Asymmetric Organocatalytic Sequential Reaction of Structurally Complex Cyclic Hemiacetals and Functionalized Nitro-olefins to Synthesize Diverse Heterocycles

Article abstract of DOI:10.1021/acs.orglett.8b01386

Structurally complex cyclic hemiacetals bearing a racemic tetrasubstituted stereocenter have been prepared in a concise manner and were successfully used in an organocatalytic enantioselective sequence to react with functionalized nitro-olefins, providing bicyclic acetal-containing compounds as two separable epimers with excellent stereoselectivity. The reaction showed broad substrate scope, with respect to the starting hemiacetals. Moreover, this protocol allows the synthetic transformation of the products to various interesting heterocyclic compounds with substantial structural diversity and broad functionality.

Full text of DOI:10.1021/acs.orglett.8b01386

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Organocatalytic Sequential Reaction of Structurally
Complex Cyclic Hemiacetals and Functionalized Nitro-olefins To
Synthesize Diverse Heterocycles
Jun-Ping Pei,† Ying-Han Chen,† and Yan-Kai Liu*,†,‡
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao 266003, People’s Republic of China
‡Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao
266003, People’s Republic of China
S
* Supporting Information
ABSTRACT: Structurally complex cyclic hemiacetals bearing
a racemic tetrasubstituted stereocenter have been prepared in a
concise manner and were successfully used in an organo-
catalytic enantioselective sequence to react with functionalized
nitro-olefins, providing bicyclic acetal-containing compounds
as two separable epimers with excellent stereoselectivity. The
reaction showed broad substrate scope, with respect to the
starting hemiacetals. Moreover, this protocol allows the
synthetic transformation of the products to various interesting
heterocyclic compounds with substantial structural diversity and broad functionality.
Scheme 1. Upgraded Version of Both Cyclic Hemiacetals and
Nitro-olefins
he chiral cyclic acetal moiety is found as a key structural
subunit in many bioactive natural products and pharma-
T
ceutically active compounds.1 This structural subunit can also be
found in many versatile synthetic building blocks of value for
constructing complex oxygen-containing heterocycles.2 Thus,
the development of concise and efficient enantioselective routes
to molecules bearing chiral cyclic acetal moieties is of great
interest.
One of the most straightforward strategies is the direct
modification of cyclic acetal- or hemiacetal-containing com-
pounds, which provides rapid access to highly functionalized
cyclic acetal- or hemiacetal-containing products for further useful
transformations. Recently, we3 and other researchers4 have
demonstrated that cyclic hemiacetals can be directly used as
attractive precursors under enamine catalysis to access function-
alized hemiacetal-containing products, which are useful inter-
mediates for the synthesis of structurally and stereochemically
diverse molecules. However, despite these impressive achieve-
ments, there are still certain shortcomings of these useful
synthetic strategies (Scheme 1, top), which include (1) the
application of starting cyclic hemiacetals with relatively simple
structures; and (2) the employment of β-nitrostyrenes as
reaction partners, with examples of such asymmetric reactions
with functionalized nitro-olefins being much less developed,4c
despite their potential to transform to structurally diverse
products.
structural moiety.6 These characteristic features led us to
speculate that, by the introduction of a racemic tetrasubstituted
carbon center to enhance the structural complexity of the starting
hemiacetals, two separated epimers might be finally obtained
from stereoselective reactions after SiO2 flash chromatography
purification. Note that this designed strategy potentially provides
an alternative approach for rapid assembly of molecules bearing a
tetrasubstituted carbon stereogenic center, since the construc-
tion of tetrasubstituted carbon stereogenic center represents a
very challenging, but demanding, area in organic synthesis.7
It is well-known that flash chromatography provides a rapid
and inexpensive general method for the preparative separation of
organic compounds.5 Indeed, we found that this widely used
purification protocol could be applied to separate the mixture of
two epimeric products, which contain an acetal or hemiacetal
Received: May 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01386
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With these considerations in mind, and as a continuation of
our ongoing investigations on the development of new
asymmetric organocatalytic approaches to construct chiral
heterocyclic molecules applying cyclic hemiacetals as the starting
materials, we herein document a highly efficient organocatalytic
process that operates under mild reaction conditions to give
structurally and stereochemically diverse molecules containing
the chiral cyclic acetal moiety. In this designed target-oriented
sequential process, the key hemiacetal intermediates could be
easily generated by the reaction of the relatively complex starting
hemiacetals with functionalized nitroolefins, and subsequent
acid-induced oxocarbenium ion formation led to bicyclic acetal
products. Note that all the required starting hemiacetals 3
bearing a racemic tetrasubstituted carbon center could be easily
obtained on a >800 mg scale in a two-step conversion (Scheme 2;
toluenesulfonic acid (p-TsOH, 10 mol %) in CH2Cl2 at 25 °C
gave the desired products 7a and 7′a in good yields (over two
steps) with excellent enantioselectivity as a single diastereomer.
With regard to the acid-induced oxocarbenium ion formation
process, the other acid examined (trifluoroacetic acid, BF3·Et2O,
diphenylphosphate) gave slightly lower yields, but still with
excellent stereoselectivities. (See the SI for full optimization
studies.)
Inspired by these preliminary results, we further explored the
scope of this sequential process with respect to the starting cyclic
hemiacetals. As can be seen from Scheme 4, the reactions
Scheme 4. Scope of the Designed Sequence
Scheme 2. Synthesis of the Required Starting Hemiacetals
see the Supporting Information (SI) for more details. DABCO =
1,4-diazabicyclo[2.2.2]octane), including (1) the Henry reaction
between the corresponding nitroalkanes 1 and paraformalde-
hyde,8 and (2) the subsequent Michael addition of 2 with
acrolein.9
Following our previously developed reaction conditions, we
initially investigated the reaction of the easily synthesized
hemiacetal ( )-3a and β-nitroacroleine dimethyl acetal 410 in
the presence of commercially available catalyst diphenylprolinol
silyl ether 511 at 60 °C, using benzoic acid (BA) as the acidic
additive (Scheme 3, Bn = benzyl; TMS = trimethylsilyl).
As expected, despite the starting cyclic hemiacetal ( )-3a
possessing a racemic tetrasubstituted carbon center, 6a and 6′a
were readily formed as two separable epimers after SiO2 flash
chromatography. Subsequent treatment of the functionalized
hemiacetals 6a and 6′a, respectively, with catalytic amounts of p-
Scheme 3. Designed Sequence to Synthesize Epimeric 7a and
7′a
proceeded smoothly to provide the desired products in good
yields with excellent stereoselectivities, regardless of the
electronic nature and the position of the aromatic substituents
(7b−7j and 7′b−7′j). Heterocyclic substituents were also
tolerated (7k and 7l, a swell as 7′k and 7′l). Except for the
methyl group, aliphatic substrates containing various functional
groups, such as cyclohexyl, ester, and even dimethyl acetal,
proved to be highly efficient in this transformation (7m−7p and
7′m−7′p). Notably, the two-step sequential reactions of both
alkene- and alkyne-bearing substrates proceeded smoothly to
afford the desired products (7q and 7r, as well as 7′q and 7′r),
which could be potentially converted into highly functionalized
chiral molecules.
It is particularly noteworthy that, in all cases examined, the
products 7 and 7′ were formed as two separable epimers with
complete stereocontrol (>99% enantiomeric excess (ee),
diastereomeric ratio (dr) >20:1). Additionally, a key feature of
this process is that a wide variety of cyclic hemiacetals, containing
B
DOI: 10.1021/acs.orglett.8b01386
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
two racemic stereogenic centers and one tetrasubstituted center,
can be employed to construct versatile and useful building blocks
as a single diastereoisomer with high levels of structural
complexity.
tion via intramolecular aminolysis of ester heating in toluene at
80 °C.
Furthermore, the Michael addition products 6 and 6′ are also
useful intermediates for further transformations. For example,
oxidation of hemiacetal 6′a with Dess−Martin periodinane
(DMP) afforded the corresponding monocyclic lactone 17 in
80% yield, and two indole groups were next installed by treating
17 with BF3·Et2O to give 18 in 79% yield. The hydrolysis of 6′m
catalyzed by p-TsOH in aqueous acetone afforded bicyclic
hemiacetal 19, which underwent BF3·Et2O-catalyzed Hosomi−
Sakurai allylation with allyltrimethylsilane15 led to acetal 20 in
high yield with excellent stereoselectivity. BF3·Et2O-catalyzed
reduction with Et3SiH gave the bicyclic acetal 21. (See Scheme
6.)
To show the preparative usefulness of this asymmetric
sequential transformation, a large-scale reaction (8 mmol, 1290
mg) was successfully performed under conditions of lower
catalyst loading (10 mol %). The products 7m and 7′m were
obtained in good yield (over two steps; 7m: 640 mg, 29%; 7′m:
574 mg, 26%) with excellent enantioselectivities a single
diastereoisomer (both of 7m and 7′m, >99% ee, dr >20:1).12
As mentioned previously, chiral cyclic acetal moieties are
versatile building blocks for the synthesis of complex hetero-
cycles. Accordingly, several selective transformations of the
representative acetal 7′m were carried out to further explore the
utility of this synthetic strategy (see Scheme 5; TFAA =
Scheme 6. Useful Transformations of Hemiacetal 6′a and 6′m
Scheme 5. Useful Transformations of Acetal 7′m
The absolute configuration of product 7′m and 10 were
unequivocally determined by X-ray crystallographic analysis (see
Figure 1; the H atoms are omitted for clarity), and all other
products were assigned by analogy.
trifluoroacetic anhydride, TEA = triethylamine, THF =
tetrahydrofuran). In the presence of BF3·Et2O, 7′m reacted
with thiophenol and TMSCN, respectively, to give bicyclic acetal
8 and 10. The S atom in 8 could be oxidized, leading to the
sulfone 9 in 92% yield with 3-chloroperbenzoic acid (m-CPBA)
as an oxidant. Treatment of 7′m with BF3·Et2O and m-CPBA
afforded lactone 11, and the subsequent denitration process with
triethylamine as the base provided the bicyclic lactone 12 bearing
an exo-methylene group.13 The conversion of nitroalkane into
nitrile 1314 and amide 14, respectively, could also be realized via a
two-step sequence under mild conditions with the enantiose-
lectivity maintained. Double addition product 15 could be readily
accessed from the reaction of 7′m and ethyl acrylate, catalyzed by
tetramethylguanidine (TMG). The conversion of 15 to lactam
16 could be achieved through a two-step process involving
reduction of the nitro group and enantioselective desymmetriza-
Figure 1. X-ray structures of products 7′m and 10.
A plausible mechanism is suggested in Scheme 7 to rationalize
the formation of two epimeric products 7m and 7′m. Initially, the
enamine intermediate A, which is generated from the reaction of
5 and ( )-3m, attacked the nitro-olefin 4 from the Re face
followed by intramolecular acetalization, leading to two isolable
epimeric hemiacetals 6m and 6′m. The nucleophilic attack of the
hydroxy group to the Si face of the oxocarbenium ion moiety,
C
DOI: 10.1021/acs.orglett.8b01386
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 7. Plausible Reaction Mechanism
ACKNOWLEDGMENTS
■
This work was supported by the NSFC-Shandong Joint Fund for
Marine Science Research Centers (No. U1606403), the
Scientific and Technological Innovation Project Financially
Supported by Qingdao National Laboratory for Marine Science
and Technology (No. 2015ASKJ02-06), and the Fundamental
Research Funds for the Central Universities (Nos. 201562031
and 201762011).
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■
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liuyankai@ouc.edu.cn.
ORCID
Yan-Kai Liu: 0000-0002-6559-2348
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b01386
Org. Lett. XXXX, XXX, XXX−XXX