Asymmetric synthesis of anti -β-amino-α-hydroxy esters via dynamic kinetic resolution of β-amino-α-keto esters

Article abstract of DOI:10.1021/ol4009206

A method for the asymmetric synthesis of enantioenriched anti-α-hydroxy-β-amino acid derivatives by enantioconvergent reduction of the corresponding racemic α-keto esters is presented. The requisite α-keto esters are prepared via Mannich addition of ethyl

Full text of DOI:10.1021/ol4009206

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Synthesis of
anti-β-Amino-r-Hydroxy Esters
via Dynamic Kinetic Resolution
of β‑Amino-r-Keto Esters
C. Guy Goodman, Dung T. Do, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina, 27599-3250, United States
jsj@unc.edu
Received April 3, 2013
ABSTRACT
A method for the asymmetric synthesis of enantioenriched anti-r-hydroxy-β-amino acid derivatives by enantioconvergent reduction of the
corresponding racemic r-keto esters is presented. The requisite r-keto esters are prepared via Mannich addition of ethyl diazoacetate to imines
followed by oxidation of the diazo group with Oxone. Implementation of a recently developed dynamic kinetic resolution of β-substituted-r-keto
esters via Ru(II)-catalyzed asymmetric transfer hydrogenation provides the title motif in routinely high diastereo- and enantioselectivity.
The presence of R-hydroxy-β-amino acids in high value
compounds is well-documented,1 and as a consequence,
methods that provide access to this structural motif are
in continual demand. Numerous methods of accessing
enantioenriched forms of these products have been re-
ported. Included among them are transformations that
use alkene derivatives such as nucleophilic addition to
chiral epoxides,2 oxyaminations of alkenes using Sharpless
conditions,3 and asymmetric hydrosilylation of R-acetoxy-
β-enamino esters.4 In addition, a number of methods
exist to access such substrates from nonalkene starting
materials. These include oxidation and subsequent reduc-
tion of chiral β-amino-R-diazo esters,5 asymmetric Henry
reactions with subsequent nitro-group reduction,6 asym-
metric “glycolate” Mannich reactions,7 and β-amination
of R-keto esters,8 among others.9
(4) Jiang, Y.; Chen, X.; Zheng, Y.; Xue, Z.; Shu, C.; Yuan, W.;
Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 7304–7307.
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29, 100–101. (d) Saiki, I.; Murata, J.; Watanabe, K.; Fujii, H.; Abe, F.;
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reviews, see: (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25,
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Juaristi, E., Soloshonok, V., Eds.; Wiley: Hoboken, NJ, 2005. (c) Sleebs,
B. E.; Nguyen, T. V.; Hughes, A. B. Org. Prep. Proced. Int. 2009, 41,
429–478.
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r
10.1021/ol4009206
XXXX American Chemical Society

In assessing various methods, we noticed that few meth-
ods provided products with easily manipulated protecting
groups while simultaneously setting both stereocenters in
a single transformation. We believed that these synthetic
issues might be addressable using chemistry previously
developed in our laboratories. Herein we describe the
application of a recently discovered Ru-catalyzed dy-
namic kinetic resolution-asymmetric transfer hydrogenation
(DKR-ATH) that provides facile access to enantioenriched
β-amino-R-hydroxy esters.
into in situ formed imines (Scheme 2). The requisite
carbamates 3a and 3b were obtained in low and variable
yields.16
Scheme 2. Aza-benzoin Addition Using Ethyl Glyoxylate
Our group has shown that various β-substituted-R-keto
esters are reduced with high stereoselectivity under DKR-
ATH conditions.10 These examples provided the basis
of a hypothesis that β-amino-R-hydroxy-esters could be
accessed from racemic β-amino-R-keto esters via dynamic
kinetic resolution (Scheme 1). Such reactions are well-
established for the isomeric R-amino-β-keto esters and
in fact comprise prototypical examples of DKR,11 but
extensions to the β-amino-R-keto esters remain limited to
enzymatic catalysis.12
Although inefficient at the present level of optimization,
this method provided us with sufficient amounts of mate-
rial with which to examine the DKR-ATH for proof
of concept. Guided by our previous work,10 we began by
screening catalyst complexes 5ꢀ7 which arise from diaryl-
ethylene diamine monosulfonamide ligands and [RuCl2-
(p-cymene)]2.17 The use of complex 5 afforded complete
anti diastereoselection18 but moderate enantioselectivity,
necessitating a switch to complexes 6 and 7, both of which
bear a terphenyl sulfonamide. Complex 6 provided high
Scheme 1. Proposed ATH-DKR of β-Amino-R-keto Esters
Table 1. Optimization of ATH-DKR for β-Amino-R-keto Esters
In principle, the most atom-efficient route toward the
requisite β-amino-R-keto esters would be to use a glyoxy-
late aza-benzoin reaction mediated by an N-heterocyclic
carbene (NHC) catalyst. This umpolung reactivity has
precedent,13 but it has not been demonstrated using glyoxy-
late as the nucleophile. Starting from readily accessed
amido-sulfones 114 and using the triazolium carbene de-
rived from 2,15 we observed addition of ethyl glyoxylate
(10) (a) Steward, K. M.; Gentry, E. C.; Johnson, J. S. J. Am. Chem. Soc.
2012, 134, 7329–7332. (b) Steward, K. M.; Corbett, M. T.; Goodman,
C. G.; Johnson, J. S. J. Am. Chem. Soc. 2012, 134, 20197–20206.
(c) Corbett, M. T.; Johnson, J. S. J. Am. Chem. Soc. 2013, 135, 594–597.
(11) Forageneralreview, see: (a)Hamada, Y.Chem. Pharm. Bull. 2012,
60, 1–20. For specific examples, see: (b) Noyori, R.; Ikeda, T.; Ohkuma,
T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, A. N.;
Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989,
temp
yieldb
(%)
€
111, 9134–9135. (c) Mordant, C.; Dunkelmann, P.; Ratovelomanana-
entry
PG
cat.
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(°C)
drc
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K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew. Chem., Int. Ed. 2004, 43,
882–884. (e) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Tetrahedron:
Asymmetry 2008, 19, 2816–2828. (f) Liu, Z.; Schults, C. S.; Sherwood,
C. A.; Krska, S.; Dormer, P. G.; Desmond, R.; Lee, C.; Sherer, E. C.;
Shpungin, J.; Cuff, J.; Xu, F. Tetrahedron Lett. 2011, 52, 1685–1688.
1
2
3
4
5
6
7
Boc
Boc
Cbz
Boc
Boc
Boc
Cbz
5
6
6
6
7
7
7
DMSO
DMSO
DMSO
DMF
23
23
23
23
23
0
59
67
77
65
73
62
71
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
77:23
94:6
97:3
97:3
99:1
98:2
94:6
€
(g) Seashore-Ludlow, B.; Villo, P.; Hacker, C.; Somfai, P. Org. Lett.
DMF
2010, 12, 5274–5277.
DMF
(12) Patel, R. N.; Banerjee, A.; Howell, J. M.; McNamee, C. G.;
Brozozowski, D.; Mirfakhrae, D.; Nanduri, V.; Thottathil, J. K.; Szarka,
L. J. Tetrahedron: Asymmetry 1993, 4, 2069–2084.
(13) (a) Murry, J. A.;Frantz, D. E.;Soheili, A.; Tillyer, R.;Grabowski,
E. J. J.;Reider, P.J. J. Am. Chem. Soc. 2001, 123, 9696–9697. (b) DiRocco,
D. A; Rovis, T. Angew. Chem., Int. Ed. 2012, 51, 5904–5906.
(14) Amido sulfones were synthesized according to known proce-
dures. For full details, please consult the Supporting Information.
(15) Vora, H. U.; Lathrop, S. P.; Reynolds, N. T.; Kerr, M. S.; Read
de Alaniz, J.; Rovis, T. Org. Synth. 2010, 87, 350–361.
DMF
23
a Reaction optimization took place using a crude mixture of com-
pounds obtained via the aza-benzoin reaction which included the desired
starting material (cf. Scheme 2). b Isolated yield calculated based on the
assumption of pure R-keto ester starting material; actual yields are
probably somewhat higher. c Determined by 1H NMR analysis of crude
reaction mixture. d Determined by chiral HPLC or SFC analysis.
B
Org. Lett., Vol. XX, No. XX, XXXX

Figure 1. Mannich addition of ethyl diazoacetate. The imine 1
was generated from the corresponding amido sulfone (see the
Supporting Information for details). Isolated yields over the two
steps are reported. For 8o, the Mannich addition was conducted
at ꢀ40 °C.
stereoselectivity for both Cbz- and Boc-protected amines
with Cbz providing slightly higher enantioselectivity
(Table 1, entries 2 and 3). When the solvent was changed
from DMSO to DMF, an increase in selectivity for the Boc
protected substrate was observed (entry 4).
Searching for higher selectivity, we switched to complex 7,
which provided 4a in 99:1 er (Table 1, entry 5). We tested
this same catalyst at 0 °C in an attempt to improve the yield
by subverting retro-Mannich reactivity,19 but this change
Figure 2. Substrate scope for the ATH-DKR. Isolated yields are
reported. The dr’s were determined by 1H NMR analysis of crude
reaction mixture. The er’s were determined by chiral HPLC or
SFC analysis. Recrystallized er values are in parentheses.
(16) The R-keto esters are not stable to column chromatography.
(17) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 7562–7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–
2522. (c) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102.
(18) For previous examples of access to anti-β-amino-R-hydroxy esters:
(a) Fringuelli, F.; Pizzo, F.; Rucci, M.; Vaccaro, L. J. Org. Chem. 2003, 68,
7041–7045. (b) Trost, B. M.; Malhotra, S.; Ellerbrock, P. Org. Lett. 2013,
resulted in a decreased yield. The brief optimization study
revealed that high levels of enantioselectivity can be ob-
tained with two convenient carbamate protecting groups
through judicious catalyst selection. Due to the superior
enantioselection provided by the Boc-protected amine, it
was selected as the protecting group for further studies.
With proof of concept for the DKR-ATH established,
attention returned to improving the synthesis of the re-
quisite β-amino-R-keto esters. A survey of the literature
revealed conditions reported by Wang and coworkers,
ꢀ
~
15, 440–443. (c) Prevost, S.; Gauthier, S.; Cano de Andrade, M. C.;
Mordant, C.; Touati, A. R.; Lesot, P.; Savignac, P.; Ayad, T.; Phansavath,
^
P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahedron: Asymmetry 2010,
21, 1436–1446. (d) Sepe, V.; D’Auria, M. V.; Bifulco, G.; Ummarino, R.;
Zampella, A. Tetrahedron 2010, 66, 7520–7526.
(19) Retro-Mannich products were observed in the crude reaction
mixture via 1H NMR spectroscopy.
Org. Lett., Vol. XX, No. XX, XXXX
C

which proved effective for generation of β-sulfonamido-
R-keto esters.20 This route employs N-sulfonyl imines in
conjunction with ethyl diazoacetate to achieve a Mannich
addition.21 On the basis of precedent, subsequent oxidation
wasexpectedtofurnishR-keto esters primed for reduction.5,20
This general strategy has previously been exploited to access
the title compounds via asymmetric Mannich addition
followed by diastereoselective reduction.5 Our hope was to
provide a method in which both stereocenters would be set
during the reduction from a racemic starting material.
The Mannich addition (Figure 1) was conducted at rt for
all aromatic substituted imines and at ꢀ40 °C for aliphatic
substrates to subvert enamine formation. With R-diazo
esters in hand, we then turned to a two-step oxidationꢀ
reduction sequence.
We employed previously described conditions for the
oxidation of R-diazo esters to their corresponding R-keto
esters using commercially available Oxone.5 The unpur-
ified R-keto esters were sufficiently pure to be used directly
in the optimized reduction conditions: exposure of β-amino-
R-keto esters (()-8 to Ru-complex 7 and HCO2H/Et3N
provided products 4aꢀo (Figure 2).
Scheme 3. Determination of Product Stereochemistry
and a single recrystallization could regularly provide er
values above 99.5:0.5 (parenthetical values in Figure 2).
To determine the stereochemistry imparted by the
DKR-ATH, (þ)-4b was independently synthesized from
the known enantioenriched epoxide 9 (Scheme 3A).22 The
stereochemistry was then assigned based on comparison of
this product and (ꢀ)-4b (prepared by DKR-ATH, Table 1)
using 1H NMR and chiral SFC analysis. Lastly, the utility
of Boc and Cbz protecting groups was demonstrated by
the deprotection of 4a under acidic conditions and 4b with
trimethylsilyl iodide, both of which result in free amine
(ꢀ)-10 (Scheme 3B).
Our substrate scope sought to probe both electronic and
steric controls for this reaction system. Heteroaromatic
(4lꢀ4n) as well as electron-rich (4f, 4h) and -poor (4g)
aromatic systems all provide a high diastereomeric ratio
(dr) and enantioselectivity. Additionally, 4j showed only
reduction of the R-ketone leaving the alkene intact,
although the reaction proceeded with negligible diaste-
reoselectivity. Products 4cꢀ4e showed that while steric
encumbrance does affect the dr, enantioselectivity remains
high. In testing 8o for the application of this method
toward aliphatic β-substitution, we observed full reduction
of the ketone, albeit with low stereoselectivity. As was
already noted, this reaction is tolerant to different amine
protecting groups (4a and 4b) providing further flexibility
in substrate design. The resultant alcohols are often solids,
Racemic β-amino-R-keto esters can be employed as an
entry point for enantiomerically enriched anti-β-amino-R-
hydroxy esters via DKR-ATH. The present work expands
the product types that are accessible using terphenyl-based
catalysts 6 and 7, establishes both of the product’s stereo-
centers in a single step, and delivers the amine in a
conveniently configured form.
Acknowledgment. The project described was supported
by Award No. R01 GM084927 from the National Institute
of General Medical Sciences. D.T.D. acknowledges a
Vietnam Education Foundation Fellowship.
Supporting Information Available. Experimental proce-
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Zhao, Y.; Jiang, N.; Chen, S.; Peng, C.; Zhang, X.; Zou, Y.;
Zhang, S.; Wang, J. Tetrahedron 2005, 61, 6546–6552.
(21) For all experimental details see the Supporting Information.
(22) Wang, B.; Wu, X.-Y.; Wong, O. A.; Nettles, B.; Zhao, M. X.;
Chen, D.; Shi, Y. J. Org. Chem. 2009, 74, 3986–3989.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX