Sequential allylic C-H amination/vinylic C-H arylation: A strategy for unnatural amino acid synthesis from α-Olefins

Article abstract of DOI:10.1021/ol300063t

Tandem reaction sequences that selectively convert multiple C-H bonds of abundant hydrocarbon feedstocks to functionalized materials enable rapid buildup of molecular complexity in an economical way. A tandem C-H amination/vinylic C-H arylation reaction s

Full text of DOI:10.1021/ol300063t

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1386–1389
Sequential Allylic CÀH Amination/Vinylic
CÀH Arylation: A Strategy for Unnatural
Amino Acid Synthesis from r-Olefins
Chao Jiang,‡ Dustin J. Covell,‡ Antonia F. Stepan,† Mark S. Plummer,† and
M. Christina White*,‡
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana,
Illinois 61801, United States, and Pfizer Worldwide Research & Development, Eastern
Point Road, Groton, Connecticut 06340, United States
white@scs.uiuc.edu
Received January 13, 2012
ABSTRACT
Tandem reaction sequences that selectively convert multiple CÀH bonds of abundant hydrocarbon feedstocks to functionalized materials enable
rapid buildup of molecular complexity in an economical way. A tandem CÀH amination/vinylic CÀH arylation reaction sequence is described
under Pd(II)/sulfoxide-catalysis that furnishes a wide range of R- and β-homophenylalanine precursors from commodity R-olefins and readily
available aryl boronic acids. General routes to enantiopure amino acid esters and densely functionalized homophenylalanine derivatives are
demonstrated.
Selective methods for CÀH oxidation,1,2 amination,1,3
alkylation,1,4 and dehydrogenation1,5 make the direct in-
stallation of functional groups into preassembled hydro-
carbon frameworks possible. Such reactions enable
orthogonal routes to complex molecules from those that
rely upon CÀC bond forming reactions between preox-
idized fragments and provide opportunities to use simple
hydrocarbons as starting materials.2eÀg,n Of these, R-olefins
are among the most abundant and inexpensive feedstock
commodity chemicals. Methods that selectively function-
alize one or more of the three distinct types of CÀH bonds
present in R-olefins (i.e., aliphatic, allylic, and vinylic)
enable the rapid buildup of molecular complexity from
inert functional groups with minimal manipulations. Here-
in, we report a one-pot allylic CÀH amination/vinylic
CÀH arylation of R-olefins to furnish unnatural amino
† Pfizer Worldwide Research & Development.
‡ University of Illinois.
(1) General C;H oxidation, aminations, alkylations: (a) Muller, P.;
€
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Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 9032. (d) Delcamp, J. H.; White, M. C. J. Am.
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r
10.1021/ol300063t
Published on Web 02/24/2012
2012 American Chemical Society

acid precursors rapidly that has been achieved using
Pd(II)/sulfoxide-catalysis.
Scheme 1. CÀH Amination Route to Homophenylalaninesa
Within recent years, our laboratory has introduced elec-
trophilic Pd(II)/sulfoxide catalysis as a general platform
for allylic CÀH activation that enables direct and selective
allylic esterification,2aÀh amination,3bÀg alkylation4 and
dehydrogenation5 of R-olefins. Additionally, we have de-
monstrated that sulfoxide ligands promote highly selective
Pd(II)-mediated vinylic CÀH arylations (Heck-type
coupling) under analogous oxidative conditions.2d,6,7 Ex-
ploiting these parallel conditions, we invented a sequential,
one-pot Pd(II)-sulfoxide-catalyzed allylic esterification/
vinylic arylation of R-olefins (Scheme 1).2d We postulated
that analogous sequential reactions would be possible with
allylic CÀH amination reactions, thus facilitating a rapid
and diversifiable route to densely functionalized carbon
skeletons such as those found in R- and β-amino acids from
simple R-olefin starting materials. Herein, we report a one-
pot Pd(II)/sulfoxide-catalyzed allylic CÀH amination/
vinylic CÀH arylation that starts with commodity chemi-
cal 3-butenol to access a wide range of homophenylalanine
(hPhe) derivatives rapidly. Additionally, by switching to
4-pentenol, analogous β-amino acid precursors may be
obtained.
a PhBQ = phenyl-benzoquinone; BisSO ligand = 1,2 bis(phenyl-
sulfinyl)ethane (refs 3b and 3e).
enzyme inhibitors (“ACE inhibitors”) benezepril,8 enala-
pril,9 imidapril,10 lisinopril11 and temocapril.12 Although a
variety of chemical methods exist for the synthesis of hPhe
derivatives that include Suzuki coupling,13 diastereoselec-
tive Michael addition14 and asymmetric hydrogenation re-
actions,15 these known routes generally rely upon lengthy
reaction sequences from chiral pool materials and often
suffer limited scope. We herein report the use of readily
available, commercial R-olefins and arylboronic acids as
suitable starting materials for the rapid synthesis of a wide
range of unnatural homophenylalanine (hPhe) amino acids.
While itwas known that palladium bis-sulfoxidecatalyst
1 could separately catalyze both the desired allylic CÀH
amination and vinylic CÀH arylation reactions, it was un-
clear if: (1) such a sequence would proceed with high yields
without requiring additional Pd(II)/sulfoxide catalyst 1
loadings, and (2) allylic oxazolidinones would serve as
nonresonance directing groups to promote high regio- and
E:Z stereoselectivities for vinylic arylation. Palladium(II)-
Pd(0) catalytic cycles generally suffer from rapid catalyst
decomposition through Pd(0)-aggregation pathways be-
cause soft donor ligands (e.g., phosphines) that are typi-
cally used to prevent aggregation are incompatible with
oxidative conditions.16 It was therefore critical to minimize
reaction times for the first step of the proposed tandem
Unnatural homophenylalanine (hPhe) amino acids are
important building blocks for pharmaceutical research as
exemplified by the commercial angiotensin-converting
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Org. Lett., Vol. 14, No. 6, 2012
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sequence so that enough active palladium catalyst remain-
ed to promote the vinylic CÀH arylation. We had pre-
viously shown that by switching from N-tosyl- to more
acidic N-nosylcarbamate nucleophiles, reactivity for intra-
molecular allylic CÀH aminations could be significantly
enhanced.3e,g We were delighted to find that using 10 mol %
Pd(II)/sulfoxide catalyst 1 the N-nosylcarbamate substrate
2 reached complete conversion in 5 h versus incomplete
conversion (80%) in 72 h for the analogous N-tosylcarba-
mate. Subsequent addition of phenylboronic acid at
fragment coupling quantities (1.5 equiv), with no addi-
tional catalyst, afforded styryl-oxazolidinone 3 in good
yield (79%) and outstanding regio- and E:Z selectivities
(>20:1, Scheme 2).
Further exploration of scope revealed that a sequential
allylic CÀH amination/vinylic CÀH arylation reaction
could be realized using just 10 mol % 1 with N-nosylcar-
bamate 2 substrate and a wide range of arylboronic acids
to afford styryl-oxazolidinones in good yields (65À87%)
and outstanding regio- and E:Z selectivities (>20:1,
Scheme 2). Methyl- and methoxy substituted homopheny-
lalanine (hPhe) precursors could be accessed in consis-
tently high yield independent of the site of substitution on
the aromatic ring (compounds 3À8). Importantly, these
substituted hPhe derivatives are intermediates en route to
compounds found in metalloproteinase inhibitor (for
compounds 4 and 6)17 and ACE inhibitor programs (for
compound 8).18 This method also enabled the rapid synt-
hesis of fluorinated styryl-oxazolidinones 9À12. Structur-
ally diverse fluorinated compounds are valuable building
blocks for medicinal chemistry research;19 for example,
hPhe analogs that may be derived from compounds 9, 10,
11 have been used on β-secretase inhibitor programs,20 and
toprepare immunosuppressiveadjuncts.21 Inaddition, this
method allows access to novel hPhe compounds that have
not yet been reported, such as compounds derived from 12.
Functional groups that can be used as handles for
further diversification (compounds 13À15) are also toler-
ated, most notably the aryl chloride and bromide in com-
pounds13and 21(Scheme 5) whichwould be incompatible
with traditional Pd(0) based Heck methods. Additionally,
robust organotrifluoroborates can be employed as alterna-
tives to boronic acids22 in this reaction with the use of B(OH)3
as an activator (compound 9).6 Notably, the Pd/sulfoxide-
catalyzed allylic CÀH amination/vinylic CÀH arylation
reaction is operationally simple, proceeding under ambient
atmosphere with no precautions taken to exclude moisture.
We were further delighted to find that this tandem process
could be extended to our previously developed 1,3-amina-
tion system, thus enabling the synthesis of β-amino acids
through this same strategy (Scheme 3). Due to the higher
kinetic barrier for 6- versus 5-membered ring formation, the
amination step took 13 h (rather than 5 h) to reach complete
conversion. Key to maintaining good catalyst regeneration
under prolonged reaction times was the addition of cata-
lytic p-nitrobenzoic acid, which we have previously shown
to promote Pd(0) oxidation.3e Subsequent addition of 4-
formylphenylboronic acid, with no additional catalyst,
afforded styryl-oxazolidinone 17 in good yield (73%) and
outstanding regio- and E:Z selectivities (>20:1).
Scheme 2. Scope of the Sequential Allylic CÀH Amination/
Vinylic CÀH Arylation Reactiona
With the ability to access a variety of homophenylalanine
core structures efficiently through a novel CÀH amination
strategy, we next sought to establish a route to transform
the key oxazolidinones into the desired amino acid pro-
ducts in high enantiomeric excess (Scheme 4). Thus, the
nosyl group in 18 was first removed under mildly nucleo-
philic conditions with potassium thiophenolate (Scheme 4).
The olefin was then hydrogenated (H2, Pd/C), the amino
alcohol unmasked under basic conditions (LiOH), and the
amine protected to furnish intermediate 19 in 76% yield
over 4 steps. Pyridinium dichromate (PDC) oxidation of
the primary alcohol to the acid, followed by Boc removal
(17) Wallberg, H; Xu, M. H.; Lin, G.-Q.; Lei, X. S.; Sun, P.; Parkes,
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a Yields reported are isolated, and the average of at least 2 independent
runs. All products were isolated as a single regio- and olefin E:Z isomer.
1388
Org. Lett., Vol. 14, No. 6, 2012

Scheme 3. Sequential Allylic CÀH Amination/Vinylic CÀH
Arylation Reaction toward β-Amino Acid Motifa
Scheme 5. Access to Functionalized Homophenylalanine Deriv-
atives through Sharpless Asymmetric Dihydroxylation
a Additives: p-nitrobenzoic acid (10 mol %), BisSO ligand (5 mol %).
Scheme 4. Synthesis of Enantiopure Homophenylalanine Deriv-
ative
four new bonds, selectively introducing new functional
groups at three of the four carbons of 3-butenol. The
ease with which densely functionalized building blocks
are constructed from robust, commercial hydrocarbons
highlights the power of selective CÀH functionalization
methods.
In conclusion, we have demonstrated a sequential CÀH
amination/vinylic CÀH arylation reaction proceeding
via Pd(II)/sulfoxide catalysis that transforms commodity
R-olefins into R-andβ-homophenylalanine precursors. This
work demonstrates the power of sequential, selective CÀH
functionalization methods to incorporate functional group
handles rapidly onto simple and inexpensive hydrocarbon
feedstocks, thereby enabling their use as starting materials
for medicinally important compounds.
Acknowledgment. M.C.W. and C.J. are grateful to Pfizer
for a grant to study the synthesis and modification of natural
products and medicinal compounds. M.C.W. and D.J.C. are
grateful to the NIH/NIGMS (grant no. GM076153) for
support in the discovery and development of Pd/bis-sulfox-
ide-catalyzed allylic CÀH aminations. M.C.W. is grateful to
Aldrich Chemical Co. for generous gifts of commercial bis-
(sulfoxide)/Pd(OAc)2 catalyst 1. C.J. is currently a senior
research scientist at Anichem Inc., and D.J.C. is currently a
postdoctoral fellow at the Center for Neurodegenerative Dis-
ease Research, University of Pennsylvania School of Medicine.
with trifluoroacetic acid (TFA) and formation of the isopro-
pyl ester afforded 20 (56% over 3 steps), a suitable precursor
for subsequent enzymatic resolution. Lipase PS mediated
kinetic resolution23 of racemate (()-20 afforded enantiopure
aminoester (À)-20 in a total of 10 steps and 16% overall yield
from the commercially available R-olefin 3-butenol.
While this route provides an efficient means of accessing
homophenylalanine derivatives, we recognized that addi-
tional structural complexity could be gained by elaborat-
ing the internal E-olefin functional groups generated via
the vinylic CÀH arylation. We were pleased tofind that the
Sharpless asymmetric dihydroxylation (SAD)24 could be
used to this end (Scheme 5). In fact, SAD of oxazolidinone
21 followed by protection of the crude mixture of diols
afforded the two diastereomers (À)-23 and (À)-24 in 39%
and 42% isolated yield of each in >99% ee. The absolute
stereochemistry of (À)-23 was confirmed by X-ray crystal-
lography (see Supporting Information). In only four steps
from commercial starting material, we are able to forge
Supporting Information Available. 1H and 13C NMR,
IR and HRMS data and experimental procedures for
compounds 2À24. X-ray data for compound (À)-23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Note Added after ASAP Publication. The version pub-
lished ASAP on February 24, 2012 contained errors in
Scheme 5 and in the Supporting Information. The correct
version reposted on February 28, 2012.
(23) Theil, F. Chem. Rev. 1995, 95, 2203.
(24) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
The authors declare no competing financial interest.
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