Metal- and Hydride-Free Pentannulative Reductive Aldol Reaction

Article abstract of DOI:10.1021/acs.orglett.8b03658

Traditionally, the reductive aldol reaction is a metal-catalyzed and hydride-promoted coupling between enones and aldehydes. We present a phosphine-mediated diastereoselective intramolecular reductive aldol reaction of α-substituted dienones and aldehydes, which is metal-free and hydride-free. The synthetic utility of the reductive aldol adducts is demonstrated by elaborating them in one step to indeno[1,2-b]furanones, indeno[1,2-b]pyrans, and dibenzo[a,h]azulen-8-ones.

Full text of DOI:10.1021/acs.orglett.8b03658

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal- and Hydride-Free Pentannulative Reductive Aldol Reaction
Bishnupada Satpathi, Lona Dutta, and S. S. V. Ramasastry*
Organic Synthesis and Catalysis Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER)
Mohali, Sector 81, Manauli PO, S. A. S. Nagar, Punjab 140306, India
S
* Supporting Information
ABSTRACT: Traditionally, the reductive aldol reaction is a
metal-catalyzed and hydride-promoted coupling between
enones and aldehydes. We present a phosphine-mediated
diastereoselective intramolecular reductive aldol reaction of α-
substituted dienones and aldehydes, which is metal-free and
hydride-free. The synthetic utility of the reductive aldol
adducts is demonstrated by elaborating them in one step to
indeno[1,2-b]furanones, indeno[1,2-b]pyrans, and dibenzo-
[a,h]azulen-8-ones.
In 1987, Revis and Hilty reported inspirational work on the
rhodium-catalyzed intermolecular RAR of enones and
aldehydes.5 Soon after, several pioneering metal-catalyzed
RARs of enones and aldehydes were developed.2 To date,
catalysts based on rhodium,6 cobalt,7 iridium,8 copper,9
ruthenium,10 palladium,11 and indium,12 in combination with
boranes, silanes, or hydrogen gas as reductants are known for
the RAR (Scheme 1a). Regarding the Michael acceptors,
interestingly, no other substrate class other than enones (A) is
known to date.13 Moreover, methods to access RA adducts
(C) bearing quaternary carbons are less common.14 Other
limitations of the existing RA strategies include the usage of
stoichiometric quantities of reductants and obtention of 1,4-
reduction products. Herein, we wish to report a metal- and
reductant-free organophosphine-mediated intramolecular RAR
of α-substituted dienone-aldehydes (D) for the synthesis of
cyclopenta-fused arenes and heteroarenes (E) incorporated
with two contiguous stereocenters, one of them being an all-
carbon quaternary center (Scheme 1b).15
egioselective or site-specific enolization of nonsymmetric
Rketones in direct aldol reactions remains a formidable
challenge. This problem in part can be addressed by employing
preformed enolates, viz., the Mukaiyama aldol reaction.1
Another solution to the regioselective formation of enolates
comes through the reductive aldol reaction (RAR), which
involves a metal-catalyzed coupling of enones (A) to aldehydes
(B) in the presence of a hydride source (Scheme 1a).2 Thus,
the RAR presents “enones as latent enolates,” the concept
which was first introduced by Stork through his seminal work
on the regiospecific generation of enolates from eneones via
dissolving metal reductions.3 This discovery paved the way for
subsequent developments in the reductive alkylation of
enones.4
Scheme 1. Background and Significance of the Present
Work
We commenced this study with the hypothesis that the α-
substituted enone-aldehyde 1a could undergo a phospha-
Michael addition followed by an aldol reaction to generate the
zwitterionic species F (Scheme 2). Furthermore, in the
presence of water, F could provide indanone 2a by eliminating
the phosphine oxide as depicted in G. The formation of 3a was
also envisaged when phosphine elimination (regeneration)
occurs as shown in G. However, the reaction of 1a with
tributylphosphine in the presence of water failed to provide
any desired product.16
Since several of our attempts to obtain RA product from 1a
were unsuccessful, we then applied the prototypical conditions
to the α-substituted dienone-aldehyde 4a (Table 1, entry 1).17
To our delight, the desired product 5a was isolated, albeit in
moderate yield.18 The structure of 5a was readily deduced
Received: November 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03658
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
observed. While optimizing the quantity of phosphine, a
marked improvement in the yield of 5a was observed with 1.2
equiv of PBu3 (entry 6). Substoichiometric quantities of PBu3
displayed poor performance (entries 7−9), indicating that the
reaction might be proceeding through the stoichiometric
pathway hypothesized in Scheme 2. A screening of various
solvents did not offer any other encouraging result (entries
10−13). Further, no other P-centered or N-centered Lewis
bases generated even traces of the expected product (entries
14−17).20
Scheme 2. Unsuccessful RAR of the α-Substituted Enone-
Aldehyde 1a
To understand the scope and generality of the method, the
optimized conditions were applied to substrates bearing
different steric and electronic features. The results are
summarized in Scheme 3. Under the optimized conditions, a
Scheme 3. Substrate Scope: Cyclopentannulated Arenes and
a b c
, ,
Heteroarenes via Intramolecular RAR
a
Table 1. Optimization of the Reaction Parameters
water
(equiv)
b
entry Lewis base (equiv)
solvent
t (h) yield (%)
c
1
PBu3 (1)
PBu3 (1)
PBu3 (1)
PBu3 (1)
5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
MeCN
toluene
1,2-DCE
DMF
DMF
DMF
DMF
96
96
40
48
48
34
96
120
160
96
96
120
96
120
120
120
120
51
58
77
75
74
87
50
39
8
21
38
31
6
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
10
30
50
75
30
30
30
30
30
30
30
30
30
30
30
30
PBu3 (1)
PBu3 (1.2)
PBu3 (0.75)
PBu3 (0.5)
PPh3 (0.25)
PBu3 (1.2)
PBu3 (1.2)
PBu3 (1.2)
PBu3 (1.2)
PCy3 (1.2)
PPh3 (1.2)
DABCO (1.2)
β-ICD (1.2)
d
−
−
−
−
e
f
a
Reaction conditions: See the Supporting Information for details.
b
c
Chromatographic yields. 5a was obtained in 2:1 diastereomeric
a
d
e
f
Reaction conditions: See Supporting Information for details.
Chromatographic yields. Diastereomeric ratio (dr) is shown in
ratio (dr). 1,2-Dichloroethane. 1,4-Diazabicyclo[2.2.2]octane. β-
b
c
Isocupreidine.
the parentheses.
from its spectral data, and the relative stereochemistry was
assigned from the X-ray diffraction analysis of 6d (vide supra;
CCDC 1848427).
To our knowledge, the transformation of 4a to 5a represents
the first metal- and hydride-free RAR of dienones. Further
encouraged by the fact that pentannulated aromatics are
privileged scaffolds owing to their occurrence in numerous
biologically active natural products, pharmaceuticals, and
organic materials, we commenced to optimize the reaction
parameters (Table 1).19
An optimization with tributylphosphine as the Lewis base
revealed that 30 equiv of water were optimal for an efficient
conversion of 4a to 5a (Table 1, entries 2−5), beyond which
no further improvement in the yield or the reaction time was
range of dienone-aldehydes engaged in cycloreduction to form
an array of cyclopenta-fused arenes and heteroarenes
possessing up to two contiguous stereogenic centers, one of
them being an all-carbon quaternary center, in good
diastereoselectivities and in excellent yields (5b−5m). A
narrow yield range (77−92%) across the substrates verified
herein is an indicative of the robustness of the method.
Dienones bearing both alkyl and aryl groups at R1 (viz., 5b, 5c,
and 5i) were well-tolerated. Contrary to the expectation, the
presence of electron-donating groups either on the dienone
moiety or on the aromatic backbone showed only marginal
influence on the efficiency of the reaction (5d, 5g−j). The
RAR proceeded smoothly even with the substrates bearing
B
DOI: 10.1021/acs.orglett.8b03658
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heteroarene backbones (5l and 5m), thereby significantly
enhancing the scope of the method. However, this method is
not without limitations. A substituent at R2 was not tolerated
(5n) and δ,δ-disubstituted dienones also remained unsuccess-
ful substrates (5o), hinting that the phosphine addition most
likely occurs from the δ-position.
Next, we investigated the mechanism of the pentannulative
RAR. First, we intended to gain evidence for an initial 1,4- or
1,6-addition of phosphine.21 Accordingly, E,Z-4a was prepared
(Scheme 4a). Under the optimized conditions, an exclusive
anionic species I (as shown in Scheme 2). A subsequent
protonation of I and isomerization of the double bond in 5a′
delivers 5a. To a certain extent, I can also undergo direct
protonation to afford 5a. Thus, the mechanistic rationale is in
concurrence with the extent of deuteration observed at β- and
δ-positions of 5a-D (see Scheme 4c). It is also in line with the
hypothesis presented in Scheme 2.
Because of the significance of indanone-fused γ-lactones,
which are important substructures in bioactive compounds
such as GR24, solanacol, and others,24 Borhan’s lactonization
protocol25 was applied on the RA products 5 (Scheme 6).
Scheme 4. Mechanistic Studies of the Pentannulative RAR
Scheme 6. Elaboration of 5 to γ-Butyrolactones 6
formation of E-5a was observed. Thus, it can be surmised that
a 1,6-addition of phosphine indeed takes place and therefore
the stereochemical integrity of the Z-configured double bond
(in E,Z-4a) is lost, leading to the formation of the
thermodynamically favorable E-configured double bond in 5a.
The most important evidence about the role of water during
the transformation of 4 to 5 came when the reaction of 4a was
performed with 18O-labeled water (Scheme 4b). The HRMS
spectrum of the crude reaction mixture showed a distinct peak
at m/z 221.1916 (expected m/z 221.1920) for 18O-containing
tributylphoshine oxide [P(18O)Bu3].22 This result suggests that
water reacts with the phosphonium center at a certain stage,
eventually converting it to phosphine oxide.
Accordingly, 5a was oxidatively converted to the lactone 6a in
good yield using a catalytic amount of OsO4 and oxone as the
co-oxidant. Employing this protocol, few other analogues (6b−
6e) were prepared. The lactones (6) can be converted in one
step to achieve the complete molecular framework present in
GR24 and solanacol, which are potent stimulants for parasitic
weed seed germination.24
On the other hand, the reaction of 4a in the presence of
D2O generated 5a-D with almost 90% ‘D’-incorporation at the
δ-position and nearly 80% ‘D’-incorporation at the β-position,
indicating that β- and δ-carbons experience anionic character
during the transformation (Scheme 4c).
Based on the experimental observations, a plausible
mechanism is proposed in Scheme 5.23 The reaction
commences with a 1,6-addition of phosphine to 4a and a
subsequent aldol reaction to generate the zwitterionic species
H. The protonation of the alkoxide (in H) follows the
elimination of the tributylphosphine oxide to provide the
On the other hand, when 5a was treated with BF3OEt2, the
indanone-fused tetrahydropyran 7a (CCDC 1848426 assigned
for 7a′)26 was isolated in 83% yield in an unexpected manner
(Scheme 7).27 This method was realized to be general and
provided efficient access to other significant analogues 7b−7f.
It is worth noting that indeno[1,2-b]pyrans are important
structural motifs prevalent in several medicinally relevant
compounds.28
To our surprise, indanones 5h and 5i upon treatment with
BF3OEt2 generated dibenzo[a,h]azulen-8-ones 8a and 8b,
respectively (Scheme 8). It was reasoned that the presence of a
methoxy group para (C-6) to the benzylic alcohol moiety in
5h and 5i promotes the formation of para-quinomethide L,
through which the formation of 8a and 8b can be explained. A
similar setup is not feasible in the case of 5g or 5j [which
afforded 7e and 7f, respectively (see Scheme 7)], where the
methoxy groups are situated meta to the benzylic alcohol
moiety. Interestingly, the tetracyclic scaffold of 8 represents
part of the structure of the immunosuppressive natural
products dalesconols A and B.29
Scheme 5. Plausible Mechanism for the RAR
Despite several efforts to develop an enantioselective version
of the RAR with 4a as the model substrate,30 we were only able
to obtain 5a in 35% ee with the exo-Kwon catalyst 9,31
although in good yield (Scheme 9).
C
DOI: 10.1021/acs.orglett.8b03658
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highly functionalized pentannulated aromatics such as indeno-
[1,2-b]furanones, indeno[1,2-b]pyrans, and dibenzo[a,h]-
azulen-8-ones. Efforts to apply the methods described herein
for the synthesis of bioactive natural products are in progress,
and the results will be communicated soon.
Scheme 7. Elaboration of 5 to Indeno[1,2-b]pyrans 7
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.8b03658.
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR) (PDF)
Accession Codes
CCDC 1848426−1848427 contain the supplementary crys-
tallographic 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ramsastry@iisermohali.ac.in.
ORCID
Scheme 8. Elaboration of 5 to Dibenzo[a,h]azulen-8-ones 8
S. S. V. Ramasastry: 0000-0001-5814-9092
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
IISER Mohali is acknowledged for funding, and for the NMR,
mass, and departmental X-ray facilities. B.S. thanks UGC and
L.D. thanks IISER Mohali for research fellowships.
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In summary, an unprecedented metal- and reductant-free
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aldehydes is established. Some of the remarkable features of
this method are (i) α-substituted dienones are employed as
substrates for the first time in a RAR, (ii) an unusual role of
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(17) See the Supporting Information for the synthesis of 5a and its
analogues.
(18) For the synthesis of structures similar to 5a, see: Chanda, T.;
Chowdhury, S.; Anand, N.; Koley, S.; Gupta, A.; Singh, M. S.
Tetrahedron Lett. 2015, 56, 981.
(19) For recent reviews on cyclopentanoids, see: (a) Satpathi, B.;
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(b) Vivekanand, T.; Satpathi, B.; Bankar, S. K.; Ramasastry, S. S. V.
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E
DOI: 10.1021/acs.orglett.8b03658
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