Solid-phase synthesis of decalin scaffolds by Robinson annulation with immobilised Nazarov reagents

Article abstract of DOI:10.1002/ejoc.200500917

A method for the synthesis of natural product-inspired decalin systems on solid support is reported. It employs the Robinson annulation as key step and immobilised Nazarov reagents as key intermediates. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500917

FULL PAPER
DOI: 10.1002/ejoc.200500917
Solid-Phase Synthesis of Decalin Scaffolds by Robinson Annulation with
Immobilised Nazarov Reagents
Svenja Röttger[a,b] and Herbert Waldmann*[a,b]
Keywords: Solid-phase synthesis / Decalin / Nazarov reagent / Robinson annulation
A method for the synthesis of natural product-inspired deca-
lin systems on solid support is reported. It employs the Robin-
son annulation as key step and immobilised Nazarov rea-
gents as key intermediates.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
The development of compound collections by means of
solid-phase synthesis is among the most frequently used
technologies in chemical biology and medical chemistry re-
search. In this context, natural product-guided compound
library development has proven to be a viable strategy that
delivers biologically prevalidated compound classes that
often show relatively high hit rates at comparably small li-
brary size.[1,2] The development of efficient methods for the
synthesis of natural product-inspired scaffolds and their
subsequent structural variation in the format of solid-phase
synthesis is therefore of considerable interest.
The decalin scaffold is among the most frequently occur-
ring compound frameworks found in nature,[3] and natural
products incorporating diversely substituted decalins dis-
play multiple biological activities (Figure 1).[4]
Given this biological relevance of the decalin scaffold we
have explored possibilities for the synthesis of decalins on
solid supports.[5] The Robinson annulation is among the
most powerful methods for assembling decalins,[6] but no
Robinson annulations on resin have yet been described.
Here we report on the development of a solid-phase Rob-
inson annulation decalin synthesis employing polymer-
bound Nazarov reagents as building blocks.
Figure 1. Examples of natural products with decalin structure and
their biological activity.
The Nazarov reagent 1 is a methyl vinyl ketone derivative
that has been broadly used in natural product synthesis.[7]
If employed in the construction of decalins it introduces an
ester that offers potential for further subsequent function-
alisation. It was therefore planned to develop analogues of
the Nazarov reagent that would incorporate an additional
alcohol (e.g., 2) as a functional group for linkage to the
polymeric carrier (Scheme 1). It was planned to investigate
whether the Wang linker itself or alternatively a silyl linker
based on the Wang linker would be more suitable for immo-
bilisation of the reagent (see 3 and 4, Scheme 1).
For the synthesis of the immobilised reagents, butynediol
5 (Scheme 2) was converted into the monoprotected diols 6
and 7 by established methods.[8] Intermediate 6 carried a
fluoride-labile TBS blocking function, whereas for 7 an
acid-labile trimethoxytrityl (TMT) group was employed.
The silyl-protected alcohol was coupled to the resin after
activation of the Wang linker as a trichloroacetimidate.[9]
The TBS group was then removed and the loading was de-
[a] Max Planck Institute of Molecular Physiology, Department of
Chemical Biology,
Otto-Hahn-Str. 11, 44227 Dortmund, Germany
Fax: +49-231-1332499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
[b] University of Dortmund, Department 3, Chemical Biology,
44221 Dortmund, Germany
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S. Röttger, H. Waldmann
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be 0.64 mmol g–1 (53% for three steps). In this case oxi-
dation to the aldehyde proceeded best if the Dess–Martin
periodinane was employed. Determination of the loading
by the FmPH method[12] revealed that the yield for this step
was 95%.
Both resins then were subjected to aldol reactions with
the lithium enolates of acetic acid ethyl or allyl ester
(Scheme 2). To obtain preparatively viable yields it was im-
portant to pre-swell the resin in THF and to activate the
aldehyde by pre-treatment with BF3·Et2O. The resulting β-
hydroxyesters were then oxidised again with IBX (Wang
linker) or Dess–Martin periodinane (Wang silyl linker) to
yield immobilised β-keto esters 10 and 11. Analogues of
Nazarov reagents 12 and 13 could be released from the so-
lid supports by treatment with TFA in CH2Cl2 (3%) or
TBAF in CH2Cl2 (1 ), respectively and were obtained in
18% (12) and 16% (13) yields over six steps on the poly-
meric carrier.[13]
For the subsequent Robinson annulation, resin-bound β-
keto ester 11 (Scheme 3) with the silyl linker was chosen
and the reaction conditions were optimised in solution with
the analogous TBS-protected compound. This exercise
found that a 1:3 mixture of dioxane and methanol, together
Scheme 1. Structure of the Nazarov reagent 1 and design of a poly-
mer-bound analogue.
termined to be 1.06 mmol g–1 by the Fmoc method.[10] Sub- with NaOMe or DBU as base, gave the best results if resin
sequent oxidation to the aldehyde 8 proceeded best if IBX 11 was treated with enamines at 50 °C. These conditions
was employed as oxidant
– use of, for example, were then employed for the Robinson annulations on the
SO3·pyridine or the Dess–Martin periodinane gave inferior solid phase. As demonstrated in Scheme 3, polymer-linked
results. The aldehyde was formed in 95% yield (DNPH β-keto ester 11 reacted with differently substituted en-
method).[5] For the synthesis of aldehyde 9 the Wang linker amines 14 (Table 1) under these conditions to yield poly-
was first treated with (iPr)2SiCl2, followed by the TMT-pro- mer-bound decalins 15. Investigation of the resin obtained
tected alcohol 7, and the selective removal of the TMT from enamine 14a by MAS-NMR confirmed product for-
group was accomplished by treating the polymer twice with mation. The desired condensation products were released
0.5  formic acid for one minute. The deprotection could from the polymeric carrier in yields of 28–37% by treatment
be readily followed by UV determination of the formed tri- with TBAF in THF.[13] GC and NMR spectroscopic exami-
tyl cation at 484 nm[11] and the loading was determined to nations showed that only one stereoisomer was formed
Scheme 2. Synthesis of immobilised analogues of the Nazarov reagent: a) LiAlH4, THF, reflux, 72%. b) NaH, THF, TBSCl, 0 °C to room
temp., 82%. c) NaH, TMTCl, toluene/DMF, 1:1, 21%. d) Resin with Wang linker, Cl3CCN, CH2Cl2, DBU, 0 °C, alcohol 6, CH2Cl2,
BF3·Et2O, room temp. e) 1  TBAF in THF, room temp. 89% (two steps, Fmoc method). f) IBX, THF/DMSO, 1:1, room temp., 95%
or Dess–Martin periodinane, CH2Cl2, room temp., 95% (DNPH/FmPH methods). g) Resin with Wang linker, CH2Cl2, (iPr)2SiCl2, luti-
dine, DMAP, alcohol, room temp. h) 0.5  HCOOH in CH2Cl2, 2×1 min, room temp., 53% (3 steps). i) (iPr)2NH, nBuLi, CH3COOEt
or CH3COOAllyl, THF, BF3·Et2O, –60 °C to rt. j) IBX, THF/DMSO, 1:1, room temp., or Dess–Martin periodinane, CH2Cl2, room temp.
k) 3%TFA/1  TBAF in CH2Cl2, room temp. (overall yield Et: 18%, Allyl: 16%).
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Solid-Phase Synthesis of Decalin Scaffolds
FULL PAPER
Scheme 3. Robinson annulation on solid phase with an immobilised Nazarov reagent: a) MeOH/dioxane 3:1, 50 °C, then base. b) TBAF,
THF, room temp., overnight, yields see Table 1.
agent and an ethanolic solution of phosphomolybdic acid and heat
as developing agents.
(de Ͼ98%), containing the proton at the angular carbon
and next to the –CH2–OH substituent at an angle of 100–
120°[14] (Table 1).
trans-Butene-1,4-diol: A solution of lithium aluminium hydride
These examples demonstrate that the method described (5.3 g) in dry THF (200 mL) was cooled to –78 °C. A solution of
butyne-1,4-diol (10 g, 0.11 mol) in dry THF (20 mL) was added
under argon with vigorous stirring. After completion of addition
the mixture was heated at reflux for 18 h, cooled (ice bath) and
quenched carefully with saturated NH4Cl solution. The resulting
precipitate was filtered through celite and the filter cake was
washed thoroughly with diethyl ether. The organic layer was con-
centrated to dryness and the crude product was purified by flash
chromatography (silica gel, cyclohexane/ethyl acetate, 1:10 to pure
ethyl acetate) to give the diol (7.02 g, 0.08 mol, 72%) as a colourless
oil. 1H NMR (500 MHz, CDCl3): δ = 5.88 (m, 2 H), 4.17 (m, 4 H),
1.89 (2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 130.5,
here gives access to differently substituted decalins in a pre-
paratively viable manner. It should be amenable to further
variation and extension (e.g., the acetal protecting group
and an appropriate N-protecting group incorporated into
enamines similar to those shown in Scheme 1 might be
cleaved on the polymeric carrier, opening up opportunities
for further derivatisations). Furthermore, selective cleavage
of the ester and/or further functionalisations through ad-
ditional substituents in an aromatic ring incorporated into
the enamine part (see Scheme 3) could be envisaged.
62.9 ppm. IR (KBr): ν = 3350 (s, alcohol) cm–1. GC-MS (m/z, rel.
˜
int.%): 88 [M]+ (5), 70 (8), 61 (12), 57 (7), 43 (100).
Experimental Section
trans-4-(tert-Butyldimethylsilyloxy)but-2-en-1-ol (6): NaH (60 wt.-
% in oil, 200 mg, 5 mmol) was added at 0 °C to a solution of trans-
butene-1,4-diol (441 mg, 5 mmol) in dry THF 20 mL and the mix-
ture was stirred for 1 h at room temperature. A solution of TBS-
Cl (0.755 g) dissolved in dry THF was added dropwise and the
mixture was stirred for 2 h at room temperature, quenched with
saturated NH4Cl solution and extracted with diethyl ether
(3×60 mL). The combined organic layers were washed with satu-
rated sodium chloride solution, dried (MgSO4) and concentrated
to dryness. The crude product was purified by flash chromatog-
raphy (silica gel, cyclohexane/ethyl acetate, 10:1) to give the alcohol
6 (829 mg, 4.1 mmol, 82%) as a colourless oil. 1H NMR (400 MHz,
CDCl3): δ = 5.87 (dt, J = 5, 11 Hz, 1 H), 5.79 (dt, J = 4, 8 Hz, 1
H), 4.18 (d, J = 4, 2 H), 4.16 (d, J = 5 Hz, 2 H), 1.48 (1 H), 0.91
(s, 9 H), 0.07 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
General Procedures: All reactions were carried out under argon. All
solvents were distilled by standard procedures before use. CH2Cl2
was distilled under argon from CaH2, MeOH was distilled under
argon from Mg. All other chemicals were purchased from commer-
cial sources and were used without further purification. Yields refer
to isolated and pure compounds unless otherwise stated. 1H and
13C NMR spectroscopic data were recorded on a Varian Mer-
cury 400 spectrometer. FAB and EI measurements were taken with
a Jeol SX instrument with use of a 3-nitrobenzyl alcohol (3-NBA)
matrix. GC-MS analysis was performed on a Hewlett–Packard
HP 5890-series II gas chromatograph with a HP 5972-series mass
selective detector. Chiral GC measurements were performed with
an Agilent 6890N and a Lipodex-E column. HPLC purifications
were performed with an Agilent 1100 Series fitted with either a
Nucleosil 102–7 C4 or a Nucleodur C18 column (Macherey–Nagel)
and with acetonitrile and Millipore water containing 0.1% of TFA.
Usual methods start with 5% acetonitrile and go up to 100%
within 20 minutes. Flash chromatography was performed with silica
gel (60, 40–63 µm) from Acros. TLC was performed with alumin-
ium-backed silica 60 F254 plates (Merck) with UV as visualising
131.0, 128.9, 63.2, 63.1, 25.9, 14.4, –5.3 ppm. IR (KBr): ν = 3338
˜
(s, alcohol) cm–1. GC-MS (m/z, rel. int.%): for C10H28O4Si, M =
202.4 g mol–1, 184 [M – H2O]+ (23), 171 (12), 145 [M – tert-butyl]+
(53), 75 (100).
trans-4-[(Trimethoxytrityl)oxy]but-2-en-1-ol (7): NaH (60 wt.-% in
oil, 200 mg, 5 mmol) was added at 0 °C to a solution of trans-but-
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S. Röttger, H. Waldmann
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Table 1. Decalins synthesized on solid support.
ene-1,4-diol (441 mg, 5 mmol) in dry toluene (20 mL) and the mix-
ture was stirred for 1 h at room temperature. A solution of TMTCl
(1.84 g) in dry toluene/DMF was added dropwise and the mixture
was stirred for a further 1 h at room temperature. The mixture was
diluted with dichloromethane, washed with saturated NaHCO3
solution, water and saturated sodium chloride solution and dried
(MgSO4). The crude product was purified by flash chromatography
itrile (1.84 mL) was added to
a
suspension of resin (1 g,
1.2 mmol g–1) swollen in dry dichloromethane (10–12 mL) and the
suspension was cooled to 0 °C. Afterwards, DBU (0.15 mL) was
added dropwise over a period of 5 minutes. The orange solution
was shaken for 40 minutes at 0 °C, and the resin was filtered and
washed five times with dichloromethane and dried under reduced
pressure. IR: ν = 1664 (nitrile) cm–1. The resin was again swollen
˜
(silica gel, cyclohexane/ethyl acetate, 4:1) to give the alcohol 7
(440 mg, 1.05 mmol, 21%) as an orange oil. H NMR (400 MHz, loxy)but-2-en-1-ol (6, 2.02 g, 4.8 mmol, 4 equiv.) was added. After
in dry dichloromethane (8 mL) and trans-4-(tert-butyldimethylsily-
1
CDCl3): δ = 7.33 (d, J = 9 Hz, 2 H), 7.24 (d, J = 9 Hz, 2 H), 7.17
(d, J = 9 Hz, 2 H), 6.83 (d, J = 9 Hz, 4 H), 6.75 (d, J = 9 Hz),
5.79–5.70 (m, 2 H), 4.22 (d, J = 2 Hz, 2 H), 4.04 (d, J = 6 Hz, 2
the mixture had been kept for 5 minutes at room temperature,
BF3·Et2O (52.5 µL) was added and the suspension was shaken at
room temperature overnight. The resin was filtered, washed five
H), 3.80–3.74 (m, 9 H), 2.18 (1 H) ppm. IR (KBr): ν = 3415 (s, times with dichloromethane and once with methanol and dried un-
˜
alcohol), 825 (m, subst. benzene) cm–1. HRMS [FAB/HR] for
C26H28O5, M = 420.5 g mol–1, calculated: [M + H]+: 420.1937;
found 420.1908.
der reduced pressure. Yield: 1.22 g colourless beads; the loading
was determined after deprotection.
Wang-Supported
trans-4-[(Trimethoxytrityl)oxy]but-2-en-1-ol.
Wang-Supported trans-4-(tert-Butyldimethylsilyloxy)but-2-en-1-ol. Loading of Resin with a Wang-Diisopropylsilyl Linker: Well dried
Loading of the Resin (Polystyrene, Wang Linker): Trichloroaceton-
Wang linker (500 mg, 1.2 mmol g–1) was swollen in dry dichloro-
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Solid-Phase Synthesis of Decalin Scaffolds
FULL PAPER
methane (5 mL) under argon. After addition of lutidine (580 µL,
10 equiv.), DMAP (61 mg, 1 equiv.) and dichlorodiisopropylsilane
(271 µL, 3 equiv.) the suspension was shaken for 3 h at room tem-
perature. The resin was washed three times with dry dichlorometh-
ane under argon and dried under reduced pressure. After swelling
in dry dichloromethane, lutidine (580 µL, 10 equiv.), DMAP
each with THF and CH2Cl2 and once with MeOH and dried under
reduced pressure. Yield: 240 mg yellow beads. IR: ν = 3496 (s,
˜
alcohol) cm–1. The product was used without further analysis. The
resin (495 mg, 0.8 mmol g–1) was swollen for 10 minutes in THF
and filtered. A solution of IBX (2.4 mmol, 671 mg, 6 equiv.) in
DMSO/THF (1:1, approximately 5 mL) was added and the suspen-
(61 mg, 1 equiv.) and trans-[4-(trimethoxytrityl)oxy]but-2-en-1-ol sion was shaken at room temperature overnight. The resin was
(7, 440 mg 2 equiv.) were added and the suspension was shaken at
room temperature overnight. The resin was filtered, washed five
times with dichloromethane and dried under reduced pressure.
Yield: 645 mg yellow beads; the loading was determined after de-
protection.
washed three times each with DMSO, DMSO/THF (1:1), THF and
CH2Cl2 and once with MeOH and dried under reduced pressure.
Yield: 480 mg yellow beads. IR: ν = 1735 (s, ester) cm–1. The prod-
˜
uct was detected by cleavage (see below).
Wang-Supported Allyl 6-Hydroxy-3-oxohex-4-enoate (11): The
anion (20 equiv.) was prepared under argon at –78 °C. To this end
a solution of n-butyllithium in hexane (2.5 , 5.45 mmol, 1.74 mL)
was added dropwise at –78 °C to a solution of diisopropylamine
(0.61 mL, 5.45 mmol) in dry THF (20 mL) and the mixture was
stirred for 25 minutes. A solution of allyl acetate (0.34 mL, 4 mmol)
in THF was added dropwise and the mixture was stirred for
50 minutes at –78 °C. Resin (330 mg Ϸ 0.6 mmol g–1) was swollen
in a small amount of dry THF and the mixture was cooled to
–60 °C, after which BF3·Et2O (0.1 mL) was added and the suspen-
sion was shaken for 5 minutes. The solution of the anion was added
and the suspension was shaken for 6 h at –60 °C and then allowed
to warm up slowly to room temperature overnight. The reaction
was quenched with THF/water and the resin was filtered. It was
washed three times each with THF and CH2Cl2 and once with
MeOH and dried under reduced pressure. The product was imme-
diately used without further analysis.
Wang-Supported trans-But-2-ene-1,4-diol: For deprotection of the
TBS-protected alcohol the resin (610 mg) was swollen for 10 min-
utes in THF and filtered. TBAF solution (1  in THF, 3 mL,
3 equiv.) was added and the suspension was shaken at room tem-
perature overnight. The resin was filtered, washed twice each with
THF, dichloromethane and methanol and dried under reduced
pressure. Yield: 550 mg yellow beads, 1.07 mmol g–1 (90%, two
steps); the loading was detected by the Fmoc method. IR: ν = 3415
˜
(s, alcohol) cm–1.
Wang-Supported trans-But-2-ene-1,4-diol: For deprotection of the
TMT-protected alcohol the resin (200 mg) was swollen for 10 min-
utes in dichloromethane and filtered. A solution of HCOOH in
CH2Cl2 solution (0.5 , 2 mL) was added to the resin (2× 1 min-
ute), followed by washing six times with dichloromethane and once
with ethyl acetate and drying under reduced pressure. Yield:
191 mg colourless beads, 0.64 mmol g–1 (53%, two steps); the load-
ing was determined by the quantitative UV detection of the re-
The resin was swollen for 10 minutes in dichloromethane and fil-
tered. A solution of 5 equiv. Dess–Martin periodinane (15 wt.-% in
CH2Cl2, 5 equiv.) was added and the suspension was shaken over-
night at room temperature. The resin was washed five times with
CH2Cl2 and once with MeOH and dried under reduced pressure.
Yield: 360 mg colourless beads. The product was detected by cleav-
age (see below).
leased trityl cation. IR: ν = 3440 (s, alcohol) cm–1.
˜
Wang-Supported trans-1-Oxobut-2-en-4-ol (8): The resin (500 mg,
1.07 mmol g–1) was swollen for 10 minutes in THF and filtered. A
solution of IBX (5 equiv.) in DMSO/THF (4 mL, 1:1) was added
and the suspension was shaken at room temperature overnight. The
resin was washed three times each with DMSO, DMSO/THF (1:1),
THF and CH2Cl2 and once with MeOH and dried under reduced
pressure. Yield: 490 mg colourless beads, 1.01 mmol g–1 (95%); the
loading was determined by the DNPH method and the yield was
Ethyl 6-Hydroxy-3-oxohex-4-enoate (12): After swelling in dichloro-
methane, resin (200 mg) was treated with TFA in CH2Cl2 (3%,
1 mL, 3×20 min). The combined solutions were neutralised with
solid Na2CO3, filtered and concentrated. The crude product was
purified by flash chromatography (silica gel, toluene/methanol, 8:1)
to give the alcohol 12 (6.1 mg, 18% overall yield) as a colourless
oil. Rf (toluene/methanol, 5:1 v/v) = 0.22. Keto/enol ratio 1.8:1. 1H
NMR (500 MHz, CDCl3): δ = 11.86 (s, 0.36 H), 6.96 (dt, J = 4,
16 Hz, 0.64 H), 6.76–6.71 (m, 0.36 H), 6.46 (d, J = 16 Hz, 0.64 H),
6.22 (s, 0.36 H), 6.07 (d, J = 16 Hz, 0.36 H), 4.38 (m, 2 H), 4.34
(q, J = 2 Hz, 2 H), 3.67 (s, 1.28 H), 2.04 (s, 1 H), 1.27 (m, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 191.9, 170.0, 169.2, 165.9, 142.0,
138.1, 127.1, 123.1, 91.4, 61.2, 60.2, 62.2, 61.5, 47.4, 14.1,
calculated from the loading. IR: ν = 1695 (s, aldehyde) cm–1.
˜
Wang-Supported trans-1-Oxobut-2-en-4-ol (9): The resin (191 mg,
0.64 mmol g–1) was swollen for 10 minutes in dichloromethane and
filtered. A solution of Dess–Martin periodinane (15 wt.-% in
DCM, 5 equiv.) was added and the suspension was shaken 5 h at
room temperature. The resin was washed five times with CH2Cl2
and once with MeOH and dried under reduced pressure. Yield:
185 mg colourless beads, 0.61 mmol g–1 (95%); the loading was de-
tected by the FmPH method and the yield was calculated from the
loading. IR: ν = 1700 (s, aldehyde) cm–1.
˜
14.0 ppm. IR: ν = 3420 (s, alcohol) cm–1. HRMS [FAB/HR] for
˜
Wang-Supported Ethyl 6-Hydroxy-3-oxohex-4-enoate (10): The
anion (20 equiv.) was prepared under argon at –78 °C. To this end
a solution of n-butyllithium in hexane (2.5 , 5.45 mmol, 1.74 mL)
was added dropwise at –78 °C to a solution of diisopropylamine
(0.61 mL, 5.45 mmol) in dry THF (20 mL) and the mixture was
stirred for 25 minutes. A solution of ethyl acetate (0.32 mL,
4 mmol) in THF was added dropwise and the mixture was stirred
C8H12O4, M = 172.18 g mol–1, calculated: [M + H]+: 173.0816;
found 173.0799.
Allyl 6-Hydroxy-3-oxohex-4-enoate (13): After swelling in dichloro-
methane, resin (200 mg) was treated overnight with TBAF in
CH2Cl2 (1 , 1 mL). After additional washing of the resin with
dichloromethane the combined solutions were washed with satu-
for 50 minutes at –78 °C. Resin (200 mg, 1.0 mmol g–1) was swollen rated NaHCO3 solution, water and saturated sodium chloride solu-
in a small amount of dry THF and cooled to –60 °C, after which
BF3·Et2O (0.1 mL) was added and the suspension was shaken for
5 minutes. The solution of the anion was added and the suspension
was shaken for 6 h at –60 °C and then allowed to warm up slowly
to room temperature overnight. The reaction was quenched with
THF/water and the resin was filtered. It was washed three times
tion and dried (MgSO4). The crude product was purified by flash
chromatography (silica gel, toluene/methanol, 9:1) to give the
alcohol 13 (4.6 mg, 16% overall yield) as a colourless oil. Rf (tolu-
ene/methanol, 5:1 v/v) = 0.26. Keto/enol ratio 3:2. 1H NMR
(500 MHz, CDCl3): δ = 11.77 (s, 0.4 H), 6.96 (dt, J = 4, 16 Hz, 0.6
H), 6.75 (dt, J = 4, 16 Hz, 0.6 H), 6.46 (dt, J = 2, 16 Hz, 0.4 H),
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6.08 (dd, J = 2, 16 Hz, 0.4 H), 5.93 (m, 1 H), 5.34 and 5.26 (m,
each 1 H), 5.05 (s, 0.4 H), 4.66 (dt, J = 1, 6 Hz, 0.8 H), 4.64 (dt, J
= 1, 6 Hz, 1.2 H), 3.64 (s, 1.2 H), 4.40 (s, 1.2 H), 4.35(s, 0.8 H),
tion was achieved by preparative HPLC. Yield: 6.7 mg (0.02 mmol,
28%), colourless oil. H NMR (400 MHz, CDCl3): δ = 7.34 (d, J
1
= 5 Hz, 2 H), 7.24–7.19 (m, 3 H), 5.99–5.82 (m, 1 H), 5.36–5.30
2.45 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 192.0, 172.4, (m, 2 H), 4.72 (d, J = 15 Hz), 3.78–3.56 (m, 2 H), 2.80–2.68 (m, 1
168.9, 167.2, 147.8, 138.4, 131.3, 131.9, 131.8, 118.8, 118.4, 90.9,
H), 2.60–2.45 (m, 2 H), 2.19–2.14 (d, J = 12 Hz, 1 H), 1.98–1.76 (m,
4 H), 1.58–1.44 (m, 3 H) ppm. HRMS [FAB/HR] for C15H20O4, M
= 340.41 g mol–1, calculated: [M + H]+: 341.1755; found 341.1802.
70.6, 67.4, 65.6, 47.0 ppm. IR: ν = 3426 (s, alcohol) cm–1. HRMS
˜
[FAB/LR] for C9H12O4, M = 184.19 g mol–1, calculated: [M + H]+:
185.08; found 185.03.
Allyl rac-2-Acetyl-1,2,3,4,6,7,8,8a-octahydro-4-(hydroxymethyl)-6-
oxoisoquinolin-5-carboxylate (16d): Resin (100 mg) was treated with
N-acetylpiperidone (10 equiv.) as described for compound 16a. IR:
Allyl
6,6-(Ethylenedioxy)-2,3,4,4a,5,6,7,8-octahydro-4-(hydroxy-
methyl)-2-oxonaphthalene-1-carboxylate (16a): A mixture of cyclo-
hexane-1,4-dione monoethylene acetal (0.11 g, 0.7 mmol), pyrroli-
dine (0.29 mL, 3.5 mmol) and toluene (5 mL) was heated at reflux
in a toluene-filled Dean–Stark water separator until the conversion
into the enamine was complete (monitored by GC-MS). The sol-
vent and excess pyrrolidine were removed under reduced pressure,
yielding the pure enamine as a pale yellow oil, which was stored
under argon and dissolved in dry (!) methanol/1,4-dioxane (3:1,
ν = 1739 (s, ester) cm–1.
˜
The crude product was cleaved from solid support by treatment of
the resin with TBAF in THF (1 ) at room temperature overnight.
The resin was again washed twice with THF and the combined
organic phases were washed with saturated NaHCO3 solution and
saturated sodium chloride solution and dried (MgSO4). Purifica-
tion was achieved by preparative HPLC. Yield: 8 mg (0.026 mmol,
1
0.7 mL).
A suspension of polymer-bound alcohol (100 mg,
37%), colourless oil. H NMR (400 MHz, CDCl3): δ = 6.08–5.84
0.7 mmol g–1) in methanol/1,4-dioxane was swollen, after which the
dissolved enamine was added. The suspension was shaken at 50 °C
for 20 h, and, after addition of base (3 equiv.), for an additional
24 h. Afterwards the solution was quenched with water/THF and
the resin was filtered off. It was washed three times each with THF
and CH2Cl2, twice with HCOOH in CH2Cl2 (0.5 , 5 s), five times
with CH2Cl2 and once with MeOH and dried under reduced pres-
(m, 1 H), 5.32 (m, 2 H), 4.74 (d, J = 15 Hz), 3.86 (dq, J = 2, 9 Hz,
1 H), 3.79–3.58 (m, 2 H), 3.21–3.13 (m, 1 H), 2.82–2.59 (m, 2 H),
2.60–2.45 (m, 2 H), 2.10–1.96 (m, 1 H), 2.00–1.72 (m, 3 H) ppm.
HRMS [FAB/HR] for C16H21NO5, M = 307.34 g mol–1, calculated:
[M + H]+: 308.1500; found 308.1524.
Acknowledgments
sure. IR: ν = 1739 (s, ester) cm–1. The crude product was cleaved
˜
from the solid support by treatment of the resin with TBAF in
THF (1 ) at room temperature overnight. The resin was washed
twice with THF and the combined organic phases were washed
with saturated NaHCO3 solution and saturated sodium chloride
solution and dried (MgSO4). Purification was achieved by prepara-
tive HPLC. Yield: 7 mg (0.022 mmol, 31%), colourless oil. 1H
NMR (400 MHz, CDCl3): δ = 6.08–5.84 (m, 1 H), 5.32 (m, 2 H),
4.74 (d, J = 15 Hz), 3.99 (s, 4 H), 3.79–3.58 (m, 2 H), 2.82–2.68
(m, 1 H), 2.60–2.45 (m, 2 H), 2.19–2.14 (d, J = 11 Hz, 1 H), 2.00–
1.72 (m, 3 H), 1.62–1.42 (m, 4 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 198.4, 166.0, 164.4, 131.6, 118.6, 107.6, 66.5, 64.6,
64.6, 67.1, 38.8, 37.1, 31.3, 29.7, 24.3, 19.9 ppm. HRMS [FAB/HR]
for C17H22O6, M = 322.35 g mol–1, calculated: [M + H]+: 323.1496;
found 323.1510.
This research was supported by the Deutsche Forschungsgemein-
schaft, the Max-Planck-Gesellschaft and the Fonds der Chem-
ischen Industrie.
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16b: Resin (100 mg) was treated with p-methylcyclohexanone
(10 equiv.) as described for compound 16a. IR: ν = 1716 (s, es-
˜
ter) cm–1. The crude product was cleaved from solid support by
treatment of the resin with TBAF in THF (1 ) at room tempera-
ture overnight. The resin was again washed twice with THF and
the combined organic phases were washed with saturated NaHCO3
solution and saturated sodium chloride solution and dried
(MgSO4). Purification was achieved by preparative HPLC. Yield:
6.2 mg (0.0224 mmol, 32%), colourless oil. 1H NMR (400 MHz,
CDCl3): δ = 6.08–5.82 (m, 1 H), 5.34–5.28 (m, 2 H), 4.74 (d, J =
15 Hz), 3.78–3.56 (m, 2 H), 2.82–2.68 (m, 1 H), 2.60–2.45 (m, 2
H), 2.19–2.14 (d, J = 12 Hz, 1 H), 1.98–1.76 (m, 4 H), 1.58–1.44
(m, 3 H), 0.82 (s, 3 H) ppm. HRMS [FAB/HR] for C16H22O4, M
= 278.34 g mol–1, calculated: [M + H]+: 279.1598; found 279.1613.
16c: Resin (100 mg) was treated with p-phenylcyclohexanone
(10 equiv.) as described for compound 16a. IR: ν = 1739 (s, es-
˜
ter) cm–1.
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The crude product was cleaved from solid support by treatment of
the resin with TBAF in THF (1 ) at room temperature overnight.
The resin was again washed twice with THF and the combined
organic phases were washed with saturated NaHCO3 solution and
saturated sodium chloride solution and dried (MgSO4). Purifica-
2098
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2093–2099

Solid-Phase Synthesis of Decalin Scaffolds
FULL PAPER
[11] F. L. Moore, L. A. Thompson, Y.-C. Moon, J. A. Ellman, J.
Org. Chem. 1998, 63, 2066–2067.
[12] G. Barany, S. K. Shannon, J. Org. Chem. 2004, 69, 4586–4594.
[13] Examination of the solvents used in the reactions and for wash-
ing of the resin by GC-MS showed that premature cleavage of
intermediates from the resin did not occur under the described
conditions.
[14] For assignment of relative configurations the NMR spectra of
the products were compared with those of analogous com-
pounds masked as tert-butyldimethylsilyl ethers and synthe-
sized by solution-phase reactions by established methods.
Received: November 24, 2005
Published Online: March 3, 2006
Eur. J. Org. Chem. 2006, 2093–2099
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2099