Asymmetric synthesis of polyfunctionalized mono-, Bi-, and tricyclic carbon frameworks via organocatalytic domino reactions

Article abstract of DOI:10.1002/adsc.200700396

An asymmetric organocatalytic multi-component domino reaction is used as a key process for the stereoselective synthesis of polysubstituted mono- and bicyclic cyclohexene-carbaldehydes. Furthermore, the extension of the domino reaction and further synthetic transformations of the cascade products were investigated. The combination of the three-step cascade with an intramolecular Diels-Alder reaction opens up an entry to tricyclic decahydroacenaphthylene and decahydrophenalene skeletons, which are valuable characteristic carbon cores of natural products.

Full text of DOI:10.1002/adsc.200700396

FULL PAPERS
DOI: 10.1002/adsc.200700396
Asymmetric Synthesis of Polyfunctionalized Mono-, Bi-, and
Tricyclic Carbon Frameworks via Organocatalytic Domino
Reactions
Dieter Enders,a,* Matthias R. M. Hüttl,a Gerhard Raabe,a and Jan W. Batsb
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2127; e-mail: enders@rwth-aachen.de
Institute of Organic Chemistry and Chemical Biology, University of Frankfurt, Marie-Curie-Str. 11, 60439 Frankfurt am
b
Main, Germany
Received: August 10, 2007; Published online: January 9, 2008
Dedicated to Professor Lutz F. Tietze on the occasion of his 65th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An asymmetric organocatalytic multi-com- Alder reaction opens up an entry to tricyclic decahy-
ponent domino reaction is used as a key process for droacenaphthylene and decahydrophenalene skele-
the stereoselective synthesis of polysubstituted tons, which are valuable characteristic carbon cores
mono- and bicyclic cyclohexene-carbaldehydes. Fur- of natural products.
thermore, the extension of the domino reaction and
further synthetic transformations of the cascade Keywords: asymmetric synthesis; cyclohexene-car-
products were investigated. The combination of the baldehydes; domino reactions; organocatalysis; triple
three-step cascade with an intramolecular Diels– cascade
Introduction
activation modes[6] for carbonyl compounds, namely
enamine and iminium formation. By merging the en-
Due to the fact that efficient and environmentally amine and iminium activation steps along with the
friendly synthetic strategies in organic synthesis are proper carbonyl compounds many domino reactions
becoming more and more important, the development can be designed.[5,7]
of innovative methods concerning these matters is an
We used this elaborate strategy to develop a triple
ongoing challenge at the forefront of organic synthe- cascade using enamine-iminium-enamine activation in
sis.[1] In particular, biomimetic approaches by which the stereoselective synthesis of cyclohexene-carbalde-
complex organic molecules bearing several stereocen- hydes A.[8] The retrosynthetic analysis of our Michael/
ters are stereoselectively assembled from simple pre- Michael/aldol condensation sequence is depicted in
cursors constitute a very promising concept.[2] In this Figure 1.
respect, organocatalytic domino reactions seem to be
Herein, we report further extensions of this method
the perfect way to achieve this goal because the ad- regarding the substrate scope including nitroalkene
vantages of both fields, organocatalysis[3] and domino
reactions,[4] are merged. By avoiding the isolation of
intermediate products and time-consuming protecting
group manipulations, domino reactions drastically
reduce the amount of chemicals, waste, and costs. Ad-
ditionally, these processes generally show very good
stereoselectivities, which often increase during the
subsequent steps. A variety of different organocata-
lysts have been employed in recent years allowing ef-
ficient asymmetric domino reactions.[5] Besides
Brønsted acid-catalyzed cascades this area is mainly
dominated by amine-catalyzed reactions due to two the synthesis of the cyclohexene-carbaldehydes A.
Figure 1. Retrosynthetic analysis of the triple cascade for
Adv. Synth. Catal. 2008, 350, 267 – 279
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267

Dieter Enders et al.
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aldehydes and diene aldehydes, transformations of
the domino products A to synthetically valuable
building blocks and the asymmetric synthesis of bi-
and tricyclic carbaldehydes that possess typical struc-
tural features of the natural products isovelleral, the
hainanolides and the amphilectanes.
Results and Discussion
We initiated our investigations towards the three-step
domino reaction according to the retrosynthesis
shown in Figure 1 based on our previous procedure
for the organocatalytic Michael addition of ketones to
nitroalkenes,[9a] by modifying a protocol of Hayashi
et al.[9b] and extended it by adding a second unsaturat-
ed aldehyde component. Thus, nearly stoichiometric
amounts of propanal 1a, nitrostyrene 2a, and cinna-
maldehyde 3a (1.20:1.00:1.05) were stirred in the
presence of the fluorinated diarylprolinol silyl ether 4
(20 mol%) using n-hexane as a solvent. Under these
Scheme 1. First test reaction for the development of the
three-step domino reaction of 6a.
conditions the Michael adduct 5a was formed very diarylprolinol ethers in the case of aldehyde sub-
slowly and only traces of the desired domino product strates, five different prolinol derivatives were
6a were observed (Scheme 1). The low reaction rate screened in this reaction (Table 1).
of the Michael addition might be due to three facts.
The catalyst screening clearly showed that the best
First, we did not use a ten-fold excess of the aldehyde results with respect to conversion and stereoselectiv-
component 1a as Hayashi did, secondly, we used a flu- ity were obtained with the silyl ethers 7 and 9. Both
orinated organocatalyst, and thirdly, only small catalysts provided the product 6a after 16 h with 99%
amounts of the nitroalkene 2a were soluble in n- conversion and good diastereo- and virtually com-
hexane.
plete enantiocontrol (78:22 and 79:21 dr, ꢀ99% ee).
Therefore, the reaction conditions were changed Interestingly, the activity of the catalyst dropped dra-
and toluene was employed as solvent, which com- matically with the increasing number of fluorine sub-
pletely dissolved all reaction components. Due to the stituents at the phenyl groups as compared to the
high stereoselectivity that can be obtained with bulky electron-rich aryl substituents of 7 and 9. The easily
Table 1. Results of the catalyst screening for the domino reaction to form 6a.[a]
No.
Catalyst
Time [h]
Conversion [%][b]
dr
ee [%][c]
ꢀ99
1
(S)-7
16
99
78:22
2
3
8
4
16
16
75
20
79:21
77:23
n.d.
n.d.
4
9
16
16
99
79:21
ꢀ99
5
10
88
76:24
n.d.
[a]
1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol), and 20 mol% of the catalyst were dissolved in toluene (1 mL) and stirred at
58C.
Conversion of 5a determined by GCof the reaction mixture.
Determined by HPLCon chiral stationary phase (n.d. =not determined).
[b]
[c]
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Asymmetric Synthesis of Polyfunctionalized Mono-, Bi-, and Tricyclic Carbon Frameworks
FULL PAPERS
accessible catalyst 7 was chosen for the further inves-
tigation (Scheme 2).
For the residue R1 of the aldehyde substrate 1,
simple to sterically demanding groups could be intro-
With the optimized conditions at hand the method duced. Even functional groups like acetals or protect-
was applied to a broad range of substrates. First of all ed alcohols were tolerated. When the protected a-hy-
the nitroalkene component 2 was varied (Table 2).
droxy aldehydes 1v–x were employed, the outcome of
the reaction was highly dependent on the protecting
group. As can be seen from Table 3, the OBn- and
OTBS-protected a-hydroxy aldehydes were only very
slowly converted to the corresponding domino prod-
ucts 6w, x. Due to the long reaction times several side
reactions took place. In case of the acetyl-protected
aldehyde 1v the reaction was slow, too, but an isola-
tion of the cyclohexene-carbaldehyde 6v was success-
ful (18% yield, 71:29 dr, ꢀ99% ee). Despite this, the
yields of the other substrates were very good with
regard to a three-step process (38–60%) and very
high stereoselectivities were obtained (78:22–89:11 dr,
ꢀ99% ee).
Scheme 2. Variation of the substrates 1, 2 and 3 of the triple
cascade.
The variation of the remaining substrate 3 was also
15 different nitroalkenes were employed in the investigated and the results are summarized in
domino reaction. Among them the aromatic and het- Table 4. Besides cinnamaldehyde (3a) as the most
eroaromatic nitroalkenes 2a–j provided the cyclohex- active substrate, five additional a,b-unsaturated alde-
ene derivatives 6a–j in good yield (23–51%) and with hydes were employed. When acrolein (R3 =H) was
good diastereo- and excellent enantioselectivity used not only relatively good yields could be obtained
(71:29–89:11 dr, ꢀ99% ee). Nitroalkenes 2k, l did not (41–50%), but also trisubstituted cyclohexene-carbal-
give the product, although they are aromatic. This dehydes were accessible. The diastereoselectivity of
might be due to the free hydroxy group of 2k and the the trisubstituted cyclohexene carbaldehydes 6y–ab
amide group of 2l, respectively. In contrast to the were slightly lower than before (65:35–86:14 dr). The
highly reactive aromatic nitroalkenes, the aliphatic ni- other four aldehydes were not as active as cinnamal-
troalkenes 2m–o reacted very slowly in the triple cas- dehyde and acrolein providing the domino products
cade. After several days only trace amounts of the 6ac–af in 18–29% yield. The diastereoselectivity in-
product could be detected.
creased with the steric demand of the residue R3
Table 2. Variation of the nitroalkene 2 leading to the cyclohexene derivatives 6a–o.[a]
No.
6
R1
R2
R3
Yield [%]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
4-MeC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
40
37
37
51
29
39
33
39
23
37
0
0
78:22
83:17
82:18
84:16
88:12
83:17
71:29
87:13
83:17
89:11
n.d.
ꢀ99
ꢀ99
ꢀ99
ꢀ99
ꢀ99
ꢀ99
ꢀ99
ꢀ99
ꢀ99
ꢀ99
n.d.
2-ClC6H4
4-BrC6H4
4-MeOC6H4
4-NO2C6H4
Piperonyl
2-Furanyl
5-Methylfuran-2-yl
3-MeO-4-OH-C6H3
4-AcHNC6H4
Et
9
10
11
12
13
14
15
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
<2[d]
<2[d]
<5[d]
n-Hex
BnOCH2
[a]
1a (1.10-1.20 mmol), 2a–o (1.0 mmol), 3a (1.05 mmol) and 20 mol% of (S)-7 were dissolved in toluene (0.8 mL) and
stirred at 08Cto room temperature.
Determined by GCof the reaction mixture.
Determined by HPLCon chiral stationary phase.
Product was not isolated.
[b]
[c]
[d]
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Dieter Enders et al.
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Table 3. Variation of the aldehyde component 1 leading to the cyclohexene derivatives 6p–x.[a]
No.
6
R1
R2
R3
Yield [%]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
9
p
q
r
s
t
u
v
w
x
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
58
56
60
38
60
54
18
<8
<8
80:20
79:21
83:17
89:11
78:22
83:17
71:29
n.d.
ꢀ99
ꢀ 99
ꢀ99
ꢀ99
ꢀ99
99
i-Pr
n-Pent
Bn
ACHRTUNEG(MeO)2CHACHRTE(UGN CH2)3-
TBSOCH2
AcO
ꢀ99
BnO[d]
n.d.
TBSO[d]
n.d.
n.d.
[a]
1p–x (1.10–1.20 mmol), 2a (1.0 mmol), 3a (1.05 mmol) and 20 mol% of (S)-7 were dissolved in toluene (0.8 mL) and
stirred at 08Cto room temeprature.
Determined by GCof the reaction mixture.
Determined by HPLCon chiral stationary phase.
Product was not isolated.
[b]
[c]
[d]
Table 4. Variation of the enal component 3 leading to the cyclohexene derivatives 6y–af.[a]
No.
6
R1
R2
R3
Yield [%]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
y
z
CH3
i-Pr
Ph
Ph
Ph
2-Furanyl
Ph
Ph
Ph
Ph
H
H
H
H
50
41
47
47
25
18
29
20
86:14
84:16
65:35
77:23
68:32
77:23
80:20
88:12
ꢀ99
ꢀ99
98
aa
ab
ac
ad
ae
af
A
(CH2)3-
CH3
CH3
CH3
CH3
CH3
97
Me
Et
n-Bu
CH3C=CH
ꢀ99
ꢀ99
ꢀ99
99
[a]
1 (1.10–1.20 mmol), 2 (1.0 mmol), 3 (1.05 mmol) and 20 mol% of (S)-7 were dissolved in toluene (0.8 mL) and stirred at
08Cto room temperature.
Determined by GCof the reaction mixture.
[b]
[c]
Determined by HPLCon chiral stationary phase.
ꢁ
(Table 4). As expected, in all eight cases the enantio-
control was excellent (97–ꢀ99% ee).
During the reaction sequence three new C C
bonds are formed, not counting the double bond of
To understand the course of this three-step cascade the final aldol condensation, and four stereocenters
reaction we already proposed a catalytic cycle based are generated with good diastereo- and virtually com-
on the knowledge of the single steps and the detected plete enantiocontrol. The minor diastereomer (5-
intermediates of the domino reaction (Figure 2).[8] epimer), which is formed, can easily be separated by
The cycle is initiated by the enamine formation of al- flash chromatography. The relative and absolute con-
dehyde 1 and catalyst (S)-7. Enamine 11 can now add figuration of the cyclohexene-carbaldehydes 6 and
to the reactive Michael acceptor 2 to yield the nitroal- their 5-epimer (epi-6) was determined by X-ray analy-
kane 5 which is in agreement with Hayashiꢁs re- sis[12] and NOE experiments. The X-ray structures of
sults.[9b] Subsequent hydrolysis liberates the catalyst, 6a, d and s are illustrated in Figure 3 whereby 6d
which now can activate the a,b-unsaturated aldehyde proved the absolute configuration. Based on the X-
3 via iminium ion formation. That allows the second ray analysis of 6 the relative and absolute configura-
Michael-type addition of 5 and 12 to take place pro- tions of the corresponding epimer epi-6 could be de-
viding the corresponding enamine intermediate 13.[10] termined by NOE experiments (Figure 4).
In the third step the six-membered ring of 14 is closed
The interpretation of the NMR data allowed an
by an enamine-catalyzed intramolecular aldol reac- easy differentiation of both epimers, which is indicat-
1
tion, which upon condensation and subsequent hy- ed by the H NMR chemical shift of the proton at the
drolysis releases the catalyst and the desired domino epimeric center, 4.87 ppm and 5.25 ppm, respectively
product 6. As we have reported recently only the first (Figure 4).
Michael adduct 5 and the product 6 were detectable
by GCanalysis.
With this new efficient method at hand we turned
our attention towards further derivatization of the cy-
[8,11]
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Asymmetric Synthesis of Polyfunctionalized Mono-, Bi-, and Tricyclic Carbon Frameworks
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Figure 2. Proposed catalytic cycle of the triple cascade.
clohexene-carbaldehydes 6. Especially, the transfor- capable to accomplish the desired reduction at all.[14]
mation to cyclic g-amino acids or amino alcohols Finally, the reduction with highly activated Raney-Ni
leads to the structurally interesting molecules such as in methanol under a hydrogen atmosphere (15 bar)
15 and 16, which might possess biological activity was successful (Scheme 5). However, under these
(Figure 5).
harsh conditions not only the nitro moiety was re-
We initiated our study by looking for a suitable re- duced, but also the double bond and the aldehyde
ducing agent, which chemoselectively reduces the al- function were attacked. The corresponding amino al-
dehyde moiety in the presence of the double bond cohol was then directly protected with acetic acid an-
and the nitro group. To our delight, the reduction hydride to give 20 in 23% yield over two steps. Fur-
with sodium borohydride in methanol at 08Cconvert-
ther oxidation of the hydroxy group would provide
ed the starting triple cascade products 6a and y quan- the g-amino acid.
titatively to the corresponding alcohols 17 and 18 iso-
lated in 95% yield, respectively (Scheme 3).
It was also of great interest to use our recently de-
veloped organocatalytic triple cascade protocol for
The chemoselective oxidation of 6 to the corre- the synthesis of polycyclic structures that bear charac-
sponding acid was accomplished with sodium chlorite. teristic structural features of natural products and
According to a literature procedure[13] the cyclohex- might be useful intermediates in the asymmetric syn-
ene derivative 6a was dissolved in a 1:1-mixture of thesis of the former. One interesting structural motif
water/acetone and subsequently treated with 2- constitutes (+)-isovelleral (21), a fungal metabolite
methyl-2-butene, NaH2PO4, and NaClO2 at 08C. found in the fruit bodies of Lactarius vellereus
After completion of the reaction the carboxylic acid (Figure 6). The sesquiterpenoid dialdehyde 21 pos-
19 was obtained in 83% yield (Scheme 4).
sesses potent antimicrobial and cytotoxic activities.[15]
In the next task the selective reduction of the nitro Interestingly, the synthetic analog tridemethylisovell-
group was investigated. Unfortunately, the nitro eral (22) was even more active and showed very good
group occupies a pseudo-axial position of the cyclo- antitumor properties in subnanomolar concentra-
hexene ring and is sterically hindered by the sur- tions.[16]
rounding phenyl groups. That makes its transforma-
Our approach towards the hexahydro-1H-indene
tion very difficult. A lot of reducing agents were not core is depicted in Scheme 6. The synthesis of the
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Figure 5. Synthetically interesting derivatives 15 and 16.
Scheme 3. NaBH4 reduction of 6a and y to the correspond-
ing alcohols 17 and 18.
Figure 3. X-Ray structures of the cyclohexene-carbaldehydes
6a, 6s and 6d.
Scheme 4. Oxidation of 6a to the corresponding carboxylic
acid 19.
Scheme 5. Raney-Ni reduction of 6a and subsequent protec-
tion of the resulting amino alcohol to 20.
Figure 4. Representative enhancements of 6a and epi-6a.
hexahydro-1H-indene-carbaldehyde 26 was achieved
by a similar reaction sequence as the earlier described
triple cascade, consisting of an intramolecular Mi-
chael/Michael/aldol condensation. First of all, the ni-
Figure 6. Structures of (+)-isovelleral (21) and tridemethyli-
troalkenal 25 was synthesized starting from cyclohex- sovelleral (22).
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Asymmetric Synthesis of Polyfunctionalized Mono-, Bi-, and Tricyclic Carbon Frameworks
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Scheme 6. Triple cascade for the synthesis of hexahydro-1H-
indene-carbaldehyde 26 ([a] after chromatography): a) O3,
DCM/MeOH (5:1), ꢁ788C; p-TSA, r.t.; then NaHCO3;
DMS, r.t.; b) MeNO2, i-PrOH, KF, 08C ! r.t.; c) DCC, cat.
Figure 7. Structures of hainanolide (27), which can be traced
back to 28 and amphilectanes 29 and 30.
Cu(I)Cl, Et2O, 0 8C ! r.t.; d) p-TSA, acetone/H2O (4:1), D,
1.5 h.
ene (23) via a four-step procedure. In the first step
the ozonolysis in DCM/MeOH followed by a reduc-
tive work-up provided the monoprotected dialdehyde
24 in 81% yield.[17] Subsequent Henry reaction[18] and
dehydration[19] of the intermediate nitro alcohol gave
the nitroalkene aldehyde 25 after acidic cleavage of
the acetal moiety. Although the reaction was slow
(four days) due to the lower reactivity of the aliphatic
nitroalkene, we were able to isolate the domino prod-
uct 26 after chromatography in diastereomerically
pure form (21%) and with an enantiomeric excess of
79%.
Besides the bicyclic structure we also envisaged to
build up tricyclic carbon cores, which are found in
biologically active diterpenoid natural products, such
as hainanolide (harringtonolide) 27[20] whereby 28 has
been envisaged as a synthetic precursor 27[20a] or the
amphilectane-type
diterpenoids
29
and
30
(Figure 7).[21]
Figure 8. Retrosynthetic analysis of the tricyclic carbalde-
Therefore, we developed a very efficient one-pot hyde E in four steps.
four-step protocol, which allowed the synthesis of
decahydroacenaphthylene and decahydrophenalene
frameworks in one operation.[22] The retrosynthetic Grignard reagent. After cooling of the reaction mix-
analysis of this strategy is illustrated in Figure 8. Ac- ture to ꢁ508Cfirst Li CuCl4 and then acetate 34 were
2
cordingly, the tricyclic carbaldehyde E should be as- added to provide the copper-catalyzed coupling prod-
sembled from the simple starting materials C,D,G uct.[24] Upon acidic acetal cleavage the free (E,E)-
achieved by the triple cascade reaction to form F nonadienal[25] (33a, 37%) and (E,E)-decadienal[26]
which is then followed by an intramolecular Diels– (33b, 58%) were obtained (Scheme 7).
Alder reaction (IMDA). Five new carbon bonds and
The heteroatom-substituted analogues 33c, d were
eight stereocenters would be generated in this Mi- synthesized in a different way. Again the bromides 31
chael/Michael/aldol condensation/IMDA reaction se- and 32 were used as starting material, but then the
quence.
ether formation was performed with sorbic alcohol
Our studies towards the polyfunctionalized tricyclic (35) under basic conditions (Williamson ether synthe-
carbaldehydes E started with the synthesis of the sis). After acidic deprotection of the O,O-acetal the
diene aldehydes G. Thus, the bromides 31 and 32[23] dienal ethers 33c, d were isolated in 24 and 37%
were treated with magnesium in THF to obtain the yield, respectively (Scheme 7).
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Due to these results, we had to alter our strategy
and it was discovered that the Lewis acid-mediated
cycloaddition[28] was a viable alternative. To complete
the reaction towards the polyfunctionalized decahy-
droacenaphthylene and decahydrophenalene deriva-
tives, the IMDA reaction of the cyclohexene carbalde-
hydes 36 was carried out in the same pot using
Me2AlCl to yield the desired tricyclic products 37
(Scheme 9).[29]
As can be seen from Table 6, all C-substituted cy-
clohexene-carbaldehydes could be successfully cy-
clized yielding the decahydroacenapthylenes and de-
hydrophenalenes 37a–f in satisfying yields and, after
chromatographic separation of the minor diastereo-
mers, in excellent diastereo- and enantiomeric purity
(ꢀ98:2 dr, 97 to ꢀ99% ee). By changing the chain
length of the diene residue, the ring size can be ad-
Scheme 7. Synthesis of the diene aldehydes 33a–d.
We now were able to carry out the three-compo- justed to five- or six-membered rings. Unfortunately,
nent domino reaction (Scheme 8). Following our pre- the ether-type domino products did not undergo the
viously described protocol the desired products 36a–h intramolecular Diels–Alder reaction.
could be obtained in 21–59% yield and, after chroma-
During this one-pot procedure out of the theoreti-
tographic separation of the minor epimer, with virtu- cally possible 256 stereoisomers only two or three
ally complete diastereo- and enantiomeric purity enantiopure diastereomers were formed. Two isomers
(98:2 to ꢀ99:1 dr, 97 to ꢀ99% ee, Table 5). Unfortu- were detected for the decahydrophenalenes 37c–f
nately, the organocatalyzed intramolecular Diels– with a ratio of the diastereomers ranging from 10:1 to
Alder reaction[27] as fourth step of the cascade (quad- 15:1. In the case of the more strained decahydroace-
ruple cascade) was not favoured and only traces of naphthylenes 37a, b three stereoisomers were formed
the cycloadduct were detected.
during the reaction sequence (5:1:1–12:2:1 dr). One
of them is the 5-epimer of 36 formed during the triple
cascade. The absolute and relative configurations of
the synthesized tricycles 37 were determined by X-ray
structure analysis of 37b (Figure 9) and NOE meas-
urements of 37c.[22] The absolute and relative configu-
ration matches the stereochemical outcome of the
triple cascade and the Lewis acid-promoted IMDA
reaction providing the trans-fused endo-selective cy-
cloadduct.
The different chain lengths (n=0 and n=1) of 36
lead to different stereochemical results of the IMDA
Scheme 8. Synthesis of the cyclohexene-carbaldehydes 36 reaction. An explanation of this behaviour can be
bearing the diene moiety.
given by comparing the relevant transition states of
Table 5. Results of the syntheses of 36.
36
R2
R3
n/X
Yield [%][a]
dr[b]
ee [%][c]
a
b
c
d
e
f
Ph
2-ClC6H4
Ph
2-ClC6H4
Ph
2-ClC6H4
Ph
Ph
Ph
Ph
Ph
H
H
Ph
Ph
0/C51
0/C59
1/C47
1/C55
1/C49
1/C51
1/O
ꢀ99:1[c]
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ98:2
ꢀ99
ꢀ99
ꢀ99
ꢀ99
98
97
g
h
20
31
ꢀ99
Ph
2/O
ꢀ99
[a]
[b]
[c]
Yield of the isolated product.
After flash chromatography; determined by 13CNMR.
Determined by HPLCon a chiral stationary phase.
274
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Asymmetric Synthesis of Polyfunctionalized Mono-, Bi-, and Tricyclic Carbon Frameworks
FULL PAPERS
Scheme 9. One-pot synthesis of the decahydroacenaphthylene and decahydrophenalene derivatives 37.
Table 6. Results of the one-pot synthesis of the triple cascade/IMDA reaction.
37
R2
R3
n/X
yield [%][a]
dr[b]
ee [%][c]
a
b
c
d
e
f
Ph
2-ClC6H4
Ph
2-ClC6H4
Ph
2-ClC6H4
Ph
Ph
Ph
Ph
Ph
H
H
Ph
Ph
0/C35
0/C45
1/C56
1/C52
1/C49
1/C22
1/O
5:1:1
12:2:1
15:1
11:1
10:1
10:1
ꢀ99
ꢀ99
ꢀ99
ꢀ99
ꢀ99
97
g
h
-
-
-
-
-
-
Ph
2/O
[a]
[b]
[c]
Yield of the isolated product.
Determined by H NMR.
Determined by HPLCon chiral stationary phase.
1
the cycloaddition as it is illustrated below (Figure 10
and Figure 11). The transition states in Figure 10
show that the endo-approach of the diene moiety is
preferred over the exo-approach due to kinetic con-
trol (Alder rule) as well as the steric interactions.
Cyclohexene-carbaldehyde 36c, possessing a longer
side chain, can approach the enal face from both
sides. In order to obtain the determined configuration
the diene moiety has to approach the enal face from
above in an “endo-manner” minimizing the steric in-
teractions compared to the other transition states
(Figure 11).
Figure 9. X-Ray structure analysis of decahydroacenaphthy-
lene 37b.[22,30]
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275

Dieter Enders et al.
FULL PAPERS
Figure 10. Propoed transition state leading to decahydroacenaphthylene 37a (n=0).
Figure 11. Proposed transition state leading to decahydrophenalene 37c (n=1).
Conclusions
hyde precursors for the cascade reaction a quick entry
to bicyclic and tricyclic carbaldehydes is opened,
We have developed a highly flexible and general or- which are structural motifs of several biologically
ganocatalytic triple cascade for the diastereo- and active natural products such as isovelleral, the haina-
enantioselective assembly of tri- and tetrasubstituted nolides, and the amphilectanes.
cyclohexene carbaldehydes. Starting from simple alde-
hyde and nitroalkene substrates the domino products
were formed in a Michael/Michael/aldol condensation
Experimental Section
sequence using the readily available diphenylprolinol
silyl ether as an universal organocatalyst for all steps.
General Remarks
ꢁ
Three new C Cbonds and up to four stereocentres
can be generated via this diverse strategy. Further-
more, the cyclohexene-carbaldehydes can be trans-
formed to the corresponding alcohols, carbocyclic
Starting materials and reagents were purchased from com-
mercial suppliers and used without further purification. Tol-
uene was freshly distilled from sodium-lead alloy under
acids or amino alcohols. By employing specific alde- argon. Dichloromethane was freshly distilled from CaH2
276
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Asymmetric Synthesis of Polyfunctionalized Mono-, Bi-, and Tricyclic Carbon Frameworks
FULL PAPERS
under argon. Preparative column chromatography was per-
formed on Merck silica gel 60, particle size 0.040–0.063 mm
(230–240 mesh, flash). Analytical TLC: silica gel 60 F254
plates from Merck, Darmstadt. Visualization of the devel-
oped chromatograms was performed by ultraviolet irradia-
tion (254 nm) or staining using Mo-stain [(NH4)6Mo7O24,
CeSO4, H2SO4, H2O]. Optical rotation values were mea-
sured on a Perkin–Elmer P241 polarimeter. Elemental anal-
with dichloromethane and dried over Na2SO4. After evapo-
ration of the organic solvents the tricyclic product 37 was
purified by flash chromatography on silica gel (diethyl
ether/n-pentane).
The detailed characterization of 37a–f can be found in the
Supporting Information.
yses were obtained with a Heraeus CHN-O-Rapid element Syntheses of the Cyclohexene-carbaldehyde
analyzer. Mass spectra were acquired on
SSQ7000 (EI 70 eV) spectrometer. High resolution mass
spectra were recorded on a Finnigan MAT95 spectrometer.
a Finnigan
Derivatives 17–20 and 26
(3S,4S,5R,6R)-3-Methyl-5-nitro-4,6-diphenylcyclohex-1-enyl-
methanol (17): (3S,4S,5R,6R)-3-Methyl-5-nitro-4,6-diphenyl-
cyclohex-1-ene-carbaldehyde (6a) (0.10 g, 0.31 mmol) was
dissolved in methanol (4 mL) and cooled to 08C. NaBH4
(15 mg, 0.56 mmol) was added and the mixture stirred until
complete conversion of the starting material. The reaction
mixture was quenched with pH 7 buffer solution and ex-
tracted with dichloromethane. The combined organic layers
were dried over Na2SO4 and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography on silica gel (diethyl ether/n-pentane, 1:2)
to afford 17 as a colourless foam; yield: 95 mg (95%).
1
IR spectra were taken on a Perkin–Elmer FT-IR 1760. H
and 13CNMR spectra were recorded on Varian Mercury
300, Inova 400 or Unity 500 spectrometers with tetramethyl-
silane as internal standard and at ambient temperature. An-
alytical GCwas performed on a Varian CP 3800 and an ana-
lytical HPLCon Hewlett–Packard 1050 and 1100 Series
chromatographs (with DAD) using chiral stationary phases
[Chiralpak OD, Chiralpak OJ, Chiralpak AD, Chiralpak AS,
Chiralpak IA, (S,S)-Whelk O1]. All racemic samples were
obtained according to general procedures by mixing equal
amounts of the enantiomers – independently obtained by
using (S)- and (R)-7. The diarylprolinol silyl ethers 4, 7, 8
and 9 as well as methyl ether 10 were prepared according to
the literature.[14,31,32] The aldehydes 1, the nitroalkenes 2 and
dienals 33a, b were either commercially available or synthe-
sized by standard literature procedures.
AHCTRE(UNG 3S,4S,5S)-3-Methyl-5-nitro-4-phenylcyclohex-1-enyl-
methanol (18): (3S,4S,5S)-3-Methyl-5-nitro-4-phenylcyclo-
hex-1-ene-carbaldehyde (6y) (0.10 g, 0.41 mmol) was dis-
solved in methanol (4 mL) and cooled to 08C. NaBH4
(27 mg, 0.73 mmol) was added and the mixture stirred until
complete conversion of the starting material. The reaction
mixture was quenched with pH 7 buffer solution and ex-
tracted with dichloromethane. The combined organic layers
were dried over Na2SO4 and the solvent removed under re-
duced pressure. The crude product was purified by flash
chromatography on silica gel (diethyl ether/n-pentane, 1:2)
to afford 18 as colourless foam;yield: 96 mg (95%).
General Procedure for the Synthesis of the
Cyclohexene-carbaldehydes 6 and 36
To a solution of catalyst (S)-7 (65 mg, 0.20 mmol) and nitro-
alkene 2 (1.0 mmol, 1.0 equiv.) in dry toluene (0.8 mL) was
added subsequently under stirring aldehyde
1 or 33
(3S,4S,5R,6R)-3-Methyl-5-nitro-4,6-diphenylcyclohex-1-
ene-carboxylic acid (19): (3S,4S,5R,6R)-3-Methyl-5-nitro-4,6-
diphenylcyclohex-1-ene-carbaldehyde
(1.1 mmol, 1.1 equivs.) and a,b-unsaturated aldehyde
3
(1.1 mmol, 1.1 equivs.) at 08C. After 1 h the solution was al-
lowed to reach 58C(room temperature) and stirred until
complete consumption of the starting materials (16 h up to
several days, monitored by GC). The reaction mixture can
be directly purified by flash chromatography on silica gel
(ethyl acetate/n-pentane) to yield the pure cyclohexene-car-
baldehydes 6 or 36, respectively.
(6a)
(50 mg,
0.16 mmol) was dissolved in a mixture of acetone/water (1:1,
1 mL) and cooled to 08C. Subsequently, 2-methyl-2-butene
(0.3 mL, 2.87 mmol), NaH2PO4·2H2O (49 mg, 0.31 mmol),
and NaClO2 (44 mg, 0.39 mmol) were added. The ice bath
was removed and the reaction mixture was stirred at room
temperature until complete conversion. After extraction
with ethyl acetate, drying of the combined organic layers
over Na2SO4 and evaporation of the solvent the crude prod-
uct was purified by flash chromatography on silica gel (ethyl
acetate) to provide 19 as a colourless foam; yield: 44 mg
(83%).
The detailed characterization of all products 6 and 36 can
be found in the Supporting Information.
General Procedure for the Synthesis of the
Decahydroacenaphthylenes and
Decahydrophenalenes 37
N-(1R,2S,5S,6S)-3-(Hydroxymethyl)-5-methyl-2,6-diphe-
nylcyclohexyl-acetamide
(20):
To
a
solution
of
To a solution of catalyst (S)-7 (65 mg, 0.20 mmol) and nitro-
alkene 2 (1.0 mmol, 1.0 equiv.) in dry toluene (0.8 mL) was
added subsequently under stirring dienal 33 (1.1 mmol,
(3S,4S,5R,6R)-3-methyl-5-nitro-4,6-diphenylcyclohex-1-ene-
carbaldehyde (6a) (0.15 g, 0.47 mmol) in ethanol (10 mL)
Raney nickel W5 (0.40 g, suspension in ethanol) was added
and the reaction was stirred under a hydrogen atmosphere
(15 atm) for 7 h. The solution was then filtered over celite,
the filtrate was concentrated under reduced pressure and
then again filtered over a short silica plug (methanol/di-
chloromethane, 1:8). After evaporation of the solvent the
crude amino alcohol was dissolved in dichloromethane
(5 mL) and in the presence of catalytic amounts of DMAP
1.1 equivs.) and a,b-unsaturated aldehyde
3 (1.1 mmol,
1.1 equivs.) at 08C. After 1 h the solution was allowed to
reach 58Cand stirred until complete consumption of the
starting materials (monitored by GC). The reaction mixture
was then diluted with dry dichloromethane (3 mLmmolꢁ1)
and cooled to ꢁ788Cunder argon. At this temperature an
excess of Me2AlCl (4 mLmmolꢁ1, 0.9M in n-heptane) was
added and the reaction mixture gradually reached 08C . The treated with triethylamine (0.30 g, 0.30 mmol) and acetic an-
reaction was quenched with pH 7 buffer solution, extracted hydride (73 mg, 0.31 mmol). The reaction mixture was
Adv. Synth. Catal. 2008, 350, 267 – 279
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277

Dieter Enders et al.
FULL PAPERS
stirred overnight followed by the evaporation of the solvent
under reduced pressure and purification via flash chroma-
tography on silica gel (EtOAc) to afford the title compound
as a colorless solid; yield: 41 mg (23% over two steps).
(3aS,6R,7R,7aR)-7-Nitro-6-phenyl-2,3,3a,6,7,7a-hexahy-
dro-1H-indene-5-carbaldehyde (26): To a solution of catalyst
(S)-7 (65 mg, 0.20 mmol) in dry toluene (0.8 mL) was added
subsequently under stirring (E)-7-nitrohept-6-enal (25)
(1.0 mmol, 1.0 equiv.) and cinnamaldehyde 3a (1.1 mmol,
1.1 equivs.) at 08C. After 1 h the solution was allowed to
reach room temperature and stirred for 4 d (monitored by
GC). The reaction mixture was directly purified by flash
chromatography on silica gel (diethyl ether/n-pentane, 1:5)
to afford 26 as a colourless oil; yield: 68 mg (21%).
362; Angew. Chem. Int. Ed. 2006, 45, 354; h) H. Pellissi-
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Gerike, Domino Reactions in Organic Chemistry,
Wiley-VCH, Weinheim, 2006; k) C. J. Chapman, C. G.
Frost, Synthesis 2007, 1.
[5] Review: D. Enders, C. Grondal, M. R. M. Hüttl,
Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed.
2007, 46, 1570.
[6] For enamine activation, see: a) B. List, Chem.
Commun. 2006, 819, and literature cited therein; for
iminium activation, see: b) K. A. Ahrendt, C. J. Borth,
D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122,
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Chem. Soc. 2002, 124, 2458.
The detailed characterization of 17–20 and 26 can be
found in the Supporting Information.
[7] Very recent examples: a) H. SundØn, I. Ibrahem, G.-L.
Zhao, L. Erkisson, A. Córdova, Chem. Eur. J. 2007, 13,
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Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (Priority Program 1179 Organocatalysis). We thank
Degussa AG, Bayer AG, BASF AG, and Wacker Chemie for
the donation of chemicals. The NOE measurements by Dr. J.
Runsink are gratefully acknowledged.
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