A stereocontrolled route to cyclohexylethanoid natural products

Article abstract of DOI:10.1055/s-1998-1851

Rengyol and seven related cyclohexylethanoid natural products have been synthesized in a stereocontrolled manner from a common starting material. In the present study the absolute configuration of the three chiral products has been determined and the first synthesis of a cyclohexylethanoid natural product bearing an oxetane ring has been accomplished.

Full text of DOI:10.1055/s-1998-1851

September 1998
SYNLETT
1001
A Stereocontrolled Route to Cyclohexylethanoid Natural Products
Masatoshi Honzumi, Takashi Kamikubo, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81-22-217-6845; E-mail konol@mail.cc.tohoku.ac.jp
Received 16 June 1998
Abstract: Rengyol and seven related cyclohexylethanoid natural
products have been synthesized in a stereocontrolled manner from a
common starting material. In the present study the absolute
configuration of the three chiral products has been determined and the
first synthesis of a cyclohexylethanoid natural product bearing an
oxetane ring has been accomplished.
of these natural products 1 – 8 from a common starting material which
determined the configuration of 5 having an oxetane ring and the
absolute configurations of 6 – 8.
8
The tricyclic enone , mp 79-80 °C, obtained diastereoselectively by
10
9
the Lewis acid-mediated reaction of the dienone
and
9
cyclopentadiene, was used as the common starting material. 1,2-
10
Reduction of
occurred stereoselectively from the convex face to
10
1,2
give the endo-alcohol (±)- . Kinetic resolution of (±)- occurred
11 11
In 1984, Endo and Hikino first isolated rengyol 1 and rengyoxide 2
cleanly with vinyl acetate in the presence of Lipase LIP (Toyobo) in
having a cyclohexylethano framework from the crude drug “rengyo”,
the fruits of Forsythia suspensa used in Oriental medicine for
antiinflammatory, diuretic, drainage and antidotal purposes. Later,
11
33
THF containing triethylamine to give the acetate (–)- , [α]
–44.7
+78.5 (c 1.1, CHCl ), the
12
D
32
(c 0.7, CHCl ), and the alcohol (+)- , [α]
11
3
D
3
29
2,3
former gave (–)-
, [α]
D
–83.6 (c 1.4, CHCl ), on alkaline
11
isorengyol 3 from the same plant and a series of the structurally
3
ethanolysis. Enantiomeric purities of the products were estimated to be
>99 and ~ 98% ee, respectively, by hplc analysis in the later stage
related cyclohexylethanoids, represented by isorengyol acetal 4,
4,5,6,7
cleroindicin A 5, cleroindicin C (–)-6, cleroindicin E
(–)-7 and
4
(
).
Scheme 1
isocleroindicin E (–)-8, were isolated along with their glucosides from
4
other medicinal plants, Millingtonia hortensis and Clerodendrum
The absolute configurations of the products were determined as shown
5
12
indicum , both used in Southeast Asia (Fig. 1).
by correlation of (–)- to the known ketone (–)- . Thus, (–)- was
11
17
11
31
transformed into the bromo-ether (+)- , [α]
16
+83.8 (c 0.1, CHCl ),
D
3
by a four-step sequence of reactions through
,
and . On the other
15
13 14
27
hand, (–)- furnished the same bromo-ether (+)- , [α]
+79.9 (c
17
16
).
19 Scheme 2
D
1.1, CHCl ), in three steps through
and
(
18
3
To establish an alternative route to the achiral natural products
–
as
1
3
well as to accomplish the first synthesis of the achiral cleroindicin A
5
and to determine enantiomeric purities of the resolved products, the allyl
alcohol (–)- was first reverted to the enone (+)- , mp 79-80 °C,
11 10
25
[α]
+92.7 (c 1.1, CHCl ), by oxidation. The enone (+)- was then
10
D
3
transformed into the ketone
by a copper (I) iodide-mediated 1,4-
20
13
reduction . The readily enolizable ketone functionality of
was
20
10
reduced with NaBH -CeCl to give the endo-alcohol , which, after
21
4
3
31
silylation, was further reduced to give the diol , [α]
23
–6.8 (c 1.1,
D
CHCl ). On thermolysis in refluxing diphenyl ether,
furnished the
23
3
31
cyclohexene (+)- , mp 46-47 °C, [α]
24
+38.9 (c 0.6, CHCl ), whose
3
D
enantiomeric purity was determined to be >99% ee by hplc analysis
(CHIRALCEL OD, iPrOH-hexane 1 : 99) after conversion into the
MTPA (R- and S-) esters. The enantiomeric cyclohexene (–)- , mp 46-
25
29
47 °C, [α]
–36.3 (c 1.0, CHCl ), obtained in the same way from the
3
D
Figure 1
enantiomeric alcohol (+)-
,
was determined to be
~
98% ee.
11
Hydrogenation of (+)- gave the achiral cyclohexane
which, on
24
desilylation, afforded rengyol
°C). On the other hand, was first transformed into the single acetal
25
1,14
1
, mp 120-122 °C (natural : mp 124
1
Because neither the synthesis nor determination of the absolute
4,5,6
25
which was desilylated to give . The Mitsunobu reaction of
26
27
configurations has been made of the chiral natural products,
were interested in developing
we
15
27
a
stereocontrolled route generally
4
yielded the inverted benzoate
which gave isorengyol acetal as the
4
28
applicable to the construction of both the achiral and the chiral natural
cyclohexylethanoids. We report here the stereocontrolled construction
single product on alkaline methanolysis. Acid-catalyzed methanolysis

1002
LETTERS
SYNLETT
3,14
3
of afforded isorengyol
°C).
, mp 106-108 °C (natural : mp 107-108
3
On the other hand, to obtain rengyoxide 2, the cyclohexene (+)-24 was
first converted into the diacetate 31. On sequential desilylation,
oxidation, hydrogenation and alkaline methanolysis, 31 furnished
rengyoxide 2 through the allyl alcohol 3, the enone 33 and the ketone
34. Of course, the synthesis of the compounds 1–5 may be carried out
using the racemic adduct (±)-10 without resolution as they are not chiral
(Scheme 3).
4
In order to establish the configuration of cleroindicin A 5 having an
oxetane ring on a unique spirobicyclic framework, the alcohol 25 was
first transformed to the tosylate 29 which then was exposed to potassium
tert-butoxide to furnish the bicyclic ether 30. Finally, 30 was desilylated
to give cleroindicin A 5 whose spectroscopic data ( H and C NMR,
mass) were identical with those reported for the natural product. Thus,
1
13
5
Having completed the synthesis of the achiral meso series of the natural
products, we next examined the synthesis of the chiral natural products
the first synthesis of cleroindicin A 5 has been accomplished.

September 1998
SYNLETT
1003
–
to determine their absolute configurations. Thus, the cyclohexene
(4) Hase, T.; Kawamoto, Y.; Ohtani, K.; Kasai, R.; Yamasaki, K.;
6
8
16
(+)- above was treated with mercury (II) trifluoroacetate followed
Picheansoonthon, C. Phytochemistry 1995, 39, 235.
24
by sodium borohydride to form the bicyclic ether (+)- , mp 40-41 °C,
35
(5) Tian, J.; Zhao, Q.-S.; Zhang, H.-J.; Lin, Z.-W.; Sun, H.-D. J. Nat.
Prod. 1997, 60, 766.
28
[α]
+2.20 (c 1.2, CHCl ), which served as the common precursor for
3
D
the construction of the three chiral natural products, in 92% yield.
(6) Synthesis of the achiral natural products 1 – 3 has been
accomplished, see: Ref. 1 – 3 and Soriente, A.; Rocca, A. D.;
Sodano, G.; Tricone, A. Tetrahedron 1997, 53, 4693.
4,5,14
Desilylation of (+)- afforded cleroindicin E
35
(–)- , mp 40-41 °C,
6
31
13
4
[α]
–5.96 (c 0.6, MeOH) [natural: [α]
–2.6 (c 1.7, MeOH) , [α]
D
D
D
5
+1.15 (c 0.046, MeOH) ]. On oxidation, (–)- afforded cleroindicin
6
(7) (+)-Enantiomer was also isolated, see: Ref. 5.
4,5,14
30
11
C
, [α]
–71.0 (c 0.2, MeOH) [natural: [α]
–5.6 (c 9.5,
8
4
D
D
5
(8) Silvero, G.; Lucero, M. J.; Winterfeldt, E.; Houk, K. N.
MeOH) ; [α] –22.32 (c 0.082, MeOH) ], while (–)- on the Mitsunobu
reaction with 4-nitrobenzoic acid followed by alkaline methanolysis
6
D
15
17
Tetrahedron 1998, 54, 7293 and references cited therein.
4,14
30
(9) Araki, S.; Katsumura, N.; Kawasaki, K.; Butsugan, Y. J. Chem.
Soc., Perkin Trans. 1, 1991, 499.
of the resulted benzoate
furnished isocleroindicin E
(–)- , [α]
7
D
36
4
16
–22.6 (c 0.1, MeOH) [natural : [α]
–6.0 (c 0.57, MeOH)]. Based on
D
the comparison of the direction of optical rotations, the absolute
configurations of the three natural products have been determined as
(10) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(11) Sugahara, T.; Kuroyanagi, Y.; Ogasawara, K. Synthesis 1996,
shown (
). The observed discrepancies in the rotation values
Scheme 4
1101.
between the natural and the synthetic products may be due to a partial
racemization of the former during their biosynthetic pathways involving
quinonoid intermediates where racemization was presumed to occur by
(12) Hiroya, K.; Kurihara, Y.; Ogasawara, K. Angew. Chem. Int. Ed.
Engl. 1995, 34, 2287.
(13) Takano, S.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1992, 169.
2,4
intramolecular elimination-addition pathway.
In summary, we have devised a general and stereocontrolled procedure
leading to both the achiral and the chiral cyclohexylethanoid natural
products using a common starting material which determined the
configuration of the one having meso structure and the absolute
structures of the three having chirality.
1
(14) Spectroscopic data (ir, H NMR, mass, high resolution MS) were
identical with those reported for the natural product.
(15) Mitunobu, O. Synthesis 1981, 1: Hughes, D. L. Organic Reactions
1992, 42, 335: Hughes, D. L. Org. Prep. Proced. Int. 1996, 28,
127.
(16) Kocovsky, P.; Pour, M. J. Org. Chem. 1990, 55, 5580.
References and Notes
(17) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(1) Endo, K.; Hikino, H. Can. J. Chem. 1984, 62, 2011.
(2) Pertinent reviews: (a) Endo, K. Tohoku Yakka Daigaku Kenkyu
Nenpo 1994, 41, 1. (b) Jimenez, C.; Riguera, R. Nat. Prod. Rep.
1994, 11, 591.
(3) Endo, K.; Seya, K.; Hikino, H. Tetrahedron 1987, 43, 2681: Seya,
K.; Endo, K.; Hikino, H. Phytochemistry 1989, 28, 1495.