-1a , was ob-
tained by radical cyclization of 1-(2-phenyl)ethylprop-2-
enyl-R-bromo-R,R-difluoro-O-(trimethylsilyl)acetal (4a )
(Table 1, entry 1). Isomer of cis-4i must be the thermo-
dynamically favored form because both have the same
geometry of trans-4a if the fluorine atom corresponds to
(25) CS Chem3D Pro was employed to calculate the steric energy
of four isomers of 3a . Calculations suggested that both (4,5-cis)-isomers
are sterically more stable than corresponding (4,5-trans)-isomers; these
well agreed with the experimental results.
(26) (a) Yadav. J . S.; Gadgil, V. R. J . Chem. Soc., Chem. Commun.
1989, 1824. (b) Yadav. J . S.; Shekaram, T.; Gadgil, V. R. J . Chem. Soc.,
Chem. Commun. 1990, 843. (c) Yadav. J . S.; Praveen Kumar, T. K.;
Maniyan, P. P. Tetrahedron Lett. 1993, 34, 2965.
(27) Pioneer examples for this field, see: (a) Corey, E. J .; Suggs, J .
W. J . Org. Chem. 1975, 40, 2554. (b) Stork, G.; Sher, P. M. J . Am.
Chem. Soc. 1986, 108, 303.
(28) (a) Hays, D. S.; Fu, G. C. J . Org. Chem. 1996, 61, 4. (b) Hays,
D. S.; Scholl, M.; Fu, G. C. J . Org. Chem. 1996, 61, 6751. (c) Hays, D.
S.; Fu, G. C. J . Org. Chem. 1997, 62, 7070. (d) Lopez, R. M.; Hays, D.
S.; Fu, G. C. J . Am. Chem. Soc. 1997, 119, 6949. (e) Hays, D. S.; Fu,
G. C. J . Org. Chem. 1998, 63, 2796.
(22) (a) Patel, S. T.; Percy, J . M.; Wilkes, R. D. Tetrahedron 1995,
51, 9201. (b) Howarth, J . A.; Owton, W. M.; Percy, J . M.; Rock, M. H.
Tetrahedron 1995, 51, 10289. (c) Crowley, P. J .; Percy, J . M.; Stansfield,
K. Tetrahedron Lett. 1996, 37, 8233. (d) Percy, J . M.; Wilkes, R. D.
Tetrahedron 1997, 53, 14749.
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(24) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.

256 J . Org. Chem., Vol. 64, No. 1, 1999
Itoh et al.
F igu r e 1. Possibility of cyclization depending on radical species.
quent alkaline treatment (2 M NaOH) released desily-
lated lactol which was finally converted to the desired
γ-lactone 1a by PDC oxidation in 40% overall yield from
3a (eq 1).
conformational energy differences between the two limit-
ing conformers; stable forms of all radical species were
S-trans-forms, which were believed to be unfavorable for
the cyclization, though the differences in heat of the
formation energy between S-trans-forms, 7‡, 2b‡, and 3b‡,
and S-cis-forms, 7#, 2b#, and 3b#, were not great (1.32-
3.86 Kcal/mol).32 Because cyclization products were ob-
tained from monofluoroacetate 712 and difluoroacetal 3b,
we found these results confusing.
Fortunately, detailed investigation of the MO calcula-
tion revealed that our experimental results could be well
explained by the differences in the spin density and
delocalization of electrons on the SOMO orbital of the
olefinic part of these radical species. The calculation
suggested very low spin density of difluoromethyl radical
of 2b to be 0.910 (S-cis-2b#) and 0.907 (S-trans-2b‡),
respectively; this explains their low reactivity and stable
nature of the difluoromethyl radicals.31 As anticipated,
MO calculation suggested much higher spin density of
O-(trimethylsilyl)acetal radical of S-cis-3b# and S-trans-
3b‡: 0.922 and 0.923, respectively. High reactivity of the
R-radical of R,R-difluoro-O-(trimethylsilyl)acetal is thus
well explained by the calculation. SOMO (-10.579 eV)
and second LUMO (0.340 eV) orbitals of S-cis-form of
monofluoroacetate 7# suggest that these harmonize well
and the cyclization is allowable (Figure 1). On the
contrary, those from 2b# do not match because electrons
of the SOMO (-10.661 eV) orbital of 2b# are completely
delocalized, so that no cyclization occurred from the
radical species derived from 2b even though it took the
S-cis-form of 2b# (Figure 1).
Conformation of the starting radical species has been
proposed to be quite important in radical cyclization,15a,26
and our experimental results clearly upheld this idea.
Because O-(trimethylsilyl)acetal radical species are free
from the restriction of geometry, this factor must be
essential to the intramolecular radical cyclization of
stable radical species such as difluoromethyl radicals.29
The results reported by Uneyama et al. strongly sup-
ported the importance of this factor in that the cyclization
was achieved efficiently to give the corresponding lactum
in more than 90% yield when N,N-bisallyl R-bromo-R,R-
difluoroacetamide was subjected to the corresponding
radical cyclization.30
To better understand the differences in the reactivity
between radicals of R,R-difluoroacetate and corresponding
O-(trimethylsilyl)acetal, semiempirical (PM3) calcula-
tions were made of radical species of allyl R-fluoroacetate
7, allyl R,R-difluoroacetate 2b, and allyl R,R-difluoro-O-
(trimethylsilyl)acetal 3b.31 The calculation estimated the
We attempted to calculate allyl dichloroacetate and
allyl dibromoacetate and observed, interestingly, that the
complete delocalization of electrons on the SOMO orbital
of the olefinic part took place only on the difluoroacetate
radical: thus difluoromethyl radical species have a very
special electron nature. This special nature of the electron
state of the olefinic part of 2b# seems due to the influence
(29) (a) Asai, H.; Uneyama, K. Chem. Lett. 1995, 1123. (b) Qiu, Z.-
M.; Burton, D. J . J . Org. Chem. 1995, 60, 5570. (c) Buttle, L. A.;
Motherwell, W. B. Tetrahedron Lett. 1994, 35, 3995.
(30) Uneyama et al. recently demonstrated successful intramolecular
radical cyclization of corresponding bisallyl R,R-difluoroamides: Un-
eyama, K.; Yanagiguchi, T.; Asai, H. Tetrahedron Lett. 1997, 38, 7763.
(31) MacSpartan Plus was employed for MO (PM3) calculation.
(32) Results of MO (PM3) calculation (heat of formation): S-cis-7#,
-83.83 kcal/mol; S-trans-7‡, -85.15 kcal/mol; S-cis-2b#, -133.54 kcal/
mol; S-trans-2b‡, -135.79 kcal/mol; S-cis-3b#, -207.58 kcal/mol;
S-trans-3b‡, -211.44 kcal/mol.

Synthesis of R,R-Difluoro-γ-lactones
J . Org. Chem., Vol. 64, No. 1, 1999 257
F igu r e 2. Successful cyclization of the radical species derived
from R,R-difluoro-O-(trimethylsilyl)acetal.
F igu r e 3. Plausible mechanism of the radical cyclization.
logical activity.34 Schlosser et al. reported the strong
similarity in properties between some fluorinated com-
pounds and their hydrogen containing sources (F/H
transposition) and contrasted this with the more dra-
matic effect of replacing a hydrogen with a methyl
group.35 The exceptional size of fluorine minimizes the
steric hindrance of the difluoromethylene group, but
steric interactions need to be considered in conjunction
with electronic factors when assessing the relations of
gem-difluorination.35 With the important feature of gem-
difluoromethylene compounds in mind, we chose R,R-
difluoroeldanolide, (3R,4R)-1f, as our target molecule for
synthesizing difluorinated analogues of the natural bio-
active compound, eldanolide, (3S,4R)-8, which is known
to be a sex pheromone of the male African sugarcane
borer, Eldana saccharina.26b,36,37
of both the low level of the SOMO orbital and the
“electric-steric effect” at R-position by the two fluorine
atoms substituted. SOMO (-9.588 eV) and LUMO orbit-
als of 3b‡ (S-trans) are also not suitable for cyclization.
However, SOMO (-9.599 eV) and third LUMO (0.869 eV)
from 3b# (S-cis) were found to match well, so that
cyclization might occur through the transition state as
illustrated in Figure 2.
From these results of MO calculation, a plausible
mechanism for the present radical cyclization is proposed
as illustrated in Figure 3. The differences of heat forma-
tion energy between S-trans-form, 2b‡ and 3b‡, and S-cis-
form, 2b# and 3b#, are not large so that these two forms
are convertible under the reaction conditions. Cyclized
product 4b is thus derived from 3b#, because reactivity
of the radical is enhanced by the trimethylsilyl substitu-
ent of its electron-donating nature. On the other hand,
radical species derived from 2b give no desired cyclized
product 1b but afford the reduction product 5b, because
neither of the transition states of 2b‡ and 2b# was
suitable for the cyclization.
2. Syn th esis of Optically Active r,r-Diflu or oeldan -
olid e. The difluoromethylene group is well-known as an
isoelectronic and isosteric substitute for oxygen in phos-
phate analogues.33 Such species, therefore, mimic the
tetrahedral transition states related to the hydrolytic
action of proteases and esterases, so that enzyme inhibi-
tion can be caused by difluorinated molecules when the
nucleophilic hydroxyl group is part of the active site.33
Geminal difluoromethylene group has been considered
as an ether-oxygen equivalent from the standpoint of
biological activity and therefore to express unique bio-
Synthesis of R,R-difluoroeldanolide, (3R,4R)-1f, was
accomplished using alcohol (R)-6f (>99% ee) as the
starting material (Scheme 3). Compound (R)-6f was
22
converted to R-chloro-R,R-difluoroacetate (R)-2fa {[R]D
+9.6 (c 1.29, CHCl3)} in 94% yield. Ester (R)-2fa was then
reduced to the corresponding acetal by DIBAL in CH2-
Cl2 at -78 °C, and subsequent treatment with (trimeth-
ylsilyl)-O-triflate (TMSOTf) in the presence of pyridine
gave O-TMS-acetal 3fa in 92% yield. To a benzene
solution of the acetal 3fa and AIBN (10 mol %) was slowly
(35) Schlosser, M.; Michel, D. Tetrahedron 1996, 52, 99.
(36) (a) Vigneron, J . P.; Me´ric, R.; Larcheveˆue, M.; Debal, A.;
Kunesch, G.; Zagatti, P.; Gallois, M. Tetrahedron Lett. 1982, 23, 5051.
(b) Vigneron, J . P.; Mic, R.; Larcheveˆue, M.; Debal, A.; Lallemand, J .
Y.; Kunesch, G.; Zagatti, P.; Gallois, M. Tetrahedron 1984, 40, 3521.
(37) For some syntheses of optically active eldanolide, see: (a)
Angert, H.; Czerwonka, R.; Reissig, H.-U. Liebigs Ann. 1996, 259. (b)
Paulsen, H.; Hoppe, D. Tetrahedron 1992, 48, 5667. (c) Suzuki, Y.;
Mori, W.; Ishizone, H.; Naito, K.; Honda, T. Tetrahedron Lett. 1992,
33, 4931. (d) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J . Am.
Chem. Soc. 1986, 108, 810. (e) Uematsu, T.; Uemura, T.; Mori, K. Agric.
Biol. Chem. 1983, 47, 587, and references therein.
(33) Nieschalk, J .; O’Hagan, D. J . Chem. Soc., Chem. Commun.
1995, 719.
(34) Chambers, R. D.; J aouhari, R.; O’Hagan, D. Tetrahedron 1989,
45, 5101.

258 J . Org. Chem., Vol. 64, No. 1, 1999
Itoh et al.
Sch em e 3. Syn th esis of Both En a n tiom er s of
Diflu or oeld a n olid ea
F igu r e 4.
natural eldanolide. We initially anticipated that R,R-
difluoro analogue would lose its pheromone activity
because it has been believed that substitutions at the
polar group of lepidoptera pheromone molecules result
in reduced recognition by the olfactory receptors. To our
surprise, the difluoroanalogues showed dose-response
curves very similar to those of natural eldanolide (Figure
4). Substituting fluorine for hydrogen results in phero-
mone analogues whose intrinsic activity varies according
to the number of substitutions and their position. Gener-
ally, substitutions at the polar group of lepidoptera
pheromone molecules result in reduced recognition by the
olfactory receptors40 and may produce potent inhibitors
of the pheromone catabolizing enzymes41 present in the
olfactory tissues. Although the lactone moiety has been
believed important to distinguish a molecule by olfactory
receptors, these results show that this idea should now
be reconsidered. This decreased affinity for the receptor
contradicts our results and makes the fluoroeldanolides
good candidates for investigation of the interaction
between eldanolide and its receptor sites. In other
lepidoptera species, whose pheromones are straight chain
compounds, in vitro trifluoromethyl ketone (TFMK)
analogues are good inhibitors of the hydrolysis of the
acetate pheromone in its alcohol moiety by antennal
esterases. They also inhibit the transformation of the
alcohol into the aldehyde. In vivo, TFMKs have very low
intrinsic activity on the receptor, and they decrease the
EAG, single cell responses, and behavior, when passed
over the antenna during the test of the pheromone or
after topical application. Those effects are not well
explained by an inhibition of the pheromone catabolism
(one would expect an increase in response due to more
pheromone being available), but rather show a direct
interaction with the receptor itself. The pathways for the
catabolism of eldanolide in the olfactory tissues and the
a
Key: (a) ClCF2CO2Li, (COCl)2, Et3N, Et2O, 0 °C; (b) DIBAL-
H, CH2Cl2, -78 °C; (c) TMSOTf, Py, -78 °C f rt; (d) n-Bu3SnH,
AIBN, benzene, reflux; (e) KF, H2O, rt; (f) PDC, MS4A, CH2Cl2,
rt; (g) BrCF2CO2Li, (COCl)2, Et3N, Et2O, 0 °C.
added a benzene solution of tributyltinhydride (2.2 equiv)
over 5 h under reflux conditions. The reaction mixture
was heated to reflux for an additional 4 h and then cooled
to room temperature. After evaporation, silica gel flash
column chromatography using hexane/ethyl acetate (200:1
to 50:1) as eluent gave the cyclized product. This step
finished regiospecifically to provide only five-membered
lactol; no six-membered lactol was obtained. TMS-lactol
was then treated with 1.0 M THF solution of tetrabutyl-
ammonium fluoride (TBAF) at room temperature for 21
h to provide the deprotected lactol which was used
immediately for oxidation without further purification.
PDC oxidation of the lactol in CH2Cl2 in the presence of
molecular sieves 4A powder at room temperature for 6
h, and subsequent purification using silica gel flash
23
column gave the desired γ-lactone (3R,4R)-1f {[R]D
+62.4 (c 1.17, EtOH)} in 51% overall yield from 2fa .
Optical purity of the final product (3R,4R)-1f was con-
firmed by GC analysis as >99% ee because no signal of
the enantiomer was observed using chiral column (Chiral-
dex G-Ta). Thus, the starting optical purity was exactly
retained during these reaction sequences. Using this
protocol, the antipode of R,R-difluoroeldanolide (3S,4S)-
22
1f {[R]D -63.3 (c 1.15, EtOH)} was also synthesized
(38) For an example of EAG experiment for insect pheromones,
see: Lucas, P.; Renou, M.; Tellier, F.; Hammoud, A.; Audemard, H.;
Descoins, C. J . Chem. Ecol. 1994, 20, 489.
from 98% ee of (S)-6f. We thus accomplished the first
synthesis of optically active R,R-difluoroeldanolide through
intramolecular radical cyclization protocol and Pseudomo-
nas cepacia lipase (PCL)-catalyzed enantioselective acy-
lation.
(39) (a) Vigneron, J . P.; Me´ric, R.; Larcheveˆue, M.; Debal, A.;
Kunesch, G.; Zagatti, P.; Gallois, M. Tetrahedron Lett. 1982, 23, 5051.
(b) Vigneron, J . P.; Me´ric, R.; Larcheveˆue, M.; Debal, A.; Lallemand,
J . Y.; Kunesch, G.; Zagatti, P.; Gallois, M. Tetrahedron 1984, 40, 3521.
(40) (a) Prestwich, G. D.; Sun, W. C.; Mayer, M. S.; Dickens, J . C.
J . Chem. Ecol. 1990, 16, 1761. (b) Ding, Y.-S; Prestwich, G. D. J . Chem.
Ecol. 1988, 14, 2033. (c) Prestwich, G. D.; Streinz, L. J . Chem. Ecol.
1988, 14, 1003. (d) Camps, F.; Gasol, V.; Guerrero, A.; Hernandez, R.;
Montoya, R. Pestic. Sci. 1990, 29, 123. (e) Riba, M.; Eizaguirre, M.;
Sans, A.; Quero, C.; Guerrero, A. Pestic. Sci. 1994, 41, 97.
(41) Graham, S. M.; Prestwich, G. D. J . Org. Chem. 1994, 59, 2956.
Duran, I.; Parilla, A.; Feixas, J .; Guerrero, A. Bioorg. Med. Chem. Lett.
1993, 3, 2953. Rosell, G.; Herrero, S.; Guerrero, A. Biochem. Biophys.
Res. Commun. 1996, 226, 227.
The biological activity of eldanolide, fluorinated el-
danolide and their antipodes was compared by electroan-
tennography. Increasing doses were tested on female
antennae according to standard procedures.38 As previ-
ously reported,39 both enantiomers of eldanolide elicited
strong EAG responses, the difluoroeldanolide (4S,5R)-
(+)-1f being slightly but significantly more active than

Synthesis of R,R-Difluoro-γ-lactones
J . Org. Chem., Vol. 64, No. 1, 1999 259
compound was immediately used for the further reaction. To
a solution of lactol 4i (450 mmg, 1.22 mmol) in THF (1.8 mL)
was added a THF (1.8 mL) solution of tetrabutylammonium
fluoride (1.8 mmol) at room temperature, and the mixture was
stirred for 12 h under ambient atmosphere. The reaction
mixture was diluted with ether (20 mL) and washed with
water and brine. The organic layer was dried over MgSO4 and
evaporated to afford desilylated lactol (470 mg) which was then
used immediately for the following Dess-Martin oxidation. A
dichloromethane (8.1 mL) solution of the crude lactol (450 mg)
was added to Dess-Martin periodinane (1.03 g, 2.44 mmol),
and the mixture was stirred for 26 h at room temperature.
The reaction was quenched by addition of 10% Na2S2O3
solution (2 mL), and the mixture was extracted with ethyl
acetate. The combined organic layers were dried, concentrated
under vacuo, and chromatographed on silica gel (hexanes/ethyl
acetate ) 12:1-3:1) and gave lacton 1i (190 mg, 0.65 mmol)
as a coloress oil in 53% yield. Lactone (cis)-(3S*,4S*)-1i: bp
100 °C/5.0 mmHg (Kugelrohr); Rf 0.61 (hexane/ethyl acetate
) 7:1); 1H NMR (200 MHz, CDCl3) 2.02-2.18 (2H, m), 2.70
(1H, dt, J ) 14.1, 8.3 Hz), 2.92 (1H, ddd, J ) 14.1, 8.5, 5.1
Hz), 4.66 (1H, ddd, J ) 18.3, 10.0, 3.4 Hz), 5.99 (1H, dt, J )
7.3, 52.4 Hz), 7.11-7.30 (5H, m); 13C NMR (50 MHz, CDCl3)
enzymes involved are totally unknown, but the activity
of the difluoroeldanolides makes them very different from
the TFMKs.
Con clu sion
In conclusion, this paper describes an efficient general
route to access a variety of new multifluorinated R,R-
difluoro-γ-lactones. We succeeded in synthesizing opti-
cally active R,R-difluoro analogues of natural pheromone,
and they showed unexpected biological activity; the
essence of fluorine chemistry is found in such “unpredict-
able reactivity” of fluorinated compounds. The impor-
tance of the development of efficient methods for the
synthesis of selectively fluorinated compounds has thus
greatly increased. Because optically active R,R-difluoro-
γ-lactones can be synthesized using the present meth-
odology, we hope that our technique will be widely used
in the field of synthetic organic chemistry for the design
of new fluorinated molecules.
29.53 (d, J C-F ) 6.6 Hz), 30.66, 77.16, 90.69 (dddt, J C-F
)
207.0, 24.3, 18.0, 24.3 Hz), 109.71 (ddt, J C-F ) 29.1, 3.5, 249.9
Hz), 122.87 (dd, J C-F ) 408.5, 397.3 Hz), 126.76, 128.41,
128.82, 139.03, 160.63 (dd, J C-F ) 31.8, 30.2 Hz); 19F NMR
(188 MHz, CDCl3) -39.32 to 38.98 (1F, m), 28.35 (1F, ddt, J
) 313.3, 52.2, 9.2 Hz), 30.72 (1F, ddt, J ) 308.9, 50.2, 6.4 Hz),
36.11 (1F, dd, J ) 294.7, 8.5 Hz), 39.00 (1F, ddd, J ) 297.7,
Exp er im en ta l Section
Gen er a l P r oced u r es. Reagents and solvents were pur-
chased from common commercial sources and were used as
received or purified by distillation from appropriate drying
agents. Reactions requiring anhydrous conditions were run
under an atmosphere of dry argon. Wako gel C-300 and Wako
gel B5F were used for flash column chromatography and thin-
layer chromatography (TLC), respectively. Chemical shifts are
expressed in δ value (ppm) downfield from tetramethylsilane
(TMS) in CDCl3 as an internal reference. 19F NMR spectra
were reported in ppm downfield from C6F6 as an internal
reference.
15.3, 7.5 Hz); IR (neat) 3030, 2935, 1826(CO), 1267, 1167 cm-1
.
Anal. Calcd for C13H11F5O2: C, 53.07; H, 3.77. Found: C, 53.15;
H, 3.87.
Using the same procedure, new γ-lactones 1 were synthe-
sized. Dess-Martin oxidation gave better yield than PDC
oxidation when lactols 4i, 4j, and 4k were subjected.
2,2-Diflu or o-3-m eth ylbu ta n -4-olid e(1b): bp 110 °C/760
1
Syn th esis of γ-Lacton es. (3R*,4S*)-2,2-Diflu or o-3-m eth -
yl-6-p h en ylh exa n -4-olid e (1a ). To a solution of 4a (130 mg,
0.413 mmol) in dry THF (1.5 mL) was added 0.5 mL of TBAF
(0.5 mmol, 1.0 M in THF) at room temperature. After 11 h of
stirring, the mixture was diluted with ether and washed brine.
The organic layer was dried over anhydrous MgSO4. After
removal of the solvent by evaporation, 85 mg of lactol was
obtained. The lactol was dissolved in dry CH2Cl2 containing
300 mg of powdered MS4A, and PDC (404 mg, 1.052 mmol)
was added at room temperature. After 6 h of stirring, the
mixture was filtered through a short column of Florisil. Silica
gel flash column chromatography (hexane/ethyl acetate ) 20:
1) gave lactone 1a as a colorless oil in 72% yield (56.7 mg,
0.236 mmol): bp 100 °C/1.0 mmHg (Kugelrohr); Rf 0.40
(hexane/ethyl acetate ) 7:1); 1H NMR (200 MHz, CDCl3) 1.21
(3H, d, J ) 6.8 Hz), 1.89-2.22 (2H, m), 2.24-2.56 (1H, m),
2.71-3.04 (2H, m), 4.16 (1h, dt, J ) 9.0 Hz, 3.3 Hz), 7.21-
7.39 (5H, m); 13C NMR (50 MHz, CDCl3) 7.49 (d, J C-F ) 7.6
mmHg (Kugelrohr); Rf 0.17 (hexane/ethyl acetate ) 4:1); H
NMR (200 MHz, CDCl3) 1.23 (3H, dd, J ) 7.0, 1.3 Hz), 2.65-
2.95 (1H, m), 4.00 (1H, t, J ) 8.5 Hz), 4.52 (1H, t, J ) 8.5 Hz);
13C NMR (50 MHz, CDCl3) 8.49 (d, J C-F ) 7.2 Hz), 37.04 (t,
J C-F ) 21.4 Hz), 70.13 (d, J C-F ) 7.6 Hz), 114.96 (dd, J C-F
)
257.1 Hz, 253.5 Hz), 165.51 (t, J C-F ) 31.6 Hz); 19F NMR (188
MHz, CDCl3) 39.46 (1F, dd, J ) 274.9, 17.0 Hz), 46.41 (1F,
dd, J ) 275.0, 13.1 Hz); IR (neat) 2980, 1810, 1460, 1350, 1220,
1105, cm-1. Anal. Calcd for C5H6F2O2: C, 44.13; H, 4.44.
Found: C, 44.53; H, 4.76.
3-Ben zyl-2,2-d iflu or ob u t a n -4-olid e(1c): bp 67 °C/7.0
1
mmHg (Kugelrohr); Rf 0.44 (hexane/ethyl acetate ) 4:1); H
NMR (200 MHz, CDCl3) 2.70 (1H, dd, J ) 13.5, 9.6 Hz), 2.82-
3.10 (1H, m), 3.13 (1H, dd, J ) 13.5, 5.4 Hz), 4.08 (2H, dd, J
) 9.3, 8.1 Hz), 4.31 (1H, dd, J ) 9.4, 7.5 Hz), 7.14-7.34 (5H,
m); 13C NMR (50 MHz, CDCl3,) 30.17 (d, J C-F ) 6.2 Hz), 43.50
(t, J C-F ) 20.3 Hz), 65.58 (d, J C-F ) 7.3 Hz), 114.60 (dd, J C-F
) 256.9, 251.8 Hz), 127.25, 128.53, 128.98, 135.85, 165.35 (dd,
J C-F ) 33.1, 32.9 Hz); 19F NMR (188 MHz, CDCl3) 41.51 (1F,
dd, J ) 276.0, 17.1 Hz), 47.88 (1F, dd, J ) 276.0, 12.6 Hz); IR
(neat) 3032, 1812, 1496, 1455, 1117, 992, cm-1. Anal. Calcd
for C11H10F2O2: C, 62.26; H, 4.75. Found: C, 62.82; H, 4.92.
2,2-Diflu or o-3-isop r op ylbu ta n -4-olid e (1d ): bp 60 °C/7.5
mmHg (Kugelrohr); Rf 0.43 (hexane/ethyl acetate ) 10:1); 1H
NMR (200 MHz, CDCl3) 0.92 (3H, d, J ) 6.7 Hz), 1.10 (3H,
dd, J ) 6.5, 1.3 Hz), 1.93-2.12 (1H, m), 2.22-2.53 (1H, m),
4.05 (1H, t, J ) 9.5 Hz), 4.50 (1H, t, J ) 8.8 Hz); 13C NMR (50
MHz, CDCl3,) 19.54, 20.16, 25.28 (d, J C-F ) 5.1 Hz), 48.19 (t,
Hz), 31.14, 35.06, 42.83 (t, J C-F ) 20.6 Hz), 81.74 (d, J C-F
)
8.1 Hz), 115.56 (dd, J C-F ) 259.6, 251.3 Hz), 126.38, 128.31,
128.62, 139.91, 165.12 (dd, J C-F ) 34.1, 32.0 Hz); 19F NMR
(188 MHz, CDCl3) 41.13 (1F, dd, J ) 274.9, 20.9 Hz), 47.30
(1F, dd, J ) 274.9, 12.4 Hz); IR (neat) 3030, 2940, 1810, 1460,
1340, 700 cm-1. Anal. Calcd for C13H14F2O2: C, 64.00; H, 5.87.
Found: C,64.00; H, 5.87.
(3S*,4S*)-2,2,3-Tr iflu or o-3-(d iflu or om eth yl)-6-p h en yl-
h exa n -4-olid e (1i). To a boiling solution of silyl acetal 3i (1.87
g, 4.2 mmol) and AIBN (21 mg, 0.125 mmol) in benzene (20.0
mL) was added a benzene (65 mL) solution of Bu3SnH (1.75
mL, 6.3 mmol) dropwise over 7 h, and the mixture was stirred
for an additional 3 h under reflux conditions. After being cooled
to room temperature, a KF-saturated aqueous solution (40 mL)
was added to the reaction mixture at room temperature and
stirred for 15 min. The reaction mixture was extracted with
ether. The combined organic layers were dried over MgSO4
and evaporated to dryness, and silica gel flash column chro-
matography (hexane/ethyl acetate ) 50:1) gave O-TMS-lactol
4i (1.20 g, 3.3 mmol) as a colorless liquid in 78% yield. This
J C-F ) 19.9 Hz), 68.41 (d, J C-F ) 9.1 Hz), 114.91 (dd, J C-F
)
259.5, 251.3 Hz), 165.86 (dd, J C-F ) 34.5, 32.2 Hz); 19F NMR
(188 MHz, CDCl3) 41.42 (1F, dd, J ) 280.4, 21.2 Hz), 50.98
(1F, dd, J ) 279.1, 12.9 Hz); IR (neat) 2971, 1815, 1473, 1365,
1208, 1106, cm-1. Anal. Calcd for C7H10F2O2: C, 51.22; H, 6.14.
Found: C, 51.43; H, 6.56.
(3R*,4S*)-2,2-Diflu or o-3-m eth ylocta n -4-olid e (1e): bp 55
°C/3.0 mmHg (Kugelrohr); Rf 0.47 (hexane/ethyl acetate ) 10:
1); 1H NMR (200 MHz, δ, CDCl3) 0.90 (3H, t, J ) 6.8 Hz), 1.19
(3H, d, J ) 6.9 Hz), 1.26-1.77 (6H, m), 2.17-2.49 (1H, m),

260 J . Org. Chem., Vol. 64, No. 1, 1999
Itoh et al.
4.12 (1H, dt, J ) 8.5, 3.6 Hz); 13C NMR (50 MHz, CDCl3,) 7.53
J ) 299.4 Hz); IR (neat) 2935, 2858, 1826, 1454, 1171 cm-1
.
(d, J C-F ) 7.6 Hz), 13.64, 22.20, 27.02, 32.88, 42.78 (t, J C-F
)
Anal. Calcd for C11H13F5O2: C, 48.54; H, 4.81. Found: C, 48.61;
H, 4.77.
20.5 Hz), 82.93 (d, J C-F ) 8.0 Hz), 115.70 (dd, J C-F ) 259.6,
251.1 Hz), 165.28 (dd, J C-F ) 33.9, 31.8 Hz); 19F NMR (188
MHz, CDCl3) 41.23 (1F, dd, J ) 274.7, 21.0 Hz), 47.30 (1F,
dd, J ) 275.0, 13.2 Hz); IR (neat) 2950, 1810, 1460, 1320, 1210,
cm-1. Anal. Calcd for C9H14F2O2: C, 56.24; H, 7.34. Found:
C, 56.69; H, 7.61.
(3S*,4S*)-3-(Diflu or om et h yl)-2,2,3-t r iflu or od eca n -4-
olid e (1k ): bp 70 °C/2.5 mmHg (Kugelrohr); Rf 0.58 (hexane/
ethyl acetate ) 10:1); 1H NMR (200 MHz, CDCl3) 0.90 (3H, t,
J ) 6.8 Hz), 1.25-1.92 (10H, m), 4.79 (1H, ddd, J ) 18.6, 8.8,
4.3 Hz), 6.15 (1H, dt, J ) 52.5, 6.7 Hz); 13C NMR (50 MHz,
CDCl3) 13.95, 22.43, 24.91, 27.97 (d, J C-F ) 7.0 Hz), 28.62,
31.37, 78.59 (d, J C-F ) 21.7 Hz), 109.85 (ddt, J C-F ) 248.0,
29.5, 2.7 Hz), 160.75 (dd, J C-F ) 33.1, 30.7 Hz); 19F NMR (188
MHz, CDCl3) -38.84 to -38.79 (1F, m), 28.72 (1F, ddt, J )
311.3, 51.9, 9.2 Hz), 30.70 (1F, ddt, J ) 308.3, 51.2, 6.4 Hz),
36.20 (1F, dd, J ) 294.4, 8.8 Hz), 38.55 (1F, ddd, J ) 297.1,
17.0, 9.2 Hz); IR (neat) 2931, 2862, 1826, 1468, 1265, 1169
cm-1. Anal. Calcd for C11H15F5O2: C, 48.18; H,5.51 Found: C,
48.00; H, 5.59.
(3R*,4S*)-2,2-Diflu or o-7,3-d im eth yl-6-octen -4-olide (1f):
bp 75 °C/2.2 mmHg (Kugelrohr); Rf 0.39 (hexane/ethyl acetate
) 10:1); 1H NMR (200 MHz, CDCl3) 1.18 (3H, dd, J ) 6.9, 1.2
Hz), 1.61 (3H, s), 1.71 (3H, s), 2.22-2.59 (3H, m), 4.17 (1H,
dt, J ) 8.8, 5.5 Hz), 5.05-5.15 (1H, m); 13C NMR (50 MHz,
CDCl3,) 7.71 (d, J C-F ) 7.7 Hz), 17.93, 25.75, 31.00, 41.70 (t,
J C-F ) 20.6 Hz), 82.53 (d, J C-F ) 8.0 Hz), 115.73 (dd, J C-F
)
259.6, 251.1 Hz), 115.94, 137.19, 165.27 (dd, J C-F ) 34.0, 32.0
Hz); 19F NMR (188 MHz, CDCl3) 41.65 (1F, dd, J ) 274.7, 21.0
Hz), 47.38 (1F, dd, J ) 274.9, 12.6 Hz); IR (neat) 2922, 1811,
1460, 1337, 1213, cm-1. Anal. Calcd for C10H14F2O2: C, 58.81;
H, 6.91. Found: C, 57.44; H, 7.03.
La ctol 4a (m ixtu r e of d ia ster eom er s): bp 100 °C/4.0
1
mmHg (Kugelrohr); Rf 0.63 (hexane/ethyl acetate ) 7:1); H
NMR (200 MHz, CDCl3) 0.12-0.13 (9H, m), 0.96-1.03 (3H,
m) 1.76-1.88 (2H, m), 1.88-2.35 (1H, m), 2.48-2.85 (2H, m),
3.58 (0.5H, dt, J ) 4.6, 4.1 Hz), 3.85 (0.5H, dd, J ) 12.7, 6.5
Hz), 5.02 (0.5H, d, J ) 6.9 Hz), 5.17 (0.5H, d, J ) 6.5 Hz),
7.08-7.24 (5H, m); 13C NMR (50 MHz, CDCl3) 0.23, 0.39, 7.45
(d, J C-F ) 7.3 Hz), 11.67 (d, J C-F ) 7.7 Hz), 31.75, 31.85, 36.21,
37.39, 40.39 (t, J C-F ) 21.3 Hz), 43.91 (t, J C-F ) 23.4 Hz), 81.96
(d, J C-F )8.3 Hz), 83.12-83.27 (m), 95.60 (dd, J C-F ) 41.1,
26.2 Hz), 97.12 (dd, J C-f ) 43.7, 23.8 Hz), 125.94, 126.45 (dd,
J C-F ) 261.6, 247.5 Hz), 128.35, 128.41, 141.50, 141.64; 19F
NMR (188 MHz, CDCl3) 36.79 (0.5F, ddd, J ) 229.4, 23.3, 6.8
Hz), 38.46 (0.5F, d, J ) 233.1 Hz), 38.74 (0.5F, dd, J ) 229.4,
10.4 Hz), 61.15 (0.5F, ddd, J ) 232.9, 24.3, 6.4 Hz); IR (neat)
2950, 1600, 1450, 1365, 1250 cm-1. Anal. Calcd for C16H24F2O2-
Si: C, 61.12; H, 7.69. Found: C, 61.55; H, 7.65.
cis-(3S*,4S*)-3-(Diflu or om eth yl)-2,2-d iflu or o-3-((m eth -
oxyeth oxy)m eth oxyh exa n -4-olid e (1g): bp 90 °C/3.8 mmHg
(Kugelrohr); Rf 0.32 (hexane/ethyl acetate ) 4:1); 1H NMR (200
MHz, CDCl3) 1.08 (3H, t, J ) 16.5 Hz), 1.60-1.96 (2H, m),
3.38 (3H, s), 3.55-3.95 (4H, m), 4.71-4.74 (1H, m), 4.93-5.24
(2H, m), 6.52 (1H, t, J ) 53.6 Hz); 13C NMR (50 MHz, CDCl3,)
9.56, 22.74, 58.88, 68.23, 71.19, 77.19-79.00 (m), 80.66 (dd,
J C-F ) 6.8 Hz, 4.4 Hz), 93.30 (d, J C-F ) 4.8 Hz), 112.21 (ddt,
J C-F ) 250.6, 247.1, 3.6 Hz), 162.10 (t, J C-F ) 31.0 Hz); 19F
NMR (188 MHz, CDCl3) 29.19 (1F, ddd, J ) 305.5, 54.3, 7.1
Hz), 31.30 (1F, ddd, J ) 305.9, 53.4, 12.2 Hz), 40.43 (1F, dd,
J ) 288.9, 12.2 Hz), 47.48 (1F, dd, J ) 289.3, 6.8 Hz); IR (neat)
2939, 1820, 1462, 1236, 1163 cm-1
11H16F4O5: C, 43.43; H, 5.30. Found: C, 43.47; H, 5.46.
t r a n s-(3S *,4R *)-3-(Diflu or om e t h yl)-2,2-d iflu or o-3-
. Anal. Calcd for
C
La ctol 4b (m ixtu r e of d ia ster eom er s): bp 50 °C/45
1
((m eth oxyeth oxy)m eth oxy)h exa n -4-olid e (1g): bp 90 °C/
3.8 mmHg (Kugelrohr); Rf 0.26 (hexane/ethyl acetate ) 4:1);
1H NMR (200 MHz, CDCl3) 1.14 (3H, t, J ) 7.4 Hz), 1.81-
2.05 (2H, m), 3.38 (3H, s), 3.52-3.57 (2H, m), 3.66-3.74 (1H,
m), 3.84-3.93 (1H, m), 4.57 (1H, dd, J ) 9.8, 4.3 Hz), 4.98
(1H, d, J ) 8.0 Hz), 5.18 (1H, d, J ) 7.9 Hz), 6.32 (1H, t, J )
52.7 Hz); 13C NMR (50 MHz, CDCl3,) 10.59, 22.53, 58.88, 68.33,
77.19-79.00 (m), 83.39 (d, J C-F ) 2.3 Hz), 93.06, 113.05 (tt,
J C-F ) 249.8, 3.7 Hz), 161.91 (t, J C-F ) 30.9 Hz); 19F NMR
(188 MHz, CDCl3) 31.27 (2F, dd, J ) 51.9, 6.8 Hz), 39.71 (1F,
dd, J ) 284.9, 6.8 Hz), 41.30 (1F, dd, J ) 285.4, 6.8 Hz); IR
mmHg (Kugelrohr); Rf 0.62 (hexane/ethyl acetate ) 7:1); H
NMR (200 MHz, CDCl3) 0.19 (9H, s), 1.08-1.16 (3H, m), 2.35-
2.60 (1H, m), 3.49-3.80 (1H, m), 4.15-4.25 (1H, m), 5.08-
5.19 (1H, m); 13C NMR (50 MHz, CDCl3) -0.01, -0.04, 7.78-
8.06 (m) 12.13 (dd, J C-F ) 7.4, 4.4 Hz), 35.67 (dt, J C-F ) 37.2,
22.3 Hz), 37.85 (dd, J C-F ) 24.4, 22.2 Hz), 70.98-72.31 (m),
72.23 (t, J C-F ) 3.8 Hz), 96.05(dd, J C-F ) 37.9, 29.2 Hz), 96.90
(dd, J C-F ) 43.7, 24.3 Hz), 125.45 (dd, J C-F ) 261.9, 255.3 Hz),
126.08 (dd, J C-F ) 266.1, 245.8 Hz); 19F NMR (188 MHz,
CDCl3) 36.18 (0.5F, d, J ) 233.8 Hz), 36.83 (0.5F, d, 20.0 Hz),
37.04 (0.5F, dd, J ) 20.0, 4.9 Hz), 59.09 (0.5 F, ddd, J ) 233.9,
23.2, 6.6 Hz); IR (neat) 2975, 1460, 1255, 1040 cm-1. Anal.
Calcd for C8H16F2O2Si: C, 45.69; H, 7.67. Found: C, 45.78; H,
7.68.
(neat) 2941, 1823, 1462, 1096 cm-1
11H16F4O5: C, 43.43; H, 5.30. Found: C, 43.54; H, 5.28.
(3S*,4S*)-3-(Diflu or om eth yl)-2,2-d iflu or o-3-((m eth oxy-
. Anal. Calcd for
C
eth oxy)m eth oxy)-3-m eth ylh exa n -4-olid e (1h ): bp 70 °C/
5.0 mmHg (Kugelrohr); Rf 0.40 (hexane/ethyl acetate ) 4:1);
1H NMR (200 MHz, CDCl3) 0.98 (3H, d, J ) 6.6 Hz), 1.04 (3H,
d, J ) 6.8 Hz), 2.09-2.26 (1H, m), 3.34 (3H, s), 3.51 (2H, t, J
) 4.0 Hz), 3.57-3.70 (1H, m), 3.82-3.93 (1H, m), 4.53 (1H, d,
J ) 6.6 Hz), 4.92 (1H, d, J ) 8.0 Hz), 5.19 (1H, d, J ) 9.4 Hz),
6.51 (1H, t, J ) 53.6 Hz); 13C NMR (50 MHz, CDCl3,) 17.39,
19.44, 28.08, 58.89, 68.30, 71.18, 78.00-79.58 (m), 83.58 (dd,
J ) 7.3, 3.8 Hz), 93.27 (d, J ) 5.3 Hz), 112.39 (t, J ) 248.1
Hz), 114.21 (dd, J ) 250.3, 246.2 Hz), 162.09 (t, J ) 31.2 Hz);
19F NMR(188 MHz, CDCl3) 31.24 (1F, d, J ) 51.9 Hz), 31.36
(1F, dd, J ) 63.6, 11.9 Hz), 41.39 (1F, ddd, J ) 289.9, 10.0,
6.1 Hz), 48.01 (1F, d, J ) 289.9 Hz); IR (neat) 2947, 1809, 1475,
1398, 1371, 1237 cm-1. Anal. Calcd for C12H18F4O5: C, 45.29;
H, 5.70. Found: C, 45.33; H, 5.81.
(3S*,4S*)-4-Cycloh exyl-3-(d iflu or om eth yl)-2,2,2-tr iflu o-
r obu ta n -4-olid e (1j): bp 60 °C/4.5 mmHg (Kugelrohr); Rf 0.44
hexane/ethyl acetate ) 10:1); 1H NMR (200 MHz, CDCl3) 1.12-
1.44 (5H, m), 1.68-2.03 (6H, m), 4.57 (1H, dd, J ) 17.6, 7.2
Hz), 6.16 (1H, dt, J ) 53.0, 5.0 Hz,); 13C NMR (50 MHz, CDCl3)
25.20, 25.41, 25.65, 27.81, 28.90, 37.23 (d, J ) 3.9 Hz), 81.92
(d, J ) 21.2 Hz), 91.59 (ddt, J ) 207.1, 26.0, 17.4 Hz), 110.54
(ddt, J ) 251.1, 34.9, 3.4 Hz), 160.81 (t, J ) 31.1 Hz); 19F NMR
(188 MHz, CDCl3) -35.65 to -35.20 (1F, m), 29.01 (1F, ddt, J
) 311.3, 51.9, 12.2 Hz), 31.86 (1F, ddt, J ) 308.6 Hz, 57.7,
11.9 Hz), 37.13 (1F, ddt, J ) 298.8, 13.6, 7.5 Hz), 40.27 (1F, d,
La ctol 4c (m ixtu r e) of d ia ster eom er s: bp 90 °C/2.6
mmHg (Kugelrohr); Rf 0.63 (hexane/ethyl acetate ) 7:1); H
1
NMR (200 MHz, CDCl3) 0.10 (3H, s), 0.22 (6H, s) 2.62-3.12
(3H, m), 3.65-4.11 (2H, m), 5.12 (0.5H, d, J ) 5.8 Hz), 5.21
(0.5H, d, J ) 6.9 Hz); 13C NMR (50 MHz, CDCl3) -0.01, 30.73
(d, J C-F ) 6.2 Hz), 33.42 (dd, J C-F ) 6.7, 3.7 Hz), 41.77 (t,
J C-F ) 21.2 Hz), 44.42 (dd, J C-F ) 23.3, 21.0 Hz), 69.99 (d,
J C-F ) 7.9 Hz), 70.39 (t, J C-F ) 3.7 Hz), 96.28 (dd, J C-F ) 39.3,
27.2 Hz), 97.10 (dd, J C-F ) 40.9, 23.6 Hz), 125.23 (dd, J C-F
)
262.1, 248.6 Hz), 126.47, 126.53, 128.56, 128.61, 138.48,
138.65; 19F NMR (188 MHz, CDCl3) 37.97 (0.5F, d, J ) 233.4
Hz), 38.29 (0.5F, dd, J ) 230.4, 10.9 Hz), 39.91 (0.5F, ddd, J
) 230.4, 20.2 Hz, 5.6 Hz), 60.31 (0.5 F, ddd, J ) 234.7, 22.8,
6.8 Hz); IR (neat) 2950, 1600, 1450, 1365, 1250 cm-1. Anal.
Calcd for C14H20F2O2Si: C, 58.71; H, 7.04. Found: C, 58.89;
H, 7.02.
La ctol 4d (m ixtu r e of d ia ster eom er s): bp 60 °C/7.5
mmHg (Kugelrohr); Rf 0.49 (hexane/ethyl acetate ) 10:1); 1H
NMR (200 MHz, CDCl3) 0.17 (4.5 H, s), 0.18 (4.5 H, s), 0.84-
0.95 (3H, m), 1.03-1.09 (3H, m), 1.79-1.98 (1H, m), 1.98-
2.43 (1H, m), 3.62-3.71 (0.5H, m), 3.86 (0.5 H, t, J ) 9.5 Hz),
4.01-4.10 (0.5H, m), 4.20 (0.5H, t, J ) 8.8 Hz), 5.05 (0.5H,
dd, J ) 7.3, 1.9 Hz), 5.21 (0.5H, d, J ) 7.3 Hz); 13C NMR (50
MHz, CDCl3) -0.10, 20.45, 20.62, 21.09, 21.45, 25.93, 26.02,
46.36 (t, J C-F ) 20.6 Hz), 51.01 (t, J C-F ) 22.1 Hz), 69.28 (dd,
J C-F ) 4.6, 2.2 Hz), 69.95 (d, J C-F ) 9.8 Hz), 96.79 (dd, J C-F
)

Synthesis of R,R-Difluoro-γ-lactones
J . Org. Chem., Vol. 64, No. 1, 1999 261
41.7, 25.5 Hz), 97.98 (dd, J C-F ) 43.8, 22.9 Hz), 125.72 (dd,
J C-F ) 258.1, 246.5 Hz), 125.92 (dd, J C-F ) 265.9, 249.4 Hz);
19F NMR (188 MHz, CDCl3) 38.91 (0.5F, ddd, J ) 233.0, 24.4,
7.8 Hz), 39.10 (0.5F, dd, J ) 238.7, 11.4 Hz), 43.42 (0.5F, dd,
J ) 232.6, 9.2 Hz), 62.45 (0.5 F, ddd, J ) 237.5, 21.5 Hz); IR
(neat) 2963, 1477, 1385, 1253 cm-1. Anal. Calcd for C10H20F2O2-
Si: C, 50.39; H, 8.46. Found: C, 50.24; H, 8.49.
NMR (200 MHz, CDCl3) 0.23 (4.5 H, s), 0.25 (4.5H, s), 1.88-
2.28 (2H, m), 2.62-3.00 (2H, m), 4.22-4.55 (1H, m), 5.24 (0.5H,
d, J ) 8.3 Hz), 5.31 (0.5H, dd, J ) 6.4, 2.7 Hz), 5.67-6.29 (1H,
m), 7.20-7.35 (5H, m); 13C NMR (50 MHz, CDCl3) -0.24,
-0.09, 29.80 (d, J C-F ) 9.1 Hz), 31.12-31.30 (m), 31.59 (d,
J C-F ) 9.1 Hz), 76.16-78.14 (m), 94.60-96.42 (m), 107.00-
116.60 (m), 126.17, 126.24, 128.39, 128.52, 140.57, 140.69;19F
NMR (188 MHz, CDCl3) -43.04 (0.5F, d, J ) 481.5 Hz), -37.11
to -36.34 (0.5F, m), 26.13-41.77 (4F, m); IR (neat) 2962, 1255,
1095 cm-1. Anal. Calcd for C16H21F5O2Si: C, 52.16; H, 5.75.
Found: C, 52.37; H, 5.64.
La ctol 4j (m ixtu r e of d ia ster eom er s): bp 80 °C/4.0
mmHg (Kugelrohr); Rf 0.49 (hexane/ethyl acetate ) 10:1); 1H
NMR (200 MHz, CDCl3) 0.20-0.21 (9 H, m), 0.98-1.38 (5H,
m), 1.55-1.98 (6H, m), 4.00 (0.5H, d, J ) 6.6 Hz), 4.10 (0.5H,
d, J ) 6.7 Hz), 5.16 (0.5H, dd, J ) 6.8, 0.9 Hz), 5.21 (0.5H, dd,
J ) 6.1, 2.8 Hz), 5.99 (1H, dt, J ) 52.6, 11.6 Hz); 13C NMR (50
MHz, CDCl3) -0.25, 25.72, 25.89, 26.20, 28.27, 29.39, 37.59
(d, J C-F ) 5.6 Hz), 80.41 (dd, J C-F ) 20.7, 4.7 Hz), 94.51 (dd,
J C-F ) 38.1, 23.6 Hz), 111.70 (ddt, J C-F ) 246.3, 25.1, 3.2 Hz),
120.50 (ddd, J C-F ) 284.2, 259.1, 15.1 Hz);19F NMR (188 MHz,
CDCl3) -46.04 (0.5F, s), -33.50 (0.5F, s), 28.34-41.53 (4F, m);
IR (neat) 2962, 1255, 1095 cm-1. Anal. Calcd for C14H23F5O2-
Si: C, 48.54; H, 6.69. Found: C, 48.69; H, 6.82.
La ctol 4e (m ixtu r e of d ia ster eom er s): bp 50 °C/2.0
mmHg (Kugelrohr); Rf 0.68 (hexane/ethyl acetate ) 50:1),
repeated development; 1H NMR (200 MHz, CDCl3) 0.09 (9 H,
s), 0.82 (3H, t, J ) 6.9 Hz), 0.98 (1.5H, d, J ) 6.9 Hz), 1.00
(1.5H, dd, J ) 7.5 Hz, 2.2 Hz), 1.20-1.56 (6H, m), 1.78-2.29
(1H, m), 3.48-3.58 (0.5H, m), 3.79 (0.5 H, q, J ) 6.3 Hz), 4.96
(0.5H, d, J ) 7.0 Hz), 5.12 (0.5H, d, J ) 6.7 Hz); 13C NMR (50
MHz, CDCl3) -0.04, 0.09, 7.47 (d, J C-F ) 6.6 Hz), 11.70 (d,
J C-F ) 7.8 Hz, 3.6 Hz), 13.93, 22.61, 22.66, 27.61, 27.70, 34.13,
35.29, 40.46 (t, J C-F ) 21.1 Hz), 43.93 (t, J C-F ) 22.6 Hz), 82.80
(d, J C-F ) 8.4 Hz), 83.95 (t, J C-F ) 3.9 Hz), 95.55 (dd, J C-F
)
40.7, 26.4 Hz), 97.10 (dd, J C-F ) 43.7 Hz, 24.0 Hz), 125.76 (dd,
J C-F ) 261.9 Hz, 247.8 Hz), 126.30 (dd, J C-F ) 266.2 Hz, 246.7
Hz); 19F NMR (188 MHz, CDCl3) 36.88 (0.5F, dd, J ) 229.7,
10.7 Hz) 38.57 (0.5F, d, J ) 232.6 Hz), 38.83 (0.5F, dd, J )
229.7, 10.7 Hz), 61.41 (0.5 F, ddd, J ) 232.6, 24.6, 6.7 Hz); IR
(neat) 2970, 1460, 1255, 1110 cm-1. Anal. Calcd for C12H24F2O2-
Si: C, 54.10; H, 9.08. Found: C, 53.91; H, 9.12.
La ctol 4k (m ixtu r e of d ia ster eom er s): bp 70 °C/3.7
La ctol 4f (m ixtu r e of d ia ster eom er s): bp 75 °C/2.5
mmHg (Kugelrohr); Rf 0.68 (hexane/ethyl acetate ) 10:1); 1H
NMR (200 MHz, CDCl3) 0.10 (4.5H, s), 0.11 (4.5H, s), 0.98
(1.5H, d, J ) 6.9 Hz), 1.00 (1.5H, dd, J ) 7.2, 2.2 Hz), 1.55
(3H, s), 1.64 (3H, s), 1.84-2.19 (1H, m), 2.24 (2H, t, J ) 6.2
Hz), 3.59 (0.5H, dt, J ) 9.3, 6.0 Hz), 3.85 (0.5H, dt, J ) 6.3,
6.4 Hz), 4.97 (0.5H, d, J ) 6.7 Hz), 5.03-5.14 (1H, m), 5.13
(0.5H, d, J ) 6.0 Hz); 13C NMR (50 MHz, CDCl3) -0.03, 0.10,
7.57 (d, J C-F ) 6.4 Hz), 11.81 (d, J C-F ) 7.7 Hz), 17.94, 25.74,
32.66, 33.88, 39.83 (t, J C-F ) 21.1 Hz), 43.14 (t, J C-F ) 22.6
Hz), 82.68 (d, J C-F ) 8.0 Hz), 83.79 (t, J C-F ) 3.8 Hz), 95.53
(dd, J C-F ) 40.3, 26.7 Hz), 97.12 (dd, J C-F ) 43.5, 24.2 Hz),
118.61, 119.11, 125.75 (dd, J C-F ) 261.4, 248.3 Hz), 126.28
(dd, J C-F ) 266.1, 247.0 Hz), 134.25, 134.63; 19F NMR (188
MHz, CDCl3) 37.04 (0.5F, ddd, J ) 229.6, 23.0, 6.8 Hz), 38.71
(0.5F, d, J ) 229.2 Hz), 38.85 (0.5F, dd, J ) 229.2, 9.8 Hz),
61.15 (0.5F, ddd, J ) 232.4, 24.4, 6.1 Hz); IR (neat) 2962, 1461,
1370, 1253, 1109 cm-1. Anal. Calcd for C13H24F2O2Si: C, 56.08;
H, 8.69. Found: C, 56.45; H, 8.84.
1
mmHg (Kugelrohr); Rf 0.7 (hexane/ethyl acetate ) 10:1); H
NMR (200 MHz, CDCl3) 0.20 (9 H, s), 0.89 (3H, t, J ) 6.5 Hz),
1.25-1.38 (8H, m), 1.50-1.84 (2H, m), 4.18-4.33 (1H, m), 5.18
(0.5H, d, J ) 8.3 Hz) 5.25 (0.5H, dd, J ) 6.5, 2.7 Hz), 5.68-
6.32 (1H, m); 13C NMR (50 MHz, CDCl3) -0.15, 13.98, 22.53,
25.32, 25.25, 28.93, 30.03 (d, J C-F ) 9.0 Hz), 31.61, 78.98 (d,
J C-F ) 21.1 Hz), 95.70 (dd, J C-F ) 40.2, 23.1 Hz), 111.15 (ddt,
J C-F ) 247.0, 27.0, 6.9 Hz), 120.52 (ddd, J C-F ) 277.6, 250.6,
19.7 Hz); 19F NMR (188 MHz, CDCl3) -36.57 to -36.41 (1F,
m), 26.12-41.85 (4F, m); IR (neat) 2960, 1468, 1255, 1095
cm-1. Anal. Calcd for C14H25F5O2Si: C, 48.26; H, 7.23. Found:
C, 48.45; H, 7.61.
5-P h en yl-1-p en ten -3-yl Diflu or oa ceta te (5a ). Difluoro-
acetate 5a was obtained in 60-70% yield when ester 2a was
subjected to the radical reaction under the same reaction
conditions described before: bp 70 °C/3.0 mmHg (Kugelrohr);
Rf 0.62 (hexane/ethyl acetate ) 7:1); 1H NMR (200 MHz,
CDCl3) 1.99-2.29 (2H, m), 2.75 (2H, t, J ) 7.9 Hz), 5.34-5.50
(3H, m), 5.82-5.99 (1H, m), 5.92 (1H, t, J ) 53.4 Hz), 7.22-
7.41 (5H, m); 13C NMR (50 MHz, CDCl3) 31.13, 35.36, 77.36,
106.69 (t, J C-F ) 249.5 Hz), 118.85, 126.19, 128.30, 128.53,
134.46, 140.57, 161.82 (t, J C-F ) 28.7 Hz); 19F NMR (188 MHz,
CDCl3) 35.19 (2F, d, J ) 52.2 Hz); IR (neat) 3025, 2930, 1792,
1765, 1500, 1230 cm-1. Anal. Calcd for C13H14F2O2: C, 64.99;
H, 5.87. Found: C, 64.94; H, 5.91.
La ctol 4g (m ixtu r e of d ia ster eom er s): bp 90 °C/5.0
1
mmHg (Kugelrohr); Rf 0.69 (hexane/ethyl acetate ) 3:1); H
NMR (200 MHz, CDCl3) 0.10-0.19 (9H, m), 0.84 (1.5H, t, J )
7.4 Hz), 0.99 (1.5H, t, J ) 7.6 Hz), 1.58-1.73 (2H, m), 3.38
(3H, s), 3.54-3.58 (2H, m), 3.61-3.92 (2H, m), 4.13-4.36 (1H,
m), 4.89-5.21 (3H, m), 5.78-6.60 (1H, m); 13C NMR (50 MHz,
CDCl3) -0.19, -0.10, -0.02, 9.86, 10.17, 10.31, 22.38, 23.08,
27.43, 58.97, 67.79, 68.16, 69.74, 69.81 (t, J C-F ) 3.2 Hz), 11.81
Syn th esis of Su bstr a tes for th e Ra d ica l Cycliza tion .
1,1,2-Tr iflu or o-5-p h en yl-1-p en ten -3-yl Br om od iflu or oa c-
eta te (2i). To a solution of lithium 2-bromo-2,2-difluoroacetate
(2.97 g, 16.4 mmol) in ether (15 mL) was added an ether (7.0
mL) solution of oxalyl chloride (2.08 g, 16.4 mmol) at 0 °C
dropwise, and the mixture was stirred for 1.5 h at the same
temperature. To this solution was added an ether (5.0 mL)
solution of 1,1,2-trifluoro-5-phenyl-1-penten-3-ol (6i) (1.78 g,
8.23 mmol) and triethylamine (3.45 mL, 24.8 mmol) at 0 °C.
After 1.5 h of stirring at the same temperature, the mixture
was filtered through a short column of silica gel and evapo-
rated to dryness. Silica gel flash column chromatography
(hexanes/ethyl acetate ) 50:1) gave 2i (2.38 g, 6.4 mmol) as a
colorless liquid in 77% yield: bp 100 °C/6.0 mmHg (Kugelrohr);
Rf 0.7 (hexane/ethyl acetate ) 10:1); 1H NMR (200 MHz,
CDCl3) 2.18-2.50 (2H, m), 2.77 (2H, t, J ) 7.8 Hz), 5.58 (1H,
dtt, J ) 25.2, 7.4, 2.2 Hz), 7.22-7.40 (5H, m); 13C NMR (50
MHz, CDCl3) 30.93, 31.05, 71.08 (dt, J C-F ) 22.0, 3.3 Hz),
108.27 (t, J C-F ) 314.6 Hz), 125.55 (ddd, J C-F ) 238.8, 49.6,
(d, J C-F ) 7.7 Hz), 17.94, 25.74, 32.66, 33.88, 39.83 (t, J C-F
)
21.1 Hz), 71.45-71.57 (m), 79.01, 80.58-80.73 (m), 81.84,
92.62 (d, J C-F ) 23.1 Hz), 94.20 (dd, J C-F ) 18.5, 6.2 Hz), 95.73
(dd, J C-F ) 40.8, 20.1 Hz), 95.63 (dd, J C-F ) 42.7, 22.8 Hz),
97.67 (t, J C-F ) 3.2 Hz), 97.95 (t, J C-F ) 3.0 Hz), 113.33 (t,
J C-F ) 248.4 Hz); 19F NMR (188 MHz, CDCl3) 31.26-61.09
(4F, m); IR (neat) 2962, 1461, 1370, 1253, 1109 cm-1. Anal.
Calcd for C13H24F2O2Si: C, 56.08; H, 8.69. Found: C, 56.45;
H, 8.84.
La ctol 4h (m ixtu r e of d ia ster eom er s): bp 80 °C/8.0
mmHg (Kugelrohr); Rf 0.68 and 0.63 (hexane/ethyl acetate )
4:1); 1H NMR (200 MHz, CDCl3) 0.18 (9H, s), 0.94 (3H, d, J )
6.6 Hz), 0.99 (3H, d, J ) 6.6 Hz), 1.88-2.17 (1H, m), 3.37 (3H,
s), 3.51-3.93 (5H, m), 4.88-5.21 (3H, m), 6.34 (1H, t, J ) 53.9
Hz); 13C NMR for the major isomer (50 MHz, CDCl3) -0.02,
18.96, 19.52, 28.57, 58.94, 67.96, 71.39, 81.54, 93.13 (d, J C-F
) 6.7 Hz), 94.36-95.75 (m), 113.34 (dt, J C-F ) 247.0, 18.6 Hz),
121.60 (ddd, J C-F ) 268.8, 259.2, 7.0 Hz), 122.26 (dd, J C-F
)
275.3, 251.2 Hz); 19F NMR (188 MHz, CDCl3) 31.26-61.09 (4F,
m); IR (neat) 2980, 1475, 1390, 1255, 1083 cm-1. Anal. Calcd
for C15H28F4O5Si: C, 45.91; H, 7.19. Found: C, 46.45; H, 7.24.
La ctol 4i (m ixtu r e of d ia ster eom er s): bp 110 °C/5.5
mmHg (Kugelrohr); Rf 0.61 (hexane/ethyl acetate ) 10:1); 1H
17.4 Hz), 126.7, 128.22, 128.78, 139.15, 153.61 (ddd, J C-F )
294.2, 283.1, 43.7 Hz), 158.57 (t, J C-F ) 32.1 Hz); 19F NMR
(188 MHz, CDCl3) -27.43 (1F, ddd, J ) 115.5, 33.6, 25.1 Hz),
48.58 (1F, dd, J ) 114.8, 62.6 Hz), 64.68 (1F, dd, J ) 62.7,
33.6 Hz), 100.68 (2F, s); IR (neat) 3030, 2931, 1792, 1776, 1286,

262 J . Org. Chem., Vol. 64, No. 1, 1999
Itoh et al.
1128 cm-1. Anal. Calcd for C13H10BrF5O2: C, 41.85; H, 2.70.
Found: C, 42.09; H, 2.83.
Using the same procedure, esters 2 were obtained in greater
than 80% yield.
118.72, 134.03, 136.12, 158.48 (t, J C-F ) 34.2 Hz); 19F NMR
(188 MHz, CDCl3) 97.80 (2F, s); IR (neat) 2919, 1778, 1302,
1171, 1133 cm-1. Anal. Calcd for C10H13ClF2O2: C,50.33;
H,5.49. Found: C, 50.13; H, 5.95.
5-P h en yl-1-p en ten -3-yl Br om od iflu or oa ceta te (2a ): bp
80 °C/3.5 mmHg (Kugelrohr); Rf 0.67 (hexane/ethyl acetate )
7:1); 1H NMR (200 MHz, CDCl3) 1.84-2.16 (2H, m), 2.57-2.67
(2H, m),5.21-5.35 (2H, m),5.77 (1H, ddd J ) 17.5, 10.6, 6.8
Hz),7.06-7.25 (5H, m); 13C NMR (50 MHz, CDCl3) 31.04, 35.44,
78.94, 108.81 (t, J C-F ) 314.7 Hz), 119.30, 126.26, 126.30,
128.57, 133.85, 140.37, 158.75 (t, J C-F ) 31.2 Hz); 19F NMR-
(188 MHz, CDCl3) 100.96 (2F, s); IR (neat) 2925, 1770, 1500,
1290, cm-1. Anal. Calcd for C13H13BrF2O2: C, 48.93; H, 4.11.
Found: C, 48.89; H, 4.23.
5-P h en yl-1-p en ten -3-yl Ch lor od iflu or oa ceta te (2a a ): bp
80 °C/5.0 mmHg; Rf 0.6 (hexane/ethyl acetate ) 7:1); 1H NMR
(200 MHz, CDCl3) 1.84-2.15 (2H, m) 2.49-2.73 (2H, m) 5.21-
5.33 (3H, m) 5.67-5.84 (1H, m) 7.05-7.25 (5H, m); 13CNMR
(50 MHz, CDCl3) 31.04, 35.43, 79.04, 116.94 (t, J ) 299.2 Hz),
119.32, 126.28, 128.30, 128.58, 133.90, 140.35, 158.37; 19F
NMR (188 MHz, CDCl3) 36.10-40.08 (m), 97.52 (2F, s); IR
(neat) 2930, 1770, 1450, 1300, 1160 cm-1. Anal. Calcd for
1,1-Diflu or o-2-((m eth oxyeth oxy)m eth oxy)-1-p en ten -3-
yl Br om od iflu or oa ceta te (2 g): bp 80 °C/4.0 mmHg (Kugel-
rohr); Rf 0.71 (hexane/ethyl acetate ) 2:1); 1H NMR (200 MHz,
CDCl3) 0.95 (3H, t, J ) 7.5 Hz), 1.80-2.03 (2H, m), 3.37 (3H,
s), 3.54 (2H, t, J ) 4.6 Hz), 3.71-3.91, (2H, m), 4.93 (1H, d, J
) 6.3 Hz), 4.97 (1H, d, J ) 6.3 Hz), 5.49 (1H, ddt, J ) 2.6, 1.8,
7.4 Hz); 13C NMR (50 MHz, CDCl3) 9.27, 23.62, 59.00, 68.62,
71.44, 76.09 (dd, J C-F ) 5.1 Hz, 2.8 Hz), 97.63 (t, J C-F ) 3.4
Hz), 108.57 (t, J C-F ) 314.7 Hz), 111.75 (dd, J C-F ) 36.0, 15.7
Hz), 155.93 (dd, J C-F ) 294.5, 290.5 Hz), 158.62 (t, J C-F ) 31.7
Hz); 19F NMR (188 MHz, CDCl3) 57.97 (1F, d, J ) 51.3 Hz),
67.09 (1F, d, J ) 51.3 Hz), 100.89 (2F, d, J ) 13.6 Hz); IR
(neat) 2884, 1780, 1750, 1290, 1128, cm-1. Anal. Calcd for
C11H15BrF4O5: C, 34.48; H, 3.95. Found: C, 35.09; H, 3.73.
1,1-Diflu or o-4-m eth yl-1-p en ten -3-yl Br om od iflu or oa c-
eta te (2h ): bp 80 °C/2.3 mmHg (Kugelrohr); Rf 0.63 (hexane/
1
ethyl acetate ) 4:1); H NMR (200 MHz, CDCl3) 0.95 (3H, d,
J ) 6.8 Hz), 1.02 (3H, d, J ) 6.6 Hz), 2.20-2.39 (1H, m), 3.36
(3H, s), 3.54 (2H, t, J ) 4.6 Hz), 3.69-3.90 (2H, m), 4.92 (1H,
d, J ) 6.1 Hz), 4.96 (1H, d, J ) 6.0 Hz), 5.21 (1H, dt, J ) 10.0,
2.3 Hz); 13C NMR (50 MHz, CDCl3) 18.07, 18.51, 29.13, 59.00,
C
13H13ClF2O2: C, 56.84; H, 4.77. Found: C, 56.90; H, 4.78.
Allyl Br om od iflu or oa ceta te (2b): bp 80 °C/6.0 mmHg
(Kugelrohr); Rf 0.71 (hexane/ethyl acetate ) 7:1); 1H NMR (200
MHz, CDCl3) 4.82 (2H, d, J ) 5.8 Hz), 5.35-5.49 (2H, m), 5.96
(1H, ddt, J ) 16.8, 10.8, 5.8 Hz); 13C NMR (50 MHz, CDCl3)
68.42, 108.62 (t, J C-F ) 312.3 Hz), 120.66, 129.64, 159.28 (t,
J C-F ) 28.7 Hz); 19F NMR (188 MHz, CDCl3) 94.75 (2F, s); IR
(neat) 2950, 1775, 1450, 1365, 1165 cm-1. Anal. Calcd for C5H5-
BrF2O2: C, 27.93; H, 2.34. Found: C,27.87; H, 2.33.
68.62, 71.46, 79.72 (dd, J C-F ) 4.8, 3.0 Hz), 97.60 (t, J C-F
)
12.2 Hz), 108.55 (t, J C-F ) 312.7 Hz), 111.49 (dd, J C-F ) 36.3,
15.6 Hz), 156.13 (dd, J C-F ) 294.4, 290.1 Hz), 158.62 (t, J C-F
) 31.5 Hz); 19F NMR (188 MHz, CDCl3) 57.67 (1F, d, J ) 51.8
Hz), 66.86 (1F, d, J ) 51.9 Hz), 100.65 (1F, d, J ) 158.0 Hz),
101.62 (1F, d, J ) 156.2 Hz); IR (neat) 2980, 1780, 1748, 1470,
1297, 955 cm-1. Anal. Calcd for C12H17BrF4O5: C, 34.30; H,
4.45. Found: C, 35.94; H, 4.39.
Cin n a m yl Br om od iflu or a cet a t e (2c): bp 103 °C/5.0
1
mmHg (Kugelrohr); Rf 0.53 (hexane/ethyl acetate ) 7:1); H
NMR (200 MHz, CDCl3) 4.90 (2H, dd, J ) 6.7, 1.3 Hz), 6.21
(1H, dt, J ) 15.9, 6.70 Hz), 6.69 (1H, d, J ) 15.9 Hz), 7.16-
7.36 (5H, m); 13C NMR (50 MHz, CDCl3) 68.69, 108.74 (t, J C-F
) 312.5 Hz), 120.19, 126.84, 128.67, 128.70, 135.48, 136.88,
159.43 (t, J C-F ) 31.3 Hz); 19F NMR (188 MHz, CDCl3) 100.46
1,1,2-Tr iflu or o-5-p h en yl-1-p en ten -3-yl Ch lor od iflu or o-
a ceta te (2ia ): bp 90 °C/6.0 mmHg (Kugelrohr); Rf 0.7 (hexane/
1
ethyl acetate ) 10:1); H NMR (200 MHz, CDCl3) 2.08-2.36
(2H, m), 2.63 (2H, t, J ) 7.8 Hz), 5.45 (1H, dtt, J ) 25.2, 7.5,
2.3 Hz), 7.06-7.27 (5H, m); 13C NMR (50 MHz, CDCl3) 30.91,
31.00, 71.15 (dt, J C-F ) 22.0, 3.4 Hz), 116.61 (t, J C-F ) 300.8
Hz), 125.65 (ddd, J C-F ) 238.7, 49.6, 17.3 Hz), 126.70, 128.21,
128.78, 139.12, 153.61 (ddd, J C-F ) 294.2, 283.0, 43.6 Hz),
158.25 (t, J C-F ) 34.7 Hz); 19F NMR (188 MHz, CDCl3) -27.49
(1F, ddd, J ) 115.3, 33.6, 24.8 Hz), 48.64 (1F, dd, J ) 114.6,
62.1 Hz), 64.75 (1F, dd, J ) 62.7, 33.6 Hz), 97.81 (2F, s); IR
(neat) 2928, 1793, 1778, 1322, 1173 cm-1. Anal. Calcd for
(2F, s); IR (neat) 3025, 1770, 1650, 1450, 1380, 1160 cm-1
.
Anal. Calcd for C11H9BrF2O2: C, 45.39; H,3.12. Found: C,
45.59; H, 3.23.
Isop r op en yl Br om od iflu or oa ceta te (2d ): bp 35 °C/3.3
mmHg (Kugelrohr); Rf 0.69 (hexane/ethyl acetate ) 10:1); 1H
NMR (200 MHz, CDCl3) 1.76 (3H, s), 1.79 (3H, s), 4.82 (2H,
dd, J ) 6.7, 1.3 Hz), 5.34-5.45 (1H,m);13C NMR (50 MHz,
CDCl3) 18.09, 25.76, 65.03, 108.93 (t, J C-F ) 314.5 Hz), 116.23,
142.49, 159.59 (t, J C-F ) 31.0 Hz); 19F NMR(188 MHz, CDCl3)
C
13H10ClF5O2: C, 47.51; H, 3.07. Found: C, 47.09; H, 3.03.
1-Cycloh exyl-2,3,3-tr iflu or o-2-p r op en yl Br om od iflu o-
10126 (2F, s); IR (neat) 2977, 2921, 1774, 1673, 1295 cm-1
.
r oa ceta te (2j): bp 70 °C/4.0 mmHg (Kugelrohr); Rf 0.66
(hexane/ethyl acetate ) 10:1); 1H NMR (200 MHz, CDCl3)
0.87-1.41 (5H,m), 1.67-2.15 (6H, m), 5.29 (1H, ddt, J ) 26.4,
9.9, 2.5 Hz); 13C NMR (50 MHz, CDCl3) 25.13, 25.28, 25.83,
28.23, 28.75, 37.41, 75.68 (dt, J C-F ) 19.3, 3.2 Hz), 108.30 (t,
J C-F ) 314.5 Hz), 124.41 (ddd, J C-F ) 239.6, 50.0, 17.1 Hz),
Anal. Calcd for C7H9BrF2O2: C, 34.59; H,3.73. Found: C,
34.89; H, 3.73.
1-Hep ten -3-yl Br om od iflu or oa ceta te (2e): bp 50 °C/2.5
1
mmHg (Kugelrohr); Rf 0.86 (hexane/ethyl acetate ) 7:1); H
NMR (200 MHz, CDCl3) 0.91 (3H, t, J ) 7.0 Hz), 1.25-1.38
(4H, m), 1.68-1.82 (2H, m), 5.26-5.41 (3H, m), 5.82 (1H, ddd,
J ) 17.3, 10.4, 6.6 Hz); 13C NMR (50 MHz, CDCl3) 13.83, 22.25,
26.91, 33.50, 79.82, 108.90 (t, J C-F ) 314.6 Hz), 118.85, 134.26,
158.87 (t, J C-F ) 31.1 Hz); 19F NMR (188 MHz, CDCl3) 100.99
(2F, s); IR (neat) 2975, 1775, 1460, 1170 cm-1. Anal. Calcd for
C9H13BrF2O2: C, 39.87; H, 4.83. Found: C, 39.89; H, 4.23.
6-Meth yl-1,5-h eptadien -3-yl Br om odiflu or oacetate (2f):
bp 65 °C/3.0 mmHg (Kugelrohr); Rf 0.70 (hexane/ethyl acetate
) 10:1); 1H NMR (200 MHz, CDCl3) 1.62 (3H, s), 1.70 (3H, s),
2.34-2.56 (2H, m), 5.02-5.12 (1H, m), 5.25-5.40 (3H, m), 5.84
(1H, ddd, J ) 17.5, 10.4, 6.2 Hz); 13C NMR (50 MHz, CDCl3)
17.91, 25.76, 32.81, 79.27, 108.89 (t, J C-F ) 314.6 Hz), 117.20,
118.71, 134.01, 136.07, 158.80 (t, J C-F ) 31.1 Hz); 19F NMR
(188 MHz, CDCl3) 101.05 (2F, s); IR (neat) 2927, 1775, 1451,
1297, 1169 cm-1. Anal. Calcd for C10H13BrF2O2: C, 42.42; H,
4.63. Found: C, 42.10; H, 4.85.
154.15 (ddd, J C-F ) 293.8, 282.0, 43.7 Hz), 158.80 (t, J C-F
)
32.0 Hz); 19F NMR (188 MHz, CDCl3) -26.88 (1F, ddd, J )
115.3, 33.2, 26.8 Hz), 47.07 (1F,dd, J ) 115.0, 65.1 Hz), 64.12
(1F, dd, J ) 65.3, 33.1 Hz), 100.86 (2F,s); IR (neat) 2935, 2858,
1793, 1776, 1452, 1271, 1126 cm-1. Anal. Calcd for C11H12
BrF5O2: C, 37.63; H, 3.44. Found: C, 37.57; H, 354.
-
1,1,2-Tr iflu or o-1-n on en -3-yl Br om odiflu or oacetate (2k):
bp 80 °C/4.0 mmHg (Kugelrohr); Rf 0.80 (hexane/ethyl acetate
1
) 10:1); H NMR (200 MHz, CDCl3) 0.88 (3H, t, J ) 6.5 Hz),
1.25-1.40 (8H, m), 1.85-1.98 (2H, m), 5.57 (1H, dddt, J ) 25.3,
2.9, 1.8, 7.8 Hz); 13C NMR (50 MHz, CDCl3) 13.91, 22.43, 24.70,
28.55, 29.39, 31.44, 71.79 (dt, J C-F ) 22.1, 3.4 Hz), 108.33 (t,
J C-F ) 314.5 Hz), 125.06 (ddd, J C-F ) 239.2, 49.7, 17.1 Hz),
153.65 (ddd, J C-F ) 294.1, 282.4, 43.9 Hz), 158.70 (t, J C-F
)
32.0 Hz); 19F NMR (188 MHz, CDCl3) -27.46 (1F, ddd, J )
114.3, 33.2, 24.8 Hz), 47.68 (1F,dd, J ) 115.0, 64.4 Hz), 64.10
(1F, dd, J ) 64.4, 33.6 Hz), 100.70 (2F,s); IR (neat) 2931, 2862,
6-Meth yl-1,5-h eptadien -3-yl Ch lor odiflu or oacetate (2fa):
bp 60 °C/3.0 mmHg (Kugelrohr); Rf 0.73 (hexane/ethyl acetate
1793, 1776, 1467, 1286, 1130 cm-1. Anal. Calcd for C11H14
BrF5O2: C, 37.41; H, 4.00. Found: C, 37.78; H, 4.21.
-
1
) 7:1); H NMR (200 MHz, CDCl3) 1.53 (3H, s), 1.71 (3H, s),
2.31-2.58 (2H, m), 5.02-5.13 (1H, m), 5.25-5.40 (3H, m), 5.85
(1H, ddd, J ) 17.3, 10.5, 6.4 Hz); 13C NMR (50 MHz, CDCl3)
17.83, 25.74, 32.83, 79.34, 116.97 (t, J C-F ) 301.0 Hz), 117.15,
Br om od iflu or oa ceta ld eh yd e 1,1,2-Tr iflu or o-5-p h en yl-
1-p en ten e-3-yl O-(Tr im eth ylsilyl)a ceta l (3i). To a solution
of ester 2i (2.27 g, 6.08 mmol) in dichloromethane (15.0 mL)

Synthesis of R,R-Difluoro-γ-lactones
J . Org. Chem., Vol. 64, No. 1, 1999 263
was added a toluene (4.97 mL) solution of DIBAL (7.35 mmol)
at -78 °C over 10 min, and the mixture was stirred for 3 h at
the same temperature. To this were added a pyridine (1.5 mL,
18.55 mmol) and a dichloromethane (5.0 mL) solution of
trimethyl-O-triflate (2.03 g, 9.13 mmol) dropwise over 5 min
at -78 °C. This solution was allowed to warm to 0 °C over 6
h with stirring. The reaction was quenched by 1 h of stirring
with potassium fluoride (1.4 g, 4 equiv) and water (0.45 mL)
at room temperature. Silica gel flash column chromatography
(hexanes/ethyl acetate ) 50:1) gave 3i (1.97 g, 4.4 mmol) as a
colorless liquid in 72% yield. Mixture of diastereomers of 3i:
bp 90 °C/4.5 mmHg (Kugelrohr); Rf 0.73 (hexane/ethyl acetate
1365 cm-1. Anal. Calcd for C10H19BrF2O2 Si: C, 37.86; H, 6.04.
Found: C, 38.26; H, 6.13.
Br om od iflu or oa cet a ld eh yd e 1-H ep t en -3-yl O-(Tr i-
m eth ylsilyl)a ceta l (3e). Mixture of diastereomers (ca. 1:1):
bp 75 °C/2.5 mmHg (Kugelrohr); Rf 0.80 (hexane/ethyl acetate
) 10:1); 1H NMR (200 MHz, CDCl3) 0.19 (4.5H, s), 0.21 (4.5H,
s), 0.89 (3H, t, J ) 7.0 Hz), 1.25-1.75 (6H, m), 3.94-4.05 (1H,
m), 4.71-4.78 (1H, m), 5.16-5.29 (2H, m), 5.60-5.87 (1H, m);
13C NMR (50 MHz, CDCl3) 0.43, 13.94, 22.45, 37.13, 34.87,
78.39, 82.23, 93.03 (t, J C-F ) 30.3 Hz), 94.94 (t, J C-F ) 29.9
Hz), 117.83, 118.46, 122.14 (t, J C-F ) 307.5 Hz), 123.19 (t, J C-F
) 311.0 Hz),137.78, 138.46; 19F NMR (188 MHz, CDCl3) 98.33-
101.11 (2F, m); IR (neat) 2950, 1250, 1130, 840 cm-1. Anal.
Calcd for C12H23BrF2O2 Si: C, 41.74; H, 6.71. Found: C, 42.35;
H, 6.86.
Br om od iflu or oa ceta ld eh yd e 6-Meth yl-1,5-h ep ta d ien -
3-yl O-(Tr im eth ylsilyl)a ceta l (3f). Mixture of diastereomers
(ca. 1:1): bp 75 °C/3.2 mmHg (Kugelrohr); Rf 0.68 (hexane/
ethyl acetate ) 10:1);1H NMR (200 MHz, CDCl3) 0.18 (4.5H,
s), 0.20 (4.5H, s), 1.59 (3H, s), 1.68 (3H, s), 2.16-2.47 (2H, m),
3.22 (1H, dd, J ) 14.0, 7.3 Hz), 4.72-4.79 (1H, m), 5.06-5.29
(3H, m), 5.69 (0.5H, ddd, J ) 17.1, 10.5, 8.1 Hz), 5.79 (0.5H,
ddd, J ) 17.3, 10.2, 7.6 Hz); 13C NMR (50 MHz, CDCl3) 0.33,
0.41, 17.96, 18.03, 25.75, 33.92, 34.12, 78.62, 81.70, 93.25 (t,
J C-F ) 30.2 Hz), 95.07 (t, J C-F ) 29.9 Hz), 117.73, 118.82,
118.90, 122.05 (t, J C-F ) 308.9 Hz), 122.98 (t, J C-F ) 311.0
Hz),134.09, 134.17, 137.37, 138.01; 19F NMR (188 MHz, CDCl3)
98.20-100.99 (2F, m); IR (neat) 2963, 1424, 1377, 1254, 1129
cm-1. Anal. Calcd for C13H23BrF2O2 Si: C, 43.70; H, 6.49.
Found: C, 44.03; H, 6.58.
1
) 10:1); H NMR (200 MHz, CDCl3) 0.19 (4.5 H, s), 0.22 (4.5
H, s), 2.01-2.40 (2H, m), 2.78 (1H, t, J ) 7.3 Hz), 2.79 (1H, t,
J ) 7.5 Hz), 4.25-4.38 (0.5 H, m), 4.38-4.51 (0.5 H, m), 4.74-
4.78 (1H, m), 7.21-7.38 (5H, m); 13C NMR (50 MHz, CDCl3)
-0.10, 1.90, 31.13, 31.21, 32.51, 32.69, 68.30 (d, J C-F ) 21.3
Hz), 71.71 (d, J C-F ) 21.4 Hz), 93.17 (t, J C-F ) 31.1 Hz), 95.41
(t, J C-F ) 30.3 Hz), 121.52 (t, J C-F ) 310.2 Hz), 122.17 (t, J C-F
) 310.6 Hz), 126.25, 126.32, 128.30, 128.52, 128.59, 140.32,
154.7 (ddd, J C-F ) 527.3, 277.8, 26.9 Hz); 19F NMR (188 MHz,
CDCl3) -25.94 (0.5F, ddd, J ) 115.6, 33.2, 27.1 Hz), -24.87
(0.5F, ddd, J ) 115.0, 31.9, 27.5 Hz), 43.32 (0.5F, dd, J ) 115.5,
74.1 Hz), 43.39 (0.5 F, dd, J ) 115.6, 76.0 Hz), 61.82 (0.5F,
dd, J ) 74.4, 32.7 Hz), 62.65 (0.5F, dd, J ) 74.9, 33.2 Hz),
98.02-101.07 (2F, m); IR (neat) 2962, 1784, 1259, 1128 cm-1
.
Anal. Calcd for C16H20BrF5O2 Si: C, 42.96; H, 4.51. Found:
C, 42.66; H, 4.79.
Using the same procedure, O-(trimethylsilyl)-acetals 3 were
synthesized as mixtures of diastereomers.
Ch lor od iflu or oa ceta ld eh yd e 6-Meth yl-1,5-h ep ta d ien -
3-yl O-(Tr im eth ylsilyl)a ceta l (3fa ). Mixture of diastereo-
mers (ca. 1:1): bp 75 °C/3.2 mmHg (Kugelrohr); Rf 0.73
(hexane/ethyl acetate ) 7:1); 1H NMR (200 MHz, CDCl3) 0.19
(4.5H, s), 0.21 (4.5H, s), 1.60 (3H, s), 1.70 (3H, s), 2.16-2.49
(2H, m), 4.00 (1H, dd, J ) 13.9, 7.2 Hz), 4.89-4.94 (1H, m),
Br om od iflu or oa ceta ld eh yd e 5-P h en yl-1-p en ten -3-yl O-
(Tr im eth ylsilyl)a ceta l (3a ). Mixture of diastereomers (ca.
1:1): bp 90 °C/1.7 mmHg (Kugelrohr); Rf 0.58 (hexane/ethyl
acetate ) 7:1); 1H NMR (200 MHz, CDCl3) 0.15 (4.5H, s), 0.16
(4.5H, s) 1.73-2.20 (2H, m), 2.59-2.88 (2H, m) 3.98-4.08 (1H,
m), 4.71-4.77 (1H, m) 5.18-5.43 (2H, m) 7.17-7.30 (5H, m);
13C NMR (50 MHz, CDCl3) 0.23, 0.40, 31.12, 31.21, 36.81,
36.86, 81.31, 92.72 (t, J C-F ) 30.4 Hz), 94.97 (t, J C-F ) 30.3
Hz), 118.19, 118.92, 123.04 (t, J C-F ) 311.0 Hz), 125.80, 128.86,
128.29, 128.37, 128.58, 137.37, 138.06, 141.55; 19F NMR (188
MHz, CDCl3) 98.39-101.20 (2F, m); IR (neat) 2950, 1600, 1495,
1360, 1255, 1120 cm-1. Anal. Calcd for C16H23BrF2O2 Si: C,
48.86; H, 5.89. Found: C, 48.57; H, 5.40.
5.06-5.16 (1H, m), 5.17-5.30 (2H, m), 5.60-5.89 (1H, m); 13
C
NMR (50 MHz, CDCl3) 0.28, 0.36, 17.93, 18.00, 25.74, 33.92,
34.11, 78.73, 81.77, 92.64 (t, J C-F ) 32.2 Hz), 94.47 (t, J C-F
)
31.9 Hz), 117.68, 118.70, 118.81, 118.85, 126.78 (t, J C-F ) 295.8
Hz), 127.44 (t, J C-F ) 297.6 Hz), 134.11, 134.18, 137.33, 138.00;
19F NMR (188 MHz, CDCl3) 92.58-95.02 (2F, m); IR (neat)
2965, 1255, 1130, 846 cm-1. Anal. Calcd for C13H23ClF2O2 Si:
C, 49.91; H, 7.41. Found: C, 49.99; H, 7.29.
Br om od iflu or oa ceta ld eh yd e Allyl O-(Tr im eth ylsilyl)-
a ceta l (3b): bp 100 °C/43 mmHg (Kugelrohr); Rf 0.73 (hexane/
Br om od iflu or oa ceta ld eh yd e 1,1-Diflu or o-2-((m eth oxy-
eth oxy)m eth oxy)-1-p en ten -3-yl O-(Tr im eth ylsilyl)a ceta l
(3g). Mixture of diastereomers (ca. 1:1): bp 80 °C/6.0 mmHg
(Kugelrohr); Rf 0.67 (hexane/ethyl acetate ) 2:1); 1H NMR (200
MHz, CDCl3) 0.19 (4.5H, s), 0.20 (4.5H, s), 0.90 (1.5H, t, J )
7.4 Hz), 0.91 (1.5H, t, J ) 7.5 Hz), 1.56-1.91 (2H, m), 3.36
(3H, s), 3.54 (1H, t, J ) 4.6 Hz), 3.55 (1H, t, J ) 4.8 Hz), 3.68-
3.94 (2H, m), 4.11-4.29 (1H, m), 4.72-4.77 (1H, m), 4.90-
5.10 (2H, m); 13C NMR (50 MHz, CDCl3) -0.26, -0.07, 9.56,
9.75, 24.63, 25.02, 58.95, 68.40, 71.55, 73.27 (t, J C-F ) 3.2 Hz),
76.48 (t, J C-F ) 3.5 Hz), 93.23 (t, J C-F ) 31.3 Hz), 95.71 (t,
J C-F ) 30.6 Hz), 97.15, 97.78 (t, J C-F ) 2.9 Hz) 112.80 (dd,
J C-F ) 36.6, 11.1 Hz), 114.38 (dd, J C-F ) 36.8, 12.2 Hz), 122.12
(t, J C-F ) 307.9 Hz), 155.34 (dd, J C-F ) 296.2, 287.4 Hz), 156.07
(dd, J C-F ) 295.0, 284.4 Hz); 19F NMR (188 MHz, CDCl3) 53.08
(0.5F, d, J ) 42.1 Hz), 53.41 (0.5F, d, J ) 40.0 Hz), 63.26 (0.5F,
d, J ) 63.4 Hz), 65.05 (0.5F, d, J ) 62.7 Hz), 98.54-101.34
(2F, m); IR (neat) 2967, 1752, 1254, 1123 cm-1. Anal. Calcd
for C14H25BrF4O5Si: C, 36.77; H, 5.51. Found: C, 35.82; H,
5.36.
Br om od iflu or oa ceta ld eh yd e 1,1-Diflu or o-4-m eth yl-1-
p en ten -3-yl O-(Tr im eth ylsilyl)a ceta l (3h ). Mixture of di-
astereomers (ca. 1:1): bp 85 °C/4.0 mmHg (Kugelrohr); Rf 0.63
(hexane/ethyl acetate ) 4:1); 1H NMR (200 MHz, CDCl3)
(major isomer) 0.19 (9H, s), 0.86 (3H, d, J ) 6.6 Hz), 1.05 (3H,
d, J ) 6.6 Hz), 1.97-2.15 (1H, m), 3.36 (3H, s), 3.54 (2H, t, J
) 4.5 Hz), 3.66-3.93 (2H, m), 4.68 (1H, t, J ) 2.8 Hz), 4.90
(1H, d, J ) 5.9 Hz), 4.99 (1H, d, J ) 5.9 Hz); 13C NMR (50
MHz, CDCl3) (major isomer) -0.09, 18.43, 19.45, 29.68, 58.97,
68.32 (d, J C-F ) 1.6 Hz), 76.96 (t, J C-F ) 3.4 Hz), 92.67 (t,
J C-F ) 31.7 Hz), 97.12, 111.54 (dd, J C-F ) 36.8, 10.7 Hz),
1
ethyl acetate ) 7:1); H NMR (200 MHz, CDCl3) 0.23 (9H, s),
4.07-4.33 (2H, m), 4.77 (1H, dd, J ) 4.5, 3.5 Hz), 5.22-5.39
(2H, m), 5.82-6.01 (1H, m); 13C NMR (50 MHz, CDCl3) 0.18,
68.87, 95.22 (t, J C-F ) 30.0 Hz), 118.18, 122.00 (t, J C-F ) 308.3
Hz), 133.11; 19F NMR (188 MHz, CDCl3) 99.50 (2F, dd, J )
245.2, 163.2 Hz); IR (neat) 2975, 1460, 1420, 1365, 1255, 1225,
1130 cm-1. Anal. Calcd for C8H15BrF2O2 Si: C, 33.23; H, 5.23.
Found: C, 33.57; H, 5.40.
Br om od iflu or oa ceta ld eh yd e Cin n a m yl O-(Tr im eth yl-
silyl)a ceta l (3c): bp 105 °C/4.5 mmHg (Kugelrohr); Rf 0.53
(hexane/ethyl acetate ) 7:1); 1H NMR (200 MHz, CDCl3) 0.07
(9H, s), 4.20 (2H, ddd, J ) 30.3, 12.7, 5.9 Hz), 4.67 (1H, dd, J
) 4.7, 3.5 Hz), 6.09 (1H, dt, J ) 16.1, 6.0 Hz), 6.48 (1H, d, J
) 16.0 Hz), 7.09-7.25 (5H, m); 13C NMR (50 MHz, CDCl3)
68.74, 95.23 (t, J C-F ) 30.1 Hz), 122.05 (t, J C-F ) 310.1 Hz),
124.15, 126.56, 128.02, 128.60, 133.65, 136.15; 19F NMR (188
MHz, CDCl3) 98.91 (1F, dd, J ) 166.0, 4.2 Hz), 100.22 (1F,
dd, J ) 165.2, 2.8 Hz); IR (neat) 3050, 2975, 1500, 1450, 1255
cm-1. Anal. Calcd for C14H19BrF2O2 Si: C, 46.03; H, 5.24.
Found: C, 47.16; H, 5.49.
Br om od iflu or oa ceta ld eh yd e Isop r op en yl O-(Tr im eth -
ylsilyl)a ceta l (3d ): bp 75 °C/3.0 mmHg (Kugelrohr); Rf 0.69
(hexane/ethyl acetate ) 10:1); 1H NMR (200 MHz, CDCl3) 0.22
(9H, s), 1.68 (3H, s), 1.76 (3H, s),4.10-4.29 (2H, m), 4.77 (1H,
dd, J ) 4.6, 3.7 Hz), 5.30-5.38 (1H, m); 13C NMR (50 MHz,
CDCl3) 68.74, 95.23 (t, J C-F ) 30.1 Hz), 122.05 (t, J C-F ) 310.1
Hz), 0.15, 18.09, 25.73, 64.85, 95.29 (t, J C-F ) 29.8 Hz), 119.51,
122.24 (t, J C-F ) 310.5 Hz), 138.47; 19F NMR (188 MHz, CDCl3)
99.64 (2F, dd, J ) 222.8, 164.5 Hz); IR (neat) 2962, 1675, 1447,

264 J . Org. Chem., Vol. 64, No. 1, 1999
Itoh et al.
Sch em e 4. Syn th esis of Op tica lly Active
122.32 (t, J C-F ) 308.2 Hz), 156.45 (dd, J C-F ) 295.2, 283.9
Hz); 19F NMR (188 MHz, CDCl3) (major isomer) 52.81 (1F, d,
J ) 63.4 Hz), 65.11 (1F, d, J ) 63.4 Hz), 99.51-102.10 (2F,
m); IR (neat) 2978, 1750, 1473, 1371, 1240, 1128 cm-1. Anal.
Calcd for C15H27BrF4O5 Si: C, 38.22; H, 5.77. Found: C, 38.60;
H, 5.86.
6-Meth ylh ep t-1,5-d ien -2-ol (6)
Ch lor od iflu or oa ceta ld eh yd e 1,1,2-Tr iflu or o-5-p h en yl-
1-p en ten -3-yl O-(Tr im eth ylsilyl)a ceta l (3ia ). Mixture of
diastereomers (ca. 1:1): bp 90 °C/4.5 mmHg (Kugelrohr); Rf
0.75 (hexane/ethyl acetate ) 10:1); 1H NMR (200 MHz, CDCl3)
0.06 (4.5 H, s), 0.09 (4.5 H, s), 1.90-2.30 (2H, m), 2.65 (1H, t,
J ) 7.9 Hz), 4.14-4.24 (0.5 H, m), 4.24-4.40 (0.5 H, m), 4.78
(1H, t, J ) 3.1 Hz), 7.10-7.30 (5H, m); 13C NMR (50 MHz,
CDCl3) -0.25, -0.17, 31.11, 31.16, 32.69, 32.49, 68.63 (dt, J C-F
) 24.0, 2.8 Hz), 71.70 (d, J C-F ) 21.2 Hz) 92.62 (t, J C-F ) 33.0
Hz), 94.78 (t, J C-F ) 32.0 Hz), 127.44 (dt, J C-F ) 297.2, 27.2
Hz), 126.25, 126.32, 126.41, 128.29, 128.46, 128.52, 128.59,
140.28, 153.72; 19F NMR (188 MHz, CDCl3) -26.20 (0.5F, ddd,
J ) 116.0, 33.6, 26.0 Hz), -24.95 (0.5F, ddd, J ) 116.0, 32.3,
27.5 Hz), 43.08 (0.5F, dd, J ) 74.3, 16.3 Hz), 43.70 (0.5 F, dd,
J ) 73.9, 15.6 Hz), 61.85 (0.5F, dd, J ) 75.3, 32.9 Hz), 62.74
(0.5F, dd, J ) 75.6, 33.2 Hz), 92.5-95.2 (2F, m); IR (neat) 2961,
1783, 1258, 1128 cm-1. Anal. Calcd for C16H20ClF5O2 Si: C,
42.96; H, 4.51. Found: C, 42.66; H,4.79.
Br om od iflu or oa ceta ld eh yd e 1-Cycloh exyl-2,3,3-tr iflu -
or o-2-p r op en yl O-(Tr im eth ylsilyl)a ceta l (3j). Mixture of
diastereomers (ca. 1:1): bp 80 °C/8.0 mmHg (Kugelrohr); Rf
0.74 and 0.61 (hexane/ethyl acetate ) 10:1); 1H NMR (200
MHz, CDCl3) 0.20 (4.5H, s), 0.21 (4.5H, s), 0.83-1.30 (6H, m),
1.62-2.20 (5H, m), 3.88-4.10 (1H, m), 4.70 (1H, t, J ) 3.3
Hz); 13C NMR (50 MHz, CDCl3) (major isomer only) -0.08,
25.45, 25.56, 26.16, 28.43, 29.45, 38.69, 73.81 (dt, J C-F ) 20.3,
2.1 Hz), 95.54 (t, J C-F ) 30.4 Hz), 122.42 (t, J C-F ) 310.8 Hz),
MHz, CDCl3) 31.42, 34.24, 65.17 (dt, J C-F ) 21.8, 2.3 Hz),
126.19, 128.29, 128.50, 128.82 (ddd, J C-F ) 239.3, 49.8, 13.1
Hz), 140.52, 152.76 (ddd, J C-F ) 291.5, 277.3, 45.5 Hz); 19F
NMR (188 MHz, CDCl3) -28.03 (1F, ddd, J ) 115.0, 31.4, 27.3
Hz), 42.08 (1F, dd, J ) 114.3, 78.0 Hz), 59.42 (1F, dd, J )
125.85 (ddd, J C-F ) 245.5, 48.8, 14.3 Hz), 154.22 (ddd, J C-F
)
293.7, 276.9, 44.2 Hz); 19F NMR (188 MHz, CDCl3) -27.30
(0.5F, dt, J ) 113.9, 29.5 Hz), -23.87 (0.5F, dt, J ) 116.0,
30.3 Hz), 40.87 (0.5F, dd, J ) 113.6, 83.1 Hz), 41.93 (0.5F, dd,
J ) 116.7, 76.0 Hz), 58.87 (0.5F, dd, J ) 81.1, 31.2 Hz), 61.77
(0.5F, dd, J ) 77.3, 32.2 Hz), 98.04-101.16 (2F, m); IR (neat)
78.5, 32.4 Hz); IR (neat) 3350, 3028, 2950, 1307, 1259 cm-1
.
Anal. Calcd for C11H11F3O: C, 61.11; H, 5.13. Found: C, 61.22;
H, 5.17.
Using the same procedure, fluoroallyl alcohols 6g, 6h , 6j,
1
and 6k were synthesized. All spectra of 6g for H and 13C NMR
2931, 2856, 1784, 1452, 1259 cm-1. Anal. Calcd for C14H22
BrF5O2 Si: C, 39.54; H, 5.21. Found: C, 40.89; H, 5.09.
-
coincided with those in reference 22a.
1,1-Diflu or o-2-((m eth oxyeth oxy)m eth oxy)-4-m eth yl-1-
p en ten -3-ol (6h ): bp 80 °C/2.3 mmHg (Kugelrohr); Rf 0.23
(hexane/ethyl acetate ) 4:1); 1H NMR (200 MHz, CDCl3) 0.81
(3H, d, J ) 5.8 Hz), 1.03 (3H, d, J ) 5.8 Hz), 1.76-1.94 (1H,
m), 3.18 (1H, brs, OH), 3.36 (3H, s), 3.52-3.57 (2H, m), 3.68-
3.77 (2H, m), 3.57-3.98 (1H, m), 4.83 (1H, d, J ) 6.6 Hz), 4.97
(1H, d, J ) 6.6 Hz); 13C NMR (50 MHz, CDCl3) 18.59, 19.07,
31.52, 58.88, 68.36, 71.35, 72.90 (d, J C-F ) 2.6 Hz), 97.93 (t,
J C-F ) 3.5 Hz), 117.84 (dd, J C-F ) 37.0, 10.0 Hz), 154.97 (dd,
J C-F ) 290.1, 283.2 Hz); 19F NMR (188 MHz, CDCl3) 51.34
(1F, d, J ) 64.8 Hz), 61.20 (1F, d, J ) 65.5 Hz); IR (neat) 3452,
Br om od iflu or oa ceta ld eh yd e 1,1,2-Tr iflu or o-1-n on en -
3-yl O-(Tr im eth ylsilyl)a ceta l (3k ). Mixture of diastereomers
(ca. 1:1): bp 70 °C/4.0 mmHg (Kugelrohr); Rf 0.73 and 0.66
(hexane/ethyl acetate ) 10:1); 1H NMR (200 MHz, CDCl3) 0.20
(4.5H, s), 0.21 (4.5H, s), 0.88 (3H, m), 1.25-1.42 (8H, m), 1.63-
1.94 (2H, m), 4.23-4.45 (1H, m), 4.71-4.76 (1H, m); 13C NMR
(50 MHz, CDCl3) (major isomer only) -0.08, 13.97, 22.50,
24.97, 28.76, 31.05, 31.57, 72.60 (d, J C-F ) 21.6 Hz), 95.42 (t,
J C-F ) 30.2 Hz), 122.32 (t, J C-F ) 310.9 Hz), 126.44 (ddd, J C-F
) 242.5, 49.6, 13.1 Hz), 153.585 (ddd, J C-F ) 293.3, 277.4, 44.8
Hz); 19F NMR (188 MHz, CDCl3) -26.28 (0.5F, ddd, J ) 115.6,
33.2, 25.8 Hz), -25.21 (0.5F, ddd, J ) 116.0, 33.6, 27.5 Hz),
42.45 (0.5F, dd, J ) 116.0, 76.3 Hz), 42.55 (0.5F, dd, J ) 116.0,
76.3 Hz), 61.37 (0.5F, dd, J ) 76.3, 32.6 Hz), 62.05 (0.5F, dd,
J ) 77.0, 32.9 Hz), 98.89-100.94 (2F, m); IR (neat) 2958, 2860,
1783, 1460, 1257, 1128 cm-1. Anal. Calcd for C14H24BrF5O2
Si: C, 39.35; H, 5.66. Found: C, 39.80; H,5.14.
2960, 1751, 1469, 1234, 1030 cm-1
10H18F2O4: C, 49.99; H, 7.55. Found: C, 50.04; H, 7.59.
1-Cycloh exyl-2,3,3-tr iflu or o-2-p r op en ol (6j): bp 60 °C/
. Anal. Calcd for
C
4.0 mmHg (Kugelrohr); Rf 0.43 (hexane/ethyl acetate ) 4:1);
1H NMR (200 MHz, CDCl3) 0.82-1.36 (5H, m), 1.59-1.80 (5H,
m), 1.95-2.08 (1H, m), 2.53 (1H, s, OH), 3.99 (1H, dddd, J )
27.9, 8.8, 4.0, 2.0 Hz); 13C NMR (50 MHz, CDCl3) 25.52, 25.58,
26.12, 28.61, 29.25, 40.17, 70.50 (dt, J C-F ) 21.1 Hz, 2.2 Hz),
1,1,2-Tr iflu or o-5-p h en yl-1-p en ten -3-ol (6i). To a solution
of 1,1,1,2-tetrafluoroethane (12.2 mmol) in THF (5.3 mL) was
added a hexane solution of n-BuLi (22.3 mmol, 1.6M) dropwise
for 10 min at -100 °C, and the resulting solution was
gradually warmed to -78 °C over 1 h with stirring. To this
solution was added a THF (5 mL) solution of phenetylaldehyde
(1.34 g, 9.9 mmol) at -78 °C, and the mixture was warmed to
-50 °C over 1 h. The reaction was quenched by addition of
methanol (3 mL), diluted with ethyl acetate (10 mL), and
washed with 5 mL of brine. The organic layer was dried over
anhydrous MgSO4 and evaporated. Silica gel flash column
chromatography (hexanes-ethyl acetate ) 10:1 to 5:1) gave
6i as a colorless liquid in 82% yield (1.78 g, 8.2 mmol): bp 85
°C/2.5 mmHg (Kugelrohr); Rf 0.20 (hexane/ethyl acetate ) 10:
128.20 (ddd, J C-F ) 239.4, 50.5, 12.6 Hz), 153.34 (ddd, J C-F
)
290.9, 276.0, 45.2 Hz); 19F NMR (188 MHz, CDCl3) -27.30 (1F,
dt, J ) 113.6, 29.3 Hz), 40.84 (1F, dd, J ) 111.9, 78.3 Hz),
58.79 (1F, dd, J ) 80.4, 31.9 Hz); IR (neat) 3349, 2929, 2855,
1789, 1452, 1254 cm-1. Anal. Calcd for C9H13F3O: C, 55.66;
H, 6.75. Found: C, 55.85; H, 6.99.
1,1,3-Tr iflu or o-1-n on en -3-ol (6k ): bp 70 °C/8.0 mmHg
(Kugelrohr); Rf 0.48 (hexane/ethyl acetate ) 4:1); 1H NMR (200
MHz, CDCl3) 0.88 (3H, t, J ) 6.6 Hz), 1.28-1.40 (6H, m), 1.67-
1.81 (4H, m), 4.37 (1H, dddt, J ) 26.7 Hz, 3.7 Hz, 1.8 Hz, 7.3
Hz); 13C NMR (50 MHz, CDCl3) 13.90, 22.50, 25.22, 28.83,
31.61, 32.82, 65.94 (dt, J C-F ) 22.0, 2.3 Hz), 128.91 (ddd, J C-F
) 239.2, 49.9, 12.6 Hz), 152.91 (ddd, J C-F ) 291.2, 276.5, 45.5
Hz); 19F NMR (188 MHz, CDCl3) -28.48 (1F, ddd, J ) 113.4,
32.4, 26.6 Hz), 41.23 (1F, dd, J ) 114.3, 80.4 Hz), 58.80 (1F,
1
1); H NMR (200 MHz, CDCl3) 1.97-2.26 (2H, m), 2.40 (1H,
brd, J ) 6.2 Hz, OH), 2.75 (2H, t, J ) 7.8 Hz), 4.41 (1H, dddt,
J ) 26.5, 3.7, 1.7, 7.3 Hz), 7.22-7.40 (5H, m); 13C NMR (50

Synthesis of R,R-Difluoro-γ-lactones
J . Org. Chem., Vol. 64, No. 1, 1999 265
23
dd, J ) 80.4, 31.8 Hz); IR (neat) 3340, 2930, 2861, 1789, 1468,
1258 cm-1. Anal. Calcd for C9H15F3O: C, 55.09; H, 7.71.
Found: C, 54.85; H, 7.88.
was confirmed by converting alcohol (R)-(-)-6f ([R]D -21.7
(c 0.90, EtOH), 91% ee) to natural eldanolide, (4S,5R)-(+)-8
([R]D22 + 53.9 (c 0.70, EtOH), lit.37c +57.8°), in 25% overall yield
through Ueno-Stork-type radical cyclization and subsequent
J ones oxidation (eq 2).20a,b Absolute configuration of the
starting alcohol (-)-6f was thus confirmed as (R)-form.
Syn th esis of Diflu or oeld a n olid e. P r ep a r a tion of Op ti-
ca lly Active Allyl Alcoh ol 6f via Lip a se-Ca ta lyzed Rea c-
tion (Scheme 4). To a THF (240 mL) solution of 15.2 g (120
mmol) of 1-methyl-3-butenyl allyl ether (9)42 was added n-BuLi
(89.0 mL, 144 mmol, 1.62 M in hexane) at -78 °C, and the
mixture was allowed to warm to 0 °C with 9 h of stirring under
argon atmosphere. Silica gel flash coloumn chromatography
of the crude products gave (()-6f26b (8.15 g, 64.5 mmol) in 54%
yield. Enantioselective acylation of (()-6f was achieved using
Pseudomonas cepacia lipase (PCL) in organic media; the
mixture of (()-6f (6.88 g, 54.5 mmol), PCL (1.38 g), 2,6-di-
tert-butyl-4-methylphenol (BHT) (240.2 mg, 1.09 mmol, 2 mol
%) vinyl acetate (7/54 mL, 81.8 mmol) in diidopropyl ether (180
mL) was stirred at room temperature for 48 h. The mixture
was filtered through a glass-sintered filter to remove the
lipase, and the filtrate was evaporated and chromatographed
on silica gel flash column to give (S)-(+)-2fb (2.72 g, 16.3 mmol,
28%) and (R)-(-)-6f (3.92 g, 31.1 mmol, 63%), respectively.
Enantiomeric excess of acetate (S)-2fb was determined by
capillary GC analysis with the chiral phase Chiraldex G-Ta
to be 98.2% ee. Acetate (S)-2fb obtained (2.72 g, 16.2 mmol)
was hydrolyzed at room temperature for 5 h with lithium
hydroxide monohydrate (1.02 g, 24.25 mmol) in a mixed solvent
(THF/water/methanol ) 32 mL/11 mL/5.5 mL) to give optically
active alcohol (S)-6f (2.01 g, 15.9 mmol) in 98% yield. The
optical purity of (R)-6f was not sufficient (91% ee) at the first
stage of resolution, so alcohol (R)-6f (91%ee) was subjected to
PCL-catalyzed acylation for 5 days at room temperature.
Optically pure (R)-6f (>99% ee) was thus obtained in 42%
overall yield from racemic (R)-6f (Scheme 4). Optical purity
of (R)-6f was confirmed by GC analysis to be >99% ee since
no signal of the enantiomer was observed using chiral column
(Chiraldex G-Ta).
Eld a n olid e 8:37 1H NMR (200 MHz, CDCl3) 1.06 (3H, d, J
) 6.4 Hz), 1.57 (3H, s), 1.66 (3H, s), 2.15 (1H, dd, J ) 16.2,
8.8 Hz), 2.15-2.35 (1H, m), 2.35-2.40 (1H, m), 2.61 (2H, dd,
J ) 9.0, 5.9 Hz), 3.99 (1H, dt, J ) 6.1, 5.9 Hz), 5.18 (tq, J )
5.9, 1.4 Hz); 13C NMR (50 MHz, CDCl3) 17.65, 17.89, 25.74,
32.08, 35.02, 37.01, 65.79, 87.06, 117.88, 135.39, 176.53.
Ack n ow led gm en t. The authors are grateful to
Professor Kenji Uneyama of Okayama University and
to Professor Kenji Mori at Science University of Tokyo
for his help in completing this work. The work was
supported by a Grant-in-Aid for Scientific Research on
Priority Areas “New Development of Organic Electro-
chemistry” nos. 06226252 and 08640757 from the Min-
istry of Education, Science and Culture of J apan. The
authors are grateful to the SC-NMR Laboratory of
Okayama University for NMR measurements and to the
MALDI-TOF MS laboratory of the Graduate School of
Okayama University for elemental analysis. They also
thank Amano Pharmaceutical Co., Ltd., for providing
lipases.
Su p p or tin g In for m a tion Ava ila ble: IR, 1H NMR, 19F
NMR, and 13C NMR spectra for new lactones, 1a -k (44 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
Because optical rotation values of (R)-6f and (S)-2fb have
not been reported, absolute configuration of these compounds
(42) Dauben, W. G.; Cogen, J . M.; Ganzer, G. A.; Behar, V. J . Am.
Chem. Soc. 1991, 113, 5817.
(43) (a) Chen, C.-S.; Fujimoto, Y.; Girdauskas, G.; Sih, C. J . J . Am.
Chem. Soc. 1982, 102, 7294. (b) Chen, C.-S.; Wu, S.-H.; Girdauskas,
G.; Sih, C. J . J . Am. Chem. Soc. 1987, 109, 2812.
J O982035B