Studies on the C22-C23 aldol coupling of spirangien

Article abstract of DOI:10.1055/s-0029-1216918

The aldol reaction is one of the most powerful and versatile methods in polyketide synthesis. Nevertheless, the subtle directing effects remain very often obscure and impede complex natural products syntheses. Here, we report studies on the pivotal aldol

Full text of DOI:10.1055/s-0029-1216918

PAPER
3061
Studies on the C22–C23 Aldol Coupling of Spirangien
C
22–C23 Aldol Coupl
i
ing in
S
c
pirangien S
h
ynthesis ael Lorenz, Nadine Bluhm, Markus Kalesse*
Leibniz Universität Hannover, Institut für Organische Chemie, Schneiderberg 1b, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: Markus.Kalesse@oci.uni-hannover.de
Received 5 March 2009; revised 6 May 2009
with an IC50 value of 0.7 ng/mL for 1. Additionally, they
exhibit antibiotic activity against yeast and fungi (diame-
ters of inhibition zones: Pichia membranaefaciens 24
mm, Rhodotorula glutins 19 mm, Botrytis cinerea 11
Abstract: The aldol reaction is one of the most powerful and versa-
tile methods in polyketide synthesis. Nevertheless, the subtle direct-
ing effects remain very often obscure and impede complex natural
products syntheses. Here, we report studies on the pivotal aldol cou-
pling employed in the spirangien synthesis. We identified condi- mm). In particular their novel yet unidentified mode of ac-
tions for the stereoselective formation of both stereoisomers in the
tion highlights them as promising tools in chemical biolo-
C22–C23 aldol juncture of spirangien.
gy and as potential drug candidates.
Key words: aldol reaction, methyl ketone, natural products, 1,4-in-
For structure elucidation, 1 was transferred into the trun-
duction, Felkin product, Cornforth model
cated spirangien 3 via cross metathesis using ethylene and
the Grubbs second generation catalyst. The relative con-
figuration has been established by X-ray crystallography
Myxobacteria are a valuable source for the isolation of
structurally diverse biologically active natural products.
of 3 (Scheme 1) and the absolute configuration of the
fourteen stereocenters was elucidated by total synthesis
In 2005 Höfle et al. isolated two novel compounds from
and gene cluster analysis.1c,d
the fermentation broth of strain So Ce90, spirangien A (1)
Up to now, two synthetic approaches towards 3 and one
synthesis of spirangien A (1) have been put forward.1 In
each approach, the pivotal disconnection was placed be-
tween C22 and C23 using an aldol reaction between a me-
thyl ketone and the corresponding aldehyde (Scheme 2).
The low selectivities obtained (ranging from 2.5:1 to 3:1)
serve as a clear indication that opposing directing effects
prevent an efficient aldol coupling.
and B (2)1 (Scheme 1).
The spirangiens attracted considerable attention due to
their complex structure and remarkable biological profile.
These unique natural products unfold remarkably high cy-
totoxic activity against L929 mouse fibroblast cell lines
R
31
Even though a large body of data analyzing the different
effects in aldol reactions is available, literature studies as-
serted a lack of mechanistic insights and explanation for
this particular set-up, incorporating a protected a-hydroxy
methyl ketone. Only few examples were reported in
which the a-substituted methyl ketone was employed
without any handicap resulting from an additional 1,5-in-
duction.2 One of the few examples was put forward in
2008 by Urpi and co-workers2d who published studies us-
ing titanium-based Lewis acids in combination with
chelating protecting groups. In order to examine the di-
recting effects of both coupling partners we initiated a
program in which substrate-controlled aldol reactions
were investigated using either the ketone or the aldehyde
with their corresponding achiral substrates. Special focus
was placed on investigating the effects of bases and
counter ions such as LDA, KHMDS, and changing the re-
action conditions from enolate activation to Lewis acid
activation as employed in Mukaiyama aldol reactions. We
had high expectations that changing the counter ions
would significantly increase the selectivities since it led to
improved results in the aldol coupling step during our
tedanolide synthesis.3
MeO
CO2H
3
27
9
5
HO
H
O
H
15
O
12
22
MeO
spirangien A (1): R = Me
spirangien B (2): R = Et
OH
HO
19
1, Grubbs II
ethylene, 15%
12
31
27
15
H
H
O
HO
O
OH
22
19
MeO
HO
3
Scheme 1 Formation of truncated spirangien 3
First, we investigated the opposing directing effects inher-
ent to aldehyde 4 with methyl ketone 10 as the achiral sub-
stitute for 5 (Scheme 3).4 The syn configuration at the a
SYNTHESIS 2009, No. 18, pp 3061–3066
Advanced online publication: 23.07.2009
DOI: 10.1055/s-0029-1216918; Art ID: T05209SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

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M. Lorenz et al.
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Kalesse et al.
Table 1 Selectivities for Reactions Depicted in Scheme 3
TES
O
TES
TES
TES
Solvent
THF
Base
Yield, de6
O
O
O
O
O
19
31
+
12
1
2
3
LiHMDS
LiHMDS
KHMDS
87%, >95:5
84%, >95:5
61%, >95:5
25
15
TESO
CH2Cl2
THF
4
5
3:1 anti-Felkin1g
stituent, which can be explained by the polar Cornforth
model.2
TES TES
O O
TES TES
O
O
OH
O
19
31
12
In order to unravel the directing effects of the methyl ke-
tone, we prepared the simplified methyl ketone analogues
13, 16, and 19, which were obtained from L-leucine in
three steps.7
27
15
22
O
TES
6
steps
The initial transformations using enolate activation
(Table 2) resulted in low yields irrespective of the protect-
ing groups and bases used. The least selective reactions
were always those when sodium was used as the counter
ion. As a general trend it became apparent that lithium
bases provided the best selectivities, albeit for the undes-
ired isomer in our case. The influence of the protecting
group was also not fundamental, with the PMB group pro-
viding the best selectivities for the undesired isomer. The
fact that in our synthesis of 3 LiHMDS provided accept-
able yields and selectivities, parallels the trends observed
for the separate coupling partners (Scheme 4, Table 2).
3
steps
O
O
O
OH
O
O
31
19
27
15
22
O
7
TES
2.5:1 anti-Felkin1d
O
O
O
O
O
O
These results can be rationalized by transition state A
(Figure 1) wherein chelation of the counter ion by the eno-
31
19
+
15
25
TESO
OH
O
O
O
8
9
Paterson et al.
+
O
O
Scheme 2 Pivotal aldol reaction of the ketone and aldehyde frag-
ments of 3
PG
PG
1,4-anti
1,4-anti
12
1,4-syn
PG = PMB 13
PG = TES 16
PG = TBS 19
PG = PMB 14 PG = PMB 15
PG = TES 17 PG = TES 18
PG = TBS 20 PG = TBS 21
TES
O
TES
10, base,
–78 °C, then 4
O
O
O
31
+
23
27
Scheme 4 Model reaction using simplified methyl ketones
Table 2 Reaction Conditions for Scheme 4
10
4
Entry Ketone PG
Base
dr anti/syn (yield)a,6
87:13 (46%)
68:32 (36%)
81:19 (38%)
62:38 (37%)
58:42 (36%)
59:41 (31%)
68:32 (43%)
50:50 (38%)
53:47 (38%)
TES
O
TES
O
OH
O
1
2
3
4
5
6
7
8
9
13
13
13
19
19
19
16
16
16
PMB
PMB
PMB
TBS
TBS
TBS
TES
TES
TES
LiHMDS
NaHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
31
23
27
11
Scheme 3 Model reaction with achiral methyl ketone 10
and b position already led to opposing directing effects.
The a-substituent favored the Felkin product whereas the
b-substituent would be Felkin opposing.5 When enolate
activation was employed, as it was the case in our synthe-
sis of 3, 84–87% yield of the single desired diastereomer
was observed (Table 1, entries 1 and 2). This result clearly
shows that the aldehyde directs the aldol reaction to the
desired anti-Felkin stereoisomer, controlled by the b-sub-
a No full conversion of the ketone could be obtained. The reaction
stopped after 16 h, but unreacted ketone could be reisolated.
Synthesis 2009, No. 18, 3061–3066 © Thieme Stuttgart · New York

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C22–C23 Aldol Coupling in Spirangien Synthesis
3063
late and the oxygen protecting group shields one face of el ketone 13 (Table 3, entry 5) at different reaction
the enolate, whereas chelation is not so prominent with temperatures did not produce improved yields.
silicon protection groups and larger cations (R = TBS,
TES; M = Na, K). In these cases an alternative transition
state B (Figure 1) can be adopted.
The observed selectivity can be explained with the aid of
the Zimmerman–Traxler transition state C and D wherein
attack on the si-face in C is favored as opposed to transi-
tion state D. In transition state C a minimum of steric hin-
drance occurs in contrast to transition state D where a
minimum of electronic effects appears (Figure 2).
PG
PG
H
M = Li+, Na+, K+
PG = PMB, TBS, TES
H
O
H
O
H
M
M
O
O
O
O
H
PG
R2
B
H
O
PG
H
O
H
O
R
B
R
O
O
B
A
H
B
O
O
H
R
R
R
O
O
Figure 1 Transition states for reactions shown in Scheme 4
PG
The outcome of our investigations corresponds to the re-
sults reported by Kobayashi, Carter, and Zhao in their
synthetic approaches towards amphidinolide B1 and H1,
respectively.8 They refer to chelation of the a-protecting
group on the methyl ketone employing MOM or PMB
ether.
D
E
C
R = n-Bu, c-Hex
PG = PMB, TES
Figure 2 Transition states of the boron-mediated aldol reactions
For aldol reactions with methyl ketones both boat and
chair transition states are reasonable.5g,h,i This possible
boat transition state combines a minimum of both steric
and electronic effects as shown in E (Figure 2).
Next, we focused on boron enolates, which have been re-
ported to change the selectivity for similar aldol reaction.9
Nevertheless, changing sterically demanding groups at
boron did not alter the selectivity and consequently we
were not able to utilize these examples to perform the 1,4-
syn-selective aldol reaction.
The Mukaiyama aldol reaction (Scheme 5) on the other
hand led to a complete change in stereochemistry and pro-
vided the 1,4-syn product in excellent selectivity (Table 3,
entries 8–10).5f,10 Both transition states shown in Figure 3
lead to the obtained 1,4-syn product. The stereochemical
outcome can be rationalized by an anti-periplanar transi-
tion state F with minimized steric hindrance compared to
transition state G (Figure 3).
The boron-mediated aldol reactions gave good to excel-
lent 1,4-anti-selectivities. Again, the reaction stopped af-
ter 16 hours and we were able to reisolate the unreacted
ketone. An optimum of yield and diastereoselectivity
(Table 3, entry 2) could be achieved with (c-Hex)2BCl as
Lewis acid at –20 °C with a TES protecting group. Unfor-
tunately, optimization studies of the PMB protected mod-
Table 3 Conditions for Boron-Mediated Aldol Reactions and Mukaiyama Aldol Reactions
Entry
Ketone
13
Lewis acid
Base/solvent
Et3N/Et2O
Et3N/Et2O
Et3N/Et2O
Et3N/Et2O
DIPEA/CH2Cl2
DIPEA/toluene
toluene
dr anti/syn (yield)a,6
77:23 (39%)
84:16 (63%)
85:15 (51%)b
72:28 (68%)c
93:7 (35%)
80:20 (84%)d,e
4:96 (35%)
1
2
(c-Hex)2BCl
16
(c-Hex)2BCl
3
16
(c-Hex)2BCl
4
16
(c-Hex)2BCl
5
13
(n-Bu)2BOTf
6
13
(n-Bu)2BOTf
8
13f
13f
16f
BF3·OEt2 (0.3 equiv)
BF3·OEt2 (1 equiv)
BF3·OEt2 (0.3 equiv)
9
toluene
6:94 (38%)
10
toluene
2:98 (36%)
a No full conversion of the ketone could be obtained.
b Reaction run at –85 °C.
c Reaction run at 0 °C.
d Yield based on recovered starting material.
e Reaction run at –78 °C.
f Mukaiyama aldol.
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3064
M. Lorenz et al.
PAPER
slowly and the mixture was stirred at this temperature for 20 h. The
reaction was stopped by the addition of sat. aq NH4Cl (2 mL), the
layers were separated, and the aqueous layer was extracted with
MTBE (3 × 2 mL). The combined organic layers were washed with
brine (5 mL), dried (MgSO4), filtered, and the solvent was removed
under reduced pressure. Column chromatography of the residue
provided the aldol product 11 (4.1 mg, 7.4 mmol, 87%); Rf = 0.45
(EtOAc–n-hexane, 1:50); [a]D20 –6.7 (c 0.31, CHCl3).
OH
O
O
OTMS
BF3⋅OEt2
+
PGO
PGO
1,4-syn
PG = PMB 15
PG = TES 18
PG = PMB 22
PG = TES 23
Scheme 5 Mukaiyama aldol reactions
1H NMR (400 MHz, CDCl3): d = 5.19 (q, J = 5.7 Hz, 1 H), 4.13 (d,
J = 6.5 Hz, 1 H), 3.54 (dd, J = 4.8, 3.4 Hz, 1 H), 3.22 (d, J = 3.8 Hz,
1 H), 2.75 (dd, J = 17.6, 2.2 Hz, 1 H), 2.59–2.63 (m, 1 H), 2.47 (dd,
J = 17.6, 9.4 Hz, 1 H), 2.11 (d, J = 13.7 Hz, 1 H), 1.80–1.84 (m, 2
H), 1.65–1.72 (m, 2 H), 1.58 (s, 6 H), 1.11 (d, J = 6.8 Hz, 6 H), 1.10
(d, J = 6.9 Hz, 3 H), 0.94–0.99 (m, 18 H), 0.80 (d, J = 6.8 Hz, 3 H),
0.77 (d, J = 6.5 Hz, 3 H), 0.60–0.68 (m, 12 H).
AL
O
OPG
O
LA
H
H
H
PGO
H
OSiMe3
HRMS (ESI): m/z calcd for C31H65O4Si2 [M + H+]: 557.4416;
found: 557.4418.
Me3SiO
H
H
Ketone 13
F
G
Camphorsulfonic acid (0.5 g, 2.2 mmol) and p-methoxybenzyl
trichloroacetimidate (4.6 g, 16.4 mmol) were dissolved in CH2Cl2
(10 mL). To this solution was added (S)-3-hydroxy-5-methylhexan-
2-one (1.4 g, 10.9 mmol) and the mixture stirred for 16 h at r.t. The
reaction was stopped by the addition of sat. aq NaHCO3 (5 mL), the
layers were separated, and the aqueous layer was extracted three
times with MTBE (3 × 5 mL). The combined organic layers were
washed with sat. aq NaHCO3 (20 mL) and brine (20 mL), dried
(MgSO4), filtered, and the solvent was removed under reduced pres-
sure. Column chromatography of the residue afforded the ketone 13
(334.0 mg, 1.3 mmol, 12%) ; Rf = 0.38 (EtOAc–n-hexane, 1:15);
[a]D20 –37.8 (c 1.0, CHCl3).
anti-periplanar
syn-clinal
PG = PMB, TES
Figure 3 Transition states of the Mukaiyama aldol reactions
In conclusion, we have presented a detailed analysis of the
subtle stereoselective contributions in the pivotal aldol re-
action of spirangien. The use of the Mukaiyama aldol re-
action will now enable us to install the new stereogenic
center in using a 1,4-syn-selective induction. We have
also provided the possibility of assembling either a 1,4-
anti or a 1,4-syn motif selectively depending on the pro-
tecting group at the a-stereocenter of oxygenated ketones.
1H NMR (400 MHz, CDCl3): d = 7.29–7.24 (m, 2 H), 6.88 (d,
J = 8.5 Hz, 2 H), 4.50 (d, J = 11.3 Hz, 1 H), 4.32 (d, J = 11.3 Hz, 1
Together with established procedures, this adds to the H), 3.81 (s, 3 H), 3.79–3.76 (m, 1 H), 2.16 (s, 3 H), 1.86–1.75 (m, 1
H), 1.65–1.58 (m, 1 H), 1.36–1.28 (m, 1 H), 0.91 (d, J = 6.5 Hz, 3
general applicability and prediction of aldol reactions in
complex natural products total synthesis.
H), 0.84 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 212.3, 159.6, 129.8, 129.6, 114.0,
83.7, 72.4, 55.4, 41.2, 25.1, 24.6, 23.4, 21.8.
HRMS (ESI): m/z calcd for C17H25NO3 + Na [M + C2H3N + Na+]:
314.1732; found: 314.1732.
All manipulations and reactions were carried out under Schlenk
technique in a N2 atmosphere. Glassware were oven-dried for sev-
eral hours, baked out with a heat gun under vacuum, and cooled in
a stream of dry N2 before reaction. THF was distilled over sodium
and benzophenone ketyl and stored under N2. CH2Cl2 was distilled
over CaH2 and stored under N2. All other chemicals were purchased
from Aldrich or Acros and used as delivered.
Ketone 16
(S)-3-Hydroxy-5-methylhexan-2-one (1.3 g, 10.0 mmol) was dis-
solved in CH2Cl2 (10 mL) and cooled to 0 °C. To this solution were
added 2,6-lutidine (2.6 mL, 11.0 mmol) and TESOTf (2.5 mL,
22.0 mmol), and the mixture was stirred for 30 min at 0 °C and an
additional 1 h at r.t. The reaction was stopped by the addition of sat.
aq NaHCO3 (10 mL), the layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The combined organ-
ic layers were washed with aq 1 M NaHSO4 (30 mL), sat. aq
NaHCO3 (30 mL), and brine (30 mL). After drying (MgSO4) and
filtration, the solvent was removed under reduced pressure. The res-
idue was purified by column chromatography to give ketone 16
(1.2 g, 4.9 mmol, 48%); Rf = 0.75 (EtOAc–n-hexane, 1:20);
[a]D20 –19.6 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 4.04 (dd, J = 8.2, 5.5 Hz, 1 H),
2.15 (s, 3 H), 1.77–1.66 (m, 1 H), 1.54–1.47 (m, 1 H), 1.46–1.33 (m,
1 H), 0.99–0.89 (m, 6 H + 6 H), 0.65–0.57 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 212.5, 74.9, 43.9, 24.7, 24.2,
23.3, 22.3, 6.9, 4.9.
Column chromatography was performed on Macherey-Nagel silica
gel (40–63 mm, 60 Å pores), using the same solvent system as spec-
ified for the Rf values. Experiments were monitored by thin layer
chromatography (TLC) performed on Merck 60 F-254 (0.2 mm
thick) silica gel aluminum-supported plates. Spots were visualized
by exposure to ultraviolet light (254 nm) or by staining with bro-
mine-cresol green or cerium reagent.
NMR spectra were recorded on Bruker AVS-400 or AVS-200 spec-
1
trometers. For H NMR spectra in CDCl3, the singlet of CHCl3 at
d = 7.26 ppm served as an internal reference. For 13C NMR spectra
in CDCl3, the triplet at d = 77.2 ppm served as an internal reference.
Values of the coupling constants are given in hertz (Hz). High-
resolution electrospray mass spectra (HRMS-ESI) were recorded on
a Waters Micromass LCT spectrometer with a Lock-Spray unit.
Ketone 11 by LiHMDS-Mediated Aldol Reaction of Ketone 10
with Aldehyde 4
HRMS (ESI): m/z calcd for C13H28NO2Si + Na [M + Na+]:
To a solution of ketone 10 (11 mL, 100 mmol) in THF (1 mL) was
added LiHMDS (1.3 M in THF, 175 mmol) dropwise at –78 °C and
the mixture stirred for 2 h. Aldehyde 4 (4 mg, 8.5 mmol) was added
267.1756; found: 267.1758.
Synthesis 2009, No. 18, 3061–3066 © Thieme Stuttgart · New York

PAPER
C22–C23 Aldol Coupling in Spirangien Synthesis
3065
Ketone 19
(dd, J = 18.1, 9.9 Hz, 1 H), 1.74–1.69 (m, 2 H), 1.52–1.49 (m, 1 H),
1.39–1.36 (m, 1 H), 0.93–0.91 (m, 9 H + 12 H), 0.07–0.06 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 216.3, 77.9, 72.3, 44.0, 40.8,
33.2, 25.9, 24.1, 23.4, 22.2, 18.5, 18.2, 17.8, –4.6, –4.8.
HRMS (ESI): m/z calcd for C17H36O3Si + Na [M + Na+]: 339.2331;
found: 339.2332.
(S)-3-Hydroxy-5-methylhexan-2-one (1.9 g, 14.6 mmol) was dis-
solved in CH2Cl2 (10 mL) and cooled to 0 °C. To this solution were
added 2,6-lutidine (3.7 mL, 16.1 mmol) and TBSOTf (3.7 mL,
32.1 mmol), and the mixture was stirred for 15 min at 0 °C and for
an additional 2 h at r.t. The reaction was stopped by the addition of
sat. aq NaHCO3 (10 mL), the layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The combined organ-
ic layers were washed with aq 1 M NaHSO4 (30 mL), sat. aq
NaHCO3 (30 mL) and brine (30 mL), dried (MgSO4), filtered, and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography to give ketone 19 (2.2 g,
9.2 mmol, 64%); Rf = 0.63 (EtOAc–n-hexane, 1:20); [a]D20 –20.8
(c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 4.02 (dd, J = 8.5, 4.8 Hz, 1 H),
2.25 (s, 3 H), 1.77–1.68 (m, 1 H), 1.54–1.48 (m, 1 H), 1.38–1.31 (m,
1 H), 0.92–0.91 (m, 9 H + 6 H), 0.06 (s, 3 H), 0.04 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 212.6, 75.2, 43.9, 25.9, 24.1,
23.5, 22.2, 18.2, –4.7, –4.9.
Boron-Mediated Aldol Reaction; Compound 14; Typical Proce-
dure
In a 2-necked flask, ketone 13 (1 equiv) was dissolved in CH2Cl2 (4
mL) and cooled to –78 °C. To this solution were added (n-
Bu)2BOTf (1 M in CH2Cl2, 1.2 equiv) and DIPEA (1.4 equiv) and
the mixture was warmed to 0 °C, stirred for 3 h and cooled to
–78 °C. Isobutyraldehyde (12; 2 equiv) was added dropwise and
stirred for 30 min. The reaction mixture was stirred for additional
16 h at –20 °C and quenched by the addition of aqueous pH 7 buffer
(5 mL). After separation, the aqueous layer was extracted with
CH2Cl2 (3 × 5 mL), the combined organic layers were concentrated
under reduced pressure, and the residue was dissolved in a mixture
of MeOH (6 mL/mmol of ketone), aqueous pH 7 phosphate buffer
(6 mL/mmol of ketone), and aq 30% H2O2 (30%, 3 mL/mmol of ke-
tone). The solution was stirred for 2 h, and after separation of the
layers, the aqueous phase was extracted with CH2Cl2 (3 × 5 mL) and
the combined organic layers were washed with sat. aq NaHCO3 (10
mL) and brine (10 mL), dried (MgSO4), filtered, and the solvent was
removed under reduced pressure. The residue was purified by col-
umn chromatography (EtOAc–n-hexane, 1:10) to give the product
14 (Table 3).
MS: Mass was not detectable in EI-HRMS and ESI-HRMS.
LiHMDS-Mediated Aldol Reactions To Give Compounds 14,
17, and 20; General Procedure
The appropriate ketone 13, 16, 19 (50 mg, 1 equiv) was dissolved in
THF (5 mL), the mixture was cooled to –78 °C, the base (2 equiv,
Table 2) was added, and the mixture was stirred for 2 h. Isobutyral-
dehyde (12; 3 equiv) in THF (0.5 mL) was added dropwise and the
mixture was stirred for 16 h. The reaction was stopped by the addi-
tion of sat. aq NH4Cl (5 mL), the layers were separated, and the
aqueous layer was extracted with MTBE (3 × 5 mL). The combined
organic layers were washed with brine (20 mL), dried (MgSO4), fil-
tered, and the solvent was removed under reduced pressure. Column
chromatography of the residue afforded the anti-aldol product as the
major compound (Table 2).
Mukaiyama Aldol Reaction; Compounds 15, 18; General Pro-
cedure
Freshly prepared LDA (1.05 equiv) in THF (1.5 mL) was added to
a solution of the respective ketone 13, 16 (1 equiv) in THF (2 mL)
at –78 °C and stirred for 90 min at 78 °C. TMSCl (1.1 equiv) was
added, the solution was warmed to r.t. and stirred for 16 h. The re-
action was stopped by the addition of aqueous pH 7 buffer (5 mL),
the layers were separated, the aqueous layer was extracted with
MTBE (3 × 5 mL) and the combined organic phases were washed
with aqueous pH 7 buffer (10 mL), dried (MgSO4), filtered, and the
solvent was removed under reduced pressure. The residue was fil-
tered through a plug of silica gel and the crude product was directly
used for the Mukaiyama aldol reaction. The freshly prepared silyl
enol ether 22, 23 (1 equiv), respectively, was dissolved in toluene
(1.5 mL), isobutyraldehyde (12; 2 equiv) and BF3·OEt2 were added
at –78 °C. The mixture was stirred for 1 h at –78 °C and the reaction
was stopped by the addition of methanolic NaHCO3 (2 mL). The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 3 mL). The combined organic layers were washed with
brine (10 mL), dried (MgSO4), filtered, and the solvent was re-
moved under reduced pressure. After column chromatography, the
syn-aldol product was obtained as the major compound (Table 3).
Major Diastereomer 14
Rf = 0.5 (EtOAc–n-hexane, 1:10).
1H NMR (400 MHz, CDCl3): d = 7.29–7.22 (m, 2 H), 6.89 (d,
J = 8.9 Hz, 2 H), 4.52 (d, J = 10.9 Hz, 1 H), 4.34 (d, J = 10.9 Hz, 1
H), 3.85–3.83 (m, 1 H), 3.82 (s, 3 H), 3.80–3.78 (m, 1 H), 2.89 (d,
J = 3.4 Hz, 1 H), 2.69 (dd, J = 17.8, 2.4 Hz, 1 H), 2.57 (dd, J = 17.8,
9.6 Hz, 1 H), 1.86–1.76 (m, 1 H), 1.74–1.65 (m, 1 H), 1.64–1.57 (m,
1 H), 1.37–1.29 (m, 1 H), 0.96–0.89 (m, 9 H), 0.86–0.82 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 215.7, 159.7, 129.9, 129.5, 114.1,
83.4, 72.5, 72.3, 55.5, 41.3, 41.1, 33.3, 24.7, 23.4, 21.8, 18.5, 17.9.
HRMS (ESI): m/z calcd for C19H30O4 + Na [M + Na+]: 345.2042;
found: 345.2047.
Major Diastereomer 17
Rf = 0.33 (EtOAc–n-hexane, 1:20).
1H NMR (400 MHz, CDCl3): d = 4.11–4.04 (m, 1 H), 3.81–3.73 (m,
1 H), 3.10 (d, J = 3.1 Hz, 1 H), 2.76 (dd, J = 18.1, 2.1 Hz, 1 H), 2.58
(dd, J = 18.0, 9.9 Hz, 1 H), 1.76–1.66 (m, 2 H), 1.53–1.48 (m, 1 H),
1.42–1.37 (m, 1 H), 0.96–0.91 (m, 6 H + 12 H), 0.65–0.57 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 215.9, 77.8, 72.3, 44.0, 40.3,
33.3, 24.2, 23.3, 22.3, 18.5, 18.1, 6.9, 4.9.
Major Diastereomer 15
Rf = 0.5 (EtOAc–n-hexane, 1:10).
1H NMR (400 MHz, CDCl3): d = 7.24 (d, J = 8.5 Hz, 2 H), 6.88 (d,
J = 8.9 Hz, 2 H), 4.47 (d, J = 11.3 Hz, 1 H), 4.37 (d, J = 11.6 Hz, 1
H), 3.85–3.82 (m, 1 H), 3.81 (s, 3 H), 3.79–3.73 (m, 1 H), 2.86 (d,
J = 3.1 Hz, 1 H), 2.86 (dd, J = 17.6, 2.2 Hz, 1 H), 2.54 (dd, J = 17.6,
9.7 Hz, 1 H), 1.86–1.75 (m, 1 H), 1.71–1.58 (m, 2 H), 1.37–1.29 (m,
1 H), 0.96–0.88 (m, 9 H), 0.87–0.83 (m, 3 H).
HRMS (ESI): m/z calcd for C17H36O3Si + Na [M + Na+]: 339.2331;
found: 339.2334.
13C NMR (100 MHz, CDCl3): d = 215.7, 159.7, 129.9, 129.6, 114.1,
83.9, 72.7, 72.4, 55.5, 41.2, 41.1, 33.3, 24.7, 23.3, 21.9, 18.5, 17.9.
Major Diastereomer 20
Rf = 0.35 (EtOAc–n-hexane, 1:20).
1H NMR (400 MHz, CDCl3): d = 4.09–4.06 (m, 1 H), 3.81–3.77 (m,
1 H), 3.08 (d, J = 3.1 Hz, 1 H), 2.74 (dd, J = 18.1, 2.1 Hz, 1 H), 2.59
HRMS (ESI): m/z calcd for C19H30O4 + Na [M + Na+]: 345.2042;
found: 345.2045.
Synthesis 2009, No. 18, 3061–3066 © Thieme Stuttgart · New York

3066
M. Lorenz et al.
PAPER
Major Diastereomer 18
Rf = 0.36 (EtOAc–n-hexane, 1:20).
1H NMR (400 MHz, CDCl3): d = 4.09–4.05 (m, 1 H), 3.81–3.76 (m,
1 H), 3.00 (br s, 1 H), 2.83 (dd, J = 18.1, 2.1 Hz, 1 H), 2.54 (dd,
J = 18.1, 9.9 Hz, 1 H), 1.73–1.68 (m, 2 H), 1.52–1.51 (m, 1 H),
1.50–1.48 (m, 1 H), 0.94–0.91 (m, 6 H + 12 H), 0.65–0.57 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 216.1, 77.8, 72.3, 44.1, 40.7,
33.2, 24.2, 23.3, 22.3, 18.5, 17.8, 6.9, 4.9.
HRMS (ESI): m/z calcd for C17H36O3Si + Na [M + Na+]: 339.233;
(4) (a) McCubbin, J. A.; Maddess, M. L.; Lautens, M. Org. Lett.
2006, 8, 2993. (b) Zhang, W. Y.; Jakiela, D. J.; Maul, A.;
Knors, C.; Lauher, J. W.; Helquist, P.; Enders, D. J. Am.
Chem. Soc. 1988, 14, 4652. (c) The analytical data were in
accord with literature values.
(5) (a) Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc. 1952,
74, 5828. (b) Cornforth, J. W.; Cornforth, R. H.; Mathew, K.
K. J. Chem. Soc. 1959, 112. (c) Cherest, M.; Felkin, H.;
Prudent, N. Tetrahedron Lett. 1968, 89, 2199. (d) Anh, N.
T.; Eisenstein, O. Nouv. J. Chem. 1977, 1, 61.
(e) Heathcock, C. H.; Pirrung, M. C.; Lampe, J.; Buse, C. T.;
Young, S. D. J. Org. Chem. 1981, 46, 2290. (f) Evans, D.
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(g) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett.
1994, 35, 8537. (h) Gustin, D. J.; VanNieuwenhze, M. S.;
Roush, W. R. Tetrahedron Lett. 1995, 36, 3443. (i) Evans,
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Synthesis 2009, No. 18, 3061–3066 © Thieme Stuttgart · New York