Diastereoselective Synthesis of Functionalized Angularly-Fused Tetracycles via an Organocatalytic Quadruple Reaction Sequence

Article abstract of DOI:10.1002/adsc.201700023

An efficient diastereoselective strategy to access complex structural tetracycles was described through an organocascade quadruple reaction sequence between (E)-2-(3-arylallylidene)-1H-indene-1,3(2H)-diones and β-keto esters. The reaction proceeded throug

Full text of DOI:10.1002/adsc.201700023

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DOI: 10.1002/adsc.201700023
Diastereoselective Synthesis of Functionalized Angularly-Fused
Tetracycles via an Organocatalytic Quadruple Reaction Sequence
Fu-Jie Chang,a Ramani Gurubrahamam,a and Kwunmin Chena,*
a
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 11677
Fax : (+886)-2-2932-4249; phone: (+886)-2-7734-6124; e-mail: kchen@ntnu.edu.tw
Received: January 8, 2017; Revised: January 25, 2017; Published online: && &&, 0000
Supporting information for this article can be found under http://dx.doi.org/10.1002/adsc.201700023.
Abstract: An efficient diastereoselective strategy to
access complex structural tetracycles was described
through an organocascade quadruple reaction se-
quence between (E)-2-(3-arylallylidene)-1H-indene-
1,3(2H)-diones and b-keto esters. The reaction pro-
ceeded through remote 1,6-addition followed by se-
quential 1,4-addition and aldol/aldol reactions to
generate angularly-fused carbocyclic motifs with fa-
vourable to excellent yields (up to 94%) and diaste-
reoselectivities (up to >20:1 dr). An enantioselec-
tive organocascade approach was attempted to
yield densely functionalized tetracycles containing
seven chiral centres including a quaternary centre.
mains elusive.[14] This approach is synthetically signifi-
cant as it can avail more reactive sites that are avail-
able either in the substrates or in key intermediates.
The use of indane-1,3-dione and 2-arylideneindane-
1,3-dione derivatives in organocascade/domino reac-
tions has been extensively studied.[15] Similarly, the ex-
quisitely explored remote 1,6-addition on activated
2,4-diene systems has also been demonstrated. How-
ever, to the best of our knowledge, no examples of
a
1,6-addition employing arylallylideneindane-1,3-
diones have been reported, although this skeleton is
abundant in numerous biologically active motifs.[16]
Building angularly-fused tetracyclic core skeletons is
a laborious process, that typically involves various
synthetic transformations and these skeletons prevail
Keywords: indane-1,3-diones; Michael reaction; or-
ganocatalysis; quadruple reaction sequence
in a
myriad of biologically active molecules.[17]
Herein, we report an unprecedented organocascade
quadruple reaction sequence to produce highly com-
plex structural motifs containing malleable functional
groups via a 1,6-/1,4-/aldol/aldol sequence (Scheme 1).
We optimized the conditions of the reaction be-
Asymmetric amino organocatalysis has advanced to
enable the generation of remote stereogenic centres tween phenylallylideneindane-1,3-dione 1a and ethyl
with optimal regio- and stereoselectivities by raising acetoacetate 2a by employing various hydrogen bond-
the highest occupied molecular orbital (HOMO) of ing (HB) catalysts (I–IV, 20 mol%) in combination
the nucleophile through dienamine,[1] trienamine,[2] with
1,4-diazabicyclo[2.2.2]octane
(DABCO,
cross-conjugated trienamine,[3] and tetraenamine[4] ac- 20 mol%) as additive in toluene. After the prelimina-
tivation modes. The principle of vinylogy[5] can also ry examination, the HB catalyst III was found to be
be applied for the lowering of the lowest unoccupied superior among the HB catalysts I–IV affording the
molecular orbital (LUMO) strategy of conjugated car- desired product with a favourable yield (84% yield)
bonyl electrophiles (iminium ion catalysis).[6–10] This and diastereoselectivity (20:1 dr) (Table 1, entries 1–
vinylogy-based strategy is implemented for linear di- 4). We also observed that only DABCO as additive
enals, diene sulfones, and extended cyclic dienones to was effective for the cascade process, and inferior re-
achieve structurally diverse motifs.[11] The recent de- sults were obtained for other additives, namely
velopment of organocascade reactions has become an DMAP, Et3N and DBU (Table 1, entries 5–7). Fur-
economical and powerful synthetic tool for producing thermore, the diastereoselectivity of the cascade prod-
highly complex structural motifs in a sustainable uct 3a improved when the reaction was conducted in
manner.[12] In addition to metal-mediated protocols,[13] CHCl3 (>20:1 dr) (Table 1, entries 8–10).
the remote asymmetric 1,6-addition was developed
The optimized conditions were generalized by using
under metal-free conditions to afford enantioenriched various arylallylideneindan-1,3-dione derivatives (1b–
structural skeletons. However, the merging of the 1,6- 1g) containing different aryls with electron-releasing
addition in triple/quadruple cascade sequences re- and electron-withdrawing groups, heteroaryls and dif-
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(Table 2, entries 7–12). However, as expected, steri-
cally more hindered tert-butyl 3-oxobutanoate (2e)
generated the desired product 3k with a moderate
yield and diastereoselectivity after 7 days (55% yield,
12:1 dr) (Table 2, entry 10). The organocascade pro-
cess was compatible even with the more reactive pen-
tane-2,4-dione (2h), because it afforded the spiro-
fused product 3n with a favourable yield (81%) and
excellent diastereoselectivity (>20:1 dr) (Table 2,
entry 13).
We also adopted an enantioselective organocascade
approach to synthesize enantioenriched, functional-
ized tetracyclic skeletons with seven chiral centres.
The organocascade process should address the follow-
ing issues: (i) delivering one enantiomer out of 128
possible stereoisomers, (ii) generating the chiral angu-
larly-fused tetracyclic core, (iii) building seven chiral
centres with absolute control over enantioselectivity,
and (iv) the reactive site in the initial 1,6-addition is
distal to the chiral environment and hence traversing
the chiral information might be practically challeng-
ing. In this scenario, to the best of our efforts, the
enantioenriched angularly-fused tetracycle (3a) was
obtained in favourable chemical yield (76%) with
moderate enantio- and diastereoselectivity (3:1 dr,
55% ee) under quinine-derived bifunctional squar-
AHCTUNGTRENNUNG
quadruple reaction sequence was proposed in
Scheme 3. The reaction was initiated by the 1,6-addi-
tion between ethyl acetoacetate and arylallylidenein-
dane-1,3-dione through HB catalysis to lead to the
formation of zwitterion intermediate 4. The protona-
tion and double-bond isomerization in 4 would gener-
ate alkylideneindane-1,3-dione derivative 5 which
would readily react with the second equivalent of
ethyl acetoacetate 2a through 1,4-addition to yield 6.
Scheme 1. Previous activated dienes utilized for organocata-
lytic 1,6-additions and indane-1,3-dione-derived diene for
the organocascade quadruple reaction.
ferent b-keto esters. The organocascade reaction be- Consequently, the intermediate 6 underwent annula-
tween electron-rich diene (1b) and ethyl acetoacetate tion through a facile intramolecular aldol reaction to
generated the corresponding angularly-fused carbocy-
cle (3b) with a favourable yield (88%) and diastereo-
selectivity (12:1 dr) (Table 2, entry 1). Subsequently,
the optimized conditions were examined using moder-
ate to strong electron-withdrawing groups on the aryl
group of the arylallylideneindane-1,3-diones (1d–1f),
and the reaction generated the corresponding cascade
products (3d–3f) with moderate to favourable yields
(53–85%) and diastereoselectivities (up to 14:1 dr)
(Table 2, entries 3–5). The use of 2-furylallylidenein-
dane-1,3-dione (1g) generated the cascade product
(3g) with a favourable yield (76%) and excellent dia-
stereoselectivity (>20:1 dr) (Table 2, entry 6). The
substrate scope was further extended using varying b-
keto esters with O-alkyl groups of different sizes. All
esters (2b–2g) afforded the corresponding cascade
products (3h–3m) with favourable yields (up to 94%)
and excellent diastereoselectivities (>20:1 dr) process.
Scheme 2. Enantioselective approach for the organocatalytic
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Table 1. Optimization for the organocascade reaction.[a]
Entry
Catalyst
Additive
Solvent
Time [days]
Yield [%][b]
dr[c]
1
2
3
4
5
6
7
8
9
10
I
II
DABCO
DABCO
DABCO
DABCO
DMAP
Et3N
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
THF
4
4
3
4
3
2
2
3
4
3
82
87
84
87
51
89
33
67
82
80
>20:4:1
4:1
20:1
>20:3:1
19:1
14:1
1:3
3:1
>20:1
9:1
III
IV
III
III
III
III
III
III
DBU
DABCO
DABCO
DABCO
[a]
The reactions were carried out with 1a (0.1 mmol, 1.0 equiv.), 2a (0.22 mmol, 2.2 equiv.) using organocatalyst I–IV
(20 mol%) at 258C in the given solvent (0.5M).
[b]
[c]
Isolated yield.
1
Determined by H NMR analysis of the crude material.
Table 2. Substrate scope for the organocascade quadruple reaction.[a]
Entry
R1
R2
Time [days]
3
Yield [%][b]
dr[c]
1
2
3
4
5
6
7
8
4-OMe
4-Cl
4-Br
4-NO2
2-NO2
2-furyl
H
H
H
H
H
OEt
OEt
OEt
OEt
OEt
OEt
OMe
O-n-Pr
O-i-Pr
O-t-Bu
O-(4-pentenyl)
OBn
6
5
6
4
6
6
6
6
7
7
6
6
6
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
88
53
68
67
85
76
58
94
75
55
78
84
81
12:1
10:1
8:1
9:1
14:1
>20:1
>20:1
>20:1
>20:1
12:1
>20:1
>20:1
>20:1
9
10
11
12
13
H
H
Me
[a]
All reactions were carried out with 1 (0.1 mmol, 1.0 equiv.), 2 (0.22 mmol, 2.2 equiv.) using organocatalyst III (20 mol%)
at 258C in CHCl3 (0.5M).
[b]
[c]
Isolated yield.
1
Determined by H NMR analysis of the crude material.
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Scheme 3. Tentative mechanism for the organocatalytic process.
afford the spiro keto ester 7, which would proceed Experimental Section
through an aldol reaction to produce angularly-fused
carbocycles 3. The relative stereochemistry of the General Procedure
products was unequivocally assigned from a single
To a solution of N,N’-bis[3,5-bis(trifluoromethyl)phenyl]-
thiourea catalyst III (10 mg, 0.02 mmol, 20 mol%), DABCO
(2.2 mg, 0.02 mmol, 20 mol%) and (E)-2-(3-arylallylide-
crystal X-ray structural analysis of 3a.[19]
In conclusion, we have demonstrated an interesting
diastereoselective organocascade reaction between ar-
ylallylideneindane-1,3-dione and b-keto esters for syn-
thesizing densely functionalized angularly-fused tetra-
cycles through a consecutive sequence. Two salient
features of the protocol are worth noting: the reaction
was initiated by an exclusive 1,6-addition over the
facile 1,4-addition,[20] and the two consecutive aldol
reactions were executed with optimal regio- and che-
moselectivities which minimized the generation of
several undesirable products. To the best of our
knowledge, this is the first example of a quadruple
cascade sequence that efficiently afford functionalized
spiro-fused carbocycles. In addition, an enantioselec-
tive organocascade approach was adopted to yield tet-
racycles with seven chiral centres including a quater-
nary centre through remote asymmetric 1,6-addition.
ne)indene-1,3-dione
1 (26.2 mg, 0.1 mmol, 1 equiv.) in
CHCl3 (0.2 mL, 0.5M) was added ethyl acetoacetate 2
(28 mL, 0.22 mmol, 2.2 equiv.) under stirring at 258C. The re-
action mixture was monitored by TLC until the consump-
tion of 1 and then the reaction mixture was quenched by
adding H2O (20 mL). The organic layer was separated and
the aqueous layer was extracted with dichloromethane (2ꢁ
20 mL). The combined organic extracts were dried over an-
hydrous MgSO4. The solvent was evaporated under reduced
pressure and crude reaction mixture was purified by silica
gel flash column chromatography (ethyl acetate/hexane=
1:3) to afford corresponding fused spirocyclic product 3.
Acknowledgements
We thank the Ministry of Science and Technology of the Re-
public of China (MOST 105-2119-M-003-005-) for financial
support of this work.
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Diastereoselective Synthesis of Functionalized Angularly-
Fused Tetracycles via an Organocatalytic Quadruple
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Fu-Jie Chang, Ramani Gurubrahamam, Kwunmin Chen*
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