Enantioselective synthesis of (-)-dendroprimine and isomers

Article abstract of DOI:10.1021/np049902u

An enantioselective and diastereoselective synthesis of six 5,7-dimethylindolizidine isomers is described via an intramolecular cyclization that involves an allylsilyl nucleophilic group and an acyliminium ion. The first total synthesis of naturally occurring (-)-dendroprimine has been achieved in five steps.

Full text of DOI:10.1021/np049902u

J . Nat. Prod. 2004, 67, 1029-1031
1029
En a n tioselective Syn th esis of (-)-Den d r op r im in e a n d Isom er s
Axelle De Saboulin Bollena, Yvonne Gelas-Mialhe,* J ean-Claude Gramain, Anne Perret, and Roland Remuson
De´partement de Chimie, UMR 6504, CNRS et Universite´ Blaise Pascal (Clermont-Ferrand), 63177 Aubie`re Cedex, France
Received March 4, 2004
An enantioselective and diastereoselective synthesis of six 5,7-dimethylindolizidine isomers is described
via an intramolecular cyclization that involves an allylsilyl nucleophilic group and an acyliminium ion.
The first total synthesis of naturally occurring (-)-dendroprimine has been achieved in five steps.
Sch em e 1a
(-)-Dendroprimine (10a ) is an alkaloid isolated from
Dendrobium primulinum Lindl (Orchidaceae) and shown
to be a 5,7-dimethylindolizidine.1 Its relative configuration
was determined after the synthesis of the four racemic
diastereomers of this indolizidine, and a conformational
analysis of these diastereomers has been discussed.2 Its
identification as (5R,7S,9R)-5,7-dimethylindolizidine has
been firmly established.3 Its asymmetric synthesis has
never been reported; only (-)-(5R,7S,9S)-9-epi-dendro-
primine has been synthesized.4
In a previous publication we have described the enan-
tioselective synthesis of indolizidine alkaloid (-)-167B.5 The
a
key step in the synthesis was an intramolecular cyclization
of acyliminium ion substituted by an allylsilyl side chain
as an internal π-nucleophile. This reaction has proved to
be a very powerful method for elaboration of the indolizi-
dine ring system. We describe here application of this
methodology to the enantioselective synthesis of (-)-
dendroprimine and its isomers.
(i) Succinic anhydride, AcCl, toluene, reflux; (ii) NaBH4, H2SO4/EtOH,
-30 °C; (iii) Me3SiCH2MgCl, CeCl3, HCl.
Sch em e 2a
Resu lts a n d Discu ssion
The first steps of our synthesis were carried out as shown
in Scheme 1. The starting material was ethyl-2-aminopro-
panoate (1). Chirality was introduced with isomers (R)-1a
and (S)-1b, which were prepared by a Michael reaction
according to Davies’ procedure from ethyl crotonate and
respectively (R)- and (S)-N-benzyl-R-methylbenzylamine.6
a
(i) LiAlH4, THF; (ii) H2, Pd/C or PtO2.
Reaction of 1a with succinic anhydride and then with
acetyl chloride in refluxing toluene gave imide 2a in
quantitative yield. Imide 2a was reduced into ethoxylactam
3a in 65% isolated yield. Ethoxylactam 3b, the enantiomer
of 3a , was synthesized in the same way from (S)-1b. These
compounds were isolated as a mixture of two diastereo-
mers, which were not separated.
Sch em e 3a
The intramolecular cyclization reaction was performed
in the next step. Ethoxylactam 3a was treated with the
cerium reagent derived from trimethylsilylmethylmagne-
sium chloride and cerium chloride. The mixture was then
hydrolyzed with 1 N HCl to give methyleneindolizidinones
5a and 6a in a 4:1 ratio and 90% yield. These diastereo-
isomers could not be separated. Their relative configuration
was deduced from their NMR spectra, by comparison with
5-propyl analogues.5 This reaction involved formation of
allylsilyl-substituted acyliminium ion 4a , which cyclized
spontaneously. In the same way, ethoxylactam 3b was also
reacted with trimethylsilylmethylmagnesium chloride and
CeCl3 to give a mixture of cyclization products (5S,9S)-5b
and (5S,9R)-6b.
a
(i) H2, Pd/C or PTO2; (ii) LiAlH4, THF.
Two ways were then studied to prepare dendroprimine
and isomers. They are summarized in Schemes 2 and 3.
According to Scheme 2, in a first step, reduction of the
lactam functional group of cyclization products 5a and 6a
with lithium aluminum hydride afforded a 4:1 mixture of
methyleneindolizidines 7a and 8a in quantitative yield.
* Corresponding author. Tel: +33473407645. Fax: +33473407717.
E-mail: gelas@chimie.univ-bpclermont.fr.
10.1021/np049902u CCC: $27.50
© 2004 American Chemical Society and American Society of Pharmacognosy
Published on Web 06/25/2004

1030 J ournal of Natural Products, 2004, Vol. 67, No. 6
De Saboulin Bollena et al.
These isomers were separated by flash column chromatog-
raphy to give 7a and 8a in 50 and 18% yields, respectively.
Enantiomers (5S,9S)-7b and (5S,9R)-8b were also prepared
from a crude mixture of methyleneindolizidinones (5S,9S)-
5b and (5S,9R)-6b.
omer 11b was also achieved in five steps, with 10% overall
yield. These results constitute the first total synthesis of
naturally occurring (-)-dendroprimine.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Optical rotations
were recorded on a J asco model DIP-370 polarimeter. 1H
(400.13 MHz) and 13C (100.61 MHz) NMR spectra were
recorded on a Bruker AC 400 spectrometer. Chemical shifts
are measured as δ values (ppm). TLC analyses were performed
on Merck 60 F254 silica gel plates and were visualized using
iodine. Flash column chromatography was carried out using
Merck silica gel (grade 60, 230-400 mesh).
Catalytic hydrogenation of the olefinic bond of these
isomers was subsequently studied.
Palladium-catalyzed hydrogenation of 7a was found to
be stereoselective, giving a mixture of 9a and 10a in a 3:1
ratio. A similar stereoselectivity was observed (9a /10a )
2:1) when hydrogenation was catalyzed over platinum
oxide. The major isomer was attributed a configuration that
corresponds to a trans orientation of the methyl groups.
Flash column chromatography afforded 9a in 70% yield.
Catalytic hydrogenation of 8a over either palladium on
carbon or platinum oxide gave one isomer in quantitative
yield. We have assigned to this isomer the structure of
compound 11a , in which the methyl groups have a trans
orientation. The reaction proceeded with excellent diaste-
reoselectivity (>90%), as the C-7 diastereomer of 11a was
only detected as a minor component in the crude reaction
mixture. Synthesis of enantiomers (5S,7S,9S)-9b and
(5S,7S,9R)-11b was achieved in 50 and 15% isolated yields,
respectively, from the product of catalytic hydrogenation
over palladium on carbon of a crude mixture of diastere-
omers 7b and 8b (7b/8b ) 4:1).
N-(1-Meth yl-2-eth oxyca r bon yleth yl)su ccin im id e (2a ).
A solution of 1a (13.1 g, 0.1 mol) and succinic anhydride (11
g, 0.11 mol) in toluene (300 mL) was refluxed for 24 h. Then
acetyl chloride (29 mL, 0.4 mol) was added, and the solution
was refluxed for 5 h. The solvent was removed in vacuo, and
the resulting mixture was taken up with 100 mL of methylene
chloride and washed with 10% HCl (50 mL), 10% NaOH (50
mL), and then with water (50 mL). The organic layer was dried
and concentrated in vacuo. Imide 2a was isolated with a
quantitative yield and was used in the next step without
purification: [R]25D -1.0 (c 1.9, CHCl3); 1H NMR (CDCl3) δ 4.56
(1H, m), 4.08 (2H, m), 3.05 (1H, dd, J ) 16.1, 9.7 Hz), 2.59
(1H, dd, J ) 16.1, 5.6 Hz), 2.57 (4H, s), 1.32 (3H, d, J ) 7.0
Hz), 1.16 (3H, t, J ) 7.1 Hz); 13C NMR (CDCl3) δ 177.1 (C),
170.7 (C), 60.5 (CH2), 44.0 (CH), 36.8 (CH2), 27.9 (CH2), 17.7
(CH3), 14.0 (CH3); anal. C 56.50%, H 7.26%, N 6.79%, calcd
for C10H15NO4, C 56.34%, H 7.04%, N 6.57%.
Another way was studied to prepare these compounds.
Hydrogenation of the double bond of methylene lactam
isomers was first studied, then the lactam functional group
was reduced. This procedure is summarized in Scheme 3.
(S)-2b: [R]25 +1.1 (c 1.6, CHCl3).
D
5-Eth oxy-N-(1-m eth yl-2-eth oxyca r bon yleth yl)p yr r oli-
d in -2-on e (3a ). NaBH4 (1.9 g, 0.05 mol) was slowly added to
a solution of 2a (2.13 g, 0.01 mol) in anhydrous ethanol (100
mL) at -10 °C under argon. After stirring for 15 min, 10 drops
of a 2 N solution of HCl in ethanol were added every 15 min
during 2 h. The NaBH4 excess was destroyed by adding a 2 N
solution of HCl in ethanol until pH ) 3. Then, the solvent was
removed and the residue, taken up with methylene chloride,
was washed with 100 mL of saturated aqueous NaHCO3. The
organic layer was dried and concentrated in vacuo. The
resulting oil (2.1 g) was purified by column chromatography
on silica gel (ethyl ether/pentane, 8:2) to give 3a (1.6 g, 65%
yield), which was isolated as a mixture of two diastereomers
Hydrogenation of a crude mixture of cyclization prducts
5a and 6a (5a /6a ) 4:1) over palladium on carbon provided
a mixture of lactams 12a , 13a , and 14a in which isomer
12a was preponderant (12a /13a /14a ) 50:30:20), whereas
in hydrogenation over platinum oxide lactam 13a was
formed as the major isomer (12a /13a /14a ) 15:65:20).
Flash column chromatography gave pure 14a in 18% yield,
but 12a and 13a could not be separated (50% yield). A
mixture of the three isomers was used without purification
for the next step.
The last step was reduction of the lactam functional
group with lithium aluminum hydride. A crude mixture of
lactam isomers (12a /13a /14a ) 15:65:20) was quantita-
tively converted to the corresponding indolizidines (9a /10a /
11a ) 15:65:20), which were separated by flash column
chromatography. Pure 10a was obtained in 30% yield. The
specific rotation found for 10a ([R]25D -37.5 (c 1.3, CHCl3))
was in agreement with the literature value1 for (-)-
dendroprimine ([R]D -38 (c 1.00, CHCl3)), thus confirming
the stereochemistry attributed to hydrogenation products.
Enantiomer (5S,7R,9S)-10b was prepared from a crude
mixture of (5S,9S)-5b and (5S,9R)-6b (5b/6b ) 4:1) after
catalytic hydrogenation over platinum oxide, reduction of
the lactam functional group, and purification by flash
column chromatography.
In conclusion, we have developed a concise method for
the enantioselective synthesis of six enantiomers of 5,7-
dimethylindolizidine, starting from readily available
materials. The key step in the synthesis is a stereoselec-
tive intramolecular cyclization that involves an allylsilyl
nucleophilic group and an acyliminium ion. The other steps
are functional group transformations. By proper choice of
reactions and hydrogenation conditions either (-)-den-
droprimine 10a or its 7-epi-isomer 9a could be obtained.
These isomers and their enantiomers 10b and 9b were
prepared in five steps with overall yields of 17 and 20%,
respectively. Synthesis of diastereomer 11a and enanti-
1
in a 3:2 ratio: H NMR (CDCl3) δ 4.99 (0.4H, d, J ) 5.5 Hz),
4.95 (0.6H, d, J ) 5.5 Hz), 4.40 (0.4H, m), 4.20 (0.6H, m,), 4.08
(0.8H, q, J ) 7.1 Hz), 4.05 (1.2H, q, J ) 7.1 Hz), 3.40 (2H, m),
2.92 (0.6H, dd, J ) 16.2, 7.4 Hz), 2.30-2.15 (1H, m), 2.65-
2.35 (2.4H, m), 2.05-1.85 (2H, m), 1.28 (1.8H, d, J ) 6.9 Hz),
1.25 (1.2H, d, J ) 6.9 Hz), 1.19 (1.8H, t, J ) 7.2 Hz), 1.18
(1.2H, t, J ) 7.2 Hz), 1.17 (1.8H, t, J ) 7.1 Hz), 1.16 (1.2H, t,
J ) 7.1 Hz); 13C NMR (CDCl3) δ 174.9 (C), 174.7 (C), 171.5
(C), 170.9 (C), 89.4 (CH), 88.2 (CH), 61.4 (CH2), 61.0 (CH2),
60.4 (CH2), 60.2 (CH2), 45.7 (CH), 45.3 (CH), 39.3 (CH2), 38.8
(CH2), 29.1 (CH2), 29.0 (CH2), 24.9 (CH2), 24.8 (CH2), 19.3
(CH3), 17.7 (CH3), 15.2 (CH3), 14.0 (CH3).
5-Meth yl-7-m eth ylen ein d olizid in -3-on es (5a a n d 6a ).
CeCl3‚7H2O (16.4 g, 0.044 mol) was dried by stirring under
0.01 mbar for 48 h at 120 °C. The flask was flushed with argon,
then dry THF (75 mL) was added and the white suspension
was stirred at room temperature for 2 h. This slurry was cooled
to -78 °C under argon, and trimethylsilylmethylmagnesium
chloride in THF [prepared from chloromethyltrimethylsilane
(6.15 mL, 0.044 mol) and magnesium pellets (1.1 g, 0.045 mol)
in dry THF (25 mL)] was added dropwise over a period of 60
min. The cold mixture was stirred for 2 h, and a solution of
3a (2.4 g, 0.01 mol) in 10 mL of dry THF was added. The
resulting mixture was allowed to warm to room temperature
and stirred for 3 days. The reaction mixture was then cooled
to 0 °C, and a 1 N HCl solution (160 mL) was added. After
stirring for 1 h the aqueous layer was extracted with ether (3
× 150 mL). The combined organic layers were dried over
MgSO4 and concentrated. The resulting crude oil (1.5 g, 90%
yield) was shown by 1H and 13C NMR spectroscopy to be a

Synthesis of (-)-Dendroprimine
J ournal of Natural Products, 2004, Vol. 67, No. 6 1031
mixture of 5a and 6a in a 4:1 ratio. These isomers could not
be separated by flash column chromatography. The mixture
was purified by flash column chromatography on silica gel
(ethyl acetate): anal. C 72.97%, H 9.20%, N 8.00%, calcd for
(2H, m, H-7, H-2b), 1.50-1.35 (2H, m, H-6a, H-6b), 1.35-1.20
(1H, m, H-8b), 0.92 (3H, d, J ) 6.7 Hz, NCHCH3), 0.85 (3H, d,
J ) 6.4 Hz, CHCH3), 0.75 (1H, m, H-1b); 13C NMR (CDCl3) δ
54.2 (CH, C-5), 49.9 (CH, C-9), 48.6 (CH2, C-3), 40.6 (CH2, C-1),
40.0 (CH2, C-6), 30.8 (CH2, C-8), 25.6 (CH, C-7), 22.4 (CH3,
CHCH3), 21.1 (CH2, C-2), 9.7 (CH3, NCHCH3).
C
10H15NO, C 72.73%, H 9.09%, N 8.48%.
5a : H NMR (CDCl3) δ 4.83 (1H, s), 4.72 (1H, s), 4.40 (1H,
1
m), 3.60-3.45 (1H, m), 2.45-1.40 (8H, m), 1.00 (3H, d, J )
7.4 Hz); 13C NMR (CDCl3) δ 174.1 (C), 141.9 (C), 113.3 (CH2),
54.8 (CH), 45.0 (CH), 43.0 (CH2), 39.6 (CH2), 31.3 (CH2), 25.9
(CH2), 19.3 (CH3).
(5R,7S,9R)-10a : [R]25 -37.5 (c 1.3, CHCl3) [lit.1 [R]D -38
D
1
(c 1.00, CHCl3)]; H NMR (CDCl3) δ 3.18 (1H, m, H-9), 3.10
(1H, m, H-3a), 2.80 (1H, m, H-3b), 2.38 (1H, m, H-5), 1.9-1.5
(8H, m), 1.00 (3H, d, J ) 6.0 Hz, NCHCH3), 0.95-0.90 (1H,
m, H-8), 0.88 (3H, d, J ) 6.3 Hz, CHCH3); 13C NMR (CDCl3) δ
60.8 (CH, C-9), 51.7 (CH2, C-3), 50.6 (CH, C-5), 43.7 (CH2, C-8),
35.9 (CH2, C-1), 27.4 (CH2, C-6), 26.1 (CH, C-7), 22.9 (CH3,
CHCH3), 22.7 (CH2, C-2), 22.6 (CH3, NCHCH3).
6a : 1H NMR (CDCl3) δ 4.80 (1H, s), 4.73 (1H, s), 3.60-3.45
(2H, m), 2.50 (1H, dd, J ) 15.4, 3.0 Hz), 2.45-1.40 (7H, m),
1.38 (3H, d, J ) 7.4 Hz); 13C NMR (CDCl3) δ 175.6 (C), 142.5
(C), 112.2 (CH2), 58.4 (CH), 50.4 (CH), 40.5 (CH2), 40.4 (CH2),
32.6 (CH2), 26.9 (CH2), 20.7 (CH3).
(5R,7R,9S)-11a : [R]25 -32.8 (c 0.4, CHCl3); 1H NMR
D
Red u ction of th e La cta m F u n ction a l Gr ou p . A mixture
of lactam (0.2 g, 0.0012 mol) and LiAlH4 (0.16 g, 0.0042 mol)
in dry THF (10 mL) was refluxed for 12 h. Ether was added,
followed by water (0.16 mL), 10% NaOH (0.16 mL), and water
(0.48 mL). After filtration, the organic layer was dried and
concentrated to give the crude reduction product in quantita-
tive yield. It was purified by flash chromatography (ethyl
ether).
Ca ta lytic Hyd r ogen a tion of th e Olefin ic Bon d . Meth-
yleneindolizidine (0.2 g) was dissolved in methanol (10 mL),
and catalyst (0.2 g Pd/C or 0.05 g PtO2) was added. The
resultant mixture was stirred under 1 atm of hydrogen at room
temperature for 5 h in a Parr apparatus. The catalyst was
removed by filtration through a Celite pad, and the solvent
was evaporated. The crude product was purified by flash
chromatography (ethyl ether).
(CDCl3) δ 3.30 (1H, td, J ) 2.8, 8.6 Hz, H-9), 2.30-1.40 (11H,
m), 1.10 (3H, d, J ) 6.4 Hz), 1.05-0.95 (1H, m), 0.90 (3H, d,
J ) 6.4 Hz); 13C NMR (CDCl3) δ 64.7 (CH), 58.1 (CH), 51.4
(CH2), 43.1 (CH2), 39.5 (CH2), 31.3 (CH), 30.3 (CH2), 21.9 (CH3),
21.6 (CH3), 21.0 (CH2).
(5S,7S,9S)-9b: [R]25 -6.9 (c 1.0, CHCl3).
D
(5S,7R,9S)-10b: [R]25 +36.8 (c 1.2, CHCl3).
D
(5S,7S,9R)-11b: [R]25 +33.7 (c 2.0, CHCl3).
D
1
5,7-Dim eth ylin d olizid in -3-on es. 12: H NMR (CDCl3) δ
4.30 (1H, m, H-5), 3.52 (1H, m, H-9), 2.23 (2H, m), 2.10 (1H,
m), 1.75 (2H, m), 1.45 (3H, m), 1.05 (3H, d, J ) 7.0 Hz,
NCHCH3), 0.86 (3H, d, J ) 6.4 Hz, CHCH3), 0.72 (1H, m,
H-8a); 13C NMR (CDCl3) δ 173.2 (C, CO), 53.0 (CH, C-9), 43.4
(CH, C-5), 42.2 (CH2, C-8), 38.1 (CH2), 30.6 (CH2), 25.4 (CH2),
25.1 (CH), 21.9 (CH3, CHCH3), 16.6 (CH3, NCHCH3).
13: 1H NMR (CDCl3) δ 4.05 (1H, m, H-5), 3.72 (1H, m, H-9),
2.3-1.3 (8H, m), 1.10-0.90 (1H, m), 1.12 (3H, d, J ) 6.9 Hz,
NCHCH3), 1.01 (3H, d, J ) 7.1 Hz, CHCH3); 13C NMR (CDCl3)
δ 173.8 (C, CO), 48.9 (CH, C-9), 44.5 (CH, C-5), 38.9 (CH2),
36.0 (CH2), 30.4 (CH2), 25.9 (CH), 25.8 (CH2), 20.9 (CH3,
CHCH3), 19.8 (CH3, NCHCH3).
5-Meth yl-7-m eth ylen ein d olizid in es. (5R,9R)-7a : 50%
yield; [R]25 +8.0 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.77 (1H,
D
q, J ) 1.8 Hz, CdCH2), 4.69 (1H, q, J ) 1.8 Hz, CdCH2), 3.30
(1H, d quin, J ) 1.9, 6.0 Hz, H-5), 2.85 (1H, dt, J ) 3.2, 8.8
Hz, H-3a), 2.60-2.46 (3H, m, H-3b, H-6a, H-9), 2.35 (1H, ddd,
J ) 1.9, 3.3, 12.8 Hz, H-8a), 2.05 (1H, dt, J ) 1.9, 13.0 Hz,
H-6b), 1.94-1.77 (3H, m, H-1a, H-2a, H-8b), 1.67 (1H, m,
H-2b), 1.36 (1H, m, H-1b), 0.91 (3H, d, J ) 6.0 Hz, NCHCH3);
13C NMR (CDCl3) δ 144.1 (C, C-7), 110.0 (CH2, CdCH2), 55.4
(CH, C-9), 50.4 (CH, C-5), 48.5 (CH2, C-3), 40.2 (CH2, C-6),
40.1 (CH2, C-8), 30.4 (CH2, C-1), 21.2 (CH2, C-2), 10.3 (CH3,
NCHCH3); anal. C 79.25%, H 11.41%, N 8.97%, calcd for
1
14: 18% yield; H NMR (CDCl3) δ 3.20 (1H, m, H-9). 3.10
(1H, m, H-5), 2.22 (2H, m, H-2a, H-2b), 2.00 (1H, m, H-1a),
1.72 (1H, d, J ) 12.8 Hz, H-8a), 1.60 (3H, d, J ) 6.5 Hz,
NCHCH3), 1.60-1.40 (3H, m, H-1b, H-6a, H-7), 0.85 (3H, d, J
) 5.8 Hz, CHCH3), 0.85 (1H, m, H-6b), 0.80 (1H, m, H-8b);
13C NMR (CDCl3) δ 175.6 (C, CO), 59.8 (CH, C-9), 52.7 (CH,
C-5), 43.6 (CH2, C-6), 41.5 (CH2, C-8), 32.2 (CH2, C-2), 30.6
(CH, C-7), 25.1 (CH2, C-1), 21.7 (CH3, CHCH3), 19.7 (CH3,
NCHCH3).
C
10H17N, C 79.47%, H 11.26%, N 9.27%.
(5R,9S)-8a : 18% yield; [R]25D -12.0 (c 0.8, CHCl3); 1H NMR
(CDCl3) δ 4.65 (2H, s, CdCH2), 3.24 (1H, dt, J ) 2.3, 8.8 Hz,
H-3a), 2.38 (1H, ddd, J ) 1.6, 1.8, 12.2 Hz, H-8a), 2.18 (1H,
dd, J ) 1.6, 10.4 Hz, H-6a), 2.00-1.60 (8H, m), 1.53-1.40 (1H,
m, H-1a), 1.13 (3H, d, J ) 5.8 Hz, NCHCH3); 13C NMR (CDCl3)
δ 146.2 (C, C-7), 108.2 (CH2, CdCH2), 65.4 (CH, C-9), 58.9 (CH,
C-5), 51.0 (CH2, C-3), 42.7 (CH2, C-6), 40.0 (CH2, C-8), 30.3
(CH2, C-1), 20.9 (CH3, NCHCH3) 20.8 (CH2, C-2).
Refer en ces a n d Notes
(1) Lu¨ning, B.; Leander, K. Acta Chem. Scand. 1965, 19, 1607-1611.
(2) Lu¨ning, B.; Lundin, C.; Acta Chem. Scand. 1967, 21, 2136-2142.
Sonnet, P. E.; Netzel, D. A.; Mendoza, R. J . Heterocycl. Chem. 1979,
16, 1041-1047.
(3) Blomquist, L.; Leander, K.; Lu¨ning, B.; Rosenblom, J . Acta Chem.
Scand. 1972, 26, 3203-3206.
(4) Diederich, M.; Nubbemeyer, U. Synthesis 1999, 286-289. Hsu, R.-
T.; Cheng, L.-M.; Chang, N.-C.; Tai, H.-M. J . Org. Chem. 2002, 67,
5044-5047.
(5S,9S)-7b: [R]25 -9.2 (c 1.9, CHCl3).
D
(5S,9R)-8b: [R]25 +12.9 (c 1.3, CHCl3).
D
5,7-Dim eth ylin d olizid in es. (5R,7R,9R)-9a : [R]25D +7.0 (c
(5) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J .-C.; Canet,
I. Tetrahedron Lett. 1999, 40, 1661-1664.
1
0.4, CHCl3); H NMR (CDCl3) δ 3.28 (1H, m, H-5); 2.75 (1H,
(6) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183-186.
dt, J ) 2.7, 8.6 Hz, H-3a), 2.50 (1H, q, J ) 8.6 Hz, H-3b), 2.40
(1H, m, H-9), 1.80-1.65 (3H, m, H-2a, H-1a, H-8a), 1.65-1.50
NP049902U