manipulations of the molecule prior to the conversion into the
lactone or hydroxy acid.
Conclusions
In conclusion, we present a general and efficient enantioselective
synthesis for alkanolides, alkenolides and hydroxy fatty acids
(>99% ee) that utilizes only simple and readily available reagents.
The procedure provides the target compounds in only three steps,
high overall yields and very high enantiomeric excess (≥99%,
depending on the ee of the starting oxirane).
Scheme 6 Synthesis of 3,4-dihydroisocoumarins.
Acknowledgements
two steps and 87% overall yield and 99% ee as shown in Scheme 6
without the need for a kinetically controlled lactonization for
enhancement of the ee as described in ref. 45.
Financial support of this work by the Deutsche Forschungsge-
meinschaft, SFB 436 “Metal Mediated Reactions Modeled After
Nature” is gratefully acknowledged.
By modification of the work-up procedure of the oxidative
degradation, chiral hydroxy fatty acids also become available
since the ring-closure of lactones (>C6) is no longer spontaneous.
For example, (S)-12-hydroxyoctadecanoic acid was obtained in
only two steps (Scheme 7) from (S)-1,2-epoxyoctane and dec-9-
enyl magnesium bromide. With acetylenic epoxides or Grignard
reagents, the sequence can also be applied to generate unsaturated
hydroxy acids.
References
1 R. Kaiser, Chem. Biodiversity, 2004, 1, 13–27.
2 J. C. G. Galindo, A. P. de Luque, J. Jorrin and F. A. Macias, J. Agric.
Food Chem., 2002, 50, 1911–1917.
3 W. Francke and S. Schulz, Comprehensive Natural Products Chemistry,
ed. D. H. R. Barton and K. Nakanishi, Elsevier, Amsterdam, 1999.
4 M. Miyazawa, H. Shimabayashi, S. Hayashi, S. Hashimoto, S. Naka-
mura, H. Kosaka and H. Kameoka, J. Agric. Food Chem., 2000, 48,
5406–5410.
5 M. T. Scotti, M. B. Fernandes, M. J. P. Ferreira and V. P. Emerenciano,
Bioorg. Med. Chem., 2007, 15, 2927–2934.
6 M. L. Entman, J. W. Cook and R. Bressler, Circ. Res., 1969, 24, 793–
798.
7 D. Lehmann, B. Maas and A. Mosandl, Z. Lebensm.-Unters.-Forsch.
A, 1995, 201, 55–61.
8 K. H. Engel, R. A. Flath, R. G. Buttery, T. R. Mon, D. W. Ramming
and R. Teranishi, J. Agric. Food Chem., 1988, 36, 549–553.
9 J. A. Maga, CRC Crit. Rev. Food Sci. Nutr., 1976, 1–56.
10 W. H. Pirkle and P. E. Adams, J. Org. Chem., 1979, 44, 2169–2175.
11 E. Fukusaki and S. Satoda, J. Mol. Catal. B: Enzym., 1997, 2, 257–269.
12 A. L. Gutman, K. Zuobi and T. Bravdo, J. Org. Chem., 1990, 55, 3546–
3552.
Scheme 7 Synthesis of chiral hydroxy fatty acids.
13 E. Santaniello, P. Ferraboschi, P. Grisenti and A. Manzocchi, Chem.
The major advantage of the protocol is the easy and efficient
access to a wide range of chiral terminal epoxides and Grignard
reagents, which allow an efficient and flexible synthesis of the
target molecule. In combination with the remarkable tolerance
of the OsO4–Oxone system towards functional groups, in partic-
ular secondary alcohols, alkynes and aromatic systems, a direct
conversion of the olefinic alcohol into c- and d-lactones could be
achieved (Table 1). The terminal double bond can be additionally
exploited as a valuable masked carboxyl group, allowing further
Rev., 1992, 92, 1071–1140.
14 E. Santaniello, P. Ferraboschi and P. Grisenti, Enzyme Microb. Technol.,
1993, 15, 367–382.
15 D. G. Hayes, J. Am. Oil Chem. Soc., 1996, 73, 543–549.
16 M. M. Enzelberger, U. T. Bornscheuer, I. Gatfield and R. D. Schmid,
J. Biotechnol., 1997, 56, 129–133.
17 M. D. Mihovilovic, Curr. Org. Chem., 2006, 10, 1265–1287.
18 S. M. Roberts and P. W. H. Wan, J. Mol. Catal. B: Enzym., 1998, 4,
111–136.
19 S. K. Taylor, C. R. Arnold, A. T. Gerds, N. D. Ide, K. M. Law, D. L.
Kling, M. G. Pridgeon, L. J. Simons, J. R. Vyvyan and J. S. Yamaoka,
Tetrahedron: Asymmetry, 2004, 15, 3819–3821.
20 J. A. Pollock, K. M. Clark, B. J. Martynowicz, M. G. Pridgeon, M. J.
Rycenga, K. E. Stolle and S. K. Taylor, Tetrahedron: Asymmetry, 2007,
18, 1888–1892.
21 C. Forzato, R. Gandolfi, F. Molinari, P. Nitti, G. Pitacco and E.
Valentin, Tetrahedron: Asymmetry, 2001, 12, 1039–1046.
22 H. C. Brown, S. V. Kulkarni and U. S. Racherla, J. Org. Chem., 1994,
59, 365–369.
23 T. Benincori, S. Rizzo, T. Pilati, A. Ponti, M. Sada, E. Pagliarini,
S. Ratti, C. Giuseppe, L. de Ferra and F. Sannicolo, Tetrahedron:
Asymmetry, 2004, 15, 2289–2297.
24 D. F. Taber, P. B. Deker and M. D. Gaul, J. Am. Chem. Soc., 1987, 109,
7488–7494.
Table 1 Representative examples
Overall
yield (%)
Entry
Compound
ee (%)
1
2
3
4
5
6
7
(4S)-Octan-4-olide
>99
>99
>99b
>99
>99b
>99
>99
70
75
71
74
64
87
57
(4S)-Dodecan-4-olide
(5S)-Tridecan-5-olide
(4S,6Z)-Dodec-6-en-4-olide
(4R,9Z)-9-Octadecen-4-olide
(S)-3-Hexyl-isochroman-1-one
(12S)-12-Hydroxy-octadecanoic acid
25 M. Movassaghi and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124,
a Enantiomeric excess (ee) was determined by chiral gas chromatography
(for details see ESI†). b ee was determined for alcohol precursors.
2456–2457.
26 C. G. Yang, N. W. Reich, Z. J. Shi and C. He, Org. Lett., 2005, 7,
4553–4556.
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