Stereocontrol in aldol addition - Synthesis of syn and anti 3-Hydroxy aldehydes

Article abstract of DOI:10.1055/s-1998-2031

syn 3-Hydroxy aldehydes were obtained with a high level of stereoselectivity by aldol addition in the presence of TiCl₄. The corresponding anti 3-hydroxy aldehydes were obtained by thermodynamic equilibration in the presence of titanium(IV) alkoxides.

Full text of DOI:10.1055/s-1998-2031

Short Papers
SYNTHESIS
262
Stereocontrol in Aldol Addition – Synthesis of syn and anti 3-Hydroxy Aldehydes
R. Mahrwald,a* B. Costisella,b B. Gündogana
a Fachbereich Chemie der Humboldt-Universität Berlin, Hessische Straße 1–2, D-10115 Berlin, Germany
b Institut für Angewandte Chemie, Rudower Chaussee 5, D-12484 Berlin, Germany
Received 23 June 1997; revised 11 August 1997
Abstract: syn 3-Hydroxy aldehydes were obtained with a high level
of stereoselectivity by aldol addition in the presence of TiCl4. The
corresponding anti 3-hydroxy aldehydes were obtained by thermo-
contrast to what has been previously observed upon the
dynamic equilibration in the presence of titanium(IV) alkoxides.
Equimolar amounts of both base and Lewis acid are nec-
essary for complete conversion. This result is in sharp
reaction of aldehydes and ketones in the presence of
Lewis acids. Catalytic amounts of TiCl4 are necessary for
Key words: stereoselective aldol addition, syn 3-hydroxy alde-
hydes, thermodynamic equilibration, anti 3-hydroxy aldehydes
this complete stereoselective conversion to their syn al-
dols.8
The aldol addition is one of the most important methods
Chemoselectivity was observed in the aldol addition be-
for forming carbon–carbon bonds, and is extensively uti-
lized for the construction of 1,3-oxygen functionalities.1
tween two different aldehydes. Lieben’s rule is followed
reacting primary and secondary aldehydes.11 A complex
mixture, with the aldol 1c as the major product is obtained
if one reacts an equimolar mixture of propanal with 2-
While the active hydrogen component can consist of ei-
ther ketones2 or carboxylic derivatives,3 very little is
known concerning aldol addition of enolized aldehydes to
methylpropanal. One overcomes this problem by reacting
other aldehydes. No method is as yet known for the direct
diastereoselective aldol addition of aldehydes.4 Corey and
an excess (4 equivalents) of pre-TiCl4 complexed active
hydrogen primary aldehyde (i.e. propanal) with one
equivalent of the carbonyl compound (entry 4, Scheme 1).
Enders have published the reaction of metalated N,N-di-
methylhydrazones with carbonyl compounds giving 3-hy-
Tertiary aldehydes (i.e. 2,2-dimethylpropanal) are not re-
droxy aldehydes which were obtained without stereo-
selectivity.5 Recently, we have described for the first time
active enough to give the expected aldols.
both diastereoselective self-addition of aldehydes and a
mixed aldol reaction between two different aldehydes in
the presence of TiCl4 and base.6
Aldehydes form complexes in the presence of Lewis ac-
ids,7 and these complexes resist aldol addition, as is ob-
served upon the reaction of ketones and aldehydes.8 Lewis
acid complexes of aldehydes are stable up to 0°C. Howev-
er, an aldol addition is observed upon the addition of base.
The temperature at which the reaction takes place strongly
depends on the substrate and base used. By working with
strong bases such as TMEDA or DABCO, the reaction
can be executed at –50°C (entry 3, Scheme 1). No aldol
addition is observed at –50°C in the presence of triethyl-
amine as base. Complete conversion occurs only at –10°C
(entries 1 and 2, Scheme 1). Aldol condensation and ace-
talization were observed at room temperature.9,10
Entry
R
Method/Temp °C Compound
Yield (%)
1
2
3
Et
i-Pr
Ph
A/–30
A/–25
A/–30
3
4
5
65
72
69
Scheme 2
Entry
R1
R2
Method/Temp °C
Compound
Yield (%)a
Ratioc
Compound Yield (%)d
Ratioc
synlanti
synlanti
1
2
3
4
Ph
Ph
Et
Me
Et
Me
Me
B/–10
B/–10
A/–50
C/–20
1a
1b
1c
1d
72
78
84
49b
97 : 3
>98 : <2
96 : 4
2a
2b
2c
2d
61
67
87
58
7 : 93
5 : 95
11 : 89
9 : 91
i-Pr
>98 : <2
a Isolated yields.
c Determined in crude products by 1H and 13C NMR.
b Based on the carbonyl componend.
d Based on pure syn hydroxy aldehyde.
Scheme 1

March 1998
SYNTHESIS
263
High syn stereoselectivity of the 3-hydroxy aldehydes
were observed in all examples [96:4]. The stereoselectiv-
ity is observed to be independent of the solvent or base.
No equilibration to the thermodynamically more stable
anti product has been observed under these conditions.
The relative syn configuration of all products was deter-
1
mined by analysis of coupling constants of the H NMR
spectra and the data of the 13C NMR spectra. The position
and the value of the coupling constants of the aldehyde
protons are very characteristic for the relative configura-
tion of the obtained aldols [dsyn < danti and Jsyn (0.8–
1.0 Hz) < Janti (1.6–2.0 Hz)]. For further identification, the
3-hydroxy aldehydes 1a and 2a were reacted with methyl
(triphenylphosphoranylidene)acetate to give the expected
a, b-unsaturated carboxylic methyl esters 6 and 7. The
physical data (1H and 13C NMR) are in agreement with
data reported in the literature (Scheme 3).12
Scheme 3
tanium ate complexes,14 were not successful. However,
equilibration was achieved by using catalytic amounts of
titanium(IV) alkoxides in the presence of base. Best re-
sults were obtained by using Ti(O-i-Pr)4, a typical Meer-
wein–Ponndorf catalyst, in the presence of base. By using
Ti(O-t-Bu)4 or Ti(OEt)4 no equilibration was observed.
Complete conversion to the expected anti 3-hydroxy alde-
hydes was carried out by treating syn 3-hydroxy alde-
hydes with 1 mol% titanium(IV) isopropoxide at –20 °C
in the presence of TMEDA. The anti-configuration was
The anti 3-hydroxy aldehydes were obtained by equilibra-
tion of the corresponding syn aldols. Known procedures
for this equilibration, i.e. in the presence of MgBr123 or ti-
Table. Spectral Data of Compounds 1–5
Prod- 1H NMR (CDCl3/TMS)
13C NMR (CDCl3/TMS)
MS (CI)
uct
d, J (Hz)
d
m/z (%)
1a
1.08 (d, 3 H, J = 7.3), 2.69 (ddq, 1 H, J = 1.1, 3.9,
7.3), 5.25 (d, 1 H, J = 3.8), 7.23 (m, 5 H arom.),
9.79 (d, 1 H, J = 1.1)
7.4, 53.0, 72.4, 125.8, 127.7, 128.4, 140.9,
204.44
182 (28), 164 (100),
147 (41)
1b
1c
0.83 (tr, 3 H, J = 7.7), 1.4–1.8 (m, 2 H), 2.57 (ddtr,
1 H, J = 2.0, 4.5, 5.1), 5.05 (d, 1 H, J = 5.1), 7.35–
7.35 (m, 5 H arom), 9.69 (d, 1 H, J = 2.0)
12.0, 17.6, 60.1, 73.0, 126.6, 127.6, 128.6,
140.9, 205.0
196 (40), 178
(100), 161 (41)
1.07 (tr, 3 H, J = 7.3), 1.23 (d, 3 H, J = 7.3), 1.53
(dq, 2 H, J = 3.2, 7.3), 2.48 (ddq, 1 H, J = 0.8, 5.5,
7.3), 4.01 (ddq, 1 H, J = 3.3, 5.3, 7.9), 9.71 (d, 1 H,
0.8)
8.9, 10.3, 27.2, 50.8, 71.6, 205.7
232 (59), 215 (35),
134 (100), 116 (4)
1d
0.89 (d, 3 H, J = 6.7), 0.94 (d, 3 H, J = 6.7), 1.02
(d, 3 H, J = 7.3), 1.72 (dsp, 1 H, J = 6.7, 8.5), 2.59
(ddq, 1 H, J = 0.8, 3.2, 7.3), 3.76 (dd, 1 H, J = 3.2,
8.5), 9.73 (d, 1 H, J = 0.8)
8.3, 18.6, 19.9, 29.7, 50.5, 76.6, 205.3
2a
2b
2c
0.93 (d, 3 H, J = 7.3), 2.77 (ddq, 1 H, J = 2.0, 8.6,
7.3), 4.81 (d, 1 H, J = 8.6), 7.23 (m, 5 H arom.),
9.84 (d, 1 H, J = 2.0)
11.0, 53.2, 75.5, 126.6, 128.3, 128.6,
141.5, 204.9
0.83 (tr, 3 H, J = 7.4), 2.58 (ddtr, 1 H, J = 2.9, 4.5,
8.5), 4.84 (d, 1 H, J =8.5), 7.33 (m, 5 H arom.),
9.78 (d, 1 H, J = 2.9)
11.3, 19.6, 60.3, 74.1, 127.0, 128.2, 128.5,
141.7, 205.1
1.10 (tr, 3 H, J = 7.5), 1.22 (d, 3 H, J = 7.3), 1.67
(dq, 2 H, J = 3.5, 7.3), 2.37 (ddq, 1 H, J = 1.6, 7.7,
8.7), 3.75 (ddq, 1 H, J = 3.7, 7,3, 8.1), 9.76 (d,
1 H, J = 1.5)
9.3, 13.2, 27.7, 51.4, 73.5, 205.9
2d
3
0.90 (d, 3 H, J = 6.7), 0.95 (d, 3 H, J = 6.7), 1.12
(d, 3 H, J = 7.3), 1.69 (dsp, 1 H, J = 2.0, 6.7),
2.57 (ddq, 1 H, J = 2.0, 7.3, 9.1), 3.43 (dd, 1 H,
J = 2.0, 9.1), 9.77 (d, 1 H, J = 2.0)
1.03 (tr, 3 H, J = 7.3), 1.05 (s, 3 H), 1.09 (s, 3 H),
1.33 (ddq 1 H, J =3.5, 7.5, 10.7), 1.51 (ddq, 1 H,
J = 2.2, 3.5, 7.4), 3.62 (dd, 1 H, J = 2.1, 10.6),
9.53 (s, 1 H)
12.8, 18.7, 19.9, 30.1, 50.6, 79.7, 205.8
11.0, 16.5, 19.0, 24.2, 50.5, 76.6, 206.8
4
5
0.9 (d, 3 H, J = 6.9), 0.97 (d, 3 H, J = 6.9), 1.88 (dsp,
1 H, J = 4.1, 6.9), 3.55 (d, 1 H, J = 4.1), 9.63 (s, 1 H)
17.2, 18.6, 19.9, 21.7, 29.9, 50.5, 80.3,
206.8
0.93 (s, 3 H), 1.09 (s, 3 H), 4.82 (d, 1 H, J = 0.8),
7.3 (m, 5 H arom.), 9.63 (d, 1 H, J = 0.8)
15.8, 19.9, 50.6, 77.4, 127.5, 127.9, 128.5, 139.8,
206.6
196 (100), 178 (8)

264
Short Papers
SYNTHESIS
13C NMR (76 MHz): d = 13.9, 43.6, 51.4, 76.7, 121.2, 126.3, 127.9,
established by the described analysis of coupling con-
stants of 1H NMR with the characteristic shifts of the sig-
nals in the 13C NMR spectrum.
128.2, 142.0, 150.7, 166.9.
Methyl (E)-(4SR,5SR)-5-Hydroxy-4-methyl-5-phenylpent-2-
enoate (7):12
1H NMR spectra were recorded on a Bruker WP 200 SY and Varian
Unity 500; the 13C NMR spectra were obtained at 75 MHz on a Varian
GEMINI 300 instrument in CDCl3 (unless otherwise stated); chemi-
cal shifts are related to TMS. Low-resolution impact mass spectra:
GC-MS Datensystem HP 5985 B. Microanalyses: Carlo Erba autoan-
alyzer 1106.
The anti product 7 was obtained by the same procedure described
above, using the corresponding anti 3-hydroxy aldehyde 2a as start-
ing material.
C13H16O3 calcd
(220.27) found
C
70.89
70.62
H
7.32
6.92.
1H NMR (300 MHz): d = 0.93 (d, J = 6.9 Hz, 3 H), 1.96 (d, J =
3.0 Hz, 1 H), 2.68 (ddq, J = 1.0, 6.9, 7.3 Hz, 1 H), 3.74 (s, 3 H), 4.52
(dd, J = 3.0, 7.5 Hz, 1 H), 5.90 (dd, J = 1.0, 15.8 Hz, 1 H), 7.09 (dd,
J = 8.1, 15.8 Hz, 1 H), 7.2–7.4 (5 H arom.).
Stereochemical assignments of all products were determined by anal-
ysis of 1H NMR coupling constants, via homodecoupling techniques.
(2RS,3RS)-3-Hydroxy-2-methylpentanal (1c);15 Method A:
Propanal (0.72 mL, 10.0 mmol) was dissolved in CH2Cl2 (20 mL)
with TMEDA (3.02 mL, 20.0 mmol). This mixture was cooled to
–78 °C. TiCl4 (2.19 mL, 20.0 mmol) was carefully added at this tem-
perature under inert conditions. The resulting yellow-brown mixture
was stirred for further 3 h at –40°C, after which water was added
(30 mL) and the resulting emulsion extracted with Et2O (100 mL) and
water (30 mL) until neutral. The organic layer was separated, dried
(Na2SO4), filtered and evaporated in vacuo. The pure 3-hydroxy alde-
hyde 1c was separated by flash chromatography using hexane/EtOAc
(90:10) as eluent (Table).
13C NMR (76 MHz): d = 16.1, 44.4, 51.5, 77.9, 121.8, 126.6, 127.8,
128.4, 142.2, 150.8, 166.9.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
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(2RS,3SR)-3-Hydroxy-3-phenyl-2-methylpropanal (1a); Method B:
Propanal (0.72 mL, 10.0 mmol) was dissolved with Et3N (2.78 mL,
20.0 mmol) in CH2Cl2 (20 mL); the solution was cooled to –78 °C.
TiCl4 (2. 19 mL, 20.0 mmol) was carefully added at this temperature
under inert conditions. Benzaldehyde (1.02 mL, 10.0 mmol) was add-
ed at –78 °C and the temperature was raised to –10°C. The yellow-
brown emulsion was stirred for a further 2 h at this temperature.
Workup is as described in Method A (Table).
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(2RS, 3SR)-3-Hydroxy-2,4-dimethylpentanal (1d);16 Method C:
Propanal (2.88 mL, 40.0 mmol) was dissolved with TMEDA
(6.04 mL, 40.0 mmol) in CH2Cl2 (40 mL). The solution was cooled to
–78 °C and TiCl4 (4.37 mL, 40.0 mmol) was carefully added under in-
ert conditions. The resulting brown solution was stirred for a further
30 min at this temperature and 2-methylpropanal (0.91 mL,
10.0 mmol) was added. The temperature was raised to –20°C and the
dark brown solution was stirred for further 12 h at this temperature.
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(2SR,3SR)-3-Hydroxy-3-phenylpropanal (2a); Typical Procedure
for Equilibration:
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syn 3-Hydroxy aldehyde 1a (328 mg, 2.0 mmol) was dissolved in
CH2Cl2 (20 mL) and then TMEDA (0.30 mL, 2.0 mmol) was added.
The solution was cooled to –60°C and Ti(O-i-Pr)4 (6 mL, 0.02 mmol)
was added. The temperature was raised to –20°C and the light-yellow
solution was allowed to stand at this temperature for 4 d. The anti 3-
hydroxy aldehyde 2a was isolated by flash chromatography using
hexane/EtOAc (9:10) as eluent (Table).
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Methyl (E)-(4RS,5SR)-5-Hydroxy-4-methyl-5-phenylpent-2-enoate
(6):12
The syn 3-hydroxy aldehyde 1a (493 mg, 3.0 mmol) was dissolved in
CH2Cl2 (20 mL). Methyl (triphenylphosphoranylidene)acetate
(2.00 g, 6.0 mmol) was added. No aldehyde 1a could be detected after
stirring for 3 h at r.t. The resulting pentenoate 6 was purified by flash
chromatography using hexane/i-PrOH (95:5) as eluent; colorless oil;
yield: 0.48 g (73%).
C13H16O3 calcd
(220.27) found
C
70.89
71.13
H
7.32
6.89
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1990, 112, 2013.
1 H), 2.72 (ddq, J = 1.2, 5.7, 6.9 Hz, 1 H), 3.71(s, 3 H), 4.67 (dd, J = (16) Fleming, 1.; Jones, G. R.; Kindon, N. D.; Landais, Y.; Leslie, C.
1H NMR (300 MHz): d = 1.08 (d, J = 6.8 Hz, 3 H), 1.90 (d, J = 3.1 Hz,
2.8, 5.5 Hz, 1 H), 5.77 (dd, J = 1.2, 15.8 Hz, 1 H), 6.44 (dd, J = 7.5,
15.8 Hz, 1 H), 7.2–7.4 (m, 5 H, arom.).
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kin Trans. 1 1996, 1171.