Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands

Article abstract of DOI:10.1016/j.tet.2019.01.018

Attempts to perform the OsO₄-catalyzed enantioselective base-free aminohydroxylation of β,β-disubstituted enoates are described. Low yields and racemic products were obtained in the presence of standard chiral ligands, suggesting the occurrence

Full text of DOI:10.1016/j.tet.2019.01.018

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Insights into base-free OsO4-catalyzed aminohydroxylations
employing chiral ligands
Joseph M. Cardon, James C. Coombs, Daniel H. Ess, Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempts to perform the OsO4-catalyzed enantioselective base-free aminohydroxylation of b,b-disub-
Received 13 November 2018
Received in revised form
5 January 2019
Accepted 9 January 2019
Available online xxx
stituted enoates are described. Low yields and racemic products were obtained in the presence of
standard chiral ligands, suggesting the occurrence of a “Second Cycle” process due to slow hydrolysis of
the amino alcohol product from the Os metal center. Support for this hypothesis was provided by the
slightly improved enantioselectivity (60:40 er) obtained with an amino alcohol ligand. Based on density
functional theory calculations, it is proposed that the lack of significant enantioselectivity is due to a low-
energy (3 þ 2) oxo/imido cycloaddition transition state without the chiral ligand in the Second Cycle that
outcompetes protonolysis in the First Cycle.
Keywords:
Aminohydroxylation
Osmium tetroxide
© 2019 Elsevier Ltd. All rights reserved.
b
-Hydroxy amino acids
Enantioselective reaction
Density functional theory
1. Introduction
components of several important bioactive peptide natural prod-
ucts [8e12]. Prompted by our interest in synthesizing the anti-
The Os-catalyzed aminohydroxylation reaction [1] provides a
direct route to valuable vicinal amino alcohols [2] from simple and
abundant alkenes. The discovery of the Sharpless asymmetric
aminohydroxylation (SAA) [3] rendered this process enantiose-
lective, greatly increasing its utility in the synthesis of natural
products and potential therapeutic agents. However, the SAA is
primarily limited to mono- or disubstituted alkenes, can sometimes
deliver modest regioselectivity, and requires the cumbersome in
situ preparation of relatively unstable N-halocarbamates [4]. In
2011, Luxenburger and co-workers introduced a convenient base-
free aminohydroxylation procedure that replaced N-hal-
ocarbamates with more robust p-chlorobenzoyloxycarbamates as
nitrogen source reagents [5]. We subsequently found that a modi-
fication of the Luxenburger protocol enabled highly regioselective
aminohydroxylations of several trisubstituted and 1,1-disubstituted
alkenes, producing racemic amino alcohols in the absence of a
chiral ligand [6]. Enoate substrates were transformed into racemic
cancer peptide yaku'amide A (1, Fig. 1) [12,13], we recognized that
an enantioselective version of the base-free aminohydroxylation
would provide a direct and powerful means of accessing b-tert-
hydroxy amino acids. Luxenburger and co-workers reported suc-
cessful enantioselective aminohydroxylations of cinnamates [5],
but our attempts with an allylic alcohol substrate [6] and the efforts
of McLeod and co-workers using styrene [14] were fruitless. Puz-
zled by these inconsistencies, we initiated an investigation of the
enantioselective synthesis of b-tert-hydroxy amino acids utilizing
the base-free aminohydroxylation protocol. Herein, we report the
results of our study, including calculations that shed some light on
the mechanism of this process.
2. Results and discussion
We began by surveying the base-free asymmetric amino-
hydroxylation (AA) of ethyl 3,3-dimethylacrylate (2, Table 1) using
standard ligands that have been employed in SAA and Sharpless
asymmetric dihydroxylation (SAD) reactions. The product of this
b
-hydroxy amino acids, which could be converted into
droamino acids via stereospecific anti dehydrations [7].
-tert-Hydroxy amino acids such as -OHVal and
a
,b
-dehy-
b
b
b-OHIle are
transformation, b-OHVal derivative 3, is a key building block for the
total synthesis of 1. AA reactions utilizing the dimeric cinchona
alkaloid ligands (DHQD)2PHAL and (DHQD)2PYR were somewhat
sluggish, requiring 3e4 days to proceed to completion and afford-
ing moderate yields of 3 as a racemic mixture (Table 1, Entries 1 and
* Corresponding author.
E-mail address: scastle@chem.byu.edu (S.L. Castle).
https://doi.org/10.1016/j.tet.2019.01.018
0040-4020/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: J.M. Cardon et al., Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands, Tetrahedron,
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J.M. Cardon et al. / Tetrahedron xxx (xxxx) xxx
Fig. 1. Yaku'amide A (1), with b-hydroxy amino acids shown in red.
Table 1
Attempted AA Reactions with Sharpless Ligands.
Scheme 1. First and Second Cycles of the SAA reaction.
Entry
Ligand
Time (h)
Yield (%)a
erb
cycle dihydroxylations and aminohydroxylations, presumably due
to their ability to chelate and remain attached to the Os metal
center for the duration of the reaction [18]. Accordingly, we eval-
uated a selection of amino alcohols in the base-free amino-
hydroxylation of 2 (Table 2). We were disappointed to find that
prototypical second-cycle ligand N-Ts-Thr furnished 3 in moderate
yield as a racemic mixture (Entry 1). Dihydroquinidine (DHQD), the
amino alcohol building block for the SAD ligands, also delivered
racemic product (Entry 2). Interestingly, the related Cinchona
alkaloid derivative dihydrocinchonidine (DHCD) afforded scalemic
3 in low yield and 60:40 er (Entry 3). Unfortunately, attempts to
optimize this result were not fruitful.
To directly evaluate the possibility of the Second Cycle versus
the First Cycle, we executed density functional theory (DFT) cal-
culations using the M06-L/6-31þG(d,p)[LANL2DZ only for Os] level
of theory [19]. All structures were optimized in the Gaussian 09 [20]
program, and confirmed as minima or transition-state structures by
normal-mode vibrational frequency analysis. The SMD continuum
1
2
3
4
5
(DHQD)2PHAL
(DHQD)2PYR
DHQD-CLB
DHQD-MEQ
DHQD-PHN
72
96
120
120
70
54
66
66
64
28
50:50
50:50
50:50
50:50
50:50
a
Isolated yield.
b
Determined by chiral HPLC (Chiralcel OD-H, 90:10 hexanes/i-PrOH, 1.0 mL/min).
2). Suspecting that the combination of a trisubstituted alkene
substrate and a large nitrogen source reagent (CbzeOMs) might
require a smaller ligand, we evaluated the monomeric cinchona
alkaloid ligands DHQD-CLB [15], DHQD-MEQ [16], and DHQD-PHN
[16]. Unfortunately, reactions employing these ligands also deliv-
ered racemic product (Table 1, Entries 3e5). McLeod and co-
workers have suggested that the generation of 1 equiv of sulfonic
acid during the base-free aminohydroxylation reaction can be
problematic [14], as a higher pH is reportedly key to obtaining
useful enantioselectivities in SAA and SAD reactions [17]. Accord-
ingly, we attempted the AA with DHQD-MEQ in the presence of a
pH 7 buffer. However, a complex mixture was obtained. Performing
the reaction under weakly basic conditions yielded copious
amounts of benzyl carbamate (CbzNH2), which was presumably
derived from hydrolysis of an osmium imido intermediate.
At this point, we wondered if the base-free AA reaction was
proceeding through the “Second Cycle” described by Sharpless,
Fokin, and co-workers [18]. In the “First Cycle” of amino-
hydroxylation, the alkene substrate undergoes addition to osmium
imido complex A, delivering B in a ligand-accelerated process
(Scheme 1). After oxidation of B by the nitrogen source reagent to
afford osmium imido complex C, hydrolysis releases the imino
alcohol product and regenerates A. In cases where the rate of hy-
drolysis (r1) is slow, C can enter the Second Cycle by undergoing
addition of a second alkene molecule, yielding complex D. In
contrast to the First Cycle, the Second Cycle is characterized by (1)
no ligand acceleration, (2) the absence of ligand from the Os
complex during the addition step, and (3) racemic products. Pre-
sumably, the lack of base in our reactions could result in a slowing
of the hydrolysis step, thereby shifting the reaction into the Second
Cycle.
Table 2
AA Reactions with Amino Alcohol Ligands.
Entry
Ligand
Time (h)
Yield (%)a
erb
1
2
3
N-Ts-Thr
DHQD
DHCD
93
66
100
52
72
31
50:50
50:50
60:40
Sharpless, Fokin, and co-workers found that chiral amino
alcohol ligands could effectively mediate enantioselective second-
a
Isolated yield.
b
Determined by chiral HPLC (Chiralcel OD-H, 90:10 hexanes/i-PrOH, 1.0 mL/min).
Please cite this article as: J.M. Cardon et al., Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands, Tetrahedron,
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J.M. Cardon et al. / Tetrahedron xxx (xxxx) xxx
3
solvent model was used for acetonitrile [21]. Electronic energies
were calculated with the def2-TZVP basis set [22], and reported free
energies correspond to M06-L/def2-TZVP//M06-L/6-31**[LANL2DZ
for Os only]. Extensive conformational evaluation was performed,
including consideration of all oxo/imido ligand coordination pat-
terns, and all reported values correspond to the lowest-energy
structures identified. We modeled the imido Cbz group as an
imido methyl carbamate. The alkene substrate was modeled as
methyl 3,3-dimethylacrylate instead of the ethyl ester 2.
One possible branching point in determining whether the First
Cycle or Second Cycle is followed during catalysis involves inter-
mediate C (Scheme 1). We considered four major pathways that
could diverge from this species: (a) Os-alkoxide water hydrolysis,
(b) Os-amido water hydrolysis, (c) cis-oxo (3 þ 2) alkene cycload-
dition, and (d) cis-oxo/imido (3 þ 2) cycloaddition. The transition-
state structures and energies are reported in Scheme 2 and Fig. 2.
Pathway (a) begins with water coordination to the 5-coordinate
Os complex C-1, which is ~10 kcal/mol endergonic, followed by
proton transfer. The D
Gz value for this proton transfer is 32.2 kcal/
mol (TSa, Scheme 2 and Fig. 2) using a single water molecule. While
this protonolysis is not viable, as expected, the more basic amido
moiety is more easily protonated. The
D
Gz value for the proton
transfer in pathway (b) is only 22.5 kcal/mol (TSb). While this
barrier might suggest the feasibility of the First Cycle, (3 þ 2)
cycloaddition is lower in energy. Cis-oxo (3 þ 2) addition has a
D
Gz
Fig. 2. Transition-state structures for protonolysis and cycloaddition pathways from
intermediate C-1.
value of 20.8 kcal/mol through TSc. The (3 þ 2) oxo/imido cyclo-
addition pathway involving TSd leading to an intermediate analo-
gous to D in Scheme 1 is the lowest in Gibbs free energy, with a D
Gz
value of 14.9 kcal/mol. This transition state is 5.9 kcal/mol lower in
energy than the transition state of the unobserved dihydroxylation
pathway and 7.6 kcal/mol lower than the transition state of the
lowest-energy hydrolysis pathway. While these calculations sug-
gest that the reactivity of intermediate C provides the key
branching point towards the Second Cycle, we did not examine the
entire catalytic cycle. We also did not explore water-assisted proton
transfer since the entropy penalty for involvement of a second
water in 8:1 CH3CNeH2O is difficult to model correctly.
3. Conclusions
We investigated the OsO4-catalyzed enantioselective base-free
aminohydroxylation as a method of constructing
amino acids such as -OHVal and -OHIle. Aminohydroxylations
b-tert-hydroxy
b
b
conducted in the presence of typical SAA ligands were sluggish and
afforded racemic products. We suspected that the reactions might
be proceeding through the Second Cycle, wherein hydrolysis of the
amino alcohol adduct from the Os catalyst is slower than addition
of a second alkene substrate. This hypothesis was supported by the
fact that a chiral amino alcohol ligand afforded some improvement
in enantioselectivity. DFT calculations indicated that the Second
Cycle is kinetically preferred over the First Cycle under the base-
free reaction conditions. It is currently unclear whether the low
enantioselectivity observed with DHCD is due to very small energy
differences between the two diastereomeric (3 þ 2) transition
states involving the chiral ligand or to competition between an
enantioselective Second Cycle pathway involving the chiral ligand
and a racemic pathway in which the ligand is not bound to the
metal. Although these studies have not yet produced a viable
enantioselective synthesis of b-tert-hydroxy amino acids, it is our
hope that the observations detailed herein will prompt a renewed
focus on the development of more effective chiral ligands for base-
free aminohydroxylations that utilize the Second Cycle. The con-
venience of the base-free aminohydroxylation protocol, its
compatibility with trisubstituted alkenes, and the utility of the b-
hydroxy amino acids accessible via this process would render such
ligands highly useful to the organic synthesis community.
4. Experimental section
General experimental details. All reagents and solvents were
purchased from commercial vendors and used without purification.
Flash chromatography was carried out using 60e230 mesh silica
gel. 1H NMR spectra were obtained on a 500 MHz spectrometer
with chloroform (7.27 ppm) as internal reference. 13C NMR spectra
Scheme 2. Transition-state structures and free energies comparing water proton
transfer pathways and (3 þ 2) cycloaddition pathways from intermediate C-1. (kcal/
mol).
Please cite this article as: J.M. Cardon et al., Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands, Tetrahedron,
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J.M. Cardon et al. / Tetrahedron xxx (xxxx) xxx
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OsO4 (4 wt % solution in H2O, 62
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m
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.01.018.
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Please cite this article as: J.M. Cardon et al., Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands, Tetrahedron,
https://doi.org/10.1016/j.tet.2019.01.018