Stereoselective synthesis of naturally occurring α-methylenebis-γ-butyrolactones: An application of novel oxiranyl "remote" anions

Article abstract of DOI:10.1021/jo010259f

Stereospecific deprotonation of the epoxy proton at the β-position of the α,β-epoxy esters 5 and 6 yielded oxiranyl "remote" anions 7 and 8, which could then be used for alkylation. The anions 7 and 8 underwent a consecutive aldol lactonization to give, r

Full text of DOI:10.1021/jo010259f

4692
J . Org. Chem. 2001, 66, 4692-4694
Ster eoselective Syn th esis of Na tu r a lly Occu r r in g
r-Meth ylen ebis-γ-bu tyr ola cton es: An Ap p lica tion of Novel
Oxir a n yl “Rem ote” An ion s
J ittiwud Lertvorachon, Yodhathai Thebtaranonth,* Tienthong Thongpanchang, and
Panumart Thongyoo
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road,
Bangkok 10400, Thailand
scytr@mucc.mahidol.ac.th
Received March 9, 2001
Stereospecific deprotonation of the epoxy proton at the â-position of the R,â-epoxy esters 5 and 6
yielded oxiranyl “remote” anions 7 and 8, which could then be used for alkylation. The anions 7
and 8 underwent a consecutive aldol lactonization to give, respectively, epoxy lactones 11 and 13
with high stereoselectivity. Generation of the remote anions as well as their stereoselective reactions
served as a new synthetic route to the naturally occurring R-methylenebis-γ-butyrolactones, 1.
In tr od u ction
transition state requirements, the consecutive aldol-
lactonization reaction between the anion derived from 2
and O-protected R-hydroxyaldehyde followed by hydro-
genolysis gives the major product, 3, with the opposite
stereochemistry at the chiral carbon bearing the alkyl
substituent.
Significantly, in an unrelated finding, we observed that
the â-proton in a ketoepoxide is the preferred site of
deprotonation, even in the case of an enolizable ketone.
Thus, after treatment of chalcone epoxide with LTMP,
the â-anion was preferentially formed and could be
trapped with an aldehyde or, in the absence of an
external electrophile, condensed with unreacted starting
material.5
Naturally occurring R-methylenebis-γ-butyrolactones
xylobovide 1a ,1 canadensolide 1b,2 and sporothriolide 1c3
are metabolites of Xylaria obovata, Penicillium ca-
nadense, and Sporothrix sp., respectively. The interest
in these compounds lies not only in their significant
biological activities (being antibacterial, antifungal, and
phytotoxic) but also in their unique stereochemical
features. Because of an all cis stereochemistry of the
three adjacent methine protons, the alkyl substituent is
interestingly situated in the sterically less accessible
concave face of the molecule.
Here, we report significant findings, which involve a
new alkylation strategy, based on stereospecific â-depro-
tonation of the epoxy ester, leading to short and conve-
nient stereoselective syntheses of xylobovide 1a , canaden-
solide 1b, and sporothriolide 1c.
(i) The epoxides 5 and 6, prepared from 2, are amen-
able to â-deprotonation by LTMP.5 The deprotonation is
stereospecific, affording the corresponding anions 7 and
8, which are stable in THF solution at -78 °C apparently
due to the ester oxygen-lithium stabilization in the form
of a five-membered cyclic intermediate.6 Significantly,
none of the six-membered chelated anion, stabilized by
the second ester group, i.e., 9, is observed (Scheme 1).
Remarkably, it should be mentioned that, as far as we
are aware, the remote carbonyl stabilized oxiranyl anion
reported here is the first example of a Li-H exchange of
the â-proton of the oxirane.7
We recently reported a general synthetic route to the
R-methylenebis-γ-butyrolactone nucleus by the use of the
dimethyl itaconate-anthracene adduct 2 in a consecutive
aldol-lactonization reaction followed by flash vacuum
pyrolysis of the resulting bislactone adduct.4 Although
extremely efficient for the preparation of the bislactone
skeleton, the method has a drawback in its application
to the said natural products, 1a -c. Because of the
(1) Isolation: Abate, D.; Abraham, W. R.; Meyer, H. Phytochemistry
1997, 44, 1443-1448.
(ii) Anions 7 and 8 react stereospecifically with various
electrophiles. For example, with aldehydes, anions 7 and
8 smoothly undergo a consecutive aldol-lactonization
(2) Isolation: (a) McCorkindale, N. J .; Wright, J . L. C.; Brain, P.
W.; Clarke, S. M.; Hutchinson, S. A. Tetrahedron Lett. 1968, 727-
730. Synthesis: (b) Al-Abed, Y.; Naz, N.; Mootoo, D.; Voelter, W.
Tetrahedron Lett. 1996, 37, 8641-8642. (c) Nubbemeyer, U. Synthesis
1993, 1120-1128. (d) Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara,
K.; Yoshikoshi, A. J . Org. Chem. 1975, 40, 1932-1941. (e) Sharma, G.
V. M.; Krishnudu, K.; Rao, S. M. Tetrahedron: Asymmetry 1995, 6,
543-548.
(5) Baramee, A.; Clardy, J .; Kongsaeree, P.; Rajviroonkit, S.; Su-
teerachanon, C.; Thebtaranonth, C.; Thebtaranonth, Y. J . Chem. Soc.,
Chem. Commun. 1996, 1511-1512.
(3) Isolation: (a) Krohn, K.; Ludewig, K.; Aust, H. J .; Draeger, S.;
Schulz, B. J . Antibiot. 1994, 47, 113-118. Synthesis: (b) Sharma, G.
V. M.; Krishnudu, K. Tetrahedron Lett. 1995, 36, 2661-2664.
(4) Lertvorachon, J .; Meepowpan, P.; Thebtaranonth, Y. Tetrahedron
1998, 54, 14341-14358.
(6) (a) Pippel, D. J .; Curtis, M. D.; Du, H.; Beak, P. J . Org. Chem.
1998, 63, 2-3. (b) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552-560. (c) Snieckus,
V. Chem. Rev. 1990, 90, 879-933. (d) Beak, P.; Meyers, A. I. Acc. Chem.
Res. 1986, 19, 356-363.
10.1021/jo010259f CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/07/2001

R-Methylenebis-γ-butyrolactones
J . Org. Chem., Vol. 66, No. 13, 2001 4693
Ta ble 2. P er cen t Yield s fr om Rea ction s betw een th e
An ion 8, Gen er a ted fr om 6, a n d Electr op h iles
Sch em e 1
electrophile
12 (%)
13 (%)
14 (%)
(a) CD3OD
(b) CH3I
64
77
(c) PhCHO
83
80
79
66
(d) C2H5CHO
(e) n-C4H9CHO
(f) n-C6H13CHO
4
6
16
Sch em e 2. Tr a n sition Sta tes of th e Rea ction
betw een An ion s 7 a n d 8 w ith a n Ald eh yd e
Ta ble 1. P er cen t Yield s fr om Rea ction s betw een th e
An ion 7, Gen er a ted fr om 5, a n d Electr op h iles
electrophile
10 (%)
11 (%)
(a) CD3OD
(b) CH3I
58
76
approach of the aldehyde to the anions via the transition
states proposed in Scheme 2.
(c) PhCHO
53
68
63
57
(d) C2H5CHO
(e) n-C4H9CHO
(f) n-C6H13CHO
The samarium iodide induced epoxide ring opening of
the epoxy lactone 11, conducted according to the pub-
lished method,10 gave the corresponding alcohol, which
lactonized after being boiled in benzene for 2 h in the
presence of DBU, to allow complete isomerization of
stereochemistry at the chiral carbon R to the lactone
group and yielded the bislactone 16 (16d ) 60%; 16e )
60%; and 16f ) 58%). Similar treatment of 13 yielded
18 (18d ) 61%; 18e ) 60%; and 18f ) 54%). Finally,
flash vacuum pyrolysis11 of 16 and 18 affected the retro
Diels-Alder reaction to cleanly furnish the R-methyl-
enebis-γ-butyrolactone, 1 (see Scheme 3).
The findings that â-oxiranyl anions can be formed and
stereospecifically trapped with electrophiles have pro-
vided a novel synthetic methodology, whereby xylobovide
1a , canadensolide 1b, and sporothriolide 1c can be
conveniently synthesized.
reaction to give respectively epoxy lactones 11 and 13
with high stereoselectivity.
(iii) Samarium iodide catalyzed ring opening of the
epoxide moieties in 11 and 13 followed by treatment with
DBU is effective in affecting the cis fused ring closure to
the respective bislactones 16 and 18, which then yield
the natural product, 1, after flash vacuum pyrolysis.
Thus, epoxidation of the anthracene adduct 4, prepared
directly from 2,8 provided two separable epoxides, 5 and
6, in almost equal amounts. Deprotonation of epoxide 5
by LTMP in THF at -78 °C followed by the addition of
electrophiles gave 10 and, in the case of an aldehyde, the
cis epoxy lactone, 11, with yields as shown in Table 1.
Likewise, epoxide 6 provided 12 and 13. However, in this
latter case, a small amount of the undesired trans isomer
14 was also isolated (Table 2). The structures and
stereochemistry of all products described are fully sup-
ported by NMR and, in certain cases, X-ray data.9
The key to obtain the “correct” cis relative stereochem-
istry between the epoxy and the alkyl groups in 11 and
13 lies in the high stereoselectivity of the reaction
between the anions 7 and 8 with aldehydes. This can be
explained in terms of the sterically more favorable
Exp er im en ta l Section
11-Ca r bom eth oxy-11-(4′-eth yl-2′-oxo-3′,6′-d ioxa bicyclo-
[3.1.0]h ex-1′-yl)-9,10-dih ydr o-9,10-eth an oan th r acen e (11d).
To a solution of the epoxide 58 (0.5 g, 1.37 mmol) in THF (80
mL) was added a solution of LTMP (4.12 mmol) in THF (10
(9) Structures of compounds 10b (E ) Me) and 13d (R ) Et) have
been confirmed by X-ray crystallography whose data have been
deposited with the Cambridge Crystallographic Data Center and
allocated the deposition numbers CCDC 144329 and CCDC 144330,
respectively. Copies of the data can be obtained free of charge on
application to The Director, Cambridge Crystallographic Data Center,
12 Union Road, Cambridge CB2 1EZ, U.K. (fax: +44-1223-336033;
e-mail: deposit@ccdc.cam.ac.uk; web site: http://www.ccdc.cam.ac.uk).
(10) Otsubo, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett. 1987,
28, 4437-4440.
(7) (a) Satoh, T. Chem. Rev. 1996, 96, 3303-3325 and references
therein. See also other works on oxiranyl anions: (b) Eisch, J . J .; Galle,
J . E. J . Am. Chem. Soc. 1976, 98, 4646-4648. (c) Ramirez, A.; Collum,
D. B. J . Am. Chem. Soc. 1999, 121, 11114-11121. (d) Dechoux, L.;
Agami, C.; Doris, E.; Mioskowski, C. J . Org. Chem. 1999, 64, 9279-
9281. (e) Kasatkin, A. N.; Whitby, R. J . Tetrahedron Lett. 2000, 41,
6201-6205.
(8) Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Tetra-
hedron Lett. 1987, 28, 6671-6674.
(11) Kodpinid, M.; Siwapinyoyos, T.; Thebtaranonth, Y. J . Am.
Chem. Soc. 1984, 106, 4862-4865.

4694 J . Org. Chem., Vol. 66, No. 13, 2001
Lertvorachon et al.
Sch em e 3a
°C under argon. The mixture was stirred for 15 min at 0 °C
and at rt for 2 h. N,N-Dimethyl-2-hydroxyethylamine (DMAE)
(0.256 mL, 2.55 mmol) was added to a solution of 11d (0.2 g,
0.51 mmol) in THF (10 mL). The solution was then added to
the resulting deep blue-green solution of SmI2 at 0 °C, and
the reaction mixture was stirred at rt for 0.5 h. Basic workup
with saturated aqueous sodium bicarbonate solution and the
crude product was extracted into dichloromethane. The com-
bined organic phase was washed with water and brine, dried
(MgSO4), filtered, and evaporated to dryness. The ben-
zene solution of the obtained product, after flash chromato-
graphic purification, was boiled with the presence of DBU (cat-
alytic amount) for 2 h, after which the mixture was quenched
with dilute hydrochloric acid and evaporated to dryness. Silica
gel PLC purification using hexane:ethyl acetate:dichloromethane
(11:1:8 as eluent) gave, after crystallization with a mixture of
dichloromethane-hexane, the bislactone adduct 16d (56.6 mg,
60%); mp 254-255 °C (colorless needles from dichlorometh-
1
ane-hexane). H NMR (400 MHz, CDCl3): δ 1.08 (t, 3H, J )
7.4 Hz), 1.82-2.01 (m, 2H), 1.97, 2.97, 4.45 (ABX, 3H, J )
2.5, 3.0, 13.3 Hz), 2.86 (d, 1H, J ) 5.2 Hz), 4.16 (s, 1H), 4.35
(dt, 1H, J ) 3.6, 7.3 Hz), 5.33 (dd, 1H, J ) 3.6, 5.2 Hz), 7.11-
7.39 (m, 8H). 13C NMR (100 MHz, CDCl3): δ 10.0, 22.4, 31.3,
44.0, 49.7, 52.1, 52.2, 76.9, 82.4, 123.6, 124.9, 125.5, 125.6,
126.5, 127.6, 128.0, 137.7, 139.2, 143.7, 144.2, 173.0, 175.7.
IR (CHCl3) νmax: 3029, 3012, 2955, 1791, 1777, 1460, 1221,
1158 cm-1. EIMS (70 eV) m/z (relative intensity): 360 (M+,
a
Key: (a) SmI2 (2.5 equiv), N,N-Dimethyl-2-hydroxyethylamine
(5 equiv), THF, 0 °C to rt, 0.5 h. (b) DBU (cat), benzene, reflux,
2 h. (c) FVP.
mL) at -78 °C, and the reaction mixture was stirred for 1 h.
Excess propanal (0.99 mL, 13.7 mmol) was added at -78 °C,
and the mixture was stirred for an additional 4 h. After the
reaction was quenched with saturated aqueous ammonium
chloride solution, the crude product was extracted several
times with dichloromethane. The combined dichloromethane
extracts were washed with water and brine and dried over
MgSO4. The solution was filtered and evaporated to dryness.
Silica gel PLC purification (hexane:ethyl acetate; 9:1 as eluent)
followed by crystallization from dichloromethane-hexane
provided the epoxy lactone 11d (0.36 g, 68%); mp 216-218 °C
(colorless crystals from dichloromethane-hexane). 1H NMR
(400 MHz, CDCl3): δ 1.0 (t, 3H, J ) 7.4 Hz), 1.62 (ddq, 1H, J
) 7.4, 7.5, 14.5 Hz), 1.83 (ddq, 1H, J ) 6.5, 7.4, 14.5 Hz), 1.64,
2.64, 4.41 (ABX, 3H, J ) 2.7, 2.9, 12.4 Hz), 3.24 (d, 1H, J )
1.0 Hz), 3.65 (s, 3H), 4.13 (ddd, 1H, J ) 1.0, 6.5, 7.5 Hz), 5.34
(s, 1H), 7.10-7.45 (m, 8H). 13C NMR (100 MHz, CDCl3): δ 9.9,
23.2, 34.9, 44.1, 48.0, 51.0, 53.2, 58.3, 62.9, 78.9, 123.6, 123.9,
125.2, 126.2, 126.4, 126.5, 127.1, 127.2, 139.7, 140.2, 143.9,
144.4, 170.5, 172.7. IR (CHCl3) νmax: 3072, 3023, 2925, 1765,
1717, 1462, 1270, 1094 cm-1. EIMS (70 eV) m/z (relative
intensity): 390 (M+, 0.4), 178 (100), 59 (10.3). Anal. Calcd for
3.3), 178 (100). ESITOF exact mass calcd for C23H20O4 (M+
H): 361.1440. Found: 361.1442.
+
Xylobovid e (1a ). Flash vacuum pyrolysis of 16d , according
to the method already described,11 provided 1a in almost
quantitative yield.4
Ack n ow led gm en t. We are grateful to Dr. P. Kong-
saeree of the Department of Chemistry, Faculty of
Science, Mahidol University, who kindly performed the
X-ray crystallographic analysis of compounds 10b (E )
Me) and 13d (R ) Et). We also thank Dr. R. B. Bates of
the Department of Chemistry, Chulalongkorn Univer-
sity, for useful discussions. The National Center for
Genetic Engineering and Biotechnology (BIOTEC)/
National Science and Technology Development Agency’s
(NSTDA) Senior Research Fellowship Award to Y.T. is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental and
spectroscopic data of compounds 10a ,b; 11c-f; 12a ,b; 13c-f;
14d -f; and 16d -f. This material is available free of charge
via the Internet at http://pubs.acs.org.
C
24H22O5: C, 73.83; H, 5.68. Found: C, 73.56; H, 5.45.
8′-Eth yl-3′,6′-dioxo-2′,7′-dioxabicyclo[3.3.0]octan -4′-spir o-
11-9,10-d ih yd r o-9,10-et h a n oa n t h r a cen e (16d ). Diiodo-
methane (0.1 mL, 1.28 mmol) was added dropwise to a slurry
of samarium powder (0.3 g, 2.13 mmol) and THF (60 mL) at 0
J O010259F