A highly enantioselective, moderately anti-selective aldol reaction using a novel hydrazone moiety as stereo director

Article abstract of DOI:10.1016/j.tetasy.2005.09.027

The use of novel hydrazones as stereo directors with a view to develop a highly enantioselective, anti-diastereoselective aldol addition procedure has been investigated. A number of proline-derived hydrazones were produced and their effectiveness in direc

Full text of DOI:10.1016/j.tetasy.2005.09.027

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3615–3618
A highly enantioselective, moderately anti-selective aldol
reaction using a novel hydrazone moiety as stereo director
Gerard P. McGlacken and Simon W. Breeden*
Department of Chemistry, National University of Ireland, Galway, Galway, Ireland
Received 1 July 2005; revised 5 August 2005; accepted 26 September 2005
Available online 14 November 2005
Abstract—The use of novel hydrazones as stereo directors with a view to develop a highly enantioselective, anti-diastereoselective
aldol addition procedure has been investigated. A number of proline-derived hydrazones were produced and their effectiveness in
directingsimple alkylation of aza-enolates investigated. The most promisingof these hydrazones were then used in the aldol reac-
tion. The substituent on the oxygen of the proline had a profound effect on both the magnitude and the sense of asymmetric induc-
tion. The optimum hydrazone for the formal aldol reaction between pentanone and propionaldehyde gave a diastereoselectivity of
37% in favour of the anti-isomer while both isomers had an ee of 83–84%.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tion.7 These were the first reported uses of the widely
investigated SAMP/RAMP methodology whose success
is evident by a recent review and a substantial number of
applications.8 Condensation of the hydrazine, SAMP,
with various ketones followed by deprotonation using
LDA and trappingwith electrophiles led to enantioen-
riched, alkylated ketones after hydrolysis.7b,9 Investiga-
tions into the aza-enolate geometry formed when
SAMP-hydrazones are treated with LDA showed only
the ECCZCN-species to be formed.10 In the transition
state, the lithium atom of the enehydrazide is intramo-
lecularly chelated: electrophilic attack on this rigidly
held intermediate occurs with good to excellent diaste-
reofacial differentiation.11
Aldol addition reactions have longbeen recognised as
one of the most useful tools in the construction of
stereochemically defined carbon–carbon bonds.1 The
formation of carbon–carbon bonds adjacent to a car-
bonyl group in a diastereo- and enantioselective manner
is amongst the most widespread of reactions used in the
production of many natural and bio-active compounds.2
Classic aldol addition reactions usingenolate chemistry
can be accompanied by side reactions, however, these
are minimised by the use of imine derivatives that often
give enhanced yields and selectivities.3 The first reported
use of an imine derived auxiliary in asymmetric synthesis
was an (S)-proline derived enamine used by Yamada
et al.4 The field was further developed by Meyers
et al.5 Concurrently, Corey was developingthe non-
asymmetric use of dimethylhydrazones as a controlled
SAMP
N
6
OMe
method for alkylatingcarbonyl compounds. The com-
NH2
E
bination and extension of these methodologies by Corey
and Enders in 1976 resulted in the publication of a meth-
od permittingthe asymmetric synthesis of a-substituted
ketones in good yield and enantiopurity; this was then
further extended to the first enantioselective aldol reac-
N
N
Li
Et
E
MeO
*
Correspondingauthor at present address: Department of Chemistry,
University of York, Heslington, York, YO10 5DD, UK. Tel.: +44
(0)1904 432 568; fax: +44 (0)1904 432 705; e-mail: SWB1@
york.ac.uk
It was felt that as differentiation relies on the rigidity of
the transition state, which in turn is due to the ability of
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.027

3616
G. P. McGlacken, S. W. Breeden / Tetrahedron: Asymmetry 16 (2005) 3615–3618
the methoxy group to donate its pair of electrons, then a
siloxy group could better donate to the lithium in the aza-
enolate intermediate leadingto improved selectivities.
to 6) usingbenzyl bromide as an electrophile to trap
the intermediate aza-enolate. The results are summa-
rised in Table 1.
Similarly, it has been shown that extra steric bulk about
the oxygen is sometimes necessary for good stereo differ-
entiation.12 Therefore, three hydrazones 1, 2 and 3 were
targeted.13
Initially, hydrazone 1 was treated with LDA in THF
and gratifyingly gave the expected product in 61% yield
with 61% ee in favour of the (S)-enantiomer (entry 1).
This is in agreement with the SAMP methodology
(R = Me) where the (S)-enantiomer is also preferred.
Changing the solvent had a substantial effect on the
reaction with both pentane and hexane causinga lower-
ingof both yield and ee (entries 2 and 3) whereas toluene
gave an improved yield and ee (entry 4). The effect of
additives was then investigated and both HMPA and
TMEDA caused a loweringof yield and a dramatic ero-
sion of ee, in comparison to lithium chloride, which
retained the enantioselection but increased the yield to
90% (entries 5–7). Changing the substituent on the oxy-
gen from a TBDMS group to the less sterically demand-
ingTMS group increased enantioselection with an ee of
86% (entry 8).
1 R=Si(CH3)2tBu
N
2 R=Si(CH3)3
3 R=CPh3
OR
N
2. Results and discussion
Nitrosation of the commercially available amino alcohol
4 was conveniently carried out usingethyl nitrite in alco-
hol.14 However, this expensive reagent could be avoided
by usingsilica sulfuric acid and sodium nitrite to give
equally good isolated yield.15 Although it was possible
to introduce the functionality onto the oxygen at this
stage and then form the hydrazone, it was practically
simpler to reduce the nitroso compound and condense
with pentanone prior to functionalisation. Reaction
with tert-butyldimethylsilyl chloride, trimethylsilyl chlo-
ride or triphenylmethyl chloride gave the desired
hydrazones.16
OR
O
N
a,b
N
Ph
6
Ph
N
Li
Ph
1-3
(R,R)-7
(S,S)-7
a,b
OH
c,d
OH
a) LDA, (R,R)-7 or (S,S)-7 (see Table 1) -78 °C to room temperature:
recool to -78 °C then benzyl bromide to room temperature;
b) amberlyst, acetone/water
N
N
N
N
H
OR
NH2
The use of lithiated chiral amines (S,S)-7 and (R,R)-7 as
a base was then investigated with a view to potentially
have a matched and a mis-matched pair of diastereo-
meric transition states. However, both enantiomers gave
a reduced ee showingthat the reaction was governed
entirely by the chiral auxiliary (entries 9 and 10). With
a change in substitution to the –CPh3 group a surprising
4
1-3
5
a) Silica sulfuric acid, NaNO2; b) LiAlH4, THF;
c) 3-Pentanone, TsOH; d) Imidazole, DMF, R-Cl.
With each of these hydrazones in hand, we investigated
their effectiveness in a standard screeningreaction ( 1–3
Table 1. Benzyl bromide trappingof aza-enolates
Entry
Hydrazone
Base
Solvent
Additive
Yield %a
ee % (configuration)b
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2
2
2
3
3
3
3
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
(R,R)-7
(S,S)-7
LDA
LDA
LDA
LDA
THF
—
—
—
—
61
41
37
74
64
57
90
65
29
29
59
63
72
64
61 (S)
41 (S)
37 (S)
74 (S)
38 (S)
29 (S)
73 (S)
86 (S)
74 (S)
55 (S)
64 (R)
59 (R)
18 (R)
7 (R)
Hexane
Pentane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
HMPA
TMEDA
Lithium chloride
—
—
—
—
—
—
—
9
10
11
12
13
14
THF
Hexane
Toluene
a Isolated yield of ketone followingin situ hydrolysis of hydrazone.
b The ee was determined by chiral GC analysis of the isolated ketones and, in some cases, confirmed by NMR investigations of the diastereomeric
hydrazones prior to hydrolysis. The configuration is assigned on the basis of the predictability of the corresponding SAMP hydrazones with the
reversal beingconfirmed by comparison of the direction of specific rotation for entries 11–14 and by chiral GC.

G. P. McGlacken, S. W. Breeden / Tetrahedron: Asymmetry 16 (2005) 3615–3618
Table 2. Enantioselective aldol addition reactions
3617
Entry
Hydrazone
R0CHO
Yielda
de (%)b
ee % syn-8 or 9c
ee % anti-8 or 9c
1
2
3
3
2
2
PhCHO
PhCHO
EtCHO
60
77
37
60 (syn- in excess)
24 (anti- in excess)
37 (anti- in excess)
54
69
83
30
77
84
a Isolated yield of a mixture of two isomeric ketones.
b Determined by 1H NMR analysis of the crude material and confirmed by GC analysis.
c Determined by chiral GC analysis of the isolated diastereomerically pure ketone.
reversal of enantioselection was noted (entries 11–14).
The change in orientation of the resulting ketone 6
was attributed to the large –CPh3 group hindering che-
lation of the oxygen to the lithium, thus disrupting the
configurationally stable intermediate. Once again, using
hexane as solvent, it caused a reduction in yield and ee.
In comparison to the silicon substituted case above,
usingtoluene as solvent was detrimental with respect
to enantioselection with the product beingisolated with
a very poor ee of 7% (entries 13 and 14).
in the case of the benzaldehyde quench, GC–MS analy-
sis showed peaks consistent with the formation of the
expected ester product 10. Benzyl alcohol was also
detected showingthat an active hydride was produced
in this reaction, as in the enolate case. The challenge is
now to enable intra-molecular transfer of this hydride
to the hydrazone double bond to produce extremely use-
ful stereochemically defined anti-1-amino-3-hydroxy
containingmaterials.
OSi(CH3)3
a,b
OSi(CH3)3
O
Having established a methodology for the generation of
aza-enolates, which gave rise to products with high lev-
els (up to 86% ee) of asymmetric induction we looked at
applyingthis to the aldol addition reaction. Thus, the
aza-enolates were generated as in entry 8 (LDA, toluene,
ꢀ78 °C) and trapped with benzaldehyde or propionalde-
hyde (Table 2). Followingin situ hydrolysis of the
hydrazones to ketones syn-/anti-8 and syn-/anti-9 the
diastereoselection was determined by comparison of
the proton NMR spectra with independently produced
samples and literature data.17 For comparison purposes,
trityl substituted hydrazone 3 was investigated and as
expected gave an excess of the syn isomer syn-8 with
moderate ees for both diastereoisomers (entry 1). Grat-
ifyingly the application of the silicon-substituted variant
2 as stereo director resulted in a reversal of diastereo-
selection with the anti-8 product beingpreferentially
formed (de 24%) with both isomers beingformed in
good ee (entry 2).
N
N
Ph
N
N
O
Ph
10
3
a) LDA -78 °C to room temperature: re-cooled to -78°C,
then aldehyde to room temperature; b) Amberlyst, acetone/water.
3. Conclusion
In conclusion, we have synthesised three novel chiral
hydrazones. Parallel reactions carried out in our labora-
tories showed hydrazones 1 and 2 gave comparable
yields and enantioselectivities (magnitude and orient-
ation) to SAMP. However, changing to a trityl sub-
stituted stereo director resulted in reversal of
enantioselection. In the aldol reaction, diastereoselec-
tion was also reversed giving an anti-selective protocol.
An initial extension of this work to a tandem aldol-
Tishtschenko reaction shows the process is viable with
active hydrides beingproduced, however, transfer of this
hydride to the hydrazone to give a 1,3-amino alcohol is
somewhat more challenging.
OR
O
OH
O
OH
N
+
N
a,b
R'
R'
R'=Ph; syn-8
R'=Et; syn-9
R'=Ph; anti-8
R'=Et; anti-9
a) LDA -78 °C to room temperature: re-cooled to -78°C, then R'CHO to
room temperature b) Amberlyst, acetone/water
Acknowledgement
The authors would like to thank Enterprise Ireland and
the Millennium Fund of NUI, Galway.
Usingpropionaldehyde as the electrophile resulted in a
further increase in de to 37% with the ees of both iso-
mers beingvery good: 83% and 84%, respectively, for
syn- and anti-9 (entry 3).
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