Enantioselective synthesis of dialkylated N-heterocycles by palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1021/ol503425t

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds.

Full text of DOI:10.1021/ol503425t

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of Dialkylated N‑Heterocycles by
Palladium-Catalyzed Allylic Alkylation
Yoshitaka Numajiri,† Gonzalo Jimenez-Oses,‡ Bo Wang,§ K. N. Houk,‡ and Brian M. Stoltz*,†
́
́
†The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United
States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
§BioTools, Inc., 17546 Bee Line Highway, Jupiter, Florida 33458, United States
S
* Supporting Information
ABSTRACT: The enantioselective synthesis of α-disubsti-
tuted N-heterocyclic carbonyl compounds has been accom-
plished using palladium-catalyzed allylic alkylation. These
catalytic conditions enable access to various heterocycles,
such as morpholinone, thiomorpholinone, oxazolidin-4-one,
1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally re-
lated lactams, all bearing fully substituted α-positions. Broad
functional group tolerance was explored at the α-position in
the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful
products to readily access a number of enantioenriched compounds.
N,O-Heterocycles such as morpholine, oxazolidine, and
isoxazolidine are important pharmacophores in medicinal
chemistry (Figure 1).1−11 Notable morpholine-containing
In addition to a wide variety of biological activity, N,O-
heterocycles shown in Figure 2 are commonly used as synthetic
Figure 2. α-Tertiary and quaternary N,O-heterocycles.
Figure 1. Representative N,O-heterocyclic-containing pharmaceuticals
and natural products.
intermediates, which provide various hydroxy acid moieties
after acetal removal or N−O bond cleavage. Oxazolidin-4-ones
have been reported as good platforms to α-hydroxyacids.12 For
example, Ye et al.12a reported that the formal [3 + 2]
cycloaddition between ketenes and oxaziridines could be
applied in an enantioselective fashion to synthesize oxazoli-
din-4-one derivatives, which could be converted into the
corresponding α-hydroxy acids. 1,2-Oxazinan-3-ones have
pharmaceuticals include edivoxetine,2 an antidepressant and a
treatment for ADHD; linezolid,6 a synthetic antibiotic; and
gefitinib,5 an EGFR inhibitor used to treat certain breast, lung,
and other cancers. Five-membered isoxazolidinone is the core
structure of cycloserine,9 an antibiotic for the treatment of
tuberculosis. Quinocarcin,8 possessing an oxazolidine ring in
the 3,8-diazabicyclo[3.2.1]octane framework, has shown
remarkable antiproliferative activity against lymphocytic
leukemia. An antibiotic, FR-66979,10 isolated from Streptomyces
sandaensis No. 6897, contains a 1,2-oxazinane moiety.
Received: November 25, 2014
Revised: February 11, 2015
© XXXX American Chemical Society
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DOI: 10.1021/ol503425t
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Letter
proved to be excellent precursors to γ-hydroxy acid and γ-
butyrolactone derivatives.13
Our group has a sustained interest in the enantioselective
synthesis of α-quaternary carbonyl compounds,14−16 which
offers a novel solution for these challenging chiral centers in
natural product synthesis. Influenced by our results, the Lupton
group17a and the Shao group17b simultaneously reported that
carbazolones are suitable substrates under our allylic alkylation
conditions and applied the resulting chiral building blocks to
total syntheses of indole alkaloids. Significant work in our
laboratory has identified conditions for the enantioselective
allylic alkylation to provide α-quaternary lactams in exceptional
yields and enantioselectivities.14b As part of that endeavor, we
reported that 2-allyl-2-methylmorpholin-3-one 2a was obtained
in a similar manner in high yield (91% yield) and outstanding
enantioselectivity (99% ee). We sought to extend the substrate
scope to morpholine derivatives and postulated that a broadly
expanded array of chiral N,O-heterocyles might be readily
accessible using our palladium-catalyzed allylic alkylation.
Herein, we describe the enantioselective allylic alkylation of
heterocycles, including morpholin-3-one, thiomorpholine-3-
one, oxazolidin-4-one, 1,2-oxazepan-3-one, and 1,3-oxazinan-
4-one.18 Furthermore, the enantioenriched products obtained
were successfully converted into useful asymmetric building
blocks containing quaternary and tetrasubstituted tertiary chiral
centers.
We prepared a collection of racemic morpholinone substrates
1a−e19 and performed palladium-catalyzed decarboxylative
allylic alkylation with Pd2(dba)3 (5 mol %) and (S)-(CF3)3-t-
BuPHOX ligand20 (12.5 mol %, PHOX = phosphinooxazoline)
in a 0.033 M solution of toluene (Figure 3). Simple α-benzyl
substitution performed well in this chemistry; the desired 2-
benzyl α-tetrasubstituted morpholinone 2b was obtained in
95% yield and 99% ee. Gratifyingly, other functionalized
substrates (benzyl ether, methyl ester, nitrile) are well tolerated,
affording α-functionalized morpholinones 2c, 2d, and 2e in
uniformly excellent enantioenrichment (99% ee), although the
yield of 2d was moderate (60%). Having demonstrated a broad
functional group tolerance within the side chain, we explored
other ring sizes and frameworks. Replacement of oxygen with
sulfur gave thiomorpholinone 2f in good yield, but slightly
decreased enantioselectivity (79% yield, 86% ee). Like
morpholinone, benzomorpholinone is also a good substrate
class, delivering allylated product 2g in 76% yield and 95% ee.
Additionally, α-tetrasubstituted oxazolidin-4-one 2h is pro-
duced in 82% yield and 96% ee with higher temperature applied
(60 °C).21 Benzyloxazolinone 2i is also produced in good yield
and enantioselectivity.
With excellent results on α,α-dialkyl 2-oxa- and thia-linked
lactams in hand, we started to investigate allylic alkylation using
cyclic hydroxamic acid derivatives to obtain α-quaternary N,O-
heterocycles (Table 1). Isoxazolidin-3-one 3a (R = Bz), 3b (R
= Boc), and 3c (R = CO2Ph) produced the desired alkylated
compounds 4a−c in excellent yields (95−98%), but with
modest enantioselectivities (72−73% ee) (entries 1−3).
Benzoyl protected 1,2-oxazinan-3-one 3d underwent an
unexpected side reaction and produced only small amounts
of 4d (entry 4).24 Despite the low yield, the enantioselectivity
of 4d is still satisfactory (88% ee), which encouraged us to
identify an effective N-protecting group to circumvent the
undesired reaction. A bulky pivaloyl group somehow suppresses
the side reaction, but decreases the enantioselectivity (entry 5).
An electron-rich N-benzylated 3f was a poor substrate for
Figure 3. Substrate scope of α-tertiary heterocycles.a a Reaction
performed with 0.1 mmol of 1, 5 mol % of Pd2(dba)3, 12.5 mol % of
(S)-(CF3)3-t-BuPHOX at 0.033 M in toluene at 50 °C. b Determined
by chiral SFC analysis. c Reactions were performed on 1g, 1h, and 1i at
60 °C. d The ee of 2g was determined by chiral SFC analysis after Bz
removal (see Supporting Information). e Pd2(pmdba)3 (pmdba =
bis(4-methoxybenzylidene)acetone) was used instead of Pd2(dba)3.
f Absolute configuration was assigned by vibrational circular dichroism
(VCD) spectroscopy22 supported by theoretical calculations (see
Supporting Information). g Absolute stereochemistry assigned by
conversion into (−)-methyl 2-hydroxy-2-methylpent-4-enoate.23
decarboxylative alkylation (entry 6).25 Finally, we discovered
that carbamates 3g−i produced the desired products in good
yields (67−89%) and acceptable enantioselectivities (84−87%
ee) (entries 7−9), with little or none of the undesired side
reactivity observed. We were delighted to find that seven-
membered 3j is an excellent substrate in this class, furnishing 4j
in a good yield and excellent enantioselectivity (entry 10, 81%
yield, 93% ee).
As shown in Scheme 1, we have also demonstrated allylic
alkylation with 1,3-oxazinan-4-one 5 as an alternative β-hydroxy
acid synthon of 3a. To our delight, 5 was successfully converted
into 6 in 90% yield and 94% ee.
We anticipate that our newly developed heterocycles could
play important roles in medicinal agent discovery and also serve
as useful chiral building blocks. To demonstrate the value and
versatility of this new class of α-tetrasubstituted heterocycles,
we implemented a number of product transformations (Scheme
2). For example, removal of the benzoyl group followed by
reduction using LiAlH4 can readily convert morpholinone 2c
into N−H morpholine 7. Acid treatment of 2h in methanol
provided α-tertiary-hydroxy ester 8 in 71% yield without
erosion of enantiopurity.26 α-Quaternary δ-lactone 9 was
B
DOI: 10.1021/ol503425t
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
formations afford a variety of important structures such as
chiral hydroxy acid derivatives. Studies utilizing this method
toward the synthesis of complex natural products and other
bioactive small molecules are ongoing in our laboratory.
Table 1. Substrate Scope of α-Quaternary Cyclic
Hydroxamic Acid Derivatives
a
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Stoltz@caltech.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank NIH-NIGMS (R01GM080269 to
B.M.S. and R01GM075962 to K.N.H), Amgen, the Gordon and
Betty Moore Foundation, the Caltech Center for Catalysis and
Chemical Synthesis, and Caltech for financial support. Y.N.
thanks Toray Industries, Inc. for a postdoctoral fellowship. G.J.-
O. and K.N.H. used the Extreme Science and Engineering
Discovery Environment (XSEDE) supported by a grant (OCI-
1053575) along with the UCLA Institute of Digital Research
and Education (IDRE). The authors are grateful to Dr. Rina
Dukor (BioTools) for helpful discussions. The authors thank
Scott Virgil (Caltech) for instrumentation assistance and Dr.
Douglas C. Behenna (Caltech) and Mr. Beau Pritchett
(Caltech) for initial experimental results.
a
b
Reaction performed under the conditions of Figure 3 at 60 °C. All
c
reported yields are for isolated products. Enantiomeric excesses were
d
determined by chiral SFC analysis. Absolute configuration was
assigned by VCD spectroscopy22 supported by theoretical calculations
(see Supporting Information).
Scheme 1. Synthesis of 1,3-Oxazinan-4-one 6
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D
DOI: 10.1021/ol503425t
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