Enzymatic kinetic resolution of 5-hydroxy-4-oxa-endo-tricyclo[5.2.1.02,6]dec-8-en-3-ones: A useful approach to D-ring synthons for strigol analogues with remarkable stereoselectivity

Article abstract of DOI:10.1021/jo9610220

Racemic 5-hydroxy-4-oxa-endo-tricyclo[5.2.1.0^2,6]dec-8-en-3-one and its 2-methyl analogue were resolved employing a lipase-catalyzed acetylation reaction. The latter compound thus gave access to a homochiral D-ring synthon for strigolactones. The enzymatic acetylation reaction occurred with a remarkable inversion of configuration at C-5, through which it is possible to achieve a highly efficient asymmetric synthesis of 5-acetoxy-2(5H)-furanone.

Full text of DOI:10.1021/jo9610220

J . Org. Chem. 1996, 61, 6931-6935
6931
En zym a tic Kin etic Resolu tion of
5-Hyd r oxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]d ec-8-en -3-on es: A Usefu l
Ap p r oa ch to D-Rin g Syn th on s for Str igol An a logu es w ith
Rem a r k a ble Ster eoselectivity
J an Willem J . F. Thuring, Gerard H. L. Nefkens, Margreth A. Wegman,
Antonius J . H. Klunder, and Binne Zwanenburg*
NSR-Center for Molecular Structure, Design and Synthesis, Department of Organic Chemistry,
University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received May 31, 1996X
Racemic 5-hydroxy-4-oxa-endo-tricyclo[5.2.1.02,6]dec-8-en-3-one and its 2-methyl analogue were
resolved employing a lipase-catalyzed acetylation reaction. The latter compound thus gave access
to a homochiral D-ring synthon for strigolactones. The enzymatic acetylation reaction occurred
with a remarkable inversion of configuration at C-5, through which it is possible to achieve a highly
efficient asymmetric synthesis of 5-acetoxy-2(5H)-furanone.
Ch a r t 1
(+)-Strigol (1) and some structurally related sesqui-
terpene lactones sorgolactone (2) and alectrol (3) are
members of the “strigolactone” family,1 which induce
germination of seeds of the parasitic weeds Striga and
Orobanche.2-4
These weeds cause severe damage to graminaceous and
leguminous crops in tropical and semitropical areas in
the eastern hemisphere.5-7 As part of our interest in the
(asymmetric) synthesis of the strigolactones and their
synthetic analogues8-12 we recently devised an asym-
metric synthesis of the tricyclic exo-chloro lactone 4a
(Scheme 1),13 which can be regarded as a homochiral
D-ring synthon. This D-ring is a common structural
feature of the strigolactones and is of prime importance
for full biological activity. Even the absolute stereochem-
istry at C-2′ is essential for optimal stimulation of
germination.12,14,15
Sch em e 1
The key step in the synthesis of 4a involves menth-
ylation with l-menthol to give a 1:1 mixture of diaster-
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) Butler, L. G. ACS Symp. Ser. 1995, 582, 158-168
(2) Siame, B. A.; Weerasuriya, Y; Wood, K.; Ejeta, G.; Butler, L. G.
J . Agric. Food Chem. 1993, 41, 1486-1491.
(3) Hauck, C.; Mu¨ller, S.; Schildknecht, H. J . Plant Physiol. 1992,
139, 474-478.
(4) Mu¨ller, S.; Hauck, C.; Schildknecht, H. J . Plant Growth Regul.
1992, 11, 77-84.
(5) Musselman, L. J ., Ed. Parasitic Weeds in Agriculture. Striga;
CRC Press: Boca Raton, FL, 1987; Vol. I, 317 pp.
(6) Parker, C. Scope of the agronomic problems caused by Orobanche
species. In Proceedings of a workshop on biology and control of
Orobanche; Ter Borg, S. J ., Ed.; LH/VPO: Wageningen, The Nether-
lands, 1986; pp 11-17.
(7) Parker, C.; Riches, C. R. Parasitic Weeds of the World: Biology
and Control; CAB International: Wallingford, UK, 1993; 332 pp.
(8) Mangnus, E. M.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas
1992, 111, 155-159.
(9) Mangnus, E. M.; Zwanenburg, B. J . Agric. Food Chem. 1992,
40, 1066-1070.
(10) Mangnus, E. M.; van Vliet, L. A.; Vandenput, D. A. L.;
Zwanenburg, B. J . Agric. Food Chem. 1992, 40, 1222-1229.
(11) Mangnus, E. M.; Dommerholt, F. J .; de J ong, R. L. P.; Zwanen-
burg, B. J . Agric. Food Chem. 1992, 40, 1230-1235.
(12) Mangnus, E. M.; Zwanenburg, B. J . Agric. Food Chem. 1992,
40, 697-700.
(13) Thuring, J . W. J . F.; Harren, F. J . M.; Nefkens, G. H. L.; Reuss,
J .; Titulaer, G. T. M.; de Vries, H. S. M.; Zwanenburg, B. Tetrahedron
1995, 51, 5047-5056.
(14) Thuring, J . W. J . F.; Mangnus, E. M.; Zwanenburg B. Ethene
production by seeds of Striga hermonthica induced by germination
stimulants. In Proceedings of the third international workshop on
Orobanche and related Striga research; Pieterse, A. H., Verkley, J . A.
C., Ter Borg, S. J ., Eds.; Royal Tropical Institute: Amsterdam, The
Netherlands, 1994; pp 225-236.
eomeric menthyl ethers, separation of the diastereomers,
followed by acidic hydrolysis to give the enantiopure
hydroxy lactone 5a . This method provides access to both
enantiomers of 5a by choosing the appropiate enantiomer
of menthol. However, the resolution is quite laborious
since it requires two steps and a careful selective recrys-
tallization. Moreover, 1 equiv of the chiral auxiliary is
required. In order to circumvent these problems, a study
was undertaken to improve the resolution, using an
enzymatic approach.
Enzymes currently find widespread use in synthetic
organic chemistry.16a-d A prominent example of an
enzymatic asymmetric transformation is the kinetic
resolution of a racemic alcohol R*OH in the presence of
(15) Bergmann, C.; Wegmann, K.; Frischmuth, K.; Samson, E.;
Kranz, A.; Weigelt, D.; Koll, P.; Welzel, P., J . Plant Physiol. 1993, 142,
338-342.
S0022-3263(96)01022-5 CCC: $12.00 © 1996 American Chemical Society

6932 J . Org. Chem., Vol. 61, No. 20, 1996
Thuring et al.
Ta ble 2. Lip a se P S-Ca ta lyzed Tr a n sester ifica tion of
Sch em e 2
en d o-Tr icyclic Hyd r oxy La cton e r a c-5b
product distribution (%)
entry time, h conversion (%) 7b (% ee)
5b (% ee)
8b
1
2
3
17
47
17 days
39.0
53.5
60.8
39.0 (>90) 61.0 (56)
50.0 (>90) 46.5 (>90)
0
3.5
45.2 (>90) 39.2 (>90) 15.6
place when other lipases were employed (lipase A, lipase
R). Along with the endo-acetates 7a and 7b, exo-acetates
8a and 8b were formed in minor amounts (Tables 1 and
2). A striking observation is the fact that this reaction
takes place with epimerization at C-5. The formation of
the endo-acetates 7a and 7b could readily be deduced
Ta ble 1. Lip a se P S-Ca ta lyzed Tr a n sester ifica tion of
en d o-Tr icyclic Hyd r oxy La cton e r a c-5a
product distribution (%)
entry time, h conversion (%)
7a (% ee)
5a (% ee) 8a
1
2
3
22
46
70
30.8
48.0
56.2
30.2 (>90) 69.2 (41) 0.6
45.7 (87)
51.6 (87)
52.0 (79) 2.3
43.8 (85) 4.6
1
from H-NMR analysis. The acetal proton H5 of the endo-
isomers 7a and 7b exhibited a doublet (3J ) 7 Hz for 7a
and 6 Hz for 7b) at ca. 0.6 ppm lower field as compared
to the corresponding exo-isomers (3J ) 1 Hz), which is in
agreement with previous observations.13 These results
suggest that the reaction takes place via the thermody-
namically unfavorable endo-hydroxy epimers 9, which
can be formed from the corresponding exo-isomers by
mutarotation (eq 2). During NMR experiments in CDCl3,
we never observed the presence of the endo-epimers in
the solution.
an acyl donor R2C(O)OR3, catalyzed by a lipase. The
charm of this methodology lies in the facts that organic
solvents can be used, workup is extremely simple, and a
large variety of substrates is tolerated in this transfor-
mation. The application of enol esters as irreversible acyl
donors16b makes this type of resolution even more attrac-
tive. In the present paper we describe the kinetic
resolution of racemic endo-tricyclic hydroxy lactones 5
employing vinyl acetate as irreversible acyl donor, cata-
lyzed by lipase PS.
Resu lts a n d Discu ssion
Starting endo-tricyclic exo-hydroxy lactones 5 were
obtained by standard literature procedures. Hydroxy
lactone 5a was prepared by a Diels-Alder reaction of
citraconic anhydride and cyclopentadiene, followed by
partial reduction according to the procedure of Canonne.17
Hydroxy lactone 5b was obtained by photooxidation of
furfural18 and subsequent Diels-Alder reaction with
cyclopentadiene.
Kin etic Resolu tion . In a recent paper Kellogg et al.
described the lipase-mediated transesterification of 5-
acyloxy-2(5H)-furanones rac-6 with 1-butanol resulting
in ee’s ranging from 68-98% (eq 1) with hitherto un-
known stereochemistry.19
It should be noted that it is not possible to obtain the
endo-acetates by any other means. Acetylation reactions
under conventional conditions, such as Ac2O/pyridine or
Ac2O/p-TsOH, gave exclusively the exo-acetates 8. In
order to gain information about the existence of the exo/
endo equilibrium (eq 2), we subjected the endo-acetate
7b to a transesterification reaction. However, employing
MeOH as a solvent in the presence of K2CO3 the expected
exo-hydroxy lactone ent-5b was not obtained, but exo-
methoxy lactone ent-10b was isolated as the main
product (eq 3). Therefore, we switched to the enzymatic
approach. Lipase PS-catalyzed transesterification in the
presence of 10 equiv of n-BuOH in CH2Cl2 led to the
exclusive formation of exo-hydroxy lactone ent-5b (eq 3).
Again, no trace of endo-hydroxy lactone could be detected.
We have studied the irreversible acetylation of endo-
tricyclic exo-hydroxy lactones 5 in the presence of vinyl
acetate in dichloromethane catalyzed by lipase PS (Scheme
2). The results are collected in Tables 1 and 2.
As can be deduced from the data shown in Tables 1
and 2, the lipase PS-mediated acetylation of hydroxy
lactones 5 is accomplished in good to excellent ee’s. It
should be emphasized that this conversion does not take
The results obtained with lipase PS-catalyzed acety-
lation of racemic hydroxy lactones 5 (Scheme 2) fit into
a model in which only one enantiomer of the thermody-
namically unfavorable endo-hydroxy lactones 9 is with-
drawn from the exo/endo equilibrium (eq 2) to undergo a
relatively fast enzymatic acetylation reaction. This
sequence is an example of the Curtin-Hammett prin-
ciple.20 This remarkably large kinetic difference between
(16) For reviews see: (a) Chen, C. S.; Sih, C. J . Angew. Chem., Int.
Ed. Engl. 1989, 28, 695-707. (b) Faber, K.; Riva, S. Synthesis 1992,
895-910. (c) Boland, W.; Fro¨ssl, C.; Lorenz, M. Synthesis 1991, 1049-
1072. (d) Santaniello, E., Ferraboschi, P., Grisenti, P.; Manzocchi, A.
Chem. Rev. 1992, 92, 1071-1140.
(17) Canonne, P.; Plamondon, J .; Akssira, M. Tetrahedron 1988, 44,
2903-2912.
(18) Yuste, F.; Sa´nchez-Obrego´n, R. J . Org. Chem. 1982, 47, 3665-
3668.
(19) Deen van der, H.; Hof, R. P.; Oeveren van, A.; Feringa, B. L.;
Kellogg, R. M. Tetrahedron Lett. 1994, 35, 8441-8444.
(20) Carey, F. A., Sundberg, R. J . Advanced Organic Chemistry, Part
A, 3rd ed.; Plenum Press: New York, 1990; pp 215-216.

D-Ring Synthons for Strigol Analogues
J . Org. Chem., Vol. 61, No. 20, 1996 6933
Sch em e 3
Ch a r t 2
The ee’s then were determined employing 400 MHz 1H-
NMR analysis in the presence of the chiral shift reagent
Eu(hfc)3 (1.5 equiv). In the case of methoxy lactones 10a
and ent-10a a difference of 0.03 ppm was observed for
the R-methyl protons. On the other hand, the ee of
methoxy lactone 10b22 was calculated on the basis of a
0.03 ppm difference of chemical shift of the acetal proton
H5 as compared to its enantiomer ent-10b. The deter-
mination of ee of acetoxy-2(5H)-furanone 11 was ac-
complished by comparison of the relative intensities of
the CH3 signals in the 1H-NMR spectrum using 0.4 equiv
of Eu(hfc)3, which resulted in a downfield shift of ap-
proximately 0.8 ppm and a difference of 0.16 ppm for both
enantiomers. On the basis of the above assignment of
the absolute stereochemistry the levorotatory 5-acetoxy-
2(5H)-furanone 11, obtained by Kellogg et al. according
to eq 1,19 can be assigned as 5(R).
the endo- and exo-hydroxy lactones results in an excellent
selectivity of product formation. It should be noted that
in the absence of the lipase no conversion into 7a ,b or
8a ,b was observed even after 17 days. This implies that
the formation of exo-acetates 8a ,b (e.g. Table 2, entry 3)
is also catalyzed by the lipase, albeit in a much lower
rate. The formation of the exo-acetates 8a and 8b, which
are diastereomeric to the initially formed products 7a ,b,
takes place via the exo-epimers 5a and 5b, respectively.
This formation of diastereomers 7 and 8, which is the
ultimate result of the exo/endo equilibrium as depicted
in eq 2, is quite unusual in kinetic resolutions.
The interesting finding shown in Scheme 2 can be
advantageously utilized to achieve a sequence with full
chiral economy (Scheme 3) in the following manner.
The crude mixture of 7b and 5b, obtained by kinetic
resolution of rac-5b is acetylated under standard condi-
tions to give the diastereomeric products 7b and 8b.
Without further purification this mixture was subjected
to a cycloreversion reaction, employing the technique of
flash vacuum pyrolysis (FVT). This reaction led to the
formation of one single isomer of 5-acetoxy-2(5H)-fura-
none 11. This remarkable result can be rationalized by
taking into account that a double stereodifferentiation
has taken place. These results demonstrate the success-
ful application of an enzymatic kinetic resolution of a
racemic mixture, providing one single enantiomer with-
out purification of any intermediate.
Con clu sion
Lipase PS-mediated acetylation proved to be a simple,
highly efficient method for the kinetic resolution of
racemic tricyclic hydroxy lactones 5. Employing this
methodology it is possible to synthesize both enantiomers
of exo-chloro lactones 4a . These optically active latent
butenolides are useful synthons for the preparation of
homochiral strigolactones.13 The kinetic resolution was
accompanied with a remarkable epimerization, which
could be used to demonstrate the synthesis of enan-
tiopure 5-acetoxy-2(5H)-furanone 11 with optimal “chiral
economy”.
Exp er im en ta l Section
Gen er a l. For general methods and instrumentation, see
ref 13. GC-MS spectra were run on a Varian Saturn 2 GC-
MS ion-trap system. Separation was carried out on a fused-
silica capillary column (DB-5, 30 m × 0.25 mm). Helium was
used as carrier gas, and electron impact (EI) was used as
ionization mode. Lipase PS was obtained from Amano as a
gift.
Gen er a l P r oced u r e for th e En zym a tic Kin etic Resolu -
tion of th e Tr icyclic Hyd r oxy La cton es r a c-5a a n d r a c-
5b. To a solution containing exo-hydroxy tricyclic lactone rac-
5a 17 (500 mg, 2.79 mmol) and vinyl acetate (2.57 mL, 27.9
mmol) in CH2Cl2 (25 mL) were added lipase PS (1.0 g) and
powdered 4A molecular sieves (0.5 g). The suspension was
stirred vigorously at room temperature. At given intervals
(Tables 1 and 2) samples were taken (3 mL) and filtered over
hyflo. The hyflo was washed with CH2Cl2, and the crude
mixture was analyzed by 100 MHz 1H-NMR (CDCl3) for
conversion. Purification by chromatography (SiO2, hexane/
ethyl acetate 3:1) afforded endo-acetate 7a as a white solid
and exo-alcohol 5a as a white solid, which were analyzed for
ee (vide infra).
Deter m in a tion of En a n tiom er ic Excess a n d Ab-
solu te Con figu r a tion . The ee’s of the tricyclic hydroxy
lactones 5a and 5b were established after menthylation
with l-menthol to give the corresponding l-menthyloxy
lactones 12a and 12b as a mixture of diastereomers with
known absolute stereochemistry.13,21 The de’s could thus
be determined by comparison of the relative intensities
1
of the acetal H5 proton signals in the H-NMR spectrum.
As there is no stereochemical preference in the menth-
ylation reaction,13 this derivatization allows the deter-
mination of the ee’s of the hydroxy lactones 5. Moreover,
this derivatization to menthyl acetals 12 with known
stereochemistry enables the unambigious assignment of
the absolute stereochemistry as is shown (Scheme 2).
Although effective, a more convenient procedure to
determine the respective ee’s involves the conversion of
hydroxy lactones 5 and endo-acetoxy lactones 7 into the
corresponding methyl acetals 10a,b and ent-10a,b. These
methylations occurred with complete exo selectivity in
almost quantitative yields.
En a n tiom er ic Excess Deter m in a tion . The hydroxy lac-
tones 5a and 5b were transformed into the corresponding
(21) de J ong, J . C.; van Bolhuis, F.; Feringa, B. L. Tetrahedron
Asymmetry 1991, 2, 1247-1262.
(22) Farina, F.; Martin, M. V.; Paredes, M. C.; Ortega, M. C.; Tito,
A., Heterocycles 1984, 22, 1733-1739

6934 J . Org. Chem., Vol. 61, No. 20, 1996
Thuring et al.
l-menthyl ethers 12.13,21 Alternatively, 5a and 5b were
converted into the corresponding exo-methoxy lactones 10a ,
10b and subsequently analyzed by 400 MHz 1H-NMR (CDCl3)
in the presence of ca. 1.5 equiv of Eu(hfc)3 (vide infra).
Similarly, endo-acetates 7a and 7b were methylated to give
ent-10a and ent-10b, respectively (vide infra), which were
analyzed for ee in the same manner.
5(S)-Meth oxy-2(R)-m eth yl-4-oxa-en do-tr icyclo[5.2.1.02,6]-
d ec-8-en -3-on e (en t-10a ). For determination of ee of endo-
5(R)-acetoxy lactone 7a . A solution of 7a (25 mg, 0.11 mmol)
in methanol (2 mL) was treated with 1 drop of thionyl chloride.
The solution was stirred for 30 min and concentrated in vacuo
to give pure ent-10a (21.1 mg, 97%), which was analyzed for
ee as described for rac-10a .
5(R)-Acetoxy-2(R)-m eth yl-4-oxa-en do-tr icyclo[5.2.1.02,6]-
d ec-8-en -3-on e (7a ) a n d 5(R)-h yd r oxy-2(S)-m eth yl-4-oxa -
en d o-tr icyclo[5.2.1.02,6]d ec-8-en -3-on e (5a ). These com-
pounds were synthesized according to the general procedure
starting from rac-5a 17 (3.00 g, 16.7 mmol). The reaction was
stopped after 73 h. Purification by chromatography (SiO2,
hexane/ethyl acetate 3:1) gave 7a (1.28 g, 34%) as a white solid
and 5a (1.18 g, 39%) as a white solid. Analytical samples of
5a and 7a were obtained by recrystallization from hexane/ethyl
acetate.
Ra cem ic exo-5-Meth oxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]-
d ec-8-en -3-on e (r a c-10b).22 For determination of ee of 5(R)-
hydroxy lactone 5b. A solution of rac-5b (50 mg, 0.31 mmol)
in methanol (2 mL) was treated with 1 drop of thionyl chloride.
The solution was stirred for 30 min and concentrated in vacuo
to give crude rac-10b, which was not sufficiently pure for ee
determination. Purification by chromatography (SiO2, hexane/
ethyl acetate 9:1) gave pure rac-10b (47.2 mg, 84%) as a white
1
solid: mp 54.5-55.5 °C; H-NMR (CDCl3, 400 MHz): δ 1.44
(dt, J ) 1.0 Hz, 8.6 Hz, 1H), 1.62 (dt, J ) 1.0 Hz, 8.6 Hz, 1H),
2.91 (m, 1H), 3.19 (m, 1H), 3.31 (m, 2H), 3.43 (s, 3H), 4.79 (d,
J ) 1.1 Hz, 1H), 6.20 (m, 1H), 6.25 (m, 1H). Addition of 1.5
equiv of the chiral shift reagent Eu(hfc)3 gave a splitting of
the signal of the acetal proton H5 of 0.03 ppm (1.37 ppm
downfield shift). GC-MS (EI, m/z, rel int (%)): 181 (M+ + 1,
10.7), 149 (12.6), 121 (14.4), 115 (9.4), 91 (54.6), 83 (15.3), 66
(100). Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found:
C, 66.12; H, 6.62.
7a : mp 98.5-101.5 °C; [R]D -88.4° (c 0.4, CH2Cl2); 1H-NMR
(CDCl3, 100 MHz): δ 1.54 (s, 3H), 1.69 (m, 2H), 2.15 (s, 3H),
2.85 (m, 1H), 2.87 (dd, J ) 3.9, 7.0 Hz, 1H), 3.04 (m, 1H), 6.26
(m, 2H), 6.50 (d, J ) 7.0 Hz, 1H); GC-MS (EI, m/z, rel int (%)):
163 (M+ - OAc, 90.4), 157 (1.7), 152 (23.4), 97 (13.6), 91 (16.9),
66 (100). Anal. Calcd for C12H14O4: C, 64.85; H, 6.35.
Found: C, 65.28; H, 6.31.
1
5a : All analytical data (Mp, [R]D, H-NMR, and mass data)
5(S)-Meth oxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]d ec-8-en -3-
on e (en t-10b). For determination of ee of endo-5(R)-acetoxy
lactone 7b. This compound was prepared from 7b (40 mg, 0.19
mmol) in the same way as described for the synthesis of ent-
10a . Yield after chromatography (SiO2, hexane/ethyl acetate
9:1) 28.2 mg, 83%. The ee was determined according to the
procedure as described for rac-10b.
Ra cem ic exo-5-Acetoxy-2-m eth yl-4-oxa -en d o-tr icyclo-
[5.2.1.02,6]d ec-8-en -3-on e (r a c-8a ). rac-5a (100 mg, 0.56
mmol) was dissolved in pyridine/acetic anhydride 2:1 v/v (1
mL) and stirred for 17 h at room temperature. The solvents
were removed in vacuo, and the residue was coevaporated with
toluene. Yield 121.8 mg, 98% of pure rac-8a as a colorless oil:
1H-NMR (CDCl3, 100 MHz): δ 1.50 (s, 3H), 1.62 (m, 2H), 2.04
(s, 3H), 2.50 (dd, J ) 0.9, 4.2 Hz, 1H), 2.80 (m, 1H), 3.12 (m,
1H), 5.87 (d, J ) 0.9 Hz, 1H), 6.19 (m, 2H), GC-MS (EI, m/z,
rel int (%)): 163 (M+ - OAc, 36.3), 157 (3.0), 97 (18.2), 91
(11.5), 66 (100); HRMS/EI: m/z calcd for C12H14O4: 222.0892.
Found 222.08931 ( 0.00088.
were in complete agreement with those reported previously.13
5(R)-Acetoxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]d ec-8-en -3-
on e (7b) a n d 5(R)-Hyd r oxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]-
d ec-8-en -3-on e (5b). These compounds were synthesized
according to the general procedure starting from rac-5b17 (3.00
g, 18.1 mmol). The reaction was stopped after 46 h. Purifica-
tion by chromatography (SiO2, hexane/ethyl acetate 3:1) gave
7b (1.65 g, 44%) as a white solid and 5b (1.41 g, 47%) as a
white solid. Analytical samples of 5b and 7b were obtained
by recrystallization from hexane/ethyl acetate.
7b: mp 116.5-118 °C; [R]D -126.0° (c 1.0, CH2Cl2); 1H-NMR
(CDCl3, 100 MHz): δ 1.47 (dt, J ) 1.0 Hz, 9.0 Hz, 1H), 1.65
(dt, J ) 1.0 Hz, 9.0 Hz, 1H), 2.15 (s, 3H), 3.11 (m, 1H), 3.36
(m, 3H), 6.25 (m, 2H), 6.48 (d, J ) 6.0 Hz, 1H); GC-MS (EI,
m/z, rel int (%)): 166 (M+ + 1 - Ac, 12.2), 149 (M+ - OAc,
49.2), 137 (12.2), 91 (42.3), 83 (9.1), 66 (100). Anal. Calcd for
C11H12O4: C, 63.45; H, 5.81. Found: C, 63.55; H, 5.79.
5b: mp 134-136.5 °C; [R]D +53.2° (c 0.2, CH2Cl2); 1H-NMR
(CDCl3, 100 MHz): δ 1.37 (dt, J ) 1.0 Hz, 8.5 Hz, 1H), 1.56
(dt, J ) 1.0 Hz, 8.5 Hz, 1H), 2.86 (m, 1H), 3.33 (m, 3H), 4.83
(br s, 1H), 5.16 (br s, 1H), 6.14 (m, 2H); GC-MS (EI, m/z, rel
int (%)): 167 (M+ + 1, 1.9), 149 (2.0), 91 (29.3), 83 (3.1), 66
(100). Anal. Calcd for C9H10O3: C, 65.05; H, 6.07. Found:
C, 64.97; H, 6.00.
Ra cem ic exo-5-Acetoxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]-
d ec-8-en -3-on e (r a c-8b). This compound was prepared from
rac-5b (100 mg, 0.60 mmol) in the same way as described for
the synthesis of rac-8a . Purification by chromatography (SiO2,
hexane/ethyl acetate 3:1) afforded rac-8b (119.8 mg, 87%) as
a white solid. An analytically pure sample was obtained by
recrystallization from hexane/ethyl acetate: mp 82.5-84 °C;
1H-NMR (CDCl3, 100 MHz): δ 1.39 (dt, J ) 1.0 Hz, 8.7 Hz,
1H), 1.60 (dt, J ) 1.0 Hz, 8.7 Hz, 1H), 2.03 (s, 3H), 2.96 (m,
1H), 3.25 (m, 3H), 5.86 (d, J ) 1.2 Hz, 1H), 6.19 (m, 2H); GC-
MS (EI, m/z, rel int (%)): 149 (M+ - OAc, 10.2), 143 (1.6), 91
(23.6), 83 (11.6), 66 (100). Anal. Calcd for C11H12O4: C, 63.45;
H, 5.81. Found: C, 63.50; H, 5.79.
5(S)-Hyd r oxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]d ec-8-en -3-
on e (en t-5b). A solution containing 7b (50 mg, 0.24 mmol)
and n-BuOH (0.22 mL, 24 mmol) in CH2Cl2 (3 mL) were
treated with lipase PS (100 mg) and powdered 4A molecular
sieves (50 mg). The suspension was stirred vigorously at room
temperature. After 24 h the suspension was filtered over hyflo
and washed with CH2Cl2, and the filtrate was concentrated
in vacuo. Yield 39.0 mg, 98% of pure ent-5b as a white solid.
An analytical sample was obtained by recrystallization from
hexane/ethyl acetate. Mp 130.5-131.5 °C; [R]D -48.6° (c 0.2,
CH2Cl2); 1H-NMR and mass data were the same as for
compound 5b.
5(R)-Acetoxy-2(S)-m eth yl-4-oxa-en do-tr icyclo[5.2.1.02,6]-
d ec-8-en -3-on e (8a ). This compound was prepared from 5a
(100 mg, 0.56 mmol) in the same way as described for the
synthesis of rac-8a . Yield 123.1 mg, 99% of 8a as a colorless
oil: [R]D -79.3° (c 0.4, CH2Cl2). 1H-NMR and mass data were
the same as for compound rac-8a .
Ra cem ic exo-5-Meth oxy-2-m eth yl-4-oxa -en d o-tr icyclo-
[5.2.1.02,6]d ec-8-en -3-on e (r a c-10a ). For determination of ee
of 5(R)-hydroxy lactone 5a . rac-5a (50 mg, 0.28 mmol) was
treated with methanol (2 mL) and 1 drop of thionyl chloride.
The solution was stirred for 30 min and concentrated in vacuo
to give pure rac-10a (53.4 mg, 96%) as a white solid: mp 86.5-
5(R)-Acetoxy-4-oxa -en d o-tr icyclo[5.2.1.02,6]d ec-8-en -3-
on e (8b). This compound was prepared from 5b (100 mg, 0.60
mmol) in the same way as described for the synthesis of rac-
8b. Yield 119.8 mg, 87% of 8b as a white solid. An analyti-
cally pure sample was obtained by recrystallization from
hexane/ethyl acetate: mp 84-86.5 °C; [R]D -27.2° (c 0.4,
CH2Cl2). 1H-NMR and mass data were the same as for
compound rac-8b.
5(R)-Acetoxy-2(5H)-fu r a n on e (11). Flash vacuum ther-
molysis of 7b (52.4 mg, 0.25 mmol) [sample temp: 80 °C; oven
temp: 500 °C; cold trap temp: -78 °C; pressure: 5 × 10-2
mbar] provided pure 11 (32.7 mg, 92%) as a colorless oil: [R]D
-30.9° (c 0.7, CH2Cl2); 1H-NMR data were the same as reported
1
89.5 °C; H-NMR (CDCl3, 400 MHz): δ 1.45 (s, 3H), 1.59 (m,
2H), 2.40 (dd, J ) 1.0, 4.2 Hz, 1H), 2.75 (m, 1H), 3.05 (m, 1H),
3.36 (s, 3H), 4.66 (d, J ) 1.0 Hz, 1H), 6.10 (m, 1H), 6.19 (m,
1H). Addition of 1.5 equiv of the chiral shift reagent Eu(hfc)3
gave a splitting of the R-methyl signal of 0.03 ppm (1.07 ppm
downfield shift). GC-MS (EI, m/z, rel int (%)): 195 (M+ + 1,
59.0), 163 (10.4), 135 (15.2), 129 (39.4), 97 (20.1), 91 (26.9), 66
(100). Anal. Calcd for C11H14O3: C, 68.02; H, 7.26. Found:
C, 67.80; H, 7.19.

D-Ring Synthons for Strigol Analogues
J . Org. Chem., Vol. 61, No. 20, 1996 6935
for rac-11.23 Addition of Eu(hfc)3 (0.4 equiv) gave a separation
of CH3 signals amounting 0.16 ppm for the corresponding
enantiomers (0.8 ppm downfield shift), ee 94%.
The same compound 11 was obtained by FVT [sample
temp: 120 °C; oven temp: 500 °C; cold trap temp: -78 °C;
pressure: 5 × 10-2 mbar] starting from a 1:1 mixture of
diastereomeric acetates 7b and 8b (110 mg, 0.53 mmol). Yield
64.9 mg, 86% as a colorless oil. [R]D -34.2° (c 0.5, CH2Cl2), ee
94%.
A. Swolfs for conducting elemental analysis, mass, and
400 MHz H-NMR measurements, respectively. These
investigations were supported by the Netherlands Foun-
dation of Chemical Research (SON) with financial aid
from the Netherlands Organization for the Advance-
ment of Research (NWO).
1
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of rac-8a , rac-8b, 7a , 7b (4 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Ack n ow led gm en t. We thank Amano Enzyme Eu-
rope Ltd. for a generous gift of lipase PS and several
other lipases. We thank H. Amatdjais, P. v Galen, and
(23) Nagao, Y.; Dai, W.; Ochiai, M.; Shiro, M. J . Org. Chem. 1989,
54, 5211-5217.
J O9610220