The enantioselective synthesis of key intermediates for the synthesis of (+)-brevifloralactone from R-(-)-carvone

Article abstract of DOI:10.1016/S0040-4039(01)00840-1

Starting from R-(-)-carvone, a sequence of reactions has been developed for the enantioselective synthesis of key intermediates, which contain ether and hemiacetal bridges that are present in antifeedant clerodanes such as brevifloralactone and jodrellin.

Full text of DOI:10.1016/S0040-4039(01)00840-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4903–4905
The enantioselective synthesis of key intermediates for the
synthesis of (+)-brevifloralactone from R-(−)-carvone
V. Olkhovik,a N. Masalov,b B. J. M. Jansenc and Aede de Grootc,*
aLaboratory of Organic Chemistry, Institute of New Materials Chemistry, Belarus Academy of Sciences, str. Kuprevicha 16,
220141 Minsk, Belarus
bDepartment of Organic and Polymer Chemistry, Belarussian State University, F. Skoriny av. 4, 220050 Minsk, Belarus
cLaboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
Received 19 March 2001; revised 24 April 2001; accepted 16 May 2001
Abstract—Starting from R-(−)-carvone, a sequence of reactions has been developed for the enantioselective synthesis of key
intermediates, which contain ether and hemiacetal bridges that are present in antifeedant clerodanes such as brevifloralactone and
jodrellin. © 2001 Elsevier Science Ltd. All rights reserved.
Clerodanes occur widely in Nature,1,2 and many show
interesting physiological properties, of which
antifeedant activity is the most documented one.2 Only
a few clerodanes with an ether bridged ring A such as
brevifloralactone (5) and jodrellin are found in Nature,
and this bridge seems to be important for strong
antifeedant activity. The synthesis of clerodanes3 is still
a challenging problem, and until now only one method
has been published for the construction of a bridged
intermediate that may be suitable for the total synthesis
of jodrellin A.4 In this paper a new approach for the
construction of a key intermediate in the synthesis of
brevifloralactone (5), containing this characteristic ether
bridge over ring A, is described. For this synthesis
new methodology concerning the introduction of sub-
stituted sidechains in carvone (1)5 and regarding
the Robinson annulation of heavily substituted
cyclohexanones6 has been developed, which gives an
easy access to intermediates of type 3. The addition of
MVK to a-cyano ketone 2 under Knoevenagel condi-
tions, led to good yields of annulated products with the
desired trans position of the nitrile group at C5 and the
major substituent at C9. Simultaneously, suitable func-
tional groups at C5 and C2 are obtained that can serve
for the construction of the ether bridge over ring A
(Scheme 1).
It was found that this annulation also proceeds
smoothly when substituted enones such as 67 are
reacted with cyano ketone 26 (Scheme 2). The annu-
lated product 7 was obtained in 86% yield as a 2:1
mixture of products epimeric at C4, with the compound
with the protected hydroxy methylene substituent in the
axial position as main product (vide infra) (Scheme 2).
For the synthesis of brevifloralactone, the configuration
at C4 is not of great importance because in this
O
O
O
O
R
O
O
O
H
H
9
5
O
O
note 6
2
O
A
B
O
B
A
B
NC
CN
TBDPSO CH2
TBDPSO CH2
HOH2C
5
1
2
3
4
Scheme 1.
Keywords: carvone; clerodane; synthesis; a-cyano ketones.
* Corresponding author. Tel.: +31-317-482370; fax: +31-317-484914; e-mail: aede.degroot@bio.oc.wag-ur.nl
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00840-1

4904
V. Olkho6ik et al. / Tetrahedron Letters 42 (2001) 4903–4905
O
O
O
O
O
O
H
O
c, d, e
O
a
O
b
O
4
NC
CN
CN
TBDPSO
TBDPSO
TBDPSO
2
6
7
8
O
H
H
H
H
TMSO
TMSO
TMSO
f
g
CN
CN
NH
TBDPSO
TBDPSO
TBDPSO
9
10
11
g, h
i
H
H
H
H
HO
l
j, k
O
O
O
NH2
NH
OH
14
TBDPSO
TBDPSO
TBDPSO
TBDPSO
15
12
13
Scheme 2. Conditions: (a) pyrrolidine, toluene, D, 65%; (b) H2, Pd/C, MeOH, 93%; (c) NaBH4, i-PrOH, 0°C; (d) PPTS, acetone,
H2O, D, 84% (two steps); (e) TMSCl, Et3N, THF, rt, 98%; (f) Ph3PCH3Br, BuLi, THF, −20 to 0°C, 92%; (g) DIBAH, toluene,
0–20°C, 95%; (h) K2CO3, MeOH, 0°C, 40 min, quant.; (i) H+, H2O; (j) NaNO2, AcOH, dioxane, H2O, 92%; (k) HCl, dioxane,
rt; (l) Et3SiH, CF3CO2H, CH2Cl2, 88% (two steps).
molecule a double bond is present at the D3 position.
The mixture could be separated by column chromatog-
raphy and the next experiments have been performed
with the indicated major epimer. Catalytic reduction of
the D10,1 double bond gives 8 with the correct configu-
ration at C10. It seemed appropriate to introduce the
D3 double bond in this stage of the synthesis, prior to
reduction of the carbonyl group at C2 and the nitrile at
C5. However, reduction of 7 with DIBAH or LiAlH4
also caused elimination of the nitrile group and DIBAH
gave ring opening of the dioxolane group. Therefore,
the dioxolane group was converted first into a methyl-
ene group, which should be inert during the reduction
of the nitrile and at the same time could serve as
precursor for the construction of the brevifloralactone
side chain.7
group was protected as its trimethylsilyl ether 9. The
aldehyde was converted, via a Wittig reaction, into the
corresponding methylene derivative 10 in high yield and
now the nitrile group could be reduced with DIBAH to
give the imine 11 in 85% yield.
It turned out that this imine is a stable compound and
its hydrolysis under different acidic conditions gave
only an equilibrium mixture consisting of the unpro-
tected imine 13 and its intramolecular cyclization
product 12. The same mixture was formed from 11
when just the trimethylsilyl group was hydrolyzed. A
nearly quantitative yield of the mixture of 12 and 13
was obtained when the crude product after reduction
with DIBAH was treated with K2CO3 in methanol at
5°C. Further hydrolysis of this mixture could only be
accomplished by treatment with sodium nitrite, to give
the hemiacetal 14. The reduction of crude 14 was
performed with trifluoracetic acid and triethylsilane to
give the desired cyclic ether 158 in 88% yield.
Thus, the carbonyl group at C2 in 8 was reduced
stereoselectively to an a-hydroxyl group, the dioxolane
was hydrolyzed to an aldehyde and the C2 hydroxyl
O
O
H
O
O
O
O
O
O
a
b, c
d, e
15
O
CN
OH
16
TBDPSO
TBDPSO
TBDPSO
7
17
Scheme 3. Conditions: (a) DIBAH (10 equiv.), toluene, −78°C, then HOAc, H2O; (b) Et3SiH, CF3CO2H, CH2Cl2, 70% (two steps);
(c) H2, Pd/C, MeOH, 50 h; (d) PPTS, acetone, H2O, reflux, 71% (two steps); (e) Ph3PCH3Br, BuLi, THF, −20 to 0°C, 60%.

V. Olkho6ik et al. / Tetrahedron Letters 42 (2001) 4903–4905
3. Tokoroyama, T. Synthesis 2000, 611–633.
4905
Later, it was discovered that a shorter route to 15
(Scheme 3) could be realized via low temperature reduc-
tion of 7 with DIBAH, which gave directly a mixture of
hemiacetals 16 in good yield after acidic work-up. This
mixture was reduced further to the cyclic ether and
hydrogenated to compound 17. Hydrolysis of the diox-
olane and a Wittig reaction again gave compound 15 in
30% overall yield from 7. NMR experiments on ether
15 showed that no NOE effect was present between the
methylene protons on the ether bridge and the protons
of the protected hydroxymethylene group at C4. This
led to the conclusion that the substituent at C4 occupies
the axial position.
4. Blaney, M.; Cunat, A. C.; Ley, S. V.; Montgomery, F. J.;
Simmonds, M. S. J. Tetrahedron Lett. 1994, 35, 4861–
4864.
5. Meulemans, T. M.; Stork, G. A.; Jansen, B. J. M.; de
Groot, A. Tetrahedron Lett. 1998, 39, 6565–6568.
6. Jansen, B. J. M.; Hendrikx, C. C. J.; Masalov, N.; Stork,
G. A.; Meulemans, T. M.; Macaev, F. Z.; de Groot, A.
Tetrahedron 2000, 56, 2075–2094.
7. Parson, P. J.; Lacrout, P.; Buss, A. D. J. Chem. Soc.,
Chem. Commun. 1995, 437–438.
8. All compounds showed correct spectral data and exact
mass spectral data. The spectral data of 15 are: [h]2D0=
1
−34.6 (c=1.07, CDCl3); H NMR (CDCl3, 200 MHz) l
Thus, a sequence of reactions has been developed,
which is suitable for the construction of molecules with
ether bridges such as 14 and 15, as they are present in
active antifeedant clerodanes like jodrellin and brev-
ifloralactone, respectively.
0.73 (d, J=6 Hz, 3H), 1.01 (s, 3H), 1.04 (s, 9H), 1.13–1.86
(m, 11H), 3.54–3.63 (m, 2H), 3.73–3.85 (m, 3H), 4.91 (dd,
J1=18 Hz, J2=1.4 Hz, 1H), 5.03 (dd, J1=10 Hz, J2=1.4
Hz, 1H), 5.43 (dd, J1=18 Hz, J2=10 Hz, 1H), 7.34–7.47
(m, 6H), 7.63–7.69 (m, 4H); 13C NMR (CDCl3, 50 MHz)
l 10.6 (q), 16.7 (q), 19.3 (s), 26.4 (t), 26.8 (q), 28.4 (t), 31.2
(t), 32.5 (t), 33.3 (s), 40.5 (d), 44.3 (s), 45.6 (d), 46.9 (d),
64.2 (t), 65.3 (t), 66.0 (d), 112.8 (t), 127.6 (d), 129.6 (d),
133.8 (s), 133.9 (s), 135.6 (d), 149.1 (d); IR wmax (liquid
film) 3070, 2955, 2930, 2856, 1427, 1112, 1071, 1050, 1000,
909, 824, 739, 702: HRMS calcd for C28H35O2Si (M−57)+
431.2406, found 431.2403 (|=0.098 mmu).
References
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