Organophosphorus reagents in organocatalysis: Synthesis of optically active α-methylene-δ-lactones and δ-lactams

Article abstract of DOI:10.1002/chem.201201325

In this paper we describe new asymmetric, catalytic strategies for the synthesis of biologically important α-methylene-δ-lactones and δ-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to α,β-unsaturated aldehydes catalyzed by (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into α-methylene-δ-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and Horner-Wadsworth-Emmons olefination of formaldehyde. On the other hand, indolo[2, 3-a]quinolizine- framework-containing products can be accessed when enantiomerically enriched Michael adducts are employed in a Pictet-Spengler reaction with tryptamine, followed by Horner-Wadsworth-Emmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and Horner-Wadsworth-Emmons olefination of formaldehyde is demonstrated to give α-methylene-δ- lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality. New asymmetric, catalytic protocols for the synthesis of biologically relevant α-methylene-δ-lactones and δ-lactams are described (see scheme). The multi-bond-forming strategies (catalyzed by (S)-(-)-α, α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether) involve a Michael addition of trimethyl phosphonoacetate to α,β-unsaturated aldehydes as the key step. The strategy benefits from the diversity of the final products obtained, practicality and broad substrate scope. Copyright

Full text of DOI:10.1002/chem.201201325

FULL PAPER
DOI: 10.1002/chem.201201325
Organophosphorus Reagents in Organocatalysis: Synthesis of Optically
Active a-Methylene-d-lactones and d-Lactams
Anna Albrecht, Fabio Morana, Alberto Fraile, and Karl Anker Jørgensen*[a]
Abstract: In this paper we describe
new asymmetric, catalytic strategies for
the synthesis of biologically important
a-methylene-d-lactones and d-lactams.
The elaborated protocols utilize imini-
um-ion-mediated Michael addition of
trimethyl phosphonoacetate to a,b-un-
saturated aldehydes catalyzed by (S)-
(À)-a,a-diphenyl-2-pyrrolidinemetha-
nol trimethylsilyl ether as the key step.
Enantiomerically enriched Michael ad-
ducts are employed in three different
reaction pathways. Transformation into
a-methylene-d-lactones is realized by
a sequence of reactions involving che-
moselective reduction of the aldehyde,
Michael adducts are employed in
a Pictet–Spengler reaction with trypta-
mine, followed by Horner–Wadsworth–
Emmons olefination. Finally, reductive
amination of the Michael adducts by
using methylamine and Horner–Wads-
worth–Emmons olefination of formal-
dehyde is demonstrated to give a-
methylene-d-lactams. The developed
strategies can be realized without the
purification of intermediates, thus
greatly increasing their practicality.
followed by
(TFA)-mediated
a
trifluoroacetic acid
cyclization and
Horner–Wadsworth–Emmons olefina-
tion of formaldehyde. On the other
hand, indoloACHTNUGTRNEUNG[2,3-a]quinolizine-frame-
work-containing products can be ac-
cessed when enantiomerically enriched
Keywords: asymmetric catalysis
·
natural products · lactams · lac-
tones · organophosphorus reagents
Introduction
synthetic applications. For example, a-methylene-d-lactams
A and B were used as key intermediates in the synthesis of
codeine analogues.[5] Moreover, a-alkylidene-d-lactam C is
The enantioselective synthesis of biologically active com-
pounds is an important goal in modern organic and life-sci-
ence chemistry. Identification of structural units responsible
for molecular recognition constitutes an important part of
the development of molecules for the life-science industry.[1]
One example of such a motif is the a-alkylidene framework,
which is present in many 5- and 6-membered lactones and
lactams.[2] These compounds often exhibit strong cytotoxic
activity, which is related to their ability to act as Michael ac-
ceptors in the reactions with various sulfur-bionucleo-
philes.[3] Importantly, many natural products containing
these structural motifs have been isolated.[2,4] Selected ex-
amples of natural a-alkylidene-d-lactones and d-lactams are
shown in Figure 1. For instance, a-methylene-d-lactones can
be found in vernolepin, which was isolated from Vernonia
hymenolepis in the 1960s.[4a] Other natural products contain-
ing d-lactones ring such as: teucriumlactone[4b] and pentale-
nolactone E[4c] are also known. Contrarily, a-alkylidene-d-
lactams are less common in nature. Gelegamine B, recently
isolated from Gelsemiumelegan, constitutes one such exam-
ple.[4d] Nonetheless, these compounds have found interesting
a synthetic precursor of geissoschizine, a natural indoloACHTUNGTRENNUNG[2,3-
a]quinolizine alkaloid.[6] This class of natural products has
recently received considerable attention.[7]
[a] Dr. A. Albrecht, F. Morana, Dr. A. Fraile, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University
8000 Aarhus C (Denmark)
Fax : (+45)8715-5956
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201325.
Figure 1. The importance of a-alkylidene-d-lactones and d-lactams.
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In the past 10 years, the synthesis of small molecules con-
taining a-alkylidene lactones and lactams structural units as
potential drug precursors has received considerable atten-
tion.[8] These heterocyclic moieties constitute an interesting
template for the drug discovery process. However, since bio-
logical activity of chiral compounds is very often related to
absolute configuration of their stereogenic centers, an enan-
tioselective synthesis of structural motifs that exhibit strong
biological activity constitutes an important challenge for
chemical society. Surprisingly, enantioselective methods
leading to these a-alkylidene-d-lactones and d-lactams are
scarcer.[2f,9]
cessible through reductive amination of 3 and HWE olefina-
tion of formaldehyde further diversifying the scope of the
methodology. However, the main challenges related to the
preservation of optical activity introduced in the first orga-
nocatalytic step and throughout the reaction sequences were
of major concern. Furthermore, in terms of practicality of
the methodology main focus was given to the development
of methods allowing for access to target products without
isolation or at least purification of the intermediates. It is
also worth noting that the present work constitutes the first
example of enantioselective synthesis of b-substituted-a-
methylene-d-lactones 4 and d-lactams 5 and 6.
Given the importance of a-alkylidene-d-lactones 4 and d-
lactams 5 and 6 structural units, studies on the development
of asymmetric organocatalytic strategies[10] for their synthe-
sis were undertaken (Scheme 1). At the outset of the stud-
Results and Discussion
The optimization studies were initiated with a goal of find-
ing the optimal reaction conditions for the Michael addition
of trialkyl phosphonoacetates 1 to a,b-unsaturated alde-
hydes 2. Triethyl phosphonoacetate 1a and cinnamaldehyde
2a were chosen as model substrates (Table 1). At the outset
of the studies different catalysts and solvents were evaluat-
ed. Initial experiments performed under conditions de-
scribed for the Michael addition of malonates to a,b-unsatu-
Table 1. Addition of trialkyl phosphonoacetate 1 to cinnamaldehyde 2a:
Screening results.[a]
Scheme 1. Asymmetric organocatalytic strategy for the synthesis of a-
methylene-d-lactones 4 and lactams 5 and 6.
ies, the diversity of the methodology was one of the main
goals. It was envisioned that the 3-substituted-2-(dialkoxy-
phosphoryl)-5-oxoalkanoates 3 can serve as common precur-
sors of various products containing the a-methylene-d-lac-
tone 4 and d-lactam 5 and 6 motifs. Importantly, the alka-
noate intermediates 3 should be readily available through
iminium-ion-mediated Michael addition of trialkyl phospho-
noacetate 1 to a,b-unsaturated aldehydes 2 catalyzed by
chiral secondary amine. It was devised that the enantiomeri-
cally enriched 3-substituted-2-(dialkoxyphosphoryl)-5-oxoal-
kanoates 3 obtained can be utilized in three different reac-
tion strategies leading to a-methylene-d-lactones 4, as well
as a-methylene-d-lactams 5 and 6. It was anticipated that
a sequence of reactions initiated by chemoselective reduc-
tion of the aldehyde, followed by lactonization and Horner–
Wadsworth–Emmons (HWE) reaction with formaldehyde
should afford a-methylene-d-lactones 4. Furthermore, a-
Entry
R
Catalyst
(loading) [oC] [h]
[mol%]
T
t
Solvent Additive[b] Conv. ee
[%][c] [%][d]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
Et 7 (10)
Et 8 (10)
Et 8 (10)
Et 9 (10)
Et 9 (10)
Et 9 (20)
Et 9 (20)
Me 8 (20)
Me 8 (20)
Me 8 (20)
Me 8 (20)
Me 8 (10)
Me 9 (20)
Me 9 (20)
Me 9 (20)
Me 8 (20)
RT 24
RT 24
RT 48
RT 72
EtOH
EtOH
EtOH
EtOH
–
–
–
–
–
–
–
–
0
50
50
55
78
0
nd
nd
nd
nd
nd
nd
nd
90
95
nd
70
nd
80
80
70
80
RT 168 EtOH
RT 24
RT 72
RT 24
RT 24
CH2Cl2
MeOH
MeOH
MeOH BzOH
MeOH BzOH
MeOH
MeOH
MeOH
MeOH BzOH
MeOH BzOH
MeOH BzOH
86
92
83
83
82
60
88
80
76
75
9
10
11
12
13
14
15
16
0
40
24
24
–
–
–
RT 24
RT 24
RT 72
40
40
24
48
methylene-d-lactams 5 possessing indoloACTHNUTRGNE[NUG 2,3-a]quinolizine
[a] All reactions were performed at 0.2 mmol scale in appropriate solvent
(0.4 mL). [b] 10 mol% applied. [c] Estimated by 31P NMR spectroscopic
analysis of the crude reaction mixture. [d] Determined by HPLC on
a chiral stationary phase after transformation into the corresponding a-
methylene-d-lactone 4a.
alkaloid framework could be obtained by means of Pictet–
Spengler reaction[11] of alkanoates 3 with tryptamines fol-
lowed by HWE reaction with formaldehyde. Importantly,
the second group of a-methylene-d-lactams 6 should be ac-
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Organophosphorus Reagents in Organocatalysis
FULL PAPER
rated aldehydes 2[12] showed that 2-[bis
ACTHNUTRGNE(UNG 3,5-bis(trifluorome-
thyl)phenyl)(trimethylsilyloxy)methyl]pyrrolidine 7 does not
catalyze the reaction (Table 1, entry 1). On the contrary,
a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether
8
and 2-(fluorodiphenylmethyl)pyrrolidine 9 proved successful
(Table 1, entries 2–5) but the conversion was unsatisfactory.
Further screening revealed that the reaction outcome
strongly depends on the solvent used. For instance, in chlori-
nated solvent such as CH2Cl2 the reaction was suppressed
(Table 1, entry 6). Gratifyingly, the best conversion was ob-
tained in MeOH (Table 1, entry 7); however, the formation
of transesterification products was observed. For this reason,
trimethyl phosphonoacetate 1b was used instead of triethyl
phosphonoacetate 1a as a nucleophilic reagent in the fur-
ther studies. To our delight, the reaction in MeOH was
faster and was terminated within 24 h and for both catalyst
8 and 9 good results (92 and 88% conversion, respectively)
were obtained (Table 1, entries 8 and 13). In the course of
further studies, the influence of acidic additive as well as re-
action temperature and amount of the catalyst on the reac-
tion outcome were evaluated. When benzoic acid was em-
ployed as acidic co-catalyst, no improvement in the conver-
sion was observed (Table 1, entries 9, 10 and 14–16). The
change of temperature did not increase the conversion
(Table 1, entries 10, 11, 15, and 16). In terms of catalyst
loading, employment of 10 mol% of the catalyst suppressed
the reaction rate significantly (Table 1, entry 12). It should
be also noted that at this stage the determination of enantio-
selectivity of the Michael addition step was impossible due
to Michael adducts being very prone to retro-Michael reac-
tion. Therefore, transformation of a model methyl 2-(dime-
thoxyphosphoryl)-5-oxo-3-phenylpentanoate 3a into the
target a-methylene-d-lactone 4a was performed in a se-
quence of reactions involving chemoselective reduction of
the aldehyde by NaBH4 followed by a trifluoroacetic acid
(TFA)-mediated cyclization and HWE olefination with
formaldehyde (for detailed optimization studies of the reac-
tion sequence, see below). Enantiomeric excess determina-
tion revealed that in terms of catalyst used, a,a-diphenyl-2-
pyrrolidinemethanol trimethylsilyl ether 8 gave better enan-
Scheme 2. Transformation of enantiomerically enriched Michael adduct
3a into optically active a-methylene-d-lactone 4a.
yphosphoryl-d-lactone 10a. This product was formed as
a mixture of two diastereoisomers in a ratio of 95:5. Howev-
er, since the main focus of the work was on the development
of a reaction sequence leading to the target a-methylene-d-
lactones 4 without purification of any intermediates, crude
a-dimethoxyphosphoryl-d-lactone 10a was utilized in the
HWE olefination applying formaldehyde. It was found that
the overall yield of the reaction sequence (consisting of four
subsequent reactions) was dependent on two main factors:
Firstly, the conditions applied in the HWE olefination step.
Secondly, the presence of acidic co-catalyst in the Michael
addition step. The use of potassium tert-butoxide as a base
and solid paraformaldehyde proved superior to potassium
carbonate/formaline combination when the Michael adduct
3a obtained in the absence of acidic co-catalyst was utilized.
On the contrary, both HWE reaction conditions performed
similarly when Michael adduct 3a obtained in the presence
of acidic co-catalyst was applied. Furthermore, the presence
of acidic additive in the Michael addition step led to lower
overall yields when compared with the reactions performed
in its absence. Delightfully, the presence of acid had a benefi-
cial influence on the stereochemical outcome of the reaction
sequence, resulting in higher enantioselectivities. These in-
teresting observations suggest that the Michael addition step
is more reversible in the presence of acidic co-catalyst lead-
ing to overall yield deterioration.
With the optimized conditions for the enantioselective
formation of a-methylene-d-lactones 4 in hand, we turned
our attention to the scope of the methodology (Table 2). To
our delight, various aromatic a,b-unsaturated aldehydes 2a–
h could participate in the reaction sequence leading to the
formation of the desired a-methylene-d-lactones 4a–h. Re-
action of the cinnamaldehydes 2e–h bearing electron-donat-
ing groups on the aromatic ring (Table 2, entries 8–12) pro-
ceeded with slightly lower yields and enantioselectivities
compared with the aromatic enals bearing electron-with-
drawing groups 2b–d (Table 2, entries 3–7). Importantly,
good enantiomeric excesses and yields were obtained inde-
pendent on the substitution pattern of the aromatic ring.
Notably, a-methylene-d-lactones 4 f–h bearing alkyl groups
on the aromatic ring were obtained with slightly reduced
tioselectivity than 2-(fluorodiphenylmethyl)pyrrolidine
9
catalyst (Table 1, entries 8, 9, 14, and 15). Furthermore, the
use of acidic additive led to increase of enantioselectivity
(Table 1, entry 9). The elevated temperature of the Michael
addition step led to diminished enantioselectivity (Table 1,
entries 11, 15, and 16). In general, the best results were ob-
tained using a,a-diphenyl-2-pyrrolidinemethanol trimethyl-
silyl ether 8 in the presence of benzoic acid or without the
acid (Table 1, entries 8 and 9).
Parallel to the optimization studies of the enantioselective
Michael addition of trimethyl phosphonoacetate 1b to cin-
namaldehyde 2a, the transformation of methyl 2-(dimethox-
yphosphoryl)-5-oxo-3-phenylpentanoate 3a into the target
a-methylene-d-lactone 4a was attempted (Scheme 2). Che-
moselective reduction of the aldehyde in 3a was performed
using NaBH4 in MeOH at 08C affording d-hydroxypenta-
noate, which cyclized in the presence of TFA to a-dimethox-
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K. A. Jørgensen et al.
Table 2. Enantioselective Synthesis of a-Methylene-d-lactones 4a–h.[a]
however, only the retro-Michael reaction was observed
(Table 3, entry 1). Delightfully, when the reaction was per-
formed in the presence of benzoic acid as acidic additive,
the formation of desired product occurred (Table 3, entry 2).
In the course of the further studies, other Brønsted acids
such as 2-fluorobenzoic acid, metanosulfonic acid, TFA, and
3,5-bis(trifluoromethyl)benzoic acid were evaluated in the
reaction (Table 3, entries 3–7). It was observed that the
strength of the acidic additive had significant influence on
the reaction outcome. The best results were obtained using
3,5-ditrifluoromethylbenzoic acid (Table 3, entry 5) provid-
ing the target a-dimethoxyphosphoryl-d-lactam 12a in 74%
yield and with good diasteroselectivity (diasteromeric ratio
(d.r.)=90:10). However, at this stage we were unable to de-
termine if the obtained diastereoisomers differed at the C3
or C12b stereogenic center. Notably, the use of TFA as
acidic additive led to an improvement in diastereoselectivity,
but with a slightly reduction of the yield to 67% (Table 3,
entry 6). Interestingly, the use of very strong acid such as
methanesulfonic acid led to the formation of complex reac-
tion mixture (Table 3, entry 7).
Entry
R
Additive
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
Ph (2a)
Ph (2a)
–
61
30
80
32
70
38
58
62
28
48
65
52
4a (90)
4a (94)
4b (92)
4b (94)
4c (91)
4c (95)
4d (93)
4e (90)
4e (94)
4 f (86)
4g (84)
4h (88)
BzOH
–
BzOH
–
BzOH
–
–
4-NO2C6H4- (2b)
4-NO2C6H4- (2b)
2-BrC6H4- (2c)
2-BrC6H4- (2c)
4-ClC6H4- (2d)
2-CH3OC6H4- (2e)
2-CH3OC6H4- (2e)
4-CH3C6H4- (2 f)
4-tBuC6H4- (2g)
3,5-(CH3)2C6H4- (2h)
It should be noted that in the case of this reaction se-
quence, the corresponding a-dimethoxyphosphoryl-d-lac-
tams 12 had to be isolated by flash chromatography. Initial
studies showed that when crude reaction mixtures were uti-
lized directly in the HWE reaction N-alkylation was occur-
ring as well. For this reason the nitrogen atom of the indole
ring was Boc-protected. It was found that efficiency of this
reaction highly depends on the purity of starting lactam 12a
9
BzOH
10[d]
11[d]
12[d]
–
–
–
[a] Michael additions performed at 0.2 mmol scale with 20 mol% of the
catalyst (S)-8 in MeOH (0.4 mL) for 24 h at RT. [b] Overall yield for 4
steps. [c] Determined by HPLC on a chiral stationary phase after trans-
formation into the corresponding a-methylene-d-lactones 4a–h. [d] Mi-
chael addition performed for 48 h.
Table 3. Optimization of the reaction conditions for the synthesis of the a-dimethoxy-
phosphoryl-d-lactam 12a.[a]
yield and enantioselectivity (Table 2, entries 10–12).
Interestingly, the same influence of the acidic addi-
tive on the overall reaction sequence outcome—sig-
nificantly lower yields and slightly better enantiose-
lectivities—was observed (Table 2, entries 2, 4, 6,
and 9). Disappointingly, when aliphatic aldehydes
were applied in the Michael addition step under op-
timized reaction conditions the desired product was
not obtained.
Having accomplished the enantioselective synthe-
sis of b-substituted-a-methylene-d-lactones 4a–h,
the reaction sequences leading to optically active a-
methylene-d-lactams 5 and 6 were investigated
(Scheme 1). We became particularly interested in
the development of reaction sequence leading to
the formation of a-methylene-d-lactams 5 having
the core of corynantheoid alkaloids incorporated.
Such products should be accessed when enantio-
merically enriched Michael adducts are employed
in Pictet–Spengler reaction with tryptamine fol-
lowed by HWE olefination. It is worth noting that
in the Pictet–Spengler reaction a new stereogenic
center is formed and diastereoselectivity of the re-
action is an important issue. In the first attempt,
enantiomerically enriched Michael adduct 3a and
Entry
1
Additive
Conv.
[%]
Yield
[%]
d.r.[b]
[%]
–
retro-Michael
reaction
75
66
76
85
85
nd
nd
2
3
4
5
6
7
BzOH
64
56
nd
74
67
nd
90:10
90:10
90:10
90:10
95:5
2-FC6H4COOH
3,5-(NO2)2C6H3CO2H
3,5-(CF3)2C6H3CO2H
TFA
CH3SO3H
decomposition
nd
[a] Michael additions performed at 0.2 mmol scale with 20 mol% of the catalyst (S)-8
in MeOH (0.4 mL) for 24 h at RT. [b] Estimated by 31P NMR spectroscopic analysis of
tryptamine 11a were heated in CH2Cl2 at 408C; the crude reaction mixture.
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Organophosphorus Reagents in Organocatalysis
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Table 4. Scope of the enantioselective synthesis of optically active a-methylene-d-lac-
tams 5a–g.[a]
indicating the necessity of purification of 12 by
means of flash chromatography. To our delight,
a subsequent reaction sequence involving Boc-pro-
tection and HWE olefination of formaldehyde
could be performed without purification of the in-
termediate affording target product 5a in good
yield. Notably, lactam 5a was formed as single dia-
stereoisomer. This result indicates that diastereoiso-
meric a-dimethoxyphosphoryl-d-lactams 12a differ
in configuration at the C3 stereogenic center and
Pictet–Spengler reaction is fully diastereoselective.
Furthermore, enantioselectivity introduced in the
Michael addition was preserved throughout the se-
quence as the final product was obtained with an
enantiomeric excess (ee) of 92%.
With optimized conditions for the reaction se-
quence leading to the formation of indoloACTHNUGRTNEUNG[2,3-
Entry
R
R1
d.r.[b] 12
Yield [%]
ee
12[c]
5[c]
[%][d]
a]quinolizines-framework-containing products 5 in
hand, the scope of the methodology was studied
(Table 4). Gratifyingly, a-dimethoxyphosphoryl-d-
lactams 12a–g derived from both electron-poor
(Table 4, entries 2–4) and electron-rich (Table 4, en-
tries 5 and 6) enals 2 could be obtained in good
yields (58–80%) and good diasteroselectivities
(90:10 to 95:5 d.r.) employing the optimized reac-
tion conditions. Importantly, substituted trypta-
mines can be utilized in the developed reaction se-
quence as demonstrated for 5-methoxy derivative
11b leading to the formation of lactam 12g in 88%
yield and with 90:10 d.r. (Table 4, entry 7). Subse-
1
Ph (2a)
H (11a)
H (11a)
H (11a)
H (11a)
H (11a)
H (11a)
OMe (11b)
90:10
95:5
90:10
95:5
90:10
90:10
90:10
80
80
70
58
61
62
88
55
69
45
72
50
53
63
5a (92)
5b (94)
5c (87)
5d (94)
5e (90)
5 f (86)
5g (92)
2[e]
3
4-NO2C6H4- (2b)
4-ClC6H4- (2d)
4-CF3C6H4- (2i)
2-CH3OC6H4- (2e)
3,5-(CH3)2C6H3- (2h)
Ph (2a)
4[e]
5
6[e]
7
[a] Michael additions performed at 0.2 mmol scale with 20 mol% of the catalyst (S)-8
in MeOH (0.4 mL) for 24 h at RT. [b] Estimated by 31P NMR spectrocopic analysis of
the crude reaction mixture. [c] Overall yield for 2 steps. [d] Determined by HPLC on
a chiral stationary phase after transformation into the corresponding a-methylene-d-
lactams 5a–g. [e] Michael addition performed for 48 h.
Table 5. Enantioselective synthesis of a-methylene-d-lactams 6a–e.[a]
quent, two step protocol enabled efficient introduction of a-
methylene moiety yielding target products 5b–g in good
yields and as single diastereoisomers. Importantly, high
enantioselectivities (86–94% ee) were obtained indicating
high compatibility of the organocatalytic step with subse-
quent transformations.
Being successful in establishing an efficient enantioselec-
tive methodology for the synthesis of indolo-
[2,3Àa]quinolizines-framework-containing products 5a–g,
the development of second synthetic pathway to a-methyl-
ene-d-lactams 6 was investigated (Table 5). For this reason,
enantiomerically enriched 5-oxopentanoates 3 were subject-
ed to reductive amination using methylamine as aminating
reagent and sodium borohydride as reducing agent.[8e]
Under these reaction conditions, the d-aminopentanoates
underwent spontaneous lactamizations yielding a-dimethox-
yphosphoryl-d-lactams 13 as single diastereoisomers. Subse-
quently, HWE olefination of paraformaldehyde in the pres-
ence of potassium tert-butoxide as a base in THF was per-
formed. The developed procedure involves only one isola-
tion protocol–an extraction performed after reductive ami-
nation step. Various electron-poor and electron-rich a,b-
unsaturated aldehydes 2 were tested in this reaction se-
quence (Table 5, entries 1–5). It is worth noting that the re-
actions of the aldehydes with electron-donating groups on
the aromatic ring, 2e and 2h (Table 5, entries 4 and 5), pro-
ceeded with lower yield (26–27%) and enantioselectivities
Entry
R
Yield
[%][b]
ee
[%][c]
1
Ph (2a)
50
49
48
26
27
6a (92)
6b (94)
6c (90)
6d (88)
6e (82)
2[d]
3[d]
4
4-NO2C6H4- (2b)
4-ClC6H4- (2d)
2-CH3OC6H4- (2e)
3,5-(CH3)2C6H3- (2h)
5[d]
[a] Michael additions performed at 0.2 mmol scale with 20 mol% of the
catalyst (S)-8 in MeOH (0.4 mL) for 24 h at RT. [b] Overall yield for 4
steps. [c] Determined by HPLC on a chiral stationary phase after trans-
formation into the corresponding a-methylene-d-lactams 6a–e. [d] Mi-
chael addition performed for 48 h.
(88 and 82% ee) when compared with enals substituted with
electron-withdrawing substituents 2b and 2d (48–49% yield,
90–94% ee; Table 5, entries 2 and 3).
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K. A. Jørgensen et al.
All of the products obtained have an electron-deficient
alkene moiety, which is well-suited for the application in the
Michael addition. For this reason and inspired by the ability
of these compounds to react with sulfur-biomolecules,[3] the
thio-Michael addition of thiophenol to a-methylene-d-
lactam 5a was performed yielding the corresponding adduct
as a single diastereoisomer.[13] This product was directly sub-
jected to meta-chloroperbenzoic acid (mCPBA) oxidation
yielding sulfone 14 (Scheme 3). Interestingly, under reaction
methylene-d-lactones and d-lactams can be accessed in
a highly stereoselective fashion.
Experimental Section
General procedure for the preparation of a-methylene-d-lactones 4a–h:
In an ordinary vial, the corresponding aldehyde (0.4 mmol) was added to
a solution of catalyst (13 mg, 0.04 mmol) in MeOH (0.4 mL). After
15 min, trimethyl phosphonoacetate (36 mg, 0.2 mmol) was added and
the resulting mixture was stirred overnight at room temperature. After
complete consumption of trimethyl phosphonoacetate (monitored by
31P NMR spectroscopy), MeOH (1 mL) was added to the vial, which was
then cooled to 08C and NaBH4 (38 mg, 1 mmol) was added in portions.
The resulting mixture was left at 08C for 1 h, quenched with 2 N HCl
(5 mL), and extracted with CH2Cl2 (3ꢁ10 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (1 mL), TFA (0.5 mL) was
added and the resulting solution was left at room temperature overnight.
Then CH2Cl2 (10 mL) was added and washed with saturated NaHCO3
(10 mL), dried over MgSO4, filtered and concentrated under reduced
pressure. Resulting crude a-dimethoxyphosphoryl-d-lactone (1.0 equiv)
was dissolved in THF (to obtain 1m solution) and potassium tert-butoxide
(1.2 equiv) was added at room temperature. The resulting mixture was
stirred at room temperature for 30 min. Then paraformaldehyde (5.0
equiv) was added at room temperature and the stirring was continued for
1 h. The mixture was then quenched with sat. NaCl solution (10 mL) and
extracted with CH2Cl2 (3ꢁ10 mL). The combined organic layers were
dried over MgSO4 and evaporated. The residue was purified by FC on
silica gel to afford the target a-methylene-d-lactone 4.
Scheme 3. Synthesis and X-ray structure of 14.[a]
conditions concomitant a-oxidation occurred enabling intro-
duction of the quaternary stereogenic center in 90:10 d.r.[14]
Importantly, this transformation allowed us to assign abso-
lute configuration of the lactams 5. Single-crystal X-ray
analysis of 14[15] indicated cis-configuration of H2 and H12b
protons (Scheme 3). This result shows that the acid-mediat-
ed Pictet–Spengler reaction leads to the formation of the
“thermodynamic” stereochemistry of quinolizidine alkaloid
core.[7d,f] Furthermore, the absolute configuration of the ste-
reogenic center originating from iminium ion-mediated Mi-
chael addition turned out to be in accordance with related
Michael reactions catalyzed by (S)-8[10l,12]-trimethyl phos-
phonoacetate, which approaches the iminium-activated enal
from the site opposite to the bulk of the catalyst. Important-
ly, since all target a-methylene-d-lactones 4 and lactams 5
and 6 obtained are derived from the same common precur-
sors 3, the absolute configuration of 4, 5, and 6 was assigned
by analogy.
General procedure for the preparation of a-dimethoxyphosphoryl-d-lac-
tams 12a–g: In an ordinary vial, the corresponding aldehyde (0.4 mmol)
was added to
a solution of catalyst (13 mg, 0.04 mmol) in MeOH
(0.4 mL). After 15 min trimethyl phosphonoacetate (36 mg, 0.2 mmol)
was added and the resulting mixture was stirred overnight at room tem-
perature. After complete consumption of trimethyl phosphonoacetate
(monitored by 31P NMR spectroscopy), MeOH was evaporated and the
crude Michael adduct 3 was dissolved in CH2Cl2 (1 mL), then tryptamine
(0.22 mmol, 35 mg) and 3,5-bis(trifluoromethyl)benzoic acid (0.3 mmol,
77 mg) were added. The reaction was stirred for 24 h at reflux. Then aq.
sat. NaHCO3 (10 mL) was added, and extracted with CH2Cl2 (3ꢁ5 mL).
The combined organic layers were dried over MgSO4. The crude product
was purified by FC to afford target a-dimethoxyphosphoryl-d-lactam 12.
General procedure for the preparation of a-methylene-d-lactams 5a–g:
Lactam 12 (0.12 mmol) was dissolved in CH2Cl2 (2 mL) and triethylamine
was added (42 mL, 0.3 mmol). After stirring for 10 min at room tempera-
ture, (Boc)2O (40 mg, 0.18 mmol) and DMAP (3.7 mg, 0.03 mmol) were
added and the reaction mixture was stirred for 24 h at room temperature.
Then the reaction was diluted with CH2Cl2 (10 mL) and washed with aq.
sat. NH4Cl (5 mL), aq. sat. NaHCO3 (5 mL), and brine (5 mL). The
crude N-protected-a-dimethoxyphosphoryl-d-lactam (1.0 equiv) was dis-
solved in THF (to obtain 1m solution) potassium tert-butoxide (1.2 equiv)
was added at 08C. The resulting mixture was stirred at 08C for 30 min.
Then paraformaldehyde (5.0 equiv) was added at room temperature and
the stirring was continued for 1 h. The mixture was then quenched with
sat. NaCl solution (10 mL) and extracted with CH2Cl2 (3ꢁ10 mL). The
combined organic layers were dried over MgSO4 and evaporated. The
residue was purified by FC on silica gel to afford target a-methylene-d-
lactam 5.
Conclusion
We have developed new asymmetric organocatalytic proto-
cols for the synthesis of a-methylene-d-lactones and d-lac-
tams with very good enantioselectivites and yields starting
from easily available substrates. Developed strategies utilize
Michael addition of trimethyl phosphonoacetate to aromatic
enals as a key enantiodifferentiating step using a,a-diphen-
yl-2-pyrrolidinemethanol trimethylsilyl ether as a catalyst.
Subsequent transformations leading to target compounds
can be realized without purification of intermediates, greatly
increasing their practicality. Importantly, enantiomeric en-
richment introduced in the first, organocatalytic step can be
preserved throughout the reaction sequences and final a-
General procedure for the preparation of a-methylene-d-lactams 6a–e:
In an ordinary vial, the corresponding aldehyde (0.4 mmol) was added to
a solution of catalyst (13 mg, 0.04 mmol) in MeOH (0.4 mL). After
15 min, trimethyl phosphonoacetate (36 mg, 0.2 mmol) was added and
the resulting mixture was stirred overnight at room temperature. After
complete consumption of trimethyl phosphonoacetate (monitored by
31P NMR spectroscopy) solution of Ti
lution of MeNH2 in MeOH (130 mL, 0.26 mmol) were added at room
ACHTUNGERTN(NUNG OiPr)4 (74 mg, 0.26 mmol), 2 N so-
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Organophosphorus Reagents in Organocatalysis
FULL PAPER
temperature. The reaction mixture was stirred for 3 h, then NaBH4
(8 mg, 0.2 mmol) was added in one portion. Stirring was continued for
24 h. The water (15 mL) was added and MeOH was evaporated under re-
duced pressure. The residue was extracted with CH2Cl2 (4ꢁ20 mL) and
the combined organic layers were dried over MgSO4. Evaporation of the
solvent under reduced pressure afforded a crude a-dimethoxyphosphor-
yl-d-lactam (1.0 equiv), which was dissolved in THF (to obtain 1m solu-
tion) and potassium tert-butoxide (1.2 equiv) was added at 08C. The re-
sulting mixture was stirred at 08C for 30 min. Then, paraformaldehyde
(5.0 equiv) was added at room temperature and the stirring was contin-
ued for 1 h. The mixture was then quenched with aq. sat. NaCl solution
(10 mL) and extracted with CH2Cl2 (3ꢁ10 mL). The combined organic
layers were dried over MgSO4 and evaporated. The residue was purified
by FC on silica gel to afford the target a-methylene-d-lactam 6.
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Acknowledgements
This work was made possible by grants from Aarhus University, OChem-
School, Carlsberg Foundation, and FNU. We thank Dr. Jacob Overgaard
for performing the X-ray analysis.
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Received: April 19, 2012
Published online: && &&, 0000
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K. A. Jørgensen et al.
New asymmetric, catalytic protocols
for the synthesis of biologically rele-
vant a-methylene-d-lactones and d-lac-
tams are described (see scheme). The
multi-bond-forming strategies (cata-
lyzed by (S)-(À)-a,a-diphenyl-2-pyrro-
lidinemethanol trimethylsilyl ether)
involve a Michael addition of trimethyl
phosphonoacetate to a,b-unsaturated
aldehydes as the key step. The strategy
benefits from the diversity of the final
products obtained, practicality and
broad substrate scope.
Asymmetric Catalysis
A. Albrecht, F. Morana, A. Fraile,
K. A. Jørgensen* ............. &&&& — &&&&
Organophosphorus Reagents in Orga-
nocatalysis: Synthesis of Optically
Active a-Methylene-d-lactones and d-
Lactams
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These are not the final page numbers!