How Understanding the Role of an Additive Can Lead to an Improved Synthetic Protocol without an Additive: Organocatalytic Synthesis of Chiral Diarylmethyl Alkynes

Article abstract of DOI:10.1002/anie.201706579

The use of additives for organic synthesis has become a common tactic to improve the outcome of organic reactions. Herein, by using an organocatalytic process for the synthesis of chiral diarylmethyl alkynes as a platform, we describe how an additive is involved in the improvement of the process. The evolution of an excellent synthetic protocol has been achieved in three stages, from 1) initially no catalyst turnover, to 2) good conversion and enantioselectivity with a superior additive, and eventually 3) even better efficiency and selectivity without an additive. This study is an important and rare demonstration that understanding the role of additive can be so beneficial as to obviate the need for the additive.

Full text of DOI:10.1002/anie.201706579

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Accepted Article
Title: Understanding the Role of Additive Leads to an Improved
Synthetic Protocol Obviating Additive: Organocatalytic Synthesis
of Chiral Diarylmethyl Alkynes
Authors: Min Chen and Jianwei Sun
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706579
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10.1002/anie.201706579
Angewandte Chemie International Edition
COMMUNICATION
Understanding the Role of Additive Leads to an Improved
Synthetic Protocol Obviating Additive: Organocatalytic Synthesis
of Chiral Diarylmethyl Alkynes**
Min Chen and Jianwei Sun*
Abstract: The use of additives for organic synthesis has become a
common tactic to improve organic reaction outcomes. In this report,
using an organocatalytic process for the synthesis of chiral
diarylmethyl alkynes as a platform, we describe how an additive is
involved in the improvement of the process. The evolution of an
excellent synthetic protocol has been achieved via three stages,
from (1) initially no catalyst turnover to (2) good conversion and
enantioselectivity with a superior additive, and eventually (3) even
better efficiency and selectivity without using additive. It is an
important and rare demonstration that understanding the role of
additive can be so beneficial as to obviate using the additive.
and efficiency would be highly desirable. In particular, an
organocatalytic approach would be complementary, but remains
unknown.
Development of perfect catalytic organic reactions is an
unwavering pursuit of synthetic organic chemists. In achieving
this goal, organic chemists typically need to devote enormous
efforts in optimizing reactions by screening catalysts/ligands and
other conditions (e.g., temperature, solvents, concentration, etc.)
to improve the efficiency and selectivity. In addition to tuning
these standard parameters, the use of additive is an additional
dimension that can sometimes lead to dramatic improvement of
reaction outcome. It is particularly well-recognized in asymmetric
catalysis, where achiral additives can sometimes enhance not
only reaction efficiency, but also enantioselectivity.[1] As a result,
it has become more and more common to consider using
additives when tuning other conditions cannot lead to
satisfactory outcome, even though the effects of the additive
may not be logically predictable. In fact, even in many
successful examples, the role of additives has been unknown or
only vaguely understood. Herein, we present an unusual
example that understanding the role of an additive leads to
achieving a better synthetic protocol that eventually obviates the
use of that additive.
Diarylmethyl alkynes with chirality at the propargylic position
are important structural motifs found in many biologically
important molecules (Figure 1).[2] However, methods to establish
such diaryl propargylic stereogenic centers are scarce, mainly
by Ru-catalyzed substitution of propargylic alcohols with
electron-rich arenes or Pd-catalyzed alkynylation of diarylmethyl
electrophiles.[3] The former approach is limited to terminal
alkynes due to the involvement of Ru-allenylidene
intermediates,[3a-c] while the latter relies on chirality transfer from
enantioenriched substrates.[3d,e] In this context, development of
alternative catalytic asymmetric methods with improved scope
Figure 1. Two representative antitumor agents bearing diarylmethyl alkyne
units.
We envisioned a one-pot process that combines dehydration
of the racemic tertiary alcohol 1a to generate the reactive para-
quinone methide (p-QM) intermediate and subsequent
asymmetric reduction to form the desired chiral alkyne product
3a. In this process, a chiral acid is proposed to catalyze both
steps and also expected to differentiate the C(sp2) and C(sp)
substituents of the p-QM intermediate in the enantiodetermining
step. The Hantzsch ester 2a was employed as a reductant.
Preliminary screening of reaction conditions identified chiral
phosphoric acid TRIP to be most efficient in asymmetric
induction.[4] The reaction in DCM solvent proceeded to form the
desired product 3a in 89% ee (Scheme 1). However, the catalyst
exhibited almost no turnover, providing only 12% yield in 60
hours (<20% conversion). Although the use of other catalysts or
solvents could improve the conversion to some extent,
unfortunately the enantioselectivity was uniformly compromised
(screening details in the SI).
[]
Dr. M. Chen and Prof. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (China)
E-mail: sunjw@ust.hk
[]
Financial support was provided by NSFC (21490570, 21572192),
Hong Kong RGC (16304115, ECS605812, 16304714, 16311616),
and Shenzhen STIC (JCYJ20160229205441091). We thank Dr.
Zhaobin Wang for preliminary studies.
Scheme 1. Preliminary results.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
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10.1002/anie.201706579
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We reasoned that the ineffective catalyst turnover might be
due to product inhibition resulting from the basic pyridine-type
side product generated from the Hantzsch ester oxidation. In
order to facilitate catalyst turnover while maintaining good
enantioselectivity, we resorted to using acid additive in hope of
recovering the catalyst activity.[5] As shown in Table 1, different
achiral Brønsted acids of various acidity were evaluated. Weak
acids, such as thiourea, NH4Cl, and phenol, could not effectively
improve the yield. Carboxylic acids, meldrum’s acid, and boric
acid could improve the yield to moderate levels, but
enantioselectivity dropped. Likewise, the use of strong acid p-
TsOH resulted in significant improvement of yield, but
unfortunately the enantioselectivity was also dramatically
decreased (entry 9). It is therefore important to balance the yield
and enantioselectivity. We reasoned that acidity of the additive
should be strong enough to solve the product inhibition issue,
a further lower loading (40 mol%) led to significant decrease in
yield (entry 14). Next, a different Hantzsch ester 2b was found to
improve the enantioselectivity to 91% ee (entry 15). The reaction
time could also be shortened at a slightly elevated temperature
(entry 16). Thus, after considerable efforts in careful tuning of
the parameters and additives, we identified this superior set of
optimum conditions to achieve both excellent yield and
enantioselectivity.
With the above optimized conditions, we next examined the
reaction scope (Scheme 2). A range of racemic tertiary
propargylic alcohols participated smoothly in the one-pot
process to form the desired diarylmethyl alkynes with both good
efficiency and good to excellent enantioselectivity. Both internal
and terminal alkynes, including silyl-protected alkynes, could be
formed. Different electron-withdrawing and electron-donating
groups did not affect the reaction efficiency. Silyl-protected
but not too strong to compete with the catalyst for enantiocontrol. alcohol can be tolerated under the acidic conditions.
With this in mind, we continued fine tuning of the additive acidity.
For example, substituted phenylboronic acids were next
evaluated.[6]
Heterocycles, such as thiophene, can be incorporated into the
products. Alkyl substitution at the propargylic position also
proceeded to form the desired product 3y. In this case,
essentially same results were observed with or without the
additive. Finally, it is worth noting that this is the first
organocatalytic approach for the establishment of such diaryl
propargylic stereogenic centers, which is complementary to the
limitedly available metal catalytic examples. [7]
Table 1: Evaluation of additives.[a]
Scheme 2. Substrate scope.[a]
Entry
Additive
yield (%)
ee (%)
1
2
thiourea
NH4Cl
21
16
12
41
24
35
37
57
86
53
20
95
95
57
95
98
76
82
81
33
77
78
81
70
33
83
80
79
83
85
91
91
3
PhOH
4
AcOH
5
PhCO2H
6
tBuCO2H
7
meldrum's acid
B(OH)3
8
9
p-TsOH
10
11
12
13
14
15[b]
16[b][c]
PhB(OH)2 (BA1)
BA2
BA3
BA3 (60 mol%)
BA3 (40 mol%)
BA3 (60 mol%)
BA3 (60 mol%)
[a] Yield was determined by1H NMR analysis of the crude mixture, and the ee
value was determined by HPLC with a chiral stationary phase. [b] Run with 2b
in place of 2a. [c] Run at 38 oC for 12 h.
To our delight, p-fluorophenylboronic acid turned out to be most
effective, leading to the best combination of yield and
enantioselectivity (95% yield, 79% ee, entry 12). Decreasing its
loading to 60 mol% still remained highly effective (entry 13), but
[a] Isolated yield. The ee value was determined by HPLC with a chiral
stationary phase. [b] Run with 1.0 equiv of 4-fluorophenylbornonic acid. [c]
Run for 36 h. [d] Run without 4-fluorophenylbornonic acid.
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To further demonstrate the utility of our process, we carried
out some representative transformations of the product 3a. For
example, hydrogenation of alkyne 3a with the Lindar catalyst
afforded Z-alkene 4 exclusively. In contrast, the reaction
catalyzed by Pd/C resulted in saturated product 5 with excellent
efficiency. Treatment of 3a with NBS led to ortho-bromination of
the phenol unit with excellent selectivity. The product
enantiopurity remained excellent in these transformations.
Furthermore, after triflation of the phenol unit, the alkyne could
isomerize to allene 8 in the presence of Pd(PPh3)Cl2, CuI, and
Et3N. Notably, in this transformation the central chirality at the
propargylic position was successfully transferred to the axial
chirality. Moreover, the triflate 7 could also undergo cross-
coupling reaction to form biaryl product 9. Finally, the alkyne unit
in product 3x could undergo smooth cycloaddition with TsN3 to
form triarylmethane 10. It is worth noting that chiral
triarylmethanes are another important family of useful
molecules.[8]
conversion in 6 hours. Subsequent addition of reductant 2b led
to rapid formation of the desired product 3a with excellent
conversion and enantioselectivity (Eq 2). The fast rate is in
sharp contrast to the slow catalyst turnover in the preliminary
results obtained with all the reagents added in one portion
(Scheme 1). Furthermore, the boronic acid additive BA3 was
added to probe the influence in rate of each step (Eq 3). It is
surprising that in the stepwise addition experiment, there is no
obvious rate acceleration by adding the additive. As alluded
earlier, we suspected that the first step (dehydration) is
significantly retarded due to catalyst deactivation by gradual
generation of the pyridine byproduct P2b (by oxidation of 2b) in
the “one-portion addition” experiment (Scheme 1). While the
second step is not as sensitive as the first step, thus it can still
proceed smoothly even without the boronic acid additive (Eq
2).[10] To further confirm this rationale, the byproduct pyridine
P2b was added to the reaction mixture at the beginning to mimic
the state at partial conversion when P2b is generated (Eq 4). As
expected, treatment of the mixture with the TRIP catalyst led to
very slow conversion. In contrast, the addition of the additive
BA3 resulted in smooth conversion, thereby mimicking the
standard optimized conditions we achieved. Finally, to confirm
that the second step is insensitive to the pyridine byproduct, we
isolated the QM intermediate and subjected it to the reduction
conditions. The reaction proceeded quantitatively with or without
additive. Taken together, these observations suggest that the
role of the additive is to facilitate catalyst turnover in the first step
to outcompete product inhibition.
Scheme 3. Product transformations.
Next, we carried out some control experiments to probe the
reaction mechanism. The reaction with substrate 1a’, in which
the phenol hydroxy group was protected as a methyl ether,
could also react to form the corresponding reduction product 3a’,
but no enantioselectivity was observed (Eq 1). The results
indicate that the para-quinone methide intermediate (QM) is
essential for the excellent enantiocontrol in the reduction step,
presumably owning to the key hydrogen bonding with the chiral
acid catalyst.[9]
In light of the above rationale, we envisioned the possibility of
eliminating additive by sequential addition of reagents. Since the
pyridine byproduct is generated in the second step and it only
inhibits the first step, in principle the second step can be initiated
by adding the reductant upon completion of the first step (i.e.
sequential addition of reagents), provided that the intermediate
is stable enough. Furthermore, we reasoned that a lower
temperature is possible to be used separately for the second
step to allow further improvement on enantioselectivity, since the
second step is facile and enantiodetermining. Gratifyingly, as
expected, this sequential addition protocol worked very
A series of experiments were next carried out to shed light on
the exact role of the additive. Firstly, we closely monitored the
two steps by sequential addition of reagents. In the absence of
the additive and reductant 2b, the reaction of substrate 1a
proceeded smoothly to form the QM intermediate with complete
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10.1002/anie.201706579
Angewandte Chemie International Edition
COMMUNICATION
successfully without the requirement of the boronic acid additive
(Table 2). The enantioselectivity could also be improved at a
as a platform, we have demonstrated that additives can be
beneficial, and moreover, understanding the role of additives
can be even more beneficial to reaction development, which has
probably not been fully recognized previously. The evolution of
the improved synthetic protocol has been described in details,
from the initial no catalyst turnover stage to high efficiency and
enantioselectivity by employing a superior aryl boronic acid
additive to enhance catalyst turnover without interfering with
enantiocontrol. Further understanding the exact role of the
additive led to a further improved protocol obviating the use of
additive. This example may serve to encourage more efforts in
understanding the role of additives to benefit organic sythesis.
o
lower temperature (-20 C) for the second step only. It is worth
noting that in the standard “one-portion addition” protocol, such
a low temperature is not feasible due to the significantly slow
conversion of the first step. Selected examples were re-run
using this improved synthetic protocol, and the products were
obtained with generally improved enantioselectivity. [11] With this
improved protocol, the more common reductant 2a could also
lead to equally good yield and enantioselectivity (Table 2, entry
5). To the best of our knowledge, this is the first example
demonstrating that understanding the role of an additive can
lead to not only improved synthetic protocol, but also eliminating
the use of the additive.
Keywords: asymmetric catalysis • additives • quinone methides
• alkynes • organocatalysis
Table 2: Selected examples with the sequential addition procedure.[a]
[1]
[2]
Reviews on additives in organic synthesis: a) E. M. Vogl, H. Gröger, M.
Shibasaki, Angew. Chem. Int. Ed. 1999, 38, 1570−1577; b) L. Hong, W.
Sun, D. Yang, G. Li, R. Wang, Chem. Rev. 2016, 116, 4006−4123.
a) C. A. Campos, J. B. Gianino, B. J. Bailey, M. E. Baluyut, C. Wiek, H.
Hanenberg, H. E. Shannon, K. E. Pollok, B. L. Ashfeld, Bioorg. Med.
Chem. Lett. 2013, 23, 6874−6878; b) A. Nagarsenkar, L. Guntuku, S. D.
Guggilapu, S. Gannoju, V. Naidu, N. B. Bathini, Eur. J. Med. Chem.
2016, 124, 782−793.
Entry
3
t (h)
yield[b]
ee[c]
1
2
3a
3e
3g
3n
3n
3q
3r
6
6
68%
93%
87%
77%
80%
82%
66%
68%
81%
97% (91%)
96% (87%)
95% (88%)
94% (88%)
94% (83%)
77% (69%)
95% (92%)
97% (92%)
96% (89%)
[3]
a) H. Matsuzawa, K. Kanao, Y. Miyake, Y. Nishibayashi, Org. Lett.
2007, 9, 5561−5564; b) K. kanao, Y. Miyake, Y. Nishibayashi,
Organometallics 2009, 28, 2920−2926; c) K. Kanao, Y. Miyake, Y.
Nishibayashi, Organometallics 2010, 29, 2126−2131. Chirality transfer:
d) S. N. Mendis, J. A. Tunge, Org. Lett. 2015, 17, 5164−5167; e) S.
Tabuchi, K. Hirano, M. Miura, Chem. Eur. J. 2015, 21, 16823−16827.
The TRIP catalyst was first introduced by List: S. Hoffmann, A. M.
Seayad, B. List, Angew. Chem. Int. Ed. 2005, 44, 7424−7427.
Examples of using achiral acid additives in chiral phosphoric acid
catalysis: a) V. N. Wakchaure, P. S. J. Kaib, M. Leutzsch, B. List,
Angew. Chem. Int. Ed. 2015, 54, 11852−11856; b) G. Li, J. C. Antilla,
Org. Lett. 2009, 11, 1075−1078; c) M. Rueping, C. Azap, Angew. Chem.
Int. Ed. 2006, 45, 7832−7835.
3
12
1
4
5[d]
6
1
[4]
[5]
12
2
7
8
3s
3t
2
[6]
For a review and selected examples of using boronic acids as (co-
)catalyst: a) D. G. Hall, Boronic Acids: Preparation and Applications in
Organic Synthesis, Medicine and Materials, John Wiley & Sons, 2012;
b) X. Mo, J. Yakiwchuk, J. Dansereau, J. A. McCubbin, D. G. Hall, J.
Am. Chem. Soc. 2015, 137, 9694−9703; c) X. Mo, D. G. Hall, J. Am.
Chem. Soc. 2016, 138, 10762−10765.
9
12
[a] 1 (0.2 mmol), 4Å MS (200 mg) and A3 (0.02 mmol) stirred at 38 oC until the
disappearance of 1a, then the reaction mixture was cooled to ‒20 oC, 2b (0.21
mmol) was added. [b] The ee value in the parentheses is abstracted from
Scheme 2 using the previous procedure for comparison. [d] Run with 2a
instead of 2b.
[7]
[8]
[9]
The absolute stereochemistry of 3x was determined to be R by
comparing the optical rotation of its derivative (after methylation) with
the data of a known compound. More details are provided in the SI.
a) V. Nair, S. Thomas, S. C. Mathew, K. G. Abhilash, Tetrahedron
2006, 62, 6731−6747; b) M. K. Parai, G. Panda, V. Chaturvedi, Y. K.
Manju, S. Sinha, Bioorg. Med. Chem. Lett. 2008, 18, 289−292.
For a review and selected pioneering examples of catalytic asymmetric
reactions of p-QMs: a) A. Parra, M. Tortosa, ChemCatChem 2015, 7,
1524−1544; b) W.-D. Chu, L.-F. Zhang, X. Bao, X.-H. Zhao, C. Zeng,
J.-Y. Du, G.-B. Zhang, F.-X. Wang, X.-Y. Ma, C.-A. Fan, Angew. Chem.
Int. Ed. 2013, 52, 9229−9233; c) L. Caruana, F. Kniep, T. K. Johansen,
P. H. Poulsen, K. A. Jørgensen, J. Am. Chem. Soc. 2014, 136,
15929−15932; d) Z. Wang, Y. F. Wong, J. Sun, Angew. Chem. Int. Ed.
2015, 54, 13711−13714.
We proposed the following transition state using (R)-TRIP as
the catalyst. In view of the steric demanding δ,δ-disubstituents,
the p-QM electrophile is placed toward the more open front-right
quadrant,[12] with the bulkier aryl-substituent pointing outside of
the catalyst pocket. Then the catalyst-linked Hantzsch ester
nucleophile approaches from the back face. This analysis is in
agreement with the observed stereochemical outcome.
[10] a) The results suggested that the first step is rate-determining; b) Under
the standard conditions, no kinetic resolution of the substrates was
observed.
[11] In the case of 3y, the attempt to use this stepwise addition procedure
led a mixture of products, presumably due to limited stability of the
quinone methide intermediate.
In conclusion, we have developed an efficient organocatalytic
reaction for the synthesis of chiral diarylmethyl alkynes,
complementing metal catalysis in the previously limited known
strategies for the establishment of such propargylic
diarylmethine stereocenters. More importantly, with this process
[12] L. Simón, J. M. Goodman, J. Org. Chem. 2011, 76, 1776−1788.
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10.1002/anie.201706579
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COMMUNICATION
COMMUNICATION
With an organocatalytic process as a
platform, we describe herein the
Min Chen and Jianwei Sun* Page No. –
Page No.
evolution of an improved synthetic
protocol from no catalyst turnover to
high efficiency and enantioselectivity
with and eventually without additives.
It is a rare demonstration of how
Understanding the Role of Additive
Leads to an Improved Synthetic
Protocol Obviating Additive:
Organocatalytic Synthesis of Chiral
Diarylmethyl Alkynes
understanding the role of additive can
significantly benefit organic synthesis.
This article is protected by copyright. All rights reserved.