1,2-dioxines as masked Cis γ-hydroxy enones and their versatility in the synthesis of highly substituted γ-lactones

Article abstract of DOI:10.1021/jo0200421

Addition of highly stabilized ester nucleophiles to 1,2-dioxines affords good to high yields of γ-lactones with high diastereoselectivity. Heterolytic or homolytic cleavage of the 1,2-dioxines under appropriate conditions generates the key reactive cis γ-hydroxy enones, which ultimately afford the observed γ-lactones. Diastereoselectivity is installed as a result of anti 1,4-addition by the ester enolate to the cis enones followed by intramolecular cyclization. The reaction is tolerant of a range of substitution patterns on the 1,2-dioxine while a broad range of esters are also accommodated. In addition to the synthesis of racemic γ-lactones, highly enantioenriched γ-lactones can also be synthesized when chiral cobalt(II) catalysts are employed for the initial homolytic ring-opening of the 1,2-dioxine.

Full text of DOI:10.1021/jo0200421

1,2-Dioxin es a s Ma sk ed Cis γ-Hyd r oxy En on es a n d Th eir
Ver sa tility in th e Syn th esis of High ly Su bstitu ted γ-La cton es
Ben W. Greatrex,† Marc C. Kimber,† Dennis K. Taylor,*,† Gary Fallon,‡ and
Edward R. T. Tiekink§
Department of Chemistry, University of Adelaide, S.A., Australia, 5005, School of Chemistry,
Monash University, Vic., Australia, 3800, and Department of Chemistry, National University of
Singapore, Singapore, 117543
dennis.taylor@adelaide.edu.au
Received J anuary 18, 2002
Addition of highly stabilized ester nucleophiles to 1,2-dioxines affords good to high yields of γ-lactones
with high diastereoselectivity. Heterolytic or homolytic cleavage of the 1,2-dioxines under
appropriate conditions generates the key reactive cis γ-hydroxy enones, which ultimately afford
the observed γ-lactones. Diastereoselectivity is installed as a result of anti 1,4-addition by the ester
enolate to the cis enones followed by intramolecular cyclization. The reaction is tolerant of a range
of substitution patterns on the 1,2-dioxine while a broad range of esters are also accommodated.
In addition to the synthesis of racemic γ-lactones, highly enantioenriched γ-lactones can also be
synthesized when chiral cobalt(II) catalysts are employed for the initial homolytic ring-opening of
the 1,2-dioxine.
SCHEME 1
In tr od u ction
Cis γ-hydroxy enones 1 have found little reported use
in synthetic organic chemistry, with the majority of their
synthetic utility being centered on furan or 1,4-diketone
formation. Furans 3 result when the reaction medium is
acidic due to facile dehydration of the isomeric cis/trans
hemiacetals 2.1-4 Conversely, under basic conditions the
hemiacetals can undergo a Kornblum-Del La Mare
rearrangement to yield the diketone, 4 (Scheme 1).5 Cis
γ-hydroxy enones have been synthesized from their trans
γ-hydroxy enone isomers, via thermal or photolytic
isomerization, but reaction yields have been poor due to
competing acid-catalyzed furanisation.6 This acid/base
sensitivity has therefore limited not only their synthetic
utility but also their synthesis.
heterolytically, to yield cis γ-hydroxy enones 1.7-10 The
dioxines are readily synthesized from their precursor
dienes, 5, by photooxidation using oxygen and a suitable
photosensitizer.7,11-13 Heterolytic ring-opening of the
dioxine can be achieved under basic conditions utilizing
mild amine base catalysis.7,14 Alternatively, homolytic
ring-opening of the 1,2-dioxines has been realized via the
use of transition metals. Ruthenium(II) has been shown
to ring-open 1,2-dioxines to give epoxides from both
1,2-Dioxines of the type shown, 6, represent a class of
compounds that are readily ring-opened homolytically or
* To whom correspondence should be addressed. Tel. (+61) 8 8303
5495. Fax. (+61) 8 8303 4358.
† University of Adelaide.
‡ Monash University.
§ National University of Singapore.
(1) Nguyen, V.; Hishino, H.; Kurosawa, K. Synthesis 1997, 899.
(2) Sammond, D. M.; Sammakia, T. Tetrahedron Lett. 1996, 37,
6065.
(7) Clennan, E. L. Tetrahedron 1991, 47, 1343.
(8) Suzuki, M.; Oda, Y.; Hamanaka, N.; Noyori, R. Heterocycles 1990,
30, 517.
(3) Nishio, T.; Omote, Y. Chem. Lett. 1976, 103.
(4) Friedrich, L. E.; Cormier, R. A. J . Org. Chem. 1971, 36, 3011.
(5) Sengul, M. E.; Ceylan, Z.; Balci, M. Tetrahedron 1997, 53, 10401.
Kornblum, N.; Del LaMare, H. J . Am. Chem. Soc. 1951, 73, 880.
(6) For representative examples of trans γ-hydroxy enone syntheses,
see: Giardina, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J . Org.
Chem. 2001, 713. Nokami, J .; Kataoka, K.; Shiraishi, K.; Osafune, M.;
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Neumann, W. P. Synlett 1994, 123. Burgess, K.; Cassidy, J .; Hender-
son, I. J . Org. Chem. 1991, 56, 2050. Nokami, J .; Nishimura, A.;
Sunami, M.; Wakabayashi, S. Tetrahedron Lett. 1987, 28, 649. Ole-
jniczak, K.; Franck, R. W. J . Org. Chem. 1982, 47, 380. Coxon, J . M.;
Hii, G. S. C. Aust. J . Chem. 1977, 30, 161.
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7, 1359. O’Shea, K. E.; Foote, C. S. J . Org. Chem. 1989, 54, 3475.
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aguchi, Y.; Aoyama, H. J . Org. Chem. 1999, 64, 493.
(12) Takahashi, Y.; Wakamatsu, K.; Morishima, S.; Miyashi, T. J .
Chem. Soc., Perkin. Trans. 2 1993, 243.
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1985, 41, 2147.
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50, 11039.
10.1021/jo0200421 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/26/2002
J . Org. Chem. 2002, 67, 5307-5314
5307

Greatrex et al.
SCHEME 2
SCHEME 3
TABLE 1. Syn th esis of La cton es 9a -d , Utilizin g
1,2-Dioxin e 6a a n d Ester s 8a -d a
entry
R
lactone
yield (%)
bicyclic and monocyclic 1,2-dioxines.9 Similarly, pal-
ladium(0) has been shown to afford epoxides as well as
cis γ-hydroxy enones; however, the cis γ-hydroxy enones
rapidly decomposed to give furan.8,15 O’Shea et al. have
also utilized cobalt(II) complexes to rearrange 1,2-diox-
ines to yield cis γ-hydroxy enones which once again
rapidly rearranged by the previously discussed mecha-
nism to yield furan (Scheme 2).10
It is apparent within the literature that the reactivity
of the cis γ-hydroxy enone functionality has precluded it
from being a viable synthetic tool. 1,2-Dioxines16 can be
visualized as masked cis γ-hydroxy enones, since they
may be efficiently converted to the enone via base or
transition metal induced ring-opening. However, control
of the ring-opening reaction, so that the cis γ-hydroxy
enone does not further rearrange by the aforementioned
processes, has been difficult to achieve due to the enones
acid and base sensitivity.
Recently our research group has developed a variety
of methods for the large-scale generation of these reactive
cis enones from their precursor 1,2-dioxines under suit-
ably mild conditions. In particular, we have explored the
mild basicity of phosphorus ylides to effect the rearrange-
ment of the 1,2-dioxines to the cis enones which then
ultimately led to di- and trisubstituted cyclopropanes in
a highly diastereoselective manner.17a-e,g This process has
also been successfully applied to 1,2-dioxines that have
been ring-opened by Co(II) catalysis.17a-d The reaction has
been shown to proceed via the reactive cis γ-hydroxy
enone, 1, which undergoes facile syn 1,4-addition with
respect to the hydroxyl moiety, in the presence of the
ylide17b-d or phosphonate17a nucleophile to yield the
desired cyclopropane. The facile nature of the syn 1,4-
addition to the cis enone is thought to be due to the
conformation of the cis enone, which can be held together
by an internal hydrogen bond between the carbonyl and
hydroxyl moieties.4 This led us to suggest that other
nucleophiles may undergo similar 1,4-additions to the
enones and in essence trap the enone before it can further
rearrange to the furan 3 or 1,4-diketone 4. This paper
describes the use of a broad range of 1,2-dioxines as
1
2
CO2Et
CN
C(O)Me
9a
9b
9c
93
93
45
70
-
-
-
3b
4c
5
Ph
9d
6d
7e
General reaction conditions contained in experimental. b1
a
equiv of ester. c2 equiv of ester. dLiHMDS used as the base. ePrior
rearrangement of dioxine with Co(Salen)2.
masked cis γ-hydroxy enones and their conversion to
highly substituted γ-lactones in both racemic and enan-
tiomeric forms.18-20
Resu lts a n d Discu ssion
The initial investigations centered on the use of
â-stabilized enolate esters such as the enolate of diethyl
malonate, with the 3,6-diphenyl dioxine 6a chosen as the
model 1,2-dioxine. The results are summarized below in
Scheme 3 and Table 1.
The enolates of the disubstituted esters 8a -c were
allowed to react with dioxine 6a affording the lactones
9a -c in excellent yield. However, 2 equiv of ester 8c was
required to generate the lactone 9c in high yield (entry
4). Monoester 8d failed to react with dioxine 6a , when
employing either sodium ethoxide (entry 5) or LiHMDS
(entry 6) as the base. In an attempt to get the enolate of
8d to react, the 1,2-dioxine 6a was rearranged to the cis
γ-hydroxy enone by the addition of Co(salen)2.10,17b,c
Subsequent addition of the enolate of 8d to the rear-
ranged 1,2-dioxine, however, failed to afford the desired
(18) For general methods of γ-lactone syntheses, see: Mulzer, J . In
Comprehensive Organic Synthesis; Winterfeld, E., Ed.; Pergamon
Press: Oxford, New York, Seoul, Tokyo, 1991; Vol. 6, p 350.
(19) For recent examples of γ-lactone syntheses via intramolecular
cyclizations, see: Huang, T.; Li, C. Tetrahedron Lett. 2000, 41, 9747.
Rodriguez, C. M.; Martin, T.; Wang, C.; Russell, G. J . Org. Chem. 1999,
64, 2066 and references therein; Kayano, A.; Yajima, Y.; Akazome, M.;
Fujita, M.; Ogura, K. Bull. Chem. Soc. J pn. 1995, 68, 3599; Ramirez,
M. A.; Martin, V. S. J . Org. Chem. 1994, 59, 4461 and references
therein.
(20) For recent examples of γ-lactone syntheses via carbonylation
methods, see: Kreimerman, S.; Ryu, L.; Minakata, S.; Komatsu, M.
Org. Lett. 2000, 2, 389 and references therein. Cao, P.; Zhang, X. J .
Am. Chem. Soc. 1999, 121, 7708. Tsunoi, S.; Ryu, L.; Okuda, T.;
Tanaka, M.; Komatsu, M.; Sonoda, N. J . Am. Chem. Soc. 1998, 120,
8692. Ogawa, A.; Kawabe, K.; Kawakami, J .; Mihara, M.; Hirao, T.
Organometallics 1998, 17, 3111 and references therein. Brunner, M.;
Alper, H. J . Org. Chem. 1997, 62, 7565. Ukaji, Y.; Miyamoto, M.;
Mikumi, M.; Takeuchi, S.; Inomata, K. Bull. Chem. Soc. J pn. 1996,
69, 735. Rieke, R. D.; Sell, M. S.; Xiong, H. J . Org. Chem. 1995, 60,
5143 and references therein. Tsunoi, S.; Ryu, L.; Sonoda, N. J . Am.
Chem. Soc. 1994, 116, 5473 and references therein. Suzuki, T.; Uozumi,
Y.; Shibasaki, M. J . Chem. Soc., Chem. Commun. 1991, 1593. Martin,
L. D.; Stille, J . K. J . Org. Chem. 1982, 47, 3630.
(15) Suzuki, M.; Oda, Y.; Noyori, R Tetrahedron Lett. 1981, 22, 4413.
(16) J efford, C. W.; Rossier, J .-C.; Boukouvalas, J . Heterocycles 1989,
28, 673.
(17) (a) Kimber, M. C.; Taylor, D. K. J . Org. Chem. 2002, in press.
(b) Avery, T. A.; Fallon, G.; Greatrex, B. W.; Pyke, S. M.; Taylor, D.
K.; Tiekink, E. R. T. J . Org. Chem. 2001, 66, 7955. (c) Avery, T. A.;
Haselgrove, T. D.; Avery, T. A.; Taylor, D. K.; Tiekink, E. R. T. J . Org.
Chem. 2000, 65, 5531. (d) Avery, T. A.; Greatrex, B. W.; Taylor, D. K.;
Tiekink, E. R. T. J . Chem. Soc., Perkin Trans. 1 2000, 1319. (e) Palmer,
F. N.; Taylor, D. K. J . Chem. Soc., Perkin Trans. 1 2000, 1323. (f)
Haselgrove, T. D.; J evric, M.; Taylor, D. K.; Tiekink, E. R. T.
Tetrahedron 1999, 55, 14739. (g) Rathbone, T. J .; Taylor, D. K.;
Tiekink, E. R. T. J . Chem. Soc., Chem. Commun. 1998, 333.
5308 J . Org. Chem., Vol. 67, No. 15, 2002

1,2-Dioxines as Masked Cis γ-Hydroxy Enones
SCHEME 4a
lactone (entry 7). In all cases where lactone was not the
product (entries 5-7) the major product was the isomeric
1,4-diketone of the cis γ-hydroxy enone. This indicates
that the resultant nucleophile, which derives from ester
8d , is too basic and instead of adding in a anti 1,4-
manner with respect to the R2 grouping, simply rear-
ranges the cis γ-hydroxy enone to the diketone via the
Kornblum-Del La Mare mechanism previously dis-
cussed, a result that mirrors that found for the cyclopro-
panation reaction.17b,c
Each reaction was highly diastereoselective with the
stereochemistry about the lactone ring system deter-
1
mined by 2-D H and 13C NMR techniques and further
confirmed by a single-crystal analysis of 9c (Supporting
Information), and the acid 10, derived from 9a .21,22
A
small amount of a minor lactone isomer (e5%) could be
seen by 1H NMR, but attempts to isolate this minor
isomer were unsuccessful. It must be noted, however,
that when the pure major isomer was allowed to stand
in d-chloroform solution, small amounts of this minor
isomer could be seen to appear over a period of days. This
is due to the ready epimerization of the proton at the C3
malonate center.
Each reaction required acidic workup due to the acidity
of the C3 proton and this therefore allowed for alkylation
at this position prior to workup. Hence the anion of 11
was readily alkylated by the addition of MeI to give a
mixture lactones, 12, epimeric at C3. Acidic decarboxyl-
ation of 12 gave lactones 13a and 13b epimeric at C3.
However, the relative stereochemistry at C4 and C5 had
inverted, with an anti relationship now existing. Simi-
larly, 11 was alkylated with BnBr to give lactone 14
which, after basic hydrolysis (with inversion) followed by
decarboxylation, gave trisubstituted lactone 15 in an
overall yield of 80% (Scheme 4).
a
(a) 50% AcOH, reflux, 16 h; (b) (i) KOH (2 M), EtOH, (ii)
toluene, reflux.
SCHEME 5
Once again the stereochemistry at C5 had inverted,
giving an anti relationship between C4 and C5. This result
can be explained by an intramolecular ‘attack’ from the
carboxyl group during the decarboxylation step, via the
intermediate 16a to generate the more stable lactone 16b
(Scheme 5). The decarboxylation and inversion sequence
is clearly a result of acid catalysis at elevated tempera-
tures, as we had previously shown that no inversion or
decarboxylation occurs during basic hydrolysis of the
ester moiety at ambient temperature as confirmed by
X-ray analysis of lactone 10. The driving force of such
an inversion is the relief of ring strain, thus yielding the
more thermodynamically stable lactone, with the ob-
served anti relationship at C4 and C5.18
electrophile. The major isomer 21 results from protona-
tion on the more hindered face and presumably repre-
sents a thermodynamic preference away from the all-cis
isomer 22. The small amounts of the other diastereomer,
22, detected by 1H NMR, presumably result from quench-
ing of intermediate 20 from the less hindered face.
Scop e of th e Rea ction . To highlight the potential of
this process, ester nucleophiles 8a -c were allowed to
react with a range of monocyclic and bicyclic 1,2-dioxines
to test the scope of the reaction. The results are sum-
marized below in Table 2.
P r op osed Mech a n ism . The mechanism of the reac-
tion is thought to be related to that of the cyclopropana-
tion reaction (Scheme 6).17a-e Initially, the ester anion
removes the most acidic proton of the 1,2-dioxine, which
then subsequently rearranges to the cis γ-hydroxy enone
1. The enone then undergoes facile anti 1,4-addition by
the ester nucleophile on the less hindered face of the
enone, as determined by R2. This intermediate 18 then
undergoes a proton transfer, and the subsequent alkoxy
intermediate 19 cyclizes to lactone 20. The latter lactone
exists as the anion until quenched with acid or an
Yields were good to excellent for all of the lactones,
and the diastereoselectivity for the lactones was also
excellent, de 80-90%. As described previously, 2 equiv
of ethyl acetoacetate were required for complete conver-
sion of the 1,2-dioxines to lactones 22c and 23c (entries
3 and 6). The 3-substituted cyano lactones, 22b and 23b
were also obtained in high yield; however, each lactone
rapidly decomposed upon standing. Dialkyl dioxine, 6d ,
required a reaction time of 5 days for conversion to the
lactone 24, and this reflects the reduced basicity of the
R-protons of the 1,2-dioxine as compared to 1,2-dioxine
6a (entry 7). As well as monocyclic 1,2-dioxines, bicyclic
dioxine 6e gave an excellent yield of the trans fused
lactone 25a (entry 8) as confirmed by 2-D 1H and 13C
(21) See Supporting Information for the X-ray data of 9c.
(22) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Fallon, G. Acta
Crystallogr. E58, 2002, o298-o299.
J . Org. Chem, Vol. 67, No. 15, 2002 5309

Greatrex et al.
TABLE 2. Rea ction of Diester Nu cleop h iles 8a -c w ith a
SCHEME 6
Ra n ge of 1,2-Dioxin esa
entry
1,2-dioxine
nucleophile
lactone
yield (%)
NMR techniques and X-ray analysis of the parent acid,
25b.23 The trans stereochemistry of 25 arises from the
1,4-addition of the malonate anion to the cis enone, with
addition now being directed by the hydroxyl group, due
to the conformation of the cyclooctyl ring system (Scheme
7).
Additionally, long alkyl-chained dioxine 6f was tolerant
of the reaction conditions as seen in entry 9. 3,5-
Disubstituted dioxine 6g gave a high yield of the lactone
27a as a 1:1 mixture, epimeric at C3 (entry 10). 3,3-
Dimethyl dioxine 6h also gave the desired lactone 28 in
excellent yield and de (entry 11). The results shown in
Table 2 indicate that this reaction is general for a range
of 1,2-dioxines and could conceivably be applied to many
other novel 1,2-dioxines.
Op tica lly En r ich ed La cton es. It has been previously
shown that 1,2-dioxines can be rearranged by cobalt(II)
to afford cis γ-hydroxy enones in high yield.17a-d Ad-
ditionally, when chiral cobalt(II) complexes are used to
rearrange the dioxines, optically active enones result.24
Hence, it was a logical progression to utilize this process
to generate optically active lactones. When dioxine 6a
was allowed to react with optically pure cobalt(II) cata-
lysts (29 and 30a ,b),25 optically enriched enone was
formed which was converted to the subsequent lactones
31, 32, and 33 when treated with the anions of 6a -c
(Scheme 8 and Table 3).26
1
6b
6b
6b
6c
6c
6c
6d
6e
6f
8a
8b
8c
8a
8b
8c
8a
8a
8a
8a
8a
22a
22b
22c
23a
23b
23c
24
25a
26
27a
28
97
78
85
92
65
74
56
65
93
84
95
2
3b
4
5
6b
7c
8
9
10d
11
6g
6h
a
General reaction conditions contained in experimental. b2
c
equiv of 8c used. Reaction time of 5 days required for complete
consumption of 6d . d27a isolated as a 1:1 mixture, epimeric at
C3, and was fully characterized as the decarboxylated product 27b.
SCHEME 7
Yields for each transformation were good to excellent
(65-95%) and the ee introduced into each lactone was
(23) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Fallon, G. Acta
Crystallogr., E58, 2002, o248-o249.
also high (77-82%). Bornoxy Co(II) catalyst 29 intro-
duced similar ee’s into each lactone, irrespective of which
ester nucleophile was utilized (entries 1-3). Menthoxy
(24) Avery, T. A.; J enkins, N. F.; Kimber, M. C.; Lupton, D. W.;
Taylor, D. K. J . Chem. Soc., Chem. Commun. 2002, 28.
(25) For general methods on the synthesis of â-ketoiminato ligands
and Co(II) complexes, see: Sugi, K. D.; Nagata, T.; Yamada, T.;
Mukaiyama, T. Chem. Lett. 1997, 493. Nagata, T.; Imagawa, K.;
Yamada, T. Inorg. Chim. Acta 1994, 220, 283. Nagata, T.; Imagawa,
K.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1994, 1259. Mukaiyama,
T.; Yamada, T.; Nagata, T.; Imagawa, K. Chem. Lett. 1993, 327.
(26) While the use of asymmetric cobalt(II) catalysis is currently
limited to symmetrical meso 1,2-dioxines, we are currently exploring
this methodology using unsymmetrical 1,2-dioxines, and this will be
reported on in due course.
5310 J . Org. Chem., Vol. 67, No. 15, 2002

1,2-Dioxines as Masked Cis γ-Hydroxy Enones
SCHEME 8
SCHEME 9a
a
(a) Cobalt(II) catalyst 29, THF, -4 °C; (b) diethyl malonate,
EtONa, 16 h, rt; (c) (i) EtONa (1 equiv), THF, (ii) 4-bromobenzyl
bromide (1 equiv); (d) (i) KOH (2 M), EtOH, (ii) toluene, reflux;
(e) recrystallized (×3).
TABLE 3. F or m a tion of Op tica lly En r ich ed La cton es
31-33 Usin g Ch ir a l Co(II) Ca ta lysts 29, 30a , a n d 30b a n d
Meso 1,2-Dioxin e 6a a
entry
lactone
ratio of a :b
eeb
Con clu sion s
1
31
32
33
31
10:90
-
80
-
82
77
78
The methodology described herein has shown cis
γ-hydroxy enones to be useful synthetic precursors for
the synthesis of γ-lactones and that the functionality of
the 1,2-dioxine presents itself as a viable masking group
for the reactive cis enone. The synthesis of the γ-lactones
is limited to the use of double stabilized esters since
monostabilized esters appear to be too basic and thus
rearrange the cis enone exclusively to the 1,4-diketone
via a Kornblum-Del La Mare mechanism. γ-Lactones are
an important class of compounds that form an integral
part of a number of natural products and are vital
synthetic intermediates in organic synthesis. Since 1,2-
dioxines can be easily prepared from readily available
dienes this methodology presents itself as a simple, yet
efficient method to generate highly substituted γ-lactones
in high yield and in high de. In addition, with the use of
chiral Co(II) catalysts in the homolytic ring opening of
1,2-dioxines, this methodology can also be extended to
the synthesis of enantio-enriched γ-lactones. We are
currently utilizing this methodology in the synthesis of
a number natural products, which will be reported on in
due course.
2c
3
9:91
4d
5e
11.5:88.5
89:11
a
See experimental for reaction conditions. Reaction carried out
using chiral Co(II) catalyst 29 unless otherwise stated. bee
determined by 1H NMR and chiral shift reagent. ee could not be
c
determined due to insolubility of 32 in chiral shift solvent.
dReaction carried out using chiral Co(II) catalyst 30a . Reaction
e
carried out using chiral Co(II) catalyst 30b.
catalysts 30a and 30b (entries 4 and 5) generated
enantio-enriched lactones of opposite absolute configu-
ration. These results therefore suggest that the ee is
being introduced into the cis γ-hydroxy enone, before the
anti 1,4-addition of the ester nucleophiles.27 Absolute
configuration of the lactones was established by X-ray
crystallographic analysis of the enantiopure lactone
3528,29 which was synthesized by the method shown in
Scheme 9 and is depicted in the Supporting Information.
The absolute configuration of lactone 35 implies that
the stereochemistry of the cis γ-hydroxy enone derived
from the action of 29 on 6a , after the 1,4-addition, is that
shown in structure 34. Additionally, it can be deduced,
from the results shown in Table 3, that catalyst 30a
generates a cis γ-hydroxy enone with the configuration
shown in structure 34, while catalyst 30b generates a
cis γ-hydroxy enone with opposite absolute configuration.
A full disclosure of the mechanism for introduction of ee
into the cis γ-hydroxy enone, by the action of chiral
cobalt(II) complexes on meso 1,2-dioxines, will be de-
scribed shortly.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were obtained
on a 600, 300 or 200 MHz instrument using d-chloroform
solutions as indicated. Optical rotation measurements were
obtained on a PO1A AR21 polarimeter referenced to the
sodium D line (589 nm) at 20 °C. Electron impact mass spectra
(EI-MS) were recorded at 70 eV. Accurate mass measurements
were performed at the Central Science Laboratory, University
of Tasmania, Tasmania, Australia. Microanalyses were per-
formed by the Department of Chemistry, University of Otago,
Dunedin, New Zealand. Flash chromatography was conducted
using Merck silica gel 60 of particle size 0.040-0.063 mm.
Thin-layer chromatography (TLC) was performed on alumi-
num backed sheets of Merck silica gel 60F (254), which were
visualized under 254 nm light or developed in vanillin dip.
All organic extracts were dried with anhydrous sodium sulfate.
Hexanes refers to the fraction boiling range 66-68 °C. Where
necessary dichloromethane was distilled from phosphorus
pentoxide and tetrahydrofuran was distilled from sodium-
(27) This result is in agreement with that found for the cyclopro-
panation process. Full details on the mechanism of chiral Co(II) ring-
opening of the 1,2-dioxine and the mode of induction of ee into the cis
γ-hydroxy enone is currently being investigated and will be reported
on in due course.
(28) The enantio-purity of 35 was established by chiral shift 1H NMR
and was shown to be >98%.
(29) See Supporting Information for X-ray data of 35.
J . Org. Chem, Vol. 67, No. 15, 2002 5311

Greatrex et al.
benzophenone ketyl. The following compounds were prepared
by standard literature methods: 3,6-diphenyl-3,6-dihydro-1,2-
dioxine, 6a ;13 3-methyl-6-phenyl-3,6-dihydro-1,2-dioxine, 6b;13
3-phenyl-3,6-dihydro-1,2-dioxine, 6c;13 3,6-dipropyl-3,6-dihy-
dro-1,2-dioxine, 6d ;17b 9,10-dioxabicyclo[4.2.2]decane, 6e;14,30
4-methyl-6-phenyl-3,6-dihydro-1,2-dioxine, 6g;12 3,3-dimethyl-
6-phenyl-3,3-dihydro-1,2-dioxine, 6h .14
3-Octyl-6-p h en yl-3,6-d ih yd r o-1,2-d ioxin e, 6f. 1-Phenyl-
1,3-dodecadiene31 (1.22 g, 5.03 mmol) was dissolved in dry
dichloromethane (100 mL), rose bengal and bis(triethyl-
ammonium) salt (0.100 g) were added, the mixture was cooled
to 4 °C, and a stream of O2 was then passed through the
solution. The reaction was then irradiated with a tungsten
halogen lamp (500 W) at a distance of 10 cm for 6 h. After
this period, the residual solvent was removed under reduced
pressure and the residue chromatographed (1:1, dichloro-
methane:hexanes). This yielded the titled compound as a
1597, 1581, 1449, 1373, 1275 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.24 (d, J ) 6.6 Hz, 1H), 1.34 (t, J ) 7.2 Hz, 3H), 3.14-3.31
(m, 2H), 3.40 (d, J ) 9.9 Hz, 1H), 3.60 (m, 1H), 4.29 (q, J )
7.2 Hz, 2H), 5.14-5.17 (m, 1H), 7.46-7.52 (m, 2H), 7.58-7.64
(m, 1H), 7.93-7.97 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.0,
15.8, 37.5, 38.5, 51.1, 62.2, 77.6, 127.9, 128.8, 133.7, 135.9,
167.2, 170.8, 196.9; MS (M+, %) 290 (M•+,15), 245 (38), 226
(31), 200 (12), 105 (100), 77 (21). Anal. Calcd for C16H18O5: C,
66.20; H, 6.25%. Found C, 65.95, H, 6.22%.
(()-Eth yl 2-Oxo-4-(2-oxo-2-p h en yleth yl)-tetr a h yd r o-3-
fu r a n ca r boxyla te, 23a . As white plates, mp 67.5-69.5 °C
(Rf 0.42, 60:40, hexanes:ethyl acetate). IR (Nujol) 2984, 1778,
1731, 1684, 1596, 1449, 1372, 1225 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.31 (t, J ) 7.1 Hz, 3H), 3.18 (dd, J ) 8.4, 18.0 Hz,
1H), 3.39 (dd, J ) 5.7, 18.0 Hz, 1H), 3.40 (d, J ) 8.7 Hz, 1H),
3.53 (ddddd, J ) 5.7, 7.8, 7.8, 8.4, 8.7 Hz, 1H), 4.01 (dd, J )
7.8, 9.0 Hz, 1H), 4.30 (q, J ) 7.8 Hz, 2H), 4.81 (dd, J ) 7.8,
9.0 Hz, 1H), 7.48-7.51 (m, 2H), 7.58-7.64 (m, 1H), 7.91-7.94
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 35.7, 40.9, 51.8,
62.3, 71.9, 128.0, 128.8, 131.4, 133.8, 167.2, 171.4, 197.8; MS
(M+, %) 277 (M•+, 100), 231 (10), 145 (63), 105 (22). Anal. Calcd
for C15H16O5: C, 65.21; H, 5.84%. Found C, 65.03; H, 5.90%.
(()-Eth yl 2-Oxo-4-(2-oxop en tyl)-5-p r op yltetr a h yd r o-3-
fu r a n ca r boxyla te, 24. As a colorless oil (Rf 0.44; 70:30,
hexanes:ethyl acetate). IR (oil) 2963, 2876, 1780, 1737, 1714,
1374, 1262, 1157 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.92 (t, J
) 7.5 Hz, 3H), 0.95 (t, J ) 6.9 Hz, 3H), 1.20-1.44 (m, 6H),
1.55-1.64 (m, 3H), 2.41 (t, J ) 7.2 Hz, 2H), 2.55-2.72 (m, 2H),
3.26 (d, J ) 9.3 Hz, 1H), 3.35-3.41 (m, 1H), 4.26 (q, J ) 7.2
Hz, 2H), 4.80-4.89 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.5,
13.6, 13.9, 17.1, 18.9, 32.3, 38.0, 41.1, 44.7, 51.7, 62.1, 81.1,
167.2, 170.9, 207.8; MS (M+, %) 285 (M•+, 30), 199 (18), 153
(30), 71 (94), 43 (100). Anal. Calcd for C15H24O5: C, 63.36; H,
8.51%. Found C, 63.52; H, 8.66%.
colorless oil (0.256 g, 19%). IR (oil) 1733, 1455, 1377, 1257 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.26-1.79 (m, 17H), 4.54-4.58
(m, 1H), 5.49-5.51 (m, 1H), 6.04-6.14 (m, 2H), 7.33-7.40 (m,
5H). MS (M+, %) 274 (M•+, 15), 242 (100), 143 (90), 129 (85),
105 (87), 77 (67), 57 (68), 43 (92). HRMS calcd for C18H26O2,
274.1933; found, 274.1919.
Gen er a l La cton iza tion P r oced u r e Usin g Dieth yl Ma -
lon a te. To a solution of sodium ethoxide (0.5 M, 2.2 mL) and
THF (4 mL) was added diethyl malonate, 8a (1 mmol), and
the reaction was stirred for 15 min under an N2 atmosphere.
To this solution was added the 1,2-dioxine (1 mmol), and the
reaction was stirred for 16 h. After this period, the reaction
was quenched by the addition of 1 M HCl (2 mL), and the
mixture was partitioned between dichloromethane (50 mL) and
1 M HCl (50 mL). The aqueous layer was then extracted, the
organic layers were dried and filtered, and the solvent was
removed under reduced pressure. Column chromatography (60:
40, hexane:ethyl acetate) yielded the following substituted
lactones:
(()-Eth yl 2-Oxo-4-(2-oxo-2-p h en yleth yl)-5-p h en yltet-
r a h yd r o-3-fu r a n ca r boxyla te, 9a . As a colorless oil (Rf 0.62,
60:40, hexanes:ethyl acetate). IR (oil): 2983, 1782, 1732, 1683,
1597, 1581, 1497, 1449, 1371, 1341 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.34 (t, J ) 7.2 Hz, 3H), 2.63 (dd, J ) 8.4, 18.3 Hz,
1H), 2.91 (dd, J ) 6.0, 18.3 Hz, 1H), 3.54 (d, J ) 9.6 Hz, 1H),
3.90 (dddd, J ) 6.0, 7.5, 8.4, 9.6 Hz, 1H), 4.30 (q, J ) 7.2 Hz,
2H), 6.04 (d, J ) 7.5 Hz, 1H), 7.11-7.14 (m, 2H), 7.26-7.30
(m, 3H), 7.36-7.42 (m, 2H), 7.51-7.54 (m, 1H), 7.68-7.71 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 38.3, 39.9, 50.9, 62.3,
82.2, 125.7, 127.7, 128.4, 128.5, 128.7, 128.8, 133.4, 135.2,
167.1, 171.3, 197.3; MS (M+, %) 353 (M•+, 20), 232 (72), 186
(32), 159 (26), 105 (100), 77 (52). Anal. Calcd for C21H20O5: C,
71.58; H, 5.72%. Found C, 71.32, H, 5.81%.
(()-Eth yl 2,5-Dioxop er h yd r ocycloocta [b]fu r a n -3-ca r -
boxyla te, 25a . As a colorless oil (Rf 0.54, 60:40, hexanes:ethyl
acetate). IR (oil) 3545, 1786, 1736, 1459, 1374, 1337, 1273 cm-1
;
1H NMR (CDCl3, 600 MHz) δ 1.32 (t, J ) 7.2 Hz, 3H), 1.41-
1.17 (m, 1H), 1.73-1.85 (m, 3H), 1.86-1.92 (m, 1H), 2.16-
2.21 (m, 1H), 2.33 (dt, J ) 5.4, 13.2 Hz, 1H), 2.41 (dd, J )
11.4, 14.4 Hz, 1H), 2.70 (dd, J ) 3.6, 14.4 Hz, 1H), 2.71-2.76
(m, 1H), 3.14-3.21 (m, 1H), 3.35 (d, J ) 12.0 Hz, 1H), 4.12-
4.16 (m, 1H), 4.25-4.30 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ
13.9, 22.0, 25.8, 31.0, 39.0, 43.9, 45.2, 53.7, 62.2, 83.9, 166.5,
169.3, 211.4; MS (M+, %) 255 (M•++ H, 100), 237 (10), 208 (25),
196 (32), 141 (18), 123 (30), 105 (52). Anal. Calcd for
C
13H18O5: C, 61.41; H, 7.14%. Found: C, 61.64; H, 7.40%.
(()-2,5-Dioxop er h yd r ocyclooct a [b ]fu r a n -3-ca r b oxyl-
ic Acid , 25b. Prepared using the same method as 10 (0.033
g, 74%). mp 128-130 °C, decomp. IR (Nujol) 1776, 1726, 1677,
1377, 1162 cm-1; 1H NMR (CDCl3, 600 MHz) δ 1.42-1.48 (m,
1H), 1.73-1.86 (m, 3H), 1.88-1.94 (m, 1H), 2.19-2.24 (m, 1H),
2.33-2.37 (m, 1H), 2.42-2.47 (dd, J ) 12, 14.4 Hz, 1H), 2.73-
2.78 (m, 1H), 3.01-3.04 (dd, J ) 3.6, 14.4 Hz, 1H), 3.10-3.16
(m, 1H), 3.39 (d, J ) 12.6 Hz, 1H), 4.18-4.21 (m, 1H); MS
(M+, %) 226 (M•+, 10), 208 (27), 153 (22), 125 (23), 124 (88), 95
(40), 68 (55), 41 (100). HRMS Calcd for C11H14O5: 226.0841;
found: 226.0849.
(()-2-Oxo-4-(2-oxo-2-p h en yleth yl)-5-p h en yltetr a h yd r o-
3-fu r a n ca r boxylic Acid , 10. Lactone 9a (0.050 g, 0.142
mmol) was dissolved in ethanol (2 mL) and stirred overnight
with 2 M KOH (2 mL). After this period, the solution was
acidified, the aqueous layer extracted with dichloromethane
(10 mL), the organic layer was dried and filtered, and the
solvent was removed under reduced pressure. The residue was
then crystallized from dichloromethane/hexanes to yield the
acid as white plates (0.035 g, 76%). mp 130-132 °C decomp.
(()-E t h yl 5-Oct yl-2-oxo-4-(2-oxo-2-p h en ylet h yl)-t et -
r a h yd r o-3-fu r a n ca r boxyla te, 26. As a viscous oil (Rf 0.55,
60:40, hexanes:ethyl acetate). IR (oil) 1778, 1735, 1686, 1449,
1372, 1344, 1229 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.86 (m,
3H), 1.17-2.04 (m, 17H), 3.21 (d, J ) 7.2 Hz, 2H), 3.38 (d, J
) 9.3 Hz, 1H), 3.58 (m, 1H), 4.22 (q, J ) 7.2 Hz, 2H), 4.93-
4.95 (m, 1H), 7.46-7.51 (m, 2H), 7.58-7.61 (m, 1H), 7.92-
7.95 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 22.6, 25.7,
29.1, 29.2, 29.3, 30.3, 31.8, 37.3, 38.5, 51.8, 62.3, 81.6, 128.0,
128.8, 133.8, 135.9, 167.3, 171.4, 197.0 (two alkyl carbons are
masked); MS (M+, %) 389 (M•+, 21), 285 (62), 257 (18), 143
(86), 105 (100), 69 (64). Anal. Calcd for C23H32O5: C, 71.11; H,
8.30%. Found: C, 70.80; H, 8.01%.
IR (Nujol) 1783, 1711, 1678, 1457, 1377, 1336, 1300, 1267 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 2.67 (dd, J ) 9.3, 18.6 Hz, 1H),
3.26 (dd, J ) 5.1, 18.6 Hz, 1H), 3.64 (d, J ) 10.8 Hz, 1H), 3.90
(dddd, J ) 5.1, 7.8, 9.3, 10.8 Hz, 1H), 6.14 (d, J ) 7.8 Hz, 1H),
7.12-7.14 (m, 2H), 7.31-7.36 (m, 3H), 7.42-7.44 (m, 2H),
7.51-7.57 (m, 1H), 7.74-7.77 (m, 2H); MS (M+, %) 324 (M•+
,
12), 280 (10), 252 (18), 174 (15), 146 (28), 120 (25), 105 (100),
77 (52). Anal. Calcd for C19H16O5: C, 70.36; H, 4.97%. Found
C, 70.31; H, 4.90%.
(()-Eth yl 5-Meth yl-2-oxo-4-(2-oxo-2-p h en yleth yl)-tet-
r a h yd r o-3-fu r a n ca r boxyla te, 22a . As a clear oil (Rf 0.55,
60:40, hexanes:ethyl acetate). IR (oil) 2983, 1778, 1732, 1685,
(()-Eth yl 4-Meth yl-2-oxo-4-(2-oxo-2-p h en yleth yl)-tet-
r a h yd r o-3-fu r a n ca r boxyla te, 27a . As a colorless oil (Rf 0.42,
70:30, hexanes:ethyl acetate). Obtained as a 1:1 mixture of
(30) Kayama, Y.; Oda, M.; Kitahara, Y. Chem. Lett. 1974, 345.
(31) Liu, R. Q.; Shlosser, M. Synlett 1996, 12, 1195.
5312 J . Org. Chem., Vol. 67, No. 15, 2002

1,2-Dioxines as Masked Cis γ-Hydroxy Enones
1
isomers, epimeric at C3 , which were assigned by 2-D H NMR.
(A) 1H NMR (CDCl3, 600 MHz) δ 1.24 (t, J ) 7.2 Hz, 3H), 1.37
(s, 3H), 3.07 (d, J ) 18.0 Hz, 1H), 3.46 (s, 1H), 3.47 (d, J )
18.0 Hz, 1H), 4.18 (q, J ) 7.2 Hz, 2H), 4.33 (d, J ) 9.0 Hz,
1H), 4.49 (d, J ) 9.0 Hz, 1H), 7.43-7.48 (m, 2H), 7.55-7.59
(m, 1H), 7.87-7.89 (m, 2H); (B) 1H NMR (CDCl3, 600 MHz) δ
1.29 (s, 3H), 1.29 (t, J ) 7.2 Hz, 3H), 3.16 (d, J ) 18.0 Hz,
1H), 3.47 (d, J ) 18.0 Hz, 1H), 3.58 (s, 1H), 4.25 (q, J ) 7.2
Hz, 2H), 4.32 (d, J ) 9.0 Hz, 1H), 4.41 (d, J ) 9.0 Hz, 1H),
7.43-7.48 (m, 2H), 7.55-7.59 (m, 1H), 7.91-7.92 (m, 2H); MS
(M+, %) 291 (M•+, 32), 245 (10), 159 (52), 120 (100), 105 (92),
77 (98). The mixture was not separated but decarboxylated
as follows. The mixture was refluxed in 50% acetic acid
solution (5 mL) for 16 h. After this period, the reaction was
cooled and basified and the aqueous layer extracted with
dichloromethane (50 mL). The combined organic extracts were
then dried and filtered, and the solvent was removed under
reduced pressure. This yielded (()-4-m eth yl-2-oxo-4-(2-oxo-
2-p h en yleth yl)-tetr a h yd r ofu r a n , 27b, as a white solid,
which was purified by chromatography (Rf 0.48, 60:40, hex-
anes:ethyl acetate), mp 64.5-66 °C. IR (Nujol) 1760, 1681,
8.7 Hz, 1H), 4.95-4.99 (m, 1H), 7.48-7.54 (m, 2H), 7.61-7.65
(m, 1H), 7.95-8.00 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 15.1,
36.2, 36.9, 39.8, 78.5, 114.4, 128.0, 128.8, 128.9, 134.0, 166.9,
196.2; MS (M+, %) 243 (M•+, 21), 159 (18), 120 (18), 105 (100),
77 (52). HRMS Calcd for C14H13NO3: 243.0895; found: 243.0905.
(()-2-Oxo-4-(2-oxo-2-p h en yleth yl)-tetr a h yd r o-3-fu r a n -
ca r bon itr ile, 23b. As a viscous oil that decomposed upon
standing (Rf 0.36, 60:40, hexanes:ethyl acetate). IR (oil) 2924,
1799, 1682, 1596, 1451, 1376, 1162 cm-1; 1H NMR (CDCl3, 300
MHz) δ 3.21 (dd, J ) 8.7, 18.0 Hz, 1H), 3.46 (ddddd, J ) 4.8,
6.3, 7.2, 8.7, 9.0 Hz, 1H), 3.58-3.65 (dd, J ) 4.8, 18.0 Hz, 1H),
3.66 (d, J ) 6.3 Hz, 1H), 4.08 (dd, J ) 9.0, 9.3 Hz, 1H), 4.87-
4.92 (dd, J ) 7.2, 9.3 Hz, 1H), 7.26-7.54 (m, 2H), 7.59-7.65
(m, 1H), 7.91-7.94 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 36.9,
37.6, 39.2, 72.0, 114.1, 128.1, 129.0, 134.2, 135.6, 167.3, 196.0;
MS (M+, %) 292.2 (M•+, 28), 145 (38), 120 (32), 105 (100), 77
(50). HRMS Calcd for C13H11NO3: 229.0739; found: 229.0741.
Gen er a l La cton iza tion P r oced u r e Usin g Eth yl Aceto-
a ceta te. To a solution of sodium ethoxide (0.5 M, 4.4 mL, 2.2
mmol) and THF (4 mL) was added ethyl acetoacetate 8c (2.1
mmol), and the reaction was stirred for 15 min under an N2
atmosphere To this solution was added the 1,2-dioxine (1
mmol), and the reaction was stirred for 16 h. After this period,
the reaction was quenched by the addition of 1 M HCl (2 mL)
and the mixture partitioned between dichloromethane (50 mL)
and 1 M HCl (50 mL). The aqueous layer was then extracted,
the subsequent organic layers were dried and filtered, and the
solvent was removed under reduced pressure. Column chro-
matography (60:40, hexanes:ethyl acetate) yielded the follow-
ing substituted lactones:
1454, 1419, 1372, 1307, 1291, 1194, 1167 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.34 (s, 3H), 2.48 (d, J ) 17.4 Hz, 1H),
2.63 (d, J ) 17.4 Hz, 1H), 3.13 (d, J ) 17.4 Hz, 1H), 3.31 (d,
J ) 17.4 Hz, 1H), 4.26-4.33 (m, 2H), 7.45-7.51 (m, 2H), 7.57-
7.61 (m, 1H), 7.91-7.95 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ
24.1, 38.3, 42.1, 46.0, 78.3, 127.8, 128.7, 133.5, 136.8, 176.2,
197.4; MS (M+, %) 219 (M•+, 92), 159 (33), 120 (100), 105 (34).
Anal. Calcd for C13H14O3: C, 71.54; H, 6.47%. Found: C, 71.81;
H, 6.34%.
(()-E t h yl 5-Dim et h yl-2-oxo-4-(2-oxo-2-p h en ylet h yl)-
tetr a h yd r o-3-fu r a n ca r boxyla te, 28. As a colorless oil that
crystallized upon standing, mp 65-67 °C (Rf 0.48, 60:40.
hexanes:ethyl acetate). IR (oil) 3533, 3062, 2981, 1772, 1687,
(()-3-Acetyl-4-(2-oxo-2-p h en yleth yl)-5-p h en yltetr a h y-
d r o-2-fu r a n on e, 9c. As colorless needles, mp 113-114 °C (Rf
0.25, dichloromethane). IR (Nujol) 1769, 1714, 1677, 1459,
1379, 1341, 1237, 1164 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1449, 1377, 1352, 1267 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
2.52 (s, 3H), 2.59 (dd, J ) 4.2, 18.3 Hz, 1H), 2.85 (dd, J ) 4.5,
18.3 Hz, 1H), 3.71 (d, J ) 7.4 Hz, 1H), 3.84 (dddd, J ) 4.2,
4.5, 7.4, 7.4 Hz, 1H), 5.95 (d, J ) 7.4 Hz, 1H), 7.17-7.20 (m,
2H), 7.26-7.55 (m, 6H), 7.66-7.70 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 29.6, 38.0, 38.1, 58.6, 82.2, 125.6, 127.7, 128.2,
128.6, 128.6, 128.8, 133.5, 135.5, 136.1, 171.1, 197.6, 200.1;
MS (M+, %) 323 (M•+ + H, 5), 202 (100), 160 (30), 105 (75).
Anal. Calcd for C20H18O4: C, 74.52; H, 5.63%. Found, C, 74.56;
H, 5.79%.
1.20 (t, J ) 7.2 Hz, 3H), 1.30 (s, 3H), 1.48 (s, 3H), 3.10-3.17
(m, 2H), 3.21-3.30 (m, 1H), 3.43 (d, J ) 11.4 Hz, 1H), 4.17 (q,
J ) 7.2 Hz, 2H), 7.40-7.45 (m, 2H), 7.53 (m, 1H), 7.87-7.90
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 22.8, 27.1, 37.9,
44.9, 53.1, 61.7, 85.3, 127.9, 128.6, 133.4, 135.9, 167.5, 170.3,
196.8; MS (M+, %) 304 (M•+, 18), 259 (30), 240 (60), 105 (100).
Anal. Calcd for C17H20O5: C, 67.09; H, 6.62%. Found: C, 67.20;
H, 6.66%.
Gen er a l La cton iza tion P r oced u r e Usin g Eth yl Cya n o-
a ceta te. To a solution of sodium ethoxide (0.5 M, 2.2 mL, 1.1
mmol) and THF (4 mL) was added ethyl cyanoacetate, 6b (1.05
mmol), and the reaction was stirred for 15 min under an N2
atmosphere. To this solution was added the 1,2-dioxine (1.0
mmol), and the reaction was stirred for 16 h. After this period,
the reaction was quenched by the addition of 1 M HCl (2 mL)
and the mixture partitioned between dichloromethane (50 mL)
and 1 M HCl (50 mL). The aqueous layer was then extracted
and the subsequent organic layers dried, filtered and the
solvent removed under reduced pressure. Column chromatog-
raphy (60:40, hexanes:ethyl acetate) yielded the following
substituted lactones:
(()-3-Acetyl-5-m eth yl-4-(2-oxo-2-p h en yleth yl)-tetr a h y-
d r o-2-fu r a n on e, 22c. As white crystals, mp 80-81 °C (Rf 0.23,
70:30, hexanes:ethyl acetate). IR (Nujol) 2983, 1767, 1717,
1683, 1597, 1449, 1357 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1.27 (d, J ) 6.6 Hz, 3H), 2.47 (s, 3H), 3.10-3.30 (m, 2H), 3.51-
3.57 (m, 2H), 5.06 (dq, J ) 6.6, 6.6 Hz, 1H), 7.45-7.51 (m,
2H), 7.58-7.63 (m, 1H), 7.92-7.95 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 16.0, 29.5, 36.3, 37.2, 58.2, 77.6, 127.9, 128.7, 133.6,
136.0, 171.3, 197.4, 200.2; MS (M+, %) 261 (M•+ + H, 25), 218
(10), 159 (14), 105 (100). Anal. Calcd for C15H16O4: C, 69.21;
H, 6.19%. Found, C, 69.29; H, 6.37%.
(()-3-Acetyl-4-(2-oxo-2-ph en yleth yl)-tetr a h yd r o-2-fu r a -
n on e, 23c. As white plates, mp 114-115 °C. (Rf 0.21, 70:30,
hexanes:ethyl acetate). IR (Nujol) 1769, 1713, 1676, 1597,
(()-2-Oxo-4-(2-oxo-2-p h en yleth yl)-5-p h en yltetr a h yd r o-
3-fu r a n ca r bon itr ile, 9b. As a fine white crystals, mp 129-
131 °C (Rf 0.54, 60:40, hexanes:ethyl acetate). IR (Nujol) 1774,
1675, 1369, 1340, 1322, 1282, 1182 cm-1; 1H NMR (CDCl3, 300
MHz) δ 3.00 (d, J ) 6.9 Hz, 2H), 3.95 (ddd, J ) 6.9, 6.9, 9.0
Hz, 1H), 4.16 (d, J ) 9.0 Hz, 1H), 5.85 (d, J ) 6.9 Hz, 1H),
7.21-7.32 (m, 5H), 7.37-7.41 (m, 2H), 7.50-7.56 (m, 1H),
7.67-7.69 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 36.1, 37.5,
38.3, 83.0, 113.3, 125.6, 125.8, 127.8, 128.5, 128.9, 129.2, 133.6,
135.8, 167.6, 196.1; MS (M+, %) 306 (M•+, 32), 256 (10), 199
(22), 120 (48), 105 (100), 77 (32). Anal. Calcd for C19H15N1O3:
C, 74.74; H, 4.95; N, 4.59%. Found C, 74.47; H, 4.91; N, 4.64%.
(()-5-Meth yl-2-oxo-4-(2-oxo-2-p h en yleth yl)-tetr a h ydr o-
3-fu r a n ca r bon itr ile, 22b. As a clear oil that decomposed
upon standing (Rf 0.40, 60:40, hexanes:ethyl acetate). IR (oil)
3062, 2986, 2903, 1786, 1686, 1597, 1449, 1415, 1380, 1322,
1
1580, 1012 cm-1; H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H),
3.11-3.16 (m, 1H), 3.31-3.34 (m, 1H), 3.51-3.57 (m, 2H),
4.69-4.73 (m, 1H), 7.47-7.50 (m, 2H), 7.59-7.61 (m, 1H),
7.92-7.95 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 29.6, 33.2,
40.8, 58.5, 71.8, 127.9, 128.8, 133.7, 136.0, 171.8, 197.2, 200.0;
MS (M•+, %) 247 (M•+ + H, 10), 145 (20), 120 (50), 105 (100).
Anal. Calcd for C14H14O4: C, 68.28; H, 5.73%. Found, C, 68.35;
H, 5.62%.
Gen er a l P r oced u r e for Alk yla tion of La cton e 9a . To a
solution of sodium ethoxide (0.5 M, 2.2 mL) and THF (4 mL)
was added diethyl malonate 8a (1 mmol), and the reaction was
stirred for 15 min under an N2 atmosphere. To this solution
was added 6a (1 mmol), and the reaction was stirred for 16 h.
After this period, alkyl halide (1.05 mmol) was added and the
reaction stirred overnight (16 h) at room temperature. The
reaction was quenched by the addition of 1 M HCl (2 mL) and
the mixture partitioned between dichloromethane (50 mL)
1
1268 cm-1; H NMR (CDCl3, 300 MHz) δ 1.25 (d, J ) 6.3 Hz,
3H), 3.40 (d, J ) 7.2 Hz, 2H), 3.51-3.54 (m, 1H), 4.00 (d, J )
J . Org. Chem, Vol. 67, No. 15, 2002 5313

Greatrex et al.
and 1 M HCl (50 mL). The aqueous layer was then extracted,
the subsequent organic layers were dried and filtered, and the
solvent was removed under reduced pressure. Column chro-
matography (60:40, hexanes:ethyl acetate) yielded the follow-
ing lactones;
mL) at -4 °C under N2 was added 6a (0.238 g, 1.0 mmol), and
the mixture was stirred until complete conversion of the 1,2-
dioxine to the enone (as determined by TLC; approximately 3
h). After this period, a solution of the ester (8a and 8b, 1.0
mmol; 8c, 2.0 mmol) in sodium ethoxide (0.5 M, 8a and 8b,
1.05 mmol; 8c, 2.1 mmol) was added and the reaction stirred
for a further 16 h at room temperature. After this period 1 M
HCL (2.0 mL) was added and the aqueous layer extracted with
dichloromethane (20.0 mL). The resultant organic layers were
dried and filtered, the solvent was removed under reduced
pressure, and the lactone was purified by chromatography (60:
40 hexanes:ethyl acetate). Spectral data for each lactone (31,
32, and 33) was identical as for their racemic counterparts
(9a -c). The enantiomeric excess (ee) for each lactone was
determined as follows: lactone (approximately 6 mg) was
dissolved in a 1:4, d6-benzene:CCl4 solution and chiral shift
reagent europium tris[3-(heptafluoropropylhydroxymethylene)-
(+)-camphorate] complex added until baseline separation was
attained. The following 1H signals were chosen: 31 (CHPh);
33 (C(O)CH3); ee could not be established for lactone 32 due
to insolubility in the d6-benzene-CCl4 solvent system.
(()-E t h yl 3-Met h yl-2-oxo-4-(2-oxo-2-p h en ylet h yl)-5-
p h en yltetr a h yd r o-3-fu r a n ca r boxyla te, 12. Obtained as a
mixture of isomers epimeric at C3 (as determined by 1H NMR)
which were not separated but decarboxylated. Hence, 12 was
refluxed in 50% AcOH (5 mL) for 16 h, and the resultant
mixture was cooled and basified. The aqueous layer was then
extracted with dichloromethane (20 mL), the resultant organic
layer dried and filtered, and the solvent removed under
reduced pressure. This yielded two products (65:35 mixture
by 1H NMR) which were separated by chromatography (70:
30, hexanes:ethyl acetate) and identified as the following:
(()-3-Meth yl-4-(2-oxo-2-p h en yleth yl)-5-p h en yltetr a h y-
d r o-3-fu r a n on e, 13a . As colorless plates, mp 147-149 °C (Rf
0.53, 60:40, hexanes:ethyl acetate). IR (Nujol) 1758, 1683,
1
1376, 1349, 1163 cm-1; H NMR (CDCl3, 600 MHz) d 1.28 (d,
J ) 7.2 Hz, 3H), 2.61-2.66 (dq, J ) 7.2, 7.2 Hz, 1H), 2.70-
2.75 (dddd, J ) 4.8, 7.2, 7.2, 9.0 Hz, 1H), 3.11-3.15 (dd, J )
7.2, 16.8 Hz, 1H), 3.20-3.23 (dd, J ) 4.8, 16.8 Hz, 1H), 5.12
(d, J ) 9.0 Hz, 1H), 7.32-7.43 (m, 7H), 7.54-7.57 (m, 1H),
7.79-7.81 (m, 2H); 13C NMR (CDCl3, 150 MHz) δ 14.5, 38.7,
41.9, 48.1, 83.8, 126.6, 128.0, 128.8, 129.1, 133.6, 136.5, 137.3,
170.2, 197.3 (one aromatic masked); MS (M+, %) 295 (M•+, 100),
174 (25), 105 (20). Anal. Calcd for C19H18O3: C, 77.53; H:
6.16%. Found: C, 77.88; H, 6.08%.
(+)-(3S,4S,5S)-3-(4-Br om ob en zyl)-4-(2-oxo-2-p h en yl-
eth yl)-5-p h en yltetr a h yd r o-2-fu r a n on e, 35. To a solution
of enantioenriched 31b (0.209 g, 0.593 mmol) in dry THF (5.0
mL) under N2 was added sodium ethoxide (1.31 mL, 0.5 M),
and the solution was stirred for 30 min. 4-Bromobenzyl
bromide (0.163 g, 0.652 mmol) was then added and the reaction
stirred for a further 16 h at room temperature. The reaction
was then treated with KOH (2 M, 2.0 mL) and stirred
overnight at room temperature. The mixture was then acidified
by the addition of 1 M HCl and the reaction diluted with CH2-
Cl2 (10.0 mL) and partitioned with brine solution (10.0 mL).
The aqueous layer was extracted with CH2Cl2 (10.0 mL), the
resultant organic layers were combined, dried, and filtered,
and the solvent was removed under reduced pressure. The
crude acid was then dissolved in toluene (10.0 mL) and
refluxed for 16 h. The toluene was then removed under reduced
pressure and the crude product purified by column chroma-
tography to yield the title compound as a white solid (0.160 g,
0.356 mmol). The product was recrystallized three times from
CH2Cl2/hexanes to yield enantiopure 35. Enantiopurity was
determined by chiral shift reagent as previously stated above;
the following 1H signal was chosen (CHPh). Obtained as a
white solid, mp 129-131 °C (Rf 0.63, 60:40, hexanes:ethyl
acetate); [R]20D 48.38° (c 0.62 M, CHCl3). IR (Nujol) 1783, 1681,
(()-3-Meth yl-4-(2-oxo-2-p h en yleth yl)-5-p h en yltetr a h y-
d r o-3-fu r a n on e 13b . As colorless prisms, mp 158-160 °C (Rf
0.68, 60:40, hexanes:ethyl acetate). IR (Nujol) 1755, 1679,
1
1376, 1350, 1165 cm-1; H NMR (CDCl3, 600 MHz) δ 1.18 (d,
J ) 7.8 Hz, 3H), 3.03 (dq, J ) 7.2, 7.8 Hz, 1H), 3.09-3.20 (m,
3H), 5.22 (d, J ) 4.8 Hz, 1H), 7.32-7.35 (m, 1H), 7.38-7.40
(m, 2H), 7.45-7.48 (m, 4H), 7.57-7.60 (m, 1H), 7.93-7.95 (m,
2H); MS (M+, %) 295 (M•+, 30), 175 (15), 174 (62), 105 (100),
77 (25). HRMS Calcd for C19H18O3 294.1256. found, 294.1244.
(()-E t h yl 3-Met h yl-2-oxo-4-(2-oxo-2-p h en ylet h yl)-5-
p h en yltetr a h yd r o-3-fu r a n ca r boxyla te, 14. Obtained as a
colorless oil (Rf 0.53, 60:40, hexanes:ethyl acetate). 1H NMR
(CDCl3, 300 MHz) δ 1.23 (t, J ) 7.2 Hz, 3H), 2.62-2.71 (dd, J
) 9.0, 18.9 Hz, 1H), 2.95-3.03 (dd, J ) 5.1, 18.9 Hz, 1H), 3.35
(d, J ) 13.8 Hz, 1H), 3.53 (d, J ) 13.8 Hz, 1H), 3.80-3.88
(ddd, J ) 5.1, 9.0, 9.3 Hz, 1H), 4.12 (q, J ) 7.2 Hz, 2H), 5.21
(d, J ) 9.3 Hz, 1H), 7.08-7.21 (m, 5H), 7.30-7.40 (m, 7H),
7.50-7.55 (m, 1H), 7.62-7.66 (m, 2H); MS (M+, %) 443.4 (M•+
,
100), 221.1 (38), 105.1 (25). 14 was decarboxylated under basic
conditions. Hence, 14 was stirred in a mixture of ethanol (10
mL) and KOH (2 M, 10 mL) for 16 h. After this period, the
mixture was acidified, the aqueous layer extracted with
dichloromethane (20 mL), the resultant organic layer dried and
filtered, and the solvent removed under reduced pressure. The
residue was then dissolved in toluene (10 mL) and refluxed
overnight. The toluene was then removed under reduced
pressure and the residue purified by chromatography to yield
the following:
1
1162 cm-1; H NMR (CDCl3, 300 MHz) δ 2.71-2.79 (m, 1H),
2.90-3.10 (m, 4H), 3.18 (dd, J ) 4.8, 13.5 Hz, 1H), 5.23 (d, J
) 8.7 Hz, 1H), 7.03-7.14 (m, 4H), 7.28-7.35 (m, 3H), 7.39-
7.45 (m, 2H), 7.55-7.60 (m, 1H), 7.68-7.72 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 34.8, 38.8, 44.4, 47.2, 83.7, 120.8, 126.2,
127.8, 128.7, 128.8, 128.9, 131.2, 131.7, 133.6, 136.2, 137.7,
137.8, 177.1, 197.5. MS (M+, %) 450 (M•+, 15), 448 (10), 250
(60), 159 (60), 105 (100). HRMS Calcd for C25H21BrO3 448.0675.
found, 448.0660. X-ray quality crystals were obtained by
recrystallization from CH2Cl2/hexanes.
(()-3-Ben zyl-4-(2-oxo-2-p h en yleth yl)-5-p h en yltetr a h y-
d r o-3-fu r a n on e, 15. White solid, mp 96-97.5 °C (Rf 0.65, 60:
40, hexanes:ethyl acetate). IR (Nujol) 1776, 1679, 1340, 1164
1
cm-1; H NMR (CDCl3, 300 MHz) δ 2.75 (dddd, J ) 5.4, 6.3,
Ack n ow led gm en t. This work was supported by the
Australian Research Council (ARC). B.G. thanks the
Adelaide University for a Postgraduate Award. We
would also like to thank Dr. Rebecca Sampson (Flinders
University) for optical rotation measurements.
8.1, 9.3 Hz, 1H), 2.88 (dd, J ) 5.4, 17.1 Hz, 1H), 2.94 (dd, J )
7.8, 13.8 Hz, 1H), 2.97 (dd, J ) 6.3, 17.1 Hz, 1H), 3.14 (ddd, J
) 4.8, 7.8, 9.3 Hz, 1H), 3.24 (dd, J ) 4.8, 13.8 Hz, 1H), 5.25
(d, J ) 8.1 Hz, 1H), 7.10-7.20 (m, 8H), 7.28-7.30 (m, 2H),
7.35-7.40 (m, 2H), 7.51-7.57 (m, 1H), 7.63-7.66 (m, 2H); 13
C
NMR (CDCl3, 50 MHz) δ 35.5, 38.6, 44.6, 47.0, 83.6, 126.3,
126.7, 127.8, 128.5, 128.6, 128.7, 129.2, 131.0, 133.3, 136.3,
137.7, 137.9, 177.3, 197.6; MS (M+, %) 371 (M•+, 28), 250 (29),
159 (82), 105 (100), 77 (35). Anal. Calcd for C25H22O3: C, 81.06;
H: 5.99%. Found: C, 80.78; H, 5.98%.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for 9c and 35 and ORTEP diagrams of structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Gen er a l P r oced u r e for th e Syn th esis of Op tica lly
En r ich ed La cton es 31-33. To a solution of the chiral cobalt-
(II) complex (29, 30a , or 30b) (0.075 mmol) in dry THF (5.0
J O0200421
5314 J . Org. Chem., Vol. 67, No. 15, 2002