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DOI: 10.1002/anie.201405074
Asymmetric Catalysis
Angew. Chem. Int. Ed. 2014, 53, 10737 –10741 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 10737
Letter
pubs.acs.org/OrgLett
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.
pubs.acs.org/OrgLett
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.
© 2014 American Chemical Society 6068 dx.doi.org/10.1021/ol502842f | Org. Lett. 2014, 16, 6068−6071
Letter
pubs.acs.org/OrgLett
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.
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
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.
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.
pubs.acs.org/OrgLett
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.
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.
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
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
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Organic &
Biomolecular Chemistry
Published on 09 July 2019. Downloaded by Indian Institute of Science Education and Research – Bhopal on 7/31/2019 11:31:59 AM.
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
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