Synthesis of chiral (tetrazolyl)methyl-containing acrylates via silicon-induced organocatalytic kinetic resolution of Morita-Baylis-Hillman fluorides

Article abstract of DOI:10.1039/c6cc08830a

Reported herein is a new approach for the asymmetric installation of a (tetrazolyl)methyl group via Si/F activation using organocatalytic kinetic resolution of racemic MBH-fluorides.

Full text of DOI:10.1039/c6cc08830a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C6CC08830A
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Synthesis of chiral (tetrazolyl)methyl-containing acrylates via
silicon-induced organocatalytic kinetic resolution of Morita–
Baylis–Hillman fluorides
Received 00th January 20xx,
Accepted 00th January 20xx
Takayuki Nishimine,a Hiromi Taira,a Satoru Mori,a Okiya Matsubara,a Etsuko Tokunaga,a Hidehiko
Akiyama,b Vadim A. Soloshonok,c and Norio Shibata*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Reported herein is a new approach for the asymmetric installation acetates
2 (X=OAc) have received a considerable attention as
of (tetrazolyl)methyl group via Si/F activation using useful synthetic intermediates for preparation of medicinally
a
organocatalytic kinetic resolution of racemic MBH-fluorides.
relevant compounds as well as complex natural products
(Scheme 1b).
Tetrazoles are entirely man-made, as this type of compound
does not occur naturally.1 Being originally introduced as an
exotic chemical entity, tetrazoles made all the way from a mere
curiosity to valuable compounds with numerous practical
applications ranging from energetic materials2 and nano-
engineering3 to the design ofnew generations of
organocatalysts4 and pharmaceuticals.5 Consequently, the
development of new methods for preparation of tetrazole-
containing compounds is in extremely high demand in current
catalysis and health-care research.1-5 Bulk of the known
methodology affords the structural type in which a tetrazole
ring is directly bonded to an aromatic moiety. On the other hand,
synthesis of N-alkyl-substituted tetrazoles, which show notable
bioactivities,6 is virtually unstudied due to the inherent problem
of poor regio-control of the tetrazole ring N-alkylation.7 Thus,
only a handful of synthetically useful examples of the regio- and
stereo-selective preparation of N-alkyl-substituted tetrazoles
has been described.8 One of the potential solutions is the
Scheme 1 (a) 2-[(trimethylsilyl)methyl]-2H-tetrazoles
adducts ; (c) Concept of substitution of MBH-fluorides
N-alkyl tetrazole acrylates accessible via enantioselective S
with (this work)
1
; (b) Well-known MBH-
; (d) Synthesis of chiral
i substitutions of
2
3
4
N
3
1
The reaction of MBH-acetates is based on the SN2’ attack of
various nucleophiles on the terminal alkene sites. Recently we
discovered a new concept for allylic substitution based on the silicon-
induced carbon-fluorine (C-F) activation of MBH-fluorides 3 by
silylated
nucleophiles
under metal-free, organocatalytic
conditions.11 In this transformation, the silicon (Si) atom activates the
application of 2-[(trimethylsilyl)methyl]-2H-tetrazoles
1
C-F bond of 3 to furnish allylic substituted compounds 4 via the SNi
(Scheme 1a).9 Reagents
1
were reported in 1986 by Ogata,9a but substitution mode (Scheme 1c). The key for this transformation is the
generation of F− in-situ followed by the in-situ generation of unstable
only a handful of data is available regarding their properties and
reactivity.9 This is presumably due to the destabilization of the
corresponding CH2 carbanion by the neighboring electron-rich
tetrazole ring.
The Morita-Baylis-Hillman (MBH) adducts 210 such as α-
methylene-β-hydroxy-carbonyl derivatives (X=OH) or α-
methylene-β-amino-carbonyl derivatives (X=NH2) are highly
valuable building blocks in organic synthesis. In particular, MBH-
carbanions such as the trifluoromethyl anion (−CF3) and acetylides
(−C≡CR). In this context, we are interested in the application of this C-
F bond-cleavage-induced allylic substitution reaction of silylated
nucleophiles for the synthesis of previously unknown N-alkyl
tetrazole
acrylates
4
by
the
reaction
of
2-
(trimethylsilyl)methyltetrazoles 1 with MBH-fluorides 3. In-situ
activation of 1 by in-situ generated F− from 3 via SNi substitution
mode should be suitable for the nucleophilic installation of the
unstable methyltetrazole anion.11c We disclose herein the first allylic
installation of a (tetrazolyl)methyl group to MBH-adducts giving rise
to N-alkyl tetrazole-acrylates 4 (Scheme 1d). Chiral N-alkyl tetrazole-
acrylates 4 are obtained by this method in the presence of a cinchona
alkaloid catalyst. The asymmetric C-F activation of MBH-fluorides 3
by the Si atom of 1 via kinetic resolution of racemic 3 by SNi
a. Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya466-8555, Japan
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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substitution is a key to its success. The products 4 with structural also successful, but again, with a variable outcome. FoVrieewxaAmrticpleleO,ntlhinee
features such as the acrylate moiety and the appendant highest yield of product (S)-4a was obtaiDnOedI: 1i0n.10t3h9o/sCe6CrCea0c8t8i3o0nAs
(tetrazolyl)methyl group were obtained in reasonable, kinetic conducted in dichloromethane (CH2Cl2) (entry 4), while the best
resolution yields with excellent enantioselectivities of up to 92% ee. enantioselectivity was observed in chloroform (entry 5). Stranger yet,
These are expected to show antitumor activity from a view point of attempts to use toluene as a solvent (entry 7) were unsuccessful,
structural similarity to the reported tetrazole acrylates12 (See ESI).
clearly indicating that medium polarity of the reaction medium is
Based on the literature data , we started to test the reactivity of essential for the substitution to take place. Considering these results,
5-phenyl-(trimethylsilyl)methyl-tetrazole (1a) towards conventional we decided to advance with a substrate generality study using 1,4-
MBH-acetate 2a and MBH-carbonate 2b. As generic reaction dioxane (entry 3) as a solvent even though highest yield had been
conditions, we used THF as a solvent and DABCO as a base (Scheme obtained in CH2Cl2 (entry 4). The asymmetric induction is supposed
2). The reactions were conducted at various temperatures (0— to be induced via kinetic resolution14 of racemic 3a by SNi substitution,
60 °C); however, not even a trace of the desired product was thus around 50% yield is considered to be a suitable outcome. An
detected in the reaction mixture. Taking advantage of the Si/F enantio-enriched (R)-3a was recovered in most cases (entries 2-6).
activation concept recently discovered by our group,11,13 MBH-
Thus, to briefly explore the substituent effect on the tetrazole ring
fluoride 3a was treated with 1a under the same conditions. In sharp in methyl-tetrazole reagents 1, we selected two series of o-, m- and
contrast to the MBH adducts 2a,b, the reaction readily took place at p-substituted derivatives bearing a bromine atom and a methyl,
0 °C, giving rise to desired product 4a with 60% isolated yield. This generically representing moderately bulky electron-withdrawing and
positive reaction outcome encouraged us to wonder whether the –donating groups (Table 2).
stereochemical outcome of this reaction could be controlled by using
a chiral base instead of DABCO.
Table
2
Substrate generality study of the substitution reactions of 2-
(trimethylsilyl)methyl-tetrazoles 1a-g with MBH-fluoride 3a.
Scheme 2 Reactivity of MBH acetate 2a, carbonate 2b and MBH-fluoride 3a
towards 2-(trimethylsilyl)methyl-tetrazole 1a
.
Table
1
(DHQD)2PHAL-catalyzed reactions of MBH-fluoride 3a with
(trimethylsilyl)methyl-tetrazole 1a
En
try
1
2
3
4
5
6
7
1
R
4
Yield (%)
(4+3a)a
74
Ratio
(4/3a) b
58/42
67/33
53/47
57/43
58/42
70/30
71/29
Ee (4/3a)
(%)c
1a
1b
1c
1d
1e
1f
Ph
4a
4b
4c
4d
4e
4f
92/75
82/95
90/94
90/96
90/97
90/96
90/99
Entry
Solvent
THF
DME
1,4-dioxane
CH2Cl2
CHCl3
ClCH2CH2Cl
toluene
4a Yield (%)a
Ee (%)b
ND
80
92
80
89
80
ND
2-BrC6H4
3-BrC6H4
4-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
64
47
67
72
83
89
1
2
3
4
5c
6
< 5d
12
51
59
12
1g
4g
43
< 5d
7
aIsolated yield. bCalculated by isolated yields. cDetermined by HPLC.
aIsolated yield. bDetermined by chiral HPLC. cCCl3 Adduct was observed.
dDetermined by 1H-NMR.
The treatment of 1 with 3a was conducted in the presence of a
catalytic amount of (DHQD)2PHAL in 1,4-dioxane at room
temperature and the reaction was stopped after stirring for 48 h. A
mixture of products 4 accompanied by the recovered 3a was
obtained in 47—89% yields, and the ratio of 4/3a were calculated
after the isolation of 4/3a. To ensure the accuracy of the reported ee
values, we conducted SDE15 tests via achiral chromatography and
sublimation. Using compound 4a as a model, we found that the
magnitude of SDE was insignificant and did not interfere with the
accurate determination of the stereochemical outcome. The major
conclusion revealed by these experiments is the consistently
excellent level of enantioselectivity of both products 4 (82—92% ee)
and recovered 3 (75—99% ee), practically not influenced by the
electronic nature or by the position of the substituents on the
aromatic ring in 5-phenyl derivatives 1. On the other hand, the total
yields and ratios of product and recovered starting material 4/3 were
After a number of experiments using various chiral organic bases
(Table S1, in ESI), we found that the excellent level of
enantioselectivity in the reaction of MBH-fluoride 3a with 1a could
be obtained with application of (DHQD)2PHAL as an organocatalyst.
Quite interestingly, the stereochemical outcome of the reactions was
unusually sensitive to the reaction solvent. As can be seen from the
data presented in Table 1, (DHQD)2PHAL did not show any catalytic
activity in THF (entry 1). On the other hand, the base was efficient in
other ether-type solvents, yet, noticeably different activity was
observed in dimethoxyethane (DME, entry 2) vs. 1,4-dioxane (entry
3). Remarkably, in both solvents, the enantioselectivity was
appreciable, recording 80 and 92% ee, respectively. The application
of (DHQD)2PHAL in a series of chlorinated solvents (entries 4-6) was
2 | J. Name., 2012, 00, 1-3
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variable, but without any clear substituent-dependent trends or particularly encouraging. Among other examples, it is worth noting
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patterns. This observation led us to examine the reaction mixtures in product 4l, which contains a cyclo-hexane rinDgOiIn: 1t0h.1e0p3l9a/cCe6oCfCp0h8e8n30yAl.
detail and subsequent isolation of MBH-fluoride (R)-3a of One may agree that this case is rather significant indicating that this
exceptionally high enantiomeric purity. Thus, virtually in almost all method is not limited to aromatic compounds and has rather great
cases studied, enantiomeric excess of (R)-3a was greater than that of methodological potential. Furthermore, we were interested to know
desired products (S)-4.
if the nature of the ester alkyl group plays any role in the
This discovery clearly indicated that we were dealing with a case stereochemical outcome of these reactions. Thus, the corresponding
of kinetic resolution,14 in which the (S)-enantiomer of starting rac-3 substitution reaction of CO2-t-Bu containing (rac)-3g proceeded at a
was significantly more reactive in the presence of (DHQD)2PHAL than slower rate, when compared with that of the CO2Me analog, but
the remaining (R)-3a. The absolute configuration of 3a was assigned afforded product 4m of virtually the same excellent enantiomeric
by chiral HPLC analysis and optical rotation after comparison with the purity.
reported data.11a Taking advantage of the high crystallinity of
derivative 4d, a single crystal X-ray analysis was performed showing
its (S) configuration (CCDC1501566). Taking into account the close
similarity of spectroscopic, chiroptical and chromatographic
properties, all major products 3 and 4 were assigned an (R) and (S)
absolute configuration, respectively.
Table
3
Substrate generality study of the substitution reactions of 2-
(trimethylsilyl)methyl-tetrazole 1a with MBH-fluorides 3a
Figure 1 Plausible transition states (TS) A, B and AA accounting for the observed
mode of substitution and the stereochemical outcome.
Finally, to account for the observed stereochemical outcome, we
propose TS-A presented in Figure 1. While a conclusive description
of all mechanistic details will require
a specially focused
investigation, we believe that the data collected in this work and our
previous reports on the Si/F activation concept,11,13 put us in a
position to confidently suggest that the present reactions proceed
via SNi substitution presented by general TS-A.11c Fully consistent with
the literature’s data17 and the observed stereochemical outcome,
highly sterically congested four-membered TS-A accounts for the
determined kinetic resolution process and excellent enantiomeric
purity of the corresponding products. To present a better view of the
molecular interactions, we depicted TS-A in a chair-like form A’,
which shows two important features: the Si-O coordination, and the
pseudo-equatorial position of the stereocontrolling, larger
substituent R, corresponding to the (S)-enantiomer of starting
compounds 3. Considering an alternative TS-B’ allowing for the
substitution of the opposite enantiomer (R)-3, one might agree that
even though the substituent R is still pseudo-equatorial, it is located
underneath the chair-like structure and is engaged in repulsive steric
interactions. By contrast, in TS-A’, the substituent R is pointing away
from any other groups, minimizing any destabilizing interactions.
Another important feature of TS-A is that the positions of the
reacting species are nearly perfectly aligned for activation of the C-F
bond to be achieved via simultaneous Si/F and organocatalyst/allylic
system interactions. These, in turn, make it possible for the
substitution to proceed under mild conditions, without the
formation of fully charged intermediates. To further corroborate the
suggested mechanistic rationale, we attempted the corresponding
reaction using (R)-3a instead of racemic 3a. Quite remarkably and at
the same time expectedly, no reaction was observed except for slow,
gradual decomposition of (R)-3a. It should be noted that only bis-
cinchona alkaloids showed high level of asymmetric induction (Table
S1, ESI). We attempted to build TS-AA depicting the mode of
substrate activation. As it clearly seen from TS-AA structure, one of
the reactive sites is entirely blocked for the incoming nucleophile 1,
although computation could be required for further discussion. The
steric effect of the tetrazolyl groups on the stereochemical outcome
could be disregarded since the other non-heteroatom derived
nucleophiles also gave similarly high enantioselectivity.11
Entry
3
R
4
Yield
(%)
(4+3)b
77
72
81
83
71
88
Ratio
Ee
(4/3)
(%)d
(4/3)c
1
2
3
4
5
6e
3b
3c
3d
3e
3f
4-BrC6H4
4-CF3C6H4
4-MeC6H4
2-naphthyl
cyclohexyl
Ph
4h
4i
4j
4k
4l
4m
68/32
64/36
46/54
59/41
39/61
51/49
86/87
85/90
91/87
86/90
86/48
87/85
3g
aThe reaction was carried out in 0.1 M except for entries 5 and 6. Reaction time is
shown in parenthesis. bIsolated yield. Calculated by isolated yields. dDetermined
c
by HPLC. et-Bu ester 3g was used instead of methyl ester.
To acquire more experimental data and gain further insight into
the reactivity and possible mechanism of this new chemical
transformation, we proceeded to perform a second substrate
generality study focusing, this time, on the structurally different
MBH-fluorides (rac)-3. The reactions presented in Table 3 were
performed under the same conditions as those described in Table 2,
using 1,4-dioxane as a solvent and 10% of (DHQD)2PHAL as an
organocatalyst. The indicated yields and enantiomeric purity of
products 3 and 4 are those of isolated analytically pure compounds.
The choice of substrates included examples of phenyl ring-bearing
electron-donating and –withdrawing groups, as well as a bulkier
naphthyl group. Considering the special role of the aromatic
trifluoromethyl group in the design of new pharmaceuticals,16
preparation of p-CF3-aryl-contaning tetrazole 4i with 85% ee was
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5, 60938–60955. (l) C.
Maleki and A. Sarvary, RSC Adv., 2015,
In summary, the results reported in this communication
convincingly demonstrate that the asymmetric allylic installation of a
(tetrazolyl)methyl group via Si/F activation under organocatalytic
kinetic resolution of racemic MBH-fluorides 3 is a new and viable
methodology of high synthetic value. Operationally convenient
conditions and excellent enantioselectivity of the key SNi-substitution
step offer a reliable, straightforward access to the target compounds
containing a pharmacophoric (tetrazolyl)methyl group. A preliminary
biological study of these structurally novel compounds against U937
cells supports the assumption of their medicinal potential (see
Figures S1 and S2, in ESI), and we are currently actively exploring this
line of research.
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for Supporting in Drug Discovery and Life Science Research
(Platform for Drug Discovery, Informatics, and Structural Life
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Development (AMED), the Advanced Catalytic Transformation
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