Enantioselective Construction of Spiro[chroman-thiazolones]: Bifunctional Phosphonium Salt-Catalyzed [2+4] Annulation between 5-Alkenyl Thiazolones and ortho-Hydroxyphenyl-Substituted para-Quinone Methides

Article abstract of DOI:10.1002/adsc.201901413

The enantioselective formal [2+4] annulation of 5-alkenyl thiazolones with hydroxyl-substituted para-quinone methides was disclosed by dipeptide-based phosphonium salt catalysts. A wide range of functionalized spiro-chroman-thiazolone molecules bearing three contiguous 3° and/or 4° stereocenters were readily constructed in high yields with excellent stereoselectivities (>20:1 dr and up to >99.9% ee) under low catalyst loading and mild reaction conditions. The practicality and utility of this protocol were demonstrated by the scaled-up preparation and elaborations of product. (Figure presented.).

Full text of DOI:10.1002/adsc.201901413

Title: Enantioselective Construction of Spiro[chroman-thiazolones]:
Bifunctional Phosphonium Salt-Catalyzed [2 + 4] Annulation
between 5-Alkenyl Thiazolones and ortho-Hydroxyphenyl-
Substituted para-Quinone Methides
Authors: Jian-Ping Tan, Hongkui Zhang, Zhiyu Jiang, Yuan Chen,
Xiaoyu Ren, Chunhui Jiang, and Tianli Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901413
Link to VoR: http://dx.doi.org/10.1002/adsc.201901413

10.1002/adsc.201901413
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Construction of Spiro[chroman-thiazolones]:
Bifunctional Phosphonium Salt-Catalyzed [2 + 4] Annulation
between 5-Alkenyl Thiazolones and ortho-Hydroxyphenyl-
Substituted para-Quinone Methides
Jian-Ping Tan,†,a Hongkui Zhang,†,a Zhiyu Jiang,a Yuan Chen,a Xiaoyu Ren,a Chunhui
Jiang,a,b and Tianli Wanga,*
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China.E-mail: wangtl@scu.edu.cn
b
School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, 2 Mengxi Road,
Zhenjiang 212003 P. R. China..
†
These authors contributed equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The enantioselective formal [2 + 4] annulation
of 5-alkenyl thiazolones with hydroxyl-substituted para-
quinone methides was disclosed by dipeptide-based
phosphonium salt catalysts.
A
wide range of
functionalized spiro-chroman-thiazolone molecules
bearing three contiguous 3o and/or 4o stereocenters were
readily constructed in high yields with excellent
stereoselectivities (>20:1 dr and up to >99.9% ee) under
low catalyst loading and mild reaction conditions. The
practicality and utility of this protocol were
demonstrated by the scaled-up preparation and
elaborations of product.
Keywords: bifunctional phosphonium salt catalysis;
spiro-chroman-thiazolone; [2 + 4] annulation; 5-alkenyl
thiazolones; para-quinone methides.
Figure 1. Representative bioactive molecules containing
either thiazolone or chroman units.
Thiazole skeletons, especially optically pure thiazol-4-
one units bearing a tetrasubstituted carbon stereocenter,
are prominent building blocks not only in many
biologically active natural products but also in
numerous medicinally important agents.[1,2] For
instance, compounds A and B are commonly
considered as 11β-hydroxysteroid dehydrogenase type
one of the most attractive and straightforward way to
construct such structural motifs in highly
stereoselective form. Generally, 5-alkenyl thiazolones
can act as either C2-synthons or C4-synthons for
annulation reactions. Recently, many impressive
examples on [4 + n] annulation of 5-alkenyl
thiazolones have been achieved by the research groups
of Wang,[6a] Ye,[6b] Guo,[6c] Li[6d] and others[6e-g] to
construct diverse chiral thiazo-fused cyclic compounds
(Scheme 1a, path A). Of note, almost all of reported
examples focused on utilizing 5-alkenyl thiazolones as
C4-syntons, and thus provided chiral thiazo-fused
cycles. In sharp contrast, there is virtually very few
1
(11β-HSD1) inhibitors, and compound
C
demonstrates antibacterial activities (Figure 1a).[3,4]
Not surprisingly, a considerable amount of effort has
thus been directed toward the development of new
technologies to access these frameworks.[5] As a
consequence, the catalytic asymmetric annulation of 5-
alkenyl thiazolones with another appropriate partner is
1
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10.1002/adsc.201901413
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions[a]
entry cat.
solvent
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
PE
base
yyield (%)[b]
ee[c]
62
Scheme 1. Catalytic asymmetric annulation reactions of 5-
alkenyl thiazolones.
1
P1
P2
P3
P4
P5
P6
P7
P8
N1
P6
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
88
90
94
91
93
94
92
92
87
2
67
3
79
progress on the use of such 5-alkenyl thiazolones as
C2-synthons for annulations (Scheme 1a, path B),
despite the fact that this type of reaction can be
synthetically highly valuable. To the best of our
knowledge, there have only three reports by Wang,[7a]
Du[7b] and Yan[7c] group, respectively, which described
that the 5-alkenyl thiazolones were used as C2-
synthons for either [2 + 1] or [2 + 3] annulation.
However, other examples on enantioselective formal
[2 + n] type annulations with employing 5-alkenyl
thiazolones as C2-substrates are not available so far.[7d]
The difficulty in achieving an adequate level of
stereochemical control in such [2 + n] reactions of 5-
alkenyl thiazolones may be attributed to the fact that
the newly formed spiro tetrasubstituted carbon
stereocenter is rather steric hindrance. It thus became
our goal to demonstrate whether the excellent
stereochemical control can be realized or not in a
bifunctional phosphonium salt promoted formal [2 + 4]
annulation via employing 5-alkenyl thiazolones as C2-
synthons.
Over the past decades, amino acid-derived
phosphine catalysis has already been well established
and widely applied in asymmetric synthesis.[8]
Accordingly, the corresponding amino acid-derived
phosphonium salt catalysis were recently developed by
Zhao[9] and Lu.[10] Such bifunctional phosphonium salt
catalysts contain both ion-pairing moiety and H-
bonding active site,[11] which can be advantageous for
asymmetric induction. Very recently, we developed a
new type of dipeptide-based bifunctional phosphonium
salts and successfully demonstrated their applications
in asymmetric synthesis of structurally dense tetra-
substituted aziridines[12a] and some other important
heterocycles.[12b-d] On the other hand, we noted that
chroman skeletons are prominent heterocyclic
frameworks and widely distributed in many
biologically active molecules and natural products
with notable examples such as compound D,
4
88
5
92
6
93
7
92
8
91
9
71
10
K3PO4∙7H2O 97
>99
>99
11[d] P6
PE
K3PO4∙7H2O
97
[a]Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol),
catalyst (10 mol%) and base (4.0 equiv.) in the solvent (1.0
mL) at room temperature for 8 h. All dr values were
determined by H NMR of crude product. [b]Isolated yields.
1
[c]The ee value was determined by chiral HPLC. [d]The
reaction run with 5 mol% catalyst for 12 h. PE = petroleum
ether (b.p. 60-90 oC).
antihypertensive activator E and estrogen receptor F
(Figure 1b).[13,14] Recently, some [4 + 2] examples by
employing
hydroxyl-substituted
para-quinone
methides (p-QMs) as C4-synthons have been
established,[15] and thus afforded various chiral
chroman molecules. In this context, we envisioned that
our dipeptide-based bifunctional phosphonium salts,
which actually possess remarkably high tunability and
structurally diversity, may guide 5-alkenyl thiazolone
as a C2-synthon to accomplish formal [2 + 4]
annulation with hydroxyl-substituted p-QMs for
offering structurally spiro chroman-thiazolone
molecules (Figure 1b). Herein, we describe the first
highly enantioselective formal [2 + 4] annulation of 5-
alkenyl thiazolones with p-QMs mediated by
dipeptide-based bifunctional phosphonium salt
catalysts, providing a facile and novel way to prepare
functionalized spiro-chroman-thiazolone skeletons
bearing three contiguous stereocenters.
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2

10.1002/adsc.201901413
Advanced Synthesis & Catalysis
We began our studies by testing this reaction Table 2. Scope for 5-alkenyl thiazolones[a]
between 5-alkenyl thiazolone 1a and p-QM 2a with
the bifunctional dipeptide phosphonium salt catalysts
in the presence of Cs2CO3 and hexane at room
temperature. To our delight, all the dipeptide-based
phosphonium salts examined were effective in
promoting this reaction to accomplish [2 + 4]
annulations (Table 1, entries 1-8). While phosphonium
iodides (P1 and P2) were used, the desired annulation
product was isolated in good yields and moderate ee
values (entries 1 and 2). Encouraged by these initial
results, we next prepared different dipeptide-based
phosphonium bromides (P3P8) and tested their
catalytic reactivities. Generally, all tested dipeptide
phosphonium bromides were found to be much
effective in promoting this reaction for affording the
cyclization products with excellent reactivity in good
asymmetric induction (entries 3-8), and the catalyst P6
turned out to be the best with affording the cyclization
product in 94% yield and 93% ee at room temperature.
Notably, dipeptide-based ammonium salt catalyst N1
also can promote this reaction, but led to the desired
product in slightly lower yield and enantioselectivity
(entry 9). At last, quick screening of bases and
solvents[16] identified that the petroleum ether (PE) was
the solvent of choice and the K3PO4.7H2O was the
suitable base (entry 10). Indeed, only 5 mol% catalyst
was also sufficient to promote this reaction, and the
corresponding product was isolated in 97% yield
with >99% ee (entry 11).
With optimized reaction conditions in hand, the
substrate scope for formal [2 + 4] annulation between
5-alkenyl thiazolones and hydroxyl-substituted p-QMs
was explored. In general, various 5-alkenyl thiazolones
[a]Reactions were performed with 1 (0.1 mmol), 2a (0.12
bearing electron-neutral, -donating, or -withdrawing
groups on the phenyl ring could be well employed
(Table 2), furnishing the corresponding products 3 in
high yields (up to 99%) with excellent both diastereo-
and enantioselectivities (up to >20:1 dr and >99.9%
ee). Specifically, the 5-alkenyl thiazolones bearing
either electron-neutral or halogenated substitutents at
the para-position of phenyl ring were perfectly
compatible with the reaction conditions, affording the
desired products 3ad in high yields (9399%) with
excellent diastereo- and enantioselectivities (>20:1 dr,
all >99% ee). Substrates bearing both electron-
donating and electron-withdrawing group at either
para- or meta-position of the phenol ring also proved
to be excellent substrates and afforded the
corresponding products (3ei) in high yields and
excellent stereoselectivities. Notably, 5-alkenyl
thiazolones containing substitutents at the ortho-
position on the phenyl ring slightly lowered the
enantioselectivities of the reaction (3j and 3k), mainly
due to the steric hindrance. Additionally, naphthyl-
substituted thiazolones also were suitable substrates
and afforded the products 3m and 3n with high ee
values as 94% and 92%, respectively. Of note, thienyl-
substituted thiazolone could work well to give the
desired product in 81% yield but with moderate ee
value (3o). The absolute configurations of the
annulation products were assigned based on the X-ray
crystal structural analysis of 3d.[17]
mmol), K3PO4.7H2O (0.40 mmol) and the catalyst P6 (5
mol%) in PE (2.0 mL) at room temperature for 12 h.
Isolated yields provided and ee values were determined by
chiral HPLC. PE = petroleum ether (b.p. 60-90 oC).
Encouraged by these results, the scope of p-QMs for
this annulation process was further investigated.
Delightedly, the annulation between 5-alkenyl
thiazolone 1a and p-QMs 2 proceeded smoothly with
affording the desirable spiro products in the presence
of dipeptide-based phosphonium P6 under the fore-
mentioned optimal conditions. As shown in Table 3,
the reaction was applicable to various hydroxyl-
substituted p-QMs bearing different aromatic rings,
regardless of the positions and electronic properties of
the substituents on the aromatic moiety, producing the
expected spiro-chroman-thiazolones 4 in high yields
(up to 95%) with excellent stereo selectivities (up
to >20:1 dr and >99% ee). Moreover, the naphthyl p-
QM was also found to be suitable substrate with
affording the product 4l in acceptable results.
Furthermore, to verify the utility and practicality of
this catalytic asymmetric [2 + 4] annulation reaction,
the scaled-up synthetic reaction between 5-alkenyl
thiazolone 1c and p-QM 2a was were conducted under
the optimal reaction conditions, and the product 3c was
isolated in high yield without any loss of
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3

10.1002/adsc.201901413
Advanced Synthesis & Catalysis
stereoselectivities. Furthermore, under oxidative bonding and ion-pair interactions in this system.
conditions, the product 3c was transferred into a chiral According to these results and our previous studies,[12]
sulfone-containing coumpond 5 (Scheme 2).[18]
Table 3. Scope for p-QMs[a]
the plausible transition state models for the formation
of major isomer were proposed (Figure 2). The high
enantioselectivity mainly originates from the
hydrogen-bonding and ion-pair interactions between
the dipeptide-based phosphonium catalyst and
generated phenolate anion (TS1 and TS2).[19]
Table 4. Asymmetric formal [2 + 4] annulation promoted by
different phosphonium salts and the proposed transition state
models[a]
entry cat.
solvent T (oC) t (h) yield(%)[b]
ee[c]
>99
4
1
2
3
4
PE
PE
PE
rt
rt
rt
12
12
12
12
97
91
90
75
P6
P6-1
P6-2
P6
51
7
MeOH rt
[a]Reactions were performed with 1a (0.05 mmol), 2a (0.06
mmol), base (0.20 mmol) and the catalyst (5 mol%) in the
solvent (1.0 mL). [b]Isolated yields. [c]The ee values were
determined by chiral HPLC.
[a]Reactions were performed with 1a (0.1 mmol), 2 (0.12
mmol), K3PO4.7H2O (0.40 mmol) and the catalyst P6 (5
mol%) in PE (2.0 mL) at room temperature for 12 h.
Isolated yields provided and ee were determined by chiral
HPLC. PE = petroleum ether (b.p. 60-90 oC).
Figure 2. Proposed transition state models.
In summary, we have disclosed the first highly
enantioselective formal [2 + 4] annulation of 5-alkenyl
thiazolones with hydroxyl-substituted p-QMs by
employing a dipeptide-based phosphonium salt as
phase transfer catalyst. A series of optically pure and
highly
functionalized
spiro-chroman-thiazolone
molecules bearing three contiguous stereocenters were
readily obtained with good isolated yields, excellent
diastereoselectivities and enantioselectivities under
mild reaction conditions. Moreover, the practicality
and utility of this protocol were demonstrated by the
scale-up synthesis and facile elaboration of product.
Detailed mechanistic investigations and applications of
this novel phosphonium salt catalysis to other
challenging asymmetric synthesis are currently
ongoing in our laboratory.
Scheme 2. Scale-up synthesis and synthetic elaboration of
product.
Subsequently, we preformed further experiments to
gain a better understanding of the reaction mechanism.
As shown in Table 4, the methylated catalysts P6-1
and P6-2 were prepared and tested for the model
reaction. When methylated phosphonium salts were
used, the enantioselectivities decreased obviously
(entries 13). Of note, when the reaction was
performed in methanol, the enantioselectivity also
dropped dramatically (entry 4). Thus, these
preliminary results indicated the importance of both H-
Experimental Section
General Procedure for [2 + 4] Annulation
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4

10.1002/adsc.201901413
Advanced Synthesis & Catalysis
[8] For selected reviews on amino acid-based
bifunctional phosphine catalysis, see: a) T. Wang, X.
Han, F. Zhong, W. Yao, Y. Lu, Acc. Chem. Res.
2016, 49, 1369. b) H. Ni, W.-L. Chan, Y. Lu, Chem.
Rev. 2018, 118, 9344. For selected examples, see: c)
T. Wang, Z. Yu, D. L. Hoon, C. Y. Phee, Y. Lan, Y.
Lu, J. Am. Chem. Soc. 2016, 138, 265. d) T. Wang,
Z. Yu, D. L. Hoon, K.-W. Huang, Y. Lan, Y. Lu,
Chem. Sci. 2015, 6, 4912. e) T. Wang, W. Yao, F.
Zhong, G. H. Pang, Y. Lu, Angew. Chem., Int. Ed.
2014, 53, 2964.
To a dried round bottle flask with a magnetic stirring bar
were added 5-alkenyl thiazolone 1 (0.1 mmol) and para-
quinone methide 2 (0.12 mmol), then K3PO4.7H2O (0.40
mmol ) and catalyst P6 (5 mol%) was added followed by the
addition of petroleum ether (2.0 mL). The reaction mixture
was stirred at rt for 12 h, and TLC show that the rection was
completed. Then, The mixture was directly purified by
column chromatography on silica gel (hexane/ethyl acetate
= 10/1) to afford desired spiro-chroman-thiazolone 3 as
white solid.
[9] For selected examples on bifunctional phosphonium
salt-catalyzed asymmetric reactions by Zhao, see: a)
D. Cao, J. Zhang, H. Wang, G. Zhao, Chem. Eur. J.
2015, 21, 9998. b) X. Wu, Q. Liu, Y. Liu, Q. Wang,
Y. Zhang, J. Chen, W. Cao, G. Zhao, Adv. Synth.
Catal. 2013, 355, 2701. c) L. Ge, X. Lu, C. Cheng,
J. Chen, W. Cao, X. Wu, G. Zhao, J. Org. Chem.
2016, 81, 9315. d) H. Wang, K. Wang, Y. Ren, N.
Li, B. Tang, G. Zhao, Adv. Synth. Catal. 2017, 359,
1819. e) X. Xia, Q. Zhu, J. Wang, J. Chen, W. Cao,
B. Zhu, X. Wu, J. Org. Chem. 2018, 83, 14617. f)
G. Fang, C. Zheng, D. Cao, L. Pan, H. Hong, H.
Wang, G. Zhao, Tetrahedron 2019, 75, 2706. g) L.
Pan, C.-W. Zheng, G.-S. Fang, H.-R. Hong, J. Liu,
L.-H. Yu, G. Zhao, Chem. Eur. J. 2019, 25, 6306.
Acknowledgements
Financial support was provided by the National Natural Science
Foundation of China (21702139), the “1000-Youth Talents
Program” (YJ201702), and the Fundamental Research Funds for
the Central Universities. We also acknowledge the comprehensive
training platform of the Specialized Laboratory in the College of
Chemistry at Sichuan University for compound testing.
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Advanced Synthesis & Catalysis
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[16] See either Table S2 or Table S3 in SI for more details.
[17] CCDC 1886139 contains the supplementary
crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[18] See Scheme S2 in SI for more details.
[19] See Figure S1 in SI for proposed reaction cycle.
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10.1002/adsc.201901413
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Construction of
Spiro[chroman-thiazolones]: Bifunctional
Phosphonium Salt-Catalyzed [2 + 4] Annulation
between 5-Alkenyl Thiazolones and ortho-
Hydroxyphenyl-Substituted para-Quinone
Methides
Adv. Synth. Catal. Year, Volume, Page – Page
Jian-Ping Tan,†,a Hongkui Zhang,†,a Zhiyu Jiang,a
Yuan Chen,a Xiaoyu Ren,a Chunhui Jiang,a,b and
Tianli Wanga,*
7
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