Preparation of bicyclo[4.3.0]nonanes by an organocatalytic intramolecular Diels-Alder reaction

Article abstract of DOI:10.1002/ejoc.200400802

The bicyclo[4.3.0]nonane substructure is on abundant structure found in several natural compounds. A novel enantioselective organocatalytic cycloaddition was used to prepare the bicyclo[4.3.0]nonane skeleton. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400802

FULL PAPER
Preparation of Bicyclo[4.3.0]nonanes by an Organocatalytic Intramolecular
Diels–Alder Reaction
Sami A. Selkälä[a] and Ari M. P. Koskinen*[a]
Keywords: Natural products / Enantioselectivity / Cycloaddition / Organocatalysis
The bicyclo[4.3.0]nonane substructure is an abundant struc-
ture found in several natural compounds. A novel enantiose-
lective organocatalytic cycloaddition was used to prepare the
bicyclo[4.3.0]nonane skeleton.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
IMDAs for the preparation of their target molecules. How-
ever, the triene precursor for the IMDA has to be chiral
itself if a racemic mixture is to be avoided without use of a
chiral catalyst. In some syntheses a Lewis acid and a coval-
ently bound chiral auxiliary are used to improve the diast-
ereo- and enantioselectivities of the IMDA cycloaddition.
For example, Oppolzer,[20] Takano,[21] and Evans[22] used
different covalently bound auxiliaries in their natural pro-
duct syntheses. Furthermore, Evans has used asymmetric
copper catalysts in IMDA during the preparation of isopu-
lo’upone.[23] Burke has used RHDA cycloreversion[24] in the
synthesis of these types of compounds. Photocyclization
also affords an elegant route to bicyclo[4.3.0]nonanes,
which has been demonstrated by Whitesell.[25] However, the
preparation of the precursor can be laborious, as in the syn-
thesis of ikarugamycin (15 steps). The oxy-Cope rearrange-
ment approach also provides a short route to bicyclo[4.3.0]-
nonanes, as demonstrated by the Paquette group.[26]
During the synthesis of amaminol A (1) we became inter-
ested in extending our recently developed organocatalytic
Diels–Alder reaction to intramolecular cases.[27] The requi-
site triene starting material for cycloaddition experiments
was prepared from readily available methyl sorbate in seven
steps by conventional methods.[28] The resulting mixture of
triene aldehydes 3 and 4 (Figure 2) was difficult to separate
by distillation or chromatography, and was thus used as
such, since only 3 would undergo the desired IMDA reac-
tion.
Introduction
A novel method for producing bicyclo[4.3.0]nonanes,
trans-fused hexahydroindenes, (Figure 1) has been devel-
oped. These types of substructure can be found in several
natural compounds. For example, Sata and Fusetani iso-
lated and identified amaminols A (1) and B (2),[1] which are
cytotoxic against P388 murine leukemia cells with an IC50
value of 2.1 μg mL–1. Amaminols A (1) and B (2) contain
an interesting trans-fused hexahydroindene substructure
(Figure 1), most probably formed from a triene through an
intramolecular Diels–Alder reaction in nature.
Figure 1. Structures of amaminols A (1) and B (2).
Results and Discussion
Natural compounds related to amaminol A (1) and B
(2), such as pulo’upones,[2] indanomycin (X-14547A),[3] 16-
deethylindanomycin (A83094A),[4] homoindanomycin,[5]
cafamycin,[6] stawamycin,[7] cochleamycin A,[8] ikarugamy-
cin,[9] and lepicidin A[10] have been synthesized by several
different methods. The research groups of Roush,[11] Nico-
laou,[12] Boeckman,[13] Ley,[14] Kurth,[15] Jones,[16] Pa-
quette,[17] Hase,[18] and Dias[19] have mostly used thermal
[a] Laboratory of Organic Chemistry, Department of Chemical
Technology, Helsinki University of Technology,
02015 Hut, Finland
Figure 2. Starting material mixture used for organocatalytic intra-
molecular Diels–Alder reactions.
Fax: +358-9-451-2538
E-mail: Ari.Koskinen@hut.fi
1620
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400802
Eur. J. Org. Chem. 2005, 1620–1624

Bicyclo[4.3.0]nonanes by an Organocatalytic Intramolecular Diels–Alder Reaction
FULL PAPER
We decided to employ the organocatalysts developed by
The starting materials for the IMDA cycloadditions were
McMillan[29] in our cycloaddition step. Imidazolidinone mixtures of linear triene aldehyde 3 and the inseparable
catalysts 5–9 (Scheme 1) were prepared by published pro- branched triene aldehyde 4 (Scheme 3). The linear triene
cedures.[29] The stereochemistries of the catalysts 5–9 were aldehyde 3 was more inclined towards polymerization, so
confirmed by NOE NMR measurements. Cyclization of the some of the experiments were performed with starting ma-
amide 8 produced a diastereomeric mixture of imidazolidi- terials containing more of the branched triene aldehyde 4.
nones 7a/b (1:3.1). Unfortunately, the cyclization favored However, both aldehydes 3 and 4 are capable of forming
the trans cycloadduct. The NOE NMR data showed coup- the iminium ion with the amine catalyst. The catalyst load-
ling between the protons 2-H and 5-H in the imidazolidi- ings were calculated according to the total aldehyde
none ring of 7a. It was interesting to note that the cis pro- amount. The branched triene aldehyde 4 resisted cycload-
duct 7a did not racemize notably during the long reaction dition and was thus easily separated from the cycloadduct
time. However, the trans product 7b was prone to racemiza- 13 by flash chromatography. The cycloadduct aldehyde 13
tion, and cycloadduct 7b was found to be entirely racemic was reduced to the corresponding alcohol 14 for analytical
by chiral HPLC analysis.
purposes.[30] The endo/exo selectivities were determined by
1H NMR spectroscopy from the crude product mixtures.
The chemical shifts of the formyl protons of the endo and
exo cycloadduct aldehydes 13 differed by about 0.08 ppm.
Scheme 3. Reagents and conditions: a) organocatalyst, solvent mix-
ture, acid; b) NaBH4, EtOH, room temp.
The results of the organocatalytic IMDA cycloadditions
are shown in Table 1. Catalyst 8 gave the highest enantio-
selectivities (Entry 2, 74% ee), yields (Entry 3, 99%), and
endo selectivities (Entries 2, 3, 4, and 7, Ͼ99:1) compared
to other organocatalysts 7a, 9, and 12a. Trimethyloxazolidi-
none 9, which has a stereogenic center only at the C-5 posi-
tion, was found to give low stereoselectivities (Entry 8), al-
though oxazolidinone 9 is an excellent catalyst for Diels–
Alder cycloaddition.[29b] The IMDA cycloaddition of triene
aldehyde 3 was observed to be solvent-dependent. Use of a
methanol solution afforded somewhat higher enantio-
selectivity (Entries 2 and 3) than use of an acetonitrile solu-
tion, but an extra step was required for cleavage of the ace-
tal formed from the aldehyde 3 during the reaction, and the
yield of the cycloadduct 13 was also lower in MeOH than
in acetonitrile. The enantioselectivities did not improve sig-
nificantly at lower temperature (Entries 9 and 10). Further-
more, the low temperature (–20 °C) retarded the reaction
significantly, so that it was not complete even after several
days. Surprisingly, the enantioselectivity was decreased at
lower temperature in the reaction catalyzed by 8 (Entry 3
and 4). This is probably due to racemization of the catalyst
during the longer reaction time. In comparison, the
enantioselectivity was increased slightly, but the endo/exo
ratio became worse when the reaction was catalyzed by 12a
at low temperature (–20 °C). Although no direct compari-
son between the acids can be made because the solvent sys-
tem was also changed, it can be inferred that p-toluenesul-
fonic acid in dichloromethane/propan-2-ol afforded worse
endo/exo selectivities and enantioselectivities than other sol-
vent/acid systems examined (Entries 5 and 11).
Scheme 1. Reagents and conditions: a) NaHCO3, CHCl3; b)
PhCHO, PTSA, MeOH, +75 °C, 4 d (44%).
We also synthesized compound 12, with an N-benzyl
group, to test it as a catalyst for this reaction. Thus, (S)-
phenylalanine methyl ester hydrochloride salt 10 was di-
rectly amidated with benzylamine in high yield (88%)
(Scheme 2). Cyclization of 11 produced an 18% yield of the
correct diastereomer 12a. The stereochemistry of the cata-
lyst 12a was confirmed by NOE NMR measurements, pro-
tons 2-H and 5-H in the imidazolidinone ring showing
NOE. No notable racemization was observed for the cis
cycloadduct 12a, but production of the trans cycloadduct
12b was accompanied by racemization.
Scheme 2. Reagents and conditions: a) BnNH2, EtOH, room temp.,
23 h (88%); b) (Me)3CCHO, PTSA, MeOH, reflux, 46 h (56%).
Eur. J. Org. Chem. 2005, 1620–1624
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S A. Selkälä, A. M. P Koskinen
Table 1. Conditions and results for the IMDA reaction of the triene aldehyde 3 catalyzed by the organocatalysts 7a, 8, 9 and 12a.
FULL PAPER
Entry Catalyst[a]
Substrate (3/4)
Temperature
Solvent
Acid
endo/exo[b]
Yield[c] (%)
ee[d] (%)
1
2
3
4
5
6
7
8
9
7a
8
21:79
73:27
21:79
65:35
65:35
65:35
65:35
68:32
65:35
65:35
65:35
65:35
room temp.
room temp.
room temp.
–20 Ǟ +6 °C
–20 Ǟ +6 °C
–20 Ǟ +6 °C
room temp.
H2O/CH3CN
H2O/MeOH
H2O/CH3CN
H2O/CH3CN
CH2Cl2/iPrOH
H2O/THF
H2O/CH3CN
H2O/MeOH
H2O/CH3CN
H2O/CH3CN
CH2Cl2/iPrOH
H2O/THF
0.1 m HCl
0.4 m HCl
0.1 m HCl
0.1 m HCl
PTSA
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
25:1
59
54
99[e]
54
45
–
79
28
40
54
38
–
10
74
72
66
41
–
72
–
56
47
12
–
8
8
8
8
TFA
–
8[f]
9
0.1 m HCl
0.4 m HCl
0.1 m HCl
0.1 m HCl
PTSA
Ͼ99:1
3.3:1
17:1
Ͼ99:1
14:1
0 °C Ǟ room temp.
–20 Ǟ +6 °C
room temp.
12a
12a
12a
12a
10
11
12
–20 Ǟ +6 °C
–20 Ǟ +6 °C
TFA
–
[a] 20 mol % of the catalyst relative to the calculated sum of total moles of aldehydes 3 and 4 was used. [b] endo/exo ratios were determined
by 1H NMR from the aldehyde product mixture. [c] Yields of isolated pure aldehydes. The yields were correlated to the amount of linear
aldehyde 3 in the beginning of the reaction. [d] For determination of the ee values, the aldehyde products were first reduced to alcohols
with excess NaBH4 in EtOH, and the resulting alcohols were analyzed by HPLC on a chiral Daicel OD column. Absolute and relative
configurations were assigned by chemical correlation to compounds obtained by known methods for Diels–Alder reactions or by analogy.
[e] The ratio of the linear triene aldehyde 3 to the branched triene aldehyde 4 in this reaction was 1:3.76. [f] 5.6 mol % of the catalyst was
used in this reaction.
0.8 mL min–1, unless otherwise noted. The eluent was a mixture of
propan-2-ol and hexane.
Conclusions
A new method to prepare bicyclo[4.3.0]nonane com-
pounds by organocatalysis was found during the develop-
ment of a route to synthesize amaminol A (1). The enanti-
(2E,7E,9E)-11-Benzyloxyundeca-2,7,9-trienal (3): Crude 11-benzyl-
oxyundeca-2,7,9-trien-1-ol (0.313 g, 1.15 mmol, 100 mol %) was
dissolved in CH2Cl2 (20 mL), and MnO2 (0.600 g, 6.9 mmol,
omer of the bicyclo[4.3.0]nonane substructure of amaminol
A (1) was synthesized by the novel organocatalytic IMDA
cycloaddition to prepare the easily modifiable intermediate
aldehyde 13. It may be possible to synthesize the amaminol
A (1) substructure as the major product if the IMDA cyclo-
addition step is catalyzed with the (R,R)-organocatalyst.
Synthesis towards amaminol A (1) will be continued and
reported on separate report.
600 mol %) was added. Stirring was continued for 15 h and a sec-
ond portion of MnO2 (0.102 g, 1.17 mmol, 102 mol %) was added,
and stirring was then continued for another 3.5 h and a third por-
tion of MnO2 (0.298 g, 3.43 mmol, 298 mol %) was added. Stirring
was continued for a further 5 h and the reaction mixture was fil-
tered through a thin pad of Celite and concentrated to give 0.461 g
of a yellowish oil. The crude product was purified by flash
chromatography (14% MTBE/hexane) to yield 3 (0.264 g, 89%
1
over 2 steps) as a clear oil. Rf (40% MTBE in hexanes) = 0.22. H
NMR (CDCl3, 400.132 MHz): δ = 9.51 (d, J = 7.8 Hz, 1 H), 7.35–
7.26 (m, 5 H), 6.83 (dt, J = 15.6, 6.8 Hz, 1 H Hz), 6.24 (dd, J =
14.8, 10.8 Hz, 1 H Hz), 6.15–6.04 (m, 2 H), 5.75–5.61 (m, 2 H),
4.51 (s, 2 H), 4.05 (d, J = 6.0 Hz, 2 H), 2.34 (qd, J = 7.3, 1.4 Hz,
2 H Hz), 2.15 (q, J = 7.3 Hz, 2 H), 1.62 (q, J = 7.3 Hz, 2 H) ppm.
13C NMR (CDCl3, 100.62 MHz): δ = 194.7, 158.9, 140.8, 139.0,
136.0, 134.4, 133.8, 133.5, 131.2, 129.0, 128.3, 72.7, 71.1, 32.7, 32.6,
28.0 ppm. LRMS (EI+): m/z (%) = 270, 180, 105, 91 (100), 79, 65.
HRMS (EI+): calcd. for [M – 43]: 227.1435; found 227.1491.
Experimental Section
General Remarks: Solvents and starting materials were used as pur-
chased from the suppliers unless otherwise noted. Distilled water
was filtered through Millipore filtration system. The glassware was
oven-dried (Ͼ120 °C) or flame-dried under oil-pump vacuum when
dry conditions were required. The reactions were performed under
argon when necessary. NMR spectra were recorded with a Var-
ian 400 spectrometer (1H NMR, 399.99 MHz, 13C NMR
100.58 MHz) and a Bruker Avance DPX 400 spectrometer (1H
NMR, 400.13 MHz, 13C NMR 100.62 MHz). Thin layer
chromatography was performed on silica mesh 60 coated alumin-
ium plates. For visualization, UV light (254 nm) and ninhydrin,
phosphomolybdenic acid, anisaldehyde, and permanganate solu-
tions were used. Mass spectra were determined with a JEOL JMS-
DX303 apparatus (Helsinki University of Technology) and an LCT
Micromass (ES+) (University of Oulu, Department of Chemistry).
Flash chromatography was performed with 60 mesh silica. FTIR
spectra were measured with a Perkin–Elmer Spectrum One instru-
ment. The melting points were determined with a Gallenkamp
MFB-595 apparatus and are not corrected. GC was performed
with a Hewlett–Packard 6810 instrument with a Supelco gamma-
dex 120 column, 30 m, 0.25 mm, 0.25 μm film with He as the car-
rier gas. Gas velocity was 28 cm s–1. An FID detector was used.
For chiral HPLC, a Daicel OD column was used (5×0.46 cm,
25×0.46 cm) with UV detection at λ = 254 nm, and a flow rate of
(2S,5S)-5-Benzyl-3-methyl-2-phenylimidazolidin-4-one (7a): The
HCl salt of amine 6 (2.37 g, 11.1 mmol, 100 mol %) was treated
with a saturated solution of NaHCO3 (45 mL). The free amine was
extracted with CHCl3 (3×50 mL). The organic layers were dried
with Na2SO4, filtered, and concentrated to give 2.05 g of a yellow-
ish oil. Methanol (20 mL), benzaldehyde (1.29 g, 12.2 mmol,
110 mol %), and para-toluenesulfonic acid monohydrate (0.21 g,
1.1 mmol, 10 mol %) were added, and the reaction mixture was
warmed with an oil bath to +75 °C. Stirring was continued for 3 d
and the reaction mixture was allowed to cool to room temp. The
solvents were evaporated to give 3.26 g of an orange oil. The crude
product was purified by flash chromatography (50–100% EtOAc/
hexane) to yield 7a (0.31 g, 11%) as a yellowish oil. The ratio of
(S,S)/(S,R/R,S) products was 1:3.1 by 1H NMR spectroscopy. Rf
(S,S) (75% EtOAc in hexanes) = 0.16. [α]2D0 = –46.5 (c = 1.12,
CHCl3). Rf (S,R/R,S) (75% EtOAc in hexanes) = 0.33. The product
was analyzed by chiral HPLC (10% iPrOH in hexane, flow rate
1.0 mL min–1) The retention times were 13.59 min for (S,S) and
1622
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1620–1624

Bicyclo[4.3.0]nonanes by an Organocatalytic Intramolecular Diels–Alder Reaction
11.8 min for (S,R); the retention time for (R,S) was 9.4 min. 1H
oil. Rf (40% MTBE in hexanes) = 0.35. UV: λ(max) = 239 nm.
FULL PAPER
NMR (CDCl3, 400.132 MHz): δ = 7.32–7.24 (m, 8 H), 6.85–6.83 HPLC (5% iPrOH in hexanes). The retention time of the minor
(m, 2 H), 5.14 (d, J = 1.5 Hz, 1 H), 3.88 (t, J = 0.5 Hz, 1 H), 3.28– diastereomer was 11.4 min, and of the major diastereomer
3.16 (m, 2 H), 2.56 (s, 3 H) ppm. 13C NMR (CDCl3, 100.62 MHz):
δ = 174.4, 138.4, 136.7, 129.8, 129.5, 129.0, 128.8, 127.1, 126.9,
77.6, 60.4, 36.8, 27.3 ppm. HRMS (ES+): calcd. for [M + 1]
(C17H19N2O): 267.1497; found 267.1484.
13.7 min. The enantiomeric excess was 72%. [α]2D0 = +92.5 (c =
0.32, MeOH). 1H NMR (CDCl3, 400.132 MHz): δ = 7.33 (m, 5 H),
5.90 (d, J = 9.8 Hz, 1 H), 5.45 (ddd, J = 9.6, 4.3, 2.4 Hz, 1 H), 4.52
(s, 2 H), 3.67–3.51 (m, 4 H), 3.35 (dd, J = 9.6, 1.7 Hz, 1 H), 2.84
(m, 1 H), 2.02 (m, 1 H), 1.80–1.68 (m, 6 H), 1.22–1.08 (m, 2 H)
ppm. 13C NMR (CDCl3, 100.62 MHz): δ = 137.2, 132.2, 128.6,
128.1, 128.0, 127.4, 73.6, 71.2, 63.2, 46.1, 44.5, 41.7, 38.7, 28.7,
27.1, 22.5 ppm. HRMS (EI): calcd. for C18H24O2: 272.1776; found
272.1786.
(2S,5S)-3,5-Dibenzyl-2-tert-butylimidazolidin-4-one (12a): Free
amine 11 (2.22 g, 8.73 mmol, 100 mol %) was dissolved in MeOH
(15 mL). Trimethylacetaldehyde (0.83 g, 9.60 mmol, 110 mol %)
and para-toluenesulfonic acid monohydrate (0.17 g, 0.87 mmol,
10 mol %) were added. The resulting mixture was warmed with an
oil bath to +75 °C. Stirring was continued under reflux for 2 d and
the reaction mixture was allowed to cool to room temp. The sol-
vents were evaporated to give 2.72 g of a yellow oil. The crude
product was purified by flash chromatography (32% EtOAc/hex-
ane) to yield 12a (0.52 g, 18%) as a clear oil. The ratio of (S,S)/
(S,R/R,S) was 1:2 by 1H NMR spectroscopy. Rf (S,S) (70% EtOAc/
hexane) = 0.49. [α]2D0 = –128.0 (c = 1.11, CHCl3). Rf (S,R/R,S)
Acknowledgments
This research was financially supported by the Ministry of Educa-
tion of Finland (Graduate School of Bioorganic Chemistry Pro-
gram) and the National Technology Agency (TEKES, Finland).
1
(70% EtOAc/hexane) = 0.65. H NMR (CDCl3, 400.132 MHz): δ
[1] N. Sata, N. Fusetani, Tetrahedron Lett. 2000, 41, 489–492.
[2] a) S. Coval, P. Scheuer, J. Org. Chem. 1985, 50, 3024–3025; b)
A. Spinella, L. Alvarez, G. Cimino, Tetrahedron 1993, 49,
3203–3210.
[3] J. Westley, R., Evans, Jr., C.-M. Liu, T. Hermann, J. Blount, J.
Am. Chem. Soc. 1978, 100, 6784–6786.
= 7.32–7.13 (m, 10 H), 5.06 (d, J = 15.7, 1 H), 4.25 (d, J = 15.7 Hz,
1 H), 4.13 (s, 1 H), 3.85 (ddd, J = 7.5, 4.1, 1.4 Hz, 1 H), 3.22 (dd,
J = 13.7, 4.1 Hz, 1 H), 3.04 (dd, J = 13.7, 7.5 Hz, 1 H), 0.76 (s, 9
H) ppm. 13C NMR (CDCl3, 100.62 MHz): δ = 174.4, 138.4, 136.7,
129.8, 129.5, 129.0, 128.8, 127.1, 126.9, 77.6, 60.4, 36.8, 27.3 ppm.
The (S,S) configuration was confirmed by COSYGPGF (coupling
between δ = 4.13 and 3.85 ppm was observed). HRMS (EI): calcd.
for C21H26N2O: 322.2045; found 321.1994 for [M – 1].
[4] S. Larsen, L. Boeck, J. Mertz, J. Paschal, J. Occolowitz, J. Anti-
biot. 1988, 41, 1170–1177.
[5] P. Toth, V. Szell, I. Koczka, G. Horvath, I. M. Szabo, M.
Szayly, G. Ambrus, J. Bedo, J. Berdy, Janos et al., Hung. Teljes
1989, HU 49909; Chem. Abstr. 1990, 113, 130720.
[6] N. Murenets, M. Kudinova, T. Korobkova, T. Drobysheva, N.
Klyuev, I. Yartseva, T. Ivanova, L. Ivanitskaya, Antibiot. Med.
Biotekhnol. 1987, 32, 811–814; Chem. Abstr. 1988, 108, 34547.
[7] S. Miao, M. Anstee, V. Baichwal, A. Park, Tetrahedron Lett.
1995, 36, 5699–5702.
[8] a) K. Shindo, H. Kawai, J. Antiobiot. 1992, 45, 292–295; b) K.
Shindo, M. Matsuoka, H. Kawai, J. Antiobiot. 1996, 49, 241–
243; c) K. Shindo, H. Iijima, H. Kawai, J. Antiobiot. 1996, 49,
244–248; d) K. Shindo, M. Sakakibara, H. Kawai, J. Antiobiot.
1996, 49, 249–252.
(3aS*,4R*,5S*,7aR*)-5-Benzyloxymethyl-2,3,3a,4,5,7a-hexahydro-
1H-indene-4-carbaldehyde (13): (2S,5S)-5-Benzyl-2-tert-butyl-3-
methylimidazolidin-4-one (8, 128 mg, 0.52 mmol, 6 mol %) was dis-
solved in CH3CN (20 mL) and an aqueous solution of HCl (0.1 m,
5.2 mL) was added. The resulting mixture was stirred for 5 min
and triene aldehyde 3 (65 wt %, 2.50 g, 9.25 mmol, 100 mol %) in
CH3CN (32 mL) was added. The reaction mixture was stirred for
20 h and diluted with diethyl ether (200 mL) and washed with H2O
(50 mL) and brine (50 mL). The organic phase was dried with
MgSO4, filtered, and concentrated to give 2.8 g of a yellow oil. The
crude product was purified by flash chromatography (5% EtOAc/
hexane) to give 13 (1.23 g, 79%, 72% ee) as a clear oil. The
[9] a) K. Jomon, M. Ajisaka, H. Sakai, J. Antibiot. 1972, 25, 271–
273; b) S. Ito, Y. Hirata, Tetrahedron Lett. 1972, 13, 1181–1184
and 1185–1188; c) S. Ito, Y. Hirata, Tetrahedron Lett. 1972, 13,
2557–2560.
branched triene aldehyde
4 was easily separated by flash
chromatography. The enantiomeric excess was determined by chiral
[10] L. Boeck, H. Chio, T. Eaton, O. Godfrey, K. Michel, W. Nakat-
sukasa, R. Yao, (Eli Lilly) Eur. Pat. Appl. EP375316, 1990;
Chem. Abstr. 1991, 114, 80066.
[11] W. Roush, A. Myers, J. Org. Chem. 1981, 46, 1509–1511; W.
Roush, S. Peseckis, Tetrahedron Lett. 1982, 23, 4879–4882; W.
Roush, S. Peseckis, A. Walts, J. Org. Chem. 1984, 49, 3429–
3432.
[12] K. Nicolaou, R. Magolda, J. Org. Chem. 1981, 46, 1506–1508;
K. Nicolaou, D. Papahatjis, D. Claremon, R. Dolle, III, J. Am.
Chem. Soc. 1981, 103, 6967–6969; K. Nicolaou, D. Claremon,
D. Papahatjis, R. Magolda, J. Am. Chem. Soc. 1981, 103, 6969–
6971. For full paper see: K. Nicolaou, D. Papahatjis, D.
Claremon, R. Magolda, R. Dolle, J. Org. Chem. 1985, 50,
1440–1456.
HPLC from the corresponding alcohol 14. Rf (20% MTBE in hex-
1
anes) = 0.34. [α]2D0 = +23.3 (c = 1.33, CDCl3). H NMR (CDCl3,
400.132 MHz): δ = 9.77 (d, J = 2.8 Hz, 1 H), 7.34–7.27 (m, 5 H),
5.96 (d, J = 9.9 Hz, 1 H), 5.47 (ddd, J = 9.9, 3.9, 2.6 Hz, 1 H), 4.41
(d, J = 11.6 Hz, 1 H), 4.33 (d, J = 11.6 Hz, 1 H), 3.44 (dd, J = 9.9,
3.6 Hz, 1 H), 3.37 (t, J = 9.4 Hz, 1 H), 3.09 (m, 1 H), 2.61 (ddd, J
= 11.6, 6.5, 2.7 Hz, 1 H), 2.06 (m, 1 H), 1.84–1.61 (m, 5 H), 1.17–
1.04 (m, 2 H) ppm. 13C NMR (CDCl3, 100.62 MHz): δ = 203.2,
137.7, 132.3, 128.4, 127.8, 127.7, 126.2, 72.8, 70.7, 55.3, 45.0, 39.8,
39.6, 28.4, 27.6, 22.4 ppm. LRMS (EI+): m/z (%) = 270, 180, 105,
91 (100), 79, 65. HRMS (EI): calcd. for C18H22O2: 270.1620; found
270.1624.
[13] R. Boeckman, E. Enholm, D. Demko, A. Charette, J. Org.
Chem. 1986, 51, 4743–4745.
[14] a) M. Edwards, S. Ley, S. Lister, Tetrahedron Lett. 1981, 22,
361–364; b) M. Edwards, S. Ley, S. Lister, B. Palmer, J. Chem.
Soc., Chem. Commun. 1983, 630–633; c) M. Edwards, S. Ley,
S. Lister, B. Palmer, D. Williams, J. Org. Chem. 1984, 49, 3503–
3516.
(3aS*,4R*,5S*,7aR*)-(5-Benzyloxymethyl-2,3,3a,4,5,7a-hexahydro-
1H-inden-4-yl)methanol (14): The cyclic aldehyde 13 (9 mg,
0.033 mmol, 100 mol %) was dissolved in EtOH (1 mL), and
NaBH4 (excess) was added at room temp. The reaction mixture was
stirred for 1 h and quenched with aqueous citric acid (5 wt %,
1 mL). The product was extracted with diethyl ether (3×2 mL) and
washed with brine (2 mL). The organic phase was dried with
Na2SO4, filtered, and concentrated to give 14 (9.3 mg) as a clear
[15] M. Kurth, D. Burns, M. O’Brien, J. Org. Chem. 1984, 49, 731–
733.
Eur. J. Org. Chem. 2005, 1620–1624
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1623

S A. Selkälä, A. M. P Koskinen
FULL PAPER
[16] R. Jones, R. Jones, Tetrahedron Lett. 1990, 31, 3363–3366.
[17] J. Chang, L. Paquette, Org. Lett. 2002, 4, 253–256.
[18] a) J. Matikainen, S. Kaltia, T. Hase, Synth. Commun. 1995, 25,
786–787; b) J. Matikainen, S. Kaltia, T. Hase, I. Kilpeläinen,
T. Drakenberg, A. Annila, Tetrahedron 1993, 49, 8007–8014.
[19] L. Dias, L. Jardim, A. Ferreira, H. Soarez, J. Braz. Chem. Soc.
2001, 12, 463–466.
[20] W. Oppolzer, D. Dupuis, G. Poli, T. Raynham, G. Bernardi-
nelli, Tetrahedron Lett. 1988, 29, 5885–5888.
[21] T. Sugahara, T. Iwata, M. Yamaka, S. Takano, Tetrahedron
Lett. 1989, 30, 1821–1824.
[26] a) L. Paquette, J. Romine, H.-S. Lin, J. Wright, J. Am. Chem.
Soc. 1990, 112, 9284–9292; b) L. Paquette, D. MacDonald, L.
Anderson, J. Am. Chem. Soc. 1990, 112, 9292–9299.
[27] S. A. Selkälä, J. Tois, P. M. Pihko, A. M. P. Koskinen, Adv.
Synth. Catal. 2002, 344, 941–945.
[28] M. Closa, P. March, M. Figueredo, J. Font, A. Soria, Tetrahe-
dron 1997, 53, 16803–16816.
[29] a) D. MacMillan, K. Ahrendt, US Patent application
US2002016473, 2002; b) K. Ahrendt, C. Borths, D. MacMil-
lan, J. Am. Chem. Soc. 2000, 122, 4243–4244; c) A. Northrup,
D. MacMillan, J. Am. Chem. Soc. 2002, 124, 2458–2460.
[22] a) D. Evans, C. Black, J. Am. Chem. Soc. 1992, 114, 2260– [30] The opposite enantiomer has been synthesized by use of the
2262; b) D. Evans, C. Black, J. Am. Chem. Soc. 1993, 115,
4497–4513.
pure (R) enantiomer of phenyloxazolidinone as a covalently
attached chiral auxiliary. Its structure and absolute and relative
stereochemistry were determined by X-ray crystallography:
S. A. Selkälä, Ph.D. Thesis (Total synthesis of amaminol A),
2003, Helsinki University of Technology.
[23] D. Evans, J. Johnson, J. Org. Chem. 1997, 62, 786–787.
[24] S. Burke, A. Piscopio, J. Buchanan, Tetrahedron Lett. 1988, 29,
2757–2760.
[25] J. Whitesell, M. Minton, J. Am. Chem. Soc. 1987, 109, 6403–
Received: November 10, 2004
6408.
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