Boron-mediated aldol reactions of ethyl α-(N,N)-dibenzylamino ketones: Control of enolisation geometry and aldehyde π-facial selectivity

Article abstract of DOI:10.1016/S0040-4039(01)01982-7

The boron-mediated aldol reactions of a range of chiral α-(N,N)-dibenzylamino ketones with aldehydes can be controlled to provide stereodefined adducts. Complementary induction can be achieved with ^cHex₂BCl/Me₂NEt leading to preferential formation of the 1,2-anti-2,4-syn adducts, while Bu₂BOTfⁱPr₂NEt provides 1,2-syn-2,4-anti adducts.

Full text of DOI:10.1016/S0040-4039(01)01982-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9269–9272
Boron-mediated aldol reactions of ethyl a-(N,N)-dibenzylamino
ketones: control of enolisation geometry and aldehyde
p-facial selectivity
Ian Paterson* and Angela C. Mackay
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Received 27 September 2001; accepted 19 October 2001
Abstract—The boron-mediated aldol reactions of a range of chiral a-(N,N)-dibenzylamino ketones with aldehydes can be
controlled to provide stereodefined adducts. Complementary induction can be achieved with cHex2BCl/Me2NEt leading to
preferential formation of the 1,2-anti-2,4-syn adducts, while Bu2BOTf/iPr2NEt provides 1,2-syn-2,4-anti adducts. © 2001 Elsevier
Science Ltd. All rights reserved.
The boron-mediated aldol reaction is one of the most
important methods for acyclic stereocontrol, enabling
the efficient synthesis of a wide variety of b-hydroxy
carbonyl compounds in a highly regio-, diastereo-, and
enantioselective manner.1 The use of lactate-derived
a-alkoxy ketones is one such method that has been
developed in our laboratory.2,3 Here the simple choice
of oxygen protecting group determines the enolisation
amine base, control of enolisation geometry and alde-
hyde p-facial selectivity results in preferential access to
stereodefined anti or syn adducts, as in 5“6 or 7.
These may be useful as precursors of novel N,O-based
chiral ligands for asymmetric catalysis,5 as well as for
incorporation into peptidomimetic and other libraries
of pharmaceutical interest.
c
geometry with Hex2BCl/R3N, leading to anti or syn
For this study, the ethyl ketones 5 and 8 were pre-
pared (Scheme 2) from the corresponding L-alanine
additions to aldehydes with high levels of p-facial
selectivity, i.e. 1“2 and 3“4 (Scheme 1). As an exten-
sion to this work, we now report a study of the aldol
reactions of ethyl a-(N,N)-dibenzylamino ketones,4 as
versatile chiral building blocks prepared from a-amino
acids. By appropriate choice of boron reagent and
and
L
-phenylalanine methyl esters, 9 and 10, via N-
benzylation and EtMgCl addition to the derived Wein-
reb amides.6 Ketone 11 was prepared by Grignard
addition to N,N-dibenzylated valinal followed by oxi-
dation.4
Scheme 1. Boron-mediated aldol reactions of lactate and a-amino acid derived ketones.
Keywords: boron aldol; amino acids; amino ketones; stereoinduction; libraries.
* Corresponding author. Fax: +44-1223-336362; e-mail: ip100@cus.cam.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01982-7

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For boron-mediated aldol reactions, substantial levels of
stereoinduction result from a tight cyclic transition state,
which is energetically responsive to quite subtle steric and
electronic influences.1 In this case (Fig. 2), the preferred
re-face attack of the (E)-enolate on the aldehyde can be
rationalised by the addition proceeding via transition
structure TS-I, where A(1,3) strain is minimised.12 Here
the large steric demands of the a-dibenzylamino group
lead to it being directed outside with the methyl group
oriented inwards. Notably, this contrasts with the pre-
ferred si-face attack of the (E)-enolate of the (S)-lactate-
derived a-benzoyloxy ketone (cf Scheme 1, 1“2);2 where
the benzoyloxy group is directed inside in TS-II.2a,c
Scheme 2. (a) BnBr, NaHCO3, THF/DMSO (4:1), 16 h, 85°C;
(b) HNMe(OMe)·HCl, iPrMgCl, THF, −5°C, 1 h, then rt, 2 h;
(c) EtMgCl, THF, 0°C“rt, 3 h.
c
By using Hex2BCl in the presence of tertiary amine
bases, suitable conditions for achieving anti-selective
aldol reactions with ketone 5 were developed.7 To ensure
optimum selectivity and conversion, Me2NEt was
selected as the preferred base with enolisation in Et2O at
0°C, followed by addition of the aldehyde to the resulting
solution of (E)-enol borinate cooled to −78°C.8 For a
range of aldehydes (Table 1), the anti adducts 6a–h and
12a–h were obtained in high yield without any detectable
syn adducts.9
For simple achiral aldehydes,
a typical level of
diastereoselection of 85:15 was obtained in favour of the
adducts 6a–f (1,2-anti-2,4-syn as depicted), correspond-
ing to preferred re-face attack on the aldehyde. In each
case, the major adduct was isolated in good yield after
chromatographic separation of the mixture. The use of
a Felkin-matched a-chiral aldehyde led to essentially
complete p-facial selectivity for 6g (>98:2 dr), whereas the
selectivity was eroded for the mismatched pair (64:36 dr).
For the addition of 5 to isobutyraldehyde (entry c), the
configuration of the major diastereomer 6c was rigor-
ously assigned by single crystal X-ray diffraction analysis
(Fig. 1), while the other examples were assigned by
1
analysis of their H NMR spectra.10,11
Table 1. Anti-selective aldol reactions of ketone (S)-5
Figure 1. Crystal structure of major aldol adducts 6c and 13e.
Figure 2. Preferred aldol transition structures.

I. Paterson, A. C. Mackay / Tetrahedron Letters 42 (2001) 9269–9272
Table 3. Syn-selective aldol reactions of ketone (S)-5
9271
Table 2. Anti-selective aldol reactions of ketones (S)-8
and (S)-11
The anti aldol reactions of the protected a-amino
ketones 8 and 11 with a range of aldehydes were also
explored under similar reaction conditions (Table 2).
For the addition of 8 to benzaldehyde, the configura-
tion of the major adduct 13e (entry e) was established
by X-ray diffraction analysis to be analogous to that
obtained in the alanine series (Fig. 1).10 On reaction
with aliphatic aldehydes, selectivities for 13a, b, g and h
were lower compared to the corresponding reactions of
5. This appears to be in line with the anticipated
destabilising effect of locating a bulkier alkyl group (iPr
or Bn in place of Me) in the inside position in TS-I.
However, reaction of 8 with methacrolein and ben-
zaldehyde gave improved stereoselectivity for 13d and
e, respectively, comparable to the Felkin-matched reac-
tion giving 13f, suggesting the contribution of other
factors. Reactions of the more highly substituted
ketone 11 proved sluggish, leading to incomplete con-
version. Here the same sense of stereoinduction towards
13g–i was assigned in analogy to the results for the
other two ketones.
Figure 3. Preferred aldol transition structure.
determined by the lack of any detectable anti adducts.
Flash chromatography allowed ready isolation of the
major diastereomers 7a–d (>80% yield), which were
stereochemically identical to those obtained using Liot-
ta’s protocol. Here the observed re-face selectivity con-
curs with that found for the (S)-lactate-derived
a-benzyloxy ketone (cf Scheme 1, 3“4). Taking
account of steric and electronic factors, this can be
rationalised in a similar manner by invoking TS-III
(re-face attack) as the preferred transition structure
(Fig. 3), where the enolate C–O and C–N dipoles are
opposed and the methyl group on the a-stereocentre is
directed outwards.
In conclusion, complementary diastereoselectivities can
be obtained in the boron-mediated aldol reactions of
ethyl a-(N,N)-dibenzylamino ketones depending on the
choice of reagent. It should be possible to manipulate
the resulting stereodefined b-hydroxy ketones along the
lines already demonstrated for the lactate-derived
series.2,14 By using the wide variety of a-amino acids
available,15 extensive stereochemical and structural
diversification should enable the parallel synthesis of
novel libraries.16
To achieve stereochemical flexibility in the aldol reac-
tions of protected a-amino ketones, we next developed
a complementary syn-selective process through the (Z)-
enol borinate (Table 3).13 Using both sodium and
lithium enolates and invoking an open transition state,
Liotta and co-workers have shown that these ethyl
ketones undergo diastereoselective aldol reactions with
aldehydes to provide the syn adducts 7.4 For the boron-
mediated reaction, enolisation of ketone
5 with
Acknowledgements
i
Bu2BOTf, in the presence of Pr2NEt, in CH2Cl2 at
−78°C generated the (Z)-enol borinate cleanly, which
added to aldehydes with a pronounced p-facial bias
towards the syn adducts 7a–d (1,2-syn-2,4-anti as
depicted) over 15a–d and in high yield.8 Once again, the
enolisation step was found to be completely selective as
We thank the EPSRC, the EC (IHP Network RTN1-
1999-00054) and Merck Sharp & Dohme for support
and Dr. John Davies (Cambridge) for the X-ray crystal
structure determinations.

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I. Paterson, A. C. Mackay / Tetrahedron Letters 42 (2001) 9269–9272
then pH 7 buffer and MeOH (1:1, 2 mL/mmol) were
References
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the major anti aldol adduct 6. In each case, the reaction
diastereoselectivity was determined by analytical HPLC
on the crude reaction mixture. A similar procedure was
used for the syn aldol reactions of ketone (S)-5, except
1. For reviews on asymmetric aldol reactions using boron
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9. All new compounds gave spectroscopic data in agreement
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throughout. The corresponding syn isomers in Table 3
3
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8. Representative experimental procedure: To a stirred solu-
c
tion of Hex2BCl (1.3 equiv.) and Me2NEt (1.5 equiv.) in
dry Et2O (1 mL/mmol of ketone) at 0°C was added a
solution of the ketone (S)-5 in Et2O. After 2 h, the
reaction mixture was cooled to −78°C. A solution of the
aldehyde (2 equiv.) in Et2O was added. After 3 h, the
reaction mixture was kept at −26°C for 14 h (freezer),