Bioinspired, base- and metal-free, mild decarboxylative aldol activation of malonic acid half thioesters under phase-transfer reaction conditions

Article abstract of DOI:10.1002/adsc.201400915

Utilizing 'off the shelf' commercially available, cheap, small synthetic molecules that mimic the efficient mediation of important bioreactions utilized by Nature is not only highly sought after but also currently highly topical. This paper details our preliminary efforts at developing a unique base- and metal-free phase-transfer-mediated malonic acid thioester (MAHT) 'activation protocol' that efficiently generates (±)-β-thioesters. Our bioinspired aldol process is exceptionally mild, conducted under near neutral pH reaction conditions, does not require an inert, oxygen-free atmosphere or anhydrous reaction conditions and is highly atom-economic. Exemplifying the utility of our protocol, the synthesis of an array of structurally and functionally diverse (±)-β-hydroxy thioesters equipped with highly prized functionality, i.e., chlorine, bromine, fluorine, nitrile and nitro groups, is reported, as is the diastereoselective potential of this important reaction.

Full text of DOI:10.1002/adsc.201400915

FULL PAPERS
DOI: 10.1002/adsc.201400915
Bioinspired, Base- and Metal-Free, Mild Decarboxylative Aldol
Activation of Malonic Acid Half Thioesters Under Phase-Transfer
Reaction Conditions
Sean P. Bew,a,* G. Richard Stephenson,a,* Jacques Rouden,b Polly-Anna Ashford,a
Manuel Bourane,a,c Agathe Charvet,a,c Virginie M. D. Dalstein,a,d
Raphael Jauseau,a,c G. D. Hiatt-Gipson,a and Luis A. Martinez-Lozanoa
a
School of Chemistry, UEA, Norwich Research Park, Norwich, NR4 7TJ, U.K.
Fax: (+44)-1603-592-003; phone: (+44)-1603-593-142 (SPB), (+44)-1603-592-019 (GRS); e-mail: s.bew@uea.ac.uk or
g.r.stephenson@uea.ac.uk
b
Laboratoire de Chimie MolØculaire et Thioorganique, UniversitØ de Caen Basse Normandie, 6, Bd MarcØchal Juin, 14032
Caen, France
c
DØpartement Chimie Fine et IngØnierie, INSA Rouen, Avenue de l’UniversitØ, 76801 Saint-Etienne-du-Rouvray, Rouen,
France
d
National High School of Chemistry, Mulhouse, 3 rue Alfred Werner, 68093 Mulhouse, France
Received: September 18, 2014; Revised: February 16, 2015; Published online: March 25, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400915.
Abstract: Utilizing ꢀoff the shelfꢁ commercially avail- conditions and is highly atom-economic. Exemplify-
able, cheap, small synthetic molecules that mimic the ing the utility of our protocol, the synthesis of an
efficient mediation of important bioreactions utilized array of structurally and functionally diverse (Æ)-b-
by Nature is not only highly sought after but also hydroxy thioesters equipped with highly prized func-
currently highly topical. This paper details our pre- tionality, i.e., chlorine, bromine, fluorine, nitrile and
liminary efforts at developing a unique base- and nitro groups, is reported, as is the diastereoselective
metal-free phase-transfer-mediated malonic acid thio- potential of this important reaction.
ester (MAHT) ꢀactivation protocolꢁ that efficiently
generates (Æ)-b-thioesters. Our bioinspired aldol
process is exceptionally mild, conducted under near Keywords: aldol reaction; base-free conditions; de-
neutral pH reaction conditions, does not require an carboxylation; metal-free conditions; phase-transfer
inert, oxygen-free atmosphere or anhydrous reaction process
Introduction
these in mind, a significant motivating force for
modern synthetic chemistry is the development of
À
Nature employs mild, ambient temperature, aqueous novel, environmentally green, laboratory-based C C
reaction conditions, polyketide synthase (PKS) and bond forming reactions that are also amenable to
acetyl-CoA derived malonic acid half thioesters aqueous conditions and, importantly, proceed via
(MAHTs, see 2, Scheme 1) as valuable building ꢀnon-metal, non-baseꢁ MAHT activation.[6]
À
blocks for C C bond formation. It is important to
In this paper we report, for the first time, an ex-
À
note that Natureꢁs use of MAHTs in C C bond for- tremely mild ꢀnon-metal, non-baseꢁ MAHT activation
mation proceeds via a ꢀnon-metal, non-baseꢁ MAHT protocol that, similar to PKS,[7] proceeds in the pres-
À
hydrogen bond-mediated ꢀactivationꢁ process. By way ence of water and generates new C C bonds via an
of an example employing aqueous conditions, the essentially neutral decarboxylative aldol reaction. Not
Streptomyces bacterium uses PKSs to generate struc- only is our phase-transfer-mediated MAHT activation
turally diverse and important bioactive metabolites unique, it is also amenable to a wide variety of struc-
such as rifamycin (antibiotic)[1] callystatin A (anti- turally and functionally diverse aldehydes, employs
cancer),[2] psymberin (anticancer),[3] pridamicin (anti- cheap ꢀoff the shelfꢁ readily available, commercial
fungal)[4] and 6-deoxyerythrolide B (antiviral).[5] With quaternary ammonium salts and generates CO2 as the
the need for sustainable syntheses of entities such as only by-product. This, in conjunction with our recent-
Adv. Synth. Catal. 2015, 357, 1245 – 1257
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1245

FULL PAPERS
Sean P. Bew et al.
species 5 which ꢀcollapsesꢁ forming an acetyl-CoA
bound b-keto thioester 6.[10]
Over the last decade numerous groups have ex-
ploited the chemistry of ꢀactivatedꢁ MAHTs in cutting
edge transition metal[11] or base-mediated[12] aldol re-
actions. Thus Shair et al. described an elegant metal-
mediated aldol reaction that afforded (Æ)-b-hydroxy
thioesters from a selection of non-activated, activated,
aliphatic or aromatic aldehydes and their reaction
with copper(II) (2-ethylhexanoate) 8, 5-methoxyben-
zimidazole 9 and 3-benzylthio-3-oxopropanoic acid
7.[11d] By way of example, non-activated benzaldehyde
afforded S-benzyl (Æ)-3-hydroxy-3-phenylpropane-
thiolate 10 in a 22% yield (Scheme 2). Similarly ele-
gant work reported by Fagnou et al. involved the
base-mediated activation of MAHT 11 and its aldol
reaction with the electron-poor ketone in ethyl pyru-
vate 12. Thus, incorporating[12f] one equivalent of tri-
ethylamine, 3-thiophenyl-3-oxopropanoic acid (11)
and 12, the initially formed addition adduct (not
shown) subsequently underwent decarboxylation af-
fording (Æ)-13 in a 70% yield.
Scheme 1. Biosynthetic acetyl-CoA-derived MAHT ꢀactiva-
tionꢁ, thioenolate formation and finally aldol condensation
forming acetyl-CoA-bound b-keto thioester 6.
ly reported two-step, solvent-free, multigram synthe-
During our recent studies on developing efficient
sis[8] of MAHTs, confers significant environmental routes to MAHTs and MAHOs we identified signifi-
benefits to our protocol over conventional base- or cant reaction rate enhancements for hydrogen/deuteri-
metal-mediated aldol reactions employing MAHTs.
um (H/D) exchanges within certain aryl thioester
As noted, Nature generates a wealth of biologically MAHTs. A considerably smaller effect was observed
active and diverse secondary metabolites via PKS bio- for aryl ester-derived MAHOs. By way of example,
synthesis.[9] Focusing in on their mode of action, PKSs MAHT 14 (X=Br) underwent an H/D exchange with
are metal-free enzymes that contain an important a k of 208 whilst its chalcogen analogue MAHO 15
triad of a-amino acids at their ꢀactive siteꢁ, i.e., His, (X=Br) had a k of only 31.[8] With a view to estab-
Cys and Asp. Critical to the biosynthetic sequence of lishing the origins of this significant rate difference
events is the requirement for both the Asp-derived (for the seemingly trivial S to O exchange) a ꢀbench-
CONH2 group and the protonated histidine 1 to hy- markꢁ DFT study concluded that the rate enhance-
drogen-bond and ꢀactivateꢁ the carbonyl group of the ment associated with the MAHTs was associated with
b-thioester within the acetyl-CoA-derived MAHT increased delocalization of the sulfur lone-pair into
anion (Scheme 1). When ꢀactivatedꢁ, 2 releases CO2 the adjacent carbonyl group affording greater levels
generating within a lipophilic ꢀpocketꢁ a thioenolate of the more reactive enol-forms, i.e., cisoid 14
similar to 3, this subsequently reacts with an adjacent (Scheme 3) and the corresponding transoid form (not
cysteine-bound thioester 4 generating a tetrahedral shown). In contrast, within MAHOs the analogous
Scheme 2. Metal- and base-activated MAHT incorporating aldol reactions generating (Æ)-10 and (Æ)-13, respectively.
1246
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 1245 – 1257

FULL PAPERS
Bioinspired, Base- and Metal-Free, Mild Decarboxylative Aldol Activation
Scheme 3. A ꢀbenchmarkedꢁ DFT study confirmed the enhanced reactivity of aryl-substituted MAHTs. i.e., cisoid-14 in H/D
exchange. This study proposes to exploit the enhanced reactivity of MAHTꢁs developing a base- and metal-free aldol reac-
tion affording entities based on (Æ)-17
oxygen atom was not so effective at donating its lone have been proposed by Fagnou et al. in using
pairs, consequently the ability of cisoid 15 and its MAHO.[12d]
transoid form (not shown) to undergo H/D exchange
was reduced.
Whilst researching for examples of ꢀbase-free
chemistryꢁ we were intrigued by a report from Maruo-
Having identified the increased reactivity associat- ka et al. that detailed a phase-transfer conjugate addi-
ed with the enol-form of aryl-derived MAHTs we tion reaction between b-nitrostyrene and rac-N-Boc-
considered the possibility that under suitable reaction 2-phenyloxindole that generated (Æ)-19. Thus in a bi-
conditions they may participate in a unique base- and phasic toluene/water solvent system, 19 was generated
metal-free aldol reaction generating b-hydroxy thio- in a 95% yield with tetrabutylammonium bromide
esters similar to (Æ)-17 (Scheme 3) derived from the (TBAB) and the base potassium carbonate. Alterna-
decarboxylation of adducts based on (Æ)-16 which tively, under base-free chiral phase-transfer conditions
optically active (S,S)-19 was afforded in a 93% yield
in the presence of an enantiomerically enriched biaryl
quaternary ammonium salt (see box, Scheme 4). Mar-
uoka et al. proposed in their asymmetric base-free
process that the optically active bifunctional phase-
transfer agent generated an in situ ꢀenolate chiral ion-
pairꢁ similar to 20 and this mediated the observed
asymmetric Michael reaction affording (S,S)-19.[13]
Results and Discussion
We pondered on the possibility that by dovetailing
the enhanced reactivity associated with aryl thioester-
derived MAHTs together with a phase-transfer proto-
col it might prove viable to generate a unique base-
free, metal-free aldol reaction. Thus in the context of
the aldol chemistry outlined in Scheme 3, we initiated
the first preliminary steps towards establishing if thio-
phenol-derived MAHT (21) and phenol-derived
MAHO (22) or their enol-forms were nucleophilic
Scheme 4. Base-free asymmetric conjugate addition reaction
between b-nitrostyrene and rac-N-Boc-2-phenyloxindole.
Adv. Synth. Catal. 2015, 357, 1245 – 1257
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1247

FULL PAPERS
Sean P. Bew et al.
Scheme 5. Comparing the reactivity of MAHT 21 and MAHO 22 with 4-nitrobenzaldehyde under phase-transfer tetrabutyl-
ammonium bromide (TBAB) reaction conditions.
enough to react with an electron-poor aldehyde. Table 1. Effect of different solvents on the ratio of (Æ)-33,
35 and 4-nitrobenzaldehyde (PNB).
Choosing 4-nitrobenzaldehyde as a ꢀmodelꢁ electro-
philic substrate it was combined with Maroukaꢁs sol-
vent system (toluene/water) and phase-transfer agent
tetrabutylammonium bromide (TBAB). Gratifyingly,
both MAHT 21 and MAHO 22 reacted, independent-
ly, with 4-nitrobenzaldehyde (PNB). Thus thioester-
derived MAHT 21 afforded (Æ)-3-hydroxy-3-(para-ni-
trophenyl)propanethiolate (Æ)-23, and MAHO 22 re-
Entry
Solvent
(Æ)-33:35:PNB
turned
(Æ)-phenyl
3-hydroxy-3-(4-
A
B
C
D
E
F
acetonitrile
ethanol
tetrahydrofuran
ethyl acetate
hexane
42:39:19
47:40:13
72:17:11
84:4:12
82:2:16
88:5:7
87:6:7
89:3:8
92:1:7
88:2:10
96:0:4
nitrophenyl)propanoate (Æ)-24 in 76% and 44%
yields, respectively (Scheme 5). These preliminary
and important results further confirmed our previous
findings[8] and established that the more reactive
MAHT 21 afforded, under essentially identical condi-
tions, a higher yield of the desired thioester aldol
adduct (Æ)-23 than the corresponding less reactive
MAHO.
It was important to ascertain if electron-donating,
i.e., 4-CH3O (25) or electron-withdrawing groups, i.e.,
4-CF3O (26) were compatible with and not detrimen-
tal to the aldol reaction when incorporated on the
xylene
G
H
I
ether
toluene
anisole
J
K
dichloromethane
chloroform
thiophenyl ring of the MAHT. Gratifyingly both 25 39%, 40% and 17% yields, respectively. Switching to
and 26 afforded the desired b-hydroxy thioesters (Æ)- an essentially completely biphasic solvent system the
30 and (Æ)-31 in excellent 84% and 75% yields, re- use of ester, aromatic or chlorinated solvent/water
spectively. Furthermore, when 4-halophenyl MAHTs combinations afforded (Æ)-33 in high purity and im-
were incorporated an interesting halogen effect was proved yields (see Table 1). Chloroform was particu-
observed. Thus 4-bromo, 27, 4-chloro, 28, and 4-fluo- larly promising with the 4-nitrobenzaldehyde rapidly
rophenyl derived 29 afforded the desired (Æ)-b-hy- consumed and the desired (Æ)-b-hydroxy thioester
droxy thioesters (Æ)-32–(Æ)-34 with increasing effi- (Æ)-33 afforded in an excellent 96% yield (see entry
ciency, i.e., in 64%, 86% and 96% yields, respectively. K, Table 1). Thus it seemed evident that an important
The efficient synthesis of (Æ)-33 using toluene, factor for the clean and efficient synthesis of the aldol
water and cheap ꢀoff the shelfꢁ starting materials af- products was the need for an aqueous biphasic solvent
forded us the opportunity to explore the effect of dif- system (vida infra). Changing the ratio of chloroform
ferent solvents (Table 1, A–K) on the base-free aldol to water from 1:1 to 1:5 had no observable effect on
reaction. Substituting toluene for acetonitrile or etha- the reaction outcome.
nol generated completely homogenous reaction mix-
The effect on the yield, efficiency, aldol reaction
tures; interestingly both afforded (Æ)-33 but in re- products and times of employing alternative phase-
duced 42% and 47% yields, respectively. Incorporat- transfer agents had not yet been investigated. In con-
ing THF a nearly homogenous reaction mixture was trast to homogeneous reactions, the incorporation of
generated; in this case (Æ)-33 was isolated in an in- a phase-transfer process involves at least one physical
creased 72% yield. In contrast to toluene, all three re- phenomenon; the transfer of the reactants between
actions also generated unwanted (E)-S-4-chlorophen- the two phases. As noted by others[14] the role of
yl 3-(4-nitrophenyl)prop-2-enethioate (35, Figure 1) in phase-transfer mediators as perhaps anion ꢀtransport-
1248
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 1245 – 1257

FULL PAPERS
Bioinspired, Base- and Metal-Free, Mild Decarboxylative Aldol Activation
Figure 1. Base-free aldol synthesis of (Æ)-30–(Æ)-34.
ersꢁ or, potentially, in the formation of non-covalent the tetraalkylammonium salts. Thus when R is
ion-pairs affords a certain amount of mechanism am- methyl, ethyl or n-propyl the ammonium salts ꢀtrans-
biguity. Thus developing a phase-transfer agent for portꢁ only trace amounts of R4N+ phenoxide into the
our previously unknown process is in the first instance organic layer resulting in poor yields of alkylated phe-
a largely empirical process. Exploring the ability of nols.
different R4N+ salts to mediate the aldol reaction, we
By analogy in our aldol reaction using tetramethyl-
started with Me4NBr (entry L, Table 2). This was ammonium bromide results in the transfer of only
a poor reaction with a low conversion rate (a large small quantities of the R4N+·MAHT ion-pair (36, R=
amount of PNB remained). In contrast, the bulkier Me group, Scheme 6) into the organic layer which
tetraheptyl (M) or tetraalkylammonium salts with one limits the potential for an aldol reaction to take place.
long, i.e., tri(methyl)-C12, tri(methyl)-C16 or two long Denmark et al. and others have established the role
aliphatic chains, i.e., di(methyl)-(C18)2 afforded (Æ)-33 and mechanism of PTCs[14] to be complicated by the
in excellent 82–93% yields (entries L–R, Table 2). In- fact they can operate via an ꢀextractionꢁ or ꢀinterfa-
terestingly, albeit it is a different reaction, the effi- cialꢁ mechanism depending on the pKa of the sub-
ciency of phenol alkylation[14] is known to be affected strate. Carboxylic acid-derived MAHTs, i.e., 21 have
by the cationic size and ꢀlengthꢁ of the R groups on pKa1 values of ~2.8 and could react either via an ꢀex-
tractionꢁ or ꢀinterfacial mechanismꢁ. A tentative ex-
traction-based mechanism based on the initial forma-
tion of a tetrabutylammonium b-carboxylate anion
Table 2. Phase-transfer-mediated synthesis of (Æ)-33.
ion-pair, i.e., 36 (R=Bu) in the aqueous layer is out-
lined in Scheme 6. Due to the enhanced lipophilicity
of 36 (relative to TBAB and 11) it migrates into the
organic layer and undergoes thioester-thioenol tauto-
merization and formation of the more reactive thio-
enol 37. Reaction with an aldehyde generates adduct
38 which decarboxylates to 39 and now undergoes
thioenol-thioester tautomerization affording the de-
sired (Æ)-b-hydroxy thioester 40.[15] A stark difference
between the phase-transfer-mediated reactions em-
ploying TBAB, TBAC (Q) and TBAI [all afforded
(Æ)-33] was the complete lack of reaction with TBAF
(not shown in Table 2). Possible reasons are the
(Bu)4N+ and FÀ are so tightly associated that generat-
ing a MAHTÀ·(Bu)4N+ ion-pair (cf. 36) is not possi-
Entry
PTC
(Æ)-33:35:PNB
L
[(CH3)4N]Br
[(C7H15)4N]Br
[(CH3)3(C12H25)N]Br
[(CH3)3(C16H33)N]Br
(CH3)2(C18H37)2N]Br
[(C4H9)4N]Cl
44:13:43
91:1:8
82:7:11
85:7:8
93:3:4
88:1:11
88:3:9
M
N
O
P
Q
R
[(C4H9)N]I
Adv. Synth. Catal. 2015, 357, 1245 – 1257
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1249

FULL PAPERS
Sean P. Bew et al.
Scheme 6. Tentative mechanistic rational that may account for the formation of aldol adducts under phase-transfer condi-
tions.
ble, alternatively the water soluble TBAF efficiently aldehydes were incorporated suggests the protocol is
solvates the FÀ to such an extent that ion-pair forma- tolerant of ortho-, meta- or para-aryl ring substitution.
tion is repressed and the synthesis of entities based on Confirming electron-deficient aldehydes as excellent
(Æ)-40 inhibited.[16]
substrates, pentafluorobenzaldehyde afforded a quan-
It was important to establish the generality of the titative yield of (Æ)-48 in less than two hours. Also
reaction. A range of different aromatic aldehydes and worthy of note is the 63% yield for (Æ)-41 which
3-(4-chlorophenylthio)-3-oxopropanoic acid (28) were compared to the 22% yield for the previously report-
added to biphasic chloroform/water that contained ed metal-catalyzed synthesis of similar (Æ)-10
TBAB. Table 3 outlines the results from this unopti- (Scheme 2) represents an encouraging and significant
mized study. The yields are good, i.e., >50%, for ex- improvement. Confident that our protocol was robust
ample, 53% for (Æ)-49 to quantitative for (Æ)-48. Fur- we wanted to ascertain, as our mechanistic overview
thermore the protocol was tolerant of diverse func- (Scheme 6) indicates, that water is indeed a critical
tionality, i.e., halide, heterocycle, thioether and cyano component for an efficient aldol reaction. Dissolving
groups. The increase in yield when 2-!4-chlorobenz- 3-(4-chlorophenylthio)-3-oxopropanoic acid (28),
TBAB and 4-nitrobenzaldehyde in anhydrous CDCl3
afforded a homogeneous solution.
Table 3. Diverse aldehydes employed and yields returned
Figure 2S outlines the informative components of
for the synthesis of b-hydroxy thioesters (Æ)-41–(Æ)-54 (see
1
the H NMR spectrum acquired in <5 min. Probing
Scheme 6).
for evidence of a reaction between these or formation
of intermediates, additional spectra were acquired
over 24 h.
(Æ)-b-Hydroxy thioester/aldehyde
(Æ)-41, benzaldehyde
Yield
63%
61%
82%
93%
42%
56%
44%
100%
53%
61%
82%
88%
56%
84%
It is clear that on comparing S, T and U (Figure 2)
no detectable changes are evident nor are the forma-
tion of other by-products in a time frame that previ-
ously successful reactions in the presence of water af-
forded excellent yields of (Æ)-33. Injecting an equal
volume of anhydrous D2O via the septum generated
a heterogeneous reaction mixture. A subsequent
1H NMR acquired in less than 5 min after the addi-
tion indicated that significant changes had occurred
within the reaction (see V, Figure 2). Additional spec-
tra were acquired at 6 and 24 h (see W and X). Com-
paring S–U (homogeneous) with V–X (biphasic), it is
evident that generating a biphasic reaction mixture
(Æ)-42, 2-chlorobenzaldehyde
(Æ)-43, 3-chlorobenzaldehyde
(Æ)-44, 4-chlorobenzaldehyde
(Æ)-45, 2-fluorobenzaldehyde
(Æ)-46, 4-fluorobenzaldehyde
(Æ)-47, 3,4-difluorobenzaldehyde
(Æ)-48, pentafluorobenzaldehyde
(Æ)-49, 3-bromo-4-fluorobenzaldehyde
(Æ)-50, 4-trifluoromethybenzaldehyde
(Æ)-51, 3-trifluoromethybenzaldehyde
(Æ)-52, 4-cyanobenzaldehyde
(Æ)-53, 4-thiobenzaldehyde
(Æ)-54, 2-furaldehyde
1250
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 1245 – 1257

FULL PAPERS
Bioinspired, Base- and Metal-Free, Mild Decarboxylative Aldol Activation
Figure 2. 24 hour 1H NMR experiment indicates the need for water in the TBAT-mediated aldol reaction.
Scheme 7. Asymmetric synthesis of S-phenyl 3-(4-fluorophenyl)-3-hydroxypropanethioate 34 using 55.
with (H)D2O is absolutely critical for the efficient mic (13% ee). This preliminary, unoptimized and en-
consumption of 28. Relating this to our tentative couraging result suggests that our base- and metal-
mechanistic rational (Scheme 6) indicates that forma- free aldol reaction is amenable to the asymmetric syn-
tion of ion-pair 36 is very slow in an anhydrous envi- thesis of b-hydroxy thioesters. Further studies on the
ronment. Presumably this can be attributed to the asymmetric synthesis of chiral non-racemic b-hydroxy
poor dissociation characteristics of 28 in chloroform; arylthioesters using quinuclidine salts are currently
the products of which are required for the exchange underway in our laboratory and will be reported in
process with TBAB that results in the formation of an due course. Unfortunately attempted mediation of the
ion-pair, cf. 36. However this situation changes radi- reaction outlined in Scheme 7 using catalytic quanti-
cally when the reaction is transformed into a heteroge- ties of TBAB or 55 afforded poor yields (<20%) of
neous system, now carboxylic acid 28 migrates into adducts 34.
the water and undergoes efficient dissociation. The
We sought ꢀlike-for-likeꢁ comparisons of our base-
resulting 3-oxo-3-(phenylthio)propanoate anion un- free aldol reaction with a metal-catalyzed, and base-
dergoes anion exchange with TBAB generating ion- mediated synthesis of (Æ)-b-hydroxy thioesters. Ini-
pair 36 which, because of its increased lipophilicity, tiating this, the copper(II)-mediated synthesis of (Æ)-
migrates out of the aqueous layer into the organic 10 in 22% yield[11a] (Scheme 2) reported by Shair
phase (CDCl3) where it tautomerizes affording the et al. was considered an appropriate benchmark
nucleophilic thioenol 37. This undergoes an aldol re- against which we could compare our protocol. After
action with the electrophilic para-nitrobenzaldehyde generating S-benzyl-derived MAHT 7 it was reacted
generating 38. This decarboxylates to 39 which is fol- with benzaldehyde and TBAB in ꢀoff the shelfꢁ
lowed by a thioenol-thioester tautomerization gener- chloroform and water – no precautions were taken to
ating the desired aldol adduct 40 (Scheme 6). It is exclude O2. Gratifyingly, (Æ)-10 (Scheme 8) was af-
also possible that 37 undergoes decarboxylation first forded in an unoptimized, slightly higher 25% yield
and generates a tetrabutylammonium thioenol ion which could probably be further improved as we also
pair that subsequently reacts with PNB (Scheme 6) af-
fording (Æ)-40 directly.
The asymmetric synthesis of 34 was attempted
using the optically active phase-transfer agent N-ben-
zyldihydroquinidine bromide 55, 3-(4-fluorophenyl-
thio)-3-oxopropanoic acid 29, para-nitrobenzaldehyde
and our standard, biphasic ambient temperature reac-
tion conditions. Demonstrating the robust nature of
our protocol, 34 was afforded in an excellent 83%
yield. Encouragingly chiral HPLC analysis confirmed
that in addition to an excellent yield 29 was not race- and (Æ)-13.
Scheme 8. Metal- and base-free aldol synthesis of (Æ)-10
Adv. Synth. Catal. 2015, 357, 1245 – 1257
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1251

FULL PAPERS
Sean P. Bew et al.
Conclusions
It is crucial that innovative, green and sustainable re-
actions be developed that imitate reactions used by
Nature for the biosynthesis of complex natural prod-
ucts. Here we have outlined our preliminary success-
ful efforts towards developing an extremely simple
À
biomimetic inspired approach to C C bond formation
that generates important synthetic and biological
building blocks based on b-hydroxy thioesters. Ex-
ploiting the enhanced reactivity associated with
a series of N-aryl malonic acid half thioesters
(MAHTs) we have established their potential to un-
dergo an efficient base- and metal-free aldol reaction
with a series of structurally and functionally diverse
Scheme 9. Probing the diastereoselectivity of a base- and
metal-free aldol reaction between 55 and (Æ)-56 generating
(Æ)-anti-57 and (Æ)-syn-58.
isolated 5% of (E)-S-benzyl 3-phenylprop-2-ene- aldehydes. Furthermore we have established that our
thioate [not shown, presumably generated via dehy- aldol reaction is readily mediated by a variety of >
dration of (Æ)-10] increasing the overall yield to C3-tetraalkyl ammonium salts but not tetramethylam-
~30%.
monium salts and that water and biphasic conditions
Comparing our base-free protocol with the Fagnou are critically important.
et al. triethylamine[12d] mediated synthesis of (Æ)-13
Employing readily available structurally and func-
we again took no precautions to remove O2 (no inert tionally diverse aldehydes and easily generated
atmosphere), and employed ꢀoff the shelfꢁ reagents/ MAHTs we have probed the scope of the reaction
solvents. Gratifyingly the TBAB-mediated aldol reac- and synthesized more than 24 different b-hydroxy
tion employing S-phenyl-derived 11 and ethyl pyru- thioesters via an environmentally benign process
vate afforded (Æ)-13 via an exceptionally mild, non- (only by-product is CO2), using cheap ꢀoff the shelfꢁ
basic or metal-containing reaction affording the prod- R4N+ salts and mild PTC conditions that do not re-
uct in an unoptimized and slightly improved 73% quire oxygen-free or anhydrous solvents.
yield (Scheme 8).
From a mechanistic point of view it is interesting to
Shair et al. outlined the diastereoselectivity of their note the contrasting anti-diastereomeric induction
metal-mediated aldol reaction generating (Æ)-syn-58 favoured in our biphasic base- and metal-free aldol
and (Æ)-anti-S-phenyl 3-hydroxy-3-(3-hydroxy-4-nitro- reaction whilst, albeit it is a different reaction, the use
phenyl)-2-methylpropanethioate 57 from readily syn- of a metal- or base-mediated processes affords syn-
thesized (Æ)-56[17] and aldehyde 55. Importantly, they diastereomers as the major component. Thus our bi-
1
assigned via H NMR the relative diastereoselectivity phasic activation of MAHTs and their subsequent ap-
of the resulting thioesters as (Æ)-anti-57 and (Æ)-syn- plication in aldol reactions is complementary in scope
58. Thus the copper(II)-catalyzed process afforded affording structurally diverse aldol adducts and sits
(Æ)-anti-57 and (Æ)-syn-58 in an 83% yield and 9:1 ꢀside-by-sideꢁ in the ꢀaldol tool boxꢁ along with base-,
(syn:anti) ratio, respectively.[11b] With ease and speed acid- and metal-MAHT ꢀactivationꢁ.
of reaction in mind we also opted to incorporate com-
In summary, a simple solution to the need for
mercially available 3-hydroxy-4-nitrobenzaldehyde 55 milder, less harsh reaction conditions that mimic Na-
[cf. the straighforward and efficient synthesis of (Æ)- tureꢁs non-metal biosynthetic activation of MAHTs in
23, Scheme 5] in to a diastereoselective reaction using fatty acid and polyketide biosynthesis has been devel-
(Æ)-56.
oped. We are exploring the enormous synthesis poten-
Gratifyingly, our metal, base-free protocol afforded tial of our remarkably mild MAHT/PTC traceless ac-
(Æ)-anti-57 and (Æ)-syn-58 in an unoptimized 49% tivation protocol within complex molecule and asym-
yield (Scheme 9). Using Shairsꢁ reported 1H NMR metric synthesis. The results of these studies will be
data the diastereomeric syn-protons at 5.18 and 3.09 reported in due course.
were integrated and compared with the anti-diastero-
meric protons observed at 4.84 and 3.03 ppm. This es-
tablished a 3.7:1 ratio in favour of (Æ)-anti-57, this
Experimental Section
diastereomeric ꢀswitchꢁ is interesting and important
because it suggests that our phase-transfer TBAB-
mediated reaction is mechanistically intriguing,
unique and complementary to current metal- and
base-mediated procedures that afford the opposite
syn-diastereomers.
General Information
All solvents and reagents were purchased from commercial
sources and used as received. Analytical thin-layer chroma-
tography (TLC) was performed on Merck Silica gel 60 F254
1252
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 1245 – 1257

FULL PAPERS
Bioinspired, Base- and Metal-Free, Mild Decarboxylative Aldol Activation
plates, with visualization by UV light and/or potassium per-
manganate stain followed by heating. Flash column chroma-
tography was performed using Davisil 40–63 mm silica gel.
1H, 13C, and 19F NMR spectra were recorded on a Bruker
Avance 500 (500 MHz) spectrometer. Chemical shifts are re-
ported in d (ppm) and referenced to residual solvent signals
(1H NMR: CDCl3 at 7.26 ppm, CD3CN at 1.94 ppm, CD3OD
at 3.31 ppm; 13C NMR: CDCl3 at 77.16 ppm, CD3CN at 1.32,
118.26 ppm). Signal multiplicities are described as follows:
s=singlet, d=doublet, dd=doublet of doublets, t=triplet,
q=quartet, p=pentuplet, m=multiplet, br=broad. IR
spectra were recorded on a Perkin–Elmer Spectrum 100
spectrometer. MALDI-TOF mass spectra were recorded on
a Shimadzu Axima-CFR spectrometer. High resolution
mass spectrometry was carried out by the EPSRC National
Mass Spectrometry Facility, Swansea, U.K. Melting points
were recorded using a Stuart Scientific SMP1 apparatus and
are uncorrected. Percentage yield refers to the isolated yield
of analytically pure material unless otherwise stated. Synthe-
sis/physicochemical data of 7,[11d] 11,[8] 21,[8] 22,[8] 23,[19a,b] 25–
29,[8] 35[18] were similar to those reported in the literature.
ReagentPlus grade TBAB (Aldrich 99%, catalogue number
193119–100 g) was used. Performing the reaction in toluene/
water (1:1) without TBAB or in either pure water of anhy-
drous toluene afforded no reaction products.
Synthesis of rac-S-4-Trifluoromethylphenyl 3-
Hydroxy-3-(4-nitrophenyl)propanethioate (Æ)-31
Column solvent: dichloromethane (100%); Rf =0.34; white
solid; yield: 211 mg (0.57 mmol, 75%); mp 98–1008C;
1H NMR (500 MHz, CDCl3): d=8.24 (d, J=8.8 Hz, 2H),
7.70 (d, J=6.0 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.54 (d, J=
7.2 Hz, 2H), 5.38–5.33 (m, 1H), 3.18–3.06 (m, 3H);
13C NMR (126 MHz, CDCl3): d=195.6, 149.2, 147.7, 134.7,
132.0 (q, J=33.3 Hz), 131.3, 126.7, 126.3 (q, J=3.9 Hz),
124.1, 123.8 (q, J=272.5 Hz), 69.9, 52.0; 19F NMR
(471 MHz, CDCl3): d=À62.9; FT-IR (thin film): n=3424
(OH), 1699 (C=O), 1520 (C=Carom), 1348, 1324 (C-N), 1169,
1128 (C-F), 1065 cmÀ1 (C-O); MS (MALDI-TOF): m/z=
409.18 [M+K]; HR-MS (ASAP): m/z=389.0785, exact
mass calculated for C16H16F3N2O4S [M+NH4]+: 389.0777.
Synthesis of rac-S-4-Bromophenyl 3-Hydroxy-3-(4-
nitrophenyl)propanethioate (Æ)-32
Following the general procedure outlined above (Æ)-32 was
generated as a white solid; yield: 189 mg (0.49 mmol, 64%).
Purification of (Æ)-32 was via silica gel chromatography
using dichloromethane (100%, Rf =0.40). (Æ)-32 had the fol-
lowing physicochemical properties: mp 110–1118C;
1H NMR (500 MHz, CDCl3): d=8.23 (d, J=8.7 Hz, 2H),
7.56 (d, J=8.4 Hz, 4H), 7.26 (d, J=8.4 Hz, 2H), 5.32 (dd,
J=7.9, 4.5 Hz, 1H), 3.11–3.05 (m, 2H), 2.54 (br s, 1H);
13C NMR (126 MHz, CDCl3): d=196.4, 149.3, 147.7, 136.0,
132.8, 126.7, 125.7, 124.8, 124.0, 69.9, 51.8; FT-IR (thin film):
General Procedure for Base-Free PTC
Decarboxylative Aldol Reaction
Malonic acid half thioester (1 equivalent) and 4-nitrobenzal-
dehyde (1 equivalent) were dissolved in an organic solvent.
N,N,N,N-Tetrabutylammonium bromide (1 equivalent) and
distilled water (same volume as the organic solvent) were
added. The resulting biphasic mixture was vigorously stirred
for 24–48 h (in some cases the mixture was warmed to 408C
to enhance reaction times). After this time, the mixture was
diluted with distilled water (10 mL) and extracted with di-
chloromethane (3”10 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and the solvent
removed under vacuum, affording a pale yellow oil. The
product was purified by flash column chromatography on
silica gel, eluting with dichloromethane/petroleum ether as
specified.
n=3495, 3088, 2920, 1684, 1607, 1516, 1472, 1343, 1066 cmÀ1
;
MS (MALDI-TOF): m/z=381.23; HR-MS (HASP): m/z=
381.9736, calculated for C15H13BrNO4S [M+H]+: 381.9743.
Synthesis of rac-S-4-Chlorophenyl 3-Hydroxy-3-(4-
nitrophenyl)propanethioate (Æ)-33
Following the general procedure outlined above (Æ)-33 was
generated as a white solid; yield: 252 mg (0.75 mmol, 86%).
Purification of (Æ)-33 was via silica gel chromatography
using dichloromethane/petroleum ether (6:4, Rf =0.16).
1
Physicochemical data for (Æ)-33 are: mp 94–968C; H NMR
(500 MHz, CDCl3): d=8.23 (d, J=8.8 Hz, 2H), 7.57 (d, J=
8.4 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.6 Hz,
2H), 5.35–5.31 (m, 1H), 3.18 (br s, 1H), 3.13–3.03 (m, 2H);
13C NMR (126 MHz, CDCl3): d=196.6, 149.2, 147.7, 136.6,
135.8, 129.8, 126.7, 125.0, 124.0, 69.9, 51.8; FT-IR (thin film):
n=3415, 1704, 1505, 1477, 1145, 1013 cmÀ1; MS (MALDI-
TOF): m/z=360.09 [M+Na]; HR-MS (ASAP): m/z=
338.0243, calculated for C15H13ClNO4S [M+H]+: 338.0248.
Synthesis of rac-S-4-Methoxyphenyl 3-Hydroxy-3-(4-
nitrophenyl)propanethioate (Æ)-30
Column solvent: dichloromethane (100%); Rf =0.21 (di-
chloromethane); white solid; yield: 248 mg (0.74 mmol,
1
84%); mp 130–1328C; H NMR (500 MHz, CDCl3): d=8.22
(d, J=7.1 Hz, 2H), 7.56 (d, J=7.4 Hz, 2H), 7.30 (d, J=
7.1 Hz, 2H), 6.96 (d, J=7.0 Hz, 2H), 5.30 (t, J=6.0 Hz,
1H), 3.83 (s, 3H), 3.36 (br s, 1H), 3.05 (d, J=6.8 Hz, 2H);
13C NMR (126 MHz, CDCl3): d=198.6, 161.2, 149.4, 147.6,
136.2, 126.6, 124.0, 117.2, 115.2, 70.0, 55.5, 51.3; FT-IR (thin
film): n =3511, 1692, 1519, 1345, 1243, 1026 cmÀ1; MS
(MALDI-TOF): m/z=372.14 [M+K]; HR-MS (HNESP):
m/z=334.0747, exact mass calculated for C16H16NO5S [M+
H]+: 334.0744.
Synthesis of rac-S-4-Fluorophenyl 3-Hydroxy-3-(4-
nitrophenyl)propanethioate (Æ)-34
Following the general procedure outlined above (Æ)-34 was
generated as a white solid; yield: 288 mg (0.90 mmol, 96%).
Purification and physicochemical data for (Æ)-34 are: puri-
fied on silica using dichloromethane/petroleum ether (7:3)
(Rf =0.35); physicochemical data for (Æ)-34: mp 85–878C;
1H NMR (500 MHz, CDCl3): d=8.24 (d, J=8.7 Hz, 2H),
7.57 (d, J=8.5 Hz, 2H), 7.38 (dd, J=8.8, 5.2 Hz, 2H), 7.14
(t, J=8.6 Hz, 2H), 5.33 (dd, J=7.3, 5.1 Hz, 1H), 3.09 (d, J=
2.6 Hz, 1H), 3.07 (s, 1H); 13C NMR (126 MHz, CDCl3): d=
Adv. Synth. Catal. 2015, 357, 1245 – 1257
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1253

FULL PAPERS
Sean P. Bew et al.
197.1, 163.4 (d, J=251.2 Hz), 149.3, 147.6, 136.7 (d, J=
Synthesis of rac-S-4-Chlorophenyl 3-(4-Chloro-
8.6 Hz), 126.6, 124.0, 121.9 (d, J=3.5 Hz), 116.9 (d, J=
22.2 Hz), 69.9, 51.6; 19F NMR (471 MHz, CDCl3): d=
À109.99; FT-IR (thin film): n=3504 (OH), 1698 (C=O),
1591–1519 (C=C aromatic), 1347 (C-F), 1491–1227 (C-NO2),
1068 cmÀ1 (C-O alcohol); MS (MALDI-TOF): m/z=344.10
[M+Na]; HR-MS (ASAP): m/z=322.0537, calculated for
C15H13FNO4S [M+H]+: 322.0544.
phenyl)-3-hydroxypropanethioate (Æ)-44
Following the general procedure outlined above (Æ)-44 was
generated as a colourless oil; yield: 264 mg (0.81 mmol,
93%). Purification of (Æ)-44 was via silica gel chromatogra-
phy using dichloromethane/petroleum ether (1:1, Rf =0.23).
Physicochemical data for (Æ)-44 are: 1H NMR (500 MHz,
CDCl3): d=7.63 (dd, J=7.7, 1.6 Hz, 1H), 7.41 (d, J=8.5 Hz,
2H), 7.37–7.33 (m, 4H), 7.25 (t, J=7.6 Hz, 1H), 5.58 (d, J=
9.3 Hz, 1H), 3.20 (dd, J=16.2, 2.5 Hz, 1H), 3.13 (br s, 1H),
2.95 (dd, J=16.2, 9.4 Hz, 1H); 13C NMR (126 MHz, CDCl3):
d=197.0, 139.5, 136.3, 135.9, 131.4, 129.7, 129.6, 129.1, 127.4,
127.2, 125.5, 67.6, 50.3; FT-IR (thin film): n=3582 (OH),
1698 (C=O), 1265 cmÀ1 (C-O); MS (MALDI-TOF): m/z=
365.06 [M+K]; HR-MS (HNESP): m/z=327.0012, calculat-
ed for C15H13Cl2O2S [M+H]+: 327.0008.
Synthesis of rac-S-Phenyl 3-Hydroxy-3-(4-nitro-
phenyl)propanethioate (Æ)-41
Following the general procedure outlined above (Æ)-41 was
generated as a white solid. Physicochemical data for (Æ)-41,
a known compound, are as reported in the literature.[19]
Column: dichloromethane (100%) Rf =0.44; yield: 160 mg
(0.55 mmol, 63%); mp 104–1068C; 1H NMR (500 MHz,
CDCl3): d=7.37–7.22 (m, 9H), 5.15 (d, J=9.0 Hz, 1H), 3.06
(dd, J=16.0, 9.1 Hz, 1H), 2.96 (dd, J=16.0, 3.4 Hz, 1H),
2.77 (br s, 1H); 13C NMR (126 MHz, CDCl3): d=196.6,
142.2, 136.3, 135.8, 129.7, 128.8, 128.2, 125.8, 125.6, 70.9,
52.4; FT-IR (thin film): n=3507 (OH), 1685 (C=O), 1387,
1045 cmÀ1 (C-O alcohol); HR-MS (HNESP): m/z=
293.0401, calculated for C15H14ClO2S [M+H]+: 293.0398.
Synthesis of rac-S-4-Chlorophenyl 3-(2-Fluoro-
phenyl)-3-hydroxypropanethioate (Æ)-45
Following the general procedure outlined above (Æ)-45 was
generated as a white solid; yield: 113 mg (0.36 mmol, 42%).
Purification of (Æ)-45 was via silica gel chromatography
using dichloromethane/petroleum ether (8:2), Rf =0.28.
1
Physicochemical data for (Æ)-45 are: mp 69–718C; H NMR
(500 MHz, CDCl3): d=7.53 (td, J=7.5, 1.4 Hz, 1H), 7.40 (d,
J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.32–7.27 (m, 1H),
7.18 (td, J=7.6, 1.2 Hz, 1H), 7.05 (ddd, J=10.6, 8.2, 1.2 Hz,
1H), 5.50 (dd, J=8.4, 3.7 Hz, 1H), 3.14 (dd, J=16.2, 3.7 Hz,
1H), 3.09 (dd, J=16.2, 8.5 Hz, 1H), 3.02 (br s, 1H);
13C NMR (126 MHz, CDCl3): d=196.6, 159.4 (d, J=
245.8 Hz), 136.2, 135.8, 129.6, 129.4 (d, J=8.2 Hz), 129.1 (d,
J=13.1 Hz), 127.3 (d, J=4.2 Hz), 125.4, 124.5 (d, J=
3.4 Hz), 115.4 (d, J=21.3 Hz), 65.0 (d, J=2.7 Hz), 50.7;
19F NMR (471 MHz, CDCl3): d=À118.9; FT-IR (thin film):
n=3419 (OH), 1705 (C=O), 1586 (C=C aromatic), 1575 (C=
C aromatic), 1390 (C-F), 1013 cmÀ1 (C-O alcohol); MS
(MALDI-TOF): m/z=311.34 [M+H]; HR-MS (ASAP):
m/z=311.0300, exact mass calculated for C15H13ClFO2S
[M+H]+: 311.0303.
Synthesis of rac-S-4-Chlorophenyl 3-(2-Chloro-
phenyl)-3-hydroxypropanethioate (Æ)-42
Following the general procedure outlined above (Æ)-42 was
generated as a white solid; yield: 173 mg (0.53 mmol, 61%).
Purification of (Æ)-42 was via silica gel chromatography
using dichloromethane/petroleum ether (8:2, Rf =0.29).
1
Physicochemical data for (Æ)-42 are: mp 93–958C; H NMR
(500 MHz, CDCl3): d=7.41 (d, J=8.5 Hz, 2H), 7.37–7.31
(m, 6H), 5.20 (dd, J=8.9, 3.3 Hz, 1H), 3.08 (dd, J=16.1,
8.9 Hz, 1H), 3.01 (dd, J=16.1, 3.5 Hz, 1H), 2.94 (br s, 1H);
13C NMR (126 MHz, CDCl3): d=196.7, 140.6, 136.4, 135.8,
133.9, 129.8, 129.0, 127.2, 125.4, 70.2, 52.1; FT-IR (thin film):
n=1698 (C=O), 1493 (Ar), 1477 (Ar), 1265 cmÀ1 (C-O); MS
(MALDI-TOF): m/z=365.06 [M+K]; HR-MS (HNESP):
m/z=674.9760, calculated for (C15H12Cl2O2S)2Na [2M+
Na]+: 674.9762.
Synthesis of rac-S-4-Chlorophenyl 3-(4-Fluoro-
phenyl)-3-hydroxypropanethioate (Æ)-46
Synthesis of rac-S-4-Chlorophenyl 3-(3-Chloro-
phenyl)-3-hydroxypropanethioate (Æ)-43
Following the general procedure outlined above (Æ)-46 was
generated as a white solid; yield: 151 mg (0.49 mmol, 56%).
Purification of (Æ)-46 was via silica gel chromatography
using 100% dichloromethane (Rf =0.53). Physicochemical
data for (Æ)-46 are: mp 76–788C, 1H NMR (500 MHz,
CDCl3): d=7.41 (d, J=8.5 Hz, 2H), 7.38–7.30 (m, 4H), 7.06
(t, J=8.6 Hz, 2H), 5.20 (dd, J=8.8, 2.8 Hz, 1H), 3.10 (dd,
J=16.0, 9.0 Hz, 1H), 3.01 (dd, J=16.1, 3.5 Hz, 1H), 2.91 (br
s, 1H); 13C NMR (126 MHz, CDCl3): d=196.6, 162.4 (d, J=
246.3 Hz), 137.8 (d, J=3.1 Hz), 136.3, 135.7, 129.6, 127.4 (d,
J=8.1 Hz), 125.3, 115.6 (d, J=21.5 Hz), 70.1, 52.2; 19F NMR
(471 MHz, CDCl3): d=À114.1; FT-IR (thin film): n=1700
(C=O), 1477 (Ar), 1510 (Ar), 1263 (C-O), 1013.62 cmÀ1 (C-
F); MS (MALDI-TOF): m/z=333.26 [M+Na]; HR-MS
(HNESP): m/z=333.0126, calculated for C15H12ClFO2SNa
[M+Na]+: 333.0123.
Following the general procedure outlined above (Æ)-43 was
generated as a white solid; yield: 233 mg (0.71 mmol, 82%).
Purification of (Æ)-43 was via silica gel chromatography
using dichloromethane/petroleum ether (8:2, Rf =0.19).
1
Physicochemical data for (Æ)-43 are: mp 60–628C; H NMR
(500 MHz, CDCl3): d=7.33–7.29 (m, 3H), 7.26–7.12 (m,
5H), 5.09 (dd, J=9.0, 3.5 Hz, 1H), 3.02 (br s, 1H), 2.99 (dd,
J=16.0, 9.0 Hz, 1H), 2.91 (dd, J=16.1, 3.5 Hz, 1H);
13C NMR (126 MHz, CDCl3): d=196.6, 144.2, 136.3, 135.8,
134.7, 130.1, 129.7, 128.2, 126.0, 125.3, 123.9, 70.1, 52.1; FT-
IR (thin film): n=3584 (OH), 1699 (C=O), 1391 (Ar), 1421
(Ar), 1265 cmÀ1 (C-O); MS (MALDI-TOF): m/z=349.08
[M+Na]; HR-MS (HNESP): m/z=348.9831, calculated for
C15H12Cl2O2SNa [M+Na]+: 348.9827.
1254
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 1245 – 1257

FULL PAPERS
Bioinspired, Base- and Metal-Free, Mild Decarboxylative Aldol Activation
429.09 [M+K]; HR-MS (ASAP): m/z=405.9679, exact
mass calculated for C15H15BrClFO2SN [M+NH4]+: 405.9674.
Synthesis of rac-S-4-Chlorophenyl 3-(3,4-Difluoro-
phenyl)-3-hydroxypropanethioate (Æ)-47
Following the general procedure outlined above (Æ)-47 was
generated as a white solid; yield: 125 mg (0.38 mmol, 44%).
Purification of (Æ)-47 was via silica gel chromatography
using 100% dichloromethane, Rf =0.42. Physicochemical
data for (Æ)-47 are: mp 78–808C; 1H NMR (500 MHz,
CD3OD): d=7.34 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz,
2H), 7.25–7.19 (m, 1H), 7.18–7.05 (m, 2H), 5.07–5.02 (m,
1H), 4.54 (s, 1H, OH), 2.98 (dd, J=15.1, 8.5 Hz, 1H), 2.90
(dd, J=15.0, 4.7 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=
196.6, 151.3 (dd, J=246.7, 69.0, 12.7 Hz), 149.3 (dd, J=
246.7, 69.0, 12.7 Hz), 139.2, 136.4, 135.8, 129.8, 121.7 (dd, J=
6.4, 3.6 Hz), 117.5 (d, J=17.3 Hz), 115.0 (d, J=18.0 Hz),
69.7, 52.0; 19F NMR (471 MHz, CDCl3): d=À136.8 (d, J=
21.1 Hz), À138.7 (d, J=21.2 Hz); FT-IR (thin film): n=
3460, 1698, 1520, 1478, 1014 cmÀ1; MS (MALDI-TOF): m/
z=350.94 [M+Na]; HR-MS (HNESP): m/z=351.0029,
exact mass calculated for C15H11ClFO2SNa [M+Na]+:
351.0029.
Synthesis of rac-S-4-Chlorophenyl 3-(4-Trifluoro-
methylphenyl)-3-hydroxypropanethioate (Æ)-50
Following the general procedure outlined above (Æ)-50 was
generated as a pale yellow solid; yield: 191 mg (0.53 mmol,
61%). Purification of (Æ)-50 was via silica gel chromatogra-
phy using 100% dichloromethane, Rf =0.48. Physicochemical
data for (Æ)-50 are: mp 92–948C; 1H NMR (500 MHz,
CD3CN): d=7.68 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz,
2H), 7.47 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 5.22
(dd, J=8.4, 4.5 Hz, 1H), 3.83 (br s, 1H), 3.09 (dd, J=15.2,
8.7 Hz, 1H), 3.02 (dd, J=15.3, 4.5 Hz, 1H); 13C NMR
(126 MHz, CDCl3): d=196.7, 146.1, 136.4, 135.8, 130.3 (q,
J=32.4 Hz), 129.8, 126.1, 125.7 (q, J=3.7 Hz), 125.2, 124.1
(q, J=272.0 Hz), 70.2, 52.0; 19F NMR (471 MHz, CD3CN):
d=À62.9; FT-IR (thin film): n=3508, 2931, 1681, 1480,
1319, 1142, 1048 cmÀ1; MS (MALDI-TOF): m/z=360.21;
HR-MS (ASAP): m/z=361.0276, exact mass calculated for
C16H13ClF3O2S [M+H]+: 361.0271.
Synthesis of rac-S-4-Chlorophenyl 3-(Pentafluoro-
phenyl)-3-hydroxypropanethioate (Æ)-48
Synthesis of rac-S-4-Chlorophenyl 3-(3-Trifluoro-
Following the general procedure outlined above (Æ)-48 was
generated as a white solid; yield: 331 mg (0.87 mmol, methylphenyl)-3-hydroxypropanethioate (Æ)-51
100%). Purification of (Æ)-48 was via silica gel chromatogra-
Following the general procedure outlined above (Æ)-51 was
phy using dichloromethane/petroleum ether (8:2) Rf =0.42.
generated as a colourless oil; yield: 257 mg (0.71 mmol,
Physicochemical data for (Æ)-48 are: mp 110–1128C;
82%). Purification of (Æ)-51 was via silica gel chromatogra-
phy using dichloromethane/petroleum ether (8:2), Rf =0.54.
Physicochemical data for (Æ)-51 are: 1H NMR (500 MHz,
CDCl3): d=7.67 (s, 1H), 7.57 (d, J=7.9 Hz, 2H), 7.52–7.48
(m, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H),
5.28 (dd, J=8.9, 3.5 Hz, 1H), 3.11 (dd, J=16.1, 8.9 Hz, 1H),
3.05 (dd, J=16.2, 3.6 Hz, 1H); 13C NMR (126 MHz, CDCl3):
d=196.7, 143.1, 136.5, 135.8, 131.2 (q, J=32.5 Hz), 129.8,
129.5 (q, J=266 Hz), 129.3, 129.2, 125.3, 125.0 (q, J=
3.6 Hz), 122.7 (q, J=3.6 Hz), 70.2, 52.1; 19F NMR (471 MHz,
CDCl3): d=À62.6; FT-IR (thin film): n=3440 (OH), 1694
(C=O), 1478, 1329, 1126 cmÀ1; MS (MALDI-TOF): m/z=
382.97 [M+Na]; HR-MS (HNESP): m/z=361.0276, exact
mass calculated for C16H13ClF3O2S [M+H]+: 361.0271.
1H NMR (500 MHz, CDCl3): d=7.41 (d, J=8.6 Hz, 1H),
7.34 (d, J=8.6 Hz, 1H), 5.62–5.57 (m, 1H), 3.49 (dd, J=
16.3, 9.0 Hz, 1H), 3.11 (dd, J=16.3, 4.3 Hz, 1H), 2.97 (d, J=
5.6 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=195.5, 146.3–
145.8 (m), 144.4–143.8 (m), 142.7–140.0 (m), 139.1–138.5
(m), 137.1–136.7 (m), 136.6, 135.8, 129.8, 125.0, 114.8 (t, J=
17.4 Hz), 62.4, 48.9; 19F NMR (471 MHz, CDCl3): d=À142.4
to À142.5 (m, 2F), À153.5 (t, J=21.0 Hz, 1F), À161.0 to
À161.2 (m, 2F); FT-IR (thin film): n=3507 (OH), 1694 (C=
O), 1499 (Ar), 1068 (C-O alcohol), 1000 cmÀ1 (C-F); MS
(MALDI-TOF): m/z=405.14 [M+Na]; HR-MS (HNESP):
m/z 404.9748, calculated for C15H8ClF5O2SNa [M+Na]+:
404.9746.
Synthesis of rac-S-4-Chlorophenyl 3-(3-Bromo-4-
fluorophenyl)-3-hydroxypropanethioate (Æ)-49
Synthesis of rac-S-4-Chlorophenyl 3-(4-Cyanomethyl-
phenyl)-3-hydroxypropanethioate (Æ)-52
Following the general procedure outlined above (Æ)-49 was
generated as a pale yellow solid; yield: 179 mg (0.46 mmol,
53%). Purification of (Æ)-49 was via silica gel chromatogra-
phy using dichloromethane/petroleum ether (8:2) Rf =0.24.
Physicochemical data for (Æ)-49 are: mp 678C; 1H NMR
(500 MHz, CDCl3): d=7.52 (d, J=6.6 Hz, 1H), 7.33 (d, J=
8.4 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.22–7.19 (m, 1H),
7.04 (t, J=8.3 Hz, 1H), 5.09 (dd, J=8.9, 3.5 Hz, 1H), 2.99
(dd, J=16.2, 8.7 Hz, 1H), 2.92 (dd, J=15.9, 3.6 Hz, 1H),
2.81 (br s, 1H); 13C NMR (126 MHz, CDCl3): d=196.6,
158.7 (d, J=247.8 Hz), 139.6 (d, J=3.7 Hz), 136.5, 135.8,
131.0, 129.8, 126.4 (d, J=7.3 Hz), 125.2, 116.7 (d, J=
22.4 Hz), 109.4 (d, J=21.1 Hz), 69.6, 52.1; 19F NMR
(CDCl3): d=À108.3; FT-IR (thin film): n=3465, 2912, 1694,
1497, 1391, 1248, 1013 cmÀ1; MS (MALDI-TOF): m/z=
Following the general procedure outlined above (Æ)-52 was
generated as a white solid; yield: 242 mg (0.76 mmol, 88%).
Purification of (Æ)-52 was via silica gel chromatography
using dichloromethane/petroleum ether (6:4) Rf =0.16.
Physicochemical data for (Æ)-52 are: mp 107–1098C;
1H NMR (500 MHz, CDCl3): d=7.66 (d, J=8.4 Hz, 2H),
7.50 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.32 (d, J=
8.5 Hz, 2H), 5.31–5.23 (m, 1H), 3.15 (br s, 1H), 3.12–2.99
(m, 2H); 13C NMR (126 MHz, CDCl3): d=196.5, 147.4,
136.5, 135.8, 132.6, 129.8, 126.5, 125.1, 118.7, 111.9, 70.1,
51.8; FT-IR (thin film): n=3508 (OH), 1694 (C=O), 1450
(Ar), 1523 (Ar), 999 cmÀ1 (C-O); MS (MALDI-TOF): m/z=
340.0 [M+Na]; HR-MS (HNESP): m/z=318.0347, exact
mass calculated for C16H13ClNO2S [M+H]+: 318.0350.
Adv. Synth. Catal. 2015, 357, 1245 – 1257
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1255

FULL PAPERS
Sean P. Bew et al.
16.1 Hz, 1H), 3.05 (d, J=16.1 Hz, 1H), 1.45 (s, 3H), 1.28 (t,
J=7.1 Hz, 3H); FT-IR (thin film): n=3499, 2987, 2932,
1727, 1476, 1445, 1210, 1112, 1011 cmÀ1.
Synthesis of rac-S-4-Chlorophenyl 3-(4-Thiomethyl-
phenyl)-3-hydroxypropanethioate (Æ)-53
Following the general procedure outlined above (Æ)-53 was
generated as a white solid; yield: 165 mg (0.49 mmol, 56%).
Purification of (Æ)-53 was via silica gel chromatography
using dichloromethane/petroleum ether (8:2) Rf =0.36.
Physicochemical data for (Æ)-53 are: mp 131–1338C;
1H NMR (500 MHz, CDCl3): d=7.40 (d, J=8.5 Hz, 2H),
7.33 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.25 (d, J=
8.5 Hz, 2H), 5.18 (dt, J=9.0, 3.2 Hz, 1H), 3.10 (dd, J=16.0,
9.1 Hz, 1H), 3.00 (dd, J=16.0, 3.5 Hz, 1H), 2.85 (d, J=
3.3 Hz, 1H), 2.49 (s, 3H); 13C NMR (126 MHz, CDCl3): d=
196.6, 139.0, 138.5, 136.3, 135.8, 129.7, 126.8, 126.3, 125.5,
70.5, 52.2, 16.0; FT-IR (thin film): n=3493 (OH), 1681 (C=
O), 1474 (Ar), 1388 (Ar), 1261 (C-H), 1049 cmÀ1 (C-O); MS
(MALDI-TOF): m/z=361.07 [M+Na]; HR-MS (HNESP):
m/z=361.0097, calculated for C16H15ClO2S2Na [M+H]+:
361.0094.
Synthesis of (Æ)-2-Methyl-3-oxo-3-(phenylthio)-
propanoic acid (Æ)-56
Employing a slightly different procedure to the literature
protocol,[21] methylmalonyl chloride half ester (0.6 g,
4.39 mmol) and thiophenol (0.161 g, 1.47 mmol) were dis-
olved in anhydrous acetonitrile (5 mL). Triflic acid
(0.013 mL, 0.146 mmol) was added via syringe and the solu-
tion heated to reflux for 3 h under nitrogen. After cooling to
room temperature, the solvents and volatiles were removed
under vacuum and the impure residue redissolved in di-
chloromethane and washed with distilled water (3”20 mL).
The organic solution was dried over magnesium sulfate and
the solvent removed to afford an impure product which was
purified via flash column chromatography (petroleum ether/
ethyl acetate 20–30%). The desired product was obtained as
a colourless oil; yield: 0.090 g (0.43 mmol, 29%). Physico-
chemical data for 56, a known compound, are as reported in
the literature.[3]
Synthesis of (Æ)-S-4-Chlorophenyl 3-(Furan-2-yl)-3-
hydroxypropanethioate (Æ)-54
Following the general procedure outlined above (Æ)-54 was
generated as a white solid; yield: 206 mg (0.73 mmol, 84%).
Purification of (Æ)-54 was via silica gel chromatography
using dichloromethane/petroleum ether (8:2), Rf =0.31.
Synthesis of anti-(2R,3R)-S-Phenyl 3-Hydroxy-2-
methyl-3-(3-methyl-4-nitrophenyl)propanethioate
(Æ)-anti-57 and syn-(2S,3R)-S-Phenyl 3-Hydroxy-2-
methyl-3-(3-methyl-4-nitrophenyl)propanethioate
(Æ)-syn-58
1
Physicochemical data for (Æ)-54 are: mp 45–478C; H NMR
(500 MHz, CDCl3): d=7.41–7.38 (m, 3H), 7.33 (d, J=
8.5 Hz, 2H), 6.36–6.33 (m, 1H), 6.30 (d, J=3.3 Hz, 1H),
5.22 (dd, J=8.5, 3.9 Hz, 1H), 3.27 (dd, J=16.1, 8.6 Hz, 1H),
3.16 (ddd, J=16.0, 3.9, 1.4 Hz, 1H), 2.86 (br s, 1H);
13C NMR (126 MHz, CDCl3): d=196.1, 154.3, 142.5, 136.3,
135.8, 129.7, 125.5, 110.5, 106.8, 64.6, 48.7; FT-IR (thin film):
n=3416 (OH), 1705 (C=O), 1506, 1477, 1266, 1146,
1013 cmÀ1; MS (MALDI-TOF): m/z=304.99 [M+Na]; HR-
MS (ASAP): m/z=300.0449, exact mass calculated for
C13H15ClO3SN [M+NH4]+: 300.0456.
MAHT (Æ)-36 (0.090 g, 0.428 mmol) and 4-nitro-3-hydroxy-
benzaldehyde (37) (0.078 g, 0.428 mmol) were dissolved in
chloroform (2 mL). Tetrabutylammonium bromide (0.138 g,
0.428 mmol) and distilled water (2 mL) were added and the
mixture stirred vigorously at 408C for 24 h. The mixture was
diluted with chloroform (101 mL) and water (10 mL) and
the aqueous layer extracted with chloroform (3”15 mL).
The organic solution was dried over magnesium sulfate, fil-
tered and the solvent removed to afford a crude product
which was purified by column chromatography on silica gel
(dichloromethane 100% Rf =0.26); to afford the desired syn
and anti compounds (syn:anti ratio=1:3.7) as a yellow solid;
yield: 70 mg (0.21 mmol, 49%). Physiochemical data for
(Æ)-syn-58 and (Æ)-anti-57 matched those previously report-
ed.[6] MS (MALDI-TOF): m/z=356.14, calculated for
C16H15NNaO5S [M+Na]+: 356.06.
Synthesis of (Æ)-S-Benzyl 3-Hydroxy-3-phenyl-
propanethioate (Æ)-10
Following the general procedure outlined above (Æ)-10 was
generated as a colourless oil; yield: 65 mg (0.24 mmol,
25%). Purification of (Æ)-10 was via silica gel chromatogra-
phy using petroleum ether/ethyl acetate (10%); Rf =0.26.
Physicochemical data for (Æ)-10, a known compound, as re-
ported in the literature:[20] 1H NMR (500 MHz, CDCl3): d=
7.38–7.24 (m, 10H), 5.21 (dt, J=9.1, 3.2 Hz, 1H), 4.22–4.12
(m, 2H), 3.03 (dd, J=15.8, 9.2 Hz, 1H), 2.98 (d, J=3.3 Hz,
1H), 2.95 (dd, J=15.8, 3.4 Hz, 1H); FT-IR (thin film): n=
3456, 3030, 2916, 1684, 1492, 1453, 1058 cmÀ1.
Acknowledgements
The authors acknowledge the EPSRC, UEA and INTER-
REG IVA (IS:CE-Chem project 4061) for financial support,
and the EPSRC Mass Spectrometry Service for HR-MS data.
Synthesis of Ethyl 2-Hydroxy-2-methyl-4-oxo-4-
(phenylthio)butanoate (Æ)-13
Following the general procedure outlined above (Æ)-13 was
generated as a colourless oil; yield: 199 mg (0.74 mmol, References
73%). Purification of (Æ)-10 was via silica gel chromatogra-
phy using petroleum ether/ethyl acetate (8:2); Rf =0.36.
Physicochemical data for (Æ)-13, a known compound, as re-
ported in the literature:[12f] 1H NMR (500 MHz, CDCl3): d=
7.40 (br s, 5H), 4.29–4.20 (m, 2H), 3.65 (s, 1H), 3.27 (d, J=
[1] Y.-O. You, C. Khosla, D. E. Cane, J. Am. Chem. Soc.
2013, 135, 7406–7409.
[2] M. T. Crimmins, B. W. King, J. Am. Chem. Soc. 1998,
120, 9084–9085.
1256
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 1245 – 1257

FULL PAPERS
Bioinspired, Base- and Metal-Free, Mild Decarboxylative Aldol Activation
[3] C.-Y. Wu, Y. Feng, E. R. Cardenas, N. Williams, P. E.
Floreancig, J. K. De Brabander, M. G. Roth, J. Am.
Chem. Soc. 2012, 134, 18998–19003.
[4] S. Shahzad-ul-Hussan, R. Ghirlando, C. I. Dogo-Isona-
gie, Y. Igarashi, J. Balzarini, C. A. Bewley, J. Am.
Chem. Soc. 2012, 134, 12346–12349.
2011, 353, 3196–3202; c) Y. Zheng, H.-Y. Xiong, J. Nie,
M.-Q. Hua, J.-A. Ma, Chem. Commun. 2012, 48, 4308–
4310; d) N. Blaquiere, D. G. Shore, S. Rousseaux, K.
Fagnou, J. Org. Chem. 2009, 74, 6190–6198.
[13] a) R. He, S. Shirakawa, K. Maruoka, J. Am. Chem. Soc.
2009, 131, 16620–16621; b) S. Shirakawa, K. Ota, T.
Shogo, K. Maruoka, Org. Biomol. Chem. 2012, 10,
5753–5755; c) S. Shirakawa, S. J. Terao, R. He, K. Mar-
uoka, Chem. Commun. 2011, 47, 10557–10559; d) L.
Wang, S. Shirakawa, K. Maruoka, Angew. Chem. 2011,
123, 5439–5442; Angew. Chem. Int. Ed. 2011, 50, 5327–
5330; e) J. Novacek, M. Waser, Eur. J. Org. Chem.
2013, 637–648; f) S. Shirakawa, L. Wang, R. He, S. Ari-
mitsu, K. Maruoka Chem. Asian J. 2014, 9, 1586.
[14] a) S. E. Denmark, R. C. Weintraub, N. D. Gould, J.
Am. Chem. Soc. 2012, 134, 13415; b) M. Rabinovitz, Y.
Cohen, M. Halpern, Angew. Chem. 1986, 98, 958–968;
Angew. Chem. Int. Ed. Engl. 1986, 25, 960–962.
[15] a) Z.-L. Wang, Adv. Synth. Catal. 2013, 355, 2745–2755;
b) H. Y. Bae, J. H. Sim, J.-W. Lee, B. List, C. E. Song,
Angew. Chem. Int. Ed. 2013, 52, 12143–12147.
[5] X. Gao, S. K. Woo, M. J. Krische, J. Am. Chem. Soc.
2013, 135, 4223–4226.
[6] L. Bernardi, M. Fochi, M. Comes, M. C. Franchini, A.
Ricci, Org. Biomol. Chem. 2012, 10, 2911–2922.
[7] a) A. Das, C. Khosla, Acc. Chem. Res. 2009, 42, 631–
639; b) J. Staunton, B. Wilkinson, Chem. Rev. 1997, 97,
2611–2629; c) J. Lubkoll, H. Wennemers, Angew.
Chem. 2007, 119, 6965–6968; Angew. Chem. Int. Ed.
2007, 46, 6841–6844; d) A. Ricci, D. Pettersen, L. Ber-
nardi, F. Fini, M. Fochi, R. Perez Herrera, V. Sgarzani,
Adv. Synth. Catal. 2007, 349, 1037–1040.
[8] S. P. Bew, G. R. Stephenson, L. A. Martinez-Lonzano, J.
Rouden, H. Seylani, Org. Lett. 2013, 15, 3805–3807.
[9] a) S. Smith, S.-C. Tsai, Nat. Prod. Rep. 2007, 24, 1041–
1072; b) A. M. Hill, Nat. Prod. Rep. 2006, 23, 256–320;
c) B. Shen, Curr. Opin. Chem. Biol. 2003, 7, 285–295;
d) B. Rawlings, J. Nat. Prod. Rep. 2001, 18, 231–281.
[10] M. B. Austin, M. Izumikawa, M. E. Bowman, D. W.
Udwary, J. L. Ferrer, B. S. Moore, J. P. Noel, J. Biol.
Chem. 2004, 279, 45162–45174.
[11] a) M. D. Shair, K. C. Fortner, J. Am. Chem. Soc. 2007,
129, 1032–1033; b) D. Magdziak, G. Lalic, H. M. Lee,
K. C. Fortner, A. D. Aloise, M. D. Shair, J. Am. Chem.
Soc. 2005, 127, 7284–7285; c) S. Orlandi, M. Benaglia,
F. Cozzi, Tetrahedron Lett. 2004, 45, 1747–1749; d) G.
Lalic, A. D. Aloise, M. D. Shair, J. Am. Chem. Soc.
2003, 125, 2852–2853.
[16] J. Baudoux, P. Lefebvre, R. Legay, M.-C. Lasne, J.
Rouden, Green Chem. 2010, 12, 252–259.
[17] I. Kovacs, Z. Kovacs, J. Label. Compd. Radiopharm.
1991, 14, 1181–1190.
[18] a) Z. Xia, W. Xin, W. Wencun, X. Wang, Tetrahedron
Lett. 2011, 52, 4906; b) S. Singh, L. D. S. Yadav, Tetrahe-
dron Lett. 2012, 53, 5136.
[19] a) J. M. Yost, G. Zhou, D. M. Coltart, Org. Lett. 2006,
8, 1503–1506; b) G. Zhou, J. M. Yost, D. M. Coltart,
Synthesis 2007, 478–482; c) H. R. Snyder Jr, S. E. Bur-
rous, R. Freedman, T. J. Hebert, J. Pharm. Sci. 1978, 67,
413–415.
[12] a) Y. Pan, C. W. Kee, Z. Jiang, T. Ma, Y. Zhao, Y.
Yang, H. Xue, C.-H. Tan, Chem. Eur. J. 2011, 17, 8363–
8370; b) H. Y. Bae, S. Some, J. H. Lee, J.-Y. Kim, M. J.
Song, S. Lee, Y. J. Zhang, C. E. Song, Adv. Synth. Catal.
[20] G. Lalic, A. D. Aloise, M. D. Shair, J. Am. Chem. Soc.
2003, 125, 2852–2853.
[21] R. Padmakumar, S. Gantla, R. Banerjee, Anal. Bio-
chem. 1993, 214, 318–320.
Adv. Synth. Catal. 2015, 357, 1245 – 1257
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1257