A simple synthesis of 6-deoxoteasterone and its 20-epimer

Article abstract of DOI:10.1016/j.tetlet.2004.02.033

6-Deoxoteasterone, a brassinolide biosynthetic intermediate, and its 20-epimer were synthesized from steroidal 17-olefin and chiral α-alkoxyaldehyde using a Lewis acid mediated carbonyl-ene reaction as the key step. In this reaction, unusual stereoselectivity was observed.

Full text of DOI:10.1016/j.tetlet.2004.02.033

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2767–2769
A simple synthesis of 6-deoxoteasterone and its 20-epimerq
Bunta Watanabe, Shuji Yamamoto, Kanako Sasaki, Yoshiaki Nakagawa*
and Hisashi Miyagawa
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
Received 10 January 2004; accepted 9 February 2004
Abstract—6-Deoxoteasterone, a brassinolide biosynthetic intermediate, and its 20-epimer were synthesized from steroidal 17-olefin
and chiral a-alkoxyaldehyde using a Lewis acid mediated carbonyl-ene reaction as the key step. In this reaction, unusual stereo-
selectivity was observed.
Ó 2004 Elsevier Ltd. All rights reserved.
Brassinolide (BL) 1 (Scheme 1) is a steroidal plant
hormone and exhibits a wide variety of biological
activity at very low concentrations.1;2 Because of its
complicated structure and low natural abundance, many
researchers have attempted the chemical synthesis of
BL. Special emphasis has been placed on the stereo-
selective construction of its side chain, where four con-
tiguous asymmetric carbons are present, requiring
multiple step reactions. This synthesis still remains a
challenging problem to the synthetic community. Here
we report a novel, and simple method for constructing
the BL side chain using a Lewis acid mediated carbonyl-
ene reaction3 as the key step.
of an appropriate combination of Lewis acid and alde-
hyde.5;7;8;11 However, previous applications seemed to
require multiple step reactions to complete construction
of the BL side chain. Here, we designed carbonyl-ene
reaction between a chiral a-alkoxyaldehyde 2 and ste-
roidal 17-olefin followed by simple hydrogenation to
introduce the C22–C28 fragment in BL (Scheme 1).
Synthesis of 2 is shown in Scheme 2. Optically active
epoxide 313 was used as a chiral template. The oxirane
ring of 3 was cleaved by copper mediated Grignard
reaction14 to give a mixture of 1,2-diol derivative 4 and
1,3-diol derivative 5 in the ratio of 87/13. After chro-
matographic separation, pure 4 was obtained in 74%
yield. The secondary hydroxyl group of 4 was protected
as the benzyl ether to yield 6 quantitatively. Subsequent
removal of trityl group gave half protected diol 7 in 73%
yield. Oxidation of 7 with the Dess–Martin period-
inane15 afforded the desired aldehyde 2 in 91% yield
without epimerization.
One of the simplest ways to form a carbon–carbon bond
under mild condition is the use of a Lewis acid mediated
ene reaction. This scheme has frequently been utilized
for the introduction of a steroidal side chain to tetra-
cyclic nucleus.4–12 It is well known that ene reaction
between various enophiles and (Z)-17-ethylidenesteroid
give only compounds with the configuration of the
naturally occurring steroids at C-20. Besides the
introduction of the alkyl side chain, carbonyl-ene reac-
tions have the advantage of generating a hydroxyl group
at C22 with the desired conformation through the choice
Carbonyl-ene reaction between 2 and (Z)-3b-acetoxy-
pregna-5,17-diene 816 using Me2AlCl, which is routinely
used as the Lewis acid in many cases, was unsuccessful.
MeAlCl2 among of various Lewis acids, was found to be
the most effective. Thus equimolar amount of 2 and 8
reacted smoothly at )78 °C in the presence of MeAlCl2
(3 equiv), and the ene adduct 9 was obtained in 65%
yield. To determine the configurations of C20and C22,
9 was subjected to basic hydrolysis followed by catalytic
hydrogenation to yield triol 10 (Scheme 3). Unexpect-
Keywords: Brassinolide; 6-Deoxoteasterone; 20-Epi-6-deoxoteaster-
one; Carbonyl-ene reaction; Methylaluminum dichloride; a-Alkoxy-
aldehyde.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.02.033
* Corresponding author. Tel.: +81-75-753-6117; fax: +81-75-753-6123;
e-mail: naka@kais.kyoto-u.ac.jp
1
edly, H NMR chemical shifts of protons in the side
chain moiety of 10 were not agreed with those reported
for BL,17 but well agreed with those reported for 20-
epibrassinolide.18 Thus 10 proved to be epimer of
Ene reaction between (E)-17-ethylidenesteroid and methyl propiolate
gave 20-ÔunnaturalÕ steroid.12
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.033

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B. Watanabe et al. / Tetrahedron Letters 45 (2004) 2767–2769
28
OH
22
OH
OH
20
17
OHC
OBn
HO
HO
+
OBn
O
H
(Z )-17-Ethylidene-
steroide
O
2
Brassinolide (1)
Scheme 1.
OH
a
d
OHC
O
+
TrO
R1O
TrO
OR2
OBn
4: R1 = Tr, R2 = H
6: R1 = Tr, R2 = Bn
7: R1 = H, R2 = Bn
3
5
2
b
c
Scheme 2. Reagents and conditions: (a) i-PrMgCl, Li2CuCl4, THF–Et2O (2/1), )78 °C to rt, overnight; (b) NaH, BnBr, DMF, rt, overnight; (c) 90%
aq AcOH, 90 °C, 15 min; (d) Dess–Martin periodinane, CH2Cl2, rt, 30min.
OH
R1
R2
OH
R1
R1
R2
R2
OH
OBn
a
b, c
AcO
HO
AcO
H
8
: R1 = Me, R2 = H
9
: R1 = Me, R2 = H
10:R1 = Me, R2 = H
13:R1 = H, R2 = Me
(6-Deoxoteasterone)
11: R1 = H, R2 = Me
12: R1 = H, R2 = Me
Scheme 3. Reagents and conditions: (a) 2, MeAlCl2, CH2Cl2–hexane (2/1), )78 °C, 30min; (b) NaOH, MeOH, reflux, 15 min; (c) H 2, Pd–C, 40 °C,
overnight.
6-deoxoteasterone 13, one of the intermediates in the
BL biosynthetic pathway, with respect to C20. This
stereochemical outcome were unusual comparing with
hitherto known ene reactions between (Z)-17-ethylid-
enesteroid and various enophile, which gave only 20-
ÔnaturalÕ steroid as mentioned above.
factor, which favors a face attack as in TSs A and B.
When the aliphatic moiety of the aldehyde is relatively
small,§ TS A is more favorable between these two TSs
since the steric repulsion between the Lewis acid and the
D-ring adversely works for the formation of TS B.
However, in the case of reaction between 2 and 8, it is
likely that the considerably bulky alkyl group of 2 also
makes TS A unstable to prevent the a face attack.
Consequently, the reaction proceeds mainly on the b
face as in TSs C or D. TS C is relatively unfavorable due
to the steric interaction between the C18 methyl group
and R. Therefore TS D is considered to be the most
stable among the four possible TSs for the present case,
giving (20R,22R)-stereochemistry.
We would like to comment on this unique reaction
mechanism. There are four possible transition states
(TSs) that can be assumed in this carbonyl-ene reaction
between (Z)-17-ethylidenesteroid and the aldehyde with
the aluminum reagent used as the Lewis acidà (Fig. 1).
In TSs A and B, the aldehyde–Lewis acid complex
locates on the a face of the steroidal D-ring to lead to
the 20-ÔnaturalÕ steroid as product. In TSs C and D, on
the other hand, the aldehyde–Lewis acid complex
locates on the b face of the D-ring to give the
20-ÔunnaturalÕ steroid. It has been considered that
repulsion between the C18 methyl group and the alde-
hyde–Lewis acid complex is the most important steric
Even in TS D, steric hindrance hampered the smooth
reaction. The acidity of Me2AlCl, a typical Lewis acid for
the carbonyl-ene reaction, was too moderate to overcome
the steric hindrance. The stronger Lewis acid, MeAlCl2,
§
Houston and co-workers reported that ene reaction proceeded via TS
B when R is aromatic, and no reaction occurred when R is t-Bu using
Me2AlCl.11
à
Alkyl moiety of aldehyde (R) and aluminum reagent are considered
to locate anti.7;11

B. Watanabe et al. / Tetrahedron Letters 45 (2004) 2767–2769
2769
H
R
18
H
R
β face
α face
R
H
H
O
R
AlL3
O
L3Al
O
H
L3Al
H
O
H
H
AlL3
TSA
(20S,22R)
TSB
TSC
(20R,22S)
TSD
(20R,22R)
20-‘unnatural’
(20S,22S)
20-‘natural’
Figure 1. Possible transition states for the carbonyl-ene reaction.
2. Khripach, V. A.; Zhabinskii, V. N.; de Groot, A. E.
Brassinosteroids: A New Class of Plant Hormones; Aca-
demic: 1999.
3. Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021–
1050.
was required for the reaction to proceed. In this regard,
Jackson and co-workers have reported that EtAlCl2
could mediate the intermolecular carbonyl-ene reactions
of olefins and ketones, an enophile with considerably low
reactivity, to give ene adducts in low to moderate yield.19
4. Wovkulich, P. M.; Batcho, A. D.; Uskokovic, M. R. Helv.
Chim. Acta 1984, 67, 612–615.
To verify the assumed reaction mechanism, we per-
formed a carbonyl-ene reaction between 2 and (E)-3b-
acetoxypregna-5,17-diene 11.20 The reaction proceeded
smoothly under the same conditions as those for (Z)-
isomer 8, and ene adduct 12 was obtained in 52% yield,
which was converted to triol 13. As expected, analytical
data of 13 was identical with those reported for 6-de-
oxoteasterone.21
5. Mikami, K.; Kishino, H.; Loh, T.-P. J. Chem. Soc., Chem.
Commun. 1994, 495–496.
6. Mikami, K.; Kishino, H.; Matsueda, H.; Loh, T.-P.
Synlett 1993, 497–498.
7. Mikami, K.; Loh, T.-P.; Nakai, T. J. Chem. Soc., Chem.
Commun. 1988, 1430–1431.
8. Mikami, K.; Loh, T.-P.; Nakai, T. Tetrahedron Lett. 1988,
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9. Dauben, W. G.; Brookhart, T. J. Am. Chem. Soc. 1981,
103, 237–238.
In summary, we have developed the shortest method
reported to date to construct the BL side chain using a
carbonyl-ene reaction as a key step. We have also syn-
thesized 6-deoxoteasterone and its 20-epimer. Further
investigation of the scope and limitations of this type
carbonyl-ene reaction are now in progress.
10. Guo, C.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 1099–
1102.
11. Houston, T. A.; Tanaka, Y.; Koreeda, M. J. Org. Chem.
1993, 58, 4287–4292.
12. Dauben, W. G.; Brookhart, T. J. Org. Chem. 1982, 47,
3921–3923.
€
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4730–4735.
14. Klunder, J. M.; Onami, T.; Sharpless, K. B. J. Org. Chem.
1989, 54, 1295–1304.
Acknowledgements
We are thankful to Dr. Craig Wheelock of the University
of California Davis for carefully reviewing manuscript.
This investigation was supported, in part, by a Grant-in-
Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology (formally
Ministry of Education, Science, and Culture) of Japan
(09660117, 10161207), and by the Fujisawa Foundation.
15. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–
4156.
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