Studies towards a novel synthesis of tubulysins: Highly asymmetric aza-Michael reactions of 2-enoylthiazoles with metalated chiral oxazolidinones

Article abstract of DOI:10.1055/s-0029-1216729

Herein we report the highly asymmetric aza-Michael reactions of α,β-enones (2-enoylthiazoles) with metalated chiral oxazolidinones under different reaction conditions and for different substituents at the β-position of the Michael acceptor. The reaction p

Full text of DOI:10.1055/s-0029-1216729

LETTER
1341
Studies towards a Novel Synthesis of Tubulysins: Highly Asymmetric Aza-
Michael Reactions of 2-Enoylthiazoles with Metalated Chiral Oxazolidinones
Aza-Michael
R
r
eaction
e
of 2-Enoy
e
lthiazoles jith Shankar P.,a Monica Sani,b,c Giancarlo Terraneo,d Matteo Zanda*c,e
a
b
c
Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘G. Natta’, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
KemoTech s.r.l., Parco Scientifico e Tecnologico della Sardegna, Loc.Piscinamanna, 09010 Pula (CA), Italy
CNR – Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, Via Mancinelli 7, 20131 Milano, Italy
Fax +39(02)23993080; E-mail: matteo.zanda@polimi.it
NFMLab-Dipartimento di Chimica, Materiali e Ingegneria Chimica "G. Natta", Politecnico di Milano, Via Mancinelli 7,
20131 Milano, Italy
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
d
e
Received 11 February 2009
Enders and co-workers developed the aza-Michael reac-
tion of (S)-1-amino-2-methoxymethylpyrrolidine (SAMP)
and its derivatives with alkenyl sulfones to afford the cor-
responding b-aminosulfonates with de up to 96%.5 Mean-
Abstract: Herein we report the highly asymmetric aza-Michael
reactions of a,b-enones (2-enoylthiazoles) with metalated chiral
oxazolidinones under different reaction conditions and for different
substituents at the b-position of the Michael acceptor. The reaction
proceeds with complete diastereoselectivity to give exclusively one while, Tomioka et al. developed an efficient chiral-ether-
of the two diastereomers. The significance of the reaction is that no
mediated asymmetric conjugate addition of lithium amide
to enoates with ee values up to 99%.6 Our group has pre-
catalyst has been used; the steric requirements of the chiral Michael
nucleophile drive the stereospecificity of the reaction and the reac-
viously reported the aza-Michael reaction between
tion time is much less compared to the reported procedures. This
nitroalkene acceptors and a-amino acid ester hydrochlo-
methodology might be useful for an improved total synthesis of the
highly cytotoxic peptides known as the tubulysins.
rides with excellent diastereoselectivities under noncata-
lytic conditions.10
Key words: asymmetric, aza-Michael Reaction, diastereoselectivi-
ty, noncatalytic, oxazolidinone
In the current investigation, the conjugate addition of
chiral 4-subsituted-2-oxazolidinones 4a–g (Scheme 1)
and imidazolidinone 4h to 2-substituted-2-enoylthiazoles
The conjugate addition of nucleophiles to a,b-unsaturated
carbonyl compounds is one of the most significant and
useful bond-forming reactions in organic chemistry.1
Thus, Michael additions are one of the best and most con-
venient ways to introduce amino-derived functionality to
a carbon b to an electron-withdrawing group, which is not
only an important segment of many natural products, but
also the synthetic precursor for b-amino ketones, b-amino
acids, 1,3-amino alcohols, and b-lactam antibiotics.2 The
so-called aza-Michael reaction is, hence, one of the most
important reactions forming C–N heterocycles containing
b-aminocarbonyl functionality.3
O
N
COOEt
R
S
3a–d
–78 °C
R3
R3
KOt-Bu
THF
R2
R1
R2
R1
X
O
O
O
N
N
H
H
The stereochemistry of the reaction is controlled mainly
by the use of chiral auxiliaries4 and reports suggest that
this asymmetric induction can be achieved following two
major routes: by using chiral amines or chiral acceptors
and by using chiral ligands or catalysts.5,6 Using optically
active amines as nucleophiles should direct aza-Michael
reactions in an asymmetric fashion, however, equimolar
amounts of the two diastereomers may be produced
through an equilibrium of a reversible addition–elimina-
tion process.7 This problem has been resolved by using
solubility differentiation of the diastereomers8 or by intro-
ducing metallic counterions,6 but there are evidences of
unexpected adverse effects for the aforementioned tech-
niques.7,9
4a–e
4f–h
R3
R3
R2
R2
R1
O
X
R1
O
O
O
N
N
O
N
COOEt
N
COOEt
R
R
S
S
5a–t
6a–z
4a R1 = Bn, R2, R3 = H
4b R1 = i-Pr, R2, R3 = H
4c R1 = Ph, R2, R3 = H
4d R1 = Bn, R2, R3 = Me
4e R1, R2 = Ph, R3 = H
3a R = i-Pr
3b R = i-Bu
3c R = c-Hex
3d R = PMP
4f R1 = Bn, R2, R3 = H, X = O
4g R1 = i-Pr, R2, R3 = H, X = O
SYNLETT 2009, No. 8, pp 1341–1345
x
x.
x
x.
2
0
0
9
4h R1 = Ph, R2 = H, R3 = Me, X = NMe
Advanced online publication: 17.04.2009
DOI: 10.1055/s-0029-1216729; Art ID: D04909ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 General scheme for the studied reactions

1342
S. Shankar P. et al.
LETTER
3a–d was selected as our model reaction and the reaction
parameters were screened. The significance of 2-enoyl-
thiazoles as Michael acceptors is that they are important
intermediates in the total synthesis of tubulysins11 and are
model compounds for substituted a,b-enones.12 Despite
all the excellent advances, completely stereocontrolled
aza-Michael reactions still remain a challenging task and
to our knowledge, this is among the first reports of accom-
plishing complete diastereoselectivity under simple non-
catalytic conditions.
The enoylthiazole moiety was prepared11,13 from L-cys-
teine ethyl ester HCl salt, which, on treatment with methyl
glyoxal, afforded the thiazolidine 1 (Scheme 2), that was
oxidized by MnO2 giving the ketothiazole 2, which, in
turn, was converted into 2-enoylthiazole 3 via TiCl4-
mediated aldol reaction with the corresponding aldehyde.
N
O
O
H
retro-Michael reaction
R
AT
R
AT
H
3
N
H
H
base
N
O
R
AT
H
5 or 6
N
COOEt
base + 3
(double aza-Michael)
AT
=
S
O
SH
H
a
b
N
COOEt
N
O
ClH.H2N
COOEt
S
R
AT
AT
1
R
O
O
O
N
COOEt
N
COOEt
c
7
R
S
S
Scheme 3 Proposed pathway for Michael–retro-Michael equilibri-
um giving the starting material and the ‘double aza-Michael’ side pro-
duct 7, along with the target products 5 and 6. The structure of
compound 7 was confirmed by mass spectrometry and NMR experi-
ments (COSY, DEPT).
2
3
Scheme 2 Preparation of the Michael acceptor. Reagents and con-
ditions: (a) NaHCO3, EtOH–H2O, 12 h; (b) MnO2, MeCN, 65 °C, 12
h; (c) TiCl4, Et3N, RCHO, –78 °C to r.t.
Table 1 Base Optimization in the Reaction of 3b and 4aa
The major concern in devising the strategy for a complete-
ly diastereoselective aza-Michael reaction was the well-
known reversibility of the reaction with reference to pro-
longed reaction times and increasing temperature. Indeed,
we observed that increase in reaction times and tempera-
ture resulted in enhanced reversibility and reduced dia-
stereoselectivity of the reaction.
Base
Yield of 5f (%)b Recovered 3b (%) 7 (%)d
Time
(min)
LDA
19
0
10
45
40
41
45
–
300
300
40
NaHc
0
KHMDS
32
22
20
15
Unexpectedly, the same was also observed during
quenching under standard conditions, probably due to an
increase in the temperature of the reaction mixture
(Scheme 3). Thus the two processes – quenching and re-
versibility – became competitive. The resulting Michael–
retro-Michael equilibrium led to the back formation of the
starting materials, as well as a ‘double-aza-Michael’ side
product 7 in some cases.
NaHMDS 31
KOt-Bu 33
60
20
a Reagents and conditions: 3b, 4a, reaction quenched by adding sat.
aq NH4Cl soln.
b Isolated yields after flash chromatography on SiO2.
c DMF, 0 °C; all other cases, THF, –78 °C.
d Calculated on 3b consumed.
The diastereoselectivity of the reaction was studied as a
function of the experimental conditions such as the base
used, temperature, and quenching techniques.
The observed low yields could be clearly ascribed to inad-
equate quenching. In fact, quenching of a small aliquot of
the cold reaction mixture on a TLC plate showed much
more product than that observed in the experiments
above.
Our first goal was to optimize the choice of base used and
we found that LDA was poorly compatible with enoyl-
thiazoles such as 3b (Scheme 1 and Table 1). Hydrides of
sodium and potassium were also found to be useless as
these bases in DMF caused either complete or partial de-
composition of the enoylthiazole. Finally, we obtained the
best results using KOt-Bu and sodium or potassium
hexamethyl disilazides.
We hypothesized that on the TLC, silica quenching was
predominant over reversibility because it takes place at
low temperature. In fact, after a screening of several
quenching conditions (Scheme 1 and Table 2), we were
Synlett 2009, No. 8, 1341–1345 © Thieme Stuttgart · New York

LETTER
Aza-Michael Reactions of 2-Enoylthiazoles
1343
Table 2 Quenching Techniquea
Table 3 Temperature Optimizationa
3
4
Product,
yield (%) (%)
Recovered 3 Dimer Quenchingd
3
Product,
yield (%) (%)
Recovered 3 Yield of 7 (%) Temp (°C)
(%)
3a
3b
3b
3b
3b
3b
3b
3b
3c
4a
4g
4g
4g
4g
4a
4f
5a, 80
6g, 28
6g, 31
6g, 20
6g, 24
5f, 49
6f, 48
13
0
A
A
B
C
C
D
E
3d
3d
3d
3d
3d
3b
3b
3b
3b
5p, 49
5p, 49
5p, 25
5p, 10
47
48
70
82
0
0
0
0
–100
–78
34
16b
11
38
–60 to –26
–15
34
15c
22c
10
38
unable to purify
0 to r.t.
–100
–78
39
5f, 48
5f, 48
5f, 47
40
39
30
8
10
–
40
10
4b
4c
4a
4a
unable to purify
F
–40
5m, 96
5p, 49
5p, 27
0
48
63
0
0
0
D
D
A
unable to purify
0
a Reaction conditions: 4a, KOt-Bu, THF; isolated yields after flash
chromatography on SiO2.
3d
3d
a Reaction conditions: KOt-Bu, THF, –78 °C; isolated yields after
flash chromatography on SiO2.
Table 4 Scope of the Reactiona
b The dimer was obtained as a diastereomeric mixture.
c The dimer contained traces of 2g.
3
4
Time (min) Product, yield (%)b Recovered 3 (%)
d Quenching A: sat. aq NH4Cl soln added to the reaction mixture at
–78 °C; quenching B: neat TFA added at –78 °C; quenching C: cold
reaction mixture poured onto a stirred slurry of SiO2 in hexane;
quenching D: cold reaction mixture cannulated or poured (rapidly)
into vigorously stirred aq NH4Cl; quenching E: into an aq 1 N HCl;
quenching F: into aq NaHCO3.
3a
3a
3a
3b
3b
3b
3c
3c
3d
3d
4a
4b
4g
4d
4h
4e
4c
4d
4a
4c
45
45
45
20
20
20
20
20
90
90
5a, 80
5b, 82
6b, 83
5i, 78
6f, 57
5j, 49
5m, 96
5n, 97
5p, 49
5r, 46
13
13
15
20
20
35c
0
pleased to find that the best way to quench the reaction
was a fast cannulation (or pouring) of the cold reaction
mixture into a vigorously stirred excess of saturated
NH4Cl solution (quenching procedure D).
We then looked into the impact of temperature on the
reaction with the system developed so far and the effect of
temperature was found to be dramatic (Scheme 1 and
Table 3). For all the reactions, excellent yields and diaste-
reoselectivity were obtained at low temperatures (–78 °C
or –100 °C). Increasing the temperature led to equilibra-
tion of the reaction and even chromatographic purification
was difficult in some cases (see Table 3).
0
48
50
a Reaction conditions: KOt-Bu, THF, –78 °C, quenching procedure D.
b Isolated yields after flash chromatography on SiO2.
c The corresponding double aza-Michael byproduct 7 was isolated in
7% yield.
After the reaction conditions had been optimized, we test-
ed the generality of the reaction over a wide range of sub-
strates, and the results are summarized in Table 4.
characterized by a metal-chelated eight-membered transi-
tion state (Figure 2).
The aza-Michael reaction reported herein achieved com-
pletion within 20–90 minutes at –78 °C. The stereochem-
istry of the product was under the complete control of the
stereochemistry at C4 of the aza-nucleophile 4 and was
thus found to be determined by steric regulations due to
the presence of the substituent at C4 of the chiral donor.
Thus, the attack of the nitrogen nucleophile [the (S)-oxa-
zolidinone 4] takes place from the diastereoface not hin-
dered by the bulky R group and the Si face of the enone 3,
leading to a new S-configured stereocenter. Mioskowski
et al. have also suggested a similar predominant transition
state in the aza-Michael reaction involving trans-3,3,3-tri-
fluoro-1-nitropropene.14
The stereochemistry of 5i was assigned by X-ray diffrac-
tion analysis (see Figure 1).15
Thus, in conclusion, we have reported a completely stere-
oselective noncatalytic aza-Michael reaction involving
a,b-unsaturated compounds leading to the formation of
b-amino ketone derivatives. Studies directed to the depro-
To explain the observed complete asymmetric induction
of the reaction we propose a p-facial selectivity model
Synlett 2009, No. 8, 1341–1345 © Thieme Stuttgart · New York

1344
S. Shankar P. et al.
LETTER
Synthesis of 3
Compound 2 (1 mmol) was dissolved in dry THF (4 mL) under N2
and cooled in an ice bath. TiCl4 (1 N soln in toluene, 2.2 mmol) was
added, and the resulting solution was stirred at 0 °C for 30 min. The
solution was then cooled to –78 °C, and dry Et3N (2.2 mmol) was
added. The red solution thus formed was stirred at the same temper-
ature for 10 min, and neat aldehyde (1.2 mmol) was then added
dropwise. The reaction mixture was stirred at –78 °C for an addi-
tional 1 h and then was allowed to warm to r.t. The reaction was then
quenched with sat. NH4Cl soln, and the organic phase was dried and
concentrated in vacuo. The residue was purified by chromatography
on SiO2.
Typical Procedure for the Aza-Michael Reaction
Figure 1 X-ray crystal structure of 5i showing S absolute configu-
ration at the newly created stereocenter. For clarity only one confor-
mer of the disordered ethyl chain on the ester moiety is reported.
The 4-substituted-2-oxazolidinone or imidazolidinone 4 (1.1 mmol)
was dissolved in dry THF (10 mL), and the solution was cooled to
0 °C. KOt-Bu (1 M soln in THF, 1.1 mmol) was added to the above
solution and was stirred at 0 °C for 30 min. Then the mixture was
cooled to –78 °C and 2-enoylthiazole 3 (1 mmol) in THF (10 mL)
was added. The reaction mixture was stirred at –78 °C for the re-
quired time (as monitored by TLC). Finally, the reaction was
quenched by pouring it abruptly into a vigorously stirred sat. soln
(50 mL) of NH4Cl. The layers were separated, and the aqueous
phase was extracted with EtOAc (2 × 20 mL), washed with brine,
dried over anhyd Na2SO4 and concentrated in vacuo. The crude ma-
terial was then purified by flash chromatography over SiO2.
(a)
(b)
H
R
H
R
R
+M-O
O
N
N
O
O
R
H
M
H
O
O
AT
approach
AT
chelated attack
Si-face (favored)
Figure 2 p-Facial selectivity model for the observed diastereoselec-
tivity: approach (a) and attack (b) of a chiral oxazolidinone (S)-4 to
the Si face of the enone 3, through a metal-chelated eight-membered
transition state leading to the corresponding product (S)-5.
Acknowledgment
CNR and Politecnico di Milano are gratefully acknowledged for
economic support. We thank Dr. Tullio Pilati (ISTM-CNR, Milan,
Italy) for his help with the X-ray crystal structure analysis of com-
pound 5i.
tection of the donor moiety to give free b-amino function-
ality are in progress. Furthermore, the formation of the
‘double-aza-Michael’ product 7 (Scheme 2) during retro-
Michael reaction should be viewed as a strategy for one-
pot a-derivatisation of the b-aminocarbonyl derivative,
which is a significant development as under normal con-
ditions, the a-position in these cases are known to be less
reactive. The reaction might even be extended to normal
a,b-unsaturated ketones without the thiazole moiety.
References and Notes
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mixture of EtOH (100 mL) and H2O (100 mL). Solid NaHCO3 (10
mmol) was added to the above stirred solution. A 40% methyl gly-
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