A Domino Aza-Piancatelli Rearrangement/Intramolecular Diels-Alder Reaction: Stereoselective Synthesis of Octahydro-1 H-cyclopenta[ cd]isoindole

Article abstract of DOI:10.1021/acs.orglett.9b01267

For the first time, an efficient one-pot method for the construction of an angularly fused 5-6-5 aza-tricyclic framework has been developed in a highly stereoselective manner. This domino reaction is a novel combination of aza-Piancatelli rearrangement an

Full text of DOI:10.1021/acs.orglett.9b01267

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Domino Aza-Piancatelli Rearrangement/Intramolecular
Diels−Alder Reaction: Stereoselective Synthesis of
Octahydro‑1H‑cyclopenta[cd]isoindole
Shaik Gouse, Narra Rajashekar Reddy, and Sundarababu Baskaran*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: For the first time, an efficient one-pot method
for the construction of an angularly fused 5−6−5 aza-tricyclic
framework has been developed in a highly stereoselective
manner. This domino reaction is a novel combination of aza-
Piancatelli rearrangement and intramolecular Diels−Alder
reaction, which readily furnishes hexahydro-2a,5-epoxy-
cyclopenta[cd]isoindole adducts, bearing six contiguous stereo-
genic centers in very good yields. The BBr3-mediated cleavage
of the oxa-bridged adduct results in the formation of octahydro-
1H-cyclopenta[cd]isoindole, an aza-tricyclic BCE core of a
gracilamine alkaloid.
Domino reactions are highly atom-economical processes as
multiple events occur in one pot, providing quick access to
complex frameworks. The efficiency of this process has
inspired much interest among the synthetic community to
design and develop novel cascade strategies.1 The angularly
fused 5−6−5 aza-tricyclic core is very common in numerous
natural products, exhibiting a broad spectrum of biological
activities such as antipyretic,2 antihypertensive,3 anti-inflam-
matory,4 antitumor,5 anti-HIV,6 and anticancer7 (Figure 1).
core, using intramolecular [3+2] cycloaddition, Diels−Alder
reaction, Mannich reaction, and radical cyclization as a key
step.3−6 Nevertheless, new synthetic strategies for the
construction of functionalized the aza-tricyclic core with
remarkable efficiency and exquisite selectivity are urgently
being sought.
Furan and its derivatives have served as powerful synthons
for the creation of structurally diverse natural and unnatural
molecules.8 Intriguingly, 2-furfurylcarbinol derivatives undergo
a wide variety of chemical transformations, including metal-
ation, cycloaddition, oxidation, and rearrangement reac-
tions.8−10 In particular, Piancatelli rearrangement is one of
the most efficient synthetic methods available for the
construction of 4-hydroxy-2-cyclopentenone from 2-furfuryl-
carbinol.10 These functionalized intermediates served as
valuable building blocks in the synthesis of a wide variety of
biologically important molecules.11,12 Alaniz et al. described a
diastereoselective synthesis of azaspiro-fused cyclopentanone
using aza-Piancatelli rearrangement as a key step,13 whereas
Winne and co-workers developed a novel Lewis acid-mediated
[4+3] cycloaddition reaction of 2-furfurylcarbinol with 1,3-
diene (Scheme 1).14a Moreover, Gou et al. have reported a
[3+2] cycloaddition of 2-furfurylcarbinol with alkyl azide,
leading to a new class of heterocyclic scaffolds.14b
Figure 1. Aza-tricyclic alkaloid framework containing biologically
important molecules.
Our continued interest in the development of novel domino
strategies for the synthesis of biologically relevant molecules15
has resulted in the design and synthesis of the bridged aza-
tricyclic core of immunosuppressant FR901483.16 Herein, we
report for the first time a simple and highly efficient one-pot
approach for the stereoselective construction of hexahydro-
Synthesis of alkaloids having an angularly fused aza-tricyclic
core has attracted significant attention due to their structural
complexity coupled with the broad spectrum of biological
activities.2−7
Natural alkaloids such as dendrobine,2 gracilamine,3
deethylibophyllidine,4 and epimeloscine5 possess the 5−6−5
aza-tricyclic core (Figure 1). As a consequence of their
remarkable structural frameworks, various approaches have
been developed for the construction of the 5−6−5 aza-tricyclic
Received: April 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01267
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Organic Letters
Letter
a
Scheme 1. Furfurylcarbinol-Based Novel Synthesis of the
Aza-Tricyclic BCE Core of Gracilamine Alkaloid
Table 1. Optimization of the Domino Reaction Conditions
yield
b
entry catalyst (10 mol %)
solvent
temp (°C) time (h)
(%)
1
2
3
4
5
6
7
8
CSA
TfOH
TFA
toluene
DCM
DCM
DCM
DCM
80
−10
−10
−10
−10
70
70
28
50
80
1.5
50
42
44
50
50
70
55
40
57
87
70
55
80
68
70
0.15
0.15
0.15
0.15
7.0
2.0
32.0
4.0
0.25
0.5
BF3·OEt2
TMSOTf
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
In(OTf)3
Sc(OTf)3
Zn(OTf)2
CH3CN
DCE
2a,5-epoxy-cyclopenta[cd]isoindole, an aza-tricyclic core of
gracilamine alkaloid, using a novel domino strategy based on
aza-Piancatelli rearrangement coupled with intramolecular
Diels−Alder (IMDA) reaction as a key step.
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
We anticipated that N-furfurylaniline 2 could serve as a
nitrogen nucleophile in the aza-Piancatelli rearrangement of 2-
furfuryl carbinol 1, resulting in the formation of 4-amino-5-
alkyl/aryl-cyclopentenone ( )-4, which in turn could undergo
IMDA reaction with tethered furan to give oxa-bridged aza-
tricyclic derivative ( )-3 (Scheme 2).
80
90
80
80
0.25
0.25
0.5
80
0.5
a
Reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2a (0.55 mmol, 1.1
equiv), and Yb(OTf)3 (10 mol %) in toluene (5 mL) at 80 °C.
Scheme 2. Domino Strategy for the Construction of the
Angularly Fused 5−6−5 Aza-Tricyclic Core of Gracilamine
b
Isolated yield.
The scope of this domino reaction involving aza-Piancatelli
rearrangement followed by IMDA reaction was investigated
with different furfuryl alcohols and furfurylamine derivatives,
and the results are summarized in Table 2. Initially, ortho- and
para-substituted 2-furfurylcarbinols (1A−1H) were allowed to
react with N-(2-furanyl)aniline derivatives bearing electron-
donating and electron-withdrawing groups, and the corre-
sponding adducts were isolated in good yields (Table 2, entries
1 and 2). The structure of the cyclized products was
established using 1H NMR, 13C NMR, 2D NMR, and
HRMS data, and the relative stereochemistry of adduct
( )-3Ab was further unambiguously confirmed by single-
crystal X-ray analysis (Table 2).17 Several functional groups
such as halides, -tBu, -OMe, and -CO2Et are found to be stable
under the reaction conditions.
Moreover, sterically demanding 2-furfurylcarbinol 1I also
reacted readily with N-(2-furanyl)aniline derivatives 2a, 2c,
and 2d to furnish the corresponding aza-tricyclic adducts
( )-3Ia, ( )-3Ic, and ( )-3Id, respectively, in very good
yields (Table 2, entry 3). Similarly, 3,5-dimethyl-N-furanylani-
line derivative 2e underwent smooth reaction with furylcarbi-
nols 1A and 1I to furnish the corresponding adducts ( )-3Ae
and ( )-3Ie, respectively, in good yields with a high degree of
stereoselectivity (Table 2, entry 4). As anticipated, electron-
deficient substrates (2d and 2e) required slightly longer
reaction times (Table 2). Moreover, 2-furfurylcarbinol bearing
thiophene (1J) and isopropyl (1K) reacted readily with N-
furfurylaniline derivatives (2a and 2b) to furnish the aza-
tricyclic adducts ( )-3Ja and ( )-3Jb and ( )-3Ka and
( )-3Kb, respectively, in good yields (Scheme 3).
Thus, to test our hypothesis, furan-2-yl-(phenyl)methanol
1A was treated with N-(furan-2-yl-methyl)aniline 2a and
camphor sulfonic acid (CSA, 10 mol %) in toluene and the
resultant mixture was stirred at 80 °C for 1.5 h. The reaction
mixture upon workup afforded the desired 5−6−5 fused aza-
tricyclic adduct ( )-3Aa in 50% yield, and the structure of
1
( )-3Aa was unambiguously established on the basis of H
NMR, 13C NMR, 2D NMR, and HRMS analyses.
To optimize the reaction condition, furan-2-yl-(phenyl)-
methanol 1A was allowed to react with N-(furan-2-yl-
methyl)aniline 2a in the presence of various Lewis and
Brønsted acid catalysts in different solvents, and the results are
summarized in Table 1. In the case of TfOH, TFA, BF3·OEt2,
and TMSOTf, the reaction was found to be very facile even at
−10 °C in DCM; however, the desired product was isolated in
low yield (Table 1, entries 2−5, respectively).
Among the catalysts screened, Yb(OTf)3 was found to be
the most ideal choice. Similarly, among the solvents screened,
toluene was found to be the most suitable medium to carry out
this reaction (Table 1, entry 10). Moreover, an extended
reaction time or an elevated temperature did not improve the
yield of the product (Table 1, entries 11 and 12). Thus, under
the optimized conditions using Yb(OTf)3 (10 mol %) in
toluene at 80 °C, the desired aza-tricyclic adduct ( )-3Aa was
isolated in 87% yield along with a small amount (∼5%) of the
uncyclized intermediate as an inseparable mixture (Table 1,
entry 10).
Evidently, the intramolecular Diels−Alder reaction of the
tethered furan ( )-4 afforded the exo adduct as the only
product. The exclusive formation of the exo adduct is further
supported by the density functional theory (DFT) calculations.
The DFT calculations showed that the formation of the exo
B
DOI: 10.1021/acs.orglett.9b01267
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Table 2. Domino One-Pot Synthesis of Aza-Tricyclic Adducts
a
entry
1
2-furylcarbinol (1)
1A, R1, R2, R3 = H
N-(2-furanyl)aniline (2)
time (h)
product [( )-3]
yield (%)
2a, R4, R5 = H
0.15
0.33
0.15
0.75
0.25
0.15
0.25
0.25
0.5
3Aa, R1, R2, R3, R4, R5 = H
87
81
80
75
87
82
86
83
81
75
80
77
74
84
80
73
78
70
80
67
2b, R4 = Cl, R5 = H
2c, R4 = OMe, R5 = H
2d, R4 = CO2Et, R5 = H
3Ab, R1, R2, R3, R5 = H, R4 = Cl
3Ac, R1, R2, R3, R5 = H, R4 = OMe
3Ad, R1, R2, R3, R5 = H, R4 = CO2Et
3Ba, R1 = Me, R2, R3, R4, R5 = H
3Bb, R1 = Me, R2, R3, R5 = H, R4 = Cl
3Ca, R1 = OMe, R2, R3, R4, R5 = H
3Cb, R1 = OMe, R2, R3, R5 = H, R4 = Cl
3Da, R1 = F, R2, R3, R4, R5 = H
3Db, R1 = F, R2, R3, R5 = H, R4 = Cl
3Ea, R1 = Ph, R2, R3, R4, R5 = H
3Eb, R1 = Ph, R2, R3, R5 = H, R4 = Cl
3Fb, R1 = Bu, R2, R3, R5 = H, R4 = Cl
3Gb, R1, R3, R5 = H, R2 = OMe, R4 = Cl
3Hb, R1, R3, R5 = H, R2, R4 = Cl
2
1B, R1 = Me, R2, R3 = H
1C, R1 = OMe, R2, R3 = H
1D, R1 = F, R2, R3 = H
1E, R1 = Ph, R2, R3 = H
2a, R4, R5 = H
2b, R4 = Cl, R5 = H
t
1F, R1 = Bu, R2, R3 = H
1G, R1, R3 = H, R2 = OMe
1H, R1, R3 = H, R2 = Cl
0.5
0.25
0.25
0.25
0.15
0.15
0.25
0.15
1.0
t
3
4
1I, R1, R2, R3 = Me
2a, R4, R5 = H
3Ia, R1, R2, R3 = Me, R4, R5 = H
2c, R4 = OMe, R5 = H
2d, R4 = CO2Et, R5 = H
2e, R4 = H, R5 = Me
3Ic, R1, R2, R3 = Me, R4 = OMe, R5 = H
3Id, R1, R2, R3 = Me, R4 = CO2Et, R5 = H
3Ae, R1, R2, R3 = H, R4 = H, R5 = Me
3Ie, R1, R2, R3, R5 = Me, R4 = H
1A, R1, R2, R3 = H
1I, R1, R2, R3 = Me
0.25
1.0
a
Isolated yield.
product (ΔG = −3.23 kcal/mol) is thermodynamically more
favored than that of the endo product (ΔG = 22.73 kcal/
mol).18
Scheme 3. Scope of Domino Aza-Piancatelli Rearrangement
and IMDA Reaction
The synthetic usefulness of the aza-Piancatelli−IMDA
adduct was further explored in a divergent manner with
respect to the stereoselective synthesis of novel oxa- and aza-
bridged aza-polycyclic frameworks [( )-12−14]19 and the
BCE−aza-tricyclic core of gracilamine ( )-16 (Scheme 1).3b
Our initial efforts to cleave the oxa bridge of ( )-3Ab under a
variety of acidic and basic reaction conditions have met with
failure. To gain additional insight into the reactivity of the oxa
bridge, the carbonyl group in 3Ab was further functionalized.
Thus, adduct ( )-3Ab upon exposure to NaBH4 underwent a
highly stereoselective reduction to furnish 6β-hydroxy
derivative ( )-5 in very good yield, which was subsequently
converted to the corresponding benzyl ether ( )-6 and acetate
derivative ( )-7, respectively, in very good yields (Scheme 4).
The β stereochemistry of the hydroxyl group in ( )-5 was
unequivocally established by single-crystal X-ray analysis of the
Scheme 4. Stereoselective Functionalization of Hexahydro-2a,5-epoxy-cyclopenta[cd]isoindole 3Ab
C
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corresponding acetate ( )-7 (Scheme 4).17 The catalytic
hydrogenation of ( )-5 afforded dihydro derivative ( )-8,
which was further converted to 6β-azido dihydro derivative
( )-11 via 6α-bromo derivative ( )-10 (Scheme 4).
Surprisingly, the oxa bridge present in octahydro-2a,5-epoxy-
cyclopenta[cd]isoindole derivatives [( )-5 and ( )-6] was
found to be stable under a wide variety of Lewis acid
conditions (see the Supporting Information).20 However, 6β-
hydroxy derivative ( )-5 upon exposure to BBr3 in DCM at 0
°C to rt resulted in a novel [1,3]-transposition of the ether
bridge, thus furnishing the 5β-hydroxy-2a,6-oxa-bridged aza-
tricyclic derivative, which was isolated as the corresponding p-
nitrobenzoate derivative ( )-12 (Table 3, entry 1). It is
Figure 2. ORTEP diagram of compounds ( )-12 and ( )-14.
BBr3 to furnish the same rearranged adduct ( )-13 in good
yields (Table 3, entries 3 and 4).
Table 3. One-Pot Stereoselective Construction of the Novel
Intriguingly, under similar reaction conditions, 6β-azido
derivative ( )-11 underwent a smooth rearrangement,22 and
subsequent reduction with NaBH4 followed by benzoylation
afforded the corresponding novel aza-bridged aza-tricyclic
derivative ( )-14 in good yield (Table 3, entry 5). The aza-
bridged structure was unambiguously confirmed by single-
crystal X-ray analysis (Figure 2).17
a
Oxa- and Aza-Bridged Aza-Tricyclic Framework
Remarkably, 6α-bromo derivative ( )-15, derived from
( )-5, upon treatment with BBr3 at room temperature,
underwent smooth oxa bridge cleavage, resulting in a novel
aza-tricyclic bromohydrin ( )-16, a BCE aza-tricyclic core of
gracilamine, in 74% yield with a high degree of regio- and
stereoselectivity. The stereo- and regioselectivity of bromohy-
1
drin ( )-16 were unambiguously established using H NMR,
13C NMR, 2D NMR, and HRMS data. Moreover, exposure of
trans-bromohydrin ( )-16 to aqueous NaOH resulted in the
formation of functionalized β-epoxide derivative ( )-17 in
very good yield (Scheme 5).
Scheme 5. Stereoselective Construction of the Angularly
Fused BCE Aza-Tricyclic Core of Gracilamine
a
Substrate (1.0 equiv) and BBr3 (1.5 equiv) in DCM at 0 °C to rt.
b
Isolated yield.
presumed that 6β-hydroxy-oxa-bridged derivative ( )-5 under-
goes a BBr3-assisted regioselective cleavage of the oxa bridge
with concomitant trapping of the resultant carbocation by the
6β-hydroxy group, leading to the formation of the novel 5β-
hydroxy-octahydro-2a,6-epoxy-cyclopenta[cd]isoindole frame-
work. The structure and relative stereochemistry of oxa-
The structure and relative stereochemistry of β-epoxide
derivative ( )-17, an aza-tricyclic core of gracilamine, were
unequivocally confirmed by single-crystal X-ray analysis
(Figure 3).17 A plausible mechanism for the formation of
angularly fused 5−6−5 aza-tricyclic bromohydrin ( )-16 is
also shown in Scheme 5.
In summary, a simple and highly efficient one-pot method
for the stereoselective synthesis of functionalized hexahydro-
2a,5-epoxy-cyclopenta[cd]isoindole derivative ( )-3 has been
developed using aza-Piancatelli rearrangement followed by
IMDA reaction as a key step. This cascade reaction is found to
be general, and the corresponding oxa-bridged aza-tricyclic
adducts are isolated in very good yields. In the presence of
BBr3, 6β-hydroxy derivatives of ( )-3 underwent smooth 1,3-
transposition of the ether bridge, leading to oxa-bridged 5β-
hydroxy-octahydro-2a,6-epoxy-cyclopenta[cd]isoindoles
1
bridged aza-tricyclic derivative ( )-12 were established by H
NMR, 13C NMR, 2D NMR, and HRMS data and further
unambiguously confirmed by single-crystal X-ray analysis
(Figure 2).17
The scope of this BBr3-mediated reaction was further tested
with 6β-functionalized oxa-bridged derivatives [( )-6, ( )-8,
and ( )-9], and the results are summarized in Table 3. The
6β-benzyloxy derivative ( )-6 also underwent a smooth
reaction to furnish 5β-hydroxy-oxa-bridged aza-tricyclic
derivative ( )-12 in very good yield (Table 3, entry 2).21
Similarly, dihydro derivatives ( )-8 and ( )-9 reacted with
D
DOI: 10.1021/acs.orglett.9b01267
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( )-12 and ( )-13, whereas the corresponding 6β-azido
derivative ( )-11 furnished a novel aza-bridged aza-tricyclic
derivative ( )-14. Under similar reaction conditions, 6α-
bromo derivative ( )-15 underwent an oxa bridge cleavage
and subsequent transformation afforded ( )-17, a function-
alized BCE aza-tricyclic core of gracilamine. Further
application of this domino strategy in the synthesis of
biologically relevant molecules will be forthcoming.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01267.
Complete experimental details and characterization data
for the synthesized compounds (PDF)
NMR spectra of compounds (PDF)
́
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Accession Codes
CCDC 1856013, 1856052, 1856057−1856058, 1856077−
1856078, 1856080, and 1857434 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sbhaskar@iitm.ac.in.
ORCID
Sundarababu Baskaran: 0000-0002-7636-2812
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank DST-SERB (EMR/2016/004040), India,
for financial support and DST-FIST for providing instrument
facilities. S.G. and N.R.R. thank CSIR-New Delhi for research
fellowships. The authors thank Mr. V. Ram Kumar and SAIF,
IIT Madras, for single-crystal X-ray analysis.
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F
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