Enantioselective Synthesis of Oxetanes Bearing All-Carbon Quaternary Stereocenters via Iridium-Catalyzed C?C Bond-Forming Transfer Hydrogenation

Article abstract of DOI:10.1002/chem.201606046

Oxetanes bearing all-carbon quaternary stereocenters are readily prepared through the iridium-catalyzed anti-diastereo- and enantioselective C?C coupling of primary alcohols and isoprene oxide. Based on this methodology, an oxetane containing analogue of haloperidol was prepared. A related azetidine formation is also described.

Full text of DOI:10.1002/chem.201606046

A Journal of
Accepted Article
Title: Enantioselective Synthesis of Oxetanes Bearing All-Carbon
Quaternary Stereocenters via Iridium Catalyzed C-C Bond
Forming Transfer Hydrogenation
Authors: Michael Joseph Krische, Yi-An Guo, and Wonchul Lee
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10.1002/chem.201606046
Chemistry - A European Journal
Enantioselective Synthesis of Oxetanes Bearing All-Carbon Quaternary
Stereocenters via Iridium Catalyzed Alcohol-Vinyl Epoxide C-C Coupling
Yi-An Guo, Wonchul Lee and Michael J. Krische
University of Texas at Austin, Department of Chemistry
1 University Station – A5300, Austin, TX 78712-1167 (USA)
<TOC Abstract>
Taming the Oxetane: Oxetanes bearing all-carbon quaternary stereocenters are
readily prepared through the iridium catalyzed anti-diastereo- and enantioselective C-C
coupling of primary alcohols and isoprene oxide. Based on this methodology, an
oxetane containing analogue of haloperidol was prepared. A related azetidine formation
also is described.
Keywords: Iridium, Enantioselective, Oxetane, Transfer Hydrogenation, Quaternary
Center.
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10.1002/chem.201606046
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Enantioselective Synthesis of Oxetanes Bearing All-Carbon Quaternary
Stereocenters via Iridium Catalyzed C-C Bond Forming Transfer Hydrogenation**
Yi-An Guo, Wonchul Lee and Michael J. Krische*
[*]
Dr. Yi-An Guo, Dr. Wonchul Lee and Prof. M. J. Krische
University of Texas at Austin
Department of Chemistry
1 University Station – A5300
Austin, TX 78712-1167 (USA)
Email: mkrische@mail.utexas.edu
[**]
Acknowledgment is made to the Robert A. Welch Foundation (F-0038) and the NIH-NIGMS
(RO1-GM069445) for partial financial support.
Introduction
Oxetanes are useful building blocks in chemical synthesis[1] and are finding
increasing use in medicinal chemistry due to their metabolic stability and capacity to
serve as structural and functional equivalents to carbonyl and gem-dimethyl moieties.[2]
Despite significant advances in the development of methods for oxetane synthesis,[3]
diastereo- and enantioselective methods for the construction of oxetanes bearing all-
carbon quaternary stereocenters are unknown beyond the context of spirocyclic
systems.[3b] As part of a broad program aimed at the development of C-C bond forming
hydrogenations and transfer hydrogenations,[4] we recently reported the byproduct-free
coupling of primary alcohols with isoprene oxide to form products of tert-(hydroxy)-
prenylation – a process that occurs with exceptional control of anti-diastereo- and
enantioselectivity.[5] It was posited that the neopentyl glycols obtained in these couplings
might serve as precursors to 2,3-trisubstituted oxetanes bearing all-carbon quaternary
stereocenters. For optimal impact on medicinal chemistry, these synthetic procedures
should be compatible with diverse N-heteroaromatic substructures, however, our initial
exploration of the iridium catalyzed tert-(hydroxy)-prenylation did not encompass this
aspect of chemoselectivity. Here, in fulfilment of these objectives, we now report the first
diastereo- and enantioselective synthesis of 2,3-trisubstituted oxetanes bearing all-
carbon quaternary stereocenters via isoprene oxide mediated alcohol C-H tert-
(hydroxy)-prenylation (Figure 1).
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Figure 1. Enantioselective synthesis of oxetanes bearing all-carbon quaternary stereocenters via iridium
catalysis.
Results and Discussion
In an initial experiment aimed at probing compatibility with Lewis basic N-
heterocycles, 2-chloro-5-hydroxymethylpyridine 1a was exposed to commercially
available isoprene oxide (300 mol%) and potassium phosphate (5 mol%) in the
presence of the chromatographically purified π-allyliridium C,O-benzoate complex
o
modified by (S)-Tol-BINAP in THF solvent at 60 C (Figure 1). To our delight, the
product of tert-(hydroxy)-prenylation 2a was formed in 91% yield with 40:1 anti-
diastereoselectivity and 93% enantiomeric excess. Encouraged by these results,
diverse aromatic N-bearing heterocycles 1a-1g were evaluated under these conditions
o
(Table 1). Notwithstanding minor variation in reaction temperature (45 or 60 C) and
loading of isoprene oxide (300-400 mol%), the products of tert-(hydroxy)-prenylation 2a-
2g were formed with comparable levels of anti-diastereo- and enantioselectivity. Here, a
substituent adjacent to nitrogen is required to enforce catalytic turnover. Fluorinated
benzylic alcohols 1h and 1i, allylic alcohol 1j and the N-Boc-protected aminopropanol
1k also participated in highly diastereo- and enantioselective tert-(hydroxy)-prenylation
to form adducts 2h-2k, respectively (Table 1). The stereochemical assignments of
adducts 2a-2k were made in analogy to that determined for adduct 2f, which was
established by single crystal x-ray diffraction analysis.
Conversion of the diol-containing adducts 2a-2k to the corresponding oxetanes
3a-3k was accomplished through a 2-step protocol.[6] First, highly chemoselective
tosylation of the primary alcohol moeity was achieved through exposure of adducts
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Table 1. Iridium catalyzed coupling of isoprene oxide with alcohols 1a-1k to form neopentyl glycols 2a-2k
and conversion to 2,3-trisubstituted oxetanes 3a-3k.a
aYields are of material isolated by silica gel chromatography. Diastereo- and enantioselectivity were determined by chiral stationary
b
c
phase HPLC analysis. See Supporting Information for further experimental details. nBuLi was added at -78 oC. MsCl (110 mol%),
d
e
Et3N (130 mol%) then NaH (400 mol%). Diastereo- and enantioselectivity determined at the stage of the monotosylate. NaH (200
mol%). fTHF (1.0 M). gDiastereo- and enantioselectivity determined for the corresponding monobenzoate.
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o
2a-2k to p-toluenesulfonyl chloride in pyridine solvent at 55 C.[6a] The resulting mono-
tosylates were dissolved in THF solvent at 0 oC and treated with butyl lithium to promote
SN2 cyclization, affording the 2,3-trisubstituted oxetanes 3a-3k.[6b] Attempted mono-
tosylatation of diol 2c under these conditions resulted in indolizidinium formation. In this
case, a one-pot procedure for succesive mesylation-sodium hydride-mediated
cyclization[7] enabled direct access to the oxetane 3c. The stereochemical assignments
of oxetanes 3a-3k were made in analogy to that determined for 3d, which was
established by single crystal x-ray diffraction analysis.
To illustrate the utility of this asymmetric protocol for oxetane formation, the p-
fluorophenyl substituted oxetane 1i was converted to an analogue of the landmark
antipsychotic agent haloperidol, which is among the WHO Model List of Essential
Medicines (Scheme 1).[8] The enhanced basicity of the oxetane oxygen is meant to
mimic the carbonyl oxygen of haloperidol.[2] Additionally, the oxetane provides a
conformational constraint.[2] Hydroboration of oxetane 3i using 9-BBN (9-
borabicyclo[3.3.1]nonane) delivered the primary alcohol 4 in 80% yield as a single
regioisomer. Interestingly, attempted use of borane itself led to significant quantities of
the corresponding Markovnikov hydration product, presumably due to the directing
effect of the relatively Lewis basic oxetane oxygen.[9] Conversion of 4 to the mesylate
followed by treatment with 4-chlorophenyl-4-hydroxy-piperidine 5 provides the
haloperidol analogue 6. (Scheme 1).
Scheme 1. Synthesis of an oxetane-bearing analogue of the antipsychotic agent haloperidol.a
aYields are of material isolated by silica gel chromatography. See Supporting Information for further experimental details.
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To further illustrate how oxetanes 3a-3k may serve as building blocks in chemical
synthesis,[1] oxetane 3b was converted to the enantiomerically enriched tetrasubstituted
cyclopropane 7 in 78% yield through exposure to phenyl magnesium bromide in the
presence of a nickel(II) catalyst (Scheme 2, eq. 1). Unlike related nickel catalyzed
processes,[11] stereospecific C-O oxidative addition is followed by olefin insertion and C-
C reductive elimination to form cyclopropane 7 a single diastereomer. Beyond the
synthesis of oxetanes, the present methodology also provides facile access to
enantiomerically enriched trisubstituted azetidines. For example, conversion of diol 2i to
the bis-mesylate[12] followed by exposure to neat benzylamine[12] provides the azetidine
8 (Scheme 2, eq. 2).
Scheme 2. Conversion of oxetane 3b to cyclopropane 7 and conversion of diol 3i to azetidine 8.a
aYields are of material isolated by silica gel chromatography. See Supporting Information for further experimental details.
Conclusion
In summary, the first asymmetric synthesis of oxetanes bearing all-carbon
quaternary stereocenters (beyond spirocyclic systems) is enabled through the anti-
diastereo- and enantioselective iridium catalyzed C-C coupling of primary alcohols and
isoprene oxide. The prospect of deploying this methodology in the context of medicinal
chemistry is established by the preparation of oxetane 6, an analogue of the
antipsychotic agent haloperidol. Finally, as demonstrated by the preparation of
cyclopropane 7 and azetidine 8, the present chemistry offers a novel means of
accessing other enantiomerically enriched small ring compounds bearing all-carbon
quaternary stereocenters – an aspect that will serve as the basis for future research.
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Experimental Section
Representative procedure for iridium catalyzed alcohol C-H tert-(hydroxy)-
prenylation
(1R, 2R)-1-(6-methoxypyridin-3-yl)-2-methyl-2-vinylpropane-1, 3-diol (2b). An oven-
dried pressure tube equipped with a magnetic stir bar was charged with K3PO4 (2.2 mg,
0.01 mmol, 5 mol%), (S)-Ir-Tol-BINAP (11.0 mg, 0.01 mmol, 5 mol%) and 2-methoxy-5-
hydroxymethylpyridine 1b (27.8 mg, 0.2 mmol, 100 mol%). Under an atmosphere of
argon, anhydrous THF (0.4 mL, 0.5 M) and isoprene monoxide (59 µL, 0.6 mmol, 300
mol%) were sequentially added via syringe. The pressure tube was sealed and the
reaction mixture was stirred at 60 ˚C for 24 h. The reaction mixture was allowed to cool
to ambient temperature and was concentrated in vacuo. The residue was subjected to
flash column chromatography (SiO2, hexanes:ethyl acetate, 1:1) to furnish the title
compound as a yellow oil (42 mg, 0.19 mmol, anti:syn > 20:1, 90% ee) in 94% yield.
Representative procedure for diol mono-tosylation
(R)-2-((R)-hydroxy(6-methoxypyridin-3-yl)methyl)-2-methylbut-3-en-1-yl 4-methyl-
benzenesulfonate (3b’). An oven-dried vial equipped with a magnetic stir bar was
charged with diol 2b (22.3 mg, 0.1 mmol, 100 mol%) and tosyl chloride (26.7 mg, 0.14
mmol, 140 mol%). Under an argon atmosphere, pyridine (0.2 mL, 0.5 M) was added via
syringe. The reaction mixture was stirred at 55 ˚C for 9 h. The reaction was allowed to
cool to ambient temperature and aqueous phosphoric acid (10 mL, 0.5 M) was added.
The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic
layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in
vacuo. The residue was subjected to flash column chromatography (SiO2, hexanes:
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ethyl acetate = 3:1) to furnish the title compound as a yellow oil (34.0 mg, 0.09 mmol) in
90% yield.
Representative procedure for oxetane formation
2-methoxy-5-((2R, 3S)-3-methyl-3-vinyloxetan-2-yl)pyridine (3b). A flame-dried vial
equipped with a magnetic stir bar was charged with the mono-tosylate derived from 2b
(30.0 mg, 0.08 mmol, 100 mol%). Under an atmosphere of argon, anhydrous THF (0.8
mL, 0.1 M) was added via syringe. The reaction mixture was cooled to 0 ˚C before n-
butyl lithium (35 μL, 0.088 mmol, 110 mol%, 2.5 M in hexanes) was added. The reaction
was stirred at 0 ˚C for 30 min and then warmed to ambient temperature. After further
stirring for 2.5 h, saturated aqueous ammonium chloride (10 mL) was added to the
reaction mixture. The aqueous layer was extracted with ethyl ether (30 mL x 2). The
combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The residue was subjected to flash column chromatography
(SiO2, pentane: ethyl ether = 10:1) to furnish the title compound as a yellow oil (13.1 mg,
0.06 mmol) in 79% yield).
References
[1] For recent reviews on the use of oxetanes as building blocks in chemical synthesis,
see: a) D. J. Mack, J. T. Njardarson, ACS Catal. 2013, 3, 272-286. b) J. T. Njardarson,
Synlett 2013, 787-803. c) Z. Wang, Z. Chen, J. Sun, Org. Biomol. Chem. 2014, 12,
6028-6032. d) C. A. Malapit, A. R. Howell, J. Org. Chem. 2015, 80, 8489-8495.
[2] For recent reviews on the use of oxetanes in medicinal chemistry, see: a) J. A.
Burkhard, G. Wuitschik, M. Rogers-Evans, K. Müller, E. M. Carreira, Angew. Chem.
2010, 122, 9236-9251; Angew. Chem. Int. Ed. 2010, 49, 9052-9067. b) D. J. St. Jean,
Jr., C. Fotsch, J. Med. Chem. 2012, 55, 6002-6020. c) J. A. Bull, R. A. Croft, O. A.
Davis, R. Doran, K. F. Morgan, Chem. Rev. 2016, 116, 12150-12233.
[3] For recent reviews on the synthesis of oxetanes, see: a) M. D’Auria, R. Racioppi,
Molecules 2013, 18, 11384-11428. b) E. M. Carreira, T. C. Fessard, Chem. Rev. 2014,
114, 8257-8322. c) O. A. Davis, J. A. Bull, Synlett 2015, 1283-1288.
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[4] For recent reviews on C-C bond forming hydrogenation and transfer hydrogenation,
see: a) A. Hassan, M. J. Krische, Org. Proc. Res. Devel. 2011, 15, 1236-1242. b) J. M.
Ketcham, I. Shin, T. P. Montgomery, M. J. Krische, Angew. Chem. 2014, 126, 9294-
9302; Angew. Chem. Int. Ed. 2014, 53, 9142-9150. c) J. Feng, Z. A. Kasun, M. J.
Krische, J. Am. Chem. Soc. 2016, 138, 5467-5478.
[5] J. Feng, V. J. Garza, M. J. Krische, J. Am. Chem. Soc. 2014, 136, 8911-8914.
[6] a) N. Kurokawa, Y. Ohfune, J. Am. Chem. Soc. 1986, 108, 6041-6043. b) K. Ito, T.
Fukuda, T. Katsuki, Heterocycles 1997, 46, 401-411.
[7] R. C. A. Isaacs, M. J. Di Grandi, S. J. Danishefsky, J. Org. Chem. 1993, 58, 3938-
3941.
[8] a) E. C. Settle, Jr.; F. J. Ayd, Jr. J. Clin. Psych. 1983, 44, 440-448. b) B. Granger,
Encephale 1999, 25, 59-66. c) F. Lopez-Munoz, C. Alamo, Brain Res.
Bull. 2009, 79, 130-141.
[9] a) J. W. Wilt, V. P. Narutis, J. Org. Chem. 1979, 44, 4899-4905; b) D. I. Coppi, A.
Salomone, F. M. Perna, V. Capriati, Angew. Chem. 2012, 124, 7650-7654; Angew.
Chem. Int. Ed. 2012, 51, 7532-7536.
[10] M. Szabo, C. Klein Herenbrink, A. Christopoulos, J. R. Lane, B. Capuano, J. Med.
Chem. 2014, 57, 4924-4939.
[11] a) E. J. Tollefson, D. D. Dawson, C. A. Osborne, E. R. Jarvo, J. Am. Chem. Soc.
2014, 136, 14951-14958. b) E. J. Tollefson, L. E. Hanna, E. R. Jarvo, Acc. Chem. Res.
2015, 48, 2344-2353.
[12] M. G. Banwell, A. J. Edwards, G. J. Harfoot, K. A. Jolliffe, Tetrahedron 2004, 60,
535-547.
[13] J. K. Maity, R. Ghosh, M. G. Drew, B. Achari, S. B. Mandal, J. Org. Chem. 2008,
73, 4305-4308.
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