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Angewandte

Chemie

DOI: 10.1002/anie.201405074
Asymmetric Catalysis

Asymmetric Alkynylation/Lactamization Cascade: An Expeditious


Entry to Enantiomerically Enriched Isoindolinones**
Vishnumaya Bisai, Arun Suneja, and Vinod K. Singh*

Dedicated to Professor Sukh Dev on the occasion of his 90th birthday

Abstract: An unprecedented CuI–pybox-diPh-catalyzed


highly enantioselective (up to > 99 % ee) alkynylation/lactam-
ization cascade has been developed as a general catalytic
system for the synthesis of diversely substituted isoindolinones
of immense biological importance. The cascade effects one
C C and two C N bond-forming events in one reaction vessel
under operationally simple, additive-free reaction conditions in
good to excellent yields. The methodology was further
extended to the synthesis of tetrahydroisoquinoline scaffolds
common to several biologically active natural products in
a two-step sequence with remarkable selectivity (up to
94 % ee).

Enantiomerically enriched isoindolinones are an important


class of synthetically useful heterocyclic compounds
(Scheme 1, 1 a–d) with an impressive diversity of biological
activity. Their biological potential is evident from observed
antihypertensive,[1] antipsychotic,[2] anti-inflammatory,[3] anes-
thetic,[4] antiulcer,[5] vasodilatory,[6] antiviral,[7] and antileuke-
mic[8a] activity. Some of these compounds show platelet- Scheme 1. Selected isoindolinones and tetrahydroisoquinolinones
aggregation-inhibitory activity.[8b] A few isoindolinones were 1 and 2.
also found to induce dose-dependent p53-dependent gene
transcription in MDM2-amplified SJSA human sarcoma cell
lines.[9] Furthermore, these compounds are also useful in the Prominent examples of asymmetric approaches to iso-
synthesis of various drugs[10] and complex natural products.[11] indolinone synthesis involve the resolution of racemates,[13] an
On the other hand, tetrahydroisoquinoline rings exist widely intramolecular Heck cyclization,[14] an asymmetric Diels–
in alkaloids and their derivatives (Scheme 1, 2 a–c),[12] which Alder approach,[15] the ring-closure of chiral hydrazones,[16]
display numerous types of biological activity. Although a few reactions of chiral acyliminium ions,[17] and a chiral-append-
elegant approaches to these targets have been reported, there age-mediated carbanion method.[18] On the other hand,
is no evidence of a straightforward synthesis of isoindolinones syntheses of enantiomerically enriched THIQs involve vari-
and tetrahydroisoquinolines (THIQs) by a unified strategy ous diastereoselective processes[12, 19] and catalytic enantiose-
from simple and readily available starting materials. lective processes. The latter include the ruthenium-catalyzed
hydrogenation of preformed N-alkyl enamides and N-alkyl
imines,[20] the copper-catalyzed allylation of cyclic imines[21]
and terminal alkynes to give isoquinoline iminium ions,[22] and
[*] Dr. V. Bisai, A. Suneja, Prof. Dr. V. K. Singh
Department of Chemistry palladium-catalyzed intramolecular allylic amination.[23]
Indian Institute of Science Education and Research Bhopal In pursuit of a practical and efficient approach to
Bhopal, M.P. – 462 066 (India) enantiomerically enriched isoindolinones and isoquinoli-
and nones, we envisaged a modular route involving an enantio-
Indian Institute of Technology selective copper(I)-catalyzed one-pot alkynylation/lactamiza-
Kanpur, U.P. – 208 016 (India) tion[24, 25] cascade of readily available o-formyl methyl ben-
E-mail: vinodks@iitk.ac.in
zoates 3 and o-formyl methyl arylacetates 7 (Scheme 2). We
[**] V.K.S. thanks the DST, India for a research grant through a J. C. Bose
delineate herein the first example of a copper(I)-catalyzed
Fellowship. A.S. thanks the CSIR, New Delhi for a fellowship (J.R.F.).
We gratefully acknowledge Dhananjay Dey and Dr. Deepak Chopra, alkynylation/lactamization cascade with an exceptionally high
IISER Bhopal for assistance with X-ray crystallography. Our sincere level of enantioselectivity.
thanks to D. Sivasankaran for his timely help. At the outset, we studied several potential catalysts to
Supporting information for this article is available on the WWW ultimately identify the most efficient catalytic system for this
under http://dx.doi.org/10.1002/anie.201405074. transformation (Scheme 3). As a model system for the

Angew. Chem. Int. Ed. 2014, 53, 10737 –10741  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 10737
Letter

pubs.acs.org/OrgLett

An Efficient Entry to syn- and anti-Selective Isoindolinones via an


Organocatalytic Direct Mannich/Lactamization Sequence
Vishnumaya Bisai,†,‡ Rajshekhar A. Unhale,†,‡ Arun Suneja,† Sivasankaran Dhanasekaran,§
and Vinod K. Singh*,†,§

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, MP - 462 066, India
§
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP - 208 016, India
*
S Supporting Information

ABSTRACT: An organocatalytic direct Mannich−lactamization sequence for the syntheses of pharmacologically important
enantioenriched isoindolinones is reported. The method utilizes simple α-amino acids to deliver syn- and anti- selective
isoindolinones with remarkably high enantioselectivity (up to >99% ee) in good to excellent yields and diastereomeric ratios. The
overall sequence involves one C−C and two C−N bond forming events in one pot starting from inexpensive starting material.

S ynthetically versatile enantioenriched isoindolinones (see


1a−f; Figure 1) are prevalently found in many naturally
CuI-iPr-pybox-diPh catalyzed alkynylation−lactamization casca-
de.10a
Although there is a report on the thio-urea catalyzed
enantioselective synthesis of isoindolinones, the enantioselec-
tivities achieved are only up to 86%.10b Hence, there is a
requirement of a deeper synthetic insight for the development
of efficient organocatalytic enantioselective approaches. Our
continued interest in this area prompted us to devise a suitable
direct organocatalytic11 enantioselective strategy. To this end,
pioneering reports by List12a and Barbas12b on organocatalytic
direct Mannich reactions drew our attention. The asymmetric
Mannich reactions13 are particularly appealing from a synthetic
perspective owing to the prevalence of nitrogen in drugs and
natural products. Herein, we report an expeditious route to
both syn- and anti-selective isoindolinones following a direct
Figure 1. Selected enantioenriched isoindolinones. organocatalytic enantioselective one-pot three-component
Mannich−lactamization sequence (Scheme 1).
Organocatalytic Mannich reactions have widely been
reported on preformed imines,14 and only a handful of catalytic
occurring alkaloids and pharmaceuticals1 with impressive asymmetric direct Mannich reactions are reported to date.12 In
biological activities.2 Therefore, synthesis of such structural general, direct aldol and Mannich reactions typically compete if
motifs in enantioenriched form has gained considerable interest imines and enol equivalents are not preformed, and their rates
in contemporary research. Prominent asymmetric approaches
depend on the equilibrium ratio between the aldehyde and the
to this class of heterocyclics include resolution of racemates,3
imine and on their respective rate constants. In this regard,
intramolecular Heck cyclization,4 Diels−Alder approach,5 ring-
closure of chiral hydrazones,6 reactions of chiral acyliminium especially, Mannich reactions which involve hydroxyacetone as
ion,7a,b allylation to chiral imines,7c and a chiral appendage the donor furnishing syn- and anti-1,2-amino alcohols in high
mediated carbanion method.8 Most of these syntheses involve a chemo-, regio-, diastereo-, and enantioselectivities play an
chiral auxiliary mediated diastereoselective approach and face a important role in organic synthesis. Thus, we selected
limited substrate scope. Only a few enantioselective syntheses hydroxyacetone as donor for the installation of syn- and anti-
of isoindolinones are known in literature using metal
catalysts.9a−c Toward this, we recently reported the concise Received: March 7, 2015
enantioselective synthesis of isoindolinones (>99% ee) via a Published: April 13, 2015

© 2015 American Chemical Society 2102 DOI: 10.1021/acs.orglett.5b00676


Org. Lett. 2015, 17, 2102−2105
Letter

pubs.acs.org/OrgLett

A General Catalytic Route to Isoindolinones and


Tetrahydroisoquinolines: Application in the Synthesis of
(±)-Crispine A
Sivasankaran Dhanasekaran,† Vishnumaya Bisai,‡ Rajshekhar A. Unhale,‡ Arun Suneja,‡
and Vinod K. Singh*,†,‡

Department of Chemistry, Indian Institute of Technology Kanpur-208 016, UP, India

Department of Chemistry, Indian Institute of Science Education and Research Bhopal-462 066, MP, India
*
S Supporting Information

ABSTRACT: An unprecedented highly efficient Lewis acid catalyzed one-pot cascade has been demonstrated as a general
catalytic system for the synthesis of diversely substituted isoindolinones and tetrahydroisoquinolines. The cascade effects one C−
C and two C−N bond-forming events in one pot. Several interesting transformations of the products into valuable synthetic
intermediates are featured with the successful total synthesis of (±)-crispine A.

I soindolinone- and tetrahydroisoquinoline-based N-hetero-


cyclic scaffolds comprise the key structural feature of a wide
range of synthetically and biologically active molecules (1 and 2;
active natural products and pharmaceuticals.10 Although there
are several reports in the literature for the synthesis of these
compounds11−13 there exists no precedence to access both of
Figure 1). 3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones 1a−d man- these two important classes of compounds employing a more
generalized and common catalytic system in one-pot. To address
this, we propose herein a practical approach to isoindolinones
and tetrahydroisoquinolinones using a Lewis acid catalyzed one-
pot three-component allylation−lactamization cascade of readily
available o-formyl methyl benzoates and o-formyl methyl
arylacetates as shown in Scheme 1.14
In order to determine what structural parameters affect catalyst
performance and to ultimately identify a more efficient catalyst,
we performed a systematic optimization of a one-pot three-
component allylation−lactamization cascade using various Lewis
acids with methyl 2-formyl benzoate (3a), p-methoxyaniline, and

Scheme 1. Proposed One-Pot Cascade

Figure 1. Selected isoindolinones and tetrahydroisoquinolines.

ifest activities such as antihypertensive,1 antipsychotic,2 anti-


inflammatory,3 anesthetic,4 antiulcer,5 vasodilatory,6 antiviral,7
and antileukemic8 and are also used in the synthesis of various
drugs.9
On the other hand, 1-substituted 1,2,3,4-tetrahydroisoquino- Received: September 26, 2014
lines 2a−d are immensely prominent in diverse biologically Published: November 13, 2014

© 2014 American Chemical Society 6068 dx.doi.org/10.1021/ol502842f | Org. Lett. 2014, 16, 6068−6071
Letter

pubs.acs.org/OrgLett

Ni(II)-Catalyzed Highly Stereo- and Regioselective Syntheses of


Isoindolinones and Isoquinolinones from in Situ Prepared Aldimines
Triggered by Homoallylation/Lactamization Cascade
Raju Karmakar,†,§ Arun Suneja,†,§ Vishnumaya Bisai,†,∥ and Vinod K. Singh*,†,‡

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal - 462
066, Madhya Pradesh, India

Indian Institute of Technology Kanpur, Kanpur - 208 016, Uttar Pradesh, India
*
S Supporting Information
Downloaded by IISER KOLKATA at 00:36:03:306 on June 13, 2019
from https://pubs.acs.org/doi/10.1021/acs.orglett.5b02932.

ABSTRACT: An efficient route to isoindolinones and isoquinolinones has been achieved via a domino Ni-catalyzed
homoallylation/lactamization from in situ prepared imines, derived from o-formyl benzoates and o-formyl arylacetates, with
conjugated dienes promoted by diethylzinc. The reaction proceeds smoothly at room temperature for a variety of aldehydes,
amines, and dienes. The method involves one C−C and two C−N bond forming events under operationally simple conditions.

I soindolinones (1a−d; Figure 1) and tetrahydroisoquinolines


(THIQs 2a−d; Figure 1) are important heterocyclic
structural motif in many biologically active natural products
and have become attractive synthetic targets.
Literature on existing approaches toward isoindolinone
synthesis include Heck cyclization,12 Diels−Alder approach,13
ring closure of hydrazones,14 reactions of acyliminium ion,15
exploitation of carbanion methodology,16 and various enantio-
selective approaches17,18 developed very recently. On the other
hand, synthesis of THIQs involves various multistep pro-
cesses11,19 and few enantioselective processes.20 Although few
elegant approaches to these targets have been reported, there is
still a need to develop a straightforward synthesis of
isoindolinones and THIQs employing a unified strategy from
readily available simple starting materials. Toward this, we
recently reported an efficient allylation−lactamization/alkyla-
tion21 cascade in the synthesis of THIQ alkaloid (±)-crispine A
(2a). Herein, we envision an expeditious approach to these
Figure 1. Selected important isoindolinones and THIQs. targets following a domino Ni-catalyzed highly stereo- and
regioselective homoallylation of aldimines of o-formyl benzoates
3 and o-formyl arylacetates 4 using 1,3-dienes 5 promoted by
compounds from a synthetic perspective. Many isoindolinones Et2Zn to afford isoindolinones 7−8 and isoquinolinones 9,
are useful advanced intermediates in the synthesis of a variety of respectively (Scheme 1).22 Due to the low nucleophilicity and
drug molecules1 and complex natural products.2 Because of their difficult availability of homoallyl metal species, unlike allylmetals,
interesting biological properties, such as antihypertensive,3 homoallylation has been less pursued. However, in the past
antipsychotic,4 anti-inflammatory,5 anesthetic,6 antiulcer,7 vaso-
decade, it is becoming an emerging method for the formation of
dilatory,8 antiviral,9 and antileukemic10 activities, these hetero-
C−C bonds as evident from Tamaru’s work.23a−e Hence, we
cyclic scaffolds are considered to be attractive synthetic targets.
On the other hand, a wide variety of tetrahydroisoquinolines intended to explore the homoallylation strategy in the synthesis
(THIQs 2a−d)11 with interesting architecture have been of isoindolinones and isoquinolinones.
isolated from different sources. Due to their fascinating biological
activities, THIQs also are of special synthetic interest. Needless Received: October 9, 2015
to say, isoindolinones and THIQs constitute a common Published: October 30, 2015

© 2015 American Chemical Society 5650 DOI: 10.1021/acs.orglett.5b02932


Org. Lett. 2015, 17, 5650−5653
ORGANIC
LETTERS

Highly Enantioselective 2007


Vol. 9, No. 6
Water-Compatible Organocatalyst for 1117-1119
Michael Reaction of Ketones to
Nitroolefins
Vishnumaya and Vinod K. Singh*

Department of Chemistry, Indian Institute of Technology Kanpur, India-208 016


Vinodks@iitk.ac.in

Received January 11, 2007

ABSTRACT

A chiral diamine was found to catalyze enantioselective addition of ketones to nitroolefins in aqueous/saline/organic media. The products
were obtained with excellent diastereoselectivities (syn/anti ) 99:1) and enantioselectivities up to 99%. The reaction could be facilitated using
a mild acid.

Enantioselective reactions catalyzed by small organic mol- clean and friendly conditions is still in progress, we got
ecules (asymmetric organocatalysis)1 have attracted attention interested in the organocatalytic direct asymmetric Michael
from a large number of organic chemists working in the area reaction of ketones with commonly used acceptors such as
of asymmetric synthesis. This is mainly due to environmental β-nitrostyrene for which some excellent papers have appeared
concern where use of metals in organic reactions could be using chiral amines as catalysts.4 The reaction is supposed
avoided. It would be a win-win situation from a green to proceed via an enamine intermediate.1c Although most of
chemistry perspective if the above reaction could be carried the reports deal with reactions in organic solvents, there are
out in aqueous media.2 In our recent study, we reported a only two papers where aqueous medium has been used for
new organocatalyst for enantioselective direct aldol reaction.3 the Michael reaction.4b,c
While the work in the area with respect to environmentally To the best of our knowledge, there is no universal catalyst
which gives high enantioselectivity for this reaction, both
(1) (a) For a special issue on asymmetric organocatalysis, see: Acc. in the presence of water and also in a wide range of organic
Chem. Res. 2004, 37, 487. (b) Review: Dalko, P. I.; Moisan, L. Angew. solvents.5 In this paper, we disclose such a catalyst which is
Chem., Int. Ed. 2004, 43, 5138. (c) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719. (d) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: compatible with water as well as with various conventional
From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley- organic solvents providing high enantioselectivity and di-
VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005.
(2) For reviews on organic reactions in aqueous media, see: (a) Brogan, astereoselectivity.
A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45, The diamine 1 (Scheme 1), having substituted nonpolar
8100. (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103. (c) Li, C.-J.
Chem. ReV. 2005, 105, 3095. (d) Lindstrom, U. M. Chem. ReV. 2002, 102, dibenzylic type groups in the tertiary amine part, was
2751. (e) Li, C.-J.; Chan, T.-H. Organic Reaction in Aqueous Media; Wiley- conceptualized based on an intuition that the binaphthyl
VCH: Weinheim, Germany, 1997.
(3) Raj, M.; Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, group would enhance the hydrophobic hydration when the
8, 4097. reaction is done in aqueous medium and should also work
10.1021/ol070082x CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/23/2007
ORGANIC
LETTERS

Methoxypyridines in the Synthesis of 2010


Vol. 12, No. 11
Lycopodium Alkaloids: Total Synthesis 2551-2553
of (()-Lycoposerramine R
Vishnumaya Bisai and Richmond Sarpong*

Department of Chemistry, UniVersity of California, Berkeley, California 94720


rsarpong@berkeley.edu

Received April 10, 2010

ABSTRACT

A methoxypyridine serves as a masked pyridone in a concise synthesis of the Lycopodium alkaloid lycoposerramine R, which has been
prepared for the first time. The key step of the synthesis is the use of an Eschenmoser Claisen rearrangement to forge a key quaternary
carbon center.

The Lycopodium alkaloid family boasts over 200 members, because the methoxy group significantly mitigates the
which possess an array of architecturally complex frame- basicity of the pyridine nitrogen via an inductive electron-
works. The construction of these molecules has presented withdrawing effect.6 This obviates the need for reversed-
synthetic challenges that have inspired highly innovative phase chromatographic purification, which is often asso-
strategic and tactical solutions.1 The emergence of the ciated with the synthesis of related alkaloids. Building
Lycopodium alkaloid huperzine A as a potential treatment upon our earlier studies, we have embarked on the
for Alzheimer’s disease has further heightened synthetic syntheses of the Lycopodium alkaloids lycopladine A (1,
interest in this family of natural products.2 Through detailed Figure 1),7 lycoposerramine R (2),8 and lannotinidine B
studies that began in 1942 with the work of Manske and, later,
Wiesner, MacLean, Conroy, McMaster and more recently
Kobayashi and Takayama, the biosynthetic connections between
many of these alkaloids continues to be uncovered.3 As a result,
synthetic strategies to the Lycopodium alkaloids that exploit their
structural connections are beginning to offer effective and
concise avenues to a wide array of these natural products.
As a part of a program to exploit methoxypyridines in
the synthesis of various alkaloids, we have reported the
Figure 1. Selected Lycopodium alkaloids.
total syntheses of the Lycopodium alkaloid lyconadin A4
and the Galbulimima alkaloid GB 13.5 The methoxypy-
ridine group is uniquely effective as a masked pyridone (3)9 with the intention of accessing all three natural
(1) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679–
products from a common intermediate.10
729.
(2) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772. (4) (a) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008,
(3) Hudlicky, T., Reed, J. W. Lycopodium alkaloids. In The Way of 130, 7222–7223. (b) West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R.;
Synthesis, 1st ed.; Wiley-VCH: Weinheim, 2007; pp 573-602. Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187–11194.

10.1021/ol100823t  2010 American Chemical Society


Published on Web 05/04/2010
ORGANIC
LETTERS

Highly Enantioselective Organocatalytic 2007


Vol. 9, No. 13
Direct Aldol Reaction in an Aqueous 2593-2595
Medium†
Vishnu Maya, Monika Raj, and Vinod K. Singh*

Deparment of Chemistry, Indian Institute of Technology Kanpur, India 208 016


Vinodks@iitk.ac.in

Received May 3, 2007

ABSTRACT

We have demonstrated that small organic molecules 1 and 2 catalyzed the direct aldol reaction of both acyclic and cyclic ketones with
different aldehydes in an excess of water/brine. Excellent enantioselectivities up to >99% and diastereoselectivities up to 99% with very good
yields were obtained by using much lower catalyst loadings (0.5 mol %).

The enantioselective aldol reaction catalyzed by small until recently when Barbas5 and Hayashi6 independently
organic molecules is an important C-C bond formation reported efficient proline-derived chiral catalysts which
reaction for which excellent enantioselectivities have been catalyzed the aldol reaction with high enantiocontrol in the
achieved.1 The reaction is presumed to proceed via an presence of a large excess of water.7 Most of the studies
enamine intermediate, mimicking nature, where the type I have been done with 10 mol % catalyst loading except in
aldolase enzyme2 catalyzes the aldol reaction in water. It one example where Hayashi has shown that the catalyst
would be a win-win situation from a green chemistry loading can be reduced to 1 mol %, but at the cost of a longer
perspective if high enantiocontrol is achieved using small reaction time (2 days). Therefore, there is a great need for
organic molecules in water.3,4 Early studies with small efficient chiral organocatalysts, which can work at a lower
organic molecules in an aqueous medium had limited success
(4) The above phrases in using water for the reaction are a matter of
semantics. However, we prefer to use “in an aqueous medium” for our
† This paper is Dedicated to Prof. (Dr.) Lutz F. Tietze, Institut für reactions.
Organische und Biomolekulare Chemie Universität Göttingen, Germany, (5) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
on his 65th birthday. Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
(1) For selected reviews on aldol and other related reactions using (6) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
asymmetric organocatalysis, see: (a) List, B. Chem. Commun. 2006, 819. T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Hayashi, Y.; Aratake,
(b) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (c) Dalko, P. I.; S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed.
Moisan, L. Angew. Chem., Int. Ed. Engl. 2004, 43, 5138. (d) Notz, W.; 2006, 45, 5527.
Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (e) List, B. (7) For some recent selected references on aldol reaction in water via
Acc. Chem. Res. 2004, 37, 548. (f) Allemann, C.; Gordillo, R.; Clemente, asymmetric organocatalysis, see: (a) Guizzetti, S.; Benaglia, M.; Raimondi,
F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc.Chem. Res. 2004, 37, 558. L.; Celentano, G. Org. Lett. 2007, 9, 1247. (b) Wu, Y.; Zhang, Y.; Yu, M.;
(2) Heine, A.; Desantis, G.; LuZ, J. G.; Mitchell, M.; Wong, C.-H.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417. (c) Jiang, Z.; Liang, Z.; Wu,
Wilson, I. A. Science 2001, 294, 369. X.; Lu, Y. Chem. Commun. 2006, 2801. (d) Dziedzic, P.; Zou, W.; Hafren,
(3) For a very interesting discussion on whether this kind of reaction J.; Cardova, A. Org. Biomol. Chem. 2006, 4, 38. (e) Chimni, S. S.; Mahajan,
should be called “in water”, “on water”, “in the presence of water”, or D. Tetrahedron: Asymmetry 2006, 17, 2108. (f) Guillena, G.; Hita, M. D.
“concentrated organic phases”, see: (a) Brogan, A. P.; Dickerson, T. J.; C.; Najera, C. Tetrahedron: Asymmetry 2006, 17, 1493. (g) Fu, Y.-Q.; Li,
Janda, K. D. Angew. Chem., Int. Ed. 2006, 45, 8100. (b) Hayashi, Y. Angew. Z.-C.; Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S. Tetrahedron:
Chem., Int. Ed. 2006, 45, 8103. (c) Blackmond, D. G.; Armstrong, A.; Asymmetry 2006, 17, 3351. (h) Pihko, P. M.; Laurikainen, K. M.; Usano,
Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 2. A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62, 317.

10.1021/ol071013l CCC: $37.00 © 2007 American Chemical Society


Published on Web 05/23/2007
Letter

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Approach to Isoindolinones, Isoquinolinones, and THIQs via Lewis


Acid-Catalyzed Domino Strecker-Lactamization/Alkylations
Sivasankaran Dhanasekaran,†,§ Arun Suneja,‡,§ Vishnumaya Bisai,‡,¶ and Vinod K. Singh*,†,‡

Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, MP - 462 066, India

Department of Chemistry, Indian Institute of Technology, Kanpur, UP - 208 016, India
*
S Supporting Information

ABSTRACT: A one-pot, three-component synthesis of


widely substituted isoindolinones and isoquinolinones, featur-
ing a Lewis acid-catalyzed efficient Strecker reaction and
lactamization sequence, affording products in good to high
yields is reported. The method has also been extended to the
Downloaded by IISER KOLKATA at 00:36:43:889 on June 13, 2019

synthesis of tetrahydroisoquinolines (THIQs) in high yields.


from https://pubs.acs.org/doi/10.1021/acs.orglett.5b03331.

I soindolinones are an important class of heterocycles found


in many biologically active natural products1 and are also
useful intermediates in the synthesis of a variety of drug
synthesize them applying a general catalytic route. To this
end, recently, we reported the Lewis acid-catalyzed allylation-
lactamization domino process25 for synthesis of diversely
molecules2 (1a−b; Figure 1) having important biological substituted isoindolinones and THIQs. Herein, we report a
practical approach to isoindolinones, isoquinolinones, and
THIQs via a Lewis acid-catalyzed domino Strecker-lactamiza-
tion/alkylations of readily available o-formyl methylbenzoates,
o-formyl methylarylacetates, and o-formyl arylethyl bromides
(Scheme 1).

Scheme 1. Proposed Strecker-Lactamization/Alkylations

Figure 1. Selected active isoindolinones and THIQs.

activities such as antihypertensive,3 antipsychotic,4 anti-


inflammatory,5 anesthetic,6 antiulcer,7 vasodilatory,8 antiviral,9 At the outset, optimization of domino Strecker-lactamization
and antileukemic10 agents. In addition, a few members of this was performed by taking 1.0 equiv of each ester-aldehyde 3a
class are known to have platelet aggregation inhibitory activity11 and PMPNH2 (p-anisidine) with 1.5 equiv of TMSCN without
and are shown to induce dose-dependent p53-dependent gene any catalyst. We found that only Strecker product 10a was
transcription in MDM2-amplified SJSA human sarcoma cell formed in 28−42% yields, and no trace of isoindolinone 4a
lines.12 On the other hand, tetrahydroisoquinolines13 (THIQs) were observed (Scheme 2). Following extensive optimization, it
(2a−g; Figure 1) are widespread in nature and have interesting was found that 10 mol % of Zn(OTf)2 and In(OTf)3 each
biological activities. They are also found to be the building afforded 4a in 93% yield (condition A) and 91% yield
blocks for synthesis of many complex alkaloids.14 (condition B), respectively, when 1.0 equiv of TFA was used
Approaches in literature for isoindolinone synthesis include (see the SI for details).
Heck cyclization,15 Diels−Alder approach,16 ring-closure of
hydrazones,17 reactions of acyliminium ion,18 exploiting Scheme 2. Domino Strecker-Lactamization Process
carbanion methodology,19 and various enantioselective ap-
proaches20 including our recent domino21 Cu(I)-catalyzed
enantioselective propargylation/lactamization and organocata-
lytic Mannich/lactamization sequence.22 On the other hand,
synthesis of isoquinolines involves various diastereoselective
processes13c,23 and catalytic enantioselective processes.21,24
Although some elegant approaches to these targets have been Received: November 19, 2015
reported, still there exist a fewer number of reports to Published: February 4, 2016

© 2016 American Chemical Society 634 DOI: 10.1021/acs.orglett.5b03331


Org. Lett. 2016, 18, 634−637
ORGANIC
LETTERS

Highly Enantioselective Direct Aldol 2006


Vol. 8, No. 18
Reaction Catalyzed by Organic 4097-4099
Molecules
Monika Raj, Vishnumaya, Sandeep K. Ginotra, and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur, India 208 016
Vinodks@iitk.ac.in
Received June 30, 2006

ABSTRACT

We have demonstrated that a new class of L-proline-based organic compounds catalyzed the direct aldol reaction between aldehydes and
acetone to provide β-hydroxy ketones in good yields. The reaction is efficient, and 5−10 mol % of the catalyst and excellent enantioselectivities
(97−99% ee) were obtained in both aromatic and aliphatic aldehydes. The presence of a gem-diphenyl group at the β-carbon is necessary for
high enantioselectivity.

An enantioselective C-C bond formation reaction catalyzed L-proline functions as a “microaldolase” similar to the Type
by chiral organic molecules (asymmetric organocatalysis)1 I aldolase enzyme.8 Since then, L-proline9 and its derivatives10
has become an important area of research in organic have been evaluated for use in enantioselective direct aldol
synthesis. Aldol is one such reaction where a great emphasis reaction. The reaction is presumed to proceed via an enamine
has been given to the design of new chiral organocatalysts2 intermediate. Initially, the enantiofacial selectivity was
where, besides avoiding transition metals, the reaction can explained with a metal-free version of the Zimmerman-
directly be done by taking an aldol donor and acceptor.3 In Traxler-type transition-state model having a tricyclic hydrogen-
this direct aldol reaction, there is no need for preactivation bonded framework.6a Later, on the basis of computational
of carbonyl compounds as is done in the Mukaiyama aldol study, it was postulated that the nitrogen of L-proline may
reaction.4,5 The major breakthrough came from a finding by not participate in hydrogen bonding with the carboxylic
List,6 Barbas III,7 and co-workers that L-proline could act hydrogen.11 According to the model for proline and its
as a catalyst in intermolecular direct aldol reaction where
(5) (a) Langner, M.; Remy, P.; Bolm, C. Chem.-Eur. J. 2005, 11, 6254-
(1) For general reviews on asymmetric organocatalysis, see: (a) Seayad, 6265. (b) Itsuno, S.; Arima, S.; Haraguchi, N. Tetrahedron 2005, 61, 12074-
J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724. (b) Dalko, P. I.; Moisan, 12080. (c) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
L. Angew. Chem., Int. Ed. 2004, 43, 5138-5175. (c) Notz, W.; Tanaka, F.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121,
Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580-591. (d) List, B. Synlett 669-685. (d) Carreira, E. M.; Singer, R. A.; Lee, W. S. J. Am. Chem. Soc.
2001, 1675-1685. 1994, 116, 8837-8838. (e) Ishita, H.; Yamashita, H.; Kobayashi, S. J. Am.
(2) For reviews on asymmetric aldol reaction using chiral organocatalysis, Chem. Soc. 2000, 122, 5403-5404. (f) Denmark, S. E.; Stavanger, R. A.
see: (a) List, B. Acc. Chem. Res. 2004, 37, 548-557. (b) Allemann, C.; J. Am. Chem. Soc. 2000, 122, 8837-8847.
Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. (6) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
Res. 2004, 37, 558-569. (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 122, 2395-2396. (b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-
37, 570-579. 7387. (c) Martin, H. J.; List, B. Synlett 2003, 1901-1902.
(3) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, (7) (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem.
T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958-961. (b) Alcaide, B.; Soc. 2001, 123, 5260-5267. (b) Cordova, A.; Notz, W.; Barbas, C. F., III.
Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858-860. (c) Modern Aldol Chem. Commun. 2002, 3024-3025.
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vols. 1 and (8) (a) For use of aldolase enzymes, see: Heine, A.; Desantis, G.; Luz,
2. J. G.; Mitchell, M.; Wong, C.-H.; Wilson, I. A. Science 2001, 294, 369-
(4) (a) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, 374 and references therein. (b) For use of a catalytic antibody, see: Zhu,
S.; Sakamoto, S.; Yamaguchi, K.; Shibaski, M. J. Am. Chem. Soc. 2003, X.; Tanaka, F.; Hu, Y.; Heine, A.; Fuller, R.; Zhing, G.; Olson, A. J.; Lerner,
125, 2169-2178. (b) Yoshikawa, N.; Shibaski, M. Tetrahedron 2001, 57, R. A.; Barbas, C. F., III.; Wilson, I. A. J. Mol. Biol. 2004, 343, 1269-
2569-2579. 1280 and references therein.

10.1021/ol0616081 CCC: $33.50 © 2006 American Chemical Society


Published on Web 07/29/2006
Highly Efficient Small Organic Molecules for Enantioselective Direct
Aldol Reaction in Organic and Aqueous Media
Monika Raj Vishnumaya and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Vinodks@iitk.ac.in
ReceiVed March 12, 2009

A series of highly efficient organocatalysts have been derived from naturally available amino acids for
carrying out enantioselective direct aldol reaction in both organic and aqueous medium. The aldol products
were obtained in high diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) for a
broader range of substrates using 1 mol % of a catalyst. The results demonstrate that the structural features
of organocatalysts play a crucial role in obtaining high optical purity of aldol adducts in an aqueous
medium. Further, the role of water in increasing the rate and enantioselectivity of the reaction has been
illustrated. Moreover, the aldol products have been employed in the synthesis of chiral amino alcohols
which act as useful intermediates for building up complex natural products.

Introduction design of new chiral organocatalysts,2 mainly for two reasons:


first, one can avoid the use of transition metals in the reaction,
Enantioselective C-C bond formation reaction catalyzed by
and second, the reaction can directly be done by taking aldol
chiral organic molecule (asymmetric organocatalysis)1 has
donors and acceptors.3 The latter objective has been achieved
become an important area of research in organic synthesis. Aldol
previously with the use of heterobimetallic catalysts,4 where
is one such reaction where a great emphasis has been given to
preactivation of carbonyl compounds, like in the asymmetric
* To whom correspondence should be addressed. Fax: +91-512-2597436. Mukaiyama aldol reaction,5 was not required. Proline has long
(1) For special issues on asymmetric organocatalysis, see: (a) List, B. Chem. been known for its use in asymmetric intramolecular aldol
ReV. 2007, 107, 5413. (b) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. ReV. 2003,
103, 3401. (c) List, B.; Bolm, C. AdV. Synth. Catal. 2004, 346, 1007. (d) Houk, reaction.6 The major breakthrough came from the findings by
K. N.; List, B. Acc. Chem. Res. 2004, 37, 487. (e) List, B. Chem. Commun. List,7 Barbas,8 and co-workers that L-proline could also act as
2006, 819. (f) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (g) Jarvo, E. R.; Miller, S. J.
a catalyst in the intermolecular direct aldol reaction. It functions
Tetrahedron 2002, 58, 2481. (h) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, as a “microaldolase” similar to type I aldolase enzyme.9 Since
107, 5713. (i) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
For reviews, see: (j) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. (2) For reviews on asymmetric aldol reaction using chiral organocatalysis,
2004, 37, 580. (k) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. see: (a) List, B. Acc. Chem. Res. 2004, 37, 548. (b) Allemann, C.; Gordillo, R.;
Chem., Int. Ed. 2008, 47, 6138. (l) Emsley, J. Chem. Soc. ReV. 1980, 9, 91. (m) Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558.
Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315. (n) Erkkila, A.; (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570. (d) Hayashi, Y.;
Majander, I.; Pihko, P. M. Chem. ReV. 2007, 107, 5416. (o) Mukherjee, S.; Yang, Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem.,
J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (p) Barbas, C. F., Int. Ed. 2006, 45, 958. (e) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed.
III. Angew. Chem., Int. Ed. 2008, 47, 42. (q) Gaunt, M. J.; Johansson, C. C. C.; 2003, 42, 858. (f) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH:
McNally, A.; Vo, N. T. Drug DiscoVery Today 2007, 12, 8. (r) de Figueiredo, Weinheim, 2004; Vols. 1 and 2.
R. M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575. (s) Enders, D.; Grondal, (3) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (t) Ting, A.; Schaus, M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Alcaide, B.; Almendros, P. Angew.
S. E. Eur. J. Org. Chem. 2007, 5797. (u) Tsogoeva, S. B. Eur. J. Org. Chem. Chem., Int. Ed. 2003, 42, 858. (c) Modern Aldol Reactions; Mahrwald, R., Ed.;
2007, 1701. (v) Marigo, M.; Jorgensen, K. A. Chem. Commun. 2006, 2001. (w) Wiley-VCH: Weinheim, 2004; Vols. 1 and 2.
Cozzi, F. AdV. Synth. Catal. 2006, 348, 1367. (x) Seayad, J.; List, B. Org. Biomol. (4) (a) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.;
Chem. 2005, 3, 719. (y) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, Sakamoto, S.; Yamaguchi, K.; Shibaski, M. J. Am. Chem. Soc. 2003, 125, 2169.
43, 5138. (z) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Yoshikawa, N.; Shibaski, M. Tetrahedron 2001, 57, 2569.

10.1021/jo900548f CCC: $40.75  2009 American Chemical Society J. Org. Chem. 2009, 74, 4289–4297 4289
Published on Web 05/07/2009
Article

pubs.acs.org/joc

Asymmetric Syntheses of Medicinally Important Isoindolinones


(S)‑PD 172938, (R)‑JM 1232, and Related Structures
Arun Suneja,† Vishnumaya Bisai,§ and Vinod K. Singh*,†,‡

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal, MP - 462 066,
India

Indian Institute of Technology Kanpur, Kanpur, UP - 208 016, India
*
S Supporting Information
Downloaded by IISER KOLKATA at 00:38:09:622 on June 13, 2019
from https://pubs.acs.org/doi/10.1021/acs.joc.6b00770.

ABSTRACT: A unified approach for the asymmetric syntheses of medicinally important isoindolinones (S)-PD 172938 and
(R)-JM 1232 has been accomplished via a Cu(I)-PYBOX-diPh catalyzed highly enantioselective (up to 99% ee) alkynylation/
lactamization sequence in a one-pot fashion. The overall sequence involves one C−C and two C−N bond forming events in one
pot starting from inexpensive starting material in ambient reaction conditions.

■ INTRODUCTION
Isoindolinones are heterocyclic compounds (1a−e; Figure 1)
literature.21−24 Toward this, transition-metal-catalyzed pro-
cesses include Rh(I)-catalyzed arylation,21a Cu(I)-catalyzed
tandem Michael−Mannich reaction,21b Pd(II)-catalyzed aza-
having potential biological activities, such as antihypertensive,1
Wacker type cyclization,21c and organocatalytic syntheses
antipsychotic,2 anti-inflammatory,3 and anesthetic.4 Some
include thio-urea catalyzed malonate addition,22 our direct
members of this class of heterocyclic scaffolds also display
organocatalytic Mannich lactamization,23 and phase transfer
antiulcer,5 vasodilatory,6 antiviral,7 and antileukemic proper-
catalyzed aza-Michael reactions.24
ties8a and platelet aggregation inhibitory8b activities. These are Toward this, we recently reported the enantioselective
also found to induce dose-dependent p53-dependent gene synthesis of isoindolinones (>99% ee) via a CuI-iPr-pybox-
transcription in MDM2-amplified SJSA human sarcoma cell diPh 4b catalyzed alkynylation−lactamization cascade (Scheme
lines.9 In addition, isoindolinones are useful in the synthesis of 1).25 We envisioned that one can achieve asymmetric syntheses
various drugs10 and complex natural products.11 Since of 1a−e from a common enatioenriched isoindolinone 2a via
enantiomers interact differently with the biological system, synthetic elaboration (Figure 1). Compound 2a could be
therefore, intense research is going on to synthesize these accessed from enantioenriched aryl ketone 2b via a Baeyer−
biologically active isoindolinones in enantioenriched form. In Villiger oxidation, which in turn could be synthesized from
fact, (S)-PD 172938 (1a) is reported as a potent dopamine D4 enantioenriched 5 following an oxidative reaction (Scheme 2).
ligand,12 and (R)-JM 1232 (1b) is a benzodiazepine receptor Utilizing the above-mentioned strategy, herein, we report the
agonist for the treatment of anxiety,13 whereas 1c is an inhibitor first unified approach for the asymmetric syntheses of
of the β-secretase enzyme for the treatment of Alzheimer’s medicinally important (S)-PD 172938, and (R)-JM 1232.


disease.14
Prominent approaches to this class of heterocyclics include
RESULTS AND DISCUSSION
Heck cyclization,15 Diels−Alder approach,16 domino three-
component coupling−lactamization,17 ring closure of chiral At the outset, we studied several potential catalysts to
hydrazones,18 reactions of a chiral acyliminium ion,19a,b ultimately identify the most efficient catalytic system (Table
allylation to chiral imines,19c aza-conjugate addition,20a and a 1) to realize this transformation. As a model system en route to
chiral appendage mediated carbanion method.20b,c Most of isoindolinone derivatives, we carried out a Cu-(I)-catalyzed
these syntheses involve a chiral auxiliary mediated diaster-
eoselective approach and face a limited substrate scope. Only a Received: April 7, 2016
few enantioselective syntheses of isoindolinones are known in Published: May 5, 2016

© 2016 American Chemical Society 4779 DOI: 10.1021/acs.joc.6b00770


J. Org. Chem. 2016, 81, 4779−4788
Tetrahedron Letters 60 (2019) 2039–2042

Contents lists available at ScienceDirect

Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

A unified approach to sesquiterpenes sharing trimethyl(p-tolyl)


cyclopentanes: Formal total synthesis of (±)-laurokamurene B
Mrinal K. Das 2, Bidyut K. Dinda 1, Vishnumaya Bisai 2,⇑
Department of Chemistry, Indian Institute of Science Education and Research Berhampur, Berhampur 462 066, Odisha, India

a r t i c l e i n f o a b s t r a c t

Article history: A unified approach to the sesquiterpenoids sharing common trimethyl(p-tolyl) cyclopentane skeleton has
Received 21 February 2019 been disclosed via a key Stork-Danheiser sequence on a cyclopentane based vinylogous ester with aryl
Revised 14 May 2019 Grignard reagent followed by a-methylation strategy. The strategy is eventually applied to the concise
Accepted 17 May 2019
formal total synthesis of (±)-laurokamurene B (1b) in only 5 steps with 45.4% overall yield.
Available online 18 May 2019
Ó 2019 Elsevier Ltd. All rights reserved.

Keywords:
Vinylogous esters
Stork-Danheiser sequence
a-Alkylations
Laurokamurene B

Red algae of the genus Laurencia Lamouroux are well-known for Structurally, laurokamurenes (1a–d) are closely related to other
their ability to biosynthesize a large variety of structurally unusual sesquiterpenoids, such as cuparenes (2a–b), deconins (3a–c) [3],
secondary metabolites having brominated and non-brominated and aplysins (4–5) with same total numbers of carbons present
sesquiterpenes [1]. The genus Laurencia is particularly distributed in them in a rearranged structural scaffold (Fig. 1). Particularly,
widely in tropical and subtropical areas [1]. More than 1100 differ- in laurokamurenes (1a–d), three methyl groups are situated at
ent metabolites with sesquiterepene (C-15 unit), diterpenes (C-20 2,2,3-fashion in 1-arylcyclopentane ring. In contrast, cuparanes
unit), and Triterpenes (30 unit) have been characterized from (2a–b) share three methyl groups at 1,2,2-fashion, whereas in lau-
approximately 80 species of this genus till date. ranes (1a–d) they follow 1,2,3-fashion [4a]. Among various
During their investigations on the isolation of biologically active sesquiterpenes isolated till date, laurokamurenes (1a–b) are the
compounds from Chinese marine organisms, Mao and Guo isolated first members with three methyl groups in the aliphatic ring
two new aromatic sesquiterpenes laurokamurenes A and B (1a–b) arranged in a 2,2,3 fashion.
from genus Laurencia in 2006 [2a]. Recently, in 2014, Mao and co- Biogenetically, they are synthesized from intermediate carboca-
workers have isolated laurokamurenes C and D (1c–d) from the red tion 6d (Scheme 1) via the rearrangement of methyl group (1,2-
alga Laurencia okamurai Yamada, together with six other known shift of methyl group) to establish a 3carbocation intermediates
sesquiterpenes [2b]. The structures of these secondary such as 7a (for lauranes e.g. debromoaplysin 4b) and 8a (e.g. lau-
metabolites, including relative configuration, were elucidated by rokamurenes 1a–d). Cyclopentane based 2° carbocation 6d can
detailed analysis of spectroscopic data (2D NMR experiments), be generated from a bisabolyl cation intermediate (6c) via a CAC
and by comparison with data for related known compounds. bond formation, which in turn can be obtained from a farnesyl
Although, elaborate study of the biological profile of majority of pyrophosphate 6a (C-15 unit) via a nerolidyl pyrophosphate 6b
these sesquiterpenes are yet to be undertaken, preliminary (C-15 unit) (Scheme 1).
findings revealed that laurokamurene B (1b) displays antifungal Owing to their diverse biological profiles and uncommon struc-
and cytotoxic activities [2b–d]. tural features, cuparane (2a–b) and laurane (3–5) based sesquiter-
penoids have gained extensive attention from the synthetic
community all over the world leading to numerous efficient syn-
⇑ Corresponding author. thetic approaches [1a]. Although laurokamurenes were isolated
E-mail address: vishnumayabisai@gmail.com (V. Bisai). more than a decade, only a few Syntheses of laurokamurene B 1a
1
Both authors contributed equally to this work. are reported till date. In 2007 [5a], Srikrishna and co-workers have
2
Current address: The AB Research Group, Department of Chemistry, Indian reported the first total synthesis of (±)-laurokamurene B 1a from
Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal 462
066, India.
isobutyric acid employing a combination of an Ireland–Claisen

https://doi.org/10.1016/j.tetlet.2019.05.032
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Tetrahedron Letters 60 (2019) 150941

Contents lists available at ScienceDirect

Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Unified approach to the sesquiterpenoids, lauranes and cyclolauranes:


Total synthesis of (±)-isolaurene
Sovan Niyogi a, Arindam Khatua a, Vishnumaya Bisai a,b,⇑,1
a
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal 462 066, Madhya Pradesh, India
b
Department of Chemistry, Indian Institute of Science Education and Research Berhampur, Berhampur 760 010, Odisha, India

a r t i c l e i n f o a b s t r a c t

Article history: A general approach to the total synthesis of sesquiterpene, isolaurene (1a) and cyclolaurene (2a) is fea-
Received 24 May 2019 tured from commercially available 3-methyl cyclopenten-2-one. The strategy includes a Stork-Danheiser
Revised 11 July 2019 sequence concomitant with a Ni(II)-catalyzed conjugate addition of methyl group onto 3-aryl 2-methyl
Accepted 16 July 2019
cyclopenten-2-one to afford the advanced intermediate 11. A methyllithium addition onto compound
Available online 17 July 2019
11 with an eventual dehydration completed the total synthesis of isolaurene (1a) in 5 steps (58.3% overall
yields).
Keywords:
Ó 2019 Elsevier Ltd. All rights reserved.
Laurane sesquiterpenoids
Isolaurene
Stork-Danheiser sequence
Vinylogous esters

Bioactive secondary metabolites originated from marine organ- 27 lg/mL, respectively). Compound 1b exhibited a significant
isms display wide range of effects on many diseases in contrast to activity against Candida albicans (MIC of 70 lg/mL) [2].
their terrestrial counterparts. Efficient synthetic ventures towards Importantly, several metabolites of Laurencia showed notice-
these molecules may lead to the discovery of newer bioactive able antibacterial [3], insecticidal [4a], antifungal [4b], antiviral
metabolites with different modes of action [1]. Laurene-type activity [5a], tyrosine inhibitor [5b] and apoptosis inducing or sup-
sesquiterpenes (1a-c; Fig. 1) include one such class having substi- pressing activity [6]. Although, detailed biological profiles of most
tuted aryl cyclopentanes with three methyl groups in 1, 2 and 3 of the laurenes are yet to be investigated, other similar class of
fashion and cyclolauranes 2a-d (Fig. 1) having two methyl groups sesquiterpenoids, such as cuparenes (5a-b) and herbertenes (6a-
in 1 and 2 position with a cyclopropane ring caught our attention. b) are found to be potent antifungal, antibiotic, neurotrophic and
Other sesquiterpenes like laurokamurenes (4a-d) [1,1,2fashion], antilipidperoxidation agents [7–9].
cuparenes (5a-b), herbertenes (6a-b) differ from lauranes only in A rare cuparane sesquiterpene, cyclolaurene 2a, was also iso-
the methylation pattern viz. 1, 2, 2 for 4a-b and 2, 2, 3 for 5a-b lated together with brominated analogs cyclolaurenol 2b and
and 6a-b, respectively (Fig. 1). cyclolaurenol acetate 2c from the sea hare A. dactylomela in
Masamune and co-workers have isolated laurene and isolau- Kohama Island (Okinawa, Japan) [9c]. Also, debromolaurenterol
rene (1a) from Laurencia glandulifera [2a,b]. Later, in 2012, Alarif dimer 3 was later identified from the same source which is also
and co-workers have isolated three laurene-type sesquiterpenes, found in the red alga Laurencia tristicha [9d].
isolaurene (1a), isolauraldehyde (1b), and 12-hydroxy isolaurene A closure view of the biogenetic connection of these sesquiter-
(1c) from the organic extract of the red alga Laurencia obtusa penoids [9b] brings them back to bisabolyl cation (8c) generating
[2c]. The newly isolated compounds were tested for their bioactiv- from farnesyl pyrophosphate (8a) via the intermediacy of nerolidyl
ity profile and found that natural products 1b-c exhibited potent pyrophosphate (8b). Intermediate 8c might be responsible for the
activity against the Gram-positive Bacillus subtilis and Staphylococ- syntheses of cuparane 5a, herbertene 6a and isolaurene 1a involv-
cus aureus, where 1b proved to be the most active (MIC 35 and ing rearrangement of methyl groups (1,2-shift of methyl group)
and carbocation intermediates (Scheme 1). This cation intermedi-
⇑ Corresponding author at: Department of Chemistry, Indian Institute of Science ate (8c) may generate cyclopentane based 2° carbocation 9a, from
Education and Research Bhopal, Bhauri, Bhopal 462 066, Madhya Pradesh, India. where oxidation-reduction events lead to the formation of cupar-
E-mail address: vishnumayabisai@gmail.com (V. Bisai). anes 5a-b and related secondary metabolites. Whereas, 2° carboca-
1
Current address: The AB Research Group, Department of Chemistry, Indian tion 9a after a 1,2-migration of methyl group generates another 2°
Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal 462 carbocation 9e enroute to herbertanes 6a-b and related natural
066, India.

https://doi.org/10.1016/j.tetlet.2019.07.032
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Biomolecular Chemistry
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Total synthesis of (+)-ar-macrocarpene†‡


Cite this: Org. Biomol. Chem., 2019, Arindam Khatua,§a Sovan Niyogi§a and Vishnumaya Bisai *a,b,c
17, 7140
Received 18th June 2019,
Accepted 9th July 2019
DOI: 10.1039/c9ob01373c

rsc.li/obc

This report features the first catalytic asymmetric total synthesis of Despite its limited natural range (only on Point Lobos and
a sesquiterpene, (+)-ar-macrocarpene (1), in 7 steps with 42.1% Cypress Point, Monterey Co., California), Cupressus macrocarpa
overall yields from commercially available inexpensive 5,5-di- Hartw. ex Gord. (Monterey cypress) is one of the most widely
methylcyclohexane 1,3-dione. This strategy relies on a key [3,3]- planted conifers in the state. The minor component of
sigmatropic rearrangement effecting reductive transposition N-hexane extract of this species contains ar-macrocarpene 1
through allylic diazene rearrangement (ADR) in a single step from (Fig. 1). The absolute configuration of ar-macrocarpene 1 has
intermediate allylic alcohol (+)-12 under the Mitsunobu reaction been assigned tentatively, on the basis of optical rotation and
conditions with o-nitrobenzenesulfonyl hydrazide (o-NBSH). correlation with the related natural products in the literature.
Enantioselective reduction of α-bromo vinylogous ester 16 under Other structurally correlated sesquiterpenoids include lauroka-
the Corey–Bakshi–Shibata reduction conditions forges the murene B (6),2 cuparane (7), cuparenic acid (8),3 aplysin (9)
required stereocenter in the allylic alcohol (+)-12 in a highly and debromoaplysin (10) having the same total numbers of
enantioenriched manner (95% ee). carbons i.e. they are structural isomers with rearranged struc-
tural scaffolds (Fig. 1). Apart from these, majapolene B (4),4 a
brominated sesquiterpene, was originally isolated from
Introduction Laurencia majuscula. Reisolation of majapolene B (4) from

Owing to their wide-ranging bioactivity profiles and many


uncommon structural features, total synthesis of sesquiterpen-
oids holds a considerable synthetic challenge. Towards this,
we found macrocarpenes (1–3) that are naturally occurring irre-
gular sesquiterpenes possessing a 3,3,4′-trimethyl-1,1′-(bicyclo-
hexyl) skeleton to be compelling synthetic targets (Fig. 1).
From the structural perspective, macrocarpenes bear only
three terminal carbons and the presence of the fourth terminal
carbon might be incorporated during the biogenesis of the di-
methylcyclohexane ring. These sesquiterpenoids were identi-
fied in foliage of Cupressus macrocarpa by Cool in 2005 in
widely varying amounts.1

a
Department of Chemistry, IISER Bhopal, Bhopal Bypass Road, Bhauri,
Bhopal - 462 066, Madhya Pradesh, India. E-mail: vishnumayabisai@gmail.com
b
Department of Chemistry, IISER Berhampur, Transit Campus (Govt. ITI Building),
Engg. School Junction, Berhampur, Odisha – 760 010, India
c
Department of Chemistry, IISER Tirupati, Rami Reddy Nagar, Karkambadi Road,
Mangalam, Tirupati – 517 507, India
† This work is dedicated respectfully to Professor Vinod K. Singh, IIT Kanpur on
the occasion of his 60th birthday.
‡ Electronic supplementary information (ESI) available: Experimental pro- Fig. 1 Selected naturally occurring sesquiterpenes, macrocarpenes
cedures, characterization data, NMR spectra. See DOI: 10.1039/c9ob01373c (1–3), majapolene B (4–5), laurokamurene B (6), cuparanes (7–8), and
§ These authors contributed equally to this work. aplysins (9–10).

7140 | Org. Biomol. Chem., 2019, 17, 7140–7143 This journal is © The Royal Society of Chemistry 2019