Asymmetric synthesis of α-alkylated aldehydes using terminal epoxide-derived chiral enamines

Article abstract of DOI:10.1002/anie.200804369

(Chemical Equation Presented) Effective discrimination: Efficient lithium amide-induced terminal epoxide-enamine transformation provides the first enamines capable of generating α-alkylated aldehydes with high asymmetric induction by intermolecular nucleophilic substitution (see scheme).

Full text of DOI:10.1002/anie.200804369

Communications
DOI: 10.1002/anie.200804369
Synthetic Methods
Asymmetric Synthesis of a-Alkylated Aldehydes using Terminal
Epoxide-Derived Chiral Enamines**
David M. Hodgson* and Naeem S. Kaka
Access to chiral a-alkyl aldehydes is important, not only for
potentially direct use in the fragrance industry,[1] but also due
to the diverse reactions they undergo [addition reactions with
ꢀ
a vast range of nucleophiles (notably C C bond formation)
generating alcohols, imines, amine formation by reductive
amination, olefination, etc.], which provide many possibilities
for introducing asymmetry into molecules. However, the
synthesis of enantioenriched mono-a-alkylated aldehydes
remains a non-trivial problem and methods to directly
access them are limited.[2] Currently, the most popular
method to generate enantioenriched aldehydes directly by
an a-alkylation strategy, Endersꢀ lithiated SAMP/RAMP
hydrazone chemistry,[3] typically involves very low temper-
atures (ꢀ808C to ꢀ1208C) and a separate step (e.g. ozonol-
ysis) is necessary to cleave the chiral auxiliary. Approaches
involving alkylation at a higher (e.g. amide) oxidation level,
such as Evansꢀ oxazolidinone and Myersꢀ pseudoephedrine
chiral auxiliary-based protocols require further manipulation
to give the aldehyde.[4] In 2004, Vignola and List reported the
intramolecular asymmetric a-alkylation of iodoalkyl alde-
hydes using a proline catalyst.[5] The well-known issue of
irreversible N-alkylation either at the free amine or, more
problematically at the enamine stage is likely avoided in this
case as the trans-enamine intermediate is unable to intra-
molecularly N-alkylate (due to geometric constraints). In
2006, Ibrahem and Cꢁrdova developed the a-allylation of
aldehydes, using a combination of palladium- and organo-
catalysis; asymmetric allylation was also reported (up to 87:13
e.r., but in 25% yield).[6] More recently, MacMillan and co-
workers disclosed efficient enantioselective catalytic inter-
molecular a-allylation of aldehydes using allylsilanes (up to
97.5:2.5 e.r.), proceeding by one-electron oxidation of tran-
sient enamine species.[7]
Scheme 1. Terminal epoxide-derived enamine synthesis and subse-
quent alkylation.[8]
whereas the formation of acyclic lithium amide derived
enamines such as 3 was less satisfactory, but the latter readily
gave a-alkylated aldehydes 4 on reaction with electrophiles.
Here, we describe the efficient preparation of a new class of
hindered enamines from terminal epoxides, where this
enamine class also undergoes synthetically viable C-alkyla-
tion, and with promising levels of asymmetric induction.
Attention focused on lithium 2,2,6-trisubstituted piper-
idide-derived enamines 5 (Figure 1). We envisaged that such
Figure 1. Enamine 5.
lithium amides would, like LTMP, be basic and hindered
enough to form enamines via a-lithiation of terminal epoxides
in good yields (with minimal allylic alcohol/1,2-amino alcohol
side products).[8,9] Also however, we anticipated that unlike
LTMP-derived enamines, such trisubstituted piperidide-
derived enamines would undergo alkylation to generate a-
alkylated aldehydes. In the latter analysis, the n!p* overlap,
essential for reactivity would be achievable by the single C-6
substituent (R2 on the piperidine) residing axial to minimize
A1,3 strain (conformer 6, Figure 1).[10]
So as to examine the above strategy, lithium 2,2,6-
trimethylpiperidide (LTriMP) 8a-Li (readily accessed by
dechloromethylation of N-chloro-2,2,6,6-tetramethylpiperi-
dine,[11,12] followed by reduction of the resulting imine and
subsequent addition of nBuLi) was reacted with 1,2-epox-
yhexane 1 giving enamine 5a in good yield (76%).[13] The
chemical shift difference between the two olefinic protons of
enamine 5a is 1.4 ppm, indicative of traditional enamine-like
character[8,14] and suggestive that reaction should be viable
with a variety of activated and unactivated electrophiles; this
was observed to be the case (Table 1).[15] Not only addition to
Michael acceptors, but also more significantly substitution
using activated organohalides (a-bromoacetates, benzyl, allyl
and propargyl bromide) gave the corresponding a-substituted
We recently reported the synthesis of enamines (e.g. 3,
Scheme 1) from terminal epoxides (e.g. 1) and hindered
lithium amides (e.g. 2).[8] In that work, lithium 2,2,6,6-
tetramethylpiperidide (LTMP) derived enamines formed
efficiently but did not satisfactorily react with electrophiles,
[*] Prof. D. M. Hodgson, N. S. Kaka
Department of Chemistry, Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
Fax: (+44)1865-285002
E-mail: david.hodgson@chem.ox.ac.uk
Homepage: http://users.ox.ac.uk/~dmhgroup
[**] We thank the EPSRC for funding (N.S.K.), Dr. C. D. Bray (Queen
Mary, University of London) and R. E. Shelton for useful discus-
sions, Dr. T. D. W. Claridge for 77Se NMR installation and the EPSRC
National Mass Spectrometry Service (Swansea) for mass spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804369.
9958
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 9958 –9960

Angewandte
Chemie
Table 1: Synthesis and reaction of enamine 5a.
Entry[a]
Electrophile [RX]
T [8C]
Product
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
methyl acrylate[b]
acrylonitrile[b]
MeO2CCH2Br
tBuO2CCH2Br
PhCH2Br
82
82
RT
RT
RT
RT
RT
40
65
75
82
94
94
4a
4b
4c
4d
4e
4 f
4g
4h
4i
80
70
89
69
98
96
87
67
71
67
67
62
61
=
CH2 CHCH2Br
ꢁ
HC CCH2Br
MeI[c]
EtI
Scheme 2. Asymmetric synthesis of 6-alkyl-2,2-dimethylpiperidines (R)-
8a and (S)-8b.
PrI
BuI
4j
4k
4l
C10H21I[b]
iPrI[d]
4m
[a] 16 h reaction time in sealed tube with 2 equivalents of electrophile,
unless otherwise stated. [b] 20 h reaction time. [c] 3 equivalents used.
[d] 42 h reaction time.
Scheme 3. Asymmetric alkylation of enamine (R)-5a.
aldehydes in good to excellent yields (Table 1, entries 1–7).
Alkylation with propargyl bromide yielded only the prop-
argyl-substituted aldehyde with none of the corresponding
allene observed; this result shows that N-alkylation followed
by [3,3] sigmatropic rearrangement is not occuring.[14] Impor-
tantly, a range of short-, longer-chain and secondary unac-
tivated alkyl iodides also proved viable (Table 1, entries 8–
13).
point should provide more efficient impediment to electro-
phile approach from the lower face [conformer 6 (R2 = iPr),
Figure 1]. (S)-6-Isopropyl-2,2-dimethylpiperidine (S)-8b was
synthesized by a similar sequence to that for (R)-TriMP
(Scheme 2). Reaction of the corresponding lithiated amide
(S)-8b-Li gave the enamine (S)-5b in very good yield (83%,
Scheme 4). Although the difference in chemical shift between
Standard work-up of representative alkylations (Table 1,
entries 6 und 9), but using deuterated materials (AcOD/
NaOAc/D2O) resulted in no deuterium incorporation at the
a-position of the alkylated aldehyde, suggesting that if an
enantiopure enamine underwent completely stereoselective
alkylation, then enantiopure aldehydes should be obtained on
hydrolysis of the iminium intermediate. So as to ascertain how
effective 2,2,6-trimethylpiperidine (TriMP) 8a would be in
this context, (R)-TriMP (R)-8a (> 99.5:0.5 e.r.) was synthe-
sized by copper-catalyzed Grignard ring-opening of enantio-
pure 2-substituted aziridine (R)-9a[16] (available from amino-
lytic kinetic resolution of the corresponding racemic epox-
ide),[17] followed by formal intramolecular hydroamination
(Scheme 2).
Enamine (R)-5a was found to undergo alkylation with
allyl bromide and EtI in 84:16 e.r. and 88:12 e.r., respectively,
with the sense of asymmetric induction as shown in
Scheme 3.[12]
Scheme 4. Synthesis and asymmetric alkylation of enamine (S)-5b.
Given the encouraging e.r. values obtained using (R)-
TriMP, we next sought an amine with a sterically more
demanding group at C-6 in order to examine if this would lead
to higher stereoselectivity. An isopropyl substituent should
still not be prevented from residing axial (Avalues for Me and
iPr-substituted cyclohexane are 7.3 and 9.3 kJmolꢀ1, respec-
the two olefinic protons of enamine (S)-5b was only 0.3 ppm
(0.5 ppm was found for the corresponding unreactive LTMP-
derived enamine),[8] enamine (S)-5b underwent reaction with
strongly electrophilic benzyl, allyl, and propargyl bromides in
very good yields and with short chain alkyl iodides, MeI and
EtI, in satisfactory yields. These data suggest that whilst the
preferred conformer of enamine (S)-5b may resemble 7 (R2 =
iPr, Figure 1), access to reactive conformer 6 (R2 = iPr) is
achievable. Significantly, improved levels of asymmetric
tively);[18] however, with the methine C H of this group
ꢀ
pointing inward (to minimize 1,3-diaxial interactions), it was
considered that one of the two methyl groups at the branch
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Communications
ˆ
[2] J. Kosmrlj, L. O. Weigel, D. A. Evans, C. W. Downey, J. Wu, J.
induction, compared with TriMP-derived enamine (R)-5a
were observed (up to 95:5 e.r.).
Am. Chem. Soc. 2003, 125, 3208 – 3209.
[3] a) D. Enders, L. Wortmann, R. Peters, Acc. Chem. Res. 2000, 33,
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b) for chiral enamine-based asymmetric a-alkylation of cyclo-
hexanone, see: J. K. Whitesell, S. W. Fellman, J. Org. Chem.
1977, 42, 1663 – 1664.
So as to exemplify the above methodology with a
functionalized terminal epoxide, aldehyde (S)-14, an inter-
mediate in Nicolaouꢀs synthesis of the ionophore antibiotic
indanomycin (X-14547A)[19] was generated in good yield
(65%) and 93.5:6.5 e.r. from the corresponding chiral
enamine (R)-13 (Scheme 5); the latter being obtained from
terminal epoxide 12[20] and (R)-8b-Li in very good yield
(78%).
[6] a) I. Ibrahem, A. Cꢁrdova, Angew. Chem. 2006, 118, 1986 – 1990;
Angew. Chem. Int. Ed. 2006, 45, 1952 – 1956; b) for a more recent
approach to asymmetric a-allylation, see: S. Mukherjee, B. List,
J. Am. Chem. Soc. 2007, 129, 11336 – 11337.
[7] a) T. D. Beeson, A. Mastraccio, J. B. Hong, K. Ashton, D. W. C.
MacMillan, Science 2007, 316, 582 – 585; b) for recent organo-
catalytic a-alkylation using a-bromocarbonyl compounds, see:
D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77 – 80.
[8] D. M. Hodgson, C. D. Bray, N. D. Kindon, J. Am. Chem. Soc.
2004, 126, 6870 – 6871.
[9] A. Yanagisawa, K. Yasue, H. Yamamoto, J. Chem. Soc. Chem.
Commun. 1994, 2103 – 2104.
[10] Molecular modeling calculations support this analysis: D. M.
Hodgson, N. S. Kaka, K. N. Houk, J. M. Um, unpublished results.
[11] A. S. Dneprovskii, S. A. Milꢀtsov, Zh. Org. Khim. 1988, 24, 2037 –
2041; J. Org. Chem. USSR 1988, 24, 1836–1840.
Scheme 5. Asymmetric synthesis of aldehyde (S)-14 using enamine
(R)-13.
[12] See the Supporting Information for details.
In summary, we describe the first lithium amides capable
of efficiently converting terminal epoxide into enamine
functionality, where the latter demonstrate effective C-
alkylation activity. With chiral lithium amides, the corre-
sponding enamines provide the first direct access to a-
alkylated aldehydes with high asymmetric induction by
intermolecular nucleophilic substitution.
[13] Enamine 5a could be prepared by aldehyde–amine condensa-
tion (benzene, Dean–Stark trap, 42 h), but in only 26% yield and
as a 4:1 E:Z mixture.
[14] a) G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz, R.
Terrell, J. Am. Chem. Soc. 1963, 85, 207 – 222; b) P. W. Hickmott,
Tetrahedron 1982, 38, 1975 – 2050; c) Enamines: Synthesis Struc-
ture and Reactions, 2nd ed. (Ed.: A. G. Cook), Marcel Dekker,
New York, 1988; d) The Chemistry of Enamines (Ed.: Z.
Rappoport), Wiley, Chichester, 1994; e) T. Sammakia, J. A.
Abramite, M. F. Sammons in Science of Synthesis, Vol. 33 (Eds.:
B. M. Trost, G. A. Molander), Thieme, Stuttgart, 2006, pp. 405 –
441.
[15] Attempted C-alkylation using MeI with the enamine derived
from MacMillanꢀs imidazolidinone (T. J. Peelen, Y. Chi, S. H.
Gellman, J. Am. Chem. Soc. 2005, 127, 11598 – 11599) was not
successful.
Experimental Section
Representative procedure for enamine alkylation: a solution of
enamine (1 mmol) and electrophile (2 mmol) in MeCN (1 mL) was
stirred in a sealed tube at the stated temperature for the indicated
time. A solution of AcOH (0.125 g), NaOAc (0.125 g) in water
(0.25 mL) was then added and the mixture allowed to stir at room
temperature for 10 min, before being partitioned between water
(10 mL) and Et2O (10 mL). The aqueous phase was washed with Et2O
(10 mL) and the combined organic layers were washed with brine
(20 mL), dried (MgSO4) and evaporated under reduced pressure.
Purification of the residue by column chromatography gave the
aldehyde.
[16] a) D. M. Hodgson, P. G. Humphreys, Z. Xu, J. G. Ward, Angew.
Chem. 2007, 119, 2295 – 2298; Angew. Chem. Int. Ed. 2007, 46,
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C. A. J. Brierley, J. G. Ward, J. Org. Chem. 2007, 72, 10009 –
10021.
[17] G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P. Melchiorre, L.
Sambri, Org. Lett. 2004, 6, 3973 – 3975.
[18] E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of
Organic Compounds, Wiley, Chichester, 1994, pp. 686 – 707.
[19] a) K. C. Nicolaou, D. P. Papahatjis, D. A. Claremon, R. L.
Magolda, R. E. Dolle, J. Org. Chem. 1985, 50, 1440 – 1456;
b) enantiomeric aldehyde (R)-14 has recently been used in the
synthesis of the antibiotic myxovirescin A1, see: A. Fꢂrstner, M.
Bonnekessel, J. T. Blank, K. Radkowski, G. Seidel, F. Lacombe,
B. Gabor, R. Mynott, Chem. Eur. J. 2007, 13, 8762 – 8783.
[20] J. W. Johannes, S. Wenglowsky, Y. Kishi, Org. Lett. 2005, 7, 3997 –
4000.
Received: September 4, 2008
Published online: November 12, 2008
Keywords: aldehydes · alkylation · asymmetric synthesis ·
.
enamines · terminal epoxides
[1] For example, see: D. Enders, M. Backes, Tetrahedron: Asym-
metry 2004, 15, 1813 – 1817.
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