Dramatic Acceleration of an Acyl Transfer-Initiated Cascade by Using Electron-Rich Amidine-Based Catalysts

Article abstract of DOI:10.1021/acs.orglett.7b03044

A tandem rearrangement of α,β-unsaturated thioesters into tricyclic ene-lactones fails with conventional amidine-based catalysts, but becomes possible when their electron-rich analogs are employed. A highly diastereo- and enantioselective version of this process has been developed using H-PIP 1b, a chiral catalyst prepared over a decade ago, but never utilized since its disclosure.

Full text of DOI:10.1021/acs.orglett.7b03044

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dramatic Acceleration of an Acyl Transfer-Initiated Cascade by Using
Electron-Rich Amidine-Based Catalysts
Nicholas A. Ahlemeyer, Emma V. Streff, Pandi Muthupandi, and Vladimir B. Birman*
Washington University Department of Chemistry, Campus Box 1134, One Brookings Drive, Saint Louis, Missouri 63130, United
States
S
* Supporting Information
ABSTRACT: A tandem rearrangement of α,β-unsaturated thioesters
into tricyclic ene-lactones fails with conventional amidine-based
catalysts, but becomes possible when their electron-rich analogs are
employed. A highly diastereo- and enantioselective version of this
process has been developed using H-PIP 1b, a chiral catalyst prepared
over a decade ago, but never utilized since its disclosure.
nantioselective acyl transfer catalysis has become an
indispensable tool of asymmetric synthesis.1 Amidine-
Scheme 1. Synthesis of Thiochromenes
E
based catalysts (ABCs) introduced by our group in 2004 (cf.
1a, Figure 1)2a have demonstrated their efficacy in a variety of
Figure 1. Representative chiral ABCs.3
Scheme 2. New Tandem Transformation
transformations employing this mode of catalysis.3 Among the
many structural variations of the basic catalyst design, catalysts
2,2b 3,2c and 4a−c2d−f have enjoyed the highest success rate.
However, even they are not without their limitations. Most of
their reported applications rely on the use of relatively reactive
acyl donors, such as anhydrides or activated esters. In this letter,
we demonstrate that electron-rich ABCs succeed in activating
substrates that remain out of reach of their “conventional”
counterparts.
Recently, we reported a highly enantioselective synthesis of
2-substituted thiochromenes 6 from o-(acylthio)benzaldehydes
5 (Scheme 1).4 Encouraged by its success, we set out to explore
a related process that would proceed via a formal [4 + 2]
cycloaddition (Scheme 2). When the enone substrate 10a was
subjected to acyl transfer catalysis by the achiral catalyst DHPB
12a,5 the expected tricyclic ene-lactone 11a formed with good
diastereoselectivity. To our dismay, however, the reaction
proceeded excruciatingly slowly, reaching only 35% conversion
in 7 days. This did not bode well for the development of the
asymmetric version of the new process. Indeed, in the presence
of the chiral catalyst 4b2e no signs of the desired reaction could
be discerned after 1 week.
We reasoned that two steps in the new tandem may be
responsible for the drastically diminished overall reaction rate:
activation of the thioester (Step 1) and the Michael addition of
Received: September 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03044
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
the zwitterionic enolate to the enone moiety (Step 3).
Employing a more Lewis basic catalyst was expected to
accelerate both of the problematic steps. With this in mind, we
performed a DFT study using a nonpolar solvent model6 to
compute the enthalpies of the isodesmic acyl transfer reaction
between the N-acetyl-DHPB cation and several types of achiral
ABCs (Figure 2).7 As expected, derivatives of DHPB bearing
Table 1. Achiral Catalyst Survey
entry
catalyst
t1/2, min
relative rate
dr
b
1
12a
12b
12c
12d
12e
17a
17b
17c
17d
18a
18b
18c
18d
19
ND
1
ND
2
7600
998
841
77
3.20
22.6
31.3
221
210
308
574
537
98
ND
3
ND
4
ND
5
97:3
95:5
96:4
96:4
96:4
93:7
93:7
92:8
91:9
96:4
6
92
7
54
8
27
9
28
10
11
12
13
14
184
96
180
392
509
431
40
33
38
a
b
Conditions: 0.1 M 10a, 0.01 M catalyst, CDCl3, rt. The reaction
stalled after 7 days at 35% conversion.
our early studies: several hundred times slower than DHPB!5b
Even though this dramatic reversal in the relative activity of the
two catalysts was easy to rationalize mechanistically, given the
much lower reactivity of the thioester moiety compared to an
anhydride, we were nevertheless surprised by the magnitude of
this effect.
Encouraged by these findings, we synthesized chiral catalysts
20−22 and 1b and tested them in the enantioselective variant
of the rearrangement (Table 2). Catalyst 20, the dimethylami-
no derivative of HBTM-2 4b, provided the highest
enantioselectivity, but required 5 days to reach completion
(entry 1). Surpisingly, 21 gave only poor ee and displayed the
lowest activity (entry 2), despite the fact that its analog 17c was
Figure 2. Relative acylation enthalpies of some achiral ABCs.
electron-donating substituents on the benzene ring (12b−e)
produced strongly negative values. More interestingly, bicyclic
isothioureas 17a and 18a disclosed recently by Okamoto et al.8
displayed considerably higher intrinsic Lewis basicities than
DHPB itself and were further enhanced by substitution on the
phenyl group (17b−d, 18b−d). Finally, the highest Lewis
basicity was predicted for DHIP 19the very first ABC that
served as the starting point for designing this whole class of
catalysts.3a With these results in hand, we synthesized the
catalysts shown in Figure 2 and tested their activity in the
rearrangement of thioester 10a.9
a
Table 2. Chiral Catalyst Survey
Electron-rich derivatives of DHPB 12b−e produced
considerably increased reaction rates compared to that of the
parent compound (Table 1, entries 2−5 vs 1). Bicyclic
isothioureas 17 and 18 (entries 6−13) were even more
activemuch more than DHPB derivatives with similar
computed acylation enthalpies (see, e.g., 17a and 18a vs 12d
or 17d and 18d vs 12e). These results were all the more
remarkable given the fact that catalysts 17a−c and 18a
performed slower than DHPB 12a in the acylation of 1-
phenylethanol with anhydrides in Okamoto’s study.8 Finally,
DHIP 19 displayed catalytic activity comparable to the fastest
bicyclic isothioureas (entry 14). This was in sharp contrast to
its poor performance in the acetylation of alcohols observed in
a
Conditions: 0.2 M 10a, 0.02 M catalyst, CDCl3, rt.
B
DOI: 10.1021/acs.orglett.7b03044
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the fastest among the achiral catalysts tested (Table 1, entry 8).
Gratifyingly, both 228 and H-PIP 1b2a produced excellent
enantioselectivity and good activity (entries 3 and 4). Because
1b was the easiest of the four catalysts to prepare, we selected it
to test the substrate scope of our new transformation (Figure
3).
group. Excellent diastereoselectivities (dr ca. 20:1) were
observed in all thiochromanes produced in the reaction.
Enantioselectivities above 90% ee were obtained in all cases
but one (11f). Finally, to demonstrate the scalability of the
rearrangement, we carried it out on 1 g (2.7 mmol) of substrate
10a and obtained an 86% yield and 95% ee.
In conclusion, we have developed a new highly enantiose-
lective and waste-free tandem transformation of thioesters into
fused thiochromanes. A simple DFT study has enabled us to
identify the most promising classes of catalysts to test and thus
greatly facilitated our undertaking. It is somewhat ironic that
the best results were achieved with H-PIP 1b, the very first
chiral ABC to be synthesized. In our original study 13 years
ago, which focused on the acylation of benzylic alcohols with
anhydrides, H-PIP proved to be considerably inferior to its
more electron-deficient derivatives (e.g., CF3−PIP 1a, Figure 1)
and, as a result, has been completely neglected by the
asymmetric catalysis community since its disclosure. Its success
in the present study underscores the potential of H-PIP and
other electron-rich ABCs in activating moderately reactive acyl
donors, such as thioesters. Studies in this direction are
underway in our laboratory and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03044.
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: birman@wustl.edu.
ORCID
Vladimir B. Birman: 0000-0003-0299-358X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation for the continued
support of our studies (CHE 1012979, CHE 1566588).
REFERENCES
■
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C
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Letter
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(10) While this manuscript was under consideration, a paper was
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D
DOI: 10.1021/acs.orglett.7b03044
Org. Lett. XXXX, XXX, XXX−XXX