Reactions of iminium ions with Michael acceptors through a Morita-Baylis-Hillman-type reaction: Enantiocontrol and applications in synthesis

Article abstract of DOI:10.1002/anie.200604715

(Chemical Equation Presented) All adducts one way: Iminium ions, generated in situ from the corresponding N,O-acetals, can be used as electrophiles in a Morita-Baylis-Hillman-type reaction with a wide range of Michael acceptors (enones, enals, S- and O-acrylates). The reaction has been rendered asymmetric using sulfide 1 (see scheme; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, TMSOTf=trimethylsilyl trifluoromethanesulfonate).

Full text of DOI:10.1002/anie.200604715

Angewandte
Chemie
DOI: 10.1002/anie.200604715
Asymmetric Synthesis
Reactions of Iminium Ions with Michael Acceptors through a Morita–
Baylis–Hillman-Type Reaction: Enantiocontrol and Applications in
Synthesis**
Eddie L. Myers, Johannes G. de Vries, and Varinder K. Aggarwal*
a-Functionalization of alkenes activated by electron-with-
biologically important and highly functionalized b’-amido-
a,b-unsaturated carbonyl compounds.[9] Herein,we describe
our success in employing this class of substrates and also in
rendering the reaction asymmetric.
À
drawing groups (EWGs) encompass an important C C bond-
forming strategy in organic synthesis,and can be realized in
one of three ways: a) metal-catalyzed functionalization of a-
halogeno[1] or a-metallo substrates;[2] b) a vinylogous enoli-
Initial investigations focused on the pyrrolidine 1 (PG =
Cbz, m = 1; Scheme 1) and reaction conditions in which a
combination of a Lewis acid (to form the iminium ion
electrophile) and a weak Lewis base (to form the enolate
nucleophile) were used.[10] The standard Lewis bases for the
MBH reaction (phosphines and amines) were ineffective with
BF3·OEt2: use of PPh3 resulted in a stable phosphine–iminium
ion adduct[11] presumably because of the poor leaving group
ability of the phosphine,[12] and pyridine caused dimerization
of the pyrrolidine presumably through base-promoted enam-
ine formation and subsequent attack on a second iminium
ion.[13] In contrast,sulfides proved effective: treatment of a
solution of pyrrolidine 1 and methyl vinyl ketone (MVK) with
BF3·OEt2 and SMe2,[10a] followed by treatment of the resultant
crude mixture with DBU,resulted in the isolation of the
MBH-type adduct 2a in 30% yield. Other Lewis acid/Lewis
base combinations were then investigated,namely TiCl 4,[10c,14]
TiCl4/SMe2,[10b,15] Et2Al-I,[16] and TMSOTf/SMe2.[7f,g] The
latter combination was found to be optimum and provided
adducts 2a–m; in good to excellent yield (Table 1). With these
conditions,the scope of the alkene was exceptionally broad
and encompassed enones,both acyclic (entry 1) and cyclic
(entries 2 and 3),enals including acrolein (entries 4 and 5),
and S-ethyl propenethiolate[17] (entry 6). Methyl acrylate
(entry 7) was only moderately successful since the dimeriza-
tion of pyrrolidine 1 was again observed as a competing
process.
[3]
zation, a-alkylation,and isomerization sequence;
or
c) nucleophilic catalysis: the Rauhut–Currier and Morita–
Baylis–Hillman (MBH) reactions.[4] The MBH transforma-
tion (Scheme 1),[5] which is traditionally effected by catalytic
Scheme 1. The Morita–Baylis–Hillman reaction andour proposed
study. Cbz=benzyloxycarbonyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-
ene, TMS=trimethylsilyl, PG=protecting group.
amounts of a tertiary amine or phosphine and uses an
aldehyde as the terminal electrophile,has become more
recently a powerful synthetic tool with the increased scope in
[6a]
Michael acceptors (for example,vinyl sulfones
and acryl-
amides[6]) and electrophiles (for example,halides,
epox-
[7a,b]
ides,[7c] allyl carbonates,[7d] acetals,[7e–h] and aryl cation equiv-
alents[7i]). A class of electrophile that has received little
attention is N-acyl iminium ions[8] which would lead to
The scope of the N,O-acetal was also explored (Table 1).
The piperidine analogue of 1 gave adducts in good to
excellent yield (entries 8 and 9). With this substrate,the
temperature had to be maintained below À608C since
dimerization of the N,O-acetal was extremely facile at
higher temperatures.[13] The Boc (entries 10 and 11) and
tosyl analogues (entries 12 and 13) of 1 also gave good to
excellent yields of adducts.
[*] Dr. E. L. Myers, Prof. Dr. V. K. Aggarwal
School of Chemistry
University of Bristol
Cantock’s Close, Bristol BS81TS (UK)
Fax: (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
Prof. J. G. de Vries
DSM Pharmaceutical Products
Advanced Synthesis, Catalysis & Development
P.O. Box 18, 6160 MD Geleen (The Netherlands)
We then chose to apply this methodology to the synthesis
of the necine base (+)-heliotridine (Scheme 2).[18] Pyrrolidine
3 was prepared from (S)-malic acid using the procedure of
Speckamp and co-workers.[19] Although the employment of
the above methodologies failed to provide MBH-type adduct
4,it was found that treatment of a solution of 3 and methyl
acrylate in CH3CN with the combination of TMSOTf,
[**] We thank Dr. J. P. H. Charmant andS. Saithong for X-ray analysis.
We thank DSM andthe EPSRC for financial support andMerck for
unrestrictedresearch support. V.K.A. thanks the Royal Society for a
Wolfson Research Merit Award.
[20]
BF3·OEt2 and SMe2 gave the required adduct 4 in 85%
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
yield,albeit as a mixture of diastereomers in favor of the trans
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Table 1: Synthesis of MBH-type adducts 2a–m.
heating a solution of 6 in THF with LiAlH4 to reflux to give
(+)-heliotridine in 38% yield. The unnatural isomer (À)-
retronecine (7) was also isolated in 12% yield. Whilst the
structure of the natural product is relatively simple,its
synthesis has prompted us to develop alternative reaction
conditions for more demanding substrates,and the problems
encountered with the RCM step clearly demonstrate the
superiority of the MBH ring closure in this context.
Entry
PG
m
n
R
X
Product
Yield [%]
To render the reaction asymmetric,enantiomerically pure
chiral sulfide was used in place of SMe2 (Table 2). Using the
camphor sulfonic acid derivative,sulfide 8,which was
1
2
3
4
5
6
7
8
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
Ts
1
1
1
1
1
1
1
2
2
1
1
1
1
0
1
2
0
0
0
0
1
2
1
2
0
0
H
H
H
H
CH3
H
H
H
H
H
H
H
H
CH3
CH2
CH2
H
H
SEt
OMe
CH2
CH2
CH2
CH2
CH3
SEt
2a
2b
2c
95
96
96
85
94
90
51
90
75
69
60
90
90
2d[c]
2e[c,d]
2 f
Table 2: Asymmetric synthesis of MBH adducts.[a]
2g[e]
2h[f]
2i[f]
2j
9
10
11
12
13
2k
2l[g]
2m[g]
Ts
[a] Alkene (2.0 equiv), TMSOTf (2.5 equiv), SMe2 (1.5 equiv), CH2Cl2,
À788C to À208C, 3 h; sat. aq NaHCO3 quench. [b] DBU (1.5 equiv),
CH2Cl2, RT, 10 min. [c] Treatment with DBU was not required. [d] E/Z 5:1
[e] Reaction was carriedout at À208C for 16 h; pyrrolidine dimerization
was a competing pathway. [f] Temperature was kept below À608C.
[g] Reaction mixture was warmedslowly from À788C to RT. Boc=tert-
butoxycarbonyl, Tf=trifluoromethanesulfonyl, Ts=tosyl=toluene-4-sul-
fonyl.
Entry
PG
m
n
Product (R/S)
Yield[%]
ee [%]
1
2
3
4
5
6
Cbz
Cbz
Boc
Boc
Cbz
Cbz
1
1
1
1
2
2
1
2
1
2
1
2
2b (S)
2c (S)
2j (S)
2k (S)
2h (S)
2i (S)
69
86
75
90
88
49
82
80
88
88
94
98
[a] Alkene (2.0 equiv), sulfide 8 (1.5 equiv), TMSOTf (2.5 equiv), CH2Cl2,
<À608C, 5 h.
designed and synthesized within our research group for use
in chemistry based on sulfonium ylides,[22] gave adducts in
good yield and with high ee values (Table 2,entries 3 and 4).
Sulfide 8,was easily recoverable ( > 90% yield) by column
chromatography of the crude mixtures.
It was found that piperidine-based rather than pyrroli-
dine-based N,O-acetals (Table 2, entries 5 and 6 versus 1 and
2),and Boc rather than Cbz carbamate (Table 2,entries 3 and
4 versus 1 and 2) provided MBH-type adducts with improved
ee values. When the acyclic enone MVK was employed,the
corresponding adduct 2a was obtained with a low ee value
(8%). The absolute stereochemistry of 2k was determined to
be S by synthesis,crystallization,and X-ray analysis of the
camphor sulfonamide derivative; the remaining adducts were
assigned by analogy.
Scheme 2. Synthesis of (+)-heliotridine. a) 3 (1 equiv), methyl acrylate
(3.0 equiv), TMSOTf (3.0 equiv), BF3·OEt2 (3.0 equiv), SMe2
(3.0 equiv), CH3CN, RT, 24 h; b) acrolein (3.0 equiv), Grubbs–Hoveyda
cat. (2ꢀ5 mol%), CH2Cl2, RT, 12 h; c) TMSOTf (3.0 equiv), BF3·OEt2
(3.0 equiv), SMe2 (3.0 equiv), CH3CN, RT, 3 h; d) LiAlH4 (7.0 equiv),
THF, reflux, 1 h.
The origin of the high asymmetric induction is intriguing.
Low-temperature NMR studies of a solution of cyclohex-
enone,sulfide 8,and TMSOTf in CD 2Cl2 at À908C revealed a
mixture of diastereomeric b-sulfonium silyl enol ethers 9a
and 9b in an unassigned ratio of 2:1 as the predominant
species (Scheme 3).[23] On warming the mixture to À108C in
increments of 208C,the equilibrium shifted in favor of
starting material 8;[24] at À308C only starting material was
detected. On recooling to À908C,the 2:1 mixture of b-
sulfonium silyl enol ethers was formed again. This reveals that
the silyl enol ethers 9a and 9b are formed reversibly and,at
the reaction temperature,are in dynamic equilibrium with the
isomer. However,all attempts to bring about ring-closing
metathesis (RCM) of diene 4 failed,with isomerization of the
allyl moiety to the enamide the only transformation
observed.[21] An alternative route to the necine base was
then devised in which metathesis precedes the MBH-type
reaction. Cross-metathesis of 3 with acrolein was achieved
using the Grubbs–Hoveyda catalyst,and subsequent MBH-
type ring closure was effected using the conditions developed
for the acyclic transformation.[8] Ultimately,bicyclic aldehyde
6 was isolated as an inseparable mixture of epimers. Multisite
reduction to the requisite oxidation state was achieved by
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À
Keywords: C C coupling · Lewis acids · Lewis bases ·
Mannich reaction · Morita–Baylis–Hillman reaction
.
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the stage of formation of the b-sulfonium silyl enol ethers. The
origin of the enantioselectivity must therefore result from a
dynamic kinetic transformation of b-sulfonium silyl enol ether
9a,b,in which either the major or minor isomer reacts faster,
thereby allowing the remaining diastereomer to revert to
starting material for repartitioning. Focusing on one of two
scenarios in which 9a reacts faster,it could be envisioned to
approach the iminium ion in several ways (Scheme 3).
The synclinal approaches can be tentatively discounted
since altering the size of the silyl moiety from trimethylsilyl to
triisopropylsilyl had little impact on the ee value. Of the two
remaining antiperiplanar approaches,attack on the Si face of
the iminium ion would be disfavored because of nonbonding
interactions between the two rings. This suggests that 9a
should favor attack on the Re face of the iminium ion,thereby
leading to the S enantiomer of the product as observed. This
analysis still leaves open the question of why one diastereo-
mer (9a/9b) is more reactive than the other,and this aspect is
under further study.
To conclude,we have developed a novel methodology
which allows a very broad range of readily available Michael
acceptors,including acrolein and acrylates,to couple with
readily available iminium ions (masked as N,O-acetals) in
both an inter- and intramolecular MBH-type reaction to give
densely functionalized heterocycles. The process has been
rendered asymmetric and high enantioselectivity has been
achieved with cyclic enones. Finally,the usefulness of the
methodology has been exemplified in a short synthesis of
(+)-heliotridine.
Kim,J. H. Park,Y. G. Kim,J. M. Lee,
J. Chem. Soc. Chem.
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[9] The reaction could also be classed as a vinylogous Mannich
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for the synthesis of
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biology,see: G. Lelais,D. Seebach, Biopolymers 2004, 76,206.
[10] Such conditions had previously been employed for MBH
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[11] It has been reported that similar adducts derived from alkyl
iminium ions are stable; see: H. Boehme,M. Haake, Chem. Ber.
1972, 105,2233.
Received: November 20,2006
Published online: February 5,2007
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Communications
[12] V. K. Aggarwal,J. N. Harvey,R. Robiette, Angew. Chem. 2005,
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and MVK,and subsequent treatment with DBU),the MBH
adduct was not produced and the starting material,N,O-acetal 1,
along with the hydroxy aminal derivative were recovered. This
result is intriguing since Goodman and co-workers have
demonstrated that the generation of the required b-chloro
titanium enolate is facile at this temperature (see Ref. [10a]). It
is possible that at À788C,NO, -acetal 1 is converted into its
kinetically stable a-chloro derivative,which only becomes
unstable with respect to an iminium ion at higher temperatures,
namely À208C. When the reaction was carried out at À208C,the
MBH adduct was isolated in 67% yield. Attempts to expand the
scope of the alkene beyond MVK were unsuccessful.
2004, 45,3047.
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[20] The structure of the complex formed between TMSOTf and
BF3·OEt2 has been studied in detail,and has been found to be
BF2OTf,which is
components: E. L. Myers,C. P. Butts,V. K. Aggarwal, Chem.
Commun. 2006,4434.
a more powerful Lewis acid than its
[21] This transformation is commonly observed when metathesis is
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exclusively at the lone pair of electrons trans to the camphor
moiety.
[15] This combination gave similar results as produced with TiCl4
alone.
[16] The reagent Et2Al-I,which is suitably active to allow generation
of the b-iodo enolate of methyl acrylate (see Ref. [10d]),did not
lead to the required adduct 2g; the delivery of the ethyl rather
than the enolate ligand to the iminium ion was the only process
observed.
[17] For the procedure for preparation of (S)-ethyl 2-propenethio-
late,see: G. Braude, J. Org. Chem. 1957, 22,1675.
[23] See the Supporting Information for 1H NMR spectra of the low-
temperature experiments.
[24] The high sensitivity of Keq to temperature suggests an entropy
(TDS) and enthalpy (DH) term which are of a similar order of
magnitude.
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1896
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