Asymmetric Synthesis of β-Amino Amides by Catalytic Enantioconvergent 2-Aza-Cope Rearrangement

Article abstract of DOI:10.1021/jacs.5b09593

Dynamic kinetic resolutions of α-stereogenic-β-formyl amides in asymmetric 2-aza-Cope rearrangements are described. Chiral phosphoric acids catalyze this rare example of a non-hydrogenative DKR of a β-oxo acid derivative. The [3,3]-rearrangement occurs with high diastereo- and enantiocontrol, forming β-imino amides that can be deprotected to the primary β-amino amide or reduced to the corresponding diamine.

Full text of DOI:10.1021/jacs.5b09593

Communication
pubs.acs.org/JACS
Asymmetric Synthesis of β‑Amino Amides by Catalytic
Enantioconvergent 2‑Aza-Cope Rearrangement
C. Guy Goodman and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
scarce.4,5 Toward the advancement of this latter process, this
ABSTRACT: Dynamic kinetic resolutions of α-stereo-
genic-β-formyl amides in asymmetric 2-aza-Cope rear-
rangements are described. Chiral phosphoric acids catalyze
this rare example of a non-hydrogenative DKR of a β-oxo
acid derivative. The [3,3]-rearrangement occurs with high
diastereo- and enantiocontrol, forming β-imino amides
that can be deprotected to the primary β-amino amide or
reduced to the corresponding diamine.
communication describes enantioconvergent and diastereose-
lective aza-Cope rearrangements of racemic β-formyl amides
for the generation of new β-amino acid derivatives.6 The
reaction is catalyzed by a chiral organic acid and concurrently
establishes new C−N and C−C bonds and vicinal stereogenic
centers (Scheme 1b).
While catalytic asymmetric sigmatropic rearrangements are
well-established,7 examples of enantioselective 2-aza-Cope
rearrangements are comparatively rare,8 and the 2-aza-Cope
reaction as a DKR process has only been demonstrated
utilizing stereochemically defined aminoallyl reagents.9 Chiral
acid catalyzed aza-allylations of simple aldehydes have been
reported from the laboratories of Rueping and Wulff, and this
body of work provided the mechanistic framework for our
experimental plan.8 Our initial investigations were guided by
our recent successes using α-keto ester ( )-1 in stereo-
convergent reactions.10 In combination with allyl amine 2a
under chiral phosphoric acid catalysis,11 productive reactivity
was observed, but we were unable to achieve any promising
diastereo- or enantioselectivity (Scheme 2a).12 A racemization
study of enantioenriched 1 revealed that under the buffered
reaction conditions racemization via tautomerization was
slower than the rate of sigmatropic rearrangement.13 Due to
the inability of 1 to achieve kinetically useful enantiomeriza-
tion, we switched to β-formyl ester 4, which we hypothesized
would favor enamine formation relative to 1, thereby
enhancing the rate of enantiomer interconversion. Unfortu-
nately, the derived enamine 5 was impervious to [3,3]-
rearrangement under any conditions that could be rendered
catalytic (Scheme 2b), a circumstance we attribute to a
debilitating thermodynamic preference for the unreactive
enamine relative to the needed iminium ion 5·H+.14
Considering our inadvertent overcorrection, we speculated
that replacing the ester with a more sterically demanding
dialkyl amide might provide a proper balance by destabilizing
the enamine tautomer through A(1,3) strain15 while still
maintaining a faster rate of enantiomerization than was
observed with α-keto ester 1.16
he hydrogenative dynamic kinetic resolution (DKR) of β-
Toxo esters is an indispensable synthetic technology used
to generate hectoton quantities of optically enriched β-hydroxy
esters annually (Scheme 1a).1 Since Noyori’s foundational
report2 describing DKRs of α-alkyl and α-amino substituted β-
oxo acid derivatives, a wide array of additional α-substitution
patterns have been reduced with high stereoselection.3
Conversely, involvement of β-oxo esters and their congeners
in non-hydrogenative DKR reactions remain surprisingly
Scheme 1. Dynamic Kinetic Resolutions with β-Oxo Acid
Derivatives
When β-formyl amide ( )-6a and allyl amine 2a were
subjected to chiral phosphoric acid A, β-amino amide 7a was
formed in 7:1 dr and 96:4 er (Table 1, entry 1). A screen of
chiral phosphoric acids revealed A17 and B18 as the best
candidates for further optimization.19 Elevating the reaction
temperature increased the reaction rate with little loss of
Received: September 11, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b09593
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
With suitable conditions in hand we began to probe the
allowable steric and electronic parameters of this rearrange-
ment, initially by varying the α-substituent (Table 2). The
Scheme 2. Primary and Secondary Substrate Designs for
Enantioconvergent 2-Aza-Cope Rearrangement
Table 2. Variation of the α-Substituent in the [3,3]-
a
Rearrangement of α-Stereogenic-β-formyl Esters
a
Table 1. Optimization of Aza-Allylation Conditions
b
c
entry
cat.
T (°C)
solvent
conv (%)
dr
er
1
2
3
4
5
6
7
8
A
B
A
B
A
B
A
B
A
rt
PhCH3
PhCH3
PhCH3
PhCH3
CPME
CPME
CHCl3
CHCl3
CHCl3
100
50
7:1
96:4
rt
80
80
60
60
60
60
60
100
100
100
100
100
100
100
7:1
95:5
87:13
98:2
89:11
97:3
93:7
20:1
8:1
a
>20:1
10:1
>20:1
10:1
All reactions were run on a 0.20 mmol scale at 60 °C for 24 h.
Diastereomeric ratios were determined by 1H NMR or HPLC analysis
of the crude reaction mixture; enantiomeric ratios by chiral SFC or
HPLC. Yields are of isolated products. Yield reported is of the
primary amine after hydrolysis of the benzophenone imine. Run at
130 °C under microwave irradiation for 6 h. Run on a 0.10 mmol
scale.
d
b
9
97:3
c
a
b
1
All reactions were run on a 0.10 mmol scale. Determined by H
NMR analysis of the crude reaction mixture. Determined by chiral
HPLC analysis. 2.5 mol % of catalyst.
d
c
d
phenylacetic acid derivative 7b was obtained in 1.1:1 dr and
85:15 er. An α-allyl aldehyde provided 7c in 8:1 dr and
91.5:8.5 er, while inclusion of a pendant heteroatom provided
7d in 2:1 dr and 90.5:9.5 er. The less sterically demanding α-
methyl substitution gave 7e in 3:1 dr and 82:18 er. The use of
stereoselection (Table 1, entry 3 and 4). Using cyclopentyl
methyl ether (CPME) as a solvent increased the stereo-
selectivity for both catalysts A and B (Table 1, entry 5 and 6).
With catalyst A and CHCl3 as the solvent, ketimine 7a was
obtained in 10:1 dr and 97:3 er (Table 1, entry 7). Lowering
the catalyst loading to 2.5 mol % had no detrimental effects on
reactivity or selectivity (Table 1, entry 9).20
c
larger α-substituents, as represented by 7f (R = Hex) and 7g
i
(R = Pr), restored higher levels of stereoselection. An X-ray
diffraction study of 7g was carried out (Scheme 3) to assign
B
DOI: 10.1021/jacs.5b09593
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 3. Determination of Relative and Absolute
Stereochemistry of the [3,3]-Aza-Cope Rearrangement
Scheme 4. Chemical Transformation of Aza-Cope Products
the product stereochemistry as (2R,3S).21 Electronically
differentiated benzyls provided 7i and 7j with >10:1 dr and
97:3 er. Using fur-2-yl and thien-2-yl variants instead of benzyl
derivatives yielded products 7k and 7l with high stereocontrol.
Cognizant that modifying the amide identity would result in
differentiated diamines after amide reduction, we next
examined structural variation at that position (Table 3). The
Table 3. Variation of Amide and Allyl Amine Identity in the
a
[3,3]-Rearrangement of α-Stereogenic-β-formyl Esters
reduction of 7a with LiAlH4 results in an intermediate
aldehyde, which can be further reduced by sodium
borohydride to form benzhydryl-protected amino alcohol 9
in 95% yield (Scheme 4b). If the benzophenone imine is
cleaved prior to reduction, the diamine 10 is obtained in good
yield (Scheme 4c). Finally, diene 7c underwent facile ring-
closing metathesis with Grubbs’s second generation catalyst to
provide cyclohexene 11 in 98% yield (Scheme 4d).
In conclusion, we have developed stereoconvergent 2-aza-
Cope reactions employing stereocontrol from a chiral organic
acid catalyst. This DKR between homoallylic amines and α-
stereogenic-β-formyl amides constitutes a rare example of a
non-hydrogenative DKR reaction of β-oxo acid derivatives and
delivers new β-amino amides in high diastereo- and
enantioselectivity. These products can be readily converted
into an array of functional small molecule building blocks.
Mechanistic studies delineating the factors that lead to the
observed stereoselectivity and the use of this information in
the development of other stereoconvergent reactions of
racemization-prone β-oxo carboxylic acid derivatives will be
reported in due course.
a
All reactions were run on a 0.20 mmol scale at 60 °C for 24 h.
Diastereomeric ratios were determined by 1H NMR or HPLC analysis
of the crude reaction mixture; enantiomeric ratios by chiral SFC or
HPLC. Yields are of isolated products. Yield reported is of the
b
ASSOCIATED CONTENT
primary amine after hydrolysis of the benzophenone imine.
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b09593.
β-amino amides generated from piperidine 7m, pyrrolidine 7n,
and dimethyl amine 7o were all formed in high yield and
stereoselectivity. We also probed the allowed variance of the
allyl amine donor. Internally substituted allyl amine 2b
provided the formal aza-methallyation adduct 7p in 60%
yield with 5:1 dr and 80:20 er. Terminally substituted allyl
amine donors condensed with the β-formyl amide 6, but did
not undergo [3,3]-rearrangement, results we attribute to
greater steric encumbrance at the reaction site.
For our final investigations we turned our attention to
assessing the reactivity of the product β-imino amides.
Hydrolysis of 7a to form primary amine 8 proceeded under
mild conditions and in 99% yield (Scheme 4a). Initial
CCDC 1423130 (CIF)
Experimental procedures and spectral and HPLC data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*jsj@unc.edu
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/jacs.5b09593
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(12) For a full account of these trials see the Supporting
Information.
(13) Under buffered conditions enantioenriched β-halo-α-keto esters
fail to fully racemize after 24 h. For full details see the Supporting
Information.
(14) Refer to the Supporting Information for details of tested
conditions.
(15) (a) Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G.
J. Am. Chem. Soc. 1984, 106, 1154−1156. (b) Nguyen, H.; Ma, G.;
Romo, D. Chem. Commun. 2010, 46, 4803−4805.
(16) A reasonable body of literature deals with stereoselective
addition reactions of α-stereogenic-β-oxo amides and imides that do
not epimerize (or racemize) at the α-carbon. For selected examples
see reference 15 and (a) Fujita, M.; Hiyama, T. J. Am. Chem. Soc.
1985, 107, 8294−8296. (b) Roush, W. R.; Palkowitz, A. D. J. Org.
Chem. 1989, 54, 3009−3011. (c) Soucy, F.; Grenier, L.; Behnke, M.
L.; Destree, A. T.; McCormack, T. A.; Adams, J.; Plamondon, L. J.
Am. Chem. Soc. 1999, 121, 9967−9976. (d) Evans, D. A.; Fitch, D.
M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033−
ACKNOWLEDGMENTS
■
The project described was supported by Award R01
GM103855 from the National Institute of General Medical
Sciences. X-ray crystallography was performed by Dr. Peter S.
White. C.G.G. acknowledges a Burroughs Wellcome Fellow-
ship in Organic Chemistry from the University of North
Carolina.
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DOI: 10.1021/jacs.5b09593
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX