Organocatalytic asymmetric tandem condensation-intramolecular rearrangement-protonation: An approach to optically active α-amino thioester derivatives

Article abstract of DOI:10.1039/c1ob06623d

An unprecedented and conceptually novel chiral Bronsted base/Bronsted acid catalytic method for the enantioselective synthesis of α-amino thioesters through a tandem condensation-intramolecular rearrangement-protonation has been developed which provides a number of important synthetic building blocks in good yield and with moderate to good enantioselectivities.

Full text of DOI:10.1039/c1ob06623d

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COMMUNICATION
Organocatalytic asymmetric tandem condensation–intramolecular
rearrangement–protonation: an approach to optically active a-amino thioester
derivatives†‡
Francesca Capitta, Angelo Frongia,* Pier Paolo Piras, Patrizia Pitzanti and Francesco Secci
Received 22nd September 2011, Accepted 21st October 2011
DOI: 10.1039/c1ob06623d
An unprecedented and conceptually novel chiral Brønsted
base/Brønsted acid catalytic method for the enantioselective
synthesis of a-amino thioesters through
a
tandem
condensation–intramolecular rearrangement–protonation
has been developed which provides a number of important
synthetic building blocks in good yield and with moderate to
good enantioselectivities.
Asymmetric protonations of prochiral enolates have received
great attention as efficient methods for the construction of
optically active a-substituted carbonyl compounds.1 The majority
of such reactions have been conducted with preformed enolates
and a stoichiometric amount of chiral proton source.2 Recent
research witnesses an increasing application of organocatalysis3
in enantioselective protonation reactions4 and notably, some
enantioselective protonations have been successfully incorporated
into tandem or cascade processes to give access to structurally
complex molecules.5 These methods are based on the use of an
enol or enolate prepared in situ from a suitable precursor in the
absence of metal components. In particular, only a few exam-
ples of organocatalytic tandem intramolecular rearrangement–
enantioselective protonation have been reported.
In pioneering work, Bolm and co-workers developed the
enantioselective protonation of an enediol prepared by a base-
promoted rearrangement yielding chiral a-hydroxy esters with up
to 83% ee.6 In 2011, Nakamura and Hayashi disclosed a highly
enantioselective protonation of ester enolates prepared through
the phospha-Brook rearrangement.7 Recently, we reported an
enantioselective organocatalytic rearrangement of a-acyloxy-b-
ketosulfides to a-acyloxy thioesters8 which involves the generation
of a transient enolate through a proton abstraction from terminal
carbon by a chiral base (cinchona alkaloid),9 followed by an in
situ enantioselective protonation. Thus, as a logical extension
Scheme 1 Competitive reaction pathways leading to a-amino thioester 3
and a-acyloxy amide 4 adducts.
of our work, we planned the application of this concept to the
preparation of chiral a-amino thioesters (Scheme 1, path b). In this
respect, it was hypothesized that catalytic asymmetric synthesis of
a-amino thioesters could be achieved through an enantioselec-
tive protonation-terminated chiral acid-catalyzed intramolecular
rearrangement,10 initiated by an in situ imine formation from an
a-acyloxy-b-ketosulfide and a primary amine.
Anyway, in planning our synthetic approach, that would start
with the formation of the necessary intermediate imine A, by
the acid catalyzed reaction of 1 with 2, it was evident that
two reaction paths were possible (Scheme 1, path a and b).
As a matter of fact, the acid catalyzed reaction of 1 with 2
could lead either to the corresponding a-acyloxy amide 4, via
a nucleophilic acyl substitution terminated intramolecular acyl
migration (path a), or to the desired a-amino thioesters 3. This last
transformation can occur through the intermediacy of the imine
Dipartimento di Scienze Chimiche, Universita` degli studi di Cagliari,
Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, I-
09042, Monserrato (Cagliari), Italy. E-mail: afrongia@unica.it, angelo.
frongia@gmail.com; Fax: (+)390706754388
† This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡ Electronic supplementary information (ESI) available: Experimental
protocols, proof of the absolute stereochemical configuration, copies of
NMR spectra and HPLC chromatograms. See DOI: 10.1039/c1ob06623d
490 | Org. Biomol. Chem., 2012, 10, 490–494
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The Royal Society of Chemistry 2012
©

Table 1 Selected screening resultsa
Entry
Tertiary amine
Acidic additive
Ratio 3aa :4aab
Yield 3aa(%)c
ee 3aa(%)d
1
I
I
I
I
I
I
I
I
TsOH
>20 : 1.0
2.3 : 1.0
>20 : 1.0
>20 : 1.0
>20 : 1.0
>20 : 1.0
1.0 : 2.8
66
40
47
48
79
20
7
66
74
68
50
16
10
56
50
n.d.
-70
74
-60
rac
-82
76
2e
(R)-BDHP
(R)-TRIP
(-)-CSA
HCl
HBr
BzOH
3
4
5
6f
7g
8h
AcOH
1.0 : 8.2
1.0 : 3.3
6
5
9i
I
p-NO2PhOH
(R)-BDHP
(R)-BDHP
(R)-BDHP
(R)-BDHP
(R)-BDHP
(S)-BDHP
(R)-BDHP
none
10
11
12
13j
14k,l
15m,n
16
17o
II
III
IV
V
VI
I
>20 : 1.0
>20 : 1.0
>20 : 1.0
10.1 : 1.0
7.3 : 1.0
>20 : 1.0
>20 : 1.0
1.0 : >20
34
33
72
30
62
66
49
—
none
I
rac
—
a Conditions: 0.22 mmol of 1a, 0.27 mmol of 2a, 0.044 mmol of tertiary amine and 0.044 mmol of acidic additive, 0.5 mL toluene. b Determined by
1H-NMR spectroscopic analysis of the crude reaction mixture. c Isolated yield after chromatography. d Determined by HPLC analysis using a chiral
stationary column. e 16% yield of 4aa was obtained. f At room temperature, 16 h. g 19% yield of 4aa was obtained. h 64% yield of 4aa was obtained. i 75%
yield of 4aa was obtained. j Reaction carried out over 8h. k 8% yield of 4aa was obtained. l Reaction carried out over 24 h. m 76% of yield after 24h. n When
decreasing the amount of catalyst to 10 mol%, a drop in both the reaction rate (27% yield) and ee value of the product 3aa (72% ee) was observed. o 50%
yield of 4aa (78% ee) was obtained. BDHP: 1,1¢-Binaphthyl-2,2¢-diylhydrogenphosphate; TRIP: 3,3¢-bis(2,4,6-triisopropylphenyl)-1,1¢-binaphthyl-2,2¢-
diylhydrogenphosphate. n.d. = not determined.
A, its tautomerisation to the corresponding enamines B and final
intramolecular rearrangement of the E geometric isomer (path b).
To test our hypothesis, the reaction between a-acyloxy-b-
ketosulfide 1a and p-anisidine 2a was chosen as a model reaction,
for catalyst screening and evaluation (Table 1).
We began our investigations by examining the ability of two
organic acids (results not shown in Table 1) to promote the
organocatalytic tandem reaction. Pleasingly, when we carried out
the reaction with TsOH (10 mol%, in CH2Cl2, 40 ◦C, 16 h) the only
isolated compound from the reaction was the a-amino thioester
Scheme 2 Working mechanistic hypothesis of cooperative catalysis for
the asymmetric synthesis of a-amino thioesters 3.
3aa (45% yield), and no trace of the corresponding a-acyloxy
◦
amide 4aa was observed. (-)-CSA (20 mol%, in CH2Cl2, 40 C,
16 h) was equally effective, affording the desired adduct 3aa in
good yields (64%) but as a racemate.
base/acid combined salt, would activate the transient intermediate
C toward an in situ transfer of the proton, in a stereoselective
manner, from the quinidine ammonium counterion (Scheme 2).4f,g
To our delight, quinidine I in combination with TsOH, in
toluene at 60 ◦C, was found to be effective (Table 1, entry 1),
affording the product 3aa in good yield (66%) and with moderate
enantioselectivity (66% ee). Encouraged by this result, we decided
to examine the importance of the counteranion for what concerns
its role in the asymmetric induction using different acidic additives
(entries 2–9).
On the basis of these observations we decided to develop an
asymmetric version of this new reaction and envisioned that
a chiral Brønsted base/Brønsted acid combined salt catalyst
(bifunctional catalytic system),11,12 made by reacting the easily
available quinidine I with an acidic additive, could be an effective
catalyst for the enantioselective tandem reaction.
In fact, we speculated that protonation of quinidine I by an acid
derivative would generate a chiral ion pair as the active catalytic
species wherein the anion, provided by the acid component of the
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Gratifyingly, the expected product 3aa was formed with good
enantioselectivity (74% ee), although, with low chemical yield
(40%) and associated with a significant amount of 4aa (16%
yield) when the (R)-BDHP salt of quinidine I was used (entry
2). The results obtained with (R)-TRIP, (-)-CSA, HCl, HBr,
BzOH, AcOH, and p-NO2PhOH did not bring any appreciable
improvement but deserve some comment (entries 3–9).
As it can be seen from the data shown in Table 1, it is interesting
that the selectivity (3 : 4 ratio) of the reaction seemed to be
dependent on the pKa differences of the acidic additive. As a
matter of fact, it is well-known that ammonium salts behave as
a dynamic complex, and are equilibrated with “free amines” and
“free acids” in solution.11a–c Depending upon the nature of the
amine and the acid from which the salt is derived, its concentration
and the nature of the organic solvent employed, the ion pairs may
either “dissociate” or “associate” into a tighter ion-pair.
The observed difference in selectivity may be, therefore, related
to the capacity of the amine salt used as catalyst to dissociate to
its “free amine” and “free acid”. Indeed, as a general trend, for a
given tertiary amine (e.g. quinidine I) acidic additives with strong
Brønsted acidity induced higher selectivity toward the formation
of 3aa (Table 1, entries 1–6) while less acidic additives offered better
4aa selectivity (entries 7–9). In these cases, probably, the “free
amine” and “free acid” rather than the corresponding ammonium
salt may be the catalytic active species in solution (Scheme 3) and
it is reasonable to expect that the preferential formation of 4aa is
promoted by the protonation of the carbonyl group via the “free
acid” and subsequent a-proton abstraction by the “free base” (a
more strongly basic base compared to the anion provided by the
acid component of the base/acid combined salt catalyst).
(entry 12) displayed good reactivity (72% yield) and moderate
enantioselectivity (-60% ee) giving, as expected, the desired
product with opposite configuration.13 DMAP V was catalytically
active, but provided 3aa in 30% yield as a racemate (entry 13).
It is worth noting that the reaction stereoselection appears to be
affected essentially by the nature of the tertiary amine, as further
demonstrated by the fact that either the (R)-BDHP or the (S)-
BDHP ammonium salt of I (entry 2 and entry 15) gave the same
product 3aa, with comparable enantiomeric excess (74% and 76%
ee respectively). Anyway, using (S)-BDHP, 3aa was obtained as
the sole product in 66% yield showing a higher catalytic activity
and a better selectivity (3 : 4 ratio).
Further catalyst evaluation screened a series of commercially
available biscinchona alkaloids under similar reaction conditions
(entry 14, see also the ESI‡). Satisfyingly, (DHQD)2PHAL VI
proved to be superior to quinine II in terms of yield (62%) and
enantioinduction, and ent-3aa was obtained with up to -82% ee.
Remarkably, (R)-BDHP alone was much less active than the
corresponding ammonium salts and afforded the product 3aa
(49% yield) with almost no enantioselectivity (entry 16), whereas
quinidine I, used as a free base, furnished the a-acyloxy amide
4aa in moderate conversion (50% yield and 78% ee) through
a base-mediated intramolecular acyl migration8 followed by a
nucleophilic acyl substitution (entry 17).
Based on the above optimization studies, we next examined
the scope and limitation of the reaction using the catalyst I/(S)-
BDHP (the results are reported in Table 2). With regard to the
substituent at the 2 position of 1, not only a methyl group but also
ethyl and ethylphenyl (Table 2, entries 2–3) can be successfully
utilized to afford derivatives 3ba and 3ca with good yields (62–
75%) although with concomitant decreasing enantioselectivities
(22 and 16% ee respectively). Notably, the reaction of 1d, bearing
a phenyl substituent at the 2 position, occurred preferentially via
a nucleophilic acyl substitution terminated intramolecular acyl
migration mechanism, affording, as a major product (67% yield
and 26% ee), the corresponding a-acyloxy amide 4da (entry 4).
In this case, the impressive reversal of selectivity between 3da
and 4da observed is likely due to the enhanced a-proton acidity
(provided by phenyl substitution) of the methine position of 1d,
which allows deprotonation by the weakly basic phosphate anion
leading to the enol and, subsequently via path a, the corresponding
a-acyloxy amide 4da.
The protocol was efficient in the presence of aromatic sub-
stituents in the phenylthio group (e.g. bromine in 1e and a methyl
group in 1f) providing the expected products in good yield (entries
5 and 6, 47% and 62% respectively) and optical purity (54–62%
ee). Moreover, there appears to be significant tolerance toward
structural and electronic variations of the primary amines 2
(entries 7–12, 52–77% yield and 54–70% ee), to enable access
to a broad variety of densely functionalized a-amino thioester
derivatives.
Scheme 3 Path a versus Path b.
The reaction can be rationalized by assuming the mechanism
shown in Scheme 4. The chiral ammonium salt catalyzes the
generation of enamine B from 1 and 2. An acyl migration may
reasonably be expected to furnish a transient 2,3-dihydro-oxazol-
2-ol C followed by an in situ enantioselective protonation. Proton
transfer from the protonated quinidine I to transient enolate D
provides the product 3 and releases the catalyst back into the cycle.
The protonation can occur within the catalyst–enolate ion pair.14
The subsequent optimization of our protocol has been carried
out by screening the catalytic performance of different tertiary
amines (entries 10–14) with (R)-BDHP as a fixed acidic additive.
Access to ent-3aa (34% yield and -70% ee) could be achieved
using quinine II (pseudo-enantiomer of I) as catalyst (entry 10).
Cinchonine III (entry 11) gave satisfying ee (74%) albeit with
low conversion (33% yield), whereas (-)-N-methylephedrine IV
492 | Org. Biomol. Chem., 2012, 10, 490–494
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Table 2 Preliminary scope of the reactiona
Entry
Substrates
Products
Ratio 3 : 4b
Product yield 3 : 4 (%)c
ee 3(%)d
1
1a; 2a
1b; 2a
1c; 2a
1d; 2a
1e; 2a
1f; 2a
1a; 2b
1a; 2c
1a; 2d
1a; 2e
1a; 2f
1a; 2g
3aa
>20 : 1.0
>20 : 1.0
>20 : 1.0
1.0 : 5.3
2.7 : 1.0
11.4 : 1.0
>20 : 1.0
3.3 : 1.0
10.0 : 1.0
1.6 : 1.0
13.0 : 1.0
5.5 : 1.0
76 : —
75 : —
62 : —
10 : 67
47 : 17
62 : 5
60 : —
60 : 18
70 : 7
76 (S)e
22
16
rac
54
62
70
64
56
58
2f
3g
4
3ba
3ca
3da : 4da
3ea : 4aa
3fa : 4aa
3ab
5
6
7h
8i
3ac : 4ac
3ad : 4ad
3ae : 4ae
3af : 4af
3ag : 4ag
9i
10i
11i
12i
53 : 34
77 : 6
52 : 9
62
54
a Conditions: 0.22 mmol of 1, 0.27 mmol of 2, 0.044 mmol of I/(S)-BDHP, 0.5 mL toluene, 24 h, 60 ◦C. b Determined by1H NMR spectroscopic analysis
of the crude reaction mixture. c Isolated yield after chromatography. d Determined by HPLC analysis using a chiral stationary column. e For proof of the
absolute stereochemical configuration, see the ESI.‡ f 36% yield of 3ba (3 : 4 ratio = 3.1 : 1.0) with -64% ee, using VI/(R)-BDHP as catalyst. g 18% yield
of 3ca (3 : 4 ratio = 1.0 : 1.3) with -64% ee, using VI/(R)-BDHP as catalyst. h Reaction carried out over 4 h. i Reaction carried out over 48 h.
protonation. Although the enantioselectivities are still moderate,
these preliminary results obtained form the basis for further
developments.
The optimisation and extension of this reaction, as well as
studies aimed at increasing the enantioselectivity are currently
under investigation in our laboratories.
Acknowledgements
Financial support from the MIUR, Rome, and by the University
of Cagliari (National Project “Stereoselezione in Sintesi Organica
Metodologie ed applicazioni”) and from CINMPIS and FIRB
2008 is gratefully acknowledged. We thank Professor David Aitken
for useful discussions.
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13 It is noteworthy that both quinine II and (-)-N-methylephedrine IV
have the same configuration (1R,2S) as the amino alcohol moiety.
14 The mechanistic details and transition state structure of this new
reaction, after further experimentation, will be published in due
course.
494 | Org. Biomol. Chem., 2012, 10, 490–494
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