Catalytic Enantioselective Intermolecular Desymmetrization of Azetidines

Article abstract of DOI:10.1021/jacs.5b03083

The first catalytic asymmetric desymmetrization of azetidines is disclosed. Despite the low propensity of azetidine ring opening and challenging stereocontrol, smooth intermolecular reactions were realized with excellent efficiency and enantioselectivity.

Full text of DOI:10.1021/jacs.5b03083

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Communication
Catalytic Enantioselective Intermolecular Desymmetrization of Azetidines
Zhaobin Wang, Fu Kit Sheong, Herman H.Y. Sung, Ian D. Williams, Zhenyang Lin, and Jianwei Sun
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2015
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Catalytic Enantioselective Intermolecular Desymmetrization
of Azetidines
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Zhaobin Wang, Fu Kit Sheong, Herman H. Y. Sung, Ian D. Williams, Zhenyang Lin,* and Jianwei Sun*
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
SAR, China
Supporting Information Placeholder
The challenge is partly due to the significantly lower ring-open-
ing propensity of azetidines relative to aziridines.4-6 Thus, to in-
crease the nucleofugacity of the amine unit, an electron-withdraw-
ing group is typically introduced (e.g., carbonyl for PG, Scheme 1).
However, it may increase the difficulty in asymmetric induction
due to the increased distance between the newly established stere-
ogenic center and the catalyst activation site (e.g., the carbonyl ox-
ygen upon LUMO-lowering activation). Therefore, it is a formida-
ble challenge to balance reactivity and stereocontrol. In this context,
herein we report the first catalytic asymmetric intermolecular
desymmetrization of azetidines with excellent efficiency and enan-
tioselectivity providing rapid access to highly functionalized chiral
amine derivatives, including those with quaternary stereocenters.
ABSTRACT: The first catalytic asymmetric desymmetrization of
azetidines is disclosed. Despite the low propensity of azetidine
ring-opening and challenging stereocontrol, smooth intermolecular
reactions were realized with both excellent efficiency and enanti-
oselectivity. These were enabled by suitable combination of cata-
lyst, nucleophile, protective group, and reaction conditions. The
highly enantioenriched densely-functionalized products are versa-
tile precursors to other useful chiral molecules. Mechanistic studies,
including DFT calculations, revealed that only one catalyst mole-
cule is involved in the key transition state, though both reactants
can be activated. Furthermore, the Curtin-Hammett principle dic-
tates the reaction proceeds via amide nitrogen activation.
Representative 3-monosubstituted azetidine substrates 1a with
various electron-withdrawing groups, including p-Ts and acyl
groups, were employed for the study (Scheme 2). Inspired by the
excellent catalytic ability of chiral phosphoric acids in a range of
efficient enantioselective desymmetrization reactions,7,8 we ran-
domly chose a chiral phosphoric acid for the initial test of azetidine
opening. However, to our disappointment, the exhaustive combina-
tion of these azetidines and various nucleophiles (including typical
amines, alcohols, and thiols, etc.) resulted in essentially no reaction
at room temperature. This observation confirmed the low reactivity
Enantioselective desymmetrization is a powerful strategy to ac-
cess enantioenriched chiral molecules.1 For example, asymmetric
nucleophilic ring-opening of meso-aziridines provides a rapid syn-
thesis of highly useful chiral amine derivatives with vicinal stereo-
centers (Scheme 1a). As a result, various catalyst systems have
been developed to achieve excellent efficiency and stereoselectiv-
ity for these processes, including those with chiral Brønsted acids,
Lewis acids/bases, and phase-transfer catalysts.2-3 However, in
contrast to these well-established reactions of aziridines, their four-
membered ring homologues— azetidines—have been much less-
studied regarding their catalytic asymmetric opening reactions, alt-
hough their synthesis, racemic reactions, and applications in me-
dicinal chemistry have received increasing attention over the past
few decades.4-5 Indeed, enantioselective desymmetrization of the
prochiral 3-substituted azetidines remains unknown (Scheme 1b).
o
of azetidines. Next, we re-evaluated these reactions at 80 C em-
ploying the relatively more acidic chiral catalyst N-triflyl phospho-
ramide A1 (Figure 1).9 While the majority of the nucleophiles were
still unreactive, 2-mercaptobenzothiazole 2a was found to be supe-
rior providing the desired ring-opening product 3.10 Quantitative
yield was obtained with p-Ts protection, albeit with low enantiose-
lectivity (27% ee). Subsequent evaluation of various N-acyl groups
showed that the enantioselectivity could be significantly improved.
Among them, the 3,4,5-trimethoxybenzoyl group proved best (95%
yield, 88% ee). Its superior performance might be partly owning to
its suitable electron-withdrawing ability, which is sufficient but not
too strong to ensure both good nucleofugacity (leaving ability) and
nitrogen basicity for effective acid activation and stereocontrol.
Scheme 1. Enantioselective Desymmetrization of Aziridines
and Azetidines
Figure 1. Chiral Catalyst Structures
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Scheme 2. Evaluation of Different Protective Groupsa
Aiming to further improve the enantioselectivity, we next carried
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out parallel optimizations of different reaction parameters (Table
1). Evaluation of various chiral phosphoric acid catalysts indicated
that the BINOL-derived catalyst A4 gave the highest enantioselec-
tivity (entry 3).11 Different analogous nucleophiles were also com-
pared (entries 8-11). Thiol 2d gave slightly better results than 2a
(entry 10). Solvent screening identified chlorobenzene as the best
solvent (entry 15). Further studies on catalyst loading and concen-
tration identified the optimal conditions with both excellent effi-
ciency and remarkable enantioselectivity (entry 17). Thiol 2e re-
mained less reactive, even at a higher temperature (entry 19).
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Under the standard conditions, a wide range of 3-azetidines
smoothly participated in the intermolecular desymmetrization re-
actions (Table 2), providing a diverse set of densely-functionalized
three-carbon chiral building blocks 3 with excellent enantioselec-
tivity. Alkyl-, aryl-, and hetero-substituents (e.g., O, S, N) at the 3-
position all worked well. 3,3-Disubstituted azetidines are also suit-
able substrates generating the corresponding quaternary stereocen-
ters with good to excellent enantioselectivity (Scheme 3). Particu-
larly noteworthy is the formation of an all-carbon quaternary
a Yield based on 1H NMR of the crude product with CH2Br2 as an
internal standard. Ee value based on HPLC. ND = not determined.
Table 2. Substrate Scope
Table 1. Condition Optimizationa
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a Yield based on HNMR of the crude product with CH2Br2 as an
internal standard. Ee value based on HPLC. b Run with 5 mol% of
A4. c Concentration = 0.08 M. d Run with 2.5 mol% of A4 and 1.5
equiv. of 2d. e Run with 10 mol% of A4 at 90 oC.
a Isolated yield. b Run at 70 oC for 96 h.
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stereocenter in 97% ee (4e). The reaction conditions could tolerate
itial methoxide substitution on the benzothiazole ring to form inter-
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a range of functional groups, including ethers (3a, 3c, and 4e),
TBS-protected alcohols (3b), ketones (3r), acetals (3t), and free
tertiary alcohols (4a-d). This is surprising considering the high
temperature and acidic conditions. It is also worth noting that ex-
amples with excellent stereocontrol at such a high temperature are
scarce in chiral phosphoric acid catalysis. All these results demon-
strate the extraordinary robustness of our process.
mediates alkylsulfide 9 and 2-methoxybenzothiazole 10, followed
by an SN2 reaction between them. Notably, no obvious erosion of
optical purity was observed in any of these derivatizations.
Scheme 4. Representative Product Transformations
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Scheme 3. Formation of Quaternary Stereocenters
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a Run at 70 oC for 96 h.
Benzoxazole-2-thiol (2f) could also serve as a nucleophile to
form the ring-opening product 5 with excellent efficiency and high
enantioselectivity (eq. 1). It is worth noting that both benzothio-
azole and benzoxazole are important subunits of a wide range of
natural products and biologically active molecules.12
To understand the reaction mechanism, we carried out a series of
experimental and theoretical studies. First of all, we were interested
to know whether the acid catalyst activates the azetidine, or the nu-
cleophile, or both species. Acid activation of the azetidine could
enhance its electrophilicity by lowering its LUMO level (Scheme
5). On the other hand, the 2-mercaptobenzothiazole may also inter-
act with the chiral phosphoric acid catalyst by forming a heterodi-
mer (e.g., HD).14 This interaction would raise its HOMO level,
thereby increasing its nucleophilicity. Either activation mode could
facilitate the reaction. Indeed, by mixing the acid catalyst with the
azetidine or the nucleophile separately, we observed both activa-
tions by 31P NMR (details in the SI). Thus, it may be envisioned
that the two activated species approach each other to react in the
rate- and stereo-determining transition state, in which two catalyst
molecules would be involved. However, kinetic studies indicated
that the reaction is first-order in catalyst (details in the SI), suggest-
ing that only one catalyst molecule is involved (e.g., via IA or IB),
which was also confirmed by DFT calculations.
The enantioenriched products from our reaction are both densely-
and diversely-functionalized. They can be readily transformed to
other useful chiral molecules (Scheme 4). Oxidation of the benzo-
thiazole thioether 3a by mCPBA generated the corresponding sul-
fone, which could serve as a Julia olefination reagent to synthesize
alkene 6 with good overall efficiency. The thioether moiety in 3a
could be cleaved to form amide 7.13 Furthermore, in the presence
of NaOMe/MeOH, substitution of the benzothiazole unit to form
methylthioether 8 was observed. The reaction might proceed by in-
Scheme 5. Proposed Mechanism and Qualitative Reaction Diagram
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Salter, M. M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc.
Although acid activation on the amide carbonyl oxygen (i.e., IB)
is generally accepted, nitrogen-activation in geometrically con-
strained amides can also be possible. Our DFT calculations indi-
cated that the oxygen-activated form IB is more stable than the ni-
trogen-activated form IA, which is consistent with the general be-
lief.15 However, further calculations suggested that it is the less sta-
ble nitrogen-activated IA that leads to lower activation barrier.
Thus, in view of the rapid equilibrium between IA and IB, the Cur-
tin-Hammett principle applies.16 Therefore, we propose that our re-
action proceeds via nitrogen activation, in which the chiral catalyst
is located closer to the reaction center for better asymmetric induc-
tion. This is also consistent with the observed excellent stereocon-
trol even at high temperature. The corresponding catalytic cycle to-
gether with a qualitative energy diagram is depicted in Scheme 5.17
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In conclusion, we have developed the first catalytic enantiose-
lective desymmetrization of azetidines. Despite the low propensity
of azetidine ring-opening and the significant challenge in stere-
ocontrol, the smooth intermolecular desymmetrization of a wide
range of 3-substituted azetidines has been achieved with both ex-
cellent efficiency and remarkable enantioselectivity, enabled by
optimal combination of catalyst, protective group, nucleophile, and
reaction conditions. Both tertiary and quaternary stereocenters can
be generated efficiently. The highly enantioenriched densely- and
diversely-functionalized products can be easily transformed to
other useful chiral building blocks. Mechanistically, although both
reaction partners could be activated by the catalyst, only one cata-
lyst molecule is involved in the bond-forming transition state ac-
cording to kinetic studies and DFT calculations. Finally, although
the carbonyl oxygen activation provides a more stable intermediate,
the reaction proceeds with lower overall barrier via nitrogen acti-
vation, which is consistent with the Curtin-Hammett principle and
the observed excellent stereocontrol. Further studies on other asym-
metric reactions of azetidines are underway.
(6) (a) Dudev, T.; Lim, C. J. Am. Chem. Soc. 1998, 120, 4450. (b)
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(7) Representative reviews on chiral phosphoric acid catalysis, see: (a)
Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun.
2008, 4097. (c) Adair, G.; Mukherjee, S.; List, B. Aldrichimica Acta. 2008,
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(8) Recent examples of enantioselective desymmetrizations catalyzed
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Soc. 2014, 136, 16982. (d) Meng, S.-S.; Liang, Y.; Cao, K.-S.; Zou, L.; Lin,
X.-B.; Yang, Y.; Houk, K. N.; Zheng, W.-H. J. Am. Chem. Soc. 2014, 136,
12249. (e) Gualtierotti, J.-B.; Pasche, D.; Wang, Q.; Zhu, J. Angew. Chem.,
Int. Ed. 2014, 53, 9926. For our efforts, see: (f) Chen, Z.; Wang, B.; Wang,
Z.; Zhu, G.; Sun, J. Angew. Chem., Int. Ed. 2013, 52, 2027. (g) Wang, Z.;
Chen, Z.; Sun, J. Angew. Chem., Int. Ed. 2013, 52, 6685. (h) Wang, Z.; Law,
W. K.; Sun, J. Org. Lett. 2013, 15, 5964. (i) Chen, Z.; Sun, J. Angew. Chem.,
Int. Ed. 2013, 52, 13593.
(9) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626.
(10) For a review on 2-mercaptobenzothiazole, see: Lu, F.-L.; Hussein,
W. M.; Ross, B. P.; McGeary, R. P. Curr. Org. Chem. 2012, 16, 1555.
(11) Catalyst A4 was first reported by List and co-workers: Cheng, X.;
Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130, 15786.
(12) (a) Dumas, J.; Brittelli, D.; Chen, J.; Dixon, B.; Hatoum-Mokdad,
H.; König, G.; Sibley, R.; Witowsky, J.; Wong, S. Bioorg. Med. Chem. Lett.
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2014, 5, 512.
(13) The amide carbonyl group in 7 could also be cleaved (see the SI).
(14) Heterodimers of chiral phosphoric acids have been proposed by
List and co-workers before. See ref 3c and 8b-c for examples.
(15) (a) Another computational study also indicated the favorable oxy-
gen protonation of N-formyl azetidine: Cho, S. J.; Cui, C.; Lee, J. Y.; Park,
J. K.; Suh, S. B.; Park, J.; Kim, B. H.; Kim, K. S. J. Org. Chem. 1997, 62,
4068. (b) We also obtained the X-ray structure of an azetidine substrate, in
which the amide dihedral angle is 17.6o (details in the SI), suggesting no
significant deviation of our azetidine substrates from ordinary amides in
terms of amide conformation.
ASSOCIATED CONTENT
Supporting Information Available
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sunjw@ust.hk; chzlin@ust.hk
ACKNOWLEDGMENT
Financial support was provided by Hong Kong RGC (GRF-604513,
GRF-603313, M-HKUST607/12, and ECS-605812).
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