Synthesis and stereochemistry of some bicyclic γ-lactones from parasitic wasps (Hymenoptera: Braconidae). Utility of hydrolytic kinetic resolution of epoxides and palladium(II)-catalyzed hydroxycyclization-carbonylation-lactonization of ene-diols

Article abstract of DOI:10.1021/jo0159237

A palladium(II)-catalyzed hydroxycyclization-carbonylation-lactonization sequence with appropriate pent-4-ene-1,3-diols provides efficient access to the bicyclic γ-lactones, 5-n-butyl- and 5-n-hexyltetrahydrofuro-[3,2-b]furan-2(3H)-ones (3) and (4), respectively, in both racemic and enantiomeric forms. Some of the substrate pent-4-ene-1,3-diols of high enantiomeric excess (ee) have been derived from racemic terminal epoxides by hydrolytic kinetic resolution (HKR) using cobalt (III) - salen complexes. (9Z,12R)-(+)-Ricinoleic acid also serves as a "chiral pool" source of other pent-4-ene-1,3-diols. These syntheses and enantioselective gas chromatography confirm the structures and absolute stereochemistry of the lactones in some species of parasitic wasps (Hymenoptera: Braconidae). The highly abundant 5-n-hexyltetrahydrofuro-[3,2-b]furan-2(3H)-one (4) in Diachasmimorpha kraussii and D. longicaudata is of high ee (>99%) with (3aR,5R,6aR) stereochemistry.

Full text of DOI:10.1021/jo0159237

J . Org. Chem. 2001, 66, 7487-7495
7487
Syn th esis a n d Ster eoch em istr y of Som e Bicyclic γ-La cton es fr om
P a r a sitic Wa sp s (Hym en op ter a : Br a con id a e). Utility of Hyd r olytic
Kin etic Resolu tion of Ep oxid es a n d P a lla d iu m (II)-Ca ta lyzed
Hyd r oxycycliza tion -Ca r bon yla tion -La cton iza tion of En e-d iols
Gregory C. Paddon-J ones,† Christopher S. P. McErlean,† Patricia Hayes,†
Christopher J . Moore,‡ Wilfried A. Konig,§ and William Kitching*,†
Department of Chemistry, The University of Queensland, Brisbane, Q. 4072, Australia, Department of
Primary Industries, Yeerongpilly, Q. 4105, Australia, and Institut fur Orga¨nische Chemie der Universita¨t,
D 20146, Hamburg, Germany
kitching@chemistry.uq.edu.au
Received J uly 13, 2001
A palladium(II)-catalyzed hydroxycyclization-carbonylation-lactonization sequence with appro-
priate pent-4-ene-1,3-diols provides efficient access to the bicyclic γ-lactones, 5-n-butyl- and 5-n-
hexyltetrahydrofuro-[3,2-b]furan-2(3H)-ones (3) and (4), respectively, in both racemic and enan-
tiomeric forms. Some of the substrate pent-4-ene-1,3-diols of high enantiomeric excess (ee) have
been derived from racemic terminal epoxides by hydrolytic kinetic resolution (HKR) using cobalt
(III)-salen complexes. (9Z,12R)-(+)-Ricinoleic acid also serves as a “chiral pool” source of other
pent-4-ene-1,3-diols. These syntheses and enantioselective gas chromatography confirm the
structures and absolute stereochemistry of the lactones in some species of parasitic wasps
(Hymenoptera: Braconidae). The highly abundant 5-n-hexyltetrahydrofuro-[3,2-b]furan-2(3H)-one
(4) in Diachasmimorpha kraussii and D. longicaudata is of high ee (>99%) with (3aR,5R,6aR)
stereochemistry.
In tr od u ction
D. longicaudata (Ashmead), D. tryoni (Cameron), and
Fopius (Biosteres) arisanus, are lactone and fragrance
rich, and possible roles for these secretions have been
discussed.7 In addition to the known octan-4-olide (1) and
dodecan-4-olide8,9 (2), Williams7 suggested that the novel
and hitherto uncharacterized bicyclic lactones (3) and (4)
((3aR,5â,6aR)-5-n-butyl-tetrahydrofuro-[3,2-b]furan-2(3H)-
one and 5-n-hexyl derivative, respectively) were also
present. The structures and relative stereochemistry of
3 and 4 were based to a substantial degree,7 on NMR
comparisons with 5-tert-butyl-tetrahydrofuro[2,3-b]furan-
2(3H)-one (5),10 a useful but not ideal model. The relative
configuration at C-5 (in 3 and 4) was assigned using
Karplus-based calculations of vic-1H-1H coupling con-
stants. The absolute stereochemistry of 1-4 was not
addressed (see Chart 1). All of the bicyclic lactones
discussed in this paper are cis fused, and it is convenient
to indicate relative stereochemistry by denoting the alkyl
group at C-5 as either cis or trans to the cis-hydrogens
at C-3a and C-6a.
Certain species of parasitic wasps in the family Bra-
conidae have been assessed for a possible role in inte-
grated pest management strategies, particularly in fruit-
fly control regimens, in Hawaii and eastern Queensland.1-3
This approach, if adopted as a field strategy, requires the
culturing and release of certified wasp populations.
Consequently, there has been considerable interest in the
morphology and taxonomy of these wasps,4,5 which has
experienced some uncertainty. This, for example, was the
case2,6 with Diachasmimorpha kraussii (Fullaway) which
was previously described as Opius kraussii. This wasp
is a natural enemy of the Queensland fruit-fly, Bactrocera
tryoni, an aggressive pest with a very wide host range.
Our interest in fruit-fly chemistry and the likelihood
that chemical profiling would assist taxonomic conclu-
sions encouraged examination of the indigenous Austra-
lian species, D. kraussii, which is closely related to
several braconid wasps previously investigated by Wil-
liams.7 These authors reported that the Hagen’s glands
(located near the abdominal tips) of the braconid wasps,
Recently we outlined efficient syntheses of these lac-
tones in both racemic and enantiomeric forms, together
with the determination of their absolute stereochemis-
try.11,12 After this brief report,11 other syntheses of the
Hagen’s gland lactones 3 and 4 appeared13-15 and in-
† The University of Queensland.
‡ Department of Primary Industries.
§ Institut fur Orga¨nische Chemie der Universita¨t.
(1) Tryon, H. Trans. Nat. Hist. Soc. Qld. 1895, 1, 8.
(2) Rungrojwanich, K. Ph.D. Thesis (Entomology), 1994, The Uni-
versity of Queensland.
(8) Wheeler, J . W.; Happ, G. M.; Araujo, J .; Pasteels, J . M.
Tetrahedron Lett., 1972, 46, 4635.
(3) Vargas, R. I.; Stark, J . D.; Nichida, G. K.; Purcell, M. Environ.
Entomol. 1993, 22, 246 and references therein.
(4) Hagen, K. L. Proc. Hawaii Entomol. Sci. 1953, 15, 115.
(5) Buckingham, G. R. Ann. Entomol. Soc. Am. 1968, 61, 233.
(6) Wharton, R. A.; Marsh, P. M. J . Washington Acad. Sci. 1978,
68, 147.
(7) Williams, H. J .; Wong, M.; Wharton, R. A.; Vinson, S. B. J . Chem.
Ecol. 1988, 14, 1727. (Since the report of Williams,7 a reclassification
of these wasps requires the names used in the present paper).
(9) For an early summary of the occurrence of lactones in insects,
Blum, M. S. Chemical Defenses of Arthropods; Academic Press: New
York, 1981; especially Part I, Chapt. 9, and Part 18.
(10) Kohma, Y.; Kato, N. Tetrahedron Lett. 1979, 48, 4667.
(11) Paddon-J ones, G. C.; Moore, C. J .; Brecknell, D. J .; Ko¨nig, W.
A.; Kitching, W. Tetrahedron Lett. 1997, 38, 3479.
(12) Paddon-J ones, G. C. Ph.D. Thesis, The University of Queen-
sland, 1998.
10.1021/jo0159237 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/29/2001

7488 J . Org. Chem., Vol. 66, No. 22, 2001
Paddon-J ones et al.
Ch a r t 1
Sch em e 1
volved multistep sequences from carbohydrate precur-
sors. In view of the interest in this family of lactones and
the general utility of the palladium(II)-based manner of
their construction,16 we now describe our work in more
detail. Furthermore, we demonstrate that hydrolytic
kinetic resolution of terminal epoxides17 provides simple
access to precursors, that with the Pd(II)-catalyzed
oxycarbonylation-lactonization sequence, deliver enan-
tiomers of cis and trans 3 and 4. The bicyclic lactone core
of 3 and 4 is of further interest as it is a key substructure
in a number of marine derived metabolites, including the
plakortones.18,19
Resu lts a n d Discu ssion
The simple γ-lactones 1 and 2 are well-known,9 and
we previously described11 routes to their enantiomers.
Enantioselective gas chromatography20 established that
1 and 2 are R-configured (>99% ee), in agreement with
considerable precedent for natural γ-lactones.20-22 More
detailed discussions are available elsewhere.9
Syn th esis of Ra cem ic Bicyclic γ-La cton es. The
bicyclic lactones cis-3 (∼8%) and cis-4 (92%) were con-
cluded by Williams7 to be present in D. longicaudata, and
our examination of D. kraussii revealed the presence of
the suspected 4 as a major component in that species.11,12
We noted in 3 and 4 the presence of the lactone and
tetrahydrofuran moieties and considered an approach
based on metal ion induced ring closure of a suitable
hydroxy alkene to deliver the tetrahydrofuran unit,
followed by reaction of the presumed intermediate pri-
mary carbon-metal bond. Carbonylation was particu-
larly attractive,16 and the early work of Semmelhack23
and later reports by J a¨ger24 with carbohydrate-based ene-
polyols suggested that appropriate pent-4-ene-1,3-diols
would be suitable starting materials. This plan is shown
above, in Scheme 1, and the trial procedure was con-
ducted with racemic, diastereomeric diols 7, derived from
either n-pentanal or n-heptanal.
The reaction of the ene-diols 7a ,b was allowed to
proceed overnight under the CO atmosphere, and the
completed reaction was beige colored, in contrast to the
initial bright green. After workup, GC-MS examination
of each series showed two products in comparable
amounts, with similar GC retention times and mass
spectra. The apparent molecular ion (M+ ) 184 for R)
n-C4H9 and 212 for R) n-C6H13), base peak (m/z 127, M+
- R) and other ions, matched the data reported by
Williams.7 On the basis of cis ring fusion, the reaction
products were considered to be the cis and trans isomers
of 3 and 4 shown above (Scheme 1).
(13) Mereyala, H. B.; Gadikota, R. R. Chem Lett. 1999, 273.
(14) Mereyala, H. B.; Gadikota, R. R.; Sunder, K. S.; Shailaja, S.
Tetrahedron 2000, 56, 3021.
(15) Mereyala, H. B.; Gadikota, R. R. Tetrahedron: Asymmetry 2000,
11, 743.
(16) For pertinent reviews, see Hegedus, L. S. Transition Metals in
the Synthesis of Complex Organic Molecules; University Science
Books: Mill Valley, CA 1994 and references therein.
(17) J acobsen, E. N. Acc. Chem. Res. 2000, 33, 421 and references
therein.
(18) Patil, A. D.; Freyer, A. J .; Bean, M. F.; Carte, B. K.; Westley,
J . W.; J ohnson, R. K. Tetrahedron 1996, 52, 377.
(19) For synthetic endeavours in the plakortone area, see (a) Bittner,
C.; Burgo, A.; Murphy, P. J .; Sung, C. H.; Thornhill, A. J . Tetrahedron
Lett. 1999, 40, 3455. (b) Paddon-J ones, G. C.; Hungerford, N. L.; Hayes,
P.; Kitching, W. Org. Lett. 1999, 1, 1905. (c) Semmelhack, M. F.;
Shanmugam, P. Tetrahedron Lett. 2000, 41, 3567. (d) For synthesis of
(-)-trans-kumausyne, see Boukouvalas, J .; Fortier, G.; Radu, I.-I. J .
Org. Chem. 1998, 63, 916.
Confirmation of the structure and assignment of the
relative stereochemistry of the suspected lactones 3 and
4 followed from a detailed analysis of the NMR spectra
of the pairs of isomers, which could be separated either
1
by careful flash chromatography or HPLC. The H NMR
spectra of the n-butyl isomers 3 although quite similar,
do exhibit significant differences in some chemical shifts
and coupling constants. The full 1H and 13C NMR
assignments are listed in the Experimental Section. The
major differences concern H6R and H6â which reverse
their order of shifts in the isomeric pairs, with that proton
located syn to the side-chain (H6â in (cis)) and H6R in
(20) For
a discussion of enantioselective gas chromagrographic
studies of lactones, see Ko¨nig, W. A. Gas Chromatographic Enantiomer
Separation with Modified Cyclodextrins; Huthig: Heidelberg, 1992;
especially pp 86-92.
(21) Scho¨ttler, M.; Boland, W. Helv. Chim. Acta 1996, 79, 1448.
(22) Reference 20, Figure 75.
(23) (a) Semmelhack, M. F.; Bodurow, C. J . Am. Chem. Soc. 1984,
106, 1496. (b) Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.;
Sanner, M.; Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035.
(24) Gracza, T.; Haseno¨hvl, T.; Stahl, V.; J a¨ger, V. Synthesis 1991,
1108.

Bicyclic γ-Lactones from Parasitic Wasps
J . Org. Chem., Vol. 66, No. 22, 2001 7489
Ch a r t 2
Sch em e 2
(trans)) appearing at higher field. The assignments and
relative configurations of these racemic compounds were
consistent with results from 1D-NOE experiments, and
fully confirmed by NOESY results on individual enanti-
omers that were acquired later.
Model structures were computer-simulated and energy-
minimized by the MM3 force field,11,12 to provide esti-
mates of dihedral angles, coupling constants, and general
geometry, and permit comparisons with the experimental
data. The minimized structures are shown above for the
simpler ethyl derivatives (Chart 2), with the comparisons
of computed and measured coupling constants (3J ) and
dihedral angles being listed in the Supporting Informa-
tion. In each isomer, the alkyl side chain is pseudo-
equatorial, and for the cis-isomer, experimental and
computed coupling constants match very well, but the
comparisons are inferior for the trans-isomer, for which
more than one conformer may be significantly populated.
The NMR and mass spectral data, when compared with
the published data7 for the lactones from D. longicaudata,
confirm that the natural bicyclic lactones are the cis-
isomers 3 and 4. (We synthesized and characterized the
cis and trans isomers of the 5-(4′-pentenyl) lactone system
in the hope of obtaining a crystalline metal-complex, e.g.,
with Pt(II), but this was not successful).12
Dir ected Syn th esis of Cis a n d Tr a n s La cton es 3
a n d 4. Consideration of the likely events in the conver-
sion of pent-4-ene-1,3-diols to the bicyclic γ-lactones
indicates that a syn-1,3-diol would provide the cis, and
an anti-1,3-diol the trans-lactones as summarized below.
(A demonstration of this is contained in a 1985 report
by Yoshida,25 who established the relative stereochem-
istry of their starting diols by NMR analysis of the
acetonide derivatives).
The kinetic enolate from 2-octanone (LDA/THF) was
quenched with acrolein to yield the hydroxyketone 8.
Reduction with NaBH(OAc)3 in benzene (reflux) or in
HOAc-CH3CN provided the same diol mixture on the
basis of stereochemical analysis of the derived acetonide.
GC-MS examination showed two components, the anti-
and syn-acetonides in a 3:1 ratio. Use of NaBH4 alone in
benzene favored the syn isomer by ca. 4:1, as shown in
Scheme 2. The acetonides were readily separated (HPLC),
and using the 13C NMR criterion emphasized by Rych-
novsky,26 the syn-acetonide 11 (δCH3 30.1, 19.7 (DEPT))
was readily distinguished from the anti 12 (δCH3 25.3,
26.4). Regeneration of the diols 9 and 10 from their
acetonides (PPTS/MeOH) was followed by the Pd(II)-
catalyzed process to yield the bicyclic lactones (trans- and
cis-4). The syn-1,3-diol 9 produced exclusively the lactone
previously deduced to be cis-4 by the NMR criteria, and
anti-1,3-diol 10 produced the isomeric trans-4. Conse-
quently, the relative stereochemistry of the isomers 3 and
4 is established.
In the original report7 of the insect lactones, the 500
MHz 1H NMR spectrum of “component 6” (acetone-d6
1
solvent) was reproduced, and the H and 13C NMR shifts
and coupling constants were tabulated. Comparisons
with our data for the authentic cis- and trans-lactones 3
and 4, confirm that both natural isomers have cis-relative
stereochemistry as suggested.7 The question of the ab-
solute stereochemistry of the natural lactones was not
considered, and our determination of this crucial feature
is now described for both D. longicaudata and D. kraussii.
En a n tiom er s of Bicyclic La cton es 3 a n d 4. Normal
gas chromatographic examination of the racemic bicyclic
lactones was uncomplicated, and we considered that
enantioselective gas chromatography was a promising
approach for determination of the chirality of the natural
lactones. Preliminary examination of the racemates of
the cis and trans lactones 3 and 4 described above, using
a noncommercial cyclodextrin based phase (see later),
confirmed this, and so acquisition of enantiomerically
enriched samples of the lactones was required for the
salient comparisons to be made.
Fr om (9Z,12R)-(+)-Ricin oleic Acid to th e (3aR,5R,-
6a R)- a n d (3a S,5R,6a S)-5-n -Hexyl-t et r a h ed r ofu r o-
[3,2-b]fu r a n -2(3H)-on es (4). This sequence commenced
with conversion of the commercially available ricinoleic
acid (13) to its methyl ester, followed by protection of the
12-hydroxyl group as the tetrahydropyran-2′-yl ether
14.27,28 Ozonolysis in methanol produced the R-config-
ured aldehyde29 which was immediately treated with an
excess of vinylmagnesium bromide in THF (-40 °C) to
(27) D’Auria, M.; DeMico, A.; D’Onofrio, F.; Scettri, A. Synthesis
1985, 10, 988.
(28) Davis, K. J .; Bhalerao, V. T.; Rao, B. V. Synth. Commun. 1999,
29, 1679.
(25) Tamara, Y.; Kobayashi, T.; Kanamura, S.; Ochiai, H.; Hojo, M.;
Yoshida, Z. Tetrahedron Lett. 1985, 26, 3207.
(26) Rychnovsky, S. D.; Slzalitzky, D. J . Tetrahedron Lett. 1990, 31,
945.
(29) (a) Kitching, W.; Lewis, J . A.; Perkins, M. V.; Drew, R. A. I.;
Moore, C. J .; Schurig, V.; Ko¨nig, W. A.; Francke, W. J . Org. Chem.
1989, 54, 3893. (b) Kula, J .; Sikora, M.; Sadowska, H.; Piwowarski, J .
Tetrahedron 1996, 52, 11, 321.

7490 J . Org. Chem., Vol. 66, No. 22, 2001
Paddon-J ones et al.
Sch em e 3
F igu r e 1. Enantioselective gas chromatographic analyses of
Hagen’s Gland lactone in D. kraussii. Column and conditions:
25 m capillary column with heptakis (6-O-tert-butyldimethyl-
silyl-2,3-di-O-methyl)-â-cyclodextrin (50% dilution in polysi-
loxane OV 1701 w/w) at 160 °C, 0.5 bar H2. (a) Enantiomers
of the cis- and trans-5-n-butyl and 5-n-hexyl-lactones (3 and
4) (refer to Scheme 4). From shorter (at left) to longer retention
times, signals correspond to 5S and 5R (trans) and 5R and 5S
(cis) of the 5-n-butyl series then 5S and 5R (trans) and 5R and
5S (cis) of the 5-n-hexyl series. Under these conditions the
eight signals have retention times from ca. 9 min (first eluting)
to 35 min (last eluting). This order of elution was established
by examination of the racemates and individual enantiomers
of the lactone series, cis- and trans-5-n-butyl; cis- and trans-
5-n-hexyl. (b) Trace of the lactone containing secretion from
D. kraussii, showing a single isomer. (c) Coinjection of a and
b demonstrating that the lactone in b is the (3aR,5R,6aR) (cis)
isomer of the 5-n-hexyl series.
provide protected ene-diol 15. Deprotection released the
(5R)-ene-diol 16 which could be converted to the sepa-
rable syn- and anti-acetonides 17, as described above for
the racemate. The palladium(II)-catalyzed cyclization-
carbonylation-lactonization sequence provided two iso-
meric lactones (∼50:50, 67% overall) which were purified
by HPLC. In this way, the cis- and trans-5-n-hexyl-tetra-
hydrofuro[3,2-b]furan-2(3H)-ones, with the (3aR,5R,6aR)
and (3aS,5R,6aS) configurations, respectively, were ac-
quired in six steps from the inexpensive, readily available
ricinoleic acid. This procedure is shown above in Scheme
3. The relative configurations of the separated lactones
were established by 2D-NOESY experiments, the main
outcomes of which are summarized on the structures in
Scheme 3. The absolute stereochemistry is enforced by
the established (12R) configuration29a of the starting
acid 13, and this is not compromised during the proce-
dure.
(()-1,2-Epoxyhexane (18a ) (from 1-hexene and m-
chloroperbenzoic acid in DCM in the normal way) was
subjected to hydrolytic kinetic resolution with (acetato)-
(aqua)(S,S)-N,N′-bis(3,5-di-tert-butylsalicylidene-1,2-
cyclohexanediamino)cobalt(III) in the manner described
by J acobsen.17 Distillation of the reaction mixture (after
16 h) provided residual (S)-epoxide 19a (∼33%) and (R)-
1,2-hexandiol (∼40%), (20a ). The (R)-diol 20a was con-
verted, via the cyclic sulfate 21a ,31 to the (R)-epoxide 22a
in good yield. A similar procedure with (()-1,2-epoxyoc-
tane (18b) provided both (S)- and (R)-1,2-epoxyoctanes
(19b) and (22b), respectively. These four epoxides were
treated with vinyl MgBr-CuI to deliver the homoallylic
alcohols which, as their THP-ethers, were ozonized and
again reacted with vinylMgBr. Deprotection afforded the
Utilizin g Hyd r olytic Kin etic Resolu tion of (()-1,2-
Ep oxyh exa n e a n d (()-1,2-Ep oxyocta n e. J acobsen17
has introduced a series of catalysts based on Co(salen)
complexes that are effective for the hydrolytic kinetic
resolution of terminal epoxides, and procedures incorpo-
rating such a step are finding increasing application in
synthesis.30 It appeared to us that this approach would
be particularly useful for accessing the enantiomers of
cis- and trans-3 and 4. This is possible because reconsti-
tuting the enantiomeric diol (the hydrolysis product from
the racemic epoxide) provides the alternative epoxide
enantiomer.
(30) For very recent examples, see Chow, S.; Kitching, W. Chem.
Commun. 2001, 1040.
(31) (a) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(b) He, L.; Byun H-S.; Bittman, R. J . Org. Chem. 1998, 63, 5696.

Bicyclic γ-Lactones from Parasitic Wasps
J . Org. Chem., Vol. 66, No. 22, 2001 7491
Sch em e 4
ene-diols (23a , 23b, 24a , 24b), ready for the Pd(II)-
catalyzed cyclization to the lactones. Flash chromatog-
raphy and HPLC provided the suite of eight enantiomers
of the n-butyl and n-hexyl lactones, which are shown in
Scheme 4, along with isomeric relationships and optical
rotations. NOESY spectra confirmed the relative stere-
ochemistry of the cis- and trans-5-n-butyl lactones, as
already shown in Scheme 3 for the 5-n-hexyl lactones,
(3aR,5R,6aR)-cis-4 and (3aS,5R,6aS)-trans-4.
enantioselective gas chromatographic conditions on a
heptakis(6-O-TBDMS-2,3-di,O-methyl)-â-cyclodextrin -
phase. The enantiomers of the cis-lactones were also well
separated on a commercial γ-cyclodextrin column, but not
the trans-isomers. The cis and trans lactones derived
from ricinoleic acid (Scheme 4) were of >99% ee as
anticipated, and the cis-isomers from the HKR route were
>98% ee (3aS,5S,6aS, n-hexyl), >80% ee (3aR,5R,6aR,
n-hexyl), >98%ee (3aS,5S,6aS, n-butyl), and >98% ee
(3aR,5R,6aR, n-butyl). The trans lactones from the HKR
route were estimated to be of >98% ee for (3aR,5S,6aR,
The enantiomers of the synthesized cis and trans
lactones (Schemes 3, 4) were well separated under

7492 J . Org. Chem., Vol. 66, No. 22, 2001
Paddon-J ones et al.
be purified by chromatography on silica (EtOAc-hexane)
n-butyl), (3aS, 5R, 6aS, n-butyl), and (3aR,5S,6aR, n-
hexyl) but of >90% ee for (3aS,5R,6aS, n-hexyl). Our
measured rotations may be compared with those reported
for the (3aR,6aR) series (see Scheme 4) acquired by
longish routes from diacetone-D-mannose (∼16 steps) or
from diacetone-D-glucose.13-15 The reported rotations are
higher than ours for the cis-isomers, but significantly
lower for the trans-isomers. It is worthy of emphasis that
the eight enantiomers (all have cis-bicyclic fusion) of the
n-butyl and n-hexyl lactones (Scheme 4) are available
from the racemic 1,2-epoxyalkanes, using the HKR
approach, by straightforward procedures involving rela-
tively few steps, and one chromatographic separation of
diastereomers.
With the availability of the racemates and enantiomers
described above, enantioselective gas chromatography
established that the (3aR,5R,6aR) (>99% ee) cis-n-hexyl
lactone was present in D. kraussii and D. longicaudata
(Figure 1). The latter species also contained the (3aR,5R,-
6aR) cis-n-butyl lactone, and racemic trans-n-butyl lac-
tone (3aR,5S,6aR and 3aS,5R,6aS) as minor components
(∼7% together). These determinations will now enable
more detailed studies of the likely behavioral role of the
lactones. In addition, further applications of these ap-
proaches to more complex bicyclic lactones are being
conducted.19b
1
(95%). H δ 0.87 (t, J 7.0, 6H), 1.22-1.85 (m, 24H), 2.72 (m,
4H), 3.47 (m, 2H), 3.64 (m, 2H), 3.89 (m, 2H), 4.65 (dt, J 15.4,
2.8, 2H), 5.05 (m, 4H), 5.86 (m, 2H). 13C NMR δ 14.1, 19.8,
22.8, 22.83, 25.4, 25.5, 27.3, 27.8, 31.0, 31.1, 33.1, 34.5, 38.0,
39.8, 62.6, 75.3, 76.7, 96.8, 98.1, 116.5, 116.9, 134.8, 135.5.
Anal. Calcd for C13H24O2: C, 73.54; H, 11.39. Found: C, 73.22;
H, 11.45. The above THP-ether (330 mg, 1.55 mmol) was
dissolved in DCM (30 mL) and cooled to -78 °C, and ozone
was bubbled through until a blue color persisted. After purging
with N2, dimethyl sulfide (1.3 mL, 18 mmol) was added, and
the reaction was allowed to warm to RT over 1 h. The solution
was washed with brine and dried (MgSO4), and the solvent
was removed. The crude aldehyde was characterized by GCMS
(m/z 214 (M+, 1), 196 (0.5), 157 (0.6), 101 (36), 95 (40), 85 (100))
and then dissolved in dry THF (5 mL) and cooled to -78 °C.
Vinylmagnesium bromide (Aldrich) (3 mL of 1 M, 3 mmol) was
slowly added and after 2 h the reaction was quenched by the
addition of saturated NH4Cl solution (5 mL). Extraction (Et2O,
2 × 5 mL), drying (MgSO4), and solvent removal provided an
oil which was purified by flash chromatography (30% Et2O-
hexane) to provide a mixture of four diastereomers of 3-h y-
d r oxy-5-(t et r a h yd r op yr a n -2′-yloxy)n on -1-en e (315 mg,
84%). 1H NMR δ0.87 (t, J 7.2, 12H), 1.23-1.76 (m, 56H), 3.44-
4.92 (m, 24H), 5.05 (m, 4H), 5.25 (m, 4H), 5.84 (m, 4H). 13C
NMR (four diastereomers) δ 14.0, 19.7, 19.9, 20.7, 21.7, 22.8
(3C), 25.1, 25.4, 27.0, 27.3, 27.6, 27.7, 31.1, 31.2, 31.4 (2C),
34.3, 34.7, 35.2, 35.5, 39.3, 41.3, 41.9, 42.1, 62.9, 63.0, 63.3,
64.2, 65.6, 67.9, 69.6, 71.9, 72.5, 74.3, 75.9, 76.9, 77.2, 78.8,
98.0, 98.7, 99.3, 100.7, 113.3, 113.6, 113.9, 114.2, 140.7, 140.8,
140.9, 141.1. Anal. Calcd for C14H26O3: C, 69.38; H, 10.81
Found: C, 69.16; H, 10.80. The above diastereomeric mixture
of THP-ethers (130 mg, 0.53 mmol) was dissolved in MeOH
(15 mL), and amberlite IR-120 resin (250 mg) was added. After
stirring overnight, the solution was filtered through Celite,
and the solvent was removed to provide the diol 7a (80 mg,
95%). 1H NMR δ 0.85 (t, J 6.8, 6H), 1.25-1.63 (m, 16H), 3.08-
3.85 (m, 6H), 4.29-4.53 (m, 2H), 5.05 (dd, J 15.1, 10.5, 2H),
5.20 (t, J 15.6, 2H), 5.83 (m, 2H). 13C NMR δ 14.0 (2C), 22.5,
22.6, 27.4, 27.8, 37.1, 37.7, 42.2, 42.8, 69.0, 70.3, 72.3, 73.6,
114.1, 114.2, 140.7 (2C).
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR spectra were recorded at 400
or 200 MHz with either TMS (δ ) 0) or the signal for residual
CHCl3 in the CDCl3 solvent (δ 7.24) as internal standard. 13C
NMR spectra were recorded at 100 or 50 MHz with either TMS
(δ ) 0) or the central peak of the CDCl3 triplet (δ 77.00). J
values are reported in hertz. Flash chromatography was
performed with Kieselgel S (0.032-0.063 mm). Enantioselec-
tive gas chromatography was conducted using a permethylated
γ-cyclodextrin column (SGE, 50 m, 0.25 µm) or heptakis(6-O-
tert-butyldimethylsilyl-2,3-di-O-methyl)-â-cyclodextrin, 25 m
(50% dilution in polysiloxane OV 1701 w/w) at 160 °C, 0.5
bar H2.
Un d ec-1-en e-3,5-d iol (7b) The procedure described above
for the conversion of oct-1-en-4-ol (6a ) to non-1-ene-3,5-diol (7a )
was applied to dec-1-en-4-ol (6b) for transformation to undec-
1-ene-3,5-diol (7b). Protection of 6b provided 4-(tetr a h yd r o-
p yr a n -2′-yloxy)-1-d ecen e. 1H NMR δ 0.86 (t, J 6.7, 6H),
1.20-1.80 (m, 26H) 2.19-2.61 (m, 8H), 3.47-3.90 (m, 8H),
4.56-4.70 (m, 2H), 5.00-5.07 (m, 4H), 5.81 (m, 2H). 13C NMR
δ14.1 (2C), 19.8 (2C), 22.6, 22.7, 25.5, 25.6, 29.3, 29.4, 29.5,
29.6, 30.9, 31.1, 31.8, 31.9, 33.4, 34.8, 37.9, 39.8, 62.5, 62.6,
75.4, 76.7, 96.8, 98.1, 116.5, 116.9, 134.9, 135.5. Anal. Calcd
for C15H28O2: C, 74.95; H, 11.74. Found: C, 75.15, H, 12.15.
Ozonolysis followed by addition of vinylmagnesium bromide
provided 3-h yd r oxy-5-(tetr a h yd r op yr a n -2′-yloxy)u n d ec-
1-en e as a diastereomeric mixture. 1H NMR δ0.87 (t, J 6.7,
12H), 1.08-1.82 (m, 64H), 2.14-2.87 (m, 12H), 3.47-4.72 (m,
24H), 5.06 (m, 4H), 5.24 (m, 4H), 5.85 (m, 4H). 13C NMR δ14.0
(2C), 14.1, 19.9 (2C), 20.7, 21.7, 22.6 (2C), 22.7, 24.8, 25.1, 25.2,
25.4 (2C), 25.6, 29.3, 29.4 (2C), 29.5, 29.6, 29.7, 31.1, 31.2, 31.4,
31.5, 31.8 (2C), 31.9, 34.6, 35.0, 35.5, 35.9, 39.6, 41.3, 41.9,
42.1, 62.9, 63.0, 64.2, 65.6, 65.8, 67.9, 69.7, 72.0, 72.5, 74.3,
75.9, 76.9, 77.2, 79.0, 98.0, 98.7, 99.3, 100.8, 113.3, 113.6, 113.9,
114.2, 140.8 (2C), 140.9, 141.1. Anal. Calcd for C16H30O3: C,
71.07; H, 11.18. Found: C, 70.91; H, 11.23. The above THP-
ether was deprotected as described above for 6b, to provide
undec-1-ene-3,5-diol (7b). 1H NMR δ 0.86 (t, J 6.7, 6H), 1.15-
1.83 (m, 22H), 2.35 (brs, 4H), 3.29-4.09 (m, 4H), 4.35-4.84
(m, 2H), 5.10 (m, 2H), 5.28 (m, 2H), 5.85 (m, 2H). 13C NMR
δ14.0 (2C), 22.5, 25.3, 25.6, 25.7, 29.2, 29.25, 31.7, 31.8, 37.4,
38.2, 42.8, 42.9, 68.9, 69.1, 72.3, 73.4, 114.4, 114.5, 140.6 (2C).
(In another preparation of this diol, a derivative acetonide was
characterized and is described later in this section). This diol
was then ready for transformation to the bicyclic lactone.
(()-Oct-1-en -4-ol (6a ) a n d (()-Dec-1-en -4-ol (6b). Pen-
tanal (10 g, 116 mmol) and powdered zinc (8.5 g, ∼130 mmol)
were added to saturated aqueous NH4Cl solution (100 mL) and
THF (20 mL). A reflux condenser was fitted, and to the stirred
contents was added allyl bromide (15.6 g, 130 mmol) dropwise.
After addition was complete, stirring was continued at RT for
1 h, and then the reaction was quenched by addition of 10%
aqueous HCl (50 mL). The resulting clear solution was
extracted with ether, washed with brine, and dried (MgSO4).
Flash distillation afforded the homoallyl alcohol 6a (10.3 g,
81 mmol, 70%) as a clear oil. 1H NMR δ 0.86 (t, J 6.7, 3H),
1.20-1.90 (m, 7H), 2.05-2.28 (m, 2H), 3.59 (m, 1H), 5.09 (m,
2H), 5.82 (m, 1H). 13C NMR δ14.1, 22.7, 27.5, 36.5, 41.9, 70.7,
118.1, 135.2. Dec-1-en -4-ol (6b) was prepared in a similar way
1
from heptanal in 81% yield. H δ 0.86 (t, J 6.5, 3H), 1.25 (m,
7H), 1.44 (m, 3H), 1.97 (brs, 1H), 2.12 (m, 1H), 2.23 (m, 1H),
3.57 (m, 1H), 5.10 (m, 2H), 5.78 (m, 1H). 13C NMR δ 14.0, 22.5,
25.6, 29.3, 31.8, 36.4, 41.9, 70.7, 117.8, 134.9. These data match
those reported previously.32,33
(()-Non -1-en e-3,5-d iol (7a ). Homoallylic alcohol 6a above
(2.56 g, 20 mmol) was dissolved in dry DCM (25 mL) and
dihydropyran (2.13 g, 25 mmol), and a catalytic amount of
p-toluenesulfonic acid was added. The reaction was stirred
overnight and then quenched by the addition of solid NaHCO3.
Filtration and solvent removal provided the crude diastereo-
meric 4-(tetr a h yd r op yr a n -2′-yloxy)-1-octen es which could
(32) Davis, A. P.; J aspars, M. J . Chem. Soc., Perkin Trans. 1 1992,
2111.
(33) J ones, P.; Knochel, P. J . Org. Chem. 1999, 64, 186.

Bicyclic γ-Lactones from Parasitic Wasps
J . Org. Chem., Vol. 66, No. 22, 2001 7493
cis- a n d tr a n s-5-n -Bu tyltetr a h yd r ofu r o[3,2-b]fu r a n -
2(3H)-on es: cis-3 and trans-3. The following is a representa-
tive procedure for the hydroxycyclization-carbonylation-
lactonization sequence. Non-1-ene-3,5-diol (7a ) and undec-1-
ene-3,5-diol (7b) to the bicyclic lactones 3 and 4, respectively.
34.7 (CH2), 36.6 (C3), 38.3 (C6), 78.2 (C5), 80.4 (C3a), 84.7
(C6a), 175.4 (C2). GCMS: m/z 212 (M+, 1), 194 (0.6), 165 (1),
152 (1), 143 (5), 127 (100), 99 (26), 81 (10), 55 (36), 43 (37).
3-Hyd r oxyu n d ec-1-en -5-on e (8). A solution of LDA in
THF (50 mL of 0.17 M solution, 8.5 mmol) under N2 was cooled
to -78 °C, and a THF solution of 2-octanone (0.97, 7 mmol)
was added slowly. After 1 h at -78 °C, a THF solution of
acrolein (7 mmol, 0.4 g in 5 mL) was added, and after ca. 20
min, the reaction was quenched by the addition of saturated
aqueous NH4Cl. The organic material was extracted into ether
(2 × 15 mL) which was dried and evaporated. The target
compound 8 was purified by flash chromatography (30%
EtOAc/hexane) (1.80 g, 4.8 mmol, 68%). 1H NMR δ0.84 (t, J
7.1, 3H, CH3), 1.24 (m, 7H), 1.52 (m, 2H), 2.38 (t, J 7.4, 2H),
2.58 (m, 2H), 4.51 (brd, J 5.3 Hz, 1H), 5.08 (dt, J 10.5, 1.5,
1H), 5.23 (dt, J 17.2, 1.5, 1H), 5.80 (ddd, J 17.2, 10.5, 5.6, 1H).
13C NMR δ 14.0, 22.4, 23.5, 28.8, 31.5, 43.7, 48.7, 68.6, 114.8,
139.1, 211.4. GCMS: m/z (184, M+, 1), 166 (1), 155 (1), 127
(2), 113 (19), 96 (4), 86 (6), 71 (11), 43 (100). HREIMS:
NaOAc (3 equiv) and CuCl2 (3 equiv) were added to a dry
three-necked flask containing ∼10 mL glacial acetic acid. The
solution was stirred until the solid dissolved, and then the
unsaturated diol (1 equiv) was added as an acetic acid solution.
The flask was then purged several times with nitrogen while
the contents were vigorously stirred, which ensured the
inertness of the atmosphere in the flask. Carbon monoxide was
added from an attached balloon, and the system was flushed
several times with this gas. A catalytic amount of PdCl2 (0.1
equiv) was then added, and stirring was continued under these
conditions. After refilling the balloon with CO, the reaction
was stirred overnight at room temperature. Generally this
resulted in a change in color from bright green to a dull brown.
The CO atmosphere was removed, and ∼50 mL H2O was added
which caused the solution to turn black. This solution was then
neutralized with solid NaHCO3 until effervescence ceased.
Extraction of this neutralized solution with EtOAc, followed
by removal of this solvent gave the crude bicyclic lactones.
Flash chromatographic purification (15% Et2O in hexane)
resulted in a sample that was then subjected to HPLC (15%
EtOAc-hexane) for separation of the isomeric lactones.
C
11H20O2 requires 184.1463. Measured, 184.1468. Anal. Calcd
for C11H20O2: C, 71.70; H, 10.94. Found: C, 71.99; H, 10.98.
1
This compound 8 was previously characterized only by its H
NMR spectrum.34
Un d ec-1-en e-3,5-d iol fr om Hyd r id e Red u ction s: 9 a n d
10. The above keto alcohol 8 was dissolved in benzene and
added to a solution of sodium triacetoxyborohydride in ben-
zene. The mixture was allowed to stir for 2h at RT and then
quenched with water. Benzene was carefully removed, and the
residue was taken up in ethyl acetate, washed with water and
brine, and then dried (MgSO4). Concentration yielded the
crude diols in a 3:1 ratio, and this mixture was converted
immediately into the acetonide derivatives. A second reduction
procedure, utilizing the mixed solvent CH3COOH-CH3CN at
- 40 °C, was employed. Again the anti-syn ratio 10:9, was
ca. 3:1, whereas use of NaBH4 in benzene at 20 °C favored
the syn diol 9 (4:1). These relative stereochemistries were
confirmed by examination of the acetonides. The diol mixture
(30 mg, 0.16 mmol) and dimethoxypropane (∼0.3 mL) were
dissolved in DCM (∼5 mL) along with a catalytic amount of
PPTS (∼ 5 mg). This mixture was allowed to stir at RT for 4
h. The solution was washed with saturated NaHCO3 solution,
and the organic phase dried and concentrated. The acetonides
were then subjected to HPLC separation, using 15% EtOAc-
hexane, and this provided the syn- and anti-acetonides 11 and
12. HREIMS: C13H23O2 (M - CH3) requires 211.1698. Mea-
sured, 211.1693.
Treatment of non-1-ene-3,5-diol (7a ) (80 mg, 0.5 mmol) in
the above way provided 75 mg (81%) of a mixture of cis- and
trans-3 (ca. 50:50) which were purified and then separated by
HPLC.
cis-3. 1H NMR δ 0.84 (t, J 6.7, 3H, CH3), 1.22 (m, 4H, 2CH2
in side-chain), 1.46 (m, 1H, in side-chain), 1.58 (m, 1H, in side-
chain), 1.68 (ddd, J 13.7 (H6R), 10.1 (H5), 4.6, (H6a), 1H, H6â),
2.35 (dd, J 13.7 (H6â), 4.6 (H5), 1H, H6R), 2.62 (d, J 18.8 (H3â),
1H, H3R), 2.74 (dd, J 18.8 (H3R), 6.5 (H3a), 1H, H3â), 4.08
(m, 1H, H5), 4.79 (dt, J 6.5 (H3â), 4.6 (H6a), 1H, H3a), 5.09
(t, J 4.6 (H3a, H6â), 1H, H6a). 13C NMR δ 13.9 (CH3) 22.6
(CH2), 28.1 (CH2) 34.3 (CH2), 36.6 (C3), 38.8 (C6), 77.3 (C5),
78.5 (C3a), 84.9 (C6a), 175.9 (C2). GCMS: m/z 184 (M+, 1),
156 (1), 143 (2), 127 (100), 95 (3), 83 (7), 71 (20). HREIMS:
C
10H16O3 requires 184.1099. Measured, 184.1099. Anal. Calcd
for C10H16O3: C, 65.19; H, 8.75. Found: C, 64.81; H, 9.07.
trans-3. 1H NMR δ 0.87 (t, J 6.4, 3H, CH3), 1.25 (m, 4H,
2CH2 in side chain), 1.56 (m, 1H, in side chain), 1.62 (m, 1H
in side chain), 1.85 (ddd, J 14.2 (H6â) 7.1 (H5), 2.3 (H6a), 1H,
H6R), 2.40 (ddd, J 14.2 (H6R), 7.1 (H5), 6.7 (H6a), 1H, H6â),
2.69 (d, J 3.8, 2H, H3R, H3â), 3.91 (m, 1H, H5), 4.47 (brdd, J
4.4 (H6a), 3.8 (H3R, 3â), 1H, H3a), 4.98 (ddd, J 6.7 (H6â), 4.4
(H3a), 2.3 (H6R), 1H, H6a). 13C NMR δ 13.9 (CH3), 22.5 (CH2),
28.2 (CH2), 35.2 (CH2), 36.4 (C3), 38.3 (C6), 78.2 (C5), 80.3
(C3a), 84.6 (C6a), 175.6 (C2). GCMS: m/z (184, M+, 1), 156
(1), 143 (2), 127 (100), 83 (7), 71 (20).
syn -4-Hexyl-2,2-dim eth yl-6-vin yl-[1,3]-dioxan e (11) (from
9): 1H NMR δ 0.85 (t, J 6.0, 3H, CH3), 1.24-1.36 (m, 10H),
1.40 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.51-1.58 (dt, J 12.9, 2.6,
2H), 3.90 (m, 1H), 4.32 (m, 1H), 5.11 (dt, J 10.6, 1.5, 1H), 5.25
(dt, J 17.2, 1.5 1H), 5.80 (ddd, J 17.2, 10.4, 5.8, 1H). 13C NMR
δ 13.9, 19.7 (CH3), 22.4, 24.7, 29.1, 30.1 (CH3), 31.6, 36.3, 36.7,
68.6, 70.2, 98.4, 115.1, 138.8.
1
cis-4. H NMR δ0.85 (t, J 6.8, 3H, CH3) 1.25 (m, 8H, 4 CH2
a n ti-4-Hexyl-2,2-dim eth yl-6-vin yl-[1,3]-dioxan e (12) (from
10): 1H NMR δ 0.90, (t, J 6.8, 3H, CH3) 1,20-1.40 (m, 10H),
1.26 (s, 3H, CH3), 1.28 (s, 3H, CH3), 1.58-1.65 (m, 2H), 3.92
(m, 1H), 4.46 (M, 1H), 5.20 (ddd, J 17.5, 2.0, 1.2, 1H), 5.29
in side chain), 1.48 (m, 1H in side-chain), 1.58 (m, 1H in side-
chain), 1.65 (ddd, J 14.0 (H6R), 10.3 (H5), 4.7 (H6a), 1H, H6â),
2.35 (dd, J 14.0 (H6â), 4.8 (H5), 1H, H6R), 2.62 (d, J 18.8 (H3â),
1H, H3R), 2.73 (dd, J 18.8 (H3R), 6.7 (3Ha), 1H, H3â), 4.05
(m, J 10.3 (H6â), 4.8 (H6R), 1H, H5), 4.78 (dd, J 6.7 (H3â), 4.7
(H6a), 1H, H3a), 5.09 (dd, J 4.7 (H3a), 4.7 (H6â), 1H, H6a).
13C NMR δ 14.0 (CH3), 22.5 (CH2), 26.0 (CH2), 29.2 (CH2) 31.7
(CH2), 34.7 (CH2), 36.6 (C3), 38.8 (C6), 77.3 (C5), 78.3 (C3a),
84.9 (C6a), 176.0 (C2). GCMS: m/z 212 (M+, 1), 194 (1), 165
(1), 152 (1), 143 (5), 128 (6), 127 (100), 99 (26), 81 (10).
HREIMS: C12H20O3 requires 212.1412. Measured, 212.1415.
Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found: C, 67.54;
H, 9.55.
(ddd, J 10.9, 2.2, 1.4, 1H), 6.00 (ddd, J 17.5, 10.9, 4.1, 1H). 13
C
NMR δ 15.2, 21.2, 23.6, 24.6 (CH3), 25.3 (CH3), 28.8, 30.2,
30.8, 38.8, 72.3 (2C), 100.3, 117.1, 137.6. Regeneration of the
pure syn- and anti-undec-1-ene-3,5-diols 9 and 10, respectively,
was effected by treating each of the acetonides (100 mg, 0.45
mmol) in methanol with a catalytic amount of PPTS. The
disappearance of the acetonide was followed by GC analysis.
After 3 h, solid NaHCO3 was added, the solution filtered, and
solvent removal provided the enediols, which were character-
ized by their 13C NMR spectra. syn-undec-1-ene-3,5-diol (9):
13C NMR δ 13.9, 22.5, 25.1, 29.1, 31.6, 38.0, 42.8, 72.4, 73.7,
114.3, 140.6. anti-Undec-1-ene-3,5-diol (10) 13C NMR δ 14.1,
25.6 (2C), 29.2, 31.8, 37.5, 42.2, 69.0, 69.2, 114.4, 140.7. These
syn and anti-diols were converted to the cis- and trans-bicyclic
lactones, respectively, as discussed in the text.
trans-4. 1H NMR δ 0.87 (t, J 6.0, 3H, CH3), 1.25 (m, 8H,
4CH2 in side-chain), 1.56 (m, 1H in side-chain), 1.62 (m, 1H
in side-chain), 1.85 (ddd, J 14.2 (H6â), 7.9 (H5), 2.3 (H6a), 1H,
H6R), 2.40 (ddd, J 14.2 (H6R), 7.1 (H5), 6.7 (H6a), 1H, H6â),
2.69 (d, J 3.5 (H3a), 2H, H3R, H3â), 3.91 (m, J 7.9 (H6R), 7.1
(H6â) 1H, H5), 4.48 (dd, J 4.5 (H3R, H3â), 4.5 (H6a), 1H, H3a),
4.99 (ddd, J 6.7 (H6â), 4.5 (H3a), 2.3 (H6R), 1H, H6a). 13C NMR
δ 14.0 (CH3), 22.5 (CH2), 26.0 (CH2), 29.1 (CH2), 31.7 (CH2),
(34) Das, N. B.; Torssell, K. B. G. Tetrahedron 1983, 39, 2247.

7494 J . Org. Chem., Vol. 66, No. 22, 2001
Paddon-J ones et al.
Meth yl (9Z,12R)-12-(Tetr a h yd r op yr a n -2′-yloxy)r icin o-
lea te (14). A solution of commercially available ricinoleic acid
(13) (8 g, 18.8 mmol, 70% by GC) in methanol (50 mL)
containing p-TsOH (15 mg) was stirred at room temperature
for 15 h. The mixture was then concentrated, diluted with
DCM, and washed with saturated aqueous NaHCO3. After
drying (MgSO4) and concentration, the crude ester was ob-
tained as an oil. This product27 was used directly in the next
step. GCMS: 294 (M+ - H2O, 1), 166 (21), 124 (15), 96 (27),
84 (30), 55 (100), 41 (58). The crude ester (3.43 g 11 mmol)
was dissolved in chloroform (50 mL) along with dihydropyran
(10 mL), and a catalytic quantity of SnCl2‚2H2O (20 mg) was
added. The mixture was stirred at RT for 4 h after which the
solution was filtered and concentrated to give the protected
methyl ester as an oil. This product was purified by flash
chromatography (silica, Et2O/hexane: 5/95) to give 2 g (46%
addition of the unsaturated 1,3-diol 16 (130 mg, 0.7 mmol) in
acetic acid (2 mL) to a mixture of NaOAc (172 mg, 2.1 mmol,
3 equiv) and CuCl2 (282 mg, 2.1 mmol, 3 equiv) in acetic acid
(10 mL), in the presence of a catalytic amount of PdCl2 (12
mg, 0.1 equiv), provided the crude bicyclic lactones 4. Purifica-
tion by flash chromatography afforded these lactones (100 mg,
67%, 50/50 mixture) as a colorless oil. Separation by HPLC
(15% ethyl acetate in hexane) provided both pure lactones
whose 1H and 13C NMR spectra and GCMS data matched these
listed above. Anal. Calcd for C12H20O3: C 67.89; H 9.50.
Found: C 67.54; H 9.55. HREIMS (70 eV) C12H20O3 requires
212.1412. Measured 212.1415. (3aR,5R,6aR)-cis-4: [R]22
+
D
40.6 (c, 0.5, CHCl3); (3aS,5R,6aS)-trans-4: [R]22D -45.4 (c, 0.54,
CHCl3).
Hyd r olytic Kin etic Resolu tion of (()-1,2-Ep oxyh exa n e
(18a ) a n d Syn t h esis of t h e (3a S,5S,6a S), (3a R,5S,6a R),
(3a S,5R,6a S), a n d (3a R,5R,6a R) Ster eoisom er s of 5-n -
Bu tyltetr a h yd r ofu r o[3,2-b]fu r a n -2(3H)-on e (3) (Sch em e
4). Freshly generated catalyst, (acetato) (aqua) ((S,S))(+)-N,N′-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino)cobal-
t(III), from the commercial precursor (120 mg, 0.196 mmol)35
was added to (()-1,2-epoxyhexane (from 1-hexene and m-
chloroperbenzoic acid in DCM in the normal way) (5 g, 50
mmol) and water (495 µL, 27.5 mmol). The slurry was stirred
for 16 h and then subjected to distillation. Epoxide 19a was
collected at 120 °C (1 atm) (1.55 g, 31%) and 1,2-hexandiol
(20a ) at 118 °C (12 mmHg) (2.48 g, 42%). The recovered
epoxide was identical spectroscopically with starting racemic
1
from ricinoleic acid) of the pure ester 14 as a colorless oil. H
NMR δ 0.85 (t, J 7.1, 3H), 1.24-1.37 (m, 18H), 1.39-1.71 (m,
8H), 1.94-2.04 (m, 2H), 2.21-2.29 (m, 4H), 3.41-3.48 (m, 1H),
3.63 (s, 3H), 3.84-3.97 (m, 1H), 4.63 and 4.69 (2dd, J 2.8, 3.0,
1H), 4.84 (m, 1H), 5.26-5.46 (m, 2H). 13C NMR δ 14.0, 22.5,
24.9, 25.3, 27.3, 29.1 (2C), 29.18, 29.2, 29.5, 31.7, 31.8, 31.0,
35.5, 34.0, 51.4, 73.6, 75.7, 96.7, 124.3, 132.5, 173.5. GCMS
(m/z %): 294 (1), 263 (1), 101 (2), 85 (100), 67 (8), 55 (12), 43
(13). These spectral data matched those reported.28
5-(Tet r a h yd r op yr a n -2′-yloxy)u n d ec-1-en -3-ol (15). A
solution of the methyl ester (14) of ricinoleic acid (2 g, 5 mmol)
in methanol (100 mL) was cooled to -78 °C, and ozone was
admitted in the until a light blue color persisted. Oxygen was
then passed through the solution until it became colorless. The
reaction mixture was treated with an excess of dimethyl sulfide
(1 mL), warmed to RT, and stirred for 1 h. After concentration
under reduced pressure, the crude aldehyde (about 2 g) was
used without purification in the next step. GCMS (m/z %): 242
(M+, 0.3), 157 (0.3), 141 (2.1), 123 (9.7), 101 (46.9), 85 (100),
81 (32.2), 67 (33.5), 57 (29.9), 56 (41.2), 55 (54.3), 43 (50.8), 41
(66.3). The crude aldehyde (∼2 g) in THF (60 mL) was cooled
to -40 °C, and an excess of vinylmagnesium bromide (16 mL,
1 M in ether) was added dropwise. At the end of this addition,
the solution was slowly warmed to RT and stirred for another
2 h. After quenching with an aqueous saturated solution of
NH4Cl, the solution was concentrated and the aqueous phase
extracted with ethyl acetate (3 × 50 mL). The organic phase
was washed with aqueous NaCl solution and then water and
dried (MgSO4). The residue was purified by flash chromatog-
raphy (20% ether in hexane) to afford 15 (450 mg, 33%,
mixture of four diastereomers) as a colorless oil. Anal. Calcd
for C16H30O3: C 71.07; H 11.18. Found C 70.91; H 11.23. GCMS
(m/z %): 213 (M+ - CH2dCHdCHOH, 1), 185 (1), 151 (5), 109
(12), 101 (20), 95 (25), 85 (100).
material and exhibited [R]22 -7.5 (c, 2.2, CHCl3) (reported36
D
[R]22 -8.3 (c, 1.0, CHCl3)).
D
(S)-(-)-1,2-epoxyhexane (19a ) (1 g, 10 mmol) was dissolved
in THF (3 mL) and added to a THF solution generated at -10
°C from CuI (76 mg, 0.4 mmol) and vinylmagnesium bromide
(20 mL of 1 M solution, 20 mmol). The reaction was stirred
and allowed to warm to 0 °C (2 h) and then quenched with
saturated NH4Cl solution. The ether extract (2 × 20 mL) was
dried (MgSO4) and the solvent removed under reduced pres-
sure. The clear oil was purified by flash chromatography (10%
DCM in hexane), to provide (S)-(-)-oct-1-en-4-ol, [R]22 -8.47
D
(c, 3.08, CHCl3). Anal. Calcd for C8H16O:C, 74.94, H, 12.58.
1
Found: C, 74.57; H, 12.54. This sample exhibited H and 13C
NMR and mass spectra that matched those for the racemic
alcohol 6a described above. The tetrahydropyran-2′-yl ether
was acquired as described above for the racemic alcohol and
1
exhibited matching H and 13C NMR spectra. Anal. Calcd for
C
13H24O2: C, 73.54, H, 11.39. Found: C, 73.22, H, 11.45. This
protected (S)-(-)-oct-1-en-4-ol was ozonized and the resulting
aldehyde treated with vinylmagnesium bromide as described
for the racemic material to yield (R,S)-3-hydroxy-(S)-5-(tet-
rahydropyran-2′-yloxy)non-1-ene, which was deprotected as
described previously to provide non-1-ene-3,5-diol (23a ) (pre-
dominantly (5S)) which was converted to a mixture of the cis-
and trans-5-n-butyltetrahydrofuro[3,2-b]furan-2(3H)-ones, with
(3aS,5S,6aS) and (3aR,5S,6aR) stereochemistry, respectively,
First isomer: 1H NMR δ 0.86 (t, J 7.0, 3H), 1.25-1.82 (m,
19H), 3.43-3.50 (m, 1H), 3.83-3.89 (m, 1H), 3.97-4.00 (m,
1H), 4.10 (brd, 3.4, 1H), 4.45-4.47 (m, 1H), 5.04 (dt, J 10.6,
1.6, 1H), 5.24 (dt, J 17.3, 1.6, 1H), 5.87 (ddd, J 17.3, 10.6, 5.2,
1H). 13C NMR δ 14.1, 21.7, 22.6, 25.1, 25.4, 29.4, 31.5, 31.8,
35.5, 42.1, 65.6, 67.9, 74.3, 100.8, 113.3, 140.7. Mixture of three
isomers: 1H NMR δ 0.86 (t, J 7.0, 9H) 1.79-2.27 (m, 57H),
3.45-3.53 (m, 3H), 3.74-3.98 (m, 6H), 4.21-4.26 (m, 1H),
4.35-4.37 (m, 2H), 4.61-4.72 (m, 3H), 5.03-5.09 (m, 3H),
5.20-5.28 (m, 3H), 5.80-5.88 (m, 3H). 13C δ 14.0 (3C), 19.9
(2C), 20.7, 22.6 (3C), 24.7, 25.1, 25.2, 25.3, 25.5, 29.4 (2C), 29.5,
31.1, 31.2, 31.4, 31.7, 31.8 (2C), 34.6, 35.0, 35.8, 39.6, 41.2,
41.9. 62.9, 63.0, 64.2, 69.7, 71.9, 72.5, 75.9, 76.8, 78.9, 98.0,
98.7, 99.3, 113.6, 113.9, 114.2, 140.8, 140.9, 141.1.
(5R)-Un d ec-1-en e-3,5-d iol (16). A solution of the mono-
tetrahydropyranyl ether 15 (218 mg, 0.8 mmol) in dry MeOH
(30 mL) in the presence of Amberlite IR-120 (300 mg) was
stirred at RT overnight. After filtration, drying (MgSO4), and
concentration, the pure diol 16 (150 mg, 100%) was obtained
as a colorless oil. This material exhibited spectral properties
that matched those listed above for diastereomers of this
enediol system, and for the derived acetonides 11 and 12.
(3a R,5R,6a R)-5-n -H e xylt e t r a h yd r ofu r o[3,2-b]fu r a n -
2(3H)-on e a n d (3a S,5R,6a S)-5-n -Hexyltetr a h yd r ofu r o-
[3,2-b]fu r a n -2(3H)-on e (4). Following the general procedure,
as described in detail above. The former isomer had [R]22
D
-47.5 (c, 1.46, CHCl3), and the latter [R]22 +55.8 (c 1.18,
D
CHCl3). The 1H and 13C NMR spectra and mass spectra
matched those described above for the racemic compounds.
(R)-Hexane-1,2-diol (20a ) (1 g, 8.4 mmol) was dissolved in
DCM (15 mL) and cooled to 0 °C. Triethylamine (4.7 mL, 33.6
mmol) was added and then thionyl chloride (920 µL, 12.6
mmol). After stirring for 5 min, the reaction was diluted with
ether (50 mL), washed with water (2 × 30 mL), dried (MgSO4),
and filtered through Celite. The solvent was removed under
reduced pressure and the crude sulfite taken up in a mixture
of CH3CN (30 mL) and H2O (30 mL). RuCl3 (20 mg, 0.1 mmol)
and NaIO4 (3.6 g, 16.8 mmol) were added, and the reaction
was stirred for 2 h. The reaction mixture was diluted with
ether (50 mL) and the aqueous phase extracted further with
ether (2 × 30 mL). The combined ether phases were dried
(35) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N.
Science 1997, 277, 936.
(36) Haase, B.; Schneider, M. Tetrahedron: Asymmetry 1993, 4 (5),
1017.

Bicyclic γ-Lactones from Parasitic Wasps
J . Org. Chem., Vol. 66, No. 22, 2001 7495
(MgSO4), and the solvent was removed. The resulting sulfate
21a was dried azeotropically with i-PrOH (15 mL) (1.22 g,
81%.). Anal. Calcd for C6H12O4S: C, 39.99; H, 6.71. Found:
NMR spectra matching those described above. Ozonolysis and
reaction of the resulting aldehyde with vinylmagnesium
bromide afforded (5S)-5-(tetrahydropyran-2′-yloxy)undec-1-en-
3-ol spectroscopically consistent with the diastereomeric diol
mixture described above. This was deprotected in the manner
described to provide predominantly (5S)-undec-1-ene-3,5-diol
(23b) identical with material characterized above.
1
C, 39.59; H, 6.87. H NMR δ 0.89, (t, J 6.9, 3H, CH3), 1.17-
1.39 (m, 4H), 1.73 (m, 1H), 1.90 (m, 1H), 4.31 (t, J 8.4, 1H),
4.68 (dd, J 8.6, 5.9, 1H), 4.94 (m, 1H). 13C NMR δ 13.6 (CH3),
22.0 (CH2), 26.5 (CH2) 31.8 (CH2) 72.9 (CH2), 83.1 (CH). [R]22
D
+6.0 (c, 5.11, CHCl3). This cyclic sulfate 21a (250 mg, 1.39
mmol) in THF (3 mL) was treated with LiBr (480 mg, 5.6
mmol) and stirred for 3 h. The solvent was removed and the
residue taken up in ether (5 mL) to which was added 20%
H2SO4 (5 mL). After vigorous stirring (∼ 12 h), the mixture
was extracted with ether (2 × 5 mL) and the organic phase
dried (MgSO4) and evaporated to provide the presumed crude
bromohydrin. This was immediately dissolved in MeOH (5 mL)
and cooled to 0 °C, and K2CO3 (775 mg, 5.6 mmol) was added.
After 3 h, saturated NH4Cl solution (15 mL) was added and
the mixture extracted with DCM (3 × 10 mL) which was then
dried (MgSO4) and the solvent carefully removed. Flash
chromatography (10% DCM in hexane) afforded the (R)-
This diol 23b was then subjected to the Pd(II)-catalyzed
lactone forming reaction and provided two lactones (59 mg,
(93%) from 60 mg of starting diol, 23b). These lactones were
separated in the normal way (HPLC) to provide the (3aS,5S,-
6aS)-cis-4 and (3aR,5S,6aR)-trans-4 lactones, with [R]22D -39.7
and [R]22 +45.6, respectively. The 1H and 13C NMR spectra
D
matched those of the racemic compounds detailed above. The
(R)-(+)-diol 20b (1 g, 6.8 mmol) was converted to the cyclic
sulfate 21b in the manner described (1.0 g, 74% from diol).
Anal. Calcd for C8H16O4S: C, 46.14; H, 7.74. Found: C, 46.03;
1
H, 7.88 [R]22 +7.1 (c 1.94, CHCl3). H NMR δ 0.87 (t, J 6.9,
D
3H, CH3), 1.17-1.49 (m, 8H), 1.73 (m, 1H), 1.93 (m, 1H), 4.31
(t, J 8.4, 1H), 4.68 (dd, J 8.7, 6.0, 1H), 4.95 (m, 1H). 13C δ 13.9
(CH3), 22.4 (CH2), 24.5 (CH2), 28.6 (CH2), 31.4 (CH2), 32.2
(CH2), 72.8 (CH2), 82.9 (CH). This cyclic sulfate 21b (300 mg,
1.44 mmol) was converted to the corresponding (R)-epoxide 22b
epoxide 22a (42 mg, ∼30%). [R]22 + 3.9 (c, 0.6, CHCl3). (This
D
rotation is low, but a realistic measure of the ee of this volatile
epoxide is indicated by the ee of the final bicyclic lactone.) This
was processed, as described above in detail for its enantiomer
19a to yield the (3aR,5R,6aR)-cis-3 and (3aS,5R,6aS)-trans-
(90 mg, 49%) (as described for (R)-hexane-1,2-diol (20a )) [R]22
D
+7.4 (c, 4.5, CHCl3). This epoxide 22b, through the (5R)-undec-
(3) lactones, with [R]22 +46.5 and -53.9, respectively. The
1-ene-3,5-diol, [R]22 +7.1 (c, 0.5, CHCl3) (24b) was processed
D
D
1H and 13C NMR spectra of these matched those described for
the racemic compounds.
to the bicyclic lactones in the manner described in detail above,
to provide the (3aR,5R,6aR)-cis-4 and (3aS,5R,6aS)-trans-4
lactones, with [R]22 +39.7 (c, 1.05, CHCl3) and [R]22 -41.0
Hyd r olytic Kin etic Resolu tion of (()-1,2-Ep oxyocta n e
(18b) a n d Syn th esis of th e (3a S,5S,6a S), (3a R,5S,6a R),
(3a S,5R,6a S), a n d (3a R,5R,6a R) Ster eoisom er s of 5-n -
Hexyltetr a h yd r ofu r o[3,2-b]fu r a n -2(3H)-on e (4). The pro-
cedures described above commencing with (()-1,2-epoxyhexane
(18a ) were followed with (()-1,2-epoxyoctane (18b). From
racemic epoxide (5.9 g, 46 mmol) and catalyst (120 mg, 0.2
mmol of precatalyst) were obtained (S)-(-)-1,2-epoxyoctane
(19b) (128 °C at 226 mmHg, 1.91 g, 33%) and (R)-(+)-diol 20b
(120 °C at 6 mm Hg, 2.7 g, 40%, mp 35°). For (S)-(-)-epoxide
D
D
(c, 1.02, CHCl3), respectively.
The bicyclic lactones prepared were separated into their
enantiomers on a heptakis (6-O-TBDMS-2,3-di,O-methyl)-â-
cyclodextrin phase (see text and Figure 1), whereas a com-
mercially available γ-cyclodextrin phase separated the enan-
tiomers of the cis-lactones but not those of the trans-lactones.
The optical rotations, directly determined ee’s (by gas chro-
matography, and comparisons of optical rotations) and the
relationships between the various stereoisomers are shown in
Scheme 4.
19b. [R]22 -8.9 (c, 1.8, CHCl3). Anal. Calcd for C8H16O: C,
D
74.94; H, 12.58. Found: C, 74.62; H, 12.78. 1H NMR δ 0.86 (t,
J 7.0, 3H, CH3), 1.22-1.53 (m, 10H), 2.43 (dd, J 5.1, 2.8, 1H),
2.71 (dd, J 5.0, 4.0, 1H), 2.88 (m, 1H). 13C NMR δ 14.0 (CH3),
22.5 (CH2), 25.9 (CH2), 29.1 (CH2), 31.7 (CH2) 32.5 (CH), 47.1
(CH2), 52.4 (CH). Reaction of this epoxide with vinylmagne-
sium bromide in the presence of CuI afforded (S)-(-)-1-decen-
4-ol: Anal. Calcd for C10H20O: C, 76.85; H, 12.91. Found: C,
77.06; H, 12.98. [R]22D -7.2 (c, 2.13, CHCl3). The NMR spectral
data were in agreement with those listed above for the
racemate. This alcohol was protected in the normal way as
its tetrahydropyran-2′-yl ether (Anal. Calcd for C15H28O2: C,
74.93; H, 11.75. Found: C, 75.15; H, 12.15), which provided
Ack n ow led gm en t. The authors are grateful to the
Australian Research Council for support of this work,
and to Dr. D. J . Brecknell for some calculations.
Su p p or tin g In for m a tion Ava ila ble: List of the computed
and measured coupling constants and dihedral angles for the
lactones in Chart 2 and copies of the enantioselective GC traces
for cis-5-n-butyl-3 and cis-n-hexyl-4. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0159237