An enantioselective Mukaiyama aldol reaction as the key step towards the tetrahydropyran core of psymberin via a γ-butyrolactone intermediate

Article abstract of DOI:10.1055/s-0031-1290379

We report an alternative synthetic route towards the tetrahydropyran core of psymberin. The key steps are a catalytic enantioselective Mukaiyama aldol reaction and a syn reduction, which allowed for the rapid assembly of a γ-lactone as a precursor for the central fragment of the natural product. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290379

LETTER
▌1625
lAettner Enantioselective Mukaiyama Aldol Reaction as the Key Step towards the
Tetrahydropyran Core of Psymberin via a γ-Butyrolactone Intermediate
Towards Psymberin
Max Bielitza, Jörg Pietruszka*
Institut für Bioorganische Chemie der Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.8,
52426 Jülich, Germany
Fax +49(2461)616196; E-mail: j.pietruszka@fz-juelich.de
Received: 30.03.2012; Accepted after revision: 23.04.2012
for stereoselective Mukaiyama aldol reactions has been
Abstract: We report an alternative synthetic route towards the tet-
developed.10 But the enantioselective addition of acetyl-
rahydropyran core of psymberin. The key steps are a catalytic enan-
derived (especially bulky) silyl enol ethers to aldehydes
tioselective Mukaiyama aldol reaction and a syn reduction, which
has still proved to be a challenge. Furthermore, it has also
been difficult to find a general catalyst system that needs
only a few mol% of catalyst. A unique Ti(IV)/Schiff-base
catalyst which seemed promising in terms of substrate
generality, stereoselectivity, and low catalyst loading was
developed by Carreira and co-workers.11
allowed for the rapid assembly of a γ-lactone as a precursor for the
central fragment of the natural product.
Key words: aldol reaction, asymmetric catalysis, antitumor agent,
lactone, enantioselectivity
Psymberin (1), also known as irciniastatin A, is a marine
cytotoxin which was concurrently isolated by Crews1 and
Pettit2 from the sponges Psammocinia sp. and Ircinia ra-
mose, respectively, in 2004. It belongs to the pederins, a
family of 36 polyketides, and displays high cytotoxicity
especially against various melanoma, breast and colon
cancer cell lines. In contrast, different leukemia cell lines
are immune to it. So far, there are several total syntheses,3
a formal synthesis,4 and partial syntheses.5 Investigations
towards the biosynthesis of some pederins including
psymberin (1) were performed by Piel and co-workers,
and it is believed that not only pederin, but also psymberin
(1) is produced by symbiotic bacteria.6
OMe
O
OMe
OH
N
H
O
OH
O
O
O
H2N
HO
OEt
O
OH
OH
2
OH
O
psymberin (1)
OH
O
CO2Et
O
TMSO
+
EtO
O
In view of our on-going endeavour towards the total syn-
thesis of psymberin (1),5g,h we anticipated that an alterna-
tive approach towards the stereoselective synthesis of the
central tetrahydropyran core 2 could be initialized by an
enantioselective Mukaiyama aldol addition7 between enol
ether 38 and ethyl glyoxylate (4, Scheme 1). γ-Lactone 5
would be obtained after syn reduction. Just recently,
Harrowven and co-workers actually proved that the con-
version of γ-lactone 5 into tetrahydropyran 2 is feasible:
The two-step sequence comprised of a ring opening with
ammonia followed by a stereoselective base-induced oxa-
Michael addition to furnish the desired intermediate 2 of
psymberin (1).9
CO2Et
O
4
3
5
Scheme 1 Retrosynthetic analysis
Usually, silylketene acetals and silyketene thioacetals are
used for these enantioselective Mukaiyama aldol reac-
tions due to their higher nucleophilicity and reactivity.12
However, the products thus obtainable would not have
been useful for the construction of the tetrahydropyran
core. Therefore, further development was necessary to ob-
tain the valuable building block. As the demanding nu-
cleophile, silyl enol ether 3 was chosen as substrate for
different reasons. Firstly, regioselective enolization was
no problem. Secondly, the enoate functionality displayed
a masked aldehyde and represented a valuable functional-
ity for Michael additions. Thirdly, the starting material
could easily be synthesized in multigram quantities in four
steps from inexpensive isobutyraldehyde (6, Scheme 2).
Enamine 7 formation13 followed by acetylation furnished
aldehyde 8 which was submitted to a Horner–
Wadsworth–Emmons reaction.14 Ketone 98b was subse-
quently quantitatively transformed into its silyl enol ether
3 by the use of trimethylsilyl trifluoromethanesulfonate
(TMSOTf) and triethylamine.
For decades the aldol reaction has been an important,
widely used, and reliable reaction to form carbon–carbon
bonds. The development of new auxiliaries and catalysts
has advanced in such a way that the outcomes of reactions
in terms of stereoselectivity can often be predicted. To ob-
tain high levels of enantio- and diastereoselectivity in cat-
alytic aldol reactions an array of chiral Lewis acids used
SYNLETT 2012, 23, 1625–1628
Advanced online publication: 14.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290379; Art ID: ST-2012-D0289-L
© Georg Thieme Verlag Stuttgart · New York

1626
M. Bielitza, J. Pietruszka
LETTER
O
Table 1 Mukaiyama Aldol Reactions Utilizing Box Complexes
a) AcCl, Et2O,
reflux 2 h, then r.t.
O
O
O
morpholine
reflux, 95%
CO2Et
CO2Et
TMSO
OH
O
N
catalyst, conditions
EtO
b) H2O, Et2O, r.t., 29%
(S)
O
8
6
O
EtO
3
10
7
O
P
O
4
CO2Et
CO2Et
EtO2C
OEt
OEt
O
TMSO
TMSOTf, Et3N
Entry
Catalyst
(loading, mol%)
Conditions
Yield
(%)
ee
(%)
NaH, THF
0 °C to r.t., 58%
Et2O, 0 °C to r.t.
99%
9
3
1
2
3
4
5
6
7
8
A (5)
CH2Cl2, –78 °C
THF, –78 °C
CH2Cl2, –30 °C
THF, –30 °C
THF, –30 °C
THF, 0 °C
8
–
85
–
Scheme 2 Synthesis of silyl enol ether 3 from isobutyraldehyde (6)
A (5)
First, racemic reference material was synthesized (ketone
9 derived Li enolate was directly added to aldehyde 4 for
chromatographic evaluation). Next, we implemented a
stereoselective method using [Cu(S,S)-t-Bu-box]OTf2 and
[Sn(S,S)-t-Bu-box]OTf2 catalysts (Figure 1) as published
by Evans and co-workers.15 They rationalized their im-
pressive results from reactions of different silylketene
(thio)acetals with, for example, pyruvates via chelation
with the Lewis acidic center [Cu(II) or Sn(II)] and thereby
discriminating the two enantiotopic faces of the ketones.
Due to its α-oxo ester moiety ethyl glyoxalate (4)15b can be
used in the same fashion, and furthermore we anticipated
that sterically demanding ketone-derived enolate 3 should
also be a suitable nucleophile. Our initial results are dis-
played in Table 1. Both catalysts A and B were not reac-
tive enough at –78 °C to catalyze the reaction sufficiently
(Table 1, entries 1, 2, and 7). Therefore, we ran the reac-
tion at –30 °C (Table 1, entries 3–5) to obtain product 10
in moderate yield (41%) and good enantiomeric excess
(88%) with 10 mol% of catalyst A in THF (Table 1, entry
5). Increasing the temperature to 0 °C provided a higher
yield of 53%, but a lower enantiomeric excess (82%; Ta-
ble 1, entry 6). Catalyst B seemed to be low in terms of re-
activity and selectivity for our system (Table 1, entries 7
and 8).
A (5)
5
75
88
88
82
0
A (5)
28
41
53
13
20
A (10)
A (10)
B (10)
B (10)
THF, –78 °C
CH2Cl2, –30 °C
20
freshly distilled ethyl glyoxalate (4) and silyl enol ether 3
were consecutively added. We screened different condi-
tions and ligands (Table 2 and Figure 2). Reactions using
BINOL (C) led to good enantiomeric excesses (75–87%)
and low to moderate yields (9–67%; Table 2, entries 1–4).
The catalytic system worked best at 0 °C by using 20
mol% of catalyst (Table 2, entry 2). The dibromobinaph-
thol ligand D18 furnished moderate to good yields (23–
84%) and the enantiomeric excess was consistently supe-
rior (≥96%; Table 2, entries 5–7). Best results were ob-
tained running the reaction at 0 °C: An excellent
enantiomeric excess of 98% and 84% yield were obtained
using 20 mol% of catalyst (Table 2, entry 6). Applying li-
gand E in the transformation did not lead to any product
formation at room temperature which was probably due to
steric reasons and was therefore not investigated any fur-
ther. The observations Keck and co-workers had men-
tioned about the narrow concentration range were also
experienced leading to lower yields. Surprisingly, the type
2+
2+
O
O
O
O
2 OTf–
2 OTf–
N
N
N
N
Cu
Sn
t-Bu
t-Bu
t-Bu
t-Bu
CF3
A
B
[Cu(S,S)-t-Bu-box]OTf2
[Sn(S,S)-t-Bu-box]OTf2
Br
Figure 1 Cu(II)– and Sn(II)–box complexes used as catalysts
CF3
OH
OH
OH
OH
OH
OH
As the results were not satisfying, we investigated other
catalytic systems. Next, we chose the titanium(IV)/1,1′-
bi(2-naphthol) (BINOL, C) system as a catalyst reported
by Mikami16 and Keck.17 To obtain the active catalyst,
BINOL (C) was dissolved in diethyl ether, charged with 4
Å molecular sieves and treated with titanium tetraisoprop-
oxide for one hour. Having adjusted the temperature,
CF3
Br
D
C
CF3
E
Figure 2 BINOL ligands applied in the enantioselective Mukaiyama
aldol reaction
Synlett 2012, 23, 1625–1628
© Georg Thieme Verlag Stuttgart · New York

LETTER
Towards Psymberin
1627
psymberin (1). Starting from silyl enol ether 3 and ethyl
glyoxalate (4) γ-lactone 5, a known building block for the
tetrahydropyran core 2, could be synthesized in just three
steps. This was achieved in a stereoselective manner
through a sequence of a highly enantioselective, catalytic
Table 2 Aldol Reactions Utilizing Ti(IV)/BINOL Catalysts
CO2Et
CO2Et
Ti(Oi-Pr)4,
ligand, 16 h
TMSO
OH
O
EtO
(S)
Et2O, 4 Å MS
O
O
3
Mukaiyama aldol reaction by applying
a titani-
10
EtO
um(IV)/6,6′-dibromobinaphthol catalyst D system fol-
lowed by a syn reduction under Prasad conditions and an
acid-catalyzed lactonization.
O
4
Entry Ligand (loading, mol%) Temp (°C) Yield (%) ee (%)
CO2Et
Et2BOMe,
CO2Et
1
2
3
4
5
6
7
8
C (20)
C (20)
C (10)
C (20)
D (20)
D (20)
D (20)
E (20)
0 (7 h) 47
86
87
84
75
96
98
96
–
OH
O
OH OH
EtO
EtO
NaBH4
0
–20
–30
r.t.
67
28
9
O
THF–MeOH
(4:1)
O
10
11
CSA,
CH2Cl2
69
84
23
–
0 °C to r.t.
0
O
HO
ref. 9
CO2Et
O
O
–15
r.t.
H2N
OEt
O
O
OH
2
5
of molecular sieves did not have a major influence leading
to similar results (not shown).
Scheme 3 The syn-selective reduction and lactonization
It was assumed that the (S)-BINOL ligands had furnished
the S enantiomer of aldol product 10 in analogy to the con-
figurational assignments by Mikami and co-workers.16
We ascribed the moderate yields at low temperatures to
the above-mentioned lower nucleophilicity and to steric
reasons which caused insufficient conversion. Overall, we
found appropriate conditions to prepare the valuable aldol
intermediate 10 in almost enantiomerically pure form in a
good yield.
Typical Synthetic Procedure
(S,E)-Diethyl 7-hydroxy-4,4-dimethyl-5-oxooct-2-enedioate
(10)
To a solution of (S)-6,6′-dibromobinaphthol (34.6 mg, 78.0 μmol,
0.20 equiv) in Et2O (1.60 mL) was added 4 Å MS (98.0 mg) and
Ti(Oi-Pr)4 (23.0 μL, 78.0 μmol, 0.20 equiv). The red-brownish sus-
pension was stirred for 1 h at r.t. and was then cooled to 0 °C. Fresh-
ly distilled ethyl glyoxalate (4) (57 μL, 485 μmol, 86% in toluene,
1.25 equiv) and silyl enol ether 3 (102 mg, 398 μmol, 1.00 equiv),
dissolved in Et2O (0.40 mL), were consecutively added via syringe.
The reaction mixture was vigorously stirred overnight, quenched
with sat. aq NH4Cl and warmed to r.t. It was diluted with a mixture
of Et2O–H2O (3:1, 20 mL) and filtered over a plug of cotton. The
layers were separated, and the aqueous layer was extracted with
Et2O (3×). The combined organic layer was washed with 1 M aq
HCl (2×), sat. aq NaHCO3 (1×), brine (1×), and dried over MgSO4.
Filtration of solids and evaporation of solvents gave a crude oil
which was purified by column chromatography (PE–EtOAc =
80:20) to obtain aldol 10 as a colorless oil (95.6 mg, 334 μmol,
84%); ee ≥98% [HPLC: n-heptane–i-PrOH (98:2), flow = 0.5
mL/min]: tR (6a) = 54.9 min; [α]D20 +3.6 (c 1.09, CHCl3); Rf = 0.40
(PE–EtOAc = 70:60). 1H NMR (600 MHz, CDCl3): δ = 1.28 (t, 3J =
7.3 Hz, 3 H, 10-H or 2′-H), 1.30 (t, 3J = 7.4 Hz, 3 H, 10-H or 2′-H),
1.29 (s, 3 H, 4-CH3a), 1.30 (s, 3 H, 4-CH3b), 2.95 (dd, 2J6a,6b = 17.7
Hz, 3J6a,7 = 5.7 Hz, 1 H, 6-Ha), 2.99 (dd, 2J6b,6a = 17.7 Hz, 3J6b,7 = 4.0
Hz, 1 H, 6-Hb), 3.11 (d, 3J7-OH,7 = 5.4 Hz, 1 H, 7-OH), 4.21 (q, 3J =
7.4 Hz, 2 H, 9-H or 1′-H), 4.24 (q, 3J = 7.3 Hz, 2 H, 9-H or 1′-H),
4.45 (ddd, 3J7,6a = 5.5 Hz, 3J7,7-OH = 5.4 Hz, 3J7,6b = 4.1 Hz, 1 H, 7-
H), 5.90 (d, 3J2,3 = 15.9 Hz, 1 H, 2-H), 7.00 (d, 3J3,2 = 15.9 Hz, 1 H,
3-H) ppm. 13C NMR (151 MHz, CDCl3): δ = 14.1, 14.2 (C-10 und
C-2′), 23.3 (4-CH3a), 23.3 (CH3b), 41.8 (C-6), 50.5 (C-4), 60.6, 61.9
After we had established the first stereogenic center in a
highly enantioselective manner, a syn reduction under
Prasad19 conditions should furnish diol 11 which should
undergo acid catalyzed cyclization to form γ-lactone 5
(Scheme 3). Therefore, aldol 10 was complexed with di-
ethylmethoxy borane at –70 °C followed by the reduction
with sodium borohydride. It was found that, depending on
the workup conditions, the formation of the lactone 5 was
more or less spontaneous, and diol 11 could not be isolat-
ed in pure form, but a mixture of both as well as their dia-
stereomers. To facilitate the purification procedure,
camphor sulfonic acid (CSA) was added in order to com-
plete lactone formation. The diastereomeric ratio was de-
termined by 1H NMR of the crude product to be 6.4:1. The
yield over the two steps was 75%. The analytical data for
lactone 5 were in full agreement with the published data10
also confirming the proposed configurational assign-
ments. Lactone 5 could be transformed to tetrahydropyran
2 by lactone opening with ammonia and an oxa-Michael (C-9 and C-1′), 66.9 (C-7), 121.4 (C-2), 150.4 (C-3), 166.1 (C-1),
173.7 (C-8), 208.6 (C-5) ppm. IR (film): ν = 3493, 2981, 2937,
addition to the α,β-unsaturated ester as described by Haar-
owven and co-workers.9
1709, 1647, 1467, 1389, 1367, 1298, 1268, 1181, 1096, 1061, 1032,
988, 865, 723 cm–1. Anal. Calcd for: C, 58.73; H, 7.74. Found: C,
In conclusion, we have developed an alternative route to-
58.46; H, 7.73.
wards the synthesis of the tetrahydropyran core 2 of
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1625–1628

1628
M. Bielitza, J. Pietruszka
LETTER
2009, 74, 5405. (g) Henßen, B.; Kasparyan, E.; Marten, G.;
Pietruszka, J. Heterocycles 2007, 245. (h) Pietruszka, J.;
Simon, R. C. Eur. J. Org. Chem. 2009, 3628.
Acknowledgment
We gratefully acknowledge the Fonds der Chemischen Industrie
(scholarship to M.B.), the Deutsche Forschungsgemeinschaft, the
Ministry of Innovation, Science, and Research of the German fede-
ral state of North Rhine-Westphalia, the Heinrich-Heine-Universi-
tät Düsseldorf, and the Forschungszentrum Jülich GmbH for their
generous support of our projects. Furthermore, we thank the analy-
tical departments of the Forschungszentrum Jülich as well as Anu
Kantharajah for her support.
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Synlett 2012, 23, 1625–1628
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