Enantioselective syntheses of isoaltholactone, 3-epi-altholactone, and 5-hydroxygoniothalamin

Article abstract of DOI:10.1021/ol000179i

A flexible enantioselective route to highly functionalized γ,β-unsaturated δ-lactones has allowed for the syntheses of the styryllactones: isoaltholactone, 3-epi-altholactone, and 5-hydroxygoniothalamin in 10%, 5%, and 13% overall yields from furfural, re

Full text of DOI:10.1021/ol000179i

ORGANIC
LETTERS
2000
Vol. 2, No. 19
2983-2986
Enantioselective Syntheses of
Isoaltholactone, 3-epi-Altholactone, and
5-Hydroxygoniothalamin
Joel M. Harris and George A. O’Doherty*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
odoherty@chem.umn.edu
Received July 6, 2000
ABSTRACT
A flexible enantioselective route to highly functionalized r,â-unsaturated δ-lactones has allowed for the syntheses of the styryllactones:
isoaltholactone, 3-epi-altholactone, and 5-hydroxygoniothalamin in 10%, 5%, and 13% overall yields from furfural, respectively. This approach
derives its asymmetry by applying the Sharpless catalytic asymmetric dihydroxylation to vinylfuran. The resulting diols are produced in high
enantioexcess and can be stereoselectively transformed into r,â-unsaturated δ-lactones via a short highly diastereoselective oxidation and
reduction sequence.
Substituted R,â-unsaturated δ-lactones are an important class
of natural products with a wide range of biological activity.1
Many natural products from various plants and fungi share
the common 5-oxygenated-5,6-dihydro-2H-pyran-2-one struc-
tural motif, such as goniodiol, acetylphomalactone, and
altholactone.1d These natural products have biological activity
including antitumor1a and antifungal properties,1f as well as
antibiotic potential.1f Due to the wide distribution of 5,6-
dihydro-2H-pyran-2-ones in plants and fungi, many synthetic
methodologies have been employed to synthesize this core
structure.1,2
As part of our synthetic efforts to enantioselectively
synthesize biologically important C-arylglycoside natural
products from achiral furans,3 we chose to devise a route to
the antitumor natural product altholactone 1b. At the outset,
we targeted a selective synthesis of the four possible C-2/
C-3 diastereomers of altholactone 1a-d. We opted for late
installation of the arene ring, to allow for simple access to
substituted arene analogues. Altholactone, a furanopyrone
member of the styryllactone family, was first isolated by
Loder and Nearn4 from the bark of an unnamed Polyathia
(Annonaceae) species and has subsequently been isolated
from various Goniothalamus species.1a Previous syntheses
of altholactone have been accomplished by Gesson,5 Shing,6
Ogawa,7 Kang,8 Honda,9 Somfai,10 and Mukai11 and range
from 11 steps from D-gluconolactone6 to 16 steps from
(1) (a) Blazquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes, D.
Phytochem. Anal. 1999, 10, 161-170. (b) Bermejo, A.; Blazquez, M. A.;
Rao, K. S.; Cortes, D. Phytochem. Anal. 1999, 10, 127-131. (c) Yasui,
K.; Tamura, Y.; Nakatani, T.; Kawada, K.; Ohtani, M. J. Org. Chem. 1995,
60, 7567-7574 and references therein. (d) Fang, X.-P.; Anderson, J. E.;
Chang, C.-J.; McLaughlin, J. L.; Fanwick, P. E. J. Nat. Prod. 1991, 54,
1034. (e) Argoudelis, A. D.; Zieserl, J. F. Tetrahedron Lett. 1966, 18, 1969.
(f) For a review of 5,6-dihydro-2H-pyran-2-ones, see: Davies-Coleman,
M. T.; A. Rivett, D. E. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Grisebach, H., Kirby, G. W., Tamm, Ch., Eds.;
Springer-Verlag: New York, 1989; Vol. 55, pp 1-35.
(2) (a) Schlessing, R. H.; Gillman, K. W. Tetrahedron Lett. 1999, 40,
1257-1260. (b) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T. Tetrahedron
1999, 55, 2493. (c) Chen, W.-P.; Roberts, S. M. J. Chem. Soc., Perkin
Trans. 1 1999, 103-105. (d) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem.
Soc., Perkin Trans. 1 1998, 3125-3126. (e) Yang, Z.-C.; Jiang, X.-B.;
Wang, Z.-M.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1997, 317-321.
(f) Gomez, A. M.; Lopez de Uralde, B.; Valverde S.; Lopez, J. C. J. Chem.
Soc., Chem. Commun. 1997, 1647. (g) Honda, T.; Sano, N.; Kanai, K.
Heterocycles 1995, 41, 425-429. (h) Yang, Z.-C.; Zhou, W.-S. Tetrahedron
Lett. 1995, 36, 5617-5618. (i) Masaki, Y.; Imaeda, T.; Oda, H.; Itoh, A.;
Shiro, M. Chem. Lett. 1992, 1209-1212. For a review, see: (j) Ogliaruso,
M. A.; Wolfe, J. F. In Synthesis of Lactones and Lactams; Patai, S.,
Rappoport, Z., Eds.; John Wiley and Sons: New York, 1993; pp 3-131,
271-396.
(3) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863-866.
(4) Loder, J. W.; Nearn, R. H. Heterocycles 1977, 7, 113.
(5) (a) Gesson, J.-P.; Jacquesy, J.-C.; Mondon, M. Tetrahedron Lett.
1987, 28, 3945-3948. (b) Gesson, J.-P.; Jacquesy, J.-C.; Mondon, M.
Tetrahedron Lett. 1987, 28, 3949-3952. (c) Gesson, J.-P.; Jacquesy, J.-C.;
Mondon, M. Tetrahedron 1989, 45, 2627-2640.
10.1021/ol000179i CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/23/2000

D-glycerldehyde acetonide.9 Many of these syntheses derive
their asymmetry from carbohydrate derivatives,5-9 diethyl
L-tartrate,10 or a substituted benzaldehyde chromium(0)
complex.11
Scheme 2
Our approach to this class of natural products involves
the diastereoselective synthesis of either double bond isomer
of compound 2, from furyl alcohol 3, and subsequent
conversion to 1a-d through a diastereoselective epoxidation
and acid-catalyzed cyclization sequence (Scheme 1).
Scheme 1
Recently, we developed an expeditious route to various
D- or L-sugars and sugar lactones from furan diols using
Sharpless’s dihydroxylation to establish the absolute stereo-
chemistry.12 Continuing our investigations on the utility of
this strategy, we turned our attention to the styryllactone class
of natural products, especially the R,â-unsaturated δ-lactone
motif. Herein, we describe our preliminary results in the
synthesis of the altholactone diastereomers. This work led
to a highly efficient enantioselective approach to 3 styryl-
lactones: isoaltholactone (1c), 3-epi-altholactone (1a), and
5-hydroxy goniothalamin (14).
We envisioned synthesizing 2a and 2b from 4, which we
previously prepared enantioselectively from furyl alcohol 3
(Scheme 2).13 Furyl alcohol 3 was synthesized from furfural
via a Peterson olefination, dihydroxylation of the resulting
vinylfuran using AD-mix-â,14 and protection of the primary
alcohol with TBSCl, in a 75% overall yield and >92% ee.15
Treatment of furyl alcohol 3 with NBS16 in aqueous THF
produces a hemiacetal pyranone through an oxidative ring
expansion (Achmatowicz reaction).17 Treatment of the crude
Achmatowicz product with excess Jones reagent gave a
ketolactone intermediate, which was taken on without
purification to a Luche reduction with NaBH4 and CeCl3 in
MeOH, to give δ-lactone 418 in 70% yield and >92% ee.
To gain access to a suitably protected aldehyde precursor
necessary to install the olefin side chain, some protecting
group manipulations were required (Scheme 2). Initial
attempts included the use of a benzoyl or ethyl carbonate
protecting group at C-4 (lactones 5a and 5b); however, C-4
carboxylate groups were incompatible with the ensuing
oxidation step. The primary TBS groups of 5a and 5b were
cleanly deprotected with 5% HF in CH3CN to give primary
alcohols 6a and 6b. Unfortunately, oxidation of either alcohol
6a or 6b under various conditions (Jones, PCC, TPAP, and
Dess-Martin) failed to give the desired aldehydes 7a and
7b; only the elimination product 8 was formed.
A practical solution was found by using a bis-TBS group
protection strategy (Scheme 2). Protection of the free hydroxy
group of lactone 4 was accomplished with TBSOTf forming
5c in 90% yield. Selective deprotection of the primary TBS
group of 5c was accomplished with 5% HF in CH3CN to
exclusively give the free primary alcohol 6c in 90% yield.
Dess-Martin oxidation of the primary alcohol gave the
desired aldehyde 7c, which was taken on without purification
due to decomposition on silica gel. Although aldehyde 7c
was unstable, Wittig olefination of crude 7c gave δ-lactone
2a in a 60% yield and a diastereoselectivity of 7:1 in favor
of the cis olefin at -78 °C (Scheme 3).19
(6) (a) Gillhouley, J. G.; Shing, T. K. M. J. Chem. Soc., Chem. Commun.
1988, 976-977. (b) Shing, T. K. M.; Gillhouley, J. G. Tetrahedron 1994,
50, 8685-8698. (c) Shing, T. K. M.; Tsui, H.-C.; Zhou, Z.-H. J. Org. Chem.
1995, 60, 3121-3130.
(7) Ueno, Y.; Tadano, K.; Ogawa, S.; McLaughlin, J. L.; Alkofahi, A.
Bull. Chem. Soc. Jpn. 1989, 62, 2328-2337.
(8) Kang, S. H.; Kim, W. J. Tetrahedron Lett. 1989, 30, 5915-5918.
(9) (a) Tsubuki, M.; Kanai, K.; Honda, T. Synlett 1993, 653-655. (b)
Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T. Tetrahedron 1999, 55,
2493-2514.
(10) Somfai, P. Tetrahedron 1994, 50, 11315-11320.
(11) (a) Mukai, C.; Hirai, S.; Kim, I. J.; Hanaoka, M. Tetrahedron Lett.
1996, 37, 5389-5392. (b) Mukai, C.; Hirai, S.; Hanaoka, M. J. Org. Chem.
1997, 62, 6619-6626.
(12) (a) Harris J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2982-2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.;
Young, V. G.; O’Doherty, G. A. Carbohydrate Res. 2000, 328(1), 17-36.
(13) Harris, J. M.; O’Doherty, G. A. Tetrahedron Lett. 2000, 41, 183-
187.
(16) (a) Grapsas, I.; Couladouros, E. A.; Georgiadis, M. P. Pol. J. Chem.
1990, 64, 823. (b) Georgiadis, M. P.; Couladoros, E. A. J. Org. Chem.
1986, 51, 2725-2727.
(17) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165.
(18) All new compounds were identified and characterized by 1H NMR,
13C NMR, FTIR, HRMS, and EA analysis.
(14) (a) Taniguchi, T.; Nakamura, K.; Ogasawara, K. Synlett 1996, 971.
(a) Taniguchi, T.; Ohnishi, H.; Ogasawara, K. Chem. Commun. 1996, 1477-
1478. For a review, see: (c) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless,
K. B. Chem. ReV. 1994, 94, 2483-2547.
(15) Enantiomeric excesses were determined by 1H NMR and 19F NMR
of the Mosher ester derivative.
(19) The cis/trans selectivity of the Wittig reaction decreased to 4:1 at 0
°C and to 2:1 at room temperature.
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Org. Lett., Vol. 2, No. 19, 2000

bridgehead hydrogens at C-3a and C-7a, whereas for 11 no
NOE enhancements were detected between the hydrogen at
C-2 to the bridgehead hydrogens at C-3a and C-7a. A pure
sample of 1a was obtained upon treatment with TBSOTf
for 10 min to give a 40% yield of unprotected 1a and a 38%
yield of the TBS-protected isoaltholactone 12.
Scheme 3
Having established the ability to prepare the connectivity
of the altholactone skeleton, we turned our attention to
selectively synthesizing the trans olefin side chain lactone
2b (Scheme 6). Treatment of the aldehyde 7c generated from
To introduce the remaining oxygenation for the altholac-
tone ring system, we needed to epoxidize lactone 2a both
regioselectively and diastereoselectively. Treatment of 2a
with mCPBA yielded 9 in favor of the diastereomer shown
(>10:1), in an 80% yield (Scheme 4). The stereochemistry
Scheme 6
Scheme 4
Dess-Martin oxidation of lactone 6c with the anion of
sulfone 1321 in THF at -78 °C gave the desired 1,2-trans
alkene 2b in 40% yield from 6c and a diastereoselectivity
of >13:1 in favor of the trans alkene.
Deprotection of the TBS group with TBAF gave the styryl-
pyrone natural product 5-hydroxy goniothalamin 14 in 10
steps from furfural and 13% overall yield.
Using the same reaction sequence as before on lactone
2b, we were able to selectively synthesize isoaltholactone
1c (Scheme 7). Treatment of 2b with mCPBA gave epoxide
of the epoxidation was assigned on the basis of the
stereochemistry of the final cyclized product. Deprotection
of the TBS group was accomplished with TBAF, followed
by acid-promoted cyclization with camphor sulfonic acid to
give an inseparable 1:1 mixture of 3-epi-altholactone 1a and
isoaltholactone20 1c in 65% yield over the last two steps.
The inseparable mixture of 3-epi-altholactone 1a and
isoaltholactone 1c was easily separated as benzoates 10 and
11, which were prepared by treatment of a CH2Cl2 solution
of 1a and 1c with BzCl and DMAP (Scheme 5). The relative
Scheme 7
Scheme 5
stereochemistries of benzoates 10 and 11 were confirmed
by a detailed NOE study. Particularly indicative for 10 were
the enhancements between the hydrogen at C-2 to the
15 as the major diastereomer (>10:1) in 80% yield. Depro-
tection of the TBS group was easily achieved with TBAF,
providing 16 in 80% yield. Treating epoxide 16 to the same
(20) Colgate, S. M.; Din, L. B.; Latiff, A.; Matsalleh, K.; Samudin, M.
W.; Skelton, B. W.; Tadano, K. I.; White, A. H.; Zakria, Z. Phytochemistry
1990, 29, 1701-1704.
(21) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26-28.
Org. Lett., Vol. 2, No. 19, 2000
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acid-promoted cyclization with CSA as before yielded
isoaltholactone 1c exclusively in 93% yield. The excellent
stereoselectivity of this acid-catalyzed epoxide opening of
16 is in contrast to that of the opening of 9 which
unfortunately gives a 1:1 mixture of diastereoisomers 1a and
1c. Isoaltholactone 1c was synthesized in 10% overall yield
and 12 steps from furfural with an enantiomeric excess
determined to be >91% ee by Mosher ester analysis.
In conclusion, this highly enantio- and diastereocontrolled
route to R,â-unsaturated δ-lactones 2a and 2b allows access
to a variety of styryllactone natural products including
5-hydroxygoniothalamin, 3-epi-altholactone, and isoaltholac-
tone in 13%, 5%, and 10% overall yields from furfural,
respectively.22 This methodology illustrates the utility of the
enantioselective dihydroxylation reaction of vinylfuran,
eliminating the need for kinetic resolution of 2-furylcarbinols.
The route provides rapid and enantioselective access to R,â-
unsaturated δ-lactones that are useful synthons for natural
product synthesis from a commercially available, inexpensive
starting material. Further biological evaluation of these
diastereomers as well as the synthesis of other styryllactone
natural products will be reported in due course.
Acknowledgment. We thank the University of Minnesota
(grant in aid program), the American Cancer Society for an
Institutional Research Grant (IRG-58-001-40-IRG-19), the
Petroleum Research Fund, administered by the American
Chemical Society (ACS-PRF#33953-G1), and the Arnold and
Mabel Beckman Foundation for their generous support of
our program.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds as well as experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Our spectral data for synthetic 1a, 11, and 1c (1H NMR, 13C NMR,
FTIR, HRMS, and optical rotation) matched the data for the isolated
material.
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