Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin, (2R,3R)-(-)-1-methoxyspirobrassinol methyl ether and their enantiomers or diastereoisomers

Article abstract of DOI:10.1016/j.tetlet.2007.09.080

Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(-)-enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (-)-menthol and subsequent oxidation of the

Full text of DOI:10.1016/j.tetlet.2007.09.080

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8200–8204
Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin,
(2R,3R)-(ꢀ)-1-methoxyspirobrassinol methyl ether
and their enantiomers or diastereoisomers
a
a,
a
ˇ
*
´
´
Zuzana Curillova, Peter Kutschy, Mariana Budovska,
Atsufumi Nakahashib and Kenji Mondeb
a
ˇ
Institute of Chemical Sciences, Faculty of Science, P.J. Safa´rik University, Moyzesova 11, 040 01 Kosˇice, Slovak Republic
bLaboratory of Advanced Chemical Biology, Graduate School of Advanced Life Science, Frontier Research Center for Post-genome
Science and Technology, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021, Japan
Received 9 August 2007; revised 3 September 2007; accepted 12 September 2007
Available online 18 September 2007
Abstract—Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(ꢀ)-
enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (ꢀ)-menthol and subsequent
oxidation of the obtained menthyl ethers. Methanolysis of menthyl ethers in the presence of TFA afforded (2R,3R)-(ꢀ)-1-methoxy-
spirobrassinol methyl ether as well its unnatural (2S,3S)-, (2R,3S)-, and (2S,3R)-isomers.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
methyl ether [( )-3] were synthesized by dioxane dibro-
mide-mediated spirocyclization of 1-methoxybrassinin
(6) in dioxane.7 The reaction probably proceeds via sul-
fenyl bromide (A), which cyclizes to indoleninium ion
(B, Scheme 1). In the presence of methanol as a nucleo-
phile attacking the intermediate methoxyiminium ion
(B), a mixture of racemic trans- and unnatural cis-diaste-
reoisomer8 of 3 was obtained, from which the natural
trans-diastereoisomer was isolated by flash chromato-
graphy. In the presence of water, another spiroindoline
phytoalexin 1-methoxyspirobrassinol (4), with as yet
unknown absolute stereochemistry, was prepared.7 This
compound exists in solution as a mixture of two diaste-
reoisomers, owing to its unstable hemiaminal structure.5
Oxidation of the mixture of isomers 4a and 4b with
CrO3 afforded racemic 2.7 ( )-1-Methoxyspirobrassinin
and trans-( )-1-methoxyspirobrassinol methyl ether
were enantioresolved by chiral HPLC and the absolute
configurations of natural (R)-(+)-2 and (2R,3R)-(ꢀ)-3
were determined by ECD, VCD, and chemical
correlation.9
Phytoalexins are defined as antimicrobial low molecular
weight secondary metabolites, produced by plants after
their exposure to physical, biological, or chemical
stress.1 About 40 indole phytoalexins have been isolated
from economically and dietary important plants of the
family Cruciferae, cultivated worldwide.2 Among them,
several spiroindoline[3,50]thiazolidine-type phytoalexins,
such as (S)-(ꢀ)-spirobrassinin [1, from Japanese radish
(Raphanus sativus)],3 (R)-(+)-1-methoxyspirobrassinin
[2, from kohlrabi (Brassica oleracea var. gongylodes)],4
or (2R,3R)-(ꢀ)-1-methoxyspirobrassinol methyl ether
[3, from Japanese radish (R. sativus)]5 have been
described. Compounds 1–3 were previously synthesized
as racemates. ( )-Spirobrassinin was prepared by cycli-
zation of ( )-dioxibrassinin (5) with SOCl2 or MsCl,
enantioresolved by (S)-(ꢀ)-1-phenylethyl isocyanate
and the absolute configuration of (S)-(ꢀ)-spirobrassinin
was determined by X-ray analysis after derivatization
with (ꢀ)-camphanoyl chloride.6 ( )-1-Methoxyspiro-
brassinin [( )-2] and ( )-1-methoxyspirobrassinol
In the present Letter we wish to report the diastereose-
lective synthesis of (R)-(+)-2 and (2R,3R)-(ꢀ)-3 as well
as their unnatural isomers. For this purpose we investi-
gated spirocyclization of 1-methoxybrassinin in the pres-
ence of chiral secondary alcohols as nucleophiles
Keywords: Indoles; Phytoalexins; Menthol; Diastereoselectivity.
*
Corresponding author. Tel.: +421 55 62 22610x256; fax: +421 55 62
22124; e-mail: peter.kutschy@upjs.sk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.080

ˇ
Z. Curillova´ et al. / Tetrahedron Letters 48 (2007) 8200–8204
8201
N
N
N
SCH3
SCH3
N
SCH3
SCH3
S
S
S
S
OCH3
OCH3
O
OCH3
N
N
N
O
N
H
OCH3
OCH3
cis-( )-3
Unnatural diastereoisomer
trans-(2R,3R)-(-)-3
(R)-(+)-2
(S)-(-)-1
S
S
N
N
SCH3
N
H
SCH3
SCH3
SCH3
HO
N
H
S
S
O
N
OH
OH
N
H
N
N
OCH3
OCH3
OCH3
( )-4a
( )-5
6
( )-4b
Figure 1.
reacting with a methoxyiminium ion (see Fig. 1). The
dioxane dibromide-mediated spirocyclization in dioxane
used previously7 appeared to be inconvenient, since it is
difficult to dry and store the dried dioxane. Any trace of
water results in the formation of 4 as the unwanted side
product. Therefore spirocyclization was performed with
bromine in dry dichloromethane. It was assumed that in
the chiral-alkyl containing ethers 7–10, one of the four
possible diastereoisomers would be major. Oxidation
with pyridinium chlorochromate (PCC)9 should afford
an enantiomer of 1-methoxyspirobrassinin (2), and
acid-catalyzed methanolysis should lead to a 1:1 mixture
of the optically active trans- and cis-diastereoisomers of
1-methoxyspirobrassinol methyl ether (3), epimeric at
C-2 (B, Scheme 1).
the most remote from the reaction center. In this model,
the (R)-methoxyiminium intermediate should be prefer-
ably attacked by the (S)-enantiomer of the alcohol from
the less hindered CH2-side of thiazoline ring (Fig. 2),
whereas in the case of (S)-methoxyiminium intermediate
the analogous attack of (S)-alcohol will be unfavored.
With the (R)-enantiomer of alcohol the situation was
expected to be opposite. By analogy the approach of
the (S)-alcohol to the (S)-methoxyiminium ion and
S
S
CH3
H
H
O
CH
O
For the first experiments, we selected the (S)-(ꢀ)- and
(R)-(+)-1-(2-naphthyl)ethanol because it possesses the
large naphthyl moiety. The prediction of diastereoselec-
tivity was based on stereoelectronic considerations. It
was supposed, that the chiral secondary alcohol would
approach methoxyiminium ion B from the less hindered
3
OH
H
OH
H3C
CH3
N
H
N
S
S
H
H
S
H
H
S
S
R
N
N
CH3
H3C
CH -side of thiazoline ring in the direction of Burgi–
¨
2
Dunitz trajectory10 with the naphthyl substituent being
Figure 2.
S
SCH3
N
N
S
N
SCH3
SCH3
SBr
NH
SCH3
S
HOR
*
Br
2
OR
*
N
N
OCH3
N
N
- HBr
OCH3
Br
OCH3
OCH3
7a-10c
A
( )-B
6
Methoxyiminium
intermediate
N
S
N
SCH3
SCH3
PCC
CH3OH
H
S
O
7a-10c
OCH3
N
N
OCH3
OCH3
3
2
Scheme 1.

ˇ
Z. Curillova´ et al. / Tetrahedron Letters 48 (2007) 8200–8204
8202
(R)-alcohol to (R)-methoxyiminium ion should be more
favored from the sulfur side of thiazoline ring.
reaction time for their oxidation was shortened from 3
days in the case of 1-(2-naphthyl)ethyl ethers to 1 day
and the yield of (R)-(+)-2 or (S)-(ꢀ)-2 increased to
68–70%. It is supposed that the cyclization of sulfenyl
bromide A to iminium ion B (Scheme 1) is reversible.
If the cyclization was not reversible, the maximum yields
of the major diastereoisomers 7a, 8c, 9a, and 10c might
not exceed 50%. Reversibility is supported by the find-
ings that the yields calculated from the yields of chro-
matographically isolated mixtures with respect to the
ratio of present isomers in all cases exceeded 50% (Table
1). Compounds 7a–10d were prepared at room tempera-
ture. At lower temperatures (up to ꢀ70 ꢁC) the stereo-
selectivity decreased, probably by participation of
another mechanism, which will be the subject of our
next studies. At higher temperatures (up to 50 ꢁC in
chloroform) decomposition was observed and therefore
did not lead to higher stereoselectivity.
The analysis of the reaction products (Table 1) con-
firmed the expected diastereoselectivity. Spirocyclization
in the presence of (S)-(ꢀ)-1-(2-naphthyl)ethanol resulted
in the formation of four diastereoisomers with the prod-
uct of nucleophilic addition of this alcohol to (R)-meth-
oxyiminium ion from the Re-face as the major product
(7a), whereas (R)-(+)-1-(2-naphthyl)ethanol attacked
the (S)-intermediate B mainly from the Si-face with
the formation of diastereoisomer 8c as the major prod-
uct. The second most abundant isomers 7b or 8d corre-
spond to the attack of the (S)-alcohol to (S)-ion and
(R)-alcohol to (R)-ion from the sulfur side of the thiaz-
olidine ring. Although the expected diastereoselectivity
was achieved, isolated yields of major products of
1-methoxyspirobrassinol 1-(2-naphthyl)ethyl ethers
were only 28% (7a) or 29% (8c) and their oxidation with
PCC afforded moderate, 50–52% yields of (R)-(+)-2 or
(S)-(ꢀ)-2. Therefore, the application of the more com-
mon chiral auxiliary, (+)- and (ꢀ)-menthol, was studied
with the aim of improving the yields. Stereoselection by
menthol was expected to work on the basis of the same
model as in the case of 1-(2-naphthyl)ethanol, with the
large isopropyl group being the most remote from the
reaction center during the approach of nucleophile to
iminium ion. Reaction with (1S,2R,5S)-(+)- and
(1R,2S,5R)-(ꢀ)-menthol proceeded with similar diaste-
reoselectivity; however, the corresponding 1-methoxy-
spirobrassinol menthyl ethers 9a (38%) or 10c (40%)
were obtained in higher isolated yields. Moreover the
The structures of individual diastereoisomers of 1-(2-
naphthyl) and menthyl ethers were determined by
NMR studies, including 2D HSQC, HMBC, and
NOESY or NOE-dif. experiments. Products 7b, 8b, 9b,
10b, 7d, 8d, 9d, and 10d exhibited in the NOESY spectra
cross peaks between H-2 and Hb protons evidencing
their structure as cis-diastereoisomers as shown for com-
pound 9b depicted in Fig. 3. The absolute configuration
at C-3 was determined after oxidation to (R)- or (S)-1-
methoxyspirobrassinin (2). Enantiomers of 2 were
identified by comparison of their CD-spectra with
already published data.9 Taking into account the cis-
diastereoisomeric structure, the configuration at C-2 of
Table 1. Stereochemistry, ratio of diastereoisomers and yields of 1-methoxyspirobrassinol 1-(2-naphthyl)ethyl and menthyl ethers
R*
Compound/ratioa (%)/yieldb (%)
Trans-
Trans-
Cis-
Cis-
SCH3
SCH3
SCH3
SCH3
N
N
N
N
R
S
S
S
S
S
S
R
S
R
R
S
*
OR
OR
OR
OR
*
*
*
N
OCH3
N
N
N
OCH3
OCH3
OCH3
(S)-(ꢀ)-Npc
7a
69
57
7b
22
18
7c
2
2
7d
7
6
(R)-(+)-Npc
8a
7
6
8b
7
6
8c
68
54
8d
18
14
(1S,2R,5S)-(+)-Mtd
(1R,2S,5R)-(ꢀ)-Mtd
9a
57
52
9b
18
19
9c
20
13
9d
5
3
10a
17
10b
3
10c
60
10d
20
14
3
56
18
a The ratio of compounds 7 and their enantiomeric compounds 8 as well as 9 and their enantiomeric compounds 10 was determined by the integration
of non-overlapping singlets of H-2 and the doublets of the Hb protons (see Fig. 3) in 1H NMR spectra of crude product mixtures.
b In the case of compounds 7a–7d and enantiomeric 8a–8d, the yields were calculated from the yield of chromatographically isolated mixture of all
four diastereoisomers (83%), with respect to the ratio of diastereoisomers. In the case of 9a–9d and enantiomeric 10a–10d, the yields were calculated
from the chromatographically isolated yields of the mixtures of trans-isomers 9a and 9c or 10a and 10c, (65% or 70%) and cis-isomers 9b and 9d or
10b and 10d, (20% or 21%), using the same observed ratio of diastereoisomers 80:20 for both mixtures of trans- and 85:15 for mixtures of
cis-isomers.
c 1-(2-Naphthyl)ethyl.
d Menthyl.

ˇ
Z. Curillova´ et al. / Tetrahedron Letters 48 (2007) 8200–8204
8203
meric excesses of synthesized enantiomers were deter-
mined by chiral HPLC, on the column CHIRACEL
OD (ID 0.46 · 5 cm + 0.46 · 25 cm), using eluent hex-
ane with 0.1% propan-2-ol at a flow rate 1.0 mL/min.
Ha
H
N
SCH3
4
Hb
4a
7C' H3
6
S
H
2
5'
7a
N
O
1'H
CH3
9'
OCH3
3'
8'CH3
10'
2. Experimental procedure for (R)-(+)-1-methoxyspiro-
brassinin and (2R,3R)-(ꢀ)-1-methoxyspirobrassinol
methyl ether
9b
NOESY
Figure 3.
2.1. (2R,3R)-1-Methoxyspirobrassinol (1S,2R,5S)-
menthyl ether 9a
cis-isomers was assigned (Table 1). In the case of com-
pounds 7a, 8a, 9a, 10a, 7c, 8c, 9c, and 10c the NOESY
and NOE-differential experiments did not show the
interaction between Hb and H-10 proton of secondary
alcohol residue, which was expected to confirm their
trans-diastereoisomeric configuration. However, the
interaction between H-2 and Hb was also not observed
and thus the structure of trans-diastereoisomers was
assigned to these products. The absolute configuration
at C-3 and C-2 was assigned as in the case of cis-
diastereoisomers.
To a stirred mixture of 1-methoxybrassinin 6 (133 mg,
˚
0.5 mmol) and powdered molecular sieves (3 A) in dry
CH2Cl2 (7 mL) at room temperature was added freshly
prepared solution of Br2 (0.028 mL, 88 mg, 0.55 mmol)
in dry CH2Cl2 (1.25 mL). After stirring for 1 min, a sus-
pension of (1S,2R,5S)-(+)-menthol (86 mg, 0.55 mmol),
triethylamine (509 mg, 0.702 mL, 5 mmol) and pow-
˚
dered molecular sieves (3 A) in dry CH2Cl2 (7 mL) was
added. Stirring was continued for 20 min, and the reac-
tion mixture was diluted with CH2Cl2 (25 mL), washed
with 1 M HCl (13 mL) and water (20 mL). The organic
layer was dried over anhydrous Na2SO4. The residue
obtained after evaporation of solvent was subjected to
chromatography on silica gel (13 g, petroleum ether/
diethyl ether 4:1), affording 137 mg (65%) of the mixture
of trans-diastereoisomers (9a, 9c) and 46 mg (22%) of
the mixture of cis-diastereoisomers (9b, 9d). Subsequent
chromatography of the mixture of trans-diastereo-
For the synthesis of targets, 1-methoxyspirobrassinol
menthyl ethers 9a and 10c, as the major products of ster-
eoselective spirocyclization, were used (Scheme 2). The
oxidation of 9a with PCC smoothly afforded the natu-
ral enantiomer of 1-methoxyspirobrassinin [(R)-(+)-2]
whereas its unnatural enantiomer [(S)-(ꢀ)-2] was
obtained by oxidation of 10c. To prepare the natural
(2R,3R)-(ꢀ)-1-methoxyspirobrassinol methyl ether
[(2R,3R)-(ꢀ)-3], the methanolysis of 9a was investigated.
It was found that TFA-catalyzed methanolysis afforded
a mixture of (2R,3R)-(ꢀ)-3 and (2S,3R)-(+)-3 in the
ratio 1:1, easily separable by column chromatography.
The analogous reaction of 10c afforded the (2S,3S)-3
and (2R,3S)-3 isomers of 1-methoxyspirobrassinol
methyl ether in the ratio 1:1 (Scheme 2). The enantio-
isomers 9a and 9c on silica gel (20 g, CH2Cl2) gave 9a
25
[79 mg (38%)] as a colorless oil, ½aꢁD ꢀ8.9 (c 0.74,
CHCl3), >99% ee.11
25
Enantiomeric product 10c (40%), ½aꢁD +11.0 (c 0.88,
CHCl3), >99% ee was prepared by the same procedure
using (1R,2S,5R)-(ꢀ)-menthol.
N
N
N
SCH3
TFA
CH3OH
SCH3
SCH3
PCC
S
S
S
9a
OCH3
OCH3
CH2Cl2
OCH3
OCH3
O
N
N
N
OCH3
(2R,3R)-(-)-3 (43%)
(R)-(+)-2 (68%)
(2S,3R)-(+)-3 (35%)
97% ee
25
97% ee
25
98% ee
25
9
[α]
+61.1 (c 1.0, CH OH)
3
[α]
-10.8 (c 0.1, CHCl )
3
D
[α]
+39.1 (c 0.1, CHCl )
3
D
D
N
N
N
SCH3
SCH3
SCH3
PCC
S
S
S
TFA
10c
OCH3
CH3OH
CH2Cl2
OCH3
N
O
N
N
OCH3
OCH3
OCH3
(2S,3S)-(+)-3 (36%)
(2R,3S)-(-)-3 (41%)
(S)-(-)-2 (70%)
95% ee
25
92% ee
25
93% ee
25
9
[α]
+7.3 (c 0.1, CHCl )
3
[α]
-38.5 (c 0.1, CHCl )
[α]
-62.7 (c 1.0, CH OH)
3
D
D
3
D
Scheme 2.

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Z. Curillova´ et al. / Tetrahedron Letters 48 (2007) 8200–8204
8204
2.2. (R)-(+)-1-Methoxyspirobrassinin 2
work was also supported by the State NMR Programme
No. 2003SP200280203.
To a vigorously stirred slurry of pyridinium chlorochro-
mate (138 mg, 0.642 mmol) and anhydrous magnesium
sulfate (116 mg, 0.936 mmol) in dry CH2Cl2 (0.45 mL),
a solution of 9a (90 mg, 0.214 mmol) in dry CH2Cl2
(1.8 mL) was added. The reaction mixture was stirred
for 24 h at room temperature and then diluted with
CH2Cl2 (2 mL). After adding a small amount of silica
gel, the solvent was evaporated and the residue pre-
absorbed on silica gel was purified by silica gel column
chromatography (4 g, petroleum ether/diethyl ether
4:1) to give 43 mg (68%) of (R)-(+)-1-methoxyspiro-
brassinin [(R)-(+)-2] as colorless needles, mp 129–
131 ꢁC (EtOAc/hexane). The spectral data were fully
identical with those of natural product.4 The absolute
configuration was determined by direct comparison of
ECD spectra with published data.9
References and notes
1. Purkayastha, R. P. In Handbook of Phytoalexin Metabo-
lism and Action; Daniel, M., Purkayastha, R. P., Eds.;
Progress in Phytoalexin Research During the Past 50
years; Marcel Dekker: New York, 1995; pp 1–39.
2. For a recent reviews on cruciferous indole phytoalexins,
see: (a) Pedras, M. S. C.; Jha, M.; Ahiahonu, P. W. K.
Curr. Org. Chem. 2003, 7, 1635–1647; (b) Pedras, M. S. C.;
Zheng, Q.; Sarma-Mampillapalle, V. K. Nat. Prod.
Commun. 2007, 2, 319–330.
3. Takasugi, M.; Monde, K.; Katsui, N.; Shirata, A. Chem.
Lett. 1987, 1631–1632.
4. Gross, D.; Porzel, A.; Schmidt, J. Z. Naturforsch., Sect. C
1994, 49, 281–285.
5. Monde, K.; Takasugi, M.; Shirata, A. Phytochemistry
1995, 39, 581–586.
6. Suchy´, M.; Kutschy, P.; Monde, K.; Goto, H.; Harada,
2.3. (2R,3R)-(ꢀ)-1-Methoxyspirobrassinol methyl ether 3
´
N.; Takasugi, M.; Dzurilla, M.; Balentova, E. J. Org.
To a solution of 9a (49 mg, 0.117 mmol) in dry methanol
(1 mL) was added TFA (15 mg, 0.01 mL, 0.13 mmol).
The reaction mixture was stirred for 12 h, solvent evap-
orated and the residue obtained subjected to chromato-
graphy on silica gel (10 g, cyclohexane/diethyl ether 2:1)
affording 15 mg (43%) of (2R,3R)-(ꢀ)-3; Rf (cyclo-
hexane/diethyl ether 2:1) 0.51 as a colorless oil, and
12 mg (35%) of (2S,3R)-(+)-3; Rf (cyclohexane/diethyl
ether 2:1) 0.31 as colorless crystals, mp 77–79 ꢁC
(hexane). The spectral data for (2R,3R)-(ꢀ)-3 were fully
identical with those of natural product,5 whereas the
data for (2S,3R)-(+)-3 were fully identical with those
of corresponding racemate.9
Chem. 2001, 66, 3940–3947.
7. Kutschy, P.; Suchy´, M.; Monde, K.; Harada, N.;
ˇ
´
´
ˇ
´
Marusˇkova, R.; Curillova, Z.; Dzurilla, M.; Miklosova,
M.; Mezencev, R.; Mojzˇisˇ, J. Tetrahedron Lett. 2002, 43,
9489–9492.
8. The trans-diastereoisomer is regarded as the one with the
sulfur of thiazoline ring and methoxy group in position 2,
located on the opposite sides of indoline ring, whereas the
cis-diastereoisomer has the sulfur and 2-methoxy group on
the same side of indoline ring.
9. Monde, K.; Taniguchi, T.; Miura, N.; Kutschy, P.;
ˇ
´
´
´
ˇ
Curillova, Z.; Pilatova, M.; Mojzˇis, J. Bioorg. Med. Chem.
2005, 13, 5206–5212.
10. Burgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153–
¨
161.
11. Data for 9a: Anal. Calcd for C22H32N2O2S2 requires: C,
62.82; H, 7.67; N, 6.66. Found: C, 62.5; H, 7.9; N, 6.4.
mmax (CHCl3) 2953, 2893, 2863, 1567, 1453, 1120, 1033,
987, 933 cmꢀ1; dH (400 MHz, CDCl3) 7.29 (dd, 1H, J 7.5,
1.2 Hz, H-4), 7.23 (dt, 1H, J 1.2, 7.7 Hz, H-6); 7.01 (dt,
1H, J 1.0, 7.5 Hz, H-5), 6.95 (dd, 1H, J 7.9, 0.6 Hz, H-7),
5.16 (s, 1H, H-2); 5.02 (d, 1H, J 15.3 Hz, Hb), 3.93 (s, 3H,
OCH3), 3.91 (d, 1H, J 15.3 Hz, Ha), 3.59 (dt, 1H, J 4.3,
10.5 Hz, H-10), 2.56 (s, 3H, SCH3); 2.41 (quinted, 1H, J
6.8, 2.0 Hz, H-80), 2.24–2.19 (m, 1H, H-60), 1.68–1.63 (m,
2H, H-30, H-40), 1.42–1.26 (m, 2H, H-20, H-50), 1.06–0.86
(m, 3H, H-30, H-40, H-60), 0.94 (d, 3H, J 6.9 Hz, H-70),
0.92 (d, 3H, J 6.9 Hz), and 0.83 (d, 3H, J 6.9 Hz) [H-90 and
H-100]; NOESY correlations Ha/H-4, Hb: OCH3/H-7:
H-2/H-10, H-60; dC (100 MHz, CDCl3) 163.3 (C@N), 148.5
(C-7a), 129.4 (C-6), 128.7 (C-4a), 124.0 (C-4), 123.8 (C-5),
112.8 (C-7), 104.1 (C-2), 79.5 (C-10), 70.1 (CH2), 69.3
(Cspiro), 63.7 (OCH3), 48.7 (C-50), 41.6 (C-60), 34.3 (C-40),
31.5 (C-20), 24.8 (C-80), 23.1 (C-30), 22.4 (C-70), 21.4 and
16.3 (C-90 and C-100), 15.0 (SCH3); MALDI-TOF MS,
m/z (%): 420.9 [M+H]+ (94); CD (CH3OH, nm) kext (De):
214 (ꢀ39.2), 238 (+8.1), 264 (ꢀ2,8), 293 (+4.6).
In summary, the diastereoselective synthesis of spiroindo-
line[3,50]thiazolidine-type phytoalexins was achieved by
the spirocyclization of 1-methoxybrassinin in the
presence of (+)- and (ꢀ)-menthol as the chiral nucleo-
phile with the formation of chiral 1-methoxyspirobrass-
inol menthyl ethers. Oxidation of menthyl ethers with
PCC afforded (R)-(+)-1-methoxyspirobrassinin and its
unnatural (S)-(ꢀ)-isomer in 26% and 28% overall yields
and enantiomeric excesses 97% and 93%. Natural
(1R,2R)-(ꢀ)-1-methoxyspirobrassinol methyl ether
(97% ee) and its other three unnatural stereoisomers
(92–98% ee) were synthesized by TFA-catalyzed meth-
anolysis of chiral 1-methoxyspirobrassinol menthyl
ethers.
Acknowledgments
We thank the Slovak Grant Agency for Science (Grant
No. 1/3553/06) for financial support of this work. This