Direct Catalytic Asymmetric Mannich-Type Reaction en Route to α-Hydroxy-β-amino Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03609

A direct catalytic Mannich-type reaction of α-oxygen-functionalized amides was achieved. The use of 7-azaindoline amide was crucial to facilitate direct enolization and subsequent stereoselective addition to imines in a cooperative catalytic system comprising a soft Lewis acid and Br?nsted base. The operationally simple room-temperature protocol furnished a syn-Mannich adduct with high stereoselectivity. Divergent functional group transformation of the amide moiety of the product allowed for expeditious access to enantioenriched syn-configured α-hydroxy-β-amino carboxylic acid derivatives, highlighting the synthetic utility of the present catalysis.

Full text of DOI:10.1021/acs.orglett.7b03609

This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Catalytic Asymmetric Mannich-Type Reaction en Route to
α‑Hydroxy-β-amino Acid Derivatives
Bo Sun,† Roman Pluta,† Naoya Kumagai,* and Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: A direct catalytic Mannich-type reaction of
α‑oxygen-functionalized amides was achieved. The use of 7-
azaindoline amide was crucial to facilitate direct enolization and
subsequent stereoselective addition to imines in a cooperative
catalytic system comprising a soft Lewis acid and Brønsted base.
The operationally simple room-temperature protocol furnished
a syn-Mannich adduct with high stereoselectivity. Divergent
functional group transformation of the amide moiety of the
product allowed for expeditious access to enantioenriched syn-
configured α-hydroxy-β-amino carboxylic acid derivatives, high-
lighting the synthetic utility of the present catalysis.
he α-hydroxy-β-amino acid unit is a privileged structural
motif in a wide variety of biologically active natural
T
products and therapeutics. Highly representative examples of this
are paclitaxel and docetaxel, marketed as Taxol and Taxotere,
respectively, which have proven potency against various types of
cancer and possess this specific unit with the syn-configuration at
the functional side chain (Figure 1a).1 Considerable effort has
been devoted to devising expeditious access to this class of
compounds in both a catalytic and stereoselective manner.2−7
The integration of a C−C bond-forming process and
stereoselective installation of the α-hydroxyl and β-amino
functional groups in a single step to efficiently furnish these
units can be achieved by Mannich reaction of imines and α-
oxygen-functionalized latent enolates.8 Recent advances in
Mannich reactions render the whole process catalytic, where
both enolate formation and stereoselective addition to imines are
driven by the designed catalysts.9 Due to the inherent difficulty of
the initial catalytic enolization of carbonyl-type pronucleophiles,
enolization−prone ketones and aldehydes have been incorpo-
rated in direct Mannich chemistry with remarkable stereo-
selectivity (Figure 1b).9a,b,d−f The limited synthetic utility of
these Mannich products, however, led us to focus on the use of
latent enolates in the carboxylic acid oxidation state to furnish
versatile α-hydroxy-β-amino carboxylic acid derivatives.
Although we developed a Mannich-type reaction of α-hydroxy-
N-acetylpyrrole utilizing N-o-Ts imines as electrophiles via
In(III) catalysis, there is much room for improvement toward
practical organic synthesis; i.e., low catalytic turnover (≤4.9),
moderate diastereoselectivity, and difficult removal of the o-Ts
group on the nitrogen (Figure 1c).9c In our continuing program
of enolization chemistry using 7-azaindoline amides, α-oxygen
functionalized amides has remained elusive, despite the
successful implementation of α-alkyl-,10 fluoroalkyl-,11 nitro-
gen-,12 thio-,13 and halo-functionalized amides.14 Herein, we
document the successful incorporation of α-oxygen function-
Figure 1. (a) Structures of taxol and taxotere. (b, c) Prior schemes of
direct catalytic asymmetric Mannich-type reactions. (d) Present work.
alized 7-azaindoline amide into a direct Mannich manifold,
delivering syn-configured β-amino-α-hydroxy amides (Figure
1d). Facile functional group transformation of the amide moiety
Received: November 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03609
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
as well as readily removable protecting groups on the oxygen and
nitrogen highlight the synthetic versatility of these Mannich
products.
solvent from THF to DME further improved the stereoselectivity
with an isolated yield of 91% (entry 11).
The substrate generality for imines under optimized reaction
conditions is summarized in Scheme 1. Mannich-type reactions
To enhance the prospective utility of the Mannich products as
chiral building blocks, a benzyloxy group was selected as an α-
substituent of 7-azaindoline amide pronucleophile 1a. As for
imine electrophiles, those with readily cleavable N-carbamoyl-
protected imines15 were suitable, and N-Boc imine 2a was used as
a model substrate for the initial screening. Based on the
properties of 7-azaindoline amide, a cooperative catalytic system
comprising Cu(I) salt and Barton’s base was tested with a variety
of chiral phosphine ligands (Table 1).14,16 Generally, the desired
Scheme 1. Direct Catalytic Asymmetric Mannich-Type
a
Reaction of α-OBn 7-Azaindoline Amide 1a
Table 1. Direct Catalytic Asymmetric Mannich-Type Reaction
a
of α-OBn 7-Azaindoline Amide 1a and N-Boc-imine 2a
b
c
d
entry
ligand
solvent
yield (%)
syn/anti
ee (%) (syn)
1
LI
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DME
91
95
88
50
93
88
72
50
93
90
1.8/1
5.4/1
4.3/1
1.5/1
1.3/1
3.4/1
1.9/1
1.1/1
2.5/1
6.0/1
9.0/1
50
31
2
L2
L3
L4
L5
L6
L7
L8
L9
L10
L10
3
−45
−45
17
4
5
6
5
7
−87
−53
73
8
9
10
11
94
e
91
95
a
1a: 0.1 mmol, 2: 0.2 mmol (except for 3ae), isolated yield shown.
1a: 5.0 mmol, 2e: 7.5 mmol, 2.36 g of 3ae was obtained. Run for 48
b
c
h.
of imines 2 bearing m- or p-substituents proceeded uneventfully
to afford corresponding syn-adducts with high enantioselectivity,
irrespective of the electronic nature of the substituents (3aa−al).
p-F-substituted imine exhibited sufficient reactivity with 5 mol %
of catalyst loading, and a gram-scale reaction proceeded with no
detrimental effect on stereoselectivity (3ae). Inherently coor-
dinative, soft Lewis basic thioether or thienyl groups were
tolerated in the present Cu(I) catalysis (3ak, 3al). The o-Me
substituent retarded the reaction, and 20 mol % of catalyst was
required for reasonable yield, while o-nitro-substituted imine was
sufficiently reactive, resulting in excellent stereoselectivity (3am,
3an). o-Halogen-substituted imines were partly compatible, and
eroded syn-selectivity was observed depending on the additional
substituents (3ao−ar). It is noteworthy that the present
Mannich method enables expeditious access to the side chains
of both Taxol and Taxotere; N-Bz imine 2s as well as N-Boc-
imine 2a afforded the desired syn-adduct 3as preferentially with
high enantioselectivity (Scheme 2).17 By taking into account the
broad scope of aromatic groups of imines in Scheme 1 and facile
hydrolytic capability of the amide moiety (vide infra), the direct
Mannich protocol allows for the synthesis of a variety of
enantioenriched derivatives for these important drugs. Amides
possessing other oxygen functionalities were also compatible
(Scheme 3). Amide 1b with a phenyl ether at the α-position gave
a Mannich adduct with an identical stereochemical configuration
a
b
1
1a: 0.1 mmol, 2: 0.2 mmol. Determined by H NMR analysis of
c
crude mixture using mesitylene as an internal standard. Determined
by H NMR analysis. Determined by HPLC analysis. Negative sign
denotes the enantiomer. Isolated yield.
d
1
e
reaction proceeded with 10 mol % catalyst in THF at room
temperature to give the desired product 3aa in a syn-selective
manner. Although the biaryl-type ligands of four different core
architectures L1−6 afforded 3aa in high yield, except for bulky
ligand L4, the diastereo- and enantioselectivity were moderate,
and conceivable trends between the selectivity and ligand
structures were barely detected (entries 1−6). Structurally
distinct alkyl phosphine ligand L7 significantly improved the
enantioselectivity, albeit with moderate syn-selectivity (entry 7).
Ferrocene-embedded bisphosphine ligands were then evaluated
and Walphos-type ligand L10 outperformed the others to afford
3aa in syn/anti = 6/1 and 94% ee (entries 8−10). Switching the
B
DOI: 10.1021/acs.orglett.7b03609
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Direct Catalytic Asymmetric Mannich-Type
Scheme 4. Transformation of the Mannich Adduct
Reaction Using N-Boc- and N-Bz-imines To Furnish Both
a
Side Chains for Taxol and Taxotere
a
Optimized conditions shown in Scheme 1 were used.
Scheme 3. Direct Catalytic Asymmetric Mannich-Type
Reaction of α-OMe and α-OPh 7-Azaindoline Amides 1b,c
a
Reagents and conditions: (a) 12 N HCl aq, 100 °C, 2 h, 82%; (b)
CuCl, 2 M HCl/MeOH, 60 °C, 8 h, 95%; (c) LiAlH4, THF, −78 °C, 2
h, 89%; (d) MeLi, Et2O, −78 °C, 1 h, 82%; (e) PhMgBr, THF, −10
°C, 1 h, 89%; (f) BH3·NH3, LDA, THF, rt, 1 h, 84%.
enantioselectivity. Application of this class of latent enolates to
the aldol reaction manifold is ongoing.
and a similar level of stereoselectivity (3be, 3bn).18 Somewhat
lower syn-selectivity was observed for methyl ether derivative 1c,
albeit with excellent enantioselectivity (3cn). The remarkable
enolization propensity and stereoselective addition to imines
were exclusive to 7-azaindoline amide 1a−c; 7-azaindole
derivative 1d, indoline derivative 1e, and N-Boc 2-pyridyl
amide 1f all failed the reaction under the optimized reaction
conditions (Figure 2).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03609.
■
S
Experimental procedures and spectroscopic data of new
compounds; NMR spectra (PDF)
Accession Codes
CCDC 1584885−1584887 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
Figure 2. Structure of reactive (1a) and unsuccessful α-OBn amides
(1d−f).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nkumagai@bikaken.or.jp.
*E-mail: mshibasa@bikaken.or.jp.
ORCID
The synthetic utility of the Mannich adduct is highlighted by
divergent transformation of the 7-azaindoline amide moiety
(Scheme 4). Treatment of 3ae with 12 N HCl aq effected
hydrolysis and global deprotection to furnish α-hydroxy-β-amino
acid 4, while Cu(I)-mediated acidic methanolysis gave methyl
ester 5 with preservation of the Bn ether.19 Due to stabilization of
the tetrahedral intermediate by 7-azaindoline upon the addition
of hydride or carbanions to amides, hydride reduction and the
addition of organolithium or Grignard reagents produced the
corresponding aldehyde 6 and ketones 7,8 without overreaction.
Primary alcohol 9 could be directly accessed using Myers’
protocol with BH3·NH3 and LDA.20 Of note, epimerization did
not occur in these transformations.
Naoya Kumagai: 0000-0003-1843-2592
Masakatsu Shibasaki: 0000-0001-8862-582X
Author Contributions
†B.S. and R.P. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by ACT-C (JPMJCR12YO)
from JST and KAKENHI (17H03025 and JP16H01043 in
Precisely Designed Catalysts with Customized Scaffolding) from
JSPS. R.P. thanks JSPS for a postdoctoral fellowship. Dr. Ryuichi
Sawa, Ms. Yumiko Kubota, and Dr. Kiyoko Iijima at the Institute
of Microbial Chemistry are gratefully acknowledged for their
assistance with the spectroscopic analysis. We thank Dr.
In summary, 7-azaindoline amides bearing α-oxygen-function-
alities were incorporated into direct enolization chemistry. The
direct Mannich-type reaction proceeded at room temperature,
affording versatile chiral building blocks of acyclic acid derivatives
possessing α-hydroxyl and β-amino groups with high syn- and
C
DOI: 10.1021/acs.orglett.7b03609
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924. (d) Paull, D. H.;
Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem.
Res. 2008, 41, 655. (e) Yamamoto, H.; Ishihara, K. Acid Catalysis in
Modern Organic Synthesis; Wiley-VCH: Weinheim, 2008. (f) Kumagai,
N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 4760. (g) Peters, R.
Cooperative Catalysis; Wiley-VCH: Weinheim, 2015.
Tomoyuki Kimura at the Institute of Microbial Chemistry for
assistance with the X-ray crystallography.
REFERENCES
■
(1) For selected reviews, see: (a) Wani, M. C.; Taylor, H. L.; Wall, M.
E.; Coggon, P.; McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325.
(b) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed. Engl.
1994, 33, 15. (c) Kingston, D. G. I. Chem. Commun. 2001, 867.
(d) Horwitz, S. B. J. Nat. Prod. 2004, 67, 136. (e) Kingston, D. G.;
Newman, D. J. Curr. Opin. Drug. Discovery Dev 2007, 10, 130.
(17) The reaction using N-Boc imines derived from α,β-unsaturated
imines was not successful.
(18) The absolute configuration of 3am was determined by X-ray
crystallographic analysis after conversion into the corresponding free
alcohol S1 via hydrogenolysis. The absolute configuration of products
3be and 3bn derived from 1b was determined by X-ray crystallographic
analysis. See the Supporting Information for details.
(19) (a) Brohmer, M. C.; Mundinger, S.; Brase, S.; Bannwarth, W.
Angew. Chem., Int. Ed. 2011, 50, 6175. (b) Jakob, U.; Mundinger, S.;
Bannwarth, W. Eur. J. Org. Chem. 2014, 2014, 6963.
(2) For selected examples using epoxide-opening reactions, see:
́
(a) Commerco̧ n, A.; Bezard, D.; Bernard, F.; Bourzat, J. D. Tetrahedron
Lett. 1992, 33, 5185. (b) Bonini, C.; Righi, G. J. Chem. Soc., Chem.
Commun. 1994, 2767. (c) Tosaki, S. Y.; Tsuji, R.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 2147.
(3) For selected examples using aminohydroxylation, see: (a) Li, G.;
Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451.
(b) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36,
2637. (c) Krishna Reddy, S. H.; Lee, S.; Datta, A.; Georg, G. I. J. Org.
Chem. 2001, 66, 8211. (d) Milicevic, S.; Matovic, R.; Saicic, R. N.
Tetrahedron Lett. 2004, 45, 955.
(20) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(4) For an example using a hetero Diels−Alder reaction, see: Swindell,
C. S.; Tao, M. J. Org. Chem. 1993, 58, 5889.
(5) For an example using hydrosilylation, see: Jiang, Y.; Chen, X.;
Zheng, Y.; Xue, Z.; Shu, C.; Yuan, W.; Zhang, X. Angew. Chem., Int. Ed.
2011, 50, 7304.
(6) For an example using hydrogenation, see: Wang, Q.; Huang, W.;
Yuan, H.; Cai, Q.; Chen, L.; Lv, H.; Zhang, X. J. Am. Chem. Soc. 2014,
136, 16120.
(7) For other selected examples, see: (a) Juhl, K.; Jørgensen, K. A. J.
Am. Chem. Soc. 2002, 124, 2420. (b) Borah, J. C.; Gogoi, S.; Boruwa, J.;
Kalita, B.; Barua, N. C. Tetrahedron Lett. 2004, 45, 3689. (c) Torssell, S.;
Kienle, M.; Somfai, P. Angew. Chem., Int. Ed. 2005, 44, 3096. (d) Qian,
Y.; Xu, X.; Jiang, L.; Prajapati, D.; Hu, W. J. Org. Chem. 2010, 75, 7483.
(e) Goodman, C. G.; Do, D. T.; Johnson, J. S. Org. Lett. 2013, 15, 2446.
(8) For reviews of Mannich reactions, see: (a) Marques, M. M. Angew.
Chem., Int. Ed. 2006, 45, 348. (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem.
2007, 2007, 5797. (c) Verkade, J. M.; van Hemert, L. J.; Quaedflieg, P. J.;
Rutjes, F. P. Chem. Soc. Rev. 2008, 37, 29. (d) Arrayas, R. G.; Carretero, J.
C. Chem. Soc. Rev. 2009, 38, 1940. (e) Kobayashi, S.; Mori, Y.; Fossey, J.
S.; Salter, M. M. Chem. Rev. 2011, 111, 2626.
(9) (a) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 4712. (b) Trost, B. M.; Terrell, L. R. J. Am. Chem.
Soc. 2003, 125, 338. (c) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki,
M. Angew. Chem., Int. Ed. 2005, 44, 4365. (d) Trost, B. M.;
Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778.
(e) Dziedzic, P.; Vesely, J.; Cor
(f) Dziedzic, P.; Schyman, P.; Kullberg, M.; Cor
2009, 15, 4044.
́
dova, A. Tetrahedron Lett. 2008, 49, 6631.
́
dova, A. Chem. - Eur. J.
(10) (a) Arteaga, F. A.; Liu, Z.; Brewitz, L.; Chen, J.; Sun, B.; Kumagai,
N.; Shibasaki, M. Org. Lett. 2016, 18, 2391. (b) Liu, Z.; Takeuchi, T.;
Pluta, R.; Arteaga Arteaga, F.; Kumagai, N.; Shibasaki, M. Org. Lett.
2017, 19, 710.
(11) (a) Yin, L.; Brewitz, L.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2014, 136, 17958. (b) Brewitz, L.; Arteaga, F. A.; Yin, L.; Alagiri, K.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2015, 137, 15929.
(c) Brewitz, L.; Kumagai, N.; Shibasaki, M. J. Fluorine Chem. 2017, 194,
1.
(12) (a) Sun, Z.; Weidner, K.; Kumagai, N.; Shibasaki, M. Chem. - Eur.
J. 2015, 21, 17574. (b) Weidner, K.; Sun, Z.; Kumagai, N.; Shibasaki, M.
Angew. Chem., Int. Ed. 2015, 54, 6236.
(13) Weidner, K.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed.
2014, 53, 6150.
(14) Sun, B.; Balaji, P. V.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2017, 139, 8295.
(15) Vesely, J.; Rios, R. Chem. Soc. Rev. 2014, 43, 611.
(16) For reviews of cooperative catalysis, see: (a) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187. (b) Kanai, M.; Kato, N.;
Ichikawa, E.; Shibasaki, M. Synlett 2005, 2005, 1491. (c) Yamamoto, H.;
D
DOI: 10.1021/acs.orglett.7b03609
Org. Lett. XXXX, XXX, XXX−XXX