Desymmetrization of diolefinic diols by enantioselective amino-thiocarbamate-catalyzed bromoetherification: Synthesis of chiral spirocycles

Article abstract of DOI:10.1002/anie.201310136

A facile, efficient, and highly diastereo- and enantioselective bromoetherification of diolefinic diols has been developed using an amino-thiocarbamate catalyst. Further manipulations of the bromoether products enabled entry into a new class of spirocycle

Full text of DOI:10.1002/anie.201310136

Angewandte
Chemie
DOI: 10.1002/anie.201310136
Asymmetric Catalysis
Desymmetrization of Diolefinic Diols by Enantioselective Amino-
thiocarbamate-Catalyzed Bromoetherification: Synthesis of Chiral
Spirocycles**
Daniel Weiliang Tay, Gulice Y. C. Leung, and Ying-Yeung Yeung*
Abstract: A facile, efficient, and highly diastereo- and
enantioselective bromoetherification of diolefinic diols has
been developed using an amino-thiocarbamate catalyst. Fur-
ther manipulations of the bromoether products enabled entry
into a new class of spirocycles which are distinctively lacking in
the literature.
tant building blocks for synthetic chemists as they typically
resemble the fundamental cores of many valuable pharma-
ceutical intermediates as well as biologically active natural
products.[6]
The challenge in developing an efficient method for
halocyclization lies in improving the rate of nucleophilic
capture as opposed to the racemization of halonium ions
through olefin-to-olefin transfer.[7] Recently, we reported
asymmetric bromolactonizations and bromoaminocycliza-
tions using amino-thiocarbamate catalysts.[8] Herein we are
pleased to disclose the catalytic enantioselective synthesis of
hetero-spirocycles through a double halocyclization strategy.
The first cyclization involves a desymmetrization/asymmetric
halogenation process which gives rise to two quaternary
stereogenic carbon atoms in the cyclic ether products
(Scheme 1). Subsequently, a diastereoselective halocycliza-
tion can be performed to yield a series of chiral hetero-
Chiral spirocycles are a special class of compounds which
has attracted much attention over the past decades. Because
of the inherent rigidity and well-defined three-dimensional
molecular structure, chiral nonracemic spiromolecules have
been used in various areas, including catalysis, metal com-
plexation, and molecular architecture.[1] The unique structural
features of spirocycles also open a new avenue for exploring
new pharmacological spacing.[2] Recently, multifunctional
chiral hetero-spirocycles, having readily modifiable handles,
have garnered significant interest as they are particularly
useful in modern drug discovery.[3] However, facile and
efficient asymmetric pathways towards enantioenriched spi-
rocycles remain sparse. The tremendous difficulty encoun-
tered in controlling the regio- and stereochemistry of
quaternary carbon centers has caused the synthesis of these
privileged scaffolds to remain a challenge for synthetic
chemists.[1]
Halocyclization of olefinic compounds, an important
synthetic transformation that was discovered more than
a century ago,[4] is a powerful method for the construction
of heterocycles. However, it was not until recently that
significant efforts were devoted to the development of
catalytic enantioselective halolactonization, haloetherifica-
tion, and haloaminocyclization.[5] The resulting heterocyclic
intermediates, having modifiable halogen handles, are impor-
Scheme 1. Synthesis of hetero-spirocycles through the asymmetric
bromination and desymmetrization of 1.
spirosystems. This protocol allows access to a class of novel
chiral spirocycles which are distintively missing in the
literature.[1] To the best of our knowledge, this report also
represents the first case of desymmetrizing bromoetherifica-
tion of a diolefinic diol system.[9]
At the initial stage of this project, we screened our library
of cinchona-alkaloid-derived amino-thiocarbamates to look
for a suitable catalyst with which to carry out the desymmet-
rization with good enantioselectivity and diastereoselectivity.
The compound 1 (R = C6H5; for structure see Table 1) and N-
bromosuccinimide (NBS) were used as the substrate and the
halogen source, respectively. We first screened for a suitable
catalyst core and observed that quinine and quinidine gave
better d.r. and e.r. values as compared to cinchonine and
cinchonidine. We then proceeded to examine various phenyl
handles and the 6-alkoxy substituents of quinoline, and the
[*] D. W. Tay, Prof. Dr. Y.-Y. Yeung
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmyyy@nus.edu.sg
Homepage: http://www.chemistry.nus.edu.sg/people/
academic_staff/yeungyy.htm
Dr. G. Y. C. Leung, Prof. Dr. Y.-Y. Yeung
Agency for Science, Technology and Research (A*STAR)
Institute of Chemical & Engineering Sciences
11 Biopolis Way, Helios, #03-08, Singapore 138667 (Singapore)
[**] We thank the National University of Singapore (grant no. 143-000-
509-112), A*STAR-Public Sector Funding (grant no. 143-000-536-
305), and GSK-EDB (grant no. 143-000-564-592) for financial
support. D.T. would like to thank and acknowledge A*STAR for
sponsoring his PhD scholarship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310136.
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Table 2: Desymmetrizing bromoetherification of mixed olefins.[a]
quinidine-derived catalyst 3a was identified to be superior
(see Table S1 in the Supporting Information).[10]
Once a suitable catalyst was identified, optimizations of
temperature, solvent, and halogen source were conducted.
The reaction was observed to perform better when carried out
using N-bromophthalimide (NBP) with a chloroform/n-hex-
ane (4:7) solvent blend at À608C (see Tables S2 and S3).[10]
Under these reaction conditions, the diastereomeric ratio was
determined to be 84:16 and enantioselectivity as 96:4 for the
cyclization of 1a (Table 1, entry 1). The reaction was found to
be readily scalable without diminishing the yield, and d.r. and
e.r. values (entry 2). By using the optimized reaction con-
ditions, we examined substrates with symmetrical olefinic
systems. In general, the reactions with different diolefinic
diols (1) proceeded smoothly to give the corresponding
bromoethers with good to excellent d.r. and e.r. values,
especially for those which have electron-rich substituents
(Table 1). The catalyst loading that was required to maintain
the performance was also examined. It was observed that
even under a low catalyst loading of 2 mol%, the d.r. and
e.r. values of the reaction remain almost unchanged (entries 3
and 4).
Diols with unsymmetrical unsaturated systems were also
investigated and the results are shown in Table 2. Again, good
to excellent d.r. values were obtained. For the relatively
bulkier alkyl-substituted olefinic substrates 4a and 4b, the
cyclization favored the phenyl olefin with good e.r. values
(Table 2, entries 1 and 2). In contrast, the methyl-substituted
mixed olefin 4c gave rise to 5c, as a result of cyclization at the
less hindered methyl olefin (entry 3).[11] The substrate 4d,
which contains a 1,1- and a 1,2-disubstituted olefin, delivered
5d (94%) with a good e.r. value of 92:8 (entry 4). The alkene-
Entry
1
Substrate
Product
2
3
4
5
[a] Reactions were carried out with 4 (0.05 mmol), catalyst 3a
(0.005 mmol), and NBP (0.06 mmol) in CHCl3/n-hexane (4:7) (5.5 mL)
at À608C for 12 h in the absence of light. The yields within parentheses
are those of the isolated products.
alkyne 4e was also examined and gave 5e exclusively in
excellent enantioselectivity (99:1 e.r.; entry 5).
Table 1: Desymmetrizing bromoetherification of 1.[a]
The substituted tetrahydrofurans 2 and 5, which contain
two stereogenic quaternary carbon centers, were further
cyclized to yield the corresponding hetero-spirocycles
(Table 3). Treatment of 2b with NBS and a catalytic amount
of triphenylphosphine sulfide in dichloromethane furnished 6
with an excellent d.r. value (94:6).[12] 2bCOOH, which was
obtained by oxidizing 2b, using PCC followed by NaClO2,
could also be cyclized stereoselectively to yield the spirocycle
7 in 98% yield and 93:7 d.r. NIS could also be used in place of
NBS to give the mixed spirocycle 8 which contains both a Br
and I handle. The reactivity between Br and I can readily be
differentiated and is beneficial for subsequent manipulation.
Under similar reaction conditions, the carboxylic acid deriv-
ative 5eCOOH (obtained by oxidizing 5e) could be cyclized to
yield the spirocycle 9 which contains a vinyl bromide
substituent. A lower diastereoselectivity was obtained when
cyclizing 5b and 5d. The absolute configuration of the
bromoethers, as well as the corresponding spirocycles, were
established based on the X-ray crystallographic study of 7.[13]
It is noteworthy that the spirocycle can be prepared in
a one-pot fashion. For instance, double cyclization of 1b in
one pot under the optimized reaction conditions gave 6 in
70% overall yield. Attempts to manipulate the Br handles in
6 by heating it in pyrrolidine with 10 mol% of NaI furnished
6’ in 72% yield (Scheme 2).
Entry
R
Product
Yield [%][b]
d.r.
e.r.
1
C6H5
C6H5
C6H5
C6H5
2-MeC6H4
3-MeC6H4
4-MeC6H4
1-naphthyl
4-FC6H4
4-ClC6H4
2a
2a
2a
2a
2b
2c
2d
2e
2 f
93
91
90
93
90
89
92
96
93
92
84:16
83:17
81:19
83:17
95:5
80:20
82:18
95:5
96:4
95:5
96:4
94:6
96:4
82:18
95:5
93:7
82:18
82:18
2[c]
3[d]
4[e]
3
4
5
6
7
79:21
76:24
8
2g
[a] Reactions were carried out with 1 (0.05 mmol), catalyst 3a
(0.005 mmol), and NBP (0.06 mmol) in CHCl3/n-hexane (4:7) (5.5 mL)
at À608C for 12 h in the absence of light. [b] Yield of the isolated product.
[c] Reaction was carried out using 1 mmol of 1a. [d] 5 mol% of 3a was
used. [e] 2 mol% of 3a was used. M.S.=molecular sieves.
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Table 3: Second cyclization to spirocycles.[a]
Entry
1
Substrate
Spirocycle
2
Scheme 3. A plausible reaction mechanism.
3[b]
4[c]
5
thus forbidding the stereoselective etherification. For diol
systems, it has been reported that the acidity of the proton is
enhanced because of the intramolecular hydrogen bonding.[14]
As such, we believe that the acidic proton in the 1,3-diol may
interact with the quinuclidine nitrogen atom of the amino-
thiocarbamate catalyst. A plausible mechanistic picture was
constructed as indicated in Scheme 3. We speculate that the
transition-state A may consist of several important compo-
nents: 1) an intramolecular hydrogen bond which helps to
lock the 1,3-diol in a pseudo six-membered ring chair
conformation; 2) the bulkier substituent sits at the pseudoe-
quatorial position; and 3) the amino-thiocarbamate bifunc-
tional pocket helps to restrict the geometry of the intermedi-
ate.
6
To gain further information on the mechanism, the
substrate 14, having one of the hydroxy groups protected as
a TBS ether, was prepared (Scheme 3b). Subjecting 14 to the
optimized bromocyclization conditions resulted in a sluggish
reaction, which further supports the importance of the
hydrogen bonding. In fact, we also examined the benzyl-
substituted substrate 16 which reacted to give good product
d.r. and e.r. values (Scheme 4). Poor diastereoselectivity was
observed when using triphenylphosphine sulfide or potassium
carbonate to mediate the reaction. This result reinforces the
importance of the bis(functionality) in which the catalyst is
controlling both the diastereoselectivity and the enantiose-
lectivity.
[a] Reactions were carried out with substrate (0.05 mmol), SPPh3
(0.005 mmol), and NBS (0.06 mmol) in CH2Cl2 (5.0 mL) at À508C for
12 h in the absence of light. The yields within parentheses are those of
the isolated products. [b] NIS was used instead of NBS. [c] NaHCO3
(1.1 equiv) was used instead of SPPh3.
With regard to the reactivity of the substrate, we realized
that the diol system was critical, as almost no reaction
occurred when cyclizing the olefinic alcohol 12 under the
optimized reaction conditions (Scheme 3a). In our previous
studies on amino-thiocarbamate catalysis, the nucleophiles
(e.g. carboxylic acid) in the olefinic substrates have relatively
low pKa values, which allowed deprotonation by the quinu-
clidine and in turn helped to increase the rate of nucleophilic
capture.[8] By comparison, we believe that the deprotonation
of the alcohol is not favorable because of its higher pKa value,
In summary, a facile, efficient, and highly diastereo- and
enantioselective desymmetrizing bromoetherification of di-
olefinic diols has been developed using an amino-thiocarba-
mate catalyst. Further manipulation of the bromoether
products enabled entry into a new class of spirocycles which
Scheme 2. Synthesis of 6 in one pot from 1b.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
Scheme 4. Cyclization of 16 using different catalysts.
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the catalyst as proposed in earlier studies.
Received: November 21, 2013
Revised: January 27, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · chemoselectivity · cyclization ·
.
furans · Lewis base
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Communications
Asymmetric Catalysis
D. W. Tay, G. Y. C. Leung,
Y.-Y. Yeung*
&&&& — &&&&
Desymmetrization of Diolefinic Diols by
Enantioselective Amino-thiocarbamate-
Catalyzed Bromoetherification: Synthesis
of Chiral Spirocycles
Seeing double: A facile, efficient, and
highly diastereo- and enantioselective
bromoetherification of diolefinic diols has
been developed using an amino-thio-
carbamate catalyst. Further manipula-
tions of the bromoether products enabled
entry into a new class of spirocycles,
having three stereogenic quaternary
carbon centers, which are distinctively
lacking in the literature.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!