Enantioselective synthesis of 5-substituted α,β-unsaturated δ- lactones: Application to the synthesis of styryllactones

Article abstract of DOI:10.1016/S0040-4039(99)02050-X

A flexible enantioselective synthesis of highly funcfionalized 5- substituted α,β-unsaturated δ-lactones has been achieved by applying the sharpless catalytic asymmetric dihydroxylation to vinylfuran as the key step. The resulting diols are produced in high enantio excess and can be stereoselectively transformed into differentially protected δ-lactones through a short reaction sequence.

Full text of DOI:10.1016/S0040-4039(99)02050-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 183–187
Enantioselective synthesis of 5-substituted α,β-unsaturated
δ-lactones: application to the synthesis of styryllactones
Joel M. Harris and George A. O’Doherty ∗
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Received 20 September 1999; accepted 22 October 1999
Abstract
A flexible enantioselective synthesis of highly functionalized 5-substituted α,β-unsaturated δ-lactones has been
achieved by applying the Sharpless catalytic asymmetric dihydroxylation to vinylfuran as the key step. The
resulting diols are produced in high enantio excess and can be stereoselectively transformed into differentially
protected δ-lactones through a short reaction sequence. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Sharpless dihydroxylation; asymmetric synthesis; lactones; carbohydrates.
Substituted α,β-unsaturated δ-lactones (e.g. styryllactones) 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 structural motif, such as goniodiol, acetylpho-
malactone, and altholactone.1d These natural products have biological activity including antitumor and
antifungal properties, as well as antibiotic potential. 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
One of the most useful methodologies employed is the kinetic resolution of 2-furylcarbinols developed
by Honda,3 Sato,4 and augmented by Zhou.5 This strategy employs the kinetic resolution of racemic 2-
furylcarbinols with the Sharpless epoxidation reaction conditions, to produce an optically active pyranone
product resulting from the selective fast oxidation of only one enantiomer of the racemic 2-furylcarbinols.
The optically pure pyranone or 2-furylcarbinol products of the kinetic resolution can both be used in the
synthesis of natural products.
Recently, we developed an expeditious route to various D- or L-sugars from furan diols using Sharpless
dihydroxylation to establish the absolute stereochemistry.6 Continuing our investigations on the utility of
this strategy, we turned our attention to the styryllactone class of natural products. For the synthesis of
these natural products we envisioned δ-lactones 3 as excellent building blocks amenable for the synthesis
of a variety of styryllactones (Scheme 1). We envisioned extending our earlier work to synthesize these
∗
Corresponding author.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02050-X
tetl 15978

184
useful building blocks from pyranone 6 with differentiated oxygen functionality in a limited number of
steps and avoiding kinetic resolution. Herein, we describe our approach to the synthesis of these key
building blocks via an efficient enantioselective and diastereoselective oxidation and reduction sequence.
Scheme 1.
A key intermediate in our six-step enantioselective route to D- and L-hexoses from furfural was
pyranone 6a (Scheme 2). The asymmetry of 6a was derived from diol 2, which can be prepared on
a one mole scale from a Sharpless dihydroxylation7 of vinylfuran in 90–92% ee, and recrystallized to
>97% ee8 from the dibenzoate formed from diol 2. Protection of diol 2 with either TBSCl or PivCl yields
the mono-protected furans 4a or 4b in 90% and 70% yields, respectively. Using NBS9 furans 4a or 4b
can be oxidatively ring expanded to yield enones 5a and 5b in 95% yield. Protection of enone 5a or 5b
with BzCl at −78°C yielded 6a exclusively and 6b in a 7:1 ratio with the axial benzoate predominating in
75% yield. With this expedient and enantioselective route to benzoate 6a or 6b, we initially investigated
a synthesis of 3 from 6a or 6b.
Scheme 2.
Luche reduction10 of enone 6a or 6b provides 7 in >96% ee,8 followed by protection provided allylic
alcohol 7a or 7b as a single diastereomer in 75% yield over two steps. Deprotection of the anomeric
benzoyl group proved troublesome, with the best results obtained using Et3N, MeOH, H2O in a 1:5:1
ratio, giving lactol 8a or 8b in 50–60% yield. Oxidation of 8a or 8b with MnO2 provided the α,β-
unsaturated δ-lactone 9a or 9b in 75–85% yield.11
Having established the feasibility of preparing the α,β-unsaturated δ-lactone 9a and 9b with complete
enantio- and diastereocontrol, we turned our attention to improving the efficiency of the route to 3. The
obvious disadvantage of the route in Scheme 2 is the requisite protection of the C-1 and C-4 hydroxyl
groups. A significant reduction in steps could be achieved by oxidation of the lactol 5 to ketolactone
10 provided the carbonyl groups could be reductively differentiated (Scheme 3). Similar approaches
have been used by other groups using CrO3 and acetic acid.12 A potential problem of this shorter

185
route is the possible racemization or β-elimination in the ketolactone. We envisioned using a reagent
for fast oxidation of lactol 5 to ketolactone 10 that would be immediately compatible for exposure to
Luche conditions.13 This was most easily accomplished by Jones oxidation followed by Luche reduction
(Scheme 3).
Scheme 3.
Treatment of an acetone solution of 5a or 5b with a slight excess of Jones reagent produced
ketolactones 10a or 10b in ∼20 min. Upon completion the reaction mixture was quenched with isopropyl
alcohol, washed with a saturated NaHCO3 solution, and extracted with ether. After solvent exchange
(ether to MeOH), 10a14 and 10b were treated with NaBH4 to yield differentially protected δ-lactones
11a15 or 11b in 60–70% yield over two-steps with no loss of enantiomeric excess.8 The observed
stereoselectivity of the reduction is explained by the apparent hydride attack on the less hindered face of
the molecule.16 Protection of the allylic alcohol using PivCl, Ac2O, or ClCO2Et provided 12a, 12b, or
12c17 in 80%, 94%, and 90% yields, respectively. The diastereomeric lactone 1318 can be prepared from
11a by a Mitsunobu reaction19 followed by hydrolysis of the p-nitro-benzoyl group in 70% yield over
two-steps (Scheme 4). This not only provides a shorter route to 11 and 13, but also provides the δ-lactone
in a higher overall yield (∼45% to 11 and 32% to 13 from diol 2 as compared to ∼20% to 9 from diol 2).
Scheme 4.
In conclusion, this highly enantio- and diastereocontrolled route to the δ-lactones described 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 a densely
functionalized molecule starting from a commercially available, inexpensive starting material. Further
studies on the use of these chiral building blocks toward the synthesis of this class of natural products
will be reported in due course.

186
Acknowledgements
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) and the American Chemical Society — Petroleum
Research Fund (ACS-PRF#33953-G1) for their generous support of our program.
References
1. (a) Yasui, K.; Tamura, Y.; Nakatani, T.; Kawada, K.; Ohtani, M. J. Org. Chem. 1995, 60, 7567–7574 and references cited
therein. (b) Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; McLaughlin, J. L.; Fanwick, P. E. J. Nat. Prod. 1991, 54, 1034. (c)
Argoudelis, A. D.; Zieserl, J. F. Tetrahedron Lett. 1966, 18, 1969. (d) For a review of 5,6-dihydro-2H-pyran-2-ones, see:
Davies-Coleman, M. T.; Rivett, D. E. A. 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, 2493–2514. (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. 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 & Sons: New York, 1993; pp. 3–131; 271–396.
3. (a) Kametani, T.; Tsubuki, M.; Tatsuzaki, Y.; Honda, T. Heterocycles 1988, 27, 2107–2110. (b) Kametani, T.; Tsubuki, M.;
Tatsuzaki, Y.; Honda, T. J. Chem. Soc., Perkin Trans. 1 1990, 639–646. (c) Honda, T.; Kametani, T.; Kanai, K.; Tatsuzaki,
Y.; Tsubuki, M. J. Chem. Soc., Perkin Trans. 1 1990, 1733–1737.
4. (a) Kobayashi, Y.; Kusakabe, M.; Kitano, Y.; Sato, F. J. Org. Chem. 1988, 53, 1587–1590. (b) Kusakabe, M.; Kitano, Y.;
Kobayashi, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085–2091.
5. (a) Yang, Z.-C.; Zhou, W.-S. Tetrahedron Lett. 1995, 36, 5617–5618. (b) Yang, Z.-C.; Jiang, X.-B.; Wang, Z.-M.; Zhou,
W.-S. J. Chem. Soc., Chem. Commun. 1995, 2389. (c) see Ref. 2e.
6. Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem. 1999, 64, 2982–2983.
7. (a) Taniguchi, T.; Nakamura, K.; Ogasawara, K. Synlett 1996, 971. (b) 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.
8. Enantiomeric excesses were determined by 1H NMR and 19F NMR of the Mosher ester derivative.
9. (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.
10. Luche, J.-L. J. Am. Chem. Soc. 1978, 110, 2226.
11. The absolute and relative stereochemistry of 9a and 9b were determined by correlation to our previous syntheses of a
protected gulose and talose whose stereochemistry were determined by X-ray crystal analysis, see Ref. 6.
12. (a) Kuo, Y.-H.; Shih, K.-S. Heterocycles 1990, 31, 1941–1949. (b) Tsubuki, M.; Kanai, K.; Honda, T. J. Chem. Soc., Chem.
Commun. 1992, 1640–1641. (c) Zhou, W.-S.; Yang, Z.-C. Tetrahedron Lett. 1993, 34, 7075–7076. (d) see Refs. 2e, 2h.
13. Ketolactone 10 decomposed when attempting to purify by silica gel chromatography.
14. Preparation of compound 10a was easily accomplished by dissolving 5a in acetone, followed by dropwise addition of Jones
reagent until the starting material was absent by TLC (∼15–20 min) and the reaction was quenched with isopropyl alcohol,
washed with sat. NaHCO3, extracted with ether, and dried with MgSO4. Data for compound 10a: [α]2D1=+55.77 (c=3.71,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 6.86 (d, J=10 Hz, 1H); 6.73 (d, J=10 Hz, 1H); 4.83 (dd, J=1.5, 2 Hz, 1H); 4.01 (dd,
J=1.5, 12.5 Hz, 1H); 3.97 (dd, J=2, 12.5 Hz, 1H); 0.74 (s, 9H); −0.04 (s, 3H); −0.07 (s, 3H); 13C NMR (125 MHz, CDCl3,
ppm) δ 192.3, 160.5, 138.8, 136.1, 84.3, 65.1, 25.4, 17.9, −5.9, −6.0; IR (thin film, cm−1) 3949, 2928, 2892, 2856, 1719,
1697, 1461, 1360, 1306, 1261, 1128, 1083, 1023; HR CIMS calcd for [(C12H20O4Si)+H]+: 257.12091, Found: 257.1218.
Anal. calcd for C12H20O4Si: C, 56.23; H, 7.87. Found: C, 56.10; H, 7.68.
15. Data for compound 11a: [α]2D1=−73.18 (c=0.9, CH2Cl2); 1H NMR (500 MHz, C6D6) δ 6.25 (dd, J=6, 9.5 Hz, 1H); 5.73 (d,
J=9.5 Hz, 1H); 3.96 (dd, J=7, 10 Hz, 1H); 3.87 (ddd, J=3, 5, 7 Hz, 1H); 3.79 (dd, J=5, 10 Hz, 1H); 3.76 (m, 1H); 3.00 (bs,
1H); 0.98 (s, 9H); 0.08 (s, 3H); 0.07 (s, 3H); 13C NMR (125 MHz, C6D6, ppm) δ 163.1, 144.2, 122.7, 79.9, 61.7, 60.4, 26.0,

187
18.4, −5.3, −5.4; IR (thin film, cm−1) 3424, 2954, 2930, 2885, 2857, 1714, 1472, 1257, 1137, 1098, 1059; HR CIMS calcd
for [(C12H22O4Si)+H]+: 259.13656, Found: 259.1355. Anal. calcd for C12H22O4Si: C, 55.79; H, 8.59. Found: C, 55.63; H,
8.45.
16. Various selectivities have been observed depending on the steric bulk of the substituent at C-5. (a) Honda, T.; Takada, H.;
Miki, S.; Tsubuki, M. Tetrahedron Lett. 1993, 34, 8275–8278. (b) Tsubuki, M.; Takada, H.; Katoh, T.; Miki, S.; Honda, T.
Tetrahedron 1996, 52, 14515–14532. (c) see Refs. 2e, 5a, 11a–c.
17. All new compounds were identified and characterized by 1H NMR, 13C NMR, FTIR, HRMS, and EA analysis.
18. Data for compound 13: [α]2D1=−20.45 (c=1.11, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 6.83 (dd, J=2.5, 10 Hz, 1H); 5.95
(dd, J=2, 10 Hz, 1H); 4.64 (ddd, J=2, 5.5, 9.5 Hz, 1H); 4.31 (ddd, J=4, 7, 9.5 Hz, 1H); 4.04 (dd, J=4, 10.5 Hz, 1H); 3.89
(dd, J=7, 10.5 Hz, 1H); 3.30 (bs, 1H); 0.90 (s, 9H); 0.12 (s, 6H); 13C NMR (125 MHz, CDCl3, ppm) δ 162.4, 148.8, 119.6,
80.0, 65.5, 64.0, 25.7, 18.2, −5.56, −5.58; IR (thin film, cm−1) 3432, 2954, 2929, 2857, 1712, 1472, 1256, 1138, 1101,
1055, 1025; HR CIMS calcd for [(C12H22O4Si)+H]+: 258.12874, Found: 259.1389. Anal. calcd for C12H22O4Si: C, 55.79;
H, 8.59. Found: C, 55.61; H, 8.59.
19. Mitsunobu, O. Synthesis 1981, 1.