Stereocontrolled syntheses of carotenoid oxidative metabolites, (-)-loliolide, (-)-xanthoxin, and their stereoisomers

Article abstract of DOI:10.1246/cl.2002.1248

We achieved the stereocontrolled syntheses of (-)-loliolide, (-)-xanthoxin, and their stereoisomers from (+)- or (-)-3-alkoxy-6-hydroxymethyl-1,1,5-trimethylcyclohexene through the corresponding syn and anti-epoxides, respectively, which were obtained by utilizing the highly diastereoselective Sharpless asymmetric epoxidation or mCPBA oxidation.

Full text of DOI:10.1246/cl.2002.1248

1248
Chemistry Letters 2002
Stereocontrolled Syntheses of Carotenoid Oxidative Metabolites,
(À)-Loliolide, (À)-Xanthoxin, and Their Stereoisomers
Masako Kuba, Noriyuki Furuichi, and Shigeo Katsumuraꢀ
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda, Hyogo 669-1337
(Received September 6, 2002; CL-020766)
We achieved the stereocontrolled syntheses of (ꢁ)-loliolide,
(ꢁ)-xanthoxin, and their stereoisomers from (þ)- or (ꢁ)-3-
alkoxy-6-hydroxymethyl-1,1,5-trimethylcyclohexene through
the corresponding syn and anti-epoxides, respectively, which
were obtained by utilizing the highly diastereoselective Sharpless
asymmetric epoxidation or mCPBA oxidation.
stereoisomers.
The desirable high diastereoselectivity was achieved by
finding the precise reaction conditions for the Sharpless
asymmetric epoxidation10 of 3.9 Thus, it was essential that all
reagents and solvents must be freshly distilled, the use of the strict
equivalent of the reagents was required ((ꢁ)-diethyl-D-tartrate
(0.3 eq.), Ti(OiPr)4 (0.2 eq.), and tert-butylhydroperoxide
(2.0 eq.)), and the reaction temperature (ꢁ20 ꢂC) was
controlled. Under these precise reaction conditions, we
obtained the desired anti-epoxide 4 in 99% yield and 92%
de (Scheme 1).11 Meanwhile, the epoxidation of 3 with
mCPBA surprisingly produced the syn-epoxide 5 with high
diastereoselectivity (94% de). The epoxides 4 and 5 were then
transformed into the corresponding aldehydes A and B by the
Swern oxidation, respectively.12 Furthermore, aldehydes C
and D were stereoselectively obtained from the (3S)-hydroxy
ketone 6 by the same procedure.
Most of the oxidative metabolites of the carotenoids possess
an eleven, thirteen, or fifteen carbon skeleton. Among them,
loliolide1 and xanthoxin2 in addition to abscisic acid,3 have been
paid much attention because of their interesting biological
activities. (ꢁ)-Loliolide (1a), which has been detected in many
higher plants and marine mollusks, are well-known to have
immunosuppressive, germination inhibitory, and repellent
activities.4 Its C-5 stereoisomer (carotenoid numbering), (þ)-
epiloliolide (1b), was also isolated from various sources, which
was found to show comparable cytotoxicity to (ꢁ)-loliolide.5
(ꢁ)-Xanthoxin (2) has been proposed as a precursor of (þ)-
abscisic acid,6 which is the primary plant hormone controlling
many biological plant processes such as acceleration of abscis-
sion, induction of dormancy, and inhibition of rooting, and it
shows similar biological activities to abscisic acid. Although a
number of synthetic efforts of these terpenoids and their
derivatives including the racemic form have been reported,7;8
only a few report controlled their stereochemistry. In particular,
controlling the relative stereochemistry between the C-3 and C-5
asymmetric carbons has remained as one of the essential unsolved
subjects in the synthesis of carotenoids and their oxidative
metabolites.
Scheme 1. Reagents and condition: a) (ꢁ)-diethyl-D-tartrate, Ti(OiPr)4,
ꢂ
ꢀ
1.5 M TBHP in toluene, MS 4 A, C HCl2, ꢁ20 C, 30 min, 99%, 92% de;
2
b) mCPBA, CH2Cl2, rt, 1 h, 90%, 94% de; c) (COCl)2, DMSO, C HCl2,
2
ꢁ78 ꢂC, 40 min; Et3N, 10 min, 100%.
We then examined the efficient synthesis of (ꢁ)-loliolide
from the epoxyaldehyde A. After several trials, we succeeded in
the stereoselective synthesis of (ꢁ)-loliolide via the Wittig
olefination with (trimethylsilyl)ethoxymethyltriphenylphospho-
nium bromide 7.13 Thus, the Wittig reaction of A with 7 yielded
the corresponding olefin 8 as a mixture of stereoisomers (Scheme
2). The acid treatment of the obtained crude olefin 8 produced the
lactol 9, which was oxidized with MnO2 and then treated with
TBAF to produce (ꢁ)-loliolide (1a) in 37% yield from A. The
spectral and physical data of the synthesized (ꢁ)-loliolide were in
good agreement with those already reported.14 The aldehydes B–
D were also transformed into (þ)-epiloliolide (1b; 40% yield
from B) and their enantiomers by the same procedure,
respectively. This is a new and efficient route for the synthesis
of optically active loliolide.
Figure 1.
Recently, during the course of our synthetic study of the
polyfunctional carotenoid, peridinin,9 we achieved the stereo-
selective synthesis of the optically active epoxyaldehyde
derivative A, which would be applicable for the syntheses of
carotenoids and the related natural products as a common chiral
intermediate. Herein, we disclose the stereocontrolled prepara-
tion of all its stereoisomers, B, C, and D, and the efficient total
syntheses of (ꢁ)-loliolide (1a), (ꢁ)-xanthoxin (2), and their
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1249
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture of Japan, and The San-Ei Gen Foundation for
Food Chemical Research. N. F. is grateful to the JSPS for a
research Fellowship for Young Scientists.
References and Notes
1
R. H. F. Manske, Can. J. Res., Sect. B, 16, 438 (1938); R. Hodges and A. L. Porte,
Tetrahedron, 20, 1463 (1964); T. Wada and D. Satoh, Chem. Pharm. Bull., 12, 752
(1964); G. R. Pettit, C. L. Herald, R. H. Ode, P. Brown, D. J. Gust, and C. Michel, J.
Nat. Prod., 43, 752 (1980).
2
R. S. Burden and H. F. Taylor, Tetrahedron Lett., 47, 4071 (1970); H. F. Taylor
and R. S. Burden, Proc. R. Soc. London, Ser. B, 180, 317 (1972); R. S. Burden and
H. F. Taylor, Pure Appl. Chem., 47, 203 (1976); M. Kobayashi, A. Kawabata, A.
Chindanondra, and A. Sakurai, Agric. Biol. Chem., 54, 2723 (1990).
F. T. Addicott, ‘‘Abscisic Acid,’’ Praeger, New York, NY (1983).
M. Kuniyoshi, Bot. Mar., 28, 501 (1985); A. L. Okunabe and D. F. Weimer, J. Nat.
Prod., 48, 472 (1985).
3
4
5
D. Behr, I. Wahlberg, T. Nishida, and C. R. Enzel, Acta Chem. Scand., Ser. B, 33,
701 (1979); B. N. Ravi, P. T. Murphy, R. O. Lidgard, R. G. Warren, and R. J.
Wells, Aust. J. Chem., 35, 171 (1982); F. J. Schmitz, D. J. Vanderah, K. H.
Hollenbeak, C. E. L. Enwall, Y. Gopichand, P. K. SanGupta, M. B. Hossain, and
D. van der Heim, J. Org. Chem., 48, 3941 (1983).
6
7
Recent review: A. J. Cutler and J. E. Krochko, Trends Plant Sci., 4, 472 (1999).
For loliolide: Z. Horii, T. Yanai, and M. Hanaoka, Chem. Commun., 1966, 634; E.
Demole and P. Enggist, Helv. Chim. Acta, 51, 481 (1968); Z. Horii, T. Yanagi, M.
Ito, and M. Hanaoka, Chem. Pharm. Bull., 16, 848 (1968); S. Isoe, S. B. Hyeon, S.
Katsumura, and T. Sakan, Tetrahedron Lett., 1972, 2517; O. Takazawa, K.
Kogami, and K. Hayashi, Chem. Lett., 1983, 63; F. Rouessac, H. Zamarlik, and N.
Gnonlofoun, Tetrahedron Lett., 24, 2247 (1983); H. Zamarlik, N. Gnonlonfoun,
and F. Rouessac, Can. J. Chem., 62, 2326 (1984); K. Mori and V. Khlebnikov,
Liebigs Ann. Chem., 1993, 77.
8
9
For xanthoxin: T. Oritani and K. Yamashita, Agric. Biol. Chem., 37, 1215 (1973);
F. Kienzle, H. Mayer, R. E. Minder, and H. Thommen, Helv. Chim. Acta, 61, 2616
(1978); K. Sakai, K. Takahashi, and T. Nukano, Tetrahedron, 48, 8229 (1992); H.
Yamamoto and T. Oritani, Planta, 200, 319 (1996), in which there is no
description concerning the diastereoselectivity.
N. Furuichi, H. Hara, T. Osaki, H. Mori, and S. Katsumura, Angew. Chem., 114,
1065 (2002); N. Furuichi, H. Hara, T. Osaki, H. Mori, and S. Katsumura, Angew.
Chem., Int. Ed., 41, 1023 (2002).
Scheme 2. Reagents and conditions: a) 7, tBuOK, ether, rt, 1 h; b) 1N HCl aq.,
THF, rt, 5 min; c) MnO2, ether, rt, 2 h, 49% for 3 steps; d) TBAF, THF, rt, 2 h,
76%; e) ClCH2PþPh3Clꢁ, nBuLi, THF, ꢁ30 ꢂC, 3 h; f) tBuOK, DMSO, rt,
20 min, 53% for 2 steps; g) nBu3SnH, PdCl2(PPh3)2, THF, rt, 10 min; h) 12,
PdCl2(CH3CN)2, CuI, DMF, 50 ꢂC, 20 h, 64% for 2 steps; i) LiAlH4, THF,
ꢁ25 ꢂC, 10 min, 83%; j) MnO2, ether, rt, 5 h, 92%.
10 T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 102, 5976 (1980); R. M.
Hanson and K. B. Sharpless, J. Org. Chem., 51, 1922 (1986); Y. Gao, R. M.
Hanson, J. M. Klunder, S. Y. Ko, H. Masamune, and K. B. Sharpless, J. Am. Chem.
Soc., 109, 5765 (1987).
Next, we examined the stereocontrolled synthesis of (ꢁ)-
xanthoxin and its stereoisomers. Thus, an acetylene derivative 10,
which was obtained from the epoxyaldehyde A9 was regio- and
stereoselectively transformed into (E)-vinylstannane 11 by the
Pd-catalyzed hydrostannylation (Scheme 2). The Stille coupling
of 11 with an ester 1215 in the presence of catalytic amounts of
PdCl2(CH3CN)2 and CuI in DMF smoothly proceeded, and the
corresponding couplingproduct 14 was obtained in 64% yield in 2
steps under complete retention of its stereochemistry. The
reaction of 11 with alcohol 13 unfortunately gave a complex
mixture due to the decomposition of the coupling product. The
synthesis of (ꢁ)-xanthoxin (2) was achieved by the hydride
reduction of 14 followed by MnO2 oxidation of the resulting allyl
alcohol moiety. The spectral and physical data of the synthesized
(ꢁ)-xanthoxin were in good agreement with those already
reported.16 Furthermore, the aldehyde B–D was transformed into
the corresponding stereoisomers of (ꢁ)-xanthoxin ((ꢁ)-epix-
anthoxin; 26% yield form B) by the same procedure. The
utilization of the Pd-catalyzed coupling thus demonstrated is a
new approach for the synthesis of xanthoxin and related
compounds.
11 In the Sharpless epoxidation of 3 with (þ)-diethyl-L-tartrate, the precise
reaction conditions applied in the case of (ꢁ)-diethyl-D-tartrate were not
needed, and the corresponding syn-epoxide 5 was obtained in 90–95% de
under reported conditions.10
22
12 Data for A: [ꢀ]D ꢁ76:84 (c 0.84, CHCl3); 1H NMR (400 MHz, CDCl3) ꢁ9.80 (s,
1H), 3.85 (m, 1H), 2.24 (ddd, 1H, J ¼ 14:6, 5.4, 1.2 Hz), 1.71 (dd, 1H, J ¼ 14:9,
7.6 Hz), 1.49 (ddd, 1H, J ¼ 13:2, 3.4, 1.2 Hz), 1.38 (s, 3H), 1.28 (dd, 1H, J ¼ 13:2,
9.0 Hz), 1.28 (s, 3H), 1.07 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13CNMR
(100 MHz, CDCl3) ꢁ 200.40, 72.25, 66.13, 64.19, 46.28, 40.78, 33.55, 27.99,
25
26.21, 25.78, 20.59, 18.01, ꢁ4:79, ꢁ4:84. Data for B: [ꢀ]D þ21:58 (c 1.41,
CHCl3); 1H NMR (400 MHz, CDCl3) ꢁ 9.67 (s, 1H), 3.85 (m, 1H), 2.06 (ddd, 1H,
J ¼ 14:9, 7.6, 1.5 Hz), 1.88 (dd, 1H, J ¼ 14:9, 9.0 Hz), 1.55 (dd, 1H, J ¼ 12:4,
12.4 Hz), 1.36 (s, 3H), 1.31 (s, 3H), 1.16 (ddd, 1H, J ¼ 12:7, 4.2, 1.5 Hz), 1.07 (s,
3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) ꢁ
201.58, 73.02, 64.82, 63.54, 43.91, 39.59, 34.02, 26.33, 25.75, 23.96, 21.59, 18.02,
ꢁ4:66, ꢁ4:72.
13 K. Schonauer and E. Zbiral, Tetrahedron Lett., 24, 573 (1983).
21
14 Data for (ꢁ)-loliolide (1a): mp 150.5–151.5 ꢂC; [ꢀ]D ꢁ103:13 (c 0.79, CHCl3);
IR (KBr, cmꢁ1) 3436, 2978, 2924, 1734, 1721, 1620; 1H NMR (400 MHz, CDCl3)
ꢁ 5.69 (s, 1H), 4.33 (m, 1H), 2.48 (ddd, 1H, J ¼ 13:9, 2.9, 2.9 Hz), 2.25 (brm, 1H),
2.00 (ddd, 1H, J ¼ 14:4, 2.4, 2.4 Hz), 1.79 (s, 3H), 1.78 (dd, 1H, J ¼ 13:9, 4.2 Hz),
1.52 (dd, 1H, J ¼ 14:6, 3.7 Hz), 1.48 (s, 3H), 1.27 (s, 3H); 13CNMR (100 MHz,
CDCl3) ꢁ 182.90, 172.15, 112.64, 86.99, 66.54, 47.17, 45.52, 35.93, 30.58, 26.90,
26.39; Anal. Found: C, 67.01; H, 8.22%. Calcd for C11H16O3: C, 67.32; H, 8.22%.
15 S. Ma and X. Lu, Tetrahedron Lett., 31, 7653 (1990); I. Marek, A. Alexakis, and J.
F. Normant, Tetrahedron Lett., 32, 5329 (1992).
In conclusion, we achieved the efficient stereocontrolled
syntheses of (ꢁ)-loliolide, (ꢁ)-xanthoxin, and their stereoi-
somers. This is the first example that the stereochemistry in the
every stereoisomers of these oxidized metabolites has been
satisfactorily controlled. Our future interest is in the relationship
between the stereochemistry of our synthesized carotenoid
metabolites and their biological activities.
21
16 Data for (ꢁ)-xanthoxin (2): mp 90.0–91.0 ꢂC; [ꢀ]D ꢁ53:30 (c 0.88, CHCl3); IR
(KBr, cmꢁ1) 3501, 2932, 1659, 1628, 1588; 1H NMR (400 MHz, CDCl3) ꢁ 10.71
(d, 1H, J ¼ 8:3 Hz), 7.19 (d, 1H, J ¼ 15:4 Hz), 6.37 (d, 1H, J ¼ 15:4 Hz), 5.85 (d,
1H, J ¼ 7:8 Hz), 3.88 (m, 1H), 2.38 (ddd, 1H, J ¼ 14:4, 5.2, 1.5 Hz), 2.08 (d, 3H,
J ¼ 0:6 Hz), 1.60–1.70 (m, 2H), 1.25 (m, 1H), 1.19 (s, 3H), 1.18 (s, 3H), 0.97 (s,
3H); 13C NMR (100 MHz, CDCl3) ꢁ 190.39, 153.27, 134.60, 128.95, 127.78,
70.02, 67.28, 63.87, 46.70, 40.64, 35.14, 29.37, 24.95, 21.07, 19.88; Anal. Found:
C, 71.98; H, 8.93%. Calcd for C15H22O3: C, 71.97; H, 8.86%.