New class of P-stereogenic chiral Br?nsted acid catalysts derived from chiral phosphinamides

Article abstract of DOI:10.1016/j.tetlet.2019.06.013

A new class of N–H Br?nsted acid organocatalysts that feature P-stereogenic chirality was developed. These catalysts were prepared from P-stereogenic chiral phosphinamides and show similar reactivity to BINOL derived phosphoric acid toward the reduction of quinolines via transfer hydrogenation. It shows that stereoselectivity is induced by the P-chiral environment that is created by the substituents attached to the phosphorous atom, which can be readily tuned and modified.

Full text of DOI:10.1016/j.tetlet.2019.06.013

Accepted Manuscript
New Class ofP-Stereogenic Chiral Brønsted Acid Catalysts Derived from Chiral
Phosphinamides
Zhengxu S. Han, Hao Wu, Bo Qu, Yuwen Wang, Ling Wu, Li Zhang, Yibo Xu,
Linglin Wu, Yongda Zhang, Heewon Lee, Frank Roschangar, Jeff J. Song, Chris
H. Senanayake
PII:
S0040-4039(19)30554-4
https://doi.org/10.1016/j.tetlet.2019.06.013
TETL 50854
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 April 2019
3 June 2019
6 June 2019
Please cite this article as: Han, Z.S., Wu, H., Qu, B., Wang, Y., Wu, L., Zhang, L., Xu, Y., Wu, L., Zhang, Y., Lee,
H., Roschangar, F., Song, J.J., Senanayake, C.H., New Class of P-Stereogenic Chiral Brønsted Acid Catalysts
Derived from Chiral Phosphinamides, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.06.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
New class of P‒stereogenic chiral Brønsted
acid catalysts derived from chiral
phosphinamides
Leave this area blank for abstract info.
Zhengxu S. Han*, Hao Wu, Bo Qu, Yuwen Wang, Ling Wu, Li Zhang, Yibo Xu, Linglin Wu, Yongda Zhang, Heewon Lee, Frank
Roschangar, Jeff J. Song, Chris H. Senanayake*

1
Tetrahedron Letters
New Class of P‒Stereogenic Chiral Brønsted Acid Catalysts Derived from Chiral
Phosphinamides
Zhengxu S. Han*, Hao Wu, Bo Qu, Yuwen Wang, Ling Wu, Li Zhang, Yibo Xu, Linglin Wu, Yongda Zhang, Heewon Lee, Frank Roschangar,
Jeff J. Song, Chris H. Senanayake*
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new class of N‒H Brønsted acid organocatalysts that feature P‒stereogenic chirality was
developed. These catalysts were prepared from P‒stereogenic chiral phosphinamides and
show similar reactivity to BINOL derived phosphoric acid toward the reduction of
quinolines via transfer hydrogenation. It shows that stereoselectivity is induced by the
P‒chiral environment that is created by the substituents attached to the phosphorous atom,
which can be readily tuned and modified.
Available online
2019 Elsevier Ltd. All rights reserved.
Keywords:
Chiral Brønsted Acid Catalysts
P‒Stereogenic chiral phosphinamide
Transfer hydrogenation
Reduction of quinoline
Introduction
Chiral Brønsted acid catalysts have emerged as powerful
organocatalysts in the past decade for number of
a
enantioselective transformations in constructing C‒C or C‒X
bonds.1 Mechanistically, the catalysts are classified into two
categories depending on their acidity. TADDOLs (1, Figure 1),2
BINOLs3 and carboxylic acids4 are weakly to modestly acidic
catalysts which promote the reaction via hydrogen bonding.
BINOL-derived phosphoric acids (e.g. 2, Figure 1), first
introduced by Akiyama5b and Terada,5c are strong Brønsted acids
that promote the reactions by substrate protonation. The axially
chiral 1,1’-bis-2-naphthol-derived phosphoric acids 2, have been
applied widely in
a
number of efficient asymmetric
transformations. Among them are Mannich-type reactions,5
Figure 1: Brønsted organocatalysts with different acidity
6
Michael reactions,
Diels-Alder reactions,7 Morita-Baylis-
Hillman reactions,3,8 Mannich reactions in the synthesis of chiral
amines,9 Aza-Friedel-Craft reactions,10 reductions via transfer
hydrogenation,11 asymmetric C-S bound formations,12
desymmetrization,13 and others.14 With increasing research
efforts in a variety of chemical transformations, catalyst 2 was
found highly reactive for activation of functional groups with
higher basicity due to its modest acidity.15 For substrates with
less basicity, stronger Brønsted acid catalysts are required. As a
result, N‒triflylphosphoramides 3 and bis(sulfuryl) imides 4 were
introduced, which have been applied successfully for more
challenging substrates.16
triflates, is a strong Brønsted acid catalyst that has been applied
to catalyze various transformations.1b,17 The chiral catalysts
derived from chiral pyrrolidine 2‒carboxamide by adding
sulfonyl groups as EWG on nitrogen have also been used as
Brønsted acids to promote stereoselective transformations.18
A
few asymmetric transformations promoted by catalysts 3 or 4
were reported. However, the structural variety of this class of
catalysts is less prevalent as it relies mostly on sterically bulky R-
groups to achieve high selectivity; and their application is also
limited.16g With increasing attention on efficient asymmetric
synthesis catalyzed by organocatalysts, a large number of acid-
promoted reactions need to be realized in
enantioselective fashion. Therefore, the development of novel
efficient catalyst systems remains an attractive endeavor.
a catalytic
Development of stronger Brønsted acids with compounds
containing amino functionalities is well known.1b The acidity of
the N‒H proton can be tuned by N-substituents. Triflylamide 5,
for example, containing two electron-withdrawing group (EWG)
______________
Corresponding author email: steve.han@boehringer-ingelheim.com

2
Tetrahedron
Results and Discussion
ester 13 promoted by catalysts 10 and 11 was studied, and the
results are presented in Scheme 2. The reaction was carried out
with 4 equiv of 13 and 10 mol% of catalysts at 60 oC for 24 h. A
solvent survey indicated that polar solvents such as THF gave
lower reactivity compared to nonpolar solvents benzene or
toluene. Benzene and toluene provided similar reactivity and
toluene was, therefore, used in our experiments. BINOL derived
phosphoric acid 15 was used as a control for this study. Results
show that phosphinamide derived catalysts can serve as Brønsted
acid catalysts that show similar reactivity compared to
phosphoric acid 15. Complete conversion was observed for the
reactions with catalysts 10a and 11a and 11c within 24 h.
Sterically bulkier catalyst 10b provided slightly diminished
activity. Catalyst 11b gave the lowest reactivity with 59%
conversion in 24 h and full conversion in 48 h, which might
result from the steric hindrance or low acidity because of
electron-donating t-butyl group. Nevertheless, these results
indicated that phosphinamide derived catalysts could potentially
be employed as Brønsted acid organocatalysts to promote
catalytic reactions.
Figure 2. Novel Brønsted acid catalysts with P‒stereogenic
chiral phosphinamide motifs
Recently, we reported a general method for the synthesis of
P‒stereogenic chiral phosphinamides
7
(Figure 2).19a We
envisioned that 7 would serve as precursors for synthesis of P-
stereogenic chiral Brønsted acid catalysts 8 by utilizing the N−H
proton that is next to the chiral center. Catalyst 8 would have
several important features that could promote its utility as a
valuable Brønsted acid catalyst. Most importantly, this class of
catalyst features flexible tunable functional groups in proximity
to the N−H proton. By modifying the R1 and R2 substituents, we
create a tunable P−stereogenic chiral environment for chiral
induction, which could also affect the acidity of the N−H proton.
Introduction of EWG on nitrogen would not only tune the acidity
of N−H but also affect the chiral environment of the
P−stereogenic center. Moreover, introduction of other functional
groups on either R1, R2 or EWG (e.g. 8b, Figure 2) might also
generate a synergistic effect on reactivity and stereoselectivity.
This class of catalysts also offers an H‒proton acceptor (P=O)
that is adjacent to the P‒stereogenic chiral center. To the best of
our knowledge, P−stereogenic chiral phosphinamide derived
Brønsted acid catalysts for asymmetric transformations are
heretofore unknown. Herein we report our preliminary results in
the synthesis of these catalysts and their use as Brønsted acid
catalysts for asymmetric induction affected by P−stereogenicity.
Scheme 2. Quinoline reduction promoted by phosphinamide
catalysts 10 and 11
Encouraged by these results, we turned our attention to the
synthesis of P‒stereogenic chiral phosphinamide Brønsted acids
derived from chiral phosphinamides 7 that were readily prepared
as reported (Scheme 3).19a Following the same procedure in the
synthesis of the racemic derivatives (Scheme 1), P‒stereogenic
chiral catalysts with substituents of aryl and alkyl (S)‒8b1, diaryl
(S)‒8b2, and more congested (R)‒8b319b and (S)‒8b4 were
prepared in good yields and excellent optical purities, in which
the bulky 2,4,6-triisopropylbenzenesulfonyl was introduced as an
EWG.
Scheme 1. Synthesis of racemic Brønsted acid catalysts with
phosphinamide motifs
Our initial studies geared toward probing the synthesis and
reactivity of this class of catalyst. Synthesis of racemic catalysts
10 or 11 was first investigated starting with commercially
available P,P‒diphenylphosphinic amide 9. The synthesis was
started with treatment of 9 with NaH in THF followed by either
phosphinic chloride or sulfonyl chloride affording the desired
products in good isolated yields. Sulfonamides (10a and 10b)
and phosphinic amides with diverse steric and electronic
properties (11a-c) were also prepared (Scheme 1).
The reactivity of these catalysts was then evaluated toward the
reduction of quinoline derivatives via transfer hydrogenation.
Asymmetric reduction of quinoline derivatives with Hantzsch
ester reagents promoted by BINOL-derived phosphoric acid
catalysts 2 was well studied,20 and excellent selectivity was
achieved by proper tuning of the steric and electronic properties
of the substituents. Therefore, reduction of 12a with Hantzsch
Scheme 3. Synthesis of P‒stereogenic chiral phosphinamide
Brønsted acid catalysts
The asymmetric reduction of 12a promoted by chiral catalysts
was then investigated and the results of enantioselectivity are
listed in Table 1. First, chiral BINOL-phosphoric acid (R)‒15 as

3
catalyst was investigated, and the reaction completed in 24 h to
afford (S)‒14a in low selectivity of 44.4:55.6 er (Entry 1 in Table
1).21 The selectivity varies with different P‒stereogenic chiral
catalysts depending on the environment created by the
substituents. When (S)‒8b1 was used, the reaction was slower
and completed in 48 h providing (R)‒14a in 53.0:47.0 er (Entry 2
in Table 1) that is lower than (R)‒15. The lower reactivity and
selectivity are rationalized by the less bulky and electron-
donating methyl group. When bulkier (S)‒8b2 was used, the
reaction gives better reactivity and selectivity. The reaction
completed in 24 h to provide (S)‒14a in 55.5:44.5 er (Entry 3 in
Table 1). Further enhancing the bulkiness of the catalyst by
replacing the phenyl with a t-butyl group in (S)‒8b2, catalyst
(R)‒8b3 provides increased selectivity at 65:35 er (Entry 4 in
Table 1). We then turned our attention to the more congested
catalyst (S)‒8b4. As reported earlier, phosphinamide 7c (R1 =
phenyl, R2 = 2,6-dimethoxy-1,1'-biphenyl) derived P‒stereogenic
chiral Lewis base catalyst-mediated reduction of conjugated
In conclusion, we have developed a new class of Brønsted
acid organocatalysts derived from P‒stereogenic chiral
phosphinamides. These catalysts were successfully applied to
promote the reduction of quinoline derivatives via transfer
hydrogenation. The asymmetric transformation is effected by the
P‒stereogenic chirality and the selectivity is tunable by the
functionality of the substituents on the phosphorous atom. This
class of catalysts has potential as tunable Brønsted acids in terms
of reactivity and selectivity. Further work is to identify more
efficient catalysts by tuning the substituents and the results will
be reported in due course.
References and notes
1. Reviews: (a) Cai, X.-H.; Xie, B. Arkivoc 2013, 264-293; (b) Akiyam, T.
Chem. Rev. 2007, 107, 5744-5758; (c) Cheng, P. H.-Y.; Lagault, C. Y.;
Um, J. M.; Celebi-Olcum, N.; Houk, K. N. Chem. Rev. 2011, 111, 5042-
5137; (d) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2014, 114, 9047-9153; (e) Rueping, M.; Kuenkel, A.; Atodiresei, I.
Chem. Soc. Rev. 2011, 40, 4539-4549; (f) Terada, M. Synthesis 2010,
1929-1982.
ketones provides excellent selectivity.19a
Therefore, when
(S)‒8b4 was used, the selectivity of the reduction was improved
further to afford (S)‒14a in 68:32 er, and the reaction completed
in 36 h.
2. Pellissier, H. Tetrahedron 2008, 64, 10279-10286.
3. McDougal, N. T.; Schaus, C. S. J. Am. Chem. Soc. 2003, 125, 12094-
12095.
Table 1. Enantioselective reduction of 12a to 14a with the new catalysts
Entry
Catalyst (l0 mol%)
Reaction T/ time
Product 14a
er of 14aa
55.6:44.4
53.0:47.0
55.5:44.5
65.0:35.0
68.2:31.8
4. Min, C.; Seidel, D. Chem. Soc. Rev. 2017, 46, 5889-5902.
5. (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964-
12965; (b) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.
Int. Ed. 2004, 43, 1566-1568; (c) Uraguchi, D.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 5356-5357; (d) Okino, T.; Hoashi, Y.; Takemoto, Y. J.
Am. Chem. Soc. 2003, 125, 12672-12673.
6. (a) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45,
9185-9188; (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119-125.
7. (a) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem. Int. Ed. 2005, 44,
4032-4035; (b) Pours, J.; Courant, T.; Bernadat, G.; Iorga, B. I.;
Blanchard, F.; Masson, G. J. Am. Chem. Soc. 2015, 137, 11950−11953.
8. Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424,
146.
9. McDougal, N. T.; Trevellini, W. L.; Rodgen, A. S.; Kliman, L. T.; Schaus,
S. E. Adv. Synth. Catal. 2004, 346, 1231-1240.
10. Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804-11805.
11. Rueping, M.; Antonchick, A.P. Angew. Chem. Int. Ed. Engl., 2007, 46,
4562–4565.
12. Chauhan, P.; Mahajan, S.; Enders, D. Chem. Rev. 2014, 114, 8807−8864.
13. Gu, Q.; Rong, Z.-Q.; Zheng, C.; Yu, S. L. J. Am. Chem. Soc. 2010, 132,
4056-4057.
o
1
2
3
4
5
(R)‒15
(S)-14
60 C/24 h
o
(S)‒8b1
(R)-14
60 C/48 h
o
(S)‒8b2
(S)-14
60 C/24 h
o
(R)‒8b3
(S)-14
60 C/24 h
o
(S)‒8b4
(S)-14
60 C/36 h
a er was obtained by chiral HPLC analysis
Furthermore, the reduction of 2-aryl substituted quinolines
12b-c was studied. Higher enantioselectivity was observed for
products 14b and 14c with 68:32 er and 71:29 er, respectively,
when catalyst (S)‒8b4 was used (Scheme 4). Similar reactivity
was observed for phosphoric acid (R)‒15, but with lower
selectivity at 56:44 er for 14b and 67:33 er for 14c. The best
selectivity was observed when (R)‒8b3 was applied in the
reduction of 12b and 12c with 72:28 er and 84:16 er,
respectively. The slightly enhanced stereoselectivity for 12b and
12c suggests that both the structure of the substrate and catalyst
might play the roles in the alternating of the transition state of the
14. (a) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156-1171; (b)
Liang, T.; Zhang, Z.; Antilla, J. C. Angew. Chem. Int. Ed. 2010, 49, 9734-
9736; (c) Meng, S.S.; Liang, Y.; Cao, K. N.; Zou, L.; Lin, X. B.; Yang,
H.; Houk, K. N.; Zheng, W. H. J. Am. Chem. Soc. 2014, 136,
12249−12252; (d) Huang, S.; tzner, L.; De, C. K.; List, B. J. Am.
Chem. Soc. 2015, 137, 3446−3449.
15. (a) Kanpmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.; Leito, I.
Angew. Chem. Int. Ed. 2013, 52, 11783-011786; (b) Min, C.; Seidel, D.
Chem. Soc. Rev. 2017, 46, 5889-5902.
reduction.
Nevertheless, these results indicate that the
stereoselectivity in the asymmetric transformations can be tuned
by modification of the substituents attached to the P‒stereogenic
center, and therefore, it offers a venue for development of more
efficient phosphinamides as a new class of Brønsted acid
catalysts.
16, (a) Enders, D.; Seppelt, M.; Beck, T. Adv. Synth. Catal. 2010, 352, 1413-
1418; (b) Johnston, J. N. Angew. Chem. Int. Ed. 2011, 50, 2891-2891; (c)
Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627;
(d) Rueping, M.; Nachtsheim, B. J.; Ieaesuwan, W.; Atodiresei, I.
Angew. Chem Int. Ed. 2011, 50, 6706-6720; (e) Kaib, P. S. J.; Schreyer,
L.; Sunggi, L.; Properzi, R.; List, B. Angew. Chem. Int. Ed. 2016, 55,
13200 –13203; (f) Sai M.; Yamamoto, H. J. Am. Chem. Soc. 2015, 137,
7091−7094; (g) Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006,
133-136.
17. Gati, W.; Yamamoto, H. Acc. Chem. Res. 2016, 49, 1757-1768.
18. Chen, C. Q.; Xiang, H. Y.; Yang, H. J. Org. Chem, 2018, 83, 12284-
12290.
19. (a) Han, Z. S.; Zhang, L.; Xu, Y.; Sieber, D. J.; Marsini, M. A.; Li, Z.;
Reeves, J. T.; Fandrick, K. R.; Patel, N. D.; Desrosiers, J. D.; Qu, B.;
Chen, A.; Rudzinski, D. M.; Samankumara, L. P.; Ma, S.; Grinberg, N.;
Roschangar, F.; Yee, N.; Wang, G.; Song, J. J.; Senanayake, C. H. Angew.
Chem, Int. Ed. 2015, 54, 5474–5477; (b) (R)‒8b3 was preparped from
secondary phosphibne oxide as described in supporting inforamtion, Han,
Scheme 4. Asymmetric reduction of 12b-c promoted by catalysts
(R)‒8b3 and (S)‒8b4

4
Tetrahedron
Z. S.; Hao, W.; Xu. Y.; Zhang, Y.; Qu, B.; Li, Z.; Caldwell, D. R.;
Frandrick, K. R.; Zhang, L.; Roschangar, F.; Song, J. J.; Senanayake, C.
H. Org. Lett. 2017, 19, 1896-1799.
20. (a) Ouellet, S. G.; Abbas, M. Walji, A. M.; Macmillan, D. W. C. Acc.
Chem. Res. 2007, 40, 1327-1339; (b) Zhang, Y.; Zhao, R.; Bao, L. Y.; Shi,
L. Eur. J. Org. Chem. 2015, 3344–3351; (c) Rueping, M.; Antonchick, A.
P.; Theissmann, T. Angew. Chem. Int. Ed. 2006, 45, 3683-3686.
21. (a) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J. Angew. Chem. 2009,
127, 6646-6650; (b) Park, D. Y.; Lee, S. Y.; Jeon, J.; Cheon, C. H. J. Org.
Chem. 2018, 83, 12486-12495; (c) Chen, Q. A.; Gao, K.; Duan, Y.; Ye, Z.
S.; Shi, L.; Yang, Y.; Zhou, Y. G. J. Am. Chem. Soc. 2012, 134,
2442−2448.
Supplementary Material
Synthesis of catalysts and their analytical data, and results on
the analysis of chiral products

5
New Class of P‒Stereogenic Chiral
Brønsted Acid Catalysts Derived from
Chiral Phosphinamides
Zhengxu S. Han, Hao Wu, Bo Qu, Yuwen Wang, Ling Wu, Li
Zhang, Yibo Xu, Linglin Wu, Yongda Zhang, Heewon Lee, Frank
Roschangar, Jeff J. Song, Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900
Ridgebury Road, Ridgefield, CT 06877, USA
Highlight


New class of P‒stereogenic chiral N-H Brønsted
acid organocatalysts prepared
Catalysts were prepared from chiral
phosphinamides or secondary phosphine
oxides



Catalysts promoted the asymmetric reduction
of quinolones by transfer hydrogenation
Asymmetric transformation effected by the
P‒stereogenic chiral environment
Easily tunable selectivity and reactivity by the
substituents of phosphorous