Asymmetric Synthesis of Functionalized Tricyclic Chromanes via an Organocatalytic Triple Domino Reaction

Article abstract of DOI:10.1021/acs.orglett.7b01322

A highly stereoselective triple domino reaction for the synthesis of functionalized tricyclic chromane scaffolds has been developed. A secondary amine-catalyzed domino Michael/Michael/aldol condensation reaction between aliphatic aldehydes, nitro-chromene

Full text of DOI:10.1021/acs.orglett.7b01322

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Functionalized Tricyclic Chromanes via an
Organocatalytic Triple Domino Reaction
Mukesh Kumar,† Pankaj Chauhan,† Arto Valkonen,‡ Kari Rissanen,‡ and Dieter Enders*,†
†Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
‡Department of Chemistry, Nanoscience Center University of Jyvaskyla, 40014 Jyvaskyla, Finland
S
* Supporting Information
ABSTRACT: A highly stereoselective triple domino reaction
for the synthesis of functionalized tricyclic chromane scaffolds
has been developed. A secondary amine-catalyzed domino
Michael/Michael/aldol condensation reaction between ali-
phatic aldehydes, nitro-chromenes, and α,β-unsaturated
aldehydes leads to the formation of synthetically important
tricyclic chromanes bearing four contiguous stereogenic
centers including a tetrasubstituted carbon in good yields
(20−66%) and excellent stereoselectivities (>20:1 dr and
>99% ee).
he chromane skeleton is a privileged structural unit
occurring in a variety of important classes of natural
chromanes via an organocatalyzed quadruple cascade reaction
using 2-((E)-2-nitrovinyl)phenol and α,β-unsaturated alde-
hydes.6 Later, this strategy was extended for the total synthesis
of (+)-conicol by the same research group.7 Recently, the groups
of Li8 and Wang9 followed Hong’s protocol and reported the
synthesis of tricyclic chromanes via asymmetric domino
reactions using 2-hydroxy α,β-unsaturated ketones or 2-
hydroxyaryl-2-oxobut-3-enoate with α,β-unsaturated aldehydes.
Hong’s research group developed an enantioselective organo-
catalytic domino reaction “on water” for the synthesis of tricyclic
chromane scaffolds using 2-hydroxynitrostyrenes and alde-
hydes.10 Although the previously reported protocols have
provided valuable contributions to the medicinal community
for the synthesis of highly valuable tricyclic chromane frame-
works, some improvements are still required in terms of substrate
scope as well as selectivities, and hence, the development of
alternate methods is still highly desirable.
T
products exhibiting a wide range of biological and pharmaceutical
properties.1 In particular, the naturally occurring and the
synthetic functionalized tricyclic chromanes bearing multiple
stereogenic centers have received much interest due to their
significant biological activities and structural complexity (Figure
1). For instance, (+)-epiconicol, a marine metabolite isolated
Recently, 3-nitro-2H-chromenes have attracted much atten-
tion due to their frequent application in medicinal chemistry and
as valuable building blocks for oxygen-containing natural
products.11 In addition, 3-nitro-2H-chromenes are highly
reactive substrates and have been widely used as Michael
acceptors and dienophiles.12 However, these substrates have
been much less explored in asymmetric transformations,
especially in the development of domino reactions.13−15 Very
recently, Du and co-workers reported a quinine-derived primary
amine-catalyzed asymmetric cascade double Michael addition for
the synthesis of chromane derivatives (Scheme 1).16
Figure 1. Natural products and synthetic bioactive tricyclic chromane
derivatives.
from Aplidium aff. Densum, exhibited anticancer and antibacterial
activities,2 whereas (+)-bisabosqual A, a Stachybotrys metabolite,
displays antifungal properties.3 (+)-Machaeriol A, isolated from
the bark of Machaerium multiflorum, shows antimicrobial and
antimalarial activity.1d,e Nabilone, a synthetic molecule, is used as
an antiemetic as well as an analgesic for neuropathic pain.4
Over the years, several elegant strategies have been reported
for the construction of this privileged skeleton.5 In 2009, Hong et
al. reported a well-designed asymmetric synthesis of tricyclic
In the past decade, asymmetric domino reactions became a hot
research area in modern organic synthesis due to many benefits,
such as time and cost effectiveness, avoiding protection/
Received: May 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01322
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. (a) Reported Methods for the Synthesis of Tricyclic
Chromane Scaffolds. (b) Asymmetric Synthesis of
Functionalized Tricyclic Chromane Scaffolds via a Triple
Domino Reaction
Table 1. Optimization of the Reaction Conditions.
b
c
d
entry
cat. (x mol %)
solvent
yield (%)
dr
ee (%)
1
4A (20)
4B (20)
4C (20)
4D (20)
4D (20)
4D (20)
4D (20)
4D (20)
4D (10)
4D (15)
4D (25)
4D (20)
4D (20)
4D (20)
toluene
toluene
toluene
toluene
CHCl3
CH2Cl2
THF
trace
8
2
10:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
85
99
99
99
99
99
99
99
99
99
99
99
99
3
37
50
36
45
15
22
27
46
48
49
48
47
4
5
6
7
8
MTBE
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
e
12
f
deprotection steps as well as the isolation of intermediates.17 Our
group has been involved in the development of new asymmetric
organocatalytic domino reactions to provide valuable virtually
enantiopure molecules.18 To the best of our knowledge,
organocatalyzed triple domino reactions using 3-nitro-2H-
chromenes have not been explored. Hence, we developed an
organocatalyzed triple domino reaction based on a Michael/
Michael/aldol condensation sequence for the asymmetric
synthesis of tricyclic chromanes bearing four contiguous
stereogenic centers including a tetrasubstituted stereocenter.
In order to develop a triple domino sequence, we started our
investigation by screening secondary amine organocatalysts 4A−
D for the domino Michael/Michael/aldol condensation reaction
between nitrochromene 1a, propanal (2a), and cinnamaldehyde
(3a) in toluene to provide the chromane product 5a (Table 1). It
turned out that (S)-proline (4A) did not provide the desired
product (entry 1), whereas an diphenylprolinol (4B) led to the
formation of chromane 5a with 8% yield, 10:1 dr, and 85% ee
(entry 2). The (S)-TMS-diarylprolinol catalysts 4C and 4D gave
37% and 50% yields of chromane 5a, respectively, with excellent
stereoselectivities (>99% ee and >20:1 dr, entries 2 and 4). After
we found the best catalyst 4D, we screened different solvents to
increase the yield of the product 5a; however, no improvement
was observed, whereas the stereoselectivities remained excellent
(entries 5−8). When the catalyst loading was decreased to 15 and
10 mol %, the yield of the desired product decreased
dramatically, whereas no significant improvement of the yield
was observed at a higher catalyst loading of 25 mol % (entries 9−
11). We also examined some additives to further increase the
yield of 5a; however, no improvements were observed (entries
12−14). Thus, the best reaction conditions for this domino
sequence include 20 mol % of catalyst 4D in toluene at 0 °C to rt.
With the optimized reaction conditions in hand, we started to
explore the substrate scope of this one-pot triple organocascade
sequence. First, we investigated the scope of nitrochromene 1
with aldehyde 2a and enal 3 (Scheme 2). The nitrochromene 1
bearing electron-neutral (H), electron-donating (Me, OMe), or
electron-withdrawing groups (F, Cl, Br, NO2) at the C6 or C7
13
g
14
a
All reactions were carried out with 0.2 mmol of 1a (1 equiv), 0.24
mmol of 2a (1.2 equiv), 0.21 mmol of 3a (1.05 equiv), and 10−25 mol
% of the catalyst in the indicated solvent (1.0 mL) at 0 °C to room
b
c
temperature for 48 h. Yield of isolated product 5a. Determined by
d
1H NMR analysis of the crude reaction mixture. The ee values were
e
determined by HPLC analysis on a chiral stationary phase. Benzoic
acid was used as additive. 2-Fluorobenzoic acid was used as additive.
f
g
4 Å M.S. were used as additive.
position of the 3-nitro-2H-chromene smoothly reacted to form
the corresponding tricyclic chromane products 5a−h in good
yields with excellent asymmetric inductions. Similar results were
obtained with dihalogenated 3-nitro-2H-chromenes at the C6
and C8 positions (5i-k). The nitrochromene-bearing tertiary
butyl groups at the C6 and C8 position furnished the desired 5l in
good yield with excellent diastereo- and enantioselectivity (>20:1
dr and >99% ee). In contrast, 2-nitro-3H-benzo[f ]chromene
afforded the product 5m in only 20% yield with good
stereoselectivities (9:1 dr, and 99% ee), whereas 3-nitro-2H-
chromene bearing a diethylamino group at the C7 position gave
only a trace amount of 5n. To increase the scope of this triple
cascade reaction, we replaced the 3-nitro-2H-chromene by 1-
nitrocyclohex-1-ene, and 2H-chromene-3-carbonitrile showed
no reactivity for this protocol.19 Further screening of aldehydes
with different groups were investigated. Aliphatic aldehydes 2
bearing ethyl, propyl, and benzyl groups at the R2 position
provided the corresponding products in slightly lower yields in
comparison to methyl and with excellent stereoselectivities 5o−
r.
It is noteworthy that isovaleraldehyde and tert-butyl
acetaldehyde did not provide the target products even after 5
days.
Next, we also screened different α,β-unsaturated aldehydes for
this triple domino reaction. An aliphatic α,β-unsaturated
aldehyde like acrylaldehyde worked well to provide the desired
product 5s in excellent yield (66%) along with >20:1 dr and
B
DOI: 10.1021/acs.orglett.7b01322
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and electron-donating groups (OMe) at the ortho and para
position of the aryl ring reacted smoothly to furnish the
corresponding chromane products 5u−w in moderate to good
yields with excellent stereoselectivities. The aromatic enals
bearing electron-withdrawing groups (F, Cl, Br) at the para
position of the aryl ring provided the desired products 5x−z in
slightly lower yield with excellent enantioselectivity (up to >99%
ee).
Scheme 2. Substrate Scope of the Asymmetric Synthesis of
Tricyclic Chromenes 5.
a−d
To demonstrate the robustness and applicability of asym-
metric organocatalytic triple domino reaction, a gram-scale
reaction between 1a, 2a, and 3a was conducted under the
standard reaction conditions (Scheme 3). The desired tricyclic
Scheme 3. Gram-Scale Synthesis of Compound 5a
chromane 5a was obtained with 42% yield (0.87 g) and excellent
stereoselectivity (>20:1 dr, > 99% ee). Moreover, functionaliza-
tion of 5a by the reduction with NaBH4 and a Wittig reaction
provided the products 6 and 7 with excellent yields and without a
change in the stereoselectivities, respectively (Scheme 4).
Scheme 4. Transformation of the Triple Cascade Product 5a
by Reduction to 6 and Wittig Olefination to 7
The relative and absolute configuration of the triple domino
products 5 was determined by X-ray crystal structure analysis of
5a (Figure 2).20
a
Figure 2. X-ray crystal structure of 5a.
All reactions were performed with 0.3 mmol of 1 (1.0 equiv), 0.36
mmol of 2 (1.2 equiv), 0.32 mmol of 3 (1.05 equiv), and 20 mol % of
b
catalyst 4D in toluene (2.0 mL) at 0 °C to rt for 24−48 h. Yields of
In conclusion, we have developed an asymmetric synthesis of
functionalized tricyclic chromane frameworks through an
organocatalyzed triple cascade Michael/Michael/aldol conden-
sation sequence. In this protocol, three new bonds and four
consecutive stereogenic centers, including a tetrasubstituted one,
are generated in good yields with excellent diastereo- and
enantioselectivities. We are currently working on the extension of
this methodology for the synthesis of heteroterpene natural
products.
c
isolated products 5 after column chromatography. The diastereomeric
d
ratios were determined by 1H NMR spectroscopy. The enantiomeric
ratios were determined by HPLC analysis on a chiral stationary phase.
e
Traces of product after 6 days.
≤99% ee. Replacing acrylaldehyde by crotonaldehyde delivered a
poor yield of 35% of 5t with excellent stereoselectivities. The
aromatic α,β-unsaturated aldehydes bearing electron-neutral (H)
C
DOI: 10.1021/acs.orglett.7b01322
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) Liu, L.; Zhu, Y.; Huang, K.; Wang, B.; Chang, W.; Li, J. Eur. J. Org.
Chem. 2014, 2014, 4342.
(9) Geng, Z.-C.; Zhang, S.-Y.; Li, N.-K.; Chen, J.; Li, H.-Y.; Wang, X.-
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01322.
W. J. Org. Chem. 2014, 79, 10772.
(10) Hong, B.-C.; Kotame, P.; Liao, J.-H. Org. Biomol. Chem. 2011, 9,
382.
X-ray data for compound 5a (CIF)
Experimental procedures, optimization details, data for all
new compounds, and NMR and HPLC spectra (PDF)
(11) (a) Ono, N.; Sugi, K.; Ogawa, T.; Aramaki, S. J. Chem. Soc., Chem.
Commun. 1993, 1781. (b) Perrella, F. W.; Chen, S.-F.; Behrens, D. L.;
Kaltenbach, R. F., III; Seitz, S. P. J. Med. Chem. 1994, 37, 2232. (c) Xiao,
G.-Q.; Liang, B.-X.; Chen, S.-H.; Ou, T.-M.; Bu, X.-Z.; Yan, M. Arch.
Pharm. 2012, 345, 767. (d) Yin, S.-Q.; Shi, M.; Kong, T.-T.; Zhang, C.-
M.; Han, K.; Cao; Zhang, B. Z.; Du, X.; Tang, L.-Q.; Mao, X.; Liu, Z.-P.
Bioorg. Med. Chem. Lett. 2013, 23, 3314. (e) Han, K.; Xu; Chen, X. G.;
Zeng, Y.; Zhu, J.; Du, X.; Zhang, Z.; Cao, B.; Liu, Z.; Mao, X. J. Hematol.
Oncol. 2014, 7, 9. (f) Majumdar, M.; Paul, N. D.; Mandal, S.; de Bruin,
B.; Wulff, W. D. ACS Catal. 2015, 5, 2329.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: enders@rwth-aachen.de.
ORCID
́
(12) (a) Nyerges, M.; Viranyi, A.; Marth, G.; Dancsο, A.; Blasko,
Toke, L. Synlett 2004, 15, 2761. (b) Lin, C.; Hsu, J.; Sastry, M. N. V.;
̋
́
G.;
Kari Rissanen: 0000-0002-7282-8419
Dieter Enders: 0000-0001-6956-7222
Notes
Fang, H.; Tu, Z.; Liu, J.-T.; Yao, C.-F. Tetrahedron 2005, 61, 11751.
(c) Muruganantham, R.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett.
2007, 9, 1125. (d) Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B.;
Barkov, A. Y.; Shklyaev, Y. V. Tetrahedron Lett. 2008, 49, 5376.
(e) Habib, P.-M.; Kavala, V.; Raju, B. R.; Kuo, C.-W.; Huang, W.-C.;
Yao, C.-F. Eur. J. Org. Chem. 2009, 2009, 4503. (f) Li, P.; Luo, L. L.; Li, X.
S.; Xie, J. W. Tetrahedron 2010, 66, 7590. (g) Chen, W. Y.; Luo, O. Y.;
Chen, R. Y.; Li, X. S. Tetrahedron Lett. 2010, 51, 3972. (h) Korotaev, V.
Y.; Sosnovskikh, V. Y.; Barabanov, M. A.; Yasnova, E. S.; Ezhikova, M.
A.; Kodess, V. I.; Slepukhin, P. A. Tetrahedron 2010, 66, 1404. (i) Jia, Y.;
Du, D.-M. RSC Adv. 2013, 3, 1970.
(13) Jia, Y.; Yang, W.; Du, D.-M. Org. Biomol. Chem. 2012, 10, 4739.
(14) Tan, F.; Lu, L.-Q.; Yang, Q.-Q.; Guo, W.; Bian, Q.; Chen, J.-R.;
Xiao, W.-J. Chem. - Eur. J. 2014, 20, 3415.
(15) Phelan, J. P.; Ellman, J. A. Adv. Synth. Catal. 2016, 358, 1713.
(16) Li, J.-H.; Du, D.-M. Org. Biomol. Chem. 2015, 13, 9600.
(17) For a book and reviews on domino reactions, see: (a) Tietze, L. F.
Domino Reactions: Concepts for Efficient Organic Synthesis; Wiley-VCH:
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the European Research Council (ERC
Advanced Grant 320493 “DOMINOCAT”) is gratefully
acknowledged.
REFERENCES
■
(1) (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;
Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939.
(b) Mahadevan, A.; Siegel, C.; Martin, B. R.; Abood, M. E.; Beletskaya,
I.; Razdan, R. K. J. Med. Chem. 2000, 43, 3778. (c) Sung, S. H.; Kim, Y. C.
J. Nat. Prod. 2000, 63, 1019. (d) Muhammad, I.; Li, X.-C.; Dunbar, D. C.;
ElSohly, M. A.; Khan, I. A. J. Nat. Prod. 2001, 64, 1322. (e) Muhammad,
I.; Li, X.-C.; Jacob, M. R.; Tekwani, B. L.; Dunbar, D. C.; Ferreira, D. J.
Nat. Prod. 2003, 66, 804. (f) Appendino, G.; Gibbons, S.; Giana, A.;
Pagani, A.; Grassi, G.; Stavri, M.; Smith, E.; Rahman, M. M. J. Nat. Prod.
2008, 71, 1427. (g) Shen, H. C. Tetrahedron 2009, 65, 3931. (h) Simon-
Weinheim, 2014. (b) Enders, D.; Grondal, C.; Huttl, M. R. Angew.
̈
Chem., Int. Ed. 2007, 46, 1570; Angew. Chem. 2007, 119, 1590. (c) Yu, X.;
Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (d) Grondal, C.; Jeanty, M.;
Enders, D. Nat. Chem. 2010, 2, 167. (e) Pellissier, H. Chem. Rev. 2013,
113, 442. (f) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev.
2014, 114, 2390. (g) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.;
Enders, D. Adv. Synth. Catal. 2015, 357, 253. (h) Klier, L.; Tur, F.;
Poulsen, P. H.; Jørgensen, K. A. Chem. Soc. Rev. 2017, 46, 1080.
̀ ̀
Levert, A.; Menniti, C.; Soulere, L.; Geneviere, A.; Barthomeuf, C.;
Banaigs, B.; Witczak, A. Mar. Drugs 2010, 8, 347. (i) Pratap, R.; Ram, V.
J. Chem. Rev. 2014, 114, 10476. (j) Tangdenpaisal, K.; Chuayboonsong,
K.; Ruchirawat, S.; Ploypradith, P. J. Org. Chem. 2017, 82, 2672.
(2) (a) Simon-Levert, A.; Arrault, A.; Canal, N. C.; Banaigs, B. J. Nat.
Prod. 2005, 68, 1412. (b) Carroll, A. R.; Bowden, B. F.; Coll, J. C. Aust. J.
Chem. 1993, 46, 1079. (c) Garrido, L.; Zubia, E.; Ortega, M. J.; Salva, J. J.
Nat. Prod. 2002, 65, 1328.
(18) For selected examples from our group, see: (a) Enders, D.; Huttl,
̈
M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861. (b) Enders, D.;
Wang, C.; Bats, J. W. Angew. Chem., Int. Ed. 2008, 47, 7539; Angew.
Chem. 2008, 120, 7649. (c) Enders, D.; Schmid, B.; Erdmann, N.; Raabe,
G. Synthesis 2010, 2010, 2271. (d) Enders, D.; Greb, A.; Deckers, K.;
Selig, P.; Merkens, C. Chem. - Eur. J. 2012, 18, 10226. (e) Enders, D.;
Joie, C.; Deckers, K. Chem. - Eur. J. 2013, 19, 10818. (f) Zeng, X.; Ni, Q.;
Raabe, G.; Enders, D. Angew. Chem., Int. Ed. 2013, 52, 2977; Angew.
Chem. 2013, 125, 3050. (g) Zou, L.-H.; Philipps, A. R.; Raabe, G.;
Enders, D. Chem. - Eur. J. 2015, 21, 1004. (h) Dochain, S.; Vetica, F.;
Puttreddy, R.; Rissanen, K.; Enders, D. Angew. Chem., Int. Ed. 2016, 55,
16153. (i) Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders,
D. Angew. Chem., Int. Ed. 2016, 55, 12104.
(3) (a) Minagawa, K.; Kouzuki, S.; Nomura, K.; Kawamura, Y.; Tani,
H.; Terui, Y.; Nakai, H.; Kamigauchi, T. J. Antibiot. 2001, 54, 896. (b) am
Ende, C. W.; Zhou, Z.; Parker, K. A. J. Am. Chem. Soc. 2013, 135, 582.
(4) (a) Notcutt, W.; Price, M.; Chapman, G. Pharmacol. Sci. 1997, 3,
551. (b) Skrabek, R. Q.; Galimova, R. Q. l.; Ethans, K.; Perry, D. J. Pain
2008, 9, 164.
(5) (a) Mechoulam, R.; McCallum, N. K.; Burstein, S. Chem. Rev. 1976,
76, 75. (b) Archer, R. A.; Blanchard, W. B.; Day, W. A.; Johnson, D. W.;
Lavagnino, E. R.; Ryan, C. W.; Baldwin, J. E. J. Org. Chem. 1977, 42,
2277. (c) Huffman, J.; Joyner, W. H. H.; Lee, M. D.; Jordan, R. D.;
Pennington, W. T. J. Org. Chem. 1991, 56, 2081. (d) William, A. D.;
Kobayashi, Y. J. Org. Chem. 2002, 67, 8771. (e) Chittiboyina, A. G.;
Reddy, C. R.; Watkins, E. B.; Avery, M. A. Tetrahedron Lett. 2004, 45,
1689. (f) Huang, Q.; Wang, Q.; Zheng, J.; Zhang, J.; Pan, X.; She, X.
Tetrahedron 2007, 63, 1014. (g) Xia, L.; Lee, Y. R. Synlett 2008, 2008,
1643. (h) Wang, Q.; Huang, Q.; Chen, B. O.; Lu, J.; Wang, H.; She, X.;
Pan, X. Angew. Chem., Int. Ed. 2006, 45, 3651. (i) Trost, B. M.; Dogra, K.
Org. Lett. 2007, 9, 861. (j) Lee, H. J.; Lee, Y. R.; Kim, S. H. Helv. Chim.
Acta 2009, 92, 1404.
(19) See the Supporting Information.
(20) CCDC 1542995 (5a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre.
(6) Kotame, P.; Hong, B.-C.; Liao, J.-H. Tetrahedron Lett. 2009, 50,
704.
(7) Hong, B.-C.; Kotame, P.; Liao, J.-H. Org. Lett. 2010, 12, 776.
D
DOI: 10.1021/acs.orglett.7b01322
Org. Lett. XXXX, XXX, XXX−XXX